Applied

Pa t h oph ysiology
A Con cept u a l Appr oa ch
t o t h e Mech a n ism s of Disea se
 Applied
Pa t h oph ysiology
A Con cept u a l Appr oa ch
t o t h e Mech a n ism s of Disea se
T h ir d E d it io n

C a r ie A. B r a u n , P h D, R N
P r ofessor of Nu r sin g
College of St . Ben edict /St . J oh n ’s Un iver sit y
St . J oseph , Min n esot a

C in d y M. An d e r s o n , P h D, R N, WH N P -B C,
AN E F, F AH A, F N AP, F AAN
Associa t e P r ofessor
College of Nu r sin g
Th e Oh io St a t e Un iver sit y
Colu m bu s, Oh io
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P r od u ction P r oject Ma n a ger: Da vid Or zech owski
Ma rketin g Ma n a ger: Lea h Th om son
Design Coor d in a tor: H olly McLa u gh lin
P r epr ess Ven d or:S4Ca r lisle P u blish in g Ser vices

3r d E dit ion

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9 8 7 6 5 4 3 2 1

P r in t ed in Ch in a

L ib r a r y o C o n g r e s s C a t a lo g in g -in -P u b lic a t io n D a t a
Na m es: Br a u n , Ca r ie An n , a u t h or. | An der son , Cin dy Miller, a u t h or.
Tit le: Applied pa t h oph ysiology : a con cept u a l a ppr oa ch t o t h e m ech a n ism s of
disea se / Ca r ie A. Br a u n , Cin dy M. An der son .
Ot h er t it les: Pa t h oph ysiology
Descr ipt ion : Th ir d edit ion . | P h ila delph ia : Wolt er s Klu wer H ea lt h , [2017] |
P r eceded by Pa t h oph ysiology / Ca r ie A. Br a u n , Cin dy M. An der son . 2n d ed.
c2011. | In clu des bibliogr a ph ica l r efer en ces a n d in dex.
Iden t ifier s: LCCN 2016023449 | ISBN 9781496335869
Su bject s: | ME SH : Pa t h ology | P h ysiology | P h ysiologica l P h en om en a
Cla ssifica t ion : LCC RB113 | NLM QZ 4 | DDC 616.07—dc23 LC r ecor d a va ila ble a t
h t t ps://lccn .loc.gov/2016023449

Th is wor k is pr ovided “a s is,” a n d t h e pu blish er discla im s a n y a n d a ll wa r r a n t ies,

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cu r r en cy of t h e con t en t of t h is wor k.

Th is wor k is n o su bst it u t e for in dividu a l pa t ien t a ssessm en t ba sed u pon h ea lt h ca r e

pr ofession a ls’ exa m in a t ion of ea ch pa t ien t a n d con sider a t ion of, a m on g ot h er t h in gs,
a ge, weigh t , gen der, cu r r en t or pr ior m edica l con dit ion s, m edica t ion h ist or y, la bor a t or y
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m edica l ju dgm en t s a n d for a n y r esu lt in g dia gn osis a n d t r ea t m en t s.

Given con t in u ou s, r a pid a dva n ces in m edica l scien ce a n d h ea lt h in for m a t ion ,

in depen den t pr ofession a l ver ifica t ion of m edica l dia gn oses, in dica t ion s, a ppr opr ia t e
ph a r m a ceu t ica l select ion s a n d dosa ges, a n d t r ea t m en t opt ion s sh ou ld be m a de
a n d h ea lt h ca r e pr ofession a ls sh ou ld con su lt a va r iet y of sou r ces. Wh en pr escr ibin g
m edica t ion , h ea lt h ca r e pr ofession a ls a r e a dvised t o con su lt t h e pr odu ct in for m a t ion
sh eet (t h e m a n u fa ct u r er ’s pa cka ge in ser t ) a ccom pa n yin g ea ch dr u g t o ver ify, a m on g
ot h er t h in gs, con dit ion s of u se, wa r n in gs a n d side effect s a n d iden t ify a n y ch a n ges in
dosa ge sch edu le or con t r a in dica t ion s, pa r t icu la r ly if t h e m edica t ion t o be a dm in ist er ed
is n ew, in fr equ en t ly u sed or h a s a n a r r ow t h er a peu t ic r a n ge. To t h e m a xim u m ext en t
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LWW.com
Th is edit ion is dedica t ed t o m y collea gu es a t t h e College of St . Ben edict /
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t ion t o becom e a r ea lit y.
—C a r ie A. B r a u n

To m y st u den t s wh o pr ovide a con st a n t sou r ce of en t h u sia sm a n d m ot iva t ion ;

t o m y h u sba n d, Kevin , a n d da u gh t er s, Ra ch el, Am y, a n d Mich elle, wh o pr ovide
u n con dit ion a l su ppor t , m ot iva t ion , a n d love; a n d t o m y fr ien ds a n d collea gu es,
especia lly Ma r en a , for t h eir con sist en t en cou r a gem en t .
—C in d y M. An d e r s o n
 P r efa ce
Th is t h ir d edit ion com es a t a t im e wh en con cept u a l
cu r r icu la a n d con cept -ba sed lea r n in g a r e ga in in g a
st r on g foot h old. Sh ou ld t h e st u den t lea r n t h r ou gh a
body-syst em s a ppr oa ch or a con cept u a l a lt er ed fu n c-
t ion a l a ppr oa ch ? Th is t ext t ea ch es pa t h oph ysiology
t h r ou gh t h e len s of body fu n ct ion con cept s a n d wh a t
h a ppen s wh en fu n ct ion is a lt er ed t h r ou gh in ju r y
or disea se. Th e t ext t h en illu st r a t es t h ese con cept s
t h r ou gh select disea ses, or clin ica l m odels. By ex-
pla in in g t h e cor e con cept s of a lt er ed h u m a n fu n c-
t ion , st u den t s ca n a pply a deeper u n der st a n din g t o
a r a n ge of disea ses, r a t h er t h a n t r yin g t o m em or ize
fa ct s a bou t specific con dit ion s. Beca u se st u den t s
lea r n t h r ou gh a pplica t ion , t h ey lea r n t o t h in k a bou t
pa t h oph ysiology a s in a clin ica l set t in g, by wor kin g
fr om sym pt om s t o t h e ca u se, r a t h er t h a n t h e ot h er
wa y a r ou n d.
At it s cor e, t h is edit ion con t in u es t o em ph a size
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vi
St u den t s ca n a lso pu r ch a se t h e st u dy gu ide, a
su pplem en t t a ilor ed specifica lly t o t h e a ppr oa ch a n d
con t en t of Pa t h oph ysiology. It con t a in s t est -t a kin g
st r a t egies, con cept -m a ppin g exer cises, ca se st u dies,
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Det a iled lesson pla n s a r e a lso a va ila ble t o h elp
in st r u ct or s t r a n sit ion fr om a st a n da r d body-syst em s
a ppr oa ch t o t h e con cept u a l a ppr oa ch pr esen t ed h er e.
Applied Pa th oph ysiology: A Con ceptu a l Appr oa ch
to th e Mech a n ism s of Disea se r epr esen t s a pa r a digm
sh ift in t h in kin g a n d lea r n in g a bou t pa t h oph ysiology
focu sed on fu n ct ion a l a lt er a t ion s in h ea lt h . Lea r n in g
pa t h oph ysiology ca n be fa scin a t in g a n d ch a llen gin g
a t t h e sa m e t im e. Th e goa l of t h is t ext is t o focu s on
t h e fa scin a t in g.
 User ’s Gu ide
In t oda y’s h ea lt h ca r e ca r eer s, a t h or ou gh u n der-
st a n din g of pa t h oph ysiology is m or e im por t a n t t h a n
ever. Applied Pa th oph ysiology: A Con ceptu a l Ap-
pr oa ch to th e Mech a n ism s of Disea se n ot on ly pr o-
vides t h e con cept u a l kn owledge you will n eed, bu t
a lso t ea ch es you h ow t o a pply it . Th is User ’s Gu ide
in t r odu ces you t o t h e fea t u r es a n d t ools of t h is in n o-
va t ive t ext book. E a ch fea t u r e is specifica lly design ed
t o en h a n ce you r lea r n in g exper ien ce, pr epa r in g you
for a su ccessfu l ca r eer a s a h ea lt h pr ofession a l.
Ta ke a few m in u t es t o look t h r ou gh t h e t ext a n d
get a cqu a in t ed wit h it s or ga n iza t ion . Th e t a ble of
con t en t s of Applied Pa t h oph ysiology: A Con cept u a l
Appr oa ch t o t h e Mech a n ism s of Disea se is st r u c-
t u r ed a r ou n d con cept s of a lt er ed h u m a n fu n ct ion .
Th e ca t egor ies, devised by a gr ou p of edu ca t or s,
wer e select ed by a n a lyzin g a n d clu st er in g h u m a n
LEARNING OBJECTIVES
H igh ligh t im por t a n t con cept s—h elpin g you
or ga n ize a n d pr ior it ize lea r n in g.
h ea lt h con dit ion s wit h h igh pr eva len ce, in ciden ce,
a n d sever it y. Clu st er s wer e for m ed by lookin g a t t h e
com m on im pa ct s a n d u lt im a t e r esu lt s of differ en t
gr ou ps of disea ses on t h e h u m a n body.
Th is n ovel a ppr oa ch sh ows you h ow disea ses a r e
r a r ely con fin ed t o on e body syst em a n d ch a llen ges
you t o bu ild on pr eviou sly ga in ed kn owledge. An in -
t egr a t ive st u dy a t t h e en d of t h e book em ph a sizes
t h e pr a ct ica l n a t u r e of t h e m a t er ia l by h elpin g you
a pply t h e com plex pa t h oph ysiologic con cept s t h a t
you h a ve lea r n ed t o a com m on con dit ion —dia bet es
m ellit u s.
Next , t a ke a look a t t h e ch a pt er s t h em selves.
We h a ve in clu ded som e im por t a n t t ools t o h elp you
lea r n a bou t pa t h oph ysiology a n d a pply you r n ew
kn owledge:
v ii
v iii User 's Gu ide

Ca rcinoge nic
a ge nt Ce ll
DNA re pa ir
(Muta tor ge ne s )

CONCEPT MAPS DNA da ma ge

Visu a lly illu st r a t e t h e im por t a n t Fa ilure of DNA re pa ir

in t er r ela t ion sh ips of key con cept s.
Muta tion in
ce ll ge ne s

Activa tion of Activa tion of Activa tion of tumor

growth-promoting a poptos is - s uppre s s ing
oncoge ne s controlling ge ne s a nti-oncoge ne s

Unre gula te d
ce ll growth a nd
diffe re ntia tion

Canc e r

Figure 7.2. Concept map. The genomic mechanisms of

cancer. (Modified from Porth CM. Essentials of Pathophysi-
ology: Concepts of Altered Health States. Philadelphia, PA:
Lippincott Williams & Wilkins; 2003, with permission.)

FROM THE LAB

E xpla in com m on la bor a t or y
pr ocedu r es a n d r esu lt s.

STOP AND CONSIDER

Ch a llen ge you t o t h in k beyon d t h e
in for m a t ion pr esen t ed in t h e t ext book a s
you pr oceed t h r ou gh t h e ch a pt er.
 User 's Gu ide ix

SUMMARY
P r ovide a con cise r eview of t h e ch a pt er,
h igh ligh t in g t h e key poin t s you sh ou ld
u n der st a n d a ft er r ea din g t h e ch a pt er.

CASE STUDIES
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You a r e en cou r a ged t o sea r ch t h e In t er n et for
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you r pr edict ion s.

PRACTICE EXAM QUESTIONS

P r ovide pr a ct ice a n d r eview for
t h e t ypes of qu est ion s t o expect on
a n exa m .
x User 's Gu ide

DISCUSSION AND
APPLICATION
H elp you ga u ge you r
u n der st a n din g of wh a t you
h a ve lea r n ed.

BONUS WEBSITE
In side t h e fr on t cover of you r t ext book,
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Websit e in clu des t h e followin g fea t u r es
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● A qu iz ba n k of a ddit ion a l r eview
qu est ion s t o h elp you st u dy for exa m s
Visit h t t p://t h ePoin t .lww.com /a ct iva t e t o
kick-st a r t you r pa t h oph ysiology su ccess
t oda y!

As you ca n see, a ll t h e ch a pt er fea t u r es a r e design ed t o h on e cr it ica l t h in kin g skills a n d

ju dgm en t , bu ild clin ica l pr oficien cy, a n d pr om ot e com pr eh en sion a n d r et en t ion of t h e m a t er ia l
by a pplyin g pa t h oph ysiologic kn owledge, r a t h er t h a n m er ely m em or izin g fa ct s a n d figu r es.
 Reviewer s

Th e pu blish er a n d a u t h or s gr a t efu lly a ckn owledge t h e m a n y pr ofession a ls wh o

sh a r ed t h eir exper t ise a n d a ssist ed in developin g t h is t ext book, h elpin g u s r e-
fin e ou r pla n , a ppr opr ia t ely t a r get in g ou r m a r ket in g effor t s, a n d set t in g t h e
st a ge for su bsequ en t edit ion s. We a r e gr a t efu l t o t h e followin g r eviewer s:

J e a n n e C a lv e r t , MS J e r e y Ku s h n e r
Associa t e P r ofessor, Biology Associa t e P r ofessor
Un iver sit y of St . F r a n cis Depa r t m en t of In t egr a t ed Scien ce a n d Tech n ology
F t . Wa yn e, In dia n a J a m es Ma dison Un iver sit y
H a r r ison bu r g, Vir gin ia
Ka r e n C h a n d r a , R N, MS N, MB A
Nu r sin g Depa r t m en t Tr e e n a L e m a y, B S c N
H a r per College P r ofessor
Pa la t in e, Illin ois H ea lt h a n d Com m u n it y St u dies
Algon qu in College
Th om a s Ch a r t r a n d , DC Pem br oke, On t a r io, Ca n a da
Associa t e Lect u r er
Clin ica l La b Scien ces Vik k i Mc C le a r y, P h D
Un iver sit y of Wiscon sin Assist a n t P r ofessor
Milwa u kee, Wiscon sin P h ysicia n Assist a n t P r ogr a m
Sch ool of Medicin e & H ea lt h Scien ces
Willia m H ill Un iver sit y of Nor t h Da kot a
An ish in a bek E du ca t ion a l In st it u t e Gr a n d For ks, Nor t h Da kot a
Nor t h Ba y, On t a r io
I r e n e L . E . Mu e lle r , E d D
Ka t h le e n H o lb r o o k , B S H IA P r ogr a m Dir ect or a n d Assist a n t P r ofessor
Dir ect or H ea lt h Scien ces
A & H Tr a in in g Cor p. West er n Ca r olin a Un iver sit y
La t h a m , New Yor k Cu llowh ee, Nor t h Ca r olin a

J o s e p h I n u n g u , MD, P h D S t e p h a n ie O ls e n
P r ofessor In st r u ct or, H ea lt h In for m a t ion
Sch ool of H ea lt h Scien ces SAIT Polyt ech n ic
Cen t r a l Mich iga n Un iver sit y Ca lga r y, Alber t a
Mt . P lea sa n t , Mich iga n
D a v id R e , B S, D D S
J o h n Kn e s e l P r ogr a m Dir ect or
Associa t e P r ofessor, Biology Den t a l Assist in g a n d Den t a l H ygien e
Un iver sit y of Lou isia n a Apollo College
Mon r oe, Lou isia n a Boise, Ida h o

L o r i Kn ig h t , C C H R A(C ) Kr is t in e S c o r d o , P h D, R N, C S, AC N P
In st r u ct or Dir ect or
H ea lt h In for m a t ion Ser vices P r ogr a m Acu t e Ca r e Nu r se P r a ct it ion er P r ogr a m
SIAST, Regin a Wr igh t St a t e Un iver sit y
Sa ska t ch ewa n , Ca n a da Da yt on , Oh io

xi
x ii Reviewer s

R a ch el Sm et a n k a , P h D D a v id We is s m a n , MD
Assist a n t P r ofessor, Biology Associa t e P r ofessor, Pa t h ology
Sou t h er n Ut a h Un iver sit y Rober t Wood J oh n son Medica l Sch ool
Ceda r Cit y, Ut a h New Br u n swick, New J er sey

J . S t e v e S m it h , MD J e a n Zo r k o , MS
P r ofessor Assist a n t P r ofessor
Medica l Tech n ology P r ogr a m St a r k St a t e College of Tech n ology
Un iver sit y of West F lor ida Ca n t on , Oh io
Pen sa cola , F lor ida

C a t h e r in e T h o m p s o n , P h D, MS, P T
Assist a n t P r ofessor, P T E du ca t ion
Rockh u r st Un iver sit y
Ka n sa s Cit y, Missou r i
 Ackn owledgm en t s

I a ckn owledge t h e t ea m a t Lippin cot t Willia m s & Wilkin s for believin g in a

con cept u a l a ppr oa ch wa y befor e it wa s vogu e.
—C a r ie A. B r a u n

I a ckn owledge t h e h elp a n d dir ect ion pr ovided by t h e st a ff a t Lippin cot t

Willia m s & Wilkin s.
—C in d y M. An d e r s o n

x iii
 Con t en t s

1. In t r od u ct ion t o H yp er t r op h y 16
P a t h op h ysiology 1 H y p e r p la s ia 16
Me t a p la s ia 16
I n t r o d u c t io n 1
D y s p la s ia 17
D e in in g P a t h o p h y s io lo g y 1
Mo d u le 3: C e llu la r I n ju r y a n d D e a t h 17
U n d e r s t a n d in g P a t h o p h y s io lo g y 1
Pa t h ogen esis 1 Me c h a n is m s o C e ll D e a t h 18
E t iology 2 Apopt osis 18
Clin ica l Ma n ifest a t ion s 2 Necr osis 18
Dia gn osis a n d Tr ea t m en t 3 C a u s e s o C e ll I n ju r y a n d D e a t h 18
Ap p ly in g P a t h o p h y s io lo g y 4 Mo d u le 4: C lin ic a l Mo d e ls 20
In dividu a l H ea lt h 4 C e r e b r a l At r o p h y 20
Popu la t ion H ea lt h 4 Pa t h oph ysiology 20
Disea se P r even t ion 5 Clin ica l Ma n ifest a t ion s 21
E v id e n c e -B a s e d P r a c t ic e 5 Dia gn osis 21
F u n c t io n a l C o n c e p t s o Alt e r e d H e a lt h 5 Tr ea t m en t 21
C a r d ia c H y p e r t r o p h y 21
Pa t h oph ysiology 21
2. Alt e r e d Ce lls a n d Tissu e s 9 Clin ica l Ma n ifest a t ion s 22
Dia gn osis 22
I n t r o d u c t io n 9
Tr ea t m en t 23
Mo d u le 1: R e v ie w o C e llu la r S t r u c t u r e a n d
F u n c t io n 10 Ac r o m e g a ly 23
Pa t h oph ysiology 23
C e llu la r C o m p o n e n t s 10
Clin ica l Ma n ifest a t ion s 24
Cellu la r Mem br a n e 10
Dia gn osis 24
Cyt opla sm a n d Or ga n elles 10
Tr ea t m en t 25
Cyt oskelet on 11
C e r v ic a l Me t a p la s ia a n d D y s p la s ia 26
C e llu la r F u n c t io n 11
Pa t h oph ysiology 26
Cellu la r Mech a n ism s of Tr a n spor t a t ion 11
Clin ica l Ma n ifest a t ion s 27
Pa ssive Tr a n spor t 11
Dia gn osis 28
Act ive Tr a n spor t 12
Scr een in g Test s 28
In gest ion 13
Dia gn ost ic Test s 29
Secr et ion 13
Tr ea t m en t 29
Respir a t ion 13
Com m u n ica t ion 14 E n v ir o n m e n t a l To x in I n ju r y a n d
C a r d io v a s c u la r D is e a s e 29
Repr odu ct ion 14
Pa t h oph ysiology 30
Mo d u le 2: C e llu la r Ad a p t a t io n a n d R e s p o n s e Clin ica l Ma n ifest a t ion s 30
t o S t r e s s 14
Dia gn osis 30
At r o p h y 15 Tr ea t m en t 30

x iv
 Con t en t s xv

3. In f a m m a t ion a n d Tissu e B u r n I n ju r ie s 52
F u n ct ion s of t h e Skin 52
R e p a ir 34 Bu r n s 53
I n t r o d u c t io n 34 Pa t h oph ysiology 53
Clin ica l Ma n ifest a t ion s 54
R e v ie w o B o d y D e e n s e Me c h a n is m s 34
Dia gn ost ic Cr it er ia 55
Mo d u le 1: Ac u t e I n la m m a t io n 36 Tr ea t m en t 55
Va s c u la r R e s p o n s e 36 Ar t h r it is 56
In fla m m a t or y Media t or s Wit h in Cells 37 F u n ct ion s of Syn ovia l J oin t s 56
In fla m m a t or y Media t or s Wit h in Wh it e Blood Rh eu m a t oid Ar t h r it is 56
Cells 37
Pa t h oph ysiology 56
In fla m m a t or y Media t or s Wit h in P la t elet s 37
Clin ica l Ma n ifest a t ion s 57
In fla m m a t or y Media t or s Wit h in E n dot h elia l or
Dia gn ost ic Cr it er ia 57
In ju r ed Tissu e Cells 38
Tr ea t m en t 58
In fla m m a t or y Media t or s Wit h in P la sm a 38
G a s t r it is 58
C e llu la r R e s p o n s e 38
F u n ct ion s of t h e St om a ch 58
Gen er a l Ma n ifest a t ion s 39
Tr ea t m en t 40 Ac u t e G a s t r it is 59
Resolu t ion of Acu t e In fla m m a t ion 41 Pa t h oph ysiology 59
Clin ica l Ma n ifest a t ion s 60
Mo d u le 2: H e a lin g a n d Tis s u e R e p a ir 42
Dia gn ost ic Cr it er ia 60
S e a lin g t h e Wo u n d 42 Tr ea t m en t 60
C le a r in g t h e D e b r is 42 C h r o n ic G a s t r it is : I n e c t io n 60
R e s t o r in g S t r u c t u r a l I n t e g r it y 43 Pa t h oph ysiology 60
R e s t o r in g F u n c t io n a l I n t e g r it y 44 Clin ica l Ma n ifest a t ion s 60
Dia gn ost ic Cr it er ia 60
C o n d it io n s T h a t P r o m o t e Wo u n d H e a lin g 45
Tr ea t m en t 61
H e a lin g b y I n t e n t io n 45
C h r o n ic G a s t r it is : Au t o im m u n e 61
Com plica t ion s of H ea lin g a n d Tissu e Repa ir 46
Pa t h oph ysiology 61
Mo d u le 3: C h r o n ic I n la m m a t io n 48 Clin ica l Ma n ifest a t ion s 61
C e lls o C h r o n ic I n la m m a t io n 48 Dia gn ost ic Cr it er ia 61
Tr ea t m en t 61
G r a n u lo m a F o r m a t io n 48
Gen er a l Ma n ifest a t ion s 48 P a n c r e a t it is 61
Tr ea t m en t 48 F u n ct ion s of t h e Pa n cr ea s 61

Mo d u le 4: Ap p lie d P a t h o p h y s io lo g y Ac u t e P a n c r e a t it is 61
C lin ic a l Mo d e ls 49 Pa t h oph ysiology 61
S in u s it is 49 Clin ica l Ma n ifest a t ion s 62
F u n ct ion s of t h e Sin u ses 50 Dia gn ost ic Cr it er ia 62
Acu t e sin u sit is 50 Tr ea t m en t 62
Pa t h oph ysiology 50 C h r o n ic P a n c r e a t it is 62
Clin ica l Ma n ifest a t ion s 50 Pa t h oph ysiology 63
Dia gn ost ic Cr it er ia 50 Clin ica l Ma n ifest a t ion s 63
Tr ea t m en t 50 Dia gn ost ic Cr it er ia 63
C h r o n ic S in u s it is 51 Tr ea t m en t 63
Pa t h oph ysiology 51 I n la m m a t o r y B o w e l D is e a s e 63
Clin ica l Ma n ifest a t ion s 51 F u n ct ion s of t h e Sm a ll In t est in e 64
Dia gn ost ic Cr it er ia 52 C r o h n D is e a s e 64
Tr ea t m en t 52 Pa t h oph ysiology 64
xvi Con t en t s

Clin ica l Ma n ifest a t ion s 65 Mo d u le 4: C lin ic a l Mo d e ls 89

Dia gn ost ic Cr it er ia 65
Tr ea t m en t 65
F u n ct ion s of t h e La r ge In t est in e
U lc e r a t iv e C o lit is 65
Pa t h oph ysiology 65
Clin ica l Ma n ifest a t ion s 66
Dia gn ost ic Cr it er ia 66
Tr ea t m en t 67
4. Alt e r e d Im m u n it y 71
I m m u n e Ma la d a p t a t io n : AI D S 89
Pa t h oph ysiology 89
65 Clin ica l Ma n ifest a t ion s 90
Dia gn ost ic Cr it er ia 91
Tr ea t m en t 91
I m m u n e Ma la d a p t a t io n :
An a p h y la c t ic R e a c t io n 92
Pa t h oph ysiology 92
Clin ica l Ma n ifest a t ion s 92
Dia gn ost ic Cr it er ia 92
Tr ea t m en t 92

I n t r o d u c t io n 71 I m m u n e Ma la d a p t a t io n : S y s t e m ic L u p u s
E r y t h e m a t o s u s 94
Mo d u le 1: R e v ie w o I m m u n e F u n c t io n 72 Pa t h oph ysiology 94
C e llu la r C o m p o n e n t s o I m m u n it y 73 Clin ica l Ma n ifest a t ion s 94
Im m u n e Cell Or igin 73 Dia gn ost ic Cr it er ia 95
Lym ph oid P r ogen it or Cells 73 Tr ea t m en t 96
Myeloid P r ogen it or Cells 74 I m m u n e Ma la d a p t a t io n : R h
Ly m p h a t ic s 75 I s o im m u n iza t io n 96
Pa t h oph ysiology 97
I m m u n e P r o c e s s e s 75
Clin ica l Ma n ifest a t ion s 97
In n a t e Im m u n it y 75
Dia gn ost ic Cr it er ia 97
Ada pt ive Im m u n it y 76
Tr ea t m en t 98
H u m or a l Im m u n it y 76
Cell-Media t ed Im m u n it y 77
Mo d u le 2: P r o c e s s o Alt e r in g
5. In e ct ion 103
I m m u n e F u n c t io n 78 I n t r o d u c t io n 103
H o s t D e e n s e Fa ilu r e 78
Mo d u le 1: Mic r o b e s 104
H y p e r s e n s it iv it y 81 P a t h o g e n s 105
Type I or Im m edia t e H yper sen sit ivit y Rea ct ion 82 Types of Pa t h ogen s 105
Type II An t ibody-Media t ed Rea ct ion s 83 Ba ct er ia 105
Type III Im m u n e Com plex–Media t ed Rea ct ion 83 Vir u ses 107
Type IV Cell-Media t ed H yper sen sit ivit y Ricket t sia e, Mycopla sm a s, a n d Ch la m ydia e 110
Rea ct ion 84
F u n gi 110
Au t o im m u n it y 85 P r ot ozoa 112
Allo im m u n it y 87 Mo d u le 2: C o m m u n ic a b le D is e a s e 113
Gr a ft Reject ion 87 R e s e r v o ir 114
Gr a ft Ver su s H ost Disea se 87
P o r t a l o E x it 114
Mo d u le 3: I m m u n e R e s p o n s e
Mo d e o Tr a n s m is s io n 114
Ma n ip u la t io n 87
P or t a l o E n t r y 114
Tr e a t m e n t o Ma la d a p t iv e I m m u n e
R e s p o n s e s 88 H o s t Fa c t o r s 114
I m m u n e R e s p o n s e in D is e a s e Mo d u le 3: Ac u t e I n e c t io n a n d
Ma n a g e m e n t 88 C o m p lic a t io n s 115

I m m u n e R e s p o n s e in t h e C o m p lic a t io n s o I n e c t io n 116
P r e v e n t io n o D is e a s e 89 C lin ic a l Ma n i e s t a t io n s 116

L a b o r a t o r y a n d D ia g n o s t ic Te s t s
Tr e a t m e n t Mo d a lit ie s 116
Mo d u le 4: C lin ic a l Mo d e ls
I n lu e n za 117
Pa t h oph ysiology 117
Clin ica l Ma n ifest a t ion s 117
Dia gn ost ic Cr it er ia 118
Tr ea t m en t 118
H e p a t it is 119
T h e F u n c t io n o t h e L iv e r
Vir a l H e p a t it is 120
Pa t h oph ysiology 120
Clin ica l Ma n ifest a t ion s 121
Dia gn ost ic Cr it er ia 121
Tr ea t m en t 121
Tu b e r c u lo s is 122
Pa t h oph ysiology 122
Clin ica l Ma n ifest a t ion s 124
Dia gn ost ic Cr it er ia 124
Tr ea t m en t 125
U r in a r y Tr a c t I n e c t io n 125
Pa t h oph ysiology 125
Clin ica l Ma n ifest a t ion s 125
Dia gn ost ic Cr it er ia 125
Tr ea t m en t 125
P y e lo n e p h r it is 126
F u n c t io n o t h e Kid n e y s
Ac u t e P y e lo n e p h r it is 126
Pa t h oph ysiology 126
Clin ica l Ma n ifest a t ion s 126
Dia gn ost ic Cr it er ia 126
Tr ea t m en t 126
Me n in g it is 126
F u n c t io n o t h e Me n in g e s
B a c t e r ia l Me n in g it is 127
Pa t h oph ysiology 127
Clin ica l Ma n ifest a t ion s 127
Dia gn ost ic Cr it er ia 129
Tr ea t m en t 129
Tin e a 129
Pa t h oph ysiology 129
Clin ica l Ma n ifest a t ion s 130
Dia gn ost ic Cr it er ia 130
Tr ea t m en t 130
Con t en t s x v ii
116 Ma la r ia 130
Pa t h oph ysiology 131
Clin ica l Ma n ifest a t ion s 131
117 Dia gn ost ic Cr it er ia 131
Tr ea t m en t 131
6. Ge n e t ic a n d De ve lop m e n t a l
Disor d e r s 135
I n t r o d u c t io n 135
119 Mo d u le 1: R e v ie w o G e n e t ic P r o c e s s e s 136
D e o x y r ib o n u c le ic Ac id 136
Gen es 136
Ch r om osom es 138
C h r o m o s o m a l R e p lic a t io n 139
Mo d u le 2: I n h e r it a n c e o G e n e t ic
D is o r d e r s 140
Tr a n s m is s io n a n d E x p r e s s io n
o G e n e t ic Tr a it s 141
I n h e r it a n c e o S in g le G e n e D is o r d e r s 142
Gen et ic Mu t a t ion s 143
Au t osom a l Dom in a n t Disor der s 143
Au t osom a l Recessive Disor der s 144
Sex-Lin ked Disor der s 145
Mit och on dr ia l Gen e Disor der s 145
I n h e r it a n c e o P o ly g e n ic D is o r d e r s 145
I n h e r it a n c e o C h r o m o s o m a l
126
Alt e r a t io n s 146
Alt er a t ion s in Ch r om osom a l Nu m ber 146
Alt er a t ion s in Ch r om osom a l St r u ct u r e 147
E p ig e n e t ic I n h e r it a n c e 147
Mo d u le 3: D e v e lo p m e n t a l D is o r d e r s 148
C o n g e n it a l D is o r d e r s 148
D e v e lo p m e n t a l O r ig in s o
127
Ad u lt D is e a s e 150
Mo d u le 4: Ma n a g e m e n t o G e n e t ic a n d
D e v e lo p m e n t a l D is o r d e r s 151
S c r e e n in g a n d D ia g n o s is 151
P r en a t a l Scr een in g a n d Dia gn osis 151
Post n a t a l Scr een in g a n d Dia gn osis 152
Tr e a t m e n t S t r a t e g ie s 152
Mo d u le 5: C lin ic a l Mo d e ls 152
Au t o s o m a l D o m in a n t G e n e t ic D is o r d e r :
H u n t in g t o n D is e a s e 152
x v iii Con t en t s

Pa t h oph ysiology 152 7. Alt e r e d Ce llu la r P r oli e r a -

Clin ica l Ma n ifest a t ion s 153
Dia gn ost ic Cr it er ia 153
t ion a n d Di e r e n t ia t ion 170
Tr ea t m en t 154 I n t r o d u c t io n 170
Au t o s o m a l R e c e s s iv e D is o r d e r : S ic k le C e ll Mo d u le 1: T h e I m p a c t o C a n c e r
D is e a s e 154 o n t h e C e ll 171
Pa t h oph ysiology 154
Alt e r e d C e llu la r P r o li e r a t io n
Clin ica l Ma n ifest a t ion s 155 a n d D i e r e n t ia t io n 171
Dia gn ost ic Cr it er ia 155 Ca r cin ogen esis 172
Tr ea t m en t 156 Gen et ic Mu t a t ion s 172
Mit o c h o n d r ia l G e n e D is o r d e r : Mit o c h o n d r ia l On cogen es 172
E n c e p h a lo m y o p a t h y, L a c t ic Ac id o s is , a n d Tu m or Su ppr essor Gen es 173
S t r o k e 156 Role of Gen e Va r ia n t s a n d E pigen et ics 174
Pa t h oph ysiology 156 Ca r cin ogen s 174
Clin ica l Ma n ifest a t ion s 157 Ra dia t ion 174
Dia gn osis 157 H or m on es 175
Tr ea t m en t 157 Ch em ica ls 175
Alt e r a t io n in C h r o m o s o m e N u m b e r Toba cco 176
(Au t o s o m e ): D o w n S y n d r o m e 157 Micr obes 176
Pa t h oph ysiology 158 I n it ia t io n –P r o m o t io n –P r o g r e s s io n
Clin ica l Ma n ifest a t ion s 158 T h e o r y 176
Dia gn ost ic Cr it er ia 159 Mo d u le 2: T h e I m p a c t o C a n c e r o n Tis s u e s ,
Tr ea t m en t 160 O r g a n s , a n d O r g a n S y s t e m s 177
Alt e r a t io n in C h r o m o s o m e N u m b e r B e n ig n Ve r s u s Ma lig n a n t 178
(S e x C h r o m o s o m e ): Tu r n e r S y n d r o m e 160
Ca n cer Sp r ea d 178
Pa t h oph ysiology 160
Clin ica l Ma n ifest a t ion s 160 C a n c e r N o m e n c la t u r e 179
Dia gn ost ic Cr it er ia 161 C a n c e r C la s s i ic a t io n s 180
Tr ea t m en t 161
C a n c e r P r o g n o s is 180
S e x -L in k e d G e n e t ic D is o r d e r : F r a g ile X G e n e r a l Ma n i e s t a t io n s 181
S y n d r o m e 161
Pa t h oph ysiology 162 D ia g n o s t ic Te s t s 182
Clin ica l Ma n ifest a t ion s 162 C a n c e r Tr e a t m e n t 183
Dia gn ost ic Cr it er ia 163
C a n c e r P r e v e n t io n 184
Tr ea t m en t 163
C h ild r e n a n d C a n c e r 184
E p ig e n e t ic I n h e r it a n c e : B e c k w it h –
Wie d e m a n n S y n d r o m e 163 Mo d u le 3: C lin ic a l Mo d e ls 185
Pa t h oph ysiology 163 L u n g C a n c e r 185
Clin ica l Ma n ifest a t ion s 163 Pa t h oph ysiology 185
Dia gn ost ic Cr it er ia 164 Clin ica l Ma n ifest a t ion s 185
Tr ea t m en t 164 Dia gn ost ic Cr it er ia 185
Tr ea t m en t 186
D e v e lo p m e n t a l Ma la d a p t a t io n : N e u r a l
Tu b e D e e c t s 164 C o lo n C a n c e r 186
Pa t h oph ysiology 164 Pa t h oph ysiology 186
Clin ica l Ma n ifest a t ion s 164 Clin ica l Ma n ifest a t ion s 187
Dia gn ost ic Test in g 165 Dia gn ost ic Cr it er ia 187
Tr ea t m en t 165 Tr ea t m en t 188

B r a in C a n c e r 188
Pa t h oph ysiology 188
Clin ica l Ma n ifest a t ion s 189
Dia gn ost ic Cr it er ia 189
Tr ea t m en t 190
L e u k e m ia 190
Ac u t e L e u k e m ia s 190
Pa t h oph ysiology 190
Clin ica l Ma n ifest a t ion s 190
Dia gn ost ic Cr it er ia 191
Tr ea t m en t 191
C h r o n ic Ly m p h o c y t ic a n d
My e lo g e n o u s L e u k e m ia s 191
Pa t h oph ysiology 191
Clin ica l Ma n ifest a t ion s 192
Dia gn ost ic Cr it er ia 192
Tr ea t m en t 192
Ly m p h o m a s 192
H o d g k in Ly m p h o m a 192
Pa t h oph ysiology 192
Clin ica l Ma n ifest a t ion s 193
Dia gn ost ic Cr it er ia 193
Tr ea t m en t 193
N o n -H o d g k in Ly m p h o m a 193
Pa t h oph ysiology 193
Clin ica l Ma n ifest a t ion s 194
Dia gn ost ic Cr it er ia 194
Tr ea t m en t 194
8. Alt e r e d F lu id a n d E le ct r olyt e
Ba la n ce 197
I n t r o d u c t io n 197
Mo d u le 1: E le c t r o ly t e I m b a la n c e
E le c t r o ly t e Tr a n s p o r t
Alt e r e d E le c t r o ly t e B a la n c e 198
Alt er ed Sodiu m Ba la n ce 199
H ypon a t r em ia 199
H yper n a t r em ia 199
Alt er ed Pot a ssiu m Ba la n ce 199
H ypoka lem ia 199
H yper ka lem ia 199
Alt er ed Ch lor ide Ba la n ce 200
H ypoch lor em ia 200
H yper ch lor em ia 200
Alt er ed Ca lciu m Ba la n ce 200
Con t en t s x ix
H ypoca lcem ia 200
H yper ca lcem ia 200
Alt er ed Ma gn esiu m Ba la n ce 200
H ypom a gn esem ia 200
H yper m a gn esem ia 200
Alt er ed P h osph a t e Ba la n ce 200
H ypoph osph a t em ia 201
H yper ph osph a t em ia 201
Mo d u le 2: F lu id I m b a la n c e 202
F lu id B a la n c e 202
F lu id Tr a n spor t 202
F lu id Regu la t ion 203
Mech a n ism s t o P r om ot e F lu id In t a ke 203
Mech a n ism s t o P r om ot e F lu id E xcr et ion 205
To n ic it y 205
Alt e r e d F lu id B a la n c e 206
Wa t er Con t en t 206
H ypovolem ia 207
H em or r h a ge 207
Deh ydr a t ion 208
Wa t er In t oxica t ion 208
H yper volem ia 208
E dem a 208
Mo d u le 3: C lin ic a l Mo d e ls 210
Alt e r e d F lu id B a la n c e : C ir r h o s is 210
Pa t h oph ysiology 210
Clin ica l Ma n ifest a t ion s 211
Dia gn ost ic Cr it er ia 211
Tr ea t m en t 211
Alt e r e d S o d iu m B a la n c e : D e h y d r a t io n 212
Pa t h oph ysiology 212
Clin ica l Ma n ifest a t ion s 212
Dia gn ost ic Cr it er ia 213
Tr ea t m en t 213
198
Alt e r e d C a lc iu m B a la n c e :
198
H y p o p a r a t h y r o id is m 214
Pa t h oph ysiology 214
Clin ica l Ma n ifest a t ion s 215
Dia gn ost ic Cr it er ia 215
Tr ea t m en t 215
9. Alt er ed Acid –Ba se Ba la n ce 218
I n t r o d u c t io n 218
Mo d u le 1: Ac id –B a s e I m b a la n c e 219
R e g u la t io n o Ac id a n d B a s e 219
xx Con t en t s

Bu ffer Syst em s 219 P r o c e s s e s o N e u r o n a l I n ju r y 233

P la sm a Bu ffer Syst em s 219
Bica r bon a t e Bu ffer Syst em 220
P r ot ein Bu ffer Syst em 220
Pot a ssiu m –H ydr ogen E xch a n ge 220
Respir a t or y Bu ffer Syst em 220
Ren a l Bu ffer Syst em 220
H ydr ogen Ion E lim in a t ion /Bica r bon a t e
Con ser va t ion 220
Tu bu la r Bu ffer Syst em s 221
Pot a ssiu m –H ydr ogen E xch a n ge 221
Ch lor ide–Bica r bon a t e E xch a n ge 221
Alt e r e d Ac id –B a s e B a la n c e 221
Met a bolic Acidosis 221
Met a bolic Alka losis 222
Mo d u le 2: C lin ic a l Mo d e ls 222
Alt e r e d Ac id –B a s e B a la n c e : H ig h ly Ac t iv e
An t ir e t r o v ir a l T h e r a p y (H AAR T )-As s o c ia t e d
Ac id o s is 222
Pa t h oph ysiology 223
Clin ica l Ma n ifest a t ion s 223
Dia gn ost ic Cr it er ia 223
Tr ea t m en t 223
Alt e r e d Ac id –B a s e B a la n c e :
R e n a l Tu b u lo p a t h y 224
Pa t h oph ysiology 224
Clin ica l Ma n ifest a t ion s 224
Dia gn ost ic Cr it er ia 224
Tr ea t m en t 224
Alt e r e d Ac id –B a s e B a la n c e : Me t a b o lic
Ac id o s is in P a r e n t e r a l N u t r it io n 225
Pa t h oph ysiology 225
Clin ica l Ma n ifest a t ion s 225
Dia gn ost ic Cr it er ia 225
Tr ea t m en t 226
10. Alt e r e d Ne u r on a l
Tr a n sm ission 228
I n t r o d u c t io n 228
Mo d u le 1: Alt e r a t io n s in N e u r o n a l
I m p u ls e C o n d u c t io n 229
Neu r on s 229
S u p p o r t in g C e lls 229
N e u r o n a l Tr a n s m is s io n 230
C o m m u n ic a t io n B e t w e e n N e u r o n s
D e v e lo p m e n t a l C o n s id e r a t io n s 233
Mo d u le 2: Alt e r a t io n s in C N S F u n c t io n 233
C N S O r g a n iza t io n 233
Br a in 233
Spin a l Cor d 234
P r o t e c t iv e S t r u c t u r e s o t h e C N S 237
Neu r ocir cu la t or y Syst em 237
Cer ebr ova scu la r Cir cu la t ion 237
Blood–Br a in Ba r r ier 237
Cer ebr ospin a l F lu id 237
C N S C e llu la r I n ju r y 238
Mech a n ism s of In ju r y t o t h e CNS 238
Tr a u m a t ic CNS In ju r y 238
Tr a u m a t ic Br a in In ju r y 238
Tr a u m a t ic Spin a l Cor d In ju r y 239
Isch em ic CNS In ju r y 239
E xcit a t ion In ju r y 241
CNS P r essu r e In ju r y 241
Mo d u le 3: Alt e r a t io n s in P e r ip h e r a l N e r v o u s
S y s t e m F u n c t io n 242
P e r ip h e r a l N e r v o u s S y s t e m
O r g a n iza t io n 242
Som a t ic Ner vou s Syst em 243
Au t on om ic Ner vou s Syst em 244
Sym pa t h et ic Ner vou s Syst em 244
Pa r a sym pa t h et ic Ner vou s Syst em 245
R e le x Ar c s 246
P e r ip h e r a l N e r v o u s S y s t e m
C e llu la r I n ju r y 247
Mech a n ism s of In ju r y t o t h e Per iph er a l Ner vou s
Syst em 247
Tr a u m a t ic Per iph er a l Ner ve In ju r y 247
Per iph er a l Ner vou s Syst em P r essu r e
In ju r y 248
P e r ip h e r a l N e r v o u s S y s t e m
Mo t o r D y s u n c t io n 248
Mo d u le 4: C lin ic a l Mo d e ls 249
C e r e b r a l P a ls y 249
Pa t h oph ysiology 249
Clin ica l Ma n ifest a t ion s 250
Dia gn ost ic Cr it er ia 251
Tr ea t m en t 252
Mu lt ip le S c le r o s is 252
Pa t h oph ysiology 252
231 Clin ica l Ma n ifest a t ion s 253
 Con t en t s xxi

Dia gn ost ic Cr it er ia 253 Ma jo r D e p r e s s iv e D is o r d e r 274

Tr ea t m en t 254 Pa t h oph ysiology 274
H y d r o c e p h a lu s 254 Clin ica l Ma n ifest a t ion s 276
Pa t h oph ysiology 254 Dia gn ost ic Cr it er ia 276
Clin ica l Ma n ifest a t ion s 255 Tr ea t m en t 276
Dia gn ost ic Cr it er ia 256 B ip o la r A e c t iv e D is o r d e r 276
Tr ea t m en t 256 Pa t h oph ysiology 276
I n c o m p le t e S p in a l C o r d Tr a n s e c t io n 256 Clin ica l Ma n ifest a t ion s 277
Pa t h oph ysiology 257 Dia gn ost ic Cr it er ia 277
Clin ica l Ma n ifest a t ion s 257 Tr ea t m en t 277
Dia gn ost ic Cr it er ia 257 At t e n t io n -D e ic it H y p e r a c t iv it y D is o r d e r 277
Tr ea t m en t 257 Pa t h oph ysiology 278
P a r k in s o n D is e a s e 257 C lin ic a l Ma n i e s t a t io n s 278
Pa t h oph ysiology 259 Dia gn ost ic Cr it er ia 278
Clin ica l Ma n ifest a t ion s 259 Tr ea t m en t 278
Dia gn osis 260 Au t is m S p e c t r u m D is o r d e r s 279
Tr ea t m en t 262 Pa t h oph ysiology 279
Clin ica l Ma n ifest a t ion s 279
11. Alt e r e d Mood , At t e n t ion , Dia gn ost ic Cr it er ia 281
Tr ea t m en t 281
a n d Be h a vior 265
S c h izo p h r e n ia 281
I n t r o d u c t io n 265 Pa t h oph ysiology 281
Mo d u le 1: R e g u la t io n o Mo o d , At t e n t io n , Clin ica l Ma n ifest a t ion s 281
a n d B e h a v io r 266 Dia gn ost ic Cr it er ia 282
Tr ea t m en t 282
R e g u la t io n o Mo o d 266
R e g u la t io n o At t e n t io n 267
R e g u la t io n o B e h a v io r 269 12. Alt e r e d Som a t ic a n d Sp e cia l
Mo d u le 2: Alt e r a t io n s in Mo o d , At t e n t io n ,
Se n sor y F u n ct ion 286
a n d B e h a v io r 269
I n t r o d u c t io n 286
Alt e r a t io n s in B r a in S t r u c t u r e a n d
Mo d u le 1: P a in 287
F u n c t io n 269
S o m a t o s e n s o r y S y s t e m 287
R e c o g n izin g Alt e r a t io n s in Mo o d , At t e n t io n ,
a n d B e h a v io r 269 Som a t osen sor y Neu r on a l Or ga n iza t ion 287
Som a t osen sor y Neu r on a l Tr a n sm ission 287
Tr e a t in g Alt e r a t io n s in Mo o d , At t e n t io n ,
Dor sa l Root Ga n glia F iber s 287
a n d B e h a v io r 270
Der m a t om e In n er va t ion 288
Mo d u le 3: C lin ic a l Mo d e ls 270 Som a t osen sor y P r ocessin g 289
G e n e r a lize d An x ie t y D is o r d e r 270 Som a t osen sor y Moda lit ies 289
Pa t h oph ysiology 272 St im u lu s Discr im in a t ion 289
Clin ica l Ma n ifest a t ion s 272 Ta ct ile St im u la t ion 289
Dia gn ost ic Cr it er ia 272 Th er m a l Sen sa t ion 289
Tr ea t m en t 272 Posit ion Sen sa t ion 289
P o s t t r a u m a t ic S t r e s s D is o r d e r 272 P a in 289
Pa t h oph ysiology 273 Ch a r a ct er iza t ion of Pa in 289
Clin ica l Ma n ifest a t ion s 274 Con du ct ion of Pa in Sen sa t ion 290
Dia gn ost ic Cr it er ia 274 Th eor ies of Pa in 290
Tr ea t m en t 274 Pa t t er n Th eor y 290
x x ii Con t en t s

Specificit y Th eor y 290 Tr ea t m en t 306

Ga t e Con t r ol Th eor y 291 Mig r a in e H e a d a c h e 307
In t en sit y Th eor y 291 Pa t h oph ysiology 307
Neu r om a t r ix Th eor y 292 Clin ica l Ma n ifest a t ion s 307
Ma n ifest a t ion s a n d E va lu a t ion of Pa in 292 Dia gn ost ic Cr it er ia 308
Tr ea t m en t of Pa in 292 Tr ea t m en t 308
Mo d u le 2: Alt e r a t io n s in Vis io n 294 O t it is Me d ia 308
Vis u a l S t r u c t u r e s a n d F u n c t io n 294 Pa t h oph ysiology 308
Con t r ol of E ye Movem en t 295 Clin ica l Ma n ifest a t ion s 309
P r ot ect ive E ye St r u ct u r es 295 Dia gn ost ic Cr it er ia 309
E xt er n a l St r u ct u r es 295 Tr ea t m en t 309
Tea r s 296 Mé n iè r e D is e a s e 310
Aqu eou s H u m or 297 Pa t h oph ysiology 310
Alt e r a t io n s in Vis u a l F u n c t io n 297 Clin ica l Ma n ifest a t ion s 310
E r r or s in Refr a ct ion 297 Dia gn ost ic Cr it er ia 310
Alt er a t ion s in E ye Movem en t 297 Tr ea t m en t 310
Alt er a t ion s in P r ot ect ive E ye St r u ct u r es 298 Ma c u la r D e g e n e r a t io n 310
Ma n ifest a t ion s a n d E va lu a t ion of Alt er a t ion s Pa t h oph ysiology 311
in Vision 299
Clin ica l Ma n ifest a t ion s 311
Tr ea t m en t of Alt er a t ion s in Vision 299
Dia gn ost ic Cr it er ia 311
Mo d u le 3: Alt e r a t io n s in H e a r in g Tr ea t m en t 311
a n d B a la n c e 300
G la u c o m a 312
St r u ct u r a l Com p on en t s o t h e E a r 300 Pa t h oph ysiology 312
Ou t er E a r 300 Clin ica l Ma n ifest a t ion s 312
Middle E a r 300 Dia gn ost ic Cr it er ia 313
In n er E a r 301 Tr ea t m en t 313
H e a r in g P r o c e s s e s 301 R e t in o p a t h y o P r e m a t u r it y 314
B a la n c e P r o c e s s e s 301 Pa t h oph ysiology 314
Alt e r a t io n s in H e a r in g a n d B a la n c e 302 Clin ica l Ma n ifest a t ion s 314
Disor der s of t h e E xt er n a l E a r 302 Dia gn osis 314
Alt er a t ion in Middle E a r F u n ct ion 302 Tr ea t m en t 314
Alt er a t ion in In n er E a r F u n ct ion 303
Ma n ifest a t ion s a n d E va lu a t ion of Alt er a t ion s in
H ea r in g 303 13. Alt e r e d H or m on a l a n d
H ea r in g E va lu a t ion 303 Me t a b olic R e gu la t ion 318
E va lu a t ion of t h e Middle E a r 303
E va lu a t ion of t h e In n er E a r 304 I n t r o d u c t io n 318

Tr e a t m e n t o Alt e r a t io n s in H e a r in g
Ta s t e a n d S m e ll 304
Ta st e 304
Sm ell 304
Mo d u le 4: C lin ic a l Mo d e ls
F ib r o m y a lg ia 305
Pa t h oph ysiology 305
Clin ica l Ma n ifest a t ion s 306
Dia gn ost ic Cr it er ia 306
304 Mo d u le 1: F u n c t io n a n d R e g u la t io n o
H o r m o n e s 319
I n t e g r a t in g E n d o c r in e , N e u r o n a l, a n d D e e n s e
Me c h a n is m s in t h e B o d y 319
R e g u la t in g H o r m o n e s 319
305
Th e H ypot h a la m ic–P it u it a r y Axis 319
Feedba ck Mech a n ism s 321
H or m on e Secr et ion , Met a bolism ,
a n d E lim in a t ion 322
Recept or Bin din g 322
 Con t en t s x x iii

Me d ia t in g C e ll-t o -C e ll C o m m u n ic a t io n 324 Ad d is o n D is e a s e 336

Mo d u le 2: T h e S t r e s s R e s p o n s e 325 Pa t h oph ysiology 336
Clin ica l Ma n ifest a t ion s 337
N e u r o lo g ic R e s p o n s e t o S t r e s s 326
Dia gn ost ic Cr it er ia 337
H or m on a l R esp on se t o St r ess 326 Tr ea t m en t 337
G e n e r a l Ad a p t a t io n S y n d r o m e 327
Mo d u le 3: Alt e r e d H o r m o n e F u n c t io n 327 14. Alt e r e d R e p r od u ct ive
D a m a g e t o t h e H y p o t h a la m ic –P it u it a r y F u n ct ion 340
Ax is 327
I n t r o d u c t io n 340
D a m a g e t o E n d o c r in e G la n d s 328
Mo d u le 1: R e g u la t io n o R e p r o d u c t io n 341
D a m a g e t o C e ll R e c e p t o r s 328
F e m a le R e p r o d u c t iv e H o r m o n e F u n c t io n 341
D a m a g e t o F e e d b a c k Me c h a n is m s 328
Ma le R e p r o d u c t iv e H o r m o n e F u n c t io n 344
D a m a g e t o Me t a b o lis m a n d E lim in a t io n
Me c h a n is m s 328 Mo d u le 2: Alt e r e d R e p r o d u c t iv e
F u n c t io n 346
G e n e r a l Ma n i e s t a t io n s o Alt e r e d H o r m o n e
F u n c t io n 328 G e n e r a l Ma n i e s t a t io n s o Alt e r e d
R e p r o d u c t iv e F u n c t io n 347
D ia g n o s in g a n d Tr e a t in g Alt e r e d H o r m o n e
F u n c t io n 329 D ia g n o s in g a n d Tr e a t in g Alt e r e d
R e p r o d u c t iv e F u n c t io n 347
Mo d u le 4: C lin ic a l Mo d e ls 329
Mo d u le 3: C lin ic a l Mo d e ls 349
S y n d r o m e o I n a p p r o p r ia t e An t id iu r e t ic
H o r m o n e S e c r e t io n 330 P e lv ic I n la m m a t o r y D is e a s e 349
Pa t h oph ysiology 330 Pa t h oph ysiology 349
Clin ica l Ma n ifest a t ion s 330 Clin ica l Ma n ifest a t ion s 349
Dia gn ost ic Cr it er ia 330 Dia gn ost ic Cr it er ia 350
Tr ea t m en t 330 Tr ea t m en t 350
D ia b e t e s I n s ip id u s 331 P o ly c y s t ic O v a r ia n S y n d r o m e 350
Pa t h oph ysiology 331 Pa t h oph ysiology 351
Clin ica l Ma n ifest a t ion s 331 Clin ica l Ma n ifest a t ion s 352
Dia gn ost ic Cr it er ia 331 Dia gn ost ic Cr it er ia 352
Tr ea t m en t 332 Tr ea t m en t 352
H y p e r t h y r o id is m 332 O v a r ia n C a n c e r 352
Pa t h oph ysiology 332 Pa t h oph ysiology 352
Clin ica l Ma n ifest a t ion s 332 Clin ica l Ma n ifest a t ion s 354
Dia gn ost ic Cr it er ia 333 Dia gn ost ic Cr it er ia 354
Tr ea t m en t 333 Tr ea t m en t 354
H y p o t h y r o id is m 333 Me n o p a u s e 354
Pa t h oph ysiology 333 Pa t h oph ysiology 354
Clin ica l Ma n ifest a t ion s 334 Clin ica l Ma n ifest a t ion s 354
Dia gn ost ic Cr it er ia 334 Dia gn ost ic Cr it er ia 355
Tr ea t m en t 334 Tr ea t m en t 355
C u s h in g S y n d r o m e 334 E r e c t ile D y s u n c t io n 356
Pa t h oph ysiology 335 Pa t h oph ysiology 356
Clin ica l Ma n ifest a t ion s 335 Clin ica l Ma n ifest a t ion s 356
Dia gn ost ic Cr it er ia 336 Dia gn ost ic Cr it er ia 357
Tr ea t m en t 336 Tr ea t m en t 357
x x iv Con t en t s

B e n ig n P r o s t a t ic H y p e r p la s ia 357 Clin ica l Ma n ifest a t ion s 380

Pa t h oph ysiology 357 Dia gn ost ic Cr it er ia 380
Clin ica l Ma n ifest a t ion s 357 Tr ea t m en t 380
Dia gn ost ic Cr it er ia 357 C h r o n ic O b s t r u c t iv e P u lm o n a r y D is e a s e 380
Tr ea t m en t 358
E m p h y s e m a 380
P r o s t a t e C a n c e r 358 Pa t h oph ysiology 381
Pa t h oph ysiology 358 Clin ica l Ma n ifest a t ion s 382
Clin ica l Ma n ifest a t ion s 359 Dia gn ost ic Cr it er ia 382
Dia gn ost ic Cr it er ia 359 Tr ea t m en t 382
Tr ea t m en t 360
C h r o n ic B r o n c h it is 383
Te s t ic u la r C a n c e r 360 Pa t h oph ysiology 383
Pa t h oph ysiology 360 Clin ica l Ma n ifest a t ion s 384
Clin ica l Ma n ifest a t ion s 361 Dia gn ost ic Cr it er ia 384
Dia gn ost ic Cr it er ia 361 Tr ea t m en t 384
Tr ea t m en t 361
As t h m a 384
Pa t h oph ysiology 384
15. Alt e r e d Ve n t ila t ion a n d Clin ica l Ma n ifest a t ion s 386
Di u sion 365 Dia gn ost ic Cr it er ia 386
Tr ea t m en t 386
I n t r o d u c t io n 365 C y s t ic F ib r o s is 387
Mo d u le 1: P u lm o n a r y S t r u c t u r e a n d Pa t h oph ysiology 387
F u n c t io n 366 Clin ica l Ma n ifest a t ion s 388
Ve n t ila t io n 367 Dia gn ost ic Cr it er ia 389
In spir a t ion 368 Tr ea t m en t 389
E xpir a t ion 368 Ac u t e R e s p ir a t o r y D is t r e s s S y n d r o m e 389
Mea su r em en t of Ven t ila t ion 368 Pa t h oph ysiology 389
D i u s io n 368 Clin ica l Ma n ifest a t ion s 391
Pa r t ia l P r essu r e 369 Dia gn ost ic Cr it er ia 391
Oxygen Diffu sion a n d Tr a n spor t 369 Tr ea t m en t 391
Ca r bon Dioxide Diffu sion a n d Tr a n spor t 369
Diffu sin g Ca pa cit y 370
16. Alt e r e d P e r u sion 395
Mo d u le 2: I m p a ir e d Ve n t ila t io n 371
Im pa ir ed Ven t ila t ion –Per fu sion Ma t ch in g 372 I n t r o d u c t io n 395
Im pa ir ed Diffu sion 372 Mo d u le 1: P e r u s io n 396
Th e E ffect s of Im pa ir ed Ven t ila t ion
F r o m Ve n t ila t io n t o P e r u s io n 396
a n d Diffu sion 373
C ir c u la t io n 397
H y p o x e m ia a n d H y p o x ia 373
P u lm on a r y Cir cu la t ion 397
H y p e r c a p n ia 373 Syst em ic Cir cu la t ion 397
Gen er a l Ma n ifest a t ion s of Im pa ir ed Ven t ila t ion a n d Cor on a r y Cir cu la t ion 397
Diffu sion 373
La bor a t or y a n d Dia gn ost ic Test s 376 Mo v e m e n t o B lo o d T h r o u g h
t h e C ir c u la t io n 398
Tr ea t in g Im pa ir ed Ven t ila t ion a n d Diffu sion 377
Ca r dia c Cycle 399
Mo d u le 3: C lin ic a l Mo d e ls 378 Con du ct ion of Im pu lses 399
P n e u m o n ia 378 Ca r dia c Ou t pu t 401
Pa t h oph ysiology 378 Blood P r essu r e 401
 Con t en t s xxv

Neu r on a l Con t r ol of Blood P r essu r e 17. Alt e r e d Nu t r it ion 428

a n d Ca r diova scu la r Ada pt a t ion 402
Mo d u le 2: Alt e r e d P e r u s io n 404 I n t r o d u c t io n 428

Ve n t ila t io n –P e r u s io n Mis m a t c h in g 404 Mo d u le 1: N u t r it io n 429

I m p a ir e d C ir c u la t io n 404 Wa t e r 429

I n a d e q u a t e C a r d ia c O u t p u t 406
E x c e s s iv e P e r u s io n D e m a n d s
G e n e r a l Ma n i e s t a t io n s o Alt e r e d
P e r u s io n 408
Ma c r o n u t r ie n t s : P r o t e in s , L ip id s ,
a n d C a r b o h y d r a t e s 429
408
Mic r o n u t r ie n t s : Vit a m in s a n d Min e r a ls 431
N u t r it io n a l I n t a k e R e q u ir e m e n t s 434

D ia g n o s in g a n d Tr e a t in g Alt e r e d
P e r u s io n 409
Mo d u le 3: C lin ic a l Mo d e ls
H y p e r t e n s io n 410
Pa t h oph ysiology 410
Clin ica l Ma n ifest a t ion s 411
Dia gn ost ic Cr it er ia 412
Tr ea t m en t 412
S h o c k 413
Pa t h oph ysiology 413
Clin ica l Ma n ifest a t ion s 414
Dia gn ost ic Cr it er ia 414
Tr ea t m en t 414
My o c a r d ia l I n a r c t io n 415
Pa t h oph ysiology 415
Clin ica l Ma n ifest a t ion s 416
Dia gn ost ic Cr it er ia 417
Tr ea t m en t 417
H e a r t Fa ilu r e 418
Pa t h oph ysiology 418
Left H ea r t Fa ilu r e 418
Righ t H ea r t Fa ilu r e 418
Clin ica l Ma n ifest a t ion s 420
Dia gn ost ic Cr it er ia 421
Tr ea t m en t 421
S t r o k e 422
Pa t h oph ysiology 422
Clin ica l Ma n ifest a t ion s 423
Dia gn ost ic Cr it er ia 423
Tr ea t m en t 423
D is s e m in a t e d I n t r a v a s c u la r
C o a g u la t io n 423
Pa t h oph ysiology 423
Clin ica l Ma n ifest a t ion s 424
Dia gn ost ic Cr it er ia 424
Tr ea t m en t 424
I n t a k e a n d S t o r a g e o N u t r ie n t s 435
Digest ion 435
Absor pt ion 438
410
G lu c o s e a n d F r u c t o s e Ab s o r p t io n 438
Am in o Ac id a n d S m a ll P e p t id e
Ab s o r p t io n 440
Fa t t y Ac id a n d G ly c e r o l Ab s o r p t io n 441
Mo d u le 2: Alt e r e d N u t r it io n 441
I n h e r it e d Me t a b o lic D is o r d e r s 442
U n d e r n u t r it io n 442
Vit a m in a n d Min er a l Deficien cies 442
P r ot ein E n er gy Ma ln u t r it ion 443
O v e r n u t r it io n 443
Ma la b s o r p t io n 443
F o o d Alle r g y 446
Gen er a l Ma n ifest a t ion s of Alt er ed Nu t r it ion 447
Dia gn ost ic a n d Tr ea t m en t St r a t egies Rela t ed t o
Alt er ed Nu t r it ion 447
Mo d u le 3: C lin ic a l Mo d e ls 448
I r o n -D e ic ie n c y An e m ia 448
Pa t h oph ysiology 448
Clin ica l Ma n ifest a t ion s 448
Dia gn ost ic Cr it er ia 448
Tr ea t m en t 449
An o r e x ia N e r v o s a 449
Pa t h oph ysiology 450
Clin ica l Ma n ifest a t ion s 450
Dia gn ost ic Cr it er ia 451
Tr ea t m en t 451
C e lia c D is e a s e (G lu t e n -S e n s it iv e
E n t e r o p a t h y ) 451
Pa t h oph ysiology 451
Clin ica l Ma n ifest a t ion s 451
Dia gn ost ic Cr it er ia 452
Tr ea t m en t 452
xxvi Con t en t s

P h e n y lk e t o n u r ia 452 Alt er a t ion in Bowel Neu r om u scu la r

Pa t h oph ysiology 452 F u n ct ion 473
Clin ica l Ma n ifest a t ion s 453 Alt er a t ion in Bowel Per fu sion 473
Dia gn ost ic Cr it er ia 453 Alt er a t ion in Bowel Pa t en cy 473
Tr ea t m en t 453 G e n e r a l Ma n i e s t a t io n s o Alt e r e d B o w e l
O b e s it y 453 E lim in a t io n 475
Pa t h oph ysiology 453 D ia g n o s is o B o w e l C o n d it io n s 476
Clin ica l Ma n ifest a t ion s 454 Tr e a t m e n t o Alt e r e d B o w e l E lim in a t io n 476
Dia gn ost ic Cr it er ia - 455
Mo d u le 3: C lin ic a l Mo d e ls 477
Tr ea t m en t 455
U r o lit h ia s is 477
Pa t h oph ysiology 477
18. Alt e r e d E lim in a t ion 460 Clin ica l Ma n ifest a t ion s 478
Dia gn ost ic Cr it er ia 478
I n t r o d u c t io n 460
Tr ea t m en t 479
Mo d u le 1: Alt e r e d U r in a r y E lim in a t io n 461
U r in a r y I n c o n t in e n c e 479
U r in e P r o d u c t io n P r o c e s s 461 Pa t h oph ysiology 480
Ur in e P r odu ct ion 461 Clin ica l Ma n ifest a t ion s 480
Ur in e Rem ova l 462 Dia gn ost ic Cr it er ia 480
U r in e C h a r a c t e r is t ic s 464 Tr ea t m en t 480
U r in e An a ly s is 465 P o ly c y s t ic Kid n e y D is e a s e 481
Alt er ed Ur in a r y E lim in a t ion 465 Pa t h oph ysiology 481
P r o c e s s e s o Alt e r e d U r in a r y Dia gn ost ic Cr it er ia 482
E lim in a t io n 465 Tr ea t m en t 482
Alt er a t ion in Ur in a r y Mot ilit y 465 D iv e r t ic u la r D is e a s e 485
Alt er a t ion in Ur in a r y Neu r om u scu la r Pa t h oph ysiology 485
F u n ct ion 465 Clin ica l Ma n ifest a t ion s 486
Alt er a t ion in Ur in a r y Per fu sion 466 Dia gn ost ic Cr it er ia 486
Alt er a t ion in Ur in a r y Pa t en cy 466 Tr ea t m en t 486
G e n e r a l Ma n i e s t a t io n s o Alt e r e d U r in a r y F u n c t io n a l F e c a l I n c o n t in e n c e 486
E lim in a t io n 467
Pa t h oph ysiology 486
D ia g n o s is o C o n d it io n s o t h e R e n a l a n d Clin ica l Ma n ifest a t ion s 486
U r in a r y S y s t e m s 468 Dia gn ost ic Cr it er ia 487
Tr e a t m e n t o Alt e r e d U r in a r y Tr ea t m en t 487
E lim in a t io n 469
Mo d u le 2: Alt e r a t io n in S t o o l
E lim in a t io n 469 19. De ge n e r a t ive Ch a n ge s
P r o c e s s e s o S t o o l E lim in a t io n 469 in Agin g 490
St ool E lim in a t ion P r ocess 469
St ool P r odu ct ion 469 I n t r o d u c t io n 490
St ool E va cu a t ion 471 Mo d u le 1: T h e o r ie s o Ag in g 491
S t o o l C h a r a c t e r is t ic s 471 T h e o r ie s o Ag in g 491
St ool An a lysis 472 Developm en t a l Th eor ies 491
Alt e r e d B o w e l E lim in a t io n 472 St och a st ic Th eor ies 492
P r ocesses of Alt er ed Bowel E lim in a t ion 472 Mo d u le 2: G e n e r a l Ma n i e s t a t io n s
Alt er a t ion in Bowel Mot ilit y 472 o Ag in g 492
 Con t en t s x x v ii

C e llu la r C h a n g e s in Ag in g 492 20. In t e gr a t e d P a t h op h ysiologic

Ag in g a n d Ap p e a r a n c e 493 Con ce p t s 507
F lu id a n d E le c t r o ly t e B a la n c e 493
I n t r o d u c t io n 507
Im m u n e R esp on se 493
Glu cose , In su lin , E n e r gy, a n d t h e P a n cr e a s 507
Ag e -R e la t e d P r o li e r a t iv e C h a n g e s 493
D ia b e t e s Me llit u s 508
N e u r o lo g ic F u n c t io n 494 In su lin Deficit : Type 1 Dia bet es Mellit u s 509
Mo b ilit y 494 Pa t h oph ysiology 509
P e r u s io n a n d Ve n t ila t io n 495 Clin ica l Ma n ifest a t ion s 510
Dia gn ost ic Cr it er ia 510
Me t a b o lic P r o c e s s e s 496
Tr ea t m en t 510
N u t r it io n a n d E lim in a t io n 496 In su lin Resist a n ce a n d Redu ct ion : Type 2
Mo d u le 3: Ma n a g in g D e g e n e r a t iv e Dia bet es 513
C h a n g e s in t h e E ld e r ly 498 Pa t h oph ysiology 513
Clin ica l Ma n ifest a t ion s 514
Mo d u le 4: C lin ic a l Mo d e ls 498
Dia gn ost ic Cr it er ia 514
H u t c h in s o n –G il o r d P r o g e r ia S y n d r o m e 498 Tr ea t m en t 514
Pa t h oph ysiology 498 Gest a t ion a l Dia bet es 515
Clin ica l Ma n ifest a t ion s 499 Acu t e Com plica t ion s of Dia bet es Mellit u s 515
Dia gn osis 499 H ypoglycem ia 516
Tr ea t m en t 499 Dia bet ic Ket oa cidosis 517
O s t e o p o r o s is 499 H yper glycem ic H yper osm ola r Non ket ot ic
Pa t h oph ysiology 499 Syn dr om e 517
Clin ica l Ma n ifest a t ion s 500 Th e Som ogyi E ffect a n d Da wn P h en om en on 518
Dia gn osis 500 Ch r on ic Com plica t ion s of Dia bet es Mellit u s 519
Tr ea t m en t 501 Micr ova scu la r Com plica t ion s 519
Ma cr ova scu la r Com plica t ion s 520
Alzh e im e r D is e a s e 502
Neu r opa t h ies 520
Pa t h oph ysiology 502
In fect ion 521
Clin ica l Ma n ifest a t ion s 503
Dia gn osis 504
Tr ea t m en t 504
Gl ossa r y 525
I n d ex 553
 Ch a pt er

1
In t r odu ct ion t o
Pa t h oph ysiology

L E AR N I N G O U T C O ME S
1. Defin e a n d u se t h e key t er m s list ed in t h is ch a pt er.
2. Discu ss t h e va lu e of pr er equ isit e scien ce cou r ses a s a fou n da t ion for lea r n -
in g pa t h oph ysiology.
3. Differ en t ia t e in dividu a l ver su s popu la t ion -focu sed ca r e.
4. St a t e a n d give exa m ples of t h e t h r ee levels of pr even t ion u pon wh ich in -
t er ven t ion s a r e ba sed.
5. Descr ibe t h e r eleva n ce of gen der, a ge, r a ce, et h n icit y, loca le, a n d socioeco-
n om ic st a t u s t o pa t h oph ysiology.
6. E xpla in t h e sign ifica n ce of eviden ce-ba sed pr a ct ice t o pa t h oph ysiology.

INTR ODUCTION
Defining Pathophysiology
Wh a t is pa t h oph ysiology? P a t h o p h y s io lo g y is t h e st u dy of t h e fu n ct ion a l
ch a n ges t h a t occu r in t h e body a s a r esu lt of a n in ju r y, disor der, or disea se. Ap-
plyin g pa t h oph ysiology com bin es wh a t we kn ow a bou t p a t h o lo g y , t h e st u dy
of ch a n ges in cells a n d t issu es a s a r esu lt of in ju r y or disea se, a n d p h y s io lo g y ,
t h e m ech a n ism s of h u m a n body fu n ct ion in g. Pa t h oph ysiology is oft en r efer r ed
t o a s a st u dy of t h e m ech a n ism s of disea se.
Wh en you st u dy pa t h oph ysiology, you m u st r ecogn ize t h e in t er depen den ce
of a lt er ed st r u ct u r e a n d fu n ct ion . S t r u c t u r e is h ow t h e h u m a n body is pu t t o-
get h er, in clu din g t h e com pon en t pa r t s a n d loca t ion of t h ose pa r t s. Th is is oft en
lea r n ed in a cou r se in h u m a n a n a t om y. F u n c t io n is con cer n ed wit h h ow t h ese
com pon en t pa r t s oper a t e t oget h er. Th is is m ost oft en discover ed in a cou r se
in h u m a n ph ysiology. In a ddit ion , pr epa r a t ion in ot h er h ea lt h scien ce t opics
su ch a s h u m a n biology, m icr obiology, a n d ch em ist r y is h elpfu l. Pa t h oph ysiology
bu ilds on pr eviou s lea r n in g a n d a pplies t h a t lea r n in g t o discer n wh a t h a ppen s
t o bot h st r u ct u r e a n d fu n ct ion in t h e h u m a n body in t h e fa ce of in ju r y, disor der,
a n d disea se.

Understanding Pathophysiology
PATHOGENESIS
Th e fir st st ep t o u n der st a n din g pa t h oph ysiology is t o r ecogn ize a n d u se key
t er m s a ppr opr ia t ely. Fir st , con sider t h e on set of t h e disea se. D is e a s e is t h e
1
2 C h a p t e r 1: In t r odu ct ion t o Pa t h oph ysiology
fu n ct ion a l im pa ir m en t of cells, t issu es, or ga n s, or or-
ga n syst em s. In t h is t ext , t h e t er m d isea se is oft en
u sed br oa dly t o in clu de in ju r ies, disor der s, illn esses,
a n d even s y n d r o m e s , defin ed a s a specific con dit ion
wit h a r ecogn iza ble, pr edict a ble pa t t er n . Th e or igin a -
t ion a n d developm en t a t t h e poin t of disea se on set is
r efer r ed t o a s it s p a t h o g e n e s is , lit er a lly t h e disea se
begin n in g. Th e pa t h ogen esis en com pa sses wh en t h e
disea se pr ocess fir st begin s t o t h e poin t wh en t h e
disea se pr esen t s it self. For exa m ple, in dia bet es m el-
lit u s, pa n cr ea t ic bet a islet cell dest r u ct ion ca n begin
yea r s befor e t h e on set of dia bet es. Th e pa t h ogen esis
is con cer n ed wit h fa ct or s a t t h e on set of pa n cr ea t ic
bet a islet cell dest r u ct ion , t h e pr ogr ession of cell de-
st r u ct ion , a n d t h e poin t of developin g sign s of dia be-
t es m ellit u s. Alt h ou gh we m a y n ot kn ow wh a t exa ct ly
t r igger ed t h e or igin a l bet a islet cell dest r u ct ion , we
ca n st ill u n der st a n d t h e pa t h ogen esis by st u dyin g
cellu la r a n d t issu e ch a n ges in t h ose wh o develop t h e
disea se. Ma n y t im es t h is occu r s in in dividu a ls wit h
specific r is k a c t o r s , or vu ln er a bilit ies. An exa m ple
of a set of r isk fa ct or s for cor on a r y a r t er y disea se is
pr ovided in Box 1.1. Modifia ble r isk fa ct or s a r e t h ose
t h a t ca n be ch a n ged by t h e in dividu a l. For exa m ple,
diet a r y in t a ke, weigh t , a n d sm okin g a r e r isk fa ct or s
t h a t a r e m odifia ble, wh er ea s gen et ic com posit ion or
gen der is n ot . Th e goa l in st u dyin g pa t h ogen esis is
oft en t o pr even t disea se fr om occu r r in g. Wh en pr e-
ven t ion is n ot possible, u n der st a n din g t h e pa t h ogen -
esis ca n fa cilit a t e ea r ly dia gn osis a n d in t er ven t ion
t o a void com plica t ion s a n d im pr ove qu a lit y of life.
ETIOLOGY
At t h e ver y begin n in g of t h e disea se pr ocess, t h er e is
a n e t io lo g y , or pr ecise ca u se of disea se. Som et im es
t h e et iology is iden t ifia ble, a s wit h t h e in h a la t ion of
a vir a l m icr oor ga n ism t h a t ca u ses in flu en za in t h e
a ir wa ys. In t h is ca se, t h e et iology is t r a ced t o a spe-
cific p a t h o g e n , or disea se-ca u sin g m icr oor ga n ism .
Som et im es t h e et iology is u n kn own or m u lt i a c t o -
r ia l (h a vin g m or e t h a n on e gen et ic a n d/or en vir on -
m en t a l ca u sin g even t s), su ch a s wit h ca r diova scu la r
disea se or ca n cer. Wh en t h er e is n o kn own et iology,
t h e disea se is t er m ed id io p a t h ic .
Box 1.1 E x a m p le s o R is k Fa c t o r s
Th e pr esen ce of on e or m or e of t h ese select r isk fa ct or s
in cr ea ses a per son ’s ch a n ces for developin g cor on a r y a r-
t er y disea se:
● E leva t ed blood ch olest er ol level
● E leva t ed blood pr essu r e
● Ciga r et t e sm okin g
● Fa m ily h ist or y/gen et ic pr edisposit ion
● Obesit y
● Seden t a r y lifest yle
N o s o c o m ia l disea se is t h e r esu lt of exposu r e t o
in fect ion in t h e h ea lt h ca r e en vir on m en t . For exa m -
ple, a n osocom ia l illn ess is on e wh er e a ch ild get s
va r icella (ch icken pox) wh ile bein g a pa t ien t in t h e
h ospit a l. Th e ch ild did n ot h a ve va r icella wh en a d-
m it t ed, bu t wa s exposed du r in g h ospit a liza t ion a n d
con t r a ct ed t h e disea se. H ea lt h ca r e pr ofession a ls
h a ve a n im por t a n t obliga t ion t o pr even t t h e spr ea d
of disea se in t h e h ea lt h ca r e set t in g t h r ou gh a ppr o-
pr ia t e h a n d h ygien e a n d in fect ion con t r ol m ea su r es.
I a t r o g e n ic disea ses a r e t h ose t h a t a r e t h e in a dver-
t en t r esu lt of m edica l t r ea t m en t . For exa m ple, a pa -
t ien t wh o develops a u r in a r y t r a ct in fect ion fr om t h e
pla cem en t of a u r in a r y ca t h et er h a s a n ia t r ogen ic
disea se.
Stop and Consider
Would you consider iatrogenic and nosocomial
diseases to be medical errors?
CLINICAL MANIFESTATIONS
C lin ic a l m a n i e s t a t io n s a r e t h e pr esen t in g sign s
a n d sym pt om s of t h e disea se. Mor e specifica lly, t h e
s ig n s of a disea se a r e t h e obser va ble or m ea su r a ble
expr ession s. For exa m ple, in h er pes sim plex (a cold
sor e), a sign wou ld be r edn ess wit h r a ised, clea r,
flu id-filled vesicles on t h e in dividu a l’s lip. Th e sign s
a r e con sider ed a s t h e o b je c t iv e m a n ifest a t ion s
t h a t ca n be seen or m ea su r ed by t h e h ea lt h ca r e
pr ofession a l. Th e s y m p t o m s a r e in dica t or s t h a t
a r e r epor t ed by t h e ill in dividu a l a n d a r e con sider ed
t h e s u b je c t iv e m a n ifest a t ion s beca u se t h ey a r e n ot
dir ect ly obser va ble by t h e pr a ct it ion er. Sym pt om s
of h er pes m a y in clu de t in glin g or discom for t a t t h e
sit e of t h e vesicles or a feelin g of let h a r gy, or t ir ed-
n ess. Th ese sym pt om s a r e difficu lt for t h e h ea lt h
ca r e pr ovider t o obser ve or t o m ea su r e. In a ddit ion ,
pa t ien t s m a y descr ibe p r e c ip it a t in g a c t o r s , or
t r igger s, t h a t pr om ot e t h e on set of clin ica l m a n ifes-
t a t ion s. E xa m ples of pr ecipit a t in g fa ct or s t h a t pr o-
m ot e sh or t n ess of br ea t h a n d cou gh in g in a st h m a
a r e list ed in Box 1.2.
Box 1.2 E xa m p le s o P r e cip it a t in g Fa ct or s
In dividu a ls wit h a st h m a oft en r epor t on e or m or e of t h ese
pr ecipit a t in g fa ct or s t h a t lea d t o a n a st h m a exa cer ba t ion :
● E xer cise
● Cold wea t h er
● Upper r espir a t or y in fect ion
● St r ess
● Du st /du st m it es
● Pollen
● An im a l da n der
● Mold
 C h a p t e r 1: In t r odu ct ion t o Pa t h oph ysiology 3

Sign s a n d sym pt om s ca n be loca l or syst em ic. L o -
c a l r efer s t o t h ose m a n ifest a t ion s t h a t a r e fou n d di-
r ect ly a t t h e sit e of disea se a n d a r e con fin ed t o t h a t
specific a r ea . E xa m ples of loca l m a n ifest a t ion s a r e
con fin ed r edn ess, swellin g, br u isin g, or pa in . S y s -
t e m ic m a n ifest a t ion s pr esen t t h r ou gh ou t t h e body
a n d a r e n ot con fin ed t o on e a r ea , su ch a s wit h fever,
let h a r gy, gen er a lized body a ch in g, or h igh blood pr es-
su r e. Tim in g is a lso im por t a n t in cla ssifyin g disea se
pr ocesses a n d clin ica l m a n ifest a t ion s. Ac u t e m a n -
ifest a t ion s or a cu t e disea ses a r e t h ose t h a t begin
a br u pt ly a n d la st a few da ys t o a few m on t h s. Th e
com m on cold is a good exa m ple of a n a cu t e disea se.
Th er e is a n ot icea ble on set , t h e disea se la st s 10 t o
14 da ys, a n d t h er e is com plet e r esolu t ion . C h r o n ic
disea ses, h owever, gen er a lly la st lon ger t h a n 6
m on t h s a n d a r e in s id io u s , or gr a du a l, in on set . Wit h
ch r on ic disea se, t h e per son ca n h a ve r e m is s io n s , or
sym pt om -fr ee per iods, a n d e x a c e r b a t io n s , t h e fla r-
in g of sym pt om s. S u b a c u t e is a t er m u sed t o de-
scr ibe disea ses t h a t fa ll som ewh er e bet ween a cu t e
a n d ch r on ic in du r a t ion a n d sever it y.
Som e con dit ion s a r e com plet ely a s y m p t o m a t ic ;
t h a t is, t h e per son does n ot h a ve a n y n ot icea ble
sym pt om s even t h ou gh dia gn ost ic t est s m a y in dica t e
t h a t t h e disea se is pr esen t . Scr een in g t est s, su ch a s
Pa p sm ea r s, br ea st m a m m ogr a m s, or blood pr essu r e
m ea su r em en t s, a r e in va lu a ble for det ect in g disea ses
t h a t a r e a sym pt om a t ic.
DIAGNOSIS AND TREATMENT
H ea lt h ca r e pr ovider s clu st er t h e pr esen t in g clin i-
ca l m a n ifest a t ion s, la bor a t or y, a n d dia gn ost ic t est s
t o det er m in e a d ia g n o s is , or la bel, for t h e disea se.
A r ecogn iza ble clu st er of clin ica l m a n ifest a t ion s ca n
be dia gn osed a s a syn dr om e, su ch a s wit h Down syn -
dr om e. You a r e pr oba bly ver y fa m ilia r wit h m a n y
differ en t m edica l dia gn oses a n d syn dr om es. Th e
clin ica l m odels in t h is t ext u se t h e m edica l dia gn o-
sis t o iden t ify t h e va r iou s con dit ion s. Som e h ea lt h
pr ofession a ls u se differ en t dia gn ost ic ca t egor ies t o
descr ibe disea se pr ocesses. For exa m ple, n u r sin g
pr ofession a ls u se n u r sin g dia gn oses t o descr ibe t h e
h u m a n r espon se t o illn ess, su ch a s a lt er ed flu id ba l-
a n ce a n d in effect ive a ir wa y clea r a n ce. Depen din g on
t h e h ea lt h pr ofession t h a t you a r e st u dyin g, you m a y
fin d t h er e a r e ot h er t er m s u sed t o dia gn ose you r
pa t ien t s.
Th e p r o g n o s is for a pa t ien t is t h e for eca st or pr e-
dict ion of h ow t h e in dividu a l will pr oceed t h r ou gh
t h e disea se pr ocess. An excellen t pr ogn osis in di-
ca t es t h a t t h e in dividu a l will m ost likely r ecover
com plet ely. A poor pr ogn osis sign ifies in cr ea sin g
r isk for m o r b id it y , a n ega t ive ou t com e wit h dis-
ea se com plica t ion s t h a t im pa ct t h e qu a lit y of life,
a n d possibly m o r t a lit y , or dea t h . P r ogn osis is of-
t en ba sed on h ea lt h st a t ist ics a cr oss popu la t ion s
wh er e t h e r a t es of su r viva l a n d ou t com es of ot h er s
wit h sim ila r disea ses h elp pr edict t h e in dividu a l
pa t ien t ’s ou t com e.
Th e t r ea t m en t of disea se is depen den t u pon t h e
et iology a n d clin ica l m a n ifest a t ion s. Tr ea t m en t is
a im ed a t elim in a t in g or r edu cin g t h e ca u se of dis-
ea se a n d t h er eby elim in a t in g or r edu cin g t h e clin ica l
m a n ifest a t ion s. For exa m ple, in a bu r n in ju r y, t r ea t -
m en t is a im ed a t r em ovin g t h e sou r ce of t h e bu r n
a n d t h en coolin g t h e skin a n d pr ot ect in g t h e body
fr om in fect ion . E a ch ch a pt er will h igh ligh t ph a r m a -
cologic, or dr u g, in t er ven t ion s u sed t o t r ea t disea se.
F igu r e 1.1 det a ils t h e r ela t ion sh ips bet ween m a n y
of t h ese t er m s.

Patho phys io lo g y

Etiology S igns
Clinica l
Pa thoge ne s is
ma nife s ta tions
Me cha nis ms S ymptoms
of dis e a s e

Dia gnos is

Tre a tme nt/

Ca re me a s ure s

Figure 1.1. Concept map. Pathophysiology terms.

4 C h a p t e r 1: In t r odu ct ion t o Pa t h oph ysiology
Applying Pathophysiology
INDIVIDUAL HEALTH
You will u n dou bt edly spen d m u ch of you r h ea lt h pr o-
fession a l ca r eer ca r in g for in dividu a ls. In wh a t ever
set t in g you ch oose t o pr a ct ice, t h e focu s m u st be on
t h e wh ole per son , defin ed by t h a t in dividu a l’s per-
cept ion of h ea lt h a n d illn ess. H e a lt h , defin ed a s t h e
per ceived wh olen ess of body, m in d, a n d spir it , a n d
illn e s s , a st a t e t h a t r esu lt s in su ffer in g or dist r ess,
a r e on a dyn a m ic con t in u u m . Th e con t in u u m im plies
t h a t in dividu a ls per ceive t h em selves t o be a n ywh er e
a lon g t h e lin e of “ext r em ely h ea lt h y” t o “ext r em ely
ill.” Th er e a r e va r yin g degr ees of h ea lt h a n d va r yin g
degr ees of illn ess. Dyn a m ic m ea n s t h e pa t ien t ’s per-
cept ion s of h ow h ea lt h y or ill h e or sh e is ca n ch a n ge
fr om da y t o da y, m on t h t o m on t h , or yea r t o yea r.
E ffect ive com m u n ica t ion wit h you r pa t ien t s ca n de-
t er m in e wh er e t h ey per ceive t h em selves a lon g t h is
con t in u u m a n d h ow you ca n best h elp t h em m a in -
t a in or r et u r n t o opt im a l h ea lt h .
Stop and Consider
Are you healthy or ill? How do you know? What
characteristics describe someone who is healthy?
When does a person often become labeled as ill?
Think about a situation where a person was diag-
nosed with an illness but considered themselves
to be healthy. How about when a person does
not have a diagnosis but considers themselves to
be ill?
In ot h er scien ce cou r sewor k , you h a ve pr oba bly
t a lked a bou t t h e con cept of h om eost a sis. H o m e o -
s t a s i s is a dyn a m ic ba la n ce in t h e body m a r k ed by
t h e a ppr opr ia t e a n d effect ive r espon se t o st im u li,
t h er eby keepin g t h e body in a st ea dy st a t e. Alt h ou gh
it oft en h a ppen s a t a cellu la r level, h om eost a sis is
a n im por t a n t body goa l a n d is oft en r eflect ed in
t h e pa t ien t ’s per cept ion of t h e h ea lt h –illn ess con -
t in u u m . Th r ou gh ou t t h is t ext you will develop a
gr ea t er a ppr ecia t ion for t h e r espon se syst em s in
t h e body t h a t a llow h om eost a sis t o con t in u e. You
will a lso lea r n wh a t h a ppen s wh en st r essor s pr es-
en t excessive a n d in su r m ou n t a ble ch a llen ges t o
h om eost a sis.
An im por t a n t t h in g t o keep in m in d wh en ca r in g
for in dividu a l pa t ien t s is t h a t people sh ou ld n ot be
defin ed by t h eir pa t h oph ysiology. Ca llin g a pa t ien t
by h is or h er disea se st a t e ign or es t h e h olist ic ph ys-
ica l, spir it u a l, em ot ion a l, a n d psych ologica l com po-
n en t s t h a t com pr ise a ll of u s. H ea lt h pr ofession a ls
sh ou ld a void ca llin g pa t ien t s “dia bet ics” or “t h e sku ll
fr a ct u r e in r oom 202” a n d r epla ce t h ese la bels wit h
“t h e wom a n wit h dia bet es” or “t h e pa t ien t in r oom
202 wit h a sku ll fr a ct u r e.” Aft er a ll, if t h e over a ll
Figure 1.2. People first. A practitioner listens to a pa-
tient. The focus needs to be on the patient; the health
problem is always secondary. (From Carter PJ, Lewsen S.
Lippincott’s Textbook for Nursing Assistants: A Humanistic
Approach to Caregiving. Philadelphia, PA: Lippincott
Williams & Wilkins; 2005.)
goa l is h igh -qu a lit y h olist ic h ea lt h ca r e, t h is ca n be-
gin on ly in a gen u in ely ca r in g en vir on m en t (F ig. 1.2).
POPULATION HEALTH
You r r ole a s a h ea lt h pr ofession a l a lso r equ ir es t h a t
you con sider t h e h ea lt h of popu la t ion s. Focu sin g on
e p id e m io lo g y , t h e st u dy of disea se in popu la t ion s,
h a s m a n y a dva n t a ges su ch a s:
1. Recogn it ion of wh er e a disea se is m ost widespr ea d
2. Recogn it ion of wh o is m ost a ffect ed by t h e disea se
3. Discover in g wh y t h e disea se is pr esen t in g in t h a t
popu la t ion
4. Discover in g h ow t o r edu ce t h e spr ea d of disea se,
r edu ce m or bidit y, or er a dica t e t h e disea se in t h a t
popu la t ion
H ea lt h st a t ist ics a r e a n im por t a n t a spect of
popu la t ion -focu sed h ea lt h ca r e. I n c id e n c e is t h e
r a t e of occu r r en ce of a disea se a t a n y given t im e. In -
ciden ce r epr esen t s t h e pr oba bilit y t h a t a disea se will
occu r in a cer t a in popu la t ion . For exa m ple, t h e in ci-
den ce of Down syn dr om e, or t h e ch a n ce t h a t on e will
be bor n wit h Down syn dr om e, is a ppr oxim a t ely 1 in
691.1 P r e v a le n c e is t h e n u m ber or per cen t a ge of a
popu la t ion t h a t is a ffect ed by a pa r t icu la r disea se a t
a given t im e. As a n exa m ple of pr eva len ce, 400,000
people in t h e Un it ed St a t es a r e cu r r en t ly livin g wit h
Down syn dr om e. 1
Wh en t h e in ciden ce a n d pr eva len ce of a disea se
a r e pr edict a ble a n d st a ble, t h is is t er m ed e n d e m ic .
A dr a m a t ic in cr ea se in disea se in ciden ce in a pop-
u la t ion is ca lled a n e p id e m ic a n d r epr esen t s a
r a t e con sider a bly a bove t h e en dem ic r a t e. Wh en
a n epidem ic spr ea ds a cr oss con t in en t s, t h e disea se
 C h a p t e r 1: In t r odu ct ion t o Pa t h oph ysiology 5

is con sider ed t o be a p a n d e m ic . Th e Wor ld H ea lt h Evidence-Based Practice

Or ga n iza t ion (WH O) is a n im por t a n t epidem iol-
ogy r esou r ce a n d pr ovides a yea r ly gu ide t o h ea lt h E viden ce-ba sed pr a ct ice is a wa y of ca r in g for ot h er s
st a t ist ics for it s m em ber st a t es. Th e a n n u a l Wor ld t h a t is cogn iza n t of t h e m ost cu r r en t r esea r ch a n d
H ea lt h Repor t s det a il m or t a lit y a n d life expect a n cy kn owledge in t h e h ea lt h pr ofession s. Th e Resea r ch
r a t es a cr oss t h e globe a n d pr ovide in ciden ce a n d Not es fea t u r e of t h is t ext h igh ligh t s som e of t h e cu r-
pr eva len ce st a t ist ics for n u m er ou s disea ses. For ex- r en t r esea r ch on t h e va r iou s pa t h oph ysiologic con -
a m ple, in t h e 2014 u pda t e, t h e 10 lea din g ca u ses of cept s a n d disea ses. H owever, eviden ce-ba sed pr a ct ice
dea t h wor ldwide wer e list ed a s isch em ic h ea r t dis- goes beyon d on e piece of r esea r ch a n d en com pa sses
ea se, st r oke, ch r on ic obst r u ct ive pu lm on a r y disea se, t h e t ot a lit y of wh a t is kn own t h r ou gh r esea r ch a n d
lower r espir a t or y in fect ion s, lu n g ca n cer, H IV/AIDS, t h e kn owledge a n d pr a ct ices of clin ica l exper t s.
dia r r h ea l disea ses, dia bet es, in ju r y, a n d h yper t en - H ea lt h pr ofession a ls m u st be pr epa r ed t o wor k
sive h ea r t disea se.2 Decr ea sin g t h e in ciden ce a n d effect ively wit h people of a ll r a ces a n d cu lt u r es. Th is
pr eva len ce of t h ese con dit ion s ca n h a ve t h e gr ea t - r equ ir es a con scien t iou s r espect for h u m a n h ea lt h
est im pa ct on t h e h ea lt h of popu la t ion s a r ou n d t h e va r ia t ion s. E viden ce-ba sed pr a ct ice a n d epidem iol-
wor ld. ogy pr ovide a fr a m ewor k for det er m in in g t h ose m ost
likely t o be a fflict ed wit h cer t a in disea ses ba sed on
Stop and Consider gen der, a ge, r a ce, loca le, socioecon om ic fa ct or s, or
Look for current reports related to health. What et h n icit y. Recogn izin g differ en ces ba sed on t h ese
epidemic conditions are currently present in your
geographic area?
What is being re-
ported around the
world? Do you no- R E S E AR C H N O T E S
tice any pandemic
condition reports? The Human Genome Project, completed in 2003, determined DNA sequence patterns among
diverse populations in order to identify “DNA regions” associated with complex diseases,
such as cancer, diabetes, heart disease, and certain types of mental illness. Current research
DISEASE PREVENTION
has taken this idea a step further in discovering that DNA sequencing is not the only deter-
P r even t ion of disea se is a minant of health and disease. 3 Epigenetics is the study of genetic control by factors other
cr it ica l r ole for t h e h ea lt h than a person’s DNA sequence. Epigenetics controls the “on” and “off” switch of genes and
pr ofession s. Disea se pr e- which proteins are transcribed. This growing body of research will provide additional clues
ven t ion is m ost oft en dis- to the human and environmental factors that increase the risk and development of disease.
cu ssed in t h r ee levels:
pr im a r y, secon da r y, a n d
t er t ia r y.
fa ct or s will h elp pr om ot e effect ive pr even t ion m ea -
1. P r im a r y p r e ve n t ion : Prima r y prevention pr ohib- su r es. H ea lt h pr ofession a ls m u st a lwa ys ba la n ce
its a disease condition from occur ring. An exam ple wh a t is kn own fr om a n epidem iologic st a n dpoin t
is wea ring a bike helmet t o prevent a head injury. wit h wh a t is u n iqu e t o ea ch h u m a n ba sed on h is or
2. S e c o n d a r y p r e v e n t io n : Secon da r y pr even t ion h er life sit u a t ion , a void st er eot ypin g, a n d be r ea dy t o
is t h e ea r ly det ect ion of disea se t h r ou gh scr een in g iden t ify a n d a ssist a ll pa t ien t s in pr om ot in g h ea lt h .
a n d ea r ly t r ea t m en t . An exa m ple is per for m in g Pa t h oph ysiology is a r gu a bly on e of t h e m ost im -
br ea st or t est icu la r self-exa m in a t ion ever y m on t h por t a n t su bject s t h a t you will ever st u dy a s a st u -
for ea r ly ca n cer det ect ion . den t in t h e h ea lt h pr ofession s. You r pa t ien t s will r ely
3. Te r t ia r y p r e v e n t io n : Ter t ia r y pr even t ion is r e- on you t o r ecogn ize h ea lt h pr oblem s a n d a ct a ccor d-
h a bilit a t ion of a pa t ien t a ft er det ect ion of disea se. in gly. Decision s a bou t ph a r m a cologic t r ea t m en t s,
Ter t ia r y pr even t ion focu ses on pr even t in g com pli- su r gica l in t er ven t ion s, h ea lt h pr om ot ion m ea su r es,
ca t ion s or pr ogr ession of t h e con dit ion ; for exa m - n u t r it ion a l in t er ven t ion s, a n d even gen et ic cou n sel-
ple, a pplyin g ph ysica l t h er a py a n d occu pa t ion a l in g a r e depen den t u pon you r lea r n in g in t h is cou r se.
t h er a py in t er ven t ion s t o im pr ove gr oss a n d fin e
m ot or fu n ct ion a ft er a st r oke.

Stop and Consider Functional Concepts of Altered Health

What activities do you participate in that would
count as primary prevention? How about sec- Th e in for m a t ion con t a in ed in t h is book r epr esen t s a
ondary prevention? Identify other examples of jou r n ey in t o t h e wor ld of con cept u a l lea r n in g. A c o n -
tertiary prevention. c e p t is a gen er a l idea t h a t ca n be a pplied t o sim ila r
6 C h a p t e r 1: In t r odu ct ion t o Pa t h oph ysiology
Box 1.3 F u n c t io n a l C o n c e p t s o Alt e r e d
H e a lt h
Ba sic a lt er a t ion s in cells a n d t issu es
In fla m m a t ion
Im m u n it y
In fect ion
Gen et ic a n d developm en t a l disor der s
Alt er ed cellu la r pr olifer a t ion a n d differ en t ia t ion
Alt er ed flu id/elect r olyt e a n d a cid/ba se ba la n ce
Alt er ed n eu r on a l t r a n sm ission
Alt er ed m ood a n d beh a vior
Alt er ed sen sor y fu n ct ion a n d pa in per cept ion
Alt er ed h or m on a l/m et a bolic pr ocesses
Alt er ed r epr odu ct ive fu n ct ion
Alt er ed ven t ila t ion a n d diffu sion
Alt er ed t issu e per fu sion
Alt er ed n u t r it ion
Alt er ed elim in a t ion
Degen er a t ive ch a n ges in a gin g
sit u a t ion s. In ot h er wor ds, a con cept u a l a ppr oa ch in
pa t h oph ysiology clu st er s cu r r en t kn owledge a bou t
h u m a n h ea lt h a n d disea se a n d or ga n izes t h a t kn owl-
edge in t o m ea n in gfu l a n d u sefu l idea s. Th ese idea s
a r e r efer r ed t o a s fu n ct ion a l a lt er a t ion s in h ea lt h .
Box 1.3 list s t h e select fu n ct ion a l a lt er a t ion s u pon
wh ich t h is t ext is ba sed.
A con cept u a l a ppr oa ch dict a t es lea r n in g gen er a l
disea se pr ocesses a n d t h en a pplyin g t h ese pr ocesses
t o specific con dit ion s. It is im possible t o det a il ever y
disea se con dit ion . A con cept u a l a ppr oa ch su pplies
you wit h t h e t ools t o be m or e effect ive a t figu r in g ou t
wh a t is kn own a n d h ow t h is a pplies t o t h a t wh ich
is u n kn own . Th e effect ive a pplica t ion of t h a t kn owl-
edge t o t h e h ea lt h ca r e set t in g is t h e dest in a t ion .
S U MMAR Y
● Pa t h oph ysiology is t h e st u dy of t h e m ech a n ism s
of disea se a n d focu ses on t h e ph ysiology of a lt er ed
h ea lt h st a t es; specifica lly, t h e fu n ct ion a l ch a n ges
t h a t a ccom pa n y a pa r t icu la r in ju r y, syn dr om e, or
disea se.
● Th ose st u dyin g pa t h oph ysiology a r e con cer n ed
wit h t h e et iology, pa t h ogen esis, a n d clin ica l m a n -
ifest a t ion s of disea se; t h is in volves t h e a n a lysis of
cellu la r, t issu e, or ga n , a n d body syst em ch a n ges
t h a t occu r in a disea se st a t e.
● H ea lt h pr ofession a ls clu st er sign s a n d sym pt om s
(a lso ca lled clin ica l m a n ifest a t ion s) t o for m u la t e
a dia gn osis, or la bel, for t h e disea se con dit ion .
Appr opr ia t e in t er ven t ion s ca n t h en be a pplied,
wit h r espect t o h u m a n diver sit y, t o pr ovide h igh -
qu a lit y h ea lt h ca r e a n d t o pr om ot e opt im a l h ea lt h
ou t com es.
● E pidem iology is a scien ce t h a t dea ls wit h t h e
st u dy of disea se t r en ds in popu la t ion s; epidem i-
ologist s iden t ify t h e in ciden ce a n d pr eva len ce of
disea ses wor ldwide, in clu din g t h e pr esen ce of en -
dem ic, epidem ic, a n d pa n dem ic con dit ion s. A m a -
jor goa l of u n der st a n din g disea se is t o effect ively
a pply t h e t h r ee levels of pr even t ion wh en ever
possible.
C AS E S T U D Y 1.1
Kim is a 10-yea r-old gir l wh o pr esen t s t o t h e u r gen t
ca r e clin ic wit h a 14-da y h ist or y of n a sa l st u ffin ess,
copiou s a m ou n t s of gr een n a sa l dr a in a ge, fever, gen -
er a lized h ea da ch e (“m y wh ole h ea d h u r t s”), fa cia l
pa in a bove a n d below t h e eyes, a n d fa t igu e. Kim
r epor t s t h a t h er you n ger sist er r ecen t ly h a d a “ba d
cold”; n o on e else in t h e fa m ily is cu r r en t ly ill. Kim ’s
m edica l h ist or y is sign ifica n t for sea son a l a ller gies,
u su a lly fla r in g u p t h is t im e of t h e yea r. Kim h a s been
u sin g h er a n t ih ist a m in e m edica t ion t o block t h e sea -
son a l a ller gies, bu t t h is t r ea t m en t h a s n ot been ef-
fect ive. Kim ’s m ot h er r epor t s t h a t Kim is “con st a n t ly
st r essed ou t a n d pu t s wa y t oo m u ch pr essu r e on h er-
self.” Kim sa ys t h a t h er biggest con cer n is m issin g
t h e sch ool m u sica l; sh e is t h e lea d a n d t h e open in g
pr odu ct ion is in 2 da ys. Upon ph ysica l exa m in a t ion ,
Kim h a s a n or a l t em per a t u r e of 100.4°F. Th e pr a ct i-
t ion er t a ps gen t ly a bove a n d below Kim ’s eyes; h er
sin u ses a r e t en der wh en t ou ch ed. Th e lym ph gla n ds
a lon g h er n eck a r e en la r ged a n d t en der. Kim u n der-
goes sin u s r a diogr a ph s (X-r a ys). Th e r a diogr a ph s
in dica t e flu id a ccu m u la t ion in t h e fr on t a l a n d m a xil-
la r y sin u ses. Kim is dia gn osed wit h sin u sit is, r ela t ed
t o a per sist en t u pper r espir a t or y in fect ion . Kim is
pr escr ibed a 3-week cou r se of a n t ibiot ics t o t r ea t t h e
sin u s in fect ion .
1. Wou ld you defin e Kim a s h ea lt h y or ill? E xpla in .
2. Wh a t r isk fa ct or s does Kim h a ve t h a t cou ld h a ve
led t o t h e developm en t of t h e sin u sit is?
3. Wh a t is t h e et iology of Kim ’s sin u sit is? Wou ld
t h e sin u sit is be con sider ed eit h er n osocom ia l or
ia t r ogen ic? E xpla in .
4. Iden t ify t h e sym pt om s t h a t Kim r epor t s.
5. Iden t ify t h e sign s lea din g t o t h e dia gn osis of
sin u sit is.
6. H ow wou ld you ca t egor ize t h is illn ess: a cu t e or
ch r on ic? E xpla in .
7. Wh ich of t h e m a n ifest a t ion s a r e loca l a n d wh ich
a r e syst em ic?
8. Wh a t is t h e pr ogn osis for Kim ?
9. Wh a t a spect s r ela t ed t o h u m a n diver sit y a n d
disea se wou ld be im por t a n t t o con sider wit h r e-
ga r d t o Kim ?
 C h a p t e r 1: In t r odu ct ion t o Pa t h oph ysiology 7

10. Wh a t a ddit ion a l dim en sion s of t h e h ea lt h h is- c. Ter t ia r y pr even t ion

t or y wou ld you n eed t o explor e t o pr ovide h olis- d. Non e of t h ese
t ic h ea lt h ca r e?
3. At you r h ea lt h scr een in g, you descr ibe t h e fol-
lowin g: a ch in ess, let h a r gy, a n d va gu e a bdom in a l
C AS E S T U D Y 1.2 discom for t . Th ese a r e ca t egor ized a s:
a . Loca l m a n ifest a t ion s
J a y is a pu blic h ea lt h wor ker a n d is ch a r ged wit h b. Syst em ic m a n ifest a t ion s
developin g a n im m u n iza t ion t r a ckin g pr ogr a m for c. Sign s
r esiden t s of h is cou n t y a ged bir t h t o 21 yea r s. J a y d. Sym pt om s
is pr im a r ily in t er est ed in m ea sles va ccin a t ion r a t es.
Th er e h a s been a m a jor in cr ea se in m ea sles dia g- 4. Th e st u dy of fu n ct ion a l a lt er a t ion s in h u m a n
n oses in you n g ch ildr en a n d a dolescen t s fr om t h e h ea lt h beca u se of a n in ju r y, disea se, or syn dr om e
yea r s 2010 t o 2015 (10 ca ses in t h e cou n t y in 2010 descr ibes wh ich of t h e followin g?
u p t o 20 ca ses in 2015). Th e cu r r en t ch a n ce of cou n t y a . Pa t h ology
r esiden t s bein g dia gn osed wit h m ea sles befor e t h e b. Pa t h oph ysiology
a ge of 21 is 1 in 200,000. J a y is in t er est ed in u n - c. P h ysiology
der st a n din g wh y t h is in cr ea se occu r r ed over su ch a d. Mor ph ology
sh or t per iod of t im e.
1. E xpla in h ow you ca n look a t t h is scen a r io fr om 5. A pa t ien t wa n t s t o kn ow wh a t h a s ca u sed h is
bot h a n in dividu a l per spect ive a n d a popu la t ion illn ess. Th is in for m a t ion is t er m ed t h e:
per spect ive. a . E t iology
2. Wh a t level of pr even t ion is in dica t ed in t h e ca se b. Pa t h ogen esis
st u dy? H ow cou ld t h e ot h er levels of pr even t ion c. E pidem iology
be r epr esen t ed wit h in t h is scen a r io? d. Nosocom ia
3. Wh a t is t h e in ciden ce a n d pr eva len ce of m ea sles
in t h is ca se st u dy? Wou ld t h is sit u a t ion be con - 6. J oe h a s m a n y r isk fa ct or s for t h e developm en t of
sider ed en dem ic, epidem ic, or pa n dem ic? E xpla in . lu n g ca n cer. Wh ich of t h ese is NOT m odifia ble?
4. Wh a t a r e som e of t h e possible expla n a t ion s for a . Sm okin g
t h e m a jor in cr ea se in m ea sles ca ses? b. Fa m ily h ist or y of lu n g ca n cer
5. Wh a t cou ld be som e of t h e wa ys t o t r a ck im m u n i- c. Wor kin g in a n a sbest os-filled a r ea
za t ion s wit h in t h e cou n t y syst em ? d. Poor n u t r it ion a l in t a ke
6. E xpla in h ow eviden ce-ba sed pr a ct ice wou ld h a ve
a r ole in J a y’s wor k.
7. Wh ich of t h e followin g t er m s in dica t es t h e dy-
n a m ic st ea dy st a t e t h a t t h e body st r ives t o
a ch ieve ever y da y?
P R AC T I C E E XAM Q U E S T I O N S a . H om eost a sis
b. Mor t a lit y
1. You a r e expect in g you r fir st ch ild a n d a r e t old
c. Mor bidit y
t h a t t h e ch ild h a s a 1 in 800 ch a n ce of bein g bor n
d. H ea lt h
wit h a con gen it a l a n om a ly. Th is st a t ist ic r efer s
t o t h e:
a . In ciden ce 8. Wh ich of t h e followin g con t r ibu t es t o eviden ce-
b. P r eva len ce ba sed pr a ct ice a n d h igh -qu a lit y pa t ien t ca r e?
c. E pidem ic a . P r im a r y r esea r ch
d. Dia gn osis b. Clin ica l exper t ise
c. Met a -a n a lysis st u dies
2. You decide t h a t it h a s been t oo lon g sin ce you r d. All of t h ese con t r ibu t e
la st ph ysica l exa m in a t ion , so you sch edu le a n
a ppoin t m en t for a r ou t in e h ea lt h scr een in g. You 9. Ca n cer is on t h e r ise a cr oss t h e globe. Wh ich
h a ve a blood ch olest er ol level ch ecked a n d it is t er m descr ibes t h is ph en om en on ?
wit h in t h e expect ed r a n ge. Th is a ct ivit y r ep- a . E pidem ic
r esen t s wh ich level of pr even t ion ? b. E n dem ic
a . P r im a r y pr even t ion c. Pa n dem ic
b. Secon da r y pr even t ion d. Mor bidit y
8 C h a p t e r 1: In t r odu ct ion t o Pa t h oph ysiology

10. You r gr a n dm ot h er is dia gn osed wit h con gest ive H ea lth y People 2020 ou t lin es t h e h ea lt h goa ls for t h e
h ea r t fa ilu r e a n d is t old t h a t sh e h a s 6 m on t h s t o Un it ed St a t es:
live. Th is pr edict ion is r efer r ed t o a s h er : h t t p://www.h ea lt h ypeople.gov
a . P r ogn osis
Un it ed St a t es Na t ion a l H ea lt h St a t ist ics:
b. Dia gn osis
h t t p://www.cdc.gov/n ch s/
c. Mor bidit y r a t e
d. P r eva len ce Ca n a dia n H ea lt h St a t ist ics:
h t t p://www.st a t ca n .gc.ca

D I S C U S S I O N AN D
AP P L I C AT I O N
1. Wh a t did I kn ow a bou t pa t h oph ysiology pr ior t o
t oda y?
2. H ow does t h e st u dy of pa t h oph ysiology bu ild on
wh a t I h a ve lea r n ed in pr eviou s cou r ses?
3. H ow ca n I u se wh a t I h a ve lea r n ed?
R e er en ces
1. Na t ion a l Down Syn dr om e Societ y. Abou t Down syn -
dr om e: Down syn dr om e fa ct sh eet . h t t p://www.n dss.or g.
Accessed Sept em ber 10, 2015.
2. Wor ld H ea lt h Or ga n iza t ion . Wor ld h ea lt h st a t ist ics 2015.
h t t p://www.wh o.in t /m edia cen t r e/fa ct sh eet s/fs310/en /. Ac-
cessed Sept em ber 10, 2015.
3. Sim m on s D. E pigen et ic in flu en ce a n d disea se. Na t E d u c.
2008;1(1):6.

R E SOUR CE S

Wor ld H ea lt h Or ga n iza t ion H ea lt h St a t ist ics:

h t t p://www.wh o.in t

F in d a d d ition a l r esou r ces for th is ch a pter a t h ttp:th ePoin t.lww.com

 Ch a pt er

2
Alt er ed Cells a n d
Tissu es

L E AR N I N G O U T C O ME S
1. Defin e a n d u se t h e key t er m s list ed in t h is ch a pt er.
2. Discu ss t h e ch a n ges in cells a n d t issu es a ft er in ju r y.
3. Com pa r e a n d con t r a st cellu la r st r u ct u r a l a da pt a t ion s t o in ju r y.
4. Iden t ify m a la da pt ive cellu la r r espon ses t o in ju r y.
5. Recogn ize h ea lt h con dit ion s t h a t ca n pr ecipit a t e m a la da pt ive cellu la r
r espon ses.
6. Descr ibe dia gn ost ic t est s a n d pot en t ia l t r ea t m en t st r a t egies r eleva n t t o
cellu la r a n d t issu e a lt er a t ion s.
7. Apply cellu la r a da pt a t ion s a n d m a la da pt a t ion s t o select clin ica l m odels.

INTR ODUCTION
Wh en con sider in g h ea lt h a n d disea se, wh a t com es t o m in d fir st ? Th e a n swer
m a y be or ga n s a n d or ga n syst em s. O r g a n s , fu lly differ en t ia t ed body pa r t s wit h
specia lized fu n ct ion s, a r e m or e fa m ilia r a n d a r e u sed m or e oft en in discu ssion
a bou t h ea lt h a n d disea se. Alt h ou gh m ost people ca n descr ibe a h ea r t , br a in , or
liver, it is h a r der t o descr ibe t h e t issu es a n d cells t h a t det er m in e or ga n st r u c-
t u r e a n d fu n ct ion . Tis s u e s a r e gr ou ps of sim ila r cell t ypes t h a t com bin e t o for m
a specific fu n ct ion . Like or ga n s, t h e fou r m a jor t issu e t ypes in t h e body (epi-
t h eliu m [skin ], con n ect ive t issu e [in clu din g blood, bon e, a n d ca r t ila ge], m u scle,
a n d n er ve) a r e fa m ilia r. C e lls , t h e ba sic u n it s t h a t m a ke u p t issu es, a r e t h e
sit es wh er e ch a n ges in st r u ct u r e a n d fu n ct ion lea d t o sym pt om s a n d disea ses
in in dividu a ls. Th is ch a pt er discu sses t h e r espon ses of cellu la r st r u ct u r e a n d
fu n ct ion ca u sed by st r ess, in ju r y, or da m a ge. Ma n y of t h e con cept s in t r odu ced
h er e a r e expa n ded in su bsequ en t ch a pt er s. Developin g a n u n der st a n din g of
t h ese r espon ses will h elp t h e st u den t t o t r a n sla t e t h ese a da pt a t ion s t o t h e
sign s a n d sym pt om s of disea se st a t es t h a t r esu lt fr om cellu la r in ju r y.

9
10 C h a p t e r 2: Alt er ed Cells a n d Tissu es

Modu le 1 R e v ie w o C e llu la r S t r u c t u r e a n d F u n c t io n

Th e cell is t h e sm a llest in depen den t u n it of t h e liv- t r a n sm em br a n e pr ot ein t h a t , beca u se of t h e t igh t

in g in dividu a l. Th e st r u ct u r a l com pon en t s of t h e cell bin din g t o lipid t a ils, becom es pa r t of t h e m em br a n e
a n d t h e fu n ct ion of it s com pon en t s con t r ibu t e t o t h e it self. In t egr a l pr ot ein s oft en for m ch a n n els t h a t a l-
in t egr it y of t h e cell a n d t h e in dividu a l. Con sequ en t ly, low for t h e t r a n spor t of ion s (a t om wit h a n elect r ica l
cell da m a ge or in ju r y ca n a ffect t h e fu n ct ion in g of or- ch a r ge) a cr oss t h e pla sm a m em br a n e. Per iph er a l
ga n s, body syst em s, a n d over a ll h ea lt h . pr ot ein s do n ot pa ss t h r ou gh t h e en t ir e m em br a n e,
pr oject in g in t o eit h er t h e in t r a cellu la r or t h e ext r a -
cellu la r en vir on m en t . Beca u se per iph er a l pr ot ein s
Cellular Components do n ot pa ss t h r ou gh t h e en t ir e m em br a n e, t h ey a r e
n ot in volved in t r a n spor t fu n ct ion s. F igu r e 2.1 sh ows
Th e com pon en t pa r t s of t h e cell in a h u m a n (eu ka r y- t h e st r u ct u r e of t h e lipid bila yer a n d pr ot ein s of t h e
ot e) pr ovide st r u ct u r e a n d det er m in e fu n ct ion a l ca - pla sm a m em br a n e.
pa cit y. P h ysiologic fu n ct ion in g a t t h e cellu la r level is
cr it ica l t o pr oper fu n ct ion in g of t issu es a n d or ga n s
CYTOPLASM AND ORGANELLES
a n d t o t h e h ea lt h of t h e in dividu a l.
Th e cyt opla sm con t a in s t h e or ga n elle st r u ct u r es es-
sen t ia l for cellu la r su r viva l. C y t o p la s m , a colloida l
CELLULAR MEMBRANE
su bst a n ce su r r ou n din g t h e cell n u cleu s, is com posed
E a ch cell is su r r ou n ded by a p la s m a m e m b r a n e , of wa t er, pr ot ein s, fa t s, elect r olyt es, glycogen , a n d
wh ich pr ot ect s t h e cell by cr ea t in g a ba r r ier t h a t
sepa r a t es t h e in t r a cellu la r com pon en t s fr om t h e ex-
t r a cellu la r en vir on m en t su r r ou n din g it . Th e pla sm a
m em br a n e r epr esen t s a n or ga n ized st r u ct u r e com - Extra ce llula r fluid
posed of lipids, ca r boh ydr a t es, a n d pr ot ein s a r-
r a n ged in a b ila y e r (t wo la yer s). Th e lipid bila yer s P hos pholipids
a r e m a in ly m a de u p of p h o s p h o lip id s (ph osph a t e Pola r he a d Inte gra l prote in Tra ns me mbra ne
(hydrophilic) prote in
[P O 4 −] bou n d t o lipid). Th e ph osph a t e con n ect ed t o
Cha nne l prote in
t h e lipid st r u ct u r e is kn own a s t h e “h ea d.” Th e lipid
st r u ct u r e is kn own a s t h e “t a il” beca u se of it s sh a pe.
Th e h ea ds a r e pola r or h y d r o p h ilic (h a vin g a ffin -
it y t o wa t er ). Th e lipid t a ils, com posed of fa t t y a cid
ch a in s, a r e n on pola r or h y d r o p h o b ic (la ckin g a n
a ffin it y t o wa t er ). Two of t h ese lipid la yer s a lign so
t h a t t h e n on pola r t a il por t ion s a r e in t er t win ed a n d
t h e pola r h ea ds lin e bot h t h e ou t er a n d in n er su r-
fa ce of t h e cell. G ly c o lip id s (ca r boh ydr a t e bou n d t o
lipid) a lso m a ke u p t h e lipid bila yer, bu t a r e pr esen t
in sm a ller n u m ber s t h a n ph osph olipids. Th e ba r r ier
cr ea t ed by t h e h ydr oph obic lipid bila yer pr even t s Fa tty a cid ta ils
(hydrophobic) Pe riphe ra l prote in
t h e u n in t en t ion a l pa ssa ge of wa t er-ba sed su b-
st a n ces a cr oss t h e h ydr oph ilic cell su r fa ce. Th e cell Pola r he a d
m em br a n e a llows for t r a n sfer of ion s a n d m olecu les (hydrophilic)
in t o a n d ou t of t h e cell for h om eost a sis, con t a in m en t
Cytos ol
of t h e essen t ia l or ga n elles a n d st r u ct u r es in side t h e
cell, a n d com m u n ica t ion of cellu la r sign a ls bet ween
t h e cell a n d t h e ext er n a l en vir on m en t . Figure 2.1. Structure of the plasma membrane. The struc-
P r ot ein s a r e oft en su spen ded in t h e pla sm a m em - ture of the plasma membrane shows the arrangement of
br a n e, a ct in g a s r ecept or s t h a t bin d su bst a n ces, in - polar heads in contact with both the extracellular fluid
clu din g h or m on es. P r ot ein s t h a t pa ss t h r ou gh t h e and cytosol, and the nonpolar tails forming the center of
en t ir e m em br a n e a r e kn own a s t r a n s m e m b r a n e the lipid bilayer. The embedded membrane proteins, in-
p r o t e in s , a llowin g com m u n ica t ion a n d t r a n spor t cluding channel, transmembrane, peripheral and integral
bet ween t h e ext r a cellu la r a n d in t r a cellu la r en vi- proteins, are shown related to their relationship with the
r on m en t s. I n t e g r a l p r o t e in s a r e a specific t ype of plasma membrane.
 R e v ie w o C e llu la r S t r u c t u r e a n d F u n c t io n
pigm en t s. O r g a n e lle s a r e st r u ct u r es wit h in a cell
t h a t per for m a dist in ct fu n ct ion ; t h ese st r u ct u r es in -
clu de t h e followin g:
● E n d o p la s m ic r e t ic u lu m
■ A com plex n et wor k of t u bu les, pr odu cin g pr o-
t ein s a n d fa t s
■ Im por t a n t in t h e r egu la t ion of ion s wit h in t h e
cell
■ Types
■ Rou gh
■ Syn t h esis of pr ot ein s via bou n d r ibosom es
■ P r odu ct ion of lysosom a l en zym es (a cid
h ydr ola ses)
■ Sm oot h
■ Syn t h esis of lipids, lipopr ot ein s, a n d st e-
r oid h or m on es
■ Regu la t ion of in t r a cellu la r ca lciu m
● G o lg i a p p a r a t u s
■ Mem br a n ou s st r u ct u r e
■ P r epa r es su bst a n ces pr odu ced by t h e en dopla s-
m ic r et icu lu m for secr et ion ou t of t h e cell
● Ly s o s o m e
■ Sm a ll sa cs su r r ou n ded by m em br a n e
■ Digest s cellu la r debr is wit h h ydr olyt ic en zym es
■ Im por t a n t in t h e m et a bolism of pa r t icu la r
su bst a n ces
● P e r o x is o m e s
■ Mem br a n e-en closed sa cs sm a ller than
lysozym es
■ Con t a in en zym es ca lled oxida ses t h a t n eu t r a l-
ize o x y g e n r e e r a d ic a ls (a t om s ca r r yin g a n
u n pa ir ed elect r on a n d n o ch a r ge)
■ P r om ot e su r viva l of t h e cell by n eu t r a lizin g
h a r m fu l su bst a n ces pot en t ia lly da m a gin g t o
t h e cell
● P r ot ea som es
■ La r ge or ga n elles t h a t r ecogn ize a bn or m a lly
folded or for m ed pr ot ein s
■ In volved in p r o t e o ly s is (br ea kdown of pr ot ein )
● Mit o c h o n d r ia
■ Sit e of a er obic (oxygen depen den t ) cellu la r
r espir a t ion
■ P r in cipa l pr odu cer of cellu la r en er gy sou r ce,
a d e n o s in e t r ip h o s p h a t e (AT P )
■ Con t a in t h e cyt och r om e en zym es of t er m in a l
elect r on t r a n spor t n ecessa r y for t h e pr odu ct ion
of ATP
E n closed by a st r u ct u r e ca lled a n u clea r en velope,
t h e n u c le u s of t h e cell con t a in s d e o x y r ib o n u c le ic
a c id (D N A), h er edit y m a t er ia l ca r r yin g t h e cell’s
gen et ic in st r u ct ion s t h a t is copied in cellu la r r epr o-
du ct ion (Ch a pt er 6). E a ch cell con t a in s 23 pa ir s of
c h r o m o s o m e s , coiled st r u ct u r es of t igh t ly pa cked
c h r o m a t in (DNA, h ist on e a n d n on h ist on e pr ot ein s),
for m in g a n in dividu a l’s gen et ic code. Th e g e n e s ,
in dividu a l u n it s of in h er it a n ce, a r e pieces of DNA
11
a r r a n ged a lon g t h e ch r om osom e. Gen es det er m in e
t h e code for pr odu ct ion of specific pr ot ein s t h a t de-
t er m in e ch a r a ct er ist ics or fu n ct ion s. Th e m em br a n e
su r r ou n din g t h e n u cleu s con t a in s “por es,” pr ovidin g
a ccess for pr ot ein pr odu ct s t o m ove fr om t h e n u cleu s
t o t h e cyt opla sm of t h e cells.
CYTOSKELETON
Th e c y t o s k e le t o n com pr ises t u bu le a n d fila m en t
st r u ct u r es t h a t con t r ibu t e t o cell sh a pe, m ovem en t ,
a n d in t r a cellu la r t r a n spor t . Th e m a in cyt oskelet on
com pon en t s in clu de:
● Micr ot u bu les
■ Th in pr ot ein st r u ct u r es com posed of t u bu lin
● Micr ofila m en t s
■ Th in
■ Com pr ise t h e pr ot ein a ct in
■ In t er m edia t e
■ Com pr ise fila m en t s wit h dia m et er sized be-
t ween t h in a n d t h ick fila m en t s
■ Th ick
■ Com pr ise t h e pr ot ein m yosin
Cellular Function
F u n ct ion s com m on t o m a n y cell t ypes in clu de:
● Tr a n spor t a t ion
● In gest ion
● Secr et ion
● Respir a t ion
● Com m u n ica t ion
● Repr odu ct ion
Specia lized cellu la r fu n ct ion is det er m in ed by cell
t ype. E xa m ples of specia lized fu n ct ion s of cells a r e
m ovem en t in m u scle cells a n d con du ct ion in n er ve
cells.
CELLULAR MECHANISMS OF TRANSPORTATION
Th e sem iper m ea ble ch a r a ct er of t h e cell m em br a n e
a llows for t h e t r a n spor t of som e su bst a n ces bu t a ct s
a s a ba r r ier t o ot h er s. For cells t o obt a in t h e n u t r i-
en t s a n d ot h er su bst a n ces n eeded for su r viva l, t h ey
m u st develop fu n ct ion a l m ech a n ism s for t h e pa s-
sa ge of su bst a n ces t h r ou gh t h e cell m em br a n e. Th e
m ovem en t of su bst a n ces is oft en cla ssified a ccor d-
in g t o t h e a m ou n t of en er gy r equ ir ed in t h e a ct of
t r a n spor t .
Passive Transport
Su bst a n ces m a y en t er t h e cell pa ssively, m ea n in g
t h a t n o en er gy is r equ ir ed by t h is pr ocess. D i -
u s io n , or m ovem en t of pa r t icles fr om a n a r ea of
12 C h a p t e r 2: Alt er ed Cells a n d Tissu es

h igh er con cen t r a t ion t o lower con cen t r a t ion (c o n - A. Diffus io n

c e n t r a t io n g r a d ie n t ), is a n exa m ple of pa ssive
t r a n spor t . E lect r ica l ch a r ge in pa r t icles ca n a lso pr o-
m ot e m ovem en t a cr oss t h e cell m em br a n e. Pa r t icles
becom e u n ifor m ly dist r ibu t ed, a ch ievin g a st a t e of
equ ilibr iu m . Sm a ll pa r t icles a n d lipid-solu ble ga ses,
in clu din g ca r bon dioxide a n d oxygen , a r e com m on
exa m ples of su bst a n ces in volved in t h is t ype of
t r a n spor t . Th e a bilit y a n d r a t e of pa r t icles t o diffu se
t h r ou gh t h e m em br a n e a r e a ffect ed by t h e pa r t icle
size a n d by t h e size of t h e m e m b r a n e p o r e , t h e
m em br a n e pa ssa ge bet ween t h e ext r a cellu la r a n d
in t r a cellu la r en vir on m en t .
Mem br a n es m a y be im per m ea ble t o pa r t icles, bu t B. Os mo s is
m ost a llow m ovem en t of wa t er (Ch a pt er 8). O s m o -
s is is t h e pr ocess by wh ich wa t er pa ssively m oves
a cr oss t h e sem iper m ea ble cell m em br a n e. A con cen -
t r a t ion gr a dien t pr om ot es m ovem en t of wa t er fr om
a r ea s of h igh con cen t r a t ion t o low con cen t r a t ion .
Wa te r
Th e pr essu r e gen er a t ed by t h is pr ocess is kn own a s
o s m o t ic p r e s s u r e .
Th e m ovem en t of som e su bst a n ces a cr oss t h e cell
m em br a n e r equ ir es a c ilit a t e d d i u s io n , a ided by
t h e u se of t r a n spor t pr ot ein s. Alt h ou gh fa cilit a t ed
diffu sion is n ot en er gy-depen den t , su bst a n ces a r e
u n a ble t o in depen den t ly cr oss t h e m em br a n e be- C. Fac ilitate d Diffus io n
ca u se of t h eir la r ge size or h ydr oph ilic ch a r a ct er ist ics
t h a t r equ ir e t r a n spor t pr ot ein s t o pr om ot e pa ssa ge. A B
Glu cose is a n exa m ple of a la r ge su bst a n ce n eedin g
t r a n spor t pr ot ein s t o a llow m ovem en t a cr oss t h e cell
m em br a n e. Fa cilit a t ed diffu sion is a lso im por t a n t in
t h e m ovem en t of ion s t h r ou gh ch a n n els of in t egr a l
pr ot ein s, bypa ssin g t h e lipid-solu ble por t ion of t h e
cell m em br a n e. Ion ch a n n els a llow pa ssa ge of spe-
cific su bst a n ces a n d a r e oft en cla ssified a ccor din g t o
t h e t ype of t r igger s t h a t pr om pt open in g a n d closin g.
Ca t egor ies of ion ch a n n els in clu de:
● Lea k ch a n n els: open wit h ou t n eed for st im u la t ion
D. Ac tive Trans po rt
● Ga t ed ch a n n els: open a n d close in r espon se t o
st im u li
■ Volt a ge-ga t ed; st im u la t ed by ch a n ge in m e m -
b r a n e p o t e n t ia l (elect r ica l ch a r ge in side a
cell m em br a n e in r ela t ion t o t h e su r r ou n din g
ATP
ext r a cellu la r flu id)
■ Liga n d-ga t ed; st im u la t ed by r ecept or –liga n d
bin din g (su bst a n ce bin din g t o t h e r ecept or ) ADP
■ Mech a n ica lly ga t ed; st im u la t ed by vibr a t ion ,
st r et ch in g, a n d pr essu r e

Active Transport
Figure 2.2. Mechanisms of cellular membrane transport.
Ac t iv e t r a n s p o r t r equ ir es en er gy wh en t r a nspor t ing
A: Particles move across the semipermeable membrane to
pa r t icles a cr oss t h e cell m em br a n e. Diffusion m oves
achieve equal distribution during diffusion. B: Water flow is
pa r t icles pa ssively a long t h e con cen t r a t ion gr a dien t ,
regulated by osmotically active particles in osmosis.
wh er ea s a ct ive t r a nspor t m oves pa r t icles a ga inst
C: Transport proteins are required for particles to move across
t he con cen t r a t ion or t h e elect r ochem ica l gr a dien t . A
the membrane in facilitated diffusion. D: ATP drives move-
com m on exa m ple of t h e a ct ive t r a n spor t m echa n ism
ment of particles across the membrane in active transport.
is t h e m ovem en t of sodiu m ou t of t h e cell a cr oss t he
 R e v ie w o C e llu la r S t r u c t u r e a n d F u n c t io n
m em br a ne wit h t h e a ssist a nce of t he sodiu m -pot a s-
sium (Na +/K +)-ATPa se pu m p. E ner gy is r equ ir ed for
t r a n spor t beca use t he con cent r a t ion of sodiu m ou t -
side t h e cell is fa r gr ea t er t h a n inside t h e cell. Th is
pum p a lso moves ext r a cellu la r pot a ssium a cr oss
a la r ge con cen t r a t ion gr a dien t t o t h e int r a cellula r
spa ce. This process r equir es t he dir ect u se of en er gy
in t h e for m of ATP, a lso kn own a s p r im a r y a c t iv e
t r a n s p o r t . When m ovem en t of a secon d subst a n ce
depends on en er gy der ived fr om t he a ct ive t r a n s-
por t of t h e pr im a r y subst a n ce, t h e pr ocess is kn own
a s s e c o n d a r y a c t iv e t r a n s p or t . Syst em s in which
su bst a n ces a r e t r a n spor t ed in t he sa m e dir ect ion a r e
kn own a s c ot r a n s p o r t or s y m p o r t . Movem ent of
su bst a n ces in opposit e dir ect ion s is con sider ed c o u n -
t e r t r a n s p or t or a n t ip o r t m ovem en t . Figur e 2.2 de-
scr ibes m echa n ism s of cellu la r m em br a n e t r a n spor t .
INGESTION
Th e cellu la r pla sm a m em br a n e ser ves a n im por t a n t
fu n ct ion a s a ba r r ier t o t h e ext er n a l en vir on m en t ;
h owever, specific pr ocesses a llow t h e cell t o in g e s t
su bst a n ces n ecessa r y for it s own u se in t o t h e cyt o-
pla sm . E n d o c y t o s is is t h e pr ocess u sed t o t r a n spor t
la r ge su bst a n ces in t o cells. Two ca t egor ies of en docy-
t osis a r e pin ocyt osis a n d ph a gocyt osis. P in o c y t o s is
is t h e ATP -r equ ir in g pr ocess of in gest in g con t en t s of
sm a ll liqu id-con t a in in g vesicles. P h a g o c y t o s is is
t h e pr ocess of in gest in g la r ge pa r t icles su ch a s cells,
ba ct er ia , a n d da m a ged cellu la r com pon en t s, r esu lt -
in g in t h e r elea se of o x y g e n r e e r a d ic a ls . P h a gocy-
t osis is cr it ica l in t h e defen se of t h e body fr om for eign
in va der s (Ch a pt er 4). An y a lt er a t ion in t h e a bilit y of
Ce ll me mbra ne
Ba cte rium
A a ppa ra tus
Endo c yto s is
P ha gos ome
Cytopla s m
Figure 2.3. Vesicular transport. A: Objects enter the cell by the process of endocytosis. B: Vesicles bind to the plasma
membrane and release their contents through a process called exocytosis. (From Premkumar K. The Massage Connection:
Anatomy and Physiology. Baltimore, MD: Lippincott Williams & Wilkins; 2004.)
13
t h e cell t o in gest su bst a n ces r equ ir ed for su r viva l or
in t h e dem a n d on cells t o in gest su bst a n ces ca n r e-
su lt in t h e cellu la r fou n da t ion of disea se.
SECRETION
Th e Golgi a ppa r a t u s wor ks wit h t h e en dopla sm ic r e-
t icu lu m t o pa cka ge pr odu ct s in t o vesicles, t h en dir ect s
t h eir deliver y wit h in t h e cell a n d ou t side t h e cell, a lso
kn own a s s e c r e t io n (ext r a cellu la r r elea se of pr od-
u ct s). Th e vesicles m ove fr om t h e Golgi in t o t h e cyt o-
pla sm a n d t h en ou t of t h e cell via t h e cell m em br a n e,
a pr ocess kn own a s e x o c y t o s is . Th e Golgi a ppa r a -
t u s con t a in s en zym es t h a t a t t a ch su ga r s t o pr ot ein s,
for m in g la r ge glycopr ot ein s. Lysosom es a r e for m ed
by t h e Golgi a ppa r a t u s a n d a r e r espon sible for di-
gest ive fu n ct ion s wit h in t h e cell. Su bst a n ces su ch
a s pr ot ein s, ca r boh ydr a t es, da m a ged cellu la r st r u c-
t u r es, a n d pa t h ogen s a r e br oken down for r em ova l
or r ecyclin g by h ydr olyt ic en zym es, ca lled a cid h y-
dr ola ses, con t a in ed wit h in t h e lysosom es. Figu r e 2.3
illu st r a t es t h e con cept s of en docyt osis a n d exocyt osis.
RESPIRATION
Th e cell’s su r viva l depen ds on t h e a va ila bilit y of ATP
pr odu ced by cellu la r r espir a t ion a s a sou r ce of en er gy
for a ll cellu la r fu n ct ion s. Cellu la r r e s p ir a t io n is a
ser ies of m et a bolic pr ocesses t h a t t r a n sfor m s fu el
m olecu les in t o en er gy (in t h e for m of ATP ) a n d wa st e
pr odu ct s. An a e r o b ic r e s p ir a t io n is t h e pr ocess
of ATP pr odu ct ion t h a t occu r s wit h ou t oxygen . Th e
ch em ica l r ea ct ion s of oxida t ion a n d r edu ct ion be-
t ween oxygen a n d n u t r ien t pr odu ct s su ch a s glu cose
Golgi
Lys os ome s
P ha gos ome fus e s with lys os ome
Exo c yto s is
S e conda ry
lys os ome
B
14 C h a p t e r 2: Alt er ed Cells a n d Tissu es
is ca lled a e r o b ic r e s p ir a t io n . G ly c o ly s is , t h e pr o-
cess of br ea kin g down glu cose in t h e cyt osol of t h e
cell, occu r s in t h e a bsen ce of oxygen a n d is com plet ed
ou t side of t h e m it och on dr ia . An a er obic glycolysis r e-
a ct ion pr odu ces a sm a ll a m ou n t of ATP (t wo m ole-
cu les for ea ch m olecu le of glu cose m et a bolized) a n d
ch em ica l pr odu ct s, in clu din g pyr u va t e. Th e c it r ic
a c id c y c le br ea ks down su ga r s, fa t s, a n d pr ot ein s t o
pr odu ce pr odu ct s u sed for en er gy pr odu ct ion in t h e
m it och on dr ia . Toget h er wit h oxygen , glycolyt ic a n d
cit r ic a cid cycle bypr odu ct s en t er in t o t h e m et a bolic
pa t h wa ys in t h e m it och on dr ia a n d r esu lt in en er gy
pr odu ct ion t h r ou gh oxida t ive ph osph or yla t ion , a
pr ocess kn own a s a er obic r espir a t ion . Th ese a er obic
pa t h wa ys pr odu ce a t ot a l of 30 t o 38 m olecu les of ATP
for ea ch m olecu le of glu cose m et a bolized. Th e wa st e
pr odu ct s pr odu ced in a er obic r espir a t ion in clu de ca r-
bon dioxide, wa t er, a n d h ea t , a ll r ea dily excr et ed.
COMMUNICATION
Th e pr ot ein s r equ ir ed for cell fu n ct ion a r e a pr odu ct
of t h e cell it self, pr odu ced by gen es in r espon se t o cel-
lu la r n eeds. Th ese pr odu ct s in clu de pr ot ein s u sed for
cell st r u ct u r e a n d cell fu n ct ion , a n d en zym es u sed t o
st im u la t e ch em ica l r ea ct ion s. Im pa ir ed pr ot eolyt ic
en zym e a ct ivit y, oft en a r esu lt of a gen et ic m u t a t ion ,
h a s been lin ked t o t h e developm en t of disea se, in -
clu din g dia bet es, ca t a r a ct s, m u lt iple scler osis, a n d
Du ch en n e m u scu la r dyst r oph y.1 F e e d b a c k m e c h a -
n is m s r egu la t e gen e a ct iva t ion t o t igh t ly con t r ol t h e
pr odu ct ion of pr ot ein s a n d t o pr even t cell da m a ge
ca u sed by over pr odu ct ion or u n der pr odu ct ion .
Optima l function of t issues requir es cell-to-cell
com munica tion. The messa ge, or signa l, t ra nsmit-
t ed from one cell to a nother cell influences cellula r
behavior a nd plays a role in det er mining function.
The ta rget cell is able t o com munica te through a spe-
cia l pr ot ein known a s a r e c e p t or . Recept or s ca n be
present on the cell membr ane (membra ne bound) or
wit hin the cell (intra cellula r). Signa ling molecu les, or
liga n d s , bind t o r eceptors in a specific way, sim ila r t o
a key t urning a lock. When a ligand binds t o a recep-
t or, t he ta r get cell begins t he process of com munica -
t ion known a s sig n a l t r a n s d u ct ion . The tightness,
or st rength of binding, is a lso r efer red to a s b in d in g
a in it y. The binding of a n extracellula r liga nd t o a
Modu le 2 C e llu la r Ad a p t a t io n a n d R e s p o n s e t o S t r e s s
Cells a r e con sist en t ly ch a llen ged wit h st r essor s t h a t
ca n lea d t o a lt er ed fu n ct ion . Cellu la r st r u ct u r es
m u st a da pt t h eir fu n ct ion wh en fa ced wit h da m -
a ge a n d in ju r y for t h e cell t o su r vive. Pot en t ia lly
m em br a ne-bound recept or begins a ca sca de of signa l-
in g event s t hat alters cell behavior. For a ligand t o
bind t o an intr a cellula r recept or, it must be able to dif-
fuse a cr oss the pla sm a membra ne a nd ent er t he cell.
A liga n d bin din g t o r ecept or s t h a t r esu lt s in sign a l
t r a n sdu ct ion wit h a loca l effect is kn own a s p a r a -
c r in e s ig n a lin g . Th e liga n ds in volved in pa r a cr in e
sign a lin g (lo c a l m e d ia t o r s ) exer t a r a pid loca l r e-
spon se. A wider r a n ge of im pa ct occu r s wh en sign a l
t r a n sdu ct ion a ffect s cell beh a vior wit h in t h e en t ir e
or ga n ism (e n d o c r in e s ig n a lin g ). Th e liga n ds in -
volved in en docr in e sign a lin g a r e ca lled h o r m o n e s .
H or m on es ca n in flu en ce cell beh a vior on a la r ger
sca le. Beca u se of t h e depen den ce on t h e r equ ir ed
pr ocesses a n d blood flow n eeded t o ca r r y t h e h or-
m on es t h r ou gh t h e body wh er e t h ey ca n bin d wit h
r ecept or s, t h is pa t h wa y is oft en slower a n d la st s lon -
ger t h a n pa r a cr in e sign a lin g. H or m on e in flu en ces in
t h e body a r e discu ssed in det a il in Ch a pt er 13.
REPRODUCTION
Repr odu ct ion of cells is a n ot h er fu n ct ion oper a t in g
u n der gen et ic con t r ol. Gen es con t r ol t h e gr owt h of
cells, t im in g of t h e division of cells, a n d differ en t ia -
t ion of cells. Th e r a t e of cell gr owt h is specific t o ea ch
cell t ype a n d is r egu la t ed t o m eet t h e con st a n t ly
ch a n gin g n eeds of t h e in dividu a l. Cell size is det er-
m in ed pr im a r ily by t h e a m ou n t of fu n ct ion a l DNA in
t h e cell. Wit h ou t DNA r epr odu ct ion , cells ca n gr ow
on ly t o a pa r t icu la r size befor e t h ey st op gr owin g.
Cell division occurs a t differ ent t im es depending on
t he cell t ype and on t he signals sent t o t he cell for di-
vision. P r oli e r a t ion is the increa se in cell number.
Di e r e n t ia t ion , or changes in physica l a nd func-
t ional properties of cells, direct s the cell t o develop
in to specific cell t ypes. As a ll cells cont a in identica l
genet ic ma teria l, this pr ocess explains why one cell
contr ibutes t o t he developm ent of one t issue while a n-
other ca n develop into a different t issue. This process
occur s by t he repression of cer ta in genes in a cell and
t he expr ession of ot hers in the sa m e cell. Alt er a tions
in t he pr olifer a tion a nd differentia tion of cells a re de-
scribed in deta il in Cha pt er 7. To see a video demon-
st ra ting t he cell cycle, visit htt p://thePoint .lww.com ,
using the scra t ch-off code on t he inside
fr ont cover.
da m a gin g con dit ion s fa ced by cells in clu de ch a n ges
in oxygen a t ion , t em per a t u r e, m olecu la r t oxin s, a n d
elect r olyt es. Th e t wo r espon ses of t h e cell t o t h ese
st r essor s a r e a d a p t a t io n or d e a t h . Mech a n ism s
 C e llu la r Ad a p t a t io n a n d R e s p o n s e t o S t r e s s
Norma l ce lls
Ba s e me nt me mbra ne
Chang e in c e ll
s ize o r numbe r
Hype rpla s ia
Hype rtrophy
Atrophy
Figure 2.4. Adaptive cell changes. Normal cells adapt to stress by altering size, number, or type/ structure. (Courtesy Ana-
tomical Chart Company.)
t h a t pr om ot e cellu la r a da pt a t ion r esu lt fr om sig-
n a ls t h a t ca u se ch a n ges in gen e fu n ct ion . Th e wa ys
in wh ich t h ese cells r espon d for m t h e cellu la r ba -
sis of disea se (Fig. 2.4). Cellu la r r espon ses in clu de
ch a n ges in size, n u m ber, a n d st r u ct u r e.
Stop and Consider
What would happen if cells did not have the
ability to adapt to stressors? What are the impli-
cations in health and disease?
Atrophy
At r o p h y is t h e decr ea se in t h e size of a cell a n d ca n
occu r for sever a l r ea son s. A decr ea se in t h e fu n c-
t ion a l dem a n d on a cell pr om pt s a decr ea se in cell
size. Th is t ype of decr ea se oft en occu r s wh en a lim b
is im m obilized in a ca st a n d a ct ive m u scle m ove-
m en t is im pa ir ed. Th e la ck of m u scle m ovem en t r e-
du ces dem a n d on m u scle cells, lea din g t o decr ea sed
cell size. Mu scle cell a t r oph y ca u ses r edu ct ion in
15
Nucle us
Chang e in c e ll
type and s truc ture
Me ta pla s ia
Dys pla s ia
t h e m u scle it self du e t o t h e la r ge n u m ber s of cells
a ffect ed. A decr ea sed oxygen su pply t o t h e cell, or
is c h e m ia , ca n a lso con t r ibu t e t o a decr ea se in cell
size. Isch em ia ca n occu r secon da r y t o a blocka ge in
t h e a r t er ia l blood su pply, wh ich r edu ces t h e deliv-
er y of oxygen . Alt h ou gh cells m a y h a ve t h e a bilit y t o
a da pt t o a ch r on ica lly r edu ced oxygen su pply via a t -
r oph y, a com plet e la ck of oxygen a t ion is m or e likely
t o r esu lt in ir r ever sible cell dea t h .
Ma n y cells depen d on specia lized sign a ls t o m a in -
t a in fu n ct ion . At r oph y is oft en t h e r espon se of t h ese
cells wh en sign a ls a r e r em oved. Th e sou r ces of t h ese
sign a ls a r e oft en h or m on es, wh ich t a r get specific
cell t ypes. A sim ila r even t occu r s wh en n eu r a l sig-
n a ls a r e r em oved fr om cells depen den t on t h em for
n or m a l fu n ct ion in g. Ch r on ic n u t r it ion a l depr iva t ion
a n d t h e pr ocess of a gin g a lso r esu lt in decr ea sed cell
size, wh ich t r a n sla t es in t o decr ea sed or ga n size. At -
r oph y a lso ca n occu r a s a r espon se t o t h e r em ova l of
h or m on a l sign a ls t h a t st im u la t e gr owt h , r esu lt in g in
in v o lu t io n , or decr ea sed size, of t issu es a n d or ga n s.
At r oph y m a y r esu lt in t h e m a n ifest a t ion of clin ica l
16 C h a p t e r 2: Alt er ed Cells a n d Tissu es
sign s a n d sym pt om s st em m in g fr om t h e decr ea se in
size a n d fu n ct ion of t h e or ga n in volved.
S p in a l m u s c u la r a t r o p h y is a n exa m ple of a n
a t r oph ic con dit ion . Spin a l m u scle a t r oph y r esu lt s
fr om disu se ca u sed by im pa ir ed n eu r a l in n er va -
t ion t o m u scle t issu e. Sign a ls t o m u scle cells a r e
decr ea sed beca u se of loss of m ot or n eu r on cells of
t h e br a in or spin a l cor d. Th e decr ea sed st im u la t ion
of m u scle cells beca u se of loss of n eu r a l sign a lin g
ca u ses a t r oph y, r esu lt in g in wea kn ess of volu n t a r y
m u scles. Th e loss of fu n ct ion a ssocia t ed wit h t h e
a t r oph ic cell a n d t issu e ch a n ges h igh ligh t s m a n y
con dit ion s ch a r a ct er ized by a t r oph y.
Hypertrophy
H y p e r t r o p h y is a n in cr ea se in cell size. Cells of-
t en r espon d wit h h yper t r oph y fr om a n in cr ea se in
t r o p h ic , or gr owt h , sign a ls. Sign a ls st im u la t in g a n
in cr ea se in sex h or m on es a r e r espon sible for t h e
developm en t of h yper t r oph ied r epr odu ct ive cells
du r in g pu ber t y a s well a s in t h e br ea st cells du r in g
pr egn a n cy t h a t a llow m ot h er s t o m a ke a n d deliver
br ea st m ilk. In cr ea sed dem a n d ca n a lso con t r ibu t e
t o h yper t r oph y. St r en gt h -bu ildin g exer cise oft en r e-
su lt s in a n in cr ea se in m u scle cell size a n d m u scle
m a ss.
H yper t r oph y of t h e a den oid t issu e is a com m on
a n d fa m ilia r con dit ion . Ad e n o id h y p e r t r o p h y is
ca u sed by en la r gem en t of lym ph oepit h elia l a den oid
t issu e in t h e ba ck of t h e n a sa l a r ea a n d ca n r esu lt
in obst r u ct ion of t h e n a sa l pa ssa ge. Th e in cr ea sed
fu n ct ion a l dem a n d r equ ir ed of t h e lym ph t issu e in
filt er in g ou t in fect iou s a gen t s in t h e u pper r espir a -
t or y t r a ct ca n lea d t o a n in cr ea se in lym ph oid a n d
epit h elia l cell size. Th e m ost com m on effect s of a de-
n oid h yper t r oph y a r e sn or in g, ba d br ea t h , a n d st u ffy
n ose. Mor e ser iou s con sequ en ces of a den oid h yper-
t r oph y ca n a ffect r espir a t or y fu n ct ion , wit h m a n ifes-
t a t ion s of sleep a pn ea , pu lm on a r y h yper t en sion , or
h ea r t fa ilu r e.
Hyperplasia
H y p e r p la s ia is a n in cr ea se in t h e n u m ber of cells.
Like h yper t r oph y, h yper pla sia ca n a lso be ca u sed
by h or m on e sign a lin g a n d a n in cr ea se in wor kloa d.
Beca u se som e of t h e sa m e con dit ion s ca u se bot h
h yper pla sia a n d h yper t r oph y, t h ey a r e oft en seen
t oget h er. For exa m ple, t h e u t er u s r espon ds t o t h e in -
cr ea se in h or m on e levels of est r ogen du r in g m on t h ly
m en st r u a l cycles by in cr ea sin g t h e n u m ber of cells
in t h e u t er u s. Also, wh en people a r e exposed t o h igh
a lt it u des, a da pt a t ion t o t h is st r essor in clu des a n in -
cr ea sed pr odu ct ion of r ed blood cells t o m a xim ize t h e
A B C
Figure 2.5. Breast tissue adaptation to trophic signals.
A: Puberty (hyperplasia). B: Pregnancy (hypertrophy).
C: Menopause (atrophy). (Courtesy Anatomical Chart
Company.)
h em oglobin oxygen -ca r r yin g a bilit y. Th is “in cr ea sed
wor kloa d” t o oxygen a t e, st r esses t h e cell t o pr odu ce
t h is a da pt a t ion .
Ada pt a t ion of cells a n d t issu es t o h or m on a l sig-
n a ls is a dyn a m ic pr ocess. On e cell or t issu e t ype
ca n u n der go a ser ies of a da pt a t ion s in r espon se t o
va r ied sign a ls over a lifet im e. Th is pr ocess is clea r ly
illu st r a t ed in t h e a da pt a t ion s of t h e du ct a l t issu e of
t h e br ea st over a wom a n ’s lifet im e, a s in Figu r e 2.5.
Th e h or m on a l ch a n ges of pu ber t y in du ce h yper pla s-
t ic ch a n ges in t h e br ea st , n ot ed by in cr ea sed size of
t h e fu n ct ion a l lobu la r a n d du ct a l t issu e. H or m on es
secr et ed du r in g pr egn a n cy pr om ot e h yper t r oph ic
ch a n ges in br ea st t issu e t o su ppor t pr odu ct ion a n d
deliver y of br ea st m ilk. Wh en h or m on e pr odu ct ion
dr ops du r in g m en opa u se, a t r oph ic ch a n ges a sso-
cia t ed wit h decr ea sed br ea st size a r e n ot ed. Th ese
ch a n ges r esu lt fr om t h e in t en sit y of t r oph ic sign a ls
in du ced by t h e h or m on es, wh ich pr om ot e t h e gen et ic
ba sis of t h ese a da pt a t ion s.
Metaplasia
Me t a p la s ia r efer s t o t h e ch a n gin g of on e cell t ype
t o a n ot h er. Th is is on e wa y t h a t cells ca n a da pt t o
a per sist en t st r essor. In t h e ca se of a per son wit h
ga st r oesoph a gea l r eflu x disea se (GE RD), t h e cells of
t h e esoph a gu s a r e exposed t o t h e da m a gin g a cidic
con t en t s of t h e st om a ch . Over t im e, t h ese cells of-
t en ch a n ge fr om a squ a m ou s epit h eliu m cell t ype
t o a gla n du la r cell t ype in r espon se t o t h e st r essor.
A sim ila r sit u a t ion occu r s wh en cells t h a t lin e t h e
br on ch ia l t u bes of t h e lu n gs a r e exposed t o ciga r et t e
sm oke over a per iod of t im e. Th is exposu r e lea ds t o
cell a da pt a t ion t o t h is st r essor by t h e developm en t
of squ a m ou s m et a pla sia , in wh ich t h e colu m n a r
cells t u r n in t o squ a m ou s cells in t h e cell’s a t t em pt
t o su r vive t h e exposu r e t o t oxin s (F ig. 2.6). Wh en t h e
st r essor t h a t ca u sed t h ese cell ch a n ges is r em oved,
cells oft en r et u r n t o t h eir n or m a l st a t e. In t h e pr es-
en ce of a per sist en t st r essor, cells m a y develop r e-
spon ses t h a t lea d t o pa t h ologic ch a n ges.
 C e llu la r I n ju r y a n d D e a t h 17

Figure 2.6. Squamous metaplasia in the transformation

zone. The proliferating cells displace the glandular epithe-
lium. The metaplastic cells mature into glycogen-rich squa-
mous cells. (From Rubin E, Farber JL. Pathology. 4th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2005.)

Dysplasia
B
D y s p la s ia r efer s t o t h e a ct u a l ch a n ge in cell size,
sh a pe, u n ifor m it y, a r r a n gem en t , a n d st r u ct u r e. As
wit h m et a pla sia , dyspla sia is oft en a cell’s r espon se
t o a ch r on ic a n d per sist en t st r essor a n d is likely t o
r esolve wh en t h e st r essor is r em oved. Dyspla sia is
ca u sed by a bn or m a l differ en t ia t ion of dividin g cells
a n d is con sider ed a pr oblem in r egu la t in g cell gr owt h .
Wh en cell r epr odu ct ion occu r s, t h e DNA m ay be r e-
pr odu ced wit h m u t a t io n s , or ch a n ges in t h e gen et ic
m a t er ia l t h a t m a kes u p t h e ch r om osom es. Th ese m u -
t a t ion s a r e oft en r epea t ed a s m or e cells divide a n d C
pr olifer a t e. Alt h ou gh t h ese cells a r e n ot ca n cer ou s,
Figure 2.7. Cellular changes in dysplasia. A: Large squa-
t h ey m a y a ppea r a s a n ea r ly ch a n ge t h a t ca n pr og-
mous cells with small nuclei. B: Nucleus increasing in size
r ess t o ca n cer. Figu r e 2.7 depict s t h e pr ogr ession
and darkening in color. C: Markedly enlarged and darkened
fr om n or m a l cells (Figu r e 2.7A) t o m ild dyspla sia
nucleus with abnormal chromatin. (Courtesy Anatomical
(Figu r e 2.7B) t o sever e dyspla sia (Figu r e 2.7C).
Chart Company.)
B r o n c h o p u lm o n a r y d y s p la s ia (B P D ) is a con -
dit ion in wh ich st r essor s pr om pt cellu la r a lt er a t ion s
t h a t lea d t o ch r on ic, ir r ever sible t issu e ch a n ges. oxygen a t e t issu es t h r ou gh ou t t h e body, a n d excr et e
Som e in fa n t s r equ ir e h igh con cen t r a t ion s of oxygen wa st e pr odu ct s, in clu din g ca r bon dioxide. Th e da m -
a n d m ech a n ica l ven t ila t ion a t bir t h , oft en beca u se a ge is t h e likely r esu lt of t h e com bin a t ion of cellu la r
of r espir a t or y dist r ess a n d t h e in a bilit y t o m a in - st r essor s a n d t h e su scept ibilit y t o da m a ge in t h e de-
t a in a dequ a t e levels of t issu e oxygen a t ion . BP D is velopm en t a lly im m a t u r e lu n g t issu e.
a ssocia t ed wit h pr olon ged su pplem en t a l oxygen
con cen t r a t ion s gr ea t er t h a n t h a t in r oom a ir (21%) Stop and Consider
du r in g t h e ea r ly n ewbor n per iod of life. Th e br on - What are the common characteristics of the dif-
ch ia l a n d a lveola r t issu es of t h e lu n gs becom e t h ick- ferent mechanisms of cellular adaptation? What
en ed, r edu cin g t h e a bilit y t o t a ke a ir in t o t h e lu n gs, are the differences?

Modu le 3 C e llu la r I n ju r y a n d D e a t h

As discu ssed ea r lier in t h e ch a pt er, in t h e pr ocess of su r vive. If t h e st r essor is t oo gr ea t or la st s t oo lon g,

cellu la r a da pt a t ion , exposu r e t o st r essor s ca n ca u se t h e cell m a y lose it s a bilit y t o a da pt , r esu lt in g in
ch a n ges in bot h cell st r u ct u r e a n d fu n ct ion . Ma n y dea t h . Con dit ion s su ch a s isch em ia ca n be over com e
of t h e a da pt a t ion s t h a t cells m a ke a llow t h e cell t o if t h e exposu r e is n ot t oo gr ea t a n d does n ot la st t oo
18 C h a p t e r 2: Alt er ed Cells a n d Tissu es

lon g. Ot h er con dit ion s, su ch a s oxida t ive st r ess, r a -

dia t ion , ch em ica ls, a n d pa t h ogen s (ba ct er ia a n d vi-
r u ses) ca n ca u se cell in ju r y, followed by cell dea t h if
t h e da m a ge is t oo gr ea t .

Mechanisms of Cell Death

Th e ch a n ges in cell a n d or ga n elle st r u ct u r e a n d
fu n ct ion pr even t t h e cell fr om r et u r n in g t o a n or m a l
con dit ion . Cellu la r da m a ge t h a t over wh elm s t h e ca -
pa bilit y for r ecover y r esu lt s in cellu la r dea t h . Th e
t wo m a jor wa ys in wh ich cells die a r e by t h e pr o-
cesses of a popt osis a n d n ecr osis.

APOPTOSIS Figure 2.8. Necrosis. Diabetic foot with necrosis of the

Ap o p t o s is ca n be bot h a ph ysiologic a n d a pa t h ologic digits. (Image provided by Stedman’s.)
cell r espon se t o cellu la r sign a ls. Apopt osis is oft en r e-
fer r ed t o a s “cellu la r su icide.” It is pr ogr a m m ed cell ph a gocyt osis. Th e r esu lt is loca l in fla m m a t ion a n d
dea t h pr om pt ed by a gen et ic sign a l a n d is design ed dea t h of cells. Wh en over gr owt h of in fect iou s a gen t s
t o r epla ce old cells wit h n ew. Cells a r e pr ogr a m m ed is com bin ed wit h decr ea sed blood flow, n ecr osis ca n
for dea t h for m a n y r ea son s, in clu din g da m a ged ge- occu r (Fig. 2.8).
n et ic m a t er ia l or m u t a t ion , old a ge of t h e cell, a n d
a n a t t em pt t o decr ea se t h e a ct u a l n u m ber of cells.
Dea t h occu r s in t h e cell beca u se of en zym e r ea ct ion s
Causes of Cell Injury and Death
in t h e cell t h a t ch a n ge t h e st r u ct u r e, a n d t h er efor e
In ju r y t o cells st em s fr om a va r iet y of sou r ces of
fu n ct ion , of t h e or ga n elles a n d ot h er cell com pon en t s.
st r ess (Fig. 2.9). Infect ion fr om ba ct er ia , vir u s, pr ot o-
Th is pr ocess is com m on du r in g t h e developm en t
zoa , or fu ngi ca n in it ia t e da m a ge t o cells (Ch a pt er 5).
of t h e em br yo wh en cells gr ow a n d develop in t o
P h ysica l injur y fr om m ech a n ica l, t her m a l, or chem i-
well-defin ed or ga n s a n d syst em s. E m br yon ic h a n ds
ca l sou r ces ca n ca use da m a ge t o t he st r uct ur e of a cell
begin a s ou t gr owt h s in t h e sh a pe of bu ds, pr ogr ess-
a nd a ffect cell fu nct ion. Me c h a n ic a l in ju r y ca n be
in g t o webbed, fla t t en ed, pa ddle sh a pes by t h e fift h
ca u sed by im pa ct of a body pa r t ca using dir ect in jur y,
week of developm en t . Ca r t ila ge a n d bon e develop-
su ch a s fa lling off a ska t eboa r d or a bike. T h e r m a l
m en t is followed by bon e ossifica t ion du r in g t h e
in ju r y is ca used by ext r em es of t em per a t ur e, a s oc-
seven t h week, a lon g wit h t h e t r a n sfor m a t ion of t h e
cu r s wit h bu r n s a nd fr ost bit e. Toxins ca n a lso ca use
webbed h a n d in t o digit s t h r ou gh t h e pr ocess of a pop-
h a r m t o cells. Th ese t oxin s ca n be e n d o ge n o u s (fr om
t osis by t h e eigh t h week. Alt er a t ion s in t h is pr ocess
wit hin t h e body syst em ). For exa m ple, wh en a per-
of a popt osis du r in g em br yologic developm en t ca n
son h a s a n a ller gic r ea ct ion, t oxins a r e r elea sed fr om
lea d t o t h e m a n ifest a t ion kn own a s s y n d a c t y ly , t h e
wit hin t h e body, which ca u se cell da m a ge a n d a ssoci-
fu sion or in com plet e sepa r a t ion of digit soft t issu e.
a t ed sym pt om s (Ch a pt er 4). Toxin s ca n a lso be e x o g-
e n ou s (fr om t h e ext er n a l envir on m en t ). A com m on
NECROSIS exogen ou s t oxin is a lcohol, wh ich ca n da m a ge t he
cells of t he liver wit h pr olon ged exposur e. Da m a ge t o
Necr osis, a n ot h er m ech a n ism of cell dea t h , is differ-
cells ca n a lso r esult fr om d e ic it in ju r y, in wh ich t h e
en t fr om a popt osis. Cell dea t h by n ecr osis is a dis-
cell is depr ived of oxygen a t ion, h ydr a t ion, a nd nu t r i-
or der ly pr ocess a ssocia t ed wit h in fla m m a t ion (see
t ion . Th is is com m on ly seen in con dit ion s of isch em ia
Ch a pt er 3). N e c r o s is is dea t h of cells r ela t ed t o cell
(see Ch a pt er 16), sever e m a ln ut r it ion , a n d ea t in g dis-
in ju r y. In ju r y ca u ses da m a ge t o cellu la r st r u ct u r es,
or der s such a s a n or exia n er vosa (Ch a pt er 17).
in clu din g t h e m it och on dr ia , deplet in g ATP. Wit h ou t
It m a y be h elpfu l t o r em em ber t h e com m on ca u ses
ATP t o en er gize cellu la r pr ocesses, or ga n elles a n d
of cell in ju r y a n d dea t h wit h t h e a cr on ym TIP S:
cells swell, disr u pt in g t h e pla sm a cell m em br a n e
ba r r ier. Th e loss of t h e cell m em br a n e ba r r ier a l- ● Toxin s (ch em ica l, pa t h ogen ic)
lows t h e spillin g ou t of t h e cell con t en t s fr om wit h in ● In fect ion s
t h e cell. E n zym es a r e r elea sed t h a t dissolve t h e cell ● P h ysica l in ju r y (m ech a n ica l, ch em ica l, t h er m a l)
com pon en t s, wh ich in t u r n t r igger wh it e blood cells ● S er u m deficit in ju r y (n u t r it ion , h ydr a t ion ,
t o r espon d a n d digest t h e cellu la r debr is t h r ou gh oxygen a t ion )
 C e llu la r I n ju r y a n d D e a t h 19

S tre s s O2

OH Pe roxida s e
OH
Superoxide O2
Dismutase
Incre a s e d Reve rs ible
functiona l ce ll injury ONOO H2 O 2 ONOO
de ma nd H2 O 2
Antioxida nt
Ca ta la s e

Pe rs is te nt s tre s s

Adaptatio n Mild S eve re

Atrophy
Hype rtrophy Me ta pla s ia Irreve rs ible
Hype rpla s ia Dys pla s ia ce ll injury
S tora ge

Re lie f of s tre s s

No rmal c e ll Ne c ro s is
Adaptive Re s po ns e Ce llular Damag e

Figure 2.9. Cellular response to stress. (Modified from

Rubin E, Farber JL. Pathology. 4th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2005.)
Cells ca n be da m a ged in a va r iet y of wa ys t h a t r e-
su lt in in ju r y or dea t h . Oxida t ive st r ess ca n be in -
cr ea sed by m a n y con dit ion s, in clu din g biologic
a gin g, in fect ion , in fla m m a t ion , isch em ia , r a dia t ion ,
a n d u se of ch em ica ls a n d dr u gs. Oxida t ive st r ess
in volves exposu r e of cells t o r e a c t iv e o x y g e n s p e -
c ie s (R O S ), t oxic oxygen m olecu les or r a dica ls t h a t
a r e for m ed by t h e r ea ct ion bet ween oxygen (O 2 ) a n d
wa t er (H 2 O) du r in g m it och on dr ia l r espir a t ion . ROS
species in clu de su per oxide (O 2 −), h ydr ogen per oxide
(H 2 O 2 ), t h e h ydr oxyl r a dica l (OH ), a n d per oxyn it r it e
(ONOO ). Cell da m a ge ca n r esu lt fr om t oo m a n y
ROS or n ot en ou gh a va ila ble en zym es, in clu din g
ca t a la se, t o con ver t t h ese r a dica ls t o less h a r m fu l
su bst a n ces. Cellu la r da m a ge r esu lt in g fr om ROS
is kn own a s r e e r a d ic a l in ju r y . ROS pr odu ces
da m a ge t o cells, oft en by t a r get in g DNA. In ju r y by
ROS exposu r e h a s been im plica t ed in m a n y disea se
con dit ion s, in clu din g h ea r t disea se, dia bet es, ca n cer,
a n d ot h er s. ROS sca ven ger s, su ch a s ca t a la se, per ox-
ida se, su per oxide dism u t a se, a n d a n t ioxida n t s, ca n
wor k wit h det oxifyin g en zym es t o lim it cell da m a ge
(F ig. 2.10). Th e u se of a n t ioxida n t s, su ch a s vit a m in
E , m a y r edu ce oxida t ive st r ess for m a n y disea se
con dit ion s.2,3
Re a ctive Oxyge n S pe cie s
Re a ctive Oxyge n S pe cie s S cave nge rs
Figure 2.10. Cellular response to oxidative stress. Oxi-
dative stress occurs as a result of increased reactive ox-
ygen species (ROS), decreasing antioxidants or inability
to neutralize or repair damage caused by ROS with ROS
scavengers.
Stop and Consider
Hydrogen peroxide (H2O2) is familiar to most
people as a product to be used on cuts and
scrapes. The solution that can be bought at the
local grocery store contains 3% of H2O2, with the
remaining 97% of the solution made up of water.
When the solution is applied to a cut or scrape,
the combination of H2O2 combines with the en-
zyme catalase, which is released from the dam-
aged cells and blood. Catalase causes a chemical
reaction, converting hydrogen peroxide into
water (H2O) and oxygen (O2). The evidence of
this reaction is the foam that is produced when
the hydrogen peroxide is applied to the injury,
releasing the oxygen gas.
H2O2 catalase
H2O + O2
Catalase works the same way in the cells of the
body to scavenge ROS, minimizing oxidative
damage.
http:/ / science.howstuffworks.com/ question115.htm
20 C h a p t e r 2: Alt er ed Cells a n d Tissu es

Da m a ge t o cells ca n r esult in disr u pt ion of m et a - a nd da m a ge t o DNA a s a r esult of r a dia t ion in ju r y a r e

bolic pr ocesses t ha t ca n pr ove fa t a l. Th e im ba la nce of exa m ples of event s t h a t m ay lea d t o a ccu m u la t ion of
elect r olyt es, isch em ia ca u sed by oxygen depr iva t ion , m et a bolit es wit hin t he cell, ca using fu r t h er inju r y.

Modu le 4 C lin ic a l Mo d e ls

Th e followin g clin ica l m odels h a ve been select ed

t o illu st r a t e t h e con cept s of cellu la r a da pt a t ion in
h ea lt h a n d disea se. Wh ile r ea din g t h e descr ipt ion s
of t h ese m odels, t h in k a bou t t h e st r essor s t h a t ca n
ca u se cellu la r a da pt a t ion , in ju r y, a n d dea t h a n d t h e
r espon ses of t h e cells t o t h e st r essor s. Con sider t h e
con cept s of cellu la r a da pt a t ion a s t h ey a pply t o t h e
specific con dit ion s t o a ssist in t h e u n der st a n din g
a n d a pplica t ion of t h ese con cept s.

Cerebral Atrophy
C e r e b r a l a t r o p h y is a com m on fea t u r e of m a n y
disea ses t h a t a ffect t h e br a in r a t h er t h a n a disea se.
Cer ebr a l a t r oph y descr ibes t h e r edu ct ion in size of
t h e cells in t h e cer ebr u m of t h e br a in . Th e pr ogr es-
sive r edu ct ion in t h e size of t h e n eu r on s lea ds t o t h e
r edu ct ion in t h e br a in t issu e it self. Neu r on s a r e t h e
fu n ct ion a l cells in br a in t issu e a n d a r e r espon sible
for con du ct in g n eu r a l im pu lses wit h in t h e br a in a n d
t o ot h er a r ea s of t h e body. Ma n y n eu r ologic disea ses
a r e a ssocia t ed wit h loss of n eu r on a l fu n ct ion du e
t o a t r oph y, sever a l of wh ich a r e in clu ded a s clin ica l
m odels in t h is t ext (Fig. 2.11).

PATHOPHYSIOLOGY
Cer ebr a l a t r oph y m a y be eit h er a ca u se or con se-
qu en ce of a n eu r ologic disor der. Decr ea sed st im -
u la t ion r esu lt in g fr om r edu ct ion in ph ysica l a n d
in t ellect u a l a ct ivit ies m a y lea d t o a t r oph y of br a in
st r u ct u r es.4,5 In dividu a ls wit h low levels of B vit a -
m in s m a y exper ien ce in cr ea sed br a in a t r oph y, a n ex-
a m ple of deficit in ju r y.6 Cer ebr a l a t r oph y ca n r esu lt
fr om m ech a n ica l in ju r y (t r a u m a t ic br a in in ju r y) or
in ju r y du e t o t oxin s (en ceph a lit is), lea din g t o loss of
n eu r ologic cells, t issu e, a n d a ssocia t ed fu n ct ion s.
Dest r u ct ion of n eu r on s a n d t h e loss of n eu r ot r a n s-
m it t er pr odu ct ion in on e pa r t of t h e br a in m a y lea d
t o a t r oph y of n eu r on s in a n ot h er r egion beca u se of
la ck of st im u la t ion . Con dit ion s lea din g t o r edu ced
per fu sion t o t h e br a in in cr ea se t h e r isk of in ju r y du e
t o a deficit in oxygen a n d n u t r ien t deliver y. Neu r o-
t oxic in ju r y r esu lt in g fr om isch em ia , h yper t h er m ia ,
in fla m m a t ion , or t r a u m a m a y exceed t h e a bilit y of
t h e n eu r on t o r ecover, lea din g t o n eu r on a l dea t h .
Figure 2.11. Cerebral atrophy. MRI of the brain shows
enlargement of the ventricles and deepening of the sulci,
evidence of cerebral atrophy.
Su bcor t ica l isch em ic va scu la r disea se r edu ces per fu -
sion t o t h e br a in , wit h a ffect ed in dividu a ls m a n ifest -
in g decr ea sed psych om ot or speed, execu t ive con t r ol,
a n d globa l cogn it ive fu n ct ion .7 Br a in a t r oph y in
m u lt iple scler osis is ch a r a ct er ized by a loss of gr a y
a n d wh it e br a in m a t t er, lea din g t o t h e m a n ifest a -
t ion s in volvin g m ot or defect s a n d cogn it ive im pa ir-
m en t .8 As n eu r on s decr ea se in size, t h eir ph ysica l
r ela t ion sh ip wit h ot h er n eu r on s ch a n ges. Th e close
con n ect ion s bet ween n eu r on s a r e r equ ir ed for effec-
t ive com m u n ica t ion ; a s n eu r on s a t r oph y, com m u n i-
ca t ion is fu r t h er im pa ir ed a s t h e dist a n ce bet ween
n eu r on s in cr ea ses. Beca u se n eu r on s a r e n ot a ble t o
r eplica t e, dea t h lea ds t o per m a n en t loss of cells a n d
fu n ct ion .

CLINICAL MANIFESTATIONS
Th e m a n ifest a t ion s of cer ebr a l a t r oph y ca n be foca l
(loca lized t o a pa r t icu la r r egion ) or globa l (a ffect -
in g t h e en t ir e br a in ). Neu r on s in ea ch a r ea of t h e
br a in pr ovide specific fu n ct ion s (see Ch a pt er 10). As
n eu r on s a t r oph y, t h e fu n ct ion a ssocia t ed wit h t h ose
n eu r on s becom es a lt er ed. Neu r on a l a t r oph y in t h e
fr on t a l a n d t em por a l lobes of t h e br a in lea ds t o cog-
n it ive im pa ir m en t . Alzh eim er ’s disea se, a con dit ion
a ffect in g m em or y a n d com pr eh en sion , is a ssocia t ed
wit h a t r oph y of t h e h ippoca m pu s a n d cer ebr a l cor-
t ex.9 Movem en t disor der s r esu lt fr om n eu r on a l a t r o-
ph y in t h e ba sa l ga n glia , r espon sible for pr odu ct ion
of t h e n eu r ot r a n sm it t er dopa m in e r equ ir ed for m o-
t or fu n ct ion .
Th e pa t t er n of br a in a t r oph y con t r ibu t es t o a wide
r a n ge of m a n ifest a t ion s r ela t ed t o degr ee of a t r oph y.
Cer ebr a l pa lsy is a con dit ion t h a t occu r s beca u se of
n eu r on a l in su lt du r in g a cr it ica l t im e in br a in devel-
opm en t , du r in g t h e pr en a t a l, per in a t a l, or post n a t a l
per iods. Ma n ifest a t ion s va r y fr om m ild t o sever e a n d
m a y in volve m ot or skills, coor din a t ion , a n d ba la n ce
a n d seizu r e a ct ivit y, r eflect in g t h e in volved a r ea s of
t h e br a in .
DIAGNOSIS
Br a in a t r oph y is a pa t h ologic fin din g r ela t ed t o a
sign ifica n t r a n ge of n eu r ologic disea ses. Th e fir st
st ep in dia gn osis is design ed t o det er m in e u n der ly-
in g pa t h ology in or der t o iden t ify t h e specific con -
dit ion a n d in it ia t e a ppr opr ia t e t r ea t m en t . E a r ly
dia gn osis is cr it ica l in n eu r ologic disea se a ssocia t ed
wit h br a in a t r oph y beca u se of t h e lim it ed a bilit y t o
r est or e fu n ct ion t h a t h a s been lost by t h e t im e t h e
dia gn osis is m a de.
A ca r efu l h ist or y t h a t in clu des sign s a n d sym p-
t om s, in clu din g on set , du r a t ion , a n d sever it y, is
t h e fir st st ep in t h e dia gn ost ic pr ocess. Th e ea r ly
m a n ifest a t ion s of br a in a t r oph y m a y be difficu lt t o
iden t ify a t fir st beca u se of t h e slow a n d su bt le de-
velopm en t of sign s. Th e sign s of br a in a t r oph y m a y
be fir st obser ved by ot h er s r a t h er t h a n t h e a ffect ed
in dividu a l wh o m a y be u n a ble or u n willin g t o dis-
close sym pt om s. P h ysica l exa m is n eeded t o defin e
specific n eu r ologic defect s, wh ich in t u r n is n eeded
for a ct u a l dia gn osis. Specific m ea su r es of br a in a t -
r oph y in clu de br a in im a gin g t o m ea su r e t issu e loss.
F u n ct ion a l im a gin g m a y in clu de posit r on em ission
t om ogr a ph y (P E T) a n d sin gle ph ot on em ission com -
pu t ed t om ogr a ph y (SP E CT) wh ich , com bin ed wit h
CT a n d m a gn et ic r eson a n ce im a gin g (MRI) t ech -
n iqu es, h a ve becom e in cr ea sin gly com m on a n d a r e
u sed in det er m in a t ion of loca t ion a n d sever it y of a t -
r oph y. 8 Toget h er, t h e st r a t egies of h ist or y, ph ysica l
exa m , a n d im a gin g t ech n iqu es a id in t h e dia gn osis,
C lin ic a l Mo d e ls 21
pr ogn osis, a n d t r ea t m en t of con dit ion s a ssocia t ed
wit h br a in a t r oph y.
TREATMENT
Tr ea t m en t of in dividu a ls wit h br a in a t r oph y is t a r-
get ed t owa r d pr even t ion or slowin g of con t in u ed pa -
t h ology. Wh en n eu r on s a r e a t r oph ied a n d da m a ged,
r ecover y is sever ely lim it ed beca u se of t h e in a bil-
it y of n eu r on s t o r eplica t e. Su ppor t ive ca r e a ssist s
in dividu a ls in com plet in g a ct ivit ies of da ily livin g.
P h ysica l, speech , or occu pa t ion a l t h er a py is cr it ica l
t o pr om ot ion of opt im a l fu n ct ion . P h a r m a cologic
t h er a pies m a y be in st it u t ed t o a ddr ess im pa ir m en t
in n eu r ologic sign a l t r a n sm ission . Tr ea t m en t is
in dividu a lized ba sed on t h e specific dia gn osis a n d
t h e t ype of br a in a t r oph y in volved, wit h a goa l of
m a xim izin g fu n ct ion a n d m in im izin g con t in u ed
pa t h ology.
Stop and Consider
Why does age and developmental maturity af-
fect the degree of brain atrophy that can be
expected?
Cardiac Hypertrophy
Myoca r dia l cells, or ca r dia c m yocyt es, differ fr om
ot h er cells beca u se t h ey do n ot con t in u a lly divide
a n d r epla ce t h em selves. Aft er t h e fir st 4 weeks of
life, gr owt h of t h e h ea r t is a ch ieved by h yper t r oph y
of exist in g ca r dia c m yocyt es. In ju r y t o t h ese cells
oft en r esu lt s in per m a n en t da m a ge a n d ch r on ic
ca r dia c disea se. C a r d ia c h y p e r t r o p h y , or h y-
per t r oph ic ca r diom yopa t h y, is a disea se of ca r dia c
m u scle t h a t r esu lt s fr om excessive wor kloa d a n d
fu n ct ion a l dem a n d. Th e m ost com m on ca u se of su d-
den u n expect ed ca r dia c dea t h in you n g in dividu a ls,
pr im a r y h yper t r oph ic ca r diom yopa t h y, is m ost com -
m on a m on g in dividu a ls less t h a n 30 yea r s of a ge.11
Th e m ost com m on ca u se of secon da r y ca r dia c h yper-
t r oph y is in cr ea sed blood pr essu r e, im posin g a ddi-
t ion a l wor kloa d on t h e ven t r icle.
PATHOPHYSIOLOGY
P r im a r y h yper t r oph ic ca r diom yopa t h y, wit h ou t
a specifica lly k n own ca u se, is oft en a r esu lt of
a n in h er it ed n on –sex-lin k ed gen et ic a u t osom a l-
dom in a n t t r a it . Secon da r y h yper t r oph y is oft en
ca u sed by a n u n der lyin g con dit ion t h a t ca u ses a n
in cr ea se in ven t r icle wor k loa d. H yper t r oph y ca n
occu r in t h e r igh t ven t r icle beca u se of in cr ea sed
pr essu r e in t h e pu lm on a r y cir cu la t ion or in t h e
left ven t r icle du e t o in cr ea sed pr essu r e in t h e sys-
t em ic cir cu la t ion , a s in h yper t en sion . In syst em ic
22 C h a p t e r 2: Alt er ed Cells a n d Tissu es
h yper t en sion , t h e left ven t r icle of t h e h ea r t m a y
be for ced t o pu m p h a r der beca u se of a n in cr ea se
in ou t flow pr essu r e fr om a st iff a or t ic va lve or in -
cr ea sed pr essu r e in t h e a or t a . Th e left ven t r icle is
t h e m a in pu m p of t h e h ea r t , m ovin g blood r eceived
fr om t h e lu n gs in t o t h e a or t a , pr ovidin g oxygen r ich
a r t er ia l cir cu la t ion t o t h e body. Im pa ir ed pu m pin g
in t h e left ven t r icle lea ds t o decr ea sed a r t er ia l ou t -
pu t fr om t h e h ea r t a n d con gest ion or ba ck flow of
blood in t o t h e left a t r iu m a n d t h e pu lm on a r y cir-
cu la t ion . Per fu sion t o t h e h ea r t m u scle it self is a lso
a ffect ed, r edu cin g deliver y of oxygen t o t h e m yo-
cyt es a n d ot h er ca r dia c cells. In left ven t r icu la r h y-
per t r oph y, t h e wa ll of t h e left ven t r icle, r espon sible
for t h e pu m pin g of blood ou t of t h e a or t a in t o t h e
syst em ic cir cu la t ion , becom es t h ick en ed a n d st iff
a s a r esu lt of t h e in cr ea se in m yoca r dia l cell size.
Th e m u scle becom es less effect ive a t con t r a ct in g
despit e t h e in cr ea sed size of t h e m yoca r dia l cells.
Th e la ck of c o m p li a n c e , or st iffn ess, of t h e ven t r i-
cle m a y pr even t a dequ a t e fillin g a n d t h er efor e m a y
lower ca r dia c ou t pu t . Th is r igidit y of t h e ven t r icle
com bin ed wit h sm a ller ch a m ber size even t u a lly
lea ds t o “pu m p fa ilu r e” a n d ca r dia c decom pen sa -
t ion . Th is con dit ion exem plifies t h e wa y in wh ich
in cr ea sed wor kloa d pr odu ces a bioch em ica l sign a l
t h a t ca u ses a gen et ic r espon se r esu lt in g in h yper-
t r oph y. F igu r e 2.12 illu st r a t es h yper t r oph y of t h e
left ven t r icle.
Figure 2.12. Hypertrophy of the left ventricle caused by
hypertension. (Courtesy Anatomical Chart Company.)
CLINICAL MANIFESTATIONS
Th e eviden ce of ca r dia c h yper t r oph y is va r ia ble
in it s expr ession . Som e in dividu a ls do n ot develop
sym pt om s, a n d ot h er s develop m a n ifest a t ion s t h a t
sever ely lim it fu n ct ion . Ma ssive ven t r icu la r h yper-
t r oph y lea ds t o t h e clin ica l m a n ifest a t ion s of t h is
con dit ion . Sym pt om s of pu m p fa ilu r e a r e ba sed on
it s sever it y a n d ca n in clu de sh or t n ess of br ea t h ,
ch est pa in , a n d s y n c o p e (fa in t in g). Syn cope is of
pa r t icu la r con cer n beca u se it s m a n ifest a t ion is a
m a r ker for su dden dea t h . Ca r dia c h yper t r oph y ca n
a lso lea d t o ir r egu la r h ea r t r a t e a n d r h yt h m . As t h e
ca r dia c m yocyt es en la r ge, t h e ph ysica l r ela t ion sh ip
of ca r dia c con du ct in g cells becom es a lt er ed, disr u pt -
in g elect r ica l sign a lin g in t h e h ea r t t issu e.
DIAGNOSIS
P r eclin ica l dia gn osis in pr im a r y ca r dia c h yper-
t r oph y ca n be a ch ieved by gen et ic t est in g wh en a
fa m ily h ist or y of t h e con dit ion exist s. For t h ose
iden t ified wit h t h e a ssocia t ed gen et ic m u t a t ion , t h e
ea r liest iden t ifica t ion of m a n ifest a t ion s of disea se is
pa r a m ou n t . In t h ose wit h secon da r y ca r dia c h yper-
t r oph y, t r ea t m en t of t h e u n der lyin g ca u se is cr it i-
ca l t o m a n a gem en t of t h e pr ogr ession of pa t h ology.
Secon da r y ca r dia c h yper t r oph y is oft en t h e r esu lt of
h igh blood pr essu r e or disea se of t h e h ea r t va lves.
Rou t in e scr een in g t o det er m in e blood pr essu r e,
exer cise t oler a n ce, a n d t h e pr esen ce of ven t r icu -
la r a r r h yt h m ia ca n be don e per iodica lly t o iden t ify
im pa ir ed ca r diova scu la r fu n ct ion . Scr een in g t ech -
n iqu es ca n in clu de:
● E lect r oca r diogr a m (E KG): eva lu a t es elect r ica l a c-
t ivit y of t h e h ea r t
■ 12-lea d E KG: iden t ifies elect r ica l defect s wh ile
a t r est
■ Am bu la t or y H olt er E KG: iden t ifies a r r h yt h -
m ia s du r in g a ct ivit ies of da ily livin g
● Two-dim ensiona l echoca r diogr a m : ult r a sound
m ea sur em ent of vent r icle dimensions, hea r t va lves,
a nd blood vessels (a or ta , pulm ona ry a r ter y)
● E xer cise st r ess t est in g: det er m in e ca r diova scu la r
r espon se t o exer cise
On ph ysica l exa m in a t ion , a h ea r t m u r m u r du r in g
ca r dia c con t r a ct ion is oft en h ea r d. Rest in g left ven -
t r icu la r ou t flow obst r u ct ion r equ ir es in cr ea sed ven -
t r icu la r wor k t o m ove blood ou t a n d is a ssocia t ed
wit h h igh blood pr essu r e, dia gn osed wh en syst olic
pr essu r e gr a dien t a cr oss t h e a or t ic h ea r t va lve
r ea ch es 30 m m H g; it is con sider ed m oder a t e t o se-
ver e wh en syst olic pr essu r e gr a dien t r ea ch es 50 m m
H g or exceeds 75 m m H g, r espect ively. Obst r u ct ion
of left ven t r icu la r ou t flow is oft en m a n ifest ed by a r-
r h yt h m ia of t h e a t r ia , br a dya r r h yt h m ia (a bn or m a lly
 C lin ic a l Mo d e ls 23

slow h ea r t r a t e), syst olic eject ion m u r m u r, or a bn or- Acromegaly

m a l per iph er a l va scu la r r espon se.
Ac r o m e g a ly is a con dit ion of h yper pla sia pr om pt ed
TREATMENT by h or m on e st im u la t ion of excessive gr owt h . Th e
con dit ion is der ived fr om t h e Gr eek wor ds for ex-
Tr ea t m en t st r a t egies t a r get sym pt om r elief a n d t r em it ies (a cr o) a n d en la r gem en t (m ega ly). Th e t er m
pr even t ion of su dden ca r dia c dea t h . P r im a r y ca r- a cr om ega ly pr ovides a n a ccu r a t e descr ipt ion of t h e
dia c h yper t r oph y sh ou ld be t r ea t ed a t t h e ea r liest m ost com m on clin ica l m a n ifest a t ion s—a bn or m a l
m a n ifest a t ion of disea se. Th e secon da r y for m of gr owt h of t h e h a n ds a n d feet .
ca r dia c h yper t r oph y ca n be im pr oved if t h e con di-
t ion a n d t h e fa ct or s ca u sin g it a r e iden t ified a n d PATHOPHYSIOLOGY
t r ea t ed befor e t h e cells u n der go per m a n en t da m a ge.
Tr ea t m en t is gea r ed t owa r d r ela xa t ion of t h e ven - A for m of h yper pit u it a r ism , secr et ion of excessive
t r icle a n d r elief of t h e ou t flow obst r u ct ion t h a t is gr owt h h or m on e fr om t h e pit u it a r y gla n d a n d sec-
in cr ea sin g t h e ven t r icu la r wor kloa d. An exa m ple of on da r y in cr ea se in in s u lin -lik e g r o w t h a c t o r 1
t h is is u se of a n t ih yper t en sive m edica t ion s t o lower (I G F -1) r esu lt s in exa gger a t ed skelet a l a n d or ga n
t h e r esist a n ce a ga in st wh ich t h e left ven t r icle m u st gr owt h occu r r in g a ft er e p ip h y s e a l, or lon g bon e os-
pu m p wh en t h e h yper t r oph y is ca u sed by u n der lyin g sifica t ion sit e, closu r e. Th e h ypot h a la m u s secr et es
h yper t en sion . t wo h or m on es t h a t r egu la t e gr owt h h or m on e se-
Tr ea t m en t in clu des ph a r m a cologic m a n a ge- cr et ion by t h e pit u it a r y. H ypot h a la m ic secr et ion of
m en t wit h dr u gs design ed t o r elieve t h e r esist a n ce som a t ost a t in h a s a n in h ibit or y effect on t h e pit u -
a ga in st wh ich t h e left ven t r icle m u st pu m p. Tr ea t - it a r y, decr ea sin g secr et ion of pit u it a r y gr owt h h or-
m en t m a y a lso lea d t o r egr ession of t h e left ven t r ic- m on e. Th e st im u la t ion of pit u it a r y gr owt h h or m on e
u la r h yper t r oph y. An giot en sin II r ecept or blocker s secr et ion is in du ced by h ypot h a la m ic pr odu ct ion
(ARBs) a r e t h e dr u gs of ch oice, followed by ca lciu m of gr owt h h or m on e r elea sin g h or m on e (GH RH ).
ch a n n el blocker s a n d a n giot en sin con ver t in g en - Gr owt h h or m on e bin ds t o it s r ecept or a n d begin s
zym e (ACE ) in h ibit or s, for effect ive t r ea t m en t of sign a lin g even t s in t h e cell, wh ich in du ces a gen et ic
left ven t r icu la r m u scle m a ss. 12 Su r ger y t o r edu ce r espon se in volvin g cell-cycle con t r ol. Th is even t
left ven t r icu la r m u scle m a ss or t o r epa ir h ea r t st im u la t es p r o li e r a t io n , or r a pid r epr odu ct ion of
va lves m a y be n eeded, bu t com plica t ion s fr om t h is cells, wh ich lea ds t o h yper pla sia . Th e secr et ion of
t r ea t m en t a r e sign ifica n t . An a lt er n a t ive t o su r ger y, gr owt h h or m on e st im u la t es t h e pr odu ct ion of IGF -1
a lcoh ol a bla t ion of t h e sept u m , ca u ses n ecr osis of in t h e liver. Th e a ct ion s of IGF -1 pr om ot e gr owt h in
t h e in t er ven t r icu la r sept u m by t h e in ject ion of a lco- bon es, ca r t ila ge, soft t issu es, a n d or ga n s. Nor m a lly,
h ol in t o a sm a ll a r t er ia l br a n ch lea din g t o t h e m u s- t h is in cr ea se in IGF -1 a lon g wit h ot h er r egu la t or y
cle sou r ce.13 Act ivit y r est r ict ion s m a y be r equ ir ed h or m on es sign a ls t h e pit u it a r y t o r edu ce t h e pr o-
t o m in im ize t h e r isk of su dden ca r dia c dea t h , es- du ct ion of gr owt h h or m on e via t h e in flu en ce of so-
pecia lly for you n g a t h let es in volved in st r en u ou s m a t ost a t in (Fig. 2.13). Wh en t h is n ega t ive feedba ck
a ct ivit ies. loop fa ils, gr owt h h or m on e secr et ion con t in u es in a n
u n r egu la t ed fa sh ion . In m or e t h a n 90% of t h ese in -
Stop and Consider dividu a ls, t h e over secr et ion of gr owt h h or m on e ca n
What is the benefit of causing necrosis of the be a t t r ibu t ed t o t h e pr esen ce of a ben ign pit u it a r y
interventricular t u m or ca lled a n a den om a .
septum in the
treatment of car-
diac hypertrophy?
F R O M T H E L AB
Stop and
Consider At the cellular level, cardiac hypertrophy is associated with disorganization of myocardial
The effect of car- cell pattern and arrangement, leading to impaired cardiac muscle contraction. Several ge-
diac hypertrophy netic mutations have been identified in familial hypertrophic cardiomyopathy that result in
involving the left alterations in proteins necessary for cardiac muscle contraction. Testing for familial hyper-
ventricle was de- trophic cardiomyopathy is done by analyzing DNA from a blood sample to identify mutations
scribed in this in genes that are known to be associated with the condition. Most commonly involved genes
clinical model. produce myosin (MYH7, MYBPC) and troponin (TNNT2, TNNI3), critical elements for contrac-
What would hap- tion of cardiac muscle. The abnormal proteins cannot function appropriately and contribute
pen if hypertrophy to the hypertrophic changes. Cells seen under a microscope are disordered, lacking the nor-
involved the right mal parallel alignment necessary to produce normal electrical conduction and contraction.
ventricle?
24 C h a p t e r 2: Alt er ed Cells a n d Tissu es
Hypo thalamus
Growth Hormone –
S oma tos ta tin Re le a s ing Hormone
(GHRH)
inhibits s timula te s
Pituitary
Growth Hormone
Live r
Ins ulin-like Growth Fa ctor 1
(IGF-1)
Bone Ca rtila ge S oft Tis s ue s Orga ns
Figure 2.13. Feedback mechanism for growth stimula-
tion. Regulation of growth hormone by growth hormone-
releasing hormone (GHRH) promotes growth through the
action of insulin-like growth factor 1 (IGF-1). Increases in
IGF-1 trigger an increase in somatostatin to inhibit growth.
Dysregulation can result in gigantism or acromegaly.
Acr om ega ly is oft en con fu sed wit h a sim ila r con -
dit ion kn own a s g ig a n t is m , a lso a con dit ion of h y-
per pla sia ch a r a ct er ized by excessive gr owt h . Th e
differ en ce bet ween t h is con dit ion a n d a cr om ega ly is
t h e t im in g of gr owt h h or m on e excess. In giga n t ism ,
gr owt h h or m on e excess occu r s pr ior t o t h e closu r e of
t h e epiph ysea l gr owt h pla t es of t h e lon g bon es. For
t h is r ea son , giga n t ism a ffect s in fa n t s a n d ch ildr en ,
in cr ea sin g t h eir h eigh t u p t o t h r ee t im es of t h e ex-
pect ed h eigh t for t h eir a ge.
CLINICAL MANIFESTATIONS
Sym pt om s of a cr om ega ly a r e r ela t ed t o excessive
gr owt h . Ma n ifest a t ion s of a cr om ega ly ca n in clu de:
● Soft t issu e swellin g (difficu lt y get t in g r in gs on
a n d off)
● E n la r ged h a n ds a n d feet
● Alt er ed fa cia l fea t u r es
■ P r om in en ce of ja w, br ow, a n d n a sa l bon e
■ E n la r gem en t of t on gu e a n d lips
■ In cr ea sed spa cin g bet ween t eet h
● Pa in a n d n u m bn ess in h a n ds
● Deepen in g voice
● Sn or in g
● Skin ch a n ges
■ Coa r se h a ir gr owt h
■ Oily a ppea r a n ce
■ Swea t in g
■ Body odor
■ Developm en t of skin t a gs
● Alt er ed r epr odu ct ive fu n ct ion in g
■ Men st r u a l cycle a lt er a t ion s (wom en )
■ Im pot en ce (m en )
■ Br ea st disch a r ge
Object ive sym pt om s of skelet a l gr owt h in clu de in -
cr ea sed size of h a n ds a n d feet , fa cia l br ow, ja w, a n d
n a sa l bon e, a s well a s in cr ea sed spa cin g of t eet h . Ar-
t h r it is a n d ca r pa l t u n n el syn dr om e m a y a lso r esu lt
fr om over gr owt h of bon e, ca r t ila ge, a n d soft t issu e.
H yper pla sia of t h e cells of sin u ses a n d voca l cor ds
m a y lea d t o a deepen ed voice a n d u pper a ir wa y ob-
st r u ct ion . E xcessive swea t in g a n d skin odor m a y r e-
su lt fr om gla n du la r h yper pla sia . Skin m a y becom e
t h ick a n d oily a n d develop skin t a gs. Men st r u a l
disor der s in wom en a n d sexu a l dysfu n ct ion in m en
m a y occu r. E n la r gem en t of or ga n s, in clu din g liver,
spleen , kidn eys, a n d h ea r t , m a y a lso r esu lt fr om h y-
per pla sia a n d lea d t o ser iou s h ea lt h con sequ en ces,
in clu din g sleep a pn ea , t ype 2 dia bet es, colon ca n cer,
a n d ca r diova scu la r disea se. Acr om ega ly ca n in du ce
bot h h yper pla st ic a n d h yper t r oph ic ch a n ges in ca r-
diova scu la r t issu e. Th e h yper pla st ic ca r dia c ch a n ges
in a cr om ega ly even t u a lly lea d t o ca r dia c h yper t r o-
ph y a n d possibly h ea r t fa ilu r e if left u n t r ea t ed. 15
Su ppr ession of gr owt h h or m on e a n d IGF -1 ca n r e-
ver se t h ese ch a n ges, decr ea sin g left ven t r icu la r
m a ss a n d r est or in g ca r dia c fu n ct ion , h igh ligh t in g
t h e cells’ a da pt ive r espon ses. F igu r e 2.14 illu st r a t es
t h e clin ica l m a n ifest a t ion s of a cr om ega ly in m en
a n d wom en .
Acr om ega ly r esu lt in g fr om pit u it a r y a den om a
ca u ses m a n ifest a t ion s r ela t ed t o ph ysica l pr essu r e
on su r r ou n din g st r u ct u r es a s t h e a den om a in cr ea ses
in size. P r essu r e on br a in t issu es a ffect s a ssocia t ed
n er ves, lea din g t o t h e developm en t of h ea da ch es a n d
im pa ir ed vision . Th e fu n ct ion of t h e pit u it a r y it self
ca n be a lt er ed beca u se of a den om a com pr ession ,
r esu lt in g in a lt er ed pr odu ct ion of ot h er pit u it a r y
h or m on es a n d con t r ibu t in g t o t h e r epr odu ct ive m a n -
ifest a t ion s of a cr om ega ly.
DIAGNOSIS
Th e dia gn osis of t h is con dit ion m a y be dela yed be-
ca u se of t h e slow a n d in sidiou s on set of clin ica l

Thicke ne d ca lva ria
S oma totropic a de noma
of pituita ry
Acrome ga lic fa cie s
Goite r
Ca rdiome ga ly
(hype rte ns ion)
Ba rre l che s t
Hype ros tos is
(thora cic ve rte bra e )
Abnorma l glucos e
tole ra nce s e conda ry
to ins ulin re s is ta nce
Incre a s e d s ize
(ha nds, fe e t)
Ma le s exua l
dys function
De ge ne ra tive
a rthritis
Pe riphe ra l ne uropa thy Thicke ne d s kin
(hype rtrophy of s e ba ce ous
a nd swe a t gla nds )
Figure 2.14. Clinical manifestations of acromegaly. Excessive growth from acromegaly causes hyperplasia and multiple
clinical manifestations in both men ( A) and women ( B) .
m a n ifest a t ion s. Con fir m a t ion of t h e dia gn osis of a c-
r om ega ly depen ds on eleva t ed levels of IGF -1 in t h e
blood followed by m ea su r em en t of gr owt h h or m on e.
A specific m et h od of gr owt h h or m on e m ea su r em en t
a n d follow-u p is r equ ir ed t o obt a in a ccu r a t e a n d r e-
lia ble r esu lt s (see F r om t h e La b, below). On ce a cr o-
m ega ly is dia gn osed, t h e n ext st ep is t o det er m in e
wh et h er t h e ca u se is r ela t ed t o pit u it a r y a den om a .
C lin ic a l Mo d e ls 25
P romine nt fronta l
orbita l ridge s
Re curre nt s e rous
otitis me dia
Coa rs e ne d fe a ture s
Ma croglos s ia
P romine nt jaw
(progna this m)
Thyrome ga ly
Incre a s e d pe rs pira tion
Bre a s t dis cha rge
J oint pa in a nd
e nla rge me nt
Ca rdiova s cula r
proble ms :
-hype rte ns ion
-he a rt fa ilure
-ca rdiome ga ly
-e de ma
-dys pne a
Impa ire d glucos e
tole ra nce
Pa re s the s ia s
Enla rge d ha nds
Me ns trua l dis orde rs
Myopa thy
Incre a s e d s kin
pigme nta tion
Incre a s e d body ha ir
Broa d fe e t
Incre a s e d he e l pa d
a nd s kin thickne s s
Th e pr esen ce of a pit u it a r y a den om a ca n be dia g-
n osed wit h im a gin g t ech n iqu es in clu din g MRI.
TREATMENT
Tr ea t m en t is design ed t o r edu ce t h e over pr odu ct ion
of IGF -1 a n d gr owt h h or m on e t o r ever se or r edu ce
t h e effect s of a cr om ega ly. Th e ch r on ic effect s ca n be
26 C h a p t e r 2: Alt er ed Cells a n d Tissu es

h a lt ed if t h e con dit ion is iden t ified ea r ly in it s cou r se in clu des a pr im a r y t u m or of less t h a n 10 m m in di-
befor e per m a n en t cell in ju r y occu r s. Tr ea t m en t op- a m et er a n d a pr eoper a t ive gr owt h h or m on e blood
t ion s in clu de: level of less t h a n 40 n g/m L. La r ge t u m or s m a y r e-
qu ir e r edu ct ion in size u sin g ph a r m a cologic t h er a -
● Dr u g t h er a py
pies pr ior t o su r gica l in t er ven t ion . Tr a n ssph en oida l
● Ra dia t ion t h er a py
h ypoph ysect om y, a t ech n iqu e for a den om a r em ova l
● Su r gica l r em ova l of a den om a
t h r ou gh a n in cision in t h e n ose, im m edia t ely r edu ces
P h a r m a cologic m a n a gem en t of a cr om ega ly is di- sym pt om s a t t r ibu t ed t o bot h excessive h or m on a l
r ect ed t owa r d r edu ct ion in pit u it a r y gr owt h h or- st im u la t ion of gr owt h a n d t h ose r ela t ed t o com pr es-
m on e secr et ion or a ct ion . Dr u gs m a y be u sed a s sole sion of su r r ou n din g t issu es. E ven a ft er su ccessfu l
t h er a py or a s a m ea n s t o r edu ce t h e size of pit u it a r y su r ger y, follow-u p for r ecu r r en ce is n ecessa r y.
a den om a , im pr ovin g pr og-
n osis for su ccessfu l su r gi-
ca l r em ova l. Dr u gs m a y
a lso be u sed a s a dju va n t F R O M T H E L AB
t h er a py a ft er su r gica l r e-
IGF-1 levels in the blood are stable and therefore provide an accurate result to support the
m ova l of t h e a den om a ,
diagnosis of acromegaly. 17 Growth hormone levels can be measured in the blood, but are
wh en com plet e cu r e is n ot
not reliable based on a single measurement because of the typical variations in secretion
a t t a in ed. Th r ee cla sses
throughout the day. Measurement of growth hormone is most accurate when measured as
of dr u gs a r e t h e m a in
a component of a glucose tolerance test as growth hormone secretion is influenced by
a gen t s for t r ea t m en t of
blood glucose levels. Under physiologic conditions, growth hormone levels decrease when
a cr om ega ly: som a t ost a t in
blood glucose levels rise via negative feedback regulation. Growth hormone levels can be
a n a logs, dopa m in e a go-
tested after a glucose tolerance test to determine if there is an alteration in negative
n ist s, a n d gr owt h h or m on e
feedback, indicating pathologic secretion of growth hormone. Within 2 hours of ingestion
a n t a gon ist s. Som a t ost a -
of 75 g of glucose, growth hormone is suppressed to less than 1 ng/ mL under physiologic
t in a n a logs wor k t h r ou gh
conditions. An elevated growth hormone level 1 hour after the glucose ingestion indi-
in h ibit ion of gr owt h h or-
cates that glucose did not suppress growth hormone secretion, leading to the diagnosis
m on e secr et ion , sim ila r t o
of acromegaly. 14
en dogen ou s som a t ost a t in .
An a ddit ion a l ben efit of
som a t ost a t in a n a log t h er-
a py is r edu ct ion in pit u it a r y a den om a size. Th e so- Stop and Consider
m a t ost a t in a n a log oct r eot ide in du ces a n in h ibit or y Why does growth hormone excess in children pro-
effect on t h e pit u it a r y, r edu cin g gr owt h h or m on e duce manifestations that are different than those
a n d IGF -1 secr et ion , wit h lon g-a ct in g r elea se for m u - in adults?
la t ion s a llowin g for less fr equ en t dosin g (on ce per
m on t h ). Dopa m in e a gon ist s a r e a secon d t r ea t m en t
ch oice, t h ou gh less effect ive t h a n t h e som a t ost a t in Cervical Metaplasia and Dysplasia
a n a logs. Th e dopa m in e a gon ist ca ber golin e is t h e
dr u g of ch oice, a ct in g a t t h e level of t h e pit u it a r y t o Cer vica l developm en t is a dyn a m ic pr ocess, evolv-
r edu ce gr owt h h or m on e a n d su bsequ en t IGF -1 se- in g t h r ou gh ou t t h e r epr odu ct ive lifet im e. Th e cells
cr et ion . Gr owt h h or m on e a n t a gon ist pegvisom a n t of t h e cer vix r espon d t o t h e h or m on a l en vir on m en t ,
bin ds t o gr owt h h or m on e r ecept or s, blockin g en dog- pr om ot in g a da pt ive a n d m a la da pt ive r espon ses.
en ou s gr owt h h or m on e a n d r ela t ed gr owt h h or m on e
effect s.
PATHOPHYSIOLOGY
Ra dia t ion ca n be u sed a s t h e pr im a r y t r ea t m en t or
in com bin a t ion wit h ph a r m a cologic a n d/or su r gica l Th e epit h elia l cells of t h e cer vix a r e a r r a n ged in a
m a n a gem en t . Ra dia t ion of t h e pit u it a r y is design ed m u lt ila yer or ga n iza t ion m u ch like t h a t of t h e skin .
t o pr om ot e cell dea t h in t h e a den om a . Com plica t ion s Act ively dividin g cells a r e loca t ed a lon g t h e ba sa l
ca n in clu de ext en sion of t h e a r ea of cell dea t h t h a t la yer a n d a r e n ot u su a lly fou n d a t t h e su r fa ce la yer.
in clu de h ea lt h y pit u it a r y t issu e, lea din g t o su b- Th e cer vix is m a de u p of t wo dist in ct cell t ypes:
n or m a l secr et ion of ot h er h or m on es, in a ddit ion t o squ a m ou s epit h eliu m a n d colu m n a r (gla n du la r ) ep-
gr owt h h or m on e. it h eliu m (F ig. 2.15). S q u a m o u s e p it h e liu m , t h e
Su r gica l r em ova l of t h e pit u it a r y a den om a is a lso cell t ype lin in g t h e ou t side of t h e cer vix a n d t h e va -
a n effect ive m a n a gem en t st r a t egy. P r ogn osis is best gin a , is a ppa r en t on ph ysica l exa m in a t ion wh en t h e
wh en t h e a den om a is sm a ll, t er m ed a m icr oa den om a cer vix is visu a lized. C o lu m n a r e p it h e liu m is t h e
(less t h a n 1 cm ). P r ogn osis for su ccessfu l su r ger y cell t ype lin in g t h e e n d o c e r v ic a l c a n a l, t h e a r ea

Endo c e rvix
Columna r e pithe lium
Inte rnal o s
Exte rnal o s
S qua mocolumna r
junction
Ec to c e rvix
S tra ti e d s qua mous
e pithe lium
Figure 2.15. Cell types comprising the transformation zone.
The endocervix is lined by columnar epithelium. The ectocer-
vix is lined with stratified squamous epithelium. The squa-
mocolumnar junction marks the merging point of these two
epithelial cell types. (Courtesy Anatomical Chart Company.)
bet ween t h e ext er n a l a n d in t er n a l cer vica l os. Th is
cell t ype pr ovides secr et ion s t h a t plu g t h e ca n a l wit h
m u cu s a n d pr ot ect t h e u t er u s fr om pa t h ogen s t h a t
ca n a scen d fr om t h e va gin a .
Th e loca t ion a t wh ich t h ese t wo cell t ypes m er ge
is kn own a s t h e s q u a m o c o lu m n a r ju n c t io n . Th is
a r ea is dyn a m ic t h r ou gh ou t a wom a n ’s r epr odu ct ive
life, m igr a t in g a n d ch a n gin g loca t ion on t h e cer vix
in r espon se t o st im u li, in clu din g h or m on es a n d pH .
Th e a r ea com pr isin g t h e m er gin g of t h ese cell t ypes
is ca lled t h e t r a n s o r m a t io n zo n e (F ig. 2.16). As
t h e t r a n sfor m a t ion zon e m igr a t es fr om in side t h e
en docer vica l ca n a l t o t h e ou t side of t h e cer vix, or
e c t o c e r v ix , it ca n oft en be visu a lized on ph ysica l
exa m in a t ion . H igh est r ogen levels, a s exper ien ced in
t h e lu t ea l ph a se of t h e m en st r u a l cycle a n d du r in g
Columna r e pithe lium
Exte rna l os of
S qua mocolumna r
the ce rvix
junction
Tra ns forma tion
zone
S qua mous e pithe lium
Figure 2.16. Transformation zone of the external cervical
os. The transformation zone comprises the area distal to
the squamocolumnar junction and is the site of squamous
metaplasia. (From Bickley LS, Szilagyi P. Bates’ Guide to
Physical Examination and History Taking. 8th ed. Philadel-
phia, PA: Lippincott Williams & Wilkins; 2003.)
C lin ic a l Mo d e ls 27
pr egn a n cy, pr om ot e t h e gr a du a l t r a n sit ion of squ a -
m ou s epit h eliu m t o colu m n a r epit h eliu m . Low es-
t r ogen levels, a s occu r in m en opa u se, ca u se t h e
squ a m o-colu m n a r ju n ct ion t o r ecede in t o t h e en do-
cer vica l ca n a l wh er e it ca n n o lon ger be visu a lized
on ph ysica l exa m in a t ion . Th e a da pt a t ion s t h a t t h ese
cell t ypes u n der go a r e exa m ples of m et a pla sia —t h e
cellu la r r espon se of ch a n gin g fr om on e t ype t o a n -
ot h er in t h e fa ce of a n en vir on m en t a l st r essor.
Alt h ou gh t h e m et a pla st ic ch a n ges of t h e cer vix
a r e n ot pa t h ologic, t h e squ a m ou s epit h elia l cell
com pon en t of t h e t r a n sfor m a t ion zon e is vu ln er-
a ble t o st r essor s, wh ich m a y ca u se t h e cells in ju r y
or da m a ge. Th e epit h eliu m ca n be in ju r ed by sev-
er a l fa ct or s, in clu din g ch r on ic in fect ion , ir r it a t ion ,
a n d t r a u m a . Th e t r a n sfor m a t ion zon e r epr esen t s
t h e m ost likely sit e for t h e cellu la r r espon se of dys-
pla sia . Cells a lt er ed wit h dyspla st ic ch a n ges a r e
ch a r a ct er ized by a n a bn or m a l gr owt h a n d a disor-
der ed pr ocess of differ en t ia t ion (dividin g cells a r e
n ot con fin ed t o t h e ba sa l la yer ). Dyspla st ic cells a r e
slou gh ed off t h e cer vica l su r fa ce pr em a t u r ely a n d
a r e oft en im m a t u r e.
Ch a n ges in cellu la r st r u ct u r es, pa r t icu la r ly in t h e
n u cleu s, a r e a ppa r en t in dyspla st ic cer vica l cells.
Alt er a t ion s in t h e c h r o m a t in , gen et ic m a t er ia l of
com pr essed DNA, a r e r espon sible for t h e da r ken ed
a ppea r a n ce of t h e cell n u cleu s a n d t h e a bn or m a l
differ en t ia t ion of dividin g cells. Cer vica l dyspla -
sia is con sider ed t o be a pr eca n cer ou s con dit ion . If
iden t ified a n d t r ea t ed ea r ly, t h e da m a ged cer vica l
cells ca n be r epla ced by n or m a l cells, lea din g t o fu ll
r ecover y. If left u n t r ea t ed, t h e cells m a y r ecover
spon t a n eou sly or m a y pr ogr ess in t o m a lig n a n c y or
ca n cer.
CLINICAL MANIFESTATIONS
Th er e a r e n o sign s a n d sym pt om s of cer vica l dyspla -
sia , em ph a sizin g t h e im por t a n ce of r ou t in e cer vica l
cyt ologic scr een in g for ea r ly det ect ion . Th e pr esen ce
of r isk fa ct or s for cer vica l dyspla sia sh ou ld be con -
sider ed wh en det er m in in g scr een in g t ype a n d fr e-
qu en cy. Risk fa ct or s in clu de:
1. E a r ly on set sexu a l a ct ivit y
2. Mu lt iple (m or e t h a n t h r ee) sexu a l pa r t n er s
3. E xposu r e t o h u m a n pa pillom a vir u s
4. Sm okin g
Th e h u m a n p a p illo m a v ir u s (H P V) is im plica t ed
a s a com m on fa ct or in t h e developm en t of cer vica l
dyspla sia .16,17 H P V en t er s t h e h ost cell a n d ca n be
in t egr a t ed in t o it s gen om e. Th e ch a n ges in t h e DNA
a r e t r a n sla t ed in t o u n r egu la t ed cellu la r r epr odu c-
t ion a n d ca n pot en t ia lly r esu lt in ca n cer, a lt h ou gh
n ot a ll st r a in s of t h e vir u s a r e con sider ed t o be po-
t en t ia lly o n c o g e n ic (ca n cer ca u sin g).
28 C h a p t e r 2: Alt er ed Cells a n d Tissu es

Stop and Consider
Can the prevalence of high-risk types of HPV vary
geographically? Why is it important to determine
the most common types of high-risk HPV in a
particular region or geographic area?
DIAGNOSIS
Iden t ifica t ion of cer vica l dyspla sia is a ch ieved
t h r ou gh bot h scr een in g a n d dia gn ost ic t est in g.
Screening Tests
Rou t in e scr een in g of cer vica l cells is don e t o iden -
t ify ch a r a ct er ist ics of cells. Cells fr om t h e ect ocer vix,
idea lly fr om t h e m or e vu ln er a ble t r a n sfor m a t ion
zon e, a n d fr om t h e en docer vica l ca n a l a r e obt a in ed
for m icr oscopic eva lu a t ion . Met a pla st ic a n d dyspla s-
t ic ch a n ges ca n be det er m in ed wit h t h is scr een in g
m et h od. 18,19 In a ddit ion t o iden t ifica t ion of cellu la r
ch a n ges, som e scr een in g t est s ca n det er m in e wh et h er
a n on cogen ic for m of H P V is pr esen t by DNA a n a ly-
sis. Th e r esu lt s of t h ese t est s a r e u sed t o det er m in e
t r ea t m en t a n d follow-u p pla n s (Ta ble 2.1).
Th e Pa pa n icola ou (Pa p) sm ea r, n a m ed for t h e
or igin a t or Dr. Geor ge Pa pa n icola ou , h a s been t h e
pr im a r y m et h od of cer vica l scr een in g sin ce t h e ea r ly
1940s. Cells fr om t h e ect ocer vix a n d en docer vix a r e
collect ed du r in g a pelvic exa m in a t ion . P la cem en t of
a specu lu m in t o t h e va gin a a llows viewin g of t h e cer-
vix. A collect in g device, oft en r efer r ed t o a s a spa t u la ,
is pla ced on t h e t r a n sfor m a t ion zon e of t h e ect ocer-
vix, a n d su per ficia l cells a r e collect ed by r ot a t in g t h e
collect ion device. Cells fr om t h e en docer vix a r e a lso
collect ed du r in g t h is pr ocedu r e. In a con ven t ion a l
Pa p sm ea r, t h e cells a r e pla ced (sm ea r ed) on a gla ss
slide a n d pr eser ved wit h fixa t ive for su bsequ en t
exa m in a t ion by a cyt ot ech n ologist or a pa t h ologist .
Cells collect ed fr om t h e cer vix ca n a lso be pla ced in
a via l of pr eser va t ive solu t ion for a n a lysis u sin g a
n ewer m et h od of Pa p sm ea r a n a lysis, liqu id-ba sed
Pa p t est in g. Th e liqu id-ba sed m et h od of a n a lysis is
u sed for det er m in a t ion of cer vica l cell in fect ion wit h
on cogen ic H P V su bt ypes.
Recom m en da t ion s for scr een in g of US wom en a t
low r isk for cer vica l dyspla sia in clu de:
● In it ia l scr een in g a t a ge 21
● Scr een in g wom en a ged 21 t o 29 yea r s wit h Pa p
t est a lon e a t in t er va ls of ever y 3 yea r s
● Pa p t est a n d H P V co-t est in g ever y 5 yea r s in
wom en ≥ 30 a n d < 65 yea r s of a ge
Am on g older wom en wh o have r isk fa ct or s (pr ior
a bnor m a l Pa p t est , sm okin g h ist or y, pr eviou s H P V-
r ela t ed disea se, or n ew pa r t n er s) or wer e in a dequ a t ely
screen ed, Pa p t est ever y 2 t o 3 yea r s or co-t est in g ev-
er y 5 yea r s is r ecom m en ded. Wom en wit h H IV in fec-
t ion or wh o a r e im m u n ocom pr om ised h ave lim it ed
a bilit y t o clea r H P V in fect ion a n d t her efor e sh ould
be scr een ed m or e a ggr essively for cer vica l dyspla sia .
Th e r esu lt s of t h e Pa p sm ea r scr een in g a r e u sed
in con sider a t ion of m a n a gem en t a n d t r ea t m en t
st r a t egies. Resu lt s of Pa p scr een in gs a r e r epor t ed
u sin g t h e Bet h esda Syst em a s follows:
● Nega t ive for in t r a epit h elia l lesion or m a lign a n cy
■ No sign s of ca n cer or pr eca n cer ou s ch a n ges
● E pit h elia l cell a bn or m a lit ies
■ At ypica l squ a m ou s cells of u n det er m in ed sig-
n ifica n ce (ASC-US)
■ At ypica l squ a m ou s cells, ca n n ot r u le ou t h igh -
gr a de squ a m ou s in t r a epit h elia l cell lesion
(ASC-H )
■ Low-gr a de squ a m ou s in t r a epit h elia l lesion
(LGSIL)
■ H igh -gr a de squ a m ou s in t r a epit h elia l lesion
(H GSIL)
■ Squ a m ou s cell ca r cin om a

Ta b le 2.1 La bor a t or y a n d Dia gn ost ic Test s Used Wit h Cer vica l Dyspla sia
L a b o r D ia g n o s t ic Te s t P u r p o s e o t h e Te s t P r oced u r e

P h ysica l exa m in a t ion
Cer vica l sa m plin g
Cer vica l a ssessm en t
Dia gn ost ic excision a l
pr ocedu r e
Visu a l eva lu a t ion of cer vix
Obt a in in g a specim en for cyt ologic
eva lu a t ion
E va lu a t ion of t h e cer vix a n d en -
docer vica l ca n a l for eviden ce of
dyspla sia
P r ovide h ist ologic sa m ple of t h e
t r a n sfor m a t ion zon e a n d en docer-
vica l ca n a l for eva lu a t ion
Specu lu m exa m in a t ion of t h e ect ocer vix t o det ect
t r a n sfor m a t ion zon e a n d gen er a l a ppea r a n ce
Pa p sm ea r r equ ir in g t h e u se of a spa t u la for ect ocer-
vica l sa m ple a n d a cyt obr u sh for en docer vica l sa m ple
or liqu id sa m plin g a lso ca pa ble of det er m in in g h u -
m a n pa pillom a vir u s (H P V) t ype
E xa m in a t ion of t h e cer vix wit h a colposcope; sa m -
plin g of en docer vica l ca n a l a n d biopsy of a ll lesion s
su spect ed of dyspla sia
La ser con iza t ion , cold-kn ife con iza t ion , loop elect r o-
su r gica l excision (LE E P ), a n d loop elect r osu r gica l
con iza t ion com pr ise t h e su r gica l pr ocedu r es em -
ployed t o obt a in specim en s
 C lin ic a l Mo d e ls 29

● Gla n du la r cell a bn or m a lit ies developm en t a ga in st pa t h ogen ic H P V t ypes in clu des

■ At ypica l en docer vica l or en dom et r ia l cells t h e qu a dr iva len t va ccin e Ga r da sil, wh ich t a r get s
■ At ypica l, fa vor n eopla st ic fou r H P V su bt ypes 6, 11, 16, a n d 18. Ga r da sil 9 ex-
■ E n docer vica l a den oca r cin om a in sit u (AIS) t en ds pr ot ect ion t o n in e H P V su bt ypes, in clu din g 6,
■ Aden oca r cin om a 11, 16, 18, 31, 33, 45, 52, a n d 58. Th e biva len t Cer-
va r ix t a r get s t h e t wo m ost com m on on cogen ic H P V
Iden t ifica t ion of h igh -r isk H P V st r a in s pr ovides
su bt ypes 16 a n d 18. Va ccin e effect iven ess is gr ea t -
fu r t h er in for m a t ion for det er m in in g t r ea t m en t a p-
est wh en a dm in ist er ed pr ior t o H P V in fect ion , t h a t
pr oa ch es. An a lysis of cells for t h e pr esen ce a n d
is, pr ior t o in it ia t in g sex. Rou t in e im m u n iza t ion is
st r a in of H P V DNA in dica t es in fect ion wit h t h e vi-
r ecom m en ded for gir ls a n d boys a ged 11 t o 12 yea r s
r u s a n d iden t ifies t h e r isk st a t u s for t h e pr esen ce of
bu t ca n be in it ia t ed a s ea r ly a s a ge 9. For t h ose n ot
on cogen ic H P V su bt ypes.
va ccin a t ed a t t h ese ea r ly a ges, ca t ch -u p im m u n iza -
t ion is r ecom m en ded for t h ose a ged 13 t o 26 yea r s.
Diagnostic Tests
Va ccin e a dm in ist r a t ion in clu des t h r ee doses over a
Dia gn ost ic t est in g is per for m ed ba sed on cellu la r m in im u m of 24 weeks.18
scr een in g t est s. E va lu a t ion of t issu e is com plet ed t o
obt a in a n a ccu r a t e dia gn osis a n d t o for m t h e ba sis of
TREATMENT
t r ea t m en t . On e of t h e m ost com m on dia gn ost ic t est s
is t h e colposcopy. Colposcopy a llows a m or e ca r efu l Tr ea t m en t t o r em ove su per ficia l cells (a bla t ive) is a n
visu a l obser va t ion of cer vica l ch a n ges a n d ser ves opt ion for wom en wit h CIN in t h e a bsen ce of gla n -
a s a gu ide for biopsy sit e select ion . An ou t pa t ien t du la r cell in volvem en t or in va sive squ a m ou s cell
pr ocedu r e, colposcopy is sim ila r t o a Pa p sm ea r in disea se. Cr yosu r ger y, a for m of cold t h er a py t h a t de-
t h e a ppr oa ch of visu a liza t ion of t h e cer vix u sin g a st r oys m ildly dyspla st ic cells, is a com m on a bla t ive
specu lu m . Ra t h er t h a n viewin g t h e cer vix wit h t h e t h er a py for cer vica l dyspla sia . Liqu id n it r ogen is a p-
n a ked eye, t h e t issu e is m a gn ified by a colposcope, plied t o t h e dyspla st ic cells on t h e ect ocer vix, iden t i-
a bin ocu la r-like device pla ced a bou t 30 cm ou t side fied by colposcopy via a pr obe pla ced in t h e desir ed
t h e open in g of t h e va gin a . An a cet ic a cid solu t ion a r ea . CO 2 la ser a bla t ion is a ccom plish ed by dir ect in g
is a pplied t o t h e cer vix, wh ich ca u ses a r ea s t o t u r n a la ser t owa r d t h e cer vica l lesion u n der colposcopic
wh it e (a cet o–wh it e), su ggest ive of dyspla sia . Sm a ll, gu ida n ce, dest r oyin g t h e t issu e by va por iza t ion . H ea t
1/8-in ch t issu e sect ion s (pu n ch biopsies) a r e t a ken a bla t ion m et h ods in clu de cold coa gu la t ion a n d elec-
fr om t h e wh it en ed a r ea s a n d sen t t o pa t h ology for t r ocoa gu la t ion dia t h er m y a bla t ion , wit h va r ia t ion s
a n a lysis. F u r t h er t issu e is collect ed by en docer vica l in t em per a t u r e a n d t im e of t r ea t m en t a ssocia t ed
cu r et t a ge, pr ovidin g a t issu e sa m ple fr om t h e en do- wit h dept h of cer vica l t issu e dest r u ct ion . In ca ses of
cer vix. A n a r r ow in st r u m en t (cu r et t e) is pa ssed in t o ca r cin om a , a h yst er ect om y m a y be in dica t ed.
t h e en docer vix t o obt a in
t h e sa m ple, pr ovidin g t is-
su e for a ccu r a t e dia gn osis.
Biopsy results are re- F R O M T H E L AB
ported as cervical intraep-
Interpretation of traditional Pap smears with cells viewed in a slide preparation is limited by
ithelial neoplasia (CIN) of
the quality of the collection. Cells may be placed too thickly on the slide, obscuring some
varying severity (CIN 1,
of the cells from view. Other cell types, such as bacteria, yeast, and blood cells, can also
mild dysplasia; CIN 2, mod-
prevent adequate viewing of the cervical cells of interest. Liquid-based preparations, also
erate dysplasia; CIN 3, se-
known as liquid-based cytology, allow the cells collected to be placed in a fixative filled vial
vere dysplasia), carcinoma
rather than on a slide. One advantage of this method is the ability of the cytotechnologist
in situ, squamous cell car-
or pathologist to view cells more clearly. Cells of interest can be analyzed more easily be-
cinoma (invasive cancer of
cause of removal of mucus, bacteria, yeast, and other cells. An additional benefit provided
squamous cells), and ade-
by liquid-based Pap preparations includes the ability to screen for oncogenic HPV subtypes.
nocarcinoma (invasive can-
cer of glandular cells).
Per sist en t in fect ion
wit h H P V t ypes 16 a n d 18 is m ost com m on ly a sso-
cia t ed wit h cer vica l ca n cer, r espon sible of a ppr ox- Environmental Toxin Injury and
im a t ely 70% of ca ses. 16 H P V t ypes 31, 33, 45, 52, Cardiovascular Disease
a n d 58 a r e a lso im plica t ed in developm en t of cer-
vica l ca n cer, a ccou n t in g for a ppr oxim a t ely a n a ddi- Resu lt s fr om n u m er ou s st u dies wor ldwide h a ve pr o-
t ion a l 19% of ca ses. Non ca r cin ogen ic gen it a l wa r t s vided a n im por t a n t lin k bet ween exposu r e t o a ir-
a r e a ssocia t ed wit h H P V t ypes 6 a n d 11. Va ccin e bor n e en vir on m en t a l t oxin s a n d pollu t ion wit h t h e
30 C h a p t e r 2: Alt er ed Cells a n d Tissu es

developm en t of ca r diova scu la r disea se. Air pollu t ion t h e la st five deca des wer e du e t o sm okin g a n d ex-
is a n im por t a n t en vir on m en t a l t oxin a ssocia t ed wit h posu r e t o secon dh a n d sm oke.
ca r diova scu la r disea se, con t a in in g pa r t icu la t e m a t -
H ea lt h con sequ en ces of sm okin g in clu de a or t ic
t er, ca r bon m on oxide, n it r ogen oxides, su lfu r dioxide,
a n eu r ysm , a cu t e m yeloid leu kem ia , ca t a r a ct , ca n -
ozon e, a n d lea d. F in e pa r t icles in a ir pollu t ion a r e
cer (cer vica l, kidn ey, pa n cr ea t ic, st om a ch , bla dder,
a ssocia t ed wit h a n in cr ea se in m or t a lit y a n d wit h
esoph a gea l, la r yn gea l, lu n g, or a l, a n d t h r oa t ), pn eu -
t h e developm en t of ca r diova scu la r disea se ca u sed by
m on ia , per iodon t it is, ch r on ic lu n g disea ses, cor on a r y
in fla m m a t ion , a t h er oscler osis, a n d a lt er ed ca r dia c
h ea r t a n d ca r diova scu la r disea ses (in clu din g isch -
fu n ct ion . Th e eviden ce is so st r on g t h a t t h e Am er-
em ic st r oke), r epr odu ct ive effect s, a n d su dden in fa n t
ica n H ea r t Associa t ion in clu des a ir pollu t ion a s a
dea t h syn dr om e. 25
kn own r isk fa ct or for ca r diova scu la r disea se.20
Ciga r et t e sm okin g is on e of t h e m ost com m on
en vir on m en t a l pollu t a n t s kn own t o ca u se cellu la r DIAGNOSIS
da m a ge. Ciga r et t e sm oke con t a in s ca n cer-ca u sin g
Sm okin g ser ves a s bot h a ca u sa t ive a n d a ddit ive fa c-
ch em ica ls (for m a ldeh yde, ben zen e), t oxic m et a ls
t or in ca r diova scu la r disea se. 26 H ist or y m a y r evea l
(lea d, a r sen ic), a n d poison ou s ga ses (ca r bon m on ox-
poor exer cise t oler a n ce beca u se of im pa ir ed a bilit y of
ide, h ydr ogen cya n ide). Th ese t oxic su bst a n ces pr o-
t h e h ea r t or blood vessels t o m eet t h e in cr ea sed de-
m ot e t h e developm en t of ph ysica l cellu la r in ju r y a n d
m a n ds of a ct ivit y. Dyspn ea is a fr equ en t com pla in t
con t r ibu t e t o disea se a n d illn ess.21
t h a t m a y in dica t e eit h er a n u n der lyin g ca r diova scu -
la r or a pu lm on a r y con dit ion . Cool, pa le, a n d pa in fu l
PATHOPHYSIOLOGY ext r em it ies m a y in dica t e t h e pr esen ce of a clot or
t h e pr esen ce of per iph er a l va scu la r disea se. P h ys-
Th e t oxin s in ciga r et t e sm oke a r e pr esen t in bot h ica l exa m in a t ion m a y r evea l in cr ea sed blood pr es-
m a in s t r e a m (a ct ive) a n d s id e s t r e a m (pa ssive su r e a n d h ea r t r a t e, a n d decr ea sed ca r dia c ou t pu t ,
or secon dh a n d) sm oke. Wh en t h e t oxin -con t a in in g a n d cor on a r y blood flow. La bor a t or y st u dies m a y
sm oke en t er s t h e lu n g, t h e fr ee r a dica ls (O 2 −, H 2 O 2 , in dica t e m a r ker s of ca r diova scu la r disea se, in clu d-
a n d ONOO −) pr om ot e t h e developm en t of oxida t ive in g decr ea sed h igh -den sit y lipopr ot ein (H DL) a n d
st r ess. Th is r esu lt s in in fla m m a t ion , r elea se of cy- in cr ea sed low-den sit y lipopr ot ein (LDL).
t okin es, va scu la r dysfu n ct ion , a n d a lt er ed gen e
a ct iva t ion a n d con t r ibu t es t o t h e developm en t of
a t h er oscler osis. Th e r esu lt in g cellu la r da m a ge in - TREATMENT
cr ea ses a n in dividu a l’s r isk of developin g cor on a r y Sm okin g cessa t ion is t h e fir st st ep in t h e pr even -
h ea r t disea se.22 St u dies h a ve dem on st r a t ed t h a t t ion of fu r t h er com plica t ion s. Sm okin g cessa t ion is a
even sm a ll exposu r es t o t h ese t oxin s ca n ca u se a sig- ch a llen ge for m a n y in dividu a ls. St eps r ecom m en ded
n ifica n t in cr ea se in ca r diova scu la r disea se.23 for su ccessfu l cessa t ion in clu de:
● Set a qu it da t e
CLINICAL MANIFESTATIONS ● Addr ess ba r r ier s
● Con sider t r ea t m en t opt ion s of beh a vior a l cou n sel-
Th e m a n ifest a t ion s of exposu r e t o fir st h a n d a n d sec- in g a n d m edica t ion
on dh a n d sm oke r eflect t h e over a ll effect s of pa t h ol- ● Lea r n n ew skills a n d beh a vior s
ogy on t h e en t ir e body. Fr om cellu la r dysfu n ct ion t o ● Be pr epa r ed for r ela pse or difficu lt sit u a t ion s
or ga n in volvem en t , sm okin g a ffect s n ea r ly a ll body
syst em s. Accor din g t o a r epor t by t h e US Su r geon Nicot ine repla cem ent ther a py is designed t o r elieve
Gen er a l,24 t h e followin g fin din gs r epr esen t t h e con - n icot ine wit hdr awa l sym ptom s. The combina t ion of de-
sequ en ces of sm okin g on h ea lt h : livery system s t ha t include the long-a ct ing pa t ch wit h
● Th er e is a ca u sa l r ela -
t ion sh ip bet ween ex-
posu r e t o secon dh a n d F R O M T H E L AB
sm oke a n d in cr ea sed
r isk of st r oke. Cotinine, a nicotine metabolite, can be measured in the blood, urine, or saliva. Cotinine
● Sm okin g is t h e lea d- levels can provide an objective measurement of exposure to active or passive smoke. After
in g ca u se of pr em a t u r e smoking cessation, it can take up to 2 weeks for cotinine levels to reach nonsmoking levels
dea t h in t h e Un it ed in blood and several weeks in urine. Since the early 1990s, cotinine levels in nonsmokers
St a t es. have decreased by more than 70% in adults, 58% in children, and 55% in adolescents, indi-
● Mor e t h a n 20 m illion cating lowered environmental smoke exposure. 27
pr em a t u r e dea t h s in

a shor t-a ct ing met hod such a s lozenge, gum , inha ler,
or na sa l spr ay is consider ed first-line t rea t ment . An-
ot her pha r ma cologic t rea t ment ta r get s t he nicot inic
r eceptor a gonist va r enicline, r educing n icotine with-
dr awa l sym ptom s a s well a s blocking t he r ewa r ding
a spects of sm oking. Bupr opion, a nor epinephr ine/do-
pa m ine r eupt a ke inhibit or is a nother pha r ma cologic
option for use in smoking cessa tion. Alt hough som e
smoking-r ela t ed da ma ge m ay be rever sible, tr ea t-
m ent of the persistent hea lth consequences of sm ok-
ing is disea se specific a nd may be r equir ed long t er m .
Stop and Consider
Who is most at risk for illness related to sec-
ondhand smoke? What increases vulnerability to
disease?
S U MMAR Y
● Cellu la r h om eost a sis depen ds on t h e pr oper fu n c-
t ion in g of cellu la r com pon en t s, wit h dir ect effect s
on t issu es a n d or ga n s.
● Cellu la r a da pt a t ion s t o st r ess, in ju r y, a n d da m a ge
for m t h e ba sis of a ll disea se.
● Alt er a t ion s in cell size (a t r oph y a n d h yper t r o-
ph y), cell n u m ber (h yper pla sia ), a n d cell st r u ct u r e
(m et a pla sia a n d dyspla sia ) ca u se ch a n ges in t is-
su e fu n ct ion a n d im pa ct t h e en t ir e per son .
● Most cellu la r a da pt a t ion s a r e n ecessa r y for cell
su r viva l.
● Wh en da m a ge exceeds t h e a bilit y of t h e cell t o
a da pt t o a st r essor, cell dea t h by a popt osis or n e-
cr osis r esu lt s.
● Th e clin ica l m odels pr esen t ed in t h is ch a pt er il-
lu st r a t e t h e a pplica t ion s of t h e con cept s of cellu -
la r a da pt a t ion , in clu din g a t r oph y, h yper t r oph y,
h yper pla sia , m et a pla sia , dyspla sia , a popt osis,
a n d n ecr osis.
C AS E S T U D Y 2.1
You a r e spen din g t h e win t er skiin g h igh in t h e
m ou n t a in s of Color a do. You n ot ice t h a t exer t ion
wh ile skiin g m a kes you t ir ed a n d t h a t you do n ot
h a ve a s m u ch en er gy a s you did befor e st a yin g in
t h e m ou n t a in s. You r ea lize you a r e feelin g t h is wa y
beca u se you r body ca n n ot t a ke in a s m u ch oxygen a t
t h e h igh er a lt it u de. On e lon g-t er m a da pt a t ion you r
body m u st m a ke is t o in cr ea se t h e pr odu ct ion of r ed
blood cells t o bet t er oxygen a t e you r t issu es a n d cells.
Ba sed on t h e in for m a t ion in t h is ch a pt er a n d on a d-
dit ion a l r ea din gs, a n swer t h e followin g qu est ion s:
1. Wh a t is t h e m ost likely st r essor t h a t will ca u se
you r cells t o a da pt ?
C h a p t e r 2: Alt er ed Cells a n d Tissu es 31
2. Wh a t a da pt a t ion s a r e you r cells likely t o m a ke t o
r espon d t o t h e st r essor ?
3. Wh a t is t h e pot en t ia l ou t com e if you r cells a r e
u n a ble t o a da pt ?
4. Wh a t la b t est s ca n be u sed t o iden t ify t h e ex-
pect ed a da pt a t ion s?
5. Ca n a n y t r ea t m en t s be u sed t o su ppor t you r
body’s a da pt a t ion ?
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r-
n a l a r t icle or Web sit e t h a t det a ils oxygen a t ion a t
h igh er a lt it u de t o con fir m you r pr edict ion s.
C AS E S T U D Y 2.2
A 56-yea r-old m a n a r r ived in t h e em er gen cy r oom ,
com pla in in g of ch est pa in . Aft er eva lu a t ion , it wa s
decided t h a t h e n eeded a cor on a r y a n giogr a m t o
det er m in e if t h er e wer e a r ea s of blocka ge ca u sin g
isch em ia . On e da y a ft er t h e a n giogr a m , h is r en a l
fu n ct ion bega n t o det er ior a t e. H e wa s dia gn osed
wit h con t r a st -in du ced n eph r opa t h y.
1. Wh a t is con t r a st -in du ced n eph r opa t h y?
2. Wh a t is t h e epidem iology of con t r a st -in du ced
n eph r opa t h y?
3. Wh a t is t h e et iology of con t r a st -in du ced
n eph r opa t h y?
4. Wh a t a da pt a t ion s a r e you r cells likely t o m a ke t o
r espon d t o t h e st r essor ?
5. H ow does t h e cellu la r in ju r y m a n ifest ?
6. Wh a t ca n be don e t o pr even t or t r ea t n eph -
r ot oxic cellu la r in ju r y in con t r a st -in du ced
n eph r opa t h y?
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r-
n a l a r t icle or Web sit e t h a t det a ils cellu la r in ju r y
a n d a da pt a t ion r esu lt in g fr om con t r a st -in du ced n e-
ph r opa t h y t o con fir m you r pr edict ion s.
P R AC T I C E E XAM Q U E S T I O N S
1. Th e or ga n elle t h a t is in volved in cellu la r r espi-
r a t ion a n d is lin ked t o t h e developm en t of oxida -
t ive st r ess is kn own a s t h e:
a . E n dopla sm ic r et icu lu m
b. Golgi a ppa r a t u s
c. Lysosom e
d. Mit och on dr ia
2. Cells develop in t o t issu es wit h specia lized st r u c-
t u r e a n d fu n ct ion t h r ou gh t h e pr ocess of:
a . Differ en t ia t ion
b. P r olifer a t ion
c. E n docyt osis
d. E xocyt osis
32 C h a p t e r 2: Alt er ed Cells a n d Tissu es
3. Th e cell’s t ypica l r espon se t o a decr ea se in t r o-
ph ic sign a l is:
a . At r oph y
b. H yper t r oph y
c. H yper pla sia
d. P h a gocyt osis
4. Cell dea t h by n ecr osis is:
a. The cell’s way of replacing aged cells with new cells
b. Also kn own a s pr ogr a m m ed cell dea t h
c. Oft en a r espon se t o in fla m m a t ion
d. Com m on ly seen du r in g t h e per iod of em br yo
developm en t
5. You a r e ca r in g for a fem a le pa t ien t wh o h a s r e-
por t ed a n ot icea ble decr ea se in br ea st size a n d
m u scle m a ss. Wh ich of t h e followin g con dit ion s
a n d ca u ses is t h e m ost likely expla n a t ion ?
a . P u ber t y
b. P r egn a n cy
c. Men opa u se
d. Acr om ega ly
6. Th e ch a n ges seen in cells a da pt in g t o st r essor s
t h a t pr om ot e m et a pla sia :
a . Ar e ir r ever sible
b. Ca n r esu lt in ca n cer
c. Ch a n ge fr om on e cell t ype t o a n ot h er
d. Sh ow a bn or m a l differ en t ia t ion
7. Cellu la r a t r oph y r esu lt s in
a . In cr ea se in t issu e volu m e du e t o in cr ea se in
cell n u m ber
b. In cr ea se in t issu e volu m e du e t o in cr ea se in
cell size
c. Decr ea se in t issu e volu m e du e t o decr ea se in
cell size
d. No ch a n ge in t issu e volu m e
8. Tr ea t m en t of ch r on ic con dit ion s a ssocia t ed wit h
cer ebr a l a t r oph y
a . Ar e effect ive a t r est or in g n eu r on a l fu n ct ion
b. Ar e t a r get ed t owa r d slowin g n eu r on a l in ju r y
a n d a t r oph y
c. Ar e best in it ia t ed wh en a dva n ced sign s a n d
sym pt om s a r e eviden t
d. Ar e n ot in dica t ed
9. Wh ich of t h e followin g h or m on es is secr et ed
fr om t h e a n t er ior pit u it a r y?
a . Gr owt h h or m on e
b. Som a t ost a t in
c. Gr owt h h or m on e r elea sin g h or m on e
d. In su lin -like gr owt h fa ct or 1
10. Wh ich on e of t h e followin g is a dia gn ost ic t est for
cer vica l dyspla sia ?
a . Liqu id-ba sed Pa p cyt ology
b. Con ven t ion a l Pa p cyt ology
c. Cer vica l pu n ch biopsy
d. H P V t est in g
11. Wh ich of t h e followin g r ea ct ive oxygen species is
sca ven ged by ca t a la se?
a . H ydr oxyl r a dica l
b. Per oxyn it r it e
c. Su per oxide
d. H ydr ogen per oxide
12. Wh ich of t h e followin g t er m s descr ibes cells t h a t
a r e en la r ged, wit h da r ken ed n u clei a n d a bn or-
m a l ch r om a t in
a . H yper pla st ic
b. Dyspla st ic
c. Met a pla st ic
d. Apla st ic
D I S C U S S I O N AN D
AP P L I C AT I O N
1. Wh a t did I kn ow a bou t ba sic a lt er a t ion s in cells
a n d t issu es befor e t oda y?
2. Wh a t body pr ocesses a r e a ffect ed by a lt er ed
cellu la r a n d t issu e a da pt a t ion ? H ow do cel-
lu la r a n d t issu e a da pt a t ion s im pa ct t h ose
pr ocesses?
3. Wh a t a r e t h e pot en t ia l et iologies for a lt er ed cel-
lu la r a n d t issu e a da pt a t ion ? H ow do cellu la r a n d
t issu e a da pt a t ion s develop?
4. Wh o is m ost a t r isk for developin g a lt er ed cellu -
la r a n d t issu e a da pt a t ion ? H ow ca n t h ese a lt er-
a t ion s be pr even t ed?
5. Wh a t a r e t h e h u m a n differ en ces t h a t a ffect t h e
et iology, r isk, or cou r se of a lt er ed cellu la r a n d
t issu e a da pt a t ion ?
6. Wh a t clin ica l m a n ifest a t ion s a r e expect ed
in t h e cou r se of a lt er ed cellu la r a n d t issu e
a da pt a t ion ?
7. Wh a t specia l dia gn ost ic t est s h elp t o det er m in e
t h e dia gn osis a n d cou r se of a lt er ed cellu la r a n d
t issu e a da pt a t ion ?
8. Wh a t a r e t h e goa ls of ca r e for in dividu a ls wit h
a lt er ed cellu la r a n d t issu e a da pt a t ion ?
9. H ow does t h e con cept of a lt er ed cellu la r a n d t is-
su e a da pt a t ion bu ild on wh a t I h a ve lea r n ed in
t h e pr eviou s ch a pt er a n d in t h e pr eviou s cou r ses?
10. H ow ca n I u se wh a t I h a ve lea r n ed?
R E SOUR CE S
Am er ica n H ea r t Associa t ion . Disea ses a n d con di-
t ion s: ca r diom yopa t h y:
h t t p://www.h ea r t .or g/H E ARTORG/Con dit ion s/Mor e/
Ca r diom yopa t h y_UCM_444459_Su bH om ePa ge.jsp
Ret r ieved Ma r ch 7, 2016.

Cen t er s for Disea se Con t r ol a n d P r even t ion . Secon d
Na t ion a l Repor t on H u m a n E xposu r e t o E n vir on -
m en t a l Ch em ica ls:
h t t p://www.cdc.gov/exposu r er epor t
Ret r ieved Ma r ch 7, 2016.
Na t ion a l In st it u t e of Dia bet es a n d Digest ive a n d
Kidn ey Disea ses. Acr om ega ly:
h t t p://en docr in e.n iddk.n ih .gov/pu bs/a cr o/a cr o.h t m
Ret r ieved Ma r ch 7, 2016.
Na t ion a l In st it u t e of Neu r ologica l Disor der s a n d
St r oke. Cer ebr a l a t r oph y:
h t t p ://w w w. n i n d s . n i h . g ov /d i s or d e r s /ce r e b r a l _
a t r oph y/cer ebr a l_a t r oph y.h t m
Ret r ieved Ma r ch 7, 2016.
Ries LAG, E isn er MP, Kosa r y CL, et a l. SE E R Ca n -
cer St a t ist ics Review, 1975–2005. Bet h esda , MD:
Na t ion a l Ca n cer In st it u t e:
h t t p://seer.ca n cer.gov/csr /1975_2005/
Ret r ieved Ma r ch 7, 2016.
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m a t t er a ir pollu t ion a n d ca r diova scu la r disea se: a n u p-
da t e t o t h e scien t ific st a t em en t fr om t h e Am er ica n H ea r t
Associa t ion . Cir cu la tion . 2010;121(21):2331–2378.
21. Am br ose J A, Ba r u a RS. Th e pa t h oph ysiology of ciga r et t e
sm okin g a n d ca r diova scu la r disea se: a n u pda t e. J Am
Coll Ca r d iol. 2004;43(10):1731–1737.
22. Wh in cu p P H , Gilg J A, E m ber son J R, et a l. Pa ssive
sm okin g a n d r isk of cor on a r y h ea r t disea se a n d st r oke:
pr ospect ive st u dy wit h cot in in e m ea su r em en t . BMJ .
2004;329(7459):200–205.
23. Pech a cek TF, Ba bb S. H ow a cu t e a n d r ever sible a r e
t h e ca r diova scu la r r isks of secon dh a n d sm oke? BMJ .
2004;328(7446):980–983.
24. U.S. Depa r t m en t of H ea lt h a n d H u m a n Ser vices. Th e
H ea lth Con sequ en ces of S m okin g—50 Yea r s of P r ogr ess:
A Repor t of th e S u r geon Gen er a l, 2014. Rockville, MD:
U.S. Depa r t m en t of H ea lt h a n d H u m a n Ser vices, Cen t er s
for Disea se Con t r ol a n d P r even t ion , Na t ion a l Cen t er for
Ch r on ic Disea se P r even t ion a n d H ea lt h P r om ot ion , Of-
fice of Sm okin g a n d H ea lt h ; 2014.
25. Pope CA III, Burnett RT, Thurston GD, et al. Cardiovas-
cular mortality and long-term exposure to particulate air
pollution: epidemiological evidence of general pathophysio-
logical pathways of disease. Circula tion. 2004;109(1):71–77.
26. Liu Y, Goodson J M, Zh a n g B. Air pollu t ion a n d a d-
ver se ca r dia c r em odelin g: clin ica l effect s a n d ba sic
m ech a n ism s. Fr on t P h ysiol. 2015;6:162. h t t p://dx.doi.
or g/10.3389/fph ys.2015.00162. Accessed J u n e 20, 2015.
27. Cen t er for Disea se Con t r ol a n d P r even t ion . CDC’s S ec-
on d Na tion a l Repor t on H u m a n E xposu r e to E n vir on -
m en ta l Ch em ica ls: S potligh t on Cotin in e. Rockville, MD:
U.S. Depa r t m en t of H ea lt h a n d H u m a n Ser vices; 2003.
 Ch a pt er

3
In fla m m a t ion a n d
Tissu e Repa ir

L E AR N I N G O U T C O ME S
1. Defin e a n d u se t h e key t er m s list ed in t h is ch a pt er.
2. Differ en t ia t e t h e t h r ee lin es of defen se.
3. Ou t lin e t h e pr ocess of a cu t e in fla m m a t ion , in clu din g t h e r ole of ch em ica l
m edia t or s.
4. Descr ibe t h e pr ocess of h ea lin g a n d r epa ir a ft er t issu e in ju r y.
5. Differ en t ia t e a cu t e a n d ch r on ic in fla m m a t ion .
6. Iden t ify t h e ca r din a l sign s of in fla m m a t ion .
7. Discu ss t r ea t m en t m et h ods u sed for a cu t e a n d ch r on ic in fla m m a t ion .
8. Apply con cept s of a cu t e a n d ch r on ic in fla m m a t ion t o select clin ica l m odels.

INTR ODUCTION
Th in k ba ck t o a ll of t h e in ju r ies, even m in or on es, t h a t you h a ve su st a in ed in
you r lifet im e. Wh en did you la st bu r n t h e r oof of you r m ou t h on h ot pizza , get a
pa per cu t , or spr a in you r a n kle? All of t h ese a ct ivit ies, a n d m a n y ot h er s, ca u se
t issu e t r a u m a t h a t r equ ir es h ea lin g. Th is ch a pt er focu ses on t h e in fla m m a t or y
r espon se, wh ich occu r s wit h a n y t ype of in ju r y. In fla m m a t ion is cr it ica l for you
t o u n der st a n d a s a st u den t in t h e h ea lt h pr ofession s. All disea se pr ocesses ca u se
in ju r y, a n d h ea lin g ca n occu r on ly wit h a n effect ive in fla m m a t or y r espon se. Th e
a cu te in fla m m a t or y r espon se is con sider ed a n expect ed body r espon se t o in ju r y;
ch r on ic in fla m m a t ion is pr esen t ed a s a n a lt er ed in fla m m a t or y r espon se be-
ca u se of u n r elen t in g in ju r y. Th e st a ges of t issu e r epa ir a n d com plica t ion s t h a t
ca n occu r du r in g t h e h ea lin g pr ocess a r e a lso det a iled in t h is ch a pt er.

Review of Body Defense Mechanisms

P r ot ect ion of t h e body depen ds on t h r ee m a jor lin es of defen se, a s depict ed in
Figu r e 3.1:
● Th e fir st lin e of defen se r elies on t h e pr ot ect ion of t h e skin a n d m u cou s
m em br a n es.
● Th e secon d lin e of defen se is wa ged t h r ou gh a n effect ive in fla m m a t or y
r espon se.
● Th e t h ir d lin e of defen se is a ct iva t ed t h r ou gh t h e im m u n e r espon se.
The skin a n d m u cou s m em br a n es com pr ise a physica l a n d ch em ica l ba r r ier t o
in va sion a n d a r e consider ed t he fir st line of defense. Skin a llows a pr ot ect ive
34
 C h a p t e r 3: In fla m m a t ion a n d Tissu e Repa ir 35

Firs t line o f de fe ns e
Blink re flex occurs Ha rmful
La s he s ca tch pa rticle s s ubs ta nce s
Te a rs wa s h pa rticle s away
Enzyme s in te a rs ne utra lize ha rmful s ubs ta nce s
Inta ct s urrounding s kin preve nts e ntry of
ha rmful s ubs ta nce s

Ina de qua te 1s t line

S e c o nd line o f de fe ns e
Infla mma tory me cha nis ms a re a ctiva te d
Va s odila tion a nd incre a s e d ca pilla ry pe rme a bility
ca us e re dne s s (e rythe ma ) a nd swe lling
P ha gocyte s move in to e ngulf a nd de s troy
ha rmful s ubs ta nce s

Third line o f de fe ns e
Immune re s pons e is a ctiva te d
Immune ce lls re cognize a nd de s troy ha rmful
s ubs ta nce s

Ade quate re s po ns e Inade quate re s po ns e

Re s olution Dis e a s e s pre a d

Figure 3.1. Lines of defense.

physica l ba r r ier a ga in st h a r m fu l subst a nces in t he Th e secon d lin e of defen se, or in fla m m a t or y r e-

ext er n a l en vir onm ent . Ar ea s n ot cover ed by skin a r e
pr ot ect ed by ch em ica lly coa t ed m u cou s m em br a nes
t ha t h elp t o neut r a lize or dest r oy m a n y h a r m ful in -
va der s. Tea r s a nd sa liva a r e exa m ples of enzym e-filled
fluids t ha t ba t h e m u cou s m em br a n es a n d offer essen -
t ia l pr ot ect ion t o t h e eyes a nd or a l cavit y. Br ea ks in
t he skin a nd m u cou s m em br a n es or loss of pr ot ec-
t ive flu ids a llow m icr oor ga nism s a n d ot her ha r m fu l
a gen t s t o en t er t he body a nd t hr ea t en hom eost a sis.
Stop and Consider
What can you do to improve or strengthen your
first line of defense?
spon se, is a ct iva t ed wh en t h e fir st lin e of defen se is
in a dequ a t e. Th e in fla m m a t or y r espon se is n on spe-
cific; t h a t is, t h e pr ocess of wa gin g a n in fla m m a t or y
r espon se is iden t ica l r ega r dless of t h e ca u se of in -
ju r y. Th e im m u n e r e s p o n s e is con sider ed t o be t h e
t h ir d lin e of defen se. Th e im m u n e r espon se wa ges
a specific defen se depen din g on t h e t ype of in va der ;
t h is is t h e focu s of Ch a pt er 4.
Stop and Consider
What lines of defense are you enhancing by put-
ting on an antibiotic ointment and covering a
laceration with a Band-Aid?
36 C h a p t e r 3: In fla m m a t ion a n d Tissu e Repa ir
Modu le 1 Ac u t e I n la m m a t io n
Acu t e in fla m m a t ion is t r igger ed by t issu e in ju r y
a n d is essen t ia l for h ea lin g. I n ju r y is defin ed in t h e
br oa dest sen se t o in clu de a n y for m of da m a ge or a l-
t er a t ion t o cells or t issu es. In ju r y ca n in clu de in va -
sion by m icr oor ga n ism s, cellu la r m u t a t ion s, h ypoxia
or a n oxia , n u t r it ion a l deficien cies, a n d ph ysica l or
ch em ica l da m a ge. Th e a cu t e in fla m m a t or y r espon se
h a s t h r ee m a jor goa ls:
1. To in cr ea se blood flow t o t h e sit e of a n in ju r y,
wh ich is r efer r ed t o a s t h e v a s c u la r r e s p o n s e
2. To a ler t t h e pr odu ct s of h ea lin g t o a t t en d t o t h e
sit e of in ju r y, wh ich is r efer r ed t o a s t h e c e llu la r
r esp on se
3. To r em ove in ju r ed t issu e a n d pr epa r e t h e sit e for
r epa ir a n d h ea lin g
The process of inflammation requires the ability to
recognize the injury, activate a response, and appro-
priately shut down the response when the injury has
passed. The result is tissue repair, regeneration, or the
formation of scar tissue. To see a video on acute inflam-
mation, visit http://thePoint.lww.com,
using the scratch-off code on the inside
front cover.
Vascular Response
Tissu e in ju r y r equ ir es a r espon se a t t h e level of t h e
blood vessel n ea r t h e sit e of t h e in ju r y. P u t sim ply,
clot t in g m u st occu r. If t h e blood vessels a r e con sid-
er ed r oa ds, in ju r y r equ ir es t h a t t h e r oa ds be wid-
en ed a n d expa n ded t o a llow for em er gen cy veh icles
t o get t o t h e scen e of t h e a cciden t . Th e object ive is t o
a t t r a ct su fficien t pr odu ct s of clot t in g a n d h ea lin g t o
t h e sit e of in ju r y a n d t o pr even t in fect ion .
An a t om ica lly, t h e st r u ct u r e of t h e blood vessels
m u st ch a n ge t o a ccom m oda t e t h is in cr ea se in em er-
gen cy veh icle t r a ffic.
● Th e blood vessels d ila t e , or widen , t o a ccom m o-
da t e in cr ea sed blood flow t o t h e sit e of in ju r y.
● Th e lin in g of t h e blood vessel becom es m or e p e r -
m e a b le , or loosen s t o a llow cells t o ea sily m ove
fr om t h e vessel in t o t h e in ju r ed t issu e.
Loosen in g of t h e blood vessel m u st occu r wit h t h e
ba sem en t m em br a n e of t h e blood vessel a n d a dja -
cen t en dot h elia l cells (Fig. 3.2). E n d o t h e lia l c e lls
for m a t igh t ju n ct ion wit h in t h e in n er lin in g of t h e
blood a n d lym ph a t ic vessels a n d t h e h ea r t . E n dot h e-
lia l cells a r e con n ect ed t o t h e ba sem en t m em br a n e.
Th e b a s e m e n t m e m b r a n e is t h e ou t er m em br a n e
S we lling
Injury s ite
Rupture d s ma ll
blood ve s s e l
with clotting
Ne utrophil
Ma cropha ge
Va s odila tion
Endothe lia l ce lls
Blood ve s s e l
Ba s e me nt
me mbra ne
Figure 3.2. Vascular response. Inflammation causes
widening of endothelial cell junctions and vasodilation.
(Modified from Werner R, Benjamin BE. A Massage Thera-
pist’s Guide to Pathology. 3rd ed. Baltimore, MD: Lippincott
Williams & Wilkins; 2005, with permission.)
of t h e vessels, wh ich sepa r a t es t h e vessel fr om t h e
t issu es of t h e body. Th e vessel wa lls a r e n eeded t o
con fin e blood cells a n d pla sm a , bu t wit h in ju r y, t h ey
m u st be loosen ed t o a llow for m ovem en t of h ea lin g
flu ids a n d cells in t o da m a ged t issu es.
In cr ea sed blood a n d flu id a r e n eeded a t t h e sit e of
t h e in ju r y for t wo r ea son s:
1. Blood is com posed of cells a ct ive in p h a g o c y t o -
s is , t h e pr ocess of en gu lfin g a n d r em ovin g h a r m -
fu l a gen t s, a s well a s cells essen t ia l in pr om ot in g
h ea lin g a n d developin g a n im m u n e r espon se.
2. In cr ea sed flu id dilu t es h a r m fu l su bst a n ces a t t h e
sit e of t h e in ju r y.
In spect ion of a scr a ped kn ee a ft er a bike a cciden t
will sh ow a la yer of wa t er y flu id t h a t seeps fr om t h e
wou n d. E x u d a t e , t h e wa t er y flu id t h a t a ccu m u la t es
a t t h e sit e of in ju r y, h a s a h igh pr ot ein a n d leu kocyt e
con cen t r a t ion . Th is is a su r e sign t h a t t h e vessels
h a ve becom e m or e per m ea ble a n d t h a t cells a ct ive in
ph a gocyt osis a r e pr esen t a n d r ea dy t o fen d off m icr o-
or ga n ism s. H ea lin g ca n t h en begin .
Th is wh ole pr ocess is or ch est r a t ed t h r ou gh t h e
wor k of pot en t ch em ica ls, r efer r ed t o a s in fla m m a -
t or y m edia t or s. I n la m m a t o r y m e d ia t o r s , specif-
ica lly va soa ct ive in fla m m a t or y m edia t or s, fa cilit a t e
t h e pr ocess of widen in g a n d loosen in g t h e blood ves-
sels a t t h e sit e of in ju r y. In fla m m a t or y m edia t or s a r e
 Ac u t e I n la m m a t io n 37

t issu e cells a r e a lso pot en t ia l sou r ces. Th e gen er a -

Tis s ue injury t ion a n d a ct iva t ion of in fla m m a t or y m edia t or s is a
Re gula te d by pla s ma com plex pr ocess. Tr y n ot t o get over wh elm ed. In t h is
prote in s ys te ms sect ion , focu s on t h e key in fla m m a t or y cells, wh er e
t h ey a r e loca t ed, exa m ples of in fla m m a t or y m edia -
t or s r elea sed fr om t h ose cells, a n d wh a t t h eir r ole is
Pro duc tio n and re le as e
o f inflammato ry me diato rs in t h e in fla m m a t or y pr ocess.
(i.e., ma s t ce lls, cytokine s )
Inflammatory Mediators Within White Blood Cells
Th e m a s t c e ll is a n im por t a n t in fla m m a t or y m e-
dia t or. Ma st cells a r e leu kocyt es (WBCs) t h a t a r e
h ou sed t h r ou gh ou t t h e con n ect ive t issu es of t h e
Vas o ac tive me diato rs , Che mo tac tic me diato rs ,
s uch a s his ta mine, body a n d n ea r a ll blood vessels. Th e pla cem en t of
or che mokine s, s timula te
le ukotrie ne s, a nd a ce llula r re s pons e t h e m a st cell a llows for a r a pid r espon se dir ect ly a t
pros ta gla ndins t h e sit e of t h e in ju r y. Ma st cells a r e sim ila r t o h a v-
in g em er gen cy fir st r espon der s t r a in ed in a ll n eigh -
bor h oods. Th ey a r e r igh t t h er e on t h e scen e. Th e
Ac tio ns Che mota xis m a st cell is r espon sible for t h e pr odu ct ion a n d im -
Va s odila tion Adhe re nce m edia t e r elea se of in fla m m a t or y m edia t or s t h r ou gh
Incre a s e d ca pilla ry Migra tion
P ha gocytos is
a pr ocess of d e g r a n u la t io n , t h e m a st cell br ea ks
pe rme a bility
a pa r t a n d r elea ses in fla m m a t or y m edia t or s in t h e
for m of ext r a cellu la r gr a n u les (gr a in -like pa r t icles).
Th e b a s o p h il, a WBC t h a t a lso con t a in s gr a n u les,
fu n ct ion s in t h e sa m e m a n n er. E xa m ples of in fla m -
Manife s tatio ns Ac ute Chro nic m a t or y m edia t or s r elea sed by m a st cells in clu de h is-
Loca lize d re dne s s, inflammatio n inflammatio n
he a t, swe lling, pa in,
t a m in e, leu kot r ien es, a n d pr ost a gla n din s.
P MNs Ma cropha ge s
los s of function P la te le ts Lymphocyte s
Ma s t ce lls Stop and Consider
Where have you heard the names of the various
inflammatory mediators listed above? What do
Figure 3.3. Concept map. An overview of the importance of you already know about these inflammatory
chemical mediators in the vascular and cellular responses of mediators?
inflammation. PMNs, polymorphonuclear neutrophils. (Modi-
fied from Rubin E, Farber JL. Pathology. 4th ed. Philadelphia, Sign a ls t o t r igger, en h a n ce, a n d discon t in u e t h e
PA: Lippincott Williams & Wilkins; 2005, with permission.) in fla m m a t or y r espon se a r e a lso gen er a t ed wit h in
ot h er WBCs, su ch a s lym ph ocyt es a n d m on ocyt es/
m a cr oph a ges. For exa m ple, c y t o k in e s a r e m or e
loca t ed in t h e blood pla sm a a n d in m a n y cells, in -
t h a n a h u n dr ed dist in ct cell pr ot ein s m ost oft en
clu din g pla t elet s, m a st cells, ba soph ils, n eu t r oph ils,
fou n d wit h in WBCs t h a t h a ve a vit a l r ole in r egu la t -
en dot h elia l cells, m on ocyt es, a n d m a cr oph a ges.
in g in fla m m a t ion ; t h ey a r e a ct ive fr om t h e on set of
Th e loca t ion of in fla m m a t or y m edia t or s is im por t -
va sodila t ion a n d in cr ea sed va scu la r per m ea bilit y t o
a n t ; t h ese su bst a n ces m u st be con st a n t ly r ea dy t o
t h e r esolu t ion of t h e in fla m m a t or y r espon se. E a ch of
r espon d t o in ju r y a n ywh er e in t h e body. F igu r e 3.3
t h e differ en t cyt okin es is r elea sed fr om a specific cell
illu st r a t es t h e m a jor r oles of t h e in fla m m a t or y m e-
a n d ser ves a specific pu r pose. For exa m ple, cyt okin es
dia t or s in t h e in fla m m a t or y pr ocess. Refer t o t h is
r elea sed fr om lym ph ocyt es a r e ca lled lym ph okin es.
figu r e fr equ en t ly a s you m ove t h r ou gh t h is ch a pt er.
Th ose r elea sed fr om m on ocyt es or m a cr oph a ges a r e
ca lled m on okin es. Ot h er exa m ples of cyt okin es in -
INFLAMMATORY MEDIATORS WITHIN CELLS clu de in t er leu kin s, gr owt h fa ct or s, in t er fer on s, a n d
ch em okin es. Now t r y n ot t o h yper ven t ila t e h er e. Th e
As m en t ion ed, som e in fla m m a t or y m edia t or s a r e
m a in poin t is t h a t pot en t in fla m m a t or y m edia t or s
for m ed wit h in t h e blood pla sm a a n d som e a r e
a r e r elea sed fr om a va r iet y of WBCs in or der t o effec-
for m ed wit h in cells. Wit h in cells, m ost of t h ese in -
t ively or ch est r a t e t h e in fla m m a t or y pr ocess.
fla m m a t or y m edia t or s a r e gen er a t ed in t h e cell
pla sm a m em br a n e or a r e m a de u p of pr ot ein s wit h in
Inflammatory Mediators Within Platelets
t h e cell. Most com m on ly, it is t h e wh it e blood cells
(WBCs) t h a t pr odu ce a n d r elea se in fla m m a t or y P la t elet s a r e a lso a ct ive in gen er a t in g a n d r elea sin g
m edia t or s; pla t elet s, en dot h elia l cells, a n d in ju r ed in fla m m a t or y m edia t or s t o pr om ot e va sodila t ion ,
38 C h a p t e r 3: In fla m m a t ion a n d Tissu e Repa ir
clot t in g, a t t r a ct ion of WBCs, a n d h ea lin g of in ju r ed
t issu es. Ser ot on in is on e exa m ple of a n in fla m m a -
t or y m edia t or fou n d in pla t elet s. Ser ot on in ca u ses
va sodila t ion a n d in cr ea sed va scu la r per m ea bilit y,
a llowin g cells of h ea lin g t o a r r ive qu ickly t o t h e sit e
of in ju r y. H ist a m in e, wh ich fu n ct ion s sim ila r ly t o se-
r ot on in , is fou n d in bot h WBCs a n d pla t elet s.
Inflammatory Mediators Within Endothelial or
Injured Tissue Cells
In fla m m a t or y m edia t or s ca n a lso be r elea sed fr om
en dot h elia l cells or in ju r ed t issu e cells. For exa m ple,
p la t e le t -a c t iv a t in g a c t o r is a com plex lipid st or ed
in cell m em br a n es, in clu din g t h ose of en dot h elia l
cells t h a t lin e blood vessels, a n d in m a n y ot h er t ypes
of cells t h a t ca n becom e in ju r ed. P la t elet -a ct iva t in g
fa ct or is a pot en t in fla m m a t or y m edia t or t h a t h a s a
key r ole in pr om ot in g vessel va sodila t ion , clot t in g,
a n d a t t r a ct in g in fect ion -figh t in g WBCs t o t h e sit e of
in ju r y.
An ot h er exa m ple is a r a ch idon ic a cid. Ar a c h i-
d o n ic a c id is a su bst a n ce der ived fr om t h e pla sm a
m em br a n e of a n in ju r ed cell, wh ich gen er a t es va r iou s
in fla m m a t or y m edia t or s t h r ou gh a com plex ch em ica l
con ver sion . In fla m m a t or y m edia t or s a ssocia t ed wit h
a r a ch idon ic a cid in clu de pr ost a gla n din s, lipoxin s,
leu kot r ien es, a n d t h r om boxa n e. Th ese in fla m m a t or y
m edia t or s a r e a ct ive in t h e pr ocesses of va sodila t ion
a n d va socon st r ict ion , in cr ea sin g va scu la r per m ea -
bilit y, br on ch odila t ion a n d br on ch ocon st r ict ion , a n d
a t t r a ct ion of leu kocyt es. Cor t icost er oids a r e a h igh ly
effect ive gr ou p of a n t i-in fla m m a t or y dr u gs t h a t wor k
t o block t h e pr odu ct ion of a r a ch idon ic a cid, t h er eby
decr ea sin g t h e in fla m m a t or y r espon se. Cor t icost e-
r oids a lso h a ve a r ole on in h ib-
it in g t h e im m u n e r espon se, a s
discu ssed in Ch a pt er 4.
Stop and Consider Ta b le 3.1 Con t in u ou sly Cir cu la t in g a n d In t er r ela t ed P la sm a
Syst em s Th a t Regu la t e In fla m m a t ion
Why would you want to
block the production Syst em
of arachidonic acid and
inhibit the work of the Com plem en t
inflammatory mediators?
INFLAMMATORY MEDIATORS
WITHIN PLASMA
In fla m m a t or y m edia t or s ca n Clot t in g
also circulate continuously wit h in
blood pla sm a . Th is is u su a lly a c-
com plish ed t h r ou gh t h e wor k of
t h r ee m a jor in t er r ela t ed pa t h - Kin in
wa ys. Th ese pa t h wa ys a r e r e-
spon sible for t h e a ct iva t ion a n d
dea ct iva t ion of in fla m m a t or y
m edia t or s t h a t cir cu la t e in t h e pla sm a . Ta ble 3.1
su m m a r izes t h ese t h r ee pa t h wa ys.
Mu lt iple sou r ces a n d pa t h wa ys t o in du ce a n d
su ppr ess in fla m m a t ion a r e n ecessa r y beca u se t h e
in fla m m a t or y r espon se m u st occu r t o h ea l t issu es,
a n d t h e in fla m m a t or y m edia t or s a r e so poten t a n d
power fu l t h a t m u lt iple pa t h wa ys a r e n eeded t o r eg-
u la t e t h ese su bst a n ces. Im pa ir ed a ct iva t ion of in -
fla m m a t ion ca n lea d t o in a dequ a t e blood flow t o t h e
in ju r ed a r ea . Th is will im pa ir h ea lin g by lim it in g
ph a gocyt osis, clot for m a t ion , a n d r epa ir of in ju r ed
t issu es. Im pa ir ed in h ibit ion of in fla m m a t ion ca n
lea d t o a n u n con t r olled in fla m m a t or y r espon se, t h e
deplet ion of pr ot ein s n eeded wit h in t h e t h r ee pa t h -
wa ys (com plem en t , clot t in g, a n d kin in ). Loss of t h e
a bilit y t o sh u t down t h e in fla m m a t or y r espon se ef-
fect ively ca n a lso lea d t o a u t o im m u n it y , a self-a t -
t a ck a ga in st body t issu es.
To su m m a r ize, t h e in it ia l st eps in t h e in fla m m a -
t or y r espon se in flu en ced by va soa ct ive in fla m m a -
t or y m edia t or s in clu de:
● Tissu e in ju r y
● Blood vessel va sodila t ion
● In cr ea sed va scu la r per m ea bilit y
● Clot t in g ca sca de a ct iva t ed
● Con t in u ed r elea se a n d cir cu la t ion of va soa ct ive
in fla m m a t or y m edia t or s
Cellular Response
Aft er t h e vessels a r e dila t ed a n d per m ea ble, t h e cells
essen t ia l for hea lin g a r e n eeded a t t h e sit e of in ju r y.
As wit h t he va scu la r r espon se, t h e cellu la r r espon se
Ke y C h a r a c t e r is t ic s
Sever a l pr ot ein s t h a t com pr ise 10%–15% of pla sm a ; pr odu ced
in liver
Tr igger ed by t h e pr esen ce of m icr oor ga n ism s
On ce t r igger ed, a ct iva t es a ca sca de of in fla m m a t or y m edia t or s
P r im a r y r ole t o dest r oy a n d r em ove m icr oor ga n ism s t o pr e-
ven t in fect ion t h r ou gh o p s o n iza t io n (m a kin g ba ct er ia vu l-
n er a ble t o ph a gocyt osis) a n d cell ly s is (dest r u ct ion )
P r om ot es coa gu la t ion t h r ou gh a ca sca de of clot t in g fa ct or s
Su ppr esses coa gu la t ion wh en clot t in g is com plet e
Va r iou s clot t in g fa ct or s pr odu ce a n d r elea se in fla m m a t or y
m edia t or s
Sou r ce of h igh ly pot en t va soa ct ive in fla m m a t or y m edia t or s
Am plify t h e in fla m m a t or y r espon se by t r igger in g ot h er in -
fla m m a t or y m edia t or s

Infla mma tion
Blood flow
Che mota xis
Figure 3.4. Cellular response: chemotaxis, adherence, and migration. (Modified from Rubin E, Farber JL. Pathology. 4th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2005, with permission.)
is r egu la t ed by in fla m m a t or y m e-
dia t or s. Thr ee st eps a r e n eeded Ta b le 3.2
for a su ccessfu l cellu la r r espon se:
C e ll
(1) ch em ot a xis, (2) cellu la r a d-
h er en ce, a n d (3) cellula r m igr a - Leu kocyt es (WBCs)
t ion (Fig. 3.4). Neu t r oph ils
C h e m o t a x is is a pr ocess of Ma cr oph a ges
m ovin g cer t a in cells t o t h e sit e
of in ju r y. Specific in fla m m a t or y
m edia t or s, r efer r ed t o a s c h e - E r yt h r ocyt e (r ed blood
m o t a c t ic a c t o r s , a r e a ct iva t ed, cells)
wh ich a t t r a ct specific t ypes of P la t elet s
cells. Th e n eu t r oph il ch em ot a ct ic
fa ct or a t t r a ct s n eu t r oph ils. Th e WBC, wh it e blood cell.
eosin oph il ch em ot a ct ic fa ct or a t -
t r a ct s eosin oph ils, a n d so for t h .
Blood cells a r e con st a n t ly m ovin g t h r ou gh t h e
va scu la r syst em . At t r a ct ion a n d bin din g, or cellu la r
a d h e r e n c e , is a n ot h er st ep essen t ia l for effect ive
ph a gocyt osis. Cellu la r a dh er en ce is r egu la t ed by:
● In fla m m a t or y m edia t or s, specifica lly, ch em ot a ct ic
fa ct or s r elea sed by en dot h elia l cells
● Recept or s t h a t bin d leu kocyt es t o t h e su r fa ce of
en dot h elia l cells n ea r t h e sit e of in ju r y
Cellu la r m igr a t ion is t h e t h ir d essen t ia l st ep in t h e
cellu la r r espon se. Th e cellu la r r espon se depen ds
on t h e a bilit y of cells, pr im a r ily leu kocyt es, er yt h -
r ocyt es, a n d pla t elet s, t o m igr a t e, or m ove a cr oss,
en dot h elia l cells a n d get t o t h e exa ct sit e of t h e in -
ju r y. In t h e pr ocess of d ia p e d e s is , cells ca n m ove
bet ween a n d t h r ou gh en dot h elia l ju n ct ion s. Th e r ole
of t h e m a jor cells a ct iva t ed in t h e cellu la r r espon se
is su m m a r ized in Ta ble 3.2. Leu kocyt e is a globa l
t er m for m a n y differ en t t ypes of WBCs, in clu din g
n eu t r oph ils, m on ocyt es, m a cr oph a ges, m a st cells, ba -
soph ils, a n d T a n d B lym ph ocyt es. Beca u se t h er e is
ext en sive cr ossover of cellu la r a ct ivit y bet ween t h e
Ac u t e I n la m m a t io n 39
Endothe lia l ce lls
Ce llula r Ce llula r
a dhe re nce migra tion
Cells Act ive in t h e Cellu la r Respon se
R o le
P h a gocyt osis; r em ova l of dea d t issu e
A t ype of WBC; ea r liest ph a gocyt ic r espon der s
A t ype of WBC; la r ge, lon g-lived ph a gocyt es a sso-
cia t ed wit h a pr olon ged (ch r on ic) in fla m m a t or y
r espon se; m on ocyt es a r e im m a t u r e m a cr oph a ges
Ca r r y oxygen t o t issu es
Tr a p h a r m fu l su bst a n ces; st op bleedin g; for m
st r u ct u r a l or igin of r epa ir
in fla m m a t or y r espon se, im m u n e r espon se, a n d t h e
su bsequ en t developm en t of in fect ion , t h is discu ssion
of t h e cells will con t in u e in t o t h e n ext t wo ch a pt er s
a n d beyon d.
Du r in g ph a gocyt osis, in fla m m a t or y cells r elea se
in fla m m a t or y m edia t or s t o a t t r a ct m or e n eu t r o-
ph ils. Th e n eu t r oph il it self a lso r elea ses pot en t
in fla m m a t or y m edia t or s a s it wor ks t o en gu lf a n d
digest im pa ir ed t issu e. Du r in g t h is a ggr essive pr o-
cess, u n a ffect ed, h ea lt h y t issu e is a lso dest r oyed.
Tissu e dest r u ct ion is m in im ized by t h e wor k of in -
h ibit or pr ot ein s in t h e pla sm a -der ived com plem en t ,
clot t in g, a n d kin in syst em s.
GENERAL MANIFESTATIONS
Th e loca l m a n ifest a t ion s of a cu t e in fla m m a t ion
a r e oft en r efer r ed t o a s t h e c a r d in a l s ig n s . Th ese
sign s in clu de e r y t h e m a (r edn ess), h ea t , swellin g,
pa in , a n d loss of fu n ct ion . Ly m p h a d e n it is , or en -
la r gem en t a n d in fla m m a t ion of t h e n ea r by lym ph
n odes, ca n occu r a s a fu n ct ion of filt er in g or dr a in in g
40 C h a p t e r 3: In fla m m a t ion a n d Tissu e Repa ir

h a r m fu l su bst a n ces a t t h e in ju r y
sit e. Loca l m a n ifest a t ion s wit h Ta b le 3.3 Loca l Ma n ifest a t ion s of Acu t e In fla m m a t ion
r a t ion a les a r e pr esen t ed in Ta ble
Ma n i e s t a t io n R a t io n a le
3.3. Th ese m a n ifest a t ion s a r e pr i-
m a r ily r ela t ed t o va sodila t ion a n d Redn ess (er yt h em a ) Va sodila t ion ; in cr ea sed blood flow t o t h e in ju r ed a r ea
flu id a ccu m u la t ion in t h e t issu es H ea t Va sodila t ion ; in cr ea sed blood flow t o t h e in ju r ed a r ea
a s a r esu lt of t h e a ct iva t ion of in - In ca pa cit a t ion Loss of fu n ct ion is r ela t ed t o t issu e da m a ge fr om in ju r y,
fla m m a t or y m edia t or s. pa in , a n d swellin g a t t h e sit e
Systemic manifestations related Pa in In cr ea sed va scu la r per m ea bilit y a n d a ccu m u la t ion of
to the inflammatory response in- flu id ca u ses com pr ession in t h e t issu es; in fla m m a t or y
clude fever, leukocytosis, and a m edia t or s ca n a lso dir ect ly elicit a pa in r espon se
higher percentage of circulating E xu da t e a n d edem a E xt r a cellu la r flu id a ccu m u la t ion oft en in t issu es be-
plasma proteins. P yr e xia , or fever ca u se of in cr ea sed va scu la r per m ea bilit y
(an elevated core body tempera-
ture), is a result of inflammatory
mediators acting directly on the hypothalamus. The wh ich expla in s t h e effor t s of t h e boom in g ph a r m a -
hypothalamus is responsible for controlling body tem- ceu t ica l in du st r y t o fin d effect ive a n t i-in fla m m a -
perature. An elevated body temperature stimulates t or y dr u gs. Da m a ge t o h ea lt h y su r r ou n din g t issu e
phagocytosis and can also inhibit the growth of cer- is a com m on occu r r en ce in t h e a cu t e in fla m m a t or y
tain microorganisms. Le u k ocyt osis is an elevation r espon se. Th er efor e, t h e in it ia l t r ea t m en t pr in ciples
in WBCs, or leukocytes, with a count usually above for a cu t e in fla m m a t ion a r e t o:
10,000/mm 3. Typically, the individual has a WBC count
1. Redu ce blood flow t o t h e loca l a r ea
of 5,000 to 10,000/mm 3. All laboratory information is
2. Decr ea se swellin g
approximate because variability in laboratory ranges
3. Block t h e a ct ion of va r iou s in fla m m a t or y
exists among various populations and sources. Leuko-
m edia t or s
cytosis demonstrates the increased circulation of WBCs
4. Decr ea se pa in
to aid in healing. Plasma proteins are also increased
as a result of the three
plasma protein systems
discussed previously. These
proteins are called acute- R E S E AR C H N O T E S
phase reactants and can be In a recent issue of Inflammation Research, scientists are uncovering new ways of thinking
measured through the use about pharmacologic treatment for inflammation. Current therapy targets one aspect of the
of laboratory tests, such as inflammatory process (e.g., blocking the production of arachidonic acid). Emerging research
C-reactive protein (CRP). is demonstrating a significant value of designer drugs created to target several aspects
Common blood tests used of tissue repair. Such drugs combine actions of multiple cells and chemicals to regulate
to detect inflammation are the complex metabolic and immune pathways underlying inflammation. The authors note,
presented in Table 3.4. “addressing multiple targets of inflammation holistically, in moderation, is probably a more
evolutionarily viable strategy, as compared to current therapy, which addresses drug targets
Stop and in isolation.”1
Consider
What does an el-
evation in leuko-
cytes, erythrocyte
sedimentation rate
F R O M T H E L AB
(ESR), or CRP lev-
els tell you about CRP and the erythrocyte sedimentation rate (ESR) are two nonspecific tests of inflamma-
the location of tion. Elevations in either test will signify inflammation is present, but neither will identify
acute or chronic the exact source or location of the inflammation. CRP is often the preferred test for acute
inflammation? inflammation. CRP signifies the presence of a specific protein triggered by plasma protein
systems during the inflammatory process. The erythrocyte sedimentation rate (also referred
to as a sed rate) is a nonspecific method of testing for inflammation. During the inflamma-
TREATMENT
tory process, the coagulation cascade results in increased circulating levels of fibrinogen,
Th e in fla m m a t or y r e- which causes cells to stick together. When measured in a tube in the lab, red blood cells
spon se has m u lt iple (RBCs) exposed to the inflammatory process will fall faster and will clump together. The ESR
com pon en t s a n d is oft en test then measures (in mm/ hr) the level of RBC stacking. 2
con sider ed “over zea lou s,”
 Ac u t e I n la m m a t io n 41

Ta b le 3.4 Com m on Blood Test s Used t o Det ect Acu t e In fla m m a t ion
B lo o d Te s t R e e r e n c e Va lu e s C h a n g e s Wit h I n la m m a t io n

Wh it e blood cell cou n t 5,000–10,000 cells/m m 3 Cir cu la t in g wh it e blood cells a r e in cr ea sed,

Wh it e blood cell
differ en t ia l
E r yt h r ocyt e sedim en t a t ion
rate
C-r ea ct ive pr ot ein
Com plem en t a ct ivit y
P r ot h r om bin t im e
Fibr in ogen
oft en a bove 10,000/m m 3
Neu t r oph ils, 45%–75% Mea su r es pr opor t ion of ea ch of t h e five t ypes
Ba n ds (im m a t u r e n eu t r oph ils), 0%–5% of wh it e blood cells; t h e pr opor t ion of im m a -
t u r e n eu t r oph ils (ba n ds) is in cr ea sed in com -
E osin oph ils, 0%–8% pa r ison t o ot h er wh it e blood cell t ypes
Ba soph ils, 0%–3%
Lym ph ocyt es, 16%–46%
Mon ocyt es, 4%–11%
0–17 m m /h r for m en Det ect s r ed blood cell clu m pin g or st a ckin g
1–25 m m /h r for wom en a s a r esu lt of in cr ea sed fibr in ogen levels;
levels in cr ea se, oft en a bove 100 m m /h r for
44–114 m m /h r in pr egn a n cy t h ose wit h in fla m m a t ion
1–13 m m /h r for ch ildr en
Rou t in e CRP , 10 m g/L . 10 m g/L in dica t es sign ifica n t in fla m m a -
H igh sen sit ivit y CRP, 0.1–3.8 m g/L t or y disea se
Tot a l com plem en t , 63–145 U/m L E leva t ed in in fla m m a t ion sign ifyin g t h e
C3 (com pr ises 70% of t ot a l pr ot ein in a ct iva t ion of com plem en t ; over t im e m ay
t h e com plem en t syst em ), 80–184 m g/dL decr ea se, in dica t in g t h a t com plem en t fa ct or s
a r e exh a u st ed
Mea su r ed in t im e t o coa gu la t e, a ppr oxi- In cr ea sed pr ot h r om bin levels r esu lt in a r e-
m a t ely 11.2–13.2 secon ds du ced t im e t o coa gu la t e
175–400 m g/dL E leva t ed du r in g in fla m m a t ion t o pr om ot e
coa gu la t ion

CRP, C-r ea ct ive pr ot ein .

Th e goa l of t r ea t m en t is t o m in im ize da m a ge t o kin in ), a lon g wit h t h e r eleva n t in fla m m a t or y m edia -

h ea lt h y, u n a ffect ed t issu e a n d pr om ot e r a pid h ea lin g.
P h a r m a cologic, or dr u g t r ea t m en t s for in fla m m a t ion
m ost com m on ly block t h e a ct ion of in fla m m a t or y
m edia t or s, t h er eby r edu cin g t h e swellin g, pa in , r ed-
n ess, a n d wa r m t h t ypica l of in fla m m a t ion . Ta ble 3.5
illu st r a t es t h e a ct ion s of com m on ph a r m a cologic
t r ea t m en t s for in fla m m a t ion . Non ph a r m a cologic
t r ea t m en t s for in fla m m a t ion in it ia lly in clu de r est ,
ice, com pr ession , a n d eleva t ion . On ce t h e in it ia l
t r ea t m en t h a s been em ployed, r esolu t ion m a y im -
pr ove wit h t h e a pplica t ion of wa r m t h /h ea t a n d in -
cr ea sed m ovem en t . As wit h a ll h ea lt h con dit ion s,
opt im a l flu id a n d n u t r it ion a l in t a ke is n eeded t o fa -
cilit a t e h ea lin g.
Stop and Consider
The RICE (rest, ice, compression, elevation) pro-
tocol is employed frequently in acute injury to
minimize the effects of inflammation. How does
each of these components reduce inflammation?
RESOLUTION OF ACUTE INFLAMMATION
Th e a cu t e in fla m m a t or y r espon se is self-lim it ed.
On ce t h e offen din g a gen t h a s been dest r oyed a n d
r em oved, feedba ck syst em s r egu la t ed by t h e t h r ee
pla sm a pr ot ein syst em s (clot t in g, com plem en t , a n d
t or s, dea ct iva t e t h e in fla m m a t or y r espon se, a llowin g
t h e t issu e t o h ea l.
Ta b le 3.5 Com m on P h a r m a cologic Agen t s
Used t o Tr ea t In fla m m a t ion
P h a r m a c o lo g ic
Ag e n t Ac t io n
Aspir in In h ibit s t h e con ver sion of a r a ch i-
don ic a cid t o pr ost a gla n din s t o
su ppr ess in fla m m a t ion , r edu ce pa in ,
a n d r edu ce fever
Non st er oida l a n t i- Sim ila r to a spir in ; in h ibit th e a n ti-in -
in fla m m a t or y flam ma tor y con version of ar a ch idon ic
dr u gs a cid t o pr osta glan din s (NSAIDs) E x-
a mples: ibu pr ofen , n a pr oxen
Glu cocor t icoids Act t h r ou gh sever a l m ech a n ism s
t o in t er r u pt t h e in fla m m a t or y pr o-
cess: in h ibit syn t h esis of ch em ica l
m edia t or s a n d r edu ce swellin g,
wa r m t h , r edn ess, a n d pa in ; su ppr ess
in filt r a t ion of ph a gocyt es a n d a ver t
t issu e da m a ge fr om r elea se of lyt ic
(cell-dest r oyin g) en zym es; su ppr ess
lym ph ocyt e pr olifer a t ion ; a n d r e-
du ce im m u n e com pon en t of in fla m -
m a t ion . E xa m ple: pr edn ison e
NSAIDs, n on st er oida l a n t i-in fla m m a t or y dr u gs.
42 C h a p t e r 3: In fla m m a t ion a n d Tissu e Repa ir

Modu le 2 H e a lin g a n d Tis s u e R e p a ir

Tissu e r epa ir is sim ila r t o h om e r epa ir. If a h om e is

da m a ged, t h e dest r oyed a r ea n eeds t o be sea led off In ju ry
t o pr even t fu r t h er exposu r e t o t h e ext er n a l en vir on -
m en t . Th en a pr ocess ca n begin t o clea r t h e debr is,
r ebu ild t h e wa lls a n d r oof, a n d r est or e t h e in t er ior
wor kin g con t en t s of t h e h om e, su ch a s t h e elect r i- Ac u te in fla m m a to ry
re s p o n s e
ca l syst em , a pplia n ces, or h ea t in g syst em . Likewise,
t h e goa l of t issu e h ea lin g a n d r epa ir is t o sea l t h e Infla mma tory
wou n d, clea r t h e debr is, a n d r est or e t h e st r u ct u r a l pha s e
a n d fu n ct ion a l in t egr it y of t h e in ju r ed a r ea . Th is Cove r the wo und
pr ocess is oft en divided in t o t h r ee ph a ses: t h e in - He mos ta s is
- pla te le ts re le a s e d
fla m m a t or y ph a se, t h e pr olifer a t ive ph a se, a n d t h e - blood ve s s e ls cons trict
r em odelin g ph a se. Wit h in t h ese ph a ses, st r u ct u r a l Thrombus forms
su ppor t s m u st be r ebu ilt a n d fu n ct ion a l cells a n d
t issu es r egen er a t ed or r epla ced (Fig. 3.5).
Th e con st r u ct ion wor ker s of t issu e r epa ir fit in t o Cle an the de bris
t h e followin g ca t egor ies: P MNs
Ma cropha ge s
● Clot t in g (coa gu la t ion ) fa ct or s t o st op bleedin g a n d Re move ne crotic tis s ue
for m a fibr in clot
● In fla m m a t or y m edia t or s t o pr om ot e ch em ot a xis P rolife ra tive
t o t h e a ffect ed a r ea Re s to re s truc tural inte g rity pha s e
● P r ot ein a ses (en zym es) t o degr a de dea d t issu e P rovis iona l ma trix
● P r ot ein a se in h ibit or s t o pr even t h ea lt h y t issu e -gra nula tion tis s ue
Re build ECM
br ea kdown - ba s e me nt me mbra ne
● Ma t r ix, or st r u ct u r a l, pr ot ein s t o r ebu ild a r ch it ec- - conne ctive tis s ue
t u r a l su ppor t s
● Molecu le r ecept or s t o a t t r a ct cells n eeded t o for m
a st r u ct u r a l m a t r ix
Re s to re func tio nal inte g rity
● Adh esion m olecu les t o pr ovide “st ickin ess” t o Re s olution
t h ese cells Re pa ir
● Gr owt h fa ct or s t o pr om ot e r egen er a t ion of n ew Re ge ne ra tion
Re mode ling
cells a n d t issu es pha s e

Sealing the Wound
In fla m m a t or y m edia t or s r elea sed fr om pla t elet s a n d
ot h er cells con st r ict blood vessels a n d for m a clot a t
t h e sit e. A pr ot ect ive sca b is for m ed fr om dr ied blood
a n d exu da t e. Th is pr ot ect ive clot a n d su bsequ en t
sca b is a lso ca lled a t h r o m b u s . Th e r ole of t h e t h r om -
bu s is t o for m a ph ysica l ba r r ier t o pr even t a ddit ion a l
h a r m fu l su bst a n ces fr om en t er in g t h e wou n d. Th is
cover in g a lso pr even t s t h e loss of pla sm a . E pit h elia l
(skin ) cells r egen er a t e u n der t h e t h r om bu s. On ce
r eepit h elia liza t ion is com plet e, en zym es degr a de t h e
sca b. To see a video on h em ost a sis, visit
h t t p://t h ePoin t .lww.com .
Stop and Consider
Why is it not a good idea to pick off a scab be-
fore a wound has healed?
Re mo de ling
Ma tura tion of ce lls
De gra da tion of provis iona l
ma trix
Figure 3.5. Concept map. Phases of healing and tissue
repair. ECM, extracellular matrix; PMNs, polymorphonuclear
neutrophils.
Clearing the Debris
Ch em ica l m edia t or s a ct iva t e n eu t r oph ils t o m ove
in t o t h e in ju r ed a r ea a n d begin t h e wor k of h ea lin g.
Th e in fla m m a t or y r espon se a ct iva t es n eu t r oph ils
a n d la t er m a cr oph a ges t o en gu lf, digest , a n d r em ove
h a r m fu l su bst a n ces a n d debr is. Th e pr ocess of h ea l-
in g ca n n ot begin u n t il t h e n ecr ot ic cells a n d t issu es
a r e r em oved.

Restoring Structural Integrity
Rest or in g st r u ct u r a l in t egr it y depen ds on t h e deli-
ca t e ba la n ce of t issu e dest r u ct ion a n d con st r u ct ion .
Tissu e lysis, or br ea kdown a n d r em ova l, is a ccom -
plish ed t h r ou gh t h e wor k of en zym es t h a t a r e n eeded
t o r id t h e body of t h e da m a ged t issu e. Gr owt h fa c-
t or s a n d m a t r ix pr ot ein s a r e r espon sible for r ebu ild-
in g t h e e x t r a c e llu la r m a t r ix (E CM), t h e la yer s of
a r ch it ect u r a l st r u ct u r es t h a t su ppor t t h e cells.
E xt r a cellu la r m a t r ices in clu de t h e ba sem en t
m em br a n e a n d con n ect ive t issu e la yer s. Th e ba se-
m en t m em br a n e ser ves t o:
1. P r ovide a su ppor t ive a r ch it ect u r a l st r u ct u r e
2. Su ppor t r e e p it h e lia liza t io n , or t h e m ovem en t of
epit h elia l cells t o for m a cover in g over t h e wou n d
3. St or e gr owt h fa ct or s
4. Rest or e n eu r om u scu la r fu n ct ion
5. Su ppor t t h e developm en t of p a r e n c h y m a l t is-
su es, t h a t is, t h ose t issu es m a de u p of cells wit h
a specific fu n ct ion (su ch a s n eu r on s, m yoca r dia l
cells, a n d epit h elia l cells)
Th e ba sem en t m em br a n e is r epr odu ced by en dot h e-
lia l, epit h elia l, m u scle, a dipose (fa t ), a n d Sch wa n n
(n er ve fiber ) cells. Th e ba sem en t m em br a n e m u st
be r est or ed befor e r eepit h elia liza t ion ca n occu r.
Ma cropha ge Amorphous inte rce llula r s ubs ta nce
Colla ge nic
fibe r
Ma s t ce ll
Ela s tic
fibe r
Fibrobla s t
Endothe lia l ce ll a nd pe ricyte
of ca pilla ry
H e a lin g a n d Tis s u e R e p a ir 43
E xt en sive da m a ge t o t h e ba sem en t m em br a n e is a
h in dr a n ce t o r eepit h elia liza t ion beca u se t h e ba se-
m en t m em br a n e m u st be r epla ced fir st .
An ot h er st r u ct u r a l E CM is con n ect ive t issu e
(Fig. 3.6). Th e con n ect ive t issu e la yer is com posed
pr im a r ily of colla gen , ela st in , a n d glycopr ot ein s. Th is
la yer is a lso r efer r ed t o a s st r om a l or in t er st it ia l t is-
su e. Th e con n ect ive t issu e la yer pr ovides st or a ge of
pr ot ein s, a n exch a n ge m ediu m bet ween pr ot ein s a n d
ot h er cells, a n d a r ch it ect u r a l su ppor t a n d ph ysica l
pr ot ect ion fr om t r a u m a by r esist in g st r et ch in g or
com pr essin g of t issu es. Cells su ch a s fibr obla st s, a di-
pose cells, en dot h elia l cells, ost eocyt es, a n d ch on dr o-
cyt es st im u la t e t h e r epla cem en t of con n ect ive t issu e.
F ib r o b la s t s a r e im por t a n t cells t h a t pr odu ce a n d
r epla ce t h e con n ect ive t issu e la yer. F ibr obla st s a r e
st im u la t ed by m a cr oph a ges. Th e fibr obla st m oves
in t o t h e a r ea t o su ppor t t h e con st r u ct ive ph a se of
wou n d h ea lin g. Fibr obla st s a ct ively m a n u fa ct u r e
a n d secr et e colla gen . C o lla g e n h elps t o fill in t h e
ga ps left a ft er t h e r em ova l of da m a ged t issu es. E x-
cess colla gen pr odu ct ion lea ds t o t issu e fibr osis a n d
ca n r esu lt in sca r r in g a t t h e sit e of in ju r y.
Th e con n ect ive t issu e la yer is a lso com posed of
ela st in a n d glycopr ot ein s. E la s t in a llows st r et ch in g
a n d r ecoil of t issu e. E la st in is r esist a n t t o da m a ge,
bu t is a lso slow a n d difficu lt t o r epla ce. Da m a ged
P la s ma ce ll
Fa t ce ll
Figure 3.6. Diagram of cells that
may be seen in loose connective
tissue. The cells lie in the extra-
cellular matrix that is bathed in
tissue fluid that originates in cap-
illaries. (From Cormack DH. Ham’s
Blood
ve s s e l
Histology. 9th ed. Philadelphia,
PA: J. B. Lippincott; 1987, with
S mooth mus cle ce ll
permission.)
44 C h a p t e r 3: In fla m m a t ion a n d Tissu e Repa ir
t issu e is oft en less flexible a ft er in ju r y. Glycopr ot ein s
a r e essen t ia l wit h in t h e ba sem en t m em br a n e a n d
con n ect ive t issu e la yer. G ly c o p r o t e in s r egu la t e cell
m ovem en t a cr oss t h e m a t r ix, pr ovide a pla ce for a t -
t a ch m en t of t h e cells t o t h e m a t r ix, a n d pr om pt t h e
cells t o fu n ct ion .
Ba sem en t m em br a n es a n d con n ect ive t issu e la y-
er s a r e con t in u ou sly pr esen t a n d m u st be r epla ced t o
su ppor t a r ch it ect u r a l st r u ct u r e a n d t issu e fu n ct ion .
A t h ir d, t em por a r y E CM a lso for m s in r espon se t o
in ju r y. Th is t em por a r y m a t r ix, ca lled a p r o v is io n a l
m a t r ix , pr om ot es h ea lin g by decr ea sin g blood a n d
flu id loss a t t h e sit e a n d a t t r a ct in g a n d su ppor t in g
fibr obla st s, en dot h elia l cells, a n d epider m a l (skin )
cells. Wh en a n in ju r y occu r s, in cr ea sed va scu la r per-
m ea bilit y a llows pr ot ein s fr om t h e pla sm a t o m ove
t o t h e sit e a n d for m t h is pr ovision a l pr ot ect ive la yer.
Ma cr oph a ge a ct ivit y con ver t s t h is pr ovision a l
m a t r ix in t o g r a n u la t io n t is s u e (F ig. 3.7). Gr a n -
u la t ion t issu e is con n ect ive t issu e ch a r a ct er ized
by ext en sive m a cr oph a ges a n d fibr obla st s, a n d
t h e pr om ot ion of a n g io g e n e s is , or t h e gen er a t ion
of n ew blood vessels, a t t h e sit e. Th e gen er a t ion of
blood vessels, pa r t icu la r ly ca pilla r ies, a t t h e sit e is
n eeded for oxygen /ca r bon dioxide exch a n ge a n d t o
pr ovide ot h er n u t r ien t s t o t h e n ewly developin g t is-
su e. Gr a n u la t ion t issu e is m ost n ot ed for t h e pr es-
en ce of a n ext en sive n et wor k of ca pilla r ies. As t h e
wou n d h ea ls, gr a n u la t ion t issu e loses t h e excessive
ca pilla r y n et wor k a n d r et a in s on ly t h a t n eeded t o
su ppor t t h e fin a l con n ect ive t issu e m a t r ix. Th e pr o-
vision a l m a t r ix a n d specia lized gr a n u la t ion t issu e
a r e n o lon ger n eeded a n d a r e r ea bsor bed on ce t h e
wou n d is h ea led a n d t h e fin a l con n ect ive t issu e m a -
t r ix is in pla ce.
Figure 3.7. Epithelial resurfacing. Note epithelial resur-
facing at superior aspect of wound, where there is healthy
granulation tissue. At the inferior aspect, there is minimal
epithelial resurfacing because of poor quality granulation.
At the left side of the wound, there is no epithelial resur-
facing because there is no granulation tissue.
Restoring Functional Integrity
A major goal in healing is to restore the functional in-
tegrity of parenchymal tissues. Parenchymal tissues
are those that perform a specific body function, such
as neuronal (brain) tissue, epithelial (skin) tissue, car-
diac myocyte (heart) tissue, or hepatocyte (liver) tis-
sue. Without restoring functional integrity, even minor
injuries would be problematic. Restoring functional in-
tegrity can be accomplished by one of three processes:
1. Resolu t ion
2. Regen er a t ion
3. Repla cem en t . To see a video on wou n d h ea lin g,
visit h t t p://t h ePoin t .lww.com
R e s o lu t io n is h ea lin g in r espon se t o m ild in ju r y
wit h m in im a l disr u pt ion t o cells, su ch a s wit h a
sm a ll su per ficia l scr a t ch or m ild su n bu r n . Th e ep-
it h elia l cells ba sica lly slou gh a n d r egen er a t e wit h -
ou t in ciden t . Resolu t ion is like “bu sin ess a s u su a l.”
H ea lin g is r a pid.
R e g e n e r a t io n of pa r en ch ym a l t issu es ca n occu r
on ly in t h ose cells t h a t u n der go m it ot ic division . Th is
is a ccom plish ed t h r ou gh (1) p r o li e r a t io n (gr owt h
a n d r epr odu ct ion ), (2) d i e r e n t ia t io n (cells m a t u r e
a n d becom e m or e specia lized), or (3) d ia p e d e s is
(m igr a t ion of n ea r by cells). Som e cells con st a n t ly
r egen er a t e t h r ou gh m it osis, pa r t icu la r ly epit h elia l
cells of t h e skin , ga st r oin t est in a l t r a ct , a n d u r in a r y
t r a ct , a n d blood cells in t h e bon e m a r r ow. Th ese cells
a r e oft en r efer r ed t o a s la b ile c e lls . Th e skin is a
com m on t issu e t h a t r equ ir es r egen er a t ion a ft er in -
ju r y. Ba sa l epit h elia l cells (t h e bot t om , or deepest ,
la yer ) a r e r eest a blish ed t h r ou gh m it osis in a pr o-
cess ca lled r eepit h elia liza t ion . On ce t h is con t in u ou s
ba sa l la yer is r eest a blish ed, t h e cells m a t u r e a n d a r e
sh ed off a n d r egen er a t ed ever y few da ys. A pr er eq-
u isit e for epit h elia l cell r epla cem en t is t h e pr esen ce
of t h e ba sem en t m em br a n e. In t h e pr ocess of r eepi-
t h elia liza t ion , t h e skin cells a t t h e per iph er y of t h e
wou n d u n der go m it osis a n d m igr a t e in wa r d u n t il t h e
pr ocess is com plet e (Fig. 3.8). Mu lt iple su bst a n ces,
in clu din g gr owt h fa ct or s, a dh esion m olecu les, a n d
r ecept or m olecu les, dir ect t h is a ct ivit y.
Ot h er cells st op r egen er a t in g wh en gr owt h is com -
plet e bu t ca n r esu m e r egen er a t ion if in ju r ed. Th ese
cells a r e r efer r ed t o a s s t a b le c e lls . H epa t ocyt es in
t h e liver a r e on e exa m ple. Sim ila r t o epit h elia l cell
r egen er a t ion , a n in t a ct E CM is n eeded t o su ppor t
cell division . Th e liver h a s t r em en dou s ca pa cit y t o
r egen er a t e wit h t h e su ppor t of t h e m a t r ix.
R e p la c e m e n t t h r ou gh t h e pr odu ct ion of sca r t is-
su e occu r s in ext en sive wou n ds a n d wh en r egen er a -
t ion is n ot possible (Fig. 3.9). P e r m a n e n t c e lls , su ch
a s n eu r on s, ca r dia c m yocyt es, a n d t h e len s of t h e eye,
do n ot u n der go m it osis a n d a r e u n a ble t o r egen er a t e.

A B
Wh en per m a n en t cells a r e da m a ged, t h e fu n ct ion a l
t issu e is r epla ced wit h con n ect ive t issu e. For exa m -
ple, if n eu r on a l t issu e of t h e br a in is dest r oyed by
a br a in t u m or, t h e n eu r on s do n ot r egen er a t e, a n d
t h e da m a ged a r ea of t h e br a in does n ot fu n ct ion a s
it h a d pr ior t o t h e in ju r y. Con n ect ive t issu e, or sca r
t issu e, ca n a lso r epla ce la bile or st a ble cells if t h e
in ju r y a n d su bsequ en t da m a ge is ext en sive. For ex-
a m ple, in a sever e bu r n t h a t cover s a la r ge a r ea of
t h e body, con n ect ive sca r t issu e will r epla ce t h e epi-
t h elia l t issu es of t h e skin . Th e sca r t issu e fills in t h e
ga p bu t does n ot fu n ct ion a s t h e pa r en ch ym a l t issu e.
Conditions That Promote Wound Healing
Wou n d h ea lin g r equ ir es cer t a in con dit ion s. P r o-
m ot ion of wou n d h ea lin g depen ds pr im a r ily on a d-
equ a cy of t h e va scu la r a n d cellu la r in fla m m a t or y
r espon ses, r efor m a t ion of t h e E CM (in clu din g colla -
gen deposit ion ), a n d r egen er a t ion of t h ose cells ca -
pa ble of m it osis.
Th ese pr ocesses a r e en h a n ced a n d su ppor t ed by
a n a dequ a t e diet a r y in t a ke of wa t er, pr ot ein s, ca r-
boh ydr a t es, fa t s, vit a m in s, a n d m in er a ls. Th e m ost
ben eficia l of t h ese n u t r ien t s a r e pr ot ein s a n d vit a -
m in s, pa r t icu la r ly vit a m in s A a n d C. P r ot ein s a r e
n eeded du r in g ever y ph a se of r epa ir, in clu din g E CM
r egen er a t ion a n d a n giogen esis. Vit a m in s A a n d C
a r e n eeded for r eepit h elia liza t ion a n d colla gen syn -
t h esis. Adequ a t e blood flow is a lso n eeded t o t r a n s-
por t in fla m m a t or y cells a n d pr odu ct s of h ea lin g t o
t h e in ju r ed sit e a n d t o oxygen a t e cells a n d t issu es.
H e a lin g a n d Tis s u e R e p a ir 45
Figure 3.8. Regeneration and migra-
tion of epidermal cells. A: The migra-
tion of epidermal cells, sustained by
the mitotic activity of neighboring
cells, fills the wound gap and dis-
places the scab. B: The gap created
by the wound has been repaired. The
mitotic activity of the epidermal cells
will restore the epidermal thickness.
(Modified from Rubin E, Farber JL. Pa-
thology. 4th ed. Philadelphia, PA: Lip-
pincott Williams & Wilkins; 2005, with
permission.)
Stop and Consider
What did you eat and drink yesterday? What
nutrients did you consume that would promote
wound healing?
Healing by Intention
Wou n ds t h a t a r e sm a ller wit h a ppr oxim a t ed wou n d
edges will h ea l m u ch m or e qu ickly a n d ea sily t h a n
wou n ds t h a t a r e la r ge a n d cr a t er like. Appr oxim a t ed
wou n d edges a r e t h ose t h a t a r e “lin ed u p” or close t o-
get h er, su ch a s t h a t wh ich occu r s wit h a pa per cu t or
a su r gica l in cision . Th ese wou n ds h ea l by p r im a r y
in t e n t io n . Wh en h ea lin g occu r s by pr im a r y in t en -
t ion , t h e wou n d is ba sica lly closed wit h a ll a r ea s of
t h e wou n d con n ect in g a n d h ea lin g sim u lt a n eou sly.
Th e r isk for in fect ion is r edu ced a n d sca r r in g is
m in im a l.
La r ger, open , cr a t er like wou n ds m u st h ea l by
s e c o n d a r y in t e n t io n . Th ese wou n ds h ea l fr om t h e
bot t om u p. Th e pr ocess is m u ch slower a n d m or e in -
volved t h a n t h e pr im a r y in t en t ion pr ocess. H ea lin g
by secon da r y in t en t ion r esu lt s in a gr ea t er r isk for
in fect ion a n d sca r r in g. Figu r e 3.10 com pa r es h ea l-
in g by pr im a r y in t en t ion wit h h ea lin g by secon da r y
in t en t ion .
Stop and Consider
How does the concept of healing by primary or
secondary intention compare to the body’s three
lines of defense?
46 C h a p t e r 3: In fla m m a t ion a n d Tissu e Repa ir

Ne crotic (de a d) myoca rdia l Mixture of fibrocyte s S ca r of de ns e fibrous tis s ue

mus cle ce lls a nd le ukocyte s

A B
Fibros is New ca pilla rie s Norma l, unda ma ge d
(a ngione oge ne s is ) myoca rdia l mus cle ce lls

Infla mma tion Fibrocyte prolife ra tion

Fibrocyte migra tion Gra nula tion tis s ue
Angione oge ne s is Colla ge n a ccumula tion
(s ca r deve lopme nt)
Figure 3.9. Granulation tissue in a healing myocardial
infarct. A: Ten days after infarct, some dead muscle cells
remain; others have been replaced by a mixture of inflam-
matory cells, edema, fibrous tissue, and new blood vessels
(granulation tissue). B: Healed myocardial infarct, months
y
t
or years old. Dead muscle cells (which cannot regenerate)
i
s
n
have been removed and replaced by dense scar tissue.
e
t
n
Nearby are normal, undamaged cardiac muscle cells.
I
C: Process timeline. After injury and inflammation, fibro-
cytes migrate into the wound and begin proliferating as
inflammation fades. New blood vessels sprout and form
a rich fibrovascular mix called granulation tissue, which
7 10 30 100 fades as collagen deposited by fibrocytes accumulates as
C Injury Days a scar.

COMPLICATIONS OF HEALING AND TISSUE REPAIR ● Keloid developm en t

● Adh esion s
Im pa ir ed wou n d h ea lin g ca n occu r a t a n y poin t in
t h e pr ocess of closin g t h e wou n d, clea r in g t h e debr is,
I n e c t io n (Ch a pt er 5) r efer s t o in va sion by m i-
a n d r est or in g st r u ct u r a l a n d fu n ct ion a l in t egr it y.
cr oor ga n ism s. Dest r oyin g t h e fir st lin e of defen se,
P r im a r y fa ct or s t h a t im pa ct wou n d h ea lin g a r e a n
a lon g wit h m a n y ot h er fa ct or s, su ch a s a poor in -
in effect ive in fla m m a t or y r espon se, in a dequ a t e im -
fla m m a t or y a n d im m u n e r espon se, will pr om ot e
m u n e r espon se, in a dequ a t e n u t r it ion a l st a t u s, a n d
in fect ion a n d u lt im a t ely im pa ir wou n d h ea lin g. As
poor t issu e per fu sion . Com m on com plica t ion s of
m en t ion ed, t issu e h ea lin g a lso r equ ir es a dequ a t e
wou n d h ea lin g in clu de:
p e r u s io n (pa ssa ge of oxygen a t ed blood) t o t h e sit e.
● In fect ion Poor per fu sion ca n lea d t o u lcer a t ion . U lc e r s a r e
● Ulcer a t ion cir cu m scr ibed, open , cr a t er like lesion of t h e skin or
● Deh iscen ce m u cou s m em br a n es. Th ese a r ea s a r e n ecr ot ic a n d

1 opens the a rea to invasion by microorganisms. This is
2 3
A He a ling by prima ry inte ntion (wounds with a pproxima te d e dge s )
1 2
3 4
B He a ling by s e conda ry inte ntion (wounds with s e pa ra te d e dge s )
Figure 3.10. Comparison of healing by primary versus sec-
ondary intention. A: Healing by primary intention. A1: A
wound with closely approximated edges and minimal tissue
loss. A2: Such a wound requires minimal cell proliferation
and neovascularization to heal. A3: The result is a small
scar. B: Healing by secondary intention. B1: A wound in
which the edges are far apart with substantial tissue loss.
B2: This wound requires extensive cell proliferation and
granulation tissue to heal. B3: The wound is reepithelial-
ized from the margins, and collagen fibers are deposited
into the granulation tissue. B4: Granulation tissue is even-
tually reabsorbed and replaced by a large scar. (Modified
from Rubin E, Farber JL. Pathology. 4th ed. Philadelphia,
PA: Lippincott Williams & Wilkins; 2005, with permission.)
H e a lin g a n d Tis s u e R e p a ir 47
open t o fu r t h er in va sion by m icr oor ga n ism s. Ulcer s
a r e oft en r esist a n t t o h ea lin g beca u se of t h e la ck of
per fu sion t o t h e sit e a n d per sist en t h a bit a t ion by
m icr oor ga n ism s. Ulcer s a r e a com m on com plica t ion
of ga st r it is, on e of t h e clin ica l m odels in t h is ch a pt er.
Wound d e h isce n ce is a problem of deficient scar
forma tion, in which the wound splits or bursts open, of-
ten a t a suture line. Wound separa tion, like u lcera tion,
a possible complication early after surgery beca use of
mecha nica l stresses put on the wound during move-
ment or coughing. Poor development of the ECM a nd
ineffective or inadequate collagen is often the ca use of
wound dehiscence la ter in the recovery period.
Keloid developm en t is t h e opposit e of deh iscen ce.
Ke lo id s a r e h yper t r oph ic sca r s t h a t r esu lt fr om
excessive colla gen pr odu ct ion a t t h e sit e of in ju r y
(Fig. 3.11). Keloids occu r wit h h igh er fr equ en cy in
t h ose wit h deeply pigm en t ed skin a n d t en d t o develop
in t h ose bet ween t h e a ges of 10 a n d 30 yea r s wit h
a fa m ilia l disposit ion t o developin g keloids. Keloids
a r e oft en seen on ly a s a cosm et ic pr oblem , bu t t h ese
la r ge a r ea s of sca r r in g r epr esen t in effect ive h ea lin g
a t t h e sit e. At t em pt s a t r em ova l of t h e keloid oft en
r esu lt in a n ot h er keloid for m in g in t h e sa m e loca t ion .
Adhesions a r e a lso a problem wit h colla gen deposi-
t ion. Colla gen fiber s ca n develop a nd form a dhesions
wit h injur ies loca t ed in or nea r by serous (wa t ery)
body cavit ies, such a s t he per itoneum (inner lining of
t he a bdomen). Ad h e s ion s a r e fibr ous conn ect ions be-
t ween ser ous cavit ies a nd n ea r by tissues, which do not
a llow t he sur rounding tissues t o move fr eely. Abdom -
ina l sur gery pr esents a n increa sed risk for a dhesion
development . The colla gen fiber s connect t o or ga ns
wit hin the per itoneum , such a s t he bowel, bla dder,
a nd ova r ies. Adhesions restr ict free m ovement of t he
or ga n a nd ca use pa in a nd loss of orga n fu nct ion.
Figure 3.11. Keloid. This woman developed a keloid as
a reaction to having her earlobe pierced. (Modified from
Rubin E, Farber JL. Pathology. 4th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2005, with permission.)
48 C h a p t e r 3: In fla m m a t ion a n d Tissu e Repa ir

Modu le 3 C h r o n ic I n la m m a t io n

Ch r on ic in fla m m a t ion r ep-

r esen t s a per sist en t or r ecu r r en t Ta b le 3.6 Com pa r ison of Acu t e a n d Ch r on ic In fla m m a t ion
st a t e of in fla m m a t ion la st in g sev-
C h a r a c t e r is t ic Ac u t e I n la m m a t io n
er a l weeks or lon ger. Th is st a t e
occu r s wh en t h e a cu t e in fla m - Tim e
m a t or y a n d im m u n e r espon ses
a r e u n su ccessfu l. Ch r on ic in -
fla m m a t ion ca n be r ela t ed t o a n Ch ief ph a gocyt ic
cells
u n r elen t in g in ju r y, per sist en t
in fect iou s pr ocess, or a n a u t o-
im m u n e con dit ion . Au t oim m u - Rest or a t ion
n it y occu r s wh en t h e im m u n e
syst em iden t ifies self-cells a s
“for eign ” a n d a t t a cks t h ese cells
(Ch a pt er 4). Oft en , in ju r ies or in fect ion s t h a t ca u se
ch r on ic in fla m m a t ion a r e su bt le a n d slow-gr owin g.
Ch r on ic in fla m m a t ion differ s fr om a cu t e in fla m m a -
t ion in m a n y wa ys, a s illu st r a t ed in Ta ble 3.6.
Cells of Chronic Inflammation
Cellu la r a ct ivit y is n ot a bly differ en t bet ween a cu t e
a n d ch r on ic in fla m m a t ion . Th e lon ger-la st in g a c-
t ivit y of m on ocyt es, m a cr oph a ges, a n d lym ph ocyt es
is m or e pr om in en t in ch r on ic in fla m m a t ion . Mon o-
cyt es cir cu la t e in t h e blood t o t h e sit e of in ju r y a n d
m a t u r e in t o m a cr oph a ges in t h e t issu es. As m on o-
cyt es m a t u r e in t o m a cr oph a ges, t h ey pr odu ce p r o -
t e in a s e s a n d fibr obla st s. P r ot ein a ses a r e en zym es
t h a t dest r oy ela st in a n d ot h er t issu e com pon en t s.
Th ese en zym es h elp t o br ea k down dea d t issu e;
u n for t u n a t ely, t h ese en zym es do n ot discr im in a t e.
P r ot ein a se a ct ivit y is r espon sible for on goin g t issu e
dest r u ct ion a t a n d su r r ou n din g t h e sit e of t h e per-
sist en t in ju r y. Fibr obla st s a r e a lso a ct ive in ch r on ic
in fla m m a t ion . Fibr obla st s a r e r espon sible for colla -
gen developm en t , wh ich con t r ibu t es t o t h e ext en -
sive sca r r in g ch a r a ct er ist ic of ch r on ic in fla m m a t ion .
Sca r r in g lea ds t o per m a n en t loss of fu n ct ion a n d de-
for m it y of t h e t issu e or or ga n .
Granuloma Formation
In som e ca ses, ch r on ic in fla m m a t ion r esu lt s in
g r a n u lo m a for m a t ion (F ig. 3.12). Gr a n u lom a s a r e
n odu la r in fla m m a t or y lesion s t h a t en ca se h a r m fu l
su bst a n ces. Gr a n u lom a for m a t ion is a lso r egu la t ed
by m a cr oph a ges. Gr a n u lom a s t ypica lly for m wh en
t h e in ju r y is t oo difficu lt t o con t r ol by t h e u su a l in -
fla m m a t or y a n d im m u n e m ech a n ism s, su ch a s wit h
C h r o n ic I n la m m a t io n
Resolu t ion wit h in a few P r esen t for a pr olon ged per iod
weeks of t im e, u su a lly gr ea t er t h a n 6
m on t h s
Neu t r oph ils Mon ocyt es
Ma cr oph a ges
Lym ph ocyt es
Min im a l sca r r in g Ma r ked by fibr osis, sca r r in g, or
gr a n u lom a for m a t ion
for eign bodies or cer t a in m icr oor ga n ism s. On e cla s-
sic exa m ple of a m icr oor ga n ism t h a t r esu lt s in gr a n -
u lom a for m a t ion is Mycoba cter iu m tu ber cu losis,
t h e ba ct er ia r espon sible for t u ber cu losis in fect ion
(Ch a pt er 5).
By for m in g gr a n u lom a s, m a cr oph a ges pr ot ect
h ea lt h y, u n a ffect ed su r r ou n din g t issu e fr om fu r t h er
da m a ge. Ma cr oph a ges a da pt in t o g ia n t c e lls or e p -
it h e lio id c e lls . Gia n t cells a r e ph a gocyt es t h a t ca n
en gu lf pa r t icles m u ch la r ger t h a n t h e t ypica l m a cr o-
ph a ge. E pit h elioid cells ga t h er a n d con t a in sm a ller
su bst a n ces by for m in g a wa ll, or fibr ot ic gr a n u lom a ,
a r ou n d t h e a ffect ed a r ea . In side t h e wa ll, m a cr o-
ph a ges a r e bu sy ph a gocyt izin g h a r m fu l su bst a n ces.
As a r esu lt , n ecr osis fills t h e in side of t h e gr a n u -
lom a . Gr a du a lly, t h e n ecr osis diffu ses t h r ou gh t h e
gr a n u lom a wa ll a n d a fibr ot ic ca psu le r em a in s.
GENERAL MANIFESTATIONS
Th e gen er a l m a n ifest a t ion s of ch r on ic in fla m m a t ion
ca n be sim ila r t o t h ose of a cu t e in fla m m a t ion du r in g
a fla r e-u p of sym pt om s, su ch a s r edn ess, h ea t , pa in ,
swellin g, a n d loss of fu n ct ion . Th ese sym pt om s m a y
lea d t o sca r r in g in t h e a ffect ed a r ea or gr a n u lom a
for m a t ion , a s discu ssed ea r lier. Ot h er syst em ic
m a n ifest a t ion s a ssocia t ed wit h ch r on ic in fla m m a -
t ion m a y in clu de fever, m a la ise, a n em ia , fa t igu e,
a n or exia , weigh t loss, or wea kn ess. Rem ission of
t h e ch r on ic in fla m m a t ion ca n occu r in som e con di-
t ion s; du r in g t h ese t im es, t h e pa t ien t will h a ve n o
sym pt om s.
TREATMENT
Th e t r ea t m en t of ch r on ic in fla m m a t ion is a im ed
a t r em ovin g t h e sou r ce of in ju r y if possible a n d
m a n a gin g sym pt om s. Lon g-t er m u se of a n t i-
in fla m m a t or y, a n a lgesic, or im m u n e-m odifyin g
 Ap p lie d P a t h o p h y s io lo g y C lin ic a l Mo d e ls 49

Pe rs is te nt Injury
Chronic infe ction
Autoimmunity
Fore ign body
Exc e s s :
Ke loids a dhe s ions

P roduce P roduce
prote ina s e s Ac c umulatio n o f prote ina s e s
Tis s ue De s troy e la s tin Colla ge n
& othe r tis s ue mo no c yte s / S ca rring
de gra da tion mac ro phag es production
compone nts

Pe rs is te nt infe ction
or fore ign body
De fic it: Los s of function
De his ce nce a nd de formity

Monocyte s /ma cropha ge s

a da pt into:

Gia nt ce lls Epithe loid ce lls

(G) (e )

Engulf la rge Ga the r s ma ll s ubs ta nce s

pa rticle s a nd form a fibrous wa ll

=e =
e G G
e
e G
=

G
=

G G e
=

e GG G
=

G
e =G G =e
=

e = e
Gra nuloma e ncircle s pe rs is te nt
injurious a ge nts tha t ca nnot
be e ngulfe d

Figure 3.12. Concept map. The process of chronic inflammation leading to granuloma formation.

dr u gs is oft en n eeded. Ch r on ic in fect ion s a s a
sou r ce of ch r on ic in fla m m a t ion wou ld be t r ea t ed
wit h a n t im icr obia l dr u gs (Ch a pt er 5). N on ph a r-
m a cologic t r ea t m en t s a r e im por t a n t a s well, su ch
a s t h e u se of h ea t or cold, im m obiliza t ion , diet a r y
ch a n ges, exer cise/ph ysica l t h er a py, a n d r est . Com -
plem en t a r y t h er a pies, su ch a s h om eopa t h ic pr epa -
r a t ion s, a cu pu n ct u r e, a n d gu ided im a ger y, sh ou ld
a lso be explor ed wit h pa t ien t s a n d m on it or ed for
sa fet y a n d effect iven ess.

Modu le 4 Ap p lie d P a t h o p h y s io lo g y C lin ic a l Mo d e ls

Th e followin g clin ica l m odels h a ve been select ed t o Sinusitis

a id in t h e u n der st a n din g a n d a pplica t ion of in fla m -
m a t or y pr ocesses. Wh en r ea din g a bou t t h e clin ica l
m odels, visu a lize t h e pr ocess of a cu t e ver su s ch r on ic
in fla m m a t ion a n d h ea lin g a n d n ot e t h e com m on a li-
t ies a n d u n iqu e fea t u r es of ea ch m odel.
S in u s it is , a lso kn own a s r h in osin u sit is, r efer s t o
sym pt om a t ic in fla m m a t ion of t h e pa r a n a sa l si-
n u ses a n d n a sa l ca vit y. Abou t 1 in 8 US a du lt s h a ve
sin u sit is, r esu lt in g in m or e t h a n 20% of a n t ibiot ic
50 C h a p t e r 3: In fla m m a t ion a n d Tissu e Repa ir
A B
Figure 3.13. Paranasal sinuses: anterior ( A) and lateral
( B) views of head.
pr escr ipt ion s.3 Ch ildr en a ver a ge a r ou n d 6 t o 8 u pper
r espir a t or y t r a ct in fect ion s (t h e com m on cold) per
yea r, wit h a r ou n d 10% of t h ese fu r t h er com plica t ed
by a cu t e ba ct er ia l sin u sit is. Sin u sit is ca n be eit h er
a cu t e or ch r on ic.
FUNCTIONS OF THE SINUSES
F igu r e 3.13 depict s t h e pa r a n a sa l sin u ses, open
spa ces lin ed wit h pr ot ect ive m u cosa , com posed of
cilia t ed, pseu dost r a t ified colu m n a r epit h elia l cells
in t er sper sed wit h goblet cells. Goblet cells a r e r e-
spon sible for secr et in g m u cin s, wh ich is t h e m a in
com pon en t of m u cu s. Th e m a in fu n ct ion of sin u ses
is t o pr odu ce m u cu s t h a t m oist u r izes a n d pr ot ect s
t h e in side of t h e n ose. Alt h ou gh t h e n a sa l ca vit y is
u su a lly colon ized wit h ba ct er ia , t h e sin u ses a r e m ost
oft en st er ile.
ACUTE SINUSITIS
Acu t e sin u sit is is in fla m m a t ion of t h e lin in g of t h e
pa r a n a sa l sin u ses la st in g 4 t o 8 weeks. Su ba cu t e si-
n u sit is la st s 8 t o 12 weeks. Recu r r en t a cu t e sin u sit is
occu r s wh en t h e pa t ien t h a s u p t o fou r episodes per
yea r, wit h t h e sin u s in fla m m a t ion r esolvin g com -
plet ely bet ween episodes.
Pathophysiology
Sin u ses pr odu ce secr et ion s, wh ich n or m a lly flow in
on e dir ect ion t owa r d t h e ost ia . Th e ost ia pr ovide ou t -
flow of t h e dr a in a ge a n d pr even t ba ckflow a n d con -
t a m in a t ion of t h e sin u ses. If t h e ost ia a n d ou t flow
of m u cu s a r e blocked, m ost oft en beca u se of a ller gy,
vir u ses, or som e ot h er for m of ir r it a t ion , t h is ca n r e-
su lt in sin u sit is. Secon dly, a s t h e n a sa l ca vit y is n ot
st er ile, im pa ir ed clea r a n ce of t h e m u cu s by pr ot ec-
t ive cilia or a lt er ed m u cu s qu a lit y or qu a n t it y ca n
a lso lea d t o sin u sit is. Pa t ien t s wit h cyst ic fibr osis
a n d ch r on ic r espir a t or y a ller gies a r e a t h igh er r isk
for sin u sit is beca u se of ch r on ic n a sa l in fla m m a t ion ,
ch a n ges in m u cu s, a n d m u cocilia r y clea r a n ce issu es.
Th e pr im a r y et iology for a cu t e sin u sit is is vir a l
in fect ion s t r a n sm it t ed via r espir a t or y dr oplet s fr om
per son t o per son . Th e m ost fr equ en t ly im plica t ed
vir u ses a r e r h in ovir u s, a den ovir u s, cor on a vir u ses,
pa r a in flu en za , a n d t h e in flu en za A a n d B vir u ses.
Th e pr esen ce of ba ct er ia l sin u sit is is oft en a com -
plica t ion of over wh elm in g vir a l in fect ion , wh ich h a s
ca u sed in cr ea sed m u cu s secr et ion , obst r u ct ion , a n d
im pa ir ed m u cocilia r y clea r a n ce. Ot h er con dit ion s
t h a t pr edispose t o ba ct er ia l in fect ion in clu de r e-
spir a t or y a ller gy, fa cia l in ju r y, den t a l in fect ion s, or
im m u n odeficien cy/im m u n osu ppr ession . On r a r e oc-
ca sion s, sin u sit is ca n be t h e r esu lt of fu n ga l in va sion .
Clinical Manifestations
Clin ica l m a n ifest a t ion s for a cu t e sin u sit is a r e r e-
la t ed t o t h e con gest ion of sin u ses wit h excessive,
obst r u ct ed m u cu s a n d in fla m m a t ion . Th ese clin ica l
m a n ifest a t ion s in clu de:
● Fa cia l pa in over t h e sin u s r egion s of t h e fa ce in -
cr ea sin g wit h st r a in in g or ben din g down (ca n be
u n ila t er a l)
● Fever
● Na sa l con gest ion a n d/or excessive n a sa l disch a r ge
a n d post n a sa l dr a in a ge
● Per sist en t cou gh
● Fa t igu e
Diagnostic Criteria
Th e dia gn osis of a cu t e sin u sit is is oft en m a de
t h r ou gh ph ysica l exa m in a t ion , r evea lin g t h e clin ica l
m a n ifest a t ion s a bove, followin g a n u pper r espir a -
t or y in fect ion t h a t h a s la st ed gr ea t er t h a n 10 da ys.
Gen er a l la bor a t or y t est s for in fla m m a t ion or in fec-
t ion , su ch a s E SR, CRP, a n d WBC cou n t s, ca n be
u sed, bu t a r e n on specific.
Sin u s r a diogr a ph s m a y be h elpfu l wh en t h e di-
a gn osis is in qu est ion . X-r a ys r evea l opa qu e, m u -
cu s-filled, t h icken ed sin u ses (Fig. 3.14).
Treatment
Th e pr im a r y goa l of t r ea t m en t is t o elim in a t e t h e
in fect ion a n d ca r e for t h e sym pt om s of sin u sit is.
Appr oxim a t ely 40% of a cu t e sin u sit is ca ses r esolve
spon t a n eou sly wit h ou t a n t ibiot ics.3 H owever, for pa -
t ien t s wit h ou t spon t a n eou s r esolu t ion , a ppr opr ia t e
a n t ibiot ics a r e n eeded for 14 t o 21 da ys. An t ih ist a -
m in e (in r espir a t or y a ller gy) a n d decon gest a n t m ed-
ica t ion s m a y be h elpfu l. Na sa l spr ays t h a t pr om ot e
 Ap p lie d P a t h o p h y s io lo g y C lin ic a l Mo d e ls
Figure 3.14. Maxillary sinusitis. This radiograph demonstrates bilateral maxillary sinusitis. There is an air–fluid level pres-
ent in the right maxillary sinus and an example of mucosal swelling demonstrated in the left maxillary sinus.
va socon st r ict ion , su ch a s oxym et a zolin e h ydr och lo-
r ide, sh ou ld be u sed on ly u p t o 5 da ys. Ot h er wise, t h e
pa t ien t cou ld exper ien ce r ebou n d n a sa l con gest ion
a n d swellin g.
F u r t h er eva lu a t ion is wa r r a n t ed if t h e clin ica l
m a n ifest a t ion s of sin u sit is per sist beyon d a n t ibiot ic
t r ea t m en t or if t h er e a r e episodes of r ecu r r en ce. If
a n t ibiot ic t h er a py h a s fa iled a n d t h ick, pu r u len t si-
n u s secr et ion s per sist , sin u ses ca n be m or e a ggr es-
sively t r ea t ed su r gica lly.
Chronic Sinusitis
Ch r on ic sin u sit is is a per sist en t low-gr a de in fla m m a -
t ion of t h e pa r a n a sa l sin u ses la st in g over 12 weeks
wit h or wit h ou t fla r es of a cu t e sin u sit is. Ch r on ic si-
n u sit is ca n occu r wit h or wit h ou t n a sa l polyps or a s
a n a ller gic or fu n ga l disea se. Risk fa ct or s in clu de 4 :
● An a t om ic a bn or m a lit ies of t h e ost iom ea t a l com -
plex (e.g., sept a l devia t ion )
● Aller gic r h in it is
● Aspir in sen sit ivit y
● Ast h m a
● Na sa l polyps
● Non a ller gic r h in it is (e.g., va som ot or r h in it is, co-
ca in e a bu se)
● Defect s in m u cocilia r y clea r a n ce
● Na sot r a ch ea l in t u ba t ion
● Na soga st r ic in t u ba t ion
● H or m on a l (e.g., pu ber t y, pr egn a n cy, or a l
con t r a cept ion )
51
● Obst r u ct ion by t u m or
● Im m u n odeficien cy
● Cyst ic fibr osis
● P r im a r y cilia r y dyskin esia , Ka r t a gen er syn dr om e
● Wegen er gr a n u lom a t osis
● Repea t ed vir a l u pper r espir a t or y t r a ct in fect ion s
● Sm okin g
● E n vir on m en t a l ir r it a n t s a n d pollu t a n t s
● Per iodon t it is/sign ifica n t den t a l disea se
Sim ila r t o a cu t e sin u sit is, ch r on ic sin u sit is oft en be-
gin s a s st a sis of secr et ion s in side t h e sin u ses, wh ich
ca n be t r igger ed by obst r u ct ion of t h e ost ia or m u co-
sa l edem a . Most ca ses of ch r on ic sin u sit is a r e du e t o
a cu t e sin u sit is t h a t eit h er is u n t r ea t ed or does n ot
r espon d t o t r ea t m en t .
PATHOPHYSIOLOGY
Cu r r en t ly, ch r on ic sin u sit is is t h ou gh t t o be a m u l-
t ifa ct or ia l in fla m m a t or y disea se com bin in g en vi-
r on m en t a l fa ct or s, su ch a s per sist en t in fect ion or
a ller gen s, wit h gen et ic fa ct or s, su ch a s m et a bolic a b-
n or m a lit ies or im m u n e deficien cies. Th ese m u lt ifa c-
t or ia l t r igger s or r isk fa ct or s, wh en pr esen t , disr u pt
m u cocilia r y clea r a n ce a n d r esu lt in m u cu s st a gn a -
t ion , cr ea t in g a n en vir on m en t con du cive t o ba ct er ia l
gr owt h a n d ch r on ic in fla m m a t ion in t h e sin u ses.
CLINICAL MANIFESTATIONS
In con t r a st t o a cu t e sin u sit is wh er e fa cia l pa in a n d
fever a r e com m on m a n ifest a t ion s, ch r on ic sin u sit is
52 C h a p t e r 3: In fla m m a t ion a n d Tissu e Repa ir
is m u ch m or e in sidiou s in it s on set . Th e com m on
clin ica l m a n ifest a t ion s in clu de:
● Na sa l con gest ion
● Na sa l a n d post n a sa l disch a r ge
● Sor e t h r oa t
● Fou l br ea t h , u n plea sa n t t a st e
● Low-gr a de fever
● Fa t igu e, a n or exia
● Ch r on ic cou gh
● H y p o s m ia , t h e r edu ced a bilit y t o sm ell
● Fa cia l fu lln ess, discom for t , pa in , a n d h ea da ch e
(wit h polyps)
DIAGNOSTIC CRITERIA
Dia gn osis is ba sed on a per sist en ce of obst r u ct ed
a n d m u cu s-filled sin u ses over 12 weeks or lon ger. At
lea st t wo of t h e followin g sym pt om s m u st be pr esen t :
● An t er ior or post er ior m u copu r u len t dr a in a ge
● Na sa l obst r u ct ion
● Fa cia l pa in , pr essu r e, fu lln ess
● H yposm ia
Th ese m u st be a ccom pa n ied by t h e pr esen ce of
ch r on ic in fla m m a t ion , r esu lt in g in a t lea st on e of t h e
followin g:
● P u r u len t m u cu s or edem a in t h e m iddle m ea t u s
or et h m oid r egion
● Polyps in t h e n a sa l ca vit y or m iddle m ea t u s
Th e a bove fin din gs a r e con fir m ed by t h e pr esen ce
of m u cosa l t h icken in g, ch a n ges t o t h e su r r ou n din g
bon es, a n d/or ch a n ges in a ir –flu id levels visu a lized
via CT sca n .
TREATMENT
Th e goa ls of t r ea t m en t a r e t o r edu ce m u cosa l swell-
in g, pr om ot e sin u s dr a in a ge, a n d clea r a n y in fect ion s
t h a t m a y be pr esen t . Th is oft en m ea n s t h a t t h e pa -
t ien t will n eed a com bin a t ion of glu cocor t icoids (or a l
or t opica l t h r ou gh a n a sa l spr a y), a n t ibiot ics, a n d
n a sa l sa lin e ir r iga t ion . If t h ese t r ea t m en t s a r e in ef-
fect ive, a r efer r a l t o a n ot ola r yn gologist for con sid-
er a t ion of sin u s su r ger y is wa r r a n t ed. If t h e ch r on ic
disea se is sever e, if t h er e a r e or bit a l or in t r a cr a n ia l
com plica t ion s, or if t h e pa t ien t is im m u n ocom pr o-
m ised, h ospit a liza t ion is r equ ir ed.
Burn Injuries
E ver y yea r in t h e U n it ed St a t es, bu r n s ca u se
2 m illion in ju r ies, wit h over 5,000 of t h ese r esu lt -
in g in dea t h . 5 Th e m ost com m on ca u ses in clu de fir e/
fla m e exposu r e (46%), sca ldin g (32%), h ot object
C L I N I C AL P R AC T I C E
Wh en t o Seek Medica l Ca r e
Clin icia n s sh ou ld a dvise pa t ien t s t o ca ll a doc-
t or wh en exper ien cin g pa in or pr essu r e in t h e
u pper fa ce a ccom pa n ied by n a sa l con gest ion or
disch a r ge, post n a sa l dr ip, fever for sever a l da ys,
or on goin g ba d br ea t h u n r ela t ed t o den t a l pr ob-
lem s. If left u n t r ea t ed, com plica t ion s of sin u sit is
ca n occu r t h a t m a y lea d t o sever e m edica l con -
dit ion s. If you h a ve t h e followin g sym pt om s, you
m a y h a ve a m edica l em er gen cy a n d sh ou ld seek
im m edia t e eva lu a t ion in a h ospit a l’s em er gen cy
depa r t m en t :
● H ea da ch e a n d fever wit h soft t issu e swellin g
over t h e fr on t a l sin u s m a y in dica t e a n in fec-
t ion of t h e fr on t a l bon e.
● Sever e pa in wh en m ovin g t h e eye, fever, eye-
lid swellin g or dr oopin g, or vision ch a n ges du e
t o in fect ion in t h e eye socket a s a r esu lt of
et h m oid sin u sit is; per m a n en t blin dn ess ca n
r esu lt .
● Sever e pa in in t h e eye, on e or bot h dila t ed pu -
pils, fever, eyelid swellin g, or vision ch a n ges
ca n a lso be r ela t ed t o a blood clot in t h e
sin u ses.
● Per son a lit y ch a n ges, h ea da ch e, n eck st iffn ess,
h igh fever, a lt er ed con sciou sn ess, visu a l pr ob-
lem s, or seizu r es a r e sign s t h a t t h e sin u sit is
h a s pen et r a t ed t h e m en in ges of t h e cen t r a l
n er vou s syst em s (m en in git is), wh ich is a m ed-
ica l em er gen cy.
con t a ct (8%), elect r ica l bu r n s (4%), a n d ch em ica l
bu r n s (3%). Bu r n in ju r ies ca u se a n in fla m m a t or y
r espon se loca lly a n d ca n h a ve m a jor syst em a t ic ef-
fect s a s well.
FUNCTIONS OF THE SKIN
Th e skin ser ves a s a n im por t a n t ba r r ier bet ween t h e
body a n d t h e ext er n a l en vir on m en t . It is com posed
of t h e der m is, wh ich is a den se, ir r egu la r con n ec-
t ive t issu e, a n d t h e epider m is, a la yer of epit h elia l
t issu e. Th e epider m is a n d der m is a r e sepa r a t ed by
t h e ba sem en t m em br a n e. Th e skin pr ot ect s in t er n a l
st r u ct u r es fr om in va sion by in fect iou s or h a r m fu l
a gen t s a n d m ech a n ica l da m a ge. Th e skin pr even t s
deh ydr a t ion , r egu la t es body t em per a t u r e, a n d pr o-
du ces vit a m in D. Un der st a n din g t h e vit a l fu n ct ion
of t h e skin is im por t a n t beca u se loss of fu n ct ion is
a cr it ica l m a n ifest a t ion of in fla m m a t or y pr ocesses.
 Ap p lie d P a t h o p h y s io lo g y C lin ic a l Mo d e ls 53

S upe rficia l pa rtia l

thickne s s (firs t
Epide rmis
de gre e )

De e p pa rtia l
thickne s s
(s e cond
De rmis
de gre e )
Figure 3.15. Classification of burns by depth of
injury. Superficial partial-thickness burns enter
Full thickne s s
(third de gre e ) the epidermis. Deep partial-thickness burns pene-
S ubcuta ne ous trate the epidermis and dermal layers. Full-thick-
tis s ue
ness burns penetrate all skin layers and can
progress to underlying structures as well. (Cour-
Mus cle
tesy Anatomical Chart Company.)

BURNS wit h h ot liqu ids, m or e sever e su n bu r n , m ild t o m od-

er a t e ch em ica l bu r n s, or fla sh fla m e exposu r e ca n
Pathophysiology lea d t o deep pa r t ia l-t h ickn ess bu r n s. E pider m a l a n d
Bu r n s ca n r esu lt fr om t h er m a l in ju r y, elect r ica l in - der m a l la yer s sepa r a t e, flu id a ccu m u la t es bet ween
ju r y, ca u st ic ch em ica l in ju r y, r a dia t ion exposu r e, or t h ese la yer s, a n d blist er s for m (F ig. 3.16). A loss of
in h a la t ion of n oxiou s fu m es. In t h er m a l in ju r ies, fu n ct ion of t h e skin a s t h e fir st lin e of defen se a llows
h igh er t em per a t u r e a n d in cr ea sed len gt h of h ea t ex- m icr oor ga n ism s t o in va de t h e t issu e. If n ecr osis oc-
posu r e in cr ea se t h e sever it y of t h e bu r n . Tem per a - cu r s in t h e u pper epider m a l cell la yer s bu t t h e ba sa l
t u r es a bove 45°C (113°F ) ca u se pr ot ein s t o den a t u r e, cell la yer r em a in s in t a ct , sca r r in g is a voided. Mor e
a n d ir r ever sible cellu la r da m a ge occu r s. Th e ext en t com m on ly, h owever, n ecr osis r esu lt s in bot h epider-
of da m a ge fr om ch em ica l in ju r ies depen ds on t h e m a l a n d u pper der m a l la yer s. Colla gen fills in t h e
t oxicit y of t h e ch em ica l, loca t ion of exposu r e (pa r t ic- ga ps left a ft er t h e r em ova l of da m a ged t issu es. E x-
u la r ly in t h e eyes, r espir a t or y t r a ct , or ga st r oin t est i- cess colla gen pr odu ct ion oft en lea ds t o t issu e fibr osis
n a l t r a ct ), a n d len gt h of exposu r e. E lect r ica l in ju r ies a n d sca r r in g a t t h e bu r n sit e. Th e pr ocess of h ea lin g
follow t h e pa t h of lea st r esist a n ce in t h e body, t h a t occu r s wit h in a ppr oxim a t ely 2 t o 4 weeks.
is, a lon g t issu e, flu ids, blood vessels, a n d n er ves. Se- F u ll-t h ic k n e s s b u r n s , a lso kn own a s t h ir d-de-
r iou s elect r ica l t r a u m a r esu lt s fr om t h e elect r ica l gr ee bu r n s, da m a ge t h e epider m is a n d der m is a n d
cu r r en t pa ssin g t h r ou gh vit a l or ga n s, n er ves, a n d ca n pen et r a t e su bcu t a n eou s la yer s a s well. Con t a ct
blood vessels. E lect r ica l cu r r en t s ca n disr u pt ca r dia c
con du ct ion a n d ca u se im m edia t e dea t h .
Wit h a ll bu r n s, t h e in ju r y t r igger s a n a cu t e in -
fla m m a t or y r espon se. Th e ext en t a n d n a t u r e of t h e
in fla m m a t ion , a lon g wit h cor r espon din g clin ica l
m a n ifest a t ion s, dia gn ost ic cr it er ia , a n d t r ea t m en t ,
pr im a r ily depen d on t h e su r fa ce a r ea t h a t is a ffect ed
a s well a s t h e dept h of t h e bu r n in ju r y (Fig. 3.15).
S u p e r ic ia l p a r t ia l-t h ic k n e s s b u r n s , a lso
known a s fir st-degr ee bur ns, da m a ge t he epider mis.
Mild sunbur n is on e exa m ple. Th is ra dia tion-in du ced
in ju r y t r igger s va sodila t ion of t he der m a l blood ves-
sels a nd incr ea sed ca pilla r y per m ea bilit y, ca usin g
er yth ema , pa in, a nd swelling of a ffect ed a rea s. Su-
per ficia l pa r t ia l-t hickness bur ns do not r esult in cell
n ecr osis or sca rr ing. The ECM gener a lly r em a ins in-
t a ct , a llowing unevent fu l h ea ling of super ficia l pa r- Figure 3.16. Deep partial-thickness (second-degree) sun-
t ia l-t hickness bur ns a s en doth elia l a nd epit helia l cells burn. Epidermal and dermal layers separate, fluid accumu-
r a pidly r egen era te. Hea lin g occu rs wit hin a week. lates between the layers, and blisters form. (From Fleisher
D e e p p a r t ia l-t h ic k n e s s b u r n s , a lso kn own a s GR, Ludwig S, Baskin MN. Atlas of Pediatric Emergency
secon d-degr ee bu r n s, da m a ge epider m a l skin la yer s Medicine. Philadelphia, PA: Lippincott Williams & Wilkins;
a n d pen et r a t e som e der m a l skin la yer s. Sca ldin g 2004, with permission.)
54 C h a p t e r 3: In fla m m a t ion a n d Tissu e Repa ir
wit h ext r em ely h ot object s, exposu r e t o a fla m e, elec-
t r ica l exposu r es, a n d ca u st ic ch em ica ls a r e likely
t o r esu lt in fu ll-t h ickn ess bu r n s. Th e sever it y de-
pen ds on t h e t em per a t u r e or t ype of ch em ica l a n d
t h e len gt h of exposu r e. Dest r u ct ion of blood vessels
is a lso com m on a s h ea t ca u t er izes t h e vessels. Th e
h ea lin g of fu ll-t h ickn ess bu r n s is ch a llen ged by
ext en sive loss of ela st in , r epla cem en t of skin cells
wit h colla gen , a n d in va sion by m icr oor ga n ism s. Re-
gen er a t ion of epit h elia l cells is im pa ir ed beca u se of
dest r u ct ion of t h e E CM. Sca r r in g is oft en ext en sive.
Loss of ela st icit y is eviden ced by c o n t r a c t u r e s , a r-
ea s of t h ick, sh or t en ed, a n d r igid t issu e.
Stop and Consider
Hematocrit is a laboratory test that indicates the
percentage of RBCs in a designated volume of
blood. Would an individual with partial-thickness
and full-thickness burns covering 20% body surface
area have a decrease or increase in this laboratory
value? What would be the impact of this change?
Th e loss of skin fu n ct ion r esu lt s in m u lt iple pot en -
t ia l com plica t ion s, pa r t icu la r ly in sever e bu r n in ju -
r ies, defin ed a s fu ll-t h ickn ess bu r n s cover in g gr ea t er
t h a n 20% of t h e a du lt body su r fa ce a r ea , in clu din g:
1. Body flu id sh ift s t h a t ca u se im pa ir ed blood cir cu -
la t ion , edem a , a n d deh ydr a t ion
2. Micr oor ga n ism in va sion t h a t lea ds t o in fect ion
3. Over wh elm in g m et a bolic dem a n ds t h a t in cr ea se
t h e r isk for m a ln u t r it ion
4. P r oblem s wit h t em per a t u r e r egu la t ion
In widespr ea d in fla m m a t ion , im pa ir ed blood cir cu -
la t ion a n d cellu la r deh ydr a t ion ca n r esu lt a s flu ids
sh ift fr om cells a n d blood vessels in t o t h e t issu es
(edem a ). Th is is du e t o m a ssive ca pilla r y per m e-
a bilit y a n d dir ect da m a ge t o blood vessels a t t h e
sit e of t h e bu r n in ju r y (F ig. 3.17). In pa t ien t s wit h
fu ll-t h ickn ess bu r n s, wa t er loss is ext en sive: Ap-
pr oxim a t ely 0.3 m L of body wa t er per squ a r e cen -
t im et er is lost per da y. Wh en fu ll-t h ickn ess bu r n s
cover 70% of t h e body, ext en sive flu id sh ift s ou t of
t h e blood vessels a n d swells in t o t h e t issu es, r esu lt -
in g in sever e h ypovolem ia (low flu id volu m e in t h e
blood vessels). Th e blood becom es viscou s (t h ick),
h ea t con ver t s RBCs fr om a con ca ve t o a sph er ica l
sh a pe, a n d t h e flow of blood is a lt er ed. At t h e loca l
sit e of t h e bu r n , t h r o m b i, or clot s, ca n develop, ox-
ygen a t ed blood flow is r est r ict ed, a n d n ecr osis ca n
develop a s t h e bu r n ed t issu e becom es h ypoxic. An
in a dequ a t e a m ou n t of blood in t h e cir cu la t ion lea ds
t o s h o c k , a st a t e of in a dequ a t e per fu sion (oxygen -
a t ed blood flow) t o per iph er a l t issu es. Poor per fu -
sion is pa r t icu la r ly pr oblem a t ic in vit a l or ga n s,
wh ich r equ ir e a con st a n t flow of oxygen t o su r vive.
In pa r t ia l-t h ickn ess bu r n s, ca pilla r y per m ea bilit y is
BURN
≠ Va s cula r pe rme a bility
Ede ma ≠ He ma tocrit
Ø Volume ≠ Vis cos ity
≠ P e riphe ra l re s is ta nce
Ø Ca rdia c output
Figure 3.17. Hemodynamic changes in burn injury. (From
Nettina S. The Lippincott Manual of Nursing Practice. 7th
ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001,
with permission.)
r est or ed a ft er 24 t o 48 h ou r s a n d in t er st it ia l flu id
sh ift s decr ea se a ft er t h is t im e. Th is a llows t h e vol-
u m e of flu id in t h e blood vessels n eeded for opt im a l
cir cu la t ion .
Th e loss of skin fu n ct ion a s a r esu lt of bu r n in ju -
r ies a lso a llows for r ea dy a ccess for m icr oor ga n ism s
a n d st r esses t h e m et a bolic a n d r epa r a t ive pr ocesses
of t h e body. Bu r n s cover in g a la r ger su r fa ce a r ea
pose a gr ea t er r isk for t h e developm en t of s e p s is ,
wh ich is a ba ct er ia l in fect ion of t h e blood, a n d sept ic
sh ock. In fu ll-t h ickn ess bu r n s, dea d t issu e a n d exu -
da t e con ver t in t o a n e s c h a r , wh ich is a t h ick, coa g-
u la t ed cr u st . Th e esch a r m u st be su r gica lly r em oved
t o pr even t ext en sive m icr oor ga n ism gr owt h . E n er gy,
pr ot ein , a n d oxygen u se a r e a lso in cr ea sed beca u se
of t h e ext en sive r epa r a t ive pr ocesses r equ ir ed in
su bst a n t ia l bu r n in ju r ies. If t h ese in cr ea sin g n eeds
a r e n ot m et , t issu e h ypoxia , t issu e wa st in g, a n d in -
fect ion a r e t h e pot en t ia l r esu lt s.
CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s pr im a r ily depen d on t h e
dept h of t h e bu r n in ju r y. Su per ficia l pa r t ia l-t h ick-
n ess bu r n s r esu lt in er yt h em a , wa r m t h , pa in , swell-
in g, a n d loss of fu n ct ion of a ffect ed a r ea s. Deep
pa r t ia l-t h ickn ess bu r n s lea d t o blist er in g, a lon g
wit h er yt h em a , wa r m t h , pa in , edem a , a n d s e r o u s
e x u d a t e , wh ich is a clea r flu id t h a t seeps ou t of
t h e t issu es. E r yt h em a , esch a r for m a t ion , edem a ,
a n d exu da t e ch a r a ct er ize fu ll-t h ickn ess bu r n s. F u ll-
t h ickn ess bu r n s dest r oy n er ve en din gs, swea t gla n ds,
a n d h a ir follicles. Dest r u ct ion of n er ve en din gs
 Ap p lie d P a t h o p h y s io lo g y C lin ic a l Mo d e ls 55

41⁄2%
Am er ica n Bu r n Associa t ion h a s pu blish ed cr it er ia
41⁄2%
for dist in gu ish in g m in or, m oder a t e, a n d m a jor bu r n s
(Ta ble 3.7).

18% 18% TREATMENT

41⁄2% 41⁄2%
In it ia l t r ea t m en t for m in or a n d m oder a t e bu r n s
41⁄2% 41⁄2% r equ ir es r em ovin g t h e sou r ce of in ju r y a n d st op-
pin g t h e bu r n in g pr ocess. Ch em ica l bu r n s sh ou ld
1% be flu sh ed wit h copiou s a m ou n t s of wa t er. In m in or
bu r n s, t h e wou n d is clea n sed wit h t epid st er ile sa -
lin e (cool bu t n ot cold) or wa t er. In som e ca ses, t h e
wou n d is cover ed wit h a n a n t im icr obia l oin t m en t
a n d dr essed wit h fin e-m esh ga u ze. Dr essin gs a r e
9% 9%
u su a lly ch a n ged ever y 1 t o 2 da ys. F r equ en t (da ily)
9% 9%
dr essin g ch a n ges a id in d e b r id e m e n t , wh ich is a
pr ocess of m ech a n ica lly r em ovin g debr is, in clu din g
n ecr ot ic t issu e, fr om t h e wou n d. An a lgesics ca n be
u sed t o t r ea t pa in .
Moder a t e a n d m a jor bu r n s r equ ir e em er gen cy
Figure 3.18. Rule of nines. Estimating the extent of burns m edica l a t t en t ion . Also, bu r n s la r ger t h a n t h e pa lm
in adults. (Courtesy Anatomical Chart Company.) of t h e h a n d or t h ose t h a t in volve t h e fa ce, h a n ds, feet ,
or gen it a l a r ea s r equ ir e specia lized in t er ven t ion in a
bu r n t r ea t m en t cen t er. Tr ea t m en t for m oder a t e a n d
in h ibit s t h e pa in r espon se in a r ea s wh er e t h e bu r n m a jor bu r n s, a s wit h ot h er em er gen cies, focu ses on
h a s pen et r a t ed a ll skin la yer s. Th e in dividu a l wit h a t h e a ir wa y, br ea t h in g, a n d cir cu la t ion . On ce t h ese
fu ll-t h ickn ess bu r n is n ot pa in fr ee, h owever. Ar ea s a r e st a bilized, a dm in ist r a t ion of in t r a ven ou s flu ids
of deep a n d su per ficia l t h ickn ess bu r n s, like a bu ll’s is in st it u t ed t o r epla ce wa t er a n d sodiu m losses. Ad-
eye, oft en su r r ou n d fu ll-t h ickn ess bu r n s. Pa in is n o- m in ist er in g flu ids h elps t o r est or e t h e cir cu la t in g
t a ble in t h ese su r r ou n din g t issu es. blood volu m e a n d im pr oves per fu sion of vit a l or ga n s.
Beca u se m et a bolic dem a n ds in cr ea se sign ifica n t ly
wit h t h e st r ess of a bu r n in ju r y, n u t r it ion su ppor t in
DIAGNOSTIC CRITERIA t h e for m of in cr ea sed ca lor ies a n d pr ot ein is n eeded.
Wou n d dept h s (su per ficia l, deep pa r t ia l, or fu ll An a lgesics a n d a n t ibiot ics a r e a lso u sed t o t r ea t
t h ickn ess) a r e cla ssified a ccor din g t o t h e a ffect ed pa in a n d in fect ion . P r ot ect ive isola t ion m ea su r es a r e
t issu e la yer s. Su r fa ce a r ea is a lso a sign ifica n t va r i- oft en in st it u t ed t o pr ot ect t h e pa t ien t fr om con t a ct
a ble in det er m in in g t h e dia gn osis a n d t r ea t m en t wit h m icr oor ga n ism s a s m u ch a s possible.
of a bu r n in ju r y. Ca lcu la t ion of a du lt body su r fa ce Wou n d m a n a gem en t for m a jor bu r n s in -
a r ea is a ided u sin g t h e “r u le of n in es” depict ed in volves clea n sin g wit h st er ile sa lin e wh ile wea r-
F igu r e 3.18. For ch ildr en u n der 5 yea r s, body pr o- in g powder-fr ee gloves (powder will ir r it a t e t h e
por t ion s do n ot m a t ch t h a t of t h e a du lt . For exa m ple, bu r n wou n d), r em ovin g blist er s or n ecr ot ic t issu e
a lt h ou gh t h e t r u n k a n d a r m s a r e sim ila r in pr opor- a s a ppr opr ia t e, cover in g t h e wou n d wit h a st er ile
t ion t o t h e a du lt , t h e in fa n t ’s
h ea d a n d n eck m a ke u p 18%
of t ot a l body su r fa ce a r ea , a n d
Ta b le 3.7 Am er ica n Bu r n Associa t ion (ABA) Bu r n Sever it y
ea ch lower ext r em it y a ccou n t s Gr a din g Sca le
for 14%. H ea lt h ca r e pr ofession -
a ls wh o t r ea t ch ildh ood bu r n s Min o r a Mo d e r a t e Ma jo r
sh ou ld r efer t o a “m odified r u le Pa r t ia l-t h ickn ess , 10% TBSA 10%–20% TBSA . 20% TBSA
of n in es” a ppr opr ia t e for t h e spe-
F u ll-t h ickn ess All
cific a ge of t h e ch ild.
Tr ea t m en t Usu a lly Adm ission t o h ospit a l; Adm ission t o
E st im a t ion of t h e r u le of t r ea t ed a t m a y r equ ir e specia lized specia lized bu r n
n in es, a lon g wit h a det er m in a - h om e bu r n cen t er t r ea t m en t cen t er
t ion of t h e t h ickn ess of t h e bu r n ,
a
a llows t h e h ea lt h pr ofession a l Min or bu r n s exclu de a n y bu r n in volvin g t h e fa ce, h a n ds, feet , a n d per in eu m ; a lso exclu de elec-
t r ica l bu r n s, in h a la t ion in ju r ies, or ot h er t r a u m a .
t o det er m in e t h e sever it y of t h e ALL, a cu t e lym ph ocyt ic leu kem ia ; TBSA, t ot a l body su r fa ce a r ea .
in ju r y a n d dir ect t r ea t m en t . Th e h t t p://www.a m er ibu r n .or g/Bu r n Cen t er Refer r a lCr it er ia .pdf
56 C h a p t e r 3: In fla m m a t ion a n d Tissu e Repa ir
dr essin g, a n d pr even t in g in fect ion . H ydr ot h er a py,
wh ich in volves soa kin g in a t u b or sh ower in g on ce
or t wice per da y, is u sed t o clea n se t h e wou n d by
r em ovin g dea d t issu e a n d exu da t e. F u ll-t h ickn ess
bu r n s a r e u n a ble t o u n der go r eepit h elia liza t ion a n d
r equ ir e su r gica l excision a n d gr a ft in g t o close t h e
wou n d. Skin gr a ft in g is a pr ocess of u sin g self or
don or t issu e t o cover a n d pr ot ect t h e exposed a r ea .
Th is t r a n spla n t ed epit h elia l t issu e su ppor t s cellu la r
r egen er a t ion , decr ea ses in va sion by m icr oor ga n -
ism s, a n d m in im izes sca r r in g. Lon g-t er m r eh a bil-
it a t ion (t er t ia r y pr even t ion ) in volves pr even t ion of
com plica t ion s su ch a s sca r for m a t ion , con t r a ct u r es,
defor m it y, a n d ch r on ic pa in . Tr ea t m en t m a y a lso in -
volve psych osocia l su ppor t beca u se t h ose wit h bu r n
in ju r ies m a y exper ien ce depr ession or ot h er psych o-
logic sequ ela e.
Arthritis
Ar t h r it is is a gen er a l t er m for degen er a t ion or in -
fla m m a t ion of t h e join t s a n d r efer s t o a gr ou p of
disea ses of va r yin g pa t h ogen esis. In fla m m a t or y a r-
t h r it is is u su a lly a r esu lt of ch r on ic in fect ion s, a u t o-
im m u n e con dit ion s, or ot h er ch r on ic ir r it a n t s in t h e
join t ca psu le. Rh eu m a t oid a r t h r it is, a syst em ic a u t o-
im m u n e disea se lea din g t o ch r on ic in fla m m a t ion of
syn ovia l t issu e, is t h e select ed clin ica l m odel.
FUNCTIONS OF SYNOVIAL JOINTS
Th e pr im a r y fu n ct ion of join t s is skelet a l st a bilit y
a n d m obilit y. Syn ovia l join t s, pa r t icu la r ly t h ose in
t h e kn ees, wr ist s, h a n ds, fin ger s, a n d feet , a r e h igh ly
m obile a n d com m on t a r get s for in fla m m a t ion . Syn o-
via l join t s a r e a lso h igh ly va scu la r. Th e t wo-la yer sy-
n ovia l m em br a n e lin es t h e join t ca psu le. On e la yer
is com posed of con n ect ive t issu e, ela st in , a dipocyt es,
fibr obla st s, m a cr oph a ges, a n d m a st cells. Th e secon d
la yer is a r ow of syn ovia l cells, wh ich a r e ca pa ble
of ph a gocyt osis a n d secr et in g syn ovia l flu id. Syn o-
via l flu id n ou r ish es, cu sh ion s, a n d pr ot ect s t h e join t
fr om m icr oor ga n ism s. Syn ovia l cells a r e la bile cells,
wh ich ca n qu ickly r egen er a t e.
Bet ween t h e bon e a n d syn ovia l m em br a n e is ca r t i-
la ge. Ca r t ila ge is com posed of ch on dr ocyt es, colla gen ,
wa t er, a n d pr ot ein glyca n s.
Colla gen for m s a n E CM,
wh ich a t t a ch es bon e t o
F R O M T H E L AB
t h e ca r t ila ge. Ca r t ila ge is
n eeded t o dist r ibu t e body Rheumatoid factor (RF), a substance that can be found in the blood, synovial fluid, and
weigh t a n d t o decr ea se synovial membranes, signifies that antibodies (IgM, IgG, or IgA) are acting against other
join t fr ict ion . Ca r t ila ge antibodies (mainly IgG). RF is present in the vast majority of patients who have RA and can
m u st be r epla ced by colla - also be found in a variety of other conditions. The presence of RF in RA often signifies more
gen if da m a ged; ch on dr o- severe disease.
cyt es do n ot r egen er a t e.
RHEUMATOID ARTHRITIS
Rh eu m a t oid a r t h r it is (RA) is a syst em ic a u t oim -
m u n e disea se ch a r a ct er ized by ch r on ic in fla m m a -
t ion a n d h yper pla sia of t h e syn ovia l m em br a n es
wit h in cr ea sed syn ovia l exu da t e, lea din g t o swell-
in g a n d t h icken in g of t h e syn ovia l m em br a n es, join t
er osion , a n d pa in . Th e on set of disea se occu r s t ypi-
ca lly bet ween t h e a ges of 36 a n d 50 yea r s. RA a ffect s
0.8% of a du lt s wor ldwide. Fem a les a r e a ffect ed t h r ee
t im es m or e oft en t h a n m a les, a n d t h e r a t e of com or-
bidit ies is h igh wit h depr ession , a st h m a , a n d ca r dio-
va scu la r pr oblem s bein g t h e m ost com m on com or bid
con dit ion s.6
Pathophysiology
Alt h ou gh t h e exa ct ca u se of RA is u n kn own , t h e et i-
ology is likely a com bin a t ion of:
● Gen et ic su scept ibilit y
● An im m u n e t r igger in g even t
● Th e su bsequ en t developm en t of a u t oim m u n it y
a ga in st syn ovia l cells
Th e t r igger in g in ju r y in RA t h a t lea ds t o in fla m m a -
t ion is difficu lt t o pin poin t a n d is oft en n ever det er-
m in ed. Despit e t h e la ck of a n iden t ifia ble t r igger,
a u t oim m u n it y pla ys a key r ole. CD4 + h elper T cells
h a ve been im plica t ed a s a ct iva t in g t h e in fla m m a -
t or y r espon se a lon g wit h t h e r elea se of cyt okin es.
Lym ph ocyt es a n d pla sm a cells t h en for m a n t ibodies
in t h e syn ovia l m em br a n e a n d ca r t ila ge. Th e a n t i-
bodies a r e for m ed a ga in st specific a n t igen s. Th e
a n t ibodies a ct u a lly see ot h er a n t ibodies wit h in t h e
body a s for eign (see F r om t h e La b).
In RA, t h e a n t igen s a n d a n t ibodies for m com -
plexes, ca lled im m u n e com plexes. Th ese im m u n e
com plexes a r e fou n d in t h e syn oviu m of m ost in di-
vidu a ls dia gn osed wit h RA. Th ese a n t igen –a n t ibody
com plexes t r igger t h e com plem en t syst em , t h er eby
st im u la t in g a n exa gger a t ed in fla m m a t or y r espon se.
Th e in fla m m a t or y r espon se is m a r ked by excess
pr odu ct ion a n d r elea se of in fla m m a t or y m edia t or s.
Th ese in fla m m a t or y m edia t or s a ct on t h e va scu la -
t u r e of t h e join t s t o ca u se in cr ea sed va sodila t ion a n d
ca pilla r y per m ea bilit y. Th e join t becom es er yt h em a -
t ou s, wa r m , swollen , pa in fu l, a n d difficu lt t o m ove.
E xu da t e a ccu m u la t es in t h e syn oviu m . Neu t r oph ils
 Ap p lie d P a t h o p h y s io lo g y C lin ic a l Mo d e ls
a n d m a cr oph a ges m ove in t o t h e sit e t o defen d
a ga in st h a r m fu l su bst a n ces. Th is pr ocess, wh ile n ec-
essa r y, a lso pr om ot es t h e pr odu ct ion of dest r u ct ive
t issu e en zym es. Syn ovia l cells a da pt by r a pidly r e-
gen er a t in g. Th e syn oviu m , a ft er t h e in it ia l bou t of
in fla m m a t ion , is a lt er ed a n d ca u ses t h e followin g
ch a n ges:
1. Mild edem a
2. Accu m u la t ion of t h e cells of ch r on ic in fla m m a t ion
(m a cr oph a ges, pla sm a cells, a n d lym ph ocyt es)
3. Acceler a t ion of a n giogen esis
4. Accu m u la t ion of fibr in
5. Syn ovia l cells con t in u e t o u n der go r ea ct ive
h yper pla sia
Th ese in it ia l syn ovia l ch a n ges u su a lly dem on st r a t e
m in im a l da m a ge t o t h e join t s.
E xa cer ba t ion s of t h e disea se pr ogr essively da m -
a ge a ffect ed join t s t h r ou gh pa n n u s for m a t ion ,
ca r t ila ge er osion , fibr osis, a n d join t fixa t ion a n d
defor m it y (F ig. 3.19). P a n n u s is gr a n u la t ion t issu e
t h a t for m s over t h e in fla m ed syn oviu m a n d ca r t i-
la ge a s a r esu lt of a cceler a t ed a n giogen esis. Pa n n u s
is filled wit h syn ovia l cells, wh ich u n der go h yper-
pla sia a n d m igr a t e, a lon g wit h t h e pa n n u s, over t h e
ca r t ila ge. Th e pa n n u s a n d syn ovia l cells a r e join ed
by m a st cells, lym ph ocyt es, a n d m a cr oph a ge gia n t
cells. Th ese cells fu r t h er exa cer ba t e in fla m m a t ion
a n d t issu e dest r u ct ion . Pa n n u s sepa r a t es t h e ca r t i-
la ge fr om syn oviu m , t h er eby depr ivin g t h e ca r t ila ge
of n u t r ien t s. Th e pa n n u s a lso pr odu ces en zym es
t h a t br ea k down t h e ca r t ila ge a n d ca n er ode t h e a d-
ja cen t bon e a s well. Th ese er osion s a r e ir r ever sible.
F ibr obla st s wor k t o for m a n d r epla ce t h e con n ect ive
t issu e la yer by pr odu cin g a n d secr et in g colla gen .
Colla gen fills in t h e ga ps t h a t r em a in a ft er t is-
su e da m a ge. As a r esu lt , fibr osis for m s in t h e join t
Pe ria rticula r
os te oporos is
Los s of
ca rtila ge
Infla mma tion
of s ynovium
Incre a s e d
s ynovia l
fluid
B C
A
Figure 3.19. Normal joint ( A) ; early rheumatoid arthritis with fluid accumulation and synovial swelling ( B) ; late rheuma-
toid arthritis with pannus formation, eroded articular cartilage, and joint space narrowing ( C) .
57
ca psu le. F ibr osis im pa ir s join t m obilit y a n d ca n
r esu lt in a debilit a t in g fixa t ion of t h e join t , a con -
dit ion t er m ed a n k y lo s is . Lim it ed join t m ovem en t
decr ea ses t h e wor kloa d of su r r ou n din g m u scle t is-
su e, lea din g t o m u scle t issu e a t r oph y. In fla m m a t or y
cells ca n a lso ir r it a t e su r r ou n din g m u scle t issu e, r e-
su lt in g in m u scle spa sm s.
CLINICAL MANIFESTATIONS
Th e sever it y of RA ca n r a n ge fr om m ild t o debili-
t a t in g. In volvem en t is ch a r a ct er ist ica lly sym m et r ic
a n d ca n in volve a n y n u m ber of join t s, pr odu cin g er y-
t h em a , pa in , swellin g, wa r m t h , a n d decr ea sed m obil-
it y. Ma la lign m en t or devia t ion of sym m et r ica l join t s
is a com m on clin ica l m a n ifest a t ion of lon g-st a n din g
RA (F ig. 3.20). Ma la lign m en t is ca u sed by a com bi-
n a t ion of ca r t ila ge a n d bon e er osion , fibr osis, a n ky-
losis, m u scle spa sm s, a n d m u scle a t r oph y. Pa in a n d
st iffn ess is oft en m ost n ot a ble u pon r isin g in t h e
m or n in g a n d a ft er per iods of im m obilit y.
Com m on syst em ic m a n ifest a t ion s du r in g disea se
exa cer ba t ion s a r e low-gr a de fever, fa t igu e, a n or exia ,
weigh t loss, a n d wea kn ess. Ch r on ic pa in ca n a lso
lea d t o isola t ion a n d depr ession . Ma n ifest a t ion s of
lon g-st a n din g RA ca n a lso be fou n d ou t side of t h e
join t ca psu le. Gr a n u lom a s, ca lled n odu les, ca n for m
on blood vessels t h r ou gh ou t t h e body. Va scu lit is, a n
in fla m m a t or y con dit ion in volvin g sm a ll- a n d m e-
diu m -sized a r t er ies, m a y a lso occu r in t h ose wit h
lon g-st a n din g disea se.
DIAGNOSTIC CRITERIA
No defin it ive t est exist s t o dia gn ose RA. Dia gn osis is
ba sed on h ist or y a n d ph ysica l exa m in a t ion (du r in g
wh ich st iffn ess a n d pa in in sym m et r ica l join t s is
Pe ria rticula r
os te oporos is
Eros ion of
bone
Pa nnus
Fibros is of
s ynovium
58 C h a p t e r 3: In fla m m a t ion a n d Tissu e Repa ir

RA pr esen t s a dia gn ost ic ch a llen ge beca u se m u lt i-

ple a u t oa n t ibodies a r e kn own t o be a ssocia t ed wit h
t h is disea se. Ma n y of t h ese t est s a r e n on specific a n d
in dica t e t h e pr esen ce of a n in fla m m a t or y or a u t o-
im m u n e pr ocess bu t do n ot dir ect ly poin t t o RA a s
t h e ca u se. E a ch t est a lso h a s a r isk of fa lse-posit ive
(posit ive r esu lt wit h ou t t h e disea se) or fa lse-n ega -
t ive (n ega t ive r esu lt wit h t h e disea se) r esu lt s. RF
a ppea r s t o h a ve t h e gr ea t est a dva n t a ge in dia gn os-
in g ea r ly RA com pa r ed wit h m u lt iple ot h er a u t o-
a n t ibody t est s; h owever, it is u n likely t h a t a sin gle
a n t igen is in volved in t h e developm en t of RA. Th e
dia gn ost ic ch a llen ge ca n lea d t o fr u st r a t ion for t h e
A pa t ien t a n d h ea lt h ca r e pr ofession a l a n d m a y lea d
t o a dela y in t r ea t m en t .

B defor m it ies. H ea t or cold t h er a py ca n be h elpfu l. In
Figure 3.20. Deviation of joints in rheumatoid arthritis,
as shown in a radiograph ( A) and a photograph ( B) .
(A: Reprinted with permission from Harris JH Jr, Harris
WH, Novelline RA. The Radiology of Emergency Medicine.
3rd ed. Baltimore, MD: Williams & Wilkins; 1993:440;
B: Reprinted with permission from Smeltzer SC, Bare
BG. Textbook of Medical–Surgical Nursing. 10th ed. Phil-
adelphia, PA: Lippincott Williams & Wilkins; 2003, with
permission.)
TREATMENT
Tr ea t m en t of RA in volves a ca r efu l ba la n ce of
ph a r m a cologic a n d n on ph a r m a cologic t r ea t m en t
st r a t egies. Medica t ion s em ployed in clu de a n t i-in -
fla m m a t or y dr u gs, im m u n osu ppr essive dr u gs, a n d
m edica t ion s t h a t ot h er wise in du ce r em ission . Non -
ph a r m a cologic st r a t egies in volve t h e ba la n ce of a c-
t ivit y a n d r est , ph ysica l t h er a py exer cises t o pr om ot e
join t m obilit y, a n d t h e u se of splin t s a n d ot h er de-
vices t h a t a llow t h e join t s t o r est a n d h elp t o pr even t
som e ca ses, syn ovect om y or t ot a l join t r epla cem en t
su r ger y m a y be n eeded t o r edu ce pa in a n d defor m it y.
Gastritis
G a s t r it is r efer s t o in fla m m a t ion of t h e lin in g of t h e
st om a ch , or ga st r ic m u cosa , t h er eby im pa ir in g ga s-
t r ic fu n ct ion . Ga st r it is ca n be bot h a cu t e a n d ch r on ic.

dem on st r a t ed), a n d it
m a y in volve sever a l dia g- R E S E AR C H N O T E S
n ost ic t est s. Test r esu lt s
t h a t in cr ea se t h e likeli- Current research is uncovering connections between RA and a number of other chronic con-
h ood of RA a s t h e dia gn o- ditions, such as cancer, cardiovascular disease, and diabetes. In a recent study, a significant
sis in clu de: increase in cardiovascular disease was noted in patients with RA who had more acute flares
than those who spent more time in remission. The researchers concluded that tight inflam-
1. An eleva t ed ser u m E SR mation control and improved flare management are critical to decreasing the cumulative
2. An eleva t ed ser u m CRP cardiovascular burden of RA. 7
level
3. Th e pr esen ce of RF sig-
FUNCTIONS OF THE STOMACH
n ifica n t for a n t ibodies a ga in st IgG
4. A posit ive a n t in u clea r a n t ibody (ANA) a ssa y in di- Th e st om a ch fu n ct ion s a s a n or ga n of pr ot ect ion , di-
ca t in g su spect ed a u t oim m u n e disea se gest ion , a n d a bsor pt ion , pr im a r ily a bsor bin g wa t er
5. Th e pr esen ce of in fla m m a t or y pr odu ct s in a syn o- a n d a lcoh ol. St om a ch a cid for m s a fir st lin e of de-
via l join t flu id a n a lysis fen se by dest r oyin g m a n y t ypes of m icr oor ga n ism s
6. Visu a liza t ion wit h a r a diogr a ph dem on st r a t in g a n d ot h er h a r m fu l su bst a n ces on con t a ct . Du r in g
join t da m a ge t h e digest ive pr ocess, foods a n d liqu ids a r e m ixed
 Ap p lie d P a t h o p h y s io lo g y C lin ic a l Mo d e ls 59

Mucos a

S ubmucos a

Mus cle laye r

Conne ctive
tis s ue
La mina propria
Ga s tric gla nds line d with
pa rie ta l, chie f, mucous,
a nd e ndocrine ce lls

Figure 3.21. Gastric lining. The lining of the stomach contains four types of glandular epithelial cells: mucous, parietal,
chief, and endocrine.

wit h ga st r ic secr et ion s, com posed of m u cu s, a cid, PATHOPHYSIOLOGY

en zym es, h or m on es, a n d in t r in sic fa ct or (IF ). Secr e-
Th e ga st r ic m u cosa is a ccu st om ed t o a n d fu n ct ion s
t ion of t h ese su bst a n ces is a ccom plish ed t h r ou gh t h e
best in t h e a cidic en vir on m en t of t h e st om a ch . E x-
wor k of ga st r ic gla n ds lin ed by specia lized epit h elia l
posu r e t o ga st r ic ir r it a n t s in h ibit s t h e pr odu ct ion of
cells (Fig. 3.21).
ga st r ic m u cosa a n d m a kes t h e m u cosa m or e vu ln er a -
E pit h elia l cells for m a t igh t con n ect ion . Th is con -
ble t o a cidic st om a ch con t en t s. Th is lea ds t o a n a cu t e
n ect ion is a n im por t a n t sou r ce of pr ot ect ion fr om t h e
in fla m m a t or y r espon se r a n gin g fr om m ild er yt h em a
cor r osive effect s of ga st r ic a cid. P r ost a gla n din s a lso
t o er osion a n d ga st r ic per for a t ion (Fig. 3.22). E pi-
pla y a key r ole in m a in t a in in g t h e in t egr it y of t h e
t h elia l cells becom e n ecr ot ic. Th e u n der lyin g ga st r ic
ga st r ic m u cosa t h r ou gh t h e st im u la t ion of a pr ot ec-
t issu e is er oded. H em or r h a gin g oft en occu r s. Ga st r ic
t ive m u cu s ba r r ier.
a cid is a llowed t o esca pe t h e con fin es of t h e ga st r ic
m u cosa a n d cor r ode n ea r by t issu es. Per for a t ion m a y
Stop and Consider
occu r in sever e ca ses.
Explain how anti-inflammatory drugs that inhibit
prostaglandins can cause or further exacerbate
gastritis.

Th e su r fa ce m u cu s ba r r ier is h igh ly va scu la r a n d

depen den t on a r ich blood su pply t o su ppor t ga st r ic Pe rfo rating Ulc e r
fu n ct ion . Rest r ict ion or loss of per fu sion t o t h is la yer P e ne tra tion of wa ll cre a ting a
ca n be a ca u se of ga st r it is. For exa m ple, a lt er ed per- pa s s a ge for ga s tric a cids , othe r fluids a nd
fu sion ca n occu r in t h e ca se of sh ock wh en blood is a ir to e nte r a dja ce nt s pa ce s of the body
sh u n t ed t o vit a l or ga n s a n d n ot t o t h e st om a ch , ca u s-
in g t h e pr ot ect ive m u cu s ba r r ier t o for m u lcer s a n d Exuda te
.
per for a t e.
Gra nula tion
tis s ue
Acute Gastritis
Acu t e ga st r it is r efer s t o in fla m m a t ion in t h e ga s-
t r ic m u cosa m ost oft en ca u sed by t h e in gest ion of
ir r it a n t s su ch a s a spir in , a lcoh ol, or cer t a in m icr oor-
ga n ism s. Acu t e ga st r it is t ypica lly occu r s over a sh or t
per iod a n d is con sider ed r ever sible wh en t h e ca u s-
a t ive a gen t is r em oved. Alt h ou gh ga st r it is is oft en
a ssocia t ed wit h h a vin g t oo m u ch st om a ch a cid, t h e Figure 3.22. Gastric perforation as a result of acute
r ole of ga st r ic a cid h yper secr et ion is u n clea r. gastritis.
60 C h a p t e r 3: In fla m m a t ion a n d Tissu e Repa ir

CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s a r e depen den t on t h e sever-
it y a n d r a n ge fr om m ild t o sever e a bdom in a l pa in ,
wh ich ca n be a ccom pa n ied by in digest ion (h ea r t -
bu r n ), loss of a ppet it e, n a u sea , vom it in g, a n d h ic-
cu ps. H e m a t e m e s is , or vom it in g blood, ca n occu r.
An em ia m a y r esu lt fr om m ild ga st r ic h em or r h a ge.
Sever e h em or r h a ge a n d per for a t ion is qu ickly fol-
lowed by sh ock a n d is a m edica l em er gen cy.

DIAGNOSTIC CRITERIA
Th e pa t ien t h ist or y oft en r evea ls a spir in or ot h er
n on st er oida l a n t i-in fla m m a t or y dr u g u se, excessive
a lcoh ol in t a ke, r ecen t con t a m in a t ed food in t a ke, or
con dit ion s ca u sin g isch em ia of t h e ga st r ic m u cosa .
Th e ph ysica l exa m in a t ion m a y r evea l a bdom in a l
t en der n ess. Dir ect visu a liza t ion of t h e st om a ch wit h
a n en doscope is n eeded t o visu a lize u lcer s in t h e m u -
cosa , a n d a st ool a n a lysis m a y sh ow occu lt blood in
t h e feca l m a t er ia l. H em oglobin or h em a t ocr it levels
pr ovide in for m a t ion a bou t a n em ia .
Figure 3.23. Infective gastritis. H. pylori appears as small
TREATMENT curved rods on the surface of the gastric mucosa. (From
Rubin E, Farber JL. Pathology. 3rd ed. Philadelphia, PA:
Tr ea t m en t begin s wit h r em ova l of t h e ga st r ic ir r i-
Lippincott-Raven; 1999:687, with permission.)
t a n t . Medica t ion s a r e t h en n eeded t em por a r ily t o
bu ffer ga st r ic a cid or decr ea se ga st r ic a cid pr odu c-
t ion . Th e h ea lin g of ga st r it is a n d ga st r ic u lcer a t ion
depen ds on r egen er a t ion of t h e epit h elia l cells t h a t in fla m m a t or y r espon se. P h a gocyt es wor k t o en gu lf,
lin e t h e ga st r ic m u cosa . Most a cu t e ga st r it is im - dest r oy, a n d r em ove t h ese a ggr essive m icr oor ga n -
pr oves r a pidly wh en t h e ir r it a n t is r em oved a n d ism s. Neu t r oph ils m igr a t e t o t h e la m in a pr opr ia a n d
t r ea t m en t is in it ia t ed. ga st r ic epit h eliu m t o ph a gocyt ize t h e ba ct er ia . As
t h e in fect ion becom es ch r on ic, m a cr oph a ges a n d T
a n d B lym ph ocyt es m ove in a n a t t em pt t o r id t h e
Chronic Gastritis: Infection body of t h e offen din g ba ct er ia . H . pylor i t en ds t o r e-
m a in con t a in ed wit h in t h e m u cosa l ba r r ier a n d su r-
Ch r on ic ga st r it is is r ela t ed t o a n u n r elen t in g in - fa ce epit h elia l cells, a n d u n like a cu t e ga st r it is, t h er e
ju r y, su ch a s wit h ch r on ic in fect ion or a u t oim m u - a r e n o er osion s of t h e ga st r ic m u cosa . In st ea d, epi-
n it y. Ch r on ic ga st r it is du e t o H elicoba cter pylor i is t h elia l cells a n d m u cosa l gla n ds a t r oph y. E ven t u a lly,
a n exa m ple ca u sed by ch r on ic in fect ion . H . pylor i t h e ch r on ic in fla m m a t or y r espon se wa n es. Th e m u -
in fect ion is m ost pr eva len t in Asia a n d in develop- cosa l lin in g of t h e st om a ch r em a in s t h in , a n d ga st r ic
in g cou n t r ies wit h poor sa n it a t ion . Abou t h a lf of t h e a cid pr odu ct ion a n d secr et ion is im pa ir ed.
wor ld’s popu la t ion is in fect ed.
CLINICAL MANIFESTATIONS
PATHOPHYSIOLOGY
D y s p e p s ia , a va gu e epiga st r ic discom for t a ssoci-
H . pylor i is a gr a m -n ega t ive pr ot eoba ct er iu m t h a t is a t ed wit h n a u sea a n d h ea r t bu r n , is a possible clin -
pa ssed fr om per son t o per son t h r ou gh in fect ed sa - ica l m a n ifest a t ion . Som e pa t ien t s m a y exper ien ce
liva a n d st ool. Th e m icr oor ga n ism is in gest ed a n d a loss of a ppet it e or vom it in g. Most in fect ed people,
m u lt iplies on t h e epit h elia l su r fa ce cells a n d m u cu s h owever, a r e a sym pt om a t ic ca r r ier s.
ba r r ier. H . pylor i pr odu ces en zym es t h a t n eu t r a lize
ga st r ic a cid, a n d t h e m icr oor ga n ism is a ble t o su r-
DIAGNOSTIC CRITERIA
vive. Th e m icr oor ga n ism s t h en pr odu ce t oxin s t h a t
ca n dest r oy t h e m u cosa l ba r r ier (F ig. 3.23). Dia gn osis of ch r on ic ga st r it is ca u sed by H . pylor i in -
In r espon se t o t h e m icr oor ga n ism -in du ced in - fect ion is a ccom plish ed t h r ou gh dir ect en doscopic vi-
ju r y, in fla m m a t or y m edia t or s t r igger a n in t en se su a liza t ion a n d biopsy of ga st r ic t issu e. A br ea t h t est
 Ap p lie d P a t h o p h y s io lo g y C lin ic a l Mo d e ls
ca n be u sed t o m ea su r e t h e pr esen ce of a n en zym e
given off wh en t h e ba ct er iu m con ver t s u r ea t o ca r-
bon dioxide in t h e lu n gs. P r ot ein a n t ibodies a ga in st
H . pylor i m a y a lso be det ect ed in t h e blood, in dica t -
in g pa st or pr esen t in fect ion wit h t h e ba ct er ia .
TREATMENT
Beca u se H . pylor i is bu r ied deep in t h e st om a ch m u -
cosa , m u lt iple a n t ibiot ics a r e n eeded t o t r ea t t h is
in fect ion a lon g wit h pr ot on pu m p in h ibit or s or bis-
m u t h , wh ich h a ve a n t im icr obia l pr oper t ies a n d r a ise
ga st r ic pH . Over t im e, cer t a in st r a in s of H . pylor i
ca n lea d t o ch r on ic u lcer s a n d ga st r ic ca n cer.
Chronic Gastritis: Autoimmune
Ch r on ic ga st r it is ca n a lso r esu lt fr om a u t oim m u n e
pr ocesses. Alt h ou gh m or e r a r e t h a n ot h er for m s of
ch r on ic ga st r it is, a n t ibodies a r e pr odu ced a ga in st
ga st r ic pa r iet a l cells or IF.
PATHOPHYSIOLOGY
Pa r iet a l cells secr et e h ydr och lor ic a cid. Wh en a n t i-
bodies a r e for m ed a ga in st pa r iet a l cells, ga st r ic a cid
secr et ion is im pa ir ed. In t r in sic fa ct or is n eeded for
in t est in a l a bsor pt ion of B 12 . Wh en a n t ibodies a r e
for m ed a ga in st IF, a bsor pt ion of B 12 is im pa ir ed. B 12
is a cr it ica l vit a m in t h a t pr om ot es DNA syn t h esis in
RBCs. Im pa ir ed DNA syn t h esis in RBCs lea ds t o a
m a r ked decr ea se in RBCs a n d low h em oglobin lev-
els. Th is con dit ion is kn own a s per n iciou s a n em ia .
Ch r on ic in fla m m a t ion r ela t ed t o a u t oim m u n it y a l-
lows T cells t o in filt r a t e t h e ga st r ic m u cosa , dest r oy-
in g epit h elia l cells a n d ca u sin g ga st r ic a t r oph y.
CLINICAL MANIFESTATIONS
Au t oim m u n e ga st r it is ca n be a sym pt om a t ic. Th e
pr esen ce of per n iciou s a n em ia m a y be t h e fir st clu e
t h a t ch r on ic ga st r it is is pr esen t . Ma n ifest a t ion s of
a n em ia in clu de wea kn ess, ligh t -h ea dedn ess, pa le
m u cou s m em br a n es, a n d fa t igu e. Clin ica l m a n ifes-
t a t ion s ca n a lso in clu de dyspepsia , va gu e a bdom in a l
pa in , n a u sea , vom it in g, a n d a n or exia .
DIAGNOSTIC CRITERIA
Dia gn osis of a u t oim m u n e ga st r it is ca n be det er m in ed
on ly wit h h ist ologic exa m in a t ion of t h e ga st r ic m u -
cosa . Sever a l biopsy sa m ples a r e obt a in ed a n d a n a -
lyzed for a t r oph ic ch a n ges in t h e cells. An t ipa r iet a l
or a n t i-IF a n t ibodies m a y pr esen t in a blood sa m ple,
wh ich in dica t e a n a u t oim m u n e pr ocess a ga in st t h e
pa r iet a l cells or IF. Beca u se a u t oim m u n it y a ga in st
61
IF im pa ir s B 12 a bsor pt ion , a low B 12 level will be
n ot ed in t h e blood.
TREATMENT
Tr ea t m en t is a im ed a t blockin g t h e a u t oim m u n e a t -
t a ck a ga in st t h e pa r iet a l cells. Th e a dm in ist r a t ion
of B 12 in t r a m u scu la r in ject ion s m on t h ly is n eeded t o
fa cilit a t e a bsor pt ion of t h is im por t a n t vit a m in . Sim -
ila r t o H . pylor i, a u t oim m u n e ga st r it is ca n lea d t o
ga st r ic ca n cer.
Pancreatitis
P a n c r e a t it is r efer s t o in fla m m a t ion of t h e pa n -
cr ea s, r esu lt in g in dest r u ct ion of t h e pa n cr ea s by
pa n cr ea t ic en zym es. Pa n cr ea t it is ca n be bot h a cu t e
a n d ch r on ic.
FUNCTIONS OF THE PANCREAS
Th e pa n cr ea s is bot h a n en docr in e a n d exocr in e gla n d
loca t ed in t h e u pper post er ior a bdom en on t h e pa -
t ien t ’s left side. Th e en docr in e pa n cr ea s (a bou t 20%
of t h e gla n d) pr odu ces in su lin ; t h e exocr in e pa n cr ea s
(80% of t h e gla n d) pr odu ces a n d secr et es digest ive
en zym es. Th ese digest ive en zym es a r e essen t ia l for
t h e m et a bolism of ca r boh ydr a t es, fa t s, a n d pr ot ein s.
Digest ive en zym es a r e pr odu ced wit h in t h e a c-
in a r cells of t h e pa n cr ea s, a r e st or ed in zym ogen s,
a n d a r e r elea sed in t o t h e pa n cr ea t ic du ct a n d t o t h e
sm a ll in t est in e, wh er e digest ion ca n t h en occu r. In
a pr ocess of n ega t ive feedba ck, t h e secr et ion of pa n -
cr ea t ic en zym es is r edu ced wh en digest ion is com -
plet e. Disr u pt ion of t h is pr ot ect ive pr ocess t r igger s
pa n cr ea t ic en zym es t o becom e a ct iva t ed a n d self-de-
st r u ct t h r ou gh a u t odigest ion .
Acute Pancreatitis
PATHOPHYSIOLOGY
Acut e pa ncr ea t it is may occur when t her e is a n injury
t o the acina r cells, zym ogen, pa ncrea tic duct, or pro-
t ective digest ive feedba ck m echa nisms in the exocr ine
pancreas. Comm on ca uses include duct blocka ge by
ga llst ones or excessive a lcohol use (Fig. 3.24). In about
10% of ca ses, t he ca use is unknown.8 Alcohol is a ma -
jor cause of pa ncrea tic a utodigestion by triggering:
● In t r a cellu la r a ccu m u la t ion of digest ive en zym es
● P r em a t u r e en zym e a ct iva t ion a n d r elea se
● In cr ea sed per m ea bilit y of du ct u les a n d ea sy pa s-
sa ge of en zym es t o t h e pa r en ch ym a
● In cr ea sed pr ot ein con t en t of pa n cr ea t ic secr et ion s
a n d cr ea t ion of pr ot ein plu gs
62 C h a p t e r 3: In fla m m a t ion a n d Tissu e Repa ir
Es opha gus S toma ch
Ga llbla dde r Duode num Pa ncre a s with
with ga lls tone s infla mma tory
exuda te on
s urfa ce
Figure 3.24. Acute pancreatitis as a result of gall stone
obstruction.
The injury triggers blocka ge of enzyma tic pa thways,
t he a ct iva t ion of trypsin a nd the zym ogen, spilling
of secr et or y enzym es, a nd ultima tely infla mm at ion.
Neut rophils, tumor necrosis fa ctor, a nd int er leukins
(ea rly responders) a nd m acropha ges (la ter) m edi-
a t e t he infla m ma tory response. Consist ent wit h the
inflam ma tory casca de, there is increa sed vascula r
per mea bilit y in t he pa ncr ea s, lea ding t o edema . This
condit ion is referred to as a cut e edema tous pa ncrea ti-
t is. La t er, hemorr hage a nd necrosis ensue, lea ding t o a
sta te of hemor rha gic or necr otizing pa ncr ea t it is wit h
event ual gr a nulom a or a bscess form at ion. In severe
ca ses, necrosis is widespr ea d, a nd there is or ga n dys-
function a nd potent ia lly system ic multior ga n fa ilure.
CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s a r e r ela t ed t o t h e in fla m -
m a t or y r espon se occu r r in g in t h e pa n cr ea s a n d it s
r esu lt in g pa in a n d digest ive im pa ct . Th ese m a n ifes-
t a t ion s in clu de:
● Upper a bdom in a l pa in of su dden on set , gr owin g
in in t en sit y, a n d lea din g t o a du ll, st ea dy a ch e of-
t en r a dia t in g t o t h e ba ck
● Na u sea , vom it in g, a n or exia , a n d/or dia r r h ea
DIAGNOSTIC CRITERIA
Dia gn osin g a cu t e pa n cr ea t it is is gen er a lly a ch ieved
t h r ou gh t h e h ist or y a n d ph ysica l exa m in a t ion , n ot -
in g t h e pr esen ce of clin ica l m a n ifest a t ion s a bove.
La bor a t or y t est in g is im plem en t ed t o a id in t h e
dia gn osis. Test s for com plet e blood cou n t , E SR,
a n d CRP levels m a y give clu es t o t h e pr esen ce of
in fla m m a t ion . Specific la bor a t or y t est s in clu de
m ea su r in g:
● S e r u m a m y la s e a n d lip a s e : Levels of t h ese en -
zym es a r e t ypica lly eleva t ed in a cu t e pa n cr ea t i-
t is. Bot h a r e digest ive en zym es (a m yla se br ea ks
down ca r boh ydr a t es a n d lipa se br ea ks down fa t s)
t h a t a r e excessively r elea sed wit h in fla m m a t ion
of t h e pa n cr ea s.
● S e r u m a lk a lin e p h o s p h a t a s e , t o t a l b ilir u b in ,
a s p a r t a t e a m in o t r a n s e r a s e (AS T ), a n d a la -
n in e a m in o t r a n s e r a s e (ALT ): Th ese a r e liver
en zym es, wh ich a r e likely t o be eleva t ed in ca ses
of pa n cr ea t it is ca u sed by ga llst on es.
Wh en t h e dia gn osis is in dou bt or t h e sym pt om s a r e
sever e, im a gin g st u dies, su ch a s u lt r a sou n d, CT, or
MRI, a r e n eeded t o a id in det er m in in g t h e loca t ion
a n d pot en t ia lly t h e ca u se of t h e pa n cr ea t ic in ju r y.
TREATMENT
Tr ea t m en t a im s t o elim in a t e t h e ca u se of pa n cr ea t ic
in ju r y if a t a ll possible a n d t o ca r e for t h e sym pt om s.
Pa t ien t s sh ou ld r eceive a ggr essive IV h ydr a t ion
in t h e fir st 24 h ou r s. In m ild pa n cr ea t it is wit h n o
n a u sea or vom it in g, pa t ien t s ca n con t in u e or a l feed-
in g. Ot h er wise, a ll pa t ien t s m u st be NP O (n ot h in g
by m ou t h ). An a lgesics sh ou ld be a dm in ist er ed t o
m a n a ge pa in . Su r gica l r em ova l of ga llst on es is wa r-
r a n t ed if t h ey a r e pr esen t .
Pa t ien t s wit h sever e pa n cr ea t it is, oft en defin ed a s
a CRP level a bove 10 m g/dL a lon g wit h sever e sym p-
t om s a n d pot en t ia l for n ega t ive sequ ela e, sh ou ld be
h ospit a lized in t h e in t en sive ca r e u n it t o pr even t
com plica t ion s of sh ock, r en a l fa ilu r e, or syst em ic
m u lt ior ga n fa ilu r e. Ra n son ’s Cr it er ia for Pa n cr ea t i-
t is Mor t a lit y 9 is a t ool t h a t h elps t o det er m in e t h e
pa t ien t ’s pr ogn osis ba sed on WBC cou n t , a ge, AST
level, h em a t ocr it , blood u r ea n it r ogen level, flu id
r equ ir em en t s, a n d ot h er in dica t or s. In t en sive t r ea t -
m en t is su ccessfu l if t h e pa t ien t h a s n o pa in , is a ble
t o t a ke in a dequ a t e n u t r it ion , a n d h a s exper ien ced
n o com plica t ion s.
Chronic Pancreatitis
Ch r on ic pa n cr ea t it is is a n on goin g in fla m m a t or y
pr ocess of t h e pa n cr ea s, ch a r a ct er ized by ir r ever s-
ible cellu la r a n d t issu e ch a n ges. Ch r on ic pa n cr ea t i-
t is differ s fr om a cu t e pa n cr ea t it is in du r a t ion , a n d
it s im pa ct on bot h t h e en docr in e a n d exocr in e fu n c-
t ion s of t h e pa n cr ea s. Th e m ost com m on ca u ses a r e
ch r on ic a lcoh ol a bu se (60% t o 70%), a u t oim m u n e or
h er edit a r y disea se (10%), a n d in 20% of ca ses t h e
ca u se is u n kn own . 10
 Ap p lie d P a t h o p h y s io lo g y C lin ic a l Mo d e ls 63

PATHOPHYSIOLOGY
As descr ibed a bove, a lcoh ol h a s a n effect on t h e pa n -
cr ea s, wh er ea s en zym es a n d pr ot ein a ccu m u la t ion
ca u se t h e pa n cr ea t ic du ct s t o becom e obst r u ct ed.
Obst r u ct ion lea ds t o isch em ia . Th e a cin a r cells be-
com e a t r oph ic a n d fibr ot ic, lea din g t o loss of fu n c-
t ion . Wh en a lcoh ol a bu se is ch r on ic, t h e dem a n ds of
m et a bolizin g a lcoh ol lea d t o oxida t ive st r ess, wh ich
pr om ot es fu r t h er cellu la r in ju r y a n d or ga n da m a ge.
Au t oim m u n it y (Ch a pt er 4) ca n occu r a ga in st t h e
pa n cr ea s, r esu lt in g in ch r on ic pa n cr ea t it is. Th e et i-
ology is oft en u n det er m in ed; h owever, a s a r esu lt of
h igh levels of cir cu la t in g a u t oa n t ibodies, t h er e is
diffu se en la r gem en t of t h e pa n cr ea s a n d n a r r owin g
of t h e du ct s. Cer t a in a u t oim m u n e disor der s, wh ich
disr u pt m et a bolic pr ocesses, h a ve a lso been a ssoci-
a t ed wit h ch r on ic pa n cr ea t it is. On e m a jor exa m ple
is r en a l t u bu la r a cidosis (Ch a pt er 9), a con dit ion of
Figure 3.25. Endoscopic retrograde cholangiopancreatog-
excess a cid a ccu m u la t ion in t h e body du e t o a fa ilu r e
raphy (ERCP) illustrates moderate dilation of the main pan-
of t h e kidn eys t o a ppr opr ia t ely a cidify u r in e. Cys-
creatic duct and ectasia of the secondary ducts associated
t ic fibr osis (Ch a pt er 15) is a n exa m ple of a gen et ic
with moderately advanced chronic pancreatitis. Arrows
con dit ion t h a t ca n pr om ot e ch r on ic pa n cr ea t ic in -
indicate intraductal pancreatic stones.
fla m m a t ion . Recu r r en t a cu t e pa n cr ea t it is ca n a lso
pr om ot e a st a t e of fibr osis a n d n ecr osis ch a r a ct er is-
be con cen t r a t ed. Alt h ou gh expen sive a n d in va sive,
t ic of ch r on ic pa n cr ea t it is. Wh a t ever t h e et iology, t h e
dir ect a spir a t ion of t h e pa n cr ea t ic du ct or t h e du ode-
pa t h oph ysiology is ba sed on t h e fibr ot ic ch a n ges of
n u m , wh er e t h e pa n cr ea s deposit s en zym es, ca n be
t h e pa n cr ea s du e t o t h e pr esen ce of ch r on ic in fla m -
t est ed t o det er m in e levels of pa n cr ea t ic bica r bon a t e
m a t or y cells a n d fibr obla st pr olifer a t ion .
a n d en zym es t h a t h a ve been secr et ed.

CLINICAL MANIFESTATIONS TREATMENT

Typica lly, a pa t ien t wit h ch r on ic pa n cr ea t it is h a s se-
ver e in t er m it t en t episodes of a bdom in a l pa in (m id or
u pper r igh t -sided, r a dia t in g t o t h e ba ck) la st in g sev-
er a l h ou r s a n d a t u n pr edict a ble in t er va ls. Th e devel-
opm en t of disea se h a s likely begu n sever a l m on t h s
t o yea r s befor e t h e on set of sym pt om s. Dia r r h ea ,
st ea t or r h ea (fa t t y st ools), a n d weigh t loss ca n a lso
occu r a s a r esu lt of da m a ge t o t h e digest ive fu n ct ion s
of t h e exocr in e pa n cr ea s; h owever, t h is occu r s on ly
a ft er 90% of t h e pa n cr ea s h a s been dest r oyed.
Tr ea t m en t for ch r on ic pa n cr ea t it is is ba sed on t h e
ca u se a n d focu sed on h ea lin g:
● Pa in m a n a gem en t
● Beh a vior m odifica t ion t o pr om ot e a h ea lt h y life-
st yle: a lcoh ol cessa t ion , sm okin g cessa t ion , exer-
cise, qu a lit y n u t r it ion
● Su r gica l in t er ven t ion t o cor r ect cyst , a bscess, ob-
st r u ct ion , or fist u la for m a t ion

DIAGNOSTIC CRITERIA Inflammatory Bowel Disease

E n doscopic r et r ogr a de ch ola n giopa n cr ea t ogr a ph y
(E RCP ) is con sider ed t h e gold st a n da r d for dia g-
n osin g ch r on ic pa n cr ea t it is (Fig. 3.25). In E RCP, t h e
st om a ch a n d du oden u m a r e visu a lized t h r ou gh a n
en doscope a n d t h en a r a diogr a ph ic con t r a st dye is
in ject ed in t o t h e du ct s of t h e bilia r y t r ee a n d pa n -
cr ea s so t h a t t h e obst r u ct ed pa n cr ea t ic pa t h wa ys ca n
be seen on r a diogr a ph s. Ser u m a m yla se a n d lipa se
(descr ibed a bove) m a y be eleva t ed in a cu t e exa cer ba -
t ion s of disea se, bu t over t im e t h e levels a r e n or m a l
t o low beca u se of fibr ot ic ch a n ges in t h e pa n cr ea s
a n d loss of fu n ct ion , wh er ea s en zym es ca n n o lon ger
In fla m m a t or y bowel disea se (IBD) r efer s t o ch r on ic
in fla m m a t or y pr ocesses m ost com m on ly in t h e sm a ll
a n d la r ge in t est in e, bu t it ca n occu r a n ywh er e a lon g
t h e ga st r oin t est in a l t r a ct fr om t h e m ou t h t o t h e
a n u s. Th e m ost com m on for m s of IBD in clu de Cr oh n
disea se a n d u lcer a t ive colit is.
Th e in ciden ce of IBD is h igh est in developed
cou n t r ies, wh er e per son s in colder clim a t es a n d
u r ba n a r ea s h a ve a n in cr ea sed r isk. Th e Am er-
ica n J ewish popu la t ion h a s a fou r t o five t im es
gr ea t er pr eva len ce t h a n in ot h er gr ou ps. Am on g
t h ose of E u r opea n descen t in t h e Un it ed St a t es, t h e
64 C h a p t e r 3: In fla m m a t ion a n d Tissu e Repa ir
pr eva len ce of u lcer a t ive colit is is est im a t ed a t 116
per 100,000 people, a n d t h is is sligh t ly in cr ea sed a t
133 per 100,000 people for Cr oh n disea se. Th e r isk
a ppea r s sim ila r for Afr ica n Am er ica n s bu t is lower
for Asia n Am er ica n s a n d H ispa n ic Am er ica n s. Ma les
a n d fem a les a r e equ a lly a ffect ed.11
FUNCTIONS OF THE SMALL INTESTINE
Th e sm a ll in t est in e is com posed of sever a l la yer s
(Fig. 3.26). F r om in n er t o ou t er, t h ese la yer s con sist
of t h e m u cosa , su bm u cosa , m u scu la r is, a n d ser osa .
Th e in n er m ost m u cosa l t issu e is com posed of t h r ee
su bla yer s: m u cou s colu m n a r epit h eliu m , la m in a
pr opr ia (con n ect ive t issu e), a n d t h e t h in m u scu -
la r is la yer. Th e m u cou s epit h eliu m la yer lin es t h e
villi, wh ich pr ovide a la r ge su r fa ce a r ea . Th ese villi
a r e lin ed wit h colu m n a r cells, wh ich secr et e m u cu s,
en zym es, a n d h or m on es. Th e su bm u cosa is a t h ick
con n ect ive t issu e la yer t h a t h ou ses n er ves, sm a ll
gla n ds, a n d blood vessels.
Th e pr im a r y fu n ct ion s of t h e sm a ll in t est in e a r e
digest ion a n d a bsor pt ion . E n zym es secr et ed by villi
pr om ot e digest ion . Vit a m in s, m in er a ls, fa t s, ca r bo-
h ydr a t es, pr ot ein s, wa t er, a n d elect r olyt es, su ch a s
sodiu m a n d pot a ssiu m , a r e a bsor bed t h r ou gh colu m -
n a r epit h eliu m of t h e in t est in a l m u cosa . Th e la m -
in a pr opr ia h ou ses in fect ion -figh t in g m a cr oph a ges,
pla sm a cells, a n d lym ph ocyt es. Repla cem en t of co-
lu m n a r epit h elia l cells is r a pid, pr im a r ily beca u se of
t h e pr esen ce of t h e cr ypt s of Lieber kü h n . Th ese pit -
like depr ession s st or e cells t h a t ca n qu ickly differ en -
t ia t e in t o r epla cem en t cells. Th e r a t e of pr odu ct ion
a n d differ en t ia t ion of epit h elia l cells is in cr ea sed
wit h in ju r y, t h er eby pr om ot in g h ea lin g a n d r epa ir.
Circula r fold
Villi
Mucos a
S ubmucos a
S e ros a
Mus cula ris
Blood ve s s e ls
Figure 3.26. Wall of small intestine.
Crohn Disease
Cr oh n disea se is select ed a s a clin ica l m odel t o
dem on st r a t e ch r on ic in fla m m a t or y pr ocess in t h e
sm a ll in t est in e. It is r ecu r r en t a n d ch a r a ct er ized by
a gr a n u lom a t ou s in fla m m a t or y pr ocess. Alt h ou gh
Cr oh n disea se ca n be fou n d a n ywh er e a lon g t h e ga s-
t r oin t est in a l t r a ct , t h e sm a ll in t est in e a n d a scen d-
in g colon , pa r t icu la r ly t h e su bm u cosa l la yer s, a r e
m ost oft en a ffect ed.
PATHOPHYSIOLOGY
Th e exa ct ca u se of Cr oh n disea se is u n kn own . Con -
sist en t wit h m a n y ot h er ch r on ic in fla m m a t or y con -
dit ion s, a u t oim m u n it y a n d gen et ic et iologies h a ve
been su ggest ed. Fa m ily h ist or y does pla y a r ole:
Th ose wit h a fa m ily h ist or y of bowel in fla m m a t ion
a r e m or e likely t o develop Cr oh n disea se. E n vir on -
m en t a l fa ct or s, su ch a s sm okin g, diet , or m icr oor-
ga n ism s, m a y t r igger t h e con dit ion a s well. As wit h
a ll con dit ion s, Cr oh n disea se h a s va r yin g levels of
disea se sever it y.
As m en t ion ed, ch r on ic in fla m m a t ion occu r s in
pa t ch y segm en t s (ca lled “skip lesion ”) of t h e in t es-
t in e a n d pen et r a t es a ll la yer s of t h ose segm en t s.
Bet ween a ffect ed a r ea s of in t est in e is u n a ffect ed,
n on in fla m ed bowel t issu e. In fla m m a t ion begin s in
t h e m u cosa a n d su bm u cosa . In cr ea sed per m ea bilit y
a n d va scu la r it y con t r ibu t es t o edem a a n d fibr osis.
Ma cr oph a ges, pla sm a cells, a n d lym ph ocyt es a r e
r elea sed in r espon se t o in fla m m a t or y m edia t or s.
Gr a n u lom a s develop t o wa ll off a ffect ed a r ea s.
As t h e a ffect ed bowel segm en t s becom e fu r t h er
in fla m ed, in t er ior su r fa ces t h icken beca u se of ex-
cessive edem a , fibr osis, a n d gr a n u lom a for m a t ion
(Fig. 3.27). Th e t h icken in g of t h e bowel ca n lea d
t o t ot a l bowel obst r u ct ion . In gest ed food is u n -
a ble t o m ove t h r ou gh t h e digest ive t r a ct , wh ich is
a life-t h r ea t en in g em er gen cy. Alt h ou gh t h icken in g
a n d gr a n u lom a for m a t ion a r e m ost ch a r a ct er ist ic of
Cr oh n disea se, u lcer s ca n for m in t h e in t est in a l m u -
cosa . Th ese u lcer s ca n becom e deep a n d pen et r a t e
t h r ou gh bowel la yer s, for m in g a fist u la . A is t u la is
a n a bn or m a l t r a ck or pa ssa ge t h a t for m s bet ween
t wo segm en t s of bowel or ot h er epit h elia l t issu e. At
t h e ba se of a fist u la , a n a b s c e s s , or pocket of pu -
r u len t (con t a in in g pu s) exu da t e, is likely t o develop.
E xt er n a l su r fa ces ca n a lso be a ffect ed by t h e ch r on ic
in fla m m a t or y r espon se. Ou t er su r fa ces ca n st ick t o
ot h er sect ion s of bowel a n d for m a dh esion s, fu r t h er
lim it in g bowel fu n ct ion .
Dest r u ct ion of t h e m u cosa a n d su bm u cosa lea ds
t o da m a ge t o t h e villi a n d cr ypt s. Th is da m a ge im -
pa ir s a bsor pt ive a n d epit h elia l r egen er a t ive fu n c-
t ion s wit h in t h e a ffect ed a r ea s. Ma ln u t r it ion fr om
t h e in a bilit y t o pr oper ly a bsor b n u t r ien t s fu r t h er
 Ap p lie d P a t h o p h y s io lo g y C lin ic a l Mo d e ls
Una ffe cte d a re a Na rrow lume n
Gra nuloma
Enla rge d
lymph node
Pe rfora tion
Abs ce s s
Figure 3.27. Major features of Crohn disease. (Modified from Rubin E, Farber JL. Pathology. 4th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2005, with permission.)
exa cer ba t es pr oblem s wit h h ea lin g. Th e m ost sever e
com plica t ion is m a ssive in fect ion a n d sh ock fr om t o-
t a l bowel obst r u ct ion a n d per for a t ion .
CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s a r e r ela t ed t o r a pid st ool
t r a n sit t im e, in t est in a l edem a a n d fibr osis, a n d loss
of a bsor pt ive fu n ct ion t h a t r esu lt s fr om bowel in -
fla m m a t ion du r in g per iods of exa cer ba t ion . Sym p-
t om s depen d on t h e loca t ion of t h e a ffect ed a r ea s.
Abdom in a l pa in , in t er m it t en t n on bloody dia r r h ea ,
m a ln u t r it ion , a n d o c c u lt , or h idden , blood in t h e
st ool a r e possible clin ica l m a n ifest a t ion s. Non bloody
dia r r h ea oft en in dica t es gr ea t er in volvem en t in t h e
su bm u cosa l la yer a s com pa r ed t o t h e m u cosa l la y-
er s. If t h e colon m u cosa l la yer is in volved, dia r r h ea
m a y con t a in m u cu s, blood, or pu s. Abdom in a l pa in is
oft en r elieved wit h defeca t ion . Syst em ic m a n ifest a -
t ion s a r e a lso com m on wit h Cr oh n disea se a n d ca n
in clu de fever, weigh t loss, a n d fa t igu e. An em ia is of-
t en pr esen t wh en t h er e is ch r on ic blood loss t h r ou gh
t h e ga st r oin t est in a l t r a ct .
DIAGNOSTIC CRITERIA
Dia gn osis of Cr oh n disea se is ba sed on t h e pa t ien t
h ist or y, ph ysica l exa m in a t ion , a n d dia gn ost ic t est s.
Dir ect visu a liza t ion wit h a n en doscope (sigm oidos-
copy) or wit h r a diogr a ph s sh ows a cobblest on e pa t -
t er n t o t h e m u cosa wit h a lt er n a t in g a ffect ed a n d
u n a ffect ed a r ea s of in fla m m a t ion . Com plica t ion s,
su ch a s a bscesses or fist u la s, ca n a lso be det ect ed
t h r ou gh r a diogr a ph s or CT sca n . St ool cu lt u r es m a y
be n eeded t o r u le ou t in fect iou s pr ocesses.
65
Una ffe cte d a re a
Fis tula into
a nothe r loop
of s ma ll inte s tine
TREATMENT
Tr ea t m en t is sym pt om a t ic. Medica t ion s t h a t su p-
pr ess t h e in fla m m a t or y a n d im m u n e r espon ses a r e
m ost oft en u sed. Diet a r y ch a n ges a r e r equ ir ed, a n d
foods t h a t ir r it a t e t h e bowel, su ch a s spicy foods,
sh ou ld be avoided. In dividu a ls wit h Cr oh n disea se
n eed a diet h igh in ca lor ies a n d pr ot ein , a n d low in
fa t a n d fiber du r in g exa cer ba t ion s. Su r gica l in t er-
ven t ion m a y be n eeded t o r em ove da m a ged bowel or
t o r epa ir fist u la s. Th ose wit h Cr oh n disea se a r e a t in -
cr ea sed r isk of sm a ll in t est in e a n d color ect a l ca n cer.
FUNCTIONS OF THE LARGE INTESTINE
Th e a n a t om y of t h e la r ge in t est in e is sim ila r t o t h e
sm a ll in t est in e, wit h t h e n ot a ble a bsen ce of villi in
t h e la r ge in t est in e. Colu m n a r epit h elia l cells a n d
m u cu s-secr et in g cells m a ke u p t h e m u cosa of t h e
la r ge in t est in e. Th e m a jor fu n ct ion of t h e la r ge in -
t est in e is t o a bsor b wa t er a n d elect r olyt es.
Ulcerative Colitis
Ulcer a t ive colit is is select ed a s a ch r on ic in fla m m a -
t or y con dit ion of t h e colon . Ulcer a t ive colit is is fou n d
exclu sively in t h e la r ge in t est in e a n d does n ot a ffect
ot h er a r ea s of t h e ga st r oin t est in a l t r a ct (Fig. 3.28).
It m ost oft en a ffect s t h e m u cosa l la yer bu t ca n ex-
t en d in t o t h e su bm u cosa .
PATHOPHYSIOLOGY
Th e exa ct ca u se of u lcer a t ive colit is is n ot kn own . Au -
t oim m u n it y h a s been im plica t ed beca u se a n t ibodies
66 C h a p t e r 3: In fla m m a t ion a n d Tissu e Repa ir
Tra ns ve rs e colon
As ce nding colon
Ce cum
Appe ndix
Re ctum
Anus
Infla mma tion
Figure 3.28. Ulcerative colitis. Chronic inflammation associated with ulcerative colitis is found exclusively in the large
intestine.
t o epit h elia l cells in t h e colon h a ve been fou n d in
som e in dividu a ls wit h u lcer a t ive colit is. Ulcer a t ive
colit is t ypica lly begin s in t h e dist a l r egion of t h e r ec-
t u m a n d ext en ds u p t h e descen din g colon . Th e a r ea
of in fla m m a t ion oft en r em a in s on t h e su r fa ce of t h e
m u cosa a n d is con t in u ou s; u lcer a t ive colit is does n ot
skip a n y a r ea s of t h e colon a lon g t h e wa y (F ig. 3.29).
Wit h u lcer a t ive colit is, in fla m m a t ion in va des t h e
su per ficia l m u cosa a n d ca u ses r ia b ilit y , a st a t e
wh er e t issu e r ea dily bleeds. Th e m u cosa becom es
Figure 3.29. Ulcerative colitis. Prominent erythema and
ulceration of the colon begin in the ascending colon and
are most severe in the rectosigmoid area. (From Ruben
E, Farber JL. Pathology. 3rd ed. Philadelphia, PA: Lippin-
cott-Raven; 1999:731, with permission.)
De s ce nding
colon
J e junum
Ile um
S igmoid colon
er yt h em a t ou s a n d gr a n u la r. H em or r h a gic lesion s
in t h e cr ypt s of Lieber kü h n , h igh ly ch a r a ct er ist ic of
u lcer a t ive colit is, ca n for m in t o a bscesses. E xt en sive
exu da t e is pr esen t ea r ly in t h e pr ocess, a n d n ecr o-
sis a n d u lcer a t ion a r e com m on . In fla m m a t or y pr o-
cesses pr om ot e t h e developm en t of pseu dopolyps.
Over t im e, epit h elia l cells of t h e m u cosa begin t o a t -
r oph y. Met a pla sia ca n occu r. Th ose wit h lon g-st a n d-
in g u lcer a t ive colit is dem on st r a t e a h igh er r isk for
color ect a l ca n cer t h a n t h ose wit h Cr oh n disea se.
Ot h er pot en t ia l com plica t ion s in clu de obst r u ct ion ,
per for a t ion , a n d m a ssive h em or r h a ge. Ta ble 3.8 a n d
F igu r e 3.30 com pa r e pa t h oph ysiologic differ en ces
wit h Cr oh n disea se a n d u lcer a t ive colit is.
CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s a r e r ela t ed t o la r ge in t est in e
ir r it a bilit y a n d fr ia bilit y. Dia r r h ea , oft en wit h r ect a l
bleedin g, is t h e m ost com m on clin ica l m a n ifest a t ion .
Abdom in a l pa in , fever, wea kn ess, fa t igu e, a n d a n e-
m ia ca n a lso occu r. F u n ct ion a l losses wit h u lcer a t ive
colit is a r e r ela t ed t o t h e ext en t of in fla m m a t ion ; im -
pa ir ed wa t er a n d elect r olyt e a bsor pt ion a r e n ot a ble
wit h ext en sive disea se.
DIAGNOSTIC CRITERIA
Ulcer a t ive colit is is dia gn osed t h r ou gh en dos-
copy, wh ich sh ows m u cosa l er yt h em a . Ra diogr a ph s
ca n det ect colon ic dila t ion , u lcer s, per for a t ion , or
 Ap p lie d P a t h o p h y s io lo g y C lin ic a l Mo d e ls 67

● Moder a t e = gr ea t er t h a n fou r
Ta b le 3.8 Com pa r ison of Cr oh n Disea se a n d Ulcer a t ive Colit is bowel m ovem en t s per da y; n o
C r o h n D is e a s e U lc e r a t iv e C o lit is syst em ic m a n ifest a t ion s
● Sever e = gr ea t er t h a n fou r
Loca t ion Sm a ll in t est in e a n d a scen din g Descen din g colon bowel m ovem en t s per da y
colon wit h syst em ic m a n ifest a t ion s
Pa t t er n Skip lesion s Con t in u ou s a n d low blood a lbu m in (pr o-
Dept h P r im a r ily su bm u cosa l P r im a r ily m u cosa l t ein ) levels
Dia r r h ea Wa t er y Bloody
Abdom in a l pa in Yes Yes
TREATMENT
Bowel obst r u ct ion Com m on Un com m on
Ca n cer r isk In cr ea sed H igh er r isk t h a n wit h Tr ea t m en t is sym pt om a t ic. An t i-
Cr oh n ’s in fla m m a t or y, a n t idia r r h ea l,
a n d im m u n osu ppr essive m edi-
ca t ion s a r e som et im es u sed. A
h ea lt h y diet a n d a dequ a t e flu id
obst r u ct ion . Sever it y is ba sed on t h e n u m ber of in t a ke a r e r ecom m en ded. Avoida n ce of cer t a in foods
bowel m ovem en t s wit h r ect a l bleedin g a n d t h e pr es- su ch a s m ilk, ca ffein e, or spicy foods m a y be r ecom -
en ce of syst em ic m a n ifest a t ion s: m en ded. Su r ger y m a y be n eeded if m edica l t h er a -
● Mild = fewer t h a n fou r bowel m ovem en t s per da y; pies a r e in effect ive, or if per for a t ion or obst r u ct ion
n o syst em ic m a n ifest a t ion s occu r s.

Cro hn dis e as e

W
v

Ulc e rative c o litis

v
W

y,

Figure 3.30. Crohn disease and ulcerative colitis. The two drawings illustrate critical differences in how the two diseases
affect the gastrointestinal tract.
68 C h a p t e r 3: In fla m m a t ion a n d Tissu e Repa ir
S U MMAR Y
● In fla m m a t ion is r equ ir ed for t issu e h ea lin g a n d
occu r s in r espon se t o t issu e in ju r y.
● In fla m m a t or y m edia t or s, u n der t h e dir ect ion of
t h e t h r ee pla sm a pr ot ein syst em s, r egu la t e t h e
in fla m m a t or y r espon se.
● In fla m m a t or y m edia t or s elicit va scu la r a n d cel-
lu la r r espon ses ch a r a ct er ized by va sodila t ion ,
in cr ea sed ca pilla r y per m ea bilit y, ch em ot a xis, cel-
lu la r a dh er en ce, a n d cellu la r m igr a t ion .
● P h a gocyt ic cells (n eu t r oph ils a n d la t er m a c-
r oph a ges) t a xi t o t h e sit e t o en gu lf a n d dest r oy
h a r m fu l su bst a n ces.
● Rem ova l of t h e in ju r y will dir ect r esolu t ion of t h e
a cu t e in fla m m a t or y r espon se.
● Tissu e h ea lin g is a m u lt ist ep pr ocess t h a t in -
volves cover in g t h e wou n d, clea r in g t h e debr is,
a n d r est or in g st r u ct u r a l a n d fu n ct ion a l in t egr it y.
● Th e r esu lt s of t h e in fla m m a t or y r espon se a r e t o
r epa ir, r egen er a t e, or r epla ce da m a ged t issu e.
● Per sist en t in ju r y, su ch a s wit h ch r on ic in fect ion
or a u t oim m u n e con dit ion s, r esu lt s in ch r on ic
in fla m m a t ion .
● Ch r on ic in fla m m a t ion differ s fr om a cu t e in fla m -
m a t ion in t h e t ypes of pr om in en t cells a n d in t h e
t issu e r epa ir pr ocess. Ma cr oph a ges a n d fibr o-
bla st s a r e m u ch m or e pr om in en t , r esu lt in g in in -
cr ea sed t issu e dest r u ct ion , fibr osis, sca r r in g, a n d
gr a n u lom a for m a t ion .
● Ch r on ic in fla m m a t or y ou t com es con t r ibu t e t o
poor wou n d h ea lin g. Ot h er com plica t ion s of
wou n d h ea lin g in clu de in fect ion , u lcer s, wou n d
deh iscen ce, keloid for m a t ion , a n d a dh esion s.
C AS E S T U D Y 3.1
A fr ien d h a s disclosed t h a t sh e h a s been h a vin g pr ob-
lem s wit h h ea r t bu r n . Sh e h a s been t old t h a t sh e h a s
ga st r oesoph a gea l r eflu x disea se (GE RD), in wh ich
st om a ch a cid ba cks u p in t o t h e esoph a gu s, ca u sin g
esoph a git is. Th in k a bou t wh ich clin ica l m odel is
m ost r ela t ed t o t h is pr ocess. Fr om you r r ea din g r e-
la t ed t o cellu la r in ju r y a n d a da pt a t ion s a s well a s
in fla m m a t ion , a n swer t h e followin g qu est ion s:
1. Wh a t a n a t om ic pr oblem m ost likely lea ds t o ga s-
t r oesoph a gea l r eflu x?
2. Wh a t is t h e in ju r y in ga st r oesoph a gea l r eflu x?
3. Wh a t wou ld t h e a cu t e in fla m m a t or y r espon se
look like?
4. Wh y m igh t t h is con dit ion becom e a ch r on ic
pr oblem ?
5. Wh a t pa t h oph ysiologic ch a n ges wou ld m ost likely
occu r wit h ch r on ic ga st r oesoph a gea l r eflu x?
6. Wh a t wou ld you expect for clin ica l m a n ifest a t ion s?
7. Wh a t dia gn ost ic t est s m igh t be u sed?
8. Wh a t t r ea t m en t m ea su r es wou ld you a n t icipa t e?
Log on t o t h e In t er n et , u sin g t h e sea r ch wor ds “ga s-
t r oesoph a gea l r eflu x.” Sea r ch for r eleva n t jou r n a l
a r t icles or Web sit es t h a t det a il t h is con dit ion , a n d
con fir m you r pr edict ion s.
C AS E S T U D Y 3.2
J a son is a lon g-dist a n ce r u n n er. H e is in t h e clin ic
t oda y com pla in in g of h eel pa in a n d t igh t n ess a lon g
t h e ba ck of h is foot a n d a n kle. H e h a s been r ecen t ly
r u n n in g in door s on t h e t r ea dm ill a s t h e wea t h er h a s
been t oo cold t o r u n ou t side. H e is dia gn osed wit h
Ach illes t en don it is. Fr om you r r ea din g r ela t ed t o
cellu la r in ju r y a n d a da pt a t ion s a s well a s in fla m m a -
t ion , a n swer t h e followin g qu est ion s:
1. Wh a t a n a t om ic pr oblem m ost likely lea ds t o
t en don it is?
2. Wh a t is t h e in ju r y in t en don it is?
3. Wh a t wou ld t h e a cu t e in fla m m a t or y r espon se
look like?
4. Wh y m igh t t h is con dit ion becom e a ch r on ic
pr oblem ?
5. Wh a t pa t h oph ysiologic ch a n ges wou ld m ost likely
occu r wit h t en don it is?
6. Wh a t wou ld you expect for clin ica l m a n ifest a t ion s?
7. Wh a t dia gn ost ic t est s m igh t be u sed?
8. Wh a t t r ea t m en t m ea su r es wou ld you a n t icipa t e?
Log on to the Internet, using the search words “tendon-
itis.” Search for relevant journal articles or Web sites
that detail this condition, and confirm your predictions.
C AS E S T U D Y 3.3
Mela n ie h a s h a d a r ecen t cold wit h sym pt om s of
r u n n y n ose, sn eezin g, cou gh in g, con gest ion , a n d
m a la ise. Toda y, sh e is con cer n ed t h a t sh e h a s a
sh a r p pa in in h er ch est . Sh e goes t o see h er h ea lt h
ca r e pr ovider, a n d is dia gn osed wit h cost och on dr it is,
a n in fla m m a t ion in t h e ca r t ila ge bet ween t h e r ibs.
F r om you r r ea din g r ela t ed t o cellu la r in ju r y a n d a d-
a pt a t ion s a s well a s in fla m m a t ion , a n swer t h e fol-
lowin g qu est ion s:
1. Wh a t a n a t om ic pr oblem m ost likely lea ds t o
cost och on dr it is?
2. Wh a t is t h e in ju r y in cost och on dr it is?
3. Wh a t wou ld t h e a cu t e in fla m m a t or y r espon se
look like?
4. Wh y m igh t t h is con dit ion becom e a ch r on ic
pr oblem ?
 C h a p t e r 3: In fla m m a t ion a n d Tissu e Repa ir 69

5. Wh a t pa t h oph ysiologic ch a n ges wou ld m ost likely a. Su per ficia l pa r t ia l-t h ickn ess bu r n
occu r wit h cost och on dr it is? b. Deep pa r t ia l-t h ickn ess bu r n
6. Wh a t wou ld you expect for clin ica l m a n ifest a t ion s? c. F u ll-t h ickn ess bu r n
7. Wh a t dia gn ost ic t est s m igh t be u sed? d. Der m a l t h ickn ess bu r n
8. Wh a t t r ea t m en t m ea su r es wou ld you a n t icipa t e?
Log on t o t h e In t er n et , u sin g t h e sea r ch wor ds “cos- 7. Th e h ospit a lized bu r n pa t ien t wa n t s t o kn ow
t och on dr it is.” Sea r ch for r eleva n t jou r n a l a r t icles wh y you n eed t o r em ove h is dr essin gs ever y da y.
or Web sit es t h a t det a il t h is con dit ion , a n d con fir m It is pa in fu l a n d h e wa n t s t o a void u n cover in g
you r pr edict ion s. h is bu r n in ju r y. You expla in t h a t r em ovin g t h e
dr essin gs pr om ot es:
a . Debr idem en t
b. In fect ion
P R AC T I C E E XAM Q U E S T I O N S c. Skin fu n ct ion
d. Dr yin g t h e exu da t e
1. You get a pa per cu t a n d exper ien ce pa in a t t h e
sit e. Th is r espon se is r ela t ed t o:
a . In cr ea sed per fu sion a t t h e sit e 8. Wh a t is t h e on e defin it ive t est t o dia gn ose r h eu -
b. In cr ea sed exu da t e a n d ch em ica l m edia t or s a t m a t oid a r t h r it is?
t h e sit e a . A posit ive r h eu m a t oid fa ct or (RF )
c. Ba ct er ia t h a t h a ve en t er ed t h e wou n d b. An eleva t ed er yt h r ocyt e sedim en t a t ion r a t e
d. Va socon st r ict ion a t t h e sit e (E SR)
c. A posit ive a n t in u clea r a n t ibody (ANA)
2. In fla m m a t ion is u lt im a t ely n eeded t o: d. On e t est is n ot defin it ive
a . In cr ea se in fla m m a t or y m edia t or s a t t h e sit e
t o va socon st r ict t h e a r ea 9. Wh ich of t h e followin g is t h e m ost com m on ca u se
b. In cr ea se pla t elet s a t t h e sit e for clot t in g of a cu t e ga st r it is?
c. Rest or e fu n ct ion a l cells a . Poor ga st r ic per fu sion
d. P r epa r e t h e sit e for h ea lin g b. Too m u ch st om a ch a cid
c. In gest ion of a spir in , a lcoh ol, or ot h er ch em ica ls
3. A wou n d is 6 cm × 6 cm × 4 cm . A wou n d wit h d . H . pylor i in fect ion
t h ese dim en sion s n eeds t o h ea l t h r ou gh :
a . Secon da r y in t en t ion 10. Wh y is Cr oh n disea se m or e likely t o ca u se in t es-
b. P r im a r y in t en t ion t in a l obst r u ct ion t h a n u lcer a t ive colit is?
c. Ter t ia r y in t en t ion a . Cr oh n disea se is loca t ed in t h e sm a ll in t est in e.
d. Sca r t issu e for m a t ion b. Cr oh n disea se ca u ses gr a n u lom a s t o for m in
t h e su bm u cosa l la yer.
4. A m a jor differ en ce bet ween t h e a cu t e a n d c. Cr oh n disea se ca u ses a bdom in a l pa in a n d wa -
ch r on ic in fla m m a t or y r espon se is t h a t in ch r on ic t er y dia r r h ea .
in fla m m a t ion : d. Cr oh n disea se is exa cer ba t ed by cer t a in foods,
a . In fla m m a t or y m edia t or s a r e r elea sed su ch a s spicy foods.
b. Neu t r oph ils a r e m u ch m or e pr om in en t
c. Gr a n u lom a s for m a r ou n d cer t a in in va der s
d. Gr a n u la t ion t issu e is pr esen t 11. A pa t ien t is t a kin g a n a n t i-in fla m m a t or y dr u g
for r h eu m a t oid a r t h r it is. Wh a t is t h e m ost likely
5. Wh ich is n ot a loca l m a n ifest a t ion of a cu t e a ct ion for t h is dr u g?
in fla m m a t ion ? a . Blocks t h e ch em ica l m edia t or s of in fla m m a t ion
a . E dem a b. E n h a n ces t h e body’s im m u n e syst em
b. Redn ess c. In cr ea ses blood flow t o t h e t issu es
c. Loss of fu n ct ion d. Decr ea ses sca r for m a t ion
d. Leu kocyt osis
12. Wh ich of t h e followin g is t h e m ost com m on ca u se
6. Dept h of in ju r y is im por t a n t t o det er m in e wit h of a cu t e pa n cr ea t it is?
bu r n s. You a r e in t h e su n t oo lon g wit h ou t su n - a . Ca n cer
scr een a n d develop r edn ess a n d blist er in g on b. Au t oim m u n it y
you r fa ce, ch est , a n d ba ck. Wh a t dept h of bu r n c. E xcess a lcoh ol in t a ke
did you exper ien ce? d. Cyst ic fibr osis
70 C h a p t e r 3: In fla m m a t ion a n d Tissu e Repa ir
13. Rh eu m a t oid a r t h r it is r esu lt s in join t im m obilit y
a s a r esu lt of:
a . Syn ovia l flu id loss
b. Pa n n u s for m a t ion
c. Rh eu m a t oid fa ct or
d. J oin t devia t ion
14. Wh ich of t h e followin g m ea ls wou ld you r ec-
om m en d t o a pa t ien t wit h a wou n d t o pr om ot e
h ea lin g?
a . E ggs a n d or a n ge ju ice
b. Spa gh et t i a n d ga r lic t oa st
c. St ea k a n d pot a t oes
d. Tom a t o sou p a n d gr illed ch eese
D I S C U S S I O N AN D
AP P L I C AT I O N
1. Wh a t did I kn ow a bou t in fla m m a t ion a n d t issu e
r epa ir pr ior t o t oda y?
2. Wh a t body pr ocesses a r e a ffect ed by in fla m m a -
t ion ? Wh a t a r e t h e expect ed fu n ct ion s of t h ose
pr ocesses? H ow does in fla m m a t ion im pa ct t h ose
pr ocesses?
3. Wh a t a r e t h e pot en t ia l et iologies for in fla m m a -
t ion ? H ow does in fla m m a t ion develop?
4. Wh o is m ost a t r isk for developin g in fla m m a -
t ion ? H ow ca n in fla m m a t ion be pr even t ed?
5. Wh a t a r e t h e h u m a n differ en ces t h a t a ffect t h e
et iology, r isk, or cou r se of in fla m m a t ion ?
6. Wh a t clin ica l m a n ifest a t ion s a r e expect ed
du r in g in fla m m a t ion ?
7. Wh a t specia l dia gn ost ic t est s a r e u sefu l in det er-
m in in g t h e dia gn osis a n d cou r se of in fla m m a t ion ?
8. Wh a t a r e t h e goa ls of ca r e for in dividu a ls wit h
in fla m m a t ion ?
9. H ow does t h e con cept of in fla m m a t ion bu ild on
wh a t I h a ve lea r n ed in t h e pr eviou s ch a pt er s
a n d in pr eviou s cou r ses?
10. H ow ca n I u se wh a t I h a ve lea r n ed?
F in d a d d ition a l r esou r ces for th is ch a pter a t h ttp:th ePoin t.lww.com
R E SOUR CE S
In fla m m a t ion Resea r ch Fou n da t ion :
h t t p://www.in fla m m a t ion r esea r ch fou n da t ion .or g/
Am er ica n Bu r n Associa t ion :
h t t p://www.a m er ibu r n .or g/
E -m edicin e:
h t t p://em edicin e.m edsca pe.com /
R e er en ces
1. Geet h a M, Un n ikr ish n a n M. Mu lt i-t a r get dr u gs t o a d-
dr ess m u lt iple ch eckpoin t s in com plex in fla m m a t or y
pa t h ologies: evolu t ion a r y cu es for n ovel “fir st in cla ss”
a n t i-in fla m m a t or y dr u g ca n dida t es. In fla m m Res.
2015;64:747–752.
2. Cor bet t J. La bor a tor y Tests a n d Dia gn ostic P r oced u r es
With Nu r sin g Dia gn oses. 8t h ed. Upper Sa ddle River,
NJ : P r en t ice H a ll; 2012.
3. Br ook I. Acu t e sin u sit is. 2015. h t t p://em edicin e
.m edsca pe.com /a r t icle/232670-over view
4. Br ook I. Ch r on ic sin u sit is. 2015. h t t p://em edicin e
.m edsca pe.com /a r t icle/232791-over view
5. Am er ica n Bu r n Associa t ion . Bu r n in ciden t fa ct sh eet .
h t t p://www.a m er ibu r n .or g/r esou r ces_fa ct sh eet .ph p.
Accessed J a n u a r y 10, 2015.
6. Dou ga dos M, Sou br ier M, An t u n ez A, et a l. P r eva len ce
of com or bidit ies in r h eu m a t oid a r t h r it is a n d eva lu a -
t ion of t h eir m on it or in g: r esu lt s of a n in t er n a t ion a l,
cr oss-sect ion a l st u dy (COMORA). An n Rh eu m Dis.
2014;73:62–68.
7. Mya soedova E , Ch a n dr a n A, Ilh a n B, et a l. Th e r ole of
r h eu m a t oid a r t h r it is (RA) fla r e a n d cu m u la t ive bu r den
of RA sever it y in t h e r isk of ca r diova scu la r disea se. An n
Rh eu m Dis. doi:10.1136/a n n r h eu m dis-2014-206411.
8. Ga r dn er T. Acu t e pa n cr ea t it is. 2015. h t t p://em edicin e.
m edsca pe.com /a r t icle/181364-over view
9. Ra n son J H . E t iologica l a n d pr ogn ost ic fa ct or s in h u -
m a n a cu t e pa n cr ea t it is: a r eview. Am J Ga str oen ter ol.
1982;77:633–638.
10. H u ffm a n J L. Ch r on ic pa n cr ea t it is. 2015. h t t p://
em edicin e.m edsca pe.com /a r t icle/181554-over view
11. Rowe WA. In fla m m a t or y bowel disea se. 2015. h t t p://
em edicin e.m edsca pe.com /a r t icle/179037-over view
 Ch a pt er

Alt er ed Im m u n it y 4
L E AR N I N G O U T C O ME S
1. Defin e a n d u se t h e key t er m s list ed in t h is ch a pt er.
2. Descr ibe t h e fu n ct ion of t h e cellu la r com pon en t s (lym ph ocyt es, m a cr o-
ph a ges, a n d a n t igen -pr esen t in g cells) in a da pt ive im m u n e defen se pr ocess.
3. Differ en t ia t e bet ween t h e in n a t e a n d a da pt ive im m u n e r espon ses.
4. Defin e t h e pr ocesses of pr im a r y a n d secon da r y a n t ibody r espon ses in t h e
developm en t of im m u n it y.
5. Ou t lin e t h e sim ila r it ies a n d differ en ces bet ween t h e t ypes of T lym ph o-
cyt es a ct ive in cell-m edia t ed im m u n it y.
6. P r edict t h e pot en t ia l a lt er a t ion s in im m u n e r espon ses r esu lt in g fr om dys-
fu n ct ion in t h e im m u n oglobu lin s IgA, IgD, IgE , IgG, a n d IgM.
7. Com pa r e a n d con t r a st t he pr ocess of a lt er ing im m u ne fun ct ion a ssocia t ed
wit h h ost defense fa ilur e, h yper sen sit ivit y, a ut oim m un it y, a n d a lloim m u nit y.
8. Recogn ize t h e in t er a ct ion s bet ween cell-m edia t ed a n d h u m or a l im m u n e
r espon ses n ecessa r y for m ou n t in g a n effect ive im m u n e r espon se.
9. Apply con cept s of a lt er ed im m u n e fu n ct ion t o select clin ica l m odels.

INTR ODUCTION
People live in a wor ld in wh ich t h er e is a con st a n t r isk of h a r m fu l su bst a n ces
en t er in g t h eir bodies. E ven wh en a sleep, t h e body’s defen ses a r e pr ot ect in g
a ga in st over wh elm in g in fect ion . Th ese defen ses a r e pr ovided by t h e coor din a -
t ion of t h e m a n y com pon en t s t h a t m a ke u p t h e im m u n e syst em . Th e fir st lin e
of defen se, t h e skin a n d m u cou s m em br a n es, a n d t h e secon d lin e of defen se,
t h e in fla m m a t or y r espon se, wer e r eviewed in det a il in Ch a pt er 3. Th e in n a t e
im m u n e r espon se is r a pid a n d n on specific, in volvin g in fla m m a t or y r espon se
pr ocesses. Th e a da pt ive im m u n e r espon se, t h e t h ir d lin e of defen se, a llows t h e
body t o seek ou t a n d dest r oy n ew a n d old for eign in va der s a n d is t h e focu s
of t h e discu ssion in t h is ch a pt er. Th e a da pt ive im m u n e r espon se is t a r get ed
a n d specific, in volvin g t wo pr im a r y pr ocesses: cell-m edia t ed im m u n it y a n d h u -
m or a l im m u n it y.
Th is ch a pt er pr ovides a br ief r eview of n or m a l fu n ct ion , followed by t h e
pa t h oph ysiology of a lt er a t ion s in im m u n e fu n ct ion . E xa m ples of con dit ion s
wit h pa t h ogen esis r esu lt in g fr om a lt er ed im m u n it y will h igh ligh t t h e a pplica -
t ion of con cept s of a lt er ed im m u n e r espon ses. Developin g a n u n der st a n din g of
t h ese r espon ses will h elp t o t r a n sla t e t h e sign s a n d sym pt om s of disea se st a t es
t h a t r esu lt fr om m a la da pt ive im m u n e r espon ses. Applica t ion of t h ese con cept s
will for m t h e ba sis for dia gn osis, pr even t ion , a n d t r ea t m en t of a va r iet y of con -
dit ion s a ssocia t ed wit h a lt er ed im m u n it y. 71
72 C h a p t e r 4: Alt er ed Im m u n it y
Modu le 1 R e v ie w o I m m u n e F u n c t io n
Th e pr ocess by wh ich t h e body r ecogn izes for eign
su bst a n ces a n d n eu t r a lizes t h em t o pr even t da m a ge
is kn own a s im m u n it y . Ada pt ive im m u n e defen se is
ch a r a ct er ized by:
● S p e c i ic it y : Th e im m u n e cells seek ou t a n d de-
st r oy t a r get ed for eign in va der s.
● Me m or y: The immune cells produce substances that
remember and more easily destroy return offenders.
To see a video on t h e im m u n e r espon se,
visit h t t p://t h ePoin t .lww.com . I m m u -
n o lo g y is t h e st u dy of t h e st r u ct u r e a n d fu n ct ion of
t h e im m u n e syst em , a s well a s t h e ph en om en a of im -
m u n it y, in du ced sen sit ivit y, a n d a ller gy. Th e im m u n e
syst em r espon se, r efer r ed t o a s a da pt ive im m u n it y,
Ta b le 4.1 F u n ct ion of Im m u n e Defen se Com pon en t s
Com p on en t
C e n t r a l I m m u n e S t r u c t u r e s : I m m u n e C e ll P r o d u c t io n a n d Ma t u r a t io n
Bon e m a r r ow
Th ym u s
P e r ip h e r a l I m m u n e S t r u c t u r e s : P r o c e s s An t ig e n a n d P r o m o t e As s o c ia t io n Wit h Ma t u r e I m m u n e C e lls
Lym ph n odes
Spleen
Lym ph oid m u cosa l t issu e (t on sils, Peyer
pa t ch es, a ppen dix)
P r im a r y C e llu la r C o m p o n e n t s
T lym ph ocyt es
B lym ph ocyt es
Ac c e s s o r y C e llu la r C o m p o n e n t s
Ma cr oph a ge
Neu t r oph il
Den dr it ic cells
is st im u la t ed wh en specia lized cells com e in con t a ct
wit h a n a n t ig e n , a su bst a n ce t h a t in du ces a st a t e of
sen sit ivit y or a n im m u n e r espon se. Typica lly, t h e a n -
t igen is for eign a n d r ecogn ized a s “n on self,” pr om pt -
in g a n im m u n e r espon se t h a t spa r es “self ” body
cells. Th e a da pt ive im m u n e r espon se is in it ia t ed by
t wo m a in com pon en t s: t h e t ype of a n t igen pr esen t ed
t o t h e cells a n d t h e t ype of cells t o wh ich t h e a n t i-
gen is pr esen t ed. Th e pr ocesses of cell-m edia t ed a n d
h u m or a l im m u n it y wor k t oget h er in t h e dest r u ct ion
of specifica lly t a r get ed cells. Th e a da pt ive im m u n e
r espon se in volves cen t r a l a n d per iph er a l im m u n e
st r u ct u r es, a s well a s pr im a r y a n d a ccessor y cellu la r
com pon en t s, in t h e developm en t of specific im m u n e
r espon ses, su m m a r ized in Ta ble 4.1. Th e cells a n d
L o c a t io n a n d /o r F u n c t io n
P r odu ct ion of lym ph ocyt es
Ma t u r a t ion of B lym ph ocyt es
Gla n d loca t ed in t h e m edia st in u m
Differ en t ia t ion a n d m a t u r a t ion of lym ph ocyt es
Rou n ded m a sses of lym ph a t ic t issu e
Spr ea d ou t a lon g lym ph a t ic vessels
Con t a in m a n y lym ph ocyt es, wh ich filt er t h e lym ph a t ic flu id
Sit e of lym ph ocyt e m igr a t ion
Sit e of lym ph ocyt e a ggr ega t ion
Ma t u r ed in t h ym u s
E ssen t ia l in a da pt ive cell-m edia t ed im m u n it y
Dest r u ct ion of cellu la r a n t igen s
P r om ot e a n t ibody pr odu ct ion by B lym ph ocyt es
Accou n t for 60% of blood lym ph ocyt es
Ma t u r ed in bon e m a r r ow
E ssen t ia l in m edia t in g a da pt ive h u m or a l im m u n it y
P r odu ct ion of a n t ibodies/im m u n oglobu lin s
Accou n t for 10%–20% of blood lym ph ocyt es
E ssen t ia l in m edia t in g in n a t e im m u n it y
Bin d in va din g m icr obes t o cell su r fa ce r ecept or s
P r ocess a n d pr esen t a n t igen t o T a n d B lym ph ocyt es, st im u la t in g a da p-
t ive im m u n e r espon se
P h a gocyt osis t o pr even t colon iza t ion , en t r y, a n d spr ea d of m icr obes
 R e v ie w o I m m u n e F u n c t io n 73

or ga n s of t h e body wor k in exqu isit e h a r m on y t o t ypes: t h e ly m p h o id p r o g e n it o r a n d t h e m y e lo id

pr ot ect t h e body a ga in st ba ct er ia , pa r a sit es, vir u ses,
a n d a ller gen s in well-defin ed pr ocesses.
Cellular Components of Immunity
Ma n y of t h e cell t ypes in volved in im m u n e r espon se
wer e fir st in t r odu ced in Ch a pt er 3 beca u se som e
of t h e sa m e cells a r e in volved in t h e in fla m m a t or y
r espon se. Th e in it ia l, r a pid r espon se t o for eign in -
va der s is kn own a s t h e in n a t e im m u n e r espon se, a
n on specific r espon se a ssocia t ed wit h in fla m m a t ion .
Th e cellu la r com pon en t s in volved in in n a t e im -
m u n it y a r e a lso im por t a n t in a da pt ive im m u n it y a s
t h ey a r e a ble t o pr ocess t h e for eign a n t igen s t h r ou gh
ph a gocyt osis a n d t h en pr esen t t h em t o t h e cells in -
volved in a da pt ive im m u n it y. Th is st ep is essen t ia l
for t h e r ecogn it ion of for eign a n t igen s by a da pt ive
im m u n it y cells. Cellu la r com pon en t s of im m u n e de-
fen se a r e illu st r a t ed in Figu r e 4.1.
IMMUNE CELL ORIGIN
Th e im m u n e cells of a da pt ive im m u n it y h a ve a com -
m on or igin in t h e plu r ipot en t h em a t opoiet ic st em
cells. Or igin a t in g in t h e bon e m a r r ow, t h e plu r ipot en t
h em a t opoiet ic st em cells pr odu ce t wo pr ecu r sor cell
p r o g e n it o r . Na t u r a l killer cells, T lym ph ocyt es a n d
B lym ph ocyt es, a r e der ived fr om t h e lym ph oid pr o-
gen it or cells. Th e m yeloid pr ogen it or cells pr odu ce
ot h er t ypes of cells t h r ou gh t h e gr a n u locyt e/m a cr o-
ph a ge pr ogen it or. Th ese cells in clu de t h e m on ocyt es,
den dr it ic cells, gr a n u locyt es, a n d m a st cells.
Lymphoid Progenitor Cells
Wh it e blood cells (WBCs), a lso kn own a s leu kocyt es,
a r e t h e ba sic fu n ct ion a l u n it s of t h e im m u n e syst em .
Lym ph ocyt es a ccou n t for 25% t o 35% of t h e leu ko-
cyt es cir cu la t in g in t h e blood, a lt h ou gh 99% of lym -
ph ocyt es a r e loca t ed in t h e lym ph flu id. Th r ee m a jor
ca t egor ies of WBCs a r e der ived fr om t h e lym ph oid
pr ogen it or cells a n d pla y a n essen t ia l r ole in im -
m u n e fu n ct ion . Th ese cell t ypes in clu de:
1. T lym ph ocyt es
2. B lym ph ocyt es
3. Na t u r a l killer cells
Th e T ly m p h o c y t e s m a t u r e a n d fu lly differ en t ia t e
in t h e th ym u s. T lym ph ocyt es r equ ir e con t a ct wit h
a n a n t igen t h a t sign a ls t h e T lym ph ocyt es t o pr olif-
er a t e a n d differ en t ia t e in t o t h e followin g cla ssifica -
t ion s of cells:
● C y t o t o x ic T ly m p h o c y t e s : dir ect dest r u ct ion of
a n t igen -ca r r yin g cells

Immune De fe ns e
No ns pe c ific S pe c ific

Innate Immunity Adaptive Immunity

Ne utrophil Na tura l kille r ce ll De ndritic ce ll Monocyte B lymphocyte s T lymphocyte s

e ffe ctor

P ha gocytos is Nonspecific cellular Antige n Ma cropha ge

antigen destruction pre s e nta tion

Cytotoxic T cell He lpe r T ce ll

Me mory ce lls P la s ma ce lls
(CD8) (CD4)
P ha gocytos is

Efficie nt, S e cre tion of S pe cific Activa tion

ra pid a ntibody a ntibody/ ce llula r of a ntige n-
re s pons e to immuno- a ntige n s pe cific
s ubs e que nt globulin (Ig) de s truction T ce ll
a ntige n
re cognition

Figure 4.1. Concept map. Cellular components involved in immune defense.

74 C h a p t e r 4: Alt er ed Im m u n it y
● H e lp e r T ly m p h o c y t e s : en h a n ce h u m or a l a n d
cell-m edia t ed r espon ses of t h e im m u n e syst em
● S u p p r e s s o r T ly m p h o c y t e s : in h ibit h u m or a l
a n d cell-m edia t ed r espon ses
Th e cyt ot oxic T lym ph ocyt e a t t a cks t u m or cells a n d
cells in fect ed wit h vir u ses, wh ile t h e h elper T lym -
ph ocyt e a ct iva t es ot h er cells n eeded for a n a ppr o-
pr ia t e im m u n e r espon se. Su ppr essor T lym ph ocyt es
pr ovide a ba la n ce, lim it in g im m u n e r espon ses.
E a ch T lym ph ocyt e h a s a u n iqu e r ecept or, or T-c e ll
r e c e p t o r (T C R ), wh ich is a ble t o bin d t o a n t igen s,
pr om ot in g a specific im m u n e r espon se.
B lym p h ocyt e s develop in the bone ma rrow. B lym-
phocytes migrate from the bone marrow to the periph-
eral lymphoid tissues, where they become activated
after contact with an antigen. Binding of the antigen
with the B lymphocyte stimulates differentiation of B
lymphocytes into antibody-secreting plasma cells. The
B lymphocytes recognize specific antigens because of
the B-ce ll r e ce p t or , or BCR , bound to the cell mem-
brane of the B lymphocytes. The uniqueness of anti-
gen–BCR binding contributes to the specificity of the
adaptive immune response. After antigen–BCR bind-
ing, the B lymphocytes differentiate into plasma cells,
which proliferate and begin to produce and secrete
large quanitities of antibodies that target the specific
antigen bound to the BCR. Antibodies are released from
the membranes of plasma cells. The secreted antibody
is known as im m u n oglob u lin , or Ig. The main classes
of immunoglobulins include IgA,
IgG, IgM, IgD, and IgE (Table 4.2).
These antibodies are designed to Ta b le 4.2 P r im a r y Role of Im m u n oglobu lin Cla sses
detect and bind to specific anti-
Im m u n oglob u lin % o To t a l C h a r a c t e r is t ic s
gens, each playing a different role
in the immune response. IgA
N a t u r a l k ille r (N K) c e lls
a r e la r ge, gr a n u la r lym ph ocyt es.
NK cells a r e a ct ive in in n a t e im -
m u n it y. NK cells cir cu la t e u n t il IgG
t h ey com e in con t a ct wit h cells
t h ey ca n r ecogn ize a s a t h r ea t ,
su ch a s vir a lly in fect ed cells or
t u m or cells. NK cells exer t t h eir
cyt ot oxic effect t h r ou gh a t t a ck
a n d killin g of t a r get ed cells.
Myeloid Progenitor Cells IgM
Myeloid progenitor cells produce
granulocytes and monocytes, which
are leukocytes essential to immune
IgD
function. Granulocytes, named for
the cytoplasmic granules common IgE
to all types, are phagocytic cells.
Monocytes are also phagocytic
cells, able to engulf larger quanti-
ties of debris than granulocytes.
Th e g r a n u lo c y t e s , a lso kn own a s polym or ph o-
n u clea r (P MN) leu kocyt es, in clu de n eu t r oph ils, eo-
sin oph ils, a n d ba soph ils. Alt h ou gh t h ese cells do
n ot live lon g, t h eir pr odu ct ion ca n be dr a m a t ica lly
in cr ea sed wh en st im u la t ed. N e u t r o p h ils a r e pr es-
en t in t h e gr ea t est n u m ber a n d a r e m ost im por t a n t
in t h e r a pid r espon se t o ba ct er ia l in fect ion . Neu t r o-
ph ils a r e ph a gocyt es t h a t a r e t h e fir st r espon der s in
t h e in fla m m a t or y r espon se. E o s in o p h ils offer t h e
gr ea t est pr ot ect ion a ga in st pa r a sit es, wh er ea s b a -
s o p h ils com plem en t t h e a ct ion s of m a st cells, im -
por t a n t in t h e est a blish m en t of a ller gic r ea ct ion s.
Mo n o c y t e s a r e la r ge, m on on u clea r leu kocyt es,
r epr esen t in g 3% t o 7% of t h e t ot a l n u m ber of cir-
cu la t in g leu kocyt es. 1 Cir cu la t in g m on ocyt es becom e
a ct iva t ed wh en in con t a ct wit h a n a n t igen , pr om pt -
in g differ en t ia t ion in t o m a c r o p h a g e s a n d m ove-
m en t ou t of t h e cir cu la t ion in t o t h e t issu es. Th e
a n t igen -ca r r yin g cell is in gest ed by t h e m a cr oph a ge,
wh er e it u n der goes ph a gocyt osis. Du r in g t h e pr o-
cessin g of t h e a n t igen , m a cr oph a ges displa y a n t igen
m a r ker s on t h e cell su r fa ce wh er e t h ey ca n be r ec-
ogn ized by t h e r ecept or s on T a n d B lym ph ocyt es.
Ma cr oph a ges a r e kn own by differ en t cell n a m es t h a t
a r e det er m in ed by t h e loca t ion of t issu es wh er e t h ey
r eside. Th ese cell t ypes in clu de:
● H ist iocyt es (loose con n ect ive t issu e)
● Micr oglia l cells (br a in )
● Ku pffer cells (liver )
15 Con cen t r a t ed in bodily secr et ion s su ch a s
br ea st m ilk, t ea r s, a n d sa liva
P r ot ect ion of m u cou s m em br a n e–lin ed
st r u ct u r es
75 Most com m on cir cu la t in g a n t ibody
P r odu ced in pr im a r y a n d secon da r y im -
m u n e r espon ses
Act iva t es com plem en t
An t ibody a ct ivit y a ga in st t oxin s, vir u ses,
a n d ba ct er ia
Pa ssive im m u n it y in n ewbor n s via pla cen -
t a l t r a n sfer
10 Fir st im m u n oglobu lin t o pr olifer a t e in im -
m u n e r espon se
Bou n d t o B lym ph ocyt es
Act iva t es com plem en t
0.2 Bou n d t o a n d a ct iva t es B cells
0.004 Bou n d t o m a st cells in skin a n d m u cou s
m em br a n es
St im u la t es m a st cell r elea se of h ist a m in e
in a ller gic im m u n e r espon se, lea din g t o
in fla m m a t ion
 R e v ie w o I m m u n e F u n c t io n 75

D e n d r it ic c e lls a r e cr it ica l t o t h e pr ocessin g a n d

displa y of a n t igen s t o T lym ph ocyt es. Ma t u r e den -
dr it ic cells t a ke u p a n t igen s wh en t h ey a r e en -
cou n t er ed in t h e cir cu la t ion . L a n g e r h a n s c e lls , Ade noids
im m a t u r e den dr it ic cells in t h e skin , ca r r y su r fa ce
r ecept or s for im m u n oglobu lin a n d com plem en t , im - Tons il
Bronchus a s s ocia te d
por t a n t in t h e im m u n e r espon se. lymphoid tis s ue
Thymus

Lymphatics
Th e lym ph a t ic syst em is com posed of cen t r a l a n d
per iph er a l or ga n s a n d is im por t a n t in t h e est a b-
Axilla ry
lish m en t of t h e im m u n e r espon se. Lym ph ocyt es a r e lymph
pr odu ced a n d differ en t ia t ed in t h e cen t r a l or ga n s, node s
bon e m a r r ow, a n d t h ym u s. Th e p e r ip h e r a l o r g a n s
S ple e n
ser ve a s sit es for m a in t en a n ce of t h e lym ph ocyt es
a n d a r e t h e or ga n s in wh ich im m u n e r espon ses a r e Inte s tine
oft en in it ia t ed. Th ese or ga n s in clu de t h e spleen ,
Peye r’s
lym ph n odes, a n d ot h er lym ph oid m u cosa l t issu e, pa tche s
su ch a s t on sils a n d t h e a ppen dix. Th e ly m p h a t ic
s y s t e m cir cu la t es t h e lym ph ocyt es in lym ph flu id. Appe ndix
Ly m p h lu id is a filt r a t ion pr odu ct of ext r a cellu la r
flu id fr om t issu es a n d is r et u r n ed t o blood. Ly m p h Bone
ma rrow
n o d e s a r e join ed segm en t s of lym ph a t ic vessels. Th e
vessels of t h e lym ph a t ic syst em wor k in con cer t wit h
t h e blood vessels t o pr om ot e a n effect ive im m u n e r e-
spon se (Fig. 4.2).
Th e lym ph a t ic syst em t r a ps a n t igen ca pt u r ed by
Inguina l
cells of t h e im m u n e syst em . Th is pr ocess a llows t h e lymph node s
a n t igen t o be pr esen t ed t o im m u n e cells a n d st im u -
la t es t h e im m u n e r espon se. Th e lym ph a lso ser ves
t o m a in t a in sign a ls t o t h e n a ïv e ly m p h o c y t e s , or
t h ose t h a t h a ve n ot yet en cou n t er ed a n a n t igen , en -
a blin g t h em t o su r vive. Th e a bsen ce of su ch a sign a l
r esu lt s in a popt osis, or pr ogr a m m ed dea t h , of cells,
a s discu ssed in Ch a pt er 2. Th is pr ocess is essen t ia l
t o t h e r egu la t ion of t h e n u m ber a n d t ype of cir cu la t -
Figure 4.2. Structures of the lymphatic system.
in g lym ph ocyt es.

Stop and Consider in n a t e im m u n it y. I n n a t e im m u n it y is t h e fir st r e-

When increased lymphocyte production is stimu-
lated, these additional cells travel to the lymph
nodes. How could you determine if this was
occurring with a physical examination? What
signs and symptoms might a person have if this
occurs?
spon der t o in su lt . Th is im m u n e r espon se is r a pid
a n d ca n be in it ia t ed by m a n y differ en t pa t h ogen s,
wit h ou t r equ ir in g pr ior exposu r e. Ad a p t iv e im -
m u n it y , h u m or a l a n d cell-m edia t ed, occu r s over a
lifet im e, pr om ot in g t h e body’s a bilit y t o a da pt t o t h e
t h r ea t of r ein fect ion .

Immune Processes
Th e im m u n e r espon se is vit a l t o a n in dividu a l’s
su r viva l. As a r esu lt , t h e im m u n e syst em in volves
pr ocesses t h a t a r e bot h r edu n da n t a n d com plem en -
t a r y t o on e a n ot h er. Th e t wo dist in ct a n d specia lized
pr ocesses of im m u n it y a r e a da pt ive im m u n it y a n d
INNATE IMMUNITY
Ma cr oph a ges, n eu t r oph ils, a n d den dr it ic cells a r e
t h e pr im a r y cell t ypes in volved in in n a t e im m u n it y.
Th e cells of t h e in n a t e im m u n e syst em a r e t h e r a pid
r espon der s t o or ga n ism s t h a t pose a t h r ea t of in fec-
t ion . In a ddit ion , t h ese cells wor k in h a r m on y wit h
t h e a da pt ive im m u n e syst em t o in it ia t e a n d dir ect
76 C h a p t e r 4: Alt er ed Im m u n it y
con t in u ed pr ot ect ion fr om in fect ion . Th e fu n ct ion s of
t h e in n a t e im m u n e syst em in clu de:
● P r even t ion of m icr obe colon iza t ion
● P r even t ion of m icr obe en t r y
● P r even t ion of m icr obe spr ea d
Th e fir st exposu r e t o a m icr oor ga n ism in it ia t es a n
im m u n e r espon se t h r ou gh det ect ion of for eign a n -
t igen s, a s discu ssed in Ch a pt er 3. An in fla m m a t or y
r espon se is t h en in it ia t ed. Th e r ecept or s on t h e su r-
fa ce of m a cr oph a ges r ecogn ize com pon en t s com m on
t o ba ct er ia l, vir a l, fu n ga l, a n d pa r a sit ic or ga n ism s.
Th e in fla m m a t or y r espon se in it ia t es t h e ph a gocyt ic
pr ocess a n d st im u la t es t h e r elea se of ch em ica l m e-
dia t or s wit h specific pu r poses. Th is r a pid, ea r ly r e-
spon se of t h e in n a t e im m u n e syst em is cr it ica l t o t h e
defen se a ga in st in fect ion , a n d it m a y be a dequ a t e t o
con t r ol in fect ion wit h ou t fu r t h er a ct ion .
Den dr it ic cells loca t ed in t h e t issu es a r e pr im a r ily
r espon sible for pr esen t in g t h e a n t igen a n d ph a go-
cyt osis, wh ich is st im u la t ed in t h e sa m e m a n n er a s
m a cr oph a ges a n d n eu t r oph ils. Den dr it ic cells a r e es-
pecia lly im por t a n t in r ecogn izin g h idden a n t igen s.
Cer t a in pa t h ogen s con cea l t h em selves in en velopes
bu t ca n be sh own t o lym ph ocyt es a ft er in gest ion by
den dr it ic cells. For t h is r ea son , m a t u r e den dr it ic
cells a r e a lso kn own a s a n t ig e n -p r e s e n t in g c e lls .
Th ey a ssist in t h e r ecogn it ion of pa r t icles t h a t a r e
n ot pa r t of t h e in dividu a l, or a r e n o n s e l . Th e in n a t e
im m u n e syst em in it ia t es t h e a ct ivit y of t h e a da pt ive
im m u n e syst em by t h is pr ocess of r ecogn it ion of
n on self.
ADAPTIVE IMMUNITY
B a n d T lym ph ocyt es a n d den dr it ic cells a r e t h e pr i-
m a r y cell t ypes in volved in a da pt ive im m u n it y. Th e
a da pt ive im m u n e syst em is st im u la t ed by ph a gocy-
t osis a n d a ct iva t ion of a n t igen -pr esen t in g cells. Key
pr oper t ies of t h e a da pt ive im m u n e syst em in clu de:
● S p e c i ic it y : t a r get ed r espon se t o a dist in ct
a n t igen
● D iv e r s it y : r ecogn it ion of a wide va r iet y of
a n t igen s
● Me m o r y : r a pid a n d r obu st r espon se t o pr eviou sly
r ecogn ized a n t igen s
● S e l a n d n o n s e l r e c o g n it io n : a bilit y t o dist in -
gu ish bet ween a n t igen s on body cells a n d for eign
a n t igen s
Ada pt ive im m u n it y is ch a r a ct er ized by a slower
r espon se t o t h e in t r odu ct ion of m icr oor ga n ism s
t h a n t h a t of t h e in n a t e im m u n e syst em . Wh en a n
or ga n ism is r ein t r odu ced, im m u n e m em or y lea ds t o
a m or e r a pid a n d in t en se im m u n e r espon se. Im m u -
n it y ca n be a cqu ir ed in differ en t wa ys:
● Act ive
■ Developm en t of a n t ibodies in r espon se t o a n
a n t igen
■ Ach ieved t h r ou gh a ct u a lly h a vin g a specific
disea se or va ccin e im m u n iza t ion a ga in st a pa r-
t icu la r disea se
● Pa ssive
■ Im m u n it y t r a n sfer fr om h ost t o r ecipien t
■ Ach ieved via m ot h er t o in fa n t t r a n sfer via
pla cen t a or br ea st m ilk or in ject ion wit h h igh
con cen t r a t ion s of a n t ibody, su ch a s im m u n e
ga m m a globu lin
Th e a da pt ive im m u n e syst em , in clu din g h u m or a l
a n d cell-m edia t ed im m u n it y, pr ovides essen t ia l de-
fen se a ga in st specific a n t igen s.
Humoral Immunity
An t ibodies, essen t ia l com pon en t s of a da pt ive im m u -
n it y, wer e fir st iden t ified in t h e pla sm a , or h u m or,
a s it on ce wa s kn own . Th e t er m h u m o r a l i m m u -
n i t y r efer s t o a da pt ive im m u n it y–in volvin g a n t i-
bodies. An t ib o d ie s a r e im m u n oglobu lin s t h a t r ea ct
wit h a n a n t igen in a specific wa y. Im m u n oglobu lin s
a r e com posed of t wo r egion s. Th e c o n s t a n t r e g io n
for m s t h e ba se of t h e Y-sh a ped a n t ibody a n d is t h e
m ost st a ble com pon en t . Th e t wo v a r ia b le r e g io n s
a r e st r u ct u r ed t o a llow bin din g t o specific a n t igen s.
IgG is t h e m ost a bu n da n t cla ss of im m u n oglobu lin .
Beca u se of it s size a n d sh a pe, IgG is a ble t o en t er
body t issu es fr om body flu ids. IgG is t h e on ly im -
m u n oglobu lin t h a t is a ble t o cr oss t h e pla cen t a ,
pr ovidin g pa ssive im m u n it y t o t h e developin g fe-
t u s. IgA pr ovides pa ssive im m u n it y fr om m ot h er t o
n ewbor n t h r ou gh br ea st m ilk, t r a n sfer r in g essen -
t ia l im m u n e defen se pr ior t o t h e developm en t of a n
a dequ a t e im m u n e r espon se in t h e in fa n t . IgM is t h e
in it ia l cir cu la t in g a n t ibody pr odu ced in r espon se
t o a n t igen ch a llen ge a n d t h e fir st t o be pr odu ced
by t h e n ewbor n . Loca t ed on t h e B lym ph ocyt e cell
m em br a n e, IgD is in volved in t h e bin din g of a n t i-
gen a n d st im u la t ion of differ en t ia t ion of B lym ph o-
cyt es in t o pla sm a cells. IgE on t h e cell su r fa ces of
m a st cells a n d ba soph ils lea ds t o cellu la r degr a n u -
la t ion u pon a n t igen bin din g, t r igger in g t h e r elea se
of ch em ica l m edia t or s in volved wit h in fla m m a t ion
a n d a ller gies.
E a ch B lym ph ocyt e ca r r ies a sin gle, specific r e-
cept or t h a t r ecogn izes a u n iqu e a n t igen pa t t er n .
Wh en a n a n t igen is r ecogn ized by t h e BCR, B lym -
ph ocyt e a ct iva t ion is in it ia t ed, ca u sin g pr olifer a t ion
a n d differ en t ia t ion of t a r get ed B lym ph ocyt es in t o
e e c t o r c e lls (pla sm a cells t h a t secr et e a n t ibodies).
Th e pr ocess of a ct iva t ion a n d differ en t ia t ion of n a ïve
lym ph ocyt es in t o effect or cells t a kes a ppr oxim a t ely
4 t o 5 da ys. Most of t h ese effect or cells u n der go a pop-
t osis (pr ogr a m m ed cell dea t h ) a ft er t h e en d of t h eir
 R e v ie w o I m m u n e F u n c t io n 77

Primary re s po ns e S e c ondary re s pons e The inva ding orga nis m

with a ntige n A a nd
a ntige n B on its ce ll
1000 s urfa ce.
)
t
i
n
IgG
u
y
100 Antige n A
r
a
r
t
i
Antibody B
b
Antige n B
r
a
10
(
r
e
Antibody A
t
i
t
1 IgM
y
d
Antibodie s A a nd B a re
o
b
produce d in re s pons e to
i
t
n
0.1 a ntige ns A a nd B,
A
O 14 28 42 56 re s pe ctive ly.

The specific antibodies

Firs t expos ure S e cond expos ure bind with the s pe cific
Days corresponding antigens
to re nde r the inva ding
orga nis m ha rmle s s.
Figure 4.3. Primary and secondary antibody responses.
The level of antibodies in the primary and secondary re-
sponses to a specific antigen. (From Premkumar K. The
Massage Connection: Anatomy and Physiology. Baltimore,
MD: Lippincott Williams & Wilkins; 2004.)

Figure 4.4. Specificity of antigen–antibody binding. Anti-

lifespa n , a lt h ou gh som e con t in u e t o exist a ft er t h e
bodies bind with specific antigens, stimulating clonal ex-
a n t igen is elim in a t ed. Th ese r em a in in g cells a r e
pansion, the proliferation of antigen-specific lymphocytes
t h en kn own a s m e m o r y c e lls , a n im por t a n t com -
capable of mounting an immune response.
pon en t of im m u n o lo g ic m e m o r y . Th ese m em or y
cells r espon d m u ch m or e r a pidly wh en r eexposed t o
t h e sa m e a n t igen , dr a m a t ica lly sh or t en in g a n d in -
3. Th e a ct iva t ion of com plem en t , wh ich su pplem en t s
t en sifyin g t h e im m u n ologic r espon se (Fig. 4.3). Th is
t h a t of t h e in n a t e syst em , fu r t h er en h a n cin g t h e
pr ocess is a ccom plish ed t h r ou gh t h e secr et ion of
a ct ion s of t h e a n t ibodies
h igh er levels of a n t ibodies a n d t h ose t h a t bin d wit h
h igh er a ffin it y t o t h e a n t igen s.
Clon es of t h e B lym ph ocyt es ca r r yin g cell su r fa ce Cell-Mediated Immunity
r ecept or s for specific a n t igen s (c lo n a l s e le c t io n )
Cyt ot oxic T lym ph ocyt es a r e t h e pr im a r y im m u n e
r espon d by differ en t ia t in g in t o pla sm a cells ca pa -
cells in volved in c e ll-m e d ia t e d im m u n it y , a
ble of secr et in g la r ge qu a n t it ies of sin gle specificit y
com pon en t of t h e a da pt ive im m u n e r espon se. Cell-
a n t ibody (c lo n a l e x p a n s io n ), t h e r esu lt of a n t igen
m edia t ed im m u n it y r esu lt s in t h e r ecogn it ion a n d
occu pyin g t h e specific BCR (F ig. 4.4). In t h is wa y, t h e
dest r u ct ion of cells ca r r yin g n on –self-a n t igen s. Cyt o-
h u m or a l im m u n e r espon se ca n gen er a t e a defen se
t oxic T lym ph ocyt es det ect pa t h ogen s in side t h e cell
t h a t r ecogn izes a n d t a r get s dist in ct a n t igen s in a
wh er e t h ey ca n n ot be r ecogn ized by a n t ibodies. Cells
specific m a n n er.
in fect ed wit h vir u ses displa yed on t h e cell su r fa ce
An t ibodies pr ot ect cells fr om pa t h ogen s in t h r ee
a r e r ecogn ized by cyt ot oxic T lym ph ocyt es. Th e cy-
m a jor wa ys:
t ot oxic T lym ph ocyt es kill t h e cells befor e vir a l r ep-
1. Th e bin din g of t h e a n t igen t o t h e a n t ibody, wh ich lica t ion is com plet e, t h er eby con t r ollin g t h e fu r t h er
pr even t s t h e a n t igen fr om in fect in g cells (n e u - spr ea d of in fect ion . Th e specificit y of T-lym ph ocyt e
t r a liza t io n ). Th e a n t igen –a n t ibody com plex is r ecogn it ion of for eign a n t igen s in volves cell su r fa ce
r em oved by a gglu t in a t ion (clu m pin g t oget h er ) or m a r ker s on a n t igen -pr esen t in g cells (AP Cs) a n d in -
pr ecipit a t ion (fa llin g ou t of solu t ion ). fect ed body cells kn own a s m a jor h ist ocom pa t ibilit y
2. Th e pr om ot ion of ph a gocyt osis a n d dest r u ct ion of com plex (MH C) m olecu les, lym ph ocyt e iden t ifica -
t h e pa t h ogen t h r ou gh t h e ph a gocyt e’s a bilit y t o t ion by m em br a n e m olecu les kn own a s clu st er s of
r ecogn ize t h e con st a n t r egion of t h e a n t ibody t h a t differ en t ia t ion (CD) a n d TCRs wit h specific a n t igen
is bou n d t o or coa t in g t h e a n t igen (o p s o n iza t io n ) bin din g sit es. In sh or t , t h e a n t igen is pr ocessed by
78 C h a p t e r 4: Alt er ed Im m u n it y
a n AP C, wit h t h e a n t igen epit ope pla ced on t o a n
MH C on t h e AP C su r fa ce. T lym ph ocyt es r ecogn ize
a n d bin d pr ocessed a n t igen s wit h a specific TCR,
lea din g t o dea t h of t h e a ffect ed cell.
T lym ph ocyt es displa y m em br a n e su r fa ce m ole-
cu les, kn own a s c lu s t e r s o d i e r e n t ia t io n , con -
t r ibu t in g t o cell specificit y. CD m olecu les det er m in e
specific fu n ct ion s a n d r espon ses of T-cell su bt ypes.
Th e m olecu le CD8 is expr essed on t h e su r fa ce of cyt o-
t oxic T lym ph ocyt es (C D 8 T ly m p h o c y t e s ). H e lp e r
T ly m p h o c y t e s expr ess CD4 on t h eir su r fa ces a n d
a r e kn own a s C D 4 T ly m p h o c y t e s . H elper T lym -
ph ocyt es pr ovide a r egu la t or y fu n ct ion , en h a n cin g
t h e r espon ses of ot h er t ypes of T lym ph ocyt es.
Two pr im a r y cla sses of CD4 T lym ph ocyt es a r e
r espon sible for differ en t r oles in im m u n e defen se.
On e su bset , T H 1 cells, is pa r t icu la r ly im por t a n t in
t h e con t r ol of ba ct er ia l in t r a cellu la r in fect ion . T H 1
cells a ct iva t e m a cr oph a ges, secr et e ch em okin es a n d
cyt okin es t o a t t r a ct m a cr oph a ges, pr om ot e fu sion
Modu le 2 P r o c e s s o Alt e r in g I m m u n e F u n c t io n
Da ily defen se a ga in st in fect ion r equ ir es in t er pla y
bet ween t h e im m u n e syst em pr ocesses. Fa ilu r e of
even on e im m u n e syst em com pon en t ca n r esu lt in
ca t a st r oph ic con sequ en ces, pr esen t in g a sign ifica n t
r isk for disea se a n d dea t h . Alt er ed im m u n it y ca n r e-
su lt fr om :
● Fa ilu r e o h o s t d e e n s e m e c h a n is m s : t h e im -
pa ir ed a bilit y t o m ou n t a n im m u n e defen se
● H y p e r s e n s it iv it y : in a ppr opr ia t e excessive im -
m u n e r espon ses
● Au t o im m u n it y : in a ppr opr ia t e r espon se t o “self ”
● Allo im m u n it y : r ea ct ion s dir ect ed a t t issu e a n t i-
gen s fr om ot h er in dividu a ls of t h e sa m e species
Host Defense Failure
Fa ilu r e of t h e h o s t (t h e per son on wh ich t h e pa t h o-
gen lives) t o defen d a ga in st in fect ion occu r s in a
va r iet y of wa ys. Pa t h ogen s ca n t r ick t h e im m u n e
syst em , eva din g t h e n or m a l sign a l t h a t st im u la t es a
defen se r espon se. Th e a bilit y of pa t h ogen s t o m u lt i-
ply in t h e h ost cell a n d spr ea d t o ot h er s is essen t ia l
t o con t in u ed pr opa ga t ion . A “su ccessfu l” pa t h ogen is
on e t h a t gr ows wit h ou t a ler t in g t h e im m u n e syst em
t o m ou n t a r espon se a n d is r eplica t ed wit h ou t ca u s-
in g im m edia t e h a r m t o t h e h ost . For exa m ple, if a
vir u s is t oo vigor ou s a n d kills t h e h ost cell, t h e vir u s
will n ot be a ble t o m u lt iply.
of lysosom es wit h vesicles con t a in in g ba ct er ia , a n d
st im u la t e ph a gocyt osis. T H 2 cells, t h e secon d su bset
of CD4 T lym ph ocyt es, a ct iva t e B cells t o pr odu ce
a n t ibodies.
Ta r get s a r e r ecogn ized by T lym ph ocyt es t h r ou gh
TCR det ect ion of a n t igen s displa yed by MH C m ol-
ecu les. MH C m olecu les a r e im por t a n t in t h e r ec-
ogn it ion of t h e body’s “self” a n t igen s fr om for eign
“n on self ” a n t igen s. MH C m olecu les a r e a lso kn own
a s h u m a n le u k o c y t e a n t ig e n s (H L A). Two su b-
set s of MH C m olecu le, MH C cla ss I a n d MH C cla ss
II, t r a p a n a n t igen wit h in t h e cell a n d t h en t r a n s-
por t it t o t h e cell su r fa ce, wh er e it ca n be displa yed
t o T lym ph ocyt es. Th e MH C c la s s I m o le c u le is
fou n d on n u clea t ed body cells a n d is r ecogn ized by
t h e CD8 cyt ot oxic T lym ph ocyt es. Th e MH C c la s s I I
m o le c u le is fou n d on AP Cs a n d is r ecogn ized by t h e
CD4 h elper T lym ph ocyt es (T H 1 or T H 2). A su m m a r y
of t h e st eps in volved in a ct iva t ion of t h e a da pt ive
im m u n e syst em is depict ed in Figu r e 4.5.
On e of t he m ost effect ive m et h ods u sed by pa t h o-
gen s t o eva de det ect ion fr om t h e im m u n e syst em is
ca lled a n t ig e n ic v a r ia t io n . Ma n y pa t h ogen s h ave
m ult iple va r ia t ion s of a nt igen s, m a kin g r ecogn it ion
by T a n d B lym ph ocyt es pot en t ia lly difficu lt . E ven
t h ou gh t h e body m ay h ave been pr eviou sly infect ed
by on e va r ia n t of t he pa t h ogen a nd wa s a ble t o m ou nt
a n effect ive im m u n e r espon se, a va r ia t ion in t h e sa m e
pa t h ogen will a ppea r n ew. Th e pa t h ogen m ay not be
r ecogn ized a n d t h er efor e does n ot st im u la t e t h e im -
m un e “m em or y.” An t igen ic va r ia t ion expla in s t h e po-
t en t ia l of r einfect ion by a pa t h ogen wit h a sligh t ly
differ en t a n t igen ic epit ope. Va r ia t ion s in a n t igen s
ca n a lso occu r beca u se of gen et ic m u t a t ion s. Mut a t ed
a n t igen s a r e gen et ica lly differ en t enou gh t o pr even t
iden t ifica t ion a s a pr eviou sly r ecogn ized pa t h ogen ,
pr even t in g t h e m ou n t in g of a r a pid a n t ibody r e-
spon se. H ea lt h concer n s r esu lt in g fr om a n t igenic
va r ia t ion occu r ea ch yea r a s in flu en za (flu ) sea son
a ppr oa ches. Beca u se of fr equ en t gen et ic m u t a t ion s,
n ew st r a in s of t h e in fluen za vir u s develop t h a t a r e
ca pa ble of esca ping det ect ion by t he im m u n e syst em .
Stop and Consider
People can suffer from the same illness, such as
a cold, many times. What is a possible explana-
tion for this?
Vir u ses ca n eva de det ect ion by t h e im m u n e sys-
t em by goin g in t o la t e n c y , or a per iod of in a ct ivit y.
 Patho g e n Entry
Virus
a ntige n AP C

Nucle a te d infe cte d
ce ll (MHC-I)
MHC-II
P ha gocytos is of
a ntige n by a ntige n-
pre s e nting ce ll
(MHC-II)

MHC-I
MHC-I binds As s ocia tion of MHC-II
with vira l
with intra ce llula r a ntige n pe ptide
e pitope
pa thoge n a ntige n fra gme nt with MHC-II
Ce ll
de a th
Ta rge t
ce ll
Moveme nt of antigen/
Antige n
MHC-II complex to
ce ll s urfa ce e pitope
TCR

MHC-II
Cytotoxic As s ocia tion of a ntige n Ass ocia tion of a ntige n
T ce ll pe ptide /MHC-I with TCR on CD4
complex with TCR on TCR T-
T lymphocyte
TCR CD8 T lymphocyte he lpe r
ce ll
CD8 Antige n CD4
MHC-I e pitope
Ce ll De s truc tio n o f
with vira l Activa tion of
de a th infe c te d c e ll
e pitope

Ta rge t
ce ll
CD8
Cytotoxic
CD8
T me mory T lymphocytes B lymphocyte
ce ll Memory T
lymphocyte
CD8
P reve nt a ntige n
binding to hos t ce ll
Me mory
Me mo ry B
S timula tion of Plas ma c e ll B lymphocyte
ce ll
infla mma tory
re s pons e

Bind with Antibody

a ntige n

P la s ma
ce ll

Antibody

Figure 4.5. Activation of the adaptive immune system. Adaptive immunity is activated on pathogen recognition, stimulating
cell-mediated and humoral immunity. Cell-mediated immunity is activated when the major histocompatibility complex (MHC) I/
antigen complex binds to the T-cell receptor (TCR) on cytotoxic (CD8) T lymphocytes. Humoral immunity is activated on associ-
ation of the MHC II/ antigen complex with the TCR on helper (CD4) T lymphocytes. B lymphocyte effector plasma cells produce
antigen-specific antibodies that prevent antigen binding to the host cell and stimulate the inflammatory response.
79
80 C h a p t e r 4: Alt er ed Im m u n it y

Wh en a vir u s is la t en t , it is n ot bein g r eplica t ed su ppr ession of t h e im m u n e syst em . Th is is som e-

a n d t h er efor e r em a in s u n det ect ed by t h e im m u n e
syst em . Th is ch a r a ct er ist ic is fu r t h er discu ssed in
Ch a pt er 5.
Som e pa t h ogen s r esist dest r u ct ion by u sin g t h e
im m u n e syst em . Pa t h ogen s t h a t u se t h e cells of t h e
im m u n e syst em a s h ost cells m a y pr even t t h eir own
dest r u ct ion . Th is is t h e ca se wit h Mycoba cter iu m tu -
ber cu losis, in wh ich t h e pa t h ogen esca pes dest r u c-
t ion by t h e lysosom e, wh ich in st ea d pr ot ect s t h e
pa t h ogen . H owever, som e pa t h ogen s ca n st im u la t e
a st r on g im m u n e r espon se, wh ich t h en pr om ot es
t im es seen a ft er in fect ion wit h t h e vir u s t h a t ca u ses
m ea sles.
Im m u n osu ppr ession r esu lt in g fr om in h ibit ion
or in ca pa cit a t ion of even on e im m u n e com pon en t
h a s sign ifica n t con sequ en ces. Th e m ost sign ifica n t
for m of im m u n osu ppr ession is t h a t ca u sed by im -
m u n o d e ic ie n c y . P r im a r y im m u n odeficien cy is
oft en ca u sed by a gen et ic m u t a t ion , im pa ir in g im -
m u n e r espon siven ess. P r im a r y im m u n odeficien cy is
fr equ en t ly iden t ified wh en r ecu r r en t , sever e in fec-
t ion s a r e seen in you n g ch ildr en . Ta ble 4.3 descr ibes

Ta b le 4.3 P r im a r y Im m u n odeficien cies

C o n d it io n I m m u n e D e ic it I m m u n e Ma n i e s t a t io n

X-lin ked a ga m m a globu lin em ia B cell No a n t ibody pr odu ct ion

(Br u t on ’s disea se) Absen t t o few B cells
Com m on va r ia ble im - Nor m a l B-cell n u m ber, bu t im -
m u n e deficien cy (CVID) pa ir ed fu n ct ion
(h ypoga m m a globu lin em ia ) Low levels of ga m m a globu lin s
Low levels of IgA
Select ive IgA deficien cy B cell
Low levels of IgA
Sever e com bin ed im m u n e T a n d B cell
deficien cy Com plet e la ck of im m u n e
defen se
Com m on for m of pr im a r y im m u n odeficien cy
Va r ia ble in m a n ifest a t ion s
Com m on for m of pr im a r y im m u n odeficien cy
(1:300)
Mild pr esen t a t ion
F r equ en t a n d u n u su a l in fect ion s
Ma y n ot be dia gn osed u n t il t h ir d or fou r t h
deca de
Most r a r e (1:500,000) m u lt iple for m s a ssocia t ed
wit h decr ea sed NK cells, cir cu la t in g T cells, a n d
ser u m Ig

DiGeor ge a n om a ly T cell F r equ en t in fect ion s dia gn osed soon a ft er bir t h

Un der developed t h ym u s
Decr ea se in cir cu la t in g T cells
X-lin ked h yper-IgM syn dr om e B cell Neu t r open ia , oppor t u n ist ic in fect ion s
Absen t IgA, h igh IgM GI a n d liver dysfu n ct ion
T cells im pa ir ed com m u n ica -
t ion for Ig t ype swit ch in g t o
B cells
Wiskot t -Aldr ich syn dr om e T a n d B cell Lym ph om a
P r ogr essive disea se in T cells E czem a
Decr ea sed IgM Au t oim m u n e disea se
At a xia -t ela n giect a sia T a n d B cell Ma lign a n cies of t h e lym ph oid t issu es
Decr ea sed IgA, IgG X-r a y sen sit ivit y
Decr ea sed cir cu la t in g T cells
Im m a t u r e t h ym u s
Ch r on ic gr a n u lom a t ou s disea se Im pa ir ed ph a gocyt osis Recu r r en t , sever e ba ct er ia l a n d fu n ga l in fect ion s
In a bilit y t o pr odu ce com -
pou n ds for oxygen t r a n spor t

GI, ga st r oin t est in a l; NK, n a t u r a l killer.

 P r o c e s s o Alt e r in g I m m u n e F u n c t io n 81

com m on for m s of pr im a r y im m u n odeficien cy. Im m u - du e t o m ilk, eggs, wh ea t , soy, pea n u t s, a n d t r ee n u t s.

n odeficien cy t h a t is a r esu lt of a n ot h er disea se is Am on g a du lt s, pea n u t s, t r ee n u t s, fish , a n d sh ellfish
kn own a s secon da r y im m u n odeficien cy. Th ese defi- a r e t h e m ost com m on cu lpr it s. Aller gies t o pen icil-
cien cies ca n in volve: lin a r e com m on ly r epor t ed, a lt h ou gh on ly a m in or it y
of in dividu a ls in dica t in g a pen icillin a ller gy h a ve
● Defect ive h u m or a l fu n ct ion a posit ive skin t est docu m en t in g a n IgE r espon se
● Deficien t ph a gocyt e n u m ber s a n d fu n ct ion a l t o t h e dr u g. If a t r u e a ller gy t o pen icillin is docu -
a bilit y m en t ed, ot h er “cillin ” dr u gs (i.e., pen icillin , a m picil-
● Alt er ed T-lym ph ocyt e sign a lin g lin , a n d a m oxicillin ) sh ou ld be a voided a s well, su ch
● Alt er ed cyt okin e pr odu ct ion a n d fu n ct ion a s t h e ceph a lospor in cla ss dr u gs. Th ese dr u gs con -
Th e a bsen ce of a n a dequ a t e im m u n e r espon se m a y t a in a com m on st r u ct u r e, t h e bet a la ct a m r in g, t h a t
lea d t o over wh elm in g in fect ion . ca n st im u la t e t h e a ller gic r espon se. H yper sen sit iv-
it y disor der s a r e cla ssified ba sed on fou r m a jor t ypes
of r ea ct ion s, descr ibed in Ta ble 4.4.
Stop and Consider
Sym pt om s of a ller gy r esu lt fr om t issu e in ju r y a n d
Some immunodeficiency diseases primarily affect
ca n va r y depen din g on t h e r ou t e a n d t h e “dose” of
one cell type. What part of the immune defense
t h e a ller gen exposu r e. Aller gen exposu r e ca n occu r
would be affected if the number of neutrophils
t h r ou gh in h a la t ion , in gest ion , in ject ion , or ph ysica l
was decreased? What would occur with a decrease
con t a ct . Sym pt om s ca n be loca l (it ch in g a n d ir r it a -
in the number of macrophages? What would occur
t ion a t t h e poin t of con t a ct ) or syst em ic (difficu lt y
with a decrease in the number of plasma cells?
br ea t h in g a n d oxygen a t in g, a s occu r s in a st h m a or
a n a ph yla xis).
Specia l t est in g t o det er m in e specific a ller gen s
Hypersensitivity ca pa ble of st im u la t in g h yper sen sit ivit y r ea ct ion s
ca n be com plet ed. Sever a l m et h ods m a y be u sed,
Disor der s t h a t r esu lt fr om excessive im m u n e r e- in clu din g:
spon ses t o a ller gen s a r e kn own a s h yper sen sit ivit y
● Scr a t ch /pr ick skin t est
r ea ct ion s. Alle r g e n s a r e a n t igen s com m on ly con -
■ A sm a ll a m ou n t of a su spect ed a ller gen is
sider ed t o be h a r m less, u n like t h e pa t h ogen ic or-
pla ced on t h e skin , followed by scr a t ch in g or
ga n ism s discu ssed pr eviou sly. Th e r espon se t o t h ese
pr ickin g t h e skin , in t r odu cin g t h e a ller gen t o
a ller gen s is in a ppr opr ia t e, r a n gin g in sever it y fr om
t h e skin su r fa ce. An a ller gen is iden t ified wh en
m ild t o sever e, a n d it ca n be pot en t ia lly life t h r ea t -
a loca l h yper sen sit ivit y r ea ct ion occu r s.
en in g. Th e a ller gen s m a y be en vir on m en t a l, su ch a s
● In t r a der m a l skin t est
pollen , du st , or food pr odu ct s (e.g., n u t s), or t h ey m a y
■ Th e a ller gen is in ject ed u n der t h e skin , fol-
be cer t a in pr ot ein s or com pon en t s fou n d in dr u gs. In
lowed by obser va t ion of a loca l h yper sen sit ivit y
ot h er wor ds, pot en t ia l a ller gen s a r e t h in gs en cou n -
r ea ct ion .
t er ed a s a pa r t of da ily life.
Aller gic r ea ct ion s t o in sect
st in gs, pr im a r ily h on eybees, yel-
Ta b le 4.4 Types of H yper sen sit ivit y Rea ct ion s
low ja cket s, h or n et s, wa sps, a n d
fir e a n t s, ca u se cu t a n eou s r ea c- Ac t iv a t e d
t ion s (swellin g, it ch in g, r edn ess), Im m u n e
wit h t h e pot en t ia l for sever e Ca t egor y E t io lo g y C e lls I n ju r y
syst em ic r ea ct ion . Th e loca t ion Type I, im m edia t e IgE -m edia t ed H elper T (T H 2) Aller gic r ea ct ion : loca l
of in sect s ca u sin g a ller gic r ea c- h yper sen sit ivit y (a t opic) in fla m m a t ion ;
Ma st cells
t ion s va r ies t h r ou gh ou t r egion s r ea ct ion syst em (a n a ph yla ct ic) life
Ba soph ils
of t h e Un it ed St a t es, wit h yel- t h r ea t en in g
low ja cket s pr om in en t in t h e Type II, a n t i- IgG- or Ma cr oph a ge Rea ct ion a ga in st n or m a l
n or t h er n r egion , wa sps in t h e body-m edia t ed IgM-mediated “self ” a n t igen s; opson iza -
sou t h west , a n d fir e a n t s in t h e r ea ct ion t ion a n d lysis of cells
sou t h ea st . Food a ller gies a ffect Type III, im m u n e IgG- a n d Com plem en t Deposit ion of in solu ble
com plex–m edia t ed IgM-mediated Neu t r oph ils a n t igen –a n t ibody com plex
bot h ch ildr en a n d a du lt s, wit h
r ea ct ion
in ciden ce declin in g wit h a dva n c-
Type IV, cell- T-cell-m edi- CD8 T In fla m m a t or y r espon se
in g a ge.1 In ch ildr en , food a ller gy m edia t ed h y- a t ed lym ph ocyt es lea din g t o cell lysis
pr eva len ce r ose fr om 3.4% t o per sen sit ivit y CD4 T H 1
5.1% over t h e la st deca de, wit h r ea ct ion lym ph ocyt es
m or e t h a n 90% of food a ller gies
82 C h a p t e r 4: Alt er ed Im m u n it y

● Skin pa t ch t est
■ Th e a ller gen is pla ced in a liqu id solu t ion on Type I
Antige n
a pa d secu r ed t o skin , followed by obser va t ion
IgE a ntibody
of a loca l h yper sen sit ivit y r ea ct ion in 24 t o 72
h ou r s.
● Mea su r em en t of ser u m IgE Ma s t ce ll
■ H yper sen sit ivit y r ea ct ion is det er m in ed by t h e
a m ou n t of specific IgE a n t ibodies in t h e blood.
● E lim in a t ion diet
■ Su spect ed food a ller gen s a r e elim in a t ed, fol-
lowed by r ein t r odu ct ion a n d obser va t ion of h y-
per sen sit ivit y r ea ct ion .
Aller gy t est in g in volves exposu r e of a n in dividu a l t o
a pot en t ia l a ller gen . Sever e r ea ct ion s ca n r esu lt , r e-
qu ir in g t est in g t o be com plet ed u n der close m edica l
su per vision . Aller gy t est in g is a n effect ive m et h od
t o det er m in e specific a ller gen ic su bst a n ces. Th is in -
for m a t ion ca n be u sed t o in for m in dividu a ls of su b-
st a n ces t o a void, if possible, a n d t o pr even t a n d t r ea t
h yper sen sit ivit y r ea ct ion s.

TYPE I OR IMMEDIATE HYPERSENSITIVITY

REACTION Re le a s e of va s oa ctive
a mine s a nd othe r me dia tors
Im m edia t e h yper sen sit ivit y r ea ct ion s a r e a lso
kn own a s IgE -m edia t ed h yper sen sit ivit y r espon ses
Figure 4.6. Type I immediate hypersensitivity reaction.
t o a n t igen ch a llen ges. In it ia l exposu r e t o a n a ller gen
Antigen–IgE antibody binding induces release of chemical
in a vu ln er a ble in dividu a l st im u la t es t h e pr odu ct ion
mediators from mast cells.

en cou n t er s a n d bin ds a n
R E S E AR C H N O T E S a ller gen , m a st cells a n d
ba soph ils degr a n u la t e, r e-
lea se ch em ica l m edia t or s
Immunotherapy for the treatment of hypersensitivity reactions resulting from insect stings
a n d ca u se in ju r y t o cells,
has been used to improve prognosis. While effective in reducing the manifestations of type
pr odu cin g t h e sym pt om s
I hypersensitivity responses, venom immunotherapy (VIT) is also associated with adverse
a ssocia t ed wit h a ller gy.
systemic effects. In a clinical trial, the use of purified and nonpurified formulations of VIT
Lipid pr odu ct s fr om cell
and the association with adverse systemic effects were investigated. The use of purified VIT
m em br a n es, in clu din g
extract reduced the incidence of severe local and systemic reactions, providing evidence
2 leu kot r ien es a n d pr ost a -
of improvement in treatment options in individuals with hypersensitivity to insect stings.
gla n din s, a r e a lso r elea sed
in t h is pr ocess. Repea t ed
exposu r e t o t h e sa m e a l-
of I g E , a n im m u n oglobu lin im por t a n t in t h e devel- ler gen pr odu ces a n IgE -m edia t ed h yper sen sit ivit y
opm en t of pr ot ect ive im m u n it y. Aller gy is m ost oft en r espon se t h a t is r espon sible for a r a n ge of sym pt om s,
ca u sed by in h a led a ller gen s t a ken in a t low doses. som e of wh ich ca n be life t h r ea t en in g. Type I h yper-
Th ese sm a ll, dr y a ller gen s dissolve a n d becom e sen sit ivit y r ea ct ion is a n exa m ple of a pa t h oph ysio-
solu ble wh en t h ey com e in con t a ct wit h m u cou s logic exa gger a t ion of a defen sive im m u n e r espon se
m em br a n es. Den dr it ic cells a r e a ct iva t ed by t h ese (Fig. 4.6).
a ller gen s. Den dr it ic cells t h en t r a vel t o t h e lym ph Im m edia t e h yper sen sit ivit y r ea ct ion s a r e in i-
n odes wh er e t h ey pr esen t t h e a ller gen s t o n a ïve T t ia t ed wit h in m in u t es of a ller gen exposu r e. Som e
lym ph ocyt es, pr om ot in g t h eir differ en t ia t ion in t o h yper sen sit ivit y r ea ct ion s, in clu din g a st h m a , a r e
T H 2 cells. Specific ch em ica l sign a ls ca n ca u se B lym - kn own t o h a ve sym pt om s a ssocia t ed wit h t wo sepa -
ph ocyt es t o pr odu ce IgE a n t ibodies in pla ce of ot h er r a t e r espon se st a ges. Th e sym pt om s a ssocia t ed wit h
t ypes of a n t ibodies. IgE pr odu ced by t h e pla sm a st a ge 1 a r e r ela t ed t o m a st cell degr a n u la t ion fol-
cells wit h in in fla m ed t issu e bin ds wit h h igh a ffin it y lowed by t h e r elea se of ch em ica l m edia t or s. Th ey in -
t o r ecept or s on m a st cells a n d ba soph ils. Wh en IgE clu de va sodila t ion a n d n on va scu la r sm oot h m u scle
 P r o c e s s o Alt e r in g I m m u n e F u n c t io n 83

con t r a ct ion t h a t la st s a ppr oxim a t ely 1 h ou r. Th e sec-

on d st a ge follows in a ppr oxim a t ely 2 t o 8 h ou r s a n d RBC Type II
r esu lt s in sym pt om s a ssocia t ed wit h t h e lipid m edia -
IgG or IgM
t or s r elea sed fr om t h e pla sm a m em br a n e of degr a n - a ntibody
u la t ed cells. Th ese sym pt om s a r e sim ila r t o t h ose in
st a ge 1 bu t la st lon ger. In a ddit ion , r ecr u it m en t of Comple me nt
eosin oph ils a n d leu kocyt es r esu lt s in a n in fla m m a -
t or y r espon se in t h e a ffect ed t issu es.
Not ever yon e develops h yper sen sit ivit y r ea ct ion s
Antige n
a ft er a ller gen exposu r e. People wh o develop sym p-
t om s a ft er exposu r e t o a wide n u m ber of com m on ly
en cou n t er ed a ller gen s a r e descr ibed a s a t o p ic ,
wh ich m ea n s t h a t IgE r espon ses a r e st im u la t ed
fr om exposu r e t o t h ese t ypica lly ben ign su bst a n ces.
Ma n y a ller gies a r e fa m ilia l, m ea n in g t h ey a r e ge-
n et ic t en den cies t h a t a r e pa ssed on fr om on e gen er a -
t ion t o a n ot h er. Avoida n ce of pot en t ia l a ller gen s m a y
pr even t t h e developm en t of a t opy, especia lly ea r ly in
developm en t .
Syst em ic m a n ifest a t ion s of t ype I im m edia t e h y-
per sen sit ivit y r ea ct ion s a r e pot en t ia lly life t h r ea t en - Lys is of RBC
in g. An a p h y la x is r epr esen t s a n ext r em ely ser iou s
P ha gocytos is
r espon se t o t ype I im m edia t e h yper sen sit ivit y r ea c-
t ion . It is ch a r a ct er ized by edem a a n d va sodila t ion
a n d lea ds t o h ypot en sion . An a ph yla xis is discu ssed
in det a il in Modu le 4: Clin ica l Models.
Figure 4.7. Type II antibody-mediated hypersensitivity
reaction. Cell-bound antigen binds to IgG or IgM antibod-
TYPE II ANTIBODY-MEDIATED REACTIONS ies, leading to a cytotoxic reaction. RBC, red blood cell.
An t ibody-m edia t ed r ea ct ion s a r e t h e r esu lt of m is-
t a ken iden t it y. Usu a lly h a r m less su bst a n ces a r e
iden t ified a s h a r m fu l; a n im m u n e r espon se is r ea ct ion s. Th is dr u g in for m a t ion is r equ est ed a n d
m ou n t ed t h a t r esu lt s in cell da m a ge. Th e r ea ct ion in m a r ked pr om in en t ly on m edica l r ecor ds t o pr even t
t ype II h yper sen sit ivit y is t issu e specific, u su a lly in - in a dver t en t a dm in ist r a t ion in t h e fu t u r e. Wh en a
volvin g dest r u ct ion of a t a r get cell by a n t ibody bin d- pa t ien t ’s t r ea t m en t in volves blood r epla cem en t wit h
in g t o a n t igen on t h e cell su r fa ce. Cell dest r u ct ion t r a n sfu sion , a la b pr ocedu r e ca lled blood t ypin g
a n d t issu e da m a ge oft en r esu lt fr om h a r m in flict ed a n d cr oss-m a t ch in g is don e on r ecipien t s t o a llow
by m a cr oph a ge ph a gocyt osis a n d com plem en t - m a t ch in g wit h don or blood. If a r ea ct ion occu r s in -
m edia t ed effect s. Th is is a dir ect r espon se r esu lt in g a dver t en t ly du r in g t r a n sfu sion , t h e a dm in ist r a t ion
fr om a n a n t igen –a n t ibody r ea ct ion . of blood is im m edia t ely h a lt ed. A sim ila r con dit ion
Respon ses of t h ese t ypes a r e seen in cer t a in dr u g kn own a s Rh isoim m u n iza t ion , t h e r esu lt of expo-
r ea ct ion s, blood t r a n sfu sion r ea ct ion s, Gr a ves dis- su r e t o t h e Rh a n t igen in a n a ïve in dividu a l, is cov-
ea se, a n d h em olyt ic disea se of t h e n ewbor n . Oft en , er ed in gr ea t er det a il in t h e clin ica l m odel sect ion of
t h e a ffect ed cells in clu de blood cells. Wh en t h e a n - t h is ch a pt er.
t ibody bin ds t o t h e a n t igen on t h e cell, t h e cell is
lysed a n d dest r oyed. Th is r esu lt s in disea se r ela t ed
TYPE III IMMUNE COMPLEX–MEDIATED REACTION
t o t h e loss of t h ese cells a n d in clu des a n em ia (de-
cr ea sed r ed blood cells [RBCs]), t h r om bocyt open ia Cellu la r a n d t issu e da m a ge ca u sed by t ype III r e-
(decr ea sed pla t elet s), a n d leu kopen ia (decr ea sed a ct ion s a r e t h e in dir ect r esu lt of com plem en t a c-
WBCs). Sym pt om s a r e r ela t ed t o t h e degr ee of loss t iva t ion st im u la t ed by t h e deposit ion of in solu ble
of t h ese blood cell t ypes (Fig. 4.7). a n t igen –a n t ibody com plexes. Im m u n e com plex a c-
Tr ea t m en t for t h is t ype of r ea ct ion in volves r e- t iva t ion of com plem en t r esu lt s in widespr ea d da m -
m ova l of t h e a n t igen ca u sin g t h e r ea ct ion . Wh en a ge fr om sever a l m ech a n ism s. Alt er ed blood flow,
a dr u g is in volved, t h e a dm in ist r a t ion of t h e dr u g va scu la r per m ea bilit y, a n d t h e r espon se of in fla m -
is h a lt ed t o pr even t fu r t h er im m u n e-m edia t ed cel- m a t or y cells r esu lt in da m a ge t o blood vessels a n d
lu la r da m a ge. Avoida n ce of t h e a n t igen is r ecom - or ga n s, in clu din g kidn ey glom er u li, sm a ll blood ves-
m en ded t o pr even t su bsequ en t , in cr ea sin gly ser iou s sels in t h e skin , a n d t h e syn ovia l lin in g of join t s. Th e
84 C h a p t e r 4: Alt er ed Im m u n it y
Antige n Type III
a ntibody
complex
Comple me nt
Infiltra tion of P MN le ukocyte s
P MN le ukocyte
Lys os oma l e nzyme s
Da ma ge to
a dja ce nt
ce lls
Figure 4.8. Type III immune complex–mediated reaction.
Type III reactions are the result of the formation and
deposition of immune complexes in tissues, causing acute
inflammation polymorphonuclear neutrophil (PMN).
deposit ion of a n t igen –a n t ibody com plexes t r igger s
t h e in fla m m a t or y im m u n e r espon se of com plem en t
a ct iva t ion a n d r ecr u it m en t of in fla m m a t or y cells
(Fig. 4.8). Th is r espon se wa s or igin a lly seen in in -
dividu a ls wh o r eceived h or se a n t iser a , on ce u sed
a s a t r ea t m en t for t et a n u s. Th ese in dividu a ls de-
veloped a con dit ion r efer r ed t o a s s e r u m s ic k n e s s
a n d r espon ded wit h loca l sym pt om s of it ch in g a n d
r a sh a t t h e in ject ion sit e a s well a s syst em ic sym p-
t om s of edem a a n d fever a ppr oxim a t ely 7 da ys a ft er
a n t iser a in ject ion . Th ese sym pt om s r esu lt ed fr om
a n t igen –a n t ibody com plex deposit ion in blood ves-
sels a n d t issu e, pr om pt in g com plem en t a ct iva t ion
a n d a n in fla m m a t or y r espon se.
Wh en t h e loca t ion of t h is com plex-m edia t ed im -
m u n e r espon se is in t h e skin , t h e r esu lt in g a r ea of
loca lized t issu e n ecr osis is r efer r ed t o a s a n Ar t h u s
r e a c t io n . Alt h ou gh t h e in it ia l exposu r e r esu lt s in
sym pt om s t h a t r esolve wit h t im e, su bsequ en t expo-
su r e ca n ca u se a m or e ser iou s r espon se, som et im es
r esu lt in g in dea t h . Con dit ion s m ost com m on ly a sso-
cia t ed wit h t h is r espon se in clu de t h e a u t oim m u n e
disea ses of syst em ic lu pu s er yt h em a t osu s (SLE ) a n d
r h eu m a t oid a r t h r it is (a s discu ssed in Ch a pt er 3).
Th e a dm in ist r a t ion of cer t a in dr u gs, in clu din g
a n t i-lym ph ocyt e globu lin (a n im m u n osu ppr essive
a gen t u sed in t r a n spla n t pa t ien t s) a n d st r ept oki-
n a se (t h r om bolyt ic a gen t u sed wit h pa t ien t s h a v-
in g a m yoca r dia l in fa r ct ion ), ca n a lso st im u la t e t h is
r espon se.
TYPE IV CELL-MEDIATED HYPERSENSITIVITY
REACTION
Th e h eigh t en ed im m u n e r espon ses in t ype IV r e-
a ct ion s a r e ca u sed by T-lym ph ocyt e-m edia t ed r ea c-
t ion s r a t h er t h a n a n t igen –a n t ibody r ea ct ion s. Two
t ypes of t h ese r ea ct ion s a r e dist in gu ish ed by dif-
fer en t m ech a n ism s a n d a ssocia t ed r espon se t im es.
Th ey in clu de dir ect cell-m edia t ed cyt ot oxicit y a n d
dela yed t ype h yper sen sit ivit y r ea ct ion s.
In d ir e c t c e ll-m e d ia t e d t o x ic it y , da m a ge oc-
cu r s in cells a n d t issu es a s a dir ect r espon se t o CD8
cyt ot oxic T-lym ph ocyt e dest r u ct ion of cells wit h
r ecogn ized a n t igen s. CD8 cyt ot oxic T lym ph ocyt es
a t t a ck a ll in fect ed cells wit h r ecogn ized a n t igen s,
wh et h er t h e a n t igen is h a r m fu l or n ot . Th is r e-
spon se ca n a ct u a lly be m or e h a r m fu l t h a n t h e da m -
a ge in flict ed by t h e pa t h ogen , a s in t h e ca se of som e
for m s of h epa t it is, in wh ich liver da m a ge is pr im a r-
ily ca u sed by t h e cell-m edia t ed t oxicit y r a t h er t h a n
by t h e vir u s it self.
D e la y e d h y p e r s e n s it iv it y r e a c t io n s a r e m e-
dia t ed by a n t igen -specific T lym ph ocyt e. T lym ph o-
cyt es r espon d t o a n t igen s pr esen t ed t o t h em , a s
descr ibed in t h e ea r lier discu ssion of t h eir n or m a l
r ole in im m u n e r espon se. Oft en , t h ese r espon ses
occu r on t h e skin a n d a r e m edia t ed by AP Cs a n d
CD4 h elper T lym ph ocyt es of t h e T H 1 t ype. An t i-
gen s m or e likely t o ca u se t h is r ea ct ion a r e sm a ll,
ca n pen et r a t e t h e skin , a n d ca n st im u la t e it ch in g.
Th ese a n t igen s r ea ct wit h “self ” pr ot ein s a n d cr ea t e
com plexes t h a t ca n bin d t o MH C m olecu les seen a s
for eign by T lym ph ocyt es, st im u la t in g a n im m u n e
r espon se (F ig. 4.9).
Th e t wo ph a ses of dela yed h yper sen sit ivit y r ea c-
t ion a r e sen sit iza t ion a n d elicit a t ion . Th e s e n s it i-
za t io n p h a s e begin s wh en t h e a n t igen cr osses t h e
skin , t h e fir st lin e of defen se. An t igen s a r e t a ken u p
by La n ger h a n s’ cells a n d t r a n spor t ed t o t h e lym ph
n odes. On ce in t h e lym ph n odes, t h ese cells develop
in t o m a t u r e den dr it ic cells, wh ich a r e a ble t o pr esen t
a n t igen s t o h elper T lym ph ocyt es a n d a ct iva t e t h em .
Mem or y cells a r e pr odu ced a n d becom e loca lized in
t h e der m is.
Du r in g t h e e lic it a t io n p h a s e , t h e m em or y T
lym ph ocyt es in t h e der m is a r e st im u la t ed by a su b-
sequ en t exposu r e t o t h e specific a n t igen . Cyt okin es
a n d ch em okin es a r e r elea sed, st im u la t in g t h e a t t r a c-
t ion of m a cr oph a ges a n d a ddit ion a l T lym ph ocyt es
t o t h e a r ea . Th is r esu lt s in a visible loca l r ea ct ion a t
t h e sit e of a n t igen en t r y. Blood vessel per m ea bilit y

Antige n-pre s e nting ce ll
Type IV
Re ce ptor
MHC
Antige n
S e ns itize d
T ce ll
Active immune
re s pons e re s ulting
in tis s ue da ma ge
Figure 4.9. Type IV T-cell-mediated delayed hypersensi-
tivity reaction. Type IV reactions occur 1 to 3 days after
antigen exposure, resulting in erythema and itching. MHC,
major histocompatibility complex.
is in cr ea sed, lea din g t o swellin g. Th e T-cell-m edia t ed
r espon se t a kes bet ween 24 a n d 72 h ou r s. Th is con -
dit ion is oft en r efer r ed t o a s con t a ct der m a t it is. It
ca n a lso be in it ia t ed by t h e in ject ion of a n a n t igen
t o det er m in e a n in dividu a l’s pr ior exposu r e t o M. tu -
ber cu losis, com m on ly r efer r ed t o a s a t u ber cu lin or
Ma n t ou x t est . Rea ct ion s fr om poison ivy a r e a lso t h e
r esu lt of t ype IV h yper sen sit ivit y r ea ct ion s.
Autoimmunity
On e of t h e cr it ica l fu n ct ion s of t h e im m u n e syst em is
t o dist in gu ish “self ” fr om “n on self.” Wh en t h is r ecog-
n it ion fa ils or is n ot con t r olled, sever e a u t o im m u n e
(dir ect ed a t a n in dividu a l’s own t issu es) disea se ca n
develop. Th e t wo m a jor wa ys in wh ich t h is occu r s
a r e by specific r ecogn it ion of “self” a n t igen s a n d
by over zea lou s r espon ses t o ch r on ic in fect ion . Th e
a cu t e a u t oim m u n e r espon se ca n con ver t t o a ch r on ic
r espon se if t h e in volved a n t igen is n ot a dequ a t ely
clea r ed or if a posit ive feedba ck loop develops in r e-
spon se t o t h e in fla m m a t or y pr ocess, a s descr ibed in
Ch a pt er 3.
P r o c e s s o Alt e r in g I m m u n e F u n c t io n 85
Au t oim m u n e disea se ca n be dir ect ed a t specific
or ga n s, a s seen in t ype II h yper sen sit ivit y r ea ct ion s,
or it ca n h a ve a syst em ic or wh ole body effect , a s
seen in t ype III h yper sen sit ivit y r ea ct ion s. For ex-
a m ple, in Gr a ves disea se, t h e or ga n a ffect ed is t h e
t h yr oid gla n d, a n d a n t ibodies a r e specifica lly di-
r ect ed a ga in st t h e t h yr oid it self (Fig. 4.10). In con -
t r a st , SLE is ch a r a ct er ized by a n t ibodies for m ed
a ga in st pr ot ein s fou n d in cells t h r ou gh ou t t h e body,
ca u sin g syst em ic disea se. We will discu ss t h e spe-
cific pa t h ology r ela t ed t o a u t oim m u n it y seen in SLE
in Modu le 4, la t er in t h is ch a pt er.
Fa ilu r e in t h e developm en t of self-t oler a n ce m a y
occu r a t va r iou s st eps of im m u n e developm en t . Sit u -
a t ion s t h a t ca n t r igger a u t oim m u n it y in clu de:
● In a dequ a t e elim in a t ion of self-r ea ct ive lym ph o-
cyt es in cen t r a l lym ph oid t issu es
● Alt er ed ly m p h o c y t e ig n o r a n c e (con ver t in g lym -
ph ocyt es fr om n on r espon sive t o self-r ea ct ive)
● St im u li, su ch a s in fect ion , over r idin g t h e n on r e-
spon sive n a t u r e of n a ïve T lym ph ocyt es
● Im pa ir ed T-lym ph ocyt e in a ct iva t ion (pr olon ged or
ir r ever sible)
● Fa ilu r e t o r ecogn ize a n t igen du e t o MH C–a n t igen
com plex in t er a ct ion
● Release of antigens sequestered during development
● Close resemblance between foreign and self-antigen,
also known as m ole cu la r m im icr y
● In a ppr opr ia t e a ct iva t ion of TCRs by
su per a n t igen s
A a m ilia l t e n d e n c y , or pr opa ga t ion of a u t oim m u -
n it y a m on g fa m ily m em ber s, is a com m on t r a it in
a u t oim m u n e disea se. Bot h gen et ic pr edisposit ion
a n d en vir on m en t a l fa ct or s a ppea r t o pr om ot e t h e
developm en t of disea se. Alt h ou gh a few t ypes of a u -
t oim m u n e disea se a r e ca u sed by a n a lt er a t ion in a
sin gle gen e, m ost in volve m a n y gen es (m ost of wh ich
a r e u n kn own ), m a kin g iden t ifyin g a r espon sible t a r-
get a n d det er m in in g a n effect ive t r ea t m en t difficu lt .
Dr u gs a n d ch em ica l t oxin s ca n a lso pr ecipit a t e t h e
developm en t of a u t oim m u n it y, a lt h ou gh t h e exa ct
m ech a n ism in volved is u n clea r.
Alt h ou gh difficu lt , t r ea t m en t a n d pr even t ion of
a u t oim m u n it y con t in u e t o be a r ea s of in t en se in t er-
est . Th e developm en t of n ewer t ech n iqu es a n d in -
cr ea sed kn owledge of t h e scien ce of im m u n ology h a ve
been in st r u m en t a l in pr om ot in g r ecen t a dva n ces t o
develop effect ive clin ica l t r ea t m en t s. Th e st u dy of
T-cell-m edia t ed r espon ses h a s u n cover ed t h e exis-
t en ce of su ppr essor cells, a lso kn own a s r e g u la t o r y
T c e lls . Th ese cells, a s t h eir n a m e im plies, a r e a ble
t o su ppr ess a u t or ea ct ive lym ph ocyt es a n d r egu la t e
t h e im m u n e r espon se. Isola t ion of t h ese specia lized
T lym ph ocyt es a n d t h e a dm in ist r a t ion of t h em t o in -
dividu a ls a r e fu t u r e pot en t ia l t h er a peu t ic st r a t eies
for t h ose dia gn osed wit h a u t oim m u n e disea se.
86 C h a p t e r 4: Alt er ed Im m u n it y

Microorga nis m Thyroid

(e.g., Ye rs inia , E. coli) follicula r ce ll

HLA-DR
Norma lly
Antige n s imila r to
occurring anti-TSH
TS H rece ptor a utoa ntibody
TS H re ce ptor

Infe ction
(e.g., e nte rocolitis )
He lpe r T ce ll
binds to TS H
receptor-HLA-DR
complex

Anti-idiotype
a ntibody

He lpe r T ce ll Forma tion of

TH
binds to antigen a nti-idiotype
a ntibodie s to
a nti-TS H
TH a ntibody

Activa te d B ce ll
Ge ne tic
fa ctors
Forma tion of
a nti-TS H re ce ptor
a ntibodie s
S uppre s s or
T ce ll

TS H re ce ptor-binding
a ntibodie s

IgG
TS H re ce ptor

Thyroid
follicula r ce ll
Ade nylyl cycla s e

Cyclic AMP
T3
T4
T3 T4 T3
T4
T3 T4
T3
T4 T3
Thyro id hype rs e c re tio n

Grave s Dis e as e

Figure 4.10. Possible mechanisms of organ-specific autoimmune disease: Graves disease. This figure depicts three possi-
ble pathways by which B cells are activated to produce anti-TSH receptor antibodies. These antibodies stimulate thyroid
cells to secrete T3 and T4. Indirect pathways shown to the left and middle involve activation of helper T cells along with
genetic factors that inhibit suppressor T cells. The pathway on the right shows antibodies against anti-TSH antibodies
cross-reacting with the TSH receptor. HLA-DR, human leukocyte antigen-D related. (Modified from Rubin E, Farber JL.
Pathology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.)

Alloimmunity
Alloim m u n it y occu r s wh en a n im m u n e r espon se is
st im u la t ed in r espon se t o t h e pr esen ce of cells fr om
a n ot h er in dividu a l of t h e sa m e species. Alloim m u -
n it y ca n occu r a ft er a llogr a ft (t r a n spla n t a t ion of
body t issu es) or a llot r a n sfu sion (t r a n sfu sion of body
flu ids, su ch a s blood or pla sm a ).
GRAFT REJECTION
G r a t s (u n a t t a ch ed t issu es or or ga n s u sed for im -
pla n t a t ion ) a r e com m on ly u sed in t h e t r ea t m en t of
disea se. Th e a ccept a n ce of gr a ft ed t issu e don a t ed
fr om on e in dividu a l t o a n ot h er depen ds on t h e
m a t ch in g of MH C m olecu les. MH C m olecu les a r e
p o ly m o r p h ic (occu r r in g in m or e t h a n on e for m )
a n d p o ly g e n ic (con t a in in g sever a l MH C cla ss I a n d
II gen es). Th ese t wo ch a r a ct er ist ics m a ke m a t ch in g
t h e MH C m olecu les ch a llen gin g. Th e likelih ood of
a m a t ch in cr ea ses wh en bot h don or a n d r ecipien t
a r e r ela t ed, bu t even t h en m a t ch in g is n ot gu a r-
a n t eed. Gr a ft s fr om differ en t sit es on t h e sa m e
per son (a u t o g r a t ) or fr om gen et ica lly iden t ica l
in dividu a ls/m on ozygot ic t win s (s y n g e n e ic ) a r e
fu lly a ccept ed; h owever, a gr a ft bet ween u n r ela t ed
in dividu a ls (a llo g r a t ) is oft en r eject ed a ft er 10 t o
13 da ys wit h ou t dr u gs t o con t r ol im m u n e r espon se.
Stop and Consider
Why is there less chance of rejection when a
transplant occurs between identical twins? Is the
chance of rejection the same if the twins are fra-
ternal (not identical)?
Ada pt ive im m u n e r espon ses m edia t ed by T lym -
ph ocyt es (CD4 a n d CD8) a r e r espon sible for r e-
ject ion of gr a ft ed t issu e du e t o t h e r ecogn it ion of
a llo a n t ig e n s (pr ot ein s t h a t va r y bet ween in divid-
u a ls) a s for eign . Wh en AP Cs fr om t h e don or lea ve
t h e gr a ft sit e a n d t r a vel via t h e lym ph a t ic syst em ,
h ost T lym ph ocyt es a r e a ct iva t ed. Th ese a ct iva t ed T
lym ph ocyt es t r a vel ba ck t o t h e gr a ft a n d a t t a ck t h e
a lloa n t igen s, dest r oyin g t h e gr a ft ed t issu e.
Modu le 3 I m m u n e R e s p o n s e Ma n ip u la t io n
As pr eviou sly discu ssed, m a n y disea ses a r e t h e r e-
su lt of a n im m u n e r espon se t h a t fa ils t o dist in gu ish
“n on self ” fr om “self ” a n t igen s. Wh en t h is occu r s,
t h e im m u n e r espon se is t h en dir ect ed t owa r d “self ”
a n d ser ves a s t h e ba sis for ch r on ic in fla m m a t ion ,
wh ich lea ds t o cellu la r a lt er a t ion s a n d in ju r y. As
t h e u n der st a n din g of t h e m ech a n ism s r egu la t in g
I m m u n e R e s p o n s e Ma n ip u la t io n 87
Th e pr esen ce of a llo a n t ib o d ie s (a n t ibodies pr o-
du ced a ga in st a lloa n t igen s) ca n con t r ibu t e t o t h e
r a pid r eject ion of gr a ft s, kn own a s h y p e r a c u t e
g r a t r e je c t io n . Th ese a n t ibodies r ecogn ize a n d
a t t a ck a n t igen s on en dot h elia l cells lin in g blood
vessels, st im u la t in g bot h t h e com plem en t a n d clot -
t in g ca sca des. Vessels becom e o c c lu d e d , or blocked,
pr even t in g per fu sion a n d r esu lt in g in cell a n d t is-
su e dea t h t o t h e a ffect ed sit e. Th is is oft en seen
in b lo o d t r a n s u s io n , t h e m ost com m on for m of
t issu e t r a n spla n t . Th e a n t ibodies in t h e r ecipien t
in t er a ct wit h a n t igen s fr om t h e don or lea din g t o
syst em ic effect s, beca u se blood t ype a n t ibodies ca n
bin d t o a ll t issu e t ypes. Th is issu e ca n be a voided by
en su r in g t h a t t h e r ecipien t ’s blood t ype is t h e sa m e
a s t h e don or (det er m in ed by b lo o d t y p in g ) a n d
t h a t t h e r ecipien t h a s n o a n t ibodies t h a t a r e a ble
t o r ea ct wit h t h e WBCs of t h e don or (det er m in ed by
c r o s s -m a t c h in g ).
GRAFT VERSUS HOST DISEASE
G r a t v e r s u s h o s t d is e a s e (G VH D ) pr esen t s a con -
t r a st t o gr a ft r eject ion . Th e m ost com m on con dit ion
r esu lt in g in GVH D is t h e t r a n spla n t a t ion of h e m a -
t o p o ie t ic s t e m c e lls , or cells t h a t ca n differ en t ia t e
in t o h ea lt h y blood cells. Th is t r ea t m en t is oft en u sed
t o figh t bon e m a r r ow ca n cer s su ch a s leu kem ia or
t o cu r e im m u n odeficien cies. Tr a n spla n t a t ion of h e-
m a t opoiet ic st em cells ca n r esu lt in a n in dividu a l’s
a bilit y t o pr odu ce n or m a l, h ea lt h y blood cells in
pla ce of t h e deficien t or da m a ged cells t h a t r esu lt
in disea se. For t r a n spla n t a t ion t o be su ccessfu l, t h e
disea sed r ecipien t bon e m a r r ow m u st fir st be de-
st r oyed. Don or st em cells m a y t h en be t r a n spla n t ed.
GVH D occu r s wh en t h e T lym ph ocyt es of t h e don or
r ecogn ize t h e r ecipien t ’s body a s bein g differ en t or
for eign . Don or-im m u n ocom pet en t T lym ph ocyt es
(CD4 a n d CD8) det ect a n t igen s in t h e r ecipien t ’s t is-
su e a n d m ou n t a n a t t a ck. Th e im m u n ocom pr om ised
r ecipien t t issu e ca n n ot m ou n t a defen se a ga in st t h e
a t t a ck, wh ich r esu lt s in a t ype IV h yper sen sit ivit y
r ea ct ion . Th is disea se, wh ich ca n be fa t a l, is ch a r a c-
t er ized by r a sh , dia r r h ea , a n d liver disea se.
im m u n e fu n ct ion gr ows, t h ese discover ies ca n be
u sed t o m a n ipu la t e t h e im m u n e syst em fa vor a bly.
Ma n y t r ea t m en t st r a t egies a r e ba sed on in t er fer-
en ce wit h t h e r espon ses seen in a u t oim m u n it y a n d
h yper sen sit ivit y. E xploit a t ion of t h ese m ech a n ism s
m a y a lso pla y a sign ifica n t r ole in t h e t r ea t m en t of
disea se.
88 C h a p t e r 4: Alt er ed Im m u n it y
Treatment of Maladaptive Immune
Responses
Im m u n e r espon ses ca n be in a ppr opr ia t e or exa gger-
a t ed a s is t h e ca se in a ller gy, a u t oim m u n e disea se,
a n d t issu e r eject ion . Con t r ol of u n wa n t ed im m u n e r e-
spon ses decr ea ses t h e sign s a n d sym pt om s a ssocia t ed
wit h illn ess a n d disea se. Su ppr ession of t h e im m u n e
syst em , wh ich a lso su ppr esses t h e in a ppr opr ia t e im -
m u n e r espon se, is t h e goa l of t r ea t m en t . Th is gen er a l
r espon se ca r r ies wit h it t h e r isks a ssocia t ed wit h im -
m u n osu ppr ession , pa r t icu la r ly t h e in cr ea sed r isk of
oppor t u n ist ic in fect ion (see Ch a pt er 5).
A n u m ber of cla sses of dr u gs a r e u sed t o r egu -
la t e im m u n e r espon ses, a n d ea ch t a r get a pa r t icu -
la r m ech a n ism . Th e fir st cla ss is a n t i-in fla m m a t or y
dr u gs, u su a lly in t h e cor t icost er oid fa m ily. On e of t h e
m ost com m on of t h ese dr u gs is pr edn ison e. P r edn i-
son e is a syn t h et ic a n a log of c o r t is o l, t h e h or m on e
syn t h esized in t h e a dr en a l cor t ex (see Ch a pt er 11).
P r edn ison e h a s a body-wide effect t ypica lly seen wit h
h or m on es beca u se a lm ost a ll body cells ca r r y t h e r e-
cept or for cor t isol. Wh en t h e in t r a cellu la r r ecept or
bin ds wit h pr edn ison e, a sign a lin g ca sca de is in it i-
a t ed t h a t r egu la t es t h e t r a n s c r ip t io n (t r a n sfer of
gen et ic in for m a t ion ) of a la r ge n u m ber of gen es. Th e
a m ou n t of pr edn ison e t a ken for t r ea t m en t t r a n sla t es
in t o blood levels m u ch h igh er, or s u p r a p h y s io lo g ic ,
com pa r ed wit h t h a t fou n d wit h t h e n or m a l secr et ion
of cor t isol. Th is ca u ses a n exa gger a t ed cellu la r r e-
spon se wit h bot h ben eficia l a n d pot en t ia lly h a r m fu l
r esu lt s. Th e ben eficia l effect s a r e t h e desir ed ou t -
com es of t r ea t m en t a n d in clu de a n t i-in fla m m a t or y
effect s a s a r esu lt of im m u n e r espon se su ppr ession .
Th e a dver se effect s a r e wide-r a n gin g beca u se of t h e
body-wide r espon ses in du ced; t h ese effect s in clu de
eleva t ed blood su ga r, loss of bon e m in er a l, t h in n in g
of skin , weigh t ga in , a lt er ed fa t deposit ion , a n d flu id
r et en t ion . A delica t e ba la n ce t o cr ea t e t h e desir ed
effect a n d m in im ize a dver se effect s is n ecessa r y for
opt im a l t r ea t m en t ou t com e.
Stop and Consider
The adrenal gland stops producing cortisol during
prednisone treatment. Why does this happen?
What are the special considerations made when
prednisone treatment is no longer needed?
A secon d cla ss of dr u gs com m on ly em ployed in
r egu la t ion of im m u n e r espon se is cyt ot oxic dr u gs.
Com m on ly u sed dr u gs in t h is fa m ily in clu de m et h -
ot r exa t e, a za t h iopr in e, m ycoph en ola t e, a n d cyclo-
ph osph a m ide. A com m on m ech a n ism a m on g t h ese
dr u gs in clu des in t er fer a n ce wit h DNA syn t h esis in
dividin g cells. Ra pidly dividin g cells a r e m ost sen si-
t ive t o t h e effect s of t h is m ech a n ism a n d in clu de t h e
cells of t h e bon e m a r r ow (lym ph ocyt es, RBCs, a n d
pla t elet s), t h e cells lin in g m u cosa l m em br a n es of t h e
ga st r oin t est in a l t r a ct , t h e cells of a developin g fet u s,
a n d h a ir follicle cells. Th e pr oposed t a r get in t h is
m et h od of t r ea t m en t is dividin g lym ph ocyt es, wit h
t h e desir ed ou t com e of decr ea sed im m u n e fu n ct ion .
As a r esu lt of t h e n on specific n a t u r e of t h e dr u gs,
t h eir u se is a ssocia t ed wit h sign ifica n t a dver se ef-
fect s. H igh doses of t h ese t oxic dr u gs a r e u sed wh en
t h e t r ea t m en t goa l is elim in a t ion of a ll dividin g
lym ph ocyt es. Th ese pa t ien t s t h en r equ ir e bon e m a r-
r ow t r a n spla n t t o r esu m e pr odu ct ion of n ecessa r y
blood cells. Lower doses, com m on ly a ccom pa n ied by
a n t i-in fla m m a t or y dr u gs, a r e u sed t o m a n a ge u n -
wa n t ed im m u n e r espon ses.
Ba ct er ia l a n d fu n ga l der iva t ive dr u gs a r e a t h ir d
cla ss of dr u gs u sed t o r egu la t e im m u n e fu n ct ion .
Th ese dr u gs a lt er sign a l t r a n sdu ct ion pa t h wa ys in
T lym ph ocyt es, r edu cin g in fla m m a t ion by a lt er a t ion
of t h e r epr odu ct ive cell cycle. Com m on ly u sed dr u gs
in t h is fa m ily in clu de cyclospor in e A, t a cr olim u s,
a n d r a pa m ycin . P r edom in a n t ly u sed in t r a n spla n t
pa t ien t s, t h ese dr u gs pr even t t issu e r eject ion by
bin din g t o a gr ou p of in t r a cellu la r pr ot ein s. Th ese
pr ot ein s t h en for m com plexes t h a t a lt er sign a l
t r a n sdu ct ion pa t h wa ys u sed in t h e pr olifer a t ion of
T lym ph ocyt es a n d t h e clon a l expa n sion of a ct iva t ed
T lym ph ocyt es. Beca u se ea ch of t h ese dr u gs h a s a
specifica lly t a r get ed m ech a n ism of a ct ion in t h e sig-
n a l pa t h wa y, t h ey a r e oft en u sed in com bin a t ion . An -
ot h er cla ss of dr u gs t a r get cyt okin e a ct ivit y, lim it in g
im m u n e r espon ses. Th ese dr u gs a r e design ed t o in -
t er fer e wit h t h e bin din g of t h e cyt okin e t u m or n ecr o-
sis fa ct or-a lph a (TNF -a lph a ) t o it s r ecept or, r edu cin g
in fla m m a t ion . In t er fer on s a lso r edu ce in fla m m a t ion
a n d a r e u sed in t h e t r ea t m en t of t h e a u t oim m u n e
con dit ion m u lt iple scler osis (Ch a pt er 9).
Idea lly, dr u gs specifica lly t a r get in g t h e m ech a -
n ism of ch r on ic in fla m m a t ion r esu lt in g fr om in a p-
pr opr ia t e im m u n e r espon ses will be developed. Th e
opt im a l t r ea t m en t effect of r egu la t in g in a ppr opr ia t e
im m u n e r espon ses a n d m a in t a in in g fu n ct ion a l r e-
spon ses is t h e object ive in t h e m a n a gem en t of r e-
la t ed disea ses. Th e u se of t h is biologic t h er a py is
on goin g clin ica lly t o specify t a r get s in t h e sign a l
t r a n sdu ct ion pa t h wa y.
Immune Response in Disease
Management
Using the body’s own immune syst em to att ack pat ho-
logic cells is anot her mechanism by which the im mune
system ca n be exploited to a chieve a positive outcome.
Ca ncer, a disea se resulting from uncont rolled pr olifer-
a tion of a single tra nsformed cell, is a centra l ta rget for

t his type of stra tegy. Pa thophysiologic processes asso-
cia ted with cancer a re discussed in det ail in Cha pter
7. Developm ent of a drug that can pr omote the a bil-
ity of t he imm une syst em t o distinguish norma l cells
fr om t ransformed ca ncer cells would be a useful tr ea t-
m en t st rat egy. The desired outcom e is the recognition
a nd destruction of ca ncer cells while avoiding the de-
st ruction of norma l cells, t hereby preserving imm une
fu nction a nd minimizing adverse effect s.
Immune Response in the
Prevention of Disease
Va c c in e s wor k by st im u la t in g im m u n it y t h r ou gh
exposu r e t o a n a n t igen . Th is im m u n e r espon se is de-
sign ed t o r ea ct iva t e qu ickly wh en r eexposu r e t o t h e
a n t igen occu r s, t h e r esu lt of im m u n ologic m em or y.
E a r ly va ccin a t ion t ech n iqu e wa s a t t em pt ed t o pr e-
ven t sm a llpox by u sin g a sm a ll a m ou n t of a ct u a l
pa t h ogen t o st im u la t e im m u n it y. H owever, t h e sa fet y
of t h is t ech n iqu e wa s n ot en su r ed—som e people a ct u -
a lly con t r a ct ed t h e illn ess a n d died. La t er, t h e u se of
va ccin es m a de fr om pa t h ogen a n a logs der ived fr om
ot h er species wa s effect ive in st im u la t in g im m u n it y
Modu le 4 C lin ic a l Mo d e ls
Th e followin g clin ica l m odels h a ve been select ed t o
illu st r a t e t h e con cept s of a lt er ed im m u n it y. As you
r ea d t h e descr ipt ion s t h a t follow, t h in k a bou t t h e
con cept s of a lt er ed im m u n e fu n ct ion a s t h ey a pply t o
t h e specific con dit ion s t o h elp u n der st a n d a n d a pply
t h ese con cept s t o t h e m odels.
Immune Maladaptation: AIDS
AIDS is a con dit ion r epr esen t a t ive of a lt er ed h ost
defen se. It is a secon da r y im m u n odeficien cy ca u sed
by in fect ion wit h t h e h u m a n im m u n o d e ic ie n c y
v ir u s (H I V). H IV is a n en veloped r et r ovir u s t h a t in -
fect s CD4 h elper T lym ph ocyt es, den dr it ic cells, a n d
m a cr oph a ges. Sym pt om s of a cu t e H IV in fect ion in -
clu de va gu e flu like com pla in t s a ssocia t ed wit h t h e a c-
t iva t ion of CD8 cyt ot oxic T lym ph ocyt es a n d CD4 T H 1
lym ph ocyt es. In it ia lly, t h is r espon se wor ks t o con t r ol
in fect ion by killin g H IV-in fect ed cells, followed by a n-
t ibody pr odu ct ion a ga in st t h e vir u s. Th e h a llm a r k of
AIDS is t h e loss of cell-m edia t ed a n d h u m or a l im m u-
n it y du e t o t h e loss of CD4 T H 1 lym ph ocyt es.
Su b-Sa h a r a n Afr ica ha s been pa r t icula r ly a ffect ed
by t h e H IV epidem ic. Accor ding t o UNAIDS, a join t
C lin ic a l Mo d e ls 89
a n d wa s a m u ch sa fer a lt er n a t ive. For va ccin es t o be
effect ive, t h e followin g r equ ir em en t s m u st be m et :
● Va ccin es m u st be sa fe a n d m u st a void t h e devel-
opm en t of a ct u a l disea se.
● Va ccin es m u st pr ot ect a ga in st illn ess ca u sed by
live pa t h ogen s.
● Va ccin es m u st pr ovide lon g-la st in g pr ot ect ion .
● Va ccin es m u st st im u la t e a n t ibody pr odu ct ion a n d
T-cell-m edia t ed im m u n it y.
● Va ccin es m u st be a ccessible a n d a ffor da ble.
● Va ccin es m u st h a ve m in im a l side effect s.
Moder n va ccin a t ion t ech n iqu es in clu de t h e u se of
a t t e n u a t e d (r edu ced a bilit y t o ca u se disea se) or
killed or ga n ism s. In som e ca ses, c o n ju g a t e d v a c -
c in e s , wh ich pr om ot e a ct iva t ion of m or e t h a n on e
cell t ype, a r e n ecessa r y t o st im u la t e a n a dequ a t e
im m u n e r espon se t o a specific pa t h ogen . Th e u se of
a dju va n t s, or su bst a n ces t h a t in cr ea se im m u n e r e-
spon se t o a n t igen s, is som et im es n ecessa r y for st im -
u la t ion of pr ot ect ive im m u n e r espon ses.
Stop and Consider
Many vaccines are available to protect against
common diseases and conditions. What are some
reasons why people do not get immunized?
Unit ed Na t ion s a n d Wor ld H ea lt h Or ga n iza t ion pr o-
gr a m on H IV/AIDS, 25.8 m illion people wer e living
wit h H IV in Su b-Sa ha r a n Afr ica in 2014, a ccou nt ing
for a ppr oxim a t ely 70% of n ew H IV infect ions wor ld-
wide.3 In t h e Un it ed St a t es, a ppr oxim a t ely 50,000
people a r e infect ed wit h H IV a nn ua lly. You t h a ged 13
t o 24 yea r s a ccou n t for 26% of new H IV in fect ion s. Men
wh o h ave sex wit h m en a r e a t h igh est r isk. Ther e a r e
1.2 m illion individu a ls a ged 13 a n d older living wit h
H IV, wit h m a les r epr esent in g 74% of ca ses a m ong a d-
olescent s a n d a du lt s.4 Am ong youn g a du lt s a ged 20
t o 24 in t h e Un it ed St a t es, a lm ost 10,000 m en a n d
wom en wer e living with AIDS a t t h e end of 2006.5 In
Nor t h Am er ica , AIDS cont in ues t o dispor por t ion a t ely
a ffect Afr ica n Am er ica n s a n d Abor igina l people in th e
Unit ed St a t es a n d Ca n a da , r espect ively.6
PATHOPHYSIOLOGY
H IV is t r a n sm it t ed by sexu a l con t a ct , blood con -
t a m in a t ion , a n d per in a t a lly bet ween in dividu a ls.
In fect ion wit h H IV occu r s a cr oss m u cosa l su r fa ces
cover ed wit h st r a t ified squ a m ou s epit h eliu m , in -
clu din g t h e va gin a , cer vix, a n d a n u s. Cell t a r get s of
H IV in fect ion in clu de den dr it ic cells, m a cr oph a ges,
90 C h a p t e r 4: Alt er ed Im m u n it y
a n d CD4 h elper T lym ph ocyt es. Den dr it ic cells bin d
H IV a n d t r a n spor t it t o t h e lym ph oid t issu es wh er e
it en cou n t er s t h e CD4 h elper T lym ph ocyt es. Wh en
t h e vir u s en t er s t h e h ost cell, t h e vir a l RNA is t r a n -
scr ibed in t o com plem en t a r y DNA, wh ich is t h en in -
t egr a t ed in t o t h e h ost cell, st im u la t in g r eplica t ion
of t h is pr ovir u s. Th e vir u s u n der goes r a pid r eplica -
t ion , a ssocia t ed wit h t h e gen er a t ion of m a n y vir a l
m u t a t ion s. Th ese m u t a t ion s a r e n u m er ou s a n d ca n
occu r wit h in a da y, pr om ot in g t h e developm en t of
a n t igen ic va r ia t ion . Vir a l dr u g r esist a n ce develops
r a pidly, r equ ir in g t h e u se of com bin a t ion t h er a py.
CLINICAL MANIFESTATIONS
Initial infection with HIV is asymptomatic. The time
period between initial infection and symptom develop-
ment is typica lly 2 to 4 weeks but can extend to a pe-
riod of severa l months. Ea rly symptoms of acute HIV
infection, also known as acute retrovira l syndrome,
a re generalized and typica lly include fever, lympha de-
nopathy, sore throat, skin rash, joint a nd muscle pa in
a long with hea dache. As the disea se progresses, the
CD4 helper T-lymphocyte number gradually declines,
promoting significant immunosuppression. The loss
of CD4 T lymphocytes is caused by the killing of in-
fected cells by viruses, the a poptosis (progra mmed cell
Symptoms of HIV infection
Memory loss, disorientation,
inability to think clearly
Persistent headaches
High fever
White patches on tongue
Swollen lymph nodes in neck,
armpits and groin
Heavy night sweats
Loss of appetite
Severe weight loss
Chronic diarrhea
Fatigue and muscle
weakness
Figure 4.11. Manifestations of HIV infection and AIDS. (Courtesy Anatomical Chart Company.)
dea th) of infected cells, a nd the killing of CD4 helper T
lymphocytes by CD8 cytotoxic T lymphocytes. Cell-me-
dia ted immunit y is lost when the CD4 helper T-lym-
phocyte level is too low, contributing to the risk of
opportunistic infection. Resista nce is lost to ma ny com-
mon pathogens, including the fungi Ca ndida . Activa-
tion of la tent viruses may occur, promoting symptoms
a nd disease. Kaposi sa rcoma, a tumor of endothelial
cells, and non-Hodgkins lymphoma are AIDS-defin-
ing ca ncers of decreasing preva lence a fter widespread
a ntiretrovira l therapy (ART) a doption. HIV-infected
individua ls wit h lowered im mune function are a t
risk for pneumonia though the incidence of Pneumo-
cystis ca rinii (jiroveci) pneumonia ha s decreased sig-
nificantly since adoption of ART. Lowered immune
function in HIV-infected individuals increases risk
for non–AIDS-defining cancers and bacterial forms
of pneumonia seen in the general population. Meta-
bolic complica tions (including dyslipidemia, dia betes
mellitus, bone disease), certain non–AIDS-defining
ca ncers, a nd coinfections a re also linked with HIV in-
fection. Hematologic, renal, and hepatic toxicities are
complications of HIV infection and treatment. Neu-
rocognitive impairment, a nxiety, a nd depression are
more common a mong individuals infected with HIV.
Figure 4.11 shows ma ny of the conditions experienced
by patients with immunosuppression due to AIDS.
AIDS-related illnesses and
opportunistic infections (OIs)
Cryptococcal meningitis
Toxoplasmosis encephalitis
Cytomegalovirus (CMV) retinitis
Herpes simplex virus (HSV)
Oral candidiasis (thrush)
Candida esophagitis
Pneumocystis carinii
(jiroveci) pneumonia
Pulmonary
tuberculosis
Cryptosporidiosis
Kaposi’s sarcoma
Malignant lymphoma
 C lin ic a l Mo d e ls 91

These conditions a re normally controlled or prevented a t h igh r isk , pr eexposu r e pr oph yla xis (P r E P ) in -
by CD4 helper T-lymphocyte-stimulated cell-mediated clu des da ily a n t ir et r ovir a l m edica t ion cou pled
immunity, lost when CD4 host T-lymphocyte numbers wit h ot h er pr even t ive st r a t egies (e.g., con dom s),
a re significa ntly decrea sed. wh ich ca n be u sed t o r edu ce t h e r isk of H IV in -
fect ion . Post exposu r e pr oph yla xis (P E P ) in clu des
Stop and Consider t h e in it ia t ion of 2 t o 3 a n t ir et r ovir a l m edica t ion s
Why are immunosuppressed patients at greater a s soon a s possible, bu t n o m or e t h a n 3 da ys, a ft er
risk for cancer? H IV exposu r e a n d sh ou ld be con t in u ed for 28 da ys.
Recom m en ded t r ea t m en t of H IV is t h e u se of ART.
In it ia t ion of ART in ea r ly H IV in fect ion is a ssoci-
DIAGNOSTIC CRITERIA
a t ed wit h su ppr ession of H IV vir a l loa d, im pr oved
Recom m en da t ion s for H IV scr een in g fr om t h e Cen - CD4 T-lym ph ocyt e cou n t s, a n d m a r k er s of im m u n e
t er s for Disea se Con t r ol a n d P r even t ion (CDC) in - fu n ct ion .
clu de r ou t in e in it ia l scr een in g in in dividu a ls a ged Th e goa ls of ART in clu de:
13 t o 64 yea r s. An n u a l r epea t scr een in g is a dvised
● Ma xim a l a n d lon g-la st in g vir a l loa d su ppr ession
for a ll t h ose a t h igh r isk for H IV in fect ion . 6 In divid-
● Rest or a t ion or pr eser va t ion of im m u n e fu n ct ion
u a ls a t r isk for in fect ion (i.e., in t r a ven ou s dr u g u s-
● Redu ct ion in m or bidit y a n d m or t a lit y r ela t ed t o
er s, dia gn osis wit h a sexu a lly t r a n sm it t ed disea se,
H IV
dia gn osis/t r ea t m en t for h epa t it is or t u ber cu losis,
sex wit h som eon e H IV posit ive or H IV st a t u s u n - Beca u se of t h e a bilit y of t h e H IV r et r ovir u s t o
kn own ) sh ou ld be scr een ed. Th e cr it er ia u sed in t h e eva de t h e im m u n e syst em by m u t a t in g in t o differ-
dia gn osis of H IV in fect ion is oft en ba sed on in it ia l en t for m s, r esist a n ce t o dr u g t h er a py is a pr im a r y
t est s t h a t iden t ify H IV vir a l loa d (H IV RNA), H IV-1 con cer n . Test in g of dr u g r esist a n ce t o det er m in e t h e
a n t igen (p24) a n d H IV-1 a n d H IV-2 a n t ibody (im m u - effect iven ess of a n t ir et r ovir a l dr u g vir u s r eplica -
n oa ssa y). It t a kes m ost people a bou t 3 m on t h s fr om t ion in h ibit ion is n ecessa r y for t h e select ion of t h e
t im e of exposu r e t o develop a n t ibodies t o H IV. Th is m ost effect ive m u lt idr u g a n t ivir a l m edica t ion r egi-
occu r r en ce is kn own a s s e r o c o n v e r s io n . People a r e m en s. Specific dr u gs in clu ded in ART a r e design ed
u su a lly a sym pt om a t ic a t t h is t im e a n d ca n u n kn ow- t o dela y disea se pr ogr ession by su ppr essin g vir a l
in gly in fect ot h er s wit h t h e vir u s. r eplica t ion a n d a ddr essin g t h e issu es of in cr ea sin g
P r ogr ession of H IV infect ion is ba sed on la b- dr u g r esist a n ce. 8 Th ese dr u gs ca n be ca t egor ized
or a t or y cr it er ia a n d on sign s a n d sym pt oms of im - in t o cla sses kn own a s n u cleoside a n d n u cleot ide
m u n osu ppr ession . La t er com plica t ion s r ela t ed t o a n a log r ever se t r a n scr ipt a se in h ibit or s (NRTIs),
im m u nosu ppr ession inclu de in fect ion wit h ca n didia - n on n u cleot ide r ever se t r a n scr ipt a se in h ibit or s
sis, cyt om ega lovir u s, m ycoba ct er iu m , t oxopla sm osis, (N NRTIs), pr ot ea se in h ibit or s (P Is), a n d in t egr a se
P n eum ocystis ca r inii (jir oveci) pn eu m on ia , movem en t st r a n d t r a n sfer in h ibit or s (IN STIs). Alt h ou gh t h e
disor der s, dem ent ia , n on -H odgkin lym ph oma , or Ka - u se of ART h a s in cr ea sed effect iven ess over m on o-
posi sa r com a of t h e skin a n d m ucou s m em br a n es. Th e t h er a py or com bin ed t wo-dr u g t h er a py, sign ifica n t
CDC cla ssifies t h e st a ges of H IV in fect ion ba sed on ba r r ier s con t r ibu t e t o fa iled t r ea t m en t r egim en s.
CD4 T-lym phocyt e coun t s for su r veilla n ce pur poses.7 To in cr ea se t h e pa t ien t ’s willin gn ess a n d a bilit y t o
St a ges of in fect ion a m on g t h ose ≥ 6 yea r s of a ge in- u se t h ese dr u gs, on goin g cou n selin g a n d a ssist a n ce
clu de st a ge 0 (ea r ly H IV in fect ion ba sed on a n ega - wit h pr oblem a r ea s a r e cr it ica l t o su ccessfu l t r ea t -
t ive H IV t est r esu lt wit h in 6 m on t h s of a con fir m ed m en t . Mor e in for m a t ion a bou t specific st r a t egies
posit ive r esu lt ), st a ge 1 (≥ 500 cells/µL), st a ge 2 (200 ca n be fou n d in t h e gu idelin es for cou n selin g by t h e
t o 499 cells/µL), a n d st a ge 3 (< 200 cells/µL). Wh en CDC list ed in t h e r esou r ce sect ion a t t h e en d of t h is
a n in dividu a l m eet s t h e cr it er ia for st a ge 3, t h a t is ch a pt er.
con sist en t wit h AIDS.
Wor sen in g disea se a n d im -
m u ne st a t u s a r e cor r ela t ed
wit h a pr ogr essively de-
F R O M T H E L AB
cr ea sed n u m ber of CD4
h elper T lym ph ocyt es. Diagnosis of HIV infection is made by the detection of the presence of HIV antibodies. A
screening test known as immunoassay detects the HIV antibody. Body fluid samples (saliva,
blood, or urine) may be tested. A positive screening test is not diagnostic of HIV infection
TREATMENT
and requires a confirmatory test. Other tests that can confirm HIV infection include tests
P r even t ion fr om H IV ex- that detect the HIV antigen. The amount of HIV in the blood can be determined by a test
posu r e is a cr it ica l fir st for viral load. The competency of the immune system can be determined by measurement of
st ep in a voidin g H IV in - the CD4 T-lymphocyte cell count.
fect ion . For in dividu a ls
92 C h a p t e r 4: Alt er ed Im m u n it y
Stop and Consider
What special considerations must a person with
AIDS take to limit illness caused by immunosup-
pression? What considerations must others make
to protect a person with AIDS?
Immune Maladaptation:
Anaphylactic Reaction
Th is clin ica l m odel r epr esen t s a syst em ic r espon se
t o a t ype I h yper sen sit ivit y r ea ct ion . An a ph yla xis
ca n occu r fr om exposu r e t o dr u gs, en vir on m en t a l
com pou n ds, in sect ven om or st in gs, or food pr odu ct s
t h a t st im u la t e a n exa gger a t ed im m u n e r espon se.
Reexposu r e t o a n a ller gen is r espon sible for t r igger-
in g t h is IgE -m edia t ed even t . Th e in du ced syst em ic
r espon se pr odu ces a h yper sen sit ivit y r ea ct ion a ffect -
in g m a n y or ga n syst em s, wh ich is pot en t ia lly fa t a l
wit h ou t t r ea t m en t .
PATHOPHYSIOLOGY
E xposu r e t o a n a ller gen in a n in dividu a l pr eviou sly
sen sit ized by t h a t a ller gen st im u la t es t h e cla ssi-
ca l a ller gic h yper sen sit ivit y r espon se of degr a n u -
la t ion of m a st cells a n d ba soph ils. Th e IgE bou n d
t o r ecept or s on t h ese cells in du ces t h e r elea se of
ch em ica l m edia t or s wh en bin din g wit h t h e a ller-
gen occu r s (F ig. 4.12). Th e r ea ct ion occu r s loca lly
bu t is spr ea d beyon d t h e sit e of a ller gen en t r y by
t h e bloodst r ea m . Va scu la r sm oot h m u scle dila t es,
br on ch ia l sm oot h m u scle con st r ict s, a n d va scu la r
per m ea bilit y in cr ea ses, a ccou n t in g for t h e clin ica l
m a n ifest a t ion s seen in t h is con dit ion . Th ese effect s
a r e pot en t ia lly fa t a l wit h ou t in t er ven t ion a n d su p-
por t ive ca r e.
CLINICAL MANIFESTATIONS
Th e clin ica l m a n ifest a t ion s st im u la t ed by a n a ph y-
la ct ic r ea ct ion a r e det er m in ed by t h e a m ou n t of
a n t igen -specific IgE pr esen t , t h e dose of t h e a n t i-
gen , a n d t h e r ou t e of a n t igen t r a n sm ission . A biph a -
sic (t wo-ph a se) r espon se r esu lt s fr om t h e r elea se
of ch em ica l m edia t or s, in clu din g h ist a m in e, pr os-
t a gla n din s a n d leu kot r ien es (br on ch ocon st r ict ion ),
a n d cyt okin es (in cr ea sed IgE pr odu ct ion a n d in fla m -
m a t ion ). Th e in it ia l r espon se occu r s wit h in m in u t es
t o a few h ou r s a n d in clu des sever e b r o n c h o s p a s m
(con t r a ct ion of t h e sm oot h m u scle in t h e br on ch i
a n d br on ch ioles of t h e lu n gs, decr ea sin g a ir wa y
size a n d m a kin g it difficu lt t o br ea t h e), skin flu sh -
in g, u r t ic a r ia (it ch in g), a n d a n g io e d e m a (su dden
su bcu t a n eou s edem a ). Th e fir st ph a se is a r espon se
t o sh or t -a ct in g ch em ica l m edia t or s, a n d t h e secon d
ph a se of t h is r ea ct ion is ca u sed by lon ger-a ct in g su b-
st a n ces occu r r in g a ppr oxim a t ely 4 h ou r s a ft er t h e
fir st ph a se r ea ct ion . Du r in g t h e secon d ph a se, se-
ver e br on ch ospa sm r ecu r s a n d is oft en a ccom pa n ied
by sever e h ypot en sion a n d edem a . Im m edia t e eva l-
u a t ion a n d t r ea t m en t of t h ese m a n ifest a t ion s m u st
be in st it u t ed beca u se of t h e em er gen cy n a t u r e of
a n a ph yla xis. Sever e r ea ct ion s ca n r esu lt in a n oxia
a n d dea t h .
Stop and Consider
Why don’t all people stung by insects develop
systemic symptoms of anaphylaxis?
DIAGNOSTIC CRITERIA
Dia gn osis is ba sed on sym pt om s a n d h ist or y. Sym p-
t om s of a cu t e on set of illn ess a ft er a n t igen /a ller-
gen exposu r e in volvin g skin (h ives, it ch , flu sh ) a n d
m u cou s m em br a n es (swellin g of lips/t on gu e), r e-
spir a t or y com pr om ise (wh eeze, br on ch ospa sm , a n d
in cr ea sed wor k of br ea t h in g) a n d dr op in blood pr es-
su r e (possibly a ssocia t ed wit h fa in t in g or in con t i-
n en ce), a n d ga st r oin t est in a l sym pt om s (a bdom in a l
cr a m pin g/vom it in g) a r e cr it er ia for a n a ph yla xis
dia gn osis. People on m u lt iple dr u gs a n d people su f-
fer in g fr om in sect st in g, a t opy, or food a ller gy a r e
especia lly su scept ible. Test in g t o det er m in e t h e r e-
spon sible a n t igen ca n be don e t o edu ca t e t h e pa t ien t
a bou t specific a ller gen s t o a void or t o pr ovide t h e ba -
sis of fu t u r e t r ea t m en t . P r ogn osis is ba sed on t h e se-
ver it y of sym pt om s a n d t h e t im e it t a kes t o pr ovide
t r ea t m en t for a cu t e sym pt om s.
TREATMENT
Rem ova l of a n a ph yla xis t r igger, if possible, is t h e
fir st st ep in m a n a gem en t . In it ia l t r ea t m en t is de-
sign ed t o t r ea t sym pt om s a n d lim it in fla m m a t ion .
Im m edia t e a dm in ist r a t ion of epin eph r in e t o r ela x
br on ch ia l sm oot h m u scle, r efor m en dot h elia l t igh t
cell ju n ct ion s in blood vessels, a n d con t r ol ca r-
diova scu la r effect s is t h e fir st lin e of t r ea t m en t .
In h a led br on ch odila t or s m a y a lso a ssist in t h e
t r ea t m en t of br on ch ospa sm . Air wa y m a n a gem en t ,
in clu din g t h e u se of su pplem en t a l oxygen , a r e im -
por t a n t in pr om ot in g oxygen deliver y t o cells a n d
t issu es. An t ih ist a m in es m a y h elp r edu ce t h e sym p-
t om s st im u la t ed by h ist a m in e r elea se, su ch a s it ch -
in g a n d in cr ea sed vessel per m ea bilit y. F lu ids m a y
be pr ovided t o r est or e in t r a va scu la r volu m e. If t h e
in it ia l t r ea t m en t is dela yed, t h e pr ogn osis wor sen s.
Th e sym pt om s a ssocia t ed wit h t h e secon d ph a se
a r e m u ch m or e difficu lt t o t r ea t a n d m a y r equ ir e
in t u ba t ion a n d m ech a n ica l ven t ila t ion t o pr ovide
oxygen a t ion .
 Antige n

CD4
TH2
IL-4
B ce ll

IL-3, IL-5

IgE-s e cre ting

pla s ma ce ll

Eos inophil Antibody

re cruitme nt
Ma s t ce ll

S e ns itiza tion
of ma s t ce ll

Re le a s e of cytokine s
Re cruitme nt a nd a ctiva tion
of infla mma tory ce lls

De gra nula tion a nd

re le a s e of me dia tors Me mbra ne phos pholipids
Ara chidonic a cid
P ros ta gla ndins Le ukotrie ne s

P rima ry e a rly re s pons e

Va s odila tion
Va s cula r da ma ge S e conda ry la te re s pons e
S mooth mus cle s pa s m Mucos a l e de ma
Mucus s e cre tion
Le ukocyte infiltra tion
Epithe lia l da ma ge
Bronchos pa s m

Norma l blood ve s s e l
Norma l bronchiole with
la rge, ope n lume n

Mucus
Ede ma

Bronchos pa s m: lume n Va s odila tion with incre a s e d

cons tricte d, fille d with ca pilla ry pe rme a bility a nd
mucus (s hortne s s of e de ma forma tion (low blood
bre a th, whe e zing) pre s s ure, we a kne s s,
tis s ue swe lling)

Figure 4.12. IgE-mediated response in anaphylactic reaction. Allergen triggers B lymphocyte differentiation into IgE-
secreting plasma cell, stimulated by an activated type II helper T lymphocyte (TH2). IgE attaches to the mast cell. When
the allergen reappears, it binds to the mast cell-bound IgE and triggers mast cell degranulation, releasing chemical medi-
ators that stimulate primary early response manifestations. Secondary late response manifestations are the result of lipid
mediators released from phospholipids in the destructed cell membrane and recruitment of eosinophils by TH2 lymphocytes.

93
94 C h a p t e r 4: Alt er ed Im m u n it y

Lon g-t er m t r ea t m en t s in clu de desen sit iza t ion

a n d sign a lin g pa t h wa y blocka de of effect or s. Th e
goa l of desen sit iza t ion is t o: CNS (s e izure s, ps ychos is )
1. Swit ch t h e IgE r espon se t o a n IgG r espon se
2. Bin d t h e a ller gen a n d pr even t st im u la t ion of S kin (butte rfly ra s h a nd
IgE -m edia t ed r espon ses by skin in ject ion of a ller- dis coid lupus )
gen in pr ogr essively la r ger doses
3. Ch a n ge t h e h elper T-lym ph ocyt e effect or s fr om
T H 2 t o T H 1 cells t o down r egu la t e t h e IgE r espon se
S e ros itis
Blocka de of sign a lin g pa t h wa ys of m edia t or s st im - itis
oca rditis
u la t in g h yper sen sit ivit y r espon ses, in clu din g cyt o-
kin es, is a n ot h er pot en t ia l lon g-t er m t r ea t m en t .
He a rt

oca rditis

Immune Maladaptation: Systemic

Lupus Erythematosus Hematologic effects
a
ope nia
Syst em ic lu pu s er yt h em a t osu s (SLE ) is a n exa m ple Thrombocytopenia
of a t ype III h yper sen sit ivit y r ea ct ion . SLE is con sid-
Glomerulonephritis
er ed a n a u t oim m u n e disea se a n d fea t u r es r espon ses
fr om bot h t h e in n a t e a n d h u m or a l im m u n e syst em s.
mphadenopathy
Th e ch r on ic n a t u r e of t h is disea se is a r esu lt of per-
sist en t a n t igen -pr om ot in g com plex deposit ion a n d
in fla m m a t ion . Au t oa n t ibodies a r e t a r get ed a ga in st
t h e self-a n t igen ic com pon en t s of t h e cell m em br a n e Arthritis
(none ros ive )
(a n t iph osph olipid), cyt opla sm (a n t icyt opla sm ic), a n d
cell n u cleu s (a n t in u clea r ), in clu din g t h e DNA. Bin d-
in g of a n t igen wit h t h ese a n t ibodies st im u la t es a ct i-
va t ion of t h e com plem en t syst em a n d a ccu m u la t ion
Figure 4.13. Complications of systemic lupus erythemato-
of im m u n e com plexes. Th e loca t ion of t h ese com -
sus. CNS, central nervous system.
plexes a n d t h e or ga n s t h a t a r e in volved det er m in e
t h e sym pt om s of t h e disea se (Fig. 4.13). Beca u se t h e
in volved a n t igen s a r e pr esen t in a ll of t h e cells, SLE
is a ch r on ic, syst em ic disea se t h a t ca n pot en t ia lly t h e B lym ph ocyt es t o develop a u t oa n t ibodies a n d cy-
da m a ge a wide r a n ge of cell t ypes a n d loca t ion s. t ot oxic T lym ph ocyt es, wh ich t h en pr om ot e in fla m -
m a t ion a n d com plex deposit ion in su scept ible or ga n s
of t h e body, ca u sin g per m a n en t or ga n da m a ge.
PATHOPHYSIOLOGY
Th e exa ct even t s t h a t st im u la t e t h e developm en t of
CLINICAL MANIFESTATIONS
SLE a r e n ot fu lly kn own . A gen et ic or fa m ilia l t en -
den cy com bin ed wit h h or m on a l a n d en vir on m en t a l Clin ica l sign s a n d sym pt om s develop in t h e or ga n s
in flu en ces seem s t o m a ke a per son m or e su scept i- a ffect ed by t h e pa t h ology a ssocia t ed wit h SLE . Or-
ble t o developin g t h e disea se (F ig. 4.14). SLE , m ost ga n s m ost com m on ly a ffect ed in clu de t h e skin , kid-
com m on ly fou n d in wom en , t en ds t o r u n a cou r se n ey, a n d m u scu loskelet a l syst em . In a ddit ion , people
wit h exa cer ba t ion s (disea se fla r e-u ps) a n d q u ie s - dia gn osed wit h lu pu s m a y develop n eu r ologic, pu l-
c e n c e (decr ea sed sym pt om s). Th e MH C a n d H LA m on a r y, a n d ca r dia c disea se. Typica l m a n ifest a t ion s
syst em s a ppea r t o be in volved in t h e developm en t in SLE in clu de:
of a u t oim m u n e a ct ivit y, t r igger ed by a n u n kn own
● J oin t pa in a n d swellin g
even t , per h a ps in fect ion or a n ot h er pa t h ologic pr o-
● Skin r a sh es
cess. A br ea kdown in self-t oler a n ce r esu lt s in t h e
● Fa t igu e
st im u la t ion of AP Cs, t h e eva sion of n or m a l im m u n e
● Per ica r dia l effu sion (swellin g a r ou n d t h e h ea r t )
r espon se by m olecu la r m im icr y, or t h e a lt er a t ion of
● P leu r a l effu sion (swellin g a r ou n d t h e lu n gs)
a n t igen s t h a t m a ke t h em u n a ble t o be r ecogn ized a s
“self.” Th e a bilit y t o r em ove cells t h a t r ecogn ize “self ” Th ese syst em ic clin ica l m a n ifest a t ion s con t r ibu t e
by a popt osis is a lt er ed. Th e r esu lt is t h e a ct iva t ion of t o t h e dia gn osis of t h e disea se a n d ca n a lso pr ovide

Po te ntial Etio lo g ic Fac to rs
Vir
Lo s s o f Ac quire d s e ns itivity
to le ranc e to auto -antig e ns
4+
Auto antibo dy Pro duc tio n
r
Tis s ue injury
V
s c . Sen sit ivit y t o t h e su n r esu lt in g in r a sh
s (p h o t o s e n s it iv it y )
Figure 4.14. Pathogenesis of systemic lupus erythema-
tosus. EBV, Epstein–Barr virus; HLA, human leukocyte
antigen. (From Rubin E, Farber JL. Pathology. 4th ed. Phil-
adelphia, PA: Lippincott Williams & Wilkins; 2005.)
va lu a ble in for m a t ion a bou t t h e a ct ivit y of t h e dis-
ea se a n d effect iven ess of t r ea t m en t st r a t egies.
DIAGNOSTIC CRITERIA
Dia gn osis of SLE is det er m in ed by a com bin a t ion
of su bject ive sym pt om s, object ive ph ysica l fin d-
in gs, a n d la bor a t or y va lu es. Cr it er ia for u se in
cla ssifyin g SLE pa t ien t s for in clu sion in clin ica l
a n d r esea r ch st u dies h a ve been est a blish ed by t h e
Am er ica n College of Rh eu m a t ology (ACR). 9 Al-
t h ou gh n ot in t en ded for dia gn ost ic pu r poses, t h ese
cr it er ia a r e oft en u sed for t h a t pu r pose. E leven cr i-
t er ia a r e ou t lin ed by t h e ACR, fou r of wh ich m u st
be pr esen t t o obt a in a dia gn osis of SLE . Th ese cr i-
t er ia in clu de:
1. Ra sh
a . Bu t t er fly r a sh over ch eeks (m a la r ) (Fig. 4.15)
C lin ic a l Mo d e ls 95
Figure 4.15. Malar (butterfly) rash in systemic lupus ery-
thematosus. (From Goodheart HP. Goodheart’s Photoguide
of Common Skin Disorders. 2nd ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2003.)
b . Red, r a ised, d is c o id (r ou n d) r a sh , som et im es
wit h sca lin g or plu gged follicles
2. U lc e r s , or open a r ea s, in t h e m ou t h or n a soph a r yn x
3. Ar t h r it is, a ssocia t ed wit h t en der n ess, swellin g, or
flu id bu ildu p (a s seen in RA) in a t lea st t wo pe-
r iph er a l join t s
4. P le u r it is (in fla m m a t ion of t h e lin in g of t h e lu n gs
or pleu r a l ca vit y) or p e r ic a r d it is (in fla m m a t ion
of t h e lin in g of t h e h ea r t )
5. P r o t e in u r ia (pr ot ein in t h e u r in e) gr ea t er t h a n
5 g/dL or +3 on a dip st ick, or c e llu la r c a s t s (com -
pa ct ed collect ion of pr ot ein , cells, a n d debr is t h a t
a r e for m ed in kidn ey t u bu les) su ggest in g r en a l
in volvem en t
6. Seizu r es or psych osis, su ggest in g n eu r ologic
in volvem en t
7. An em ia , leu kopen ia , or t h r o m b o c y t o p e n ia (a b-
n or m a lly low n u m ber of pla t elet s), su ggest in g h e-
m a t ologic in volvem en t
8. La b va lu es in clu din g a n t i-DNA a n t ibody, a n t i-Sm
(a n t ibody t o Sm it h n u clea r a n t igen ), or a fa lse-
posit ive t est for syph ilis
9. Abn or m a l a n t in u clea r a n t ibody (ANA)
Th e cr it er ia r ein for ce t h e im por t a n ce of lookin g a t
t h e en t ir e per son , r a t h er t h a n ju st a la b t est , t o iden -
t ify t h e disea se a n d illn ess a ccu r a t ely. Th e en t ir e
clin ica l pict u r e is n ecessa r y t o pr ovide pr oper t r ea t -
m en t a n d ca r e for a specia lized con dit ion .
96 C h a p t e r 4: Alt er ed Im m u n it y

effect s. Th e disea se is oft en m a n -

Ta b le 4.5 Tr ea t m en t Opt ion s for Syst em ic Lu pu s E r yt h em a t osu s
Dr u g D e s ir e d E e c t Ad v e r s e E e c t
Sa licyla t es An t i-in fla m m a t or y GI bleedin g a n d u pset
NSAIDs An t i-in fla m m a t or y GI bleedin g a n d u pset
Glu cocor t icoids An t i-in fla m m a t or y H yper t en sion
H yper glycem ia
H yper lipidem ia
H ypoka lem ia
Ost eopor osis
In fect ion
F lu id r et en t ion
Weigh t ga in
H ydr oxych lor oqu in e Im m u n osu ppr ession Ma cu la r da m a ge
P h ot osen sit ivit y
Ra sh
Aza t h iopr in e Im m u n osu ppr ession Myelosu ppr ession (a n em ia ,
t h r om bocyt open ia )
H epa t ot oxicit y
Cycloph osph a m ide Im m u n osu ppr ession Myelosu ppr ession
Ma lign a n cy
In fect ion
Cyst it is
In fer t ilit y
Met h ot r exa t e Im m u n osu ppr ession Myelosu ppr ession
H epa t ot oxicit y
P u lm on a r y disea se
GI, ga st r oin t est in a l; NSAIDs, n on st er oida l a n t i-in fla m m a t or y dr u gs.
a ged wit h ot h er dr u gs design ed t o
dela y t h e pr ogr ess a n d r esu lt in g
da m a ge, in clu din g disea se-m od-
ifyin g a n t i-r h eu m a t oid dr u gs
(DMARD) a s a r e u sed in RA. Th e
a n t im a la r ia l dr u g P la qu en il m a y
be u sed t o slow disea se pr ogr ess.
In m or e a ggr essive ca ses, im m u -
n osu ppr essa n t dr u gs, in clu din g
cycloph osph a m ide, r it u xa m id,
a n d m ycoph en ola t e, m ay be n ec-
essa r y. P r ovidin g a ppr opr ia t e
dr u g t r ea t m en t t o pr even t da m -
a ge wh ile sim u lt a n eou sly de-
cr ea sin g pot en t ia lly da m a gin g
side effect s is difficu lt a n d oft en
r equ ir es ca r e pla n n ed by a r h eu -
m a t ologist wh o specia lizes in
t h ese t ypes of con dit ion s.
Immune Maladaptation:
Rh Isoimmunization
Th is clin ica l m odel r ep-
r esen t s a t ype II cyt ot oxic a n -
t ibody-m edia t ed r ea ct ion . Rh
isoim m u n iza t ion is a dir ect a n -
t igen –a n t ibody h yper sen sit ivit y

TREATMENT
Trea t ment for SLE va ries
F R O M T H E L AB
a m ong individua ls. Con- Lab tests used to diagnose SLE are designed to detect the antibodies directed against cell
sider a tions for tr ea tm ent components in the cytoplasm and nucleus. These include antinuclear antibodies (ANA)
include clinica l m a nifest a - and extractable nuclear antigens (ENA), a group of several cellular proteins and antibodies
t ions, dura t ion of desir ed that include antibodies to Smith antigen (anti-Sm). Once SLE is diagnosed, laboratory
t r ea t m ent , a n d tolera t ion tests used to evaluate disease activity and prognosis include measurement of anti-dsDNA
of a ssocia t ed side effect s. (anti-double stranded DNA, detecting antibodies against DNA) and complement (C3 and
E a rly tr ea tm ent is essen- C4). Future work in determining more specific and sensitive biomarkers of SLE includes
t ia l to m inim ize mor bidity evaluation of the products of complement activation and inhibition, cytokines (including
a nd m or t a lit y, a lt hough the interleukins and TNF-alpha), circulating immune complexes (CICs), measurement of the
t his must be ba la nced number of abnormal T-cell types by cell surface marker (i.e., CD4, CD8), and markers of
with t he significa nt r isk B-cell activation.
of a dverse effect s from t he
t r ea t m ent s them selves, in-
cluding t he developm ent of
a t heroscler otic hea r t disea se, ost eopor osis, hyper t en- r ea ct ion bet ween a m ot h er a n d h er fet u s. Th e da m -
sion, dia bet es, infect ion, a nd even dea t h (Ta ble 4.5). a ge t h a t r esu lt s fr om t h is r ea ct ion in clu des cell de-
In it ia lly, ph a r m a cologic m a n a gem en t m a y in volve st r u ct ion of t h e a n t igen t a r get s, wh ich a r e t h e fet a l
n on st er oida l a n t i-in fla m m a t or y dr u gs (NSAIDs), RBCs. Th is con dit ion , kn own a s h e m o ly t ic (dest r u c-
a lt h ou gh u lt im a t ely it oft en in volves t h e u se of cor t ico- t ion of blood cells) disea se of t h e fet u s a n d n ewbor n ,
st er oids for sym pt om con t r ol a n d a n t i-in fla m m a t or y is a r esu lt of t h is blood cell dest r u ct ion .
 C lin ic a l Mo d e ls 97

a ga in st t h e a n t igen a n d is
R E S E AR C H N O T E S a ble t o m ou n t a r a pid, r o-
bu st im m u n e r espon se if
Currently, a great deal of research is being conducted that focuses on the development t h e a n t igen pr esen t s it self
of a pharmacologic treatment for SLE that is both effective and has minimal side effects. t o t h e m a t er n a l syst em in
Increasingly refined approaches are being investigated to achieve maximum benefit and t h e fu t u r e beca u se of im -
improve treatment outcome. A treatment approach in individuals with significant renal in- m u logic m em or y.
volvement based on histologic characteristics has the potential to reduce drug dosage and If t h e Rh -n ega t ive
duration of use. In lupus nephritis, the site of accumulation of immunoglobulins in the renal m ot h er becom es pr egn a n t
glomeruli, the specificity of the immunoglobulins to antigens and the inflammation induced a ga in wit h a n Rh -posit ive
upon antigen–antibody complex deposition are factors that may be used to determine opti- fet u s, m a t er n a l a n t i-D
10
mal therapy for this serious manifestation of SLE. IgG will cr oss t h e pla cen t a
in t o t h e fet a l cir cu la t ion .
Ma t er n a l a n t i-D IgG will
r ecogn ize a n d t a r get t h e D a n t igen -bea r in g fet a l
PATHOPHYSIOLOGY RBCs for dest r u ct ion . Th e m em or y cells, a com po-
H em olyt ic disea se of t h e fet u s a n d n ewbor n is ca u sed n en t of t h e h u m or a l im m u n ologic m em or y r espon se,
by m a t er n a l a lloa n t ibodies, wh ich t a r get pa t er n a lly r espon d r a pidly a n d a r e a ble t o pr odu ce in cr ea sed
in h er it ed a n t igen s. Ma n y a n t igen s ca n be t a r get ed levels of a n t ibodies wit h a h igh er a ffin it y t o t h e fet a l
in t h is disea se, bu t t h e a n t igen u su a lly in volved is D a n t igen . Th e t r a n spla cen t a l pa ssa ge of m a t er n a l
D (Rh o), on e of t h e pr im a r y a n t igen s r espon sible for a n t ibody (IgG) in t o t h e fet u s r esu lt s in RBC dest r u c-
t h e det er m in a t ion of Rh -posit ive blood t ype. If a per- t ion a n d t h e con dit ion kn own a s h em olyt ic a n em ia
son is D a n t igen posit ive, h e or sh e is iden t ified a s (Fig. 4.16).
bein g Rh -posit ive; a per son wit h ou t t h e D a n t igen is
kn own a s Rh -n ega t ive.
CLINICAL MANIFESTATIONS
A fet u s oft en h a s a differ en t R fa ct or fr om t h e
m ot h er. Th is does n ot u su a lly ca u se a n y im m u n e r e- Fet u ses su ffer in g fr om Rh isoim m u n iza t ion a r e
spon se beca u se ea ch h a s a sepa r a t e cir cu la t ion n ot a t in cr ea sed r isk for t h e developm en t of a n em ia ,
design ed t o m ix. Ma t er n a l blood cir cu la t es t h r ou gh h ydr ops (a ccu m u la t ion of edem a ), a n d dea t h . Se-
t h e m a t er n a l por t ion of t h e p la c e n t a , a specia lized ver e h em olysis of fet a l RBCs ca n be wor sen ed by
or ga n su st a in in g t h e fet u s, by pr ovidin g oxygen - in cr ea sed er yt h r opoiesis, r esu lt in g in t h e pr o-
a t ion , n u t r it ion , en docr in e, a n d excr et ion fu n ct ion s. du ct ion of la r ge n u m ber s of im m a t u r e n u clea t ed
Th e ch or ion ic villi con t a in fet a l ca pilla r ies t h a t a l- er yt h r ocyt es, kn own a s er yt h r obla st osis fet a lis.
low exch a n ge of su bst a n ces bet ween m ot h er a n d fe- Dest r u ct ion of RBCs a llows t h e r elea se of cellu la r
t u s a cr oss a m em br a n e, wit h ou t t h e a ct u a l m ixin g of com pon en t s, som e of wh ich ca n pr odu ce a ddit ion a l
m a t er n a l a n d fet a l cir cu la t ion s. Most su bst a n ces in pa t h ology. On e of t h e com pon en t s of t h e br ea kdown
t h e m a t er n a l a n d fet a l cir cu la t ion s, wit h t h e excep- of h em oglobin in RBCs is bilir u bin . Bilir u bin , in it s
t ion of h igh m olecu la r weigh t com pou n ds, ca n cr oss u n con ju ga t ed for m , is lipid solu ble, a ch a r a ct er is-
t h e pla cen t a l m em br a n e u sin g a va r iet y of t r a n spor t t ic t h a t pr even t s excr et ion of t h is pot en t ia lly t oxic
m ech a n ism s. Th ese t r a n spor t m ech a n ism s in clu de su bst a n ce. Aft er bir t h , in fa n t s m a y h a ve a n ewbor n
pa ssive diffu sion , fa cilit a t ed diffu sion , a n d a ct ive cou r se com plica t ed by ker n ict er u s (u n con ju ga t ed
t r a n spor t . If t h e m ot h er h a s n ot h a d pr ior exposu r e bilir u bin deposit s in t h e ba sa l ga n glia of t h e br a in ),
t o t h e D a n t igen a n d t h er efor e n o pr odu ct ion of a n t i- let h a r gy, h ea r in g loss, cer ebr a l pa lsy, a n d lea r n in g
bodies a ga in st it , t h e m ot h er is u n a ble t o st im u la t e pr oblem s.
a n im m u n e r espon se t o a n a n t igen it ca n n ot r ecog-
n ize in t h e sepa r a t e fet a l cir cu la t ion .
If fet a l blood en t er s t h e m a t er n a l cir cu la t ion u n -
DIAGNOSTIC CRITERIA
in t en t ion a lly, fet a l D a n t igen on t h e fet a l RBCs ca n Iden t ifica t ion of a m ot h er a t r isk for sen sit iza t ion
pa ss in t o t h e m a t er n a l blood su pply. In a D a n t igen a n d t h ose wh o a r e sen sit ized is com plet ed a s a com -
n a ïve Rh -n ega t ive in dividu a l, t h e D a n t igen is r ecog- pon en t of r ou t in e pr en a t a l ca r e. Ma t er n a l blood
n ized a s for eign , st im u la t in g a n a n t ibody r espon se is scr een ed t o det er m in e wh et h er t h e m ot h er is
a ga in st t h e a n t igen . Th ou gh IgG h a s t h e a bilit y t o Rh -posit ive or -n ega t ive a s t h e in it ia l st ep in iden -
cr oss t h e pla cen t a t o r ea ch t h e t a r get of t h e D a n t i- t ifyin g r isk. In a ddit ion , a scr een for a n t ibodies t o
gen on RBCs in t h e fet a l cir cu la t ion , t h e r espon se of t h e D a n t igen is com plet ed t o iden t ify wh et h er t h e
m a t er n a l pr im a r y a n t ibody pr odu ct ion is slow a n d m ot h er is a lr ea dy sen sit ized.
t h er efor e does n ot sever ely a ffect t h e fet u s. On ce a n - Fet a l blood t ype a n d Rh a r e n ot det er m in ed in
t ibodies a r e pr odu ced, t h e m ot h er is t h en “sen sit ized” r ou t in e pr egn a n cies beca u se t h a t wou ld r equ ir e
98 C h a p t e r 4: Alt er ed Im m u n it y
Figure 4.16. Maternal sensitization. (From Nath J. Using Medical Terminology: A Practical Approach. Baltimore, MD: Lippincott
Williams & Wilkins; 2006.)
a n in va sive pr ocedu r e wit h m or e r isk t h a n ben efit .
In a sen sit ized m ot h er, t h e h igh -r isk n a t u r e of t h e
pr egn a n cy r equ ir es ca r efu l scr een in g of fet a l st a t u s
du r in g gr owt h in t h e u t er u s. Det ect ion of t h e fet a l
RBCs a n t igen ca n be det er m in ed by per for m in g
a n a m n io c e n t e s is (in ser t ion of a n eedle in t o t h e
u t er in e ca vit y t o obt a in a sa m ple of a m n iot ic flu id)
a n d by u sin g t h e t ech n iqu e of gen ot ypin g. If t h e fe-
t u s is a lso Rh -n ega t ive, n o fu r t h er t est in g n eeds t o
be don e beca u se t h e fet u s does n ot ca r r y D a n t igen
a n d t h er efor e is u n a ble t o st im u la t e t h e m a t er n a l
m em or y cells t o in it ia t e a n im m u n e r espon se. A n on -
in va sive m et h od of det er m in in g fet a l Rh st a t u s is
t o m ea su r e cir cu la t in g fet a l DNA in t h e m a t er n a l
pla sm a .
In a n Rh -posit ive fet u s, m ea su r em en t s of a m -
n iot ic com pon en t s, in clu din g bilir u bin , pr ovide a n
in dir ect m ea su r e of h em olysis a n d a n em ia . Am n io-
cen t esis m a y be r equ ir ed sever a l t im es du r in g t h e
pr egn a n cy, or ser ia lly, t o det er m in e disea se sever-
it y a n d pr ogr ession . A n on in va sive pr ocedu r e m a y
be u sed t o r elia bly qu a n t ify fet a l a n em ia a n d gu ide
t r ea t m en t decision s. Mea su r em en t s of fet a l m iddle
cer ebr a l a r t er y pea k syst olic velocit y (MCA P SV) u s-
in g u lt r a sou n d ca n a lso pr ovide in for m a t ion a bou t
fet a l h ea r t r a t e, t issu e oxygen a t ion , or blood v is c o s -
it y (con cen t r a t ion ) t o det ect fet a l a n em ia .
S e cond
Rh + fe tus
TREATMENT
Wh en h em olysis of fet a l RBCs occu r s, fet a l oxygen -
a t ion is decr ea sed beca u se of t h e decr ea sed h em oglo-
bin a va ila ble t o t r a n spor t oxygen t o cells a n d t issu es.
On e of t h e pr im a r y t r ea t m en t s of a fet u s wit h se-
ver e a n em ia is t o pr ovide h ea lt h y RBCs in exch a n ge
for h em olyzed RBCs, u sin g a n in -u t er o exch a n ge
t r a n sfu sion . Th e n eed for t r a n sfu sion is ba sed on
t h e det er m in a t ion s by a m n iocen t esis or MCA P SV,
a s descr ibed pr eviou sly. Th e t r a n sfu sion pr ocedu r e,
com plet ed u n der u lt r a sou n d gu ida n ce, u ses t h e fe-
t a l u m bilica l cor d a r t er ies a n d vein t o a dd h ea lt h y
cells a n d r em ove da m a ged cells. Th e r isks a ssocia t ed
wit h t h is pot en t ia lly da n ger ou s pr ocedu r e in clu de
in fect ion , pr egn a n cy loss, pr em a t u r e la bor, r u pt u r e
of m em br a n es, wor sen in g isoim m u n iza t ion , a n d de-
cr ea sed fet a l h ea r t r a t e. Th e t r a n sfu sion pr ocedu r e
m a y a lso n eed t o be com plet ed in a ser ia l m a n n er,
depen din g on t h e pr ogr ess of fet a l disea se. On ce a
m ot h er is sen sit ized a ga in st t h e fet a l D a n t igen ,
t h er e a r e n o pr ocedu r es t o desen sit ize h er. Th e fo-
cu s of m a n a gin g disea se in t h e fet u s is t h e pr im a r y
in t er ven t ion .
Th e developm en t of pr even t ion st r a t egies h a s r e-
du ced t h e r a t e of sen sit iza t ion in a t -r isk m ot h er s.
Th is is a ccom plish ed by pr ovidin g t h e Rh -n ega t ive
 C h a p t e r 4: Alt er ed Im m u n it y 99

m ot h er wit h Rh im m u n o-
globin (Rh Ig) wh en t h er e
is a r isk of m a t er n a l ex- F R O M T H E L AB
posu r e t o fet a l RBCs.
In it ia t ed in 1968, Rh Ig Maternal antibodies to the fetal D antigen can be detected in the serum using an indirect
wa s a dm in ist er ed t o Rh - Coombs test to determine whether the mother is sensitized. For sensitization to be pre-
n ega t ive m ot h er s by in - vented after maternal exposure to fetal D antigen, an adequate dosage of RhIg must be
ject ion wit h in 72 h ou r s given. The standard prenatal dose is 500 IU and 1,500 IU at the time of delivery. If there is
of deliver in g a n Rh -posi- an increased risk of an excessive maternal exposure to fetal cells (i.e., after blunt trauma),
t ive fet u s, wh en t h e r isk testing to quantify the number of fetal cells present in the maternal circulation, the Klei-
of m a t er n a l a n d fet a l cir- hauer–Betke test, can be completed to assure adequate dosing of RhIg.
cu la t ion s m ixin g is h igh .
Th e Rh Ig bin ds t o D a n -
t igen on fet a l cells cir cu -
la t in g in t h e m a t er n a l R E S E AR C H N O T E S
cir cu la t ion , pr ovidin g a
pr ot ect ive coa t in g a r ou n d RhIg has drastically reduced the number of women who become sensitized to the D fetal an-
t h e cells a n d pr even t in g tigen. As a result, sensitization to other antigens in the Rh system (anti-FYa, anti-c, anti-E,
det ect ion by t h e m a t er n a l and anti-K) is now getting more attention. No specialized treatments exist to prevent other
im m u n e syst em a n d su b- forms of Rh sensitization. RhIg is often the treatment of choice in the protection against
sequ en t a n t i-D a n t ibody sensitization and has proven to be an effective strategy. 12
pr odu ct ion .
Cu r r en t pr even t ion
st r a t egies in clu de pr ovi-
sion of Rh Ig a dm in ist r a t ion t o Rh -n ega t ive n on sen - ● B lym ph ocyt es pr odu ce a n d secr et e a n t ibodies,
sit ized m ot h er s du r in g pr egn a n cy a t t im es wh en t h e ea ch ca pa ble of det ect in g specific a n t igen s, lea d-
likelih ood of com bin ed cir cu la t ion s is gr ea t est a n d in g t o h u m or a l im m u n it y.
t h e fet a l Rh fa ct or is u n kn own . Rh Ig ca n be a dm in is- ● Gr a n u locyt es r espon d qu ickly a n d br oa dly t o in -
t er ed du r in g in va sive pr ocedu r es, su ch a s a m n iocen - fect iou s a gen t s.
t esis, u pon ea r ly t er m in a t ion of pr egn a n cy (a s in t h e ● Th e lym ph a t ic syst em t r a ps a n t igen s ca pt u r ed by
ca ses of a bor t ion a n d ect opic pr egn a n cy), followin g cells of t h e im m u n e syst em , a llowin g t h e a n t igen
ph ysica l t r a u m a a n d a t 28 weeks’ gest a t ion t o pr o- t o be pr esen t ed t o a n t ibody.
vide pr ot ect ion fr om in a dver t en t a n t igen exposu r e. ● Molecu les kn own a s m a jor h ist ocom pa t ibilit y
Rh IG con t in u es t o be a dm in ist er ed t o Rh -n ega t ive com plex (MH C) or h u m a n leu kocyt e a n t igen
m ot h er s wit h in 72 h ou r s of deliver y if t h e n ewbor n (H LA) displa y a n t igen s t o T cells, st im u la t in g t h e
is Rh -posit ive. Th e opt im a l dosa ge a n d a dm in ist r a - im m u n e r espon se.
t ion r egim en of Rh Ig con t in u es t o be r eeva lu a t ed t o ● Recept or s on T a n d B lym ph ocyt es r ecogn ize
m a xim ize effect iven ess a n d sa fet y.11 u n iqu e a n t igen a n d a n t igen –MH C com plexes in a
specific m a n n er r esu lt in g in t a r get ed dest r u ct ion
Stop and Consider of a n t igen -bea r in g cells.
Is an Rh-positive mother at risk of becoming ● Alt er ed im m u n e fu n ct ion m a y be ca u sed by in -
sensitized to her Rh-negative fetus? Why or a bilit y t o m ou n t a n im m u n e defen se, exa gger a t ed
why not? im m u n e r espon ses, in a ppr opr ia t e im m u n e r e-
spon ses t o “self,” a n d im m u n e r espon se dir ect ed
t owa r d t r a n spla n t ed t issu es.
S U MMAR Y ● Ma la da pt a t ion s in im m u n e r espon se, eit h er ex-
a gger a t ed or im pa ir ed, con t r ibu t e t o a cu t e a n d
● Th e cellu la r com pon en t s of t h e im m u n e r espon se ch r on ic disea se.
wor k t oget h er t o m ou n t t h e t h ir d lin e of defen se ● Im m u n osu ppr ession is t h e r esu lt of a pr im a r y or
a ga in st in va sion of pa t h ogen s. secon da r y im m u n odeficien cy.
● In n a t e a n d a da pt ive (cell-m edia t ed a n d h u m or a l) ● H yper sen sit ivit y r espon ses a r e m edia t ed by IgE ,
im m u n e r espon ses com bin e t o pr ovide pr ot ect ion a n t igen –a n t ibody, im m u n e com plex, or cyt ot oxic
a ga in st in fect ion a n d illn ess. r ea ct ion s.
● T lym ph ocyt es pr olifer a t e a n d differ en t ia t e in t o ● Au t oim m u n it y is t h e fa ilu r e t o dist in gu ish “self ”
cyt ot oxic or h elper T cells wh en pr esen t ed wit h a n fr om “n on self,” lea din g t o a n im m u n e r espon se
a n t igen , lea din g t o cell-m edia t ed im m u n it y. a ga in st a n in dividu a l’s own t issu es.
100 C h a p t e r 4: Alt er ed Im m u n it y
● Alloim m u n it y r esu lt s fr om a n im m u n e r e-
spon se dir ect ed a ga in st t h e t issu es of a n ot h er
in dividu a l of t h e sa m e species, oft en seen in
t r a n spla n t a t ion .
● P r ot ect ion of im m u n e fu n ct ion a n d t h e m a n ipu -
la t ion of t h e im m u n e syst em t o pr even t disea se
a r e excit in g pr ospect s t h a t will sign ifica n t ly de-
cr ea se m or bidit y a n d m or t a lit y r esu lt in g fr om
m a n y ch r on ic disea ses in t h e Un it ed St a t es a n d
t h r ou gh ou t t h e wor ld.
CAS E S T U D Y 4.1
C.J., a 19-yea r-old Wh it e fem a le, h a s a h ist or y of h a y
fever, wh ich seem s t o get wor se du r in g t h e su m m er
m on t h s. Aft er a weeken d ca m pin g t r ip, sh e devel-
oped difficu lt y br ea t h in g a n d n eeded t o seek ca r e for
t h ese sym pt om s, wh ich wer e dia gn osed a s a n exa cer-
ba t ion of a st h m a . Th in k a bou t wh ich clin ica l m odel
is m ost r ela t ed t o t h is pr ocess. Fr om you r r ea din g r e-
la t ed t o in fla m m a t ion a n d im m u n e fu n ct ion , a n swer
t h e followin g qu est ion s:
1. Wh a t a n a t om ic pr oblem wou ld m ost likely lea d
t o difficu lt y br ea t h in g a s a con sequ en ce of a ller gy
a n d a st h m a ?
2. Wh a t is t h e in ju r y in a st h m a ?
3. H ow wou ld t h e im m u n e syst em r espon d?
4. Wh y is t h is a ch r on ic pr oblem ?
5. Wh a t pa t h oph ysiologic ch a n ges wou ld m ost likely
occu r wit h ch r on ic a st h m a a n d a ller gy?
6. Wh a t wou ld you expect t o fin d a s clin ica l
m a n ifest a t ion s?
7. Wh a t dia gn ost ic t est s m igh t be u sed?
8. Wh a t t r ea t m en t m ea su r es wou ld you a n t icipa t e?
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r n a l
a r t icle or Web sit e t h a t det a ils a st h m a wit h a n a ller-
gic com pon en t t o con fir m you r pr edict ion s.
C AS E S T U D Y 4.2
A.L., a 25-yea r-old Na t ive Am er ica n fem a le, is pr eg-
n a n t wit h h er secon d ch ild. Sh e wa s exposed t o a
ch ild wit h ch icken pox a t a r ecen t fa m ily even t . A.L.
h a s n ot h a d ch icken pox, a n d sh e h a s n ot been im -
m u n ized. H er 4-yea r-old son wa s im m u n ized (in it ia l
a n d boost er ) a ga in st t h e va r icella vir u s t h a t ca u ses
ch icken pox. F r om you r r ea din g r ela t ed t o im m u n it y,
a n swer t h e followin g qu est ion s:
1. Wh a t is A.L.’s r isk for in fect ion wit h t h e va r icella
vir u s?
2. E xpla in A.L.’s son ’s r isk for in fect ion wit h t h e
va r icella vir u s.
3. Discu ss t h e r isk for A.L.’s u n bor n ch ild for in fec-
t ion wit h va r icella .
4. Discu ss pr even t ion a n d t r ea t m en t st r a t egies t h a t
ca n be u sed t o pr even t va r icella in fect ion in ea ch
of t h ese in dividu a ls.
5. Wh a t st r a t egies sh ou ld be u sed t o pr ot ect ot h er
h ou seh old fa m ily m em ber s?
6. Iden t ify wh et h er pr even t ion st r a t egies for A.L.,
h er son a n d fet u s st im u la t e pa ssive or a ct ive im -
m u n e r espon ses.
7. H ow ca n it be det er m in ed if a n in dividu a l h a s im -
m u n it y t o va r icella ?
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r n a l
a r t icle or Web sit e t h a t det a ils va r icella in fect ion
pr even t ion du r in g pr egn a n cy a n d ch ildh ood a n d
specia l con sider a t ion s in im m u n e r espon ses in t h ese
gr ou ps t o con fir m you r pr edict ion s.
P R AC T I C E E XAM Q U E S T I O N S
1. Du r in g flu sea son , you get exposed t o t h e in flu -
en za vir u s. Wh ich com pon en t of you r im m u n e
syst em will be t h e fir st t o r espon d t o t h is for eign
pa t h ogen ?
a . In n a t e
b. Ada pt ive
c. H u m or a l
d. T-cell m edia t ed
2. Th e followin g sea son , you a r e con cer n ed a bou t
get t in g t h e flu a ga in . Wh ich of t h e followin g
st a t em en t s is t r u e?
a . You con t in u e t o be a t r isk beca u se n ot h in g ca n
pr ot ect you fr om r ein fect ion .
b. Va ccin a t ion for pr eva len t st r a in s of in flu en za
vir u s ca n pr ovide im pr oved pr ot ect ion a ga in st
t h e disea se.
c. P r em edica t ion wit h im m u n osu ppr essa n t s will
pr ovide pr ot ect ion a ga in st in fect ion .
d. Beca u se you h a ve h a d t h e flu on ce, you will be
pr ot ect ed fr om get t in g it a ga in .
3. Im m u n e su ppr ession in AIDS is r ela t ed t o:
a . Decr ea sed pla t elet cou n t
b. Decr ea sed r ed blood cell cou n t
c. Decr ea sed lym ph ocyt e cou n t
d. E leva t ed lym ph ocyt e cou n t
4. Wh ich of t h e followin g con dit ion s r epr esen t s
pa t h ologic r espon ses ca u sed by im m u n ologic
m em or y?
a . Com m on cold
b. An a ph yla xis
c. Sh in gles
d. St r ep t h r oa t

5. Th e pa t h ology r ela t ed t o syst em ic lu pu s er yt h e-
m a t osu s is du e t o:
a . Neu t r oph il a ct iva t ion
b. Dela yed im m u n it y
c. Im m u n osu ppr ession
d. Im m u n e com plex deposit ion
6. Im m u n odeficien cy is t h e r esu lt of:
a . Fa ilu r e of h ost defen se m ech a n ism s
b. H yper sen sit ive im m u n e r espon ses
c. In a ppr opr ia t e im m u n e r espon se t o self
d. Im m une response st im ula t ed by a nt igens fr om
ot her individua ls
7. A h yper sen sit ivit y r ea ct ion r esu lt in g fr om a yel-
low ja cket st in g is a n exa m ple of:
a . Type I, im m edia t e h yper sen sit ivit y r ea ct ion
b. Type II, a n t ibody-m edia t ed r ea ct ion
c. Type III, im m u n e com plex r ea ct ion
d. Type IV, cell-m edia t ed r ea ct ion
8. A h yper sen sit ivit y r ea ct ion r esu lt in g fr om com -
plem en t a ct iva t ion du e t o in solu ble a n t igen –
a n t ibody deposit ion is a n exa m ple of:
a . Type I, im m edia t e h yper sen sit ivit y r ea ct ion
b. Type II, a n t ibody-m edia t ed r ea ct ion
c. Type III, im m u n e com plex r ea ct ion
d. Type IV, cell-m edia t ed r ea ct ion
9. Au t oim m u n it y m a y be t r igger ed by wh ich on e of
t h e followin g?
a . E lim in a t ion of self-r ea ct ive lym ph ocyt es in
cen t r a l lym ph oid t issu es
b. Per sist en t lym ph ocyt e ign or a n ce
c. Im pa ir ed T-cell a ct iva t ion
d. Close r esem bla n ce bet ween for eign a n d self-
a n t igen
10. Tr ea t m en t of a n a lt er ed im m u n e r espon se wit h
cor t icost er oids is a ssocia t ed wit h wh ich on e of
t h e followin g a dver se effect s?
a . Decr ea sed blood su ga r
b. Loss of bon e m in er a l
c. Th icken in g of skin
d. Weigh t loss
11. Th e t r a n sfer of secr et or y IgA fr om m ot h er t o in -
fa n t du r in g br ea st feedin g is a n exa m ple of
a . H yper sen sit ivit y r ea ct ion
b. Act ive im m u n it y
c. Pa ssive im m u n it y
d. Alloim m u n it y
12. Wh ich of t h e followin g is t r u e r ega r din g cyt o-
t oxic T lym ph ocyt es?
a . Recogn ize t h e MH C cla ss I–a n t igen com plex
b. Recogn ize t h e MH C cla ss II–a n t igen com plex
C h a p t e r 4: Alt er ed Im m u n it y 101
c. Ca r r y t h e CD4 m a r ker
d. P r esen t a n t igen t o B lym ph ocyt es for a n t i-
body pr odu ct ion
13. Wh ich of t h e followin g a r e con sider ed a n t igen -
pr esen t in g cells?
a . Den dr it ic cells
b. E osin oph ils
c. B lym ph ocyt es
d. T lym ph ocyt es
14. Wh ich of t h e followin g m a r ker s iden t ifies a n u -
clea t ed body cell?
a . CD4
b. BCR
c. MH C I
d. MH C II
15. Wh ich of t h e followin g is t r u e r ega r din g ph a r-
m a cologic t r ea t m en t for AIDS?
a . Dr u gs a r e u sed t o t a r get in cr ea sed r ed blood
cell n u m ber
b. Dr u gs a r e u sed t o t a r get in cr ea sed wh it e
blood cell n u m ber
c. Dr u gs a r e u sed t o in cr ea se h ost DNA
r eplica t ion
d. Dr u gs a r e u sed t o in h ibit H IV r eplica t ion
D I S C U S S I O N AN D
AP P L I C AT I O N
1. Wh a t did I kn ow a bou t ba sic a lt er a t ion s in im -
m u n it y befor e t oda y?
2. Wh a t body pr ocesses a r e a ffect ed by a lt er ed
im m u n e fu n ct ion ? H ow does im m u n it y im pa ct
t h ose pr ocesses?
3. Wh a t a r e t h e pot en t ia l et iologies for a lt er ed im -
m u n e fu n ct ion ? H ow do a lt er a t ion s in im m u n e
fu n ct ion develop?
4. Wh o is m ost a t r isk for developin g a lt er ed
im m u n it y? H ow ca n t h ese a lt er a t ion s be
pr even t ed?
5. Wh a t a r e t h e h u m a n differ en ces t h a t a ffect t h e
et iology, r isk, or cou r se of a lt er ed im m u n it y?
6. Wh a t clin ica l m a n ifest a t ion s a r e expect ed in t h e
cou r se of a lt er ed im m u n it y?
7. Wh a t specia l dia gn ost ic t est s a r e u sefu l in det er-
m in in g t h e dia gn osis a n d cou r se of illn ess du e t o
a lt er ed im m u n e fu n ct ion ?
8. Wh a t a r e t h e goa ls of ca r e for in dividu a ls wit h
a lt er ed im m u n it y?
9. H ow does t h e con cept of a lt er ed im m u n it y bu ild
on wh a t I h a ve lea r n ed in t h e pr eviou s ch a pt er
a n d in t h e pr eviou s cou r ses?
10. H ow ca n I u se wh a t I h a ve lea r n ed?
102 C h a p t e r 4: Alt er ed Im m u n it y
R E SOUR CE S
AIDSin fo (a ser vice of t h e US Depa r t m en t of H ea lt h
a n d H u m a n Ser vices):
h t t p://a idsin fo.n ih .gov
Th e Am er ica n College of Rh eu m a t ology:
h t t p://www.r h eu m a t ology.or g/
Th is sit e is a r esou r ce for in for m a t ion a bou t a u t oim -
m u n e disor der s.
Im m u n e Deficien cy Fou n da t ion :
h t t p://www.pr im a r yim m u n e.or g/
Lea r n m or e a bou t pr im a r y im m u n e deficien cy.
Na t ion a l In st it u t e of Aller gy a n d In fect iou s Disea se
(NIAID):
h t t p://www3.n ia id.n ih .gov/
F in d ou t m or e a bou t gen er a l im m u n e fu n ct ion .
R e er en ces
1. J a ckson KD, H owie LD, Akin ba m i LJ. Tr en d s in Aller-
gic Con d ition s Am on g Ch ild r en in th e Un ited S ta tes,
1997–2011. NCH S Da t a Br ief. No. 121. H ya t t sville, MD:
Na t ion a l Cen t er for H ea lt h St a t ist ics; 2013.
2. Bilò MB, Sever in o M, Cilia M, et a l. Th e VISYT t r ia l:
ven om im m u n ot h er a py sa fet y a n d t oler a bilit y wit h pu r i-
fied vs n on pu r ified ext r a ct s. An n Aller gy Asth m a
}Im m u n ol. 2009;103(1):57–61.
3. UNAIDS, Wor ld H ea lt h Or ga n iza t ion . Fa ct sh eet s. 2015.
h t t p://www.wh o.in t /m edia cen t r e/fa ct sh eet s/fs360/en /.
Accessed Novem ber 11, 2015.
F in d a d d ition a l r esou r ces for th is ch a pter a t h ttp:th ePoin t.lww.com
4. Cen t er s for Disea se Con t r ol a n d P r even t ion . H IV in t h e
Un it ed St a t es: a t a gla n ce. h t t p://www.cdc.gov/h iv/
st a t ist ics/over view/a t a gla n ce.h t m l. Accessed Novem ber
11, 2015.
5. Ga vin L, Ma cKa y AP, H a r r ier S, et a l. Sexu a l a n d
r epr odu ct ive h ea lt h of per son s a ged 10–24 yea r s—
Un it ed St a t es, 2002–2007. MMWR S u r veill S u m m .
2009;58(SS06):1–58.
6. Br a n son BN, H a n sfield H H , La m pe MA. Revised r ec-
om m en da t ion s for H IV t est in g of a du lt s, a dolescen t s,
a n d pr egn a n t wom en in h ea lt h ca r e set t in gs. MMWR
Recom m Rep. 2006;55(RR14):1–17.
7. Selik RM, Mokot off E D, Br a n son B, et a l. Revised su r-
veilla n ce ca se defin it ion for H IV in fect ion —Un it ed
St a t es, 2014. MMWR Recom m Rep. 2014;63(RR03):
1–10.
8. Sor ia n o V. Upda t e of t h e DH H S a n t ir et r ovir a l t r ea t m en t
gu idelin es. AIDS Rev. 2014;16(2):117–118.
9. Am er ica n College of Rh eu m a t ology Ad H oc Com m it -
t ee on Syst em ic Lu pu s E r yt h em a t osu s Gu idelin es.
Gu idelin es for r efer r a l a n d m a n a gem en t for syst em ic
lu pu s er yt h em a t osu s in a du lt s. Ar th r itis Rh eu m .
1999;42(9):1788–1796.
10. Molin o C, Fa bbia n F, Lon gh in i C. Clin ica l a ppr oa ch t o
lu pu s n eph r it is: r ecen t a dva n ces. E u r J In ter n Med .
2009;20(5):447–453.
11. P ilgr im H , Lloyd-J on es M, Rees A. Rou t in e a n t en a t a l
a n t i-D pr oph yla xis for Rh -D n ega t ive wom en : a syst em -
a t ic r eview a n d econ om ic eva lu a t ion . H ea lth Tech n ol
Assess. 2009;13(10):1–126.
12. Got t va ll T, F ilbey D. Alloim m u n iza t ion in pr egn a n cy
du r in g t h e yea r s 1992–2005 in t h e cen t r a l west r egion of
Sweden . Acta Obstet Gyn ecol S ca n d . 2008;87(8):
843–848.
 Ch a pt er

In fect ion 5
L E AR N I N G O U T C O ME S
1. Defin e a n d u se t h e key t er m s list ed in t h is ch a pt er.
2. Rela t e t h e developm en t of in fect ion t o br ea ks in t h e t h r ee lin es of
defen se.
3. Iden t ify t h e wa ys in wh ich m icr obes ca n becom e pa t h ogen s t o h u m a n
h ost cells.
4. Differ en t ia t e t h e ba sic t ypes of m icr obes.
5. Det er m in e m ea su r es t o br ea k t h e ch a in of in fect ion a t ea ch lin k.
6. Iden t ify t h e ph a ses of a cu t e in fect ion .
7. Discu ss t h e pot en t ia l com plica t ion s of a cu t e in fect ion .
8. Dist in gu ish com m on clin ica l m a n ifest a t ion s r ela t ed t o in fect ion .
9. Iden t ify la bor a t or y a n d dia gn ost ic t est s r eleva n t t o in fect ion .
10. Discu ss t r ea t m en t m oda lit ies effect ive a ga in st va r iou s t ypes of in fect ion .
11. Apply con cept s of in fect ion t o t h e clin ica l m odels in t h is ch a pt er.

INTR ODUCTION
H ow m a n y in fect ion s h a ve you h a d in you r lifet im e? You h a ve pr oba bly h a d
t oo m a n y t o cou n t ! I n e c t io n is a st a t e of cellu la r, t issu e, a n d som et im es even
or ga n dest r u ct ion r esu lt in g fr om in va sion by m icr oor ga n ism s. Mu lt iple sit es
t h r ou gh ou t t h e body con t a in specia lized defen se m ech a n ism s t o pr ot ect a ga in st
m icr obe in va sion (Fig. 5.1). Un for t u n a t ely, wit h in fect ion , h a r m fu l m icr oor ga n -
ism s h a ve pen et r a t ed t h e t h r ee lin es of defen se a n d h a ve ca u sed disea se.
E ven wit h t h e a dven t of n ew a n t ibiot ics a n d va ccin a t ion s, in fect iou s disea se
r em a in s a h ea lt h ca r e ch a llen ge. Th e over u se or in com plet e u se of a n t im icr obia l
dr u gs h a s led t o m u lt iple dr u g-r esist a n t m icr obes. Globa liza t ion h a s pr om ot ed
t h e r a pid spr ea d of h a r m fu l m icr obes a r ou n d t h e wor ld. Im por t a t ion a n d m a ss
dist r ibu t ion of per ish a ble food it em s h a s a lso con t r ibu t ed t o in fect iou s disea se
spr ea d. A t h or ou gh u n der st a n din g of in fect ion is t h er efor e cr it ica l t o you r wor k
in t h e h ea lt h pr ofession s.

103
104 C h a p t e r 5: In fect ion

1 Eye s 1 6 w
W
2
2 L
7

3
8
3 S kin

4
4
6 9
5

8 ia
7
5 10
ine
9

10

Figure 5.1. Nonimmune antimicrobial protective mechanisms. The numbered areas show the functions of various organs
and systems that defend against bacteria and other microbes.

Modu le 1 Mic r o b e s

Micr obes, in clu din g ba ct er ia , vir u ses, fu n gi, a n d
pr ot ozoa , a r e ever ywh er e in t h e h u m a n en vir on -
m en t . R e s i d e n t lo r a a r e m icr oor ga n ism s t h a t
live on or wit h in t h e body in n on st er ile a r ea s,
su ch a s t h e skin , m u cou s m em br a n es, bowel, r ec-
t u m , or va gin a , wit h ou t ca u sin g h a r m . In fla m m a -
t or y a n d im m u n e a t t a cks a r e gen er a lly n ot wa ged
a ga in st t h ese in h a bit a n t s a s lon g a s t h e skin a n d
m u cosa r em a in in t a ct . Residen t flor a com pet e wit h
disea se-pr odu cin g m icr oor ga n ism s t o pr ot ect t h e
body a ga in st cer t a in in fect ion s a n d t o pr ovide a
t ype of n a t u r a l im m u n it y.
A delica t e ba la n ce of h om eost a sis is n eeded be-
ca u se oft en m or e t h a n on e t ype of r esiden t flor a ca n
be fou n d in n on st er ile a r ea s. Dest r oyin g on e t ype of
r esiden t flor a ca n a llow over pr olifer a t ion of a n ot h er
com pet in g t ype. For exa m ple, if a per son exper ien ces
a ba ct er ia l in fect ion a n d is pr escr ibed a n a n t ibiot ic,
t h e a n t ibiot ic m a y a lso dest r oy t h e h elpfu l r esiden t
ba ct er ia livin g in n on st er ile a r ea s of t h e body. Th e
r esiden t fu n gi n o lon ger h a ve t o com pet e wit h t h e
dest r oyed r esiden t ba ct er ia . Th e fu n gi over pr olif-
er a t e, r esu lt in g in a fu n ga l in fect ion . Th is exa m ple
h elps t o expla in wh y va gin a l yea st (fu n ga l) in fec-
t ion s a r e com m on in wom en wh o a r e on a n t ibiot ics.

Pathogens
A p a t h o g e n is a disea se-pr odu cin g m icr obe. To
ca u se disea se in h u m a n s, a pa t h ogen m u st be ca pa -
ble of bin din g t o specific r ecept or s on t h e h u m a n h ost
cell. Th is is a ver y im por t a n t con cept t o u n der st a n d.
If t h e m icr oor ga n ism is n ot a ble t o bin d t o t h e r ecep-
t or s, t h e h ost cell r em a in s u n a ffect ed. Th is expla in s
wh y som e m icr oor ga n ism s fou n d in t h e en vir on m en t
a r e n ot h a r m fu l t o h u m a n s. Recept or s a lso pr ovide
clu es t o t h e t ypes of cells t o wh ich t h e pa t h ogen will
a t t a ch . For exa m ple, in flu en za vir u s a t t a ch es t o r e-
cept or s on ly in r espir a t or y t r a ct epit h elia l cells. Th e
ba sic loca l clin ica l m a n ifest a t ion s (i.e., cou gh , n a sa l
con gest ion , a n d sor e t h r oa t ) r eflect r espir a t or y ep-
it h elia l cell n ecr osis elicit ed by t h e pa t h ogen . Re-
cept or bin din g offer s som e clu es t o t h e r a cia l a n d
geogr a ph ic differ en ces in h u m a n in fect ion . For ex-
a m ple, som e Afr ica n Am er ica n in dividu a ls la ck r e-
cept or s for t h e m icr oor ga n ism t h a t ca u ses m a la r ia
a n d a r e t h er efor e n ot su scept ible t o t h is in fect ion .
On ce r ecept or a t t a ch m en t h a s been est a blish ed,
t h e m ech a n ism by wh ich t h e pa t h ogen ca u ses dis-
ea se in t h e h u m a n h ost cell in clu des on e or m or e of
t h e followin g:
1. Dir ect dest r u ct ion of t h e h ost cell by t h e pa t h ogen
2. In t er fer en ce wit h t h e h ost cell’s m et a bolic fu n ct ion
3. E xposin g t h e h ost cell t o t oxin s pr odu ced by t h e
pa t h ogen
Th e p a t h o g e n ic it y , or qu a lit ies t h a t pr om ot e t h e
pr odu ct ion of disea se, in volves m u lt iple fa ct or s, in -
clu din g t h e pa t h ogen ’s pot en cy, in va siven ess, a bilit y
t o eva de t h e im m u n e syst em , speed of r eplica t ion ,
pr odu ct ion of t oxin s, a dh er en ce t o t h e h u m a n h ost
cell, a n d degr ee of t issu e da m a ge t h a t is elicit ed. Th e
followin g fa ct or s a ffect t h e va r ia bilit y wit h wh ich
t h e pa t h ogen is a ble t o elicit disea se.
● Vir u le n c e is t h e pot en cy of t h e pa t h ogen in di-
ca t ed by t h e r a t io of t h e n u m ber of ca ses of dis-
ea se in a popu la t ion com pa r ed wit h t h e n u m ber
of people exposed t o t h e m icr oor ga n ism . A m or e
vir u len t m icr oor ga n ism is on e t h a t ca u ses sever e
disea se in a la r ge pr opor t ion of t h ose exposed t o
t h e m icr oor ga n ism .
● I n e c t iv it y is t h e pr opor t ion of exposu r es n eeded
t o ca u se in fect ion in a n in dividu a l ba sed on t h e
pa t h ogen ’s a bilit y t o en t er, su r vive in , a n d m u l-
t iply in t h e h ost . Vir u len ce a n d in fect ivit y a r e r e-
la t ed. A m or e in fect ive or ga n ism is on e t h a t t a kes
on e exposu r e, t a kes h old, m u lt iplies, a n d ca u ses
disea se in t h e h ost .
● To x ig e n ic it y is t h e a bilit y of t h e pa t h ogen t o
pr odu ce h a r m fu l t oxin s t h a t in cr ea se h ost cell
a n d t issu e da m a ge.
Mic r o b e s 105
● An t ig e n ic it y is t h e level t o wh ich a pa t h ogen
is viewed by t h e h ost im m u n e syst em a s for eign .
A m or e a n t igen ic pa t h ogen elicit s a m or e pr om -
in en t im m u n e r espon se. Th ose wit h low a n t ige-
n icit y ca n r ea dily elu de im m u n e m ech a n ism s a n d
con t in u e t o su r vive in t h e h ost .
● An t ig e n ic v a r ia b ilit y is a pr ocess of elu din g t h e
h u m a n h ost defen ses a n d is oft en a r esu lt of a lt er-
in g t h e a n t igen s pr esen t wit h in or on t h e su r fa ce
of t h e m icr oor ga n ism . Th is m ea n s t h a t m a n y in -
fect iou s m icr oor ga n ism s ca n esca pe h u m a n h ost
defen ses t h r ou gh sligh t gen et ic va r ia t ion s u n r ec-
ogn ized by t h e h ost . Th ese m u t a t ion s a r e r espon -
sible for m u ch of t h e in fect iou s disea se bu r den
t h r ou gh ou t t h e wor ld.
● P a t h o g e n ic d e e n s e m e c h a n is m s a r e t h e
wa ys in wh ich m a n y pa t h ogen s h a ve developed
wa ys t o a void dest r u ct ion by t h e h ost , su ch a s
t h r ou gh t h ick pr ot ect ive ca psu les, wh ich pr even t
ph a gocyt osis.
● C o in e c t io n is a ph en om en on of h ost in g t wo or
m or e pa t h ogen s sim u lt a n eou sly. Cer t a in pa t h o-
gen s, su ch a s t h ose t h a t ca u se ch la m ydia a n d gon -
or r h ea , a r e m or e likely t o be t r a n sm it t ed a n d t o
coexist in t h e h ost . Coin fect ion pr esen t s a gr ea t er
ch a llen ge t o t h e im m u n e syst em .
● S u p e r in e c t io n is wh en a n in fect ion a r ises in
a ddit ion t o on e t h a t is a lr ea dy pr esen t . Su per in -
fect ion oft en r esu lt s fr om com pr om ised h ost de-
fen ses a n d over pr olifer a t ion of r esiden t flor a .
TYPES OF PATHOGENS
Ba sic t ypes of m icr oor ga n ism s t h a t ca n ca u se dis-
ea se in clu de ba ct er ia , vir u ses, fu n gi, a n d pr ot ozoa .
Un der st a n din g t h e dist in ct ive qu a lit y of ea ch m icr o-
or ga n ism ca n pr ovide clu es t o t h e t r a n sm ission a n d
spr ea d of in fect iou s disea se.
Som e m icr oor ga n ism s live a n d r epr odu ce in de-
pen den t ly of t h e h ost . Ot h er m icr oor ga n ism s a r e con -
sider ed pa r a sit es. O b lig a t e p a r a s it e s r equ ir e t h e
h ost for m et a bolism a n d r epr odu ct ion . Fa c u lt a t iv e
p a r a s it e s m a y live on t h e h ost bu t ca n a lso su r vive
in depen den t ly. H elm in t h s (wor m s) a r e a lso ca pa ble
of elicit in g disea se in h u m a n s. Th ey a r e n ot con sid-
er ed m icr oor ga n ism s bu t r a t h er a r e a h igh ly diver se
gr ou p of m u lt icellu la r pa r a sit es. H elm in t h eggs ca n
be fou n d in con t a m in a t ed food, wa t er, or soil, a s well
a s wit h in in fect ed in sect s. On ce in fect ed, t h e h el-
m in t h m a t u r es wit h in t h e h ost a n d ca n gr ow t o be
qu it e la r ge.
Bacteria
B a c t e r ia a r e sin gle-celled m icr oor ga n ism s (F ig. 5.2).
Most ca n r epr odu ce ou t side of h ost cells. Ba ct er ia
t h a t r equ ir e oxygen for gr owt h a r e ca lled a e r o b ic ;
106 C h a p t e r 5: In fect ion
A r esist a n t t o ph a gocyt osis. Th e va r ia bilit y of ea ch
Fla ge llum
Ca ps ule
Ce ll wa ll
Ce ll
me mbra ne
Nucle oid
Cytopla s m
B ●
Figure 5.2. Bacterial cell ( A) scanning electron micro-
scopy; basic structure of bacteria ( B) .
t h ose t h a t do n ot a r e ca lled a n a e r o b ic . Oxygen r e-
qu ir em en t s dict a t e wh er e t h e ba ct er ia ca n best su r-
vive. An a er obic ba ct er ia su r vive best in deep t issu es
of t h e body wh er e oxygen su pply is lim it ed. Th is t ype
is difficu lt t o t r ea t beca u se a n t im icr obia l dr u gs oft en
t r a vel wit h in t h e va scu la r syst em t o a ffect loca l t is-
su es. Deeper t issu es a r e m u ch m or e difficu lt t o pen e-
t r a t e. Som e ba ct er ia ca n su r vive in bot h a er obic a n d
a n a er obic en vir on m en t s.
Ba ct er ia a r e oft en r efer r ed t o by t h eir sh a pe: cocci
(sph er es), ba cilli (r ods), vibr io (com m a -sh a ped), a n d
spir och et es (spir a ls). Th ey con t a in a n in discr et e
n u cleu s, a cyt opla sm , a n d a n ou t er cell m em br a n e.
Th e “in discr et e” n u cleu s does n ot h a ve a n u clea r
m em br a n e a n d is t h er efor e n ot sepa r a t e fr om t h e
cyt opla sm . Like t h e n u cleu s, t h e cyt opla sm is a lso
differ en t fr om h u m a n cells. Th e cyt opla sm of ba ct e-
r ia is r efer r ed t o a s c y t o s o l. Cyt osol con t a in s ext en -
sive r ibosom es, pr ot ein s, a n d ca r boh ydr a t es bu t does
n ot con t a in m it och on dr ia , en dopla sm ic r et icu lu m , or
ot h er m em br a n ou s com pon en t s.
Th e in n er m ost cell m em br a n e, a lso ca lled t h e cell
en velope, h a s m u lt iple fu n ct ion s:
● For m a t ion of a ba r r ier su r r ou n din g t h e ba ct er ia l
cell
● P r ot ein a n d DNA syn t h esis
● Cell division
Most ba ct er ia a lso in clu de a r igid cell wa ll t h a t su r-
r ou n ds t h is in n er m em br a n e. Th e cell wa ll pr ovides
sh a pe a n d st r u ct u r e. Beca u se h u m a n cells do n ot
h a ve a cell wa ll, a n t ibiot ic t r ea t m en t is com m on ly
a im ed a t in h ibit in g syn t h esis of t h e ba ct er ia l cell
wa ll du r in g ba ct er ia l r eplica t ion . Th er efor e, t h e
ba ct er ia a r e dest r oyed a n d t h e h u m a n h ost cell is
u n h a r m ed. Som e ba ct er ia ca n a lso h a ve a ca psu le
cover in g t h is cell wa ll. Ba ct er ia wit h a ca psu le m or e
ea sily a dh er e t o h ost cells. Th e ca psu le is a lso h igh ly
t ype of cell en velope, cell wa ll, a n d ca psu le is im por t -
a n t in t h e pa t h ogen icit y of t h e ba ct er ia , a n d will of-
t en dir ect t r ea t m en t decision s.
Stop and Consider
What aspects of bacteria would be effective tar-
gets for pharmacologic treatment?
Th e da m a ge ca u sed by ba ct er ia ca n r esu lt fr om
ba ct er ia l st r u ct u r a l pr oper t ies a n d exot oxin r elea se.
St r u ct u r a l pr oper t ies cr it ica l t o t h e pa t h ogen icit y of
ba ct er ia in clu de:
I n d e p e n d e n t s u r v iv a l: Ba ct er ia ca n su r vive
ou t side t h e h u m a n h ost a n d ca n in fect a n d r ein -
fect if n ot dest r oyed.
● S t im u la t io n o a n in la m m a t o r y r e s p o n s e :
Ba ct er ia st im u la t e a n in fla m m a t or y a n d im m u n e
r espon se t h a t will dest r oy su r r ou n din g h ost t is-
su es in a n effor t t o r id t h e body of t h e in va der.
● B a c t e r ia l c a p s u le : E n ca psu la t ed ba ct er ia a r e
a dh er en t a n d h igh ly r esist a n t t o ph a gocyt osis.
● E n d o t o x i n : Th e pr esen ce of en dot oxin in t h e
gr a m -n ega t ive ba ct er ia l cell en velope a ct iva t es
t h e pla sm a pr ot ein syst em s (Ch a pt er 3). E n d o -
t o x in is a com plex of ph osph olipid– polysa cch a r ide
m olecu les t h a t for m t h e st r u ct u r a l com pon en t of
t h e gr a m -n ega t ive cell wa ll. E n dot oxin ca u ses in -
fla m m a t or y m edia t or s t o be r elea sed, lea din g t o a
m a ssive in fla m m a t or y r espon se (F ig. 5.3). Th is in
t u r n ca n r esu lt in a st a t e of sept ic sh ock a ccom pa -
n ied by sever e dia r r h ea , fever, a n d leu kocyt osis.
Wh en in du cin g fever, t h ese en dot oxin -con t a in in g
ba ct er ia a r e r efer r ed t o a s p y o g e n i c ba ct er ia .
● E n d o s p o r e s : Som e ba ct er ia ca n pr odu ce spor es
t h a t su r vive in a la t en t st a t e t h a t is r esist a n t t o
en vir on m en t a l ext r em es a n d la ck of n u t r ien t s.
Wh en t h e en vir on m en t is m or e con du cive t o r ep-
lica t ion , t h e ba ct er ia will em er ge fr om t h e spor e
st a t e, m u lt iply, a n d m a y ca u se in fect ion in a su s-
cept ible h ost .
Ma n y ba ct er ia a r e a lso ca pa ble of pr odu cin g t oxin s,
ca lled e x o t o x in s , a n d en zym es, wh ich r esu lt in h ost
cell dysfu n ct ion or lysis. E xot oxin s a r e pot en t su b-
st a n ces, oft en ba ct er ia l-der ived pr ot ein s, r elea sed
 Mic r o b e s 107

Gra m-ne ga tive

ba cte ria

Endotoxin

Ba cte ria l LP S
lys is

LP S -binding prote in (LP B)

Forma tion of
LP S –LP B complex
in blood LP S –LP B complex

Monocyte /
ma cropha ge

TNF-a lpha
Endothe lia l ce lls
TNF-a lpha re ce ptor

TNF-a lpha P rocoa gula nt

tis s ue fa ctor
P MNs IL-1 Dire ct
injury

ENDOTHELIAL CELL INJ URY

S EPTIC S HOCK

Figure 5.3. Pathogenesis of endothelial cell injury in endotoxic shock. In sepsis caused by gram-negative bacteria, the
lysis of the organisms releases endotoxin into the circulation in the form of lipopolysaccharide (LPS), where it binds to the
LPS-binding protein (LBP). The LPS–LPB complex binds to monocytes/ macrophages, which are stimulated to secrete sub-
stantial quantities of tumor necrosis factor-alpha (TNF-alpha), a potent inflammatory mediator. TNF-alpha mediates septic
shock by causing endothelial cell injury by a number of mechanisms: (1) direct cytotoxicity; (2) enhancing the adherence
of polymorphonuclear leukocytes; (3) stimulating the release of interleukin-1 (IL-1), a cytokine that injures endothelial
cells; and (4) promoting the expression of procoagulant tissue factor, thereby leading to thrombosis and local ischemia.

in t o t h e su r r ou n din g t issu es t h a t ca u se loca l or sys- Viruses

t em ic in ju r y t o t h e h ost . Th e t a r get t issu e ca n be in
t h e br a in a n d spin a l cor d (n eu r ot oxic), t h e ga st r o-
in t est in a l t r a ct (en t er ot oxic), t h e liver (h epa t ot oxic),
t h e blood (h em ot oxic), a n d so for t h . Figu r e 5.4 de-
pict s exa m ples of pa t h ogen ic ba ct er ia a n d t h e sit es
of in fect ion for ea ch t ype.
Vir u s e s a r e con sider ed obliga t e in t r a cellu la r pa r-
a sit es. Th is m ea n s t h a t vir u ses ca n n ot r eplica t e
ou t side of t h e h ost cell. Th e vir u s bin ds t o specific
r ecept or s on t h e h ost cell a n d t h en m oves in t o t h e
h ost cell. On ce in side t h e h ost cell, t h e vir u s con ver t s
108 C h a p t e r 5: In fect ion

Pathoge nic Bac te ria S it e s o f In fe c tio n

Ne is s e ria m e n in g it id is

Typ e s of
in fe c t io n : Ke y
A A—Bra in
B —Lung
C —He a rt
Stre ptococcus pyoge nes D —Live r
E—S toma ch
a F—La rge inte s tine
os itis G—S ma ll inte s tine
H—Bla dde r
fa s citis

Stre ptococcus pne um onia e

Sta ph yloc occu s a ure us

B
ye litis
a

Es c h e ric h ia c o li
C

tra ct infe ction

D
S a lm o n e lla t yp h i

E
T
d
infe ctions F

Ps e udom onas ae ruginos a

ina ry
infe ction G
Wound
infe ction

Figure 5.4. Sites of bacterial infection for each type of pathogenic bacteria. (Courtesy Anatomical Chart Company.)
 Mic r o b e s 109

Som e vir u ses a r e su s-

F R O M T H E L AB t a in ed for lon ger per iods
in t h e h ost . If t h e in i-
Laboratory tests are important in differentiating the specific types of bacteria that are t ia l, a cu t e in fect ion does
causing the infection. The goal is to “match the bug to the drug,” that is, aiming treatment n ot pr ovoke a st r on g
at the specific bacteria without harming the host cells or resident flora. Cultures can be vir a l-er a dica t in g im m u n e
obtained and the bacteria grown and identified. This usually takes 3 days or more. Two other r espon se, t h e in dividu a l
important clues that allow more rapid identification of bacterial characteristics are the Gram is m or e likely t o h ost a
stain and tests for coagulation. Bacterial cell walls, when exposed to a Gram stain in the lab, ch r on ic vir a l in fect ion .
become either dark blue or red (when counterstained). Bacterial cell walls that preserve the Ch r on ic vir a l in fect ion s
stain and turn dark blue are considered gram-positive. Examples of gram-positive bacteria a r e pr om ot ed by va r iou s
include Staphylococcus aureus, Streptococcus pneumoniae, and Clostridium difficile. Those vir a l a n d h ost fa ct or s:
that do not retain the dark blue color and instead turn red when another stain is applied
are considered gram-negative. Examples of gram-negative bacteria include Neisseria gon- 1. Th e size of t h e vir u s
orrhoeae, Helicobacter pylori, and Escherichia coli. Coagulase tests differentiate potentially t h a t is in ocu la t ed in t o
pathogenic Staphylococcus species from other gram-positive cocci. Staphylococcal bacteria t h e body
that cause coagulation (clotting) in the blood are more resistant to phagocytosis or anti- 2. Th e pr ocess of vir a l
body destruction. A coagulase-positive test indicates a pathogenic strain of staphylococcal r eplica t ion
bacteria that should be treated aggressively. 3. Th e vir a l gen ot ype
4. H ost su scept ibilit y
For example, in an im-
munocompetent healthy
adult, hepatitis B becomes
a chronic infection in 10%
R E S E AR C H N O T E S
of cases. This same virus,
Prions, transmissible protein particles that lack DNA or RNA, have been found to cause when spread to a fetus
infectious disease in humans. Prion diseases, also known as spongiform encephalopathies, from an infected mother,
are implicated in rare, progressive neurodegenerative conditions such as Creutzfeldt–Jakob becomes chronic in 90% of
disease and bovine spongiform encephalopathy, also known as mad-cow disease. Interest- newborns. The major dif-
ingly, prion diseases are not known to elicit a notable immune response by the host, and the ference between the two
mechanism by which they destroy brain tissue is poorly understood. Prion diseases progress scenarios is the immaturity
rapidly and are always fatal. Animal prion diseases pose a significant public health risk, with of the newborn’s immune
recent reports of secondary person-to-person spread. 1 system, allowing the virus
to continue to replicate.
Also ch a r a ct er ist ic of
t h e h ost cellu la r m et a bolism t o n u cleic a cids a n d ch r on ic vir a l in fect ion s is
pr ot ein s t h a t a r e en coded a n d con t r olled by t h e vi- a per iod of la t e n c y , or dor m a n cy. Du r in g t h is per iod,
r u s. Vir u ses h a ve t h e a bilit y t o eit h er dir ect ly kill t h e vir u s is in t egr a t in g it self in t o t h e h ost cell’s ge-
t h e cell or m odify cer t a in cellu la r fu n ct ion s, su ch a s n et ic m a t er ia l. Th e vir u s will r eside in a h ost cell a n d
pr ot ein syn t h esis. Vir u ses ca n ca u se cells t o pr olif- ca u se m in im a l or n o loss of fu n ct ion a l ca pa bilit ies
er a t e r a pidly a n d r a n dom ly, ca u sin g t u m or s t o for m for t h a t cell. Th e vir u s dem on st r a t es low a n t igen ic-
in t h e body. Th e cell u lt im a t ely loses it s a bilit y t o it y, a lt h ou gh cellu la r m it osis con t in u es a n d n ew cells
fu n ct ion . Th e vir u s n ext r elea ses pa r t icles ou t side of t h a t con t a in vir a l m a t er ia l a r e gen er a t ed. Im m u n o-
t h e cell, ca lled v ir io n s , wh ich ca n en t er a n d in fect com pr om ise, in clu din g t h a t in du ced by ph ysica l a n d
ot h er n ea r by cells (Fig. 5.5). em ot ion a l st r ess, pr ovides a m ediu m for a ct ive vir a l
In it ia lly, vir u ses eva de m a n y defen se m ech a n ism s r eplica t ion . Act ive vir a l r eplica t ion ca n be t r igger ed
by h idin g wit h in h ost cells. As t h e vir u s m oves fr om weeks t o yea r s a ft er t h e in it ia l in ocu la t ion wit h t h e
cell t o cell, t h e im m u n e r espon se is a ct iva t ed. Vir a l vir u s. Th is pr ocess r esu lt s in h ost cell dea t h . Cell
in fect ion s a r e oft en sever e en ou gh t o spa r k a st r on g, dea t h lea ds t o r ecogn iza ble sign s a n d sym pt om s
er a dica t in g im m u n e r espon se. Th is exa gger a t ed im - of disea se. A com m on exa m ple of a la t en t vir u s is
m u n e r espon se a llows n eu t r a liza t ion of t h e vir u s a n d h er pes sim plex vir u s, wh ich ca u ses cold sor es. Th e
r esolu t ion of t h e in fect ion . Th e in fect ed h ost cells a r e vir u s r em a in s dor m a n t . Replica t ion is t r igger ed by
elim in a t ed, a n d t h e vir u s ca n n o lon ger r eplica t e. In im m u n ocom pr om ise (oft en st r ess r ela t ed). Th e loca l
t h is r ega r d, m a n y vir u ses, su ch a s t h ose a ssocia t ed clin ica l m a n ifest a t ion s ch a r a ct er ist ic of h er pes sim -
wit h t h e com m on cold, a r e con sider ed self-lim it in g; plex in fect ion (e.g., it ch in g, blist er in g, a n d er yt h em a )
t h a t is, t h e in fect ion cea ses a ft er a cer t a in per iod of t h en becom e a ppa r en t . Th ese loca l n ecr ot ic cells a r e
t im e. r em oved fr om t h e body by in fla m m a t or y/im m u n e
110 C h a p t e r 5: In fect ion

Nucle us
Cytopla s m Ma ligna ncy

Virus

B. Budding re le a s e
of e nve lope d
virus e s
Hos t

Pe ne tra tion
D. Tumor forma tion
A. Hos t ce ll
lys is

Uncoa ting

Vira l
ma tura tion
Vira l
re plica tion C. La te ncy

P rote in coa t
s ynthe s is

Figure 5.5. Consequences of viral infection in host cells. A: Cell lysis. B: Continuous release of budding viral particles.
C: Latency. D: Tumor formation. (Modified from Porth CM. Pathophysiology: Concepts of Altered Health States. 7th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2004, with permission.)

m ech a n ism s; h owever, ot h er cells con t a in in g vir a l
m a t er ia l r em a in a n d ca n ca u se a ct ive disea se a ga in
a t a n ot h er t im e.
An ot h er exa m ple of la t en cy is a disea se con dit ion
ca u sed by h er pes zost er vir u s. Th e or igin a l in fect ion
wit h h er pes zost er vir u s ca u ses va r icella , or ch icken
pox. Du r in g t h e in it ia l ba t t le a ga in st t h e vir u s, som e
of t h e vir a l pa r t icles lea ve t h e skin blist er s fr om
t h e ch icken pox a n d m ove in t o t h e n er vou s syst em .
Wh en t h e va r icella vir u s r ea ct iva t es, oft en yea r s
la t er, t h e vir u s m oves ba ck down t h e lon g n er ve fi-
ber s fr om t h e sen sor y cell bodies t o t h e skin , ca u sin g
sever e pa in a lon g t h ese n er ves. Blist er s a r e oft en
pr esen t a s well. Th is disea se r ecu r r en ce is kn own a s
sh in gles. E xa m ples of ot h er select vir a l disea ses a r e
list ed in Ta ble 5.1.
Stop and Consider
Why are antiviral drugs difficult to develop and
use effectively?
in t r a cellu la r pa r a sit es t h a t ca nn ot r eplica t e out side
t he h ost . H owever, r icket t sia e a r e a lso gr a m -n ega t ive
ba ct er ia t h a t a r e ca pa ble of pr oducin g ener gy. Rick-
et t sia e t a r get h u m a n en dot h elia l cells of t h e blood
vessels a n d ca pilla r ies. Mycopla sm a s la ck a cell wa ll
a n d su r vive on t h e su r fa ce of h ost cells, bu t t h ey do
n ot en t er t he h ost cell for r eplica t ion . Ch la m ydia e r e-
pr odu ce t h r ou gh bin a r y fission yet a r e obliga t e in t r a -
cellu la r pa r a sit es (Fig. 5.6). Th ese pa t hogens u se t h e
h ost m et a bolism t o r epr odu ce. Th e life cycle of ch la -
m ydia e h a s t he followin g dist in ct ph a ses:
1. Th e m et a bolica lly in a ct ive elem en t a l body en t er s
t h e body, a t t a ch es t o, a n d in t er n a lizes t h e h ost cell.
2. Th e elem en t a l body becom es m et a bolica lly a ct ive
a n d t r a n sfor m s in t o a r et icu la t e body, wh ich t a kes
over t h e h ost cell.
3. Th e ch la m ydia e a r e t h en ca pa ble of r eplica t ion .
4. E a ch r eplica t ed pa t h ogen goes t h r ou gh t h e life cy-
cle, ca u sin g epit h elia l cell n ecr osis.

Rickettsiae, Mycoplasmas, and Chlamydiae Fungi

Ricket t sia e, m ycopla sm a s, a n d ch la m ydia e a r e u n iqu e F u n gi a r e r ela t ively la r ge or ga n ism s com pa r ed t o
pa t h ogen s t ha t h ave ch a r a ct er ist ics of bot h ba ct er ia ba ct er ia a n d vir u ses. Th ey h a ve a n u clea r m em -
a n d vir uses. Ricket t sia e, like vir uses, a r e obliga t e br a n e, cyt opla sm , a n d or ga n elles. Un icellu la r for m s
 Mic r o b e s 111

Ta b le 5.1 Select Vir u ses a n d Rela t ed Disea se Con dit ion s

Vir u s Tr a n s m is s io n D is e a s e C o n d it io n C lin ic a l Ma n i e s t a t io n s

Respir a t or y Respir a t or y dr oplet s Lower r espir a t or y Fever, r u n n y n ose, cou gh ,

syn cyt ia l vir u s t r a ct in fect ion in wh eezin g
(RSV) you n g ch ildr en
Paramyxovirus Respir a t or y dr oplet s Mea sles Fever, r u n n y n ose, cou gh , r a sh
Rot a vir u s P r im a r ily feca l–or a l Ga st r oen t er it is Sever e, wa t er y dia r r h ea ;
vom it in g
Coxsa ckievirus Dir ect con t a ct wit h or H a n d-foot -m ou t h Fever, sor es in t h e m ou t h , r a sh
st ool in fect ed secr et ion s disea se wit h blist er s, especia lly on
h a n ds a n d feet
H u m a n pa r- Respir a t or y dr oplet s Fift h disea se Mild r a sh wit h “sla pped ch eek”
vovir u s B19 a ppea r a n ce on fa ce, fever,
m a la ise
Aden ovir u s Respir a t or y dr oplet s or Com m on cold wit h Com m on cold: r u n n y n ose, sor e
feca l-or a l r espir a t or y dr oplet s, t h r oa t , fever, m a la ise; ga st r o-
ga st r oen t er it is wit h en t er it is: dia r r h ea , vom it in g
feca l–or a l
t r a n sm ission
Rh in ovir u s Respir a t or y dr oplet s Com m on cold Fever, r u n n y n ose, sor e t h r oa t ,
body a ch es, m a la ise
Cor on avir u s Respir a t or y dr oplet s Sever e a cu t e r espir a - H igh fever, h ea da ch e, body
t or y syn dr om e (SARS) a ch es, cou gh , pn eu m on ia ,
dia r r h ea

a r e ca lled y e a s t s ; m u lt icellu la r for m s a r e ca lled fu n gi ca n gr ow a s eit h er yea st s or m olds. Su per ficia l

m o ld s (F ig. 5.7). Yea st s r epr odu ce by bu ddin g a n d or deep-t issu e in va sion occu r s wh en pseu doh yph a e
for m a n elon ga t ed ch a in , ca lled p s e u d o h y p h a e . or h yph a e m u lt iply. Th is in va sion r esu lt s in in fla m -
Mold colon ies h a ve t u bu les t h a t br a n ch t o for m h y - m a t or y a n d im m u n e r espon ses. In fect ion s wit h fu n gi
p h a e ; clu st er s of h yph a e for m m y c e liu m . Som e a r e r efer r ed t o a s m y c o s e s or m ycot ic in fect ion s.

P ha gocytos is
Tra ns cription
Re orga niza tion of
EB EB a tta chme nt of DNA
EB into re ticula te
body (RB)
0 hour
RNA a nd prote in 8 hours
0 hour s ynthe s is in EBs Bina ry fis s ion
Ce ll re ce ptor
12 hours of RB
Hos t DNA
Re le a s e of EBs
s ynthe s is de cline s .
Chlamydial
RBs produce the ir
g ro wth
own ma cromole cule
48 hours c yc le
of DNA, RNA, a nd
prote in. 24 hours
Lys is of Continue d
the ce lls 40 hours multiplica tion
Infe ctivity 30 hours
incre a s e s RB
Inclus ion forms
conta in mos tly
Inclus ion forms Furthe r re orga niza tion
EBs
conta in EBs a nd EB of RBs to EBs
RBs (low infe ctivity)

Figure 5.6. Chlamydial growth cycle. EB, elementary body; RB, reticulate body. (From Thompson SE, Washington AE.
Epidemiology of sexually transmitted Chlamydia trachomatis infections. Epidemiol Rev. 1983;5:96–123, with permission.)
112 C h a p t e r 5: In fect ion

Ye a s ts Hypha e a n d or a l m u cosa in su scept ible in dividu a ls. Ma c e r a -

t io n , a soft en in g a n d br ea kin g down of t h ese t issu es,
is oft en r ela t ed t o excessive m oist u r e a n d is r equ ir ed
for ca n dida l in fect ion s t o ga in a foot h old. Deep-
t issu e in fect ion s, su ch a s t h ose fou n d in t h e lu n gs,
kidn ey, a n d h ea r t , a r e life-t h r ea t en in g a n d a r e
fou n d a lm ost exclu sively in im m u n ocom pr om ised
pa t ien t s.
Clin ica l m a n ifest a t ion s of su per ficia l Ca n d id a cu -
t a n eou s in va sion in clu de skin r edn ess, it ch in g, a n d
bu r n in g a t t h e sit e. In or a l ca n didia sis, lesion s a r e
wh it e a n d r esem ble cot t a ge ch eese a t t a ch ed t o a n
er yt h em a t ou s or a l ca vit y; t h ese lesion s bleed ea sily
a n d ca n be pa in fu l if scr a ped (F ig. 5.8). Vu lvova gi-
n a l ca n didia sis a lso pr odu ces r edn ess, it ch in g, a n d
bu r n in g a t t h e sit e a lon g wit h a t h ick, wh it e, va gin a l
disch a r ge.

Protozoa
P r ot ozoa a r e u n icellu la r, com plex m icr oor ga n ism s.
Th ey a r e ch a r a ct er ized by a n ir r egu la r or flu ct u -
a n t sh a pe wit h ou t a cell wa ll, a n d m a n y a r e m ot ile.
Tr a n sm ission ca n occu r t h r ou gh sexu a l con t a ct , con -
t a m in a t ed food or wa t er, or by a n in sect or ot h er a r-
t h r opod, wh ich ca r r ies t h e pr ot ozoa . Som e pr ot ozoa
Myce lium P s e udohypha e
a r e pa r a sit es a n d som e a r e ca pa ble of livin g in de-
Figure 5.7. Basic structure of fungi. Molds grow as pen den t ly of t h e h ost . Th ose t h a t a r e pa r a sit es com -
branching hyphae, forming a mycelium. Yeasts multiply by pet e for a n d depr ive h ost cells of n u t r it ion , ca u sin g
budding and form elongated pseudohyphae. (Courtesy Ana- t issu e dest r u ct ion .
tomical Chart Company.)

F u n gi a r e com m on r esiden t m icr obes. Th ese or-

ga n ism s fr equ en t ly in h a bit t h e skin su r fa ce or
m u cou s m em br a n es a n d a r e kept a t ba y by in t a ct
in t egu m en t , in fla m m a t or y, a n d im m u n e cells. Resi-
den t ba ct er ia a lso com pet e wit h a n d r egu la t e gr owt h
of r esiden t fu n gi. As pr eviou sly m en t ion ed, r edu c-
t ion of r esiden t ba ct er ia , oft en via a n t ibiot ics, dis-
t u r bs t h is ba la n ce a n d a llows fu n ga l over gr owt h .
F u n ga l in fect ion s ca n a lso be oppor t u n ist ic. O p -
p o r t u n is t ic p a t h o g e n s a r e t h ose t h a t ca u se dis-
ea se on ly in a h ost wit h a com pr om ised im m u n e
syst em . Pa t ien t s wit h fu n ga l in va sion of t issu es a r e
fr equ en t ly im m u n ocom pr om ised, su ch a s per son s
wit h AIDS (Ch a pt er 4). On e of t h e m ost com m on op-
por t u n ist ic yea st in fect ion s in volves Ca n d id a . Yea st
gr ows well in wa r m , m oist , da r k en vir on m en t s; com -
m on sit es for su per ficia l ca n dida l epit h elia l cell in - Figure 5.8. Oral candidiasis. These curd-like lesions can be
fect ion in clu de t h ose wit h skin –skin con t a ct , su ch easily removed with gauze. (From Goodheart HP. Goodheart’s
a s ben ea t h t h e br ea st s in wom en , t h e dia per a r ea in Photoguide of Common Skin Disorders. 2nd ed. Philadelphia,
in fa n t s, a n d t h e per in eu m , bet ween t oes, n a il beds, PA: Lippincott Williams & Wilkins; 2003, with permission.)
 C o m m u n ic a b le D is e a s e 113

Modu le 2 C o m m u n ic a b le D is e a s e

C o m m u n ic a b le disea ses a r e t h ose t h a t a r e spr ea d
fr om per son t o per son , oft en t h r ou gh con t a ct wit h
in fect ed blood a n d body flu ids. Alt h ou gh a ll com -
m u n ica ble disea ses a r e in fect iou s, n ot a ll in fect iou s
disea ses a r e com m u n ica ble. Com m u n ica ble disea ses
a r e in fect ion s ca u sed by m icr oor ga n ism s t h a t live
a n d r epr odu ce in a h u m a n h ost .
Stop and Consider
What sources of infection would not be consid-
ered communicable?
Th e ch a in of in fect ion is a u sefu l or ga n iza t ion for
r ecogn izin g t h e fa ct or s in h er en t in t h e t r a n sm is-
sion a n d spr ea d of com m u n ica ble disea ses (F ig. 5.9).
Th e in fect iou s a gen t lin k r efer s t o t h e pa t h ogen s
descr ibed a bove. In fect ion con t r ol m ea su r es seek
t o br ea k on e or m or e of t h ese lin ks. For exa m ple,
br ea kin g t h e ch a in of in fect ion a t t h e level of t h e
pa t h ogen r equ ir es st er iliza t ion of t h e en vir on m en t
t o r em ove a ll pa t h ogen s fr om con t a ct wit h t h e h u -
m a n cell. St er iliza t ion is per for m ed u sin g ph ysica l
or ch em ica l a gen t s, h ea t bein g t h e m ost im por t a n t .

S te rilizatio n

INFECTIOUS AGENT
Tre a tme nt of ia e nvironme nt
unde rlying dis e a s e s
Virus e s
e tts ia e RES ERVOIRS
S US CEPTIBLE oa e ople
HOS T
Immunos uppres s ion drugs
Wa te r

PORTAL OF EXIT
PORTAL OF ENTRY

Ha nd
wa s hing

Cove ring pote ntia l MEANS OF TRANS MIS S ION

e ntry points Cove ring

Tra s h dis pos a l

Ha nd wa s hing

Is ola tion

Unive rs a l Airflow ood ha ndling

Figure 5.9. Chain of infection. Sources of infection are depicted along with interventions used to break the chain of
infection at each link. GI, gastrointestinal; GU, genitourinary. (Modified from Smeltzer SC, Bare BG. Textbook of Medical–
Surgical Nursing. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003, with permission.) To see a video on the
chain of infection, visit http:/ / thePoint.lww.com, using the scratch-off code on the inside front cover.
114 C h a p t e r 5: In fect ion
An a u t o c la v e is a device t h a t u ses st ea m h ea t a t
h igh pr essu r es t o st er ilize object s.
Reservoir
Th e r eser voir is t h e “h oldin g t a n k” for t h e m icr oor-
ga n ism . Th e r eser voir cou ld in clu de a n in fect ed per-
son , a n a n im a l, or t h e en vir on m en t , su ch a s pon d
wa t er. Br ea kin g t h e ch a in a t t h e level of t h e r eser-
voir in clu des pr ovidin g a n t im icr obia l dr u gs t o t h e
ca r r ier or t a kin g a ct ion t o dest r oy t h e pr esen ce of
t h e m icr oor ga n ism in t h e en vir on m en t .
Portal of Exit
Th e por t a l of exit r epr esen t s t h e pa ssa ge by wh ich
t h e m icr oor ga n ism lea ves t h e r eser voir. In h u m a n
h ost s, com m on por t a ls of exit in clu de t h e r espir a -
t or y t r a ct , ga st r oin t est in a l t r a ct , skin , m u cou s m em -
br a n es, pla cen t a , a n d blood. If you h a ve a r espir a t or y
in fect ion , wea r in g a m a sk or ot h er wise cover in g you r
m ou t h a n d n ose du r in g sn eezin g will h elp t o block
t h e por t a l of exit .
Mode of Transmission
All in fect ion s will occu r t h r ou gh som e for m of con -
t a ct wit h a pa t h ogen . Th is con t a ct ca n be dir ect or
in dir ect . Th e m ode of t r a n sm ission r efer s t o t h e
m ech a n ism of t r a n sfer en ce fr om t h e r eser voir t o t h e
por t a l of en t r y. Th e m odes of t r a n sm ission in clu de:
● D ir e c t c o n t a c t : As a m ode of t r a n sm ission , dir ect
con t a ct im plies ph ysica lly t ou ch in g or ot h er wise
com in g in con t a ct wit h t h e r eser voir. E xa m ples of
dir ect con t a ct t r a n sm ission in clu de t ou ch in g t h e
blood or body flu ids of a n in fect ed per son , kiss-
in g, or sexu a l in t er cou r se. Th is m ode ca n a lso in -
volve close con t a ct by t ou ch in g a n ot h er per son or
a su r fa ce in t h e en vir on m en t t h a t is h oldin g t h e
pa t h ogen .
● D r o p le t t r a n s m is s io n : La r ger r espir a t or y pa r-
t icles, pr odu ced by sn eezin g, cou gh in g, or t a lkin g,
ca n pa ss t h r ou gh t h e a ir fr om t h e r eser voir t o t h e
h ost . For dr oplet t r a n sm ission t o occu r, t h e h ost
m u st be wit h in 3 feet of t h e r eser voir. Th e h ea vy
dr oplet pa r t icles dr op t o t h e gr ou n d beyon d t h is
dist a n ce. Most r espir a t or y illn esses a r e spr ea d
t h r ou gh dr oplet t r a n sm ission .
● Air b o r n e t r a n s m is s io n : Sm a ller r espir a t or y
pa r t icles ca n r em a in su spen ded in t h e a ir a n d
a r e su bject t o a ir bor n e t r a n sm ission . Th e pa r t i-
cles ca n r em a in in t h e a r ea of t h e r eser voir for a n
ext en ded per iod. In fect ion ca n be t r a n sm it t ed t o
a per son wh o en t er s t h is a r ea a n d br ea t h es t h e
a ir. Tu ber cu losis a n d va r icella (ch icken pox) a r e
exa m ples of r espir a t or y disea ses spr ea d t h r ou gh
a ir bor n e t r a n sm ission .
● Ve c t o r t r a n s m is s io n : A v e c t o r is a veh icle t h a t
h a r bor s t h e pa t h ogen a n d ca r r ies it t o t h e h ost .
Biologic vect or s a r e t h ose t h a t su ppor t t h e life
cycle of t h e pa t h ogen . Ar t h r opods, su ch a s m it es,
t icks, a n d spider s, a n d in sect s, a r e exa m ples of
biologic vect or s. Mech a n ica l vect or s a r e n ot es-
sen t ia l t o t h e life cycle of t h e pa t h ogen a n d ca n
in clu de dogs, m osqu it oes, a n d even food.
U n iv e r s a l p r e c a u t io n s a r e a st a n da r d of h ea lt h
ca r e t h a t r ecogn izes a ll blood a n d body flu ids a s po-
t en t ia lly in fect ed. Un iver sa l pr eca u t ion s dict a t e t h a t
h ea lt h ca r e pr ovider s wea r gloves wh en h a vin g a n y
con t a ct wit h blood a n d body flu ids. Ma sks a n d pr o-
t ect ive eyewea r a r e a lso r ecom m en ded if spla t t er in g
of blood or body flu ids is a n t icipa t ed. Addit ion a l pr e-
ca u t ion s a r e im plem en t ed depen din g on t h e m ode of
t r a n sm ission .
Stop and Consider
How can you break the chain of infection at each
of the different modes of transmission?
Portal of Entry
Th e por t a l of en t r y r efer s t o t h e a ccess poin t for t h e
m icr oor ga n ism in t o t h e h o s t , or t h e in dividu a l wh o
is exposed t o, a n d con t r a ct s t h e in fect ion . Th e m ost
com m on loca t ion s for m icr oor ga n ism s t o en t er t h e
body in clu de t h r ou gh t h e m u cou s m em br a n es, eyes,
r espir a t or y t r a ct , gen it ou r in a r y t r a ct , ga st r oin t est i-
n a l t r a ct , or pla cen t a .
Loss of ph ysica l (skin ) a n d ch em ica l ba r r ier s ca n
a lso pr ovide a ccess t o t h e por t a l of en t r y. Br ea kin g
t h e ch a in of in fect ion a t t h e level of t h e por t a l of en -
t r y in volves cover in g a n d pr ot ect in g pot en t ia l en t r y
poin t s. E xa m ples in clu de wea r in g gloves, m a sk, pr o-
t ect ive eyewea r, a n d con dom s. E a ch of t h ese m ea -
su r es pr even t s en t r y of t h e m icr oor ga n ism in t o h ost
t issu es.
Host Factors
Wh en h ost lin es of defen se a r e com pr om ised a n d
m icr obes ga in a ccess t o vu ln er a ble a r ea s, in fect ion
ca n r esu lt . Fa ct or s t h a t in cr ea se h ost su scept ibilit y
t o exper ien cin g in fect ion a r e pr im a r ily r ela t ed t o im -
pa ir ed h ost defen se m ech a n ism s (pr oblem s wit h skin /
m u cou s m em br a n es, im pa ir ed in fla m m a t ion , a n d/or
 Ac u t e I n e c t io n a n d C o m p lic a t io n s 115

decr ea sed im m u n it y). Im m u n osu ppr ession is oft en a n d su per in fect ion im pa ct t h e loa d pla ced on t h e
r ela t ed t o poor n u t r it ion , t h e ext r em es of a ge, con - h ost im m u n e defen ses a n d ca n fu r t h er com plica t e
cu r r en t ch r on ic illn ess, a n d sever e st r ess. Coin fect ion in fect iou s pr ocesses.

Modu le 3 Ac u t e I n e c t io n a n d C o m p lic a t io n s

Acu t e in fect ion in bot h com m u n ica ble a n d n on com - 1. E x p o s u r e : E xposu r e is con t a ct wit h t h e pa t h o-
m u n ica ble in fect iou s disea se pr ogr esses a lon g five gen t h r ou gh a n y of t h e m odes of t r a n sm ission de-
dist in ct ph a ses (Fig. 5.10): scr ibed a bove.

Corresponding
Phases of Infection Clinical Manifestations

Lo c al S ys te mic

Patho g e n e nte rs ho s t

Infla mma tory None None

+ immune
proce s s e s
wa ge d

Incuba tion

None Fa tigue, low-gra de

P rodrome feve r, we a kne s s,
S ubclinica l illne s s : na us e a
dis e a s e pre s e nt but
few s ymptoms
Clinica l illne s s

S uboptima l Ade qua te Ina de qua te Site-dependent Feve r, ma la is e,

immune de fe ns e immune immune pa in, he a t, we a kne s s , a norexia ,
a nd/or incomple te de fe ns e s de fe ns e s re dne s s, he a da che, na us e a
tre a tme nt a nd/or a de qua te a nd/or ina de qua te swe lling,
tre a tme nt tre a tme nt pus, los s of
function

Chronic Conva le s ce nce / Ove rwhe lming

infe ctions re cove ry infe ction

Tre a tme nt Tre a tme nt S e ptice mia

S hock

Death

Figure 5.10. Concept map. Phases of infection and corresponding clinical manifestations.
116 C h a p t e r 5: In fect ion
2. I n c u b a t io n : Th e in cu ba t ion ph a se ext en ds fr om
exposu r e t o t h e on set of a n y sign s or sym pt om s.
Du r in g t h e in cu ba t ion per iod, t h e in dividu a l of-
t en h a s n o idea t h a t h e or sh e h a s been exposed
t o, or will develop, t h e illn ess. Wit h com m u n ica ble
disea se, it is oft en du r in g t h is in cu ba t ion per iod
t h a t t r a n sm ission of m icr oor ga n ism s t o ot h er s is
gr ea t est . For exa m ple, ch icken pox h a s a n in cu ba -
t ion per iod of 7 t o 21 da ys fr om exposu r e t o r ecog-
n iza ble sign s a n d sym pt om s.
3. P r o d r o m e : Th e pr odr om a l ph a se in volves t h e
on set of va gu e, n on specific sign s a n d sym pt om s,
in clu din g fa t igu e, low-gr a de fever, n a u sea , wea k-
n ess, a n d gen er a lized m u scle a ch es. Th is ph a se
is oft en descr ibed a s feelin g “u n der t h e wea t h er.”
Th e specific sign s a n d sym pt om s r ela t ed t o t h e
disea se h a ve n ot yet em er ged.
4. Ac u t e c lin ic a l illn e s s : Th e clin ica l illn ess ph a se
r epr esen t s t h e m a n ifest a t ion of sign s a n d sym p-
t om s specific t o t h e disea se. Oft en , t h e a ccu r a t e
m edica l dia gn osis is a pplied m or e con fiden t ly
du r in g t h is t im e. In m a n y ca ses, t h e im m u n e r e-
spon se pea ks or t r ea t m en t is in it ia t ed a n d t h e
body is a ble t o over com e t h e pa t h ogen .
5. C o n v a le s c e n c e : Th e con va lescen t ph a se ext en ds
fr om wa n in g clin ica l m a n ifest a t ion s t o fu ll r ecov-
er y fr om t h e disea se. Fa t igu e is a com m on con cer n
du r in g t h is t im e of r ecover y.
Complications of Infection
Acu t e in fect ion ca n r esu lt in t wo m a jor com plica -
t ion s: sept icem ia a n d ch r on ic in fect ion . S e p t ic e m ia
occu r s wh en m icr oor ga n ism s ga in a ccess t o t h e blood
a n d cir cu la t e t h r ou gh ou t t h e body. Wh en sept icem ia
is ca u sed by ba ct er ia , t h e t er m b a c t e r e m ia is oft en
u sed. Th e developm en t of over wh elm in g syst em ic
in fect ion is ba sed on t h e degr ee of m icr oor ga n ism
pa t h ogen icit y a n d im m u n ocom pr om ise in t h e h ost .
On ce pa t h ogen s en t er t h e blood a n d ga in a ccess t o
a ll per fu sed t issu es, t h e in fect ion ca n r esu lt in sep-
t ic sh ock a n d becom e life-t h r ea t en in g. S e p t ic s h o c k
is a pr ocess of syst em ic va sodila t ion du e t o sever e
in fect ion , oft en wit h gr a m -n ega t ive ba ct er ia (t h e en -
dot oxin com pon en t ). Ma ssive va sodila t ion lea ds t o
poor per fu sion of vit a l or ga n s.
Ch r on ic in fect ion is defin ed a s a n in fect ion t h a t
la st s for sever a l weeks t o yea r s. Th e m ech a n ism for
elicit in g a ch r on ic vir a l in fect ion wa s discu ssed ea r-
lier in t h e ch a pt er. Ch r on ic ba ct er ia l in fect ion ca n
r esu lt wh en pa t h ogen s a r e n ot fu lly dest r oyed a s
a r esu lt of a su bopt im a l in fla m m a t or y or im m u n e
r espon ses or in com plet e a n t ibiot ic t r ea t m en t . Th e
pa t h oph ysiologic pr ocesses a n d ou t com es a r e t h e
sa m e a s wit h ch r on ic in fla m m a t ion (Ch a pt er 3).
C L I N I C AL P R AC T I C E
An t ibiot ic Tea ch in g E ssen t ia ls
An t ibiot ic r esist a n ce is on e of t h e m ost ser iou s
pu blic h ea lt h pr oblem s fa cin g h ea lt h ca r e t o-
da y. Over exposu r e t o a n t ibiot ics or in com plet e
t r ea t m en t ca n r esu lt in ba ct er ia ch a n gin g a n d
becom in g r esist a n t t o t h e pr escr ibed a n t ibiot ic.
Pa t ien t s n eed t o be clea r ly in for m ed of t h e im -
por t a n ce of t a kin g a n en t ir e cou r se of a n a n -
t ibiot ic (even if feelin g bet t er ) t o pr even t t h is
com plica t ion . H ea lt h ca r e pr ovider s ca n a ssist
by t ea ch in g pr oper h a n dwa sh in g t ech n iqu es
a n d n ot pr escr ibin g a n t ibiot ics t o t r ea t vir a l
in fect ion s. To m a in t a in t h e ben efit of a n t ibiot ic
t h er a py, a n t ibiot ics sh ou ld on ly be u sed wh en
a bsolu t ely n ecessa r y.
Clinical Manifestations
In fect ion wit h a m icr oor ga n ism t r igger s t h e in fla m -
m a t or y a n d im m u n e r espon ses. Clin ica l m a n ifest a -
t ion s a r e con sist en t wit h t h ese r espon ses. Acu t e loca l
in fect ion is u su a lly m a n ifest ed by pa in , h ea t , r edn ess,
swellin g, lym ph n ode en la r gem en t a n d t en der n ess,
a n d sit e-depen den t loss of fu n ct ion . Th e pr esen ce
of exu da t e is com m on a n d ca n be p u r u le n t , or con -
t a in in g pu s. Syst em ic m a n ifest a t ion s in clu de fever,
m a la ise, wea kn ess, a n or exia , h ea da ch e, a n d n a u sea .
Laboratory and Diagnostic Tests
Th e dia gn osis of in fect ion is ba sed on a t h or ou gh
h ist or y a n d ph ysica l exa m in a t ion a lon g wit h t h e
per for m a n ce of r eleva n t la bor a t or y a n d dia gn ost ic
t est s. Com m on la bor a t or y a n d dia gn ost ic t est s a r e
su m m a r ized in Ta ble 5.2.
Treatment Modalities
An t im icr obia l dr u gs a r e oft en u sed t o t r ea t in fect ion .
An t im icr obia ls fu n ct ion t o dest r oy pa t h ogen s or t o
decr ea se t h e gr owt h of t h e offen din g m icr oor ga n -
ism s. Th e m a jor m ech a n ism s of a ct ion a r e t o a lt er
t h e cellu la r st r u ct u r e of t h e m icr oor ga n ism or t o
disa ble en zym es pr odu ced by pa t h ogen s. An t iba ct e-
r ia l dr u gs ca n in h ibit syn t h esis of t h e ba ct er ia cell
wa ll, da m a ge t h e cyt opla sm ic m em br a n e, a n d dis-
a ble n u cleic a cid m et a bolism or pr ot ein syn t h esis.
An t ifu n ga ls fu n ct ion by bin din g t o t h e fu n ga l cell

Ta b le 5.2 Com m on La bor a t or y a n d Dia gn ost ic Test s t o Det ect In fect ion
Te s t P u r p ose
Wh it e blood A n on specific t est t h a t exa m in es a n in cr ea se or
cell cou n t decr ea se in wh it e blood cells t o a ssist in det er-
m in in g t h e pr esen ce of in fla m m a t or y or in fec-
t iou s pr ocess
Ser u m a n t i- A specific blood t est t h a t det ect s t h e pr esen ce
body levels of cer t a in a n t ibodies a ga in st pa t h ogen s (see
h epa t it is)
Cu lt u r es Iden t ifies pr esen ce a n d den sit y of m icr oor ga n -
ism s t h a t gr ow in a specific m ediu m over a per iod
of t im e (u su a lly 3 da ys or so); sa m ple ext r a ct ed
fr om body t issu es (in clu din g blood) or exu da t es
Sen sit ivit ies Iden t ifies wh ich a n t im icr obia l dr u gs wou ld be
m ost effect ive for a specific pa t h ogen
m em br a n e, in cr ea sin g per m ea bilit y, a n d r edu cin g
via bilit y of t h e fu n ga l cells. Beca u se ba ct er ia do n ot
con t a in t h e sa m e com pon en t s a s fu n ga l cells, a n -
t ifu n ga l m edica t ion s a r e n ot a ct ive a ga in st ba ct e-
r ia . An t ivir a l t r ea t m en t h a s been m et wit h lim it ed
Modu le 4 C lin ic a l Mo d e ls
Th e followin g clin ica l m odels h a ve been select ed t o
a id in t h e a pplica t ion of kn owledge r ela t ed t o in -
fect ion . Wh en r ea din g t h r ou gh t h e clin ica l m odels,
differ en t ia t e t h e t ype of pa t h ogen , a cu t e or ch r on ic
fea t u r es of t h e disea se, a n d t h e r ole of in fla m m a t or y
a n d im m u n e r espon ses.
Influenza
In flu en za is a vir a l in fect ion of t h e epit h elia l cells of
t h e a ir wa y. Th e vir u s is t r a n sm it t ed via r espir a t or y
dr oplet s fr om a n ot h er in fect ed per son or con t a m -
in a t ed su r fa ce. Th r ee differ en t t ypes of in flu en za
vir u ses (A, B, or C) ca n ca u se in flu en za disea se; ea ch
of t h ese t ypes a lso h a s sever a l st r a in s, or su bt ypes.
PATHOPHYSIOLOGY
Th e r espir a t or y epit h elia l cells a r e a r m ed wit h cilia ,
m u cu s, a n d a n t ibodies. Th e in flu en za vir u s en t er s
t h e r espir a t or y t r a ct , a t t a ch es t o t h e su r fa ce epi-
t h elia l cells, im pa ir s cilia , m u cu s, a n d a n t ibodies,
m oves in t o t h e cells, a n d r eplica t es (Fig. 5.11). Th e
vir u s ca u ses t h ese epit h elia l cells t o die, r esu lt in g
C lin ic a l Mo d e ls 117
I n t e r p r e t a t io n
L e u k o c y t o s is : eleva t ion in wh it e blood cells, wh ich
m a y in dica t e a n in fect iou s pr ocess, oft en ba ct er ia l
in or igin
L e u k o p e n ia : decr ea se in wh it e blood cells, wh ich
m a y in dica t e a vir a l in fect ion or a pr oblem wit h su p-
pr ession of wh it e blood cell pr odu ct ion
P r esen ce of specific a n t ibodies in dica t es a n exposu r e
t o t h e a n t igen a t som e poin t
Posit ive t est in dica t es t h e m icr oor ga n ism is pr esen t
If t h e m icr oor ga n ism is sen sit ive t o a cer t a in a n t ibi-
ot ic, t h a t is t h e r ecom m en ded t r ea t m en t
su ccess beca u se vir a l gr owt h em ploys t h e h ost cell.
Th er efor e, dest r u ct ion of t h e vir u s ca n sign ifica n t ly
da m a ge h ost cells a s well. Sym pt om a t ic t r ea t m en t ,
su ch a s flu ids, r est , a n d a n a lgesics, a r e oft en r ecom -
m en ded wit h a ll in fect ion s.
in n ecr osis a n d slou gh in g of t h e dea d cells. In m a n y
ca ses, in flu en za r esu lt s in a n u n com plica t ed u pper
r espir a t or y in fect ion or ca n pr ogr ess t o vir a l pn eu -
m on ia . In m or e sever e ca ses, vir a l in fect ion in t h e
lu n g t issu e ca n lea d t o ba ct er ia l pn eu m on ia , im -
pa ir ed a ir exch a n ge, a n d even dea t h . You n g ch ildr en
(u n der 2 yea r s of a ge), a du lt s 65 yea r s of a ge a n d
older, pr egn a n t wom en , a n d in dividu a ls wit h ch r on ic
ca r diopu lm on a r y, r en a l, m et a bolic, or im m u n odefi-
cien t con dit ion s a r e pr edisposed t o gr ea t er m or bid-
it y a n d m or t a lit y wh en in fect ed wit h in flu en za .
In flu en za vir u ses a r e well a da pt ed t o esca pe h ost
defen ses a n d gr a du a lly ch a n ge gen et ic com posi-
t ion du r in g r eplica t ion in t h e h u m a n h ost cell in a
pr ocess ca lled r e a s s o r t m e n t . Th is pr ocess r esu lt s
in vir a l offspr in g wit h a lt er ed a n t igen ic pr oper t ies.
Th ese m in or gen et ic m odifica t ion s r esu lt in on goin g
h ost su scept ibilit y t o t h e in flu en za vir u s. Th e devel-
opm en t of va ccin es is a dju st ed yea r ly t o t a ke in t o
a ccou n t t h ese sh ift s.
CLINICAL MANIFESTATIONS
Th e clin ica l m a n ifest a t ion s of in flu en za a r e ba sed
on t h e in fla m m a t or y r espon se a n d cell n ecr osis in
118 C h a p t e r 5: In fect ion

He ma gglutinin
Vira l e nve lope
Ne ura minida s e

Nucle oprote in

Polyme ra s e

RNA

Figure 5.11. Influenza type A virus. A: Model of the RNA influenza A virus, showing the hemagglutinin and neuramini-
dase envelope glycoproteins that provide access to host cells. B: Negative-stained transmission electron micrograph (TEM)
depicting the ultrastructural details of a number of influenza viral particles, or “virions.” C: TEM revealing ultrastructural
features of the 1918 influenza pandemic virus virions. (B and C: From the Centers for Disease Control and Prevention Pub-
lic Health Image Library. Nos. 8432, 8996. B: Courtesy of F. A. Murphy; C: Courtesy of Cynthia Goldsmith.)

m a la ise, a n d a dr y cough .
R E S E AR C H N O T E S Du r ing influenza ou t -
br ea ks, r a pid vir a l a ssays
Epidemiologists are concerned with tracking the movement of influenza viruses worldwide to a r e ava ila ble t o iden t ify
predict the most effective vaccine strategy. Selection of the most appropriate vaccine com- t ype A a n d B vir uses.
bination is based on antigenic analyses of recently isolated influenza viruses, epidemiologic Th ese t est s u sin g na so-
data, and postvaccination serologic studies in humans. The Food and Drug Administration’s pha r yn gea l secr et ions a r e
Vaccines and Related Biological Products Advisory Committee (VRBPAC) makes a final vac- qu ick (10 t o 20 m inu t es)
cine recommendation for the United States based on these data. 2 bu t ca n have a fa lse-posi-
t ive or fa lse-nega t ive er r or
r a t e a r ou nd 20% t o 30%.
t h e r espir a t or y t r a ct a n d in clu de cou gh , sor e t h r oa t ,
n a sa l con gest ion a n d dr a in a ge, a n d sh or t n ess of
br ea t h . Syst em ic sign s of in fla m m a t ion a r e a lso
TREATMENT
com m on a n d in clu de ch ills, fever, body a ch es, wea k-
n ess, a n d m a la ise. Influenza is highly contagious a nd epidemics a re com-
mon worldwide. Because this infection is vira l, treat-
ment is usua lly symptomatic and focuses on hydration,
DIAGNOSTIC CRITERIA
a dequate nutrition, a nd control of body a ches with an-
Dia gn osis is ba sed on a hea lt h hist or y sign ifica n t a lgesics. Aspirin use should be avoided in children to
for t h e clin ica l m a n ifest a t ions descr ibed pr eviou sly. prevent the development of Reye syndrome. Antiviral
In flu en za is a clin ica l dia gnost ic ch a llenge beca u se drugs may help reduce the duration of disea se if they
m a n y sym pt om s r esem ble t ha t of t he com m on cold. a re start ed ea rly in the course of infection. Preventing
H owever, in flu en za is m or e likely t o h ave a n a br u pt the infection is a n importa nt stra tegy, such as through
onset , sever e body a ch es, fever, a n or exia , h ea da ch e, effective ha ndwashing a nd annual vaccination.

Hepatitis
H epa t it is is in fla m m a t ion of t h e liver. Th er e a r e n u -
m er ou s ca u ses, t h e m ost n ot a ble bein g vir a l in fec-
t ion . H epa t it is ca n a lso r esu lt fr om a lcoh ol a bu se or
in gest ion of ot h er t oxic su bst a n ces t h a t da m a ge t h e
liver.
The Function of the Liver
Th e m a jor r oles of t h e liver in clu de:
● Secr et ion of bile
● Met a bolism of bilir u bin
● Blood st or a ge
● Syn t h esis of clot t in g fa ct or s
● Met a bolism of n u t r ien t s
● Met a bolic det oxifica t ion
● St or a ge of m in er a ls a n d vit a m in s
Th e liver h a s a m a jor im pa ct on h ea lt h st a t u s a n d
m u lt iple im por t a n t fu n ct ion s, bu t it a lso h a s excel-
len t r egen er a t ive a n d r est or a t ive ca pa bilit ies. In ju r y
t o t h e liver oft en a ffect s t h e blood vessels, lym ph a t -
ics, a n d n er ves, wh ich a r e con cen t r a t ed in t h e ou t er
coa t in g of t h e liver, ca lled t h e Glisson ca psu le. Wh en
in fla m ed or en la r ged, t h e Glisson ca psu le ca u ses
r igh t u pper-qu a dr a n t a bdom in a l pa in .
Th e liver h a s a n a ct ive r ole in ven ou s blood r et u r n
for t h e cir cu la t or y syst em . Deoxygen a t ed blood fr om
t h e ga st r oin t est in a l (GI) t r a ct , spleen , a n d pa n cr ea s
t r avels t o t h e liver by wa y of t h e por t a l vein befor e
m ovin g on t o t h e ven a ca va a n d h ea r t . Th is blood
bypa ss is ca lled p o r t a l c ir c u la t io n (F ig. 5.12). Ob-
st r u ct ion of por t a l cir cu la t ion fr om liver da m a ge
ca u ses ba cku p of blood flow t o t h e GI t r a ct , spleen ,
a n d pa n cr ea s.
Wit h in t h e ca psu le a r e h epa t ocyt es, t h e fu n ct ion a l
cells of t h e liver t h a t a r e ca pa ble of r egen er a t ion . H e-
pa t ocyt es a r e r espon sible for secr et ion of bile. Bile
con t a in s bile sa lt s, ch olest er ol, bilir u bin , elect r o-
lyt es, a n d wa t er. Bile is n eeded for fa t em u lsifica t ion
a n d a bsor pt ion . Da m a ge t o h epa t ocyt es t h er efor e in -
h ibit s bile pr odu ct ion a n d ca n a ffect fa t a bsor pt ion .
Th e liver con ver t s fa t s (pr im a r ily t r iglycer ides) t o
glycer ol a n d fr ee fa t t y a cids t o pr ovide en er gy t o t h e
cells. Glu cose is a n ot h er sou r ce of en er gy a ffect ed
by liver disea se, wh ich ca u ses blood glu cose flu ct u a -
t ion s. Th e liver is ca pa ble of r elea sin g glu cose du r in g
h ypoglycem ia , con ver t in g a m in o a cids a n d glycer ol
t o glu cose if n eeded, a n d t a kin g u p glu cose fr om t h e
blood du r in g h yper glycem ia . Blood volu m e a n d pr es-
su r e r egu la t ion is a lso a ided by t h e wor k of t h e liver
in pr odu cin g pla sm a pr ot ein s.
Th e liver pla ys a cr it ica l r ole in det oxifica t ion . Th e
liver a lt er s su bst a n ces, su ch a s a lcoh ol, m edica t ion s,
C lin ic a l Mo d e ls 119
He pa tic ve ins
Infe rior ve na cava
S toma ch
Porta l
ve in
Ga llbla dde r
S upe rior
me s e nte ric S ple e n
ve in
Pa ncre a s
Bowe l
Figure 5.12. The portal circulation. Blood from the gas-
trointestinal tract, spleen, and pancreas travels to the liver
via the portal vein before moving into the vena cava for
return to the heart.
a n d h or m on es, a n d h elps r em ove t h ese fr om t h e
body. Da m a ge t o t h e liver will a ffect t h e levels of
t oxic su bst a n ces cir cu la t in g in t h e body. Alwa ys u se
ca u t ion wh en a dm in ist er in g m edica t ion s t o pa t ien t s
wit h liver disea se, su ch a s h epa t it is. Most m edica -
t ion s a r e m et a bolized in t h e liver a n d, wit h poor
liver fu n ct ion , m a y con t in u e t o cir cu la t e a t h igh lev-
els wit h ou t bein g in a ct iva t ed a n d r em oved.
Not t o be con fu sed wit h bile pr odu ct ion , bilir u bin
m et a bolism is a n ot h er m a jor r ole of t h e liver. Reca ll
t h a t bile con t a in s bilir u bin . Bilir u bin r esu lt s fr om
t h e dest r u ct ion of a ged r ed blood cells. Th e liver is
r espon sible for br ea kin g down a n d r em ovin g t h ese
dyin g r ed blood cells. Th e a ged r ed blood cells a r e
en gu lfed a n d dest r oyed by ph a gocyt es h ou sed in t h e
liver ca lled Ku p e r c e lls . Sm a ll ca pilla r ies per fu se
t h e liver a n d a r e lin ed wit h Ku pffer cells. Ku pffer
cells a r e ph a gocyt es t h a t r ea dily en gu lf h a r m fu l
su bst a n ces. Th is h elps t o expla in wh y ba ct er ia l a n d
120 C h a p t e r 5: In fect ion

ca n r esu lt in ja u n dice. Th e pr esen ce of liver dis-

ea se m a r ked by ja u n dice is oft en r efer r ed t o a s t h e
ic t e r ic p h a s e . Newbor n s oft en exper ien ce som e
degr ee of ph ysiologic (expect ed) ja u n dice beca u se of
liver im m a t u r it y. In n ewbor n s, t h is ph ysiologic ja u n -
dice t ypica lly r esolves spon t a n eou sly wit h in a week.
Ku pffer cells sepa r a t e h em oglobin in t o h em e a n d
globin . Th e globin is degr a ded in t o a m in o a cids. Th e
a m in o a cids a r e t h en u sed a ga in t o for m n ew pr o-
t ein . Th e ir on clea ved fr om t h e h em e com pon en t ca n
be st or ed in t h e liver or u sed by t h e bon e m a r r ow
for e r y t h r o p o ie s is , wh ich is t h e for m a t ion of n ew
r ed blood cells. In pa t ien t s wit h pr ot ein a n d ir on
m a ln ou r ish m en t , deficien cies a r e even m or e st r ik-
in g wh en liver disea se is pr esen t . Th e liver a lso
pr odu ces clot t in g fa ct or s, m a kin g t h ose wit h liver
disea se m or e pr on e t o bleedin g a n d br u isin g.

Figure 5.13. Jaundice marked by the presence of a yellow
sclera. (From Bickley LS, Szilagyi P. Bates’ Guide to Physical
Examination and History Taking. 8th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2003, with permission.)
ot h er for eign in va der s in t h e liver a r e less likely
t o ca u se disea se t h a n vir a l m icr oor ga n ism s. Wh en
da m a ge t o t h e liver occu r s, bilir u bin is a llowed t o
cir cu la t e fr eely. Bilir u bin is r espon sible for t h e
yellow-t in ged skin color a n d scler a of t h e eyes
(ja u n d ic e ) in in dividu a ls wit h liver disea se
(Fig. 5.13). Sim ila r ly, t h e obst r u ct ion of bile flow
Viral Hepatitis
Vir a l h epa t it is r efer s t o in fla m m a t ion of t h e liver
ca u sed by vir a l in fect ion . Th e h epa t it is vir u ses (A,
B, C, D, a n d E ) a r e oft en im plica t ed in t h is disea se.
Th ese a r e r efer r ed t o a s H AV, H BV, a n d so for t h .
Ta ble 5.3 det a ils t h e r ou t e of t r a n sm ission , in cu ba -
t ion , a n d ot h er ch a r a ct er ist ics of t h e m a jor h epa t i-
t is vir u ses. Ot h er vir u ses, in clu din g h er pes sim plex
vir u s, E pst ein –Ba r r vir u s, a n d even E bola vir u s, ca n
a lso ca u se liver in fla m m a t ion .
PATHOPHYSIOLOGY
Th e m a jor r ou t es of t r a n sm ission for t h e h epa t it is
vir u ses in clu de feca l–or a l con t a ct or con t a ct wit h

Ta b le 5.3 Ch a r a ct er ist ics of H epa t it is Vir u ses

C a r r ie r
Tr a n s m is s io n I n c u b a t io n St a t e C h r o n ic Va c c in e D ia g n o s is

H epa t it is A Feca l–or a l fr om a n ot h er in fect ed 1–2 m on t h s No No Yes Blood det ect ion
per son ; con t a m in a t ed food a n d of a n t i-H AV
wa t er su pplies
H epa t it is B Con t a ct wit h in fect ed blood a n d 2–3 m on t h s Yes Yes Yes Blood det ect ion
body flu ids; in fect ed m ot h er t o of H BsAg
fet u s
H epa t it is C Con t a ct wit h in fect ed blood 2–3 m on t h s Yes Yes No Blood det ect ion
of a n t i-H CV
H epa t it is D Con t a ct wit h in fect ed blood a n d 2–3 m on t h s Yes Yes No Blood det ect ion
body flu ids; in fect ed m ot h er t o of a n t i-H DV
fet u s; MUST h ave H BsAg t o be
in fect ed wit h h epa t it is D
(coin fect ion or su per in fect ion )
H epa t it is E Feca l–or a l fr om a n ot h er in fect ed 1–2 m on t h s No No No Blood det ect ion
per son of a n t i-H E V

in fect ed blood a n d body flu ids. Feca l–or a l t r a n sm is-
sion is a pr oblem of h a n d con t a ct wit h in fect ed feces
in wh ich t h e vir u s is t r a n sm it t ed t o a n ot h er wh en
en cou n t er in g t h e or a l m u cosa . For exa m ple, if a food
pr epa r a t ion wor ker does n ot t h or ou gh ly wa sh h is
or h er h a n ds a ft er t oilet in g, h e or sh e ca n t r a n sm it
t h e vir u s t o r est a u r a n t pa t r on s wh o con su m e t h e
h a n dled food. Con t a ct wit h blood a n d body flu ids, a s
wit h h epa t it is B, C, a n d D, is of pa r t icu la r con cer n
for h ea lt h ca r e wor ker s wh o a r e a t h igh r isk of con -
t r a ct in g t h ese in fect ion s beca u se of fr equ en t con t a ct
wit h blood a n d body flu ids.
On ce in fect ed, h epa t it is ca n lea d t o a cu t e or ch r on ic
disea se. H epa t it is B ca n a lso exist in a n a sym pt om -
a t ic ca r r ier st a t e. In gen er a l, feca l–or a l t r a n sm is-
sion lea ds t o a cu t e h epa t it is, wh er ea s t r a n sm ission
by blood a n d body flu ids r esu lt s in ch r on ic disea se.
Th e level of da m a ge in a cu t e vir a l h epa t it is ca n va r y
fr om dea t h of a few h epa t ocyt es t o m a ssive h epa t ic
n ecr osis. An in fla m m a t or y r espon se is wa ged a n d
t h e loca l Ku pffer cells h elp r em ove n ecr ot ic cells.
Affect ed h epa t ocyt es r egen er a t e. Regen er a t ion gen -
er a lly begin s wit h in 48 h ou r s of h epa t ocyt e n ecr osis.
Wit h sever e in fect ion , u lm in a n t h e p a t it is , wh ich
is h epa t ic fa ilu r e fr om sever e a cu t e h epa t it is, ca n oc-
cu r. Obst r u ct ion ca n occu r in t h e blood vessels t h a t
per fu se t h e liver, r esu lt in g in t issu e h ypoxia . Bile
flow ca n a lso becom e obst r u ct ed.
Stop and Consider
What is the role of bile and why is obstruction of
bile flow problematic?
Likewise, ch r on ic h epa t it is ca n r a n ge fr om m in -
im a l da m a ge t o widespr ea d h epa t ocyt e n ecr osis,
fibr osis, diffu se sca r r in g, a n d cir r h osis. Ch r on ic
h epa t it is is r epr esen t ed by im pa ir ed liver fu n ct ion
for m or e t h a n 6 m on t h s. Th e liver is in filt r a t ed
wit h m a cr oph a ges a n d lym ph ocyt es. Pa t ien t s wit h
ch r on ic h epa t it is a lso ca r r y a n in cr ea sed r isk of de-
velopin g h epa t ocellu la r ca r cin om a r ela t ed t o per-
sist en t cell in ju r y.
C ir r h o s is is a n en d-st a ge liver disea se m a r ked
by in t er fer en ce of blood flow t o t h e liver a n d wide-
spr ea d h epa t ocyt e da m a ge. In t er fer en ce of blood
flow t o t h e liver (1) exa cer ba t es h ypoxia of t h e h e-
pa t ocyt es a n d r esu lt s in fu r t h er cell dea t h ; (2) ca u ses
blood a n d bile t o ba ck u p in t o t h e liver r esu lt in g in
fu r t h er in ju r y a n d in fla m m a t ion ; a n d (3) obst r u ct s
blood flow fr om por t a l cir cu la t ion . Liver fa ilu r e a n d
dea t h m ay r esu lt .
Stop and Consider
Compare fulminant hepatitis and cirrhosis to
general infection complications (septicemia and
chronic infection).
C lin ic a l Mo d e ls 121
CLINICAL MANIFESTATIONS
All t ypes of vir a l h epa t it is ca n ca u se a cu t e, ict er ic
illn ess. Th r ee ph a ses, sim ila r t o t h e gen er a l ph a ses
of in fect ion , ch a r a ct er ize a cu t e h epa t it is in fect ion :
1. P r o d r o m e : a per iod of fa t igu e, a n or exia , m a la ise,
h ea da ch e, a n d low-gr a de fever. Th e pr odr om e
u su a lly la st s a bou t 2 weeks.
2. I c t e r u s : m a r ked by t h e on set of ja u n dice, da r k
u r in e, a n d cla y-color ed st ools 2 weeks a ft er expo-
su r e t o t h e vir u s. Th is ph a se cor r espon ds t o t h e
clin ica l illn ess ph a se discu ssed pr eviou sly a n d
la st s a ppr oxim a t ely 2 t o 6 weeks. Th e liver is en -
la r ged a n d t en der.
3. R e c o v e r y : m a r ked by t h e r esolu t ion of ja u n dice
a r ou n d 8 weeks a ft er t h e in it ia l exposu r e t o t h e
vir u s. Sign s a n d sym pt om s im pr ove wit h t h e ex-
cept ion of t h e liver, wh ich r em a in s en la r ged a n d
t en der for a n a ddit ion a l 1 t o 4 weeks.
A ca r efu l st u dy of F igu r e 5.14 will r evea l t h e con n ec-
t ion bet ween pa t h oph ysiologic pr ocesses a n d clin ica l
m a n ifest a t ion s of liver fa ilu r e.
DIAGNOSTIC CRITERIA
Dia gn osis is oft en ba sed on det ect ion of vir a l a n t i-
bodies, su ch a s a n t i-H AV, a n t i-H CV, a n t i-H DV, a n d
a n t i-H E V, in t h e blood of t h e in fect ed per son . Th e
cor e of t h e h epa t it is B vir u s con t a in s t wo a n t igen s:
t h e cor e a n t igen (H BcAg) a n d t h e e a n t igen (H BeAg).
Sin ce t h er e a r e t h r ee possible clin ica l cou r ses for
h epa t it is B: com plet e r ecover y, a sym pt om a t ic ca r r ier
st a t e, or ch r on ic in fect ion , t h e h ea lt h pr ofession a l
m u st look a t t h e cor r espon din g a n t igen a n d a n t ibody
levels. An t ibodies t o t h e h epa t it is B cor e a n t igen (IgM
a n t i-H Bc) a r e r equ ir ed for t h e dia gn osis of a cu t e
h epa t it is B in fect ion . Cells in fect ed wit h h epa t it is B
vir u s a lso pr esen t su r fa ce a n t igen s on t h e ou t er coa t -
in g. Th e h epa t it is B su r fa ce a n t igen (H BsAg) m a y be
pr esen t in a cu t e in fect ion or in t h ose wh o a r e ch r on ic
a sym pt om a t ic ca r r ier s. Ot h er fin din gs t h a t m ay a id
in dia gn osis a n d pr ogn osis in clu de t h e det ect ion of
bilir u bin in t h e u r in e, eleva t ed ser u m bilir u bin lev-
els (m or e t h a n 30 m g/dL in dica t es m or e sever e dis-
ea se), a n d pr olon ged clot t in g t im e (a gr a ve fin din g
t h a t in dica t es im pa ir ed liver fu n ct ion ).
TREATMENT
H epa t it is A a n d h epa t it is B ca n be pr even t ed t h r ou gh
va ccin a t ion . Tr ea t m en t of a cu t e vir a l h epa t it is, a s
wit h ot h er vir a l in fect ion s, is sym pt om a t ic. F lu ids,
r est , a n d a n a lgesics a r e r ecom m en ded, pa r t icu la r ly
du r in g t h e ict er ic ph a se of illn ess. Avoida n ce of
st r en u ou s ph ysica l a ct ivit y or con t a ct spor t s is oft en
122 C h a p t e r 5: In fect ion

Live r failure

Dis o rde rs o f s ynthe s is and s to rag e func tio ns Dis o rde rs o f me tabo lic and e xc re to ry func tio ns

Glucos e P rote ins Lipoprote in Bile Amino S te roid Drugs Bilirubin

chole s te rol s a lts a cids hormone s

Hype rglyce mic De cre a s e d Conve rs ion Drug inte ra ctions

eve nts chole s te rol of a mmonia a nd toxicitie s
to ure a

Hypo- Impa ire d fa t Ence pha lopa thy Hype rbilirubine mia
a lbumine mia a bs orption

Ede ma / De cre a s e d De ficie ncy of Fa tty Incre a s e d Incre a s e d Ja undice

a s cite s coa gula tion fa t-s oluble s tools a ldos te rone a ndroge ns /
fa ctors vita mins e s troge ns

Ble e ding Ede ma /

a s cite s

Gyne coma s tia a nd Me ns trua l

te s ticula r a trophy irre gula ritie s
in me n in wome n

Figure 5.14. Concept map. Alterations in liver function and manifestations of liver failure. (Modified from Porth CM. Patho-
physiology: Concepts of Altered Health States. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004, with permission.)

r ecom m en ded t o avoid liver in ju r y. A low-fa t diet is
r ecom m en ded beca u se bile h elps wit h fa t em u lsifi-
ca t ion a n d a bsor pt ion a n d bile pr odu ct ion m ay be
im pa ir ed du r in g liver disea se. An t ivir a l m edica t ion s
m ay be u sed in ch r on ic vir a l h epa t it is t o decr ea se vi-
r a l r eplica t ion . Avoida n ce of t r a n sm ission t o ot h er s is
cr it ica l t h r ou gh ca r efu l h a n d wa sh in g, a voida n ce of
con t a ct wit h in fect ed feca l m a t er ia l, a n d a voida n ce of
con t a ct wit h blood a n d body flu ids wh er e a ppr opr ia t e.
Tuberculosis
Tu ber cu losis (TB) is t h e m ost pr eva len t a n d dea dly
in fect iou s disea se wor ldwide. Th e Cen t er s for Dis-
ea se Con t r ol a n d P r even t ion (CDC) est im a t es t h a t
on e-t h ir d of t h e wor ld’s popu la t ion is in fect ed wit h
TB, a n d in 2013, 9 m illion n ew ca ses wer e r epor t ed.
An ot h er 3 m illion people wor ldwide die ever y yea r
beca u se of a ct ive TB in fect ion a n d t h e a ccom pa n yin g
com plica t ion s. 3
PATHOPHYSIOLOGY
Tu b e r c u lo s is is a n in fect iou s disea se ca u sed by
a n a er obic, r od-sh a ped ba ct er iu m (ba cillu s) ca lled
M. tu ber cu losis. H u m a n s a r e t h e on ly kn own r es-
er voir. Th e pr im a r y sit e of in fect ion is in t h e lu n gs,
a lt h ou gh TB ca n in fect a n y or ga n in t h e body. TB dif-
fer s fr om ot h er r espir a t or y in fect ion s in m a n y wa ys,
in clu din g t h e pa t h ogen , m ode of t r a n sm ission , loca -
t ion of in fect ion , clin ica l pr esen t a t ion , a n d ch r on icit y.
 C lin ic a l Mo d e ls 123

con ta inm ent a nd destr uc-

F R O M T H E L AB tion of t he ba cilli is less
likely, a nd la r ger a rea s of
The cell-mediated hypersensitivity reaction that occurs with TB is a key diagnostic feature necrosis ca n develop. The
of this condition. Exposure to Mycobacterium tuberculosis is determined via a tuberculin skin infect ion ca n t hen m or e
test using a purified protein derivative (PPD), formerly known as a Mantoux test. The health ea sily spr ea d t hr ough
provider injects 5 tuberculin units of PPD intradermally. Exposure to TB is measured as the th e lym ph nodes t o ot her
amount of induration (swelling at the local site) at 48 to 72 hours as a result of exposure orga ns in t he body.
to the PPD antigen. The size of induration, rather than erythema (redness), is critical for Th e in it ia l con t a in -
the diagnosis. m en t a n d dest r u ct ion of
t h e ba cilli occu r s t h r ou gh
Wit h TB, t h e r ou t e of t r a n sm ission is t h r ou gh in h a l- a gr a n u lom a t ou s in fla m -
in g a ir bor n e dr oplet n u clei fr om a n in fect ed per son . m a t or y r espon se. Th e for m a t ion of a gr a n u lom a , or
Air bor n e dr oplet n u clei, r elea sed wit h in r espir a t or y wa lled-off a r ea of ba ct er ia , is r efer r ed t o a s a G h o n
secr et ion s t h r ou gh cou gh in g, t a lkin g, or sn eezin g, o c u s . Th e Gh on focu s is con sider ed t h e pr im a r y
a r e ext r em ely sm a ll a n d r em a in su spen ded in t h e lu n g lesion . Oft en , pa r t icu la r ly wh en t h e n u m ber of
a ir lon ger t h a n m ost ot h er m icr oor ga n ism s. TB is in fect in g ba cilli is la r ge, t h e cen t er of t h e gr a n u lom a
t h er efor e likely t o in fect a gr ea t er n u m ber of people develops a dist in ct t ype of n ecr osis, t er m ed c a s e o u s
wit h in a com m on a ir spa ce com pa r ed wit h illn esses n e c r o s is , wh ich is pa st y, yellow, a n d ch eeselike. Th e
spr ea d by la r ger, h ea vier r espir a t or y dr oplet s t h a t M. tu ber cu losis wit h in t h e Gh on focu s dr a in a lon g
fa ll qu ickly t o t h e floor. lym ph ch a n n els t o lym ph n odes in t h e lu n gs a n d
Wh en in h a led, dr oplet n u clei m ove pa st t h e br on - for m fu r t h er gr a n u lom a s. Th e Gh on focu s a n d t h e
ch i dir ect ly t o t h e t er m in a l br on ch ioles a n d a lveoli a ddit ion a l gr a n u lom a s t h a t develop t h r ou gh t h e
of t h e lu n g. Qu ick m ovem en t of t h e t in y m icr obes lym ph ch a n n els a r e r efer r ed t o a s t h e G h o n c o m -
beyon d t h e u pper r espir a t or y t r a ct oft en pr even t s p le x (Fig. 5.15). An in t a ct in fla m m a t or y a n d im -
a ct iva t ion of t h e a ppr opr ia t e defen se m ech a n ism s m u n e r espon se even t u a lly r esu lt s in t h e for m a t ion of
in t h e u pper a ir wa y, in clu din g t h e cou gh a n d sn eeze sca r t issu e a n d ca lcifica t ion of t h ese Gh on com plex
r eflexes. Upon en cou n t er in g t h e ba cilli, a lveola r lesion s. H owever, sm a ll n u m ber s of dor m a n t ba ct e-
m a cr oph a ges in gest bu t a r e u n a ble t o dest r oy t h e r ia ca n su r vive wit h in t h ese ca lcifica t ion s for yea r s.
ba ct er ia . As t h e ba cilli pr olifer a t e wit h in t h e m a cr o-
ph a ges, t h e m a cr oph a ges pr esen t t h e ba cilli a s a n t i-
gen s t o T lym ph ocyt es (cell-m edia t ed im m u n it y). In
a n a t t em pt t o dest r oy t h e ba cilli, t h e in fla m m a t or y
a n d cellu la r im m u n e r espon ses a r e elicit ed, lea din g
t o on e of t h e followin g:
1. Con t a in m en t t h r ou gh a n effect ive cellu la r im -
m u n e r espon se (a sym pt om a t ic pr im a r y TB)
2. Mu lt iplica t ion a n d t h e developm en t of a ggr essive,
sym pt om a t ic disea se (pr ogr essive pr im a r y TB)
3. Dor m a n cy wit h fu t u r e m u lt iplica t ion or r ein fec-
t ion lea din g t o a ggr essive, sym pt om a t ic disea se
(secon da r y TB)
Destr uct ion or cont a inm ent of TB la rgely depends
on a n effect ive cell-m edia t ed im m une response of
t he host , compr ised of t h e pr oduct ion of lyt ic (killing)
en zym es by sensitized m a cr oph a ges a nd t he devel-
opm ent of a ct iva ted T lym phocyt es. Sever a l cha r-
a ct er istics of M. tuber culosis a r e im por ta nt in th e
pa t h ogenesis of TB. The ba cilli a r e slow gr owin g a n d
r esist a n t t o destr uct ion. The ba cilli do n ot pr odu ce
t oxins; da ma ge t o t he lu ng a nd ot her body t issues
is t hr ough t he h yper sen sit ivit y r ea ction elicit ed by
t he ba cilli. When t he num ber of inha led pa t hogen s is
sm a ll a nd t he host ha s a compet ent im m un e system , Figure 5.15. Tuberculosis showing a healed Ghon complex.
t he ba cilli ca n be successfu lly ingest ed, con ta ined, (From Rubin E, Farber JL. Pathology. 4th ed. Philadelphia,
a nd killed. If t he im m une syst em is com pr om ised, t he PA: Lippincott Williams & Wilkins; 2005, with permission.)
124 C h a p t e r 5: In fect ion

Tu ber cu losis is oft en dist in gu ish ed a s eit h er

pr im a r y or secon da r y TB. P r im a r y in fect ion is t h e Inha la tion of
tube rcle ba cillus
in it ia l exposu r e a n d gr owt h of t h e ba cilli in a n in di-
vidu a l wit h or wit h ou t sym pt om s. In dividu a ls with
sym pt om s a r e believed t o h a ve a n a ggr essive a n d
dest r u ct ive disea se, t er m ed a ct ive in fect ion . In divid-
u a ls with ou t sym pt om s exh ibit a n effect ive in fla m -
m a t or y a n d im m u n e r espon se, a n d a h ea led Gh on
com plex even t u a lly for m s, su r r ou n din g dor m a n t
ba cilli. If t h e im m u n e syst em becom es com pr om ised
a n d t h e ba ct er ia a r e a llowed t o a ga in pr olifer a t e,
t h e in fect ion becom es a ct ive a n d pr ogr esses t o sec-
on da r y TB. Secon da r y TB is ch a r a ct er ized by r ea c-
t iva t ion of t h e pr im a r y in fect ion a ft er a lon g per iod
of dor m a n cy or by r ein fect ion wit h t h e pa t h ogen s
kn own t o ca u se TB. Secon da r y TB, wh ich ca n spr ea d
t o ot h er or ga n s, is m a r ked by a ggr essive, dest r u ct ive
ca vit a t ion s of t h e lu n g t issu e. C a v it a t io n s a r e a r ea s Primary S e c o ndary
tube rc ulo s is tube rc ulo s is
of n ecr osis t h a t er ode su r r ou n din g st r u ct u r es of t h e
lu n gs, in clu din g t h e br on ch ioles, br on ch i, a n d su r-
r ou n din g blood vessels. If u n t r ea t ed, secon da r y TB
ca n con t in u e t o spr ea d, dest r oyin g t issu es t h r ou gh - Ce ll-me dia te d Deve lopme nt of
ou t t h e body. Th e pa t h ogen esis of TB is depict ed in hype rs e ns itivity ce ll-me dia te d Re infe ction
re s pons e immunity
F igu r e 5.16.

Stop and Consider

How does the development of granulomas, fibro- Gra nuloma tous
sis, and calcification in TB compare with other infla mma tory Pos itive s kin te s t
re s pons e
chronic inflammatory conditions, such as rheu-
matoid arthritis?
P rogre s s ive or
Ghon’s complex dis s e mina te d
CLINICAL MANIFESTATIONS tube rculos is

Most (90%) of in dividu a ls in fect ed wit h pr im a r y TB

a r e a sym pt om a t ic. In t h ose in dividu a ls wit h pr o-
gr essive pr im a r y TB (10%), clin ica l m a n ifest a t ion s
m a y r esem ble t h ose of ch r on ic in fla m m a t ion , su ch
a s m a la ise, weigh t loss, fa t igu e, a n or exia , low-gr a de
fever, a n d possibly n igh t swea t s. On goin g dest r u c-
t ion of lu n g t issu e r esu lt s in a sever e ch r on ic pr o-
du ct ive cou gh wit h h e m o p t y s is (bloody spu t u m ).
Th e ba ct er ia r ea dily r eside in spu t u m a n d ca n be
t r a n sm it t ed t o ot h er s. Beca u se secon da r y TB in fec-
t ion ca n r eside in ot h er or ga n s of t h e body, clin ica l
m a n ifest a t ion s m a y ext en d ou t side of t h e lu n gs. For
exa m ple, TB fou n d in t h e m en in ges of t h e br a in will
pr esen t wit h h ea da ch e a n d m en t a l st a t u s ch a n ges
t h a t m a y pr ogr ess t o com a over a per iod of da ys t o
weeks a ft er in fect ion .
DIAGNOSTIC CRITERIA
Act ive in fect ion wit h TB is dia gn osed t h r ou gh t u -
ber cu lin skin t est s (see Fr om t h e La b), ch est r a -
diogr a ph , spu t u m cu lt u r e, a n d spu t u m n u cleic a cid
a m plifica t ion . A ch est r a diogr a ph in pr im a r y TB
oft en sh ows pa t ch y or n odu la r in filt r a t es or pleu r a l
He a le d dorma nt Re a ctiva te d
le s ion tube rculos is
Figure 5.16. Pathogenesis of tuberculosis. (Modified from
Porth CM. Pathophysiology: Concepts of Altered Health
States. 7th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2004, with permission.)
effu sion . Th e u pper lobe of t h e lu n g is m ost com -
m on ly a ffect ed. Adva n ced in fect ion is n ot ed by t h e
pr esen ce of ca vit a t ion . In a ct ive “old” disea se is n ot ed
by t h e pr esen ce of ca lcifica t ion . A CT sca n m a y be
n eeded if t h e r esu lt s of t h e ch est r a diogr a ph a r e u n -
clea r or in con clu sive.
Spu t u m specim en s sh ou ld be collect ed in t h e
ea r ly m or n in g of t h r ee con secu t ive da ys. F iber op-
t ic br on ch oscopy wit h t r a n sbr on ch ia l biopsy a n d
br on ch ia l wa sh in gs m a y be n eeded t o obt a in spu -
t u m a n d t issu e specim en s for fu r t h er a n a lysis,
pa r t icu la r ly in t h ose pa t ien t s wh o a r e u n a ble t o

expect or a t e su fficien t spu t u m . Th e a dva n t a ge t o
u sin g n u cleic a cid a m plifica t ion over spu t u m cu l-
t u r e is t h a t t h ese n ewer t ech n ologies iden t ify TB
wit h in 24 h ou r s com pa r ed t o a week or m or e wit h
spu t u m cu lt u r es.
TREATMENT
Tr ea t m en t is a ch ieved t h r ou gh t h e u se of m u lt i-
ple a n t im icr obia l dr u gs over sever a l m on t h s. Th e
t r ea t m en t pr ot ocol sh ou ld in clu de dir ect ly obser ved
t h er a py (DOT). Th is m ea n s t h a t t h e pa t ien t m u st
be obser ved t a kin g t h e m edica t ion s a t ea ch a dm in -
ist r a t ion by t h e h ea lt h pr ofession a l or design a t ed
per son n el. DOT is r equ ir ed t o pr om ot e com plet e
er a dica t ion of t h e ba ct er ia t h r ou gh im pr oved pa t ien t
com plia n ce wit h t h e pr olon ged t r ea t m en t r egim en .
Typica lly, t r ea t m en t in volves t h e u se of fou r a n t im i-
cr obia l dr u gs: ison ia zid, r ifa m pin , pyr a zin a m ide, a n d
eit h er et h a m bu t ol or st r ept om ycin . Mu lt iple dr u g
r esist a n ce is a m a jor t r ea t m en t issu e r ela t ed t o TB.
Resist a n ce t o t h e pr escr ibed a n t im icr obia ls is su s-
pect ed if t h e pa t ien t sh ows n o im pr ovem en t wit h in
1 t o 2 weeks a ft er st a r t in g t h e fou r fir st -lin e dr u gs.
Th ose in dividu a ls wit h m u lt iple dr u g-r esist a n t TB
a r e pr escr ibed m edica t ion s for wh ich t h e ba ct er ia
a r e su scept ible. To pr even t t r a n sm ission t o ot h er s,
h ospit a lized pa t ien t s wit h su spect ed or dia gn osed
TB m u st be pla ced in isola t ion . Th is in clu des a pr i-
va t e r oom wit h n ega t ive pr essu r e a n d a dequ a t e a ir
exch a n ge m ech a n ism s. Per son s en t er in g t h e r oom
m u st wea r m a sks or r espir a t or s ca pa ble of filt er in g
dr oplet n u clei.
Ba cilli Ca lm et t e-Gu ér in (BCG) is a va ccin e for TB
t h a t is u sed in m a n y cou n t r ies wit h a h igh pr eva len ce
of TB t o pr even t ch ildh ood t u ber cu lou s m en in git is or
m ilia r y (dissem in a t ed in t h e blood) t u ber cu losis. It is
n ot widely r ecom m en ded in Nor t h Am er ica beca u se
of t h e r ela t ively low r isk of in fect ion a n d va r ia ble
effect iven ess a ga in st a du lt pu lm on a r y TB. In divid-
u a ls wh o h a ve been va ccin a t ed wit h BCG will h a ve
a posit ive t u ber cu lin r ea ct ion wh en t h e P P D is a d-
m in ist er ed; t h er efor e, t h e t u ber cu lin skin t est is n ot
a n effect ive scr een in g t ool t o det ect TB exposu r e in
t h ose in dividu a ls va ccin a t ed wit h BCG.
Urinary Tract Infection
Ur in a r y t r a ct in fect ion s (UTIs) ca n occu r a n ywh er e
a lon g t h e u r in a r y t r a ct , fr om t h e u r et h r a l m ea t u s
(u r et h r it is) t o t h e bla dder (cyst it is). Th ese in fect ion s
a r e a s c e n d in g ; t h a t is, m icr oor ga n ism s en t er a t t h e
dist a l u r et h r a a n d m ove u p t owa r d t h e bla dder. Th e
ba ct er ia a t t a ch t o t h e u r in a r y t r a ct epit h eliu m , r e-
su lt in g in a n a cu t e in fla m m a t or y r espon se.
C lin ic a l Mo d e ls 125
PATHOPHYSIOLOGY
E sch er ich ia coli is t h e m ost com m on m icr oor ga n -
ism im plica t ed in u r in a r y t r a ct in fect ion . E . coli is
a n a er obic, gr a m -n ega t ive ba ct er iu m a n d is r esiden t
flor a in t h e ga st r oin t est in a l t r a ct . Wh en ga in in g a c-
cess in t o t h e u r in a r y t r a ct (wh ich is a st er ile a r ea
of t h e body), E . coli ca u ses in fect ion . Wom en a r e
pa r t icu la r ly vu ln er a ble beca u se of a sh or t u r et h r a
a n d close pr oxim it y bet ween t h e u r et h r a a n d a n u s.
Mech a n ica l obst r u ct ion of t h e u r in a r y t r a ct , su ch
a s wit h r en a l ca lcu li (kidn ey st on es) or a n en la r ged
pr ost a t e, a n d in t r odu ct ion of u r in a r y ca t h et er s in t o
t h e u r et h r a a n d bla dder ca n a lso in cr ea se t h e likeli-
h ood of developin g a u r in a r y t r a ct in fect ion .
CLINICAL MANIFESTATIONS
Th e t issu es in t h e u r in a r y t r a ct becom e edem a t ou s
a n d h yper em ic, wh ich r esu lt s in d y s u r ia (pa in
wit h u r in a t ion ), u r in a r y u r g e n c y (t h e n eed t o im -
m edia t ely u r in a t e), a n d u r in a r y fr equ en cy. Tis-
su e dest r u ct ion in t h e u r in a r y t r a ct m a y r esu lt in
h e m a t u r ia , or blood in t h e u r in e. Th e in fla m m a t or y
r espon se t o t h ese ba ct er ia pr odu ces a pu r u len t exu -
da t e, wh ich ca n be det ect ed a s clou dy u r in e fr om t h e
in cr ea se in leu kocyt es.
DIAGNOSTIC CRITERIA
Dia gn osis is ba sed on t h e h ist or y of pr esen t in g sym p-
t om s a lon g wit h ph ysica l exa m in a t ion a n d dia gn os-
t ic t est s. P h ysica l exa m in a t ion m a y dem on st r a t e
su pr a pu bic t en der n ess wit h pa lpa t ion . Ur in a lysis
a n d u r in e cu lt u r e a r e r equ ir ed a n d m u st be obt a in ed
u sin g a m idst r ea m or ca t h et er ized sa m ple u sin g t h e
a ppr opr ia t e t ech n iqu e. P y u r ia , or pu r u len t exu da t e
(pu s) in t h e u r in e, fou n d by per for m in g t h e leu kocyt e
est er a se dip t est , in cr ea ses t h e likelih ood of ba ct er ia l
in fect ion . Th e defin it ion of UTI is ba sed on a u r in e
cu lt u r e n ot in g gr ea t er t h a n 1,000 colon ies of a sin gle
or ga n ism per m L. Im a gin g st u dies m a y be n eeded if
u r in a r y obst r u ct ion is su spect ed.
TREATMENT
Th e pr ocess of u r in a t ion a ssist s in “flu sh in g” ou t
m u ch of t h e ba ct er ia t h a t a t t em pt t o a scen d t h e
u r et h r a . For t h is r ea son , in cr ea sin g flu id in t a ke is
im por t a n t for pa t ien t s wit h UTI. Dr u g t h er a py wit h
a n a n t ibiot ic effect ive a ga in st gr a m -n ega t ive a er o-
bic ba ct er ia is t h e pr im a r y t r ea t m en t in t er ven t ion .
Pa t ien t s wit h dia bet es m ellit u s, im m u n osu ppr es-
sion , or u r in a r y t r a ct obst r u ct ion , or pa t ien t s wh o
a r e pr egn a n t , a r e m or e likely t o develop com plica -
t ion s wit h a UTI a n d m u st be a ggr essively t r ea t ed
wit h a pr olon ged cou r se of a n t ibiot ics. If UTI is
126 C h a p t e r 5: In fect ion
u n t r ea t ed, t h e ba ct er ia ca n con t in u e t o a scen d in t o
t h e kidn eys a n d r esu lt in pyelon eph r it is.
Pyelonephritis
P y e lo n e p h r it is r efer s t o in fect ion a n d r esu lt in g
in fla m m a t ion of t h e r en a l pa r en ch ym a r esu lt in g
in sca r r in g. P yelon eph r it is ca n be bot h a cu t e a n d
ch r on ic. Acu t e pyelon eph r it is is discu ssed h er e.
Ch r on ic pyelon eph r it is occu r s a lm ost exclu sively in
pa t ien t s wit h r en a l a n a t om ic a bn or m a lit ies, su ch
a s in ch ildr en wit h vesicou r et er a l r eflu x, a con di-
t ion ch a r a ct er ized by a n in com pet en t u r et er ovesica l
va lve a llowin g r et r ogr a de u r in e flow. Repa ir of t h e
a n a t om ica l a bn or m a lit y is in dica t ed for t h ose wit h
ch r on ic pyelon eph r it is.
Function of the Kidneys
E a ch kidn ey is com pr ised of a bou t a m illion filt er-
in g u n it s ca lled n eph r on s. E a ch n eph r on is r espon si-
ble for filt er in g a sm a ll a m ou n t of blood. Wit h in t h e
n eph r on a r e a glom er u lu s a n d a t u bu le. Th e glom er-
u lu s let s flu id a n d wa st e pr odu ct s pa ss t h r ou gh bu t
pr even t s t h e pa ssa ge of r ed blood cells a n d la r ge
m olecu les, su ch a s pr ot ein s. Th e filt er ed flu id t h en
pa sses t h r ou gh t h e t u bu le, wh ich sen ds n eeded m in -
er a ls ba ck t o t h e bloodst r ea m a n d r em oves wa st es.
Th e kidn eys ser ve a n u m ber of cr it ica l fu n ct ion s
essen t ia l for h om eost a sis. E ver y da y, t h e t wo kid-
n eys filt er a bou t 120 t o 150 qu a r t s of blood t o pr o-
du ce a bou t 1 t o 2 qu a r t s of u r in e. Ur in e is com posed
of wa st es a n d excess flu id. Ot h er im por t a n t kidn ey
fu n ct ion s in clu de:
● Keepin g levels of elect r olyt es st a ble, su ch a s so-
diu m , pot a ssiu m , a n d ph osph a t e
● P r odu cin g h or m on es t h a t r egu la t e blood pr essu r e,
pr om ot e r ed blood cells, a n d st r en gt h en bon es
Acute Pyelonephritis
PATHOPHYSIOLOGY
Acu t e pyelon eph r it is r esu lt s fr om ba ct er ia l in fect ion
of t h e r en a l pa r en ch ym a . Th e m ost com m on ly im pli-
ca t ed ba ct er ia is E . coli. Ba ct er ia r ea ch t h e kidn ey
by a scen din g fr om t h e lower u r in a r y t r a ct t h r ou gh
t h e u r et er s a n d t o t h e n eph r on s (Fig. 5.17). Upon
a scen sion , ba ct er ia a t t a ch t o t h e epit h eliu m of t h e
u r in a r y t r a ct a n d t r igger t h e a cu t e in fla m m a t or y
r espon se. Ch em ica l m edia t or s a r e r elea sed pr om ot -
in g t h e fu r t h er m ovem en t of ba ct er ia in t o t h e u r in e.
Risk fa ct or s, wh ich pr om ot e t h e developm en t of
pyelon eph r it is in clu de:
● Ur in a r y obst r u ct ion , su ch a s wit h r en a l ca lcu li
● In com plet e bla dder em pt yin g ca u sin g u r in e
st a gn a t ion
● F r equ en t in t er cou r se, wh ich ca n ir r it a t e t h e
u r et h r a
● E xposu r e t o sexu a lly t r a n sm it t ed in fect ion
● P r egn a n cy/h or m on a l ch a n ges decr ea se u r et er a l
per ist a lsis
CLINICAL MANIFESTATIONS
Acu t e pyelon eph r it is oft en pr esen t s clin ica lly a s a
t r ia d of sign s/sym pt om s: fever, cost over t ebr a l a n -
gle pa in , a n d n a u sea a n d/or vom it in g. Sym pt om s
m a y be m ild t o sever e a n d u su a lly develop over t h e
cou r se of a da y t o sever a l da ys. Pa t ien t s m a y a lso
r epor t dysu r ia , u r in a r y fr equ en cy, h esit a n cy, lower
a bdom in a l pa in , u r in a r y u r gen cy, a n d even blood in
t h e u r in e.
DIAGNOSTIC CRITERIA
Th e dia gn osis of pyelon eph r it is is su ggest ed by t h e
clin ica l m a n ifest a t ion t r ia d a bove a n d is su ppor t ed
by u r in e st u dies. Ur in a lysis scr een s for ba ct er iu r ia ,
m icr oscopic eva lu a t ion r evea ls h em a t u r ia , a n d u r in e
cu lt u r e iden t ifies t h e pa t h ogen . Im a gin g st u dies m a y
be u sed t o visu a lize r en a l a bn or m a lit ies.
TREATMENT
Un com plica t ed pyelon eph r it is ca n be t r ea t ed in
t h e em er gen cy depa r t m en t wit h IV flu ids, IV a n t i-
biot ics, a n d pa in m edica t ion s. Or a l a n t ibiot ics a r e
con t in u ed on ce t h e pa t ien t r et u r n s h om e. H ospit a l-
iza t ion is a ppr opr ia t e for t h ose wit h sever e disea se,
or t h ose wh o a r e pr egn a n t , elder ly, or h a ve a n ot h er
ch r on ic disea se t h a t m a y im pa ct r esolu t ion . Su r-
ger y m a y be r equ ir ed t o r em ove a n y a bscesses or
obst r u ct ion s t h a t m a y h a ve occu r r ed or t o cor r ect
con gen it a l a n om a lies t h a t h a ve con t r ibu t ed t o t h e
pyelon eph r it is.
Meningitis
Men in git is is in fla m m a t ion of t h e m em br a n es
(m en in ges) of t h e br a in a n d spin a l cor d. Men in git is
com m on ly r esu lt s fr om in fect ion wit h ba ct er ia or
vir u ses. Th is sect ion will focu s on ba ct er ia l m en in -
git is. Wor ldwide, t h e r a t es of m en in gococca l disea se
a r e h igh est in in fa n t s. Adolescen t s, you n g a du lt s,
a n d t h e elder ly a r e a lso a t in cr ea sed r isk.
 C lin ic a l Mo d e ls 127
End Phas e
Atrophie d pa re nchyma
P rogre s s ive
s ca rring

ic
n
Pro g re s s ive

ro
h
Phas e

C
Foca l Ac ute pye lo ne phritis and
pa re nchyma pro g re s s ive s c arring fro m
s ca rring re pe ate d infe c tio n.

Na rrowe d
ca lyx ne ck
A
cu
te

Early Phas e
(e de ma tous )

Figure 5.17. Acute pyelonephritis and progressive scarring from repeated infection.

Function of the Meninges t r a ct a n d a t t a ch es t o epit h elia l cells. In fla m m a t or y

Th e m en in ges a r e com pr ised of t h e du r a m a t er,
a r a ch n oid, a n d pia m a t er (F ig. 5.18). Th e du r a m a t er
is t h e du r a ble la yer ; it is t h e t ou gh est a n d ou t er m ost
la yer of t h e m en in ges. Th is la yer h a s it s own blood
su pply a n d is pa in sen sit ive. Th e a r a ch n oid la yer is
a web of colla gen t h a t pr ovides a cu sh ion . Th e pia
m a t er for m s t h e delica t e in n er lin in g of t h e br a in .
Th e m a in fu n ct ion s of t h e m en in ges a r e t o:
1. P r ot ect t h e br a in a n d spin a l cor d fr om in ju r y
2. P r ovide blood su pply t o t h e sku ll a n d br a in t issu e
3. Allow for t h e flow of cer ebr a l spin a l flu id
Bacterial Meningitis
PATHOPHYSIOLOGY
Th e m ost com m on ba ct er ia l ca u se of m en in git is is N.
m en in gitid es, a n a er obic, gr a m -n ega t ive ba ct er iu m .
Th er e a r e a t lea st 13 differ en t N. m en in gitid is su b-
t ypes. Vir a l m en in git is is oft en r efer r ed t o a s a sept ic
m en in git is. It is gen er a lly less sever e t h a n ba ct er ia l
m en in git is a n d oft en r esolves wit h ou t specific t r ea t -
m en t . F u n gi ca n r esu lt in m en in git is in in dividu a ls
wh o a r e im m u n ocom pr om ised. Ta ble 5.4 com pa r es
t h e differ en t t ypes of m en in git is.
Th e m ode of t r a n sm ission for m en in git is is r espi-
r a t or y dr oplet s pa ssed fr om a n in fect ed per son t o
t h e h ost . Th e m icr oor ga n ism en t er s t h e r espir a t or y
a n d im m u n e r espon ses a r e wa ged. Im m u n oglobu lin s
in t h e r espir a t or y m u cosa ca n pr ovide pr ot ect ive im -
m u n it y a ga in st t h e m icr oor ga n ism s. H owever, in
som e ca ses, t h e ba ct er ia m ove t h r ou gh t h e m u cosa
a n d get in t o t h e cen t r a l n er vou s syst em or t h e blood.
Th e m ech a n ism for en t r y in t o t h e blood a n d cen t r a l
n er vou s syst em is oft en u n kn own .
In the centra l nervous system, the ba cteria m ul-
tiply a long t he meninges and in the cerebra l spinal
fluid (CSF). The ra pid prolifer ation of bacteria is re-
lated to few antibodies, complement components,
a nd white blood cells in the CSF. The inflam mat ory
response ca uses the br ain tissues to becom e edema-
tous (swollen) and h yp e r e m ic (filled wit h blood). The
infectious process is perpet ua ted by the replica tion of
bacteria (a long with the influx of inflamm at ory cells)
a nd increa sed ca pilla ry per mea bility. Exudat e a ccu-
mula tes thr oughout t he CSF, causing dam age to cr a-
nia l nerves, obstruction of CSF pa thways, obstruction
of blood flow to bra in tissue, a nd reduced oxygen to the
bra in. Meningitis ca n result in sept icemia . Septicemia
da ma ges endothelia l cells of t he vessels. Ma ssive, sys-
temic infla mma tion can then lead t o septic shock.
CLINICAL MANIFESTATIONS
Acu t e ba ct er ia l m en in git is is n ot ed for a r a pid a n d
sever e on set of sym pt om s (oft en wit h in less t h a n
24 h ou r s). Ir r it a t ion of t h e m en in ges r esu lt s in
t h e ch a r a ct er ist ic clin ica l m a n ifest a t ion s: sever e
128 C h a p t e r 5: In fect ion

Bone

Dura ma te r
(oute r laye r)
Dura l
(ve nous s inus )

Dura ma te r
(inne r laye r)
S ubdura l

Ara chnoid
ma te r
Ce re bra l cortex
(A) S uba ra chnoid
P ia ma te r

Ve rte bra

Epidura l s pa ce
(a dipos e tis s ue )
Dura ma te r
S ubdura l
Ara chnoid
ma te r
S uba ra chnoid

(B)
P ia ma te r

S pina l cord

Figure 5.18. Meninges of the brain ( A) and spinal cord ( B) . (From Nath J. Using Medical Terminology: A Practical Approach.
Baltimore, MD: Lippincott Williams & Wilkins; 2006, with permission.)

Ta b le 5.4 Com pa r ison of t h e Types of Men in git is

B a c t e r ia l Vir a l F u n ga l

Com m on pa t h ogen s S. pn eu m on ia e, N. m en in gitid is, Asept ic; va r iet y of vir a l Oppor t u n ist ic
a n d H a em oph ilu s in flu en za e (in a gen t s in clu din g en t er ovi- fu n gi
t h ose u n im m u n ized) r u ses, h er pesvir u ses, H IV
On set Ra pid (less t h a n 24 h ou r s) 1–7 da ys > 7 da ys
Sever it y of sym pt om s Sever e Mild t o m oder a t e Oft en m ild
P r edom in a n t cells Neu t r oph ils Lym ph ocyt es Lym ph ocyt es
Ch a n ges in in t r a cr a n ia l In cr ea sed Nor m a l or sligh t ly in cr ea sed Ma y be in cr ea sed
pr essu r e
CSF Gr a m st a in Posit ive ba ct er ia Nega t ive Nega t ive
Glu cose in CSF Decr ea sed Nor m a l Decr ea sed
Tr ea t m en t An t ibiot ics Sym pt om a t ic, su ppor t ive An t ifu n ga ls

CSF, cer ebr a l spin a l flu id.


h ea da ch e, ligh t sen sit ivit y (p h o t o p h o b ia ), a n d a
h yper ext en ded st iff n eck (n u c h a l r ig id it y ). Th e
in cr ea se in in t r a cr a n ia l pr essu r e (ICP ) fr om br a in
edem a a n d r esu lt a n t h ypoxia (low oxygen ) in t h e
br a in lea ds t o decr ea sed a ler t n ess, loss of con -
sciou sn ess, ch a n ges in m en t a l st a t u s, vom it in g, a n d
seizu r es. Syst em ic m a n ifest a t ion s in clu de fever, leu -
kocyt osis, a n d a n or exia .
DIAGNOSTIC CRITERIA
Th e dia gn osis of m en in git is is oft en m a de t h r ou gh
h ist or y a n d ph ysica l exa m in a t ion , blood cu lt u r es,
a n d CSF a n a lysis a n d cu lt u r es. Men in gea l ir r it a -
t ion is r ela t ed t o t h e in flu x of ch em ica l m edia t or s,
in fla m m a t or y cells, a n d exu da t e in t o t h e CSF a n d
m en in gea l t issu es. Ker n ig a n d Br u dzin ski sign s a r e
t wo com m on ph ysica l exa m in a t ion t est s per for m ed
t o det er m in e t h e pr esen ce of m en in gea l ir r it a -
t ion (F ig. 5.19). To elicit m en in gea l pa in u sin g t h e
Ke r n ig s ig n , t h e pa t ien t is pla ced su pin e wit h t h e
kn ees ben t a n d h ips flexed. Th e pr a ct it ion er lift s a n d
ext en ds on e kn ee u pwa r d. Th e Ker n ig sign is con -
sider ed posit ive if m ovin g t h e leg u pwa r d st r et ch es
t h e ir r it a t ed m en in ges a n d elicit s pa in . Sim ila r ly,
wit h t h e B r u d zin s k i s ig n , t h e pa t ien t is su pin e.
Th e pr a ct it ion er qu ickly flexes t h e n eck t o t h e ch est .
Aga in , t h is a ct ivit y st r et ch es t h e ir r it a t ed m en in ges
a t t h e n eck. A posit ive Br u dzin ski sign occu r s wh en
t h e pa t ien t pr ot ect s t h e ir r it a t ed m en in ges by in vol-
u n t a r ily flexin g t h e h ips a n d kn ees.
TREATMENT
Tr ea t m en t in volves in t r a ven ou s a n t ibiot ics, cor t i-
cost er oids, flu ids, a n d ot h er m et h ods t o decr ea se
in fla m m a t ion , m a in t a in a dequ a t e blood pr essu r e,
a n d m a in t a in vit a l or ga n per fu sion . Tr ea t m en t
sh ou ld be st a r t ed ea r ly in t h e disea se t o a void
Pa in
A Brudzins ki's S ign
Figure 5.19. Signs of meningeal irritation include nuchal rigidity and positive Brudzinski and Kernig signs. A: Flexion of
hips, knees, and ankles with neck flexion indicates meningeal irritation. B: Extension of the upper leg places a stretch
on the meninges and causes pain. (From Nettina SM. Lippincott Manual of Nursing Practice. 9th edition. Philadelphia, PA:
Wolters Kluwer Health; 2010.)
C lin ic a l Mo d e ls 129
sept icem ia a n d sept ic sh ock . Th e m or t a lit y r a t e is
50% t o 90% for pa t ien t s wh o a r e n ot dia gn osed u n -
t il a ft er t h e on set of sever e n eu r ologic im pa ir m en t .
Appr opr ia t e a n t ibiot ic t r ea t m en t of m ost com m on
t ypes of ba ct er ia l m en in git is sh ou ld r edu ce t h e
r isk of dyin g fr om m en in git is t o below 15%. H ow-
ever, even wit h ea r ly r ecogn it ion a n d t r ea t m en t ,
t h e m or t a lit y r isk is h igh er a m on g t h e elder ly.
Tr ea t m en t is a lso in dica t ed for close h ou seh old
con t a ct s wh o m a y h a ve been exposed t o N. m en -
in gitid is. H ospit a liza t ion m a y r equ ir e r espir a t or y
isola t ion u n t il t h e pa t ien t h a s been on a n t ibiot ics
for a t lea st 24 h ou r s t o pr even t ba ct er ia l spr ea d t o
ot h er pa t ien t s.
Im m u n iza t ion is a n im por t a n t st ep in pr even t in g
ba ct er ia l m en in git is in a ll popu la t ion s. Va ccin a t ion
for H . in flu en za e a n d m en in gococca l disea se is pa r t
of t h e r ecom m en ded va ccin e sch edu le for ch ildr en
a n d a dolescen t s. College st u den t s a r e a t pa r t icu la r
r isk beca u se of close livin g qu a r t er s, a n d sh ou ld be
a ppr opr ia t ely va ccin a t ed.
Tinea
Tin ea is a gr ou p of fu n ga l skin disea ses t h a t occu r
in va r iou s loca t ion s, in clu din g t h e feet (t in ea pedis),
n a ils (t in ea u n gu iu m ), sca lp (t in ea ca pit is), gr oin
(t in ea cr u r is), a n d skin (t in ea cor por is a n d t in ea ver-
sicolor ). F u n ga l in fect ion s of t h e skin , h a ir, a n d n a ils
a r e a lso ca lled d e r m a t o p h y t e in fect ion s a n d a r e
con sider ed m in or bu t ext r em ely com m on .
PATHOPHYSIOLOGY
Th e m a jor m ode of t r a n sm ission is dir ect con t a ct
wit h a n ot h er per son or su r fa ce r eser voir. Risk fa c-
t or s for t h e developm en t of der m a t oph yt e in fect ion s
Pa in
B Ke rnig's S ign
130 C h a p t e r 5: In fect ion

P r even t ion m ea su r es a r e
F R O M T H E L AB a lso cr it ica l t o a void r e-
cu r r en ce of in fect ion s.
The CSF in bacterial meningitis has a high concentration of neutrophils and protein related P r a ct icin g pr oper h ygien e
to the inflammatory response. The CSF has a low concentration of glucose related to energy a n d a voidin g con t a ct wit h
needs and utilization by leukocytes and the bacterial cells. ot h er s wh o h a ve su spi-
ciou s lesion s ca n det er
in clu de exposu r e t o m oist con dit ion s, gen et ic pr e- in fect ion .
disposit ion , im m u n ocom pr om ise, a n d sh a r in g of
h ygien e fa cilit ies (su ch a s pu blic sh ower s) wit h in -
fect ed per son s. Th e der m a t oph yt e a t t a ch es t o a n d Malaria
pr odu ces t h icken in g of ker a t in ized cells. Th e in fec-
t ion oft en r em a in s loca lized. Com plica t ion s in clu de Ma la r ia is a pot en t ia lly life-t h r ea t en in g disea se
ba ct er ia l su per in fect ion or gen er a lized in va sive der- ca u sed by in fect ion wit h P la sm od iu m pr ot ozoa t r a n s-
m a t oph yt e in fect ion . m it t ed by m osqu it o. Ma la r ia is cu r r en t ly er a dica t ed
in t h e Un it ed St a t es a n d a lm ost a ll ca ses in t h e US
occu r in pa t ien t s wh o h a ve r ecen t ly t r aveled t o t h e
CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s va r y depen din g on t h e loca -
t ion of in fect ion . All for m s r esu lt in ch a n ges in t h e
skin , h a ir, or n a ils. Tin ea cor por is is kn own a s “r in g-
wor m ” beca u se t h e in fect ion spr ea ds cir cu m fer en -
t ia lly like a n er yt h em a t ou s bu ll’s eye (Fig. 5.20A).
Tin ea ver sicolor pr esen t s a s pa t ch es of h ypopig-
m en t a t ion on t h e skin of t h e t r u n k a n d ext r em it ies.
Tin ea ca pit is r esu lt s in h a ir loss or br ea ka ge a t t h e
sit e of in fect ion . Tin ea pedis is n ot a ble for sca lin g,
fissu r in g, a n d m a cer a t ion , m ost oft en bet ween or
a r ou n d t h e t oes. Tin ea cr u r is (“jock it ch ”) is ch a r a c-
t er ized by er yt h em a t ou s lesion s t h a t h a ve cen t r a l
clea r in g a n d r a ised bor der s. Tin ea u n gu iu m a ffect s
t h e n a ils a n d lea ds t o t h icken ed, discolor ed (wh it e,
yellow, br own , or bla ck), dyst r oph ic ch a n ges a n d n a il
pla t e sepa r a t ion fr om t h e n a il bed (F ig. 5.20B). Most
for m s of t in ea ca n a lso ca u se pr u r it u s (it ch in g). A

DIAGNOSTIC CRITERIA
The dia gnosis of tinea is ba sed on physica l exa m-
ina tion a nd la bor a tory st udies, including direct mi-
croscopic exa m ina tion of infect ed skin, na il, or hair,
funga l cult ures, a nd wood light exa mina t ion. Hypha e
on skin or na ils a nd spores within or a round the ha ir
sha ft ca n be detect ed with m icroscopic exa m ina tion.
Wood light is a pr ocedur e of moving a por ta ble ultr avi-
olet ligh t over the site of infect ion a nd noting a br ight
yellow-gr een or dull green fluor escence (i.e., glowing).
This procedure is used prima r ily for t inea ca pit is.

TREATMENT
F u n ga l in fect ion s a r e t r ea t ed wit h t opica l or or a l
a n t ifu n ga l a gen t s. Tr ea t m en t wit h t opica l t h er a py
for der m a t oph yt e in fect ion s of t h e skin com m on ly
ext en ds fr om 2 t o 8 weeks. Topica l t h er a py is in ef-
fect ive for t r ea t in g t in ea in t h e h a ir a n d n a ils. Th ese
t ypes r equ ir e pr olon ged or a l a n t ifu n ga l t h er a py.
B
Figure 5.20. Tinea. A: Tinea corporis (ringworm).
(Image provided by Stedman’s.) B: Tinea unguium.
(From Goodheart HP. Goodheart’s Photoguide of Com-
mon Skin Disorders. 2nd ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2003, with permission.)

US fr om m a la r ia -en dem ic a r ea s. Wor ldwide, h ow-
ever, m a la r ia ca u ses over a m illion dea t h s per yea r,
oft en a ffect in g ch ildr en fr om su b-Sa h a r a n Afr ica .
P la sm od iu m fa lcipa r u m is t h e m ost let h a l species
a n d is r espon sible for 95% of t h ese dea t h s.4
PATHOPHYSIOLOGY
Ma la r ia l in fect ion is t ypica lly a cqu ir ed in a n en -
dem ic a r ea followin g a m osqu it o bit e. Th e An oph eles
species of m osqu it o t r a n sm it s pla sm odia , con t a in ed
in it s sa liva , in t o t h e h ost . P la sm odia en t er cir cu -
la t in g r ed blood cells a n d feed on h em oglobin a n d
ot h er pr ot ein s wit h in t h e cells. Th e in cu ba t ion pe-
r iod va r ies depen din g on t h e P la sm od iu m species,
bu t in fect ion t ypica lly develops wit h in a m on t h of
exposu r e. In dividu a ls wit h su fficien t im m u n it y ca n
spon t a n eou sly clea r t h e pa r a sit es a n d r equ ir e n o
t r ea t m en t . In m a n y ca ses, h owever, t h e pa r a sit es
eva de t h e im m u n e r espon se a n d ca u se in fect ion .
CLINICAL MANIFESTATIONS
A h igh in dex of su spicion is wa r r a n t ed if a pa t ien t
h a s r ecen t ly t r a veled t o a t r opica l a r ea a n d pr esen t s
wit h t h e t ypica l m a la r ia sym pt om s a few weeks a f-
t er t h e in fect ion . Clin ica l m a n ifest a t ion s in clu de:
● H ea da ch e
● Sh iver in g a n d ch ills
● H igh fever
● E xcessive swea t in g
● Cou gh
● Fa t igu e
● Ma la ise
● J oin t /m u scle a ch in g
DIAGNOSTIC CRITERIA
Th e dia gn osis of m a la r ia is m a de t h r ou gh h ist or y
of t r a vel t o a n en dem ic a r ea , ph ysica l exa m in a t ion ,
a n d la bor a t or y t est in g. Given t h e pa t h oph ysiol-
ogy of m a la r ia , wh ich a t t a cks pr ot ein s in r ed blood
cells, h em oglobin levels a r e oft en low, a s a r e pla t elet
cou n t s, a n d liver fu n ct ion t est s a r e a bn or m a l. A cla s-
sica l t r ia d of t h r om bocyt open ia , eleva t ed la ct a t e
deh ydr ogen a se (LDH ), a liver en zym e, a n d a t ypica l
lym ph ocyt es is a com m on pr esen t a t ion . Per iph er a l
blood sm ea r s will sh ow r ed blood cells in fect ed wit h
t h e m a la r ia pa r a sit e (Fig. 5.21).
TREATMENT
Th e best t r ea t m en t is pr even t ion . Th is occu r s by lim -
it in g exposu r e t o in fect ive m osqu it oes, pa r t icu la r ly
a t da wn a n d du sk, wh en feedin g is h igh est , u sin g a
bed n et du r in g sleep, wea r in g lon g-sleeve clot h in g,
C lin ic a l Mo d e ls 131
Figure 5.21. Peripheral blood smear shows several eryth-
rocytes parasitized by malaria (arrows).
a n d u sin g in sect r epella n t s wit h 35% or gr ea t er
DE E T con cen t r a t ion (for a du lt s); ch ildr en sh ou ld
u se con cen t r a t ion s of DE E T a t less t h a n 35%. Use
t h is pr odu ct spa r in gly on exposed skin a n d r em ove
wh en ou t of r a n ge of in fect ive m osqu it oes. An t im a -
la r ia l dr u gs ca n be pr escr ibed t o t h ose t r a velin g t o
a r ea s en dem ic t o m a la r ia .
An t im a la r ia l dr u gs fa ll in t o fou r m a jor dr u g
cla sses: qu in olin es, a n t ifola t es, a r t em isin in s, a n d a n -
t im icr obia ls. Mu lt iple dr u gs m u st be u sed a s n o sin -
gle dr u g h a s been sh own t o er a dica t e a ll for m s of t h e
pa r a sit e a t a ll st a ges of it s life cycle. A t ypica l dr u g
com bin a t ion u sed is ch lor oqu in e (qu in olin e) a n d
su lfa doxin e-pyr im et h a m in e (a n t ifola t e). An t ipyr et -
ics ca n be u sed t o r edu ce fever a n d pr om ot e com for t .
S U MMAR Y
● E xposu r e t o a m icr oor ga n ism elicit s t h e in fla m -
m a t or y a n d im m u n e r espon ses. In fect ion r esu lt s
fr om in a dequ a cies of t h e t h r ee lin es of defen se
a n d r epr esen t s a st a t e of t issu e dest r u ct ion r e-
su lt in g fr om in va sion by m icr oor ga n ism s.
● Th e ch a in of in fect ion is a u sefu l or ga n iza t ion for
r ecogn izin g t h e fa ct or s in h er en t in t h e t r a n sm is-
sion a n d spr ea d of com m u n ica ble disea se. Th e
lin ks in t h e ch a in in clu de t h e pa t h ogen , por t a l of
en t r y, r eser voir, por t a l of exit , m ode of t r a n sm is-
sion , a n d h ost . In fect ion con t r ol m ea su r es seek t o
br ea k on e or m or e of t h ese lin ks.
● Micr oor ga n ism s t h a t ca u se in fect ion a r e ca lled
pa t h ogen s. Th e pa t h ogen icit y, or qu a lit ies t h a t
pr om ot e t h e pr odu ct ion of disea se, in volves
m u lt iple fa ct or s, in clu din g t h e pa t h ogen ’s po-
t en cy, in va siven ess, a bilit y t o eva de t h e im m u n e
syst em , speed of r eplica t ion , pr odu ct ion of t oxin s,
132 C h a p t e r 5: In fect ion
a dh er en ce t o t h e h u m a n h ost cell, a n d degr ee of
t issu e da m a ge t h a t is elicit ed.
● Ba ct er ia , vir u ses, fu n gi, a n d pr ot ozoa a r e com m on
t ypes of pa t h ogen s. Un der st a n din g t h e dist in ct ive
qu a lit y of ea ch ca n pr ovide clu es t o t r a n sm ission
a n d spr ea d of ea ch pa t h ogen .
● Ma jor m odes of t r a n sm ission in clu de dir ect con -
t a ct , dr oplet , a ir bor n e, a n d vect or t r a n sm ission .
H a n d wa sh in g is a cr it ica l st ep in pr even t in g t h e
spr ea d of in fect ion by dir ect con t a ct . Un iver sa l
pr eca u t ion s a r e a st a n da r d of h ea lt h ca r e t h a t
r ecogn izes a ll blood a n d body flu ids a s pot en -
t ia lly in fect ed. Un iver sa l pr eca u t ion s dict a t e t h a t
h ea lt h ca r e pr ovider s wea r gloves wh en h a vin g
a n y con t a ct wit h blood a n d body flu ids. Ma sks
a n d pr ot ect ive eyewea r a r e a lso r ecom m en ded if
spla t t er in g of blood or body flu ids is a n t icipa t ed.
● P h a ses of a n a cu t e in fect ion in clu de exposu r e, in -
cu ba t ion , pr odr om e, clin ica l illn ess, a n d con va les-
cen ce. Clin ica l sym pt om s a r e dict a t ed by t h e cells
t h a t a r e da m a ged by t h e in va din g m icr oor ga n ism .
● Com plica t ion s of a cu t e in fect ion in clu de sept ice-
m ia a n d ch r on ic in fect ion wit h loss of fu n ct ion in
t h e a ffect ed t issu es.
C AS E S T U D Y 5.1
You a r e t h e pa r ent of a 6-m on t h -old child wh o is fu ssy
a n d is t uggin g on h er ea r s. You t a ke her t o t h e clinic
a n d a r e t old t h a t sh e h a s ot it is m edia , a m iddle ea r in -
fect ion . Fr om your r ea din g a n d exper ien ce r ega r din g
in fect ious pr ocesses, a n swer t h e followin g qu est ions:
1. Ou t lin e t h e pr ocess t h a t is m ost likely occu r r in g
in t h is ch ild’s body.
2. Wh a t a n a t om ic differ en ces in a ch ild wou ld pr e-
dispose t o t h is t ype of in fect ion ?
3. Wh a t a r e t h e pr oba ble sou r ces of t h is in fect ion ?
4. Wh a t wou ld you expect for loca l a n d syst em ic
clin ica l m a n ifest a t ion s?
5. Wh a t dia gn ost ic t est s cou ld be u sed? H ow cou ld
you differ en t ia t e bet ween vir a l or ba ct er ia l
pa t h ogen s?
6. Wh a t t r ea t m en t m ea su r es wou ld you a n t icipa t e?
7. Wh a t wou ld be t h e pot en t ia l com plica t ion s?
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r n a l
a r t icle or Web sit e t h a t det a ils ot it is m edia a n d con -
fir m you r pr edict ion s.
C AS E S T U D Y 5.2
J a m ie is a 48-yea r-old bla ck wom a n wh o com es in t o
t h e em er gen cy depa r t m en t com pla in in g of pa in fu l
swellin g, dr a in a ge, a n d r edn ess over t h e pa st 5 da ys
in t h e left h a n d. Sh e spen ds a lot of t im e ou t door s
wor kin g in h er ga r den a n d sa id sh e h a d a “pr et t y
n a st y” m osqu it o bit e on t h e t op of t h a t h a n d befor e
t h e swellin g st a r t ed. Aft er 3 da ys of in cr ea sed swell-
in g a n d r edn ess, sh e wen t t o h er doct or a n d r eceived
a n or a l a n t ibiot ic a n d wa s t old it wa s pr oba bly a
m ild in fect ion fr om t h e in sect bit e. Now, sh e pr esen t s
beca u se h er h a n d is in cr ea sin gly pa in fu l, t igh t , a n d
t h e dr a in a ge h a s wor sen ed. Sh e n ot iced t h a t sh e h a d
a fever t h is m or n in g of 102.9°F. La bor a t or y t est r e-
su lt s t oda y sh ow a WBC cou n t of 18,500. Aft er in t r a -
ven ou s a n t ibiot ic t r ea t m en t a n d h ospit a liza t ion , t h e
wou n d cu lt u r e is fou n d t o be posit ive for m et h icillin -
r esist a n t S. a u r eu s (MRSA). Fr om you r r ea din g a n d
exper ien ce r ega r din g in fect iou s pr ocesses, a n swer
t h e followin g qu est ion s:
1. Ou t lin e t h e pr ocess t h a t is m ost likely occu r r in g
in J a m ie’s body.
2. Wh a t is t h e pr oba ble sou r ce of t h is in fect ion ?
3. Wh a t wou ld you expect for loca l a n d syst em ic
clin ica l m a n ifest a t ion s?
4. Wh a t dia gn ost ic t est s wer e u sed or cou ld be u sed?
H ow cou ld you differ en t ia t e bet ween vir a l or ba c-
t er ia l pa t h ogen s?
5. Wh a t a ddit ion a l t r ea t m en t m ea su r es wou ld you
a n t icipa t e? H ow is MRSA t r ea t ed differ en t ly
t h a n n on r esist a n t pa t h ogen s?
6. Wh a t wou ld be t h e pot en t ia l com plica t ion s?
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r n a l
a r t icle or Web sit e t h a t det a ils MRSA a n d con fir m
you r pr edict ion s.
C AS E S T U D Y 5.3
Ka t h y is a 55-yea r-old Ca u ca sia n wom a n wh o lives
in n or t h er n Min n esot a . Ka t h y wa s ou t wa lkin g h er
dog in t h e woods a n d u pon r et u r n in g h om e fou n d
a deer t ick cr a wlin g on t h e ba ck of h er h a n d. La t er
t h a t week sh e n ot iced a r a sh on h er leg, for m in g t h e
sh a pe of a bu ll’s eye a r ou n d h er kn ee. Sh e exper i-
en ced a fever, h ea da ch e, a n d gen er a lized body a ch es.
Sh e wa s t est ed a n d fou n d posit ive for Lym e dis-
ea se. Lym e disea se is in fect ion wit h t h e spir och et e
Bor r elia bu r gd or fer i t r a n sm it t ed t h r ou gh a t ick bit e.
F r om you r r ea din g a n d exper ien ce r ega r din g in fec-
t iou s pr ocesses, a n swer t h e followin g qu est ion s:
1. Ou t lin e t h e pr ocess t h a t is m ost likely occu r r in g
in Ka t h y’s body.
2. Wh a t is t h e sou r ce of t h is in fect ion ?
3. Wh a t wou ld you expect for loca l a n d syst em ic
clin ica l m a n ifest a t ion s?
4. Wh a t dia gn ost ic t est s wer e u sed or cou ld be u sed?
5. Wh a t a ddit ion a l t r ea t m en t m ea su r es wou ld you
a n t icipa t e?
6. Wh a t wou ld be t h e pot en t ia l com plica t ion s?

Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r-
n a l a r t icle or Web sit e t h a t det a ils Lym e disea se a n d
con fir m you r pr edict ion s.
P R AC T I C E E XAM Q U E S T I O N S
1. You a r e lookin g t o br ea k t h e ch a in of in fect ion by
wa sh in g you r h a n ds fr equ en t ly a s you pr ovide
ca r e for pa t ien t s. Wh ich of t h e followin g lin ks in
t h e ch a in will be br oken by t h is a ct ivit y?
a . Reser voir
b. H ost
c. Por t a l of en t r y
d. Mode of t r a n sm ission
2. Wh ich of t h e followin g m a y m a ke a per son m or e
su scept ible t o get t in g a n in fect ion ?
a . Age bet ween 6 a n d 46 yea r s
b. E xper ien cin g a su r ger y t h a t is h ea lin g by pr i-
m a r y in t en t ion
c. F in a l exa m s week
d. A fu n ct ion in g im m u n e syst em
3. Th e feelin g t h a t “som et h in g is n ot qu it e r igh t ” is
con sider ed wh ich st a ge in in fect ion ?
a . Poin t of in fect ion wit h pa t h ogen
b. In cu ba t ion
c. P r odr om e
d. Acu t e sym pt om s
4. Wh ich of t h e followin g clin ica l m a n ifest a t ion s
is n ot t ypica lly fou n d wit h in fla m m a t ion bu t is
m or e ch a r a ct er ist ic of a ba ct er ia l in fect ion ?
a . P u r u len t exu da t e
b. Redn ess a n d swellin g a t t h e sit e
c. Lym ph a den opa t h y
d. Fever
5. A wh it e blood cell differ en t ia l sh ows a n in cr ea se
in t h e n u m ber of m on ocyt es a n d m a cr oph a ges in
t h e blood. Th is t ypica lly m ea n s t h a t :
a . Th is is a n ew in fect ion
b. Th is is a ch r on ic in fect ion
c. Th is is a vir a l in fect ion
d. Th e differ en t ia l pr ovides n o u sefu l in for m a t ion
6. Given t h e m ode of t r a n sm ission for in flu en za ,
h ow wou ld you br ea k t h e ch a in of in fect ion a n d
pr even t spr ea d?
a . Adm in ist er a n t ibiot ics a s dir ect ed
b. Wa sh h a n ds a ft er t oilet in g
c. Disin fect t a ble su r fa ces in t h e r oom
d. Wea r a m a sk
C h a p t e r 5: In fect ion 133
7. Wh ich of t h e followin g dia gn ost ic t est s wou ld
give in for m a t ion t o t h e pr esen ce of a ca r r ier-st a t e
a sym pt om a t ic h epa t it is B in fect ion ?
a . H epa t it is B su r fa ce a n t igen (H BsAg)
b. H epa t it is B cor e a n t igen (H BcAg)
c. P r ot h r om bin t im e (P TT)
d. Th er e is n o wa y t o dist in gu ish t h e differ en t
for m s of h epa t it is B
8. Wh a t is t h e m ost likely com plica t ion of a n u n -
t r ea t ed UTI?
a . Glom er u lon eph r it is
b. P yelon eph r it is
c. F u lm in a n t UTI
d. Ur et h r it is
9. Tr ea t m en t for t in ea u n gu iu m m u st in clu de:
a . Or a l a n t ifu n ga ls
b. Topica l a n t ifu n ga ls
c. Bot h t opica l a n d or a l a n t ifu n ga ls
d. Na il r em ova l a n d t opica l a n t ifu n ga ls
10. Wh ich of t h e followin g scen a r ios is m ost
lik ely in t h e CSF of a pa t ien t wit h ba ct er ia l
m en in git is?
a . CSF h a s h igh n eu t r oph il cou n t a n d h igh pr o-
t ein cou n t .
b. CSF h a s h igh n eu t r oph il cou n t a n d low pr o-
t ein cou n t .
c. CSF h a s h igh glu cose level a n d h igh r ed blood
cell cou n t .
d. CSF h a s h igh lym ph ocyt e cou n t a n d low r ed
blood cell cou n t .
11. Wh ich of t h e followin g is a n im por t a n t ch a r-
a ct er ist ic of M. tu ber cu losis (t h e m icr obe
t h a t ca u ses TB) a n d h elps t o expla in it s
pa t h ogen esis?
a . It is a la r ge a n d fa st -gr owin g m icr obe.
b. It pr odu ces t oxin s a n d t h ese t oxin s dest r oy
lu n g t issu e.
c. It is r esist a n t t o dest r u ct ion a n d ca n sit dor-
m a n t for yea r s.
d. It ca n n ot be det ect ed or dia gn osed u n t il t h e
disea se is well a dva n ced.
12. An im por t a n t a spect of in fect ion is pr even t ion .
Wh ich of t h e followin g wou ld be a n effect ive pr e-
ven t ion m ea su r e for m a la r ia ?
a . An t ibiot ics
b. Avoidin g in t er n a t ion a l t r a vel
c. H a n dwa sh in g
d. Wea r in g lon g sleeves a n d pa n t s
134 C h a p t e r 5: In fect ion
13. In fect ion s ca u se a loca l in fla m m a t or y r espon se
a t t h e sit e of in fect ion , wh ich lea ds t o spe-
cific clin ica l m a n ifest a t ion s. In t h e ca se of py-
elon eph r it is, wh a t wou ld be a likely clin ica l
m a n ifest a t ion ?
a . Dysu r ia
b. H yper glycem ia
c. Ta ch yca r dia
d. P r u r it is
14. Th e pa t ien t is dia gn osed wit h in flu en za . Wh ich
of t h e followin g best descr ibes t h e r ou t e of t r a n s-
m ission for t h is disea se?
a . Air bor n e
b. Respir a t or y dr oplet s
c. Dir ect con t a ct
d. Feca l–or a l
D I S C U S S I O N AN D
AP P L I C AT I O N
1. Wh a t did I kn ow a bou t in fect ion pr ior t o t oda y?
2. Wh a t body pr ocesses a r e a ffect ed by in fec-
t ion ? Wh a t a r e t h e expect ed fu n ct ion s of t h ose
pr ocesses? H ow does in fect ion a ffect t h ose
pr ocesses?
3. Wh a t a r e t h e pot en t ia l et iologies for in fect ion ?
H ow does in fect ion develop?
4. Wh o is m ost a t r isk for developin g a n in fect ion ?
H ow ca n in fect ion be pr even t ed?
5. Wh a t a r e t h e h u m a n differ en ces t h a t a ffect t h e
et iology, r isk, or cou r se of in fect ion ?
6. Wh a t clin ica l m a n ifest a t ion s a r e expect ed in t h e
cou r se of in fect ion ?
7. Wh a t specia l dia gn ost ic t est s a r e u sefu l in de-
t er m in in g t h e dia gn osis a n d cou r se of in fect ion ?
8. Wh a t a r e t h e goa ls of ca r e for in dividu a ls wit h
in fect ion ?
F in d a d d ition a l r esou r ces for th is ch a pter a t h ttp:th ePoin t.lww.com
9. H ow does t h e con cept of in fect ion bu ild on wh a t
I h a ve lea r n ed in t h e pr eviou s ch a pt er s a n d in
pr eviou s cou r ses?
10. H ow ca n I u se wh a t I h a ve lea r n ed?
R E SOUR CE S
The Wor ld H ea lt h Or ga niza t ion (WH O) pr ovides va lu -
a ble in for m a t ion a bout t h e globa l infect ious disea se
t h r ea t . The or ga n iza t ion Web sit e ca n be a ccessed a t :
h t t p://www.wh o.in t /
An excellen t r eview of t h e WH O St r a t egy for
Con t a in m en t of An t im icr obia l Resist a n ce ca n be
fou n d a t :
www.wh o.in t /dr u gr esist a n ce/en /
Th e Cen t er s for Disea se Con t r ol a n d P r even t ion
(CDC) pr ovides a wea lt h of in for m a t ion on in fect iou s
disea se pr even t ion a n d spr ea d. Th e Web sit e ca n be
a ccessed a t :
h t t p://www.cdc.gov/
Th e Na t ion a l In st it u t e of H ea lt h pr ovides r esea r ch -
ba sed in for m a t ion r ela t ed t o a ller gy a n d in fect iou s
disea se a t :
h t t p://www.n ia id.n ih .gov
R e er en ces
1. Cen t er s for Disea se Con t r ol a n d P r even t ion . P r ion dis-
ea ses. 2015. h t t p://www.cdc.gov/pr ion s/
2. Cen t er s for Disea se Con t r ol a n d P r even t ion . Va ccin es
a n d pr even t a ble disea ses. 2015. h t t p://www.cdc.gov/
va ccin es/vpd-va c/defa u lt .h t m
3. Cen t er s for Disea se Con t r ol a n d P r even t ion . Globa l
t u ber cu losis (TB). 2014. h t t p://www.cdc.gov/t b/t opic/
globa lt b/defa u lt .h t m
4. Per ez-J or ge E . Ma la r ia . 2014. h t t p://em edicin e.m edsca pe
.com /a r t icle/221134-over view
 Gen et ic a n d Ch a pt er

Developm en t a l
Disor der s 6
L E AR N I N G O U T C O ME S
1. Defin e a n d u se t h e key t er m s list ed in t h is ch a pt er.
2. Iden t ify t h e im plica t ion s of a lt er a t ion in t h e st r u ct u r e a n d fu n ct ion of
gen es a n d ch r om osom es.
3. Descr ibe in h er it a n ce pa t t er n s in sin gle gen e disor der s a n d ch r om osom a l
disor der s.
4. Com pa r e a n d con t r a st t h e in h er it a n ce pa t t er n s of m u lt ifa ct or ia l a n d
a lt er ed ch r om osom a l disor der s.
5. Discu ss t h e in flu en ce of gen e–en vir on m en t in t er a ct ion s on developm en t a l
disor der s a n d fu t u r e developm en t of disea se.
6. An a lyze t h e biologic, socia l, a n d et h ica l im plica t ion s of gen et ic scr een in g.
7. Apply con cept s of a lt er a t ion s in gen et ics a n d developm en t t o clin ica l
m odels.

INTR ODUCTION
H ow do you feel t oda y? H ow will you feel a week fr om n ow? H ow a bou t a m on t h
or yea r fr om t oda y? Alt h ou gh you pr oba bly do n ot t h in k t h a t fa r a h ea d, t h e
st or y of you r fu t u r e h ea lt h a n d r isk of disea se ca n be t old by you r gen et ic
m a keu p. Th e st u dy of gen et ics is t h e st u dy of h e r e d it y , t h e pa ssa ge of ch a r a c-
t er ist ics fr om pa r en t t o offspr in g. You r st or y is bu t on e ch a pt er in you r fa m ily’s
book of h er edit y. You r h ea lt h h a s been in flu en ced by t h e gen et ic con t r ibu t ion s
of you r pa r en t s a n d t h e con t r ibu t ion s fr om a ll of t h e gen er a t ion s befor e t h em .
You r gen es will con t r ibu t e t o fu t u r e ch a pt er s wh en pa ssed on t o you r ch ildr en .
Th e r oa dm a p of you r life’s jou r n ey t owa r d h ea lt h is design ed by t h e gen es t h a t
m a ke you wh o you a r e. You r gen et ic m a keu p ca n som et im es lea d dir ect ly t o
disea se or ca n ju st poin t you in t h a t dir ect ion , wh ich ca n be ch a n ged by ot h er
t h in gs t h a t you en cou n t er a lon g t h e wa y. An u n der st a n din g of t h e gen et ic in -
flu en ces of h ea lt h a n d disea se pr ovides t h e ba sis for t h e a pplica t ion of t h ese
con cept s t o t h e pr om ot ion of h ea lt h a n d t h e pr even t ion of disea se.
Th e a dva n cem en t of kn owledge in t h e gen et ic ba sis for disea se is r a pid, r e-
vea lin g n ew a ppr oa ch es t o disea se t r ea t m en t a n d pr even t ion . Th e P r ecision
Medicin e In it ia t ive is a n ew a ppr oa ch , wh ich t a kes in t o a ccou n t ea ch in divid-
u a l’s gen et ics, en vir on m en t , a n d lifest yle in det er m in a t ion of disea se r isk a n d
per son a lized t r ea t m en t (Fig. 6.1). Th e P r ecision Medicin e In it ia t ive in clu des
volu n t a r y con t r ibu t ion of h ea lt h in for m a t ion by in dividu a ls, in clu din g h ea lt h
h ist or y a n d gen om ic da t a , for m in g a la r ge r eposit or y of h ea lt h da t a t h a t will
lea d t o n ew wa ys t o pr even t a n d t r ea t disea se. Th e h ea lt h a n d gen om ic da t a
will be m a de a va ila ble t o t h e in dividu a ls pr ovidin g t h e da t a , pr ovidin g con t r ol
135
136 C h a p t e r 6: Gen et ic a n d Developm en t a l Disor der s
Modu le 1 R e v ie w o G e n e t ic P r o c e s s e s
Ch a pt er 2 in t r odu ced t h e ba sic com pon en t s of t h e
gen et ic syst em in t h e discu ssion of cellu la r st r u c-
t u r e. Th is ch a pt er expa n ds on t h e gen et ic com po-
n en t s of t h e cell a n d in t r odu ces ot h er in flu en ces t h a t
a r e im por t a n t in gen et ic r egu la t ion of h ea lt h a n d
disea se. Th e n u cleu s h ou ses t h e gen et ic com pon en t s
essen t ia l t o life pr ocesses. Th e or ga n iza t ion of t h ese
com pon en t s will be pr esen t ed in a n or der ed fa sh ion
t o pr ovide a n over view of bot h st r u ct u r e a n d fu n c-
t ion . Th e pr ocesses of t r a n scr ipt ion a n d t r a n sla t ion
of gen es a n d t h e r eplica t ion of ch r om osom es will be
h igh ligh t ed a s t h e ba sis for im pr oved a pplica t ion t o
gen et ic a n d developm en t a l a lt er a t ion s discu ssed in
t h e m odu les t h a t follow t h is r eview.
Deoxyribonucleic Acid
D e o x y r ib o n u c le ic a c id (D N A) is a t ype of n u -
cleic a cid t h a t con t a in s a su ga r (deoxyr ibose), a n d
it is u su a lly fou n d in t h e cell n u cleu s a n d m it och on -
dr ia . DNA is r espon sible for t h e st or a ge of gen et ic
over t h eir own in for m a t ion . Da t a will a lso be a va il-
a ble t o r esea r ch er s in deiden t ified a ggr ega t e for m .
Th is com plex in it ia t ive lever a ges h ea lt h in for m a t ion
t ech n ology a n d t h e r a pidly evolvin g m et h ods n eeded
t o a n a lyze la r ge a m ou n t s of h ea lt h da t a t h a t ca n be
u sed t o for ge n ew a ppr oa ch es t o pr ecise ca r e, fr om
popu la t ion s t o in dividu a ls.
Stop and Consider
What are the potential risks to security and
privacy posed by provision of health and genomic
data?
Figure 6.1. Precision Medicine Initiative. The Precision
Medicine Initiative is a National Institutes of Health-
supported approach to advancing novel methods to pre-
vent and treat genomic-based disease in individuals.
in for m a t ion . It is m a de u p of fou r n it r ogen ou s ba ses,
in clu din g t h e p u r in e s , a den in e (A) a n d gu a n in e (G),
a n d t h e p y r im id in e s , cyt osin e (C) a n d t h ym in e (T).
DNA is u su a lly dou ble-st r a n ded, wit h t wo sin gle
st r a n ds lin ked by t h e pu r in e/pyr im idin e com bin a -
t ion s of A–T a n d C–G, a lso kn own a s b a s e p a ir s .
Th ese lin ked com bin a t ion s br in g t h e t wo sin gle
st r a n ds t oget h er in a dou ble h elix st r u ct u r e, con -
n ect ed by h ydr ogen bon ds. Th ese pr odu ct s com bin e
in specific wa ys, for m in g gen es a n d ch r om osom es.
Genes
Gen es a r e sm a ll fu n ct ion a l h er edit a r y u n it s loca t ed
on a specific sit e of a ch r om osom e. Ma de u p of pieces
of DNA, m ost gen es con t a in t h e in for m a t ion , or
g e n e t ic c o d e , for m a kin g a specific pr ot ein . Gen es
va r y in size, a n d a ssocia t ed DNA n it r ogen ou s ba se
pa ir s t ot a l a n ywh er e bet ween sever a l h u n dr eds a n d
on e m illion . Gen es occu r in pa ir s in som a t ic (body)
cells a n d sin gly in ga m et es su ch a s ova a n d sper m ,
 R e v ie w o G e n e t ic P r o c e s s e s 137

com plem ent a r y st r a n d of DNA

Ta b le 6.1 Am in o Acids a n d Th eir Gen et ic Codes (cDNA). Thr ough t he pr ocess
of a lt e r n a t iv e s p lic in g , cer-
Am in o Ac id Sym b ol Cod on s
t a in pieces of t he RNA ca lled
Ala n in e Ala GCA, GCC, GCG, GCU e xo n s a r e r et a ined, a nd ot her
Cyst ein e Cys UGC, UGU segm en ts, in t r on s , a r e excised.
Aspa r t ic a cid Asp GAC, GAU The genet ic code dir ect s t he spe-
Glu t a m ic a cid Glu GAA, GAG
cific splice loca t ion, a llowing for
a la r ge va r iet y of m RNA m ol-
P h en yla la n in e Phe UUC, UUU
ecules t o be t r a nscr ibed fr om
Glycin e Gly GGA, GGC, GGG, GGU
a single gene. Tr a n s e r R N A
H ist idin e H is CAC, CAU (t R N A) deliver s t hese product s
Isoleu cin e Ile AUA, AUC, AUU for pr ot ein pr odu ct ion (Fig. 6.3).
Lysin e Lys AAA, AAG E a ch t RNA r ecognizes a nd binds
Leu cin e Leu UUA, UUG, CUA, CUC, CUG, CUU a specific a min o a cid, which
Met h ion in e Met AUG it th en tr a n sfer s t o or ga nelles
Aspa r a gin e Asn AAC, AAU ca lled r ibosom es. Ribosom es
P r olin e Pro CCA, CCC, CCG, CCU a r e for m ed by a com bina t ion of
r ib os om a l R N A (r R NA) pr o-
Glu t a m in e Gln CAA, CAG
duced in t he nu cleolus a nd nu -
Ar gin in e Ar g AGA, AGG, CGA, CGC, CGG, CGU
clea r r ibosom a l pr ot eins. These
Ser in e Ser AGC, AGU, UCA, UCC, UCG, UCU
r ibosom es a r e t r a nspor ted fr om
Th r eon in e Th r ACA, ACC, ACG, ACU t he nucleus t o t he cytopla sm
Va lin e Va l GUA, GUC, GUG, GUU wher e m a ny a t ta ch t o t he en-
Tr ypt oph a n Tr p UGG dopla sm ic r et icu lum , a ssocia t e
Tyr osin e Tyr UAC, UAU wit h m RNA, a nd begin pr ot ein
synt hesis, a lso known a s t r a n s -
la t ion of t he genet ic code.
con sist en t wit h t h e ch r om osom e m a keu p of t h ose Th e pr ocess of m a kin g a pr ot ein fr om a gen e is
sa m e cell t ypes. h igh ly com plex a n d som et im es difficu lt t o u n der-
Th e fou r n it r ogen ou s ba ses (a den in e, gu a n in e, st a n d. On e wa y t o t h in k of t h is pr ocess in a m or e
cyt osin e, a n d t h ym in e) t h a t a r e t h e fou n da t ion s for sim plified wa y is t o con sider t h e ba sic st eps of t r a n -
DNA ba se pa ir s a r e a lso im por t a n t in t h e for m a t ion scr ibin g a n d t r a n sla t in g a gen e wit h som et h in g m or e
of t h e gen et ic code. Th e sequ en ce of t h r ee of t h ese fa m ilia r, like r ea din g. Th e n u cleu s is like t h e libr a r y.
ba ses for m s a c o d o n (n u cleot ide t r iplet ), a fu n da - It con t a in s t h e com plet e com plem en t of gen et ic
m en t a l t r iplet code n ecessa r y for pr ot ein syn t h esis. m a t er ia ls a s t h e libr a r y h a s a fu ll r a n ge of books
Th e ba sic com pou n ds pr odu ced by t h ese codon s a r e n eeded t o sa t isfy a n y r ea der. Wit h in t h e n u cleu s a r e
a m in o a c id s . Twen t y differ en t t ypes of a m in o a cids t h e ch r om osom es t h a t con t a in gen es. Th e gen es a r e
com bin e t o for m t h e ba sis of h u m a n pr ot ein s, pr o- loca t ed a lon g specific a r ea s of ea ch n u m ber ed ch r o-
du ced by r ib o n u c le ic a c id (R N A) a s a r esu lt of m osom e. Th is is like t h e books a r r a n ged in t h e li-
r ea din g t h e gen et ic code. Redu n da n cy is bu ilt in t o br a r y by t h e Dewey Decim a l or Libr a r y of Con gr ess
t h is pr ocess, a llowin g pr odu ct ion of a sin gle a m in o Cla ssifica t ion Syst em s so t h a t wh a t is sou gh t ca n be
a cid fr om m or e t h a n on e com bin a t ion of t r iplet n i- ea sily fou n d. Wit h in ea ch sect ion of books a r e t h ose
t r ogen ou s ba ses in m ost ca ses (Ta ble 6.1). Th e ba se t h a t a r e a r r a n ged by t opic or su bject m a t t er. Th is
pa ir s in RNA a r e sim ila r t o t h ose descr ibed for DNA, is sim ila r t o t h e a r r a n gem en t of t h e or ga n iza t ion of
wit h t h e except ion t h a t T is su bst it u t ed by u r a cil (U) exon s a n d in t r on s a lon g gen es t h a t ser ve t o pr ovide
in t h e gen et ic code, r esu lt in g in pu r in e/pyr im idin e t h e code a n d r egu la t ion for t h e t r a n scr ipt ion of t h e
com bin a t ion s of A–U a n d C–G (F ig. 6.2). RNA de- DNA n u cleot ide ba ses. Th e m RNA r ea ds t h e ser ies
liver s DNA’s gen et ic m essa ge t o t h e cyt opla sm of a of DNA n u cleot ide ba ses a n d tr a n scr ibes t h em in t o
cell wh er e pr ot ein s a r e m a de. Th e pr ocess of pr ot ein com plem en t a r y RNA n u cleot ide ba ses, a pr ocess
pr odu ct ion by gen es is com plex. A br ief over view is sim ila r t o iden t ifyin g t h e let t er s in a wor d. E a ch let -
pr esen t ed in Figu r e 6.3 t o h elp a pply t h is in for m a - t er is t a ken so t h a t pieces of wor ds or sylla bles a r e
t ion t o h ea lt h a n d disea se. for m ed, like t h e pr ocess of sou n din g ou t ea ch pa r t of
Thr ee t ypes of RNA a r e involved in t he pr ocess a wor d in t h e pr ocess of r ea din g. Th is pr ocess is sim i-
of pr ot ein pr odu ct ion. Me s s e n ge r R N A (m R NA) la r t o t a kin g t h e t r a n scr ibed m RNA n u cleot ide ba ses
pr ovides a t em pla t e for pr ot ein synt hesis depen- a n d tr a n sla tin g t h em in t o t h e n u cleot ide t r iplet , or
dent on a codon sequen ce t ha t is ba sed on t ha t of t he codon . Th e n u cleot ide ba ses t h a t m a ke u p ea ch codon
138 C h a p t e r 6: Gen et ic a n d Developm en t a l Disor der s

Nitroge nous ba s e s

Cytos ine Cytos ine

NH2 NH2

H C H C
C N C N

C C C C
H N O H N O

H H

Gua nine Ba s e pa ir Gua nine

O O

N C H N C H
C N C N
H H H H
N C C H N C C H
N N N N
H H H H
S uga r
phos pha te
Ade nine ba ckbone Ade nine
NH2 NH2

N C N C
C N C N
H H H H
N C C N C C
N H N H
H H

Ura cil Thymine

O O

H C H H3 C C H
C N C N

C C C C
H N O H N O
Figure 6.2. Base pairs in RNA and DNA. Uracil is the H RNA DNA H
nitrogenous base in RNA, corresponding with the thy-
mine base in DNA. Note the single helix structure of Nitroge nous Ribonucle ic De oxyribonucle ic Nitroge nous
ba s e s a cid a cid ba s e s
RNA in contrast to the double helix structure of DNA.

a r e t r a n sla t ed by t h e t RNA, com plem en t in g t h ose
t r a n scr ibed by t h e m RNA. H er e, ea ch sylla ble com es
t oget h er t o m a ke a wor d. Specific t RNAs r ecogn ize
ea ch codon , bin din g t o t h e codon in t h e r ibosom e a n d
t r a n sfer r in g it t o t h e gr owin g ch a in of a m in o a cids,
t h e pr ocess con t in u in g u n t il t h e pr odu ct ion of t h e
in dividu a l pr ot ein is com plet e. Th e a m in o a cids com -
bin e in pa r t icu la r wa ys t o for m polypept ide ch a in s,
sim ila r t o h ow wor ds for m sen t en ces. F in a lly, poly-
pept ide ch a in s com bin e t o for m la r ge pr ot ein s of va r-
iou s sizes in a wa y t h a t sen t en ces com e t oget h er t o
for m pa r a gr a ph s, ch a pt er s, a n d wh ole books.
Chromosomes
C h r om os o m e s a r e com posed of double-st r a nded
DNA con t a in ing t h r ea dlike sect ion s of gen es, m ost
com m on ly fou n d in t he cell n ucleus (Fig. 6.4). Du r in g
cell division , ch r om osom es r epr odu ce t h eir ph ysica l
a n d ch em ica l st r u ct u r es, pa ssin g on gen et ic in for-
m a t ion . Th e pr ocess of cell division a n d cr ea t ion of
n ew cells a r e a r esu lt of t h e pr ocesses of m it osis a nd
m eiosis. In m it osis, t h e chr om osom es in t h e n u clei of
som a t ic cells go t h r ou gh a ser ies of pha ses (pr oph a se,
pr om et a ph a se, m et a ph a se, a na pha se, a n d t eloph a se),
r esult in g in t h e cr ea t ion of da u gh t er cells wit h t he
sa m e ch r om osom e n u m ber a n d gen et ic m a keu p a s
t h e or igina l som a t ic cell. Ch r om a t ids, one of t wo
st r a n ds n ewly for m ed du r in g t h e ea r ly pr ocess of
ch r om osom e du plica t ion , is join ed t oget her by a cen -
t r om er e. Th e som a t ic cells of t h e body ea ch con t a in
ch r om osom e pa ir s. Th e end of ea ch ch r om osom e is
com posed of DNA segm en t s kn own a s t elom er es.
DNA is woun d a r oun d spool-like pr ot ein cor es kn own
a s h ist on es. E a ch h u m a n som a t ic body cell con t a in s
23 pa ir s of ch r om osom es, or a t ot a l of 46, a lso kn own
a s t h e d ip lo id n um ber of ch r om osom es. Of t h e t ot a l
n u m ber of ch r om osom es, 44 a r e a u t o s o m e s (ch r om o-
som es ot h er t h a n a sex chr om osom e) a n d 2 a r e s e x
c h r o m o s o m e s . Th e t wo sex ch r om osom es, known a s
X a n d Y, a r e t h e gen et ic det er m in a n t s of t h e sex of a n
in dividua l. Fem a les possess t wo X ch r om osom es a n d
m a les one X a n d on e Y.
G a m e t e s (ova a n d sper m ) con t a in on ly on e of
t h e ch r om osom e pa ir s, k n own a s t h e h a p lo i d n u m -
ber of ch r om osom es. Ger m cells (ova a n d sper m )
a r e pr odu ced t h r ou gh a pr ocess k n own a s m eio-
sis. In m eiosis, on e cell pr odu ces fou r cells, ea ch
wit h h a lf t h e n u m ber of ch r om osom es, kn own a s
ga m et ocyt es. Wh en sper m divide, fou r sper m a t ids
r esu lt . Wh en ova divide, t h r ee pola r bodies a n d
on ly on e ovu m a r e pr odu ced. Th ese cell n u m ber s
r eflect t h eir r oles in r epr odu ct ion . Th e com bin a t ion
of ova a n d sper m gen et ic m a t er ia l a t t h e t im e of
con cept ion r esu lt s in a cell wit h t h e diploid n u m ber
of ch r om osom es. In t h is wa y, ea ch pa r en t con t r ib-
u t es on e ch r om osom e; t h er efor e, ch ildr en get h a lf
of t h eir ch r om osom es fr om t h eir m ot h er s a n d h a lf
fr om t h eir fa t h er s.
 R e v ie w o G e n e t ic P r o c e s s e s 139

DNA Exon
mRNA tra ns cription

Nucle us Intron

mRNA Ge ne

Exon Exo n cons titute the mRNA a nd

tra ns la tion into prote in
Tra ns port to
tRNA Intro n inte rve ning s e que nce
cytopla s m for
prote in s ynthe s is Tra ns cription Tra ns la tion
(tra ns la tion) DNA mRNA tRNA Amino Polype ptide
Acid cha in
A
C
G U A
mRNA C G C
C G Exon G ribos ome
C G
A
H T
G C
C G
R A
U A
Ce ll G
O
ME
C A U
me mbra ne T U A
Intron G C G
O A A U
S A C G
Figure 6.3. RNA in protein production. In the
O N
G A U
T
cell nucleus, the gene exon sequence is copied by G U A
M T G C
mRNA, forming a template of the DNA nucleotide E A A U
bases for transcription of the genetic code. The S E Exon C
T
C
U
G
A
mRNA sequence of the 3 bases comprising a codon G
A
U A
is translated to a specific amino acid. The codon is A
read in the ribosome, with the specific amino acid
transferred by tRNA to the growing chain of amino
acids leading to peptide and protein production.

Te lome re Chromos ome Chromosomal Replication

Nucle us
Chroma tid E a ch of t h e DNA st r a n ds of t h e dou ble h elix is im -
por t a n t in r eplica t ion of gen et ic in for m a t ion , bu t
Ce ll
Ce ntrome re on ly on e for m s t h e t em pla t e for t r a n s c r ip t io n , or
t h e t r a n sfer of t h e gen et ic code fr om on e t ype of
n u cleic a cid t o a n ot h er. Th e ot h er st r a n d ser ves a s
a com plem en t t o t h e st r a n d u sed in t r a n scr ipt ion .
Befor e cellu la r r epr odu ct ion , t h e t wo DNA st r a n ds
u n win d fr om t h e h elix, a n d ea ch for m s n ew st r a n ds
m a de u p of m a t ch in g ba se pa ir s n ext t o ea ch or igin a l
DNA
(double he lix) st r a n d. Th e r esu lt is fou r st r a n ds, dou bles of ea ch
of t h e t wo or igin a l st r a n ds (Fig. 6.5). Wh en t h e cell
divides by t h e pr ocess of m it osis, t h ese du plica t ed
m olecu les a r e sepa r a t ed a n d pla ced in a da u gh t er
His tone s Ba s e pa ir cell, ea ch wit h a dou ble st r a n d for m ed by t h e t r a n -
scr ipt ion st r a n d a n d it s com plem en t .

Stop and Consider

Figure 6.4. Nuclear chromosomes. Chromosomes are com-
prised of two chromatids joined by a centromere. Chromo-
somes contain compacted DNA with an individual’s unique
genetic information.
What would happen to protein synthesis if
the gene didn’t turn on? If one of the
nucleotide bases was substituted for another?
If one extra nucleotide base was added to
an exon?
140 C h a p t e r 6: Gen et ic a n d Developm en t a l Disor der s
Figure 6.5. Genetic replication. The DNA strands in the double helix
replicate to form two identical double helices to be placed in the
daughter cells when the cell divides.
Modu le 2 I n h e r it a n c e o G e n e t ic D is o r d e r s
Sin ce t h e 1850s, wh en Gr egor Men del bega n t h e fir st
wor k on t h e st u dy of gen et ics in h is exper im en t s wit h
ga r den pea s, m u ch h a s been lea r n ed a bou t h u m a n
gen et ics a n d t h e wa y t r a it s a r e pa ssed on fr om on e
gen er a t ion t o t h e n ext . Alt h ou gh n on e of t h e gen et ic
con cept s wa s kn own a t t h e t im e, Men del r ecogn ized
t h e pr esen ce of fa ct or s t h a t con t r olled t h e ph ys-
ica l fea t u r es of pla n t s. H e a lso r ea lized t h a t som e
of t h ese “fa ct or s” h a d m or e in flu en ce, or wer e m or e
dom in a n t , t h a n ot h er s. Men del det er m in ed la ws of
gen et ic t r a it s, descr ibed by t h e followin g ca t egor ies:
● Au t osom a l dom in a n t
● Au t osom a l r ecessive
● Sex-lin ked dom in a n t
● Sex-lin ked r ecessive
Th e discover y of t h e dou ble h elix st r u ct u r e of
DNA by Wa t son a n d Cr ick in 1953 wa s followed by
ot h er discover ies t h a t gr ea t ly im pr oved ou r u n der-
st a n din g of gen et ics.
St u dy of t h e h u m a n gen om e, or t h e fu ll DNA se-
qu en ce, is kn own a s g e n o m ic s . Gen om ics r eflect s n ot
ju st t h e st u dy of sin gle gen es bu t t h e fu n ct ion s a n d
in t er a ct ion s of a ll t h e gen es in t h e gen om e, in clu din g
in t er a ct ion s bet ween gen es a n d wit h gen es a n d t h e
en vir on m en t . An in t er n a t ion a l r esea r ch pr oject , t h e
H u m a n Gen om e P r oject , wa s st a r t ed in 1990 wit h
G C
A T
Ne w s tra nds
goa ls t o m a p ea ch h u m a n gen e a n d t o com plet ely se-
qu en ce h u m a n DNA. Aft er com plet ion of t h e pr oject
in 2003, wor k con t in u es t o a n a lyze t h e t r em en dou s
a m ou n t of da t a gen er a t ed by t h is pr oject . Th e iden -
t ifica t ion of t h e loca t ion of specific gen es on ch r o-
m osom es pr ovides a n oppor t u n it y for scien t ist s t o
pin poin t t h e ca u se of gen et ic disea se, a n d is t h e ba sis
for cu r r en t a n d fu t u r e st r a t egies t o pr even t or t r ea t
gen et ic defect s. Th e in t er a ct ion s bet ween gen es a n d
t h e en vir on m en t pr ovide t h e ba sis for a pplica t ion in
ot h er a r ea s of st u dy in clu din g n u t r igen om ics (t h e ef-
fect of n u t r ien t s on h ea lt h t h r ou gh n u t r ien t –gen om e
in t er a ct ion s) a n d ph a r m a cogen om ics (in t er a ct ion s
bet ween dr u gs a n d t h e gen om e t h a t a ffect t h e effi-
ca cy or t oxicit y in t h e h u m a n r espon se).
It m a y be possible t o im pr ove h ea lt h by u n der-
st a n din g t h e m ech a n ism s of disea se con t r ibu t in g t o
com plex con dit ion s su ch a s h yper t en sion , dia bet es,
a n d a st h m a t h r ou gh t h e st u dy of t h e h u m a n ge-
n om e.1 In st ea d of t a r get in g specific in dividu a ls for
scr een in g of gen et ic in for m a t ion t o pr edict disea se,
gen et ic scr een in g in t h e fu t u r e will be don e on en -
t ir e popu la t ion s, a llowin g t h e iden t ifica t ion of r isk
gr ou ps t o det er m in e su scept ibilit y t o disea se. 2
Identification of individuals with risks for specific
conditions provides an opportunity to intervene and ini-
tiate strategies to prevent the development of disease
 I n h e r it a n c e o G e n e t ic D is o r d e r s 141

Ta b le 6.2 Com m on Newbor n Scr een in g Test s

New b or n s Con seq u en ces i
D is e a s e P a t h o lo g y A ect ed Le t Un t r ea t ed Tr e a t m e n t

P h en ylket on u r ia In a bilit y t o br ea k 1 in 14,000 Br a in da m a ge, m en t a l Avoid foods wit h

(P KU) down a m in o a cid
ph en yla la n in e
H ypot h yr oidism Th yr oid h or m on e
deficien cy
Ga la ct osem ia In a bilit y t o con ver t t h e
su ga r ga la ct ose in t o glu -
cose for en er gy
Sickle cell a n em ia In h er it ed blood disea se
ca u sin g a bn or m a l sh a pe
a n d fu n ct ion in r ed
blood cells
Con gen it a l a dr en a l Gr ou p of disor der s fr om
h yper pla sia (CAH ) deficien cies in h or m on es
Biot in ida se Deficien cy of biot in ida se,
a n en zym e t h a t r ecycles
biot in , a B vit a m in
Ma ple syr u p u r in e In a bilit y t o br ea k down
disea se t h e essen t ia l a m in o
a cids leu cin e, va lin e, a n d
isoleu cin e
H om ocyst in u r ia In a bilit y t o br ea k
down t h e a m in o a cid
m et h ion in e
Mediu m -ch a in a cyl- In a bilit y t o u se fa t for
CoA deh ydr ogen a se en er gy
deficien cy
r et a r da t ion
1 in 3,000 Ret a r ds gr owt h a n d
br a in developm en t
1 in 50,000 Dea t h , blin dn ess,
m en t a l r et a r da t ion
1 in 400 Afr ica n In fect ion , pa in , or ga n
Am er ica n s da m a ge, a n d dea t h
1 in 19,000 Alt er ed gen it a l devel-
opm en t , kidn ey fu n c-
t ion , a n d dea t h
1 in 60,000 F r equ en t in fect ion s,
h ea r in g loss, m en t a l
r et a r da t ion , dea t h
1 in 230,000 Men t a l r et a r da t ion ,
seizu r e, a n d dea t h
1 in 340,000 Gr owt h pr oblem s,
developm en t a l dela y,
m en t a l r et a r da t ion
1 in 20,000 Su dden in fa n t
dea t h a n d m en t a l
r et a r da t ion
ph en yla la n in e
Repla cem en t of
t h yr oid h or m on e
Avoid foods wit h
ga la ct ose
E a r ly iden t ifica t ion
a n d t r ea t m en t of
sym pt om s a n d pr e-
ven t ion of in fect ion
a n d t r igger s
Repla cem en t of
m issin g h or m on es
Repla cem en t wit h
a ddit ion a l biot in
Diet low in leu -
cin e, va lin e, a n d
isoleu cin e
Vit a m in B 6 t h er a py
St ea dy food in t a ke
a n d a voida n ce of
fa st in g

before it begins. Newborn screening is an example of a n in dividu a l, or t he ge n ot y p e . The gen ot ype of a

this type of screening and has been in place since the
1960s. All states require newborns to be screened for
certain genetic disorders, although not all states have
the same requirements. Recommendations include
testing for more than 30 specific conditions though
states retain the legal authority to determine screen-
ing requirements based on criteria that include cost,
frequency of the disorder, and treatment availability
(genes-r-us.uthscsa.edu). Some of the most commonly
tested newborn diseases are included in Table 6.2.
Transmission and Expression
of Genetic Traits
Tr a it s a r e t r a n sm it t ed t o ea ch gen er a t ion by t h e
ga m et es; t he ova , a nd t h e sper m . E a ch pa r en t con -
t r ibut es one set of ch r om osom es, ensu r ing t h a t ea ch
offspr in g h a s t wo gen es a t ea ch locu s, or loca t ion
on t he ch r om osom e, wh en t h ese ch r om osom es com -
bin e. Th e com bin a t ion of t h e ova a nd sper m a t t he
t im e of con cept ion det er m in es t h e genet ic m a keu p of
per son is n ot a lways a ppa r ent or visible. A per son’s
p h e n o t y p e r efer s t o t he t r a it s t h a t a r e a ppa r en t or
obser va ble. E xa m ples of t h ese kinds of t r a it s in clude
gen der, blood t ype, a n d eye or h a ir color. Gen es m ay
h ave m a n y for m s, such a s t hose det er m in in g h a ir or
eye color, t h a t det er m in e offspr ing t r a it s, du e t o a l-
le le s (a ser ies of t wo or m or e differ en t gen es occu -
pyin g t h e sa m e loca t ion on a specific ch r om osom e).
Ot h er t r a it s, kn own a s p oly g e n ic , r esu lt fr om t h e in -
t er a ct ion of sever a l gen es a n d a r e in flu en ced by en vi-
r on m en t a l fa ct or s. The t r a n sm ission of gen et ic t r a it s
is specific for t h e t r a it a n d ca n be a com plex pr ocess.
Ma n y disea ses r esu lt fr om da m a ge t o gen es or
ch r om osom es. Th ese defect s ca n be t h e r esu lt of
spon t a n eou s da m a ge (de n ovo), en vir on m en t a l in -
su lt or t h ey ca n be a n in h er it a ble defect . E r r or s in
DNA du plica t ion ca n occu r a n d r esu lt in gen et ic m u -
t a t io n s . Th ese m u t a t ion s becom e per m a n en t st r u c-
t u r a l a lt er a t ion s in DNA. Th ey a r e oft en r esolved
by DNA r epa ir m ech a n ism s, wh ich pr even t ser iou s
h a r m . H owever, wh en t h ese r epa ir m ech a n ism s fa il,
t h e da m a ged gen et ic m a t er ia l ca n be pa ssed on . Th e
effect s of m u t a t ion s ca n be va r ia ble, r a n gin g fr om n o
142 C h a p t e r 6: Gen et ic a n d Developm en t a l Disor der s

effect a t a ll, t o ch a n ge in t h e expr ession of a t r a it or Fa the r

t h e fu n ct ion of a cell. Occa sion a lly, a s o m a t ic m u - B B
t a t io n (n ot in h er it a ble) ca n r esu lt in a p o ly m o r -
p h is m (gen e occu r r in g in m or e t h a n on e for m ). Th is b bB bB
com m on DNA va r ia t ion ca n occu r a m on g in dividu a ls Mothe r
a n d h a ve n o im pa ct on h ea lt h (e.g., h a vin g on e br own
eye a n d on e blu e eye). Ot h er m u t a t ion s r esu lt in per- b bB bB
m a n en t ch a n ge in gen et ic m a t er ia l, for m in g t h e ba -
sis of disea se. In som e ca ses, m u t a t ion s a ffect in g t h e
con t r ol of cellu la r pr olifer a t ion ca n r esu lt in ca n cer, Fa the r
wh ich is discu ssed in Ch a pt er 7. Th e t r a n sm ission B b
of gen et ic m u t a t ion is a ffect ed by t h e e x p r e s s iv it y
of t h e m u t a t ion , or t h e wa y t h e gen e is expr essed b bB bb
in t h e ph en ot ype, wh ich ca n r a n ge fr om m ild t o se- Mothe r
ver e. P e n e t r a n c e , t h e a bilit y of a gen e t o expr ess
b bB bb
a m u t a t ion , ca n a lso in flu en ce t h e effect s of gen et ic
m u t a t ion s. Obviou sly, m a n y va r ia bles in flu en ce t h e
com plexit y of t h e t r a n sm ission of gen et ic t r a it s.
Fa the r
B B
Inheritance of Single Gene Disorders
B BB BB
Som e t ra its a r e pa ssed on by t he t ra nsm ission of a Mothe r
single gene a nd a r e kn own a s s in g le ge n e t r a it s . b bB bB
When people have ident ica l a lleles on ea ch chr om o-
som e, t hey a r e h om ozy gou s for th a t gene. If t hey
h ave t wo differ ent a lleles on ea ch chr omosom e, t hey
Fa the r
a re h e t e r o zyg ou s (only one copy) for t ha t gen e. In-
B b
h erit a n ce of single gene t r a it s follows a Me n d e lia n
p a t t e r n of pr edict a ble t r a it tr a n sm ission ba sed on B BB Bb
a ut osom a l dom ina n t or r ecessive genot ypes. On a u-
Mothe r
t osom a l ch rom osom es, som e a lleles have m ore influ -
en ce t ha n ot hers. D om in a n t for m s of a gene a re m or e b bB bb
likely to be expr essed in a per son. R e c e s s ive genes
a re less in fluent ia l, r equ irin g hom ozygous a lleles t o
be expressed. A dom ina n t a llele, when combined wit h
B = brown (domina nt)
a r ecessive a llele, m ay pr event t he ph enot ypic expr es-
b = blue (re ce s s ive )
sion of th e r ecessive gene, a lt hough bot h a lleles com -
pr ise t he genotype. An exa m ple of t he a pplica t ion of
t his concept is a per son wh o is h eter ozygou s for th e Figure 6.6. Eye color inheritance. Brown eye color will
a lleles t ha t cont r ibut e to eye color. Tha t per son may result if any of the combinations contain the dominant
h ave a dom ina nt a llele for brown eyes a n d a r eces- allele (BB, bB, Bb). Blue eyes will result from a combina-
sive a llele for blue eyes in his or her genot ype but ex- tion of the recessive alleles (bb).
pr ess t he t r a it of br own eyes in his or h er ph enot ype a lleles. A per son m ust be h om ozygous for a r ecessive
beca use of th e imba la nce in t he influence of t h e t wo gene in or der for it t o be expr essed in t he phen otype.
Ther efore, for a per son to
expr ess t he r ecessive t r a it
F R O M T H E L AB of blu e eyes, he or she m ust
be h omozygou s for t he a l-
Newborn screening is done using a variety of different types of tests. One of the oldest lele for blue eyes (Fig. 6.6).
tests is the Guthrie bacterial inhibition assay, initially developed to identify infants with The sex chromosomes, X
the metabolic disorder phenylketonuria (PKU). The use of tandem mass spectrometry allows and Y, determine gender at
for the identification of a wide array of amino acid, fatty acid, and organic acid metabolic conception. X chromosomes
disorders from a sample of dried blood on filter paper. 3 DNA testing of newborns for such are much larger than Y and
diseases as cystic fibrosis can be done to get an early diagnosis and to initiate treatment carry much more genetic
for optimal wellness. material. Females have two
copies of the X chromosome
 I n h e r it a n c e o G e n e t ic D is o r d e r s 143

(XX), whereas males have one copy of X and one of Y De le tion Duplica tion Inve rs ion
(XY). The X chromosome is inherited from both par-
ents in the female but only from the mother in the
male. Traits passed on by sex chromosomes are known
as se x-lin k e d . These traits are most often recessive
and are linked to the X chromosome. While females
possess two copies of the X chromosome, one becomes
inactivated, leading to variable expression patterns of
X-linked genes. In males, the genes are inherited on
the single copy of the X chromosome. Males are usually
affected by this recessive disorder because they have
Ins e rtion
only one X chromosome. Females are usually carriers
because they have two copies of the X chromosome.

GENETIC MUTATIONS
Inherit able single gene muta tions follow th e Mende-
lia n pa ttern of inherit ance in a clea rly identifiable and
predicta ble ma nner. Single gene disorder s occur a t a
specific, single site on the st rand of DNA a s a result of:
Tra ns loca tion
● Delet ion
● Du plica t ion
● In ver sion
● In ser t ion
● Tr a n sloca t ion

These mutations are caused by the substitution of a

base pair that leads to an error in the transcription of
a single codon, which in turn leads to the abnormal for-
mation of proteins (Fig. 6.7). The resulting alteration in
cellular function leads to the manifestation of disease.
Specific mechanisms of genetic alterations can now be
considered as causative factors of damage in autoso-
mal and sex-linked gene errors. Table 6.3 describes the
patterns of inheritance in single gene disorders.
AUTOSOMAL DOMINANT DISORDERS
Most h er edit a r y disor der s in volve t h e gen es on
a u t osom es beca u se t h er e a r e m or e of t h ese t ypes
Figure 6.7. Common forms of genetic mutations. The
alterations in cellular function caused by genetic mutation
lead to the manifestation of disease.
of ch r om osom es (22 pa ir s) t h a n sex ch r om osom es
(1 pa ir ). Beca u se t h e gen et ic m u t a t ion s occu r on a u -
t osom es, t h e r esu lt in g disor der s a ffect m a les a n d fe-
m a les equ a lly (F ig. 6.8). If on e pa r en t is h et er ozygou s
for t h e a u t osom a l dom in a n t disor der, ea ch ch ild h a s
a 50% ch a n ce of in h er it in g t h e da m a ged gen e. In off-
spr in g wh o in h er it t h e da m a ged a llele, t h e dom in a n t
n a t u r e of t h e gen e is likely t o lea d t o disea se, even

Ta b le 6.3 Pa t t er n s of In h er it a n ce in Sin gle Gen e Disor der s

I n h e r it a n c e Alle le
Patter n C o n ig u r a t io n Tr a n s m is s io n E x p r e s s io n C a r r ie r N o n -C a r r ie r

Au t osom a l dom i- H et er ozygou s On e h et er ozygou s pa r en t 50% 0% 50%

n a n t disor der s
Au t osom a l r ecessive H om ozygou s On e h om ozygou s a n d on e Non e 100% 0%
disor der s n on ca r r ier pa r en t
Two h et er ozygou s pa r en t s 25% 50% 25%
Sex-lin ked disor der s Pa t er n a l X lin k Transmitted to daughters only 0% 100% 0%
Ma t er n a l X lin k Tr a n sm it t ed t o da u gh t er s 50% son s 50% 50% son s
a n d son s da u gh t er s 50% da u gh t er s
Mit och on dr ia l gen e Ma t er n a l lin k Tr a n sm it t ed t o da u gh t er s Va r ia ble Va r ia ble Va r ia ble
disor der s a n d son s
144 C h a p t e r 6: Gen et ic a n d Developm en t a l Disor der s

B
Una ffe cte d fe ma le Una ffe cte d ma le

Una ffe cte d fe ma le Una ffe cte d ma le As ymptoma tic As ymptoma tic
fe ma le ca rrie r ma le ca rrie r
Affe cte d fe ma le Affe cte d ma le Affe cte d fe ma le Affe cte d ma le

Figure 6.8. Autosomal dominant inheritance patterns. Figure 6.9. Autosomal recessive inheritance patterns.
A: When only one parent is heterozygous for the dominant Recessive genes are expressed in the phenotype when the
diseased gene, the child has a 50% chance of having the child is homozygous for the disease gene. If the inherited
disease and a 50% chance of being unaffected. B: When genotype is heterozygous, the child is a carrier of the disease
both parents are heterozygous for the diseased gene, the gene and has the ability to continue this inheritance pat-
child has only a 25% chance of being unaffected and a tern. When one parent is a carrier, the children have a 50%
75% chance of having the disease. chance of being a carrier themselves. If both parents are
carriers, 25% of the children will be unaffected, 25% will be
affected, and 50% will become carriers of the disease gene.
wh en t h e offspr in g is h et er ozygou s for t h e a llele.
E xa m ples of disea ses h a vin g t h is t ype of a u t osom a l
dom in a n t in h er it a n ce pa t t er n in clu de H u n t in gt on be pa ssed on t o t h eir ch ildr en . Th e m u t a t ed r ecessive
disea se (H D) (descr ibed in det a il in Clin ica l Models), gen e m ay be pr esen t in t h eir gen ot ype bu t n ot in t h eir
Ma r fa n syn dr om e, a n d ost eogen esis im per fect a . ph en ot ype. In ot h er wor ds, t h ey m ay be u n a wa r e t h a t
t h ey h ave t h e m u t a t ed gen e beca u se t h ey do n ot h ave
t h e disea se. In dividu a ls wh o a r e h et er ozygou s for a
AUTOSOMAL RECESSIVE DISORDERS r ecessive gen e m u t a t ion a r e kn own a s c a r r ie r s .
Au t osom a l r ecessive in h er it a n ce pa t t er n s r esu lt in a If bot h pa r en t s a r e ca r r ier s, t h eir ch ild h a s a 25%
differ en t pa t t er n of disea se expr ession t h a n t h e a u - ch a n ce of expr essin g t h e disor der. If on ly on e pa r en t
t osom a l dom in a n t disor der s (Fig. 6.9). Beca u se of t h e is a ca r r ier, t h e ch ild h a s a n equ a l ch a n ce of bein g
r ecessive n a t u r e of t h e gen es in volved, a ch ild m u st a ca r r ier (50%) or be com plet ely u n a ffect ed (50%).
be h om ozygou s for t h e m u t a t ed gen e t o expr ess t h e If bot h pa r en t s a r e h om ozygou s for t h e gen e a n d
disea se. Th is m ea n s t h a t bot h pa r en t s m u st h ave a t h a ve t h e disea se, a ll of t h eir ch ildr en will a lso h a ve
lea st on e copy of t h e da m a ged gen e for t h e disea se t o t h e disea se by in h er it in g bot h da m a ged a lleles fr om
t h eir pa r en t s. Wh en on e pa r en t is h om ozygou s for
t h e gen e m u t a t ion a n d
h a s t h e disea se a n d t h e
ot h er does n ot ca r r y t h e
R E S E AR C H N O T E S r ecessive gen e m u t a t ion ,
a ll of t h eir ch ildr en will
Prostate cancer is the most common cancer among American men (usually over 65 years be ca r r ier s wit h t h e a bil-
old), causing more than 40,000 deaths. It is estimated that approximately 181 of 100,000 it y t o pa ss on t h e m u t a t ed
African American men will be diagnosed with prostate cancer this year, with 54 of those gen e. Au t osom a l r ecessive
dying from the disease. This disease appears to run in families, leading to investigation disor der s a ppea r m or e
into the genetic link to the disease by scientists at the National Human Genome Research fr equ en t ly wit h in spe-
Institute (NHGRI). These scientists have identified the location of a gene, called HPC-1, that cific popu la t ion s, wh er e
is associated with increased risk of prostate cancer. 4 t h e likelih ood of ca r r ier s
is gr ea t er. E xa m ples of

a u t osom a l r ecessive disor der s a r e cyst ic fibr osis,
Ta y-Sa ch s disea se, t h a la ssem ia , a n d sickle cell dis-
ea se (descr ibed fu r t h er u n der Clin ica l Models).
SEX-LINKED DISORDERS
Mu t a t ion s of gen es loca t ed on t h e sex ch r om osom es,
X or Y, a r e ca lled sex-lin ked disor der s. Ma n y of t h ese
disor der s a r e lin ked t o gen es on t h e X ch r om osom e, or
X-lin ked, a n d a r e u su a lly r ecessive. For t h is r ea son ,
t h er e is a gen der differ en ce in expr ession of X-lin ked
disor der s. Beca u se fem a les h a ve t wo copies of t h e
X ch r om osom e, t h ey a r e u su a lly ca r r ier s of disea se.
Ma les h ave on ly on e copy of t h e X ch r om osom e a n d
t h er efor e a r e m or e likely t o expr ess t h e gen et ic dis-
or der. Y-lin ked disea ses r esu lt fr om t h e in h er it a n ce
of a gen e m u t a t ion on t h e Y ch r om osom e fr om t h e
fa t h er a n d a r e less com m on t h a n X-lin ked disor der s.
Sex-lin ked disor der s a r e in h er it ed ba sed on wh ich
pa r en t h a s t h e gen e m u t a t ion . Wh en t h e fa t h er ca r-
r ies t h e defect ive gen e on t h e X ch r om osom e, a ll
da u gh t er s will be ca r r ier s a n d son s will be u n a f-
fect ed (Fig. 6.10A). Wh en t h e m ot h er is a ca r r ier a n d
pa sses t h e defect ive gen e t o h er ch ild, h er da u gh -
t er s will h a ve a 50% ch a n ce of bein g a ca r r ier, a n d
h er son s will h a ve a 50% ch a n ce of bein g a ffect ed
(Fig. 6.10B). H em oph ilia a n d X-lin ked sever e com -
bin ed im m u n odeficien cy (XSCID), oft en r efer r ed t o
a s “bu bble boy disea se,” a r e exa m ples of X-lin ked
disor der s, wit h fem a les ca r r yin g t h e defect a n d on ly
m a les expr essin g t h e disea se.
A fa ct or s t h a t im pa ct t h e in t er a ct ion bet ween gen es a n d
B fa ct or s, in clu din g n u t r it ion a n d h or m on es.
Una ffe cte d fe ma le Una ffe cte d ma le
As ymptoma tic As ymptoma tic
fe ma le ca rrie r ma le ca rrie r
Affe cte d ma le
Figure 6.10. Sex-linked inheritance patterns. A: Expres-
sion of recessive X-linked traits occurs only in males when
the defective gene is inherited from the mother. B: Carrier
status is limited to female children and males are unaf-
fected when the damaged gene is inherited from the father.
I n h e r it a n c e o G e n e t ic D is o r d e r s 145
MITOCHONDRIAL GENE DISORDERS
Th e pa t t er n of m it och on dr ia l gen e t r a n sm ission is
differ en t fr om t h e t r a n sm ission of n u clea r gen es.
Alt hough m ost genes ca n be foun d in t h e cell nu -
cleu s, sever a l dozen genes ca n be fou nd in t h e m it o-
chon dr ia . Th e fun ct ion s of t hese genes a r e a ssocia t ed
wit h t he over a ll fun ct ion of m it ochon dr ia a nd a r e of-
t en r ela t ed t o ener gy pr oduct ion. Sper m do not ca r r y
a significa n t n um ber of m it ochon dr ia l gen es; t her e-
for e, m en do n ot pa ss m it ochondr ia l gene disor der s
on t o t heir offspr ing. Most m it och ondr ia l gen es a r e
pa ssed on t h r ough t he m a t er na l ga m et es (ova ), wh ich
a r e dense wit h t hese gen es. For t h is r ea son , m it och on-
dr ia l genes a r e t r a nsm it t ed on ly t hr ou gh fem a le or
m a t er na l lin es, in a m a t r ilin e a l in her it a nce pa t t er n .
Leigh syn dr om e is a con dit ion in volvin g m it o-
ch on dr ia l DNA (m t DNA). Ma n ifest a t ion s u su a lly
occu r in t h e fir st yea r of life a n d in clu de h ypot on ia ,
spa st icit y, per iph er a l n eu r opa t h y, en ceph a lopa t h y,
a t a xia , a n d vision a n d h ea r in g loss. Ma n ifest a t ion s
of m it och on dr ia l gen e disor der s a r e va r ia ble beca u se
of t h e h et er opla sm ic fea t u r es of t h ese disor der s.
H e t e r o p la s m y r efer s t o t h e r a n dom dist r ibu t ion
of m it och on dr ia t o da u gh t er cells du r in g em br yon ic
cell division , lea din g t o a va r ia ble dist r ibu t ion of
m u t a n t m it och on dr ia l gen es in t issu es of a n in divid-
u a l a n d bet ween r ela t ed in dividu a ls. Ma n ifest a t ion s
a r e r evea led wh en t h e m u t a n t m it och on dr ia r ea ch a
cr it ica l level, or t h r esh old.
Inheritance of Polygenic Disorders
Polygen ic in h er it a n ce in volves m u lt iple a lleles a t dif-
fer en t loci a ffect in g ph en ot ype. Th e expr ession of dis-
ea se oft en in volves a com plex in t er a ct ion of m u lt iple
en vir on m en t . E n vir on m en t a l in flu en ces m odu la t e
t h e ph en ot ypic expr ession of a t r a it in m u lt ifa ct or ia l
in h er it a n ce. An exa m ple of t h is t ype of in h er it a n ce
is t h e h eigh t of a n in dividu a l. H eigh t is in flu en ced
by t h e com bin a t ion of gen es in h er it ed fr om bot h pa r-
en t s, bu t it ca n a lso be in flu en ced by en vir on m en t a l
Cer t a in en vir on m en t a l con dit ion s m u st be pr es-
en t for expr ession of a gen et ic t r a it t h a t lea ds t o
disea se. Fa ct or s t h a t ca n in cr ea se expr ession of dis-
ea se in clu de ch em ica ls (a lcoh ol, t oba cco, dr u gs, a n d
h or m on es), n u t r it ion , a n d a lt it u de. Clin ica l m a n i-
fest a t ion s of m u lt ifa ct or ia l disor der s m a y be seen a t
bir t h a n d in clu de su ch disor der s a s cleft lip/pa la t e,
clu bfoot , a n d n eu r a l t u be defect s, in clu din g a n en -
ceph a ly a n d spin a bifida (discu ssed in m or e det a il
in Clin ica l Models). Ot h er m u lt ifa ct or ia l disor der s
a r e n ot expr essed u n t il t h e per son a ges, in clu din g
h yper t en sion , cor on a r y a r t er y disea se, dia bet es, a n d
m a n y ca n cer s.
146 C h a p t e r 6: Gen et ic a n d Developm en t a l Disor der s

wit h t h e r egu la r ch r om o-
R E S E AR C H N O T E S som e n u m ber a n d t h ose
wit h a n a lt er ed n u m ber of
Human genome mapping and improved technology identifying DNA patterns have stimulated ch r om osom es; t h e effect s
applications of the gleaned information in areas beyond human health. These include the a r e det er m in ed by t h e
use of DNA as evidence in identifying criminals. First used in 1983, DNA evidence has been r a t io. Th e r isk of n on dis-
6,7
used to convict individuals of crimes and to exonerate innocent individuals. This practice ju n ct u r e in cr ea ses wit h
is commonly referred to as “DNA fingerprinting.” Current DNA technology uses short tandem pa r en t a l a ge.
repeats (STRs), lengths of DNA stretches that are unique to an individual. STRs from suspect Mo n o s o m y occu r s
individuals are compared with national databases for rapid and accurate identification. In wh en n on disju n ct ion r e-
addition, mtDNA provides information about maternal lineage, and Y-specific STRs provide su lt s in cells wit h on e
evidence for paternal lineage. These techniques are most often used in historical identifica- copy of a ch r om osom e in -
tion, such as the determination of lineage of the Russian royal family, the Romanovs. These st ea d of t wo. If t h is occu r s
techniques were especially useful in identifying the remains of victims of the World Trade in a u t osom es, t h is defect
Center disaster, leading to positive identification of more than 1,500 individuals. is n ot com pa t ible wit h
life. Alt h ou gh m on osom y
in t h e sex ch r om osom e is
Stop and Consider com pa t ible wit h life, sig-
The process of genetic selection is based on re- n ifica n t ph ysica l a n d m en t a l defect s r esu lt . An ex-
productive practices that result in offspring with a m ple of a con dit ion t h a t r esu lt s fr om m on osom y of
desired traits. These practices are in use today in t h e sex ch r om osom e in clu des Tu r n er syn dr om e (TS),
the animal industry, where animals are bred for descr ibed in m or e det a il u n der clin ica l m odels.
desired qualities such as increased milk produc- Tr is o m y r efer s t o t h e pr esen ce of t h r ee copies of a
tion in dairy cows or desired characteristics in ch r om osom e in a cell. Th e via bilit y of t h e in dividu a l
show dogs. Food products are genetically manip- is det er m in ed ba sed on wh ich specific ch r om osom e is
ulated to have traits of disease resistance. What a ffect ed. If a la r ge ch r om osom e is a ffect ed, t r isom y
are the health implications of genetic selection is in com pa t ible wit h life beca u se la r ge ch r om osom es
in humans? What are the social and ethical con t a in a gr ea t dea l of gen et ic m a t er ia l. Wh en t r i-
implications? som y occu r s in ch r om osom e 21, t h e con dit ion kn own
a s Down syn dr om e r esu lt s. Ch ildr en bor n wit h
Down syn dr om e h a ve ch a r a ct er ist ic fa cia l fea t u r es,
Inheritance of Chromosomal
Alterations
Ch r om osom a l a lt er a t ion s m a y r esu lt fr om t h e loss,
a ddit ion , or r ea r r a n gem en t of gen et ic m a t er ia l.
Ch r om osom a l a lt er a t ion s ca n be det ect ed by a s-
1 2 3 4 5
sessin g a n in dividu a l’s ka r yot ype, or ch r om osom a l
com plem en t . A k a r y o t y p e is a pict u r e of a r r a n ged,
pa ir ed, like ch r om osom es in or der of la r gest t o
sm a llest (F ig. 6.11). Ch r om osom es a r e m a t ch ed by
cen t r om er e loca t ion a n d ba n din g pa t t er n (see Fr om 6 7 8 9 10 11 12
t h e La b).

ALTERATIONS IN CHROMOSOMAL NUMBER 13 14 15 16 17 18

Ch r om osom es sepa r a t e du r in g m it osis a n d m eiosis

in a pr ocess kn own a s disju n ct ion . Wh en ch r om o-
som es fa il t o sepa r a t e, t h e r esu lt is n o n d is ju n c t io n 19 20 21 22 XY
(Fig. 6.12). Non disju n ct ion r esu lt s in a n u n equ a l
n u m ber of ch r om osom es bet ween cells. Th e t im in g
of n on disju n ct ion det er m in es t h e n u m ber of cells in - Figure 6.11. Karyotype. The karyotype shows the 23 pairs
volved. If it occu r s soon a ft er con cept ion , it m a y a f- of chromosomes from a man. Notice the size of the Y chro-
fect a ll of t h e r esu lt in g cells. If it h a ppen s la t er, som e mosome compared with the X chromosome. (From Bear MF,
cells will be a ffect ed a n d ot h er s will be n or m a l. Th e Connors B, Paradiso M. Neuroscience: Exploring the Brain.
t er m m o s a ic is m r efer s t o t h e com bin a t ion of cells Baltimore, MD: Lippincott Williams & Wilkins; 2006.)
 I n h e r it a n c e o G e n e t ic D is o r d e r s 147

Firs t me io tic
divis io n
Nondis junction Norma l dis junction

S e c o nd me io tic
divis io n

Norma l Nondis junction

Fe rtilizatio n
with
no rmal s pe rm

Norma l Tris omy Monos omy

Figure 6.12. Chromosomal nondisjunction. Process of nondisjunction at the first and second meiotic divisions of the
ovum and fertilization with normal sperm. (Modified from Pillitteri A. Maternal and Child Nursing. 4th ed. Philadelphia,
PA: Lippincott Williams & Wilkins; 2003.)

sm a ll st a t u r e, ph ysica l defect s, a n d n eu r ologic in - a n d m et a bolic a gen t s t h a t st im u la t e ch em ica l m od-

volvem en t . Th e clin ica l m a n ifest a t ion s for a per son ifica t ion s of gen es. Th e ch em ica l m odifica t ion s t ypi-
wit h Down syn dr om e ca n be m odified by t h e degr ee ca lly in clu de ch em ica l m odifica t ion s t o h ist on es (e.g.,
of m osa icism (see Clin ica l Model: Down Syn dr om e). a cet yla t ion ) a n d DNA (e.g., m et h yla t ion ). Th e epi-
gen et ic m odifica t ion s ch a n ge t h e expr ession of t h e
gen e wit h ou t ca u sin g gen et ic m u t a t ion . Th e ch a n ge
ALTERATIONS IN CHROMOSOMAL STRUCTURE
in gen e expr ession in du ced by epigen et ic m odifica -
Tr a n s lo c a t io n occu r s wh en a la r ge segm en t of DNA t ion m a y per sist even a ft er r em ova l of t h e in it ia t in g
br ea ks fr om on e ch r om osom e a n d r ea t t a ch es t o a dif- a gen t a n d h a s t h e pot en t ia l t o be pa ssed t o offspr in g.
fer en t ch r om osom e, oft en occu r r in g du r in g m eiosis. If E pigen et ic m odifica t ion s of gen e expr ession a r e h er-
t h e t r a n sloca t ion is ba la n ced, t h is a bn or m a l a r r a n ge- it a ble, wit h t h e pot en t ia l t o in flu en ce t h e h ea lt h of
m en t does n ot a ffect t h e in dividu a l beca u se h e or sh e fu t u r e gen er a t ion s.
st ill r et a in s t h e sa m e a m ou n t of gen et ic m a t er ia l. It Wh en gen es a r e in a ppr opr ia t ely silen ced or a c-
ca n ser iou sly a ffect a n y offspr in g wh o in h er it s t h e t iva t ed t h r ou gh epigen t ics, disea se m a y r esu lt .
defect ive ch r om osom e, a s t h e gen et ic com plem en t E xa m ples in clu de Wilm s t u m or, ost eosa r com a ,
in h er it ed on t h e a lt er ed
ch r om osom e will r esu lt in
eit h er m issin g or exces-
sive gen es in t h e offspr in g. FROM THE L AB
Chromosomal abnormalities can be determined by examining the number and structure of
chromosomes through evaluation of the karyotype. The first step in evaluating a person’s
karyotype is obtaining a cell sample. Cells are prepared and chromosomes removed during
Epigenetic mitosis, at which time they can best be seen under a microscope. The chromosomes are
Inheritance attached to a slide and stained with a special dye called Giemsa. A striped, or banded,
appearance results from the dye staining of regions rich in adenine and thymine base pairs.
E pigen et ic is defin ed a s A picture of the chromosomes is then taken and the single chromosomes are matched with
“a bove t h e gen om e.” E pi- their pairs and arranged from largest to smallest. There are three criteria for matching chro-
gen et ic m odifica t ion s a r e mosomes: size, Giemsa banding pattern, and centromere position.
ca u sed by en vir on m en t a l
148 C h a p t e r 6: Gen et ic a n d Developm en t a l Disor der s

or igin . Gen om ic im -
F R O M T H E L AB pr in t in g is a n epi-
gen et ic ph en om en on
Prader–Willi (PWS) and Angelman (AS) syndromes are two separate diseases caused by r esu lt in g in r egu la -
changes in an identical region of DNA on the long arm (q) of chromosome 15. These dis- t ion of t h e expr es-
eases are the result of genomic imprinting expressed by differences in DNA modification by sion of gen e a ct ivit y
methylation and are determined by inheritance of the abnormality from either the mother or wit h ou t a lt er a t ion
the father. When the methylated gene is inherited from the mother, the defect is expressed of gen et ic st r u ct u r e.
as AS. When this same defect is inherited from the father, it is expressed as PWS. A lab test Th e pr ocess of gen et ic
to determine the methylation-induced changes in the affected region of the chromosome is im pr in t in g is u su a lly
available to assist in the diagnosis and differentiation of these diseases. This test is called t h e r esu lt of DN A
5
methylation-specific polymerase chain reaction (MSPCR). m et h yla t ion , pr even t -
in g t r a n scr ipt ion of
t h e gen e. Gen om ic im -
pr in t in g occu r s wh en
bot h m a t er n a l a n d
R E S E AR C H N O T E S pa t er n a l a lleles a r e
pr esen t , wit h on ly on e
a llele expr essed a n d
Environmental factors that may contribute to disease in adulthood can be linked to events t h e ot h er im pr in t ed
that occur during fetal development. Many adult diseases have been linked to a fetal en- a llele in a ct ive du e t o
vironment that impairs growth of the developing fetus. The study of the fetal origins of epigen et ic silen cin g
disease suggests that the fetus whose intrauterine growth is restricted may be programmed t h r ou gh DN A m et h yl-
to develop diseases, including hypertension, diabetes, and breast cancer. It may be that all a t ion . Appr oxim a t ely
of these individuals are born susceptible to these diseases, and therefore the expression of 20 k n own gen es a r e
8,9
disease is determined by environmental influences. a ffect ed by im pr in t -
in g, ca u sin g differ en t
disea ses ba sed on
bila t er a l r et in obla st om a , a n d em br yon a l r h a bdo- wh et h er t h ey wer e in h er it ed fr om t h e m ot h er or
m yosa r com a , for m s of ca n cer r esu lt in g fr om gen e t h e fa t h er. Two cla ssic con dit ion s t h a t illu st r a t e
silen cin g t h r ou gh DNA m et h yla t ion . Som e disea ses t h e in flu en ce of a n im pr in t in g defect on ch r om o-
a r e a ssocia t ed wit h r epea t ed expa n sion s of cyt osin e som e 15 in clu de P r a der –Willi (pa t er n a l-r ela t ed)
ba ses, t a r get s for m et h yla t ion , t h a t m a y ch a n ge a n d An gelm a n (m a t er n a l-r ela t ed) syn dr om es (see
gen e expr ession . E xa m ples of disea ses in volvin g r e- F r om t h e La b).
pea t cyt osin e-lin ked expa n sion s in clu de m yot on ic
m u scu la r dyst r oph y (MMD) a n d fr a gile X syn dr om e
(F XS) (see descr ipt ion in clin ica l m odel). Stop and Consider
G e n o m i c i m p r i n t i n g is t h e m ech a n ism t h a t Why does it take four generations for evidence of
con t r ols expr ession of gen es ba sed on pa r en t a l epigenetic inheritance?

Modu le 3 D e v e lo p m e n t a l D is o r d e r s

Developmental disorders are usually the result of envi-
ronmental influences that alter gene function, contrib-
uting to the expression of altered structure or function
of the affected tissue or organ system. Developm en t a l
disorders occur after conception and therefore are not
inherited and are hence disorders of development.
Congenital Disorders
Developm en t a l disor der s ca n be t h e r esu lt of
ch em ica ls, h or m on es, dr u gs, pa t h ogen s, or ot h er
en vir on m en t a l fa ct or s t h a t ca u se con gen it a l dis-
or der s in t h e developin g ch ild. Th e r esu lt of
gen e–en vir on m en t in t er a ct ion s t h a t occu r du r in g
fet a l developm en t , con gen it a l disor der s a r e lin ked t o
even t s t h a t occu r a t cr it ica l poin t s in developm en t .
Fa ct or s m a y in clu de t h e in t r a u t er in e a n d n u t r it ion a l
en vir on m en t s t h a t im pa ir a ppr opr ia t e a n a t om ic a n d
ph ysiologic developm en t of t h e em br yo a n d fet u s.
E n vir on m en t a l in flu en ces m a y a lso be t h e r esu lt
of a pa t h ogen ch a llen ge pr ior t o t h e fet u s’ a bilit y t o
m ou n t a n a dequ a t e im m u n e r espon se. E xposu r e t o
dr u gs a n d t oxin s in t h e m a t er n a l syst em m a y a lso

r esu lt in er r or s in m or ph ogen esis, or t h e a ppr opr i-
a t e st r u ct u r e of or ga n s a n d t issu es. Th e per iod of
in t r a u t er in e em br yon ic a n d fet a l developm en t is
ch a r a ct er ized by t h e dyn a m ic pr ocesses of cellu la r
pr olifer a t ion a n d differ en t ia t ion , in cr ea sin g vu ln er-
a bilit y t o en vir on m en t a l in su lt s t h a t lea d t o a lt er ed
fu n ct ion a cr oss t h e lifespa n .
Th e r isk of da m a ge t o a developin g ch ild is gr ea t -
est du r in g t h e em br yologic per iod (weeks 3 t h r ou gh 8
of gest a t ion ). Du r in g t h is t im e, o r g a n o g e n e s is (de-
velopm en t of or ga n syst em s) is occu r r in g. If da m a ge
occu r s du r in g t h is per iod, t h e or ga n syst em s m ost
su scept ible a t t h e t im e of exposu r e a r e specifica lly
a ffect ed. Da m a ge pr ior t o t h is t im e, t h e pr eem br yo-
logic per iod, m a y in t er fer e wit h im pla n t a t ion or m a y
be so sign ifica n t t h a t t h e pr egn a n cy en ds in spon t a -
n eou s a bor t ion . Th e fet a l per iod begin s du r in g ges-
t a t ion a l week 9 a n d con t in u es t h r ou gh t h e en d of
pr egn a n cy (F ig. 6.13). E n vir on m en t a l in su lt du r in g
t h e fet a l per iod h a s t h e pot en t ia l t o a lt er developin g
or ga n syst em s ba sed on t h e t im in g of t h e ch a llen ge.
Su bst a n ces t h a t ca u se da m a ge t o developin g em -
br yos or fet u ses a r e kn own a s t e r a t o g e n s . Ma n y
su bst a n ces t h a t en t er t h e m ot h er ’s syst em a r e a ble
t o cr oss t h e pla cen t a a n d en t er t h e fet a l cir cu la t ion .
If t er a t ogen exposu r e is ser iou s a n d occu r s ver y
ea r ly in t h e pr egn a n cy, it ca n ca u se da m a ge in com -
pa t ible wit h life, r esu lt in g in spon t a n eou s a bor t ion
or m isca r r ia ge. Da m a ge la t er in fet a l life is u su a lly
seen in specific or ga n s, wh ich wer e a ct ively devel-
opin g a t t h e t im e of exposu r e. Ter a t ogen s ca n t a ke
2 4
Ce ntra l ne rvous s ys te m
He a rt
Extre mitie s
Eye s
P re na ta l
Ma xima l s e ns itivity to de ve lopme nt of morphologic a bnorma litie s
de a th
Figure 6.13. Critical periods of vulnerability. Preembryologic (weeks 0 to 2) exposure to teratogenic insult is often in-
compatible with life. The embryologic period (3 to 8 weeks) represents the most vulnerable period of teratogenic damage.
During the fetal period (9 weeks to delivery), risk for teratogenic insult remains, especially for tissues of the neurologic
system. (Modified from Rubin E, Farber JL. Pathology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.)
D e v e lo p m e n t a l D is o r d e r s 149
m a n y for m s, in clu din g pa t h ogen s, dr u gs, a lcoh ol,
a n d en vir on m en t a l ch em ica ls.
It is difficu lt t o pr edict t h e effect s of t er a t ogen ex-
posu r e beca u se t h e effect s a r e in flu en ced by m a n y
va r ia bles. For exa m ple, it is kn own t h a t m a t er n a l a l-
coh ol con su m pt ion du r in g pr egn a n cy is t h e sole ca u s-
a t ive fa ct or iden t ified for t h e developm en t of e t a l
a lc o h o l s y n d r o m e (F AS ). FAS is a con dit ion ch a r-
a ct er ized by sign ifica n t m en t a l h a n dica p, gr owt h
deficit , a n d ph ysica l disa bilit y. Th e da m a ge in FAS
is lin ked t o t h e a m ou n t a n d t im in g of a lcoh ol expo-
su r e t o t h e developin g fet u s. Not a ll ba bies exposed
t o a lcoh ol develop FAS, su ggest in g t h e in flu en ce of
en vir on m en t a l fa ct or s a n d va r yin g su scept ibilit y.
Ma t er n a l a bst in en ce fr om a lcoh ol du r in g pr egn a n cy
wou ld r esu lt in t h e elim in a t ion of FAS, t h e lea din g
ca u se of m en t a l r et a r da t ion in t h e Un it ed St a t es.
Ma t er n a l in fect ion du r in g pr egn a n cy ca n a lso r e-
su lt in con gen it a l disor der s in t h e fet u s. Th e gr ou p
of disea ses descr ibed by t h e a cr on ym kn own a s
TORCH is kn own t o ca u se da m a ge t o t h e fet u s if
exposu r e occu r s. Th ese disea ses a r e:
● Toxopla sm osis
● Ot h er (h epa t it is)
● Ru bella
● Cyt om ega lovir u s
● H er pes
Ma n y pa t h ogen s in a ddit ion t o t h ose descr ibed in
t h e TORCH gr ou p h a ve t er a t ogen ic effect s a n d
a r e oft en m a n ifest ed by fet a l loss, m u lt iple fet a l
We e ks
6 8 16 38
Exte rna l ge nita lia
150 C h a p t e r 6: Gen et ic a n d Developm en t a l Disor der s

m a lfor m a t ion s, a n d n eu r ologic in volvem en t . E xa m -bir t h weigh t a n d fu t u r e developm en t of h ea r t disea se,

ples of com m on con dit ion s in clu de va r icella (ch icken su ggest in g t h a t u n der n u t r it ion du r in g pr egn a n cy
pox) a n d pa r vovir u s (fift h disea se). per m a n en t ly ch a n ged fet a l st r u ct u r e, fu n ct ion , a n d
Th e pr esen ce or a bsen ce of a gen t s in t h e en vir on - m et a bolism , pr ogr a m m in g t h e fet u s for fu t u r e de-
m en t ca n pose a r isk for t h e developm en t of gen et ic velopm en t of disea se. 12 Cu r r en t eviden ce im plica t es
defect s. An exa m ple of a n en vir on m en t a l in su lt t h a tepigen et ic m odifica t ion s t r igger ed by t h e a dver se
ca n ca u se gen et ic da m a ge is ion izin g r a dia t ion . in t r a u t er in e en vir on m en t du r in g fet a l developm en t
Ra dia t ion exposu r e t o t h e fet u s ca n ca u se gen et ic a s t h e likely et iology of gen et ic pr edisposit ion t o dis-
m u t a t ion s. DNA r epa ir m ech a n ism s exist for t h is ea se. As in ot h er con dit ion s wit h com plex et iologies
specific t ype of da m a ge. If t h ese r epa ir m ech a n ism s in volvin g gen e–en vir on m en t in t er a ct ion s, t h e pr e-
disposit ion t o a du lt disea se du e t o fet a l in t r a u t er in e
fa il or if t h e da m a ge is t oo gr ea t for a dequ a t e r epa ir,
per m a n en t da m a ge t o DNA m a y r esu lt , lea din g a da pt a t ion s r equ ir es a n en vir on m en t a l t r igger for
t o defect s. Th er e is n o eviden ce t h a t t h e r a dia t ion expr ession of disea se.13
exposu r e deliver ed du r in g dia gn ost ic pr ocedu r es Th e developin g fet u s is depen den t on t h e m a -
ca u ses da m a ge, bu t wom en wh o a r e pr egn a n t a r e t er n a l syst em for t h e deliver y of oxygen a n d n u -
ca u t ion ed t o a void r a diogr a ph s u n less a bsolu t ely t r ien t s a n d t h e r em ova l of wa st es. Th e pla cen t a
n ecessa r y. is t h e in t er fa ce bet ween t h e m a t er n a l a n d fet a l
syst em s, pla yin g a n im por t a n t r ole in su ppor t of
Ma t er n a l n u t r ien t deficien cy is lin ked t o t h e de-
velopm en t of con gen it a l defect s. Ma t er n a l folic a cid fet a l gr owt h a n d developm en t . Th e pla cen t a h a s
deficien cy is kn own t o be a r isk fa ct or for t h e develop- a sign ifica n t en docr in e fu n ct ion , pr ovidin g h or-
m en t of n eu r a l t u be defect s (NTDs), in clu din g a n en - m on es t h a t su ppor t fet a l a n d m a t er n a l a da pt a -
t ion s n eeded for a n opt im a l pr egn a n cy ou t com e.
ceph a ly a n d spin a bifida . Adequ a t e m a t er n a l in t a ke
Redu ced m a t er n a l blood flow a n d va r ia t ion s in
of folic a cid pr ior t o pr egn a n cy is a ssocia t ed wit h a r e-
du ct ion in t h e occu r r en ce of NTDs. Sin ce 1998, foods con st it u en t s in t h e m a t er n a l blood cr ea t e a n a d-
h a ve been for t ified wit h folic a cid, r esu lt in g in t h e ver se in t r a u t er in e en vir on m en t con t r ibu t in g t o
pr even t ion of NTDs by 50% in t h e Un it ed St a t es.10 fet a l a da pt a t ion s t h a t pr om ot e su r viva l in u t er o,
Th er e h a s been a ca ll for a sim ila r st r a t egy in t er n a -
bu t m a y be m ism a t ch ed wit h t h e en vir on m en t a l
t ion a lly, wh er e diet a r y r ecom m en da t ion s a lon e a r e
con dit ion s of post n a t a l life.
n ot a dequ a t e t o r edu ce t h e in ciden ce of NTDs.11 Ma t er n a l n u t r it ion a l st a t u s is cen t r a l t o t h e pr o-
m ot ion of fet a l developm en t . Va r ia t ion s in m a t er n a l
n ut r it ion a l st a t u s in clu din g obesit y, m a cr on u t r ien t
a n d m icr on u t r ien t excesses, a n d deficien cies a r e a s-
Developmental Origins of socia t ed wit h fu t u r e developm en t of obesit y, dia bet es,
Adult Disease a n d h ea r t disea se.14 Alt er a t ion s in m a t er n a l h or-
m on a l st a t u s m ay st im u la t e fet a l a da pt a t ion s t h a t
Obser va t ion s fr om t h e “Ba r ker H ypot h esis” du r in g m ay pr edispose t o fu t u r e developm en t of disea se. E x-
t h e 1980s dem on st r a t ed t h e lin k bet ween low in fa n t a m ples of m a t er n a l hor m on a l con dit ion s t h a t h ave
been lin ked t o fu t u r e dis-
ea se in clu de st r ess du e t o
a lt er a t ion in st r ess h or-
R E S E AR C H N O T E S m on e deliver y t o t h e fet u s
Many adult-onset disorders can be predicted by genetic testing. Individuals should be coun- a n d deficien cy in m a t er-
seled on the issues related to the knowledge that they have a predisposition to develop a n a l pr oh or m on e vit a m in D
disease. Identification of gene mutations that lead to disease may prevent a person from levels. Im pa ir ed n u t r it ion
obtaining adequate insurance coverage for medical care. In addition, it is important to share a n d st r ess a r e som e of t h e
this information with other family members who may also be at risk. Ethically, individuals ch a llen ges in t h e ext r a -
should be encouraged to share their diagnosis of a genetic disorder, which the medical u t er in e en vir on m en t t h a t
providers cannot themselves disclose to others because of patient confidentiality. 15 It is m ay pr ovide t h e t r igger
important to share knowledge of hereditary genetic disease with family members for them for expr ession of disea se,
to make informed decisions about their future reproduction and health. in clu din g h yper t en sion ,
obesit y, a n d dia bet es.
 Ma n a g e m e n t o G e n e t ic a n d D e v e lo p m e n t a l D is o r d e r s
Modu le 4 Ma n a g e m e n t o G e n e t ic a n d
D e v e lo p m e n t a l D is o r d e r s
Un like ot h er pa t h ologic a lt er a t ion s t h a t pr esen t
wit h sym pt om s r est r ict ed t o on e pa r t icu la r or ga n
syst em , t h e clin ica l m a n ifest a t ion s of developm en t a l
a n d gen et ic disor der s a r e specific t o t h e a ffect ed t is-
su es a n d or ga n syst em s a t t h e t im e of in su lt . E ven
a m on g in dividu a ls wit h sim ila r gen et ic a lt er a t ion s,
m a n ifest a t ion s a r e in flu en ced by pen et r a n ce a n d
expr essivit y. Clin ica l m a n ifest a t ion s of specific syn -
dr om es a r e pr esen t ed in t h e clin ica l m odels in t h is
ch a pt er t h a t r epr esen t a va r iet y of developm en t a l,
gen et ic, ch r om osom a l, a n d epigen et ic pa t h ologies.
Gen er a l m et h ods of iden t ifica t ion a n d m a n a gem en t
of a lt er a t ion s in gen et ics a n d developm en t a r e dis-
cu ssed in t h e n ext sect ion .
Screening and Diagnosis
Scr een in g a n d dia gn osis ca n be com plet ed in a n
in dividu a l a cr oss t h e lifespa n . In dividu a ls m a y r e-
qu est gen et ic scr een in g wh en fa m ily h ist or y in di-
ca t es a h er it a ble gen et ic r isk. Gen et ic scr een in g m a y
be don e in or der t o det er m in e t r ea t m en t decision s
wh en fa ced wit h a dia gn osis a ssocia t ed wit h kn own
gen et ic r isk. In dividu a ls du r in g t h e ch ildbea r in g
yea r s m a y con sider gen et ic scr een in g t o det er m in e
t h e pr oba bilit y of gen et ic r isk in offspr in g ba sed on
cu es in m a t er n a l a n d pa t er n a l h ist or y or fa ct or s
su ch a s pa r en t a l a ge. In a ll ca ses, t h e decision t o
pu r su e gen et ic scr een in g h a s em ot ion a l, et h ica l, a n d
econ om ic im plica t ion s.
PRENATAL SCREENING AND DIAGNOSIS
Idea lly, cou n selin g on t h e in h er it a n ce of gen et ic r isk
is com plet ed pr ior t o con cept ion . Gen et ic r isk ca n
be det er m in ed wh en a com plet e fa m ily a n d pr eg-
n a n cy h ist or y is obt a in ed. Ma t er n a l a ge (older t h a n
35 yea r s) or t h e fa m ily h ist or y of gen et ic disor der s
r epr esen t s som e of t h e m ost com m on r ea son s for
seekin g pr en a t a l dia gn osis. Th e decision t o u n der go
scr een in g m a y be m a de wh en a wom a n h a s h a d
r epet it ive (t h r ee or m or e) spon t a n eou s a bor t ion s,
wh ich su ggest s t h e pot en t ia l for a ch r om osom a l a b-
n or m a lit y. In dividu a ls wh o pr esen t wit h m a n ifest a -
t ion s cla ssica lly lin ked t o sin gle gen e a lt er a t ion s or
clin ica l su bject ive a n d object ive fin din gs t h a t for m a
syn dr om e m a y u n der go gen et ic scr een in g t o iden t ify
a defect a n d det er m in e wh et h er t h e defect ca n be
pa ssed on t o offspr in g.
151
Th e goa l of pr en a t a l dia gn osis is t o det er m in e
r ecogn iza ble ch r om osom a l or gen et ic defect s in t h e
gr owin g fet u s. In it ia lly, scr een in g t ech n iqu es ca n
be u sed t o det er m in e gen et ic r isk. Scr een in g of m a -
t er n a l ser u m m a y be com plet ed t o iden t ify NTDs or
Down syn dr om e r isk. Ult r a sou n d is u sed t o scr een
for a bn or m a lit ies in t h e ph ysica l st r u ct u r e of t h e fe-
t u s. Alt h ou gh t h ese t ech n iqu es su ggest r isk, t h ey a r e
n ot dia gn ost ic. Scr een in g t est s t h a t su ggest gen et ic
a bnor m a lit ies a r e u su a lly followed by dia gn ost ic
t est in g. Cell sa m ples of fet a l or igin m u st be u sed t o
dia gn ose fet a l a bn or m a lit ies. Fet a l cells ca n be ob-
t a in ed fr om t h e ch or ion ic villi, wh ich con t a in cells of
t r oph obla st ic or igin a n d t h er efor e a r e fet a l. Th e a m -
n iot ic flu id t h a t su r r ou n ds t h e fet u s is a n ot h er sou r ce
of fet a l gen et ic m a t er ia l a n d ca n a lso be u sed t o iden -
t ify gen et ic disor der s. Fin a lly, per cu t a n eou s blood
sa m plin g ca n be u sed t o exa m in e fet a l cells obt a in ed
fr om a sa m ple of fet a l blood fr om t h e u m bilica l cor d.
Wh en t h e r isk of t r a n sm ission of a gen et ic defect
is iden t ified, pr en a t a l cou n selin g sh ou ld in clu de t h e
opt ion of pr eim pla n t a t ion gen et ic dia gn osis. P r e im -
p la n t a t io n g e n e t ic d ia g n o s is is a n a lt er n a t ive t o
pr en a t a l dia gn osis, a n d it a llows for iden t ifica t ion
of a bn or m a lit ies befor e im pla n t a t ion . P r eim pla n -
t a t ion gen et ic dia gn osis r equ ir es t h e u se of in vi-
t r o fer t iliza t ion , em br yo cu lt u r e, a n d biopsy of t h e
b la s t o m e r e (ea r ly em br yo). Th is pr ocedu r e is cost ly
a n d in va sive, a n d it s u se is r est r ict ed t o t h ose in di-
vidu a ls wit h iden t ified r isks, in clu din g sin gle gen e
defect s, X-lin ked disor der s, a n e u p lo id y (a bn or m a l
ch r om osom e n u m ber ), a n d t h ose wit h ba la n ced
t r a n sloca t ion . 16 Ba la n ced t r a n sloca t ion r efer s t o t h e
exch a n ge of en t ir e ch r om osom e segm en t s bet ween
t wo differ en t ch r om osom es. In dividu a ls wit h ba l-
a n ced t r a n sloca t ion s h a ve t h e a ppr opr ia t e a m ou n t
of gen et ic m a t er ia l, so a ppea r ph en ot ypica lly n or-
m a l. H owever, t h ese in dividu a ls a r e ca r r ier s of t h is
ch r om osom a l a n om a ly a n d a r e a ble t o pa ss on e of
t h e a lt er ed ch r om osom es, pr odu cin g a n u n ba la n ced
ch r om osom a l com plem en t in t h e offspr in g.
A t h or ou gh fa m ily h ist or y is oft en t h e fir st st ep
t owa r d a gen et ic dia gn osis. Review of gen er a t ion a l
in for m a t ion is im por t a n t in t h e det er m in a t ion of
t r en ds. Th is in for m a t ion is oft en depict ed gr a ph i-
ca lly a s a pedigr ee, t r a cin g gen et ic disor der s t h r ou gh
gen er a t ion s. Pedigr ees a r e h elpfu l in t h e t r a ckin g of
in h er it a ble sin gle gen e, ch r om osom a l, a n d m u lt ifa c-
t or ia l disor der s. A ka r yot ype h elps det er m in e t h e
pr esen ce of ch r om osom a l a bn or m a lit ies. Wh en u sin g
a ka r yot ype t o iden t ify ch r om osom a l a bn or m a lit ies
152 C h a p t e r 6: Gen et ic a n d Developm en t a l Disor der s
a s a ca u se for r epea t ed a bor t ion , cell sa m ples fr om
bot h pa r en t s a r e n eeded. P r en a t a l cou n selin g of
fa m ilies wit h gen et ic disor der s in volves pr ovidin g
in for m a t ion t o su ppor t decision s a bou t pr egn a n cy
ou t com e a n d det er m in in g su ppor t ser vices n eeded
for t h e best possible ou t com e.
POSTNATAL SCREENING AND DIAGNOSIS
In t h e n ewbor n per iod, scr een in g for t h e m ost com -
m on gen et ic con dit ion s r esu lt s in ea r lier iden t ifi-
ca t ion a n d t r ea t m en t of m a n y disor der s. Lea r n in g
m or e a bou t gen et ics in cr ea ses t h e a bilit y t o iden t ify
gen et ic ca u ses of m a n y disea ses, in clu din g ca n cer,
Pa r kin son disea se, a n d Alzh eim er disea se. Alt h ou gh
n ot a ll in dividu a ls wit h t h ese disea ses h a ve a r ea dily
iden t ifia ble gen et ic m u t a t ion , m a n y wh o h a ve a fa m -
ily h ist or y of t h e disea se h a ve a gen et ic lin k. On ce
t h e gen e r espon sible for t h e disea se is iden t ified, in -
dividu a ls a t r isk ca n be scr een ed for t h e pa r t icu la r
m u t a t ion . Disor der s a r e discover ed by det er m in in g
t h e sequ en cin g of DNA a n d iden t ifyin g va r ia t ion s
con sist en t wit h m u t a t ion s t h a t r esu lt in disea se.
Gen et ic scr een in g of ca r r ier s a n d a ffect ed in -
dividu a ls m a y pr ovide pr edict ive, pr even t ive, a n d
per son a lized m edica l ca r e. Th e t r en d of t h e fu t u r e
is t o u se popu la t ion -ba sed scr een in g t o pr edict r isk
for a du lt -on set disor der s in differ en t et h n ic a n d
cu lt u r a l gr ou ps. Kn owledge of t h e m olecu la r ba sis
of disea se is pr ogr essin g fa st er t h a n ou r gr a sp on
t h e et h ica l a n d socia l im plica t ion s of t h a t kn owl-
edge. Com plex im plica t ion s r ela t ed t o t h e n a t u r e of
pa t ien t r ela t ion sh ips, a n t idiscr im in a t ion la ws, a n d
lega l r u les r ela t ed t o m edica l ca r e a n d pu blic h ea lt h
a r e ch a llen ges t h a t n eed t o be det er m in ed.17
Modu le 5 C lin ic a l Mo d e ls
Th e followin g clin ica l m odels h a ve been select ed
t o illu st r a t e t h e con cept s of a lt er a t ion s in gen et ics
a n d developm en t . As you r ea d t h e descr ipt ion s t h a t
follow, t h in k a bou t t h e pr ocesses of a lt er in g gen et ic
t r a it s a s t h ey a pply t o t h e specific con dit ion s t o h elp
in t h e u n der st a n din g a n d a pplica t ion of t h ese con -
cept s. Figu r e 6.14 pr ovides a su m m a r y of gen et ic a l-
t er a t ion s in h u m a n disea se.
Autosomal Dominant Genetic Disorder:
Huntington Disease
H D is a n eu r ologic disor der ca u sed by degen er a t ion
of t h e ba sa l ga n glia a n d cor t ica l r egion s of t h e br a in .
Stop and Consider
What are some instances in which identifying ge-
netic information can be harmful?
Treatment Strategies
Tr ea t m en t of gen et ic disor der s is disea se specific.
Wh en a n a t om ic a n om a lies exist , su r gica l cor r ect ion
is oft en im plem en t ed. If t h e disea se r esu lt s in de-
ficien cy of a pa r t icu la r en zym e, r epla cem en t of t h e
m issin g pr ot ein is in st it u t ed, if possible. Tr ea t m en t
of disor der s is u n iqu e t o t h e gen et ic deficit a n d is
pr im a r ily gea r ed t owa r d a llevia t ion of t h e a ssoci-
a t ed clin ica l m a n ifest a t ion s.
Counseling individua ls a nd fa milies with genetic al-
tera tions must include com municat ion of implica tions
of the defect and the risk of r eoccurrence. Counseling
ca n occur in fa milies when a risk of having children
with genetic defects exist s or when an affected child
is born. It is im port ant to understa nd the effects of
the genet ic condition on the individua l as well a s the
fa mily. A complet e expla na tion of diagnostic st rat e-
gies necessary to help the fam ily identify risk is im-
porta nt . Discussion of genetic r isk with fa milies must
be pr esented in a ma nner tha t is understood by the
pa tients a nd tha t meets individual pa tient and family
needs. The following a re some of the st rat egies used:
1. Assess lit er a cy level of t h e in dividu a l a n d fa m ily
2. Ask for in t er pr et a t ion of in for m a t ion a bou t t est -
in g pr ocedu r es a n d possible ou t com es
3. P r ovide in for m a t ion a bou t r a t es of r isk in bot h
posit ive a n d n ega t ive t er m s
4. P r om ot e a bilit y t o m a ke in for m ed decision s
H D a ffect s a ppr oxim a t ely 5 of 100,000 pr edom in a n t ly
Wh it e m a les a n d fem a les of n or t h er n E u r opea n
a n cest r y.18 A pa r en t wit h H D h a s a 50% ch a n ce of
pa ssin g t h e con dit ion on t o ea ch ch ild beca u se of t h e
a u t osom a l dom in a n t t r a n sm ission of t h is con dit ion .
All in dividu a ls wh o in h er it t h e sign ifica n t ly m u t a t ed
gen e will even t u a lly develop t h e clin ica l m a n ifest a -
t ion s of t his fa t a l con dit ion (fu ll pen et r a n ce). Ma n i-
fest a t ion s usu a lly a ppea r by t h e m id-40s a n d in clu de
im pa ir ed fu n ct ion of m ovem en t , em ot ion , a n d cogn i-
t ion . Th er e is n o kn own cu r e for t h is con dit ion .
PATHOPHYSIOLOGY
H D is a pr ogr essive, a u t osom a l dom in a n t disor-
der ca u sed by a defect in t h e h u n t in gt in gen e on
 C lin ic a l Mo d e ls 153

Epige ne tic Multifa ctoria l

dis orde rs dis orde rs

Ge ne s Enviro nme nt Chro mo s o me s

Te ra toge nic
dis orde rs

S ing le g e ne Alte ratio n in Alte ratio n in

traits s truc ture numbe r

Autos oma l Mitochondria l Tra ns loca tion Monos omy Tris omy

Domina nt Re ce s s ive

S e x-linke d

X-linke d Y-linke d

Figure 6.14. Concept map. Genetic alterations in human disease.

ch r om osom e 4. Th e gen e defect r esu lt s in a t r iplet ch a n ges, loss of m em or y, a n t isocia l a n d im pu lsive

cyt osin e–a den in e–gu a n in e (CAG) expa n sion m u t a - beh a vior s, a n d em ot ion a l la bilit y. Alt er ed m ot or
t ion in t h e h u n t in gt in (H TT) gen e, wit h a n in cr ea sed fu n ct ion in t h e ea r ly st a ge of disea se m a n ifest a -
n u m ber of m u t a t ion s a ssocia t ed wit h ea r lier on set of t ion in clu des r est lessn ess, fidget -like a ct ivit y a n d
t h e clin ica l m a n ifest a t ion s of t h e disea se. F u ll pen e- a bn or m a l eye m ovem en t s, r epr esen t in g ea r ly sign s
t r a n ce is obser ved wh en t h er e is a n expa n sion of >38 of d y s k in e s ia (difficu lt y in per for m in g volu n t a r y
CAG r epea t s. Th e gen et ic m u t a t ion gen er a t es a code m ovem en t s). Ch or ea (r a pid, in volu n t a r y, n on r epet -
for t h e a bn or m a l h u n t in gt in pr ot ein , wh ich t h en a c- it ive m ovem en t of t h e fa ce, t r u n k, a n d lim bs) is a
cu m u la t es t o t oxic levels a n d dest r oys n er ve cells, key fea t u r e of H D. Th e pr ogr essive n a t u r e of t h e
r esu lt in g in a t r oph y in t h e br a in . A pr ot ein fr a gm en t con dit ion lea ds t o im m obilit y, sever e loss of cogn i-
of t h e h u n t in gt in pr ot ein pr odu ced by ca spa se (a n t ive fu n ct ion , in t ellect u a l det er ior a t ion , delu sion s,
en zym e t h a t br ea ks down pr ot ein ) m a y a lso be in - a n d pa r a n oia .
volved in t h e pa t h ology a ssocia t ed wit h H D. As t h e
CAG expa n sion is a t a r get for m et h yla t ion , epigen -
et ic m ech a n ism s u n der lyin g t h e da m a ge of H D a r e DIAGNOSTIC CRITERIA
u n der in vest iga t ion . Dia gn osis of H D is ba sed on a com plet e fa m ily a n d
per son a l m edica l h ist or y a n d ph ysica l exa m in a t ion .
CLINICAL
MANIFESTATIONS
F R O M T H E L AB
In dividu a ls wit h HD
su ffer fr om in volu n t a r y Screening for HD can be accomplished by analyzing DNA from a blood sample to determine
m ovem en t s, cogn it ive if the genetic mutation is present. CAG repeats are counted, with the number of repeats
im pa ir m en t , a n d em o- considered in diagnosis. CAG repeats of 28 or fewer do not indicate HD. Individuals with
t ion a l dist u r ba n ce. E a r ly CAG repeats greater than 40 are diagnosed with HD. Because of the serious nature of the
psych ologic m a n ifest a - diagnosis and lack of an available cure, the decision to test for the defect is a difficult one.
t ion s in clu de per son a lit y
154 C h a p t e r 6: Gen et ic a n d Developm en t a l Disor der s

Men t a l, cogn it ive, a n d em ot ion a l eva lu a t ion m a y Autosomal Recessive Disorder: Sickle
pr ovide in dica t ion s of ea r ly sign s of disea se, espe-
cia lly wh en cou pled wit h ea r ly sign s of m ovem en t Cell Disease
disor der s. Gen et ic t est in g ca n defin it ively dia g-
n ose H D, r evea lin g t h e a ssocia t ed m u t a t ion on t h e Sickle cell disea se is a n inher it ed hom ozygous dis-
h u n t in gt in gen e. Blood sa m ples fr om t h e a ffect ed or der a ffect ing hemoglobin in red blood cells. H em o-
in dividu a l, a s well a s a close fa m ily m em ber, ca n globin A (a dult ) in the red blood cells is repla ced by
pr ecisely dia gn ose H D. In sym pt om a t ic in dividu a ls, a not her form of hemoglobin, hem oglobin S (sickled).
CT, MRI, or posit r on em ission t om ogr a ph y (P E T) Following a n a ut osoma l r ecessive inher it a nce pa t ter n,
sca n s ca n be don e t o det ect t h e ch a r a ct er ist ic br a in sickle cell disea se is t ra nsmit ted fr om pa r ent t o child.
a n om a lies a ssocia t ed wit h H D, in clu din g sh r in ka ge Sickle cell disea se is comm only found in individua ls
of t h e ba sa l ga n glia com pon en t s, ca u da t e n u clei a n d of Afr ica n a ncest ry. In t he Un it ed St a tes, 9% of Afri-
pu t a m en , a n d en la r gem en t of t h e ven t r icles of t h e ca n Am erica ns have sickle cell t ra it a nd 1 in 600 have
br a in . sickle cell disea se.24 As a r esult of im proved scr een ing,
In dividu a ls wit h a fa m ily h ist or y of H D h a ve t rea t ment , a nd educa tion, life expect a ncy is incr ea s-
t h e opt ion of gen et ic t est in g pr ior t o on set of sym p- ing.25,26 Media n sur viva l for individua ls wa s 14 yea rs
t om s; t h is is k n own a s pr esym pt om a t ic t est in g. in 1973. Recent ly, m edia n surviva l ha s increa sed to 42
Cou n selin g sh ou ld be pr ovided befor e pr esym p- yea r s for ma les a nd 48 yea r s for fem a les.27
t om a t ic t est in g con sider in g t h e pr ofou n d im pa ct a
dia gn osis of H D ca n h a ve on a n in dividu a l a n d t h e
fa m ily.
PATHOPHYSIOLOGY
Sickle cell disea se is t h e r esu lt of a sin gle gen e m u -
t a t ion t h a t follows Men delia n in h er it a n ce pa t t er n s.
TREATMENT
Red blood cells con t a in h em oglobin A (H bA), or a du lt
Th er e is cu r r en t ly n o cu r e for t h is con dit ion . Su p- h em oglobin . H em oglobin S (H bS) is a n a bn or m a l
por t ive ca r e in clu din g occu pa t ion a l, ph ysica l, a n d t ype of h em oglobin fou n d in people wit h sickle cell
speech t h er a pies, a n d n u t r it ion m a n a gem en t m a y a n em ia . Red blood cells wit h H bA a r e soft , r ou n d,
opt im ize qu a lit y of life. Un der lyin g m ovem en t a n d a n d plia ble en ou gh t o cir cu la t e t h r ou gh t h e sm a ll
psych ia t r ic disor der s m a y be t r ea t ed wit h ph a r m a - blood vessels in t h e m icr ocir cu la t ion . H bS ch a n ges
cologic t h er a py. Resea r ch in t o pot en t ia l t r ea t m en t t h e ph en ot ype of r ed blood cells, m a kin g t h em st iff
opt ion s h a s iden t ified n ew pa t h wa ys t o pr eser vin g a n d dist or t ed. Red blood cell life spa n is r edu ced
br a in fu n ct ion a n d pr even t in g disea se. E pigen et ic fr om a ppr oxim a t ely 120 da ys t o 16 da ys wh en r ed
t a r get s a r e bein g st u died a s t h e ba sis for t r ea t m en t , blood cells ca r r y H bS, fu r t h er con t r ibu t in g t o sym p-
t a r get in g r egu la t ion of gen e expr ession .19 Th e u se of t om s of a n em ia a n d in cr ea sed dem a n d t o pr odu ce
st em cells t o fost er pr ot ect ion of t h e n eu r ologic sys- a ddit ion a l r ed blood cells. Th e for m of h em oglobin
t em is a lso a pot en t ia l fu t u r e t r ea t m en t .20 In vest iga - pr odu ced is det er m in ed by t h e t wo bet a globin gen es
t ion in t o ph a r m a cot h er a py t o t r ea t or cu r e H D h a s loca t ed on ch r om osom e 11. Th e defect in sickle cell
sh own pr om ise for t h e u se of ca spa se in h ibit or s 21 a n em ia is a poin t m u t a t ion , in wh ich t h e a m in o a cid
a n d ca n n a bin oids,22 t h ou gh effica cy is u n cer t a in . va lin e is su bst it u t ed for glu t a m in e on t h e bet a ch a in
Clin ica l t r ia ls will pr ovide da t a on pa t ien t s t h a t of h em oglobin of r ed blood cells. Th e ph en ot ypic ex-
will u lt im a t ely det er m in e t h e effect iven ess of t h ese pr ession of t h is gen et ic m u t a t ion in a n in dividu a l
t r ea t m en t s. wh o is h om ozygou s for t h e sickle bet a globin gen e
(bS) is sickle cell a n em ia .
Stop and Consider Wh en exposed t o con dit ion s of low oxygen t en sion ,
What are the risks and benefits of testing for t h e h em oglobin ’s sh a pe is dist or t ed in t o a sickled
HD? Are there reasons why a person would not sh a pe, kn own a s h e m o g lo b in S (F ig. 6.15). Th e ir-
want testing? r egu la r ly sh a ped h em oglobin ca u ses da m a ge t o t h e
en dot h elia l cells t h a t lin e
blood vessels a n d t o t h e
r ed blood cells t h em selves.
R E S E AR C H N O T E S
Tr a ppin g of t h e r ed blood
A group of researchers studied residents from an endemic population of people afflicted with cells in t h e spleen ca u ses
HD in Venezuela. A model was developed that determined the variables contributing to age h e m o ly s is , or br ea kdown
of onset of symptoms. Variables accounting for age of onset included number of repetitive of r ed blood cells, r esu lt -
triplets in the Huntington gene as the primary determinant (72%), although other genes and in g in a n em ia . Th e a lt er ed
environmental factors, including poverty and nutrition, explained the remaining variation. 23 sh a pes of t h e r ed blood
cells ca u se difficu lt y in
 C lin ic a l Mo d e ls 155

of tissue oxygena tion. Tissue ischem ia oft en results,

promoting t he developm ent of recur rent, pa inful
episodes. Because of t he r esulta nt syst emic tissue
ischem ia , the locat ion of pa in ca n occur in the chest,
extr em it ies, or a bdom en. St roke a nd pria pism (pa in-
ful, pr olonged er ection) ca n a lso result . Organ da ma ge
S ickle d
ce lls t o the spleen, kidneys, a nd liver ca n result from sickle
cell cr isis, contr ibuting t o significa nt mor bidity a nd
m or ta lity. Splenic dam a ge can contr ibute to decr ea sed
imm une defense, incr ea sing the risk of over whelming
infection. In childr en, infect ion a nd str oke a re com-
m on m a nifest at ions of sickle cell a nem ia .26 Micr ova s-
cula r occlusion may lea d t o necrosis a nd cell dea t h.
Neur ologic com plica tions include risk for stroke, neu-
Norma l re d r ocognitive decline, a nd int ra cr a nia l hem orrha ge.
blood ce ll

Figure 6.15. Red blood cells in sickle cell anemia. When

DIAGNOSTIC CRITERIA
red blood cells are exposed to conditions of low oxy-
gen tension, it results in the sickle shape of the cells. E a r ly iden t ifica t ion of in dividu a ls wit h sickle cell
(Courtesy Anatomical Chart Company.) disea se is vit a l t o decr ea sed m or bidit y a n d m or t a lit y.
P r en a t a l a n d n ewbor n scr een in g for sickle cell dis-
ea se h a s im pr oved t r ea t m en t of com plica t ions, pa r-
t h eir pa ssa ge t h r ou gh sm a ll blood vessels, r esu lt in g t icula r ly for in fect ion in t he newbor n per iod wh en
in decr ea sed oxygen a t ion . Pa in r ela t ed t o isch em ia t he r isk is h igh est . La bor a t or y t est in g for sickle cell
r esu lt s a n d ca n develop in t o n ecr osis a n d or ga n fa il- disea se in clu des:
u r e if left u n t r ea t ed.
● H em oglobin elect r oph or esis (see F r om t h e La b
As expect ed in a u t osom a l r ecessive disor der s, t h e
below)
gen et ic m u t a t ion a ssocia t ed wit h sickle cell a n em ia
■ Iden t ifies h em oglobin t ypes (H bA, H bS)
is r ecessive. For in dividu a ls t o h a ve t h e disea se ph e-
■ Differ en t ia t es h om ozygosit y fr om h et er ozygos-
n ot ype, t h eir gen ot ype m u st be h om ozygou s for t h e
it y by pr opor t ion of h em oglobin t ypes
defect ive a llele. An in dividu a l wh o is h et er ozygou s
■ H om ozygou s: 80% t o 90% H bS of t ot a l
for t h e gen et ic m u t a t ion is a ca r r ier a n d is con sid-
h em oglobin
er ed t o h a ve s ic k le c e ll t r a it .
■ H et er ozygou s: 35% t o 40% H bS of t ot a l
h em oglobin
CLINICAL MANIFESTATIONS ● Isoelect r ic focu sin g
■ Met h od u sed t o sepa r a t e pr ot ein s ba sed on
Clinica l m a n ifest a t ions inclu din g h a llm a r ks of
t h eir isoelect r ic poin t , ba sed on t h e pH wh en
va so-occlu sion a nd hem olysis a r e r ela t ed t o t h e pr o-
t h e pr ot ein n et ch a r ge is zer o
por t ion of H bS in t h e cir cu la t ion . Pa in is a lso ch a r-
■ Adju n ct in det er m in a t ion of h em oglobin t ype
a ct er ist ic of sickle cell disea se, oft en st im u la t ed by
● H igh -per for m a n ce liqu id ch r om a t ogr a ph y (H P LC)
even t s in clu din g in fect ion , deh ydr a t ion , a n d st r ess,
■ Met h od u sed in t h e iden t ifica t ion of h em oglo-
t h ou gh a pr ecipit a t in g even t is not a lways iden t ifia ble.
bin va r ia n t s
H em olysis, sh or tened r ed blood cell life, and splenic
● DNA a n a lysis
t ra pping result in brea kdown of red blood cells, re-
leasing contents int o t he cir cula tion. The t wo clinica l P r en a t a l dia gn osis ca n be don e by a n a lysis of fet a l
m a nifesta t ions, jaundice a nd a nem ia , result. J a un- DNA obt a in ed fr om ch or ion ic villu s sa m plin g or a m -
dice results fr om t he relea se of b ilir u b in , a yellow, n iot ic flu id. Newbor n scr een in g sh ou ld be in it ia t ed
lipid-soluble byproduct of
h emoglobin, as a r esult of
RBC da ma ge. The loss of F R O M T H E L AB
RBCs results in an emia ,
m a king it difficult to oxy- Hemoglobin electrophoresis is used to identify specific forms of hemoglobin. This test is
gena te tissues adequ a tely. completed on a blood sample drawn from a person suspected or known to have sickle cell
This, com bined with t he anemia. An electric charge is passed through a solution of hemoglobin. Hemoglobin variet-
blockade of sma ll vessels ies move to specific distances through the solution, based on composition. A person with
by t he sickled RBCs, fur- sickle cell disease will have a predominance of HbS.
t her adds t o th e problems
156 C h a p t e r 6: Gen et ic a n d Developm en t a l Disor der s

P h a r m a cologic m ea -
R E S E AR C H N O T E S su r es for t h e pr even t ion
of com plica t ion s in clu de
Gene therapy in the treatment of sickle cell anemia represents an effective strategy in the t h e u se of h ydr oxyu r ea .
prevention of disease-associated complications. Research is currently in the early stages, H ydr oxyu r ea in cr ea ses
but recent studies show promise for this potential therapy. One approach reported in a re- t h e pr odu ct ion of H bF,
cent study of gene therapy involved the manipulation of the differential expression of the pr even t in g t h e for m a t ion
28
globin genes, inducing preferential expression of HbF. Therapy involving substitution of of H bS. H ydr oxyu r ea kills
HbS with HbF through the transcriptional control of globin genes was studied as a potential bon e m a r r ow cells, in du c-
therapy for sickle cell anemia. The focus of this study was to find the right DNA sequence in g a n in cr ea sed pr odu c-
to target and to test its effectiveness in promoting expression of HbF. Using an in vitro t ion of cells wit h h igh er
method involving cells, the researchers were able to selectively express HbF, reinforcing h em oglobin F con t en t ,
the importance of the continued development of this strategy as an effective treatment for pr om ot in g life spa n of
sickle cell anemia. cells a n d depr essin g pr o-
du ct ion of H bS. In cr ea ses
in H bF h a ve been a sso-
cia t ed wit h im pr ovem en t of t h e clin ica l m a n ifest a -
in t h e fir st 6 m on t h s of life, wit h h em oglobin F t ion s r ela t ed t o sickle cell a n em ia . Th e u se of n it r ic
(H bF ) in clu ded in t h e dist r ibu t ion of h em oglobin oxide du r in g a cu t e ch est cr isis m a y pr om ot e r ela x-
t ypes expect ed. La bor a t or y follow-u p of in dividu a ls a t ion of t h e r esist a n ce a r t er ies t o pr om ot e per fu sion
dia gn osed wit h sickle cell a n em ia wh o a r e n ot expe- t o isch em ic t issu es. F u t u r e t r ea t m en t s in clin ica l de-
r ien cin g com plica t ion s in clu des eva lu a t ion of h em o- velopm en t in clu de t h e u se of gen e t h er a py a n d st em
lysis a n d a n em ia wit h yea r ly com plet e blood cou n t s cell a llogen ic a ppr oa ch es t h a t wou ld n ot on ly t r ea t
(CBC) a n d u r in a lysis. Test s of liver (liver fu n ct ion t h e sym pt om s, bu t wou ld pr ovide t h e pot en t ia l for
t est s: AST, ALT) a n d kidn ey (ser u m cr ea t in in e a n d a cu r e.29
blood u r ea n it r ogen [BUN]) fu n ct ion sh ou ld be com -
plet ed ever y 2 t o 3 yea r s. Ret in a l exa m in a t ion s Stop and Consider
sh ou ld a lso be com plet ed t o det er m in e eviden ce of What are the risks to the fetus when the father
da m a ge or disea se. has sickle cell anemia? What are the risks to the
fetus when the mother has sickle cell anemia?
TREATMENT
P r even t ion of com plica t ion s r ela t ed t o in fect ion is
im por t a n t in t h e m a n a gem en t of sickle cell a n em ia . Mitochondrial Gene Disorder:
Im m u n iza t ion a ga in st ch ildh ood a n d com m u n it y Mitochondrial Encephalomyopathy,
illn esses, su ch a s pn eu m ococca l pn eu m on ia , in flu -
en za , a n d m en in gococca l m en in git is, a r e im por t a n t Lactic Acidosis, and Stroke
t o pr ot ect fr om in fect ion . Pen icillin pr oph yla xis is a n
im por t a n t in t er ven t ion design ed t o su ppor t im m u n e Mit och on dr ia l en ceph a lom yopa t h y, la ct ic a cidosis,
defen se. a n d st r oke (ME LAS) is m it och on dr ia l gen e disor der.
Tr ea t m en t for pa t ien t s wit h sickle cell a n em ia Alt h ou gh u n com m on , ME LAS is con sider ed a sign if-
is u su a lly sym pt om specific. Pa in m a n a gem en t is ica n t ca u se of st r oke-like m a n ifest a t ion s in in divid-
cr it ica l t o t h e m a n a gem en t of sickle cell a n em ia . u a ls less t h a n 45 yea r s of a ge. 30 Mea n life spa n of
Iden t ifica t ion a n d a voida n ce of pr ecipit a t in g fa c- t h ose wit h t h e fu ll clin ica l syn dr om e r a n ges fr om 20
t or s, in clu din g in fect ion , ext r em es of t em per a t u r e, t o 40 yea r s, wit h ca r diopu lm on a r y fa ilu r e, pu lm o-
a n d em ot ion a l/ph ysica l st r ess, is im por t a n t for pa in n a r y disea se, a n d st a t u s epilept icu s t h e m ost com -
pr even t ion . La b eva lu a t ion of a com plet e blood cou n t m on ly r epor t ed ca u ses of dea t h . Th er e is n o gen der
(h em oglobin , r et icu locyt es, wh it e blood cells, gr a n u - or et h n ic pr edilect ion for ME LAS. 31
locyt es, a n d ba n ds) ca n h elp det er m in e a n em ia a n d
in fect ion . Sever e episodes of pa in oft en r equ ir e t h e
PATHOPHYSIOLOGY
u se of opia t es. Blood t r a n sfu sion a ddr esses t h e a n e-
m ia a ssocia t ed wit h sickle cell disea se a n d decr ea ses ME LAS is a m a t er n a lly in h er it ed con dit ion , ch a r a c-
t h e pr opor t ion of cir cu la t in g H bS by a ddin g h ea lt h y t er ized by m t DNA poin t m u t a t ion s. Th e ovu m is t h e
don or RBCs wit h H bA. Tr a n sfu sion h a s a lso been sou r ce of m t DNA; t h er efor e, t h is con dit ion is m a t er-
sh own t o decr ea se t h e r isk of st r oke in ch ildr en . Fo- n a lly in h er it ed. To da t e, eigh t m t DNA poin t m u t a -
lic a cid su pplem en t a t ion is fr equ en t ly u sed t o pr e- t ion s a n d on e delet ion m u t a t ion h a ve been iden t ified
ven t m ega lobla st ic er yt h r opoiesis. a s gen et ic ca u ses of ME LAS. Most of t h e m u t a t ion s
 C lin ic a l Mo d e ls 157

a r e in gen es t h a t en code
t RNA for t h e a m in o a c- F R O M T H E L AB
ids leu cin e a n d va lin e. A
su bst it u t ion of a den in e Diagnosis of mitochondrial abnormalities is often determined by biochemical assays that
t o gu a n in e in t h e gen e- detect specific disease markers. The most common of these markers are COX and succinate
en codin g t RNA a ccou n t s dehydrogenase (SDH), both of which play a significant role in mitochondrial cellular respi-
for a ppr oxim a t ely 80% of ration. 32 An increase in SDH leads to altered structure of muscle fibers, impairing muscle
ME LAS ca ses. Mu t a t ion s function. On microscopic evaluation, muscle fibers exposed to trichrome stain turn a bright
m a y a lso a ffect c y t o - red color, leading to the common term “ragged red fibers,” characteristic of many mitochon-
c h r o m e o x id a s e (C O X), drial gene disorders. Ragged red fibers may also be stained with other dyes to characterize
a n en zym e im por t a n t presence of COX and SDH.
in ca t a lyzin g oxida t ion –
r edu ct ion m it och on dr ia l
Im a gin g st u dies ca n be a dded t o la bor a t or y st u dies
r ea ct ion s in cellu la r r espir a t ion . Th e pr eva ilin g t h e-
t o con fir m a dia gn osis of ME LAS. CT or MRI br a in
or y on t h e u n der lyin g m ech a n ism in volved in ME -
sca n s ca n det ect n eu r ologic da m a ge r ela t ed t o sei-
LAS is t h a t a decr ea se in oxida t ive ph osph or yla t ion
zu r e a ct ivit y a n d st r oke. P E T sca n s ca n det er m in e
cr ea t es a n im ba la n ce bet ween ATP pr odu ct ion a n d
t h e cer ebr a l m et a bolic r a t e for oxygen . E lect r oen -
u sa ge, con t r ibu t in g t o n eu r on a l dysfu n ct ion .30
ceph a logr a m (E E G) is u sefu l in iden t ifyin g n eu r a l
a ct ivit y in dica t in g a seizu r e disor der. Ca r diom yop-
a t h y ca n be det ect ed wit h ech oca r diogr a ph y (u lt r a -
CLINICAL MANIFESTATIONS
sou n d det er m in a t ion of h ea r t st r u ct u r e a n d fu n ct ion )
Th e m a n ifest a t ion s of ME LAS a r e va r ia ble beca u se or elect r oca r diogr a ph y (E CG), a t est t h a t in dica t es
of t h e h et er opla sm ic n a t u r e of t h is con dit ion . Clin i- t h e n eu r a l con du ct ion in t h e h ea r t .
ca l m a n ifest a t ion s of ME LAS develop wh en m u t a n t
m t DNA r ea ch es a t h r esh old of 56% t o 95%. Th e a ge
of on set of clin ica l m a n ifest a t ion s a ver a ges 10 yea r s. TREATMENT
Cla ssic sym pt om s of ME LAS in clu de: Cu r r en t ly, t r ea t m en t st r a t egies a r e focu sed on m a n -
● St r oke-like episodes in in dividu a ls you n ger t h a n a gem ent of m a n ifest a t ion s. E xa m ples in clu de t he u se
40 yea r s of a ge of a n t icon vu lsa nt m edica t ion s dir ect ed a t con t r ollin g
● E n ceph a lopa t h y, in clu din g seizu r es a n d dem en t ia seizu r e a ct ivit y a n d coch lea r im pla n t s t o im pr ove
● La ct ic a cidosis h ea r in g. Tr ea t m ent st r a t egies in developm en t in clude
t he u se of a gen t s t h a t a ffect oxida t ive ph osph or yla -
Ot h er a ssocia t ed m a n ifest a t ion s in clu de h ea r in g t ion . Agen t s of t h is t ype inclu de coen zym e Q, r ibofla -
loss, blin dn ess, m igr a in e h ea da ch es, vom it in g, sh or t vin , a n d cr ea t in e. Clin ica l t r ia ls a r e invest iga t in g t he
st a t u r e, h em ipa r esis, h em iplegia , ca r diom yopa t h y, u se of dich lor oa cet a t e, a com pou n d t h a t pr om ot es t h e
dia bet es, a n d m yopa t h y. con ver sion of pyr u va t e (a bypr odu ct of ca r bohydr a t e
m et a bolism ) t o a cet yl-CoA inst ea d of t h e u su a l pr od-
u ct la ct a t e, r edu cing t h e r isk for developm en t of la c-
DIAGNOSIS t ic a cidosis (fu r t h er discussed in Ch a pt er 8).
Dia gn osis of ME LAS is ba sed on fa m ily h ist or y a n d
docu m en t a t ion of clin ica l m a n ifest a t ion s, a n d it is
con fir m ed wit h la bor a t or y st u dies. Bioch em ica l Alteration in Chromosome Number
a n a lyses ca n det er m in e r espir a t or y ch a in dysfu n c-
t ion a n d la ct ic a cidosis. Mu scle biopsy dem on st r a t es (Autosome): Down Syndrome
t h e ch a r a ct er ist ic fin din gs of m yopa t h y in ME LAS:
t h e pr esen ce of r a gged r ed fiber s (see F r om t h e La b, Tr isom y t h a t r esu lt s in excess gen et ic m a t er ia l is
below). Com m on la b st u dies u sed in t h e dia gn osis of oft en in com pa t ible wit h life, especia lly wh en t h e de-
ME LAS in clu de: fect in volves la r ger ch r om osom es. Wh en t r isom y oc-
cu r s on ch r om osom e 18, t h e clin ica l m a n ifest a t ion s
● Ser u m a n d cer ebr ospin a l flu id levels of la ct ic a cid a r e sever e. Con gen it a l h ea r t defect s, m u lt iple join t
a n d pyr u vic a cid con t r a ct u r es, spin a bifida , h ea r in g loss, u n der devel-
● Ser u m cr ea t in e kin a se opm en t or m issin g r a dia l bon e of for ea r m , cleft lip,
● Skelet a l m u scle biopsy t o det er m in e a ct ivit y of bir t h defect s of t h e eye, a n d sm a ll size a t bir t h a r e
su bst a n ces in volved in cellu la r r espir a t ion t h e m ost com m on developm en t a l com plica t ion s of
● Blood, skelet a l m u scle, or h a ir follicle sa m ples for t h is syn dr om e. Am on g in fa n t s bor n wit h t r isom y 18,
det er m in a t ion of m t DNA m u t a t ion s m edia n su r viva l is est im a t ed a t 6 da ys.33
158 C h a p t e r 6: Gen et ic a n d Developm en t a l Disor der s

Down syn dr om e is n a m ed for Dr. J oh n La n gdon t h r ee copies of ch r om osom e 21. Th e a ddit ion a l ch r o-
Down , wh o iden t ified t h e syn dr om e in t h e 1860s m osom e ca n be ca u sed by fer t iliza t ion of a ga m et e
ba sed on t h e pa t t er n of m a n ifest a t ion s h e r ecog- wit h t wo copies of ch r om osom e 21, by n on disju n c-
n ized in t h e r esiden t s of a n a sylu m for ch ildr en t u r e du r in g cell division , or by t r a n sloca t ion . Wh en
wit h m en t a l illn ess in E n gla n d. Th e gen et ic ba sis a n er r or in cell division occu r s a ft er fer t iliza t ion , t h e
of ch r om osom e 21 t r isom y wa s n ot iden t ified u n t il ch ild m a y develop t wo cell lin es: on e wit h t h e u su a l
1959. Down syn dr om e is on e of t h e m ost com m on ch r om osom e com plem en t a n d on e wit h t r isom y 21,
gen et ic bir t h defect s, a ffect in g a ppr oxim a t ely 1 in kn own a s m osa ic Down syn dr om e.
800 t o 1,000 ba bies of bot h gen der s. Accor din g t o t h e
Na t ion a l Down Syn dr om e Societ y, t h er e a r e a ppr ox-
CLINICAL MANIFESTATIONS
im a t ely 350,000 people livin g wit h Down syn dr om e
in t h e Un it ed St a t es. Life expect a n cy a m on g a du lt s Ch ildr en bor n wit h Down syn dr om e h a ve a com -
wit h Down syn dr om e is a bou t 55 yea r s, a lt h ou gh life bin a t ion of bir t h defect s, in clu din g m en t a l r et a r-
spa n va r ies depen din g on t h e in dividu a l a n d h is or da t ion , ch a r a ct er ist ic fa cia l fea t u r es, a n d h ea lt h
h er m edica l con dit ion . An in cr ea se in t h e in ciden ce pr oblem s in clu din g ca r dia c defect s, in t est in a l m a l-
of Down syn dr om e wa s expect ed beca u se of dela yed for m a t ion s, a n d visu a l a n d h ea r in g im pa ir m en t .
ch ildbea r in g a n d a n in cr ea sed bir t h r a t e in wom en Th e sever it y of expr ession of t h ese pr oblem s va r-
over 35 yea r s. ies gr ea t ly a m on g a ffect ed in dividu a ls. In cr ea sed
r isk of in fect ion , t h yr oid pr oblem s, a n d leu k em ia
a r e a lso possible sequ ela e of Down syn dr om e. Fa -
PATHOPHYSIOLOGY
cia l fea t u r es ch a r a ct er ist ic of Down syn dr om e in -
Down syn dr om e is a con dit ion ch a r a ct er ized by a l- clu de eyes t h a t sla n t u pwa r d, sm a ll, low-set ea r s
t er a t ion in ch r om osom e n u m ber. Also kn own a s t r i- t h a t fold a t t h e t op, sm a ll m ou t h , fla t t en ed n ose
som y 21, ch ildr en bor n wit h Down syn dr om e h a ve br idge, a n d sh or t n eck (F ig. 6.16). Sh or t st a t u r e,
sh or t fin ger s, a n d de-
cr ea sed m u scle t on e a r e
a lso ch a r a ct er ist ic ou t -
F R O M T H E L AB wa r d m a n ifest a t ion s of
Down syn dr om e.
Screening for Down syndrome can be done during the prenatal period. Noninvasive methods Wh en pa r en t s h a ve a
of screening may include biochemical analysis of substances in maternal blood, using the ba la n ced t r a n sloca t ion ,
quadruple test, which includes measurement of serum alpha-fetoprotein, unconjugated es- t h ey m a y be fr ee of t h e
tradiol, human chorionic gonadotropin (hCG) hormone, and inhibin A during the second tri- disea se ph en ot ype bu t
mester, after 14 weeks’ gestation. When the quadruple test was combined with an ultrasound ca n pa ss on t h e defect , r e-
evaluation of nuchal translucency and pregnancy-associated plasma protein-A (PAPP-A) at su lt in g in t r isom y of t h eir
10 weeks (integrated test), this two-step evaluation was very accurate in detecting Down ch ild. Ba la n ced t r a n slo-
34
syndrome (see Research Notes, below). ca t ion in a pa r en t is t h e
on ly in h er it a ble for m of
t r isom y. Ot h er m ech a -
n ism s lea din g t o t r isom y
R E S E AR C H N O T E S 21 r epr esen t spon t a -
n eou s even t s. Th e r isk
Traditionally, determination of effective antenatal screening for Down syndrome was hin- of t r isom y a s a r esu lt of
dered by variations in study design, preventing generalizability of study findings to the n on disju n ct u r e in cr ea ses
population. In a recent large prospective study of 47,053 singleton pregnancies, testing of wit h a ge. Ma t er n a l a ge
maternal serum and urine samples, as well as nuchal translucency, was conducted to deter- over 35 yea r s is a ssoci-
mine reliable biomarkers of Down syndrome. 35 The false-positive rates for specific prenatal a t ed wit h a gr ea t er r isk
tests were as follows: of Down syn dr om e. Th e
Integrated test (nuchal translucency and PAPP-A at 11 weeks of pregnancy; r isk of Down syn dr om e
alpha-fetoprotein, unconjugated estriol, free beta or total hCG, and inhibin A in the early in cr ea ses wit h a ge, fr om
second trimester): 0.9% a bou t 1 in 1,250 for a
wom a n a t a ge 25, t o 1 in
Serum integrated test (nuchal translucency, free beta hCG and PAPP-A at 11 weeks of
1,000 a t a ge 30, 1 in 400
pregnancy): 4.3%
a t a ge 35, a n d 1 in 100 a t
Quadruple test (alpha-fetoprotein, free beta, or total hCG and inhibin A): 6.2% a ge 40. St r ikin gly, t h e r isk
Nuchal translucency at 11 weeks: 15.2% is in cr ea sed t o 1:60 by
a ge 42, fu r t h er r isin g t o
 C lin ic a l Mo d e ls 159

Growth fa ilure
Me nta l re ta rda tion S la nte d e ye s
Fla t occiput Epica ntha l fold
Brus hfie ld s pots

Conge nita l he a rt
dis e a s e Dys pla s tic
e a rs

Me ga colon
P rotruding,
big, wrinkle d
tongue

S hort, broa d
ha nds with
s imia n cre a s e

Acute
lymphobla s tic
le uke mia

Wide ga p
be twe e n 1s t a nd
2nd toe s
A

B
Figure 6.16. Typical clinical manifestations of a child with Down syndrome. The clinical manifestations of Down syndrome
include organ system anomalies with long-term health implications ( A) in addition to characteristic physical features ( B) .
(Modified from Rubin E, Farber JL. Pathology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.)

1:12 by a ge 49. H owever, it is im por t a n t t o n ot e t h a t ch r om osom a l a bn or m a lit ies. E va lu a t ion of NT u ses

a bou t 75% of ba bies wit h Down syn dr om e a r e bor n
t o wom en wh o a r e u n der a ge 35, a s you n ger wom en
h a ve fa r m or e ba bies.
DIAGNOSTIC CRITERIA
Scr een in g for Down syn dr om e in t h e fir st t r im es-
t er ca n be a ccom plish ed by lookin g for in cr ea sed
n u c h a l t r a n s lu c e n c y (N T ) or t h ickn ess of t h e
n a pe of t h e n eck, a com m on fin din g in fet u ses wit h
u lt r a sou n d t o m ea su r e a flu id-filled sa c a t t h e ba ck
of t h e fet u s’ n eck du r in g ea r ly pr egn a n cy. Th e best
t im e for NT t est in g is bet ween 10 a n d 14 weeks. Af-
t er t h a t t im e, t h e flu id collect ed is a ble t o dr a in via
a m or e developed lym ph syst em . Wh en NT is com -
bin ed wit h m a t er n a l ser u m PAP P -A a n d fr ee or t ot a l
h CG h or m on e, scr een in g r elia bilit y is in cr ea sed. Di-
a gn ost ic gen et ic t est in g r equ ir es t h e m or e in va sive
pr ocedu r es of ch or ion ic villu s sa m plin g (com plet ed
bet ween 11 a n d 13 weeks of pr egn a n cy). Th ese
160 C h a p t e r 6: Gen et ic a n d Developm en t a l Disor der s
in va sive pr ocedu r es ca r r y m or e r isk a n d a r e a ssoci-
a t ed wit h a 1% r isk of pr egn a n cy loss.
Th e secon d t r im est er qu a dr u ple scr een , a m ea su r e
of fou r bioch em ica l m a r ker s, is idea lly con du ct ed be-
t ween 15 a n d 18 weeks of pr egn a n cy. E leva t ion of
h GG a n d in h ibin A a n d r edu ct ion in m a t er n a l ser u m
a lph a -fet opr ot ein a n d u n con ju ga t ed est r iol su ggest
r isk for Down syn dr om e. Mor e specific scr een in g
for Down syn dr om e in clu des a pa t t er n of a n a t om ic
a n om a lies det ect ed by u lt r a sou n d. Som e of t h e dis-
t in ct ive ph ysica l fea t u r es det ect a ble by u lt r a sou n d
in clu de:
● Sh or t h u m er u s
● Sh or t fem u r
● H ydr on eph r osis
● E ch ogen ic ca r dia c foci (a r ea s in t h e h ea r t , u su a lly
t h e left ven t r icle, iden t ified a s ech oes or br igh t
a r ea s)
● E ch ogen ic bowel (br igh t a r ea s in t h e in t est in e)
● Ot h er m a jor a n a t om ic defect s
Th ese fin din gs in dividu a lly m a y n ot be u n u su a l, bu t
wh en t h ey a ppea r in com bin a t ion , t h e r isk of Down
syn dr om e m u st be a ddr essed.
A lim it a t ion of som e scr een in g t est s in clu des a
h igh r a t e of “fa lse-posit ive” r esu lt s, m ea n in g t h a t t h e
posit ive scr een in g r esu lt is pr esen t in t h e a bsen ce
of disea se. F u r t h er, t h er e is a r isk of “fa lse-n ega -
t ive” r esu lt s, m ea n in g t h e a ct u a l disea se con dit ion
wa s n ot det ect ed by t h e scr een in g t est , lea vin g fa m -
ilies wit h a fa lse a ssu r a n ce. Test s wit h h igh r a t es
of “fa lse-posit ive” a n d “fa lse-n ega t ive” r esu lt s h a ve
lim it ed u se in t h e iden t ifica t ion a n d m a n a gem en t of
disea se. Wh en t h e fin din gs fr om a n y scr een in g t est s
su ggest Down syn dr om e, fu r t h er t est in g is offer ed t o
pr ovide a n a ccu r a t e dia gn osis.
Secon d t r im est er a m n iocen t esis (com plet ed be-
t ween 15 a n d 19 weeks of pr egn a n cy) pr ovides a n
oppor t u n it y t o collect sa m ples of a m n iot ic flu id, gr ow
fet a l cells in cu lt u r e, a n d eva lu a t e t h e fet a l ka r yo-
t ype t o det er m in e t h e pr esen ce of ch r om osom a l a b-
n or m a lit ies. F u t u r e dia gn ost ic t est s cell fr ee DNA
collect ed fr om m a t er n a l blood a s a r elia ble m et h od
for r a pid pr en a t a l dia gn osis of Down syn dr om e. 36
TREATMENT
Tr ea t m en t in Down syn dr om e is focu sed on pr om o-
t ion of m a xim a l in depen den ce a n d qu a lit y of life.
E a r ly in t er ven t ion pr ogr a m s, in clu din g speech , la n -
gu a ge, a n d ph ysica l t h er a py, pr om ot e opt im a l fu n c-
t ion . Con gen it a l h ea r t disea se r em a in s t h e m ost
fr equ en t ca u se for ea r ly dea t h . Tr ea t m en t of ca r dia c
or ga st r oin t est in a l com plica t ion s m a y r equ ir e su r gi-
ca l r epa ir. Over a ll life expect a n cy is sh or t er t h a n t h e
gen er a l popu la t ion .
Alteration in Chromosome Number
(Sex Chromosome): Turner Syndrome
Tu r n er syn dr om e is a con dit ion n a m ed a ft er Dr.
H en r y Tu r n er, who fir st iden t ified t h e condit ion in t h e
1930s ba sed on t he pa t t er n of m a n ifest a t ions iden t i-
fied in h is pa t ien t s. Th e gen et ic ba sis of t he syn dr om e
wa s n ot iden t ified for a n ot h er 30 yea r s. TS is t h e
m ost com m on fet a l m on osom y in fem a les, occur r in g
wit h a fr equ en cy of a ppr oxim a t ely 3%. Of t h ose fe-
t uses a ffect ed, a ppr oxim a t ely 99% a r e spon t a n eou sly
a bor t ed.37 TS occu r s in 1 in 2,500 t o 1 in 3,000 gir ls
a t bir t h, or in 25 t o 55/100,000 pr edom in a n t ly whit e
fem a les. Individu a ls wit h TS h ave a decr ea sed life
expect a n cy, usua lly r ela t ed t o t h e a ssocia t ed m edica l
com plica t ion s of dia bet es a n d h ea r t disea se.
PATHOPHYSIOLOGY
TS occu r s in fem a les wh en t h e ch r om osom e n u m ber
is a lt er ed, r esu lt in g fr om t h e loss of a ll or pa r t of t h e
sex ch r om osom e X. Of t h ose a ffect ed by TS, a bou t
50% h a ve t r u e m on osom y wit h on ly on e X ch r om o-
som e (45, X), 10% h a ve st r u ct u r a l a bn or m a lit y of t h e
X ch r om osom e, a n d r em a in in g ca ses exh ibit on e or
m or e a ddit ion a l cell lin es or a m osa ic ka r yot ype (45,
X/46, XY).38
CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s va r y ba sed on t h e t ype of
a bn or m a lit y, t h e poin t in t im e wh en n on disju n ct u r e
occu r r ed, a n d t h e pr opor t ion of da m a ged cells in
ea ch t issu e t ype (t r u e m on osom y ver su s m osa icism ).
Ma n ifest a t ion s com m on a cr oss TS in clu de sh or t
st a t u r e a n d ova r ia n fa ilu r e. In t elligen ce is u su a lly
n or m a l, bu t gir ls wit h TS oft en h a ve som e lea r n in g
a n d socia l pr oblem s. Ot h er a ssocia t ed sym pt om s ca n
be gr ou ped in t o t h r ee ca t egor ies:
● Skelet a l a bn or m a lit ies
■ Sh or t fin ger s
■ Sh or t n eck
■ Cleft pa la t e
■ Ost eopor osis
● Soft t issu e a bn or m a lit ies
■ Lym ph a t ic obst r u ct ion
■ Webbed n eck
■ Low h a ir lin e
● Or ga n a bn or m a lit ies
■ Ca r dia c a bn or m a lit ies
■ Kidn ey a bn or m a lit ies
■ Liver a bn or m a lit ies
■ H ea r in g loss
In a ddit ion t o r epr odu ct ive effect s, a du lt wom en
wit h TS m a y a lso su ffer fr om h ypot h yr oidism ,
 C lin ic a l Mo d e ls 161

dea fn ess, ost eopor osis, a n d pr oblem s r ela t ed t o es- a n d in fer t ilit y r ela t ed t o pr em a t u r e ova r ia n fa ilu r e
t r ogen deficien cy.39 Alt er ed m or ph ology of st r u ct u r es a r e com m on pr oblem s t h a t lea d t o t h e iden t ifica t ion
in t h e in n er ea r r esu lt s in con du ct ive h ea r in g loss of TS in wom en wit h ou t ot h er cla ssic ch a r a ct er ist ics.
a n d ot it is m edia .40 Gr owt h h or m on e a dm in ist r a t ion P u ber t y a n d t h e developm en t of a du lt fem a le ph ysi-
pr om ot es opt im a l h eigh t developm en t . Life spa n in ca l ch a r a ct er ist ics m u st oft en be in du ced by est r ogen
t h ese wom en is decr ea sed secon da r y t o ca r diova scu - h or m on e a dm in ist r a t ion . 45,46 Alt h ou gh ova r ia n folli-
la r pr oblem s, in clu din g a t h er oscler osis.41 Con gen i- cle developm en t in fet a l life is sign ifica n t ly r edu ced,
t a l m a lfor m a t ion s of t h e
left h ea r t , a or t ic r u pt u r e
a n d dissect ion , h yper t en - F R O M T H E L AB
sion , a n d isch em ic h ea r t
disea se a r e a ll r isks for Karyotyping is used to identify partially or completely missing X chromosomes, diagnostic
wom en wit h TS. of TS. Efforts to find a more affordable and quicker method are ongoing. Molecular detection
Klin efelt er syn dr om e of nonmethylated segments of the X chromosome, characteristic in TS, may be useful in
(KS) is a n ot h er con dit ion screening high-risk groups. 42 MSPCR may also prove effective in diagnosing TS. 43
ch a r a ct er ized by a bn or-
m a l n u m ber of sex ch r o-
m osom es, a n d it is con sider ed a cou n t er pa r t t o TS. in dividu a ls wh o h a ve a m osa ic ka r yot ype m a y h a ve
In KS, a n a bn or m a l ovu m ca r r yin g a n a ddit ion a l spon t a n eou s pr egn a n cies.48 Repea t ed spon t a n eou s
X ch r om osom e (XX) is fer t ilized by a n or m a l m a le m isca r r ia ge m a y be t h e ch a r a ct er ist ic lea din g t o
sper m (Y). Th e ch ild, wit h
a ka r yot ype of 46XXY, is
ph en ot ypica lly m a le. Th e R E S E AR C H N O T E S
m a le ph en ot ype a ft er pu - Individuals with TS are at increased risk of type 2 diabetes because of decreased insulin
ber t y in clu des sca n t pu bic secretion. 49 Prolonged treatment with growth hormone, commonly used in TS, can also con-
h a ir, a t r oph ic t est es, a n d a tribute to an increased risk of insulin resistance.
sm a ll pen is. F u n ct ion a lly,
m en wit h KS a r e in fer t ile.
Th ey m a y a lso h a ve fem -
in in e fea t u r es, in clu din g la ck of fa cia l h a ir, fem a le scr een in g a n d dia gn osis in t h ese wom en . Wom en
h ip sh a pe, a n d br ea st developm en t . Figu r e 6.17 il- wit h TS oft en exper ien ce pr em a t u r e m en opa u se.
lu st r a t es som e of t h e ph ysica l ch a r a ct er ist ics of TS
a n d KS.
TREATMENT
DIAGNOSTIC CRITERIA Th er e is n o specific m a n a gem en t pla n for t r ea t m en t
of TS. Th e ph en ot ypes a r e va r ied a n d det er m in e
E a r ly u lt r a sou n d (14 t o 16 weeks) ca n iden t ify ch a r- scr een in g for r ela t ed h ea lt h con cer n s a n d t r ea t m en t
a ct er ist ics t h a t in cr ea se su spicion of TS. Th ese fin d- of a lt er ed fu n ct ion . In a ddit ion t o m a n a gem en t of
in gs in clu de a la r ge, sept a t ed, cyst ic h y g r o m a (cyst m edica l com plica t ion s, a ssist a n ce in socia liza t ion
wit h a dia m et er la r ger t h a n t h e bipa r iet a l dia m et er fa cilit a t es in depen den t livin g a n d fu n ct ion . Som e
of t h e h ea d) on t h e ba ck of t h e n eck, edem a , sh or t wom en r equ ir e a ssist ed r epr odu ct ion t ech n iqu es t o
fem u r, a n d n a r r ow a or t ic a r ch . Live bor n fem a les a ch ieve pr egn a n cy, su ppor t ed by h or m on e a dm in is-
a r e n ot r ou t in ely scr een ed u n less t h ey pr esen t wit h t r a t ion . In vit r o fer t iliza t ion via a n oocyt e don a t ion
beh a vior a l or ph ysica l ch a r a ct er ist ics con sist en t m a y be n eeded t o pr om ot e pr egn a n cy, a lt h ou gh t h ese
wit h t h e dia gn osis of TS. 44 Pa r en t s r epor t beh a v- wom en m a y fa ce in cr ea sed r isk of a or t ic r u pt u r e r e-
ior s of dela yed developm en t , feedin g pr oblem s, a n d la t ed t o t h e ph ysica l st r essor s of pr egn a n cy. 50
cr yin g du r in g in fa n cy in t h eir da u gh t er s dia gn osed
wit h TS.45 P h ysica l fin din gs in t h e n ewbor n per iod
in clu de pu ffy h a n ds a n d feet fr om lym ph edem a , ex-
t r a n u ch a l skin fr om t h e r em a in in g cyst ic h ygr om a , Sex-Linked Genetic Disorder:
a n d h ea r t defect s, in clu din g h ypopla st ic h ea r t a n d Fragile X Syndrome
coa r ct a t ion of t h e a or t a .38 Sh or t st a t u r e m a y be t h e
on ly ph ysica l ch a r a ct er ist ic in gir ls dia gn osed in F XS is a n exa m ple of a sex-lin ked gen et ic disor der
m id-ch ildh ood. t h a t follows Men delia n in h er it a n ce pa t t er n s. As it s
Ma n y m osa ic in dividu a ls a ffect ed wit h TS a r e n ot n a m e im plies, t h e defect t h a t ca u ses t h e disor der is
dia gn osed u n t il la t er in life, wh en gon a da l fa ilu r e loca t ed on t h e X ch r om osom e. F r a gile X is t h e lea d-
a lt er s r epr odu ct ive developm en t . Dela yed pu ber t y in g ca u se of in h er it ed in t ellect u a l disa bilit y in t h e
162 C h a p t e r 6: Gen et ic a n d Developm en t a l Disor der s

S ma ll S ta ture FS H, LH

We bbe d ne ck
Ta ll, s lim
e unuchoid s ta ture
Coa rcta tion of
the a orta

P oor bre a s t
de ve lopme nt Gyne coma s tia
Wide ly s pa ce d
nipple s

Wide ca rrying
a ngle of a rms

Fe minize d ha bitus
( e s tra diol)

Rudime nta ry Te s ticula r a trophy

ova rie s -gona da l
s tre a k
P rima ry Ba rr body
a me norrhe a
Multiple
A pigme nte d ne vi B

XXY

Figure 6.17. Clinical manifestations of Turner syndrome ( A) and Klinefelter syndrome ( B) . Turner syndrome is charac-
terized by physical manifestations of altered female reproductive development resulting from complete or partial mono-
somy of the X chromosome. (Modified from Rubin E, Farber JL. Pathology. 4th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2005.)

Un it ed St a t es. Th e pr eva len ce of F XS wit h t h e fu ll cyt osin e– gu a n in e–gu a n in e (CGG). Th e n u m ber of

m u t a t ion a ffect s a n est im a t ed 1:4,000 m a les a n d CGG r epea t s wit h in a gen e det er m in es if a per son
1:5,000–8,000 fem a les, t h ou gh it is felt t h a t t h is h a s a t ypica l a llele (less t h a n 55 r epea t s), pr em u t a -
syn dr om e is u n der dia gn osed.51 Appr oxim a t ely 1:250 t ion (55 t o 200 r epea t s), or a fu ll m u t a t ion (m or e t h a n
wom en a r e ca r r ier s of t h e defect ive gen e. 200 r epea t s). 52 Th is defect r esu lt s in t h e im pa ir ed
a bilit y t o pr odu ce t h e fr a gile X m en t a l r et a r da t ion
pr ot ein (F MRP ). Un der n or m a l cir cu m st a n ces, DNA
PATHOPHYSIOLOGY
m et h yla t ion of F MR1 r edu ces gen e a ct ivit y, decr ea s-
Loca t ed on t h e lon g a r m of t h e X ch r om osom e, a in g F MRP pr odu ct ion . As t h e CGG t r iplet r epea t s
n u cleot ide m u t a t ion in t h e fr a gile X m en t a l r e- in cr ea se, t h e t a r get s for DNA m et h yla t ion in cr ea se
t a r da t ion 1 (F MR1) gen e h a s been iden t ified a s r esu lt in g in fu r t h er r edu ct ion of F MRP pr ot ein pr o-
t h e m olecu la r ba sis of t h e syn dr om e. Th e u n u su a l du ct ion a n d r isk for im pa ir ed post n a t a l br a in devel-
m u t a t ion is ch a r a ct er ized by a va r ia ble t r in u cle- opm en t a n d wor sen in g sever it y of ph en ot ype. As is
ot ide r epea t of t h e n it r ogen ba se com bin a t ion of t ypica l in sex-lin ked disor der s, m a les a r e a ffect ed by
t h e disor der a n d fem a les
a r e ca r r ier s.
F R O M T H E L AB
CLINICAL
The FMR1 gene test is specific for diagnosing FXS. Laboratory testing for FXS is done by
MANIFESTATIONS
detection of the triplet expansion region of the FMR1 gene. The laboratory test polymerase
chain reaction (PCR) amplifies the specific alleles. After amplification, Southern blot anal- Th e h a llm a r ks of F XS
ysis is performed to detect the expanded alleles. 53 This test has been shown to detect and in clu de beh a vior a l a n d
measure the CGG repeat effectively, with more than 99% sensitivity and 100% specificity. cogn it ive m a n ifest a t ion s.
Un like ot h er sex-lin ked

disor der s, t h e va r ia t ion s
in t h e gen e m u t a t ion ca n R E S E AR C H N O T E S
lea d t o clin ica l sign s in fe-
m a le ca r r ier s. The use of gene therapy in the treatment of FXS holds promise for a potential treatment or
Beh a vior a l m a n ifes- cure. With current technology, significant challenges exist in determining the delivery of
t a t ion s in m a les in clu de gene therapy and an effective method
a t t en t ion deficit /h yper-
a ct ivit y, expr essive dela y,
n ega t ive r espon se t o t ou ch , r epet it ive speech , a n d
socia l a n xiet y, t h e com m on m a n ifest a t ion s of a u -
t ism spect r u m disor der. Cogn it ive m a n ifest a t ion s
in clu de m en t a l im pa ir m en t , wit h som e a ffect ed
m a les a ffect ed by seizu r es. Typica l ph ysica l fea t u r es
in clu de dist in ct ive fa cia l fea t u r es (pr ot r u din g lower
ja w, la r ge h ea d wit h br oa d for eh ea d), con n ect ive t is-
su e pr oblem s (h yper flexible join t s), below-a ver a ge
h eigh t , a n d m a cr oor ch idism (en la r ged t est icles);
h owever, t h ey a r e n ot specific en ou gh t o dia gn ose
t h e con dit ion .
Fem a le ca r r ier s h a ve fewer a n d less sever e clin i-
ca l m a n ifest a t ion s in clu din g m ild cogn it ive or beh a v-
ior a l defect s, possible a u t ist ic beh a vior s, pr em a t u r e
ova r ia n fa ilu r e, a n d fr a gile-X-a ssocia t ed t r em or /
a t a xia syn dr om e (F XTAS) in m or e sever e degr ees of
m u t a t ion .52
DIAGNOSTIC CRITERIA
Scr een in g for t h e disor der in clu des fa m ily h ist or y or
m a n ifest a t ion s of fr a gile X. Th e r isk of r ecu r r en ce
is h igh in ca r r ier r ela t ives, pr esen t in g a n im por t a n t
con sider a t ion for pr en a t a l t est in g. P r en a t a l scr een -
in g is com plet ed u sin g t h e t ech n iqu es of ch or ion ic
villu s sa m plin g or a m n iocen t esis t o collect sa m ples
for defin it ive gen et ic dia gn osis ba sed on t h e len gt h
of CGG r epea t s in t h e F MR1 gen e. Beca u se t h e clin -
ica l m a n ifest a t ion s a r e va gu e a n d ca n be a ssocia t ed
wit h m a n y ot h er disor der s, in dividu a ls wit h a fa m ily
h ist or y of F XS sh ou ld be scr een ed for t h e disor der.
Cu r r en t ly, F XS is n ot a m on g t h e u su a l disor der s de-
t ect ed by r ou t in e n ewbor n scr een in g.
TREATMENT
No cu r e cu r r en t ly exist s for F XS. Beh a vior a l a n d
edu ca t ion a l m a n a gem en t a n d t r ea t m en t of ph ysi-
ca l sym pt om s a r e r ecom m en ded. Tr ea t m en t of t h e
beh a vior a l pr oblem s a ssocia t ed wit h F XS is im -
por t a n t t o in dividu a l a n d fa m ily fu n ct ion in g a n d
in clu de developm en t a l, edu ca t ion a l, a n d beh a vior a l
in t er ven t ion s. Th e u se of ph a r m a cot h er a py t o m a n -
a ge dist r a ct ibilit y, h yper a ct ivit y, a n d im pu lsivit y
h a s been sh own t o be h elpfu l. An t idepr essa n t s ca n
h elp m a n a ge a n xiet y, obsessive-com pu lsive beh a v-
ior s, a n d m ood ch a n ges. Aggr ession m a y be t r ea t ed
wit h t h e u se of a n t ipsych ot ic m edica t ion s. Th e com -
bin a t ion of t h ese psych oph a r m a cologic a gen t s for
C lin ic a l Mo d e ls 163
54
to target the damaged cells.
specific m a n ifest a t ion s of fr a gile X ca n con t r ibu t e t o
en h a n ced in dividu a l fu n ct ion in g. 55
Stop and Consider
What are the benefits of early prenatal diagnosis
in a child with FXS?
Epigenetic Inheritance: Beckwith–
Wiedemann Syndrome
Beckwit h –Wiedem a n n Syn dr om e (BWS) is a ssoci-
a t ed wit h pedia t r ic over gr owt h a n d pr edisposit ion
t o t u m or gr owt h , lin ked t o gen et ic a n d epigen et ic
a lt er a t ion s. Th e ph en ot ype r a n ges in sever it y a n d
h a s equ a l pr eva len ce a m on g m a les a n d fem a les, oc-
cu r r in g spon t a n eou sly in t h e m a jor it y of in dividu a ls
a ffect ed.
PATHOPHYSIOLOGY
BWS r esu lt s fr om disor der ed epigen et ic r egu la t ion
of im pr in t ed gen es. Regu la t ion of t h e im pr in t ed
gen es in su lin -like gr owt h fa ct or 2 (IGF 2) a n d
H 19, loca t ed in t h e sa m e r egion of ch r om osom e 11
(11p15.5, ba n d 15.5 on t h e sh or t a r m of ch r om osom e
11), is a lt er ed beca u se of ch a n ges in DNA m et h yl-
a t ion in t h e im pr in t in g cen t er in t h e KCNQ1 gen e.
Nea r by KCNQ10T1 a n d CDKN1C gen es m a y h a ve
a ch a n ge in expr ession beca u se of DNA m et h yla t ion
ch a n ges or gen et ic m u t a t ion . Like ot h er im pr in t ed
gen es, bot h IGF 2 a n d H 19 a r e m on oa llelic, t r a n s-
m it t ed by a sin gle pa r en t . IGF 2 is pa t er n a lly in h er-
it ed a n d expr essed, fu n ct ion in g a s a gr owt h fa ct or.
Alt er ed IGF 2 im pr in t in g a n d loss of DNA m et h yla -
t ion in cr ea se gen e expr ession a n d a ssocia t ed gr owt h
fu n ct ion . H 19 is m a t er n a lly in h er it ed a n d expr essed,
fu n ct ion in g a s a t u m or su ppr essor. Alt er ed H 19 im -
pr in t in g a n d ga in of DNA m et h yla t ion decr ea se
gen e expr ession a n d a ssocia t ed t u m or su ppr essor
fu n ct ion . Ch a n ges in gen e expr ession con t r ibu t e t o
over gr owt h a n d t u m or developm en t .
CLINICAL MANIFESTATIONS
Characteristic manifestations of BWS are associated
with overgrowth, including macrosomia (increased
birth weight), macroglossia (large tongue), cardiomeg-
aly, and enlarged abdominal organs. Abdominal wall
164 C h a p t e r 6: Gen et ic a n d Developm en t a l Disor der s
defects (omphalocele) may also be part of the BWS phe-
notype. Metabolic disorders including hypoglycemia
appear soon after birth. Tumors of embryonic origin in-
cluding Wilms tumor, neuroblastoma, hepatoblastoma,
and rhabdomyosarcoma may occur in children during
the first 8 years of life. Clinical manifestations of over-
growth and metabolic disorders can range from mild to
severe and do not reflect tumor risk.56
DIAGNOSTIC CRITERIA
BWS is su spect ed ba sed on clin ica l m a n ifest a t ion s
a n d fa m ily h ist or y, t h ou gh few ca ses of BWS a r e fa -
m ilia l. Gen et ic t est in g is in dica t ed in t h e com plex
dia gn osis of BWS a n d in clu des a n a lysis of epigen e-
t ic a n d gen et ic a lt er a t ion s. As DNA m et h yla t ion ca n
va r y by t issu e t ype, oft en t wo t issu es/cell popu la t ion s
a r e r equ ir ed for defin it ive t est in g. Ka r yot ype det er-
m in a t ion ca n iden t ify t r a n sloca t ion s, in ver sion s, a n d
du plica t ion s. DNA sequ en cin g t o det ect gen et ic m u -
t a t ion s m a y a lso be con du ct ed.
TREATMENT
Ma n a gem en t of BWS du r in g in fa n cy in clu des a ssu r-
in g a ir wa y su fficien cy a n d feedin g a bilit y, bot h pot en -
t ia lly lim it ed by m a cr oglossia . Tu m or su r veilla n ce
in clu des a bdom in a l u lt r a sou n d, MRI, CT exa m in a -
t ion , a n d ch est X-r a y con du ct ed a t r egu la r in t er va ls
t h r ou gh t h e fir st 8 yea r s of life. Alph a -fet opr ot ein
m a y a lso be m ea su r ed for det ect ion of h epa t obla s-
t om a . Ca r dia c eva lu a t ion in clu din g elect r oca r dio-
gr a m a n d ech oca r diogr a m m a y be con du ct ed beca u se
of ca r diom yopa t h y. Tr ea t m en t of m et a bolic disor der s,
in clu din g h ypoglycem ia , is cr it ica lly im por t a n t in t h e
n ewbor n per iod t o r edu ce t h e r isk of cen t r a l n er vou s
syst em com plica t ion s. Gen et ic t est in g is in dica t ed in
t h e a ffect ed in dividu a l a n d fa m ily if t h e gen et ic et i-
ology is fou n d t o be a m u t a t ion or t r a n sloca t ion .
Developmental Maladaptation:
Neural Tube Defects
NTDs are a group of serious birth defects involving the
tissues of the nervous system (the brain and spine).
The fortification of foods with folic acid is recognized
as an important public health strategy in the preven-
tion of NTDs. Pregnancies affected by spina bifida de-
creased from 2,490 to 1,640 annually since fortification
of food with folic acid began in 1998. The number of
infants born with anencephaly decreased from 1,640
to 1,380 annually during the same period. The overall
risk for development of NTDs decreased by 26%.57
To see a video on lumbar myelomeningocele, visit http://
thePoint.lww.com, using the scratch-of code
on the inside ront cover.
PATHOPHYSIOLOGY
NTDs a r e exa m ples of developm en t a l disor der s
du r in g em br yologic developm en t . NTDs r esu lt fr om
in com plet e closu r e of t h e n eu r a l t u be du r in g em br y-
on ic life, t ypica lly du r in g t h e fir st 3 t o 4 weeks a ft er
con cept ion . Th e degr ee of n eu r a l t u be closu r e dist in -
gu ish es bet ween t h e differ en t t ypes of defect s. Th e
m ost com m on con dit ion s r esu lt in g fr om n eu r a l t u be
a n om a lies in clu de spin a bifida a n d a n en ceph a ly.
E a ch of t h ese con dit ion s h a s clin ica l m a n ifest a t ion s
specific t o t h e con dit ion . Ca u ses t h a t m a y con t r ib-
u t e t o t h ese disor der s in clu de t er a t ogen ic or gen et ic
in su lt . Th is defect m a y occu r a lon e or in com bin a -
t ion wit h ot h er a n om a lies a s pa r t of a syn dr om e or
r esu lt fr om a gen et ic or ch r om osom a l a bn or m a lit y.
On e of t h e m a jor r isks iden t ified wit h t h e in cr ea sed
in ciden ce of NTDs is m a t er n a l folic a cid deficien cy.
Th er e is st ill m u ch t o u n der st a n d a bou t t h e u n der ly-
in g bioch em ica l a n d gen et ic m ech a n ism s t h a t lea d t o
folic a cid-a ssocia t ed NTDs.58 Despit e t h e cu r r en t ly
u n expla in ed m ech a n ism of disea se developm en t , t h e
r ecogn it ion of folic a cid a s a ca u se of NTDs h a s r e-
su lt ed in su ccessfu l effor t s in pr even t ion . In 1992,
t h e US Depa r t m en t of H ea lt h a n d H u m a n Ser vices,
P u blic H ea lt h Ser vice, a n d t h e Cen t er s for Disea se
Con t r ol a n d P r even t ion issu ed r ecom m en da t ion s
for t h e u se of folic a cid su pplem en t a t ion t o r edu ce
t h e n u m ber of NTDs in ch ildbea r in g wom en . Rec-
om m en da t ion s in clu ded t h e diet a r y con su m pt ion of
folic a cid 0.4 m g/da y, or a s a su pplem en t . Beca u se fo-
lic a cid deficien cy in t er fer ed wit h NTD developm en t
ea r ly in pr egn a n cy, t h e r ecom m en da t ion s in clu ded
a ll ch ildbea r in g-a ge wom en , in clu din g t h ose n ot
cu r r en t ly pr egn a n t . Not a ll wom en wh o a r e fola t e
deficien t h a ve ba bies wit h NTDs, su ggest in g t h e in -
flu en ce of gen et ic m ech a n ism s in t h e developm en t of
t h e disea se ph en ot ype.
CLINICAL MANIFESTATIONS
Th e st im u lu s t h a t r esu lt s in in com plet e n eu r a l
t u be closu r e is in it ia t ed ea r ly, oft en befor e m a n y
wom en even r ea lize t h ey a r e pr egn a n t . N eu r a l t u be
closu r e occu r s bet ween em br yologic da ys 24 a n d
28, begin n in g cr a n ia lly a t t h e h ea d a n d m ovin g dis-
t a lly t owa r d t h e spin e. In a n en ceph a ly, t h e closu r e
defect is loca t ed in t h e sk u ll a r ea , wit h a ll or pa r t
of t h e t op of t h e sku ll a n d por t ion s of t h e br a in a b-
sen t . Spin a bifida is t h e r esu lt of a closu r e defect in
t h e spin e. Th er e a r e t h r ee m a in va r ia t ion s of spin a
bifida :
1. S p in a b i id a o c c u lt a : in com plet e closu r e of
ver t ebr a e wit h ou t pr ot r u sion of t h e m en in ges or
spin a l cor d
2. Me n in g o c e le : in com plet e closu r e wit h pr ot r u -
sion of m en in ges a n d cer ebr ospin a l flu id
 C lin ic a l Mo d e ls 165

3. My e lo m e n in g o c e le : in com plet e closu r e wit h S ma ll de fe ct of

pos te rior ve rte bra l a rch
pr ot r u sion of m en in ges, cer ebr ospin a l flu id, a n d S kin
spin a l cor d/n er ve r oot s
In m ost ca ses, a n en ceph a ly in volves a sign ifica n t Me ninge s
por t ion of t h e br a in , r esu lt in g in fa t a lit y. Th e sever it y S pina l cord
of spin a l bifida is det er m in ed by t h e in volvem en t of
S uba ra chnoid
t h e spin a l n er ves. Clin ica l m a n ifest a t ion s ca n r a n ge s pa ce
fr om a dim ple a t t h e ba se of t h e spin e in occu lt a t o
Ve rte bra l
lower body pa r a lysis in m yelom en in gocele. Va r ia - body
t ion s in t ypes of NTDs a r e depict ed in Figu r e 6.18. No rmal S pina bifida o c c ulta

DIAGNOSTIC TESTING La rge de fe ct of

pos te rior ve rte bra l
P r ena t a lly, wh en m enin ges a r e in com m unica t ion a rch
wit h a m niotic fluid, a lph a -fet opr otein lea ks fr om t he Me ninge s
cer ebr ospin a l fluid int o t he a m niot ic flu id. Th is ca n
be m ea sur ed indir ect ly th rou gh det er min a t ion of
a lph a -fet opr otein fr om a m a t ern a l blood sa m ple (ma - S pina l
t er na l ser um a lpha -fetopr ot ein [MSAF P]). A m or e cord
dir ect m ea su rem en t of a lph a -fet oprot ein ca n be ob-
Me ning o c e le Mye lo me ning o c e le
t a in ed using a m niot ic fluid via a m niocen tesis. Ana -
t om ic a nom a lies m ay a lso be det ect ed by ult ra soun d,
Acra nia
det ect ion in flu enced by t he loca t ion, a nd size of defect.
Ne ura l groove P rotruding e ye s
(no me ninge s ) Long a rms
TREATMENT
Tr ea t m en t in a n en ceph a ly is u su a lly lim it ed t o su p-
por t ive ca r e a n d com for t . Tr ea t m en t for m en in gocele
a n d m yelom en in gocele r equ ir es su r gica l cor r ect ion
t o pr even t com plica t ion s, bu t it does n ot a lt er n eu -
r ologic da m a ge.
S pina bifida
Ane nc e phaly
Stop and Consider
Are there any risks related to fortifying foods Figure 6.18. Neural tube defects. Variations in neural
with folic acid? Are there risks in other non– tube defects result from incomplete fusion of the neural
childbearing populations (elderly, children, men) tube with bone, soft tissues, or skin. (Modified from Rubin
to folic acid food fortification? Is the economic E, Farber JL. Pathology. 4th ed. Philadelphia, PA: Lippin-
cost associated with food fortification justified? cott Williams & Wilkins; 2005.)

F R O M T H E L AB
Maternal serum alpha-fetoprotein levels were measured in a large study that compared mea-
surements before and after mandatory supplementation in the United States. 57 Consistent
with the decreased incidence of NTDs, the incidence of high MSAFP values was similarly
decreased by 32%, supporting the effectiveness of folic acid fortification efforts.

R E S E AR C H N O T E S
Technologic advances in fetal surgery have contributed to the possibility of intrauterine
closure of myelomeningocele as a preferred therapy for the future. 59 Current studies are un-
derway to determine whether the benefits of intrauterine surgical closure are great enough
to overcome the risks associated with this type of surgery.
166 C h a p t e r 6: Gen et ic a n d Developm en t a l Disor der s
S U MMAR Y
● Alt er a t ion s in gen et ic st r u ct u r e a n d fu n ct ion for m
t h e ba sis of m a n y disea ses.
● Com pon en t s of t h e gen et ic syst em in clu de gen es
a n d ch r om osom es.
● Th e dou ble h elix st r u ct u r e, DNA, is com posed of
specific com bin a t ion s of fou r n it r ogen ou s ba ses,
for m in g gen es a n d ch r om osom es.
● Th e sequ en ce of n it r ogen ou s ba ses in gen es
pr odu ces a m in o a cids, wh ich com bin e t o for m
pr ot ein s.
● Th r ee t ypes of RNA a r e in volved in pr ot ein pr o-
du ct ion a n d in clu de m essen ger RNA, t r a n sfer
RNA, a n d r ibosom a l RNA.
● Th e som a t ic cells of t h e body ea ch con t a in 46 ch r o-
m osom es: 44 a u t osom es a n d 2 sex ch r om osom es.
● Th e in flu en ce of gen et ics ca n be exer t ed by ex-
pr ession of a t r a it , t h e in h er it a n ce of a t r a it , or
t h e est a blish m en t of a pr edisposit ion for disea se.
● Sin gle gen e t r a it s a r e in h er it ed in a n a u t osom a l
dom in a n t , a u t osom a l r ecessive, or sex-lin ked pa t -
t er n or via a m it och on dr ia l gen e disor der.
● Syn dr om es ca u sed by a lt er a t ion s in ch r om osom e
n u m ber or st r u ct u r e a r e a ssocia t ed wit h m u lt iple
clin ica l m a n ifest a t ion s.
● E pigen et ics r egu la t e gen e expr ession t h r ou gh
ch em ica l m odifica t ion s of gen es.
● E pigen et ic m odifica t ion s dir ect gen e expr ession
du r in g developm en t a n d disea se a n d a r e in flu -
en ced by en dogen ou s a n d exogen ou s fa ct or s in -
clu din g en vir on m en t a n d lifest yle.
● Mu lt ifa ct or ia l disor der s in volve bot h gen et ic a n d
en vir on m en t a l fa ct or s.
● Iden t ifica t ion of r isk for gen et ic disor der s is ba sed
on fa m ily h ist or y a n d gen et ic scr een in g.
● Th e com bin a t ion of en vir on m en t a n d gen et ics
m a y u n der lie disea ses t h a t a ffect m or bidit y a n d
m or t a lit y in t h e Un it ed St a t es a n d t h r ou gh ou t
t h e wor ld.
● As con t in u ed in vest iga t ion r evea ls in for m a t ion
t h a t u n locks m a n y gen et ic m yst er ies, t h e socia l
a n d et h ica l im plica t ion s of su ch fin din gs m u st
keep pa ce wit h t h e scien ce.
C AS E S T U D Y 6.1
J.S., a 13-yea r-old m a le, h a s h em oph ilia A. H e is en -
t er in g m iddle sch ool a n d wa n t s t o pla y in t r a m u r a l
foot ba ll. Th in k a bou t a clin ica l m odel m ost r ela t ed t o
t h is dia gn osis. Fr om you r r ea din g r ela t ed t o gen et ic
disor der s, a n swer t h e followin g qu est ion s:
1. Wh a t is t h e pa t h ology a ssocia t ed wit h h em oph ilia ?
2. Wh a t a r e t h e clin ica l m a n ifest a t ion s?
3. Wh a t a r e t h e r isks of h is pa ssin g h em oph ilia on
t o h is fu t u r e da u gh t er s? Son s?
4. Wh a t a r e t h e t r ea t m en t opt ion s for h em oph ilia ?
5. Wh a t a r e t h e r isks r ela t ed t o t r ea t m en t of
h em oph ilia ?
6. Wh a t r ecom m en da t ion s sh ou ld be m a de in ligh t
of h is r equ est t o pla y foot ba ll?
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r n a l
a r t icle or Web sit e t h a t det a ils h em oph ilia t o con fir m
you r pr edict ion s.
C AS E S T U D Y 6.2
Willia m , a 2-yea r-old m a le, h a s a h ist or y of dela yed
m ot or m ilest on es. H e wa s dela yed in r ollin g over, sit -
t in g, a n d st a n din g. H e bega n t o wa lk a t 18 m on t h s.
H e h a s a wa ddlin g ga it a n d difficu lt y clim bin g st a ir s.
Aft er gen et ic t est in g, Willia m wa s dia gn osed wit h
Du ch en n e m u scu la r dyst r oph y (DMD).
1. Wh a t is t h e gen et ic defect a ssocia t ed wit h DMD?
2. Wh a t a r e t h e clin ica l m a n ifest a t ion s of DMD?
3. Wh a t a r e t h e r isks of h is pa ssin g DMD on t o h is
fu t u r e da u gh t er s? Son s?
4. Wh a t a r e t h e t r ea t m en t opt ion s for DMD?
5. Wh a t is t h e life expect a n cy for Willia m ?
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r n a l
a r t icle or Web sit e t h a t det a ils DMD t o con fir m you r
pr edict ion s.
C AS E S T U D Y 6.3
Su sie is a 30-yea r-old fem a le dia gn osed wit h leu ke-
m ia . Leu kem ia is a ca n cer t h a t t a r get s blood for m -
in g t issu e a n d is a ssocia t ed wit h silen cin g of t u m or
su ppr essor gen es.
1. Wh a t effect does silen cin g of t u m or su ppr essor
gen es h a ve in leu kem ia ?
2. Iden t ify h ow DNA m et h yla t ion con t r ibu t es t o t u -
m or su ppr essor gen e silen cin g?
3. Su bst a n ces ca lled DNA m et h ylt r a n sfer a ses
(DNMT) in h ibit or s a r e u sed t o r ever se epigen e-
t ic silen cin g. H ow m igh t t h is h a ve pot en t ia l for
t r ea t m en t of leu kem ia ?
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r n a l
a r t icle or Web sit e t h a t det a ils epigen et ic et iology in
ca n cer a n d epigen et ic m odifier s in t h e t r ea t m en t of
ca n cer t o con fir m you r pr edict ion s.
 C h a p t e r 6: Gen et ic a n d Developm en t a l Disor der s
P R AC T I C E E XAM Q U E S T I O N S
1. A per son ’s ph en ot ype ca n be best descr ibed a s:
a . Th e gen et ic m a keu p of a n in dividu a l
b. Tr a it s t h a t a r e obser va ble or a ppa r en t
c. Tr a it s t h a t a r e in h er it ed in a r ecessive pa t t er n
d. Tr a it s t h a t a r e in h er it ed in a dom in a n t
pa t t er n
2. A per son ’s gen ot ype ca n be best descr ibed a s:
a . Th e gen et ic m a keu p of a n in dividu a l
b. Tr a it s t h a t a r e obser va ble or a ppa r en t
c. Tr a it s t h a t a r e in h er it ed in a r ecessive pa t t er n
d. Tr a it s t h a t a r e in h er it ed in a dom in a n t
pa t t er n
3. Wh ich of t h ese con dit ion s follows a Men delia n
pa t t er n of r ecessive in h er it a n ce?
a . Cor on a r y a r t er y disea se
b. Down syn dr om e
c. Ma r fa n syn dr om e
d. Ta y-Sa ch s disea se
4. Wh ich of t h ese con dit ion s follows a m u lt ifa ct o-
r ia l pa t t er n of in h er it a n ce?
a . Cor on a r y a r t er y disea se
b. Down syn dr om e
c. Ma r fa n syn dr om e
d. Ta y-Sa ch s disea se
5. For t ifica t ion of foods wit h folic a cid h a s r esu lt ed
in a sign ifica n t r edu ct ion in t h e in ciden ce of:
a . H u n t in gt on disea se
b. Tu r n er syn dr om e
c. Neu r a l t u be defect s
d. Cleft lip a n d pa la t e
6. Wh ich of t h e followin g ch r om osom a l a bn or m a li-
t ies ca n r esu lt in a n in h er it a ble for m of t r isom y?
a . Non disju n ct ion du r in g m eiosis
b. Ba la n ced t r a n sloca t ion
c. In ser t ion
d. Delet ion
D I S C U S S I O N AN D
AP P L I C AT I O N
1. Wh a t did I kn ow a bou t gen et ic a n d developm en -
t a l disor der s befor e t oda y?
2. Wh a t body pr ocesses a r e a ffect ed by gen et ic a n d
developm en t a l disor der s? H ow do gen et ic a n d
developm en t a l disor der s a ffect t h ose pr ocesses?
3. Wh a t a r e t h e pot en t ia l et iologies for gen et ic a n d
developm en t a l disor der s? H ow do gen et ic a n d
developm en t a l disor der s develop?
167
4. Wh o is m ost a t r isk for developin g gen et ic a n d
developm en t a l disor der s? H ow ca n t h ese a lt er-
a t ion s be pr even t ed?
5. Wh a t a r e t h e h u m a n differ en ces t h a t a ffect t h e
et iology, r isk, or cou r se of gen et ic a n d develop-
m en t a l disor der s?
6. Wh a t clin ica l m a n ifest a t ion s a r e expect ed in t h e
cou r se of gen et ic a n d developm en t a l disor der s?
7. Wh a t specia l dia gn ost ic t est s a r e u sefu l in det er-
m in in g t h e dia gn osis a n d cou r se of gen et ic a n d
developm en t a l disor der s?
8. Wh a t a r e t h e goa ls of ca r e for in dividu a ls wit h
gen et ic a n d developm en t a l disor der s?
9. H ow does t h e con cept of a lt er a t ion in gen et ics
bu ild on wh a t I h a ve lea r n ed in t h e pr eviou s
ch a pt er a n d in t h e pr eviou s cou r ses?
10. H ow ca n I u se wh a t I h a ve lea r n ed?
R E SOUR CE S
F r a gile X Syn dr om e: NIH Gen et ics H om e Refer en ce
h t t ps://gh r.n lm .n ih .gov/con dit ion /fr a gile-x-syn dr om e
Na t ion a l In st it u t e of Neu r ologica l Disor der s a n d
St r oke H u n t in gt on ’s Disea se In for m a t ion Pa ge:
h t t p://n in ds.n ih .gov/h ea lt h _a n d_m edica l/disor der s/
h u n t in gt on .h t m
Ma r ch of Dim es:
h t t p://m odim es.or g
F in d ou t m or e a bou t n ewbor n scr een in g, in clu din g
st a t e-specific r equ ir em en t s.
Na t ion a l Down Syn dr om e Societ y:
h t t p://www.n dss.or g/
Na t ion a l H u m a n Gen om e Resea r ch In st it u t e, Na -
t ion a l In st it u t es of H ea lt h :
h t t p://www.gen om e.gov/
F in d ou t a bou t gen et ic disor der s, defin it ion s of com -
m on gen et ic t er m s, a n d cu r r en t gen et ic r esea r ch .
Sickle Cell Disea se Associa t ion of Am er ica :
h t t p://www.sicklecelldisea se.or g/
Am er ica n H ea r t Associa t ion . H ea r t Disea se a n d
St r oke St a t ist ics—2009 Upda t e. Da lla s, TX: Am er-
ica n H ea r t Associa t ion ; 2009.
h t t p : / / w w w. a m e r i c a n h e a r t . o r g / p r e s e n t e r
.jh t m l?iden t ifier =3000090
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 Ch a pt er
Alt er ed Cellu la r
7 P r olifer a t ion a n d
Differ en t ia t ion

L E AR N I N G O U T C O ME S
1. Defin e a n d u se t h e key t er m s list ed in t h is ch a pt er.
2. Recogn ize t h e r ole of gen et ic m u t a t ion s in t h e developm en t of n eopla sm s.
3. Discu ss m a jor ca r cin ogen s a n d t h eir r ole in ca r cin ogen esis.
4. Ou t lin e t h e ch a r a ct er ist ics of t u m or cells.
5. Differ en t ia t e ben ign a n d m a lign a n t t u m or s.
6. E xpla in t h e m ech a n ism s of ca n cer spr ea d.
7. Cla ssify t u m or s ba sed on st a gin g a n d gr a din g cr it er ia .
8. Iden t ify loca l a n d syst em ic clin ica l m a n ifest a t ion s of n eopla sia .
9. Descr ibe ca n cer t r ea t m en t st r a t egies.
10. Apply t h e pr in ciples of ca r cin ogen esis t o select clin ica l m odels.

INTR ODUCTION
“You h a ve ca n cer.” Ver y lit t le st r ikes m or e fea r t h a n t h ose t h r ee wor ds.
Alt h ou gh m a n y ca n cer s a r e cu r a ble a n d cu r r en t r esea r ch con t in u es t o su ppor t
pr even t ion , ea r ly det ect ion , a n d effect ive t r ea t m en t opt ion s, ca n cer con t in u es
t o a ffect m illion s of lives ea ch yea r a n d is on e of t h e lea din g ca u ses of dea t h in
t h e Un it ed St a t es.

Brain tumor, 3D-rendered illustration. © Sebastian Kaulitzki.

170
 T h e I m p a c t o C a n c e r o n t h e C e ll 171

Modu le 1 T h e I m p a c t o C a n c e r o n t h e C e ll

Cellu la r p r o li e r a t io n is t h e gen er a t ion of n ew,

da u gh t er cells divided fr om pr ogen it or (pa r en t ) cells.
S te m c e ll
Meiosis is a pr ocess of dividin g ger m cells, r esu lt in g
in ovu m a n d sper m . Mit osis is t h e division a n d pr o-
lifer a t ion of a ll ot h er n on ger m cells. Cellu la r pr olif-
er a t ion t h r ou gh m it osis occu r s con t in u ou sly a n d/or
in r espon se t o n eeds. For exa m ple, epit h elia l cells of S te m ce ll P roge nitor ce ll
t h e skin con st a n t ly r epr odu ce t o r epla ce t h ose da m -
a ged by t h e ext er n a l en vir on m en t . Th ese cells ca n
in cr ea se t h e r a t e of division in t im es of n eed, su ch a s
occu r s wit h a wou n d in ju r y. Sim ila r ly, r ed blood cell Da ughte r ce lls
(RBC) pr olifer a t ion r epla ces RBCs a t t h e en d of t h e
cell’s 120-da y lifespa n a n d a lso in cr ea ses expon en -
t ia lly in t h e ca se of excessive blood loss t o m a in t a in
blood volu m e a n d oxygen a t e t issu es. A r egu la t ed ba l-
a n ce of cell gr owt h a n d cell dea t h is n eeded t o m a in -
t a in h om eost a sis in t h e body. We a r e con cer n ed h er e
wit h t h e loss of r egu la t ed ba la n ce of cell division r e-
su lt in g in t h e over pr olifer a tion a n d cr owdin g of cells.
D i e r e n t ia t io n r efer s t o t h e or der ly pr ocess of
cellu la r m a t u r a t ion t o a ch ieve a specific fu n ct ion .
Regu la t ion of pr olifer a t ion a n d differ en t ia t ion a r e
u n der t h e con t r ol of gen es, gr owt h fa ct or s, n u t r ien t s,
a n d st im u la t ion fr om t h e ext er n a l en vir on m en t . As
wit h pr olifer a t ion , a ba la n ce of differ en t ia t ed (cells Diffe re ntia te d ce ll
wit h a specific fu n ct ion , su ch a s RBCs) a n d u n differ- Figure 7.1. Cellular differentiation is the process by which
en t ia t ed cells (st em cells a n d pr ogen it or cells) is n ec- cells become more specialized. Undifferentiated stem cells
essa r y t o r espon d t o t h e n eeds of t h e body (Fig. 7.1). divide into like stem cells and parent (progenitor) cells,
S t e m c e lls a r e h igh ly u n differ en t ia t ed u n it s t h a t which continue to divide and further differentiate into
h a ve t h e pot en t ia l t o divide in t o pr ogen it or cells, highly specialized and functional cells. (Modified from
t h en da u gh t er cells, wh ich ca n t h en m a t u r e in t o Porth CM. Essentials of Pathophysiology: Concepts of Altered
m or e differ en t ia t ed u n it s wit h a specific fu n ct ion . Health States. Philadelphia, PA: Lippincott Williams &
Un differ en t ia t ed cells a r e va lu ed for t h eir flexibilit y Wilkins; 2003, with permission.)
a n d a da pt a bilit y. Wit h ea ch st ep t owa r d differ en t ia -
t ion , t h e cell loses it s a bilit y t o flexibly r espon d a n d
a da pt bu t ga in s t h e a bilit y t o ca r r y ou t a n im por t a n t cell r epr odu ct ion , gr owt h , differ en t ia t ion , a n d/or
ph ysiologic fu n ct ion . For exa m ple, wit h ext en sive dea t h . Th e cell is t h er efor e a llowed t o gr ow u n con -
blood loss, da u gh t er cells a r e dir ect ed t o differ en t i- t r olla bly (a lt er ed pr olifer a t ion ). Th e cell a lso loses
a t e in t o RBCs t o r epla ce t h e lost blood. Aga in , a ba l- it s a bilit y t o ca r r y ou t it s specified fu n ct ion (a lt er ed
a n ce of u n differ en t ia t ed a n d differ en t ia t ed cells is differ en t ia t ion ) a n d does n ot die wh en expect ed.
n eeded t o m a in t a in h om eost a sis. We a r e con cer n ed C a n c e r is a t er m u sed t o descr ibe h igh ly in va sive
in t h is ch a pt er wit h t h e loss of differ en t ia t ion , r en - a n d dest r u ct ive n e o p la s m s , wh ich a r e ir r ever sible
der in g t h e cell in ca pa ble of ca r r yin g ou t a design a t ed devia n t cell clu st er s. Th ese n eopla st ic cells ign or e
fu n ct ion . t h e gen et ic con t r ols pla ced on cellu la r pr olifer a -
t ion a n d differ en t ia t ion ; t h ey a r e u n con t r olled a n d
u n r egu la t ed.
Neopla sm s ca n em er ge fr om pr olifer a t in g pa -
Altered Cellular Proliferation r en ch ym a l (fu n ct ion a l t issu e a n d or ga n ) or st r om a l
and Differentiation (su ppor t ive st r u ct u r e) cells. Ra pidly dividin g la bile
cells, su ch a s epit h elia l cells a n d blood cells, a r e
At t h e cellu la r level, ca n cer occu r s beca u se of gen e h igh ly pr on e t o t h e developm en t of n eopla sm s. Per-
m a lfu n ct ion t h a t goes u n r epa ir ed. Mor e specifica lly, m a n en t (u n dividin g) cells, su ch a s ca r dia c m yocyt es,
ca n cer is ca u sed by a lt er in g t h ose gen es t h a t con t r ol m a t u r e n eu r on s, a n d t h e len s of t h e eye, a r e n ot .
172 C h a p t e r 7: Alt er ed Cellu la r P r olifer a t ion a n d Differ en t ia t ion

CARCINOGENESIS Ca rcinoge nic

a ge nt
Mu t a t ion s, gen e va r ia n t s, a n d epigen et ics a r e h ea v- Ce ll
ily im plica t ed in c a r c in o g e n e s is , wh ich is t h e DNA re pa ir
or igin a n d developm en t of ca n cer ou s n eopla sm s. (Muta tor ge ne s )
Mu t a t ion s a r e a bn or m a l ch a n ges in t h e DNA of
DNA da ma ge
a gen e (Ch a pt er 6). Th er e a r e t wo m a jor t ypes of
gen e m u t a t ion s wh ich ca n a ffect cell gr owt h a n d Fa ilure of DNA re pa ir
division :
● In h er ited gen e m u t a t ion s (a bou t 5% of ca n cer s) Muta tion in
ce ll ge ne s
a r e pr esen t in t h e egg or sper m a s t h ey com bin e
t o becom e t h e zygot e. Th ese a r e ca lled ger m lin e
or h er edit a r y m u t a t ion s. In gen er a l, in h er it ed
Activa tion of Activa tion of Activa tion of tumor
m u t a t ion s lea din g t o ca n cer h a ve in com plet e growth-promoting a poptos is - s uppre s s ing
pen et r a n ce, m ea n in g n ot ever yon e wit h t h e m u - oncoge ne s controlling ge ne s a nti-oncoge ne s
t a t ion will get ca n cer. Sin ce it t a kes m or e t h a n
on e m u t a t ion in a cell for ca n cer t o occu r, t h ose
wh o h a ve in h er it ed a n a bn or m a l copy of a gen e
a lr ea dy h a ve on e st r ike a ga in st t h em . Addit ion a l Unre gula te d
ce ll growth a nd
m u t a t ion s lea d t o a gr ea t er likelih ood of develop- diffe re ntia tion
in g ca n cer a n d developin g it ea r lier in life. Also,
a ll cells in t h e per son wit h t h e in h er it ed gen e m u -
t a t ion h old t h is m u t a t ion (in clu din g som e of t h e
per son ’s ger m cells) a n d ca n be pa ssed on t o t h e Canc e r
n ext gen er a t ion .
● Acqu ir ed gen e m u t a t ion s (a bou t 95% of ca n cer s)
a r e t h ose t h a t occu r a ft er con cept ion (a r e n ot Figure 7.2. Concept map. The genomic mechanisms of
pr esen t in t h e pa r en t egg or sper m ). Som e a c- cancer. (Modified from Porth CM. Essentials of Pathophysi-
qu ir ed m u t a t ion s a r e ca u sed by en vir on m en t a l ology: Concepts of Altered Health States. Philadelphia, PA:
exposu r es, su ch a s sm oke or r a dia t ion , a n d ot h er s Lippincott Williams & Wilkins; 2003, with permission.)
h a ve n o clea r ca u se. Sin ce we h a ve t wo copies of
m ost gen es (on e fr om ea ch ch r om osom e pa ir ), bot h ● O n c o g e n e s : gen es t h a t code for pr ot ein s in volved
copies m u st m u t a t e for t h e gen e t o lea d t o u n r egu - in cell gr owt h or r egu la t ion
la t ed cell gr owt h a n d division . Acqu ir ed gen e m u - ● Tu m o r s u p p r e s s o r g e n e s : gen es t h a t pr oh ibit
t a t ion s lea din g t o ca n cer oft en occu r m u ch la t er over pr olifer a t ion of cells a n d r egu la t e a popt osis
in life beca u se t h e n u m ber of gen e m u t a t ion s
r equ ir ed t o ca u se ca n cer bu ild u p over t im e. Mu - Oncogenes
t a t ion s, u pon cell division , a r e pa ssed on t o n ew
On cogen e lit er a lly m ea n s “ca n cer gen e.” On cogen es
cells. Th ese m u t a t ion s a r e ca lled som a t ic or spon -
pr om ot e u n r egu la t ed cell gr owt h a n d developm en t
t a n eou s m u t a t ion s a n d a r e n ot pa ssed on t o su bse-
a n d ca n a lso in h ibit cell dea t h . Th e a ct iva t ion of on -
qu en t gen er a t ion s.
cogen es in ger m lin e cells is oft en in com pa t ible wit h
life a n d r esu lt s in spon t a n eou s a bor t ion . Th ose ger-
GENETIC MUTATIONS m lin e m u t a t ion s t h a t a r e n ot let h a l ca n develop in t o
in h er it a ble n eopla sm s. Mor e com m on ly, h owever,
DNA is con st a n t ly bein g da m a ged by t h e en vir on -
a ct iva t ion of on cogen es is seen in t h e spon t a n eou s
m en t . Mu t a t or gen es r epa ir DNA a n d pr ot ect t h e
m u t a t ion of som a t ic cells.
gen om e. By disa blin g t h e pr ot ect ive, DNA-r epa ir in g
Th e con ver sion fr om a “n or m a l” gen e t o on e t h a t
m u t a t or gen es, t h e en vir on m en t is con du cive t o n eo-
in du ces n eopla sia depen ds on t h e m u t a t ion of pr o-
pla st ic developm en t a s m u t a t ion s go u n r epa ir ed
t oon cogen es. P r o t o o n c o g e n e s a r e im por t a n t “n or-
a n d t h e cell becom es u n st a ble. Two m a jor ca t egor ies
m a l” gen es in t h e body wit h a vit a l r ole in r egu la t in g
of gen es exist t h a t , wh en a lt er ed, ca n lea d t o ca n -
cell fu n ct ion . P r ot oon cogen es a r e a lso con sider ed
cer ou s t r a n sfor m a t ion s. Typica lly, a com bin a t ion of
pr ecu r sor gen es t h a t , wh en a ct iva t ed, becom e on co-
m u t a t ion s in volvin g m or e t h a n on e gen e ca t egor y
gen es t h r ou gh on e of t h r ee wa ys:
is n eeded for n eopla sm s t o develop. Th is m u t a t ion –
t r a n sfor m a t ion –n eopla sia evolu t ion is u n iqu e t o 1. Poin t m u t a t ion
ea ch ca n cer t ype, a n d t h e pr ocess oft en t a kes sever a l 2. Tr a n sloca t ion
yea r s (Fig. 7.2). Th ese ca t egor ies in clu de: 3. Gen e a m plifica t ion
 T h e I m p a c t o C a n c e r o n t h e C e ll 173

A poin t m u t a t ion da m a ges a sin gle n u cleot ide ba se c-n eu on cogen e a n d lu n g ca n cer t o t h e c-L-m yc gen e.
pa ir in t h e DNA t h a t lea ds t o t h e developm en t of Mor e t h a n 40 h u m a n on cogen es h a ve been iden t ified.
a lt er ed, u n r egu la t ed pr ot ein s in som a t ic cells. Poin t
m u t a t ion s ca n a r ise spon t a n eou sly or fr om exposu r e
Tumor Suppressor Genes
t o en vir on m en t a l in flu en ces, su ch a s ca n cer-in du cin g
ch em ica ls or u lt r a violet r a dia t ion . Tu m or su ppr essor gen es a r e t h e gen es t h a t r egu la t e
Ch r om osom a l t r a n sloca t ion s h a ve a lso been im - t h e r a t e a t wh ich cells divide a n d die. A m a jor m ech -
plica t ed in t h e a ct iva t ion of on cogen es. Th e ch r o- a n ism for r egu la t in g pr olifer a t ion is t o con t r ol a pop-
m osom e br ea ks, r eloca t es, a n d u n it es wit h a n ot h er t osis (pr ogr a m m ed cell dea t h ) so t h a t t h e opt im a l
ch r om osom e. E n coded pr ot ein s becom e excessive, n u m ber of cells is m a in t a in ed for h om eost a sis. Wh en
a n d t h e cell devia t es fr om expect ed gr owt h , differ- m u t a t ed, t u m or su ppr essor gen es a r e in a ct iva t ed
en t ia t ion , a n d dea t h cycles. Com m on t ypes of ca n - a n d t h e cell becom es “im m or t a l,” m ost likely t h r ou gh
cer s t h a t r esu lt fr om ch r om osom a l t r a n sloca t ion s a lt er a t ion of t h e cell m it och on dr ia . Th is ca n occu r
in clu de leu kem ia s, lym ph om a s, a n d m a n y solid in ger m lin e or som a t ic cells a s in h er it ed or spon t a -
t u m or s. n eou s m u t a t ion s. Th e cell u n der goes u n r est r ict ed
Gen e a m plifica t ion is a pr ocess of a lt er in g t h e pr olifer a t ion , a n d n eopla st ic t r a n sfor m a t ion s a r e
ch r om osom e by a cceler a t in g t h e r eplica t ion of gen es. su ppor t ed. Tu m or su ppr essor gen es ca n be liken ed
Sim ila r t o t r a n sloca t ion s, t h is is a pr oblem of over- t o a wa ll or ga t e. Wh en in t a ct , gr owt h is r est r ict ed.
pr odu cin g gen e pr odu ct s. Gen e a m plifica t ion is im pli- A m u t a t ion is like a la r ge h ole in t h e ga t e, a llowin g
ca t ed in m a n y solid t u m or s, in clu din g br ea st ca n cer u n r est r ict ed gr owt h of t h e cell.
a n d n eu r obla st om a . In m a n y ca ses, t h e gr ea t er t h e Sever a l t u m or su ppr essor gen es exist . Th r ee com -
gen e a m plifica t ion , t h e poor er t h e pr ogn osis. m on t u m or su ppr essor gen es t h a t ca n a llow n eo-
Wit h ea ch t ype of on cogen e t r a n sfor m a t ion , t h e pla sia s t o for m wh en m u t a t ed a r e t h e TP 53 gen e,
ba sic m ech a n ism s of a ct ion in clu de: r et in obla st om a (Rb) gen e, a n d BCL-2 gen e. Th e
TP 53 gen e h a s been im plica t ed a s t h e m ost com m on
● E n codin g gr owt h fa ct or s t o st im u la t e cell
m u t a t ion t h a t lea ds t o t h e developm en t of ca n cer.
over pr olifer a t ion
Loca t ed on ch r om osom e 17, t h is gen e is delet ed or
● Dist u r bin g cell su r fa ce r ecept or s a n d r est r ict in g
m u t a t ed in t h r ee of fou r t ypes of color ect a l ca n cer
cell-t o-cell com m u n ica t ion
a n d is fou n d in m a n y ot h er m a lign a n cies. Th e TP 53
● E n codin g pr ot ein s in t h e cell n u cleu s t o a lt er t h e
gen e is r espon sible for opposin g cell division in r e-
cell cycle, r est r ict a popt osis, a n d im pa ct differ en -
spon se t o cell DNA da m a ge by dela yin g cell develop-
t ia t ion of t h e cell
m en t . Th is dela y a llows t im e for DNA t o be r epa ir ed.
Alt h ou gh on cogen es a r e oft en ca t egor ized a s eit h er If t h e cell ca n n ot be r epa ir ed, t h e TP 53 gen e ca n a lso
vir a l or cellu la r /ch r om osom a l, bot h t ypes r esu lt in for ce t h e da m a ged cell t o u n der go a popt osis. Wit h -
sim ila r a lt er a t ion s t o t h e cell ph en ot ype. Wit h vir a l ou t TP 53, cells a r e u n r espon sive t o t h e n eed for r e-
on cogen es, t h e vir u s in ser t s it self in t o t h e gen et ic pa ir. Cells wit h da m a ged DNA a r e a ble t o r epr odu ce
m a t er ia l of t h e h ost cell, r eplica t es, a n d t h en m oves a n d ca n becom e n eopla st ic.
on t o in fect ot h er cells. Du r in g t h is pr ocess, t h e vir u s Th e Rb gen e is a t u m or su ppr essor gen e t h a t ,
m ay ca pt u r e a por t ion of t h e h ost cell’s gen et ic m a - wh en m u t a t ed, ca n r esu lt in a r a r e ch ildh ood ca n -
t er ia l a lon g wit h it s own . Th e pr oper r egu la t ion of cer of t h e r et in a of t h e eye (r et in obla st om a ). J u st
gen es m a y n ot be possible
if t h is occu r s beca u se t h e
gen et ic r eper t oir e of t h e
F R O M T H E L AB
r et r ovir u s is lim it ed.
Th e n ot a t ion s for on - Genetic testing may be sought by individuals newly diagnosed with cancer or those who
cogen es a r e t h r ee-let t er have family members with cancer. Gene testing involves examining a person’s DNA, typically
a bbr evia t ion s, su ch a s taken from cells in a sample of blood, for mutations linked to that type of cancer. Specific
r a s, n eu , or m yc. Th e or i- genetic mutations have been linked to certain types of cancer, and for some cancer types,
gin or loca t ion of t h e gen e this information has been converted into a clinical test. An accurate gene test can deter-
is in dica t ed by t h e pr efix mine whether a mutation is present but does not guarantee that the disease will develop.
of “v-” for vir u s or “c-” for For example, a woman with the BRCA1 breast cancer susceptibility gene has an 80% chance
cell or ch r om osom e; a ddi- of developing breast cancer by age 65. A woman in that same family could test negative for
t ion a l pr efixes, su ffixes, BRCA1 and still acquire the disease over time at the same rate as the general population. Al-
a n d su per scr ipt s pr ovide though gene testing poses little physical discomfort or risk, the emotional and psychological
fu r t h er delin ea t ion . For consequences may be severe, particularly if there are limited prevention, early detection, or
exa m ple, br ea st ca n cer treatment interventions.
h a s been lin ked t o t h e
174 C h a p t e r 7: Alt er ed Cellu la r P r olifer a t ion a n d Differ en t ia t ion
less t h a n h a lf of t h e ca ses a r e ger m lin e cell m u t a -
t ion s; t h e r em a in in g a r e spon t a n eou s m u t a t ion s in
som a t ic cells. In h er it a n ce of r et in obla st om a follows
a dom in a n t pa t t er n . Th e Rb gen e h a s a m a jor r ole
in su ppr essin g t u m or pr olifer a t ion . Developm en t
of ot h er t ypes of ca n cer, in clu din g ost eosa r com a ,
br ea st ca n cer, pa n cr ea t ic ca n cer, a n d lu n g ca n cer,
h a s a lso been con n ect ed t o in a ct iva t ion of t h e Rb
gen e.
Th e BCL-2 gen e h a s been discover ed t o in h ibit
a popt osis. If gen e BCL-2 becom es m u t a t ed a n d
per m a n en t ly a ct iva t ed, t h e cell wit h t h e a lt er ed
gen e ign or es a ll of t h e n or m a l t r igger s t o die a n d
t h er eby becom es im m or t a l. Th is a lt er ed cell con t in -
u es t o divide by m it osis, pa ssin g a lon g t h e a lt er ed
gen e t o pr ogen y cells. Th ese cells a ccu m u la t e a n d
for m n eopla sm s. BCL-2 m u t a t ion s wer e fir st fou n d
in leu k ocyt es a n d a r e kn own t o lea d t o on e for m of
leu kem ia .
ROLE OF GENE VARIANTS AND EPIGENETICS
Gen e va r ia n t s a r e in h er it ed differ en ces in gen es
t h a t a r e n ot m u t a t ion s bu t ca n st ill h a ve a n im -
pa ct on cell gr owt h a n d division . Gen e va r ia n t s
a r e r efer r ed t o a s polym or ph ism s. Com m on ly, in di-
vidu a ls h a ve a n in h er it ed differ en ce in on e n u cle-
ot ide of a gen e (a sin gle n u cleot ide polym or ph ism ).
Som e of t h ese va r ia n t s h a ve n o obviou s effect on t h e
gen e; som e ca n h a ve m in or effect s, su ch a s im pa ct -
in g est r ogen levels a n d con t r ibu t in g t o h or m on e-
depen den t ca n cer s. Gen e va r ia n t s do n ot ca u se ca n cer
dir ect ly bu t ca n set t h e st a ge for t h e developm en t of
n eopla sm s.
E pigen et ic ch a n ges (t u r n in g gen es on a n d off
bu t n ot a s a r esu lt of polym or ph ism s or m u t a t ion s)
ca n a lso in flu en ce ca r cin ogen esis. Th ese epigen et ic
ch a n ges a r e pr im a r ily t h r ou gh on e of t h e followin g:
● DNA m et h yla t ion
● H ist on e m odifica t ion
● RNA in t er fer en ce
E a ch of t h ese pr ocesses in t er r u pt t h e gen e expr es-
sion by a ddin g or su bt r a ct in g su bst a n ces t h a t a ct i-
va t e or dea ct iva t e DNA, ch r om osom es, or RNA. In
effect , epigen et ic ch a n ges ca n a lt er t h e pa r t s of t h e
gen es t h a t con t r ol cell gr owt h a n d division .
Stop and Consider
Why would someone with Down syndrome
(trisomy 21) have an increased risk of developing
leukemia?
In su m m a r y, gen et ic m u t a t ion s, gen e va r ia n t s,
a n d/or epigen et ic ch a n ges a r e n ecessa r y bu t n ot su f-
ficien t fa ct or s in developin g ca n cer ou s n eopla sm s.
Addit ion a l a lt er a t ion s in t h e h ost cell gen et ic
m a t er ia l, in flu en ced by ca r cin ogen s, is r equ ir ed t o
develop in t o in va sive ca n cer ou s t r a n sfor m a t ion s.
CARCINOGENS
Th e iden t ifica t ion of ca n cer-ca u sin g a gen t s is ba sed
on epidem iologica l st u dies, exper im en t a l r esea r ch ,
a n d kn owledge of cellu la r a n d m olecu la r pa t h ology.
A c a r c in o g e n is a kn own ca n cer-ca u sin g a gen t .
Ca r cin ogen s a r e a gen t s t h a t in t er fer e wit h m olecu -
la r pa t h wa ys a n d ca n in it ia t e or pr om ot e t u m or s t o
for m in t h e body. Som e ca r cin ogen s a r e con sider ed
dir ect beca u se t h ey ca u se m odifica t ion of cell DNA
a n d in t er fer e wit h cell fu n ct ion . Ot h er s a r e con sid-
er ed in dir ect beca u se t h ey in du ce im m u n osu ppr es-
sion or ch r on ic in fla m m a t ion or a ct in con ju n ct ion
wit h ot h er ca r cin ogen s t o in du ce DNA da m a ge.
Cer t a in su bst a n ces or exposu r es a r e kn own t o
ca u se or pr om ot e cellu la r m u t a t ion s, su ch a s r a dia -
t ion , exposu r e t o r ea ct ive oxygen species (fr ee r a di-
ca ls), h or m on es, t oba cco, in fect iou s m icr oor ga n ism s,
a n d ch em ica ls (Fig. 7.3). Beca u se ca n cer exh ibit s a
pr olon ged la t en t per iod bet ween t h e in it ia t ion a n d
on set of clin ica l m a n ifest a t ion s, iden t ifica t ion of a
pr ecise ca r cin ogen ca n be difficu lt .
Radiation
Ion izin g r a dia t ion is bot h a pot en t ia l ca u se of, a n d
t r ea t m en t for, ca n cer. Alt h ou gh r a dia t ion h a s m a n y
dia gn ost ic a n d t h er a peu t ic a pplica t ion s, h igh -en er gy
ion izin g r a dia t ion (ga m m a r a ys, X-r a ys, a n d u lt r a vi-
olet ) is ca pa ble of ca u sin g gen et ic da m a ge in a cell
a n d ca n a lso kill cells dir ect ly. Ra dia t ion in du ces
in ju r y by pr odu cin g r ea ct ive oxygen species. Th ese
u n st a ble m olecu les da m a ge t h e cell m em br a n e, a l-
lowin g t h e r a dia t ion en er gy t o in t er r u pt cell DNA
a n d in voke m u t a t ion s.
La bile cells a r e m ost a ffect ed by r a dia t ion expo-
su r e. Ra dia t ion t r ea t m en t t a kes a dva n t a ge of t h is
fea t u r e wit h t h e t r ea t m en t a im ed a t dir ect ly killin g
cells t h a t a r e h igh ly pr olifer a t ive—m ost n ot a bly,
ca n cer cells. Th e a ccu m u la t ive effect of low-dose
r a dia t ion exposu r e is a n a r ea of ext en sive deba t e.
Beca u se a ll in dividu a ls a r e exposed t o low-dose r a -
dia t ion over t im e, it is difficu lt t o discer n wh et h er
t h e r a dia t ion is t o bla m e for ca r cin ogen esis.
Ult r a violet r a dia t ion is sh or t wa velen gt h elect r o-
m a gn et ic en er gy t h a t , wit h in a cer t a in r a n ge, is a lso
ca pa ble of in du cin g ca r cin ogen esis. Su n exposu r e
is t h e pr im a r y sou r ce. Th e r isk for developin g n eo-
pla sm s, su ch a s wit h skin ca n cer, fr om r a dia t ion ex-
posu r e depen ds on t h e len gt h of exposu r e, fr equ en cy
of bu r n in ju r ies fr om su n exposu r e, a n d skin t on e.
Sim ila r t o ot h er t ypes of r a dia t ion in ju r y, t h e u lt r a -
violet exposu r e (290 t o 320 n m wa velen gt h s) dir ect ly
kills cells a n d ca n in du ce cellu la r m u t a t ion .
 T h e I m p a c t o C a n c e r o n t h e C e ll 175

S unlight
(ultra viole t ra dia tion)
Ra dia tion
S kin c anc e r
Thyro id c anc e r

Inha la tion ca rcinoge ns

(ciga re tte s moke ) Virus e s

Lung c anc e r Lympho ma (thymus ,

lymph no de s )

Live r ca rcinoge ns
(milde we d gra in)

Live r c anc e r

Die ta ry ca rcinoge ns
(s moke d foods )

S to mac h and
inte s tinal c anc e r

Excre tory ca rcinoge ns Conta ct

(indus tria l che mica ls ) ca rcinoge ns

Bladde r c anc e r S kin c anc e r

Huma n pa pilloma virus

(unprote cte d s e x)

Ce rvic al c anc e r
Figure 7.3. Potential carcinogens and corresponding cancers.

Stop and Consider a n d ca n in h ibit m it osis. Th ese dr u gs a lso h a ve po-

Do you think microwave ovens, electromagnetic
fields, and ultrasound, as energy transmitters,
would induce cellular injury?
Hormones
H or m on es, like r a dia t ion , a r e a lso a ca n cer pr om ot er
a n d t r ea t m en t . Som e t u m or cells a r e r espon sive
t o, or depen den t on , h or m on es for gr owt h . Tu m or s
of t h e br ea st , u t er u s, pr ost a t e, a n d a dr en a l gla n ds
oft en con t a in r ecept or s t h a t a r e r espon sive t o h or-
m on e levels in t h ese t issu es.
H or m on es ca n a lso be con sider ed a ca n cer t r ea t -
m en t . Th ey ca n be t h er a peu t ica lly a dm in ist er ed t o
block t h e effect s of t u m or gr owt h . For exa m ple, t h e
a dr en a l cor t icost er oid h or m on es (i.e., pr edn ison e)
ca n dir ect ly kill t u m or cells, especia lly lym ph cells,
t en t a n t i-in fla m m a t or y effect s. Rem ova l of or ga n s
or t issu es t h a t secr et e specific h or m on es in t h e
body will a lso a ffect t u m or gr owt h . H or m on es su ch
a s est r ogen a n d t est ost er on e ca n be m a n ipu la t ed
t o “st a r ve” t h e t u m or a n d pr oh ibit fu r t h er gr owt h .
Ta m oxifen is a dr u g com m on ly u sed in br ea st ca n cer
t r ea t m en t . Ta m oxifen blocks t h e a ct ion of est r ogen
a n d in h ibit s t u m or gr owt h in t h e est r ogen -sen sit ive
br ea st t issu es.
Chemicals
Ma n y ch em ica ls h a ve been im plica t ed in ca r cin ogen -
esis, su ch a s t oba cco, a sbest os, ben zen e, in sect icides,
a n d for m a ldeh yde. Th e ba sic m ech a n ism for dir ect
or in dir ect ch em ica l ca r cin ogen esis in clu de t h e de-
velopm en t of h igh ly r ea ct ive species, su ch a s fr ee
176 C h a p t e r 7: Alt er ed Cellu la r P r olifer a t ion a n d Differ en t ia t ion
r a dica ls, t h a t in du ce cell m u t a t ion or a lt er cell pr o-
t ein s or en zym es t o in t er fer e wit h cell r egu la t ion . E n -
zym es in t h e body a r e r espon sible for m et a bolizin g
a n d in a ct iva t in g pot en t ia lly ca r cin ogen ic ch em ica ls.
Gen et ic fa ct or s, en vir on m en t a l fa ct or s, a n d lifest yle
(especia lly diet ) in flu en ce t h ese en zym e levels a n d
t h er efor e in flu en ce t h e developm en t of ch em ica l
ca r cin ogen esis. P r edict in g wh o will develop ca n cer
fr om exposu r e t o specific ch em ica ls is ver y difficu lt
given ou r fr equ en t con t a ct wit h n u m er ou s sou r ces of
va r yin g pot en cies. A com plet e list of kn own , pr oba -
ble, a n d possible ch em ica l ca r cin ogen s is m a in t a in ed
by t h e Am er ica n Ca n cer Societ y a n d is fou n d in t h e
r efer en ce sect ion of t h is ch a pt er.
Tobacco
Ciga r et t e t a r con t a in s t h ou sa n ds of su bst a n ces,
m a n y of wh ich a r e ca r cin ogen ic. Appr oxim a t ely
on e in t h r ee ca n cer dea t h s in t h e Un it ed St a t es ca n
be lin ked t o t oba cco. 1 In h a lin g ciga r et t e a n d ciga r
sm oke is t oxic t o r espir a t or y m u cosa a n d is kn own
t o ca u se lu n g ca n cer. Use of t oba cco is a lso r espon -
sible for in it ia t in g or pr om ot in g m a n y ot h er t ypes of
ca n cer, su ch a s la r yn gea l, lip, esoph a gea l, a n d bla d-
der ca n cer. Sm okin g, a s wit h ot h er ch em ica l ca r cin -
ogen s, exh ibit s a dose effect ; t h a t is, t h e lon ger a n d
h ea vier t h e sm okin g or t oba cco u se or exposu r e, t h e
gr ea t er t h e r isk for t h e developm en t of n eopla sm s.
Microbes
Vir a l in fect ion s a r e est im a t ed t o be r espon sible for
15% of a ll h u m a n ca n cer s. Th e m ost pr eva len t of
t h ese is ca u sed by h u m a n pa pillom a vir u s (H P V) a n d
t h e h epa t it is vir u ses. H P V is t r a n sm it t ed du r in g
sexu a l in t er cou r se t o t h e fem a le cer vix wh er e cer-
t a in st r a in s of t h e vir u s ca n lea d t o cer vica l ca n cer.
Th e h epa t it is B or C vir u ses ca n lea d t o h epa t ocel-
lu la r ca n cer.
Vir u ses va r y by t h e m ech a n ism s lea din g t o n eo-
pla sia . For exa m ple, r et r ovir u ses, su ch a s H IV, ca n
a lt er gen es or pr ot ein s t h a t r egu la t e t h ese gen es
dir ect ly a n d a lso r en der t h e im m u n e syst em de-
fen seless. In t h e pr ocess of ca r cin ogen esis, vir a l pr o-
t ein s a r e n ecessa r y t o in it ia t e, m a in t a in , or en h a n ce
t h e m a lign a n t ph en ot ype. A few ba ct er ia , su ch a s
H elicoba cter pylor i, a r e a lso con sider ed ca r cin ogen ic.
Ch r on ic in fla m m a t ion , a com m on com plica t ion of
ch r on ic in fect ion , is kn own t o su ppor t t u m or gr owt h .
Initiation–Promotion–Progression
Theory
Ca r cin ogen esis is a h igh ly com plex pr ocess. Mu lt i-
ple st eps a r e in volved in t h e developm en t of n eo-
pla sm s, a n d sever a l t h eor ies h a ve been su ggest ed.
On e su ch t h eor y pr oposes t h a t a n in it ia t in g even t
m u st be com bin ed wit h a pr om ot in g even t for ca n cer
t o develop a n d t h en pr ogr ess (F ig. 7.4). Th is in it ia -
t ion –pr om ot ion –pr ogr ession t h eor y u n der scor es t h e
idea of cofa ct or s in ca n cer et iology. Th e in it ia t in g
e v e n t ca u ses a m u t a t ion in a cell. Th e in it ia t in g
even t m a y even t u a lly be iden t ified, bu t m a n y t im es
it is n ot . Th e p r o m o t in g e v e n t is a n expa n sion of
t h e m u t a t ed cell’s gr owt h a n d r epr odu ct ion . Th e con -
t in u ed gr owt h of t h e cell depen ds on con t in u ed expo-
su r e t o t h e pr om ot er. A com m on ca n cer pr om ot er is
ch r on ic in fla m m a t ion . For exa m ple, ch r on ic ga st r it is
h a s been im plica t ed in t h e developm en t of ga st r ic
ca n cer. Ot h er ca n cer pr om ot er s in clu de h or m on es
a n d ch em ica ls in t h e en vir on m en t . P r o g r e s s io n
is a n ext en sion of t h e pr om ot ion ph a se wit h on e
except ion : n ow t h e ca n cer ou s gr owt h is n o lon ger
depen den t on con t in u ed exposu r e t o t h e pr om ot er.
Th e gr owt h n ow becom es a u t on om ou s. Th e cell is
ca pa ble of fu n ct ion in g ou t side of t h e r u les t h a t r eg-
u la t e cell gr owt h , division , a n d dea t h . If eit h er t h e
Norma l ce ll
Ca rcinoge nic a ge nt
(che mica ls , ra dia tion,
virus e s )
DNA da ma ge Initiatio n
a nd ce ll muta tion
Activa tion of
onconge ne s by Pro mo tio n
promote r a ge nt
Ma ligna nt tumor Pro g re s s io n
Figure 7.4. Initiation–promotion–progression theory.
Initiation involves the exposure of cells to a carcinogenic
agent. A promoter agent activates promotion and unregu-
lated cell growth begins. Progression is the acquisition of
independent growth of tumor cells. (Modified from Porth
CM. Essentials of Pathophysiology: Concepts of Altered
Health States. Philadelphia, PA: Lippincott Williams &
Wilkins; 2003, with permission.)
 T h e I m p a c t o C a n c e r o n Tis s u e s , O r g a n s , a n d O r g a n S y s t e m s 177

in it ia t in g or pr om ot in g even t occu r s in isola t ion , or im por t a n t ly, n ot a ll in dividu a ls wh o a r e exposed t o a

if t h e pr om ot er occu r s befor e t h e in it ia t or, ca n cer ca n cer-ca u sin g a gen t develop ca n cer ou s n eopla sm s.
does n ot develop. Th is fa ct h igh ligh t s t h e com plex in t er a ct ion of h e-
Oft en , t h e exa ct in it ia t or-pr om ot er even t is r edit y a n d t h e en vir on m en t in t h e et iology a n d pr o-
n ot clea r ly iden t ified. Also, a n d per h a ps m ost m ot ion of ca n cer.

Modu le 2 T h e I m p a c t o C a n c e r o n Tis s u e s ,
Or ga n s, a n d Or ga n Syst em s

Neopla sm s exh ibit a u t on om y a n d a n a pla sia .

Au t o n o m y r efer s t o t h e u n r egu la t ed pr olifer a -
t ion of t h e n eopla sm . An a p la s ia r efer s t o t h e loss
of cell differ en t ia t ion a n d t h er efor e t h e loss of cell
fu n ct ion . Th e gr ea t er t h e degr ee of a n a pla sia t h e
m or e a ggr essive, or m a lign a n t , t h e t u m or will be.
Wh en a n a lyzin g cells u n der a m icr oscope, t h ose
wit h gr ea t er a n a pla sia sh ow wide va r ia t ion in size
a n d sh a pe wit h en la r ged n u clei a n d r a pid, a t ypica l
m it osis (F ig. 7.5).
Neopla sm s exh ibit sever a l ot h er dist in ct
ch a r a ct er ist ics:

● Loss of cell-t o-cell com m u n ica t ion , wh ich a llows

fu r t h er u n r est r ict ed gr owt h of t u m or cells
● In cr ea sed en er gy expen dit u r e, wh ich depr ives u n -
a ffect ed cells of n u t r ien t s
● In cr ea sed m ot ilit y a n d loss of coh esion /a dh esion ,
wh ich pr om ot es m ovem en t t o ot h er loca t ion s
● Ra pid a n giogen esis, wh ich pr ovides ext en sive
blood flow t o t h e t u m or cells
● Su bst a n ce secr et ion , wh ich a lt er s t h e m et a bolism
a n d degr a des n eigh bor in g u n a ffect ed cells
● P r esen ce of for eign a n t igen s on t h e ca n cer cell
su r fa ce, wh ich ca n t r igger t h e im m u n e r espon se

P r olifer a t in g cells a r e t ypica lly sen sit ive t o t h e pr es-

en ce of n eigh bor in g cells. Du r in g wou n d h ea lin g,
wh en cell-t o-cell con t a ct is est a blish ed, t h e cells n o
lon ger r epr odu ce. Wh en t h is con t a ct is lost , DNA,
RNA, a n d pr ot ein s a r e t r igger ed t o syn t h esize n ew
cells. Neopla st ic cells a r e n ot sen sit ive t o cell-t o-cell
m essa ges. Th e n eopla st ic cells do n ot r ecogn ize t h a t Figure 7.5. Cells with greater anaplasia show wide variation
ot h er cells a r e n ea r by a n d do n ot r espon d a ccor d- in size and shape with enlarged nuclei.
in gly by decr ea sin g t h e r a t e of r epr odu ct ion . Neo-
pla sm s exh ibit devia n t a n d excessive gr owt h fa ct or s
t h a t a llow r a pid r epr odu ct ion a n d a n giogen esis (de- ext r a cellu la r m a t r ix a n d a llow t h e t u m or t o m ove
velopm en t of n ew blood vessels) t o m eet t h e ext r em e in t o n eigh bor in g t issu es.
n u t r ien t dem a n ds of t h e t u m or cells. Th e blood flow Cellu la r m u t a t ion s a n d a ber r a t ion s a r e seen a s a
dem a n ds of n eopla st ic cells depr ive n eigh bor in g t is- t ype of cellu la r in ju r y t h a t is su bject t o dest r u ct ion
su es of a dequ a t e oxygen a n d ot h er n u t r ien t s, wh ich by t h e in fla m m a t or y a n d im m u n e r espon ses. Th e
r esu lt in t issu e isch em ia a n d n ecr osis. Th e t u m or t u m or cells expr ess a n t igen s seen a s for eign t o t h e
cells ca n a lso secr et e en zym es t h a t degr a de t h e h ost . Ma n y cellu la r t r a n sfor m a t ion s a r e r em oved
178 C h a p t e r 7: Alt er ed Cellu la r P r olifer a t ion a n d Differ en t ia t ion
fr om t h e body by t h ese a ct ive defen se m ech a n ism s
a n d n ever pr ogr ess t o for m t u m or s in t h e body. Im -
m u n odeficien cy, t h er efor e, r esu lt s in a m u ch h igh er
r isk for t h e developm en t of ca n cer.
Benign Versus Malignant
Tu m or s a r e cla ssified a s ben ign or m a lign a n t
(Fig. 7.6). Th e t er m s ben ign a n d m a lign a n t r efer t o
t h e t u m or loca t ion a n d a ppea r a n ce r ela t ed t o t h e
t issu e of or igin (t h e u n a ffect ed t issu e su r r ou n d-
in g t h e n eopla sm ). Typica lly, t u m or s t h a t r em a in
loca lized a n d closely r esem ble t h e t issu e of or igin
a r e con sider ed b e n ig n . In ot h er wor ds, ben ign t u -
m or s over pr olifer a t e bu t do n ot dem on st r a t e a sig-
n ifica n t loss of differ en t ia t ion . Ben ign t u m or s a r e
oft en m et wit h a sigh of r elief; h owever, ben ign is
n ot a lwa ys equ iva len t t o h a r m less. La r ge ben ign
t u m or s ca n im pin ge on n ea r by st r u ct u r es, obst r u ct
vit a l fu n ct ion s, a n d ca n even r esu lt in dea t h . In
som e ca ses, ben ign gr owt h s, su ch a s polyps or skin
t a gs, a r e r ecogn ized a s t u m or s bu t a r e n ot a ct u a lly
n eopla st ic.
Tu m or s t h a t a r e in va sive, dest r u ct ive, pr olifer-
a t e r a pidly, spr ea d t o ot h er sit es (m et a st a size), a n d
do n ot r esem ble t h e t issu e of or igin a r e con sider ed
m a lig n a n t . Ma lign a n t t u m or s ca n pr om ot e isch -
em ia a n d n ecr osis of t issu e beca u se t h e t u m or u ses
en er gy a n d n u t r ien t s n eeded by u n a ffect ed t issu es.
As st a t ed pr eviou sly, t h e t er m ca n cer is u su a lly
equ a t ed wit h m a lign a n t n eopla sm s.
A
B
Figure 7.6. Benign versus malignant tumors. A: Benign
tumor shows a slow-growing mass that has not yet invaded
nearby tissues. B: Malignant tumor shows aggressive cell
growth and invasion into nearby tissues and blood vessels.
Cancer Spread
Neopla sm s in va de loca lly by im pin gin g on a n d m ov-
in g in t o n ea r by t issu es. L o c a l s p r e a d is t h e pr olif-
er a t ion of t h e n eopla sm wit h in t h e t issu e of or igin .
E n la r gem en t of t u m or s wit h in t h e t issu e or or ga n
pr om ot es loss of fu n ct ion a n d ca n r esu lt in obst r u c-
t ion , h em or r h a ge, a n d n ecr osis. Alt h ou gh t h e t u m or
is get t in g la r ger, it r em a in s loca lized a t t h is ea r ly
st a ge. Obviou sly, con fin ed n eopla st ic gr owt h s equ a t e
t o a m or e fa vor a ble pr ogn osis.
D ir e c t e x t e n s io n is a pr ocess of t u m or cells m ov-
in g in t o a dja cen t t issu es a n d or ga n s. Th is a spect of
in va sion beyon d t h e loca l t issu es is a defin in g ch a r-
a ct er ist ic of m a lign a n cy. Pen et r a t ion of t h e ba sem en t
m em br a n e is t h e fir st st ep for epit h elia l t u m or s.
Th ose t u m or s loca t ed in a r ea s wit h ou t a ba sem en t
m em br a n e in cu r less r esist a n ce t o in va de dist a lly.
Th e n eopla st ic cells a dh er e t o t h e ext r a cellu la r m a -
t r ix by expr essin g su r fa ce a dh esion m olecu les. Th e
t u m or pr oceeds by r elea sin g en zym es t h a t dissolve
t h e ext r a cellu la r m a t r ix. On ce fr ee of t h e con fin es
of t h e loca l t issu e or or ga n , t h e t u m or t r a vels t o
n ea r by st r u ct u r es, a dh er es t o a dja cen t ext r a cellu la r
m a t r ices, a n d a ga in r elea ses en zym es t h a t degr a de
t h e n eigh bor in g m a t r ix a n d a llow t h e t u m or t o m ove
in t o t h e n ea r by t issu es a n d or ga n s. S e e d in g is a
for m of dir ect ext en sion in wh ich n eopla st ic pr olif-
er a t ion occu r s wit h in per it on ea l a n d pleu r a l ca vit ies
su r r ou n din g t h e a ffect ed t issu e or or ga n . Th e m a lig-
n a n t t u m or s m ove a lon g t h ese m em br a n es a n d ca n
ga in ea sy a ccess t o ot h er or ga n s su ppor t ed wit h in
t h ese ca vit ies.
Me t a s t a s e s occu r wh en n eopla sm s a r e spr ea d t o
dist a n t sit es oft en by wa y of t h e lym ph a t ics or blood
vessels (F ig. 7.7). Th e let h a l a spect of ca n cer is m et -
a st a t ic gr owt h . On ce t h e n eopla sm h a s m oved t o a
dist a n t sit e, det ect ion a n d t r ea t m en t becom e m u ch
m or e com plex.
Th e m ech a n ism for m ovem en t of n eopla sm s t o
dist a n t sit es is a pr ocess of a dh er en ce a n d degr a da -
t ion wit h t h e a ddit ion of a ccess t o t h e blood a n d lym -
ph a t ics. Th e t u m or cells a ccom plish t h is by:
1. Br ea kin g t h r ou gh t h e ba sem en t m em br a n e (if
pr esen t ) a n d ext r a cellu la r m a t r ix
2. Ga in in g a ccess t o a n d cir cu la t in g wit h in t h e blood
vessels or lym ph syst em
3. Lea vin g t h e blood vessels or lym ph syst em a n d
a dh er in g t o dist a n t t issu es
4. E st a blish in g a n ew n u t r ien t n et wor k a t t h e dis-
t a n t t issu es t h r ou gh a pr ocess of a n giogen esis
Tu m or s ca n a ccess dist a n t sit es m ost r ea dily
t h r ou gh t h e lym ph a t ic syst em . Lym ph a t ic ca pilla r-
ies a n d ven u les a r e t h in n er t h a n ot h er blood a n d
lym ph a t ic vessels a n d a r e t h er efor e less r esist a n t t o
 T h e I m p a c t o C a n c e r o n Tis s u e s , O r g a n s , a n d O r g a n S y s t e m s
P rima ry tumor
Extra ce llula r ma trix
P la te le ts
Hos t lymphocyte s
Me ta s ta tic tumor
Angioge ne s is
Figure 7.7. Metastatic spread of tumors through the
vascular system. A primary benign tumor shows a
slow-growing mass that has not invaded nearby tissues.
A malignant tumor shows aggressive cell growth and
invasion into nearby tissues and blood vessel.
in va sion by n eopla sm s. Th e n eopla sm bin ds t o en -
dot h elia l cells in t h e vessels, r elea ses en zym es t h a t
degr a de t h e vessel wa ll, a n d m oves in t o t h e blood
or lym ph cir cu la t ion . If t h e im m u n e defen se is u n -
su ccessfu l, t h e t u m or cells t h en t r a vel t h r ou gh t h e
cir cu la t ion t o dist a n t sit es, a t t a ch a n d m ove t h r ou gh
vessel wa lls, exit t h e cir cu la t ion , a n d m ove in t o t h e
dist a n t sit e. On ce in side t h e n ew loca t ion , t h e n eo-
pla sm m u st r eest a blish a n u t r ien t n et wor k t h r ou gh
a pr ocess of a n giogen esis. Th e t u m or secr et es gr owt h
fa ct or s t h a t a llow t h e developm en t of va scu la r flow
t o t h e pr olifer a t in g n eopla sm a t t h e dist a n t sit e.
Vessels a r e gen er a t ed, a n d t h e t u m or con t in u es t o
pr olifer a t e.
Th e pr efer r ed loca t ion of t h e n ewly set t led n eo-
pla sm is som ewh a t pr edict a ble. Or ga n t r o p is m is a
t er m u sed t o descr ibe t h e a ffin it y of a pr im a r y t u m or
179
t o a specific dist a n t sit e. Fa ct or s t h a t pr om ot e pr ef-
er en t ia l r eloca t ion in clu de:
1. A fa vor a ble en vir on m en t offer ed by t h e n ew t is-
su e or or ga n
2. Adh er en ce m olecu le com pa t ibilit y bet ween t h e
n eopla sm a n d t h e n ew t issu e or or ga n
3. Th e loca t ion of t h e or ga n in r ela t ion t o t h e pa t h
of blood flow
For exa m ple, t u m or s t h a t or igin a t e in t h e colon a r e
pr on e t o m et a st a sizin g in t h e liver. Th is is r ela t ed
t o ea sy a ccess of colon t u m or cells t h r ou gh t h e vein s
of t h e por t a l cir cu la t ion , wh ich t r a vels dir ect ly t o
t h e liver, a llowin g a dh er en ce of t u m or cells t o t h is
or ga n . An ot h er com m on sit e for m et a st a t ic gr owt h
is t h e lu n g, wh er e t u m or cells a dh er e a ft er bein g
t r a n spor t ed t h r ou gh t h e ven a ca va . Or ga n t r opism
is a lso dem on st r a t ed in t u m or s t h a t m ove fr om t h e
lu n g t o t h e br a in a n d fr om t h e br ea st or pr ost a t e t o
t h e bon e.
Cancer Nomenclature
Iden t ifica t ion of t h e t u m or t ype ba sed on t h e t issu e
of or igin is a com m on m et h od of n a m in g n eopla sm s.
Alt h ou gh n ot u sed con sist en t ly, t h e su ffix “om a ” is
oft en em ployed t o design a t e t u m or s ba sed on cell or
t issu e of or igin . Th e cell or t issu e of or igin is pla ced
dir ect ly befor e t h is su ffix in ben ign t u m or s. For ex-
a m ple, a ben ign t u m or of t h e squ a m ou s epit h eliu m
is r efer r ed t o a s a n e p it h e lio m a . Wh en t h e sa m e
cell or igin pr esen t s a s fin ger like pr oject ion s, it is r e-
fer r ed t o a s a p a p illo m a . Ben ign t u m or s of gla n -
du la r epit h elia l or igin a r e t er m ed a d e n o m a s ; t h ose
t h a t a r ise fr om ger m cells a r e ca lled t e r a t o m a s ;
t h ose t h a t a r ise fr om bon e cells a r e kn own a s o s t e -
o m a s ; a n d t h ose st em m in g fr om ch on dr ocyt es a r e
ca lled c h o n d r o m a s .
Wh en t h e t u m or is m a lign a n t, t h e cell or t issu e
pr efix a n d t h e su ffix “om a ” r em a in wit h on e a ddit ion :
“ca r cin ” is pla ced in t h e m iddle t o design a t e m a lig-
n a n t epit h elia l cells, a n d “sa r c” is pla ced in t h e m id-
dle t o design a t e m a lign a n t con n ect ive t issu e cells.
For exa m ple, a m a lign a n t t u m or of epit h elia l cells is
ca lled a n a d e n o c a r c in o m a . A m a lign a n t t u m or of
ch on dr ocyt es is a c h o n d r o s a r c o m a . As in dica t ed,
t h is n om en cla t u r e does n ot a lwa ys follow a con sis-
t en t pa t t er n . Lym ph om a , m ela n om a , leu kem ia , a n d
h epa t om a a r e a ll m a lign a n t n eopla sm s. Ta ble 7.1
fu r t h er dist in gu ish es ben ign a n d m a lign a n t t u m or
n om en cla t u r e.
C a r c in o m a in s it u is a u n iqu e t er m u sed t o de-
scr ibe ca r cin om a s con fin ed t o t h e epit h eliu m t h a t
h a ve n ot yet pen et r a t ed t h e ba sem en t m em br a n e.
Th ese n eopla sm s r em a in “in sit u ” for a n in defin it e
180 C h a p t e r 7: Alt er ed Cellu la r P r olifer a t ion a n d Differ en t ia t ion

Tu m or g r a d in g is a pr ocess of
Ta b le 7.1 Tu m or Nom en cla t u r e differ en t ia t in g t h e level of a n a -
Tis s u e T y p e B e n ig n Tu m o r s Ma lig n a n t Tu m o r s pla sia depict ed by t h e t u m or.
Tu m or s a r e gr a ded fr om I (well
E p it h e lia l
differ en t ia t ed) t o IV (h igh ly
Su r fa ce Pa pillom a Squ a m ou s cell ca r cin om a u n differ en t ia t ed). As t h e t u -
Gla n du la r Aden om a Aden oca r cin om a m or gr a de in cr ea ses, t h e cells
E n d o t h e lia l becom e m or e devia n t fr om t h e
Blood vessels H em a n giom a H em a n giosa r com a t issu e of or igin . Th ose t h a t a r e
Lym ph vessels Lym ph a n giom a Lym ph a n giosa r com a gr a ded lower (I or II) r esem ble
t h e t issu e of or igin in t er m s
C o n n e c t iv e
of size, sh a pe, st r u ct u r e, a n d
F ibr ou s F ibr om a F ibr osa r com a
m it ot ic a ct ivit y. Th ose wit h a
Adipose Lipom a Liposa r com a h igh er gr a de (III or IV) dem on -
Ca r t ila ge Ch on dr om a Ch on dr osa r com a st r a t e lit t le r esem bla n ce t o t h e
Bon e Ost eom a Ost eosa r com a t issu e of or igin .
Mu s c le
Sm oot h m u scle Leiom yom a Leiom yosa r com a
St r ia t ed m u scle Rh a bdom yom a Rh a bdom yosa r com a Cancer Prognosis
Neu r a l
Glia l t issu e Gliom a Gliobla st om a , a st r ocy- Ma n y fa ct or s a ffect t h e likely
cou r se a n d ou t com e a ft er a pa -
t om a , m edu llobla st om a , or
oligoden dr ogliom a t ien t is dia gn osed wit h ca n cer,
Men in ges Men in giom a Men in gea l sa r com a in clu din g t h e t ype, loca t ion ,
B lo o d a n d st a ge of t h e disea se, a s
Gr a n u locyt e Myelocyt ic leu kem ia well a s t h e per son ’s a ge, over a ll
E r yt h r ocyt e Polycyt h em ia ver a h ea lt h , a n d r espon se t o t r ea t -
m en t . Ca n cer pr ogn osis is t yp-
P la sm a cells Mu lt iple m yelom a
ica lly com m u n ica t ed ba sed on
Lym ph ocyt e Lym ph ocyt ic leu kem ia or
lym ph om a
a 5-yea r su r viva l r a t e. A 5-yea r
r ela t ive su r viva l r a t e is t h e
per cen t a ge of per son s wh o a r e
livin g 5 yea r s a ft er dia gn osis. Th e 5-yea r su r viva l
r a t e in clu des t h ose wh o a r e ca n cer fr ee, in r em is-
per iod. Du r in g t h is t im e, t h e t u m or is oft en a sym p- sion , or livin g wit h ca n cer.
t om a t ic. Det ect ion of t u m or s in sit u r epr esen t s a fa -
vor a ble pr ogn osis. H owever, m a n y ca r cin om a s a r e
n ot det ect ed u n t il t h e t u m or cells pen et r a t e t h e ba se-
m en t m em br a n e a n d m et a st a size t o dist a n t or ga n s.

Cancer Classifications
S t a g in g is a pr ocess of cla ssifyin g t h e ext en t or
spr ea d of n eopla sm s a n d r efer s t o t h e t u m or size,
loca t ion , lym ph n ode in volvem en t , a n d spr ea d
(Fig. 7.8). Th e h igh er t h e n u m ber, t h e m or e ext en -
sive t h e t u m or size a n d spr ea d. Tr ea t m en t decision s
a r e oft en ba sed on st a gin g cr it er ia . Th e TNM cla ssi-
fica t ion syst em is fr equ en t ly u sed t o st a ge t u m or s I
(Ta ble 7.2). TNM st a n ds for : IV
II III
● T = t u m or size. In dica t es t h e pr esen ce a n d size of
t h e pr im a r y t u m or. Figure 7.8. Tumor staging, I through IV. The size of the
● N = n ode (lym ph ) in volvem en t . In dica t es in volve- tumor and local to distant invasion increases with higher
m en t of r egion a l lym ph n odes. numeric staging. (Asset provided by Anatomical Chart
● M = m et a st a ses. In dica t es t h e ext en t of m et a st a ses. Company.)
 T h e I m p a c t o C a n c e r o n Tis s u e s , O r g a n s , a n d O r g a n S y s t e m s 181

wit h in t h e in fla m m a t or y r e-
Ta b le 7.2 TNM Cla ssifica t ion Syst em spon se ca u sed by t h e pr esen ce
of cir cu la t in g ch em ica l m edia -
C la s s i ic a t io n D e s c r ip t io n
t or s. An or exia ca n a lso r esu lt
P r im a r y Tu m o r (T ) fr om ch a n ges in t a st e r ecept or s
TX P r im a r y t u m or ca n n ot be eva lu a t ed (t h e m ech a n ism is u n clea r )
T0 No eviden ce of pr im a r y t u m or t h a t ca n a ccom pa n y t u m or cell
Tis Ca r cin om a in sit u (ea r ly ca n cer t h a t h a s n ot gr owt h .
spr ea d t o n eigh bor in g t issu e) Neopla st ic cells r equ ir e a
T1, T2, T3, T4 Size or ext en t of t h e pr im a r y t u m or lot of en er gy for r a pid, u n con -
R e g io n a l Ly m p h N o d e s (N ) t r olled pr olifer a t ion . In fla m -
NX Region a l lym ph n odes ca n n ot be eva lu a t ed
m a t or y m edia t or s, a lon g wit h
excess en er gy u se by t h e pr o-
N0 No r egion a l lym ph n ode in volvem en t (n o ca n cer
fou n d in t h e lym ph n odes) lifer a t in g n eopla st ic cells, ca n
N1, N2, N3 In volvem en t of r egion a l lym ph n odes (n u m ber
r esu lt in u n expla in ed weigh t
a n d/or ext en t of spr ea d) loss a n d t issu e wa st in g. Wh en
D is t a n t Me t a s t a s is (M)
sever e, n eopla sia s ca n lea d t o
a syn dr om e ca lled c a c h e x ia
MX Dist a n t m et a st a sis ca n n ot be eva lu a t ed
(Fig. 7.9). Ca ch exia is believed
M0 No dist a n t m et a st a sis (ca n cer h a s n ot spr ea d t o
t o be a r esu lt of ea r ly feelin gs
ot h er pa r t s of t h e body)
of fu lln ess wit h ea t in g cou pled
M1 Dist a n t m et a st a sis (ca n cer h a s spr ea d t o dist a n t
pa r t s of t h e body)
wit h t h e r elea se of ch em ica l
m edia t or s, su ch a s t u m or n e-
TNM, t u m or size, n ode, m et a st a ses. cr osis fa ct or, t h a t in du ce a la ck
Repr in t ed wit h per m ission fr om Gr een e F, Pa ge D, Mor r ow M, et a l. AJ CC Ca n cer S ta gin g
Ma n u a l. 6t h ed. New Yor k, NY: Spr in ger ; 2002.

General Manifestations
E a r ly m a n ifest a t ion s of n eopla sm s a r e oft en va gu e
a n d ign or ed a n d a r e a r esu lt of:
1. In fla m m a t or y a n d im m u n e r espon ses t o t h e
n eopla sm
2. In cr ea sed m et a bolic r a t e in du ced by t h e n eopla sm
3. Loca l effect s of n eopla st ic cell en cr oa ch m en t or
obst r u ct ion on n eigh bor in g t issu es
4. Syst em ic effect s of t h e n eopla sm seem in gly u n r e-
la t ed t o ca n cer (pa r a n eopla st ic syn dr om es)
Gen er a l m a n ifest a t ion s in dica t in g in fla m m a t or y
a n d im m u n e r espon ses in clu de lym ph a den opa t h y,
fever, a n d a n or exia . Lym ph a den opa t h y, a con dit ion
of en la r ged lym ph n odes t h r ou gh ou t t h e body, is a
con dit ion of h yper pla sia of t h e lym ph n odes fr om
lym ph ocyt e a ct ivit y, specifica lly a ga in st t h e devel-
opin g n eopla sm . Th e im m u n or ea ct ivit y t h a t a c-
com pa n ies n eopla sia s is oft en a low-gr a de, ch r on ic
h yper pla sia t h a t is n on t en der. Th e su pr a cla vicu la r
n odes a r e oft en descr ibed a s sen t in el lym ph n odes—
t h ese a r e oft en t h e fir st lym ph n odes t o r eceive lym -
ph a t ic dr a in a ge fr om a m a lign a n t t u m or.
Un expla in ed fever is a lso a com m on m a n ifest a -
t ion of ca n cer. Fever r esu lt s fr om t h e r elea se of pyr o-
gen s dir ect ly fr om ca n cer cells a n d ot h er cells a ct ive Figure 7.9. Cachexia of malignancy. This photo is of a
in t h e in fla m m a t or y r espon se (Ch a pt er 3). Sim ila r ly, patient with pancreatic carcinoma. The wasting away of
a n or exia (loss of a ppet it e) is a m a n ifest a t ion pr esen t body tissue is not entirely a matter of lost appetite.
182 C h a p t e r 7: Alt er ed Cellu la r P r olifer a t ion a n d Differ en t ia t ion
of a ppet it e. Tu m or n ecr osis fa ct or a lso su ppr esses
t h e en zym es t h a t a r e n eeded t o r elea se fa t t y a cids
fr om lipopr ot ein s for u se by t issu es. Th e pr esen ce
of h igh levels of t u m or n ecr osis fa ct or m a kes lipid
en er gy u n a va ila ble t o t h e t issu es a n d pr om ot es t is-
su e wa st in g.
Loca l m a n ifest a t ion s a r e sit e depen den t a n d a r e
r ela t ed t o (1) t h e spa ce occu pied by t h e t u m or t h a t
im pin ges on t h e loca l st r u ct u r es; a n d (2) t h e loss of
fu n ct ion in t h e t issu e or or ga n t h a t is bein g “t a ken
over ” by t h e t u m or. Tu m or cells a r e dest r u ct ive t o
n eigh bor in g t issu es a n d ca u se bleedin g, br u isin g,
a n d poor wou n d h ea lin g. Cr owdin g of blood cells in
t h e bon e m a r r ow ca n r esu lt in su ppr ession of RBC
a n d pla t elet pr odu ct ion . H em or r h a ge, a lso a com -
m on m a n ifest a t ion of t issu e dest r u ct ion ca u sed by
t u m or-secr et ed en zym es, con t r ibu t es t o loss of blood
cells. An em ia , br u isin g, a n d poor clot t in g a r e com -
m on effect s of t h ese a lt er a t ion s in t h e blood.
A pa lpa ble m a ss is oft en t h e fir st clin ica l m a n i-
fest a t ion t h a t m a y pr esen t in t u m or s su ch a s t h ose
fou n d in t h e br ea st , t est icle, a n d lym ph n odes. In
la t er st a ges, com pr ession on n ea r by st r u ct u r es ca n
elicit a pa in r espon se, su ch a s a ch r on ic h ea da ch e
wit h br a in t u m or s, bon e pa in wit h pr olifer a t in g cells
cr owdin g in t h e bon e m a r r ow, a n d a bdom in a l pa in
t h a t ca n occu r in pa n cr ea t ic ca n cer. Loss of fu n ct ion
m a y a lso pr ovide clu es t o t h e pr esen ce of n eopla sm s.
Con st ipa t ion , dia r r h ea , a n d blood in t h e st ool m a y
be eviden t in colon ca n cer. Cou gh , h em opt ysis (blood
in spu t u m ), a n d sh or t n ess of br ea t h a r e oft en pr es-
en t in lu n g ca n cer (Box 7.1).
Stop and Consider
How is delayed wound healing, as a clinical man-
ifestation of cancer, explained by the deregula-
tion of the destruction and regeneration/ repair
balance of the extracellular matrix during tumor
invasion?
P a r a n e o p la s t ic s y n d r o m e s a r e h or m on a l, n eu -
r ologic, h em a t ologic, a n d ch em ica l dist u r ba n ces in
t h e body, wh ich a r e n ot dir ect ly r ela t ed t o in va sion
by t h e pr im a r y t u m or or m et a st a sis. Alon g wit h
Box 7.1 AB C D E : T h e Wa r n in g S ig n s
o S k in C a n c e r
Th e followin g ch a r a ct er ist ics wa r r a n t fu r t h er exa m in a -
t ion by a h ea lt h ca r e pr a ct it ion er :
Asym m et r y: A m ole t h a t is ir r egu la r ly sh a ped
B or der : A m ole wit h ja gged edges wit h ou t clea r defin it ion
C olor : A gr owt h t h a t is m u lt icolor ed or t h a t ch a n ges color
D ia m et er : A su dden in cr ea se in a m ole size, especia lly on e
t h a t is gr ea t er t h a n 6 m m a cr oss (t h e size of a pen cil
er a ser )
E leva t ion : A fla t m ole t h a t becom es eleva t ed
t h e loca l effect s exer t ed by a gr owin g t u m or, pa r a -
n eopla st ic syn dr om es a r e oft en r espon sible for t h e
r a n ge of clin ica l m a n ifest a t ion s t h a t ca n occu r. For
exa m ple, a sign ifica n t ch a r a ct er ist ic of m a n y n eo-
pla sm s is t h e a bilit y t o pr odu ce a n d secr et e ect opic
h or m on es. E c t o p ic r efer s t o h or m on e secr et ion fr om
a sit e ou t side of a n en docr in e gla n d. Th e ect opic h or-
m on es a r e n ot u n der t h e r egu la t or y con t r ol of t h e
en docr in e syst em a n d do n ot r espon d t o t h e feed-
ba ck m ech a n ism s t ypica l of t h a t syst em . In som e
ca ses, su bst a n ces a r e secr et ed by t h e t u m or t h a t
m im ic t h e h or m on e fu n ct ion a n d r esu lt in clin ica l
m a n ifest a t ion s ch a r a ct er ist ic of a n over secr et ion
of t h a t h or m on e. For exa m ple, som e t u m or s secr et e
excess a n t idiu r et ic h or m on e. Th is h or m on e sign a ls
t h e body t o r et a in wa t er a n d sodiu m . Th e in dividu a l
will pr esen t wit h widespr ea d edem a ; t h is con dit ion ,
wh en sever e, ca n lea d t o com a a n d dea t h .
Pa r a n eopla st ic syn dr om es ca n a lso pr esen t a s a
dist u r ba n ce in n eu r ologic fu n ct ion . As pr esen t ed in
t h e pr eviou s exa m ple, t u m or s ca n secr et e h or m on es
t h a t dist u r b flu id a n d elect r olyt e ba la n ce, a n d t h is
dir ect ly a ffect s n eu r ologic fu n ct ion in g. Tu m or s ca n
a lso ca u se gen er a lized n u m bn ess, wea kn ess, a n d
loss of n eu r ologic fu n ct ion t h r ou gh sever a l m ech a -
n ism s, in clu din g pr om ot in g br a in h em or r h a ge, pr o-
m ot in g in fect ion in t h e cen t r a l n er vou s syst em , or
den yin g t h e va scu la r su pply a n d oxygen t o n eu r on a l
t issu es.
Diagnostic Tests
Cou pled wit h a com plet e h ist or y a n d ph ysica l exa m -
in a t ion , t h e followin g dia gn ost ic t est s ca n be u sed
t o det er m in e t h e pr esen ce a n d ext en t of n eopla sm s:
● Im a gin g st u dies
● Biopsy a n d cyt ology st u dies
● Tu m or m a r ker s a n d ot h er blood, u r in e, or t issu e
t est s
Im a gin g st u dies a llow dir ect visu a liza t ion of t u -
m or m a sses via r a diogr a ph s (X-r a ys), en doscopic
exa m in a t ion , u lt r a sou n d, com pu t ed t om ogr a ph y
(CT), or m a gn et ic r eson a n ce im a gin g (MRI) sca n s.
Th ese t est s a r e u sefu l in det er m in in g t h e pr es-
en ce, size, a n d loca t ion of t u m or s. On ce t h e t u m or
h a s been loca t ed, t issu e sa m ples ca n be r em oved
(biopsy) a n d t h ese cells exa m in ed (cyt ology) t o de-
t er m in e t h e pr esen ce a n d st a ge of n eopla sm s. In
m ost ca ses, a defin it ive dia gn osis of ca n cer ca n be
m a de on ly wit h a m icr oscopic exa m in a t ion of t u -
m or cells.
Tu m o r m a r k e r s a r e su bst a n ces t h a t m a y be de-
t ect ed in cells or body flu ids a n d ca n pr ovide clu es
t o t h e pr esen ce, ext en t , a n d t r ea t m en t r espon se of
 T h e I m p a c t o C a n c e r o n Tis s u e s , O r g a n s , a n d O r g a n S y s t e m s 183

cer t a in n eopla sm s. Tu m or m a r ker s m a y be pr odu ced t r ea t m en t effect iven ess a n d t o det er m in e r ecu r r en ce
by t h e t u m or it self or by u n a ffect ed cells in t h e body of t h e t u m or a ft er t r ea t m en t .
in r espon se t o t h e pr esen ce of a m a lign a n t or ben ign
t u m or. H u n dr eds of t u m or m a r ker s a r e u sed t o iden - Cancer Treatment
t ify va r iou s t ypes of t u m or s.
Tu m or m a r ker s ca n be com pr ised of h or m on es, Tr ea t m en t of ca n cer h a s t h r ee possible goa ls:
en zym es, a n d im m u n oglobu lin s. Ma n y t u m or m a r k-
er s a r e expr essed a s pr ot ein a n t igen s. For exa m ple, 1. Com plet ely er a dica t e t h e n eopla sm s
pr ost a t e-specific a n t igen (P SA), pr odu ced by cells in 2. Con t r ol con t in u ed gr owt h a n d spr ea d
t h e pr ost a t e, is pr esen t in low con cen t r a t ion s in a du lt 3. Redu ce sym pt om s wit h ou t cu r in g t h e ca n cer
m a les. E leva t ion s of P SA m a y be fou n d in t h e blood Ma jor t r ea t m en t st r a t egies t o a ch ieve t h ese goa ls
of m en wit h in fla m m a t ion (pr ost a t it is), ben ign en - in clu de su r ger y, ch em ot h er a py, r a dia t ion , h or m on es,
la r gem en t (ben ign pr ost a t ic h yper t r oph y), a n d m a - a n d im m u n ot h er a py. E a ch of t h ese t h er a peu t ic
lign a n t n eopla sm s of t h e pr ost a t e. Sim ila r ly, CA 125 st r a t egies ca n be u sed a lon e or in com bin a t ion . Su r-
is a n a n t igen -expr essed t u m or m a r ker for ova r ia n ger y, ch em ot h er a py, a n d r a dia t ion a r e com pa r ed in
ca n cer, bu t it m a y a lso be in cr ea sed in u t er in e, cer vi- Ta ble 7.3. Bon e m a r r ow t r a n spla n t a t ion m a y a lso be
ca l, pa n cr ea t ic, lu n g, colon , br ea st , a n d ga st r oin t est i-
u sed t o r epla ce or su pplem en t blood cells in t h e bon e
n a l ca n cer s. Th is t u m or m a r ker ca n a lso be in cr ea sed m a r r ow. St em cell t r a n spla n t a t ion in t h e bon e m a r-
in n on ca n cer ou s con dit ion s, su ch a s pr egn a n cy, pel- r ow h a s a lso sh own pr om ise a s a t h er a peu t ic st r a t -
vic in fla m m a t or y disea se, pa n cr ea t it is, liver disea se, egy for som e t ypes of ca n cer.
a n d in fla m m a t or y con dit ion s of t h e lu n g. Mea su r e-
m en t of ca r cin oem br yon ic
a n t igen (CE A) is pr im a r ily
u sed t o m on it or color ect a l Ta b le 7.3 Ca n cer Tr ea t m en t St r a t egies
ca n cer disea se a n d t r ea t m en t ;
Tr e a t m e n t Ad v e r s e E e c t s /
h owever, a wide va r iet y of ot h er St r a t egy Me c h a n is m o Ac t io n C o m p lic a t io n s
ca n cer s ca n a lso pr odu ce eleva -
t ion s in CE A, in clu din g ca n cer Su r ger y Dir ect ly r em ovin g t h e t u m or, In a bilit y t o r em ove a ll of
or ga n , or a ffect ed lym ph n odes t h e t u m or cells; bleedin g;
of t h e lu n g, br ea st , pa n cr ea s, t h r ou gh a va r iet y of su r gica l in fect ion .
st om a ch , cer vix, bla dder, kid- t ech n iqu es; pa t h ologic speci-
n ey, t h yr oid, liver, a n d ova r y. m en s a r e exa m in ed for clea r
In fla m m a t or y con dit ion s, su ch m a r gin s den ot in g com plet e t u -
a s in fla m m a t or y bowel disea se, m or r em ova l
pa n cr ea t it is, a n d h epa t it is, ca n Ch em ot h er a py Adm in ist er in g m edica t ion s Na u sea , vom it in g, h a ir loss,
syst em ica lly t o in t er r u pt t u m or poor wou n d h ea lin g, im m u -
a lso ca u se eleva t ion s in CE A
gr owt h or kill t u m or cells; com - n osu ppr ession , in fect ion s,
levels. bin a t ion t h er a py wit h t wo or bleedin g.
As in dica t ed pr eviou sly, t u - m or e a gen t s is com m on
m or m a r ker s ca n a lso be ex- Ra dia t ion Usin g foca l ion izin g r a dia t ion Skin pen et r a t ion ca u ses skin
pr essed in som e n on ca n cer ou s t o da m a ge cell DNA a n d pr e- r edn ess, ir r it a t ion , it ch in g,
con dit ion s a n d a r e n ot eleva t ed ven t fu r t h er r eplica t ion of t h e poor wou n d h ea lin g, skin
in ever y per son wit h ca n cer, es- pr olifer a t in g cells; ext er n a l r a - u lcer a t ion , a n d, over t im e,
dia t ion (m ost com m on ) is a im ed h yper pigm en t a t ion a n d a t -
pecia lly in t h e ea r ly st a ges. In r oph y. Bleedin g, in fect ion ,
a t t h e t u m or fr om ou t side of
a ddit ion , m a n y t u m or m a r ker s t h e body; in t er n a l r a dia t ion is a n d a n em ia ca n r esu lt fr om
a r e n ot specific t o on e t ype of im pla n t ed in t o or n ea r t h e t u - loss of blood cells. F ibr osis of
ca n cer ; t h a t is, a t u m or m a r ker m or in sm a ll ca psu les or ot h er t issu es a n d or ga n s ca n occu r,
level ca n be eleva t ed by m or e con t a in er ; syst em ic r a dia t ion lea din g t o dia r r h ea , esoph a -
is a pr ocess of a dm in ist er in g gea l or in t est in a l st r ict u r es,
t h a n on e t ype of ca n cer. Th er e- a n d fibr osis of t h e h ea r t a n d
(or a l or in ject ed) u n sea led r a -
for e, t u m or m a r ker r esu lt s a r e dioa ct ive m a t er ia ls t h a t t r a vel lu n gs.
in t er pr et ed wit h ca u t ion . Th e t h r ou gh ou t t h e body
m ea su r em en t of t u m or m a r ker Biologic Alt er in g t h e biologic r espon se Few, if a n y, a dver se effect s;
levels a lon e is n ot su fficien t t o r espon se m od- of t h e h ost m ost oft en a ch ieved BMRs select ively a id in de-
dia gn ose ca n cer. Ra t h er, t h ese ifier s (BMRs) t h r ou gh st im u la t in g t h e h ost st r oyin g t u m or cells wit h ou t
t est s a r e m ost in for m a t ive a f- im m u n e r espon se a ffect in g t h e h ost cells.
t er dia gn osis wh en r esu lt s a r e H or m on es Ma n ipu la t in g t u m or s t h a t de- Depen den t on t h e expect ed
pen d on h or m on es by in h ibit in g r espon se of t h e h or m on e
com pa r ed over t im e. Mon it or-
RNA a n d pr ot ein syn t h esis a n d u sed; t h e a ct ion s of t h e h or-
in g t u m or m a r ker t r en ds a l- bin din g t o r ecept or sit es m on e a r e exa gger a t ed.
lows t h e a bilit y t o det er m in e
184 C h a p t e r 7: Alt er ed Cellu la r P r olifer a t ion a n d Differ en t ia t ion

Alt h ou gh t r ea t m en t of t h e t u m or is im por t a n t , pr even t a ble ca n cer dea t h s ca n be lin ked t o n u t r i-

ca r e of t h e pa tien t wit h ca n cer a n d h is or h er fa m - t ion a l fa ct or s, ph ysica l in a ct ivit y, or obesit y. 1 Va c-
ily in volves t h e pr ovision of psych osocia l su ppor t cin a t ion a ga in st cer t a in vir a l in fect ion s m a y a lso
n eeded t o a ddr ess t h e a n xiet y a n d depr ession t h a t r edu ce t h e ca n cer in ciden ce. For exa m ple, va ccin a -
m a y a ccom pa n y su ch a dia gn osis. Th is su ppor t m a y t ion a ga in st h epa t it is B vir u s sh ou ld decr ea se t h e
in clu de a ddr essin g sexu a lit y, spir it u a lit y, a n d ot h er in ciden ce of h epa t ocellu la r ca n cer.
per son a l issu es r ela t ed t o t h e dia gn osis, t r ea t m en t ,
a n d copin g wit h ca n cer. Th e h ea lt h pr ofession a l
m u st a lso be a wa r e of a n d open t o discu ssin g a lt er- Children and Cancer
n a t ive, com plem en t a r y, or exper im en t a l t h er a pies.
Pa llia t ive ca r e is a n ot h er im por t a n t a spect of Alt h ou gh r a r e, ca n cer is t h e lea din g ca u se of dea t h
ca n cer t r ea t m en t . P a llia t iv e ca r e is t h e t er m fr e-
by disea se in ch ildr en a ges 1 t h r ou gh 14 yea r s.
qu en t ly u sed t o descr ibe t r ea t in g sym pt om s, su ch a s Wh er ea s m ost a du lt ca n cer s in volve t issu es a n d
pa in , wit h ou t cu r in g t h e ca n cer. Com m on side effect s solid or ga n s wit h a n epit h elia l or igin (ca r cin om a s),
of t r ea t m en t in clu de fa t igu e, n a u sea , vom it in g, pr u -
su ch a s colon ca n cer, lu n g ca n cer, a n d br ea st ca n cer,
r it u s, a n d dia r r h ea . Ca r e of t h e pa t ien t in clu des a d-
m ost ch ildh ood ca n cer s or igin a t e in t h e m esoder m a l
dr essin g com plica t ion s of t r ea t m en t a n d pr ovidin g ger m la yer, wh ich develops in t o bon e, blood, blood
n u t r it ion a l su ppor t for opt im a l h ea lt h . vessels, m u scle, lym ph a t ics, con n ect ive t issu e, a n d
kidn eys. Th er efor e, t h e t ypes of ca n cer m ost pr eva -
len t in ch ildh ood a r e leu kem ia (31%), br a in /spin a l
Cancer Prevention cor d t u m or s (21%), n eu r obla st om a (7%), Wilm s t u -
m or (6%), H odgkin lym ph om a (4%), n on -H odgkin
Prevention of cancer involves avoiding known carcino- lym ph om a (4%), r h a bdom yosa r com a (3%), r et in o-
gens, participating in health promotion activities, such bla st om a (3%), ost eosa r com a (3%), a n d E win g sa r-
com a (2%). Neopla sm s
t h a t r esem ble em br y-
R E S E AR C H N O T E S on ic t issu e ca n or igin a t e
du r in g em br yon ic a n d fe-
t a l developm en t a n d per-
Cancer drugs are broadly classified into two categories: cytotoxic chemotherapies (those sist t o for m t u m or s in t h e
that directly kill cancer cells) and targeted therapies (those that modulate the activity of body. Th ese em br yon ic
one or more proteins involved in cancer). Research has focused more recently on developing t u m or s a r e m ost oft en
targeted therapies, specifically to interfere with oncogenes. The researchers report, “… m a n ifest ed pr ior t o a ge 5
novel approaches, including synthetic lethality and collateral vulnerability screens, are now yea r s.
being developed to target gene defects in p53, PTEN, and BRCA1/ 2.” These show promise in Th e ca u se of ch ildh ood
2
targeting tumor suppressors in cancer therapeutics. ca n cer m or e oft en h a s a n
in h er it ed, gen e va r ia n t , or
epigen et ic ba sis beca u se
as exercising moderately and consuming a balanced ch ildr en h a ve h a d lim it ed exposu r e t o en vir on m en -
healthy diet, accepting vaccinations when indicated, t a l exposu r es, su ch a s ch em ica ls, a n d lim it ed t im e
and taking measures to protect against chronic injury, t o pa r t icipa t e in h a r m fu l h ea lt h beh a vior s, su ch a s
including exposure to reactive oxygen species. Indi- sm okin g. Th ose wit h in h er it ed m u t a t ion s in clu de
viduals with light skin are most at risk for basal cell r et in obla st om a (r et in a ), Wilm s t u m or (kidn ey), a n d
carcinoma and melanoma. Those with darker skin a re ost eosa r com a (bon e).
protected by melanin pigment. The melanin absorbs Det ect ion of ca n cer in ch ildr en is oft en difficu lt .
ultraviolet radiation. Although those with darker skin U n expla in ed clin ica l m a n ifest a t ion s t h a t sh ou ld
are more protected, the skin is still vulnerable to burn a ler t pa r en t s a n d h ea lt h pr ofession a ls t o a pot en -
injuries, and cancer can develop. Using sunscreen t ia l pr oblem in clu de: u n u su a l m a ss or swellin g,
and keeping exposed skin areas covered help protect pa llor, per sist en t m a la ise, br u isin g, su dden a n d
against and prevent skin cancers. per sist en t pa in , lim pin g ga it , fever, pr olon ged ill-
Ma n y ot h er t ypes of ca n cer a r e a lso con sider ed n ess, h ea da ch es, vision ch a n ges, a n d excessive,
pr even t a ble, in clu din g t h ose ca u sed by t oba cco u se, r a pid weigh t loss. Dr a m a t ic im pr ovem en t s in su r-
h ea vy a lcoh ol con su m pt ion , in fect ion wit h ca r cin o- viva l of ch ildr en h a ve occu r r ed over t h e pa st 20
gen ic m icr oor ga n ism s, a n d obesit y. Th e Am er ica n yea r s beca u se of a dva n ces in t r ea t m en t . Th e a v-
Ca n cer Societ y est im a t es t h a t on e in t h r ee ca n - er a ge 5-yea r su r viva l r a t e for a ll ca n cer t ypes is
cer dea t h s a r e ca u sed by t oba cco u se.1 In a ddit ion , gr ea t er t h a n 75%.
 C lin ic a l Mo d e ls 185

Modu le 3 C lin ic a l Mo d e ls

Th e followin g clin ica l m odels wer e select ed t o h elp

a pply kn owledge r ela t ed t o a lt er ed cellu la r pr olif-
er a t ion a n d differ en t ia t ion . Not e t h e com m on a lit ies
of cellu la r a u t on om y a n d a n a pla sia . Recogn ize t h e
differ en ces in clin ica l m a n ifest a t ion s a n d dia gn osis
ba sed on t h e t u m or t ypes a n d loca t ion s.

Lung Cancer
Ca r cin om a of t h e lu n g is t h e lea din g ca u se of ca n cer
dea t h s in t h e wor ld. Sm okin g a n d ot h er en vir on m en -
t a l t oxin exposu r es a r e u n equ ivoca lly im plica t ed in
t h e ca r cin ogen esis.

PATHOPHYSIOLOGY
Th e on set of lu n g ca n cer is m ost oft en t h e r esu lt of
en vir on m en t a l exposu r es t o pa r t icu la r t oxin s com -
bin ed wit h a gen et ic su scept ibilit y t o t h ese t oxin s.
Act ive sm okin g is r espon sible for a ppr oxim a t ely
90% of lu n g ca n cer ca ses. Th e m a jor it y of r em a in -
in g ca ses a r e a t t r ibu t ed t o occu pa t ion a l exposu r es,
su ch a s wit h a sbest os a n d r a don . In a ver y sm a ll per-
cen t a ge, t h er e a r e n o kn own en vir on m en t a l t r igger s.
For t h e va st m a jor it y, r epea t ed exposu r e t o sm okin g
a n d en vir on m en t a l t oxin s ca u se DNA da m a ge a n d
in du ce m u t a t ion s in t h e r a s fa m ily of on cogen es, Rb,
p53 a n d ot h er t u m or su ppr essor gen es. Specific t o
a den oca r cin om a , wh ich is t h e m ost com m on t ype of
lu n g ca n cer, r a s gen e a ct iva t ion con t r ibu t es t o t u m or
pr ogr ession . Th er e a r e t wo m a jor ca t egor ies of lu n g
ca n cer :
● Non -sm a ll cell lu n g ca n cer (85%)
■ Aden oca r cin om a s a r e t h e m ost com m on for m
of lu n g ca n cer in t h e Un it ed St a t es. Neopla sm s
develop in t h e per iph er a l br on ch iola r a n d a lve-
ola r lu n g t issu e lea din g t o pleu r a l fibr osis a n d
a dh esion s (F ig. 7.10).
■ Squ a m ou s cell ca r cin om a begin s wit h in ju r y t o
t h e br on ch ia l colu m n a r epit h eliu m (i.e., fr om
sm okin g) a n d lea ds t o squ a m ou s m et a pla sia ,
dyspla sia , ca r cin om a in sit u , a n d a n in va sive
t u m or.
■ La r ge cell ca r cin om a s a r e t h ose t h a t a r e n ei-
t h er a den oca r cin om a s n or squ a m ou s cell. Th e
t u m or cells a r e la r ge a n d sh ow a h igh level of
a n a pla sia .
● Sm a ll cell lu n g ca n cer (15%) is a h igh ly m a lig-
n a n t epit h elia l t u m or t h a t gr ows a n d m et a st a -
sizes r a pidly. Th is for m of ca n cer is h igh ly lin ked
t o sm okin g.
Figure 7.10. Adenocarcinoma of the lung. Adenocarci-
noma is the most common type of lung cancer and often
begins in the peripheral bronchiolar and alveolar lung
tissue. This tumor is found in the upper right lobe of the
lung. (Modified from Rubin E, Farber JL. Pathology. 4th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2005.)
In a ll for m s of lu n g ca n cer, t h e n eopla sm s ca n pen e-
t r a t e epit h elia l la yer s a n d m ove in t o t h e lu n g t issu e,
pleu r a l ca vit y, ch est wa ll, a n d beyon d. Th e loca t ion of
la r ge lu n g t u m or s a llows com pr ession on lower cer-
vica l a n d u pper t h or a cic n er ves. Met a st a t ic spr ea d
occu r s via lym ph ch a n n els a n d t h e va scu la r syst em .
Lu n g ca r cin om a is or ga n t r opic t o t h e bon e, liver,
a n d t h e br a in .
CLINICAL MANIFESTATIONS
Th e m ost com m on clin ica l m a n ifest a t ion s for a ll
lu n g ca n cer su bt ypes a r e per sist en t cou gh , h em op-
t ysis (bloody spu t u m ), ch est pa in , a n d sh or t n ess of
br ea t h . Th ese clin ica l m a n ifest a t ion s a r e oft en ig-
n or ed a n d expla in ed a wa y a s “sm oker ’s cou gh ” or
br on ch it is. Gen er a l syst em ic m a n ifest a t ion s a n d
pa r a n eopla st ic syn dr om es discu ssed ea r lier a lso a p-
ply t o lu n g ca r cin om a .
DIAGNOSTIC CRITERIA
A ph ysica l exa m in a t ion , com plet e blood cou n t , a n d
ch est X-r a y a r e com plet ed wh en t h e pa t ien t pr esen t s
186 C h a p t e r 7: Alt er ed Cellu la r P r olifer a t ion a n d Differ en t ia t ion
wit h cou gh , h em opt ysis, ch est pa in , a n d or sh or t n ess
of br ea t h . Th e dia gn osis is con fir m ed a n d t h e t ype of
cell iden t ified t h r ou gh br on ch oscopy, spu t u m cyt ol-
ogy, a n d t issu e biopsy.
St a gin g lu n g ca n cer is ba sed on wh et h er or n ot
t h e ca n cer h a s spr ea d fr om t h e lu n gs t o t h e lym ph
n odes or ot h er or ga n s. Beca u se sign s a n d sym pt om s
a r e oft en ign or ed, ea r ly-st a ge lu n g ca n cer (st a ges I
a n d II) is difficu lt t o det ect . Most people wit h lu n g
ca n cer a r e dia gn osed a t st a ges III a n d IV.
● S t a g e I : Th e ca n cer is loca t ed on ly in t h e lu n gs
a n d h a s n ot spr ea d t o a n y lym ph n odes.
● S t a g e I I : Th e ca n cer is in t h e lu n g a n d n ea r by
lym ph n odes.
● S t a g e I I I : Ca n cer is fou n d in t h e lu n g a n d in t h e
lym ph n odes in t h e m iddle of t h e ch est , a lso de-
scr ibed a s loca lly a dva n ced disea se.
● S t a g e I V: Th is is t h e m ost a dva n ced st a ge of lu n g
ca n cer, a n d is a lso descr ibed a s a dva n ced disea se.
Th is is wh en t h e ca n cer h a s spr ea d t o bot h lu n gs,
t o flu id in t h e a r ea a r ou n d t h e lu n gs, or t o a n -
ot h er pa r t of t h e body, su ch a s t h e liver or ot h er
or ga n s.3
TREATMENT
Lu n g ca n cer h a s a h igh m or t a lit y r a t e. Tr ea t m en t
select ion is ba sed on iden t ifica t ion of t h e t u m or t ype
a s eit h er sm a ll cell or n on –sm a ll cell (a den oca r ci-
n om a , squ a m ou s cell, a n d la r ge cell) lu n g ca r cin om a .
Sm a ll cell ca r cin om a is m or e likely t o r espon d t o ch e-
m ot h er a py, yet is a lso m or e likely t o be widely dis-
sem in a t ed a t dia gn osis. Beca u se pa t ien t s wit h sm a ll
cell ca r cin om a t en d t o develop dist a n t m et a st a ses,
su r gica l r esect ion a n d r a dia t ion r a r ely con t r ibu t e t o
lon g-t er m su r viva l.
Tr ea t m en t of n on –sm a ll cell ca r cin om a s is oft en
ba sed on t h e a bilit y or in a bilit y t o r esect (su r gica lly
r em ove) a ll or pa r t of t h e t u m or. If n on –sm a ll cell
ca r cin om a s (a den oca r cin om a , squ a m ou s ca r cin om a ,
a n d la r ge cell ca r cin om a ) ca n be su r gica lly r em oved,
t h e ca n cer m a y be cu r ed by su r ger y a lon e or by su r-
ger y a n d ch em ot h er a py. If t h e t u m or ca n n ot be su r-
gica lly r em oved, loca l con t r ol of t h e t u m or m a y be
a ch ieved wit h r a dia t ion t h er a py, bu t cu r e is u n likely.
Th e 5-yea r su r viva l r a t e is depen den t u pon t h e st a ge
a t dia gn osis. For t h ose wit h ea r ly r ecogn it ion a n d a
loca l t u m or, t h e 5-yea r su r viva l r a t e is 49%; h owever,
t h is dr ops t o 16% for t h ose wit h r egion a l in volve-
m en t , a n d t o 2% for t h ose wit h dist a n t m et a st a ses. 3
Colon Cancer
Colon ca n cer is t h e m ost fr equ en t ly occu r r in g t ype
of ga st r oin t est in a l (GI) t r a ct ca n cer. As wit h ot h er
for m s of ca n cer, it is m u lt ifa ct or ia l in or igin a n d oc-
cu r s a s a r esu lt of gen et ic ch a n ges, en vir on m en t a l
exposu r es, diet a r y in flu en ces, a n d is in cr ea sed wit h
t h ose wh o h a ve ch r on ic in fla m m a t or y con dit ion s of
t h e GI t r a ct .
PATHOPHYSIOLOGY
Alt h ou gh t h e exa ct ca u se is oft en n ot clea r ly est a b-
lish ed, t h e pr im a r y r isk fa ct or is a ge. Mor e t h a n
90% of ca ses a r e dia gn osed in a du lt s over t h e a ge
of 50 yea r s. Ot h er r isk fa ct or s in clu de fa m ily h is-
t or y of color ect a l ca n cer, sm okin g, a lcoh ol con su m p-
t ion , ch r on ic in fla m m a t or y bowel disea se, obesit y,
a n d ph ysica l in a ct ivit y, a n d a diet h igh in fa t a n d
low in fr u it s a n d veget a bles. Alt h ou gh t h is fin din g
is con t r over sia l, h igh er a m ou n t s of fiber in t h e diet
h a ve been sh own t o bin d t o pot en t ia l m u t a gen s a n d
m ove con t en t s m or e qu ickly t h r ou gh t h e colon a n d
t h er efor e m a y pr even t n eopla sm s. A r edu ced fa t
diet m a y decr ea se t h e secr et ion of bile in t o t h e in -
t est in e a n d lim it t h e exposu r e of t h e bowel t o t h e
t u m or-pr om ot in g effect s of bile a cids. Nu t r ien t s wit h
a pr ot ect ive effect a ga in st color ect a l ca n cer in clu de
selen iu m a n d vit a m in s E , C, a n d A, a s well a s veg-
et a bles su ch a s br occoli, ca u liflower, ca bba ge, a n d
br u ssels spr ou t .
Tu m or s in t h e colon or r ect u m ca n r a n ge fr om
ben ign polyps t o in va sive t u m or s a n d a r e m ost of-
t en of epit h elia l or igin , t er m ed a den om a s or a den o-
ca r cin om a s. Th ese a r e cla ssified a ccor din g t o t h r ee
gr ou ps:
1. Non n eopla st ic polyps (n ot gen er a lly con sider ed a
ca n cer pr ecu r sor )
2. Neopla st ic polyps (a den om a t ou s polyps, a den o-
m a s; in cr ea sed r isk of developin g ca r cin om a of
t h e colon /r ect u m )
3. Ca n cer s (m ost oft en a den oca r cin om a s)
An a ver a ge of n in e m a jor delet er iou s m u t a t ion s a r e
h a r bor ed wit h in ca n cer ou s t u m or s of t h e colon /r ec-
t u m a n d five t o seven m u t a t ion s a r e n eeded t o pr o-
m ot e t h e developm en t of m a lign a n t t u m or s. At lea st
t wo pa t h wa ys h a ve been iden t ified t h a t ca n lea d
fr om h ea lt h y epit h eliu m t o ca r cin om a :
1. A ser ies of even t s t r igger in g ch r om osom a l in st a -
bilit y (85%)
2. Replica t ion er r or s (15%)
Ch r om osom a l in st a bilit y is ba sed on a lt er a t ion s in
ch r om osom e n u m ber (a n eu ploidy) a n d ch r om osom a l
delet ion s, pa r t icu la r ly of ch r om osom es 5q, 18q, 17p,
a n d t h e m u t a t ion of t h e KRAS on cogen e.4 Ch r om o-
som a l in st a bilit y lea ds t o a loss of t u m or su ppr es-
sor fu n ct ion , a n d im pa ir ed DNA r epa ir is h ea vily
im plica t ed in t h e t r a n sfor m a t ion t o a den oca r cin o-
m a s. E a r ly a ct iva t ion of n eopla sia is oft en r ela t ed
 C lin ic a l Mo d e ls 187

t o a m u t a t ed loss of a t u m or su ppr essor gen e ca lled CLINICAL MANIFESTATIONS

AP C (a den om a t ou s polyposis coli) gen e. Mu t a t ion s
Beca u se of t h e widespr ea d pu blic h ea lt h ca m pa ign
in t h e AP C gen e lea d t o a den om a t ou s polyps, wh ich
pr om ot in g scr een in g, colon ca n cer is n ow oft en de-
a r e con sider ed a m a jor pr ecu r sor t o m a lign a n t t u -
t ect ed befor e it st a r t s t o ca u se sym pt om s. Wh en
m or developm en t . Replica t ion er r or s differ in t h a t
pr esen t , clin ica l m a n ifest a t ion s of color ect a l ca n cer
t h e ch r om osom es r em a in in t a ct , bu t t h e pa t ien t h a s
depen d on t h e loca t ion a n d ch a r a ct er ist ics of t h e t u -
st ill a cqu ir ed defect s in DNA r epa ir, a llowin g m u -
m or. E a r ly st a ges of t u m or developm en t a r e oft en a s-
t a t ed n eopla sia -pr om ot in g gen es t o pr om ot e ca n cer-
ym pt om a t ic. As t h e t u m or en la r ges, u lcer a t ion a n d
ou s t r a n sfor m a t ion s.
h em or r h a ge ca n r esu lt in o c c u lt , or h idden , blood in
In bot h scen a r ios (ch r om osom a l in st a bilit y a n d
t h e st ool if t h e t u m or is a lon g t h e a scen din g colon .
r eplica t ion er r or s), t h e cellu la r t r a n sfor m a t ion t h a t
F r a n k , or visible, blood in t h e st ool, a bdom in a l pa in ,
for m s in t h e m u cosa l epit h eliu m of t h e bowel begin s
a n d bowel obst r u ct ion a r e m or e likely if t h e t u m or
a t t h e ba se of t h e c r y p t s , or m u cosa l epit h elia l de-
is loca t ed a lon g t h e descen din g colon or in t h e r ec-
pr ession s (Fig. 7.11). Th is is t h e a r ea wh er e m it osis
t u m . An em ia , ca u sed by blood loss in t h e st ool, or a
occu r s. As t h e cell m a t u r es, it m oves u p t h e cr ypt a n d
ch a n ge in bowel h a bit s m a y be t h e fir st dia gn ost ic
even t u a lly r ea ch es t h e su r fa ce of t h e bowel wh er e
clu e. Gen er a l syst em ic m a n ifest a t ion s a n d pa r a n e-
t h e cell t h en dies a n d is slou gh ed off a n d r em oved
opla st ic syn dr om es a lso a pply for color ect a l ca n cer.
t h r ou gh t h e colon . Wit h AP C gen e m u t a t ion , t u m or
cells in t h e bowel r esist
a popt osis a n d a ccu m u la t e
on t h e bowel su r fa ce. Th e
F R O M T H E L AB
cells con t in u e t o pr olifer-
a t e t o for m ben ign a den o- Testing for occult blood in the stool involves taking a small sample of the stool and combin-
m a t ou s polyps. Rem ova l ing this with a chemically impregnated test strip. Guaiac or orthotolidine is an often-used
of ben ign a den om a t ou s chemical. These tests are often referred to as guaiac or Hemoccult tests. A positive test
polyps ca n r edu ce t h e indicates the presence of occult blood in the stool and warrants further evaluation.
r isk of t h e developm en t of
a den oca r cin om a s. Ot h er
m u t a t ion s fu r t h er pr o-
DIAGNOSTIC CRITERIA
m ot e t h e t r a n sfor m a t ion t o a m a lign a n t t u m or, su ch
a s t h e delet ion of ot h er t u m or su ppr essor gen es: Gu idelin es fr om t h e Am er ica n College of Ga st r o-
t h e DCC (“delet ed in colon ca n cer ”) gen e a n d t h e en t er ology r ecom m en d colon oscopy ever y 10 yea r s,
p53 gen e. begin n in g a t a ge 50, a s t h e pr efer r ed scr een in g

Be nig n c o lo nic ne o plas ms

Tubula r a de noma Villous a de noma

Pro g re s s ive
No rmal Initial pro life rative
pro life rative abno rmality
abno rmality
Colonic crypt

5% 40%

Invas ive Invas ive

ade no c arc ino ma ade no c arc ino ma

Figure 7.11. From adenomatous polyps to adenocarcinoma. Cellular transformation begins at the base of the crypts where
mitosis occurs. Tumor cells resist apoptosis and accumulate on the bowel surface. The cells continue to proliferate to form
benign adenomatous polyps. Further mutations promote the transformation to adenocarcinoma. (Modified from Rubin E,
Farber JL. Pathology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.)
188 C h a p t e r 7: Alt er ed Cellu la r P r olifer a t ion a n d Differ en t ia t ion

st r a t egy.4 La bor a t or y st u dies a n d dia gn ost ic t est s in Ta ble 7.4. Dist a n t m et a st a ses, wh en pr esen t , a r e
t h a t m a y be h elpfu l in clu de: m ost oft en fou n d in t h e liver.

● Com plet e blood cou n t TREATMENT

● Liver fu n ct ion t est s (colon ca n cer is or ga n t r opic
t o t h e liver )
● Ser u m ca r cin oem br yon ic a n t igen (CE A)
● Colon oscopy
● Sigm oidoscopy
● Biopsy of su spiciou s lesion s
Th e Am er ica n J oin t Com m it t ee on Ca n cer (AJ CC)
h a s design a t ed st a gin g of color ect a l ca n cer u sin g a
m odified TNM cla ssifica t ion . Noda l a n d m et a st a t ic
design a t ion s a r e iden t ica l t o t h e cla ssic TNM sys-
t em . Th e t u m or a spect of t h e cla ssifica t ion depen ds
on t h e ext en t of t u m or pr ogr ession t h r ou gh t h e
bowel wa ll ver su s t h e size of t h e t u m or. Th e m odi-
fica t ion s a n d st a gin g for color ect a l ca n cer a r e fou n d
Color ect a l ca n cer is h igh ly t r ea t a ble a n d oft en cu r-
a ble wh en loca lized in t h e bowel. Su r gica l t r ea t -
m en t is r equ ir ed a n d r esu lt s in cu r e (wit h loca lized
t u m or s) in a bou t 50% of pa t ien t s. Th ose wit h u n -
r esect a ble, loca lly a dva n ced, or m et a st a t ic disea se
a r e t r ea t ed wit h com bin a t ion dr u g ch em ot h er a py,
biologica l a gen t s, a n d r a dia t ion a s in dica t ed. Th e
pr ogn osis of color ect a l ca n cer is dir ect ly r ela t ed t o
t h e loca t ion a n d degr ee of pen et r a t ion of t h e t u m or
t h r ou gh t h e bowel, t h e pr esen ce of bowel obst r u ct ion
or per for a t ion , lym ph n ode in volvem en t , a n d t h e
pr esen ce of dist a n t m et a st a ses. Th e 5-yea r su r viva l
r a t e r a n ges fr om 95% for t h ose wit h st a ge I disea se
t o 10% for t h ose dia gn osed a t st a ge IV. 4

Ta b le 7.4 TNM Cla ssifica t ion a n d St a gin g for Color ect a l Ca n cer
C la s s i ic a t io n o r S t a g e D e s c r ip t io n Brain Cancer
P r im a r y Tu m o r (T ) Br a in ca n cer is h igh ly fea r ed
TX P r im a r y t u m or ca n n ot be a ssessed beca u se of t h e possibilit y of
T0 No eviden ce of pr im a r y t u m or developin g sever e disa bilit y,
Tis Ca r cin om a in sit u seizu r es, pa r a lysis, a n d cogn i-
T1 Tu m or in va des su bm u cosa t ive im pa ir m en t . Br a in t u m or s
T2 Tu m or in va des m u scu la r is pr opr ia a r e on e of t h e m ost com m on
T3 Tu m or in va des t h r ou gh a n d in t o su bser osa , or
ca n cer s in ch ildr en , secon d t o
in t o per ir ect a l t issu es leu kem ia . Br a in ca n cer, a s a r e-
T4 Tu m or dir ect ly in va des ot h er or ga n s or st r u c- su lt of m et a st a t ic spr ea d fr om
t u r e, a n d/or per for a t es viscer a l per it on eu m a n ot h er sit e su ch a s t h e lu n gs,
R e g io n a l Ly m p h N o d e s (N ) is m u ch m or e com m on t h a t pr i-
m a r y br a in t u m or s (t h ose or ig-
NX Region a l lym ph n odes ca n n ot be a ssessed
in a t in g fr om t h e n eu r a l t issu e).
N0 No r egion a l lym ph n ode m et a st a sis
For exa m ple, it is est im a t ed
N1 Met a st a sis in 1–3 r egion a l lym ph n odes t h a t u pon a u t opsy, a r ou n d 20%
N2 Met a st a sis in 4 or m or e r egion a l lym ph n odes of pa t ien t s wit h syst em ic ca n -
D is t a n t Me t a s t a s is (M) cer h a ve br a in m et a st a ses.5
MX Dist a n t m et a st a sis ca n n ot be a ssessed Th is m a y be du e in pa r t t o
M0 No dist a n t m et a st a sis exposu r e t o ca n cer t r ea t m en t
M1 Dist a n t m et a st a sis wit h ion izin g r a dia t ion , wh ich
in cr ea ses t h e r isk of developin g
S t a g in g B a s e d o n T N M
t u m or s in t h e n er vou s syst em .
St a ge 0 Tis, N0, M0
St a ge I T1 or T2, N0, M0
St a ge IIA T3, N0, M0 PATHOPHYSIOLOGY
St a ge IIB T4, N0, M0
Br a in m et a st a sis (spr ea d fr om
St a ge IIIA T1 or T2, N0, M0 ot h er t u m or sit es) a lon g wit h
St a ge IIIB T3 or T4, N1, M0 gliom a s, m en in giom a s, pit u -
St a ge IIIC An y T, N2, M0 it a r y a den om a s, a n d a cou st ic
St a ge IV An y T, An y N, M1 n eu r om a s a ccou n t s for 95% of
a ll br a in t u m or s. Adu lt s a r e
TNM, t u m or size, n ode, m et a st a ses.
Repr in t ed wit h per m ission fr om Gr een e F, Pa ge D, Mor r ow M, et a l. AJ CC Ca n cer S ta gin g m or e likely t o develop pr im a r y
Ma n u a l. 6t h ed. New Yor k, NY: Spr in ger ; 2002. su pr a t en t or ia l br a in t u m or s.

Ch ildr en a r e m or e likely t o develop pr im a r y in fr a -
t en t or ia l br a in t u m or s. F igu r e 7.12 depict s t h e dis-
t r ibu t ion of t h ese a n d ot h er com m on in t r a cr a n ia l
t u m or s.
Gliom a s, m or e specifica lly a st r ocyt om a s, a r e t h e
m ost com m on t u m or t ype or igin a t in g in t h e br a in .
Th e specific gen et ic m u t a t ion or ch r om osom a l a b-
er r a t ion is va r ia ble depen din g on t h e su bt ype. For
exa m ple, gr a de II diffu se a st r ocyt om a s m ost of-
t en occu r in pa t ien t s wit h in h er it ed p53 ger m lin e
m u t a t ion s or wit h a delet ion of ch r om osom e ba n d
17p13.1.5 Ast r ocyt om a s m ost oft en pr esen t in t h e
br a in st em or cer ebellu m of t h e ch ild, spin a l cor d of
you n g a du lt s, a n d cer ebr a l h em isph er es of t h e a du lt .
Ast r ocyt om a s va r y in t h e level of differ en t ia t ion a t
dia gn osis. Appr oxim a t ely 20% a r e well differ en t i-
a t ed, 40% a r e h igh ly u n differ en t ia t ed, a n d t h e r e-
m a in in g a r e som ewh er e in bet ween . Gliom a s ca n
be ben ign or m a lign a n t . As gliom a s en la r ge, t u m or s
im pin ge on vit a l br a in st r u ct u r es a n d becom e fa t a l.
Un like ot h er t u m or s, gliom a s r a r ely m et a st a size
ou t side of t h e CNS. P r ogn osis is ba sed on t h e level
of a n a pla sia ; t h a t is, t h e m or e u n differ en t ia t ed t h e
t u m or, t h e poor er t h e pr ogn osis.
Th e TNM cla ssifica t ion is n ot u sed for br a in t u -
m or s t h e followin g r ea son s:
● Tu m or size is less r eleva n t t h a n t h e loca t ion a n d
h ist ology
● Th e br a in a n d spin a l cor d h a ve n o lym ph a t ics
● Most pa t ien t s wit h CNS t u m or s do n ot live lon g
en ou gh t o develop m et a st a t ic disea se
Ra t h er, t h e Wor ld H ea lt h Or ga n iza t ion cla ssifica -
t ion of CNS t u m or s is oft en u sed a s it in cor por a t es
Extra cra nia l e xte ns ion
of me ningioma
Lipoma
(mos t commonly
in corpus collos um)
P ine a l tumors
As trocytoma
(childhood)
Me dullobla s toma
Epe ndymoma
(fourth ve ntricle )
Figure 7.12. The most common locations for select intracranial tumors. Note that most tumors arise in the cerebral hemi-
spheres. (Modified from Rubin E, Farber JL. Pathology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005, with
permission.)
C lin ic a l Mo d e ls 189
m or ph ology, gen et ics, a n d im m u n ologic m a r ker s
(Ta ble 7.5).
CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s of in t r a cr a n ia l t u m or s de-
pen d on t h e size a n d loca t ion of t h e t u m or. Neu r o-
logic deficit s a r e cr ea t ed wh en t h e t u m or er odes
fu n ct ion a l n eu r on s. Th is r esu lt s in specific m ot or or
sen sor y losses, su ch a s vision ch a n ges, n u m bn ess,
wea kn ess, or pa r a lysis. Cogn it ive, beh a vior a l, a n d
per son a lit y ch a n ges a r e a lso com m on a n d m a y m a n -
ifest a s ir r it a bilit y, for get fu ln ess, a n d depr ession .
P r essu r e in cr ea ses in t h e cr a n iu m fr om t h e gr owin g
t u m or, a lon g wit h in fla m m a t ion a n d flu id a ccu m u la -
t ion , lea d t o h ea da ch es (oft en a la t er sign ) a n d vom -
it in g. Seizu r es ca n a lso r esu lt fr om ir r it a t ion a n d t h e
su bsequ en t disor der ly disch a r ge of n eu r on s. Tu m or
com pr ession on t h e r espir a t or y a n d ca r dia c cen t er s
ca n r esu lt in dea t h .
DIAGNOSTIC CRITERIA
Dia gn osis of br a in t u m or s is ba sed on h ist or y a n d
ph ysica l exa m in a t ion , in clu din g a com plet e n eu -
r ologic exa m in a t ion . Th is n eu r ologic exa m in a t ion
in volves t est in g cr a n ia l n er ves, r eflexes, sen sor y
fu n ct ion , a n d m ot or fu n ct ion . Dir ect visu a liza t ion of
t u m or gr owt h via br a in sca n s, r a diogr a ph s, CT, MRI,
a n d cer ebr a l a n giogr a ph y will a lso a id in t h e dia g-
n osis a n d pr epa r e for r em ova l of t h e t u m or. Posit r on
em ission t om ogr a ph y (P E T) sca n n in g a n d spect r o-
scopic eva lu a t ion s a r e cu r r en t st r a t egies for dia g-
n osin g m et a st a sis in t h e cer ebr u m . Th ese t est s a r e
Me ningioma
Glioma s (ce re brum)
P ituita ry a de noma
Acous tic s chwa nnoma
(VII cra nia l ne rve )
P ontine glioma (childhood)
190 C h a p t e r 7: Alt er ed Cellu la r P r olifer a t ion a n d Differ en t ia t ion

Th e leu kem ia s a r e cla ssified

Ta b le 7.5 Wor ld H ea lt h Or ga n iza t ion Gr a din g of Cen t r a l Ner vou s
Syst em Tu m or s
Gr a d e D e s c r ip t io n
Gr a de I Lesion s wit h low pr olifer a t ive pot en t ia l, discr et e bor der s, a n d
likely t o be cu r ed wit h su r gica l r esect ion
Gr a de II Lesion s t h a t a r e gen er a lly in filt r a t in g a n d low in m it ot ic a c-
t ivit y bu t r ecu r ; m ay pr ogr ess t o h igh er gr a des of m a lign a n cy
Gr a de III Lesion s wit h h ist ologic eviden ce of m a lign a n cy a ssocia t ed
wit h eleva t ed m it ot ic a ct ivit y, a r e in filt r a t ive, a n d a n a pla st ic
Gr a de IV Lesion s t h a t a r e m it ot ica lly a ct ive, n ecr osis-pr on e, a n d gen er-
a lly a ssocia t ed wit h r a pid pr olifer a t ion
Repr in t ed wit h per m ission fr om Kleih u es P, Bu r ger P, Sch eit h a u er B. Th e n ew WH O cla ssifica -
t ion of br a in t u m ou r s. Br a in Pa th ol. 1993;3:255–268.
a lso u sefu l for differ en t ia t in g t h e m et a st a ses fr om
ot h er lesion s in t h e br a in .
TREATMENT
Th e t r ea t m en t of br a in ca n cer va r ies depen din g on
t h e loca t ion , ext en t , a n d n a t u r e of t h e n eopla sm s.
P r im a r y t u m or s a r e t r ea t ed wit h su r gica l r esect ion
wh en ever fea sible. Th e goa l of su r ger y is t o r em ove
t h e t u m or a s com plet ely a s possible wh ile st ill pr e-
ser vin g n eu r ologic fu n ct ion . Ra dia t ion t h er a py a lso
h a s a m a jor r ole in t r ea t m en t a n d is a lm ost u n iver-
sa lly in dica t ed. Ch em ot h er a py, oft en a dm in ist er ed
in t o t h e spin a l ca n a l, m a y a lso be u sed t o t r ea t cer-
t a in ch em osen sit ive t u m or t ypes, su ch a s gliom a s,
m edu llobla st om a s, a n d som e ger m cell t u m or s. Ch e-
m ot h er a py m a y a lso be pla ced dir ect ly in t h e br a in
du r in g su r ger y a s a loca l t r ea t m en t . For pa t ien t s
wit h m et a st a ses t o t h e br a in , wh ole br a in r a dia t ion
t h er a py (WBRT) m a y be n eeded beca u se of wide-
spr ea d t u m or s. Pa llia t ive ca r e is essen t ia l a n d m a y
in clu de t h e u se of a n t icon vu lsa n t s t o t r ea t seizu r es.
Leukemia
Leu kem ia s a r e m a lign a n t n eopla sm s of t h e blood
a n d blood-for m in g or ga n s. Leu kem ia (lit er a lly,
“wh it e blood”) is m ost oft en a ssocia t ed wit h over pr o-
lifer a t ion a n d la ck of differ en t ia t ion in wh it e blood
cells, bu t it ca n a lso a ffect ot h er cell t ypes. Leu kem ia
r epla ces cells in t h e bon e m a r r ow wit h im m a t u r e,
pr olifer a t in g n eopla sm s. Im m a t u r e cells a r e ca lled
b la s t c e lls . Non fu n ct ion in g leu kem ic bla st cells
t h en cir cu la t e in t h e va scu la r syst em .
DNA ch a n ges in t h e blood cells ca n r esu lt fr om
en vir on m en t a l exposu r es t o ion izin g r a dia t ion , a l-
kyla t in g dr u gs, ch em ica ls, or in t er n a l fa ct or s, su ch
a s ch r om osom a l a bn or m a lit ies. Ch r om osom a l a b-
n or m a lit ies ca n a ct iva t e cellu la r on cogen es t h a t pr o-
m ot e pr olifer a t ion of bla st cells.
a s a cu t e or ch r on ic a n d a r e a lso
cla ssified a ccor din g t o cell t ype.
Acu t e leu kem ia s, a s is t h e ca se
wit h ot h er a cu t e con dit ion s, a r e
su dden a n d r esu lt in a r a pid
a n d n ot icea ble loss of fu n ct ion .
Ch r on ic leu kem ia s a r e m or e
gr a du a l in on set , a n d ea r ly
sym pt om s, if a n y, a r e va gu e.
Th e differ en t cells a ffect ed by
leu kem ia a r e eit h er lym ph oid
or m yeloid t ypes. Lym ph ocyt ic
leu kem ia s in volve im m a t u r e
lym ph ocyt es t h a t or igin a t e in
t h e bon e m a r r ow. Myelogen ou s
leu kem ia s in volve m yeloid st em cells in t h e m a r r ow.
Leu kem ia s ca n in t er fer e wit h t h e m a t u r a t ion of a ll
blood cells, in clu din g er yt h r ocyt es a n d pla t elet s.
Acute Leukemias
Acu t e lym ph ocyt ic leu kem ia (ALL) is t h e m ost com -
m on ca n cer in ch ildr en wh er ea s a cu t e m yeloid leu -
kem ia (AML) m or e com m on ly occu r s in a du lt s. In
ALL, lym ph oid pr ogen it or cells (lym ph obla st s) a r e
a r r est ed in t h eir ea r ly st a ge of developm en t beca u se
of fa u lt y expr ession of gen es. In AML, it is t h e h em a -
t opoiet ic pr ecu r sor cells of t h e bon e m a r r ow wh ich
a r e a ffect ed (Fig. 7.13).
PATHOPHYSIOLOGY
On ce est a blish ed, t h e devia n t bla st cells r epla ce t h e
n or m a l m a r r ow elem en t s, r esu lt in g in a m a r ked de-
cr ea se in t h e pr odu ct ion of fu n ct ion a l wh it e blood
cells, RBCs, a n d pla t elet s. Th e devia n t cells ca n t h en
m ove in t o or ga n s ot h er t h a n t h e m a r r ow, pa r t icu -
la r ly t h e liver, spleen , a n d lym ph n odes.
CLINICAL MANIFESTATIONS
Th e clin ica l m a n ifest a t ion s a r e sim ila r in ALL a n d
AML. Th ey a r e su dden in on set a n d a r e r ela t ed t o:
1. Im m a t u r it y of wh it e blood cells a n d ot h er cells
or igin a t in g in t h e bon e m a r r ow
2. Cr owdin g of leu kem ic cells in t h e bon e m a r r ow
3. In filt r a t ion of leu kem ic cells in t h e CNS, lym ph
n odes, liver, a n d spleen
Im m a t u r it y of wh it e blood cells lea ds t o in cr ea sed
in fect ion s. Cr owdin g of leu kem ic cells in t h e bon e
m a r r ow ca n su ppr ess er yt h r ocyt e a n d pla t elet pr o-
du ct ion , lea din g t o a n em ia , br u isin g, a n d bleedin g
pr oblem s, su ch a s fr equ en t e p is t a x is , or n ose bleeds.
An em ia lea ds t o fa t igu e. Cell cr owdin g a lso in cr ea ses

Figure 7.13. Acute lymphoblastic leukemia. The lympho-
blasts contain irregular, prominent, and indented nuclei.
(From Rubin E, Farber JL. Pathology. 4th ed. Philadelphia,
PA: Lippincott Williams & Wilkins; 2005, with permission.)
pr essu r e a n d r esor pt ion wit h in t h e bon e a n d ca n r e-
su lt in bon e pa in . In filt r a t ion in t o t h e CNS ca u ses
h ea da ch es, visu a l dist u r ba n ces, n a u sea , vom it in g,
seizu r es, a n d com a . In filt r a t ion in t h e lym ph n odes,
spleen , a n d liver ca u ses en la r gem en t a n d t en der-
n ess of t h ese or ga n s. Un expla in ed weigh t loss a n d
fever a r e a lso com m on clin ica l m a n ifest a t ion s.
DIAGNOSTIC CRITERIA
Dia gn osis is ba sed on pa t ien t h ist or y a n d ph ysica l
exa m in a t ion . Th e blood cell cou n t dem on st r a t in g
bla st (im m a t u r e wh it e blood cells) cells gr ea t er t h a n
20% a n d m icr oscopic exa m in a t ion of blood cells is
dia gn ost ic. F u r t h er cyt ologic a n a lysis differ en t ia t es
t h e specific leu kem ia su bt ype.
TREATMENT
Th e m ost com m on t r ea t m en t pr ot ocol for ALL in -
clu des a syst em ic com bin a t ion of ch em ot h er a py
a n d specific pr oph yla ct ic cen t r a l n er vou s syst em
in t r a t h eca l ch em ot h er a py wit h or wit h ou t cr a n ia l
r a dia t ion . Th e t r ea t m en t pr ot ocol is divided in t o
st a ges t h a t in clu de in du ct ion , in t en sifica t ion , a n d
m a in t en a n ce. Close m on it or in g is r equ ir ed du r in g
t r ea t m en t beca u se of t h e m yelosu ppr ession a n d im -
m u n osu ppr ession t h a t is expect ed wit h in t en se ch e-
m ot h er a py. Th e goa l is t o a ch ieve r em ission (bla st
cells less t h a n 5%). Am on g ch ildr en wit h ALL, m or e
t h a n 95% a t t a in r em ission a n d t h e 5-yea r su r viva l
r a t e is over 80%.
Tr ea t m en t for AML a lso in clu des syst em ic com -
bin a t ion ch em ot h er a py in t wo ph a ses: in du ct ion (t o
a ch ieve r em ission ) a n d post r em ission . Beca u se on ly
5% of t h ose wit h AML develop CNS disea se, pr o-
ph yla ct ic CNS in t r a t h eca l ch em ot h er a py is r a r ely
C lin ic a l Mo d e ls 191
in dica t ed. Appr oxim a t ely 70% of a du lt s wit h AML
ca n expect t o a t t a in com plet e r em ission a ft er in -
du ct ion t h er a py. Su ccess wit h t h er a py is r ela t ed t o
you n ger a ge, la ck of CNS in volvem en t , la ck of sys-
t em ic in fect ion a t dia gn osis, a n d lower im m a t u r e
WBC cou n t s.
Chronic Lymphocytic and
Myelogenous Leukemias
Ch r on ic leu kem ia s h a ve a m or e gr a du a l on set
a n d a r e fou n d m ost com m on ly in m iddle a n d older
a du lt s. Ch r on ic lym ph ocyt ic leu kem ia (CLL) r esu lt s
in h ypopr olifer a t ive, im m u n ologica lly dysfu n ct ion a l
sm a ll B lym ph ocyt es (Fig. 7.14). Th e cells do n ot r ea d-
ily for m a n t ibodies in t h e pr esen ce of a n t igen s, a n d
in fect ion is com m on . Ch r on ic m yelogen ou s leu kem ia
(CML) is sim ila r ly in sidiou s in on set a n d ch a r a ct er-
ized by u n con t r olled pr olifer a t ion of gr a n u locyt es,
er yt h r oid cells, a n d m ega ka r yocyt es (m yelogen ou s
cells t ypes); a ga in , t h ese cells a r e r ela t ively m a t u r e
bu t n ot fu lly fu n ct ion a l.
PATHOPHYSIOLOGY
Th e ch r on ic leu kem ia s a r e a cqu ir ed m u t a t ion s r e-
su lt in g in clon a l B cells or h em a t opoiet ic st em cells
disr u pt ed a lon g t h e differ en t ia t ion pa t h wa y. In 50%
of t h ose wit h CLL, a n a bn or m a l delet ion of 13q is
n ot ed. Ot h er ch r om osom e a bn or m a lit ies a ssocia t ed
wit h CLL in clu de t h e delet ion of t h e sh or t a r m of
ch r om osom e 17 (a ssocia t ed wit h loss of fu n ct ion of
t u m or su ppr essor gen e p53) a n d t h e pr esen ce of t r i-
som y 12. Sim ila r ly, in CML, a 9 a n d 22 ch r om osom e
Figure 7.14. Chronic lymphocytic leukemia. A peripheral
blood smear shows numerous small-to-medium sized lym-
phocytes. (From Rubin E, Farber JL. Pathology. 4th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2005, with
permission.)
192 C h a p t e r 7: Alt er ed Cellu la r P r olifer a t ion a n d Differ en t ia t ion
t r a n sloca t ion is pr esen t in 95%. Th e r esu lt a n t sh or t -
en in g of ch r om osom e 22, r efer r ed t o a s t h e P h ila d e l-
p h ia c h r o m o s o m e , a ct iva t es on cogen es. Th e BCR
a n d ABL gen es becom e r ea r r a n ged, a llowin g pr odu c-
t ion of a bn or m a l t yr osin e kin a se pr ot ein , lea din g t o
disor der ed m yelopoiesis (for m a t ion of bon e m a r r ow).
CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s for ch r on ic leu kem ia s a r e
oft en su bt le or n ot pr esen t u n t il t h e disea se is well
a dva n ced. Wh en pr esen t , t h e clin ica l m a n ifest a t ion s
a r e sim ila r t o a cu t e leu kem ia s: fa t igu e, lym ph n ode
en la r gem en t (pa r t icu la r ly wit h CLL), h epa t om eg-
a ly, splen om ega ly, r ecu r r en t or per sist en t in fect ion s,
low-gr a de fever, a n em ia , weigh t loss, bleedin g, br u is-
in g, a n d bon e pa in .
DIAGNOSTIC CRITERIA
Dia gn osis pr ior t o t h e on set of r ecogn iza ble sym p-
t om s is oft en m a de in ciden t a lly; t h e in dividu a l is
seeking ca r e for a n ot h er pur pose, a blood cell cou n t
is per for m ed, a n eleva t ion in t h e WBC cou n t is n ot ed,
a n d t h e pa t ien t u n der goes fu r t h er in vest iga t ion . The
pa t ien t m ay h ave det ect a ble spleen en la r gem en t on
ph ysica l exa m in a t ion. A bone m a r r ow biopsy is oft en
per for m ed a n d det ect s a gr ea t er pr opor t ion of im m a -
t u r e m yeloid cells. Cyt ologic a n a lysis is u sed t o de-
t er m in e specific ch r om osom a l a ber r a t ion s or genet ic
m u t a t ion s. For exa m ple, CML is fu r t h er dist ingu ish ed
by t h e pr esence of t h e P h ila delph ia ch r om osom e.
TREATMENT
Th e opt im a l t r ea t m en t for CML a n d CLL a t dia g-
n osis h a s n ot yet been est a blish ed. Pa t ien t s wit h
ea r ly-st a ge CLL a r e oft en n ot t r ea t ed u n t il becom -
in g sym pt om a t ic. Mor e t h a n h a lf of pa t ien t s m a y be
cu r ed wit h bon e m a r r ow or st em cell t r a n spla n t a -
t ion . H owever, eligibilit y is r est r ict ed by a ge, over-
a ll h ea lt h st a t u s, a n d in a bilit y t o loca t e a su it a ble
don or. Pa t ien t s wit h ext r em ely h igh cir cu la t in g
WBCs (gr ea t er t h a n 100,000/m m 3 ) r equ ir e im m edi-
a t e ch em ot h er a peu t ic t r ea t m en t t o a void dea t h fr om
obst r u ct ion of blood vessels lea din g t o vit a l or ga n s.
Splen ect om y m a y be r equ ir ed in t h ose wit h ph ysi-
ca l discom for t a n d h em a t ologic disor der s r ela t ed t o
m a ssive splen ic en la r gem en t . Th e m edia n su r viva l
r a t e is a r ou n d 5 t o 10 yea r s, wit h a 5-yea r su r viva l
r a t e of 50% t o 60%.
Lymphomas
Lym ph om a s, m a lign a n t lym ph ocyt es or lym ph o-
bla st s, a r e com m on ly cla ssified a s eit h er H odgkin
lym ph om a or n on -H odgkin lym ph om a . Lym ph om a s,
like leu kem ia , a r e der ived fr om WBCs (n a m ely lym -
ph ocyt es) a n d lym ph t issu es. Lym ph om a s for m solid
or ga n t u m or s in t h e lym ph t issu e a n d la t er in t h e
bon e m a r r ow. Lym ph om a s ca n a lso be pr esen t in t h e
spleen a n d liver.
Hodgkin Lymphoma
H o d g k in ly m p h o m a (H L ) is a m a lign a n t bu t po-
t en t ia lly cu r a ble disor der of t h e lym ph oid t issu e
oft en ch a r a ct er ized by t h e pa in less, pr ogr essive
en la r gem en t of cer vica l (n eck) lym ph n odes. Risk
fa ct or s in clu de exposu r e t o vir u ses su ch a s E pst ein –
Ba r r vir u s (E BV), gen et ic fa ct or s, a n d im m u n osu p-
pr ession . In ciden ce is h igh est in t h ose bet ween t h e
a ges of 10 a n d 30 yea r s a n d in t h ose older t h a n 50
yea r s. In t er est in gly, t h e ch ildh ood for m of H L is sim -
ila r in biology a n d pa t h ogen esis t o t h e a du lt -on set
for m . Th e m or t a lit y r a t e h a s declin ed dr a m a t ica lly
for a du lt s wit h H L a t a gr ea t er pa ce t h a n a n y ot h er
m a lign a n cy, a lso la r gely beca u se of t h e effect iven ess
of con t em por a r y r a dia t ion a n d ch em ot h er a peu t ic
t r ea t m en t s.
PATHOPHYSIOLOGY
Cla ssic H L is ch a r a ct er ized by t h e pr esen ce of m u l-
t in u clea t ed gia n t cells (m a cr oph a ges), ca lled Reed–
St er n ber g cells, or m on on u clea r gia n t cells, ca lled
H odgkin cells, su r r ou n ded by m u lt iple ot h er in -
fla m m a t or y cells, su ch a s n eu t r oph ils, eosin oph ils,
pla sm a cells, sm a ll lym ph ocyt es, a n d fibr obla st s. H L
ca n be cla ssified in t o five t ypes. Th e fir st fou r t ypes
en com pa ss “cla ssic H L,” a n d t h e fift h t ype is a dis-
t in ct en t it y wit h it s own clin ica l pr esen t a t ion a n d
t r ea t m en t pla n .
1. Nodu la r scler osin g
2. Mixed cellu la r it y
3. Lym ph ocyt e deplet ion
4. Lym ph ocyt e r ich
5. Nodu la r lym ph ocyt e-pr edom in a n t
Th e pa t h ogen esis of H L is st ill u n der in vest iga -
t ion . Th e Reed–St er n ber g or H odgkin cell h a s been
iden t ified a s t h e n eopla st ic or igin , ca pa ble of clon a l
expa n sion . In cla ssic H L, t h e R e e d –S t e r n b e r g
c e ll (Fig. 7.15) or igin a t es in t h e cell com pon en t s of
lym ph n odes followin g a B-lym ph ocyt e lin ea ge; it is
t h e n eopla st ic cell dia gn ost ic for H L. Su scept ibilit y
t o specific vir a l on cogen es or cer t a in H LA su bt ypes
su ggest s a m u lt ifa ct or ia l et iology wit h a gen et ic
in flu en ce. H L t ypica lly a r ises in B cells t h a t ca n -
n ot syn t h esize im m u n oglobu lin a n d a r e r esist a n t
t o a popt osis. Specu la t ion a bou t a vir a l et iology is
 C lin ic a l Mo d e ls 193

● St a ge I: A sin gle lym ph n ode a r ea or sin gle ex-

t r a n oda l sit e
● St a ge II: Two or m or e lym ph n ode a r ea s on t h e
sa m e side of t h e dia ph r a gm
● St a ge III: Lym ph n ode a r ea s on bot h sides of t h e
dia ph r a gm
● St a ge IV: Dissem in a t ed or m u lt iple in volvem en t
of t h e ext r a n oda l or ga n s

TREATMENT
Tr ea t m en t is ba sed on clin ica l st a gin g of H L. Ch e-
m ot h er a py, r a dia t ion , a n d h em a t opoeit ic st em cell
t r a n spla n t a t ion a r e t h e pr im a r y t r ea t m en t m oda li-
Figure 7.15. Classic Reed–Sternberg cell. The Reed–
t ies. Pa t ien t s wit h st a ge I or II disea se a r e con sider ed
Sternberg cell is derived from B lymphocytes and suggests
t o h a ve clin ica l ea r ly-st a ge disea se a n d a r e t r ea t ed
the presence of Hodgkin lymphoma. The cell is large and
wit h ch em ot h er a py, com bin ed ch em ot h er a py–
binucleated or multinucleated with eosinophilic nucleoli.
r a dia t ion t h er a py, or r a dia t ion t h er a py a lon e. Pa -
(From Rubin E, Farber JL. Pathology. 4th ed. Philadelphia,
t ien t s wit h st a ge III or IV disea se or t h ose wit h
PA: Lippincott Williams & Wilkins; 2005, with permission.)
t h e pr esen ce of syst em ic sym pt om s a t a n y st a ge
r equ ir e com bin a t ion ch em ot h er a py wit h or wit h -
ou t a dju n ct r a dia t ion t h er a py. Redu ced dosa ges,
pa r t icu la r ly lower-dose r a dia t ion , a r e u sed wh en
eviden ced by E BV gen et ic m a t er ia l, wh ich ca n oft en
t r ea t in g ch ildr en . Poor pr ogn osis is ba sed on t h e
be det ect ed in t h ese a ffect ed cells. Th e r isk of de-
pr esen ce of syst em ic sym pt om s, t h e st a ge of t h e
velopin g E BV-posit ive H L is in cr ea sed sign ifica n t ly
disea se, t h e pr esen ce of la r ge m a sses, t r ea t m en t ef-
in t h ose in fect ed wit h t h is vir u s. Ot h er in cr ea sed
fect iven ess, t h e ext r em es of a ge, expa n sive disea se
in ciden ce is fou n d in ch ildr en wh o h a ve pa r en t s
spr ea d, a n d t h e pr esen ce of im m u n odeficien cy. Th e
wit h a h ist or y of H L. On ce t h e pr im a r y t u m or is es-
over a ll 5-yea r su r viva l r a t e for pa t ien t s wit h H L is
t a blish ed, t h e n eopla sm m a y spr ea d t o con n ect in g
a r ou n d 85%.
lym ph ch a n n els a n d ca n a lso in filt r a t e t h e va scu la r
syst em . H L is or ga n t r opic t o t h e lu n g, liver, bon es,
Stop and Consider
a n d bon e m a r r ow.
How are leukemias and lymphomas similar?

CLINICAL MANIFESTATIONS
Th e va st m a jor it y of in dividu a ls wit h H L pr esen t
wit h a n on t en der en la r ged lym ph n ode or gr ou p of
Non-Hodgkin Lymphoma
n odes in t h e n eck. Th e en la r ged n odes a r e gen er a lly
N o n -H o d g k in ly m p h o m a (N H L ) is a gen er ic cla s-
fir m a n d r u bber y in t ext u r e. Ot h er m a n ifest a t ion s,
sifica t ion m a de u p of a br oa d r a n ge of B-cell a n d
su ch a s low-gr a de fever, fa t igu e, weigh t loss, pr u r i-
T-cell m a lign a n cies wit h in t h e lym ph n odes. NH L
t u s, a n d dr en ch in g n igh t swea t s, a r e a ssocia t ed wit h
occu r s m u ch m or e fr equ en t ly t h a n H L, does n ot
t h e r elea se of lym ph okin es a n d cyt okin es (in fla m m a -
exh ibit t h e m a lign a n t Reed–St er n ber g cell, a n d is
t or y m edia t or s) by Reed–St er n ber g or H odgkin cells.
m or e likely t o a ffect n on con t igu ou s (u n con n ect ed)
Appr oxim a t ely 20% of pa t ien t s will h a ve a m a ss a t
lym ph n odes. Sim ila r t o H L, t h e et iology of NH L is
t h e m edia st in u m t h a t is gr ea t er t h a n on e-t h ir d of
oft en u n kn own ; h owever, ch r om osom a l t r a n sloca -
t h e ch est dia m et er. Splen om ega ly a n d h epa t om ega ly
t ion s, in fect ion s, ch r on ic in fla m m a t ion , vir u ses, im -
m a y a lso be det ect ed.
m u n odeficien cy, en vir on m en t a l fa ct or s, a n d gen et ic
fa ct or s a r e im plica t ed.
DIAGNOSTIC CRITERIA
Th e dia gn osis a n d st a gin g of H L is ba sed on t h e pa -
PATHOPHYSIOLOGY
t ien t h ist or y, ph ysica l exa m in a t ion , la bor a t or y st u d-
ies, a n d t h or a cic a n d a bdom in a l CT sca n s. Th e m ost Th e pr ecise gen et ic m u t a t ion for NH L is h igh ly
sign ifica n t dia gn ost ic fea t u r e of H odgkin lym ph om a va r ia ble, depen din g on t h e specific cell a ffect ed by
is t h e pr esen ce of Reed–St er n ber g cells. Th e An n Ar- n eopla sia . Mu t a t ion s ca n a ffect pr ot oon cogen es or
bor cla ssifica t ion is u sed t o st a ge H L: t u m or su ppr essor gen es r esu lt in g in a devia n t clon a l
194 C h a p t e r 7: Alt er ed Cellu la r P r olifer a t ion a n d Differ en t ia t ion
expa n sion of B cells (85%) or T cells (15%). Th er e
a r e a t lea st 10 NH L su bt ypes. As wit h H L, spr ea d
ca n occu r via t h e lym ph a t ic a n d va scu la r syst em s.
NH L is or ga n t r opic t o t h e liver, spleen , a n d bon e
m a r r ow.
CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s ca n va r y som ewh a t depen d-
in g on t h e t u m or t ype a n d ext en t of disea se. Th e
m ost com m on occu r r en ce, a s wit h H L, is pa in less
a n d slowly pr ogr essive en la r gem en t of lym ph n odes.
Th ose wit h NH L ca n exper ien ce syst em ic m a n ifes-
t a t ion s, su ch a s fever, n igh t swea t s, weigh t loss, a n
in cr ea sed r isk of in fect ion , a n d pa r a n eopla st ic syn -
dr om es a s wit h ot h er m a lign a n t n eopla sm s.
DIAGNOSTIC CRITERIA
Dia gn osis is ba sed on pa t ien t h ist or y a n d ph ysica l
exa m in a t ion , a lon g wit h con fir m a t ion via lym ph
n ode biopsy. Ch est a n d a bdom in a l CT sca n s ca n a lso
be u sed t o visu a lize t h e t u m or size a n d loca t ion . E x-
a m in a t ion of t h e cells in t h e cer ebr ospin a l flu id m a y
be posit ive for m et a st a ses in pa t ien t s wit h a ggr es-
sive NH L.
Th e st a gin g syst em (I t h r ou gh IV) is sim ila r t o
t h a t of H L. H ist ologic cla ssifica t ion is ba sed on t h r ee
m a jor ca t egor ies of lym ph oid m a lign a n cies ba sed
on m or ph ology a n d cell lin ea ge: B-cell n eopla sm s,
T-cell/n a t u r a l killer (NK)-cell n eopla sm s, a n d H L.
Bot h t h e lym ph om a s (solid t u m or s in lym ph ) a n d
leu kem ia s (cir cu la t in g n eopla sm s wit h im m u n e cell
lin ea ge) a r e in clu ded in t h is cla ssifica t ion a n d t h er e
ca n be cr ossover bet ween leu kem ia s a n d lym ph o-
m a s given t h e im pa ct on lym ph ocyt es. For exa m ple,
B-cell CLL a n d B-cell sm a ll lym ph ocyt ic lym ph om a
a r e, in essen ce, t h e sa m e n eopla sm .
TREATMENT
Cu r r en t ly, t r ea t m en t is ba sed on ca t egor izin g t h e
NH Ls in t o t wo pr ogn ost ic gr ou ps: t h e in dolen t
(pa in less, pa ssive) lym ph om a s a n d t h e a ggr essive
lym ph om a s. E a r ly-st a ge (st a ge I a n d st a ge II) in do-
len t NH L ca n be t r ea t ed effect ively wit h r a dia t ion
t h er a py. La t er-st a ge in dolen t a n d a ggr essive NH Ls
r equ ir e in t en sive com bin a t ion ch em ot h er a py r egi-
m en s wit h or wit h ou t r a dia t ion t h er a py a n d st em
cell t r a n spla n t a t ion . P r ogn osis for NH L is ba sed
on t h e st a ge, cell ch a r a ct er ist ics, a ge, t r ea t m en t r e-
spon se, t u m or size, la ct a t e deh ydr ogen a se (LDH )
va lu es, a n d t h e n u m ber of a ffect ed lym ph n ode sit es
ou t side of t h ose su r r ou n din g t h e pr im a r y t u m or. In
gen er a l, t h e 5-yea r su r viva l r a t e for a ll t ypes of NH L
is a r ou n d 60%.
S U MMAR Y
● Neopla sia is a disor der of cellu la r pr olifer a t ion
a n d differ en t ia t ion .
● Mu t a t ion s of gen es t h a t r egu la t e cell gr owt h , r e-
pr odu ct ion , a n d dea t h a r e r espon sible for n eopla s-
t ic t r a n sfor m a t ion s.
● Ca r cin ogen esis is com plex a n d in volves m u lt iple
st a ges.
● Cer t a in su bst a n ces or exposu r es a r e kn own t o
ca u se or pr om ot e cellu la r m u t a t ion s, su ch a s r a -
dia t ion , exposu r e t o r ea ct ive oxygen species (fr ee
r a dica ls), h or m on es, t oba cco, in fect iou s m icr oor-
ga n ism s, a n d ch em ica ls.
● Ca n cer oft en exh ibit s a pr olon ged la t en t per iod
bet ween t h e in it ia t ion a n d on set of clin ica l m a n i-
fest a t ion s, m a kin g iden t ifica t ion of a pr ecise ca r-
cin ogen difficu lt .
● Neopla st ic cells a r e a u t on om ou s, a n a pla st ic, a n d
en er gy-depen den t . Th ey u n der go ext en sive a n gio-
gen esis, depr ive u n a ffect ed t issu es of oxygen a n d
ot h er n u t r ien t s, a n d secr et e su bst a n ces t h a t ca n
a lt er m et a bolic pr ocesses.
● Gen er a l m a n ifest a t ion s r ela t ed t o syst em ic in -
fla m m a t or y a n d im m u n e syst em s in clu de lym ph -
a den opa t h y, fever, a n d a n or exia .
● Loca l clin ica l m a n ifest a t ion s a r e sit e depen den t
a n d a r e r ela t ed t o (1) t h e spa ce occu pied by t h e
t u m or t h a t im pin ges on t h e loca l st r u ct u r es; a n d
(2) t h e loss of fu n ct ion in t h e t issu e or or ga n t h a t
is bein g “t a ken over ” by t h e t u m or.
● Tu m or s spr ea d loca lly a n d t o dist a n t sit es t h r ou gh
t h e va scu la r a n d lym ph a t ic syst em s.
● Met a st a ses a r e dist a n t r eloca t ion s of t h e t u m or
t h a t con t r ibu t e t o t h e let h a l a spect of ca n cer.
● Ma jor t r ea t m en t st r a t egies for n eopla sia in clu de
su r ger y, ch em ot h er a py, r a dia t ion , h or m on es, a n d
im m u n ot h er a py.
C AS E S T U D Y 7.1
A 65-yea r-old H ispa n ic wom a n r ecen t ly u n der wen t
a m a m m ogr a m offer ed by a com m u n it y “h ea lt h on
wh eels” clin ic. Th e r a diologist det ect ed a br ea st
m a ss on t h e r igh t side. Sh e h a s a you n ger sist er wh o
h a d br ea st ca n cer a s well. H er sist er died 2 yea r s
a go a t t h e a ge of 62. H er m en ses bega n a t a ge 11 a n d
cessa t ion of m en st r u a t ion occu r r ed a r ou n d a ge 58.
Sh e is over weigh t a n d is on est r ogen r epla cem en t
t h er a py. Sh e does n ot h a ve a n y ch ildr en .
1. Ou t lin e t h e pr ocess t h a t h a s occu r r ed in h er body.
2. Wh a t wer e t h e r isk fa ct or s t h a t sh e dem on st r a t ed?
3. Wh a t wou ld you expect for clin ica l m a n ifest a t ion s?
4. Wh a t a ddit ion a l dia gn ost ic t est s cou ld be u sed?
5. Wh a t t r ea t m en t m ea su r es wou ld you a n t icipa t e?
 C h a p t e r 7: Alt er ed Cellu la r P r olifer a t ion a n d Differ en t ia t ion 195

Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r- P R AC T I C E E XAM Q U E S T I O N S

n a l a r t icle or Web sit e (su ch a s www.ca n cer.gov/
ca n ce r t op i cs /p d q /g e n e t i cs /b r e a s t -a n d -ova r i a n /
h ea lt h pr ofession a l) t h a t det a ils br ea st ca n cer a n d 1. A pa t ien t com es t o t h e clin ic con cer n ed a bou t a
con fir m you r pr edict ion s. pa in less lym ph n ode in t h e n eck. A dia gn osis of
lym ph om a is m a de. Wh ich of t h e followin g wou ld
in dica t e t h a t t h e lym ph om a wa s H odgkin lym -
ph om a ver su s n on -H odgkin lym ph om a ?
C AS E S T U D Y 7.2 a . Th e loca t ion of t h e en la r ged lym ph n odes
b. Th e pr esen ce of Reed–St er n ber g cells
A 51-yea r-old Ca u ca sia n m a n is bein g eva lu a t ed for c. Spr ea d t o t h e spleen , liver, a n d bon e m a r r ow
h ea da ch es, h yper t en sion , sever e skin it ch in g, a n d d. Th e a ge of t h e pa t ien t
liver a n d spleen en la r gem en t . H e h a s a r u ddy com -
plexion . La bor a t or y a n d dia gn ost ic t est s r evea l t h a t 2. Wh ich of t h e followin g gen es, when m u t a t ed, is
h e h a s a n eleva t ed h em a t ocr it a n d RBC cou n t . H e NOT im plica t ed in t h e developm en t of n eopla sm s?
is dia gn osed wit h polycyt h em ia ver a , on over pr o- a . Ca n cin ogen es
lifer a t ion of RBCs. Alt h ou gh n ot descr ibed in you r b. Tu m or su ppr essor gen es
r ea din g, u se wh a t you kn ow a bou t over pr olifer a t ion / c. On cogen es
differ en t ia t ion a n d a pply t h is t o wh a t m igh t h a ppen d. Mu t a t or gen es
if RBCs wer e in volved.
3. Wh ich of t h e followin g cells is lea st likely t o de-
1. Ou t lin e t h e pr ocess t h a t h a s m ost ly likely oc- velop in t o a n eopla sia ?
cu r r ed in h is body. a . E pit h elia l cell
2. Wh a t wou ld you expect for clin ica l m a n ifest a t ion s? b. Ca r dia c m yocyt e
3. Wh a t dia gn ost ic t est s wer e u sed a n d wh a t do c. Lym ph ocyt e
t h ese t ell you ? d. H epa t ocyt e
4. Wh a t t r ea t m en t m ea su r es wou ld you a n t icipa t e?
4. Wh ich gen e h a s been im plica t ed m ost fr equ en t ly
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r-
in t h e developm en t of ca n cer ?
n a l a r t icle or Web sit e (su ch a s h t t p://www.ca n cer.
a . p53 gen e
gov/ca n cer t opics/pdq/t r ea t m en t /m yelopr olifer a t ive/
b. Rb gen e
H ea lt h P r ofession a l/pa ge4) t h a t det a ils polycyt h e-
c. T21 gen e
m ia ver a a n d con fir m you r pr edict ion s.
d. Non e of t h ese is im plica t ed in t h e develop-
m en t of ca n cer.

5. Wh ich of t h e followin g is ch a r a ct er ist ic of ben ign

C AS E S T U D Y 7.3 n eopla sm s?
a . H igh ly u n differ en t ia t ed
An 11-yea r-old boy pr esen t s t o t h e em er gen cy b. In va sive
d ep a r t m en t wit h low ba ck pa in a n d a pa lpa ble c. Dest r u ct ive
m a ss on h is r igh t side n ea r h is h ip. H is pa r en t d. Cell over pr olifer a t ion
a lso r epor t s in t er m it t en t , low-gr a de fever a n d
weigh t los s over t h e pa s t 3 m on t h s. Aft er ca r e- 6. Wh ich is t h e m ost sign ifica n t differ en ce be-
fu l ph ysica l exa m in a t ion , la bor a t or y st u dies, a n d t ween a cu t e lym ph ocyt ic a n d a cu t e m yelogen ou s
im a gin g st u dies, a d ia gn osis of E win g sa r com a is leu kem ia ?
d et er m in ed. a . ALL a ffect s a du lt s a n d AML a ffect s ch ildr en
m ost oft en
1. Ou t lin e t h e pr ocess t h a t h a s m ost ly likely oc- b. Cell t ype a ffect ed
cu r r ed in h is body. c. Dia gn ost ic t est s u sed
2. Wh a t wou ld you expect for clin ica l m a n ifest a t ion s? d. Clin ica l m a n ifest a t ion s
3. Wh a t dia gn ost ic t est s wer e u sed a n d wh a t do
t h ese t ell you ? 7. You r gr a n dfa t h er h a s colon ca n cer bu t t h en it
4. Wh a t t r ea t m en t m ea su r es wou ld you a n t icipa t e? m igr a t es t o t h e liver. Th e a ffin it y for m ovem en t
t o a n ot h er specific or ga n is ca lled:
Log on t o t he Int er n et . Sea r ch for a r eleva n t jou r- a . Tr opism
n a l a r t icle or Web sit e (su ch a s h t t p://www.ca n cer b. Migr a t ism
.gov/t ypes/bon e/h p/ewing-t r ea t m ent -pdq) t h a t det a ils c. Ma gn et ism
E wing sa r com a a n d con fir m you r pr edict ions. d. Ma lign a n cy
196 C h a p t e r 7: Alt er ed Cellu la r P r olifer a t ion a n d Differ en t ia t ion
8. You a r e a pu blic h ea lt h officia l a n d wa n t t o m a ke
t h e gr ea t est differ en ce in r edu cin g ca n cer dea t h s
a cr oss t h e globe. Wh ich in t er ven t ion wou ld h a ve
t h e gr ea t est im pa ct ?
a . Sm okin g cessa t ion pr ogr a m s
b. Rou t in e gen et ic t est in g
c. Dist r ibu t e su n scr een t o a ll a du lt s a n d ch ildr en
d. E lim in a t e u n n ecessa r y u ses of r a dia t ion
9. Wh a t sign /sym pt om m igh t in dica t e t h a t you a r e
exper ien cin g a pa r a n eopla st ic syn dr om e?
a . Bon e pa in
b. E dem a
c. Cou gh
d. H em a t u r ia
10. Wh ich t ype of ca n cer wou ld m ost likely spr ea d
t h r ou gh t h e pr ocess ca lled seedin g?
a . Lu n g
b. Colon
c. Ova r ia n
d. Bon e
D I S C U S S I O N AN D
AP P L I C AT I O N
1. Wh a t did I kn ow a bou t a lt er ed cellu la r pr olifer a -
t ion a n d differ en t ia t ion pr ior t o t oda y?
2. What body processes are affected by altered prolif-
eration and differentiation? What are the expected
functions of those processes? How does altered pro-
liferation and differentiation affect those processes?
3. Wh a t a r e t h e pot en t ia l et iologies for a lt er ed cel-
lu la r pr olifer a t ion a n d differ en t ia t ion ? H ow does
a lt er ed pr olifer a t ion a n d differ en t ia t ion develop?
4. Who is most at risk for developing altered cellular
prolifera tion and differentiation? How ca n altered
prolifera tion a nd differentiation be prevented?
5. Wh a t a r e t h e h u m a n differ en ces t h a t a ffect t h e
et iology, r isk, or cou r se of a lt er ed cellu la r pr olif-
er a t ion a n d differ en t ia t ion ?
F in d a d d ition a l r esou r ces for th is ch a pter a t h ttp:th ePoin t.lww.com
6. Wh a t clin ica l m a n ifest a t ion s a r e expect ed in
t h e cou r se of a lt er ed cellu la r pr olifer a t ion a n d
differ en t ia t ion ?
7. Wh a t specia l dia gn ost ic t est s a r e u sefu l in de-
t er m in in g t h e dia gn osis a n d cou r se of a lt er ed
pr olifer a t ion a n d differ en t ia t ion ?
8. Wh a t a r e t h e goa ls of ca r e for in dividu a ls wit h a l-
t er ed cellu la r pr olifer a t ion a n d differ en t ia t ion ?
9. H ow does t h e con cept of a lt er ed cellu la r pr olif-
er a t ion a n d differ en t ia t ion bu ild on wh a t I h a ve
lea r n ed in t h e pr eviou s ch a pt er s a n d in pr evi-
ou s cou r ses?
10. H ow ca n I u se wh a t I h a ve lea r n ed?
R E SOUR CE S
Am er ica n Ca n cer Societ y:
h t t p://www.ca n cer.or g/docr oot /h om e/in dex.a sp
Na t ion a l Ca n cer In st it u t e:
h t t p://www.n ci.n ih .gov/
Am er ica n Associa t ion for Ca n cer Resea r ch :
h t t p://ca n cer r es.a a cr jou r n a ls.or g/
In t er cu lt u r a l Ca n cer Cou n cil:
h t t p://www.iccn et wor k.or g
R e er en ces
1. Am er ica n Ca n cer Societ y. Ca n cer Fa cts a n d Figu r es,
2014. At la n t a , GA: Am er ica n Ca n cer Societ y; 2014.
h t t p://www.ca n cer.or g
2. Yu n h u a L, Xia oxia o H , Cecil H , et a l. Ta r get in g
t u m or su ppr essor gen es for ca n cer t h er a py. Bioessa ys.
2015;37(12):1277–1286. doi:10.1002/bies.201500093.
3. Ta n WW. Non -sm a ll cell lu n g ca n cer. 2015. h t t p://em edi
cin e.m edsca pe.com /a r t icle/279960-over view
4. Dr a govich T. Colon ca n cer. 2015. h t t p://em edicin e.m ed-
sca pe.com /a r t icle/277496-over view
5. SE E R ca n cer st a t ist ics fa ct sh eet s: br a in a n d ot h er
n er vou s syst em ca n cer. Bet h esda , MD: Na t ion a l Ca n cer
In st it u t e; 2015. h t t p://seer.ca n cer.gov/st a t fa ct s/h t m l/
br a in .h t m l
 Ch a pt er

8
Alt er ed F lu id a n d
E lect r olyt e Ba la n ce

L E AR N I N G O U T C O ME S
1. Defin e a n d u se t h e key t er m s list ed in t h is ch a pt er.
2. Com pa r e a n d con t r a st t h e dist r ibu t ion of flu id in body com pa r t m en t s.
3. Differ en t ia t e bet ween ca t ion s a n d a n ion s, in clu din g expect ed con cen t r a -
t ion s wit h in specific body com pa r t m en t s.
4. Iden t ify t h e in flu en ces t h a t pr om ot e flu id m ovem en t bet ween a n d wit h in
com pa r t m en t s.
5. List fou r pot en t ia l sou r ces of body flu id loss.
6. Descr ibe t h e clin ica l im plica t ion s of a lt er a t ion s in flu id a n d elect r olyt e
ba la n ce.
7. Apply con cept s of a lt er ed flu id a n d elect r olyt e ba la n ce t o select ed clin ica l
m odels.

INTR ODUCTION
H a ve you ever been t h ir st y on a h ot , su n n y da y? Wh a t a bou t a ft er a lon g wor k-
ou t or a ft er ea t in g a ba g of pr et zels? Th ir st is t h e wa y t h e body com m u n ica t es
t h e n eed t o in cr ea se flu id in t a ke. F lu id in t a ke m u st m a ke u p for flu id lost
t h r ou gh swea t in g, br ea t h in g, a n d u r in a t in g. In a ddit ion t o flu ids, elect r olyt es
a n d specia lized com pou n ds t h a t con t r ol a cid–ba se ba la n ce a r e n ecessa r y for
cell a n d or ga n fu n ct ion in g. Th is ch a pt er r eviews t h e m ech a n ism s in volved
in t h e dysr egu la t ion of flu id, elect r olyt e, pr esen t ed in in dividu a l m odu les. It
a lso cover s in t er a ct ion s bet ween t h ese con cept s a n d t h e clin ica l con sequ en ces
t h a t m a y r esu lt . Select ed clin ica l m odels t h a t h igh ligh t specific a lt er a t ion s a r e
pr esen t ed in m odu le 3 t o a llow t h e st u den t t o a pply t h e lea r n ed con cept s.

Lymphedema
197
198 C h a p t e r 8: Alt er ed F lu id a n d E lect r olyt e Ba la n ce

Modu le 1 E le c t r o ly t e I m b a la n c e

Body flu id con t a in s dissolved pa r t icles kn own a s n ega t ively ch a r ged ion occu r s, it is ca lled a n io n e x -
elect r olyt es. E le c t r o ly t e s a r e elect r ica lly ch a r ged c h a n g e . Th e exch a n ge of like-ch a r ged ion s bet ween
pa r t icles, or io n s . Ion s wit h a posit ive ch a r ge a r e cellu la r com pa r t m en t s pr ovides a h om eost a t ic m ech -
ca lled c a t io n s a n d inclu de sodiu m (Na + ), ca lciu m a n ism t o m a in t a in elect r olyt e a n d a cid–ba se ba la n ce.

Stop and
Consider
F R O M T H E L AB Calcium is one of
The amount of electrolytes in body fluids is described by the concentration of solute in the electrolytes
a particular volume of fluid. Measurements are often described as milligrams per deciliter important in mus-
(mg/ dL), the solute weight in one-tenth of a liter (dL), also equivalent to 100 microliters (µL) cle contraction.
of solution. Electrolytes can also be expressed in measurements of milliequivalents per liter Large amounts of
(mEq/ L), which considers the charge equivalency for a specific weight of electrolyte. Based calcium must be
on electroneutrality, cations and anions must be balanced in the body. The combination available inside
of anions and cations results from the attraction based on ionic charge rather than mo- the cell to promote
lecular weight. Therefore, 1 mEq of sodium has the same number of charges as 1 mEq of the development of
chloride. Clinical measurements of electrolytes are determined by their concentration in tension in muscle
the plasma. cells. What must
happen to intracel-
lular calcium levels
(Ca 2+ ), h ydr ogen (H + ), a n d pot a ssiu m (K + ). Nega - for this to occur?
t ively ch a r ged ion s a r e ca lled a n io n s a n d in clu de
ch lor ide (Cl−), bica r bon a t e (H CO 3 −), su lfa t e (SO 4 2−), Altered Electrolyte Balance
a n d ph osph a t e (P O 4 3−). Ion s wit h opposit e ch a r ges
a r e a t t r a ct ed t o ea ch ot h er a n d for m m olecu les. An Regu la t ion of elect r olyt e ba la n ce is cr it ica l t o m et a -
exa m ple of t h is is t h e bon din g of t h e ca t ion Na + t o bolic fu n ct ion of cells. Alt er a t ion s in elect r olyt es ca n
t he a nion Cl− t o for m t he m olecu le Na Cl, or sodiu m disr u pt m a n y pr ocesses, in clu din g gen er a t ion of a c-
ch lor ide. t ion pot en t ia ls a n d m a in t en a n ce of flu id a n d a cid–
Th e pla sm a wit h in t h e va scu la r spa ce a n d t h e ba se ba la n ce.
in t er st it ia l flu id of t h e ext r a cellu la r com pa r t m en t
a r e h igh in sodiu m , ch lor ide, a n d ca lciu m ; low in
pot a ssiu m , m a gn esiu m , a n d ph osph a t e; a n d con t a in Extrac e llular
m oder a t e levels of bica r bon a t e. Th e in t r a cellu la r
flu id con t a in s ext r em ely low levels of ca lciu m ; sm a ll
Na +
a m ou n t s of sodiu m , bica r bon a t e, a n d ch lor ide; a n d
m oder a t e a m ou n t s of ph osph a t e a n d m a gn esiu m . 135–145 mEq/L 10 –14 mEq/L
K+
Pot a ssiu m is fou n d in gr ea t est con cen t r a t ion s in t h e 140–150 mEq/L 3.5–5 mEq/L
in t r a cellu la r flu id. F igu r e 8.1 illu st r a t es t h e con cen -
t r a t ion s of elect r olyt es in side a n d ou t side of a cell. Cl Intrace llular

98–106 mEq/L 3– 4 mEq/L

Electrolyte Transport HCO 3

Th e cell m em br a n e for m s a ba r r ier bet ween t h e in t r a -
cellu la r a n d ext r a cellu la r com pa r t m en t s. Movem en t
of elect r olyt es a cr oss t h e cell ba r r ier occu r s by t r a n s-
por t m ech a n ism s, som e t h a t r equ ir e en er gy (a ct ive
t r a n spor t ) a n d ot h er s t h a t follow gr a dien t s det er-
m in ed by ch a r ge/elect r ica l or con cen t r a t ion (pa ssive
t r a n spor t ), a s det a iled in Ch a pt er 2. Th e t r a n spor t
of on e posit ively ch a r ged ion for a n ot h er in opposit e
dir ect ion s a cr oss t h e cell m em br a n e is ca lled c a t io n
e x c h a n g e . Sim ila r ly, wh en r ecipr oca l t r a n spor t of
Ca 2+ 7–10 mEq/L 24–31 mEq/L
8.5 –10.5 mg/dL < 1 mEq/L
Figure 8.1. Intracellular and extracellular distribution of
ions. Distribution of electrical charge across the membrane.
Electroneutrality of cations and anions promote balanced
charges across the membrane. (From Bear MF, Connors BW,
Paradiso MA. Neuroscience: Exploring the Brain. 3rd ed. Bal-
timore, MD: Lippincott Williams & Wilkins; 2006.)

ALTERED SODIUM BALANCE
Sodiu m is t h e m ost a bu n da n t ca t ion in t h e ext r a -
cellu la r com pa r t m en t a n d ser ves a s t h e pr im a r y
det er m in a n t of blood osm ola lit y. Tr a n spor t of so-
diu m ou t of t h e cell occu r s a ga in st it s con cen t r a -
t ion gr a dien t , r equ ir in g a ct ive t r a n spor t t h r ou gh
t h e en er gy-depen den t N a + /K + -2ATPa se m em -
br a n e pu m p (F ig. 8.2). Alt er a t ion s in sodiu m ba l-
a n ce ca n a lt er a cid–ba se ba la n ce, flu id ba la n ce,
a n d n eu r a l con du ct ion . Diet a r y sou r ces pr ovide
sodiu m , wh ich is excr et ed m a in ly by t h e k idn eys,
a lon g wit h wa t er.
Hyponatremia
H y p o n a t r e m ia is ch a r a ct er ized by decr ea sed levels
of sodiu m in t h e blood. Sodiu m loss m ost oft en occu r s
t h r ou gh vom it in g, dia r r h ea , a n d swea t in g. Blood so-
diu m levels of less t h a n 135 m E q/L a r e dia gn ost ic of
h ypon a t r em ia . Osm ot ic swellin g of cells con t r ibu t es
t o m u scle t wit ch in g a n d wea kn ess. Redu ced ext r a -
cellu la r cir cu la t in g volu m e m a y lea d t o h ypot en sion ,
t a ch yca r dia , a n d r edu ced or a bsen t u r in e ou t pu t (o l-
ig u r ia a n d a n u r ia , r espect ively). Alt er ed n eu r on a l
fu n ct ion m a y lea d t o n a u sea a n d vom it in g, let h a r gy,
con fu sion , seizu r es, or com a .
Stop and Consider
Why is sodium balance especially critical to fluid
balance?
Hypernatremia
E xcessive diet a r y in t a ke of sodiu m a n d loss of body
wa t er a r e t h e pr im a r y ca u ses of h yper n a t r em ia .
H y p e r n a t r e m ia is ch a r a ct er ized by blood sodiu m
Extra ce llula r S odium–pota s s ium pumps
fluid
Na +
K+
Na +
K+
Na +
Cytos ol
Figure 8.2. The sodium-potassium pump. This membrane-associated ion pump uses energy in the form of ATP to transport
sodium and potassium across the membrane against their concentration gradient. (From Bear MF, Connors BW, Paradiso
MA. Neuroscience: Exploring the Brain. 3rd ed. Baltimore, MD: Lippincott Williams & Wilkins; 2006.)
E le c t r o ly t e I m b a la n c e 199
levels of gr ea t er t h a n 145 m E q/L. Cell m et a bolism
is a lt er ed, a s eviden ced by a git a t ion , r est lessn ess,
a n d decr ea sed levels of con sciou sn ess. F lu id sh ift s
ca u sed by h yper n a t r em ia m a y r esu lt in t h ir st , h y-
per t en sion , t a ch yca r dia , edem a , a n d weigh t ga in .
ALTERED POTASSIUM BALANCE
Pot a ssiu m is t h e m ost a bu n da n t in t r a cellu la r ca t -
ion . Beca u se m ost pot a ssiu m is fou n d in m u scle, t o-
t a l body pot a ssiu m is det er m in ed in la r ge pa r t by
body size a n d m u scle m a ss.
Hypokalemia
Loss of pot a ssiu m m a y r esu lt fr om excessive loss
du e t o diu r et ic u se, sever e vom it in g, or dia r r h ea . Po-
t a ssiu m levels of less t h a n 3.5 m E q/L in t h e blood
in dica t e h y p o k a le m ia . Th ese levels of pot a ssiu m
a lt er m em br a n e pot en t ia l, wh ich m a y r esu lt in diz-
zin ess, h ypot en sion , ca r dia c a r r h yt h m ia s, m u scle
wea kn ess, a n d leg cr a m ps. Decr ea sed sm oot h m u s-
cle m ot ilit y con t r ibu t es t o n a u sea , a n or exia (loss of
a ppet it e), a n d a bdom in a l dist en t ion .
Hyperkalemia
Pot a ssiu m levels of m or e t h a n 5 m E q/L in t h e blood
a r e dia gn ost ic of h y p e r k a le m ia . Ca u ses of h yper ka -
lem ia a r e oft en ia t r ogen ic, t h a t is, ca u sed by in a ppr o-
pr ia t e u se of dr u gs or t h eir m a n a gem en t , lea din g t o
in cr ea sed pot a ssiu m levels. Movem en t of pot a ssiu m
fr om t h e in t r a cellu la r t o t h e ext r a cellu la r spa ce m a y
a lso lea d t o h yper ka lem ia . In a dequ a t e excr et ion
of pot a ssiu m , a s in r en a l fa ilu r e (see Ch a pt er 18),
ca n a lso lea d t o h yper ka lem ia . Th ese levels ca n a l-
t er m em br a n e pot en t ia l a n d a r e a ssocia t ed wit h t h e
Na +
K+
Na +
+
Na + K
Me mbra ne
200 C h a p t e r 8: Alt er ed F lu id a n d E lect r olyt e Ba la n ce
developm en t of ca r dia c a r r est , a bdom in a l cr a m pin g,
a n d fla ccid pa r a lysis beca u se of t h eir effect s on so-
diu m ch a n n els.
ALTERED CHLORIDE BALANCE
Ch lor ide is a m a jor ext r a cellu la r a n ion . Ch lor ide
m ovem en t is oft en a ssocia t ed wit h sodiu m a n d pla ys
a r ole in r egu la t ion of a cid–ba se ba la n ce.
Hypochloremia
H y p o c h lo r e m ia is det er m in ed wh en blood ch lor ide
levels a r e less t h a n 98 m E q/L. Com m on r ea son s for
ch lor ide loss in clu de vom it in g, dia r r h ea , a n d t h e u se
of diu r et ics. H ypoch lor em ia is oft en a ssocia t ed wit h
h ypon a t r em ia , h ypoka lem ia , a n d m et a bolic a lka lo-
sis. Mu scle effect s in clu de excessive t on e a n d t et a n y
(su st a in ed con t r a ct ion ), wea kn ess, a n d t wit ch in g.
Sh a llow, depr essed br ea t h in g, pa r a lysis, or m en t a l
con fu sion m a y r esu lt .
Hyperchloremia
H y p e r c h lo r e m ia ca n r esu lt fr om sever e deh ydr a -
t ion , kidn ey fa ilu r e, h em odia lysis, a n d t r a u m a t ic
br a in in ju r y. Dia gn osed by blood ch lor ide levels of
m or e t h a n 108 m E q/L, h yper ch lor em ia m a y r esu lt
in h yper ch lor em ic m et a bolic a cidosis. Deep r a pid
br ea t h in g, wea kn ess, h ea da ch e, dim in ish ed cog-
n it ive a bilit y, a n d ca r dia c a r r est m a y r esu lt fr om
h yper ch lor em ia .
ALTERED CALCIUM BALANCE
Most ca lciu m is con t a in ed wit h in bon es a n d t eet h ;
on ly a sm a ll fr a ct ion is loca t ed in t h e ext r a cellu la r
flu id. Alt h ou gh t h e con cen t r a t ion of ca lciu m in t h e
ext r a cellu la r flu id is r ela t ively sm a ll, ca lciu m pla ys
a n essen t ia l r ole in m a n y m et a bolic pr ocesses, in -
clu din g a ct ivit y of en zym e syst em s, gen er a t ion of
a ct ion pot en t ia ls, a n d m u scle con t r a ct ion .
Hypocalcemia
Ca lciu m blood levels of less t h a n 8.5 m g/dL, in dica -
t ive of h y p o c a lc e m ia , lea d t o en h a n ced n eu r om u s-
cu la r ir r it a bilit y. Medica t ion s, su ch a s h epa r in a n d
glu ca gon , ca n ca u se decr ea sed blood ca lciu m levels.
In a ddit ion , t h yr oid disor der s, sever e bu r n s (see
Ch a pt er 16), kidn ey fa ilu r e, vit a m in D deficien cy
(see Ch a pt er 17), a n d sepsis m a y lea d t o h ypoca l-
cem ia . Clin ica l m a n ifest a t ion s in clu de a n xiet y, ir r i-
t a bilit y, m u scle t wit ch in g, cr a m ps, spa sm s, t et a n y,
la r yn gospa sm , a n d seizu r e. H ypot en sion a n d ca r dia c
a r r h yt h m ia m a y occu r beca u se of decr ea sed ca lciu m
en t r y in t o t h e cell.
Hypercalcemia
Blood ca lcium levels grea ter tha n 10.5 mg/dL in dica te
h yp e r c a lc e m ia . Incr ea sed blood ca lcium levels may
r esult from excessive bone br ea kdown, t hyroid disea se,
a nd excessive int a ke of ca lcium supplements, includ-
in g ca lcium-cont aining ant acids. Decreased neur o-
m uscula r irr it ability ca used by increa sed t hreshold
a ccounts for the ma in ma nifesta tions of hyper ca lce-
m ia . These ma nifest a tions include confusion, fa tigue,
const ipat ion, na usea a nd vom it ing, muscle wea kness,
car dia c a rr hythmia , hea da ches, a nd irr it ability.
ALTERED MAGNESIUM BALANCE
Ma gn esiu m h a s fu n ct ion s sim ila r t o t h e ca t ion s ca l-
ciu m a n d pot a ssiu m . Mu ch of t h e body’s m a gn esiu m
is con t a in ed in bon e, sim ila r t o ca lciu m . Soft t issu es
a n d m u scle cells a lso con t a in sign ifica n t con cen t r a -
t ion s of m a gn esiu m .
Hypomagnesemia
H y p o m a g n e s e m ia , ch a r a ct er ized by blood levels
less t h a n 1.5 m E q/L, u su a lly occu r s in a ssocia t ion
wit h h ypoka lem ia a n d h ypoca lcem ia . In a dequ a t e
in t a ke of m a gn esiu m beca u se of m a ln u t r it ion , m a l-
a bsor pt ion syn dr om es, sever e bu r n s, or a lcoh olism
is t h e m ost com m on ca u se of h ypom a gn esem ia . Di-
u r et ic u se is a lso a ssocia t ed wit h a r isk of h ypom a g-
n esem ia . Tet a n y, m u scle cr a m pin g, a n d seizu r es a r e
possible m a n ifest a t ion s r esu lt in g fr om a lt er ed n eu -
r om u scu la r t r a n sm ission . Ca r dia c a r r h yt h m ia a n d
h ypot en sion occu r fr om t h e a lt er a t ion of elect r ica l
cu r r en t s beca u se of t h e con cu r r en t effect s of sodiu m ,
pot a ssiu m , a n d ca lciu m im ba la n ces.
Hypermagnesemia
Ma gn esiu m levels gr ea t er t h a n 2.5 m E q/L m ea su r ed
in t h e blood defin e h y p e r m a g n e s e m ia . Th is im ba l-
a n ce occu r s wit h less fr equ en cy t h a n ot h er elect r o-
lyt e im ba la n ces, a n d it oft en r esu lt s fr om excessive
in t a ke of m a gn esiu m -con t a in in g pr odu ct s or su pple-
m en t s or fr om en d-st a ge r en a l disea se. Neu r om u s-
cu la r t r a n sm ission a n d cell excit a bilit y a r e r edu ced,
r esu lt in g in h ypot en sion , dim in ish ed r eflexes, m u s-
cle wea kn ess, fla ccid pa r a lysis, a n d r espir a t or y de-
pr ession . Ca r dia c a r r h yt h m ia a n d br a dyca r dia m a y
r esu lt secon da r y t o decr ea sed m ovem en t of sodiu m
in t o t h e cell.
ALTERED PHOSPHATE BALANCE
A com pon en t of ATP, ph osph a t e, is essen t ia l t o cel-
lu la r m et a bolism . Cellu la r fu n ct ion s of glycolysis
a n d m a n y en zym e r ea ct ion s depen d on ph osph a t e.
Th e m a jor in t r a cellu la r a n ion ph osph a t e is st or ed in
bon es a n d t eet h , in con ju n ct ion wit h ca lciu m .
 E le c t r o ly t e I m b a la n c e 201

Hypophosphatemia
Blood ph osph a t e levels less t h a n 2.5 m g/dL a r e
a ssocia t ed wit h h y p o p h o s p h a t e m ia . Oft en a s-
socia t ed wit h h ypom a gn esem ia a n d h ypoka lem ia ,
h ypoph osph a t em ia m a y r esu lt fr om sever e bu r n s,
m a ln u t r it ion , m a la bsor pt ion , a lcoh olism , kidn ey dis-
ea se, vit a m in D deficien cy, or pr olon ged diu r et ic u se.
Ma n ifest a t ion s of h ypoph osph a t em ia in clu de m u s-
cle wea kn ess, t r em or, p a r e s t h e s ia (a bn or m a l sen -
sa t ion su ch a s t in glin g or bu r n in g), weigh t loss, a n d
bon e defor m it ies.
Hyperphosphatemia
H y p e r p h o s p h a t e m ia occu r s wh en blood ph osph a t e
levels r ise a bove 4.5 m g/dL, a n d it oft en occu r s in
t a n dem wit h h ypoca lcem ia . Con dit ion s r esu lt in g in
h yper ph osph a t em ia in clu de fr a ct u r es, bon e disea se,
h ypopa r a t h yr oidism , a cr om ega ly (see Ch a pt er 2),
syst em ic in fect ion (see Ch a pt er 5), a n d in t est in a l ob-
st r u ct ion (see Ch a pt er 18). Th er e a r e n o a ssocia t ed
sym pt om s of h yper ph osph a t em ia , u n less it is a ccom -
pa n ied by ot h er elect r olyt e im ba la n ces.
Ma n ifest a t ion s of elect r olyt e im ba la n ces a r e su m -
m a r ized in Ta ble 8.1.

Ta b le 8.1 Ma n ifest a t ion s of E lect r olyt e Im ba la n ces

E le c t r o ly t e B lo o d L e v e l I m b a la n c e Ma n ife s t a t io n s
Sodiu m < 135 m E q/L H ypon a t r em ia Mu scle cr a m ps, t wit ch in g, wea kn ess
Volu m e deficit , h ypot en sion , oligu r ia
H ea da ch e, a n xiet y, a lt er ed con sciou sn ess
> 145 m E q/L H yper n a t r em ia Th ir st , dr y skin a n d m u cou s m em br a n es
Decr ea sed excr et ion s
H ea da ch e, r est lessn ess, a lt er ed con sciou sn ess
Pot a ssiu m < 3.5 m E q/L H ypoka lem ia Dizzin ess, m u scle wea kn ess, leg cr a m ps
Ca r dia c a r r h yt h m ia , h ypot en sion
Th ir st , n a u sea , a n or exia
Poor ly con cen t r a t ed u r in e, polyu r ia
> 5 m E q/L H yper ka lem ia Ca r dia c a r r est
Abdom in a l cr a m pin g, fla ccid pa r a lysis
Ch lor ide < 98 m E q/L H ypoch lor em ia In cr ea sed m u scle t on e, t wit ch in g, wea kn ess, t et a n y
Sh a llow, depr essed br ea t h in g, r espir a t or y a r r est
Men t a l con fu sion
> 108 m E q/L H yper ch lor em ia H yper ch lor em ic m et a bolic a cidosis
Deep, r a pid br ea t h in g
Wea kn ess, h ea da ch e, dim in ish ed cogn it ive a bilit y
Ca r dia c a r r est
Ca lciu m < 8.5 m g/dL H ypoca lcem ia E n h a n ced n eu r om u scu la r ir r it a bilit y
An xiet y, ir r it a bilit y, seizu r e
Mu scle t wit ch in g, cr a m ps, spa sm , t et a n y, la r yn gospa sm
H ypot en sion , ca r dia c a r r h yt h m ia
> 10.5 m g/dL H yper ca lcem ia Decr ea sed n eu r om u scu la r ir r it a bilit y
Con fu sion , fa t igu e, h ea da ch e, ir r it a bilit y
Con st ipa t ion , n a u sea , vom it in g
Ca r dia c a r r h yt h m ia
Ma gn esiu m < 1.5 m E q/L H ypom a gn esem ia Tet a n y, m u scle cr a m pin g
Seizu r es
Ca r dia c a r r h yt h m ia , h ypot en sion
> 2.5 m E q/L H yper m a gn esem ia Redu ced n eu r om u scu la r t r a n sm ission a n d cell excit a bilit y
F la ccid pa r a lysis, dim in ish ed r eflexes, m u scle wea kn ess
H ypot en sion , r espir a t or y depr ession
P h osph a t e < 2.5 m g/dL H ypoph osph a t em ia Mu scle wea kn ess, t r em or, pa r est h esia
Weigh t loss, bon e defor m it y
> 4.5 m g/dL H yper ph osph a t em ia No a ssocia t ed m a n ifest a t ion s
202 C h a p t e r 8: Alt er ed F lu id a n d E lect r olyt e Ba la n ce

Modu le 2 F lu id I m b a la n c e

Th e body is m ost ly flu id, a ccou n t in g for a sign ifica n t join t spa ces. Th is r ela t ively sm a ll com pa r t m en t of
per cen t a ge of body weigh t . Tot a l body wa t er ca n flu id is oft en r efer r ed t o a s a “t h ir d spa ce” beca u se it
va r y by gen der, a ge, a n d a m ou n t of body fa t . Sixt y is u n a va ila ble for exch a n ge bet ween t h e ot h er ext r a -
per cen t of t h e body is com pr ised of flu ids dist r ib- cellu la r com pa r t m en t s.
u t ed bet ween t wo com pa r t m en t s: 40% is loca t ed in
t h e in t r a cellu la r com pa r t m en t a n d 20% is loca t ed in
t h e ext r a cellu la r com pa r t m en t (Fig. 8.3). Th e in t r a - Fluid Balance
c e llu la r c o m p a r t m e n t con sist s of t h e flu id in side
t h e cells, con t a in in g a ppr oxim a t ely t wo-t h ir ds of t h e Body flu id volu m e is r egu la t ed dir ect ly in t h e ext r a -
body wa t er a n d a ccou n t in g for 40% of body weigh t . cellu la r com pa r t m en t a n d in dir ect ly in t h e in t r a -
Th e sm a ller e x t r a c e llu la r c o m p a r t m e n t con - cellu la r com pa r t m en t by t h e kidn eys. Th is pr ocess
t a in s t h e r em a in in g on e-t h ir d, or 20%, of body flu id in volves wa t er a n d ion m ovem en t a cr oss t h e cell
in t h e in t er st it ia l t issu e a n d pla sm a ou t side t h e m em br a n es of t h e r en a l t u bu les a n d close a ssocia -
cells. F lu id in t h e pla sm a com pa r t m en t a ccou n t s for t ion wit h t h e va scu la t u r e of t h e kidn eys (F ig. 8.4).
5% of body weigh t , a n d t h e in t er st it ia l flu id a ccou n t s
for 14% of body weigh t . A t h ir d, m in or ext r a cellu la r
com pa r t m en t is t h e t r a n scellu la r com pa r t m en t , sep- FLUID TRANSPORT
a r a t ed by a la yer of en dot h eliu m . Th e flu id in t h is
Wa t er is a ble t o m ove bet ween com pa r t m ent s
com pa r t m en t is con t a in ed in body spa ces su ch a s
t h r ough specia l ch a n n els in t h e cell m em br a n e, ca lled
t h e spin a l cor d, per it on ea l, pleu r a l, per ica r dia l, a n d
a q u a p or in s . Movem en t of wa t er is st im u la t ed by a
concen t r a t ion gr a dient , m ovin g t o a n a r ea of high er
concen t r a t ion of pa r t icles (less wa t er con t en t ) fr om a n
a r ea of lower con cent r a t ion of pa r t icles (m or e wa t er
cont en t ). This pr ocess, o s m o s is , is r egu la t ed by t h e
concen t r a t ion of pa r t icles t ha t do n ot diffu se a cr oss
:
t
s
t h e sem iper m ea ble m em br a n e. Som e ch a r a ct er ist ics
h
t
n
g
e
i
t h a t m a ke pa r t icles nondiffu sible in clude la r ge size
e
n
w
o
or lipid solubilit y. O s m o t ic p r e s s u r e is gener a t ed
p
y
m
d
a s wa t er m oves t h r ough t h e m em br a ne. An osm ole
o
o
b
c
is t h e u nit of m ea sur e r eflect in g t h e osm ot ic a ct iv-
f
d
o
e
it y t h a t n on diffu sible pa r t icles exer t in pu llin g wa t er
%
m
r
0
fr om on e side of t h e sem iper m ea ble m em br a n e t o t h e
o
4
F
ot her. Osm ola r it y is t he osm ola r concent r a t ion in 1 L
t
t
:
h
h
r
e
g
of solut ion (m Osm /L) a nd is u sed when r efer r ing t o
g
t
i
i
a
e
e
w
w
fluids out side t h e body. Osm ola lit y is t h e osm ola r con-
w
r
y
a
Inte rs titia l volume : 14%
d
y
l
cent r a t ion in 1 kg of wa t er (m Osm /kg of H 2 O), a nd is
o
u
d
l
b
l
o
e
u sed t o descr ibe flu ids wit h in t he body. Ta ble 8.2 su m -
f
b
c
o
t
a
h
l
%
:
r
P la s ma volume : 5% m a r izes a ct ive a n d pa ssive t r a n spor t m echa nism s.
r
a
xt
g
0
t
e
i
E
o
2
t
e
F lu id a lso m oves bet ween ext r a cellu la r com pa r t -
T
a
w
w
Tra ns ce llula r volume : 1%
m en t s, wit h for ces pr om ot in g flu id m ovem en t ba l-
y
t
y
:
h
d
r
d
g
e
a n ce. H y d r o s t a t ic fo r c e s (pr essu r e of flu id) ca n
o
i
t
o
e
b
a
w
b
w
pr om ot e m ovem en t of flu id ba sed on t h e pr essu r e
f
l
y
o
r
a
d
a
%
t
l
gr a dien t , a lso kn own a s filt r a t io n p r e s s u r e . Th e
o
u
o
b
l
T
l
0
e
f
pr essu r e of t h e blood on t h e ca pilla r y wa lls (sem i-
6
o
c
a
%
r
per m ea ble m em br a n es) ca n for ce flu id m ovem en t
t
n
0
I
4
fr om wit h in t h e vessel t o t h e in t er st it ia l spa ce; t h is
m ovem en t is ca lled filt r a t ion . Ca pilla r y filt r a t ion
pr essu r e is cou n t er ed by in t er st it ia l flu id pr essu r e,
wh ich opposes flu id m ovem en t ou t of t h e ca pil-
Figure 8.3. Body fluid compartments. Extracellular water la r y. Con ver sely, ca pilla r y osm ot ic pr essu r e ca u sed
makes up 20% of body weight, and intracellular water by pr ot ein s or ot h er m olecu les ca n pu ll flu id fr om
makes up 40% of body weight. t h e in t er st it ia l spa ce in t o t h e in t r a va scu la r spa ce;
 F lu id I m b a la n c e 203

Filtratio n Re abs o rptio n S e c re tio n

Effe re nt Ce lls a nd prote in
a rte riole re ma in in blood
Drugs H+ K+

Glome rula r P roxima l Dis ta l

ca pilla rie s convolute d convolute d
tubule tubule
Wa te r
Affe re nt Glucos e (ADH e ffe ct)
a rte riole
Amino
a cids Re abs o rptio n Na +(Aldos te rone e ffe ct)

p
Bica rbona te

o
Na +

o
p
l
o
g
o
n
l
Wa te r

i
g
d
Na +

n
n
i
e
d
Cl Ve nule
c
n
s
e
a
c
k
s
c
e
i
D
h
T
P e ritubula r
ca pilla rie s Wa te r Colle cting
(by os mos is ) duct
Loop of He nle

Figure 8.4. Renal regulation of fluid and electrolytes. Filtration, reabsorption, and secretion processes are illustrated
between the renal structures and associated vasculature. Note the movement of ions and water along the tubules. ADH,
antidiuretic hormone. (Modified from Premkumar K. The Massage Connection: Anatomy and Physiology. Baltimore, MD: Lip-
pincott Williams & Wilkins; 2004.)

t h is m ovem en t is ca lled r ea bsor pt ion . Th is for ce is h ypot h a la m ic t h ir st cen t er t h a t pr om ot e t h ir st a r e

cou n t er ed by t issu e osm ot ic pr essu r e, wh ich opposes
su ch m ovem en t (Fig. 8.5). In vessels wit h in t a ct en -
dot h elia l cells, flu id m oves ou t of t h e ca pilla r y a t t h e
a r t er iola r en d of t h e ca pilla r y bed wh er e t h e h ydr o-
st a t ic pr essu r e is gr ea t er, a n d it m oves ba ck in a t
t h e ven ou s en d wh er e on cot ic pr essu r e is gr ea t er.
Th e sm a ll a m ou n t of flu id t h a t r em a in s in t h e in -
t er st it iu m is r em oved by t h e lym ph a t ic syst em a n d
r et u r n ed t o t h e cir cu la t ion .
FLUID REGULATION
Mech a n ism s r egu la t in g t ot a l body wa t er in clu de
t h ose t h a t pr om ot e t h ir st a n d wa t er excr et ion . Neu -
r a l a n d h or m on a l m ech a n ism s wor k in con cer t t o a t -
t a in or m a in t a in flu id ba la n ce.
Mechanisms to Promote Fluid Intake
Th ir st is a n im por t a n t m ech a n ism con t r ibu t -
in g t o in cr ea sed flu id in t a ke. Th ir st is ch a r-
a ct er ized by a desir e t o dr in k flu ids h igh in
wa t er con t en t , wh ich is pr om pt ed by u n com for t -
a ble sen sa t ion s in t h e m ou t h a n d ph a r yn x.1 Th e
sen sor y n eu r on s kn own a s o s m o r e c e p t o r s in t h e
a ct iva t ed by:
● Cellu la r deh ydr a t ion r esu lt in g fr om in cr ea sed ex-
t r a cellu la r osm ola lit y
● Decr ea se in blood volu m e
Stop and Consider
Are there any risks to drinking too much water?
St r et ch r ecept or s in t h e ca r ot id a n d a or t a (h igh -
pr essu r e ba r or ecept or s) a n d t h e left a t r iu m (low-
pr essu r e ba r or ecept or s) sen se ch a n ge in a r t er ia l blood
pr essu r e a n d con t r ibu t e t o t h e developm en t of t h ir st .
Th e h or m on e, a n giot en sin II, a lso in dir ect ly con t r ib-
u t es t o t h ir st in r espon se t o low blood volu m e a n d low
blood pr essu r e. Th e r en a l h or m on e, r en in , is r elea sed
fr om t h e kidn eys a n d ser ves a s a n en zym e, con ver t -
in g a n giot en sin ogen t o a n giot en sin I. An giot en sin I is
con ver t ed t o a n giot en sin II by a n giot en sin -con ver t in g
en zym e, pr im a r ily in t h e lu n gs. An giot en sin II
a lso r egu la t es a ldost er on e, a h or m on e pr odu ced in
t h e a dr en a l cor t ex. Th e in cr ea se in sodiu m r et en t ion
t h a t r esu lt s fr om t h e effect s of a ldost er on e m a y h a ve
t h e in dir ect effect of in cr ea sin g t h ir st .
204 C h a p t e r 8: Alt er ed F lu id a n d E lect r olyt e Ba la n ce

Ta b le 8.2 Mech a n ism s of Mem br a n e Tr a n spor t

Typ e of S t im u lu s fo r Ou t com e of
Tr a n s p o r t Me c h a n is m Tr a n s p o r t Tr a n s p o r t Tr a n s p o r t

Diffu sion Pa ssive Ch em ica l or Pa r t icles a r e even ly

elect r ica l gr a dien t dist r ibu t ed a cr oss t h e
m em br a n e

Osm osis Pa ssive Con cen t r a t ion F low of wa t er is di-

gr a dien t r ect ed by osm ot ica lly
a ct ive pa r t icles

Wa te r

Fa cilit a t ed diffu sion Pa ssive Bin din g of A ca r r ier syst em m oves

su bst a n ce t o pa r t icles a cr oss t h e
t r a n spor t er m em br a n e

Act ive Act ive P r ot ein s u sin g E n er gy (ATP ) m oves

t r a n spor t en er gy pu m p t o pa r t icles a ga in st
ion s a cr oss t h e a gr a dien t a cr oss t h e
m em br a n e m em br a n e

ATP

ADP
 F lu id I m b a la n c e 205

r edu ce r ea bsor pt ion of sodiu m in t h e t h ick a scen d-

Filtratio n Re abs o rptio n in g loop of H en le, ca u sin g a decr ea sed osm ola lit y
in t h e in t er st it ia l flu id of t h e collect in g du ct s a n d
P if Inte rs titium
P if im pa ir t h e a bilit y t o con cen t r a t e u r in e a t t h e loop.
T h i a z i d e d i u r e t i c s pr even t N a Cl r ea bsor pt ion
in t h e dist a l con volu t ed t u bu le. Th is a ct ion is cou -
pled wit h in cr ea sed pot a ssiu m loss in t h e u r in e
Pc Pc a n d u r ic a cid r et en t ion . Pot a ssiu m -spa r in g diu r et -
ics, a lso k n own a s a ldost er on e a n t a gon ist s, r edu ce
sodiu m r ea bsor pt ion in t h e la t e dist a l t u bu le a n d
Arte ry Ca pilla ry Ve in collect in g t u bu le, fu n ct ion s r egu la t ed by a ldost e-
r on e. Th e effect s of a ldost er on e a t t h is sit e a r e in -
h ibit ed, pr om ot in g excr et ion of sodiu m a n d wa t er.
Th e sim u lt a n eou s effect of in cr ea sed pot a ssiu m
r ea bsor pt ion pr even t s t h e pot en t ia l for excessive
Lympha tics loss a ssocia t ed wit h ot h er t ypes of diu r et ics. Th e
secr et ion of h ydr ogen ion s m a y be a lt er ed, in cr ea s-
in g t h e r isk for m et a bolic a cidosis, discu ssed la t er
in t h is ch a pt er.
Figure 8.5. Forces for fluid movement across the capillary.
Pc is the capillary lumen hydrostatic pressure, and Pif is the
interstitial hydrostatic pressure. When Pc is greater than
Pif, filtration processes are dominant. When Pif is greater Tonicity
than Pc, reabsorption processes are “favored” or dominant.
The osm ot ic pr essu r e or t en sion of a solu t ion is
known a s t onicit y.1 Tonicit y is det er m in ed by sol-
u t es t ha t ca nn ot cr oss t h e sem iper m ea ble cell m em -
An t idiu r et ic h or m on e (ADH ) r egu la t es flu id vol-
br a ne, pr oducin g a n osm ot ic for ce t ha t t r a n spor t s
u m e by con t r ollin g excr et ion of t ot a l body wa t er.
wa t er. Cell size ca n be a ffect ed by t onicit y, pr om ot -
P r odu ced in t h e h ypot h a la m u s, ADH is t r a n spor t ed
in g flu id m ovem ent in or out of cells. H yp e r t o n ic
t o t h e post er ior pit u it a r y wh er e it is st or ed u n t il
solu t ion s h ave a gr ea t er osm ola lit y t ha n t h e int r a -
n eeded. P r odu ct ion a n d r elea se of ADH is st im u -
cellula r flu id (ICF). Wh en cells a r e in a h yper t onic
la t ed by h ypot h a la m ic osm or ecept or det ect ion of
solu t ion in wh ich t he ext r a cellu la r osm ot ic for ce is
in cr ea sed blood osm ola lit y. Also kn own a s va sopr es-
gr ea t er, wa t er m oves out of t he cell ca u sing cells t o
sin , ADH wor ks a t t h e level of t h e kidn ey t o pr om ot e
shr ink. H y p o t o n ic solut ions have a lower osm ola l-
t h e r ea bsor pt ion of wa t er via a qu a por in s fr om t h e
it y t h a n t he ICF. The osm ot ic for ces out side t he cells
r en a l-collect in g du ct s in t o t h e va scu la t u r e, r edu c-
a r e less t ha n t h a t of t he in t r a cellula r en vir onm ent ,
in g flu id loss t h r ou gh decr ea se in u r in e ou t pu t . Th e
pr om ot ing wa t er m ovem en t int o t he cell a nd ca u s-
m ech a n ism s t h a t pr om ot e flu id in t a ke a r e illu s-
in g cells t o swell. An exa m ple of cellu la r cha nges
t r a t ed in F igu r e 8.6.
in r esponse t o sodium concent r a t ion is shown in
Figur e 8.7, wit h h yper n a t r em ia ser vin g a s a n exa m -
Mechanisms to Promote Fluid Excretion
ple of a h yper t on ic solu t ion , a n d h ypon a t r em ia r ep-
Th e m ost com m on m et h od for in cr ea sin g flu id excr e- r esen t in g a h ypot on ic solu t ion . Cells in a n is o t o n ic
t ion is t h e u se of diu r et ics. D iu r e t ic s a r e dr u gs t h a t
solu t ion , wh ich h a s t h e sa m e osm ola lit y a s t h e ICF,
in cr ea se u r in e pr odu ct ion .
Th e kidn eys a r e t h e t a r-
get of t h e effect s of diu r et -
ics, wh ich a r e design ed t o R E S E AR C H N O T E S
decr ea se r ea bsor pt ion of
sodiu m in t h e kidn ey. Th is In addition to chemical diuretics, certain foods can have diuretic effects. The American
m ech a n ism is effect ive Heart Association has long advocated the Dietary Approaches to Stop Hypertension (DASH)
beca u se wa t er m oves t o- diet for blood pressure-lowering effects. The DASH diet is rich in fruits and vegetables.
get h er wit h sodiu m . Although it was recognized that the DASH diet lowered blood pressure, the explanation
Differ en t t ypes of di- for these effects was unknown until a group of researchers determined that the DASH diet
u r et ics wor k on differ en t promoted salt excretion and increased urine production, similar to the mechanism of action
st r u ct u r es of t h e k id- of diuretic drugs. 2
n ey. Th e lo o p d i u r e t i c s
206 C h a p t e r 8: Alt er ed F lu id a n d E lect r olyt e Ba la n ce

Blood volume
s S e rum os mola lity
te
u la ( Thirs t a nd wa te r inta ke )

tim S
S ti

m
Conce ntra te d Arte ria l BP

u
urine excre te d (s timula te s ba rore ce ptors )

la
te
s
ADH production S ympa the tic dis cha rge
in hypotha la mus
(os more ce ptors )

Re na l pe rfus ion
s

H2 O & Na +
t

ADH re le a s e into
i

Diure s is re s ults Re nin re le a s e ( GFR)

b

filte re d by kidney
i

bloods tre a m from s tora ge

h

in pos te rior pituita ry

nI

Angiote ns in I & II

Blood volume Aldos te rone by Re a bs orption of H2 O

S e rum os mola lity a dre na l cortex by kidneys

Na + & H2 O excre tion; Urine excre tion

blood pre s s ure

Circula ting volume of H2 O

& Na + (los s of K+)

Figure 8.6. Fluid regulation cycle. Negative feedback mechanisms promote regulation of body fluid. Decreased blood
volume and increased serum osmolality promote water intake via thirst. Decreased blood pressure (BP) increases sym-
pathetic nervous stimulation, triggering reduced renal perfusion and the renin–angiotensin–aldosterone system. Reab-
sorption of water through the actions of antidiuretic hormone (ADH) combined with reduced sodium and water secretion
through the effects of aldosterone leads to increased circulating volume of water and sodium. Increased blood volume and
low serum osmolality inhibit ADH production, promoting diuresis. GFR, glomerular filtration rate. (From Smeltzer SC, Bare
BG. Textbook of Medical-Surgical Nursing. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.)

a r e un ch a nged wit h osm ot ic for ces ba la nced wit hin sign ifica n t ly a lt er flu id ba la n ce. F lu id ga in or loss
a nd ou t side of t he cell. ca n be m ea su r ed by ser ia l (r epea t ed) m ea su r es of
body weigh t , a s 1 L of wa t er weigh s 1 kg or 2.2 lb.

Altered Fluid Balance WATER CONTENT

Th e im ba la n ce of h ydr ost a t ic a n d osm ot ic for ces
ca n r esu lt in a lt er a t ion s in flu id ba la n ce. Tot a l body
flu id ca n a lso be a lt er ed by in cr ea ses or decr ea ses
in flu id in gest ion a n d excr et ion . E xcr et ion of bodily
flu ids, su ch a s u r in e, em esis, swea t , or blood, a s
well a s in sen sible flu id loss du r in g r espir a t ion , ca n
Alt er a t ion s in wa t er a n d sodiu m ca n a ffect t ot a l body
flu id ba la n ce. Decr ea sed va scu la r volu m e is kn own
a s h y p o v o le m ia , oft en t h e r esu lt of in a dequ a t e
flu id in t a ke or excessive excr et ion . H y p e r v o le m ia
is a n excessive in cr ea se of flu id in t h e ext r a cellu la r
com pa r t m en t .

H2O
A. Hypona tre mia :
Na + le s s tha n 130 mEq/L
B. Hype rna tre mia :
+
Na gre a te r tha n 150 mEq/L
Figure 8.7. Effect of tonicity on cell size. A: The cell
swells as water is pulled in from extracellular fluid. B: The
cell shrinks as water is pulled out into extracellular fluid.
Hypovolemia
H ypovolem ia is a deficit of body flu id volu m e. Ca u ses
of h ypovolem ia ca n be a t t r ibu t ed t o excessive body
flu id loss, r edu ct ion of flu id in t a ke, or loss of flu id
t o a t h ir d spa ce r esu lt in g in decr ea sed ext r a cellu -
la r flu id volu m e. Decr ea sed in t r a va scu la r volu m e
r esu lt s in decr ea sed ca pilla r y h ydr ost a t ic pr essu r e.
Blood cir cu la t ion a n d t r a n spor t of oxygen a n d n u t r i-
en t s t o t issu es m a y be im pa ir ed.
Clin ica l m a n ifest a t ion s of h ypovolem ia , fr om
lea st t o m ost sever e, in clu de:
● Th ir st
● Dr y m u cou s m em br a n es
● Weigh t loss
● F la t t en ed n eck vein s
● Dim in ish ed skin t u r g o r (fu lln ess) (Fig. 8.8)
● P r olon ged t im e for ca pilla r ies t o r efill a ft er
bla n ch in g (m or e t h a n 3 secon ds)
● Decr ea sed u r in e ou t pu t
● In cr ea sed h ea r t r a t e
● Decr ea sed blood pr essu r e
● Alt er ed level of con sciou sn ess
The body a t t em pt s t o com pen sa t e wit h ph ysiologic r e-
spon ses t o cou n t er t h e m a n ifest a t ions of h ypovolem ia .
Decr ea sed blood flow t o t h e kidneys t r igger s t h e a ct i-
va t ion of t h e r en in –a n giot en sin – a ldost er on e syst em
(RAAS), incr ea sin g sodiu m a nd wa t er r ea bsor pt ion .
F lu id I m b a la n c e 207
Figure 8.8. Skin turgor evaluation. After squeezing the
skin together, release should result in the ridges imme-
diately returning to a normal appearance. Dehydration
should be suspected when evidence of ridges remain after
release. (Courtesy Lesha Studios, with permission.)
Decr ea sed blood pr essu r e sen sed by ba r or ecept or s
st im u la t es t he sym pa t h et ic n er vou s syst em t o in -
cr ea se h ea r t r a t e, con st r ict a r t er ies, a n d in cr ea se
con t r a ct ilit y of t h e hea r t . The expect ed r esponse t o
com pensa t e for decr ea sed in t r ava scu la r flu id volu m e
is in cr ea sed ca r dia c ou t pu t a n d m ea n a r t er ia l pr es-
su r e. ADH a n d a ldost er on e wor k t oget h er t o decr ea se
u r in e ou t pu t a nd in cr ea se flu id in t a ke by st im u la t in g
t hir st . Fa ilu r e t o com pen sa t e a dequ a t ely m ay im pa ir
cellu la r fu n ct ion sign ifica n t ly, r esu lt in g in m u lt isys-
t em fa ilu r e.
Th e t ype of flu id loss t h a t lea ds t o h ypovolem ia
m a y a ffect t on icit y of t h e ext r a cellu la r flu id. Th e di-
a gn osis a n d m a n a gem en t of a lt er a t ion s in flu id ba l-
a n ce m a y depen d on t h e cir cu m st a n ces con t r ibu t in g
t o h ypovolem ia . La bor a t or y t est in g of h em oglobin ,
h em a t ocr it , blood u r ea n it r ogen (BUN), ser u m cr e-
a t in in e, u r in e-specific gr a vit y, blood glu cose, elec-
t r olyt es, a n d pla sm a pr ot ein s ca n pr ovide ddit ion a l
in for m a t ion t o gu ide t r ea t m en t st r a t egies.
Hemorrhage
H em or r h a ge, or excessive bleedin g, m a y r esu lt in
h ypovolem ia . Beca u se wa t er a n d sodiu m a r e lost a t
com pa r a ble r a t es, t h is con dit ion is isot on ic. H em o-
globin a n d h em a t ocr it a r e decr ea sed a n d BUN m a y
be in cr ea sed ea r ly in h em or r h a ge. Da m a ge t o ot h er
or ga n syst em s m a y be eviden t if h ypovolem ia is n ot
cor r ect ed. F lu id r epla cem en t for volu m e expa n sion is
208 C h a p t e r 8: Alt er ed F lu id a n d E lect r olyt e Ba la n ce

oft en n ecessa r y a n d is det er m in ed by t h e a m ou n t of Wh en excess sodiu m a n d wa t er a r e r et a in ed in

blood loss. Repla cem en t of volu m e wit h blood pr od- sim ila r pr opor t ion s, t h e in cr ea sed volu m e is isot on ic.
u ct s, eit h er wh ole blood or pa cked (con cen t r a t ed) r ed Ca u ses of h yper volem ia in clu de:
blood cells, pr ovides t h e n ecessa r y ext r a cellu la r flu id
● H ea r t fa ilu r e
expa n sion a s well a s t h e cellu la r com pon en t s lost
● Cir r h osis of t h e liver
wit h bleedin g. Th e cr yst a lloid solu t ion R in g e r la c -
● Kidn ey fa ilu r e
t a t e in t r a ven ou s flu id con t a in s sodiu m , ch lor ide, po-
● E xcessive flu id r epla cem en t
t a ssiu m , ca lciu m , a n d la ct a t e in con cen t r a t ion s t h a t
● Adm in ist r a t ion of osm ot ica lly a ct ive flu ids
m ir r or t h ose fou n d in pla sm a a n d m ay a lso be a n
a ppr opr ia t e t r ea t m en t in la r ge volu m e flu id r esu s- Mea n a r t er ia l blood pr essu r e is in cr ea sed in h yper-
cit a t ion .3 F lu id r epla cem en t wit h osm ot ica lly a ct ive volem ia , in h ibit in g t h e secr et ion of ADH a n d a ldo-
flu ids h elps pr om ot e t h e m ovem en t of flu id fr om t h e st er on e, r esu lt in g in in cr ea sed u r in a r y sodiu m a n d
in t er st it ia l spa ce t o t h e in t r a va scu la r spa ce. wa t er elim in a t ion . In in dividu a ls wh o a r e u n a ble t o
m ou n t t h ese com pen sa t or y m ech a n ism s, h ea r t fa il-
Dehydration u r e a n d pu lm on a r y edem a m a y r esu lt .
Deh ydr a t ion is t h e r esu lt of decr ea sed ext r a cellu -
Edema
la r flu id volu m e or in cr ea sed sodiu m con t en t in r e-
la t ion t o wa t er con t en t , r epr esen t in g a h yper t on ic Edem a r esults from increases in the extr acellula r com -
con dit ion . E xcessive wa t er y dia r r h ea , swea t in g, a n d par tm ent of the interst it ia l fluid. Movem ent of fluid
in sen sible r espir a t or y wa t er loss du r in g h yper ven t i- in to the int er stitia l compa r tment ca n be driven by:
la t ion or fever m ay lea d t o deh ydr a t ion . In t r a va scu -
● In cr ea sed ca pilla r y filt r a t ion pr essu r e: h ydr o-
la r volu m e m a y becom e viscou s, wit h eviden ce of a n
st a t ic pr essu r e for ces wa t er fr om ca pilla r ies in t o
in cr ea se in h em a t ocr it ca u sed by h em ocon cen t r a t ion .
in t er st it ia l flu id
Th ir st m ay be st im u la t ed, a n d u r in a r y ou t pu t de-
● Decrea sed capillary osmotic pressure: fluid moves to
cr ea sed. Movem en t of flu id fr om t h e in t r a cellu la r t o
the interstitium across the concentration gradient
t h e ext r a cellu la r com pa r t m en t pr om ot es cell sh r in k-
● In cr ea sed ca pilla r y per m ea bilit y: a lt er ed in t eg-
a ge. Deh ydr a t ion of br a in a n d n er ve cells m a y r esu lt
r it y of t h e ca pilla r y wa ll a llows pr ot ein s t o lea k
in h ea da ch e, decr ea sed r eflexes, seizu r es, a n d com a .
fr om t h e ca pilla r ies in t o t h e in t er st it ia l spa ce, in -
E xpa n sion of ext r a cellu la r volu m e wit h or a l or in t r a -
cr ea sin g in t er st it ia l osm ot ic pr essu r e
ven ou s r eh ydr a t ion , su ch a s Rin ger la ct a t e, is in di-
● Obst r u ct ed lym ph flow (ly m p h e d e m a ): flu id in
ca t ed t o pr even t or ga n da m a ge. Wh en ch lor ide loss
t h e in t er st it iu m ca n n ot be r et u r n ed t o t h e sys-
com plica t es deh ydr a t ion , in t r aven ou s r epla cem en t
t em ic cir cu la t ion
wit h a n isot on ic solu t ion of n or m a l sa lin e m a y be
in dica t ed t o a ddr ess t h e u n der lyin g ion ic a lt er a t ion . The m ech a n ism s for t h e developm en t of edem a
a r e depict ed in Figu r e 8.9. E dem a t ou s t issu es m ay
Water Intoxication be a t r isk for da m a ge beca u se of t h e r esu lt in g in -
cr ea sed dist a n ce for diffu sion a n d t h e com pr ession
H ypot on ic h ypovolem ia , a lso kn own a s wa t er in -
of t h e va scu la t u r e su pplyin g oxygen a n d r em ovin g
t oxica t ion , r esu lt s fr om decr ea sed sodiu m con cen -
wa st e. Th e clin ica l m a n ifest a t ion s of edem a a r e de-
t r a t ion , oft en t h e r esu lt of wa t er r epla cem en t a ft er
t er m in ed by t h e sit es of occu r r en ce. Wh en loca t ed in
st r en u ou s a ct ivit y or excessive loss of sodiu m fr om
t h e join t s, pa in a n d im pa ir ed m ovem en t m ay r esu lt .
diu r et ic t h er a py in h ibit in g ADH . Cellu la r swellin g
When loca t ed in t h e br a in or lu n gs, fu n ct ion m a y be
occu r s beca u se of m ovem en t of wa t er fr om t h e ext r a -
so im pa ir ed t h a t dea t h m ay r esu lt . Wh en flu id a ccu -
cellu la r spa ce t o t h e in t r a cellu la r spa ce. In cr ea ses
m u la t ion in t h e per iph er a l in t er st it iu m exceeds t h e
in cellu la r wa t er t r igger clin ica l m a n ifest a t ion s, in -
t issu es’ a bilit y for a bsor pt ion , t h e flu id becom es m o-
clu din g m u scle wea kn ess, cr a m ps, a n d fa t igu e, a n d
bile wh en pr essu r e is exer t ed u pon it . Wh en pr essu r e
cen t r a l n er vou s syst em in volvem en t su ch a s h ea d-
over a n edem a t ou s a r ea for ces flu id m ovem en t a n d
a ch e, con fu sion , a n d depr ession of deep t en don r e-
leaves a n in den t a t ion , t h e edem a is r efer r ed t o a s
flexes (DTRs). Tr ea t m en t s in clu din g lim it in g wa t er
p it t in g (Fig. 8.10). E dem a m a y be r ecogn ized a s a lo-
or in cr ea sin g sodiu m in t a ke t a r get t h e u n der lyin g
ca l a r ea of swellin g, in cr ea sed body weigh t , a n d pa in .
ca u se of t h e con dit ion . H yper t on ic sa lin e solu t ion s
Body weight m ea su r em ent s pr ovide a n effect ive
a n d loop diu r et ics t o in cr ea se wa t er elim in a t ion a r e
evalua t ion of edem a , wit h incr ea sed body weigh t r e-
a lso opt ion a l t r ea t m en t s.
flect ing a n incr ea se in t ot a l body flu id. Visu a l in spec-
t ion of ext r em it ies h elps t o iden t ify per iph er a l edem a .
Hypervolemia
E va lua t ion of edem a wit hin or ga n syst em s not r ea d-
H yper volem ia is a n expa n sion of ext r a cellu la r ily visible depen ds on t he involved t issues. Auscult a -
volu m e in volvin g t h e in t er st it ia l or va scu la r spa ce. t ion of hea r t a nd lu ngs m ay r evea l excessive flu id.
 A No rmal
Ca pilla ry

Inte rs titia l s pa ce

12 mL/min
Lympha tic

2 mL/min
Ve nule

Arte ria l

B Inc re as e d hydro s tatic pre s s ure C De c re as e d o nc o tic pre s s ure

Ede ma Ede ma

D Inc re as e d pe rme ability E Lymphatic o bs truc tio n

Ede ma
Tumor

Ede ma

Figure 8.9. Mechanisms of edema in the capillary system. A: Normal. The differential between the hydrostatic and on-
cotic pressures at the arterial end of the capillary system is responsible for the filtration into the interstitial space of
approximately 14 mL of fluid per minute. The fluid is reabsorbed at the venous end at the rate of 12 mL/ min. Lymphatic
capillaries drain fluid at a rate of 2 mL/ min. B: Edema caused by increased hydrostatic pressure. Elevation at the venous
end of the capillary decreases reabsorption. If the lymphatic capacity to drain fluid is exceeded, fluid accumulates.
C: Edema caused by decreased oncotic pressure. Decreased oncotic pressure in the vascular space promotes reduced fluid
reabsorption. D: Edema caused by increased permeability results from endothelial injury, allowing fluid to leak from the
vascular space. E: Lymphedema results from accumulation of fluid caused by lymphatic obstruction. (From Rubin E, Farber
JL. Pathology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.)
210 C h a p t e r 8: Alt er ed F lu id a n d E lect r olyt e Ba la n ce
Figure 8.10. Pitting edema. Palpation causes a depression when released because of movement of fluid in the interstitium.
(From Rubin E, Farber JL. Pathology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.)
Modu le 3 C lin ic a l Mo d e ls
The clinical models presented in this chapter incorpo-
rate the concepts of altered fluid and electrolyte bal-
ance. Each concept is individually highlighted, although
clearly each is related to the other. When reviewing the
clinical models, the student should apply the concepts
he or she has learned about these alterations.
Altered Fluid Balance: Cirrhosis
Chapter 5 introduced the liver disease known as cir-
rhosis. In this chapter, the discussion of cirrhosis fo-
cuses on the implications of this disease related to
alterations in fluid balance. Cirrhosis and chronic liver
disease represent leading causes of mortality, although
the rates are decreasing. From 1980 to 1989, hospital-
ization rates for women were less than that for men
by one-third. Hospitalization rates were 20% to 30%
lower in Whites as compared to Blacks. Increasing age
was associated with increased death rates in men (15.2
to 49 in 100,000) and in women (4.8 to 26.7 in 100,000)
when rates for age groups in the 35 to 44 and 65 to 74
(men) and 75 to 84 (women) range were compared.4
PATHOPHYSIOLOGY
As pr eviou sly discu ssed, c ir r h o s is is a for m of liver
disea se ch a r a ct er ized by t h e in t er fer en ce of loca l
blood flow a n d h epa t ocyt e da m a ge. Cir r h osis is of-
t en (bu t n ot a lwa ys) t h e r esu lt of h epa t it is a n d liver
da m a ge fr om a lcoh ol exposu r e. Th e m ost com m on
com plica t ion of cir r h osis is a s c it e s , a ccu m u la t ion of
flu id in t h e per it on ea l ca vit y. Th is is a n exa m ple of
flu id loss t o a “t h ir d spa ce,” m a kin g it u n a va ila ble
for u se in t h e r em a in in g ext r a cellu la r or in t r a cellu -
la r com pa r t m en t s.
Ascit es is t h e m a n ifest a t ion of t h e com bin a t ion of
h ydr ost a t ic pr essu r e, on cot ic pr essu r e, a n d ca pilla r y
per m ea bilit y, sim ila r t o ot h er for m s of edem a . E xa m -
ples of con dit ion s lea din g t o a scit es a n d t h e u n der ly-
in g ca u ses in clu de:
● In cr ea sed h ydr ost a t ic pr essu r e
■ Budd–Chia ri syndrome (hepatic vein obstruction)
■ Con gest ive h ea r t fa ilu r e
● Decr ea sed colloid osm ot ic pr essu r e
■ Ma ln u t r it ion
■ Neph r ot ic syn dr om e
● In cr ea sed ca pilla r y per m ea bilit y
■ Ma lign a n cy
■ Ba ct er ia l per it on ea l in fect ion
In cr ea sed va scu la r r esist a n ce t o blood flow in t h e
liver ca u ses a con dit ion kn own a s p o r t a l h y p e r t e n -
s io n , eleva t ion in t h e por t a l (h epa t ic) pr essu r e of t h e
liver. In cr ea sed pr essu r e pr om ot es m ovem en t of flu id
ou t of ca pilla r ies t h r ou gh h ydr ost a t ic m ech a n ism s.
 C lin ic a l Mo d e ls 211

Th e m ovem en t of flu id in t o t h e in t er st it iu m exceeds

t h e a bilit y of t h e lym ph a t ic syst em t o r ecir cu la t e
flu id t o t h e syst em ic cir cu la t ion , lea din g t o a ccu -
m u la t ion . In cr ea sed va scu la r r esist a n ce t r igger s
t h e pr odu ct ion of va sodila t or s t o decr ea se va scu la r
r esist a n ce a n d in cr ea se blood flow. Th e dila t ion of
t h e por t a l a r t er ies even t u a lly r esu lt s in a decr ea se
in blood volu m e a n d a dr op in a r t er ia l pr essu r e. To Tympa ny
com pen sa t e for t h e dr op in blood pr essu r e, a r t er ia l
pr essu r e is m a in t a in ed by a ct iva t in g m ech a n ism s,
wh ich r esu lt s in sodiu m a n d wa t er r et en t ion a n d ex-
pa n ds pla sm a volu m e. In t est in a l ca pilla r y pr essu r e Dullne s s
a n d per m ea bilit y a r e a lt er ed by t h e com bin a t ion of
por t a l h yper t en sion a n d a r t er ia l dila t ion , pr om ot in g
t h e t r a n spor t of flu id t o t h e a bdom in a l ca vit y. In t h e Bulging
a dva n ced st a t e, cir r h osis is a ssocia t ed wit h pr ot ein fla nk
wa st in g. Th is lea ds t o loss of a lbu m in in t h e cir cu -
la t ion , fu r t h er a lt er in g flu id ba la n ce t h r ou gh loss of
flu id t o t h e ext r a va scu la r spa ce.
P r ogr essive pa t h ology m a y lea d t o r en a l im pa ir-
m en t , in clu din g im pa ir ed fr ee wa t er excr et ion t h a t
lea ds t o dilu t ion a l h ypon a t r em ia a n d r en a l va so- Figure 8.11. Clinical evidence of ascites. Fluid accumula-
con st r ict ion , wh ich in cr ea ses t h e r isk of h e p a t o - tion in the abdominal cavity causes distention and bulg-
r e n a l s y n d r o m e (r en a l fa ilu r e ca u sed by sever e ing flanks and umbilicus. Tympany over the intestines
r en a l va socon st r ict ion ). In cr ea sed levels of r en in and dullness over fluid in abdomen and flanks are also
a n d a ldost er on e fu r t h er con t r ibu t e t o a lt er ed flu id noted.
ba la n ce.

CLINICAL MANIFESTATIONS
Th e sever it y of a scit es is r ela t ed t o t h e m a n ifest a -
t ion of clin ica l sign s a n d sym pt om s (F ig. 8.11). Asci-
t es ca n be descr ibed ba sed on volu m e of flu id in t h e
per it on eu m (m oder a t e t o la r ge volu m e) a n d is oft en
a ssocia t ed wit h t h e followin g m a n ifest a t ion s:
● Moder a t e t o sever e a bdom in a l discom for t
● In cr ea sed a bdom in a l gir t h
● In cr ea sed weigh t
● Sever e sodiu m r et en t ion
● Dilu t ion a l h ypon a t r em ia
● Ren a l fa ilu r e (oligu r ia a n d in cr ea se in ser u m
cr ea t in in e)
TREATMENT
Th e volu m e of a scit es is a pr im a r y det er m in a n t of
t r ea t m en t . Diu r et ics a r e oft en u sed t o pr om ot e a s-
cit ic flu id loss a n d n or m a lize sodiu m ba la n ce. Ca u -
t ion m u st be u sed t o a void excessive diu r esis, wh ich
r esu lt s in h ypovolem ia a n d in cr ea ses r isk of r en a l
fa ilu r e. In sever e ca ses, pa r a cen t esis m a y be n ec-
essa r y. P a r a c e n t e s is is t h e in ser t ion of a ca n n u la
in t o t h e per it on ea l ca vit y t o r em ove a scit ic flu id
(Fig. 8.12). In t r a ven ou s a lbu m in m a y be a dm in is-
t er ed t o expa n d pla sm a volu m e in in dividu a ls wh o
h a ve h a d a la r ge volu m e of flu id r em oved t o r edu ce
t h e r isk of cir cu la t or y dysfu n ct ion a n d r a pid r ecu r-
r en ce of a scit es.

DIAGNOSTIC CRITERIA
P h ysica l exa m in a t ion a n d
ch a n ge in body weigh t a r e
u sed t o dia gn ose a scit es.
Mea su r em en t of a bdom i-
n a l gir t h or cir cu m fer en ce
m a y be u sefu l. E va lu a -
t ion of liver, r en a l, a n d
ca r dia c fu n ct ion sh ou ld
be com plet ed t o det er-
m in e syst em ic da m a ge or
dysfu n ct ion .
R E S E AR C H N O T E S
Ascites can lead to the development of shock, renal failure, respiratory failure, and hy-
poperfusion as a result of abdominal pressure. In a recent case report, a 67-year-old woman
came into the emergency room who reported mild difficulty breathing. Her abdomen was
obese and tense on examination. While being evaluated in the emergency room, the patient
developed severe hypotension, oliguria (decreased urine output), and an increased serum
creatinine level consistent with acute onset renal failure. She required ventilatory support
because of decreased oxygen saturation of her tissues. An ultrasound revealed severe asci-
tes. Paracentesis was done with removal of 4,500 mL of fluid, reducing abdominal pressure. 5
212 C h a p t e r 8: Alt er ed F lu id a n d E lect r olyt e Ba la n ce

● Fluid shift between com-

F R O M T H E L AB pa r t m en t s
■ Ascit es
Urinary sodium concentration provides a measurement of renal sodium retention. In patients ■ Ca pilla r y lea ka ge
with large volume ascites, urine sodium concentrations of 10 mmol/ L are consistent with (bu r n s a n d sepsis)
severe sodium retention. Analysis of ascitic fluid should be done to help determine etiology.
Ascitic fluid analysis involves: Dehydrat ion is cat egor ized
Determination of serum-ascitic albumin gradient (SAAG): calculated from the differ- ba sed on blood sodium
ence between ascitic fluid albumin concentration and serum albumin concentration concentra tion, pr oviding
informa tion about the
Gradients greater than or equal to 1.1 g/ dL indicate portal hypertension or transu- t ype of fluid loss a nd the
dative ascites potent ia l com plica tions
Gradients lesser than 1.1 g/ dL indicate exudative ascites a ssocia ted with coexisting
Amylase concentration: elevated in ascites of pancreatic origin electrolyte im ba la nce. Ca t-
White blood cell (WBC) count: increase indicates infection egories of dehydra tion a re
descr ibed in Table 8.3. Vol-
Predominantly polymorphonuclear WBC indicates bacterial infection ume deficit coupled wit h
Predominantly mononuclear WBC indicates fungal or tuberculin infection a lt ered sodium ba la nce
Red blood cell (RBC) count: increased concentration indicates hemorrhagic ascites, st imula tes further fluid
often caused by malignancy shifts, determined by the
Gram stain and culture: determination of pathogen involved in infection a mount of circula ting so-
dium in the blood. In hypo-
Cytology: examination of cells for signs of malignancy na tremic dehydra tion, the
fluid lost conta ins more
sodium than the amount
Stop and Consider cont ained in the blood, lea ding t o a hypotonic st ate.
Why does ascites often return after fluid removal Seeking equilibrium , fluid shifts fr om the intr ava s-
by paracentesis? cula r compa rtment t o the extr ava scular compart -
ment because of t he low level of sodium in the blood.
This step results in furt her volum e depletion of t he
intr ava scular spa ce, exagger at ing the effect of a ctual
Altered Sodium Balance: Dehydration volum e loss. Conversely, hyperna trem ic dehydra tion
is a ssocia ted with hypot onic fluid loss. Beca use less
Deh ydr a t ion is ch a r a ct er ized by n ega t ive flu id ba l-
sodium is lost rela tive to the fluid a mount, loss of hy-
a n ce. Dia r r h ea is t h e m ost com m on ca u se of deh y-
potonic fluid lea ds to a hypertonic st at e, prom oting
dr a t ion , a lt h ou gh a va r iet y of ot h er con dit ion s ca n
fluid m ovem ent fr om the extr ava scula r space to the
lea d t o deh ydr a t ion . Accor din g t o t h e Wor ld H ea lt h
intr ava scular spa ce. This t ype of fluid shift a ctually
Or ga n iza t ion , deh ydr a t ion secon da r y t o dia r r h ea l
minimizes the effects of the fluid loss, ma inta ining
illn ess is t h e lea din g ca u se of in fa n t a n d ch ild m or-
va scular volume and potentia l for perfusion.6
t a lit y. It wa s est im a t ed t h a t bet ween 2000 a n d 2003,
dia r r h ea wa s t h e ca u se of dea t h in 17% of ch ildr en
you n ger t h a n 5 yea r s a n d in 3% of ba bies you n ger CLINICAL MANIFESTATIONS
t h a n 28 da ys of a ge. A wor ldwide pr oblem lin ked
Iden t ifica t ion of clin ica l m a n ifest a t ion s of deh ydr a -
t o 4% of a ll dea t h s, dia r r h ea kills a ppr oxim a t ely
t ion h elps t o det er m in e deh ydr a t ion sever it y. E st i-
2.2 m illion people in t h e wor ld ea ch yea r, m ost ly a f-
m a t es of flu id deficit a r e ba sed on a ge a n d body size.
fect in g ch ildr en in developin g cou n t r ies.
In n ewbor n s, deh ydr a t ion is cla ssified by loss of body
weigh t , wit h 5% con sider ed m ild, 10% con sider ed
PATHOPHYSIOLOGY m oder a t e, a n d 15% con sider ed sever e. In ch ildr en
wh o weigh m or e t h a n 10 kg, m ild deh ydr a t ion is a s-
F lu id deficit a ssocia t ed wit h deh ydr a t ion in volves socia t ed wit h a 3% weigh t loss, m oder a t e is a ssoci-
bot h in t r a cellu la r a n d ext r a cellu la r volu m e. Ca u ses a t ed wit h a 6% loss, a n d sever e equ a t es t o a 9% loss.
of deh ydr a t ion r esu lt in g in flu id deplet ion in clu de: Mild deh ydr a t ion is a ssocia t ed wit h m ild m a n ifes-
t a t ion s, wit h sign s a n d sym pt om s wor sen in g a s t h e
● Decr ea sed flu id in t a ke
sever it y of deh ydr a t ion in cr ea ses. Ma n ifest a t ion s of
● In cr ea sed flu id ou t pu t
deh ydr a t ion in clu de:
■ Ren a l
■ Ga st r oin t est in a l ● Decr ea sed level of con sciou sn ess
■ In sen sible ● P r olon ged ca pilla r y r efill t im e
 C lin ic a l Mo d e ls 213

Re ctus a bdominis in s he a th B
S kin
S upe rficia l fa s cia

External oblique

Inte rna l oblique

Coils of s ma ll inte s tine Tra ns ve rs e
a bdominis
Tra ns ve rs e
fa s cia
Extra pe ritone a l fa t
P a rie ta l pe ritone um
P e ritone a l ca vity

Figure 8.12. Paracentesis of the abdominal cavity. A: Midline approach. B: Lateral approach. (From Snell MD. Clinical
Anatomy. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.)

st ools, em esis, a n d swea t ), a r e

Ta b le 8.3 Cla ssifica t ion s of Deh ydr a t ion : Sodiu m Con sider a t ion s im por t a n t in det er m in in g flu id
ba la n ce. Appet it e pa t t er n s a n d
Deh y- S o d iu m Fr e- Typ e of
d r a t io n Con cen - qu en cy of F lu id r ecen t weigh t loss m a y pr ovide
Ca t egor y t r a t io n D ia g n o s is Loss F lu id S h ift s a n in dica t ion of m a ln u t r it ion .
Un der lyin g m edica l con dit ion ,
H ypon a t r em ic <130 m E q/L 5%–10% H yper t on ic In t r a va scu la r t o
E xt r a va scu la r r ecen t exposu r e t o illn ess, or r e-
Ison a t r em ic 130–150 80% Isot on ic Non e
cen t t r a vel m a y poin t t o a n in -
m E q/L fect iou s ca u se of flu id im ba la n ce.
H yper n a t r em ic > 150 m E q/L 5%–10% H ypot on ic E xt r a va scu la r t o H ist or y a n d eva lu a t ion of clin -
In t r a va scu la r ica l m a n ifest a t ion s pr ovide t h e
ba sis of dia gn osis. La bor a t or y
a n a lyses a r e gen er a lly r eser ved for sever e ca ses of
● Dr y m u cou s m em br a n es deh ydr a t ion . Blood con cen t r a t ion s of sodiu m , pot a s-
● Decr ea sed or a bsen t t ea r s siu m , a n d ch lor ide m a y in dica t e a ssocia t ed elect r o-
● Ch a n ge in vit a l sign s lyt e a n d a cid–ba se im ba la n ces. Poor per fu sion m a y
■ In cr ea sed r espir a t or y r a t e pr om ot e bu ildu p of la ct ic a cid, con su m in g bica r-
■ Decr ea sed blood pr essu r e bon a t e. Mea su r es of cir cu la t in g bica r bon a t e m a y
■ Wea k pu lse pr ovide a n ot h er in dica t ion of a cid–ba se ba la n ce. H y-
● Depr essed fon t a n el (a r ea s n ot en closed by cr a - poper fu sion m a y a lso lea d t o r en a l da m a ge, wh ich
n iu m , or “soft spot s” on in fa n t s h ea ds) ca n be det er m in ed by eva lu a t ion of BUN a n d cr ea t -
● Su n ken eye in in e. Ur in e ca n be eva lu a t ed for con cen t r a t ion by
● Decr ea sed or a bsen t u r in e ou t pu t m ea su r em en t of specific gr a vit y a n d for elect r olyt e
con t en t (see Fr om t h e La b, below). Resu lt s of t h e la b-
DIAGNOSTIC CRITERIA or a t or y eva lu a t ion m a y a ssist in t h e t r ea t m en t pla n .

A r ecen t h ist or y h elps det er m in e t h e ca u se a n d se-

TREATMENT
ver it y of deh ydr a t ion . F lu id in t a ke, in clu din g vol-
u m e a n d t ype (h yper t on ic or h ypot on ic), a s well a s Or a l r eh ydr a t ion for m ild t o m oder a t e deh ydr a -
flu id ou t pu t , qu a n t it y, a n d ch a r a ct er ist ics (u r in e, t ion h elps r est or e flu id ba la n ce. F lu ids in t en ded for
214 C h a p t e r 8: Alt er ed F lu id a n d E lect r olyt e Ba la n ce

loss of n ega t ive feedba ck

F R O M T H E L AB r egu la t ion , lea din g t o a l-
t er a t ion s in blood ca lciu m
Urine-specific gravity measures the concentration of particles in the urine, comparing the levels.
weight of urine to the weight of water. A value between 1.010 and 1.025 suggests fluid H ypopa r a t h yr oidism is
balance. Concentrated urine contains more particles and has a higher specific gravity (more a con dit ion ch a r a ct er ized
than 1.025). Dilute urine has a lower concentration of particles and has a lower specific by a low level of pa r a t h y-
gravity (less than 1.010). Urine osmolality measures indicate the kidney’s ability to excrete r oid h or m on e secr et ion .
or conserve water, or the ability to concentrate urine, providing additional information on On e of t h e m ost com m on
the renal contributions to fluid and electrolyte balance. r ea son s for h ypopa r a -
t h yr oidism is da m a ge t o
t h e pa r a t h yr oid gla n ds
du r in g t h yr oid su r ger y or
t h yr oid r a dia t ion t r ea t -
R E S E AR C H N O T E S m en t beca u se of t h e close
pr oxim it y of t h e pa r a t h y-
Hyponatremia is becoming an increasing concern for marathon runners, contributing to r oid a n d t h yr oid gla n ds.
7
race-related morbidity and mortality. In a recent study of 488 athletes participating in the H ypopa r a t h yr oidism m a y
Boston Marathon, researchers found that 13% had hyponatremia and 0.6% had critical hypo- a lso be con gen it a l, iden -
natremia with extremely low serum sodium concentrations. Excessive fluid intake during the t ified in in fa n t s ea r ly in
race was the strongest single predictor for the development of hyponatremia. The research- life. Au t oim m u n e ca u ses
ers found no association with the type of fluid intake among the runners (plain water or of h ypopa r a t h yr oidism
electrolyte solutions) and the risk for hypovolemia, emphasizing the greater role of volume in volvin g pa r a t h yr oid in -
in the development of fluid imbalance. The risk was significantly increased in women and in ju r y du e t o a u t oa n t ibodies
individuals with extremes of body mass index. ca n a lso lea d t o r edu ced
pa r a t h yr oid fu n ct ion . Re-
r eh ydr a t ion con t a in sodiu m , pot a ssiu m , a n d glu cose du ct ion or loss of pa r a t h y-
in t h e a ppr opr ia t e pr opor t ion s, pr om ot in g r ea dy a b- r oid fu n ct ion a n d r esu lt in g con sequ en ces in ca lciu m
sor pt ion fr om t h e ga st r oin t est in a l syst em in t o t h e h om eost a sis is t h e focu s of t h is clin ica l m odel.
cir cu la t ion . Reh ydr a t ion flu ids m u st be a dm in is-
t er ed fr equ en t ly a n d in sm a ll a m ou n t s. Sever e de-
h ydr a t ion wit h h ypovolem ia r equ ir es in t r a ven ou s PATHOPHYSIOLOGY
a dm in ist r a t ion of Rin ger la ct a t e or isot on ic sa lin e Ther e a r e four pa r a t hyr oid gla nds loca t ed post er ior
solu t ion t o pr om ot e in t r a va scu la r volu m e. Idea lly, t o t h e t hyr oid gla nd. Th e pa r a t h yr oid gla n ds pr odu ce
volu m e r epla cem en t sh ou ld be det er m in ed ba sed pa r a t h yr oid h or m on e in r espon se t o t h e n eed t o in -
on ca lcu la t ion of flu id deficit . Ca r e m u st be t a ken cr ea se blood ca lciu m . Pa r a t h yr oid h or m on e t a r get s
t o a void r a pid cor r ect ion of h ypon a t r em ia , wh ich sou r ces of ca lciu m , m obilizin g ca lciu m fr om in t r a cel-
is a ssocia t ed wit h n eu r ologic com plica t ion s. Ra pid lu la r ca lciu m st or es t o t h e blood for pa r t icipa t ion in
r eh ydr a t ion in h yper n a t r em ia m a y ca u se cellu la r ca lciu m -r equ ir ed fu n ct ion s. Th e bon es r epr esen t a
swellin g t o t h e poin t of cellu la r r u pt u r e. m a jor t a r get for pa r a t h yr oid h or m on e a s t h ey ser ve
a s a la r ge ca lciu m st or a ge sit e. Th e kidn eys a r e a lso
r espon sive t o pa r a t h yr oid h or m on e, in cr ea sin g r e-
a bsor pt ion of ca lciu m fr om t h e u r in a r y filt r a t e a n d
Altered Calcium Balance: m ovin g t h e ca lciu m ba ck in t o t h e blood. In dir ect ly,
Hypoparathyroidism pa r a t h yr oid h or m on e a ssist s in in t est in a l r ea bsor p-
t ion of ca lciu m via a ct iva t ed vit a m in D. Wh en ca lciu m
Ca lciu m h om eost a sis is t igh t ly con t r olled t h r ou gh levels r ise t o t a r get levels in t h e blood, t h e pa r a t h y-
n ega t ive feedba ck r egu la t ion . Ava ila bilit y of ca lciu m r oid gla n ds r eceive sign a ls t o r edu ce pr odu ct ion of
wit h in a n a r r ow r a n ge in t h e blood pr om ot es opt im a l pa r a t h yr oid h or m on e. Th is n ega t ive feedba ck sys-
cellu la r a n d t issu e fu n ct ion in clu din g gen er a t ion of t em is essen t ia l in m a in t a in in g ca lciu m h om eost a sis.
a ct ion pot en t ia ls, m u scle con t r a ct ion a n d en zym e a c- Wh en t h e pa r a t h yr oid gla n d fu n ct ion is im pa ir ed
t ivit y t h r ou gh ou t t h e body. Th e pa r a t h yr oid gla n ds a n d u n a ble t o r espon d t o sign a ls t o in cr ea se pr o-
pla y a n essen t ia l r ole in r egu la t ion of ca lciu m , pa r- du ct ion of pa r a t h yr oid h or m on e in r espon se t o low
t icipa t in g in n ega t ive feedba ck r egu la t ion t o m a in - ca lciu m levels, t h e t r igger s for m obilizin g ca lciu m
t a in ca lciu m blood levels bet ween 8.5 a n d 10.5 m g/ st or es a n d en h a n cin g r en a l r ea bsor pt ion h a ve r e-
dL. Alt er a t ion s in pa r a t h yr oid fu n ct ion con t r ibu t e t o du ced or n o effect iven ess. Th e in a bilit y t o in cr ea se
 C h a p t e r 8: Alt er ed F lu id a n d E lect r olyt e Ba la n ce 215

ca lciu m levels du e t o la ck
of pa r a t h yr oid h or m on e R E S E AR C H N O T E S
lea ds t o h ypoca lcem ia .
Recombinant parathyroid hormone (rhPTH) was investigated in clinical trial designed to
determine effectiveness in treatment of hypoparathyroidism. Research participants received
CLINICAL injections of rhPTH in a variety of doses to determine effectiveness in regulating calcium
MANIFESTATIONS levels while reducing supplemental calcium and vitamin D treatments. FDA approval of
Th e sign s a n d sym pt om s rhPTH was based on the clinical trials results, providing the foundation of current treatment
of h ypopa r a t h yr oidism recommentations. 8
a r e gen er a l a n d m a y
m a ke dia gn osis ch a llen g-
ca lciu m levels a t t h e lower r a n ge of n or m a l a n d
in g wit h ou t la bor a t or y con fir m a t ion . Th er e is sig-
opt im a l ca lciu m r ea bsor pt ion . Ach ievem en t of ca l-
n ifica n t over la p bet ween t h e clin ica l m a n ifest a t ion s
ciu m h om eost a sis will r edu ce m a n ifest a t ion s a n d
of h ypopa r a t h yr oidism wit h h ypoca lcem ia in clu din g
lon g-t er m con sequ en ces of h ypoca lcem ia . Recen t ly,
en h a n ced n eu r om u scu la r ir r it a bilit y, seizu r e a n d
a n ew t r ea t m en t for h ypopa r a t h yr oidism wa s a p-
m u scle cr a m pin g. Clin ica l m a n ifest a t ion s of h ypo-
pr oved. Recom bin a n t pa r a t h yr oid h or m on e, given
t h yr oidism in a du lt s in clu de:
in con ju n ct ion wit h ca lciu m a n d vit a m in D su p-
● H a ir dr yn ess a n d loss plem en t a t ion , h a s been a ppr oved for t r ea t m en t of
● Na il r idges a n d br ea ka ge h ypopa r a t h yr oidism . 8
● Skin dr yn ess
● Bon e loss
● Tin glin g in ext r em it ies (pa r a t h esia ) Stop and Consider
● Visu a l ch a n ges What changes in other electrolytes would be
● Mu scle cr a m ps expected in hypoparathyroidism-associated hypo-
● Seizu r es calcemia, and what are the expected manifesta-
● Fa t igu e tions that are likely?

Ch ildr en wit h con gen it a l h ypopa r a t h yr oidism a r e

pa r t icu la r ly su scept ible t o t h e n eu r ologic con se-
qu en ces of low ca lciu m levels. Con gen it a l h ypo-
pa r a t h yr oidism is a ssocia t ed wit h seizu r es, gr owt h
a n d n eu r ologica l deficit s a lon g wit h u n u su a l fa cia l
ch a r a ct er ist ics.
DIAGNOSTIC CRITERIA
Pa st m edica l a n d su r gica l h ist or y a r e im por t a n t
con sider a t ion s in t h e det er m in a t ion of h ypopa r a -
t h yr oidism . P h ysica l exa m in a t ion t h a t in clu des t h e
object ives sign s of h ypopa r a t h yr oidism will pr ovide
eviden ce of clin ica l m a n ifest a t ion s, pr om pt in g la bo-
r a t or y eva lu a t ion t o con fir m dia gn osis. La bor a t or y
m ea su r es of pa r a t h yr oid h or m on e, blood ca lciu m ,
ph osph or u s, a n d m a gn esiu m will be im por t a n t
t o det er m in e elect r olyt e im ba la n ce a n d t h e u n -
der lyin g ca u se. Mea su r em en t of u r in a r y ca lciu m
pr ovides eviden ce for efficien cy of r en a l ca lciu m
r ea bsor pt ion .
TREATMENT
H ypopa r a t h yr oidism is a ch r on ic con dit ion r e-
qu ir in g lon g-t er m t r ea t m en t wit h su pplem en t a l
ca lciu m (ca r bon a t e or cit r a t e) a n d vit a m in D (ca l-
cit r iol) wit h t h e object ive of m a in t en a n ce of blood
S U MMAR Y
● F lu id a n d elect r olyt e ba la n ce a r e im por t a n t t o h o-
m eost a sis a n d cellu la r fu n ct ion .
● F lu id r epr esen t s 60% of body weigh t , wit h
t wo-t h ir ds of body flu ids con t a in ed in t h e in t r a cel-
lu la r com pa r t m en t a n d t h e r em a in in g on e-t h ir d
con t a in ed in t h e ext r a cellu la r com pa r t m en t .
● F lu id t r a n spor t is a ccom plish ed ba sed on con cen -
t r a t ion a n d ch em ica l gr a dien t s. Osm ot ic pr essu r e
is gen er a t ed by ch a r ged pa r t icles a n d pr essu r e
gr a dien t s a r e gen er a t ed by h ydr ost a t ic for ces.
● Th ir st , st im u la t ed by h or m on a l m ech a n ism s, is
im por t a n t in t h e r egu la t ion of flu id in t a ke. Di-
u r et ics st im u la t e excr et ion of flu id t h r ou gh a c-
t ion s wit h in t h e kidn eys.
● Alt er a t ion s in flu id ba la n ce m a y r esu lt fr om im -
ba la n ce bet ween h ydr ost a t ic a n d osm ot ic for ces
a n d fr om a lt er ed ca pilla r y per m ea bilit y. H yper-
volem ia a n d h ypovolem ia a r e exa m ples of a lt er ed
flu id ba la n ce.
● Alt er a t ion s in flu id a n d elect r olyt e ba la n ce ca n oc-
cu r beca u se of ot h er disea ses or ca n ca u se illn ess.
● E lect r olyt es con t a in posit ive ch a r ges (ca t ion s) or
n ega t ive ch a r ges (a n ion s) t h a t det er m in e a t t r a c-
t ive for ces a n d m ovem en t ca u sed by differ in g con -
cen t r a t ion s bet ween com pa r t m en t s.
216 C h a p t e r 8: Alt er ed F lu id a n d E lect r olyt e Ba la n ce

● Low blood levels of elect r olyt es a r e in dica t ed by 3. Wh ich com pa r t m en t con t a in s the gr ea t est
t h e pr efix “h ypo”; in cr ea sed blood levels of elect r o- a m ou n t of body wa t er ?
lyt es a r e in dica t ed by t h e pr efix “h yper,” followed a . Tr a n scellu la r
by t h e t er m for t h e specific elect r olyt e in volved b. P la sm a
(i.e., -n a t r em ia [sodiu m ], -ka lem ia [pot a ssiu m ], c. In t er st it ia l
a n d -ph osph a t em ia [ph osph a t e]). d. In t r a cellu la r
● Cor r ect ion of flu id a n d elect r olyt e im ba la n ces is
cr it ica l t o t h e m a in t en a n ce of bodily fu n ct ion s. 4. Wh ich of t h e followin g t r a n spor t m ech a n ism s
● To cor r ect im ba la n ces in flu id a n d elect r o- is a ssocia t ed wit h m ovem en t of wa t er a cr oss a
lyt e, ca r efu l con sider a t ion m u st be given t o sem iper m ea ble m em br a n e?
t h e pot en t ia l im pa ct a cr oss body syst em s a n d a . Diffu sion
com pa r t m en t s. b. Osm osis
c. Fa cilit a t ed diffu sion
d. Act ive t r a n spor t

C AS E S T U D Y 8.1 5. Wh ich on e of t h e followin g con dit ion s will m ost

J en n y, a 19-yea r-old college st u den t , wa s in ju r ed in
a fir e r esu lt in g fr om a ca r a cciden t . Sh e exper ien ced
fu ll-t h ickn ess bu r n s over a ppr oxim a t ely 10% of h er
body. Con sider t h e clin ica l m odel t h a t is m ost r e-
la t ed t o t h is pr ocess. Fr om you r r ea din g r ela t ed t o
flu id, elect r olyt e, a n d a cid–ba se ba la n ce, a n swer t h e
followin g qu est ion s:
likely r esu lt in edem a ?
a . In t r a va scu la r filt r a t ion pr essu r e gr ea t er t h a n
in t er st it ia l filt r a t ion pr essu r e
b. In t r a va scu la r r ea bsor pt ion gr ea t er t h a n in -
t er st it ia l r ea bsor pt ion
c. In t r a va scu la r on cot ic pr essu r e gr ea t er t h a n
in t er st it ia l on cot ic pr essu r e
d. In cr ea sed lym ph a t ic r ea bsor pt ion

1. Wh a t a n a t om ic pr oblem wou ld m ost likely lea d t o 6. Ascit es is t h e pr im a r y m ech a n ism of body flu id
flu id sh ift s beca u se of bu r n in ju r y? im ba la n ce in wh ich of t h e followin g con dit ion s?
2. Wh a t is t h e ca u se of flu id sh ift s in bu r n in ju r y? a . Sa lt -losin g t u bu lopa t h y
3. H ow wou ld you m a n a ge flu id sh ift s in bu r n b. Cir r h osis
in ju r y? c. AIDS
4. Wh a t wou ld you expect for clin ica l m a n ifest a t ion s? d. Ison a t r em ic deh ydr a t ion
5. Wh a t dia gn ost ic t est s m igh t be u sed?
7. H ypoka lem ia is a h a llm a r k of t h e followin g
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r n a l
con dit ion s?
a r t icle or Web sit e t h a t det a ils flu id r esu scit a t ion a f-
a . Sa lt -losin g t u bu lopa t h y
t er bu r n in ju r y, t o con fir m you r pr edict ion s.
b. Cir r h osis
c. AIDS
d. Ison a t r em ic deh ydr a t ion
P R AC T I C E E XAM Q U E S T I O N S
8. H ypot on ic flu id loss m a y r esu lt in
a . H ypon a t r em ic deh ydr a t ion
1. F lu id loss in r espon se t o h yper volem ia is pr o-
b. Ison a t r em ic deh ydr a t ion
m ot ed by:
c. H yper n a t r em ic deh ydr a t ion
a . St im u la t in g secr et ion of ADH , pr om ot in g u r i-
d. Non e of t h e a bove
n a r y sodiu m a n d wa t er elim in a t ion
b. In h ibit in g t h e secr et ion of a ldost er on e, pr o-
m ot in g u r in a r y sodiu m a n d wa t er elim in a t ion
c. Lower in g m ea n a r t er ia l pr essu r e D I S C U S S I O N AN D
d. Adm in ist er in g osm ot ica lly a ct ive flu ids AP P L I C AT I O N

2. Wh ich of t h e followin g ion s is m ost closely r e- 1. Wh a t did I kn ow a bou t a lt er a t ion s in flu id a n d

la t ed t o wa t er m ovem en t ? elect r olyt e ba la n ce befor e t oda y?
a . Pot a ssiu m 2. Wh a t body pr ocesses a r e a ffect ed by a lt er-
b. Sodiu m a t ion s in flu id a n d elect r olyt e ba la n ce? H ow do
c. Ch lor ide flu id a n d elect r olyt e im ba la n ces a ffect t h ose
d. Ca lciu m pr ocesses?
 C h a p t e r 8: Alt er ed F lu id a n d E lect r olyt e Ba la n ce
3. Wh a t a r e t h e pot en t ia l et iologies for a lt er a t ion s
in flu id a n d elect r olyt e ba la n ce? H ow do flu id
a n d elect r olyt e im ba la n ces develop?
4. Wh o is m ost a t r isk for developin g flu id a n d
elect r olyt e im ba la n ces? H ow ca n t h ese a lt er-
a t ion s be pr even t ed?
5. Wh a t a r e t h e h u m a n differ en ces t h a t a ffect t h e
et iology, r isk, or cou r se of a lt er a t ion s in flu id
a n d elect r olyt e ba la n ce?
6. Wh a t clin ica l m a n ifest a t ion s a r e expect ed
du r in g flu id a n d elect r olyt e im ba la n ces?
7. Wh a t specia l dia gn ost ic t est s a r e u sefu l in de-
t er m in in g t h e dia gn osis a n d cou r se of a lt er-
a t ion s in flu id a n d elect r olyt e ba la n ce?
8. Wh a t a r e t h e goa ls of ca r e for in dividu a ls wh o
h a ve a lt er a t ion s in flu id a n d elect r olyt e ba la n ce?
9. How does the concept of a lterations in fluid a nd
electrolyte balance build on what I have lea rned in
the previous chapter and in the previous courses?
10. H ow ca n I u se wh a t I h a ve lea r n ed?
R E SOUR CE S
Am er ica n Bu r n Associa t ion :
h t t p://www.a m er ibu r n .or g/
US F DA Na t pa r a (pa r a t h yr oid h or m on e) for in jec-
t ion : US pr escr ibin g in for m a t ion . 2015:
h t t p://www.fda .gov/
F in d a d d ition a l r esou r ces for th is ch a pter a t h ttp:th ePoin t.lww.com
217
R e fe r e n c e s
1. S ted m a n ’s E lectr on ic Diction a r y. P h ila delph ia , PA: |
Lippin cot t Willia m s & Wilkin s; 2004.
2. Akit a S, Sa cks F M, Svet key LP, et a l. E ffect s of t h e
Diet a r y Appr oa ch es t o St op H yper t en sion (DASH ) diet
on t h e pr essu r e-n a t r iu r esis r ela t ion sh ip. H yper ten sion .
2003;42(1):8–13.
3. Lia m is G, Filippa t os TD, E lisa f MS. Cor r ect ion of h ypo-
volem ia wit h cr yst a lloid flu ids: in dividu a lizin g in fu sion
t h er a py. Postgr a d Med . 2015;127(4):405–412.
4. Cen t er s for Disea se Con t r ol a n d P r even t ion . Dea t h s a n d
h ospit a liza t ions fr om ch r onic liver disea se a n d cir r h osis—
Un it ed St a t es, 1980–1989. MMWR Mor b Mor ta l Wkly
Rep. 1993;41(52/53):969–973.
5. E t zion Y, Ba r ski L, Alm og Y. Ma lign a n t a scit es pr esen t -
in g a s a bdom in a l com pa r t m en t syn dr om e. Am J E m er g
Med . 2004;22(5):430–431.
6. Reyn olds RM, Pa dfield P L, Secki J R. Disor der s of
sodiu m ba la n ce. BMJ . 2006;332(7543):702--705.
7. Alm on d CS, Sh in AY, For t escu e E B, et a l. H ypon a t r em ia
a m on g r u n n er s in t h e Bost on m a r a t h on . N E n gl J Med .
2005;352(15):1550–1556.
8. Kim E S, Kea t in g GM. Recom bin a n t pa r a t h yr oid h or-
m on e (1–84): a r eview in h ypopa r a t h yr oidism . Dr u gs.
2015;75(11):1293–1303.
 Ch a pt er

9
Alt er ed Acid–Ba se
Ba la n ce

L E AR N I N G O U T C O ME S
1. Defin e a n d u se t h e key t er m s list ed in t h is ch a pt er.
2. Differ en t ia t e bet ween a cids a n d ba ses, in clu din g expect ed con cen t r a t ion s
t o pH .
3. Com pa r e a n d con t r a st bu ffer syst em s in volved in a cid–ba se ba la n ce.
4. Ou t lin e t h e cr it ica l com pon en t s t h a t det er m in e pH .
5. Descr ibe t h e clin ica l im plica t ion s of a lt er a t ion s in a cid–ba se ba la n ce.
6. Com pa r e a n d con t r a st m ech a n ism s lea din g t o m et a bolic a cidosis a n d
m et a bolic a lka losis.
7. Apply con cept s of a lt er ed flu id, elect r olyt e, a n d a cid–ba se ba la n ce t o
select ed clin ica l m odels.

INTR ODUCTION
Wh en wa s t h e la st t im e you t h ou gh t a bou t t h e in t r ica t e ba la n ce of in t egr a t ed
body syst em s t h a t a r e r equ ir ed t o su st a in a ph ysiologic pH ? For t u n a t ely, t h e
syst em s in volved in r egu la t ion of a cid–ba se ba la n ce t o m a in t a in a n or m a l pH
a r e a ct ive con t in u a lly, r espon sive t o even sm a ll ch a n ges t h a t t h r ea t en t h e del-
ica t e ba la n ce. Th e r edu n da n cy in syst em s t o a ch ieve opt im a l pH is n eeded in
or der for cells t o fu n ct ion opt im a lly. Th is ch a pt er bu ilds on con t en t r ela t ed t o
flu id a n d elect r olyt e ba la n ce a n d in clu des a r eview of t h e m ech a n ism s in volved
in a cid–ba se ba la n ce, pr esen t ed in in dividu a l m odu les. It a lso cover s in t er a c-
t ion s bet ween con cept s a n d t h e clin ica l con sequ en ces t h a t m a y r esu lt . Select ed
clin ica l m odels t h a t h igh ligh t specific a lt er a t ion s a r e pr esen t ed in Modu le 2 t o
a llow t h e st u den t t o a pply t h e lea r n ed con cept s.

pH-bicarbonate diagram. The 60

120 110 100 90 80 70 60 50 40

diagram shows the relationship

48
between arterial pH, bicarbonate, Me ta b o lic 35
a lka lo s is
and Pco2 and provides a useful 30
40 Ch ro n ic
way of determining a patient’s
)
L
re s p ira to ry
/
l
o
a c id o s is
acid–base disturbance. Normal
m
25
m
32
(
values are shown in the elliptical
]
–
3
O
area in the center. Values left of 20
C
24 Ac u te
H
normal represent acidemia, which
[
re s p ira to ry
a
a c id o s is Norma l
m
15
may be caused by respiratory aci-
s
Ac u te
a
16
l
re s p ira to ry
p
dosis or metabolic acidosis. Values a lka lo s is
l
a
Ch ro n ic
i
10
r
e
re s p ira to ry
to the right of normal represent
t
r
8 a lka lo s is
A
Me ta b o lic
alkalemia, which may be caused by a c id o s is

respiratory alkalosis or metabolic 0 P CO 2 (mm Hg)

alkalosis. Pco2, partial pressure 7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8
of carbon dioxide (mm Hg). From Arte ria l blood pH
Rhoades RA, Bell DR. Medical
Physiology. Philadelphia: Wolters
Kluwer Health, 2012.
218
 Ac id –B a s e I m b a la n c e 219

Modu le 1 Ac id –B a s e I m b a la n c e

Regu la t ion of a cids a n d ba ses is cr it ica l t o t h e m et a - mEq/L

bolic a ct ivit ies of t h e body. A n a r r ow ph ysiologic pH 150 Acidos is Acidos is
r a n ge is r equ ir ed for t h e fu n ct ion of cells, t issu es, due to e xce s s due to e xce s s
Norma l orga nic a cids chloride le ve ls
a n d or ga n s. 140

L
L
p
p
L
/
/
a
a
/
q
q
q
g
g
E
E
E
n
n
m
m
m
o
o
i
i
2
2
n
n
5
1
1
A
A
Regulation of Acid and Base

2
130

p
L
L
L
a
/
/
/
q
q
g
q
L
E
L
E
E
n
L
/
L
/
m
m
q
m
o
q
/
/
q
E
i
q
E
Ac id s a r e su bst a n ces t ha t dona t e hydr ogen ions,

n
2
2
E
2
m
E
120

A
m
4
4
4
m
m
1
1
1
4
a n d b a s e s a r e subst a nces t ha t a ccept h ydr ogen ions.

7
L
6
m
1
m
3
L
2
/
m
q
1
/
0
u
q
e
E
u
e
u
1
1
Wea k a cids in pla sm a in clu de a lbum in a n d in or ga nic

i
E
t
i
m
t
i
d
d
a
d
m
a
e
e
o
n
o
4
n
o
d
d
3
1
S
o
110

S
i
o
phosphor u s. St r on g ion s a lm ost com plet ely dissocia t e,

S
i
0
r
r
b
e
b
o
1
o
t
r
r
l
a
l
a
e
h
a
h
n
or sepa r a t e, wh en in solu t ion. In pla sm a , t h e st r on g

d
c
C
c
o
C
i
i
r
i
b
B
B
o
r
l
a
h
ca t ion s inclu de Na + , K + , Ca 2+ , a nd Mg 2+ . The st r on g

c
C
100

a n ion s a r e Cl− a n d la ct a t e.1 Th e r a t io bet ween a cids
a n d ba ses in t he ext r a cellula r fluid of t he body is
closely r egula t ed t o pr ovide a favor a ble envir on m en t
for m et a bolic cellula r fu nct ions. Th e clin ica l m ea -
su r em en t of t his ba la n ce is known a s p H . H ydr ogen
ion con cent r a t ion r epr esent s t h e inver se of t h e pH so
t ha t wh en t he pH is low, t her e is a h igh a m oun t of
H + ; wh en t h e pH is high, t h er e is a low a m ou nt of H + .
Th e ion s in volved in a cid–ba se ba la n ce a r e r e-
flect ed in t h e det er m in a t ion of t h e a n ion ga p. Th e
a n io n g a p is a ca lcu la t ion of t h e m a jor m ea su r ed
ca t ion s a n d a n ion s in t h e pla sm a , pr ovidin g a n in -
dica t ion of a cid–ba se ba la n ce. Th e clin ica l ca lcu la -
t ion of a n ion ga p u ses sodiu m (m a jor m ea su r a ble
ca t ion ), ch lor ide, a n d bica r bon a t e (m a jor m ea su r-
a ble a n ion s), a n d it r eflect s t h e differ en ce bet ween
t h e u n m ea su r a ble a n ion s, in clu din g ph osph a t es,
su lfa t es, or ga n ic a cids, a n d pr ot ein s. Th e differ en ce
in t h e con cen t r a t ion s of t h e ca t ion sodiu m (140
m E q/L) a n d t h e a n ion s ch lor ide (102 m E q/L) a n d bi-
ca r bon a t e (26 m E q/L) in t h e blood is kn own a s t h e
a n ion ga p. In ot h er wor ds, Na + − (Cl − + H CO 3 −) =
140 m E q/L − (102 m E q/L + 26 m E q/L) = a n ion ga p
(Fig. 9.1). Th er efor e, t h e a n ion ga p is 12 m E q/L, wit h
a va r ia t ion of 2 m E q/L, wh ich r esu lt s in a n or m a l
r a n ge of 10 t o 14 m E q/L. Th e a n ion ga p ser ves a s
a m ea su r em en t of a cid–ba se ba la n ce. Occa sion a lly,
ot h er elect r olyt es m a y be con sider ed, r esu lt in g in a
differ en t r efer en ce r a n ge dist in gu ish in g a n or m a l
fr om a n a bn or m a l va lu e. An exa m ple of t h is va r ia -
t ion in clu des t h e a ddit ion of t h e ca t ion pot a ssiu m t o
sodiu m , wh ich ch a n ges t h e a n ion ga p t o 16 m E q/L
(r a n ge 14 t o 18 m E q/L).
BUFFER SYSTEMS
Th e ba la n ce of pH in volves b u e r s y s t e m s (m ix-
in g of a cid a n d ba se t o r esist pH ch a n ge), wh ich a r e
r espon sible for t r a din g st r on ger a cids a n d ba ses for
i
B
Figure 9.1. Anion gap. Excess organic acids replace
bicarbonate in metabolic acidosis with increased anion
gap. Rise in chloride is offset by decline in bicarbonate
in hyperchloremic acidosis with normal anion gap.
wea ker va r iet ies. Acid–ba se ba la n ce is r egu la t ed by
t h e a ct ion s of bu ffer syst em s, wor kin g t oget h er t o r e-
spon d t o con dit ion s t h r ea t en in g a cid–ba se ba la n ce.
Th e on set of a ct ion in ea ch syst em va r ies, lea din g
t o r a pid r espon ses t o cor r ect a cu t e in su lt s, followed
by m or e pr olon ged cor r ect ion via a slower on set of
a ct ion . Th ese bu ffer syst em s in clu de:
1. P la s m a b u e r s y s t e m : r ea ct s wit h in secon ds in
r espon se t o h ydr ogen ion con cen t r a t ion
2. R e s p ir a t o r y b u e r s y s t e m : r ea ct s wit h in m in -
u t es t o excr et e CO 2 t h r ou gh ch a n ge in r espir a t or y
rate
3. R e n a l b u e r s y s t e m : r ea ct s wit h in h ou r s t o
da ys t h r ou gh t h e pr odu ct ion , a bsor pt ion , a n d ex-
cr et ion of a cids, ba ses, a n d ion s
Plasma Buffer Systems
P la sm a bu ffer syst em s depen d on r a pid r espon ses
of ch em ica l syst em s in t h e ext r a cellu la r a n d in t r a -
cellu la r com pa r t m en t s. Th e pr im a r y pla sm a bu ffer
syst em s in clu de t h e bica r bon a t e a n d pr ot ein bu ffer
syst em s a n d t h e H + /K + ca t ion exch a n ge syst em .
Th e bu ffer in g of fr ee h ydr ogen ion s is cen t r a l t o t h e
effect iven ess of ea ch of t h e pla sm a bu ffer syst em s.
H ydr ogen ion ca n be in cor por a t ed in t o su bst a n ces,
wh ich r edu ces t h e a m ou n t of fr eely cir cu la t in g H + .
Con ver sely, h ydr ogen ion ca n be r elea sed fr om su b-
st a n ces t o in cr ea se t h e a m ou n t of fr ee H + cir cu la t -
in g in t h e blood. In t h is wa y, ch a n ges in pH ca n be
a ddr essed in a r a pid wa y by sim ply r egu la t in g t h e
a m ou n t of fr ee H + in t h e blood. On e of t h e pr im a r y
220 C h a p t e r 9: Alt er ed Acid–Ba se Ba la n ce
ch em ica l r ea ct ion s t h a t r egu la t e t h ese pr ocesses
in volves wa t er, ca r bon dioxide, ca r bon ic a cid, a n d
bica r bon a t e. Th e ch em ica l a lt er a t ion of wa t er a n d
ca r bon dioxide is ca t a lyzed by t h e en zym e ca r bon ic
a n h ydr a se, pr esen t in m a n y body cells. Th e r ea ct ion
is r ever sible a n d r a pid, pr om ot in g im m edia t e r e-
spon ses t o la r ge ch a n ges in pH .
H 2 O + CO 2 ↔ H 2 CO 3 ↔ H + + H CO 3 −
Th e im m edia t e r espon ses of t h ese syst em s pr ot ect
a ga in st m a jor sh ift s in pH u n t il t h e r espir a t or y a n d
r en a l bu ffer syst em s a r e a ct iva t ed.
Bicarbonate Buffer System
Th e bica r bon a t e bu ffer syst em is t h e pr im a r y ext r a -
cellu la r bu ffer. Th e wea k a cid H 2 CO 3 a n d t h e wea k
ba se sodiu m bica r bon a t e (Na H CO 3 ) a r e t h e pr im a r y
su bst a n ces in volved in t h e bica r bon a t e bu ffer sys-
t em (F ig. 9.2). Th e bica r bon a t e bu ffer syst em m a kes
CO 2 a va ila ble, wh ich ca n r epla ce H CO 3 − lost a s a r e-
su lt of a dded ba se or elim in a t ed wit h t h e a ddit ion
of a cid.
Protein Buffer System
The pr ot ein bu ffer syst em r esponds t o t he
m om ent -t o-m om ent cha nges t o r et a in pH in t he
n a r r ow r a n ge necessa r y for opt im a l cell fu nct ion .
P r ot ein s ser ve a s t he la r gest bu ffer ing syst em . The
pr ot ein bu ffer syst em involves int r a cellula r pr ot ein s
a nd t he pr ot ein s a lbu m in a n d pla sm a globulins in t h e
va scu la r com pa r t m ent . Able t o fun ct ion as eit her a cid
or ba se, pr ot eins a r e r efer r ed t o a s a m p h ot e r ic . The
pr ot ein bu ffer s ca n bot h a ccept or don a t e H + ion s. The
H + a nd CO 2 ions t h a t a r e r elea sed beca use of t h ese r e-
a ct ion s ca n th en fr eely diffuse a cr oss cell m em br a nes.
Potassium–Hydrogen Exchange
Ion ic exch a n ge of t h e pot a ssiu m (K + ) a n d h ydr ogen
(H + ) ca t ion s con t r ibu t es t o r egu la t ion of a cid–ba se
ba la n ce. E xcess H + in t h e ext r a cellu la r com pa r t m en t
ca n diffu se a cr oss t h e cell m em br a n e in side t h e cell
for bu ffer in g. Th e en t r y of H + pr om pt s t h e exit of
A. HCL + Na HCO 3 H2 CO 3 + Na Cl
B. Na OH + H2 CO 3 Na HCO 3 + H2 O
Figure 9.2. Bicarbonate buffer systems. A: The strong
acid HCl is substituted for the weaker acid H2CO3 through
a reaction with the weak base NaHCO3. B: The strong base
sodium hydroxide (NaOH) is substituted for the weak base
NaHCO3 through a reaction with the weak acid H2CO3.
K + fr om wit h in t h e cell t o t h e ext r a cellu la r spa ce,
pot en t ia lly r esu lt in g in h yper ka lem ia . Con ver sely, if
t h e ext r a cellu la r level of K + fa lls, a s in t h e ca se of
h ypoka lem ia , K + t h en m oves ou t of t h e cell in pa r a l-
lel wit h H + en t r y in t o t h e cell, decr ea sin g ext r a cel-
lu la r con cen t r a t ion s of H + , t h er eby in cr ea sin g pH .
Th e r egu la t ion of a cid–ba se a n d elect r olyt e ba la n ce
is closely t ied in a n effor t t o m a in t a in h om eost a sis.
Respiratory Buffer System
Th e r espir a t or y bu ffer syst em is t h e secon d syst em
t h a t r espon ds t o ch a n ges in pH , con t r ibu t in g t o r eg-
u la t ion of CO 2 . H 2 CO 3 is a n a cid t h a t is est im a t ed by
blood levels of dissolved ca r bon dioxide (CO 2 ). CO 2
in ga s for m is con sider ed v o la t ile beca u se it ca n be
excr et ed by t h e lu n gs. Beca u se CO 2 is excr et ed by
t h e lu n gs, r espir a t or y fu n ct ion con t r ibu t es t o H 2 CO 3
levels. Wh en pH levels fa ll (a cidosis), in cr ea sed r e-
spir a t or y r a t e in cr ea ses excr et ion of CO 2 a n d low-
er s H 2 CO 3 levels, pr om ot in g r est or a t ion of a cid–ba se
ba la n ce. In t h e ca se of a n in cr ea se in pH (a lka losis),
r edu ced r espir a t or y r a t e pr om ot es r et en t ion of CO 2 ,
in cr ea sin g H 2 CO 3 levels. Th e r espir a t or y bu ffer sys-
t em is im por t a n t in com pen sa t ion for a lt er a t ion s in
a cid–ba se ba la n ce bu t is u n a ble t o com plet ely r e-
st or e h om eost a t ic pH . Respir a t or y com pen sa t ion is
essen t ia l t o pr ovide t h e a ddit ion a l t im e n eeded for
r en a l cor r ect ion of a cid–ba se im ba la n ces.
Renal Buffer System
Th e kidn eys a r e t h e pr im a r y r egu la t or s of t h e ba l-
a n ce bet ween a cids a n d ba ses. Cir cu la t in g fixed a cids
a r e con sider ed n o n v o la t ile beca u se t h ey a r e u n a ble
t o be excr et ed by t h e lu n gs a n d r equ ir e bu ffer in g
a n d excr et ion by t h e kidn eys. Ren a l r egu la t ion of pH
is a ccom plish ed t h r ou gh gen er a t in g, bu ffer in g, a n d
elim in a t in g a cids a n d ba ses. Th e m a in m ech a n ism s
of r en a l r egu la t ion of pH in clu de h ydr ogen ion elim i-
n a t ion /bica r bon a t e con ser va t ion , t u bu la r bu ffer sys-
t em s (ph osph a t e, a m m on ia ), pot a ssiu m – h ydr ogen
exch a n ge, a n d ch lor ide–bica r bon a t e exch a n ge.
Hydrogen Ion Eliminat ion/ Bicarbonat e Conservat ion
E xcr et ion of excess H + pr om ot es r egu la t ion of pH .
Wh en pH is low, excess H + ion s a r e secr et ed fr om
t h e blood in t o t h e r en a l t u bu la r filt r a t e wh er e t h ey
ca n u lt im a t ely be excr et ed in t h e u r in e. Th e k idn ey
ca n r egu la t e H CO 3 − , con ser vin g it wh en excess a cid
is a dded a n d excr et in g it in t h e pr esen ce of excess
ba se. Th e kidn eys con t r ibu t e t o pla sm a r egu la t ion
of H CO 3 − by t h e r ea bsor pt ion of H CO 3 − fr om t h e
u r in e in t o t h e bloodst r ea m , or by t h e elim in a t ion
of bu ffer ed h ydr ogen ion s. Rea bsor pt ion of ba sic
bica r bon a t e ion s is a m on g t h e wa ys t h e k idn eys
wor k t o obt a in a pH bet ween 7.35 a n d 7.45, t h er eby
pr om ot in g opt im a l cellu la r fu n ct ion in g. A pH of

7.4 r equ ir es a 20:1 r a t io of bica r bon a t e (H CO 3 −)
ba se t o ca r bon ic a cid (H 2 CO 3 ). Ra t h er t h a n t h e a b-
solu t e con cen t r a t ion of a su bst a n ce, t h e r a t io of su b-
st a n ces pr ovides t h e ba la n ce, wh ich ser ves a s t h e
det er m in a n t of pH .
Tubular Buffer Systems
Th e t ubu le st r u ct u r es of t he kidney a r e pr ot ect ed by
t h e r egu la t ion of u r in e pH . Int r a t u bu la r buffer s bin d
u n bu ffer ed H + t o m a in t a in loca l pH for kidn ey cell
fun ct ion . Th e phospha t e bu ffer syst em u ses H P O 4 2−
t o bind H + , r esu lt in g in H 2 P O 4 −, a llowin g t h e kidn ey
t o secr et e H + ion s. Th e a m m onia bu ffer syst em pr o-
m ot es excr et ion of H + a n d gen er a t es H CO 3 − in a se-
r ies of ion exch a n ges bet ween a m m on iu m (NH 4 + ) a n d
H CO 3 −. Th e secr et ed H + ion s com bin e wit h a m m on ia
(NH 3 ) a n d a r e t hen elim in a t ed in t h e ur in e a s NH 4 Cl.
Potassium–Hydrogen Exchange
Ca t ion exch a n ge of K + a n d H + occu r s in t h e r en a l t u -
bu la r cells in a sim ila r m a n n er descr ibed in t h e dis-
cu ssion of pla sm a bu ffer in g syst em s. H ypoka lem ia
pr om ot es m ovem en t of K + ou t of t h e t u bu la r cells in
exch a n ge for H + m ovem en t in t o t h e cells, pr om ot in g
loss of cir cu la t in g H + a n d in cr ea se in pH . A lower-
in g of pH occu r s in h yper ka lem ia , wh en K + m oves
in t o t h e t u bu la r cells in exch a n ge for H + , lea din g t o
a n in cr ea se in cir cu la t in g H + . Th e ca t ion exch a n ge
bet ween H + a n d K + is t igh t ly a lign ed wit h ch a n ges
in pH , wit h a cidosis pr om ot in g a n in cr ea se in H +
excr et ion a n d decr ea se in K + excr et ion wh ile a lka -
losis pr om ot es a decr ea se in elim in a t ion of H + a n d
in cr ea se in elim in a t ion of K + .
Chloride–Bicarbonate Exchange
Ren a l r egu la t ion of H CO 3 − ca n a lso be a ccom plish ed
by a n ion exch a n ge wit h Cl − Ch lor ide t ypica lly is a b-
sor bed a lon g wit h sodiu m in t h e r en a l t u bu le cells.
Un der cer t a in con dit ion s in clu din g volu m e deple-
t ion du e t o vom it in g a n d ot h er ca u ses of ch lor ide
loss, a n ion exch a n ge bet ween H CO 3 − a n d Cl − occu r s.
An ion exch a n ge bet ween H CO 3 − a n d Cl − ca n lea d t o
a lt er a t ion s in a cid–ba se ba la n ce beca u se of m a n ipu -
la t ion of H CO 3 −. In h ypoch lor em ia a lka losis, a n ex-
cess H CO 3 − r esu lt s fr om in cr ea sed r ea bsor pt ion of
H CO 3 − fr om t h e filt r a t e t o t h e blood du e t o low cir cu -
la t in g Cl − levels, in cr ea sin g pH . A decr ea se in pH is
t h e r esu lt of r edu ced H CO 3 − r ea bsor pt ion du e t o a n
in cr ea se in cir cu la t in g Cl− levels, kn own a s h yper-
ch lor em ic a cidosis. Beca u se t h e ch a n ge in H CO 3 − is
offset by t h e ch a n ge in Cl −, t h e a n ion ga p is n or m a l
in h yper ch lor em ic a cidosis (Fig. 9.1).
Stop and Consider
What other organ systems are important in the
regulation of fluid, electrolyte, and acid–base
balance?
Ac id –B a s e I m b a la n c e 221
Altered Acid–Base Balance
Acid a n d ba se disor der s ca n be r espir a t or y or m et -
a bolic in or igin . Respir a t or y a cidosis is descr ibed in
det a il in Ch a pt er 15. Th is ch a pt er focu ses on m et -
a bolic a lt er a t ion s in a cid–ba se ba la n ce. Met a bolic
disor der s r esu lt in a n a lt er a t ion in H CO 3 − ca u sed by
t h e a ddit ion or loss of n on vola t ile a cid or ba se in t h e
ext r a cellu la r flu id. Met a bolic a cidosis r esu lt s in a
r edu ct ion of H CO 3 −, pr om pt in g a decr ea se in ph . In -
cr ea sed levels of H CO 3 − r esu lt in a n in cr ea se of pH ,
kn own a s m et a bolic a lka losis. In it ia t in g even t s t h a t
ca u se a lt er ed H CO 3 − levels t r igger com pen sa t or y
m ech a n ism s t o m a in t a in a cid–ba se ba la n ce. Kid-
n eys com pen sa t e efficien t ly by con ser vin g H CO 3 − or
H + ion s u n t il t h e pH h a s r et u r n ed t o n or m a l. Th ese
com pen sa t or y m ech a n ism s a dju st pH wit h ou t a l-
t er in g u n der lyin g ca u se. Ar t er ia l blood ga s (ABG)
a n a lysis is t h e la b t est u sed t o det er m in e a cid–ba se
ba la n ce. An ion ga p, ba se excess or deficit , CO 2 a n d
H CO 3 − levels, a n d pH ca n be m ea su r ed in a n a r t er ia l
blood sa m ple. Th ese va r ia bles n ot on ly det er m in e
ba la n ce bu t poin t t o ca u ses t h a t m igh t r esu lt in a l-
t er ed ba la n ce. Ba se excess or deficit r epr esen t s t h e
a m ou n t of fixed a cid or ba se n eeded t o a ch ieve a pH
of 7.4 in t h e blood sa m ple.
METABOLIC ACIDOSIS
A ba se deficit of H CO 3 − ch a r a ct er izes m et a bolic a ci-
dosis. Met a bolic a cidosis m a y occu r secon da r y t o a n
in cr ea se in st r on g a n ion s (Cl −) or t o a n in cr ea se in
wea k a cids. Th e levels of cir cu la t in g a lbu m in m u st
a lso be con sider ed wh en det er m in in g t h e pr esen ce of
m et a bolic a cidosis. H ypoa lbu m in em ia m a y m a sk t h e
pr esen ce of m et a bolic a cidosis ca u sed by a n a lka liz-
in g effect .2 Mech a n ism s con t r ibu t in g t o t h e develop-
m en t of m et a bolic a cidosis in clu de:
● In cr ea sed pr odu ct ion of n on vola t ile a cids; ca u sed
by fa st in g, ket oa cidosis, a n d la ct ic a cidosis
● Decr ea sed secr et ion of a cids by t h e kidn eys; lea ds
t o r en a l fa ilu r e
● In cr ea sed loss of bica r bon a t e; ca u sed by dia r r h ea ,
ga st r oin t est in a l su ct ion
● In cr ea se in Cl −; ca u sed by excessive ch lor ide r ea b-
sor pt ion in t h e kidn ey, sodiu m ch lor ide in fu sion
Th e clin ica l m a n ifest a t ion s of m et a bolic a cidosis
in clu de a n or exia , n a u sea , vom it in g, wea kn ess, let h -
a r gy, con fu sion , com a , va sodila t ion , decr ea sed h ea r t
r a t e, a n d flu sh ed skin . La bor a t or y fin din gs in clu de
decr ea sed pH (less t h a n 7.35) a n d H CO 3 − less t h a n 24
m E q/L. Th e a n ion ga p m a y in cr ea se wh en t h e ca u se
of t h e m et a bolic a cidosis is du e t o excess m et a bolic
a cids. Wh en a cidosis is ca u sed by in cr ea sed ch lo-
r ide, t h e a n ion ga p r em a in s n or m a l. Com pen sa t or y
222 C h a p t e r 9: Alt er ed Acid–Ba se Ba la n ce

m ech a n ism s in m et a bolic a cidosis in clu de in cr ea sed Im pa ir ed excr et ion of excess H CO 3 − m a y be pr o-

br ea t h in g r a t e a n d dept h , h yper ka lem ia , a n d in -
cr ea sed a m m on ia in u r in e. Tr ea t m en t is a im ed t o
cor r ect t h e pr im a r y ca u se of m et a bolic a cidosis, r e-
pla ce flu id a n d elect r olyt es, a n d cor r ect t h e pH .
METABOLIC ALKALOSIS
In cr ea sed pH ca used by pla sm a excess of H CO 3 − ch a r-
a ct er izes m et a bolic a lka losis. Mech a n ism s cont r ibut -
ing t o t h e developm en t of m et a bolic a lka losis in clu de:
● Decr ea sed H + ion s
● In cr ea sed H CO 3 − ion s
● Loss of Cl − ion s
m ot ed by con t r a ct ion of ext r a cellu la r flu id volu m e,
h ypoka lem ia , a n d h ypoch lor em ia . Clin ica l m a n ifes-
t a t ion s of m et a bolic a lka losis by be a sym pt om a t ic
or h a ve sign s r ela t ed t o ext r a cellu la r volu m e deple-
t ion , or h ypoka lem ia . La bor a t or y fin din gs in clu de
in cr ea sed pH (gr ea t er t h a n 7.45) a n d H CO 3 − gr ea t er
t h a n 31 m E q/L. Tr ea t m en t of t h e u n der lyin g ca u se
is a pr im a r y t a r get of t h er a py, in a ddit ion t o cor r ec-
t ion of ch lor ide deficit (if pr esen t ) a n d cir cu la t in g po-
t a ssiu m in a ddit ion t o volu m e r epla cem en t .
Stop and Consider
Why can excessive, prolonged vomiting promote
the development of metabolic alkalosis?

Modu le 2 C lin ic a l Mo d e ls

Th e clin ica l m odels pr esen t ed in t h is ch a pt er in cor- Altered Acid–Base Balance: Highly

por a t e t h e con cept s of a lt er ed a cid–ba se ba la n ce.
Th e clin ica l m odels will h igh ligh t con cept s of flu id
a n d elect r olyt e ba la n ce cover ed in Ch a pt er 8 a s t h ey
a r e in t r ica t ely r ela t ed t o a cid–ba se ba la n ce. Wh en
r eviewin g t h e clin ica l m odels, t h e st u den t sh ou ld
a pply t h e con cept s h e or sh e h a s lea r n ed a bou t t h e
a lt er a t ion s in flu id, elect r olyt e a n d a cid–ba se ba l-
a n ce in t h e a pplica t ion t o clin ica l m odels t h a t illu s-
t r a t e t h ese con cept s. An over view of t h e r ela t ion sh ip
bet ween flu id, elect r olyt e, a n d a cid–ba se ba la n ce is
sh own in F igu r e 9.3.
Active Antiretroviral Therapy
(HAART)-Associated Acidosis
As discu ssed in Ch a pt er 4, t h e t r ea t m en t of H IV
h a s been effect ive in pr olon gin g life a n d decr ea sin g
t h e in ciden ce a n d sever it y of m a n y H IV-a ssocia t ed
pa t h ologies. Alt h ou gh H IV t r ea t m en t s h a ve im -
pr oved ou t com es, t h er e a r e kn own dr u g-r ela t ed a d-
ver se effect s. Th e u se of n u cleoside-a n a log r ever se
t r a n scr ipt a se in h ibit or s (N RTIs) for t h e t r ea t m en t

Fluid Vas c ular s pac e

Hydros ta tic force s

Intrac e llular Extrac e llular Os motic pre s s ure
c o mpartme nt c o mpartme nt
Inte rs titium
Na +
Acidos is
K+
Acids
5
.3

Mg +
7
<

P la s ma
m
r
Ca 2+
e
e
Re s pira tory
f
pH
f
t
u
ys
B
Re na l
s
Cl
>
7
.4

P hos Ba s e s
5

HCO 3 Alka los is

Move me nt
Diffus ion Os mos is Fa cilita te d Active
diffus ion tra ns port

Figure 9.3. Concept map. Fluid, electrolyte, and acid–base balance.

 C lin ic a l Mo d e ls 223

of H IV h a s im pr oved m or bidit y a n d m or t a lit y sig- liver ), eleva t ed liver en zym es, a n d h epa t ic fa ilu r e,
n ifica n t ly. As m or e in fect ed in dividu a ls t a ke N RTIs is oft en a ssocia t ed wit h LAS. LAS m a y pot en t ia lly
a n d a r e on t h em for lon ger per iods, som e sign ifi- r esu lt in com a a n d m u lt ior ga n fa ilu r e.
ca n t a dver se dr u g effect s a r e bein g u n cover ed.
Am on g t h em is t h e developm en t of h y p e r la c t a t e -
DIAGNOSTIC CRITERIA
m ia , or a n eleva t ion of la ct ic a cid in t h e blood.
Ma n y in dividu a ls wh o develop h yper la ct a t em ia , E a r ly r ecogn it ion a n d t r ea t m en t of h yper la ct a t e-
a lso kn own a s la c t i c a c id e m ia , a r e n ot sym pt om - m ia in H IV-in fect ed in dividu a ls t a kin g NRTIs a r e
a t ic, a n d t h ey exper ien ce su bclin ica l episodes t h a t cr it ica l fa ct or s in decr ea sin g m or bidit y a n d m or t a l-
a r e self-lim it in g. Ot h er in dividu a ls su ffer fr om a it y beca u se of t h is a dver se dr u g effect . Th e clin ica l
life-t h r ea t en in g for m of m et a bolic a cidosis kn own m a n ifest a t ion s a n d la bor a t or y det er m in a t ion of t h e
a s la c t ic a c id o s i s t h a t r esu lt s fr om h yper la ct a t e- a m ou n t of la ct a t e in t h e blood a ssist in t h e dia gn o-
m ia , 3 a r a r e, bu t ser iou s, com plica t ion of NRTI u se. sis a n d for m t h e ba sis of t r ea t m en t st r a t egies. Liver
Asym pt om a t ic la ct ic a cidem ia a ssocia t ed wit h ele- fu n ct ion t est s m a y be com plet ed t o iden t ify h epa t ic
va t ed la ct a t e levels a n d n or m a l pH a ffect s a ppr oxi- dysfu n ct ion . E lect r olyt e a n d blood pH levels m a y
m a t ely 8% t o 21% of in dividu a ls t a kin g a t lea st on e a lso be a n a lyzed.
N RTI, wit h la ct ic a cidosis occu r r in g in a bou t 1.5%
t o 2.5%. 4
TREATMENT
Su bclin ica l h yper la ct a t em ia r equ ir es n o t r ea t m en t .
PATHOPHYSIOLOGY
Th is con dit ion is u su a lly t r a n sien t a n d r esolves
In h ibit ion of t h e en zym e DNA polym er a se by NR- wit h ou t in t er ven t ion . Dr u g select ion m a y in flu en ce
TIs m a y lea d t o m it och on dr ia l dysfu n ct ion a n d is t h e developm en t of h yper la ct a t em ia ; cer t a in dr u gs
believed t o be r espon sible for t h e developm en t of h y- deplet e m it och on dr ia l DNA m or e t h a n ot h er s. NRTI
per la ct a t em ia . Loss of m it och on dr ia l DNA pr even t s t r ea t m en t m a y be st opped or a lt er ed in in dividu a ls
pr odu ct ion of t h e n ecessa r y com pon en t s of t h e elec- wh o develop sym pt om s of h yper la ct a t em ia , bu t h a ve
t r on t r a n spor t ch a in in t h e m it och on dr ia . Oxida t ive n ot developed m et a bolic a cidosis, in a n a t t em pt t o
ph osph or yla t ion is im pa ir ed, pr om ot in g t h e for m a - pr even t t h e developm en t of LAS. NRTI t r ea t m en t is
t ion of la ct ic a cid for u se by t h e cells for en er gy. Th e st opped in in dividu a ls wit h LAS, a lt h ou gh r ecover y
bu ildu p of la ct ic a cid in t h e blood r edu ces pH a n d ca n n ot be a ssu r ed. In t r a ven ou s a dm in ist r a t ion of
pr edisposes a ffect ed in dividu a ls t o developin g la ct ic flu ids ca n be u sed t o expa n d in t r a va scu la r volu m e,
a cidosis. pr even t ca r diova scu la r colla pse, a n d pr om ot e r en a l
clea r a n ce of la ct a t e. A per iod of weeks m a y be n eeded
befor e la ct a t e levels r et u r n t o n or m a l. Resolu t ion of
CLINICAL MANIFESTATIONS
LAS is con fir m ed by:
Sym pt om s a r e r ela t ed t o t h e sever it y of t h e m et -
● Nor m a liza t ion of sodiu m bica r bon a t e
a bolic a cidosis developin g fr om h yper la ct a t em ia .
● Nor m a liza t ion of pH
Most in dividu a ls wit h h yper la ct a t em ia a r e a s-
● Ser u m la ct a t e of less t h a n 3.0 m m ol/L
ym pt om a t ic a n d do n ot dem on st r a t e a n y clin ica l
● Nor m a liza t ion of liver fu n ct ion
m a n ifest a t ion s. 4 Mild h y-
per la ct a t em ia ca n in du ce
sym pt om s su ch a s n a u - R E S E AR C H N O T E S
sea , vom it in g, a bdom in a l
discom for t , a n d weigh t The influence of mitochondrial DNA depletion and increases in serum lactate levels vary
loss. H e p a t ic s t e a t o s is among different NRTIs. A study was done on patients taking NRTIs to determine the ori-
(fa t t y liver ) is oft en a sso- gin of hyperlactatemia. Blood samples were taken to determine serum lactate levels, and
cia t ed wit h sym pt om a t ic mitochondrial DNA concentrations were determined from liver biopsy samples. Depletion
h yper la ct a t em ia , r esu lt - of mitochondrial DNA was increased by 47% in individuals taking the NRTIs zalcitabine,
in g fr om NRTI-st im u la t ed didanosine, and stavudine when compared to patients taking zidovudine, lamivudine, and
fa t deposit ion in t h e liver. abacavir. Increased lactate levels were also associated with the use of the drugs, which
Sever e h yper la ct a t em ia depleted mitochondrial DNA at a higher rate. 6F
is t h e disea se su bt ype
a ssocia t ed wit h a for m of
m et a bolic a cidosis kn own
a s la ct ic a cidosis syn dr om e (LAS). La ct ic a cidosis Stop and Consider
is a ssocia t ed wit h pH levels of less t h a n 7.3.5 Liver How is lactic acidosis different from other types
in volvem en t , in clu din g h e p a t o m e g a ly (en la r ged of metabolic acidosis?
224 C h a p t e r 9: Alt er ed Acid–Ba se Ba la n ce

Altered Acid–Base Balance: a lso be excr et ed, r esu lt in g in h ypoka lem ia . E xces-
sive loss of t h e st r on g ca t ion s sodiu m a n d pot a ssiu m
Renal Tubulopathy lea d t o t h e developm en t of m et a bolic a lka losis.

H ypoka lem ic sa lt -losin g t u bu lopa t h ies (SLTs) a r e a

gr ou p of a u t osom a l r ecessive disor der s ch a r a ct er ized
by m et a bolic a lka losis. Ma n y of t h e sa m e ph ysiologic
a bn or m a lit ies a r e com m on bet ween t h e gr ou ps, a l-
t h ou gh t h e a ge of on set va r ies bet ween con dit ion s.
Fou r va r ia n t s of t h is disor der a r e kn own :
1. Cla ssic Ba r t t er syn dr om e (cBS)
2. Git elm a n syn dr om e (GS)
3. H yper pr ost a gla n din -E syn dr om e (H P S), a lso
kn own a s a n t en a t a l Ba r t t er syn dr om e (a BS)
4. H yper pr ost a gla n din -E syn dr om e wit h sen sor i-
n eu r a l dea fn ess (H P S + SND)
Ba r t t er a n d Git elm a n syn dr om es a r e ch a r a ct er ized
by h ypoka lem ia a n d h ypoch lor em ic m et a bolic a lka -
losis.7 Th e pr eva len ce of Ba r t t er syn dr om e wor ld-
wide is n ot cu r r en t ly kn own . St u dies h a ve been
con du ct ed in Au st r a lia , E u r ope, t h e Middle E a st ,
a n d t h e Un it ed St a t es. A st u dy of pa t ien t s in Cost a
Rica r evea led a h igh fr equ en cy of Ba r t t er syn dr om e
(1.2 ca ses per 100,000 live bir t h s). Th e in ciden ce of
Ba r t t er syn dr om e is est im a t ed t o be 25.4 ca ses per
100,000 in pr et er m bir t h s. 8
CLINICAL MANIFESTATIONS
Manifesta tion of HPS occurs in utero; neonates pres-
ent with severe effects. The initial ma nifestation is ma-
ternal hydramnios (excessive a mniotic fluid) because
of increased fetal urine output. Bartter syndrome and
Gitelma n syndrome often present in early infa ncy
through childhood a nd adolescence. The neonatal
(first 28 days of life) course is complica ted by polyuria
(excessive urine output), hypercalciuria (excessive
calcium excreted in urine), and a ffects from increased
levels of prostaglandin, including fever, vomiting, and
diarrhea, further contributing to altered fluid and
electrolyte balance.10
Met a bolic a lka losis is a ssocia t ed wit h con t r a ct ed
ext r a cellu la r flu id volu m e beca u se of sodiu m ch lo-
r ide loss. Th is decr ea sed in t r a va scu la r volu m e lim it s
t h e spa ce for dist r ibu t ion of bica r bon a t e, a m plifyin g
t h e h yper bica r bon a t em ia . Sodiu m ch lor ide loss a lso
con t r ibu t es pot a ssiu m loss a n d in cr ea sed r en a l r e-
a bsor pt ion of bica r bon a t e, fu r t h er in cr ea sin g blood
pH a n d wor sen in g m et a bolic a lka losis. 11

PATHOPHYSIOLOGY
In SLTs, elect r olyt e r ea bsor pt ion in t h e r en a l t u -
bu les is im pa ir ed beca u se of a gen e defect a lt er in g
five r en a l m em br a n e pr ot ein s. Th e effect s a r e r e-
la t ed t o specific pr ot ein a lt er a t ion s ch a r a ct er ist ic of
ea ch con dit ion a n d h a ve been liken ed t o t h e effect s
of diu r et ics.9 Th e cBS a n d H P S syn dr om es m a n ifest
a lt er a t ion s sim ila r t o t h ose in du ced by t h e loop di-
u r et ics, in h ibit in g r ea bsor pt ion of sodiu m a n d ch lo-
r ide in t h e loop of H en le. GS-a ssocia t ed elect r olyt e
a lt er a t ion s m im ic t h ose in du ced by t h ia zide diu r et -
ics, blockin g sodiu m r ea bsor pt ion in t h e dist a l r en a l
t u bu le. In h ibit ion of sodiu m r ea bsor pt ion is desir-
a ble beca u se excr et ion of sodiu m in t h e u r in e is a c-
com pa n ied by t h e excr et ion of wa t er. Pot a ssiu m m a y
DIAGNOSTIC CRITERIA
Ren a l st r u ct u r es ca n be eva lu a t ed wit h u lt r a sou n d.
Det er m in a t ion of elect r olyt e a n d flu id im ba la n ces
ca n be eva lu a t ed by m ea su r em en t s of elect r olyt es in
ser u m a n d u r in e. ABGs, a n ion ga p, a n d ba se excess
m ea su r es ca n be u sed t o det er m in e t h e pr esen ce of
m et a bolic a lka losis a n d t o gu ide t r ea t m en t st r a t egies.
F lu id ba la n ce m ay be det er m in ed by u r in e-specific
gr a vit y m ea su r em en t . La bor a t or y eva lu a t ion s t o
det ect r en a l fa ilu r e (discu ssed in m or e det a il in
Ch a pt er 18) a r e don e ser ia lly in t h ese ch r on ic con di-
t ion s. In fa m ilies wit h kn own r isk for t h ese disor der s,
DNA t est in g for t h e gen et ic defect loca t ed on ch r o-
m osom e n u m ber 1 ca n be a ccom plish ed on a m n iot ic
flu id in t h e a n t en a t a l per iod or fr om a cell sa m ple
t a ken dir ect ly fr om t h e n eon a t e a ft er bir t h .

TREATMENT
F R O M T H E L AB
Tr ea t m ent st r a t egies a r e
As in evaluation of ascites, urinary sodium concentration can be used to provide a measure- focused on t he cor r ect ion of
ment of renal sodium retention. In patients with dehydration, urine sodium concentrations r en a l sa lt a nd fluid losses.
help determine etiology. Urinary sodium concentrations of less than 20 mEq/ L indicate a Sodiu m a nd pota ssium
nonrenal cause of fluid loss, such as ascites, vomiting, or diarrhea. Hypovolemia associated supplem ent s a r e used t o
with urinary sodium concentration of more than 20 mEq/ L indicates fluid loss of renal or- cor r ect hypona tr em ia a nd
igin. Fluid loss of renal origin may be caused by drugs such as thiazide diuretics because h ypoka lem ia . Diur etics
they alter urine concentration. Renal causes of hypovolemia can also include excessive salt t ha t spa r e pot a ssium ex-
loss because of renal failure. cr et ion, in cluding spir ono-
la ct on e a nd a m ilor ide, m ay
 C lin ic a l Mo d e ls 225

a lso be u sed. Indom et ha -

cin , a prost a gla ndin in hib-
it or, m ay be used t o reduce
pr ost a gla n din pr oduction .
Ca lcium a nd m a gnesium
supplem ent s m ay a lso be
u sed t o cor r ect hypoca lce-
m ia a nd hypom a gnesemia .
R E S E AR C H N O T E S
Salt transport depends on the recycling of potassium in the thick ascending limb of the
loop of Henle. The genetic alterations associated with Bartter syndrome contribute to the
loss of potassium channel secretory activity, accounting for the alteration in electrolytes
characteristic of the syndrome. 12

Stop and Consider elect r olyt es, a cet a t e, a n d t r a ce elem en t s t h r ou gh t h e

Why are potassium-sparing diuretics the pre-
ferred treatment of fluid and electrolyte imbal-
ances associated with Bartter syndrome?
Altered Acid–Base Balance: Metabolic
Acidosis in Parenteral Nutrition
Pa r en t er a l n u t r it ion is a n exa m ple of su pplem en t a l
n u t r it ion t h a t bypa sses t ypica l pr ocesses of ea t in g
a n d digest ion (Fig. 9.4). Alt er a t ion s in t h e a bilit y for
in dividu a ls t o obt a in or a l n u t r it ion ca n r esu lt fr om
a va r iet y of con dit ion s in clu din g a lt er ed fu n ct ion of
t h e ga st r oin t est in a l t r a ck. In ca ses wh er e in dividu -
a ls a r e u n a ble t o ea t or dr in k, su pplem en t a l n u t r i-
t ion m u st be pr ovided t o deliver y essen t ia l en er gy
a n d n u t r ien t s n ecessa r y for su r viva l. Th e du r a t ion
of pa r en t er a l n u t r it ion is t ypica lly sh or t , t h ou gh
m a y be ext en ded over a lon ger t er m in u n iqu e
cir cu m st a n ces.
PATHOPHYSIOLOGY
Pa r en t er a l n u t r it ion is design ed t o m eet n u t r i-
t ion a l n eeds t h r ou gh t h e deliver y of wa t er, glu cose
or dext r ose, a m in o a cids, lipids, vit a m in s, m in er a ls,
ven ou s syst em . Th e for m u la t ion of pa r en t er a l n u t r i-
t ion is design ed t o m eet t h e u n iqu e n eeds of t h e in -
dividu a l. H ydr och lor ic a n d or ga n ic a cids a r e a dded
t o t h e for m u la t ion of pa r en t er a l n u t r it ion a s t h ey
a r e r equ ir ed for ch em ica l in t er a ct ion bet ween solu -
t ion com pon en t s. Th e solu t ion a cidit y is cou n t er ed
by t h e a ddit ion of ba se t o r ea ch a pH of 7.4 pr ior t o
in fu sion . H ydr och lor ic a cid in fu sed a s a com pon en t
of pa r en t er a l n u t r it ion m a y con t r ibu t e t o in cr ea se
blood ch lor ide levels wit h a sim u lt a n eou s r edu ct ion
in ba se, pr om ot in g con dit ion s t h a t fa vor m et a bolic
a cidosis. Met a bolic a cidosis m a y a lso r esu lt fr om m e-
t a bolism of a m in o a cids, lea din g t o in cr ea sed H + pr o-
du ct ion a n d n eed for bu ffer in g by H CO 3 −. F u r t h er
com plica t in g t h e developm en t of m et a bolic a cidosis
a r e t h e disr u pt ed ca r boh ydr a t e a n d lipid m et a bolic
pa t h wa ys t h a t pr odu ce a cidic bypr odu ct s a n d im -
pa ir ed bu ffer syst em s a m on g sever ely ill pa t ien t s
wh o a r e likely ca n dida t es for pa r en t er a l n u t r it ion .
Wh en t h e in dividu a l’s con dit ion is com plica t ed by
t h ia m in e deficien cy, t h e r isk for m et a bolic a cidosis
is even gr ea t er beca u se of a bu ildu p of la ct ic a cid a s
t h ia m in e is r equ ir ed for la ct ic a cid m et a bolism .13
CLINICAL MANIFESTATIONS
Th e sym pt om s of m et a bolic a cidosis a r e va r ia ble, de-
pen den t in pa r t on t h e sever it y of t h e con dit ion . Typ-
ica l m a n ifest a t ion s of a n or exia , n a u sea , vom it in g,
wea kn ess, let h a r gy, con fu sion , com a , va sodila t ion ,
decr ea sed h ea r t r a t e, a n d flu sh ed skin ca n be m a sked
by t h e u n der lyin g con dit ion , pr om pt in g t h e n eed for
pa r en t er a l n u t r it ion . E xt r em e sym pt om s m ay in -
clu de n eu r ologic m a n ifest a t ion s in clu din g com a a n d
seizu r es a s well a s a lt er a t ion in ca r dia c r h yt h m .

Figure 9.4. Parenteral nutrition. Delivery of intravenous
nutrition, bypassing the gastrointestinal system.
DIAGNOSTIC CRITERIA
As wit h ot h er ca u ses, in dividu a ls wit h m et a bolic
a cidosis secon da r y t o pa r en t er a l n u t r it ion a r e di-
a gn osed t h r ou gh ABG sa m plin g t o det er m in e pH .
Alon g wit h a pH of < 7.35, decr ea sed H CO 3 − levels
a n d possible sign s of r espir a t or y com pen sa t ion (de-
cr ea sed CO 2 ) m a y be a ssocia t ed wit h low pH . E lec-
t r olyt e ba la n ce a n d ca lcu la t ion of a n ion ga p will
pr ovide gr ea t er det a il r ega r din g t h e n a t u r e of t h e
a cidosis.
226 C h a p t e r 9: Alt er ed Acid–Ba se Ba la n ce
TREATMENT
Th e a ppr oa ch t o t r ea t m en t is depen den t on t h e
la bor a t or y a ssessm en t a n d com plica t in g fa ct or s
a ssocia t ed wit h t h e a cidosis. Adju st m en t of pa r-
en t er a l n u t r it ion solu t ion com pon en t s a n d in t a ke
a r e im por t a n t t a r get s t o con sider. Tr ea t m en t wit h
H CO 3 − ba se m a y be n eeded t o cor r ect a ba se deficit .
H ydr a t ion a n d oxygen m a y a lso im pr ove r espon se t o
defin it ive t r ea t m en t of m et a bolic a cidosis.
S U MMAR Y
● Acid–ba se ba la n ce is im por t a n t t o h om eost a sis
a n d cellu la r fu n ct ion .
● Alt er a t ion s in a cid–ba se ba la n ce ca n occu r be-
ca u se of ot h er disea ses or ca n ca u se illn ess.
● Alt er a t ion s in a cid–ba se ba la n ce a r e a ssocia t ed
wit h a lt er ed r egu la t ion of flu id a n d elect r olyt e.
● Acid–ba se ba la n ce is r egu la t ed by bu ffer syst em s,
wor kin g in con cer t t o m a in t a in pH ba la n ce.
● Cor r ect ion in pH a lt er a t ion s r esu lt in g fr om a cid
ba se im ba la n ce a r e r edu n da n t a n d in clu de r a pid
a ct in g a n d lon g a ct in g bu ffer syst em s t h a t r e-
spon d t o im m edia t e a n d lon g t er m n eed t o r est or e
a cid–ba se ba la n ce.
● An ion ga p, ba sed on ca lcu la t ion of m ea su r a ble
ca t ion s a n d a n ion s, pr ovides a n in dica t ion of
a cid–ba se ba la n ce.
● Met a bolic a cidosis is ch a r a ct er ized by a deficit in
ba se. Met a bolic a lka losis is ch a r a ct er ized by a n
excess in ba se.
● Cor r ect ion of a cid–ba se im ba la n ces is cr it ica l t o
t h e m a in t en a n ce of bodily fu n ct ion s.
● To cor r ect im ba la n ces in a cid–ba se, ca r efu l con -
sider a t ion m u st be given t o t h e pot en t ia l im pa ct
of in t er a ct ion s wit h a ll body syst em s.
C AS E S T U D Y 9.1
Scot t , a 2-yea r-old m a le, wa s in t h e ga r a ge wit h
h is fa t h er wh ile h e wa s wor kin g on h is ca r. Wh en
h is fa t h er wa s dist r a ct ed, Scot t dr a n k fr om a con -
t a in er of a n t ifr eeze con t a in in g m et h a n ol a n d et h -
ylen e glycol. Con sider t h e im pa ct of t h is even t on
Scot t ’s a cid–ba se ba la n ce a n d a n swer t h e followin g
qu est ion s:
1. Wh a t a r e t h e pa t h ologic con sequ en ces on or ga n
syst em s r esu lt in g fr om in gest ion of m et h a n ol a n d
et h ylen e glycol?
2. Wh a t a r e t h e sym pt om s a ssocia t ed wit h m et h a -
n ol a n d et h ylen e glycol in gest ion ?
3. Wh a t a r e t h e a cid–ba se a lt er a t ion s t h a t a r e ex-
pect ed wit h in gest ion of m et h a n ol a n d et h ylen e
glycol?
4. Wh a t wou ld you expect for clin ica l m a n ifest a -
t ion s r ela t ed t o a cid–ba se im ba la n ce a ft er m et h -
a n ol a n d et h ylen e glycol in gest ion ?
5. Wh a t dia gn ost ic t est s m igh t be u sed?
6. Wh a t t r ea t m en t is n eeded?
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r n a l
a r t icle or Web sit e t h a t det a ils m et h a n ol a n d et h -
ylen e glycol in gest ion t o con fir m you r pr edict ion s.
P R AC T I C E E XAM Q U E S T I O N S
1. Wh ich of t h e followin g is a n exa m ple of a st r on g
a cid?
a . Albu m in
b. In or ga n ic ph osph or u s
c. Sodiu m
d. La ct a t e
2. An a n ion ga p of 16 ca n be ca lcu la t ed by wh ich of
t h e followin g scen a r ios?
a. Sodium 146, chloride 102, bicarbonate 26 mEq/L
b. Sodium 140, chloride 102, bicarbonate 26 mEq/L
c. Sodium 136, chloride 122, bicarbonate 30 mEq/L
d. Sodium 148, chloride 100, bicarbonate 28 mEq/L
3. A pH of 7.5 is defin ed a s
a . Alka losis
b. Acidosis
c. Acidem ia
d. Alka lem ia
4. An exa m ple of a n ion exch a n ge in clu des:
a . Sodiu m a n d h ydr ogen exch a n ge
b. Sodiu m a n d ch lor ide exch a n ge
c. Bica r bon a t e a n d ch lor ide exch a n ge
d. H ydr ogen a n d bica r bon a t e exch a n ge
5. H ypoka lem ia is oft en a ssocia t ed wit h wh ich on e
of t h e followin g con dit ion s?
a . Met a bolic a lka losis
b. Met a bolic a cidosis
c. H yper ch lor em ia
d. Non e of t h e a bove
6. Met a bolic a cidosis m a y be a ssocia t ed wit h
a . In cr ea sed ch lor ide levels
b. In cr ea sed m et a bolic a cids
c. Decr ea sed bica r bon a t e
d. All of t h e a bove
7. H yper la ct a t em ia du e t o dr u g t r ea t m en t is a com -
plica t ion in wh ich of t h e followin g con dit ion s?
a . Sa lt -losin g t u bu lopa t h y
b. Cir r h osis
c. AIDS
d. Ison a t r em ic deh ydr a t ion

D I S C U S S I O N AN D
AP P L I C AT I O N
1. Wh a t did I kn ow a bou t a lt er a t ion s in a cid–ba se
ba la n ce befor e t oda y?
2. Wh a t body pr ocesses a r e a ffect ed by a lt er a t ion s
in a cid–ba se ba la n ce? H ow do a cid–ba se im ba l-
a n ces a ffect t h ose pr ocesses?
3. Wh a t a r e t h e pot en t ia l et iologies for a lt er a t ion s
in a cid–ba se ba la n ce? H ow do a cid–ba se im ba l-
a n ces develop?
4. Who is m ost a t risk for developing a cid–ba se
im ba la nces? How ca n t hese a lt era t ions be
pr even ted?
5. Wh a t a r e t h e h u m a n differ en ces t h a t a ffect t h e
et iology, r isk, or cou r se of a lt er a t ion s in a cid–
ba se ba la n ce?
6. Wh a t clin ica l m a n ifest a t ion s a r e expect ed du r in g
a cid–ba se im ba la n ces?
7. Wh a t specia l dia gn ost ic t est s a r e u sefu l in det er-
m in in g t h e dia gn osis a n d cou r se of a lt er a t ion s in
a cid–ba se ba la n ce?
8. Wh a t a r e t h e goa ls of ca r e for in dividu a ls wh o
h a ve a lt er a t ion s in flu id, elect r olyt e, a n d a cid–
ba se ba la n ce?
9. H ow does t h e con cept of a lt er a t ion s in flu id, elec-
t r olyt e, a n d a cid–ba se ba la n ce bu ild on wh a t I
h a ve lea r n ed in t h e pr eviou s ch a pt er a n d in t h e
pr eviou s cou r ses?
10. H ow ca n I u se wh a t I h a ve lea r n ed?
R E SOUR CE S
Ren a l Tu bu la r Acidosis—Na t ion a l Kidn ey a n d Ur o-
logic Disea ses In for m a t ion Clea r in g H ou se:
h t t p ://w w w.n i d d k .n i h .g ov /h e a l t h -i n for m a t i on /
h e a l t h -t op i cs /k i d n e y -d i s e a s e /r e n a l -t u b u l a r -
a cid os is -r t a /Docu m en t s /r en a lt u bu la r a cidos is _508
.pdf
F in d a d d ition a l r esou r ces for th is ch a pter a t h ttp:th ePoin t.lww.com
C h a p t e r 9: Alt er ed Acid–Ba se Ba la n ce 227
Ch r on ic Kidn ey Disea se a n d Diet : Assessm en t , Ma n -
a gem en t a n d Tr ea t m en t :
h t t p ://w w w.n i d d k .n i h .g ov /h e a l t h -i n for m a t i on /
h ea lt h -com m u n ica t ion -pr ogr a m s /n k dep /a -z/Docu -
m en t s/ckd-diet -a ssess-m a n a ge-t r ea t -508.pdf
R e er en ces
1. Lebla n c M. Acid-ba se ba la n ce in a cu t e r en a l fa ilu r e
a n d r en a l r epla cem en t t h er a py. Best P r a ct Res Clin
An a esth esiol. 2004;18(1):113–127.
2. Levr a u t J, Gr im a u d D. Tr ea t m en t of m et a bolic a cidosis.
Cu r r Opin Cr it Ca r e. 2003;9(4):260–265.
3. Izzedin e H , H a r r is M, Per a zella MA. Th e n eph r ot oxic ef-
fect s of H AART. Na t Rev Neph r ol. 2009;5(10):563–573.
4. McCom sey GA, Ya u L. Asym pt om a t ic h yper la ct a t a em ia :
pr edict ive va lu e, n a t u r a l h ist or y a n d cor r ela t es. An tivir
Th er. 2004;9(2):205–212.
5. Mon ier P L, Wilcox R. Met a bolic com plica t ion s a ssocia t ed
wit h t h e u se of h igh ly a ct ive a n t ir et r ovir a l t h er a py in
H IV-1-in fect ed a du lt s. Am J Med S ci. 2004;328(1):48–56.
6. Wa lker UA, Ba u er le J, La gu n o M, et a l. Deplet ion of m i-
t och on dr ia l DNA in liver u n der a n t ir et r ovir a l t h er a py
wit h dida n osin e, st a vu din e, or za lcit a bin e. H epa tology.
2004;39(2):311–317.
7. Seyber t h H W. An im pr oved t er m in ology a n d cla ssifica -
t ion of Ba r t t er-like syn dr om es. Na t Clin P r a ct Neph r ol.
2008;4(10):560–567.
8. Ma dr iga l G, Sa bor io P, Mor a F, et a l. Ba r t t er syn dr om e
in Cost a Rica : a descr ipt ion of 20 ca ses. Ped ia tr Neph r ol.
1997;11(3):296–301.
9. Rein a lt er SC, J eck N, Pet er s M, et a l. P h a r m a cot ypin g of
h ypoka la em ic sa lt -losin g t u bu la r disor der s. Acta P h ysiol
S ca n d . 2004;181(4):513–521.
10. J eck N, Rein a lt er SC, H en n e T, et a l. H ypoka lem ic
sa lt -losin g t u bu lopa t h y wit h ch r on ic r en a l fa ilu r e a n d
sen sor in eu r a l dea fn ess. Ped ia tr ics. 2001;108(1):E 5.
11. Adr ogu e H J, Ma dia s NE . Ma n a gem en t of
life-t h r ea t en in g a cid-ba se disor der s. Secon d of t wo pa r t s.
N E n gl J Med . 1998;338(2):107–111.
12. Lu M, Wa n g T, Ya n Q, et a l. ROMK is r equ ir ed for expr es-
sion of t h e 70-pS K ch a n n el in t h e t h ick a scen din g lim b.
Am J P h ysiol Ren a l P h ysiol. 2004;286(3):F 490–F 495.
13. Dou n ou si E , Zikou X, Kou lou r a s V, et a l. Met a bolic a cido-
sis du r in g pa r en t er a l n u t r it ion : pa t h oph ysiologic m ech a -
n ism s. In d ia n J Cr it Ca r e Med . 2015;19:270–274.
 Ch a pt er

10
Alt er ed Neu r on a l
Tr a n sm ission

L E AR N I N G O U T C O ME S
1. Defin e a n d u se t h e key t er m s list ed in t h is ch a pt er.
2. Descr ibe ou t com es r ela t ed t o a lt er ed volt a ge du r in g t h e ph a ses of a ct ion
pot en t ia l.
3. Differ en t ia t e bet ween t ypes of in ju r y in t h e cen t r a l a n d per iph er a l
n er vou s syst em s.
4. An a lyze pot en t ia l t a r get s of im pa ir ed fu n ct ion in a lt er ed r eflex r espon se.
5. Descr ibe fa ct or s a ssocia t ed wit h a lt er ed syn a pt ic t r a n sm ission .
6. Com pa r e a n d con t r a st n eu r ologic t r a n sm ission pa t t er n s a n d ou t com es in
t h e som a t ic, sym pa t h et ic, a n d pa r a sym pa t h et ic n er vou s syst em s.
7. Iden t ify com m on sign s a n d sym pt om s of a lt er ed n eu r on a l t r a n sm ission .
8. Descr ibe dia gn ost ic t est s a n d t r ea t m en t st r a t egies r eleva n t t o a lt er ed
n eu r on a l t r a n sm ission .
9. P r edict expect ed fu n ct ion a l im pa ir m en t fr om a lt er ed n eu r ologic t r a n s-
m ission ba sed on t ype, sever it y, a n d sit e of n eu r ologic in ju r y.
10. Apply con cept s of a lt er ed n eu r on a l t r a n sm ission t o select clin ica l m odels.

INTR ODUCTION
We oft en t a ke for gr a n t ed t h e sim ple t h in gs t h a t a r e pa r t of ou r da ily life, su ch
a s wa lkin g, swa llowin g food, ba la n cin g a ch eckbook, or sin gin g a fa vor it e son g.
Th ese a ct ivit ies a r e a r eflect ion of t h e h igh -level fu n ct ion in g of n er vou s cells a n d
t issu es. Th is ch a pt er h igh ligh t s im pa ir ed n eu r a l fu n ct ion a n d t h e con sequ en ces
of t h ese a lt er a t ion s. A r eview of n or m a l n eu r a l t r a n sm ission is pr esen t ed, fol-
lowed by a discu ssion of t h e pa t h ologic ch a n ges a ssocia t ed wit h im pa ir ed con -
du ct ion of n eu r a l im pu lses in t h e va r iou s n er vou s syst em t issu es a n d or ga n s.
Fin a lly, t h ese con cept s a r e a pplied t o select ed m odels of clin ica l disea se.

Digital illustration of a neuron. Image © vitstudio.

228
 Alt e r a t io n s in N e u r o n a l I m p u ls e C o n d u c t io n 229

Modu le 1 Alt e r a t io n s in N e u r o n a l
I m p u ls e C o n d u c t io n
Neu r on a l t r a n sm ission of im pu lses is cr it ica l t o
m a in t a in vit a l fu n ct ion s. Disr u pt ion of a n y com po-
n en t r equ ir ed for con du ct ion of n er ve im pu lses m a y
a lt er n eu r a l sign a lin g. Th e ba sic st r u ct u r a l com -
pon en t s of t h e n eu r on m u st be in t a ct t o fu n ct ion
pr oper ly. Th e or ga n elles m u st su ppor t t h e fu n ct ion
of n eu r a l cells t h r ou gh su ch t h in gs a s t h e gen et ic
r egu la t ion of essen t ia l fu n ct ion s a n d t h e pr odu ct ion
of pr ot ein s, n eu r ot r a n sm it t er s, a n d en er gy r equ ir ed
for opt im a l cell fu n ct ion in g. Th e pr opa ga t ion of t h e
n eu r a l im pu lses t h r ou gh developm en t of syn a pses,
a va ila bilit y of r ecept or s, r elea se a n d u pt a ke of n eu -
r ot r a n sm it t er s, gen er a t ion of a ct ion pot en t ia ls, a n d
t a r get or ga n r espon siven ess is a lso r equ ir ed. Th e
ext er n a l en vir on m en t , in clu din g ion con cen t r a t ion s
a n d flu id ba la n ce, m u st be in h a r m on y for opt im a l
n eu r a l cell fu n ct ion in g. Neu r a l im pu lse con du ct ion
r equ ir es a com plex or ga n iza t ion of n eu r a l st r u ct u r es
for ph ysiologic fu n ct ion in g.
Neurons
Th e n e u r o n (n er ve cell) is t h e fu n da m en t a l fu n c-
t ion a l u n it of t h e n er vou s syst em . Com posed of a
cen t r a l cell body, on e a xon , a n d a va r ia ble n u m ber of
den dr it es, n eu r on s a r e excit a ble cells t h a t con t r ibu t e
t o t h e h igh ly specia lized cell fu n ct ion of t h e t r a n s-
m ission of n er ve im pu lses t h r ou gh ou t t h e body. Th e
c e ll b o d y , or s o m a , is filled wit h cyt opla sm a n d con -
t a in s pr ocesses, in clu din g t h e n u cleu s, t h a t su ppor t
t h e m et a bolic dem a n ds of t h e cell. Th e cyt opla sm of
t h e cell body is a lso con t a in ed in t h e den dr it es a n d
a xon s. D e n d r it e s a r e m u lt iple, br a n ch ed ext en sion s
of t h e cell body t h a t t r a n sm it im pu lses t o t h e cell
body. Th e a x o n ca r r ies im pu lses a wa y fr om t h e cell
body. Th e t r a n sm ission speed of n er ve im pu lses fr om
t h e den dr it es t o t h e syn a pt ic t er m in a ls is en h a n ced
by t h e m yelin sh ea t h , wh ich is in t er r u pt ed by t h e
n odes of Ra n vier. F igu r e 10.1 illu st r a t es t h e st r u c-
t u r es of a n eu r on .
Neu r on s a r e ca t egor ized ba sed on t h eir h igh ly spe-
cia lized fu n ct ion s. S e n s o r y n e u r o n s , a lso kn own a s
a e r e n t n e u r o n s , ca r r y im pu lses fr om r ecept or s in
t h e per iph er y t o t h e br a in a n d spin a l cor d in t h e cen -
t r a l n er vou s syst em (CNS). Mo t o r n e u r o n s , a lso
kn own a s e e r e n t n e u r o n s , ca r r y sign a ls a wa y
fr om t h e spin a l cor d a n d br a in t o t a r get s in t h e body
t h a t r egu la t e a ct ivit y. I n t e r n e u r o n s a r e t h e m ost
a bu n da n t n eu r on t ype. In t er n eu r on s pr ovide con -
n ect ion s bet ween n eu r on s, t r a n sm it t in g sign a ls be-
t ween a ffer en t a n d effer en t n eu r on s.
Supporting Cells
Th e br a in con t a in s a ppr oxim a t ely 100 billion n eu -
r on s a n d m a n y t r illion s of glia , n eu r a l su ppor t cells.
Glia , der ived fr om t h e Gr eek m ea n in g “glu e,” pr o-
vide su ppor t a n d n u t r it ion , m a in t a in h om eost a sis,
a n d for m t h e m yelin t h a t cover s t h e n eu r on s of t h e
br a in . Su ppor t cells pr ovide n eu r on s wit h pr ot ec-
t ion a n d m et a bolic su ppor t , a n d t h ey h elp segr ega t e
n eu r on s t o pr om ot e opt im a l fu n ct ion in g. Su ppor t
cell t ypes va r y depen din g on t h e com pon en t of t h e
n er vou s syst em ; t h a t is, cen t r a l n er vou s syst em or
per iph er a l n er vou s syst em , wh ich is discu ssed fu r-
t h er in t h e n ext sect ion . Th e specific cell t ypes a r e
ou t lin ed in Ta ble 10.1.
Myelin , a pr ot ein h igh in lipid con t en t , is im por t -
a n t t o n eu r a l cell fu n ct ion in g. Th e in su la t in g pr oper-
t ies of m yelin in cr ea se t h e speed of n er ve im pu lse by

Nucle us

Axon S yna ptic te rmina ls

De ndrite s

Node of Mye lin

Ra nvie r s he a th

Ce ll body (s oma )

Figure 10.1. Components of the neuron.

230 C h a p t e r 10: Alt er ed Neu r on a l Tr a n sm ission
Ta b le 10.1 Su ppor t in g Cells of t h e Ner vou s Syst em
Ner vou s Syst em S u p p o r t in g C e ll T y p e
Cen t r a l n er vou s syst em Glia l cells
Oligoden dr oglia (a lso kn own a s
oligoden dr ocyt es)
Ast r oglia (a lso kn own a s a st r ocyt es)
Micr oglia
E pen dym a l cells
Per iph er a l \ n er vou s syst em Sch wa n n cells
Sa t ellit e cells
con t a in in g t h e cu r r en t in a sm a ll spa ce su r r ou n din g
t h e a xon . Th e specific cell t ype su ppor t in g pr odu c-
t ion a n d m a in t en a n ce of m yelin va r ies depen din g on
t h e t ype of n eu r on in volved. O lig o d e n d r o c y t e s a r e
r espon sible for t h e for m a t ion of m u lt ila yer ed m yelin
segm en t s a r ou n d m u lt iple a xon s in t h e br a in , pr o-
m ot in g t h e speed of n er ve im pu lse con du ct ion in t h e
CNS. S c h w a n n c e lls pr odu ce m yelin on lon g, sin gle
a xon s of t h e per iph er a l n er vou s syst em . In m yelin -
a t ed a xon s, t h e m yelin sh ea t h is in t er r u pt ed a t in -
t er va ls by t h e n o d e s o R a n v ie r . Th ese n odes a r e
r ich in sodiu m ch a n n els a n d a r e n ecessa r y t o pr o-
m ot e t h e m ovem en t of t h e n er ve im pu lse over lon g
dist a n ces. Im pu lses t r a velin g down t h e a xon ju m p
fr om n ode t o n ode in a st epwise fa sh ion in a pr ocess
kn own a s s a lt a t o r y c o n d u c t io n .
Neuronal Transmission
Tr a n sm ission of n eu r on a l im pu lses r equ ir es com plex
coor din a t ion bet ween n eu r on a l st r u ct u r es a n d t h e
su r r ou n din g en vir on m en t . Alt er a t ion s in a n y a spect
of n eu r on a l com m u n ica t ion m a y r esu lt in m a n ifes-
t a t ion s of im pa ir ed fu n ct ion . Neu r on s com m u n ica t e
wit h ot h er n eu r on s a n d cells in t h e body t h r ou gh t h e
gen er a t ion of elect r ica l sign a ls ca lled a c t io n p o -
t e n t ia ls . Act ion pot en t ia ls a r e elect r ica l even t s t h a t
t r a vel a lon g t h e en t ir e n eu r on by a llowin g ch a r ged
ion s t o flood t h r ou gh ch a n n els in t h e sem iper m ea ble
m em br a n e a r ou n d t h e n er ve cell. Act ion pot en t ia ls
a r e r egu la t ed by ch a n ges in m em br a n e pot en t ia l.
Me m b r a n e p o t e n t ia l is t h e differ en ce in elect r ica l
ch a r ge bet ween t h e in side a n d ou t side of t h e cell. An
excit a ble n eu r on a l cell is p o la r ize d wh en a t r est .
Th e in side of t h e cell is m or e n ega t ive com pa r ed wit h
t h e ou t side of t h e cell; t h e differ en ce is m ea su r ed a t
F u n c t io n
Con t r ol m yelin pr odu ct ion a n d m a in t en a n ce
P r ovide t r a n spor t m ech a n ism s for t h e
exch a n ge of oxygen , ca r bon dioxide, a n d
m et a bolit es bet ween blood vessels a n d n eu -
r on s; st im u la t e ph a gocyt osis; pr ovide su ppor t
t o n eu r a l st r u ct u r es
Con t r ol ph a gocyt osis of in ju r ed or da m a ged
cells
Lin e t h e ven t r icu la r syst em
St im u la t e m yelin pr odu ct ion a n d
m a in t en a n ce
P r ovide ph ysica l su ppor t of n eu r on s
a ppr oxim a t ely −70 m V. Cell bodies a n d den dr it es
h a ve few volt a ge-ga t ed ch a n n els, wh ich r esu lt s in
ch a n ges in m em br a n e pot en t ia l t h a t do n ot r ea ch
t h e t h r esh old (s u b t h r e s h o ld ), or t h e poin t a t wh ich
t h e cell is com m it t ed t o a n a ct ion pot en t ia l. Volt -
a ge-ga t ed ch a n n els a r e fou n d in t h e a x o n h illo c k ,
t h e poin t a t wh ich t h e a xon is join ed t o t h e cell body.
Su bt h r esh old pot en t ia ls con ver ge fr om t h e cell body
a n d den dr it es a t t h e a xon h illock, wh er e a fu ll a c-
t ion pot en t ia l is gen er a t ed a n d con du ct ed down t h e
len gt h of t h e a xon .
At r est , t h e n eu r on a n d t h e su r r ou n din g spa ce a ct
a s a c a p a c it o r , st or in g cu r r en t , wh ich is r elea sed
du r in g t h e a ct ion pot en t ia l. Myelin in su la t ion r e-
du ces loss of cu r r en t , lim it in g dr ift of sodiu m ion s
a wa y fr om t h e n eu r on . Act ion pot en t ia l is det er m in ed
a t t h e poin t wh en sodiu m ch a n n els open , a llowin g
t h e flow of sodiu m in t o t h e cell. Th er e a r e t h r ee com -
pon en t s of t h e a ct ion pot en t ia l in t h e n eu r on :
1. Rest in g m em br a n e pot en t ia l
2. Depola r iza t ion ph a se
3. Repola r iza t ion ph a se
Th e m em br a n e pot en t ia l of a cell a t r est is kn own
a s t h e r e s t in g m e m b r a n e p o t e n t ia l (R MP ). RMP
r efer s t o t h e m em br a n e pot en t ia l (or st a t e of t en -
sion ) in side a cell m em br a n e, m ea su r ed r ela t ive t o
t h e flu id ju st ou t side in t h e a bsen ce of sign ifica n t
elect r ica l a ct ivit y. D e p o la r iza t io n is t h e r esu lt of
r a pid m ovem en t of sodiu m in t o t h e cell t h r ou gh so-
diu m ch a n n els in t h e cell m em br a n e. Th is in flow
gen er a t es a n elect r ica l im pu lse. Th is im pu lse is
t r a n sm it t ed a lon g t h e a xon t o t r igger t h e r elea se
of n eu r ot r a n sm it t er s. Th e r e p o la r iza t io n ph a se is
in it ia t ed by t h e flow of pot a ssiu m ion s ou t of t h e cell.
Th e efflu x of pot a ssiu m ion s pr om ot es r et u r n of t h e
cell t o RMP (Fig. 10.2).
 Alt e r a t io n s in N e u r o n a l I m p u ls e C o n d u c t io n 231

–80 mV Re s ting s tate (uns timulate d s tate )

K+ K+ 0

–80 mV

Na+ Cl-

+40 mV
De po larizatio n (s timulate d s tate )

–80 mV
Na+ Cl-

–80 mV
Re po larizatio n (re turn to re s ting s tate )
Action pote ntia l
De pola riza tion
K+
0
Re pola riza tion
–80 mV Re s ting pote ntia l
Na+ Hype rpola riza tion
S timulus

Ne rve impuls e
0

–80 mV
S ite of s umma tion
of multiple s timuli
All-or-none a ction pote ntia ls with
tra ns ie nt reve rs a l of pola rity

Figure 10.2. Electrical charges at rest and with stimulation. Influx of sodium ions into the cell promotes depolarization
and the development of an action potential. Efflux of potassium ions causes repolarization and return to resting mem-
brane potential. (Modified from Snell R. Clinical Neuroanatomy. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.)

Communication Between Neurons C h e m ic a l s y n a p s e s in volve specific st r u ct u r es

In for m a t ion fr om on e n eu r on flows t o a n ot h er n eu -
r on a cr oss a s y n a p s e . Th e syn a pse is a sm a ll ga p or
ju n ct ion sepa r a t in g n eu r on s. E lect r ica l a n d ch em ica l
syn a pses a r e t ypica lly fou n d in t h e n er vou s syst em .
E le c t r ic a l s y n a p s e s t r a n sm it im pu lses by pa s-
sa ge of cu r r en t -ca r r yin g ion s t h r ou gh sm a ll open -
in gs kn own a s g a p ju n c t io n s . Th e t r a n sm ission of
elect r ica l im pu lses t h r ou gh ga p ju n ct ion s is fa st a n d
dir ect . Th is m ode of n eu r a l t r a n sm ission is m u lt idi-
r ect ion a l. Ga p ju n ct ion s a r e com m on ly in volved in
t h e t r a n sm ission of elect r ica l im pu lses t h a t lea d t o
ca r dia c con t r a ct ion s.
im por t a n t for im pu lses st im u la t ed by n e u r o t r a n s -
m it t e r s , ch em ica l a gen t s a ffect in g t h e fu n ct ion of
a n ot h er n ea r by cell or cells. Neu r ot r a n sm it t er s ca r r y
sign a ls bet ween n er ve cells a n d ot h er excit a ble cells,
in clu din g ot h er n er ve cells a n d m u scle cells, t o t r igger
a r espon se in a n ot h er cell. Th e syn a pt ic st r u ct u r es
in volved in t h is t ype of n eu r a l t r a n sm ission in clu de:
● P r esyn a pt ic t er m in a ls
● Syn a pt ic cleft
● Post syn a pt ic m em br a n e
Ch em ica l syn a pt ic t r a n sm ission is u n idir ect ion a l,
lim it ed t o on e-wa y com m u n ica t ion bet ween n eu r on s.
232 C h a p t e r 10: Alt er ed Neu r on a l Tr a n sm ission

Syn a pt ic a r r a n gem en t s ca n in clu de con t a ct s be-
t ween a xon a n d den dr it e, a xon a n d som a , a n d a xon
a n d a xon . P r esyn a pt ic t er m in a ls con t a in n eu -
r ot r a n sm it t er s pa cka ged in vesicles, m it och on dr ia ,
a n d ot h er cellu la r or ga n elles. Relea se of n eu r ot r a n s-
m it t er s per m it s diffu sion of t h ese n eu r ot r a n sm it t er s
in t o t h e syn a pt ic cleft . Neu r ot r a n sm it t er s r elea sed
fr om vesicles a t t h e syn a pt ic cleft a r e t h en a va ila ble
t o bin d wit h specific r ecept or s on t h e post syn a pt ic
m em br a n e, pr om ot in g excit a t ion or in h ibit ion of
t h e post syn a pt ic n eu r on . Th ese effect s a r e ca u sed
by ch a n ges in m em br a n e pot en t ia l of t h e post syn -
a pt ic n eu r on in du ced by n eu r ot r a n sm it t er – r ecept or
bin din g, t h er eby r esu lt in g in h ypopola r iza t ion or
h yper pola r iza t ion . H y p o p o la r iza t io n ch a n ges
m em br a n e pot en t ia l t owa r d t h e poin t of t h r esh old
pot en t ia l (less n ega t ive), pr om ot in g t h e excit a t or y
effect of pr opa ga t ion of t h e im pu lse or n eu r on fir in g.
H y p e r p o la r iza t io n h a s t h e opposit e effect of m ov-
in g t h e m em br a n e pot en t ia l a wa y fr om t h r esh old
(m or e n ega t ive), pr om ot in g a n in h ibit or y effect .
Neu r ot r a n sm it t er r elea sed in t o t h e syn a pt ic cleft
m u st bin d t o r ecept or s on t h e post syn a pt ic n eu -
r on t o a ch ieve im pu lse gen er a t ion . In t er r u pt ion in
n eu r ot r a n sm it t er –r ecept or bin din g m a y r esu lt fr om
r eu pt a ke of t h e n eu r ot r a n sm it t er in t o t h e pr esyn a pt ic
n eu r on , diffu sion of n eu r ot r a n sm it t er ou t of t h e syn -
a pt ic cleft , en zym a t ic br ea kdown of n eu r ot r a n sm it -
t er in t h e syn a pse or post syn a pt ic r ecept or a lt er a t ion
t h a t im pa ir s n eu r ot r a n sm it t er bin din g (Fig. 10.3). Al-
t er a t ion in t h e con t r ol of n eu r ot r a n sm it t er – r ecept or
bin din g im pa ir s post syn a pt ic im pu lse gen er a t ion
a n d t h e ph ysiologic ou t com e a ssocia t ed wit h n eu r a l
con du ct ion in t h e t a r get cells.
Neu r a l im pu lses r equ ir e pr ecise con t r ol, det er-
m in ed in pa r t by t h e n eu r ot r a n sm it t er t ype, t h e
post syn a pt ic r ecept or wit h a ffin it y for bin din g a
specific n eu r ot r a n sm it t er a n d m odu la t or s of n eu -
r a l t r a n sm ission . Neu r ot r a n sm it t er s a r e pr odu ced
in t h e n eu r on , det er m in ed by t h e en zym e syst em s
pr esen t in t h e n eu r on . Neu r ot r a n sm it t er s ca n be
gr ou ped in t o t h r ee m a jor t ypes:
1. Am in o a cids (e.g., glu t a m ic a cid and
ga m m a -a m in obu t yr ic a cid [GABA])
2. Peptides (e.g., endorphins, enkephalins, sub-
stance P)
3. Mon oa m in es (e.g., ser ot on in , dopa m in e, n or e-
pin eph r in e)
Neu r on s a r e cla ssified by t h e pr im a r y n eu r ot r a n s-
m it t er pr odu ced. For exa m ple, dopa m in er gic n eu r on s
pr odu ce dopa m in e a s t h e pr im a r y n eu r ot r a n sm it t er ;
n or epin eph r in e is t h e pr im a r y n eu r ot r a n sm it t er pr o-
du ced by a dr en er gic n eu r on s; ga m m a -a m in obu t yr ic
a cid is t h e pr im a r y n eu r ot r a n sm it t er pr odu ced by
GABA-er gic n eu r on s.
Typica lly, t h er e a r e m u lt iple r ecept or t ypes a n d
su bt ypes t h a t ca n bin d a sin gle n eu r ot r a n sm it t er.

Ne rve
impuls e

P re s yna ptic
re ce ptor
Diffus ion Re upta ke

Ne urotra ns mitte r
Enzyma tic de gra da tion
Pos ts yna ptic re ce ptor
Ne urotra ns mitte r
Re ce ptor
Ne rve
impuls e Na +
S yna ptic
cle ft

Ion cha nne l

Figure 10.3. The action potential generated at the axon hillock of the presynaptic neuron leads to release of neurotrans-
mitter from the synaptic vesicle. Neurotransmitter enters the synaptic cleft and either binds to a receptor on the post-
synaptic neuron, is taken back up into the presynaptic receptor, is degraded by enzymes in the synaptic cleft or diffuses
away from the synapse. When neurotransmitter binding to a postsynaptic receptor occurs, a change in potential occurs. An
inhibitory impulse results in a more negative potential, moving further away from threshold. An excitatory impulse raises
voltage to a less negative membrane potential. When threshold is reached, an action potential results. The impulse is
transmitted on the length of the postsynaptic neuron to the target cells, resulting in a physiologic outcome.

Th e r ecept or det er m in es t h e ch a r a ct er of t h e n eu r a l
im pu lse, eit h er in h ibit or y or excit a t or y. Th e im pu lses
gen er a t ed by n eu r ot r a n sm it t er-r ecept or bin din g a r e
lin ked t o a ph ysiologic ou t com e in t h e t a r get cells.
For exa m ple, wh en n or epin eph r in e bin ds t o t h e a l-
ph a -a dr en er gic r ecept or, sm oot h m u scle con t r a ct ion
r esu lt s. Nor epin eph r in e bin din g t o t h e bet a -a dr en er-
gic r ecept or r esu lt s in sm oot h m u scle r ela xa t ion . In
t h is wa y, a sm a ll n u m ber of n eu r ot r a n sm it t er s ca n
in du ce m u lt iple effect s du e t o t h e m u ch la r ger n u m -
ber of r ecept or s a va ila ble for bin din g. Th e effect s of
n eu r ot r a n sm it t er s ca n be a lt er ed by n e u r o m o d u -
la t o r s , r elea sed fr om a xon t er m in a ls. Th e effect s of
n eu r om odu la t or s m a y in h ibit , pot en t ia t e, or pr olon g
t h e effect s of n eu r ot r a n sm it t er s.
Processes of Neuronal Injury
Ma t u r e n eu r on s do n ot divide, a fa ct t h a t is a n im -
por t a n t con sider a t ion wh en n eu r on s a r e in ju r ed.
Un like m ost ot h er cells, n ew n eu r on s a r e n ot gen er-
a t ed t o r epla ce t h ose t h a t h a ve lost fu n ct ion t h r ou gh
da m a ge or dea t h . Myelin t h a t h a s been da m a ged is
n ot r epla ced, lea din g t o per m a n en t n eu r ologic defi-
cit s. Th e loss of n eu r on s t h r ou gh cell da m a ge or a s a
pr ocess of a gin g con t r ibu t es t o disa bilit y a n d is t h e
ba sis for a va r iet y of n eu r ologic disor der s. Da m a ge
t o n eu r on s r esu lt s fr om t h e followin g pr ocesses:
● C h r o m a t o ly s is : Th e swellin g of a n eu r on be-
ca u se of in ju r y
● At r o p h y : Decr ea se in t h e size of t h e cell (n eu r on )
Modu le 2 Alt e r a t io n s in C N S F u n c t io n
Th e n er vou s syst em is divided in t o syst em s wh ich
con n ect a n d fu n ct ion a s a u n it . F u n ct ion a l dist in c-
t ion s a r e som et im es m a de, t h ou gh it is im por t a n t t o
r ecogn ize t h e br oa d scope of im pa ct of n eu r on a l im -
pa ir m en t a cr oss syst em s. Th is ch a pt er discu sses t h e
n er vou s syst em by or ga n izin g t h e n er vou s syst em
in t o t h e CNS a n d t h e per iph er a l n er vou s syst em ,
wh ich is fu r t h er divided in t o t h e a u t on om ic a n d so-
m a t ic n er vou s syst em s. In volu n t a r y n er vou s con t r ol
is r egu la t ed by t h e viscer a l a n d a u t on om ic n er vou s
syst em s. Th e s o m a t ic n e r v o u s s y s t e m r efer s t o
volu n t a r y n er vou s con t r ol in skelet a l m u scles.
CNS Organization
Th e CNS is com posed of t h e br a in a n d spin a l cor d.
Th e br a in weigh s a ppr oxim a t ely 3 lb (1.36 kg) in a n
Alt e r a t io n s in C N S F u n c t io n 233
● N e u r o n o p h a g ia : P h a gocyt osis a n d in fla m m a -
t or y r espon ses ca u sed by a dea d n eu r on da m a gin g
n eigh bor in g cells
● I n t r a n e u r o n a l in c lu s io n s : Dist in ct ive st r u c-
t u r es for m ed in t h e n u cleu s or cyt opla sm
Developmental Considerations
Th e n eu r a l t u be develops ea r ly in em br yon ic life.
Alt er a t ion s in cellu la r differ en t ia t ion , pr olifer a t ion ,
or m igr a t ion ca n r esu lt in sign ifica n t n eu r ologic im -
pa ir m en t . At bir t h , a lm ost a ll of t h e n eu r on s n eces-
sa r y for fu n ct ion in g du r in g a du lt life a r e pr esen t . By
t h e a ge of 2 yea r s, t h e br a in a ch ieves 80% of it s a du lt
size. Th e br a in con t in u es t o develop a n d m a t u r e for
t h e fir st few yea r s of life. Glia l cells divide a n d m u l-
t iply, m yelin deposit ion on n eu r a l fiber s in cr ea ses,
a n d n ew con n ect ion s a r e for ged.
As in dividu a ls a ge, a lt er ed n er vou s syst em fu n c-
t ion m a y r esu lt fr om a decr ea sed n u m ber of n eu -
r on s, a lt er ed st r u ct u r e, or r espon siven ess of n eu r a l
t issu es. Th e ch a r a ct er ist ic br a in ch a n ges t h a t m a y
occu r wit h a gin g in clu de:
● E n la r gem en t in t h e size of t h e ven t r icle syst em
● Widen in g of su lci
● Decr ea sed br a in volu m e a n d weigh t
● In cr ea se in t h e a ppea r a n ce of n eu r ologic dis-
or der s, su ch a s st r oke, Alzh eim er disea se, a n d
Pa r kin son disea se (P D)
● Sen sor y ch a n ges, in clu din g ca t a r a ct developm en t ,
loss of focu s, h ea r in g, sm ell, a n d t a st e
a ver a ge a du lt a n d is com posed of n eu r on s a n d su p-
por t cells. Th e br a in r eceives a n d pr ocesses sen sor y
in for m a t ion , in it ia t in g a n d coor din a t in g m ot or r e-
spon ses. Th e spin a l cor d con du ct s sen sor y in for m a -
t ion fr om t h e per iph er a l n er vou s syst em a n d m ot or
in for m a t ion fr om m u scle t o t h e br a in for pr ocessin g.
BRAIN
Th e br a in is divided in t o lobes a n d h em isph er es.
Fou r sepa r a t e lobes of t h e br a in a r e divided by s u lc i
(fissu r es) a n d g y r i (ir r egu la r con volu t ion s on t h e
su r fa ce) a n d h a ve specia lized fu n ct ion s (Fig. 10.4).
Th e lobes a n d t h eir fu n ct ion s in clu de:
● F r on t a l lobe: r ea son in g, pla n n in g, speech , a n d
m ovem en t
● Pa r iet a l lobe: per cept ion of t ou ch , pr essu r e, t em -
per a t u r e, a n d pa in
234 C h a p t e r 10: Alt er ed Neu r on a l Tr a n sm ission

Ce ntra l s ulcus S e ns ory a re a

Motor cortex (pa in, touch, e tc)

Fronta l lobe Pa rie ta l lobe

Gyri

Writte n
s pe e ch a re a
Vis ua l
Motor a s s ocia tion
s pe e ch a re a a re a
Occipita l
lobe

Vis ua l
La te ra l s ulcus re ce iving
a re a
Te mpora l lobe

Auditory re ce iving a re a Pons Ce re be llum

Auditory a s s ocia tion a re a Me dulla

S pina l cord

Figure 10.4. Lobes of the brain. External view with motor and sensory areas. (Modified from Bear MF, Connors BW,
Parasido MA. Neuroscience: Exploring the Brain. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006.)

● Tem por a l lobe: per cept ion , m em or y, a n d r ecogn i- ■ Am ygda la

t ion of a u dit or y st im u li ■ Dien ceph a lon
● Occipit a l: vision ■ H ypot h a la m u s
■ Th a la m u s
Th e br a in is a lso divided in t o t wo h a lves, or h em i-
● Midbr a in
sph er es, ea ch con t a in in g t h e fou r lobes of t h e br a in .
■ Mesen ceph a lon
Th e r igh t a n d left h em isph er es com m u n ica t e wit h
■ Tect u m
ea ch ot h er t h r ou gh a bu n dle of n er ve fiber s kn own
■ Tegm en t u m
a s t h e c o r p u s c a llo s u m . Neu r a l a ct ivit y in t h e r igh t
● H in dbr a in
h em isph er e of t h e br a in in volves fu n ct ion a l ca pa cit y
■ Met en ceph a lon
of t h e left side of t h e body. Th e left h em isph er e of t h e
■ Cer ebellu m
br a in a lso dem on st r a t es t h is con t r a la t er a l pa t t er n .
■ Pon s
F u n ct ion s h a ve been a t t r ibu t ed t o t h e con t r ol of spe-
■ Myelen ceph a lon
cific br a in h em isph er es a s follows:
■ Medu lla oblon ga t a
● Left h em isph er e Th e st r u ct u r es of t h e br a in a n d r ela t ed fu n ct ion s
■ Speech a n d la n gu a ge a r e ou t lin ed in Ta ble 10.2. Th e cer ebr u m in clu des
■ Ca lcu la t ion s t h e t elen ceph a lon st r u ct u r es cer ebr a l cor t ex a n d
■ Ma t h ba sa l ga n glia . F igu r e 10.5 h igh ligh t s t h e loca t ion of
■ Logica l a bilit ies specific br a in st r u ct u r es, wh ich ca n be seen wit h a
● Righ t h em isph er e cor on a l view. Th e st r u ct u r e of t h e br a in is a lso r e-
■ Visu a l im a ger y vea led by t h e com posit ion of t issu e in t h e lobes of
■ Fa ce r ecogn it ion
ea ch h em isph er e. Th e t issu e of t h e cer ebr a l cor t ex,
■ Mu sic ba sa l ga n glia , h ypot h a la m u s, a n d t h a la m u s is g r a y
■ Spa t ia l a bilit ies m a t t e r , pr im a r ily com posed of cell bodies; wh er ea s
Br a in st r u ct u r es ca n be ch a r a ct er ized fu r t h er by ot h er br a in st r u ct u r es a r e com posed of w h it e
t h eir loca t ion . Th ese ca t egor ies in clu de: m a t t e r , t issu e com posed pr im a r ily of m yelin a t ed
a xon s a n d den dr it es.
● For ebr a in
■ Telen ceph a lon
SPINAL CORD
■ Cer ebr a l cor t ex
■ Ba sa l ga n glia Th e spin a l cor d ser ves a s t h e pr im a r y pa t h wa y for
■ H ippoca m pu s com m u n ica t ion of m essa ges or im pu lses fr om t h e
 Alt e r a t io n s in C N S F u n c t io n 235

Ta b le 10.2 Br a in St r u ct u r es a n d F u n ct ion s
B r a in S t r u c t u r e An a t o m ic S ig n i ic a n c e
Cer ebr a l cor t ex Loca t ed in t h e t elen ceph a lon of t h e for ebr a in ;
con volu t ed la yer of cer ebr u m t h a t con t a in s
gr a y m a t t er (u n m yelin a t ed cell bodies)
Ba sa l ga n glia Loca t ed in t h e t elen ceph a lon of t h e for ebr a in ;
in clu des st r u ct u r es of t h e globu s pa llidu s,
ca u da t e n u cleu s, su bt h a la m ic n u cleu s,
pu t a m en a n d su bst a n t ia n igr a
H ippoca m pu s Com pon en t of t h e lim bic syst em loca t ed in
t h e t elen ceph a lon of t h e for ebr a in ; con volu t ed
st r u ct u r e loca t ed in t h e t em por a l lobe; for m s
t h e m edia l m a r gin of t h e cer ebr a l h em isph er e
Am ygda la Com pon en t of t h e lim bic syst em loca t ed
in t h e t elen ceph a lon of t h e for ebr a in ; a l-
m on d-sh a ped st r u ct u r e of gr a y m a t t er in t h e
t em por a l lobe
H ypot h a la m u s Loca t ed in t h e dien ceph a lon of t h e for ebr a in ;
t h e h ypot h a la m u s is cr it ica l t o t h e in t egr a t ion
of h om eost a t ic con t r ol of t h e in t er n a l en vi-
r on m en t ; bor der s t h e post er ior pit u it a r y, t h e
t h ir d ven t r icle, a n d t h e t h a la m u s
Th a la m u s Loca t ed in t h e dien ceph a lon of t h e for ebr a in ;
con sist s of t wo la r ge egg-sh a ped m a sses of t is-
su e, on e on ea ch side of t h e t h ir d ven t r icle
Tect u m Loca t ed in t h e dor sa l r egion of t h e m esen -
ceph a lon (m idbr a in ); con t a in s visu a l a n d a u -
dit or y r ecept or s
Tegm en t u m Loca t ed in t h e ven t r a l r egion of t h e m esen -
ceph a lon (m idbr a in ); con sist s of t h e cer ebr a l
a qu edu ct a n d r et icu la r for m a t ion
Cer ebellu m Loca t ed in t h e m et en ceph a lon of t h e h in d-
br a in ; sepa r a t ed fr om t h e cen t r a l h em i-
sph er es by a fold in t h e du r a m a t er su per ior
t o t h e pon s
Pon s Loca t ed in t h e m et en ceph a lon of t h e h in d-
br a in ; ser ves a s t h e con n ect ion bet ween t h e
cer ebellu m a n d t h e cer ebr u m a n d bet ween
t h e m idbr a in a n d t h e m edu lla oblon ga t a
Medu lla oblon ga t a Loca t ed in t h e m yen ceph a lon of t h e h in d-
br a in ; a com pon en t of t h e br a in st em , t h e
m edu lla is t h e m ost ca u da l segm en t of t h e
n eu r a l t u be of t h e br a in
Ret icu la r a ct iva t in g A n et wor k of h yper excit a ble n eu r on s ext en d-
syst em (RAS) in g fr om t h e br a in st em t h r ou gh t h e cer ebr a l
cor t ex
F u n c t io n
Con t r ols h igh er-or der fu n ct ion s in clu din g la n -
gu a ge a n d in for m a t ion pr ocessin g
Con t r ol volu n t a r y m ovem en t ; est a blish
post u r e
Con t r ols im pu lses of em ot ion , h u n ger, sexu a l
a r ou sa l, a n d a ggr ession ; in volved in m em or y
a n d lea r n in g
P r odu ces a n d r espon ds t o n on ver ba l sign s of
a n ger, a voida n ce, defen siven ess, fea r, a n d in -
spir in g a ver sive cu es
Con t r ols body t em per a t u r e, a ppet it e, wa t er
ba la n ce, secr et ion fr om t h e pit u it a r y gla n d,
em ot ion s, a n d a u t on om ic fu n ct ion s, in clu din g
sleep a n d wa kefu ln ess
Rela ys sen sor y in for m a t ion (in clu din g pa in )
t h r ou gh a n a scen din g pa t h wa y via t h e t h a la -
m u s t o t h e cer ebr a l cor t ex, focu sin g of a t t en -
t ion a n d or ga n iza t ion of in com in g st im u li
Con t r ols a u dit or y a n d visu a l r espon ses
Con t r ols m ot or fu n ct ion s; r egu la t es a wa r e-
n ess, a t t en t ion , a n d som e a u t on om ic fu n ct ion s
Ma in t a in s m u scle t on e; coor din a t es m u scle
m ovem en t a n d ba la n ce
Assist s in con t r ollin g a u t on om ic fu n ct ion s,
a r ou sa l, a n d sleep
Regu la t ion of va som ot or, ca r dia c, a n d r espir a -
t or y fu n ct ion
Rou t es in com in g in for m a t ion t o t h e a ppr o-
pr ia t e loca t ion in t h e br a in ; RAS a ct ivit y a lso
in volved in wa kefu ln ess

per iph er y a n d t h e br a in . Th e spin a l cor d is a lso cen -
t r a l t o t h e con t r ol of r eflex r espon ses. Th e len gt h
of t h e spin a l cor d va r ies fr om a n a ver a ge of 43 cm
in a n a du lt fem a le t o 45 cm in a n a du lt m a le. Th e
ver t ebr a l colu m n h ou sin g t h e spin a l cor d is a ppr ox-
im a t ely 70 cm lon g, fa r exceedin g t h e len gt h of t h e
spin a l cor d. Beca u se t h e spin a l cor d en ds a t t h e la st
of t h e t h or a cic ver t ebr a , n er ves br a n ch in g fr om t h e
spin a l cor d below t h e lu m ba r a n d sa cr a l levels m u st
ext en d for a dist a n ce befor e t h ey exit t h e ver t ebr a l
colu m n . Th e ext en sion of n er ves in t h is por t ion of
t h e ver t ebr a l ca n a l is ca lled t h e c a u d a e q u in a .
Th e n er vou s t issu e of t h e spin a l cor d is com posed
of bot h wh it e a n d gr a y m a t t er, ba sed on t h e pr esen ce
or a bsen ce of m yelin . Th e pr opor t ion of gr a y m a t -
t er t o wh it e m a t t er in t h e spin a l cor d is det er m in ed
by t h e a m ou n t of t issu e in n er va t ed. Differ en ces in
pr opor t ion of gr a y a n d wh it e m a t t er a r e seen in
t h e va r iou s segm en t s of t h e cor d. Th e lower lu m -
ba r a n d u pper sa cr a l segm en t in n er va t e t h e lower
236 C h a p t e r 10: Alt er ed Neu r on a l Tr a n sm ission

Tha la mus

Motor cortex
(gray ma tte r)

Ca uda te
nucle us S tria tum
P uta me n

Third ve ntricle

S ubtha la mic
nucle us

Globus pa llidus
inte rna

Optic ne rve

S ubs ta ntia
nigra

Ce re be llum

S pina l cord

Figure 10.5. Coronal view of the brain. (Courtesy Anatomical Chart Company.)

ext r em it ies a n d con t a in la r ger a m ou n t s of gr a y m a t - Ve ntra l horn

t er. Th e wh it e m a t t er pr opor t ion in cr ea ses a s t h e White ma tte r
cor d a ppr oa ch es t h e br a in du e t o t h e gr ea t er n u m ber Dors a l horn
Gray ma tte r
of a scen din g fiber s.
Th e gr a y m a t t er con t a in s syn a pses bet ween sen -
sor y, m ot or, a n d in t er n eu r on s. On cr oss-sect ion of t h e
spin a l cor d, t h e gr a y m a t t er h a s a bu t t er fly-like a p-
pea r a n ce a n d con t a in s n er ve cell bodies. Th e post e-
r ior ext en sion s a r e t h e d o r s a l h o r n s , wh ich con t a in
sen sor y n eu r on s t h a t r eceive a ffer en t im pu lses via
t h e dor sa l r oot s. Th e a n t er ior ext en sion s a r e kn own
a s t h e v e n t r a l h o r n s , wh ich con t a in effer en t m o-
t or n eu r on s t h a t lea ve t h e cor d t h r ou gh t h e ven t r a l
r oot s. U p p e r m o t o r n e u r o n s (UMN) in clu de cell
bodies in t h e m ot or cor t ex a n d t h e a xon s ext en din g
t o t h e br a in st em a n d spin a l cor d. L o w e r m o t o r
n e u r o n s (LMN) a r e loca t ed in t h e ven t r a l h or n s of
t h e spin a l cor d. In t er n eu r on s con n ect UMNs wit h
LMNs in t h e spin a l cor d. Figure 10.6. Spinal cord structures. The spinal cord runs
Su r r ou n din g t h is gr a y m a t t er is t h e wh it e m a t - inside the vertebral column. Axons enter the spinal cord
t er, com posed of t h e a xon s of t h e spin a l cor d. Th e through the dorsal roots and exit by the ventral roots.
wh it e m a t t er con t a in s m yelin a t ed a xon s, givin g t h e
ligh t er-color ed a ppea r a n ce r eflect ed by it s n a m e com m u n ica t e im pu lses wit h in t h e CNS. Th e a scen d-
(Fig. 10.6). Myelin pr odu ced by Sch wa n n cells in - in g t r a ct s com m u n ica t e sen sor y in for m a t ion fr om
cr ea ses t h e velocit y a n d su r viva l of n er ve im pu lses t h e per iph er y t o t h e CNS a n d will be discu ssed in
a lon g lon ger n eu r on a l pr ocesses. m or e det a il in Ch a pt er 12. Th e p y r a m id a l m o t o r
Th e wh it e m a t t er con t a in s a scen din g sen - s y s t e m , com posed of t h e a xon s in t h e descen din g
sor y a n d descen din g m ot or t r a ct s wit h a xon s t h a t cor t icospin a l a n d cor t icobu lba r t r a ct s, pr ovides

con t r ol of volu n t a r y m ovem en t . Mot or n er ves of t h e
pyr a m ida l t r a ct or igin a t e in bot h h em isph er es of
t h e sen sor im ot or a r ea s of t h e cer ebr a l cor t ex a n d
ext en d t h r ou gh t h e m edu lla r y br a in st em , con den s-
in g t o for m pyr a m ids. Th e m a jor it y of UMNs of t h e
cor t icospin a l t r a ct cr oss over in t h e m edu lla , de-
scen din g on t h e con t r a la t er a l side. Th e UMNs syn -
a pse on t o t h e LMNs, lea vin g t h e spin a l cor d via t h e
ven t r a l r oot . Th e UMNs t h a t do n ot cr oss over in
t h e m edu lla t r a vel down t h e ipsila t er a l spin a l cor d,
cr ossin g over a n d syn a psin g on t h e LMN a t t h e level
of spin a l cor d exit . Th e LMNs syn a pse on t o m ot or
fiber s in t h e per iph er a l n er vou s syst em , pr ovidin g
in n er va t ion a n d m ot or fu n ct ion t o t h e legs. In ju r y
t o a xon s befor e t h ey cr oss over r esu lt s in spa st ic pa -
r a lysis on t h e opposit e side of t h e body, wh er ea s in -
ju r y t o a xon s a ft er t h ey cr oss over exer t s it s effect on
t h e sa m e side of t h e body. Axon s of t h e cor t icobu lba r
t r a ct pr ovide in n er va t ion t o t h e m u scles of t h e fa ce,
con t r ollin g m ot or n eu r on s loca t ed in cr a n ia l n er ve
br a in n u clei.
Th e e x t r a p y r a m id a l s y s t e m , sepa r a t e fr om t h e
pyr a m ida l m ot or syst em , m odu la t es m ot or fu n ct ion ,
a t t en u a t in g er r a t ic m ot ion s a n d m a in t a in in g m u s-
cle t on e a n d st a bilit y of t h e t r u n k. F u n ct ion s a ssoci-
a t ed wit h t h e ext r a pyr a m ida l syst em a r e a ssocia t ed
wit h t h e ba sa l ga n glia . Th e su bcor t ica l n u clei of t h e
ba sa l ga n glia in clu de t h e st r u ct u r es of t h e ca u da t e
n u cleu s, pu t a m en , su bt h a la m ic n u cleu s, su bst a n t ia
n igr a , a n d globu s pa llidu s, wh ich com pr ise t h e m a in
st r u ct u r es of t h e ext r a pyr a m ida l syst em .
Protective Structures of the CNS
Th e m a in t en a n ce of a st a ble en vir on m en t pr ovides
a sou r ce of pr ot ect ion for t h e n eu r ologic syst em .
Th e in t er con n ect ed cir cu la t or y syst em s con fer n eu -
r ologic pr ot ect ion via t h e blood–br a in ba r r ier a n d
cer ebr ospin a l flu id (CSF ).
NEUROCIRCULATORY SYSTEM
Th e n er vou s syst em is per fu sed by t wo pa r a llel
com m u n ica t in g syst em s. Th ese syst em s in clu de t h e
cer ebr ova scu la r cir cu la t ion a n d t h e CSF cir cu la t ion .
Cerebrovascular Circulation
Th e va scu la r su pply of t h e CNS pr ovides oxygen -
a t ion a n d n u t r ien t s for opt im a l m et a bolism a n d
fu n ct ion . Ma in t en a n ce of per fu sion t o t h e br a in
is essen t ia l for pr even t ion of cellu la r in ju r y a n d
dea t h . N eu r on s in t h e br a in a r e sen sit ive t o h y-
poxia , r equ ir in g a dequ a t e per fu sion . Ar t er ia l su p-
ply t o t h e br a in in clu des t h e ver t ebr a l, ba sila r, a n d
ca r ot id a r t er ies. Th e cir cle of Willis is a cer ebr a l
Alt e r a t io n s in C N S F u n c t io n 237
a r t er ia l st r u ct u r e t h a t con n ect s t h e ver t ebr a l a n d
ca r ot id cir cu la t ion s. Th is st r u ct u r e is im por t a n t a s
a r ou t e of colla t er a l cir cu la t ion in ca se per fu sion is
im pa ir ed in a n ot h er a r t er ia l syst em . Th e pr im a r y
va scu la r dr a in a ge of t h e br a in occu r s via t h e ju gu -
la r vein s. Per fu sion t o t h e spin a l cor d is su pplied by
t h e spin a l a r t er ies a n d dr a in ed by t h e spin a l vein s.
Rem ova l of excess flu id in t h e CNS occu r s bet ween
t h e pia m a t t er of t h e m en in ges a n d t h e blood ves-
sels beca u se t ypica l lym ph a t ics a r e a bsen t in t h e
br a in .
Stop and Consider
The preferred energy source for the brain is glu-
cose. What manifestations can be expected when
adequate levels of glucose are unavailable?
Blood–Brain Barrier
Th e br a in is pr ot ect ed fr om exposu r e t o pot en t ia lly
h a za r dou s su bst a n ces by r edu ced per m ea bilit y
in ca pilla r ies t h a t su pply t h e br a in , kn own a s t h e
b lo o d –b r a i n b a r r ie r (B B B ). Th e BBB t r a n spor t s
su bst a n ces in a select ive m a n n er beca u se of t h e
t igh t ju n ct ion s in t h e en dot h elia l cells lin in g t h e
ca pilla r ies of t h e br a in . Tr a n spor t a cr oss t h e BBB
of la r ge m olecu les, m olecu les wit h low lipid solu bil-
it y, a n d m olecu les wit h h igh elect r ica l ch a r ge a r e
r esist ed. Su bst a n ces t h a t a r e sm a ll, h igh ly lipid
solu ble, a n d h a ve a low elect r ica l ch a r ge a r e a ble
t o cr oss t h e BBB m or e r ea dily. Th e BBB fu n ct ion s
in clu de:
● P r ot ect ion of t h e br a in fr om for eign su bst a n ces
● P r ot ect ion of t h e br a in fr om h or m on es a n d n eu -
r ot r a n sm it t er s in t h e syst em ic cir cu la t ion
● P r ot ect ion a ga in st dr a st ic en vir on m en t a l
flu ct u a t ion s
Cerebrospinal Fluid
Th e m e n in g e s of t h e CNS in clu de t h r ee m em br a n es
t h a t pr ot ect t issu e su r fa ces, con t a in in g CSF. Th ese
m em br a n es a n d t h eir r ela t ive loca t ion s in clu de:
1. Du r a m a t er (ou t er la yer )
2. Ar a ch n oid m a t er (m iddle la yer )
3. P ia m a t er (in n er la yer )
Th e su r fa ce of t h e CNS is ba t h ed by t h e c e r e -
b r o s p in a l lu id , wh ich flows fr om fou r flu id-filled
in t er con n ect in g ca vit ies of t h e br a in , kn own a s
t h e v e n t r ic le s . CSF is pr odu ced by t h e c h o r o id
p le x u s , a st r u ct u r e loca t ed in t h e t wo la t er a l a n d
sin gle t h ir d a n d fou r t h ven t r icles of t h e br a in . CSF
flows fr om t h e la t er a l ven t r icle t o t h e t h ir d ven t r i-
cle t h r ou gh t h e in t e r v e n t r ic u la r o r a m e n (a lso
ca lled t h e for a m en of Mon r o). Th e t h ir d a n d fou r t h
ven t r icles a r e con n ect ed by t h e c e r e b r a l a q u e d u c t
(a lso kn own a s t h e a qu edu ct of Sylviu s). CSF t h en
238 C h a p t e r 10: Alt er ed Neu r on a l Tr a n sm ission
P ia ma te r
Ara chnoid ma te r
Dura ma te r
Aque duct of S ylvius
(ce re bra l a que duct)
Figure 10.7. Cerebrospinal fluid flow in the ventricular sys-
tem. Arrows indicate the direction of cerebrospinal fluid flow.
flows in t o t h e su ba r a ch n oid spa ce (F ig. 10.7). CSF
pr ot ect s t h e CNS by:
● P r ovidin g a cu sh ion for br a in st r u ct u r es
● Redu cin g t h e pr essu r e on br a in st r u ct u r es
● Rem ovin g h a r m fu l su bst a n ces
● Tr a n spor t in g h or m on es t o r em ot e sit es in t h e br a in
Th e t ot a l volu m e of CSF in t h e CNS a t a n y on e
t im e is a ppr oxim a t ely 125 t o 150 m L. Th e ch or oid
plexu s pr odu ces 400 t o 500 m L CSF per da y t o m a in -
t a in a r est in g pr essu r e of 150 t o 180 m m H 2 O. Wh en
CSF pr essu r e exceeds ven ou s pr essu r e, CSF ca n
be a bsor bed in t o t h e blood via t h e a r a ch n oid. Th is
m ovem en t of flu id fr om t h e CSF t o t h e cir cu la t ion
is u n idir ect ion a l, pr even t in g t h e a bsor pt ion of flu id
fr om t h e blood in t o t h e CSF.
Stop and Consider
How would CSF volume be altered if fluid could
move directly from the blood into the CSF?
CNS Cellular Injury
Respon ses t o in ju r y va r y ba sed on t h e specific cell
t ype in volved. Th ese r espon ses m ir r or t h e m a jor
fu n ct ion a l pr oper t ies of t h e cells. In t h e CNS, a st r o-
cyt es r espon d t o loca l t issu e in ju r y t h r ou gh pr olifer-
a t ion , for m in g a “glia l sca r.” Th is pr ocess is kn own a s
a s t r o g lio s is . Com m on t issu e in ju r ies t h a t a r e likely
t o ca u se t h is r espon se in clu de con t u sion s, wou n ds,
t u m or s, a bscesses, a n d h em or r h a ges. Un ch ecked
pr olifer a t ion m a y r esu lt in n eopla st ic t r a n sfor m a -
t ion r espon sible for t h e developm en t of gliom a s, a s
discu ssed in Ch a pt er 7.
Micr oglia , like a st r ocyt es, m ou n t a n im m u n e r e-
spon se t o a r ea s of in ju r y. Rea ct ive ch a n ges seen in
m icr oglia in clu de ext en sion of t h e n u cleu s, lea din g
t o t h eir descr ipt ion a s “r od cells” wh en in t h is st a t e.
Wh en join ed t oget h er wit h a st r ocyt es, m icr oglia
com bin e t o for m m ic r o g lia l n o d u le s . Oligoden -
dr oglia l da m a ge lea ds t o dem yelin a t ion of a xon s.
E pen dym a l cell da m a ge is lin ked t o a lt er a t ion s in
CSF pr odu ct ion a n d t r a n sfer, a ffect in g in t r a cr a n ia l
pr essu r e (ICP ).
Neu r ologic t r a n sm ission is im pa ir ed in t h e pr es-
en ce of sign ifica n t n eu r on a l da m a ge or dea t h . Th e
m a n ifest a t ion s of a lt er ed fu n ct ion r eflect t h e sit e of
in ju r y a n d t h e fu n ct ion s t h a t a r e con t r olled by t h ose
pa r t icu la r n eu r on s. Th e n er vou s syst em r espon ses t o
in ju r y in clu de degen er a t ion of a xon s, dem yelin a t ion ,
a n d n eu r opa t h y. Alt er a t ion in n eu r on a l t r a n sm is-
sion u n der lies t h e m a n ifest a t ion s t h a t r esu lt fr om
t h ese t ypes of in ju r ies.
MECHANISMS OF INJURY TO THE CNS
F u n ct ion s of t h e br a in a n d spin a l cor d ca n be im -
pa ir ed beca u se of in ju r y. Mech a n ism s of in ju r y m a y
r esu lt fr om t r a u m a , isch em ia , excit a t or y r espon se t o
n eu r ot r a n sm it t er s, or pr essu r e.
Traumatic CNS Injury
Tr a u m a t ic in ju r y ca n im pa ir n eu r ologic fu n ct ion in g
loca lly or syst em ica lly. Wh en in ju r y is r est r ict ed t o
a st r u ct u r e in n er va t in g a specific a r ea , a loca l effect
m a y be seen . In ju r y t o n eu r a l t issu e r espon sible for
t h e in t egr a t ed t r a n sm ission of im pu lses t o m u lt iple,
dist a n t sit es is likely t o h a ve a m or e syst em ic effect .
E xa m ples of t h ese t ypes of m a jor in ju r ies in clu de
t r a u m a t o t h e com pon en t s of t h e CNS (t h e br a in a n d
spin a l cor d).
Traumatic Brain Injury
Au t om obile a cciden t s, fa lls, spor t s-r ela t ed a cciden t s,
a n d “sh a ken ba by syn dr om e” a r e con dit ion s t h a t
m a y r esu lt in t r a u m a t ic br a in in ju r y (TBI), a lso
kn own a s con cu ssion . Gr ou ps a t h igh est r isk for TBI
in clu de per son s 65 yea r s of a ge or older du e t o fa lls,
ch ildr en a n d you n g a du lt s a ge 5 t o 24 du e t o m ot or
veh icle a cciden t s a n d ch ildr en a ge 0 t o 4 du e t o a s-
sa u lt . 1 H ea d t r a u m a t h a t r esu lt s in TBI m a y lea d t o
ch a n ges in ph ysica l, in t ellect u a l, em ot ion a l, or socia l
a bilit ies. H ea d t r a u m a fr om a blu n t for ce in ju r y (e.g.,
wh en t h e h ea d st r ikes a h a r d su r fa ce or is st r u ck
by a r a pidly m ovin g object [cou p/cou n t er cou p]) is a n
exa m ple of a closed h ea d in ju r y. Th e for ce of t h e a c-
celer a t ion im pa ct ca u ses in ju r y t o t h e t issu e in t h e
loca l a r ea (cou p), a n d t h e deceler a t ion im pa ct lea ds
t o in ju r y on t h e opposit e side of t h e sku ll (cou n t er-
cou p). La cer a t ion s a n d con t u sion s of t h e br a in t is-
su e m a y r esu lt fr om con t a ct wit h t h e r ou gh su r fa ce
of t h e sku ll. Th e cer ebr a l cor t ex m a y su ffer effect s

of m ovem en t wit h in t h e sku ll, in cr ea sin g t h e likeli-
h ood of da m a ge t o t h e fr on t a l, t em por a l, a n d occipi-
t a l lobes of t h e br a in a s well a s t h e u pper m idbr a in .
Open t r a u m a t ic in ju r y in volves exposu r e of br a in
st r u ct u r es (e.g., du r a , m en in ges, a n d br a in t issu e) t o
t h e en vir on m en t . Th e r isk of in fect ion a n d in ju r y t o
br a in t issu e is sign ifica n t wit h t h is t ype of in ju r y.
TBI m a y lea d t o seizu r e a ct ivit y, con cu ssion ,
con t u sion , h em a t om a (epidu r a l, su bdu r a l, or in t r a -
cer ebr a l), edem a , or sku ll fr a ct u r e. In cr ea sed ICP,
r espir a t or y depr ession /fa ilu r e, a n d h er n ia t ion of t h e
br a in st em m a y a lso occu r. Ma n ifest a t ion s a r e ca u sed
by a xon a l in ju r y fr om t h e or igin a l t r a u m a a n d by
spr ea d of da m a ge t h a t ca u ses secon da r y in ju r y.
Dia gn osis is oft en m a de u sin g br a in im a gin g t ech -
n iqu es, in clu din g com pu t er ized t om ogr a ph y (CT) or
m a gn et ic r eson a n ce im a gin g (MRI). Br a in a ct ivit y
ca n be det er m in ed wit h a n elect r oen ceph a logr a m
(E E G). Lu m ba r pu n ct u r e (spin a l t a p) wit h r em ova l
a n d a n a lysis of CSF m a y det er m in e t h e pr esen ce of
blood, in dica t in g in t r a cr a n ia l h em or r h a ge.
Tr ea t m en t is dir ect ed t owa r d t h e specific in ju r y
a n d dia gn osis. Su r ger y m a y be n ecessa r y t o eva cu -
a t e a h em a t om a or t o r em ove for eign fr a gm en t s fr om
br a in t issu e. Su ppor t ive ca r e in clu des det er m in a t ion
of t h e ext en t a n d pr ogr ession of n eu r ologic da m a ge,
r edu ct ion of in cr ea sed ICP, pa in con t r ol, pr ovision of
a n t icon vu lsa n t m edica t ion s t o pr even t seizu r es, r e-
spir a t or y su ppor t , a n d a n t ibiot ics t o pr even t or t r ea t
in fect ion .
Traumatic Spinal Cord Injury
Accor din g t o t h e Na t ion a l Spin a l Cor d In ju r y St a -
t ist ica l Cen t er, spin a l cor d in ju r y (SCI) pr im a r ily
a ffect s you n g a du lt s. Th e a ver a ge a ge a t in ju r y h a s
in cr ea sed fr om 28.7 yea r s in t h e 1970s t o a n a ver-
a ge a ge of 40.7 yea r s sin ce 2005. Most spin a l cor d
in ju r ies (a ppr oxim a t ely 81%) a r e a m on g m a les. Al-
t h ou gh fr equ en cy a m on g Ca u ca sia n s h a s st ea dily
decr ea sed over t h e pa st t wo deca des, t h e in ciden ce
of SCI h a s in cr ea sed a m on g Afr ica n Am er ica n s,
Asia n s, a n d H ispa n ics.2 Th e lea din g ca u ses of SCI
in clu de m ot or veh icle a cciden t s a n d a ct s of violen ce
(e.g., gu n sh ot ). Spin a l cor d in ju r ies m a y be t h e r e-
su lt of fr a ct u r es, con t u sion s, or com pr ession of t h e
ver t ebr a l colu m n . Th ese in ju r ies m a y a lso st em fr om
t r a u m a t o t h e h ea d or n eck. Neu r ologic da m a ge r e-
su lt in g fr om pu llin g, t wist in g, sever in g, or com pr ess-
in g t h e n eu r a l t issu e of t h e spin a l cor d is a ser iou s,
pot en t ia lly life-t h r ea t en in g con dit ion . Th e level of
in ju r y wit h in t h e spin a l cor d is t h e det er m in in g fa c-
t or for t h e clin ica l con sequ en ces. Th e m ost com m on
spin a l cor d in ju r ies occu r a t C5-C7, T12, a n d L1.
Tr a u m a t ic in ju r y t o t h e spin a l cor d is oft en sec-
on da r y t o m ot or veh icle a cciden t s, fa lls, a ct s of vio-
len ce a n d r ecr ea t ion a l in ju r ies, sim ila r t o t h e even t s
lea din g t o br a in in ju r y. In ju r y oft en ext en ds t wo
Alt e r a t io n s in C N S F u n c t io n 239
segm en t s a bove a n d below t h e sit e of da m a ge. Div-
in g in t o sh a llow wa t er m a y a lso ca u se ser iou s spin a l
cor d da m a ge. Da m a ge r esu lt s fr om h yper ext en sion
a n d h yper flexion du e t o r a pid a cceler a t ion /decel-
er a t ion , excessive pr essu r e t o t h e t op of t h e h ea d
ca u sin g com pr ession in ju r y, a n d r ot a t ion a l for ces
ca u sin g t r a u m a fr om t wist in g of t h e spin a l cor d.
H em or r h a ge in t h e gr a y m a t t er a n d t h e pia m a t er /
a r a ch n oid m a y lea d t o n ecr osis. E xt en sion of h em or-
r h a ge in t o t h e wh it e m a t t er a n d t h e developm en t of
loca l edem a decr ea ses per fu sion t o t h e cor d, lea din g
t o isch em ia . P h a gocyt ic a ct ivit y in t h e gr a y m a t t er
r esu lt s in m a cr oph a ge en gu lfm en t of a xon s, r epla c-
in g n eu r a l t issu e wit h n on fu n ct ion a l con n ect ive t is-
su e. Sca r r in g a n d t h icken in g of t h e m en in ges a lt er s
n eu r a l con du ct ion a n d fu n ct ion .
A clin ica l m a n ifest a t ion of ver t ebr a e fr a ct u r e
m a y be pa in . Wh en SCI r esu lt s, r espon ses ca n r a n ge
fr om m ild p a r e s t h e s ia (a bn or m a l sen sa t ion , su ch
a s bu r n in g, pr ickin g, t icklin g, or t in glin g) t o q u a d -
r ip le g ia (pa r a lysis of a ll fou r ext r em it ies). Th e level
of t h e SCI a n d t h e sever it y of in ju r y (com plet e or
in com plet e t r a n sect ion ) a lso con t r ibu t e t o t h e n eu r o-
logic deficit . Ta ble 10.3 pr esen t s t h e possible con se-
qu en ces of ser iou s SCI.
Dia gn osis of SCI ca n be m a de by r a diogr a ph (fr a c-
t u r e), n eu r ologic exa m in a t ion , lu m ba r pu n ct u r e, CT
sca n , or MRI sca n . Im m edia t e t r ea t m en t in clu des
im m obiliza t ion of t h e spin e t o pr even t fu r t h er in -
ju r y. On ce t h e spin e is st a bilized, cor t icost er oids a r e
given t o lessen in fla m m a t ion . Tr a ct ion , ca st in g, a n d
su r ger y m a y a lso be n ecessa r y.
Ischemic CNS Injury
Isch em ic in ju r y occu r s wh en t h er e is in a dequ a t e per-
fu sion t o n eu r ologic t issu e, r esu lt in g in im pa ir ed ox-
ygen a t ion . F o c a l is c h e m ia in t h e br a in is con fin ed
t o a specific br a in r egion wh ile glo b a l is c h e m ia in -
clu des la r ger a r ea s of br a in t issu e. Redu ct ion in t h e
su pply of oxygen lea ds t o t issu e n ecr osis. Th e ca u se
of decr ea sed per fu sion a n d oxygen a t ion m ay be loca l
or m ay be a syst em ic con dit ion . For exa m ple, occlu -
sion of blood su pply m ay r esu lt fr om a t h r om bosis in
a loca l vessel, em bolism fr om a t h r om bu s or igin a t in g
in a dist a n t sit e, or fr om loca l h em or r h a ge. A globa l
isch em ic even t is a ssocia t ed wit h a wide a r ea of h y-
poxia , a s is seen in t h e ca se of ca r dia c a r r est or pr o-
fou n d h em or r h a ge (Fig. 10.8). Spin a l cor d isch em ia is
oft en du e t o occlu sion of spin a l blood vessels r esu lt -
in g fr om dissect in g a or t ic a n eu r ism or em boli. Ma l-
for m a t ion s in t h e spin a l va scu la t u r e m ay a lso im pa ir
per fu sion lea din g t o isch em ia a n d n eu r a l in ju r y.
Th e pa t h ology u n der lyin g isch em ic in ju r y is r e-
la t ed t o oxygen a n d n u t r ien t depr iva t ion t o n eu r ologic
t issu e. Im pa ir ed blood flow for lon ger t h a n a few m in -
u t es r esu lt s in t issu e in fa r ct ion in br a in t issu e wit h
240 C h a p t e r 10: Alt er ed Neu r on a l Tr a n sm ission

h igh m et a bolic dem a n ds. Cellu la r fu n ct ion cea ses spea kin g or swa llowin g, im pa ir ed vision , a n d pa r-
beca u se of t h e in a bilit y t o u se a n a er obic m et a bolic est h esia s m a y r esu lt .
pr ocesses or u pt a ke glu cose a n d glycogen . In fa r ct ion CT sca n , MRI, a n d a n giogr a ph y ca n be u sed t o
st im u la t es a r espon se t o t issu e in ju r y t h a t r esu lt s in dia gn ose isch em ic blocka ges. Alt er ed m et a bolism in
a n in fla m m a t or y r espon se a n d t h e developm en t of su r r ou n din g r egion s m a y be iden t ified by posit r on
edem a , lea din g t o in cr ea sed ICP.
Cell in ju r y lea ds t o ch a n ges in
Ta b le 10.3 Pot en t ia l Resu lt s of Ser iou s Spin a l Cor d In ju r y
t h e t r a n spor t of ion s lea din g t o
loca l wa t er a n d elect r olyt e im - C o n d it io n P a t h o p h y s io lo g y C lin ic a l Ma n i e s t a t io n s
ba la n ces (Ch a pt er 8) a n d a cido- Spin a l sh ock Loss of a u t on om ic, r eflex, F la ccid (wit h ou t t on e) pa r a lysis
sis (Ch a pt er 9). Ca lciu m , sodiu m , m ot or, a n d sen sor y a ct ivit y Loss of deep t en don r eflexes
a n d wa t er bu ild u p in t h e a r ea below t h e in ju r y (DTRs)
of cellu la r da m a ge. Fr ee r a dica l Loss of per ia n a l r eflexes
for m a t ion a n d in cr ea sed r elea se
Loss of m ot or a n d sen sor y
of excit a t or y n eu r ot r a n sm it t er s fu n ct ion
m ay pot en t ia t e t h e effect s of t h e Au t on om ic Occu r s a ft er r esolu t ion of Alt er a t ion in h ea r t r a t e
isch em ic in ju r y. dysr eflexia spin a l sh ock H yper t en sion
Clin ica l m a n ifest a t ion s of Associa t ed wit h in ju r ies a t Cold/gooseflesh skin below t h e
isch em ic in ju r y a r e r ela t ed t o or a bove T6 lesion
t h e fu n ct ion a l a r ea s in volved. St im u la t ed by n oxiou s
Sen sor y a n d m ot or fu n ct ion s st im u li (dist en ded bowel or
a r e oft en a ffect ed. Wh en t h e bla dder, skin lesion )
in ju r y occu r s in t h e br a in , t h e Neu r ogen ic Alt er ed va som ot or r espon se Or t h ost a t ic h ypot en sion
m a n ifest a t ion s r eflect t h e spe- sh ock secon da r y t o im pa ir ed sym - Br a dyca r dia
cific a ssocia t ed fu n ct ion s wit h pa t h et ic im pu lse t r a n sm is-
sion fr om t h e br a in st em t o Loss of a bilit y t o swea t below
m ot or deficit s eviden t on t h e t h e t h or a colu m ba r r egion t h e level of in ju r y
c o n t r a la t e r a l, or opposit e, Most com m on wit h cer vica l
side of t h e body. Loss of con - spin a l cor d in ju r y
sciou sn ess, wea kn ess, difficu lt y

Ante rior
ce re bra l a rte ry
Wa te rs he d zone
of infa rction

Middle
ce re bra l a rte ry

La mina r
ne cros is

S hort
pe ne tra ting
a rte rie s
Ne cros is in
S omme rs s e ctor
of hippoca mpus

Ne cros is of
P urkinje ce lls
of ce re be llum

Figure 10.8. Global ischemia. Consequences of global ischemia include lesions related to cerebral vasculature and the
sensitivity of individual neurons. (From Rubin E, Farber JL. Pathology. 4th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2005.)

em ission t om ogr a ph y (P E T) sca n n in g. Tr ea t m en t
in clu des m a n a gem en t of in cr ea sed ICP, in ser t ion of
a st en t t o r est or e per fu sion , t h r om bolyt ic t h er a py
t o dissolve t h e obst r u ct ive clot , a n d a n t icoa gu la t ion
t h er a py t o pr even t fu t u r e clot developm en t .
EXCITATION INJURY
Neu r on s t h a t a r e ea sily depola r ized or h yper ex-
cit a ble m a y ca u se a lt er ed t r a n sm ission of sign a ls.
In cr ea sed n eu r on im pu lse fr equ en cy, in t en sit y,
or ca sca de of t r a n sm ission ca n lea d t o pa t h ologic
con sequ en ces beca u se of excit a t ion in ju r y. In ju r y
t o br a in n eu r on s m a y r esu lt fr om t h e effect s of
excit a t or y n eu r ot r a n sm it t er s, su ch a s t h e a m in o
a cid glu t a m a t e. G lu t a m a t e is t h e m a in excit a t or y
n eu r ot r a n sm it t er in t h e body, a ct ive in t h e pr om o-
t ion of m a n y h igh er-or der fu n ct ion s. Th e effect s of
glu t a m a t e a r e exer t ed wh en it bin ds t o it s r ecep-
t or s, st im u la t in g a ca sca de of sign a l t r a n sdu ct ion
even t s. On e r ecept or wit h a ffin it y for glu t a m a t e is
t h e N -m e t h y l-D -a s p a r t a t e (N MD A) r e c e p t o r .
Wh en glu t a m a t e bin ds t o t h e NMDA r ecept or, a l-
t er a t ion s in ion ch a n n el open in gs lea d t o pr olon ged
a ct ion pot en t ia ls. Da m a ge t o n eu r on s fr om pr ot ein
br ea kdown , fr ee r a dica l for m a t ion , DNA da m a ge,
a n d br ea kdown of t h e n u cleu s is st im u la t ed by t h ese
pr olon ged a ct ion pot en t ia ls.
E xcit a t ion in ju r y m a y r esu lt fr om t h e in a bilit y
t o m eet t h e m et a bolic dem a n ds of t h e cells. Oxygen
n eeds dr a m a t ica lly in cr ea se wit h en h a n ced n eu r o-
logic a ct ivit y, in cr ea sin g t h e r isk of h ypoxia develop-
m en t in a ffect ed t issu es. P r olon ged isch em ia per m it s
in t r a cellu la r glu t a m a t e t o m ove fr om t h e h igh ly
con cen t r a t ed in t r a cellu la r spa ce t o t h e ext r a cellu la r
en vir on m en t , m a kin g m or e glu t a m a t e a va ila ble for
Fle xe d
A Adducte d Fle xe d
Inte rna lly rota te d
B Adducte d Exte nde d
P rona te d
Figure 10.9. Posturing in brain injury. A: Flexor, or decorticate posturing response, is characterized by flexion of elbows,
wrists, and fingers. B: Extensor, or decerebrate posturing response, is characterized by neck extension and clenching of
the jaw. Arms are extended with flexion of wrists and fingers.
Alt e r a t io n s in C N S F u n c t io n 241
r ecept or bin din g, t h er eby in t en sifyin g t h e excit a t or y
effect s. In t issu es sen sit ive t o h ypoxia , su ch a s t h e
br a in , per m a n en t br a in in ju r y m a y r esu lt .
Th e n eu r on s of t h e h ippoca m pu s a n d cer ebr a l cor-
t ex a r e pa r t icu la r ly sen sit ive t o t h e excit a t or y effect s
of glu t a m a t e a n d in cr ea ses in ca lciu m t h a t r esu lt
fr om ch a n ges in ion t r a n spor t . Th e n eu r ot oxic effect s
m a y be m a n ifest ed by r edu ct ion s in h igh er-or der
fu n ct ion s a n d cogn it ive a n d m em or y a bilit ies. Neu -
r on a l cell dea t h m a y r esu lt fr om pr olon ged exposu r e
t o t h e effect s of glu t a m a t e.
Cell dea t h may be pr event ed if the effect s of glu-
t a ma t e ca n be blocked or t he excessive level of gluta -
m a te rem oved fr om t he neur ona l syna pses. Beca use
glut a ma t e is r equir ed by a wide va riety of cells for
nor ma l funct ioning, the developm ent of dr ugs t o block
or pr om ot e r eupt a ke of glut a ma t e ha s been ha mpered.
E xcit a t or y r espon ses m a y pr edom in a t e du r in g
per iods of det er ior a t in g br a in fu n ct ion . Loss of con -
sciou sn ess m a y pr om ot e t h e developm en t of d e c e r -
e b r a t e p o s t u r in g , t h e r esu lt of in cr ea sed ext en sor
m u scle excit a bilit y, or d e c o r t ic a t e p o s t u r in g ,
t h e r esu lt of in cr ea sed flexor m u scle excit a bilit y
(Fig. 10.9).
CNS PRESSURE INJURY
Th e sku ll a n d ver t ebr a l colu m n pr ovide t h e r igid
st r u ct u r e su r r ou n din g t h e br a in a n d spin a l cor d, r e-
st r ict in g t h e pot en t ia l a r ea of expa n sion . In cr ea ses
in pr essu r e m a y r esu lt in n eu r on a l in ju r y a n d cell
dea t h . In cr ea sed pr essu r e in t h e br a in a n d spin a l
cor d m a y r esu lt fr om excessive CSF volu m e, cer ebr a l
edem a , or spa ce-occu pyin g lesion s.
In cr ea sed CSF volu m e is t h e r esu lt of in -
cr ea sed pr odu ct ion or decr ea sed a bsor pt ion of CSF.
P la nta r fle xe d
Fle xe d P la nta r fle xe d
242 C h a p t e r 10: Alt er ed Neu r on a l Tr a n sm ission
Obst r u ct ion of t h e ven t r icu la r syst em pr even t s CSF
fr om r ea ch in g t h e a r a ch n oid villi. F low of t h e CSF
m a y be obst r u ct ed by in fla m m a t ion , t u m or, h em -
or r h a ge, or con gen it a l a n om a ly, pr om ot in g bu ildu p
in t h e ven t r icu la r syst em . Cer ebr a l h em isph er e en -
la r gem en t a n d dila t ion of t h e ven t r icles r esu lt fr om
pr essu r e in cr ea ses. Br a in st r u ct u r es a ffect ed by t h e
in cr ea sed pr essu r e r espon d wit h a lt er ed fu n ct ion a l
ca pa cit y. Respon ses m a y be a lt er ed by a ge a n d a sso-
cia t ed br a in developm en t .
Cer ebr a l edem a ca u sed by a bn or m a l wa t er a c-
cu m u la t ion m a y a lso con t r ibu t e t o pr essu r e in ju r y.
E dem a m a y be a r esu lt of t h e t r a n sfer of wa t er a n d
pr ot ein fr om t h e va scu la r t o t h e in t er st it ia l spa ce, a s
discu ssed in Ch a pt er 8. E dem a m a y a lso be ca u sed
by a n in cr ea se in in t r a cellu la r flu id ca u sed by a h y-
poosm ot ic st a t e, su ch a s occu r s wit h wa t er in t oxica -
t ion . Sever e isch em ia ca n a lso con t r ibu t e t o cer ebr a l
edem a . Swellin g of br a in cells in cr ea ses t issu e vol-
u m e, ca u sin g in ju r y t o cells. Ma n ifest a t ion s of cer e-
br a l edem a in clu de dist u r ba n ces in con sciou sn ess,
in t r a cr a n ia l h yper t en sion , a n d n eu r ologic deficit .
CNS t u m or s (discu ssed in Ch a pt er 7) ca n a lso
pr om ot e pr essu r e in ju r y. Br a in a n d spin a l cor d com -
pr ession , t u m or in filt r a t ion , a lt er ed blood flow, a n d
edem a a r e oft en t h e sequ ela e of pr essu r e in ju r ies r e-
su lt in g fr om t u m or s. Tu m or s m a y obst r u ct CSF flow
a n d pr om ot e br a in displa cem en t t o a n a r ea of lower
pr essu r e, kn own a s br a in h er n ia t ion . St im u la t ion of
Modu le 3 Alt e r a t io n s in P e r ip h e r a l N e r v o u s
S y s t e m F u n c t io n
Th e per iph er a l n er vou s syst em con n ect s t h e CNS
t o lim bs a n d or ga n s, t r a n sm it t in g n eu r a l im pu lses
via sen sor y pa t h wa ys in t o t h e dor sa l h or n a n d ex-
t en din g m ot or pa t h wa ys beyon d t h e ven t r a l h or n .
Loca t ed ou t side of t h e bou n da r ies of t h e CNS, t h e
per iph er a l n er vou s syst em is n ot pr ot ect ed by t h e
blood–br a in ba r r ier or bon y su ppor t of t h e CNS, in -
cr ea sin g t h e pot en t ia l for da m a ge du e t o t oxic a n d
m ech a n ica l in ju r y.
Peripheral Nervous System Organization
F u n ct ion a lly, t h e per iph er a l n er vou s syst em in -
clu des t h e som a t ic a n d t h e a u t on om ic n er vou s
syst em s. Mot or a n d sen sor y n er ves ca r r yin g n er ve
im pu lses t o a n d fr om t h e per iph er y of t h e body
a r e pa r t of t h e per iph er a l n er vou s syst em , in clu d-
in g t h e cr a n ia l a n d spin a l n er ves. Cr a n ia l n er ves
t h e vom it in g cen t er of t h e m edu lla m a y con t r ibu t e
t o sever e n a u sea . Per son a lit y a n d m en t a l ch a n ges,
in clu din g loss of m em or y a n d t h e developm en t of
depr ession , m a y r esu lt . Th e t u m or loca t ion a n d sit e
of pr essu r e in ju r y det er m in e t h e specific sign s a n d
sym pt om s eviden ced. Clin ica l m a n ifest a t ion s of
pr essu r e in ju r y a r e det er m in ed by t h e sit es of in ju r y
a n d sever it y of da m a ge, r a n gin g fr om leg wea kn ess
t o r espir a t or y a r r est .
A common response to pathologic events in the brain
is ICP. Increa sed ICP can lead to blood flow reduction,
dea th of brain cells, and da mage to brain structures.
Common symptoms of increa sed ICP include:
● H ea da ch e
● Vom it in g
● P a p ille d e m a (edem a of t h e opt ic disc)
● Men t a l det er ior a t ion
Wh en in cr ea sed ICP is ca u sed by excessive CSF
ven t r icu la r flu id volu m e, su r gica l sh u n t in g of CSF
fr om t h e in t r a ven t r icu la r spa ces t o t h e per it on eu m
m ay be r equ ir ed. A ca t h et er is in ser t ed in t o t h e left
la t er a l ven t r icle a n d pa ssed t h r ou gh t h e in t er n a l
ju gu la r vein in t o t h e r igh t a t r iu m (ven t r icu loa t r ia l
sh u n t ) or t h e per it on ea l ca vit y (ven t r icu loper it on ea l
sh u n t ). For in cr ea sed ICP ca u sed by cer ebr a l edem a ,
osm ot ic diu r et ics su ch a s m a n n it ol a r e oft en u sed t o
pr om ot e flu id r em ova l a n d excr et ion . Cor t icost er oids
m ay a lso be u sed t o st a bilize cell m em br a n es.
t h a t m edia t e per iph er a l r espon ses or igin a t e in t h e
br a in . Th er e a r e t welve pa ir ed cr a n ia l n er ves, ea ch
n a m ed, n u m ber ed, a n d specific in t h e sen sor y a n d
m ot or fu n ct ion s t h ey m edia t e (Ta ble 10.4). Th er e a r e
31 pa ir s of spin a l n er ves, ea ch con sist in g of sen sor y/
a ffer en t a n d m ot or /effer en t n eu r on s. Th ey a r e n a m ed
for t h e ver t ebr a im m edia t ely below t h eir exit poin t
fr om t h e spin a l cor d a n d in clu de 8 cer vica l, 12 t h o-
r a cic, 5 lu m ba r, 5 sa cr a l, a n d 1 coccygea l n er ve pa ir s.
Ta ble 10.5 pr ovides fu r t h er det a il on t h e loca t ion
a n d fu n ct ion of t h ese n er ves. Spin a l n er ves ca r r y
in for m a t ion t o a n d fr om pa r t icu la r body r egion s, or
d e r m a t o m e s (Fig. 10.10). Ma n ifest a t ion s of pa in ,
n u m bn ess, or t in glin g ca n be lin ked t o pr essu r e or
in fla m m a t ion of t h e spin a l n er ves a ssocia t ed wit h
specific der m a t om es. Spin a l n er ves for m t oget h er
in a n in t er con n ect ion of fiber s kn own a s a p le x u s .
Per iph er a l n er ves a r ise in n ew com bin a t ion s fr om
ea ch plexu s. Com m on plexu ses in clu de t h e cer vica l,
br a ch ia l, lu m ba r, a n d sa cr a l.
 Alt e r a t io n s in P e r ip h e r a l N e r v o u s S y s t e m F u n c t io n 243

Ta b le 10.4 Cr a n ia l Ner ves

Nu m b er Na m e L o c a t io n Typ e F u n c t io n
I Olfa ct or y Cer ebr a l cor t ex, a m ygda la , Sen sor y Sm ell r eflexes
h ippoca m pu s, ba sa l ga n glia
(ca u da t e n u cleu s, pu t a m en ,
globu s pa llidu s)
II Opt ic H ypot h a la m u s, t h a la m u s Sen sor y Vision
III Ocu lom ot or Ba sa l ga n glia , su bst a n t ia Mot or E xt r a ocu la r eye m ovem en t (su per ior, m e-
n igr a , cen t r a l gr a y m a t t er dia l a n d in fer ior la t er a l), pu pil con st r ict ion ,
u pper eyelid eleva t ion
IV Tr och lea r Pon s Mot or E xt r a ocu la r eye m ovem en t (in fer ior m edia l)
V Tr igem in a l Pon s Sen sor y Cor n ea l r eflex, t r a n sm ission of st im u li fr om
fa ce t o h ea d
Mot or La t er a l ja w m ovem en t , ch ewin g, bit in g
VI Abdu cen s Pon s Mot or E xt r a ocu la r eye m ovem en t (la t er a l)
VII Fa cia l Pon s Sen sor y Ta st e (a n t er ior t wo-t h ir ds of t on gu e)
Mot or Movem en t of fa cia l m u scles a n d m u scles
of expr ession in for eh ea d, a r ou n d eyes a n d
m ou t h
VIII Acou st ic Pon s Sen sor y H ea r in g, ba la n ce
(vestibulocochlear )
IX Glossoph a r yn gea l Medu lla Sen sor y Ta st e (post er ior on e-t h ir d of t h e t on gu e),
sen sa t ion s of t h e t h r oa t
Mot or Swa llow
X Va gu s Medu lla Sen sor y Sen sa t ion s of la r yn x, t h r oa t , a bdom in a l
(ga st r oin t est in a l t r a ct ), a n d t h or a cic viscer a
(h ea r t , lu n gs, br on ch i)
Mot or Pa la t e m ovem en t , swa llow, ga g, a ct ivit y of
t h or a cic a n d a bdom in a l viscer a (in clu din g
h ea r t r a t e a n d per ist a lsis)
XI Spin a l a ccessor y Medu lla Mot or Movem en t of sh ou lder s, h ea d r ot a t ion
XII H ypoglossa l Medu lla Mot or Ton gu e m ovem en t

Ta b le 10.5 Spin a l Ner ves

S p in a l N e r v e s L o c a t io n F u n c t io n
Lower cer vica l C5-C8 P r opr iocept ion , deep t en don r eflexes, m ovem en t , post u r e
Th or a cic T1-T12 P r opr iocept ion , m ovem en t , post u r e, r espir a t ion , sen sa t ion , sym pa -
t h et ic r eflexes (va som ot or con t r ol, swea t in g, piloer ect ion )
Lu m ba r L1-L5 P r opr iocept ion , deep t en don r eflexes, m ovem en t , post u r e, r eflexes
Sa cr a l S1-S5 P r opr iocept ion , r eflexes, defeca t ion , u r in a t ion , er ect ion
Coccygea l Co1-2 P r opr iocept ion , post u r e

Stop and Consider con sciou s con t r ol a r e t h e pr im a r y fu n ct ion s of t h e so-

When having a heart attack, a common
manifestation is pain in the left arm or shoul-
der. How are dermatomes related to this
phenomenon?
SOMATIC NERVOUS SYSTEM
Coor din a t ion of body m ovem en t , r ecept ion of ex-
t er n a l st im u li a n d r egu la t ion of a ct ivit ies u n der
m a t ic n er vou s syst em . Th e som a t ic n er vou s syst em
in clu des t h e per iph er a l fiber s t h a t t r a n sm it sen sor y
im pu lses in clu din g body posit ion , pa in , t em per a t u r e,
a n d t ou ch t o t h e CNS a n d m ot or im pu lses t o skelet a l
m u scle fr om cell bodies loca t ed in t h e br a in or spin a l
cor d. Ta r get s for in n er va t ion in clu de skelet a l m u s-
cle, skin a n d sen sor y or ga n s. A r eview of som a t ic a n d
specia l sen sor y fu n ct ion a n d dysfu n ct ion is in clu ded
in Ch a pt er 12.
244 C h a p t e r 10: Alt er ed Neu r on a l Tr a n sm ission

C2
C3
C2 C4
C3 C5
C4 C6
C5 C7
T1 T1 C8
T2 C6 T2
T3 T3
T4
T4 T6 T5
T5 T8 T7
T6 T10 T9
T7 T11
T8 T12
T9 L1
T10 L2
T11 L3
T12 L4
L5
L1 S1 S2
L2 S3
S2 S5 S4
S3 C8
C7
L3 C8
C7 L5

L4 L2

L5
L3

S1 L4
L5

Figure 10.10. Distribution of dermatomes. Spinal nerves transmit impulses to specific areas known as dermatomes.

AUTONOMIC NERVOUS SYSTEM n eu r on s, ext en din g sh or t post ga n glion ic fiber s in t o

t h e or ga n wa lls. P N S is oft en lin ked wit h va ga l
Th e a u t on om ic n er vou s syst em (ANS) con t r ols in vol-
stim u la tion beca u se a ppr oxim a t ely 75% of a ll P NS
u n t a r y fu n ct ion s of or ga n s. All in t er n a l or ga n s a r e
im pu lses t r a vel a lon g t h e va gu s n er ve (cr a n ia l
in n er va t ed by t h e ANS, wh ich t r a n sm it s m essa ges
n er ve X). On e of t h e differ en ces bet ween t h e AN S
fr om t h e br a in a n d n eu r oen docr in e syst em . Th e t wo
a n d t h e som a t ic n er vou s syst em is t h a t t h e la t t er
m a jor division s of t h e ANS a r e t h e sym pa t h et ic n er-
in volves on ly on e n eu r on , wh er ea s t h e ANS r e-
vou s syst em (SNS) a n d pa r a sym pa t h et ic n er vou s
qu ir es t wo.
syst em (P NS). Th ese syst em s gen er a lly wor k in op-
posit ion t o on e a n ot h er, wor kin g t owa r d h om eost a t ic
ba la n ce. Sympathetic Nervous System
Axon fiber s ext en din g fr om cell bodies in eit h er
Th e s y m p a t h e t ic n e r v o u s s y s t e m is a lso kn own
t h e br a in or spin a l cor d pr oject t o a n a u t on om ic
a s t h e t h o r a c o lu m b a r n e r v o u s s y s t e m beca u se
g a n g lio n (gr ou p of n er ve cell bodies) kn own a s p r e -
of t h e loca t ion of t h e n er ve exit sit es. Spin a l cor d
g a n g lio n ic n e u r o n s . F iber s pr oject in g fr om t h e
exit sit es of t h e SNS n eu r on s a r e loca t ed bet ween
a u t on om ic ga n glion t o a t a r get or ga n a r e kn own a s
t h e fir st t h or a cic a n d secon d lu m ba r ver t ebr a e. Th e
p o s t g a n g lio n ic n e u r o n s . Th e SNS h a s sh or t pr e-
n er ves lea ve t h e spin a l cor d t o m er ge wit h ga n -
ga n glion ic fiber s t h a t syn a pse ou t side t h e spin a l
glia . Th e pr ega n glion ic n eu r on s en t er ga n glia n ea r
cor d wit h secon da r y n eu r on s. Lon g SNS post ga n gli-
t h e cor d, wh er e t h e im pu lse is t h en ca r r ied t o t h e
on ic fiber s syn a pse on t a r get or ga n s. Th e except ion
post ga n glion ic n eu r on s (Fig. 10.11). Sym pa t h et ic a c-
t o t h is pa t t er n is in t h e ca se of t h e a dr en a l m edu lla .
t ivit y is r espon sible for :
H er e, t h e u n u su a lly lon g pr ega n glion ic fiber s of t h e
SNS syn a pse dir ect ly on t o t h e a dr en a l m edu lla , wit h ● In cr ea sed h ea r t r a t e a n d con t r a ct ilit y
t h e a dr en a l m edu lla it self ser vin g a s t h e secon da r y ● Sm oot h m u scle r ela xa t ion of t h e br on ch ioles
fiber. ● Decr ea sed per ist a lsis of t h e ga st r oin t est in a l (GI)
Th e P N S or ga n iza t ion differ s fr om t h e SN S, wit h t r a ct a n d con st r ict ion of a n a l sph in ct er
lon g pr ega n glion ic fiber s ext en din g t o t h e wa lls of ● Decr ea sed bla dder t on e a n d con st r ict ion of
t a r get or ga n s. Th er e, t h ey syn a pse wit h secon da r y u r in a r y sph in ct er
 Alt e r a t io n s in P e r ip h e r a l N e r v o u s S y s t e m F u n c t io n 245
Blood ve s s e ls of vis ce ra l s tructure s,
blood ve s s e ls, swe a t gla nds, a nd
a rre ctor mus cle s of ha irs
Eye (iris )

Ca rotid
pe ria rte ria l
plexus
La crima l a nd
s a liva ry gla nds

Lungs

He a rt

T1
T2
T3
T4 Live r
T5
T6 Ce lia c
ga nglion S toma ch
T7
Ga llbla dde r
T8
T9 Pa ncre a s
T10
T11
T12
Adre na l S ma ll
L1
gla nd inte s tine
L2
La rge inte s tine
Re ctum
S upe rior
me s e nte ric
ga nglion
Infe rior Bla dde r
me s e nte ric
S ympa the tic
ga nglion
trunk
Pe nis (clitoris )

Gona ds
S ympathe tic fibe rs
P re s yna ptic
Pos ts yna ptic

Figure 10.11. Distribution of sympathetic nerve fibers. (Modified from Moore KL, Agur A. Essential Clinical Anatomy.
2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2002.)

● Va socon st r ict ion a n d eleva t ed blood pr essu r e
● In cr ea sed r espir a t or y r a t e
● P u pil dila t ion a n d cilia r y m u scle r ela xa t ion
● Redu ced secr et ion of t h e pa n cr ea s
● In cr ea sed swea t gla n d secr et ion
Parasympathetic Nervous System
Th e n eu r on s of t h e P NS lea ve t h e CNS via t h e cr a -
n ia l n er ves fr om t h e m idbr a in a n d t h e m edu lla ,
a n d wit h t h e spin a l n er ves bet ween S2 a n d S4 (cr a -
n iosa cr a l). Th e pr ega n glion ic n eu r on s of t h e P NS
a r e lon g, t r a velin g close t o or ga n s or gla n ds. Th e
sh or t er post ga n glion ic fiber s in n er va t e or ga n s a n d
gla n ds, st im u la t in g specific r espon ses in t h e t a r get s
(Fig. 10.12). Th e t ypica l effect s of P NS in n er va t ion
in clu de:
● Decr ea sed h ea r t r a t e, con t r a ct ilit y, a n d velocit y of
con du ct ion
● Con st r ict ion of br on ch ia l sm oot h m u scle
● In cr ea sed per ist a lsis a n d GI t on e wit h r ela xa t ion
of a n a l sph in ct er
● In cr ea sed bla dder t on e a n d r ela xa t ion of u r in a r y
sph in ct er
● Va sodila t ion of a r t er ies su pplyin g ext er n a l
gen it a lia
● Con st r ict ion of pu pils
● In cr ea se in pa n cr ea t ic, sa liva r y, a n d eye secr et ion s
246 C h a p t e r 10: Alt er ed Neu r on a l Tr a n sm ission

Eye (iris, Cilia ry

cilia ry mus cle s ) ga nglion
Oculomotor
ne rve (CNIII)
P te rygopa la tine
ga nglion
S ubma ndibula r
La crima l a nd ga nglion
s a liva ry gla nds Fa cia l ne rve (CNVII)
Otic
ga nglion Glos s opha rynge a l
ne rve (CNIX)
Va gus ne rve
(CNX)
Lungs

He a rt

Live r

Ga llbla dde r S toma ch

Pa ncre a s
S ma ll
inte s tine

La rge inte s tine

Re ctum

Bla dde r S2
S3
S4
Pe nis
(clitoris )
Paras ympathe tic fibe rs
P re s yna ptic
Pos ts yna ptic

Figure 10.12. Distribution of parasympathetic nerve fibers. (Modified from Moore KL, Agur A. Essential Clinical Anatomy.
2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2002.)

Reflex Arcs of t h e a n t er ior t h igh m u scles t h r ou gh con du ct ion of

Com m u n ica t ion bet ween va r iou s segm en t s of t h e
n er vou s syst em ca n be illu st r a t ed by t h e r eflex a r c. A
ba sic fu n ct ion a l pa t h wa y of t h e n er vou s syst em , t h e
r e le x a r c r epr esen t s t h e pr ocess by wh ich st im u li
a r e r eceived a n d in t er pr et ed, a n d in t u r n st im u la t e
a r espon se. For exa m ple, t h e kn ee-jer k r espon se, a lso
kn own a s t h e pa t ella r or deep t en don r eflex (DTR),
is a ba sic r eflex r equ ir in g on e sen sor y n eu r on a n d
on e m ot or n eu r on wit h a syn a pse in t h e CNS. A t a p
on t h e pa t ella r t en don ca u ses a su dden con t r a ct ion
t h e n er ve im pu lse t h r ou gh t h e sen sor y a ffer en t t o
t h e dor sa l h or n of t h e spin a l cor d. Th er e, t h e im pu lse
is con du ct ed t o a n in t er n eu r on , t h en t o t h e m ot or
n eu r on , a n d a wa y t o t h e per iph er a l t a r get , wh ich
is t h e skelet a l m u scle spin dle of t h e a n t er ior t h igh
(Fig. 10.13). Usin g t h is sim ple t est , t h e fu n ct ion of
t h e followin g com pon en t s of t h e n er vou s syst em ca n
be det er m in ed:
● Per iph er a l a ffer en t n eu r on
● Per iph er a l m u scle sen sor y r espon se
 Alt e r a t io n s in P e r ip h e r a l N e r v o u s S y s t e m F u n c t io n 247

S e ns ory a ffe re nt oft en t h e r esu lt of da m a ge du e t o t r a u m a or pr es-

ne uron su r e. In ju r y t o t h e cells of t h e per iph er a l n er vou s
syst em sh ows a m or e lim it ed scope of r espon ses,
in clu din g degen er a t ion of t h e a xon s a n d segm en -
t a l dem yelin a t ion . Respon ses of per iph er a l n er-
Qua drice ps vou s syst em cells t o in ju r y differ fr om CN S cell
r espon ses in t h a t per iph er a l n er vou s syst em cells
h a ve som e ca pa cit y for r egen er a t ion , r epa ir, a n d
r ein n er va t ion .
Alpha motor
ne uron
MECHANISMS OF INJURY TO THE
PERIPHERAL NERVOUS SYSTEM
Mus cle Axon a l degen er a t ion is ca u sed by n ecr osis in r e-
s pindle spon se t o sign ifica n t in ju r y t o t h e cell body or a xon
Te ndon of of t h e n eu r on . In t h is pr ocess, a n in fla m m a t or y r e-
qua drice ps spon se is st im u la t ed, lea din g t o ph a gocyt osis of cel-
lu la r debr is by m a cr oph a ges. D is t a l a x o n o p a t h y
occu r s wh en t h e in ju r y a ffect s cells in dist a l a r ea s
of t h e body, su ch a s t h e h a n ds a n d feet . Regen er a -
t ion of a xon s m a y be possible if t h e cell body a n d
pr oxim a l a xon s a r e n ot da m a ged. Wh en a xon a l
degen er a t ion occu r s beca u se of da m a ge t o t h e cell
body (n e u r o n o p a t h y ), t h e ch a n ce for r egen er a t ion
is gr ea t ly r edu ced. Wh en degen er a t ion of t h e a xon is
ca u sed by a cr u sh in g in ju r y, it is kn own a s a Wa lle -
r ia n d e g e n e r a t io n . Th e clin ica l m a n ifest a t ion s of
Figure 10.13. Reflex arc pathway. Reflex arc demon- da m a ge t o per iph er a l n er ves a r e ca lled p e r ip h e r a l
strating the pathway of impulses between the receptor, n e u r o p a t h y . Ba sic r espon ses of per iph er a l n er ves
spinal cord, and target organ. (From Bear MF, Connors BW, t o in ju r y a r e descr ibed in Figu r e 10.14.
Parasido MA. Neuroscience: Exploring the Brain. 3rd ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2006.)
Traumatic Peripheral Nerve Injury
Tr a u m a t ic in ju r y t o per iph er a l n er ves ca n occu r
beca u se of t h e cr u sh in g or cu t t in g of n eu r on s. Th e
a r ea of n er ve fiber t h a t is sever ed fr om t h e cell body
● Dor sa l r oot ga n glia degen er a t es (Wa ller ia n degen er a t ion ), st im u la t in g
● Dor sa l a n d ven t r a l h or n t h e in fla m m a t or y pr ocesses in du ced by n ecr osis.
● Mot or n eu r on Ch r om a t olysis is in du ced in t h e in ju r ed n eu r on s.
● Neu r om u scu la r syn a pse Da m a ge t o per iph er a l n er ves fr om t r a u m a t ic in -
● Mu scle fiber con t r a ct ile r espon se ju r y m a n ifest s wit h sen sor y sym pt om s. Th ese m a y
● Select ed spin a l a n d cr a n ia l n er ves in clu de:
● Br a in st em
● Nu m bn ess
Alt h ou gh t h is exa m ple r epr esen t s t h e r eflex a r c in ● Pa r est h esia
it s sim plest for m , st im u la t ion of DTRs a n d ot h er ● Pa in
m or e com plex r eflex a r cs a r e sign ifica n t clin ica l
t ools u sed t o qu ickly eva lu a t e n eu r ologic st a t u s. Th e sym pt om s t h a t r esu lt fr om per iph er a l n er ve
t r a u m a a r e r ela t ed t o t h e n u m ber of a xon s in volved
a n d t h e a bilit y of a xon s t o r egen er a t e. Regen er a t ion
of per iph er a l n er ve fiber s depen ds on t h e dist a n ce
Peripheral Nervous System t h e r egr owin g fiber m u st go t o r est or e com m u n i-
Cellular Injury ca t ion . Beca u se cr u sh in g in ju r ies do n ot in volve
t h e com plet e sepa r a t ion of t h e a xon a n d cell body
Th e per iph er a l n er ves a n d t h eir con n ect ive t issu e fr om t h e t a r get or ga n , r egen er a t ion su ccess is m u ch
su ppor t a r e vu ln er a ble t o in ju r y du e t o t h e la ck of gr ea t er in t h ese in ju r ies t h a n in fiber s da m a ged by
pr ot ect ion a ffor ded by t h e blood–br a in ba r r ier a n d cu t t in g in ju r ies. Wh en n er ve t r a u m a is lim it ed t o a
bon y lim it s of t h e CN S. Per iph er a l n er ve in ju r y is sin gle a r ea (m o n o n e u r o p a t h y ), con dit ion s su ch a s
248 C h a p t e r 10: Alt er ed Neu r on a l Tr a n sm ission

Inta ct mye lina te d fibe r Per iph er a l n er ve da m a ge in volvin g m u lt iple a x-

S tria te d
Nucle us S chwa nn ce ll Node of mus cle on s is kn own a s p o ly n e u r o p a t h y . Polyn eu r opa t h y
nucle us Ra nvie r ca n occu r secon da r y t o disea se pr ocesses su ch a s
m u lt iple scler osis (MS), dia bet es m ellit u s, n u t r ien t
deficien cy, a n d t oxic a gen t s (a r sen ic). It con t r ibu t es
Inte rnode Mye lin Axon t o m u lt isyst em ic r espon ses ch a r a ct er ized by n eu r a l
s he a th
degen er a t ion , n eu r om a for m a t ion , dem yelin a t ion ,
a n d gen er a t ion of a bn or m a l, spon t a n eou s n er ve im -
Dis ta l a xona l de ge ne ra tion
pu lses fr om in ju r ed n eu r on s. Respon ses m a y in volve
De bris from bre a kdown a lt er a t ion s in sen sa t ion , m ot or, or m ixed r espon ses.
of mye lin s he a th
If t h e a u t on om ic n er vou s syst em is in volved, sys-
t em ic a lt er a t ion s a ffect in g blood pr essu r e, eva cu a -
t ion of bowel or bla dder, a n d er ect ile fu n ct ion m a y
r esu lt .
De ge ne ra tion of ce ll body a nd a xon

Peripheral Nervous System Pressure Injury

P r essu r e on per iph er a l n er ves m a y a lso con t r ibu t e
t o n er ve in ju r y a n d a ssocia t ed sym pt om s. E dem a
in con st r ict ed spa ces m a y ca u se t h is t ype of in ju r y.
S e gme nta l de mye lina tion
Sym pt om s m a y be m ild, a s in t h e ca se of ca r pa l
t u n n el syn dr om e wh en edem a ca u ses pa in a n d pa r-
est h esia in t h e h a n ds. Th is da m a ge is u su a lly r e-
ver sible by cor r ect in g t h e edem a . Tr a u m a m a y lea d
t o edem a for m a t ion im pin gin g on a n er ve plexu s,
a s in t h e ca se of bir t h t r a u m a lea din g t o b r a c h i a l
p le x u s p a ls y . Th e br a ch ia l plexu s pr ovides in n er-
Re mye lina tion
va t ion t o t h e sh ou lder, a r m , for ea r m , wr ist , a n d
h a n d. F la ccid pa r a lysis of t h e a ffect ed a r m , wh ich
is u su a lly t em por a r y, occu r s fr om a lt er ed n eu r a l
t r a n sm ission ca u sed by edem a -in du ced com pr es-
sion . N eu r om a m a y develop du r in g t h e pr ocess
of in ju r y r epa ir, r esu lt in g in m or e sign ifica n t
Re ge ne ra tion a xon im pa ir m en t .
Axona l s prouts

P rolife ra ting S chwa nn ce lls wa iting Peripheral Nervous System

to e ns he a th re ge ne ra ting a xon
Re ge ne ra te d ne rve fibe r
Figure 10.14. Basic responses of peripheral nerve
fibers to injury. (From Rubin E, Farber JL. Pathology.
4th ed. Philadelphia, PA: Lippincott Williams & Wilkins;
2005.)
n er ve en t r a pm en t a n d com pr ession m a y con t r ibu t e
t o im pa ir ed fu n ct ion a l r espon ses. Sen sor y r espon ses
t o t r a u m a t ic n er ve in ju r y ca n r esu lt fr om sca r t issu e
for m a t ion en t r a ppin g a r egen er a t in g n er ve.
Motor Dysfunction
Disor der s of m ot or fu n ct ion m a y be t h e r esu lt of
per iph er a l n er ve in ju r y t h a t a lt er s r eflex cir cu it s.
Th ese disor der s a lso ca n r esu lt fr om n eu r om u scu -
la r ju n ct ion a bn or m a lit ies, da m a ge in skelet a l m u s-
cle fiber s, or SCI wit h da m a ge t o t h e cor t icospin a l
syst em or spin a l n er ve r oot s. Ch a n ges in skelet a l
m u scle m a ss, su ch a s occu r s wit h a t r oph y or dys-
t r oph y, m a y con t r ibu t e t o im pa ir ed r espon ses t o
a dequ a t e n eu r a l t r a n sm ission . Movem en t disor-
der s m a y be ca u sed by excessive in h ibit or y or ex-
cit a t or y r espon ses in n er vou s t issu e t h a t con t r ol
fu n ct ion s su ch a s coor din a t ion a n d pr opr iocept ion .
Movem en t disor der s a r e ch a r a ct er ist ic of e x t r a p y -
r a m id a l d is o r d e r s , wh ich in volve br a in st r u ct u r es
wit h t h e exclu sion of t h e m ot or n eu r on s, m ot or cor-
t ex, a n d pyr a m ida l t r a ct (cor t icobu lba r a n d cor t ico-
spin a l). Th e ext r a pyr a m ida l syst em (E P S) is oft en

Box 10.1 Mo v e m e n t D is o r d e r s
At a xia —In a bilit y t o coor din a t e m u scle a ct ivit y
At h et osis—In volu n t a r y m ovem en t s of flexion a n d ext en -
sion , pr on a t ion a n d su pin a t ion of h a n ds, t oes, a n d feet ;
slow, wr it h in g-t ype m ovem en t s
Ba llism u s—J er kin g, swin gin g, sweepin g m ot ion s of t h e
pr oxim a l lim bs
Br a dykin esia /h ypokin esia —Decr ea se in spon t a n eit y a n d
m ovem en t
Ch or ea —Ir r egu la r, spa sm odic, in volu n t a r y m ovem en t s
of t h e lim bs or fa cia l m u scles, oft en a ccom pa n ied by
h ypot on ia
Cogwh eel—Resist a n ce t o m ovem en t ; r igidit y decr ea sin g t o
st iffn ess a ft er m ovem en t begin s
Dystonia—Abnormal tonicity; difficulty maintaining posture
H yper kin esis—E xcessive m ot or a ct ivit y
Tic—Repea t ed, h a bit u a l m u scle con t r a ct ion s; m ovem en t s
t h a t ca n be volu n t a r ily su ppr essed for sh or t per iod on ly
Tr em or —Oscilla t in g, r epet it ive m ovem en t s of wh ole m u s-
cles; ir r egu la r, in volu n t a r y con t r a ct ion s of t h e opposin g
m u scle
Modu le 4 C lin ic a l Mo d e ls
Ma n ifest a t ion s of n eu r ologic a lt er a t ion s a r e oft en
specific t o t h e loca t ion of in ju r y or da m a ge. Alt er-
a t ion s in m en t a l st a t u s m a y in clu de sym pt om s of a l-
t er ed con sciou sn ess, con fu sion , depr ession , a n xiet y,
psych osis, in a t t en t iven ess, loss of r a t ion a l t h ou gh t ,
im pa ir ed m em or y, a n d poor ju dgm en t . Alt er a t ion s in
coor din a t ion lea d t o poor ba la n ce, in ju r y fr om fa lls,
difficu lt y in per for m in g t h e a c t iv it ie s o d a ily liv -
in g (AD L ), a n d m ovem en t disor der s. Sen sor y defi-
cit s in clu de blin dn ess, dea fn ess, pa in , loss of t h e
a bilit y t o sm ell or t a st e, a n d la ck of sen sa t ion . Ma n -
ifest a t ion s of m ot or deficit s m a y in volve pa r a lysis,
im pa ir ed volu n t a r y m ovem en t s, or en h a n ced in vol-
u n t a r y m ovem en t .
A com plet e n eu r ologic exa m in a t ion m a y be n eces-
sa r y t o iden t ify a n d dia gn ose n eu r ologic disor der s.
Wh en specific sym pt om s poin t t o a pa r t icu la r in ju r y
or t ype of disor der, a m or e focu sed exa m in a t ion m a y
be per for m ed. Ta ble 10.6 ou t lin es t h e com pon en t s
of a gen er a l n eu r ologic exa m in a t ion . Tr ea t m en t of
n eu r ologic disor der s is focu sed on cu r in g, t r ea t in g,
or a llevia t in g sym pt om s. P sych ia t r ic disor der s of a l-
t er ed m en t a l st a t u s a r e oft en m a n a ged wit h beh a v-
ior a l, cogn it ive, a n d ph a r m a cologic m et h ods a n d a r e
det a iled in Ch a pt er 11. Syn t h et ic dr u gs t h a t a lt er
n eu r ot r a n sm it t er fu n ct ion m a y h elp m a n a ge psych i-
a t r ic, m ot or, coor din a t ion , a n d sen sor y a lt er a t ion s.
Sym pt om m a n a gem en t ca n in clu de t r ea t m en t s t o
r edu ce spa st icit y, in cr ea se m u scle st r en gt h a n d
t on e, a n d im pr ove m em or y. A r eview of u n der lyin g
C lin ic a l Mo d e ls 249
specifica lly r efer r in g t o t h e st r u ct u r es of t h e ba sa l
ga n glia , su bst a n t ia n igr a , a n d su bt h a la m ic n u cleu s.
Neu r ot r a n sm it t er excesses or deficien cy m a y a lso
con t r ibu t e t o m ovem en t disor der s. Box 10.1 list s
t er m s u sed t o descr ibe specific disor der s of m ove-
m en t . Sen sor y deficit s m a y a lso r esu lt fr om a lt er ed
n eu r on a l t r a n sm ission . Th ese a lt er a t ion s a r e ex-
plor ed in Ch a pt er 12.
Stop and Consider
Why is it important to characterize specific types
of altered movement?
Stop and Consider
What are the challenges of maintaining a
treatment plan for a person with clinical signs
and symptoms related to altered neuronal
transmission?
m ech a n ism s lea din g t o m a n ifest a t ion s of n eu r on a l
disea se is su m m a r ized in F igu r e 10.15.
Th e clin ica l m odels pr esen t ed in t h is ch a pt er in -
cor por a t e t h e con cept s of a lt er ed n eu r on a l t r a n sm is-
sion . In dividu a l con cept s a r e h igh ligh t ed, a lt h ou gh ,
clea r ly, ea ch is r ela t ed t o t h e ot h er. Wh en r eviewin g
t h e clin ica l m odels, a pply pr eviou sly lea r n ed con -
cept s t o ea ch a lt er a t ion .
Cerebral Palsy
Cer ebr a l pa lsy (CP ) is a gr ou p of disor der s r esu lt -
in g fr om da m a ge t o u pper m ot or n eu r on s. Sym pt om s
a ppea r du r in g t h e fir st few yea r s of life. Th e n eu r o-
m u scu la r disor der s t h a t com pr ise CP st em fr om a n
even t t h a t occu r s du r in g t h e pr en a t a l, per in a t a l (20
weeks’ gest a t ion t h r ou gh 28 n ewbor n da ys), or post -
n a t a l (a ft er bir t h ) per iods. Accor din g t o t h e Ma r ch of
Dim es, CP a ffect s a ppr oxim a t ely 1 in 300 ch ildr en ,
dia gn osed a t t h e a ge of 2 yea r s.3
PATHOPHYSIOLOGY
Cen t r a l con t r ol of m ovem en t by t h e br a in is a lt er ed
in CP. Alt h ou gh t h e exa ct ca u se is n ot fu lly kn own ,
cer ebr a l a n oxia , h em or r h a ge, a n d ot h er n eu r ologic
in su lt s a r e likely in volved. Cla ssifica t ion s of CP ca n
be ba sed on t h e t ype of m ot or dysfu n ct ion or by t h e
a n a t om y a ffect ed, a s list ed below:
250 C h a p t e r 10: Alt er ed Neu r on a l Tr a n sm ission

● Mot or dysfu n ct ion cla ssi fica -

t ion s Ta b le 10.6 Com pon en t s of a Gen er a l Neu r ologic E xa m in a t ion
■ Sp a st ic: inability of mus-
E x a m in a t io n C o m p o n e n t F in d in g s
cles to relax
■ Hemiplegia: involving one Men t a l st a t u s Or ien t a t ion : t im e, pla ce, a n d per son ; m em or y,
a t t en t ion , ju dgm en t , r ea son in g
arm and one leg on the
same side of the body La n gu a ge E xpr essive a ph a sia ; pr oblem s wit h expr ession :
r ecept ive a ph a sia ; pr oblem s wit h u n der st a n d-
■ Diplegia : in volvin g bot h
in g: dysa r t h r ia ; pr oblem s wit h wor d for m a t ion
legs
Sen sor y fu n ct ion Vision : pu pil r espon siven ess, a cu it y, visu a l
■ Qu a dr iplegia : in volvin g fields, ext r a ocu la r eye m ovem en t s
a ll fou r ext r em it ies, t h e
H ea r in g, t ou ch , pa in , t em per a t u r e, pr essu r e,
t r u n k, a n d n eck m u scles t a st e, posit ion sen se, ga g r eflex
■ At h e t o id o r d y s k in e t ic :
Coor din a t ion Tr em or, r a pid a lt er n a t in g foot a n d h a n d m ove-
in a bilit y t o con t r ol m u scle m en t s, fin ger t o n ose, t oe t o fin ger
m ovem en t Ga it
■ At a x ic : in a bilit y t o con t r ol
Mot or fu n ct ion Movem en t : volu n t a r y, r eflexive
ba la n ce a n d coor din a t ion
Mu scle t on e Cogwh eelin g, spa st icit y, r igidit y
Mu scle st r en gt h H a n d gr a sp, st r en gt h of flexor s a n d ext en sor s
CLINICAL MANIFESTATIONS
Sym pt om s of CP va r y a m on g
in dividu a ls, in volvin g a lt er ed body m ovem en t a n d Im pa ir m en t m a y be m a n ifest ed by m ild m ot or dys-
m u scle coor din a t ion . E a r ly sign s of m ot or in volve- fu n ct ion du r in g ph ysica l a ct ivit ies, su ch a s r u n n in g,
m en t in clu ded dela y in r ea ch in g m ilest on es in in - or by sever e disa bilit y. In dividu a ls wit h CP m a y
fa n cy. Typica l developm en t a l m ilest on es in in fa n cy h a ve t r ou ble wit h t h eir fin e m ot or skills or coor di-
a r e ba sed on m ot or fu n ct ion , in clu din g: n a t ion for ba la n ce a n d wa lkin g. Cogn it ive fu n ct ion ,
● Rea ch in g for t oy, 3 t o 4 m on t h s speech , a n d seizu r e disor der s a r e a lso com m on m a n -
● Sit t in g, 6 t o 7 m on t h s ifest a t ion s a ssocia t ed wit h CP. Seizu r es a n d m en t a l
● Wa lkin g, 10 t o 14 m on t h s disor der s r epr esen t t h e m or e sever e con sequ en ces of

Ne uro nal injury

Tra uma tic Is che mic Excita tion P re s s ure

Ce ntra l ne rvous Pe riphe ra l ne rvous

s ys te m s ys te m

Alte re d ne uro nal trans mis s io n

Mental status alteration Movement and coordination disorders Sensory disorders

Coma Paralysis Blindness
Confusion Impaired voluntary movement Deafness
Memory loss Altered balance Pain

Figure 10.15. Concept map. Mechanisms of neuronal disorders.


CP. Sign s of m ilder for m s of CP m a y be seen du r in g
in fa n cy, wh en developm en t a l m ilest on es a r e n ot
a ch ieved a s expect ed. CP is n ot a pr ogr essive dis-
ea se; t h er efor e, wor sen in g disa bilit ies a n d det er io-
r a t ion of n eu r a l fu n ct ion a r e n ot expect ed wit h t h is
dia gn osis.
Th e developm en t of seizu r es is oft en a ssocia t ed
wit h CP, especia lly wh en t h e u n der lyin g even t r e-
su lt s in h ypoxic in su lt .4 E xcit ot oxic in ju r y of t h e
br a in ca u sed by excessive glu t a m a t e-m edia t ed
t r a n sm ission m a y r epr esen t sequ ela e of n eon a t a l
br a in in ju r y. Glia l u pt a ke of glu t a m a t e m a y be im -
pa ir ed, r esu lt in g in over st im u la t ion of glu t a m a t e
r ecept or s, NMDA, a n d a lph a -a m in o-3-h ydr oxy-5-
m et h yl-4-isoxa zole pr opion ic a cid (AMPA).5
Th e n eon a t a l br a in , st ill u n der goin g m a t u r a t ion ,
is ext r em ely vu ln er a ble t o cell dea t h beca u se of t h is
excit ot oxic in ju r y. Neon a t a l seizu r es m a y r eflect t h e
con sequ en ces of br a in in ju r y. Seizu r e disor der, or ep-
ilepsy, is t h e r esu lt of im pa ir ed ch em ica l a n d elec-
t r ica l n eu r ot r a n sm ission . Im pu lses a r e spr ea d in
a disor der ly wa y r esu lt in g fr om a bn or m a l fir in g of
n eu r on s in t h e cer ebr a l cor t ex. Du r in g t h e n eon a t a l
per iod, seizu r es m a y be su bt le, lim it ed t o eye m ove-
m en t s, su st a in ed eye open in g, t on gu e m ovem en t , or
lip sm a ckin g. Over t im e, seizu r e a ct ivit y m a y becom e
m or e obviou s.
Pa r t ia l seizu r es begin loca lly in a sm a ll gr ou p
of n eu r on s in on e h em isph er e, spr ea din g im pu lses
t h r ou gh ou t t h a t h em isph er e or t o t h e ot h er side of
t h e br a in . S im ple pa r tia l seizu r es a r e lim it ed t o t h e
or igin a t in g h em isph er e a n d ca n in volve eit h er m ot or
or sen sor y br a in com pon en t s. Sym pt om s a r e sen sor y
a n d a u t on om ic wit h ou t pr om ot in g a n a lt er ed st a t e
of con sciou sn ess. Com plex pa r tia l seizu r es in volve
bot h h em isph er es a n d r esu lt in loss of con sciou sn ess
a n d la ck of m em or y a bou t even t s du r in g a n d a ft er
seizu r e. Pa r t ia l seizu r es a r e sh or t lived, la st in g a
S imple
Complex
S pre a d of e le ctrica l
impuls e s
A
Figure 10.16. Seizure activity in the brain. A: Simple and complex partial seizures. B: Generalized seizures.
C lin ic a l Mo d e ls 251
few secon ds in sim ple seizu r es a n d a few m in u t es in
com plex seizu r es.
Gen er a lized seizu r es a r e ca u sed by a m or e gen -
er a lized elect r ica l t r a n sm ission . Absen ce seizu r es,
ch a r a ct er ized by a br ief ch a n ge in level of con sciou s-
n ess (LOC) a n d eye a n d m ou t h m ovem en t s, ca n occu r
u p t o 100 t im es a da y. Myoclon ic seizu r es a r e ch a r a c-
t er ized by in volu n t a r y m u scle m ovem en t s of t h e ex-
t r em it ies or body, a n d a r e n ot a ssocia t ed wit h LOC.
Ton ic–clon ic seizu r es a r e con vu lsive a n d a r e a ssoci-
a t ed wit h t o n ic (a st a t e of con t in u ou s m u scle con -
t r a ct ion ) or c lo n ic (r a pid su ccession s of a lt er n a t in g
m u scle con t r a ct ion a n d r ela xa t ion ) m ot ion s. Loss of
con sciou sn ess a n d t r a u m a t ic in ju r y r ela t ed t o a fa ll
m a y r esu lt . Th e seizu r es r esolve in 2 t o 5 m in u t es,
depen din g on t h e du r a t ion of t h e a lt er ed elect r ica l
cu r r en t . Recover y fr om t h e seizu r e is m a n ifest ed by
ext r em e fa t igu e, h ea da ch e, m u scle pa in , a n d wea k-
n ess, a lso r efer r ed t o a s t h e p o s t -ic t a l st a t e. S ta tu s
epilepticu s is a pot en t ia lly life-t h r ea t en in g con dit ion
ch a r a ct er ized by a con t in u ou s t on ic–clon ic seizu r e,
wh ich lea ds t o h ypoxia (F ig. 10.16).
DIAGNOSTIC CRITERIA
P in poin t in g a specific t im e or even t t h a t r esu lt ed in
t h e m a n ifest a t ion s of CP is oft en difficu lt . Th e Am er-
ica n College of Obst et r icia n s a n d Gyn ecologist s h a s
a t t em pt ed t o defin e cr it er ia t o h elp det er m in e t h e
effect s of a da m a gin g n eu r ologic even t du r in g la bor
or deliver y. 6 Th ese cr it er ia in clu de:
1. Apga r scor e (m ea su r es of h ea r t r a t e, r espir a t or y
effor t , color, r eflexes, m u scle t on e) less t h a n 7 a t
5 m in u t es a ft er bir t h .
2. Met a bolic a cidosis det er m in ed fr om a n a lysis of
t h e fet a l u m bilica l a r t er y cor d blood a t deliver y
t h a t in clu des a ba se deficit of 12 m m ol/L or m or e
a n d pH less t h a n 7.
S pre a d of
e le ctrica l impuls e s
B
252 C h a p t e r 10: Alt er ed Neu r on a l Tr a n sm ission

3. E viden ce of cer ebr a l h ypoxic–isch em ic in ju r y Ne uron

ba sed on MRI im a gin g.
4. Or ga n syst em fa ilu r e (r en a l, liver, ca r dia c,
Mye lin s he a th
ga st r oin t est in a l) du e t o h ypoxic–isch em ic
en ceph a lopa t h y.
Th e t im in g a n d ch a r a ct er of even t s du r in g pr eg-
n a n cy a n d in la bor m a y pr ovide fu r t h er eviden ce of
ca u se of h ypoxic–isch em ic in ju r y con sist en t wit h CP. Axon of
A com bin a t ion of a t h or ou gh n eu r ologic exa m in a t ion , A ne rve fibe r
in clu din g t est in g of m ot or skills a n d r eflexes, a lon g
wit h a com plet e m edica l h ist or y pr ovides eviden ce Ne rve fibe r Mye lin
for a dia gn osis con sist en t wit h spa st ic qu a dr iplegia
or dyskin et ic CP. Con sider a t ion of developm en t a l
m ilest on es, eva lu a t ion of m u scle t on e, a n d pr esen ce
of a bn or m a l m ovem en t s a n d r eflexes con t r ibu t e t o
t h e dia gn osis of CP. Ch ildr en m a y be a s old a s 18
m on t h s befor e a dia gn osis ca n be m a de. B

TREATMENT
No cu r e exist s for CP. In dividu a ls a r e t r ea t ed ba sed
on t h e sign s a n d sym pt om s t h ey m a n ifest . Dr u gs t o
con t r ol seizu r es (e.g., la m ot r igin e, va lpr oa t e) a n d C
m u scle spa sm s (e.g., bot u lin u m t oxin t ype A, da n -
t r olen e, ba clofen ) m a y be n ecessa r y. Mobilit y m a y
be im pr oved wit h t h e u se of specia l br a ces a n d m e-
ch a n ica l a ids. P h ysica l, occu pa t ion a l, em ot ion a l, a n d
speech t h er a py m a y su ppor t m a xim a l fu n ct ion in g
a n d in depen den ce. D

Stop and Consider Figure 10.17. Process of demyelination. A and B: Show

Why is it important to determine the timing of normal nerve cells with intact myelin sheaths. C and D: Show
neurologic injury related to CP? degenerating myelin, disrupting signal transduction in
the axon.

Multiple Sclerosis
Mu lt iple scler osis is a disea se of t h e CNS n eu r on s
a n d is ch a r a ct er ized by t h e degen er a t ion of m yelin ,
a pr ocess kn own a s d e m y e lin a t io n (F ig. 10.17). MS
is a pr ogr essive n eu r odegen er a t ive disea se a ffect in g
n er ves in t h e CNS a n d per iph er a l n er vou s syst em .
Alt h ou gh a gr ea t dea l of r esea r ch h a s been don e t o
det er m in e t h e exa ct ca u se of MS, cu r r en t ly n on e
h a s been iden t ified. Dem ogr a ph ic ch a r a ct er ist ics of
people m ost likely t o develop MS in clu de Ca u ca sia n
wom en of n or t h er n E u r opea n a n cest r y, a ges 25 t o
49 yea r s. E n vir on m en t a l fa ct or s in clu din g vir a l in -
fect ion s, geogr a ph ic loca t ion , pla ce of bir t h , su n ligh t
exposu r e, a n d vit a m in D levels in flu en ce r isk for
MS. Th er e a r e geogr a ph ic differ en ces t h a t m a y be
a ssocia t ed wit h t h e developm en t of MS. In dividu a ls
wh o a r e bor n a n d con t in u e t o live in r egion s n or t h of
40 degr ee la t it u de for t h e fir st 15 yea r s of life h a ve
a h igh er r isk (F ig. 10.18) t h ou gh ot h er fa ct or s m a y
a lso con t r ibu t e t o obser va t ion s of geogr a ph ic r isk.
P r eva len ce is h igh est in n or t h er n a n d cen t r a l E u -
r ope; n or t h er n r egion s of Nor t h Am er ica ; It a ly; a n d
sou t h er n Au st r a lia . Fa m ily h ist or y a lso con t r ibu t es
t o a n in dividu a l’s r isk of developin g MS.
PATHOPHYSIOLOGY
MS is a disea se of m u lt ifa ct or ia l or igin ch a r a ct er ized
by m icr oglia l a ct iva t ion a n d ch r on ic n eu r odegen er a -
t ion . In fla m m a t or y T a n d B lym ph ocyt es a n d m a c-
r oph a ges a n d pr esen ce of IgG a n d IgM in t h e CSF
pr ovide eviden ce for im m u n opa t h ology a n d pr edom -
in a n ce of t h e Th 1 im m u n e r espon se. Axon in ju r y a n d
for m a t ion of dem yelin a t ed pla qu es pr edom in a n t ly
in t h e opt ic n er ves, spin a l cor d, br a in st em , cer ebel-
lu m , a n d t h e ju xt a cor t ica l a n d per iven t r icu la r wh it e
m a t t er im pa ir n eu r a l t r a n sm ission a n d a r e a sso-
cia t ed wit h t h e clin ica l m a n ifest a t ion s of t h e dis-
ea se. Gen et ic a n d en vir on m en t a l fa ct or s pla y a r ole
in a n in dividu a l’s r isk for developin g MS. Region a l

High ris k
P roba ble high ris k
Low ris k
P roba ble low ris k
North–S outh gra die nt ris k
Othe r ris k
Figure 10.18. Worldwide distribution of multiple sclerosis.
va r ia t ion s m a y be ca u sed by pr edom in a n t pa t h ogen s
of t h e r egion s, t r igger in g MS t h r ou gh t h e pr ocess of
m olecu la r m im icr y in gen et ica lly su scept ible in di-
vidu a ls, a s discu ssed in Ch a pt er 4. Fa ct or s in clu din g
exposu r e t o vir a l pa t h ogen s, vit a m in D deficien cy,
exposu r e t o su n ligh t a n d u lt r a violet r a dia t ion , a n d
gen et ic pr edisposit ion h a ve been im plica t ed in t h is
com plex disea se of u n kn own or igin . 7
CLINICAL MANIFESTATIONS
Th e clin ica l m a n ifest a t ion s of MS r ela t e t o t h e
slowin g of n er ve con du ct ion im pu lses down t h e
n er ve a xon . Specific n er ves a r e a ffect ed a t differ-
en t t im es, con t r ibu t in g t o t h e va r ia t ion s seen in
t h e t im e cou r se a n d in t h e sign s a n d sym pt om s of
t h e disea se. Clin ica l cla ssifica t ion of r ela psin g a n d
pr ogr essive disea se ca n be fu r t h er ca t egor ized in t o
su bt ypes ba sed u pon t h e t im in g a n d ch a r a ct er of
clin ica l m a n ifest a t ion s:
1. Clin ica lly isola t ed syn dr om e (CIS): in it ia l pr esen -
t a t ion of sym pt om s
2. Rela psin g-r em it t in g (RR): ch a r a ct er ized by per i-
ods of a cu t e n eu r ologic sym pt om s (fla r e-u ps, ex-
a cer ba t ion s, r ela pses) a lt er n a t in g wit h per iods of
sym pt om r elief or r et u r n of n eu r ologic fu n ct ion
(r em ission s)
3. P r im a r y pr ogr essive: slow, ch r on ic det er ior a t ion
of n eu r ologic fu n ct ion wit h occa sion a l pla t ea u s,
n ot a ssocia t ed wit h exa cer ba t ion s or r em ission s
4. Secon da r y pr ogr essive: in it ia lly pr esen t in g wit h
RR ch a r a ct er ist ics of exa cer ba t ion s a n d r em is-
sion s, followed by a pa t t er n of slow, ch r on ic det e-
r ior a t ion a s seen in pr im a r y pr ogr essive
C lin ic a l Mo d e ls 253
MS e x a c e r b a t io n , 8 a dem yelin a t in g even t of a t
lea st 24-h ou r du r a t ion in t h e a bsen ce of fever or
in fect ion , r esu lt s in sym pt om s a ssocia t ed wit h im -
pa ir ed n eu r ologic t r a n sdu ct ion . Com m on effect s of
MS a r e m a n ifest ed by u n ila t er a l vision loss, cogn i-
t ive loss, bowel a n d bla dder dysfu n ct ion , a lt er ed ga it
a n d ba la n ce, spa st icit y, pa r est h esia s, slu r r ed speech ,
fa t igu e, a n d pa in . Mor e r a r ely, a con dit ion kn own a s
p s e u d o b u lb a r a e c t (u n con t r olla ble la u gh in g or
cr yin g) ca n r esu lt fr om cer ebr a l in volvem en t , lea d-
in g t o a lt er ed con t r ol of em ot ion a l r espon siven ess.
Im pa ir ed vision , on e of t h e m ost com m on sym pt om s
of MS, m a y be ca u sed by opt ic n eu r it is or im pa ir ed
ext r a ocu la r eye m ovem en t s, con t r ibu t in g t o loss
of visu a l fields, u n ila t er a l vision loss, a lt er ed color
per cept ion , n y s t a g m u s (ir r egu la r eye m ovem en t s),
a n d pa in .
DIAGNOSTIC CRITERIA
Dia gn osis of MS is ba sed on t h e pr esen ce of sign s
a n d sym pt om s con sist en t wit h t h e disea se. A com -
plet e m edica l h ist or y a n d a t h or ou gh n eu r ologic ex-
a m in a t ion a r e t h e fir st st eps t owa r d dia gn osis. An
MRI m a y be com plet ed t o det ect sca r r in g or pla qu es
in t h e CNS (Fig. 10.19). It is a lso im por t a n t t o de-
t er m in e t h e r espon se of t h e CNS t o per iph er a l sen -
sor y st im u li, in du cin g evoked poten tia ls wh ich m a y
be in dica t ive of a bn or m a l n er vou s syst em fu n ct ion .
Lu m ba r pu n ct u r e t o eva lu a t e CSF m a y be don e t o
det er m in e t h e pr esen ce of IgG. Th e Revised Mc-
Don a ld Cr it er ia is u sed in dia gn osis of in dividu a ls
pr esen t in g wit h MS sym pt om s con sist en t wit h CIS.
MRI eviden ce of a t lea st on e lesion in t wo t o fou r
254 C h a p t e r 10: Alt er ed Neu r on a l Tr a n sm ission

in cr ea sed pr odu ction of cir cu la t ing lym phocyt es. Tec-

fidera modula tes disea se t hr ou gh a n ti-infla m m a t or y
a ct ions. Ta ble 10.7 pr ovides a mor e t hor ough descrip-
t ion of t r ea t men t opt ions in MS.9

Stop and Consider

How will regrowth of myelin help treat or cure
other neurologic diseases?

Hydrocephalus
H ydr oceph a lu s, fr om t h e Gr eek “h ydr o” m ea n in g
wa t er a n d “ceph a lu s” m ea n in g h ea d, is a con dit ion of
in cr ea sed ven t r icu la r or su ba r a ch n oid a ccu m u la t ion
Figure 10.19. Plaque formation in multiple sclerosis. of CSF. H ydr oceph a lu s ca n be a con gen it a l disor der
Plaques in the white matter of the brain are indicated by iden t ified soon a ft er bir t h , or it ca n be a cqu ir ed la t er
arrows. (From Rubin E, Farber JL. Pathology. 4th ed. in life. Accor din g t o t h e Na t ion a l H ydr oceph a lu s
Philadelphia, PA: Lippincott Williams & Wilkins; 2005.) Fou n da t ion , a ppr oxim a t ely 1 in 500 bir t h s a r e a f-
fect ed by h ydr oceph a lu s in t h e Un it ed St a t es. Mor e
loca t ion s in a r ea s of t h e ju xt a cor t ica l, per iven t r ic- t h a n h a lf of t h e ca ses of h ydr oceph a lu s a r e con gen -
u la r, in fr a t en t or ia l, a n d spin a l cor d a n d lesion s in it a l. Lon g-t er m con sequ en ce of h ydr oceph a lu s m a y
a r ea s a ssocia t ed wit h sym pt om s in clu din g t h e opt ic in clu de m ot or disa bilit y, in t ellect u a l disa bilit y a n d
n er ve, br a in st em /cer ebellu m , spin a l cor d, or cer ebr a l pr oblem s wit h m em or y. Th e in ciden ce of a cqu ir ed
h em isph er es su ggest a dia gn osis of MS.8 h ydr oceph a lu s is u n kn own beca u se of t h e r ela t ion -
sh ip t o t h e u n der lyin g ca u ses.
TREATMENT
PATHOPHYSIOLOGY
Ther e is cur r ent ly no cur e for MS. A gr ea t dea l of prog-
r ess h a s been m a de in t h e use of dr ugs, known a s dis- Beca u se of a n im ba la n ce bet ween t h e a m ou n t of flu id
ea se-m odifyin g dr u gs, t o t a r get sym pt om s a nd delay pr odu ced a n d t h e r a t e of flu id r ea bsor pt ion , t h e a c-
pr ogr ession of th e disea se. In t he most com m on for m cu m u la t ion of CSF lea ds t o ven t r icu la r en la r gem en t
a n d in cr ea sed ICP. Cla ssifica t ion s of h ydr oceph a lu s
of MS (r ela psin g-rem it t ing), ea r ly init ia t ion of dr ugs is
h ighly recom m ended. The im m unom odula tor s Bet a - r eflect t h e u n der lyin g ca u se a n d in clu de n o n c o m -
ser on, Avonex, Extavia , a nd Rebif, a ll for m s of beta m u n ic a t in g h y d r o c e p h a lu s beca u se of CSF flow
in ter fer on (IFN-β), a r e t he m a inst ays of t r ea t m ent . obst r u ct ion a n d c o m m u n ic a t in g h y d r o c e p h a lu s
In a ddit ion, Copa xone, a dr ug t ha t m im ics t he effects beca u se of im pa ir ed CSF a bsor pt ion .
of myelin, is com m only used. Au ba gio works t hr ough H ydr oceph a lu s ca n be con gen it a l, oft en iden t ified
in hibit ion of m it ochon dr ia l enzymes needed for du r in g fet a l life or a t bir t h . Con gen it a l h ydr oceph -
a lu s m a y be ca u sed by n eu r a l t u be defect s, in clu d-
in g spin a bifida , or by a n
a lt er a t ion in t h e st r u c-
F R O M T H E L AB t u r e of t h e cer ebr a l a q-
u edu ct or ch or oid plexu s.
Evoked potential testing provides information about the electrical activity in specific sen- Acqu ir ed h ydr oceph a lu s
sory nerve pathways. The altered transduction along these pathways may be too subtle to is secon da r y t o a n ot h er
determine by routine neurologic examination. Stimulation of the pathways is measured by disea se pr ocess. Com m on
wires placed on the scalp over the areas of interest of the brain. There are three types of con dit ion s r esu lt in g in
evoked potential tests: a cqu ir ed h ydr oceph a lu s
1. Visual evoked potentials (VEP): stimulation induced by viewing an alternating in clu de:
checkerboard pattern ● Br a in t u m or
2. Brainstem auditory evoked potentials (BAEP): stimulation induced by clicking sounds ● In t r a ven t r icu la r
in each ear h em or r h a ge
3. Sensory evoked potentials (SEP): stimulation induced by electrical impulses to the arm ● Men in git is
or leg ● Tr a u m a t ic in ju r y t o t h e
h ea d
 C lin ic a l Mo d e ls 255

Ta b le 10.7 Tr ea t m en t Opt ion s in Mu lt iple Scler osis

Br a n d G e n e r ic F D A Ap p r o v a l Ad m in is t r a t io n
Na m e Na m e Da te I n o r m a t io n C o m m o n S id e E e c t s
Avon ex In t er fer on bet a -1a 1996 Weekly in t r a m u scu la r F lu -like sym pt om s
in ject ion
Bet a ser on In t er fer on bet a -1b 1993 E ver y ot h er day su bcu t a n e- F lu -like sym pt om s
ou s in ject ion
E xt avia In t er fer on bet a -1b 2009 E ver y ot h er day su bcu t a n e- F lu -like sym pt om s
ou s in ject ion
Rebif In t er fer on bet a -1a 2002 Th r ee t im es/week su bcu t a - F lu -like sym pt om s
n eou s in ject ion
Copa xon e Gla t ir a m er a cet a t e 1996 Da ily su bcu t a n eou s in ject ion In ject ion sit e r ea ct ion
Au ba gio Ter iflu n om ide 2012 Or a l t a blet da ily Dia r r h ea , a bn or m a l liver
t est s, n a u sea , a n d h a ir loss
Tecfider a Dim et h yl fu m a r a t e 2013 Or a l ca psu le, t wice da ily in F lu sh in g, n a u sea , vom it in g,
fir st week, t h en da ily a n d dia r r h ea , decr ea sed
wh it e blood cell cou n t
Gilen va Fin golim od 2010 Or a l ca psu le t wice da ily H ea da ch e, dia r r h ea , ba ck
pa in , eleva t ion of liver
en zym es, cou gh , r edu ced
h ea r t r a t e
Lem t r a da Alem t u zu m a b 2014 In t r a ven ou s in fu sion Ra sh , h ea da ch e, fever,
n a u sea , in fect ion , fa t igu e,
in som n ia , t h yr oid gla n d
disor der s, pa in in join t s,
ext r em it ies a n d ba ck, di-
a r r h ea , sor e m ou t h a n d
t h r oa t , t in glin g, dizzin ess
Tysa br i Na t a lizu m a b 2004/2006 In t r a ven ou s in fu sion H ea da ch e, fa t igu e, u r in a r y
t r a ct in fect ion
F DA, Food a n d Dr u g Adm in ist r a t ion .

H ydr oceph a lu s oft en r esu lt s fr om a n episode of
in t r a ven t r icu la r h em or r h a ge in t h e n ewbor n per iod,
a lso a com m on con sequ en ce of pr em a t u r it y.10 Ma n -
a gem en t st r a t egies a r e dir ect ed t owa r d con t r ollin g
CSF volu m e a n d flow t o m a in t a in ven t r icle size a n d
n or m a l ICP (15 m m H g or 150 t o 200 m m of wa t er ).
In cr ea sed ICP is a com m on con sequ en ce of h ydr o-
ceph a lu s. Th e pa t h ology a ssocia t ed wit h in cr ea sed
ICP in clu des:
1. Im pa ir ed per fu sion lea din g t o isch em ia a n d cell
dea t h
2. At r oph y ca u sed by im pa ir ed cir cu la t ion
CLINICAL MANIFESTATIONS
Age of on set , u n der lyin g pa t h ology, a n d sever it y of
br a in t issu e com pr ession con t r ibu t e t o t h e clin ica l
m a n ifest a t ion s of h ydr oceph a lu s. Th e sku ll of t h e
n ewbor n is less r est r ict ive beca u se of t h e pr esen ce
of fon t a n els (oft en r efer r ed t o a s soft spot s) a n d t h e
u n fu sed su t u r es of t h e sku ll bon es. Th ese con di-
t ion s a llow for t h e in cr ea se in h ea d cir cu m fer en ce,
a ca r din a l sign in a n ewbor n wit h h ydr oceph a lu s.
Sca lp vein dist en t ion , bu lgin g fon t a n els, sepa r a t ion
of bon y su t u r es, a n d vom it in g m a y a lso be seen .
In fa n t s wit h h ydr oceph a lu s m a y h a ve difficu lt y
feedin g a n d m a y h a ve a sh r ill, h igh -pit ch ed cr y.
Sym pt om s in older ch ildr en a n d a du lt s in clu de im -
pa ir ed m ot or a n d cogn it ive fu n ct ion a n d in con t i-
n en ce (F ig. 10.20). Un r esolved h ydr oceph a lu s m a y
lea d t o im pa ir ed n eu r ologic fu n ct ion a n d dea t h be-
ca u se of in cr ea sed ICP.
Sign s a n d sym pt om s r esu lt in g fr om in cr ea sed
ICP in clu de:
● In cr ea sed blood pr essu r e in a n a t t em pt t o pr o-
m ot e per fu sion in cer ebr a l vessels
● Alt er ed h ea r t r a t e
■ In it ia lly in cr ea sed (t a ch yca r dia ) t o in cr ea se ce-
r ebr a l blood flow; followed by a decr ea sed h ea r t
r a t e (br a dyca r dia ) ca u sed by st im u la t ion of t h e
ba r or ecept or r eflex
● H ea da ch e r esu lt in g fr om st r et ch in g of t h e vessel
wa lls or m en in ges
● Vom it in g
● Decr ea sed level of con sciou sn ess
● Pa pilledem a
256 C h a p t e r 10: Alt er ed Neu r on a l Tr a n sm ission

P romine nt S e pa ra te d Tube ins e rte d into

s ca lp ve ins s uture line la te ra l ve ntricle through
hole in s kull

"Bos s ing" of Enla rge d

fore he a d fonta ne lle s
"S uns e t"
eye s Incre a s e d he a d
circumfe re nce
S hrill
cry S igns of incre a s e d
intra cra nia l pre s s ure :
Le tha rgy P uls e
or irrita bility Te mpe ra ture
Re s pira tions
Hype ra ctive Blood pre s s ure
re flexe s

Figure 10.20. Clinical manifestations of hydrocephalus.

DIAGNOSTIC CRITERIA
Dia gn osis of h ydr oceph a lu s m a y be m a de by t h e n on -
in va sive t ech n iqu es of m ea su r em en t of h ea d cir cu m - Dra ina ge tube, us ua lly
fer en ce a n d t r a n sillu m in a t ion . Tr a n s illu m in a t io n introduce d into pe ritone a l
cavity, with extra le ngth
is a ccom plish ed by sh in in g a ligh t a ga in st t h e h ea d t o to a llow for growth of child
see a ccu m u la t ion s of flu id in t h e t issu e. Ult r a sou n d
exa m in a t ion is lim it ed t o in fa n t s wit h open a n t er ior Figure 10.21. Ventriculoperitoneal shunt placement in
fon t a n elle a n d pr ovides eviden ce of la t er a l ven t r icle hydrocephalus. (From Bear MF, Connors BW, Parasido MA.
size. In ch ildr en a n d a du lt s, dia gn ost ic t ech n iqu es Neuroscience: Exploring the Brain. 3rd ed. Philadelphia, PA:
in clu de CT or MRI sca n of t h e h ea d for exa m in a t ion Lippincott Williams & Wilkins; 2006.)
of ven t r icle size a n d CSF flow. Sku ll r a diogr a ph m a y
be u sed t o det er m in e sepa r a t ion of sku ll bon es.
r egu la t ion . Obser va t ion of sh u n t -r ela t ed com plica -
t ion s, in clu din g in fect ion , blocka ge, a n d m a lfu n ct ion ,
TREATMENT m u st be ca r r ied ou t t o pr om ot e m a in t en a n ce of n or-
m a l CSF volu m e a n d ICP.
Th e t r ea t m en t of h ydr oceph a lu s in clu des est a blish -
A possible a lt er n a t ive t r ea t m en t for obst r u ct ive
in g a n d m a in t a in in g n or m a l CSF volu m es a n d ICP.
n on com m u n ica t in g h ydr oceph a lu s is a pr ocedu r e
On e of t h e m ost com m on t r ea t m en t s for com m u n i-
kn own a s en doscopic t h ir d ven t r icu lost om y (E TV).
ca t in g or n on com m u n ica t in g h ydr oceph a lu s is t h e
Th is pr ocedu r e in volves su r gica lly pla cin g a n open in g
su r gica l pla cem en t a ven t r icu loper it on ea l sh u n t , a
in t h e floor of t h e t h ir d ven t r icle t o a llow fr ee-flowin g
flexible t u be pla ced in t o t h e ven t r icle t o sh u n t excess
r elea se of CSF in t o t h e ba sa l cist er n a for a bsor pt ion .
CSF in t o t h e per it on ea l ca vit y (Fig. 10.21). An ot h er
pot en t ia l t r ea t m en t opt ion in clu des pla cem en t of a
sh u n t t h a t dr a in s CSF flu id in t o t h e r igh t a t r iu m of
t h e h ea r t , ca lled a ven t r icu loa t r ia l sh u n t . Th e flow Incomplete Spinal Cord Transection
of CSF ou t of t h e ven t r icu la r syst em is con t r olled
by a on e-wa y va lve, wh ich h elps con t r ol a ppr opr ia t e Ma n y va r ia bles a r e a ssocia t ed wit h t h e degr ee of
dysfu n ct ion exper ien ced
beca u se of SCI. Spin a l
F R O M T H E L AB segm en t a l level, t ype of
in ju r y, a n d degr ee of cor d
The circulatory dynamics of both cerebral blood flow and cerebral spinal fluid contribute to t r a n sect ion con t r ibu t e t o
ICP. Direct determinations of ICP measurements require invasive monitoring. This monitor- t h e m a n ifest a t ion s a n d
ing is achieved via an intraventricular drain connected externally to a transducer. Measure- com plica t ion s a ssocia t ed
ments are averaged over a minimum 30-minute period to take into account the dynamic wit h SCI. An est im a t ed
fluctuations characteristic of CSF pressure. 11 ICP should be monitored for a period of 24 to 250,000 t o 400,000 in di-
48 hours to determine trends or effectiveness of treatments to reduce pressure. vidu a ls live wit h SCI or
spin a l dysfu n ct ion . Th e
 C lin ic a l Mo d e ls 257

con dit ion of m a n y in divid-

u a ls wit h SCI im pr oves F R O M T H E L AB
fr om t h e t im e of dia gn o-
sis, bu t few fu lly r ecover. Bowel and bladder storage require autonomic reflexes to coordinate involuntary smooth
muscle activity of the urinary tract and voluntary contraction of the sphincter. Complex
mechanisms involving the spinal and supraspinal nerve pathways may be impaired because
PATHOPHYSIOLOGY of SCI. A process known as functional electrical stimulation (FES) may serve to generate
SCI is du e t o n er ve r oot or artificial autonomic reflexes to promote mechanisms regulating bowel and bladder function.
m yelin a t ed t r a ct da m a ge, Electrical stimulation of efferent nerves to promote muscle contraction is accomplished
im pa ir in g t h e t r a n sdu c- through a process known as neurostimulation. Microstimulation provides electrical stimuli
t ion of a ffer en t or effer en t to preganglionic neurons and interneurons controlling bladder function via a microelectrode
n eu r a l im pu lses. Da m a ge implanted within the spinal cord. Afferent fibers may be activated to adjust stimuli, a func-
t o t h e gr a y m a t t er of t h e tion known as neuromodulation. 12
cen t r a l cor d m a y r esu lt in
loss of m ot on eu r on s a n d
ba sed on fin din gs fr om t est in g of cogn it ive, m ot or,
in t er n eu r on s. Th e pa t h ogen esis is r ela t ed t o t h e lo-
a n d sen sor y fu n ct ion . If t h e in ju r ed in dividu a l h a s
ca t ion , cla ssifica t ion , t ype, a n d sever it y of t h e in ju r y.
m a n ifest a t ion s of n eck pa in or wea kn ess or is u n -
SCI m a y r esu lt fr om com plet e or pa r t ia l t r a n sect ion
a ble t o r espon d beca u se of loss of con sciou sn ess, di-
(F ig. 10.22). In com plet e in ju r y, sen sa t ion a n d m o-
t or fu n ct ion below t h e level of in ju r y a r e lost . Pa r- a gn ost ic t est in g m a y be don e. Com m on ly u sed t est s
t ia l cor d t r a n sect ion s ca n be ca t egor ized in t o t h r ee t o dia gn ose SCI in clu de r a diogr a ph , CT sca n , MRI,
t ypes of syn dr om es (cen t r a l cor d, a n t er ior cor d, a n d a n d m yelogr a ph y (im a gin g a ft er in ject ion of dye in t o
Br own –Séqu a r d syn dr om e), descr ibed in Ta ble 10.8. t h e spin a l ca n a l).

CLINICAL MANIFESTATIONS TREATMENT

SCI m a y be com plica t ed by isch em ia , h em or r h a ge,
or n ecr osis. In ju r y t o t h e n eu r on a l fiber s t h a t ca r r y
im pu lses m a y be wor sen ed by pr essu r e fr om t h e
edem a r ela t ed t o t h e pr im a r y in ju r y. Th e level of in -
ju r y det er m in es t h e n er ves in volved a n d h elps a n t ic-
ipa t e t h e degr ee of fu n ct ion a l loss. Loss of fu n ct ion
in in com plet e t r a n sect ion ca n be va r ia ble, ba sed on
t h e a r ea a n d level of cor d in volved. In gen er a l, in ju -
r ies t o t h e cer vica l spin e oft en r esu lt in qu a dr iple-
gia . H igh in ju r ies a t t h e level of C1-C2 m a y r esu lt
in loss of in volu n t a r y fu n ct ion , in clu din g swea t in g,
blood pr essu r e r egu la t ion , a n d body t em per a t u r e
r egu la t ion . Respir a t or y su ppor t wit h a r t ificia l ven t i-
la t ion m a y be r equ ir ed for in ju r ies a bove C4. In ju r y
t o lower cer vica l segm en t s is a ssocia t ed wit h pr eser-
va t ion of u pper body fu n ct ion . C7 t h r ou gh T1 in ju -
r ies a llow in dividu a ls t o st r a igh t en t h eir a r m s, bu t
t h ey m a y r esu lt in im pa ir ed fin e m ot or skills. Pa r a -
plegia u su a lly r esu lt s fr om in ju r ies a t t h e t h or a cic
level. Tr u n k a n d lower body con t r ol a r e lost a t T1,
wit h r et u r n of sit t in g ba la n ce a n d a bdom in a l m u scle
con t r ol fr om T9 t h r ou gh T12. In ju r ies in t h e lu m ba r
a n d sa cr a l segm en t s r esu lt in loss of con t r ol of t h e
lower ext r em it ies. Bowel, bla dder, a n d sexu a l fu n c-
t ion m a y be a ffect ed wit h SCI.
DIAGNOSTIC CRITERIA
Wh en SCI is su spect ed, it is im por t a n t t o dia gn ose,
begin im m edia t e t r ea t m en t , a n d pr even t fu r t h er
da m a ge. SCI ca n be dia gn osed in a con sciou s per son
Tr a ct ion m a y be u sed t o im m obilize t h e spin e in t h e
a cu t e ph a se of SCI in a n a t t em pt t o pr even t fu r t h er
da m a ge. Su r gica l t r ea t m en t t o cor r ect fr a ct u r es
a n d decom pr ess t h e spin a l cor d m a y be in dica t ed.
La ck of eviden ce t o su ppor t t h e u se of ph a r m a cologic
a gen t s lim it s u se in a cu t e SCI.12 P r om ot ion of fu n c-
t ion a l a bilit ies is a pr ior it y of t r ea t m en t a ft er t h e
a cu t e ph a se of in ju r y. Th e wor k of m a n y r esea r ch er s
is t a r get ed t owa r d a cu r e for SCI.
To a ch ieve a r et u r n of m ot or, sen sor y, a n d a u t o-
n om ic fu n ct ion , t h e r egen er a t ion of a xon s a n d r ees-
t a blish m en t of n eu r on a l t r a n sm ission m u st occu r.
Regen er a t ion of t h e pyr a m ida l, ext r a pyr a m ida l,
a u t on om ic, sen sor y, a n d cer ebella r pa t h wa ys, in -
t egr a t ed r eflex r espon ses, a n d t h e r equ ir ed n eu -
r ot r a n sm it t er s a r e n ecessa r y for r et u r n of fu n ct ion .
Parkinson Disease
Pa r kin son disea se is a ch r on ic, pr ogr essive n eu r ologic
con dit ion t h a t a ffect s t h e pigm en t ed dopa m in er gic
n eu r on s of t h e su bst a n t ia n igr a a n d locu s cer u leu s of
t h e ba sa l ga n glia . Degen er a t ion of n eu r on s is a ssoci-
a t ed wit h im pa ir ed m ot or fu n ct ion , a n d on set occu r s
pr edom in a n t ly in in dividu a ls of m iddle t o old a ge.
Fir st descr ibed in t h e ea r ly 1800s a s “sh a kin g pa lsy”
by Dr. J a m es Pa r kin son , t h e disea se did n ot bea r h is
n a m e u n t il h a lf a cen t u r y la t er, wh en J ea n -Ma r t in
Ch a r cot h on or ed t h e ea r ly pion eer.13 Alt h ou gh m u ch
h a s been lea r n ed, t h e con dit ion st ill h a s n o cu r e.
258 C h a p t e r 10: Alt er ed Neu r on a l Tr a n sm ission

Figure 10.22. Functional alterations in incomplete spinal cord in-

juries. A: Central cord syndrome. B: Anterior cord syndrome.
C: Brown–Séquard syndrome. (From Hickey JV. The Clinical Practice
Los s of motor powe r of Neurological and Neurosurgical Nursing. 5th ed. Philadelphia,
a nd s e ns a tion
PA: Lippincott Williams & Wilkins; 2003:420–421.)
Incomple te los s

C T
S

L
T
C

S
L
C T
Ce ntra l a re a of
cord da ma ge
A
Los s of pa in a nd
te mpe ra ture
s e ns a tion on
oppos ite s ide

Los s of motor powe r,

pa in, a nd te mpe ra ture Los s of volunta ry
s e ns a tion, with pre s e rva tion motor control on
of pos ition, vibra tion, a nd the s a me s ide
touch s e ns e a s the cord
da ma ge

Pos ition a nd
vibra tion, touch s e ns e Right Le ft

Motor

Pa in,
te mpe ra ture
Are a of cord
da ma ge
Are a of cord
da ma ge

B C
 C lin ic a l Mo d e ls 259

Ta b le 10.8 Ca t egor ies of Pa r t ia l Spin a l Cor d Tr a n sect ion s

Syn d r om e Ar e a o C o r d A e c t e d Com m on Ca u se Ma n i e s t a t io n s
Cen t r a l cor d Cen t er cor d a ffect ed Usu a lly ca u sed by h yper ext en - Mot or deficit s pr om in en t in u pper
syn dr om e sion in ju r y ext r em it ies
Bla dder dysfu n ct ion of va r ia ble
sever it y
An t er ior cor d An t er ior cor d a ffect ed Occlu sion of t h e a n t er ior spin a l Loss of m ot or fu n ct ion , t em per a t u r e,
syn dr om e a r t er y a n d pa in below t h e level of in ju r y
Bon e fr a gm en t s Sen sa t ion s of t ou ch , pr essu r e, vibr a -
t ion , a n d posit ion in t a ct
Br own –Séqu a r d H em isect ion of t h e a n t er ior Usu a lly t h e r esu lt of st a bbin g Ipsila t er a l (sa m e side) com plet e or
syn dr om e a n d post er ior cor d or gu n sh ot in ju r y wit h da m a ge pa r t ia l pa r a lysis, loss of t ou ch , pr es-
loca lized t o on ly on e side of su r e, vibr a t ion , a n d posit ion s sen se
t h e cor d below t h e level of in ju r y
Loss of t em per a t u r e sen sa t ion s
con t r a la t er a lly

Accor din g t o t h e Na t ion a l In st it u t e on Neu r ologic
Disor der s a n d St r oke, a ppr oxim a t ely 500,000 people
in t h e Un it ed St a t es a r e dia gn osed wit h P D.14 An n u -
a lly, a ppr oxim a t ely 50,000 n ew ca ses a r e r epor t ed.
Mor e com m on in m en t h a n in wom en , t h e aver a ge
a ge of on set is 60 yea r s, wit h pr eva len ce a n d in ci-
den ce in cr ea sin g wit h a ge.
PATHOPHYSIOLOGY
Th e ba sa l ga n glia a r e im por t a n t in t h e con t r ol of
m ovem en t t h r ou gh r egu la t ion of in h ibit or y a n d ex-
cit a t or y st im u li. Th e ba sa l ga n glia a r e com posed of
t h e for ebr a in st r u ct u r es of t h e st r ia t u m (ca u da t e
n u cleu s a n d pu t a m en ) a n d globu s pa llidu s in t er n a ,
t h e su bt h a la m ic n u cleu s (dien ceph a lon ), a n d t h e
su bst a n t ia n igr a (m idbr a in ) (F ig. 10.23). Th e su b-
st a n t ia n igr a is n a m ed for t h e bla ck a ppea r a n ce of
cells ca u sed by t h e pigm en t m ela n in . Secr et ed by t h e
cells of t h e su bst a n t ia n igr a , t h e n eu r ot r a n sm it t er
dopa m in e is t r a n spor t ed t o t h e st r ia t u m via t h e n i-
gr ost r ia t a l pa t h wa y. P D is ch a r a ct er ized by degen er-
a t ion of t h e n igr ost r ia t a l pa t h wa y, wh ich lea ds t o a
r edu ct ion in t h e n eu r ot r a n sm it t er dopa m in e. Dopa -
m in e m odu la t es ba la n ce bet ween t h e excit a t or y a n d
in h ibit or y n eu r a l m ot or pa t h wa ys.
Im pa ir ed t r a n spor t of dopa m in e a lt er s excit a bil-
it y of t h e st r ia t u m a n d t h e r elea se of ot h er n eu -
r ot r a n sm it t er s. Neu r on s in t h e su bst a n t ia n igr a lose
t h eir pigm en t a n d t h eir ch a r a ct er ist ic bla ck color. In
a ddit ion t o pigm en t loss in t h e cells of t h e su bst a n t ia
n igr a , n eu r on s a r e a t r oph ied, wit h som e con t a in in g
Lewy bodies. Lewy bodies a r e pr ot ein a ggr ega t ion s
com posed of t h e pr ot ein a lph a -syn u clein loca t ed pr i-
m a r ily in t h e cells of t h e su bst a n t ia n igr a .
No specific m ech a n ism expla in in g P D h a s been
fou n d. Neu r on a l in ju r y fr om oxida t ive da m a ge is
su spect ed t o pla y a r ole in t h e pa t h ology a ssocia t ed
wit h P D, pot en t ia lly ca u sin g im pa ir ed m it och on dr ia l
fu n ct ion a n d a n t ioxida n t pr ot ect ion of n eu r on s. Th e
on set of t h e disea se m a y a lso be r ela t ed t o a declin e
in t h e en dogen ou s defen se m ech a n ism s a ssocia t ed
wit h a gin g. Depigm en t a t ion of n eu r on s m a y con -
t r ibu t e t o a n in fla m m a t or y r espon se t o ext r a cellu la r
m ela n in in su r r ou n din g br a in t issu e.
P D ca n be a n in h er it ed disea se, or it m a y occu r
spor a dica lly. Alt h ou gh t h e gen et ic pr edisposit ion t o
P D in fa m ilies is well kn own , r ecen t developm en t s
in m olecu la r biology h a ve led t o t h e iden t ifica t ion
of sever a l gen et ic loci a n d a lt er a t ion in m it och on -
dr ia l fu n ct ion a ssocia t ed wit h fa m ilia l P D. 15 Recen t
in sigh t s m a y lea d t o m or e effect ive t r ea t m en t s a n d
m a r ker s of disea se befor e t h e on set of sym pt om s.
CLINICAL MANIFESTATIONS
Most n eu r a l degen er a t ion in P D occu r s befor e t h e
on set of t h e m a n ifest a t ion s of t h is disea se, a lso
kn own a s t h e pr eclin ica l per iod. Th e fou r pr im a r y
m a n ifest a t ion s of over t P D in clu de (F ig. 10.24):
1. Tr em or
2. Rigidit y
3. Br a dykin esia
4. Post u r a l in st a bilit y
Tr em or s u su a lly in volve t h e h a n ds, a r m s, legs,
a n d fa ce, a n d t h ey occu r wh en t h e body is a t r est .
Tr em or s a r e pr ogr essive, in it ia lly m a n ifest in g in
a n isola t ed a r ea a n d oft en begin n in g in on e h a n d.
Br a dykin esia (slowed m ovem en t ) is a ssocia t ed wit h
in it ia t ion of m ovem en t a n d m a y pr ogr ess t o a ki-
n esia , or t h e in a bilit y t o m ove (Fig. 10.25). Su dden
h a lt in g of m ovem en t is a lso a ca r din a l sign of br a -
dykin esia . In dividu a ls wit h P D oft en wa lk wit h a
260 C h a p t e r 10: Alt er ed Neu r on a l Tr a n sm ission

Tha la mus

Motor cortex
(gray ma tte r)

S tria tum

S ubtha la mic
nucle us

Globus pa llidus
inte rna

Optic ne rve

S ubs ta ntia
nigra

Ce re be llum

S pina l cord

Figure 10.23. Pigmented neurons of the substantia nigra. Neurons of the substantia nigra and the locus ceruleus are
heavily pigmented with neuromelanin.

sh u fflin g ga it a n d st ooped post u r e. Rigidit y ca u sed DIAGNOSIS

by r esist a n ce t o m ovem en t by bot h flexor s a n d ex-
t en sor s m a n ifest a s jer ky m ovem en t s, a lso kn own a s
cogwh eel r igidit y. In volvem en t of t h e t on gu e, t h r oa t ,
a n d pa la t e m a y in cr ea se t h e likelih ood of feedin g
difficu lt ies a n d a spir a t ion ca u sed by m u scle r igidit y.
Speech m a y a lso be a ffect ed by or a l m a n ifest a t ion s,
r esu lt in g in m on ot on e, expr ession less in flect ion s in
voice. St iffn ess of t h e lim bs a n d t r u n k, br a dykin e-
sia , a n d post u r a l in st a bilit y con t r ibu t e t o decr ea sed
coor din a t ion a n d im pa ir ed ba la n ce. A fla t , or expr es-
sion less, a ffect m a y be t h e r esu lt of fa cia l st iffn ess
(Fig. 10.26).
In dir ect m a n ifest a t ion s of P D in volve t h e in flu -
en ce of ba sa l ga n glia in a u t on om ic n er vou s syst em
r espon ses. In cr ea sed seba ceou s, swea t , a n d sa liva se-
cr et ion s a r e com m on . Ot h er a u t on om ic dysfu n ct ion s,
in clu din g a lt er ed blood pr essu r e a n d t h er m a l r eg-
u la t ion , con st ipa t ion , in con t in en ce, a n d im pot en ce,
m a y occu r. Cogn it ive a n d per son a lit y ch a n ges m a y
be a ssocia t ed wit h P D. Dem en t ia is a lso a com m on
m a n ifest a t ion of P D.16
Stop and Consider
Why are individuals on antipsychotic medications
at risk for development of Parkinsonian-like
symptoms?
No sin gle, defin it ive t est exist s t o dia gn ose P D. Clin -
ica l fin din gs ba sed on t h e h ist or y a n d m a n ifest a -
t ion s of t h e disea se a r e u sed t o obt a in dia gn osis. Th e
Movem en t Disor der Societ y Ta sk For ce for Ra t in g
Sca les for P D con fir m s t h e r elia bilit y of t h e H oeh n
a n d Ya h r (H Y) sca le a s a n in dica t or of st a ge pr o-
gr ession a n d sever it y.17 Th e H oeh n a n d Ya h r sca le
in clu des t h e followin g cr it er ia 18 :
● St a ge on e
■ Sign s a n d sym pt om s on on e side on ly
■ Sym pt om s m ild
■ Sym pt om s in con ven ien t bu t n ot disa blin g
■ Usu a lly pr esen t s wit h t r em or of on e lim b
■ F r ien ds h a ve n ot iced ch a n ges in post u r e, loco-
m ot ion , a n d fa cia l expr ession
● St a ge t wo
■ Sym pt om s a r e bila t er a l
■ Min im a l disa bilit y
■ Post u r e a n d ga it a ffect ed
● St a ge t h r ee
■ Sign ifica n t slowin g of body m ovem en t s
■ E a r ly im pa ir m en t of ba la n ce u pon wa lkin g or
st a n din g
■ Gen er a lized dysfu n ct ion t h a t is m oder a t ely
sever e
 C lin ic a l Mo d e ls 261

Corpus s tria tum

He a d be nt forwa rd

Tre mors of the he a d

Ba s a l ga nglia Fla t fa cia l expre s s ion

S ubs ta ntia nigra S pe e ch a nd fe e ding

difficultie s

De s truction of dopa mine rgic Rigidity

ne urona l ce lls in the s ubs ta ntia
S toope d pos ture
nigra in the ba s a l ga nglia
Bra dykine s ia a nd
a kine s ia

De ple tion of dopa mine s tore s Tre mor

Los s of pos tura l re flexe s

De ge ne ra tion of the
dopa mine rgic nigros tria ta l
pa thway

S huffling ga it
Imba la nce of excita tory
(a ce tylcholine ) a nd inhibiting
(dopa mine ) ne urotra ns mitte rs
in the corpus s tria tum
Figure 10.25. Mobility deficits in Parkinson disease.
Musculoskeletal manifestations of Parkinson disease
include tremors, rigidity, bradykinesia, and postural
Impa irme nt of
extra pyra mida l tra cts instability affecting the entire body. (Modified from
controlling complex body Rosdahl CB. Book of Basic Nursing. 7th ed. Philadelphia,
move me nts PA: Lippincott-Raven; 1999, with permission.)

Pos tura l
Tre mors Rigidity Bra dykine s ia
ins ta bility

Figure 10.24. Pathophysiology and clinical manifesta- S ta re

tions of Parkinson disease. The nuclei in the substantia
nigra project fibers to the corpus striatum, the pathway
of dopamine transport. Loss of dopaminergic neurons in
the substantia nigra is associated with manifestations
of Parkinson disease. (Modified from Smeltzer SC, Bare
BG. Textbook of Medical-Surgical Nursing. 10th ed. Phil-
adelphia, PA: Lippincott Williams & Wilkins; 2003, with
permission.)
De cre a s d
mobility
Figure 10.26. Facial features of Parkinson disease. Blunted
expression, decreased blinking, and stare are characteristic
manifestations. (Bickley LS, Szilagyl P. Bates’ Guide to Phys-
ical Examination and History Taking. 8th ed. Philadelphia,
PA: Lippincott Williams & Wilkins; 2003, with permission.)

● St a ge fou r
■ Sever e sym pt om s ● St a ge five
■ Ca n st ill wa lk t o a lim it ed ext en t ■ Ca ch ect ic st a ge
■ Rigidit y a n d br a dykin esia ■ Com plet e in va lidism (i.e., disa bilit y)
■ No lon ger a ble t o live a lon e ■ Ca n n ot st a n d or wa lk
■ Tr em or m a y be less t h a n ea r lier st a ges ■ Requ ir es con st a n t n u r sin g ca r e
262 C h a p t e r 10: Alt er ed Neu r on a l Tr a n sm ission
F R O M T H E L AB
Development of an early marker of disease before the onset of symptoms has been a focus
of investigation in PD. No tests have demonstrated adequate sensitivity or specificity of
practical use for the early diagnosis of PD.
TREATMENT
P h a r m a cologic m a n a gem en t is a fir st -lin e t r ea t m en t
for P D. Levodopa is a dopa m in e pr ecu r sor u sed a s
t h er a py t o r epla ce dopa m in e. E ffect ive a t a m elio-
r a t in g t h e sym pt om s a ssocia t ed wit h P D, t h er e a r e
m a n y side effect s, in clu din g n a u sea a n d vom it in g,
t h a t m a ke t h e dr u g difficu lt t o t oler a t e. Aft er pr o-
lon ged u se, a ddit ion a l dosin g is oft en r equ ir ed a n d
m a y r esu lt in ot h er side effect s, in clu din g dyskin esia s
a n d per iods of t im e wh en t h e m edica t ion seem s in ef-
fect ive. Levodopa is oft en com bin ed wit h ca r bidopa
(Sin em et ) wh ich dela ys t h e con ver sion of levodopa t o
dopa m in e u n t il it r ea ch es t h e br a in . Wh en com bin ed
wit h t h e dr u g ca r bidopa , lower doses of levodopa a n d
a declin e in t h e in ciden ce of side effect s a r e possible
wh ile r et a in in g effect iven ess. A com bin a t ion dr u g
t h a t a dds en t a ca pon e t o ca r bidopa a n d levodopa in
t h e sa m e for m u la t ion (St a levo) ext en ds t h e du r a -
t ion of a ct ion of levodopa . Am a n t a din e (Sym m et r el),
a lon e or com bin ed wit h a n a n t ich olin er gic dr u g, m a y
r edu ce t h e sym pt om s of P D a lon g wit h t h e dyskin e-
sia t h a t r esu lt s fr om u se of levodopa . An t ich olin er gic
a gen t s oft en in cr ea se t h e effect iven ess of levodopa ,
a lt h ou gh t h e u n desir a ble side effect s of dr y m ou t h ,
blu r r ed vision , a n d u r in a r y r et en t ion m a y occu r a n d
sh ou ld be r eser ved for u se in you n ger in dividu a ls.
Dopa m in e a gon ist s a ct iva t e r ecept or s a n d a r e a u se-
fu l st r a t egy for t h e t r ea t m en t of P D. Dr u gs in t h is
cla ss in clu de br om ocr ipt in e (Pa r lodel), pr a m ipex-
ole (Mir a pex), r ot igot in e (Neu pr o) a n d r opin ir ole
(Requ ip). Th e dr u g Apokyn (a pom or ph in e) is u sed
for t h e t r ea t m en t of h ypom obilit y or “off per iods”
wh en im m obilit y pr even t s com plet ion of a ct ivit ies of
da ily livin g.
Su r gica l opt ion s for t h e t r ea t m en t of P D in clu de
pa llidot om y a n d deep br a in st im u la t ion . Th ese
st r a t egies a r e r eser ved for m or e a dva n ced disea se
beca u se of t h e r isk in volved wit h t h e t r ea t m en t s.
Pa llidot om y, a n ir r ever sible pr ocedu r e in volvin g
dest r u ct ion of t h e globu s pa llidu s, is design ed t o
decr ea se n er ve fir in g in t h e da m a ged t issu e. Deep
br a in st im u la t ion (DBS) is a r ever sible pr ocedu r e
design ed t o a lt er a bn or m a l fu n ct ion of t h e br a in t is-
su e t h r ou gh in ser t ion of a n eu r ost im u la t or design ed
t o deliver elect r ica l sign a ls t o a t a r get ed a r ea of t h e
br a in . St im u la t ion is in t en ded t o block a bn or m a l
n er ve sign a ls, r esu lt in g in t r em or a n d ot h er P D
sym pt om s. Th e exa ct lo-
ca t ion of t h e br a in t issu e
r espon sible for gen er a t ion
of n er ve sign a ls ca u sin g
P D sym pt om s is iden t i-
fied befor e t h e pr ocedu r e
via a n MRI or a CT sca n .
S U MMAR Y
● Th e n eu r on is t h e fu n da m en t a l u n it of t h e n er-
vou s syst em ; it h a s h igh ly specia lized fu n ct ion s in
im pu lse t r a n sm ission .
● Su ppor t in g cells pr ovide n eu r on s wit h m et a bolic
su ppor t a n d pr ot ect ion .
● Im pu lse t r a n sm ission is r egu la t ed by ch a n ges
in m em br a n e pot en t ia l, in du ced by a va r iet y
of st im u li, in clu din g ch em ica l, elect r ica l, a n d
m ech a n ica l.
● Th e n er vou s syst em is com posed of t h e cen t r a l
n er vou s syst em (br a in a n d spin a l cor d) a n d t h e
per iph er a l n er vou s syst em (spin a l a n d cr a n ia l
n er ves; som a t ic a n d a u t on om ic [sym pa t h et ic a n d
pa r a sym pa t h et ic] n er vou s syst em s).
● Ner vou s t issu e of t h e CNS is com posed of bot h
wh it e a n d gr a y m a t t er, ba sed on t h e pr im a r y
t ypes of com pon en t n eu r on s.
● Men in ges (du r a , a r a ch n oid, pia ) a n d t h e CSF
pr ovide pr ot ect ive a n d m et a bolic fu n ct ion s in t h e
CNS.
● Th e br a in is divided bot h by lobes (fr on t a l, pa r i-
et a l, t em por a l, occipit a l) a n d h em isph er es (r igh t ,
left ), ea ch a ssocia t ed wit h h igh ly specia lized
fu n ct ion s.
● Th e spin a l n er ves a r e ca t egor ized ba sed on t h eir
r ela t ion sh ip wit h spin a l ver t ebr a e (cer vica l, t h o-
r a cic, lu m ba r, sa cr a l).
● Au t on om ic fu n ct ion s a r e ca r r ied ou t by t h e sym -
pa t h et ic a n d pa r a sym pa t h et ic n er vou s syst em .
● Neu r on a l in ju r y con t r ibu t es t o disa bilit y a n d is
t h e ba sis for a va r iet y of n eu r ologic disor der s. Pe-
r iph er a l n er ves h a ve lim it ed ca pa cit y for r egen er-
a t ion a n d r ein n er va t ion .
● Tr a u m a r epr esen t s t h e m ost com m on ca u se of in -
ju r y t o t h e n er vou s syst em , lea din g t o n eu r ologic
im pa ir m en t beca u se of br a in , spin a l cor d, or pe-
r iph er a l n er ve in ju r y. Isch em ic, excit a t ion , a n d
pr essu r e in ju r y m a y r epr esen t pr im a r y or secon d-
a r y ca u ses of n eu r ologic im pa ir m en t .
● Disor der s of n eu r ologic fu n ct ion m a y be ch a r a c-
t er ized by specific m a n ifest a t ion s, poin t in g t o t h e
or igin of pa t h ology.
● Alt er ed n eu r on a l t r a n sm ission a n d con du ct ion
h a s im plica t ion s for a ll body syst em s a n d wh ole
body fu n ct ion .
 C h a p t e r 10: Alt er ed Neu r on a l Tr a n sm ission 263

● A t h or ou gh u n der st a n din g of t h e con cept s t h a t 5. Wh ich cell t ype h a s t h e m ost pot en t ia l for r egen -
gover n n eu r on a l t r a n sm ission will pr om ot e you r er a t ion a ft er in ju r y?
a bilit y t o a pply you r kn owledge in a va r iet y of a . Ast r ocyt e
con dit ion s a n d pa t h ologies. b. Per iph er a l a xon
c. Glia l cell
d. Oligoden dr ocyt es
C AS E S T U D Y 10.1
6. Cou p/cou n t er cou p occu r s du e t o wh ich t ype of
Ca r olyn, a 17-yea r-old soccer player, ha d a collision in ju r y m ech a n ism ?
wit h a n oth er player a n d lost consciousness for a few a . Tr a u m a t ic in ju r y
m inu tes. Wh en she rega ined con sciousness, she ha d b. P r essu r e in ju r y
com pla int s of a hea da che a nd dizziness. She wa s con- c. E xcit a t ion in ju r y
fu sed a nd bega n t o vom it , pr om pt ing her t o go t o t he d. Isch em ic in ju r y
em er gen cy r oom for eva lu a t ion. She wa s dia gnosed
wit h concussion, a for m of m ild t r a um a t ic br a in injur y. 7. Neu r ogen ic sh ock is du e t o a lt er ed t r a n sm ission
in wh ich con du ct ion syst em ?
1. In a ddit ion t o t h ose t h a t Ca r olyn pr esen t ed, wh a t a . Sym pa t h et ic
a r e t h e clin ica l m a n ifest a t ion s a ssocia t ed wit h b. Pa r a sym pa t h et ic
m ild t r a u m a t ic br a in in ju r y? c. Som a t ic
2. Wh a t is t h e et iology of Ca r olyn ’s in ju r y? d. Per iph er a l
3. H ow is con cu ssion dia gn osed?
4. Wh a t is t h e st a n da r d m a n a gem en t for TBI? 8. Seizu r e disor der s a r e a ssocia t ed wit h wh ich t ype
5. Post con cu ssion syn dr om e m a y r esu lt fr om m ild of in ju r y m ech a n ism ?
TBI. Descr ibe t h e sym pt om s a n d t r ea t m en t of a . Tr a u m a t ic in ju r y
t h is syn dr om e. b. P r essu r e in ju r y
c. E xcit a t ion in ju r y
d. Isch em ic in ju r y
P R AC T I C E E XAM Q U E S T I O N S
9. Wh ich t ype of spin a l cor d in ju r y is a ssocia t ed
1. Neu r on s t h a t ca r r y sen sor y in for m a t ion t o wit h t h e clin ica l m a n ifest a t ion of ipsila t er a l loss
dist a n t pa r t s of t h e br a in a n d spin a l cor d a r e of m ot or a n d sen sor y fu n ct ion ?
ca lled: a . An t er ior cor d syn dr om e
a . E ffer en t n eu r on s b. Cen t r a l cor d syn dr om e
b. Affer en t n eu r on s c. Br own –Séqu a r d syn dr om e
c. In t er n eu r on s d. Com plet e cor d t r a n sect ion
d. E xt r a n eu r on s
10. Wh ich t ype of n eu r on syn t h esizes a n d se-
2. Depola r iza t ion in volves: cr et es n or epin eph r in e a s t h e pr im a r y n eu r o-
a . Th e r a pid m ovem en t of sodiu m in t o t h e cell t r a n sm it t er ?
b. Th e m ovem en t of pot a ssiu m ion s ou t of t h e cell a . Ser ot on er gic
c. Movem en t of pot a ssiu m ion s in t o t h e cell b. Ch olin er gic
d. Th e a bsen ce of elect r ica l a ct ivit y c. Nicot in ic
d. Adr en er gic
3. Th e lobe of t h e br a in pr im a r ily in volved in fu n c-
t ion s r ela t ed t o vision is t h e: 11. Pa r kin son disea se is ch a r a ct er ized by
a . F r on t a l lobe a . Neu r ofibr illa r y t a n gles
b. Pa r iet a l lobe b. Am yloid pla qu e
c. Tem por a l lobe c. Lewy bodies
d. Occipit a l lobe d. Ta u

4. Wh ich of t h e followin g a r ea s of t h e spin a l cor d 12. Wh ich on e of t h e followin g n eu r ot r a n sm it t er s is

con t a in s 12 segm en t s? deficien t in Pa r kin son disea se?
a . Cer vica l a . Dopa m in e
b. Th or a cic b. Ser ot on in
c. Sa cr a l c. Nor epin eph r in e
d. Lu m ba r d. Acet ylch olin e
264 C h a p t e r 10: Alt er ed Neu r on a l Tr a n sm ission
D I S C U S S I O N AN D
AP P L I C AT I O N
1. Wh a t did I kn ow a bou t a lt er ed n eu r on a l t r a n s-
m ission befor e t oda y?
2. Wh a t body pr ocesses a r e a ffect ed by a lt er ed n eu -
r on a l t r a n sm ission ? H ow do n eu r on a l t r a n sm is-
sion pa t t er n s a ffect t h ose pr ocesses?
3. Wh a t a r e t h e pot en t ia l et iologies for a lt er ed n eu -
r on a l t r a n sm ission s? H ow do con du ct ion defect s
develop?
4. Wh o is m ost a t r isk for developin g a lt er ed n eu -
r on a l t r a n sm ission ? H ow ca n t h ese a lt er a t ion s
be pr even t ed?
5. Wh a t a r e t h e h u m a n differ en ces t h a t a ffect
t h e et iology, r isk, or cou r se of a lt er ed n eu r on a l
t r a n sm ission ?
6. Wh a t clin ica l m a n ifest a t ion s a r e expect ed in t h e
cou r se of a lt er ed n eu r on a l t r a n sm ission ?
7. Wh a t specia l dia gn ost ic t est s a r e u sefu l in det er-
m in in g t h e dia gn osis a n d cou r se of a lt er ed n eu -
r on a l t r a n sm ission ?
8. Wh a t a r e t h e goa ls of ca r e for in dividu a ls wit h
a lt er ed n eu r on a l t r a n sm ission ?
9. H ow does t h e con cept of a lt er ed n eu r on a l t r a n s-
m ission bu ild on wh a t I h a ve lea r n ed in t h e pr e-
viou s ch a pt er a n d in pr eviou s cou r ses?
10. H ow ca n I u se wh a t I h a ve lea r n ed?
R E SOUR CE S
Ma r ch of Dim es:
h t t p://www.m odim es.or g
Na t ion a l H ydr oceph a lu s Fou n da t ion :
h t t p://n h fon lin e.or g/
Na t ion a l In st it u t e of Neu r ologica l Disor der s a n d
St r oke:
h t t p://www.n in ds.n ih .gov/
Na t ion a l Pa r kin son Fou n da t ion :
h t t p://www.pa r kin son .or g/
R e er en ces
1. Cen t er s for Disea se Con t r ol a n d P r even t ion , Na t ion a l
Cen t er for H ea lt h In ju r y P r even t ion a n d Con t r ol. Tr a u -
m a tic Br a in In ju r y. Bet h esda , MD: US Depa r t m en t of
H ea lt h a n d H u m a n Ser vices. h t t p://www.cdc.gov/
t r a u m a t icbr a in in ju r y/get _t h e_fa ct s.h t m l. Accessed
Novem ber 24, 2015.
F in d a d d ition a l r esou r ces for th is ch a pter a t h ttp:th ePoin t.lww.com
2. Na t ion a l Spin a l Cor d In ju r y St a t ist ica l Cen t er. Spi-
n a l cor d in ju r y: fa ct s a n d figu r es a t a gla n ce. J S pin a l
Cor d Med . 2012;35(1):68–69. doi:10.1179/2045772
12X13237783484262.
3. Ma r ch of Dim es. Cer ebr a l pa lsy. h t t p://www.m a r ch
ofdim es.com /pr ofession a ls/14332_1208.a sp#h owcom m on .
Accessed Novem ber 25, 2015.
4. P isa n i F, Spa gn oli C. Neon a t a l seizu r es: a r eview of
ou t com es a n d ou t com e pr edict or s. Neu r oped ia tr ics.
2016;47(1):12–19. doi:10.1055/s-0035-1567873.
5. Fer r ier o DM. Neon a t a l br a in in ju r y. N E n gl J Med .
2004;351(19):1985–1995.
6. Am er ica n College of Obst et r icia n s a n d Gyn ecolo-
gist s. Ta sk for ce on n eon a t a l en ceph a lopa t h y n eo-
n a t a l en ceph a lopa t h y a n d n eu r ologic ou t com e.
Obstet Gyn ecol. 2014;123(4):896–901. doi:10.1097/01.
AOG.0000445580.65983.d2.
7. Milo R, Ka h a n a E . Mu lt iple scler osis: geoepidem iology,
gen et ics a n d t h e en vir on m en t . Au toim m u n
Rev. 2010;9(5):A387–A394.
8. Polm a n CH , Rein gold SC, Ba n well B, et a l. Dia gn ost ic
cr it er ia for m u lt iple scler osis: 2010 r evision s t o t h e
McDon a ld Cr it er ia . An n Neu r ol. 2011;69(2):292–302.
doi:10.1002/a n a .22366.
9. Tor kildsen Ø, Myh r KM, Bø L. Disea se-m odifyin g t r ea t -
m en t s for m u lt iple scler osis—a r eview of a ppr oved
m edica t ion s. E u r J Neu r ol. 2016;23(su ppl 1):18–27.
doi:10.1111/en e.12883.
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a gem en t of h ydr oceph a lu s secon da r y t o in t r a ven t r icu la r
h em or r h a ge in t h e pr et er m in fa n t [pu blish ed on lin e
a h ea d of pr in t Novem ber 13, 2015]. J Neu r osu r g Ped ia tr.
1–7. P MID: 26565942.
11. Czosn yka M, P icka r d J D. Mon it or in g a n d in t er pr et a t ion
of in t r a cr a n ia l pr essu r e. J Neu r ol Neu r osu r g P sych ia tr y.
2004;75(6):813–821.
12. H u r lber t J R, H a dley MN, Wa lt er s BC, et a l. P h a r m a co-
logic t h er a py for a cu t e spin a l cor d in ju r y. Neu r osu r ger y.
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13. Bu r ch D, Sh eer in F. Pa r kin son ’s disea se. La n cet.
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Pa r kin son ’s disea se ba ckgr ou n der. Wa sh in gt on , DC:
Na t ion a l In st it u t e of H ea lt h ; 2004. h t t p://www.n in ds
.n ih .gov/disor der s/pa r kin son s_disea se/pa r kin son s_
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 Ch a pt er

11
Alt er ed Mood,
At t en t ion , a n d
Beh a vior

L E AR N I N G O U T C O ME S
1. Defin e a n d u se t h e key t er m s list ed in t h is ch a pt er.
2. Differ en t ia t e m ood, a t t en t ion , a n d beh a vior.
3. Recogn ize n eu r on a l pa t h wa ys t h a t r egu la t e m ood, a t t en t ion , a n d beh a vior.
4. Iden t ify com m on sign s a n d sym pt om s of a lt er ed m ood, a t t en t ion , a n d
beh a vior.
5. Descr ibe dia gn ost ic t est s a n d t r ea t m en t st r a t egies r eleva n t t o a lt er ed
m ood, a t t en t ion , a n d beh a vior.
6. Apply con cept s of a lt er ed m ood, a t t en t ion , a n d beh a vior t o select clin ica l
m odels.

INTR ODUCTION
H ow does bein g a st u den t of pa t h oph ysiology a ffect you r m ood, a t t en t ion , a n d
beh a vior ? H opefu lly it t r igger s a good m ood a n d posit ive r ega r d a s you a ccom -
plish you r lea r n in g goa ls. Or m a ybe it ca u ses you a n xiet y a n d ch a llen ges you r
focu s. No m a t t er h ow you wou ld a n swer t h a t open in g qu est ion , t h is ch a pt er ’s
focu s on m ood, a t t en t ion , a n d beh a vior is a n im por t a n t lin k in t h e st u dy of
pa t h oph ysiology. Pa t ien t s a r e biopsych osocia l bein gs. Th e pr eviou s ch a pt er s
h a ve focu sed on t h e “bio” pa r t of t h is equ a t ion . Now it is t im e t o t u r n ou r a t t en -
t ion t o t h e “psych osocia l” a spect s a n d t h e cor r espon din g a lt er a t ion s.

Areas of the Brain Affected by D epression

Several areas of the brain are involved in the em otional and physical changes seen in d epression.
While the brain of a d ep ressed ind ivid ual is generally u nd eractive, certain areas d isp lay overactivity.

Thalamus Cingulate gyrus

The thalam u s is associated In d epression, there is increased activity in the
w ith changes in em otion and is know n cingu late gyru s. This area help s associate
to stim ulate the am ygd ala. sm ells and sights w ith p leasant m em ories of
This area d isp lays p ast em otions. It also takes p art in
increased levels of em otional reaction to pain and the
activity regu lation of aggression.
in d ep ressed
ind ivid u als. Prefrontal cortex
Parts of the p refrontal cortex
help regu late em otion. People
w ho are d epressed have
d ecreased activity in this section
of the brain.
Amygdala
The am ygd ala, w hich is resp onsible for
negative feelings, d isp lays overactivity
in d ep ressed peop le.

Areas of the brain affected by depression. Image from Anatomical Chart Company.
265
266 C h a p t e r 11: Alt er ed Mood, At t en t ion , a n d Beh a vior
Modu le 1 R e g u la t io n o Mo o d ,
At t e n t io n , a n d B e h a v io r
Regulation of Mood
Mo o d is a n in t er n a l, su bject ive psych ologica l st a t e,
wh ich dir ect s h ow a per son feels a n d per ceives t h e
wor ld. It is u su a lly r efer r ed t o a s a good m ood or
ba d m ood. A posit ive (good) m ood h a s been sh own
in n u m er ou s st u dies t o en h a n ce cr ea t ive t h in kin g,
im a gin a t ion , a n d pr oblem solvin g. Mood ch a n ges
gr a du a lly over t im e a n d is in flu en ced by in t er n a l
a n d ext er n a l st im u li, su ch a s sleep or st r ess. Sim ila r
t er m s u sed t o descr ibe m ood a r e feelin gs, em ot ion s,
a n d t em per a m en t , bu t t h er e a r e differ en ces. Ba sed
on t im in g flu ct u a t ion s, e m o t io n s (feelin gs) wou ld
be t h e m ost flu id, qu ickly m ovin g m in u t e-by-m in u t e
fr om h a ppy t o sa d t o disa ppoin t ed. Te m p e r a m e n t
(per son a lit y), a st a ble r epr esen t a t ion of ou t look, is
less likely t o ch a n ge over t im e. Mood fa lls som e-
wh er e in bet ween t h ese t wo ext r em es.
Th e m a jor br a in st r u ct u r es t h a t r egu la t e m ood
a r e fou n d in F igu r e 11.1. E a ch st r u ct u r e h a s a
specific fu n ct ion :
● H y p o t h a la m u s : Regu la t es t h e a u t on om ic n er-
vou s syst em du r in g expr ession of em ot ion s.
Orbita l A B
pre fronta l
cortex
Ve ntrome dia l
pre fronta l
cortex
C D
Amygda la
Hippoca mpus
Figure 11.1. Key brain regions involved in mood regulation. A: Orbital prefrontal cortex and the ventromedial prefrontal
cortex. B: Dorsolateral prefrontal cortex. C: Hippocampus and amygdala. D: Anterior cingulate cortex. (From Sadock BJ,
Sadock VA, Ruiz P. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2009.)
● P r e r on t a l cor t ex: Con t r ols ju dgm en t ,
decision -m a kin g, a n d pr oblem solvin g; in volved
in em ot ion a l r espon ses; con t r ols a m ygda la du r in g
st r ess; in volved in sh or t -t er m m em or y a n d in
r et r ievin g lon g-t er m m em or ies. Th e left h a lf a p-
pea r s t o est a blish posit ive feelin gs a n d t h e r igh t
h a lf est a blish es n ega t ive feelin gs. Sect ion s of t h e
pr efr on t a l cor t ex a lso h a ve sign ifica n t fu n ct ion s:
■ L a t e r a l: Con t r ols con sider a t ion of a lt er n a t ives
a n d ch oosin g a cou r se of beh a vior.
■ O r b it o r o n t a l: Con t r ols dela yed gr a t ifica t ion ;
su ppr esses im pu lses.
■ Ve n t r o m e d ia l: Con n ect s em ot ion s wit h
m ea n in g.
● Am y g d a la : Th e cen t er s of em ot ion a lly ch a r ged
m em or ies, sen ses da n ger, a n d con t r ols per sist en t
n ega t ive t h ou gh t s, especia lly fea r a n d a ggr ession ,
a r e a ct ive du r in g st r ess, a n xiet y, a n d depr ession .
Con n ect s wit h h ippoca m pu s, sept a l n u clei, t h a la -
m u s, a n d pr efr on t a l cor t ex.
● H ip p o c a m p u s : H elps t o cr ea t e a n d file lon g-t er m
m em or y.
● An t e r io r c in g u la t e c o r t e x : H a s a wide va r iet y
of a u t on om ic fu n ct ion s; r egu la t es blood pr essu r e
Dors ola te ra l
pre fronta l
cortex
Ante rior
cingula te
cortex
 R e g u la t io n o Mo o d , At t e n t io n , a n d B e h a v io r
a n d h ea r t r a t e; in volved in cogn it ive fu n ct ion s
a n d em ot ion , su ch a s em pa t h y, im pu lse con t r ol,
a n d decision -m a kin g.
● C in g u la t e g y r u s : Loca t ed bet ween t h e cin gu la t e
su lcu s a n d cor pu s ca llosu m ; coor din a t es sigh t s
a n d sm ells wit h pr eviou s em ot ion a lly ch a r ged
m em or ies, in volved in t h e em ot ion a l r ea ct ion t o
pa in a n d im pa ct s a ggr essive beh a vior.
Mor e im por t a n t , h owever, a r e t h e cir cu it s wh ich
con n ect on e’s cogn it ive a ct ivit y, expr ession of em o-
t ion s, a n d beh a vior. Th is idea wa s fir st su ggest ed in
1930 by J a m es Pa pez (ca lled t h e cir cu it of Pa pez)
a n d la t er expa n ded by Pa u l Ma cLea n , wh er e it wa s
r efer r ed t o a s t h e lim b ic s y s t e m . Th ese com plex
m ood–a t t en t ion –beh a vior con n ect ion s of t h e lim bic
syst em ca n be t r a ced t h r ou gh t h e h ypot h a la m u s,
t h a la m u s, h ippoca m pu s, a n t er ior cin gu la t e cor t ex,
cin gu la t e gyr u s, a m ygda la , a n d pr efr on t a l cor t ex
(F ig. 11.2).
Neu r ot r a n sm it t er s a lso pla y a cr it ica l r ole in
m ood r egu la t ion . P h a r m a cologic in t er ven t ion in
m ood disor der s m ost oft en t a r get s on e or m or e n eu -
r ot r a n sm it t er s. Th e va r iou s n eu r ot r a n sm it t er s a n d
Nucle us a ccumbe ns ,
proje cting to ve ntra l pa llidum
Cingulum
Cingula te
gyrus
P re fronta l corte x
S e pta l a re a
P re optic a re a a nd
a nte rior hypotha la mus
S tria te rmina lis
a nd dia gona l ba nd
Entorhina l
a re a
Amygda la
Figure 11.2. Complex connections of the hippocampal formation and amygdala in the forebrain and diencephalon, includ-
ing the circuit of Papez (red) and other limbic system connections (blue).
267
t h eir a ct ion s on m ood, a t t en t ion , a n d beh a vior a r e
su m m a r ized in Ta ble 11.1.
Regulation of Attention
At t e n t io n is a cu lt u r a lly in flu en ced pr ocess of se-
lect ively con cen t r a t in g on in for m a t ion . It is bot h a
cogn it ive pr ocess a n d a beh a vior a s it in volves t h e
in t er a ct ion of sen sor y cu es a n d t h e cor r espon d-
in g a ct ion s. At t en t ion pr ocessin g a n d a ct ion occu r s
t h r ou gh ou t t h e br a in in bot h a r eflexive, r ea ct ive
m a n n er a n d a t h ou gh t fu l, in t en t ion a l m a n n er. For
exa m ple, people a u t om a t ica lly a t t en d t o a lou d u n ex-
pect ed n oise. Th is r eflexive a t t en t ion occu r s “bot t om
u p” a n d is la r gely r egu la t ed by t h e r et icu la r a ct iva t -
in g syst em (RAS). Th e RAS is com pr ised of sever a l
n eu r on a l pa t h wa ys begin n in g wit h st a r t lin g sen sor y
in pu t m ovin g t h r ou gh r et icu la r for m a t ion t o t h e n u -
clei of t h e t h a la m u s a n d ou t wa r d t o t h e pa r iet a l a n d
t em por a l cor t ices a n d lim bic syst em . In t h is wa y,
t h e RAS fa cilit a t es n eu r on a l a ct ivit y du r in g t a sks
r equ ir in g a ler t n ess a n d a t t en t ion (Fig. 11.3). On
Fornix
Ha be nula r nucle i
Me diodors a l tha la mic
nucle us
Ante rior a nd la te ra l
dors a l tha la mic nucle i
Ma millotha la mic
fa s ciculus
Ma milla ry body
S ubiculum a nd
hippoca mpus
P a ra hippoca mpa l gyrus
Te mpora l ne ocorte x
268 C h a p t e r 11: Alt er ed Mood, At t en t ion , a n d Beh a vior

t h e ot h er h a n d, people ca n filt er
Ta b le 11.1 Neu r ot r a n sm it t er s Regu la t in g Mood, At t en t ion , dist r a ct ion s a n d a t t en d on ly t o
a n d Beh a vior t h in gs t h a t a r e im por t a n t t o h im
N e u r o t r a n s m it t e r F u n c t io n C o n t r o ls or h er. Th is is r efer r ed t o a s “t op
Dopa m in e In h ibit or y Volu n t a r y m ovem en t s of t h e
down ,” or execu t ive pr ocessin g,
body a n d is m edia t ed by t h e fr on t a l
Mood lobe a n d ba sa l ga n glia . E xecu -
P lea su r a ble em ot ion s
t ive pr ocessin g a llows a t t en t ion
t o becom e con n ect ed wit h wor k-
Nor epin eph r in e E xcit a t or y P h ysica l a n d m en t a l a r ou sa l
(figh t or fligh t ) in g m em or y, pr oblem solvin g,
Mood
a n d ot h er h igh er-or der fu n c-
t ion s. Neu r ot r a n sm it t er s a r e
H ea r t r a t e a n d blood pr essu r e
a lso a ct ive in a t t en t ion pr ocesses
Ser ot on in In h ibit or y Mood
a s illu st r a t ed in Ta ble 11.1.
Per cept ion Visu a l a t t en t ion , su ch a s you
Appet it e a r e exper ien cin g a s you r ea d
Sleep t h is t ext , is a n im por t a n t for m
Body t em per a t u r e of sen sor y in pu t r equ ir in g exec-
Glu t a m a t e E xcit a t or y At t en t ion u t ive pr ocessin g. Wit h visu a l in -
Lea r n in g pu t , a t t en t ion is dist r ibu t ed over
Mem or y t h e wh ole scen e (or ch a pt er col-
Ga m m a -a m in obu t yr ic In h ibit or y Mood or s, h ea din gs, pict u r es, a s in t h is
a cid (GABA) Mu scle a ct ivit y
ca se). Secon d, a t t en t ion is con -
cen t r a t ed a n d focu sed on a spe-
Visu a l sen sor y in pu t
cific a r ea (su ch a s t h is sen t en ce).
Acet ylch olin e E xcit a t or y At t en t ion
Th is r esu lt s in h igh a t t en t ion
Ar ou sa l a n d visu a l r esolu t ion t owa r d t h e
Lea r n in g focu s, less a t t en t ion a n d “blu r r i-
Mem or y n ess” a t t h e fr in ge, a n d vir t u a lly
Mu scle a ct ivit y n o a t t en t ion beyon d t h e m a r gin .
Tr y t h is wh ile you a r e r ea din g.
See wh er e you r a t t en t ion lies a s
you r eyes m ove a cr oss t h e pa ge.
Sim u lt a n eou sly, h igh er-level cogn it ive pr ocesses
a r e pla cin g t h e a t t en ded it em s in t o m em or y a n d
Ce re bra l cortex
givin g t h e in for m a t ion m ea n in g. Th er e a r e sever a l
RAS proje ctions
t h eor ies r ela t ed t o a t t en t ion a n d va r iou s cla ssifica -
to ce re bra l cortex t ion s. On e wa y t o or ga n ize a t t en t ion is in five t ypes,
m ovin g fr om sim ple t o com plex:

Tha la mus ● F o c u s e d : Not icin g a n d r espon din g t o on e specific

st im u lu s.
● S u s t a in e d : Su st a in in g con cen t r a t ion wit h vigi-
la n ce over t im e.
● S e le c t iv e : Not icin g a n d r espon din g t o a st im u lu s
wh ile filt er in g dist r a ct ion s.
Ce re be llum
● Alt e r n a t in g : Movin g bet ween t a sks h a vin g dif-
Re ticula r forma tion fer en t cogn it ive r equ ir em en t s.
● D iv id e d : Respon din g sim u lt a n eou sly t o m u lt iple
t a sks or dem a n ds.

Figure 11.3. The reticular activating system (RAS).
Ascending sensory tracts send axon collateral fibers to
the reticular formation. These give rise to fibers synapsing
in the nonspecific nuclei of the thalamus. From there, the
nonspecific thalamic projections influence widespread
areas of the cerebral cortex and limbic system.
Th e a t t en t ion syst em h a s lim it s on wh a t a n d h ow
m u ch ca n be pr ocessed. For exa m ple, dr ivin g wh ile
t a lkin g or t ext in g on a cell ph on e lea ds t o poor dr iv-
in g per for m a n ce, m or e a cciden t s, a n d veer in g t o-
wa r d t h e m edia n or sh ou lder of t h e r oa d. In a ddit ion ,
a t t en t ion is divided a n d it is m u ch m or e difficu lt t o
 Alt e r a t io n s in Mo o d , At t e n t io n , a n d B e h a v io r
con cen t r a t e on bot h wh en st u dyin g wh ile list en in g
t o t h e r a dio.
Stop and Consider
What are some examples of situations where you
have experienced the types of attention above?
What are other activities in which you partici-
pate where your attention is divided and atten-
tion resources are taxed?
Regulation of Behavior
B e h a v io r is h ow people r espon d a n d a ct in a given
sit u a t ion . As wit h m ood, t h e fr on t a l lobe of t h e
Modu le 2 Alt e r a t io n s in Mo o d ,
At t e n t io n , a n d B e h a v io r
Alterations in Brain Structure
and Function
Alt er a t ion s in t h e br a in , lim bic syst em con n ec-
t ion s, or n eu r ot r a n sm ission ca n r esu lt in im pa ir-
m en t s of m ood, a t t en t ion , a n d beh a vior. A m a jor
ca u se of m ood, a t t en t ion , a n d beh a vior disor der s is
t r a u m a t ic br a in in ju r y. Th e fr on t a l lobe a n d cor r e-
spon din g lim bic syst em st r u ct u r es a r e pa r t icu la r ly
vu ln er a ble. Wh en t h e pr efr on t a l cor t ex su ffer s a n
in ju r y, t h e pa t ien t loses t h e sen se of socia l r espon si-
bilit y, con cen t r a t ion , a bst r a ct t h in kin g, a n d pr oblem
solvin g. Th e pa t ien t displa ys a fla t a ffect , a n ob-
ser ved em ot ion a l r espon se, wit h n o sign s of joy, sa d-
n ess, h ope, or a ffect ion . Dest r u ct ion of t h e a m ygda la
a lso h a s a sign ifica n t im pa ct . Th er e is a r edu ct ion
of fea r a n d a ggr ession a n d a loss of socia l in t elli-
gen ce. Wh en bot h a m ygda la s a r e im pa ir ed, t h e con -
n ect ion bet ween socia l in t elligen ce a n d m em or y is
a lso im pa ir ed. Pa t ien t s lose fa cia l expr ession r ecog-
n it ion a n d ca n n ot in t er pr et wh a t t h e ot h er per son is
t h in kin g or feelin g. Sim ila r ly, em ot ion a l r ea ct ivit y is
im pa ir ed wit h da m a ge t o lim bic syst em st r u ct u r es
in clu din g t h e t h a la m u s, pr efr on t a l cor t ex, a n d h y-
pot h a la m u s. Lesion s of t h e h ypot h a la m u s in t er fer e
wit h a ppr opr ia t e r espon ses t o t h er m a l r egu la t ion ,
h u n ger, t h ir st , sexu a lit y, a n d a ggr ession t owa r d
ot h er s.
N eu r ot r a n sm ission im pa ir m en t s, su ch a s levels
of n eu r ot r a n sm it t er s or r ecept or issu es, ca n lea d t o
269
br a in is t h e pr im a r y r egion r espon sible for r egu la t -
in g beh a vior. Th is lobe in t egr a t es a ll a spect s of be-
h a vior in clu din g per son a lit y, per cept ion , pla n n in g,
self-a wa r en ess, ju dgm en t , m ood, a t t en t ion , m em or y,
m ot iva t ion , sexu a lit y, expr essive la n gu a ge, a n d so-
cia l a n d em ot ion a l in t elligen ce.
Gen er a t in g a ppr opr ia t e beh a vior s for a given sit -
u a t ion r equ ir es a com plex in t er pla y of cogn it ive a n d
beh a vior a l pr ocesses. For exa m ple, con sider r eceiv-
in g ba d n ews. Beh a vior will be ba sed on n ot icin g,
per ceivin g, sh or t -t er m a n d lon g-t er m m em or y (pa st
exper ien ces), cu r r en t socia l expect a t ion s, m ood, per-
son a lit y, m ot iva t ion /in h ibit ion , cu lt u r e, con sider-
a t ion of a ll possible a ct ion s, pla n n in g, a n d decidin g.
All t h ese occu r wit h in a m a t t er of secon ds a n d wit h
lit t le con sciou s effor t .
a pa t h y, in a t t en t iven ess, a n d m ot or deficit s a s wit h
low levels of dopa m in e, or a git a t ion , r est lessn ess,
a n d psych osis a s wit h h igh levels of dopa m in e.
Deficit s in ser ot on in h a ve been a ssocia t ed wit h
a n xiet y, obsession s, a n d com pu lsion s. Th ese va r i-
ou s a lt er a t ion s a r e discu ssed in gr ea t er det a il in
Modu le 3.
Recognizing Alterations in Mood,
Attention, and Behavior
Ra r ely a r e t h er e la bor a t or y t est s or im a gin g st u dies
t h a t ca n con fir m a psych ia t r ic dia gn osis. Dia gn osis
m ost oft en r elies on pa t ien t h ist or y a n d r epor t ed ob-
ser va t ion s of ot h er s. A n u m ber of va lid a n d r elia ble
scr een in g t ools a r e cu r r en t ly bein g u sed t o a t t em pt
t o iden t ify pa t ien t s wit h m ood, a t t en t ion , a n d be-
h a vior a l disor der s, su ch a s t h e Mood Disor der Qu es-
t ion n a ir e. Som et im es t h e dia gn osis is a ch ieved on ly
a ft er ot h er a lt er n a t ives h a ve been r u led ou t .
Th e m ost widely u sed ca t egor ica l cr it er ia for dia g-
n osin g a lt er a t ion s in m ood, a t t en t ion , a n d beh a vior
a r e fou n d in t h e Am er ica n P sych ia t r ic Associa t ion ’s
fift h edit ion of t h e Dia gn ostic a n d S ta tistica l Ma n -
u a l of Men ta l Disor d er s (DSM-5), a n d t h e Wor ld
H ea lt h Or ga n iza t ion ’s In ter n a tion a l S ta tistica l
Cla ssifica tion of Disea ses a n d Rela ted H ea lth P r ob-
lem s (ICD-10). Th e DSM-5 is com m on ly u sed in t h e
270 C h a p t e r 11: Alt er ed Mood, At t en t ion , a n d Beh a vior

Cate g o ric al Traits Treating Alterations in Mood,

Attention, and Behavior
Tr ea t m en t for a lt er a t ion s in m ood, a t t en t ion , a n d
Bipo lar Dis o rde r S c hizo phre nia beh a vior m u st be in dividu a lized a n d ca n in clu de
Ele vate d Mo o d
(a lon e or in com bin a t ion ) in h ospit a l or com m u n it y
Dis o rg anize d S pe e c h
Flig ht o f Ide as Dis o rg anize d Be havio r set t in gs t h e followin g:
Pre s s ure d S pe e c h
Halluc inatio ns
S uic idality
● P sych ot h er a py—Con du ct ed wit h a qu a lified
De lus io ns m en t a l h ea lt h pr ofession a l; explor es t h ou gh t s,
Ins o mnia feelin gs, a n d beh a vior s, a n d seeks t o im pr ove
Flat Affe c t
Irritability
Impaire d Co nc e ntratio n
Avo litio n well-bein g, su ch a s t h r ou gh cogn it ive-beh a vior a l
t h er a py, exposu r e t h er a py, et c.
● P h a r m a cot h er a py—P r escr ibed by a qu a lified
Majo r De pre s s io n m en t a l h ea lt h pr ofession a l; dr u g t h er a py ca n h elp
De pre s s e d Mo o d
Appe tite Dis turbanc e wit h m a n a gem en t of sym pt om s r ela t ed t o a lt er-
Ane rg y
Guilt/Wo rthle s s ne s s a t ion s in m ood, a t t en t ion , a n d beh a vior, su ch a s
wit h a n t idepr essa n t dr u gs.
● Cou n selin g—Ca n h elp fa cilit a t e a n u m ber of
st r a t egies t o pr om ot e welln ess, in clu din g st r ess
Figure 11.4. Categorical traits as conceptualized by the
r edu ct ion , lifest yle ch a n ges, a n d com m u n it y r e-
Diagnostic and Statistical Manual (DSM-5) represent a
sou r ce u t iliza t ion .
“menu-based” approach to psychiatric disorders. Individu-
● Alt er n a t ive/com plem en t a r y t h er a pies—A n u m -
als are assessed for a checklist of signs and symptoms that
ber of a lt er n a t ive a n d com plem en t a r y t h er a pies
are then used to categorize the individual as “affected”
ca n be u sed t o a llevia t e sym pt om s, su ch a s h er ba l
according to a specific diagnosis. Not all symptoms are
r em edies, a cu pu n ct u r e, h om eopa t h y, a n d m a n y
present in samples of individuals who carry a particular
ot h er s.
DSM diagnosis, and many of these symptoms occur across
● In dividu a l or fa m ily su ppor t gr ou p—Offer s su p-
diagnostic boundaries, as illustrated in this Venn diagram.
por t a n d a dvice fr om ot h er s wh o h a ve h a d sim ila r
(From Sadock BJ, Sadock VA, Ruiz P. Kaplan & Sadock’s
n eeds a n d exper ien ces, wh er e t h e gr ou p is wor k-
Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia,
in g t owa r d a sh a r ed goa l.
PA: Lippincott Williams & Wilkins; 2009:325.)
Stop and Consider
Un it ed St a t es a n d t h e ICD-10 is u sed in t er n a t ion - There is an inordinate amount of stigma involved
a lly. Figu r e 11.4 illu st r a t es t h e ca t egor ica l a ppr oa ch in mental illness. What do you see in your
t o dia gn osin g a lt er a t ion s in m ood, a t t en t ion , a n d community as barriers to patients seeking
beh a vior. appropriate mental health treatment?

Modu le 3 C lin ic a l Mo d e ls

Th e followin g clin ica l m odels wer e select ed t o h elp
a pply kn owledge r ela t ed t o a lt er ed m ood, a t t en t ion ,
a n d beh a vior. Wh a t you will n ot ice is t h a t t h ese
clin ica l m odels r ely h ea vily on pa t ien t h ist or y a n d
obser va t ion s u sin g scr een in g t ools for dia gn osis.
Tr ea t m en t s m ost oft en in volve a com bin a t ion of psy-
ch ot h er a py a n d ph a r m a cot h er a py a n d a n em ph a sis
on fa m ily su ppor t .
Generalized Anxiety Disorder
An x ie t y d is o r d e r s a r e a gr ou p of ch r on ic psych i-
a t r ic con dit ion s ch a r a ct er ized by over wh elm in g a n d
ir r a t ion a l feelin gs of fea r or wor r y. Th ese feelin gs
m a y ca u se ph ysica l sym pt om s, su ch a s a st om a ch -
a ch e, h ea da ch e, r a cin g h ea r t , a n d sh a kin ess. It is of-
t en t h e ph ysica l sym pt om s t h a t ca u se t h e pa t ien t t o
seek m edica l ca r e. Th er e a r e sever a l t ypes of a n xiet y
disor der s, oft en or ga n ized in t o t h r ee dist in ct gr ou ps:
1. An xiet y disor der s
2. Obsessive-com pu lsive disor der s
3. Tr a u m a /st r ess-r ela t ed disor der s
F igu r e 11.5 illu st r a t es a decision -t r ee, wh ich ca n be
u sed t o differ en t ia t e t h e va r iou s t ypes of a n xiet y. Th e
a n xiet y disor der s a r e t h e m ost com m on ca t egor y a n d
 C lin ic a l Mo d e ls 271

Exce s s ive a nd
Pe rs is te nt Anxie ty

Anxie ty due
to the dire ct e ffe cts Ye s S ubs ta nce -Induce d
of a me dica tion Anxie ty Dis orde r
or s ubs ta nce ?

No

Anxie ty due
to the dire ct e ffe cts Anxie ty Dis orde r
Ye s Due to a Ge ne ra l
of a ge ne ra l me dica l
condition? Me dica l Condition

No
S ymptoms of
Anxie ty in re -expe rie ncing,
re s pons e to re ce nt avoida nce , numbing,
Ye s No
N Adjus tme nt Dis orde r
tra uma or a nd ≠ a rous a l With Anxious Mood
ps ychos ocia l cha ra cte ris tic of
s tre s s ors ? P TS D?
No Ye s

His tory of re curre nt, S ymptom dura tion No

N Acute S tre s s
unexpe cte d pa nic >4 we e ks ? Dis orde r
Pa nic Ye s a tta cks tha t ca us e
Dis orde r pe rs is te nt conce rn or
worry or a cha nge
in be havior? Ye s
(s e e Ta ble 80-11)
No
N
Avoida nce of P TS D
pla ce s or s itua tions
due to P re s e nce of
fe a r of having a obs e s s ions or
pa nic a tta ck? compuls ions Ye s OCD
cha ra cte ris tic
No Ye s
of OCD? (s e e
Ta ble 80-14)
Pa nic Dis orde r Pa nic Dis orde r
Without With No
Agora phobia Agora phobia

Anxie ty re la te d Anxie ty a nd fe a r
prima rily to fe a r of Ye s re la te d prima rily to Ye s S ocia l Anxie ty
ce rta in specific objects expos ure of s ocia l Dis orde r
or s itua tions ? s itua tions ?

No No

S pe cific
Exce s s ive a nd P hobia
Ye s pe rs is te nt a nxie ty
GAD
characteristic of GAD?
(s e e Ta ble 80-3)

No
N

Anxie ty Dis orde r Not

Othe rwis e S pe cifie d

Figure 11.5. Diagnostic decision-tree for anxiety disorders. GAD, generalized anxiety disorder; OCD, obsessive-compulsive
disorder; PTSD, posttraumatic stress disorder. (From Alldredge BK, Corelli RL, Ernst ME, et al. Koda-Kimble and Young’s
Applied Therapeutics. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2012.)
272 C h a p t e r 11: Alt er ed Mood, At t en t ion , a n d Beh a vior
in clu de pa n ic disor der, gen er a lized a n xiet y, socia l
a n xiet y, ph obia s, sepa r a t ion a n xiet y, a n d m edica -
t ion /illn ess-in du ced a n xiet y. Th is sect ion will focu s
on g e n e r a lize d a n x ie t y d is o r d e r (G AD ), wh ich
is ch a r a ct er ized by excessive, u n con t r olla ble, a n d ir-
r a t ion a l wor r y la st in g gr ea t er t h a n 6 m on t h s. Th e
a n xiet y in t er fer es wit h da ily life du e t o ir r a t ion a l
t h in kin g a bou t ever yda y m a t t er s, su ch a s h ea lt h ,
m on ey, dea t h , fa m ily, fr ien ds, wor k, et c. Ar ou n d 6%
of t h e US popu la t ion is a ffect ed by GAD.1 Post t r a u -
m a t ic st r ess disor der is a lso discu ssed in gr ea t er de-
t a il a s a select clin ica l m odel in t h is m odu le.
PATHOPHYSIOLOGY
Br a in st r u ct u r e a n d fu n ct ion st u dies in dica t e t ha t t h e
a m ygda la is key in m odula t in g fea r a n d a n xiet y. Pa -
t ien t s wit h a n xiet y disor der s oft en show a gr ea t er r e-
sponse in t h e a m ygda la t o a n xiet y-pr ovokin g event s.
Th e a m ygda la a n d ot h er lim bic syst em st r u ct ur es
a r e closely con nect ed t o t h e pr efr ont a l cor t ex. Wh en
t r ea t ed wit h psych ologic t h er a pies or m edica t ion s,
a m ygda la a bn or m a lit ies exer t ed on t h e lim bic syst em
a n d pr efr on t a l cor t ex h ave been sh own t o be r elieved.
In t h e cen t r a l n er vou s syst em (CNS), t h e m a jor
m edia t or s of t h e sym pt om s of a n xiet y disor der s a p-
pea r t o be n or epineph r in e, ser ot on in , dopa m in e, a nd
ga m m a -a m in obu t yr ic a cid (GABA). Th e a u t on om ic
n er vou s syst em , especia lly t h e sym pa t h et ic ner vou s
syst em , m edia t es t h e sym pt om s of a n xiet y.
Th e ca u se of GAD is oft en n ot kn own . Gen et ic fa c-
t or s ca n in flu en ce r isk; a n xiet y disor der s a r e m or e
likely t o occu r in t h ose wit h a fa m ily h ist or y of a n xi-
et y. E n vir on m en t a l fa ct or s m a y a lso pla y a r ole, pa r-
t icu la r ly exposu r e t o t r a u m a t ic even t s.
CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s of GAD in clu de excessive,
u n con t r olled, ir r a t ion a l wor r y or a n xiet y la st in g
gr ea t er t h a n 6 m on t h s, a ccom pa n ied by a t lea st
t h r ee of t h e followin g:
● Rest lessn ess
● Fa t igu e
● Difficu lt y con cen t r a t in g
● Ir r it a bilit y
● Ten sion
● Sleep dist u r ba n ce
Pa t ien t s wit h GAD a r e a lso a t r isk for su icida l
idea t ion a n d sh ou ld be eva lu a t ed a n d t r ea t ed
a ccor din gly.
DIAGNOSTIC CRITERIA
Dia gn osis of GAD r equ ir es a t h or ou gh m edica l h is-
t or y a n d ph ysica l exa m in a t ion t o r u le ou t a m edica l
con dit ion or su bst a n ce-a bu se pr oblem t h a t m a y be
t h e u n der lyin g ca u se for t h e gen er a lized a n xiet y. In
t h e a bsen ce of a n u n der lyin g ca u se for GAD sym p-
t om s, st a n da r dized r a t in g sca les ca n be u sed t o
a ssess sever it y a n d t o m on it or pr ogr ess wit h t h er a -
peu t ic in t er ven t ion s.
TREATMENT
Cogn it ive-beh a vior a l t h er a py (CBT), a lon e or in a d-
dit ion t o ph a r m a cot h er a py, is cu r r en t ly t h e m ost ef-
fect ive t r ea t m en t for GAD. Cogn it ive t h er a py open s
t h e door s t o kn owledge a n d u n der st a n din g so t h a t
t h e pa t ien t ca n m or e clea r ly u n der st a n d h ow ir r a t io-
n a l t h ou gh t s a n d beliefs lea d t o a n xiet y. Beh a vior a l
t h er a py in volves gr a du a l exposu r e of t h e pa t ien t t o
a n xiet y-pr ovokin g st im u li. Over t im e, t h e pa t ien t
becom es desen sit ized a n d r ea lizes t h a t t h e fea r ed,
ca t a st r oph ic, ir r a t ion a lly a n t icipa t ed even t does n ot
occu r. Rela xa t ion t ech n iqu es, in clu din g effect ive a b-
dom in a l br ea t h in g, ca n a lso h elp con t r ol a n xiet y.
P h a r m a cologic t r ea t m en t for GAD m ost com -
m on ly in volves select ive ser ot on in r eu pt a ke in h ib-
it or s (SSRIs). Th ese dr u gs wor k by pr ovidin g m or e
ser ot on in a t t h e syn a pse t o a llow for a m plified n er ve
cell con du ct ion r esu lt in g in a n eleva t ion of m ood.
Th e exa ct m ech a n ism for t r ea t in g a n xiet y is less
u n der st ood. Ben zodia zepin es a r e a lso som et im es
in dica t ed for sh or t t er m or a s n eeded t o r edu ce im -
m edia t e over wh elm in g feelin gs of a n xiet y. Th e ex-
a ct m ech a n ism of a ct ion of ben zodia zepin es is n ot
kn own ; t h ese dr u gs a ppea r t o in cr ea se a ct ivit y of
GABA, a n eu r ot r a n sm it t er t h a t su ppr esses t h e a c-
t ivit y of n er ves. Ben zodia zepin es do ca r r y a r isk for
depen den ce a n d sh ou ld be u sed ca u t iou sly.
Posttraumatic Stress Disorder
P o s t t r a u m a t ic s t r e s s d is o r d e r (P TSD) is a n a n x-
iet y disor der ca u sed by ext r em e t r a u m a t ic even t s,
com m on ly a ffect in g t h ose wh o h a ve exper ien ced m il-
it a r y com ba t , vict im s of n a t u r a l disa st er s, con cen -
t r a t ion ca m p su r vivor s, a n d vict im s of violen t cr im e.
Th e sym pt om s of P TSD a r e a r esu lt of wit n essin g
even t s su ch a s dea t h or life-t h r ea t en in g in ju r y of
ot h er s a n d/or ser iou s per son a l h a r m wh er e feelin gs
of in t en se h or r or, fea r, power lessn ess, a n d gu ilt wer e
exper ien ced. It is est im a t ed t h a t m or e t h a n 60%
of m en a n d 50% of wom en exper ien ce a t lea st on e
t r a u m a t ic even t in t h eir life. Th e m ost fr equ en t ly r e-
por t ed t r a u m a t ic even t s by m en a r e r a pe, com ba t ,
a n d ch ildh ood n eglect or ph ysica l a bu se. Wom en
m ost fr equ en t ly r epor t in st a n ces of r a pe, sexu a l m o-
lest a t ion , ph ysica l a t t a ck, bein g t h r ea t en ed wit h a
wea pon , a n d ch ildh ood ph ysica l a bu se. H owever, n ot
 C lin ic a l Mo d e ls 273

a ll people wh o exper ien ce t r a u m a develop P TSD. In Sim ila r t o ot h er m en t a l h ea lt h disor der s, t h er e is

t h e Un it ed St a t es, it is est im a t ed t h a t 10% of wom en
a n d 4% of m en will develop P TSD a t som e poin t in
t h eir lives. Ra t es a m on g vet er a n s va r y by ser vice
a r ea bu t is est im a t ed a t 11% t o 20% per yea r wit h a
r a t e of 30% over a vet er a n ’s lifet im e.2
PATHOPHYSIOLOGY
P TSD is ca u sed by a com bin a t ion of exper ien cin g
on e or m or e t r a u m a t ic even t s cou pled wit h biologic
su scept ibilit y. Th e m or e sever e t h e t r a u m a a n d t h e
m or e su scept ible t h e in dividu a l, t h e m or e likely
t h a t per son is t o develop P TSD. Risk fa ct or s in clu de
pr ior exposu r e t o t r a u m a , pa r t icu la r ly in ch ildh ood,
wh er e t h e ch ild dissocia t ed fr om t h e t r a u m a . Ot h -
er s in clu de close pr oxim it y, lon g du r a t ion , a n d h igh
sever it y of t h e t r a u m a , a n xiet y, depr ession , a h eigh t -
en ed st a r t le r espon se, sm a ller h ippoca m pa l volu m e,
a lcoh ol a n d dr u g a bu se, a fa m ily h ist or y of m en -
t a l h ea lt h issu es, im pa ir ed socia l su ppor t , a n d t h e
a bsen ce of ea r ly in t er ven t ion s.
a h er edit a r y com pon en t t o P TSD wit h a bou t 30% of
t h e r isk expla in ed by gen et ics. E xper ien cin g t r a u -
m a t ic even t s ca n r esu lt in fea r r ea ct ion s, wh ich a ct i-
va t e t h e pr efr on t a l cor t ex a n d a m ygda la , a n d r elea se
st r ess h or m on es, wh ich su ppr ess t h e h ypot h a la m u s
(Fig. 11.6). Th e a dr en a l r espon se r esu lt s in t h e cr e-
a t ion of n eu r oen docr in e pa t t er n s t h a t per sist beyon d
t h e t r a u m a t ic even t (s). Most n ot a bly, im pa ir m en t
in h ypot h a la m ic–pit u it a r y a xis, a n d su bsequ en t ly
t h e figh t or fligh t r espon se occu r s, wh er e cor t isol
levels becom e su ppr essed a n d ca t ech ola m in e lev-
els (su ch a s epin eph r in e, a lso kn own a s a dr en a lin e,
n or epin eph r in e, a n d dopa m in e) a r e eleva t ed. H igh
n or epin eph r in e levels in t h e pr efr on t a l cor t ex pr o-
m ot e fla sh ba cks a n d n igh t m a r es. H igh dopa m in e
levels in du ce a n xiet y a n d psych osis. Su ppr ession of
cor t isol levels pr oh ibit s t h e r est or a t ion of h om eost a -
sis a ft er t h e t r a u m a t ic even t . F u t u r e fea r fu l even t s
a r e m a r ked by a n over exa gger a t ed figh t or fligh t r e-
spon se (h igh ca t ech ola m in es) wit h a r est r ict ed a bil-
it y t owa r d h om eost a sis (low cor t isol).

S e ns o rimo to r c o rtex
Function: Coordina tion of s e ns ory Ante rio r c ing ulate c o rtex
a nd motor functions
Function: utonomic functions, cognition
In P TS D: S ymptom provoca tion re s ults
In P TS D: Re duce d volume , highe r re s ting
in incre a s e d a ctiva tion
me ta bolic a ctivity
Thalamus
Pre fro ntal c o rtex
Function: S e ns ory re lay s ta tion
In P TS D: De cre a s e d ce re bra l Function:
blood flow

In P TS D:
y a nd white
ma tte r de ns ity
e ne s s
to tra uma a nd e motiona l s timuli

Orbito fro ntal c o rte x:

Parahippo c ampal g yrus Function: e cutive function
Function: Importa nt for me mory In P TS D: De cre a s e s in volume
e ncoding a nd re trieva l
In P TS D: S how s tronge r conne ctivity Amyg dala
with me dia l pre fronta l cortex; Function:
de cre a s e s in volume fe a r
ve le a rning
Fe ar re s po ns e Hippo c ampus
Function: In P TS D:
Function:
olutiona ry s urviva l e ne s s
fe a r
to tra uma tic a nd e motiona l
e le a rning
In P TS D: s timuli
In P TS D:
ear e ne s s
re s pons e to tra uma tic a nd e motional
xtinction s timuli

Figure 11.6. Brain regions associated with PTSD. (From Mahan AL, Ressler KJ. Fear conditioning, synaptic plasticity and
the amygdala: implications for posttraumatic stress disorder. Trends Neurosci. 2012;35(1):24–35.)
274 C h a p t e r 11: Alt er ed Mood, At t en t ion , a n d Beh a vior
CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s in P TSD a ppea r a ft er t h e
t r a u m a t ic even t , oft en wit h in 3 m on t h s, bu t em er-
gen ce ca n occu r beyon d t h is t im e. In it ia l clin ica l
m a n ifest a t ion s ca n in clu de a voida n ce a n d su ppr es-
sion of t h ou gh t s a n d em ot ion s a bou t t h e t r a u m a .
H owever, P TSD is ch a r a ct er ized by r elivin g t h e
t r a u m a t ic even t t h r ou gh in t r u sive n igh t m a r es a n d
fla sh ba cks.
For ch ildr en , clin ica l m a n ifest a t ion s gen er a lly dif-
fer fr om a du lt s a n d ca n in clu de excessive r ea ct ion s
t o ca r egiver sepa r a t ion , cr yin g, scr ea m in g, t r em -
blin g, r egr ession , wit h dr a wa l, disr u pt ive beh a vior,
in a t t en t iven ess, a n ger ou t bu r st s, sleep pr oblem s,
ir r a t ion a l fea r s, a n d som a t ic com pla in t s.
DIAGNOSTIC CRITERIA
Th e DSM-5 ou t lin es t h e dia gn ost ic cr it er ia for P TSD
(see Resou r ces). Clin ica l m a n ifest a t ion s m u st be
pr esen t for a t lea st 1 m on t h , m u st ca u se im pa ir ed
fu n ct ion in g, a n d ca n n ot be a t t r ibu t ed t o a n y ot h er
m edica l con dit ion . Ot h er com pon en t s m u st a lso be
m et t o be dia gn ost ic:
1. E xper ien cin g/wit n essin g t h e t r a u m a t ic even t (s).
2. Per sist en t ly r eexper ien cin g t h e t r a u m a t ic even t (s)
t h r ou gh t h ou gh t s, dr ea m s, h a llu cin a t ion s, disso-
cia t ive fla sh ba cks, et c.
3. Avoidin g st im u li a ssocia t ed wit h t h e t r a u m a t ic
even t (s) a n d n u m bin g of r espon siven ess.
4. Dist or t in g cogn it ion s a n d m ood a ssocia t ed wit h
t h e t r a u m a t ic even t (s) su ch a s a per sist en t n eg-
a t ive em ot ion a l st a t e or com plet e in a bilit y t o r e-
m em ber im por t a n t a spect s of t h e even t .
5. Rea ct in g in a n exa gger a t ed or im pa ir ed wa y
su ch a s t h r ou gh ir r it a bilit y, a n ger, r eck less-
n ess, h yper vigila n ce, or a n exa gger a t ed st a r t le
r espon se.
TREATMENT
E a r ly in t er ven t ion for t h ose exper ien cin g t r a u -
m a t ic even t s, even pr ior t o dia gn osis wit h P TSD,
ca n h elp t o effect ively a m elior a t e t h e sym pt om s.
For t h ose dia gn osed wit h P TSD, psych ot h er a py of-
t en wit h m edica t ion s for sym pt om m a n a gem en t is
t h e cu r r en t t r ea t m en t . P sych ot h er a py a ppr oa ch es,
pa r t icu la r ly t h r ou gh t h e u se of t r a u m a -focu sed
cogn it ive-beh a vior a l t h er a py (TF CBT) a n d eye m ove-
m en t desen sit iza t ion a n d r epr ocessin g (E MDR),
h a ve been sh own t o be effect ive. Bot h seek t o ch a n ge
t h e t r a u m a vict im ’s t h in kin g a n d beh a vior s su r-
r ou n din g t h e t r a u m a t ic exper ien ce. In E MDR, eye
m ovem en t s a r e a dded t o a id in t h e in for m a t ion -pr o-
cessin g m ech a n ism s of t h e br a in . P la y t h er a py is
com m on ly em ployed for ch ildr en wit h P TSD.
Medica t ion s a r e im por t a n t for r elievin g sym p-
t om s, su ch a s a n xiet y, depr ession , n igh t m a r es, a n d
im pu lsivit y. Com m on ly pr escr ibed a r e a n t idepr es-
sa n t dr u gs, ben zodia zepin es for sh or t -t er m a n xiet y
r elief, glu cocor t icoids (sh or t t er m ) t o a ssist wit h n eu -
r ocellu la r h om eost a sis, a n t icon vu lsa n t s for im pu l-
sivit y, a n d clon idin e (a cen t r a lly a ct in g a lph a -a gon ist
h ypot en sive a gen t ) for n igh t m a r es.
Major Depressive Disorder
Depr ession is a con dit ion of a lt er ed m ood, wh ich ca n
be sh or t t er m a n d sit u a t ion a lly depen den t , su ch a s
wit h n or m a l ber ea vem en t , or ch r on ic a n d sever e, a s
ca n occu r wit h a m a jor depr essive disor der. Ma jo r
d e p r e s s iv e d is o r d e r (MD D ) is a con dit ion ch a r a c-
t er ized by a per va sive a n d per sist en t low m ood t h a t
is a ccom pa n ied by low self-est eem a n d a n h e d o n ia ,
or loss of in t er est or plea su r e in n or m a lly en joya ble
a ct ivit ies. It is a disa blin g con dit ion t h a t a dver sely
a ffect s t h e pa t ien t ’s fa m ily, wor k or sch ool life, sleep,
ea t in g h a bit s, a n d over a ll h ea lt h .
MDD is dia gn osed u pon t h e pa t ien t exper ien cin g
m a jor depr essive episodes, wh ich a r e ch a r a ct er ized
by t h e pr esen ce of a sever ely depr essed m ood t h a t
per sist s for a t lea st 2 weeks. E pisodes m a y be a cu t e
or ch r on ic/r ecu r r en t a n d a r e ca t egor ized a s m ild,
m oder a t e, or sever e. Th e DSM-5 fu r t h er differ en t i-
a t es five su bt ypes of MDD:
● S ea son a l a ffective—Ch a r a ct er ized by depr essive
episodes occu r r in g in t h e la t e fa ll a n d win t er, r e-
solvin g in t h e spr in g/su m m er.
● Postpa r tu m —Ch a r a ct er ized by disa blin g depr es-
sion a ft er givin g bir t h la st in g u p t o 3 m on t h s.
● Mela n ch olic—Ch a r a ct er ized by pr on ou n ced de-
pr ession oft en m ost n ot a ble in t h e ea r ly m or n in g,
excessive weigh t loss, excessive gu ilt , loss of plea -
su r e in m ost /a ll a ct ivit ies.
● Ca ta ton ic—Ra r e a n d sever e, ch a r a ct er ized by im -
m obilit y or pu r poseless m ovem en t s, in a bilit y t o
spea k, st u por.
● Atypica l—Ch a r a ct er ized by m ood r ea ct ivit y,
weigh t ga in , excessive sleep, socia l im pa ir m en t .
Du r in g 2009 t o 2012, 7.6% of Am er ica n s a ged 12 a n d
over h a d depr ession (m oder a t e or sever e depr essive
sym pt om s in t h e pa st 2 weeks). Depr ession wa s
m or e pr eva len t a m on g fem a les a n d per son s a ged
40 t o 59 a n d per son s livin g below t h e pover t y level
wer e n ea r ly 2½ t im es m or e likely t o h a ve depr ession
t h a n t h ose a t or a bove t h e pover t y level. 3
PATHOPHYSIOLOGY
Alt h ou gh t h e exa ct ca u se of depr ession h a s n ot
been iden t ified, a biopsych osocia l m odel illu st r a t es

biologic, psych ologic, a n d socia l fa ct or s a ll pla y a r ole.
Th e h er it a bilit y of depr ession , t h a t is, t h e degr ee t o
wh ich gen et ics pla ys a r ole, h a s been est im a t ed a t
40% for wom en a n d 30% for m en .4 Sign ifica n t r e-
sea r ch on biologic fa ct or s h a s poin t ed t o sever a l po-
t en t ia l in flu en ces:
● Da m a ge t o t h e cer ebellu m ca n dir ect ly ca u se
depr ession ;
● Th ose wit h on e or t wo sh or t a lleles of t h e 5-H TT
gen e (t h e ser ot on in t r a n spor t er gen e) a r e m or e
likely t o develop depr ession given ver y st r essfu l
life even t s;
● E xcessive u se a n d/or wit h dr a wa l fr om a lcoh ol,
illicit dr u gs, a n d cer t a in seda t ive/h ypn ot ic dr u gs
a r e a ssocia t ed wit h t h e developm en t of m a jor
depr ession ;
● Th e levels of br a in -der ived n eu r ot r opic fa ct or, r e-
spon sible for n eu r on gen er a t ion , a r e r edu ced in
t h ose wit h depr ession ;
● Br a in st r u ct u r a l differ en ces in n eu r oim a gin g
st u dies h a ve n ot ed:
■ In cr ea sed a dr en a l gla n d a n d la t er a l ven t r icle
volu m es
■ Redu ced volu m es of t h e ba sa l ga n glia , t h a la -
m u s, h ippoca m pu s, a n d fr on t a l lobe
■ Loss of n eu r on s in t h e h ippoca m pu s
● A h yper a ct ive pit u it a r y–a dr en a l a xis a n d su bse-
qu en t in cr ea sed levels of cor t isol h a ve been a sso-
cia t ed wit h depr ession ;
● E st r ogen levels m a y pla y a r ole given t h e h igh er
in ciden ce in wom en , pa r t icu la r ly a ft er pu ber t y,
befor e m en opa u se, a n d du r in g pr egn a n cy;
● H igh er levels of cir cu la t in g in fla m m a t or y cyt o-
kin es, pa r t icu la r ly IL-6 a n d TNF -a lph a , a r e a sso-
cia t ed wit h depr ession .
Most n ot a bly, depr ession is believed t o be a con di-
t ion r esu lt in g fr om a deficien cy in n eu r ot r a n sm it -
t er s or a lt er a t ion s in t h e syn a pses t h a t u se t h ese
n eu r ot r a n sm it t er s in cr it ica l a r ea s of t h e br a in . Al-
t h ou gh , a s you will soon see, t h e ph r a se “ch em ica l
im ba la n ce” is a n over sim plifica t ion .
Th e specific n eu r ot r a n sm it t er syst em s in volved
in clu de n or epin eph r in e (NE ), dopa m in e (DA), a n d
ser ot on in (5-H T). Th ese n eu r ot r a n sm it t er s a r e a lso
r efer r ed t o a s m on oa m in es. For per fect n eu r ot r a n s-
m ission , t h e followin g m u st t a ke pla ce:
● P r esyn a pt ic n eu r on s a r e fu n ct ion a l a n d r elea se
n eu r ot r a n sm it t er s a t a n or m a l r a t e;
● E n zym es a r e effect ively a ct ive a n d br ea k down
n eu r ot r a n sm it t er s;
● Mem br a n e t r a n spor t er s fr om t h e syn a pt ic cleft
a r e fu n ct ion a l, a llowin g u pt a ke, r eu pt a ke, a n d r e-
cyclin g of t h e a ct ive n eu r ot r a n sm it t er s;
● Recept or s t h a t det ect n eu r ot r a n sm it t er s a n d con -
t r ol t h e r elea se a n d flow of im pu lse t h r ou gh t h e
n eu r on a r e fu n ct ion a l;
C lin ic a l Mo d e ls 275
● Post syn a pt ic n eu r on s con t a in n eeded r egu la t or y
m ech a n ism s t o pr om ot e sign a l t r a n sdu ct ion .
Th e m on oa m in e h ypot h esis of depr ession em ph a -
sizes t h e in t er pla y of t h e NE , DA, a n d 5-H T n eu -
r ot r a n sm it t er s in r egu la t in g m ood. In t h is t h eor y,
ser ot on in (5-H T) r egu la t es t h e ot h er n eu r ot r a n sm it -
t er syst em s. Th er efor e, low levels of ser ot on in wou ld
r esu lt in low levels of n or epin eph r in e a n d dopa m in e
a n d lea d t o depr ession . Th is t h eor y is su ppor t ed
by cu r r en t ph a r m a cologic t r ea t m en t of depr ession ,
wh ich t a r get s t h e n eu r ot r a n sm it t er s a n d r ecept or s,
t o im pr ove m ood (F ig. 11.7). Th e cou n t er a r gu m en t
is t h a t a n t idepr essa n t dr u gs t a ke weeks for t h eir
fu ll effect , even t h ou gh t h e boost of m on oa m in es oc-
cu r s wit h in h ou r s of t a kin g t h e dr u gs. Also, n ot a ll
pa t ien t s wit h low m on oa m in es exh ibit sym pt om s of
depr ession . Th ese t h eor ies a n d cou n t er a r gu m en t s
illu st r a t e t h e com plexit y of pin poin t in g t h e biologic
ba sis of depr ession .
Socia l a n d psych ologica l in flu en ces on depr es-
sion ca n n ot be ign or ed. Isola t ion , socia l r eject ion ,
loss or la ck of sign ifica n t r ela t ion sh ips, issu es wit h
fa m ily fu n ct ion in g, u n em ploym en t , pover t y, a bu se,
Bre a kdown e ffe ct
MAO
NE NE
S
S
D P os ts yna ptic
re ce ptors
NE
D
S
D
Re upta ke
P re s yna ptic P os ts yna ptic
ne uron ne uron
Figure 11.7. Schematic representation of the mechanism
of action of antidepressant agents. Neurotransmitters
(NE, S, D) are released from the presynaptic neuron into
the synaptic space. They interact with the postsynaptic
receptors and continue the neuronal transmission. After
release from the postsynaptic neuron, these agents can
be broken down by the enzyme monoamine oxidase (MAO)
and the components recycled into the presynaptic neu-
ron or they can be taken up again through the reuptake
mechanism. Antidepressant agents can (1) block the
MAO enzymes—MAO inhibitors; or (2) block the reuptake
of the neurotransmitter. In effect, each mechanism
increases the intrasynaptic concentration of the particular
neurotransmitter.
276 C h a p t e r 11: Alt er ed Mood, At t en t ion , a n d Beh a vior

a lcoh ol/dr u g a bu se, a n d ot h er sever e life st r essor s TREATMENT

a r e im por t a n t socia l in flu en ces. P sych ologica lly,
Th e t h r ee m ost com m on t r ea t m en t s for depr ession
n ega t ive a ppr oa ch es t o copin g wit h a dver sit y, low
a r e psych ot h er a py/cou n selin g, a n t idepr essa n t m ed-
self-est eem , self-con cept , a n d/or self-effica cy, dis-
ica t ion s, a n d elect r ocon vu lsive t h er a py (E CT). Th e
t or t ed t h in kin g, a n d low r esilien ce a r e sign ifica n t
cla sses of dr u gs u sed t o t r ea t depr ession in clu de
r isk fa ct or s.
select ive ser ot on in r eu pt a ke in h ibit or s (SSRI), se-
lect ive n or epin eph r in e r eu pt a ke in h ibit or s (SNRI),
CLINICAL MANIFESTATIONS n or epin eph r in e a n d dopa m in e r eu pt a ke in h ibit or s
(NDRI), t r icyclic a n t idepr essa n t s (TCA), a n d m on o-
Sa dn ess is a n expect ed pa r t of bein g h u m a n . MDD,
a m in e oxida se in h ibit or s (MAOIs). E CT is u sed
h owever, is ch a r a ct er ized by a per sist en t ver y low
a s a la st lin e of t h er a py for MDD. Ot h er pot en t ia l
m ood a n d a n h edon ia , wh ich per va des a ll a spect s of
t h er a pies in clu de t r a n scr a n ia l m a gn et ic st im u la -
life. Feelin gs of wor t h lessn ess, gu ilt , h elplessn ess,
t ion (TMS), h er ba l or ot h er a lt er n a t ive t h er a pies,
h opelessn ess, a n d self-h a t r ed a r e a lso oft en r epor t ed.
a n d ligh t t h er a py. Tr ea t m en t sh ou ld be t a ilor ed
Pa t ien t s h a ve in t er r u pt ion s in sleep pa t t er n s, u n r e-
ba sed on sever it y of sym pt om s, effect iven ess of pr ior
len t in g fa t igu e, a n d ch a n ges in a ppet it e, weigh t , a n d
t r ea t m en t s, pr esen ce of
com or bid con dit ion s, a n d
pa t ien t pr efer en ce.
R E S E AR C H N O T E S
Research on which therapies are most effective for depression in children and adolescents
has shown mixed results. For example, a 2014 Cochrane review suggested that an overall Bipolar Affective
prevalence of depressive disorders in children under 13 years is 2.8% compared to adoles- Disorder
cents at 5.7%. In this review, 11 randomized-controlled studies compared psychotherapy,
medications, and the combination of these with over 1,300 pediatric patients. Results of the B ip o la r a e c t iv e d is -
trials showed differing conclusions, some of which were directly contradictory. At the con- o r d e r , a lso kn own a s
clusion of the review, the researchers noted: we do not know whether psychological therapy, m a n ic-depr ession , is a
antidepressant medication, or a combination of the two is most effective to treat depressive con dit ion ch a r a ct er ized
disorders in children and adolescents. 5 by per iods of m a n ia (el-
eva t ed m ood a n d er r a t ic
beh a vior ) a n d depr ession .
Ma n ia is t h e defin in g fea t u r e of bipola r a ffect ive
sex dr ive. Cogn it ive fea t u r es in clu de ch a n ges in a t - disor der. In h y p o m a n ia (a m ild for m of m a n ia ), pa -
t en t ion spa n a n d m em or y, fr u st r a t ion , in t oler a n ce, t ien t s a r e en er get ic, excit a ble, h yper a ct ive, a n d m a y
a n d n ega t ive cogn it ive dist or t ion s. P sych osom a t ic be h igh ly pr odu ct ive. As m a n ia wor sen s, pa t ien t s
com pla in t s in clu de m u scle t en sion , ch r on ic pa in , becom e er r a t ic a n d display im pu lsive beh a vior, r e-
st om a ch a ch es, digest ive pr oblem s, a n d h ea da ch es. su lt in g in poor decision s, a n d r equ ir e ver y lit t le, if
Ch a n ges in im pu lse con t r ol m a y lea d t o su icida l or a n y, sleep. At t h e m ost sever e level, m a n ic pa t ien t s
h om icida l idea t ion s a n d a ct ion s. ca n exper ien ce p s y c h o s is , a com plet e m en t a l a n d
em ot ion a l loss of t ou ch wit h r ea lit y. A depr essive
episode com m on ly follows a n episode of m a n ia . Th e
DIAGNOSTIC CRITERIA biologic m ech a n ism s r espon sible for swit ch in g be-
The dia gnosis of MDD is ba sed on the patient history, t ween m a n ia a n d depr ession a r e poor ly u n der st ood.
reported behaviors observed by relatives or friends, Abou t 3% of people in t h e Un it ed St a t es h a ve bipola r
a nd a menta l status examination. There is no labo- disor der a t som e poin t in t h eir life; lower r a t es a r e
ratory test for major depression, a lthough it is im- fou n d in ot h er cou n t r ies. Th e m ost com m on a ge a t
portant to rule out any physical conditions that may wh ich sym pt om s begin is fr om la t e a dolescen ce t o
cause similar symptoms. Dia gnostic criteria, using the ea r ly a du lt h ood.
DSM-5, indica te tha t a major depressive episode must
include the onset of five or more symptoms persisting
over a 2-week period. One of these symptoms must re-
PATHOPHYSIOLOGY
flect depressed mood or loss of interest or pleasure. Th e exa ct ca u se of bipola r a ffect ive disor der h a s n ot
There are many reliable and valid rating scales that been iden t ified; h owever, a st r on g h er edit a r y com po-
may assist the practitioner in determining the se- n en t (est im a t ed t o expla in 60% t o 80% of t h e r isk)
verity of MDD. One example is the Beck Depression poin t s t o com plex gen et ic a n d epigen et ic in flu en ces.
Inventory. Resea r ch er s h a ve iden t ified m u lt iple differ en t

disea se a lleles (h et er ogen eit y). In isola t ion , on e of
t h ese a lleles, wh en a ffect ed, does n ot in cr ea se disea se
r isk. H owever, wh en cer t a in clu st er s of t h ese disea se
a lleles (r efer r ed t o a s loci) a r e a ffect ed, t h e pa t ien t is
m u ch m or e likely t o develop bipola r a ffect ive disor-
der. Th ese differ en t disea se a llele clu st er s a ssocia t ed
wit h bipola r a ffect ive disor der a r e r efer r ed t o a s t h e
m a jor a ffect ive disor der (MAF D) loci. At t h is t im e,
t h er e a r e a r ou n d n in e MAF D loci cen t r a lized on dif-
fer en t ch r om osom es, bu t r efin em en t of discover y is
likely a s r esea r ch con t in u es. Th e expr ession s of t wo
pa r t icu la r gen es (ANK3 a n d CACNA1C) a n d t h eir
gen e va r ia n t s h a ve been a ssocia t ed wit h t h e va r iou s
bipola r ph en ot ypes. In a ddit ion , gen et ic sim ila r it ies
bet ween bipola r a ffect ive disor der, sch izoph r en ia ,
a n d ot h er psych ia t r ic disor der s in dica t e com m on ex-
pr ession of gen et ic va r ia n t s a n d biologic or igin s.
Post m or t em a n d n eu r oim a gin g st u dies h a ve u n -
cover ed a n u m ber of br a in fin din gs a ssocia t ed wit h
bipola r a ffect ive disor der, wh ich fu r t h er t h e u n der-
st a n din g of it s pa t h oph ysiology:
● Alt er a t ion s in h ippoca m pa l n eu r on s (a t r oph y a n d
cell loss);
● In cr ea sed br a in volu m e in t h e la t er a l ven t r icles
a n d dor sa l pa llidu m ;
● Poor m odu la t ion bet ween pr efr on t a l a n d lim bic
r egion s of t h e br a in , pa r t icu la r ly t h e a m ygda la ;
● H igh dopa m in e levels du r in g t h e m a n ic ph a se
a n d low levels in t h e depr essive ph a se;
● H igh glu t a m a t e (excit a t or y n eu r ot r a n sm it t er )
levels in t h e pr efr on t a l cor t ex du r in g t h e m a n ic
ph a se.
In dividu a l psych ologica l, en vir on m en t a l, a n d socia l
fa ct or s, wh ich in t er a ct wit h t h e gen et ic r isk fa ct or s,
play a sign ifica n t r ole in t h e developm en t of bipo-
la r a ffect ive disor der. E xa m ples in clu de t r a u m a t ic
life even t s, su ch a s ch ildh ood a bu se, a h a r sh h om e
en vir on m en t , a n d disr u pt ion s in in t er per son a l
r ela t ion sh ips.
CLINICAL MANIFESTATIONS
Bipola r a ffect ive disor der is m a r ked by clin ica l
m a n ifest a t ion s in dica t ive of m a n ia , wh ich in t er r u pt
wor k a n d/or r ela t ion sh ips, a n d la st a t lea st 1 week.
Th ese in clu de a sign ifica n t eleva t ion in m ood or ir-
r it a bilit y, r a pid a n d excessive speech , dist r a ct ibilit y,
r a cin g t h ou gh t s, im pa ir ed ju dgm en t , im pu lsivit y,
especia lly wit h spen din g m on ey, h yper sexu a lit y, ex-
t r em e focu s or goa l-or ien t a t ion , or fr u st r a t ion . Pa -
t ien t s a lso exh ibit a decr ea sed n eed for sleep a n d
ca n h a ve issu es wit h su bst a n ce a bu se. Th e m ost ex-
t r em e clin ica l m a n ifest a t ion s a r e delu sion s, h a llu ci-
n a t ion s, a n d psych osis. H ypom a n ia is a m ilder for m
of m a n ia a n d does n ot t ypica lly in t er r u pt wor k a n d/
C lin ic a l Mo d e ls 277
or r ela t ion sh ips. Sign s a n d sym pt om s of t h e depr es-
sive ph a se in clu de t h ose descr ibed wit h MDD a bove.
DIAGNOSTIC CRITERIA
Th e dia gn osis of bipola r a ffect ive disor der is ba sed
on t h e pa t ien t h ist or y, r epor t ed beh a vior s obser ved
by r ela t ives or fr ien ds, a n d a m en t a l st a t u s exa m -
in a t ion . Th e dia gn osis is oft en dela yed beca u se it
ca n be difficu lt t o dist in gu ish bipola r fr om depr es-
sive (u n ipola r ) disor der s. Th er e is n o la bor a t or y t est ,
a lt h ou gh it is im por t a n t t o r u le ou t a n y ph ysica l con -
dit ion s t h a t m a y ca u se sim ila r sym pt om s.
Dia gn ost ic cr it er ia , u sin g t h e DSM-5, dist in gu ish
seven differ en t su bt ypes of bipola r a ffect ive disor-
der : bipola r I disor der, bipola r II disor der, cyclot h y-
m ic disor der, su bst a n ce/m edica t ion -in du ced bipola r,
bipola r a n d r ela t ed disor der du e t o a n ot h er m edica l
con dit ion , ot h er specified bipola r, a n d u n specified
bipola r. E a ch su bt ype h a s a va r ia t ion in it s dia gn os-
t ic cr it er ia . For exa m ple, t h e bipola r I disor der cr i-
t er ia r epr esen t cla ssica l m a n ic-depr essive disor der
bu t wit h ou t t h e exper ien ce of a n MDD. Bipola r II
r equ ir es a t lea st on e lifet im e exper ien ce of m a jor de-
pr ession a n d a t lea st on e h ypom a n ic episode. Th e cy-
clot h ym ic disor der dia gn osis is given t o a du lt s wh o
exper ien ce a t lea st 2 yea r s (for ch ildr en , a fu ll yea r )
of bot h h ypom a n ic a n d depr essive per iods wit h ou t
ever fu lfillin g t h e cr it er ia for a n episode of m a n ia ,
h ypom a n ia , or m a jor depr ession a n d so for t h . Dia g-
n osis is con fir m ed wit h t h e specified clin ica l pr esen -
t a t ion over t h e r equ isit e a m ou n t of t im e a n d wit h ou t
a n ot h er u n der lyin g ca u se.
TREATMENT
Bipola r a ffect ive disor der is t r ea t ed wit h psych o-
t h er a py a n d m edica t ion s. P sych ot h er a py goa ls a r e
t o a llevia t e sym pt om s, r ecogn ize a n d r edu ce t r ig-
ger s, a n d bu ild r esilien ce. Medica t ion s gen er a lly fa ll
in t o t h e ca t egor ies of m ood st a bilizer s or a t ypica l
a n t ipsych ot ic dr u gs. Lit h iu m ca r bon a t e a n d sodiu m
va lpr oa t e, bot h m ood st a bilizer s, a r e com m on ly
pr escr ibed a n d h a ve st r on g eviden ce su ppor t in g
effica cy. A ch a llen ge of ph a r m a cologic t r ea t m en t is
a dh er en ce t o t h e m edica t ion r egim en . Th ose in a
m a n ic ph a se oft en feel gr ea t , en er get ic, a n d focu sed,
a r e im pu lsive, a n d m a ke poor decision s. Th is, a lon g
wit h pot en t ia l m edica t ion side effect s of h a n d t r em -
or s, n a u sea , polyu r ia , a n d t h ir st a m on g ot h er s ca n
r esu lt in r efu sa l t o t a ke m edica t ion s.
Attention-Deficit Hyperactivity Disorder
At t e n t ion -d e icit h yp e r a ct ivit y d isor d e r (ADHD),
a s it s n a m e su ggest s, is a n eu r odevelopm en t a l
278 C h a p t e r 11: Alt er ed Mood, At t en t ion , a n d Beh a vior

disor der of cogn it ive fu n ct ion s, ca u sin g a t t en t ion
deficit , h yper a ct ivit y, a n d im pu lsiven ess. Th e DSM-5
fu r t h er dist in gu ish es t h r ee su bt ypes: (1) ADH D in a t -
t en t ive t ype; (2) ADH D h yper a ct ive-im pu lsive t ype;
a n d (3) ADH D com bin ed t ype (in a t t en t ive a n d h yper-
a ct ive-im pu lsive). Affect ed cogn it ive (execu t ive) fu n c-
t ion s in clu de t h ose n eeded t o m a n a ge da ily life t a sks
su ch a s a t t en din g t o, or ga n izin g, a n d pr ocessin g in -
for m a t ion , r egu la t in g em ot ion s, m ot iva t ion , a n d cr e-
a t in g a wor kin g m em or y. ADH D a ffect s a r ou n d 5%
of t h ose u n der a ge 18, m ost ly boys, a n d per sist s t o
a du lt h ood in a bou t 30% t o 50% of ca ses.6
PATHOPHYSIOLOGY
Th e exa ct ca u se of ADH D is oft en u n kn own a n d,
sim ila r t o ot h er a lt er a t ion s in m ood, a t t en t ion , a n d
beh a vior, a ppea r s t o be t r igger ed by a com bin a t ion
of gen et ic a n d en vir on m en t a l fa ct or s. P r eviou s in fec-
t ion or t r a u m a of t h e br a in h a s been im plica t ed in
som e ca ses. H er it a bilit y h a s been est im a t ed a t 75%;
siblin gs wit h ADH D a r e t h r ee t o fou r t im es m or e
likely t o develop ADH D t h a n t h ose wit h ou t a ffect ed
siblin gs.6 Specifica lly, gen e va r ia n t s a ssocia t ed wit h
im pa ir m en t of dopa m in e t r a n sm ission a r e t h e likely
gen et ic con t r ibu t or. In a bou t 9% of ca ses, t h e gen e
va r ia n t LP H N3 is im plica t ed. Pot en t ia l en vir on -
m en t a l r isk fa ct or s, in ch ildr en wh o a r e gen et ica lly
su scept ible, in clu de a lcoh ol u se or sm okin g du r in g
pr egn a n cy, exposu r e t o lea d, in sect icides, or food pr e-
ser va t ives a n d dyes, ver y low bir t h weigh t , exper i-
en cin g violen ce or a bu se, a n d t r a u m a t ic br a in in ju r y.
Ch a n ges in t h e br a in st r u ct u r e a n d fu n ct ion a sso-
cia t ed wit h ADH D in clu de t h e followin g:
● Im pa ir m en t of dopa m in e a n d n or epin eph r in e a n d
la ck of m odu la t ion of execu t ive fu n ct ion s in t h e
pr efr on t a l cor t ex
● Redu ced volu m e of t h e left -sided pr efr on t a l cor t ex
● Th in n in g of t h e post er ior pa r iet a l cor t ex
Clinical Manifestations
Clin ica l m a n ifest a t ion s a r e r ela t ed t o r edu ced ex-
ecu t ive fu n ct ion in g a n d pr esen t a s in a t t en t ion ,
h yper a ct ivit y, r est lessn ess, im pu lsivit y, disr u pt ive
beh a vior, difficu lt ies in sch ool or wor k, a n d difficu l-
t ies in socia l sit u a t ion s. Ta ble 11.2 differ en t ia t es
pr edom in a n t ly in a t t en t ive t ype fr om pr edom in a n t ly
h yper a ct ive-im pu lsive t ype.
DIAGNOSTIC CRITERIA
Th e dia gn osis of ADH D is ba sed on t h e pa t ien t
h ist or y, r epor t ed beh a vior s obser ved by pa r en t s or
t ea ch er s, a n d a m en t a l st a t u s exa m in a t ion . Th er e is
n o la bor a t or y t est for ADH D, a lt h ou gh it is im por t -
a n t t o r u le ou t a n y ph ysica l or ot h er m en t a l h ea lt h
con dit ion s t h a t m a y ca u se sim ila r sym pt om s. Th e
DSM-5 cr it er ia a r e t h r ee t o fou r t im es m or e likely
t o r ea ch t h e con clu sion of ADH D t h a n t h e ICD-10.
As m en t ion ed, t h er e a r e t h r ee su bt ypes. Dia gn osis
is ba sed on t h e pr esen ce of clin ica l m a n ifest a t ion s
on set pr ior t o a ge 12, a cr oss m u lt iple set t in gs (h om e,
sch ool, et c.), for a t lea st 6 m on t h s, a n d u lt im a t ely
ca u sin g in t er r u pt ion s in sch ool or wor k, h om e, a n d
socia l sit u a t ion s.

Ta b le 11.2 Ma n ifest a t ion s of ADH D Ba sed on DSM-5 Su bt ype TREATMENT

P r e d o m in a n t ly I n a t t e n t iv e
E a sily dist r a ct ed
Missin g det a ils
For get fu l
Difficu lt y focu sin g a t t en t ion on a
t a sk or wh en lea r n in g som et h in g n ew
Losin g pen cils, books, or ot h er t h in gs
n eeded t o com plet e a ssign m en t s or
t a sks
Daydr ea m in g
E a sily con fu sed
Difficu lt y pr ocessin g in for m a t ion a s
qu ickly a n d a ccu r a t ely a s ot h er s
St r u ggles t o follow in st r u ct ion s
Miss socia l cu es
ADH D, a t t en t ion -deficit h yper a ct ivit y disor der.
P r e d o m in a n t ly
H y p e r a c t iv e -I m p u ls iv e
Un a ble t o sit st ill a t sch ool, du r in g
din n er, doin g h om ewor k, or wh ile do-
in g a n y a ct ivit ies r equ ir in g st illn ess
Con t in u ou s t a lkin g
Tou ch a n d pla y wit h ever yt h in g,
m ovin g qu ickly fr om on e it em t o t h e
n ext
Con st a n t ly in m ot ion
Difficu lt y doin g qu iet t a sks or
a ct ivit ies
Im pa t ien t
E m ot ion a lly dem on st r a t ive
Act wit h ou t r ega r d for con sequ en ces
Difficu lt y wa it in g
In t er r u pt ive
Difficu lt y m a n a gin g a n ger
Tr ea t m en t in volves psych ot h er-
a py a n d m edica t ion s a lon e or
in com bin a t ion . P h ysica l exer-
cise h a s been sh own in m u lt iple
st u dies t o im pr ove beh a vior a n d
m ot or skills in t h ose wit h ADH D.
Cogn it ive-beh a vior a l t h er a py
or ju st beh a vior a l t h er a py a r e
m a in st a ys of t r ea t m en t a n d
h a ve sh own t o be h igh ly effect ive
a n d oft en u sed a s fir st -lin e t r ea t -
m en t . Pa r a doxica lly, st im u la n t
dr u gs a r e t h e m ost oft en u sed
m edica t ion s t o t r ea t ADH D. Al-
t h ou gh u su a lly sa fe, t h eir u se
is con t r over sia l a n d h igh ly de-
ba t ed du e t o t h e pot en t ia l for
a dver se effect s, a ddict ion , a n d
depen den ce if m isu sed or if u se
is pr olon ged. In sh or t -t er m u se,
 C lin ic a l Mo d e ls 279

h owever, t h e va st m a jor it y of pa t ien t s exper ien ce a t in socia l a nd emot iona l funct ioning. Pa tient s with
lea st som e im pr ovem en t s in a t t en t ion , h yper a ct ivit y, a ut ism show a st rong preference for nonsocia l sit ua -
a n d im pu lsivit y. t ions a nd stim uli, difficulties wit h la ngua ge a nd fa ce
processing, difficult ies em pa thizing, a nd delays in
processing or r eject ion of cer ta in visua l a nd a udit ory
Autism Spectrum Disorders stim uli (Fig. 11.8). On e t h eor y posit s t h a t a u t ism r e-
su lt s fr om low con n ect ivit y a n d t h er eby u n der fu n c-
Au t is m is a n eu r odevelopm en t a l disor der wit h it s t ion in g of n eu r on s in h igh -level pr ocesses, su ch a s
on set in ea r ly ch ildh ood. It is ch a r a ct er ized by t h e t h ose bet ween t h e cor t ex a n d fr on t a l lobe. Th is is
cla ssica l t r ia d of: im pa ir ed socia l in t er a ct ion , im - cou pled wit h h igh con n ect ivit y in lower-or der br a in
pa ir ed ver ba l a n d n on ver ba l com m u n ica t ion , a n d a r ea s, su ch a s wit h in t h e h em isph er es of t h e cor t ex.
a r epet it ive pa t t er n of m ovem en t , in t er est s, or be- Specific fin din gs in clu de:
h a vior s. Au t ism is con sider ed on e of t h e a u t ism
● Redu ced n eu r oa n a t om ica l con n ect ion s t o t h e
spect r u m disor der s (ASDs). Th e ot h er t wo ASDs
fr on t a l lobe
a r e Asper ger syn dr om e, sim ila r t o a u t ism bu t wit h
● Disr u pt ed syn a pt ic for m a t ion
h igh er cogn it ive fu n ct ion in g a n d la n gu a ge develop-
● Th in n in g of t h e cor pu s collosu m
m en t , a n d per va sive developm en t disor der, wh ich is
● Gr ea t er m yelin a t ion in t h e fr on t a l cor t ex a n d less
dia gn osed wh en t h e com plet e cr it er ia for a u t ism or
m yelin a t ion in t h e t em por a l/pa r iet a l ju n ct ion
Asper ger syn dr om e a r e n ot m et . Au t ism a ffect s over
● Redu ced GABA-β r ecept or s in t h e lim bic cor t ex
20 m illion people wor ldwide. In t h e Un it ed St a t es,
● Disor ga n iza t ion of t h e a r ch it ect u r e of t h e pr efr on -
a bou t 1 in 68 ch ildr en wer e iden t ified wit h a n ASD;
t a l cor t ex a n d t em por a l cor t ex
boys a r e dia gn osed five t im es m or e oft en t h a n gir ls. 7
E n docr in e a n d im m u n e syst em s a lso a ppea r t o pla y
a n im por t a n t r ole. A n u m ber of st u dies h a ve u n cov-
PATHOPHYSIOLOGY
er ed bioch em ica l ch a n ges t h a t m a y occu r wit h a u -
Autism affects the inform ation-processing centers of t ism . For exa m ple, eleva t ed ser ot on in levels, la ct ic
th e brain, a ltering nerve cell-to-synapse connections. a cid, a n d cyt okin es a r e n ot ed in som e pa t ien t s wit h
Although t he exa ct etiology has not been determined, a u t ism poin t in g t owa r d n eu r oen docr in e a n d in fla m -
a complex interplay of environmenta l and genetic m a t or y in flu en ces.
fa ctors is suspected. The risk for autism is known to
be increased with ma terna l exposure to tera togens, CLINICAL MANIFESTATIONS
such a s pollution, infections, heavy meta ls, and toxins,
Clin ica l m a n ifest a t ion s in ASD t en d t o becom e n ot ice-
most nota bly within the first 8 weeks a fter conception.
a ble a ft er 6 m on t h s of a ge a n d a r e well-est a blish ed
There is also a high risk with maternal va lproa te (a
by 3 yea r s of a ge. Ma n ifest a t ion s a r e h igh ly va r ia ble
seizure drug) use during pregna ncy. For these rea sons,
a n d r epr esen t t h e spect r u m of a u t ism fr om ver y m ild
it is believed tha t a utism is triggered very ea rly in fe-
displa ys of odd socia l, com m u n ica t ion , a n d beh a vior
ta l development. The genetic basis is still under in-
(Asper ger ’s) t o com plet ely silen t , sever e r epet it ive
vestigation. Autism cannot be traced to a single-gene
beh a vior s a s wit h per va sive developm en t a l disor der.
mutation or to a single chr omosomal a bnormality. The
Th e followin g a r e pot en t ia l m a n ifest a t ion s t h a t ca n
genetic defect is not inherited, that is, it is not found
occu r in ea ch ch a r a ct er ist ic of t h e ASD t r ia d:
in th e (pa rent) germ cells. There is evidence, however,
th at a utism is heritable a nd involves multiple genes, ● Im pa ir ed socia l in t er a ct ion
th e environment, a nd epigenetic fa ctors. For example, ■ La ck in t u it ion a n d in a t t en t ive t o socia l cu es
in identical twins, the ra te
of autism in one sibling is
significantly increased if
th e other twin is dia gnosed R E S E AR C H N O T E S
with autism .
The pa t hophysiologic The media is saturated with reports of children getting autism from the measles, mumps, and
cha nges a nd clinica l m a n- rubella (MMR) vaccine. The concern is most notably the time of diagnosis, which often occurs
ifesta t ions t ha t occur a s a just weeks to months after routine scheduled childhood vaccinations. These anecdotes that
r esult of a utism a re evident autism may be linked with vaccinations have not been supported by research. A large study
a m ong severa l r egions of of 1,000 children over 5 years, conducted by the Centers for Disease Control and Prevention,
t he bra in, including t he found that vaccinations have no effect on the risk of developing an ASD. More specifically,
cerebellum, a nd front a l exposure to antibody-stimulating proteins or polysaccharides from vaccines administered be-
a nd t em pora l lobes. Defi- tween the ages of 3 months and 2 years did not increase a child’s risk of developing an ASD. 8
cits a r e un iver sa lly found
280 C h a p t e r 11: Alt er ed Mood, At t en t ion , a n d Beh a vior

A
Control AS D

S FG

S TS
IFG
A
S TS FFA

B
La te ra l Me dia l

Figure 11.8. Functional magnetic resonance imaging (MRI) abnormalities observed in autism spectrum disorder (ASD).
A: These coronal MRI images show the cerebral hemispheres above, the cerebellum below, and a circle over the fusiform
gyrus of the temporal lobe. The examples illustrate the frequent finding of hypoactivation of the fusiform gyrus to faces
in an adolescent boy with ASD ( right) compared with an age- and IQ-matched unaffected control subject ( left) . Note
the lack of face activation in the boy with ASD but average levels of nonface object activation. B: Schematic diagrams of
the brain from lateral and medial orientations illustrating the broader array of brain areas found to be hypoactive in ASD
during a variety of cognitive and perceptual tasks that are explicitly social in nature. Some evidence suggests that these
areas are linked to form a “social brain” network. A, amygdale (hypoactive during a variety of social tasks); FG, fusiform
gyrus, also known as the fusiform face area (hypoactive during perception of personal identity); IFG, inferior frontal gyrus
(hypoactive during facial expression imitation); pSTS, posterior superior temporal sulcus (hypoactive during perception of
facial expressions and eye gaze tasks); SFG, superior frontal gyrus (hypoactive during theory of mind tasks, i.e., when tak-
ing another person’s perspective). (Reprinted from Volkmar F, Lord C, Klin A, et al. Autism and the pervasive developmen-
tal disorders. In: Martin A, Volkmar F, eds. Lewis’ Child and Adolescent Psychiatry. Philadelphia, PA: Lippincott Williams &
Wilkins; 2007:387.)

■ Less eye con t a ct , sm ilin g, r espon siven ess t o
own n a m e
■ Un a ble t o r ecogn ize em ot ion s or em pa t h ize
wit h ot h er s
■ Difficu lt y wit h im a gin a t ive pla y
■ E xa gger a t ed n ega t ive r espon se t o socia l st im -
u li, su ch a s bein g t ou ch ed
● Im pa ir ed ver ba l a n d n on ver ba l com m u n ica t ion
■ Dela yed speech developm en t
■ La ck of in t egr a t ion bet ween gest u r es, wor ds,
a n d in t en t (i.e., do n ot poin t a t object s t o sh ow
wa n t or in t er est )
■ Displa y e c h o la lia (r epea t in g a n ot h er ’s wor ds)
● Repet it ive pa t t er n of m ovem en t , in t er est s, or
beh a vior s
■ H a n d fla ppin g, h ea d r ollin g, body r ockin g, pick-
in g a t skin , h ea d ba n gin g
■ Com pu lsive or r it u a list ic beh a vior s, su ch a s r e-
pea t edly a r r a n gin g object s in a lin e or sor t in g
■ Resist a n ce t o ch a n ge in t h e en vir on m en t a n d
r ou t in e
■ Na r r ow or r est r ict ed focu s, in t er est s, or
a ct ivit ies
In a ddit ion , m a n y of t h ose wit h a u t ism h a ve poor
m u scle t on e, in coor din a t ion , or t oe wa lkin g. Th er e
 C lin ic a l Mo d e ls 281

ca n be developm en t a l r e g r e s s io n , t h a t is, loss of ju m ps t o 40% for t h e ch ild wh en bot h pa r en t s h a ve

pr eviou sly a ch ieved developm en t a l m ilest on es, su ch been dia gn osed wit h sch izoph r en ia . Sim ila r ly, con -
a s loss of ver ba l skills. A h igh pa in t oler a n ce a n d cor da n ce a m on g m on ozygot ic t win s is 40% t o 50%.
la ck of r espon se t o in ju r y ca n occu r. Gen e st u dies h a ve iden t ified over 100 pot en t ia l
gen e loci a n d pot en t ia l st r u ct u r a l va r ia n t s, som e of
wh ich over la p wit h bipola r disor der a n d a lcoh ol de-
DIAGNOSTIC CRITERIA
pen den ce. In pa t ien t s wh o h a ve n o fa m ily h ist or y of
Th e DSM-5 ou t lin es dia gn ost ic cr it er ia for ASD u s- sch izoph r en ia , t h is m a y be t h e r esu lt of a spon t a -
in g t h e cla ssica l t r ia d of sym pt om s a bove. Relia ble n eou s m u t a t ion .
a n d va lid scr een in g t ools h a ve been developed t o a id P r en a t a l/per in a t a l in fect ion (pa r t icu la r ly cer t a in
in det er m in in g t h e pr esen ce of sym pt om s, sever it y, vir a l in fect ion s su ch a s in flu en za ), fet a l h ypoxia ,
a n d im pa ct . Th e cla ssica l t r ia d of sym pt om s a bove a n d m a ln ou r ish m en t h a ve been fou n d t o a ct in a
m u st be pr esen t st a r t in g in ea r ly ch ildh ood a n d im - syn er gist ic wa y t o pr om ot e t h e on set of sch izoph r e-
pa ir or lim it da ily fu n ct ion in g. Bot h com pon en t s a r e n ia in offspr in g wh o a r e gen et ica lly su scept ible.
r equ ir ed for dia gn osis of ASD. H ea vy m a r iju a n a a n d ot h er dr u g u se m a y h a st en
t h e on set of sch izoph r en ia a s well in su scept ible
in dividu a ls.
TREATMENT
Th e developm en t of sch izoph r en ia lea ds t o
Tr ea t m en t for a u t ism in clu des in t en sive, in dividu - ch a n ges in t h e im m u n e syst em , specifica lly over a c-
a lized, socia lly a n d beh a vior a lly or ien t ed t h er a peu - t ive in fla m m a t or y cyt okin es, a n d su bt le st r u ct u r a l
t ic a n d edu ca t ion a l pr ogr a m s gu ided by a qu a lified a n d fu n ct ion a l br a in ch a n ges in t h e fr on t a l lobes,
t h er a pist a n d specia l edu ca t ion t ea ch er. Th er a py h ippoca m pu s, a n d t em por a l lobes. Specific ch a n ges
m a y in clu de speech , occu pa t ion a l, a n d ph ysica l in clu de (Fig. 11.10) t h e followin g:
t h er a pies. Com m on ly em ployed t h er a pies in clu de
● E n la r ged ven t r icles
cogn it ive-beh a vior a l in t er ven t ion s a n d la n gu a ge
● Decr ea sed br a in volu m e in t em por a l a n d pr efr on -
t r a in in g. P h a r m a cologic a ppr oa ch es a r e n ot in di-
t a l a r ea s
ca t ed for a u t ism bu t m a y h elp wit h com or bid con di-
● Loss of gr a y a n d wh it e m a t t er
t ion s, su ch a s a n xiet y or ADH D.
● Dopa m in e cor t ica l h yper a ct ivit y a n d lim bic
h ypoa ct ivit y
● Redu ced glu t a m a t e (n eu r ot r a n sm it t er ) r ecept or
fu n ct ion a n d low glu t a m a t e levels
Schizophrenia
S c h izo p h r e n ia is a psych ot ic m en t a l h ea lt h dis- CLINICAL MANIFESTATIONS
or der t h a t a ffect s h ow pa t ien t s per ceive t h e wor ld.
Th e on set of clin ica l m a n ifest a t ion s oft en occu r s in
Pa t ien t s wit h sch izoph r en ia exper ien ce h a llu cin a -
a dolescen ce a n d you n g a du lt h ood a n d ca n r a n ge
t ion s, seein g or h ea r in g t h in gs t h a t a r e n ot a ct u a lly
fr om m ild t o sever e psych osis. Sign s a n d sym pt om s
t h er e, delu sion s, fixed fa lse beliefs, a n d disor ga n ized
in clu de h a llu cin a t ion s (su ch a s h ea r in g voices),
speech a n d beh a vior. Th e on set is m ost com m on ly
delu sion s, a n d disor ga n ized t h ou gh t s a n d speech .
in la t e a dolescen ce a n d ea r ly a du lt h ood. Wor ldwide
Pa t ien t s wit h sch izoph r en ia ca n a lso pr esen t wit h
pr eva len ce is est im a t ed a t 4 per 1,000 popu la t ion . 9
socia l wit h dr a wa l, poor h ygien e, poor ju dgm en t ,
a n d loss of m ot iva t ion . Th er e ca n be pa r a n oia a n d
PATHOPHYSIOLOGY
Th e exa ct ca u se of sch izo-
ph r en ia is n ot kn own . Th e
com plex in t er a ct ion s of R E S E AR C H N O T E S
gen et ics, per in a t a l r isks, The National Autism Center has completed the second phase of the National Standards
a n d socioen vir on m en t a l Project, which has the goal of establishing a set of evidence-based standards for educa-
t r igger s a r e im plica t ed. tional and behavioral interventions for children and young adults with ASDs. From this 2014
Th e gr ea t est r isk fa ct or is report, 14 interventions were identified as established and known to be effective. These
h a vin g a fa m ily h ist or y of include cognitive-behavioral interventions, language training, modeling, parent training,
sch izoph r en ia (F ig. 11.9). scripting, and peer training. Examples of therapies with a lack of evidence supporting effec-
Pa t ien t s wh o h a ve a tive use include auditory integration training, facilitated communication, gluten-free diets,
fir st -degr ee r ela t ive wit h and others. A full copy of this report can be requested at: http:/ / www.nationalautismcenter
sch izoph r en ia h a ve a 10% .org/ resources/ .
h igh er r isk. Th is per cen t
282 C h a p t e r 11: Alt er ed Mood, At t en t ion , a n d Beh a vior

Ge ne s s ha re d

Ge ne ra l popula tion 1%

17.5% Firs t cous ins 2%

(third-de gre e
re la tive s ) Uncle s , a unts 2%

25% Ne phe ws , nie ce s 4%

(s e cond-de gre e
re la tive s ) Gra ndchildre n 5%

Ha lf-s iblings 6%

P a re nts 6%

50% S iblings 9%
(firs t-de gre e
re la tive s ) Childre n 13%

Fra te rna l twins 17%

100% Ide ntica l twins 48%

0 10 20 30 40 50
Life time ris k of de ve loping s chizophre nia (%)

Figure 11.9. The familial nature of schizophrenia. The risk of developing schizophrenia increases with the number
of shared genes, suggesting a genetic basis for the disease. (Adapted from Gottesman II. Schizophrenia Genesis.
New York: WH Freeman, 1991, p. 96.)

35-ye a r-old fe ma le ide ntica l twins im pa ir m en t s of m em or y, a t t en t ion , a n d cogn it ive

pr ocessin g speed.

28-ye a r-old ma le ide ntica l twins
DIAGNOSTIC CRITERIA
Th e dia gn osis of sch izoph r en ia is ba sed on t h e pa -
t ien t h ist or y, r epor t ed beh a vior s obser ved by ot h er s,
a n d a com pr eh en sive clin ica l a ssessm en t . Th er e is
n o la bor a t or y t est for sch izoph r en ia , a lt h ou gh it is
im por t a n t t o r u le ou t a n y ph ysica l or ot h er m en t a l
h ea lt h con dit ion s t h a t m a y ca u se sim ila r sym pt om s.
To be dia gn osed wit h sch izoph r en ia , a t lea st t wo in -
dica t or s (delu sion s, h a llu cin a t ion s, or disor ga n ized
speech ) h a ve t o be m et for a t lea st 1 m on t h , wit h a
sign ifica n t im pa ct on sch ool or wor k, h om e, a n d so-
cia l fu n ct ion in g for a t lea st 6 m on t h s.

Figure 11.10. Coronal magnetic resonance imaging of two
sets of twins discordant for schizophrenia. The enlarged
lateral ventricles are readily apparent in the subjects on
the right. (Courtesy of Drs. E. Fuller Torrey and Daniel
Weinberger.)
TREATMENT
Sch izoph r en ia is t r ea t ed wit h a n t ipsych ot ic m edica -
t ion s, a n d psych ologica l a n d socia l su ppor t . Tr ea t -
m en t ca n be a ch a llen ge sin ce m a n y pa t ien t s wit h
sch izoph r en ia h a ve ir r a t ion a l or even pa r a n oid
t h in kin g a n d do n ot believe t h ey h a ve a disea se.
Medica t ion side effect s a r e a lso a m a jor issu e a n d
oft en im pa ct a dh er en ce. H ospit a liza t ion m a y be n ec-
essa r y if t h e beh a vior is t h r ea t en in g t o t h e pa t ien t
or societ y.
 C h a p t e r 11: Alt er ed Mood, At t en t ion , a n d Beh a vior
S U MMAR Y
● Mood is a n in t er n a l, su bject ive psych ologica l
st a t e, wh ich dir ect s h ow a per son feels a n d per-
ceives t h e wor ld. Regu la t ion of m ood ca n be t r a ced
t h r ou gh t h e lim bic syst em .
● Neu r ot r a n sm it t er s a lso pla y a cr it ica l r ole in
m ood r egu la t ion . P h a r m a cologic in t er ven t ion in
m ood disor der s m ost oft en t a r get s on e or m or e
n eu r ot r a n sm it t er s.
● At t en t ion is a cu lt u r a lly in flu en ced pr ocess of se-
lect ively con cen t r a t in g on in for m a t ion . It is bot h a
cogn it ive pr ocess a n d a beh a vior a s it in volves t h e
in t er a ct ion of sen sor y cu es a n d t h e cor r espon d-
in g a ct ion s. At t en t ion pr ocessin g a n d a ct ion a r e
la r gely r egu la t ed by t h e r et icu la r a ct iva t in g sys-
t em (RAS). Th e RAS is com pr ised of sever a l n eu -
r on a l pa t h wa ys begin n in g wit h st a r t lin g sen sor y
in pu t m ovin g t h r ou gh r et icu la r for m a t ion t o t h e
n u clei of t h e t h a la m u s a n d ou t wa r d t o t h e pa r iet a l
a n d t em por a l cor t ices a n d lim bic syst em . E xecu -
t ive pr ocessin g (fr on t a l lobe a n d ba sa l ga n glia ) a l-
lows a t t en t ion t o becom e con n ect ed wit h wor kin g
m em or y, pr oblem solvin g, a n d ot h er h igh er-or der
fu n ct ion s.
● Beh a vior is h ow people r espon d a n d a ct in a given
sit u a t ion . As wit h m ood, t h e fr on t a l lobe of t h e
br a in is t h e pr im a r y r egion r espon sible for r egu -
la t in g beh a vior. Th is lobe in t egr a t es a ll a spect s of
beh a vior in clu din g per son a lit y, per cept ion , pla n -
n in g, self-a wa r en ess, ju dgm en t , m ood, a t t en t ion ,
m em or y, m ot iva t ion , sexu a lit y, expr essive la n -
gu a ge, a n d socia l a n d em ot ion a l in t elligen ce.
● Gen er a t in g a ppr opr ia t e beh a vior s for a given sit -
u a t ion r equ ir es a com plex in t er pla y of cogn it ive
a n d beh a vior a l pr ocesses. Beh a vior will be ba sed
on n ot icin g, per ceivin g, sh or t -t er m a n d lon g-t er m
m em or y (pa st exper ien ces), cu r r en t socia l expec-
t a t ion s, m ood, per son a lit y, m ot iva t ion /in h ibit ion ,
cu lt u r e, con sider a t ion of a ll possible a ct ion s, pla n -
n in g, a n d decidin g. All t h ese occu r wit h in a m a t -
t er of secon ds a n d wit h lit t le con sciou s effor t .
● Alt er a t ion s in t h e br a in , lim bic syst em con n ec-
t ion s, or n eu r ot r a n sm ission ca n r esu lt in im -
pa ir m en t s of m ood, a t t en t ion , a n d beh a vior. Th e
fr on t a l lobe a n d cor r espon din g lim bic syst em
st r u ct u r es a r e pa r t icu la r ly vu ln er a ble.
● Wh en t h e pr efr on t a l cor t ex su ffer s a n in ju r y, t h e
pa t ien t loses t h e sen se of socia l r espon sibilit y,
con cen t r a t ion , a bst r a ct t h in kin g, a n d pr oblem
solvin g. Im pa ir ed a m ygda la s sever t h e con n ect ion
bet ween socia l in t elligen ce a n d m em or y. Lesion s
of t h e h ypot h a la m u s in t er fer e wit h a ppr opr ia t e
r espon ses t o t h er m a l r egu la t ion , h u n ger, t h ir st ,
sexu a lit y, a n d a ggr ession t owa r d ot h er s.
283
● Neu r ot r a n sm ission im pa ir m en t s ca n lea d t o a p-
a t h y, in a t t en t iven ess, a n d m ot or deficit s a s wit h
low levels of dopa m in e, or a git a t ion , r est lessn ess,
a n d psych osis a s wit h h igh levels of dopa m in e.
Deficit s in ser ot on in h a ve been a ssocia t ed wit h
a n xiet y, obsession s, a n d com pu lsion s.
● Ra r ely a r e t h er e la bor a t or y t est s or im a gin g st u d-
ies t h a t ca n con fir m a psych ia t r ic dia gn osis. Di-
a gn osis m ost oft en r elies on pa t ien t h ist or y a n d
r epor t ed obser va t ion s of ot h er s.
● Th e m ost widely u sed ca t egor ica l cr it er ia for di-
a gn osin g a lt er a t ion s in m ood, a t t en t ion , a n d
beh a vior a r e fou n d in t h e Am er ica n P sych ia t r ic
Associa t ion ’s fift h edit ion of t h e Dia gn ostic a n d
S ta tistica l Ma n u a l of Men ta l Disor d er s (DSM-5)
a n d t h e Wor ld H ea lt h Or ga n iza t ion ’s In ter n a -
tion a l S ta tistica l Cla ssifica tion of Disea ses a n d
Rela ted H ea lth P r oblem s (ICD-10).
● Tr ea t m en t s for a lt er a t ion s in m ood, a t t en t ion ,
a n d beh a vior in clu de psych ot h er a py, ph a r m a co-
t h er a py, cou n selin g, a lt er n a t ive/com plem en t a r y
t h er a pies, a n d socia l su ppor t .
C AS E S T U D Y 11.1
KT, a ge 42, pr esen t s t o t h e em er gen cy depa r t m en t
wit h a com pla in t of h a vin g a “h ea r t a t t a ck.” Sh e r e-
por t s ch est pa in , a ppr eh en sion , t r em blin g, sh a kin g,
con fu sion , dizzin ess, n a u sea , a n d difficu lt y br ea t h -
in g. H er E KG is n or m a l a n d sh e is fou n d n ot t o be
exper ien cin g a m yoca r dia l in fa r ct ion . Aft er fu r t h er
explor a t ion , it is discover ed t h a t KT h a s a sign ifi-
ca n t n u m ber of life st r essor s a n d a fa m ily h ist or y of
a n xiet y. Sh e is dia gn osed wit h pa n ic disor der.
1. Ou t lin e t h e pr ocess t h a t is m ost likely occu r r in g
in t h is wom a n ’s body.
2. Wh a t is t h e et iology of pa n ic disor der ?
3. H ow do t h e expect ed clin ica l m a n ifest a t ion s
m a t ch wh a t sh e is pr esen t in g?
4. Wh a t dia gn ost ic t est s cou ld be u sed?
5. Wh a t t r ea t m en t m ea su r es wou ld you a n t icipa t e?
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r-
n a l a r t icle or Web sit e (su ch a s h t t p://em edicin e
.m edsca pe.com /a r t icle/287913-over view) t h a t det a ils
pa n ic disor der, a n d con fir m you r pr edict ion s.
C AS E S T U D Y 11.2
P J, 21 yea r s old, is a n u r sin g st u den t a t a sm a ll lib-
er a l a r t s college. H e h a s a lwa ys been t old t h a t h e
is “qu ir ky” by ot h er s bu t h a s r ecen t ly begu n r epet i-
t ively cou n t in g t h e st a ir s t o h is a pa r t m en t a n d, if h e
m isses on e or it is n ot t im ed per fect ly, h e m u st go t o
284 C h a p t e r 11: Alt er ed Mood, At t en t ion , a n d Beh a vior
t h e bot t om a n d begin a ga in . H e is n ot su r e wh y h e
pa r t icipa t es in t h is r it u a l, bu t h e expla in s t h a t h e is
t er r ified of per son a l h a r m if h e does n ot . H e is dia g-
n osed wit h obsessive-com pu lsive disor der.
1. Ou t lin e t h e pr ocess t h a t is m ost likely occu r r in g
in t h is m a n ’s body. Wh a t specific br a in ch a n ges
a r e seen in OCD?
2. Wh a t is t h e et iology of OCD?
3. H ow do t h e expect ed clin ica l m a n ifest a t ion s
m a t ch wh a t h e is pr esen t in g?
4. Wh a t dia gn ost ic t est s cou ld be u sed?
5. Wh a t t r ea t m en t m ea su r es wou ld you a n t icipa t e?
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r-
n a l a r t icle or Web sit e (su ch a s h t t p://em edicin e
.m edsca pe.com /a r t icle/1934139-over view) t h a t de-
t a ils OCD, a n d con fir m you r pr edict ion s.
P R AC T I C E E XAM Q U E S T I O N S
1. A pa t ien t is con sider in g va r iou s t r ea t m en t a lt er-
n a t ives a n d ch oosin g a cou r se of a ct ion . Wh ich
pr efr on t a l r egion is a ct ive du r in g t h is pr ocess?
a . La t er a l
b. Or bit ofr on t a l
c. Ven t r om edia l
d. Ret r opa r iet a l
2. Given t h e a ct ion of ea ch , wh ich n eu r ot r a n sm it -
t er is r espon sible for you r h eigh t en ed a ler t n ess
du r in g you r t ou r t h r ou gh a h a u n t ed h ou se?
a . E pin eph r in e
b. Nor epin eph r in e
c. Ser ot on in
d. Dopa m in e
3. E xecu t ive pr ocessin g r efer s t o t h e a bilit y t o:
a . Move qu ickly t o get ou t of h a r m ’s wa y
b. Apply for a job
c. Solve pr oblem s
d. See a n on com in g ca r
4. P sych osis, or t h e loss of t ou ch wit h r ea lit y, is
ch a r a ct er ized by:
a . Aggr essive a n ger
b. E xcess n eu r ot r a n sm it t er s
c. An h edon ia
d. Delu sion s
5. Wh ich of t h e followin g is n ot a gen er a l t r ea t -
m en t m ea su r e for a lt er ed m ood, a t t en t ion , or
beh a vior ?
a . E lect ocon vu lsa n t t h er a py
b. P h a r m a cot h er a py
c. P sych ot h er a py
d. Socia l su ppor t
6. Th ose wit h gen er a lized a n xiet y disor der a r e
likely t o h a ve over a ct iva t ion of _______ wit h
a n xiet y-pr ovokin g even t s:
a . Ser ot on in
b. Th e a m ygda la
c. Nor epin eph r in e
d. Th e h ypot h a la m u s
7. Wh ich of t h e followin g clin ica l m a n ifest a t ion s is
t ypica l of P TSD?
a . H yper t h yr oidism
b. E xa gger a t ed st a r t le r espon se
c. Repea t ed t r a u m a t ic even t s
d. Apa t h y
8. Wh ich of t h e followin g best descr ibes m ela n -
ch olic depr ession , on e of t h e su bt ypes of m a jor
depr essive disor der ?
a . Depr essive episodes in t h e la t e fa ll a n d win -
t er wit h excessive a n h edon ia
b. Depr essive episodes m ost n ot a ble in t h e ea r ly
m or n in g wit h excessive weigh t loss a n d gu ilt
c. Disa blin g depr ession a ft er givin g bir t h a n d
la st in g u p t o 3 m on t h s
d. Depr ession ch a r a ct er ized by im m obilit y
or pu r poseless m ovem en t s, t h e in a bilit y t o
spea k, a n d st u por
9. Wh ich of t h e followin g is n ot a br a in ch a n ge
n ot ed in t h ose wit h ADH D?
a . Im pa ir m en t of dopa m in e a n d n or epin eph r in e
b. Redu ced volu m e of t h e left -sided pr efr on t a l
cor t ex
c. Th in n in g of t h e post er ior pa r iet a l cor t ex
d. E n la r ged bila t er a l ven t r icles
10. A ch ild wit h a u t ism r epea t s ever yt h in g you sa y.
You r ecogn ize t h is beh a vior a s:
a . E ch ola lia
b. In t en t ion a l a n t isocia l beh a vior
c. La ck of in t egr a t ion bet ween gest u r es, wor ds,
a n d in t en t
d. Dela yed speech developm en t
D I S C U S S I O N AN D
AP P L I C AT I O N
1. Wh a t did I kn ow a bou t a lt er ed m ood a n d beh a vior
befor e t oda y?
2. Wh a t body pr ocesses a r e a ffect ed by a lt er ed m ood
a n d beh a vior ?
3. Wh a t a r e t h e pot en t ia l et iologies for a lt er ed m ood
a n d beh a vior ?
4. Wh o is m ost a t r isk for developin g a lt er ed m ood
a n d beh a vior ? H ow ca n t h ese a lt er a t ion s be
pr even t ed?
 C h a p t e r 11: Alt er ed Mood, At t en t ion , a n d Beh a vior
5. What are the human differ ences t ha t a ffect
t he etiology, r isk, or course of a ltered mood a nd
behavior ?
6. Wh a t clin ica l m a n ifest a t ion s a r e expect ed in t h e
cou r se of a lt er ed m ood a n d beh a vior ?
7. Wh a t specia l dia gn ost ic t est s a r e u sefu l in det er-
m in in g t h e dia gn osis a n d cou r se of a lt er ed m ood
a n d beh a vior ?
8. Wh a t a r e t h e goa ls of ca r e for in dividu a ls wit h
a lt er ed m ood a n d beh a vior ?
9. H ow does t h e con cept of a lt er ed m ood a n d beh a v-
ior bu ild on wh a t I h a ve lea r n ed in t h e pr eviou s
ch a pt er a n d in pr eviou s cou r ses?
10. H ow ca n I u se wh a t I h a ve lea r n ed?
R E SOUR CE S
At t en t ion Deficit Disor der Associa t ion :
h t t p://www.a dd.or g
Au t ism Societ y:
h t t p://www.a u t ism -societ y.or g/
Dia gn ostic a n d S ta tistica l Ma n u a l of Men ta l Disor-
d er s (DSM-5):
h t t p ://www.p s ych ia t r y.or g/p s ych ia t r is t s /p r a ct ice/
dsm /dsm -5
In ter n a tion a l Cla ssifica tion of Disea ses (ICD-10):
h t t p://www.icd10da t a .com /
Na t ion a l In st it u t e of Men t a l H ea lt h :
h t t p://www.n im h .n ih .gov
F in d a d d ition a l r esou r ces for th is ch a pter a t h ttp:th ePoin t.lww.com
285
R e er en ces
1. Kessler RC, McGon a gle KA, Zh a o S, et a l. Lifet im e a n d
12-m on t h pr eva len ce of DSM-III-R psych ia t r ic disor der s
in t h e Un it ed St a t es: r esu lt s fr om t h e Na t ion a l Com or-
bidit y Su r vey. Ar ch Gen P sych ia tr y. 1994;51(1):8–19.
2. U.S. Depa r t m en t of Vet er a n s Affa ir s. P TSD: Na t ion a l
Cen t er for P TSD. h t t p://www.pt sd.va .gov/pu blic/
P TSD-over view/ba sics/h ow-com m on -is-pt sd.a sp.
Accessed Novem ber 13, 2015.
3. P r a t t LA, Br ody DJ. Depr ession in t h e Un it ed St a t es
h ou seh old popu la t ion , 2009–2012. h t t p://www.cdc.gov/
n ch s/da t a /da t a br iefs/db172.pdf. Accessed Novem ber 13,
2015. Na t ion a l Cen t er for H ea lt h St a t ist ics Da t a Br ief,
Decem ber 2014, No. 172.
4. Ken dler KS, Ga t z M, Ga r dn er CO, et a l. A Swedish
n a t ion a l t win st u dy of lifet im e m a jor depr ession . Am
J P sych ia tr . 2006;163(1):109–114. doi:10.1176/a ppi.
a jp.163.1.109. P MID: 16390897.
5. Cox GR, Ca lla h a n P, Ch u r ch ill R, et a l. P sych olog-
ica l t h er a pies ver su s a n t idepr essa n t m edica t ion ,
a lon e a n d in com bin a t ion for depr ession in ch ildr en
a n d a dolescen t s. Coch r a n e Da ta ba se of S yst Rev.
2014;11:CD008324. doi:10.1002/14651858.CD008324.
pu b3. P MID: 25433518.
6. Centers for Disease Con trol a nd Preven tion. Atten -
tion -deficit/h ypera ctivity disorder (ADH D). h ttp://www.cdc
.gov/ncbddd/adhd/data .html. Accessed November 13, 2015.
7. Cen t er s for Disea se Con t r ol a n d P r even t ion . P r eva len ce
of a u t ism spect r u m disor der —a u t ism a n d developm en t a l
disa bilit ies m on it or in g n et wor k, 11 sit es, Un it ed St a t es,
2010. MMWR 2014;63(No. SS 2):1–21.
8. H a m m er LD, Cu r r y E S, H a r lor AD, et a l. In cr ea sin g im -
m u n iza t ion cover a ge. Ped ia tr ics. 2010;125(6):1295–1304.
9. Sa h a S, Ch a n t D, Welh a m J, et a l. A syst em a t ic r e-
view of t h e pr eva len ce of sch izoph r en ia . P LoS Med .
2005;2(5):e141. doi:10.1371/jou r n a l.pm ed.0020141.
 Ch a pt er

12
Alt er ed Som a t ic
a n d Specia l Sen sor y
F u n ct ion

L E AR N I N G O U T C O ME S
1. Defin e a n d u se t h e key t er m s list ed in t h is ch a pt er.
2. Descr ibe t h e m ode of t r a n sm ission of n eu r a l im pu lses in volved wit h t h e
sen sa t ion s of pa in , vision , a n d h ea r in g.
3. Iden t ify pa t h wa ys for t h e in t egr a t ion of n eu r a l a n d sen sor y exper ien ces.
4. In dica t e com m on m ech a n ism s of a lt er a t ion s in vision a n d h ea r in g.
5. Det er m in e pr ocesses t h a t con t r ibu t e t o t h e per cept ion of pa in .
6. Descr ibe a lt er a t ion s in sen sor y exper ien ces a n d t h e a ssocia t ed pa t h o-
ph ysiologic m a n ifest a t ion s.
7. Iden t ify com m on sign s a n d sym pt om s of a lt er a t ion s in sen sa t ion .
8. Descr ibe dia gn ost ic t est s a n d t r ea t m en t st r a t egies r eleva n t t o a lt er a t ion s
in h ea r in g, vision , a n d pa in m a n a gem en t .
9. P r edict fu n ct ion a l im pa ir m en t s r esu lt in g fr om a lt er a t ion s in sen sa t ion .
10. Apply con cept s of sen sor y a lt er a t ion s t o select clin ica l m odels.

INTR ODUCTION
H ow do you feel wh en you see a bea u t ifu l su n set ? H ea r t h e voice of som eon e
specia l? Sm ell you r fa vor it e m ea l cookin g on t h e st ove? Close you r fin ger s in
t h e ca r door ? Ma n y sen sa t ion s ca u se r espon ses su ch a s won der, h a ppin ess,
con t en t m en t , a n d pa in . You r per cept ion s of t h e wor ld a r ou n d you a r e sh a ped
by t h e m a n y sen sor y cu es you t a ke in , wh ich st im u la t e pr edict a ble r ea ct ion s.
Alt er a t ion s in t h ese sen sa t ion s ca n ca u se sign ifica n t im pa ir m en t in ph ysica l,
psych ologic, a n d socia l fu n ct ion in g. A ba sic u n der st a n din g of t h e fu n ct ion of
sen sor y syst em s pr om ot es t h e a bilit y t o a n t icipa t e deficit s t h a t m a y occu r
wh en t h ese syst em s a r e a lt er ed. Th e focu s of t h is ch a pt er is a lt er a t ion in so-
m a t osen sor y a n d specia l sen sor y fu n ct ion . Ta ble 12.1 pr ovides a descr ipt ion
of sen sa t ion s r esu lt in g fr om st im u la t ion of specific som a t osen sor y a n d spe-
cia l sen sor y r ecept or s. Th e m odu les t a r get pa in a n d a lt er a t ion s in t h e specia l
sen ses of vision a n d h ea r in g. Th e clin ica l m odels in t h is ch a pt er a r e select ed t o
h elp a pply con cept s of a lt er ed som a t osen sor y a n d sen sor y fu n ct ion .

286
 P a in 287

Ta b le 12.1 Neu r on s of t h e Som a t osen sor y Syst em

Neu r on Typ e R e c e p t o r L o c a t io n S e n s a t io n
Gen er a l som a t ic a ffer en t Wide dist r ibu t ion wit h br a n ch es Pa in , t ou ch ,
n eu r on s t h r ou gh ou t t h e body t em per a t u r e
Specia l som a t ic a ffer en t Mu scle, t en don s, a n d join t s Posit ion a n d body
n eu r on s m ovem en t
Gen er a l viscer a l a ffer en t Viscer a l st r u ct u r es F u lln ess a n d
n eu r on s discom for t

Modu le 1 P a in

Pa in is a com m on , yet com plex sen sa t ion . Th e t yp-
ica lly u n plea sa n t sen sa t ion is oft en a ssocia t ed
wit h a n em ot ion a l r espon se a n d eviden ce of t issu e
da m a ge. P r ot ect ive r eflex r espon ses oft en lim it t h e
da m a ge ca u sed by a n in ju r y-pr ovokin g st im u lu s.
Con t in u ed pa in sen sa t ion r em in ds u s of t h e da m a ge
a n d u s h elps t o pr ot ect t h e in ju r y du r in g t h e h ea lin g
pr ocess. Pa in is t r a n sm it t ed by t h e som a t osen sor y
syst em , a lon g wit h t h e sen sa t ion s of t ou ch , t em per a -
t u r e, a n d body posit ion .
Somatosensory System
Sen sor y syst em s r ela y in for m a t ion t h r ou gh ou t t h e
body fr om t h e per iph er y t o t h e cen t r a l n er vou s
syst em (CNS) u sin g sen sor y r ecept or s, a scen din g
pa t h wa ys, a n d pr ocessin g cen t er s. St im u li a r e r e-
ceived, wh ich a llow people t o r espon d t o t h e wor ld
a r ou n d t h em . Affer en t pa t h wa ys, in t r odu ced in
Ch a pt er 10, pr om ot e com m u n ica t ion fr om st r u ct u r es
in t h e per iph er y t o pr ocessin g cen t er s in t h e br a in .
Th e diver sit y of t h e som a t osen sor y syst em is t h e
r esu lt of t h e r ecept or s a n d pa t h wa ys t h a t a r e a ssoci-
a t ed wit h t h e sen sa t ion s of pa in (n ocicept ion ), t ou ch ,
t em per a t u r e, a n d pr opr iocept ion (body posit ion ).
A va r iet y of r ecept or t ypes r esu lt in specific som a t o-
sen sor y r espon ses. Th ese t ypes in clu de:
1. Mech a n or ecept or s: m ech a n ica l for ces—r ecept or
st r et ch in g a lt er s m em br a n e per m ea bilit y
a . St r et ch r ecept or s of m u scles
b . Skin r ecept or s: t ou ch , pa in , cold, h ea t
2. Th er m or ecept or s: r a dia n t h ea t en er gy
3. Nocicept or s: pa in
Ta ble 12.2 descr ibes t h e n eu r on s r espon sible for
som e of t h ese specific fu n ct ion s.
Stop and Consider
Based on the sensations involved, what other
nerves do you think are involved in the somato-
sensory system?
SOMATOSENSORY NEURONAL ORGANIZATION
Neu r on s a r e or ga n ized in a n or der ed ser ies, a n d
in for m a t ion is dir ect ed t owa r d t h e pr ocessin g cen -
t er s in t h e t h a la m u s a n d cer ebr a l cor t ex (F ig. 12.1).
Th ese n eu r on s a r e ca t egor ized a s follows:
● F ir st -or der n eu r on s: com m u n ica t e sen sor y in for-
m a t ion fr om t h e per iph er y t o t h e CNS
● Secon d-or der n eu r on s: r ela y sen sor y in pu t fr om
r eflex n et wor ks a n d sen sor y pa t h wa ys dir ect ly t o
t h e t h a la m u s
● Th ir d-or der n eu r on s: com m u n ica t e sen sor y in for-
m a t ion fr om t h e t h a la m u s t o t h e cer ebr a l cor t ex
In t er n eu r on s a r e a ct ive t h r ou gh ou t t h is n et wor k
a n d m odify t h e sen sor y in for m a t ion befor e it a r r ives
a t t h e pr ocessin g cen t er s. Th e n u m ber s of n eu r on s
in cr ea se con sist en t wit h t h eir or der ; t h ir d-or der
n eu r on s a r e pr esen t in t h e gr ea t est qu a n t it y.
SOMATOSENSORY NEURONAL TRANSMISSION
Som a t osen sor y im pu lses a r e t r a n sm it t ed by a u n iqu e
syst em of r ecept or s a n d pa t h wa ys. Th e sen sor y u n it
com pr isin g t h e dor sa l r oot ga n glia (cell body, per iph -
er a l br a n ch , a n d cen t r a l a xon ) r espon ds in dist in ct
wa ys t o differ en t st im u li beca u se of t h e specific n a -
t u r e of t h eir a ssocia t ed r ecept or s a n d n er ve fiber s.
Dorsal Root Ganglia Fibers
Tr a n sm ission of n er ve im pu lses a lon g t h e fiber s
of t h e dor sa l r oot ga n glia depen ds on t h e dia m et er
288 C h a p t e r 12: Alt er ed Som a t ic a n d Specia l Sen sor y F u n ct ion

t ype A delt a fiber s in clu de pr es-

Ta b le 12.2 Sen sor y Recept or For m s a n d F u n ct ion s su r e, t ou ch , cold sen sa t ion , a n d
h ea t pa in . Type A a lph a a n d bet a
R ecep t or Typ e F u n c t io n E x a m p le
fiber s m a y pr om ot e in h ibit or y ef-
Mech a n or ecept or Ta ct ile skin sen sa t ion Mer kel cells fect s, dim in ish in g t h e sen sa t ion
Deep-t issu e sen sa t ion Ru ffin i en din gs of pa in . Type B fiber s a r e a lso
Meissn er cor pu scles m yelin a t ed bu t h a ve a sm a ller
Pa cin ia n cor pu scle dia m et er t h a n t ype A fiber s, a c-
H a ir follicle en d or ga n cou n t in g for t h eir slower r a t e of
F r ee n er ve en din gs con du ct ion . Mech a n or ecept or s
H ea r in g Coch lea r sou n d r ecept or s in t h e cu t a n eou s a n d su bcu t a n e-
ou s a r ea s of t h e skin st im u la t e
P r opr iocept ion Mer kel cells
n er ve im pu lses a lon g t ype B
Ru ffin i en din gs
fiber s. Type C fiber s a r e u n m y-
Pa cin ia n cor pu scles
elin a t ed a n d h a ve t h e sm a llest
P h ot or ecept or Vision Rods a n d con es dia m et er, lea din g t o t h e slowest
Ch em or ecept or Ta st e Ta st e bu d r ecept or s con du ct ion r a t e of t h ese t h r ee
Sm ell Olfa ct or y epit h eliu m fiber t ypes. Wa r m -h ot sen sa t ion ,
r ecept or s a s well a s m ech a n ica l, ch em ica l,
Nocicept or Pa in F r ee n er ve en din gs h ea t -in du ced, a n d cold-in du ced
pa in sen sa t ion s, is t r a n sm it t ed
a lon g t ype C fiber s.
of t h e n er ve fiber a n d n er ve fiber m yelin a t ion . Th e
Dermatome Innervation
t h r ee t ypes of n er ve fiber s t h a t a r e in volved in t h e
con du ct ion of som a t osen sor y im pu lses a r e t ype A, B, Der m a t om es a r e in n er va t ed by a sin gle pa ir of dor-
a n d C. Type A fiber s h a ve t h e la r gest dia m et er a n d sa l r oot ga n glia a n d r eflect t h e segm en t a l or ga n iza -
a r e m yelin a t ed, a ccou n t in g for t h eir r a pid r a t e of t ion of t h e spin a l cor d, a s descr ibed in Ch a pt er 10.
im pu lse con du ct ion . Th e sen sa t ion s t r a n sm it t ed by Over la p of der m a t om e pr ocesses occu r s in per iph er a l

P rima ry
Third-orde r s oma tos e ns ory
ne uron cortex

S e cond-orde r
ne uron
Firs t-orde r Tha la mus
ne uron

S pina l cord

Re ce ptors

Figure 12.1. Arrangement of first-, second-, and third-order neurons of the somatosensory system.

pr ocesses on t h e body su r fa ce a n d cen t r a l pr ocesses
in t h e spin a l cor d, pr ovidin g som e r edu n da n cy of t h e
con du ct ion syst em .
Two sepa r a t e pa t h wa ys a r e in volved in t h e
t r a n sm ission of in for m a t ion in volved in per cep-
t ion , a r ou sa l, a n d m ot or con t r ol. Th e d is c r im in a -
t iv e p a t h w a y com m u n ica t es sen sor y in for m a t ion ,
in clu din g discr im in a t ive t ou ch a n d spa t ia l or ien t a -
t ion . Th is pa t h wa y in t egr a t es in pu t fr om m u lt iple
r ecept or s u sin g t h e pr im a r y dor sa l r oot ga n glion
n eu r on , t h e dor sa l colu m n n eu r on , a n d t h e t h a la m ic
n eu r on . St im u la t ion of t h is pa t h wa y r esu lt s fr om vi-
br a t ion , t ou ch , m u scle, or join t m ovem en t . Th e dis-
cr im in a t ive pa t h wa y a llows t h e iden t ifica t ion of a n
object ba sed on t ou ch or t h e loca t ion of skin t ou ch in
t wo differ en t a r ea s, kn own a s t w o -p o in t d is c r im i-
n a t io n . Th e a n t e r o la t e r a l p a t h w a y in volves bot h
t h e a n t er ior a n d la t er a l spin ot h a la m ic pa t h wa ys
a n d is ch a r a ct er ized by m u lt iple syn a pses a n d slow
con du ct ion . Th e sen sa t ion s of pa in , t em per a t u r e,
cr u de t ou ch , a n d pr essu r e n ot r equ ir in g t h e specific
loca t ion of t h e or igin of t h e st im u lu s a r e t r a n sm it t ed
a lon g t h is pa t h wa y. In cr ea sed wa kefu ln ess st im u -
la t ed by a “st a r t le” r ea ct ion exist s du e t o t h e m a n y fi-
ber s t h a t t r a vel t o t h e r et icu la r a ct iva t in g syst em by
sen sor y con du ct ion in t h is pa t h wa y. Au t on om ic r e-
spon ses, su ch a s in cr ea sed blood pr essu r e a n d h ea r t
r a t e, a ct iva t ion of swea t gla n ds, dila t ion of pu pils,
a n d con st r ict ion of blood vessels, a r e a lso st im u la t ed
wh en im pu lses a r e con du ct ed a lon g t h is pa t h wa y.
SOMATOSENSORY PROCESSING
Th e a wa r en ess, r ecogn it ion , iden t ifica t ion , a n d in t er-
pr et a t ion of st im u li in volve pr ocessin g. Aft er st im u li
r ea ch t h e t h a la m u s, fu r t h er r efin em en t occu r s in
t h e som a t osen sor y cor t ex of t h e br a in . Th e pr im a r y
som a t osen sor y cor t ex r eceives sen sor y in for m a t ion
fr om t h e t h a la m u s. Th is in for m a t ion is r ela yed t o
t h e som a t osen sor y a ssocia t ion a r ea s, wh ich in t er-
pr et t h e st im u li in t o lea r n ed per cept ion s.
SOMATOSENSORY MODALITIES
S o m a t o s e n s o r y m o d a lit ie s r efer t o t h e specific
n a t u r e of t h e per cept ion of va r iou s st im u li. Th e
su bject ive in t er pr et a t ion of a st im u lu s, su ch a s t h e
differ en ce bet ween t em per a t u r e a n d t ou ch , is det er-
m in ed by t h e a bilit y of a r ecept or t o det ect a n im -
pu lse, t h e t r a n sm ission of t h e im pu lse t o t h e CNS,
a n d t h e in t er pr et a t ion of t h e r efin ed im pu lse.
Stimulus Discrimination
Ac u it y r efer s t o t h e a bilit y t o loca t e t h e sit e of t h e
in it ia t ion of a st im u lu s. H igh a cu it y a llows for fin e
dist in ct ion a n d r equ ir es a gr ea t er den sit y of n eu r on s.
P a in 289
Acu it y r eflect s t h e t h r esh old n ecessa r y for a n eu r on
t o a ch ieve a n a ct ion pot en t ia l (see Ch a pt er 10). Va r i-
a t ion s of a cu it y in sen sor y fields con t r ibu t e t o differ-
en t levels of dist in ct ion bet ween im pu lses.
Tactile Stimulation
Tr a n sm ission of t a ct ile st im u li u su a lly occu r s via
la r ge, m yelin a t ed n er ve fiber s. Tou ch , pr essu r e, a n d
vibr a t ion st im u li a r e r ecogn ized by r ecept or s in a n d
n ea r t h e skin (F ig. 12.2) a n d in clu de:
● F r ee n er ve en din gs (det ect ion of t ou ch a n d
pr essu r e)
● Meissner corpuscle (highly developed sense of touch)
● Mer kel disks (m ovem en t of ligh t object s over skin ,
vibr a t ion )
● Pa cin ia n cor pu scle (det ect ion of vibr a t ion )
● H a ir follicle r ecept or (det ect ion of m ovem en t on
t h e su r fa ce of t h e body)
● Ru ffin i en din g (det ect ion of h ea vy a n d con t in u ou s
t ou ch a n d pr essu r e)
Thermal Sensation
T h e r m o r e c e p t o r s (r ecept or s t h a t r ecogn ize t h er-
m a l sen sa t ion ) a r e loca t ed u n der t h e skin a n d in -
clu de cold, wa r m t h , a n d pa in r ecept or s (discu ssed
la t er in t h is ch a pt er ). Th er m a l (wa r m a n d cold) r e-
cept or s a r e sen sit ive t o t h e differ en ces in t h e t em -
per a t u r e of object s t h a t con t a ct t h e skin . Th er m a l
pa in r ecept or s r espon d t o ext r em es in t em per a t u r e.
Tr a n sm ission of t h er m a l sen sa t ion is m u ch slower
t h a n t a ct ile im pu lse con du ct ion .
Position Sensation
Lim b/body m ovem en t a n d posit ion sen sa t ion , in de-
pen den t of vision , a r e m edia t ed by pr opr iocept ive
r ecept or s, m u scle spin dle r ecept or s, a n d Golgi t en -
don or ga n s. St r et ch r ecept or s in t h e skin (Ru ffin i
en din gs, pa cin ia n cor pu scles, a n d Mer kel cells) a lso
a ssist in pr opr iocept ion . Som a t osen sor y sign a ls a r e
t r a n sm it t ed via t h e post er ior colu m n a n d t h e vest ib-
u la r syst em , a n d t h ey a r e pr ocessed in t h e t h a la m u s
a n d cer ebr a l cor t ex.
Pain
Th e sen sa t ion of pa in is disr u pt ive t o t h e qu a lit y of
life. Det er m in a t ion of pa in ch a r a ct er pr ovides clu es
t o t h e u n der lyin g ca u se a n d pr ovides a t a r get for
t r ea t m en t .
CHARACTERIZATION OF PAIN
Th e sen sa t ion of pa in is t h e r esu lt of a n oxiou s st im -
u la t ion of pa in fiber s. Wh en t h e st im u lu s is in it ia t ed
290 C h a p t e r 12: Alt er ed Som a t ic a n d Specia l Sen sor y F u n ct ion

Ha iry s kin Nonha iry s kin

Me rke l’s Epide rmis

dis k

Fre e ne rve
e nding

Me is s ne r’s De rmis
corpus cle

Ha ir follicle
re ce ptor

Pa cinia n
corpus cle

Ruffini’s
e nding

Figure 12.2. Cutaneous somatic sensory receptors. Distribution of sensory receptors in skin with and without hair.
(Modified from Bear MF, Connors BW, Parasido MA. Neuroscience: Exploring the Brain. 3rd ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2006.)

ou t side of t h e n er vou s syst em , t h e pa in is ch a r a c- Pattern Theory

t er ized a s n o c ic e p t iv e . Pa in or igin a t in g wit h in t h e
n er vou s syst em is t er m ed n e u r o g e n ic or n e u r o -
p a t h ic . Nocicept ive pa in in volves specific r ecept or s
a n d pa t h wa ys r esu lt in g in t h e sen sa t ion of pa in .
Neu r ogen ic or n eu r opa t h ic pa in does n ot a ct iva t e
t h ese r ecept or s a n d does n ot follow a t ypica l t r a n s-
m ission pa t t er n of im pu lse con du ct ion .
CONDUCTION OF PAIN SENSATION
Nocicept ion (pa in sen sa t ion ) in volves fr ee n er ve
en din gs st im u la t ed by ch em ica l, m ech a n ica l, or
t h er m a l st im u li, in du cin g a u t on om ic a n d m ot or
r eflexes, wh ich r esu lt in t h e in t er pr et a t ion of t h e
st im u li a s pa in (Fig. 12.3). E ven t s in volved in t h is
pr ocess in clu de t r a n sdu ct ion , t r a n sm ission , m odu -
la t ion , a n d per cept ion . Box 12.1 su m m a r izes t h ese
pr ocesses.
THEORIES OF PAIN
Th e t h eor et ic or igin s of pa in a r e ba sed on a n u n der-
st a n din g of t h e n eu r oph ysiologic even t s a ssocia t ed
wit h t h e in it ia t ion , t r a n sm ission , a n d per cept ion of
pa in . Two well a ccept ed, t r a dit ion a l t h eor ies t h a t
a t t em pt t o expla in t h e pa in r espon se in clu de t h e
pa t t er n t h eor y a n d t h e specificit y t h eor y, n eit h er of
wh ich fu lly expla in s t h e or igin , t r a n sm ission , a n d
per cept ion of pa in . Th e evolu t ion of pa in t h eor y r e-
flect s t h e com plexit y of t h e pa in sen sa t ion , in cor po-
r a t in g t h e m u lt iple dim en sion s a n d det er m in a n t s
of pa in .
P a t t e r n t h e o r y su ggest s t h a t n er ves t r a n sm it t in g
pa in im pu lses a r e sh a r ed wit h ot h er sen ses. Th e per-
cept ion of pa in is der ived fr om a specific pa t t er n of
n eu r on a l im pu lse gen er a t ion ba sed on t h e t ype of
st im u lu s a n d in t en sit y, specifica lly t h e t im in g a n d lo-
ca t ion of im pu lse gen er a t ion .1 Th e sh a r ed pa t h wa ys
bet ween pa in a n d ot h er som a t osen sor y m oda lit ies
in flu en ce t h e per ceived sen sa t ion . Th e ch a r a ct er is-
t ics of r ecept or st im u la t ion con t r ibu t e t o t h e specific
som a t osen sor y pa t t er n s, in flu en ced by:
1. Du r a t ion of pa in sen sa t ion
2. Qu a n t it y of t issu e in volved
3. Th e su m m a t ion of im pu lses
An exa m ple of va r yin g pa t t er n s of r ecept or st im u -
la t ion a n d sen sor y per cept ion in clu des t h e r espon se
of im pu lse gen er a t ion t h r ou gh ligh t t ou ch a n d deep
pr essu r e. Accor din g t o pa t t er n t h eor y, ligh t , su per-
ficia l skin pr essu r e wou ld gen er a t e low-fr equ en cy
r ecept or fir in g a n d t h e per ceived sen sa t ion of ligh t
t ou ch . Con ver sely, deep skin pr essu r e wou ld gen er-
a t e h igh -fr equ en cy fir in g of t h e sa m e r ecept or r e-
su lt in g in t h e per ceived sen sa t ion of pa in .
Specificity Theory
Th e s p e c i ic it y t h e o r y pr oposes t h a t sen sa t ion s
of t ou ch , wa r m t h , cold, a n d pa in in volve dist in ct
r ecept or s a n d pa t h wa ys u n iqu e t o t h e specific sen -
sa t ion . Th e specific n a t u r e of im pu lse gen er a t ion is
pr oposed t o begin in a specific pa in r ecept or, t r a n sm it -
t ed a lon g specific pa t h wa ys lea din g t o pa in cen t er s

RAS
Re ce ptors
Me diato r re le as e S ubs ta nce P
P ros ta gla ndins
S e rotonin
Ace tylcholine
Inflammatio n
Tis s ue injury
Figure 12.3. Mechanism of acute pain. Nociceptor stimulation is induced after tissue injury by release of inflammatory
mediators. Impulses are transmitted to the dorsal horn of the spinal cord, synapsing with second-order neurons. Neurons
cross and ascend via the spinothalamic pathway to the reticular activating system (RAS) and thalamus. The localization
and perception of pain occurs in the somatosensory cortex.
in t h e br a in wh er e pa in is per ceived. Pa in im pu lses
t r a vel fr om t h e per iph er y t o t h e spin a l cor d, cr ossin g
t o t h e opposit e side a t t h e syn a pses of t h e s u b s t a n -
t ia g e la t in o s a (gr a y m a t t er ext en din g t h r ou gh ou t
t h e post er ior h or n of t h e spin a l cor d t o t h e m edu lla
oblon ga t a ). Im pu lses t h en a scen d t h e specific pa in
pa t h wa ys of t h e spin ot h a la m ic t r a ct . Th e in t en sit y
of t h e pa in is a ssocia t ed wit h t h e a m ou n t of t issu e
in ju r ed or da m a ged. For exa m ple, wh en t h e m ech a -
n or ecept or is st im u la t ed, t h e im pu lse is t r a n sm it t ed
on dedica t ed pr im a r y a ffer en t n eu r on s pr oject in g t o
m ech a n or ecept or secon d-or der n eu r on s t h a t syn a pse
on t o specific m ech a n or ecept ive a r ea s in t h e br a in .1
Gate Control Theory
Th e g a t e c o n t r o l t h e o r y is on e of t h e m ost
well-kn own t h eor ies on t h e ph ysiologic ba sis of pa in ,
r epr esen t in g a n expla n a t ion for pa in t h a t u n it es t h e
con t r a st in g pr in ciples u n der lyin g pa t t er n a n d spec-
ificit y t h eor y. Accor din g t o t h e ga t e con t r ol t h eor y,
P a in 291
Pain
S oma tos e ns ory cortex
Tha la mus
S pinotha la mic
pa thway
per iph er a l r ecept or s gen er a t in g im pu lses a lon g t h e
pr im a r y a ffer en t n eu r on s en t er t h e spin a l cor d in
t h e su bst a n t ia gela t in osa of t h e dor sa l h or n , ser v-
in g a s a ga t e, r egu la t in g t h e t r a n sm ission of pa in
im pu lses.1 Th e ga t e con t r ol t h eor y pr oposes t h a t
st im u la t ion of t h e la r ge t ype A bet a a n d a lph a in -
h ibit or y fiber s “close t h e ga t e” a t t h e su bst a n t ia ge-
la t in osa , pr even t in g cr ossover a n d in h ibit in g pa in
im pu lse con du ct ion a lon g t ype A delt a a n d t ype C
fiber s, dim in ish in g pa in per cept ion . St im u li t h ou gh t
t o pr om ot e t r a n sm ission a lon g t ype A bet a a n d a l-
ph a fiber s n eeded t o close t h e ga t e in clu de elect r i-
ca l st im u la t ion , m a ssa ge, scr a t ch in g, or r u bbin g of
t h e skin . St im u la t ion of sm a ll pa in fiber s pr om ot es
“open in g t h e ga t e,” a ct iva t in g n eu r a l t r a n sm ission
a n d per cept ion of pa in .
Intensity Theory
Th e in t en sit y t h eor y su ggest s t h a t pa in is a n em ot ion
t h a t is t h e r esu lt of a st r on ger t h a n u su a l st im u lu s.1
292 C h a p t e r 12: Alt er ed Som a t ic a n d Specia l Sen sor y F u n ct ion

Box 12.1 P r o c e s s e s o N o c ic e p t io n com pon en t s, in t egr a t in g m u lt iple sou r ces of in pu t

Tr a n sd u ction of n oxiou s st im u li in t o a n er ve im pu lse a n d
depola r iza t ion of t h e n er ve st im u la t es t h e con du ct ion of
t h e sen sor y im pu lse
● Th e elect r ica l im pu lses pr om ot e t h e r elea se of a lge-
sic (ca u sin g pa in ) su bst a n ces, in clu din g su bst a n ce P,
h ydr ogen a n d pot a ssiu m ion s, ser ot on in , h ist a m in e,
pr ost a gla n din s, a n d br a dykin in
Tr a n sm ission of n er ve im pu lses fr om t issu es t o t h e CNS
● Occu r s a lon g t ype A (delt a ) a n d t ype C fiber s
■ Ra pidly con du ct in g t ype A fiber s
■ P r odu ce sen sa t ion s of sh a r p, st in gin g, or
pin -pr ick–t ype loca l sen sa t ion s
■ In du ced by m ech a n ica l or t h er m a l st im u li
■ Im pu lses a lon g t ype C fiber s pr odu cin g a du ll a ch e
or bu r n in g gen er a l r espon se
■ In du ced by ch em ica l st im u li
● Respon ses of t h e br a in r esu lt in g fr om t h e t r a n sm is-
sion of im pu lses m u st be deliver ed ba ck t o t h e or igi-
n a l sit e of st im u la t ion .
Mod u la tion of t h e pa in occu r s du r in g t r a n sm ission of t h e
im pu lse
● Su bst a n ces r elea sed in r espon se t o pa in st im u li r esu lt
fr om a ct iva t ion of in h ibit or y pr ocesses
■ Ser ot on in , n or epin eph r in e, a n d en dor ph in s
■ In h ibit t h e t r a n sm ission of t h e pa in im pu lse by slow-
in g t h e r elea se of n ocicept ive n eu r ot r a n sm it t er s
Per ception of t h e pa in r espon se
● In volves t h e sen sor y (som a t osen sor y cor t ex), em o-
t ion a l (lim bic syst em ), a n d su bject ive r ea ct ion s t o t h e
st im u li
● Per cept ion is va r ied a m on g in dividu a ls beca u se of t h e
in flu en ce of
■ Pa in t h r esh old: t h e in t en sit y of t h e pa in r equ ir ed t o
a ch ieve a r espon se
■ Per cept u a l dom in a n ce: t h e exist en ce of pa in a t a n -
ot h er loca t ion wh ich is given m or e a t t en t ion
■ Pa in t oler a n ce: t h e degr ee t o wh ich pa in is en du r ed
(du r a t ion or in t en sit y) befor e in it ia t in g a r espon se
Ra t h er t h a n a u n iqu e m oda lit y, t h is t h eor y su ggest s
r esu lt in g in t h e cogn it ive, a ffect ive, a n d sen sor y per-
cept ion s of pa in .2 Va r ia t ion s in t h e syn a pt ic a r ch it ec-
t u r e of t h e n eu r om a t r ix a r e t h ou gh t t o be in flu en ced
by gen et ic, em ot ion a l, cu lt u r a l, pa st exper ien ce, a n d
st r ess r egu la t ion in flu en ces, con t r ibu t in g t o in di-
vidu a lized pa in r espon ses. Sen sa t ion pa t t er n s m a y
be in du ced in t h e a bsen ce of a sen sor y t r igger. Th e
n eu r om a t r ix t h eor y ca n h elp expla in ph a n t om a n d
ch r on ic pa in .
Stop and Consider
Have you ever banged your head and began
rubbing it in response to pain? How might this
action decrease the pain sensation?
MANIFESTATIONS AND EVALUATION OF PAIN
Ma n a gem en t of pa in in clu des a ca r efu l eva lu a t ion
of t h e su bject ive per cept ion of pa in . Th e n a t u r e, se-
ver it y, loca t ion , in it ia t in g t r igger s, a n d pa t t er n s of
r a dia t ion h elp t o det er m in e t h e ca u se a n d pot en t ia l
m et h ods of t r ea t m en t . Met h ods t o object ively qu a n -
t ify a n in dividu a l’s pa in , su ch a s a pa in dr a win g, ca n
h elp det er m in e sever it y of pa in or eva lu a t e pa in con -
t r ol m ea su r es (Fig. 12.4). Th e cla ssifica t ion s of pa in
a r e list ed in Box 12.2.
TREATMENT OF PAIN
Pa in r elief, or a n a lgesia , is t h e goa l of pa in t r ea t m en t .
Con t r ollin g pa in t o a llow in dividu a ls t o per for m
Box 12.2 C la s s i ic a t io n s o P a in
Pa in ca n be cla ssified a ccor din g t o:
● Loca t ion
■ Cu t a n eou s
■ Deep
■ Viscer a l
■ Refer r ed

t h a t pa in occu r s a s a r esu lt of in t en se st im u la t ion ● Qu a lit y

■ Sh a r p
of a n y sen sor y m oda lit y in t h e a bsen ce of dist in ct
■ Bu r n in g
pa t h wa ys for low- a n d h igh -t h r esh old st im u li. An ex- ■ Diffu se
a m ple of t h is t ype of pa in gen er a t ion is t a ct ile st im u - ■ Th r obbin g
la t ion t h a t , a s a sin gle even t , is n ot per ceived a s pa in ■ St a bbin g

bu t wh en r epea t ed a n u m ber of t im es a ch ieves a n ● Du r a t ion

■ Acu t e
in t en sit y level t h a t is per ceived a s pa in fu l.
■ Resu lt s fr om disea se, in fla m m a t ion , or in ju r y t o
t issu e
Neuromatrix Theory ■ Su dden on set
■ Respon sive t o t r ea t m en t
Th e n e u r o m a t r ix t h e o r y su ggest s t h a t pa in is a ■ Self-lim it in g (la st in g less t h a n 3 m on t h s)
m u lt idim en sion a l exper ien ce. Pa in per cept ion is t h e ■ Associa t ed wit h a u t on om ic r espon ses
r esu lt of im pu lses gen er a t ed a lon g a widely dist r ib- ■ Ch r on ic

u t ed n eu r a l n et wor k in t h e br a in (b o d y -s e l n e u - ■ Per sist en t (la st in g lon ger t h a n 3 m on t h s)

■ Resist a n t t o t r ea t m en t
r o m a t r ix ), t r igger ed eit h er by sen sor y in pu t s or
■ Associa t ed wit h a n or exia , in som n ia , a n d
in depen den t of iden t ified st im u la t ion .1 Th e n eu r o- depr ession
m a t r ix con t a in s som a t ic, lim bic, a n d t h a la m ocor t ica l
 P a in 293

PAIN DRAWING
Ins truc tio ns : Ma rk the s e drawings a ccording to whe re you hurt (if the right s ide of your ne ck hurts, ma rk the
drawing on the right s ide of the ne ck, e tc.). P le a s e indica te which s e ns a tions you fe e l by the key be low.

RIGHT HANDED
LEFT HANDED

KEY
///////// S ta bbing Right Le ft Right
XXXX Burning
0000 P ins & Ne e dle s
==== Numbne s s
++++ Aching
PAIN LEVEL
0 No pa in
1 Mild pa in; you a re
awa re of it but it
doe s n't bothe r you
2 Mode ra te pa in tha t
you ca n tole ra te
without me dica tion
3 Mode ra te pa in tha t
re quire s me dica tion
to tole ra te
4–5 More s eve re pa in;
you be gin to fe e l
a ntis ocia l
6 S eve re pa in
7–9 Inte ns e ly s eve re pa in
Circle your curre nt pa in leve l
10 Mos t s eve re pa in;
it may ma ke you 1 2 3 4 5 6 7 8 9 10
conte mpla te s uicide

Figure 12.4. Tool for characterization of pain. Individuals are asked to mark body figures to identify location, severity,
and character of pain. (Courtesy American Academy of Physical Medicine and Rehabilitation.)

a ct ivit ies of da ily livin g is a n ot h er goa l of t r ea t m en t . a r e com m on ly su bject ed t o pa in fu l pr ocedu r es, su ch

Sever a l m ech a n ism s of pa in con t r ol a r e a va ila ble.
Box 12.3 list s a va ila ble m et h ods of pa in con t r ol in
a du lt s. Newbor n s h a ve com plex beh a vior a l, ph ysio-
logic, a n d bioch em ica l r espon ses t o pa in a n d r equ ir e
specia l con sider a t ion s in pa in m a n a gem en t . In fa n t s
a s h eel la n cin g a n d cir cu m cision . Th e n on ph a r m a -
cologic in t er ven t ion s wit h t h e best eviden ce in t h e
r edu ct ion of pa in in in fa n t s in clu de t h e beh a vior a l
st r a t egies of n on n u t r it ive su ckin g (e.g., pa cifier ),
swa ddlin g, r ockin g, a n d h oldin g. 3

Box 12.3 Me t h o d s o P a in C o n t r o l ■ Im a ger y

■ Use of im a gin a t ion t o develop a soot h in g m en -
● Non ph a r m a cologic t a l pict u r e
■ Cogn it ive beh a vior in t er ven t ion s ■ Biofeedba ck
■ Rela xa t ion ■ Awa r en ess of bodily fu n ct ion on a cogn it ive
■ Focu s on lessen in g m u scle t en sion level
■ Dist r a ct ion ■ P h ysica l a gen t s
■ Focu s a t t en t ion on st im u li n ot a ssocia t ed wit h ■ H ea t
pa in ■ In cr ea se in loca l cir cu la t ion , r edu cin g loca l
■ Cogn it ive r ea ppr a isa l isch em ia a n d n ocicept ive st im u la t ion
■ Self-dist r a ct ion ■ Modu la t ion of pa in
■ Focu s on t h e posit ive a spect s of t h e exper ien ce ■ Relea se of en dogen ou s opioids
294 C h a p t e r 12: Alt er ed Som a t ic a n d Specia l Sen sor y F u n ct ion

■ Cold
■ Va socon st r ict ion t o decr ea se swellin g a n d
st im u la t ion of n ocicept ive pa in fiber s
■ Redu ced a ffer en t a ct ivit y
■ Tr a n scu t a n eou s elect r ica l n er ve st im u la t ion
■ Tr a n sm ission of elect r ica l im pu lses a cr oss t h e
skin t o per iph er a l n er ve fiber s
■ St im u la t ion of la r ge fiber s t o m odu la t e pa in
t r a n sm ission
■ Acu pu n ct u r e
■ In ser t ion of n eedles a t specific poin t s on t h e body
su r fa ce
■ St im u la t e secr et ion of en dor ph in s
■ St im u la t e la r ge fiber s t o m odu la t e pa in
t r a n sm ission
● P h a r m a cologic
■ Nonnarcotic analgesia (e.g., aspirin [acetylsalicylic acid],
nonsteroidal anti-inflammatories, or acetaminophen)
■ Centr a l a nd peripher al blocka de of ner ve impu lses
■ In h ibit ion of cyclooxygen a se en zym es, decr ea s-
in g pr odu ct ion of pr ost a gla n din s
■ Decr ea sed sensitivit y to br a dykinin a nd hist am ine
■ Opioid a n a lgesics (e.g., m or ph in e, codein e)
■ Bin d t o m u , delt a , a n d ka ppa r ecept or s, m odu la t -
in g pa in a t t h e level of t h e spin a l cor d
■ St im u la t e r elea se of en dogen ou s opioids, in clu d-
in g en keph a lin s, en dor ph in s, a n d dyn or ph in s
■ Adju va n t a n a lgesics (t r icyclic a n t idepr essa n t s)
■ Block r eupta ke of serotonin fr om the synaptic cleft
■ Pa r t icu la r ly u sefu l in ch r on ic pa in

Modu le 2 Alt e r a t io n s in Vis io n

Vision is a n im por t a n t sen sor y fu n ct ion t h a t in for m s t h a t en t er s t h e eye, dila t in g t o en h a n ce ligh t en t r y

u s a bou t t h e wor ld a r ou n d u s. Th e pr ocesses r esu lt -
in g in sigh t a r e com plex, in volvin g t h e in t egr a t ion
of eye st r u ct u r es, m ot or con t r ol, a n d n eu r a l con t r ol
(Fig. 12.5).
Visual Structures and Function
Sigh t is a ch ieved wh en ligh t is r eflect ed in t o t h e c o r -
n e a , t h e clea r, t r a n spa r en t st r u ct u r e t h a t cover s t h e
ext er ior wa ll of t h e eye. Ligh t t h en pa sses t h r ou gh
t h e p u p il, a n open in g in t h e ir is (color ed pa r t of t h e
eye). Th e pu pil is a ble t o con t r ol t h e a m ou n t of ligh t
a n d con st r ict in g t o decr ea se. Ligh t en t er in g t h e eye
con t a ct s t h e clea r le n s , r espon sible for fin e-t u n in g
of focu s. Th e a bilit y of t h e len s t o ch a n ge it s sh a pe,
or a c c o m m o d a t e , a llows clea r vision a t a va r iet y
of dist a n ces. C ilia r y m u s c le s con t r a ct , pr om ot in g a
r ou n der len s sh a pe t o focu s a n object a t close r a n ge.
Rela xa t ion of cilia r y m u scles a llows fla t t en in g of t h e
len s a n d t h e a bilit y t o see object s a t a dist a n ce.
Ch a m ber s a r e com pa r t m en t s in t h e eye. Th e a n -
t er ior ch a m ber sit s beh in d t h e cor n ea . Th e len s a n d
t h e ir is a r e t h e r em a in in g bou n da r ies. Th e post e-
r ior ch a m ber is posit ion ed dir ect ly beh in d t h e ir is,
in fr on t of t h e len s. Th e a n t er ior ch a m ber con t a in s

Re tina

Iris

Le ns Fove a

P upil

Light Optic dis k

Ante rior
cha mbe r

Corne a

Pos te rior
cha mbe r
Optic ne rve
Cilia ry
mus cle
Vitre ous
humor
Figure 12.5. Structures of the eye.

t h e flu id, kn own a s a qu eou s h u m or, t h a t n ou r ish es
t h e len s a n d cor n ea . Th e vit r eou s body, a ch a m ber
con t a in in g clea r, gela t in ou s flu id kn own a s vit r eou s
h u m or, is loca t ed beh in d t h e len s. Th e ligh t t h a t en -
t er s t h e eye pa sses t h r ou gh t h e len s a n d t h e vit r e-
ou s h u m or wh er e it is r efr a ct ed, or ben t , on t o t h e
r et in a .
Stop and Consider
Why is it necessary to control the amount of
light entering the eye?
Th e r e t in a , loca t ed over t h e post er ior t wo-t h ir ds
of t h e eye, con t a in s p h o t o r e c e p t o r (r ecept or sen si-
t ive t o ligh t ) cells ca lled r ods a n d con es. R o d s pr o-
du ce a ph ot opigm en t , r h o d o p s in , a llowin g vision
in dim ligh t . Opsin (a pr ot ein ) a n d r et in en e (a vit a -
m in A der iva t ive) com bin e t o for m r h odopsin , wh ich
br ea ks down wh en in con t a ct wit h ligh t , st im u la t -
in g a n er ve im pu lse. E ven low levels of ligh t pr o-
m ot e t h e br ea kdown of r h odopsin , a llowin g n igh t
vision .
Stop and Consider
Why does a vitamin A deficiency cause the devel-
opment of night blindness?
Th e ph ot or ecept or s ca lled c o n e s pr ovide t h e a bil-
it y t o see br igh t ligh t a n d color ; t h ese con es a r e in -
volved in visu a l a cu it y (cla r it y). Th e ph ot opigm en t s
in con es a lso con t a in r et in en e a n d opsin s differ in g
fr om t h e t ype fou n d in r ods. In con t r a st t o r ods, con e
ph ot opigm en t s r equ ir e br igh t ligh t for br ea kdown
a n d gen er a t ion of n er ve im pu lse. Th er e a r e t h r ee
t ypes of r et in a l con es. E a ch con t a in s a differ en t com -
bin a t ion of r et in en e a n d opsin , wh ich r esu lt s in a b-
sor pt ion of ligh t of differ en t wa velen gt h s a n d color s.
1. E r yt h r ola be: r ed con e a bsor bs ligh t a t 625 n m
wa velen gt h
2. Ch lor ola be: gr een con e a bsor bs ligh t a t 530 n m
wa velen gt h
3. Cya n ola be: blu e con e a bsor bs ligh t a t 455 n m
wa velen gt h
Color vision is det er m in ed by t h e com bin a t ion of
con es st im u la t ed by ligh t fr om a pa r t icu la r im a ge.
Th e a bsen ce of a sin gle gr ou p of color-r ecept ive
con es r esu lt s in t h e in a bilit y t o dist in gu ish pa r t icu -
la r color s fr om ot h er s, a con dit ion com m on ly kn own
a s color blin dn ess. Th is con dit ion is ca u sed by a sex-
lin ked r ecessive gen et ic t r a it , a n d it pr edom in a n t ly
a ffect s m a les.
Th e cen t er of t h e r et in a , t h e m a c u la , is t h e a r ea
r espon sible for cen t r a l vision , color vision , a n d fin e
det a il. Th e o v e a , a n a r ea in t h e cen t er of t h e m a c-
u la , is t h e sit e a t wh ich t h e con es a r e m ost den se.
Alt e r a t io n s in Vis io n 295
Con es a r e t h e on ly ph ot or ecept or s loca t ed in t h e fo-
vea , in cr ea sin gly in t er sper sed wit h r ods t owa r d t h e
r et in a per iph er y. Rods a r e m ost h igh ly con cen t r a t ed
in t h e per iph er a l r et in a , pr om ot in g per iph er a l a n d
n igh t vision . Rods a n d con es con ver t ligh t in t o elec-
t r ica l im pu lses, wh ich a r e t r a n sm it t ed fir st t o t h e
bipola r n eu r on s, t h en t o ga n glion n eu r on s. Th e a x-
on s of t h e ga n glion n eu r on s m eet a t t h e opt ic disk
a n d exit t h e eye a s t h e opt ic n er ve (F ig. 12.6). Th e
im pu lse con t in u es t o t h e opt ic ch ia sm wh er e t h e m e-
dia l h a lves of t h e r et in a l n er ves cr ossover. Th e im -
pu lse t r a vels t o t h e opt ic t r a ct , t h e t h a la m u s, a n d
t h e occipit a l lobe for pr ocessin g. E a ch eye t r a n s-
m it s a sligh t ly differ en t im a ge, focu sed u pside down
on t h e r et in a . Mir r or r ever sa l a lso occu r s beca u se
of ligh t r eflect ed fr om t h e r igh t side of a n object
t o t h e left side of t h e r et in a a n d vice ver sa . Visu a l
im a ges a r e coor din a t ed in t h e br a in du r in g v is u a l
p r o c e s s in g .
CONTROL OF EYE MOVEMENT
E xt r a ocu la r m u scles a r e r espon sible for t h e r ot a -
t ion , h or izon t a l a n d ver t ica l m ovem en t of t h e eyes
(Fig. 12.7). A ba la n ce of con t r a ct ion a n d r ela xa t ion
of specific m u scles a llows con t r olled eye m ovem en t
(Ta ble 12.3). Th e six m u scles t h a t con t r ol eye m ove-
m en t s a r e in n er va t ed by t h e ocu lom ot or (III), t r och -
lea r (IV), a n d a bdu cen s (VI) cr a n ia l n er ves. E ye
m ovem en t s ca n be descr ibed a s follows:
● Sa cca des: lookin g fr om object A t o object B
● P u r su it : sm oot h ly followin g a m ovin g object
● Con ver gen ce/diver gen ce: bot h eyes t u r n in g in -
wa r d/ou t wa r d sim u lt a n eou sly
● Vest ibu la r : eyes sen sin g a n d a dju st in g t o h ea d
m ovem en t via con n ect ion s wit h n er ves in t h e in -
n er ea r
● F ixa t ion m a in t en a n ce: m in u t e eye m ovem en t s
t h a t posit ion a n d a ccom m oda t e bot h eyes
PROTECTIVE EYE STRUCTURES
Th e st r u ct u r es of t h e eye a r e pr ot ect ed by bot h ph ys-
ica l a n d ch em ica l ba r r ier s. P r ot ect ive eye st r u ct u r es
m a in t a in fu n ct ion a n d pr om ot e opt im a l vision .
External Structures
E yelids pr ovide a pr ot ect ive ba r r ier for t h e eye.
Open in g a n d closin g of eyelids (blin kin g) pr om ot es
t h e r em ova l of debr is a n d pr ovides m oist u r e for t h e
eye su r fa ce. E yela sh es a lso pr ot ect t h e eye a n d r e-
m ove sm a ll pa r t icles of debr is. Th e con ju n ct iva is a
m u cou s m em br a n e lin in g t h e u n der su r fa ce of t h e
eyelid a n d fr on t of t h e eye.
296 C h a p t e r 12: Alt er ed Som a t ic a n d Specia l Sen sor y F u n ct ion

Re tina

S cle ra
Choroid

Re tina

Cone s
Light Fove a

Le ns

Rods

Figure 12.6. Lateral view of the eye. Impulses initiated in the photoreceptors, rods, and cones are transmitted by the
bipolar cells to the ganglion cells of the retina. The fovea in the center of the macula is made entirely of cones. Surround-
ing tissue and blood vessels are displaced from the central area, fovea centralis, allowing light to pass unimpeded to the
cones. (Modified from Bear MF, Connors BW, Parasido MA. Neuroscience: Exploring the Brain. 3rd ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2006.)

Superior rectus muscle

Superior oblique muscle

Medial rectus muscle

Lateral rectus muscle

Inferior rectus muscle

Inferior oblique muscle

Figure 12.7. Extraocular eye muscles. Paired extraocular muscles control eye movement and include the superior/ inferior
rectus, medial/ lateral rectus, and the superior/ inferior oblique. The paired muscles have reciprocal responses, so that as
one contracts, the other relaxes. (Courtesy Anatomical Chart Company.)

Tears Closu r e of t h e eyelid for ces t ea r s down wa r d, t owa r d

Th e la c r im a l g la n d s a r e t h e pr im a r y pr odu cer s of
t ea r s. Tea r s pr ot ect t h e eyes by:
● P r ot ect in g a ga in st ba ct er ia l in fect ion
● P r ovidin g n u t r ien t s a n d m oist u r e
● Rem ovin g debr is a n d wa st e fr om t h e eye
t h e n ose, a n d in t o t h e pu n ct a (open in gs in t h e u p-
per a n d lower lids). Tea r s a r e for ced in t o t h e la c-
r im a l sa c t h r ou gh n a r r ow ch a n n els. Upon m u scle
r ela xa t ion a n d eye open in g, t ea r s m ove fr om t h e
la cr im a l sa c t o t h e n a sola cr im a l du ct a n d in t o t h e
n ose.
 Alt e r a t io n s in Vis io n 297

Ta b le 12.3 E xt r a ocu la r Mu scle F u n ct ion

Alterations in Visual
Function
E x t r a o c u la r E y e Mu s c le E y e Mo v e m e n t
La t er a l r ect u s Ou t wa r d, a wa y fr om n ose Sigh t depen ds on t h e in t egr a -
Media l r ect u s In wa r d, t owa r d t h e n ose t ion of m u lt iple st r u ct u r es a n d
Su per ior r ect u s Upwa r d, sligh t ly ou t wa r d pr ocesses wit h in t h e eye a n d
In fer ior r ect u s Down wa r d, sligh t ly in wa r d
in su r r ou n din g t issu es a n d or-
ga n s. Alt er a t ion s in vision ca n
Su per ior obliqu e In wa r d a n d down wa r d
be in du ced by m u lt iple ca u ses,
In fer ior obliqu e Ou t wa r d a n d u pwa r d
in clu din g da m a ge t o eye st r u c-
t u r es, m ot or dysfu n ct ion , a n d
im pa ir ed n eu r a l con du ct ion .
Stop and Consider Con sequ en ces ca n r a n ge fr om m ild visu a l im pa ir-
What is the most likely explanation for the runny m en t a m en a ble t o cor r ect ion or sever e im pa ir m en t ,
nose that occurs during crying? r esu lt in g in blin dn ess.

Aqueous Humor
Th e n u t r it ive, wa t er y flu id pr odu ced by t h e c ilia r y
b o d y is kn own a s a q u e o u s h u m o r (F ig. 12.8). Re-
lea sed in t h e spa ce bet ween t h e ir is a n d t h e len s (t h e
post er ior ch a m ber ), t h e a qu eou s h u m or m a in t a in s
eye pr essu r e a n d pr ovides n u t r ien t s t o t h e cor n ea
a n d t h e len s. Movem en t of a qu eou s h u m or fr om t h e
post er ior ch a m ber t o t h e a n t er ior ch a m ber occu r s by
diffu sion via t h e pu pil, a llowin g r ea bsor pt ion in t o
t h e ven ou s syst em for r em ova l. Th e pr im a r y m ech a -
n ism for r ea bsor pt ion occu r s t h r ou gh t h e t r a b e c u -
la r n e t w o r k (a m esh like st r u ct u r e) in t o t h e ca n a l of
Sch lem m , pr om ot in g m ovem en t in t o t h e ven ou s sys-
t em . A sm a ller qu a n t it y of a qu eou s h u m or is r ea b-
sor bed dir ect ly in t o la r ger blood vessels t h r ou gh t h e
a n t er ior cilia r y body, kn own a s t h e u v e a l-s c le r a l
o u t lo w p a t h w a y .
Aque ous
humor
Le ns
Corne a
Figure 12.8. Aqueous humor. Aqueous humor flows from
the posterior to the anterior chamber for reabsorption by
the venous system to maintain eye pressure.
ERRORS IN REFRACTION
Ben din g of ligh t , or r efr a ct ion , ca n be a lt er ed a t a n y
st ep fr om ligh t en t r y in t o t h e eye t h r ou gh t h e con -
t a ct of ligh t on t o t h e r et in a (Fig. 12.9). On e com m on
er r or in r efr a ct ion is m y o p ia , com m on ly kn own
a s n ea r sigh t edn ess. In m yopia , t h e eye focu ses a n
im a ge in fr on t of t h e r et in a du e t o len s t h ickn ess.
H y p e r o p ia , com m on ly r efer r ed t o a s fa r sigh t ed-
n ess, is ca u sed by t h e focu sin g of a n im a ge beh in d
t h e r et in a , wh ich a lt er s t h e t r a n sm ission of ligh t .
Th ese con dit ion s a r e ea sily cor r ect ed wit h t h e pr ovi-
sion of a len s t h a t r egu la t es ligh t r a ys. A bicon ca ve
len s ca u ses ligh t t o diver ge, pr ovidin g cor r ect ion of
m yopia . A bicon vex len s is t h e n ecessa r y cor r ect ion
for h yper opia , pr om ot in g t h e con ver gen ce of ligh t
r a ys. As t ig m a t is m , ca u sed by ir r egu la r cu r va t u r e
of t h e cor n ea or len s, pr even t s t h e focu sin g of im -
a ges, blu r r in g vision . Cor r ect ion of a st igm a t ism ca n
be a ccom plish ed t h r ou gh gla sses, con t a ct len ses, or
r efr a ct ive la ser su r ger y, discu ssed in m or e det a il
la t er in t h e ch a pt er. P r e s b y o p ia , a con dit ion of
fa r sigh t edn ess a ssocia t ed wit h a gin g, r esu lt s fr om
t h e in a bilit y of t h e cilia r y m u scle a n d len s t o a ccom -
m oda t e for n ea r vision . Th is con dit ion is ea sily cor-
r ect ed wit h bifoca ls.
ALTERATIONS IN EYE MOVEMENT
S t r a b is m u s is a t er m t h a t descr ibes t h e la ck of coor-
din a t ed ext r in sic eye m u scle fu n ct ion t h a t pr even t s
t h e eyes fr om lin in g u p in t h e sa m e dir ect ion . Kn own
com m on ly a s “cr ossed eyes,” t h e m isa lign m en t of vi-
su a l a xes r esu lt s in t h e in a bilit y t o focu s on a sin gle
object . Am b ly o p ia , com m on ly kn own a s “la zy eye,”
m a y r esu lt fr om st r a bism u s, lea din g t o t h e loss of
visu a l det a il fr om u n coor din a t ed eye m ovem en t a n d
focu s. Wh en visu a l a xes a r e m isa lign ed in ch ildr en ,
t h e br a in is a ble t o su ppr ess on e of t h e im a ges, r e-
su lt in g in visu a l im pa ir m en t in t h e ign or ed eye.
298 C h a p t e r 12: Alt er ed Som a t ic a n d Specia l Sen sor y F u n ct ion

Accommoda tion

Hype ropia Hype ropia corre ction

Myopia Myopia corre ction

Figure 12.9. Error in refraction. Light entering the eye is focused onto the retina. Refraction errors misdirect light onto
the retina, causing distortion of vision. (Modified from Bear MF, Connors BW, Parasido MA. Neuroscience: Exploring the
Brain. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006.)

Th e im pa ir m en t m a y r a n ge fr om dim n ess of vision eye. Va r ia t ion s in ca t egor ies of con ju n ct ivit is a r e

t o t h e loss of per m a n en t loss of vision in on e eye. Vi-
su a l im pa ir m en t r esu lt in g fr om a m blyopia m a y n ot
be fu lly cor r ect a ble.
D ip lo p ia , a con dit ion oft en r esu lt in g fr om a la ck
of coor din a t ion of t h e ext r a ocu la r m u scles, m ay r esu lt
in dou ble vision . Im a ges fa ll on n on cor r espon din g
a r ea s of t h e r et in a , ca u sin g t h e visu a l defect . In vol-
u n t a r y oscilla t ion s of t h e eye, kn own a s n y s t a g m u s ,
r esu lt fr om a bn or m a l fu n ct ion in t h e br a in , la byr in t h
of t h e in n er ea r, a n d vest ibu la r pa t h ways r espon si-
ble for con t r ollin g eye m ovem en t . Con gen it a l n ys-
t a gm u s oft en r esu lt s fr om ocu lo-m ot or a bn or m a lit ies
du r in g n eu r a l developm en t , m a n ifest in g a t t h e a ge
of 2 m on t h s. In t h e post n a t a l per iod, n yst a gm u s ca n
be a cqu ir ed fr om a va r iet y of visu a l in pu t disr u pt ion s
bu t is oft en t h e r esu lt of a h ea d in ju r y or spa ce occu -
pyin g lesion t h a t in t er fer es wit h vest ibu la r pa t h ways
or cer ebella r fu n ct ion . Ot h er con dit ion s kn own t o
con t r ibu t e t o t h e developm en t of n yst a gm u s in clu de
br a in st em or cer ebella r lesion s, st r oke, Mén ièr e dis-
ea se, m u lt iple scler osis, a n d dr u g or a lcoh ol t oxicit y.
ALTERATIONS IN PROTECTIVE EYE STRUCTURES
In fla m m a t ion of t h e m u cou s m em br a n e lin in g t h e
eye, c o n ju n c t iv it is , is com m on ly kn own a s pin k
lin ked t o t h e followin g ca u sa t ive fa ct or s:
● Vir a l con ju n ct ivit is
■ Usu a lly a ffect s on ly on e eye
■ Associa t ed wit h excessive eye wa t er in g a n d a
sm a ll a m ou n t of disch a r ge
● Ba ct er ia l con ju n ct ivit is
■ Usu a lly a ffect s bot h eyes
■ Associa t ed wit h h ea vy disch a r ge
● Aller gic con ju n ct ivit is
■ Usu a lly a ffect s bot h eyes
■ Associa t ed wit h it ch in g, r edn ess, a n d excessive
t ea r in g
C a t a r a c t s r esu lt fr om t h e clou din g of t h e len s,
wh ich a lt er vision focu s by sca t t er in g t h e in com in g
ligh t on t o t h e r et in a (F ig. 12.10). Clou din g oft en r e-
su lt s fr om t h e clu m pin g or a ggr ega t ion of t h e pr o-
t ein com pon en t of t h e len s. As t h e size of t h e opa qu e
a r ea in cr ea ses, vision is in cr ea sin gly im pa ir ed. Ca t -
a r a ct s a r e cla ssified in t o t h r ee t ypes:
1. Nu clea r
a . Most com m on t ype
b . For m s in t h e cen t er, or n u cleu s, of t h e len s
c . Dist a n ce vision a ffect ed m or e t h a n n ea r vision
d . Slow pr ogr ession (yea r s), a ssocia t ed wit h a gin g

Corne a (cut)
Iris
Le ns with:
prote in a ggre ga tion
Re tina
oxida tive injury
incre a s e d pigme nta tion
Figure 12.10. Cataract. Cross-section of the cornea showing
cloudy lens. (Asset provided by Anatomical Chart Company.)
2. Cor t ica l
a . For m s in t h e len s cor t ex
b . E xt en ds fr om t h e ou t er len s t owa r d t h e cen t er
c . Min im a l vision im pa ir m en t
3. Post er ior su bsca pu la r
a . Begin s a t t h e ba ck of t h e len s
b . Gla r e im pa ir ed vision
c . Ra pid pr ogr ession (m on t h s)
MANIFESTATIONS AND EVALUATION
OF ALTERATIONS IN VISION
In dividu a ls oft en seek ca r e wh en t h ey n ot ice t h a t
t h eir vision h a s ch a n ged. Oft en , decr ea sin g a cu it y or
cla r it y of vision occu r s over t im e. In t h e ca se of ch il-
dr en , vision scr een in g or ch a n ge in a ca dem ic per-
for m a n ce m a y pr ovide t h e im pet u s t o seek fu r t h er
scr een in g a n d dia gn osis. A com pr eh en sive vision
scr een in g is n ecessa r y t o iden t ify a r ea s of deficit or
dysfu n ct ion . Th e com pon en t s of a vision scr een in g
a r e pr esen t ed in Box 12.4.
Visu a l a cu it y, or sh a r pn ess, is com m on ly in clu ded
in ba sic vision scr een in g. It is im por t a n t t o eva lu a t e
bot h fa r a n d n ea r vision . E va lu a t ion of fa r dist a n ces
is a ccom plish ed by u sin g a st a n da r dized eye ch a r t ,
su ch a s t h e Sn ellen or E ch a r t . Th e r esu lt s a r e r e-
por t ed a s a fr a ct ion , “20/X,” wit h t h e n u m er a t or in di-
ca t in g wh a t ca n be seen clea r ly a t a 20-foot dist a n ce
a n d t h e den om in a t or in dica t in g t h e dist a n ce a t
wh ich t h e a ver a ge eye ca n r ea d t h e lin e. A r epor t of
20/20 m ea n s t h a t a per son ca n see clea r ly a t 20 feet
wh a t sh ou ld be seen a t 20 feet . A m ea su r em en t of
20/40 m ea n s t h a t wh a t is seen clea r ly a t 20 feet , t h e
a ver a ge per son ca n r ea d a t 40 feet .
Th e r esu lt s of a n ea r vision t est sh ow a per son ’s
a bilit y t o see t h e det a ils of n ea r object s (wit h in a r m ’s
dist a n ce fr om t h e body). Nea r vision is t est ed wit h
Alt e r a t io n s in Vis io n 299
Box 12.4 C o m p o n e n t s o Vis io n
S c r e e n in g
Vision eva lu a t ion oft en in clu des t h e followin g:
● Acu it y-dist a n ce: visu a l a cu it y (sh a r pn ess, clea r n ess)
a t 20 feet dist a n ce
● Acu it y-n ea r : clea r vision for sh or t dist a n ce (a s in
r ea din g)
● Focu sin g skills: m a in t en a n ce of clea r vision a t va r y-
in g dist a n ces
● E ye t r a ckin g a n d fixa t ion skills: t h e a bilit y of t h e eyes
t o look a t a n d a ccu r a t ely follow a n object ; a skill im -
por t a n t in t h e pr ocess of r ea din g
● Bin ocu la r fu sion : t h e a bilit y t o u se bot h eyes t oget h er
a t t h e sa m e t im e
● St er eopsis: bin ocu la r dept h per cept ion
● Con ver gen ce a n d eye t ea m in g skills: coor din a t ion of
t h e eyes t o a im , m ove, a n d wor k a s a t ea m
● H yper opia : a r efr a ct ive con dit ion t h a t ca u ses diffi-
cu lt y in focu s of n ea r object s
● Color vision : t h e a bilit y t o dist in gu ish color s
● Rever sa l fr equ en cy: con fu sin g let t er s or wor ds (b, d;
p, q: sa w, wa s)
● Visu a l m em or y: t h e a bilit y t o st or e a n d r et r ieve visu a l
in for m a t ion
● Visu a l for m discr im in a t ion : t h e a bilit y t o det er m in e
wh et h er t wo sh a pes, color s, sizes, posit ion s, or dis-
t a n ces a r e t h e sa m e or differ en t
● Visu a l m ot or in t egr a t ion : t h e a bilit y t o com bin e vi-
su a l in pu t wit h ot h er sen sor y in pu t (e.g., h a n d a n d
body m ovem en t s, ba la n ce, a n d h ea r in g); t h e a bilit y t o
t r a n sfor m im a ges fr om a ver t ica l t o a h or izon t a l pla n e
(su ch a s fr om t h e bla ckboa r d t o t h e desk su r fa ce)
● In t r a ocu la r pr essu r e m ea su r em en t : m ea su r em en t of
10–21 m m H g con sider ed n or m a l
a h a n dh eld ca r d h eld a t a com for t a ble dist a n ce.
Th e pa t ien t r ea ds t h e sm a llest lin e possible, wh ich
is r ecor ded a lon g wit h t h e dist a n ce. Som e t est s of
n ea r a cu it y u se a st a n da r d h a n dh eld ca r d a t a pr e-
scr ibed dist a n ce. For exa m ple, wh en a J a eger ch a r t
is u sed, it is pla ced 12 t o 14 in ch es a wa y. In dividu a ls
a r e a sked t o r ea d t h e sm a llest of 10 a va ila ble lin es,
r a n gin g fr om 4- t o 14-poin t t ype fon t s, t h a t t h ey a r e
a ble t o r ea d. Th e r esu lt s a r e t h en con ver t ed t o st a n -
da r ds u sed in fa r vision eva lu a t ion .
TREATMENT OF ALTERATIONS IN VISION
Tr ea t m en t of a lt er a t ion s in vision is specific t o t h e
iden t ified im pa ir m en t . Mu scle im ba la n ces ca n be
cor r ect ed by gla sses, pa t ch in g, or su r ger y, depen din g
on t h e specific im pa ir m en t s iden t ified. E r r or s in r e-
fr a ct ion m a y be cor r ect ed by gla sses, con t a ct len ses,
or su r ger y. L a s e r -a s s is t e d in s it u k e r a t o m ile u s is
(L AS I K) is a su r gica l pr ocedu r e u sed t o t r ea t m yo-
pia , h yper opia , a n d a st igm a t ism . Ca t a r a ct s m a y a lso
n eed t o be su r gica lly r em oved a n d r epla ced wit h a
clea r pr ost h et ic len s. Gla u com a , cover ed in gr ea t er
det a il in t h e clin ica l m odel in t h is ch a pt er, m a y r e-
qu ir e su r gica l or ph a r m a cologic m a n a gem en t .
300 C h a p t e r 12: Alt er ed Som a t ic a n d Specia l Sen sor y F u n ct ion

Modu le 3 Alt e r a t io n s in H e a r in g
a n d B a la n c e

H ea r in g a n d ba la n ce in volve a com plex in t er a ct ion t h a t secr et e wa x (c e r u m e n ). Th ese st r u ct u r es in t h e

bet ween st r u ct u r a l com pon en t s of t h e ea r a n d t r a n s- ea r ca n a l ser ve a s pr ot ect ion a ga in st for eign bodies
m ission of n er ve im pu lses for sen sor y in t er pr et a t ion . a n d en vir on m en t a l debr is. At t h e dist a l en d, t h e ea r
Th e sen ses of h ea r in g a n d ba la n ce a r e m a xim ized ca n a l becom es bon y wit h a t igh t skin cover in g.
by opt im a l fu n ct ion of bot h ou t er ea r a n d in n er ea r
st r u ct u r es.
MIDDLE EAR
Th e t y m p a n ic m e m b r a n e , or ea r dr u m , is loca t ed
a t t h e en d of t h e ea r ca n a l opposit e t h e ext er n a l a u -
Structural Components of the Ear dit or y m ea t u s, m a r kin g t h e bou n da r y of t h e m iddle
ea r. Th e m iddle ea r con t a in s t h r ee bon es, or o s s i-
St r u ct u r es of t h e ou t er, m iddle, a n d in n er ea r coor-
c le s , t h a t for m a con n ect ion bet ween t h e ea r dr u m
din a t e t o fu n n el st im u li (sou n d) t o t h e h ea r in g r e-
a n d in n er ea r. Sou n d wa ves t h a t con t a ct t h e t ym -
cept or s, in it ia t in g t h e sign a l t h a t t r a vels a lon g t h e
pa n ic m em br a n e ca u se a ba ck a n d for t h m ovem en t .
n eu r a l pa t h wa ys t o t h e br a in . Figu r e 12.11 illu s-
Tym pa n ic m em br a n e m ovem en t ca u ses r eposit ion -
t r a t es t h e st r u ct u r es of t h e ea r.
in g of t h e ossicles, wh ich ch a n ges sou n d wa ves in t o
m ech a n ica l vibr a t ion (Fig. 12.12).
OUTER EAR Th e t h r ee bon es com pr isin g t h e ossicles a r e t h e
m a lle u s , in c u s , a n d s t a p e s . Th ese bon es a r e a lso
Th e t issu e t h a t com pr ises wh a t is viewed a s t h e
kn own a s t h e h a m m er, a n vil, a n d st ir r u p, r espec-
ou t er ea r is kn own a s t h e p in n a . Com posed of ca r t i-
t ively. Con n ect ion s bet ween t h e t ym pa n ic m em -
la ge a n d soft t issu e, t h e pin n a m a in t a in s it s sh a pe,
br a n es a n d ossicles pr om ot e t r a n sdu ct ion of t h e
bu t it is a lso flexible a n d plia ble. Th e pin n a collect s
m ech a n ica l vibr a t ion , pr odu cin g sou n d. Th e pr ogr es-
a n d fu n n els sou n d vibr a t ion s in t o t h e open in g of t h e
sive con n ect ion s bet ween t h e t ym pa n ic m em br a n e,
ea r ca n a l, or e x t e r n a l a u d it o r y m e a t u s . Th e ea r
m a lleu s, in cu s, a n d st a pes ca u se a n in -a n d-ou t
ca n a l is a ppr oxim a t ely 1 in ch lon g in a n a du lt a n d,
m ovem en t a t t h e ba se of t h e st ir r u p, or t h e st a pes
sim ila r t o t h e pin n a , is a lso com pr ised of ca r t ila ge.
foot pla t e. Th ese in -a n d-ou t m ovem en t s r epr esen t
Th e ea r ca n a l is cover ed wit h sm a ll h a ir s a n d gla n ds
pa t t er n s m a t ch in g t h e in it ia t in g sou n d wa ves.
Th e m iddle ea r is loca t ed in
t h e a ir-filled m a st oid por t ion
He lix
of t h e t em por a l bon e of t h e sku ll.
Inne r e a r Th e eu st a ch ia n t u be con n ect in g
Auditory os s icle s S e micircula r t h e m iddle ea r t o t h e n a soph a r-
S ta pe s ca na ls
Incus yn x r u n s a lon g t h e fr on t wa ll of
Cochle a
Ma lle us t h e m iddle ea r t o t h e ba ck of t h e
Cochle a r n ose a n d t h r oa t , pr ovidin g pr es-
ne rve
su r e equ a liza t ion on bot h sides
Antihe lix of t h e t ym pa n ic m em br a n e. Th e
eu st a ch ia n t u be is sh or t er a n d
n a r r ower in ch ildr en , in cr ea s-
Tympa nic
me mbra ne in g t h e likelih ood of eu st a ch ia n
(e a rdrum) t u be blocka ge a n d pr essu r e. Th e
Exte rna l a n a t om ic con st r a in t s in ch il-
a cous tic Eus ta chia n dr en m a y in cr ea se t h e r isk of ea r
me a tus tube
in fect ion .
Round
Tympa nic window
Lobule cavity S
Stop and Consider
of a uricle What are the ways that we can
vvoluntarily manipulate pressure
Figure 12.11. Structures of the ear. (Courtesy Anatomical Chart Company.) changes in the ear?
 Alt e r a t io n s in H e a r in g a n d B a la n c e 301

S ta pe s
footpla te
S ta pe s S te re ocilia
Incus S e micircula r ca na ls
Ma lle us
Utricle
Tympa nic
me mbra ne
Ve s tibula r
ne rve Ha ir
ce ll
Cochle a r
ne rve
S e ns ory
ne uron
Cochle a
Norma l Hype rpola riza tion De pola riza tion
S a ccule Figure 12.13. Hair cell. Hair cells hyperpolarize or depolar-
Ova l
Round
window
window
ize depending on the direction in which the stereocilia bend.

Figure 12.12. Vestibular structures of the ear. Sound

vibrations contact the tympanic membrane, causing vi-
bration of the ossicles and footplate of the stapes at the
oval window. Movement of the oval window promotes fluid
movement against the cochlea stimulating nerve impulses,
which are transmitted to the brain via the cochlear nerve.
INNER EAR
Th e st a pes foot pla t e of t h e m iddle ea r fit s in t o t h e
o v a l w in d o w , m a r kin g t h e bou n da r y bet ween t h e
m iddle ea r a n d t h e begin n in g poin t of t h e in n er ea r.
Th e in n er ea r is com pr ised of t h e ou t er bon y la by-
r in t h a n d in n er m em br a n ou s la byr in t h . Recept or
st im u li r esu lt s in sign a l t r a n sdu ct ion a lon g t h e
eigh t h cr a n ia l n er ve (a cou st ic), com pr ised of t h e
coch lea r n er ve (h ea r in g) a n d t h e vest ibu la r n er ve
(ba la n ce).
Hearing Processes
Th e per ilym ph -filled bon y la byr in t h con t a in s t h e
c o c h le a , im por t a n t for h ea r in g. Wit h in t h e coch lea ,
t h e O r g a n o C o r t i con t a in s h a ir cells, t h e r ecep-
t or s r espon sible for t h e n eu r a l im pu lse t h a t a llows
h ea r in g. Th e m em br a n ou s la byr in t h is a closed sys-
t em of en dolym ph -filled ca n a ls lyin g wit h in t h e co-
ch lea . Th e ion ic con cen t r a t ion differ en ce bet ween
per ilym ph flu id ou t side t h e m em br a n ou s la byr in t h
a n d t h e in t er n a l en dolym ph flu id cr ea t es a n en do-
lym ph a t ic pot en t ia l, gen er a t in g a cu r r en t t h a t sen -
sit izes t h e coch lea r h a ir cells in t h e Or ga n of Cor t i
t o sou n d. Coch lea r h a ir cells a r e in n er va t ed by t h e
coch lea r por t ion of t h e a cou st ic n er ve. Im pu lses a r e
t h en t r a n sm it t ed t o t h e visu a l cor t ex in t h e occipit a l
lobe, r egu la t in g h ea r in g.
Mech a n ica l en er gy fr om t h e ossicles for ces t h e
ova l win dow in t o t h e coch lea . Th e m ot ion of t h e
coch lea ’s flu id st im u la t es h a ir cells. St er ocilia on
ea ch h a ir cell con t r ibu t e t o t h e a bilit y t o r espon d t o
u n iqu e sou n d fr equ en cies, or pit ch es. Movem en t of
st er eocilia lea ds t o h yper pola r iza t ion or depola r iza -
t ion (Fig. 12.13). Depola r iza t ion of h a ir cells ca u ses
im pu lse gen er a t ion a n d t r a n sm ission t o t h e br a in via
t h e a cou st ic (vest ibu lococh lea r ) VIII cr a n ia l n er ve t o
t h e r ela y cen t er in t h e m idbr a in , t h e coch lea r n u -
cleu s. At t h a t poin t , n er ve fiber s fr om ea ch ea r divide
in t o t wo pa t h wa ys. On e pa t h wa y a scen ds dir ect ly t o
t h e a u dit or y cor t ex on t h e sa m e side h em isph er e,
wh ile t h e secon d pa t h wa y cr osses over a n d a scen ds
t o t h e a u dit or y cor t ex on t h e con t r a la t er a l h em i-
sph er e. Th is m ech a n ism a llows im pu lses fr om ea ch
ea r t o r ea ch bot h h em isph er es.
Th e cen t r a l a u dit or y syst em pr ocesses a u dit or y
in for m a t ion , su ppor t in g t h e followin g fu n ct ion s:
● Sou n d loca liza t ion
● Au dit or y discr im in a t ion (r ecogn izin g differ en ces
bet ween differ en t sou n ds)
● Sou n d pa t t er n r ecogn it ion
● Tim e, or t em por a l, a spect s of h ea r in g
● In t egr a t ion of m u lt iple a u dit or y st im u li by r edu c-
t ion in t h e a u dit or y per for m a n ce of com pet in g or
in com plet e sign a ls
Balance Processes
Th e t h r ee sem icir cu la r ca n a ls a n d vest ibu le (con -
t a in in g t h e u t r icle a n d sa ccu le, con n ect ed m em br a -
n ou s sa cs) a r e a lso loca t ed in t h e bon y la byr in t h
a n d a r e im por t a n t for ba la n ce a n d equ ilibr iu m .
Th e per ilym ph in t h e sem icir cu la r ca n a ls sen ses
m ot ion ca u sed by body m ovem en t , st im u la t in g t h e
h a ir cells lin in g t h e vest ibu la r a ppa r a t u s. Vest ibu la r
h a ir cells a r e in n er va t ed by t h e vest ibu la r por t ion of
t h e a cou st ic n er ve. Im pu lses a r e t h en t r a n sm it t ed
302 C h a p t e r 12: Alt er ed Som a t ic a n d Specia l Sen sor y F u n ct ion
t o t h e cer ebellu m via t h e vest ibu la r br a n ch of t h e
a cou st ic n er ve, r egu la t in g equ ilibr iu m a n d ba la n ce.
Th e sem icir cu la r ca n a ls a n d vest ibu le (vest ibu la r
a ppa r a t u s) det ect h ea d posit ion a n d a cceler a t ion ,
m a in t a in in g body posit ion a n d st a ble visu a l fields.
Posit ion ed a t r igh t a n gles t o ea ch ot h er, t h e sem icir-
cu la r ca n a ls r espon d t o h ea d m ovem en t (u p/down ,
side/side, t ilt ), t r igger in g per ilym ph m ovem en t a n d
h a ir cell r ecept or a ct iva t ion a n d gen er a t ion of im -
pu lses. Th e sem icir cu la r ca n a ls pr ovide in for m a t ion
a bou t h ea d posit ion t o t h e vest ibu la r a ppa r a t u s
t h r ou gh sem icir cu la r ca n a l con n ect ion t o t h e u t r icle
a n d u t r icle-sa ccu le con n ect ion . Th e u t r icle sen ses
ch a n ge in h or izon t a l h ea d posit ion wh ile t h e sa ccu le
is r espon sive t o ver t ica l a cceler a t ion .
Alterations in Hearing and Balance
Most disor der s of t h e ea r a r e n ot fa t a l, bu t t h ey sig-
n ifica n t ly a ffect a n in dividu a l’s da ily fu n ct ion in g.
E a r disor der s ca n r esu lt in im pa ir ed h ea r in g, a l-
t er ed ba la n ce, discom for t , a n d pa in .
DISORDERS OF THE EXTERNAL EAR
Disorders of the ear canal are frequently caused by in-
flammation, drainage, or obstruction. Obstruction can
result from the accumulation of cerumen or the pres-
ence of a tumor, diminishing the movement of sound to
the middle ear. Cerumen may be removed by a process
of ir r iga t ion , or rinsing the external canal with warm
water, after it is determined that the tympanic mem-
brane is intact. In the case of an obstructive tumor,
surgical excision is usually the preferred treatment.
Stop and Consider
What are the risks to ear structures when the
ears are irrigated?
O t it is e x t e r n a , in fla m m a t ion of t h e skin of t h e
ext er n a l ea r, is a con dit ion a ssocia t ed wit h pa in a n d
discom for t . Com m on ly kn own a s “swim m er ’s ea r,”
ot it is ext er n a oft en r esu lt s fr om m oist u r e in t h e ea r
ca n a l or a lt er ed in t egr it y of t h e skin in t h e ea r ca n a l.
Ma n ifest a t ion s in clu de it ch in g, r edn ess, t en der n ess,
a n d n a r r owin g of t issu es in t h e ea r ca n a l ca u sed by
swellin g in r espon se t o in fla m m a t ion . Mild h ea r in g
loss m a y r esu lt fr om dr a in a ge a n d fr om t h e r edu ced
dia m et er of t h e ea r ca n a l.
ALTERATION IN MIDDLE EAR FUNCTION
In fla m m a t ion , t r a u m a , a n d obst r u ct ion a r e oft en
r ela t ed t o m iddle ea r h ea r in g loss. E u st a ch ia n t u be
dysfu n ct ion m a y lea d t o loss of h ea r in g du e t o a lt er ed
pa t en cy or obst r u ct ion , or a s a con t r ibu t in g fa ct or t o
ot h er m iddle ea r pa t h ologies. Abn or m a lly pa t en t eu -
st a ch ia n t u bes pr om ot e m ovem en t of flu id fr om t h e
n a soph a r yn x in t o t h e m iddle ea r. Th is pa r t icu la r ly
con cer n s in fa n t s a n d ch ildr en beca u se cr yin g m a y
pr ecipit a t e t h e m ovem en t of secr et ion s in t o t h e t u be.
Obst r u ct ion of t h e eu st a ch ia n t u be m a y pr om ot e t h e
a bsor pt ion of a ir fr om t h e m iddle ea r, wh ich is r e-
pla ced by ser ou s flu id esca pin g fr om su r r ou n din g
ca pilla r ies. H ea r in g loss m a y r esu lt fr om t h e loss of
m obilit y of t h e t ym pa n ic m em br a n e ca u sed by m id-
dle ea r flu id, exu da t es com pr om isin g t h e con du ct ion
of vibr a t ion in t h e ossicles of t h e m iddle ea r, or n ega -
t ive pr essu r e in t h e m iddle ea r r esu lt in g fr om eu st a -
ch ia n t u be obst r u ct ion .
Su dden ch a n ges in a t m osph er ic pr essu r e ca n r e-
su lt in b a r o t r a u m a , or in ju r y r esu lt in g fr om t h e in -
a bilit y of t h e ea r t o equ a lize ba r om et r ic st r ess. Most
com m on ly seen in a ir t r a vel a n d sea divin g, ba r o-
t r a u m a r esu lt s fr om m iddle ea r pr essu r e in pa r a llel
wit h a t m osph er ic pr essu r e. Per son s a t pa r t icu la r
r isk a r e t h ose su ffer in g fr om a n u pper r espir a t or y
in fect ion wit h lim it ed a bilit y t o n or m a lize pr essu r e
in t h e eu st a ch ia n t u be.
Stop and Consider
What strategies can a person use to avoid
barotrauma caused by air travel during an upper
respiratory infection?
O t it is m e d ia , in fect ion of t h e m iddle ea r, is on e of
t h e m ost com m on disor der s of t h e m iddle ea r. H ea r-
in g loss m a y r esu lt fr om im m obilit y of t h e t ym pa n ic
m em br a n e, flu id a ccu m u la t ion of t h e m iddle ea r, a n d
sca r r in g fr om r u pt u r e of t h e t ym pa n ic m em br a n e,
a lt er in g fu n ct ion . Ot it is m edia m a y be a cu t e or r e-
cu r r en t , a n d it is a ssocia t ed wit h effu sion (flu id) in
t h e m iddle ea r. Th is con dit ion m a y be seen a cr oss
a ll a ge gr ou ps bu t h a s t h e gr ea t est pr eva len ce in in -
fa n t s a n d ch ildr en . Th e clin ica l m odel in t h is ch a pt er
pr ovides a com plet e r eview of t h is con dit ion . Ma s -
t o id it is , a ba ct er ia l in fect ion ca u sin g in fla m m a t ion
of t h e a ir cells of t h e m a st oid bon e, m a y r esu lt a s a
com plica t ion of ot it is m edia . Risks r ela t ed t o m a s-
t oidit is in clu de m en in git is, br a in a bscess, or fa cia l
pa lsy if it is n ot r espon sive t o a n t ibiot ic t h er a py.
O t o s c le r o s is , a n a u t osom a l-dom in a n t con dit ion ,
r epr esen t s t h e m ost com m on ca u se of ch r on ic, pr o-
gr essive, con du ct ive h ea r in g loss. Slow for m a t ion
of spon gy bon e a t t h e ova l win dow im m obilizes t h e
foot pla t e of t h e st a pes, im pa ir in g t h e con du ct ion of
vibr a t ion . Most pr eva len t in fem a les 15 t o 30 yea r s
of a ge, a ffect ed in dividu a ls in dica t e a fa m ily h is-
t or y of t h is con dit ion , con sist en t wit h t h e gen et ic
ba sis of t h e disea se. Su r gica l r em ova l of t h e st a pes
wit h r epla cem en t of a pr ost h et ic device r est or es pa r-
t ia l or t ot a l h ea r in g.

ALTERATION IN INNER EAR FUNCTION
H ea r in g loss ca u sed by in n er ea r dysfu n ct ion is r e-
la t ed t o dest r u ct ion of coch lea r h a ir cells or da m -
a ge t o n eu r a l pa t h wa ys. Tin n it u s m a y be ca u sed by
n oise-in du ced h ea r in g loss, sen sor in eu r a l h ea r in g
loss con sist en t wit h a gin g (p r e s b y c u s is ), h yper-
t en sion , a t h er oscler osis, h ea d in ju r y, or coch lea r
in fect ion /in fla m m a t ion .
Ba la n ce a n d equ ilibr iu m a r e dist u r bed in a lt er ed
fu n ct ion of t h e in n er ea r. Mé n iè r e d is e a s e , a con -
dit ion a ssocia t ed wit h sever e ver t igo, sen sor in eu r a l
h ea r in g loss, a n d t in n it u s, is r ela t ed t o over pr odu c-
t ion or decr ea sed a bsor pt ion of en dolym ph . Also
kn own a s en dolym ph a t ic h ydr ops or en dolym ph a t ic
h yper t en sion , h ea r in g loss is ca u sed by t h e pr ogr es-
sive degen er a t ion of vest ibu la r a n d coch lea r h a ir
cells, descr ibed in gr ea t er det a il in t h e clin ica l m od-
els. L a b y r in t h it is , or in fla m m a t ion of t h e la byr in t h
of t h e in n er ea r, a lso pr ecipit a t es sever e ver t igo a n d
sen sor in eu r a l h ea r in g loss.
MANIFESTATIONS AND EVALUATION
OF ALTERATIONS IN HEARING
Not icea ble ch a n ge in t h e a bilit y t o h ea r is com m on ly
wh y in dividu a ls seek h ea r in g eva lu a t ion . Difficu lt y
h ea r in g a r ou n d gr ou ps of people, difficu lt y h ea r-
in g com pet in g sou n ds, or difficu lt y h ea r in g specific
t ypes of pit ch es den ot es a pot en t ia l for h ea r in g loss.
H ea r in g scr een in g is r ou t in e in pa r t icu la r gr ou ps of
in dividu a ls, su ch a s n ewbor n s or t h ose in dividu a ls
wor kin g in a r ea s t h a t in cr ea se r isk for h ea r in g loss.
H ea r in g eva lu a t ion sh ou ld in clu de a t h or ou gh ex-
a m in a t ion of a ll st r u ct u r a l a n d fu n ct ion a l a u dit or y
com pon en t s. Defor m it ies a n d lesion s of t h e pin n a
a n d ext er n a l a u dit or y ca n a l m a y in dica t e a n a cu t e,
ch r on ic, or con gen it a l con dit ion a s t h e ca u se of h ea r-
in g im pa ir m en t . Au diom et r ic t est in g ca n h elp det er-
m in e t h e specific n a t u r e of h ea r in g loss. Au dit or y
a cu it y is t h e ba sic a ssessm en t of h ea r in g, a n d pr o-
vides a gen er a l sen se of h ea r in g sen sa t ion . F u r t h er
t est in g ca n be pu r su ed wh en eviden ce is pr esen t for
h ea r in g loss.
Scr een in g pr ocedu r es a r e per for m ed t o iden t ify
t h e t ype of loss (u n ila t er a l or bila t er a l, sen sor in eu -
r a l, a n d/or con du ct ive) a n d t o qu a n t ify t h e degr ee
of h ea r in g loss. A t h or ou gh h ist or y sh ou ld be com -
plet ed t o det er m in e t h e du r a t ion , sever it y, a n d qu a l-
it y of t h e h ea r in g loss. Associa t ed sym pt om s sh ou ld
a lso be iden t ified, su ch a s pa in or t in n it u s (r in gin g
or wh ist lin g in t h e ea r s).
Hearing Evaluation
Th e degr ee of h ea r in g loss ca n be qu a n t ified u sin g
a u n it of m ea su r e kn own a s d e c ib e ls (d B ). Th e
fr equ en cy or pit ch of t h e sou n d is r efer r ed t o in
Alt e r a t io n s in H e a r in g a n d B a la n c e 303
H e r t z (H z). Ba sed on pu r e-t on e a ver a ge, h ea r in g
levels ca n be ca t egor ized ba sed on fr equ en cies fr om
500 t o 4,000 H z. In dividu a ls wh o h a ve n or m a l h ea r-
in g a r e a ble t o det ect sou n ds a t a m in im a l fr equ en cy
of −10 t o + 15 dB. In dividu a ls wh o h a ve h ea r in g im -
pa ir m en t r equ ir e sou n ds wit h in cr ea sin g decibels
for det ect ion . Min im a l decibels n eeded for sou n d r ec-
ogn it ion m a y h elp det er m in e t h e degr ee of h ea r in g
loss, descr ibed a s follows:
1. Min im a l h ea r in g loss: 16 t o 25 dB
2. Mild h ea r in g loss: 26 t o 40 dB
3. Moder a t e h ea r in g loss: 41 t o 55 dB
4. Moder a t e t o sever e h ea r in g loss: 56 t o 70 dB
5. Sever e h ea r in g loss: 71 t o 90 dB
6. P r ofou n d h ea r in g loss: 91 dB or m or e
Th e t ype of h ea r in g loss ca n be det er m in ed ba sed on
t h e iden t ifica t ion of t h e even t or st r u ct u r e in volved.
C o n d u c t iv e h e a r in g lo s s is loca lized t o t h e ou t er
or m iddle ea r, a n d it m a y be t em por a r y or per m a -
n en t . S e n s o r in e u r a l h e a r in g lo s s is oft en per-
m a n en t , r esu lt in g fr om disea se, t r a u m a , or gen et ic
in h er it a n ce of a defect in t h e coch lea n er ve cells. Th e
in n er ea r or t h e a u dit or y n er ve is u su a lly in volved
in sen sor in eu r a l h ea r in g loss. Mix e d h e a r in g lo s s
r efer s t o a com bin a t ion of bot h sen sor in eu r a l a n d
con du ct ive h ea r in g loss. C e n t r a l a u d it o r y p r o -
c e s s in g d is o r d e r is a disor der in volvin g a n a lt er-
a t ion in a u dit or y sign a l pr ocessin g in t h e br a in .
In a ddit ion t o det er m in in g t ype a n d degr ee of
h ea r in g loss, a u dit or y t est in g ca n det er m in e wh et h er
t h e h ea r in g loss is bila t er a l or u n ila t er a l, sym m et r ic
or a sym m et r ic, or h igh fr equ en cy or low fr equ en cy.
Specific t est s in clu ded in h ea r in g eva lu a t ion in clu de
a n a u diogr a m , wit h t h e followin g t h r ee com pon en t s:
1. P u r e-t on e a u diom et r y
a . Recogn it ion of fa in t est t on es a t select ed pit ch es
in t h e a bsen ce of ba ckgr ou n d n oise
b . Resu lt s a r e gr a ph ed on a n a u diogr a m
2. Speech r ecept ion t h r esh old
a . Iden t ifica t ion of t h e fa in t est level of speech
h ea r d, con fir m in g pu r e-t on e a u diom et r y
b . Min im a l decibel m ea su r em en t of t h e “lou d-
n ess” of speech r equ ir ed for det ect ion r ecor ded
3. Speech discr im in a t ion scor e
a . Recogn it ion of wor ds a t a n or m a l level of
speech
b . Mea su r ed by t h e per cen t a ge of spoken wor ds
iden t ified wh en spoken a t a h ea r in g level
a bove t h r esh old
EVALUATION OF THE MIDDLE EAR
Test s t h a t pr ovide in for m a t ion a bou t st r u ct u r es in
t h e ou t er a n d m iddle ea r a r e kn own a s a cou st ic im -
m it t a n ce m ea su r es. T y m p a n o m e t r y m ea su r es t h e
304 C h a p t e r 12: Alt er ed Som a t ic a n d Specia l Sen sor y F u n ct ion
degr ee of m ovem en t of t h e t ym pa n ic m em br a n e t o
iden t ify m iddle ea r flu id, per for a t ion , or cer u m en
blocka ge of t h e ea r ca n a l. Ac o u s t ic r e le x m e a -
s u r e m e n t ca n be u sed t o det er m in e m ovem en t of
t h e t ym pa n ic m em br a n e in r espon se t o sou n d.
EVALUATION OF THE INNER EAR
Th e p u r e -t o n e b o n e c o n d u c t io n h ea r in g t est ca n
be u sed t o eva lu a t e t h e in n er ea r, in depen den t of
m iddle a n d ou t er ea r fu n ct ion . A sm a ll vibr a t or is
pla ced on eit h er t h e for eh ea d or t h e m a st oid bon e,
dir ect ly st im u la t in g t h e a u dit or y n er ve. Th is t est is
lim it ed t o t h e iden t ifica t ion of sen sor in eu r a l h ea r in g
loss. Air con du ct ion t est s ca n be u sed t o iden t ify bot h
con du ct ive a n d sen sor in eu r a l h ea r in g loss.
Th e vest ibu la r evoked m yogen ic pot en t ia l (VE MP )
t est u ses evoked pot en t ia l t ech n iqu es (see Ch a pt er 10)
t o st im u la t e a sou n d-in du ced r eflex. Th is t est a llows
eva lu a t ion of t h e sa ccu le (a sen sor y or ga n of t h e
in n er ea r ), t h e vest ibu la r n er ve, t h e m edia l vest ib-
u lospin a l t r a ct , a n d t h e spin a l a ccessor y n er ve. Gen -
er a t ion of a r espon se t o sou n d is ca u sed by a cou st ica l
st im u la t ion of t h e sa ccu le, r esu lt in g in t r a n sdu ct ion
of t h e im pu lse ben ea t h t h e st a pes foot pla t e.
In dividu a ls wh o exper ien ce a cu t e or ch r on ic ex-
posu r e t o en vir on m en t a l n oise a r e a t r isk for h ea r-
in g loss. E xposu r e t o n oise a n d h igh -level sou n d ca n
ca u se da m a ge t o ou t side h a ir cells, t h e m a in t a r get s
of h igh -level sou n d. Test s specific t o ou t er h a ir cell
fu n ct ion in clu de o t o a c o u s t ic e m is s io n (O AE ).
OAE s a r e fa in t sou n ds pr odu ced by t h e ou t er h a ir
cells in t h e coch lea of t h e in n er ea r. Sou n d r ecor d-
in gs, obt a in ed by a sm a ll m icr oph on e pla ced in t h e
ea r ca n a l, m a y iden t ify t h e specific r ea son for h ea r-
in g loss. OAE s m a y occu r spon t a n eou sly or m a y be
in du ced by a st im u lu s, su ch a s a click or a pu r e-t on e
a u dit or y st im u lu s.
Treatment of Alterations in Hearing
Alt er a t ion s in h ea r in g m a y be cor r ect ed by t h e u se of
h ea r in g a ids or a ssist ive list en in g devices t o a m plify
sou n d. Wh en t h ese devices pr ovide lit t le im pr ove-
m en t in h ea r in g, a coch lea r im pla n t m a y be con -
sider ed. C o c h le a r im p la n t s a r e a r t ificia l devices
su r gica lly pla ced beh in d t h e ea r. Usin g elect r ica l
st im u la t ion of n er ve en din gs, elect r odes im pla n t ed
in t h e coch lea t r a n sm it sou n ds t o t h e a u dit or y n er ve,
bypa ssin g st r u ct u r es in t h e m iddle a n d ou t er ea r.
Th e device does n ot r est or e n or m a l h ea r in g, bu t it
does pr ovide a sen se of sou n d t h a t is pr ocessed in t o
m ea n in gfu l com m u n ica t ion by t h e br a in .
H ea r in g deficit s in you n g ch ildr en m a y be a ssoci-
a t ed wit h im pa ir ed la n gu a ge a n d cogn it ive develop-
m en t . E a r ly scr een in g of h ea r in g loss h a s pr ovided
a n oppor t u n it y t o t r ea t loss a t you n ger a ges in a n ef-
for t t o pr om ot e la n gu a ge a n d cogn it ive developm en t .
Use of coch lea r im pla n t s a t you n ger a ges h a s t h e po-
t en t ia l t o en h a n ce cogn it ive developm en t .4
Taste and Smell
Th e sen ses of t a st e a n d sm ell a r e lin ked su ch t h a t if
on e is im pa ir ed, t h e ot h er is a lso a ffect ed. Wh ile im -
pa ir m en t of t a st e a n d sm ell is n ot life-t h r ea t en in g,
a lt er a t ion s in t h ese sen ses h a ve t h e pot en t ia l t o n eg-
a t ively im pa ct qu a lit y of life.
TASTE
Th e sen sa t ion of t a st e is a lso kn own a s gu st a t ion .
Ta st e is m edia t ed by t h e ch em or ecept or s in t h e t a st e
bu ds of t h e or a l ca vit y. Ta st e or gu st a t or y cells, on e
of t h e cell t ypes t h a t m a ke u p t a st e bu ds, a r e t h e
sen sor y r ecept or s r espon sible for t r igger in g t h e im -
pu lse t h a t is per ceived a s t a st e. Ta st e bu ds det ect
five t ypes of ba sic t a st es, in clu din g:
1. Sweet
2. Sou r
3. Sa lt y
4. Bit t er
5. Sa vor y
Su bst a n ces m u st be dissolved in sa liva t o st im u la t e
a t a st e r espon se. On ce dissolved, m olecu les r elea sed
fr om food a n d dr in k by ch ewin g, dr in kin g or digest -
in g food pen et r a t e t h e t a st e bu ds, bin d t o t h e t a st e
r ecept or on t h e gu st a t or y h a ir s of t h e t a st e cell, a n d
t r a n sm it t h e t a st e sign a l via a ct ion pot en t ia ls a lon g
a ssocia t ed den dr it es. Im pu lses t r a vel pr im a r ily
a lon g t h e fa cia l n er ve (cr a n ia l n er ve VII) a n d glosso-
ph a r yn gea l n er ve (cr a n ia l n er ve IX) wh er e t h ey syn -
a pse in t h e m edu lla a n d t h e t h a la m u s, t h en pr oceed
t o t h e gu st a t or y cor t ex in t h e pa r iet a l lobe.
Ta st e is a lso in dir ect ly a ffect ed by ot h er st im u li.
Visu a l, t h er m a l, scen t , a n d even pa in r ecept or s a r e
st im u la t ed t o en h a n ce t h e t a st e sen sa t ion . Of t h ese,
t h e olfa ct or y st im u la t ion of t h e sen se of sm ell h a s
t h e gr ea t est in flu en ce. Recept or sen sit ivit y of t a st e
cells m a y be a lt er ed by en vir on m en t a l fa ct or s (su ch
a s ciga r et t e sm okin g), dr u g r ea ct ion s (ch em ot h er-
a py), a n d clin ica l con dit ion s (ch r on ic liver disea se).
Ta st e disor der s oft en in volve sm ell. Con dit ion s
of t a st e disor der s in clu de ph a n t om t a st e per cept ion
(lin ger in g, u n plea sa n t t a st e), r edu ced a bilit y t o t a st e
on e or a ll of t h e five ba sic t a st es, or dist or t ion of fla -
vor su ch a s per sist en t m et a llic t a st e.
SMELL
Th e sen se of sm ell is oft en plea su r a ble, en h a n cin g
en joym en t of t h e food we ea t a n d t h e wor ld a r ou n d
 C lin ic a l Mo d e ls 305

u s. An in t a ct sen se of sm ell ca n a lso be pr ot ect ive, Affer en t fiber s a scen d fr om t h e olfa ct or y bu lb t o t h e

wa r n in g u s of pot en t ia l t h r ea t s su ch a s ga s lea ks
or en vir on m en t a l t oxin s. O l a c t io n , or t h e sen se
of sm ell, is r egu la t ed by olfa ct or y r ecept or s loca t ed
in ea ch n a sa l ca vit y. A secon d olfa ct or y pa t h wa y is
t h r ou gh t h e r oof of t h e t h r oa t r egion t o t h e n ose. Ol-
fa ct or y h a ir s pr ot r u de fr om t h e r ecept or segm en t s
t h a t ext en d t h r ou gh t h e n a sa l epit h eliu m . Un m y-
elin a t ed a xon s com pr ise t h e opposit e en d of t h e ol-
fa ct or y r ecept or, wh ich m er ge wit h ot h er olfa ct or y
a xon s t o for m t h e olfa ct or y n er ve (cr a n ia l n er ve I).
olfa ct or y cor t ex a n d a r e r espon sible for in t er pr et a -
t ion a n d pr ocessin g of olfa ct or y st im u li.
Alt er a t ion s in olfa ct or y sen sa t ion , wh ile u n plea s-
a n t , a r e n ot pa t h oph ysiologica lly sign ifica n t . Th e
m ost com m on sm ell disor der s a r e a ssocia t ed wit h
r ecen t illn ess or in ju r y. Con dit ion s m ost fr equ en t ly
a ssocia t ed wit h sm ell disor der s in clu de u pper r espi-
r a t or y in fect ion s, fr on t a l h ea d in ju r ies, ch em ica l ex-
posu r e (in clu din g som e m edica t ion s), a n d sm okin g.
Loss of sm ell a cu it y is a lso a ssocia t ed wit h a gin g.

Modu le 4 C lin ic a l Mo d e ls

Th e followin g clin ica l m odels h a ve been select ed t o
a id in t h e u n der st a n din g a n d a pplica t ion of a lt er ed
sen sa t ion . Th e st u den t sh ou ld pa y a t t en t ion t o t h e
com m on a lit ies a n d u n iqu e fea t u r es of ea ch con dit ion
wh en st u dyin g t h ese m odels. Alt er a t ion s in sen sor y
fu n ct ion s oft en lea d t o ph ysica l a n d em ot ion a l dis-
t r ess a n d disr u pt ion of da ily life (Fig. 12.14).
fibr ou s t issu e a n d t h e Gr eek wor ds “m yo” for m u scle
a n d “a lgia ” for pa in . E st im a t ed t o a ffect 2% of t h e
popu la t ion , fibr om ya lgia is a n in cr ea sin gly r ecog-
n ized pr oblem wh ich h a s led t o a r en ewed em ph a sis
on im pr oved m a n a gem en t st r a t egies. Fibr om ya lgia
occu r s in wom en seven t im es m or e fr equ en t ly t h a n
in m en . Wom en in t h e sixt h or seven t h deca de of life
h a ve t h e h igh est pr eva len ce of fibr om ya lgia .5

Fibromyalgia PATHOPHYSIOLOGY
F ibr om ya lgia , a con dit ion of t h e soft t issu es a n d F ibr om ya lgia ca u ses sign ifica n t pa in a n d fa t igu e bu t
m u scles, is der ived fr om t h e La t in wor ds “fibr o” for is n ot lin ked t o a well-defin ed pa t h ogen esis. Th er e is

S e ns o ry alte ratio ns

He a ring a nd Vis ion

Pa in
ba la nce

Ve rtigo Erro r in S truc tural

tinnitus re frac tio n impairme nt
hype ropia gla ucoma
myopia ca ta ra cts
pre s byopia ma cula r
Lo c atio n Quality Duratio n a s tygma tis m de ge ne ra tion
Conductive S e ns orine ura l
cuta ne ous s ha rp a cute he a ring he a ring los s
de e p burning chronic los s
vis ce ra l diffus e Eye move me nt
re fe rre d throbbing impairme nt
s ta bbing s tra bis mus
Ce ntra l a mblyopia
proce s s ing nys ta gmus
dis orde r diplopia

Figure 12.14. Concept map. Sensory alterations.

306 C h a p t e r 12: Alt er ed Som a t ic a n d Specia l Sen sor y F u n ct ion
n o defin it ive eviden ce of in fla m m a t ion , m u scle st r u c-
t u r a l or fu n ct ion a l a lt er a t ion s in fibr om ya lgia . Th e
com plexit y of fibr om ya lgia pa t h ogen esis in volves
gen et ics, developm en t a l in flu en ces, t r igger in g fa c-
t or s, a n d n eu r oph ysiologic a n d em ot ion a l va r ia bles.5
Wit h in fa m ilies, t h e eviden ce of fa m ilia l a ggr ega t ion
su ggest s a gen et ic pr edisposit ion t o fibr om ya lgia .
No r elia ble gen e t a r get s in volvin g pa in pa t h wa ys
h a ve been iden t ified t h ou gh t h er e is em er gin g evi-
den ce for a lt er a t ion s in DNA m et h yla t ion in wom en
wit h fibr om ya lgia in dica t in g a pot en t ia l epigen et ic
fou n da t ion .6 Alt h ou gh t h er e is n o kn own ca u se or
cu r e, r esea r ch con t in u es t o det er m in e t h e u n der-
lyin g m ech a n ism s a n d effect ive t r ea t m en t s for t h e
syn dr om e.
CLINICAL MANIFESTATIONS
H eigh t en ed sen sit ivit y t o n oxiou s st im u li ch a r a c-
t er izes t h e clin ica l m a n ifest a t ion s of fibr om ya lgia .
A com m on ly dia gn osed con dit ion , fibr om ya lgia is
ch a r a ct er ized by disor der ed sleep, t en der n ess, st iff-
n ess a n d pa in in t h e n eck, sh ou lder s, u pper ba ck,
elbows, lower ba ck, a n d h ips.7 Non r est or a t ive sleep,
con sist en t wit h m a n ifest a t ion s of fa t igu e, oft en a c-
com pa n y fibr om ya lgia .
Difficu lt y in con cen t r a t ion , depr ession a n d a n xiet y
m a y coexist in in dividu a ls wh o h a ve fibr om ya lgia .
Ser ot on in levels a r e decr ea sed in som e in dividu a ls,
con sist en t wit h sym pt om s of depr ession , pa in , sleep
a lt er a t ion , a n xiet y, a n d a lt er ed m u scle fu n ct ion . Al-
t er a t ion s in br a in st r u ct u r e a n d fu n ct ion in clu din g
Lowe r c e rvic al
(Ante rior a s pe cts
of the inte rtra ns ve rs e
s pa ce s a t C5 to C7)
S e c o nd rib
(S e cond
cos tochondra l
junctions )
Late ral e pic o ndyle
(2 cm dis ta l to the
e picondyle s )
Kne e
(Me dia l fa t pa d
proxima l to the
joint line )
Figure 12.15. Tender points of fibromyalgia.
ch a n ges in br a in m a t t er volu m e a n d cer ebr a l blood
flow h a ve been a ssocia t ed wit h fibr om ya lgia . It is
n ot kn own if t h ese a lt er a t ion s a r e ca u ses of or r e-
spon ses t o fibr om ya lgia .
DIAGNOSTIC CRITERIA
Dia gn ost ic cr it er ia in clu de su bject ive fin din gs of fa -
t igu e a n d ch r on ic m u scu loskelet a l pa in of a t lea st
3 m on t h s’ du r a t ion . E igh t een a r ea s of pa in , or t en der
poin t sit es, loca t ed in t h e n eck, sh ou lder s, r ib ju n c-
t ion s, join t s, glu t eu s, t r och a n t er s, a n d kn ees h a ve
been iden t ified in pa t ien t s su ffer in g fr om fibr om ya l-
gia (F ig. 12.15). Pa in m u st be pr esen t in 12 of t h e 18
t en der poin t sit es for dia gn osis. 7 Som e people wit h
fibr om ya lgia develop t r igger poin t s or r opy ba n ds oc-
cu r r in g t h r ou gh ou t t h e body. Th e t r igger poin t s in -
du ce r efer r ed pa in t o ot h er pa r t s of t h e body, wh ich
is t h ou gh t t o be ca u sed by pr essu r e on blood vessels
a n d n er ves by fibr ou s ba n ds ca u sin g t igh t en in g of
m y o a s c ia (ou t er m em br a n e of m u scle t issu e).
TREATMENT
Tr ea t m en t of fibr om ya lgia is focu sed on sym pt om
m a n a gem en t , a n d it in clu des bot h n on ph a r m a co-
logic a n d ph a r m a cologic opt ion s.8 Cogn it ive beh a v-
ior a l t h er a py, cou pled wit h st r ess r edu ct ion m et h ods
a n d m edica t ion t o pr om ot e sleep, a r e t h e m ost ef-
fect ive t r ea t m en t r egim en s. Applica t ion of h ea t a n d
cold, u lt r a sou n d, a n d deep m a ssa ge m a y pr ovide
t em por a r y r elief of sym pt om s. Gen t le exer cise is
Oc c iput
(S uboccipita l
mus cle ins e rtions )
Trape zius
(Midpoint of the
uppe r borde r)
S upras pinatus
(Above the me dia l
borde r of the
s ca pula r s pine )
Glute al
(Uppe r oute r
qua dra nts of
buttocks )
Gre ate r tro c hante r
(Lowe r oute r
qua dra nts of
buttocks )

cr it ica l t o m a in t a in in g
m u scle fit n ess. St r et ch - F R O M T H E L AB
in g a n d exer cise pr om ot e
m u scle st r en gt h a n d fa - No diagnostic tests exist to confirm fibromyalgia. It is a diagnosis of exclusion, meaning that
cilit a t e sleep. Alt er n a t ive tests to confirm other likely diagnoses (including hypothyroidism or hyperparathyroidism)
t r ea t m en t opt ion s m a y rule out other possibilities, leaving fibromyalgia as the most likely diagnosis.
in clu de a cu pu n ct u r e, bio-
feedba ck, yoga , h ypn osis,
or ot h er r ela xa t ion t ech n iqu es.
Tr ea t m en t wit h a n a lgesics, a n t idepr essa n t s,
a n t icon vu lsa n t s a n d m u scle r ela xa n t s a r e t h e
m a in st a ys of ph a r m a cologic m a n a gem en t of fi-
br om ya lgia .5 Tr icyclic a n t idepr essa n t s (e.g., a m i-
t r ipt ylin e, cycloben za pr in e) a r e u sed a s fir st -lin e
t h er a py t o m a n a ge sym pt om s. Medica t ion s t h a t
block ser ot on in n or epin eph r in e (SNRI) r eu pt a ke
h a ve a lso dem on st r a t ed effect iven ess for r elief of
ph ysica l a n d em ot ion a l sym pt om s. An t iseizu r e m ed-
ica t ion s (e.g., ga ba pen t in , pr ega ba lin ) h a ve been
sh own t o h ave pa in -r elievin g effect s, r edu cin g se-
ver it y of st iffn ess a n d join t discom for t . Non st er oida l
a n t i-in fla m m a t or y m edica t ion s m a y h elp r edu ce dis-
com for t , pa r t icu la r ly wh en com bin ed wit h a t r icyclic
a n t idepr essa n t .
Stop and Consider
Why aren’t anti-inflammatory medications used
as the primary pharmacologic treatment of
fibromyalgia?
Migraine Headache
Migr a in es a r e ch a r a ct er ized by n eu r ologic dysfu n c-
t ion in volvin g im pa ir m en t of cor t ica l, su bcor t ica l,
a n d br a in st em a r ea s lea din g t o a lt er ed a u t on om ic, a f-
fect ive, cogn it ive, a n d sen sor y fu n ct ion s.9 Migr a in es
a r e r ecu r r en t , m oder a t e t o sever e h ea da ch es t h a t
la st 1 t o 2 days a n d a r e oft en a ssocia t ed wit h n a u -
sea , vom it in g, a n d sen sit ivit y t o n oise a n d ligh t . Th e
m a n ifest a t ion s of m igr a in e m ay be sever e, r esu lt in g
in sign ifica n t loss of pr odu ct ivit y a n d qu a lit y of life.
Migr a in e is r epor t ed t o be m or e com m on in wom en .
PATHOPHYSIOLOGY
Th e pr ecise ca u se of m igr a in es is n ot clea r. Th e ge-
n et ic fou n da t ion of m igr a in e is a cu r r en t focu s of
in vest iga t ion of t h is com plex con dit ion . Migr a in es
a r e oft en in it ia t ed wit h a pr odr om e, ea r ly even t s
t h a t pr ecede t h e cla ssica l m igr a in e sym pt om s in -
clu din g a u r a a n d h ea da ch e. A cu r r en t ph en om en on
t h a t m a y expla in t h e pa t h oph ysiology of m igr a in e is
cor t ica l spr ea din g depr ession , a wa ve of depola r iza -
t ion t h a t spr ea ds a cr oss t h e cer ebr a l cor t ex, lea din g
t o m igr a in e a u r a .9 Act iva t ion of n ocicept or s in t h e
C lin ic a l Mo d e ls 307
m en in ges a n d t r a n sm ission a lon g pa in fiber s in t h e
t r igem in ova scu la r pa t h wa y t o t a r get s in t h e br a in
dist in gu ish es pa in or igin a t in g in t h e cr a n ia l r egion
fr om h ea da ch es st im u la t ed by ext er n a l even t s su ch
a s st r ess a n d t en sion . Over t im e, t h e n eu r on s becom e
sen sit ized t o st im u la t ion , con t r ibu t in g t o t h e t r a n s-
for m a t ion of episodic t o ch r on ic m igr a in es. Com plex
n eu r ologic a n d bioch em ica l even t s m a y in it ia t e clin -
ica l sym pt om s. P r im a r y fa ct or s im plica t ed in m i-
gr a in e pa t h oph ysiology in clu de ser ot on in , ca lcit on in
gen e-r ela t ed pept ide (CGRP ). Decr ea sed ser ot on in
levels m a y pr ecipit a t e t h e r elea se of ch em ica l m edi-
a t or s fr om t h e t r igem in a l n er ve, a lt er in g blood ves-
sel fu n ct ion .
CLINICAL MANIFESTATIONS
Migr a in es t ypica lly h a ve fou r ph a ses, ea ch wit h dis-
t in ct ive clin ica l m a n ifest a t ion s. Migr a in e ph a ses
in clu de pr odr om e, a u r a , h ea da ch e a n d post dr om e.
Affect ive sym pt om s (e.g., m ood ch a n ges), food cr a v-
in gs, con st ipa t ion , n eck st iffn ess a n d ya wn in g ch a r-
a ct er ize t h e pr odr om e, occu r r in g 24 t o 48 h ou r s
befor e h ea da ch e. Addit ion a l com m on m a n ifest a t ion s
of pr odr om e in clu de:
● In cr ea sed en er gy
● Sweet cr a vin gs
● Fa t igu e
● Ir r it a bilit y
Cla ssica l or u n com m on m igr a in es a ffect in g a ppr ox-
im a t ely 15% of in dividu a ls in clu de a u r a a ppr ox-
im a t ely 15 t o 30 m in u t es befor e t h e on set of t h e
m igr a in e. Migr a in e a u r a in clu des sh or t -du r a t ion ,
foca l n eu r ologic even t s in clu din g visu a l, a u dit or y,
som a t osen sor y, or m ot or sym pt om s. Th e ch a r a ct er-
ist ics of m igr a in e h ea da ch e pa in a r e descr ibed a s
u n ila t er a l, pu lsin g, a n d t h r obbin g. Na u sea , vom it -
in g, a n d ph ot osen sit ivit y a r e oft en a ssocia t ed wit h
in cr ea sin g m igr a in e h ea da ch e sever it y. Wit h r eso-
lu t ion of m igr a in e h ea da ch e, t h e post dr om e per iod
begin s. Du r in g t h is per iod, h ea d m ovem en t m a y
pr ecipit a t e t h e on set of pa in in t h e a r ea pr eviou sly
exper ien ced du r in g m igr a in e h ea da ch e. Ot h er sym p-
t om s in clu de fa t igu e a n d posit ive em ot ion a l feelin gs.
Loss of pr odu ct ivit y a n d r edu ct ion in wor k a n d lei-
su r e t im e m a y r esu lt .
308 C h a p t e r 12: Alt er ed Som a t ic a n d Specia l Sen sor y F u n ct ion
DIAGNOSTIC CRITERIA
Migr a in es a r e oft en dia gn osed ba sed on a t h or ou gh
r eview of h ist or y a n d ph ysica l exa m in a t ion . If h ea d-
a ch es develop a cu t ely, ot h er t est s, su ch a s com pu t ed
t om ogr a ph y or m a gn et ic r eson a n ce im a gin g sca n ,
m a y be don e t o r u le ou t ot h er pa t h ology su ch a s m en -
in git is, t u m or, or in cr ea sed in t r a cr a n ia l pr essu r e.
Th e dia gn ost ic cr it er ia for m igr a in e h ea da ch e wit h -
ou t a u r a in clu des a t lea st five m igr a in e h ea da ch e
episodes m eet in g ea ch of t h e followin g cr it er ia 10 :
● H ea da ch e of 4 t o 72 h ou r s du r a t ion (u n t r ea t ed or
t r ea t m en t r esist a n t )
● H ea da ch e ch a r a ct er ist ics of lea st t wo of t h e
followin g:
■ Un ila t er a l loca t ion
■ P u lsa t in g qu a lit y
■ Moder a t e or sever e in t en sit y
■ Associa t ed wit h r ou t in e ph ysica l a ct ivit y
● H ea da ch e a ssocia t ed wit h a t lea st on e of t h e
followin g:
■ Na u sea , vom it in g, or bot h
■ Sen sit ivit y t o ligh t or sou n d
TREATMENT
Tr ea t m en t of m igr a in e h ea da ch e in clu des n on ph a r-
m a cologic a n d ph a r m a cologic m ea su r es for pr even -
t ion a n d t r ea t m en t of exist in g pa in . In su scept ible
people, m igr a in es a r e oft en disa blin g a n d ca n be
t r igger ed by a va r iet y of fa ct or s, in clu din g h or m on a l
ch a n ges, a n xiet y, st r ess, a n d la ck of food or sleep.
P r even t ion m a y be in dica t ed wh en a n in dividu a l:
● E xper ien ces t wo or m or e m igr a in es ea ch m on t h
● Uses pa in -r elievin g m edica t ion s m or e t h a n t wo
t im es a week
● Does n ot get r elief fr om a n a lgesic t r ea t m en t s
● H a s u n com m on m igr a in es
Non ph a r m a cologic st r a t egies effect ive in pr even t -
in g m igr a in es in clu ded a voida n ce of t r igger s, r egu -
la r exer cise, sm okin g cessa t ion , a n d st a biliza t ion of
h or m on e levels wit h or a l con t r a cept ives or h or m on e
r epla cem en t t h er a py.
P h a r m a cologic m a n a gem en t for m igr a in e h ea d-
a ch es in clu des sim ple a n a lgesics, t r ipt a n s, a n d er-
got s.11 P r odr om e or a u r a , if pr esen t , sign a ls t h e n eed
for pr om pt a n d ea r ly t r ea t m en t . Acu t e t r ea t m en t is
in it ia t ed du r in g m igr a in e t o r elieve sym pt om s a n d
in clu des sim ple a n a lgesics (e.g., a cet a m in oph en ,
n on st er oida l a n t i-in fla m m a t or y dr u gs [NSAIDs],
a spir in ) a s t h e fir st -lin e t h er a py for m ild m igr a in e
h ea da ch e.12 If sym pt om s a r e u n r elieved a n d a r e m od-
er a t e t o sever e, t r ipt a n s a r e r ecom m en ded. Tr ipt a n s
m im ic t h e a ct ion of ser ot on in , pr om ot in g con st r ict ion
of blood vessels a n d in t er r u pt ion of pa in pa t h wa ys.
Th e a dva n t a ge of t r ipt a n s is t h e r a pid on set of a c-
t ion (wit h in 15 m in u t es in t h e in ject a ble for m ) a n d
t h e h igh r a t e of effect iven ess. Tr ea t m en t effect ive-
n ess is in cr ea sed wh en in it ia t ed ea r ly pr ior t o t h e
on set of m oder a t e t o sever e sym pt om s. An t iem et ic
m edica t ion s m a y a lso be n eeded t o t r ea t n a u sea a n d
vom it in g a ssocia t ed wit h m igr a in e h ea da ch e. E r got s
(e.g., dih ydr oer got a m in e, DH E -45) m a y be u sed t o
a bor t m igr a in e, wor kin g t h r ou gh ser ot on in r ecept or s
sim ila r t o t h e t r ipt a n s. Novel ph a r m a cologic t r ea t -
m en t s in clu de t h e u se of CGRP r ecept or a n t a gon ist s
for t r ea t m en t of a cu t e m igr a in e. 13 P h a r m a cologic
pr even t ion for in dividu a ls wit h m igr a in e h ea da ch es
in clu des a n t icon vu lsa n t t h er a py (e.g., t opir a m a t e).
Stop and Consider
What is the most likely mechanism for the
prevention of migraines with antiseizure
medications?
Otitis Media
Ot it is m edia is a com monly dia gnosed condit ion in
children. A com plet e histor y of illness combined wit h
physical exam ina t ion is impor ta nt in determ ining an
a ccura te diagnosis. Otitis media is a condition com-
m only dia gnosed in infa nts a nd young children, a l-
t hough a dults ca n a lso be affected. Accor ding t o the
Na tiona l Inst it ute of Dea fness and Other Com muni-
cat ion Disorder s, 75% of childr en experience a t lea st
one episode of otitis media by their t hird birt hday. The
high pr eva lence of otitis media is estima ted to cost a p-
proxim at ely $5 billion per yea r in t he Unit ed Sta tes.
PATHOPHYSIOLOGY
Acu t e ot it is m edia (AOM), in fect ion in t h e m iddle
ea r, is t h e m ost fr equ en t dia gn osis in febr ile ch ildr en
in t h e Un it ed St a t es a n d t h e wor ld.14 Most a n t ibi-
ot ic a gen t s for ch ildr en a r e pr escr ibed for AOM. Th e
cou r se of in fect ion is a ssocia t ed wit h a pr ecedin g r e-
spir a t or y in fect ion , in fla m m a t ion a n d a ccu m u la t ion
of secr et ion s pr odu ced by t h e m iddle ea r m u cosa . Th is
en vir on m en t pr esen t s a n opt im a l m edium for gr owt h
of u pper a ir way vir u ses a n d ba ct er ia l pa t h ogen s in
t h e m iddle ea r, lea din g t o AOM. Occlu sion of t h e eu -
st a ch ia n t u bes ca u sed by secr et ion s a nd in fla m m a -
t ion pr om ot es developm en t of n ega t ive pr essu r e a n d
ser ou s effu sion in t h e m iddle ea r. Per for a t ion of t h e
t ym pa n ic m em br a n e a n d spr ea d of in fect ion in t o t h e
m a st oid a ir cells a r e t h e m ost fr equ en t com plica t ion s.
AOM is con sider ed r ecu r r en t wh en t h r ee or m or e ep-
isodes occu r over 6 m on t h s or fou r or m or e episodes
occu r over 1 yea r. Ot it is m edia wit h effu sion (OME )
is m or e com m on t h a n AOM a n d is ch a r a ct er ized by
 C lin ic a l Mo d e ls 309

flu id/effu sion in t h e m iddle ea r wit h ou t in fect ion . TREATMENT

OME r esu lt s fr om t h e t r a ppin g of flu id in t h e m iddle
ea r by obst r u ct ion in t h e eu st a ch ia n t u be.
CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s of ot it is m edia in clu de:
● Acu t e ea r pa in
● E n la r ged per ia u r icu la r lym ph n odes
● Rh in or r h ea (r u n n y n ose)
● Fever
● Im pa ir ed h ea r in g
E xa m in a t ion of t h e ea r s u sin g a n ot oscope m a y r e-
vea l gr a y or r ed t ym pa n ic m em br a n e in OME a n d
AOM, r espect ively (Fig. 12.16). F lu id m a y be visible
beh in d t h e t ym pa n ic m em br a n e, wh ich m a y a lso
a ppea r t o be bu lgin g beca u se of in cr ea sed flu id vol-
u m e. Wh it e a r ea s on t h e t ym pa n ic m em br a n e m a y
be sca r r in g fr om pr eviou s per for a t ion s. Disch a r ge in
t h e ea r ca n a l in dica t es possible a cu t e per for a t ion .
DIAGNOSTIC CRITERIA
Dia gn osis of ot it is m edia is u su a lly m a de ba sed on
t h e h ist or y of sym pt om s a n d clin ica l fin din gs, pa r-
t icu la r ly t h ose iden t ified wit h ot oscopic exa m in a -
t ion . It is im por t a n t t o dist in gu ish OME fr om AOM
for a ppr opr ia t e t r ea t m en t . Cr it er ia for dia gn osis of
AOM in clu de 14 :
● Moder a t e t o sever e bu lgin g of t ym pa n ic m em br a n e
● Mild bu lgin g of t ym pa n ic m em br a n e a n d n ew on -
set ea r pa in or er yt h em a of t ym pa n ic m em br a n e
● New on set ot or r h ea (disch a r ge in t h e ea r ca n a l)
Ma n a gem en t of AOM in clu des m a n a gem en t of
pa in a n d t r ea t m en t of in fect ion . 14 Con cer n s a bou t
in cr ea sin g r a t es of a n t ibiot ic r esist a n ce a n d la ck
of sou n d eviden ce for a n t ibiot ic effect iven ess h a ve
en cou r a ged a ca r efu l look a t pr a ct ice gu idelin es
u sed in t h e t r ea t m en t of AOM. As OME is n ot a n
in fect iou s pr ocess, n o a n t ibiot ic t r ea t m en t is r ec-
om m en ded t h ou gh m a n a gem en t of pa in m a y be
in dica t ed. Accor din g t o clin ica l pr a ct ice gu idelin es
pu blish ed by t h e Am er ica n Aca dem y of Pedia t r ics, 14
t h e followin g r ecom m en da t ion s for AOM t r ea t m en t
in clu de:
● An t ibiot ic t h er a py in ch ildr en ≥ 6 m on t h s of a ge
wit h sever e sign s or sym pt om s
■ Moder a t e or sever e ea r pa in for a t lea st 48
h ou r s
■ Fever wit h t em per a t u r e ≥ 39°C (102.2°F )
● An t ibiot ic t h er a py in ch ildr en ≥ 24 m on t h s of a ge
wit h ou t sever e sign s or sym pt om s
■ Mild ea r pa in for a t lea st 48 h ou r s
■ Tem per a t u r e < 39°C (102.2°F )
● Opt ion a l a n t ibiot ic t h er a py or obser va t ion ba sed
on join t pa r en t a l/ca r egiver decision in ch ildr en
bet ween 6 a n d 23 m on t h s of a ge wit h ou t sever e
sign s or sym pt om s
● Obser va t ion in ch ildr en bet ween ≥ 23 m on t h s of
a ge wit h ou t sever e sign s or sym pt om s
F ir st -lin e a n t ibiot ic t h er a py in clu des a m oxicillin if
a n t ibiot ics a r e n ecessa r y a n d if n ot pr eviou sly u sed
in t h e pa st 30 da ys. Alt er n a t ive a n t ibiot ic t ype is r ec-
om m en ded if t h e in fect ion is u n r espon sive t o in it ia l
a n t ibiot ic t h er a py (a ft er 48 t o 72 h ou r s).

A Otoscopic view B C

Acute otitis media Perforation Otitis media with effusion

Infected uid in middle ear Ahole in the tympanic membrane caused by chronic negative Relatively asymptomatic uid in the middle ear
Rapid onset and short duration middle ear pressure, in ammation, or trauma May be acute, subacute, or chronic in nature

Figure 12.16. Classification of otitis media. A: Otoscopic examination in acute otitis media reveals infected fluid in the
middle ear and a red tympanic membrane. B: Otitis media with effusion reveals middle ear fluid with a gray tympanic
membrane. C: Tympanic membrane perforation reveals a hole in the tympanic membrane with possible fluid in the ear ca-
nal. (Courtesy Anatomical Chart Company.)
310 C h a p t e r 12: Alt er ed Som a t ic a n d Specia l Sen sor y F u n ct ion

Ménière Disease t h e pr esen ce of sen sor in eu r a l h ea r in g loss. Au dit or y

br a in st em r espon ses t h a t m ea su r e elect r ica l a ct ivit y
Mén ièr e disea se is a con dit ion of a lt er ed vest ibu la r of t h e a u dit or y n er ve a n d t h e br a in st em h elp t o iden -
fu n ct ion . Th e pa t h ology is t a r get ed t o t h e la byr in t h t ify t h e t ype of h ea r in g loss. E lect r ococh leogr a ph y, a
com pon en t of t h e in n er ea r, ca u sin g ver t igo, t in n i- t est t h a t r ecor ds sou n d-in du ced elect r ica l a ct ivit y in
t u s, h ea r in g loss, pr essu r e, a n d pa in . Appr oxim a t ely t h e in n er ea r, a ssist s wit h dia gn osis. Videon yst a g-
615,000 in dividu a ls a r e dia gn osed wit h Mén ièr e dis- m ogr a ph y (VNG) det er m in es com m u n ica t ion be-
ea se in t h e Un it ed St a t es. Wor ldwide, t h e in ciden ce t ween ba la n ce-r ela t ed sen sor s a n d h ea d m ovem en t
of Mén ièr e disea se is est im a t ed t o r a n ge fr om 0.5 t o on eye con t r ol.
100 per 1,000, depen den t on t h e dia gn ost ic cr it er ia
a pplied. Age of on set is u su a lly bet ween 20 a n d 60 TREATMENT
yea r s,15 a n d t h e con dit ion is equ a lly com m on be-
t ween gen der s. Tr ea t m en t of Mén ièr e disea se is sym pt om a t ic. Reg-
u la t ion of body flu id t h r ou gh r edu ct ion in sa lt in -
t a ke or diu r et ic t h er a py, sm okin g cessa t ion , a n d
PATHOPHYSIOLOGY st r ess r edu ct ion m a y r edu ce sym pt om occu r r en ce.
Th e u n der lyin g et iology of Mén ièr e disea se is swell- An t iem et ics t o pr even t n a u sea a n d dr u gs t o r edu ce
in g of t h e m em br a n ou s la byr in t h in t h e coch lea a n d ver t igo a r e t h e m a in ph a r m a cologic t r ea t m en t s.
vest ibu la r syst em of t h e in n er ea r. Th e la byr in t h is Tr ea t m en t for a cu t e sym pt om s in clu des vest ibu la r
com posed of t wo pa r t s: t h e body a n d m em br a n ou s su ppr essa n t s. Bet a h ist in e, a h ist a m in e a n a log, is
com pon en t s. Th e in cr ea sed volu m e of en dolym ph t h e fir st -lin e t r ea t m en t in t h e r edu ct ion of t h e fr e-
(en dolym ph h ydr ops) ca u ses dila t ion of t h e m em - qu en cy a n d sever it y of sym pt om s. Dest r u ct ive pr o-
br a n ou s la byr in t h , a lt er in g h ea r in g a n d ba la n ce. cedu r es m a y be a t t em pt ed wh en m edica l t h er a py is
Mild r u pt u r e of t h e m em br a n ou s la byr in t h r edu ces n ot effect ive. Dir ect a dm in ist r a t ion of t h e a n t ibiot ic
sym pt om s. On set a n d du r a t ion of sym pt om s a r e u n - gen t a m icin in t o t h e m iddle ea r pr om ot es ot ot oxicit y,
pr edict a ble wit h debilit a t in g effect s. Sym pt om s ca n r edu cin g ver t igo t h ou gh loss of h ea r in g m a y r esu lt .
occu r a s oft en a s da ily or a s in fr equ en t ly a s yea r ly. Vest ibu la r n eu r ect om y, sever in g of t h e vest ibu la r
n er ve, a lso h elps r edu ce ver t igo wit h n o dir ect effect
on h ea r in g. La byr in t h ect om y, or su r gica l r em ova l of
CLINICAL MANIFESTATIONS t h e la byr in t h , m a y h elp r edu ce ver t igo; h owever, loss
Ma n ifest a t ion s of Mén ièr e disea se a r e r ela t ed t o of h ea r in g m a y r esu lt . Non dest r u ct ive t h er a pies in -
vest ibu la r dysfu n ct ion , oft en u n ila t er a l. Sever it y of clu de en dolym ph a t ic sa c decom pr ession or sh u n t in g,
sym pt om s ca n va r y fr om m ild t o disa blin g. Ver t igo, a design ed t o im pr ove dr a in a ge of en dolym ph .
feelin g of spin n in g, is a h a llm a r k of Mén ièr e disea se
a n d is oft en a ssocia t ed wit h n a u sea a n d vom it in g.
Nyst a gm u s a n d t in n it u s m a y a lso develop. A feelin g
of fu lln ess a n d pa in in t h e ea r a n d sen sor in eu r a l Macular Degeneration
h ea r in g loss m a y a lso com plica t e t h e con dit ion .
Degen er a t ion of t h e cen t r a l por t ion of t h e r et in a l
m a cu la , t h e fovea , is t h e cen t r a l pa t h ology of m a c-
DIAGNOSTIC CRITERIA u la r degen er a t ion (MD). Fa ct or s con t r ibu t in g t o t h e
Th e pr im a r y com pla in t of episodic dizzin ess pr om pt s developm en t of MD in clu de a gin g, in fla m m a t ion ,
eva lu a t ion for Mén ièr e disea se. H ea r in g a n d ba l- in ju r y, a n d in fect ion . Gen e–gen e a n d gen e–en vi-
a n ce a ssessm en t a r e im por t a n t t o t h e dia gn osis of r on m en t in t er a ct ion s in flu en ce su scept ibilit y of
16
Mén ièr e disea se. Au dit or y exa m in a t ion ca n in dica t e MD. Accor din g t o t h e Am er ica n Ma cu la r Degen -
er a t ion Fou n da t ion , MD
is t h e lea din g ca u se of
blin dn ess a m on g older
Am er ica n s in t h e Un it ed
F R O M T H E L AB
St a t es. Over a ll, the
Electronystagmography (ENG) is a group of tests that determine vestibular function based pr eva len ce a m on g t h e
on eye movement. Nystagmus and other eye movements provide an evaluation of some brain US popu la t ion is 9.2%.17
functions. Eye movements are measured by small electrodes or are recorded by infrared Age-specific pr eva len ce
video. Eye movements are evaluated as the eyes follow a target, when the head is positioned r a t es a r e com pa r a ble
in different directions and during the caloric test. The caloric test uses warm and cool water bet ween r a ces u n t il a ge
or air irrigation to induce nystagmus, diagnostic of Ménière disease. 75, wh en t h e pr eva len ce
in cr ea ses sign ifica n t ly

Drusen
Optic disk
Macula
Hardening
and obstruction
of retinal arteries
Figure 12.17. Retinal changes in macular degeneration.
(Courtesy Anatomical Chart Company.)
a m on g Wh it e in dividu a ls, a ccor din g t o t h e Na t ion a l
E ye In st it u t e a n d P r even t Blin dn ess Am er ica .
PATHOPHYSIOLOGY
MD ca n be ca t egor ized in t o t wo for m s: d r y (a t r o -
p h ic ) MD a n d w e t (e x u d a t iv e ) MD . Most ca ses of
MD a r e of t h e dr y va r iet y, wit h r et in a l det er ior a t ion
r esu lt in g fr om deposit ion of d r u s e n , sm a ll yellow de-
posit s, u n der t h e m a cu la n ext t o t h e ba sem en t m em -
br a n e of t h e r et in a l pigm en t epit h eliu m (Fig. 12.17).
Dr u sen t h in s a n d dr ies ou t t h e m a cu la , pr om ot in g
loss of fu n ct ion . Loss of vision is cor r ela t ed wit h in -
cr ea ses in dr u sen deposit s.
Wet or exu da t ive MD is ca u sed by t h e for m a t ion
of n ew blood vessels u n der t h e r et in a a n d m a cu la ,
kn own a s c h o r o id a l n e o v a s c u la r iza t io n a n d
ca u ses fa r m or e vision loss t h a n dr y MD. Ch or oida l
n eova scu la r iza t ion m a y be a com pen sa t or y r espon se
t o poor per fu sion of t h e a r t er ies of t h e r et in a beca u se
of obst r u ct ion . Lea ka ge of flu id a n d bleedin g fr om
t h ese n ew vessels a lt er t h e sh a pe of t h e m a cu la , dis-
t or t in g cen t r a l vision . On ce ch or oida l n eova scu la r-
iza t ion occu r s in on e eye, it will likely develop in t h e
ot h er, especia lly wh en t h e r isk fa ct or s of m or e t h a n
five la r ge dr u sen , pigm en t a l clu m pin g, a n d h yper-
t en sion a r e pr esen t . Th e t wo ca t egor ies of ch or oida l
n eova scu la r iza t ion in clu de cla ssica l a n d occu lt .
1. Cla ssica l
a . Well defin ed
b . Associa t ed wit h m or e lea ka ge t h a n occu lt
c . Vision r a n ges bet ween 20/250 a n d 20/800
2. Occu lt
a . Poor ly defin ed
b . Associa t ed wit h less lea ka ge t h a n cla ssica l
c . Vision r a n ges bet ween 20/80 a n d 20/200
CLINICAL MANIFESTATIONS
Dr y, a t r oph ic MD is ch a r a ct er ized by flu ct u a t in g vi-
sion , difficu lt y r ea din g, a n d lim it ed n igh t vision . Th e
C lin ic a l Mo d e ls 311
pr ogr ession of sym pt om s in t h e dr y for m of MD is
u su a lly slow. In wet , exu da t ive MD, vision loss m a y
be r a pid a n d sever e. E a r ly sym pt om s a r e n ot a lwa ys
a ppa r en t , a lt h ou gh som e a ffect ed in dividu a ls m a y
r epor t a da r k cen t r a l spot . Con sequ en ces of MD in -
clu de dist or t ion of cen t r a l vision ; decr ea sed a bilit y
t o r ea d, r ecogn ize fa ces or color s, or dr ive ca r s; a n d
blin dn ess.
Risk fa ct or s for developm en t of MD in clu de 18 :
1. Age older t h a n 50 yea r s
2. Wh it e r a ce
3. Sm okin g
4. Diet low in a n t ioxida n t s
5. Su n exposu r e
DIAGNOSTIC CRITERIA
Regu la r eye exa m in a t ion s by a n oph t h a lm ologist or
a n opt om et r ist a r e im por t a n t t o iden t ify MD ea r ly.
An exa m in a t ion wit h a n oph t h a lm oscope ca n det er-
m in e if t h e ch a r a ct er ist ic ch a n ges a ssocia t ed wit h
MD a r e pr esen t . Beca u se sym pt om s a r e n ot a lwa ys
a ppa r en t , a t h or ou gh eye exa m in a t ion , in clu din g
dila t ion of t h e eyes for visu a liza t ion of t h e r et in a
a n d m a cu la , is n ecessa r y in a t -r isk in dividu a ls, es-
pecia lly older a du lt s. Dila t ion of t h e eyes a n d visu -
a liza t ion of t h e r et in a a llow det ect ion of lea ka ge,
bu lgin g m a cu la , a n d dr u sen deposit ion . Th is exa m -
in a t ion com pon en t sh ou ld com plem en t t h e r ou t in e
scr een in g eye exa m in a t ion . If MD is su spect ed, fu r-
t h er eva lu a t ion m a y in clu de:
● Am sler ch a r t eva lu a t ion (see F r om t h e La b)
■ Uses a gr id (10 × 10 cm ) con t a in in g 20.5-m m
squ a r es t o a side, wit h wh it e lin es on a bla ck
ba ckgr ou n d con t a in in g a cen t r a l bla ck spot
■ E va lu a t es ch a n ges in vision con sist en t wit h
pr ogr essive MD
● F lu or escein a n giogr a ph y
■ Color ed dye is in ject ed in t o a per iph er a l vein
■ P ict u r es of t h e r et in a a r e t a ken a s dye pa sses
t h r ou gh it t o det ect t h e pr esen ce of a bn or m a l
flu id or pr ogr essive ch a n ges
● Opt ica l coh er en ce t om ogr a ph y
■ Im a gin g t ech n iqu e u sed t o obt a in det a iled r et -
in a l im a ges
TREATMENT
Th er e a r e cu r r en t ly n o t r ea t m en t opt ion s for dr y
MD. For t u n a t ely, dr y MD is a slowly pr ogr essive
con dit ion . Tr ea t m en t of wet MD is t a r get ed t owa r d
lim it in g pr ogr ession of r et in a l da m a ge a n d loss of
vision . In wet MD, t h e goa l of t h er a py is t o r edu ce
ch or oida l n eova scu la r iza t ion , r edu cin g lesion size
a n d lea ka ge. In t r a ocu la r u se of dr u gs t h a t block
va scu la r en dot h elia l gr owt h fa ct or (VE GF ) is t h e
312 C h a p t e r 12: Alt er ed Som a t ic a n d Specia l Sen sor y F u n ct ion
pr im a r y ph a r m a cologic t r ea t m en t effect ive in block-
in g t h e for m a t ion of n ew blood vessels.19 La ser or
con ven t ion a l ph ot ocoa gu la t ion ca n be u sed t o t a r get
n eova scu la r iza t ion , t h ou gh r edu ct ion in vision is a
pot en t ia l r isk. P h ot odyn a m ic t h er a py in volves ir r a -
dia t ion of r et in a l n eova scu la r iza t ion t h r ou gh a ct iva -
t ion of a n in ject ed dr u g by la ser.
Stop and Consider
Why do people with MD have difficulty with
night vision and color differentiation?
Glaucoma
Gla u com a is t h e secon d lea din g ca u se of blin dn ess
a m on g t h e elder ly a n d t h e lea din g ca u se of pr even t -
a ble blin dn ess in t h e Un it ed St a t es. Accor din g t o
t h e Na t ion a l E ye In st it u t e a n d P r even t Blin dn ess
Am er ica , 2.2 m illion Am er ica n s over a ge 40 (a p-
pr oxim a t ely 1.9% of t h e popu la t ion ) a r e a ffect ed by
gla u com a . P r eva len ce is in cr ea sed a m on g Bla cks,
H ispa n ics, a n d t h e elder ly. Gen der differ en ces a r e
eviden t —wom en a r e a ffect ed a t in cr ea sed pr ev-
a len ce r a t es u p t h r ou gh t h e a ge of 65 yea r s, a ft er
wh ich t im e r a t es becom e com pa r a ble. P r eva len ce
r a t e for Wh it e fem a les a ged 65 t o 69 yea r s is 1.6%,
com pa r ed wit h a r a t e of 4.8% a m on g Bla ck fem a les
a t t h e sa m e a ge. It is oft en silen t , wit h da m a ge r e-
su lt in g in t h e a bsen ce of wa r n in g sign s.
PATHOPHYSIOLOGY
Gla u com a r esu lt s in blin dn ess, t h e r esu lt of pr ogr es-
sive n eu r odegen er a t ion of ga n glion cells.20 Vision
loss is t h e r esu lt of da m a ge t o t h e opt ic n er ve. In -
cr ea sed in t r a ocu la r pr essu r e (IOP ) is a r isk fa ct or,
a lt h ou gh gla u com a m a y be pr esen t despit e n or m a l
IOP. P r im a r y open -a n gle gla u com a is t h e m ost com -
m on for m of gla u com a , t ypica lly a ssocia t ed wit h in -
cr ea sed IOP du e t o in cr ea sed a qu eou s pr odu ct ion
a n d decr ea sed ou t flow of a qu eou s h u m or (F ig. 12.18).
An gle r efer s t o t h e poin t wh er e t h e ir is a n d cor n ea
m eet . A ch r on ic disea se, pr im a r y open -a n gle gla u -
com a is likely h er edit a r y. Th e t r a becu la r n et wor k
dr a in in g t h e a qu eou s h u m or becom es obst r u ct ed or
“clogged,” ca u sin g a n in cr ea se in IOP in m ost ca ses.
IOP of 22 m m H g or m or e is con sider ed a bn or m a l,
exceedin g t h e expect ed n or m a l pr essu r e r a n ge of
14 t o 16 m m H g.
An gle-closu r e gla u com a , a lso kn own a s a cu t e or
n a r r ow a n gle, is ch a r a ct er ized by a r a pid r ise in IOP
ca u sed by blocka ge of a qu eou s h u m or dr a in a ge du e
t o n a r r owin g or closu r e of t h e a n t er ior ch a m ber a n -
gle. Bu ildu p of flu id a n d pr essu r e pr om ot es fu r t h er
n a r r owin g of t h e a n gle. Com plet e closu r e is a n a cu t e
Obs truction dis ta l to
a nte rior cha mbe r a ngle
Figure 12.18. Open-angle glaucoma. Obstruction of the
trabecular network leads to increased intraocular pressure.
cr isis kn own a s a cu t e gla u com a . Th is for m is m or e
com m on in people of Asia n descen t a n d in people
wit h h yper opia . An gle-closu r e gla u com a is a n in h er-
it a ble t r a it .
Nor m a l- (or low-) t en sion gla u com a is ch a r a ct er-
ized by n or m a l IOP a n d pr ogr essive opt ica l n er ve
da m a ge wit h loss of visu a l fields. Appr oxim a t ely on e-
t h ir d of in dividu a ls wit h open -a n gle gla u com a h a ve
n or m a l IOP. Th e u n der lyin g pa t h ology is r ela t ed t o
poor blood flow t o t h e opt ic n er ve or in cr ea sed sen -
sit ivit y of t h e r et in a t o ocu la r pr essu r e (Fig. 12.19).
Ma n a gem en t is focu sed on lower in g ocu la r pr essu r e
t o below “n or m a l” t o r edu ce r et in a l da m a ge.
CLINICAL MANIFESTATIONS
Risk fa ct or s in t h e developm en t of gla u com a in clu de:
1. Age
2. Bla ck r a ce
3. Dia bet es
4. E ye t r a u m a
5. Lon g-t er m st er oid u se
In pr im a r y open -a n gle gla u com a , t h e cor n ea a da pt s
t o t h e in cr ea sin g pr essu r e wit h ou t swellin g, t h er eby
n ot ca u sin g su bject ive sym pt om s. If u n t r ea t ed,
open -a n gle gla u com a ca n r esu lt in gr a du a l, bu t ir r e-
ver sible, loss of vision . Ma n ifest a t ion s of vision loss
in clu de “blin d spot s” in t h e field of vision . In it ia lly
lim it ed t o t h e per iph er y, cen t r a l vision is soon a f-
fect ed. Th is for m of gla u com a r espon ds well t o ph a r-
m a cologic m a n a gem en t .
An a cu t e episode of a n gle-closu r e gla u com a m a y
be in du ced by in cr ea sed pu pil dila t ion ca u sed by
dr u gs or by bein g in a da r ken ed r oom , su ch a s a m ovie
t h ea t er. Sym pt om s m a y in clu de eye pa in , h ea da ch e,
n a u sea , blu r r ed vision , a n d “r a in bows” a r ou n d ligh t s
a t n igh t . Sca r r in g of t h e t r a becu la r n et wor k m a y r e-
su lt in ch r on ic gla u com a a n d ca t a r a ct s. Da m a ge t o
t h e opt ic n er ve m a y r esu lt in per m a n en t loss of vi-
sion . Su r gica l m a n a gem en t is oft en in dica t ed.
 C lin ic a l Mo d e ls 313

Normal optic disk opt om etr ist s or opht ha lmologists. Com m on scr eening
t ests for gla u com a include:
● Ton om et r y
■ Mea su r e IOP
● Oph t h a lm oscopy
■ Det ect s ch a n ges in t h e opt ic n er ve (cu ppin g,
pa llor, h em or r h a ge) by u sin g a n oph t h a lm o-
Optic disk scope in a fu n du scopic exa m in a t ion
● Visu a l field t est in g
Central retinal artery
and vein ■ Det er m in es da m a ge t o t h e opt ic n er ve
Inferior macular artery ● Con foca l la ser opt ica l coh er en ce
and vein ■ Th r ee-dim en sion a l im a gin g t o det ect cu ppin g
a n d t h ickn ess of t h e r et in a l n er ve
A
TREATMENT
Disk changes
Th e goa l of gla u com a t r ea t m en t is t o lower IOP
t h r ou gh decr ea sed pr odu ct ion a n d in cr ea sed ou t flow
Decreased blood of a qu eou s h u m or. Tr ea t m en t of gla u com a m a y be
supply to retina ph a r m a cologic or su r gica l.
● P h a r m a cologic
Blood vessels ■ Miot ics: in cr ea se t h e ou t flow of flu id
displaced nasally
■ E pin eph r in e-ba sed: in cr ea se t h e ou t flow of flu id
■ Bet a blocker s: decr ea se flu id levels
■ Ca r bon ic a n h ydr a se in h ibit or s: decr ea se flu id
Enlarged physiologic levels
cup ■ Alph a -a dr en er gic a gon ist s: decr ea se flu id levels
■ P r ost a gla n din a n a logs: in cr ea se flu id flow
t h r ou gh secon da r y dr a in a ge
B ● La ser su r ger y
Figure 12.19. Glaucoma-induced changes in the optic ■ Tr a becu lopla st y: cor r ect ion of t h e t r a becu la r
disk ( A) . Increased intraocular pressure reduces blood n et wor k t o pr om ot e flu id ou t flow fr om t h e eye
supply to the retina, leading to “blind spots” in the optic in open -a n gle gla u com a
disk ( B) . ■ Ir idot om y: in cision in t o t h e ir is t o pr om ot e flu id
ou t flow in a n gle-closu r e gla u com a 21
■ Cycloph ot ocoa gu la t ion : cor r ect ion of cilia r y t is-
DIAGNOSTIC CRITERIA su e t o decr ea se t h e pr odu ct ion of flu id
● Con ven t ion a l su r ger y
E a r ly det ect ion of gla u com a m a y pr om ot e effect ive ■ Tr a becu lect om y: su r gica l r em ova l of a sm a ll
t r ea t m en t a n d m a n a gem en t , decr ea sin g a ssocia t ed por t ion of t h e t r a becu la r m esh wor k u n der t h e
loss of visu a l fu n ct ion . E ffor t s t o det er m in e t h e best lid t o cr ea t e n ew dr a in a ge
scr een in g t ype a n d fr equ en cy t o det ect ea r ly disea se
a r e on goin g. Pa t t er n elect r or et in ogr a m (P E RG), Stop and Consider
elect r ic pot en t ia l der ived fr om r et in a l ga n glion cells, What are the implications for older Americans
is u sed t o eva lu a t e IOP lower in g a ft er t opica l t r ea t - who develop glaucoma? What lifestyle changes
m en t in gla u com a pa t ien t s wit h ea r ly visu a l field can they expect to experience?
im pa ir m en t . F u n ct ion of
r et in a l ga n glion cells m a y
be a t lea st pa r t ia lly r e- F R O M T H E L AB
st or ed a ft er IOP r edu ct ion
in ea r ly disea se. Evaluation of the anterior chamber and angle can be accomplished by gonioscopy. Gonios-
Scr eenin g for gla ucom a copy allows direct visualization of these structures via a special lens containing a mirror,
is com plet ed in a t -r isk eliminating the view-obstructing effects of the cornea and sclera. Indications for this eval-
in dividua ls a s a compo- uation include the need to visualize the anterior chamber, determine the angle, and classify
n en t of com pr ehensive vi- glaucoma.
sion scr eening, usua lly by
314 C h a p t e r 12: Alt er ed Som a t ic a n d Specia l Sen sor y F u n ct ion
Retinopathy of Prematurity
Ret in opa t h y of pr em a t u r it y (ROP ) is t h e lea din g
ch ildh ood ca u se of blin dn ess. As t h e n a m e im plies,
in fa n t s bor n pr em a t u r ely h a ve t h e h igh est r isk for
developin g ROP. P r em a t u r e in fa n t s bor n a t or less
t h a n 28 weeks gest a t ion a n d t h ose wit h low bir t h
weigh t of less t h a n 1,250 g (2.75 lb) a r e a t h igh -
est r isk for t h e developm en t of ROP. In t h e Un it ed
St a t es, it is est im a t ed t h a t of t h e 10,000 in fa n t s bor n
wit h a bir t h weigh t of less t h a n 1,250 g, 68% of t h em
will develop ROP, wit h a ppr oxim a t ely on e-t h ir d pr o-
gr essin g t o sever e ROP a n d n on r ever sible loss of
vision .21
PATHOPHYSIOLOGY
Th e r et in a is on e of t h e la st or ga n s t o develop t h e
va scu la r blood su pply. In fet u s, r et in a l developm en t
begin s a t 16 weeks gest a t ion in a low-oxygen in -
t r a u t er in e en vir on m en t a n d con t in u es u n t il bir t h .
Du r in g t h a t per iod, t h e r et in a l blood vessels gr ow
ou t fr om t h e opt ic n er ve t owa r d t h e per iph er y, pr o-
vidin g t h e r et in a wit h essen t ia l oxygen a n d n u -
t r ien t s. By t h e en d of fu ll t er m gest a t ion a t 38 t o
40 weeks of pr egn a n cy, fet a l r et in a l va scu la r iza t ion
is t ypica lly com plet e.
Wh en r et in a l blood vessel gr owt h is pr em a t u r ely
st opped wit h ea r ly deliver y, r et in a l blood vessel
gr owt h is im pa ir ed. F u r t h er r et in a l blood vessel
developm en t m u st n ow occu r in t h e h igh oxygen
ext r a -u t er in e en vir on m en t . As m ost in fa n t s a t r isk
for ROP a lso h a ve r espir a t or y r isks du e t o in a de-
qu a t ely developed lu n gs, su pplem en t a l oxygen is
pr ovided t o a ssu r e a dequ a t e ven t ila t ion a n d oxy-
gen deliver y t o cells a n d t issu es. Th e r esu lt is a r-
r est ed gr owt h of r et in a l blood vessels, t h e fir st ph a se
of ROP.
Th e secon d ph a se of ROP is ch a r a ct er ized by u n -
r egu la t ed gr owt h of r et in a l blood vessels in t o t h e
vit r eou s ca vit y. Th e r elea se of VE GF a n d ot h er a n gio-
gen ic fa ct or s pr om ot es excessive gr owt h of a bn or m a l,
lea ky blood vessels. H em or r h a ge a n d con t r a ct ion of
sca r r ed, fr a gile blood vessels pu lls t h e r et in a a wa y,
lea din g t o r et in a l det a ch m en t a n d vision loss.
Accor din g t o t h e Na t ion a l E ye In st it u t e, ROP is
cla ssified in five st a ges ba sed on disea se sever it y.
Th e st a ges a r e:
● St a ge I: Mildly a bn or m a l blood vessel gr owt h
● St a ge II: Moder a t ely a bn or m a l blood vessel
gr owt h
● St a ge III: Sever ely a bn or m a l blood vessel gr owt h
● St a ge IV: Sever ely a bn or m a l blood vessel gr owt h
a n d pa r t ia lly det a ch ed r et in a
● St a ge V: Com plet ely det a ch ed r et in a
CLINICAL MANIFESTATIONS
Th e iden t ifica t ion of clin ica l m a n ifest a t ion s is ch a l-
len gin g. Am on g in fa n t s a t r isk for ROP, a t h or ou gh
oph t h a lm ologic exa m in a t ion is n ecessa r y t o det ect
t h e su bt le ch a n ges a ssocia t ed wit h ROP. Ma n ifest a -
t ion s of sever e ROP m a y in clu de:
● Leu kocor ia (wh it e pu pils)
● Nyst a gm u s (a bn or m a l eye m ovem en t s)
● St r a bism u s (cr ossed eyes)
● Myopia (sever e n ea r sigh t edn ess)
DIAGNOSIS
Oph t h a lm ologic exa m in a t ion t a r get s r et in a l blood
vessels. In m ild ROP, t h er e m a y be eviden ce of n or-
m a l gr owt h of r et in a l blood vessels. Abn or m a lit ies
of r et in a l blood vessels a r e eviden t in sever e ca ses
of ROP a n d in clu de dila t ion , t or t u osit y a n d ven ou s
con gest ion of r et in a l blood vessels. E viden ce of sca r-
r in g a n d r et in a l det a ch m en t is obser ved in t h e m ost
sever e st a ges of ROP.
TREATMENT
The init ia l lessons a bout prevent ion of ROP ca m e a s
a r esu lt of a n epidem ic t ha t occur red in th e 1940s a nd
1950s. At t ha t tim e, h ospit a l nur series bega n u sing
high concent r a t ions of oxygen t o ma na ge t he ot her
cr it ica l pr oblem s of prem a t ur it y r ela t ed t o im pa ir ed
vent ila t ion. It is now r ecognized t ha t deliver y of h igh
concent r a t ions of oxygen t o prem a t u re infa n t s in-
cr ea ses t he r isk of ROP. Tha t risk for ROP m ust be
ba la nced wit h t he need to oxygena t e oth er cells a nd
t issues in t he prem a t ur e infa nt with im pa ir ed ven-
t ila t ion. Today, oxygen a t ion of pr em a t ur e infa nt s is
m onit or ed t o pr ovide concent r a t ions of oxygen t ha t do
not exceed wha t is necessa r y t o suppor t t he m et a bolic
r equir em ent s of th e infa nt , r educing r isk for ROP.
In st a ges I a n d II, spon t a n eou s r esolu t ion will r e-
su lt in ch ildr en n ot r equ ir in g t r ea t m en t . Ch ildr en
wit h st a ge I a n d st a ge II disea se will likely develop
n or m a l vision . In st a ge III, som e in fa n t s im pr ove
a n d develop n or m a l vision wit h ou t t r ea t m en t . Ot h -
er s wit h a bn or m a l gr owt h pa t t er n s of en la r ged or
t wist ed r et in a l blood vessels r equ ir e t r ea t m en t , t h e
st a ge r efer r ed t o a s st a ge III plu s.
If in it ia t ed ea r ly, r et in a l det a ch m en t m a y be pr e-
ven t ed. Ret in a l det a ch m en t in st a ges IV a n d V r e-
qu ir es im m edia t e t r ea t m en t t o in cr ea se pot en t ia l for
m a xim a l vision . Tr ea t m en t of in fa n t s wit h St a ge III
plu s t h r ou gh st a ge V ROP in volves in va sive su r gica l
in t er ven t ion on t h e eye wit h eit h er la ser t r ea t m en t s
or cr yot h er a py (fr eezin g t r ea t m en t ). La t er st a ges of
ROP m a y r equ ir e ot h er t r ea t m en t s t h a t a r e t a r get ed
t owa r d cor r ect ion of r et in a l det a ch m en t . Applica t ion
 C h a p t e r 12: Alt er ed Som a t ic a n d Specia l Sen sor y F u n ct ion 315

of a scler a l bu ckle, a silicon e ba n d t igh t en ed a r ou n d of con dit ion s a n d pa t h ologies a ssocia t ed wit h sen -
t h e eye, r edu ces t r a ct ion of t h e vit r eou s h u m or on sor y deficit .
t h e r et in a . Th e r et in a ca n r ela x on t o t h e wa ll of t h e
eye. A vit r ect om y, r epla cem en t of t h e vit r eou s h u -
m or wit h sa lin e, m a y a lso be don e in st a ge V disea se. C AS E S T U D Y 12.1
Th e r em ova l of r et in a l sca r t issu e du r in g t h e pr oce-
du r e is don e t o pr om ot e fla t t en in g of t h e r et in a on t o A 75-yea r-old m a n discu sses vision con cer n s wit h h is
t h e eye wa ll. oph t h a lm ologist a t h is yea r ly visit . Aft er a ca r efu l
h ist or y a n d ph ysica l exa m in a t ion , h e is dia gn osed
wit h bila t er a l ca t a r a ct s.
S U MMAR Y 1. Wh a t a r e t h e clin ica l m a n ifest a t ion s a ssocia t ed
wit h ca t a r a ct s?
● Sen sor y syst em s r ela y in for m a t ion fr om t h e pe- 2. Wh a t is t h e u n der lyin g pa t h oph ysiology a ssoci-
r iph er y t o t h e CNS. a t ed wit h ca t a r a ct s?
● Th e sen sa t ion s of pa in , t ou ch , pr essu r e, t em per a - 3. H ow a r e ca t a r a ct s dia gn osed?
t u r e, a n d pr opr iocept ion a r e t r a n sm it t ed by t h e 4. Wh a t a r e t h e possible t r ea t m en t s for ca t a r a ct s?
som a t osen sor y syst em via specia lized r ecept or s 5. Wh a t a r e t h e issu es r ela t ed t o a ppr opr ia t e
a n d pa t h wa ys. m a n a gem en t of ca t a r a ct s?
● Vision r esu lt s fr om ligh t en t r y t h r ou gh t h e pu pil,
st im u la t in g ph ot or ecept or s in t h e r et in a a n d gen - Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r n a l
er a t in g a n er ve im pu lse. Vision pr ocessin g occu r s a r t icle or Web sit e t h a t det a ils ca t a r a ct t o con fir m
in t h e occipit a l lobe of t h e br a in , wh er e visu a l im - you r pr edict ion s.
a ges a r e coor din a t ed.
● H ea r in g r esu lt s fr om con n ect ion s bet ween t h e
t ym pa n ic m em br a n e a n d t h e ossicles, lea din g t o P R AC T I C E E XAM Q U E S T I O N S
t h e t r a n sdu ct ion of t h e m ech a n ica l vibr a t ion , pr o-
du cin g sou n d. 1. Wh ich sen sor y r ecept or is r espon sible for
● Ba la n ce a n d equ ilibr iu m a r e r egu la t ed by t h e im pu lses r esu lt in g in t h e sen sa t ion of t ou ch ?
sem icir cu la r ca n a ls of t h e ea r, gen er a t in g a n a . Mech a n or ecept or
im pu lse, wh ich is t h en t r a n sm it t ed t o t h e cer e- b. Ch em or ecept or
bellu m via t h e vest ibu la r br a n ch of t h e a cou st ic c. Nocicept or
n er ve. d. Osm or ecept or
● Pa in sen sa t ion is gen er a t ed by st im u la t ion of
n ocicept or s, t h e im pu lse t r a n sm it t ed a n d m odu - 2. Wh ich som a t osen sor y n eu r on s a r e r espon sible
la t ed a lon g pa in fiber s u n t il it r ea ch es t h e br a in for com m u n ica t ion of sen sor y in for m a t ion fr om
for pr ocessin g. t h e t h a la m u s t o t h e cer ebr a l cor t ex a n d a r e pr es-
● Alt er a t ion s in vision m a y r esu lt fr om er r or s in in - en t in t h e gr ea t est qu a n t it y?
ju r y or da m a ge t o visu a l st r u ct u r es, er r or s in r e- a . F ir st or der
fr a ct ion , im pa ir ed eye m ovem en t , a n d a lt er a t ion s b. Secon d or der
in pr ot ect ive st r u ct u r es. c. Th ir d or der
● Disor der s of h ea r in g a r e a ffect ed by ou t er, m iddle, d. In t er n eu r on
a n d in n er ea r st r u ct u r a l a n d fu n ct ion a l in t egr it y.
H ea r in g loss m a y be con du ct ive, sen sor in eu r a l, 3. Th e m ost likely sit e of pa t h ology lea din g t o
m ixed, or ca u sed by a cen t r a l a u dit or y pr ocessin g a lt er a t ion s in ba la n ce is:
disor der. a . Th e ou t er ea r
● Pa in ca n be ch a r a ct er ized by loca t ion , qu a lit y, b. Th e m iddle ea r
a n d du r a t ion . Ma n a gem en t of pa in is r eflect ed by c. Th e in n er ea r
pa in ch a r a ct er ist ics a n d is ba sed on r egu la t ion of d. Th e t ym pa n ic m em br a n e
im pu lse in h ibit ion . Opt ion s for pa in t r ea t m en t
in clu de n on ph a r m a cologic a n d ph a r m a cologic 4. Wh ich t ype of pa in in volves a t ypica l pa t t er n of
m ea su r es. im pu lse con du ct ion a n d or igin a t es ou t side of t h e
● Alt er ed sen sor y t r a n sm ission a n d con du ct ion n er vou s syst em ?
h a ve im plica t ion s for a ll body syst em s a n d wh ole a . Neu r ogen ic
body fu n ct ion . A t h or ou gh u n der st a n din g of t h e b. Nocicept ive
con cept s t h a t gover n n eu r on a l t r a n sm ission pr o- c. Neu r opa t h ic
m ot es t h e a bilit y t o a pply kn owledge in a va r iet y d. An a lgesic
316 C h a p t e r 12: Alt er ed Som a t ic a n d Specia l Sen sor y F u n ct ion

5. H yper opia is a con dit ion ch a r a ct er ized by: 13. F ibr om ya lgia is dia gn osed by
a . Alt er a t ion s in eye m ovem en t a . Loss of bon e m a ss
b. In fect ion of t h e con ju n ct iva b. Mu scle in fla m m a t ion
c. In cr ea sed sen sit ivit y t o ligh t c. Weigh t loss
d. E r r or in r efr a ct ion d. Mu lt iple t en der poin t s

6. In fect ion of t h e m iddle ea r is a lso kn own a s: 14. Wh ich of t h e followin g is a sym pt om ?

a . Ma st oidit is a . Pa in
b. Vest ibu lit is b. H ea r in g loss
c. Ot it is m edia c. Loss of pr opr iocept ion
d. La byr in t h it is d. Non e of t h e a bove

7. Sen sor in eu r a l h ea r in g loss is: 15. Wh ich of t h e followin g r epor t s of pa in level

a . Oft en per m a n en t , r esu lt in g fr om disea se, (0 t o 10) is con sider ed m oder a t e, r equ ir in g
t r a u m a , or gen et ic defect m edica t ion s?
b. Localized to the middle ear and is often temporary a. 1
c. Ca u sed by a lt er a t ion in a u dit or y sign a l pr o- b. 2
cessin g in t h e br a in c. 3
d. A r espon se t o im m obilit y of t h e t ym pa n ic d. 4
m em br a n e
16. Neu r om a t r ix pa in t h eor y st a t es
8. Th e m ech a n ism of a ct ion of opioid a n a lgesics is: a . Specific st im u li ca u se pr edict a ble pa in
a . Blocka de of ser ot on in r eu pt a ke a t t h e syn a p- r espon ses
t ic cleft b. Specific st im u li r esu lt s in pr even t ion of im -
b. In h ibit ion of cyclooxygen a se en zym es a n d pu lse cr ossin g in spin a l cor d
pr ost a gla n din pr odu ct ion c. Neu r a l n et wor k in t egr a t ion of m u lt iple in -
c. St im u la t ion of la r ge fiber s t o m odu la t e pa in pu t s det er m in es pa in per cept ion
t r a n sm ission d. Pa in per cept ion is det er m in ed by du r a t ion of
d. Modu la t e pa in a t t h e level of t h e spin a l cor d im pu lse a n d a m ou n t of t issu e in volved
by bin din g t o m u , delt a , a n d ka ppa r ecept or s

9. Th e m ech a n ism of a ct ion of opiod a n a lgesics is: D I S C U S S I O N AN D

a . Blocka de of ser ot on in r eu pt a ke a t t h e syn a p- AP P L I C AT I O N
t ic cleft
b. In h ibit ion of cyclooxygen a se en zym es a n d 1. Wh a t did I kn ow a bou t pa in a n d a lt er a t ion s in
pr ost a gla n din pr odu ct ion sen sa t ion befor e t oda y?
c. St im u la t ion of la r ge fiber s t o m odu la t e pa in 2. Wh a t body pr ocesses a r e a ffect ed by pa in a n d
t r a n sm ission a lt er a t ion in sen sa t ion ? H ow do pa in a n d a lt er-
d. Modu la t e pa in a t t h e level of t h e spin a l cor d a t ion in sen sa t ion a ffect t h ose pr ocesses?
by bin din g t o m u , delt a , a n d ka ppa r ecept or s 3. Wh a t a r e t h e pot en t ia l et iologies for pa in a n d
a lt er a t ion in sen sa t ion ? H ow do pa in a n d a lt er-
10. Wh ich on e of t h e followin g eye con dit ion s is t h e a t ion in sen sa t ion develop?
r esu lt of in cr ea sed in t r a ocu la r pr essu r e? 4. Wh o is m ost a t r isk for developin g pa in a n d a l-
a . Ret in opa t h y of pr em a t u r it y t er a t ion in sen sa t ion ? H ow ca n t h ese a lt er a t ion s
b. Gla u com a be pr even t ed?
c. Wet m a cu la r degen er a t ion 5. Wh a t a r e t h e h u m a n differ en ces t h a t a ffect t h e
d. Dr y m a cu la r degen er a t ion et iology, r isk, or cou r se of pa in a n d a lt er a t ion in
sen sa t ion ?
11. Ba la n ce a n d body posit ion a r e t h e fu n ct ion of 6. Wh a t clin ica l m a n ifest a t ion s a r e expect ed in t h e
a . Ut r icle cou r se of pa in a n d a lt er a t ion in sen sa t ion ?
b. Sa ccu le 7. Wh a t specia l dia gn ost ic t est s a r e u sefu l in de-
c. Sem icir cu la r ca n a ls t er m in in g t h e dia gn osis a n d cou r se of pa in a n d
d. All of t h e a bove a lt er a t ion in sen sa t ion ?
8. Wh a t a r e t h e goa ls of ca r e for in dividu a ls wit h
12. Da m a ge t o t h e coch lea r h a ir cells m a y r esu lt in pa in a n d a lt er a t ion in sen sa t ion ?
a . H ea r in g loss 9. H ow does t h e con cept of pa in a n d a lt er a t ion in
b. Loss of ba la n ce sen sa t ion bu ild on wh a t I h a ve lea r n ed in t h e
c. La ck of pr opr iocept ion pr eviou s ch a pt er s a n d in t h e pr eviou s cou r ses?
d. Non e of t h e a bove 10. H ow ca n I u se wh a t I h a ve lea r n ed?
 C h a p t e r 12: Alt er ed Som a t ic a n d Specia l Sen sor y F u n ct ion
R E SOUR CE S
Na t ion a l Pa in St r a t egy: A Com pr eh en sive Popu la -
t ion H ea lt h -Level St r a t egy for Pa in
h t t p://ipr cc.n ih .gov/docs/H H SN a t ion a l_Pa in _St r a t
egy.pdf
Am er ica n Ma cu la r Degen er a t ion Fou n da t ion :
h t t p s ://w w w.m a cu la r.or g/?gclid =C LP r w _L 2h M w
CF Qkya Qodvn sF jQ
Am er ica n Speech , La n gu a ge and H ea r in g
Associa t ion :
h t t p://www.a sh a .or g/pu blic/h ea r in g/disor der s/t ypes
.h t m
In for m a t ion on t ypes of h ea r in g loss
Na t ion a l E ye In st it u t e (NE I):
h t t p://www.n ei.n ih .gov
Con du ct s a n d su ppor t s r esea r ch on eye disea ses a n d
vision disor der s.
Na t ion a l In st it u t e for Dea fn ess a n d ot h er Com m u -
n ica t ion Disor der s (NIDCD):
h t t p://www.n idcd.n ih .gov/Pa ges/defa u lt .a spx
In for m a t ion a bou t h ea r in g disor der s
Na t ion a l In st it u t e of Neu r ologic Disor der s a n d
St r oke:
h t t p ://www.n in d s.n ih .gov/d is or d er s /ch r on ic_p a in /
ch r on ic_pa in .h t m
In for m a t ion on ch r on ic pa in
P r even t Blin dn ess Am er ica :
h t t p://www.pr even t blin dn ess.or g
U.S. Food a n d Dr u g Adm in ist r a t ion , Cen t er for Dr u g
E va lu a t ion a n d Resea r ch :
h t t p://www.fda .gov/dr u gs /r esou r cesfor you /con su m
er s /bu yin gu s in gm ed icin es a fely/u n d er s t a n d in gov
er-t h e-cou n t er m edicin es/sa feu seofover-t h e-cou n t er
pa in r eliever sa n dfever r edu cer s/defa u lt .h t m
In for m a t ion a bou t over-t h e-cou n t er a n a lgesics
R e er en ces
1. Moa yedi M, Davis KD. Th eor ies of pa in : fr om speci-
ficit y t o ga t e con t r ol. J Neu r oph ysiol. 2013;109:5–12.
doi:10.1152/jn .00457.2012.
2. Melza ck R, Ka t z J. Pa in . Wiley In ter d iscip Rev Cogn S ci.
2013;4(1):1–15. doi:10.1002/wcs.1201.
3. P illa i RRR, Ra cin e NM, Gen n is H G, et a l.
Non -ph a r m a cologic m a n a gem en t of in fa n t a n d you n g
ch ild pr ocedu r a l pa in . Coch r a n e Da ta ba se S yst Rev.
2015;12:CD006275.
F in d a d d ition a l r esou r ces for th is ch a pter a t h ttp:th ePoin t.lww.com
317
4. DeGia com o A, Cr a ig F, D’E lia A, et a l. Ch ildr en wit h
coch lea r im pla n t s: cogn it ive skills, a da pt ive beh avior s,
socia l a n d em ot ion a l skills. In t J Ped ia tr Otor h in ola r yn -
gol. 2013;77(12):1975–1990.
5. Bor ch er s AT, Ger sh win E M. F ibr om yla gia : a cr it ica l
a n d com pr eh en sive r eview. Clin ic Rev Aller g Im m u n ol.
2015;49:100–151.
6. Men zies V, Lyon DE , Ar ch er KJ, et a l. E pigen et ic
a lt er a t ion s a n d a n in cr ea sed fr equ en cy of m icr on u -
clei in wom en wit h fibr om ya lgia . Nu rs Res P r a ct.
2013;2013:795784. doi:10.1155/2013/795784.
7. Wolfe F, Sm yt h e H A, Yu n u s MB, et a l. Th e Am er ica n Col-
lege of Rh eu m a t ology 1990 cr it er ia for t h e cla ssifica t ion
of fibr om ya lgia . Repor t of t h e Mu lt icen t er Cr it er ia Com -
m it t ee. Ar th r itis Rh eu m . 1990;33(2):160–172.
8. Pet er son J. Un der st a n din g fibr om ya lgia a n d it s t r ea t -
m en t opt ion s. Nu r se P r a ct. 2005;30(1):48–55.
9. Bu r st ein R, Noseda R, Bor sook D. Migr a in e: m u lt i-
ple pr ocesses, com plex pa t h oph ysiology. J Neu r osci.
2015;35(17):6619–6629.
10. H ea da ch e Cla ssifica t ion Com m it t ee of t h e In t er n a -
t ion a l H ea da ch e Societ y. Th e In t er n a t ion a l Cla ssifica -
t ion of H ea da ch e Disor der s, 3r d edit ion . Ceph a la lgia .
2013;33(9):629–808.
11. F r eit a g F G, Sch loem er F. Medica l m a n a gem en t of a du lt
h ea da ch e. Otola r yn gol Clin Nor th Am . 2014;46:221–237.
12. For de G, Du a r t e RA, Rosen N. Ma n a gin g ch r on ic h ea d-
a ch e disor der s. Med Clin Nor th Am . 2016;100(1):
117–141. doi:10.1016/j.m cn a .2015.09.006.
13. Mit sikost a s DD, Ra popor t AM. New pla yer s in t h e pr e-
ven t ive t r ea t m en t of m igr a in e. BMC Med . 2015;13:279.
doi:10.1186/s12916-015-0522-1.
14. Lieber t h a l AS, Ca r r oll AE , Ch on m a it r ee T, et a l. Th e
dia gn osis a n d m a n a gem en t of a cu t e ot it is m edia . Ped ia t-
r ics. 2013;131(3):e964–e969. doi:10.1542/peds.2012-3488.
15. H a r cou r t J, Ba r r a clou gh K, Br on st ein AM. Men ier e’s dis-
ea se. BMJ . 2014;349:g6544. doi:10.1136/bm j.g6544.
16. Ka t t a S, Ka u r I, Ch a kr a ba r t i S. Th e m olecu la r gen et ic
ba sis of a ge-r ela t ed m a cu la r degen er a t ion : a n over view.
J Gen et. 2009;88(4):425–449.
17. Klein R, Rowla n d ML, H a r r is MI. Ra cia l/et h n ic differ-
en ces in a ge-r ela t ed m a cu lopa t h y. Th ir d Na t ion a l H ea lt h
a n d Nu t r it ion E xa m in a t ion Su r vey. Oph th a lm ology.
1995;102:371–381. h t t ps://n ei.n ih .gov/eyeda t a /a m d. Ac-
cessed Decem ber 6, 2015.
18. Meh t a S. Age-r ela t ed m a cu la r degen er a t ion . P r im Ca r e.
2015;42(3):377–391. doi:10.1016/j.pop.2015.05.009.
19. Ga r cia -La va n a A, F igu er oa MS, Ar ia s L, et a l. In divid-
u a lized t h er a py wit h r a n ibizu m a b in wet a ge-r ela t ed
m a cu la r degen er a t ion . J Oph th a lm ol. 2015;2015:412903.
doi:10.1155/2015/412903.
20. Tia n K, Sh iba t a -Ger m a n os S, Pa h lit zsch M, et a l. Cu r-
r en t per spect ive of n eu r opr ot ect ion a n d gla u com a . Clin
Oph th a lm ol. 2015;9:2109–2118.
21. Pen n J S, Ma da n A, Ca ldwell RR, et a l. Va scu la r en do-
t h elia l gr owt h fa ct or in eye disea se. P r og Retin E ye Res.
2008;27(4):331–371.
 Ch a pt er

13
Alt er ed H or m on a l a n d
Met a bolic Regu la t ion

L E AR N I N G O U T C O ME S
1. Defin e a n d u se t h e key t er m s list ed in t h is ch a pt er.
2. Iden t ify fea t u r es t h a t ch a r a ct er ize h or m on es.
3. Discu ss t h e r ole of t h e h ypot h a la m ic–pit u it a r y a xis in r egu la t in g h or m on e
levels.
4. Iden t ify pa t h wa ys for m edia t in g cell-t o-cell com m u n ica t ion .
5. Descr ibe t h e r ole of t h e n eu r oen docr in e syst em in t h e st r ess r espon se.
6. An a lyze t h e m ech a n ism s of im pa ir m en t t h a t ca n lea d t o a lt er ed h or m on a l
a n d m et a bolic r egu la t ion .
7. Discu ss com m on m ea su r es t o dia gn ose a n d t r ea t h or m on e dysfu n ct ion .
8. Apply con cept s of a lt er ed h or m on a l a n d m et a bolic r egu la t ion t o select
clin ica l m odels.

INTR ODUCTION
H ow m a n y t ext s, e-m a ils, ph on e ca lls, a n d in st a n t m essa ges did you r eceive
t oda y? Com m u n ica t ion bet ween h u m a n s r equ ir es a sen der, m essa ge, a n d r e-
ceiver. Likewise, com m u n ica t ion bet ween cells r elies u pon n eu r on a l a n d en do-
cr in e sign a ls t o r egu la t e body fu n ct ion s. Th is ch a pt er r eviews ba sic m ech a n ism s
for cell-t o-cell com m u n ica t ion , pa r t icu la r ly a s it r ela t es t o h or m on e-dr iven m es-
sa ges. You a r e a lr ea dy fa m ilia r wit h t h is idea ; a ll pr eviou s ch a pt er s in on e wa y
or a n ot h er r elied on t h e con cept of sen der, m essa ge, a n d r eceiver. Th is ch a pt er
bu ilds on t h a t lea r n in g. A ba sic u n der st a n din g of com m u n ica t ion m ech a n ism s
wit h in t h e body will h elp t o pr edict t h e im pa ct of h igh or low h or m on e levels on
t h e fu n ct ion of en docr in e gla n ds. Clin ica l m odels a r e pr esen t ed t o h elp u n der-
st a n d specific disea se con dit ion s a ffect ed by h or m on e a lt er a t ion s.

318 Healthcare practitioner measuring patient’s blood sugar value. Image © Syda Productions.

Modu le 1 F u n c t io n a n d R e g u la t io n
o H or m on es
H o r m o n e s a r e ch em ica ls, for m ed or igin a lly in t is-
su es or or ga n s, wh ich a ffect t h e gr owt h a n d/or fu n c-
t ion of ot h er t a r get t issu es or or ga n s. Th e st r u ct u r e
of h or m on es ca n va r y in com posit ion fr om a sin -
gle a m in o a cid, su ch a s wit h t h yr oid h or m on e, t o
a com plex com bin a t ion of pr ot ein s, ca r boh ydr a t es,
or lipids, a s occu r s wit h cor t isol. H or m on es h a ve
m a n y im por t a n t r egu la t or y fu n ct ion s, in clu din g
m et a bolism , gr owt h a n d developm en t , m u scle a n d
fa t dist r ibu t ion , flu id a n d elect r olyt e ba la n ce, sex-
u a l developm en t , a n d r epr odu ct ion . H or m on es a r e
a lso in st r u m en t a l in t h e st r ess r espon se. Ta ble 13.1
ou t lin es t h e fu n ct ion s specific t o select h or m on es
a n d sh ou ld be r efer r ed t o fr equ en t ly a s h or m on e
pr ocesses a r e discu ssed.
Stop and Consider
In Table 13.1, hormones are organized alphabet-
ically. How else could you organize this table?
What type of organization is most useful to you
as a learner?
Integrating Endocrine, Neuronal, and
Defense Mechanisms in the Body
H or m on es a r e com m on ly con n ect ed wit h t h e e n d o -
c r in e s y s t e m , a collect ive gr ou p of t issu es ca pa ble
of secr et in g h or m on es (F ig. 13.1). Th e pa n cr ea s a n d
t h yr oid a r e exa m ples of en docr in e gla n ds. Not e, h ow-
ever, t h a t en docr in e gla n ds a r e n ot t h e on ly t issu es
ca pa ble of secr et in g h or m on es. Neu r on s ca n syn -
t h esize a n d r elea se h or m on es. Neu r ot r a n sm it t er s,
su ch a s epin eph r in e, dopa m in e, ser ot on in , a n d n or-
epin eph r in e, a r e ch em ica l m essen ger s, syn t h esized
by n eu r on s, wh ich r a pidly st im u la t e a n eu r on a l
r espon se. In t h is r ega r d, n eu r ot r a n sm it t er s a ct a s
h or m on es. In fla m m a t or y a n d im m u n e cells r elea se
ch em ica l m edia t or s, su ch a s cyt okin es, leu kot r ien es,
a n d pr ost a gla n din s, wh ich a lso fu n ct ion a s h or-
m on es. Th e in fla m m a t or y a n d im m u n e r espon ses
r equ ir e t h ese su bst a n ces t o t r igger t h e m ech a n ism s
of defen se. Som e t u m or cells a lso syn t h esize a n d
r elea se ect opic h or m on es, wh ich ign or e t h e body’s
con t r ol a n d feedba ck m ech a n ism s a n d u lt im a t ely
con t r ibu t e t o a loss of h om eost a sis.
Like a n or ch est r a , t h e n eu r ologic, in fla m m a t or y,
im m u n e, a n d en docr in e syst em s colla bor a t e in a
u n ified sym ph on y. Neu r ot r a n sm it t er s a ct qu ickly,
wh er ea s en docr in e h or m on es oft en t a ke da ys t o
F u n c t io n a n d R e g u la t io n o H o r m o n e s 319
exer t t h eir m a xim u m effect on t a r get t issu es. Yet
t h ese syst em s a r e h igh ly depen den t on on e a n ot h er.
Regu la t or y pr ocesses in t egr a t e wit h a n over a ll goa l
of pr ot ect in g t h e body fr om in ju r y a n d m a in t a in in g
h om eost a sis.
Regulating Hormones
Sever a l fea t u r es a r e com m on t o a ll h or m on es. E a ch
of t h ese fea t u r es is discu ssed below.
● C o n t r o l: h or m on e syn t h esis a n d r elea se is con -
t r olled by t issu es a n d or ga n s; t h e h ypot h a la m ic–
pit u it a r y a xis in t h e br a in is a n im por t a n t
con t r ol-cen t er for m a n y h or m on es
● P a t t e r n s : h or m on es exh ibit pr edict a ble pa t t er n s
of secr et ion , m et a bolism , a n d elim in a t ion
● F e e d b a c k : h or m on es list en a n d a dju st ba sed on
n ega t ive or posit ive feedba ck loops
● Ac t io n : h or m on es exh ibit t wo pr im a r y fu n ct ion s:
(1) t o a ct on t a r get or ga n s t o a ch ieve a n effect or
(2) t o a ct on gla n ds t o pr odu ce a n ot h er h or m on e
R e c e p t o r b in d in g : t o exer t a n effect h or m on es
●
m u st loca t e a n d a t t a ch on t o t a r get t issu es
THE HYPOTHALAMIC–PITUITARY AXIS
Th e h y p o t h a la m ic –p it u it a r y a x is con t r ols t h e
syn t h esis a n d secr et ion of m a n y h or m on es. Th e h y-
poth a la m u s con t a in s n eu r on s t h a t syn t h esize pr o-
la ct in , in h ibit in g h or m on es, a n d r elea sin g h or m on es
t o a ct on t h e a n t er ior pit u it a r y gla n d. Th ese in clu de:
● Relea sin g h or m on es
■ Gr owt h h or m on e-r elea sin g h or m on e (GH RH )
■ Th yr ot r opin -r elea sin g h or m on e (TRH )
■ Cor t icot r opin -r elea sin g h or m on e (CRH )
■ Gon a dot r opin -r elea sin g h or m on e (Gn RH )
● In h ibit in g h or m on es
■ Som a t ost a t in (in h ibit s gr owt h h or m on e a n d
t h yr oid-st im u la t in g h or m on e)
■ Dopa m in e (in h ibit s pr ola ct in )
Th e pitu ita r y gla n d r espon ds t o t h ese h ypot h a la m ic
t r igger s a n d a ct s a ccor din gly. It is im por t a n t t o u n -
der st a n d t h a t t h e pa t h wa ys a n d h or m on es r elea sed
fr om t h e a n ter ior pit u it a r y gla n d a r e differ en t t h a n
t h e h or m on es r elea sed fr om t h e poster ior pit u it a r y.
Mor e specifica lly, t o get fr om t h e h ypot h a la m u s t o
t h e a n t er ior pit u it a r y, pr ola ct in , r elea sin g, or in h ib-
it in g h or m on es (t h ose list ed a bove) t r a vel t h r ou gh
320 C h a p t e r 13: Alt er ed H or m on a l a n d Met a bolic Regu la t ion
Ta b le 13.1 F u n ct ion s of Select H or m on es
H or m on e
An dr ogen s
An t idiu r et ic h or m on e
(ADH )
Adr en ocor t icot r opic h or-
m on e (ACTH )
Cor t icot r opin -
r elea sin g h or m on e (CRH )
E pin eph r in e a n d
n or epin eph r in e
E st r ogen
Follicle-st im u la t in g
h or m on e (F SH )
Glu ca gon
Glu cocor t icoids (cor t isol)
Gon a dot r opin -r elea sin g
h or m on e (Gn RH )
Gr owt h h or m on e-
r elea sin g h or m on e
(GRH R)
Gr owt h h or m on e (GH )
In su lin
Lu t ein izin g h or m on e
(LH )
Min er a locor t icost er oids
(a ldost er on e)
Oxyt ocin
Pa r a t h yr oid h or m on e
(P TH )
P r ogest er on e
Th yr oid h or m on es (TH ):
t r iiodot h yr on in e (T 3 ) a n d
t h yr oxin e (T 4 )
Th yr ot r opin -r elea sin g
h or m on e (TRH )
Th yr oid-st im u la t in g h or-
m on e (TSH )
Sou r ce
Test es
H ypot h a la m u s–
post er ior pit u it a r y
An t er ior pit u it a r y
H ypot h a la m u s
Adr en a l m edu lla
Ova r ies
An t er ior pit u it a r y
Pa n cr ea t ic islet cells
Adr en a l cor t ex
H ypot h a la m u s
H ypot h a la m u s
An t er ior pit u it a r y
Pa n cr ea t ic islet cells
An t er ior pit u it a r y
Adr en a l cor t ex
H ypot h a la m u s–
post er ior pit u it a r y
Pa r a t h yr oid gla n ds
Ova r ies
Th yr oid gla n d
H ypot h a la m u s
An t er ior pit u it a r y
Ta r g e t
Repr odu ct ive or ga n s
Kidn ey
Adr en a l cor t ex
P it u it a r y gla n d
Sym pa t h et ic n er vou s
syst em
Repr odu ct ive or ga n s
Repr odu ct ive or ga n s
Blood glu cose
Mu lt iple t a r get s
P it u it a r y gla n d
P it u it a r y gla n d
Bon e, m u scle, or ga n s,
a n d ot h er t issu es
Blood glu cose
Repr odu ct ive or ga n s
Kidn ey
Ut er u s a n d br ea st s
Bon e, blood
Repr odu ct ive or ga n s
Mu lt iple t a r get s
P it u it a r y gla n d
Th yr oid gla n d
F u n c t io n
Con t r ol t h e developm en t of r epr o-
du ct ive or ga n s, (t est ost er on e) sper m
pr odu ct ion , a n d secon da r y sex ch a r a c-
t er ist ics a n d gr owt h in m a les
P r om ot es wa t er r ea bsor pt ion (r et en t ion
of flu ids)
St im u la t es r elea se of h or m on es fr om
t h e a dr en a l cor t ex (pr im a r ily a ldost e-
r on e a n d cor t isol)
Con t r ols r elea se of pit u it a r y h or m on es
Tr a n sm it s n eu r a l im pu lses
P r om ot es developm en t of r epr odu ct ive
or ga n s a n d secon da r y sex ch a r a ct er is-
t ics in wom en
St im u la t es gr owt h of ova r ia n follicle
a n d ovu la t ion in wom en ; st im u la t es
sper m pr odu ct ion in m en
St im u la t es glycogen br ea kdown in t h e
liver t o in cr ea se glu cose in t h e blood
Affect s m et a bolism of a ll n u t r ien t s a n d
gr owt h ; r egu la t es blood glu cose levels;
h a s a n t i-in fla m m a t or y pr oper t ies
Con t r ols r elea se of pit u it a r y h or m on es
Con t r ols r elea se of pit u it a r y h or m on es
St im u la t es gr owt h , pr ot ein syn t h esis,
a n d fa t m et a bolism ; in h ibit s ca r boh y-
dr a t e m et a bolism
Fa cilit a t es glu cose t r a n spor t in t o t h e
m u scle, a dipose, or liver cell t o u se for
en er gy a n d gr owt h
St im u la t es r elea se of oocyt e a n d pr o-
du ct ion of est r ogen a n d pr ogest er on e in
wom en ; st im u la t es secr et ion of t est os-
t er on e in m en
In cr ea ses sodiu m r ea bsor pt ion a n d po-
t a ssiu m loss
St im u la t es con t r a ct ion of t h e u t er u s
du r in g la bor a n d m ilk r elea se fr om t h e
br ea st s a ft er ch ildbir t h
Regu la t es ca lciu m levels in t h e blood
Affect s m en st r u a l cycle; in cr ea ses
t h ickn ess of u t er in e wa ll; su ppor t s/
m a in t a in s pr egn a n cy
In cr ea ses m et a bolic r a t e, n eeded for fe-
t a l a n d in fa n t gr owt h a n d developm en t
Con t r ols r elea se of pit u it a r y h or m on es
St im u la t es syn t h esis a n d secr et ion of
t h yr oid h or m on es (T 3 a n d T 4 )

P ituita ry gla nd
P ine a l gla nd
Thyroid a nd
pa ra thyroids
Thymus
Adre na ls
Pa ncre a s
Ova rie s
(in ma le , te s te s
loca te d in s crotum)
Figure 13.1. Organs of the endocrine system. (Courtesy
Anatomical Chart Company.)
t h e h ypoph ysea l por t a l syst em (blood vessels) t o t h e
a n t er ior pit u it a r y gla n d. Th r ee possible scen a r ios
t h a t ch a r a ct er ize r elea se t h r ou gh t h e a n t er ior pi-
t u it a r y a r e illu st r a t ed in Box 13.1. E a ch scen a r io
dem on st r a t es in cr ea sin g com plexit y in t h e pr ocess
a n d a n exa m ple is pr ovided. In con t r a st , t h e h ypo-
t h a la m u s pr odu ces a n t idiu r et ic h or m on e (ADH ) a n d
oxyt ocin , wh ich t h en t r a vel a lon g n er ve a xon s t o t h e
post er ior pit u it a r y for u n ch a n ged r elea se in t o t h e
syst em ic cir cu la t ion . Th is pa t h wa y t h r ou gh t h e pos-
t er ior pit u it a r y is n ot n ea r ly a s com plica t ed a s t h e
a n t er ior pit u it a r y scen a r ios.
Stop and Consider
What are the major differences and similarities
between the actions of the hypothalamus on
the anterior pituitary gland versus the poste-
rior pituitary gland? Why would this difference
matter? What is an effective way to remember
this difference?
A few h or m on es a r e secr et ed wit h ou t in it ia t ion
t h r ou gh t h e h ypot h a la m u s a n d com e dir ect ly fr om
t h e pit u it a r y. On e exa m ple is m ela n ocyt e-st im u la t -
in g h or m on e, wh ich is a h or m on e t h a t r egu la t es skin
F u n c t io n a n d R e g u la t io n o H o r m o n e s 321
Box 13.1 R e le a s e o H o r m o n e s r o m t h e
H y p o t h a la m u s t o t h e An t e r io r P it u it a r y
Act ion 1:
■ Th e h ypot h a la m u s pr odu ces t h e h or m on e.
■ Th e h or m on e t r a vels t o t h e a n t er ior pit u it a r y.
■ Th e h or m on e is r elea sed u n ch a n ged in t o t h e
cir cu la t ion .
E xa m ple: pr ola ctin
Act ion 2:
■ Th e h ypot h a la m u s pr odu ces a r elea sin g h or m on e.
■ Th e r elea sin g h or m on e t r a vels t o a n d a ct s u pon t h e
a n t er ior pit u it a r y.
■ Th e pit u it a r y is st im u la t ed t o pr odu ce a n d r elea se
a differ en t h or m on e in t o t h e cir cu la t ion .
E xa m ple: gr owth h or m on e
Act ion 3:
■ Th e h ypot h a la m u s pr odu ces a r elea sin g h or m on e.
■ Th e a n t er ior pit u it a r y is a ct iva t ed t o r elea se a
st im u la t in g h or m on e.
■ Th e st im u la t in g h or m on e a ct s on t h e gla n d t o pr o-
du ce a n d secr et e a fin a l h or m on e t h a t is r elea sed
in t o t h e cir cu la t ion .
E xa m ple: th yr oid h or m on e
pigm en t . Pa t h wa ys a n d a ct ion s for select h or m on es
a r e depict ed in F igu r e 13.2.
FEEDBACK MECHANISMS
Wh a t t r igger s t h e h ypot h a la m u s or pit u it a r y t o in i-
t ia t e a h or m on e r elea se? Mu lt iple m ech a n ism s, su ch
a s n eu r ot r a n sm it t er s, in ju r y a n d t h e r esu lt in g r e-
lea se of ch em ica l m edia t or s, a n d n eu r oen docr in e sig-
n a ls pr ovide in pu t t o t h e h ypot h a la m u s. Th is m ost
com m on ly occu r s t h r ou gh a n e g a t iv e e e d b a c k
lo o p (Fig. 13.3). Th e m ech a n ism of n ega t ive feed-
ba ck is like a n in t er n a l t h er m ost a t . Wh en t h e t em -
per a t u r e get s t oo h ot , t h e t h er m ost a t sh u t s down t h e
h ea t sou r ce; wh en t h e t em per a t u r e is t oo cool, t h e
fu r n a ce is a ct iva t ed t o r elea se h ea t . Am a zin gly, t h e
h ypot h a la m u s a n d pit u it a r y a ct a s sen sor s t h a t a r e
con st a n t ly ga u gin g t h e levels of h or m on es in t h e
body. Wh en levels r ise a bove t h e expect ed r a n ge, t h e
st im u la t ion , pr odu ct ion , or secr et ion of h or m on e is
decr ea sed. Wh en levels fa ll, st im u la t ion , pr odu ct ion ,
or secr et ion of h or m on e is in cr ea sed. Th e n ega t ive
feedba ck m ech a n ism is a ffect ed by en vir on m en t a l
a n d body t em per a t u r e, st r ess, n u t r it ion , a n d t h e
pr esen ce of specific body su bst a n ces. For exa m ple,
a ldost er on e levels a dju st ba sed on sodiu m a n d po-
t a ssiu m levels in t h e body. An t idiu r et ic h or m on e is
r espon sive t o flu id levels in t h e body.
Alt h ou gh m u ch less com m on , a few h or m on es
a r e r egu la t ed by a p o s i t i v e e e d b a c k lo o p . In
posit ive feedba ck, pr esen ce of t h e h or m on e st im -
u la t es in cr ea sed pr odu ct ion of t h e h or m on e u n t il
t h er e is a n in t er r u pt ion of t h e cycle. Oxyt ocin is on e
322 C h a p t e r 13: Alt er ed H or m on a l a n d Met a bolic Regu la t ion

Inte rna l/exte rna l

s timuli
Ne urotra ns mitte rs

Hypo thalamus

Blood leve ls exe rt Re le a s ing hormone s

re gula tory influe nce s Thyrotropin-re le a s ing hormone (TRH)
upon the a nte rior ADH a nd oxytocin Kidney
Corticotropin-re le a s ing hormone (CRH)
pituita ry gla nd a nd one
Gona dotropin-re le a s ing hormone (GnRH) o r m
the hypotha la mus re tic h s in)
Growth hormone -re le a s ing hormone (GHRH) id iu re s
An t v aso
p
H ,
(AD
Ne rve a xons
Blood ve s s e ls Pos te rior Oxytocin Bre a s t
pituita ry

O xy
to ci
n
d LH
an Ante rior
H Ute rus
FS
pituita ry
H

G
L

H
d
n

Corpus
)
a

P
H

ro
lute um
S

(C
F

la
A
H

Ova ry

ct
C
S

in
T
T

H
Es troge n

Te s te s Bone a nd
s oft tis s ue
Thyroid
Adre na l Bre a s t
gla nd
Te s tos te rone gla nd

Thyroid
hormone s Adre nocorticos te roids

Figure 13.2. The hypothalamic–pituitary axis regulates the release of hormones. (Modified from Smeltzer SC, Bare BG.
Textbook of Medical-Surgical Nursing. 10th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003, with permission.)

exa m ple (F ig. 13.4). Specific feedba ck m ech a n ism s
for ea ch h or m on e a r e discu ssed in dept h wit h in t h e
clin ica l m odels.
HORMONE SECRETION, METABOLISM,
AND ELIMINATION
Ma ny hor m on es exhibit pr edict a ble pa t t er ns of secr e-
t ion. For exa m ple, a 28-day cyclic secr et ion of est r ogens,
pr ogest er one, lut einizing, a nd follicle-st im u la t in g
h or m on es r egu la t es t he fem a le m enst r ua l cycle. Som e
h or m on es h ave 24-h our diur n a l pa t t er ns of secr et ion.
For exa m ple, gr owt h h or m on e levels incr ea se du r ing
sleeping h our s a n d decr ea se du r ing wa kin g hou r s.
Secr et ion pa t t er n s high light t he com plex, flu ct ua nt ,
a nd r espon sive n a t u r e of h or m on es.
Th e a ccu m u la t ion of h or m on es is pr even t ed
t h r ou gh a pr ocess of in a ct iva t ion a n d elim in a t ion .
A com m on m ech a n ism for in a ct iva t ion is t h r ou gh
en zym es t h a t br ea k down t h e h or m on e a ft er a t t a ch -
in g t o t h e cell r ecept or a n d exer t in g a n effect . Som e
h or m on es a r e a lso in a ct iva t ed in t h e liver. E lim in a -
t ion com m on ly occu r s t h r ou gh t h e u r in e or a lon g
wit h bile, via t h e feces.
RECEPTOR BINDING
Recept or bin din g a llows h or m on es t o a ct select ively
on cer t a in cells. Th e n u m ber of r ecept or s on ea ch
cell ca n r ea ch u p t o 100,000 or m or e. To a ccess t h e
cell, h or m on es seek ou t a n d a t t a ch t o specific r ecep-
t or s, sim ila r t o a key t h a t m u st fit a cer t a in lock.
 F u n c t io n a n d R e g u la t io n o H o r m o n e s 323

Cold te mpe ra ture, At the ons e t of la bor,

s tre s s, TH leve ls ute rine contra ctions pus h he a d
(or body) of the ba by into
the ce rvix

Co ntro l Ce nte r

Brain Re s ults in s tre tch

of ce rvix
TRH

TS H Re c e pto rs

S tre tch de te cte d by

ne rve ce lls in ce rvix

Ne g ative fe e dback Ne rve

Input
1. T3, T4 = TRH + TS H Impuls e s Po s itive fe e dback
Thyro id g land
2. T3, T4 = TRH + TS H S tre tch a t ce rvix
re s ults in re le a s e of
TH production more oxytocin, which
a nd s e cre tion Co ntro l Ce nte r
in turn ca us e s furthe r
s tre tching of ce rvix
Brain
(Pituitary
g land)

Oxyto c in

Output
Circ ulating
T3, T4
Effe c to r

Oxytocin produce s
more force ful
contra ctions
of the ute rus

Figure 13.3. An example of a negative feedback loop.

Circulating thyroid hormone (TH) levels (T3 + T4) alert
the hypothalamus and anterior pituitary to increase Re s is ta nt de s ce nt
of the ba by s tre tche s
or decrease thyrotropin-releasing hormone (TRH) and the ce rvix more
thyroid-stimulating hormone (TSH) secretion.

Inte rruption of cycle ;

H or m on es ca n bin d t o a su r fa ce or in n er r ecept or of
a cell (Fig. 13.5). A su r fa ce r ecept or r equ ir es a secon d
m essen ger t o elicit a r espon se fr om t h e cell. Wit h ou t
t h e a ppr opr ia t e r ecept or, t h e h or m on e m oves a lon g
a n d h a s n o im pa ct on t h a t cell. For exa m ple, skelet a l
m u scle cells h a ve r ecept or s for gr owt h h or m on e bu t
a r e u n r espon sive t o a n t idiu r et ic h or m on e. Recept or
bin din g is a lt er ed wh en t h e n u m ber of r ecept or s is
r edu ced, a s m a y occu r wit h a u t oim m u n e con dit ion s,
or wh en t h e a ffin it y, or a t t r a ct ion , for t h e h or m on e is
r edu ced. Th e a ffin it y ca n be r edu ced by m a n y fa ct or s,
su ch a s gen et ics, h or m on e levels, a n d body flu id pH .
Birth of ba by which
de cre a s e s s tre tching of
ce rvix, bre a king the
pos itive fe e dba ck cycle
Figure 13.4. An example of a positive feedback loop.
Oxytocin levels during labor and delivery increase release
of additional oxytocin until the birth of the baby which
decreases stretching of the cervix and the cycle is inter-
rupted. (From Premkumar K. The Massage Connection: Anat-
omy and Physiology. Baltimore, MD: Lippincott Williams &
Wilkins; 2004, with permission.)
324 C h a p t e r 13: Alt er ed H or m on a l a n d Met a bolic Regu la t ion

Hormone

S e cond
me s s e nge r

Enzyme a ctivity S urfa ce

re ce ptor
A Hormone -producing Ne a rby re s ponding/
ce ll ta rge t ce ll
Ce ll
re s pons e
A

Nucle us

Hormone Hormone -producing

B
ce ll

P rote in
s ynthe s is Circula tion
Hormone -re ce ptor
complex

C Hormone -producing Ca pilla ry

ce ll

Figure 13.5. Two types of hormone–receptor interactions:

the surface receptor ( A) and the intracellular receptor
( B) . (From Porth CM. Essentials of Pathophysiology:
Concepts of Altered Health States. Philadelphia,
PA: Lippincott Williams & Wilkins; 2003, with D Hormone -producing
permission.) ce ll (ne uron)

Mediating Cell-to-Cell Circula tion

Communication
F ive m a jor pa t h wa ys ch a r a ct er ize cell-t o-cell com -
m u n ica t ion , wh er e h or m on es m ove fr om pr odu ct ion
a n d secr et ion , t o r espon se (F ig. 13.6):
● P a r a c r in e p a t h w a y : h or m on es a r e pr odu ced in
a cell, secr et ed, a n d a ct dir ect ly on n ea r by r ecep-
t ive cells.
● Au t o c r in e p a t h w a y : t h e sa m e a s t h e pa r a -
cr in e pa t h wa y except t h a t t h e r ecept or cells
a r e a lso secr et or y cells so, in essen ce, t h e cell is
a ble t o pr odu ce t h e h or m on e a n d exer t a n effect
on it self.
● E n d o c r in e p a t h w a y : h or m on es a r e pr odu ced in
a cell, secr et ed, a n d t r a vel t h r ou gh blood vessels
t o dist a n t cells, a t t a ch t o r ecept or s, a n d a ct on
t h a t cell.
● S y n a p t ic p a t h w a y : h or m on es a r e pr odu ced in
t h e n eu r on , secr et ed, a n d t r a vel a lon g t h e a xon t o
t h e syn a pse wh er e t h ey a r e r elea sed a n d t a ken u p
E Hormone -producing Ca pilla ry
ce ll (ne uron)
Figure 13.6. Hormonal mechanisms of mediating
cell-to-cell communication. A: Paracrine pathway. B: Auto-
crine pathway. C: Endocrine pathway. D: Synaptic pathway.
E: Neuroendocrine pathway.
by a n ea r by n eu r on wit h t h e a ppr opr ia t e r ecep-
t or s t o exer t a n effect .
● N e u r o e n d o c r i n e p a t h w a y : h or m on es a r e pr o-
du ced in a n eu r on , secr et ed, t r a vel a lon g t h e
a xon t o t h e syn a pse, a r e r elea sed, a r e t a ken u p
in t o t h e va scu la r syst em , a n d t r a vel t o dist a n t
cells wit h t h e a ppr opr ia t e r ecept or s t o exer t a n
effect .
 Th e St r ess R esp on se 325

Modu le 2 Th e St r ess R esp on se

Cell-t o-cell com m u n ica t ion is a n in t egr a l pa r t of
t h e st r ess r espon se. S t r e s s is t h e body’s r ea ct ion
t o h a r m fu l for ces (st r essor s) ca pa ble of dist u r bin g
h om eost a sis. An in dividu a l’s r espon se depen ds on
m a n y fa ct or s su ch a s a ge, gen er a l h ea lt h , t ype of
st r essor, t h e per sist en ce of t h e st r essor, per cept ion
of t h e st r essor, socia l su ppor t , a n d gen et ic in flu -
en ces. H om eost a sis is depen den t on a n a dequ a t e
r espon se t o st r ess t h r ou gh m obilizin g en er gy, a c-
t iva t in g defen se m ech a n ism s, a n d r epa ir in g a n y
da m a ge. An in a dequ a t e or even excessive r espon se
t o st r ess ca n r esu lt in dest r u ct ion of body t issu es.
Th e n eu r oen docr in e r espon se a n d h or m on es pla y a
vit a l r ole in t h is pr ocess. F igu r e 13.7 det a ils h ow
t h e st r ess r espon se in volves n eu r ologic a n d h or-
m on a l in flu en ces.

Brains te m

Ce re bral c o rtex

Thalamus

Limbic s ys te m

Hypo thalamus

Pituitary g land

Auto no mic ne rvo us

s ys te m

Adre nal c o rte x

Inc re as e d c o rtis o l

Immune s ys te m

Figure 13.7. Concept map. Stress pathways. The broken line represents negative feedback. (Modified from Porth CM.
Essentials of Pathophysiology: Concepts of Altered Health States. Philadelphia, PA: Lippincott Williams & Wilkins; 2003,
with permission.)
326 C h a p t e r 13: Alt er ed H or m on a l a n d Met a bolic Regu la t ion
Neurologic Response to Stress
Neu r ologic in flu en ces, pa r t icu la r ly t h e cen t r a l n er-
vou s syst em (CNS), a r e in st r u m en t a l in t h e st r ess
r espon se. Th e br a in st em coor din a t es t h e per for-
m a n ce of t h e a u t on om ic n er vou s syst em , cer ebr a l
cor t ex, lim bic syst em , a n d h ypot h a la m u s a n d pr o-
du ces n or epin eph r in e so t h e body ca n qu ickly defen d
a ga in st t h e st r essor. Specific st r u ct u r es in t h e CNS
t h a t pla y a m a jor r ole in clu de:
● Au t on om ic n e r vou s syst e m : increases heart rate,
blood pressure, respiratory rate, pupil dilation, and
sweating. Blood flow is increased to the muscles,
heart, and lungs in preparation of “fight or flight.”
Gastric function decreased to shunt blood to vital
organs. Altered blood flow, decreased oxygenation to
gastric tissues, and prolonged cortisol exposure may
result in “stress ulcers” of the gastrointestinal tract.
● Ce r e b r a l cor t e x: regulates cognitive activities such
as intense focus, planning, attention, and persistence.
● L im b ic s y s t e m : r egu la t es em ot ion a l a ct ivit ies
su ch a s fea r, a n xiet y, a n ger, a n d excit em en t , a n d
st im u la t es t h e r et icu la r a ct iva t in g syst em .
● T h a la m u s : in t en sifies sen sor y in pu t r ela t ed t o
t h e st r essor su ch a s vision , h ea r in g, a n d sm ell.
● H y p o t h a la m u s : r elea ses h or m on es t o in it ia t e
t h e n eu r oen docr in e r espon se; a ct s on t h e a u t o-
n om ic n er vou s syst em .
● R e t ic u la r a c t iv a t in g s y s t e m : in cr ea ses a ler t -
n ess a n d m u scle t en sion a n d con t r ibu t es t o st im -
u la t ion of t h e a u t on om ic n er vou s syst em .
Hypo thalamus
Adre na l
me dulla
Cortis ol ACTH
Figure 13.8. Stimulation of cortisol and catecholamines in the stress response. ACTH, adrenocorticotropic hormone; CRH,
corticotropin-releasing hormone.
Hormonal Response to Stress
Fou r m a jor h or m on es or gr ou ps of h or m on es a r e in -
st r u m en t a l in t h e en docr in e r espon se t o st r ess. F ir st ,
st r ess st im u la t es t h e r elea se of CRH fr om t h e h ypo-
t h a la m u s. CRH st im u la t es t h e pit u it a r y t o secr et e
a dr en ocor t icot r opic h or m on e (ACTH ), wh ich in t u r n
st im u la t es t h e a dr en a l gla n ds t o secr et e cor t isol. As
depict ed in Ta ble 13.1, cor t isol is n eeded t o in cr ea se
m et a bolism a n d r egu la t e blood glu cose levels for
en er gy a n d a lso a ct s a s a pot en t a n t i-in fla m m a t or y.
Secon d, r elea se of t h e ca t ech ola m in es (epin eph r in e,
n or epin eph r in e, a n d dopa m in e) is t r igger ed by t h e
sym pa t h et ic n er vou s syst em , wh ich a lso a ct s on t h e
a dr en a l gla n ds (Fig. 13.8). Ca t ech ola m in es in du ce a
n eu r ologic r espon se t o r ecept ive or ga n s. For exa m -
ple, blood flow is sh u n t ed t o vit a l or ga n s, su ch a s
t h e h ea r t , br a in , a n d lu n gs. As a r esu lt , h ea r t r a t e
in cr ea ses, blood pr essu r e in cr ea ses, r espir a t or y r a t e
in cr ea ses, a n d t h e per son becom es m u ch m or e a ler t .
Th e skelet a l m u scles a lso becom e a ct iva t ed t o a llow
a r a pid esca pe. Blood is sh u n t ed a wa y fr om t h e skin
a n d st om a ch . So, t h e per son will look pa le or a sh en
a n d digest ion is decr ea sed.
Stop and Consider
How do you usually respond to stress? Think
about the last time you were in a haunted
house or were really scared. How did your body
respond? How does this correlate to the neuroen-
docrine response described in this section?
Ca te chola mine s
CRH
Pituitary Brains te m
Corticotropin
Autonomic
ne rvous s ys te m
ma nife s ta tions

General Adaptation Syndrome
Th e n eu r oen docr in e r espon se is oft en in it ia t ed by a
st r essor. G e n e r a l a d a p t a t io n s y n d r o m e is a t er m
u sed t o descr ibe t h is n eu r oen docr in e r espon se a n d
t h e cor r espon din g ph ysiologic ch a n ges. Gen er a l a d-
a pt a t ion syn dr om e is gen er a lly divided in t o t h r ee
m a jor st a ges: (1) t h e a la r m st a ge; (2) t h e r esist a n ce
st a ge; a n d (3) t h e exh a u st ion st a ge. In t h e a la r m
st a ge, ca t ech ola m in es a n d cor t isol a r e r elea sed in
r espon se t o st im u la t ion of t h e sym pa t h et ic n er vou s
syst em , t h e h ypot h a la m ic–pit u it a r y a xis, a n d t h e
a dr en a l gla n ds. Th is st a ge is oft en r efer r ed t o a s t h e
“figh t or fligh t ” st a ge. Th ese h or m on es pr epa r e t h e
body for defen se a ga in st t h e st r essor. In sh or t -t er m
a n d m ild st r ess sit u a t ion s, t h e r espon se m a y r esolve
wit h in t h e a la r m st a ge a n d m a y be lim it ed in in t en -
sit y a n d du r a t ion .
Ot h er h or m on es a r e a lso a t pla y ea r ly in t h e st r ess
r espon se. Su ppr ession of cer t a in h or m on es, su ch a s
gr owt h h or m on e, t h yr oid h or m on e, a n d t h e r epr o-
du ct ive h or m on es, is n ecessa r y t o con ser ve en er gy
t h a t will be n eeded t o fen d off t h e st r essor. An t idi-
u r et ic h or m on e is in cr ea sed t o r et a in flu id t h er eby
m a in t a in in g t h e blood pr essu r e n eeded t o per fu se
vit a l t issu es. On ce t h e st r ess is r esolved, pr est r ess
h or m on e levels a r e r esu m ed.
Modu le 3 Alt e r e d H o r m o n e F u n c t io n
A n u m ber of m ech a n ism s ca n im pa ct h or m on es
(Box 13.2). Most com m on ly, h or m on e excesses or
deficit s a r ise fr om im pa ir m en t of t h e en docr in e (se-
cr et in g) gla n d, la ck of h or m on e syn t h esis, excessive
h or m on e syn t h esis, im pa ir ed r ecept or bin din g, im -
pa ir ed feedba ck m ech a n ism s, or a n a lt er ed cellu la r
r espon se t o t h e h or m on e. P r oblem s wit h h or m on e
fu n ct ion ca n m a n ifest t h r ou gh in a dequ a t e or ex-
cessive pr odu ct ion , com posit ion , secr et ion , r ecept or
bin din g, u pt a ke, m et a bolism , or elim in a t ion .
Damage to the Hypothalamic–Pituitary
Axis
Da m a ge t o t h e h ypot h a la m ic–pit u it a r y a xis du e t o
in fect ion , in fla m m a t ion , t u m or s, degen er a t ion , h y-
poxia , h em or r h a ge, or gen et ic defect s ca n lea d t o
pr oblem s wit h t h e pr odu ct ion a n d secr et ion of m u l-
t iple h or m on es. Refer t o Ta ble 13.1 t o r eview wh ich
h or m on es a r e syn t h esized a n d secr et ed t h r ou gh t h e
h ypot h a la m ic–pit u it a r y a xis. H y p o p it u it a r is m
Alt e r e d H o r m o n e F u n c t io n 327
Per sist en t st r ess is followed by t h e r esist a n ce
st a ge, wh er eby cor t isol levels decr ea se t h r ou gh
n ega t ive feedba ck m ech a n ism s. E xcess cor t isol is
h elpfu l in t h e ea r ly st a ges of st r ess t o in cr ea se m e-
t a bolism by br ea kin g down pr ot ein s, r elea sin g lipids,
a n d in cr ea sin g cir cu la t in g glu cose. Th is gives t h e
body en er gy for figh t or fligh t . H owever, over t im e,
h yper cor t isolism is det r im en t a l, lea din g t o exh a u s-
t ion of in fla m m a t or y a n d im m u n e r espon ses, exces-
sive loss of body pr ot ein s a n d br ea kdown of t issu es,
a n d glu cose in t oler a n ce. Th er efor e, cor t isol secr et ion
is n ot a n effect ive m et h od of a da pt in g t o pr olon ged
st r ess. As in dica t ed, som e h or m on e levels a r e su p-
pr essed wit h st r ess a n d r em a in so du r in g t h e r esis-
t a n ce st a ge. Th is a lso h a s det r im en t a l effect s. Loss
of cir cu la t in g t h yr oid, gr owt h , a n d r epr odu ct ive h or-
m on es ca n h a ve lon g-t er m effect s on lin ea r gr owt h ,
m et a bolism , a n d r epr odu ct ion . Th e per sist en t in -
cr ea se in a n t idiu r et ic h or m on e t h r ou gh pr olon ged
st r ess is m a n ifest ed by excessive flu id r et en t ion a n d
su bsequ en t h yper t en sion (h igh blood pr essu r e).
Ch r on ic over wh elm in g st r ess lea ds t o exh a u st ion .
Th e exh a u st ion st a ge is ch a r a ct er ized by en er gy
deplet ion a n d degen er a t ion of cells, t issu es, or ga n s,
a n d or ga n syst em s. Sever e, pr olon ged st r ess con t r ib-
u t es t o poor h ea lt h a n d m a r ks a sign ifica n t loss t o
h om eost a sis.
is a gen er ic t er m in dica t in g decr ea sed secr et ion of
on e or m or e pit u it a r y h or m on es. H y p e r p it u it a -
r is m is a n excess of pit u it a r y h or m on e secr et ion .
P a n h y p o p it u it a r is m in dica t es a decr ea se in pi-
t u it a r y h or m on es. Beca u se t h e pit u it a r y secr et es
Box 13.2 P r o c e s s o Alt e r in g H o r m o n e
F u n c t io n
Th e followin g qu est ion s a ddr ess t h e pot en t ia l pr oblem s
t h a t ca n a lt er h or m on e fu n ct ion :
1. Is t h er e im pa ir m en t of t h e h ypot h a la m ic–pit u it a r y
a xis?
2. Is t h er e im pa ir m en t of t h e en docr in e gla n d?
3. Is t h er e t oo lit t le or t oo m u ch h or m on e t h a t is bein g
pr odu ced a n d secr et ed?
4. Is t h e gla n d pr odu cin g a ct ive h or m on e?
5. Is r ecept or bin din g a dequ a t e?
6. Is t h e t a r get cell r espon din g t o t h e h or m on e?
7. Is t h e n ega t ive feedba ck loop im pa ir ed?
8. Is h or m on e bein g pr odu ced ect opica lly?
9. Is h or m on e m et a bolism (in a ct iva t ion ) a n d elim in a t ion
im pa ir ed?
328 C h a p t e r 13: Alt er ed H or m on a l a n d Met a bolic Regu la t ion

ACTH , t h yr oid-st im u la t in g h or m on e (TSH ), gr owt h pr oblem s wit h in t h e cell ca n lea d t o im pa ir ed cell-

h or m on e (GH ), follicle-st im u la t in g h or m on e (F SH ),
lu t ein izin g h or m on e (LH ), a n d pr ola ct in , da m a ge t o
t h e pit u it a r y h a s a br oa d r a n ge of clin ica l m a n ifes-
t a t ion s r ela t ed t o t h e loss of t h yr oid, a dr en a l, a n d
r epr odu ct ive gla n ds a n d pr oblem s wit h gr owt h .
Damage to Endocrine Glands
Dest r u ct ion of en docr in e gla n ds or t h e la ck of a c-
t ive h or m on e secr et ion ca n a lso lea d t o pr oblem s
wit h t a r get -t issu e fu n ct ion . E n docr in e gla n ds ca n be
im pa ir ed t h r ou gh gen et ic defect s, a u t oim m u n e con -
dit ion s, degen er a t ion , a t r oph y, in fect ion , in fla m m a -
t ion , n eopla st ic gr owt h s, h ypoxia , r a dia t ion , cer t a in
m edica t ion s, a n d ot h er t ypes of in ju r y. Th e gla n d
becom es in ca pa ble of a dequ a t ely r espon din g t o n eu -
r oen docr in e m essa ges, a n d h or m on e secr et ion is
depr essed or a bsen t . E xcessive st im u la t ion of t h e
en docr in e gla n d ca n r esu lt in h yper pla sia a n d a n
excessive a m ou n t of h or m on e pr odu ct ion a n d se-
cr et ion . In som e ca ses, t h e en docr in e gla n d is fu n c-
t ion in g a ppr opr ia t ely, bu t t h e h or m on e m a y la ck
t h e n ecessa r y biologic a ct ivit y t o elicit t h e cellu la r
r espon se. Th is oft en occu r s wh en a n t ibodies dest r oy
biologica lly a ct ive h or m on e even a ft er t h e h or m on e
is secr et ed fr om t h e gla n d.
t o-cell com m u n ica t ion a n d h or m on e r espon siven ess.
In t r a cellu la r disor der s in volve m a lfu n ct ion of t h e in -
n er m ech a n ism s of t h e cell. For exa m ple, if h or m on e
m ech a n ism s wer e a r ela y r a ce, t h e ba t on wou ld h a ve
been pa ssed fr om sever a l r u n n er s (t h e h ypot h a la -
m u s, t h e pit u it a r y, t h e secr et in g gla n d, t h e va scu la r
syst em , a n d t h e r ecept or on t h e t a r get cell) a n d t h en
dr opped on ce in side t h e cell. In t r a cellu la r in a dequ a -
cies m ost oft en in volve im pa ir ed en zym e or pr ot ein
pr odu ct ion or u sa ge wit h in t h e cell.
Damage to Feedback Mechanisms
Feedba ck m ech a n ism s m a y fa il t o r espon d t o h or-
m on e levels a n d con t in u e t o su ppr ess or st im u la t e
h or m on e pr odu ct ion a n d secr et ion . Th is im pa ir m en t
ca n occu r a t a n y poin t a lon g t h e h ypot h a la m ic–pi-
t u it a r y a xis, a t t h e level of t h e secr et in g gla n d, t h e
r ecept or s, or t a r get t issu es. Im pa ir m en t of feedba ck
m ech a n ism s m a y be a pr oblem of ect opica lly pr o-
du ced h or m on e. Som e n eopla sm s a r e ca pa ble of pr o-
du cin g a n d secr et in g ect opic h or m on es. Th e t u m or
is n ot pa r t of t h e n ega t ive feedba ck m ech a n ism a n d
con t in u es t o pr odu ce a n d secr et e excessive h or m on es
despit e h igh ser u m levels. Rem ova l of t h e t u m or will
oft en r esu lt in r esolu t ion of h or m on e h yper secr et ion .
Th e m ost com m on ect opica lly pr odu ced h or m on es
a r e ADH a n d ACTH .

Damage to Cell Receptors Damage to Metabolism and

Recept or bin din g a n d cell-t o-cell com m u n ica t ion Elimination Mechanisms
a r e r equ ir ed t o elicit a cellu la r r espon se. Disor der s
of r ecept or bin din g m a y in volve on e or m or e of t h e Th e m et a bolism (in a ct iva t ion ) a n d elim in a t ion of
followin g: h or m on es is essen t ia l t o m a in t a in in g h om eost a -
sis. Th e im pa ir ed a bilit y t o m et a bolize or elim in a t e
1. A decr ea sed n u m ber of r ecept or s h or m on es, su ch a s t h a t wh ich m a y occu r wit h liver
2. Th e la ck of r ecept or sen sit ivit y t o t h e h or m on e or kidn ey disea se, will r esu lt in excess cir cu la t in g
3. Th e pr esen ce of a n t ibodies t h a t block r ecep- h or m on e.
t or sit es or occu py t h e r ecept or sit e a n d m im ic t h e
h or m on e
4. Th e pr esen ce of t u m or cells wit h r ecept or a ct ivit y General Manifestations of Altered
t h a t depr ives t h e u n a ffect ed cells of t h e h or m on e Hormone Function
Im pa ir ed r ecept or bin din g is m a n ifest ed t h r ou gh
H ypopit u it a r ism , a deficit of on e or m or e pit u it a r y
cir cu la t in g levels of h or m on es t h a t a r e in ca pa ble of
elicit in g a n a ppr opr ia t e cellu la r r espon se. Likewise, h or m on es, u su a lly h a s a gr a du a l on set , a n d clin -
ica l m a n ifest a t ion s a r e
n ot eviden t u n t il m ost of
F R O M T H E L AB t h e pit u it a r y gla n d h a s
been dest r oyed. Th e gen -
Hormone function is measured directly or indirectly. Current detection of hormone activity er a l m a n ifest a t ion s a r e
is assayed with nonradioactive immunoassays with fluorescence labels, enzymes, and other oft en va gu e a n d m a y in -
techniques. Chemiluminescence is one such technique that uses light-producing chemical clu de fa t igu e, wea kn ess,
reactions to detect amounts of hormone in ligand-binder assays. a n or exia , sexu a l dysfu n c-
t ion , gr owt h im pa ir m en t ,
 C lin ic a l Mo d e ls 329

Ta b le 13.2 Gen er a l Ma n ifest a t ion s of Select H or m on e E xcesses a n d Deficit s

H or m on e Excess D e ic it
An t idiu r et ic F lu id r et en t ion , low u r in e ou t pu t , h ypon a t r em ia E xcessive wa t er losses t h r ou gh t h e
h or m on e u r in e, lea din g t o n a u sea , vom it in g, fa -
t igu e, m u scle t h ir st , deh ydr a t ion , ca n
pr ogr ess t o sh ock t wit ch in g; ca n pr ogr ess
t o con vu lsion s a n d dea t h
Glu cocor t icoids Tr u n ca l obesit y, m oon fa ce, bu ffa lo h u m p, glu cose H ypoglycem ia , a n or exia , n a u sea , vom it -
(cor t isol) in t oler a n ce, a t r oph ic skin , st r ia e, ost eopor osis, psy- in g, fa t igu e, wea kn ess, weigh t loss, poor
ch ologica l ch a n ges, poor wou n d h ea lin g, in cr ea sed st r ess r espon se
in fect ion s
Gr owt h h or m on e Befor e pu ber t y (ca lled giga n t ism ): excessive skele- Sh or t st a t u r e, obesit y, im m a t u r e fa cia l
t a l gr owt h . Aft er pu ber t y (ca lled a cr om ega ly): bon y fea t u r es, dela yed pu ber t y, h ypoglycem ia ,
pr olifer a t ion of spin e, r ibs, a n d fa ce, h a n ds, a n d feet , seizu r es in ch ildr en ; obesit y, in su lin r e-
en la r ged t on gu e, edem a , over a ct ive seba ceou s gla n ds, sist a n ce, a n d h igh cir cu la t in g lipids in
coa r se skin a n d body h a ir, pa in , wea kn ess, a n d in - a du lt s
fla m m a t ion r ela t ed t o excessive gr owt h ; h yper t en sion
a n d left h ea r t fa ilu r e m a y a lso occu r
Min er a lo- H yper t en sion , h ypoka lem ia , h yper n a t r em ia , m u scle Wea kn ess, n a u sea , a n or exia , h ypon a t r e-
cor t icoids wea kn ess, fa t igu e, polyu r ia , polydipsia , m et a bolic m ia , h yper ka lem ia , deh ydr a t ion , h ypo-
(a ldost er on e) a lka losis t en sion , sh ock, dea t h
Th yr oid h or m on e H yper m et a bolism , weigh t loss, dia r r h ea , exoph t h a l- H ypom et a bolism , weigh t ga in , con st ipa -
m os, a n xiet y, goit er t ion , goit er, dr y skin , coa r se h a ir
Pa r a t h yr oid H yper ca lcem ia , excessive ost eocla st ic a ct ivit y a n d H ypoca lcem ia , m u scle spa sm s, h yper r e-
h or m on e bon e r esor pt ion , pa t h ologic fr a ct u r es, for m a t ion of flexia , seizu r es, bon e defor m it ies
r en a l ca lcu li

dr y skin , con st ipa t ion , a n d cold in t oler a n ce.
H yper pit u it a r ism , a n excess of on e or m or e pit u -
it a r y h or m on es, a lso h a s a wide r a n ge of m a n ifes-
t a t ion s depen din g on wh ich h or m on es a r e eleva t ed.
Ta ble 13.2 det a ils gen er a l m a n ifest a t ion s of specific
h or m on es excesses a n d deficit s.
Diagnosing and Treating Altered
Hormone Function
Dia gn osin g a lt er a t ion s in h or m on a l or m et a bolic
fu n ct ion begin s wit h a com plet e pa t ien t h ist or y a n d
ph ysica l exa m in a t ion a n d oft en r elies on m ea su r in g
h or m on e levels or ot h er in dica t or s in t h e blood or
u r in e. H or m on e su ppr ession or st im u la t ion t est s ca n
be u sed t o det ect h or m on e r espon ses. Beca u se secr e-
t ion r a t es ca n flu ct u a t e over t im e, u r in e h or m on e
levels a r e oft en collect ed over a 24-h ou r per iod.
Ser u m elect r olyt e, glu cose, ca lciu m , a n d ot h er la b
t est s m a y pr ovide in dir ect in for m a t ion on h or m on e
fu n ct ion in g. Im a gin g st u dies, su ch a s com pu t ed
t om ogr a ph y (CT) or m a gn et ic r eson a n ce im a gin g
(MRI) sca n s, m a y be n eeded t o loca t e a t u m or t h a t
cou ld be su ppr essin g or st im u la t in g h or m on e secr e-
t ion . Gen et ic t est in g m a y a lso be n eeded t o iden -
t ify a gen et ic a lt er a t ion t h a t is a ffect in g h or m on e
fu n ct ion .
Tr ea t in g h or m on e a lt er a t ion s va r ies depen din g
on t h e ca u se. H or m on e eleva t ion s r equ ir e elim i-
n a t in g t h e excess h or m on e. Th is oft en occu r s by
r em ovin g t u m or s t h a t m a y be secr et in g ect opic
h or m on e, r em ovin g a ll or pa r t of t h e cor r espon d-
in g en docr in e gla n d, or a dm in ist er in g m edica t ion s
t h a t block t h e effect s of t h e h or m on e. Low h or m on e
levels oft en r equ ir e lifelon g r epla cem en t t h r ou gh
ph a r m a cot h er a py.

Modu le 4 C lin ic a l Mo d e ls

Th e followin g clin ica l m odels h a ve been select ed fu n ct ion , a n d a lt er ed fu n ct ion of t h e r epr odu ct ive or-
t o a id in t h e u n der st a n din g a n d a pplica t ion of a l- ga n s a n d t h e en docr in e pa n cr ea s h a ve been r eser ved
t er ed h or m on a l pr ocesses a n d effect s. Th e st r u ct u r e, for Ch a pt er s 14 a n d 20, r espect ively.
330 C h a p t e r 13: Alt er ed H or m on a l a n d Met a bolic Regu la t ion
Syndrome of Inappropriate
Antidiuretic Hormone Secretion
ADH is pr odu ced in t h e h ypot h a la m u s, t r a vels t o
t h e post er ior pit u it a r y, a n d is r elea sed in t o t h e cir-
cu la t ion . ADH con t r ols flu id ba la n ce by r egu la t in g
r ea bsor pt ion of wa t er by t h e kidn eys (F ig. 13.9). Se-
cr et ion r a t es of ADH a r e ba sed on ser u m osm ola lit y
a n d ext r a cellu la r flu id volu m e. Th e h ypot h a la m u s
sen ses ch a n ges in ser u m osm ola lit y a n d a lt er s secr e-
t ion of ADH . Sim ila r ly, sen sor s in t h e blood vessels
r ecogn ize ch a n ges in blood volu m e a n d ca n a ffect
ADH secr et ion . H igh levels of ADH st im u la t e wa -
t er r et en t ion ; low levels of ADH t r igger wa t er loss
t h r ou gh u r in a t ion .
Th e s y n d r o m e o in a p p r o p r ia t e a n t id iu r e t ic
h o r m o n e (S I AD H ) secr et ion is a con dit ion of exces-
sive pr odu ct ion a n d r elea se of ADH despit e ch a n ges
in ser u m osm ola lit y a n d blood volu m e. Alt h ou gh
ADH levels ca n t r a n sien t ly in cr ea se wit h cer t a in
m edica t ion s a n d st r essfu l st im u li, su ch a s t r a u m a ,
exposu r e t o t em per a t u r e ext r em es, pa in con dit ion s,
su r ger y, or in fect ion , t h e dia gn osis of SIADH is t yp-
ica lly r eser ved for t h ose wit h ou t su ch st im u li t o
expla in excessive ADH r elea se. Th e m ost com m on
Hypotha la mus
S e rum os mola lity Blood volume
Pos te rior
pituita ry
S e cre tion of
Thirs t
ADH
Re a bs orption of
Wa te r Inge s tion
wa te r by the kidney
Extra ce llula r
wa te r volume
Figure 13.9. Pathways for regulation of extracellular fluid
volume by thirst and antidiuretic hormone. ADH, antidi-
uretic hormone. (Modified from Porth CM. Essentials
of Pathophysiology: Concepts of Altered Health States.
Philadelphia, PA: Lippincott Williams & Wilkins; 2003,
with permission.)
ca u se of SIADH is a t u m or, som ewh er e in t h e body,
wh ich is secr et in g ect opic ADH .
PATHOPHYSIOLOGY
An t idiu r et ic h or m on e pr om ot es wa t er r et en t ion by
in cr ea sin g t h e per m ea bilit y of t h e n eph r on s in t h e
kidn eys. Most of t h e body wa t er a ccu m u la t es in t r a -
cellu la r ly a n d a lt er s cell fu n ct ion . Th e CNS is m ost
sen sit ive t o t h ese ch a n ges. Beca u se wa t er in it ia lly
a ccu m u la t es in t r a cellu la r ly, edem a or flu id over loa d
in t h e va scu la r syst em is u n com m on . Th e excess cir-
cu la t in g flu id wit h in cells in cr ea ses t ot a l body wa -
t er con cen t r a t ion a n d even t u a lly dilu t es t h e sodiu m
con cen t r a t ion in t h e ext r a cellu la r spa ce.
CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s a r e r ela t ed t o h ypot on ic
h ypon a t r em ia a n d in clu de a decr ea sed a n d con -
cen t r a t ed u r in e ou t pu t . Th e sever it y of sym pt om s
depen ds on t h e ser u m sodiu m level a n d t h e r a t e of
on set . Sign ifica n t sym pt om s u su a lly do n ot m a n ifest
u n t il ser u m sodiu m is less t h a n 115 t o 120 m E q/L.
A m or e r a pid on set of h ypon a t r em ia lea ds t o gr ea t er
sever it y of sym pt om s. In it ia lly, t h ese sym pt om s in -
clu de a n or exia , n a u sea , vom it in g, h ea da ch e, ir r it a -
bilit y, disor ien t a t ion , m u scle cr a m ps, a n d wea kn ess.
As t h e ser u m sodiu m level dr ops below 110 m E q/L,
a ddit ion a l sym pt om s em er ge, in clu din g psych osis,
ga it dist u r ba n ces, seizu r es, or com a .
DIAGNOSTIC CRITERIA
Dia gn osis is ba sed on t h e followin g clin ica l a n d la b-
or a t or y fin din gs:
● H ypon a t r em ia (ser u m sodiu m less t h a n
135 m E q/L)
● H ypot on icit y (pla sm a osm ola lit y less t h a n
280 m Osm /kg)
● Decr ea sed u r in e volu m e
● H igh ly con cen t r a t ed u r in e wit h a h igh sodiu m
con t en t
● Absen ce of r en a l, a dr en a l, or t h yr oid a bn or m a lit ies
TREATMENT
Tr ea t m en t focu ses on r em ovin g t h e ca u se of
SIADH if possible. For pa t ien t s wit h m ild sym pt om s
of h ypon a t r em ia , wa t er r est r ict ion is oft en t h e on ly
n ecessa r y t h er a py. Sever e h ypon a t r em ia gen er a lly
r equ ir es isot on ic or h yper t on ic sa lin e a dm in ist er ed
in t r a ven ou sly. H yper t on ic in t r a ven ou s (IV) solu -
t ion s a r e r eser ved for t h ose in dividu a ls wit h sever e
h ypon a t r em ia wh o displa y a lt er a t ion s in m en t a l
st a t u s. Medica t ion s m a y be a dm in ist er ed t o block
 C lin ic a l Mo d e ls 331

t h e effect s of ADH or t o
in cr ea se u r in e ou t pu t if
r em ovin g t h e ca u se is R E S E AR C H N O T E S
n ot fea sible.
Like dominoes, clinical manifestations of endocrine disorders can have a direct effect on
many other aspects of homeostasis. For example, a recent large study confirmed that hy-
Diabetes ponatremia, a common clinical manifestation of SIADH, was associated with subsequent
Insipidus development of osteoporosis and fractures due to bone fragility in a matched case-control
study of over 80,000 patients. In addition, the odds of developing osteoporosis or fragility
D ia b e t e s in s ip id u s fracture increased incrementally with each reduction in serum sodium level. 1
(D I ) is a con dit ion of in -
su fficien t ADH t h a t r e-
su lt s in t h e in a bilit y of
t h e body t o con cen t r a t e
or r et a in wa t er (Fig. 13.10). Th e pr eva len ce h a s been
est im a t ed a t 3 per 100,000 popu la t ion . 2 Th r ee m a jor
ca u ses of DI in clu de:
Ante rior Pos te rior
● In su fficien t pr odu ct ion of ADH by t h e h ypot h a l- pituita ry pituita ry
a m u s or in effect ive secr et ion by t h e post er ior
pit u it a r y
● In a dequ a t e kidn ey r espon se t o t h e pr esen ce of
ADH , a lso ca lled n eph r ogen ic DI
● In gest ion of ext r em ely la r ge volu m es of flu ids
a n d decr ea sin g ADH levels; wa t er in t oxica t ion
ca n som et im es be a t t r ibu t ed t o a psych ia t r ic
dist u r ba n ce
ADH De ficie ncy

PATHOPHYSIOLOGY
Im pa ir m en t of h ypot h a la m ic osm or ecept or s a ft er
t r a u m a or su r ger y t o a r egion a t or n ea r t h e h ypot h a l- H2 O
a m u s is t h e m ost com m on ca u se. Neph r ogen ic DI ca n
be obser ved in t h ose wit h ch r on ic r en a l in su fficien cy, Colle cting
duct
lit h iu m (a dr u g u sed t o t r ea t m a n ic-depr essive dis-
or der ) t oxicit y, h yper ca lcem ia , h ypoka lem ia , or wit h
disea se of t h e r en a l t u bu les. Ra r ely, n eph r ogen ic DI
is in h er it ed a s a n X-lin ked disor der. Impa irme nt of wa te r
re a bs orption

Stop and Consider Urine

What effect would drinking alcohol have on ADH
levels? De cre a s e d re na l wa te r
re a bs orption

CLINICAL MANIFESTATIONS
Ma n ifest a t ion s depen d on t h e sever it y of DI. Loss Ina ppropria te ly dilute
of ADH or in a dequ a t e kidn ey r espon se t o ADH r e- urine
su lt s in p o ly u r ia (la r ge volu m e u r in e ou t pu t ) a n d
excessive t h ir st . Th e u r in e is h igh ly dilu t e wit h a low
specific gr a vit y. Loss of flu ids lea ds t o ser u m h yper-
osm ola lit y a n d sever e deh ydr a t ion . Sh ock a n d dea t h Diabe te s Ins ipidus
Polyuria , Polydips ia
ca n occu r if u n t r ea t ed.

Figure 13.10. The mechanism of diabetes insipidus. ADH,

DIAGNOSTIC CRITERIA
antidiuretic hormone. (Modified from Rubin E, Farber JL.
Dia gn osis is m a de t h r ou gh a ca r efu l pa t ien t h is- Pathology. 4th ed. Philadelphia, PA: Lippincott Williams &
t or y a n d ph ysica l exa m in a t ion . Th e pa t ien t h ist or y Wilkins; 2005, with permission.)
332 C h a p t e r 13: Alt er ed H or m on a l a n d Met a bolic Regu la t ion
oft en in clu des r ecen t su r ger y t o r em ove a t u m or of
t h e br a in , or ot h er cr a n ia l su r ger y, or h ea d t r a u m a .
Th e ph ysica l exa m in a t ion m a y det ect sign s of deh y-
dr a t ion a n d possibly a n en la r gem en t of t h e bla dder
du e t o con st a n t over-fillin g. La bor a t or y m ea su r e-
m en t of ser u m solu t e con cen t r a t ion , ADH levels,
a n d u r in e-specific gr a vit y is u sed t o con fir m t h e di-
a gn osis. A u r in e-specific gr a vit y of 1.005 or less a n d
a u r in e osm ola lit y less t h a n 200 m Osm /kg a r e oft en
fou n d in DI.
TREATMENT
E xcept for t h ose wit h ou t a ccess t o wa t er, m ost pa -
t ien t s ca n dr in k en ou gh flu id t o r epla ce u r in e losses.
H ydr a t ion is a n im por t a n t a spect of t r ea t m en t . In
som e ca ses, pa r t icu la r ly in t h ose wit h in a dequ a t e
t h ir st , IV h ydr a t ion wit h a h ypot on ic solu t ion is r e-
qu ir ed. P h a r m a cologic t r ea t m en t m a y in clu de t h e
u se of desm opr essin (DDAVP ), a syn t h et ic va sopr es-
sin a n a log, wh ich a ct s a s a pot en t a n t idiu r et ic. If t h e
ca u se ca n n ot be cor r ect ed, t h is dr u g m a y be r equ ir ed
for t h e in dividu a l’s lifet im e.
Hyperthyroidism
H y p e r t h y r o id is m is a st a t e of excessive t h yr oid
h or m on e. H yper t h yr oidism ca n r esu lt fr om exces-
sive st im u la t ion t o t h e t h yr oid gla n d, disea ses of
t h e t h yr oid gla n d, or excess pr odu ct ion of TSH by
a pit u it a r y a den om a . Cer t a in m edica t ion s con t a in
la r ge a m ou n t s of iodin e, su ch a s cou gh expect or a n t s,
h ea lt h food su pplem en t s t h a t con t a in sea weed, a n d
iodin a t ed con t r a st dyes, wh ich ca n in du ce h yper t h y-
r oidism in t h yr oid-sen sit ive in dividu a ls.
Th e pr odu ct ion of t h yr oid h or m on e is a m u l-
t ist ep pr ocess. Th yr ot r opin -r elea sin g h or m on e
fr om t h e h ypot h a la m u s t r igger s t h e r elea se of
t h yr oid-st im u la t in g h or m on e fr om t h e a n t er ior pi-
t u it a r y, wh ich in t u r n st im u la t es t h e pr odu ct ion a n d
r elea se of t h e t h yr oid h or m on es fr om t h e t h yr oid
gla n d (see F ig. 13.3). Th e t h yr oid h or m on es a r e pr o-
du ced in t h e follicu la r (epit h elia l) cells of t h e t h y-
r oid. Th e follicles u se iodide fr om diet a r y in t a ke of
iodized sa lt , com bin e t h is wit h t yr osin e (a n a m in o
a cid) a n d secr et e t h is com bin a t ion in t o t h e cen t r a l
colloid por t ion of t h e follicle t o for m t h e t h yr oid h or-
m on es: t et r a iodot h yr on in e (T 4 ), a lso r efer r ed t o a s
t h yr oxin e, a n d t r iiodot h yr on in e (T 3 ). Wh en n eeded,
T 3 a n d T 4 a r e r ea bsor bed in t o t h e follicu la r cells a n d
t h en r elea sed in t o t h e cir cu la t ion . T 4 is r edu ced by
deiodin a t ion in t h e per iph er a l t issu es t o T 3 , t h e a c-
t ive for m of t h e h or m on e. Cir cu la t in g t h yr oid h or-
m on e pr ovides feedba ck t o t h e h ypot h a la m u s a n d
pit u it a r y gla n d. TSH is su ppr essed or a ct iva t ed
depen din g on cir cu la t in g t h yr oid h or m on e levels.
St r ess a n d cold en vir on m en t a l t em per a t u r es a lso
a ct t o st im u la t e t h yr oid h or m on e pr odu ct ion .
Stop and Consider
What would happen if you had a diet that did
not include iodized salt?
Th yr oid h or m on e h a s a n im pa ct t h r ou gh ou t t h e
body a n d pla ys a cr it ica l r ole in st im u la t in g m et a bo-
lism . Ot h er fu n ct ion s in clu de fa cilit a t in g t h e br ea k-
down of ca r boh ydr a t es, pr ot ein s, a n d fa t s for en er gy,
st im u la t in g h ea t a n d glu cose pr odu ct ion , pr odu cin g
st r u ct u r a l pr ot ein s, en zym es, a n d ot h er h or m on es,
a n d pr om ot in g gr owt h a n d developm en t in ch ildr en .
As a r esu lt of t h yr oid h or m on e r elea se, t h er e is:
● In cr ea sed glu cose a bsor pt ion
● Relea se of lipids fr om a dipose t issu e
● Met a bolism of pr ot ein s fr om m u scle t issu e
● In cr ea sed ch olest er ol br ea kdown in t h e liver
● In cr ea sed pr odu ct ion of m et a bolic by-pr odu ct s
● In cr ea sed oxygen con su m pt ion
● In cr ea sed body h ea t pr odu ct ion
● In cr ea sed ca r dia c ou t pu t
● In cr ea sed ga st r ic m ot ilit y
● In cr ea sed m u scle t on e a n d r ea ct ivit y
● In cr ea sed a ct iva t ion of cogn it ive pr ocesses
PATHOPHYSIOLOGY
G r a v e s d is e a s e , a n excessive st im u la t ion of t h e
t h yr oid gla n d, is t h e m ost com m on ca u se of h yper-
t h yr oidism a n d is t h e m ost com m on a u t oim m u n e
con dit ion in t h e Un it ed St a t es. P r eva len ce is es-
t im a t ed a t 0.5 per 1,000 popu la t ion . Wom en a r e
7 t o 10 t im es m or e likely t o develop Gr a ves disea se
t h a n m en .3 As wit h m a n y a u t oim m u n e con dit ion s,
t h e t r igger in g even t is oft en u n kn own ; gen et ic (e.g.,
fa m ily h ist or y or gen der ) a n d en vir on m en t a l (e.g.,
st r ess or sm okin g) fa ct or s a r e im plica t ed. In Gr a ves
disea se, IgG a n t ibodies bin d t o t h e TSH r ecept or on
t h yr ocyt es (t h yr oid cells) a n d st im u la t e excessive
t h yr oid h or m on e secr et ion , ca u sin g a st a t e of t h y -
r o t o x ic o s is . Ch r on ic t h yr ot oxicosis ca n be com pli-
ca t ed by pr ogr essive t h yr oid fa ilu r e a n d r esu lt in
h ypot h yr oidism . Th e t h yr oid gla n d u n der goes h y-
per pla sia du e t o excessive st im u la t ion . T h y r o t o x ic
c r is is , or t h yr oid st or m , is a su dden , sever e wor sen -
in g of h yper t h yr oidism t h a t m a y r esu lt in dea t h .
CLINICAL MANIFESTATIONS
Ma jor clin ica l m a n ifest a t ion s a r e r ela t ed t o en -
la r gem en t of t h e t h yr oid gla n d a n d t h e excessive
m et a bolic r a t e of t h e body (F ig. 13.11). Weigh t loss,
a git a t ion , r est lessn ess, swea t in g, h ea t in t oler a n ce,

Fine ha ir
Exophtha lmos
Goite r
Mus cle S we a ting
wa s ting
Ta chyca rdia ,
high output
fa ilure
We ight los s
Oligome norrhe a
Tre mor
Figure 13.11. Major clinical manifestations of Graves
disease.
dia r r h ea , t a ch yca r dia , pa lpit a t ion s, t r em or s, fin e
h a ir, oily skin , ir r egu la r m en st r u a l cycle in wom en ,
a n d wea kn ess a r e com m on fin din gs. Th e develop-
m en t of a g o it e r (en la r gem en t of t h e t h yr oid gla n d)
m a y occu r beca u se of follicu la r epit h elia l cell h yper-
pla sia . E x o p h t h a lm o s (a pr ot r u sion of t h e eyeba lls)
is a lso ch a r a ct er ist ic of Gr a ves disea se. Th is pr ot r u -
sion is u su a lly bila t er a l a n d r esu lt s fr om t h e in t er-
a ct ion of TSH -sen sit ized a n t ibodies in t er a ct in g wit h
fibr obla st a n t igen s fou n d in ext r a ocu la r m u scles a n d
t issu es. Th e in t er a ct ion r esu lt s in lym ph ocyt e in fil-
t r a t ion , edem a , a n d fibr obla st a ccu m u la t ion , wh ich
displa ces t h e eyeba lls for wa r d. E xoph t h a lm os oft en
per sist s despit e t r ea t m en t of h yper t h yr oidism .
DIAGNOSTIC CRITERIA
Dia gn osis of Gr a ves disea se is ba sed on t h e pa t ien t
h ist or y a n d ph ysica l exa m in a t ion ; com m on clin ica l
m a n ifest a t ion s a r e n ot ed. Th e pa t ien t h ist or y m a y
be sign ifica n t for a fa m ily h ist or y of a u t oim m u n e
disea se, t h yr oid disea se, or em igr a t ion fr om a n
iodin e-deficien t loca t ion . Th e ph ysica l exa m in a t ion
oft en r evea ls a n en la r ged a n d sligh t ly fir m t h yr oid
gla n d a s well a s pr ot r u sion of t h e eyes. Mea su r e-
m en t of ser u m TSH level is a u sefu l scr een in g t est
for t h e pr esen ce of h yper t h yr oidism ; h owever, t h e
dia gn osis of h yper t h yr oidism m u st be con fir m ed
C lin ic a l Mo d e ls 333
by t h e m ea su r em en t of ser u m -fr ee t h yr oxin e. In
t h yr ot oxicosis, TSH levels a r e gr ea t ly su ppr essed.
Th is is ca u sed by t h e n ega t ive feedba ck loop, wh ich
com m u n ica t es h igh t h yr oid h or m on e levels t o t h e
h ypot h a la m ic–pit u it a r y a xis a n d ca u ses su ppr es-
sion of TSH . La bor a t or y st u dies m a y a lso r evea l ele-
va t ed ser u m levels of T 3 a n d T 4 . In cr ea sed u pt a ke of
r a dioa ct ive iodin e by t h e t h yr oid gla n d con fir m s t h e
dia gn osis.
TREATMENT
Tr ea t m en t m ea su r es a r e ba sed on r edu cin g t h yr oid
h or m on e levels oft en t h r ou gh gla n d dest r u ct ion
via r a dioa ct ive iodin e, m edica t ion s t h a t block t h y-
r oid h or m on e pr odu ct ion , or, less com m on ly, su r gi-
ca l r em ova l of a ll or pa r t of t h e gla n d. F u ll a bla t ion
(r em ova l) of t h e t h yr oid gla n d r equ ir es lifelon g su p-
plem en t a t ion wit h or a l t h yr oid h or m on e r epla ce-
m en t t h er a py.
Hypothyroidism
H y p o t h y r o id is m is a st a t e of deficien t t h yr oid h or-
m on e. P r eva len ce is est im a t ed a t 3.7% of t h e popu -
la t ion wit h a five t im es gr ea t er r isk in t h ose older
t h a n a ge 80. 4 H ypot h yr oidism ca n be con gen it a l or
a cqu ir ed. Con gen it a l h ypot h yr oidism occu r s du r in g
fet a l developm en t a n d r esu lt s in a la ck of t h yr oid
gla n d developm en t , a la ck of a ppr opr ia t e syn t h esis
of t h yr oid h or m on e, or pr oblem s wit h TSH secr et ion .
In u t er o, m a t er n a l T 4 cr osses t h e pla cen t a ; t h er efor e,
t h e n ewbor n a ppea r s u n a ffect ed a t bir t h . If t h e ch ild
is u n t r ea t ed a ft er bir t h , t h e la ck of t h yr oid h or m on e
pr odu ct ion a n d secr et ion r esu lt s in m en t a l r et a r da -
t ion a n d im pa ir ed gr owt h , a con dit ion r efer r ed t o a s
c r e t in is m . Neon a t a l scr een in g, wh en in st it u t ed, de-
t ect s con gen it a l h ypot h yr oidism , a llowin g t r ea t m en t
wit h t h yr oid h or m on e r epla cem en t t o be in it ia t ed.
PATHOPHYSIOLOGY
Acqu ir ed h ypot h yr oidism ca n r esu lt fr om (1) defi-
cien t t h yr oid h or m on e syn t h esis; (2) dest r u ct ion of
t h e t h yr oid gla n d; or (3) im pa ir ed TSH or TRH se-
cr et ion . Com m on ca u ses of a cqu ir ed h ypot h yr oidism
in clu de a u t oim m u n it y, iodin e deficien cy, su r gica l r e-
m ova l of or r a dia t ion t h er a py t o t h e t h yr oid gla n d,
m edica t ion s t h a t dest r oy t h e t h yr oid gla n d, a n d ge-
n et ic defect s t h a t a ffect t h e t h yr oid h or m on es. Au t o-
im m u n e pr ocesses a t t a ck t h e t h yr oid gla n d or m a y
block TSH or t h e TSH r ecept or wit h ou t a ct iva t in g
t h e t h yr oid gla n d, a s in h yper t h yr oidism . H a sh im ot o
t h yr oidit is is a n a u t oim m u n e h ypot h yr oidism t h a t
ca n r esu lt in t ot a l dest r u ct ion of t h e t h yr oid gla n d.
334 C h a p t e r 13: Alt er ed H or m on a l a n d Met a bolic Regu la t ion

Th is con dit ion a ffect s wom en u p t o 10 t im es m or e
fr equ en t ly t h a n m en .5
CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s a r e oft en gr a du a l a n d in clu de
fa t igu e, cold in t oler a n ce, wea kn ess, weigh t ga in , dr y
skin , coa r se h a ir, con st ipa t ion , let h a r gy, im pa ir ed
r epr odu ct ion , a n d im pa ir ed m em or y (Fig. 13.12).
Goit er m a y a lso be pr esen t in h ypot h yr oidism a s t h e
gla n d en la r ges in a n effor t t o in cr ea se fu n ct ion . Di-
et a r y iodin e deficien cy, excess, or t h e u se of m edica -
t ion s t h a t su ppr ess t h yr oid h or m on es ca n st im u la t e
t h e developm en t of h ypot h yr oid goit er. My x e d e m a
is a u n iqu e ch a r a ct er ist ic fin din g of h ypot h yr oidism .
P r ot ein –ca r boh ydr a t e com plexes a ccu m u la t e in t h e
ext r a cellu la r m a t r ix dr a win g wa t er in t o t h e t issu es,
r esu lt in g in boggy, n on pit t in g, edem a t ou s t issu es es-
pecia lly of t h e fa ce a n d m u cou s m em br a n es, h a n ds,
a n d feet .
DIAGNOSTIC CRITERIA
Dia gn osis of h ypot h yr oidism is ba sed on pa t ien t h is-
t or y a n d ph ysica l exa m in a t ion , du r in g wh ich ch a r a c-
t er ist ic clin ica l m a n ifest a t ion s a r e n ot ed. La bor a t or y
st u dies in clu de t h e sen sit ive TSH a ssa y, fr ee T 4 , t o-
t a l T 4 , a n d T 3 u pt a ke, t h yr oid a u t oa n t ibodies, a n d
a n t it h yr oglobu lin t est s t o con fir m t h e dia gn ose a n d
pr ovide eviden ce a s t o ca u sa lit y. Ser u m t h yr oid h or-
m on es m a y be decr ea sed, a n d TSH is oft en eleva t ed.
TREATMENT
Tr ea t m en t focu ses on r epla cin g t h e deficien t h or-
m on e wit h t h e goa ls of n or m a liza t ion of TSH , T 4,
a n d T 3 levels, a lon g wit h a llevia t ion of t h e clin i-
ca l sign s a n d sym pt om s. Lifelon g t h yr oid h or m on e
r epla cem en t t h er a py is in it ia t ed a n d in cr ea sed
gr a du a lly u n t il opt im a l h or m on e levels a n d clin -
ica l im pr ovem en t a r e a ch ieved. Th e m ost com m on
dr u g u sed t o t r ea t h ypot h yr oidism is levot h yr oxin e
(Syn t h r oid, Levoxyl). Levot h yr oxin e is a syn t h et ic
for m of T 4 .
Cushing Syndrome
Th e a dr en a l gla n ds a r e loca t ed a t t h e a pex of
t h e k idn eys a n d con t a in t wo dist in ct pa r t s: (1)
a n ou t er a dr en a l cor t ex a n d (2) a n in n er a dr en a l
m edu lla (F ig. 13.13). Th e a dr en a l h or m on es pla y
a cr it ica l r ole in t h e st r ess r espon se. Th e a dr en a l
m edu lla secr et es epin eph r in e a n d n or epin eph r in e.
Ta ble 13.3 illu st r a t es t h e t h r ee ca t egor ies a n d
fu n ct ion s of st er oid h or m on es secr et ed by t h e a d-
r en a l cor t ex.

Coa rs e , brittle ha ir Stop and Consider

Would loss of the adrenal cortex or the adrenal
Pe riorbita l
Los s of la te ra l eye brows medulla be more problematic?
e de ma

Pa llor La rge tongue

C u s h in g s y n d r o m e r efer s t o a con dit ion of pr o-
lon ged exposu r e t o eleva t ed levels of eit h er en doge-
Hoa rs e ne s s n ou s (fr om t h e a dr en a l cor t ex or cor t isol-pr odu cin g
t u m or s) or exogen ou s glu cocor t icoids (a s wh en t a k-
Mus cle
wa s ting "Myxe de ma " he a rt in g glu cocor t icoid dr u gs). Glu cocor t icoids con t r ibu t e
(ca rdiome ga ly) t o m et a bolic fu n ct ion , t h e in fla m m a t or y a n d im m u n e

Ga s tric a trophy
Caps ule
Co rtex
Cons tipa tion
Mine ra locorticoids
Glucocorticoids
Anovula tory
Androge ns
cyle s
Es troge ns

Me dulla
Nore pine phrine
Epine phrine
Pe riphe ra l e de ma Adre na l gla nd
(ha nds, fe e t, e tc.)

Figure 13.12. Major clinical manifestations of Figure 13.13. Hormone secretion from the adrenal cortex
hypothyroidism. and adrenal medulla.

Ta b le 13.3 Ca t egor ies of St er oid H or m on es Secr et ed by t h e Adr en a l
Cor t ex
Ca t egor y Ma jo r E x a m p le
Min er a locor t icoids Ald oster on e (secr et ion
st im u la t ed by t h e r en in –
a n giot en sin syst em a n d
ser u m pot a ssiu m levels)
Glu cocor t icoids Cor tisol (secr et ion st im u -
la t ed by cor t icot r opin -r e-
lea sin g h or m on e fr om t h e
h ypot h a la m u s a n d a dr en o-
cor t icot r opic h or m on e fr om
t h e a n t er ior pit u it a r y)
Adr en a l sex An d r ogen s (secr et ion ; see
cor t isol)
r espon ses, a n d t h e st r ess r espon se. Mor e specifica lly,
glu cocor t icoids fu n ct ion t o:
● St im u la t e glu cose pr odu ct ion
● Decr ea se t issu e glu cose u t iliza t ion
● In cr ea se br ea kdown a n d cir cu la t ion of pla sm a
pr ot ein s
● In cr ea se m obiliza t ion of fa t s
● P r even t t h e r elea se of ch em ica l m edia t or s t h a t
t r igger t h e in fla m m a t or y r espon se
● Decr ea se ca pilla r y per m ea bilit y a n d in h ibit
edem a for m a t ion
● In h ibit t h e im m u n e r espon se
● In h ibit bon e for m a t ion
● St im u la t e ga st r ic a cid secr et ion s
● Con t r ibu t e t o em ot ion a l beh a vior
● Con t r ibu t e t o a n effect ive st r ess r espon se
PATHOPHYSIOLOGY
Fou r m a jor pr ocesses ca n lea d t o Cu sh in g syn dr om e:
1. Lon g-t er m a dm in ist r a t ion of cor t icost er oid m edi-
ca t ion s (su ch a s pr edn ison e)
2. Tu m or s of t h e pit u it a r y gla n d t h a t st im u la t e
excess ACTH pr odu ct ion
3. Tu m or s of t h e a dr en a l gla n d t h a t st im u la t e excess
cor t isol pr odu ct ion
4. E ct opic pr odu ct ion of ACTH or CRH fr om a t u m or
a t a dist a n t sit e, su ch a s sm a ll cell ca r cin om a of
t h e lu n g
Lon g-t er m a dm in ist r a t ion of cor t icost er oid m ed-
ica t ion s is in dica t ed for a wide va r iet y of ch r on ic
in fla m m a t or y a n d a u t oim m u n e con dit ion s. E xog-
en ou s cor t icost er oids su ppr ess t h e in fla m m a t or y
a n d im m u n e r espon ses a n d ca n decr ea se t h e dele-
t er iou s effect s of ch r on ic in fla m m a t ion . Lon g-t er m
u se of t h ese m edica t ion s will r esu lt in su ppr ession
C lin ic a l Mo d e ls 335
of cor t isol pr odu ct ion by t h e a d-
r en a l cor t ex a n d sh ou ld n ot be
discon t in u ed a br u pt ly.
F u n c t io n s
Regu la t es sodiu m a n d po-
Stop and Consider
t a ssiu m levels; r egu la t es You are on a 1-week hiking
wa t er ba la n ce a n d blood trip and one of your friends
pr essu r e forgets her glucocorticoid
Regu la t es m et a bolism , medication that she takes
in fla m m a t or y/im m u n e for severe asthma. Should
r espon ses, a n d t h e st r ess she go back and get the
r espon se
medication or is she okay
without it for that week?
Con t r ibu t e t o pu bic a n d
a xilla r y h a ir gr owt h Excessive ACTH production,
h or m on es in wom en ; through pituitary or ectopic tu-
m in im a lly im pa ct sexu a l mors, overstimulates the adrenal
fu n ct ion
cortex. This results in adrenal
hyperplasia and excess cortisol
production. This form of hypercor-
tisolism depends on ACTH, and reduction of cortisol lev-
els may require removal of the ACTH-secreting tumor
or CRH-secreting tumor if this is stimulating the excess
ACTH production. Adrenal tumors, however, hyperse-
crete cortisol directly and are not directed by ACTH.
Stop and Consider
Map out how the negative feedback loop is im-
pacted by an ACTH-dependent hypercortisolism
versus a non–ACTH-dependent hypercortisolism.
CLINICAL MANIFESTATIONS
E xcess secr et ion of glu cocor t icoids ca n r esu lt in m et -
a bolic a lt er a t ion s, excessive cir cu la t in g glu cose a n d
su bsequ en t glu cose in t oler a n ce, su ppr ession of t h e
in fla m m a t or y a n d im m u n e r espon ses, beh a vior a l
ch a n ges, a n d a n im pa ir ed st r ess r espon se. Mobiliza -
t ion of fa t s a n d ch a n ges in fa t m et a bolism lea d t o
obesit y of t h e t r u n k, fa ce, a n d u pper ba ck. Obesit y
of t h e fa ce a n d post er ior n eck a n d ba ck h a s been
ch a r a ct er ized by t h e t er m s “m oon fa ce” a n d “bu ffa lo
h u m p” (Fig. 13.14). St r ia e, or st r et ch m a r ks, ca n de-
velop fr om t r u n ca l obesit y. P r ot ein degr a da t ion r e-
su lt s in ext r em it y wea kn ess a n d m u scle wa st in g.
Th e skin becom es a t r oph ic a n d t h in . Bon es exh ibit
ost eopor osis. Su ppr ession of t h e in fla m m a t or y a n d
im m u n e r espon ses lea ds t o in cr ea sed in fect ion s,
skin u lcer a t ion s, a n d poor wou n d h ea lin g. Glu cose
in t oler a n ce, fr om excess cir cu la t in g glu cose a n d loss
of t issu e u t iliza t ion , ca n lea d t o dia bet es m ellit u s.
Ch a n ges in beh a vior ca n r a n ge fr om eu ph or ia t o m i-
n or em ot ion a l dist u r ba n ces t o psych osis.
St im u la t ion of t h e a dr en a l cor t ex t o over pr odu ce
cor t isol ca n a lso st im u la t e t h e pr odu ct ion of t h e
ot h er a dr en a l cor t ex h or m on es, pr im a r ily a n dr ogen s
a n d a ldost er on e. Clin ica l m a n ifest a t ion s ca n r eflect
336 C h a p t e r 13: Alt er ed H or m on a l a n d Met a bolic Regu la t ion

Thinning of s ca lp ha ir
Incre a s e d Round (moon) fa ce
fa cia l ha ir
Os te oporos is
S ubclavicula r fa t pa ds on
the ba ck (buffa lo hump)
DIAGNOSTIC CRITERIA
Diagnosis of Cushing syndrome is often based on a
24-hour urine collection during which elevations in
cortisol excretion are noted. False-positive tests may
result in those with obesity, a lcoholism, chronic renal
failure, a norexia, or bulimia, because these also ra ise
cortisol secretion. Imaging studies are needed to locate
tumors that may be secreting excess ACTH or cortisol.

Re na l ca lculi
P rotruding a bdome n
Abdomina l s tria e
TREATMENT
Tr ea t m en t is focu sed on r em ovin g t h e ca u se of ex-
cess h or m on e pr odu ct ion . Su r ger y or r a dia t ion m a y
be n eeded t o r em ove t u m or s. Cor t icost er oid m ed-
ica t ion s m a y be n eeded t o a ver t a n a dr en a l cr isis
du r in g a cu t e illn ess a n d t h en t h ey m u st be gr a du -
a lly wit h dr a wn .

Mus cle we a kne s s Stop and Consider

How would a deficiency of cortisol present in
Thin terms of clinical manifestations?
extre mitie s

Addison Disease
Alt h ou gh r a r e, a cu t e ACTH deficien cy is con sider ed
on e of t h e m ost ser iou s en docr in e disor der s beca u se
it ca n lea d t o sever e h ypot en sion , sh ock, a n d dea t h .
Adr en a l cor t ica l in su fficien cy ca n r esu lt fr om la ck of
CRH or ACTH , or la ck of secr et ion of h or m on es fr om
t h e a dr en a l cor t ex. Disea se t ypica lly pr esen t s wh en
90% or m or e of t h e a dr en a l cor t ices a r e dest r oyed or
Figure 13.14. Dominant features of Cushing syndrome.
n on fu n ct ion a l.

eleva t ion s of t h ese h or m on es. E xcess a ldost er on e r e- PATHOPHYSIOLOGY

su lt s in h yper t en sion a n d h ypoka lem ia . E xcess a n -
La ck of ACTH pr odu ct ion fr om t h e pit u it a r y is m ost
dr ogen s ca n r esu lt in h ir s u t is m , t h e developm en t
oft en ca u sed by dest r u ct ion of t h e pit u it a r y gla n d
of excessive body a n d fa cia l h a ir, or ch a n ges in pa t -
fr om t u m or s, h em or r h a ge, t r a u m a , r a dia t ion , or su r-
t er n s of pu bic a n d a xilla r y h a ir gr owt h (pr im a r ily in
gica l r em ova l. Adr en a l cor t ica l in su fficien cy ca n a lso
wom en ).
r esu lt fr om la ck of h or m on es secr et ed fr om t h e a dr e-
n a l cor t ex. Au t oim m u n e
dest r u ct ion of t h e la yer s
of t h e a dr en a l cor t ex is
R E S E AR C H N O T E S t h e m ost com m on ca u se
Scientists have noted that somewhere between 5% and 13% of cases of hypertension are of Ad d is o n d is e a s e .
caused by abnormally high aldosterone levels. Research continues to explore the long-term Th is dest r u ct ion lea ds t o
effects of excess aldosterone, particularly on cardiovascular function. Improved treatment t h e in a bilit y of t h e a dr e-
of hypertension may rely on blocking aldosterone when indicated, preventing hypertension, n a l gla n d t o pr odu ce a n y
and limiting harmful cardiovascular effects of hyperaldosteronism. The high prevalence of glu cocor t icoids, m in er-
hypertension in Black individuals may be explained, in part, by the role of aldosterone in a locor t icoids, or a n dr o-
maintaining the antioxidant–oxidant balance. Aldosterone decreases the activity of the en- gen s. As a r esu lt , ACTH
zyme glucose-6-phosphate dehydrogenase (G-6-PD). This enzyme has a role in antioxidant levels a r e eleva t ed t o
defenses. A deficiency of G-6-PD is seen in 10% to 15% of Black people, perhaps related in cr ea se t h e secr et ion
to high aldosterone levels. This may also explain the levels of high blood pressure in this of t h ese t h r ee m a jor st e-
population. 6 r oid h or m on es fr om t h e
a dr en a l gla n ds.
 C h a p t e r 13: Alt er ed H or m on a l a n d Met a bolic Regu la t ion
CLINICAL MANIFESTATIONS
Ta b le 13.4 Clin ica l Ma n ifest a t ion s of Addison Disea se
Clin ica l m a n ifest a t ion s a r e
ba sed on in su fficien t levels of D e ic ie n t H o r m o n e s
t h e st er oid h or m on es a s de- Glu cocor t icoids
pict ed in Ta ble 13.4. E leva t ion s
in ACTH levels st im u la t e skin
m ela n ocyt es, r esu lt in g in a Min er a locor t icoids
ch a r a ct er ist ic h yper pigm en t a -
t ion , or da r ken in g, of t h e skin An dr ogen s
a n d m u cou s m em br a n es.
DIAGNOSTIC CRITERIA
Dia gn osis of Addison disea se is ba sed on t h e clin ica l
pr esen t a t ion a n d la bor a t or y a n a lysis of elect r olyt e
levels dem on st r a t in g h ypon a t r em ia a n d h yper ka -
lem ia . Ser u m cor t icost er oid levels ca n a lso be m ea -
su r ed, a n d r esu lt s will sh ow cor t icost er oid levels t h a t
r em a in depr essed a ft er a dm in ist r a t ion of ACTH .
TREATMENT
In a cu t e illn ess, isot on ic IV flu id r epla cem en t is in -
fu sed a lon g wit h h ydr ocor t ison e sodiu m su ccin a t e or
ph osph a t e. Im pr ovem en t in blood pr essu r e sh ou ld
occu r wit h in 4 t o 6 h ou r s. Gr a du a lly, t h e IV in fu sion
of h ydr ocor t ison e is t a per ed a n d or a l r epla cem en t of
glu cocor t icoid a n d m in er a locor t icoid h or m on es en -
su es for t h e r em a in der of t h e in dividu a l’s life. Be-
ca u se of eleva t ion s in sodiu m excr et ion , sa lt in t a ke
m a y n eed t o be in cr ea sed in h ot wea t h er. Th e excep-
t ion t o t h is is for t h ose pa t ien t s wit h Addison disea se
ca u sed by t u ber cu losis. Th e t u ber cu losis ba ct er ia
ca n a lso dest r oy t h e a dr en a l gla n d. Tr ea t m en t of t h e
ba ct er ia wit h a n t ibiot ics is r equ ir ed, a n d a dr en a l
fu n ct ion r esu m es wit h ou t lifelon g glu cocor t icoid a n d
m in er a locor t icoid r epla cem en t .
S U MMAR Y
● H or m on e m essen ger s h a ve m a n y im por t a n t r eg-
u la t or y fu n ct ion s, in clu din g en er gy m et a bolism ,
gr owt h a n d developm en t , m u scle a n d fa t dist r ibu -
t ion , flu id a n d elect r olyt e ba la n ce, sexu a l develop-
m en t , a n d r epr odu ct ion .
● H or m on es a r e in st r u m en t a l in t h e st r ess r espon se
a n d a r e essen t ia l for m a in t a in in g h om eost a sis.
● Th e in it ia t ion of h or m on e secr et ion a n d r egu la -
t ion for m a n y h or m on es r elies on n eu r on a l con t r ol
t h r ou gh t h e h ypot h a la m ic–pit u it a r y a xis, r ecep-
t or bin din g, in t r a cellu la r com m u n ica t ion , a n d
feedba ck m ech a n ism s.
● F u n ct ion a l deficit s u su a lly a r ise fr om im pa ir-
m en t of t h e en docr in e (secr et in g) gla n d, la ck of,
or excessive h or m on e syn t h esis, im pa ir ed r ecep-
t or bin din g, im pa ir ed feedba ck m ech a n ism s, or a n
a lt er ed cellu la r r espon se t o t h e h or m on e.
337
C lin ic a l Ma n i e s t a t io n s
H ypoglycem ia , wea kn ess, poor st r ess r espon se, fa t igu e,
a n or exia , n a u sea , vom it in g, weigh t loss, per son a lit y
ch a n ges
Deh ydr a t ion , h ypon a t r em ia , h yper ka lem ia , h ypot en -
sion , wea kn ess, fa t igu e, sh ock
Spa r se a xilla r y a n d pu bic h a ir in wom en
● P r oblem s wit h h or m on e fu n ct ion ca n m a n ifest
t h r ou gh in a dequ a t e or excessive pr odu ct ion , com -
posit ion , secr et ion , r ecept or bin din g, u pt a ke, m e-
t a bolism , or elim in a t ion of h or m on es.
● The gener a l m anifesta tions of hypopituita r ism ar e
often va gue and may include fat igue, wea kness, a n-
orexia , sexua l dysfunction, growt h im pa irm ent, dr y
skin, const ipat ion, a nd cold int oler a nce; likewise,
hyperpit uit a rism a lso ha s a wide ra nge of m anifes-
t at ions depending on which hor mones a r e eleva ted.
● Dia gn osin g a lt er a t ion s in h or m on a l or m et a bolic
fu n ct ion begin s wit h a com plet e pa t ien t h ist or y
a n d ph ysica l exa m in a t ion a n d oft en r elies on m ea -
su r in g h or m on e levels or ot h er in dica t or s in t h e
blood or u r in e; im a gin g st u dies, su ch a s CT or MRI
sca n s, m ay be n eeded t o loca t e a t u m or t h a t cou ld
be su ppr essin g or st im u la t in g h or m on e secr et ion .
Gen et ic t est in g m ay a lso be n eeded t o iden t ify a ge-
n et ic a lt er a t ion t h a t is a ffect in g h or m on e fu n ct ion .
● Tr ea t in g h or m on e a lt er a t ion s va r ies depen din g
on t h e ca u se; h or m on e deficit s oft en r equ ir e ex-
ogen ou s r epla cem en t a n d h or m on e eleva t ion s r e-
qu ir e elim in a t in g t h e excess h or m on e. Th is oft en
occu r s by r em ovin g t u m or s t h a t m a y be secr et in g
ect opic h or m on e, r em ovin g a ll or pa r t of t h e cor r e-
spon din g en docr in e gla n d, or a dm in ist er in g m edi-
ca t ion s t h a t block t h e effect s of t h e h or m on e.
C AS E S T U D Y 13.1
A 43-yea r-old m a le is dia gn osed wit h a som a t ot r ope
a den om a . Som a t ot r opes a r e pit u it a r y cells t h a t se-
cr et e gr owt h h or m on e. As a r esu lt , h e is dia gn osed
wit h a c r o m e g a ly , or a n excess of gr owt h h or m on e
t h a t occu r s a ft er pu ber t y.
1. Ou t lin e t h e pr ocess t h a t is m ost likely occu r r in g
in t h is m a n ’s body.
2. Wh a t h or m on e is a lt er ed?
3. Wh a t wou ld you expect for clin ica l m a n ifest a t ion s?
4. Wh a t dia gn ost ic t est s cou ld be u sed?
5. Wh a t t r ea t m en t m ea su r es wou ld you a n t icipa t e?
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r-
n a l a r t icle or Web sit e (su ch a s h t t p://www.em edicin e
338 C h a p t e r 13: Alt er ed H or m on a l a n d Met a bolic Regu la t ion

.com /m ed/t opic27.h t m ) t h a t det a ils a cr om ega ly, a n d 2. Th e r elea se of h or m on es fr om gla n ds is m ost
con fir m you r pr edict ion s. oft en con t r olled by:
a . Nega t ive feedba ck m ech a n ism s
C AS E S T U D Y 13.2 b. Neph r ogen ic m ech a n ism s
c. E ct opic h or m on e pr odu ct ion
A fa t h er h a s n ot iced t h a t h is ch ild is qu it e a bit d. Act ive t r a n spor t
sh or t er t h a n t h e ot h er kids h is a ge. Th e ch ild, n ow
2 yea r s old, wa s of n or m a l bir t h len gt h . Over t im e, 3. Th e m ost com m on ca u se of en docr in e disor der s
t h ou gh , h e h a s n ot kept u p wit h t h e lin ea r gr owt h is:
of ot h er ch ildr en h is a ge. H e a ppea r s t o lea r n n ew a . Su r gica l r em ova l of en docr in e gla n ds
t h in gs wit h ou t difficu lt y bu t is over weigh t a n d h a s b. In fect ion
im m a t u r e fa cia l fea t u r es. H e does h a ve a h ist or y of c. Aden om a s
h ypoglycem ia a n d seizu r es. H e is dia gn osed wit h d. Im m u n odeficien cy
con gen it a l gr owt h h or m on e deficien cy.
1. Ou t lin e t h e pr ocess t h a t is m ost likely occu r r in g 4. E xcess cor t isol is r epr esen t ed by wh ich
in t h is ch ild’s body. con dit ion ?
2. Wh a t h or m on e is a lt er ed? a . Addison disea se
3. Wh a t wou ld you expect for clin ica l m a n ifest a t ion s? b. Cu sh in g syn dr om e
4. Wh a t dia gn ost ic t est s cou ld be u sed? c. Dia bet es in sipidu s
5. Wh a t t r ea t m en t m ea su r es wou ld you a n t icipa t e? d. H yper t h yr oidism
Log on to the Internet. Search for a relevant journal ar-
ticle or Web site that details congenital growth hormone 5. Dia bet es in sipidu s, if left u n t r ea t ed, will r a pidly
deficiency (such as: http://emedicine.medscape.com/ar- develop in t o:
ticle/117012-clinical) and confirm your predictions. a . Ma lign a n t h yper t en sion
b. Dia bet ic com a
c. Deh ydr a t ion
C AS E S T U D Y 13.3 d. Met a bolic a lka losis
A 4-yea r-old boy pr esen t s wit h sym pt om s of a n dr o-
gen excess, in clu din g r a pid gr owt h , pu bic h a ir, a n d 6. A pa t ien t is a sked t o collect a 24-h ou r u r in e t est
a ggr essive beh a vior. H is bon e a ge wa s det er m in ed t o t o ch eck a h or m on e level. Wh y is t h e 24-h ou r
be a dva n ced. Th e ch ild wa s a lso fou n d t o h a ve sign if- u r in e n eeded?
ica n t h yper t en sion . H e is dia gn osed wit h con gen it a l a . To m ea su r e fem a le r epr odu ct ive h or m on e
a dr en a l h yper pla sia . levels
b. To obt a in a m ea su r em en t of h or m on e secr e-
1. Ou t lin e t h e pr ocess t h a t is m ost likely occu r r in g t ion over t im e
in t h is ch ild’s body. c. It is ea sier t h a n obt a in in g a blood sa m ple
2. Wh a t h or m on e is a lt er ed? d. Ur in e is n ot a n effect ive m et h od of m ea su r in g
3. Wh a t wou ld you expect for clin ica l m a n ifest a t ion s? h or m on e levels
4. Wh a t dia gn ost ic t est s cou ld be u sed?
5. Wh a t t r ea t m en t m ea su r es wou ld you a n t icipa t e?
7. You a r e exper ien cin g con st ipa t ion , dr y skin ,
Log on t o t he Int er n et . Sea r ch for a r eleva nt jou r na l weigh t ga in , a n d cold in t oler a n ce. Wh ich con di-
a r t icle or Web sit e, such a s h t t p://em edicine.m edsca pe t ion a r e you m ost likely exper ien cin g?
.com /a r t icle/117012-clinica l, t h a t det a ils congenit a l a . H yper t h yr oidism
a dr ena l hyper pla sia , a nd con fir m you r pr edict ions. b. Addison disea se
c. Cu sh in g syn dr om e
P R AC T I C E E XAM Q U E S T I O N S d. H ypot h yr oidism

1. Wh ich of t h e followin g is n ot a m a jor r ole of 8. Wh ich of t h e followin g occu r s wit h eleva t ed

h or m on es? levels of cor t isol?
a . Gr owt h st im u la t ion a . Fa t t y a cids a r e m obilized
b. E r yt h r ocyt e syn t h esis b. Glu cose levels a r e su ppr essed
c. F lu id ba la n ce a n d r egu la t ion c. P la sm a pr ot ein levels in cr ea se
d. Met a bolic r a t e r egu la t ion d. In fla m m a t ion in cr ea ses
 C h a p t e r 13: Alt er ed H or m on a l a n d Met a bolic Regu la t ion
9. Wh ich t ype of h or m on e is n ot pr odu ced in t h e
a dr en a l cor t ex?
a . Min er a locor t icoids
b. Glu cocor t icoids
c. Adr en a l sex h or m on es
d. Neu r ot r a n sm it t er s
10. Dia gn osis of SIADH is ba sed on wh ich of t h e
followin g?
a . H ypon a t r em ia
b. H yper t on icit y
c. In cr ea sed u r in e volu m e
d. Dilu t e u r in e wit h a low sodiu m con t en t
11. Release of hormones from the anterior pituitary dif-
fers from those released by the posterior pituitary.
What is the major way in which these are different?
a . Th e post er ior pit u it a r y is m u ch less
com plica t ed
b. The anterior pituitary releases only two hormones
c. Th e post er ior pit u it a r y follows t h e posit ive
feedba ck loop
d. Th e a n t er ior pit u it a r y is con t r olled by t h e
h ypot h a la m u s
12. Which of the following major pathways occurs
when a hormone is produced in a cell and can have
an impact on neighboring cells and on its own cell?
a . Pa r a cr in e pa t h wa y
b. Au t ocr in e pa t h wa y
c. Syn a pt ic pa t h wa y
d. Neu r oen docr in e pa t h wa y
13. A pa t ien t pr esen t s wit h SIADH a n d a ser u m so-
diu m level of 100 m E q/L. Wh a t wou ld you expect
for clin ica l m a n ifest a t ion s for t h is pa t ien t ?
a . Polyu r ia , polydipsia , polyph a gia
b. Na u sea , vom it in g, h ea da ch e
c. Mu scle cr a m ps, wea kn ess, ir r it a bilit y
d. Seizu r es, psych osis, ga it dist u r ba n ces
14. A pa t ien t pr esen t s wit h exoph t h a lm os. Wh a t
con dit ion is sh e likely exper ien cin g?
a . Addison disea se
b. Cu sh in g disea se
c. Gr a ves disea se
d. Dia bet es in sipidu s
D I S C U S S I O N AN D
AP P L I C AT I O N
1. Wh a t did I kn ow a bou t a lt er ed h or m on a l a n d
m et a bolic r egu la t ion pr ior t o t oda y?
F in d a d d ition a l r esou r ces for th is ch a pter a t h ttp:th ePoin t.lww.com
339
2. Wh a t body pr ocesses a r e a ffect ed by a lt er ed h or-
m on a l a n d m et a bolic r egu la t ion ? Wh a t a r e t h e
expect ed fu n ct ion s of t h ose pr ocesses? H ow does
a lt er ed h or m on a l a n d m et a bolic r egu la t ion a f-
fect t h ose pr ocesses?
3. What are the potentia l etiologies for altered hor-
monal a nd metabolic regulation? How does al-
tered hormonal and meta bolic regulation develop?
4. Wh o is m ost a t r isk for developin g a lt er ed h or-
m on a l a n d m et a bolic r egu la t ion ? H ow ca n a l-
t er ed h or m on a l a n d m et a bolic r egu la t ion be
pr even t ed?
5. Wh a t a r e t h e h u m a n differ en ces t h a t a ffect t h e
et iology, r isk, or cou r se of a lt er ed h or m on a l a n d
m et a bolic r egu la t ion ?
6. Wh a t clin ica l m a n ifest a t ion s a r e expect ed in
t h e cou r se of a lt er ed h or m on a l a n d m et a bolic
r egu la t ion ?
7. Wh a t specia l dia gn ost ic t est s h elp det er m in e
t h e dia gn osis a n d cou r se of a lt er ed h or m on a l
a n d m et a bolic r egu la t ion ?
8. Wh a t a r e t h e goa ls of ca r e for in dividu a ls
wh o h a ve a lt er ed h or m on a l a n d m et a bolic
r egu la t ion ?
9. H ow does t h e con cept of a lt er ed h or m on a l a n d
m et a bolic r egu la t ion bu ild on wh a t I h a ve
lea r n ed in t h e pr eviou s ch a pt er s a n d in pr evi-
ou s cou r ses?
10. H ow ca n I u se wh a t I h a ve lea r n ed?
R E SOUR CE S
Th e H or m on e H ea lt h Net wor k is a n in t er n a -
t ion a l r esou r ce clin ica l a n d scien t ific exper t ise in
en docr in ology:
h t t p://www.h or m on e.or g/
R e er en ces
1. Usa la RL, Fer n a n dez SJ, Met e M, et a l. H ypon a t r em ia
is a ssocia t ed wit h in cr ea sed ost eopor osis a n d bon e fr a c-
t u r es in a la r ge US h ea lt h syst em popu la t ion . J Clin
E n d ocr in ol Meta b. 2015;100(8):3021–3031.
2. Kh a r dor i R. Dia bet es in sipidu s. 2015. h t t p://em edicin e
.m edsca pe.com /a r t icle/117648-over view#a 6
3. Lee S. H yper t h yr oidism . 2015. h t t p://em edicin e
.m edsca pe.com /a r t icle/121865-over view#a 6
4. Or la n der P. H ypot h yr oidism . 2015. h t t p://em edicin e
.m edsca pe.com /a r t icle/122393-over view#a 5
5. Ru bin E , Gor st ein F, Ru bin R, et a l. Ru bin ’s Pa th ology:
Clin icopa th ologic Fou n d a tion s of Med icin e. 4t h ed. Ba lt i-
m or e, MD: Lippin cot t Willia m s & Wilkin s, 2005.
6. Mikt a M. Scien t ist s pr obe a ldost er on e’s r ole in h yper t en -
sion a n d h ea r t disea se. J AMA. 2004;292:2704–2705.
 Ch a pt er

14
Alt er ed Repr odu ct ive
F u n ct ion

L E AR N I N G O U T C O ME S
1. Defin e a n d u se t h e key t er m s list ed in t h is ch a pt er.
2. Iden t ify st r u ct u r es a n d pr ocesses r equ ir ed for effect ive r epr odu ct ive
fu n ct ion .
3. An a lyze t h e m ech a n ism s of im pa ir m en t t h a t ca n lea d t o a lt er ed r epr odu c-
t ive fu n ct ion .
4. Discu ss com m on m ea su r es t o dia gn ose a n d t r ea t a lt er ed r epr odu ct ive
fu n ct ion .
5. Apply con cept s of a lt er ed r epr odu ct ive fu n ct ion t o select clin ica l m odels.

INTR ODUCTION
Con sider t h e com plexit y of cr ea t in g a n ew h u m a n bein g. Repr odu ct ive fu n c-
t ion is r elia n t u pon st r u ct u r a l in t egr it y, n eu r ologic, a n d h or m on a l pr ocesses of
m a les a n d fem a les. Bot h a r e n eeded, a n d t h ey m u st wor k t oget h er in or der t o
be su ccessfu l. Th is ch a pt er focu ses on st r u ct u r a l a n d fu n ct ion a l expect a t ion s in
or der t o r epr odu ce a n d pr ocesses t h a t ca n a lt er r epr odu ct ive fu n ct ion .

Female and male reproductive systems. Image © BlueRingMedia

340

Modu le 1 R e g u la t io n o R e p r o d u c t io n
Female Reproductive Hormone
Function
St r u ct u r a l in t egr it y is r equ ir ed t o a ch ieve r epr odu c-
t ion . For fem a les, t h is in clu des t h e ext er n a l gen it a lia
a n d in t er n a l r epr odu ct ive st r u ct u r es. E xt er n a l gen -
it a lia fea t u r es t h e m on s pu bis, la bia m a jor a , vest i-
bu le, Ba r t h olin gla n ds, la bia m in or a , clit or is, Sken e
gla n ds a t t h e u r et h r a l open in g, a n d t h e va gin a l
or ifice (Fig. 14.1). Th e pr im a r y pu r pose of ext er n a l
st r u ct u r es is pr ot ect ion a n d lu br ica t ion . Th e clit or is,
a n a logou s t o t h e m a le pen is, is h igh ly sen sit ive a n d
dist en ds du r in g sexu a l st im u la t ion .
In t er n a l r epr odu ct ive st r u ct u r es in clu de t h e va -
gin a , u t er u s, fa llopia n t u bes, a n d ova r ies, loca t ed in
t h e pelvic ca vit y (F ig. 14.2). Th e va gin a is n eeded a s
a n ou t let for m en ses a n d ot h er secr et ion s a n d a lso
ser ves t h e fu n ct ion of sexu a l fu lfillm en t a n d en t r y
for sper m fr om t h e m a le pen is. Th e cer vix for m s t h e
in let t o t h e u t er u s. Secr et ion s fr om t h e cer vix offer
som e pr ot ect ion fr om in fect ion a n d a llow in cr ea sed
or decr ea sed r ecept ivit y t o sper m depen din g on
Mons pubis
Clitoris
Ure thra l
ope ning
Ve s tibule
La bia ma jora
La bia minora
Va gina
Hyme n
Anus
Figure 14.1. Female external genitalia. (From Westheimer
R, Lopater S. Human Sexuality. Baltimore, MD: Lippincott
Williams & Wilkins; 2003.)
R e g u la t io n o R e p r o d u c t io n 341
h or m on e in flu en ces. Th e u t er u s, a m u scu la r or ga n ,
h a s t h r ee la yer s: a n in n er en dom et r iu m , a m iddle
m yom et r iu m , a n d a n ou t er per im et r iu m . Th e fu n c-
t ion a l la yer of t h e en dom et r iu m pr olifer a t es a s t h e
u t er in e lin in g bu ilds a n d slou gh s a s m en ses ea ch
m on t h . Th e m u scu la r m yom et r iu m con t r a ct s t o ex-
pel m en ses a n d pr ovides u t er in e con t r a ct ion s du r in g
ch ildbir t h .
Fa llopia n t u bes ext en d fr om t h e u t er u s t o a
fu n n el-sh a ped open in g wit h fin ger-like pr oject ion s
t owa r d t h e ova r ies t o a t t r a ct t h e ovu m (F ig. 14.3). Th e
fa llopia n t u bes for m a n im por t a n t con n ect ive pa s-
sa gewa y for t h e ova a n d sper m . Th e a lm on d-sh a ped
ova r ies h a ve fou r pa r t s:
● St r om a , t h e su ppor t in g t issu e
● In t er st it ia l cells, wh ich secr et e est r ogen
● Follicles, wh ich con t a in t h e ova (ger m cells)
● Cor pu s lu t eu m , for m s a ft er t h e ovu m h a s been r e-
lea sed fr om t h e ova r ia n follicle
Led by t h e h ypot h a la m u s, pit u it a r y, a n d ova r ies,
h or m on a l pr ocesses a r e a lso n eeded t o fa cilit a t e r e-
pr odu ct ion (Fig. 14.4). Th e ova r ies pr odu ce t h e fem a le
sex h or m on es: est r ogen s, pr ogest er on e, a n d a n dr o-
gen s. Th ese h or m on es a r e secr et ed in a m on t h ly
cyclica l pa t t er n u n der t h e dir ect ion of t h e h ypot h a la -
m u s (gon a dot r opin -r elea sin g h or m on e [Gn RH ]) a n d
t h e a n t er ior pit u it a r y (follicle-st im u la t in g h or m on e
[F SH ], lu t ein izin g h or m on e [LH ]).
If pr egn a n cy occu r s, t h r ee a ddit ion a l h or m on es
com e in t o pla y. H u m a n ch or ion ic gon a dot r opin (h CG)
a ppea r s wit h in 2 t o 3 da ys a ft er t h e zygot e im pla n t s
in t o t h e en dom et r iu m . h CG is pr odu ced by t h e zy-
got e a n d a ct s on t h e cor pu s lu t eu m t o m a in t a in it s
est r ogen a n d pr ogest er on e-secr et in g fu n ct ion . H om e
pr egn a n cy t est s m ea su r e t h e pr esen ce of h CG in t h e
u r in e. Th e a n t er ior pit u it a r y a lso secr et es pr ola ct in
du r in g a n d a ft er pr egn a n cy t o a llow la ct a t ion t o oc-
cu r. Oxyt ocin is a h or m on e secr et ed fr om t h e pos-
t er ior pit u it a r y t h a t st im u la t es con t r a ct ion s du r in g
la bor a n d m ilk eject ion du r in g la ct a t ion .
As in dica t ed, t h e in t er st it ia l cells of t h e ova r y
secr et e est r ogen s. Th e est r ogen s (est r a diol, est r on e,
a n d est r iol) a r e t h e pr im a r y fem a le sex h or m on es.
Th ese a r e secr et ed t h r ou gh ou t t h e m on t h ly m en -
st r u a l cycle a n d dom in a t e fr om t h e en d of m en ses
t o ovu la t ion . Th e m a jor a ct ion s of t h e est r ogen s
in clu de:
● Fem a le r epr odu ct ive or ga n developm en t
● Fem a le body fa t con t ou r dist r ibu t ion
● Br ea st developm en t a n d skelet a l gr owt h du r in g
pu ber t y
342 C h a p t e r 14: Alt er ed Repr odu ct ive F u n ct ion

L5

S us pe ns ory
liga me nt
of ova ry S a crum

Ure te r

Ova ry
Fa llopia n tube
Ova ria n liga me nt Re ctum

Ute rus
Round liga me nt
Me dia n umbilica l P os te rior fornix of va gina
liga me nt
Re ctoute rine pouch
Urina ry bla dde r
Ce rvix
P ubic s ymphys is
Ure thra Le va tor a ni mus cle
Clitoris
Va gina
P re puce of clitoris
Ure thra l orifice Anus

La bium minus
La bium ma jus
Va gina l orifice

S ag ittal s e c tio n

Figure 14.2. Female reproductive structures.

● Ovu la t ion a n d su ppor t of pr egn a n cy a n d la ct a t ion
● Cer vica l m u cu s a lt er a t ion s (copiou s, t h in , wa t er y,
a n d m or e r ecept ive t o sper m )
● Axilla r y a n d pu bic h a ir gr owt h
● Fem a le skin m a in t en a n ce
● Decr ea sed bon e r esor pt ion ; m a in t en a n ce of bon e
in t egr it y
● Ret en t ion of sodiu m a n d wa t er
P r ogest er on e is a n ot h er im por t a n t fem a le sex h or-
m on e, secr et ed in la r ge a m ou n t s fr om ovu la t ion t o
t h e on set of m en st r u a t ion . Th e cor pu s lu t eu m of t h e
ova r y secr et es pr ogest er on e a n d est r ogen . P r oges-
t er on e t h icken s t h e lin in g of t h e u t er u s t o su ppor t
im pla n t a t ion a n d n ou r ish es t h e em br yo in ea r ly
pr egn a n cy. P r ogest er on e a lso h elps t o m a in t a in t h e
pr egn a n cy by r ela xin g sm oot h m u scles in t h e u t er u s
t o a void expu lsion of t h e em br yo. P r ogest er on e el-
eva t es t h e cor e body t em per a t u r e sligh t ly a n d ca n
in du ce n a u sea , h ea da ch es, con st ipa t ion , in digest ion ,
a n d swellin g in pr egn a n cy.
Ovu la t ion is t h e pr ocess of r elea sin g a n oocyt e
fr om a n ova r ia n follicle. Ovu la t ion occu r s on ce ever y
21 t o 40 da ys for m ost wom en (t h e a ver a ge is a p-
pr oxim a t ely 28 da ys). Ovu la t ion r elies on h or m on e
r egu la t ion a n d is t ypica lly divided in t o t wo pa r t s:
(1) t h e follicu la r ph a se in t h e fir st h a lf of t h e ovu la -
t or y cycle; a n d (2) t h e lu t ea l ph a se in t h e secon d h a lf
of t h e ovu la t or y cycle (Fig. 14.5). Follicles a r e epit h e-
lia l ca psu les t h a t h old oocyt es. Follicles a r e fu r t h er
dist in gu ish ed a s pr im a r y a n d secon da r y follicles.
P r im a r y follicles a r e in a ct ive. Du r in g ea ch ovu la t or y
cycle, a ppr oxim a t ely 10 pr im a r y follicles a r e st im u -
la t ed by F SH a n d LH a n d becom e secon da r y, or a c-
t ive, follicles.
Du r in g t h e follicu la r ph a se, secon da r y follicles
en la r ge, fu r t h er develop, a n d becom e ca pa ble of se-
cr et in g est r ogen a n d pr ogest er on e. In a pr ocess t h a t
is n ot com plet ely u n der st ood, on e of t h ese follicles
becom es dom in a n t by secr et in g la r ge a m ou n t s of
est r ogen , a n d t h e r em a in in g follicles su bsequ en t ly
becom e a t r e t ic (a t r oph ic). Th e dom in a n t follicle
 S us pe ns ory
liga me nt of ova ry
Fa llopia n
tube
Fundus of
Is thmus
ute rus

Ampulla
Infundibulum
Fimbria Ova ry

Ova ria n liga me nt

Ca vity of ute rus Ve s icula r

S e conda ry Corpus Ute rus : Broa d liga me nt a ppe ndix
Abdomina l
oocyte lute um
ope ning of P e rime trium Inte rna l ute rine ope ning
fa llopia n tube
Myome trium Ce rvix
Endome trium Ce rvica l ca na l

Exte rna l ute rine ope ning

Va gina

La bium minus

Figure 14.3. Cross-section of ovaries, fallopian tubes, uterus, and vagina.

Hypotha la mus
GnRH

Follicula r pha s e

Atre tic S e conda ry

Ante rior (a trophic) follicle P rima ry
pituita ry follicle P rimordia l
follicle s Ova ria n
LH follicle s
blood
P re ovula tory ve s s e ls
FS H follicle

Corpus
Ova ry a lbica ns

Ma ture corpus
lute um
Ovula tion
Ea rly corpus
P roge s te rone Es troge n lute um

Figure 14.4. Feedback regulation of ovarian function.
FSH, follicle-stimulating hormone; GnRH, gonadotropin-
releasing hormone; LH, luteinizing hormone. (Modified from
Premkumar K. The Massage Connection: Anatomy and Physi-
ology. Baltimore, MD: Lippincott Williams & Wilkins; 2004.)
Lute a l pha s e
Figure 14.5. Sequence of ovulatory events showing ovar-
ian follicle origin, growth, and rupture and the formation
and degradation of the corpus luteum. The atretic (atro-
phic) follicle was one that did not fully mature.
343
344 C h a p t e r 14: Alt er ed Repr odu ct ive F u n ct ion
con t in u es t o secr et e est r ogen , wh ich a ler t s t h e pi-
t u it a r y t o decr ea se F SH . LH levels r em a in eleva t ed
a n d t h en su r ge a t t h e pea k of est r ogen secr et ion
fr om t h e dom in a n t follicle, ca u sin g t h e oocyt e t o
br ea k t h r ou gh t h e flu id-filled follicle. Th is is t h e
poin t of ovu la t ion .
Th e r u pt u r ed follicle for m s a cor pu s lu t eu m in t h e
lu t ea l ph a se of ovu la t ion . Th e cor pu s lu t eu m secr et es
la r ge a m ou n t s of pr ogest er on e a n d est r ogen . If pr eg-
n a n cy occu r s, t h e pr ogest er on e fr om t h e cor pu s lu -
t eu m h or m on a lly su ppor t s t h e pr egn a n cy u n t il t h e
pla cen t a h a s developed (a ppr oxim a t ely 14 weeks). If
pr egn a n cy does n ot occu r, pr ogest er on e a n d est r ogen
levels dr op wit h in a bou t 14 da ys a ft er ovu la t ion a n d
m en st r u a t ion begin s.
Cor r espon din g t o t h e ovu la t or y cycle is t h e
gr owt h of t h e en dom et r iu m , or lin in g of t h e u t er u s
(Fig. 14.6). Th e gr owt h of t h e en dom et r iu m , a lso
u n der t h e dir ect ion of h or m on es, a llows zygot e im -
pla n t a t ion a n d n ou r ish m en t . E n dom et r ia l gr owt h is
divided in t o t h r ee ph a ses:
● P r olifer a tive (en d of m en st r u a t ion t o ovu la t ion )
ph a se: At t h e en d of m en st r u a t ion , t h e en dom e-
t r iu m is t h in . E st r ogen a ct s t o su ppor t gr owt h
(pr olifer a t ion ) of t h e su per ficia l la yer of t h e en do-
m et r iu m . Th e en dom et r iu m t h ickn ess in cr ea ses
t o six t o eigh t t im es gr ea t er t h a n t h a t fou n d a t
t h e en d of m en st r u a t ion .
● S ecr etor y (ovu la t ion t o t h e begin n in g of m en -
st r u a t ion ) ph a se: P r ogest er on e, in a ddit ion t o
Antrum fille d
Ma ture gra a fia n with liquor
follicle folliculi
P rima ry De ve loping
oocyte follicle s
Ovary
Ute rus Ovulatio n
Endome trium: Ute rine gla nd
S tra tum
functiona le
S tra tum
ba s a le
Myome trium
Day 0 4 14
Me ns trual Pro life rative
phas e phas e
Figure 14.6. Corresponding ovulatory cycle and growth of the endometrium.
est r ogen , fu r t h er su ppor t s pr olifer a t ion of t h e
en dom et r iu m . Th e lin in g becom es t h ick, va scu la r,
a n d swollen . Th e fer t ilized ovu m ca n em bed in t o
t h is t h ick lin in g.
● Men str u a l ph a se: In t h e a bsen ce of fer t iliza t ion
of t h e ovu m , t h e cor pu s lu t eu m becom es u seless.
Disin t egr a t ion of t h e cor pu s lu t eu m r esu lt s in
cessa t ion of est r ogen a n d pr ogest er on e pr odu c-
t ion fr om t h ese cells. Th is lea ds t o sh eddin g of t h e
su per ficia l en dom et r ia l la yer, wh ich is a lso ca lled
t h e m en st r u a l per iod.
Male Reproductive Hormone Function
Th e m a le r epr odu ct ive or ga n s a n d t issu es in clu de
t h e t est es, epididym is, va s defer en s, sem in a l ves-
icles, pr ost a t e, a n d pen is (Fig. 14.7). Th e m a le
gen it ou r in a r y syst em is r espon sible for u r in e elim -
in a t ion , sexu a l fu n ct ion , a n d r epr odu ct ion . An dr o-
gen s, t h e m a le sex h or m on es, pr om ot e m et a bolism
a n d gr owt h . Th e pa t t er n of m a le sex h or m on e secr e-
t ion does n ot follow a cyclica l pa t t er n a s seen wit h
fem a les; t h e h or m on e secr et ion r a t es r em a in fa ir ly
con st a n t t h r ou gh ou t t h e m a le’s a du lt life.
St im u la t ion of a n dr ogen pr odu ct ion a n d r elea se
begin s in t h e h ypot h a la m u s (F ig. 14.8). Th e h ypo-
t h a la m u s r elea ses Gn RH , wh ich st im u la t es t h e a n -
t er ior pit u it a r y t o r elea se LH a n d F SH . LH a ct s on
t h e Leydig cells in t h e t est es t o pr odu ce t est ost er on e,
Expuls ion of
s e conda ry oocyte
Corpus lute um
Ve nous la cuna e
Endome tria l ve in
S pira l a rte ry
Ba s a l a rte ry
Arcua te a rte ry
26 28
S e c re to ry Pre me ns trual
phas e phas e
 R e g u la t io n o R e p r o d u c t io n 345

Pe ritone a l Kidney
cavity

Ure te r
Urina ry
bla dde r Ampulla of
ductus de fe re ns
P ubic
s ymphys is
S e mina l ve s icle
Ductus (va s )
de fe re ns

Re ctum
Cave rnous body
Gla ns pe nis Eja cula tory duct
P re puce
(fore s kin) P ros ta te

Bulboure thra l
Epididymis (Cowpe r's ) gla nd

Te s tis Anus
S crotum
Ure thra
Figure 14.7. Male reproductive structures.

t h e pr im a r y m a le sex h or m on e. Test ost er on e h a s
m u lt iple effect s, in clu din g:
● Developm en t a n d fu n ct ion of m a le r epr odu ct ive
or ga n s
● Sper m pr odu ct ion a n d m a t u r a t ion
● P r ot ein m et a bolism
● Mu scle m a ss pr om ot ion
● Skin t h ickn ess pr om ot ion
● Seba ceou s gla n d a ct ivit y
● Gr owt h of pu bic, ch est , a n d fa cia l h a ir
● Ma t u r a t ion of t h e la r yn x, r esu lt in g in a deeper
voice t on e
E xcess t est ost er on e levels a ler t t h e h ypot h a la m u s
t o decr ea se secr et ion of Gn RH a n d t h e pit u it a r y t o
decr ea se pr odu ct ion of LH .
Th e secon d m a jor sex h or m on e secr et ed fr om t h e
pit u it a r y is F SH . Wh en gon a dot r opin (F SH , LH )
levels in cr ea se, F SH a ct s on t h e Ser t oli cells wit h in
t h e sem in ifer ou s t u bu les t o secr et e in h ibin , a h or-
m on e t h a t a ler t s t h e pit u it a r y t o su ppr ess secr et ion
of t h e gon a dot r opin s. Ser t oli cells a lso pla y a r ole in
sper m a t ogen esis.
Sper m a t ogen esis occu r s in t h e sem in ifer ou s t u -
bu les of t h e t est es. Sper m a t ozoa a r e r elea sed fr om
t h e epit h elia l lin in g of t h e t u bu les in t o t h e lu m en .
Ser t oli cells pla y a n a ct ive r ole in r elea sin g sper m
in t o t h e lu m en . Sper m a t ogen esis r equ ir es a 2° t o
3° cooler scr ot a l t em per a t u r e t h a n t h a t fou n d wit h
t h e cor e body t em per a t u r e. Fa ilu r e of t h e t est es t o
descen d in t o t h e scr ot u m or excessive h ea t t o t h e
scr ot u m , su ch a s occu r s wh en sit t in g in a h ot t u b,
ca n im pa ir sper m a t ogen esis. Test ost er on e pr odu c-
t ion is n ot a ffect ed by t em per a t u r e. Ma t u r a t ion of
t h e sper m t a kes pla ce wit h in a ppr oxim a t ely 60 da ys.
Sper m a t ozoa t h en t r a n sit t o t h e epididym is (t h e
r eser voir ), t h en even t u a lly t o t h e va s defer en s, a n d
t h en exit t h e body t h r ou gh t h e u r et h r a (Fig. 14.9).
Th e a ccessor y gla n ds, sem in a l vesicles, pr ost a t e, a n d
Cowper gla n ds fa cilit a t e t h e t r a n spor t of sper m a t o-
zoa du r in g t h e eja cu la t or y pr ocess a n d a id in sper-
m a t ozoa su r viva l.
346 C h a p t e r 14: Alt er ed Repr odu ct ive F u n ct ion
Hypotha la mus
GnRH
Ante rior
pituita ry
LH
FS H
Te s tis
Inhibin Te s tos te rone
Figure 14.8. Feedback regulation of testicular function.
FSH, follicle-stimulating hormone; GnRH, gonadotropin-re-
leasing hormone; LH, luteinizing hormone. (From Premku-
mar K. The Massage Connection: Anatomy and Physiology.
Baltimore, MD: Lippincott Williams & Wilkins; 2004.)
Modu le 2 Alt e r e d R e p r o d u c t iv e F u n c t io n
Ach ievin g pr egn a n cy is a com plex in t er a ct ion of
ovu la t ion , sper m a t ogen esis, in t er cou r se, eja cu la t ion ,
con cept ion , im pla n t a t ion , a n d em br yo gr owt h . In fer-
t ilit y, defin ed a s t h e in a bilit y t o a ch ieve pr egn a n cy
a ft er 1 yea r of u n pr ot ect ed in t er cou r se, ca n r esu lt
fr om pr oblem s in a n y of t h ese st eps. Abou t 10% t o
15% of cou ples a r e in fer t ile. In m a n y ca ses, t h e exa ct
ca u se of in fer t ilit y is n ot iden t ified.
Alt er ed r epr odu ct ion ca n r esu lt fr om a fu n ct ion a l
im pa ir m en t in t h e m a le or fem a le pa r t n er, or bot h .
F igu r e 14.10 illu st r a t es ca u ses of a cqu ir ed in fer t ilit y
im pa ct in g fem a les. Fa ct or s in volved wit h a lt er ed r e-
pr odu ct ion m a y in clu de:
● H or m on a l im ba la n ce ca u sin g t h e a bsen ce of,
or in fr equ en t , ovu la t ion , wh ich im pa ir s oocyt e
He a d
Acros ome
Ne ck
Nucle us
Midpie ce Mitochondria
Ta il (fla ge llum)
Figure 14.9. Structure of spermatozoa.
developm en t a n d r elea se; t est ost er on e losses r e-
su lt in im pa ir ed sper m pr odu ct ion .
● Motility im pa ir m en t ca u sed by a dh esion s or ob-
st r u ct ion in t h e pa t h wa y fr om t h e cer vix t o t h e
ova r y, wh ich r esu lt s in pr oblem s wit h oocyt e or
sper m t r a n sit a n d block t h e join in g of t h ese cells.
E xa m ples in clu de in h ospit a ble cer vica l m u cu s
t h a t block s sper m fr om en t er in g t h e u t er u s or
pr eviou s or cu r r en t in fect ion t h a t r esu lt s in a d-
h esion s a n d obst r u ct ion of r epr odu ct ive st r u c-
t u r es. L e i o m y o m a s , fibr ou s t u m or s t h a t m a y
for m in t h e u t er u s, dist or t t h e en dom et r ia l
ca vit y.
● Im m u n e pr oblem s ca u sed by a n t ibodies t o t h e
m a le sper m , wh ich qu ickly dest r oy sper m , r en der-
in g it u n a ble t o r ea ch t h e oocyt e.

Hypotha la mus -
pituita ry hormone s
(via ova ria n s e cre tion)
Gona dotropin de ficie ncy,
hype rprola ctine mia
P re ma ture me nopa us e
Endome tria l a dhe s ions
Chronic ce rvicitis with
a bnorma l mucus s e cre tion
Anti-s pe rm a ntibodie s ?
Figure 14.10. Causes of acquired infertility in females. (From Rubin E, Farber JL. Pathology. 3rd ed. Philadelphia,
PA: Lippincott Williams & Wilkins; 1999.)
General Manifestations of Altered
Reproductive Function
Th e in a bilit y t o con ceive a n d m a in t a in a pr egn a n cy
is a u n iver sa l clin ica l m a n ifest a t ion for in fer t ilit y.
In m a n y ca ses, pa r t icu la r ly in m en , t h er e a r e n o
ot h er sign s or sym pt om s. Wit h h or m on e a lt er a t ion s,
ir r egu la r m en st r u a l per iods or a m e n o r r h e a (a b-
sen t m en st r u a l per iods) m a y be r epor t ed. Th is of-
t en sign ifies a n o v u la t io n , t h e a bsen ce of ovu la t ion
m a n ifest ed by t h e excess or deficit of on e or m or e
r epr odu ct ive h or m on es. Am en or r h ea ca n a lso r e-
su lt fr om em ot ion a l st r ess, or pr olon ged st r en u ou s
exer cise. Wit h t h e except ion of pr egn a n cy-in du ced
a m en or r h ea , a bsen t m en st r u a l per iods is oft en t h e
r esu lt of cen t r a l n er vou s syst em (CNS) a lt er a t ion s
t h a t a ffect t h e r elea se of Gn RH fr om t h e h ypot h a l-
a m u s a n d t h er efor e su ppr ess or over st im u la t e t h e
pr odu ct ion of r epr odu ct ive h or m on es. For exa m ple, a
pit u it a r y a den om a m a y in du ce h yper pr ola ct in em ia ,
a con dit ion t h a t r esu lt s in a n ovu la t ion a n d su bse-
qu en t ly pr odu ces a m en or r h ea .
Alt e r e d R e p r o d u c t iv e F u n c t io n 347
Pe lvic infla mma tory dis e a s e
(e.g., hydros a lpinx, fimbria l da ma ge )
Endome tritis
(e.g., Tb)
Polycys tic ova ry
(S te in-Leve ntha l
Endome trios is s yndrome )
Pa in is a n ot h er possible clin ica l m a n ifest a t ion .
Test icu la r /scr ot a l pa in in m en or pelvic pa in in
wom en m a y occu r wit h in fect ion or in fla m m a t ion of
r epr odu ct ive st r u ct u r es. D y s m e n o r r h e a , or sever e
pa in wit h m en st r u a l per iods, d y s p a r e u n ia , or pa in
wit h in t er cou r se, a n d ot h er for m s of pelvic pa in m a y
be pr esen t wit h in fect ion s or st r u ct u r a l im pa ir m en t
in wom en . E n d o m e t r io s is , a con dit ion in volvin g
en dom et r ia l t issu e t h a t is loca t ed ou t side of t h e
u t er u s, ca n r esu lt in pelvic a dh esion s, dist or t ion of
pelvic st r u ct u r es, a n d dysm en or r h ea (F ig. 14.11).
Diagnosing and Treating Altered
Reproductive Function
Th e dia gn osis of a lt er ed r epr odu ct ion is ba sed on t h e
cou ple’s in a bilit y t o con ceive or t h e pr esen ce of clin i-
ca l m a n ifest a t ion s descr ibed a bove. Det er m in in g t h e
ca u se r equ ir es a syst em a t ic h ist or y, ph ysica l exa m -
in a t ion , a n d specia lized dia gn ost ic t est s. In it ia lly, a
sem en a n a lysis m u st be com plet ed in t h e m a le a lon g
348 C h a p t e r 14: Alt er ed Repr odu ct ive F u n ct ion
Figure 14.11. Endometriosis implants on the ovary appear
as red-blue nodules. (From Rubin E, Farber JL. Pathology. 3rd
ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999.)
wit h a n a n a lysis of ovu la t ion in t h e fem a le. Det er m i-
n a t ion of ovu la t ion ca n in volve obser vin g for cer vica l
m u cu s ch a n ges a t t h e t im e of ovu la t ion , m ea su r-
in g t h e ba sa l body t em per a t u r e over 2 t o 3 m on t h s
(n ot in g t h e 0.5°F in cr ea se a t t h e t im e of ovu la t ion
a s pr ogest er on e levels r ise), or u sin g a h om e ovu la -
t ion pr edict or kit , wh ich m ea su r es t h e LH su r ge ju st
pr ior t o ovu la t ion . F igu r e 14.12 illu st r a t es a pa t h -
wa y for dia gn osis for t h ose wit h a m en or r h ea .
Pa t en cy of t h e r epr odu ct ive st r u ct u r es ca n be vi-
su a lized u sin g h yst er osa lpin gogr a ph y (Fig. 14.13).
Figure 14.12. The evaluation of amenorrhea. CNS, central nervous system; FSH, follicle-stimulating hormone; hCG, human
chorionic gonadotropin; MRI, magnetic resonance imaging; PCOS, polycystic ovary syndrome; POF, premature ovarian fail-
ure; Prl, prolactin; TSH, thyroid-stimulating hormone.
Th is pr ocedu r e in volves in ject in g a r a diopa qu e m a -
t er ia l in t o t h e u t er u s a n d fa llopia n t u bes, t h en u sin g
a flu or oscope a n d r a diogr a ph t o det er m in e t h e pr es-
en ce of obst r u ct ion s t h r ou gh t h e r epr odu ct ive pa t h -
wa y. La pa r oscopy, a scope pla ced t h r ou gh a n in cision
in t h e a bdom en , ca n view per it on ea l a n d a bdom in a l
st r u ct u r es ou t side of t h e u t er u s a n d fa llopia n t u bes.
Gen er a l t r ea t m en t in volves su ppor t ive cou n sel-
in g, edu ca t ion a bou t in t er cou r se fr equ en cy, a void-
a n ce of lu br ica n t s, wh ich ca n a ct a s a sper m icide,
a n d ba sic h ea lt h m a in t en a n ce. Focu sed t r ea t m en t
is a im ed a t t h e ca u se, if iden t ified. Sexu a lly t r a n s-
m it t ed or ot h er pelvic in fect ion s pla ce t h e fem a le a t
h igh r isk for in fer t ilit y a n d m u st be t r ea t ed qu ickly
a n d com plet ely. Obst r u ct ive pr ocesses, su ch a s leio-
m yom a s, en dom et r iosis, or pelvic a dh esion s, m a y
r equ ir e su r gica l in t er ven t ion . Ovu la t or y fa ilu r e r e-
qu ir es a det er m in a t ion of t h e en docr in e pr oblem a n d
a cor r espon din g t r ea t m en t . Som e in dividu a ls m a y
r equ ir e clom iph en e cit r a t e, a m edica t ion t h a t in -
du ces ovu la t ion . In t h ose wit h h yper pr ola ct in em ia ,
m edica t ion s m a y be n eeded t o r edu ce pr ola ct in a n d
t h er efor e in du ce ovu la t ion . Ar t ificia l in sem in a t ion
m a y be u sed t o in ject sper m in t o t h e u t er u s if cer vi-
ca l m u cu s is t h ick or if t h e sper m qu a n t it y or qu a lit y
is com pr om ised. Som e cou ples seek a dva n ced r epr o-
du ct ive t ech n ologies su ch a s in vit r o fer t iliza t ion .
Th e eva lu a t ion a n d t r ea t m en t of in fer t ilit y is h igh ly
com plex a n d em ot ion a lly ch a r ged. Sen sit ivit y t o t h e
r a n ge a n d in t en sit y of em ot ion s is a n im por t a n t a s-
pect of ca r e.

Figure 14.13. Anteroposterior radiograph of the female pelvis after injection of radiopaque compound into the uterine cav-
ity (hysterosalpingogram). (From Snell RS. Clinical Anatomy. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.)
Modu le 3 C lin ic a l Mo d e ls
Pelvic Inflammatory Disease
Pelvic in fla m m a t or y disea se (P ID) is t h e r esu lt of
a sexu a lly t r a n sm it t ed in fect ion of t h e r epr odu c-
t ive t r a ct (F ig. 14.14). Th e m ost fr equ en t ca u se is
a com bin a t ion of sexu a lly t r a n sm it t ed m icr oor ga n -
ism s in clu din g Ch la m yd ia tr a ch om a tis a n d N eis-
ser ia gon or r h oea e. In wom en , sexu a l in t er cou r se
pr opels m icr oor ga n ism s in t o t h e va gin a wh er e t h e
in fect ion t h en a scen ds in t o t h e cer vix, u t er u s, fa l-
lopia n t u bes, ova r ies, a n d even in t o t h e per it on ea l
ca vit y.
PATHOPHYSIOLOGY
Aft er a t t a ch in g t o t h e epit h elia l cells lin in g t h e
r epr odu ct ive t r a ct , t h e offen din g m icr oor ga n ism s
elicit a cu t e in fla m m a t or y a n d im m u n e r espon ses.
Th e r epr odu ct ive t r a ct becom es h yper em ic a n d
edem a t ou s. Th e fa llopia n t u bes becom e obst r u ct ed
C lin ic a l Mo d e ls 349
wit h pu r u len t exu da t e. Repea t ed or ch r on ic in -
fect ion r esu lt s in sca r for m a t ion . Th is sca r r in g is
pa r t icu la r ly pr oblem a t ic in t h e fa llopia n t u bes a n d
ova r ies, wh er e ovu la t ion a n d fr ee m ovem en t of t h e
ovu m t o t h e u t er u s is pr oh ibit ed. E ct opic pr egn a n cy,
t u bo-ova r ia n a bscess, pelvic a dh esion s, a n d in fer t il-
it y a r e pot en t ia l com plica t ion s of P ID. In t h e m a le
r epr odu ct ive t r a ct , sexu a lly t r a n sm it t ed in fect ion s
ca n r esu lt in a sim ila r pr oblem in t h e u r et h r a , epi-
didym is, a n d t est es.
CLINICAL MANIFESTATIONS
E a r ly in fect ion is oft en a sym pt om a t ic, in cr ea sin g
t h e likelih ood of t r a n sm ission t o ot h er s. As t h e in -
fect ion a scen ds a n d t h e in fla m m a t or y a n d im m u n e
r espon ses becom e m or e in t en sified, com m on clin ica l
m a n ifest a t ion s in clu de pelvic a n d lower a bdom in a l
pa in , pu r u len t cer vica l disch a r ge, cer vica l m ot ion
t en der n ess, fever, a n d m a la ise.
350 C h a p t e r 14: Alt er ed Repr odu ct ive F u n ct ion
Multiple a dhe s ions
Fa llopia n tube infla me d (froze n pe lvis )
a nd e de ma tous
Infla me d Tuboova ria n
a dnexa a bs ce s s
(cros s -s e ction)
Figure 14.14. Clinical manifestations and complications of pelvic inflammatory disease.
DIAGNOSTIC CRITERIA
Dia gn osis of P ID is ba sed on h ist or y, ph ysica l ex-
a m in a t ion , a n d la bor a t or y st u dies. Th e m in im u m
cr it er ia for t h e dia gn osis of P ID in clu de lower a b-
dom in a l t en der n ess on pa lpa t ion , a dn exa l (t issu es
su ppor t in g t h e u t er u s) t en der n ess, a n d cer vica l
m ot ion t en der n ess. Cer vicit is a n d a pu r u len t dis-
ch a r ge fr om t h e cer vix m a y be visu a lized du r in g
pelvic exa m in a t ion . Th e pr esen ce of fever, eleva t ion
in t h e er yt h r ocyt e sedim en t a t ion r a t e or C-r ea ct ive
pr ot ein (n on specific t est s of in fla m m a t ion ), a n d pos-
it ive ba ct er ia l cu lt u r es of in fect ed gen it ou r in a r y
secr et ion s pr ovide a ddit ion a l clu es for dia gn osis.
La pa r oscopy m a y be u sed t o con fir m t h e dia gn osis
a s n eeded.
TREATMENT
Tr ea t m en t of P ID r equ ir es a n im m edia t e a n d oft en
pr olon ged cou r se of or a l or in t r a ven ou s a n t ibiot ics.
H ospit a liza t ion wit h in t r a ven ou s a n t ibiot ics a n d
flu ids is r equ ir ed if t h e pa t ien t is:
● P r egn a n t
● Im m u n odeficien t
● P r esen t in g wit h sever e illn ess, n a u sea , vom it in g,
or a h igh fever
● Un a ble t o follow or t oler a t e t h e ou t pa t ien t t r ea t -
m en t wit h or a l a n t ibiot ics
● Pot en t ia lly in n eed of em er gen cy su r ger y, su ch a s
if a ppen dicit is ca n n ot be exclu ded
● Dia gn osed wit h a t u bo-ova r ia n a bscess
S ca rring of
fa llopia n tube
Ce rvicitis
(s hows a s re dne s s
with purule nt
dis cha rge )
Introduction of
orga nis ms via
s exua l
inte rcours e
C L I N I C AL P R AC T I C E
Tr ea t m en t of sexu a l con t a ct s for t h ose wit h
sexu a lly t r a n sm it t ed in fect ion s is im por t a n t t o
a void r ein fect ion . Th e pa t ien t m u st a bst a in fr om
in t er cou r se du r in g t h e t r ea t m en t r egim en a n d
u n t il pa r t n er s a r e t r ea t ed a n d cu r e is a ch ieved.
Th e goa l of t r ea t m en t is t o pr even t com plica t ion s
su ch a s pelvic a dh esion s, ect opic pr egn a n cy, a b-
scesses, a n d in fer t ilit y.
Polycystic Ovarian Syndrome
P o ly c y s t ic o v a r y s y n d r o m e (P C O S ) is a con di-
t ion of excess a n dr ogen pr odu ct ion fr om t h e ova r ies
a n d occu r s in a bou t t h r ee-qu a r t er s of wom en wit h
a n ovu la t or y in fer t ilit y (Fig. 14.15).
In P COS, excess a n dr ogen exposu r e r esu lt s in :
● Mu lt iple im m a t u r e ova r ia n follicles
● Decr ea sed pr ogest er on e pr odu ct ion
● In cr ea sed a cyclic (con st a n t ) est r ogen pr odu ct ion
● An ovu la t ion
● H ir s u t is m (a bn or m a l gr owt h of h a ir on fa ce a n d
body, see Fig. 14.16)
 C lin ic a l Mo d e ls 351

Lute inizing
Hype rins uline mia
Ins ulin ● Acn e
hormone re s is ta nce ● Obesit y fr om con ver sion of a n dr ogen s t o est r ogen
in a dipose t issu es
Dys re gula tion
● H yper t en sion
of a ndroge n ● Dia bet es
s e cre tion ● Obst r u ct ive sleep a pn ea

/Intra -ova ria n a ndroge n Long te rm e ffe cts ; PATHOPHYSIOLOGY

(The ca ce ll/lute inize d s troma l ce ll) e ndome tria l
hype rpha s ia /ca rcinoma Th e exa ct ca u se of P COS is u n kn own . A gen et ic
ca u se h a s been su ggest ed a n d t h ose wit h P COS
a r e m or e likely t o h a ve a m ot h er or sist er a lso wit h
Hype ra ndroge ne mia Follicula r a tre s ia P COS. Th e r epr odu ct ive cycle is r egu la t ed by ch a n g-
in g h or m on e levels pr odu ced by t h e pit u it a r y a n d by
t h e ova r ies. In P COS, t h e pit u it a r y gla n d secr et es
Hirs utis m h igh levels of LH a n d t h e ova r ies m a ke excess a n -
Acne Es trone
(pe riphe ra lly conve rte d) dr ogen s. Th e con t in u ed pr esen ce of F SH a llows for
Androge n-de pe nde nt
a lope cia P roge s te rone follicle developm en t bu t m a t u r a t ion of t h e follicles
does n ot occu r. In t h e a bsen ce of ovu la t ion , est r o-
Ame norrhe a gen a lt er s Gn RH r esu lt in g in h igh LH levels wit h
Infe rtility eleva t ion of a n dr ogen r elea se a n d su ppr ession of
Polycys tic ova rie s
F SH . Th e m en st r u a l cycle is disr u pt ed. Ch r on ic a n -
ovu la t ion pr odu ces bila t er a lly dist en ded a n d cyst ic
CHRONIC ANOVULATION ova r ies. A r ela t ion sh ip h a s been n ot ed bet ween h igh
Figure 14.15. Concept map. Pathogenesis of polycystic a n dr ogen levels a n d in su lin r esist a n ce, wh er e in su -
ovary syndrome. (From Rubin E, Farber JL. Pathology. 3rd lin excess pr om ot es excessive a n dr ogen pr odu ct ion
ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1999.) by t h e ova r ies. In su lin sen sit izin g dr u gs h a ve been

Figure 14.16. Typical facial hirsutism

in polycystic ovarian syndrome. (From
Berek JS. Berek & Novak’s Gynecology.
15th ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2012.)
352 C h a p t e r 14: Alt er ed Repr odu ct ive F u n ct ion
Figure 14.17. Polycystic disease of the ovary. Cut sec-
tions of an ovary show numerous cysts embedded in a scle-
rotic stroma. (From Rubin E, Farber JL. Pathology. 3rd ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 1999.)
sh own t o pr om ot e ovu la t ion a n d, u lt im a t ely, pr eg-
n a n cy in som e ca ses.
CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s wit h P COS a r e a ssocia t ed
wit h m en st r u a l ir r egu la r it ies, excess a n dr ogen
pr odu ct ion , a n d, in m a n y ca ses, polycyst ic ova r ies
(Fig. 14.17). P r olon ged m en st r u a l per iods a n d m en -
st r u a l in t er va ls lon ger t h a n 35 da ys or fewer t h a n
eigh t m en st r u a l cycles per yea r a r e n ot u n com m on .
E xcess a n dr ogen pr odu ct ion m a y r esu lt in ph ysi-
ca l sign s, su ch a s h ir su t ism (excess fa cia l a n d body
h a ir ), a cn e, a n d m a le-pa t t er n ba ldn ess, wit h som e
va r ia bilit y ba sed on et h n icit y. Obesit y is pr esen t
in a bou t h a lf of wom en wit h P COS. Aca n t h osis n i-
gr ica n s (da r ken ed, velvet y skin ) on t h e n a pe of t h e
n eck, a r m pit s, in n er t h igh s, vu lva , or u n der t h e
br ea st s ca n occu r a s a r esu lt of in su lin r esist a n ce. In
som e ca ses, P COS is on ly iden t ified wh en fer t ilit y is
desir ed a n d n ot a ch ieved.
DIAGNOSTIC CRITERIA
In 2013, t h e E n docr in e Societ y r elea sed pr a ct ice
gu idelin es for t h e dia gn osis a n d t r ea t m en t of P COS. 1
In t h ose gu idelin es, t h e Rot t er da m cr it er ia sh ou ld
be u sed for dia gn osis. Th ese cr it er ia r equ ir e t h e
pr esen ce of t wo of t h e followin g: a n dr ogen excess,
ovu la t or y dysfu n ct ion , a n d/or polycyst ic ova r ies.
La bor a t or y t est s a r e u sed t o iden t ify h or m on e a lt er-
a t ion s a n d r u le ou t h yper pr ola ct in em ia a n d ova r-
ia n or a dr en a l t u m or s. E n la r ged ova r ies con t a in in g
n u m er ou s sm a ll cyst s ca n be det ect ed by t r a n sva g-
in a l u lt r a sou n d. Addit ion a lly, fa st in g ch olest er ol
a n d t r iglycer ide levels a r e n eeded t o det er m in e h y-
per ch olest er olem ia a n d a glu cose t oler a n ce t est is
n eeded t o det er m in e in su lin r esist a n ce.
TREATMENT
Tr ea t m en t is a im ed a t su ppr essin g a n dr ogen pr o-
du ct ion a n d m a n a gin g t h e clin ica l m a n ifest a t ion s.
To in du ce pr egn a n cy, t r ea t m en t wit h a n t iest r ogen
m edica t ion s t o in du ce ovu la t ion , su ch a s clom iph en e
cit r a t e, is n eeded. Ca u t ion m u st be u sed beca u se of
t h e r isk for ova r ia n h yper st im u la t ion . Met for m in is
a n or a l m edica t ion t h a t lower s in su lin levels a n d
im pr oves ovu la t ion t h er eby r egu la t in g m en st r u a l
cycles. Th is dr u g is oft en u sed in com bin a t ion wit h
clom iph en e cit r a t e. If u n su ccessfu l, in ject a ble F SH
a n d LH (gon a dot r opin s) m a y be u sed. La pa r oscopic
la ser su r ger y t o pu n ct u r e t h e m u lt iple in effect ive
follicles m a y im pr ove follicu la r fu n ct ion .
If pr egn a n cy is n ot desir ed, low-dose bir t h con t r ol
pills decr ea se a n dr ogen pr odu ct ion a n d cor r ect ir r eg-
u la r bleedin g. P r ogest er on e ca n a lso be t a ken for 10
t o 14 da ys ea ch m on t h t o r egu la t e m en st r u a l per iods
bu t does n ot im pr ove a n dr ogen levels. Ma n a gin g obe-
sit y, h igh ch olest er ol, dia bet es, a n d h yper t en sion a r e
im por t a n t t o pr even t lon g-t er m ca r diova scu la r r isks.
Spir on ola ct on e m a y be u sed t o block t h e skin effect s
of a n dr ogen s, in clu din g t h e r edu ct ion of excessive
h a ir gr owt h a n d a cn e. Sh a vin g, wa xin g, depila t or y
cr ea m s, la ser h a ir r em ova l, a n d even elect r olysis a r e
a lso u sed t o r edu ce excessive h a ir.
Ovarian Cancer
Neopla sia ca n occu r a n ywh er e t h r ou gh ou t t h e r e-
pr odu ct ive t r a ct . Un com m on ly, wom en ca n develop
ca n cer of t h e vu lva or va gin a . Mor e com m on ly, n eo-
pla sia s ca n be fou n d in t h e cer vix, u t er u s, a n d ova -
r ies. E n dom et r ia l ca n cer of t h e u t er u s is t h e m ost
com m on in va sive ca n cer in t h e r epr odu ct ive t r a ct
for wom en . E pit h elia l ca r cin om a of t h e ova r y is t h e
secon d m ost com m on gen it ou r in a r y ca n cer (70% t o
90% of a ll ova r ia n m a lign a n cies) a n d t h e fift h m ost
fr equ en t ca u se of dea t h in wom en . Mor e t h a n 48% of
a ll ca ses occu r in wom en over t h e a ge of 65.2
PATHOPHYSIOLOGY
Ova r ia n ca n cer a r ises du e t o a com bin a t ion of ge-
n et ic a n d en vir on m en t a l r isk fa ct or s. Fa m ily h is-
t or y h a s a n im por t a n t r ole in t h e developm en t of
ova r ia n ca n cer. Appr oxim a t ely 5% t o 10% of ova r ia n
ca n cer s a r e h er edit a r y, pr esen t in g a s on e of t h r ee
 C lin ic a l Mo d e ls 353

pa t t er n s: ova r ia n ca n cer a lon e, ova r ia n -br ea st

ca n cer, or ova r ia n -colon ca n cer. In t h ese t ypes, t h e
m ost im por t a n t r isk fa ct or is a fa m ily h ist or y of a
fir st -degr ee r ela t ive (m ot h er, da u gh t er, or sist er )
wit h t h e disea se. Th is r isk in cr ea ses in wom en wit h
t wo or m or e fir st -degr ee r ela t ives wit h ova r ia n
ca n cer. Th e BRCA1 gen e, loca t ed on ch r om osom e
17q21, h a s been lin k ed t o fa m ilies a ffect ed wit h
ova r ia n ca n cer a n d in t h e br ea st -ova r ia n ca n cer
com bin a t ion . Th e r isk h a s been r epor t ed a t 15% t o
45% in t h ose wit h t h e BRCA1 m u t a t ion . BRCA2,
loca t ed on ch r om osom e 13q14, is a lso r espon sible
for som e in st a n ces of in h er it ed ova r ia n a n d br ea st
ca n cer. Bot h follow a n a u t osom a l dom in a n t pa t -
t er n . Gen e m u t a t ion s, im plica t ed in a lm ost a ll h igh
gr a de ser ou s ova r ia n ca n cer, occu r a t TP 53 a n d
wit h over 100 sign ifica n t foci. Th ose wit h br ea st
ca n cer a lso h a ve a sign ifica n t r isk of developin g ep-
it h elia l ova r ia n ca n cer. Figure 14.18. Ovarian cancer. A cross-section of the en-
E n vir on m en t a l fa ct or s a lso pla y a sign ifica n t r ole. larged ovary shows a solid tumor with focal hemorrhages.
For exa m ple, ova r ia n ca n cer developm en t a ppea r s (Modified from Rubin E, Farber JL. Pathology. 4th ed. Phil-
cor r ela t ed wit h in cr ea sed t r a u m a t o t h e ova r ies. adelphia, PA: Lippincott Williams & Wilkins; 2005.)
Mon t h ly ovu la t ion r esu lt s in t h e ovu m br ea kin g
t h r ou gh t h e epit h elia l su r fa ce of t h e ova r y, ca u sin g per it on eu m . Th is is followed by loca l in va sion of t h e
a n in fla m m a t or y r espon se a n d r equ ir in g t issu e r e- bowel a n d bla dder. In filt r a t ion of t h e pelvic lym ph
pa ir. Over t im e wit h r epea t ed ovu la t ion , t h e r isk n odes is com m on , a n d it s in ciden ce in cr ea ses wit h
for ova r ia n ca n cer in cr ea ses. P r egn a n cy, t h e u se gr ea t er sever it y of disea se. At t h e t im e of dia gn osis,
of con t r a cept ives, a n d ot h er even t s t h a t su ppr ess ova r ia n ca n cer is st a ged fr om I t o IV:
ovu la t ion m a y h a ve a pr ot ect ive effect . Also, r isk I. Lim it ed t o on e or bot h ova r ies
for ova r ia n ca n cer h a s been sh own t o in cr ea se wit h II. E xt en ds in t o pelvis
post m en opa u sa l u se of h or m on e t h er a py. III. Met a st a ses in per it on eu m ou t side t h e pelvis
Th e pa t h oph ysiology of ova r ia n ca n cer follows I V. Dist a n t m et a st a ses
t h a t of ot h er a lt er a t ion s in cellu la r pr olifer a t ion a n d
differ en t ia t ion . Cla ssifica t ion of ova r ia n ca n cer is As wit h ot h er t ypes of ca n cer, m et a st a ses ca n r elo-
ba sed on t issu e of or igin a n d in clu des: ca t e in t h e ova r ies fr om a pr im a r y t u m or t h a t or igi-
n a t es elsewh er e. Ova r ia n ca n cer is cu r a ble in a h igh
● E p it h e lia l t u m o r s : Ar ise fr om t h e su r fa ce of per cen t a ge of pa t ien t s if det ect ed in t h e ea r ly st a ges.
t h e ova r y. Ser ou s a den oca r cin om a , a n epit h elia l Un for t u n a t ely, a t t h e t im e of dia gn osis, t h r ee of ev-
t u m or t h a t r esem bles t h e epit h elia l t issu e of t h e er y fou r wom en h a ve loca l spr ea d t o t h e pelvis or dis-
fa llopia n t u be, is t h e m ost com m on t ype. t a n t m et a st a ses, m a kin g ova r ia n ca n cer on e of t h e
● G e r m c e ll t u m o r s : Com pr ise 25% of ova r ia n t u - m ost let h a l fem a le r epr odu ct ive ca n cer s (F ig. 14.18).
m or s bu t a r e m ost ly ben ign in a du lt wom en . Ger m Mor e t h a n h a lf of t h ese in dividu a ls a r e a t a st a ge III
cell t u m or s ca n a lso occu r in ch ildr en bu t a r e m or e or gr ea t er a t dia gn osis. For st a ge III or IV t u m or s
oft en m a lign a n t in ch ildr en a n d you n g a du lt s. t h a t ca n n ot be r em oved a dequ a t ely via su r ger y, t h e
Ger m cell t u m or s r esem ble em br yon ic t issu es. De- 5-yea r su r viva l r a t e is less t h a n 10%. Th e com posit e
velopm en t is sim ila r t o t h a t of t est icu la r ca n cer. 5-yea r su r viva l r a t e for a ll pa t ien t s dia gn osed wit h
● S e x c o r d t u m o r s : Com pr ise 10% of ova r ia n t u - ova r ia n ca n cer is 35%. 3
m or s. Th ese t u m or s
a r ise fr om pr im it ive
sex cor d or con n ect ive
t issu e of t h e developin g FROM THE L AB
ova r y.
The serum CA-125 level, a tumor marker (antigen), indicates a high probability of epithelial
Th e spr ea d of ova r ia n ovarian cancer. However, CA-125 has no prognostic significance when measured at diagno-
ca n cer occu r s via loca l sis. This tumor marker has greater utility in monitoring treatment efficacy and determining
sh eddin g in t o t h e per it o- recurrence of disease in those with an elevated CA-125 at diagnosis. This test can also be
n ea l ca vit y wit h seedin g elevated in other malignant and nonmalignant conditions, such as endometriosis.
a n d im pla n t a t ion on t h e
354 C h a p t e r 14: Alt er ed Repr odu ct ive F u n ct ion
CLINICAL MANIFESTATIONS
Ovarian cancer is often asymptomatic in the early stages.
Vague abdominal bloating may be noticed in some. As
with pregnancy, the peritoneum allows for growth of
tumors without immediate obstruction on other nearby
structures. Therefore, most patients have widespread
disease at the time of diagnosis. Large tumors may man-
ifest as abdominal distention, pressure, or pain.
DIAGNOSTIC CRITERIA
Dia gn osis is ba sed on pa t ien t h ist or y, ph ysica l exa m -
in a t ion (bim a n u a l pa lpa t ion of t h e ova r ies), la pa r o-
scopic or ot h er su r gica l explor a t ion of t h e per it on ea l
ca vit y, a n d cyt ologic exa m in a t ion of ova r ia n epit h e-
lia l cells. If t h e t u m or a ppea r s t o be isola t ed t o t h e
ova r y or pelvis, la pa r ot om y is u sed t o exa m in e t h e
per it on eu m a n d obt a in ova r ia n , lym ph , a n d su r-
r ou n din g t issu es for a n a lysis. Ser u m t u m or m a r ker
levels a r e a lso obt a in ed a t dia gn osis.
TREATMENT
Tr ea t m en t is ba sed on t h e st a ge of ova r ia n ca n cer
a t dia gn osis. For t h ose dia gn osed a t st a ges I or II,
a t u m or t h a t is well differ en t ia t ed or m oder a t ely
well differ en t ia t ed is t r ea t ed t h r ou gh su r gica l
(debu lkin g) r em ova l of t h e u t er u s, bot h ova r ies, a n d
su r r ou n din g om en t u m . Th e dia ph r a gm is biopsied
a lon g wit h m u lt iple lym ph n odes t o det ect spr ea d. In
t h ose pa t ien t s con sider in g ch ildbea r in g wit h st a ge I
well-differ en t ia t ed t u m or s, t h e r em ova l of r epr odu c-
t ive or ga n s m a y be lim it ed t o t h e a ffect ed ova r y a n d
fa llopia n t u be. In a ll st a ges wit h a less-differ en t ia t ed
t u m or a n d gr ea t er spr ea d, su r ger y is a ccom pa n ied
by ext en sive in t er n a l a n d ext er n a l r a dia t ion t h er a py
a n d loca l a n d syst em ic com bin a t ion ch em ot h er a py.
Th e goa l of t h er a py is t o r em ove a ll n eopla st ic cells
a n d in du ce com plet e r em ission .
Menopause
Me n o p a u s e , t h e com plet e cessa t ion of ova r ia n a c-
t ivit y, is a n expect ed biologica l st a ge m a r kin g t h e en d
of a wom a n ’s r epr odu ct ive life. Th is occu r s gen er a lly
a r ou n d 48 t o 55 yea r s of a ge. P e r im e n o p a u s e is t h e
4- t o 5-yea r gr a du a l t r a n sit ion bet ween pr edict a ble
r epr odu ct ive cycles a n d m en opa u se. Su bt le ch a n ges
in bleedin g pa t t er n s a r e t h e ea r liest m a n ifest a t ion
of t h e per im en opa u sa l per iod.
PATHOPHYSIOLOGY
F r om m e n a r c h e (t h e t im e lea din g t o t h e fir st m en -
st r u a l per iod) on wa r d, t h e cells of t h e r epr odu ct ive
syst em r espon d t o t r oph ic sign a ls pr odu ced by t h e
ova r ia n st er oid h or m on es, est r ogen a n d pr ogest er-
on e. Th e feedba ck m ech a n ism s of t h e h ypot h a la m u s–
pit u it a r y a xis a ct in g u pon t h e ova r ies r egu la t e bot h
t h e st im u la t ion a n d su ppr ession of est r ogen t o a llow
for a dequ a t e ph ysiologic fu n ct ion in g. Th e loss of h or-
m on es a ssocia t ed wit h ova r ia n cycles pr ecipit a t es
a t r oph ic ch a n ges in t h e cells of t h e r epr odu ct ive or-
ga n s a n d t h e sym pt om s com m on ly a ssocia t ed wit h
m en opa u se.
As t h e ova r ies a ge, t h e follicles becom e exh a u st ed
a n d u n a ble t o r espon d t o fu n ct ion a l dem a n ds despit e
a dequ a t e st im u la t ion . Redu ced r elea se of ova r ia n
h or m on es t r igger s t h e h ypot h a la m u s t o in cr ea se se-
cr et ion of Gn RH . As a r esu lt , t h e a n t er ior pit u it a r y
secr et es a ddit ion a l F SH a n d LH yet t h is a ct ivit y is
in effect ive in pr odu cin g t h e desir ed effect beca u se
t h e a gin g ova r ies a r e n o lon ger a ble t o pr odu ce es-
t r ogen a n d pr ogest er on e.
CLINICAL MANIFESTATIONS
Th e clin ica l m a n ifest a t ion s occu r a s a r esu lt of loss
of t h e est r ogen effect on cells of t a r get or ga n s. E s-
t r ogen depr iva t ion ca n ca u se obviou s effect s lea din g
t o a cu t e sym pt om s, a n d ca n a lso ca u se ch a n ges t h a t
a r e n ot det ect ed u n t il m u ch la t er. Th e fu ll effect s of
est r ogen depr iva t ion m a y n ot be det ect ed for m a n y
yea r s bu t in clu des cessa t ion of t h e m en st r u a l cycle,
effect s on in t er n a l a n d ext er n a l gen it a lia a n d sex-
u a l fu n ct ion in g, br ea st s, va som ot or r espon se, m ood,
sleep, a n d bon e m in er a liza t ion (Fig. 14.19).
At r oph ic ch a n ges occu r in ot h er est r ogen -
st im u la t ed t issu es. Br ea st size is decr ea sed beca u se
of a t r oph y of in t er n a l br ea st st r u ct u r es, in clu din g
t h e du ct s a n d lobes. Skin ela st icit y r edu ces. Body
h a ir a n d su bcu t a n eou s fa t levels decr ea se. Th e ova -
r ies a n d u t er u s a t r oph y. Th e wa lls of t h e va gin a
becom e t h in . Dyspa r eu n ia (pa in fu l in t er cou r se) is of-
t en a con sequ en ce of va gin a l a t r oph y beca u se t h ese
cells ca n n o lon ger pr odu ce a dequ a t e a m ou n t s of
lu br ica t ion for com for t . Ur in a r y difficu lt ies, su ch a s
u r gen cy a n d st r ess in con t in en ce, ca n be a t t r ibu t ed
t o a t r oph y of bla dder cells a s a r esu lt of t h e loss
of h or m on a l st im u la t ion n ecessa r y for opt im a l cell
fu n ct ion in g.
H ot fla sh es or flu sh es a r e t h e com m on descr ipt ion
of t h e va som ot or sym pt om s a ssocia t ed wit h m en o-
pa u se. Loca lized in t h e u pper h a lf of t h e body, h ot
fla sh es a r e descr ibed a s a su dden feelin g of wa r m t h
a n d a r e a ssocia t ed wit h r edden ed skin a n d swea t -
in g. Va som ot or sym pt om s a r e br ief, la st in g bet ween
30 secon ds a n d 5 m in u t es. F r equ en cy a n d sever it y
ca n va r y fr om m ild t o sever e a n d ca n be qu it e dis-
r u pt ive. Alt h ou gh t h e ph ysiologic expla n a t ion is n ot
com plet ely u n der st ood, va som ot or sym pt om s a r e
likely t h e r esu lt of a lt er ed t h er m or egu la t ion .

Figure 14.19. Changes in both the ovary and the hypothalamus contribute to the physiologic changes of menopause.
Alt er a t ion s in sleep a n d m ood, in clu din g sym p-
t om s of depr ession a n d fa t igu e, h a ve been a ssocia t ed
wit h m en opa u se. Alt h ou gh t h is is n ot a u n iver sa l
m a n ifest a t ion , wom en wit h a pr ior h ist or y of depr es-
sion a r e m or e likely t o develop sym pt om s, especia lly
in ea r ly per im en opa u se. Ir r it a bilit y, m ood la bilit y,
a n d a n xiet y a r e a lso com m on . Tr ou ble fa llin g a sleep
or disr u pt ed sleep m a y be a r espon se t o h ot fla sh es,
depr ession a n d ot h er m ood ch a n ges, or ch r on ic pa in
a n d lea d t o sever e fa t igu e.
Sexu a l fu n ct ion in g m a y be a ffect ed by t h e h or-
m on a l ch a n ges of m en opa u se. In a ddit ion t o t h e
ph ysica l ch a n ges of t h e r epr odu ct ive or ga n s de-
scr ibed pr eviou sly, m ot iva t ion t o en ga ge in sexu a l
a ct ivit ies (libido) m a y be a ffect ed. Wom en r epor t less
fr equ en t sexu a l a ct ivit y a n d less sa t isfa ct ion du r in g
t h is developm en t a l per iod.
Bon e dem in er a liza t ion occu r s wit h a dva n cin g
a ge bu t is m or e r a pid a ft er m en opa u se. Men opa u sa l
bon e loss, t h e m a n ifest a t ion of bon e a t r oph y, r esu lt s
fr om t h e effect s of cyt okin es in t h e a bsen ce of t h e
pr ot ect ive effect s of t h e ova r ia n h or m on es. Th is
im ba la n ce pr om ot es dela yed a popt osis of cells t h a t
br ea ks down bon e (ost eocla st s) a n d en h a n ces a pop-
t osis of cells fa vor in g bon e gr owt h (ost eobla st s).
Ca r diova scu la r disea se is a sign ifica n t ca u se of
m or t a lit y in wom en older t h a n 50 yea r s. Ma r ker s of
ca r diova scu la r disea se a r e a lt er ed a ft er m en opa u se,
in cr ea sin g r isk of st r oke a n d h ea r t a t t a ck. Ch oles-
t er ol levels, in clu din g t h e com pon en t s h igh -den sit y
lipopr ot ein (H DL) a n d low-den sit y lipopr ot ein
(LDL), a r e a lt er ed in fa vor of a n in cr ea sed r a t io of
LDL:H DL, in cr ea sin g ca r diova scu la r r isk.
DIAGNOSTIC CRITERIA
The dia gnosis of menopa use is based on history of
a menorrhea for a t least 12 months in the a bsence of
C lin ic a l Mo d e ls 355
a ny other ca uses, such as pregna ncy. There is no sin-
gle, relia ble dia gnostic test. La bora tory ma rkers for
menopause include a n increase in serum FSH; this is
the most significant ma rker for ova rian failure. FSH
levels rise higher than LH levels; however, both in-
crea se at a ra te greater tha n seen during the surge of
the menstrua l cycle. Also noted a re decreases in estra -
diol a nd inhibin, which no longer demonstrate large
cyclical varia tions a s seen during the menstrual years.
TREATMENT
Alt h ou gh m a n y wom en do n ot r equ ir e t r ea t m en t ,
ot h er s r ely on ph a r m a cologic a n d n on ph a r m a cologic
t r ea t m en t for t h e m a n a gem en t of disr u pt ive sym p-
t om s, su ch a s h ot fla sh es or m ood swin gs. Tr ea t m en t
is best wh en in dividu a lized a n d t a r get ed t owa r d t h e
specific con cer n .
Until 2002, hor mone replacem ent thera py (HRT)
with est rogen wa s the st anda rd tr ea tm ent for women
t o a m eliora t e symptoms a nd pr event long-term hea lt h
r isks a ssocia ted wit h menopause, includin g ca rdio-
va scula r disea se. Resear ch ha s since shown a la ck of
evidence t o suppor t t he use of estr ogen a lone for t he
expect ed protect ive effects, a nd a higher r isk for mor-
bidity, such a s t he development of endometr ia l ca ncer.
Most r ecen t ly in Ma y 2013, t h e Br it ish Men o-
pa u se Societ y a n d Wom en ’s H ea lt h Con cer n issu ed
u pda t ed gu idelin es on t h e u se, ben efit s, a n d r isks of
H RT.4 In t h ese r ecom m en da t ion s, H RT u sin g a com -
bin a t ion of est r ogen a n d pr ogest er on e ca n be a dm in -
ist er ed t o syn t h et ica lly in cr ea se ova r ia n h or m on e
levels, r ever se t h e a t r oph ic ch a n ges, a n d decr ea se
sym pt om s a ssocia t ed wit h m en opa u se u sin g t h e fol-
lowin g cr it er ia :
● Sever e sym pt om s r equ ir in g t r ea t m en t
● Sh or t -t er m du r a t ion
356 C h a p t e r 14: Alt er ed Repr odu ct ive F u n ct ion
De e p dors a l
ve in
Dors a l a rte ry
Cave rnous ne rve
Dors a l ne rve (a utonomic)
(s oma tic)
Circumflex a rte ry
a nd ve in
Ve in
Ve in
A
Corpora cave rnos a
S inus oida l s pa ce s
Arte ry
B US st u dy, a r ou n d 51% of m en bet ween t h e a ges of
Figure 14.20. Anatomic depiction of penile erection.
A: Innervation and arterial and venous blood supply to
the penis. B: Cross-section of corpora cavernosa.
● Lowest effect ive dose
● Topica l a pplica t ion (su ch a s wit h a va gin a l cr ea m )
t o a void syst em ic effect s
In it ia t ion of H RT in wom en older t h a n 65 yea r s is
n ot r ecom m en ded beca u se of t h e in cr ea sed a ssoci-
a t ed r isk of dem en t ia in t h is a ge gr ou p.
Tissu e-t a r get ed t h er a pies a r e a lso u sefu l wh en
m a n a gin g specific m a n ifest a t ion s. Beca u se of t h e
specificit y of h or m on e bin din g t o select ive r ecept or s,
dr u g effect s ca n be m odu la t ed ba sed on t h e t a r get -
in g of specific r ecept or s loca t ed pr edom in a n t ly in a
cer t a in t issu e t ype. Select ive est r ogen r ecept or m od-
u la t or s (SE RM) a r e dr u gs design ed t o ca pit a lize on
t h ese ph a r m a cologic pr in ciples. Th e dr u g r a loxifen e
is oft en u sed for pr even t ion of ost eopor osis in post -
m en opa u sa l wom en . Ra loxifen e bin ds t o specific
r ecept or s a n d r esu lt s in a n t a gon ist effect s in t h e
en dom et r iu m a n d br ea st t issu e, decr ea sin g bon e
br ea kdown , t ot a l ch olest er ol, a n d LDL levels.
Non ph a r m a cologic st r a t egies sh ou ld be con sid-
er ed in t h e m a n a gem en t of m en opa u sa l sym pt om s.
Th e followin g m ea su r es m a y h elp m in im ize t h e dis-
com for t a n d u n plea sa n t n ess a ssocia t ed wit h m a n y
com m on m en opa u se-r ela t ed con cer n s:
● Dr ess in la yer s
● Avoid spicy foods
● Avoid ca ffein e a n d a lcoh ol
● In it ia t e deep br ea t h in g m ea su r es a t t h e st a r t of
a h ot fla sh
● Use r ela xa t ion t ech n iqu es
● In cor por a t e soy pr odu ct s con t a in in g ph yt oest r o-
gen s in t h e diet
● Per for m pelvic floor exer cises t o st r en gt h en m u s-
cles of t h e pelvis a n d va gin a
● Use wa t er-ba sed lu br ica n t s du r in g in t er cou r se
Erectile Dysfunction
Sexu a l dysfu n ct ion is on e of t h e m ost com m on
h ea lt h pr oblem s a ffect in g m en a n d in clu des su ch
pr oblem s a s low sexu a l in t er est , er ect ile dysfu n c-
t ion , pr em a t u r e eja cu la t ion , a n d st r u ct u r a l a bn or-
m a lit ies of t h e pen is. E r e c t ile d y s u n c t io n (E D )
is t h e in a bilit y t o a ch ieve or m a in t a in a n er ect ion
su fficien t for sa t isfa ct or y sexu a l per for m a n ce. E D
is on e of t h e m a in t ypes of sexu a l dysfu n ct ion in
m en , a n d t h e pr eva len ce in cr ea ses wit h a ge. In on e
40 a n d 70 yea r s r epor t ed exper ien cin g E D. Ot h er
cou n t r ies t h r ou gh ou t t h e wor ld h a ve dem on st r a t ed
a sim ila r pr eva len ce.5
PATHOPHYSIOLOGY
Ach ievin g a n er ect ion is a com plex in t er a ct ion of
a r ou sa l a n d pa r a sym pa t h et ic n er vou s st im u la t ion
a t t h e S2-S4 level, sign a lin g in cr ea sed blood flow
t h a t becom es t r a pped in t h e cor por a ca ver n osa of
t h e pen is (Fig. 14.20). Th is t r a ppin g of blood in t h e
cor por a ca ver n osa depen ds on sm oot h m u scle r e-
la xa t ion t h a t occlu des t h e vein s a n d does n ot a llow
blood flow ou t . Th e er ect ion is r ever sed u n der t h e
in flu en ces of t h e sym pa t h et ic n er vou s syst em . All of
t h ese a ct ivit ies a r e fa cilit a t ed by a n dr ogen a ct ivit y
on t h e h ypot h a la m u s a n d a n t er ior pit u it a r y.
CLINICAL MANIFESTATIONS
Th e in a bilit y t o a ch ieve a n d m a in t a in a n er ect ion is
t h e pr im a r y clin ica l m a n ifest a t ion . Th e com plexit y
of E D is illu st r a t ed by sever a l ca u ses t h a t m a y lea d
t o ot h er m a n ifest a t ion s. Th ese ca u ses in clu de:
● H o r m o n a l a c t o r s : H ypogon a dism , h ypot h y-
r oidism , or a dr en a l cor t ica l h or m on e dysfu n ct ion ,
r esu lt in g in in a dequ a t e h or m on a l “pr im in g” of t h e
sexu a l cen t er s of t h e br a in
● N e u r o lo g ic a l a c t o r s : Spin a l cor d or per in ea l
n er ve in ju r y r esu lt in g in in a dequ a t e n er ve sign a l-
in g t o t h e pen ile vessels
● P s y c h o lo g ic a l a c t o r s : An xiet y, low self-est eem ,
or depr ession r esu lt in g in in a dequ a t e a r ou sa l
● Va s c u la r o b s t r u c t io n : H yper t en sion , a t h er oscle-
r osis, va scu la r obst r u ct ion , a n d sm okin g disa llow
blood flow t o t h e cor por a ca ver n osa a n d spon giosa ,
t h er eby pr even t in g er ect ion fr om occu r r in g
 C lin ic a l Mo d e ls 357

● I m p a ir e d v e n o -o c c lu s iv e a b ilit y : Th e in a bilit y cell gr owt h . Over t im e, lower ed t est ost er on e levels

t o t r a p blood wit h in t h e cor por a ca ver n osa r esu lt in h igh er pr opor t ion s of est r ogen , wh ich pr o-
● C e r t a in m e d ic a t io n s : An t ih yper t en sives, ca n m ot es pr ost a t ic cell pr olifer a t ion . In a ll m en , t est os-
in h ibit h or m on e a n d er ect ile fu n ct ion t er on e is con ver t ed t o dih ydr ot est ost er on e (DTH )
a n d est r a diol in cer t a in t issu es. DTH is in volved in
pr ost a t e gr owt h a n d m a y a ccu m u la t e over t im e, a lso
DIAGNOSTIC CRITERIA r esu lt in g in over pr olifer a t ion of pr ost a t ic epit h elia l
Dia gn osis of E D is ba sed on a com pr eh en sive h is- cells of t h e a cin i a n d du ct u les, sm oot h m u scle cells,
t or y a n d ph ysica l exa m in a t ion t o iden t ify t h e pot en - a n d st r om a l fibr obla st s. Th e cell pr olifer a t ion occu r s
t ia l ca u se. La bor a t or y m ea su r em en t of t est ost er on e, pr im a r ily in t h e per iu r et h r a l pa r t of t h e gla n d. BP H
LH , t h yr oid, a n d pr ola ct in levels m a y su ggest a h y- is n ot con sider ed a pr ecu r sor t o pr ost a t e ca n cer.
pot h a la m ic, pit u it a r y, or h or m on a l pr oblem . H ypo-
gon a dism —specifica lly, a r edu ct ion in t h e levels of
t est ost er on e—ca n con t r ibu t e t o E D. CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s of BP H a r e r ela t ed t o u r e-
t h r a l obst r u ct ion fr om t h e en la r ged pr ost a t e, wh ich
TREATMENT
im pedes t h e flow of u r in e fr om t h e bla dder t o t h e
Treatment is individualized and directed by the etiology u r in a r y m ea t u s. Th is r esu lt s in u r in a r y fr equ en cy,
(physical, psychological, or both). Testosterone replace- dr ibblin g, h esit a n cy, in con t in en ce, u r gen cy, a n d r e-
ment therapy, or other hormone intervention, may be in- t en t ion . Com plet e obst r u ct ion lea ds t o a cu t e u r in a r y
dicated. Psychological influences may be addressed and r et en t ion a n d a n a bsolu t e in a bilit y t o u r in a t e. Th is
treated by a mental health
professional. Medications,
such as sildenafil (Viagra), R E S E AR C H N O T E S
vardenafil, and tadalafil,
are often prescribed for Lifestyle, most notably obesity, smoking, and alcohol use, affects the development of ED.
men with ED. These drugs One study aimed to determine the impact of lifestyle changes (weight loss and physical
act to promote smooth mus- activity) on male erectile function. After a 2-year diet and exercise intervention, those
cle relaxation and vascular men who had significant decreases in body weight, body mass index, waist–hip ratio, blood
congestion in the corpora pressure, glucose levels, and total cholesterol demonstrated a statistically significant im-
cavernosa, thereby main- provement in sexual function. The researchers suggested that obesity resulted in a state
taining an erection. Penile of chronic oxidative stress and inflammation throughout the body. The inflammation was
implants or other devices responsible for blood vessel lining obstruction. Weight reduction saw a corresponding de-
6
may be used to help main- crease in inflammatory markers and a subsequent improvement in sexual function.
tain an erection.

lea ds t o sever e pa in a n d ca n pr ogr ess t o r en a l fa ilu r e

Benign Prostatic Hyperplasia
Th e pr ost a t e gla n d is a sm a ll or ga n a bou t t h e size
of a wa ln u t , wh ich lies below t h e bla dder a n d su r-
r ou n ds t h e u r et h r a . Th e pr ost a t e t issu e pr odu ces
pr ost a t e-specific a n t igen a n d pr ost a t ic a cid ph os-
ph a t a se, a n en zym e fou n d in sem in a l flu id. Th e m a -
jor r ole of t h e pr ost a t e is t o secr et e a flu id, wh ich
com bin es wit h sem en , t o in cr ea se sper m m ot ilit y a n d
decr ea se va gin a l a cidit y. Ben ign pr ost a t ic h yper pla -
sia (BP H ) a ffect s m or e t h a n 50% of m en over a ge 60
a n d a s m a n y a s 90% of m en over a ge 70.7 BP H is a
con dit ion of a gin g; n ea r ly a ll m en over t h e a ge of 50
h a ve som e level of en la r gem en t of t h e pr ost a t e.
PATHOPHYSIOLOGY
Th e ca u se of BP H is u n kn own . H or m on e ch a n ges
a ssocia t ed wit h a gin g h a ve a n im pa ct on pr ost a t ic
a n d dea t h if n ot t r ea t ed.
DIAGNOSTIC CRITERIA
Dia gn osis is ba sed on pa t ien t h ist or y, ph ysica l ex-
a m in a t ion , la bor a t or y t est s, a n d eva lu a t ion of sym p-
t om s. Th e ph ysica l exa m in a t ion in clu des a digit a l
r ect a l exa m in a t ion . Th is pr ocedu r e a llows t h e h ea lt h
pr a ct it ion er t o det er m in e t h e size, sh a pe, a n d con -
sist en cy of t h e pr ost a t e gla n d, a s pa lpa t ed t h r ou gh
t h e r ect a l wa ll (F ig. 14.21). Ben ign en la r gem en t of
t h e pr ost a t e t issu e is soft ; m a lign a n t t issu e is h a r d,
a sym m et r ica l, a n d oft en h a s a cobblest on e t ext u r e.
P r ost a t e-specific a n t igen (P SA) is oft en m ea su r ed
t o det er m in e eleva t ion s t h a t m a y in dica t e pr ost a t e
h yper pla sia or dyspla sia . E leva t ion s in P SA a r e fol-
lowed by a biopsy t o con fir m or r u le ou t m a lign a n cy.
Th e Am er ica n Ur ologica l Associa t ion (AUA) Sym p-
t om s In dex m a y be u sed. Th is in dex is a 7-qu est ion
su r vey on a 1 t o 5 sca le r ela t ed t o pr esen ce a n d
358 C h a p t e r 14: Alt er ed Repr odu ct ive F u n ct ion
Re ctum
P ros ta te
Te s ticle
Figure 14.21. Digital rectal examination of the prostate. (Nath JL. Using Medical Terminology: A Practical Approach.
Baltimore, MD: Lippincott Williams & Wilkins; 2005.)
fr equ en cy of sym pt om s r ela t ed t o BP H . A h igh er
poin t t ot a l (i.e., 20 t o 35) equ a t es t o gr ea t er sever it y
of sym pt om s. Ur odyn a m ic t est s ca n be u sed t o m ea -
su r e t h e volu m e a n d pr essu r e of u r in e in t h e bla dder
a n d t o eva lu a t e t h e flow of u r in e.
TREATMENT
Tr ea t m en t is r eser ved for t h ose m en wit h sign ifi-
ca n t sym pt om s. P h a r m a cologic t r ea t m en t s m a y be
pr escr ibed t h a t r ela x t h e sm oot h m u scles of t h e a r-
t er ies, pr ost a t e, a n d bla dder n eck t o r elieve u r in a r y
obst r u ct ion . Beca u se t h e pr ost a t e a lso depen ds on
h or m on a l st im u la t ion , dr u gs m a y be pr escr ibed t h a t
in h ibit t h e a ct ion of t est ost er on e by r est r ict in g con -
ver sion t o DTH . Th e la ck of h or m on a l st im u la t ion r e-
su lt s in pr ost a t e a t r oph y. La ser or ot h er h ea t -ba sed
t r ea t m en t s m a y a lso be a pplied t o dest r oy a ll or pa r t
of t h e pr ost a t e gla n d. Su r gica l in t er ven t ion m a y a lso
be in clu ded in t h e t r ea t m en t r egim en , depen din g on
t h e sever it y of sym pt om s a n d pot en t ia l r isks t o t h e
pa t ien t . Th e m ost com m on pr ocedu r e is t h e t r a n s-
u r et h r a l r esect ion of t h e pr ost a t e (TURP ). In t h is
pr ocedu r e, pa r t of t h e pr ost a t e is r em oved u sin g a
su r gica l in st r u m en t pla ced in t o t h e u r et h r a via t h e
pen is. For pa t ien t s wh o a r e n ot a ppr opr ia t e ca n di-
da t es for ph a r m a cologic, la ser, or su r gica l t r ea t -
m en t s, a st en t m a y be pla ced in t h e u r et h r a . A st en t
is a sm a ll, r igid t u be t h a t h olds t h e u r et h r a open a n d
a llows u r in e t o dr a in . Th e disa dva n t a ges t o st en t s
a r e t h a t t h ey ca n illicit ir r it a t ion , fr equ en t u r in a -
t ion , pa in , a n d in con t in en ce, a n d t h ey a r e difficu lt t o
r em ove if r em ova l is n ecessa r y.
P ubic bone
Pe nis
Prostate Cancer
Du r in g a m a n ’s lifet im e, t h e r isk of developin g pr os-
t a t e ca n cer is on e in six, m a kin g it t h e secon d lea d-
in g ca u se of ca n cer dea t h in m en a ft er lu n g ca n cer.
Abou t 85% of m en wit h pr ost a t e ca n cer a r e dia g-
n osed a ft er t h e a ge of 65. 8
PATHOPHYSIOLOGY
Sim ila r t o BP H , ca r cin om a of t h e pr ost a t e is pr edom i-
n a t ely a disea se of older m en . Th e exa ct ca u se is oft en
u n kn own. Risk fa ct or s for t h e developm en t of pr os-
t a t e ca ncer in clu de a dva n cing a ge, fa m ily h ist or y of
pr ost a t e ca n cer, Bla ck r a ce, sm okin g, a n d n u t r it ion a l
fa ct or s, su ch a s h igh int a ke of fa t s a n d m ea t , low in-
t a ke of lycopen e (fou n d pr im a r ily in t om a t o-ba sed
pr odu ct s) a n d fr u it , a n d h igh diet a r y ca lciu m .
Th e m a lign a n t t r a n sfor m a t ion of pr ost a t e epit h e-
lia l cells, a s wit h ot h er for m s of ca n cer, is a r esu lt
of a com plex ser ies of in it ia t or a n d pr om ot er even t s
wit h gen et ic a n d en vir on m en t a l in flu en ces. Appr ox-
im a t ely 5% t o 10% of pr ost a t e ca n cer ca ses a r e es-
t im a t ed t o be r ela t ed t o in h er it ed gen et ic fa ct or s or
pr ost a t e ca n cer su scept ibilit y gen es. 8 On e m a jor lo-
cu s of su scept ibilit y is fou n d a t ch r om osom e 1q24,
design a t ed a s H P C1 (h er edit a r y pr ost a t e ca n cer ).
Th is m u t a t ion is a ssocia t ed wit h a you n ger a ge a t
dia gn osis, a h igh er t u m or gr a de, a n d m or e a dva n ced
st a ge a t dia gn osis. Sever a l ot h er ch r om osom e r e-
gion s, wh ich h a ve been lin ked t o su scept ibilit y in in -
h er it ed a n d spor a dic for m s of pr ost a t e ca n cer, h a ve
a lso been iden t ified.
 C lin ic a l Mo d e ls 359

No rmal Pro life rative Pro s tatic Pro s tate

pro s tate inflammato ry intrae pithe lial c anc e r
atro phy ne o plas ia

Columna r
ce lls

Ba s a l
ce lls

Infla mma tory ce lls

Figure 14.22. Proliferative inflammatory atrophy is hypothesized to be a precursor to prostatic intraepithelial neopla-
sia, which in turn is the precursor of prostate cancer. (From Nelson WG, De Marzo AM, Isaacs WB. Prostate cancer. N Engl
J Med. 2003;349:366, with permission.)

Mor e t h a n 95% of pr im a r y pr ost a t e ca n cer s a r e for m et a st a t ic spr ea d, su ch a s pa in a s t h e t u m or

cla ssified a s a den oca r cin om a s. An dr ogen s a n d es- spr ea ds t o t h e bon e, a lso a pply t o pr ost a t e ca ncer.
t r ogen s a r e t wo h or m on es t h a t a ppea r t o su ppor t
ca r cin ogen esis by in flu en cin g pr ost a t e epit h elia l
DIAGNOSTIC CRITERIA
pr olifer a t ion , a lt h ou gh eleva t ion s in a n dr ogen s a r e
n ot fou n d u n iver sa lly in t h ose wit h pr ost a t e ca n cer. Digit a l r ect a l exa m in a t ion , t r a n sr ect a l u lt r a sou n d,
P r em a lign a n t ch a n ges in pa t ien t s wit h pr ost a t e a n d P SA levels a r e u sed t o scr een for pr ost a t e ca n cer.
ca n cer a r e design a t ed a s pr ost a t ic in t r a epit h elia l Dia gn osis is con fir m ed t h r ou gh a cyt ologic a n a lysis
n eopla sia a n d a r e ch a r a ct er ized by a t ypica l lu - of pr ost a t e t issu e (biopsy) via fin e n eedle a spir a -
m en cells lin in g t h e pr ost a t ic du ct s (F ig. 14.22). t ion u su a lly per for m ed t r a n sr ect a lly. Pelvic lym ph
Th ese lesion s a r e believed t o pr ogr ess t o pr ost a t e n ode dissect ion du r in g su r gica l t r ea t m en t for t h ose
a den oca r cin om a , wit h t h e n eopla sm a r isin g in t h e u n der goin g r a dica l pr ost a t ect om y is oft en r equ ir ed
per iph er a l por t ion of t h e gla n d. Th is per iph er a l t o det er m in e lym ph n ode in volvem en t . Ra dion u cle-
loca t ion is clin ica lly sign ifica n t in t h a t t h e t u m or ot ide bon e sca n s a r e u sed t o det ect m et a st a ses t o t h e
does n ot com pr ess t h e u r et h r a u n t il la t er in it s bon e, t h e m ost com m on sit e of dist a n t spr ea d. On ce
pr ogr ession . dia gn osed, pr ost a t e ca n cer is st a ged u sin g t h e TNM
cla ssifica t ion syst em , wit h sligh t m odifica t ion s in
t h e t u m or design a t ion :
CLINICAL MANIFESTATIONS
● T 1: Th e t u m or is clin ica lly in a ppa r en t , n ot pa lpa -
P r ost a t e ca n cer is oft en a sym pt om a t ic a n d is fou nd in -
ble or visible by im a gin g.
ciden t a lly a ft er a digit a l r ect a l exa m in a t ion a n d P SA
● T 2: Th e t u m or is con fin ed t o t h e pr ost a t e.
scr eenin g. Wh en clin ica l m a nifest a t ion s a r e pr esent ,
t h e t u m or h a s oft en expa n ded a n d is obst r u ct in g t he
u r et hr a . In t his ca se, t h e
m a nifest a t ion s a r e iden -
t ica l t o t h a t of BP H a nd F R O M T H E L AB
in clu de u r in a r y fr equ en cy,
dr ibbling, h esit a n cy, in con - PSA in the blood may be bound to proteins or may exist in an unbound state. Total PSA is the
t in en ce, ur gency, a n d r e- sum of levels of both forms. Free PSA measures only the levels of unbound PSA. Some studies
t en t ion . Com m on syst em ic suggest that malignant prostate cells produce more bound PSA; therefore, a low level of free
m a nifest a t ion s, pa r a ne- PSA compared to total PSA may indicate malignant prostatic neoplasia. A high level of free
opla st ic syn dr om es, a n d PSA compared to total PSA might indicate BPH or an inflammatory condition of the prostate.
m a nifest a t ion s significa n t
360 C h a p t e r 14: Alt er ed Repr odu ct ive F u n ct ion
● T 3: Th e t u m or ext en ds t h r ou gh t h e pr ost a t e
ca psu le.
● T 4: Th e t u m or is fixed or in va des a dja cen t st r u c-
t u r es ot h er t h a n t h e sem in a l vesicles.
Su r viva l r a t e a n d pr ogn osis is ba sed on t h e h ist o-
logic fea t u r es (differ en t ia t ion a n d dist r ibu t ion ) of
t h e t u m or a n d st a gin g. Th e 5-yea r su r viva l is m or e
t h a n 99% for pa t ien t s wit h loca l or r egion a l disea se
spr ea d. Th e 5-yea r su r viva l dr ops sign ifica n t ly t o
33.5% in t h ose pa t ien t s wit h dist a n t m et a st a ses. 8
TREATMENT
Tr ea t m en t is ba sed on t u m or gr a din g, TNM cla ssi-
fica t ion , a ge, a n d h ea lt h st a t u s. Ra dica l pr ost a t ec-
t om y (r em ova l of t h e en t ir e pr ost a t e) is oft en u sed
t o t r ea t pr ost a t e ca n cer, pa r t icu la r ly in you n ger m en
(less t h a n 70 yea r s of a ge) wit h ou t ot h er h ea lt h com -
plica t ion s or su r gica l r isk fa ct or s. Ra dia t ion t h er a py
a n d ch em ot h er a py m a y be u sed a s a su r gica l a d-
ju n ct or for t h ose wh o a r e n ot su r gica l ca n dida t es.
An dr ogen -depr iva t ion h or m on e t h er a py m a y a lso be
u sed t o decr ea se pr ost a t e cell pr olifer a t ion . Beca u se
pr ost a t e ca n cer is con sider ed a slow-gr owin g t u m or
a n d is t ypica lly dia gn osed la t er in life, “wa t ch fu l
wa it in g” m a y be t h e t r ea t m en t of ch oice in t h ose
wit h ou t clin ica l sym pt om s. Th is a ppr oa ch a voids t h e
com plica t ion s in h er en t wit h su r gica l, r a dia t ion , a n d
ch em ot h er a peu t ic in t er ven t ion s, a n d it a ppr ecia t es
t h e r ea lit y t h a t m a n y m en wit h clin ica lly u n det ect -
a ble pr ost a t e ca n cer die fr om ot h er ca u ses.
Testicular Cancer
Test icu la r ca n cer is a h igh ly t r ea t a ble a n d oft en cu r-
a ble ca n cer, wh ich is m ost com m on ly fou n d in m en
bet ween 20 a n d 40 yea r s of a ge. Appr oxim a t ely 90%
of t u m or s a r ise fr om ger m cells. Th e r em a in in g t u -
m or s a r e of sex cor d cell or igin or m et a st a ses fr om
ot h er sit es.
PATHOPHYSIOLOGY
Ger m cell t u m or s a r e cla ssified a ccor din g t o cell or i-
gin a n d in clu de t h e followin g:
● Sem in om a s—Ma lign a n t ger m cells t h a t r esem ble
pr im it ive sper m cells
● Non sem in om a s—Ma lign a n t ger m cells t h a t do
n ot r esem ble pr im it ive sper m cells a n d a ct u a lly
a ppea r a s em br yon ic or u n differ en t ia t ed som a t ic
(e.g., skin , m u scle, gla n ds, et c.) com pon en t s
Th e ger m cell divides t h r ou gh m it osis a n d differ-
en t ia t es in t o a pr im it ive sper m cell, ca lled a s p e r -
m a t o g o n ia , a n d fin a lly in t o a m a t u r e sper m a t ocyt e.
Sem in om a s a r e t h e m ost com m on t ype of t est icu la r
ca n cer. Sem in om a for m a t ion begin s wit h a ger m cell
m u t a t ion , m or e t h a n likely du r in g fet a l develop-
m en t , wh ich h a s st a gn a t ed sper m cell developm en t
a n d h a s r esu lt ed in pr olifer a t ion of im m a t u r e sper-
m a t ogon ia . Th e sper m a t ogon ia pr olifer a t e a n d t h e
t est icu la r t issu e becom es en la r ged a n d fibr ot ic.
Non sem in om a s a r e a com plex der iva t ive of em -
br yon ic developm en t . Not a ble su bca t egor ies of n on -
sem in om a s in clu de em br yon a l ca r cin om a s, yolk sa c
t u m or s, ch or ioca r cin om a s (a r isin g fr om t h e ch or ion ),
a n d t er a t oca r cin om a s (Fig. 14.23). E m b r y o n ic
c a r c in o m a s r esem ble pr im it ive u n differ en t ia t ed
em br yon ic t issu e. Te r a t o c a r c in o m a s a r e a com -
bin a t ion of em br yon ic ca r cin om a s a n d u n differ en -
t ia t ed som a t ic (e.g., skin , m u scle, bon e, a n d gla n ds)
t issu es. Th e u n differ en t ia t ed som a t ic t issu e a r ises
fr om st em cell em br yon ic t issu e or igin t h a t t h en
differ en t ia t es in t o t h e em br yon ic ger m la yer s (ect o-
der m , m esoder m , a n d en doder m ). Th ese t issu es t h en
fu r t h er differ en t ia t e in t o va r iou s som a t ic t issu es. In
ot h er wor ds, t er a t oca r cin om a s a ppea r a s u n differ en -
t ia t ed em br yon ic t issu e a n d skin or bon e cells wh er e
m a t u r e sper m a t ocyt es sh ou ld be fou n d. Th e or igin
of som e n on sem in om a s m a y r esu lt fr om m ispla ced
fet a l ger m cells t h a t did n ot m igr a t e t o sem in ifer ou s
t u bu les du r in g fet a l t est icu la r or ga n ogen esis. Th e
n on sem in om a s gr ow fa st er, a r e m or e in va sive, a n d
a r e m or e likely t o m et a st a size t h a n t h e sem in om a s.
Alt h ou gh t h e exa ct ca u se is oft en u n kn own , a n
a lt er a t ion in ch r om osom e 14 m a y be im plica t ed in
t h ose wit h t est icu la r ca n cer. A m a jor r isk fa ct or is
c r y p t o r c h id is m , or u n descen ded t est is, a n d ot h er
pr oblem s wit h t est icu la r developm en t . Th ose wit h
cr ypt or ch idism a r e 20 t o 40 t im es m or e likely t o de-
velop t est icu la r ca n cer. On e t h eor y of ca r cin ogen e-
sis in dica t es t h a t a n in it ia t in g even t a n d m u t a t ion
occu r s du r in g fet a l developm en t . Au t on om y a n d
a n a pla sia a r e t h en pr om ot ed t h r ou gh h or m on a l
st im u la t ion du r in g pu ber t y. Tu m or developm en t
oft en pr ogr esses t h r ou gh t wo m a jor st a ges: (1) ca r-
cin om a in sit u a n d (2) in va sive ca r cin om a . Th e ca r-
cin om a in sit u com m on wit h t est icu la r ca n cer is
con fin ed t o t h e sem in ifer ou s t u bu les. Test icu la r ca n -
cer is oft en m a lign a n t a t dia gn osis.
Alt h ou gh t est icu la r ca n cer is h igh ly t r ea t a ble a n d
cu r a ble, t h e pr ogn osis for t est icu la r ca n cer is less fa -
vor a ble wh en t h e followin g fa ct or s exist :
● Th e pr esen ce of bon e, liver, or br a in m et a st a ses
● H igh ser u m t u m or m a r ker s
● The presence of a primary mediastinal nonseminoma
● A la r ge n u m ber of lu n g m et a st a ses
Th e la r gest pr opor t ion of pa t ien t s wit h sem in om a s
(90%) is dia gn osed wit h pr im a r y t u m or s wit h ou t
m et a st a ses or eleva t ion s in t u m or m a r ker s. Pa -
t ien t s wit h sem in om a s a t a pr im a r y sit e wit h ou t

Ge rm c e ll
No diffe re ntia tion
Dys g e rmino ma Embryo nic
(te s ticula r s e minoma ) ca rcinoma
Yo lk s ac tumo r
Figure 14.23. Classification of germ cell tumors of the testes. (Modified from Rubin E, Farber JL. Pathology. 4th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2005.)
m et a st a ses or eleva t ion s in t u m or ser u m m a r ker s
dem on st r a t e a 5-yea r su r viva l of 95%.9 In con t r a st ,
t h ose pa t ien t s wit h m edia st in a l n on sem in om a s wit h
m et a st a sis or eleva t ed t u m or m a r ker s h a ve a 73%
5-yea r su r viva l. E ven wit h widespr ea d m et a st a ses,
t h ose wit h pr im a r y t est icu la r ca n cer m a y a lso be
cu r ed a n d sh ou ld be t r ea t ed a s su ch .
CLINICAL MANIFESTATIONS
Com m on clin ica l m a n ifest a t ion s in clu de a sm a ll
pa in less t est icu la r m a ss, sligh t en la r gem en t of t h e
t est icle, h ea vin ess or en la r gem en t of t h e scr ot u m ,
a n d m ild t est icu la r discom for t .
DIAGNOSTIC CRITERIA
Self-t est icu la r exa m in a t ion is a n im por t a n t a spect
of ea r ly det ect ion a n d sh ou ld be pr a ct iced by a ll m en
on a m on t h ly ba sis. Dia gn osis of t h e pr im a r y t u m or
is t h r ou gh ph ysica l exa m in a t ion a n d r a dica l or ch iec-
t om y (r em ova l of t h e t est icle). Tr a n sscr ot a l biopsy is
n ot r ecom m en ded beca u se it m a y r esu lt in seedin g
of t h e t u m or in t o t h e scr ot u m or spr ea d t o in gu in a l
lym ph n odes. Tu m or m a r ker s pr ovide a ddit ion a l
clu es t o t h e dia gn osis a n d t r ea t m en t effica cy. Im a g-
in g st u dies, su ch a s u lt r a sou n d, CT sca n , a n d MRI,
ca n iden t ify t h e t u m or loca t ion a n d spr ea d.
TREATMENT
Tr ea t m en t of t est icu la r ca n cer in volves su r gica l r e-
m ova l of t h e t u m or a n d a ffect ed t est icle or t est icles.
Ra dia t ion a n d ch em ot h er a py m a y a lso be u sed in
C h a p t e r 14: Alt er ed Repr odu ct ive F u n ct ion 361
Diffe re ntia tion
Extra e mbryonic Embryonic
tis s ue tis s ue
Te rato c arc ino ma
Cho rio c arc ino ma (e ctode rm, me s ode rm,
e ndode rm)
t r ea t m en t . Th e r isks in volved wit h r a dia t ion a n d
ch em ot h er a peu t ic t r ea t m en t in t est icu la r ca n cer in -
clu de in fer t ilit y, secon da r y leu kem ia s (or ot h er t ypes
of ca n cer ), a n d possible r en a l fu n ct ion im pa ir m en t .
Th is t ype of ca n cer is oft en cu r a ble.
S U MMAR Y
● Repr odu ct ive fu n ct ion is r elia n t u pon st r u ct u r a l
in t egr it y, n eu r ologic, a n d h or m on a l pr ocesses of
m a les a n d fem a les.
● Fem a le r epr odu ct ive or ga n s in clu de t h e va gin a ,
u t er u s, fa llopia n t u bes, a n d ova r ies. Th e ova r ies
pr odu ce t h e fem a le sex h or m on es: est r ogen s, pr o-
gest er on e, a n d a n dr ogen s. Th ese h or m on es a r e
secr et ed in a m on t h ly cyclica l pa t t er n u n der t h e
dir ect ion of t h e h ypot h a la m u s (Gn RH ) a n d t h e
a n t er ior pit u it a r y (F SH , LH ).
● Th e m a le r epr odu ct ive or ga n s a n d t issu es in clu de
t h e t est es, epididym is, va s defer en s, sem in a l vesi-
cles, pr ost a t e, a n d pen is. An dr ogen s, t h e m a le sex
h or m on es, pr om ot e m et a bolism a n d gr owt h . Th e
pa t t er n of m a le sex h or m on e secr et ion does n ot
follow a cyclica l pa t t er n a s seen wit h fem a les; t h e
h or m on e secr et ion r a t es r em a in fa ir ly con st a n t
t h r ou gh ou t t h e m a le’s a du lt life.
● St im u la t ion of a n dr ogen pr odu ct ion a n d r elea se
in m a les begin s in t h e h ypot h a la m u s. Th e h ypo-
t h a la m u s r elea ses Gn RH , wh ich st im u la t es t h e
a n t er ior pit u it a r y t o r elea se LH a n d F SH . LH a ct s
on t h e Leydig cells in t h e t est es t o pr odu ce t est os-
t er on e, t h e pr im a r y m a le sex h or m on e.
362 C h a p t e r 14: Alt er ed Repr odu ct ive F u n ct ion
● Ach ievin g pr egn a n cy is a com plex in t er a ct ion of
ovu la t ion , sper m a t ogen esis, in t er cou r se, eja c-
u la t ion , con cept ion , im pla n t a t ion , a n d em br yo
gr owt h .
● In fer t ilit y, defin ed a s t h e in a bilit y t o a ch ieve pr eg-
n a n cy a ft er 1 yea r of u n pr ot ect ed in t er cou r se.
Abou t 10% t o 15% of cou ples a r e con sider ed in fer-
t ile. In m a n y ca ses, t h e exa ct ca u se of in fer t ilit y is
n ot iden t ified. Pot en t ia l ca u ses, wh en iden t ified,
in clu de h or m on e im ba la n ce, m ot ilit y im pa ir m en t ,
a n d im m u n e pr oblem s.
● Clin ica l m a n ifest a t ion s a r e som et im es a bsen t .
Wit h h or m on e a lt er a t ion s, ir r egu la r m en st r u a l
per iods or a m en or r h ea m a y be r epor t ed oft en a s
a r esu lt of a n ovu la t ion . Test icu la r /scr ot a l pa in in
m en or pelvic pa in in wom en m a y occu r wit h in fec-
t ion or in fla m m a t ion of r epr odu ct ive st r u ct u r es.
● Th e dia gn osis of a lt er ed r epr odu ct ion is ba sed on
t h e cou ple’s in a bilit y t o con ceive or t h e pr esen ce
of clin ica l m a n ifest a t ion s. In it ia lly, a sem en a n a l-
ysis m u st be com plet ed in t h e m a le a lon g wit h a n
a n a lysis of ovu la t ion in t h e fem a le. Pa t en cy of t h e
fem a le r epr odu ct ive st r u ct u r es ca n be visu a lized
u sin g h yst er osa lpin gogr a ph y or la pa r oscopy.
● Tr ea t m en t in volves su ppor t ive cou n selin g, edu -
ca t ion a bou t in t er cou r se fr equ en cy, a voida n ce of
lu br ica n t s t h a t ca n a ct a s a sper m icide, a n d ba -
sic h ea lt h m a in t en a n ce. Sexu a lly t r a n sm it t ed or
ot h er pelvic in fect ion s pla ce t h e fem a le a t h igh
r isk for in fer t ilit y a n d m u st be t r ea t ed qu ickly
a n d com plet ely. Obst r u ct ive pr ocesses, su ch a s
leiom yom a s, en dom et r iosis, or pelvic a dh esion s,
m a y r equ ir e su r gica l in t er ven t ion .
● Som e in dividu a ls m a y r equ ir e clom iph en e cit r a t e,
a m edica t ion t h a t in du ces ovu la t ion . In t h ose wit h
h yper pr ola ct in em ia , m edica t ion s m a y be n eeded
t o r edu ce pr ola ct in a n d t h er efor e in du ce ovu la -
t ion . Ar t ificia l in sem in a t ion m a y be u sed t o in ject
sper m in t o t h e u t er u s if cer vica l m u cu s is t h ick or
if t h e sper m qu a n t it y or qu a lit y is com pr om ised.
Som e cou ples seek a dva n ced r epr odu ct ive t ech -
n ologies su ch a s in vit r o fer t iliza t ion .
● Th e eva lu a t ion a n d t r ea t m en t of in fer t ilit y is
h igh ly com plex a n d em ot ion a lly ch a r ged. Sen si-
t ivit y t o t h e r a n ge a n d in t en sit y of em ot ion s is a n
im por t a n t a spect of ca r e.
C AS E S T U D Y 14.1
A cou ple seeks r epr odu ct ive cou n selin g for in a bilit y
t o a ch ieve a pr egn a n cy a ft er 14 m on t h s of u n pr o-
t ect ed in t er cou r se. Aft er m u lt iple dia gn ost ic t est s
wit h bot h in dividu a ls, t h e m a le pa r t n er is det er-
m in ed t o h a ve a m oder a t ely decr ea sed sper m cou n t
a n d m ot ilit y. Upon ph ysica l exa m in a t ion of t h e
scr ot u m , en la r gem en t of scr ot a l vein s is det er m in e,
descr ibed by t h e clin icia n a s feelin g like “a ba g of
wor m s.” Th e con dit ion is t er m ed va r icocele.
1. Ou t lin e t h e pr ocess t h a t h a s occu r r ed in h is body.
2. Wh a t wer e t h e r isk fa ct or s t h a t h e dem on st r a t ed?
3. Wh a t wou ld you expect for clin ica l m a n ifest a t ion s?
4. Wh a t a ddit ion a l dia gn ost ic t est s cou ld be u sed?
5. Wh a t t r ea t m en t m ea su r es wou ld you a n t icipa t e?
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r n a l
a r t icle or Web sit e (su ch a s h t t p://em edicin e.m ed-
sca pe.com /a r t icle/438591-over view), wh ich det a ils
va r icocele, a n d con fir m you r pr edict ion s.
C AS E S T U D Y 14.2
J.T. is a 62-yea r-old wom a n wh o h a s been on est r ogen
t h er a py wit h ou t pr ogest er on e for m en opa u sa l sym p-
t om s for t h e pa st 6 yea r s. Sh e is seekin g m edica l ca r e
for u n expla in ed va gin a l bleedin g. Sh e is obese a n d
h a s been m en opa u sa l for 8 yea r s a n d h a s n ot h a d
a n y m en st r u a l bleedin g u n t il a week a go. Sh e does
n ot h a ve a n y pelvic discom for t . Aft er exa m in a t ion ,
sh e is sch edu led for a dila t a t ion a n d cu r et t a ge (D&C)
wit h biopsy. Th e biopsy r evea ls en dom et r ia l ca n cer.
1. Ou t lin e t h e pr ocess t h a t h a s m ost ly likely oc-
cu r r ed in h er body.
2. Wh a t wou ld you n ot ice for clin ica l m a n ifest a t ion s?
3. Wh a t dia gn ost ic t est s wer e u sed a n d wh a t do
t h ese t ell you ?
4. Wh a t t r ea t m en t m ea su r es wou ld you a n t icipa t e?
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r n a l
a r t icle or Web sit e (su ch a s h t t p://www.ca n cer.gov/
ca n cer t opics/t ypes/en dom et r ia l/), wh ich det a ils en -
dom et r ia l ca n cer, a n d con fir m you r pr edict ion s.
P R AC T I C E E XAM Q U E S T I O N S
1. You r pa t ien t is com pla in in g of m en opa u sa l h ot
fla sh es a n d ot h er sym pt om s. Wh ich of t h e fol-
lowin g wou ld you r ecom m en d a s a n on ph a r m a -
cologic m et h od for r elief of t h ese sym pt om s?
a . In cr ea se spicy foods
b. In cr ea se ca ffein e in t a ke
c. Use r ela xa t ion t ech n iqu es
d. Avoid soy pr odu ct s con t a in in g ph yt oest r ogen s
2. You r n eigh bor is t a kin g a n a n a t om y a n d ph ysi-
ology cou r se a n d a sks you wh a t wou ld h a ppen if
a per son did n ot h a ve ova r ia n in t er st it ia l cells.
Wh a t wou ld you sa y?
a . Th e per son wou ld be la ckin g ova r ia n su ppor t
st r u ct u r es
b. Th e per son wou ld n ot be a ble t o secr et e
est r ogen
 C h a p t e r 14: Alt er ed Repr odu ct ive F u n ct ion 363

c. Th e per son wou ld n ot h a ve a pla ce t o h ou se 8. Pelvic in fla m m a t or y a . H or m on a l

ger m cells disea se im ba la n ce
d. Th e per son wou ld h a ve n o difficu lt ies a s in -
t er st it ia l cells a r e n ot loca t ed in t h e ova r ies 9. Ova r ia n ca n cer b. Mot ilit y pr oblem

3. You r fa m ily is wor r ied beca u se you r cou sin h a s
a t est ost er on e deficien cy. Wh a t wou ld you n ot ice
for clin ica l m a n ifest a t ion s?
a . In cr ea sed skin t h ickn ess
b. Clea r skin , fr ee of a cn e
c. E xcessive ch est a n d fa cia l h a ir
d. Bu lky skelet a l m u scle developm en t
4. You r pr egn a n t fr ien d is com pla in in g of n a u sea ,
h ea da ch es, con st ipa t ion , in digest ion , a n d swell-
in g. Wh a t h or m on e is wr ea kin g h a voc in h er
body?
a . P r ogest er on e
b. E st r ogen
c. Th yr oid-st im u la t in g h or m on e
d. H u m a n ch or ion ic gon a dot r opin h or m on e
5. Wh ich of t h e followin g wou ld be illu st r a t ive of a
m obilit y im pa ir m en t lea din g t o in fer t ilit y?
a . An ovu la t ion
b. P r esen ce of leiom yom a s
c. Low sper m pr odu ct ion
d. Men opa u se
6. You r 16-yea r-old n iece con fides in you t h a t sh e
h a s n ot h a d a per iod for 2 m on t h s. Sh e does n ot
t h in k sh e is pr egn a n t a n d den ies h a vin g sexu a l
in t er cou r se. Wh a t is a n ot h er likely expla n a t ion ?
a . E n dom et r ia l ca n cer
b. Sever e em ot ion a l st r ess
c. La ck of ph ysica l a ct ivit y
d. F SH deficien cy
7. Da ve a n d h is wife h a ve been t r yin g t o con ceive
for t h e pa st 2 yea r s. Th ey go on a lon g a wa it ed
va ca t ion a n d h e wa n t s t o sit in t h e h ot t u b. Wh y
is t h is n ot r ecom m en ded for m en wh o a r e t r yin g
t o con ceive?
a . LH a n d F SH r elea se a r e in h ibit ed wit h expo-
su r e t o ch lor in a t ed wa t er
b. Tem per a t u r e does n ot m a ke a differ en ce; h e
ca n fr eely en joy t h e h ot t u b
c. Sper m a t ogen esis r equ ir es a h igh er body t em -
per a t u r e t h a n t h a t fou n d wit h t h e cor e body
t em per a t u r e
d. Sper m a t ogen esis r equ ir es a cooler body t em -
per a t u r e t h a n t h a t fou n d wit h t h e cor e body
t em per a t u r e
8–15. Ma t ch t h e clin ica l m odel wit h t h e t ype of
a lt er ed r epr odu ct ive fu n ct ion :
10. Polycyst ic ova r ia n c. Im m u n e
syn dr om e pr oblem
11. Men opa u se
12. E r ect ile dysfu n ct ion
13. Ben ign pr ost a t ic h yper t r oph y
14. P r ost a t e ca n cer
15. Test icu la r ca n cer
D I S C U S S I O N AN D
AP P L I C AT I O N
1. Wh a t did I kn ow a bou t a lt er ed r epr odu ct ion
fu n ct ion pr ior t o t oda y?
2. Wh a t body pr ocesses a r e a ffect ed by a lt er ed r e-
pr odu ct ion fu n ct ion ?
3. Wh a t a r e t h e pot en t ia l et iologies for a lt er ed r e-
pr odu ct ion fu n ct ion ? H ow does a lt er ed r epr odu c-
t ion fu n ct ion develop?
4. Wh o is m ost a t r isk for developin g a lt er ed r epr o-
du ct ion fu n ct ion ? H ow ca n a lt er ed r epr odu ct ion
fu n ct ion be pr even t ed?
5. Wh a t a r e t h e h u m a n differ en ces t h a t a ffect t h e
et iology, r isk, or cou r se of a lt er ed r epr odu ct ion
fu n ct ion ?
6. Wh a t clin ica l m a n ifest a t ion s a r e expect ed in t h e
cou r se of a lt er ed r epr odu ct ion fu n ct ion ?
7. Wh a t specia l dia gn ost ic t est s a r e u sefu l in de-
t er m in in g t h e dia gn osis a n d cou r se of a lt er ed
r epr odu ct ion fu n ct ion ?
8. Wh a t a r e t h e goa ls of ca r e for in dividu a ls wit h
a lt er ed r epr odu ct ion fu n ct ion ?
9. H ow does t h e con cept of a lt er ed r epr odu ct ion
fu n ct ion bu ild on wh a t I h a ve lea r n ed in t h e pr e-
viou s ch a pt er s a n d in pr eviou s cou r ses?
10. H ow ca n I u se wh a t I h a ve lea r n ed?
R E SOUR CE S
Am er ica n Ca n cer Societ y:
h t t p://www.ca n cer.or g/
Am er ica n Societ y for Repr odu ct ive Medicin e (ASRM):
h t t p://www.a sr m .or g
Th e Men opa u se Societ y:
h t t p://www.m en opa u se.or g/for-pr ofession a ls
364 C h a p t e r 14: Alt er ed Repr odu ct ive F u n ct ion
R e er en ces
1. Legr o RS, Ar sla n ia n SA, E h r m a n n DA, et a l. Dia gn osis
a n d t r ea t m en t of polycyst ic ova r y syn dr om e: a n E n do-
cr in e Societ y clin ica l pr a ct ice gu idelin e. J Clin
E n d ocr in ol Meta b. 2013;98(12):4565–4592.
2. Na t ion a l Ca n cer In st it u t e Su r veilla n ce, E pidem iology,
a n d E n d Resu lt s P r ogr a m . SE E R st a t fa ct sh eet s: ova r y
ca n cer. Bet h esda , MD: Na t ion a l Ca n cer In st it u t e.
h t t p://seer.ca n cer.gov/st a t fa ct s/h t m l/ova r y.h t m l.
Accessed Novem ber 11, 2015.
3. Am er ica n Ca n cer Societ y. Ca n cer fa ct s & figu r es 2015.
At la n t a , GA: Am er ica n Ca n cer Societ y. h t t p://www
.ca n cer.or g/a cs/gr ou ps/con t en t /@edit or ia l/docu m en t s/
docu m en t /a cspc-044552.pdf. Accessed Novem ber 11, 2015.
4. Ba r cla y L. H RT u se: n ew gu idelin es fr om t h e Br it ish
Men opa u se Societ y. Med sca pe Med ica l News. h t t p://www
.m edsca pe.com /viewa r t icle/804778. Accessed Novem ber
11, 2015.
F in d a d d ition a l r esou r ces for th is ch a pter a t h ttp:th ePoin t.lww.com
5. Selvin E , Bu r n et t AL, P la t z E A. P r eva len ce a n d r isk
fa ct or s for er ect ile dysfu n ct ion in t h e US. Am J Med .
2007;120(2):151–157.
6. E sposit o K, Giu glia n o F, DiPa lo C, et a l. E ffect of lifest yle
ch a n ges on er ect ile dysfu n ct ion in obese m en : a r a n dom -
ized con t r ol t r ia l. J AMA. 2004;291:2978–2987.
7. Na t ion a l Kidn ey a n d Ur ologic Disea ses Clea r in gh ou se.
P r ost a t e en la r gem en t : ben ign pr ost a t ic h yper pla sia .
2014. h t t p://www.n iddk.n ih .gov/h ea lt h -in for m a t ion /
h ea lt h -t opics/u r ologic-disea se/ben ign -pr ost a t ic-h yper pla -
sia -bph /Pa ges/fa ct s.a spx#9. Accessed Novem ber 12, 2015.
NIH pu blica t ion n o. 14-3012.
8. Na t ion a l Ca n cer In st it u t e. Gen et ics of pr ost a t e ca n cer.
h t t p://www.ca n cer.gov/t ypes/pr ost a t e/h p/pr ost a t e-
gen et ics-pdq. Accessed Novem ber 12, 2015.
9. Ca n cer.Net . Test icu la r ca n cer st a t ist ics. 2015.
h t t p://www.ca n cer.n et /ca n cer-t ypes/t est icu la r-ca n cer /
st a t ist ics. Accessed Novem ber 12, 2015.
 Ch a pt er

15
Alt er ed Ven t ila t ion
a n d Diffu sion

L E AR N I N G O U T C O ME S
1. Defin e a n d u se t h e key t er m s list ed in t h is ch a pt er.
2. E xpla in t h e r ole of ven t ila t ion a n d diffu sion in oxygen /ca r bon dioxide ga s
exch a n ge.
3. Descr ibe t h e pr ocesses t h a t ca n im pa ir ven t ila t ion a n d diffu sion .
4. Recogn ize t h e effect s of im pa ir ed ven t ila t ion a n d diffu sion .
5. Iden t ify t h e com m on sign s a n d sym pt om s of a lt er ed ven t ila t ion a n d
diffu sion .
6. Descr ibe dia gn ost ic t est s a n d t r ea t m en t st r a t egies r eleva n t t o disor der ed
ven t ila t ion a n d diffu sion .
7. Apply t h e con cept s of a lt er ed ven t ila t ion a n d diffu sion t o select clin ica l
m odels.

INTR ODUCTION
Ta ke a deep br ea t h . E xh a le. Oxygen fr om t h e a ir goes in ; ca r bon dioxide goes
ou t . Wh en you br ea t h e, fou r m a jor pr ocesses a r e occu r r in g a s you r ch est
r ises a n d fa lls: ven t ila t ion , diffu sion , per fu sion , a n d r espir a t ion . Ve n t ila t io n
is t h e pr ocess of m ovin g a ir in t o a n d ou t of t h e t r a ch ea , br on ch i, a n d lu n gs.
D i u s io n is t h e pr ocess of m ovin g a n d exch a n gin g t h e oxygen a cqu ir ed du r in g
ven t ila t ion a n d ca r bon dioxide wa st e a cr oss t h e a lveola r ca pilla r y m em br a n es.
P e r u s io n is a pr ocess of su pplyin g oxygen a t ed blood t o t h e lu n gs a n d or-
ga n syst em s via t h e blood vessels. R e s p ir a t io n is a pr ocess in wh ich cells
t h r ou gh ou t t h e body u se oxygen a er obica lly t o m a ke en er gy. As a h ea lt h ca r e
pr ovider, it is cr it ica lly im por t a n t t o r ecogn ize pr oblem s a ssocia t ed wit h a lt er ed
ven t ila t ion a n d diffu sion .

365
366 C h a p t e r 15: Alt er ed Ven t ila t ion a n d Diffu sion

Modu le 1 P u lm o n a r y S t r u c t u r e a n d F u n c t io n

Th e pu lm on a r y, or r espir a t or y, syst em is r espon si- syst em is oft en divided in t o t h e u pper a n d lower

ble for ven t ila t ion a n d diffu sion . Th e m a jor fu n ct ion
is t h e exch a n ge of ga ses bet ween t h e en vir on m en t
a n d t h e blood. Th e pu lm on a r y syst em com pr ises t h e
lu n gs, a ir wa ys, ch est wa ll, a n d pu lm on a r y cir cu la -
t ion (Fig. 15.1). Th e st r u ct u r a l pa t h of t h e pu lm on a r y
a ir wa ys. Th e u pper a ir wa y com pr ises t h e n ose or
m ou t h , n a soph a r yn x, a n d or oph a r yn x. Th e la r yn -
gea l ph a r yn x con n ect s t h e u pper a n d lower a ir wa ys.
Th e lower a ir wa y com pr ises t h e t r a ch ea , br on ch i,
a n d br on ch ioles. Th e br a n ch in g a n a t om ic st r u ct u r e

Nasal cavity
Na s opha rynx

Oropha rynx
Epiglottis
La rynge a l pha rynx
Es opha gus Tra che a

Vis ce ra l ple ura

P a rie ta l ple ura Le ft ma in bronchus

Uppe r lobe of right lung

Right ma in bronchus

Uppe r lobe of le ft lung

Middle lobe
Bronchiole s Lowe r lobe
Lowe r lobe

Me dia s tinum
Dia phra gm

P ulmona ry ve in
Re s pira tory bronchiole s

Lobule s
Alve ola r duct
Alve ola r
Alve olus ma cropha ge Re d blood ce ll
Ca pilla ry

P ulmona ry a rte ry
S urfa cta nt

Alve ola r e pithe lium Alve ola r ca pilla ry junction

Alve ola r ba s e me nt me mbra ne

Figure 15.1. Anatomy of the airways.


of t h e pu lm on a r y syst em is idea l for m a xim izin g
su r fa ce a r ea t o a llow for opt im a l ga s diffu sion , or
m ovem en t of ga ses a cr oss t h e a lveoli.
Beca u se t h e pu lm on a r y syst em is vu ln er a ble t o
t h e ext er n a l en vir on m en t , defen se m ech a n ism s a r e
n eeded t o pr ot ect t h e lu n gs fr om en vir on m en t a l in -
ju r y. Th ese defen se m ech a n ism s a r e h igh ly effect ive
a n d in clu de:
● P r otective str u ctu r es, su ch a s h a ir s a n d t u r bin a t es
(sh ell-sh a ped st r u ct u r es) in t h e n ose a n d cilia in
t h e u pper a n d lower a ir wa ys, wh ich t r a p a n d r e-
m ove for eign pa r t icles fr om t h e a ir
● Mu cosa l lin in g of t h e u pper a n d lower a ir wa ys,
wh ich wa r m s a n d h u m idifies a ir
● Ir r ita n t r eceptor s t h r ou gh ou t t h e n ose a n d a ir-
wa ys, wh ich r ecogn ize in ju r iou s a gen t s a n d r e-
spon d by t r igger in g a sn eeze or cou gh r eflex t o
r em ove for eign pa r t icles
● Im m u n e pr otection s, su ch a s a n im m u n e coa t in g
in t h e r espir a t or y t r a ct m u cosa a n d m a cr oph a ges
in t h e a lveoli, wh ich in gest a n d r em ove ba ct er ia
a n d ot h er for eign m a t er ia ls via ph a gocyt osis
Stop and Consider
How are defense mechanisms and the body pro-
tections affected in the person who is a mouth
breather?
In t er cost a l m u scles, r ibs, a n d skin su r r ou n d t h e
lu n gs a n d pr ovide pr ot ect ion a ga in st in ju r y. Th e
m u scles of t h e ch est ca vit y a n d t h e dia ph r a gm per-
for m t h e m u scu la r wor k of br ea t h in g. Two m a jor
m em br a n e la yer s lin e t h e lu n gs a n d ch est ca vit y: t h e
(ou t er ) pa r iet a l pleu r a a n d (in n er ) viscer a l pleu r a .
Th ese la yer s a r e sepa r a t ed by a pleu r a l spa ce, wh ich
is filled wit h a lu br ica t in g flu id, secr et ed by t h e
pleu r a , t h a t a llows t h e t wo la yer s t o slide over ea ch
ot h er wit h m in im a l fr ict ion .
Th e pu lm on a r y cir cu la t ion is r espon sible for t h e
deliver y of oxygen a n d ot h er n u t r ien t s t o t h e lu n g
t issu es. It is a lso r espon sible for t h e filt r a t ion of
clot s, a ir, or ot h er for eign m a t er ia ls fr om t h e cir cu -
la t ion . Th e ca pilla r ies of t h e lu n gs n ea r t h e a lveoli
fa cilit a t e t h e exch a n ge of oxygen a n d ca r bon dioxide.
Th e pu lm on a r y cir cu la t ion is discu ssed fu r t h er in
Ch a pt er 16.
Ventilation
Th e pr ocess of ven t ila t ion in volves bot h a cqu ir in g
oxygen (in spir a t ion ) a n d r em ovin g ca r bon dioxide
(expir a t ion ) fr om t h e blood. Th e t r a n spor t of ox-
ygen t h r ou gh t h e lu n gs is t h e on ly m ech a n ism for
a cqu ir in g oxygen . Oxygen is n ecessa r y for cellu la r
P u lm o n a r y S t r u c t u r e a n d F u n c t io n 367
m et a bolism , wh ich m ea n s t h a t for t h e cell t o expen d
en er gy efficien t ly a n d per for m it s design a t ed fu n c-
t ion , t h er e m u st be oxygen pr esen t . Th e r elea se of
ca r bon dioxide is equ a lly a s im por t a n t . Opt im a l cell
fu n ct ion in g occu r s wit h in a ver y n a r r ow pH r a n ge.
Th e r elea se a n d r et en t ion of ca r bon dioxide is on e
m ech a n ism for m a in t a in in g t h is ba la n ce.
Th e r a t e a n d volu m e of ven t ila t ion is r egu la t ed by
t h e followin g com pon en t s:
● A fu n ct ion in g r espir a t or y con t r ol cen t er in t h e
br a in
● Lu n g r ecept or s
● Ch em or ecept or s
Th e dr ive t o ven t ila t e is st im u la t ed by t h e r espir a -
t or y con t r ol cen t er in t h e br a in st em in r espon se t o
ch em ica l m essa ges in t h e body. Th e r espir a t or y con -
t r ol cen t er com pr ises n eu r on s in t h e pon s a n d m e-
du lla . It sen ds n eu r on a l im pu lses t o t h e dia ph r a gm ,
in t er cost a l m u scles, st er n ocleidom a st oid m u scles,
a n d ot h er a ccessor y m u scles a n d ca u ses t h em t o con -
t r a ct or r ela x. Th e a u t on om ic n er vou s syst em (ANS)
a lso in n er va t es t h e lu n gs a n d a ct s on t h e sm oot h
m u scles of t h e con du ct in g a ir wa ys t o pr om ot e a ir-
way con st r ict ion (pa r a sym pa t h et ic division ) or dila -
t ion (sym pa t h et ic division ). Th e a ct ivit y of t h e ANS
will in cr ea se or decr ea se t h e dia m et er of t h e a ir wa ys
a n d a ffect t h e a m ou n t of a ir t h a t is a ble t o get in a n d
ou t of t h e lu n gs.
Neu r on a l im pu lses a r e dir ect ed by lu n g r ecept or s
t h a t m a p t h e cu r r en t st a t e of br ea t h in g a n d lu n g
fu n ct ion . Lu n g r ecept or s a r e loca t ed in t h e epit h e-
liu m a n d sm oot h m u scle of t h e a ir wa ys, a n d t h ey a r e
n ea r t h e a lveola r ca pilla r y ju n ct ion s. Specific lu n g
r ecept or s h a ve pa r t icu la r r oles. For exa m ple, lu n g
r ecept or s loca t ed in t h e epit h eliu m of t h e con du ct -
in g a ir wa ys a r e r espon sible for sen sin g ir r it a n t s in
t h e lu n gs a n d st im u la t in g t h e cou gh r eflex. Lu n g
r ecept or s in t h e sm oot h m u scles of t h e a ir wa ys a r e
a ct iva t ed t o pr om ot e expir a t ion in or der t o pr even t
excessive lu n g in fla t ion . Lu n g r ecept or s in t h e ca p-
illa r ies det ect in cr ea ses in ca pilla r y pr essu r e a n d
st im u la t e a r edu ct ion in t h is pr essu r e.
Ch em or ecept or s det ect ga s exch a n ge n eeds ba sed
on t h e Pa O 2 , Pa CO 2 , a n d pH levels in t h e blood a n d
cer ebr ospin a l flu id (CSF ). Cen t r a l ch em or ecept or s
a r e loca t ed n ea r t h e r espir a t or y con t r ol cen t er a n d
r espon d t o pH ch a n ges in t h e CSF. Beca u se CO 2
diffu ses a cr oss t h e blood–br a in ba r r ier u n t il bot h
t h e a r t er ia l Pa CO 2 a n d CSF Pa CO 2 a r e equ a l, t h e
CO 2 levels det ect ed by t h e cen t r a l ch em or ecept or s
r eflect t h a t in t h e blood. Th e cen t r a l ch em or ecep-
t or s t h en a lt er t h e r a t e of br ea t h in g t o a da pt t o t h e
h igh er or lower levels of CO 2 in t h e body. Reca ll t h a t
ca r bon dioxide is a cidic. If t h e blood is m or e a cidic,
t h e r espir a t or y cen t er in cr ea ses t h e r a t e a n d dept h
of br ea t h in g t o r elea se or “blow off ” excess ca r bon
368 C h a p t e r 15: Alt er ed Ven t ila t ion a n d Diffu sion
dioxide. If t h e blood is m or e a lka lin e, t h e r espir a t or y
cen t er decr ea ses t h e r a t e a n d dept h of br ea t h in g t o
r et a in ca r bon dioxide. Per iph er a l ch em or ecept or s,
wh ich a r e m ost sen sit ive t o oxygen levels in t h e
a r t er ia l blood (Pa O 2 ), a r e loca t ed in t h e a or t a a n d
ca r ot id a r t er ies. Per iph er a l ch em or ecept or s t r igger
a n in cr ea se in ven t ila t ion in r espon se t o low oxygen
levels in t h e blood. Cer vica l a n d t h or a cic n er ves a r e
t h en st im u la t ed a ccor din gly t o con du ct t h e specified
br ea t h in g a da pt a t ion .
Stop and Consider
How does your breathing change when you
exercise? Why do you think this happens?
Th e m essa ges sen t by t h e lu n g a n d ch em or ecep-
t or s a r e u lt im a t ely sen t t o t h e cer vica l a n d t h or a cic
n er ves, wh ich a ct on t h e pu lm on a r y syst em t o a da pt
t h e br ea t h in g pa t t er n t o m a in t a in h om eost a sis. Th e
wor k of br ea t h in g is im pr oved wit h fu n ct ion a l a n d
st r on g m u scles of ven t ila t ion , su ch a s t h e in t er cos-
t a l m u scles, dia ph r a gm , a n d st er n ocleidom a st oid
m u scles, a lon g wit h pr oper lu n g com plia n ce (a llows
m a xim a l in spir a t ion ), ela st ic r ecoil (pr om ot es expi-
r a t ion ), a n d low a ir wa y r esist a n ce. C o m p lia n c e is
t h e expect ed dist en sibilit y, or expa n da bilit y, of t h e
lu n g t issu e a n d ch est wa ll. Air wa y r esist a n ce is
ba sed on t h e a r ea of t h e in n er lu m en of t h e a ir wa y
a n d on pr oper t ies, su ch a s viscosit y a n d velocit y, of
t h e ga s m ovin g t h r ou gh t h a t a ir wa y.
INSPIRATION
I n s p ir a t io n is t h e pr ocess of br ea t h in g in t o a cqu ir e
oxygen . Sim ila r t o in fla t in g a ba lloon , m ovem en t
of a ir is a lwa ys u n idir ect ion a l a n d t r a vels fr om a n
a r ea of h igh pr essu r e t o low pr essu r e. In t h is exa m -
ple, t h e pr essu r e in side t h e ba lloon (t h e “lu n gs”) is
lower t h a n t h a t of t h e per son blowin g a ir in t o t h e
ba lloon (t h e “a t m osph er e”). A m a jor differ en ce is
t h a t t h e ch est ca vity ch a n ges size to a lter th e pr es-
su r e gr a d ien t, t h er eby dr a win g a ir in t o t h e lu n gs, a s
opposed t o t h e a ir m ovin g in a n d ch a n gin g t h e size,
a s you wou ld see wit h a ba lloon . Neu r on a l st im u la -
t ion a n d t h e m ovem en t of t h e dia ph r a gm down wa r d
a n d ext er n a l in t er cost a l m u scles ou t wa r d a llow t h is
in cr ea se in ch est ca vit y size, r edu ce pr essu r e in side
t h e lu n gs, a n d pu ll a ir in t o t h e lu n gs.
EXPIRATION
E x p ir a t io n , t h e pr ocess of r em ovin g ca r bon diox-
ide ou t of t h e body t h r ou gh t h e lu n gs, is a lso r egu -
la t ed wit h in t h e r espir a t or y cen t er of t h e br a in . In
expir a t ion , t h e dia ph r a gm a n d ext er n a l in t er cost a l
m u scles r ela x. Th e ch est wa ll m oves in wa r d a n d t h e
dia ph r a gm m oves u pwa r d. Th e in t r a t h or a cic (in side
t h e t h or a cic ca vit y) pr essu r e becom es gr ea t er t h a n
t h e a t m osph er ic pr essu r e. Th is st im u la t es a ir t o
flow pa ssively ou t in t o t h e a t m osph er e. E xh a la t ion
ca n a lso be for ced if t h e a bdom in a l a n d in t er cost a l
m u scles a r e con t r a ct ed volu n t a r ily, t h er eby in cr ea s-
in g pr essu r e t o m ove t h e dia ph r a gm u pwa r d a n d
pu ll t h e r ibs in wa r d. Th e idea is t o com pr ess t h e
lu n gs a n d in cr ea se t h e pr essu r e in side t h e a ir wa ys.
Air t h en m oves fr om t h e r egion of h igh er t o lower
pr essu r e, or, in t h is exa m ple, fr om t h e lu n gs t o t h e
a t m osph er e.
MEASUREMENT OF VENTILATION
Th e m ea su r em en t of lu n g volu m es ca n det er m in e
t h e effect iven ess of in spir a t ion a n d expir a t ion . Mea -
su r em en t s a r e com plet ed by br ea t h in g in or ou t
t h r ou gh a spir om et er wh er e m ea su r em en t of a ir vol-
u m e occu r s. Ch a n ges in lu n g volu m es or pu lm on a r y
fu n ct ion ca n be a n ea r ly sign of im pa ir ed ven t ila t ion .
P r edict ed va lu es (t h e m ea su r em en t r ea din gs t h a t
a r e expect ed) va r y ba sed on a ge, h eigh t , a n d gen der.
Th e followin g a r e exa m ples of m a jor m ea su r em en t s
of ven t ila t or y ca pa cit y:
● Tid a l v o lu m e (T V) is t h e a m ou n t of a ir t h a t is
exh a led a ft er pa ssive in spir a t ion ; t h is is t h e vol-
u m e of a ir goin g in a n d ou t of t h e lu n gs a t r est ; in
a du lt s, t h is volu m e is a ppr oxim a t ely 500 m L.
● Vit a l c a p a c it y (VC ) is t h e m a xim a l a m ou n t of
a ir t h a t ca n be m oved in a n d ou t of t h e lu n gs wit h
for ced in h a la t ion a n d exh a la t ion .
● F o r c e d v it a l c a p a c it y (F VC ) is t h e m a xim a l
a m ou n t of a ir t h a t is exh a led fr om t h e lu n gs
du r in g a for ced exh a la t ion .
● F o r c e d e x p ir a t o r y v o lu m e in 1 s e c o n d (F E V 1 )
is t h e m a xim a l a m ou n t of a ir t h a t ca n be expir ed
fr om t h e lu n gs in 1 secon d.
● R e s id u a l v o lu m e (R V) is t h e volu m e of a ir t h a t
r em a in s in t h e lu n gs a ft er m a xim a l expir a t ion .
● To t a l lu n g c a p a c it y (T L C ) is t h e t ot a l a m ou n t
of a ir in t h e lu n gs wh en t h ey a r e m a xim a lly ex-
pa n ded a n d is t h e su m of t h e VC a n d RV.
Diffusion
Oxygen a n d ca r bon dioxide a r e exch a n ged a t t h e a l-
veola r ca pilla r y ju n ct ion s in t h e pr ocess of diffu sion .
Th e a lveola r ca pilla r y ju n ct ion is a t h in m em br a n e
com posed of a la yer of a lveola r epit h elia l cells wit h
a ba sem en t m em br a n e a n d t h e ca pilla r y epit h eliu m
wit h a ba sem en t m em br a n e. Th ese a r e sepa r a t ed by
a n a r r ow in t er st it ia l spa ce a n d a r e su ppor t ed by con -
n ect ive t issu e. Bet ween t h e a lveolu s a n d ca pilla r y,
oxygen m oves in t o t h e cir cu la t ion a n d ca r bon dioxide
m oves ou t t o t h e a t m osph er e. F igu r e 15.1 depict s t h e

pr oxim it y of t h e a lveolu s a n d ca pilla r y. Th e a lveoli
t h a t com pr ise t h e a lveola r por t ion of t h is ju n ct ion
a r e com m on ly design a t ed t ype I a lveola r cells (t h ose
t h a t pr ovide st r u ct u r e a n d a ir exch a n ge) or t ype
II (t h ose t h a t a r e a ct ive in secr et in g s u r a c t a n t ,
a lipopr ot ein lu br ica n t t h a t coa t s t h e in n er por-
t ion of t h e a lveolu s, pr om ot es ea se of expa n sion ,
a n d r epels flu id a ccu m u la t ion ). Su r fa ct a n t is es-
sen t ia l t o m a in t a in t h e in t egr it y, a ir exch a n ge,
a n d diffu sion fu n ct ion of t h e pu lm on a r y syst em .
Wit h ou t su r fa ct a n t , in fla t ion of t h e a lveoli wou ld
be a lm ost im possible a n d wou ld m a ke br ea t h in g
difficu lt .
Du r in g diffu sion , t wo m a jor pr ocesses a r e occu r-
r in g sim u lt a n eou sly: (1) oxygen is t r yin g t o get t o
a ll cells a n d (2) ca r bon dioxide is t r yin g t o esca pe
t h e body t h r ou gh t h e lu n gs. Th e effect iven ess of t h is
t r a n sa ct ion depen ds on :
● P r essu r e: Th e a m ou n t of pa r t ia l pr essu r e of t h e
oxygen or ca r bon dioxide in t h e blood
● Solu bilit y: Ca r bon dioxide is m u ch m or e solu ble
t h a n oxygen ; t h er efor e, ca r bon dioxide is a ble t o
diffu se a t a gr ea t er r a t e t h a n oxygen .
● Mem br a n es: Th e t h ickn ess a n d su r fa ce a r ea s of
t h e a lveola r a n d ca pilla r y m em br a n es
PARTIAL PRESSURE
Oxygen a n d ca r bon dioxide a r e com posed of cou n t -
less pa r t icles in con st a n t collision . Th e for ce of t h ese
collision s r esu lt s in t h e for m a t ion of pr essu r e. Wit h
oxygen , a ppr oxim a t ely 1% t o 13% is ca r r ied in t h e
cir cu la t ion a s a dissolved ga s in t h e pla sm a . Th is
por t ion cr ea t es a pr essu r e in t h e pla sm a , wh ich is
r efer r ed t o a s t h e p a r t ia l p r e s s u r e a n d is r epor t ed
in m m H g. Th e sym bol for t h e pa r t ia l pr essu r e of
oxygen in t h e a r t er ia l blood is P a o 2 . Pa O 2 is m ea -
su r ed a s pa r t of t h e a r t er ia l blood ga s pa n el by dr a w-
in g blood fr om a sm a ll a r t er y. Beca u se t h er e is n o
dir ect m et h od t o m ea su r e oxygen con cen t r a t ion s in
t h e body, t h e Pa O 2 gives a r ea son a ble est im a t e of t h e
pr esen ce of oxygen in t h e blood ba sed on t h e pr es-
su r e exer t ed by t h is ga s. Pa O 2 is in flu en ced by sev-
er a l fa ct or s, su ch a s t h e pr esen ce a n d con cen t r a t ion
of oxygen , a lt it u de, or even a gin g. Sim ila r t o oxygen ,
t h e dissolved CO 2 in t h e pla sm a for m s a pa r t ia l
pr essu r e. Th e sym bol for t h e pa r t ia l pr essu r e of ca r-
bon dioxide in a r t er ia l blood is P a c o 2 . Pa CO 2 is a lso
pa r t of t h e a r t er ia l blood ga s pa n el. It is m ea su r ed
t h r ou gh a n a r t er ia l blood sa m ple a n d is r epor t ed
in m m H g.
OXYGEN DIFFUSION AND TRANSPORT
Aft er in spir a t ion a n d diffu sion a cr oss t h e a lveola r
ca pilla r y ju n ct ion occu r, oxygen dissolves in t h e
P u lm o n a r y S t r u c t u r e a n d F u n c t io n 369
pla sm a , for m in g a pa r t ia l pr essu r e (Pa O 2 ). As t h e
Pa O 2 in cr ea ses, oxygen dissocia t es fr om t h e pla sm a
a n d con n ect s wit h h em oglobin m olecu les on r ed
blood cells. Th e oxygen –h em oglobin com bin a t ion is
n ow ca lled o x y h e m o g lo b in (H b o 2 ). Th e con n ec-
t ion t o h em oglobin is ba sed on oxygen ’s a t t r a ct ion t o
ir on . Ir on is t h e m a gn et t h a t pu lls oxygen on t o t h e
h em oglobin m olecu le. Th e oxygen t h en cir cu la t es
t h r ou gh ou t t h e body. Wh en t h e oxygen is on t h e h e-
m oglobin , it is n ot a ccessible t o t h e cell.
Stop and Consider
What happens to your oxygen-attracting ability if
you eat a diet low in iron?
Th is bin din g by a t t r a ct ion t o h em oglobin con t in -
u es u n t il t h e h em oglobin m olecu les a r e com plet ely
sa t u r a t ed wit h oxygen . O x y g e n s a t u r a t io n (S a o 2 )
r efer s t o t h e a m ou n t of oxyh em oglobin ; t h a t is, t h e
a m ou n t of h em oglobin t h a t is com bin ed, or sa t u -
r a t ed, wit h oxygen . Fou r oxygen m olecu les ca n r ide
on ea ch h em oglobin veh icle. Wh en a ll fou r sea t s a r e
filled, t h e h em oglobin is t er m ed u lly s a t u r a t e d or
100% sa t u r a t ed. Less t h a n t h is a m ou n t in dica t es a
r edu ct ion in t h e pr esen ce of oxygen or ca r r yin g ca -
pa cit y of t h e h em oglobin veh icle. Sa O 2 is n ot a ffect ed
by blood volu m e or h em oglobin level. Th e Sa O 2 is
sim ply sa yin g t h a t for t h e h em oglobin pr esen t , t h is
per cen t is sa t u r a t ed wit h oxygen . Fea sibly, a n in -
dividu a l cou ld h a ve a sever e h em or r h a ge a n d st ill
m ea su r e a n Sa O 2 of 100%.
On ce sa t u r a t ion h a s been a ch ieved, oxygen con -
t in u es t o diffu se a n d dissolve in t h e pla sm a u n t il
t h e pa r t ia l pr essu r e in t h e a r t er ies is equ a l t o t h a t
of t h e pa r t ia l pr essu r e of t h e oxygen in t h e a lveoli.
Diffu sion a cr oss t h e a lveoli cea ses u n t il t h e n eed for
oxygen is a ga in det ect ed by ch a n ges in t h e Pa O 2 . Th e
dissolved oxygen in t h e pla sm a is diffu sed in t o a n d
u sed by t h e cells for cellu la r m et a bolism . Oxygen is
m u ch less solu ble t h a n ca r bon dioxide; t h er efor e, a t
a n y t im e, a ppr oxim a t ely 87% t o 99% of t h e oxygen is
com bin ed wit h h em oglobin ; t h e r em a in der is fou n d
dissolved in t h e pla sm a of t h e blood.
CARBON DIOXIDE DIFFUSION AND TRANSPORT
A m a jor wa st e pr odu ct of cellu la r fu n ct ion a n d r es-
pir a t ion is ca r bon dioxide. If t h e cell is for ced in t o
a n a er obic r espir a t ion , a cidic m et a bolic wa st es a r e
pr odu ced in a ddit ion t o CO 2 . On e m ech a n ism for r id-
din g t h e body of t h is excess a cid is t o fr ee t h e CO 2
in t o t h e cir cu la t ion , wh er e it t h en t r a vels t o t h e a l-
veoli a n d t h r ou gh t h e lu n gs for exh a la t ion . Ca r bon
dioxide diffu ses m u ch m or e r ea dily t h a n oxygen
a n d m oves ea sily a cr oss t h e a lveola r ca pilla r y ju n c-
t ion s. On ce r elea sed fr om t h e cells, ca r bon dioxide is
370 C h a p t e r 15: Alt er ed Ven t ila t ion a n d Diffu sion

t r a n spor t ed t h r ou gh t h e cir cu la t ion sim ila r t o oxy- r ea dily t h r ou gh a lveola r ca pilla r y ju n ct ion , a n d is
gen in t h a t it is: exh a led t h r ou gh t h e lu n gs. Con dit ion s t h a t ca n de-
cr ea se expir a t or y efficien cy, su ch a s fibr osis a n d a ir
● Dissolved in t h e pla sm a (a ppr oxim a t ely 10% of
t r a ppin g in t h e a lveoli, gr ea t ly a ffect CO 2 t r a n spor t .
t h e CO 2 )
Th e CO 2 will n ot be a ble t o cr oss t h e a lveola r m em -
● Bou n d t o h em oglobin (a ppr oxim a t ely 20% t o 30%
br a n e, will be r et a in ed in t h e body, a n d will lea d
of t h e CO 2 )
t o a cidosis.
● Diffu sed in t o t h e r ed blood cells a s bica r bon a t e
(a ppr oxim a t ely 60% t o 70% of t h e CO 2 )
DIFFUSING CAPACITY
Stop and Consider Th e a bilit y of t h e a lveola r ca pilla r y ju n ct ion t o ex-
What happens to oxygen and carbon dioxide ch a n ge oxygen a n d ca r bon dioxide bet ween t h e a t m o-
transport if there is a lack of red blood cells, sph er e a n d t h e blood ca n be m ea su r ed qu a n t it a t ively.
such as occurs in severe hemorrhaging? Th e d i u s in g c a p a c it y is defin ed a s a m ea su r e-
m en t of ca r bon m on oxide (CO), oxygen , or n it r ic ox-
Th e m a jor por t ion of t h e CO 2 fou n d diffu sed in t o ide t r a n sfer fr om in spir ed ga s t o pu lm on a r y ca pilla r y
t h e r ed blood cell is con ver t ed t h r ou gh t h e bu ffer- blood a n d r eflect s t h e volu m e of a ga s t h a t diffu ses
in g syst em s t o eit h er ca r bon ic a cid or bica r bon a t e t h r ou gh t h e a lveola r ca pilla r y m em br a n e ea ch m in -
ion s. Next , t h e ca r bon ic a cid or bica r bon a t e con t in - u t e. Th is volu m e is det er m in ed m ost com m on ly by
u es in t h e pla sm a t o h elp r egu la t e blood pH . E xcess com pa r in g h ow m u ch ca r bon m on oxide (CO) a t n on -
CO 2 is r elea sed ea sily fr om t h e h em oglobin , diffu ses t oxic levels is t a ken u p by t h e blood a n d dividin g t h is
by t h e pr essu r e a cr oss
t h e a lveola r ca pilla r y
m em br a n e. In dividu a ls
wit h a lveola r fibr osis
or obst r u ct ion wou ld be
F R O M T H E L AB a ppr opr ia t e ca n dida t es
Oxygen saturation (oxyhemoglobin) (SaO2) is often measured using pulse oximetry, a nonin- for u n der goin g a n a n a l-
vasive method of determining hypoxemia even before clinical signs and symptoms are noted. ysis of diffu sin g ca pa c-
The principle of pulse oximetry is based on red (600 to 750 nm wavelength) and infrared it y. Du r in g t h e t est , t h e
(850 to 1,000 nm wavelength) light absorption levels for oxygenated and deoxygenated in dividu a l br ea t h es in a
hemoglobin. Oxygenated hemoglobin absorbs more infrared light and allows more red light ga s con t a in in g CO a n d
to pass through. Deoxygenated hemoglobin absorbs more red light and allows more infrared on e or m or e t r a cer ga ses
light to pass through. A sensor is placed on the finger, toe, nose, earlobe, or forehead. Both t o a llow det er m in a t ion
red and infrared light are transmitted to a photo detector. The sensor measures the amount of t h e ga s-exch a n gin g
of red and infrared light absorbed by hemoglobin. The expected range of SaO2 is generally ca pa bilit y of t h e lu n gs.
95% to 100%. An SaO2 below 70% may be life-threatening. For exa m ple, t h e oxy-
gen -diffu sin g ca pa cit y in
a st a t e of r est aver a ges
a bou t 21 m L per m in u t e
per m m H g. If t h e a ver-
a ge pr essu r e differ en ce
bet ween t h e a lveoli a n d
a r t er ia l blood is 11 m m
H g, t h e a m ou n t of ox-
ygen t h a t diffu ses per
m in u t e wou ld aver a ge
21 × 11 = 230 m L.

Stop and Consider

Based on what you
know about why and
how SaO2, PaO2, and
PaCO2 are measured,
A fingertip oximeter sensor (adult). (From Evans-Smith P. Taylor’s Clinical Nursing Skills. Philadelphia, what factors do you
PA: Lippincott Williams & Wilkins; 2004.) think would affect
these readings?
 I m p a ir e d Ve n t ila t io n 371

Modu le 2 I m p a ir e d Ve n t ila t io n

Im pa ir ed ven t ila t ion is a pr oblem of blockin g a ir flow
in a n d ou t of t h e lu n gs, t h er eby r est r ict in g oxygen
in t a ke a n d ca r bon dioxide r em ova l fr om t h e body.
Two m a jor m ech a n ism s a r e im plica t ed: (1) com pr es-
sion or n a r r owin g of t h e a ir wa ys a n d (2) disr u pt ion
of t h e n eu r on a l t r a n sm ission s n eeded t o st im u la t e
t h e m ech a n ics of br ea t h in g. Com pr ession or n a r r ow-
in g of t h e a ir wa ys a n ywh er e fr om t h e n ose or m ou t h
t o a lveoli in cr ea ses a ir wa y r esist a n ce a n d lea ds t o
difficu lt ies wit h a ir wa y clea r a n ce. Th is occlu sion ca n
be pa r t ia l or com plet e. E xa m ples of pr ocesses t h a t
con t r ibu t e t o in effect ive a ir wa y clea r a n ce in clu de
in fla m m a t ion , edem a , a n d exu da t e a ccu m u la t ion
fr om a n in fect iou s pr ocess, a st r u ct u r a l n a r r owin g
of t h e pa ssa gewa y, st r a n gu la t ion , or t h e pr esen ce of
a for eign body. In t h ese ca ses, a ir is r est r ict ed fr om
m ovin g in a n d ou t of t h e body.
Disr u pt ion of n eu r on a l t r a n sm ission t o t h e lu n gs
a lso a lt er s ven t ila t or y ca pa cit y by ign or in g t h e m es-
sa ges sen t by ch em or ecept or s a n d lu n g r ecept or s a n d
in t er r u pt in g t h e m ech a n ics of br ea t h in g. Over seda -
t ion du r in g a su r gica l pr ocedu r e or a dr u g over dose
ca n pr om ot e a loss of n eu r ologic st im u la t ion on t h e
r espir a t or y cen t er. Da m a ge t o t h e r espir a t or y cen -
t er of t h e br a in , cer vica l n er ves, or t h or a cic n er ves
lea ds t o a n u n r espon sive or in effect ive br ea t h in g
pa t t er n t h a t does n ot a da pt t o oxygen in t a ke n eeds
a n d ca r bon dioxide r em ova l n eeds of t h e body. For
exa m ple, sever in g t h e cer vica l n er ves r esu lt s in ces-
sa t ion of spon t a n eou s lu n g fu n ct ion a n d r equ ir es ex-
t er n a l m ech a n ica l ven t ila t ion . Ta ble 15.1 h igh ligh t s
effect ive a n d in effect ive br ea t h in g pa t t er n s r ela t ed
t o select ph ysiologic a n d pa t h oph ysiologic pr ocesses.
Wh en a per son ’s br ea t h in g pa t t er n is r espon sive,
t h e r a t e, dept h , a n d r h yt h m ic pa t t er n of br ea t h in g
a da pt t o ph ysiologic ch a n ges occu r r in g in t h e body.
Br ea t h in g pa t t er n s becom e in effect ive wh en t h ese
qu a lit ies (r a t e, dept h , a n d r h yt h m ) do n ot su ccess-
fu lly m a in t a in h om eost a sis, pa r t icu la r ly in m a in -
t a in in g a cid–ba se ba la n ce. All of t h e clin ica l m odels
in t h is ch a pt er dem on st r a t e som e level of in effect ive
a ir wa y clea r a n ce a n d m odifica t ion in br ea t h in g pa t -
t er n s r ela t ed t o obst r u ct ive, r est r ict ive, or a lt er ed
n eu r on a l pr ocesses.
Stop and Consider
How long can you hold your breath? How do you
feel while you are holding your breath? When
you cannot hold your breath any longer and you
start to breathe, how does your body respond?

Ta b le 15.1 Ada pt a t ion s in Br ea t h in g Pa t t er n s

T y p e o B r e a t h in g D e s c r ip t io n o
Patter n Pa tter n
E u pn ea Th e expect ed pa t t er n of
br ea t h in g ch a r a ct er ized
by a r a t e bet ween 10
a n d 20 br ea t h s/m in in
a du lt s, 500 a n d 800 m L
in dept h , a n d a r egu la r
r h yt h m
Ta ch ypn ea Ra pid, sh a llow br ea t h -
in g ch a r a ct er ized by
a r a t e of br ea t h in g
a bove 24 br ea t h s/m in
in a du lt s
Apn ea Cessa t ion of br ea t h in g
for 10 secon ds or lon ger,
u su a lly in t er sper sed
wit h a n ot h er br ea t h in g
pa t t er n descr ibed in
t h is t a ble
D ia g r a m o P a t t e r n
R ea son or Occu r r en ce
E ffect ive a n d r espon sive ga s
exch a n ge
Th e body n eeds t o r elea se
excess ca r bon dioxide a n d
r espon ds by in cr ea sin g t h e
r a t e of br ea t h in g. Th is is a n
expect ed r espon se t o fever,
fea r, or exer cise; ca n a lso oc-
cu r wit h r espir a t or y in su ffi-
cien cy pn eu m on ia , or in ju r y
t o r espir a t or y cen t er.
Ca n r esu lt fr om br a in in -
ju r y, pr em a t u r e bir t h , or
a s a n obst r u ct ive pr ocess
du r in g sleep
(con tin u ed )
372 C h a p t e r 15: Alt er ed Ven t ila t ion a n d Diffu sion

Ta b le 15.1 Ada pt a t ion s in Br ea t h in g Pa t t er n s (con tin u ed )

T y p e o B r e a t h in g
Patter n
H yper pn ea (Ku ss-
m a u l r espir a t ion s),
h yper ven t ila t ion
Br a dypn ea ,
h ypoven t ila t ion
Ch eyn e–St okes
At a xic br ea t h in g
Obst r u ct ive br ea t h in g
D e s c r ip t io n o
Pa tter n
In cr ea se in t h e r a t e a n d
t h e dept h of br ea t h in g.
H yper pn ea is r espon -
sive t o Pa O 2 /Pa CO 2
r equ ir em en t s; h yper-
ven t ila t ion occu r s in ex-
cess of wh a t is n eeded
t o m a in t a in Pa CO 2 .
Slow br ea t h in g wit h
r egu la r dept h a n d r a t e.
H ypoven t ila t ion r efer s
t o decr ea sed a n d in a de-
qu a t e ven t ila t ion .
A br ea t h in g pa t t er n
t h a t a lt er n a t es h yper p-
n ea in a cr escen do–de-
cr escen do pa t t er n a n d
per iods of a pn ea
A br ea t h in g pa t t er n of
u n pr edict a ble ir r egu -
la r it y. Ca n com bin e a n y
or a ll br ea t h in g pa t -
t er n s a bove.
P r olon ged a n d in com -
plet e expir a t ion t o
over com e in cr ea sed a ir-
wa y r esist a n ce a n d a ir
t r a ppin g
D ia g r a m o P a t t e r n R ea son or Occu r r en ce
E xcess ca r bon dioxide n eeds
t o be r elea sed. Th is ca n oc-
cu r wit h ext r em e exer t ion ,
fea r, or a n xiet y, or wit h di-
a bet es ket oa cidosis, a spir in
over dose, or br a in in ju r y.
H yper ven t ila t ion blows off
excessive CO 2 , ca u sin g a de-
cr ea sed level in t h e blood.
Dr u g-in du ced depr ession
of t h e r espir a t or y cen t er,
in cr ea sed in t r a cr a n ia l pr es-
su r e, dia bet ic com a
In cr ea sed in t r a cr a n ia l pr es-
su r e, br ea t h in g bila t er a l
da m a ge t o cer ebr a l h em i-
sph er es or dien ceph a lon s,
dr u g-in du ced r espir a t or y
depr ession , h ea r t fa ilu r e,
u r em ia
Sever e h ea d t r a u m a a n d
da m a ge t o r espir a t or y
cen t er, br a in a bscess, h ea t
st r oke, spin a l m en in git is,
en ceph a lit is
Ch r on ic obst r u ct ive lu n g
disea se, a st h m a , ch r on ic
br on ch it is

E u pn ea , t a ch ypn ea , a pn ea , br a dypn ea , a n d Ch eyn e–St okes fr om Nu r sin g P r oced u r es. 4t h ed. Am bler, PA: Lippin cot t Willia m s & Wilkin s; 2004;
H yper pn ea , a t a xic br ea t h in g, a n d obst r u ct ive br ea t h in g fr om Bickley LS, Szila gyi P. Ba tes’ Gu id e to P h ysica l E xa m in a tion a n d H istor y Ta kin g.
8t h ed. P h ila delph ia , PA: Lippin cot t Willia m s & Wilkin s; 2003.

IMPAIRED VENTILATION–PERFUSION MATCHING a lveola r ca pilla r y ju n ct ion . Beca u se t h e r a t e of diffu -

sion depen ds on t h e solu bilit y a n d pa r t ia l pr essu r e
A secon d m ech a n ism for im pa ir in g ga s exch a n ge is
of t h e ga s, a n d on su r fa ce a r ea a n d t h ickn ess of t h e
t er m ed ven t ila t ion –per fu sion (V/Q) m ism a t ch in g.
m em br a n e, im pa ir ed ga s exch a n ge ca n occu r wit h
Th is m ea n s eit h er t h a t a r ea s of t h e lu n g a r e ven t i-
ch a n ges in a n y of t h ese pr oper t ies. All of t h e clin i-
la t ed bu t n ot per fu sed or t h a t t h e lu n g is per fu sed
ca l m odels in t h is ch a pt er dem on st r a t e som e level of
bu t n ot ven t ila t ed. E xa m ples of pr oblem s t h a t ca n
im pa ir ed ga s exch a n ge r ela t ed t o a decr ea se in t h e
im pa ir ven t ila t ion a r e descr ibed in t h e pr eviou s sec-
fu n ct ion a l a lveola r ca pilla r y ju n ct ion su r fa ce a r ea .
t ion . Wit h im pa ir ed ven t ila t ion , in a dequ a t e oxygen
Pa r t ia l pr essu r e is in cr ea sed wh en m or e m ole-
com es in t o t h e lu n gs even t h ou gh t h e blood flow is
cu les a r e pa cked in t o a spa ce, wh en t h e t em per a t u r e
r ea dy a n d a ble t o ca r r y t h e oxygen t h a t is pr esen t .
in cr ea ses (pr om ot in g a n in cr ea se in pa r t icle colli-
If t h e per fu sion a spect is im pa ir ed, t h e blood flow t o
sion s), a n d wh en t h e ba r om et r ic pr essu r e in cr ea ses.
t h e lu n gs is r est r ict ed in on e or m or e a r ea s. Oxygen
A loss of pa r t ia l pr essu r e, a n d su bsequ en t decr ea se
m a y be com in g in t o t h e body bu t t h er e is n o blood
in oxygen pr esen ce, ca n occu r du r in g a st a t e of oxy-
flow t o ca r r y t h is a wa y t o ot h er body cells. A m or e
gen depr iva t ion , du r in g h ypot h er m ia , or wh en t h e
com plet e discu ssion of ven t ila t ion –per fu sion m is-
body is r espon din g t o ch a n ges in a t m osph er ic pr es-
m a t ch in g is r eser ved for Ch a pt er 16.
su r e (h igh a lt it u de). Th e pa r t ia l pr essu r e of oxygen
gen er a lly in cr ea ses du r in g t h e a dm in ist r a t ion of
IMPAIRED DIFFUSION
h igh con cen t r a t ion s of oxygen a n d pot en t ia lly du r in g
Im pa ir ed diffu sion is a pr ocess of r est r ict in g t h e a fever. Th e pa r t ia l pr essu r e of ca r bon dioxide is in -
t r a n sfer of oxygen or ca r bon dioxide a cr oss t h e cr ea sed du r in g st a t es of gr ea t er t issu e m et a bolism ,

su ch a s occu r s wit h fever or st r en u ou s exer cise. Th is
r esu lt s in h igh er levels of ca r bon dioxide in t h e blood.
Ch a n ges in t h e a lveola r ca pilla r y m em br a n e a lso
im pa ir diffu sion . Da m a ge t o t h e a lveoli or ca pilla r-
ies lim it s t h e a ccessible a n d u sa ble su r fa ce a r ea a n d
r est r ict s oxygen a n d ca r bon dioxide t r a n spor t . Ma n y
disea se pr ocesses, su ch a s pn eu m on ia , pu lm on a r y
edem a , a n d a cu t e r espir a t or y dist r ess syn dr om e
(ARDS), fill t h e a lveola r ca pilla r y ju n ct ion wit h t h e
pr odu ct s of in fla m m a t ion or in fect ion . Th is obst r u ct s
t h e pa ssa ge of ga ses n eeded for cell fu n ct ion a n d for
t h e m a in t en a n ce of opt im a l pH in t h e blood. Ch r on ic
in ju r y t o t h e a lveoli, su ch a s wit h em ph ysem a , ca n
lea d t o fibr osis, or t h icken in g of t h e a lveola r ca pil-
la r y m em br a n e, a n d ca n a lso im pa ir ga s exch a n ge.
THE EFFECTS OF IMPAIRED VENTILATION
AND DIFFUSION
Ma n y con dit ion s, even disea ses ou t side of t h e “r e-
spir a t or y” syst em , ca n ch a llen ge t h e ven t ila t or y a n d
diffu sion ca pa bilit ies of t h e body. An y sit u a t ion t h a t
pr esen t s a dem a n d for h igh er levels of oxygen or a n
in cr ea se in cellu la r m et a bolism r equ ir es pu lm on a r y
a da pt a t ion t o m a in t a in h om eost a sis. For exa m ple,
st r en u ou s exer cise r equ ir es ext en sive a da pt a t ion
t o pr ovide a dequ a t e oxygen t o cells a n d t o r em ove
t h e excess ca r bon dioxide (a s a by-pr odu ct of cellu -
la r m et a bolism ). Wh en t h e body is u n a ble t o keep u p
wit h t h e dem a n ds, eit h er beca u se t h e dem a n ds a r e
t oo gr ea t or t h e ven t ila t ion or diffu sion ca pa bilit ies
a r e r est r ict ed, t h is ca n lea d t o:
1. H ypoxem ia
2. H ypoxia
3. H yper ca pn ia
Th ese t h r ee effect s dir ect ly r esu lt fr om decr ea sed
oxygen pr esen ce or u t iliza t ion , or t h e r et en t ion of
ca r bon dioxide. Ba sica lly, t h e body is u n a ble t o t a ke
in en ou gh oxygen or is u n a ble t o r elea se en ou gh ca r-
bon dioxide. Th ese ba sic effect s dir ect ly a pply t o t h e
select ed clin ica l m odels in t h is ch a pt er a n d a ll ot h er
con dit ion s t h a t a ffect ven t ila t ion a n d diffu sion .
Hypoxemia and Hypoxia
H y p o x e m ia is decr ea sed oxygen in t h e a r t er ia l
blood lea din g t o a decr ea se in t h e pa r t ia l pr essu r e
of oxygen (Pa O 2 ). Th e m a jor ca u ses of h ypoxem ia in -
clu de oxygen depr iva t ion , h ypoven t ila t ion , pr oblem s
wit h a dequ a t e diffu sion , a n d in a dequ a t e u pt a ke of
oxygen in t h e blood. H ypoxem ia ca n r a n ge fr om m ild
t o sever e a n d becom es pr oblem a t ic wh en cells a r e
depr ived of a dequ a t e oxygen , a con dit ion r efer r ed t o
a s h y p o x ia . Wh en h ypoxem ia lea ds t o h ypoxia , t h e
I m p a ir e d Ve n t ila t io n 373
effect s a r e widespr ea d. All cells t h a t depen d on oxy-
gen for efficien t cellu la r m et a bolism a r e vu ln er a ble,
pa r t icu la r ly cells wit h in t h e vit a l or ga n s (t h e br a in ,
h ea r t , a n d lu n gs). Th e br a in h a s a n in cr edibly h igh
dem a n d for oxygen a n d h a s m in im a l st or a ge ca pa c-
it y. Oxygen depr iva t ion t h r ou gh ou t t h e body r esu lt s
in r edu ced cell m et a bolism a n d fu n ct ion . Th is, in
t u r n , for ces t h e cell t o u se a n a er obic m et a bolism . An -
a er obic m et a bolism lea ds t o t h e r a pid developm en t
of m et a bolic a cidosis. Th e body n eeds t o m a in t a in a
r ela t ively con st a n t pH for opt im a l cell fu n ct ion in g.
Cellu la r dea t h r esu lt s fr om ext r em e or pr olon ged
h ypoxia . Th e cer ebr a l effect s of ch r on ic h ypoxia ca n
r a n ge fr om r est lessn ess (a n ea r ly sign , pa r t icu la r ly
in ch ildr en ) t o let h a r gy, com a , a n d even t u a lly, dea t h .
Alt h ou gh h ypoxem ia ca n lea d t o h ypoxia , h ypoxia
ca n r esu lt even wh en t h er e is a dequ a t e a r t er ia l ox-
ygen . For exa m ple, a r edu ct ion in cir cu la t ion ca u sed
by a n a r t er ia l blocka ge ca n depr ive t h e cells dist a l t o
t h e blocka ge of oxygen even t h ou gh t h e t ot a l a m ou n t
of cir cu la t in g oxygen is a dequ a t e. In t h is ca se, cell
dea t h r esu lt s on ly in t h ose cells depr ived of oxygen .
Hypercapnia
H y p e r c a p n ia r efer s t o a st a t e of in cr ea sed ca r bon
dioxide in t h e blood. Ca r bon dioxide is m u ch m or e
ea sily diffu sed t h a n oxygen ; t h er efor e, h yper ca pn ia
pr esen t s on ly in ca ses of sever e a lveola r h ypoven -
t ila t ion a n d su bsequ en t h ypoxia . Con dit ion s t h a t
in h ibit ven t ila t ion or pr om ot e t r a ppin g of a ir in t h e
a lveoli con t r ibu t e t o t h e developm en t of h yper ca p-
n ia . Th e m a jor effect is r espir a t or y a cidosis ca u sed
by CO 2 r et en t ion . Th is ca n lea d t o elect r olyt e dist u r-
ba n ces, wh ich ca n a lt er ca r dia c con du ct ion a n d br a in
fu n ct ion , r esu lt in g in a n in effect ive h ea r t r h yt h m ,
com a , a n d dea t h . Th e det er m in a t ion of t h e level of
h yper ca pn ia r equ ir es m ea su r em en t of a r t er ia l blood
ga ses. Figu r e 15.2 su m m a r izes t h e pr ocesses fr om
ven t ila t ion a n d diffu sion t o h ypoxem ia , h ypoxia , a n d
h yper ca pn ia .
Stop and Consider
How does the body respond to low oxygen or
increased carbon dioxide in the blood or tissues?
GENERAL MANIFESTATIONS OF IMPAIRED
VENTILATION AND DIFFUSION
Alt h ou gh som e su bt le va r ia t ion s in m a n ifest a t ion s
exist a cr oss con dit ion s, t h e loca l a n d syst em ic clin -
ica l m a n ifest a t ion s of a lt er ed ven t ila t ion a n d diffu -
sion h a ve m a n y com m on a lit ies. Loca l m a n ifest a t ion s
(t h ose t r igger ed in t h e a ir wa ys a n d lu n g t issu es) a r e
m ost oft en r ela t ed t o in fla m m a t or y pr ocesses in r e-
spon se t o in ju r y. Th e in ju r y t r igger s va sodila t ion ,
374 C h a p t e r 15: Alt er ed Ven t ila t ion a n d Diffu sion

Ve ntilatio n Diffus io n
Goa l: a cquire O 2 ne e de d for ce ll me ta bolis m Goa l: excha nge O 2 + CO 2 a t the
re move CO 2 ne e de d to ma inta in pH a lve ola r ca pilla ry junction (ACJ )
& optima l ce ll functioning

Alte re d by: Alte re d by:

Inhibition of Incre a s e d thickne s s of ACJ

Obs truction or De cre a s e d pa rtia l pre s s ure
ne urona l s timula tion De cre a s e d us a ble s urfa ce
re s triction of a irflow De cre a s e d s olubility
+ me cha nics of bre a thing a re a of ACJ
Exa mple s : Exa mple s : Exa mple s : Exa mple s :
iction ug ove rdos e ys e ma
oca tion vica l ne rve da ma ge s ypothe rmia
e ction O 2 de priva tion

Blocke d tra ns fe r of O 2
Blocke d or inhibite d a irflow to circula tion + CO 2
to a tmos phe re

Hypoxe mia
Hypoxia
Hype rca pnia

Acidos is

Ce ll de ath

Figure 15.2. Concept map. Altered ventilation and diffusion.

in cr ea sed ca pilla r y per m ea bilit y, exu da t e for m a t ion , A cou gh wit h or wit h ou t excessive spu t u m pr odu c-
a n d pa in in t h e a ffect ed r egion of t h e a ir wa ys, lu n gs, t ion is a com m on clin ica l m a n ifest a t ion of a lt er ed
or ch est ca vit y. Pot en t ch em ica l m edia t or s r egu la t e ven t ila t ion a n d diffu sion . Th e cou gh r eflex is a pr o-
t h ese in fla m m a t or y pr ocesses a n d a r e r espon sible t ect ive m ech a n ism t h a t is t r igger ed t o r id t h e a ir-
for m a n y of t h e loca l a n d syst em ic m a n ifest a t ion s. wa ys of a n ir r it a t in g a gen t . An a cu t e cou gh t ypica lly
Th e followin g a r e pot en t ia l loca l m a n ifest a t ion s: la st s less t h a n 3 t o 8 weeks a n d is com m on ly a sso-
cia t ed wit h vir a l in fect ion s, sea son a l a ller gies, a s p i-
● Cou gh r a t io n (in h a lin g a for eign su bst a n ce in t o t h e lu n gs),
● E xcess m u cou s pr odu ct ion or pu lm on a r y em bolu s (a blocka ge t h a t occlu des a
● H em opt ysis pu lm on a r y blood vessel). A ch r on ic cou gh is on e t h a t
● Dyspn ea ext en ds beyon d 8 weeks a n d is com m on ly a ssoci-
● Use of a ccessor y m u scles a t ed wit h a st h m a , ga st r oesoph a gea l r eflu x (ga st r ic
● Ch est pa in con t en t s ba ck u p in t o t h e esoph a gu s a n d st im u la t e
● Ba r r el ch est t h e cou gh r eflex), or ch r on ic post n a sa l dr a in a ge.

In sm oker s, ch r on ic cou gh is a com m on m a n ifest a -
t ion of ch r on ic br on ch it is or lu n g ca n cer.
E xcess m u cou s pr odu ct ion of t h e a ir wa ys is r e-
la t ed t o t h e in fla m m a t or y r espon se. Th is m u cu s is
oft en t h e ir r it a t in g a gen t t h a t t r igger s t h e cou gh
r eflex a n d oft en pr ovides clu es t o t h e offen din g
a gen t or pr ocess. Th is con dit ion ca n be obser ved
by h a vin g t h e in dividu a l e x p e c t o r a t e , or spit
ou t , t h e m u cu s t h a t is eject ed du r in g t h e cou gh .
S p u t u m r efer s t o t h is expect or a t ed m a t er ia l.
P h le g m is a t er m t h a t descr ibes la r ge a m ou n t s of
spu t u m expect or a t ed fr om t h e or oph a r yn x. Specific
pa t h ogen s m a y pr odu ce spu t u m wit h a dist in ct color
or odor. For exa m ple, ba ct er ia l in fect ion s a r e oft en
ch a r a ct er ized by t h ick, pu r u len t spu t u m . P n eu m o-
cocca l pn eu m on ia m a y lea d t o a r u st -color ed, da r k
spu t u m . Typica lly, t h e on set of a vir a l a cu t e u pper
r espir a t or y in fect ion (a com m on cold) begin s wit h
clea r, t h in m u cu s. As ph a gocyt es m ove in t o t h e a r ea
of in fla m m a t ion t o wa r d off a n y in fect ion , t h ese cells
t h en die a n d a r e sh ed off a s yellow or gr een m u cu s.
H e m o p t y s is (cou gh in g u p blood fr om t h e r espir a -
t or y t r a ct ) is defin ed by t h e pr esen ce of r ed blood
cells in t h e spu t u m . Blood in t h e spu t u m is oft en sig-
n ifica n t a n d ca n be ca u sed by h ea vy exer t ion du r in g
cou gh in g (blood st r ea kin g wit h in t h e m u cu s) or fr om
t u ber cu losis, a t u m or, or m or e sever e t r a u m a . Wh en
com bin ed wit h edem a in t h e lu n g t issu es (pu lm o-
n a r y edem a ), t h e spu t u m oft en becom es n ot on ly
blood-t in ged bu t a lso fr ot h y or foa m y.
Difficu lt y br ea t h in g is a com m on r epor t in in -
dividu a ls wit h a lt er ed ven t ila t ion or diffu sion .
D y s p n e a is t h e su bject ive feelin g of sh or t n ess of
br ea t h or t h e in a bilit y t o get en ou gh a ir. Th e st im u -
lu s is ba sed on t h e pr esen ce of h ypoxem ia , h yper ca p-
n ia , a n d t h e su bsequ en t r edu ct ion in pH ; h owever,
t h e exa ct m ech a n ism is oft en u n kn own . On e t h eor y
is t h a t lu n g r ecept or s or ch em or ecept or s a ct on t h e
br a in a n d m u scles a ct ive in br ea t h in g t o st im u la t e
t h is sen sa t ion . Dyspn ea oft en lea ds t o cer t a in ph ys-
ica l a n d em ot ion a l r espon ses, su ch a s t h e ph ysica l
n eed t o sit in a n u pr igh t or st a n din g posit ion , a
con dit ion ca lled o r t h o p n e a , t o m a xim ize lu n g ex-
pa n sion . An in dividu a l m a y a lso u se a ccessor y m u s-
cles a n d dem on st r a t e n a sa l fla r in g t o pr om ot e t h e
wor k of br ea t h in g. R e t r a c t io n s a r e t h e pu llin g in
of a ccessor y m u scles u su a lly in t h e in t er cost a l, su b-
st er n a l, a n d su pr a cla vicu la r spa ces t o pr om ot e m or e
effect ive in spir a t ion . Alon g wit h posit ion a n d effor t
ch a n ges, in dividu a ls exper ien cin g a ir t r a ppin g m a y
per for m p u r s e d lip b r e a t h in g , a pr ocess of h oldin g
t h e lips pu cker ed t igh t ly t oget h er wh ile slowly ex-
h a lin g, t o m a in t a in posit ive a ir wa y pr essu r e in t h e
a lveoli t o m in im ize a ir t r a ppin g a n d pr om ot e expi-
r a t ion of ca r bon dioxide. E m ot ion a l m a n ifest a t ion s
of dyspn ea in clu de a n xiet y, a sen se of pa n ic, fr u st r a -
t ion , a n d a n ger.
I m p a ir e d Ve n t ila t io n 375
Ch est pa in ca n or igin a t e in t h e viscer a l a n d pa r i-
et a l pleu r a , t h e a ir wa ys, or t h e ch est wa ll. In fla m m a -
t or y pr ocesses wit h in t h e pleu r a oft en lea d t o pleu r a l
pa in , wh ich in cr ea ses wit h deep in spir a t ion , a n d is
oft en descr ibed a s sh a r p or st a bbin g pa in . Au s c u l-
t a t io n (list en in g wit h a st et h oscope) will r evea l a
gr a t in g, scr a t ch in g sou n d (ca lled a pleu r a l fr ict ion
r u b) wit h in spir a t ion . Cost och on dr it is, in fla m m a t ion
of on e or m or e cost a l ca r t ila ges, is a lso ch a r a ct er ized
by pa in in t h e a n t er ior ch est wa ll a n d m a y be t r ig-
ger ed by cou gh in g. Sim ila r ly, in fla m m a t ion of t h e
a ir wa ys, in t er cost a l m u scles, or a ccessor y m u scles
ca n a lso pr esen t a s loca lized pa in a n d be t r igger ed
by cou gh in g. Ch est pa in , a lt h ou gh fr equ en t ly of pu l-
m on a r y or igin , m u st be differ en t ia t ed fr om ca r dia c
pa in beca u se of t h e possibilit y of t h e in dividu a l ex-
per ien cin g a m yoca r dia l in fa r ct ion .
Ch a n ges in t h e sh a pe of t h e ch est wa ll, kn own a s
ba r r el ch est , ca n a lso occu r wit h ch r on ic lu n g dis-
ea se. Typica lly, t h e ch est wa ll sh a pe is a n ova l, in
wh ich t h e a n t er ior –post er ior (AP ) pla n e is n a r r ower
t h a n t h e t r a n sver se (T) pla n e (a n AP :T r a t io of a p-
pr oxim a t ely 1:2). Ch r on ic dila t ion a n d dist en t ion of
t h e a lveoli, a s seen in em ph ysem a , oft en r esu lt s in
a ba r r el ch est a ppea r a n ce, in wh ich t h e AP :T r a t io
becom es 1:1 (Fig. 15.3).
Ch a n ges in br ea t h in g pa t t er n s (see Ta ble 15.1)
a n d in t h e ch a r a ct er ist ics of br ea t h sou n ds a r e a lso
com m on loca l m a n ifest a t ion s of a lt er ed ven t ila t ion
a n d diffu sion . Th e sou n ds em it t ed by t h e lu n gs
du r in g in spir a t ion a n d expir a t ion a lso give clu es t o
t h e pr esen ce a n d ext en t of a lt er ed ven t ila t ion a n d
diffu sion . Ad v e n t it io u s , or a lt er ed, br ea t h sou n ds
a r e t ypica lly t h e r esu lt of eit h er a ir wa y con st r ict ion
or flu id a ccu m u la t ion (Box 15.1). Air wa y con st r ict ion
r esu lt s in wh eezin g br ea t h sou n ds. F lu id a ccu m u la -
t ion lea ds t o fin e or cou r se cr a ckles. Th e ch a r a ct er is-
t ics of t h ese sou n ds va r y ba sed on a n a t om ic loca t ion
(la r ger vs. sm a ller a ir wa ys) or t ype of secr et ion s
(t h in , wa t er y vs. t h icker m u cu s).
Syst em ic m a n ifest a t ion s of a lt er ed ven t ila t ion
a r e ca u sed by t h e effect s of h ypoxem ia , h ypoxia ,
a n d h yper ca pn ia . In t h e pr esen ce of in fla m m a t ion ,
syst em ic m a n ifest a t ion s, su ch a s fever, m a la ise, leu -
kocyt osis, a n d h igh er levels of cir cu la t in g pla sm a
pr ot ein s, ca n a pply t o pr oblem s of a lt er ed ven t ila -
t ion a n d diffu sion . Th e in t en sit y of t h e h ypoxic or
h yper ca pn ic r espon se is va r ia ble depen din g on t h e
ext en t of oxygen depr iva t ion a n d ca r bon dioxide r e-
t en t ion . Respon ses m a y in clu de:
● Du sky or cya n ot ic m u cou s m em br a n e color
● Ch a n ges in a r t er ia l blood ga ses
● Men t a l st a t u s ch a n ges
● F in ger clu bbin g
Ch a n ges in a r t er ia l blood ga ses, pH , Pa O 2 , a n d Pa CO 2 ,
a n d m en t a l st a t u s ch a n ges a r e discu ssed a bove a s
376 C h a p t e r 15: Alt er ed Ven t ila t ion a n d Diffu sion

B o x 15.1 Ad v e n t it io u s B r e a t h S o u n d s
Cr a ckles a r e sn a ppin g, poppin g, or bu bblin g sou n ds em it -
t ed du r in g in spir a t ion a n d expir a t ion a n d ca u sed by
flu id a ccu m u la t ion in t h e a ir ways; fin e cr a ckles a r e
h igh er pit ch ed wit h a sh or t er du r a t ion a n d sign ify flu id
in sm a ller a ir wa ys; coa r se cr a ckles a r e lou der a n d lower
pit ch ed a n d sign ify flu id in t h e la r ger a ir wa ys.
Ra les is a pr eviou sly u sed t er m t o descr ibe fin e cr a ckles
fr om flu id secr et ion s in t h e a ir wa ys; t h e t er m r a les h a s
been r epla ced wit h cr a ckles.
Wh eezin g is a con t in u ou s, h igh -pit ch ed, wh ist lin g sou n d;
it is sign ifica n t for obst r u ct ion or t igh t n ess in t h e sm a ll
a ir wa ys.
Rh on ch i is a t er m u sed t o descr ibe bot h low-pit ch ed wh eez-
in g sou n ds wit h a sn or in g qu a lit y (son or ou s wh eezin g)
wh en t h e a ir wa y n a r r owin g is in t h e la r ger a ir wa ys,
a n d h igh -pit ch ed wh eezin g sou n ds wit h a squ ea kin g
qu a lit y (sibila n t wh eezin g) wh en t h e a ir way n a r r owin g
is in t h e sm a ller a ir wa ys. Rh on ch i occu r wh en t h ick
m u cu s pa r t ia lly blocks t h e a ir wa ys.
S tr id or is a h a r sh , h igh -pit ch ed, cr ea kin g sou n d, wh ich is
A B
Norma l a dult Ba rre l che s t
sign ifica n t for obst r u ct ion in t h e u pper a ir way, espe-
cia lly of t h e t r a ch ea or la r yn x.
Dim in ish ed br ea th sou n d s is a t er m u sed t o descr ibe qu i-
et er br ea t h sou n ds t h a t a r e ba r ely a u dible; t h is is sign if-
ica n t for com plet e obst r u ct ion in on e or m or e a ir wa ys.
Absen t br ea th sou n d s sign ifies n o a ir m ovem en t t h r ou gh
t h e lu n gs.

Ch r on ic pr oblem s wit h ven t ila t ion a n d diffu sion

m ay r esu lt in clu bbin g of t h e fin ger s. C lu b b in g is
a pa in less en la r gem en t a n d fla t t en in g of t h e t ips of
A-P dia me te r A-P dia me te r
= 1 = 1 fin ger s or t oes ca u sed by ch r on ic h ypoxia (F ig. 15.4).
Tra ns ve rs e dia me te r 2 Tra ns ve rs e dia me te r 1
Alt h ou gh t h e exa ct m ech a n ism is u n kn own , clu b-
Figure 15.3. Comparison of expected anatomy and bar- bin g is con sist en t ly a ssocia t ed wit h ch r on ic con di-
rel chest alteration that occurs with emphysema. A: The t ion s t h a t dist u r b oxygen a t ion , su ch a s pr olon ged
expected chest cross-section. B: The barrel chest. obst r u ct ion or fibr osis of t h e a ir wa ys.

LABORATORY AND DIAGNOSTIC TESTS

effect s of h ypoxem ia , h ypoxia , a n d h yper ca pn ia . Det ect ion of a lt er ed ven t ila t ion a n d diffu sion is
Ch a n ges in skin a n d m u cou s m em br a n e color ca n ba sed on a t h or ou gh pa t ien t h ist or y a n d ph ysica l
a lso r esu lt fr om sever e h ypoxem ia . C y a n o s is is exa m in a t ion su ppor t ed by r eleva n t dia gn ost ic a n d
ca u sed by a gr ea t er pr opor t ion of desa t u r a t ed h em o-
globin in t h e blood, wh ich gives t h e blood a blu ish
h u e. Cen t r a l cya n osis, a pr oblem of low oxygen sa t -
u r a t ion in t h e a r t er ia l blood, oft en pr esen t s a s color
ch a n ges in t h e skin a n d m u cou s m em br a n es. In in di-
vidu a ls wit h da r k skin , t h e skin color ch a n ge is oft en
descr ibed a s a sh en or du sky. In ligh t skin , t h e color
is oft en descr ibed a s pa le or blu ish . Beca u se skin
color va r ies a m on g in dividu a ls, t h e m ost r elia ble
in dica t or of cen t r a l cya n osis on exa m in a t ion is t h e
fin din g of a blu ish color of t h e m u cou s m em br a n es.
In dividu a ls wit h per iph er a l cya n osis, a pr oblem of
slu ggish blood flow in t h e fin ger s a n d t oes, oft en
pr esen t wit h slu ggish ca pilla r y r efill (dem on st r a t ed Figure 15.4. Clubbing of the fingers. (From Crapo JD,
by a slow r et u r n of blood wh en t h e n a il bed is com - Glassroth J, Karlinsky JB, et al. Baum’s Textbook of
pr essed a n d t h en r elea sed) a n d a pa le or blu ish h u e Pulmonary Diseases. 7th ed. Philadelphia, PA: Lippincott
in t h e n a il beds. Williams & Wilkins; 2004.)
 I m p a ir e d Ve n t ila t io n 377

la bor a t or y t est s. Ta ble 15.2 pr es-

en t s com m on la bor a t or y a n d di-
a gn ost ic t est s per for m ed wh en
a n in dividu a l h a s a su spect ed
a lt er a t ion in ven t ila t ion a n d
diffu sion .
TREATING IMPAIRED
VENTILATION AND DIFFUSION
Th e t r ea t m en t of a n y h ea lt h
con dit ion is ba sed on det er m in -
in g t h e ca u se. Occa sion a lly, in
con dit ion s of a lt er ed ven t ila t ion
a n d diffu sion , t h e ca u se ca n n ot
be r ever sed. Th e pr in ciples t h a t
gu ide im pr ovin g ven t ila t ion a r e
ba sed on :
1. Rem ovin g obst r u ct ion s (i.e.,
for eign body, t u m or, edem a )
2. Rest or in g t h e in t egr it y of t h e
ch est wa ll, lu n gs, a n d ot h er
r espir a t or y st r u ct u r es
3. Decr ea sin g in fla m m a t ion
4. Decr ea sin g, t h in n in g, a n d
m ovin g m u cu s ou t of t h e
a ir wa y
5. Open in g a n d m a in t a in in g in -
t egr it y of t h e a ir wa ys
6. Su pplem en t in g oxygen
7. Con t r ollin g in fect iou s
pr ocesses
8. Usin g m ech a n ica l ven t ila t ion ,
a s in dica t ed
Ta ble 15.3 ou t lin es com m on
t r ea t m en t m oda lit ies for im -
pa ir ed ven t ila t ion a n d diffu sion .
Ta b le 15.2 La bor a t or y a n d Dia gn ost ic Test s Per for m ed t o Det er m in e
Alt er ed Ven t ila t ion a n d Diffu sion
La b or
D ia g n o s t ic Te s t P u r p o s e o t h e Te s t
P u lm on a r y fu n ct ion Br oa d r a n ge of n on in va sive t est s in clu din g spir om et r y,
t est s (P F Ts) lu n g volu m e m ea su r em en t s, a n d diffu sion ca pa cit y t h a t
in volve br ea t h in g in t o a t u be t h a t m ea su r es t h e pr es-
su r e exer t ed du r in g ven t ila t ion . Spir om et r y is u sefu l in
det ect in g obst r u ct ive lu n g disea se by m on it or in g h ow
well t h e lu n gs exh a le.
Ar t er ia l blood ga ses Det er m in es pr esen ce of a cid–ba se im ba la n ces a n d de-
(ABGs) gr ee of h ypoxem ia a n d h yper ca pn ia fr om a n a r t er ia l
blood sa m ple
P u lse oxim et r y Non in va sive t est t h a t m ea su r es oxygen sa t u r a t ion (see
F r om t h e La b)
Br on ch oscopy Dir ect visu a liza t ion of br on ch ioles; ca n be u sed t o t a ke
biopsy, t a ke spu t u m sa m ples, or r em ove for eign object s
fr om a ir way
Ra diogr a ph , CT, MRI Used t o det ect st r u ct u r a l pr oblem s, pr esen ce of con sol-
ida t ion , obst r u ct ion , or ca vit a t ion in t h e a ir wa ys a n d
lu n g t issu e
Nu clea r (V/Q) lu n g Det ect s pu lm on a r y em bolism (lu n g blocka ge) a n d lu n g
sca n disea se, su ch a s em ph ysem a a n d ch r on ic obst r u ct ive
pu lm on a r y disea se, by u sin g a n u clea r m edicin e ca m er a
a n d com pu t er im a gin g t o visu a lize t h e a m ou n t a n d dis-
t r ibu t ion of m in u t e a m ou n t s of r a dioa ct ive m a t er ia ls in -
spir ed in t o t h e lu n gs (V) or in ject ed in t o a vein (Q) t h a t
t h en flows t o a n d per fu ses t h e lu n g
Cu lt u r e a n d sen sit iv- Det er m in es pr esen ce a n d t ype of m icr oor ga n ism s in t h e
it y t est s blood a n d/or spu t u m ; t h e r esu lt s dict a t e t h e a ppr opr ia t e
a n t ibiot ic t r ea t m en t if in dica t ed
Th or a cen t esis Det er m in es t h e pr esen ce of a pleu r a l effu sion (excess
flu id in t h e pleu r a l spa ce) by in ser t in g a n eedle fr om
t h e ch est or ba ck in t o t h e lu n g pleu r a l spa ce; t h e flu id is
exa m in ed t o det er m in e t h e cellu la r a n d ch em ica l com po-
sit ion , t h e pr esen ce of m a lign a n t cells, a n d t h e pr esen ce
of m icr oor ga n ism s
V, ven t ila t ion (a ir flow in a n d ou t of t h e lu n gs); Q, per fu sion (blood flow t o t h e lu n gs); CT, com -
pu t ed t om ogr a ph y; MRI, m a gn et ic r eson a n ce im a gin g.

Ta b le 15.3 Alt er ed Ven t ila t ion a n d Diffu sion Tr ea t m en t P r in ciples

Tr e a t m e n t
An t i-in fla m m a t or y
m edica t ion s
H u m idifica t ion
Decon gest a n t s
An t it u ssives
Br on ch odila t or s
Me c h a n is m o Ac t io n
Redu ces in fla m m a t or y r espon se by a ct in g on
ch em ica l m edia t or s t o decr ea se excess blood flow,
swellin g, h ea t , r edn ess, a n d pa in t o t h e a ffect ed
a r ea
Moist en s a n d liqu efies secr et ion s t o a id in
expect or a t ion
Decr ea ses n a sa l con gest ion t h r ou gh va scu la r va -
socon st r ict ion , wh ich decr ea ses blood flow, r edu ces
exu da t e, a n d sh r in ks swollen m u cou s m em br a n es
Su ppr esses cou gh by in h ibit in g cou gh r ecept or s in
t h e m edu lla (som e h a ve loca l effect s a s well)
Open s a ir wa ys by r ela xin g br on ch ia l sm oot h
m u scles
Ap p r o p r ia t e U s e s
In fla m m a t ion t h a t im pin ges on ven t ila t or y
fu n ct ion su ch a s wit h a st h m a
Use in t h e pr esen ce of excessive, t h ick, or
st icky m u cu s
Use in t h e pr esen ce of excessive, t h ick, or
st icky m u cu s
Use wh en cou gh is excessive a n d in t er fer es
wit h sleep
Con dit ion s t h a t ca u se br on ch ocon st r ict ion :
a st h m a , COP D

(con tin u ed )
378 C h a p t e r 15: Alt er ed Ven t ila t ion a n d Diffu sion

Ta b le 15.3 Alt er ed Ven t ila t ion a n d Diffu sion Tr ea t m en t P r in ciples (con tin u ed )
Tr e a t m e n t
Ch est ph ysiot h er a py
An t im icr obia ls
Oxygen t h er a py
Mech a n ica l ven t ila t ion
Su r ger y
Me c h a n is m o Ac t io n
Usin g a pou n din g m ot ion or vibr a t ion on t h e ch est
t o ph ysica lly loosen t h ick secr et ion s
An t ibiot ics h a ve a r a n ge of m ech a n ism s focu sed
on dest r oyin g or r edu cin g im pa ct of ba ct er ia ; a n t i-
vir a ls m a y a lso be pr escr ibed a s a ppr opr ia t e
P r ovides dir ect oxygen su pplem en t a t ion
Life su ppor t m ea su r e t h a t pr ovides t h e wor k of
br ea t h in g
Su r gica l r em ova l of a bn or m a l t issu es or st r u ct u r es
wit h in t h e ch est (t h or a cot om y)
Ap p r o p r ia t e U s e s
Con dit ion s t h a t r esu lt in t h ick, t en a ciou s
secr et ion s su ch a s in cyst ic fibr osis
Ba ct er ia l in fect ion (a n t ibiot ics) su ch a s
ba ct er ia l pn eu m on ia
H ypoxia
Respir a t or y fa ilu r e
Mu lt iple u ses, in clu din g con fir m a t ion of t h e
dia gn osis of lu n g disea se, r epa ir of t h e lu n g,
r em ova l of lu n g t u m or s, or r em ova l of pu s
fr om pleu r a l spa ce (em pyem a )

COP D, ch r on ic obst r u ct ive pu lm on a r y disea se.

Modu le 3 C lin ic a l Mo d e ls

Th e followin g clin ica l m odels h a ve been select ed
t o a id in t h e u n der st a n din g a n d a pplica t ion of a l-
t er ed ven t ila t ion a n d diffu sion pr ocesses a n d effect s.
Com m on a lit ies a n d u n iqu e fea t u r es of ea ch clin ica l
m odel sh ou ld be n ot ed wh en r ea din g t h is sect ion .
Pneumonia
P n eu m on ia is select ed a s a clin ica l m odel t o dem on -
st r a t e t h e im pa ct of a com m on a cu t e in fect iou s
pr ocess on ven t ila t ion a n d diffu sion . P n e u m o n ia
r efer s t o in fla m m a t ion of t h e lu n gs occu r r in g com -
m on ly in t h e br on ch ioles, in t er st it ia l lu n g t issu e, or
t h e a lveoli. Th e elder ly, t h e ver y you n g, a n d t h ose
in dividu a ls wh o sm oke or a r e im m u n osu ppr essed or
h ospit a lized a r e m ost a t r isk for developin g pn eu m o-
n ia . It is in t h e t op 10 lea din g ca u ses of dea t h in t h e
Un it ed St a t es.
PATHOPHYSIOLOGY
Micr oor ga n ism s, in clu din g ba ct er ia , vir u ses, a n d
fu n gi, spr ea d by r espir a t or y dr oplet s, a r e t h e m ost
com m on ca u se of pn eu m on ia . P n eu m on ia s a r e of-
t en dist in gu ish ed a s eit h er com m u n it y a cqu ir ed or
h ospit a l a cqu ir ed (n osocom ia l) depen din g on wh er e
t h e disea se wa s con t r a ct ed. Nosocom ia l pn eu m o-
n ia s, pa r t icu la r ly in t h e im m u n osu ppr essed in di-
vidu a l, t en d t o be m or e sever e a n d lea d t o a less
fa vor a ble pr ogn osis t h a n com m u n it y-a cqu ir ed pn eu -
m on ia s. Typica l com m u n it y-a cqu ir ed pn eu m on ia is
m ost com m on ly ca u sed by S tr eptococcu s pn eu m o-
n ia e, H a em oph ilu s in flu en za e, a n d S ta ph ylococcu s
species. At ypica l for m s of com m u n it y-a cqu ir ed
pn eu m on ia a r e ca u sed by Mycopla sm a pn eu m on ia e,
Legion ella , a n d Ch la m yd ia species. Th e in flu en za
vir u s is t h e m ost com m on vir a l pa t h ogen kn own t o
ca u se pn eu m on ia . Nosocom ia l, or h ospit a l-a cqu ir ed,
pn eu m on ia is m ost com m on ly ca u sed by in fect ion
wit h P seu d om on a s a er u gin osa or S ta ph ylococcu s
a u r eu s. In fect ion wit h a n oppor t u n ist ic fu n ga l in -
fect ion in t h e lu n gs, su ch a s wit h Ca n d id a a lbica n s
or P n eu m ocystis ca r in ii, in dica t es im m u n osu ppr es-
sion or im m u n odeficien cy. P n eu m on ia ca n a lso occu r
wh en br ea t h in g in it em s n ot in t en ded for t h e lu n gs,
su ch a s foods, flu ids, a n d st om a ch con t en t s, a con di-
t ion ca lled a spir a t ion pn eu m on ia .
In m a n y ca ses, t h e defen se m ech a n ism s in t h e
n a soph a r yn x a n d or oph a r yn x of t h e u pper r espi-
r a t or y t r a ct effect ively t r a p a n d expel m icr oor ga n -
ism s befor e ca u sin g in fect ion . For pa t h ogen s t h a t
h a ppen t o esca pe t h e cou gh r eflex a n d m u cocilia r y
bla n ket , m a cr oph a ges loca t ed in t h e a lveoli a r e oft en
a dequ a t e t o en gu lf a n d dest r oy t h e offen din g m icr o-
or ga n ism . Wh en t h ese defen se m ech a n ism s a r e in -
a dequ a t e, t h e in fla m m a t or y a n d im m u n e r espon ses
a r e t r igger ed, pa r t icu la r ly in t h e in t er st it ia l lu n g
t issu e a n d a lveoli. Th e in fla m ed a lveoli fill wit h exu -
da t e. Ot h er pr odu ct s of in fla m m a t ion (r ed blood cells
[RBCs], wh it e blood cells [WBCs], a n d fibr in ) a ccu -
m u la t e a s well a n d ca u se c o n s o lid a t io n , or a solid
m a ss in t h e lu n g t issu e. Th ese a r ea s of con solida t ion
a r e eviden t on r a diogr a ph a n d a r e oft en t h e key di-
a gn ost ic fea t u r e of t ypica l pn eu m on ia (Fig. 15.5).
Wit h t ypica l pn eu m on ia , t h e pr esen ce of a n ot h er
vir a l in fect ion , su ch a s in flu en za , pr om ot es a t t a ch -
m en t of t h e pn eu m ococca l ba ct er ia t o t h e r ecept or s
 C lin ic a l Mo d e ls 379

B o x 15.2 P o t e n t ia l C a u s e s o
R e s p ir a t o r y Fa ilu r e
Respir a t or y fa ilu r e ca n be a life-t h r ea t en in g con -
sequ en ce of:
● Im pa ir ed ven t ila t ion
■ Tot a l a ir way obst r u ct ion
■ H ea d in ju r y lea din g t o sever e h ypoven t ila t ion
■ Wea kn ess or pa r a lysis of r espir a t or y m u scles
■ Ch est wa ll in ju r y
● Im pa ir ed m a t ch in g of ven t ila t ion a n d per fu sion
● Ch r on ic obst r u ct ive pu lm on a r y disea se
■ At elect a sis
■ Sever e in fect ion
● Im pa ir ed diffu sion
■ P u lm on a r y edem a
■ Acu t e r espir a t or y dist r ess syn dr om e

a n d epit h elia l cells degen er a t e. Th e pn eu m ococ-

ca l ba ct er ia r elea se t oxin s t h a t con t r ibu t e t o cell
dea t h . E ven t u a lly t h e ba ct er ia a r e opson ized by
Figure 15.5. Chest radiograph in a 50-year-old patient WBCs, a yellow exu da t e for m s, t h ese exu da t es a r e
with pneumonia shows opacity characteristic of lung con- t h en a bsor bed, a n d r esolu t ion begin s.
solidation. (From Crapo JD, Glassroth J, Karlinsky JB, et al.
Th e gen er a l effect s of a lt er ed ven t ila t ion a n d
Baum’s Textbook of Pulmonary Diseases. 7th ed. Philadel-
diffu sion a pply t o pn eu m on ia : oxygen diffu sion is
phia, PA: Lippincott Williams & Wilkins; 2004.)
gr ea t ly im pa ir ed, h ypoxia set s in , m et a bolic a cido-
sis occu r s, a n d deh ydr a t ion m a y r esu lt . Deh ydr a t ion
is r ela t ed t o flu id losses t h r ou gh h yper ven t ila t ion
on t h e r espir a t or y epit h eliu m . Th e ba ct er ia ca n t h en a n d fever, a n d it is exa cer ba t ed by in a dequ a t e flu id
in fect t h e t ype II a lveola r cells. Th e pn eu m ococci in t a ke. Alt h ou gh m ost ca ses of pn eu m on ia r esolve
m u lt iply a lon g t h e a lveolu s a n d pen et r a t e t h e a lveo- wit h in 2 weeks wit h a ppr opr ia t e t r ea t m en t , in divid-
la r epit h eliu m , t h er eby m ovin g a cr oss t o in fect a dja - u a ls wit h pr eexist in g r espir a t or y disea se a r e m or e
cen t a lveoli. In con t r a st , a t ypica l pn eu m on ia ca u ses likely t o exper ien ce a det er ior a t ion of r espir a t or y
da m a ge oft en t h r ou gh im m u n e-m edia t ed m ech a - st a t u s, lea din g t o r espir a t or y fa ilu r e a n d dea t h .
n ism s r a t h er t h a n dir ect da m a ge ca u se by t h e ba ct e- R e s p ir a t o r y a ilu r e ca n r esu lt fr om a n y pr ob-
r ia . Th e spr ea d of in fect ion wit h a t ypica l pn eu m on ia lem t h a t sever ely a ffect s ven t ila t ion , ven t ila t ion -per-
is m or e likely t o spr ea d beyon d t h e loba r bou n da r ies fu sion m a t ch in g, or diffu sion . It ca n occu r qu ickly or
a n d is oft en bila t er a l. in sidiou sly. Box 15.2 ou t lin es m a jor ca u ses of r espi-
H ist ologic cha n ges in t he lungs dur ing t he pr ogr es- r a t or y fa ilu r e a n d r eleva n t exa m ples. Respir a t or y
sion of pneum on ia ca n be ca t egor ized in t hr ee st a ges: fa ilu r e r epr esen t s t h e fa ilu r e of t h e lu n gs t o a de-
qu a t ely oxygen a t e t h e cells of t h e body a n d r em ove
1. Recen t in fect ion sh ows r a pid fillin g of t h e a lve-
ca r bon dioxide. It is a life-t h r ea t en in g em er gen cy.
ola r ca pilla r ies wit h a fr ot h y, ser ou s, a n d blood-
Respir a t or y fa ilu r e ca n lea d t o a st a t e of a n o x ia , a
t in ged flu id.
2. A “r ed h epa t iza t ion ”
st a ge follows a n d is
m a r ked by t h e fillin g
of a lveoli wit h fibr in -
R E S E AR C H N O T E S
ou s exu da t es, wh ich Mechanical ventilation with gas has been a mainstay of treatment for severe altered ventila-
a ppea r a s a r ea s of dr y, tion. This approach can sometimes cause more harm than good by exacerbating lung injury
gr a n u la r, da r k-r ed lu n g through structural damage and release of inflammatory chemical mediators within the lung.
t issu e. For more than 40 years, researchers have been investigating methods to reduce a patient’s
3. Wit h in 72 h ou r s, t h e time on a mechanical ventilator without risking reintubation. In a recent Cochrane review,
“gr a y h epa t iza t ion ” researchers found that using noninvasive positive pressure ventilation (such as with a CPAP)
st a ge occu r s m a r ked as a weaning strategy for intubated adults with respiratory failure was an effective way to
by WBCs pa ckin g in t o reduce mechanical ventilation time and prevented reintubation. 1
t h e a lveoli a s RBCs
380 C h a p t e r 15: Alt er ed Ven t ila t ion a n d Diffu sion
t ot a l la ck of oxygen a t ion . Th e cells qu ickly becom e
h ypoxic a n d t h e blood ca n becom e a cidot ic. If n ot r e-
ver sed, dea t h ca n en su e wit h in m in u t es.
CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s r eleva n t t o pn eu m on ia in -
clu de su dden on set of fever, ch ills, cou gh , spu t u m
pr odu ct ion , fa t igu e, loss of a ppet it e, dyspn ea , t a ch y-
pn ea , t a ch yca r dia , pleu r it ic pa in , a n d a dven t it iou s
br ea t h sou n ds ca u sed by flu id a ccu m u la t ion in t h e
lu n gs (cr a ckles). Th ese m a n ifest a t ion s a r e r ela t ed t o
t h e in fla m m a t or y a n d in fect iou s pr ocesses. In a du lt s
(pa r t icu la r ly in t h e elder ly), h ea da ch e a n d even con -
fu sion ca n occu r.
DIAGNOSTIC CRITERIA
Dia gn osis is ba sed on a t h or ou gh pa t ien t h ist or y
a n d ph ysica l exa m in a t ion , n ot in g t h e ch a r a ct er is-
t ic clin ica l m a n ifest a t ion s. A com plet e blood cou n t
is per for m ed t o det er m in e a n eleva t ion in t h e WBC
cou n t , wh ich su ggest s ba ct er ia l in fect ion . A ch est
r a diogr a ph or possibly a t h or a cic CT sca n is a lso
n eeded t o iden t ify a r ea s of con solida t ion a n d t o r u le
ou t ot h er disea ses or com plica t ion s t h a t m a y pr esen t
wit h sim ila r sym pt om s, su ch a s b r o n c h ie c t a s is (ir-
r ever sible dila t ion a n d dest r u ct ion of t h e br on ch ia l
t r ee m ost oft en ca u sed by ch r on ic obst r u ct ion or in -
fect ion ), lu n g t u m or s, or h ea r t fa ilu r e.
Iden t ifyin g t h e ca u sa t ive m icr oor ga n ism is im -
por t a n t for dir ect in g t h e t r ea t m en t r egim en a n d for
pr edict in g t h e sever it y of disea se a n d pr ogn osis. Th is
is com plet ed t h r ou gh a Gr a m st a in a n d cu lt u r e a n d
sen sit ivit y t est s of expect or a t ed spu t u m . In a ddi-
t ion , cer t a in ch a r a ct er ist ics of spu t u m m a y su ggest
a specific pa t h ogen . For exa m ple, in dividu a ls wit h
pn eu m ococca l pn eu m on ia oft en pr esen t wit h bloody
or r u st -color ed, da r k spu t u m . In dividu a ls wit h in -
fect ion s ca u sed by H a em oph ilu s or P seu d om on a s
a r e likely t o expect or a t e gr een spu t u m . An a er obic
in fect ion s a r e t ypica lly fou l sm ellin g. P leu r a l flu id
m a y a lso be a spir a t ed via t h or a cen t esis a n d t est ed if
t h er e is a pleu r a l effu sion (flu id in t h e pleu r a l spa ce)
or em pyem a (lu n g a bscess).
Mon it or in g t h e ven t ila t ion a n d per fu sion st a t u s
of t h e in dividu a l wit h pn eu m on ia r equ ir es m ea su r e-
m en t of oxygen a t ion t h r ou gh t h e u se of pu lse oxim -
et r y a n d a r t er ia l blood ga ses. A n u clea r (V/Q) lu n g
sca n m a y a lso be n ecessa r y t o det er m in e ven t ila t ion
a n d per fu sion effica cy.
TREATMENT
Th e goa l of t r ea t m en t for pn eu m on ia is t o r est or e op-
t im a l ven t ila t ion a n d diffu sion . Th e pla n of ca r e, pa r-
t icu la r ly t h e loca t ion of t r ea t m en t (h ospit a l or h om e)
a n d t h e a ppr opr ia t e a n t ibiot ic, depen ds on t h e t ype of
pn eu m on ia (com m u n it y or h ospit a l a cqu ir ed), t h e se-
ver it y of disea se, t h e pr esen ce of com or bid con dit ion s,
a n d t h e t ype of pa t h ogen . For exa m ple, t h e in it ia l
a n t ibiot ic t o t r ea t com m u n it y-a cqu ir ed pn eu m on ia s
in low-r isk pa t ien t s is a m a cr olide, su ch a s a zit h r o-
m ycin . Ma cr olides h elp t o er a dica t e gr a m -posit ive
m icr oor ga n ism s, a lon g wit h Mycopla sm a a n d Legio-
n ella species. Com m u n it y-a cqu ir ed pn eu m on ia s in
h igh -r isk in dividu a ls (t h ose older t h a n 60 or wit h a
com or bid con dit ion ) wou ld be pr escr ibed a m a cr olide
a lon g wit h a n a n t ibiot ic t h a t pr ovides cover a ge of
gr a m -n ega t ive ba ct er ia . Sever e pn eu m on ia r equ ir es
h ospit a liza t ion t o pr ovide a dequ a t e oxygen t h er a py,
in t r a ven ou s a n t ibiot ics (if ba ct er ia l), a n d in t r a ve-
n ou s flu ids t o pr even t or r ever se deh ydr a t ion . Ch est
ph ysiot h er a py, deep br ea t h in g, a n d cou gh in g m a y
be n eeded t o h elp loosen secr et ion s a n d pr om ot e ex-
pect or a t ion of spu t u m . Tr ea t m en t m a y a lso in volve
fever m a n a gem en t a n d com for t m ea su r es.
Chronic Obstructive Pulmonary Disease
C h r o n ic o b s t r u c t iv e p u lm o n a r y d is e a s e (C O P D )
is a gen er ic t er m t h a t descr ibes a ll ch r on ic obst r u c-
t ive lu n g pr oblem s, in clu din g a st h m a , em ph ysem a ,
a n d ch r on ic br on ch it is, sepa r a t ely or in com bin a -
t ion . COP D is on e of t h e lea din g ca u ses of dea t h
wor ldwide.
COP D is pr im a r ily u sed t o den ot e t h e pr esen ce of
bot h em ph ysem a a n d ch r on ic br on ch it is (a n d, t o som e
ext en t , a st h m a ). In fla m m a t or y pr ocesses in bot h t h e
a lveoli a n d in t h e br on ch i/br on ch ioles ch a r a ct er ize
COP D. Th e disea se is pr ogr essive, u n r em it t in g, a n d
ir r ever sible, a lt h ou gh pr ogr ession ca n be slowed if
t r ea t m en t is im plem en t ed ea r ly in t h e cou r se of t h e
disea se. Alt h ou gh sm okin g h a s been im plica t ed in
t h e developm en t of COP D, a ppr oxim a t ely 10% t o
20% of t h ose a ffect ed h a ve n ever sm oked. Beca u se
of sign ifica n t lu n g r eser ves, sym pt om s m a y on ly
becom e a ppa r en t wh en lu n g fu n ct ion is a t or below
50%. In t h is sect ion , em ph ysem a , ch r on ic br on ch it is,
a n d a st h m a a r e discu ssed sepa r a t ely.
Emphysema
E m p h y s e m a is a n ir r ever sible en la r gem en t of t h e
a ir spa ces beyon d t h e t er m in a l br on ch ioles, m ost n o-
t a bly in t h e a lveoli, r esu lt in g in dest r u ct ion of t h e
a lveola r wa lls a n d obst r u ct ion of a ir flow. Th e m ost
n ot a ble ca u se of em ph ysem a is ch r on ic sm okin g,
a lt h ou gh in n on sm oker s, developm en t of em ph y-
sem a is oft en du e t o t h e gen et ica lly in h er it ed defi-
cien cy of a lph a 1 -a n t it r ypsin (AAT). Less com m on ly,

pu lm on a r y va scu la r da m a ge fr om t h e in solu ble
filler s (e.g., cor n st a r ch or cot t on fiber s) fou n d in in -
t r a ven ou s dr u gs (su ch a s m et h a don e or coca in e),
im m u n e deficien cy syn dr om es, or con n ect ive t issu e
disor der s (su ch a s Ma r fa n syn dr om e) ca n lea d t o t h e
developm en t of em ph ysem a .
PATHOPHYSIOLOGY
In ea r ly or m ild em ph ysem a , t h e pr im a r y sou r ce of
obst r u ct ion is t h e developm en t of in fla m m a t ion in
t h e sm a ll a ir wa ys dist a l t o t h e r espir a t or y br on ch i-
oles. If dia gn osed ea r ly, t h e in fla m m a t ion in t h e sm a ll
a ir wa ys ca n be r edu ced, t h er eby pr ovidin g som e r e-
lief fr om a ir wa y obst r u ct ion . In m oder a t e-t o-sever e
disea se, t h e loss of ela st ic r ecoil in t h e a lveoli is t h e
pr im a r y m ech a n ism of a ir flow obst r u ct ion . Th is is
n ot r ever sible. Va scu la r ch a n ges in t h e lu n gs de-
velop sim u lt a n eou sly a lon g wit h t h e a ir wa y obst r u c-
t ion . Th e in n er lin in g of t h e a r t er ies a n d a r t er ioles
t h a t per fu se t h e lu n gs becom e t h ick a n d fibr ot ic.
Th is fu r t h er con t r ibu t es t o a lveola r a n d ca pilla r y de-
st r u ct ion . Pa t t er n s of a lveola r dest r u ct ion ca n occu r
in t h e r espir a t or y br on ch ioles a n d spr ea d per iph er-
a lly, t er m ed cen tr ia cin a r , or u n ifor m ly dest r oy t h e
en t ir e a lveolu s, t er m ed pa n a cin a r . Cen t r ia cin a r em -
ph ysem a is t ypica lly a ssocia t ed wit h ch r on ic sm ok-
in g a n d pr im a r ily a ffect s t h e u pper h a lf of t h e lu n gs,
wh er ea s pa n a cin a r em ph ysem a occu r s in t h ose wit h
AAT deficien cy (Fig. 15.6).
Re s pira tory
Te rmina l bronchiole s
bronchiole
Alve oli
Chronic
infla mma tion
a nd fibros is
Ce ntrilobula r e mphys e ma
Figure 15.6. Types of emphysema. The acinus, the gas-exchanging structure of the lung distal to the terminal bronchi-
ole, consists of the terminal bronchiole, respiratory bronchioles, alveolar ducts, alveolar sacs, and alveoli. In centrilobular
(proximal acinar) emphysema, the respiratory bronchioles are mainly involved. In paraseptal (distal acinar) emphysema,
the alveolar ducts are mainly affected. In panacinar (panlobular) emphysema, the acinus is uniformly damaged.
C lin ic a l Mo d e ls 381
Chr on ic sm oking im pa ir s a lveola r funct ion t hr ou gh
t h e followin g ca sca de of event s:
1. In h a la t ion of sm oke t r igger s t h e in fla m m a t or y
r espon se.
2. Neu t r oph ils a n d la t er m a cr oph a ges a r e a ct iva t ed
a n d r et a in ed in t h e lu n g t issu e.
3. Neu t r oph ils a n d m a cr oph a ges r elea se pr ot eolyt ic
en zym es, su ch a s pr ot ein a ses a n d ela st a ses, t h a t
dest r oy com pon en t s of t h e ext r a cellu la r m a t r ix,
su ch a s ela st in , in t h e lu n gs.
4. Th e ela st icit y of t h e lu n g is sign ifica n t ly r edu ced
lea din g t o t h e in a bilit y of t h e a lveoli t o r ecoil a n d
r elea se CO 2 in t o t h e a t m osph er e.
E la st icit y is essen t ia l in t h e a lveoli. Loss of ela st ic-
it y a ffect s t h e a bilit y of t h e a lveoli t o con t r a ct a n d
m ove a ir ba ck ou t of t h e body. Th e a ir spa ces becom e
en la r ged a n d in effect ive. If t h e a lveola r wa lls col-
la pse, a ir r em a in s t r a pped in t h e a lveoli (F ig. 15.7).
Air t r a p p in g decr ea ses effect ive O 2 in t a ke a n d
especia lly CO 2 r elea se. Th e exper ien ce of a ir t r a p-
pin g is dem on st r a t ed t h r ou gh t a kin g a fu ll br ea t h
a n d r elea sin g h a lf of t h e a ir a n d t h en a ga in t a kin g a
fu ll deep br ea t h a n d r elea sin g h a lf of t h e a ir. Wh en
a per son t a kes a deep br ea t h a n d r elea ses on ly h a lf
of t h e a ir, h yper in fla t ion occu r s in t h e lu n gs. Th e a l-
veoli becom e fu r t h er st r et ch ed a n d con t in u e t o lose
ela st icit y. CO 2 is r et a in ed a n d blood pH is r edu ced.
Th e lu n gs r equ ir e pr ot ect ion a ga in st t h e dest r u c-
t ion im posed by pr ot eolyt ic en zym es. Th is is t h e
Alve ola r duct
S e ptum
Norma l a cinus
P a ra cina r e mphys e ma
382 C h a p t e r 15: Alt er ed Ven t ila t ion a n d Diffu sion
A B
Bronchiole
Alve oli
Ma xima l
e xpa ns ion
No rmal e xpiratio n Impaire d expiratio n
Figure 15.7. Elastic recoil in the alveoli. A: Unaffected
alveolus. B: Air trapping seen in emphysema caused by the
loss of alveolar elastic recoil.
pr im a r y r ole of a n t ipr ot ea se en zym es, pa r t icu la r ly
AAT, a n en zym e t h a t is syn t h esized by cells in t h e
lu n gs. Th is en zym e wor ks t o com ba t t h e dest r u c-
t ive en zym es fr om digest in g st r u ct u r a l pr ot ein s a n d
h elps t o m a in t a in t h e in t egr it y of t h e lu n gs. Wit h
em ph ysem a , a n im ba la n ce of t h e dest r u ct ive (pr o-
t eolyt ic) a n d pr ot ect ive (a n t ipr ot eolyt ic) en zym es
exist s, fa vor in g t h e dest r u ct ive. In sm oker s, lu n g
dest r u ct ion is a m a n ifest a t ion of excess pr ot ein a se
r elea se a n d a loss of a n t ipr ot ein a se defen ses wit h in
t h e lu n gs.
Th e developm en t of em ph ysem a in n on sm oker s is
m ost oft en r ela t ed t o t h e m a n ifest a t ion of a gen et ic
disor der a t t r ibu t ed t o a r edu ct ion or a bsen ce of a n -
t ipr ot ea se en zym es. In AAT deficien cy, t h e a ffect ed
in dividu a l h a s in h er it ed a n a u t osom a l-codom in a n t
disor der loca t ed on t h e lon g a r m of ch r om osom e
14. In codom in a n t disor der s, t h e ph en ot ype is ex-
pr essed in t h e in dividu a l wh o h a s in h er it ed t wo
equ a lly dom in a n t gen es. Th is gen et ic defect ca u ses
a n a cceler a t ion of t h e br ea kdown of cells a n d t is-
su es in t h e lu n gs wit h t h e ea r ly on set of pa n a cin a r
em ph ysem a .
CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s a r e r ela t ed t o obst r u ct ion of
t h e sm a ll a ir wa ys a n d a lveoli, ch r on ic h ypoxem ia ,
a n d h yper ca pn ia . Most pa t ien t s wit h em ph ysem a
h a ve sm oked h ea vily for 20 or m or e yea r s a n d pr es-
en t wit h a ch r on ic pr odu ct ive cou gh , m ost n ot a ble
u pon wa kin g in t h e m or n in g. Dyspn ea a n d wh eez-
in g m a y occu r wit h m in im a l exer t ion . As t h e dis-
ea se pr ogr esses, a ba r r el ch est develops beca u se of
ch r on ic h yper in fla t ion of t h e a ir wa ys. Pa t ien t s wit h
em ph ysem a com m on ly per for m pu r sed lip br ea t h in g
t o in cr ea se t h e pr essu r e in t h e a ir wa ys, t o pr even t
a lveola r wa ll colla pse, a n d t o a llow t h e a ir t o esca pe
t h e a lveoli. In sever e disea se, sim ple a ct ivit ies, su ch
a s br u sh in g on e’s t eet h , ca n ca u se t a ch ypn ea a n d r e-
spir a t or y dist r ess.
DIAGNOSTIC CRITERIA
Dia gn osis of em ph ysem a is ba sed on a t h or ou gh
pa t ien t h ist or y a n d ph ysica l exa m in a t ion , n ot in g
a sign ifica n t sm okin g h ist or y a n d ch a r a ct er ist ic
clin ica l m a n ifest a t ion s. E xpir a t or y a ir flow sh ou ld
be m ea su r ed u sin g pu lm on a r y fu n ct ion t est s. In
n on sm oker s wh o h a ve su spect ed em ph ysem a , AAT
levels ca n be m ea su r ed a n d will be fou n d t o be well
below t h e expect ed r a n ge. In gen er a l, in dividu a ls
wit h AAT deficien cy a n d a n in cr ea sed r isk for t h e
developm en t of em ph ysem a will h a ve 10% t o 15%
of t h e expect ed AAT level. P h ysica l exa m in a t ion in -
clu des a u scu lt a t ion of lu n g sou n ds a n d obser va t ion
of expir a t or y effor t wit h sim ple a ct ivit ies. Th e r espi-
r a t or y r a t e t en ds t o in cr ea se in pr opor t ion t o disea se
sever it y. Cya n osis a n d per iph er a l edem a m a y a lso
be obser ved. Ch est r a diogr a ph will sh ow sign s of
h yper in fla t ion .
P u lm on a r y fu n ct ion t est s a r e cr it ica l in t h e dia g-
n osis of em ph ysem a a n d t h e level of a ir flow obst r u c-
t ion . Spir om et r y a llows a det er m in a t ion of disea se
pr ogr ession a n d t h e r espon se t o t r ea t m en t . F E V1
is t h e m ost com m on t est t o det er m in e a ir flow ob-
st r u ct ion ; a pr olon ged for ced expir a t or y t im e (F E T)
gr ea t er t h a n 6 secon ds in dica t es sever e disea se. H y-
per ca pn ia , m ea su r ed in t h e a r t er ia l blood ga s pa n el,
is com m on ly obser ved wh en t h e F E V1 fa lls below
30% of t h e pr edict ed volu m e. For exa m ple, if a pa -
t ien t (ba sed on a ge, gen der, a n d h eigh t ) is expect ed
t o for cefu lly exh a le 4 L of a ir per secon d, h yper ca p-
n ia will pr esen t wh en for ced exh a la t ion expels less
t h a n 1.2 L of a ir per secon d. Th is in dica t es sever e
ou t flow obst r u ct ion . H ypoxem ia is oft en pr esen t in
ea r ly disea se a n d con t in u es t h r ou gh ou t t h e disea se
pr ogr ession ; h owever, h yper ca pn ia pr edom in a t es a s
t h e disea se pr ogr esses.
TREATMENT
Beca u se em ph ysem a is ir r ever sible, t h e goa ls of
t r ea t m en t a r e t o m a in t a in opt im a l lu n g fu n ct ion
in or der t o a llow t h e in dividu a l t o per for m t h e de-
sir ed a ct ivit ies of da ily livin g. Tr ea t m en t begin s
wit h sm okin g cessa t ion a n d m a y a lso in clu de dr u g
t h er a py (wit h da n a zol or t a m oxifen ) t o in cr ea se pr o-
du ct ion of AAT by t h e liver or by a dm in ist er in g ex-
ogen ou s AAT via in t r a ven ou s in fu sion or in h a la t ion .
Br on ch odila t or s, st er oid a n t i-in fla m m a t or y dr u gs,
m u colyt ic a gen t s (t o r edu ce t h ickn ess a n d pr om ot e
 C lin ic a l Mo d e ls 383

clea r a n ce of spu t u m ), a n d a n t ibiot ics a r e t h e m a in - PATHOPHYSIOLOGY

st a ys of t h er a py for in dividu a ls wit h em ph ysem a .
Su pplem en t a l oxygen is oft en r equ ir ed. Lu n g vol-
u m e r edu ct ion or lu n g t r a n spla n t a r e possible su r gi-
ca l t r ea t m en t m ea su r es.
Chronic Bronchitis
C h r o n ic b r o n c h it is is defin ed by t h e pr esen ce of a
per sist en t , pr odu ct ive cou gh wit h excessive m u cou s
pr odu ct ion t h a t la st s for 3 m on t h s or lon ger for t wo
or m or e con secu t ive yea r s. Th e ch r on ic br on ch it is la -
bel is a pplied on ly a ft er a ll ot h er pot en t ia l ca u ses
of ch r on ic cou gh a r e exclu ded. Th e ca u se of ch r on ic
br on ch it is is m ost com m on ly ch r on ic sm okin g or ex-
posu r e t o en vir on m en t a l pollu t a n t s t h a t ir r it a t e t h e
a ir wa ys.
Ch r on ic br on ch it is r esu lt s fr om sever a l ch a n ges in
t h e br on ch i a n d br on ch ioles of t h e lu n gs in r espon se
t o ch r on ic in ju r y in clu din g (Fig. 15.8):
● Ch r on ic in fla m m a t ion a n d edem a of t h e a ir wa ys
● H yper pla sia of t h e br on ch ia l m u cou s gla n ds a n d
sm oot h m u scles
● Dest r u ct ion of cilia
● Squ a m ou s cell m et a pla sia
● Br on ch ia l wa ll t h icken in g a n d developm en t of
fibr osis
Th e ch r on ic in fla m m a t or y pr ocess, m et a pla sia , fi-
br osis, a n d m u cou s gla n d h yper pla sia ca u se a ir wa y
defor m it ies a n d obst r u ct a ir flow by n a r r owin g t h e
a ir wa y lu m en a n d fu r t h er occlu din g t h is n a r r owed
lu m en t h r ou gh over pr odu cin g m u cu s. Th is is pa r-
t icu la r ly pr oblem a t ic in t h e sm a ller a ir wa ys a n d

Norma l
bronchia l
tube
He a lth y Bro n c h i

Lume n

Mucus
Cilia
Goble t ce ll

Mucus
gla nds

Na rrowe d
bronchia l
tube Ch ro n ic Bro n c h itis

Lume n
Exce s s ive
mucus
re te ntion
Ba cte ria
Da ma ge d
cilia
Enla rge d Incre a s e d
mucous gla nds numbe r of
goble t ce lls

Figure 15.8. In chronic bronchitis, irritants inhaled for a prolonged period inflame the tracheobronchial tree. The inflam-
mation leads to increased mucus production and a narrowed or blocked airway. As inflammation continues, the mucus-pro-
ducing goblet cells undergo hypertrophy, as do the ciliated epithelial cells that line the respiratory tract. Hypersecretion
from the goblet cells blocks the free movement of the cilia, which normally sweep dust, irritants, and mucus.
384 C h a p t e r 15: Alt er ed Ven t ila t ion a n d Diffu sion
a ccou n t s for m ost a ir wa y obst r u ct ion s. Th e loss of
cilia t ed epit h eliu m a llows fin e pa r t icles t o en t er
t h e a ir wa y ea sily a n d pr edispose t h e in dividu a l t o
in fect ion .
CLINICAL MANIFESTATIONS
Th e clin ica l m a n ifest a t ion s of ch r on ic br on ch it is
a r e oft en sim ila r t o t h a t of em ph ysem a beca u se t h e
t wo con dit ion s oft en occu r sim u lt a n eou sly. A ch r on ic
pr odu ct ive cou gh , oft en wit h pu r u len t spu t u m , is
fr equ en t . Dyspn ea occu r s wit h m in im a l exer t ion .
Ch r on ic br on ch it is lea ds t o a pr olon ged expir a t or y
ph a se a lon g wit h wh eezin g a n d cr a ckles u pon a u s-
cu lt a t ion of t h e lu n gs. H ypoxem ia , h yper ca pn ia , a n d
cya n osis a r e m or e com m on ly fou n d in t h ose wit h
ch r on ic br on ch it is com pa r ed wit h in dividu a ls wit h
em ph ysem a beca u se of t h e pr esen ce of excessive
br on ch ia l m u cu s a n d obst r u ct ed ven t ila t ion .
DIAGNOSTIC CRITERIA
Th e dia gn osis of ch r on ic br on ch it is is ba sed on t h e
clin ica l pr esen t a t ion of a per sist en t , pr odu ct ive
cou gh over a per iod of 3 m on t h s or m or e wit h in
t wo con secu t ive yea r s. A h ist or y of sm okin g is oft en
pr esen t a lon g wit h r ecu r r en t u pper a n d lower r espi-
r a t or y in fect ion s. Ar t er ia l blood ga ses m a y be sign if-
ica n t for h ypoxem ia a n d h yper ca pn ia . La bor a t or y
t est s m a y in dica t e polycyt h em ia (t h e over pr odu c-
t ion of RBCs) a s a com pen sa t or y m ea su r e t o com ba t
ch r on ic h ypoxem ia . As wit h em ph ysem a , pu lm on a r y
fu n ct ion t est s a r e per for m ed a n d dem on st r a t e a r e-
du ct ion in F E V1 a n d pr olon ged F E T. Spu t u m speci-
m en s a r e oft en exa m in ed a n d t est ed for t h e pr esen ce
of pa t h ogen s.
TREATMENT
As wit h em ph ysem a , t r ea t m en t of ch r on ic br on -
ch it is is a im ed a t a llevia t in g sym pt om s, im pr ovin g
a ir wa y a n d lu n g fu n ct ion , slowin g t h e pr ogr ession
of t h e disea se, a n d im pr ovin g over a ll qu a lit y of life.
Tr ea t m en t st r a t egies a r e m ost effect ive wh en im ple-
m en t ed ea r ly in t h e cou r se of t h e disea se. Sm okin g
cessa t ion is a cr it ica l com pon en t of su ccess, a s a r e
pu lm on a r y r eh a bilit a t ion , br on ch odila t or t h er a py,
st er oid a n t i-in fla m m a t or y dr u gs, m u colyt ic a gen t s,
su pplem en t a l oxygen wh en in dica t ed, a n d a n t ibi-
ot ic t h er a py a n d im m u n iza t ion s t o t r ea t a n d pr ot ect
a ga in st in fect ion .
Asthma
As t h m a is a ch r on ic in fla m m a t or y disor der of t h e
a ir wa ys t h a t r esu lt s in in t er m it t en t or per sist en t
a ir wa y obst r u ct ion beca u se of br on ch ia l h yper r e-
spon siven ess, in fla m m a t ion , br on ch ocon st r ict ion ,
a n d excess m u cou s pr odu ct ion . Th e developm en t of
a st h m a oft en occu r s in ch ildh ood, bu t t h e con dit ion
ca n em er ge a t a n y poin t in t h e life spa n . Wor ldwide,
a r ou n d 18.7 m illion a du lt s h a ve a st h m a . 2 In dividu -
a ls m ost likely t o develop a st h m a in clu de t h ose con -
sider ed a t o p ic , or h a vin g a gen et ic pr edisposit ion t o
developin g h yper sen sit ivit ies.
PATHOPHYSIOLOGY
Alt h ou gh t h e exa ct ca u se is u n kn own , a st h m a is in -
cr ea sed in in dividu a ls wh o a r e fr equ en t ly exposed
t o en vir on m en t a l a ller gen s, su ch a s ciga r et t e sm oke
or du st m it es. Th is discu ssion of a st h m a com bin es
wh a t is kn own a bou t h yper sen sit ivit y r ea ct ion s a n d
t h e in fla m m a t or y pr ocess, beca u se bot h of t h ese con -
cept s pla y a m a jor r ole.
Th e in fla m m a t or y a n d im m u n e r espon se is oft en
st im u la t ed t h r ou gh exposu r e t o a n a ller gen . Th is a l-
ler gen va r ies ba sed on t h e in dividu a l a n d is oft en
r efer r ed t o a s t h e a st h m a “t r igger.” Com m on en vi-
r on m en t a l exposu r es t h a t a r e kn own t o r esu lt in
h yper sen sit ivit y r ea ct ion s a n d t r igger t h e in fla m m a -
t or y r espon se in clu de sm oke, du st , du st m it es, m old,
or a n im a l h a ir. Ot h er com m on t r igger s t h a t ca n
r esu lt in br on ch ospa sm in clu de exer cise, t em per a -
t u r e ext r em es, illn ess, a n d a n xiet y. E xer cise-in du ced
a st h m a (E IA) is a con dit ion in wh ich exer cise or
vigor ou s ph ysica l a ct ivit y t r igger s a cu t e br on -
ch ospa sm , cou gh in g, a n d wh eezin g in su scept ible
per son s.
Aft er a n in dividu a l is exposed t o t h e t r igger, a n
IgE -m edia t ed h yper sen sit ivit y r ea ct ion is im m edi-
a t e (F ig. 15.9A). IgE m a st cells a r e st im u la t ed t o r e-
lea se ch em ica l m edia t or s. Th ese ch em ica l m edia t or s
pr om ot e in cr ea sed edem a a n d su bsequ en t br on ch oc-
on st r ict ion in t h e a ir wa ys. F u r t h er pr odu ct s of in -
fla m m a t ion t h en m ove in t o t h e a r ea . Ma st cells ca ll
for t h a ddit ion a l ch em ica l m edia t or s, su ch a s h ist a -
m in e a n d pr ost a gla n din s. H ou r s la t er, leu kot r ien es
a r e r elea sed. Th ese ch em ica l m edia t or s st im u la t e
fu r t h er br on ch ospa sm , swellin g, a n d excessive m u -
cou s pr odu ct ion in t h e a ir wa ys (F ig. 15.9B). Th e la t e
in fla m m a t or y r espon se occu r s a ppr oxim a t ely 6 t o
24 h ou r s a ft er exposu r e t o t h e t r igger a n d is m a r ked
by a ir wa y edem a a n d t h e for m a t ion of m u cou s plu gs
fr om exu da t e a n d cell debr is in t h e a ir wa ys. Th e
m u cou s plu gs ca n t a ke weeks t o r esolve. Over t im e,
t h e cells of ch r on ic in fla m m a t ion , a lon g wit h eosin -
oph ils, in filt r a t e t h e a ir wa ys a n d ca u se dest r u ct ion
of t h e r espir a t or y epit h eliu m , sm oot h m u scle h yper-
pla sia , a n d n a r r owin g of t h e a ir wa ys. Th ese st r u c-
t u r a l ch a n ges, ca lled a ir wa y r em odelin g, st r on gly
a ffect t h e ir r ever sibilit y of t h e con dit ion .
 C lin ic a l Mo d e ls 385

Alle rge n

Ma s t ce lls
Re le a s e his ta mine, le ukotrie ne s, Bronchos pa s m
inte rle ukins, a nd pros ta gla ndins

Infiltra tion of infla mma tory ce lls

Airflow
Re le a s e cytokine s, inte rle ukins, limita tion
a nd othe r infla mma tory me dia tors

Airway infla mma tion Incre a s e d a irway re s pons ive ne s s

Ede ma Epithe lia l injury

Impa ire d mucocilia ry function

A

Unobs tructe d a irway

Blood ve s s e l

Engorge d blood ve s s e l

S mooth mus cle

Mus cle s pa s m

Airway obs tructe d

with mucous plug

Epithe lium

Ba s e me nt me mbra ne Thicke ning of ba s e me nt me mbra ne

B Unaffe c te d bro nc hio le Obs truc te d bro nc hio le

Figure 15.9. Asthma. A: Pathogenesis. (Modified from Porth CM. Pathophysiology: Concepts of Altered Health States.
7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004.) B: Narrowed bronchiole.
386 C h a p t e r 15: Alt er ed Ven t ila t ion a n d Diffu sion
CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s depen d on t h e st a t e of a ir-
wa y h yper r ea ct ivit y a n d in fla m m a t ion . In per iods
of r em ission , t h e in dividu a l is sym pt om fr ee. As a n
exa cer ba t ion is em er gin g, t h e in dividu a l m a y n ot
n ot ice a n y sym pt om s, a lt h ou gh pu lm on a r y fu n c-
t ion t est s begin t o declin e. In t im es of exa cer ba t ion ,
h yper r ea ct ivit y a n d in fla m m a t ion in t h e a ir wa ys
ca u ses wh eezin g, br ea t h lessn ess, ch est t igh t n ess,
excessive spu t u m pr odu ct ion , a n d cou gh in g, pa r t ic-
u la r ly a t n igh t or in t h e ea r ly m or n in g. Du r in g a n
a st h m a episode, t h e in dividu a l m a y exh ibit a n xiet y,
t a ch ypn ea , a n d t h e u se of a ccessor y m u scles. H yper-
ven t ila t ion in it ia lly lea ds t o r espir a t or y a lka losis;
h owever, com pen sa t ion is u su a lly t em por a r y, a n d
a cidosis develops beca u se of in effect ive expir a t ion .
E ven wit h a pa r t ia l a ir wa y obst r u ct ion , h ypoxia
qu ickly r esu lt s.
Stop and Consider
Based on the basic pathophysiologic processes,
construct a treatment plan for a person with
asthma. What environmental modifications would
you make? What would be the goals of pharma-
cologic therapy?
DIAGNOSTIC CRITERIA
Th e pa t ien t m a y r equ est a n eva lu a t ion for a st h m a
du r in g a t im e of r em ission or m a y pr esen t t o t h e
h ea lt h pr ofession a l in a cu t e dist r ess. Th e dia gn osis
in clu des eva lu a t in g sign s a n d sym pt om s a n d de-
t er m in in g t h e t r igger s t o det er m in e t h e likelih ood
t h a t t h e m a n ifest a t ion s a r e a ct u a lly a t t r ibu t a ble t o
a st h m a . Th e pa t ien t h ist or y is oft en sign ifica n t for
a t opy or a st h m a in t h e fa m ily. Th e pa t ien t m a y or
m a y n ot be cu r r en t ly exper ien cin g t h e ch a r a ct er ist ic
clin ica l m a n ifest a t ion s. P h ysica l fin din gs in dica t ive
of a st h m a in clu de:
● E viden ce of r espir a t or y dist r ess
● P u lsu s pa r a doxu s, a n exa gger a t ed decr ea se in
syst olic blood pr essu r e du r in g in spir a t ion
● Wh eezin g br ea t h sou n ds
● A pr olon ged expir a t or y ph a se
● At opic der m a t it is, eczem a , or ot h er a ller gic skin
con dit ion s t h a t m a y in dica t e h yper sen sit ivit ies
La bor a t or y fin din gs m a y r evea l eosin oph ilia (in -
dica t in g a ller gy) a n d a r t er ia l blood ga ses in dica t ive
of h ypoxem ia a n d h yper ca pn ia . P u lse oxim et r y is
u sefu l in scr een in g for h ypoxem ia a n d m a y be u sed
t o gr a de a st h m a sever it y. Spir om et r y is u sed t o de-
t er m in e t h e effect iven ess of a ir flow. Th e pea k expir a -
t or y flow r a t e (P E F R) is a com m on m ea su r e u sed t o
t r a ck for ced expir a t ion . Th e pea k flow m et er is a con -
ven ien t , por t a ble, in expen sive t ool. Mea su r em en t s
B o x 15.3 As t h m a C la s s i ic a t io n a n d
Tr e a t m e n t B a s e d o n S e v e r it y
● Mild in t er m it t en t
■ In t er m it t en t sym pt om s occu r r in g less t h a n on ce a
week wit h br ief exa cer ba t ion s
■ Noct u r n a l (n igh t t im e) sym pt om s occu r r in g less
t h a n t wice a m on t h
■ Asym pt om a t ic wit h n or m a l lu n g fu n ct ion bet ween
exa cer ba t ion s
■ No da ily m edica t ion n eeded
■ F E V1 or P E F R gr ea t er t h a n 80%, wit h less t h a n
20% va r ia bilit y
● Mild per sist en t
■ Sym pt om s occu r r in g m or e t h a n on ce a week bu t
less t h a n on ce a da y
■ E xa cer ba t ion s a ffect a ct ivit y a n d sleep
■ Noct u r n a l sym pt om s occu r r in g m or e t h a n t wice a
m on t h
■ Low-dose in h a led a n t i-in fla m m a t or y on e t o fou r
t im es per day a n d in h a led br on ch odila t or a s n eeded
■ F E V1 or P E F R gr ea t er t h a n 80% pr edict ed, wit h
va r ia bilit y of 20 t o 30%
● Moder a t e per sist en t
■ Da ily sym pt om s
■ E xa cer ba t ion s a ffect a ct ivit y a n d sleep
■ Noct u r n a l sym pt om s occu r r in g m or e t h a n on ce a
week
■ Mediu m -dose in h a led a n t i-in fla m m a t or y on e t o
fou r t im es per da y, a lon g-a ct in g br on ch odila t or, es-
pecia lly for n igh t t im e sym pt om s, a n d sh or t -a ct in g
br on ch odila t or a s n eeded
■ F E V1 or P E F R 60 t o 80% of pr edict ed, wit h va r i-
a bilit y gr ea t er t h a n 30%
● Sever e per sist en t
■ Con t in u ou s sym pt om s wit h fr equ en t exa cer ba t ion s,
n oct u r n a l a st h m a sym pt om s
■ P h ysica l a ct ivit ies lim it ed by a st h m a sym pt om s
■ H igh -dose in h a led a n d or a l a n t i-in fla m m a t or y, a
lon g-a ct in g br on ch odila t or, a n d sh or t -a ct in g br on -
ch odila t or a s n eeded
■ F E V1 or P E F R less t h a n 60%, wit h va r ia bilit y
gr ea t er t h a n 30%
over t im e ca n pr ovide in for m a t ion a bou t t h e pa t ien t ’s
r espon se t o t h er a py a n d ca n in dica t e t h e em er gen ce
of a n a st h m a exa cer ba t ion . Ch est r a diogr a ph m a y
dem on st r a t e h yper in fla t ion or in filt r a t es of t h e lu n g
fields a n d ca n be u sed t o r u le ou t ot h er sou r ces of
pleu r it ic ch est pa in , su ch a s pn eu m on ia or p n e u -
m o t h o r a x (t h e pr esen ce of a ir in t h e pleu r a l spa ce
t h a t ca u ses t h e lu n g t o colla pse). On ce dia gn osed,
a st h m a ca n t h en be cla ssified ba sed on sever it y, fr e-
qu en cy, a n d du r a t ion of disea se. Th e cla ssifica t ion
gu ides t r ea t m en t m ea su r es a r e fou n d in Box 15.3.
TREATMENT
Th e t r ea t m en t of a st h m a is com pr ised of fou r m a jor
com pon en t s:
1. Mon it or in g lu n g fu n ct ion t h r ou gh pea k flow
t est in g
 C lin ic a l Mo d e ls 387

2. Con t r ollin g en vir on -

m en t a l t r igger s
3. P h a r m a cologic t h e-
r a py to r ever se
in fla m m a t ion , br on -
ch ocon st r ict ion , a n d
m u cou s secr et ion
4. Pa t ien t edu ca t ion t o
fa cilit a t e a dh er en ce
t o t h e t r ea t m en t pla n
R E S E AR C H N O T E S
Alternative and complementary therapies have been implemented as possible treatments for
conditions of altered ventilation and diffusion. One group of researchers explored the effec-
tiveness of acupressure in promoting relaxation, decreasing anxiety, and alleviating dyspnea
in patients with COPD. In this randomized clinical trial, patients were either provided true
acupoint acupressure or a sham treatment. Those patients undergoing true acupoint acu-
pressure demonstrated significant improvements in pulmonary function, dyspnea scores,
6-minute walking distance measurements, and state anxiety scale scores. 3

A wr it t en a ct ion pla n
is a n essen t ia l a spect of
ca r e for t h e in dividu a l wit h a st h m a . Th e a ct ion pla n
ou t lin es m et h ods for a voidin g t r igger s a n d descr ibes
wh a t t o do wh en a n a st h m a exa cer ba t ion is occu r-
r in g. Th e pla n is ba sed on t h e m ea su r em en t of t h e
P E F R u sin g a pea k flow m et er. Th e in dividu a l det er-
m in es h is or h er h igh est P E F R, or “per son a l best ,”
over a sym pt om -fr ee per iod of 1 t o 3 weeks. Th e in -
a bilit y t o expir e a t or a bove 80% of t h e per son a l best
r equ ir es a t t en t ion beca u se a n a st h m a exa cer ba t ion
m a y be occu r r in g.
P h a r m a cologic t r ea t m en t s a r e pr escr ibed ba sed
on t h e cla ssifica t ion of a st h m a sever it y. Medica t ion s
u sed t o t r ea t a st h m a a r e divided in t o t wo m a jor ca t e-
gor ies: br on ch odila t or s a n d a n t i-in fla m m a t or y dr u gs.
In h a led bet a 2 -a dr en er gic a gon ist s (br on ch odila t or s),
su ch a s a lbu t er ol, pr ovide qu ick r elief of br on ch ocon -
st r ict ion a n d ca n pr even t E IA. An t ich olin er gics a n d
m et h ylxa n t h in es a r e ot h er dr u g ca t egor ies u sed t o
pr om ot e br on ch odila t ion . Th ese m edica t ion s r ela x
t h e sm oot h m u scles of t h e a ir wa y bu t do n ot effec-
t ively r edu ce a ir wa y in fla m m a t ion . Lon g-t er m con -
t r ol m edica t ion s, su ch a s glu cocor t icoids, cr om olyn ,
a n d leu kot r ien e m odifier s, a r e n eeded t o pr even t t h e
fr equ en cy a n d sever it y of t h e in fla m m a t or y com -
pon en t of a st h m a . Th ese m edica t ion s a lso pr even t
ch r on ic da m a ge t o t h e a ir wa ys. For exa m ple, in h a led
glu cocor t icoids su ppr ess t h e a ct iva t ion of m a st cells
a n d ot h er com pon en t s a ct ive in in fla m m a t ion a n d
decr ea se a ir wa y h yper r ea ct ivit y.
Ast hm a , a lthough m ost oft en r ever sible, ca n lea d t o
t ot a l a ir way obst r uct ion if t he in fla m m a t ion is sever e.
In s t a t u s a s t h m a t ic u s , or in t r a ct a ble a st hm a , br on -
chospa sm is not r ever sed by t h e pa t ien t ’s m edica t ions
or ot her m ea sur es. Obst r u ct ion lea ds t o decr ea sed ex-
pir a t ion , a ir tr a pping, hypoxem ia , hyper ca pn ia , a nd
a cidosis. Absen t lu ng sou nds a nd sign ifica n t eleva -
t ions in t he Pa CO 2 (a bove 70 m m H g) in dica t e a poor
pr ogn osis. St a t us ast h m a t icu s is life-t hr ea t en ing a n d
r equir es im m edia te em er gency t r ea t m ent .
Cystic Fibrosis
C y s t ic ib r o s is (C F ) is a n a u t osom a l r ecessive
disor der of elect r olyt es a n d su bsequ en t ly wa t er
t r a n spor t t h a t a ffect s cer t a in epit h elia l cells, su ch
a s t h ose lin in g r espir a t or y, digest ive, a n d r epr odu c-
t ive t r a ct s. CF m ost com m on ly a ffect s Ca u ca sia n s
of E u r opea n descen t a n d is t h e m ost com m on let h a l
in h er it ed disea se in t h a t gr ou p. In ciden ce a ppea r s
gr ea t est in h om ogen ou s popu la t ion s. Th is disor der
lea ds t o t h e pr odu ct ion of excessive a n d t h ick exo-
cr in e secr et ion s (e.g., m u cu s) lea din g t o obst r u ct ion ,
in fla m m a t ion , a n d in fect ion . CF is a lso a ssocia t ed
wit h im pa ir ed loca l im m u n e defen ses in t h e lu n gs a s
well a s pa n cr ea t ic in su fficien cy. Most a ffect ed in di-
vidu a ls a r e dia gn osed by 1 yea r of a ge. A sm a ll per-
cen t a ge of in dividu a ls exh ibit a m ild pr esen t a t ion
a n d a r e n ot dia gn osed u n t il a ft er 10 yea r s of a ge.
E n d-st a ge lu n g disea se is t h e m ost com m on ca u se
of dea t h .
PATHOPHYSIOLOGY
Cyst is fibr osis is ca u sed by a m u t a t ion of t h e CF (a lso
ca lled t h e cyst ic fibr osis t r a n sm em br a n e con du c-
t a n ce r egu la t or, or CF TCR) gen e loca t ed on t h e lon g
a r m of ch r om osom e 7. Beca u se CF is a n a u t osom a l
r ecessive disea se, a delet er iou s m u t a t ion is r equ ir ed
on bot h in h er it ed CF TCR a lleles for developm en t of
t h e disea se. Mor e t h a n 1,000 possible CF TCR m u -
t a t ion s, if fou n d on bot h a lleles in a n y com bin a t ion ,
h a ve been iden t ified. Con sist en t wit h a u t osom a l r e-
cessive in h er it a n ce, t h ose wit h on e m u t a t ed a llele
a n d on e n on m u t a t ed a llele a r e con sider ed ca r r ier s
a n d h a ve n o sym pt om s of t h e disea se.
Th e CF TCR m u t a t ion lea ds t o im pa ir ed elect r o-
lyt e t r a n spor t a t ion a cr oss epit h elia l cells on m u cosa l
su r fa ces (Fig. 15.10). For exa m ple, t h e effect ive fu n c-
t ion in g of ch lor ide ion ch a n n els depen ds on CF TCR,
wh ich en codes for a pr ot ein t h a t ser ves a s a ch lor ide
ch a n n el a n d is r egu la t ed by cyclic a den osin e m on o-
ph osph a t e (cAMP ). Mu t a t ion s in t h e gen e for CF TCR
lea d t o im pa ir m en t in t h e cAMP -r egu la t ed ch lor ide
t r a n spor t a cr oss m a n y differ en t t ypes of epit h elia l
cells on m u cosa l su r fa ces, su ch a s t h ose fou n d lin -
in g t h e r espir a t or y t r a ct , pa n cr ea s, bile du ct s, swea t
du ct s, a n d va s defer en s. Th e in a bilit y of t h ese epi-
t h elia l cells t o con du ct ch lor ide a n d t h er efor e t r a n s-
por t wa t er a cr oss t h e m u cosa l su r fa ces lea ds t o t h ick
388 C h a p t e r 15: Alt er ed Ven t ila t ion a n d Diffu sion

● Adh er en ce of t h e m u cu s t o t h e epit h eliu m wit h

im pa ir ed cilia r y a ct ion r equ ir ed t o clea r t h e m u -
Chromos ome 7 cu s fr om t h e a ir wa ys
Mu cou s plu ggin g, t h e for m a t ion of t en a ciou s secr e-
CFTR ge ne muta tion
t ion s, a n d a r edu ced a bilit y t o clea r t h e secr et ion s
a r e opt im a l con dit ion s for t h e gr owt h a n d r et en t ion
of ba ct er ia . P r ogr essive lu n g disea se oft en begin s
Re s pira tory tra ct
sh or t ly a ft er bir t h wit h t h e em er gen ce of a per-
s e cre tions
sist en t r espir a t or y in fect ion . Im pa ir m en t of loca l
im m u n e fu n ct ion lea ds t o fa ilu r e of opson iza t ion a n d
Airwa y e pithe lia l ph a gocyt osis a n d con t r ibu t es t o t h is per sist en t lu n g
Na + H2 O ce ll
Cl-
in fect ion wit h dist in ct ive ba ct er ia , su ch a s S ta ph -
ylococcu s a u r eu s a n d P seu d om on a s a er u gin osa .
De fe ctive Cl- s e cre tion with
e xce s s ive Na + a nd H2 O a bs orption
Th e pr ogr ession fr om br on ch it is t o br on ch iolit is, t o
br on ch iect a sis, a n d even t u a lly t o per m a n en t lu n g
da m a ge la r gely depen ds on a n in t en se, ch r on ic in -
fla m m a t or y r espon se dom in a t ed by n eu t r oph ils. Th e
Abnorma l thick a nd vis cid
sign ifica n ce of t h e excessive pr esen ce of n eu t r oph ils
re s pira tory tra ct s e cre tions
is t h e r elea se of pr ot ea ses by t h ese cells. P r ot ea ses
pr om ot e a n in t en se in fla m m a t or y r espon se, ca u se
De fe ctive mucocilia ry
dest r u ct ion of lu n g t issu e, in h ibit dest r u ct ion or
De ve lopme nt of a
microe nvironme nt tha t is cle a ra nce n eu t r a liza t ion of ba ct er ia , a n d pr om ot e a ddit ion a l
prote ctive of microbia l a ge nts m u cou s pr odu ct ion . Over t im e, t h e a ir wa ys a n d lu n g
t issu e in CF a r e ch a r a ct er ized by a ir t r a ppin g, h y-
per in fla t ion , a bscess for m a t ion , lu n g t issu e con sol-
Chronic a irwa y obs truction
ida t ion , per sist en t pn eu m on ia , lu n g t issu e fibr osis,
a nd ba cte ria l infe ction a n d cyst for m a t ion , h en ce t h e n a m e CF. E r osion of
lu n g t issu es a n d n ea r by br on ch ia l a r t er ies ca n lea d
t o h em opt ysis. E ven t u a lly, pu lm on a r y in volvem en t
Ne utrophil influx; ca n lea d t o r igh t -sided h ea r t fa ilu r e (cor pu lm on a le)
re le a s e of e la s ta s e a nd
a n d en d-st a ge lu n g disea se.
infla mma tory me dia tors
CF a lso h a s effect s t h a t go beyon d ven t ila t ion a n d
diffu sion . Redu ced ch lor ide secr et ion a n d r est r ict ed
De ve lopme nt of chronic bronchitis , wa t er in t o t h e in t est in a l t r a ct (a lon g wit h in fla m -
bronchie cta s is , re s pira tory fa ilure m a t ion , sca r r in g, a n d st r ict u r es) lea d t o obst r u ct ion
of in t est in a l con t en t s. Alon g wit h in t est in a l m ot ilit y
pr oblem s, m ost in dividu a ls wit h CF (90% t o 95%)
Figure 15.10. Pathogenesis of cystic fibrosis.
h a ve pa n cr ea t ic in su fficien cy. Pa n cr ea t ic in su ffi-
cien cy decr ea ses digest ion a n d t h e a bsor pt ion of
secr et ion s a n d obst r u ct ion in t h e r espir a t or y t r a ct , in t est in a l con t en t s. Th e r ole of pa n cr ea t ic en zym es,
pa n cr ea s, ga st r oin t est in a l t r a ct , swea t gla n ds, a n d digest ion , a n d a bsor pt ion is descr ibed in det a il in
ot h er exocr in e t issu es. Alt h ou gh t h e m a n ifest a t ion s Ch a pt er 17. Th e liver m a y a lso be a ffect ed in CF be-
a ppea r m ost ly r ela t ed t o im pa ir ed t r a n spor t of elec- ca u se t h e m u t a t ion of CF TCR lea ds t o im pa ir m en t
t r olyt es, t h e com plet e m ech a n ism of disea se, pa r t ic- of pa ssive t r a n spor t of ch lor ide a n d wa t er a cr oss t h e
u la r ly t h ose lea din g t o t h e com plica t ion s a ssocia t ed epit h elia l cells t h a t lin e t h e bilia r y du ct u les. Th is
wit h t h e lu n gs, is u n kn own . lea ds t o a n in cr ea sed viscosit y of bile. Bilia r y ob-
CF is m ost st r on gly a ssocia t ed wit h m u cou s plu g- st r u ct ion ca n lea d t o obst r u ct ive cir r h osis.
gin g, in fla m m a t ion , a n d in fect ion in t h e lu n gs wit h
r espir a t or y fa ilu r e a s t h e m ost com m on ca u se of
dea t h . Mu cou s plu ggin g is a r esu lt of: CLINICAL MANIFESTATIONS
● A gr ea t er volu m e of m u cu s pr odu ced by a la r ger Th e pr esen t in g clin ica l m a n ifest a t ion s, a ge a t dia g-
n u m ber of m u cou s-secr et in g cells in t h e a ir wa ys n osis, sym pt om sever it y, a n d r a t e of disea se pr ogr es-
● Air wa y deh ydr a t ion a n d t h icken ed m u cu s ca u sed sion va r y widely a m on g in dividu a ls wit h CF. Clin ica l
by im pa ir ed ch lor ide secr et ion , excessive sodiu m m a n ifest a t ion s a r e a ssocia t ed wit h t en a ciou s (t h ick)
a bsor pt ion , a n d decr ea sed wa t er con t en t in t h e secr et ion s lea din g t o r espir a t or y a n d ga st r oin t est i-
a ir wa y t issu es n a l im pa ir m en t . Recu r r en t r espir a t or y in fect ion s,

a lon g wit h a ch r on ic cou gh oft en a ccom pa n ied by
m u coid or pu r u len t spu t u m , a r e com m on m a n ifest a -
t ion s of CF. Cou gh in g ca n be for cefu l a n d ca n lea d t o
vom it in g. Ot h er r espir a t or y m a n ifest a t ion s in clu de
t a ch ypn ea , r ecu r r en t wh eezin g or cr a ckles, h em op-
t ysis, dyspn ea on exer t ion , ch est pa in , a n d r espir a -
t or y dist r ess wit h ch est r et r a ct ion s, cya n osis, ba r r el
ch est , r ecu r r en t sin u sit is, a n d t h e developm en t of
n a sa l polyps. F in ger clu bbin g ca n a lso be ca u sed by
ch r on ic h ypoxia .
Newbor n s m a y pr esen t wit h in t est in a l obst r u c-
t ion (a m econ iu m ileu s) a t bir t h wit h a dela yed or
a bsen t pa ssa ge of m econ iu m st ool. In fa n t s a n d ch il-
dr en m ost com m on ly dem on st r a t e in cr ea sed fr e-
qu en cy of la r ge, gr ea sy, m a lodor ou s st ools, wh ich
in dica t e fa t m a la bsor pt ion . Th is con dit ion ca n be a c-
com pa n ied by r ecu r r en t a bdom in a l pa in , dist en t ion ,
a n d poor a bsor pt ion of fa t -solu ble vit a m in s. Weigh t
loss or poor weigh t ga in is com m on . Addit ion a l clin i-
ca l m a n ifest a t ion s in clu de swea t a bn or m a lit ies a n d
excessive sa lt deplet ion . A ch ild, wh en kissed by a
ca r egiver, m a y h a ve a sa lt y t a st e t o t h e skin . J a u n -
dice, ga st r oin t est in a l bleedin g, a n d r ect a l pr ola pse
m a y occu r.
Ma les wit h CF a r e fr equ en t ly st er ile beca u se of
a n a bsen ce of t h e va s defer en s. Th e m a le ch ild m a y
a lso h a ve u n descen ded t est icles or h ydr ocele. Sec-
on da r y sexu a l developm en t is oft en dela yed in fe-
m a les wit h CF, a lt h ou gh fer t ilit y is m a in t a in ed or
som ewh a t decr ea sed.
DIAGNOSTIC CRITERIA
Th e dia gn osis of CF is ba sed on a t h or ou gh pa t ien t
h ist or y a n d ph ysica l exa m in a t ion , n ot in g t h e ch a r-
a ct er ist ic clin ica l m a n ifest a t ion s. Th e dia gn osis ca n
be con fir m ed by a swea t t est , wh ich will r evea l a
swea t ch lor ide con cen t r a t ion of 60 m E q/L or gr ea t er.
Va lu es of 40 t o 60 m E q/L a r e con sider ed bor der lin e,
a n d t h e t est m u st be r epea t ed beca u se va lu es in t h is
r a n ge ca n be in con sist en t wit h t h e dia gn osis in som e
pa t ien t s wit h t ypica l fea t u r es. Gen et ic t est in g m a y
be per for m ed t o det ect cer t a in CF TCR m u t a t ion s.
Th e iden t ifica t ion of t wo CF TCR m u t a t ion s wit h
a ssocia t ed clin ica l sym pt om s is dia gn ost ic; h owever,
n ega t ive r esu lt s on gen ot ype a n a lysis do n ot exclu de
t h e dia gn osis. Th e a bilit y t o sequ en ce t h e en t ir e
gen e will en a ble clin icia n s t o det ect a ll kn own m u t a -
t ion s in a n y given in dividu a l a n d will h a ve gr ea t er
r elia bilit y in dia gn osin g CF. Ot h er dia gn ost ic t est s,
su ch a s ch est a n d sin u s r a diogr a ph y a n d spu t u m
a n a lysis, ca n a lso con t r ibu t e t o t h e dia gn osis. Ch est
r a diogr a ph y will r evea l h yper in fla t ion a n d per ibr on -
ch ia l t h icken in g. Sin u sit is t h r ou gh ou t a ll sin u ses is
u n com m on in ch ildr en a n d you n g a du lt s, a n d it s
pr esen ce st r on gly su ggest s CF. Th e flu id obt a in ed
fr om a br on ch oa lveola r la va ge u su a lly sh ows a h igh
C lin ic a l Mo d e ls 389
per cen t a ge of n eu t r oph ils a n d t h e det ect ion of P seu -
d om on a s a er u gin osa su ppor t s t h e dia gn osis of CF in
a n in dividu a l wit h ou t t h e t ypica l pr esen t a t ion . Be-
ca u se ea r ly det ect ion a n d t r ea t m en t is cr it ica l in t h e
cou r se a n d pr ogn osis of disea se, n ewbor n scr een in g
h a s been r ecom m en ded in m a n y developed cou n t r ies.
TREATMENT
Tr ea t m en t goa ls for CF in volve m a xim izin g ven t ila -
t ion , diffu sion , a n d n u t r it ion t h r ou gh :
● Liqu efyin g a n d clea r in g t h e a ir wa ys of m u cu s
● Avoidin g a n d con t r ollin g r espir a t or y in fect ion s
● Redu cin g in fla m m a t ion a n d pr om ot in g br on ch o-
dila t ion in t h e a ir wa ys
● P r ovidin g or en cou r a gin g opt im a l n u t r it ion
t h r ou gh t h e u se of en zym e su pplem en t s t o r edu ce
m a la bsor pt ion , m u lt ivit a m in a n d m in er a l su pple-
m en t s, a n d a h igh -ca lor ie diet
● Ma n a gin g disea se com plica t ion s, su ch a s dia bet es
m ellit u s, bowel obst r u ct ion , fa t t y liver, bilia r y cir-
r h osis, a n d por t a l h yper t en sion
In dividu a ls wit h en d-st a ge lu n g disea se m a y con -
sider lu n g t r a n spla n t a t ion . Cu r r en t ly, t h e m edia n
a ge of su r viva l is 30 yea r s; m a les su r vive sign ifi-
ca n t ly lon ger t h a n fem a les, a lt h ou gh m a n y in divid-
u a ls wit h CF a r e livin g in t o t h eir 40s a n d 50s.
Acute Respiratory Distress Syndrome
AR D S is a con dit ion of sever e a cu t e in fla m m a t ion
a n d pu lm on a r y edem a wit h ou t eviden ce of flu id
over loa d or im pa ir ed ca r dia c fu n ct ion (F ig. 15.11).
Th is con dit ion wa s pr eviou sly r efer r ed t o a s a du lt
r espir a t or y dist r ess syn dr om e, bu t ARDS does occu r
in ch ildr en .
PATHOPHYSIOLOGY
Da m a ge t o t h e a lveola r epit h eliu m a n d va scu la r en -
dot h eliu m t r igger s t h e on set of sever e in fla m m a t ion .
In ju r y ca n r esu lt fr om in h a la t ion of excessive sm oke
or t oxic ch em ica ls, over wh elm in g lu n g in fect ion s,
a spir a t ion of ga st r ic con t en t s in t o t h e lu n gs, lu n g
t r a u m a , a n a ph yla xis, la ck of pu lm on a r y blood flow,
a n d ot h er con dit ion s t h a t im pa ir t h e a lveoli. Th e
pr esen ce of sepsis (ba ct er ia l in fect ion in t h e blood)
a n d t h e syst em ic in fla m m a t or y r espon se syn dr om e
(SIRS) a r e clin ica l con dit ion s a ssocia t ed wit h t h e de-
velopm en t of ARDS. In ARDS, t h e t im e fr om lu n g
in ju r y t o r espir a t or y dist r ess is a bou t 24 t o 48 h ou r s.
Th e in fla m m a t or y r espon se is con sist en t wit h t h e
pr ocess discu ssed in Ch a pt er 3. Ch em ica l m edia t or s
pr om ot e va sodila t ion a n d in cr ea sed ca pilla r y per-
m ea bilit y in t h e lu n gs. In fla m m a t or y cells, pr ot ein s,
390 C h a p t e r 15: Alt er ed Ven t ila t ion a n d Diffu sion

Alveolus

Capillary

Phase 1. Injury reduces blood flow to the lungs. Platelets

Phase 2. Those substances, especially histamine, inflame and dam-
aggregate and release histamine (H), serotonin (S), and
age the alveolocapillary membrane, increasing capillary permeabili-
bradykinin (B).
ty. Fluids then shift into the interstitial space.

Phase 3. As capillary permeability increases, proteins and fluids Phase 4. Decreased blood flow and fluids in the alveoli damage
leak out, increasing interstitial osmotic pressure and causing pul- surfactant and impair the cell’s ability to produce more. As a re-
monary edema. sult, alveoli collapse, impeding gas exchange and decreasing lung
compliance.

Phase 5. Sufficient oxygen can’t cross the alveolocapillary mem-

brane, but carbon dioxide (CO 2 ) can and is lost with every exha- Phase 6. Pulmonary edema worsens, inflammation leads to fibro-
lation. Oxygen (O 2 ) and CO 2 levels decrease in the blood. sis, and gas exchange is further impeded.

Figure 15.11. Phases of acute respiratory distress syndrome. (Courtesy Anatomical Chart Company.)

B o x 15.4 P o t e n t ia l C a u s e s o At e le c t a s is
At elect a sis, a con dit ion of colla pse a n d n on a er a t ion of t h e
a lveoli ca n h a ve a n u m ber of ca u ses, in clu din g:
● Com pr ession of t h e a lveoli by a m a ss or flu id a ccu -
m u la t ion , su ch a s wit h a t u m or or pleu r a l effu sion ,
wh ich exer t s pr essu r e on t h e lu n g a n d pr even t s a ir
fr om en t er in g t h e a lveoli
● Obstr u ction , wh ich pr even t s a ir fr om en t er in g t h e a ir-
ways a n d a lveoli; exist in g a ir is r ea bsor bed in t o t h e
t issu es a n d t h e a lveoli becom e em pt y
● Destr u ction of su r fa ct a n t , a s wit h t h e in fla m m a t or y
r espon se, in cr ea ses su r fa ce t en sion in t h e a lveoli a n d
pr om ot es colla pse
● F ibr osis, su ch a s wit h em ph ysem a , r est r ict s a lveola r
expa n sion a n d pr om ot es colla pse
a n d flu ids esca pe t h e in -
t r a va scu la r spa ce a n d F R O M T H E L AB
lea k in t o t h e in t er st it iu m
(lu n g t issu es) a n d a lve- Arterial blood gas analyses are the method of measuring arterial blood and determining lev-
ola r spa ce, r esu lt in g in els of pH, PaO2, and PaCO2. In respiratory failure, pH falls below 7.3, PaO2 falls below 50 mm
pu lm on a r y edem a , wh ich Hg (the expected range is 80 to 100 mm Hg), and PaCO2 rises above 50 mm Hg (the expected
da m a ges t h e a lveola r ca p- range is 35 to 45 mm Hg).
illa r y ju n ct ion . Da m a ge t o
t ype II a lveola r cells, in -
cr ea sed pr ot ein , a n d flu id a ccu m u la t ion disr u pt s t h e
pr odu ct ion of su r fa ct a n t r esu lt in g in a t e le c t a s is
(a lveola r n on a er a t ion a n d colla pse). Ot h er pot en t ia l
ca u ses of a t elect a sis a r e su m m a r ized in Box 15.4.
In it ia lly, oxygen diffu sion is gr ea t ly im pa ir ed, bu t
CO 2 is st ill a ble t o cr oss t h e a lveola r ca pilla r y ju n c-
t ion t o be expir ed. As t h e pr ocess of a lveola r im pa ir-
m en t a dva n ces, a h ya lin e m em br a n e for m s, a n d CO 2
r elea se is a lso in t er r u pt ed. Th e h ya lin e m em br a n e is
a t h in , clea r-ba sem en t m em br a n e t h a t is im per viou s
t o ga ses. Th is lea ds t o a st a t e of im pa ir ed ven t ila t ion
a n d diffu sion m a r ked by poor lu n g expa n sion , h y-
poxem ia , h yper ca pn ia , a n d a cidosis.
ARDS ca n be r ever sed if t h e sym pt om s a r e iden t i-
fied ea r ly. H ea lin g in volves r ea bsor pt ion of t h e a lve-
ola r edem a , r egen er a t ion of t h e epit h elia l cells a n d
t ype II a lveola r cells, a n d st r u ct u r a l r em odelin g of
t h e a ir wa y. In som e ca ses, t h e pa t ien t h a s a n u n com -
plica t ed a cu t e in fla m m a t or y r espon se wit h r a pid
r esolu t ion . Ot h er pa t ien t s exper ien ce a per m a n en t
loss of lu n g volu m e a n d fu n ct ion a t t r ibu t ed t o lu n g
t issu e edem a , n ecr osis, a n d a lveola r fibr osis in a f-
fect ed a r ea s. If u n t r ea t ed, dea t h ca n en su e wit h in
48 h ou r s. Th e m or t a lit y r a t e, a s a r esu lt of m u lt isys-
t em or ga n fa ilu r e, is a ppr oxim a t ely 30% t o 40%.
CLINICAL MANIFESTATIONS
E a r ly clin ica l m a n ifest a t ion s in clu de t a ch ypn ea ,
dyspn ea , r et r a ct ion s, cr a ckles ca u sed by flu id a ccu m u -
la t ion , a n d r est lessn ess. Som e pa t ien t s m a y pr esen t
C h a p t e r 15: Alt er ed Ven t ila t ion a n d Diffu sion 391
in t h e cou r se of disea se wit h ou t a n y sign s or sym p-
t om s except for m ild t a ch ypn ea . Wit h in 48 h ou r s, se-
ver e r espir a t or y dist r ess becom es a ppa r en t .
DIAGNOSTIC CRITERIA
Th e dia gn osis of ARDS is ba sed on a ca r efu l pa t ien t
h ist or y, ph ysica l exa m in a t ion , la bor a t or y, a n d im -
a gin g st u dies. A h igh in dex of su spicion is r equ ir ed
wh en en cou n t er in g a n y in dividu a l wh o h a s lu n g
in ju r y. Ar t er ia l blood ga ses oft en depict h ypoxem ia
wit h ea r ly r espir a t or y a lka losis qu ickly pr ogr ess-
in g t o h yper ca pn ia a n d r espir a t or y a lka losis. Blood
cu lt u r es m a y be n eeded t o det ect sepsis, t h e m ost
com m on ca u se of ARDS. Ch est r a diogr a ph is oft en
n or m a l ea r ly in t h e cou r se of disea se bu t t h en r e-
vea ls bila t er a l diffu se in filt r a t es a dva n cin g t o t ot a l
opa cit y a s t h e disea se pr ogr esses.
TREATMENT
Tr ea t m en t st r a t egies a r e su ppor t ive a n d focu sed
on r em ovin g t h e ca u sa t ive fa ct or s t r igger in g t h e in -
fla m m a t or y r espon se. Adm in ist r a t ion of 100% oxy-
gen is oft en wa r r a n t ed t o keep oxygen sa t u r a t ion s
a bove 90%. If t h e oxygen sa t u r a t ion s r em a in below
t h is level a n d t h e pa t ien t becom es fa t igu ed or a c-
idot ic, in t u ba t ion wit h m ech a n ica l ven t ila t ion m a y
be n ecessa r y. If m ech a n ica l ven t ila t ion is in effect ive
in m a in t a in in g oxygen sa t u r a t ion s a bove 90%, posi-
t ive en d-expir a t or y pr essu r e (P E E P ) is in st it u t ed t o
m a in t a in pr essu r e in t h e a ir wa ys du r in g expir a t ion
a n d pr om ot e r ein fla t ion of a lveoli. In pa t ien t s wit h
ARDS, m a in t en a n ce of a dequ a t e a lveola r ven t ila t ion
is a n im por t a n t m a r ker for su r viva l.
S U MMAR Y
● Th e pr ocess of ven t ila t ion in volves bot h a cqu ir in g
oxygen (in spir a t ion ) a n d r em ovin g ca r bon dioxide
(expir a t ion ) fr om t h e blood.
● Th e t r a n spor t of oxygen t h r ou gh t h e lu n gs is t h e
on ly m ech a n ism for a cqu ir in g oxygen .
● Oxygen is n ecessa r y for cellu la r m et a bolism ,
wh ich m ea n s t h a t for t h e cell t o expen d en er gy
392 C h a p t e r 15: Alt er ed Ven t ila t ion a n d Diffu sion
efficien t ly a n d per for m it s design a t ed fu n ct ion ,
oxygen m u st be pr esen t .
● Opt im a l cell fu n ct ion in g occu r s wit h in a n a r r ow
pH r a n ge, a n d t h e r elea se a n d r et en t ion of ca r bon
dioxide is on e m ech a n ism for m a in t a in in g t h is
ba la n ce.
● Oxygen a n d ca r bon dioxide a r e exch a n ged a t
t h e a lveola r ca pilla r y ju n ct ion s in t h e pr ocess of
diffu sion .
● Im pa ir ed ven t ila t ion is a pr oblem of blockin g a ir-
flow in a n d ou t of t h e lu n gs, t h er eby r est r ict in g
oxygen in t a ke a n d ca r bon dioxide r em ova l fr om
t h e body. Two m a jor m ech a n ism s a r e im plica t ed:
(1) com pr ession or n a r r owin g of t h e a ir wa ys a n d
(2) disr u pt ion of t h e n eu r on a l t r a n sm ission s
n eeded t o st im u la t e t h e m ech a n ics of br ea t h in g.
● Im pa ir ed diffu sion is a pr ocess of r est r ict in g t h e
t r a n sfer of oxygen or ca r bon dioxide a cr oss t h e
a lveola r ca pilla r y ju n ct ion . Beca u se t h e r a t e of
diffu sion depen ds on t h e solu bilit y a n d pa r t ia l
pr essu r e of t h e ga s, a n d su r fa ce a r ea a n d t h ick-
n ess of t h e m em br a n e, im pa ir ed ga s exch a n ge ca n
occu r wit h ch a n ges in a n y of t h ese pr oper t ies.
● An y sit u a t ion t h a t pr esen t s a dem a n d for h igh er
levels of oxygen or a n in cr ea se in cellu la r m et a b-
olism r equ ir es pu lm on a r y a da pt a t ion t o m a in t a in
h om eost a sis, beca u se oxygen depr iva t ion a n d ca r-
bon dioxide r et en t ion a ffect a ll cells in t h e body.
● Th e m a jor im plica t ion s of a lt er ed ven t ila t ion a n d
diffu sion in clu de h ypoxem ia , h ypoxia , h yper ca p-
n ia , a n d a cidosis.
● Loca l m a n ifest a t ion s of im pa ir ed ven t ila t ion a n d
diffu sion in clu de cou gh , m u cou s pr odu ct ion , spu -
t u m ch a n ges, dyspn ea , u se of a ccessor y m u scles,
a dven t it iou s lu n g sou n ds, ch est pa in , ba r r el ch est ,
a n d pu r sed lip br ea t h in g.
● Syst em ic m a n ifest a t ion s of a lt er ed ven t ila t ion
a r e ca u sed by t h e effect s of in fla m m a t ion , h y-
poxem ia , h ypoxia , a n d h yper ca pn ia . Th ese m a n -
ifest a t ion s in clu de fever, m a la ise, leu kocyt osis,
cya n osis, ch a n ges in a r t er ia l blood ga ses, m en t a l
st a t u s ch a n ges, a n d fin ger clu bbin g.
C AS E S T U D Y 15.1
A 6-m on t h -old ch ild h a s a n a cu t e r espir a t or y syn -
cyt ia l vir u s (RSV) in fect ion , wh ich is a n a cu t e vir a l
in fect ion in t h e lu n gs. Th in k a bou t wh ich clin ica l
m odel discu ssed in t h is ch a pt er is m ost r ela t ed t o
t h is pr ocess. F r om you r r ea din g a n d exper ien ce
r ega r din g in fect iou s pr ocesses a n d n ow a lt er ed
ven t ila t ion a n d diffu sion , a n swer t h e followin g
qu est ion s:
1. Wh a t pr ocess is m ost likely occu r r in g in t h is
ch ild’s body?
2. Wh a t a r e t h e pr oba ble ven t ila t ion a n d diffu sion
effect s of exposu r e t o t h is vir u s?
3. Wh a t wou ld you expect for clin ica l m a n ifest a t ion s?
4. Wh a t dia gn ost ic t est s cou ld be u sed?
5. Wh a t t r ea t m en t m ea su r es wou ld you a n t icipa t e?
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r n a l
a r t icle or Web sit e, su ch a s h t t p://em edicin e.m ed-
sca pe.com /a r t icle/971488-over view, t h a t det a ils RSV,
a n d con fir m you r pr edict ion s.
C AS E S T U D Y 15.2
J oa n a ccom pa n ies h er h u sba n d Da n t o t h e clin ic a n d
r epor t s t o t h e n u r se t h a t Da n ’s sn or in g seem s t o be
get t in g wor se over t h e pa st yea r. Sh e h a s r esor t ed
t o sleepin g in a n ea r by bedr oom wit h ea r plu gs. Da n
st a t es t h a t wh en h e wa kes u p h e doesn ’t feel t h a t
r est ed, a lt h ou gh h e does r efer t o h im self a s a “good
sleeper ” a n d st a t es h e is “a ble t o fa ll a sleep ea sily.”
Da n u n der goes a sleep st u dy a n d is dia gn osed wit h
obst r u ct ive sleep a pn ea . Th in k a bou t wh ich clin ica l
m odel discu ssed in t h is ch a pt er is m ost r ela t ed t o
t h is pr ocess. Fr om you r r ea din g a n d exper ien ce r e-
ga r din g obst r u ct ed ven t ila t ion , a n swer t h e followin g
qu est ion s:
1. Wh a t pr ocess is m ost likely occu r r in g in t h is
m a n ’s body?
2. Wh a t a r e t h e pr oba ble ven t ila t ion a n d diffu sion
effect s fr om obst r u ct ive sleep a pn ea ?
3. Wh a t wou ld you expect for clin ica l m a n ifest a t ion s?
4. Wh a t dia gn ost ic t est s cou ld be u sed?
5. Wh a t t r ea t m en t m ea su r es wou ld you a n t icipa t e?
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r-
n a l a r t icle or Web sit e, su ch a s h t t p://em edicin e.m ed
sca pe.com /a r t icle/295807-over view, t h a t det a ils ob-
st r u ct ive sleep a pn ea , a n d con fir m you r pr edict ion s.
C AS E S T U D Y 15.3
Pa t t y h a s ju st u n der gon e a bdom in a l h yst er ect om y
a n d, du e t o com plica t ion s, h a s been bed-bou n d for
a week. Sh e develops a n a br u pt on set of ch est pa in
a n d sh or t n ess of br ea t h . Sh e is t a ken t o t h e em er-
gen cy depa r t m en t a n d dia gn osed wit h a pu lm on a r y
em bolism , wh ich is a blocka ge in on e of h er blood
vessels in t h e lu n gs, m ost likely fr om a t h r om bu s
t h a t t r a veled fr om h er legs. Th in k a bou t wh ich clin -
ica l m odel discu ssed in t h is ch a pt er is m ost r ela t ed
t o t h is pr ocess. Fr om you r r ea din g a n d exper ien ce
r ega r din g ven t ila t ion a n d diffu sion , a n swer t h e fol-
lowin g qu est ion s:
1. Wh a t pr ocess is m ost likely occu r r in g in t h is
wom a n ’s body?
 C h a p t e r 15: Alt er ed Ven t ila t ion a n d Diffu sion 393

2. Wh a t a r e t h e pr oba ble ven t ila t ion a n d diffu sion a . Rela xa t ion of br on ch ia l sm oot h m u scle wit h
effect s fr om a pu lm on a r y em bolism ? dr y m u cou s m em br a n es
3. Wh a t wou ld you expect for clin ica l m a n ifest a t ion s? b. Con st r ict ion of t h e br on ch ia l sm oot h m u scle
4. Wh a t dia gn ost ic t est s cou ld be u sed? a n d a ir t r a ppin g
5. Wh a t t r ea t m en t m ea su r es wou ld you a n t icipa t e? c. Acu t e dest r u ct ion of lu n g t issu e
d. Con t r a ct ion of t h e ela st ic fiber s of t h e lu n g
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r-
n a l a r t icle or Web sit e, su ch a s h t t p://em edicin e
7. Wh ich of t h e followin g clin ica l m a n ifest a t ion s
.m edsca pe.com /a r t icle/300901-over view, t h a t det a ils
a r e r ela t ed t o h ypoxem ia ?
pu lm on a r y em bolism , a n d con fir m you r pr edict ion s.
a . Cya n osis
b. Cou gh
c. Ch est pa in
P R AC T I C E E XAM Q U E S T I O N S
d. H em opt ysis
1. Wh ich of t h e followin g does n ot a ffect diffu sin g
8. H ow wou ld you kn ow you h a ve h ypoxem ia ?
ca pa cit y?
a . Ra diogr a ph
a . Th e pa r t ia l pr essu r e of oxygen a n d ca r bon
b. Mea su r e t h e pa r t ia l pr essu r e of oxygen in
dioxide
blood
b. Th e a lveola r su r fa ce a r ea
c. Mea su r e t h e pa r t ia l pr essu r e of ca r bon diox-
c. Th e den sit y of t h e a lveola r m em br a n e
ide in blood
d. Th e volu m e of a ir in t h e a t m osph er e
d. All of t h ese det ect h ypoxem ia
2. Tota l obst r u ct ion of t h e a ir wa y by a spir a t ed m a -
9. Wh ich of t h e followin g ca n t r igger a cu t e r espir a -
t er ia l is m a n ifest ed by:
t or y dist r ess syn dr om e?
a . H oa r se cou gh
a . Sever e lu n g in fect ion
b. Ra pid loss of con sciou sn ess
b. In h a lin g t oxic fu m es
c. Dyspn ea
c. Aspir a t in g st om a ch con t en t s in t o t h e lu n gs
d. In fla m m a t ion of t h e m u cosa
d. All of t h ese
3. A r edu ced n u m ber of er yt h r ocyt es (RBCs) in t h e
blood r esu lt s in t h e followin g ch a n ge in t h e oxy- 10. Wh a t is t h e m a jor pr oblem in cyst ic fibr osis?
gen sa t u r a t ion (Sa O 2 ) of t h e blood: a . For m a t ion of cyst s in fibr ot ic t issu es
a . Th e Sa O 2 wou ld in cr ea se b. Pa n cr ea t it is
b. Th e Sa O 2 wou ld decr ea se c. Lu n g in ju r y
c. Th e n u m ber of RBCs will n ot a ffect t h e Sa O 2 d. E lect r olyt e a n d wa t er t r a n spor t
d. Th er e will be a decr ea se on ly if t h e osm ot ic
pr essu r e of t h e blood is a lso decr ea sed 11. Wh ich of t h e followin g disea ses is m ost likely t h e
ca u se of you r pa t ien t ’s ba r r el ch est ?
4. Wh ich is a m a jor ca u se of r espir a t or y fa ilu r e? a . E m ph ysem a
a . Aspir a t ion b. P n eu m on ia
b. At elect a sis c. Tu ber cu losis
c. Sepsis d. Acu t e r espir a t or y dist r ess syn dr om e
d. All of t h ese
12. Wh ich of t h e followin g is lea st likely t o be a pa r t
5. E m ph ysem a differ s fr om ch r on ic br on ch it is in
of t h e da ily r ou t in e for a pa t ien t wit h sever e
t h a t em ph ysem a :
a st h m a ?
a . Is ch a r a ct er ized by m u cou s pr odu ct ion a n d
a . In h a led br on ch odila t or s
in fla m m a t ion
b. In h a led cor t icost er oids
b. Obst r u ct s t h e la r ge a ir wa ys
c. Oxygen t h er a py
c. Obst r u ct s t h e a lveoli
d. Avoidin g t r igger s
d. Th er e a r e n o differ en ces bet ween t h e t wo
con dit ion s
13. If a pa t ien t get s a ir in h is or h er pleu r a l spa ce,
6. You h a ve a dm it t ed a 20-yea r-old m a le t o t h e t h is r esu lt s in :
em er gen cy r oom wit h a h ist or y of a st h m a . H e a . P n eu m on ia
is h a vin g a n a cu t e a st h m a a t t a ck a n d is wh eez- b. P n eu m ot h or a x
in g, figh t in g for a ir, h ypoxic, a n d a fr a id. Wh a t is c. P leu r it is
ca u sin g t h ese a cu t e sym pt om s? d. P let h or a
394 C h a p t e r 15: Alt er ed Ven t ila t ion a n d Diffu sion
14. Wh ich of t h e followin g pa t h wa ys best descr ibes
t h e pa t h oph ysiology of a cu t e r espir a t or y dis-
t r ess syn dr om e?
a . In ju r y–in fla m m a t ion –pu lm on a r y edem a –
a lveola r colla pse–h ypoxem ia –fibr osis
b. I n fe ct i on – e d e m a – fi b r os i s – h y p ox e m i a –
a lveola r colla pse–pu lm on a r y edem a
c. Gen et ic m u t a t ion –sodium t r a n spor t im pa ir ed–
m u cous st a sis–infect ion–hypoxem ia
d. Tr igger –in fla m m a t ion –a ir wa y con st r ict ion –
a lveola r colla pse–h ypoxem ia –fibr osis
D I S C U S S I O N AN D
AP P L I C AT I O N
1. Wh a t did I kn ow a bou t a lt er ed ven t ila t ion a n d
diffu sion pr ior t o t oda y?
2. Wh a t body pr ocesses a r e a ffect ed by a lt er ed ven -
t ila t ion a n d diffu sion ? Wh a t a r e t h e expect ed
fu n ct ion s of t h ose pr ocesses? H ow does a lt er ed
ven t ila t ion a n d diffu sion a ffect t h ose pr ocesses?
3. Wh a t a r e t h e pot en t ia l et iologies for a lt er ed ven -
t ila t ion a n d diffu sion ? H ow does a lt er ed ven t ila -
t ion a n d diffu sion develop?
4. Wh o is m ost a t r isk for developin g a lt er ed ven -
t ila t ion a n d diffu sion ? H ow ca n a lt er ed ven t ila -
t ion a n d diffu sion be pr even t ed?
5. Wh a t a r e t h e h u m a n differ en ces t h a t a ffect t h e
et iology, r isk, or cou r se of a lt er ed ven t ila t ion a n d
diffu sion ?
6. Wh a t clin ica l m a n ifest a t ion s a r e expect ed in t h e
cou r se of a lt er ed ven t ila t ion a n d diffu sion ?
7. Wh a t specia l dia gn ost ic t est s h elp det er m in e t h e
dia gn osis a n d cou r se of a lt er ed ven t ila t ion a n d
diffu sion ?
F in d a d d ition a l r esou r ces for th is ch a pter a t h ttp:th ePoin t.lww.com
8. Wh a t a r e t h e goa ls of ca r e for in dividu a ls wit h
a lt er ed ven t ila t ion a n d diffu sion ?
9. H ow does t h e con cept of a lt er ed ven t ila t ion a n d
diffu sion bu ild on wh a t I h a ve lea r n ed in t h e
pr eviou s ch a pt er s a n d in pr eviou s cou r ses?
10. H ow ca n I u se wh a t I h a ve lea r n ed?
R E SOUR CE S
Th e Am er ica n Lu n g Associa t ion is a n im por t a n t
sou r ce of in for m a t ion r ela t ed t o sever a l t ypes of lu n g
disea ses a n d in clu des cu r r en t r esea r ch u pda t es a t :
h t t p://www.lu n g.or g
Th e Cyst ic F ibr osis Fou n da t ion pr ovides gu idelin es,
r epor t s, a n d ot h er r esou r ces a t :
h t t ps://www.cff.or g/
Th e Globa l In it ia t ive for Ast h m a pr ovides gu ide-
lin es, r epor t s, a n d ot h er r esou r ces a t :
h t t p ://www.gin a s t h m a .or g/Gu id e lin es Re s ou r ces.
a sp?l1=2&l2=0
R e er en ces
1. Bu r n s KE , Mea de MO, P r em ji A, et a l. Non in va sive
posit ive-pr essu r e ven t ila t ion a s a wea n in g st r a t -
egy for in t u ba t ed a du lt s wit h r espir a t or y fa ilu r e.
Coch r a n e Da ta ba se S yst Rev. 2013;12:CD004127.
doi:10.1002/14651858.CD004127.pu b3.
2. Cen t er for Disea se Con t r ol a n d P r even t ion , Na t ion a l
Cen t er for H ea lt h St a t ist ics. Fa st St a t H ea lt h St a t ist ics
2015. h t t p://www.cdc.gov/n ch s/fa st a t s/a st h m a .h t m . Ac-
cessed Decem ber 19, 2015.
3. Wu H , Wu S, Lin J, et a l. E ffect iven ess of a cu pr essu r e
in im pr ovin g dyspn ea in ch r on ic obst r u ct ive pu lm on a r y
disea se. J Ad v Nu r s. 2004;45(3):252–259.
 Ch a pt er

Alt er ed Per fu sion 16

L E AR N I N G O U T C O ME S
1. Defin e a n d u se t h e key t er m s list ed in t h is ch a pt er.
2. E xpla in t h e r ole of per fu sion in m a in t a in in g h ea lt h .
3. Iden t ify t h e key r equ ir em en t s for effect ive per fu sion .
4. Det er m in e pr ocesses t h a t ca n a lt er per fu sion .
5. Iden t ify t h e com m on sign s a n d sym pt om s of a lt er ed per fu sion .
6. Descr ibe dia gn ost ic t est s a n d t r ea t m en t st r a t egies r eleva n t t o a lt er ed
per fu sion .
7. Apply con cept s of a lt er ed t issu e per fu sion t o select clin ica l m odels.

INTR ODUCTION
Th in k for a m om en t a bou t t h e m a gn it u de of a bea t in g h ea r t . You r h ea r t bea t s
a bou t 70 t im es a m in u t e, ever y m in u t e of ever y da y of ever y yea r of ever y
deca de of you r life. Wit h ou t fa il, t h e h ea r t bea t s, for wit h ou t it we wou ld die.
Wh a t is it a bou t t h e bea t in g h ea r t t h a t keeps u s a live? Wh a t ot h er fa ct or s pla y
a r ole in per fu sin g t h e body? Wh a t effect does r edu ct ion in per fu sion h a ve on
t h e body? Th is ch a pt er t a kes a ca r efu l look a t t h ese qu est ion s.

395
Pulmonary trunk, vein, and aorta in heart. Image © CLIPAREA
396 C h a p t e r 16: Alt er ed Per fu sion
Modu le 1 P e r u s io n
P e r u s io n is t h e pr ocess of for cin g blood or ot h er
flu id t o flow t h r ou gh a vessel a n d in t o t h e va scu la r
bed of a t issu e t o pr ovide oxygen a n d ot h er n u t r i-
en t s. Requ ir em en t s for effect ive per fu sion in clu de:
● Ad e q u a t e v e n t ila t io n a n d d i u s io n : Th e a bil-
it y t o br ea t h e in a n d t r a n spor t oxygen a cr oss t h e
ca pilla r ies is m a n da t or y for effect ive dist r ibu t ion
of oxygen t o t h e t issu es.
● I n t a c t p u lm o n a r y c ir c u la t io n : P u lm on a r y cir-
cu la t ion is r equ ir ed for t h e u pt a ke of oxygen fr om
in spir ed a ir.
● Ad e q u a t e b lo o d v o lu m e a n d c o m p o n e n t s : An
expect ed blood volu m e is r equ ir ed t o ca r r y oxy-
gen (on h em oglobin ) a n d m a in t a in blood pr essu r e.
Th e r ole of h em oglobin a n d oxygen sa t u r a t ion in
t h e blood is discu ssed in Ch a pt er 15.
● Ad e q u a t e c a r d ia c o u t p u t : An opt im a l st r oke
volu m e, a n opt im a l h ea r t r a t e, a n d a n efficien t
h ea r t r h yt h m a r e n eeded t o m a xim ize per fu sion
t o t h e t issu es.
● I n t a c t c a r d ia c c o n t r o l c e n t e r in t h e m e d u lla
o t h e b r a in : Th e ca r dia c con t r ol cen t er is n eeded
t o r egu la t e h ea r t r a t e a n d for ce of ca r dia c con -
t r a ct ion s, a n d t o det ect a n d r espon d t o ch a n ges in
blood pr essu r e.
● I n t a c t r e c e p t o r s : Recept or s pla y a m a jor r ole
in sen sin g ch a n ges in ca r dia c fu n ct ion a n d blood
pr essu r e, a n d t h ey pr ovide feedba ck t o t h e ca r dia c
con t r ol cen t er in t h e br a in .
● I n t a c t p a r a s y m p a t h e t ic a n d s y m p a t h e t ic
n e r v o u s s y s t e m s : Th e a u t on om ic n er vou s
Arte ria l ca pilla ry
Pe rfus ion without
ve ntila tion
Figure 16.1. Matching ventilation and perfusion. Optimal matching of ventilation and perfusion ( Center) . Perfusion
without ventilation ( Left) . Ventilation without perfusion ( Right) .
syst em is r espon sible for m edia t in g ch a n ges in
t h e ca r diova scu la r syst em ba sed on dem a n ds.
● I n t a c t c a r d ia c c o n d u c t io n : Con du ct ion of
im pu lses is essen t ia l in st im u la t in g ca r dia c
con t r a ct ilit y.
● I n t a c t c o r o n a r y c ir c u la t io n : Cor on a r y cir cu -
la t ion m a in t a in s per fu sion t o ca r dia c st r u ct u r es,
en a blin g t h e h ea r t t o dist r ibu t e oxygen a t ed blood
t o t h e r em a in der of t h e body.
● I n t a c t s y s t e m ic c ir c u la t io n : Th e cor on a r y a n d
syst em ic cir cu la t ion is design ed t o dist r ibu t e oxy-
gen a t ed blood t o t issu es a n d or ga n s.
● Ad e q u a t e t is s u e u p t a k e o o x y g e n : Oxygen -
depen den t cells a n d t issu es m u st be r ecept ive t o
oxygen a n d n u t r ien t s t o su r vive.
From Ventilation to Perfusion
Adequ a t e ven t ila t ion a n d diffu sion a r e r equ ir ed for
in t a ke a n d t r a n spor t of oxygen a n d t h e r em ova l of
ca r bon dioxide. Per fu sion wit h oxygen a t ed blood
ca n n ot occu r wit h ou t t h e in h a la t ion a n d diffu sion
of oxygen . On ce oxygen en t er s t h e lu n gs a n d m oves
a cr oss t h e a lveola r –ca pilla r y ju n ct ion , t h e pu lm o-
n a r y cir cu la t ion is cr u cia l in t a kin g u p a n d dist r ib-
u t in g t h e oxygen . Th er efor e, effect ive ga s exch a n ge
r elies on a r ea son a bly equ a l in t a ke of oxygen (ven t i-
la t ion ) a n d t h e m ovem en t of t h is oxygen (per fu sion )
fr om a ll a r ea s of t h e lu n gs t o t h e blood (Fig. 16.1).
Th e r ela t ion sh ip bet ween ven t ila t ion a n d per-
fu sion is expr essed a s t h e v e n t ila t io n –p e r u s io n
Bronchia l tube
Ve nous ca pilla ry
Alve olus
Optima l Ve ntila tion
without pe rfus ion

r a t io , wh ich is t ypica lly 0.8:0.9. Th is m ea n s t h a t t h e
r a t e of ven t ila t ion is u su a lly sligh t ly less t h a n t h e
r a t e of per fu sion . Th e la r gest volu m e of ven t ila t ion
a n d per fu sion is per for m ed in t h e lower lobes of t h e
lu n gs. In t h e lower lobes:
1. Ven t ila t ion is opt im a l beca u se t h e su r fa ce t en sion
for t h e a lveoli is lowest a n d t h e lu n gs a r e m ost
ea sily in fla t ed.
2. Per fu sion is opt im a l a s t h e blood pr essu r e t h r ou gh
t h e lower lobes a llows m a xim a l blood flow.
Ven t ila t ion –per fu sion is a lso a ffect ed by gr a vit y. Th e
lu n g t issu es t h a t a r e m ost depen den t , or closest t o
t h e gr ou n d, a r e t h e m ost ven t ila t ed a n d per fu sed.
Stop and Consider
Given that ventilation–perfusion is gravity
dependent, how does your body position impact
where the greatest volume of ventilation–
perfusion occurs?
Circulation
For effect ive per fu sion , blood vessels m u st deliver
oxygen a n d n u t r ien t s t o t issu es a n d r em ove wa st e.
Th ese st eps occu r t h r ou gh a pr ocess of cir cu la t ion .
In t h is ch a pt er, cir cu la t ion is discu ssed ba sed on
t h r ee cr it ica l, bu t in t er con n ect ed, pa t h wa ys:
● Th e pu lm on a r y cir cu la t ion , wh er e cir cu la t ion
t h r ou gh t h e lu n gs pr ovides t h e a bilit y t o t r a n sfer
oxygen fr om t h e a t m osph er e in t o t h e body
● Th e ca r dia c cir cu la t ion , wh er e blood flow t o t h e
h ea r t m u scle su ppor t s t h e h ea r t ’s wor k in pu m p-
in g oxygen a t ed blood t o t h e body
● Th e syst em ic cir cu la t ion , wh er e oxygen a n d n u t r i-
en t s a r e dist r ibu t ed t o ot h er body t issu es
E ffect ive cir cu la t ion depen ds on t h e pa t en cy of
blood vessels a n d on t h e a dju st m en t of t h e m icr o-
cir cu la t ion t o m eet t h e dem a n ds of t issu es. Ar t er ies
t r a n spor t oxygen a t ed a n d n u t r ien t -r ich blood t o t is-
su es; vein s t r a n spor t deoxygen a t ed blood a n d wa st e
pr odu ct s a wa y fr om t issu es for r em ova l ou t of t h e
body. Ar t er ioles, ca pilla r ies, a n d ven u les for m t h e
m icr ocir cu la t ion a r e t h e pr im a r y loca le for exch a n ge
of n u t r ien t s a t t h e cellu la r level. A la r ge n et wor k of
ca pilla r ies in a t issu e or or ga n in cr ea ses t h e su r fa ce
a r ea for exch a n ge of n u t r ien t s a n d wa st es a n d a l-
lows for in cr ea sed per fu sion . For exa m ple, t h e h ea r t ,
a n or ga n t h a t r equ ir es h igh levels of oxygen , h a s a n
ext en sive ca pilla r y n et wor k. Wh en dem a n ds on t h e
h ea r t in cr ea se, va sodila t ion occu r s a n d m or e blood
flow is ch a n n eled t o t h is or ga n . Sim ila r ly, oxygen
t r a n spor t t o ot h er or ga n s a dju st s r ela t ed t o dem a n ds,
su ch a s skelet a l m u scles du r in g exer cise. Cellu la r
P e r u s io n 397
dem a n ds, m ea su r ed by in cr ea sed cell m et a bolism or
en er gy expen dit u r e, in cr ea se per fu sion t o t h e cells.
Th is pr ocess in volves a com plex in t er a ct ion of ch em -
ica l m edia t or s, m et a bolic wa st e pr odu ct s, a n d n u cle-
ot ides t h a t a ct on t h e blood, en dot h elia l cells of t h e
vessels, sm oot h m u scle cells, a n d t h e ext r a cellu la r
m a t r ix t o open a n d widen ca pilla r y ch a n n els.
PULMONARY CIRCULATION
Th e pu lm on a r y cir cu la t ion for m s t h e con du it by
wh ich oxygen a n d ca r bon dioxide ca n be exch a n ged
bet ween t h e a t m osph er e a n d t h e body. Th e pu lm o-
n a r y cir cu la t ion com pr ises t h e r igh t side of t h e h ea r t
a n d t h e pu lm on a r y a r t er y, ca pilla r ies, a n d vein s.
Not e t h a t t h e pu lm on a r y a r t er y ca r r ies deoxygen -
a t ed blood t o t h e lu n gs a n d t h a t t h e pu lm on a r y vein s
ca r r y oxygen a t ed blood t o t h e left side of t h e h ea r t .
Th is por t ion of t h e cir cu la t ion fu n ct ion s a t a m u ch
lower pr essu r e t h a n t h e syst em ic cir cu la t ion . Blood
m oves slowly pa st t h e lu n gs t o a llow m a xim u m ga s
exch a n ge.
Stop and Consider
How would an ineffective right ventricle affect
the pulmonary and systemic circulation?
SYSTEMIC CIRCULATION
Th e syst em ic cir cu la t ion com pr ises a ll a r t er ies, ca p-
illa r ies, a n d vein s except t h ose of t h e pu lm on a r y
cir cu la t ion . Th e syst em ic cir cu la t ion fu n ct ion s a t a
m u ch h igh er pr essu r e t h a n t h e pu lm on a r y cir cu la -
t ion , beca u se blood m u st wor k a ga in st r esist a n ce t o
get t o per iph er a l t issu es. Th e syst em ic cir cu la t ion
is m ot or ed by t h e left side of t h e h ea r t , pa r t icu la r ly
t h e left ven t r icle, wh ich is t h e st r on gest pu m pin g
ch a m ber.
CORONARY CIRCULATION
Th e cor on a r y cir cu la t ion is con sider ed pa r t of t h e
syst em ic cir cu la t or y n et wor k bu t is sin gled ou t pr i-
m a r ily beca u se t h e h ea r t is t h e pu m p t h a t pu sh es
oxygen a t ed blood t o t h e r est of t h e body. Th e h ea r t is
t h er efor e con sider ed a vit a l or ga n , a n d per fu sion of
t h is or ga n is essen t ia l for life. Ca r dia c m u scle cells
r equ ir e a con st a n t su pply of oxygen a n d n u t r ien t s;
t h ese cells h a ve lit t le st or a ge ca pa cit y. Per fu sin g t h e
h ea r t , by con t in u ou sly pr ovidin g oxygen a n d n u t r i-
en t s, occu r s via t h e cor on a r y cir cu la t ion . Two m a jor
vessels, t h e r igh t a n d left cor on a r y a r t er y, br a n ch
dir ect ly off t h e a or t a t o per fu se t h e r igh t a n d left
side of t h e m yoca r diu m (m u scle) of t h e h ea r t . Th e
h ea r t is a lso per fu sed by ext en sive colla t er a l cir cu la -
t ion (a ccessor y a r t er ia l a n d ven ou s br a n ch es) st em -
m in g fr om t h ese m a jor vessels. Addit ion a l colla t er a l
398 C h a p t e r 16: Alt er ed Per fu sion

S upe rior Le ft S upe rior

Aortic pulmona ry
ve na cava ve na cava
a rch ve ins

Le ft a trium Right
pulmonary
Circumflex branch of veins
left coronary artery
Right Right
Anterior descending atrium
a trium branch of left
Right coronary artery Inferior
corona ry vena cava
a rte ry Le ft circumflex
bra nch
Right
Right ve ntricle Le ft ve ntricle ventricle
Corona ry s inus Pos te rior de s ce nding
bra nch of right
corona ry a rte ry
Ne a rby ca pilla rie s
ope n & expa nd Obs truction
to provide colla te ra l Los s of pe rfus ion
circulation to perfus e
the a re a beyond
the obs truction

Figure 16.2. Coronary circulation and the development of collateral circulation.

cir cu la t ion develops wh en a n in cr ea sed n eed exist s S ys te mic c irc ulatio n Pulmo nary c irc ulatio n
for blood flow t o a specific a r ea of t h e h ea r t , su ch a s
wit h gr ea t er ca r dia c dem a n ds or obst r u ct ion of blood
flow t o h ea r t t issu es (F ig. 16.2).
P ulmona ry
Stop and Consider S upe rior a rte ry
How would moderate-to-heavy aerobic exercise ve na cava
affect the development of collateral circulation Aorta
of the heart?

LA
Movement of Blood Through
LV
the Circulation RA P ulmona ry ve in
Mitra l va lve
RV
Th e u n iqu e st r u ct u r a l design of t h e h ea r t pr om ot es Aortic va lve
t h e m ovem en t of blood t h r ou gh t h e a r t er ies t o t h e Infe rior ve na cava
ca pilla r ies (Fig. 16.3). Th e h ea r t h a s t h r ee dist in ct Tricus pid va lve S e ptum
la yer s: P ulmonic va lve
● P e r ic a r d iu m : Th e ou t er cover in g of t h e h ea r t , Pe rica rdium Myoca rdium
wh ich h olds t h e h ea r t in pla ce in t h e ch est ca vit y, Endoca rdium
con t a in s r ecept or s t h a t a ssist wit h t h e r egu la t ion Figure 16.3. Layers of the heart and direction of continuous
of blood pr essu r e a n d h ea r t r a t e, a n d for m s a fir st blood flow through the valves and heart chambers. LA, left
lin e of defen se a ga in st in fect ion a n d in fla m m a - atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.
t ion . Per ica r dia l flu id is fou n d bet ween t h e la yer s
of t h e per ica r diu m , pr ovidin g a cu sh ion a n d lu br i-
ca n t t o m in im ize fr ict ion a s t h e h ea r t bea t s. ven t r icle wor ks h a r der t h a n ot h er h ea r t ch a m -
● My o c a r d iu m : Th e t h ick m u scu la r la yer of t h e ber s t o over com e t h e r esist a n ce of pu m pin g blood
h ea r t . Th e t h ickn ess of t h e m yoca r diu m va r ies t o t h e a or t a a n d t o t h e syst em ic cir cu la t ion . Th e
depen din g on loca t ion . Th e left ven t r icle oft en m yoca r diu m u n der goes h yper t r oph y if t h e h ea r t
h a s t h e t h ickest m yoca r dia l a r ea , beca u se t h is wor kloa d in cr ea ses.

● E n d o c a r d iu m : Th e in n er lin in g of t h e h ea r t t h a t
for m s a con t in u ou s la yer of en dot h eliu m t h a t
join s t h e a r t er ies a n d vein s t o t h e h ea r t , for m in g
a closed cir cu la t or y syst em .
Stop and Consider
What is pericarditis? What would be the problem
with this condition? What clinical manifestations
do you think would be present?
Th e h ea r t h a s fou r ch a m ber s: a r igh t a n d left
a t r iu m a n d a r igh t a n d left ven t r icle. Th e left a n d
r igh t sides of t h e h ea r t a r e sepa r a t ed by a sept u m .
Blood pa sses t h r ou gh va lves t h a t sepa r a t e t h e a t r ia
fr om t h e ven t r icles, a n d t h e ven t r icles fr om t h e pu l-
m on a r y a r t er y a n d t h e a or t a . Th e loca t ion s a n d ch a r-
a ct er ist ics of h ea r t va lves a r e depict ed in Figu r es
16.3 a n d 16.4. Th ese on e-wa y va lves a r e n eeded t o
pr om ot e for wa r d m ovem en t of blood.
Th e m ovem en t of blood follows a pr edict a ble, con -
t in u ou s pa t h . Th is discu ssion st a r t s wit h t h e r et u r n
of ven ou s blood t o t h e h ea r t , wh ich depen ds on skel-
et a l m u scle con t r a ct ion s a n d on e-wa y va lves wit h in
t h e vein s t h a t pr even t ba ckflow of blood. Blood t h a t
is r et u r n ed fr om t h e h ea d a n d a r m s t r a vels t h r ou gh
t h e su per ior ven a ca va , a n d blood t h a t is r et u r n ed
fr om t h e t r u n k a n d legs t r a vels t h r ou gh t h e in fe-
r ior ven a ca va . Bot h pa t h s lea d t o t h e r igh t a t r iu m .
F r om h er e, t h e blood goes t h r ou gh t h e t r icu spid
va lve t o t h e r igh t ven t r icle, t h r ou gh t h e pu lm on ic
va lve t o t h e pu lm on a r y a r t er y a n d t o t h e lu n gs. Th is
Aortic
(s e miluna r) va lve
P ulmonic
(s e miluna r)
va lve
Mitra l Tricus pid
(a triove ntricula r) (a triove ntricula r)
va lve va lve
Figure 16.4. Superior view of the heart. Characteristics of
semilunar versus atrioventricular valves.
P e r u s io n 399
deoxygen a t ed blood becom es oxygen a t ed t h r ou gh
t h e ven t ila t ion –per fu sion exch a n ge. Th e blood r e-
t u r n s t o t h e h ea r t via t h e pu lm on a r y vein t o t h e left
a t r iu m , t h r ou gh t h e bicu spid (m it r a l) va lve t o t h e
left ven t r icle, t h r ou gh t h e a or t ic va lve t o t h e a or t a ,
t h en t o t h e syst em ic cir cu la t ion , a n d a ga in r et u r n -
in g via ven ou s r et u r n t o t h e r igh t side of t h e h ea r t .
CARDIAC CYCLE
Th e m yoca r diu m of t h e h ea r t con t r a ct s a n d r ela xes,
for m in g t h e pu m pin g a ct ion of t h e h ea r t t h a t pr o-
m ot es per fu sion . Th e c a r d ia c c y c le r efer s t o on e
con t r a ct ion a n d on e r ela xa t ion ph a se. Con t r a ct ion s,
ca lled s y s t o le , for cefu lly m ove blood ou t of t h e ven -
t r icles. Rela xa t ion , r efer r ed t o a s d ia s t o le , a llows
blood t o fill t h e ven t r icles. Aft er t h e ven t r icles fill,
syst ole begin s wit h t h e closu r e of a t r ioven t r icu la r
(AV) va lves. Th e AV va lves a r e t h e bicu spid (m it r a l)
va lve a n d t h e t r icu spid va lve. AV va lve closu r es cor-
r espon d t o t h e fir st h ea r t sou n d. Tr a dit ion a lly, h ea r t
sou n ds a r e descr ibed a s “lu b du b.” AV va lve closu r es
a r e t h e fir st pa r t (“lu b”) of t h is descr ipt ion . Th e fir st
h ea r t sou n d is a lso r efer r ed t o a s S 1 .
Aft er AV va lve closu r e, t h e ven t r icles con t r a ct , a n d
pr essu r e in t h e ven t r icles t h en becom es gr ea t er t h a n
t h a t in t h e a or t a a n d pu lm on a r y a r t er y. Th e sem i-
lu n a r va lves, com posed of t h e a or t ic a n d pu lm on ic
va lves, open t o eject blood fr om t h e ven t r icles. On ce
t h e blood is eject ed a n d a t t h e en d of syst ole, t h e ven -
t r icles r ela x. P r essu r e is n ow gr ea t er in t h e a or t a
a n d pu lm on a r y a r t er y. Th e va lves pr even t blood
fr om flowin g ba ck in t o t h e ven t r icles. Ra pid closu r e
of t h e a or t ic a n d pu lm on ic va lves pr even t s ba ckflow
of blood. Closu r e of t h ese va lves cor r espon ds t o t h e
secon d h ea r t sou n d (“du b” of lu b du b). Th is secon d
h ea r t sou n d is a lso r efer r ed t o a s S 2 .
Du r in g dia st ole, pr essu r e a ga in dir ect s t h e va lves.
Th e ven t r icles a r e n ow r ela xed a n d em pt y. Blood
flow is a ccu m u la t in g, a n d pr essu r e becom es gr ea t er
in t h e a t r ia . Th e AV va lves open a n d t h e blood m oves
in t o t h e ven t r icles. Addit ion a l h ea r t sou n ds ca n
som et im es be h ea r d du r in g t h is t im e. S 3 m igh t be
h ea r d if t h er e is r a pid fillin g of t h e ven t r icle a n d t h e
ven t r icle is wea k, dist en ded, or ot h er wise im pa ir ed.
S 4 m a y be h ea r d du r in g a t r ia l con t r a ct ion .
CONDUCTION OF IMPULSES
Ca r dia c con t r a ct ion s r ely on t h e pa ssa ge of ion s
a n d elect r ica l im pu lses fr om on e m yoca r dia l cell
t o a n ot h er. Th ese im pu lses a r e gen er a t ed a n d con -
du ct ed a s a wea k elect r ica l cu r r en t wit h in t h e h ea r t
it self. Th is pr ocess is gen er a t ed t h r ou gh a ct ion
pot en t ia ls, or elect r ica l cu r r en t s m ovin g ch a r ged
ion s (specifica lly, sodiu m , ca lciu m , a n d pot a ssiu m )
a lon g t h e cell m em br a n e t h r ou gh ch a n n els. Gen er a l
400 C h a p t e r 16: Alt er ed Per fu sion

a ct ion pot en t ia ls a n d con du ct ion a r e discu ssed in R

Ch a pt er 10. In t h e ca r dia c cycle, t wo m a jor t ypes of ECG Trac ing
a ct ion pot en t ia ls (slow or fa st r espon ses) st im u la t e
ca r dia c con t r a ct ion a n d r ela xa t ion . Th ese t ypes of De lay in
AV node
a ct ion pot en t ia ls wor k in a n or ga n ized m a n n er t o
in du ce: T
P
1. Ra pid depola r iza t ion U
Ba s e line
2. E a r ly r epola r iza t ion
3. P la t ea u Q
4. Ra pid r epola r iza t ion De pola riza tion S Re pola riza tion
of a tria of ve ntricle s
5. A r est in g ph a se
A
De pola riza tion
Th e cell m em br a n e is t ypica lly fou n d t o h a ve a of ve ntricle s
posit ive n et ch a r ge on it s ou t er su r fa ce a n d n ega - B
t ive ch a r ge on it s in n er su r fa ce. Depola r iza t ion is a
ch a n ge in pola r it y, in wh ich ion s sh ift , r esu lt in g in
a su dden ch a n ge in volt a ge. In depola r iza t ion , fa st
sodiu m ch a n n els open , a llowin g a r a pid in flu x of so-
diu m (posit ively ch a r ged) ion s in t o t h e cell. As t h e
cell volt a ge pea ks, t h e fa st sodiu m ch a n n el closes
a n d t h e cell m oves in t o t h e ea r ly st a ge of r epola r-
iza t ion . Th is ea r ly r epola r iza t ion is followed by a
pla t ea u ph a se, in wh ich ca lciu m a n d sodiu m ion s S A node A
slowly en t er t h e cell t h r ou gh slow ca lciu m –sodiu m AV node
ch a n n els. Th is ca lciu m in flu x fa cilit a t es t h e pr o- B
Bundle of His P urkinje
lon ged con t r a ct ion of ca r dia c m u scle fiber s. Th e cell fibe rs
t h en m oves in t o r a pid r epola r iza t ion . Repola r iza t ion Right bundle
bra nch
is ba sica lly a r egr ou pin g ph a se, in wh ich t h e cell
m em br a n e becom es pola r ized a ga in wit h a posit ive
ch a r ge on t h e ou t er a n d a n ega t ive ch a r ge on t h e
in n er su r fa ce of t h e cell m em br a n e. In t h e ca se of Le ft bundle bra nch
ca r dia c m yocyt es, t h e sodiu m a n d ca lciu m ch a n n els Figure 16.5. Conduction system of the heart and action
close a n d sodiu m a n d ca lciu m n o lon ger m ove in t o potentials represented in the electrocardiogram (ECG) trac-
t h e cell. To r eest a blish t h e pola r it y wit h in t h e cell, ing. A: Depolarization of the atria. B: Depolarization
t h e cell m em br a n e becom es m or e per m ea ble t o po- of the ventricles. AV, atrioventricular; SA, sinoatrial.
t a ssiu m . Th is posit ively ch a r ged ion (K +) exit s t h e
cell. Th is pr ocess is r epea t ed a ga in a n d a ga in t o pr o-
An im por t a n t pa r a llel pr ocess t o t h e for m a t ion
du ce ca r dia c con t r a ct ion a n d r ela xa t ion t h a t is ch a r-
of a ct ion pot en t ia ls is t h e or der ly con du ct ion of
a ct er ist ic of t h e h ea r t .
im pu lses t h r ou gh t h e h ea r t . Th e con du ct ion sys-
Th e elect r ica l a ct ivit y im posed by ion s on ca r dia c
t em in volves specia lized m yoca r dia l cells in t h e
cells ca n be m ea su r ed by u sin g a n elect r oca r diogr a m
s in o a t r ia l (S A) n o d e , or pa cem a ker, wh ich gen er-
(E CG, a lso r efer r ed t o a s a n E KG). E lect r odes a r e
a t e a r h yt h m ic im pu lse in t h e a t r ia (see Fig. 16.5).
pla ced on t h e body in design a t ed a r ea s a n d t h e elec-
As m en t ion ed pr eviou sly, a ct ion pot en t ia ls con sist of
t r ica l a ct ivit y is t r a n sm it t ed t o a scr een . Figu r e 16.5
t wo t ypes of r espon ses: fa st a n d slow. Th e SA n ode
illu st r a t es t h e E CG ou t pu t a n d h ow t h is m ea su r e-
is st im u la t ed by t h e slow r espon se t h a t occu r s wh en
m en t cor r espon ds t o t h e a ct ion pot en t ia l. It a lso
t h e ca lciu m –sodiu m ch a n n els open . As st a t ed pr e-
dem on st r a t es h ow t h e let t er s P, Q, R, S, a n d T r epr e-
viou sly, t h is wa s wh er e st im u la t ion of a pr olon ged
sen t cer t a in poin t s on t h e E CG. Th ese let t er s cor r e-
con t r a ct ion ph a se of t h e h ea r t wa s gen er a t ed. Th e
spon d t o t h e followin g a spect s of t h e a ct ion pot en t ia l:
elect r ica l m essa ge t o con t r a ct t h en pa sses a lon g t h e
● P wa ve = t h e depola r iza t ion of t h e a t r ia via t h e m yoca r dia l cell pa t h wa y t o t h e a t r io v e n t r ic u la r
sin oa t r ia l n ode (AV) n o d e . Th e AV n ode, a s it s n a m e su ggest s, con -
● P –Q in t er va l = t h e depola r iza t ion of t h e AV n ode n ect s t h e con du ct ion of im pu lses bet ween t h e a t r ia
a n d bu n dle fiber s a n d ven t r icles. Th e im pu lse is slowed u pon r ea ch -
● QRS = depola r iza t ion of t h e ven t r icles in g t h e AV n ode t o a llow t h e a t r ia t o em pt y blood
● T = r epola r iza t ion of t h e ven t r icles com plet ely in t o t h e ven t r icles befor e st im u la t in g t h e
● U = r epola r iza t ion of P u r kin je fiber s ven t r icles t o con t r a ct . Th e AV n ode gen er a t es t h e

im pu lse t h a t t r a vels a lon g specia lized fiber s, kn own
a s t h e AV bu n dle a t t h e bu n dle of H is, for m in g t h e
left a n d r igh t bu n dle br a n ch es a n d cu lm in a t in g in t o
P u r kin je fiber s. Th ese fiber s con du ct elect r ica l im -
pu lses t h a t st im u la t e t h e ven t r icle t o con t r a ct . Blood
is t h en eject ed fr om t h e ven t r icles.
Stop and Consider
What would happen if the AV node conduction
was blocked? What would happen if the bundle
branch conduction was blocked?
CARDIAC OUTPUT
Mea su r em en t of t h e h ea r t ’s efficien cy t o pu m p op-
t im a l a m ou n t s of blood is r efer r ed t o a s ca r dia c
ou t pu t . C a r d ia c o u t p u t (C O ) depen ds on st r oke
volu m e (SV) a n d h ea r t r a t e (H R) a n d is expr essed
a s: CO = SV × H R. S t r o k e v o lu m e is t h e a m ou n t
of blood pu m ped ou t of on e ven t r icle of t h e h ea r t in a
sin gle bea t . H e a r t r a t e is t h e n u m ber of h ea r t bea t s
t h a t occu r in 1 m in u t e. Ca r dia c ou t pu t va r ies wit h
a ge, body size, a n d m et a bolic n eeds of body t issu es.
Th e a ver a ge ca r dia c ou t pu t in a du lt s is a bou t 3.5 t o
8.0 L/m in . Th is m ea n s t h a t ever y m in u t e, u p t o 8 L
of blood m oves t h r ou gh t h e h ea r t . Du r in g exer cise,
wh en m et a bolic n eeds in cr ea se, ca r dia c ou t pu t ca n
in cr ea se fou r fold. Respon sive ca r dia c ou t pu t is ba sed
on five m a jor fa ct or s, ou t lin ed in Box 16.1.
Stop and Consider
What happens to preload when venous return is
diminished? What happens to preload when ve-
nous return is excessive and cardiac muscle fibers
get stretched too far?
BLOOD PRESSURE
B lo o d p r e s s u r e is t h e pr essu r e or t en sion of t h e
blood wit h in t h e syst em ic a r t er ies. Blood pr essu r e
is n eeded t o con t in u ou sly per fu se vit a l or ga n s. P r es-
su r e in t h e a r t er ies is m a in t a in ed by:
1. Con t r a ct ion of t h e left ven t r icle
2. Per iph er a l va scu la r r esist a n ce
3. E la st icit y of t h e a r t er ia l wa lls
4. Viscosit y a n d volu m e of t h e blood
In ot h er wor ds, blood pr essu r e is a pr odu ct of
ca r dia c ou t pu t a n d t h e a m ou n t of r esist a n ce in t h e
a r t er ies.
Stop and Consider
What would your body need to do to maintain
optimal blood pressure if you had increased
peripheral vascular resistance as may occur with
arteriosclerosis (a condition of stiffening of the
arteries)?
P e r u s io n 401
Box 16.1 Ma jo r Fa c t o r s I m p a c t in g
C a r d ia c O u t p u t
● P r eloa d
■ Wor k im posed on t h e h ea r t ju st befor e con t r a ct ion
■ Also ca lled ven t r icu la r en d-dia st olic volu m e be-
ca u se it r epr esen t s t h e pr essu r e in t h e ven t r icles
ju st befor e syst ole
■ Opt im a l pr eloa d depen ds on a dequ a t e ven ou s r e-
t u r n t o fill t h e h ea r t wit h blood a n d a dequ a t e
ca r dia c m u scle st r et ch in g t o pr om ot e a st r on g
con t r a ct ion
■ An in dica t or of t h e fillin g a n d m u scle st r et ch in g
n eeded t o eject a n opt im a l a m ou n t of blood fr om
t h e ven t r icles
● Ca r dia c con t r a ct ilit y
■ Th e a bilit y of t h e h ea r t t o in cr ea se t h e for ce of t h e
con t r a ct ion wit h ou t ch a n gin g t h e dia st olic, or r est -
in g, pr essu r e
■ Affect ed by ca lciu m ion s t h a t a id in m u scle
con t r a ct ion s
● Aft er loa d
■ Th e a m ou n t of pr essu r e in t h e ven t r icle t owa r d t h e
en d of t h e ca r dia c con t r a ct ion
■ Th e ca r dia c m u scle fiber s a r e sh or t en ed a n d con -
t r a ct ed a n d t h e ven t r icles h ave been em pt ied
■ Squ eezin g pr essu r e a ga in st t h e r esist a n ce of blood
t r yin g t o ba ck u p in t o t h e ven t r icles
■ Affect ed by in cr ea sed r esist a n ce fr om t h e a or t a a n d
pu lm on a r y a r t er y
■ In cr ea ses wh en va lves a r e im pa ir ed
● H ea r t r a t e
■ Pa r t of t h e equ a t ion t h a t pr edict s ca r dia c ou t pu t
■ Mu st a lso r espon d t o ch a n ges in dem a n ds t o m a xi-
m ize per fu sion
■ Slower h ea r t r a t e equ a ls gr ea t er dia st olic fillin g
■ E xcessively r a pid h ea r t r a t e ca n m ove blood qu ickly
bu t does n ot a llow m a xim a l a m ou n t s of blood t o be
m oved wit h ea ch con t r a ct ion
● Blood volu m e
■ Qu a n t it y a n d qu a lit y of blood a ffect t h e wor kloa d
on t h e h ea r t
■ E xcessive blood in cr ea ses pr essu r e; deficien t blood
lower s pr essu r e
■ In cr ea sed blood viscosit y (t h ickn ess) in cr ea ses
pr essu r e; t h in n er blood viscosit y lower s va scu la r
r esist a n ce a n d blood pr essu r e
■ Th e h ea r t m u st a dju st t o t h ese pr essu r es t o m a in -
t a in a n opt im a l st r oke volu m e
Blood pr essu r e is m ea su r ed in m illim et er s of m er-
cu r y (m m H g). Th e a ver a ge blood pr essu r e for a du lt s
is a bou t 120/80. Th e fir st n u m ber (120 in t h e exa m -
ple) is ca lled t h e syst olic blood pr essu r e. Th e secon d
n u m ber (80 in t h e exa m ple) is ca lled t h e dia st olic
blood pr essu r e. F igu r e 16.6 illu st r a t es t h e fa ct or s in -
volved in blood pr essu r e. S y s t o lic b lo o d p r e s s u r e
is t h e a m ou n t of pr essu r e exer t ed du r in g con t r a c-
t ion of t h e left ven t r icle a n d eject ion of blood in t o t h e
a or t a . Th e st r oke volu m e, h ea r t r a t e, a n d r esist a n ce
in t h e a or t a a ffect syst olic blood pr essu r e. Specific
a ct ivit ies t h a t ca n eleva t e syst olic blood pr essu r e in -
clu de exer cise, sm okin g, ca r diova scu la r disea se, a n d
402 C h a p t e r 16: Alt er ed Per fu sion

S ys to le

Pe riphe ra l va s cula r re s is ta nce

Ela s ticity of
S ys tolic
ve s s e l wa ll
blood
pre s s ure

Contra ction of
A le ft ve ntricle

Dias to le

Re ma ining
re s is ta nce
during re s t

Dia s tolic
blood
pre s s ure

Re la xa tion of le ft ve ntricle

Figure 16.6. Factors involved with systolic and diastolic blood pressure. A: Systolic blood pressure represents the ejec-
tion of blood into the aorta during systole, or contraction of the left ventricle. B: Diastolic blood pressure represents the
pressure in the arterial system during diastole, or resting of the left ventricle.

st r ess. D ia s t o lic b lo o d p r e s s u r e is t h e a m ou n t of dia st olic pr essu r e r em a in s u n ch a n ged. Th e m e a n

pr essu r e t h a t r em a in s in t h e a or t a du r in g t h e r est -
in g ph a se of t h e ca r dia c cycle. E leva t ion s in dia st olic
blood pr essu r e m a y in dica t e t h a t t h e a r t er ies a r e n ot
a llowed t o a ppr opr ia t ely r est bet ween ca r dia c con -
t r a ct ion s. Depr ession s in dia st olic blood pr essu r e a r e
r ela t ed t o eit h er la ck of a dequ a t e r esist a n ce in t h e
a or t a or ba ckflow of blood (a n d su bsequ en t ly a loss
of ba selin e pr essu r e) t h r ou gh t h e a or t ic va lve. Th e
differ en ce bet ween t h e syst olic a n d dia st olic blood
pr essu r e is ca lled t h e p u ls e p r e s s u r e . Con ver gen ce,
or n a r r owin g, of t h e syst olic a n d dia st olic pr essu r e
oft en r eflect s a loss of syst olic pr essu r e r a t h er t h a n
a n eleva t ion in dia st olic pr essu r e. For exa m ple, ex-
t en sive blood loss decr ea ses syst olic pr essu r e wh ile
a r t e r ia l p r e s s u r e , con sider ed a n a dequ a t e m ea -
su r e of system ic t issu e per fu sion , is on e-t h ir d t h e
pu lse pr essu r e plu s dia st olic pr essu r e.
Stop and Consider
Do you think that it is more problematic to have
persistent elevations in systolic or diastolic
blood pressure?
NEURONAL CONTROL OF BLOOD PRESSURE
AND CARDIOVASCULAR ADAPTATION
H ow does t h e ca r diova scu la r syst em a dju st t o t h e
va r ia ble per fu sion dem a n ds of t h e cells a n d t issu es?
 P e r u s io n 403

Regu la t ion a n d a da pt a t ion of ca r dia c a n d va scu la r 1. Ba r or ecept or s a n d ch em or ecept or s in t h e a r t er ies

fu n ct ion a r e con t r olled by n eu r on s in t h e m edu lla
a n d pon s, wh ich a ct on t h e a u t on om ic n er vou s sys-
t em (ANS). Th e sym pa t h et ic division of t h e ANS
st im u la t es in cr ea sed h ea r t r a t e, ca r dia c con t r a ct il-
it y, a n d t h e t en sion or r esist a n ce of blood vessels.
Th e pa r a sym pa t h et ic division of t h e ANS a lso a ct s
on t h e h ea r t t o decr ea se h ea r t r a t e. All of t h ese a d-
a pt a t ion s a r e in r espon se t o m u lt iple sign a ls in t h e
br a in a n d ca r diova scu la r syst em .
Blood pr essu r e r egu la t ion r equ ir es a dju st m en t in
ca r dia c ou t pu t (t h e pu sh in g pr essu r e) a n d per iph -
er a l va scu la r r esist a n ce (t h e r esist in g pr essu r e)
pr im a r ily t h r ou gh n eu r on a l a n d h or m on a l m ech -
a n ism s (F ig. 16.7). Sim ila r t o r egu la t ion of ca r dia c
con du ct ion , t h e ANS a dju st s blood pr essu r e. Th e
sym pa t h et ic n er vou s br a n ch in cr ea ses h ea r t r a t e
a n d ca r dia c con t r a ct ilit y a n d ca n select ively pr odu ce
a r t er y a n d a r t er iole va socon st r ict ion t o in cr ea se pe-
r iph er a l va scu la r r esist a n ce. Ch a n ges in blood pr es-
su r e occu r in r espon se t o:
2. Th e r en in –a n giot en sin syst em
3. Th e kidn eys
B a r o r e c e p t o r s , loca t ed t h r ou gh ou t t h e blood ves-
sels a n d t h e h ea r t , sen se pr essu r e ch a n ges in t h e a r-
t er ies. For exa m ple, wh en t h e r esist a n ce, or st r et ch ,
of t h e a r t er y decr ea ses (t h e blood pr essu r e is sen sed
a s low), t h e ba r or ecept or s a ler t t h e ca r dia c con t r ol
cen t er in t h e br a in st em . Th e br a in st em a ct s on t h e
sym pa t h et ic n er vou s syst em t o st im u la t e bet a -1 r e-
cept or s in t h e h ea r t . Bet a -1 r ecept or s in cr ea se ca r-
dia c ou t pu t . Sim u lt a n eou sly, a lph a -1 r ecept or s in
t h e blood vessels a r e st im u la t ed, ca u sin g va socon -
st r ict ion . Th ese r ecept or s a r e m en t ion ed beca u se
t h ey a r e m a jor t a r get s of ph a r m a cologic t r ea t m en t
wit h h yper t en sion . Blockin g t h ese r ecept or s r edu ces
ca r dia c ou t pu t a n d r edu ces va scu la r va socon st r ic-
t ion . Wh en opt im a l blood pr essu r e is a ch ieved, sym -
pa t h et ic st im u la t ion by t h e ba r or ecept or s su bsides.
Ch em or ecept or s in t h e a or t a a n d ca r ot id a r t er ies

Arte rial blo o d pre s s ure

Ca rdia c output Pe riphe ra l va s cula r re s is ta nce

S ympa the tic

S troke volume He a rt ra te a ctivity

Va ga l a nd
s ympa the tic a ctivity

He a rt
Ve nous re turn Ba rore cptors

Angiote ns in II
Blood volume
Adre na l gla nd
S a lt a nd wa te r Aldos te rone
re te ntion Re nin-a ngiote ns in
me cha nis m

Kidney

Figure 16.7. Mechanisms of blood pressure regulation. Dashed lines represent stimulation of blood pressure regulation.
Solid lines represent response to stimulation of kidneys and baroreceptors. (From Porth CM. Essentials of Pathophysiology:
Concepts of Altered Health States. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.)
404 C h a p t e r 16: Alt er ed Per fu sion
a lso pla y a vit a l r ole in blood pr essu r e r egu la t ion by
det ect in g ch a n ges in oxygen , ca r bon dioxide, a n d pH
of t h e blood. Ch em or ecept or s t h en pr ovide feedba ck
t o a lt er ven t ila t ion a n d pr om ot e va socon st r ict ion a s
n eeded t o m a xim ize oxygen a t ion of vit a l or ga n s.
Cir cu la t in g en zym es, h or m on es, pla sm a pr ot ein s,
a n d n eu r ot r a n sm it t er s a lso a ffect blood pr essu r e
r egu la t ion . Ren in , a n en zym e pr odu ced a n d secr et ed
fr om t h e kidn eys, con ver t s t h e pla sm a pr ot ein a n -
giot en sin ogen t o a n giot en sin I. An giot en sin I is con -
ver t ed t o a n giot en sin II by a n en zym e in t h e lu n gs.
An giot en sin II is a pot en t cir cu la t in g va socon st r ic-
t or. An giot en sin II t h er efor e wor ks t o pr om ot e a n in -
cr ea se in blood pr essu r e wh en a ct in g on t h e a r t er ies
a n d a r t er ioles. An giot en sin II a lso st im u la t es t h e
a dr en a l cor t ex t o in cr ea se pr odu ct ion a n d secr et ion
of a ldost er on e (Ch a pt er 8). Aldost er on e in cr ea ses
Modu le 2 Alt e r e d P e r u s io n
Alt er ed per fu sion is defin ed a s t h e in a bilit y t o a d-
equ a t ely oxygen a t e t issu es a t t h e ca pilla r y level
(Fig. 16.8). Th is in a bilit y cou ld be t h e r esu lt of low
oxygen pr esen ce or poor u t iliza t ion of oxygen .
Ma n y fa ct or s ca n a lt er per fu sion , in clu din g:
● Ven t ila t ion –per fu sion m ism a t ch in g
● Im pa ir ed cir cu la t ion
● In a dequ a t e ca r dia c ou t pu t
● E xcessive per fu sion dem a n ds
Ventilation–Perfusion Mismatching
P r oblem s wit h t h e ven t ila t ion –per fu sion r a t io a r e
t h e m ost com m on ca u se of h ypoxem ia . A ven t ila t ion –
per fu sion m ism a t ch ca n occu r beca u se of t h e follow-
in g con dit ion s:
● In a dequ a t e ven t ila t ion in well-per fu sed a r ea s of
t h e lu n gs. Th is occu r s wit h con dit ion s su ch a s
a st h m a , pn eu m on ia , a n d pu lm on a r y edem a .
● In a dequ a t e per fu sion in well-ven t ila t ed a r ea s of
t h e lu n gs. Th is occu r s wit h va scu la r obst r u ct ive
pr ocesses in t h e lu n g, su ch a s wit h a pu lm on a r y
em bolu s.
Impaired Circulation
P r oblem s wit h cir cu la t ion lea d t o in a dequ a t e or
excess blood flow t o t issu es or or ga n s. Im pa ir ed
sa lt a n d wa t er r et en t ion by t h e kidn eys a n d ca n
con t r ibu t e t o expa n din g blood volu m e. An t idiu r et ic
h or m on e (va sopr essin ) a lso pla ys a r ole in blood
pr essu r e r egu la t ion . In h igh doses, a n t idiu r et ic
h or m on e, secr et ed fr om t h e post er ior pit u it a r y, is
a pot en t va socon st r ict or. An t idiu r et ic h or m on e a lso
pr om ot es r et en t ion of flu ids, wh ich ca n en h a n ce
blood volu m e. E pin eph r in e, a n eu r ot r a n sm it t er, a ct s
t o pr om ot e blood pr essu r e dir ect ly by st im u la t in g
h ea r t r a t e a n d ca r dia c con t r a ct ilit y a n d pr om ot in g
t en sion in t h e vessels.
Stop and Consider
Think back to the last time that you felt dizzy
when you stood up too fast. Why do you think
this occurred? How did the baroreceptors
respond?
cir cu la t or y pa t en cy a n d fu n ct ion in g ca n r esu lt fr om
in ju r y t o t h e vessels, obst r u ct ive pr ocesses, in a de-
qu a t e m ovem en t of blood, or in a dequ a t e blood vol-
u m e. In ju r y t o t h e vessels lea ds t o loss of in t egr it y
a n d h em or r h a ge. H e m o r r h a g e , t h e loss of blood
t h r ou gh t h e vessel wa ll, is m ost com m on ly ca u sed
by va scu la r in ju r y oft en du e t o t r a u m a . H em or r h a ge
ca n a lso occu r beca u se of a n eu r ysm s, coa gu la t ion dis-
or der s, a n d degr a da t ion of t h e vessel by n eopla sm s.
Obst r u ct ion wit h in t h e vessel a lso con t r ibu t es t o
a lt er ed per fu sion by blockin g fr ee m ovem en t of blood
t h r ou gh t h e cir cu la t or y syst em . Occlu ded a r t er ies do
n ot a llow oxygen a t ed blood t o r ea ch per iph er a l t is-
su es. For exa m ple, a pplyin g a t ou r n iqu et or ot h er-
wise com pr essin g a vessel will disa llow blood flow
t o t h e per iph er a l t issu es. Occlu ded vein s r est r ict ve-
n ou s r et u r n a n d lea d t o cir cu la t or y con gest ion . Ob-
st r u ct ion com m on ly occu r s t h r ou gh t h e developm en t
of a t h r om bu s, or blood clot . Rem em ber t h a t t h e for-
m a t ion of a blood clot , or t h r o m b o s is , occu r s in r e-
spon se t o in ju r y a n d is essen t ia l du r in g t h e wou n d
h ea lin g pr ocess. Un desir ed t h r om bi ca n a lso for m
in eit h er a r t er ies or vein s a n d su bsequ en t ly occlu de
blood flow.
In bot h a r t er ies a n d vein s, t h r ee m a jor fa ct or s a r e
r espon sible for t h r om bu s for m a t ion . Th ese fa ct or s,
list ed below, a r e collect ively kn own a s Vir c h o w
t r ia d :
1. Vessel wa ll da m a ge
2. E xcessive clot t in g
3. Alt er a t ion s in blood flow, su ch a s t u r bu len ce or
slu ggish blood m ovem en t
 Alt e r e d P e r u s io n 405

Alte re d Pe rfus io n

Ve ntilatio n Inade quate

Impaire d Exc e s s ive
pe rfus io n c ardiac
c irc ulatio n pe rfus io n de mands
mis match o utput

Re s pira tory P ulmona ry He morrha ge Ina de qua te Impa ire d Exce s s ive P rolonge d Me ta bolic Ane mia
dis e a s e e mbolus blood ve ntricula r pe riphe ra l exe rtion a lte ra tions
compos ition pumping va s cula r
or volume re s is ta nce

Obs truction
or dis ruptions S tructura l Conduction
in blood flow de fe cts de fe cts

Figure 16.8. Concept map. Altered perfusion.

In ju r y t o vessel en dot h eliu m , followed by t h e for- a n eu r ysm s, a n d ven ou s st a sis) a ll im pede for wa r d
m a t ion of a t h er oscler osis, is t h e m ost com m on ca u se m ovem en t of blood. Th is a llows t h e a ccu m u la t ion of
of t h r om bu s for m a t ion in a r t er ies a n d a lso con t r ib- clot t in g fa ct or s n eeded t o for m t h r om bi.
u t es t o ven ou s t h r om bosis.
At h e r o s c le r o s is is a con dit ion of ir r egu la r ly dis- Stop and Consider
t r ibu t ed lipid deposit s in t h e in n er lin in g, or in t im a , What is the mechanism for development of
of la r ge or m ediu m a r t er ies. Th e on set of a t h er oscle- venous thrombi formation in an individual on
r osis is t h eor ized t o begin a s a pr ocess of in ju r y t o bed rest?
t h e in t im a (in n er lin in g of t h e vessel), per h a ps fr om
h yper t en sion , sm okin g, or en vir on m en t a l exposu r es.
Low-den sit y lipopr ot ein (LDL) filt er s in t o t h e lin in g Carotid atherosclerosis
of t h e a r t er y a n d becom es t r a pped a lon g t h e in ju r ed
in t im a . Th e lipopr ot ein becom es oxidized a n d en -
gu lfed by m a cr oph a ges, pr odu cin g foa m cells. Foa m
cells a ccu m u la t e a n d com bin e wit h a ddit ion a l lipids
t o for m fa t t y st r ea ks. Th ese fa t t y st r ea ks gr a du a lly
becom e fibr ou s pla qu es. F ibr ou s pla qu es a ccu m u la t e
a t t h e sit es of in ju r y cover ed by pla t elet ca ps t h a t
con t in u e t o expa n d. Th ese a r ea s of a t h er oscler osis
m a y even t u a lly occlu de t h e a r t er y.
Tu r bu len t or st a gn a n t blood flow a lso con t r ibu t es
t o t h r om bu s for m a t ion . Bifu r ca t ion s, a n eu r ysm s,
a n d a r ea s of ven ou s st a sis a r e com m on sit es of a l-
t er ed blood flow. B i u r c a t io n s a r e r egion s wh er ein
a vessel br a n ch es. Blood flow slows or ba cks u p in Aortic aneurysm
a n effor t t o n egot ia t e t h e n a r r owed pa t h wa y. Ar t e-
r ia l a n e u r y s m s a r e loca l ou t pou ch in gs ca u sed by
wea kn ess in t h e vessel wa ll (F ig. 16.9). Da m a ge t o
Aortic atherosclerosis
t h e vessel wa ll, a s m a y occu r wit h a t h er oscler osis,
pr om ot es t h e developm en t of a n eu r ysm s. Th e loss of
vessel wa ll pr essu r e a llows slower t r a n sit of blood.
Bifurcation
Ve n o u s s t a s is occu r s in vein s wit h r edu ced ven ou s
Iliac artery aneurysm
r et u r n . Sit u a t ion s t h a t pr om ot e ven ou s st a sis in -
clu de h ea r t fa ilu r e, va r icose vein s, or pr olon ged bed
r est or im m obiliza t ion . Ven ou s st a sis is m ost com -
m on ly fou n d in t h e legs, wh er e blood pools in t h e Figure 16.9. Bifurcation, aneurysm, and atherosclerosis.
ext r em it ies. Th ese t h r ee sit u a t ion s (bifu r ca t ion s, These conditions cause turbulent blood flow.
406 C h a p t e r 16: Alt er ed Per fu sion

Disor der s of excess clot t in g a llow u n r egu la t ed

for m a t ion of t h r om bi t h r ou gh ou t t h e body. H yper-
coa gu la bilit y ca n be con gen it a l or a cqu ir ed. Gen et ic
m u t a t ion s ca n r esu lt in excess coa gu la n t fa ct or s
or deficien t a n t icoa gu la n t m ech a n ism s. Acqu ir ed
ca u ses of h yper coa gu la bilit y in clu de:
● Au t oim m u n e m ech a n ism s t h a t a ct iva t e pla t elet s
a n d a lt er coa gu la t ion fa ct or s
● Cer t a in t ypes of ca n cer, or m yelopr olifer a t ive
disor der s, su ch a s t h r o m b o c y t h e m ia (excess
pla t elet s)
● Sickle cell a n em ia
● Polycyt h em ia ver a
● Use of or a l con t r a cept ives
● Va scu la r ch a n ges in t h e la t e st a ge of pr egn a n cy
A
Th e followin g ou t com es m a y pot en t ia lly occu r
wit h t h r om bu s for m a t ion :
1. Th e t h r om bu s con t in u es t o gr ow a n d occlu de t h e
vessel com plet ely
2. Th e t h r om bu s is degr a ded by en zym es a n d de-
cr ea ses in size B
3. All or pa r t of t h e t h r om bu s br ea ks off a n d t r a vels
t h r ou gh t h e cir cu la t ion (F ig. 16.10)
On ce a t h r om bu s br ea ks off a n d t r a vels, it is r efer r ed
t o a s a t h r o m b o e m b o lu s , or sim ply a n em bolu s. An
e m b o lu s is a n y plu g of m a t er ia l, su ch a s t h r om bi,
a ir, n eopla sm s, m icr oor ga n ism s, or a m n iot ic flu id, C
t h a t t r a vels in t h e cir cu la t ion a n d ca n obst r u ct t h e
lu m en of a vessel. Figure 16.10. Potential outcomes of thrombus formation.
A: Partial or total occlusion of the vessel. B: Enzymes
Stop and Consider degrade thrombus. C: The thrombus dislodges, forming an
When preparing an intravenous fluid or medica- embolus, which travels within the vessels and occludes a
tion, all air must be removed from the tubing or smaller blood vessel at a distant site.
syringe. Describe the consequence of being care-
less in air removal.
lower ext r em it ies, or kidn eys. Myoca r dia l in fa r ct ion
(MI) a n d st r oke a r e t wo clin ica l m odels t h a t a r e pr e-
Wh en a vessel becom es obst r u ct ed, it ca n r esu lt in
sen t ed in t h is ch a pt er t o illu st r a t e t h e im pa ct of in -
a n in fa r ct . An in a r c t is a n a r ea of n ecr osis r esu lt -
fa r ct ion on vit a l or ga n s.
in g fr om a su dden in su fficien cy of a r t er ia l or ven ou s
blood su pply. Th e pr ocess of obst r u ct in g t h e vessel
is r efer r ed t o a s a n in a r c t io n . Loss of blood su pply
a n d n ecr osis for m a t ion r esu lt s in loss of fu n ct ion of
Inadequate Cardiac Output
t h e a ffect ed t issu e. Th e sever it y of t h e in fa r ct ion de-
Ca r dia c ou t pu t is in a dequ a t e wh en t h e h ea r t is u n -
pen ds on t h e size a n d loca t ion of t h e em boli. Sm a ll
a ble t o su ccessfu lly eject t h e n ecessa r y a m ou n t of
em boli r esu lt in sm a ll a n d less sign ifica n t a r ea s of
blood t o t h e pu lm on a r y a n d syst em ic cir cu la t ion .
n ecr osis. Ar ea s wit h ext en sive colla t er a l cir cu la -
Ma jor ca t egor ies of pr oblem s lea din g t o in a dequ a t e
t ion a r e ca pa ble of per fu sin g t issu e a r ou n d t h e ob-
ca r dia c ou t pu t in clu de:
st r u ct ed vessel. La r ger em boli ca n lodge in t o la r ger
vessels, occlu de t h e la r ge vessel a n d a ll of t h e la r ge ● Ch a n ges in blood volu m e, com posit ion , or viscosit y
vessel’s t r ibu t a r ies, a n d ca u se su dden dea t h . Ven ou s ● Im pa ir ed ven t r icu la r pu m pin g
t h r om boem boli m ost oft en or igin a t e in t h e deep ● St r u ct u r a l h ea r t defect s, su ch a s va lve defect s
vein s of t h e legs, br ea k off, t r a vel a lon g t h e vein , t h a t a llow lea kin g or r egu r git a t ion of blood
a n d lodge in t h e pu lm on a r y a r t er ies wh er e t h e ves- ● Con du ct ion defect s t h a t lea d t o a n u n r espon sive
sels n a r r ow a n d bifu r ca t e. Ar t er ia l t h r om boem boli h ea r t r a t e a n d r h yt h m
m ost oft en or igin a t e in t h e h ea r t a s a t h er oscler ot ic ● E xcessive or sign ifica n t ly r edu ced per iph er a l va s-
pla qu es, a n d t h ey ca n t r a vel t o t h e br a in , in t est in es, cu la r r esist a n ce
 Alt e r e d P e r u s io n 407

Ch a n ges in blood volu m e, com posit ion , or viscosit y
ca n a ffect ca r dia c ou t pu t a n d r esu lt in a lt er ed per-
fu sion . Blood volu m e a n d viscosit y is a lt er ed wit h
su ch con dit ion s a s h yper coa gu la t ion , deh ydr a t ion ,
or h em or r h a ge. Dissem in a t ed in t r a va scu la r coa g-
u la t ion is a clin ica l m odel in t h is ch a pt er u sed t o
illu st r a t e t h e im pa ct of coa gu la t ion disor der s a n d
h em or r h a ge on ca r dia c ou t pu t a n d per fu sion . Ba si-
ca lly, blood ou t side of t h e cir cu la t ion is n ot a ccessi-
ble t o t issu es. Blood com posit ion , pa r t icu la r ly wit h
a n em ia , a lt er s oxygen t r a n spor t . In a n em ia , in
wh ich t h er e a r e n ot en ou gh r ed blood cells t o ca r r y
oxygen , t h e h ea r t t r ies t o m ove t h e sm a ll n u m ber of
cells a t a fa st er h ea r t r a t e a n d becom es over t a xed.
Im pa ir ed ven t r icu la r pu m pin g is a secon d m a jor
ca t egor y of pr oblem s t h a t lea d t o im pa ir ed ca r dia c
ou t pu t . Th e h ea r t is a m u scle. Loss of m u scle a ct ivit y
lea ds t o t h e in a bilit y t o m ove blood effect ively for-
wa r d t h r ou gh t h e a r t er ia l cir cu la t ion . Th is lea ds t o
con gest ion of ven ou s blood a n d im pa ir ed ven ou s r e-
t u r n . H ea r t fa ilu r e is a clin ica l m odel select ed t o fu r-
t h er illu st r a t e pr oblem s wit h im pa ir ed ven t r icu la r
pu m pin g a n d ven ou s in su fficien cy.
St r u ct u r a l h ea r t defect s a r e a t h ir d ca t egor y of
pr oblem s lea din g t o im pa ir ed ca r dia c ou t pu t . Sev-
er a l pot en t ia l st r u ct u r a l h ea r t defect s exist t h a t ca n
a ffect ca r dia c ou t pu t . St r u ct u r a l h ea r t defect s ba -
sica lly im pa ir t h e sm oot h , dir ect ion a l flow of blood
t h r ou gh t h e h ea r t ch a m ber s (F ig. 16.11). H ea r t de-
fect s ca n in volve:
● Open in gs bet ween t h e ch a m ber sept a , su ch a s
wit h a n a t r ia l sept a l defect (ASD) or ven t r icu la r
sept a l defect (VSD)

A B C

D E G

Figure 16.11. Examples of structural heart defects. A: Atrial septal defect. Blood is shunted from the higher pressure left
atria to the lower pressure right atria. B: Ventricular septal defect. Blood is shunted from the higher pressure left ventricle
to the lower pressure right ventricle. C: Transposition of the great vessels. The pulmonary artery is attached to the left
side of the heart and the aorta to the right side. D: Coarctation (narrowing) of the aorta. E: Patent ductus arteriosis.
The high pressure blood of the aorta is shunted back to the pulmonary artery. F: Thickened and stenotic valve leaflets.
G: Regurgitant valve that does not completely close.
408 C h a p t e r 16: Alt er ed Per fu sion
● Tr a n sposit ion or coa r ct a t ion (n a r r owin g) of t h e
gr ea t vessels
● La ck of closu r e of t h e du ct u s a r t er iosis a t or
sh or t ly a ft er bir t h
● Va lve defect s su ch a s st en osis, r egu r git a t ion , or
pr ola pse
Open in gs bet ween t h e a t r ia a n d ven t r icles a llow
blood t o m ove bet ween t h e r igh t a n d left side of t h e
h ea r t . At r ia l sept a l defect is a n open in g bet ween
t h e left a n d r igh t a t r ia . Ven t r icu la r sept a l defect
is a n open in g bet ween t h e left a n d r igh t ven t r icle.
Two m a jor pr oblem s wit h sept a l defect s a r e (1) t h e
co-m in glin g of oxygen a t ed a n d deoxygen a t ed blood
wit h in t h e h ea r t ch a m ber s a n d (2) ch a n ges in blood
flow volu m e a n d su bsequ en t ca r dia c ou t pu t .
Blood m ovem en t a cr oss t h e ch a m ber s is r efer r ed
t o a s s h u n t in g . Th e dir ect ion of blood m ovem en t
a cr oss ch a m ber s will go fr om t h e a r ea of gr ea t er t o
lesser pr essu r e. A left -t o-r igh t sh u n t is t h e m ove-
m en t of blood fr om t h e left side (oxygen a t ed) of t h e
h ea r t t o t h e r igh t side (deoxygen a t ed). Th e pr essu r e
on t h e r igh t side of t h e h ea r t a n d in t h e pu lm on a r y
cir cu la t ion becom es gr ea t er. La r ger defect s a llow
gr ea t er volu m es of blood t o m ove left t o r igh t , lea d-
in g t o excessive pr essu r e in t h e r igh t ven t r icle a n d
pu lm on a r y edem a . Ca r dia c ou t pu t fr om t h e left ven -
t r icle t o t h e syst em ic cir cu la t ion is com pr om ised be-
ca u se of loss of blood fr om t h e left side of t h e h ea r t
t h r ou gh t h e defect . A r igh t -t o-left sh u n t is t h e m ove-
m en t of blood fr om t h e r igh t side (deoxygen a t ed) of
t h e h ea r t t o t h e left side (oxygen a t ed). Movem en t of
blood fr om r igh t t o left ca u ses deoxygen a t ed blood t o
be pu m ped in t o t h e syst em ic cir cu la t ion . Sm a ll de-
fect s ca n be a sym pt om a t ic. La r ger defect s ca n lea d
t o a n over t a xed left ven t r icle a n d sever e h ypoxem ia .
Stop and Consider
Based on the pressure differential between the
right and left sides of the heart, do you think
it is more common to have a left-to-right or
right-to-left shunt? Which one would most likely
result in cyanosis?
Va lvu la r defect s a r e con gen it a l or a cqu ir ed. Th e
bicu spid (m it r a l) a n d a or t ic va lves a r e m ost oft en a f-
fect ed. Acqu ir ed ca u ses of t h ese defect s in clu de in fec-
t ion , in fla m m a t ion , t r a u m a , a n d degen er a t ion . Su ch
pr oblem s ca u se t h e va lve t o open or close im pr oper ly.
S t e n o s is is a pr oblem in wh ich n a r r owin g of t h e
va lve occu r s, m a kin g t h e va lve u n a ble t o open a de-
qu a t ely. Th is n a r r owin g ca u ses in cr ea sed r esist a n ce
a n d t u r bu len ce a s t h e blood m oves pa st t h e va lve.
Th e h ea r t ven t r icle m u st wor k h a r der t o pu m p blood
pa st t h e st en ot ic va lve. R e g u r g it a t io n is a pr oblem
of in com pet en ce of t h e va lve, in wh ich it is u n a ble t o
pr oper ly close, a llowin g r eflu x of blood. Aga in , t h e
h ea r t ch a m ber s m u st wor k h a r der a ga in st t h e con -
st a n t ba ckflow of blood.
A fou r t h pr oblem of ca r dia c ou t pu t , con du ct ion
defect s a lt er a n opt im a l h ea r t r a t e a n d r h yt h m .
C a r d ia c d y s r h y t h m ia s a r e in dica t ive of pr oblem s
wit h m a in t a in in g a n efficien t h ea r t r h yt h m . Dys-
r h yt h m ia s ca n st em fr om pr oblem s wit h t h e SA n ode,
AV n ode, ca r dia c cells t h a t join t h e SA a n d AV n odes,
or con du ct ion syst em s in t h e a t r ia or ven t r icles. Wit h -
ou t a r egu la r, pr odu ct ive, efficien t h ea r t r h yt h m , t h e
h ea r t is u n a ble t o per fu se body t issu es a dequ a t ely.
Th e m ost pr oblem a t ic dysr h yt h m ia s a r e fou n d wit h
t h e ven t r icu la r con du ct ion syst em , wh ich r est r ict s t h e
h ea r t ’s a bilit y t o pu m p blood t o t h e a or t a or pu lm o-
n a r y a r t er y. On e exa m ple is ven t r icu la r ib r illa t io n ,
wh ich is a pr oblem of t h e h ea r t ven t r icle vibr a t in g
in st ea d of effect ively pu m pin g. Th is pr oblem ca n a lso
occu r in t h e a t r ia a n d is t h en r efer r ed t o a s a t r ia l
fibr illa t ion . A defibr illa t or u ses a n elect r ica l cu r r en t
t o sh ock t h e h ea r t in a n a t t em pt t o r eest a blish t h e
efficien t h ea r t r h yt h m . An ot h er pot en t ia l pr oblem
t h a t r esu lt s in dysr h yt h m ia s is obst r u ct ion of ca r dia c
con du ct ion , oft en a t t h e AV n ode, a con dit ion r efer r ed
t o a s h e a r t b lo c k . Wit h ou t coor din a t ion of t h e a t r ia
a n d ven t r icles, t h e m ovem en t of blood t h r ou gh t h e
h ea r t is u n coor din a t ed a n d in efficien t .
Excessive Perfusion Demands
Alt er ed, or excessive, t issu e m et a bolism ca n lea d t o
a lt er ed per fu sion fr om la ck of m eet in g t h is excessive
dem a n d. E ven t h ou gh a ll ot h er a spect s of ven t ila t ion
a n d diffu sion a r e fu n ct ion in g opt im a lly, t h e t issu es
a r e a skin g t oo m u ch . Th is ca n r esu lt fr om ext r em e
a n d pr olon ged exer t ion or m et a bolic a lt er a t ion s, a s
wit h h yper t h yr oidism (Ch a pt er 13).
General Manifestations
of Altered Perfusion
Th e gen er a l m a n ifest a t ion s of a lt er ed per fu sion de-
pen d on t h e ca u se. Th e effect s of ch r on ic h ypoxia wer e
discu ssed in Ch a pt er 15. Im pa ir ed ca r dia c ou t pu t
pr odu ces clin ica l m a n ifest a t ion s, su ch a s cya n osis,
edem a , sh or t n ess of br ea t h , im pa ir ed gr owt h , t a ch y-
ca r dia , t a ch ypn ea , a n d fa t igu e. Ch a n ges in blood
volu m e or per iph er a l va scu la r r esist a n ce ca n lea d t o
h ypot en sion or h yper t en sion . Obst r u ct ive pr ocesses,
su ch a s m yoca r dia l or cer ebr a l in fa r ct ion , gen er a lly
r esu lt in loss of fu n ct ion of t h a t or ga n beca u se of
isch em ia , a lon g wit h pa in a n d edem a . Th e for m a t ion
of deep vein t h r om bosis, a lso a n obst r u ct ive pr ocess,
m a y m a n ifest a s t en der n ess in t h e ca lf, especia lly
wit h dor siflexion of t h e foot , ca lled H o m a n s s ig n .
 Alt e r e d P e r u s io n 409

Tot a l occlu sion of vein s lea ds t o edem a , cooln ess, pa l-
lor, a n d cya n osis of t h e lower ext r em it y. H em or r h a ge
a lso lea ds t o a lt er ed per fu sion . Skin m a n ifest a t ion s
of h em or r h a ge a r e e c c h y m o s e s , br u ises fr om su -
per ficia l bleedin g in t o t h e skin , p e t e c h ia e , pin poin t
h em or r h a ges, or p u r p u r a , diffu se h em or r h a ges of
t h e skin or m u cou s m em br a n es. La r ger a ccu m u la -
t ion s of blood in t h e t issu e for m a h e m a t o m a . H ea r t
m u r m u r s a r e a dia gn ost ic clu e t o t h e pr esen ce of
va lve or sept a l defect s.
Diagnosing and Treating
Altered Perfusion
Mu lt iple dia gn ost ic a ids a r e a va ila ble t o iden t ify a l-
t er ed per fu sion . Tr ea t m en t m ea su r es a r e a im ed a t
im pr ovin g ca r dia c ou t pu t a n d m a in t a in in g t h e in -
t egr it y of cir cu la t ion . Ta bles 16.1 a n d 16.2 illu st r a t e
select dia gn ost ic t ools a n d t r ea t m en t m ea su r es in di-
ca t ed in a lt er ed per fu sion .

Ta b le 16.1 Select Dia gn ost ic Aids t o Det ect Alt er ed Per fu sion
D ia g n o s t ic
Te s t T y p e o Te s t
E ch oca r diog- Ult r a sou n d pict u r e of ca r dia c st r u ct u r es a n d gr ea t
r a ph y (ca r dia c vessels
u lt r a sou n d)
Ca r dia c In ser t ion of a ca t h et er (sm a ll t u be) t h a t is pa ssed
ca t h et er iza t ion in t o t h e h ea r t fr om a vein or a r t er y
Ch est Ra diogr a ph ic pict u r e of ch est
r a diogr a ph
E lect r oca r diog- Mea su r em en t of elect r ica l im pu lses in t h e h ea r t
r a ph y (E CG)
P r essu r e Sph ygm om a n om et r y is a n in dir ect , n on in va sive
m ea su r em en t s m ea su r em en t of syst olic a n d dia st olic blood pr es-
su r e u sin g a blood pr essu r e cu ff a n d sph ygm om a -
n om et er ; in va sive pr essu r e m ea su r em en t s in volve
dir ect ly t h r ea din g a ca t h et er (oft en fr om t h e fem o-
r a l a r t er y) in t o t h e st r u ct u r e of in t er est
St r ess t est Tr ea dm ill or bicycle exer cise is u sed in con ju n ct ion
wit h E CG, blood pr essu r e m on it or in g, or ot h er im -
a gin g st u dies; st r ess ca n a lso be in du ced t h r ou gh
ph a r m a cologic a gen t s a n d is t ypica lly u sed in com -
bin a t ion wit h im a gin g st u dies, su ch a s r a dion u cle-
ot ide im a gin g a n d ech oca r diogr a ph y
Ca r dia c n u - Uses in t r a ven ou s r a dioa ct ive com pou n ds, wh ich
clea r sca n n in g collect in t h e h ea r t , a n d a ga m m a ca m er a t o pr o-
du ce dia gn ost ic im a ges; m yoca r dia l per fu sion sca n -
n in g a llows t h e visu a liza t ion of blood flow pa t t er n s
t o t h e m yoca r diu m ; ca r dia c ga t in g syn ch r on izes
im a ges of t h e h ea r t wit h ca r dia c con du ct ion ba sed
on t h e E CG ou t pu t
Doppler u lt r a - A n on in va sive for m of u lt r a sou n d t h a t m ea su r es
son ogr a ph y t h e ch a n ges in sou n d fr equ en cies t o det ect m ove-
m en t , m ost com m on ly of r ed blood cells
R a t io n a le o r U s e
Det ect s ca r diova scu la r a n d va lvu la r lesion s,
ch a n ges in h ea r t size, ch a n ges in h ea r t posit ion ,
a n d wa ll m ot ion a bn or m a lit ies; t r a n sesoph a gea l
ech oca r diogr a ph y pr ovides a clea r er view of h ea r t
a n d gr ea t vessel st r u ct u r es wit h a pr obe t h a t is
posit ion ed in t h e esoph a gu s
Used t o wit h dr a w blood sa m ples, m ea su r e pr es-
su r es, or in ject con t r a st m edia t o det ect fu n ct ion a l
a n d st r u ct u r a l defect s (cor on a r y a n giogr a ph y); a lso
u sed t o su r gica lly cor r ect cer t a in ca r dia c defect s
Sh ows h ea r t bor der s; det ect s ch a n ges in h ea r t size
a n d posit ion ; det ect s pu lm on a r y con gest ion a n d
pleu r a l effu sion
Det ect s dist u r ba n ces in ca r dia c con du ct ion a n d
in cr ea ses in ch a m ber size, t h e pr esen ce of isch -
em ia , or m yoca r dia l in fa r ct ion ; a H olt er m on it or
is a por t a ble device t h a t r ecor ds 24-h ou r E CG
a ct ivit y a s a pa t ien t per for m s h is or h er u su a l
da ily a ct ivit ies
Det er m in es h ypot en sion or h yper t en sion ; ca r dia c
ca t h et er iza t ion m ea su r es pr essu r e in t h e a r t er ies,
vein s, a n d h ea r t ch a m ber s
Det er m in es elicit a t ion of ch est pa in , E CG, or im -
a gin g st u dy ch a n ges sign ifica n t for m yoca r dia l
isch em ia
In dica t ed for in dividu a ls wit h u n expla in ed or exer-
cise-in du ced ch est pa in t o per m it t h e ea r ly det ec-
t ion of h ea r t disea se or t o det er m in e t h e effect ive
r eva scu la r iza t ion of t h e h ea r t a ft er P TCA or by-
pa ss su r ger y; det ect s m yoca r dia l a ct ivit y a n d blood
flow; m a y be u sed in com bin a t ion wit h a st r ess t est
Mea su r es a or t ic a n d ot h er blood vessel flow veloc-
it ies; ca n be u sed t o a u gm en t ech oca r diogr a ph y t o
det er m in e flow velocit ies wit h in t h e ech oca r dio-
gr a ph ic im a ge; Doppler color flow u ses com pu t -
er-gen er a t ed im a ges t o depict differ en t dir ect ion s
of flow (r epr esen t ed by differ en t color s)
410 C h a p t e r 16: Alt er ed Per fu sion

Ta b le 16.2 Tr ea t m en t Mea su r es Rela t ed t o Alt er ed Per fu sion

Tr e a t m e n t
St r a tegy R a t io n a le o r U s e
Su r ger y Su r ger y h a s m u lt iple a pplica t ion s t o r elieve a lt er ed per fu sion :
Cor on a r y a r t er y bypa ss gr a ft in g is a pr ocedu r e u sed t o bypa ss a n obst r u ct ed cor on a r y a r t er y
Per cu t a n eou s t r a n slu m in a l cor on a r y a n giopla st y is per for m ed du r in g ca r dia c ca t h et er iza t ion t o com -
pr ess fa t t y deposit s in t h e cor on a r y a r t er ies a n d r elieve t h e occlu sion
La ser a n giopla st y va por izes fa t t y deposit s wit h a h ot -t ip la ser device
Su r ger y is a lso u sed t o r epa ir va lve defect s, r em ove va r icose vein s, a n d dr a in excess flu id fr om t h e
per ica r dia l ca vit y
P h a r m a cologic ASA (a spir in ) t h er a py m a y be in st it u t ed t o r edu ce pla t elet a ggr ega t ion a n d clot for m a t ion t h er a pies
Medica t ion s m a y be pr escr ibed t o dila t e blood vessels, r edu ce or in cr ea se blood pr essu r e, con t r ol t h e
h ea r t r a t e/r h yt h m , in cr ea se m yoca r dia l con t r a ct ilit y, r edu ce m yoca r dia l wor kloa d, or im pr ove ca r dia c
ou t pu t
Th r om bolyt ic a gen t s m a y be n eeded t o br ea k t h r ou gh a n obst r u ct ion a n d r eva scu la r ize m yoca r dia l
t issu e
Pa in m edica t ion s a r e oft en n eeded for a cu t e m yoca r dia l in fa r ct ion
Oxygen t h er a py is fr equ en t ly in dica t ed t o r edu ce h ypoxem ia
In t r a ven ou s F lu id volu m e or blood r epla cem en t wit h sever e h em or r h a ge or deh ydr a t ion a dm in ist r a t ion of blood or
flu ids
Pa cem a ker A pa cem a ker m a y be pla ced t o m ech a n ica lly con t r ol h ea r t r a t e a n d r h yt h m
pla cem en t
Lifest yle Redu ct ion of r isks or m odifica t ion of lifest yle a ft er a dia gn osis r ela t ed t o a lt er ed per fu sion m odifica -
t ion s sh ou ld in clu de weigh t r edu ct ion , blood pr essu r e m a n a gem en t , st r ess r edu ct ion , sm okin g cessa -
t ion , exer cise, h ea lt h y n u t r it ion , a n d dia bet es m a n a gem en t

Modu le 3 C lin ic a l Mo d e ls

Th e followin g clin ica l m odels h a ve been select ed t o
a id in t h e u n der st a n din g a n d a pplica t ion of a lt er ed
per fu sion pr ocesses a n d effect s. We a r e in t h e m idst
of a t r u e ca r diova scu la r pa n dem ic. H ea r t disea se is
n ot on ly t h e lea din g ca u se of dea t h , disa bilit y, a n d
h ea lt h ca r e expen se in t h e Un it ed St a t es, it is a lso
t h e lea din g ca u se of dea t h wor ldwide. Ca r diova scu -
la r disea se is t h e lea din g ca u se of m or t a lit y in ev-
er y r egion of t h e wor ld except su b-Sa h a r a n Afr ica ,
a n d it is a n t icipa t ed t h a t ca r diova scu la r disea se will
eclipse in fect iou s disea se t h er e wit h in t h e n ext few
yea r s. All of t h e issu es t h a t con t r ibu t e t o t h e con t in -
u ed im pa ct of ca r diova scu la r disea se in t h e Un it ed
St a t es—a ccess t o ca r e, qu a lit y of ca r e, a gin g of t h e
popu la t ion , explosion in t h e pr eva len ce of obesit y
a n d dia bet es, t oba cco con su m pt ion , a n d ph ysica l
in a ct ivit y—h a ve pr ofou n d globa l im plica t ion s.
Hypertension
H y p e r t e n s io n is a pr ogr essive ca r diova scu la r syn -
dr om e det ect ed by a n eleva t ion in blood pr essu r e
(syst olic pr essu r e a bove 140 m m H g or a dia st olic
pr essu r e a bove 90 m m H g), a ccor din g t o t h e Am er-
ica n H ea r t Associa t ion . H yper t en sion is a ssocia t ed
wit h m u lt iple fa ct or s in clu din g obesit y, dia bet es
a n d ch r on ic kidn ey disea se, a n d is on e of t h e m ost
com m on con dit ion s t h a t r equ ir e m a n a gem en t wor ld-
wide. 1 As h yper t en sion is oft en pr esen t in t h e a b-
sen ce of su bject ive sym pt om s, m a n y people m a y n ot
be a wa r e if t h ey h a ve eleva t ed blood pr essu r e wit h -
ou t r ou t in e scr een in g.
PATHOPHYSIOLOGY
Th e m a jor it y of in dividu a ls wit h h yper t en sion (90%
t o 95%) a r e dia gn osed a s h a vin g pr im a r y h yper t en -
sion , a lso ca lled essen t ia l h yper t en sion . Secon da r y
h yper t en sion is h igh blood pr essu r e t h a t is a m a n i-
fest a t ion of a n ot h er con dit ion , su ch a s a n a r r owin g of
t h e a or t a (coa r ct a t ion ) or kidn ey disea se. If t h e sys-
t olic blood pr essu r e is eleva t ed wit h ou t a n eleva t ion
in t h e dia st olic blood pr essu r e, t h is is r efer r ed t o a s
is o la t e d s y s t o lic h y p e r t e n s io n . Sim ila r ly, if t h e
dia st olic blood pr essu r e is eleva t ed wit h ou t a n ele-
va t ion in t h e syst olic blood pr essu r e, t h is is r efer r ed
 C lin ic a l Mo d e ls 411

t o a s is o la t e d d ia s t o lic
h y p e r t e n s io n . Wh en R E S E AR C H N O T E S
bot h syst olic a n d dia -
st olic blood pr essu r es The systolic blood pressure goal for individuals greater than 60 years of age established
2
a r e eleva t ed, t h is is cla s- in the current guidelines for managing high blood pressure in adults is higher than the
3
sified a s m ixed syst olic/ goal established in the previous guidelines , changing from ≤ 140 mm Hg to ≤ 150 mm Hg.
dia st olic h yper t en sion . Researchers conducted a study to determine the impact of the current guidelines on reclas-
4
Th e specific ca u se of sification of hypertension diagnosis in older black and white individuals. Among more than
pr im a r y h yper t en sion is 6,000 participants, the prevalence of those achieving blood pressure goals increased from
oft en u n kn own . It is con - 62.8% to 79.4% using the new, less aggressive blood pressure goals. However, blood pres-
sider ed a m u lt ifa ct or ia l sure remained uncontrolled in more than 20% of participants in the study.
disea se r esu lt in g fr om
a com plex in t er a ct ion
of gen et ic a n d en vir on m en t a l t r igger s. Cer t a in r isk Th r ee m a jor body syst em s a r e a ffect ed by h y-
fa ct or s for t h e developm en t of pr im a r y h yper t en sion per t en sion : t h e cen t r a l n er vou s syst em (CNS), ca r-
h a ve been iden t ified a n d in clu de: diova scu la r syst em , a n d r en a l syst em . In sever e
h yper t en sion , t h e CNS is a ffect ed beca u se t h e ele-
● Fa m ily h ist or y of h yper t en sion
va t ed BP over wh elm s t h e cer ebr a l blood flow. Usu -
● Agin g
a lly, a s blood pr essu r e in cr ea ses, cer ebr a l a r t er ioles
● Bla ck r a ce
va socon st r ict , a n d cer ebr a l blood flow r em a in s con -
● Decr ea sed n eph r on n u m ber
st a n t . Du r in g a h yper t en sive cr isis (a r a pid a n d se-
● Dia bet es m ellit u s
ver e eleva t ion in blood pr essu r e), t h e h yper t en sion
● E xcessive diet a r y sodiu m in t a ke
over wh elm s a r t er iola r con t r ol over va socon st r ict ion .
● Obesit y
P r essu r ized flu id lea ks a cr oss t h e ca pilla r ies a n d
● Seden t a r y lifest yle
in t o t h e br a in t issu e a n d ot h er br a in st r u ct u r es.
● Nu t r it ion
Ar t er ioles a r e da m a ged du r in g t h is pr ocess. In t r a -
● E xcessive a lcoh ol in t a ke
cr a n ia l pr essu r e in cr ea ses, oxygen t r a n spor t is im -
● Sm okin g
pa ir ed, a n d br a in fu n ct ion is r edu ced.
H yper t en sion is a m a n ifest a t ion of in cr ea sed ca r dia c H yper t en sion a lso a ffect s t h e ca r diova scu la r sys-
ou t pu t or per iph er a l r esist a n ce a n d is ch a r a ct er ized t em . H yper t en sion wa s pr eviou sly m en t ion ed a s a
by st r u ct u r a l a n d fu n ct ion a l ch a n ges in t h e h ea r t fa ct or in t h e developm en t of a t h er oscler osis a n d ca n
a n d va scu la r syst em . Ca r dia c ou t pu t is eleva t ed con t r ibu t e t o obst r u ct ion in a r t er ies. P r essu r e in t h e
by con dit ion s t h a t in cr ea se st r oke volu m e or h ea r t sm a ll a r t er ioles, or m icr ova scu la t u r e, ca n lea d t o
r a t e. Per iph er a l r esist a n ce is eleva t ed by con dit ion s a lt er ed fu n ct ion of t h e t a r get or ga n . Th e sm a ll ves-
t h a t r est r ict per iph er a l blood flow, su ch a s in cr ea sed sels in t h e kidn eys, eyes, br a in , a n d h ea r t a r e pa r-
blood viscosit y or va socon st r ict ion . Reca ll t h e m ech a - t icu la r ly vu ln er a ble. H yper t en sive pr essu r e is a lso
n ism s for r egu la t in g blood pr essu r e. Au t or egu la t or y a st r a in on t h e h ea r t , wh ich m u st con t in u e t o wor k
syst em s a r e design ed t o a dju st t o ch a n ges in ca r dio- a ga in st t h is pr essu r e t o per fu se t h e body. Th e left
va scu la r dem a n d. Im pa ir m en t s in t h ese r egu la t or y ven t r icle is m ost a ffect ed by t h e pr essu r e r esist a n ce.
m ech a n ism s ca n in cr ea se per iph er a l va scu la r r esis- Th e left ven t r icle becom es h yper t r oph ic. In effect ive
t a n ce a n d pr om ot e t h e developm en t of h yper t en sion : left ven t r icle pu m pin g im pa ir s ven ou s r et u r n a n d
syst em ic per fu sion . Th is lea ds t o pu lm on a r y edem a ,
● Sym pa t h et ic n er vou s syst em over st im u la t ion
m yoca r dia l isch em ia , a n d per iph er a l h ypoxem ia .
(syst em ic va socon st r ict ion )
P r olon ged pr essu r e in t h e kidn ey a r t er ioles pr o-
● Ren in –a n giot en sin –a ldost er on e over st im u la t ion
m ot es ch r on ic in ju r y a n d in fla m m a t ion . Th is lea ds
(syst em ic va socon st r ict ion , sa lt a n d wa t er r et en -
t o n eph r oscler osis, wh ich is ba sica lly a n over gr owt h
t ion by kidn eys, in cr ea sed blood volu m e)
a n d h a r den in g of t h e con n ect ive t issu es of t h e kid-
● Im pa ir ed sodiu m excr et ion by t h e kidn eys (sa lt
n ey. H yper t en sion is per pet u a t ed a s r en in a n d a l-
a n d wa t er r et en t ion , in cr ea sed blood volu m e)
dost er on e secr et ion is st im u la t ed by r edu ced blood
Ch r on ic h yper t en sion da m a ges t h e blood vessel wa lls flow t o t h e kidn eys. Blood volu m e expa n ds a n d in -
t h r ou gh dir ect in ju r y t o t h e in t im a (in n er lin in g) cr ea ses blood pr essu r e.
fr om pr olon ged va socon st r ict ion a n d h igh pr essu r es.
Th e in fla m m a t or y r espon se in cr ea ses syst em ic ca p-
illa r y per m ea bilit y a n d fu r t h er da m a ges t h e vessel
CLINICAL MANIFESTATIONS
wa ll. Th e vessel wa lls a da pt t h r ou gh h yper t r oph y P r im a r y h yper t en sion is oft en a sym pt om a t ic a n d
a n d h yper pla sia t o wit h st a n d t h is st r ess. Th e vessel m a y be det ect ed on ly t h r ou gh a ser ies of blood pr es-
lu m en per m a n en t ly n a r r ows. su r e scr een in gs. Wh en clin ica l m a n ifest a t ion s a r e
412 C h a p t e r 16: Alt er ed Per fu sion

pr esen t , t h is oft en r eflect s yea r s of u n det ect ed h y- ● S ta ge 1: syst olic BP 140–159 m m H g, dia st olic BP
per t en sion . CNS m a n ifest a t ion s in clu de h ea da ch e, 90–99 m m H g
n ew-on set blu r r ed vision , n a u sea , vom it in g, wea k- ● S ta ge 2: syst olic BP gr ea t er t h a n 159 m m H g, dia -
n ess, fa t igu e, con fu sion , a n d m en t a l st a t u s ch a n ges. st olic BP gr ea t er t h a n 99 m m H g
Ru pt u r e of cer ebr a l vessels du e t o h yper t en sion
E ven befor e a n eleva t ed blood pr essu r e is n ot iced,
lea ds t o st r oke (see clin ica l m odel discu ssed below).
som e in dividu a ls a r e a t r isk for t h e developm en t of
Ca r diova scu la r m a n ifest a t ion s m a y in clu de t h e
ca r diova scu la r disea se. For exa m ple, a n in dividu a l
sign s a n d sym pt om s of pu lm on a r y edem a a n d ot h er
wit h a blood pr essu r e of 130/80 m m H g m a y h a ve
m a n ifest a t ion s of h ea r t fa ilu r e (see H ea r t Fa ilu r e
sign s of da m a ge t o t h eir h ea r t , kidn eys, or eyes
below). Ren a l in su fficien cy m a n ifest s a s poor u r i-
ca u sed by blood pr essu r e, wh er ea s a n ot h er in divid-
n a r y ou t pu t , h em a t u r ia , pr ot ein u r ia , a n d pr oblem s
u a l wit h t h e sa m e blood pr essu r e r ea din g m a y h a ve
wit h elim in a t in g u r in a r y wa st e.
n o su ch or ga n da m a ge a n d t h er efor e be a t lower r isk
for a h ea r t a t t a ck or st r oke. Th e poin t is t h a t t h e
DIAGNOSTIC CRITERIA dia gn osis of h yper t en sion is su ppor t ed by eleva t ion s
in blood pr essu r e, bu t t h e em ph a sis sh ou ld be on
Beca u se h yper t en sion is a ssocia t ed wit h eleva t ed eva lu a t in g t h e per son ’s over a ll r isk for ca r diova scu -
r isks of ca r diova scu la r disea ses (especia lly st r oke, la r disea se.
m yoca r dia l in fa r ct ion , a n d ca r diova scu la r dea t h ), Releva n t la bor a t or y st u dies t h a t con t r ibu t e t o
ea r ly r ecogn it ion is cr it ica l t o pr even t su ch com plica - t h is eva lu a t ion in clu de elect r olyt e levels, u r in a lysis,
t ion s. Dia gn osis is ba sed on a ca r efu l pa t ien t h ist or y, blood u r ea n it r ogen (BUN), a n d cr ea t in in e, wh ich de-
ph ysica l exa m in a t ion , a n d la bor a t or y a n d dia gn os- t ect eviden ce of r en a l im pa ir m en t . A lipid pr ofile is
t ic t est s. Th e pa t ien t h ist or y sh ou ld in clu de iden t i- u sefu l t o det ect h yper ch olest er olem ia . Blood glu cose
fyin g h yper t en sive fa m ily m em ber s a n d ot h er r isk t est in g is n eeded t o det ect dia bet es. In a h yper t en -
fa ct or s descr ibed pr eviou sly. P h ysica l exa m in a t ion sive cr isis, a ch est r a diogr a ph m a y be n eeded t o de-
m u st in clu de t h e n on in va sive a u scu lt a t or y-m et h od t er m in e con gest ive h ea r t fa ilu r e, pu lm on a r y edem a ,
m ea su r em en t of blood pr essu r e a s well a s a focu s on or coa r ct a t ion of t h e a or t a . A com pu t ed t om ogr a ph y
det ect in g t a r get or ga n da m a ge a n d ca r diova scu la r (CT) sca n of t h e br a in m a y be n eeded t o det er m in e
disea se. in t r a cr a n ia l bleedin g, edem a , or in fa r ct ion a s ca u ses
Dia gn osis of h yper t en sion is n ot ba sed on a n iso- for secon da r y h yper t en sion . An E CG m a y a lso be
la t ed eleva t ion in blood pr essu r e. Ra t h er, a ser ies of u sefu l t o a ssess for ca r dia c isch em ia or in fa r ct ion .
pr oper ly per for m ed blood pr essu r e m ea su r em en t s
(u su a lly t h r ee) over a 3- t o 6-m on t h per iod is n eeded
t o con fir m t h e pr esen ce of pr im a r y h yper t en sion . TREATMENT
Am on g in dividu a ls over a ge 60, t h e goa l for blood
pr essu r e is < 150 m m H g syst olic a n d < 90 m m H g Redu ct ion of ca r diova scu la r r isk t h r ou gh lifest yle is
dia st olic.2 Am on g in dividu a ls less t h a n 60 yea r s of idea l. Tr ea t m en t of h yper t en sion in clu des con sider-
a ge, syst olic blood pr essu r e of < 140 m m H g or dia - a t ion of ph a r m a cologic a n d n on ph a r m a cologic in t er-
st olic blood pr essu r e of < 90 m m H g a r e t h e t a r get ven t ion s. Th e followin g m ea su r es a r e a ppr opr ia t e
blood pr essu r e goa ls. On ce a per sist en t eleva t ion in in a ll per son s wit h h yper t en sion : weigh t r edu ct ion ;
blood pr essu r e is iden t ified, t h e level of h yper t en - decr ea sed a lcoh ol, sa lt , a n d sa t u r a t ed fa t in t a ke;
sion ca n be cla ssified a ccor din g t o sever it y.2 in cr ea sed a er obic ph ysica l a ct ivit y a n d fr u it a n d
veget a ble (pot a ssiu m ) a n d vit a m in D in t a ke; a n d
● P r eh yper ten sion : syst olic BP 120–139 m m H g, di- sm okin g cessa t ion . P h a r m a cologic t r ea t m en t s, wh en
a st olic BP 80–89 m m H g in dica t ed, wor k t o decr ea se flu id volu m e (diu r et ics),
decr ea se ca r dia c con t r a c-
t ilit y or ca r dia c ou t pu t
(ca lciu m ch a n n el block-
er s), or decr ea se per iph -
F R O M T H E L AB
er a l va scu la r r esist a n ce
Plasma lipids and lipoproteins include total cholesterol, triglycerides, high-density lipopro- (a n giot e n s in -con ve r t in g
tein (HDL) cholesterol, and LDL cholesterol. Total cholesterol reflects the sum of LDL and en zym e [ACE ] in h ibit or s,
HDL cholesterol plus 20% of total triglyceride levels. Lipid levels are typically measured after a n giot en sin II r ecept or
a 14-hour fast (water permitted). LDL cholesterol level of ≥ 190 mg/ dL or triglyceride levels blocker [ARB]). Th e over-
≥ 500 mg/ dl in people 21 years of age or older indicate need for cholesterol lowering treat- a ll goa l of ph a r m a cologic
ment with statins. 5 For individuals with diabetes or clinical heart disease, statin treatment t h er a py is t o decr ea se
is recommended for LDL cholesterol levels of 70–189 mg/ dL. per iph er a l va scu la r r e-
sist a n ce a n d r edu ce t h e
 C lin ic a l Mo d e ls 413

Ta b le 16.3 Select P h a r m a cologic Opt ion s for Tr ea t m en t of H yper t en sion

T y p e o D r u g (E x a m p le )
Th ia zide diu r et ics
Ca lciu m ch a n n el blocker s
(CCB)
An giot en sin -con ver t in g en -
zym e in h ibit or (ACE -I)
An giot en sin II r ecept or
blocker s (ARB)
S it e o Ac t io n
Ren a l t u bu les of t h e
kidn eys
Va scu la r a n d ca r dia c
m u scle cells
ACE
An giot en sin II
r ecept or s
Ac t io n
P r even t Na Cl r ea bsor pt ion in t h e
dist a l con volu t ed t u bu le
Blocks t h e m ovem en t of ca lciu m in t o
t h e a r t er ia l sm oot h m u scle cells,
t h er eby decr ea sin g va socon st r ict ion
In h ibit s t h e con ver sion of a n gio-
t en sin I t o a n giot en sin II, t h er eby
pr even t in g va socon st r ict ion a n d de-
cr ea sin g a ldost er on e levels
Blocks t h e a ct ion s of a n giot en sin II,
pr even t in g a n giot en sin
II-m edia t ed va socon st r ict ion a n d
a ldost er on e-m edia t ed flu id r et en t ion
R a t io n a le o r U s e
Decr ea se ca r dia c ou t pu t
a n d flu id volu m e over loa d
wit h a n even t u a l r edu ct ion
in per iph er a l va scu la r
r esist a n ce
Decr ea ses per iph er a l va s-
cu la r r esist a n ce
Decr ea ses per iph er a l va s-
cu la r r esist a n ce
Decr ea ses per iph er a l
va scu la r r esist a n ce a n d
decr ea ses flu id volu m e t o
r edu ce ca r dia c ou t pu t

wor kloa d of t h e h ea r t by r edu cin g a r t er ia l pr es-
su r e below 140/90. Most in dividu a ls wit h h yper t en -
sion r equ ir e t wo or m or e a n t ih yper t en sive dr u gs t o
a ch ieve t h is goa l. P h a r m a cot h er a py is n ot cu r a t ive,
bu t it r edu ces bot h t h e sym pt om s a n d t h e r isk for
lon g-t er m com plica t ion s. Ta ble 16.3 pr ovides m or e
det a il on ph a r m a cologic opt ion s.
Shock
Sh ock is a con dit ion of cir cu la t or y fa ilu r e a n d im -
pa ir ed per fu sion of vit a l or ga n s. Sh ock is oft en
equ a t ed wit h h y p o t e n s io n , or r edu ced blood pr es-
su r e, a lt h ou gh t h is is con sider ed a la t e sign a n d sig-
n a ls in effect ive com pen sa t ion .
PATHOPHYSIOLOGY
E ffect ive blood cir cu la t ion depen ds on ca r dia c ou t -
pu t (in clu din g a n opt im a l blood volu m e) a n d on
per iph er a l va scu la r r esist a n ce. Sh ock r epr esen t s a
deficit in on e or m or e of t h ese r equ isit es a n d is oft en
cla ssified a ccor din gly:
● In effect ive ca r dia c pu m pin g: ca r d iogen ic sh ock
● Decr ea sed blood volu m e: h ypovolem ic sh ock
● Ma ssive syst em ic va sodila t ion :
■ F r om sever e in fect ion : septic sh ock
■ F r om br a in or spin a l cor d in ju r y: n eu r ogen ic
sh ock
■ F r om sever e im m u n oglobu lin E (IgE )-m edia t ed
h yper sen sit ivit y r ea ct ion : a n a ph yla ctic sh ock
C a r d io g e n ic s h o c k r esu lt s fr om in a dequ a t e
or in effect ive ca r dia c pu m pin g. Th e m ost com m on
ca u se is m yoca r dia l in fa r ct ion , a lt h ou gh a n y ca r dia c
con dit ion t h a t r edu ces h ea r t efficien cy ca n lea d t o
ca r diogen ic sh ock. Th e ba sic pr oblem is t h a t im -
pa ir ed pu m pin g lea ds t o r edu ced ca r dia c ou t pu t ,
low blood pr essu r e, a n d r est r ict ed m ovem en t of ox-
ygen a t ed blood t h r ou gh t h e cir cu la t ion . Th is lea ds
t o syst em ic h ypot en sion or pu lm on a r y edem a . Th e
m or t a lit y r a t e is a ppr oxim a t ely 70% for pa t ien t s
wh o do n ot u n der go r a pid r eva scu la r iza t ion t o pr o-
m ot e m yoca r dia l blood flow.
H y p o v o le m ic s h o c k is t h e r esu lt of in a dequ a t e
blood/pla sm a volu m e a n d t ypica lly occu r s wh en t h is
volu m e is r edu ced by 15% t o 20%. Th is t ype of sh ock
ca n r esu lt fr om sever e h em or r h a ge, bu r n s, dia r r h ea ,
or polyu r ia , a s occu r s wit h dia bet es in sipidu s. Th e
pr oblem is t h a t blood a n d flu id losses in t h e va scu la r
spa ce lea d t o deficien t ven ou s r et u r n a n d r edu ced
cir cu la t ion . Redu ct ion in t h e volu m e of r ed blood
cells a lso r edu ces oxygen t r a n spor t t h r ou gh t h e cir-
cu la t ion . Wit h ou t cor r ect in g t h e u n der lyin g ca u se,
in a dequ a t e per fu sion lea ds t o m u lt iple or ga n fa ilu r e.
S e p t ic s h o c k is t h e r esu lt of over wh elm in g
syst em ic in fect ion wh er e a bou t h a lf a r e ca u sed by
gr a m -posit ive m icr oor ga n ism s, followed closely by
gr a m -n ega t ive m icr oor ga n ism s, a lt h ou gh in som e
ca ses t h e exa ct pa t h ogen is u n kn own . Gr a m -n ega t ive
m icr oor ga n ism s con t a in en dot oxin t h a t ca n pr odu ce
a m a ssive in fla m m a t or y r espon se by r elea sin g po-
t en t ch em ica l m edia t or s. Th ese ch em ica l m edia t or s
in du ce widespr ea d t issu e in ju r y. E n dot h elia l cells
t h a t lin e blood vessels va sodila t e a n d becom e per-
m ea ble. In ju r y t o t h ese en dot h elia l cells n ot on ly
a llows flu id t o esca pe t h e in t r a va scu la r com pa r t -
m en t bu t a lso da m a ges t h ese cells, dir ect ly ca u sin g
va scu la r colla pse. Sept ic sh ock is con sider ed a gr a ve
con dit ion t h a t h a s a m or t a lit y r a t e of a ppr oxim a t ely
30% t o 50%.
414 C h a p t e r 16: Alt er ed Per fu sion
N e u r o g e n ic s h o c k is a r esu lt of br a in or spin a l
cor d in ju r y, t h e depr essa n t a ct ion s of cer t a in dr u gs,
gen er a l a n est h esia , h ypoglycem ia , or h ypoxia . Al-
t er ed n eu r on a l t r a n sm ission lea ds t o a loss of sym -
pa t h et ic con t r ol of t en sion in t h e blood vessels. Th is
loss of t en sion a llows u n r egu la t ed va sodila t ion . Va -
sodila t ion decr ea ses per iph er a l va scu la r r esist a n ce,
blood pr essu r e is r edu ced, a n d per fu sion t o vit a l
or ga n s is r edu ced. Neu r ogen ic sh ock is t h e r a r est
ca u se of sh ock, is r ea dily t r ea t a ble, a n d gen er a lly r e-
spon ds well t o m edica l t h er a py.
An a p h y la c t ic s h o c k is t h e r esu lt of a m a ssive
im m u n e (t ype 1 or IgE -m edia t ed) h yper sen sit iv-
it y r espon se (Ch a pt er 4). Sim ila r t o sept ic sh ock,
a n a ph yla xis lea ds t o m a ssive va sodila t ion a n d in -
cr ea sed va scu la r per m ea bilit y. Per iph er a l va scu la r
r esist a n ce is r edu ced sign ifica n t ly, flu id is a llowed t o
m ove ou t side of t h e va scu la r spa ce, blood pr essu r e is
r edu ced, a n d cir cu la t ion is im pa ir ed.
All t ypes of sh ock depr ive t h e cells of oxygen a n d
n u t r ien t s a n d t h u s im pa ir cellu la r m et a bolism , r e-
su lt in g in a cidosis. In it ia lly, h ypoxia a n d a cidosis a r e
m et wit h com pen sa t or y m ech a n ism s t h a t in volve:
● S tim u la tin g th e sym pa th etic n er vou s system : Th e
sym pa t h et ic n er vou s syst em is st im u la t ed t o in -
cr ea se h ea r t r a t e a n d ca r dia c con t r a ct ilit y a n d t o
a lt er blood vessel t on e. Regu la t ion of vessel t on e
pr om ot es (1) va sodila t ion of vessels lea din g t o t h e
h ea r t a n d br a in a n d (2) va socon st r ict ion t o ot h er,
less vit a l a r ea s of t h e body.
● S tim u la tin g th e r en in –a n gioten sin –a ld oster on e
m ech a n ism : Ren in a n d a n giot en sin pr om ot e com -
pen sa t or y va socon st r ict ion . Th ese h or m on es a lso
pr om ot e sodiu m a n d wa t er r ea bsor pt ion t o in -
cr ea se in t r a va scu la r volu m e.
Th e gen er a l goa ls of com pen sa t ion a r e t o (1) sh u n t
blood t o t h e h ea r t a n d br a in a n d (2) pr om ot e ca r dia c
ou t pu t by in cr ea sin g in t r a va scu la r volu m e, h ea r t
r a t e, a n d ca r dia c con t r a ct ilit y. Som et im es t h ese
com pen sa t or y m ech a n ism s a r e a dequ a t e t o r ever se
sh ock. Un for t u n a t ely, in m a n y ca ses, t h ese com pen -
sa t ion s a r e t em por a r y. A down wa r d spir a l fr om pr o-
lon ged r elia n ce on com pen sa t or y m ech a n ism s lea ds
t o in cr ea sin g h ypoxia m a r ked by:
1. E n dot h elia l (vessel lin in g) in ju r y, a llowin g fu r-
t h er loss of in t r a va scu la r flu ids
2. F lu id depr iva t ion in t h e vessel, pr om ot in g fu r t h er
difficu lt ies wit h ca r dia c ou t pu t
3. Con t in u ed r edu ct ion in per fu sion , pr om ot in g cel-
lu la r in ju r y, a n a er obic m et a bolism , a n d m et a bolic
a cidosis
All cells becom e depr ived of oxygen a n d ot h er n u t r i-
en t s a n d con ver t t o in efficien t a n a er obic m et a bolism .
E ven t u a lly, cellu la r m et a bolism is u n a ble t o gen er-
a t e en ou gh en er gy t o m a in t a in cellu la r h om eost a sis.
Th is lea ds t o im pa ir m en t of t h e cell m em br a n e ion
pu m p, a ccu m u la t ion of in t r a cellu la r sodiu m , a n d
t h e loss of in t r a cellu la r pot a ssiu m . Th e cell swells,
r u pt u r es, a n d dies. In 50% of t h ose exper ien cin g se-
ver e sh ock, m u lt iple or ga n fa ilu r e, pa r t icu la r ly of
t h e h ea r t , br a in , kidn eys, lu n gs, a n d skelet a l m u scle,
lea ds t o som a t ic dea t h .
CLINICAL MANIFESTATIONS
E a r ly clin ica l m a n ifest a t ion s of sh ock a r e r ela t ed
t o t h e t r igger in g even t . Beca u se t h e pr im a r y ca u se
of ca r diogen ic sh ock is m yoca r dia l in fa r ct ion , ea r ly
clin ica l m a n ifest a t ion s m a y in clu de ch est pa in ,
sh or t n ess of br ea t h , la bor ed br ea t h in g, dia ph or esis,
n a u sea , or vom it in g. In h ypovolem ic sh ock, m a n ifes-
t a t ion s a r e r ela t ed t o t h e ext en t of blood or pla sm a
loss. In fect ion lea din g t o sept ic sh ock pr om ot es fever
a n d flu sh ed, wa r m skin . An a ph yla ct ic sh ock t r igger s
gen er a lized skin flu sh in g a n d m a y lea d t o a ir wa y
obst r u ct ion .
Clin ica l m a n ifest a t ion s con sist en t a cr oss t h e po-
t en t ia l et iologies a r e t h ose in dica t ive of cir cu la t or y
im pa ir m en t a n d colla pse a n d in clu de m a r ked t a ch y-
ca r dia , t a ch ypn ea , cool a n d cla m m y ext r em it ies, poor
per iph er a l pu lses, decr ea sed a r t er ia l blood pr essu r e
(a la t e sign in dica t ive of decom pen sa t ion ), cya n osis,
pa llor, r est lessn ess, a ppr eh en sion , decr ea sed m en t a l
fu n ct ion , a n d poor u r in a r y ou t pu t . Beca u se sh ock
r edu ces per fu sion t h r ou gh ou t t h e body, m u lt iple
m a n ifest a t ion s a r e possible r ela t ed t o gen er a l or ga n
dysfu n ct ion .
DIAGNOSTIC CRITERIA
No on e t est is com plet ely specific or sen sit ive for
sh ock. Th e dia gn osis of sh ock is ba sed on a t h or ou gh
pa t ien t h ist or y, ph ysica l exa m in a t ion , a n d la bor a -
t or y a n d dia gn ost ic t est s. Th e pa t ien t h ist or y r evea ls
a t r igger in g even t , su ch a s m yoca r dia l in fa r ct ion ,
m a ssive h em or r h a ge, syst em ic in fect ion , spin a l cor d
in ju r y, or a n a ph yla xis. P h ysica l a ssessm en t in clu des
obser va t ion of skin color, t em per a t u r e, pu lses, ca pil-
la r y r efill, h ea r t r a t e, blood pr essu r e, u r in e ou t pu t ,
a n d m en t a l st a t u s. La bor a t or y st u dies va r y a n d
a r e dir ect ed a t t h e pot en t ia l ca u se. For exa m ple, in
ca r diogen ic sh ock, la bor a t or y t est s in clu de ca r dia c
en zym es (cr ea t in e kin a se, t r opon in , m yoglobin ), a
com plet e blood cou n t , elect r olyt es, a r t er ia l blood
ga ses, a n d blood coa gu la t ion t est s. An E CG a n d
ech oca r diogr a m a r e u sed t o det ect t h e pa t t er n a n d
loca t ion of h ea r t in ju r y.
TREATMENT
Sh ock is con sider ed a m edica l em er gen cy a n d r e-
qu ir es a t t en t ion t o t h e pa t ien t ’s a ir wa y, br ea t h in g,
 C lin ic a l Mo d e ls 415

a n d cir cu la t ion . Th e
ch oice of a ct ion on t h e R E S E AR C H N O T E S
per iph er a l vessels de-
pen ds on t h e sh ock et i- Risk for cardiovascular disease can be calculated using established tools that predict the
ology, flu id volu m e, a n d likelihood of a cardiac event within a period of time. The established Framingham Risk
con t r a ct ile a bilit y of t h e Score and the new American College of Cardiology/ American Heart Association (ACC/ AHA)
h ea r t . Un less con t r a in - Pooled Cohort Equations Risk Estimator were used to compare risk for cardiovascular risk in
dica t ed, h ypovolem ic pa - > 30,000 adult men. 7 The ACC/ AHA assessment identified lower absolute risk and more tem-
t ien t s sh ou ld be pla ced porary “intermediate risk” groups as compared to the Framingham Risk Score calculation.
in a su pin e posit ion wit h
legs eleva t ed t o m a xi-
m ize cer ebr a l blood flow. Th e u se of bla n ket s is oft en pr oblem s, in clu din g im pa ir ed con du ct ion , im pa ir ed
n eeded t o keep t h e pa t ien t wa r m . Tr ea t m en t is fo- m yoca r dia l pu m pin g, a n d h ea r t fa ilu r e.
cu sed on r em ovin g or r edu cin g t h e u n der lyin g ca u se.
In ca r diogen ic sh ock, t r ea t m en t in volves su r gi-
PATHOPHYSIOLOGY
ca lly r eva scu la r izin g t h e h ea r t a t t h e poin t of ob-
st r u ct ion (see t r ea t m en t of m yoca r dia l in fa r ct ion My o c a r d ia l in a r c t io n is t h e t ot a l occlu sion of on e
below). Medica l t r ea t m en t is a im ed a t im pr ovin g or m or e cor on a r y a r t er ies r esu lt in g in isch em ia a n d
ca r dia c ou t pu t , m a in t a in in g blood pr essu r e, r edu cin g dea t h of m yoca r dia l t issu es (F ig. 16.12). Con sist en t
t h e wor kloa d on t h e h ea r t , pr ovidin g oxygen t h er a py, wit h CH D, t h e m ost com m on ca u se is a t h er oscler o-
a n d r egu la t in g flu id volu m es in t h e body. In ot r opic sis. At h er oscler ot ic a ccu m u la t ion s ca n eit h er dir ect ly
m edica t ion s in cr ea se m yoca r dia l con t r a ct ilit y. Va r i- obst r u ct t h e a r t er y, or br ea k off, ca u sin g pla t elet s t o
ou s dr u gs in t h is gr ou p h a ve eit h er va socon st r ict in g a ggr ega t e a t t h e sit e of in ju r y a n d for m a t h r om bu s
(epin eph r in e, n or epin eph r in e) or va sodila t in g (dobu - t h a t occlu des t h e a r t er y. Fa ct or s t h a t con t r ibu t e t o
t a m in e) effect s on per iph er a l va scu la r r esist a n ce. In ca r diova scu la r r isk in clu de a ge, sex, r a ce, t ot a l ch o-
h ypovolem ic sh ock, t r ea t m en t is focu sed on im pr ov- lest er ol, H DL ch olest er ol, syst olic blood pr essu r e,
in g t issu e per fu sion t h r ou gh in t r a ven ou s flu id/blood blood pr essu r e lower in g m edica t ion u se, dia bet es
r epla cem en t . Sou r ces of bleedin g or flu id loss m u st st a t u s, a n d sm okin g st a t u s. 6 Ma jor r isk fa ct or s for
be iden t ified a n d cor r ect ed. Oxygen m a y be a dm in - t h e developm en t of a t h er oscler osis a n d su bsequ en t
ist er ed depen din g on t h e level of h ypoxem ia . Sept ic m yoca r dia l in fa r ct ion in clu de:
sh ock t r ea t m en t is a im ed a t t r ea t in g t h e sou r ce of
in fect ion a n d su ppor t in g cir cu la t ion . P h a r m a cologic ● Fa m ily h is t o r y : In dividu a ls wit h a fa m ily h is-
t r ea t m en t in clu des br oa d-spect r u m a n t im icr obia l t or y of a t h er oscler osis a n d m yoca r dia l in fa r ct ion
dr u gs t h a t pr ovide cover a ge for possible pa t h ogen s a r e a t gr ea t er r isk, pa r t icu la r ly t h ose wit h a fa -
a n d va sopr essor dr u gs t h a t pr om ot e va socon st r ic- t h er or ot h er m a le fir st -degr ee r ela t ive wh o expe-
t ion . Cor t icost er oids a r e oft en n eeded in a n a ph y- r ien ced a m yoca r dia l in fa r ct ion or su dden dea t h
la ct ic sh ock t o decr ea se t h e syst em ic in fla m m a t or y fr om a cor on a r y even t pr ior t o 55 yea r s of a ge; or
r espon se. Neu r ogen ic sh ock t r ea t m en t is a im ed a t a m ot h er or ot h er fem a le fir st -degr ee r ela t ive ex-
iden t ifyin g a n d cor r ect in g t h e ca u se if possible a n d per ien cin g t h e sa m e pr ior t o 65 yea r s of a ge.
su ppor t in g va socon st r ict ion wit h in ot r opic m edica - ● H y p e r t e n s io n a n d s m o k in g : H yper t en sion a n d
t ion s. Fr equ en t m on it or in g of vit a l or ga n fu n ct ion sm okin g in ju r e t h e en dot h elia l lin in g, pr om ot in g
a n d h em odyn a m ic st a t u s is r equ ir ed for a ll pa t ien t s t h e developm en t of a t h er oscler osis. Syst olic blood
wit h sh ock. pr essu r e a bove 160 m m H g is a ssocia t ed wit h a
t h r ee-fold in cr ea se in r isk of developin g CH D.
Dia st olic eleva t ion s a r e sign ifica n t con t r ibu t or s
a s well.
Myocardial Infarction ● B lo o d c h o le s t e r o l le v e ls : Th e a m ou n t of ch oles-
t er ol, pa r t icu la r ly h igh LDL (see Fr om t h e La b,
Cor on a r y h ea r t disea se (CH D) is a t er m u sed t o below), in t h e blood, pr om ot in g lipid a ccu m u la t ion
iden t ify a n y pr oblem of im pa ir ed cor on a r y cir cu la - in t h e vessels.
t ion . At h er oscler osis is pr im a r ily im plica t ed in t h e ● C o n c u r r e n t d ia b e t e s m e llit u s : Type 2 dia be-
developm en t of CH D. Con sequ en ces of CH D r a n ge t es is a ssocia t ed wit h eleva t ion s in blood lipid
fr om com pen sa t ion t h r ou gh t h e developm en t of col- levels. Th e r ole of dia bet es m ellit u s in t h e devel-
la t er a l cir cu la t ion t o t h e m yoca r dia l cells t o su dden opm en t of a t h er oscler osis is fu r t h er discu ssed in
dea t h fr om m yoca r dia l a n oxia . Beca u se m u lt iple Ch a pt er 16.
pr ocesses a r e a t wor k du r in g ca r dia c per fu sion , t h e ● H ig h -s e n s it iv it y C -r e a c t iv e p r o t e in (C R P ):
loss of cor on a r y cir cu la t ion ca n lea d t o a spect r u m of CRP is a n on specific a cu t e ph a se pr ot ein t h a t is
416 C h a p t e r 16: Alt er ed Per fu sion
Obs truction
Is che mia
Ne cros is
A
Figure 16.12. Myocardial infarction. A: Left coronary artery obstruction shows zones of necrosis and ischemia.
B: A cross section of the left ventricle reveals a sharply circumscribed, soft, yellow area of necrosis. (From Rubin E,
Farber JL. Pathology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.)
pr odu ced by t h e liver in r espon se t o t issu e in ju r y
a n d is con sider ed a sen sit ive m a r ker of in fla m -
m a t ion . E leva t ed CRP is a n em er gin g in dica t or of
r isk for t h e developm en t of m yoca r dia l in fa r ct ion
beca u se in fla m m a t ion h a s been lin ked wit h t h e
pa t h ogen esis of a t h er oscler osis.
● H y p e r h o m o c y s t e in e m ia : H om ocyst ein e is on e
of m a n y pot en t ia l r isk fa ct or s for t h e developm en t
of MI. H om ocyst ein e is der ived pr im a r ily fr om a
diet a r y a m in o a cid fou n d in a n im a l pr ot ein . H o-
m ocyst ein e pla ys a r ole in coa gu la t ion . H igh
levels of cir cu la t in g h om ocyst ein e a r e t oxic t o en -
dot h elia l cells a n d m a y pr om ot e excessive blood
coa gu la t ion a n d t h r om bu s for m a t ion . Abou t h a lf
of t h ose exper ien cin g a n a cu t e m yoca r dia l in fa r c-
t ion or st oke h a ve h yper h om ocyst ein em ia .
Th e size, loca t ion , du r a t ion of occlu sion , a n d pr es-
en ce of colla t er a l cir cu la t ion dict a t e t h e m a jor effect s
of t h e MI. La r ger a r t er ies, wh en obst r u ct ed, r esu lt
in m or e widespr ea d da m a ge t o t h e m yoca r diu m . Lo-
ca t ion of occlu sion a lso dict a t es m a jor effect s. Th e
left cor on a r y a r t er y su pplies blood t o t h e left side of
t h e h ea r t . Th e left cor on a r y a r t er y br a n ch es in t o t h e
a n t er ior descen din g left cor on a r y a r t er y, wh ich per-
fu ses pr im a r ily t h e left ven t r icle, a n d t h e cir cu m flex
left cor on a r y a r t er y, wh ich per fu ses pr im a r ily t h e
left a t r iu m a n d por t ion s of t h e left ven t r icle. Ob-
st r u ct ion im pa ir s t h e left ven t r icle a n d a ffect s t h e
a bilit y of t h e h ea r t t o pu m p blood syst em ica lly. Ven -
t r icu la r fibr illa t ion is a m a jor ca u se of su dden dea t h
fr om m yoca r dia l in fa r ct ion . Th e r igh t cor on a r y a r-
t er y a n d br a n ch es per fu se t h e r igh t side of t h e h ea r t ,
m ost n ot a bly t h e SA a n d AV n odes. Obst r u ct ion im -
pa ct s ca r dia c con du ct ion of im pu lses a n d ca n lea d t o
ir r egu la r it ies in h ea r t r h yt h m . Righ t h ea r t fa ilu r e
a lso im pedes t h e a bilit y t o m a n a ge ven ou s r et u r n
effect ively. Th e m yoca r diu m ca n wit h st a n d oxygen
depr iva t ion for a ppr oxim a t ely 20 m in u t es. Beyon d
t h is, m yoca r dia l cell dea t h is ir r ever sible. Myoca r-
dia l cells a r e r epla ced by n on fu n ct ion a l sca r t issu e.
Stop and Consider
Low-dose daily aspirin is commonly used to pre-
vent MI. Aspirin reduces platelet aggregation.
How would this medication help to prevent MI?
CLINICAL MANIFESTATIONS
Th e clin ica l m a n ifest a t ion s of MI a r e va r ia ble bu t
m a y in clu de: ch est pa in or a cr u sh in g pr essu r e, oft en
 C lin ic a l Mo d e ls 417

r a dia t in g t o t h e left a r m ,
sh ou lder, or ja w. Dizzi- F R O M T H E L AB
n ess, swea t in g, in diges-
t ion (h ea r t bu r n ) pa in , Established biomarkers of myocardial infarction include troponin-T, troponin-I, myocardial
n a u sea , vom it in g, fa - infarction of creatine kinase (CK) and myoglobin. Troponin, a complex of three proteins
t igu e, wea kn ess, a n xiet y, (troponin-C, troponin-I, and troponin-T) is present in skeletal and cardiac muscle and is
cool, m oist skin , pa llor, important in the regulation of muscle contractions. As troponin-C is found in both skeletal
or sh or t n ess of br ea t h and cardiac muscle, it is not a specific biomarker of cardiac injury. Troponin-T is specific
m a y a lso be r epor t ed. It for cardiac muscle, located in the contractile elements of the myocardial cells. Troponin-I
is com m on for t h e in di- is also specific to cardiac muscle and when combined with troponin-T, serves as a primary
vidu a l t o den y t h e ch est biomarker for cardiac injury associated with myocardial infarction. After MI, troponin-T and
pa in a s r ela t ed t o a MI. troponin-I are detected in the blood within 6 to 8 hours, peak at 12 to 24 hours, and remain
Wom en a r e pa r t icu la r ly elevated for 7 to 10 days after MI. Creatine kinase has three isoenzymes: MM, MB, and BB.
vu ln er a ble beca u se clin - Only CK-MB is found in cardiac cells and rises after myocardial injury. Four to 9 hours after
ica l m a n ifest a t ion s a r e myocardial injury, CK-MB levels increase, peak at 24 hours, and return to baseline at 48 to
con sider ed a t ypica l or 72 hours. Myoglobin, present in both skeletal and cardiac muscle, is released into the blood
su bt le (fa t igu e, syn cope, 1 hour after myocardial injury, peaks at 4 to 12 hours, and returns to normal soon after
or wea kn ess), a n d m a y peaking. When combined with troponin or CK-MB biomarkers, myoglobin can be used to rule
8
be ign or ed. An g in a p e c - out myocardial infarction if levels are inconsistent with myocardial injury.
t o r is is a t er m u sed t o
descr ibe ch est pa in or
pr essu r e t h a t is in t er-
m it t en t a n d a ssocia t ed wit h m yoca r dia l isch em ia , a m bu la n ce per son n el sh ou ld obt a in in t r a ven ou s a c-
a r edu ct ion in blood flow t o t h e cor on a r y a r t er ies cess, pr ovide su pplem en t a l oxygen , a n d a dm in ist er
ca u sed a t h er oscler osis t h a t is oft en a ccom pa n ied or a l a spir in . Aspir in in a ddit ion t o a n t icoa gu la n t
by va sospa sm . Th e pr esen ce of isch em ia a n d su bse- t h er a py m a y be u sed t o im pr ove per fu sion in t h e
qu en t a n gin a a r e exa cer ba t ed wit h in cr ea sed ca r dia c cor on a r y cir cu la t ion . Nit r oglycer in e (va sodila t or )
wor kloa d, su ch a s wit h exer cise, a n d a r e t ypica lly r e- a n d m or ph in e (a n a lgesic) sh ou ld be a dm in ist er ed
du ced wit h r est . Wit h MI, r est or n it r oglycer in e t a b- for a ct ive ch est pa in . E m er gen cy t r ea t m en t in volves
let s do n ot a llevia t e t h e pr esen ce of a n gin a . m edica l or su r gica l in t er ven t ion s. Per cu t a n eou s cor-
on a r y in t er ven t ion (P CI) is t h e t r ea t m en t of ch oice
for m a n y pa t ien t s wit h MI. P CI is a gr ou p of t ech -
DIAGNOSTIC CRITERIA
n iqu es ca pa ble of r elievin g cor on a r y a r t er y n a r-
Dia gn osis of m yoca r dia l in fa r ct ion is ba sed on r owin g. On e exa m ple is per cu t a n eou s t r a n slu m in a l
pr esen t in g sym pt om s (if a n y), E CG fin din gs, a n d cor on a r y a n giopla st y (P TCA), a pr ocedu r e t h a t in -
ca r dia c biom a r ker s (see F r om t h e La b, below). De- volves in ser t in g a t h in wir e in t o t h e cor on a r y a r t er y
pen din g on t h e loca t ion of t h e m yoca r dia l in fa r c- fr om a dist a n t a ccess poin t via ca r dia c ca t h et er iza -
t ion , E CG t r a cin gs m a y dem on st r a t e ST segm en t , t ion , in fla t in g a ba lloon wit h in t h is wir e a t t h e sit e
(see F ig. 16.5) eleva t ion s, in dica t in g pr oblem s wit h of obst r u ct ion , a n d pu sh in g open t h e st en ot ic vessel.
ven t r icu la r r epola r iza t ion . In la r ger in fa r ct s, t h e Th is pr ocedu r e oft en in clu des pla cem en t of a st en t
Q wa ve m a y a lso be pr olon ged. An giogr a ph y in t h e t o keep t h e vessel open a n d pa t en t . Som e pa t ien t s
ca r dia c ca t h et er iza t ion la bor a t or y det er m in es t h e r equ ir e cor on a r y a r t er y bypa ss su r ger y wh en ot h er
loca t ion a n d ext en t of obst r u ct ion . E ch oca r diogr a - m edica l or su r gica l in t er ven t ion s h a ve been in ef-
ph y will r evea l wa ll m ot ion a bn or m a lit ies a n d ven - fect ive (Fig. 16.13). Th r om bolyt ic a gen t s, com bin ed
t r icu la r fu n ct ion . A ch est r a diogr a ph m a y be u sed t o wit h a pot en t pla t elet in h ibit or, a r e r ecom m en ded
det ect com plica t ion s of a cu t e m yoca r dia l in fa r ct ion , wh en P CI is n ot a va ila ble wit h in a 90-m in u t e t im e
pa r t icu la r ly con gest ive h ea r t fa ilu r e a n d pu lm on a r y fr a m e. Th ese dr u gs br ea k t h ou gh t h r om boses a n d
edem a . r edu ce pla t elet a ggr ega t ion a t t h e sit e. Oxygen , n i-
t r oglycer in , a n a lgesics, a n d a spir in t h er a py a r e con -
t in u ed wh ile t h e pa t ien t is u n der em er gen cy ca r e.
TREATMENT
Lon g-t er m t r ea t m en t is a im ed a t su ppor t in g ca r dia c
Th e in it ia l st r a t egies for m a n a gin g m yoca r dia l in - con du ct ion , ou t pu t , a n d blood pr essu r e t h r ou gh m ed-
fa r ct ion a r e t o st a bilize a ir wa y, br ea t h in g a n d cir- ica t ion t h er a py (oft en wit h a spir in , bet a blocker s,
cu la t ion . Ra pid t r ea t m en t (wit h in 90 m in u t es) is ACE in h ibit or s, or a n giot en sin r ecept or blocker s)
pr efer r ed t o r eest a blish cor on a r y per fu sion a n d t o a n d pr escr ibed r est , exer cise, a n d m odifica t ion of
sa lva ge t h e m yoca r diu m a s m u ch a s possible. Befor e r isk fa ct or s (i.e., n o sm okin g, r edu ced a lcoh ol in t a ke,
t h e pa t ien t a r r ives a t t h e em er gen cy depa r t m en t , n u t r it iou s diet , a n d weigh t loss).
418 C h a p t e r 16: Alt er ed Per fu sion
Ve in gra ft
A Tr a dit ion a lly, h ea r t fa ilu r e is discu ssed ba sed on
Le ft
S ubclavia n a rte ry
Inte rna l
ma mma ry a rte ry
Ante rior de s ce nding
bra nch of the le ft
corona ry a rte ry
B
Figure 16.13. Coronary artery revascularization. A: Saphe-
nous vein bypass graft. The vein segment is sutured to the
ascending aorta and the right coronary artery at a point
distal to the occlusion. B: Mammary artery bypass. The
mammary artery is connected to the anterior descending
left coronary artery at a point distal to the occlusion.
Heart Failure
H e a r t a ilu r e r eflect s a n in a dequ a cy of h ea r t
pu m pin g so t h a t t h e h ea r t fa ils t o m a in t a in t h e cir-
cu la t ion of blood. Th e ba sis for t h e developm en t of
a lt er ed per fu sion of t issu es is a r esu lt of im pa ir ed
ca r d ia c fu n ction in g or excessive workloa d d em a n d s
t h a t ca n n ot be m et by t h e h ea r t . H ea r t fa ilu r e oc-
cu r s secon da r y t o ot h er con dit ion s t h a t per pet u a t e
im pa ir ed ca r dia c fu n ct ion in g or wor kloa d. E xa m ples
of con dit ion s t h a t r esu lt in im pa ir ed ca r dia c fu n c-
t ion in g in clu de m yoca r dia l in fa r ct ion , st r u ct u r a l de-
fect s of t h e h ea r t , or in fect ion a n d in fla m m a t ion of
t h e h ea r t t issu e la yer s. E xa m ples of con dit ion s t h a t
cr ea t e excessive wor k dem a n ds on t h e h ea r t in clu de
h yper t en sion , flu id volu m e over loa d, or a n em ia .
PATHOPHYSIOLOGY
Beca u se for wa r d m ovem en t of blood is r est r ict ed,
h ea r t fa ilu r e r esu lt s in con gest ion a n d edem a in pu l-
m on a r y or per iph er a l t issu es. In t h ose wit h h ea r t
fa ilu r e, ca r dia c r eser ve (t h e a bilit y t o in cr ea se ou t -
pu t du r in g in cr ea sed a ct ivit y) is expen ded du r in g
r est . Sim ple t a sks becom e exceedin gly t a xin g t o t h e
h ea r t .
Left Heart Failure
t h e loca t ion of or igin , eit h er t h e left or r igh t side of
t h e h ea r t . Despit e isola t in g left a n d r igh t , r em em -
ber t h a t t h ese a r e bot h pa r t of a con t in u ou s syst em .
Th er efor e, im pa ir ed pu m pin g a n d excessive per iph -
er a l va scu la r r esist a n ce even t u a lly com pr om ise bot h
t h e left a n d t h e r igh t sides of t h e h ea r t .
In left h ea r t fa ilu r e, t h e left ven t r icle is u n a ble
t o effect ively m eet ca r diova scu la r dem a n ds, for wa r d
m ovem en t of blood t h r ou gh t h e cir cu la t ion is in h ib-
it ed, a n d flu id a ccu m u la t es in t h e lu n g t issu es. Loss
of con t r a ct ile a bilit y, ca lled s y s t o lic a ilu r e , r esu lt s
in t h e h ea r t bein g u n a ble t o pu m p en ou gh blood in t o
t h e cir cu la t ion . St iffn ess of t h e ven t r icle a n d loss of
r ela xa t ion a bilit y, ca lled d ia s t o lic a ilu r e , im pa ir s
t h e a bilit y t o opt im a lly fill wit h blood bet ween ca r-
dia c con t r a ct ion s.
Stop and Consider
How do you think pharmacologic interventions
differ between systolic and diastolic left ventric-
ular failure?
Reca ll t h a t t h e left ven t r icle r eceives blood fr om
t h e pu lm on a r y vein a n d left a t r iu m . Wh en t h e left
ven t r icle is in effect ive a n d is u n a ble t o eject en ou gh
blood in t o t h e a or t a du r in g ven t r icu la r syst ole, blood
ba cks u p in t o t h e pu lm on a r y vein , a n d su bsequ en t ly
in t o t h e lu n g t issu es, r esu lt in g in pu lm on a r y edem a .
C o n g e s t iv e h e a r t a ilu r e is a n ot h er t er m u sed t o
descr ibe left h ea r t fa ilu r e. Ca u ses of left h ea r t fa il-
u r e in clu de a n y con dit ion t h a t (1) im pa ir s left ven -
t r icu la r pu m pin g, su ch a s wh a t occu r s wit h MI; or
(2) in cr ea ses t h e wor kloa d on t h e left ven t r icle, su ch
a s va lvu la r disor der s (a or t ic a n d bicu spid), in wh ich
t h e left ven t r icle m u st pu m p h a r der t o com pen sa t e
for st en osis or r egu r git a t ion (Fig. 16.14).
Right Heart Failure
Righ t h ea r t fa ilu r e begin s on t h e r igh t side of t h e
h ea r t . Th is im pa ir s t h e h ea r t ’s a bilit y t o m ove
 C lin ic a l Mo d e ls 419

Figure 16.14. Congestive heart failure. A: An unaffected heart. B: Notable enlargement of the heart related to chronic
heart failure secondary to ischemic injury.

deoxygen a t ed blood for-

wa r d t o t h e pu lm on a r y R E S E AR C H N O T E S
cir cu la t ion . Th e r esu lt is
The progression of heart failure from initial pathophysiology to the development of symp-
con gest ion of blood ba ck-
tomatic heart failure was estimated based on a review of 11 large studies that included
wa r d in t o t h e syst em ic
25,369 participants. Individuals with systolic dysfunction developed heart failure at a rate
cir cu la t ion . Th e syst em ic
of 8.4 per 100 person-years compared to 2.8 per 100 person-years in people with diastolic
con gest ion pr odu ces pe-
heart failure. The importance of early heart failure identification and initiation of effective
r iph er a l edem a . Th e de-
management of systolic and diastolic heart failure prior to overt symptoms has the potential
velopm en t of edem a wa s
to slow disease progression. 9
discu ssed in Ch a pt er 8.
Depen den t a r ea s of t h e
body (i.e., ext r em it ies
t h e dem a n d. Com pen sa t or y m ech a n ism s a r e t r ig-
or a r ea s closest t o t h e gr ou n d) becom e swollen . Th e
ger ed t o m a in t a in a s m u ch oxygen a t ion a s possible
lower ext r em it ies a r e m ost com m on ly a ffect ed. Th e
(Fig. 16.15). Th e in it ia l r espon se of com pen sa t or y
liver, spleen , ga st r oin t est in a l t r a ct , a n d per it on eu m
m ech a n ism s t o h elp t o ea se con gest ion a n d im pr ove
ca n becom e en gor ged wit h flu id a s blood ba cks u p
ca r dia c pu m pin g st r en gt h a n d efficien cy con t r ibu t e
in t o t o t h e h epa t ic vein s a n d por t a l cir cu la t ion .
t o pa t h ology a n d wor sen in g h ea r t fa ilu r e m a n ifest a -
Ca u ses of r igh t h ea r t fa ilu r e in clu de a n y pr ocess
t ion s over t im e. Com pen sa t or y m ech a n ism s in clu de:
t h a t r est r ict s blood flow in t o t h e lu n gs. C o r p u lm o -
n a le is a n a lt er a t ion in t h e st r u ct u r e a n d fu n ct ion ● Im pr ovin g ven ou s r etu r n : Th e t en sion in t h e vein s
of t h e r igh t ven t r icle ca u sed by a pr im a r y disor der in cr ea ses, a llowin g im pr oved m ovem en t of blood
of t h e r espir a t or y syst em . Lu n g in ju r y, in fect ion s, in - for wa r d. Th is in cr ea ses pr eloa d a n d im pr oves
fla m m a t ion , a n d pu lm on a r y edem a a r e m ost oft en ca r dia c ou t pu t by in cr ea sin g t h e a m ou n t of blood
im plica t ed. Th e r esu lt in g pu lm on a r y h yper t en sion t h a t fills t h e ven t r icles a t t h e en d of dia st ole. Di-
is t h e com m on lin k bet ween t h ese lu n g in ju r ies a n d u r et ics m a y be u sed t o su ppor t t h is com pen sa t or y
t h e developm en t of cor pu lm on a le. Beca u se left h ea r t m ech a n ism by decr ea sin g flu id volu m e a n d r e-
fa ilu r e r esu lt s in pu lm on a r y edem a , r igh t h ea r t lievin g per iph er a l va scu la r r esist a n ce.
fa ilu r e ca n be a con sequ en ce of left h ea r t fa ilu r e. ● S tim u la tin g th e sym pa th etic n er vou s system : Th e
H owever, on ly pr im a r y lu n g con dit ion s a r e t er m ed sym pa t h et ic n er vou s syst em is st im u la t ed t o in -
cor pu lm on a le. Va lvu la r defect s of t h e t r icu spid a n d cr ea se h ea r t r a t e, ca r dia c con t r a ct ilit y, a n d vessel
pu lm on ic va lves ca n a lso pu t a st r a in on t h e r igh t t on e t o per fu se vit a l or ga n s.
ven t r icle a n d con t r ibu t e t o t h e developm en t of r igh t ● S tim u la tin g th e r en in –a n gioten sin m ech a n ism :
h ea r t fa ilu r e. Th e kidn eys in cr ea se r en in secr et ion , r esu lt in g in
Th e t issu es n eed oxygen . Wit h bot h left a n d r igh t eleva t ion s of a n giot en sin . Th is pr om ot es com pen -
h ea r t fa ilu r e, t h e h ea r t is u n a ble t o keep u p wit h sa t or y va socon st r ict ion .
420 C h a p t e r 16: Alt er ed Per fu sion
Ve nous re turn
(pre loa d)
Myoca rdia l Cardiac
hype rtrophy o utput
Re na l blood flow
Va s cula r volume S a lt a nd wa te r
re te ntion
Figure 16.15. Compensatory mechanisms in heart failure. (Modified from Porth CM. Essentials of Pathophysiology:
Concepts of Altered Health States. Philadelphia, PA: Lippincott Williams & Wilkins; 2003.)
● E n la r gin g th e h ea r t m u scle: H yper t r oph y of t h e
h ea r t m u scle occu r s in r espon se t o wor kloa d de-
m a n ds of t h e ven t r icles. Com pen sa t or y h yper t r o-
ph y in it ia lly im pr oves ca r dia c con t r a ct ilit y.
Stop and Consider
How are compensatory mechanisms similar be-
tween shock and heart failure? How are these
different?
Th ese com pen sa t or y m ech a n ism s becom e in effec-
t ive wit h sever e, pr olon ged h ea r t fa ilu r e. Alt h ou gh
ven ou s r et u r n is in it ia lly im pr oved, pr olon ged
ven ou s con gest ion is t oo over wh elm in g for com -
pen sa t or y m ech a n ism s. Sym pa t h et ic st im u la t ion
pr om ot es per fu sion t o vit a l or ga n s. Over t im e, t h is
m ech a n ism ca n t r igger dysr h yt h m ia s a n d depr ive
“n on vit a l” or ga n s (i.e., skin , m u scle, a n d kidn eys) of
oxygen . Most n ot a bly, poor r en a l per fu sion lea ds t o
in cr ea sed sodiu m a n d wa t er r et en t ion , t h er eby fu r-
t h er t a xin g ven ou s r et u r n . An ot h er fa ct or con t r ibu t -
in g t o sodiu m a n d wa t er r et en t ion is t h e st im u la t ion
of a ldost er on e pr odu ct ion by a n giot en sin II. Myoca r-
dia l h yper t r oph y ca n in it ia lly con t r ibu t e t o con t r a c-
t ilit y bu t even t u a lly im pa ir s dia st ole a n d pr om ot es
oxygen depr iva t ion t o t h e m yoca r diu m . Th e m yoca r-
diu m becom es n on com plia n t , or t en se, a n d t h e h ea r t
Va s cula r re s is ta nce
(a fte rloa d)
Ca rdia c contra ctility
He a rt ra te
S ympa the tic
re flexe s
Va s cula r tone
Re nin-
a ngiote ns in- Angiote ns in II
a ldos te rone
me cha nis m
Aldos te rone
ch a m ber size is r edu ced. Th ese com pen sa t or y m ech -
a n ism s a r e h elpfu l in t h e ea r ly st a ges of h ea r t fa il-
u r e, bu t over t im e m a y ca u se m or e h a r m t h a n good.
CLINICAL MANIFESTATIONS
F igu r e 16.16 com pa r es t h e clin ica l m a n ifest a t ion s
bet ween r igh t a n d left h ea r t fa ilu r e. In r igh t h ea r t
fa ilu r e, t h e clin ica l m a n ifest a t ion s a r e r ela t ed t o
con gest ion in per iph er a l t issu es fr om t h e in effect ive
r igh t ven t r icle. E a r ly clin ica l m a n ifest a t ion s in left
h ea r t fa ilu r e ca n be a bsen t . Wh en pr esen t , clin ica l
m a n ifest a t ion s specific t o left h ea r t fa ilu r e a r e r e-
la t ed t o decr ea sed ca r dia c ou t pu t a n d pu lm on a r y
con gest ion fr om a fa ilin g left ven t r icle, wh ich lea ds
t o poor t issu e a n d or ga n per fu sion . F lu id con gest ion
in t h e lu n gs lea ds t o sh or t n ess of br ea t h , cou gh in g,
a n d lu n g cr a ckles wit h a u scu lt a t ion . Poor t issu e a n d
or ga n per fu sion lea ds t o m a n y pot en t ia l in dica t or s,
in clu din g cya n osis, exer cise in t oler a n ce, poor u r i-
n a r y ou t pu t , flu id a n d sodiu m r et en t ion , a n or exia ,
a n d fa t igu e.
Likewise, ea r ly clin ica l m a n ifest a t ion s in r igh t
h ea r t fa ilu r e ca n be a bsen t or su bt le, su ch a s fa -
t igu e, exer t ion a l dyspn ea , or syn cope wit h exer t ion .
Alt h ou gh t h ese ea r ly m a n ifest a t ion s a r e oft en a t -
t r ibu t ed t o t h e u n der lyin g pu lm on a r y disea se, t h e
 C lin ic a l Mo d e ls 421

Rig ht he art failure Le ft he art failure

Conge s tion of De cre a s e d P ulmona ry

pe riphe ra l tis s ue s ca rdia c output conge s tion

De pe nde nt Live r Activity Impa ire d ga s P ulmona ry

e de ma conge s tion intole ra nce excha nge e de ma
a nd a s cite s a nd s igns of
de cre a s e d
tis s ue
S igns re la te d pe rfus ion Cya nos is Cough with
GI tra ct
to impa ire d a nd s igns of frothy
conge s tion
live r function hypoxia s putum

Orthopne a

Pa roxys ma l
Anorexia , GI dis tre s s,
nocturna l
we ight los s
dys pne a

Figure 16.16. Comparison of the clinical manifestations between right and left heart failure. GI, gastrointestinal.
(Modified from Porth CM. Essentials of Pathophysiology: Concepts of Altered Health States. Philadelphia, PA: Lippincott
Williams & Wilkins; 2003.)

sym pt om s r eflect t h e r ela t ive in a bilit y t o in cr ea se va lvu la r a bn or m a lit ies, a n d m ea su r em en t s of va r i-

ca r dia c ou t pu t a n d a decr ea se in syst em ic a r t er ia l
pr essu r e wit h exer t ion . Isch em ia of t h e r igh t ven t r i-
cle a n d pu lm on a r y a r t er y st r et ch in g ca n ca u se ch est
pa in wit h exer t ion . In a dva n ced st a ges, a n or exia ,
weigh t loss, ga st r ic a n d r igh t u pper qu a dr a n t pa in ,
a n d ja u n dice ca n r esu lt fr om flu id con gest ion in t h e
ga st r oin t est in a l t r a ct a n d liver. Swellin g in t h e ex-
t r em it ies is a lso r ela t ed t o syst em ic edem a .
DIAGNOSTIC CRITERIA
Th e dia gn osis of h ea r t fa ilu r e is est a blish ed ba sed on
a t h or ou gh pa t ien t h ist or y a n d ph ysica l exa m in a t ion ,
du r in g wh ich t h e pr esen ce of clin ica l m a n ifest a t ion s
list ed a bove a r e n ot ed. Ch est r a diogr a ph y ca n det ect
pu lm on a r y con gest ion , wh er ea s t wo-dim en sion a l
ech oca r diogr a ph y det ect s t h e h ea r t ’s pu m pin g a bil-
it y, ch a m ber size a n d t h ickn ess, t h e pr esen ce of
ou s h ea r t pr essu r es. E CG su pplies in for m a t ion on
con du ct ion im pa ir m en t s. Ca r dia c ca t h et er iza t ion
m a y be n eeded t o visu a lize st r u ct u r a l defect s or t o
det er m in e pr essu r e levels in t h e h ea r t ch a m ber s.
Sever it y is ba sed on t h e level of a ct ivit y r est r ict ion
im posed by t h e h ea r t fa ilu r e.
TREATMENT
Tr ea t m en t of h ea r t fa ilu r e is focu sed on cor r ect in g
t h e ca u se if possible. Su r gica lly r epla cin g defect ive
va lves, t r ea t in g a n u n der lyin g r espir a t or y in fec-
t ion , or t r ea t in g a n em ia a r e exa m ples of cor r ect -
in g a h ea r t fa ilu r e ca u se. In m a n y ca ses, t h e ca u se
ca n n ot be r ever sed. Lifest yle m odifica t ion s a r e im -
por t a n t in t h e m a n a gem en t of h ea r t fa ilu r e a n d in -
clu de sm okin g cessa t ion , lim it a t ion or cessa t ion of
a lcoh ol in t a ke, sa lt a n d flu id r est r ict ion a s well a s
422 C h a p t e r 16: Alt er ed Per fu sion
weigh t m a n a gem en t . Tr ea t m en t focu ses on pr ovid-
in g su pplem en t a l oxygen , im pr ovin g ca r dia c ou t pu t ,
a n d ph a r m a cologic in t er ven t ion t o cor r ect volu m e
over loa d a n d r edu ce per iph er a l va scu la r r esist a n ce
(see h yper t en sion ) wit h a n over a ll goa l of im pr ovin g
qu a lit y of life. H ea r t fa ilu r e is oft en a pr ogr essive,
ch r on ic pr oblem wit h a poor pr ogn osis. Th e 5-yea r
su r viva l r a t e is a ppr oxim a t ely 50%.
Stroke
S t r o k e is a n a cu t e n eu r ologic in ju r y t h a t r esu lt s
fr om pa t h ologic even t s su ch a s sh ock, cer ebr a l
h em or r h a ge, isch em ia , or in fa r ct ion , lea din g t o t h e
im pa ir m en t of cer ebr a l cir cu la t ion . St r oke is oft en
r efer r ed t o a s a cer ebr ova scu la r a cciden t . Ma jor r isk
fa ct or s in clu de h yper t en sion , sm okin g, a n d dia bet es.
PATHOPHYSIOLOGY
St r oke is oft en differ en t ia t ed a s t h r om bot ic, em bolic,
or h em or r h a gic t o dist in gu ish t h e pr ocess lea din g t o
a lt er ed cer ebr a l per fu sion . Th r om bot ic st r okes a r e
ca u sed by occlu sion s of cer ebr a l a r t er ies, oft en fr om
a t h er oscler osis. Th e m ost com m on sit e for a t h er o-
scler osis for m a t ion is in t h e com m on ca r ot id a r t er y
wh er e t h e a r t er y bifu r ca t es. Figu r e 16.17 illu st r a t es
Occlus ion of trifurca tion of
middle ce re bra l a rte ry a nd
a re a of ne cros is
Occlus ion of s tria te a rte ry
with infa rction a nd a re a of
ne cros is
Occlus ion of inte rna l ca rotid a rte ry
Exte rna l ca rotid a rte ry
Common ca rotid a rte ry
A cott Williams & Wilkins; 2005.)
t h e dist r ibu t ion of cer ebr a l in fa r ct s a n d a r ea s of
n ecr osis. Th e pr ocess is sim ila r t o t h e developm en t
of m yoca r dia l in fa r ct ion . Tr a n s ie n t is c h e m ic a t -
t a c k (T I A) is a t er m u sed t o descr ibe a per iod of
t r a n sien t n eu r ologic dysfu n ct ion a n d foca l t r a n sien t
n eu r ologic sym pt om s wit h r isk of per m a n en t n eu -
r ologic in ju r y a n d st r oke. Risk of st oke followin g
TIA is gr ea t est wh en t h e in dividu a l is > 60 yea r s
of a ge, h a s h igh blood pr essu r e (syst olic ≥ 140 m m
H g or dia st olic ≥ 90 m m H g), sym pt om s of st r oke
(e.g., u n ila t er a l wea kn ess, speech dist u r ba n ce), a n d
du r a t ion of sym pt om s of 1 h ou r or m or e. TIAs a r e
fr equ en t ly t h e r esu lt of in t er m it t en t va scu la r ob-
st r u ct ion lea din g t o im pa ir ed cer ebr a l per fu sion . A
com plet ed st r oke, h owever, ca u ses per m a n en t n eu -
r ologic deficit s. E m bolic st r oke sim ila r ly ca u ses ob-
st r u ct ion bu t r esu lt s fr om em boli t h a t dislodge fr om
dist a n t sit es, t r a vel t o t h e br a in , a n d occlu de sm a ll
a r t er ies. St r oke fr om cer ebr a l h em or r h a ge ca n be
ca u sed by t r a u m a or defect s in t h e cer ebr a l vessels.
Per sist en t h yper t en sion a n d n eopla sia ca n lea d t o
cer ebr a l vessel wea kn ess, er osion , a n d r u pt u r e. Th e
bleedin g vessel fills a n d com pr esses a dja cen t br a in
t issu e a n d br a in ven t r icles.
On t h e cellu la r level, a n y pr ocess t h a t disr u pt s
blood flow t o a por t ion of t h e br a in u n lea sh es a ca s-
ca de of even t s t ypica l of isch em ia a n d in fla m m a t ion ,
lea din g t o t h e dea t h of n eu r on s. Wit h in secon ds t o
m in u t es of t h e loss of per fu sion t o a por t ion of t h e
Figure 16.17. Cerebral infarction. A: Distribution of cere-
bral infarcts and areas of necrosis. B: A horizontal section
of the brain depicting expansion and softening in the cor-
tex from an occluded middle cerebral artery. (From Rubin
E, Farber JL. Pathology. 4th ed. Philadelphia, PA: Lippin-

br a in , t h e isch em ic n eu r on becom es depola r ized.
ATP is deplet ed a n d m em br a n e ion -t r a n spor t sys-
t em s fa il. Neu r ot r a n sm it t er s a r e r elea sed t h r ou gh
t h e in flu x of ca lciu m , a n d excit a t or y r ecept or s on
ot h er n eu r on s a r e a ct iva t ed. Th ese n eu r on s t h en
becom e depola r ized, ca u sin g fu r t h er ca lciu m in flu x,
fu r t h er n eu r on a l excit a t ion , a n d expa n ded isch em ia .
Neu r on a l da m a ge is exa cer ba t ed by t h e excessive
ca lciu m in flu x, wh ich r elea ses dest r u ct ive en zym es,
t h e r elea se of fr ee r a dica ls, a n d t h e pr esen ce of po-
t en t ch em ica l m edia t or s. Th is isch em ic a r ea co-
a lesces in t o a n in fr a ct ed cor e wit h in h ou r s of t h e
on set of t h e st r oke.
CLINICAL MANIFESTATIONS
St r oke t ypica lly r esu lt s in t h e a br u pt on set of clin -
ica l m a n ifest a t ion s ch a r a ct er ist ic of a foca l br a in
in ju r y. Th e level of cer ebr a l edem a va r ies ba sed
on t h e ext en t of cellu la r in ju r y. Loss of fu n ct ion is
ba sed on t h e pa r t of t h e br a in t h a t is isch em ic or
com pr essed by t h e a ccu m u la t ion of blood. For exa m -
ple, h em or r h a ge of vessels lea din g t o t h e m edu lla
a ffect vit a l r espir a t or y a n d ca r dia c cen t er s a n d will
r esu lt in su dden dea t h . Cer ebella r st r oke im pa ir s co-
or din a t ion . Com m on sym pt om s of st r oke in clu de t h e
a br u pt on set of h em ipa r esis (wea kn ess on on e side
of t h e body), vision loss, visu a l field deficit s, diplopia
(dou ble vision ), dizzin ess, a t a xia (la ck of coor din a t ed
m ovem en t ), a ph a sia (la n gu a ge im pa ir m en t ), or a
su dden decr ea se in t h e level of con sciou sn ess.
In t h e cer ebr u m , h em or r h a ge or occlu sion on on e
side of t h e br a in r esu lt s in h em ipa r esis or h em iple-
gia (pa r a lysis) on t h e opposit e side of t h e body. Th er e-
for e, if t h e st r oke m a n ifest s a s left -sided wea kn ess,
t h e obst r u ct ion or h em or r h a ge m ost likely exist s on
t h e r igh t side of t h e cer ebr u m . Ot h er possible m a n i-
fest a t ion s of st r oke in clu de sever e h ea da ch e, sen sor y
deficit s, a n d vom it in g. Aga in , t h e clin ica l pr esen t a -
t ion is ext en t a n d sit e depen den t a s isch em ic br a in
t issu e becom es n ecr ot ic a n d n on fu n ct ion a l.
DIAGNOSTIC CRITERIA
Th e dia gn osis of st r oke is ba sed on a ca r efu l pa -
t ien t h ist or y a n d ph ysica l exa m in a t ion , a s well a s
la bor a t or y a n d dia gn ost ic st u dies. If t h e pa t ien t is
a ph a sic a n d u n a ble t o spea k, t h e h ist or y m u st in -
clu de obser ver r epor t s of t im e of on set a n d pr ogr es-
sion of sym pt om s, if possible. E ssen t ia l com pon en t s
of t h e ph ysica l exa m in a t ion in clu de t h e n eu r ologic
eva lu a t ion of m en t a l st a t u s a n d t h e level of con -
sciou sn ess, cr a n ia l n er ves, m ot or fu n ct ion , sen sor y
fu n ct ion , cer ebella r fu n ct ion , ga it , a n d deep t en don
r eflexes. Th is exa m in a t ion ca n be gu ided a n d qu a n -
t ified by pu blish ed st r oke sca les t o det er m in e st r oke
sever it y a n d pr ogr ess. La bor a t or y t est s, in clu din g a
C lin ic a l Mo d e ls 423
com plet e blood cou n t , blood ch em ist r y pa n el, coa gu -
la t ion st u dies, a n d ca r dia c en zym es m a y be n eeded
t o det er m in e t h e ca u se of st r oke or t o r u le ou t ot h er
h ea lt h pr oblem s t h a t ca n m im ic a st r oke. Th e pr i-
m a r y dia gn ost ic t ool is br a in im a gin g (e.g., CT sca n ,
MRI), wh ich ca n be u sed t o dist in gu ish t h e t ype a n d
loca t ion of in fa r ct ion . Br a in im a gin g is cr it ica l for
det er m in in g t h e m ost a ppr opr ia t e t r ea t m en t pa t h -
wa y; pa t ien t s wit h t h r om bot ic st r oke m a y r eceive
t h r om bolyt ic t h er a py, wh er ea s in dividu a ls wit h a
br a in h em or r h a ge do n ot .
TREATMENT
Tr ea t m en t is ba sed on t h e ca u se. E ffor t s a r e in it ia lly
a im ed a t r edu cin g cer ebr a l edem a a n d t h e r esu lt in g
in cr ea sed in t r a cr a n ia l pr essu r e. Th r om bot ic or em -
bolic st r oke m a y be t r ea t ed wit h in t r a ven ou s t h r om -
bolyt ic or a n t icoa gu la n t t h er a py ea r ly in t h e a cu t e
ph a se followed by lon g-t er m or a l a n t it h r om bot ic
t h er a py t o r edu ce r isk for r ecu r r en t st r oke. H em -
or r h a gic st r oke will r equ ir e pr even t ion of fu r t h er
bleedin g, a n d a spir a t ion of a ccu m u la t ed blood m a y
be in dica t ed. Tr ea t m en t is oft en focu sed on r eh a bil-
it a t ion in a n effor t t o a da pt t o r edu ced fu n ct ion a n d
m a xim ize in depen den ce.
Disseminated Intravascular
Coagulation
D is s e m in a t e d in t r a v a s c u la r c o a g u la t io n (D I C )
is a con dit ion of u n con t r olled a ct iva t ion of clot t in g
fa ct or s t h a t r esu lt s in widespr ea d t h r om bi for m a -
t ion , followed by deplet ion of coa gu la t ion fa ct or s a n d
pla t elet s lea din g t o m a ssive h em or r h a ge. DIC is in i-
t ia t ed by en dot h elia l or t issu e in ju r y, su ch a s occu r s
wit h t r a u m a , su r ger y, bu r n s, m a lign a n t n eopla sm s,
in fect ion s, or sh ock. Obst et r ic com plica t ion s du r in g
la bor a n d deliver y a r e a lso com m on ly cit ed a s a t r ig-
ger for DIC.
PATHOPHYSIOLOGY
Wit h DIC, in ju r y t r igger s a n im ba la n ce bet ween
clot t in g a n d ib r in o ly s is , t h e dissolu t ion of clot s.
Clot t in g fa ct or s, t h r om bin , a n d pla t elet s a ccu m u la t e
t h r ou gh ou t t h e ca r diova scu la r syst em . Th is is pa r-
t icu la r ly pr oblem a t ic in t h e m icr ovessels, wh er e t h e
clot s ca u se widespr ea d t issu e isch em ia . Th e im ba l-
a n ce of clot t in g a n d clot dissolu t ion is dem on st r a t ed,
a s blood-clot t in g m ech a n ism s ca n t h en becom e de-
plet ed or clot -dissolvin g m ech a n ism s in cr ea sed. Th is
a llows m a ssive syst em ic h em or r h a ge. DIC is a se-
r iou s con dit ion t h a t r equ ir es im m edia t e r ecogn it ion
a n d t r ea t m en t .
424 C h a p t e r 16: Alt er ed Per fu sion

wh ich is sign ifica n t for

F R O M T H E L AB bot h t h r om bu s for m a t ion
a n d br ea kdown , a n d de-
Coagulation results from a sequence of events involving proteins (coagulation factors) pro- t ect s t h e sim u lt a n eou s
duced by the liver and secreted into the bloodstream. Prothrombin time (PT), aPTT, and for m a t ion of bot h t h r om -
fibrinogen levels are screening tests for DIC. PT is used to evaluate the adequacy of the bin a n d pla sm in . Th is is
extrinsic clotting system (clotting that is triggered by the release of tissue thromboplastin), con sider ed a con fir m a t or y
including factors I (fibrinogen), II (prothrombin), V, VII, and X. PT is measured in seconds, t est t h a t st r on gly su g-
the expected range is usually approximately 11 to 14 seconds, and a prolonged PT indicates gest s t h e pr esen ce of DIC.
a deficiency in one or more of these factors. aPTT detects clotting factor deficiencies in
the intrinsic clotting system (those factors already present in the plasma) and is a broader
screening tests for deficiencies in factors I, II, V, VIII, IX, X, XII, and XII. aPTT is measured TREATMENT
in seconds; the expected range is approximately 22 to 34 seconds and is significant when Tr ea t m en t is focu sed on
prolonged. Typically, when a prolonged PT or aPTT is noted, more specific tests are needed cor r ect in g t h e u n der ly-
to identify the affected coagulation factor. Fibrinogen levels screen specifically for the pres- in g ca u se, a n d it depen ds
ence of factor I. The most common cause for a reduced fibrinogen level is DIC. on t h e pr esen ce of h em -
or r h a ge ver su s t h r om bo-
ses. Th e goa l is t o r epla ce
CLINICAL MANIFESTATIONS t h e m issin g blood com -
pon en t s. Ma ssive clot t in g r equ ir es a n t icoa gu la t ion
Th e effect s of DIC a r e va r ia ble a n d depen d on t h e t h er a py. Ma ssive h em or r h a ge r equ ir es exogen ou s
pr esen ce of excessive clot t in g or h em or r h a ge. DIC ca n a dm in ist r a t ion of clot t in g fa ct or s a n d pla t elet s t o
m a n ifest a s a n a cu t e h em or r h a gic disor der ca u sed r epla ce wh a t wa s lost . Tr ea t m en t of DIC is a ca r efu l
by widespr ea d clot dissolu t ion fr om excess pla sm in ba la n cin g a ct focu sed on r est or in g t h e body’s a bilit y
for m a t ion . Th is developm en t is m ost com m on ly t o coa gu la t e a ppr opr ia t ely.
ca u sed by in fect ion , a cu t e t issu e in ju r y, or obst et r ic
com plica t ion s a n d lea ds t o br u isin g, pet ech ia e, a n d
epist a xis. Blood m a y be fou n d in t h e spu t u m , st ool,
em esis, a n d u r in e. Sever e bleedin g a n d h em or r h a ge S U MMAR Y
ca n lea d t o h ypovolem ic sh ock. Alt er n a t ively, DIC
ca n m a n ifest a s a ch r on ic or su ba cu t e st a t e ch a r a c- ● Per fu sion is t h e pr ocess of for cin g blood or ot h er
t er ized by excess clot t in g (t h r om bin ) for m a t ion . Th is flu id t o flow t h r ou gh a vessel a n d in t o t h e va s-
occu r s m or e com m on ly wit h m a lign a n cy, ch r on ic r e- cu la r bed of a t issu e t o pr ovide oxygen a n d ot h er
n a l disea se, ven ou s t h r om bosis, a n d cer t a in con n ec- n u t r ien t s.
t ive t issu e disor der s. Widespr ea d clot t in g ca n lea d t o ● E ffect ive per fu sion is a com plex in t er a ct ion of
m u lt iple m a n ifest a t ion s, depen din g on t h e loca t ion ven t ila t ion , r espon sive n eu r on a l con t r ol of ca r-
of t h r om boses. In t h e br a in , it ca n lea d t o h ea da ch e, dia c im pu lses, ca r dia c m u scle con t r a ct ion , a n d
wea kn ess, seizu r es, a n d even com a . Wit h in t h e kid- cir cu la t ion .
n eys, t h r om boses a r e m a n ifest ed a s poor u r in e ou t - ● Alt er ed per fu sion im pa ir s t issu e oxygen a t ion a n d
pu t , wh ich ca n pr ogr ess t o r en a l fa ilu r e. In t h e h ea r t ca n st em fr om a lt er ed ven t ila t ion , diffu sion , or
a n d lu n gs, m a n ifest a t ion s in clu de cou gh , sh or t n ess cir cu la t ion .
of br ea t h , r espir a t or y dist r ess, or ch est pa in . Va scu - ● E xa m ples of sit u a t ion s t h a t ca n im pa ir cir cu la -
la r occlu sion s in la r ger vessels lea d t o t h e m a n ifes- t ion in clu de br a in in ju r y a t t h e ca r dia c con t r ol
t a t ion s of in fa r ct ion in t h e a ffect ed or ga n . cen t er in t h e m edu lla , blocka ge of t h e con du ct ion
syst em of t h e h ea r t , st r u ct u r a l defect s, over t a x-
in g, or n ecr osis of t h e h ea r t (wh ich r edu ces ca r-
DIAGNOSTIC CRITERIA
dia c ou t pu t ), a n d obst r u ct ion a n d h em or r h a ge in
Iden t ifica t ion of t h e u n der lyin g pr oblem lea din g t o t h e a r t er ies a n d vein s.
DIC is cr it ica l. A t h or ou gh pa t ien t h ist or y a n d ph ys- ● Gen er a l m a n ifest a t ion s of a lt er ed per fu sion de-
ica l exa m in a t ion a r e n eeded t o iden t ify t h is u n der- pen d on t h e pr ocess bu t m a y in clu de t a ch yca r dia ,
lyin g ca u se, su ch a s in fect ion , m a lign a n cy, m a jor t a ch ypn ea , fa t igu e, h ea r t m u r m u r s, E CG ch a n ges,
t r a u m a t ic in ju r y, la bor a n d deliver y com plica t ion s, pa llor or er yt h em a , cya n osis, edem a , sh or t n ess of
or r ecen t su r ger y. Scr een in g la bor a t or y t est s in clu de br ea t h , im pa ir ed gr owt h , h ypot en sion or h yper-
P T, a ct iva t ed pa r t ia l t h r om bopla st in t im e (a P TT), t en sion , h em or r h a ge, a n d pa in .
pla t elet cou n t , a n d fibr in ogen level. Th e D-dim er ● Mu lt iple dia gn ost ic t est s a r e u sed t o det ect pr ob-
t est m ea su r es t h e degr a da t ion of fibr in pr odu ct s, lem s wit h per fu sion , in clu din g blood t est s for

h yper ch olest er olem ia , a n em ia , a n d h ypoxem ia .
Visu a liza t ion , t h r ou gh t h e u se of ech oca r diogr a -
ph y, n u clea r sca n n in g, a n d r a diogr a ph y, a llows
det ect ion of st r u ct u r a l a n d fu n ct ion a l pr oblem s
wit h t h e h ea r t ’s pu m pin g ca pa bilit ies a n d blood
flow. E CG is fr equ en t ly u sed t o det er m in e con du c-
t ion pr oblem s wit h t h e h ea r t .
C AS E S T U D Y 16.1
J a m es is a 55-yea r-old m a le wh o pr esent s in th e
em er gen cy depa r t m ent (ED) wit h su dden swelling
in his left leg. H e r epor ts a dull a che in his ca lf t ha t
in cr ea ses when he is wa lking. H e st a t es, “My left leg
feels r ea lly tight a nd h ot.” H e wor ks a s a tr uck dr iver
a nd h a s just finished a long r out e t ha t la st ed 10 days.
H e does a dm it to a n in jur y t o his lower leg a bou t
2 weeks a go but he th ought t ha t inju ry wa s r esolved.
H e does n ot exer cise r egu la r ly. H e is a sm oker. H e re-
por t s no ot h er significa nt hea lth hist ory. Aft er physi-
ca l exa min a t ion, he under goes a Doppler com pr ession
u ltr a sound, a n d a deep vein t hr om bosis is det ect ed.
1. Ou t lin e t h e pr ocess t h a t is m ost likely occu r r in g
in t h is m a n ’s body.
2. Wh a t wou ld you expect for clin ica l m a n ifest a t ion s?
3. Wh a t dia gn ost ic t est s cou ld be u sed?
4. Wh a t t r ea t m en t m ea su r es a n d com plica t ion s
wou ld you a n t icipa t e?
Log on to the Internet. Search for a relevant journal ar-
ticle or Web site that details deep vein thrombosis, such
as http://www.emedicine.com/med/ topic2785.htm, to con-
firm your predictions.
C AS E S T U D Y 16.2
J a m ie is a 15-yea r-old fem a le wh o h a s con cer n s
a bou t excessive bleedin g wit h h er la st m en st r u a l pe-
r iod. Sh e h a s n ot iced r ecen t ly t h a t sh e br u ises ea sily
a n d bleeds r ea dily, pa r t icu la r ly wit h h er gu m s wit h
br u sh in g h er t eet h . Sh e a lso h a s h a d n osebleeds r e-
cen t ly a s well. Sh e com es in t o you r clin ica l for exa m -
in a t ion . You n ot e n on pa lpa ble pet ech ia e of h er legs
a n d a r m s, pu r pu r a , a n d gin giva l bleedin g. H er pla t e-
let cou n t is less t h a n 20,000/m m 3 . Sh e is dia gn osed
wit h idiopa t h ic t h r om bocyt open ic pu r pu r a .
1. Ou t lin e t h e pr ocess t h a t is m ost likely occu r r in g
in t h is a dolescen t ’s body.
2. Wh a t wou ld you expect for clin ica l m a n ifest a t ion s?
3. Wh a t dia gn ost ic t est s cou ld be u sed?
4. Wh a t t r ea t m en t m ea su r es a n d com plica t ion s
wou ld you a n t icipa t e?
C h a p t e r 16: Alt er ed Per fu sion 425
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r-
n a l a r t icle or Web sit e t h a t det a ils idiopa t h ic t h r om -
bocyt open ic pu r pu r a , su ch a s h t t p://em edicin e
.m edsca pe.com /a r t icle/779545-over view, t o con fir m
you r pr edict ion s.
P R AC T I C E E XAM Q U E S T I O N S
1. In eva lu a t in g m odifia ble ca r diova scu la r r isk
fa ct or s for you r pa t ien t , wh ich on e is NOT con -
sider ed m odifia ble?
a . Poor ly con t r olled dia bet es m ellit u s
b. H yper lipidem ia
c. H yper t en sion
d. Fem a le gen der
2. You r pa t ien t is exper ien cin g per iph er a l edem a ,
h epa t om ega ly, a scit es, a n d splen om ega ly. Wh ich
of t h e followin g con dit ion s wou ld be con sist en t
wit h t h e pa t ien t ’s fin din gs?
a . E n doca r dit is
b. Myoca r dia l in fa r ct ion
c. Righ t -sided h ea r t fa ilu r e
d. Left -sided h ea r t fa ilu r e
3. It is a h ot su m m er da y. You r n eigh bor st ops a t
you r h ou se a ft er joggin g 5 m iles. Sh e is swea t -
in g a n d t ells you sh e feels dizzy a n d t h ir st y a n d
ca n ’t m a ke it h om e. You ch eck h er blood pr es-
su r e a n d fin d it t o be LOW. Wh a t cou ld you do
r igh t in you r h om e t o r a ise h er blood pr essu r e?
a . P la ce a cold wa sh clot h on h er h ea d
b. H a ve h er dr in k a la r ge gla ss of cool wa t er
c. H a ve h er t a ke a sh ower wit h wa r m wa t er
d. E n cou r a ge h er t o t a ke slow, deep br ea t h s
4. You r n eigh bor a ga in com es t o you r door (see
pr eviou s qu est ion ). Sh e h a s been r u n n in g in t h e
sn ow a n d it is cold ou t side. Sh e h a s a h ea da ch e
a n d h er h ea r t is pou n din g. Aga in you ch eck h er
blood pr essu r e a n d fin d it t o be H IGH . Wh a t
cou ld you do t h is t im e r igh t in you r h om e t o de-
cr ea se h er blood pr essu r e?
a . H a ve h er dr in k som e h ot ch ocola t e
b. H a ve h er la y down on you r cou ch
c. Let h er t a ke a h ot sh ower
d. Give h er som et h in g r ea lly sa lt y t o ea t
5. Wh ich of t h e followin g sit u a t ion s of a lt er ed per-
fu sion cou ld be t r igger ed by ch r on ic obst r u ct ive
pu lm on a r y disea se?
a . Im pa ir ed ca r dia c ou t pu t
b. Im pa ir ed cir cu la t ion
c. Ven t ila t ion –per fu sion m ism a t ch in g
d. E xcessive ca r dia c dem a n d
426 C h a p t e r 16: Alt er ed Per fu sion
6. Wh ich m ech a n ism in cr ea ses per iph er a l va scu la r
r esist a n ce a n d con t r ibu t es t o t h e developm en t of
h yper t en sion ?
a . Im pa ir ed sodiu m excr et ion by t h e kidn eys
b. Pa r a sym pa t h et ic n er vou s syst em over-
st im u la t ion
c. Redu ced r en in –a n giot en sin –a ldost er on e se-
cr et ion
d. Non e of t h ese
7. Wh ich is n ot a r equ ir em en t for effect ive
per fu sion ?
a . Absen ce of ch r on ic disea se
b. Adequ a t e blood volu m e
c. F u n ct ion a l syst em ic cir cu la t ion
d. An open a ir wa y
8. You r n eigh bor t ells you t h a t sh e wa s in t h e h os-
pit a l a n d t h ey t old h er sh e h a d a bu n dle br a n ch
block. Wh a t does t h is m ea n ?
a . Sh e ca n n ot con du ct elect r ica l im pu lses t o
st im u la t e t h e h ea r t ven t r icle t o con t r a ct
b. Sh e h a s h a d a ca r dia c a r r est
c. Sh e is exper ien cin g obst r u ct ed P wa ve depo-
la r iza t ion of t h e a t r ia
d. Sh e h a s a n excessive ca lciu m in flu x ca u sin g
pr olon ged m yoca r dia l con t r a ct ion
9. You a r e list en in g t o you r la b pa r t n er s h ea r t
in skills la b a n d you h ea r t h e “lu b du b” sou n d.
Wh a t a r e you h ea r in g?
a . Th e sodiu m ion s r a pidly in flu xin g in t o t h e
cells
b. Th e closu r e of t h e h ea r t va lves
c. Th e con t r a ct ion of t h e left ven t r icle
d. Blood for cin g it s wa y t h r ou gh t h e a or t a
10. At wh a t poin t in t h e ca r dia c cycle do you m ea -
su r e pr eloa d?
a . J u st a ft er syst ole
b. J u st befor e syst ole
c. Du r in g syst ole
d. It is n ot possible t o m ea su r e pr eloa d
D I S C U S S I O N AN D
AP P L I C AT I O N
1. Wh a t did I kn ow a bou t a lt er ed per fu sion pr ior
t o t oda y?
2. Wh a t body pr ocesses a r e a ffect ed by a lt er ed per-
fu sion ? Wh a t a r e t h e expect ed fu n ct ion s of t h ose
pr ocesses? H ow does a lt er ed per fu sion a ffect
t h ose pr ocesses?
3. Wh a t a r e t h e pot en t ia l et iologies for a lt er ed per-
fu sion ? H ow does a lt er ed per fu sion develop?
4. Wh o is m ost a t r isk for developin g a lt er ed per fu -
sion ? H ow ca n a lt er ed per fu sion be pr even t ed?
5. Wh a t a r e t h e h u m a n differ en ces t h a t a ffect t h e
et iology, r isk, or cou r se of a lt er ed per fu sion ?
6. Wh a t clin ica l m a n ifest a t ion s a r e expect ed in t h e
cou r se of a lt er ed per fu sion ?
7. Wh a t specia l dia gn ost ic t est s h elp det er m in e t h e
dia gn osis a n d cou r se of a lt er ed per fu sion ?
8. Wh a t a r e t h e goa ls of ca r e for in dividu a ls wit h
a lt er ed per fu sion ?
9. H ow does t h e con cept of a lt er ed per fu sion bu ild
on wh a t I h a ve lea r n ed in t h e pr eviou s ch a pt er s
a n d in pr eviou s cou r ses?
10. H ow ca n I u se wh a t I h a ve lea r n ed?
R E SOUR CE S
Am er ica n H ea r t Associa t ion :
h t t p://www.h ea r t .or g/H E ARTORG/#
Am er ica n Societ y of H yper t en sion :
h t t p://www.a sh -u s.or g/
Na t ion a l St r oke Associa t ion :
h t t p://www.st r oke.or g/
R e er en ces
1. Fa r ooq U, Ra y SG. 2014 Gu idelin e for t h e m a n a ge-
m en t of h igh blood pr essu r e (E igh t h J oin t Na t ion a l
Com m it t ee): t a ke-h om e m essa ges. Med Clin Nor th
Am . 2015;99:733–738. h t t p://dx.doi.or g/10.1016/j.
m cn a .2015.02.004
2. J a m es PA, Opa r il S, Ca r t er BL, et a l. 2014
E viden ce-ba sed gu idelin e for t h e m a n a gem en t of h igh
blood pr essu r e in a du lt s: r epor t fr om t h e pa n el m em -
ber s a ppoin t ed t o t h e E igh t h J oin t Na t ion a l Com m it t ee
(J NC 8). J AMA. 2014;311(5):507–520. doi:10.1001/
ja m a .2013.284427.
3. Th e U.S. Depa r t m en t of H ea lt h a n d H u m a n Ser vices.
Th e seven t h r epor t of t h e J oin t Na t ion a l Com m it t ee on
det ect ion , eva lu a t ion , a n d t r ea t m en t of h igh blood
pr essu r e. 2003. h t t p://www.n h lbi.n ih .gov/gu idelin es/
h yper t en sion /expr ess.pdf. Accessed Decem ber 13, 2015.
4. Miedem a MD, Lopez F L, Bla h a M, et a l. Im plica -
t ion s of t h e E igh t h J oin t Na t ion a l Com m it t ee gu ide-
lin es for t h e m a n a gem en t of h igh blood pr essu r e for
a gin g a du lt s: a t h er oscler osis r isk in com m u n it ies
st u dy. H yper ten sion . 2015;66(3):474–480. doi:10.1161/
H YP E RTE NSIONAH A.115.05560.
5. Am er ica n College of Ca r diology/Am er ica n H ea r t Associ-
a t ion Ta sk For ce on P r a ct ice Gu idelin es. 2013 ACC/AH A
Gu idelin e on t h e t r ea t m en t of blood ch olest er ol t o r edu ce
a t h er oscler ot ic ca r diova scu la r r isk in a du lt s. Cir cu la tion .
2014;129(su ppl 2):S1–S45.
6. Goff DC, Lloyd-J on es DM, Ben n et t G, et a l. 2013 ACC/
AH A Gu idelin e on t h e a ssessm en t of ca r diova scu la r r isk:
a r epor t of t h e Am er ica n College of Ca r diology/
Am er ica n H ea r t Associa t ion Ta sk For ce on pr a ct ice
 C h a p t e r 16: Alt er ed Per fu sion 427

gu idelin es. J Am Coll Ca r d iol. 2014;63(25, pt B):2935–
2959. doi:10.1016/j.ja cc.2013.11.005.
7. Bla h a MJ, Da r da r i ZA, Blu m en t h a l RS, et a l. Th e n ew
“in t er m edia t e r isk” gr ou p: a com pa r a t ive a n a lysis of t h e
n ew 2013 ACC/AH A r isk a ssessm en t gu idelin es ver su s
pr ior gu idelin es in m en . Ath er oscler osis. 2014;237(1):1–4.
doi:10.1016/j.a t h er oscler osis.2014.08.024.
8. Myt h ili S, Ma la t h i N. Dia gn ost ic m a r ker s of a cu t e
m yoca r dia l in fa r ct ion . Biom ed Rep. 2015;3(6):743–748.
doi:10.3892/br.2015.500.
9. E ch ou ffo-Tch eu gu i J B, E r qou S, Bu t ler J, et a l. Assessin g
t h e r isk of pr ogr ession fr om a sym pt om a t ic left ven t r ic-
u la r dysfu n ct ion t o over t h ea r t fa ilu r e: a syst em a t ic
over view a n d m et a -a n a lysis [pu blish ed on lin e a h ea d of
pr in t Decem ber 7, 2015]. J ACC H ea r t Fa il. doi:10.1016/j.
jch f.2015.09.015. pii: S2213-1779(15)00683-6.

F in d a d d ition a l r esou r ces for th is ch a pter a t h ttp:th ePoin t.lww.com

 Ch a pt er

17 Alt er ed Nu t r it ion

L E AR N I N G O U T C O ME S
1. Defin e a n d u se t h e key t er m s list ed in t h is ch a pt er.
2. E xpla in t h e r ole of n u t r it ion in m a in t a in in g h ea lt h .
3. Iden t ify t h e pr ocesses t h a t ca n a lt er n u t r it ion .
4. Iden t ify com m on sign s a n d sym pt om s r ela t ed t o a lt er ed n u t r it ion .
5. Descr ibe dia gn ost ic t est s a n d t r ea t m en t st r a t egies r eleva n t t o a lt er ed
n u t r it ion .
6. Apply con cept s of a lt er ed n u t r it ion t o select clin ica l m odels.

INTR ODUCTION
Wh a t did you ea t for br ea kfa st ? H ow did t h a t food con t r ibu t e t o you r h ea lt h ?
E ver y da y we pu t n u t r ien t s in t o ou r bodies wit h lit t le con sider a t ion of exa ct ly
wh a t t h ose n u t r ien t s a r e doin g t o m a in t a in h om eost a sis. Adequ a t e n u t r it ion
r elies on opt im a l in t a ke, digest ion , a bsor pt ion , a n d t r a n spor t a t ion of n u t r ien t s,
a s well a s t h e excr et ion of wa st e pr odu ct s. We ch oose t o ea t a va r iet y of foods
beca u se t h ey a r e a ppea lin g t o u s in on e wa y or a n ot h er. On ce t h e food goes
t h r ou gh t h e pr ocess of digest ion , t h e ext r a ct ed n u t r ien t s a r e m a de su it a ble for
a bsor pt ion a n d t r a n spor t a t ion . Th e n u t r ien t s in t h eir sim plest for m a r e t h en
u sed for a pr edict a ble pu r pose. Th is ch a pt er t a kes a closer look a t essen t ia l
food-der ived n u t r ien t s a n d t h e r ole t h ese n u t r ien t s pla y in fa cilit a t in g ba sic
ph ysiologic pr ocesses. Clin ica l m odels a r e select ed t o illu st r a t e t h e effect s of
n u t r ien t deficien cies or excesses on h ea lt h y fu n ct ion in g.

Fruits and vegetables at a farmers market. Image © Adisa

428
 N u t r it io n 429

Modu le 1 N u t r it io n

N u t r it io n is t h e pr ocess of in gest ion a n d u t iliza t ion per spir a t ion or ot h er m ech a n ism s. Alt h ou gh in divid-
of n u t r ien t s for en er gy. Ult im a t ely, we obt a in n u t r i- u a ls ca n su r vive sever a l weeks wit h ou t food, a du lt s
t ion a n d e n e r g y , or t h e ca pa cit y t o do wor k, fr om (in m oder a t e wea t h er ) ca n su r vive on ly 10 da ys
t h e su n via or ga n ism s a n d pla n t s t h a t u n der go ph o- wit h ou t wa t er a n d ch ildr en ca n su r vive on ly 5 da ys. 1
t osyn t h esis. E n er gy fr om in gest ed n u t r ien t s is r e- Met a bolica lly a ct ive cells, su ch a s m u scle cells, h a ve
lea sed wh en food is m et a bolized. Met a bolism a llows t h e h igh est con cen t r a t ion s of wa t er a n d a r e m ost
ch em ica l r ea ct ion s t h a t (1) pr odu ce h ea t t o m a in t a in deva st a t ed by deficien cies. Th e m a jor poin t is t h a t
body t em per a t u r e, (2) con du ct n eu r on a l im pu lses, wa t er is a n essen t ia l n u t r ien t ; a r edu ct ion in t ot a l
a n d (3) con t r a ct m u scles. Nu t r it ion a lso pr ovides t h e body wa t er of 20% or gr ea t er m a y ca u se dea t h .
su bst a n ces n eeded for gr owt h , r epa ir, a n d m a in t e-
n a n ce of cells.
A n u t r ie n t is a food or liqu id t h a t su pplies t h e
body wit h t h e ch em ica ls n eeded for m et a bolism .
Macronutrients: Proteins, Lipids,
Nu t r ien t s a r e fr equ en t ly ca t egor ized a s m a cr on u t r i- and Carbohydrates
en t s, m icr on u t r ien t s, a n d wa t er. Ma c r o n u t r ie n t s
a r e pr ot ein s, ca r boh ydr a t es, a n d fa t s. Mic r o n u t r i- Th e m a jor m a cr on u t r ien t s t h a t a r e con ver t ed t o
e n t s a r e vit a m in s a n d m in er a ls. Th e body is ca pa ble u sa ble sou r ces of en er gy a r e pr ot ein s, lipids, a n d
of syn t h esizin g cer t a in n u t r ien t s fr om ot h er pr od- ca r boh ydr a t es. P r ot ein is com posed of lin ea r ch a in s
u ct s (e.g., t h e syn t h esis of glu cose fr om a m in o a c- of a m in o a cids t h a t a r e lin ked a s dir ect ed by DNA
ids a n d glycer ol). Ma n y n u t r ien t s, h owever, m u st be codin g. Du r in g digest ion , pr ot ein s a r e br oken down
con su m ed r egu la r ly in t h e diet , beca u se t h e body is in t o a m in o a cids a n d a bsor bed in t o t h e cir cu la t ion
u n a ble t o syn t h esize t h e n u t r ien t in qu a n t it ies su f- (Fig. 17.1). Th e body con t a in s 20 differ en t t ypes of
ficien t t o m eet it s n eeds. Th ese a r e ca lled e s s e n t ia l a m in o a cids. Of t h ese, n in e a r e con sider ed essen t ia l
n u t r ie n t s . a n d t h er efor e m u st be con su m ed wit h in t h e diet .
F r om a m in o a cids, body pr ot ein s a r e syn t h esized.
P r ot ein is n eeded t o bu ild a n d m a in t a in st r u ct u r a l
Water
Wa t er is t h e la r gest sin -
gle com pon en t of t h e F R O M T H E L AB
body a n d is essen t ia l Unique to macronutrients, protein contains nitrogen. Nitrogen balance is a biochemical
for a ll body fu n ct ion s, technique used to determine protein status. Nitrogen balance is calculated based on daily
in clu din g digest ion , a b- protein intake and the amount of nitrogen excretion in the urine. A correction is added for
sor pt ion , t r a n spor t a t ion , insensible losses of nitrogen, such as through the skin and gastrointestinal (GI) tract. In
a n d excr et ion . Specifi- healthy adults, the nitrogen balance should equate to zero. If the person has a positive
ca lly, wa t er fu n ct ion s t o: nitrogen balance, this individual is taking in more protein than is being excreted, which
● Ser ve a s a solven t pr o- should occur in times of growth, pregnancy, and healing. If the person has a negative nitro-
m ot in g a va ila bilit y of gen balance, this individual is excreting more protein than is being consumed, as occurs in
solu t es t o t h e cell a state of tissue destruction, such as with burns, infection, or other tissue trauma.
● P r om ot e a n d m a in -
t a in flu id ba la n ce
● P r ovide a t r a n spor t m ediu m for n u t r ien t s a n d body t issu es su ch a s m u scle, bon e m a t r ix, a n d con -
wa st e pr odu ct s n ect ive t issu e. It a lso com pr ises blood, cell m em -
● Ser ve a s a lu br ica n t br a n es, im m u n e fa ct or s, en zym es, a n d h or m on es.
● Con t r ibu t e t o t h e r egu la t ion of body t em per a t u r e P r ot ein s t r a n spor t ot h er su bst a n ces a cr oss m em -
● P r ovide t h e fou n da t ion for m et a bolic r ea ct ion s br a n es a n d t h r ou gh ou t t h e body a n d ca n com bin e
● Con t r ibu t e t o t h e st r u ct u r e of t h e cells a n d cir cu - wit h ot h er su bst a n ces t o for m n ew su bst a n ces. For
la t or y syst em exa m ple, pr ot ein s ca n com bin e wit h n u cleic a cids t o
for m DNA a n d RNA, ca r boh ydr a t es t o for m glyco-
Beca u se t h e body is u n a ble t o st or e wa t er, r egu la r pr ot ein s, lipids t o for m lipopr ot ein s, a n d m et a ls t o
in t a ke of wa t er is r equ ir ed t o offset t h a t lost t h r ou gh for m h em oglobin .
430 C h a p t e r 17: Alt er ed Nu t r it ion

Die ta ry prote in

S to mac h: Pe ps in

S mall inte s tine : P olype ptide s

Panc re atic
pro te as e s : Tryps in, c hymo tryps in, c arbo xype ptidas e

S toma ch Tripe ptide s , dipe ptide s , a mino a cids

Inte s tinal wall
s e c re tio ns : Amino pe ptidas e

Dipe ptide s , a mino a cids

P a ncre a s
Dipe ptidas e
End pro duc ts
fo r abs o rptio n: Amino a cids

La rge inte s tine S ma ll inte s tine

Figure 17.1. Protein digestion. Chemical digestion of protein begins in the stomach. Hydrochloric acid converts pepsino-
gen to the active enzyme pepsin, which begins the process of breaking down proteins into small polypeptides and some
amino acids. The majority of protein digestion occurs in the small intestine, where pancreatic proteases reduce polypep-
tides into shorter chains, tripeptides, dipeptides, and amino acids. Enzymes located on the surface of the cells that line
the small intestine complete the digestion: aminopeptidase splits amino acids from the amino ends of short peptides, and
dipeptidase reduces dipeptides to amino acids.

L ip id s a r e a lso con sider ed m a cr on u t r ien t s a n d a m ou n t of lipids ca n be st or ed in ot h er loca t ion s,

a r e a gr ou p of su bst a n ces t h a t a r e in solu ble in wa t er.
Lipids a r e ca t egor ized a s:
1. Sim ple lipids or fa t s: fa t t y a cids a n d glycer ol
2. Com pou n d lipids or lipoids: ph osph olipids, lipo-
pr ot ein s, a n d glycolipids
3. St er ols: ch olest er ol a n d bile sa lt s
Tr iglycer ides, a fa t t y a cid a n d glycer ol com plex, a r e
a for m of sim ple lipids r ea dily fou n d in diet a r y fa t .
S a t u r a t e d a t t y a c id s a r e fa t t y a cids t h a t h a ve n o
dou ble bon ds a n d eleva t e blood ch olest er ol levels.
Th ese fa t t y a cids a r e fou n d in a n im a l sou r ces a n d
a r e solid a t r oom t em per a t u r e. U n s a t u r a t e d a t t y
a c id s h a ve on e or m or e dou ble bon ds a n d a r e n ot
kn own t o eleva t e blood ch olest er ol levels. Th ese a r e
u su a lly fou n d in pla n t sou r ces a n d a r e oft en liqu id
a t r oom t em per a t u r e.
Lipids pr ovide a r ich sou r ce of en er gy. Most di-
et a r y fa t is st or ed in t h e body wit h in a dipose cells,
a lso ca lled a dipocyt es. Adipose cells con t a in st or a ge
fa t s, wh ich a ccu m u la t e a r ou n d t issu es a n d wit h in
body ca vit ies a n d a r e u sed wh en en er gy is n eeded.
Adipose cells ca n su st a in t h e body’s en er gy pr ovi-
sion for weeks. Th e a ccu m u la t ion of st or a ge fa t s is
con sider ed a h ea lt h epidem ic, pa r t icu la r ly for t h ose
con su m in g a West er n diet . Obesit y is select ed a s
a clin ica l m odel wit h in t h is ch a pt er t o illu st r a t e
t h e h ea lt h effect s of excessive st or a ge fa t . A sm a ll
su ch a s wit h in liver cells. An a ccu m u la t ion of fa t in
liver cells in h ibit s liver cell fu n ct ion .
St r u ct u r a l fa t is a t ype of fa t t h a t is n ot a ccessed
for en er gy; r a t h er, it pr ovides su ppor t a n d pr ot ec-
t ion t o body or ga n s a n d n er ves. St r u ct u r a l fa t s a r e
fou n d in side cell st r u ct u r es of t h e br a in , liver, kid-
n ey, lu n g, h ea r t , spleen , m u scle, a n d ot h er cells, a n d
t h ey a r e essen t ia l for su r viva l. Th e su bcu t a n eou s fa t
la yer pr ovides in su la t ion a n d m a in t en a n ce of body
t em per a t u r e.
Aside fr om bein g a r ich sou r ce of en er gy, lipids
fa cilit a t e n u m er ou s pr ocesses a ft er in gest ion a n d
a bsor pt ion in t o t h e body (Fig. 17.2). Diet a r y fa t
su ppor t s digest ion by decr ea sin g ga st r ic m ot ilit y
a n d secr et ion s. Alon g wit h t h is fu n ct ion , diet a r y fa t
st im u la t es pa n cr ea t ic a n d bile secr et ion a n d fa cili-
t a t es t h e digest ion , a bsor pt ion , a n d t r a n spor t a t ion
of fa t -solu ble vit a m in s. Th e br a in , cen t r a l n er vou s
syst em (CNS), a n d cell m em br a n es t h r ou gh ou t t h e
body r equ ir e essen t ia l fa t t y a cids t o fu n ct ion opt i-
m a lly. E ssen t ia l fa t t y a cids in flu en ce cell m em br a n e
flu idit y, r ecept or fu n ct ion , en zym e a ct ivit y, a n d cy-
t okin e pr odu ct ion . Lin oleic a cid, a n om ega -3 fa t t y
a cid der ived fr om fish a n d pla n t oils, is con sider ed
a n essen t ia l fa t t y a cid a n d h a s been dem on st r a t ed t o
r edu ce m a n y disea se st a t es, in clu din g h ea r t disea se.
Th is su bst a n ce a ct s by (1) r edu cin g fibr in ogen a n d
ot h er clot t in g pr ot ein s a n d decr ea sin g t h e likelih ood
 N u t r it io n 431

Mouth Inge s te d fa t—Triglyce ride s

Tongue
Mo uth Ling ual lipas e
(limite d role s )
S to mac h Gas tric lipas e

Ga llbla dde r
S toma ch S mall inte s tine
Gallbladde r Bile

Emuls ifie d fa t (triglyce ride s )

Inte s tinal and

Common P a ncre a s panc re atic lipas e s Lipas e s
bile duct
End-pro duc ts fo r Monoglyce ride s ,
abs o rptio n fa tty a cids , a nd glyce rol

La rge inte s tine S ma ll inte s tine

Re ctum
Anus

Figure 17.2. Fat digestion. A minimal amount of chemical digestion of fat occurs in the mouth and stomach through the
action of lingual lipase and gastric lipases, respectively. As fat enters the duodenum, it stimulates the release of the hor-
mone cholecystokinin, which in turn stimulates the gallbladder to release bile. Bile prepares fat for digestion by suspend-
ing the hydrophobic molecules in the watery intestinal fluid. Most fat digestion occurs in the small intestine. Pancreatic
lipase splits off one fatty acid at a time from the triglyceride molecule, working from the outside in until two free fatty
acids and a monoglyceride remain. Usually, the process stops at this point, but sometimes digestion continues and the
monoglyceride splits into a free fatty acid and glyceride molecule. The end products of digestion—mostly monoglycerides
with free fatty acids and little glycerol—are absorbed into intestinal cells. It is normal for a small amount of fat (4–5 g)
to escape digestion and be excreted in the feces.

t h a t a clot will for m a n d (2) st im u la t in g en dot h elia l
cells t o pr odu ce su bst a n ces t h a t pr om ot e va scu la r
r ela xa t ion . P h osph olipids, a for m of com plex lipid,
a r e a n im por t a n t st r u ct u r a l com pon en t of cell m em -
br a n es. Lipids a r e a lso a n in t egr a l a spect of h or-
m on es t h a t m edia t e m u lt iple body pr ocesses.
Ca r boh ydr a t es a r e a lso con sider ed m a cr on u t r i-
en t s. Th e t h r ee ca t egor ies of ca r boh ydr a t es a r e:
1. Mon osa cch a r ides: glu cose or fr u ct ose
2. Disa cch a r ides a n d oligosa cch a r ides: su cr ose or
la ct ose
3. Polysa cch a r ides: st a r ch es a n d fiber
Diet a r y ca r boh ydr a t es a r e digest ed a n d con ver t ed
pr im a r ily in t o glu cose (Fig. 17.3). On ce digest ed, t h e
glu cose is a bsor bed a cr oss t h e in t est in a l wa ll a n d
t r a n spor t ed t o t h e liver via t h e por t a l cir cu la t ion ,
wh er e a bou t 50% is u sed for oxida t ion or st or ed a s
glycogen . Th e r em a in in g glu cose exit s t h e liver a n d
is cir cu la t ed t h r ou gh ou t t h e body t o be u sed by cells
for en er gy.
Th e m a jor r ole of ca r boh ydr a t es is t o pr ovide en -
er gy. In t er est in gly, ca r boh ydr a t es a r e n ot con sider ed
essen t ia l. Glu cose is im por t a n t a n d t h e br a in is t h e
la r gest con su m er ; h owever, lipids a n d pr ot ein s ca n
pr ovide t h is en er gy sou r ce. Glu cose ca n be syn t h e-
sized by con ver t in g a m in o a cids a n d glycer ol fr om
t r iglycer ides in t o glu cose. Th is is n ot t h e m ost effi-
cien t wa y of a ch ievin g a n a dequ a t e glu cose level (see
Ma ln u t r it ion discu ssed below u n der Alt er ed Nu t r i-
t ion ); t h er efor e, ca r boh ydr a t es sh ou ld com pr ise t h e
la r gest pr opor t ion of da ily food in t a ke. Com plex ca r-
boh ydr a t es a r e pr efer r ed over sim ple su ga r s beca u se
t h ese food sou r ces pr ovide ot h er n u t r ien t s, su ch a s
vit a m in s a n d m in er a ls. F iber, a n on digest ible ca r-
boh ydr a t e, is im por t a n t in t h e r edu ct ion of ser u m
ch olest er ol levels a n d wor ks pr im a r ily by bin din g t o
bile a cids, a sou r ce of ch olest er ol, a n d by pr even t in g
ch olest er ol a bsor pt ion . Fiber a lso pla ys a key r ole in
ga st r ic m ot ilit y.
Micronutrients: Vitamins and Minerals
Vit a m in s a r e or ga n ic su bst a n ces t h a t t h e body is
u n a ble t o m a n u fa ct u r e a n d t h er efor e m u st be con -
su m ed. Vit a m in s a r e oft en cla ssified a ccor din g t o
 432 C h a p t e r 17: Alt er ed Nu t r it ion

P olys a ccha ride s Dis a ccha ride s Monos a ccha ride s

Mouth Fibe r S ta rch, de xtrin Ma ltos e S ucros e La ctos e Glucos e Fructos e Ga la ctos e
S a liva ry S ome Mos t
Tongue
gla nds Mo uth S alivary amylas e

S to mac h De xtrin

Es opha gus
Ga llbla dde r Live r
S mall inte s tine Panc re atic amylas e
( S ma ll a mounts
of s ucros e
fructos e + glucos e
)
S toma ch
Ma ltos e
Maltas e S uc ras e Lac tas e
P a ncre a s

Inte s tinal Glucos e Glucos e Glucos e

brus h bo rde r + + +
Glucos e Fructos e Ga la ctos e Glucos e Fructos e Ga la ctos e
Larg e Ba cte ria
inte s tine Abs orbe d through the inte s tina l mucos a
S hort-cha in fa tty
a cids a nd ga s
La rge inte s tine S ma ll inte s tine
Excre te d Abs orbe d
undige s te d through colon

Figure 17.3. Carbohydrate digestion. Dietary carbohydrates include the polysaccharides or complex carbohydrates (fiber,
starch, and dextrin), the disaccharides (maltose, sucrose, and lactose), and the monosaccharides (glucose, fructose, and
galactose). Digestion begins in the mouth, where food is chewed into pieces and salivary amylase begins the process of
chemical digestion. The stomach churns and mixes the carbohydrate, but stomach acids halt residual action of the salivary
amylase. The small intestine is the site of most carbohydrate digestion, and pancreatic amylase reduces complex carbohy-
drates into disaccharides. Disaccharide enzymes (maltase, sucrase, and lactase) on the surface of the small intestine cells
split maltose, sucrose, and lactose into monosaccharides, thus completing the process of carbohydrate digestion. Fiber is
not digested per se, but most is fermented by bacteria in the large intestine to yield gas, water, and short-chain fatty acids.

1. Mem br a n e st a bilizer s
R E S E AR C H N O T E S (su ch a s wit h a n t ioxi-
da n t s)
A multitude of studies have attempted to determine the effects of antioxidants on health. 2. Hydr ogen a nd elect r on
A search of ClinicalTrials.gov revealed almost 400 studies in progress related to antioxidant don ors a nd a ccept or s
use to treat a variety of conditions. Completed studies have focused on the impact of anti- 3. H or m on es
oxidants on everything from reducing pregnancy-induced hypertension to Alzheimer disease. 4. Coen zym es
However, clinical trials of antioxidant supplementation have been conducted, and questions
about the efficacy and safety of these supplements have emerged. More recent studies have Ba sica lly, vit a m in s a r e
also found that in most instances antioxidant supplements did not help to prevent disease pa r t of en zym e syst em s
and, in some cases, high doses of antioxidants actually contributed to morbidity or mortal- t h a t r elea se en er gy fr om
ity, such as an increase in hemorrhagic stroke in men on vitamin E supplements. 2 m a cr on u t r ien t s. Ot h er
m a jor r oles of vit a m in s
a r e t o h elp develop ge-
solu bilit y (fa t or wa t er solu ble) or by m et a bolic fu n c- n et ic m a t er ia ls, r ed blood cells, h or m on es, colla gen ,
t ion . Fa t-solu ble vita m in s in clu de vit a m in s A, D, a n d n er vou s syst em t issu e.
E , a n d K. Wa ter-solu ble vita m in s a r e a scor bic a cid
(vit a m in C), t h ia m in (B 1 ), r ibofla vin (B 2 ), n ia cin , Stop and Consider
pyr idoxin e (B 6 ), biot in , pa n t ot h en ic a cid, fola t e, a n d How do you think vitamin A and C deficiencies
coba la m in (B 12 ). Th e ph ysiologic im pa ct of ea ch of affect wound healing?
t h e vit a m in s is depict ed in Ta ble 17.1. As is eviden t
in t h is t a ble, m a n y vit a m in s pla y a cr it ica l r ole in Min er a ls a r e in or ga n ic su bst a n ces cr it ica l t o t h e
t h e m et a bolism of ca r boh ydr a t es, a m in o a cids, a n d r egu la t ion of h u n dr eds of cellu la r pr ocesses. Min er-
fa t t y a cids. Th e m et a bolic va lu e of vit a m in s in clu des a ls con st it u t e bon e, h em oglobin , en zym es, h or m on es,
ca t egor ies su ch a s: a n d ch em ica l m edia t or s. Ch a r ged (ion ic) m in er a ls
 N u t r it io n 433

Ta b le 17.1 Vit a m in s a n d Th eir Ma jor P h ysiologic F u n ct ion s

Vit a m in F u n c t io n s T h is Vit a m in P la y s a Ke y R o le in
Vit a m in A Ma in t en a n ce of visu a l pigm en t a n d ph ot or ecept ion
Ma in t en a n ce of epit h elia l cells a n d m u cou s m em br a n es
Cellu la r gr owt h a n d differ en t ia t ion by con t r ibu t in g t o glycopr ot ein (cell su r fa ce r egu la t or )
syn t h esis
Syn t h esis of colla gen a n d bon e
Regu la t ion of gen e expr ession
Repr odu ct ion a n d im m u n e fu n ct ion
Vit a m in D Absor pt ion a n d m et a bolism of ca lciu m a n d ph osph or u s
Regu la t ion of gen e expr ession
St im u la t ion of differ en t ia t ion of in t est in a l epit h elia l cells a n d ost eobla st s
Vit a m in E P r ot ect ion a ga in st oxida t ive degr a da t ion fr om r ea ct ive oxygen species (fr ee r a dica ls)
Vit a m in K Coa gu la t ion of blood
For m a t ion of bon e
Ascor bic a cid Syn t h esis of colla gen a n d m u cou s m em br a n e in t egr it y
(vit a m in C) P r ot ect ion a ga in st oxida t ive degr a da t ion fr om r ea ct ive oxygen species (fr ee r a dica ls)
Fa cilit a t ion of ir on a bsor pt ion
Ma in t en a n ce of lu n g fu n ct ion
Met a bolism of a m in o a cids
Syn t h esis of st er oid h or m on es
P r om ot ion of r esist a n ce t o in fect ion
Th ia m in Ca r boh ydr a t e m et a bolism —ser ves a s a coen zym e in t h e pr ocess of en er gy m et a bolism
(vit a m in B 1 ) Regu la t ion of n eu r on a l fu n ct ion , a lt h ou gh t h e m ech a n ism is u n clea r
Ribofla vin Ca r boh ydr a t e, a m in o a cid, a n d fa t t y a cid m et a bolism
(vit a m in B 2 ) Su ppor t for a n t ioxida n t pr oper t ies
Nia cin Ca r boh ydr a t e, a m in o a cid, a n d fa t t y a cid m et a bolism
P yr idoxin e Am in o a cid m et a bolism
(vit a m in B 6 ) Relea se of glu cose fr om glycogen
Biosyn t h esizin g n eu r ot r a n sm it t er s a n d h ist a m in e
Biosyn t h esizin g m yelin sh ea t h s of n er ve cells
Modu la t ion of st er oid h or m on e r ecept or s
Cr it ica l for t h e pr odu ct ion of a n t ibodies
Fola t e Am in o a cid a n d n u cleot ide m et a bolism
DNA/RNA syn t h esis
E m br yogen esis
For m a t ion of r ed a n d wh it e blood cells in t h e bon e m a r r ow
Redu ct ion of h om ocyst ein e levels
Biot in Ca r boh ydr a t e, a m in o a cid, a n d fa t t y a cid m et a bolism
Pa n t ot h en ic a cid Ca r boh ydr a t e, a m in o a cid, a n d fa t t y a cid m et a bolism
Coba la m in Am in o a cid m et a bolism
(vit a m in B 12 ) E ssen t ia l for m et a bolism of a ll cells, pa r t icu la r ly t h ose of t h e ga st r oin t est in a l t r a ct , bon e m a r r ow,
a n d n er vou s t issu e
Redu ct ion of h om ocyst ein e levels

m edia t e im pu lse con du ct ion wit h in t h e n er vou s sys-
t em . Min er a ls m a in t a in wa t er ba la n ce, a cid–ba se
ba la n ce, a n d osm ot ic pr essu r e. Min er a ls a r e cr it ica l
for m u scle con t r a ct ion a n d for m t h e st r u ct u r a l com -
pon en t s of bon es a n d t eet h .
Min er a ls a r e su bca t egor ized a s m a cr om in er a ls
or m icr om in er a ls. Th e m a cr om in er a ls in clu de so-
diu m , pot a ssiu m , ca lciu m , ph osph or u s, m a gn esiu m ,
a n d su lfu r. Th ese su bst a n ces a r e pr im a r ily ion s a n d
t h er efor e exist in a ch a r ged st a t e. Th e m icr om in er a ls
434 C h a p t e r 17: Alt er ed Nu t r it ion

in clu de ir on , zin c, flu or ide, a n d copper. Micr om in er-
a ls do n ot exist in blood, t issu es, a n d cellu la r flu ids
in a fr ee ion ic st a t e; r a t h er, t h ese su bst a n ces a r e
bou n d t o pr ot ein s. Micr om in er a ls a r e oft en r efer r ed
t o a s t r a ce m et a ls. Th ese m et a ls a ct on en zym es a n d
h or m on es t o elicit a specific r espon se. Th ey a lso in -
t er a ct wit h DNA t o r egu la t e t h e t r a n scr ipt ion of pr o-
t ein s. In t h is wa y, m icr om in er a ls, or m et a ls, a ffect
t h e wh ole body. Micr om in er a ls ca n be fu r t h er su b-
divided a s u lt r a t r a ce m in er a ls, in wh ich ext r em ely
m in u t e a m ou n t s a r e r equ ir ed. Th e u lt r a t r a ce m in er-
a ls a r e iodin e, selen iu m , m a n ga n ese, m olybden u m ,
coba lt , bor on , a n d ch r om iu m . Th e specific con t r ibu -
t ion s of select m in er a ls a r e pr esen t ed in Ta ble 17.2.
Nutritional Intake Requirements
Nu t r it ion a l in t a ke r equ ir em en t s, su ch a s t h e Rec-
om m en ded Da ily Allowa n ces (RDAs), h a ve been
pu blish ed t o design a t e t h e r ecom m en ded in t a ke for
m ost n u t r ien t s. Th e goa l of a dh er in g t o t h e RDAs is
t o m in im ize t h e h ea lt h effect s t h a t ca n occu r wit h
over n u t r it ion or u n der n u t r it ion . Ca lor ic r equ ir e-
m en t s a r e det er m in ed ba sed on t h e kca l/kg n eeded
t o m a in t a in body weigh t . Ca lor ic in t a ke r equ ir e-
m en t s depen d on a ge, gen der, a ct ivit y level, cu r r en t
weigh t , pr egn a n cy, a n d la ct a t ion . Du r in g t im es of
gr owt h , ca lor ic r equ ir em en t s a r e h igh er. For exa m -
ple, ca lor ic r equ ir em en t s a r e 117 kca l/kg a t bir t h .
Th is r equ ir em en t decr ea ses t o 80 kca l/kg bet ween
a ges 1 a n d 10 yea r s a n d is a bou t h a lf of t h a t (30 t o
40 kca l/kg) in a du lt h ood. P r egn a n cy dem a n ds a dd
a n a ddit ion a l 300 kca l/da y. La ct a t ion (br ea st feedin g)
in cr ea ses t h e r equ ir em en t by 500 kca l/da y.
Stop and Consider
What is your approximate caloric requirement per
day to maintain your body weight?
Micr on u t r ien t r equ ir em en t s a r e expr essed pr i-
m a r ily in m icr ogr a m s (µg) or m illigr a m s (m g) per
da y. For exa m ple, t h e RDA for vit a m in A for a du lt s
is 700 µg/da y for wom en a n d 900 µg/da y for m en .
Ma cr on u t r ien t in t a ke r ecom m en da t ion s for a du lt s
a r e ba sed on per cen t a ge of ca lor ies con su m ed 3 :

Ta b le 17.2 P h ysiologic Con t r ibu t ion s of Select Min er a ls

Min e r a l F u n c t io n
Ca lciu m Ca lciu m is t h e m ost a bu n da n t m in er a l in t h e body a n d is essen t ia l for bon e a n d t eet h for m a t ion , m u s-
cle con t r a ct ion , blood coa gu la t ion , t r a n sm ission of n er vou s im pu lses, cell m em br a n e per m ea bilit y, a n d
en zym e a ct iva t ion
P h osph or u s P h osph or u s is t h e secon d m ost a bu n da n t m in er a l in t h e body a n d is a n essen t ia l com pon en t of DNA
a n d RNA, cellu la r en er gy (t h e P of ATP ), m em br a n e r ecept or s, cell m em br a n es, a cid–ba se bu ffer sys-
t em s (ph osph a t e syst em ), bon es, a n d t eet h
Ir on Ir on is essen t ia l for m u lt iple pr ocesses, in clu din g r ed blood cell fu n ct ion , t r a n spor t a t ion of oxygen , m yo-
globin fu n ct ion , a n d m odu la t ion of en zym e a ct ivit y in volved in cellu la r r espir a t ion a n d en er gy (ATP )
pr odu ct ion . Ir on su ppor t s im m u n e fu n ct ion a n d m a y pla y a r ole in pr om ot in g cogn it ive per for m a n ce
Zin c Zin c is a n in t r a cellu la r ion t h a t m odu la t es t h e effect s of n u m er ou s en zym es; t h e m a jor r oles a r e in m e-
t a bolism of m a cr on u t r ien t s a n d n u cleic a cids, a s a com pon en t of pr ot ein st r u ct u r e, gen e expr ession , cell
division , ost eobla st ic a ct ivit y, im m u n e fu n ct ion , a n d n eu r on fu n ct ion
F lu or ide F lu or ide su ppor t s t oot h en a m el a n d h a s a n t iba ct er ia l pr oper t ies lea din g t o r esist a n ce a ga in st den t a l
ca r ies
Copper Copper is a com pon en t of n u m er ou s en zym es a n d t h er efor e pla ys a r ole in n u m er ou s pr ocesses, su ch
a s t h e syn t h esis of en er gy, ca t ech ola m in es, colla gen , ela st in , a n d m ela n in . Copper a lso pr ot ect s a ga in st
r ea ct ive oxygen species a n d pr om ot es ir on oxida t ion
Iodin e Iodin e is n eeded for t h e syn t h esis of t h yr oid h or m on es
Selen iu m Selen iu m h a s a n t ioxida n t pr oper t ies a n d pla ys a r ole in lipid m et a bolism a n d t h yr oid h or m on e pr odu c-
t ion , a n d it m a y r edu ce ca n cer r isk
Ma n ga n ese Ma n ga n ese is a com pon en t of n u m er ou s en zym es. It pla ys a r ole in ca r boh ydr a t e a n d lipid m et a bolism ,
gr owt h , r epr odu ct ion , a n d for m a t ion of con n ect ive t issu es a n d bon e
Ch r om iu m Ch r om iu m is a ct ive in m a cr on u t r ien t m et a bolism a n d gen e expr ession
Molybden u m Molybden u m is a ct ive in m u lt iple en zym a t ic r ea ct ion s
Bor on Bor on is a com pon en t of cell m em br a n es a n d pla ys a r ole in m odu la t in g en zym a t ic r ea ct ion s, m ost n ot a -
bly su ppor t in g br a in a n d bon e fu n ct ion
Coba lt Coba lt is a com pon en t of B 12 ; it s pr im a r y r ole is r ed blood cell m a t u r a t ion . Coba lt a lso su ppor t s t h e
fu n ct ion of a ll ot h er cells a n d pr om ot es en zym es a ct ive in DNA t o RNA t r a n scr ipt ion

● Ca r boh ydr a t es: 45% t o 65%
● P r ot ein s: 10% t o 35%
● Fa t s: 20% t o 35%
Intake and Storage of Nutrients
Ma in t en a n ce of body weigh t a n d com posit ion r e-
qu ir es a ba la n ce of en er gy in t a ke a n d expen dit u r e.
Du r in g t im es of gr owt h , en er gy r equ ir em en t s in -
cr ea se t o offset t h e eviden t gr owt h expen dit u r es.
E n er gy in t a ke is r egu la t ed by n u m er ou s fa ct or s,
in clu din g h u n ger, s a t ie t y , or a feelin g of fu lln ess,
food a va ila bilit y, a n d em ot ion a l a n d ph ysica l h ea lt h .
H u n ger a n d sa t iet y a r e r egu la t ed in t h e br a in by t h e
h ypot h a la m u s, ba sed on feedba ck fr om t h e diges-
t ive t r a ct on t h e qu a n t it y a n d qu a lit y of food in t h e
st om a ch a n d in t est in es (F ig. 17.4). Som e exa m ples of
feedba ck m essa ges fr om GI t r a ct a n d n u t r ien t st or-
a ge sit es t o t h e h ypot h a la m u s in clu de:
● Th e pr esen ce of low blood glu cose or a la ck of food
in t h e GI t r a ct in du ces h u n ger.
● Th e pr esen ce of food in t h e GI t r a ct t r igger s
st r et ch r ecept or s a n d in su lin secr et ion a n d su bse-
qu en t ly r edu ces a ppet it e.
● Th e pr esen ce of fa t st im u la t es ch olecyst okin in , a
GI h or m on e t h a t con t r ibu t es t o sa t iet y.
● In cr ea ses in fa t st or es st im u la t e t h e r elea se of
lept in , a h or m on e wit h t h e a bilit y t o su ppr ess
a ppet it e, in cr ea se en er gy expen dit u r es, a n d u lt i-
m a t ely in cr ea se m et a bolism .
Th e h ypot h a la m u s r espon ds by secr et in g h or m on es
t h a t con t r ibu t e t o en er gy in t a ke, expen dit u r e, a n d
m et a bolism . In r espon se, t h e sh or t -t er m desir e t o
ea t is r edu ced or st im u la t ed. Over a lon ger per iod,
body weigh t a n d com posit ion a r e m a in t a in ed.
St or a ge of n u t r ien t s is a lso cr it ica l t o h ea lt h . Adi-
pocyt es (fa t cells) st or e lipids a s a key en er gy sou r ce
wh en t h e n eed a r ises. Th e liver st or es cer t a in vit a -
m in s a n d m in er a ls, su ch a s vit a m in s A, B 12 , D, E , K,
ir on , a n d copper, a n d t h en r elea ses t h ese in t im es of
n eed. Th e liver a lso st or es glycogen , a n d wh en gly-
cogen st or es a r e exh a u st ed, t h e liver t h en con ver t s
a m in o a cids a n d glycer ol t o glu cose.
DIGESTION
Th e digest ive syst em is essen t ia l for (1) digest in g
a n d ext r a ct in g m a cr on u t r ien t s, (2) a bsor bin g n u -
t r ien t s, a n d (3) for m in g a ph ysiologic a n d ch em ica l
ba r r ier a ga in st m icr oor ga n ism s a n d ot h er for eign
m a t er ia ls in t r odu ced du r in g food in gest ion . St om -
a ch a cid for m s a fir st lin e of defen se by dest r oyin g
m a n y t ypes of m icr oor ga n ism s a n d ot h er h a r m fu l
su bst a n ces on con t a ct . Figu r e 17.5 illu st r a t es t h e
N u t r it io n 435
Food inta ke
S NS + Ene rgy
expe nditure
Ghre lin
Food inta ke
Le ptin
Fa t oxida tion
Ins ulin
Glucos e
a mino a cids Ins ulin
Fructos e, β -Ce ll
fa t
GIP Le ptin
GLP -1 Glucos e
Inte s tine me ta bolis m
Adipos e
Figure 17.4. Long-term signals regulating food intake
and energy homeostasis. Insulin and leptin are important
long-term regulators of food intake and energy balance.
Both insulin and leptin act in the central nervous system
to inhibit food intake and to increase energy expendi-
ture, most likely by activating the sympathetic nervous
system (SNS). Insulin is secreted from the β cells in the
endocrine pancreas in response to circulating nutrients
(glucose and amino acids) and to the incretin hormones,
glucose-dependent insulinotropic polypeptide (GIP) and
glucagon-like peptide-1 (GLP-1), which are released during
meal ingestion and absorption. Insulin can also act indi-
rectly by stimulating leptin production from adipose tissue
through increased glucose metabolism. Ghrelin, a hormone
produced by endocrine cells in the stomach, increases food
intake and decreases fat oxidation and appears to have an
anabolic role in long-term regulation of energy balance.
Ghrelin secretion is normally suppressed after meals, but
it is not suppressed by fat or fructose consumption. The
long-term signals interact with the short-term signals in
the regulation of energy homeostasis and appear to set
sensitivity to the satiety-producing effects of short-term
signals such as cholecystokinin. (Adapted with permission
from Havel PJ. Peripheral signals conveying metabolic
information to the brain: short-term and long-term regula-
tion of food intake and energy homeostasis. Exp Biol Med
[Maywood]. 2001;226:963–977.)
digest ive syst em , com pr ised of t h e ga st r oin t est in a l
t r a ct a n d a ccessor y or ga n s.
D ig e s t io n is t h e pr ocess by wh ich food is br o-
ken down m ech a n ica lly a n d ch em ica lly in t h e ga s-
t r oin t est in a l t r a ct a n d con ver t ed in t o a bsor ba ble
436 C h a p t e r 17: Alt er ed Nu t r it ion

Pa rotid s a liva ry gla nd

S ubma ndibula r a nd
s ublingua l s a liva ry
gla nds

Es opha gus

Live r

He pa tic duct
Cys tic duct S toma ch

Ga llbla dde r Pa ncre a s

S ple nic flexure

Common bile duct
He pa tic flexure La rge inte s tine
S ma ll Duode num
inte s tine J e junum Tra ns ve rs e colon
Ile um De s ce nding colon
As ce nding colon
Ce cum
Ha us tra
Appe ndix

Re ctum
S igmoid colon

Anus

Figure 17.5. The digestive system.

com pon en t s. Figu r es 17.1 t o 17.3 h igh ligh t ed t h ese
pr ocesses for ea ch of t h e m a cr on u t r ien t s. Th e m ou t h ,
st om a ch , a n d sm a ll in t est in e ea ch h a ve a sign ifica n t
r ole in m ech a n ica l a n d ch em ica l digest ive pr ocesses.
Mech a n ica l digest ion is t h e pr ocess of ph ysica lly
br ea kin g down a n d m ovin g su bst a n ces t h r ou gh t h e
digest ive t r a ct . Ch ewin g food is a m a jor m ech a n ism
for m ech a n ica l digest ion . Con t in u ed m ech a n ica l
ch u r n in g of food occu r s in t h e st om a ch .
Ch em ica l digest ion is t h e wor k of digest ive en -
zym es a n d bile, wh ich con ver t in gest ed su bst a n ces
in t o a bsor ba ble com pon en t s. Accessor y or ga n s, m ost
n ot a bly t h e sa liva r y gla n ds, pa n cr ea s, a n d liver a r e
cr it ica l in pr odu cin g a n d secr et in g digest ive en zym es
a n d bile in t o t h e ga st r oin t est in a l t r a ct . Ch em ica l
digest ion is st im u la t ed by ch ewin g a n d begin s in t h e
m ou t h a s food m ixes wit h sa liva , a su bst a n ce con -
sist in g m ost ly of wa t er, bica r bon a t e, ch lor ide, pot a s-
siu m , a n d sa liva r y a m yla se. Sa liva r y a m yla se, fr om
sa liva r y gla n ds, is a n en zym e r espon sible for in it ia t -
in g ca r boh ydr a t e digest ion .
In t h e st om a ch , food is m ixed wit h h ydr och lor ic
a cid, pepsin , a n d ot h er digest ive en zym es. Fou r m a -
jor secr et or y cells a r e fou n d in t h e st om a ch :
● Mu cou s cells, wh ich secr et e a lka lin e m u cu s
a n d pr ot ect t h e epit h eliu m fr om st r ess a n d a cid
con t a ct
● Pa r ieta l cells, wh ich secr et e bot h h ydr och lor ic
a cid, a st r on g a cid, n eeded t o a ct iva t e pepsin ogen

a n d dest r oy pa t h ogen s a n d in t r in sic fa ct or, a gly-
copr ot ein n eeded for in t est in a l a bsor pt ion of vit a -
m in B 12
● Ch ief cells, wh ich secr et e pepsin , a pr ot eolyt ic en -
zym e, cr it ica l t o pr ot ein digest ion
● G cells, wh ich secr et e ga st r in , a h or m on e r espon -
sible for con t r ollin g a cid secr et ion a n d st im u la t -
in g ga st r ic m ot ilit y
Ga st r ic epit h elia l cells a r e a lso st im u la t ed t o secr et e
ot h er en zym es, su ch a s lipa se a n d gela t in a se. Th e
m ost im por t a n t digest ive con t r ibu t ion of t h e st om -
a ch is t h e in it ia t ion of pr ot ein digest ion .
Th e fin a l st a ges of ch em ica l digest ion occu r
t h r ou gh sm a ll in t est in a l villi, t h e fu n ct ion a l u n it s of
t h e sm a ll in t est in e, wh ich a r e lin ed wit h colu m n a r
a n d m u cu s-secr et in g epit h elia l cells. Villi a r e ca pa -
ble of bot h en zym e secr et ion a n d a bsor pt ion of n u t r i-
en t s. Micr ovilli, loca t ed on t h e colu m n a r epit h eliu m ,
a r e r efer r ed t o a s t h e “br u sh bor der ” a n d ser ve t o
gr ea t ly in cr ea se t h e su r fa ce a r ea of t h e sm a ll in t es-
t in e. In t est in a l m u cosa l folds slow t h e pa ssa ge of
food t o pr ovide a dequ a t e t im e for digest ion . As t h e
n u t r ien t s m ove in t o t h e sm a ll in t est in e, t h ey a r e
m et wit h bile sa lt s fr om t h e liver (cr it ica l for fa t di-
gest ion ), bica r bon a t e fr om t h e pa n cr ea s (n eeded t o
n eu t r a lize h ydr och lor ic a cid), a n d en zym es a lso fr om
t h e pa n cr ea s (cr it ica l for digest ion of fa t s, pr ot ein s,
a n d ca r boh ydr a t es). Wit h in t h e sm a ll in t est in e,
n u t r ien t s a r e m ixed wit h bile a n d t h e pa n cr ea t ic
en zym es. Th e specific loca t ion s a n d r oles of select di-
gest ive en zym es a r e discu ssed in Ta ble 17.3. E m u lsi-
fyin g a gen t s, cr it ica l for fa t digest ion , a r e discu ssed
below t o illu st r a t e t h e a bsor pt ion of fa t t y a cids a n d
glycer ol.
Th e r egu la t ion of digest ion , wit h t h e except ion
of ch ewin g, swa llowin g, a n d defeca t ion , is dir ect ed
Ta b le 17.3 E n zym es Act ive in t h e Ch em ica l Digest ive P r ocess
E n zy m e L o c a t io n
Sa liva r y a m yla se (pt ya lin ) Mou t h a n d
st om a ch
Pepsin St om a ch
Pa n cr ea t ic a m yla se Pa n cr ea s
La ct a se, m a lt a se, su cr a se (“br u sh Sm a ll
bor der en zym es”) in t est in e
Tr ypsin , ch ym ot r ypsin , a n d ca r boxy- Pa n cr ea s
pept ida se (pa n cr ea t ic en zym es)
Am in opept ida ses a n d dipept ida ses Sm a ll
(“br u sh bor der en zym es”) in t est in e
Pa n cr ea t ic lipa ses Pa n cr ea s
In t est in a l lipa se Sm a ll
in t est in e
N u t r it io n 437
t h r ou gh h or m on e feedba ck m ech a n ism s a n d t h e a u -
t on om ic n er vou s syst em . Bot h t h e sym pa t h et ic a n d
pa r a sym pa t h et ic br a n ch es of t h e a u t on om ic n er-
vou s syst em a ct on t h e wa lls of t h e ga st r oin t est in a l
t r a ct t o pr om ot e digest ion . Th e wa lls of t h e ga st r o-
in t est in a l t r a ct con t a in fou r ba sic la yer s (t h e in n er
m u cosa , su bm u cosa , m u scu la r is, a n d ser osa ). Th e
in n er m u cosa , wh ich lin es t h e lu m en a n d is in di-
r ect con t a ct wit h n u t r ien t s, va r ies in st r u ct u r e a n d
fu n ct ion depen din g on t h e loca t ion wit h in t h e ga s-
t r oin t est in a l t r a ct . Th e epit h elia l cells t h a t com pr ise
t h e m u cosa a r e ca pa ble of secr et ion , a bsor pt ion ,
a n d t h e pr odu ct ion of h or m on es. In a ddit ion t o ot h er
im m u n e pr ot ect ion s, Peyer pa t ch es (lym ph oid fol-
licles) a n d lym ph ocyt es (pr im a r ily IgA-secr et in g
B cells) a r e a lso loca t ed wit h in t h e m u cosa a n d ex-
t en d in t o t h e su bm u cosa . Peyer pa t ch es a r e n eeded
t o h ou se lym ph ocyt es a n d u lt im a t ely pr ot ect t h e
ga st r oin t est in a l t r a ct a ga in st pa t h ogen s.
Th e su bm u cosa is a con n ect ive t issu e la yer. It
con t a in s blood a n d lym ph a t ic vessels a n d t h e su b-
m u cou s plexu s (n er ve br a n ch es), wh ich pr ovide lo-
ca l a n d a u t on om ic n er vou s syst em st im u li t o t h e
ga st r oin t est in a l t r a ct . Th e m u scu la r is la yer, com -
pr ised pr im a r ily of t wo t h ick la yer s of sm oot h m u s-
cle, pr om ot es m ech a n ica l m ovem en t of n u t r ien t s
t h r ou gh t h e lu m en a n d, sim ila r t o t h e su bm u cosa ,
a lso con t a in s a m yen t er ic plexu s t o a llow n eu r on a l
st im u la t ion . Th e ser osa is t h e ou t er m ost cover in g
of t h e ga st r oin t est in a l t r a ct . Wit h in t h e a bdom in a l
ca vit y, t h e m esen t er y, a su spen sor y st r u ct u r e, con -
n ect s t o t h e ser osa a n d su ppor t s t h e digest ive t r a ct
a n d pr ovides pa t h wa ys for va scu la r a n d n eu r on a l
st im u la t ion .
Gla n ds a n d du ct s wit h in t h e m u cosa a n d su bm u -
cosa a llow t h e secr et ion of digest ive su bst a n ces in t o
t h e ga st r oin t est in a l lu m en . Ga st r in a n d m ot ilin a r e
F u n c t io n
In it ia t es ca r boh ydr a t e digest ion
Br ea ks down pr ot ein a n d for m s polypept ides in t h e st om a ch
P r om ot es con ver sion of oligosa cch a r ides a n d dext r in s (ca r boh y-
dr a t es) in t o la ct ose, m a lt ose, a n d su cr ose
Con ver t disa cch a r ides (la ct ose, m a lt ose, a n d su cr ose) in t o
m on osa cch a r ides (ga la ct ose, glu cose, a n d fr u ct ose)
Con ver t pr ot ein polypept ides in t o sm a ller pr ot ein u n it s
Con ver t pr ot ein polypept ides a n d dipept ides in t o a m in o a cids
Con ver t fa t s in t o m on oglycer ides, glycer ol, a n d fa t t y a cids
Con ver t s fa t t y a cids in t o glycer ol
438 C h a p t e r 17: Alt er ed Nu t r it ion
t wo h or m on es t h a t a ct on t h e ga st r oin t est in a l t r a ct
t o stim u la te ga st r ic em pt yin g. Ga st r in st im u la t es
ga st r ic gla n ds t o secr et e pepsin ogen (a pr oen zym e
t h a t la t er con ver t s t o pepsin ) a n d h ydr och lor ic a cid.
Secr et in , ga st r ic in h ibit or y pept ide, a n d ch olecyst o-
kin in , fr om t h e du oden u m , a r e t h r ee h or m on es t h a t
in h ibit ga st r ic em pt yin g. Secr et in is r espon sible
for t r igger in g t h e r elea se of bica r bon a t e fr om t h e
pa n cr ea s a n d bile fr om t h e liver. Ga st r ic in h ibit or y
pept ide decr ea ses st om a ch ch u r n in g. Ch olecyst oki-
n in st im u la t es t h e r elea se of digest ive en zym es in
t h e pa n cr ea s a n d t h e em pt yin g of bile fr om t h e ga ll
bla dder.
Th e over a ll goa l of digest ion is t o pr epa r e n u t r i-
en t s for a bsor pt ion by:
1. Con ver t in g ca r boh ydr a t es t o m on osa cch a r ides
2. Con ver t in g pr ot ein s in t o a m in o a cids
3. Con ver t in g fa t s t o fa t t y a cids a n d glycer ol
4. Un lea sh in g vit a m in s a n d m in er a ls fr om
m a cr on u t r ien t s
5. Sepa r a t in g wa t er fr om n u t r ien t s t o pr om ot e wa -
t er a bsor pt ion
F igu r e 17.6 illu st r a t es t h e con ver sion of n u t r ien t s
in t o a bsor ba ble com pon en t s a n d sh ou ld be r efer r ed
t o fr equ en t ly du r in g t h e discu ssion of a bsor pt ion
below.
ABSORPTION
Ab s o r p t io n is a com plex pr ocess of t a kin g in n u t r i-
en t s a n d m ovin g t h ese t o t h e cir cu la t ion t o be u sed
by cells. Cer t a in loca t ion s wit h in t h e digest ive sys-
t em a r e bet t er equ ipped t o a bsor b specific n u t r ien t s.
F igu r e 17.7 det a ils t h e m a jor sit es of a bsor pt ion for
specific n u t r ien t s a lon g t h e ga st r oin t est in a l t r a ct .
Recogn it ion of t h ese m a jor sit es of a bsor pt ion a llows
t h e a bilit y t o a n t icipa t e n u t r it ion pr oblem s t h a t ca n
occu r wit h in a dequ a t e a bsor pt ion a t cer t a in loca -
t ion s wit h in t h e ga st r oin t est in a l t r a ct .
Th e sm a ll in t est in e is a n idea l sit e for a bsor pt ion
of n u t r ien t s beca u se of t h e ext en sive su r fa ce a r ea
a n d a bsor pt ive flu id la yer a lon g t h e br u sh bor der.
Also u n iqu e t o t h e sm a ll in t est in e is t h e pr esen ce
of la c t e a ls , or lym ph a t ic ch a n n els wit h in ea ch vil-
lu s, wh ich a r e cr it ica l t o t h e a bsor pt ion of fa t m ole-
cu les. Som e su bst a n ces, su ch a s wa t er, a r e a bsor bed
pr im a r ily in t h e la r ge in t est in e a n d st om a ch . Vit a -
m in D ca n be a bsor bed t h r ou gh t h e skin .
Aft er a bsor pt ion a n d t r a velin g wit h in t h e cir cu la -
t ion , t h e liver r eceives t h e n u t r ien t s t h a t wer e on ce
in t h e in t est in a l lu m en . On ce in t h e liver, t h e n u t r i-
en t s a r e m et a bolized, con ver t ed, or syn t h esized in t o
ot h er n u t r ien t s, or t h ey a r e st or ed for la t er u se. Th e
liver t h en r elea ses t h e n u t r ien t s ba ck in t o t h e cir cu -
la t ion t o be u sed by body cells.
Glucose and Fructose Absorption
Ca r boh ydr a t es r epr esen t t h e la r gest pr opor t ion
of n u t r ien t s a bsor bed wit h in t h e digest ive t r a ct .
Mon osa cch a r ides (glu cose or fr u ct ose) a r e r a r ely
con su m ed in a t ypica l diet . Th er efor e, m or e com plex
ca r boh ydr a t es (su cr ose, la ct ose, a n d st a r ch es) m u st
be degr a ded by en zym es a n d r edu ced t o m on osa c-
ch a r ides for a bsor pt ion . Th e followin g list ou t lin es
key a spect s of ca r boh ydr a t e a bsor pt ion :
● Pa n cr ea t ic a m yla se a ct s on diet a r y ca r boh ydr a t es
t o begin t h e r edu ct ion in t o sim ple su ga r s (pr im a r-
ily st a r ch es in t o m a lt ose).
● Th e fin a l en zym a t ic digest ion , wh ich liber a t es
m or e com plex ca r boh ydr a t es in t o m on osa cch a -
r ides (pr im a r ily glu cose, a lso fr u ct ose a n d ga -
la ct ose), is t h e wor k of br u sh bor der en zym es
(disa cch a r ida ses, su ch a s su cr a se a n d la ct a se, a n d
oligosa cch a r ida se, su ch a s m a lt a se) secr et ed fr om
t h e sm a ll in t est in e.
● Glu cose r equ ir es t h e cot r a n spor t of sodiu m t o be
a bsor bed in t o t h e lu m en of t h e sm a ll in t est in e.
Glu cose a n d ga la ct ose a r e a bsor bed in t o t h e en -
t er ocyt e (in t est in a l cell) with sod iu m via a ct ive
t r a n spor t . Ac t iv e t r a n s p o r t is a pr ocess t h a t u ses
en er gy t o m ove n u t r ien t s a cr oss a pr essu r e gr a dien t
(Fig. 17.8). Th e sou r ce of t h is en er gy is a den osin e
t r iph osph a t e (ATP ), wh ich is t h e pr odu ct of a ch em -
ica l r ea ct ion bet ween oxygen a n d n u t r ien t pr odu ct s.
E n er gy is r equ ir ed for t h e t r a n spor t of glu cose a n d
sodiu m beca u se t h e con cen t r a t ion of sodiu m ou t side
t h e cell is fa r gr ea t er t h a n in side t h e cell. In fa ct ,
m a n y n u t r ien t s in clu din g ga la ct ose, ca lciu m , ir on ,
a m in o a cids, pot a ssiu m , fa t t y a cids, a n d m a gn esiu m ,
r equ ir e en er gy-depen den t t r a n spor t pu m ps t o be a b-
sor bed a cr oss t h e m u cosa .
For glu cose t r a n spor t , t wo sodiu m ion s bin d t o t h e
t r a n spor t er. A ch a n ge in t h e t r a n spor t er t h en occu r s,
a llowin g glu cose t o bin d t o t h e t r a n spor t er, a n d on ly
t h en ca n t h ese m olecu les m ove in t o t h e cell. Th e en -
er gy st or ed in t h e m em br a n e gr a dien t dr ives glu cose
t h r ou gh t h e en t er ocyt e. Glu cose t h en diffu ses down
it s con cen t r a t ion gr a dien t in t o t h e ca pilla r ies wit h in
t h e villu s of t h e sm a ll in t est in e.
F r u ct ose en t er s t h e en t er ocyt e t h r ou gh t h e pr o-
cess of pa ssive fa cilit a t ed diffu sion t h r ou gh a t r a n s-
por t er. P a s s iv e d i u s io n , wh ich is t h e r a n dom
m igr a t ion of n u t r ien t s a cr oss t h e m u cosa fr om a r ea s
of h igh er t o lower con cen t r a t ion or pr essu r e, ca n be
a sim ple or fa cilit a t ed pr ocess. S im ple d iffu sion a l-
lows n u t r ien t s t o m ove t h r ou gh or bet ween ch a n n el
pr ot ein s. Fa cilita ted d iffu sion u ses ca r r ier pr ot ein s
t h a t m ove n u t r ien t s a cr oss t h e ga st r oin t est in a l m u -
cosa . Pa ssive diffu sion is a lso r epr esen t ed by t h e
a bsor pt ion of m ost vit a m in s a n d wa t er, wh ich pa ss
 N u t r it io n 439

“Brus h borde r”
S mall inte s tine

Abs orptive ce lls

Die tary pro te in Die tary c arbo hydrate Die tary fat
Glyce rol
Triglyce ride s
Fa tty a cid

Pa ncre a tic prote a s e s Pa ncre a tic a myla s e Pa ncre a tic lipa s e + bile s a lts

S ma ll pe ptide s Monosaccharides Dis a ccha ride s Oligosaccharides +

Fa tty a cids

Fatty acids and

monoglycerides
Pe ptida s e s Dis a ccha rida s e Oligosaccharidase
Bile s a lts

S odium

Monoglyce ride s
a nd fa tty a cids
Amino a cids Monos a ccha ride s

Lymphatics Diglyce ride

Capillary

Triglyce ride

P rote in
P hos pholipid

Triglyce ride
Chole s te rol

Chylomicron

Figure 17.6. Mechanisms of nutrient digestion and absorption within the small intestine. (Modified from Rubin E, Farber
JL. Pathology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005, with permission.)
440 C h a p t e r 17: Alt er ed Nu t r it ion

Mo uth

Intestinal
lumen Capillary
Nutrie nts

Es o phag us

S imple diffus io n:
Wa te r fa cilita te s a bs orption
Stomach
through cha nne l
Alcohol prote ins

Mine ra ls
Duo de num
Fa ts Facilitated diffus ion:
(through lacteals) utilize s ca rrie r
Glucos e , prote ins to fa cilita te
galactose, fructose a bs orption
Je junum
Wa te r-s oluble
vita mins
Amino a cids Fa ts
(through la cte a ls )
Fat-soluble vitamins Ac tive trans po rt:
Ile um ATP
Fats (through lacteals) us e s e ne rgy to
fa cilita te a bs orption ATP
S odium, pota s s ium

Figure 17.8. Passive diffusion and active transport mech-

anisms of absorption.

Co lo n u n ch a n ged fr om t h e ga st r oin t est in a l t r a ct t o t h e

cir cu la t ion .
Wa te r

Amino Acid and Small Peptide

Fe ce s
Figure 17.7. Major sites for absorption in the gastroin-
testinal tract. The gastrointestinal tract absorbs specific
nutrients at specific locations.
Absorption
Th e fa cilit a t ion of a m in o a cid a n d sm a ll pept ide
(t wo or t h r ee lin ked a m in o a cids) a bsor pt ion is a c-
com plish ed t h r ou gh t h e wor k of pr ot eolyt ic en zym es,
wh ich degr a de diet a r y pr ot ein s in t o sm a ller pept ides
a n d t h en in t o a m in o a cids. Th r ee m a jor sou r ces of pr o-
t eolyt ic en zym es in clu de t h e (1) a ct ive pr ot ea se pep-
sin (fr om t h e st om a ch ); (2) pa n cr ea t ic pr ot ea ses (su ch
a s t r ypsin , ch ym ot r ypsin , a n d ca r boxypept ida ses);
a n d (3) pept ida ses fou n d in t h e in t est in a l br u sh bor-
der. Th e m ech a n ism for a bsor pt ion of a sin gle a m in o
a cid is essen t ia lly t h e sa m e a s m on osa cch a r ides.
 Alt e r e d N u t r it io n 441

Sodiu m -depen den t t r a n spor t er s a r e n eeded, u sin g 1. Fa t t y a cids a n d m on oglycer ides r esyn t h esize ba ck
en er gy a cr oss a n elect r och em ica l gr a dien t , t o m ove in t o t r iglycer ides a ft er m ovin g a cr oss t h e pla sm a
a m in o a cids in t o t h e in t est in a l epit h eliu m . In t er est - m em br a n e.
in gly, sm a ll pept ides a r e a bsor bed wit h ou t depen d- 2. Tr a n spor t in t o t h e cir cu la t ion occu r s via la ct ea ls,
in g on sodiu m . Ra t h er, t h ese sm a ll-ch a in a m in o a cids lym ph a t ic vessels wit h in ea ch villu s, r a t h er t h a n
t r a vel t h r ou gh a sin gle t r a n spor t m olecu le. On ce in t h r ou gh t h e blood vessels.
t h e en t er ocyt e, sm a ll pept ides a r e r edu ced t o a m in o
Aft er a bsor pt ion in t he en terocytes of t he sma ll int es-
a cids a n d m ove wit h ot h er t r a n spor t m olecu les in t o
t ina l m ucosa , t he tr iglycer ides a r e r esynt hesized a n d
t h e cir cu la t ion . Th is fin a l st a ge of a bsor pt ion for a ll
m a de soluble a ga in th rou gh t he pr oduct ion of lipopro-
a m in o a cids does n ot r ely on sodiu m cot r a n spor t a n d
t ein com plexes (chylom icr ons). Chylom icr on s fr om t he
is n ot a cr oss a n en er gy gr a dien t .
int est ine a re r elea sed int o t he blood t hr ough la ctea ls
a n d a r e delivered to t issues or st or ed for th e la t er pr o-
duct ion of ener gy t hr ough oxida t ion. Fa tt y a cids a re
Fatty Acid and Glycerol Absorption st ored a s t r iglycer ides, pr im a r ily wit hin a dipocyt es.
These fa t t y a cids ca n be m obilized when needed. The
Th e con ver sion of diet a r y fa t s in t o fa t t y a cids a n d
a ct iva tion of m obiliza tion occur s in r esponse t o hor-
glycer ol r equ ir es t wo m a jor st eps: em u lsifica t ion
m ones t ha t bind cell sur fa ce r ecept ors. In a ser ies of
a n d en zym a t ic digest ion . E m u lsifica t ion pr om ot es
com plex event s, free fa tt y a cids diffuse fr om a dipo-
fa t solu bilit y a n d is a ccom plish ed via bile sa lt s,
cyt es, com bin e with a lbu min, a re t ra nspor t ed t o ot her
wh ich a r e syn t h esized in t h e liver a n d secr et ed fr om
t issues, a nd pa ssively diffu se int o cells.
t h e ga ll bla dder. E m u lsifica t ion is a pr ocess of coa t -
Absor pt ion is a ffect ed by sever a l fa ct or s. Com pe-
in g t h e lipid m olecu les wit h bile sa lt s, wh ich h a ve
t it ion for ca r r ier s blocks a bsor pt ion of cer t a in n u -
bot h h ydr oph ilic (wa t er-a t t r a ct in g) a n d h ydr oph obic
t r ien t s. Sa t u r a t ion of ca r r ier s slows t h e a bsor pt ion
(wa t er-r epellen t ) com pon en t s. Ult im a t ely, t h e lipid
pr ocess. Absor pt ion ca n be en h a n ced or in h ibit ed
m olecu les a r e br oken down in t o sm a ller a n d sm a ller
wh en select su bst a n ces coexist . For exa m ple, a scor-
dr oplet s, t h e h ydr oph obic en d a dh er es t o t h e lipid
bic a cid (vit a m in C), su ch a s t h a t fou n d in or a n ge
m olecu le, a n d t h e h ydr oph ilic en d com pr ises a n
ju ice, en h a n ces t h e a bsor pt ion of ir on . An ot h er ex-
ou t er solu ble su r fa ce.
a m ple is t h e pr esen ce of diet a r y fa t , wh ich is n eeded
for a bsor pt ion of fa t -solu ble vit a m in s. P h ysiologic
Stop and Consider
fa ct or s, su ch a s ga st r ic pH a n d m ot ilit y, m a y a ffect
What dietary recommendations would you make
bioa va ila bilit y a n d su bsequ en t a bsor pt ion of m in -
for the individual who is not able to effectively
er a ls. B io a v a ila b ilit y in dica t es t h a t t h e m in er a l
produce or use bile?
is u n bou n d a n d m u st r em a in u n bou n d (a lso ca lled
a n ion ic st a t e) t o be a bsor bed, su ch a s wit h ca lciu m .
On ce em u lsified, pa n cr ea t ic lipa se (a wa t er-solu ble
Bou n d m in er a ls a r e u n u sed a n d a r e elim in a t ed in
en zym e) a ct s on t h e su r fa ce of t r iglycer ide dr oplet s
t h e feces. Ir on is on e except ion . Ir on ca n be a bsor bed
t o fu r t h er degr a de t r iglycer ides in t o fr ee fa t t y a cids,
in a bou n d st a t e. To a dd a ddit ion a l com plexit y, t h e
m on oglycer ides, a n d diglycer ides. Th ese su bst a n ces
st r u ct u r e a n d fu n ct ion of t h e in t est in a l cells r egu -
for m a com plex wit h bile sa lt s a n d ot h er lipids ca lled
la t e a n d pr om ot e m a xim a l a bsor pt ion a n d ca n a lso
m icelles. Th e m icelles m ove a lon g t h e br u sh bor der
lim it t h e pot en t ia l for n u t r ien t t oxicit y.
of t h e sm a ll in t est in e, wh er e t h ey ca n be a bsor bed
t h r ou gh a pr ocess of sim ple diffu sion (discu ssed be-
low) or via a fa t t y a cid t r a n spor t er pr ot ein a cr oss t h e Stop and Consider
pla sm a m em br a n e. What will happen to nutrient absorption in Crohn
Two m a jor differ en ces ch a r a ct er ize t h e a bsor p- disease when large portions of the small intes-
t ion of fa t s a s com pa r ed t o a m in o a cids a n d su ga r s: tine are inflamed?

Modu le 2 Alt e r e d N u t r it io n

Alt er ed n u t r it ion , or m a ln u t r it ion , is a st a t e of in a d- ● Gen et ic defect s t h a t im pa ct m et a bolism or a b-

equ a t e or excessive exposu r e t o n u t r ien t s (Fig. 17.9). sor pt ion of n u t r ien t s
Th is exposu r e ca n in clu de in t a ke, digest ion , a bsor p- ● Ma lfor m a t ion or da m a ge t o t h e ga st r oin t est in a l
t ion , or m et a bolism of n u t r ien t s. Alt er ed n u t r it ion m u cosa
h a s m u lt iple pot en t ia l ca u ses, in clu din g:
442 C h a p t e r 17: Alt er ed Nu t r it ion
Alte re d Nutritio n
Ove rnutrition
Obe s ity Vita min/mine ra l Ina de qua te
toxicity inta ke
Ma cronutrie nt
de ficie ncie s
Figure 17.9. Concept map. Altered nutrition. PKU, phenylketonuria.
● In a dequ a t e or excessive diet a r y in t a ke of r equ ir ed
n u t r ien t s
● E xcessive n u t r ien t losses, su ch a s t h r ou gh vom it -
in g, dia r r h ea , or la xa t ive u se
● H yper m et a bolic st a t es t h a t exer t excessive de-
m a n ds, su ch a s wit h h yper t h yr oidism , ca n cer,
bu r n s, fever, or sever e in fect ion
● Ma la bsor pt ive syn dr om es
● In gest ion of u n sa fe food a n d wa t er sou r ces
Inherited Metabolic Disorders
In h er it ed m et a bolic disor der s, m ost oft en r ela t ed t o
er r or s in a m in o a cid a n d lipid m et a bolism , com m on ly
r esu lt fr om a gen et ica lly ba sed defect in en zym e a c-
t ivit y. Th ese a r e a lso ca lled in bor n er r or s of m et a b-
olism . Nu t r it ion a l gen om ics is a field of scien ce t h a t
con sider s t h e r ole of n u t r ien t s on gen e expr ession .
For exa m ple, in ph en ylket on u r ia (P KU), ph en yla l-
a n in e h ydr oxyla se deficien cy ca u ses a n in a bilit y t o
con ver t ph en yla la n in e, a n essen t ia l a m in o a cid, t o
t yr osin e. Accu m u la t ion s of ph en yla la n in e, wit h ou t
t h e n ecessa r y con ver sion t o t yr osin e, r esu lt in im -
pa ir ed CNS developm en t , im pa ir ed m yelin a t ion ,
a n d br a in degen er a t ion . Diet a r y m odifica t ion s a r e
n eeded t o r est r ict ph en yla la n in e con su m pt ion . P KU
is on e of t h e clin ica l m odels fea t u r ed in t h is ch a pt er.
A secon d m a jor ca t egor y of in h er it ed m et a bolic
disor der s is lysosom a l st or a ge disea ses. Th ese dis-
ea ses a r e defect s of lipid m et a bolism a s a r esu lt of a
m issin g lysosom a l en zym e. An exa m ple is Ta y-Sa ch s
disea se, wh ich is in h er it ed a s a n a u t osom a l r ecessive
disor der a n d fou n d m ost com m on ly in t h ose of Ash ke-
n a zi J ewish a n d E a st er n E u r opea n descen t . In Ta y–
Sa ch s disea se, a deficien cy of bet a -h exosa m in ida se
Alte re d
Unde rnutrition
me ta bolis m
Lys os oma l
Impa ire d a mino
s tora ge
Alte re d Ma la bs orption a cid or lipid
dis e a s e s,
dige s tion me ta bolis m,
s uch a s
s uch a s P KU
Tay-S a chs
Micronutrie nt
de ficie ncie s
A (a n en zym e) r esu lt s in t h e im pa ir ed ca t a bolism
a n d a ccu m u la t ion of fa t t y su bst a n ces, ca lled GM2
ga n gliosides, in side n eu r on a l lysosom es in t h e br a in .
Th is lea ds t o sever e n eu r ologic im pa ir m en t m a r ked
by developm en t a l dela ys, n eu r odegen er a t ion , blin d-
n ess, dea fn ess, m u scle a t r oph y, pa r a lysis, a n d dea t h
(oft en by 4 yea r s of a ge). P r esen t ly, t h er e is n o t r ea t -
m en t . Th e m a jor pr oblem wit h in h er it ed m et a bolic
disor der s is t h e a ccu m u la t ion of su bst a n ces wit h in
t h e cells of t h e body, lea din g t o cell dea t h .
Undernutrition
U n d e r n u t r it io n is a la ck of in t a ke of n u t r ien t s
m ost oft en r ela t ed t o in a dequ a t e ca lor ie con su m p-
t ion , in a dequ a t e in t a ke of essen t ia l vit a m in s a n d
m in er a ls, or pr oblem s wit h digest ion , a bsor pt ion , or
dist r ibu t ion of n u t r ien t s in t h e body. P r ot ein , ir on ,
a n d vit a m in s a r e t h e m ost com m on n u t r ien t s t h a t
a r e in a dequ a t ely con su m ed or in gr ea t dem a n d in
t h ose pr esen t in g wit h u n der n u t r it ion . E xcess u se of
m u scle m a ss a n d a dipose st or es for en er gy r esu lt s
in weigh t loss a n d m u scle wa st in g. In sever e or pr o-
lon ged illn ess, loss of m u scle m a ss a n d fu n ct ion is
n ot lim it ed t o t h e skelet a l m u scle a n d ca n a ffect ca r-
dia c a n d r espir a t or y fu n ct ion in g. Th e elder ly, pa r t ic-
u la r ly t h ose in n u r sin g h om es, a r e a t pa r t icu la r r isk
for u n der n u t r it ion du e t o poor a ppet it e, a lt er a t ion s
in t h e sen se of t a st e, pr oblem s wit h ea t in g or swa l-
lowin g, lim it ed in com e, in a dequ a t e socia l su ppor t ,
a n d m obilit y lim it a t ion s.
VITAMIN AND MINERAL DEFICIENCIES
Vit a m in a n d m in er a l deficien cies ca n r esu lt fr om
t h e in a dequ a t e in t a ke or m a la bsor pt ion of diet a r y

sou r ces. Min er a l bioa va ila bilit y a lso a ffect s m in -
er a l a bsor pt ion . Beca u se fa t in t a ke is cr it ica l for
fa t -solu ble vit a m in a bsor pt ion , la ck of diet a r y fa t
im pa ir s t h e cellu la r a va ila bilit y of vit a m in s A, D, E ,
a n d K. Ta ble 17.4 com pa r es t h e pr oblem s a ssocia t ed
wit h select vit a m in a n d m in er a l deficit s.
PROTEIN ENERGY MALNUTRITION
P r ot ein en er gy m a ln u t r it ion is r ela t ed t o eit h er
(1) depr iva t ion of a ll food, a con dit ion of st a r va t ion
t h a t lea ds t o m a r a s m u s , or (2) pr ot ein depr iva t ion
in per son s con su m in g a dequ a t e ca r boh ydr a t es, a
con dit ion ca lled k w a s h io r k o r . Glu cose is a m a jor
en er gy sou r ce for body t issu es. In m a r a sm u s, diet a r y
glu cose is u n a va ila ble for glu cose-depen den t t issu es,
su ch a s t h e br a in a n d m u scle t issu e. Th e body a t -
t em pt s t o m a n u fa ct u r e glu cose in a pr ocess ca lled
glu con eogen esis by br ea kin g down m u scle pr ot ein s.
Th e m u scle t h en r elea ses a cidic by-pr odu ct s, pr o-
m ot in g m et a bolic a cidosis.
P r ot ect ive m ech a n ism s a r e n eeded a t t h is poin t
beca u se con t in u ed glu con eogen esis pr odu ces sign if-
ica n t m u scle wa st in g, dest r u ct ion of vit a l or ga n s,
a n d dea t h . Wh et h er t h e body effect ively a da pt s, or
pr eser ves, m u scle t issu e du r in g t h e st a t e of st a r va -
t ion depen ds on in su lin . In su lin is a h or m on e t h a t
pr om ot es glu cose pr odu ct ion a n d u pt a ke by cells
a n d in h ibit s t h e u se of fa t st or es for en er gy. If t h e
body is t o a da pt t o st a r va t ion effect ively, in su lin
pr odu ct ion m u st be su ppr essed t o in h ibit glu cose
u pt a ke a n d glu con eogen esis, a n d a n ot h er en er gy
sou r ce m u st be u sed a t a gr ea t er level t h a n glu -
cose. Th is is a ccom plish ed t h r ou gh a com pen sa t or y
in cr ea se in glu ca gon , cor t ison e, epin eph r in e, a n d
gr owt h h or m on e. Th ese h or m on es a ll h a ve a n t i-in -
su lin effect s a n d a lso st im u la t e en zym es on t h e a d-
ipocyt es t o r elea se fa t t y a cids for en er gy. Th e fa t t y
a cids t r a vel t o t h e liver a n d a r e con ver t ed t o ket on es.
Ket on es a r e t h e r epla cem en t en er gy sou r ce t h a t a l-
lows spa r in g of m u scle ca t a bolism . Th e br a in a n d
ot h er glu cose-depen den t t issu es pr efer glu cose bu t
will u se ket on es for en er gy a s a n a da pt ive r espon se.
Wh en ket on es a r e u sed for en er gy, pr ot ein losses a r e
m in im ized a n d m u scle t issu e is spa r ed.
A st a t e of st a r va t ion ca n be m a in t a in ed for a p-
pr oxim a t ely 1 m on t h in som eon e wh o m a in t a in s
wa t er in t a ke. Un for t u n a t ely, a dipose st or es even t u -
a lly becom e deplet ed. Th e body m u st a ga in t u r n t o
glu cose, lea din g t o in cr ea sed m u scle ca t a bolism for
glu con eogen esis. Vit a l or ga n s t h a t r ely on m u scle,
in clu din g t h e h ea r t a n d lu n gs, a r e im pa ir ed a n d t h e
in dividu a l will die.
Stop and Consider
Inflammation, particularly that which occurs
with infection, stimulates the release of chemical
Alt e r e d N u t r it io n 443
mediators that promote insulin secretion. Insulin
presence promotes the use of glucose for energy.
How do you think this affects the adaptation to
starvation?
Kwa sh ior k or, a con dit ion of pr ot ein deficit , lea ds
t o pr oblem s wit h pr ot ein syn t h esis, r epa ir a n d
h ea lin g, flu id ba la n ce, a n d en er gy. In k wa sh ior kor,
t h e con t in u ed in t a ke of ca r boh ydr a t es st im u la t es
in su lin pr odu ct ion , wh ich en cou r a ges glu cose u p-
t a ke for en er gy. Th is m ea n s t h a t wh en a n in divid-
u a l is st ill ea t in g ca r boh ydr a t es a n d n ot t a k in g in
pr ot ein s, t h e body does n ot effect ively spa r e m u scle
t issu e a n d a ccess fa t st or es for en er gy. St im u la t ion
of in su lin pr odu ct ion a lso lim it s t h e body’s a bilit y
t o syn t h esize n ew pr ot ein s fr om t h ose a lr ea dy pr es-
en t in m u scle t issu e a n d a lso lim it s ATP (en er gy)
pr odu ct ion . Th e la ck of pr ot ein in t a k e, cou pled wit h
t h e in a bilit y t o syn t h esize n ew pr ot ein s wit h in t h e
body, lea ds t o sever e edem a . Th e pr ot u ber a n t a b-
dom en ch a r a ct er ist ic of k wa sh ior k or is r ela t ed t o
liver en la r gem en t , wea k a bdom in a l m u scles, a n d
a scit es fr om in a dequ a t e pr ot ein (a lbu m in ) in t a k e
a n d syn t h esis (F ig. 17.10). Th e liver en la r ges be-
ca u se of fa t a ccu m u la t ion . Th is a ccu m u la t ion is a
pr oblem of su ppr essed u se of fa t st or es for en er gy
a n d a la ck of pr ot ein s t o t r a n spor t t h e lipids ou t of
t h e liver. Ot h er m a n ifest a t ion s a r e r ela t ed t o ga s-
t r oin t est in a l dist u r ba n ces, im pa ir m en t of n eu r o-
logic, h ea r t , a n d lu n g fu n ct ion , im m u n odeficien cy
a n d dea t h .
Overnutrition
O v e r n u t r it io n is a st a t e of excessive exposu r e
t o n u t r ien t s. Over n u t r it ion is gen er a lly r ela t ed t o
over con su m pt ion of n u t r ien t s, in clu din g in gest in g
excessive ca lor ies or t oxic levels of vit a m in s a n d
m in er a ls. Th e h ea lt h effect s of vit a m in a n d m in -
er a l excesses a r e det a iled in Ta ble 17.4. Obesit y is
a m a jor h ea lt h con cer n of epidem ic pr opor t ion s a n d
is select ed a s on e of t h e clin ica l m odels discu ssed in
t h is ch a pt er.
Malabsorption
Ma la b s o r p t io n in dica t es a la ck of m ovem en t of
specific n u t r ien t s a cr oss t h e ga st r oin t est in a l m u -
cosa . Ma la bsor pt ion ca n a ffect on e n u t r ien t , su ch a s
la ct ose or vit a m in B 12 , or it ca n a ffect a ll n u t r ien t s
a t on e segm en t or t h e en t ir e len gt h of t h e in t est in a l
m u cosa . Th e m a la b s o r p t io n s y n d r o m e is a con di-
t ion in wh ich sever a l n u t r ien t s a r e n ot a dequ a t ely
a bsor bed. Fa t a n d fa t -solu ble su bst a n ces a r e a lm ost
a lwa ys in clu ded in t h e m a la bsor pt ion syn dr om e.
444 C h a p t e r 17: Alt er ed Nu t r it ion

Growth fa ilure Va r iou s ca u ses of m a la bsor pt ion a r e depict ed in

F igu r e 17.11 a n d m a y in clu de:
● P r oblem s wit h pr ocessin g or digest in g n u t r ien t s:
Ha ir cha nge s Apa thy, irrita bility pa n cr ea t ic dysfu n ct ion , en zym e deficien cies, or
in a dequ a t e bile secr et ion
● P r oblem s wit h m ovin g su bst a n ces a cr oss t h e m u -
cosa : in fla m m a t or y con dit ion s, ga st r oin t est in a l
Ane mia a t r oph y, excessive in gest ion of a n u t r ien t , u se of
cer t a in m edica t ion s, or pr ot ein deficien cies
● Lymphatic obstruction: inhibits transport of nutri-
Mus cle
wa s ting ents once they have been absorbed across the mucosa
Fa tty live r
and may occur with neoplasms or infectious processes

Stop and Consider

Why would pancreatic dysfunction lead to prob-
lems with absorption?
De rma tos e s
Ma la bsor pt ion of a specific vit a m in or m in er a l
Atrophy of villi
of s ma ll inte s tine , pr esen t s clin ica lly a s a deficien cy of t h a t n u t r ien t .
dia rrhe a E xocr in e pa n cr ea s in su fficien cy a n d im pa ir ed bile
pr odu ct ion a r e m a jor pr oblem s t h a t lea d t o fa t m a l-
De pigme nta tion a bsor pt ion . Th ese pr oblem s con t r ibu t e t o weigh t loss
of s kin a n d t o deficien cies in fa t -solu ble vit a m in s. As wit h
fa t m a la bsor pt ion , pa n cr ea t ic en zym e deficien cy
con t r ibu t es t o t h e developm en t of pr ot ein m a la b-
sor pt ion . Th e loss of pr ot ein in t h e st ool, a s m a y oc-
cu r beca u se of in fla m m a t ion in t h e m u cosa , ca n a lso
con t r ibu t e t o pr ot ein deficien cy.
Ede ma
(hypoa lbumine mia )
Ca r boh ydr a t e m a la bsor pt ion is oft en t h e r esu lt of
pa n cr ea t ic en zym e deficien cies, a bsen ce or r edu ct ion
of br u sh bor der disa cch a r ida ses, con gen it a l deficien cy
of t h e glu cose–ga la ct ose t r a n spor t er, or ba ct er ia l
flor a over gr owt h in t h e in t est in e. Ca r boh ydr a t e m a l-
Figure 17.10. Manifestations of kwashiorkor. (Modified a bsor pt ion r esu lt s in a n in cr ea se in fer m en t a t ion , or
from Rubin E, Farber JL. Pathology. 4th ed. Philadelphia, br ea kdown , of ca r boh ydr a t es by in t est in a l ba ct er ia l
PA: Lippincott Williams & Wilkins; 2005.) flor a t o con ver t t h ese ca r boh ydr a t es in t o sh or t -ch a in

Ta b le 17.4 Clin ica l Ma n ifest a t ion s a n d H ea lt h Con dit ion s Resu lt in g fr om Select Vit a m in a n d Min er a l
Deficit s a n d E xcesses
Ca u ses o
Vit a m in D e ic ie n c y
A In a dequ a t e in t a ke or
m a la bsor pt ion , in su ffi-
cien t diet a r y fa t , liver
or pa n cr ea t ic disea se,
pr ot ein en er gy m a ln u -
t r it ion , zin c deficien cy
C lin ic a l Ma n i e s t a t io n s a n d
H e a lt h P r o b le m s Ca u ses o
R e la t e d t o D e ic ie n c y E xcess
Im pa ir ed vision , im pa ir ed em - E xcessive diet a r y
br yon ic developm en t , a n em ia , or su pplem en t in -
poor gr owt h , im pa ir ed im m u n it y, t a ke; a lso fou n d in
im pa ir ed ost eocla st a ct ivit y (bon e r et in oic a cid (Accu -
a ccu m u la t ion ), ker a t in iza t ion of t a n e), a pot en t
m u cou s m em br a n es, dr y/sca ly/ a n t i-a cn e m edica -
r ou gh skin t ion , wh ich a ffect s
fet a l gr owt h a n d
developm en t in
pr egn a n t wom en
wh o a r e t a kin g t h is
dr u g
C lin ic a l Ma n i e s -
t a t io n s a n d H e a lt h
P r o b le m s R e la t e d
to E xcess
Vit a m in A in t oxica -
t ion lea ds t o liver
disea se, dr y m u cou s
m em br a n es, dr yn ess,
er yt h em a , sca lin g, or
peelin g of skin , h a ir,
a n d n a ils, h ea da ch e,
n a u sea , vom it in g, a n d
bon e fr a ct u r es

Ta b le 17.4 Clin ica l Ma n ifest a t ion s a n d H ea lt h Con dit ion s Resu lt in g fr om Select Vit a m in a n d Min er a l
Deficit s a n d E xcesses (con tin u ed )
Ca u ses o
Vit a m in D e ic ie n c y
D In a dequ a t e in t a ke of
vit a m in D, lipid m a l-
a bsor pt ion , pr olon ged
br ea st feedin g in in -
fa n t s wit h ou t su n ligh t
exposu r e, deficien cies
of ca lciu m a n d ph os-
ph or u s, a n d lon g-
t er m a n t icon vu lsa n t
t h er a py
Th ia m in In a dequ a t e in t a ke or
m a la bsor pt ion ; su b-
clin ica l t h ia m in defi-
cien cy m a y r esu lt in
people wit h a lcoh olism
beca u se of in a dequ a t e
in t a ke a n d im pa ir ed
a bsor pt ion
Nia cin In a dequ a t e in t a ke or
a bsor pt ion
B 12 In a dequ a t e in t a ke or
m a la bsor pt ion
Fola t e In a dequ a t e in t a ke or
m a la bsor pt ion
C In a dequ a t e in t a ke or
m a la bsor pt ion
Alt e r e d N u t r it io n 445
C lin ic a l Ma n i e s -
C lin ic a l Ma n i e s t a t io n s a n d t a t io n s a n d H e a lt h
H e a lt h P r o b le m s Ca u ses o P r o b le m s R e la t e d
R e la t e d t o D e ic ie n c y E xcess to E xcess
Vit a m in D deficien cy is m a n ifest ed E xcessive in t a ke Vit a m in D in t oxica t ion
a s r icket s in ch ildr en a n d ost eo- lea ds t o h yper ca lcem ia
m a la cia in a du lt s. Ricket s in volves a n d h yper ph osph a -
im pa ir ed m in er a liza t ion of gr owin g t em ia , ca lcifica t ion
bon es r esu lt in g in st r u ct u r a l a b- of soft t issu es of kid-
n or m a lit ies, bon e pa in , a n d m u scle n eys, lu n gs, h ea r t a n d
t en der n ess. Ost eom a la cia in volves t ym pa n ic m em br a n e,
gen er a lized r edu ct ion s in bon e h ea da ch e, n a u sea ,
den sit y, m u scle wea kn ess, bon e bon e fr a gilit y, a n d r e-
t en der n ess, a n d fr a ct u r es t a r ded gr owt h
Th ia m in deficien cy r esu lt s in ber i- E xcessive in t a ke E xcessive t h ia m in
ber i, a con dit ion m a n ifest ed by r esu lt s in h ea da ch e,
a n or exia , weigh t loss, con fu sion , seizu r es, m u scle
m u scu la r wa st in g, edem a , per iph - wea kn ess, ca r dia c
er a l n eu r opa t h y, t a ch yca r dia , a n d dysr h yt h m ia s, a n d a l-
ca r diom ega ly ler gic r ea ct ion s; m a s-
sive doses r esu lt in
r espir a t or y depr ession
a n d dea t h
E a r ly m a n ifest a t ion s a r e m u scle E xcessive in t a ke Nia cin excess pr o-
wea kn ess, a n or exia , in digest ion , is r a r e, a lt h ou gh m ot es h ist a m in e
a n d skin lesion s; pella gr a is a con - n ia cin h a s been r elea se, wh ich r esu lt s
dit ion of sever e n ia cin deficien cy u sed in h igh doses in flu sh in g; h igh -dose
ch a r a ct er ized by der m a t it is, de- t o t r ea t h yper ch o- n ia cin is a lso t oxic t o
m en t ia , dia r r h ea , t r em or s, in fla m - lest er olem ia , a n d t h e liver
m a t ion of m u cou s m em br a n es; ca n t oxicit y m a y r esu lt
lea d t o dea t h in t h ese in dividu a ls
DNA syn t h esis is im pa ir ed lea d- Not a pplica ble Vit a m in B 12 is n ot
in g t o pr oblem s wit h cell division ; kn own t o r esu lt in se-
clin ica l m a n ifest a t ion s in clu de ver e t oxicit y
a n em ia , n eu r opa t h y ch a r a ct er ized
by n u m bn ess, t in glin g, a n d bu r n -
in g in ext r em it ies, a n d gen er a lized
wea kn ess, st om a t it is, a n d skin
lesion s; a ll r a pidly dividin g cells
a r e a ffect ed; per n iciou s a n em ia is
a con dit ion of B 12 m a la bsor pt ion
ca u sed by a la ck of in t r in sic fa ct or
in t h e st om a ch fr om a t r oph ic pa r i-
et a l cells (Ch a pt er 3)
Im pa ir ed syn t h esis of DNA a n d E xcessive in t a ke No m a jor a dver se
RNA, cell division is r edu ced; h o- effect s h a ve been doc-
m ocyst ein e levels in cr ea se; clin ica l u m en t ed t h a t a r e di-
m a n ifest a t ion s in clu de a n em ia , r ect ly r ela t ed t o fola t e
im pa ir ed skin in t egr it y, im pa ir ed excess
im m u n it y, wea kn ess, depr ession ,
n eu r opa t h y, a n d poor gr owt h ; em -
br yon ic developm en t is im pa ir ed in
pr egn a n t wom en deficien t in fola t e
r esu lt in g in n eu r a l t u be defect s
Scu r vy is a con dit ion of vit a m in C E xcessive in t a ke Vit a m in C excess r e-
deficien cy r esu lt in g in skin lesion s, su lt s in ga st r ic u pset
im pa ir ed wou n d h ea lin g, let h a r gy, a n d dia r r h ea a n d
a t r oph y, edem a , bleedin g, im pa ir ed m a y con t r ibu t e t o t h e
bon e, ca r t ila ge, t oot h , a n d con n ec- developm en t of r en a l
t ive t issu e developm en t ca lcu li
(con tin u ed )
446 C h a p t e r 17: Alt er ed Nu t r it ion

Ta b le 17.4 Clin ica l Ma n ifest a t ion s a n d H ea lt h Con dit ion s Resu lt in g fr om Select Vit a m in a n d Min er a l
Deficit s a n d E xcesses (con tin u ed )
C lin ic a l Ma n i e s -
C lin ic a l Ma n i e s t a t io n s a n d t a t io n s a n d H e a lt h
Ca u ses o H e a lt h P r o b le m s Ca u ses o P r o b le m s R e la t e d
Vit a m in D e ic ie n c y R e la t e d t o D e ic ie n c y E xcess to E xcess
Ca lciu m In a dequ a t e in t a ke, Con t r ibu t es t o r edu ced bon e m a ss, E xcessive in t a ke E xcessive in t a ke ca n
bioa va ila bilit y, or wea kn ess, a n d ost eom a la cia ; m a y lea d t o h yper ca lcem ia
a bsor pt ion im pa ct t h e developm en t of colon a n d lea d t o ca lcifica -
ca n cer a n d h yper t en sion t ion in soft t issu es;
in t er fer es wit h a bsor p-
t ion of ot h er m in er a ls;
ca n im pa ir ca r dia c
con du ct ion
P h osph or us Deficien cies a r e P h osph or u s deficit h a s let h a l con - Ch r on ic con - Toxicit y ca n lea d t o
r a r e beca u se of wide sequ en ces; clin ica l m a n ifest a t ion s su m pt ion of a fr equ en t bon e fr a c-
ava ila bilit y of diet a r y a r e r ela t ed t o loss of ATP syn t h esis low-ca lciu m a n d t u r es t h r ou gh ou t t h e
sou r ces a n d ca n in clu de pr oblem s wit h t h e h igh -ph osph or u s skelet on
n er vou s syst em , bon es, blood cells, diet
skin , kidn eys, h ea r t , a n d lu n gs
beca u se of a bn or m a lit ies in a ll en -
er gy-depen den t cells
Zin c In a dequ a t e in t a ke, Zin c deficien cy wa s pr eviou sly com - Toxicit y is r a r e bu t Ma n ifest a t ion s of t ox-
m a la bsor pt ion , or m on bu t h a s declin ed beca u se of ca n occu r wit h ex- icit y in clu de a n em ia ,
excessive losses t h e for t ifica t ion in cer ea l pr odu ct s; cessive in t a ke fever, vom it in g, dia r-
t h r ou gh u r in e or ot h er clin ica l m a n ifest a t ion s in clu de im - r h ea , a n d im pa ir ed
secr et ion s pa ir ed gr owt h , dela yed sexu a l m a t - cen t r a l n er vou s sys-
u r a t ion , h a ir loss, delayed wou n d t em fu n ct ion
h ea lin g, skin lesion s, a n or exia ,
im pa ir ed im m u n e fu n ct ion , visu a l
dist u r ba n ces, a n d im pa ir ed t a st e
Copper In a dequ a t e in t a ke, Copper deficien cy lea ds t o a n em ia , E xcessive copper Ma n ifest a t ion s of
m a la bsor pt ion , or ex- n eu t r open ia , bon e dem in er a liza - su pplem en t in t a ke t oxicit y a r e r ela t ed
cessive losses t ion a n d ost eopor osis, ch a n ges in a n d ch r on ic liver t o liver cir r h osis
skin pigm en t , im pa ir ed colla gen disea se ca n lea d a n d r ed blood cell
a n d ela st in pr odu ct ion , gr owt h t o copper t oxicit y. m a lfor m a t ion
im pa ir m en t , a n d br a in t issu e Copper is excr et ed
degen er a t ion in bile. Liver dis-
ea se pr om ot es bile
r et en t ion a n d cop-
per t oxicit y

fa t t y a cids (for a bsor pt ion ) a n d ga ses. Th e sh or t -ch a in
fa t t y a cids a r e n eeded t o (1) m a in t a in GI fu n ct ion , (2)
r ecou p som e of t h e en er gy t h a t wou ld be lost , a n d (3)
fa cilit a t e sodiu m a n d wa t er a bsor pt ion in t h e la r ge
in t est in e. Th e u n digest ed ca r boh ydr a t es dr a w ext en -
sive flu id in t o t h e in t est in es. Th e pr ocess of fer m en t a -
t ion lea ds t o t h e clin ica l m a n ifest a t ion s ch a r a ct er ist ic
of ca r boh ydr a t e m a la bsor pt ion , in clu din g a bdom in a l
dist en t ion , bloa t in g, pa in , dia r r h ea , weigh t loss, a n d
fla t u len ce.
Food Allergy
Food a ller gies a r e im m u n e syst em m edia t ed a dver se
r ea ct ion s t o foods. An y food pr ot ein ca n t r igger a n
a ller gic r espon se, h owever, t h e va st m a jor it y of food
a ller gies a r e t r igger ed by eggs, pea n u t s, m ilk, soy,
fish , sh ellfish , t r ee n u t s, a n d wh ea t . Con su m pt ion of
foods t h a t t r igger a ller gy ca n r esu lt in or oph a r yn -
gea l it ch in g, la r yn gea l edem a , cou gh , sh or t n ess of
br ea t h , wh eezin g, n a u sea , vom it in g, dia r r h ea , skin
flu sh in g, skin it ch in g, h ives, a bdom in a l pa in , a n d
ot h er sym pt om s a ssocia t ed wit h sever e a ller gic r e-
a ct ion . Th e exa ct a ller gy-in du cin g food m u st be iden -
t ified t h r ou gh diet a r y h ist or y a n d possibly im m u n e
t est in g. As wit h ot h er h yper sen sit ivit ies, in ject a ble
epin eph r in e m a y be n eeded for in it ia l m a n a gem en t
of food-in du ced a n a ph yla ct ic r ea ct ion . Th e pr im a r y
goa l is com plet e a voida n ce of t h a t t ype of food. Pa -
t ien t s n eed t o be pa r t icu la r ly a wa r e of food la bels
a n d t h e loca t ion s a n d m ech a n ism s wit h wh ich foods
 Alt e r e d N u t r it io n 447

Live r dis e a s e dr y skin , or pa llor. Mu cou s m em br a n es becom e in -

Bile fla m ed a n d fr ia ble. An gu la r ch eilit is, a pr oblem wit h
fissu r e developm en t in t h e cor n er s of t h e m ou t h ,
is oft en a ssocia t ed wit h r ibofla vin deficien cy. Th e
m a n ifest a t ion s of m a la bsor pt ion a r e oft en r ela t ed
t o t h e r a pid t r a n sit of n u t r ien t s t h r ou gh t h e in t es-
Obs truction
t in a l lu m en . As m en t ion ed pr eviou sly, pr oblem s
Pa ncre a tic
wit h ca r boh ydr a t e a bsor pt ion t ypica lly m a n ifest a s
dis e a s e
P roble ms weigh t loss, dia r r h ea , bloa t in g, a bdom in a l cr a m pin g,
with Pa ncre a tic a n d excessive fla t u len ce. Fa t m a la bsor pt ion lea ds
proce s s ing e nzyme s
t o fou l-sm ellin g, gr ea sy, dia r r h ea st ools. E xcessive
or dige s ting
n u t r ien t in t a ke lea ds t o a n in cr ea se in weigh t a n d
body fa t n ess. Toxicit y of vit a m in s a n d m in er a ls ca n
Infla mma tion a lso occu r.
P roble ms with
move me nt through DIAGNOSTIC AND TREATMENT STRATEGIES
lume n or a cros s mucos a
Atrophy RELATED TO ALTERED NUTRITION
Dia gn ost ic t est s r ela t ed t o a lt er ed n u t r it ion a r e
u sed t o det er m in e t h e ca u se for t h e n u t r it ion im -
ba la n ce a s well a s t h e pot en t ia l effect s. A com plet e
S horte ne d n u t r it ion a l a ssessm en t is in dica t ed, wh ich in clu des
bowe l = le s s a m u lt iple-da y diet a r y in t a ke r eca ll, t o det er m in e
a re a for a dequ a t e or excessive n u t r ien t in t a ke, a n d m ea -
a bs orption
su r em en t of h eigh t , weigh t , a n d body m a ss in dex.
Lympha tic obs truction La bor a t or y eva lu a t ion is oft en h elpfu l a n d m a y
in clu de a com plet e blood cou n t wit h r ed blood cell
Lymphoma in dices a n d a per iph er a l sm ea r, sedim en t a t ion r a t e
(t o det ect in fla m m a t ion ), ser u m elect r olyt es, u r in a l-
ysis a n d u r in e cu lt u r e. Th e eva lu a t ion m a y a lso in -
clu de m ea su r es of pr ot ein st a t u s, in clu din g ser u m
Figure 17.11. Potential causes of malabsorption. a lbu m in , t r a n sfer r in , cr ea t in in e, a n d blood u r ea n i-
t r ogen levels. Ot h er ser u m t est s a r e u sed t o det ect
blood levels of specific n u t r ien t s, su ch a s ir on , B 12 ,
or fola t e. E n zym e levels ca n a lso be m ea su r ed t o de-
a r e pr epa r ed t o a void a cciden t a l in gest ion . Food a l- t er m in e wh et h er digest ive or a bsor pt ive pr oblem s
ler gies do n ot ca u se n u t r it ion a l deficien cies a s ot h er a r e pr esen t . H or m on e levels m a y be in vest iga t ed if
foods ca n be con su m ed t o a ssu r e a dequ a t e n u t r it ion . m et a bolic r egu la t ion is im pa ir ed. St ool specim en s
H owever, t h ese a r e m en t ion ed h er e a s t h ey do r esu lt m a y a lso be eva lu a t ed for t h e pr esen ce of pa t h o-
in cr it ica l diet a r y m odifica t ion s. gen s t h a t a ffect a bsor pt ion . Dir ect visu a liza t ion or
biopsy of t h e ga st r oin t est in a l t r a ct m a y be r equ ir ed
t o det er m in e a st r u ct u r a l ca u se for t h e n u t r it ion
GENERAL MANIFESTATIONS OF ALTERED
im ba la n ce.
NUTRITION
Tr ea t m en t m oda lit ies a r e dir ect ed a t elim in a t -
Th e clin ica l m a n ifest a t ion s of a lt er ed n u t r it ion a r e in g t h e ca u se of t h e n u t r it ion im ba la n ce or r edu c-
r eflect ive of t h e ca u se a n d pa t h oph ysiologic pr ob- in g t h e h a r m fu l effect s. Th is oft en in clu des specific
lem s. Beca u se cells a n d body t issu es r ely on a dequ a t e diet a r y in t er ven t ion s, su ch a s in cr ea sin g in t a ke of
n u t r it ion for opt im a l fu n ct ion in g, clin ica l m a n ifest a - pa r t icu la r m a cr on u t r ien t s, t a kin g vit a m in a n d m in -
t ion s a r e exh ibit ed t h r ou gh ou t t h e body. In gen er a l, er a l su pplem en t s, r edu cin g over a ll ca lor ic in t a ke, or
m a ln u t r it ive pr ocesses in volvin g u n der n u t r it ion ca n a voidin g specific foods t h a t exa cer ba t e sym pt om s.
lea d t o weigh t loss, m u scle wa st in g, m u scle wea k- Tr ea t m en t m a y a lso in clu de ph a r m a cologic in t er-
n ess, deh ydr a t ion , fa t igu e, a n d eviden ce of vit a m in ven t ion s, su ch a s t h e a dm in ist r a t ion of exogen ou s
a n d m in er a l deficien cies (Ta ble 17.4). Ra pidly divid- digest ive en zym es, t o su ppor t digest ion a n d a bsor p-
in g cells, su ch a s t h ose of t h e skin , a r e pa r t icu la r ly t ion . Dia gn ost ic a n d t r ea t m en t m oda lit ies a r e dis-
vu ln er a ble t o m a ln ou r ish m en t . Skin m a n ifest a t ion s cu ssed in gr ea t er det a il wit h in t h e clin ica l m odels of
in clu de poor wou n d h ea lin g, pu r pu r a , u lcer a t ion , t h is ch a pt er.
448 C h a p t e r 17: Alt er ed Nu t r it ion

Modu le 3 C lin ic a l Mo d e ls

Th e followin g clin ica l m odels h a ve been select ed t o ga st r oin t est in a l u lcer s, ca n cer, or h em or r h oids, is a
a id in t h e u n der st a n din g a n d a pplica t ion of a lt er ed com m on ca u se of excessive loss of body ir on . Cer t a in
n u t r it ion pa t h oph ysiology, m a n ifest a t ion s, dia gn o- m edica t ion s, su ch a s a n t a cids, ca n bin d wit h ir on
sis, a n d t r ea t m en t . a n d im pa ir a bsor pt ion .

CLINICAL MANIFESTATIONS
Iron-Deficiency Anemia
Clinica l m a nifest a t ions usua lly pr esent wh en
An e m ia is t h e r edu ct ion in t h e m a ss of cir cu la t in g hem oglobin cont ent is less t ha n t ha t r equ ired t o
blood cells a n d su bsequ en t ly r edu ced h em oglobin m eet th e oxygen-ca rr ying dem a nds of t he body.
levels. An em ia is t ypica lly n ot con sider ed a n isola t ed Iron -deficien cy a nem ia ca n develop slowly a nd
disea se; r a t h er, it r epr esen t s a m a n ifest a t ion of a n - t h er efore be a sym pt om a t ic. When pr esent , clinica l
ot h er pr oblem . In Ch a pt er 6, sickle cell a n em ia wa s m a nifesta tion s a re r ela t ed t o decrea sed hem oglo-
pr esen t ed a s a clin ica l m odel r ela t ed t o a gen et ic de- bin synt hesis, a lt ered blood com position , a nd subse-
fect t h a t r esu lt s in r ed blood cell dest r u ct ion . Th e qu ent ly poor oxygen-ca rr ying ca pa city a n d hypoxia .
developm en t of a n em ia ca n a lso r esu lt fr om sever e These m a nifest a t ions in clude pa llor of t he skin a n d
h em or r h a ge, decr ea sed r ed blood cell pr odu ct ion , or m ucous m embr a nes, fa tigue, wea kness, light h ea ded-
vit a m in a n d m in er a l deficien cies. Th e vit a m in s a n d ness, br ea t hlessness, pa lpit a t ions, h ea da che, t a chy-
m in er a ls r ela t ed t o r ed blood cell a n d h em oglobin ca r dia , a nd syncope. Chr onic hypoxia impa irs cell
in t egr it y in clu de B 12 , fola t e, a n d ir on . Th e m ost com - funct ioning, pa r t icula r ly in epit helia l cells, a nd lea ds
m on ca u se of a ll a n em ia s is ir on deficien cy; it is a lso t o br it tle ha ir a nd n a ils a n d m out h sor es. P ic a (pa -
t h e m ost pr eva len t n u t r it ion a l deficien cy wor ldwide. goph a gia ), th e com pulsion t o ea t ice or non food sub-
st a nces such a s dir t or clay, is a not her m a nifest a t ion
of ir on-deficient a n emia t ha t is not clea r ly un derst ood.
PATHOPHYSIOLOGY
I r o n -d e ic ie n c y a n e m ia r epr esen t s a pr oblem of DIAGNOSTIC CRITERIA
ir on dem a n d on r ed blood cell developm en t t h a t ca n - P r elim in a r y dia gn osis of ir on -deficien cy a n em ia is
n ot be m et wit h cu r r en t ir on st or es. Ir on is r equ ir ed ba sed on a t h or ou gh pa t ien t h ist or y a n d ph ysica l ex-
for h em oglobin syn t h esis, oxygen a n d elect r on t r a n s- a m in a t ion . A h igh er in dex of su spicion is pr esen t in
por t , a n d DNA syn t h esis. Ir on is fou n d wit h in h e- in dividu a ls wh o a r e veget a r ia n or wh o r epor t m a n i-
m oglobin , m yoglobin , a n d en zym es, a n d it is st or ed fest a t ion s of ch r on ic blood loss. In ir on deficien cy, la b-
in t r a n spor t pr ot ein s su ch a s fer r it in , h em osider in ,
or a t or y t est s m a y r evea l r edu ced ser u m h em oglobin
a n d t r a n sfer r in . Ir on ba la n ce is m a in t a in ed t h r ou gh
a n d h em a t ocr it levels a n d r edu ced m ea n cor pu scu la r
t h e ca r efu l r egu la t ion of ir on a bsor pt ion in t h e sm a ll
volu m e (MCV) a n d m ea n cor pu scu la r h em oglobin
in t est in e. Most ir on is r ecycled in t h e body a ft er r e- con cen t r a t ion (MCH C). MCV is a n in dica t or of r ed
lea se fr om dyin g r ed blood cells. Min u t e a m ou n t s a r e blood cell size; t h er efor e, a r edu ct ion in h em oglobin
lost t h r ou gh defeca t ion , swea t in g, a n d slou gh in g of a n d h em a t ocr it , a lon g wit h a r edu ced MCV, in dica t es
skin cells. m icr ocyt ic a n em ia . Over a ll, t h e n u m ber a n d qu a l-
Th e m a jor ca u ses of ir on -deficien cy a n em ia a r e it y of r ed blood cells a r e r edu ced; RBCs a r e h y p o -
in a dequ a t e ir on in t a ke, ch r on ic h em or r h a ge, m a l- c h r o m ic (pa le) a n d m ic r o c y t ic (sm a ll) (Fig. 17.12).
a bsor pt ion , a n d h igh ir on dem a n ds a s occu r s in in - P o ik ilo c y t o s is is a t er m u sed t o descr ibe t h e ir r eg-
fa n cy, a dolescen ce, a n d wit h pr egn a n cy or la ct a t ion . u la r sh a pe of ir on -deficien t r ed blood cells.
Ch r on ic blood loss, a s wit h a m on t h ly m en st r u a t ion , If in dividu a ls a r e u n -
r espon sive t o t r ea t m en t ,
a ddit ion a l con fir m a t or y
t est s a r e n eeded t o dist in -
F R O M T H E L AB
gu ish ir on deficien cy fr om
Serum ferritin is often used as a confirmatory test of iron deficiency. Ferritin is a protein ot h er t ypes of a n em ia , a s
that stores iron. When the iron supply increases, ferritin levels expand to store the addi- depict ed in Ta ble 17.5.
tional iron. Ferritin levels can then be measured as an indicator of iron stores. Con fir m a t or y t est s m a y
in clu de ser u m ir on , t ot a l
 C lin ic a l Mo d e ls 449

Microcytic, hypochromic Una ffe cte d re d blood ce lls ● Age: H em oglobin levels a r e t ypica lly m u ch lower
re d blood ce ll in a du lt s t h a n n ewbor n s.
● Gen d er : Ma les h a ve h igh er h em oglobin levels
t h a n wom en .
● P r egn a n cy sta tu s: Th e ph ysiologic dem a n ds of
pr egn a n cy a n d h em odilu t ion r esu lt in lower h e-
m oglobin levels in pr egn a n cy.
● Altitu d e: Redu ced oxygen exposu r e a t h igh a lt i-
t u des in du ces er yt h r opoiesis a n d ca n a ffect h em o-
globin levels.

TREATMENT
Tr ea t m en t is focu sed on t h e ca u se. Poor ir on in t a ke
is t r ea t ed wit h ir on su pplem en t s a n d a n ir on -r ich
diet , oft en t a ken wit h a sou r ce of a scor bic a cid t o
in cr ea se a bsor pt ion . Ir on ca n a lso be a dm in ist er ed
pa r en t er a lly if or a l su pplem en t s a r e in a dequ a t e or
n ot t oler a t ed. Ir on deficien cy r ela t ed t o blood loss
r equ ir es st oppin g t h e sou r ce of bleedin g a n d m a y r e-
qu ir e a blood t r a n sfu sion .

P la te le t Poikilocyte s
Figure 17.12. Peripheral blood smear in iron-deficiency
anemia. (Courtesy Anatomical Chart Company.)
ir on -bin din g ca pa cit y, t r a n sfer r in sa t u r a t ion , a n d
fer r it in levels (see F r om t h e La b, below). Addit ion a l
t est s m a y be n eeded t o det er m in e sou r ces of a cu t e or
ch r on ic blood loss.
Th e dia gn osis of a n em ia m u st t a ke in t o con sider-
a t ion t h a t cer t a in fa ct or s a ffect h em oglobin levels,
su ch a s:
Anorexia Nervosa
An o r e x ia n e r v o s a (AN ) is a n ea t in g disor der ch a r-
a ct er ized by:
1. Th e in a bilit y t o m a in t a in a m in im a lly h ea lt h y
body weigh t
2. An in t en se fea r of ga in in g weigh t
3. Relen t less diet a r y h a bit s t h a t pr even t weigh t
ga in
4. Sever e body im a ge dist or t ion s
Th e t er m a n or exia design a t es a la ck of a ppet it e, a l-
t h ou gh wit h AN, h u n ger is la r gely ign or ed. AN pr i-
m a r ily a ffect s a dolescen t a n d you n g a du lt wom en ,

Ta b le 17.5 Differ en t ia t ion of Va r iou s Types of An em ia Ba sed on La bor a t or y Test Resu lt s

Ir on B 12 F o la t e An e m ia o C h r o n ic
D e ic ie n c y D e ic ie n c y D e ic ie n c y T h a la s s e m ia D is e a s e s
RBC size Micr ocyt ic Ma cr ocyt ic Ma cr ocyt ic Micr ocyt ic Nor m ocyt ic
Ret icu locyt e Low Low Low Nor m a l Low/n or m a l
(im m a t u r e RBC)
cou n t
MCH Low Nor m a l Nor m a l Low Nor m a l
Ser u m ir on Low H igh H igh Nor m a l Va r ia ble
Tot a l ir on -bin din g H igh Nor m a l Nor m a l Nor m a l Nor m a l
ca pa cit y
Fer r it in level Low H igh H igh Nor m a l Nor m a l
B 12 level Nor m a l Low Nor m a l Nor m a l Nor m a l
Fola t e level Nor m a l Nor m a l Low Nor m a l Nor m a l

MCH , m ea n cor pu scu la r h em oglobin ; RBC, r ed blood cell.

450 C h a p t e r 17: Alt er ed Nu t r it ion
pa r t icu la r ly in developed cou n t r ies t h a t va lu e a t h in
body t ype. Alt h ou gh less com m on , AN ca n a ffect m en
a s well. Mor t a lit y r a t e is est im a t ed a t 10% wit h m ost
dea t h s r ela t ed t o ca r diova scu la r com plica t ion s.4
PATHOPHYSIOLOGY
Th e exa ct et iology of AN is u n kn own , bu t sever a l
for ces (biologic, psych ologic, gen et ic, fa m ilia l, a n d
cu lt u r a l) m a y con t r ibu t e t o t h e developm en t of t h is
con dit ion . Gen et ic in flu en ces a r e in dica t ed by a t win
con cor da n ce of 50% t o 80%. 4 Ot h er specific r isk fa c-
t or s in clu de:
● Fem a le sex
● Fa m ily h ist or y of ea t in g disor der s
● An in t r over t ed, obsessive, a n d per fect ion ist
per son a lit y
● In a bilit y t o r esolve con flict
● Low self-est eem
● Fa m ily dysfu n ct ion , su ch a s en m esh m en t , over-
pr ot ect iven ess, or u n r esolved fa m ily con flict
● Con cu r r en t m en t a l h ea lt h con dit ion s, su ch a s a
per son a lit y, depr essive, or a n xiet y disor der
● Cu lt u r a l pr essu r es t o becom e t h in n er
An or exia n er vosa lin ks a sever e m en t a l h ea lt h dis-
or der wit h deva st a t in g ph ysica l h ea lt h pr oblem s
ca u sed by self-st a r va t ion (F ig. 17.13). Th e dist u r-
ba n ce in body im a ge con t r ibu t es t o m a ln u t r it ion .
Ma ln u t r it ion en com pa sses bot h m a cr on u t r ien t
a n d m icr on u t r ien t deficien cies, a lt h ou gh t h e u se
of su pplem en t s m a y pr ot ect a ga in st m icr on u t r ien t
deficien cies. Ma cr on u t r ien t , pa r t icu la r ly ca lor ic, r e-
st r ict ion lea ds t o m obiliza t ion of lipid st or es, pr ot ein
Effe cts of a norexia ne rvos a
Hair
Ha ir thins a nd ge ts brittle
Blo o d
Ane mia
Kidneys
Kidney s tone s, kidney fa ilure
Bo dy fluids
Low pota s s ium, ca lcium,
ma gne s ium, a nd s odium
S kin
Bruis e e a s ily, dry s kin, growth of
fine ha ir a ll ove r body, ge ts cold e a s ily,
ye llow s kin, na ils ge t brittle
Figure 17.13. Physical effects that accompany anorexia nervosa. C-section, cesarean section.
ca t a bolism , a n d m et a bolic st r ess wit h a r edu ced
m et a bolic r a t e. Ma ln u t r it ion ca n t h en fu r t h er exa c-
er ba t e depr ession a n d psych ologic det er ior a t ion .
All body syst em s a r e a ffect ed by m a ln u t r it ion .
F lu id a n d elect r olyt e levels becom e im ba la n ced.
Skelet a l m u scle wa st in g a n d a loss of body fa t a r e
eviden t a s m a cr on u t r ien t levels a r e in a dequ a t e; t h e
body u ses a ll a va ila ble fa t a n d pr ot ein st or es for en -
er gy. Th e br a in m a ss a n d CNS fu n ct ion a r e r edu ced.
Seizu r es ca n develop, a n d t in glin g in t h e ext r em it ies
is com m on . Th e h ea r t size a n d fu n ct ion a r e r edu ced
beca u se of h ypovolem ia a n d h ypot en sion . Th e h ea r t
r a t e slows, dysr h yt h m ia s a n d con du ct ion defect s ca n
develop, a n d va lves ca n becom e in effect ive wit h a
r edu ct ion in ca r dia c ou t pu t . Ga st r oin t est in a l effect s
dem on st r a t e r edu ced ga st r ic em pt yin g t im e wit h
a st r u ct u r a l fu n ct ion a l loss of GI t r a ct t on e. Ga ll-
st on es a r e m or e pr eva len t , a n d t h e liver ca n becom e
n ecr ot ic. Liver dysfu n ct ion ca n lea d t o eleva t ed ch o-
lest er ol a n d blood lipid levels. Bon es becom e por ou s
a n d pr on e t o fr a ct u r es. Th e developm en t of blood
cells a n d clot t in g fa ct or s is im pa ir ed. Th is lea ds t o
pr oblem s wit h bleedin g, a n em ia , a n d in fect ion a s
t h e in fla m m a t or y a n d im m u n e r espon ses becom e
com pr om ised. E n docr in e fu n ct ion is a lso a ffect ed:
(1) a n t idiu r et ic h or m on e secr et ion is r est r ict ed,
lea din g t o t h e in a bilit y t o con cen t r a t e u r in e; (2) r e-
pr odu ct ive h or m on e levels declin e; a n d (3) cor t isol
levels in cr ea se beca u se of t h e st r ess of m a ln u t r it ion .
CLINICAL MANIFESTATIONS
In dividu a ls wit h AN ca n exh ibit m a n y clin ica l m a n -
ifest a t ion s r ela t ed t o r est r ict ed ca lor ic (en er gy) a n d
Brain and ne rve s
Ca n’t think right, fe a r of ga ining we ight, s a d, moody,
irrita ble , ba d me mory, fa inting, cha nge s in bra in che mis try,
low body te mpe ra ture
He art
Low blood pre s s ure , s low he a rt ra te, flutte ring of the he a rt,
(pa lpita tions ), he a rt fa ilure
Mus cle s and jo ints
We a k mus cle s, swolle n joints, fra cture s, os te oporos is
Inte s tine s
Cons tipa tion, bloa ting
Ho rmo ne s
Pe riod s tops, bone los s, proble ms growing, trouble ge tting
pre gna nt. If pre gna nt, highe r ris k for mis ca rria ge, having a
C-s e ction, ba by with low birth we ight, a nd pos tpa rtum
de pre s s ion.

n u t r ien t in t a ke. Com m on ph ysica l ch a r a ct er ist ics
a r e r ela t ed t o t h e pa t h oph ysiologic pr ocesses dis-
cu ssed pr eviou sly a n d in clu de a n ext r em ely t h in
st a t u r e, la n u g o (a fin e down y h a ir t h a t cover s
t h e body), a m en or r h ea in wom en , br it t le h a ir a n d
n a ils, per iph er a l cya n osis, dr y skin , br a dyca r dia ,
h ypot en sion , h ypot h er m ia , a bdom in a l bloa t in g, a n d
con st ipa t ion .
DIAGNOSTIC CRITERIA
Dia gn osis is ba sed on h ist or y a n d ph ysica l exa m -
in a t ion . Th e DS M-5 cr it er ia for dia gn osis of AN a r e
su m m a r ized:
1. Rest r ict ion of food in t a ke r ela t ive t o ca lor ic r e-
qu ir em en t s lea din g t o low body weigh t .
2. In t en se fea r of ga in in g weigh t or becom in g fa t ,
even t h ou gh u n der weigh t , or per sist en t beh a vior
t o a void weigh t ga in , even t h ou gh u n der weigh t .
3. Dist u r ba n ce in t h e wa y in wh ich on e’s body weigh t
or sh a pe is exper ien ced, u n du e in flu en ce of body
weigh t or sh a pe on self-eva lu a t ion , or per sist en t
la ck of r ecogn it ion of t h e ser iou sn ess of t h e cu r-
r en t low body weigh t .
A n u t r it ion a l a ssessm en t oft en r evea ls r est r ict ion
of ca lor ic in t a ke t o less t h a n 1,000 kca l/ da y. La b-
or a t or y st u dies ca n det er m in e t h e r esu lt in g h ea lt h
effect s a n d h elp t o dir ect t r ea t m en t st r a t egies.
St a r va t ion m a y r evea l n or m ocyt ic, n or m och r om ic
a n em ia a n d leu kopen ia fr om bon e m a r r ow su ppr es-
sion . Sever e h ypoka lem ia m a y be n ot ed fr om la xa -
t ive a bu se or vom it in g. Addit ion a l blood t est s m a y
r evea l h ypoca lcem ia , pr ot ein deficien cy, r edu ced
liver fu n ct ion , a n d sign ifica n t elect r olyt e im ba la n ce,
in clu din g low sodiu m a n d ch lor ide levels. Possible
elect r oca r diogr a m ch a n ges in clu de n on specific ST-
a n d T-segm en t a bn or m a lit ies, a t r ia l t a ch yca r dia ,
idioven t r icu la r con du ct ion dela y, h ea r t block, a n d
pr em a t u r e ven t r icu la r con t r a ct ion s. Th e ba sis for
ca r dia c con du ct ion im pa ir m en t is a t t r ibu t ed t o st a r-
va t ion , elect r olyt e im ba la n ce, a n d n eu r oen docr in e
a lt er a t ion s.
TREATMENT
An in t er disciplin a r y t ea m t r ea t m en t a ppr oa ch is
r ecom m en ded. Th is t ea m sh ou ld in clu de t h e pa t ien t ,
t h e pa t ien t ’s fa m ily, psych ot h er a pist s, ph ysicia n s,
n u r ses, diet icia n s, a n d r ecr ea t ion a l a n d occu pa -
t ion a l t h er a pist s. Th e goa l of t r ea t m en t is a ch ievin g
a n d m a in t a in in g a h ea lt h y weigh t a n d n u t r it ion a l
in t a ke a lon g wit h psych ot h er a py for body im a ge
dist u r ba n ces. Nu t r it ion a l su ppor t in clu des a gr a d-
u a l r efeedin g pr ocess t h a t in du ces a 1 t o 2 lb weigh t
ga in per week. Th e h ea lt h ca r e t ea m m u st m on it or
for com plica t ion s of AN t h r ou gh ou t t r ea t m en t a n d
C lin ic a l Mo d e ls 451
wa t ch for ga st r oin t est in a l, flu id, elect r olyt e, a n d ca r-
dia c dist u r ba n ces. Alt h ou gh close m on it or in g, effec-
t ive r efeedin g, a n d in it ia t in g of psych ot h er a py h a s
sh own a decr ea se in m or t a lit y r a t es a m on g t h ose
wit h AN, t wo-t h ir ds or m or e will h a ve on goin g food
a n d weigh t pr eoccu pa t ion s.
Celiac Disease (Gluten-Sensitive
Enteropathy)
C e lia c d is e a s e , a lso ca lled glu t en -sen sit ive en -
t er opa t h y or celia c spr u e, is a disor der of glu t en
m a la bsor pt ion ca u sed by a T-cell m edia t ed h yper sen -
sit ivit y m a r ked by t h e in a bilit y t o t oler a t e glia din ,
t h e a lcoh ol-solu ble fr a ct ion of glu t en , in per son s wh o
a r e gen et ica lly pr edisposed t o developin g t h is con di-
t ion . Th e pr eva len ce of t h e con dit ion in fir st -degr ee
r ela t ives is a ppr oxim a t ely 10%. 5 G lu t e n s a r e spe-
cific pr ot ein s fou n d in wh ea t , r ye, oa t s, a n d ba r ley.
Com m on foods t h a t a r e m a de wit h glu t en s, wh ich
a r e ever ywh er e in t h e h u m a n diet , a r e difficu lt t o
a void. Th ese in clu de m a n y t ypes of cer ea ls, br ea ds,
a n d pa st a s. Th e con dit ion is m ost oft en det ect ed be-
t ween in fa n cy a n d you n g a du lt h ood.
PATHOPHYSIOLOGY
Alt h ou gh t h e exa ct ca u se of celia c disea se is oft en
u n kn own , a st r on g h er edit a r y com pon en t exist s
(Fig. 17.14). E xposu r e t o glu t en elicit s a h yper sen si-
t ivit y r espon se t h a t r esu lt s in ch r on ic in fla m m a t ion
a n d a t r oph y of t h e m u cosa of t h e sm a ll in t est in e.
Da m a ge t o t h e in t est in a l m u cosa in h ibit s digest ion
beca u se of da m a ge t o t h e villi t h a t pr odu ce a n d se-
cr et e digest ive h or m on es a n d en zym es. In a dequ a t e
secr et ion of h or m on es a n d en zym es in h ibit s ga ll-
bla dder a n d pa n cr ea t ic fu n ct ion . Th is fu r t h er r e-
st r ict s t h e digest ive pr ocesses. Absor pt ion is a lso
im pa ir ed beca u se t h ese villi u n der go a t r oph y, wh ich
disa llows t h e effect ive pa ssa ge of n u t r ien t s a cr oss
t h e m u cosa . Absor pt ion is fu r t h er disr u pt ed wit h a
loss of ca r r ier su bst a n ces n eeded t o t r a n spor t n u t r i-
en t s a cr oss t h e m u cosa .
CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s a r e con sist en t wit h ot h er
m a la bsor pt ion con dit ion s a n d in clu de weigh t loss,
dia r r h ea , fla t u len ce, st ea t or r h ea , m a lodor ou s st ools,
weigh t loss, bor bor ygm u s (lou d st om a ch /in t est in a l
r u m blin g), a bdom in a l bloa t in g a n d pa in , fa t igu e,
a n d m a cr on u t r ien t , m in er a l, a n d vit a m in deficien -
cies. Beca u se t h e clin ica l m a n ifest a t ion s a r e n on spe-
cific a n d som et im es even n on exist en t , t h e con dit ion
is fr equ en t ly m isdia gn osed a n d u n der dia gn osed.
452 C h a p t e r 17: Alt er ed Nu t r it ion

DIAGNOSTIC CRITERIA
Dia gn ost ic su spicion is r a ised in t h e pr esen ce of
clin ica l m a n ifest a t ion s. La bor a t or y scr een in g m a y
in clu de ser u m det ect ion of a n t ibodies a ga in st (1) t h e
en dom ysiu m , or m u scle fiber con n ect ive t issu e;
(2) t h e glia din fou n d in glu t en ; or (3) IgA t issu e
GLUTEN t r a n sglu t a m in a se, t h e a u t oa n t igen t h a t t r igger s t h e
im m u n e r espon se. Dia gn ost ic con fir m a t ion is m a de
wit h a sm a ll bowel biopsy dem on st r a t in g in fla m m a -
Ade novirus Ge ne tic fa ctors t or y a n d a t r oph ic ch a n ges.
s e rotype 12? HLA B8
HLA DR3-DQw2
TREATMENT
Tr ea t m en t is focu sed on per m a n en t ly elim in a t in g
sou r ces of glu t en fr om t h e diet . Cor n a n d r ice do n ot
con t a in glu t en s a n d for m a m a jor por t ion of gr a in
in t a ke for t h ose wit h celia c disea se. Sym pt om s u su -
Epithe lia l a lly im pr ove wit h in 1 t o 2 m on t h s of elim in a t in g
ce ll of s ma ll glu t en sou r ces. In t h e a bsen ce of glu t en in t h e diet ,
inte s tine t h e in t est in a l m u cosa som et im es r esu m es opt im a l
st r u ct u r e a n d fu n ct ion . An t i-in fla m m a t or y a n d h y-
per sen sit ivit y-blockin g m edica t ion s m a y be n eeded
if elim in a t ion of glu t en is n ot com plet ely effect ive.
Vit a m in a n d m in er a l su pplem en t a t ion is oft en wa r-
r a n t ed. La ck of t r ea t m en t lea ds t o ch r on ic in t est in a l
u lcer a t ion s a n d ca n possibly lea d t o m a lign a n cy of
t h e bowel a n d lym ph gla n ds.
Lymphoid
ce lls of Stop and Consider
la mina propria
You are providing nutritional counseling for a
person with celiac disease. What specific foods
would you recommend avoiding? What foods
would you suggest as substitutions?
IMMUNOLOGIC RES P ONS E
Phenylketonuria
PATHOPHYSIOLOGY
P h e n y lk e t o n u r ia (P KU ) is a n a u t osom a l r eces-
sive disor der ca u sed by a m u t a t ion in t h e PAH gen e,
Epithe lial of wh ich m or e t h a n 500 differ en t m u t a t ion s h a ve
c e ll been iden t ified. P KU r esu lt s wh en a deficien cy of
injury t h e en zym e ph en yla la n in e h ydr oxyla se (PAH ) im -
pa ir s t h e body’s a bilit y t o m et a bolize ph en yla la n in e,
a n essen t ia l a m in o a cid. Th e disor der is det ect ed in
a bou t 350 of ever y 1 m illion bir t h s, m a kin g it t h e
m ost com m on in bor n er r or of m et a bolism . 6
Deficien t PAH en zym e lea ds t o t h e m a r ked a ccu -
CELIAC S PRUE m u la t ion of ph en yla la n in e in body flu ids a n d a lso
(villous a trophy, ma la bs orption) t h e in a bilit y t o con ver t ph en yla la n in e in t o t yr osin e
(Fig. 17.15). Tyr osin e is n eeded for t h e syn t h esis of
Figure 17.14. Celiac disease (villous atrophy, malabsorp- pr ot ein s, t h yr oxin e (a t h yr oid h or m on e), ca t ech ol-
tion). Hypothetical mechanism in the pathogenesis of a m in es (n eu r ot r a n sm it t er s), a n d m ela n in (skin pig-
celiac disease. HLA, human leukocyte antigen. (From m en t ). Su bt le n eu r opsych ologica l deficit s ca n r esu lt
Rubin R, Strayer DS, eds. Rubin’s Pathophysiology: Clinico- fr om r edu ced pr odu ct ion of n eu r ot r a n sm it t er s a s a
pathologic Foundations of Medicine. 6th ed. Philadelphia, r esu lt of deficien t t yr osin e t r a n spor t a cr oss t h e n eu -
PA: Lippincott Williams & Wilkins; 2012:642.) r on a l cell m em br a n e.

+
NH3
–
CH2 CH COO
C C
Phe nylalanine
P KU P he nyla la nine hydroxyla s e
+
NH3
HO CH2 CH COO –
C C
Tyro s ine
Figure 17.15. Degradation of phenylalanine. PKU,
phenylketonuria.
CLINICAL MANIFESTATIONS
E xcess cir cu la t in g ph en yla la n in e n ega t ively im -
pa ct s cogn it ive fu n ct ion . Pa t ien t s wit h P KU a lm ost
a lwa ys h a ve in t ellect u a l disa bilit y u n less ph en yla la -
n in e levels a r e con t r olled t h r ou gh diet or dr u g t r ea t -
m en t . In a ddit ion , im pa ir m en t of m ela n in syn t h esis
r esu lt s in fa ir skin a n d h a ir a n d h ypopigm en t a t ion
of eyes. Pa t ien t s oft en h a ve a m u st y odor a n d a bou t
h a lf a r e a lso dia gn osed wit h a seizu r e disor der.
DIAGNOSTIC CRITERIA
Dia gn osis oft en occu r s a t bir t h a s a r esu lt of r ou t in e
m et a bolic scr een in g (blood t est ). In cou n t r ies wh er e
n ewbor n scr een in g pr ogr a m s do n ot exist , P KU of-
t en goes u n det ect ed u n t il sever e developm en t a l de-
la y a n d in t ellect u a l disa bilit y occu r.
TREATMENT
Pa t ien t s wit h P KU oft en r equ ir e specia lt y ca r e. Th e
con dit ion is t r ea t ed wit h ca r efu l lifet im e diet a r y
m a n a gem en t , a voidin g ph en yla la n in e, a n d a dd-
in g a m in o a cid (especia lly t yr osin e), vit a m in , a n d
m in er a l su pplem en t s. P h a r m a cologic t h er a py wit h
sa pr opt er in dih ydr och lor ide, wh ich is a n en zym e
cofa ct or, m a y su ppor t ph en yla la n in e m et a bolism in
som e pa t ien t s. Resea r ch is u n der wa y t o develop a n
in ject a ble ph en yla la n in e en zym e su bst it u t e.
Specific food r est r ict ion s in clu de t h ose h igh in
pr ot ein (m ea t s, da ir y, n u t s, bea n s) a n d st a r ch (br ea d,
pot a t oes). Accept a ble foods wou ld be t h ose t h a t a r e
low in pr ot ein , in clu din g fr u it s a n d n on st a r ch y
veget a bles. Pa t ien t s wit h P KU obt a in pr ot ein s pr i-
m a r ily fr om m edica l food, su ch a s t h ose fou n d in
specia lly-for m u la t ed pr ot ein powder s. Aspa r t a m e
a lso m u st be elim in a t ed a s ph en yla la n in e is a m a -
jor com pon en t of t h is su ga r su bst it u t e. P h en yla la -
n in e levels a r e m on it or ed r egu la r ly. Th e pr ogn osis
is excellen t wh en pa t ien t s con t in u e on a diet low in
ph en yla la n in e.
C lin ic a l Mo d e ls 453
Obesity
O b e s it y is a st a t e of excessive body fa t a n d is a
m a jor pu blic h ea lt h cr isis. Th e pr eva len ce wor ld-
wide h a s been in cr ea sin g wit h est im a t es of 1 billion
people wh o a r e over weigh t or obese. Th e wor ldwide
t r en d is ca u sed in pa r t t o t h e in cr ea sin g west er n i-
za t ion of m a n y t r a dit ion a l diet s—fr u it s, veget a bles,
a n d wh ole gr a in s a r e bein g r epla ced by ca lor ie-den se,
ea sily a ccessible foods t h a t a r e h igh in sa t u r a t ed fa t ,
su ga r, a n d r efin ed ca r boh ydr a t es. Obesit y is a m a -
jor con t r ibu t or t o m or bidit y a n d m or t a lit y, especia lly
in west er n ized cou n t r ies su ch a s t h e Un it ed St a t es,
wh er e a n est im a t ed 35% of t h e popu la t ion is obese.7
PATHOPHYSIOLOGY
Body weigh t is t h e com posit e of bon e, m u scle, or ga n s,
body flu ids, a n d a dipose t issu e. Body fa t is divided
in t o essen t ia l fa t , wh ich is n eeded for ph ysiologic
fu n ct ion in g, a n d s t o r a g e a t , wh ich a ccu m u la t es
u n der t h e skin a n d a r ou n d in t er n a l or ga n s.
Adipocyt es, t h e pr im a r y cell in volved in obesit y,
a r e h igh ly a ct ive m et a bolic, en docr in e, a n d in fla m -
m a t or y cells. Th e a dipocyt e sh ou ld be t h ou gh t of a s
a n en docr in e gla n d, wit h a m a jor r ole in con t r ollin g
body weigh t , a n d a pr oin fla m m a t or y cell, ca pa ble of
secr et in g pr oin fla m m a t or y cyt okin es a n d im pa ct in g
blood coa gu la t ion , in su lin sen sit ivit y, a n d a ppet it e.
Im por t a n t t o t h e m et a bolism a n d fu n ct ion of a dipo-
cyt es a r e t h e en zym es a n d h or m on es t h a t con t r ol
t h ese fu n ct ion s. On e exa m ple of a n en zym e t h a t con -
t r ibu t es t o obesit y is lipopr ot ein lipa se, wh ich a ct s
on t h e a dipocyt e t o pr om ot e lipid st or a ge. Ot h er ex-
a m ples a r e list ed below.
Stop and Consider
How could drug therapy target obesity with what
you know about the role of lipoprotein lipase
enzymes?
Obesit y occu r s wh en a dipocyt es a r e in cr ea sed in
size (h yper t r oph ic) a n d/or n u m ber (h yper cellu la r ).
In h yper t r oph ic obesit y, a dipocyt es becom e en la r ged
a n d fa t a ccu m u la t es in t h e a bdom in a l r egion . H yper-
t r oph ic fa t a ccu m u la t ion u su a lly st a r t s in a du lt h ood
a n d weigh t r edu ct ion m ea su r es, su ch a s exer cise
a n d h ea lt h y diet , a r e gen er a lly su ccessfu l. In con -
t r a st , h yper cellu la r obesit y oft en pr esen t s in ch ild-
h ood or a dolescen ce, ca u ses m or e sever e obesit y, a n d
is t ypica lly n ot r espon sive t o n on su r gica l weigh t loss
in t er ven t ion s.
Th e ca u ses of h yper t r oph ic or h yper cellu la r obe-
sit y a r e n ot a s sim ple a s ca lor ies in ver su s ca lor ies
ou t ; obesit y is a h igh ly com plex ph en om en on a n d in -
volves m et a bolic, en docr in e, gen et ic, lifest yle, r a ce,
et h n ic, a ge, sex, socioecon om ic, a n d en vir on m en t a l
454 C h a p t e r 17: Alt er ed Nu t r it ion
fa ct or s. Th e m a n y pieces t o t h e obesit y pu zzle
in clu de:
● Gen etics is est im a t ed t o be r espon sible for a bou t
on e-t h ir d of t h e in dividu a l’s body m a ss in dex. Th e
n u m ber a n d size of a dipose cells, dist r ibu t ion of
body fa t , a n d r est in g m et a bolic r a t e a r e gen et i-
ca lly in flu en ced; m or e t h a n 200 gen es a r e in -
volved in obesit y.
● Lifestyle fa ct or s, in clu din g con su m pt ion of a diet
wit h excessive ca lor ies com bin ed wit h a seden -
t a r y lifest yle, a lso con t r ibu t es t o t h e developm en t
of obesit y.
● Neu r ologic m ech a n ism s a n d h or m on es a ct on t h e
h ypot h a la m u s, st im u la t e a n d su ppr ess h u n ger
a n d sa t iet y.
■ Lept in, a horm one secreted by a dipocytes, ha s a
m a jor r ole in body weight regu la tion. It signa ls
sat iety t o the hypot ha la mus, reduces food inta ke
a n d lipid st or a ge, a nd promotes ener gy expendi-
t ure. In obesit y, pa tient s a re found t o have high
levels of lept in but a re r esista nt to t his hor mone.
■ E st r ogen , wh ich st im u la t es lipid m ovem en t
in t o a dipocyt es in t h e h ip a n d u pper t h igh
r egion s a n d r est r ict s m ovem en t in t o t h e a b-
dom in a l r egion , expla in in g t h e sh a pe of m a n y
wom en wh o h a ve a dequ a t e est r ogen levels.
Ce re bra l a the ros cle ros is,
s troke
S le e p a pne a
Hypove ntila tion
Ga lls tone s
Os te oa rthritis
■ Th yr oid h or m on e is a ct ive in m et a bolic pr o-
cesses (see Ch a pt er 13).
■ In su lin , secr et ed by t h e pa n cr ea s, a ct s on t h e
CNS t o in h ibit food in t a ke a n d is in volved in
t h e syn t h esis a n d st or a ge of lipids.
■ Mela n ocor t in h or m on e a ct s on m ela n ocor t in
r ecept or s a n d m odifies a ppet it e.
■ Gh r elin h or m on e, secr et ed fr om t h e st om a ch , is
a m a jor h u n ger h or m on e.
● E n zym es m edia t e m et a bolic pr ocesses a n d m ove-
m en t of diet a r y lipids in t o t h e a dipocyt e; lipopr o-
t ein lipa ses pr om ot e lipid st or a ge.
● H or m on es a lso m edia t e m ovem en t of diet a r y lip-
ids fr om t h e blood, a cr oss t h e ca pilla r y wa ll, a n d
in t o t h e a dipocyt e.
CLINICAL MANIFESTATIONS
Th e pr im a r y clin ica l m a n ifest a t ion for obesit y is
excessive weigh t a n d body fa t . H owever, beyon d ex-
cessive weigh t ga in a n d body fa t , obesit y ca r r ies a
lon g list of com or bidit ies, in clu din g dia bet es, h ea r t
disea se, h yper t en sion , h yper lipidem ia , st r oke, ost eo-
a r t h r it is, liver disea se, ga ll st on es, poor wou n d h ea l-
in g, sleep a pn ea , a n d cer t a in ca n cer s (Fig. 17.16).
Hype rlipoprote ine mia
Hype rte ns ion,
le ft ve ntricula r
hype rtrophy
Corona ry a rte ry
a the ros cle ros is,
myoca rdia l
infa rction
Dia be te s
Poor wound
he a ling
Figure 17.16. Obesity comorbidities.
 0
4
5
3
C lin ic a l Mo d e ls 455

0
3
5
2
BMI

9
1
78
77
76
75

t
h
74

ig
73

e
W
72

e
y

I
s
71

s
lt

b
70

II
a

la
-o
69

s
C
re
H

s
He ig ht

la
68

s III
)
P

y
(in inc he s )

C
s

it
67

b s
e
b

o s
e
66

la
O

s
e

m C
65

b
O

e e
e
64

tr s
x e
63

(e Ob
62
61
60
59
58
50 75 100 125 150 175 200 225 250 275 300 325 350

We ig ht
(in po unds )
Figure 17.17. Body mass index and the classification of obesity. (Courtesy Anatomical Chart Company and modified ac-
cording to the WHO International Classification of Adult Obesity According to BMI, 2010.)

Stop and Consider Dia gn osis of obesit y sh ou ld a lso in clu de a com -

Take a minute to calculate your BMI. Do this by
measuring your weight in pounds and converting
this to kilograms (1 lb = 0.45 kg). Then, mea-
sure your height in inches and convert this to
meters squared (multiply inches × 2.54 cm; di-
vide this number by 100 cm/ m; multiply this fi-
nal number × itself to get meters squared). Then
the final step is to take your weight in kilograms
and divide it by your height in meters squared.
What number did you get?
DIAGNOSTIC CRITERIA-
Body fa t is m ost oft en det er m in ed u sin g a m a t h e-
m a t ica l ca lcu la t ion t er m ed b o d y m a s s in d e x , or
BMI (Fig. 17.17). Th e Wor ld H ea lt h Or ga n iza t ion
cla ssifies BMI a s follows:
● Gr a de 1 (over weigh t ): BMI of 25 t o 29.9 kg/m 2
● Gr a de 2 (obese): BMI of 30 t o 39.9 kg/m 2
● Gr a de 3 (sever ely obese): BMI ≥ 40 kg/m 2
pr eh en sive eva lu a t ion for com or bidit ies, su ch a s
h yper t en sion , h yper ch olest er olem ia , dia bet es, h ypo-
t h yr oidism , ven ou s va r icosit ies, ost eoa r t h r it is, sleep
a pn ea , depr ession , r epr odu ct ive a lt er a t ion s, a n d
in fect ion .
TREATMENT
Tr ea t m en t of obesit y is lifelon g a n d is focu sed on
a t t a in in g a n d m a in t a in in g t h e best possible weigh t
for opt im a l h ea lt h . Ba sic t r ea t m en t pr in ciples focu s
on diet , exer cise, a n d beh a vior a l m odifica t ion . P h a r-
m a cologic t h er a py or su r ger y m a y be in dica t ed, bu t
t h ese do n ot r epla ce lifest yle m odifica t ion s. P h a r-
m a cologic t h er a pies pr im a r ily a im t o su ppr ess a p-
pet it e, in cr ea se m et a bolism , or in t er fer e wit h fa t
a bsor pt ion . Tr ea t m en t m a y a lso in clu de in su lin for
dia bet es or a n t ih yper t en sives. Ga st r ic su r ger y m a y
be n eeded in som e ca ses t o r edu ce st om a ch size a n d
t h er eby r edu ce food in t a ke a n d fa t a bsor pt ion .
456 C h a p t e r 17: Alt er ed Nu t r it ion

in a dequ a t e in t a ke of essen t ia l vit a m in s a n d m in -

S U MMAR Y er a ls, or pr oblem s wit h digest ion , a bsor pt ion , or
dist r ibu t ion of n u t r ien t s in t h e body. Un der n u t r i-
● Adequ a t e n u t r it ion r elies on opt im a l in t a ke, di-
t ion ca n lea d t o weigh t loss, m u scle wa st in g, m u s-
gest ion , a bsor pt ion , m et a bolism , a n d t r a n spor t a -
cle wea kn ess, deh ydr a t ion , fa t igu e, a n d eviden ce
t ion of n u t r ien t s, a s well a s on t h e excr et ion of
of vit a m in a n d m in er a l deficien cies. Skin m a n i-
wa st e pr odu ct s.
fest a t ion s a r e oft en pr esen t a n d m a y in clu de poor
● Th e m a jor m a cr on u t r ien t s t h a t a r e con ver t ed t o
wou n d h ea lin g, pu r pu r a , u lcer a t ion , dr y skin , or
u sa ble sou r ces of en er gy a r e pr ot ein s, lipids, a n d
pa llor. Mu cou s m em br a n es becom e in fla m ed a n d
ca r boh ydr a t es. Micr on u t r ien t s in clu de vit a m in s
fr ia ble.
a n d m in er a ls. Ma cr on u t r ien t s h a ve m u lt iple r oles,
● Ma la bsor pt ion is a for m of u n der n u t r it ion in
in clu din g t h e pr ovision of ca lor ies t h a t a r e con -
wh ich specific n u t r ien t s do n ot m ove a cr oss t h e
ver t ed in t o en er gy. P r ot ein s bu ild a n d m a in t a in
ga st r oin t est in a l m u cosa . Ma la bsor pt ion t ypica lly
st r u ct u r a l body t issu es, com pr ise blood, cell m em -
m a n ifest s a s weigh t loss, dia r r h ea , bloa t in g, a b-
br a n es, im m u n e fa ct or s, en zym es, a n d h or m on es,
dom in a l cr a m pin g, a n d excessive fla t u len ce.
a n d t r a n spor t su bst a n ces a cr oss m em br a n es.
● Over n u t r it ion is a st a t e of excessive exposu r e t o
Lipids a r e a r ich sou r ce of en er gy a n d fa cilit a t e
n u t r ien t s. Over n u t r it ion is gen er a lly r ela t ed t o
n u m er ou s pr ocesses, su ch a s su ppor t in g digest ion
over con su m pt ion of n u t r ien t s, in clu din g exces-
a n d a bsor pt ion . Th ey in flu en ce cell m em br a n e
sive ca lor ies or in gest in g t oxic levels of vit a m in s
flu idit y, r ecept or fu n ct ion , h or m on e fu n ct ion , en -
a n d m in er a ls. Over n u t r it ion lea ds t o in cr ea ses in
zym e a ct ivit y, a n d cyt okin e pr odu ct ion . St r u c-
weigh t a n d body fa t n ess.
t u r a l fa t pr ovides su ppor t a n d pr ot ect ion t o body
● Toxicit y of vit a m in s or m in er a ls ca n h a ve va r yin g
or ga n s. Th e m a jor r ole of ca r boh ydr a t es is t o pr o-
clin ica l m a n ifest a t ion s depen din g on t h e ph ysio-
vide en er gy.
logic fu n ct ion of t h e specific n u t r ien t a n d m a y in -
● Ma n y vit a m in s pla y a cr it ica l r ole in m et a bolism
clu de h ea da ch e, seizu r es, n a u sea , vom it in g, skin
of ca r boh ydr a t es, a m in o a cids, a n d fa t t y a cids. Ba -
ch a n ges, liver disea se, skelet a l im pa ir m en t , a n d
sica lly, vit a m in s a r e pa r t of en zym e syst em s t h a t
ca r dia c dysr h yt h m ia s.
r elea se en er gy fr om m a cr on u t r ien t s. Th e ot h er
● Dia gn ost ic a n d t r ea t m en t st r a t egies for a lt er ed
m a jor r ole of vit a m in s is t o a id in t h e developm en t
n u t r it ion a r e focu sed on det er m in in g t h e ca u se
of gen et ic m a t er ia ls, r ed blood cells, h or m on es,
for t h e n u t r it ion im ba la n ce a n d t h e pot en t ia l
colla gen , a n d n er vou s syst em t issu e.
effect s.
● Min er a ls r egu la t e h u n dr eds of cellu la r pr ocesses.
Min er a ls con st it u t e bon e, h em oglobin , en zym es,
h or m on es, a n d ch em ica l m edia t or s. Ch a r ged
(ion ic) m in er a ls m edia t e im pu lse con du ct ion C AS E S T U D Y 17.1
wit h in t h e n er vou s syst em . Min er a ls m a in t a in
wa t er ba la n ce, a cid–ba se ba la n ce, a n d osm ot ic J ill is a 14-yea r-old Afr ica n -Am er ica n gir l wh o pr es-
pr essu r e. Min er a ls a r e cr it ica l for m u scle con t r a c- en t s t o t h e clin ic r epor t in g in t er m it t en t dia r r h ea ,
t ion a n d for m t h e st r u ct u r a l com pon en t s of bon es bloa t in g, a bdom in a l pa in , a n d ga s 30 m in u t es a ft er
a n d t eet h . ea t in g som e m ea ls, pa r t icu la r ly br ea kfa st . F u r t h er
● Th e in t a ke a n d st or a ge of n u t r ien t s is cr it ica l t o h ist or y elicit ed t h a t sh e ea t s a bowl of cer ea l wit h
over a ll h ea lt h a n d is r egu la t ed pr im a r ily by n eu - m ilk ea ch m or n in g. Ot h er s in h er fa m ily h a ve la c-
r oen docr in e syst em s. Digest ion a n d a bsor pt ion t ose in t oler a n ce. Sh e t h in ks t h a t wh en sh e a voids
is a pr ocess in volvin g m ech a n ica l a n d en zym a t ic m ilk t h a t sh e doesn ’t h a ve t h e sym pt om s. You su s-
degr a da t ion of n u t r ien t s in t o u sa ble com pon en t s pect la ct ose in t oler a n ce in h er a s well.
t h a t ca n be a bsor bed. Th e ga st r oin t est in a l t r a ct ,
1. Ou t lin e t h e pr ocess t h a t is m ost likely occu r r in g
m ost n ot a bly t h e sm a ll in t est in e, is a m a jor sit e
in t h is per son ’s body.
for digest ion a n d a bsor pt ion of n u t r ien t s.
2. Wh a t wou ld you expect for clin ica l m a n ifest a t ion s?
● Alt er ed n u t r it ion , or m a ln u t r it ion , is a st a t e of in -
3. Wh a t dia gn ost ic t est s cou ld be u sed?
a dequ a t e or excessive exposu r e t o n u t r ien t s. Th is
4. Wh a t t r ea t m en t m ea su r es wou ld you
ca n in clu de in t a ke, digest ion , or a bsor pt ion of
a n t icipa t e?
n u t r ien t s. P r ot ein en er gy m a ln u t r it ion is r ela t ed
t o depr iva t ion of a ll food (m a r a sm u s) or pr ot ein Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r n a l
depr iva t ion in in dividu a ls con su m in g a dequ a t e a r t icle or Web sit e, su ch a s h t t p://www.n iddk.n ih .gov/
ca r boh ydr a t es (kwa sh ior kor ). h ea lt h -in for m a t ion /h ea lt h -t opics/digest ive-disea ses/
● Un der n u t r it ion is a la ck of in t a ke of n u t r ien t s m ost la ct ose-in t oler a n ce/Pa ges/ez.a spx, wh ich det a ils la c-
oft en r ela t ed t o in a dequ a t e ca lor ie con su m pt ion , t ose in t oler a n ce a n d con fir m you r pr edict ion s.

C AS E S T U D Y 17.2
Pa m is a 40-yea r-old wom a n wh o h a s been seein g a n
ea t in g disor der specia list for t h e pa st 6 m on t h s du e t o
a pr olon ged bin ge ea t in g disor der. Sh e is obese wit h
a BMI of 34. H er ea t in g disor der beca m e pr oblem a t ic
a r ou n d a ge 18 wh en h er weigh t con t in u ed t o eleva t e
over t im e. Sh e bin ges a bou t on ce per week n ow a n d
it is u su a lly t r igger ed by fa m ily-r ela t ed st r ess. Sh e
ea t s r a pidly a t a ll m ea ls. Sh e n ot iced t h ou gh t h a t
sh e h a s been bin gin g on ly wh en sh e is a lon e. Aft er
a bin gin g episode, Pa m feels em ba r r a ssed bu t h elp-
less. Sh e is n ot a ble t o st op t h e beh a vior.
1. Ou t lin e t h e pr ocess t h a t is m ost likely occu r r in g
in t h is per son ’s body.
2. Wh a t wou ld you expect for clin ica l m a n ifest a t ion s?
3. Wh a t dia gn ost ic t est s cou ld be u sed?
4. Wh a t t r ea t m en t m ea su r es wou ld you a n t icipa t e?
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r n a l
a r t icle or Web sit e, su ch a s h t t p://www.m a yoclin ic
.com /h ea lt h /bin ge-ea t in g-disor der /DS00608, wh ich
det a ils bin ge ea t in g disor der, a n d con fir m you r
pr edict ion s.
C AS E S T U D Y 17.3
Th om a s is a 49-yea r-old wh o h a s been sever ely
obese sin ce a dolescen ce. H e h a s t r ied ever y diet a n d
weigh t loss pr ogr a m wit h ou t su ccess. H e decides
t h a t h e wou ld like t o pu r su e ga st r ic bypa ss su r ger y
a n d is fou n d t o be a good ca n dida t e. Aft er m on t h s of
pr epa r a t ion , Th om a s u n der goes a la pa r oscopic by-
pa ss pr ocedu r e.
1. H ow is t h e pr ocedu r e per for m ed? H ow is t h e
a n a t om y a n d ph ysiology ch a n ged?
2. Wh a t wou ld be t h e con t r a in dica t ion s t o ga st r ic
bypa ss? Wh o wou ld n ot be a good ca n dida t e?
3. H ow wou ld t h e pa t ien t det er m in e su ccess a ft er
t h e pr ocedu r e?
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r-
n a l a r t icle or Web sit e, su ch a s h t t p://em edicin e
.m edsca pe.com /a r t icle/143954-over view#a 1, wh ich
det a ils ga st r ic bypa ss, a n d con fir m you r pr edict ion s.
P R AC T I C E E XAM Q U E S T I O N S
1. You h a ve in fla m m a t ion of t h e la r ge in t est in e, a
con dit ion ca lled u lcer a t ive colit is. Wh a t is t h e
m ost pr oba ble r ea son t h a t you wou ld develop
ir on -deficien cy a n em ia ?
a . You a r e exper ien cin g ch r on ic blood loss in
you r st ools
C h a p t e r 17: Alt er ed Nu t r it ion 457
b. You h a ve in a dequ a t e h ydr och lor ic a cid for a b-
sor pt ion of ir on
c. You h a ve lost u sa ble su r fa ce a r ea in t h e la r ge
in t est in e for a bsor pt ion of ir on
d. You do n ot h a ve a n a dequ a t e ir on in t a ke in
you r diet
2. You a r e pa r t of t h e h ea lt h ca r e t ea m a t a clin ic
for a dolescen t s wit h a n or exia n er vosa . Wh ich of
t h e a ssessm en t s t h a t you per for m is focu sed on
r ecogn izin g t h e m ost com m on ca u se for m or t a l-
it y in t h ose wit h AN?
a . Lu n g a ssessm en t
b. Ca r diova scu la r a ssessm en t
c. Skin a ssessm en t
d. Neu r ologic a ssessm en t
3. Wh ich diet a r y ch a n ge wou ld be r ecom m en ded
for t h e in dividu a l wit h celia c disea se?
a . Avoid m ilk or m ilk pr odu ct s
b. Avoid wh ea t , ba r ley, r ye, a n d oa t s
c. Avoid r ice, soy, a n d n u t s
d. Avoid lon g-ch a in fa t t y a cids
4. Wh ich of t h e followin g a ffect s t h e sen sa t ion s of
h u n ger a n d sa t iet y a n d t h er efor e pla ys a m a jor
r ole in t h e developm en t of obesit y?
a . Th e h ypot h a la m u s
b. Th e pit u it a r y gla n d
c. Th e t h yr oid gla n d
d. Th e pa n cr ea s
5. Wh ich of t h e followin g does n ot con t r ibu t e a s a n
en er gy sou r ce in t h e diet ?
a . Ca r boh ydr a t es
b. Fa t s
c. P r ot ein s
d. Vit a m in s
6. You a r e ca r in g for a n in dividu a l wit h liver dis-
ea se. Wh a t a r e you m ost con cer n ed a bou t in
t er m s of n u t r it ion ?
a . Th e pa t ien t m a y be u n a ble t o a dequ a t ely
st or e n u t r ien t s
b. Th e pa t ien t m a y be u n a ble t o syn t h esize
n u t r ien t s
c. Th e pa t ien t m a y be u n a ble t o m et a bolize
m a cr on u t r ien t s
d. All of t h ese a r e m a jor con cer n s
7. You r pa t ien t h a s ga ll bla dder disea se a n d is u n -
a ble t o st or e a n d r elea se a dequ a t e bile t o t h e
sm a ll in t est in e. Wh a t diet a r y m odifica t ion s do
you su ggest ?
a . In cr ea se pr ot ein in t a ke
b. Decr ea se fa t in t a ke
c. In cr ea se com plex ca r boh ydr a t es
d. No diet a r y ch a n ges a r e n eeded
458 C h a p t e r 17: Alt er ed Nu t r it ion

8. You a r e wor kin g in t h e n ewbor n n u r ser y a n d a r e a n d wa s fou n d t o h a ve m u lt iple bon e fr a ct u r es.

a n a dvoca t e for br ea st feedin g. It is t h e win t er Wh ich of t h e followin g su pplem en t s, in t oxic lev-
in n or t h er n Min n esot a a n d you a r e con cer n ed els, ca u ses m u lt iple skelet a l fr a ct u r es?
a bou t low su n ligh t exposu r e in in fa n t s wh o a r e a . P h osph or u s
br ea st feedin g a s t h ey m a y develop vit a m in D b. Ir on
deficien cy. Wh a t is t h e m a jor m a n ifest a t ion of c. Zin c
vit a m in D deficien cy? d. Ca lciu m
a . Im pa ir ed m in er a liza t ion in gr owin g bon es
b. Im pa ir ed r et in a l developm en t
c. Im pa ir ed ost eocla st a ct ivit y D I S C U S S I O N AN D
d. Ker a t in iza t ion of m u cou s m em br a n es AP P L I C AT I O N

9. You a r e pla n n in g a n u t r it ion a l in ser vice t o you r

1. Wh a t did I kn ow a bou t a lt er ed n u t r it ion pr ior
clin ic’s ser vice a r ea in Ca lifor n ia . Wh a t con cept
t o t oda y?
of a lt er ed n u t r it ion sh ou ld you focu s you r t a lk in
2. Wh a t body pr ocesses a r e a ffect ed by a lt er ed n u -
or der t o a ddr ess t h e la r gest n u t r it ion a l pr oblem
t r it ion ? Wh a t a r e t h e expect ed fu n ct ion s of t h ose
in you r a r ea ?
pr ocesses? H ow does a lt er ed n u t r it ion a ffect
a . Alt er ed m et a bolism
t h ose pr ocesses?
b. Un der n u t r it ion
3. Wh a t a r e t h e pot en t ia l et iologies for a lt er ed n u -
c. Over n u t r it ion
t r it ion ? H ow does a lt er ed n u t r it ion develop?
d. All of t h ese a r e equ a lly pr eva len t
4. Wh o is m ost a t r isk for developin g a lt er ed n u t r i-
t ion ? H ow ca n a lt er ed n u t r it ion be pr even t ed?
10. Wh a t is kn own a bou t glu cose t r a n spor t in t o t h e
5. Wh a t a r e t h e h u m a n differ en ces t h a t a ffect t h e
sm a ll in t est in e?
et iology, r isk, or cou r se of a lt er ed n u t r it ion ?
a . Requ ir es cot r a n spor t wit h sodiu m
6. Wh a t clin ica l m a n ifest a t ion s a r e expect ed in t h e
b. Occu r s t h r ou gh a ct ive t r a n spor t
cou r se of a lt er ed n u t r it ion ?
c. Mu st fir st be r edu ced a s is r a r ely con su m ed in
7. Wh a t specia l dia gn ost ic t est s a r e u sefu l in de-
t h e t ypica l diet
t er m in in g t h e dia gn osis a n d cou r se of a lt er ed
d. All of t h ese a r e t r u e a bou t glu cose t r a n spor t
n u t r it ion ?
8. Wh a t a r e t h e goa ls of ca r e for in dividu a ls wit h
11. Wh a t is t h e fir st pla n of a ct ion for t h e for m u la -fed
a lt er ed n u t r it ion ?
n ewbor n wh o is ju st dia gn osed wit h P KU?
9. H ow does t h e con cept of a lt er ed per fu sion bu ild
a . Swit ch t o a specia l for m u la wit h ph en yla la n in e
on wh a t I h a ve lea r n ed in t h e pr eviou s ch a pt er s
b. P r epa r e for a blood t r a n sfu sion
a n d in pr eviou s cou r ses?
c. Swit ch t o a ph en yla la n in e-fr ee for m u la
10. H ow ca n I u se wh a t I h a ve lea r n ed?
d. Requ ir e t h e m ot h er t o br ea st feed

12. Wh ich of t h e followin g vit a m in s is su pplem en t ed

in pr egn a n cy beca u se of it s im por t a n t r ole in em -
R E SOUR CE S
br yogen esis a n d t h e pr even t ion of n eu r a l t u be
defect s in t h e fet u s?
Aca dem y of Nu t r it ion a n d Diet et ics:
a . Vit a m in A
h t t p://www.ea t r igh t .or g/
b. Cit r ic a cid
c. Fola t e Body Ma ss In dex ca lcu la t or :
d. Vit a m in B 12 h t t p://www.cdc.gov/h ea lt h yweigh t /a ssessin g/in dex.
html
13. Wh a t a r e t ypica l m a n ifest a t ion s for m a la bsor p-
Ca n a da ’s Food a n d Nu t r it ion Websit e:
t ion syn dr om es?
h t t p://www.h c-sc.gc.ca /fn -a n /in dex-en g.ph p
a . Con st ipa t ion , dr y m ou t h , wea kn ess
b. Dia r r h ea , bloa t in g, st om a ch pa in Na t ion a l Societ y for P KU:
c. Bloody st ools, fissu r es, r ect a l bleedin g h t t p://www.n spku .or g/
d. Na u sea , vom it in g, st om a ch cr a m pin g
Obesit y Societ y:
h t t p://www.obesit y.or g
14. You r n eigh bor, a s sh e pu t it , is a “la ct ose in t oler-
a n t h ea lt h n u t ” a n d sh e is a lwa ys exper im en t in g Un it ed St a t es Depa r t m en t of Agr icu lt u r e (USDA)
wit h va r iou s su pplem en t s. Recen t ly, sh e wen t “MyP la t e”:
in t o t h e clin ic for eva lu a t ion of pa in in h er leg h t t p://www.ch oosem ypla t e.gov/

R e er en ces
1. Ma h a n L, E scot t -St u m p S. Food , Nu tr ition , a n d Diet
Th er a py. P h ila delph ia , PA: Sa u n der s; 2004.
2. J er om e-Mor a is A, Dia m on d AM, Wr igh t ME . Diet a r y
su pplem en t s a n d h u m a n h ea lt h : for bet t er or for wor se?
Mol Nu tr Food Res. 2011;55(1):122–135.
3. U.S. Depa r t m en t of Agr icu lt u r e, U.S. Depa r t m en t of
H ea lt h a n d H u m a n Ser vices. Dieta r y Gu id elin es for
Am er ica n s, 2010. 7t h ed. Wa sh in gt on , DC: U.S. Gover n -
m en t P r in t in g Office; 2010.
4. Ber n st ein BE . An or exia Ner vosa . h t t p://em edicin e
.m edsca pe.com /a r t icle/912187-over view#a 3. Accessed
Novem ber 22, 2015.
F in d a d d ition a l r esou r ces for th is ch a pter a t h ttp:th ePoin t.lww.com
C h a p t e r 17: Alt er ed Nu t r it ion 459
5. Goebel SU. Celia c disea se. h t t p://em edicin e.m edsca pe.
com /a r t icle/171805-over view. Accessed Novem ber 23,
2015.
6. Ar n old G. P h en ylket on u r ia . h t t p://em edicin e.m edsca pe.
com /a r t icle/947781-over view. Accessed Novem ber 23,
2015.
7. H a m dy O. Obesit y. h t t p://em edicin e.m edsca pe.com /
a r t icle/123702-over view#a 5. Accessed Novem ber 24,
2015.
 Ch a pt er

18 Alt er ed E lim in a t ion

L E AR N I N G O U T C O ME S
1. Defin e a n d u se t h e key t er m s list ed in t h is ch a pt er.
2. Descr ibe t h e pr ocesses of t h e pr odu ct ion a n d elim in a t ion of u r in e a n d
st ool.
3. Iden t ify t h e r ole of n eu r a l, m ot or, en docr in e, a n d ph ysica l pr ocesses in
a lt er ed elim in a t ion .
4. Ou t lin e t h e pr ocesses in volved in a lt er ed elim in a t ion .
5. Ch a r a ct er ize t h e clin ica l m a n ifest a t ion s in a lt er ed u r in a r y a n d ga st r oin -
t est in a l elim in a t ion .
6. Recogn ize h ea lt h con dit ion s t h a t ca n pr ecipit a t e im pa ir ed elim in a t ion .
7. Det a il a lt er a t ion s in syst em ic or ga n syst em s a s a r espon se t o a lt er ed
elim in a t ion .
8. List t h e com m on dia gn ost ic pr ocedu r es u sed t o iden t ify a lt er ed u r in a r y
a n d bowel elim in a t ion .
9. Descr ibe t r ea t m en t m oda lit ies u sed in a lt er ed u r in a r y a n d bowel
elim in a t ion .
10. Apply con cept s of a lt er ed elim in a t ion t o select clin ica l m odels.

INTR ODUCTION
As you h a ve seen in t h e pr eviou s ch a pt er s, m a in t en a n ce of h om eost a sis r e-
qu ir es a delica t e ba la n ce a n d ca r efu l coor din a t ion of m a n y body syst em s. Th e
sa m e is t r u e of t h e pr ocess of elim in a t ion . Wh en you ea t a n d dr in k in r espon se
t o h u n ger a n d t h ir st , you feel sa t isfied. We oft en t a ke for gr a n t ed wh a t h a p-
pen s t o t h e food a n d dr in k a ft er ou r n eeds a r e m et . On ce n u t r ien t s h a ve been
ext r a ct ed fr om t h e foods a n d liqu ids we ea t , t h e r em a in in g con t en t s m u st be
elim in a t ed. Ur in e a n d st ool a r e t h e fin a l wa st e pr odu ct s of wh a t wer e on ce ou r
fa vor it e foods a n d dr in ks. For t h e body t o fu n ct ion efficien t ly, t h e wa st e pr od-
u ct s t h a t r em a in a ft er en er gy is ext r a ct ed a n d n u t r ien t s a r e a bsor bed m u st be
excr et ed. Im pa ir m en t of t h e a bilit y t o elim in a t e wa st e pr odu ct s r esu lt s in t h e
clin ica l m a n ifest a t ion s a n d pa t h oph ysiologic a lt er a t ion s a ssocia t ed wit h dis-
ea se. In t h is ch a pt er, t h e pr ocesses of a lt er ed u r in a r y a n d ga st r oin t est in a l (GI)
elim in a t ion a n d t h eir clin ica l m a n ifest a t ion s a r e descr ibed in Modu les 1 a n d 2.
Th e a pplica t ion of t h ese a lt er ed pr ocesses is con sider ed in Modu le 3, select ed
clin ica l m odels of a lt er ed elim in a t ion .

460

Modu le 1 Alt e r e d U r in a r y E lim in a t io n
E lim in a t ion pr ocesses r equ ir e m ot ilit y a n d pa t en cy
of st r u ct u r es in volved in t h e m ovem en t of wa st e for
excr et ion . Th ese pr ocesses a r e r egu la t ed by n eu r o-
m u scu la r sign a lin g a n d a r e in flu en ced by t r a n spor t
fu n ct ion s a n d a dequ a cy of per fu sion . Regu la t ion of
body flu id a n d t h e ba la n ce bet ween a cids a n d ba ses
a r e t wo of t h e pr im a r y r oles of t h e kidn ey, a s de-
scr ibed in Ch a pt er s 8 a n d 9. Wa t er a n d ion m ove-
m en t a cr oss t h e cell m em br a n es of t h e r en a l t u bu les
in close a ssocia t ion wit h t h e va scu la t u r e of t h e kid-
n eys is t h e m ech a n ism t h a t a llows flu id a n d wa st e
secr et ion in t h e for m of u r in e.
Urine Production Process
Ur in e is pr odu ced by t h e kidn ey, is st or ed in t h e
bla dder, a n d is excr et ed via t h e u r et h r a t h r ou gh a
com plex in t er pla y bet ween n eu r a l, m ot or, a n d h or-
m on a l m ech a n ism s. Th e ba sic pr ocesses of t h e r en a l
syst em in clu de:
● Regu la t ion of body flu id volu m e a n d com posit ion
● E lim in a t ion of m et a bolic wa st es
● Syn t h esis, r elea se, or a ct iva t ion of h or m on es
■ E r yt h r opoiet in
■ Ren in
■ Vit a m in D
● Regu la t ion of blood pr essu r e
Th e r en a l syst em is illu st r a t ed in F igu r e 18.1, wh ich
pr ovides a visu a l r eview of t h e u r in a r y syst em loca -
t ion in r ela t ion t o ot h er a n a t om ic st r u ct u r es in t h e
body (Fig. 18.1A), a n over view of t h e in t er n a l st r u c-
t u r es of t h e kidn ey (Fig. 18.1B), a n d a det a iled view
of t h e fu n ct ion a l u n it of t h e kidn ey, t h e n eph r on
(Fig. 18.1C).
URINE PRODUCTION
Th e n e p h r o n is t h e fu n ct ion a l u n it of t h e kidn ey
a n d is com posed of t h e g lo m e r u lu s (ca pilla r y n et -
wor k a n d Bowm a n ca psu le), t h e pr oxim a l t u bu le,
loop of H en le, dist a l t u bu le, a n d collect in g du ct .
Th er e a r e a ppr oxim a t ely 1 m illion n eph r on s in t h e
cor t ex of ea ch kidn ey. Th e r ole of t h e n eph r on is t o:
● F ilt er wa t er-solu ble su bst a n ces fr om t h e blood
● Rea bsor b filt er ed n u t r ien t s, wa t er, a n d elect r olyt es
● Secr et e wa st e
Th e kidn eys a r e r espon sible for pr ocessin g 20% t o
25% of t h e ca r dia c ou t pu t , a ppr oxim a t ely 1,000 m L
Alt e r e d U r in a r y E lim in a t io n 461
of blood per m in u t e. Th is a llows t h e kidn eys t o be
per fu sed wit h en ou gh blood su pply t o m eet t h e h igh
oxygen a n d m et a bolic dem a n ds of t h e or ga n . Blood
en t er s t h e kidn ey t h r ou gh t h e r en a l a r t er y, dividin g
in t o in t er lobu la r a r t er ies, a r cu a t e a r t er ies, a ffer en t
a r t er ioles, a n d glom er u la r ca pilla r ies. Blood en t er-
in g t h e glom er u la r ca pilla r ies via t h e a ffer en t a r t er i-
ole is filt er ed wit h t h e r esu lt in g flu id ca lled ilt r a t e .
F ilt r a t e en t er s Bowm a n ca psu le, wh er e it t h en en -
t er s t h e r en a l t u bu la r syst em . Th e blood r em a in in g
in t h e glom er u la r ca pilla r ies exit s t h e glom er u lu s
via t h e effer en t a r t er iole, wh ich t h en br a n ch es in t o
t h e per it u bu la r ca pilla r ies. Th e per it u bu la r ca pil-
la r ies su r r ou n d t h e pr oxim a l a n d dist a l con volu t ed
t u bu les. Addit ion a l ca pilla r ies, va sa r ect a , su r r ou n d
t h e loops of H en le deep wit h in t h e m edu lla , ser v-
in g a n im por t a n t r ole in t h e con cen t r a t ion of u r in e
t h r ou gh exch a n ge of wa t er a n d solu t es fr om t h e fil-
t r a t e flowin g in t h e opposit e dir ect ion of t h e blood
(c o u n t e r c u r r e n t e x c h a n g e r ). Blood t r a vels in t o
t h e in t er lobu la r ven u les a n d vein s a n d r et u r n s t o
t h e ven ou s cir cu la t ion via t h e r en a l vein .
F ilt r a t e t r a vels fr om Bowm a n ca psu le t o t h e
pr oxim a l t u bu le, wh er e t h e m a jor it y of sodiu m is
r ea bsor bed ba ck in t o t h e blood. Ot h er r ea bsor bed
su bst a n ces in clu de glu cose, pot a ssiu m , a m in o a c-
ids, H CO 3 − , P O 4 − , u r ea , a n d wa t er. H ydr ogen is se-
cr et ed fr om t h e r esu lt in g isot on ic flu id. F lu id m oves
down t h e loop of H en le wh er e it is pr ogr essively
m or e con cen t r a t ed (c o u n t e r c u r r e n t m u lt i p li e r ).
Wa t er is r ea bsor bed a n d sodiu m diffu ses in t o t h e
descen din g loop, wit h sodiu m a ct ively r ea bsor bed
in t h e a scen din g loop. Th e c o u n t e r c u r r e n t m e c h -
a n i s m in volves t h e cou n t er cu r r en t exch a n ger a n d
m u lt iplier a n d is r espon sible for m a in t a in in g t h e
ver t ica l gr a dien t in t h e in t er st it iu m (F ig. 18.2).
In t h e dist a l t u bu le, sodiu m (t h r ou gh t h e a ct ion s
of t h e h or m on e, a ldost er on e) a n d H CO 3 − a r e r ea b-
sor bed. E pit h elia l cells a dja cen t t o t h e dist a l t u -
bu le, t h e m a cu la den sa , pr ovide in for m a t ion a bou t
sodiu m con t en t in t h e filt r a t e t o t h e cells of t h e
ju xt a glom er u la r a ppa r a t u s, r egu la t in g a ldost er on e
r elea se via t h e r en in –a n giot en sin –a ldost er on e
syst em (RAAS). Secr et ion of pot a ssiu m , u r ea , h y-
dr ogen , a n d a m m on ia (N H 3 ) occu r s; t h e r em a in in g
filt r a t e m oves in t o t h e collect in g du ct . H er e, a ddi-
t ion a l wa t er is r ea bsor bed in a n a n t idiu r et ic h or-
m on e (ADH )-depen den t m ech a n ism , in a ddit ion t o
sodiu m , h ydr ogen , pot a ssiu m , a n d N H 3. Th e en d
pr odu ct pr odu ced by t h e n eph r on is u r in e, wh ich is
t r a n spor t ed via t h e u r et er s t o t h e bla dder, wh er e it
is st or ed u n t il it is elim in a t ed t h r ou gh t h e u r et h r a .
462 C h a p t e r 18: Alt er ed E lim in a t ion

Dia phra gm Re na l cortex

T11
T12
Re na l me dulla
Adre na l (re na l pyra mid)
gla nd Inte rlobula r
a rte ry Re na l column

Re na l
pa pilla e
Re na l
Le ft ve in
kidney Ca lyx
Right Re na l
kidney (cut e dge )
Re na l a rte ry
a rte ry
Re na l pe lvis
Re na l
ve in
Ure te r
Infe rior Aorta
ve na cava Ca ps ule

Ure te r
B

Bla dde r

Bowma n's ca ps ule

P roxima l convolute d tubule
Glome rulus
Effe re nt a rte riole

Juxta glome rula r

a ppa ra tus

Affe re nt
a rte riole

Inte rlobula r
a rte ry
Inte rlobula r
ve in
Dis ta l
convolute d
tubule
Cortex
Me dulla
Colle cting
tubule Figure 18.1. Urinary system anatomy. A: The primary struc-
De s ce nding tures of the urinary system are located in the abdomen, with
Pe ritubula r limb
ca pilla ry the right kidney placed slightly lower than the left. B: The
internal structures of the kidney are a complex combination
As ce nding of tissues that produce urinary filtrate from the circulation,
limb
supplied by the renal artery. C: A detailed view of one of
the many structural units of the kidney, the nephron shows
the arrangement of the vascular and tubular structures, nec-
Loop of He nle
essary for the dynamic exchange of fluid, electrolytes, and
C To pa pilla other particles.

Ta ble 18.1 descr ibes t h e m ech a n ism s of t u bu la r URINE REMOVAL

t r a n spor t for select ed su bst a n ces. Ur in e en t er s t h e u r et er s via t h e r en a l pelvis, pr o-
m ot in g flow ou t of t h e kidn eys. Ur et er s a r e com -
Stop and Consider posed of sm oot h m u scle fiber s t h a t pr opel t h e u r in e
Why is it necessary for urine to become concen- t o t h e bla dder by t h e pr ocess of per ist a lsis. Ur in e
trated before it is excreted? en t er s t h e bla dder via t h e t r igon e. Th e t r ig o n e is
 Alt e r e d U r in a r y E lim in a t io n 463
Dis ta l tubule
Glome rulus
H2 O
Figure 18.2. Urinary filtrate flow and con-
P roxima l
tubule 200 300
centration. Movement of water and solutes
H2 O
between the vasa recta and loops of Henle in
300 the juxtamedullary nephrons promotes con-
Corte x K+ Na +

Me dulla centration of urine. The flow of filtrate in the

400 150
loop of Henle runs in the opposite direction

e
l
u
e
Na Cl H2 O Na Cl 200

b
l
of the flow of blood in the parallel vasa recta.
)
b
u
m
a
t
g
e
s
g
De s ce nding

n
This countercurrent design combined with the
O
m
n
i
d
p
i
m
r
loop

t
n
o
e
c
selective permeabilities of the loop of Henle
(
e
o
P
Na Cl

e
l
l
c
d
l
600
i
o
s
600
u
A
contributes to the concentration of osmotically

C
l
f
y
400
r
H2 O
active particles in the medullary interstitium.
a
l
l
u
H2 O H2 O
In the collecting tubule, ADH allows water

H
d
D
e
m
A
H2 O H2 O H2 O
to move from filtrate into the interstitium,
a
800 800
r
t
Na Cl a nd H2 O
n
drawn by osmotic forces. Water then is reab-
I
NaCl a nd Ure a
H2 O
1,000
Ure a
1,200
sorbed into the blood to achieve optimal water
balance. (Modified from Premkumar K. The
1,200 1,200 Massage Connection: Anatomy and Physiology.
Inte r-
Inte rs titia l
s titia l Baltimore, MD: Lippincott Williams &
Va s a Re cta fluid Loop of He nle
fluid Wilkins; 2004.)

Ta b le 18.1 Tu bu la r Tr a n spor t
Su b st a n ce Me c h a n is m s a n d S it e s o Tr a n s p o r t
Sodiu m Filt er ed a t t h e glom er u lu s
Rea bsor bed in t h e pr oxim a l t u bu le by fa cilit a t ed diffu sion a n d in t h e pr oxim a l t u bu le, t h ick a scen din g loop
of H en le, a n d dist a l con volu t ed t u bu le by a ct ive t r a n spor t
Pot a ssiu m Filt er ed a t t h e glom er u lu s
Rea bsor bed pa ssively in t h e pr oxim a l t u bu le a n d a ct ively in t h e t h ick a scen din g loop of H en le
Secr et ed or a ct ively r ea bsor bed in t h e dist a l con volu t ed or collect in g t u bu les; depen ds on blood pot a ssiu m
levels
Ch lor ide Filt er ed a t t h e glom er u lu s
Rea bsor bed pa ssively in t h e la t e pr oxim a l a n d dist a l con volu t ed t u bu le
Rea bsor bed a ct ively in t h e pr oxim a l t u bu le, a scen din g loop of H en le, a n d dist a l con volu t ed t u bu le
H ydr ogen Secr et ed a ct ively in t h e pr oxim a l, dist a l con volu t ed, a n d collect in g t u bu les
Rea bsor bed by ca t ion exch a n ger s in t h e pr oxim a l con volu t ed t u bu les
Bica r bon a t e Filt er ed a t t h e glom er u lu s
Rea bsor bed pa ssively in t h e pr oxim a l a n d dist a l con volu t ed t u bu les
Glu cose Filt er ed a t t h e glom er u lu s
E n t ir ely r ea bsor bed by a ct ive m ech a n ism s u n less t u bu la r m a xim u m is exceeded
Ur ea Filt er ed a t t h e glom er u lu s
Rea bsor bed pa ssively in t h e pr oxim a l, la t e dist a l t u bu les, a n d collect in g du ct
E n t r y in t o t h e descen din g a n d t h in a scen din g loops of H en le depen ds on con cen t r a t ion gr a dien t in t h e su r-
r ou n din g in t er st it iu m
Ca lciu m Filt er ed a t t h e glom er u lu s
Rea bsor bed pa ssively in t h e pr oxim a l t u bu le a n d t h e t h in loop of H en le
Rea bsor bed a ct ively in t h e a scen din g t h ick loop of H en le a n d ea r ly dist a l con volu t ed t u bu le
P h osph a t e Filt er ed a t t h e glom er u lu s
Rea bsor bed a ct ively in pr oxim a l t u bu le
Ma gn esiu m Filt er ed a t t h e glom er u lu s
Rea bsor bed a ct ively a n d pa ssively in t h e t h ick a scen din g loop of H en le
Ur ic a cid Filt er ed a t t h e glom er u lu s
Rea bsor bed in t h e ea r ly a n d la t e pr oxim a l t u bu le
Secr et ed in t h e m idpr oxim a l t u bu le
P r ot ein Lim it ed filt r a t ion a t t h e glom er u lu s ca u sed by la r ge size a n d n ega t ive ch a r ge
Am in o a cids a ct ively r ea bsor bed in t h e pr oxim a l dist a l t u bu le
La r ge pept ides r ea bsor bed by en docyt osis for en t r y in t o lysozym es (m et a bolized in t o a m in o a cids)
464 C h a p t e r 18: Alt er ed E lim in a t ion
a t r ia n gu la r, sm oot h a r ea a t t h e ba se of t h e bla d-
der bet ween t h e open in gs of t h e t wo u r et er s a n d t h e
u r et h r a , ser vin g a s a fu n ct ion a l sph in ct er, wh ich
pr even t s u r in e fr om m ovin g in a r et r ogr a de m a n n er
ba ck in t o t h e u r et er fr om t h e bla dder. Th e b la d d e r
is a m u scu la r or ga n lin ed wit h t r a n sit ion a l epit h e-
liu m a n d in n er va t ed by t h e pelvic n er ves. Th e body
of t h e bla dder is com posed of t h e d e t r u s o r m u s c le
(skelet a l m u scle). F illin g of t h e bla dder a ct iva t es
sen sor y st r et ch r ecept or s, a n d t h e gen er a t ed a ct ion
pot en t ia l is t r a n sm it t ed t o t h e sa cr a l r egion of t h e
spin a l cor d. Con t r a ct ion of t h e det r u sor m u scle is
st im u la t ed by pa r a sym pa t h et ic ch olin er gic m ot or
fiber s. Rela xa t ion of t h e m u scle of t h e bla dder n eck,
t h e in t e r n a l u r e t h r a l s p h in c t e r (com posed of a
r in g of cir cu la r sm oot h m u scle), pr om ot es r elea se
of u r in e fr om t h e bla dder (m ic t u r it io n ). Som a t ic
con t r ol of t h e e x t e r n a l u r e t h r a l s p h in c t e r m u scle
(skelet a l m u scle) in n er va t ed by t h e pu den da l n er ve
a llows for volu n t a r y r elea se of u r in e. Ton ic con t r a c-
t ion of t h e sm oot h m u scle of t h e u r et h r a pr even t s
t h e lea ka ge of u r in e u n t il pr essu r e in t h e bla dder
exceeds t h r esh old. Ur et h r a l len gt h differ s bet ween
gen der s; t h e fem a le u r et h r a is m u ch sh or t er t h a n
t h e m a le u r et h r a , wh ich spa n s t h e len gt h of t h e
pen is. Figu r e 18.3 illu st r a t es t h e st r u ct u r es of t h e
Epithe lium whe n Epithe lium whe n
bla dde r is e mpty bla dde r is full
De trus or
mus cle
Ure te r
Trigone
Inte rna l s phincte r
Exte rna l s phincte r
Figure 18.3. Bladder structures in urinary excretion. The
path of urine excretion through the ureters, trigone area,
and internal and external sphincters is shown. Contraction
of the detrusor muscle promotes passage of urine. The
structural relationship of the epithelium lining the bladder
cavity depends on bladder volume. (Modified from Porth
CM. Pathophysiology: Concepts of Altered Health States. 7th
ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004.)
Box 18.1 Mic t u r it io n R e le x
Bla dder fillin g st im u la t es t h e m ict u r it ion r eflex. Th e
st eps in volved in t h e m ict u r it ion r eflex a r e pr im a r ily
in volu n t a r y, bu t t h ey m a y be m odu la t ed by t h e cer ebr a l
cor t ex, en a blin g con sciou s con t r ol. Th e m ict u r it ion r eflex
in volves fou r m a jor st eps:
1. St im u la t ion of st r et ch r ecept or s in bla dder wa lls t r a n s-
m it s im pu lse t o t h e sa cr a l spin a l cor d.
2. Neu r a l im pu lse a scen ds fr om t h e sa cr a l cor d segm en t s
t o t h e m ict u r it ion cen t er in t h e pon s of t h e br a in .
3. Neu r a l im pu lse descen ds fr om t h e m ict u r it ion cen t er,
in it ia t in g con t r a ct ion of t h e det r u sor m u scle a n d r ela x-
a t ion of t h e in t er n a l sph in ct er.
4. Volu n t a r y r ela xa t ion of t h e ext er n a l sph in ct er st im u -
la t es r elea se of u r in e.
bla dder. A su m m a r y of t h e st eps in volved in t h e m ic-
t u r it ion r eflex is h igh ligh t ed in Box 18.1.
Urine Characteristics
U r in e is a clea r yellow flu id com posed pr im a r ily
of wa t er, wh ich con t a in s a va r iet y of wa t er-solu ble
wa st e pr odu ct s. Tot a l volu m e pr odu ced is a ppr oxi-
m a t ely 750 t o 2,000 m L over a 24-h ou r per iod. Ur in e
h a s a sligh t a m m on ia odor fr om t h e br ea kdown of
u r ea . Va r ia t ion s in color, der ived fr om u r och r om e
pigm en t s, in dica t e h ydr a t ion st a t u s. Con cen t r a t ed,
da r k, st r on g-sm ellin g u r in e m a y in dica t e deh ydr a -
t ion , wh er ea s dilu t e, pa le-color ed u r in e m a y in dica t e
in cr ea sed flu id volu m e.
Ur in e sa m ples ca n be collect ed t o det er m in e t h e
specific ch a r a ct er ist ics. Met h ods of u r in e collect ion
for a n a lysis in clu de:
● Ra n dom collect ion
■ Ma y be t a ken a t a n y t im e of t h e da y
■ No specia l pr epa r a t ion r equ ir ed
● Clea n -ca t ch
■ Requ ir es specia l clea n sin g of t h e ext er n a l u r e-
t h r a l m ea t u s
■ Midst r ea m u r in e collect ion (u r in e collect ed
does n ot in clu de flu id fr om t h e in it ia l or fin a l
u r in a r y st r ea m )
● Bla dder ca t h et er iza t ion
■ St er ile in ser t ion of a ca t h et er t h r ou gh t h e u r i-
n a r y m ea t u s in t o t h e bla dder t o collect u r in e
sa m ple
● Su pr a pu bic a spir a t ion
■ In ser t ion of a st er ile n eedle t r a n sa bdom in a lly
in t o t h e bla dder for u r in e collect ion
Stop and Consider
Why would the indication for urine collection in-
fluence the method selection?

Urine Analysis
Ur in e is a n a lyzed in t wo differ en t wa ys: m a cr oscopic
a n d m icr oscopic. Ma c r o s c o p ic a n a ly s is con sist s
of t h e visu a l det er m in a t ion of color a n d cla r it y. In
a ddit ion , bioch em ica l a n a lyses ca n be obt a in ed by
t est in g u r in e wit h a u r in e d ip s t ic k . Color ch a n ges
in dica t e t h e a bsen ce or pr esen ce (in clu din g a gr oss
est im a t e of qu a n t it y) of su bst a n ces in u r in e. Th ese
su bst a n ces pr ovide in for m a t ion su ch a s:
● pH
● Specific gr a vit y
● P r ot ein
● Glu cose
● Ket on es
● Nit r it e
● Leu kocyt e est er a se
Micr oscopic a n a lysis is per for m ed by u sin g a specia lly
pr epa r ed u r in e sa m ple. A sm a ll sa m ple (10 t o 15 m L)
of u r in e is cen t r ifu ged for a ppr oxim a t ely 10 m in u t es
u n t il t h e sedim en t for m s a t t h e bot t om of t h e t est
t u be. All bu t a sm a ll a m ou n t of flu id is r em oved a n d
t h e sedim en t is r esu spen ded in t h e r em a in in g flu id.
A sa m ple is pla ced on t o a gla ss slide wit h a cover s-
lip for viewin g u n der t h e m icr oscope. Low-power ex-
a m in a t ion ca n det ect t h e pr esen ce of cr yst a ls, ca st s,
squ a m ou s cells, a n d ot h er la r ge com pon en t s. H igh -
power exa m in a t ion ca n det ect cr yst a ls, cells (wh it e
blood cells [WBCs] a n d r ed blood cells [RBCs]), a n d
ba ct er ia .
Ur in e sh ou ld be fr ee
of pr ot ein , glu cose, ke-
t on es, n it r it e, ba ct er ia ,
leu kocyt e est er a se, cr ys- F R O M T H E L AB
t a ls, a n d st on es. C a s t s , The number of specific sediment components seen under microscopic examination can be
st r u ct u r es con sist in g of quantified. The degree of magnification is also indicated and is determined with low-power
a pr ot ein m esh wor k of field (LPF) or high-power field (HPF). Several fields, or areas, are counted and then averaged
en t r a pped cells for m ed to provide an accurate estimate.
in t h e dist a l collect in g
t u bu les a n d collect in g
du ct s, a r e a lso a bsen t
in n or m a l u r in e. E pit h elia l cells m a y be pr esen t in
sm a ll n u m ber s, bu t in cr ea sed a m ou n t s det ect ed in
u r in e m a y in dica t e pa t h ology. Iden t ifica t ion of t h ese
a bn or m a l fin din gs pr ovides eviden ce of clin ica l
disea se.
ALTERED URINARY ELIMINATION
E lim in a t ion in volves a com plex in t er pla y bet ween
n eu r a l, va scu la r, m u scu la r, a n d h or m on a l in flu en ces.
Addit ion a lly, t h e st r u ct u r es in volved in t h e m ove-
m en t of u r in e fr om it s pr odu ct ion t o it s exit m u st be
pa t en t a n d fu n ct ion a l.
Alt e r e d U r in a r y E lim in a t io n 465
Processes of Altered Urinary
Elimination
Alt er a t ion in m ot ilit y, n eu r om u scu la r fu n ct ion , va s-
cu la r in su fficien cy, a n d obst r u ct ion a r e m ost com -
m on ly a ssocia t ed wit h a lt er ed u r in a r y elim in a t ion .
Th e followin g r eview of et iology a n d im plica t ion s of
a lt er ed m ot ilit y, n eu r om u scu la r fu n ct ion , per fu sion ,
a n d pa t en cy in t h e u r in a r y syst em pr ovides t h e es-
sen t ia l con t en t for con cept a pplica t ion in Modu le 3,
Clin ica l Models.
ALTERATION IN URINARY MOTILITY
Alt er a t ion in m ot ilit y ca n pr om ot e st a sis of filt r a t e
in t h e r en a l t u bu les a s well a s st a sis of u r in e in t h e
bla dder. Ca st s m a y for m beca u se of low flow r a t e, in -
cr ea sed sodiu m con cen t r a t ion , a n d low pH , a ll fa ct or s
fa vor in g pr ecipit a t ion . P r ecipit a t ion of u r in a r y flu id
com pon en t s m a y con t r ibu t e t o blocka ge of essen t ia l
r en a l st r u ct u r es. Th e specific t ype of cell t r a pped in
t h e ca st m esh wor k m a y pr ovide in for m a t ion on t h e
sit e of pa t h ology. Tr a ppin g of RBCs wit h in ca st s m a y
in dica t e glom er u lon eph r it is. E pit h elia l cells m a y
in dica t e slou gh in g of t u bu la r cells (a c u t e t u b u la r
n e c r o s is ) (F ig. 18.4), wh er ea s WBCs m a y in dica t e
pyelon eph r it is (Fig. 18.5). St a sis of u r in e in t h e bla d-
der m a y pr om ot e gr owt h of ba ct er ia , lea din g t o loca l
a n d a scen din g in fect ion in t h e kidn eys.
ALTERATION IN URINARY NEUROMUSCULAR
FUNCTION
Alt er a t ion in n eu r om u scu la r fu n ct ion in u r in a r y
elim in a t ion m a y r esu lt in u r in a r y r et en t ion or in -
con t in en ce. Im pa ir ed n eu r a l con t r ol of u r in a r y elim -
in a t ion m a y in volve t h e n eu r on s of t h e per iph er a l
a n d cen t r a l n er vou s syst em s, n eu r ot r a n sm it t er pr o-
du ct ion a n d a va ila bilit y or coor din a t ion of n eu r a l
im pu lses fr om in it ia t ion t o a ct ion . Fr om gen er a t ion
of a n a ct ion pot en t ia l t o t r a n sdu ct ion of t h e n er ve
im pu lse (see Ch a pt er 10), fa ilu r e t o pr ovide a n a p-
pr opr ia t e st im u lu s for t h e desir ed r espon se will r e-
su lt in a lim it ed or a bsen t a bilit y t o elim in a t e u r in e.
E xa gger a t ed r espon ses m a y pr om pt st im u la t ion t o
466 C h a p t e r 18: Alt er ed E lim in a t ion

Dis ta l Bowma n's P roxima l per ist a lsis in t h e r en a l t u bu les, con t r a ct ion or r ela x-
convolute d convolute d
tubule
ca ps ule
tubule
a t ion of sm oot h a n d skelet a l m u scles. Con sciou s con -
t r ol of t h e cir cu m st a n ces in volvin g t im in g of u r in a r y
Colle cting
elim in a t ion m a y be im pa ir ed a s a con sequ en ce of
duct a lt er ed m obilit y a n d t h e r esu lt in g r edu ct ion in t oi-
let in g in depen den ce.

ALTERATION IN URINARY PERFUSION

In a dequ a t e a r t er ia l blood su pply r esu lt s in isch em ia
Ne cros is a n d in fa r ct ion . Decr ea sed oxygen deliver y by t h e a r-
t er ia l blood su pply m a y r esu lt in da m a ge t o r en a l
Ca s ts a nd st r u ct u r es beca u se of in a bilit y t o m eet m et a bolic
ce llula r
de bris dem a n ds. Decr ea sed per fu sion lea din g t o im pa ir ed
oxygen a t ion of t issu e m a y be du e t o excessive con -
st r ict ion of a r t er ioles, in a dequ a t e va scu la r volu m e,
or obst r u ct ed pa t en cy of t h e a r t er ia l su pply, a s occu r s
wit h a n em bolism . Loss of fu n ct ion a l t issu e t h r ou gh
n ecr osis lea ds t o pa in , bleedin g, a n d obst r u ct ion of
t h e br a n ch es of t h e ven ou s syst em , dr a in in g t h e a f-
Loop of He nle fect ed t issu e. Con ver sely, en h a n ced per fu sion r ep-
r esen t s a ddit ion a l wor kloa d a n d h a s t h e pot en t ia l
Figure 18.4. Acute tubular necrosis. Casts and cellular de- t o st r ess t h e in dividu a l or ga n syst em . Th e gen er a l
bris are sloughed into the tubular lumen in both ischemic con sequ en ces of im pa ir ed per fu sion a r e det a iled in
necrosis and nephrotoxic injury. Ch a pt er 2 a n d Ch a pt er 16.

P rogre s s ive s ca rring 3. End phas e

ALTERATION IN URINARY PATENCY
Atrophie d Blocka ge of st r u ct u r es in volved in t h e pa ssa ge of
Na rrowe d pa re nchyma
u r in e m a y r esu lt in obst r u ct ion .
ca lyx ne ck
Th e con sequ en ces of obst r u ct ion a r e in flu en ced
by t h e:
2. Pro g re s s ive phas e
● Degr ee of t h e obst r u ct ion (com plet e or pa r t ia l)
Foca l
● Du r a t ion of t h e obst r u ct ion
pa re nchyma l ● Acu it y or ch r on icit y of t h e con dit ion
s ca rring
Obst r u ct ion s a r e ch a r a ct er ized by a bu ildu p of
pr essu r e beh in d t h e blocka ge. P r olon ged or sever e
pr essu r e r esu lt s in st r u ct u r a l da m a ge a n d im pa ir ed
fu n ct ion . Isch em ia a n d n ecr osis m a y r esu lt , a ddin g
t o t h e con sequ en ces of per fu sion im pa ir m en t , be-
ca u se of m ech a n ica l obst r u ct ion of t h e a r t er ia l or
ven ou s syst em . Blocka ge m a y be ca u sed by pr ecip-
it a t ion of su bst a n ces in sm a ller lu m en st r u ct u r es,
or st r u ct u r a l blocka ge r esu lt in g fr om en dogen ou s
or exogen ou s sou r ces su ch a s polyps or t u m or s.
Mech a n ica l obst r u ct ion s m a y r esu lt fr om u r in e
1. Early phas e pr ecipit a t ion , sca r t issu e or a dh esion s, t u m or, or
(e de ma tous )
in fla m m a t ion .
Figure 18.5. Phases of damage in pyelonephritis. Ur in e flow is im peded in t h e obst r u ct ion of t h e
r en a l a n d u r in a r y syst em s (Ta ble 18.2). Dila t ion of
t h e st r u ct u r es pr oxim a l t o t h e obst r u ct ion ca u ses di-
pr em a t u r ely r elea se u r in e. Addit ion a lly, m u scles la t ion a n d st a sis, lea din g t o in fect ion a n d st r u ct u r a l
m u st h a ve t h e a bilit y t o r espon d t o a gen er a t ed da m a ge. H y d r o u r e t e r , a ccu m u la t ion of flu id in t h e
n er ve im pu lse t o a ch ieve t h e in t en ded effect . Mu s- u r in a r y u r et er, is a con sequ en ce of com plet e u r et -
cle fu n ct ion in volved in u r in a r y elim in a t ion in clu des er a l obst r u ct ion (Fig. 18.6). In cr ea sed h ydr ost a t ic
 Alt e r e d U r in a r y E lim in a t io n 467

Ta b le 18.2 Types of Obst r u ct ive Disea se

Typ e o C lin ic a l La b or a t or y S e q u e la e I
O b s t r u c t io n P a t h o lo g y Ma n i e s t a t io n s F in d in g s Le t Un tr ea t ed
Ur in a r y St a sis of u r in e beh in d Pa in Ba ct er u r ia H ydr on eph r osis
t h e obst r u ct ion of r en a l P r essu r e H em a t u r ia Ren a l fa ilu r e
st r u ct u r es, u r et er s, or
u r et h r a F r equ en cy of u r in a t ion In fect ion
Oligu r ia H yper t en sion
In t est in e Collect ion of ga s Abdom in a l dist en t ion H em a t ocr it Deh ydr a t ion
a n d flu id beh in d t h e Abdom in a l pa in , n a u sea , (h em ocon cen t r a t ion ) H ypovolem ia
obst r u ct ion vom it in g Ket osis, a cidosis
Sh ock
Dia ph r a gm a t ic pr essu r e, H ypoka lem ia ,
h ypoch lor em ia P n eu m on ia
r espir a t or y volu m e
Per it on it is
E dem a ca u sed by
ca pilla r y per m ea bilit y
Fever ca u sed by r elea se of
t oxin s

pr essu r e ext en ds u p t o t h e r en a l pelvis a n d t u bu les,

Cross section of kidney lea din g t o h ydr on eph r osis. Th e glom er u la r filt r a -
Dilated calyces t ion r a t e (GF R) decr ea ses, r eflect in g im pa ir m en t of
Atrophied parenchyma r en a l fu n ct ion . F lu id esca pes fr om t h e t u bu les in t o
and tubules
t h e su r r ou n din g ca pilla r y syst em . E xcr et ion of so-
Atrophied papilla
diu m , u r ea , a n d wa t er is im pa ir ed. Loca l h or m on a l
Dilated pelvis r espon ses t o pr om ot e r en a l per fu sion a r e effect ive
for a sh or t t im e. Im pa ir ed per fu sion develops wit h in
24 h ou r s, lea din g t o isch em ia , t u bu la r a t r oph y, a n d
da m a ged glom er u li if t h e con dit ion is n ot cor r ect ed.
Hydronephrotic kidney Sequ ela e in clu de in fect ion , sepsis, a n d loss of r en a l
fu n ct ion lea din g t o r en a l fa ilu r e.

General Manifestations of Altered

Urinary Elimination
Im pa ir m en t of t h e pr ocesses in volved in u r in a r y
elim in a t ion r esu lt in a va r iet y of clin ica l m a n ifes-
t a t ion s. Specific m a n ifest a t ion s a r e r ela t ed t o t h e
Ureter
u n der lyin g pa t h ology. Gen er a lly, m a n ifest a t ion s
in clu de:

Kinking and dilation of ● Alt er ed volu m e of excr et ion

ureter (hydroureter) ● Alt er ed excr et ion ch a r a ct er ist ics
● Bleedin g
● Pa in
● Dist en t ion
Persistent impacted stone
● An or exia
Bladder ● Na u sea
Urethral opening ● Vom it in g
● Fever
Figure 18.6. Hydronephrosis. Obstruction of the ureter Ur in a r y volu m e m a y be in cr ea sed or decr ea sed. In t h e
causes pressure to build, resulting in hydroureter and ca se of obst r u ct ion or da m a ge t o t h e r en a l st r u ct u r es
hydronephrosis. (Courtesy Anatomical Chart Company.) t h em selves, oligu r ia (sca n t y u r in e pr odu ct ion ) or
468 C h a p t e r 18: Alt er ed E lim in a t ion

Ta b le 18.3 Pa t h ologic In dica t ion s of Alt er ed Ur in a r y E lim in a t ion

C o n d it io n D e s c r ip t io n o C o n d it io n L a b o r a t o r y C o n ir m a t io n P o s s ib le E t io lo g ie s
P r ot ein u r ia P r ot ein in u r in e 150 m g/24-h ou r sa m ple Ren a l fa ilu r e
Neph r ot ic syn dr om e P r eecla m psia
Ren a l a r t er y/vein t h r om bosis
Glom er u la r disea se
Tu bu lopa t h y
Glu cosu r ia Glu cose in u r in e > 130 m g/24-h ou r sa m ple Dia bet es m ellit u s
Ket on u r ia Ket on es in u r in e (a cet on e, Acet on e 20 m g/dl (sm a ll); Dia bet es m ellit u s
a cet oa cet ic a cid, bet a - 30–40 m g/dl (m oder a t e); Ket oa cidosis
h ydr oxybu t yr ic a cid) > 80 m g/dl (la r ge)
St a r va t ion
H em a t u r ia Red blood cells in u r in e > 1 RBC/H P F Glom er u la r da m a ge
Tu m or s
Kidn ey t r a u m a
Ur in a r y t r a ct in fect ion
Acu t e t u bu la r n ecr osis
Ur in a r y t r a ct obst r u ct ion
P yu r ia Wh it e blood cells in u r in e 2 WBC/H P F Upper a n d lower u r in a r y t r a ct
+ leu kocyt e est er a se in fect ion
> 100,000 CF U Acu t e glom er u lon eph r it is
Ren a l ca lcu li
Ba ct er u r ia Ba ct er ia in u r in e + n it r it es Upper a n d lower u r in a r y t r a ct
in fect ion
CF U, colon y-for m in g u n it ; H P F, h igh -power field; RBC, r ed blood cell; WBC, wh it e blood cell.

a n u r ia (a bsen t u r in e pr odu ct ion ) m ay be seen . Ot h er Ch a pt er 5 t o illu st r a t e t h e t ypica l pa t h ology, clin ica l

con dit ion s m a y be a ssocia t ed wit h in cr ea sed u r in e
ou t pu t a n d a r e oft en t h e r esu lt of h or m on a l st im u -
la t ion of a com pen sa t or y r espon se or r egu la t ion of
flu id ba la n ce. Ur in e com posit ion m ay a lso be a lt er ed,
r eflect in g t h e or igin of t h e pa t h ology. An a n a lysis of
u r in e a ssocia t ed wit h kidn ey disor der s is det a iled in
Ta ble 18.3. H em a t u r ia , eviden ced by fr a n k bleedin g
or clot s, ca n be iden t ified ba sed on u r in e color. Sm a ll
a m ou n t s of blood r equ ir e m icr oscopic det ect ion .
Pa in is a fr equ en t sym pt om a ssocia t ed wit h a l-
t er ed r en a l a n d u r in a r y fu n ct ion . Ren a l a n d u r et er a l
n ocicept or s t r a n sm it pa in im pu lses t o t h e spin a l cor d
bet ween T10 a n d L1. Th e a ssocia t ed der m a t om es in -
clu de t h e lower a bdom en a n t er ior ly a n d post er ior ly
a t t h e level of t h e c o s t o v e r t e b r a l a n g le (C VA) or
fla n k a r ea . Most n ocicept ive r ecept or s a r e loca t ed
in t h e r en a l ca psu le r a t h er t h a n in t h e kidn ey it -
self a n d a r e st im u la t ed by st r et ch in g a n d in fla m m a -
t ion . St r et ch in g in du ced by dist en t ion pr odu ces t h e
sen sa t ion of du ll, per sist en t pa in . In con t r a st , m a n y
pa in r ecept or s a r e loca t ed in t h e r em a in in g pa r t s of
t h e descen din g u r in a r y syst em . Th e pa in sen sa t ion s
fr om t h is r egion a r e u su a lly in t er m it t en t a n d sh a r p.
Ma n ifest a t ion s of in fect ion pr om ot e feelin gs of
gen er a l m a la ise, a n or exia , a n d fever. In fect ion in t h e
lower u r in a r y t r a ct is pr esen t ed a s a clin ica l m odel in
m a n ifest a t ion s, dia gn osis, a n d t r ea t m en t of t h is con -
dit ion . Ascen din g in fect ion of t h e pa t h ogen t h r ou gh
t h e u r et er s in t o t h e kidn eys r epr esen t s t h e pot en t ia l
for r en a l st r u ct u r a l da m a ge, sign ifica n t ly a ffect in g
t h e a bilit y t o pr odu ce u r in e. Na u sea a n d vom it in g
m a y occu r in a scen din g in fect ion or syst em ic illn ess,
su ch a s pyelon eph r it is.
Stop and Consider
What mechanisms of infection and inflammation
may contribute to damage to renal structures?
Diagnosis of Conditions of the Renal
and Urinary Systems
Dia gn osis of a lt er ed elim in a t ion pr ocesses is im por t -
a n t t o pr even t fu r t h er da m a ge t o in volved or ga n s.
Bot h t h e ca u se a n d effect of a lt er ed elim in a t ion a r e
cr it ica l t o t h e effect ive m a n a gem en t a n d t r ea t m en t
of in dividu a ls wit h t h ese con dit ion s. Micr oscopic a n d
m a cr oscopic u r in a lysis pr ovides a u sefu l r esou r ce
in t h e dia gn osis of con dit ion s r esu lt in g in a lt er ed
elim in a t ion . Nor m a l va lu es for u r in a r y elect r olyt es
a r e n ot st a n da r dized beca u se t h e kidn eys fu n ct ion

dyn a m ica lly t o m a in t a in elect r olyt e h om eost a sis
in t h e pla sm a . Ca lcu la t ion of GF R a n d cr ea t in in e
clea r a n ce in dica t es n eph r on fu n ct ion . Ra diogr a ph ic
dia gn ost ic t est in g u sefu l in t h e det er m in a t ion of a n -
a t om ic a n d fu n ct ion a l a n om a lies in clu des:
● In t r a ven ou s pyelogr a m (IVP ): In t r a ven ou s in jec-
t ion of a r a diocon t r a st m ediu m t o a llow r a dio-
gr a ph ic visu a liza t ion of t h e kidn eys, u r et er s, a n d
bla dder.
● Voidin g cyst ou r et h r ogr a m (VCUG): X-r a y exa m -
in a t ion of t h e bla dder a n d u r et h r a com plet ed
a ft er in ser t ion of con t r a st in t o bla dder via a u r i-
n a r y ca t h et er. F lu or oscopy is u sed t o det er m in e
u r et er a l r eflu x a n d bla dder /u r et h r a con figu r a t ion
du r in g voidin g.
● Ren a l a n giogr a m : Con t r a st in ject ed in t o t h e r en a l
a r t er y via t h e a or t a t o dia gn ose r en a l a r t er y st e-
n osis or in t r a r en a l va scu la r obst r u ct ion s.
● Ren a l u lt r a sou n d: Non in va sive im a ge pr odu ced
by sou n d wa ves. Usefu l in t h e det er m in a t ion of
Modu le 2 Alt e r a t io n in S t o o l E lim in a t io n
Processes of Stool Elimination
Th e pr ocess of st ool elim in a t ion in volves t h e or ga n s
of t h e GI syst em . F r om or a l n u t r ien t in t a ke t o t h e
elim in a t ion of wa st e by t h e pa ssa ge of st ool, ex-
ch a n ge a n d pr ocessin g of t h e pr odu ct s is com plex.
Th is ch a pt er will descr ibe t h e fin a l pr ocesses of st ool
pr odu ct ion a n d elim in a t ion by t h e la r ge in t est in e
wh ich occu r a ft er n u t r ien t ext r a ct ion det a iled in
Ch a pt er 17.
Th e la r ge in t est in e is a h ollow or ga n su r r ou n d-
in g t h e sm a ll in t est in e in t h e a bdom in a l ca vit y. Th e
la r g e in t e s t in e /c o lo n is com pr ised of t h e cecu m ,
a ppen dix, colon , r ect u m , a n d a n a l ca n a l. Th e colon
ca n be divided fu r t h er in t o t h e a scen din g, t r a n sver se,
descen din g, a n d sigm oid por t ion s. Th e ileoceca l va lve
dir ect s t h e flow of feca l m a t t er fr om t h e ileu m of t h e
sm a ll in t est in e t o t h e cecu m of t h e la r ge in t est in e.
Com pr ised of t h e cecu m , colon (a scen din g, t r a n s-
ver se, descen din g, sigm oid) a n d r ect a l segm en t s, t h e
la r ge in t est in e begin s a t t h e en d of t h e ileu m of t h e
sm a ll in t est in e a n d t er m in a t es a t t h e a n u s. Th e a p-
pen dix is a lon g, n a r r ow blin d pou ch pr oject in g fr om
t h e cecu m . Mea su r in g a ppr oxim a t ely 1.5 m , t h e di-
a m et er of t h e la r ge in t est in e r edu ces a s it pr ogr esses
t owa r d t h e r ect u m . At t h e r ect u m , t h e colon dila t es
lea din g t o in cr ea sed ca pa cit y for st ool. Th e su per ior
a n d in fer ior m esen t er ic a r t er ies a r e t h e or igin for
blood su pply t o t h e la r ge in t est in e. Th e a u t on om ic
Alt e r a t io n in S t o o l E lim in a t io n 469
kidn ey size, h ydr ou r et er, cyst s, obst r u ct ion s, or
flu id collect ion . Ren a l a r t er y flow ca n a lso be de-
t er m in ed wit h Doppler u lt r a sou n d.
Treatment of Altered Urinary
Elimination
Tr ea t m en t of con dit ion s con t r ibu t in g t o a lt er ed
u r in a r y elim in a t ion is det er m in ed by t h e con dit ion
u n der lyin g t h e clin ica l m a n ifest a t ion s. A t h or ou gh
r eview of m edica l h ist or y, descr ipt ion of sym pt om s,
ph ysica l exa m in a t ion , a n d dia gn ost ic t est in g m a y be
n ecessa r y t o specify t r ea t m en t . Alt er ed u r in a r y elim -
in a t ion is oft en a ssocia t ed wit h im pa ir ed r egu la t ion
of flu id ba la n ce. Con t r ol of flu id ba la n ce t h r ou gh a d-
m in ist r a t ion of su pplem en t a l flu ids t o cor r ect body
flu id deficit or t h e u se of diu r et ics t o cor r ect body
flu id excess m a y be in dica t ed.
n er vou s syst em pr ovides t h e pr im a r y n eu r a l con t r ol
of t h e GI t r a ct (F ig. 18.7).
STOOL ELIMINATION PROCESS
Food in gest ion begin s t h e digest ive pr ocesses a n d
r esu lt s in t h e excr et ion of st ool. Bowel m ot ilit y, per-
fu sion , pa t en cy, a n d r espon se t o n eu r a l sign a ls a r e
cr it ica l t o st ool elim in a t ion .
Stool Production
St ool is a pr odu ct of digest ion , a s det a iled in
Ch a pt er 17. As digest ive pr ocesses con t in u e t h r ou gh -
ou t t h e len gt h of la r ge in t est in e, feca l m a t t er en t er-
in g a t t h e cecu m via t h e ileoceca l va lve is pr opelled
t owa r d t h e r ect u m for excr et ion . Wa t er a n d elect r o-
lyt es a r e r em oved fr om t h e feca l m a t t er a s it m oves
t h r ou gh t h e la r ge in t est in e. Con t in u ed pr ocessin g of
feca l m a t t er a s it exit s t h e la r ge in t est in e r esu lt s in
t h e fin a l pr odu ct , st ool.
La r ge in t est in e fu n ct ion a l r espon ses a r e r ela t ed
t o t h e r a t e of m ovem en t of con t en t s, wit h m or e r a pid
m ovem en t a llowin g less t im e for in t est in a l pr ocesses
a n d slower m ovem en t lea din g t o ext en ded t im e.
Wh ile t h e gr ea t est a bsor pt ion of n u t r ien t s occu r s in
t h e sm a ll in t est in e, t h e la r ge in t est in e pr ovides t h e
fin a l oppor t u n it y for a ch ievem en t of wa t er a n d elec-
t r olyt e ba la n ce. Of t h e 7 t o 10 L of wa t er en t er in g
t h e sm a ll in t est in e, on ly 1 t o 1.5 L en t er s t h e la r ge
470 C h a p t e r 18: Alt er ed E lim in a t ion

Va gus ne rve (X)

Gre a te r
s pla nchnic
ne rve
Le s s e r
s pla nchnic
T1 Tra ns ve rs e
ne rve
T2 colon
T3 As ce nding
colon
T4
T5 Ce lia c
T6 ga nglion
T7
T8 De s ce nding
T9 colon
T10
T11 Ce cum
T12
L1 Appe ndix
L2 S igmoid
colon
Le a s t S upe rior
s pla nchnic me s e nte ric
ne rve ga nglion Re ctum
Infe rior
me s e nte ric
S2 ga nglion

S3
S4
Pe lvic ne rve

Cha in of pa rave rte bra l Pa ra s ympa the tic inne rva tion
s ympa the ic ga nglion S ympa the tic inne rva tion

Figure 18.7. Gastrointestinal structures and innervation. Large colon structures and their sources of innervation are
labeled. (Modified from Porth CM. Pathophysiology: Concepts of Altered Health States. 7th ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 2004.)

in t est in e on a da ily ba sis. Th e fin a l pr odu ct of t h e
la r ge in t est in e, st ool, in clu des a ppr oxim a t ely 100 t o
200 m L of wa t er. Absor pt ion of wa t er a n d elect r o-
lyt es occu r s in a n d a r ou n d t h e epit h elia l cells t h a t
lin e t h e la r ge in t est in e. Th e sm a ll in t est in e ch ym e
is a lt er ed fr om a liqu id t o a sem isolid for m in t h e
a scen din g a n d t r a n sver se la r ge in t est in e segm en t s.
Th e in t est in a l con t en t s r et a in in digest ible ca r boh y-
dr a t es, in clu din g diet a r y fiber, a s well a s r em a in in g
sodiu m , m a gn esiu m , a n d ch lor ide. Th e t im e fr om
diet a r y in t a ke t h r ou gh elim in a t ion of r em a in in g in -
t est in a l con t en t s va r ies fr om 2 t o 5 da ys, on a ver a ge.
As t h e feca l m a t t er pr ogr esses t h r ou gh t h e la r ge
in t est in e, t h e m a jor it y of wa t er is r ea bsor bed a lon g
wit h sever a l B com plex vit a m in s a n d vit a m in K,
m u ch of wh ich is pr odu ced by in t est in a l ba ct er ia .
Th e r em a in in g feca l m a t t er com bin es wit h in t est in a l
m u cou s a n d r esiden t ba ct er ia , kn own a s in t e s t in a l
lo r a , a n d becom es feces. Th e gr ea t est con cen t r a t ion
of GI ba ct er ia r esides in t h e la r ge colon . Th e com plex
ba ct er ia l flor a con t a in s pr im a r ily a n a er obic or ga n -
ism s, t h ou gh com posit ion a m on g a du lt s is va r ia ble
a n d in la r ge pa r t depen den t on diet . Th e food a n
in dividu a l ea t s pr ovides sou r ces of en er gy a n d ca r-
bon for in t est in a l ba ct er ia , dir ect in g t h e per sist en ce
of pa r t icu la r t ypes of ba ct er ia . In t est in a l ba ct er ia
br ea k down som e r em a in in g diet a r y fiber, r elea sin g
bypr odu ct s in clu din g sh or t ch a in fa t t y a cids u sed by
t h e epit h elia l cells of t h e colon . Residen t in t est in a l
flor a pr ot ect t h e in t est in e fr om h a r m fu l pa t h ogen s
t h r ou gh t h e m a in t en a n ce of a loca l h om eost a t ic
ba la n ce.

Stool Evacuation
St ool is st or ed in t h e la r ge in t est in e u n t il t h e t im e of
eva cu a t ion (d e e c a t io n ). It is est im a t ed t o t a ke 18
h ou r s for t h e con t en t s of t h e in t est in e t o pa ss fr om
t h e pr oxim a l en d of t h e la r ge in t est in e t o t h e dist a l
en d. Th e con t in u ou s in n er la yer of cir cu la r sm oot h
m u scle of t h e m u scu la r is ext er n a is su r r ou n ded
by a n ou t er, discon t in u ou s la yer of lon git u din a l
sm oot h m u scle. Con t r a ct ion of sm oot h m u scle occu r s
t h r ou gh t h e slidin g fila m en t m ech a n ism . Alon g t h e
len gt h of t h e la r ge in t est in e, t h e lon git u din a l m u s-
cle for m s t h r ee dist in ct ba n ds kn own a s t e n ia e c o li.
Wh en con t r a ct ed, h a u s t r a s (pou ch es) a r e cr ea t ed.
Sm oot h m u scle con t r a ct ion of t h e lon git u din a l a n d
cir cu la r m u scle la yer s of t h e la r ge in t est in e pr o-
vides t h e pr im a r y m ech a n ism for t h e m ovem en t of
st ool, gen er a t in g pr opu lsive m ovem en t s. Th e close-
n ess of sm oot h m u scle fiber s t o ea ch ot h er m a kes
it ea sier for a ct ion pot en t ia ls t o be t r a n sm it t ed t o
a dja cen t fiber s, pr opa ga t in g t h e n er ve im pu lse a lon g
t h e len gt h of t h e la r ge in t est in e. Th e r esu lt is p e r i-
s t a ls is ca u sed by squ eezin g of cir cu la r fiber s, wh ich
pr om ot es a for wa r d m ovem en t of in t est in e con t en t s.
Cir cu la r fiber con t r a ct ion a n d r ela xa t ion occu r s a t
differ en t loca t ion s, pr odu cin g t h e ch a r a ct er ist ic s e g -
m e n t a l m o v e m e n t of t h e la r ge in t est in e. Ma s s
m o v e m e n t s , or st r on g per ist a lt ic m ovem en t s, occu r
t h r ee t o fou r t im es a da y, pr om ot in g t h e pr opu lsion
of st ool.
Stop and Consider
Reduced peristalsis would slow the movement of
stool through the large intestine. How might this
affect water concentration in the stool?
Mu scle fiber s a r e in n er va t ed loca lly by t h e in -
t r in sic e n t e r ic n e r v o u s s y s t e m , in clu din g t h e
m y e n t e r ic (Au e r b a c h ) p le x u s fou n d bet ween
t h e lon git u din a l a n d cir cu la r m u scle la yer s a n d
t h e Me is s n e r p le x u s , loca t ed in t h e su bm u cosa .
Myen t er ic im pu lses pr om ot e con t r ol of GI m ove-
m en t , wh ile t h e Meissn er plexu s t r a n sm it s sen sor y
im pu lses t h r ou gh st r et ch r ecept or s. Bot h syst em s
a r e in volved in t h e r eflexes n ecessa r y for st ool
m ovem en t a n d eva lu a t ion . Myen t er ic plexu s st im u -
la t ion pr ovides in cr ea sed t on ic con t r a ct ion s a s well
a s in cr ea sed in t en sit y, r a t e, a n d velocit y of r h yt h m ic
con t r a ct ion s. It is in du ced via colon dist en t ion . Th e
en t er ic n er vou s syst em is m odu la t ed by t h e a u t o-
n om ic n er vou s syst em . Sym pa t h et ic st im u la t ion via
t h e sa cr a l n er ves of t h e spin a l cor d h a s a n in h ibit or y
effect , wh er ea s pa r a sym pa t h et ic st im u la t ion ser ves
a n excit a t or y fu n ct ion via t h e va gu s n er ve.
Two sph in ct er s a r e in volved in t h e pr ocess of def-
eca t ion . Th e in t e r n a l r e c t a l s p h in c t e r is m a de u p
of a t h ick la yer of sm oot h m u scle a n d is t on ica lly
Alt e r a t io n in S t o o l E lim in a t io n 471
Co rtex
S a cra l
De fe ca tion
s pina l cord
Affe re nt
impuls e
No? Ye s ?
Dis te nde d
re ctum Effe re nt Effe re nt
impuls e impuls e
inhibition s timula tion
Ana l Ana l
s phincte r s phincte r
cons triction re la xa tion
Figure 18.8. Voluntary control of defecation. Conscious
intent provides voluntary control of defecation.
con st r ict ed beca u se of sym pa t h et ic con t r ol. Move-
m en t of st ool in t o t h e r ect u m st im u la t es t h e r eflex
t o defeca t e, a lso kn own a s t h e r e c t a l r e le x . Pa r a -
sym pa t h et ic st im u la t ion pr om pt s r ela xa t ion of t h e
in t er n a l a n a l sph in ct er. Th e skelet a l m u scle of t h e
e x t e r n a l a n a l s p h in c t e r su r r ou n ds t h e in t er n a l
r ect a l sph in ct er a n d is in n er va t ed by t h e pu den da l
n er ve (som a t ic n er vou s syst em ), pr ovidin g volu n -
t a r y con t r ol. Th e ext er n a l sph in ct er ca n over r ide t h e
defeca t ion r eflex, a llowin g for volu n t a r y con t r ol of
defeca t ion (Fig. 18.8). St r a in in g t h r ou gh Va ls a lv a
m a n e u v e r s , t h e gen er a t ion of in t r a -a bdom in a l pr es-
su r e t h r ou gh in h a la t ion t h a t for ces t h e dia ph r a gm
a n d ch est m u scles a ga in st t h e glot t is, st im u la t es
t h e va gu s n er ve a n d a ssist s in st ool eva cu a t ion . A
su m m a r y of t h e st eps in volved in t h e r ect a l r eflex is
h igh ligh t ed in Box 18.2.
Stool Characteristics
On e of t h e m a in fu n ct ion s of t h e la r ge in t est in e is
com pa ct ion of feces. As wa t er is a bsor bed a s t h e feca l
m a t t er m oves a lon g t h e len gt h of t h e la r ge in t est in e,
t h e solid m a t t er in t h e feces becom es m or e com pa ct .
Appr oxim a t ely 400 t o 800 m L of wa t er, a lon g wit h so-
diu m , ch lor ide, a n d bica r bon a t e, a r e a bsor bed ou t of
t h e la r ge in t est in e a n d a ppr oxim a t ely 5 m E q pot a s-
siu m is secr et ed in t o t h e lu m en of t h e la r ge in t est in e
da ily. Con st it u en t s of st ool in clu de a ppr oxim a t ely
100 m L of wa t er a n d 25 t o 50 g of solids con sist in g
472 C h a p t e r 18: Alt er ed E lim in a t ion
Box 18.2 R e c t a l R e le x
Dist en t ion or ir r it a t ion of t h e r ect a l wa ll st im u la t es t h e
r ect a l r eflex. Th e st eps in volved in t h e r ect a l r eflex a r e
pr im a r ily in volu n t a r y, bu t t h ey m a y be m odu la t ed by
volu n t a r y con t r ol su ppr ession . If su ppr essed, t h e r eflex
is su bsequ en t ly st im u la t ed wh en r ect a l m a ss in cr ea ses.
Th e r ect a l r eflex in volves five m a jor st eps:
1. St im u la t ion of st r et ch r ecept or s in t h e r ect a l wa ll t r a n s-
m it s sen sor y im pu lse t o t h e sa cr a l spin a l cor d.
2. Sen sor y n eu r on s syn a pse on pa r a sym pa t h et ic n er ves,
pr om ot in g r ela xa t ion of t h e in t er n a l a n a l sph in ct er
(sm oot h m u scle).
3. In t er n eu r on st im u la t ion pr om ot es con t r a ct ion of
a bdom in a l m u scles.
4. Mot or sign a l fr om t h e cer ebr a l cor t ex st im u la t es open -
in g of t h e ext er n a l a n a l sph in ct er (skelet a l m u scle).
5. Defeca t ion a ssist ed by volu n t a r y con t r a ct ion s of t h e
a bdom in a l m u scles.
of r em a in in g u n a bsor bed n u t r ien t s, slou gh ed epit h e-
lia l cells, bile pigm en t s, ba ct er ia (30%), fa t (10% t o
20%), u n digest ed diet a r y fiber (30%), a n d in or ga n ic
solids (20%). Wa t er com pr ises a ppr oxim a t ely 75% of
st ool con t en t .
Nor m a l a du lt st ool a ppea r s fir m a n d m oist . Th e
ch a r a ct er ist ic br own color is der ived fr om t h e bilir u -
bin pigm en t in bile, s t e r c o b ilin . Ch em ica l r ea ct ion s
r esu lt in g in t h e br ea kdown of feca l com pon en t s
du r in g digest ion pr odu ce com pou n ds, in clu din g h y-
dr ogen su lfide, t h a t pr ovide t h e ch a r a ct er ist ic odor
of feces. Upon defeca t ion , st ool is soft , m oist a n d
sem isolid. For m ed in t h e sh a pe of t h e r ect u m , st ool
a ver a ges a ppr oxim a t ely 1 in ch in dia m et er a n d
sh ou ld be ea sy t o pa ss. Th e a m ou n t a n d fr equ en cy of
defeca t ion is va r ia ble a m on g in dividu a ls, t h ou gh t h e
a ver a ge for a du lt s is 200 t o 300 g st ool on ce per da y.
Th e ch a r a ct er ist ics of st ools in n ewbor n s a n d
in fa n t s a r e qu it e differ en t fr om t h ose of a du lt s.
Ma n y of t h ese differ en ces ca n be expla in ed by t h e
m a jor sou r ces of or a l in t a ke du r in g developm en t .
In u t er o, t h e fet u s swa llows a m n iot ic flu id, wh ich
pa sses t h r ou gh t h e GI syst em . Per ist a lsis a n d st ool
pr odu ct ion a r e t ypica l fin din gs in t h e developin g fe-
t u s. Nor m a lly, t h e fet u s does n ot pa ss st ool in u t er o
bu t is expect ed t o pa ss t h e fir st st ool in t h e ea r ly
n ewbor n per iod a ft er bir t h . Th is fir st st ool, m e c o -
n iu m , r epr esen t s t h e digest ion of a m n iot ic flu id
a n d is bla ck, st icky, a n d odor less. On ce feedin gs a r e
begu n , t h e st ool t r a n sit ion s t o r eflect t h e n ewbor n ’s
m a in sou r ce of or a l in t a ke. Br ea st fed ba bies h a ve
st ool t h a t is soft , u n for m ed, a n d yellow. Th e odor is
m ild a n d u n ch a r a ct er ist ic of a n or m a l feca l scen t .
Ba bies fed a r t ificia l m ilk, or for m u la , h a ve ligh t
br own st ools. Fr equ en cy of bowel m ovem en t s is of-
t en in cr ea sed in br ea st fed ba bies du e t o t h e efficien t
digest ion of br ea st m ilk, com pa r ed t o t h e less fr e-
qu en t st oolin g pa t t er n s ch a r a ct er ist ic of for m u la -fed
ba bies. As t a ble foods a n d su pplem en t a l liqu ids a r e
in t r odu ced in la t e in fa n cy, st ool pa t t er n s a lt er t o r e-
flect t h e com posit ion of t h ese in gest ed foods.
Stool Analysis
St ool a n a lysis is ba sed u pon elim in a t ion pa t t er n s
a n d ch a r a ct er ist ics. La bor a t or y a n a lysis of st ool
m a y in clu de m icr oscopic exa m in a t ion or ch em ica l
eva lu a t ion . Color, con sist en cy, volu m e, sh a pe a n d
odor sh ou ld be con sist en t wit h ch a r a ct er ist ics de-
scr ibed pr eviou sly. St ool sh ou ld be fr ee of blood, m u -
cou s, pu s, a n d h a r m fu l pa r a sit es. St ool pH sh ou ld be
6 a n d it sh ou ld con t a in less t h a n 2 m g of r edu cin g
fa ct or s (i.e., su ga r s).
Altered Bowel Elimination
Im pa ir ed la r ge in t est in e fu n ct ion m a y a lt er t h e fin a l
st eps of r et r ieva l of wa t er a n d elect r olyt es fr om t h e
feca l m a t t er t h a t en t er s t h e cecu m fr om t h e sm a ll
in t est in e. Absor pt ion of vit a m in s pr odu ced by in t es-
t in a l ba ct er ia l flor a m a y a lso be a lt er ed if t h er e is
im pa ir ed fu n ct ion of t h e la r ge in t est in e. F u r t h er, t h e
socia l a n d per son a l con cer n s r ega r din g a lt er a t ion in
bowel elim in a t ion h a ve t h e pot en t ia l t o im pa ct qu a l-
it y of life.
St ool elim in a t ion is a pa r t of da ily life for m ost in -
dividu a ls. E ven t h ou gh st oolin g is a com m on a ct ivit y
for a ll, t h e pr ocess is im pa ct ed by per cept ion s of so-
cia l a ccept a bilit y. Th e socia l n or m s a n d r u les of st ool
elim in a t ion m ay r epr esen t a m a jor sou r ce of st r ess
in in dividu a ls. Ma n y people a r e con cer n ed a bou t
t h e pu blic per cept ion of st oolin g a n d t h e a ssocia t ed
odor t h a t a ccom pa n ies t h e pr ocess. Con cer n m ay be
so gr ea t t h a t t h ey m ay a t t em pt t o over r ide t h e n eed
t o pa ss st ool u n t il a pr iva t e oppor t u n it y is ava ila ble.
Som e in dividu a ls h ave gr ea t a n xiet y if t h ey a r e u n -
a ble t o t oilet in t h eir h om e, lea din g t o r est r ict ed t r avel
a n d a ct ivit ies ou t side of t h eir h om e en vir on m en t .
PROCESSES OF ALTERED BOWEL ELIMINATION
Th e for wa r d m ovem en t of t h e feca l m a t t er is essen -
t ia l, pr opellin g t h e in t est in a l con t en t s t owa r d t h e
a n u s, lea vin g t h e body a s st ool t h r ou gh t h e pr ocess
of defeca t ion . Im pa ir ed bowel elim in a t ion oft en r e-
su lt s fr om a lt er a t ion s in bowel m ot ilit y, n eu r om u s-
cu la r fu n ct ion , per fu sion , or pa t en cy.
Alteration in Bowel Motility
Mot ilit y of t h e la r ge in t est in e det er m in es t h e r a t e
a t wh ich feca l m a t t er pa sses t h r ou gh for eva cu a t ion .
In cr ea sed m ot ilit y m a y im pa ir n u t r it ion , pr even t -
in g a dequ a t e oppor t u n it y for n u t r ien t a n d wa t er
a bsor pt ion , a n d it m a y en h a n ce loss of wa t er a n d

elect r olyt es. Decr ea sed m ot ilit y pr olon gs st or a ge
t im e in t h e la r ge in t est in e, pr om ot in g a n en h a n ced
loss of flu id fr om feca l m a t t er a n d pot en t ia lly pr o-
m ot in g t h e r et u r n of wa st e pr odu ct s t o t h e cir cu la -
t ion . Th e com posit ion of for m s of ba ct er ia l in t est in a l
flor a m a y a lso in flu en ce m ot ilit y of t h e la r ge in t es-
t in e, wit h La ctoba cillu s a cid oph ilu s a n d Bifid oba c-
ter iu m bifid u m pr om ot in g m ot ilit y, a n d E sch er ich ia
coli in h ibit in g m ot ilit y. Dia r r h ea a n d con st ipa t ion
a r e t h e m ost com m on clin ica l m a n ifest a t ion s of a l-
t er ed m ot ilit y of t h e la r ge in t est in e.
Fa ct or s t h a t a lt er t h e t r a n sit t im e of st ool a lso
pr esen t pot en t ia l st r essor s t o t h e pr ocess of st ool
elim in a t ion . Cer t a in foods m a y ser ve a s ir r it a n t s t o
t h e in t est in e, en h a n cin g t h e speed a t wh ich t h e feces
m oves fr om t h e cecu m t o t h e a n u s. Sh or t en ed t r a n sit
t im e lim it s wa t er a bsor pt ion , lea din g t o st ool t h a t
is less for m ed du e t o t h e in cr ea sed wa t er con t en t .
Su ch st ools a r e oft en pa ssed wit h m or e fr equ en cy
a n d u r gen cy. In con t r a st , som e in dividu a ls r espon d
t o pa r t icu la r foods wit h a slowed t r a n sit t im e, lea d-
in g t o in cr ea sed wa t er m ovem en t ou t of t h e feces.
Th e r esu lt is oft en h a r d, for m ed st ools wit h r edu ced
fr equ en cy in elim in a t ion .
Alteration in Bowel Neuromuscular Function
Coor din a t ion of n eu r ologic a n d m u scu la r fu n ct ion a l
com pon en t s is essen t ia l t o opt im a l bowel fu n ct ion .
An y a lt er a t ion in n eu r a l sign a l t r a n sdu ct ion or
m u scle r espon siven ess m a y r esu lt in a lt er ed bowel
fu n ct ion . Im pa ir ed fu n ct ion a ssocia t ed wit h loss
of pr opu lsive a ct ivit y m a y r esu lt fr om a bdom in a l
su r ger y or fr om elect r olyt e im ba la n ces a ffect in g
con t r a ct ile fu n ct ion , per it on it is, or spin a l t r a u m a .
Im pa ir ed m ot ilit y is oft en seen a s a side effect of
n a r cot ic a n a lgesia . E m ot ion a l st r ess m a y a lt er st ool
elim in a t ion pr ocesses beca u se of t h e in flu en ce of t h e
cen t r a l n er vou s syst em in t h e in t egr a t ive pr ocesses
in volved in bowel fu n ct ion .
Redu ced a ct ivit y m a y a lso slow t h e pr ocess of st ool
elim in a t ion . Wa lkin g, r u n n in g, swim m in g, a n d ot h er
a ct ive m ovem en t s en h a n ce n eu r om u scu la r a ct ivit y
a n d coor din a t ion in t h e la r ge in t est in e, pr om ot in g
per ist a lsis a n d bowel elim in a t ion . Loss of m obilit y
oft en ser ves a s a st r essor t o bowel elim in a t ion , lea d-
in g t o r edu ced in t est in a l sm oot h m u scle con t r a ct ion s.
As t h e t im e t h a t feces r em a in s in t h e la r ge in t est in e
in cr ea ses, m or e wa t er is r em oved a n d st ool becom es
h a r der. F u r t h er, t h e pr odu ct s of digest ion in t h e for m
of ga s bu ild u p, lea din g t o dist en t ion of t h e a bdom en
a n d pa in if t h e pa ssin g of fla t u s is im pa ir ed.
Stop and Consider
What are some common reasons that intesti-
nal mobility can be reduced, leading to slowed
intestinal smooth muscle contraction?
Alt e r a t io n in S t o o l E lim in a t io n 473
Alteration in Bowel Perfusion
A con t in u ou s sou r ce of per fu sion t o t h e la r ge in t es-
t in e is essen t ia l for opt im a l cellu la r fu n ct ion . Dis-
r u pt ion in per fu sion m a y be t h e r esu lt of eit h er foca l
or globa l et iologies (Ch a pt er 16). Per fu sion ca n be
r edu ced or a bsen t t o a por t ion of bowel a s a r esu lt
of obst r u ct ed flow fr om a va r iet y of r ea son s, in clu d-
in g a clot or pr essu r e fr om a spa ce-occu pyin g m a ss.
E r osion of blood vessels su pplyin g per fu sion t o t h e
in t est in e du e t o u lcer a t ion or t r a u m a m a y a lso lea d
t o im pa ir ed cir cu la t ion . Isch em ia r esu lt in g fr om im -
pa ir ed oxygen a t ion is oft en m a n ifest ed by pa in a n d
a lt er ed bowel fu n ct ion . If h ypoxia per sist s, n ecr osis
of cells a n d t issu es m a y r esu lt .
Ven t ila t ion /per fu sion m ism a t ch , in a dequ a t e va s-
cu la r volu m e a n d in a dequ a t e ca r dia c ou t pu t a r e
com m on et iologies t h a t m a y lea d t o globa l cir cu la -
t ion deficit s, den yin g per fu sion t o cells a n d t issu es
of t h e lower in t est in e. Du r in g t im es of cir cu la t or y
ch a llen ge, blood is r edist r ibu t ed a wa y fr om t h e di-
gest ive syst em t o t h e vit a l or ga n s. Alt er ed per fu sion
m a y occu r a s a r esu lt of excessive per fu sion de-
m a n ds, su ch a s in fect ion . A com m on in fect ion of t h e
GI syst em is a ppen dicit is. Appen dicit is is t h e r esu lt
of t r a pped feca l m a t er ia l in t h e a ppen dix of t h e colon
(Fig. 18.9). Th e obst r u ct ion ca u ses a n in fla m m a t or y
r espon se, followed by in fect ion . On ce t h e obst r u ct ion
is iden t ified, su r gica l r em ova l of t h e a ppen dix is t h e
m et h od of t r ea t m en t . Un t r ea t ed, r u pt u r e of t h e a p-
pen dix is likely t o occu r. Upon r u pt u r e, t h e ba ct er ia l
flor a esca pes in t o t h e per it on ea l ca vit y, r esu lt in g in
per it on it is a n d sept ic sh ock. Redu ced per fu sion t o a ll
or ga n syst em s, especia lly t h e GI t r a ct , r esu lt s fr om
sept ic sh ock.
Alteration in Bowel Patency
Bowel obst r u ct ion is du e t o a spa ce-occu pyin g lesion
wh ich blocks t h e in t est in a l lu m en , eit h er pa r t ia lly
or t ot a lly. Com m on spa ce-occu pyin g lesion s in clu de
t u m or s, polyps, a n d im pa ct ed feces (Fig. 18.10). Of-
t en a ssocia t ed wit h fluid a n d ga s a ccu m ula t ion , bowel
obst r uct ion is m a nifest ed by a bdom ina l dist en t ion
a n d pa in (see Ta ble 18.2). Wh en t h e spa ce-occu pyin g
lesion im pa ir s ca pa cit y for ven ou s r et u r n , t h e devel-
opm en t of edem a in t h e wa ll of t h e la r ge in t est in e
lea ds t o r edu cin g t h e a bsor pt ive ca pa cit y. E dem a
pr om ot es con t in u ed flu id a n d ga s a ccu m u la t ion
beca u se of t h e m ovem en t of wa t er a n d ga s in t o
t h e bowel lu m en . H ydr ost a t ic for ces m a y in cr ea se
so t h a t flu id is for ced t h r ou gh t h e bowel wa ll in t o
t h e per it on eu m . F u r t h er, ba ct er ia m a y ga in a c-
cess t o t h e cir cu la t ion , pr om ot in g t h e developm en t
of sepsis. Per for a t ion m a y r esu lt fr om pr essu r e
t h a t exceeds t h e a bilit y of t h e t issu e t o r et a in it s
st r u ct u r e.
474 C h a p t e r 18: Alt er ed E lim in a t ion

Tra ns ve rs e colon

De s ce nding
As ce nding colon colon

J e junum

Ce cum

Appe ndix
Ile um

S igmoid colon

Re ctum

Anus

Fe ca lith
obs tructing lume n

Infla mma tion

Figure 18.9. Obstruction and inflammation in appendicitis. Fecal mass obstruction stimulates an inflammatory response,
leading to appendicitis.

Ade noca rcinoma

of tra ns ve rs e colon
Tra ns ve rs e colon

As ce nding De s ce nding
colon colon

Polyps

Ile oce ca l Ade noca rcinoma

va lve of je junum

Ce cum

Appe ndix
S igmoid colon
Ade noca rcinoma
of re ctos igmoid
Re ctum
re gion

Anus

Figure 18.10. Colon obstruction. The formation of polyps and tumors represents potential sites for obstruction along the
length of the colon.

General Manifestations of Altered
Bowel Elimination
Iden t ifica t ion of a lt er ed in t est in a l fu n ct ion ca n be
a ccom plish ed by list en in g t o bowel sou n ds. Bowel
sou n ds a r e a r eflect ion of in t est in a l sm oot h m u scle
con t r a ct ion s t h a t a r e a ct ive in t er m it t en t ly. Bowel
sou n ds ca n oft en be h ea r d by t h e n a ked ea r, bu t a r e
m or e ca r efu lly eva lu a t ed t h r ou gh a u s c u lt a t io n , or
list en in g wit h a st et h oscope. Th e qu a lit y, loca t ion ,
a n d fr equ en cy of bowel sou n ds pr ovide a n in dica t ion
of per ist a lt ic fu n ct ion .
Th e a ppea r a n ce of t h e a bdom en is a n ot h er in di-
ca t or of bowel fu n ct ion . Th e a bdom en sh ou ld be soft
wh en pr essed or pa lpa t ed a n d fla t r ela t ive t o body
size. Abdom in a l size m a y in cr ea se du e t o t h e t r a p-
pin g of ga s, lea din g t o h a r den in g a n d t igh t en in g of
t h e a bdom en . Typica lly, t h e ga seou s bypr odu ct s of
digest ion , fla t u s, a r e pa ssed, in dica t in g bowel fu n c-
t ion . Oft en wh en st ool t r a n sit is slowed du e t o slowed
in t est in a l sm oot h m u scle con t r a ct ion a n d coor din a -
t ion , t h e ga seou s pr odu ct s of digest ion bu ild a n d
ca u se t h e a bdom en t o en la r ge, or becom e dist en ded.
Th e volu m e a n d ch a r a ct er ist ics of st ool m a y be
a lt er ed in con dit ion s t h a t a ffect t h e la r ge in t est in e.
Loose, wa t er y st ools a r e ch a r a ct er ist ic of dia r r h ea .
Bowel in fla m m a t ion , in fect ion , a n d in cr ea sed m ot il-
it y a r e oft en a ssocia t ed wit h dia r r h ea . Con st ipa t ion ,
or a bsen ce of bowel m ovem en t , m a y be a con se-
qu en ce of im pa ir ed m obilit y or obst r u ct ion . In com -
plet e obst r u ct ion , feca l m a t t er ca n n ot pa ss beyon d
t h e obst r u ct ion . Th e ch a r a ct er ist ics of feca l m a t t er
pa ssed in t h e pr esen ce of pa r t ia l obst r u ct ion m a y
pr ovide clu es a s t o t h e loca t ion of t h e obst r u ct ion .
Obst r u ct ion s occu r r in g closest t o t h e cecu m m a y a l-
low wa t er y st ool t o pa ss beca u se t h e wa t er con t en t
of t h e st ool is h igh . Pa r t ia l obst r u ct ion s loca t ed a t
t h e dist a l en d of t h e colon m a y a llow t h e pa ssa ge
of sm a ll qu a n t it ies of h a r der, m or e solidly for m ed
st ool.
Stop and Consider
Why would you expect stool in the ascending
colon to have more water content than stool in
the descending colon?
St ool m a y a lso h a ve color ch a n ges ch a r a ct er ist ic of
specific disea se st a t es. Br igh t r ed blood a r ou n d st ool
or seen on t oilet pa per a ft er defeca t ion is gen er a lly
ca u sed by h em or r h oids. H em or r h oids ca n be seen on
t h e ou t side of t h e a n u s or t h ey m a y be loca t ed in t er-
n a lly. La r ger a m ou n t s of fr a n k r ed blood m a y in di-
ca t e in t er n a l bleedin g of a m or e ser iou s n a t u r e, su ch
a s occu r s in colon ca n cer. A da r ker pigm en t of r ed, or
m a r oon , ch a r a ct er izes bleedin g fr om a sou r ce in t h e
m idpor t ion of t h e GI t r a ct , su ch a s t h a t seen wit h
Alt e r a t io n in S t o o l E lim in a t io n 475
diver t icu lit is (see clin ica l m odel). Bla ck st ool (m e -
le n a ) a lso sign ifies a bleedin g con cer n . Th e da r k-
en ed color r epr esen t s a sou r ce of bleedin g h igh er u p
in t h e GI syst em . Blood in st ools sh ou ld be iden t ified
a n d a defin it ive ca u se det er m in ed beca u se of t h e po-
t en t ia l ser iou s con sequ en ces of t h is sign .
Stop and Consider
Why do bloody stools suggest the potential diag-
nosis of cancer?
Ligh t -color ed st ools in dica t e t h e a bsen ce of bile
pigm en t s. Th is is a com m on fin din g a ssocia t ed
wit h con dit ion s of t h e a ccessor y or ga n s of t h e GI
t r a ct (pa n cr ea s, ga ll bla dder, a n d liver ). For exa m -
ple, t h e st ool fr om a per son in fect ed wit h h epa t it is
m a y be wh it e, gr a y, or yellow. Bile a cids a r e a bsen t
in som e m a la bsor pt ion syn dr om es a n d a r e a ssoci-
a t ed wit h la r ge fa t con t en t , kn own a s s t e a t o r r h e a .
St ools la ckin g bile pigm en t s ca u sed by obst r u ct ion
of bile en t r y in t o t h e in t est in e m a y ca u se st ools t o
h a ve a “silver ” color. Am pu lla r y ca n cer is a pa n cr e-
a t ic n eopla sm t h a t a r ises fr om t h e a m pu lla of Va t er.
Th e a m pu lla of Va t er is a sm a ll pr oject ion fr om t h e
pa n cr ea s in t o t h e du oden u m , ser vin g a s t h e open in g
of t h e pa n cr ea t ic a n d bile du ct s. Obst r u ct ion of t h e
a m pu lla of Va t er blocks t h e en t r y of pa n cr ea t ic a n d
bilia r y secr et ion s in t o t h e in t est in e. Ma n ifest a t ion s
of secr et ion blocka ge in clu de ja u n dice ca u sed by
im pa ir ed bilir u bin pr ocessin g a n d elim in a t ion a n d
ligh t -color ed “silver ” st ools ca u sed by a bsen ce of bile
in feca l m a t t er.
Alt er a t ion s in t ext u r e ca n pr ovide in for m a t ion on
a ca u sa t ive fa ct or. Th ese a lt er a t ion s in clu de:
● Wa t er y
■ Acu t e on set ca u sed by ga st r oen t er it is or
a n xiet y.
■ Ch r on ic pa t t er n lin ked t o in fla m m a t or y con -
dit ion s or a h igh -fiber diet . Also ca u sed by in -
t oler a n ce t o pa r t icu la r foods or t h e effect s of
cer t a in m edica t ion s.
● Hard
■ Wa t er con t en t low, r esu lt in g in a dr y st ool t h a t
is difficu lt t o pa ss.
■ Ma y con t r ibu t e t o t h e developm en t of h em or-
r h oids. Lin ked t o low-fiber diet , side effect s of
cer t a in m edica t ion s, or volu n t a r y a voida n ce of
st ool eva cu a t ion .
● St r in gy
■ Ma y be ca u sed by pa r a sit ic in fect ion s.
● Fa t t y
■ Ca u sed by m a la bsor pt ion of fa t .
■ Likely t o floa t .
● Fou l odor
■ Ma y be ca u sed by st ea t or r h ea , pa r a sit ic in fec-
t ion , or m a la bsor pt ion syn dr om es.
476 C h a p t e r 18: Alt er ed E lim in a t ion
Pa in is oft en a ch a r a ct er ist ic of in t est in a l disor der s,
a lt h ou gh it seldom occu r s wit h ou t ot h er sym pt om s.
Or igin s of pa in in clu de m ech a n ica l, in fla m m a t or y, or
isch em ic ca u ses. Th e bioch em ica l m edia t or s of pa in
(h ist a m in e, br a dykin in , a n d ser ot on in ) pr ovide st im -
u la t ion t o n er ve en din gs, r esu lt in g in t h e pa in r e-
spon se (det a iled in Ch a pt er 10). Abdom in a l pa in ca n
be ca t egor ized in t o t h r ee m a in t ypes:
1. Viscer a l
■ Ch a r a ct er ized a s diffu se, r a dia t in g a n d gen er-
a lized; difficu lt t o det er m in e pr ecise loca t ion
■ Ca u sed by st r et ch in g, dist en t ion , or in fla m m a -
t ion , in du cin g edem a a n d va scu la r con gest ion
2. Som a t ic (a lso kn own a s pa r iet a l)
■ Descr ibed a s sh a r p, in t en se, a n d loca lized t o a
specific sit e
■ Ca u sed by in ju r y t o t h e a bdom in a l wa ll or pa -
r iet a l per it on eu m
3. Refer r ed
■ Felt a t a loca t ion differ en t fr om or igin of pa in
■ Ca u sed by t h e sh a r in g of a com m on a ffer en t
pa t h wa y bet ween or igin of pa in a n d r efer r ed
loca t ion
Acu t e on set of pa in is u su a lly ca u sed by a pr ecipit a t -
in g even t , su ch a s per for a t ion . Per sist en t pa in wit h
a gr a du a l on set is oft en a ssocia t ed wit h ch r on ic con -
dit ion s, su ch a s u lcer a t ive colit is.
An or exia (loss of a ppet it e) is oft en a ssocia t ed wit h
n a u sea a n d vom it in g. Th ese sym pt om s a r e gen er a l
a n d do n ot poin t t o a specific con dit ion . Abdom in a l
dist en t ion oft en in dica t es in cr ea sed pr essu r e fr om
flu id or feces in t h e bowel lu m en , in fla m m a t ion a n d
edem a of t h e in t est in e, or in cr ea sed pr odu ct ion of
ga s. Fever is a com m on fin din g r esu lt in g fr om in fec-
t ion , su ch a s p e r it o n it is (in fla m m a t ion of t h e per i-
t on ea l m em br a n e).
Diagnosis of Bowel Conditions
Specific con dit ion s ca n be iden t ified by exa m in a -
t ion of st ool. Th ese con dit ion s in clu de a ller gy t o a
diet a r y su bst a n ce (su ch a s m ilk pr ot ein in in fa n t s),
in fla m m a t ion , in fect ion , bleedin g, or m a la bsor pt ion .
In ca ses of in fect ion , st ool ca n be exa m in ed t o det er-
m in e t h e specific or ga n ism in volved. Ma n y or ga n -
ism s a r e n a t u r a lly fou n d in t h e in t est in e (n or m a l
flor a , m icr obiot a ) a n d a r e im por t a n t for specific GI
fu n ct ion s. H a r m fu l ba ct er ia or pa r a sit es t h a t in -
fect t h e GI t r a ct m u st be iden t ified t o det er m in e
t h e m ost effect ive t r ea t m en t . Fa t con t en t ca n be
det er m in ed t o in dica t e t h e pr esen ce or a bsen ce of
a disor der of m a la bsor pt ion . Th ese det er m in a t ion s
m a y r equ ir e eit h er m icr oscopic a n a lysis or cu lt u r e
of st ool. Det er m in a t ion of o c c u lt (t oo sm a ll t o be
seen ) blood in st ool ca n be m a de by pla cin g a sm a ll
sa m ple on a collect ion ca r d a n d a pplyin g a ch em i-
ca l solu t ion . A color ch a n ge in dica t es t h e pr esen ce
or a bsen ce of blood. Th is t est is com m on ly r efer r ed
t o a s a gu a ia c test. St ool sa m ples for m icr oscopic
a n a lysis or cu lt u r e sh ou ld be collect ed in clea n , dr y,
disposa ble con t a in er s. Im m edia t e deliver y t o t h e
la bor a t or y pr ovides t h e best con dit ion s for a n a lysis
of t h e sa m ple.
Mech a n ica l obst r u ct ion s r esu lt in g fr om gr owt h s
ext en din g in t o t h e colon lu m en , in clu din g t u m or s or
polyps, ca n be dia gn osed u sin g t ech n iqu es t h a t a llow
visu a liza t ion of t h e colon lu m en . Dia gn ost ic t est s for
disor der s of t h e colon in clu de:
● Ba r iu m en em a : Det er m in a t ion of colon a n d r ect a l
a n a t om ic a bn or m a lit ies wit h t h e a id of con t r a st
m ediu m (ba r iu m ) in ser t ed via t h e a n u s. Visu a l-
iza t ion of t h e r ect u m a n d colon is com plet ed by r a -
diogr a ph . Com m on con dit ion s iden t ified in clu de
diver t icu lit is, a lt er a t ion s in m ot ilit y, obst r u ct ion ,
a n d colon dim en sion s.
● Sigm oidoscopy: In ser t ion of a flexible t u be in t o
t h e a n u s t o visu a lize t h e r ect u m a n d t h e lower
colon . Th is dia gn ost ic t est m a y be in dica t ed for
m a n ifest a t ion s of bleedin g, a lt er ed bowel h a bit s,
r ect a l pa in , a n d dia r r h ea .
● Colon oscopy: In ser t ion of a flexible t u be in t o t h e
a n u s for obser va t ion of t h e en t ir e colon , fr om t h e
sm a ll in t est in e t o t h e r ect u m . Th is t est is oft en
don e in r espon se t o m a n ifest a t ion s of a bdom in a l
pa in , dia r r h ea , a lt er a t ion in bowel h a bit s, or a s a
follow-u p t o a n a bn or m a lit y fou n d du r in g a n ot h er
pr ocedu r e, su ch a s t h e ba r iu m en em a or com pu t ed
t om ogr a ph y (CT) sca n .
Treatment of Altered Bowel
Elimination
Sim ila r t o t r ea t m en t of a lt er ed u r in a r y elim in a -
t ion , t r ea t m en t of con dit ion s ca u sin g a lt er ed GI
elim in a t ion is det er m in ed by t h e con dit ion u n der-
lyin g t h e clin ica l m a n ifest a t ion s. Dia r r h ea , a for m
of excessive GI elim in a t ion , m a y be a ssocia t ed wit h
im pa ir ed r egu la t ion of flu id ba la n ce. Dia r r h ea m a y
r esu lt fr om a va r iet y of pr im a r y con dit ion s, or it m a y
r epr esen t a n a dver se effect of t r ea t m en t . P h a r m a co-
t h er a py m a y be u sed t o dim in ish excessive flu id loss
fr om dia r r h ea . An t idia r r h ea l dr u gs wor k by:
● Slowin g t h e pa ssa ge of st ool t h r ou gh t h e in t est in e
■ An t im ot ilit y a gen t s (Im odiu m )
■ P r om ot es wa t er r em ova l fr om feca l m a t t er
■ Usefu l for ch r on ic con dit ion s
● Movin g dia r r h ea -ca u sin g fa ct or s ou t of t h e st ool
■ Adsor ben t s (Ka opect a t e)
■ Ma y a lso pu ll ou t ot h er essen t ia l pr odu ct s
 C lin ic a l Mo d e ls 477

Ta b le 18.4 Im pa ct of Select ed In t est in a l Con dit ion s on t h e H ea lt h of In dividu a ls

Am b u la t o r y C a r e P r e-
C o n d it io n Im p a ct Dea th s H o s p it a liza t io n s Vis it s (P e r Ye a r ) s c r ip t io n s
H em or r h oids 75% of in dividu a ls 20 266,000 1.1 m illion 2 m illion
over 45 yea r s of a ge
Ch r on ic 63 m illion people 132 1.1 m illion 4 m illion 5.3 m illion
con st ipa t ion (pr eva len ce)
Ir r it a ble 15.3 m illion 21 280,000 1.6 m illion 5.9 m illion
bowel syn dr om e (pr eva len ce)
Abdom in a l 526,000 (su r gica l 132 380,000 3.6 m illion 3.7 m illion
wa ll h er n ia pr ocedu r es)
Diver t icu la r 2.2 m illion 2,889 814,000 2.8 m illion 2.8 m illion
disea se (pr eva len ce)

NIDDK. Digest ive disea ses st a t ist ics for t h e Un it ed St a t es. h t t p://www.n iddk.n ih .gov/h ea lt h -in for m a t ion /h ea lt h -st a t ist ics/Pa ges/digest ive-
disea ses-st a t ist ics-for-t h e-u n it ed-st a t es.a spx#6. Ret r ieved on J a n u a r y 2, 2016

● Decr ea sin g secr et ion of flu id in t o in t est in e
■ Redu ce in fla m m a t or y r espon se t o pa t h ogen s
(a n t ibiot ics)
■ Decr ea ses flu id m ovem en t in t o in t est in a l
con t en t s
● Usin g bu lk-for m in g a gen t s
■ Absor bs excess flu id (psylliu m )
■ F ir m s st ool
Con st ipa t ion ca n be m a n a ged wit h exer cise, h igh
diet a r y fiber, a dequ a t e flu id in t a ke, st ool soft en -
er s, la xa t ives, a n d en em a s. Bu lk-for m in g la xa -
t ives a bsor b wa t er fr om t h e in t est in e t o m a ke st ool
soft er. St im u la n t s pr om ot e per ist a lsis, en h a n cin g
pr opu lsion of feca l m a t t er t h r ou gh t h e colon . St ool
soft en er s pr om ot e m oist u r e con t en t in st ool wit h ou t
t h e st im u la n t effect . Lu br ica n t s pr om ot e sm oot h er
pa ssa ge a n d eva cu a t ion of feca l m a t t er. Sa lin e la xa -
t ives wor k by a t t r a ct in g wa t er in t o t h e colon .
Obstr uct ive a bn orm a lit ies m ay r equire su rgica l
t r ea t m ent for r emova l. Alt er a t ions in n eur om uscu-
la r fu nct ion may requir e a ssistive devices or bla dder/
bowel t r a ining progr a m s for elim ina t ion of ur ine a nd
st ool. Tr ends for select ed condit ions r ela t ed t o la r ge in -
t estin e im pa ir m ent a r e pr ovided in Ta ble 18.4, ba sed
on inform a t ion from th e Na t iona l In st it ut es of Dia -
bet es a nd Digest ive a nd Kidney Disea ses (NIDDK).

Modu le 3 C lin ic a l Mo d e ls

Th e followin g clin ica l m odels h a ve been select ed t o
a id in t h e u n der st a n din g a n d a pplica t ion of a lt er ed
elim in a t ion . Th e st u den t sh ou ld pa y a t t en t ion t o t h e
com m on a lit ies a n d u n iqu e fea t u r es of ea ch con dit ion
wh en st u dyin g t h ese m odels. Alt er a t ion s in elim in a -
t ion oft en lea d t o ph ysica l a n d em ot ion a l dist r ess
a n d disr u pt ion of da ily life. P r ocesses lea din g t o a l-
t er ed elim in a t ion a r e su m m a r ized in Figu r e 18.11.
Urolithiasis
Ur olit h ia sis, com m on ly kn own a s kidn ey st on es, is
t h e developm en t of ca lcu li in t h e r en a l syst em . Re-
n a l ca lcu li a r e solid m a sses, oft en com posed of sa lt s,
a n d in or ga n ic or or ga n ic a cids, wh ich pr ecipit a t e ou t
of u r in a r y filt r a t e. Th e dia gn osis of kidn ey st on es
r epr esen t s on e of t h e m ost pr eva len t con dit ion s of
t h e u r in a r y t r a ct syst em . Th e con dit ion occu r s m or e
fr equ en t ly in m en com pa r ed t o wom en , a n d in Ca u -
ca sia n s com pa r ed t o Afr ica n Am er ica n s.1 Recen t
t r en ds lin k in cr ea sin g r a t es a ssocia t ed wit h obesit y
a n d dia bet es m ellit u s.
PATHOPHYSIOLOGY
Ca lciu m (oxa la t e a n d ph osph a t e) is t h e m ost com -
m on com pon en t of st on es, wh ich m a y a lso for m
beca u se of m a gn esiu m a m m on iu m ph osph a t e (s t r u -
v it e ), u r ic a cid, or cyst in e. Diet a r y fa ct or s in clu din g
low ca lciu m in t a ke, h igh oxa la t e in t a ke, h igh a n im a l
pr ot ein in t a ke, h igh sodiu m in t a ke, or low flu id in -
t a ke m a y pr edispose in dividu a ls t o developm en t of
ca lcu li. E leva t ed u r in a r y levels of ca lcu li-for m in g
su bst a n ces (h yper ca lciu r ia , h yper oxa lu r ia , h ypoci-
t r a t u r ia ) or st a sis fr om u r in a r y filt r a t e m a y pr om ot e
478 C h a p t e r 18: Alt er ed E lim in a t ion

t h e lower ba ck (fla n k) a t t h e cost over t ebr a l a n gle.

Alte re d e liminatio n
Alte re d motility
Alte re d ne uromus cula r function
Urina ry
Alte re d pe rfus ion
Alte re d pa te ncy
Alte re d volume of
excre tion
Pa in ca n be fu r t h er descr ibed in t wo wa ys:
1. Colic
■ Ca u sed by st r et ch in g of t h e collect in g syst em
or u r et er fr om obst r u ct ed flow
Bowe l ■ Ch a r a ct er ized a s a cu t e, in t er m it t en t , r a dia t -
in g, a n d excr u cia t in g
2. Non colic
■ Ca u sed by dist en t ion of r en a l ca lices or pelvis
■ Ch a r a ct er ized a s du ll a n d deep
■ Ra n gin g in in t en sit y fr om m ild t o sever e

H em a t u r ia m a y be pr esen t wit h r en a l ca lcu li. Ma n -

Alte re d body fluid ifest a t ion s r a n ge fr om gr oss h em a t u r ia , ca u sin g a
ba la nce r ed-t in ged color ch a n ge in u r in e, t o h em a t u r ia wh ich
is n ot iden t ifia ble wit h ou t visu a liza t ion wit h m icr o-
Figure 18.11. Concept map. Processes of altered scopic a n a lysis. Addit ion a l m a n ifest a t ion s m a y in -
elimination. clu de n a u sea , vom it in g, dysu r ia , a n d u r gen cy.

developm en t of ca lcu li. As st on es pr ogr ess t h r ou gh DIAGNOSTIC CRITERIA

t h e u r in a r y syst em , fr om t h e r en a l t u bu les t o t h e
Im aging of t he renal ca lculi with CT or r ena l ultra -
u r et h r a , t h ey oft en r esu lt in obst r u ct ion of t h ese
sonogr a phy is t he prefer red a ppr oa ch for diagnosis.
n a r r ow lu m en st r u ct u r es.
Dia gnosis of r ena l calculi ca n a lso be ma de using a
In dividu a ls a t r isk for developm en t of kidn ey
r outine ra diogra ph beca use m ost stones a re ra di-
st on es in clu de t h ose wit h :
opa que. IVP m ay be used t o obta in informa t ion a bout
● Gen et ic pr edisposit ion t he collecting system a nd ur et er s beca use t he contr ast
● Ur in a r y t r a ct in fect ion m edia is filtered by t he glomerulus a nd ca n be tr acked
● Cyst ic kidn ey disea se t hr ough t he urina r y syst em. Hydronephrosis ca n be
● Dia bet es det ected using ult ra sound t o pr ovide additiona l infor-
● Obesit y m at ion a bout the consequences of the obstruction.
● Gou t Det er m in a t ion of u n der lyin g ca u ses con t r ibu t -
● H yper pa r a t h yr oidism in g t o st on e developm en t a n d t h e com posit ion of
● Ga st r ic bypa ss t h e st on e it self h elps est a blish effect ive t r ea t m en t .
In dividu a ls a r e oft en pr ovided a device t h a t st r a in s
t h e u r in e, collect in g a n y st on es t h a t a r e excr et ed.
Stop and Consider
Th e st on es ca n t h en be a n a lyzed t o det er m in e con -
Why are people with hyperparathyroidism and
t en t a n d in fer ca u se. Types of ca lcu li a r e sh own in
hypercalciuria at risk for development of renal
F igu r e 18.12 a n d in clu de:
calculi?
● Ca lciu m oxa la t e a n d ph osph a t e
■ H yper ca lcem ia /h yper ca lciu r ia
CLINICAL MANIFESTATIONS
■ Im m obilit y
Th e m ost obviou s clin ica l m a n ifest a t ion of kidn ey ■ Ren a l t u bu la r a cidosis
st on es is pa in . Th is pa in is ch a r a ct er ized a s sever e ● Ma gn esiu m a m m on iu m ph osph a t e/st r u vit e
a n d sh oot in g a n d is loca lized in t h e la t er a l a spect of ■ Ur in a r y t r a ct in fect ion

Slight renal edema

Urate deposits
in renal
parenchyma Stone forming in Small calcium
calyx stones
Large “staghorn” Large calcium
stone
stone in
Urate stones in
renal pelvis
pelvis
B C
A
Figure 18.12. Common forms of renal calculi. A: Uric acid/ urate stones. B: Magnesium ammonium phosphate (struvite)
stones. C: Calcium oxalate/ calcium phosphate stones. (Courtesy Anatomical Chart Company.)

● Ur ic a cid/u r a t e
■ P r ecipit a t ed in a cidic u r in e (pH of 5.5 or less)
■ Diet h igh in pu r in es
■ Gou t
TREATMENT
Tr ea t m en t of ca lcu li in volves su ppor t ive ca r e, in -
clu din g pa in con t r ol. F lu ids m a y be en cou r a ged t o
pr om ot e filt r a t e flow a n d m ovem en t of st on e t h r ou gh
t h e u r in a r y syst em . Medica l t h er a py t o pr om ot e
st on e pa ssa ge in clu des a n t ispa sm odic a gen t s, ca l-
ciu m ch a n n el blocker s, a n d a lph a blocker s. If st on es
do n ot pa ss spon t a n eou sly or in r espon se t o m edica l
t h er a py, r em ova l of ca lcu li is oft en n ecessa r y t o pr e-
ven t da m a ge t o r en a l st r u ct u r es. Th e in dica t ion s for
su r gica l r em ova l in clu de 2
● Ret a in in g t h e st on e a n d con st a n t pa in over a r ea -
son a ble per iod
● St on e size t oo la r ge t o pa ss
● Obst r u ct in g u r in e flow
● Ca u sin g on goin g u r in a r y t r a ct in fect ion
● Ca u sin g da m a ge t o kidn ey or eviden ce of con st a n t
h em a t u r ia
● Con t in u in g t o gr ow in size
Su r gica l pr ocedu r es t o r em ove kidn ey st on es a r e se-
lect ed in con sider a t ion of t h e gr ea t est effect iven ess
a n d lowest com plica t ion r a t e t o a ch ieve desir ed r e-
su lt .3 E x t r a c o r p o r e a l s h o c k w a v e lit h o t r ip s y
(E S WL ) is t h e m ost com m on pr ocedu r e for kidn ey
st on e r em ova l. La r ge st on es a r e loca lized by u lt r a -
sou n d or r a diogr a ph a n d t h en a r e br oken down in t o
sm a ll, sa n dlike bit s u sin g a cou st ic sh ock wa ves. Th e
decr ea sed size pr om ot es spon t a n eou s pa ssa ge of t h e
st on e in t h e u r in e. Pa ssa ge is occa sion a lly a ssist ed
by pla cin g a st en t (a sm a ll t u be) t h r ou gh t h e bla dder
in t o t h e u r et er. Th is pr ocedu r e is u sefu l wh en st on es
a r e loca t ed in t h e r en a l ca lyx, pelvis, a n d u pper t h ir d
of t h e u r et er. P e r c u t a n e o u s n e p h r o lit h o t o m y is a bilit y of t h e m in er a ls a n d a lt er s pH , r edu cin g t h e
a n a lt er n a t e su r gica l pr ocedu r e u sed for t r ea t m en t
4
of r en a l ca lcu li r em ova l. Th e st on e is loca t ed a n d
r em oved u sin g a n eph r oscope, in ser t ed in t o t h e kid-
n ey t h r ou gh a sm a ll fla n k in cision . St on es t oo la r ge
for r em ova l a r e fr a gm en t ed u sin g a n en er gy pr obe.
Th e in ser t ion of a n eph r ost om y t u be a ssist s in h ea l-
in g a ft er t h e pr ocedu r e. U r e t e r o s c o p ic s t o n e r e -
m o v a l is u sed wh en st on es a r e loca t ed in t h e m id
or dist a l por t ion s of t h e
u r et er s. Ca lcu li r em ova l
is a ccom plish ed t h r ou gh
a u r et er oscope pla ced F R O M T H E L AB
in t o t h e u r et er t h r ou gh
t h e u r et h r a a n d bla d- Urinalysis in a person with renal calculi may show hematuria, infection, crystals, or altered
der. Aft er loca liza t ion , urine pH. The urinalysis findings may provide clues about the cause of calculi formation,
t h e st on e is r em oved or which is useful in directing treatment strategies.
fr a gm en t ed wit h a sh ock
C lin ic a l Mo d e ls 479
wa ve device. P la cem en t of a u r et er a l st en t is oft en
don e a lon g wit h t h is pr ocedu r e.
P r even t ion st r a t egies t o a void developm en t a n d
r ecu r r en ce of ca lcu li in h igh -r isk in dividu a ls m a y be
u sefu l, pa r t icu la r ly wh en pr even t ive st r a t egies a r e
specific t o u r in a r y, m et a bolic, n u t r it ion a l, en vir on -
m en t a l, a n d lifest yle r isk fa ct or s for pa r t icu la r t ypes
of st on e for m a t ion .5 Adequ a t e flu id in t a ke a n d a lka -
lin iza t ion of u r in e a r e st r a t egies t h a t ca n be u sed in
pr even t ion of r en a l ca lcu li a s t h ey r edu ce u r in e sa t -
u r a t ion a n d pr ecipit a t ion of ca lciu m -for m in g sa lt s.2
Diet m a n ipu la t ion t o in cr ea se flu id in t a ke, r edu ce
diet a r y oxa la t e, r egu la t e a n im a l pr ot ein in t a ke t o 4
t o 5 oz ser vin g per da y, in cr ea se low-oxa la t e-con t a in -
in g fr u it a n d veget a ble in t a ke, a n d t o lim it sodiu m
in t a ke t o 2 t o 3 g/d m a y decr ea se r isk for ca lcu li
developm en t . Rest r ict ion of diet a r y ca lciu m is n ot
a ssocia t ed wit h r edu ced r isk of ca lcu li for m a t ion in
m ost ca ses. Foods h igh in oxa la t e sh ou ld be a voided
in per son s wit h ca lciu m oxa la t e-ba sed st on es. Th ese
foods in clu de:
● Beet s
● Ch ocola t e
● Coffee
● Cola
● Nu t s
● Rh u ba r b
● Spin a ch
● St r a wber r ies
● Tea
● Wh ea t br a n
Com bin in g ca lciu m r est r ict ion wit h diu r et ic t h er a py
pr om ot es m ovem en t of filt r a t e t h r ou gh t h e r en a l
syst em , r edu cin g t h e likelih ood of ca lcu li develop-
m en t . Tr ea t m en t a n d pr even t ion of u r in a r y t r a ct
in fect ion s m a y decr ea se t h e r isk for st r u vit e-ba sed
ca lcu li. Ma n a gem en t of pr im a r y con dit ion s, su ch a s
gou t a n d h yper pa r a t h yr oidism , r edu ces t h e a va il-
r isk of ca lcu li for m a t ion .
Urinary Incontinence
Ur in a r y in con t in en ce, or e n u r e s is , is defin ed a s
t h e in a bilit y t o volu n t a r ily pr even t t h e disch a r ge of
u r in e. A sym pt om r a t h er t h a n a dia gn osis, u r in a r y
480 C h a p t e r 18: Alt er ed E lim in a t ion
in con t in en ce is oft en t h e m a n ifest a t ion of con dit ion s
t h a t a lt er t h e st r u ct u r e or fu n ct ion of t h e u r in a r y
t r a ct . Ur in a r y in con t in en ce is oft en con sider ed a
wom en ’s disea se, a lt h ou gh it is kn own t o occu r in
17% of a n est im a t ed 34 m illion m en older t h a n
60 yea r s in t h e Un it ed St a t es.6 It is est im a t ed t h a t
u p t o 75% of wom en in t h e Un it ed St a t es r epor t oc-
ca sion a l u r in a r y lea ka ge, wit h 20% t o 50% r epor t in g
m or e fr equ en t lea ka ge.7,8
PATHOPHYSIOLOGY
A va r iet y of pr ocesses ca n im pa ir voidin g, in clu din g
t h ose in volvin g m u scu la r con t r a ct ion , n eu r a l t r a n s-
m ission , h or m on a l st im u la t ion , or m ech a n ica l fa c-
t or s. In wom en , r ela xa t ion of pelvic st r u ct u r es m a y
occu r, especia lly a ft er pr egn a n cy. Ma le in con t in en ce
m a y be ca u sed by m ech a n ica l obst r u ct ion by t h e
pr ost a t e on t h e pen ile u r et h r a . In bot h gen der s, n eu -
r ologic disea se, in clu din g Pa r kin son disea se, m u l-
t iple scler osis, spin a l cor d in ju r y, a n d st r oke, m a y
con t r ibu t e t o voidin g dysfu n ct ion . Adva n cin g a ge,
obesit y a n d loss of m obilit y a n d dext er it y m a y a lso
con t r ibu t e t o fu n ct ion a l in con t in en ce.
A det a iled h ist or y a bou t t h e specific ch a r a ct er-
ist ics of t h e in con t in en ce is cr it ica l t o t h e det er m i-
n a t ion of in con t in en ce t ype, wh ich a lso a ffect s t h e
ch oice of t r ea t m en t m oda lit ies. Th e pa t ien t sh ou ld
keep a r ecor d, or voidin g dia r y, on u r in a r y fr equ en cy,
lea ka ge, voidin g volu m es, a n d flu id in t a ke. Th is r e-
cor d sh ou ld spa n a t lea st 3 da ys, bu t 1 week is pr ef-
er a ble t o a ccu r a t ely iden t ify pa t t er n s. Lea ka ge ca n
a lso be qu a n t ified by a pa d cou n t or weigh t , pr ovid-
in g det a ils of volu m e.
CLINICAL MANIFESTATIONS
Tem por a r y in con t in en ce m a y r esu lt fr om t h e u se of
cer t a in m edica t ion s or fr om illn ess, im m obilit y, or
con st ipa t ion . Ch r on ic t ypes of in con t in en ce ca n be
cla ssified in t o fou r differ en t for m s. S t r e s s in c o n t i-
n e n c e occu r s beca u se of a n exer t ion a l st im u lu s. Th e
st im u lu s m a y be a s ben ign a s cou gh in g, sn eezin g,
or la u gh in g. Ot h er exer t ion a l a ct ivit ies t h a t pr om pt
in con t in en ce in clu de exer cise or lift in g object s. Im -
pa ir ed sph in ct er fu n ct ion a n d con t r ol is oft en a ssoci-
a t ed wit h st r ess in con t in en ce. U r g e in c o n t in e n c e ,
a lso kn own a s o v e r a c t iv e b la d d e r , r efer s t o u r in e
lea kin g t h a t is a ccom pa n ied or im m edia t ely pr e-
ceded by a st r on g u r ge t o void (u r gen cy), n oct u r ia ,
a n d fr equ en cy.9 Th is im pu lse is oft en so su dden t h a t
in con t in en ce r esu lt s befor e t h e in dividu a l ca n t oilet .
Over a ct ivit y of t h e det r u sor m u scle of t h e bla dder
is r espon sible for t h is t ype of in con t in en ce. Oft en ,
in dividu a ls m ay h a ve a m ix of sym pt om s of bot h
u r ge a n d st r ess in con t in en ce. In con t in en ce m a y
a lso r esu lt fr om u r in e volu m es exceedin g bla dder
ca pa cit y, kn own a s o v e r lo w in c o n t in e n c e . Over-
flow in con t in en ce is oft en a ssocia t ed wit h det r u sor
u n der a ct ivit y or bla dder ou t let obst r u ct ion . F u n c -
t io n a l in c o n t in e n c e is ch a r a ct er ized by n or m a l
bla dder con t r ol cou pled wit h a n im pa ir ed a bilit y t o
t r a n spor t t o t oilet fa cilit ies, su ch a s wit h im pa ir ed
m obilit y. In con t in en ce ca n be cla ssified fu r t h er a s
n oct u r n a l en u r esis, con t in u ou s lea ka ge, post void
dr ibble, a n d ext r a u r et h r a l (u r in e loss t h r ou gh fis-
t u la ) in con t in en ce.
DIAGNOSTIC CRITERIA
Dia gn osis is ba sed on ca r efu l h ist or y in a ddit ion t o
ph ysica l exa m in a t ion a n d specia lized t est in g. Test -
in g is a lso in flu en ced by gen der-specific a n a t om ica l
con sider a t ion s. Ur odyn a m ic a n d en doscopic t est in g,
in a ddit ion t o t h e im a gin g st u dies pr eviou sly de-
scr ibed, a r e t h e gold st a n da r d bu t a r e n ot n ecessa r y
t o est a blish a dia gn osis. Th e followin g a r e t est s a n d
dia gn ost ic fin din gs for in con t in en ce:
● Bla dder st r ess t est
■ St a n din g posit ion wit h a com for t a bly fu ll
bla dder
■ Obser va t ion of u r in e pa ssa ge wit h Va lsa lva or
vigor ou s cou gh
● Post r esidu a l volu m e (P RV)
■ Aft er voidin g, r esidu a l u r in e in t h e bla dder is
m ea su r ed
■ P RV of less t h a n 50 m L in dica t es a dequ a t e
bla dder em pt yin g
● Ur odyn a m ic t est in g
■ Cyst om et r y
■ Mea su r es a n a t om ic a n d fu n ct ion a l a bilit y of
t h e bla dder a n d u r et h r a
■ Mea su r es ca pa cit y of t h e bla dder, pr ovidin g
eva lu a t ion of t h e fu n ct ion of t h e det r u sor
m u scle
■ Cyst om et r ogr a m
■ Mea su r es pr essu r es of t h e t ot a l bla dder, de-
t r u sor, a n d in t r a -a bdom en
■ Voidin g cyst om et r ogr a m
■ Iden t ifies ou t let obst r u ct ion du r in g voidin g
● E n doscopic t est s
■ Cyst oscopy
■ Visu a lizes bla dder m u cosa t o iden t ify t h e
pr esen ce of lesion s
TREATMENT
Tr ea t m en t for in con t in en ce r eflect s beh a vior a l st r a t -
egies, u se of m edica t ion , a n d su r ger y. Assist a n ce
wit h t oilet in g, b la d d e r t r a in in g (lea r n in g t o h old
u r in e for in cr ea sin g in t er va ls), in t r a va gin a l su ppor t
devices, a n d st r en gt h en in g of t h e pelvic m u scles a r e
com m on st r a t egies u sed for fu n ct ion a l a n d st r ess
 C lin ic a l Mo d e ls 481

in con t in en ce.10 Pelvic m u scles ca n be st r en gt h en ed Polycystic Kidney Disease

by Kegel exer cises, va gin a l weigh t s, a n d elect r ica l
st im u la t ion . An t ich olin er gic m edica t ion s h elp u r ge
in con t in en ce beca u se t h ey decr ea se t h e con t r a ct ile
for ce of t h e det r u sor m u scle. Im pr oved u r et h r a l t on e
ca n be a ssist ed by t h e u se of α-a dr en er gic a n t a gon ist
dr u gs t o im pr ove t on e a n d con t r a ct ile fu n ct ion .
In fem a les, su r gica l cor r ect ion for r en ewed a n a -
t om ic su ppor t ca n be per for m ed wit h a n a bdom in a l
bla dder su spen sion . Also kn own a s t h e Bu r ch or
Ma r sh a ll–Ma r ch et t i–Kr a n t z (MMK) pr ocedu r e, t h e
bla dder a n d u r et h r a a r e r et u r n ed t o t h eir n or m a l
posit ion , pr om ot in g in cr ea sed volu n t a r y con t r ol of
u r in e. Th is pr ocedu r e ca n be don e t h r ou gh a n a bdom -
in a l in cision or it ca n be don e la pa r oscopica lly. An -
ot h er pr ocedu r e, t h e slin g pr ocedu r e, pla ces su ppor t
m a t er ia l dir ect ly u n der t h e u r et h r a a n d a t t a ch es t o
a bdom in a l m u scle con n ect ive t issu e. On e of t h e n ew-
est pr ocedu r es, t h e t en sion -fr ee va gin a l t a pe pr oce-
du r e (TVT) u ses a t h in st r ip of su ppor t in g t a pe t o
for m a h a m m ock u n der t h e u r et h r a . Th is pr ocedu r e,
sim ila r t o t h e slin g pr ocedu r e, is per for m ed t h r ou gh
a sm a ll in cision in t h e va gin a . Th ese pr ocedu r es a r e
in t en ded t o su ppor t t h e u r et h r a du r in g st r a in t h a t
wou ld in du ce st r ess in con t in en ce. Su r gica l t ech -
n iqu es in m a les wit h in con t in en ce a r e design ed t o
r em ove m ech a n ica l obst r u ct ion of t h e u r et h r a fr om
a n en la r ged pr ost a t e.
P o ly c y s t ic k id n e y d is e a s e (P KD ) is a con dit ion
ch a r a ct er ized by gr owt h of flu id-filled cyst s in kidn ey
t issu e bila t er a lly, lea din g t o pr ogr essive loss of r en a l
n eph r on s. P KD m ay be in h er it ed or a cqu ir ed. Th e
in h er it ed for m of P KD is t h e m ost com m on gen et ic
ca u se of ch r on ic kidn ey disea se.11 Th e pr ogr essive
n a t u r e of P KD m a y r esu lt in in cr ea sin g loss of r e-
n a l fu n ct ion , lea din g t o r en a l fa ilu r e. Of t h e pr im a r y
con dit ion s a ssocia t ed wit h n eed for t r ea t m en t of en d-
st a ge r en a l disea se a m on g over 500,000 US r esiden t s
in 2006, P KD r epr esen t ed t h e fou r t h lea din g ca u se.12
PATHOPHYSIOLOGY
Cyst s of in cr ea sin g size a n d n u m ber r epla ce fu n c-
t ion a l t issu e, lea din g t o en d-st a ge r en a l disea se.
P r essu r e on r en a l blood vessels obst r u ct s per fu sion ,
lea din g t o t issu e degen er a t ion a n d obst r u ct ed t u bu la r
flow (Fig. 18.13). A va r ia ble pa t t er n of cyst in volve-
m en t exist s in n eph r on s—cyst -a ffect ed n eph r on s a r e
in t er sper sed wit h n or m a l, u n a ffect ed n eph r on s.
Th r ee ca t egor ies of P KD a r e kn own :
1. Gen et ic, a u t osom a l dom in a n t
2. Gen et ic, a u t osom a l r ecessive
3. Acqu ir ed

Re nal damag e in
po lyc ys tic kidney
dis e as e

De cre a s e d re na l Tubula r Glome rula r

blood flow ce ll da ma ge da ma ge

De cre a s e d
glome rula r
blood flow

Incre a s e d Na Cl De cre a s e d
Tubula r Ba ckle a k glome rula r
de live ry to
obs truction of filtra te ultra filtra tion
ma cula de ns a

De c re as e d
g lo me rular
filtratio n rate

Figure 18.13. Renal damage in polycystic kidney disease. (Courtesy Anatomical Chart Company.)
482 C h a p t e r 18: Alt er ed E lim in a t ion

Th e a u t osom a l dom in a n t for m of P KD is t h e m ost Cross section

com m on in h er it ed for m , a ccou n t in g for 90% of
P KD ca ses. Gen et ic m u t a t ion s in t h e P KD1 a n d
P KD2 gen es lea d t o a lt er ed pr ot ein pr odu ct ion of
polycyst in -1 a n d polycyst in -2. Th e less com m on r e- Cysts
cessive for m is t h e r esu lt of m u t a t ion s in t h e P KH D1
gen e, en codin g t h e fibr ocyst in pr ot ein . Clin ica l m a n -
ifest a t ion s of kidn ey disea se u su a lly a ppea r bet ween Renal pelvis
Infundibulum
t h e a ges of 30 a n d 40 yea r s in t h e a u t osom a l dom i- Ureter
n a n t for m , a lt h ou gh in dividu a ls ca n h a ve sym pt om s
a t a you n ger a ge. Sym pt om s a ppea r ea r ly in t h e a u -
t osom a l r ecessive for m of P KD, u su a lly in t h e ea r ly
in fa n t per iod or even du r in g fet a l life. P KD ca n a lso
be a cqu ir ed, wh ich is u su a lly a ssocia t ed wit h ot h er
lon g-t er m kidn ey pr oblem s. E viden ce of t h is for m of
P KD does n ot pr esen t u n t il m u ch la t er in life a n d is Figure 18.14. Polycystic kidney. Cysts in nephrons and in
m or e fr equ en t a m on g t h e elder ly. the renal cortex alter renal function. (Courtesy Anatomical
Cyst s begin t o gr ow in t h e n eph r on s of t h e kidn ey, Chart Company.)
fillin g wit h glom er u la r filt r a t e, even t u a lly gr owin g
la r ger a n d m ovin g a wa y in t o a dja cen t t issu e. Kid-
n ey size in cr ea ses in pr opor t ion t o t h e size a n d n u m - m u lt iple or ga n syst em s becom e eviden t a s r en a l
ber of cyst s, wh ich ca n n u m ber in t o t h e t h ou sa n ds fu n ct ion wor sen s.
(Fig. 18.14). On e of t h e ea r liest m a n ifest a t ion s of
t h e disea se is h yper t en sion fr om com pr ession of
t h e r en a l vessels a n d su bsequ en t a ct iva t ion of t h e
DIAGNOSTIC CRITERIA
RAAS (see Ch a pt er 8). Ot h er com m on sym pt om s Polycyst ic kidn ey disea se dia gn osis is con fir m ed by
in clu de: t h e pr esen ce of t h r ee or m or e kidn ey cyst s ver ified
by u lt r a sou n d. Fa m ily h ist or y of P KD a n d ext r a r en a l
● F la n k pa in
cyst s a lso su ggest P KD. P r ogr ession of t h e disea se
● H ea da ch es
m a y be slow, dela yin g on set of sym pt om s. Gen et ic
● Na u sea , a n or exia
t est in g m a y a lso be u sefu l in det ect in g m u t a t ion s
● Ur in a r y t r a ct in fect ion
in gen es a ssocia t ed wit h t h e disea se, su ch a s P KD1
● Liver a n d pa n cr ea t ic cyst s
(ch r om osom e 18) a n d P KD2 (ch r om osom e 4). Th ese
● Ca r dia c va lvu la r disea se
fin din gs a r e lim it ed t o det er m in in g dia gn osis bu t do
● H yper t en sion
n ot in dica t e pr ogn osis.
● Ren a l ca lcu li
● Cer ebr a l a n eu r ysm s
● Diver t icu la r disea se TREATMENT
Accu m u la t ion of n it r ogen ou s wa st es, a lt er ed flu id/Tr ea t m en t of P KD in clu des sym pt om a t ic ca r e, st r a t -
elect r olyt e ba la n ce, a n d im pa ir ed fu n ct ion in egies t o pr om ot e r en a l fu n ct ion , a n d su ppor t ive
ca r e du r in g en d-st a ge
r en a l disea se. Lifest yle
m odifica t ion s in clu din g
F R O M T H E L AB m a in t en a n ce of h ea lt h y
Glomerular filtration can indicate the development and progression of renal failure. Glo- weigh t , ph ysica l a ct ivit y
merular filtration rate (GFR) normally ranges between 120 and 130 mL/ minute, with a GFR a n d n u t r it iou s diet t h a t
≥ 90 mL/ minute considered within normal limits. Progressive decline in GFR is characteris- in clu des m oder a t e pr o-
tic of decline in kidney function as follows: t ein (0.75 t o 1.0 g/kg/d),
low sodiu m (≤6 g sa lt per
Mild disease, GFR 60 to 89 mL/ minute da y), flu id in t a ke t o sa t -
Moderate disease, GFR 30 to 59 mL/ minute isfy t h ir st , a n d sm okin g
Severe disease, GFR 15 to 29 mL/ minute cessa t ion a r e im por t a n t
Renal failure, GFR < 15 mL/ minute
t o im plem en t pr ior t o
a dva n ced ch r on ic kidn ey
Blood urea nitrogen (BUN), serum creatinine, and potassium levels become elevated. disea se.13 In a u t osom a l
Decreased hemoglobin, arterial pH, and bicarbonate also indicate worsening renal function. dom in a n t P KD, ph a r-
m a cologic m a n a gem en t
 C lin ic a l Mo d e ls 483

in clu des t r ea t m en t of h yper t en sion u sin g a n giot en -
sin -con ver t in g en zym e in h ibit or (ACE -I) a n d a n -
giot en sin r ecept or blocker (ARB) a n t ih yper t en sive
a gen t s t o a t a r get blood pr essu r e of ≤ 130/80 m m
H g.14 For in dividu a ls wit h en d-st a ge r en a l fa ilu r e,
kidn ey t r a n spla n t a t ion m a y be in dica t ed. 15 Pa in is
con t r olled by a n a lgesics. Ur in a r y t r a ct in fect ion s a r e
t r ea t ed wit h a n t ibiot ics, bu t t h ey do pr esen t ch a l-
len ges beca u se t h e pa t h ogen s ca n a scen d m or e ea s-
ily a n d a r e m or e difficu lt t o t r ea t (a n t ibiot ics h a ve
poor pen et r a t ion in t o t h e cyst ic t issu e).
Th e pr ogr ession of disea se over t im e m ay r esu lt
in ch r on ic r en a l fa ilu r e (F ig. 18.15). E n d-st a ge r en a l
disea se r equ ir es dia lysis or t r a n spla n t for in dividu -
a ls t o su r vive. Dia lysis opt ion s in clu de h em odia lysis
a n d per it on ea l dia lysis. H e m o d ia ly s is u ses specia l
filt er s t h r ou gh t h e m ech a n ism s of diffu sion , osm osis,
a n d u lt r a filt r a t ion t o r em ove wa st es t h a t t h e kidn eys
n o lon ger ca n r em ove on t h eir own . Th is pr ocedu r e
r equ ir es a ccess t o t h e blood su pply so t h a t blood ca n
t r a vel t h r ou gh a set of t u bes in t o a dia lyzer, wh er e
wa st e pr odu ct s a n d excess wa t er a r e r em oved. All
m olecu les wit h t h e except ion of blood cells a n d
pla sm a pr ot ein s ca n m ove fr eely bet ween t h e sem i-
per m ea ble filt er m em br a n e bet ween t h e blood a n d
dia lysis flu id. Th e pu r ified blood is t h en r et u r n ed
t h r ou gh a n ot h er set of t u bes ba ck in t o t h e body for
cir cu la t ion (F ig. 18.16). Tr ea t m en t s a r e sch edu led
for t h r ee t im es per week, ea ch la st in g 3 t o 5 h ou r s.
Access t o blood ca n be a ch ieved by t h e su r gica l a t -
t a ch m en t of a n a r t er y t o a vein , kn own a s a n a r -
t e r io v e n o u s (AV) is t u la . Th e blood pr essu r e fr om
t h e a r t er y en la r ges t h e m or e pa ssive vein , m a kin g it
a n idea l st r u ct u r e for r epea t ed ven ipu n ct u r e (n eedle
in ser t ion ). Th is pr ocedu r e r equ ir es en ou gh t im e for
a dequ a t e en la r gem en t of t h e vein , lim it in g it s im m e-
dia t e u se. An ot h er m et h od u sed t o obt a in a ccess t o
t h e blood su pply is a gr a ft or a r t e r io v e n o u s s h u n t ,
con n ect in g t h e a r t er y t o t h e vein u sin g a syn t h et ic
t u be. Th is m et h od ca n be u sed m or e qu ickly, bu t it
ca r r ies a n in cr ea sed r isk for clot developm en t a n d
in fect ion . H epa r in , a n a n t icoa gu la n t , is u sed du r in g

Chro nic re nal failure

S odium a nd wa te r Pota s s ium Elimina tion Erythropoie tin Acid-ba s e Activa tion P hos pha te
ba la nce ba la nce of nitroge nous production ba la nce vita min D e limina tion
wa s te s

S ke le ta l
Hype rte ns ion Hype rka le mia Ane mia Hypoca lce mia
buffe ring

Incre a s e d Ede ma Coa gulopa thie s Acidos is Hype rpa ra thyroidis m

va s cula r
volume

Ure mia

He a rt fa ilure Pe rica rditis

S kin Ga s trointe s tina l Ne urologic S exua l

dis orde rs Os te odys trophie s
ma nife s ta tions ma nife s ta tions dys function

Figure 18.15. Pathophysiology of chronic renal failure. Clinical manifestations are present in multiple organ systems as a
result of renal failure. (Modified from Porth CM. Pathophysiology: Concepts of Altered Health States. 7th ed. Philadelphia,
PA: Lippincott Williams & Wilkins; 2004.)
484 C h a p t e r 18: Alt er ed E lim in a t ion

Dia lys is inflow

pre s s ure monitor Ve nous pre s s ure
monitor
He pa rin pump
(preve nts
clotting)

Air tra p a nd
Dia lyze r a ir de te ctor

Air de te ctor
cla mp

Cle a n blood
re turns to
body

Blood re move d
Arte ria l for cle a ns ing
pre s s ure
Blood pump monitor

Arte ry

Ve in
From dia lys is
ma chine

Loope d
gra ft

To dia lys is
ma chine

B C

Figure 18.16. Hemodialysis. A: Hemodialysis uses special filters to remove wastes that the kidneys no longer can do on
their own through the mechanisms of diffusion, osmosis, and ultrafiltration. B: Arteriovenous fistula. C: Arteriovenous shunt.

dia lysis t o pr even t t h e for m a t ion of clot s du r in g t h e design ed t o dr a w ou t wa st es fr om sm a ll ca pilla r ies

pr ocedu r e. H em odia lysis ca n be don e eit h er a t a dia l-
ysis cen t er or a t h om e wit h pr oper pa t ien t t r a in in g.
P e r it o n e a l d ia ly s is pr ovides a n ot h er opt ion
for t r ea t m en t in r en a l fa ilu r e. Wa st e a n d excess
wa t er is r em oved u sin g t h e per it on ea l m em br a n e
a s t h e sem iper m ea ble “filt er,” wit h t h e sa m e t r a n s-
por t m ech a n ism s u sed in h em odia lysis. Solu t ion
in t h e per it on eu m is in ser t ed in t o t h e a bdom en via
a t u be, pr eviou sly pla ced su r gica lly. Aft er sever a l
h ou r s, t h is solu t ion is dr a in ed a n d disca r ded a lon g
wit h t h e wa st e pr odu ct s, a n d wa t er is r em oved. Th is
cycle is con sider ed a n exch a n ge. Risks in clu de per i-
t on it is, wh ich is m in im ized wit h t h e u se of st er ile
t ech n iqu e. Th e t ypes of per it on ea l dia lysis in clu de:

● Con t inu ous a m bu la t or y per it onea l dia lysis (CAP D)
■ Most com m on t ype
■ Dia lysis flu id is in ser t ed in t o t h e a bdom en ,
wh er e it r em a in s for 4 t o 6 h ou r s (dwell t im e),
followed by dr a in a ge
■ Repea t ed wit h fr esh dia lysis solu t ion u p t o fou r
t im es a da y on a da ily ba sis
● Con t in u ou s cycler-a ssist ed (a u t om a t ed) per it o-
n ea l dia lysis (CCP D)
■ A specia l m a ch in e (cycler ) fills a n d em pt ies
a bdom en of dia lysis flu id t h r ee t o five t im es a
n igh t du r in g sleep
■ F lu id is in ser t ed in t h e m or n in g wit h a dwell
t im e la st in g t h e en t ir e da y
● Com bin a t ion CAP D a n d CCP D
In dividu a ls wh o r equ ir e dia lysis sh ou ld ea t a diet
low in pr odu ct s likely t o pr odu ce h a r m fu l wa st e.
Recom m en da t ion s for diet in clu de:
● Ba la n ced a m ou n t s of pr ot ein (ch icken , m ea t , a n d
fish )
● Low pot a ssiu m , sodiu m , a n d ph osph or u s
● F lu id r est r ict ion
Kidn ey t r a n spla n t m ay be n ecessa r y in sever e ca ses
of PKD. Th e sou r ces of t h e kidn ey ca n be fr om a fa m -
ily m em ber (livin g, r ela t ed don or ), a n ot h er per son
n ot r ela t ed (livin g, u n r ela t ed don or ), or fr om a per son
wh o r ecen t ly died (decea sed don or ). On e of t h e gr ea t -
est r isks in t r a n spla n t a t ion is t h a t of r eject ion , a s
det a iled in Ch a pt er 4. Fa ct or s con sider ed wh en de-
t er m in in g a m a t ch or lower r isk of r eject ion in clu de:
● Blood t ype
■ Most im por t a n t a spect
■ Mu st be com pa t ible
● H u m a n leu kocyt e a n t igen s (H LAs)
■ A t ot a l of six H LAs exist
■ Risk of r eject ion is decr ea sed wit h in cr ea sed
n u m ber of H LA m a t ch es
● Cr oss-m a t ch in g a n t igen s
■ An t igen –a n t ibody r ea ct ion s bet ween don or a n d
r ecipien t blood
■ Risk of r eject ion is decr ea sed in t h e a bsen ce of
r ea ct ion (n ega t ive cr oss-m a t ch )
Im m u n osu ppr essa n t a dm in ist r a t ion h elps decr ea se
r eject ion r isk a ft er su r ger y.
Stop and Consider
Why do individuals suffering from renal failure
become anemic?
Diverticular Disease
Diver t icu la r disea se a ffect s t h e la r ge in t est in e. Ap-
pr oxim a t ely h a lf of a ll Am er ica n s > 60 yea r s old a r e
C lin ic a l Mo d e ls 485
a ffect ed by diver t icu la r disea se wit h t h e m a jor it y
80 yea r s of a ge or older. 16 P r ocesses t h a t ch a r a ct er-
ize diver t icu la r disea se in clu de decr ea sed m ot ilit y,
obst r u ct ion , a n d im pa ir ed per fu sion .
PATHOPHYSIOLOGY
A d iv e r t ic u lu m (sm a ll sa c or ou t pou ch in g) for m s
a lon g t h e wa ll of t h e colon , m ost oft en in t h e a scen d-
in g colon . Typica lly, diver t icu lu m develops a t a sit e
of wea kn ess in t h e in t est in a l wa ll. Mor e t h a n on e
diver t icu lu m is ca lled d iv e r t ic u la . Th e pr esen ce
of diver t icu la is com m on ly r efer r ed t o a s t h e con -
dit ion d iv e r t ic u lo s is . Feca l m a t t er ca u gh t in sa cs
m a y pr om ot e t h e developm en t of in fect ion , kn own
a s d iv e r t ic u lit is . St r on g segm en t a l con t r a ct ion s in
t h e colon pr om ot e in cr ea se in in t r a lu m in a l pr essu r e,
in cr ea sin g r isk for h er n ia t ion . H er n ia t ion of t h e di-
ver t icu lu m m a kes t h e blood vessels su pplyin g t h e
in t est in a l wa ll su scept ible t o t r a u m a a n d bleedin g. 17
Ch r on ic con st ipa t ion is lin ked t o t h e developm en t
of diver t icu la r disea se. Slow m ovem en t of feca l m a t -
t er lea ds t o in cr ea sed, pr olon ged pr essu r e on t h e
wa lls of t h e la r ge in t est in e, a lt er in g st r u ct u r e a n d
fu n ct ion . Most people a r e u n a wa r e of t h e pr oblem
u n t il it lea ds t o bleedin g, in fect ion , obst r u ct ion , a n d
isch em ia of t h e a ffect ed a r ea of t h e colon . Per for a -
t ion r esu lt in g fr om t h ese pr ocesses r esu lt s in h em -
or r h a ge, a bscess, sepsis, or per it on it is (Fig. 18.17).
In amed and
edematous
peritoneum
Figure 18.17. Peritonitis. The peritoneal membrane be-
comes edematous and inflamed in peritonitis. (Courtesy
Anatomical Chart Company.)
486 C h a p t e r 18: Alt er ed E lim in a t ion
CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s of diver t icu lit is m ir r or t h ose
descr ibed ea r lier u n der gen er a l m a n ifest a t ion s a n d
in clu de a bdom in a l pa in , fever, n a u sea , a n d vom it -
in g. Pa in is t h e m ost com m on m a n ifest a t ion , t ypi-
ca lly pr esen t in t h e left lower qu a dr a n t a r ea of t h e
sigm oid colon , t h e m ost fr equ en t sit e for diver t icu li-
t is. Na u sea a n d vom it in g m a y be du e t o obst r u ct ion
or r edu ced per ist a lsis fr om in fla m m a t ion . In som e
ca ses, diver t icu lit is m a y be com plica t ed by per fo-
r a t ion , fist u la or a bscess developm en t . Abdom in a l
t en der n ess m a y be pr esen t , wit h in dividu a ls dem on -
st r a t in g gu a r din g, r igidit y, a n d r ebou n d t en der n ess
of t h e a bdom en . Sym pt om s a r e oft en sever e en ou gh
t o pr om pt m edica l a t t en t ion . Su dden on set of r ect a l
bleedin g m a y occu r wh en blood vessels a r e in ju r ed.
DIAGNOSTIC CRITERIA
Acu t e diver t icu lit is is det er m in ed by exa m in a t ion
of st ool for blood, eva lu a t ion of blood sa m ples for
a n em ia a n d sign s of a ct ive in fect ion , or iden t ifica -
t ion of in fla m ed or r u pt u r ed sa cs u sin g u lt r a sou n d,
m a gn et ic r eson a n ce im a gin g, or CT sca n . On ce t h e
a cu t e in fect ion h a s r esolved, diver t icu la ca n be eva l-
u a t ed wit h a ba r iu m en em a , flexible sigm oidoscopy,
or colon oscopy.
TREATMENT
Im m edia t e t r ea t m en t goa ls in clu de con t r ol of in fec-
t ion , r est in g of t h e bowel, a n d pr even t ion of com -
plica t ion s. Acu t e diet a r y m a n a gem en t m a y in clu de
a clea r liqu id diet for 2 t o 3 da ys u n t il sym pt om s
r esolve. P r even t ion in volves diet a r y a n d lifest yle
a lt er a t ion s design ed t o pr even t con st ipa t ion . Th ese
st r a t egies in clu de:
● Diet h igh in fiber a n d low in fa t
● Avoida n ce of foods t h a t m a y lea d t o con st ipa t ion ,
su ch a s ba n a n a s a n d r ice
● Avoida n ce of foods m or e likely t o be r et a in ed in di-
ver t icu la , in clu din g n u t s, seeds, a n d st r a wber r ies
● F lu id in t a ke, pr efer a bly wa t er, of a t lea st 2 L/d
● Da ily exer cise
An t ibiot ic a n d a n t i-in fla m m a t or y t h er a py m a y be
in dica t ed in u n com plica t ed diver t icu lit is. P h a r m a -
cot h er a py m a y a lso in clu de t h e u se of bu lk-for m in g
la xa t ives a n d a n t ispa sm odic dr u gs for a bdom in a l
cr a m pin g. Su r gica l t r ea t m en t m a y be r equ ir ed for
em er gen cies, in clu din g per for a t ion or in fa r ct ion of
diver t icu la . B o w e l r e s e c t io n , or r em ova l of a por-
t ion of t h e la r ge in t est in e, m a y be r equ ir ed. A c o -
lo s t o m y (est a blish m en t of a n a r t ificia l open in g of
t h e la r ge in t est in e ext er n a lly on t h e a bdom en ) m a y
be r equ ir ed a s a t em por a r y m ea su r e u n t il t h e colon
is h ea led, a t wh ich t im e it m a y be r econ n ect ed (r e-
a n a st om osis). Or a l in t a ke is wit h h eld a ft er su r ger y
beca u se of t h e expect ed decr ea se in m ot ilit y com m on
a ft er a bdom in a l su r ger y. Or a l in t a ke slowly r esu m es
a ft er a ssu r a n ce of t h e r et u r n of bowel fu n ct ion , in -
dica t ed by t h e pr esen ce of bowel sou n ds a n d t h e
pa ssin g of fla t u s (ga s pa ssed t h r ou gh t h e a n u s). In -
t r odu ct ion of food or flu id in t o t h e GI t r a ct befor e
t h is t im e m a y r esu lt in a p a r a ly t ic ile u s , a n on m e-
ch a n ica l bowel obst r u ct ion ch a r a ct er ized by a la ck
of per ist a lsis.
Functional Fecal Incontinence
F u n c t io n a l e c a l in c o n t in e n c e , for m er ly kn own
a s en copr esis or soilin g, is a con dit ion of r epet it ive,
volu n t a r y or in volu n t a r y, pa ssa ge of st ool in in a ppr o-
pr ia t e pla ces in ch ildr en 4 yea r s of a ge a n d older. 18
F u n ct ion a l feca l in con t in en ce m a y be cla ssified a s
r et en t ive or n on r et en t ive. Th e clin ica l m odel of fu n c-
t ion a l feca l in con t in en ce h igh ligh t s t h e volu n t a r y
con t r ol m ech a n ism s t h a t ca n be u sed t o im pa ir st ool
elim in a t ion .
PATHOPHYSIOLOGY
F u n ct ion a l feca l in con t in en ce is oft en a ssocia t ed
wit h con st ipa t ion a n d is cla ssified a s r et en t ive or
n on r et en t ive. Key developm en t a l t r igger s a r e a ssoci-
a t ed wit h t h e developm en t of fu n ct ion a l feca l in con -
t in en ce, in clu din g in t r odu ct ion of solid foods, t oilet
t r a in in g, a n d st a r t of sch ool a t t en da n ce. Con st ipa t ion
m a y r esu lt fr om t h e ch a n ge in diet a n d, in older ch il-
dr en , t h e st r ess a ssocia t ed wit h defeca t ion t h a t lea ds
t o volu n t a r y r et en t ion , a m plifyin g t h e pr oblem of
con st ipa t ion . No a n a t om ic or ph ysiologic a n om a lies
a r e a ssocia t ed wit h fu n ct ion a l feca l in con t in en ce. In -
st ea d, t h e fu n ct ion a l feca l in con t in en ce pr ovides a n
illu st r a t ion of t h e volu n t a r y con sciou s con t r ol over
defeca t ion in n eu r ologica lly com pet en t in dividu a ls.
CLINICAL MANIFESTATIONS
Sym pt om -ba sed dia gn ost ic cla ssifica t ion s, kn own a s
t h e Rom e III cr it er ia , wer e developed t o h elp r ecog-
n ize a n d t r ea t defeca t ion a n d ot h er GI disor der s.18
Th e r et en t ive for m of fu n ct ion a l feca l in con t in en ce
in a ch ild a ged 4 yea r s or older is a ssocia t ed wit h
r et en t ive post u r in g or excessive volit ion a l st ool r e-
t en t ion , h ist or y of h a r d or pa in fu l bowel m ovem en t s,
pr esen ce of la r ge feca l m a ss in t h e r ect u m , or h ist or y
of pa ssin g la r ge dia m et er st ool. Th e fa ct or s a ssoci-
a t ed wit h fu n ct ion a l feca l in con t in en ce a r e a bsen t
in t h e n on r et en t ive for m a n d in clu de socia l con t ext
in a ppr opr ia t e for defeca t ion , a bsen ce of u n der ly-
in g disor der s of m ot ilit y or a n or ect a l sen sor im ot or

fu n ct ion , a bsen ce of excessive st ool a n d feca l r et en -
t ion , sym pt om fr equ en cy a t lea st on ce per m on t h
a n d du r a t ion of a t lea st 2 m on t h s.
DIAGNOSTIC CRITERIA
It is im por t a n t t o det er m in e iden t ify ch a r a ct er ist ics
of in con t in en ce. Th e a bsen ce of a pot en t ia l m edica l,
developm en t a l, or beh a vior a l pa t h ology is t h e fir st
st ep in det er m in in g t h e dia gn osis. A h ist or y of in con -
t in en ce is exa m in ed, in clu din g st ool pa t t er n (size,
con sist en cy, a n d in t er va l), eviden ce of con st ipa t ion ,
fa ct or s r ela t ed t o defeca t ion episodes (a ge of on set ,
t ype, a n d a m ou n t ), diet h ist or y, a ssocia t ed pa in , cu r-
r en t m edica t ion s, a ssocia t ed u r in a r y sym pt om s (en -
u r esis, in fect ion ), fa m ily h ist or y of con st ipa t ion , a n d
em ot ion a l st r ess. Developm en t a l r ea din ess for t oilet -
in g is a lso im por t a n t t o eva lu a t e. P h ysica l exa m in a -
t ion , in clu din g n eu r ologic exa m in a t ion , m a y poin t t o
a n a n a t om ic or fu n ct ion a l con dit ion . Most ca ses of
fu n ct ion a l r et en t ive feca l in con t in en ce a r e ca u sed by
con st ipa t ion , wh er ea s fu n ct ion a l n on r et en t ive feca l
in con t in en ce is u su a lly ca u sed by n on or ga n ic fa c-
t or s. Con sider a t ion m u st be given t o t h e pr esen ce of
n eu r ogen ic, n eu r om u scu la r, en docr in e, or a n a t om ic
con dit ion s t o m a ke t h ese det er m in a t ion s.
TREATMENT
Beh a vior s con t r ibu t in g t o t oilet -r efu sa l beh a vior
sh ou ld be a ddr essed, a n d st r a t egies sh ou ld be u sed
t o pr om ot e posit ive, m or e en joya ble t oilet in g expe-
r ien ces.19 Met h ods pr om ot in g soft st ool m in im ize
discom for t du r in g defeca t ion , h elpin g in dividu a ls
t o over com e t h e fea r of pa in -a ssocia t ed bowel m ove-
m en t s. An ot h er effect ive st r a t egy in clu des h a vin g
sch edu led t im e on t h e t oilet a n d cr ea t in g a r ela xed
a t m osph er e t h a t pr om ot es bowel t r a in in g a n d effec-
t ive t oilet in g skills. In cen t ives for posit ive exper i-
en ces m ay m ot iva t e t h e ch ild a n d pr om ot e even t u a l
self-in it ia t ion of bowel m ovem en t s. Men t a l h ea lt h
a n a lysis t o explor e r oot s of opposit ion a l a n d defia n t
beh a vior s m u st a lso be con sider ed.
Stop and Consider
Why is the diagnosis of functional nonretentive
fecal incontinence limited to children at least 4
years of age?
S U MMAR Y
● Alt er a t ion s in elim in a t ion ca n develop beca u se of
t h e pr ocesses r egu la t in g pr odu ct ion or elim in a -
t ion of u r in e a n d st ool, ca u sin g sym pt om s r a n gin g
fr om in con ven ien t t o life t h r ea t en in g.
C h a p t e r 18: Alt er ed E lim in a t ion 487
● Ur in e is a pr odu ct of t h e r en a l syst em , com pr ised
of wa t er a n d wa t er-solu ble wa st e pr odu ct s filt er ed
fr om t h e cir cu la t ion . Ch a r a ct er ist ics ca n pr ovide
eviden ce of a lt er ed elim in a t ion pr ocesses.
● Tr a n spor t pr ocesses t h r ou gh ou t t h e n eph r on con -
t r ibu t e t o t h e ch a r a ct er ist ics of u r in e filt r a t e.
● The renal system is importa nt in the regula tion
of body fluid volume a nd composition, elimination
of meta bolic wastes, regulation of blood pressure
and the synthesis, and release or activation of
hormones.
● St ool is t h e wa st e pr odu ct elim in a t ed by t h e GI
t r a ct . St ool ch a r a ct er ist ics a n d pa t t er n s pr ovide
eviden ce of a lt er ed pr ocesses of GI elim in a t ion .
● Ur in a r y a n d st ool elim in a t ion m a y be im pa ir ed
beca u se of a lt er a t ion s in m ot ilit y, n eu r om u scu la r
fu n ct ion , per fu sion , a n d pa t en cy. Ma n ifest a t ion s
ca n in clu de a lt er ed volu m e a n d color, bleedin g,
pa in , dist en t ion , a n d a n or exia .
● Dia gn ost ic st r a t egies in clu de a n a lysis of u r in e
a n d st ool con t en t a n d t est in g for st r u ct u r a l
a n om a lies.
● Im pa ir ed elim in a t ion ca n be t h e ca u se of ot h er
body syst em a lt er a t ion s, a n d it ca n con t r ibu t e
t o t h e developm en t of im pa ir m en t in ot h er sys-
t em s a s well. A t h or ou gh u n der st a n din g of t h ese
a lt er ed pr ocesses h elps t o r a pidly iden t ify a n d ef-
fect ively m a n a ge r ela t ed con dit ion s.
C AS E S T U D Y 18.1
A fem a le n eon a t e wa s bor n 8 weeks pr em a t u r e a t
32 weeks’ gest a t ion . Sh e is cu r r en t ly 3 weeks of a ge
a n d h a s r ecen t ly a dva n ced t o or a l feedin gs wit h
a r t ificia l in fa n t for m u la a s h er sole sou r ce of n u -
t r it ion . Sh e developed sym pt om s t h a t su ggest t h a t
sh e is developin g n ecr ot izin g en t er ocolit is (NE C).
F r om you r r ea din g on NE C, a n swer t h e followin g
qu est ion s:
1. Wh a t a n a t om ic pr oblem wou ld m ost likely lea d t o
t h e sym pt om s a ssocia t ed wit h NE C?
2. Wh a t ca u ses t h e u n der lyin g pa t h ology a ssocia t ed
wit h NE C?
3. Wh a t a r e t h e r isk fa ct or s for t h is n eon a t e t h a t
wou ld su ggest NE C?
4. Wh a t a r e t h e clin ica l m a n ifest a t ion s you wou ld
expect wit h NE C?
5. Wh a t dia gn ost ic t est s m igh t be u sed t o iden t ify
NE C?
6. H ow wou ld you m a n a ge a n in fa n t wit h NE C?
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r n a l
a r t icle or Web sit e t h a t det a ils NE C t o con fir m you r
pr edict ion s.
488 C h a p t e r 18: Alt er ed E lim in a t ion

P R AC T I C E E XAM Q U E S T I O N S 8. Th e a r ea of t h e la r ge in t est in e t h a t a bsor bs t h e

m a jor it y of wa t er is t h e:
1. Wh ich of t h e followin g pr ovides t h e m ost objec- a . Ileu m
t ive m ea su r em en t of r en a l dysfu n ct ion ? b. Ascen din g colon
a . Wh it e blood cell cou n t c. Descen din g colon
b. Glom er u la r filt r a t ion r a t e d. Rect u m
c. Alt er ed u r in a r y elect r olyt es
d. P r esen ce of n it r it es in u r in e 9. Th e pr ocess by wh ich feca l con t en t s en t er s t h e
r ect u m is kn own a s:
a . Per ist a lsis
2. A ch a r a ct er ist ic ch a n ge in st ool t h a t m a y in di-
b. Segm en t a l con t r a ct ion s
ca t e t h e pr esen ce of blood in clu des wh ich on e of
c. Ma ss m ovem en t
t h e followin g?
d. Tet a n y
a . Melen a
b. H em a t u r ia 10. Th e a ver a ge volu m e of u r in e elim in a t ed ea ch
c. F loa t in g da y t ot a ls:
d. Gr a y-like color a . 200 m L
b. 800 m L
3. Wh ich of t h e followin g dia gn ost ic pr ocedu r es a l- c. 1,500 m L
lows a n a lysis of t h e en t ir e la r ge colon ? d. 3,000 m L
a . Ba r iu m en em a
b. F lexible sigm oidoscopy 11. Th e _________ sph in ct er is m a de of skelet a l
c. F lexible ga st r oscopy m u scle a n d is u n der volu n t a r y con t r ol.
d. Colon oscopy a . In t er n a l
b. E xt er n a l
4. Wh ich of t h e followin g foods sh ou ld be a voided c. An t er ior
in people wit h r en a l ca lcu li? d. Post er ior
a . Gr a pe ju ice
b. Gr ou n d beef 12. Ur in e specific gr a vit y of 1:030 in dica t es:
c. St r a wber r ies a . Con cen t r a t ed u r in e
d. Cin n a m on b. Dilu t e u r in e
c. Ur in e h igh in ba ct er ia
5. Wh ich of t h e followin g foods sh ou ld be a voided d. Ca st s in u r in e
in people wit h diver t icu la r disea se?
a . Gr a pe ju ice 13. Wh ich of t h e followin g dia gn ost ic cr it er ia is con -
b. Gr ou n d beef sist en t wit h t h e dia gn osis of fu n ct ion a l feca l
c. St r a wber r ies in con t in en ce?
d. Cin n a m on a . Age of 1 yea r
b. Age of 3 yea r s
c. Age of 5 yea r s
6. Wh ich t ype of u r in a r y in con t in en ce ca n be a t -
d. All of t h e a bove
t r ibu t ed t o m u scle over a ct ivit y?
a . St r ess in con t in en ce 14. A GF R of 95 m L/m in u t e in dica t es
b. Ur ge in con t in en ce a . Nor m a l r en a l fu n ct ion
c. Over flow in con t in en ce b. Mild r en a l disea se
d. F u n ct ion a l in con t in en ce c. Moder a t e r en a l disea se
d. Sever e r en a l disea se
7. Th e en t er ic n er vou s syst em com pon en t loca t ed
bet ween t h e cir cu la r a n d lon git u din a l m u scle 15. Wh ich of t h e followin g in cr ea ses t h e r isk for r e-
la yer s of t h e la r ge in t est in e: n a l ca lcu li?
a . Myen t er ic plexu s a . Ru n n in g 5 m iles
b. Su bm u cosa l plexu s b. Dr in kin g 32 ou n ces of m ilk per da y
c. Meissn er plexu s c. Seden t a r y lifest yle
d. Sola r plexu s d. Deh ydr a t ion

D I S C U S S I O N AN D
AP P L I C AT I O N
1. Wh a t did I kn ow a bou t a lt er ed elim in a t ion be-
for e t oda y?
2. Wh a t body pr ocesses a r e a ffect ed by a lt er ed
elim in a t ion ? H ow does a lt er ed elim in a t ion a ffect
t h ose pr ocesses?
3. Wh a t a r e t h e pot en t ia l et iologies for a lt er ed elim -
in a t ion ? H ow does a lt er ed elim in a t ion develop?
4. Wh o is m ost a t r isk for developin g a lt er ed elim i-
n a t ion ? H ow ca n t h ese a lt er a t ion s be pr even t ed?
5. Wh a t a r e t h e h u m a n differ en ces t h a t a ffect t h e
et iology, r isk, or cou r se of a lt er ed elim in a t ion ?
6. Wh a t clin ica l m a n ifest a t ion s a r e expect ed in t h e
cou r se of a lt er ed elim in a t ion ?
7. Wh a t specia l dia gn ost ic t est s a r e u sefu l in de-
t er m in in g t h e dia gn osis a n d cou r se of a lt er ed
elim in a t ion ?
8. Wh a t a r e t h e goa ls of ca r e for in dividu a ls wit h
a lt er ed elim in a t ion ?
9. H ow does t h e con cept of a lt er ed elim in a t ion
bu ild on wh a t I h a ve lea r n ed in t h e pr eviou s
ch a pt er a n d in t h e pr eviou s cou r ses?
10. H ow ca n I u se wh a t I h a ve lea r n ed?
R E SOUR CE S
Na t ion a l Kidn ey a n d Ur ologic Disea ses In for m a t ion
Clea r in gh ou se:
h t t p://kidn ey.n iddk.n ih .gov/in dex.h t m
Na t ion a l In st it u t e of Dia bet es & Digest ive & Kidn ey
Disea se, Na t ion a l In st it u t es of H ea lt h :
h t t p://www.n iddk.n ih .gov
R e er en ces
1. Sca les CD J r, Sm it h AC, H a n ley J M, et a l. P r eva -
len ce of kidn ey st on es in t h e Un it ed St a t es. E u r Ur ol.
2012;62(1):160–165. doi:10.1016/j.eu r u r o.2012.03.052.
2. H a ll P M. Neph r olit h ia sis: t r ea t m en t , ca u ses a n d pr even -
t ion . Cleve Clin J Med . 2009;76(10):583–591.
3. Zilber m a n DE , Yon g D, Alba la DM. Th e im pa ct of soci-
et y ch a n ges on pa t t er n s of u r olit h ia sis. Cu r r Opin Ur ol.
2010;20(2):1480153.
4. Ra ssweiler J, Ra ssweiler MC, Klein J. New t ech n ol-
ogy in u r et er oscopy a n d per cu t a n eou s n eph r olit h ot -
om y. Cu r r Opin Ur ol. 2016;26(1):95–106. doi:10.1097/
MOU.0000000000000240.
5. Rober t son WG. Diet a r y r ecom m en da t ion s a n d t r ea t -
m en t of pa t ien t s wit h r ecu r r en t idiopa t h ic ca lciu m
st on e disea se. Ur olith ia sis. 2016;44(1):9–26. doi:10.1007/
s00240-015-0849-2.
F in d a d d ition a l r esou r ces for th is ch a pter a t h ttp:th ePoin t.lww.com
C h a p t e r 18: Alt er ed E lim in a t ion 489
6. St ot h er s L, Th om D, Ca lh ou n E . Ur in a r y in con t in en ce
in m en . In : Lit win MS, Sa iga l C, eds. Ur ologic Disea ses
in Am er ica . US Depa r t m en t of H ea lt h a n d H u m a n
Ser vices, P u blic H ea lt h Ser vice, Na t ion a l In st it u t es of
H ea lt h , Na t ion a l In st it u t e of Dia bet es a n d Digest ive a n d
Kidn ey Disea ses. Wa sh in gt on , DC: US Gover n m en t P u b-
lish in g Office; 2004.
7. Nyga a r d I, Th om D, Ca lh ou n E . Ur in a r y in con t in en ce
in wom en . In : Lit win MS, Sa iga l C, eds. Ur ologic Dis-
ea ses in Am er ica . US Depa r t m en t of H ea lt h a n d H u m a n
Ser vices, P u blic H ea lt h Ser vice, Na t ion a l In st it u t es of
H ea lt h , Na t ion a l In st it u t e of Dia bet es a n d Digest ive a n d
Kidn ey Disea ses. Wa sh in gt on , DC: US Gover n m en t P u b-
lish in g Office; 2004.
8. Va n don in ck V, Bem elm a n s BL, Ma zzet t a C,
et a l. Th e pr eva len ce of u r in a r y in con t in en ce in
com m u n it y-dwellin g m a r r ied wom en : a m a t t er of defin i-
t ion . BJ U In t. 2004;94(9):1291–1295.
9. Yosh ida M, Ma su n a ga K, Na ga t a T, et a l. Th e for efr on t
for n ovel t h er a peu t ic a gen t s ba sed on t h e pa t h oph ysiol-
ogy of lower u r in a r y t r a ct dysfu n ct ion : pa t h oph ysiology
a n d ph a r m a cology of over a ct ive bla dder. J P h a r m a col
S ci. 2010;112(2):128–134.
10. Fa ien a I, Pa t el N, Pa r ih a r J S, et a l. Con ser va t ive m a n -
a gem en t of u r in a r y in con t in en ce in wom en . Rev Ur ol.
2015;17(3):129–139.
11. Ra n ga n GK, Lopez-Va r ga s P, Na n kivell BJ, et a l. Au t o-
som a l dom in a n t polycyst ic kidn ey disea se: a pa t h for-
wa r d. S em in Neph r ol. 2015;35(6):524–537. doi:10.1016/j.
sem n eph r ol.2015.10.002.
12. NIDDK. Kidney and urologic disease statistics for the
United States. http://kidney.niddk.nih.gov/kudiseases/pubs/
kustats/index.htm#kidney. Retrieved on February 6, 2010.
13. Ca m pbell KL, Ra n ga n GK, Lopez-Va r ga s P, et a l.
KH A-CARI a u t osom a l dom in a n t polycyst ic kidn ey
disea se gu idelin e: diet a n d lifest yle m a n a gem en t . S e-
m in Neph r ol. 2015;35(6):572–581.e17. doi:10.1016/j.
sem n eph r ol.2015.10.008.
14. Ma llet t A, Lee VW, Ma i J, et a l. KH A-CARI a u t osom a l
dom in a n t polycyst ic kidn ey disea se gu idelin e: ph a r m a co-
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582–589.e17. doi:10.1016/j.sem n eph r ol.2015.10.009.
15. Lee VW, Tu n n icliffe DJ, Ra n ga n GK. KH A-CARI a u -
t osom a l dom in a n t polycyst ic kidn ey disea se gu ide-
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Neph r ol. 2015;35(6):595–602.e12. doi:10.1016/j.
sem n eph r ol.2015.10.011.
16. Lidor AO, Sega l J B, Wu AW, et a l. Older pa t ien t s wit h
diver t icu lit is h a ve low r ecu r r en ce r a t es a n d r a r ely n eed
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in g. Am Fa m P h ysicia n . 2009;80(9):977–983.
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jpu r ol.2015.09.008.
 Ch a pt er

19
Degen er a t ive
Ch a n ges in Agin g

L E AR N I N G O U T C O ME S
1. Defin e a n d u se t h e key t er m s list ed in t h is ch a pt er.
2. Descr ibe t h e ba sis of t h eor et ic expla n a t ion s of a gin g.
3. Recogn ize t h e im plica t ion s of degen er a t ive ch a n ges in a gin g on t h e h ea lt h
of t h e in dividu a l.
4. Iden t ify com m on m a n ifest a t ion s of a ge-r ela t ed degen er a t ive ch a n ges.
5. Det a il m et h ods t o m a xim ize h ea lt h st a t u s in t h e elder ly popu la t ion .
6. List t h e com m on dia gn ost ic pr ocedu r es u sed t o iden t ify degen er a t ive
ch a n ges in a gin g.
7. Descr ibe t r ea t m en t st r a t egies a ppr opr ia t e for degen er a t ive ch a n ges in
a gin g.
8. Apply con cept s of a ge-r ela t ed a lt er a t ion s in cells, t issu es, a n d or ga n
syst em s t o select clin ica l m odels.

INTR ODUCTION
“You ’r e on ly a s old a s you feel” is a ph r a se oft en qu ot ed, bu t wh a t m a kes u s old?
Agin g is a n or m a l, expect ed pr ocess t h a t occu r s in a ll livin g in dividu a ls. E ven
t h ou gh it is a n or m a l, ph ysiologic pr ocess, t h e effect s ca n ca u se clin ica l m a n -
ifest a t ion s t h a t r a n ge fr om m in im a lly im pa ir ed fu n ct ion t o ser iou s disa bilit y.
Kn owledge of t h e degen er a t ive ch a n ges t h a t a r e in volved in t h e a gin g pr ocess
ca n pr ovide t h e ba sis of a da pt a t ion s t h a t ca n pr om ot e t h e gr ea t est degr ee of
fu n ct ion a n d in depen den ce.

R E S E AR C H N O T E S
By 2050, the number of people who will be older than 60 years is set to double. A new
report from the World Health Organization (WHO) calls for a dramatic shift in the way we
think about and approach a rapidly growing older population. The 245-page report defines
healthy aging as “the process of developing and maintaining the functional ability that en-
ables well-being in older age.” The full report can be found at http:/ / www.medscape.com/
viewarticle/ 851954.

490
 T h e o r ie s o Ag in g 491

Modu le 1 T h e o r ie s o Ag in g

Ag in g is com m on ly defin ed a s t h e gr a du a l a ssu r e r epr odu ct ive fu n ct ion a n d su r viva l of t h e spe-

det er ior a t ion of a m a t u r e or ga n ism r esu lt in g fr om cies. Gen es t h a t det er m in e su r viva l a t you n ger a ges,
t im e-depen den t , ir r ever sible ch a n ges in st r u ct u r e. t h er efor e, h a ve gr ea t er in flu en ce t h a n gen es t h a t
S e n e s c e n c e is oft en u sed in t er ch a n gea bly wit h a g- a r e expr essed a t older a ges.
in g a n d r efer s t o post m a t u r a t ion a l pr ocesses t h a t Th e a c c u m u la t e d m u t a t io n s t h e o r y su ggest s
lea d t o dim in ish ed h om eost a sis a n d in cr ea sed vu l- t h a t over t im e, t h e a ccu m u la t ion of gen et ic m u -
n er a bilit y. Agin g is a t im e-r ela t ed pr ocess t h a t de- t a t ion s du r in g cell division m a y con t r ibu t e t o a l-
t er m in es r espon ses lea din g t o illn ess a n d dea t h . Life t er ed cellu la r fu n ct ion a ssocia t ed wit h a gin g. Th e
expect a n cy, t h e a ge a t wh ich 50% of a given popu la - gr a du a l declin e in cellu la r a n d m et a bolic fu n ct ion
t ion is expect ed t o su r vive, is a t er m u sed t o descr ibe likely r esu lt s fr om a com bin a t ion of DNA m u t a t ion
dem ogr a ph ics a ssocia t ed wit h a gin g. a n d t elom er e sh or t en in g. Telom er es a r e t h e ca pped
st r u ct u r es on ch r om osom es t h a t pr ot ect ch r om o-
som e en ds (Fig. 19.1). E a ch t im e a ch r om osom e is
r eplica t ed, t h e t elom er es sh or t en . Wh en ch r om o-
Theories of Aging som es r ea ch a cr it ica l len gt h , cellu la r sen escen ce, or
t h e in t r in sic loss of t h e ca pa cit y of t h e cell t o pr olif-
Th eor ies of a gin g h a ve been developed t o expla in
er a t e, is t r igger ed.
ph ysiologic pr ocesses t h a t lea d t o clin ica l m a n ifes-
Obser va t ion s of decr ea sed im m u n e fu n ct ion wit h
t a t ion s. Th e m ech a n ism s t h a t pr ogr a m cells t o a ge
in cr ea sed a ge h a ve led t o t h e developm en t of t h e im -
a r e n ot clea r ly u n der st ood, bu t t h ey a r e kn own t o
m u n o lo g ic t h e o r y o a g in g . Redu ced r esist a n ce
con t r ibu t e t o im pa ir ed st r u ct u r e a n d fu n ct ion . Ag-
t o disea se secon da r y t o r edu ced T-cell fu n ct ion a n d
in g is a ssocia t ed wit h r edu ced fu n ct ion a l ca pa cit y
en h a n ced a u t oim m u n e r espon ses a r e com m on ch a r-
beca u se t h e body fa ils t o pr odu ce su fficien t n u m ber s
a ct er ist ics of in cr ea sin g a ge. An ot h er t h eor y, t h e a n -
of r epla cem en t cells, especia lly t h ose t h a t a r e n ot
t a g o n is t ic p le io t r o p y t h e o r y, su ggest s t h a t gen es
ca pa ble of m it ot ic division . Iden t ifyin g t h e cellu la r
m a y h a ve ben eficia l effect s du r in g ea r ly life bu t
m ech a n ism s u n der lyin g degen er a t ive ch a n ges of
h a r m fu l effect s a s t h e in dividu a l a ges. Th e or igin
a gin g is n ecessa r y for effect ive dia gn osis a n d t r ea t -
m en t of r ela t ed pa t h ology.
Th eor ies of a gin g a r e u su a lly ca t egor ized a s devel-
opm en t a l or st och a st ic. D e v e lo p m e n t a l t h e o r ie s Te lome re
poin t t o t h e in flu en ce of gen et ics a s t h e m a jor det er-
m in a n t of a gin g. S t o c h a s t ic t h e o r ie s su ppor t t h e
idea t h a t a gin g is t h e r esu lt of cu m u la t ive cellu la r
da m a ge. Th e pr ocess of a gin g is likely m u lt ifa ct or ia l,
r eflect in g m ech a n ism s of bot h gen et ics a n d en vi-
r on m en t . Da m a ge t o cells m a y be du e t o cu m u la t ive
ext r in sic even t s t h a t ca u se in ju r y t o cells or fr om
in t r in sic even t s r egu la t in g cell dea t h det er m in ed
by gen et ic con t r ol. Cellu la r da m a ge r esu lt in g fr om
m ech a n ica l or ch em ica l in ju r y ca u sed by a ccu m u la -
t ion of m et a bolit es a n d u lt r a violet r a dia t ion da m a ge
t o DNA a r e a m on g t h e pot en t ia l ca u ses t h ou gh t t o
con t r ibu t e t o a gin g. Cell dea t h t h a t is pr ogr a m m ed
(a popt osis) or occu r r in g beca u se of in ju r y (n ecr osis)
oft en con t r ibu t es t o t h e clin ica l m a n ifest a t ion s of a g-
in g (see Ch a pt er 2).

DEVELOPMENTAL THEORIES Te lome re

Developm en t a l t h eor ies su ppor t t h e exist en ce of a Figure 19.1. Telomere location on a single chromosome.
gen et ica lly pr ogr a m m ed a n d con t r olled con t in u u m Each chromatid is capped by a telomere. (Modified from
of developm en t a n d m a t u r a t ion . At ea r lier a ges, McClatchey KD. Clinical Laboratory Medicine. 2nd ed.
bioch em ica l pa t h wa ys opt im a lly m a in t a in gen es t o Philadelphia, PA: Lippincott Williams & Wilkins; 2002.)
492 C h a p t e r 19: Degen er a t ive Ch a n ges in Agin g
for t h is select ion m a y be ba sed on t h e pr om ot ion of
r epr odu ct ive su ccess r a t h er t h a n n ega t ive effect s a s-
socia t ed wit h a gin g. Mu t a t ion s t h a t occu r la t er in
life lim it t h e in flu en ce of evolu t ion a r y select ion . Th e
n e u r o e n d o c r in e t h e o r y su ggest s t h e in t er r ela -
t ion sh ip bet ween n eu r on s a n d a ssocia t ed h or m on es
a s t h e st im u lu s for a gin g. Th e h ypot h a la m ic–
pit u it a r y a xis is in st r u m en t a l in con t r ibu t in g t o t h e
r egu la t ion of m a n y bodily fu n ct ion s, in clu din g devel-
opm en t , gr owt h , pu ber t y, r epr odu ct ion , m et a bolism ,
a n d a gin g. Men opa u se is a n exa m ple of t h e m a n i-
fest a t ion of a lt er ed n eu r oen docr in e r espon siven ess
ch a r a ct er ist ic of wom en wit h in cr ea sin g a ge.
STOCHASTIC THEORIES
St och a st ic t h eor ies su ggest t h a t r a n dom a ccu m u -
la t ed cellu la r da m a ge lea ds t o a gin g. Ta r get s for cel-
lu la r da m a ge in clu de m it och on dr ia a n d DNA. Th e
Modu le 2 G e n e r a l Ma n i e s t a t io n s o Ag in g
A pa t t er n of gr a du a l loss is ch a r a ct er ist ic of t h e
ch a n ges a ssocia t ed wit h a gin g (F ig. 19.2). Th ese
ch a n ges a r e ph ysiologic r a t h er t h a n pa t h ologic.
H owever, t h ese sa m e ch a n ges m a y r esu lt in a lt er ed
st r u ct u r e a n d fu n ct ion , lea din g t o fin din gs t h a t a r e
oft en a ssocia t ed wit h pa t h ologic m a n ifest a t ion s.
Agin g pr ocesses a n d disea se st a t es a r e n ot a lwa ys
clea r ly delin ea t ed.
Com m on ch a r a ct er ist ics of a gin g in clu de:
1. In cr ea sed m or t a lit y wit h a ge a ft er m a t u r a t ion
2. Ch a n ges in bioch em ica l com posit ion in t issu es
3. P r ogr essive decr ea se in ph ysiologic ca pa cit y
Alte re d
e limina tion
Alte re d
nutrition
Appe a ra nce Manife s tatio ns
o f ag ing
Fluid/e le ctrolyte
imba la nce
Impa ire d immune
re s pons e
Figure 19.2. Concept map. Manifestations of aging.
r e e r a d ic a l t h e o r y of a gin g lin ks cellu la r da m -
a ge wit h t h e pr odu ct ion of r ea ct ive oxygen species
(ROS). Accor din g t o t h is t h eor y, in t r a cellu la r pr odu c-
t ion of ROS con t r ibu t es t o t h e fin a l det er m in a t ion
of life spa n . Mit och on dr ia a r e especia lly a t r isk for
da m a ge fr om ROS beca u se of by-pr odu ct s pr odu ced
in t h e elect r on t r a n spor t ch a in t h a t pr odu ce en er gy
in t h e for m of a den osin e t r iph osph a t e (ATP ). Oxida -
t ive da m a ge t o m it och on dr ia l DNA a n d ot h er cellu -
la r st r u ct u r es is t h ou gh t t o be cu m u la t ive, lea din g t o
t h e m a n ifest a t ion s of a gin g.
Th e s o m a t ic m u t a t io n t h e o r y st a t es t h a t t h e
a gin g pr ocess is ca u sed by im pa ir ed DNA r epa ir,
a n t ioxida n t defen se, or er r or s in pr ot ein expr ession .
Ca lor ic r est r ict ion h a s been sh own exper im en t a lly
t o pr olon g life expect a n cy. Alt h ou gh t h e u n der lyin g
m ech a n ism is u n clea r, lon gevit y m a y be ca u sed by
a sh ift in en er gy fr om gr owt h a n d r epr odu ct ion t o-
wa r d r epa ir a n d m a in t en a n ce of t h e som a , or cell.
4. Dim in ish ed a bilit y t o r espon d a da pt ively t o en vi-
r on m en t a l st im u li
5. In cr ea sed vu ln er a bilit y a n d su scept ibilit y t o
disea se
Cellular Changes in Aging
Cellu la r ch a n ges ch a r a ct er ist ic of a gin g in clu de
a t r oph y a n d h yper t r oph y a n d t h e im pa ir ed a bilit y
t o u n der go m it osis. Cell fu n ct ion m a y be im pa ir ed by
t h e deposit ion of lipids or da m a ge fr om fr ee r a dica ls.
Tissu e effect s of a gin g in clu de t h e a ccu m u la t ion of
Ce llula r
cha nge s
Alte re d me ta bolic
proce s s e s
Alte re d
pe rfus ion
Impa ire d
mobility
P rolife ra tive
cha nge s

m et a bolic wa st e pr odu ct s a n d t h e deposit ion of lip o -
u s c in , a fa t t y br own lipid pigm en t , ca u sin g st iffen -
in g or r igidit y. Loss of m a ss by a t r oph y is a com m on
a ge-r ela t ed effect t h a t occu r s in or ga n s a n d bon es.
Alt h ou gh t h ese ch a n ges a r e pa r t of t h e n or m a l pr o-
cesses of a gin g, t h e r esu lt in g ch a n ges oft en im pa ct
body fu n ct ion .
Aging and Appearance
Appea r a n ce is a lt er ed in a gin g. Typica l skin ch a n ges
in clu de a dr y, wr in kled a ppea r a n ce wit h a va r ied
pa t t er n of pigm en t a t ion (Fig. 19.3). Colla gen ch a n ges
decr ea se ela st icit y. Decr ea sed va scu la r it y a n d in -
cr ea sed fr a gilit y m a y lea d t o skin discolor a t ion a n d
t h icken ed n a il a ppea r a n ce. Ch a n ges in h a ir in clu de
loss, gr owt h , dist r ibu t ion , a n d gr a yin g beca u se of
m ela n in deficien cy in t h e h a ir follicle.
Stop and Consider
Why do “age spots” form as individuals age?
Fluid and Electrolyte Balance
Agin g is a ssocia t ed wit h ch a nges in body ma ss ch a r a c-
t er ized by a decr ea se in m u scle a n d a n incr ea se in fa t .
These cha nges cont r ibut e to a decr ea se in tot a l body
wa ter, fur t her enha n ced by t he kidney’s dimin ished
a bilit y t o regula t e sodium a nd wa t er ba la nce, which is
im por t a nt in t he est a blishm ent of ext ra cellula r fluid
volum e a nd ton icit y. Tot a l body wa t er ba la nce is a key
elem ent in t he deter m ina tion of sodiu m concent r a -
t ion in th e blood, which in cr ea ses t he r isk for h ypona -
t r em ia in ca ses of wa t er r et ent ion a nd hypern a t rem ia
Figure 19.3. Hands with wrinkling and overlapping folds
common to aging skin. (From Smeltzer SC, Bare BG. Text-
book of Medical-Surgical Nursing. 9th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2000.)
G e n e r a l Ma n i e s t a t io n s o Ag in g 493
ca used by wa t er loss. Addit iona l st r essor s in t he for m
of disea se, a lt er ed elim ina t ion, or a lt er ed nut r ition
m ay r esult in significa nt consequences r ela t ed t o a l-
t er ed fluid a nd elect r olyt e ba la n ce.
Immune Response
Th e pr ocesses of in fla m m a t ion, im m un it y, a n d pr ot ec-
t ion fr om in fect ion a r e a lt er ed wit h a gin g. Im m u n e
senescen ce, pr ogr essive dysfu n ct ion of t he im m un e
syst em a ssocia t ed wit h a gin g, is ch a r a ct er ized by
bot h dim in ish ed a n d en h a n ced im m un e r esponses.
An t igen ic im m u ne r esponses pr ogr essively dim in ish
wit h a ging beca u se of decr ea sed T-cell fu nct ion even
in t he a bsen ce of a n y significa n t decr ea se in a ct ua l
T-cell nu m ber. Thym u s degen er a t ion occur s a ft er a ge
50 yea r s a nd is r educed t o 15% of it s pea k size, which
wa s r ea ch ed a t sexu a l m a t u r it y. This degener a t ion
r esult s in decr ea sed t h ym ic hor m on e pr odu ct ion a n d
T-cell differ en t ia t ion . Mon oclon a l a n t ibody pr odu ct ion
m ay occu r, even in t h e a bsen ce of B-cell m a ligna n-
cies. Au t oim m u ne r espon ses m ay becom e enh a nced
beca u se of t h e in cr ea sed cir cula t ion of a ut oa nt ibodies
a nd im m u ne com plexes. IgE -m edia t ed h yper sen sit iv-
it y r espon ses a r e decr ea sed a n d a r e a ssocia t ed wit h a
lessen in g of a ller gy-m edia t ed sym pt om s.
Stop and Consider
How can the elderly protect themselves from
infection?
Ma n ifest a t ion s of decr ea sed im m u n e r espon sive-
n ess in clu de a t t en u a t ed dela yed h yper sen sit ivit y
r espon ses, dim in ish ed T-cell a ct ivit y, a n d r espon -
siven ess t o pa t h ogen s. Loss of pr eviou sly a cqu ir ed
im m u n it y m a y in cr ea se t h e r ea ct iva t ion of pa t h o-
gen s, r esu lt in g in r ein fect ion . Th e in ciden ce of h er-
pes zost er a n d t u ber cu losis in fect ion is in cr ea sed in
t h e elder ly. Mor t a lit y r a t es a r e in cr ea sed in t h e el-
der ly in r espon se t o pn eu m on ia a n d in flu en za . Ra t es
of n osocom ia l in fect ion a r e a lso in cr ea sed in t h is
popu la t ion . Im pa ir ed wou n d h ea lin g m a y r esu lt a s
a r espon se t o a lt er ed im m u n e fu n ct ion du e t o a gin g
or fr om decr ea sed fu n ct ion in du ced by m edica t ion s
for ch r on ic illn ess, su ch a s st er oids. Typica l ph ysica l
ch a n ges of a gin g, in clu din g loss of su bcu t a n eou s fa t ,
decr ea sed ela st icit y of colla gen , a n d a t r oph ied epi-
der m is a n d su ppor t in g ca pilla r ies, a lso con t r ibu t e t o
im pa ir ed h ea lin g.
Age-Related Proliferative Changes
Ch r on ic m yelopr olifer a t ive disor der s, su ch a s poly-
cyt h em ia ver a a n d pr im a r y t h r om bocyt h em ia ,
494 C h a p t e r 19: Degen er a t ive Ch a n ges in Agin g

a r e m or e com m on in in dividu a ls gr ea t er t h a n a ge of cells in t h e spin a l cor d, a lt h ou gh t h e fu n ct ion a l

60 yea r s. Th e in ciden ce of m a n y of t h e m ost com m on effect s a r e n ot clea r ly lin ked. Most fu n ct ion a l a l-
ca n cer s is a lso in cr ea sed in m a n y older in dividu a ls, t er a t ion s r esu lt fr om t h e in volvem en t of per iph er a l
wit h t h e gr ea t est in ciden ce occu r r in g bet ween t h e n er ves a n d degen er a t ive ch a n ges of t h e spin e a n d
a ges of 65 a n d 80 yea r s. Th e pot en t ia l ca u ses for m u scles. Slowin g of n er ve con du ct ion a n d less effi-
t h ese fin din gs m a y r esu lt fr om m a n y of t h e ch a r a c- cien t a xon r espon se t o in ju r y a n d r epa ir a r e t ypi-
t er ist ic ch a n ges of a gin g con t r ibu t in g t o in cr ea sed ca l wit h a gin g. Fa ct or s cr it ica l t o t h e pr om ot ion of
r isk or a t t en u a t ed defen se t o ca r cin ogen s. Th ese n eu r ologic r espon ses, in clu din g n eu r ot r a n sm it t er s,
pot en t ia l ca u ses in clu de: en zym es, a n d r ecept or s, a r e a lso a lt er ed du r in g t h e
a gin g pr ocess.
● Im pa ir ed im m u n e fu n ct ion
Ma n ifest a t ion s of im pa ir ed fu n ct ion in g oft en r e-
● Gen et ic m u t a t ion a ccu m u la t ion
su lt fr om t h ese st r u ct u r a l ch a n ges. Th ese ch a n ges
● P r olon ged ca r cin ogen exposu r e
in clu de sen sor y deficit s (t a st e, sm ell, vibr a t ion , vi-
● Im pa ir ed a bilit y for DNA r epa ir
sion , a n d h ea r in g), m ot or dysfu n ct ion (a lt er ed ga it
Ma n ifest a t ion s of a lt er a t ion s in pr olifer a t ion a r e a n d post u r e), sleep dist u r ba n ces, a n d im pa ir ed
specific t o t h e in volved cells a n d t issu es. Tr ea t m en t m em or y a n d cogn it ion . Slowin g of cen t r a l pr ocess-
is oft en ba sed on t h e t ype of m a lign a n cy, t h e effect s in g m a y pr olon g t h e t im e it t a kes t o com plet e t a sks.
r esu lt in g fr om t h e m a lign a n cy, t h e per son ’s a ge a n d Declin es in m ot or st r en gt h , r eflex r espon ses, a n d
qu a lit y of life, a n d con sen t . r ea ct ion t im e a r e r ela t ed t o sen sor im ot or ch a n ges.
Ch a n ges a ssocia t ed wit h a gin g in clu de m ild for get -
fu ln ess, a decr ea se in voca bu la r y, a n d lea r n in g dif-
Neurologic Function ficu lt ies. Th ese ch a n ges t ypica lly do n ot occu r u n t il
t h e seven t h deca de of life.
Age-r ela t ed n eu r ologic m a n ifest a t ion s m a y in clu de Cogn it ive fu n ct ion ca n be com pr om ised by t h e
a lt er a t ion in cogn it ion , sen sa t ion , pa in , a n d m ot or coexist in g con dit ion s r ela t ed t o declin e in m en t a l
r espon ses. Th ese m a n ifest a t ion s oft en r esu lt fr om h ea lt h . Oft en r ela t ed t o en vir on m en t a n d socia l con -
ch a n ges in bot h st r u ct u r e a n d fu n ct ion of cells a n d dit ion s, depr ession a n d a n xiet y a m on g t h e elder ly is
t h e t issu es r espon sible for t h e st im u la t ion of ph ysi- m or e pr eva len t in lon g-t er m ca r e set t in gs com pa r ed
ologic r espon ses. Neu r ologic fu n ct ion m a y be a lt er ed wit h elder ly wh o a r e com m u n it y dwellin g. P sych o-
a s a r espon se t o cellu la r pr ocesses, r esu lt in g in fu n c- logica l disor der s m a y com plica t e ph ysica l h ea lt h ,
t ion a l ch a n ges in bot h t h e cen t r a l, som a t osen sor y, r edu cin g m ot iva t ion or a bilit y t o m a in t a in h ea lt h
a n d per iph er a l n er vou s syst em s. Typica l st r u ct u r a l t h r ou gh ever yda y a ct ivit ies, su ch a s pr oper ly a d-
ch a n ges in clu de: m in ist er in g m edica t ion s, a ssu r in g a dequ a t e n u t r i-
t ion , obt a in in g a dequ a t e exer cise, a n d m a in t a in in g
● Decr ea se in br a in m a ss
per son a l h ygien e.
● E n la r gem en t of cer ebr a l ven t r icles
● Decr ea se in n u m ber of n eu r on s, den dr it ic pr o-
cesses, a n d syn a pses
● Decr ea se in m yelin
Mobility
● Alt er ed pr odu ct ion of n eu r ot r a n sm it t er s
P h ysica l a ct ivit y is oft en decr ea sed a m on g t h e el-
H ist ologica lly, in t h e br a in , eviden ces of lipofu scin der ly. Th e occu r r en ce of o s t e o p e n ia (r edu ced ca lcifi-
pigm en t in n er ve cells a n d a m yloid in t h e va scu la r ca t ion a n d/or skelet a l bon e m a ss) a n d o s t e o p o r o s is
t issu e a r e fin din gs con sist en t wit h a gin g. Neu r o- (a t r oph y of skelet a l t issu e) in in dividu a ls over a ge
fibr illa t or y t a n gles a n d pla qu es m a y occu r (see Clin - 50 yea r s is in cr ea sed, pla cin g t h is popu la t ion a t
ica l Models). E viden ce exist s of a declin in g n u m ber r isk for in ju r y ca u sed by fa lls. Wom en exper ien ce a
m or e r a pid ph a se of bon e
loss a ft er m en opa u se,
kn own a s m e n o p a u s a l
b o n e lo s s , followed by
R E S E AR C H N O T E S
a slower loss ph a se t h a t
A recent study examined the the link between age and cerebral gray matter in long-term a ffect s bot h m en a n d
meditators versus control subjects (n = 100) between 24 and 77 years of age. Negative wom en (sen escen t bon e
correlations were detected in gray matter when compared with age (higher age, lower gray loss). Men opa u sa l bon e
matter). However, the slopes of the regression lines were steeper and the correlation coeffi- loss is cyt okin e-in du ced
cients were stronger in controls than in meditators. These findings suggest less age-related (in t er leu kin -6 [IL-6]),
gray matter atrophy in those who meditate over the long term. 1 occu r r in g in t h e a bsen ce
of a dequ a t e levels of

pr ot ect ive ova r ia n h or m on es. Th is r espon se is a s-
socia t ed wit h dela yed a popt osis of ost eocla st s a n d
en h a n ced a popt osis of ost eobla st s, r esu lt in g in a n
im ba la n ce fa vor in g bon e loss. Sen escen t bon e loss is
r ela t ed t o dim in ish ed bon e r em odelin g a n d for m a -
t ion . Ost eobla st pr odu ct ion is decr ea sed, slowin g t h e
r a t e of bon e for m a t ion a n d r edu cin g bon e m in er a l
den sit y. Ost eopor osis is discu ssed in m or e det a il in
t h is ch a pt er a s a clin ica l m odel.
Stop and Consider
What types of physical activity are considered
weight-bearing? What types are not?
Loss of bon e wit h pr ogr essive a ge a ffect s t h e a x-
ia l (tr a becu la r ) a n d a ppen d icu la r (cor tica l) skelet on
a n d is m a n ifest ed by pa in , st iffn ess, loss of h eigh t ,
a n d developm en t of k y p h o s is , a n exa gger a t ed
a n t er ior con ca ve cu r va t u r e of t h e t h or a cic spin e
(Fig. 19.4). Fr a ct u r es of t h e ver t ebr a e a n d h ips a r e
com m on . Ca r t ila ge ch a n ges m a y a lso im pa ir m obil-
it y, decr ea sin g fu n ct ion via join t lim it a t ion s. E n zym e
a ct ivit y in ch on dr ocyt es m a y lea d t o cr yst a l deposi-
t ion , pr om ot in g t h e developm en t of c h o n d r o c a lc i-
n o s is (ca lcifica t ion of ca r t ila ge). Ca r t ila ge m a y t h in
in weigh t -bea r in g join t s, su ch a s t h e kn ees, ca u sin g
pa in a n d decr ea sed m obilit y.
Figure 19.4. Kyphosis versus normal. Kyphosis ( right)
versus normal spinal column ( left) . (Courtesy LifeART im-
age copyright (c) [2016] Lippincott Williams & Wilkins. All
rights reserved.)
G e n e r a l Ma n i e s t a t io n s o Ag in g 495
Loss of lea n body m a ss t ypica l in a gin g is pr im a r-
ily ca u sed by t h e decr ea sed n u m ber a n d size of skel-
et a l m u scle fiber s. S a r c o p e n ia , or loss of skelet a l
m u scle, is a com m on a ge-r ela t ed ch a n ge t h a t lim it s
fu n ct ion . Ca u ses of sa r copen ia in clu de:
● Decr ea sed ph ysica l a ct ivit y
● Ch a n ges in t h e n er vou s syst em (cen t r a l a n d
per iph er a l)
● P r ot ein u n der n u t r it ion
Fa st er-con t r a ct in g m u scle fiber s (t ype II) a r e lost
m or e qu ickly com pa r ed t o t h e slower-con t r a ct in g fi-
ber s (t ype I), lea din g t o loss of isom et r ic con t r a ct ile
for ce. Post u r e a n d t h e a bilit y t o per for m r h yt h m ic
m ovem en t s a r e a ffect ed m or e slowly. Decr ea sed
m obilit y ca u sed by ot h er com or bid con dit ion s ca n
gr ea t ly a cceler a t e t h e pr ocess of m u scle loss in t h e
elder ly.
Perfusion and Ventilation
Age-r ela t ed ch a n ges in t h e ca r diova scu la r syst em
m a y lea d t o a lt er ed per fu sion . Va r ia bles a ffect in g
ca r dia c fu n ct ion in clu de:
● Com plia n ce
● Ca r dia c fillin g
● P r eloa d
● Aft er loa d
● Con t r a ct ilit y
● E ject ion fr a ct ion
● St r oke volu m e
● H ea r t r a t e
● Ca r dia c ou t pu t
Con n ect ive t issu e ch a n ges pr om ot e decr ea sed
ela st icit y in t h e sm oot h m u scle of t h e va scu la r sys-
t em . In cr ea sed a ft er loa d ca u sed by a r t er ia l st iffen in g
a n d lim it ed dist en t ion m a y a lt er ca r dia c ou t pu t . Left
ven t r icu la r wa ll t h ickn ess m a y in cr ea se beca u se of
h yper t en sion , a com m on com or bid con dit ion in t h e
elder ly. At h er oscler osis m a y r esu lt fr om in cr ea sed
in t im a l t h ickn ess fr om cellu la r a ccu m u la t ion , oft en
cou pled wit h da m a ge t o t h e in t er n a l ela st ic la yer of
t h e va scu la r sm oot h m u scle. Alt er a t ion s in ca r dio-
va scu la r fu n ct ion in g m a y a ffect a n y or ga n syst em ,
pr om ot in g t h e developm en t of or ga n -specific m a n -
ifest a t ion s. Decr ea sed cer ebr a l blood flow m a y be
lin ked t o a lt er a t ion s in n eu r ologic fu n ct ion , fu r t h er
det er m in ed by t h e specific a r ea of t h e br a in in volved.
P u lm on a r y ch a n ges in a gin g, cou pled wit h de-
cr ea sed den sit y of pu lm on a r y ca pilla r ies, m a y lim it
t h e a va ila bilit y of oxygen t o a dequ a t ely su pply t is-
su es. Typica l ch a n ges in clu de:
● Decr ea sed in spir a t or y r eser ve volu m e
● In cr ea sed r esidu a l volu m e
496 C h a p t e r 19: Degen er a t ive Ch a n ges in Agin g
● Redu ced ven t ila t or y ca pa cit y
● Redu ced ven t ila t ion –per fu sion r a t io
Decr ea sed m u scle a n d bon e m a ss in t h e ch est ca v-
it y m a y in cr ea se t h e wor k of br ea t h in g. In n on sm ok-
er s, t h ese t ypica l ch a n ges a ffect in g ven t ila t ion , ga s
exch a n ge, a n d com plia n ce a r e n ot a ssocia t ed wit h
sign ifica n t m a n ifest a t ion s. Dyspn ea m a y in dica t e
a ir wa y obst r u ct ion , oft en seen in in dividu a ls wit h
com or bid con dit ion s su ch a s em ph ysem a . Lim it ed
im m u n e defen se a lon g wit h dysph a gia , loss of cou gh
m ech a n ism s, a n d declin e of m u cocilia r y t r a n spor t
m ay pr edispose elder ly in dividu a ls t o pu lm on a r y
in fect ion a n d a spir a t ion .
Metabolic Processes
At r oph y, decr ea sed h or m on a l secr et ion , im pa ir ed
r ecept or /liga n d bin din g, a n d a lt er a t ion s in in t r a cel-
lu la r sign a lin g m a y in flu en ce t h e ch a n ges t ypica l
in t h e h or m on a l pr ocesses a ssocia t ed wit h a gin g.
Beca u se h or m on a l a n d m et a bolic effect s a r e body-
wide, t h e m a n ifest a t ion s of a lt er a t ion s oft en a ffect
m a n y or ga n syst em s. Th e m ost com m on ly a ffect ed
pr ocesses in clu de:
● Min er a l m et a bolism
■ Ca lciu m
■ P h osph a t e
■ Ma gn esiu m
● Vit a m in a n d t r a ce m in er a l m et a bolism
● Acid–ba se m et a bolism
● Nu t r ien t m et a bolism
■ Obesit y
■ Un der n u t r it ion
● E n docr in e m et a bolism
■ Th yr oid
■ Pa r a t h yr oid
■ Adr en a l
■ P it u it a r y
■ An t er ior
■ Post er ior
■ Ova r ia n /t est icu la r
Ca lciu m levels in t h e elder ly a r e r egu la t ed by pa r a -
t h yr oid h or m on e (P TH ), vit a m in D, a n d ca lcit on in .
C a lc it o n in , a h or m on e pr odu ced by t h e pa r a t h yr oid,
t h yr oid, a n d t h ym u s gla n ds, pr om ot es t h e deposit ion
of ca lciu m a n d ph osph a t e in bon e. P TH pr om ot es r e-
m ova l of ca lciu m a n d ph osph a t e fr om bon e, opposin g
t h e effect s of ca lcit on in . Th e a ct iva t ed for m of vit a -
m in D, 1,25-dih ydr oxych oleca lcifer ol, pr om ot es ca l-
ciu m a bsor pt ion in t h e in t est in e. Ca lciu m levels va r y
dependin g on t h e con cen t r a t ion of pla sm a pr ot ein s
(i.e., a lbu m in ), t h e con cen t r a t ion bou n d t o a n ion s (i.e.,
ph osph a t e a n d bica r bon a t e), a n d t h e blood pH a lt er-
in g ca lciu m –pr ot ein bin din g (decr ea sed in a cidosis;
in cr ea sed in a lka losis). Ca lciu m levels m ay be a f-
fect ed by a ge-r ela t ed decr ea sed in t est in a l a bsor pt ion
of ca lciu m , a blu n t ed r espon se t o vit a m in D a ct iva -
t ion , a n d t h e a ge-r ela t ed in cr ea se in P TH (Fig. 19.5).
Nu t r it ion a l in t a ke of ca lciu m a n d vit a m in D is a lso
im por t a n t in t h e r egu la t ion of ca lciu m m et a bolism .
P r olifer a t ive disea se, pa r t icu la r ly br ea st ca n cer, lu n g
ca n cer, a n d m u lt iple m yelom a , m ay r esu lt in da n ger-
ou sly h igh levels of ser u m ca lciu m .
Stop and Consider
Why would metastatic disease increase calcium
levels in the blood?
P h osph a t e levels a r e t ypica lly lower in t h e elder ly.
P h osph a t e in t a ke is decr ea sed in t h e elder ly a n d is
cou pled wit h poor in t est in a l a bsor pt ion . In cr ea sed
a ct ivit y of t h e pa r a t h yr oid gla n d m a y r esu lt in pr o-
m ot ion of r en a l excr et ion of ph osph a t e r ela t ed t o a l-
t er ed t u bu la r a bsor pt ion . Ch r on ic r en a l fa ilu r e m a y
r esu lt in h yper ph osph a t em ia . H ypom a gn esem ia is
a lso com m on a m on g t h e elder ly a n d oft en r esu lt s
fr om decr ea sed diet a r y in t a ke, excessive r en a l ex-
cr et ion , or loss via t h e ga st r oin t est in a l syst em (i.e.,
vom it in g, dia r r h ea , or im pa ir ed a bsor pt ion ). Ma in t e-
n a n ce of a cid–ba se ba la n ce is im pa ir ed beca u se of a
dim in ish ed a bilit y of t h e a gin g r espir a t or y a n d r en a l
syst em s t o cor r ect a lt er a t ion s. Im pa ir m en t of t h ese
h om eost a t ic m ech a n ism s r epr esen t s a sign ifica n t
r isk of a lt er ed a cid–ba se ba la n ce in t h e elder ly.
Decr ea sed T3 levels a n d eleva t ed t h yr oid-
st im u la t in g h or m on e (TSH ) levels ch a r a ct er ize t yp-
ica l t h yr oid fu n ct ion a lt er a t ion s in t h e elder ly. Th e
in ciden ce of h ypot h yr oidism in cr ea ses wit h a ge a n d
m a y m a n ifest su bclin ica lly or wit h over t sym pt om s.
Th e pr eva len ce of h yper t h yr oidism does n ot in cr ea se
wit h a ge. Tem per a t u r e r egu la t ion is a lso com pr o-
m ised in t h e elder ly, m or e so if cou pled wit h ch r on ic
illn ess. Th e a bilit y t o cool t h e body via swea t in g is
im pa ir ed beca u se of a decr ea se in t h e n u m ber, size,
a n d a ct ivit y of swea t gla n ds, m a kin g t h e elder ly
pa r t icu la r ly su scept ible t o h ea t st r ess. F r a il elder ly
in dividu a ls a r e especia lly a t r isk for h ypot h er m ia be-
ca u se of dim in ish ed cold per cept ion , a lt er ed r espon -
siven ess t o ca t ech ola m in e-in du ced va socon st r ict ion
a n d sh iver, a n d lim it ed a bilit y t o pr odu ce h ea t .
Nutrition and Elimination
P r ocesses t h a t r egu la t e digest ion a n d elim in a t ion
a r e a lt er ed in a gin g beca u se of m or ph ologic a n d fu n c-
t ion a l ch a n ges wit h in t h e en t er ic n er vou s syst em , a
division of t h e a u t on om ic n er vou s syst em . Im pa ir ed
n u t r it ion t h a t lea ds t o deficien cies in m a cr on u t r ien t s
a n d m icr on u t r ien t s a r e com m on a m on g t h e elder ly.
Th ese deficit s ca n lea d t o cogn it ive im pa ir m en t ,
 G e n e r a l Ma n i e s t a t io n s o Ag in g 497

S unlig ht

Fo o d

S kin Vita min D

7-de hydro-
chole s te rol

Live r

Vita min D-25-hydroxyla s e

25(OH)D

Pa ra thyroids

Kidney

1α -hydroxyla s e PTH

Inte s tine

1,25 (OH)2 D

Kidney
Bone

↑ Bone re mode ling

↑ Ca 2+ a bs orption
↑ Ca 2+ re a bs orption

Blo o d c alc ium

Figure 19.5. Metabolism of vitamin D and the regulation of calcium. Calcium regulation involves multiple organ systems.
Reduced function in any of the involved systems may result in altered calcium homeostasis. (From Rubin E, Farber JL.
Pathology. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2005.)

in cr ea sed r isk of in fect ion ca u sed by im pa ir m en t of
im m u n e fu n ct ion , a n em ia , a n d poor wou n d h ea lin g.
In a dequ a t e in t a ke of pr ot ein a n d en er gy-pr odu cin g
foods m a y r esu lt in u n der n u t r it ion , oft en a ssocia t ed
wit h deficien cies in wa t er-solu ble vit a m in s B a n d C
a s well a s fa t -solu ble vit a m in s A, D, E , a n d K.
Th e pr oblem of u n der n u t r it ion is even m or e pr ev-
a len t a m on g elder ly in lon g-t er m ca r e a n d in h ospi-
t a ls, wh ich in cr ea ses t h e r isk for t h e developm en t
of ch r on ic illn ess. Im pa ir ed n u t r it ion m a y be ca u sed
by t oot h loss or poor ly fit t in g den t u r es, m a kin g t h e
pr ocess of ch ewin g food difficu lt . Oft en in a gin g, t h e
ph ysiologic r espon se t o h u n ger is blu n t ed, cou pled
wit h a feelin g of fu lln ess even t h ou gh t a kin g in less
food.
F u n ct ion a l r espon ses of t h e kidn eys decr ea se wit h
a ge. Ren a l ch a n ges ch a r a ct er ist ic in a gin g in clu de:
● Redu ced r en a l blood flow
● Decr ea sed glom er u la r filt r a t ion r a t e
498 C h a p t e r 19: Degen er a t ive Ch a n ges in Agin g
● Redu ced r en a l m a ss
● Declin e in pr oxim a l t u bu la r fu n ct ion
● Redu ced r en in a n d a ldost er on e levels
Reduction in nephron number may alter the renal
function of urine concentration, placing additional im-
portance on the regulation of total water balance. Drug
excretion may be impaired, increasing the risk of toxicity.
Im pa ir ed ga st r oin t est in a l elim in a t ion in el-
der ly in dividu a ls is m ost fr equ en t ly m a n ifest ed
Modu le 3 Ma n a g in g D e g e n e r a t iv e
C h a n g e s in t h e E ld e r ly
P r im a r y a n d secon da r y pr even t ion of in ju r y a n d
illn ess a r e t h e m a jor ch a llen ges in m a n a gem en t
of a ge-r ela t ed degen er a t ive ch a n ges. Scr een in g for
fu n ct ion a l im pa ir m en t a n d select in g m a n a gem en t
st r a t egies m u st be in dividu a lized beca u se of t h e
wide r a n ge of m a n ifest a t ion s exh ibit ed a m on g t h e
elder ly. St r a t egies m u st t a ke in t o a ccou n t com or bid
con dit ion s, ph ysica l h ea lt h , cogn it ive st a t u s, fu n c-
t ion a l a bilit y, a n d socia l su ppor t .
H ea lt h ou t com es a r e im pr oved a m on g t h e el-
der ly popu la t ion wit h r egu la r exer cise, weigh t con -
t r ol, ca n cer scr een in g, a voida n ce of sm okin g a n d
bin ge dr in kin g, a n d disea se pr even t ion t h r ou gh
Modu le 4 C lin ic a l Mo d e ls
Clin ica l m odels for t h is ch a pt er wer e select ed t o
dem on st r a t e t h e a pplica t ion of pr eviou sly descr ibed
pr ocesses wit h in a gin g popu la t ion s. As you r ea d t h e
descr ipt ion s t h a t follow, con sider t h e cellu la r m ech -
a n ism s t h a t con t r ibu t e t o t h e a lt er a t ion s in t issu es
a n d body syst em s a ssocia t ed wit h a gin g.
Hutchinson–Gilford Progeria Syndrome
H u t ch in son –Gilfor d P r oger ia Syn dr om e (H GP S) is
a n ext r em ely r a r e h er edit a r y disea se t h a t a ffect s
a bou t 1 in 4 m illion people wor ldwide. It is a syn -
dr om e a ffect in g t h e skin , m u scu loskelet a l syst em ,
a n d ca r diova scu la r syst em a n d is ch a r a ct er ized by
a cceler a t ed a gin g. Ch ildr en a ffect ed by pr oger ia
h a ve a life expect a n cy of a ppr oxim a t ely 13 yea r s.
Mor t a lit y is oft en r ela t ed t o a cceler a t ed a t h er oscle-
r osis of t h e ca r ot id a n d cor on a r y a r t er ies.
a s con st ipa t ion , dia r r h ea , feca l in con t in en ce, a n d
im pa ct ion . Th e st r ess of flu id a n d elect r olyt e loss
via dia r r h ea r epr esen t s a sign ifica n t t h r ea t t o wa -
t er ba la n ce, oft en r esu lt in g in sever e deh ydr a t ion .
In cr ea sed r ect a l com plia n ce a n d im pa ir ed r ect a l
sen sa t ion r epr esen t a ge-r ela t ed ch a n ges t h a t pr edis-
pose elder ly in dividu a ls t o con st ipa t ion . Feca l in con -
t in en ce is ca u sed by decr ea sed r est in g a n d m a xim a l
a n a l sph in ct er pr essu r es.
va ccin a t ion . A ca r efu l eva lu a t ion of t h e h om e en -
vir on m en t ca n h elp wit h pr even t in g fa lls, bu r n s,
a n d ot h er h ou seh old a cciden t s. Fa m ily m em ber s
or in dividu a ls r espon sible for pr ovidin g elder ca r e
sh ou ld be a wa r e of ch a n ges in fu n ct ion a l or cogn i-
t ive a bilit ies. Assu r a n ce of a ppr opr ia t e m edica t ion
a dm in ist r a t ion m a y pr even t in ju r y r ela t ed t o im -
pr oper dosin g. A well-ba la n ced diet t h a t in clu des
essen t ia l pr ot ein in t a ke, m a cr on u t r ien t s, a n d m i-
cr on u t r ien t s is im por t a n t t o m a in t a in h om eost a sis.
Assu r a n ce of a dequ a t e flu id in t a ke is essen t ia l t o
volu m e r egu la t ion a n d m a y lessen t h e in ciden ce of
con st ipa t ion .
PATHOPHYSIOLOGY
Au t osom a l dom in a n t m u t a t ion s in t h e LMNA gen e
a r e r espon sible for m ost ca ses of H GP S, wit h a d-
va n ced pa t er n a l a ge bein g a m a jor r isk fa ct or. In
a ddit ion , a u t osom a l r ecessive t r a n sm ission ca n a lso
occu r a s dem on st r a t ed by set s of a ffect ed siblin gs
bor n t o u n a ffect ed pa r en t s. Th e LMNA gen e en codes
t h e n u clea r en velope pr ot ein ca lled la m in s, wh ich
a r e im por t a n t for m a in t a in in g cell n u cleu s st a bilit y
a n d r egu la t in g gen e expr ession , DNA syn t h esis, a n d
DNA r epa ir. Wh en t h e LMNA gen e m u t a t es, t h is
r esu lt s in a t r u n ca t ed (sh or t en ed) pr ela m in -A pr o-
t ein , ca lled pr oger in . P r oger in (a n a bn or m a l pr ot ein )
pr even t s t h e n or m a l a ssem bly of la m in s. Th e for ced
a bsen ce of la m in A in t h e cell n u cleu s ca u ses t h e n u -
cleu s t o becom e a bn or m a lly sh a ped a n d st r u ct u r ed.
Cellu la r ch r om osom es ca n n ot segr ega t e n or m a lly
a n d m it osis is dela yed. Th e gen e expr ession a f-
fect s m u lt iple cellu la r pr ocesses, in clu din g colla gen

r em odelin g a n d t h e for m a t ion of t h e ext r a cellu la r
m a t r ix. A ch a r a ct er ist ic fin din g is a lso h igh levels of
h ya lu r on ic a cid secr et ion (wh ich ca n a lso in in cr ea se
wit h n or m a l a gin g). H ya lu r on ic a cid levels im pa ct
t h e pr esen ce of ca r diova scu la r disea se, ca lcifica t ion
of t h e blood vessels, a n d scler oder m a t ou s ch a n ges in
t h e skin . In gen er a l, ch a n ges in gen e a ct ivit y com -
m on ly a ssocia t ed wit h older a du lt s a r e fou n d in
t h ose wit h pr oger ia .
CLINICAL MANIFESTATIONS
Clin ica l m a n ifest a t ion s oft en pr esen t s wit h in t h e
fir st yea r of life wh en scler oder m a l skin ch a n ges
a n d a lopecia (h a ir loss) a r e fir st n ot ed a n d wh en t h e
in fa n t dem on st r a t es gr owt h fa ilu r e. By a ge 2 yea r s,
ch ildr en wit h pr oger ia sh ow pr om in en t sign s of ea r ly
a gin g (Fig. 19.6). Addit ion a l m a n ifest a t ion s in clu de:
● P r om in en t sca lp vein s
● Feedin g difficu lt ies
● Scler oder m a (sh in y, in ela st ic skin ) a n d wr in kled
(a ged) skin
● Loss of su bcu t a n eou s fa t a n d m u scle
● Dela yed den t it ion
● H ea r in g loss
● H igh -pit ch ed voice
● Sh or t st a t u r e a n d skelet a l dyspla sia
● In com plet e sexu a l m a t u r a t ion
Figure 19.6. Manifestations of progeria. A 10-year-old girl
affected by progeria shows signs of accelerated aging.
C lin ic a l Mo d e ls 499
Affect ed pa t ien t s oft en develop ost eopor osis, a t h -
er oscler osis, fibr osis, h yper t en sion , a n d a r t h r it is.
H GP S is n ot a ssocia t ed wit h in cr ea sed t u m or for m a -
t ion , ca t a r a ct developm en t , or sen ilit y a s m a y occu r
in a gin g a du lt s.
DIAGNOSIS
Th e dia gn osis of H GP S is ba sed on h ist or y a n d ph ys-
ica l exa m n ot in g t h e ch a r a ct er ist ic sign s a n d sym p-
t om s. H ya lu r on ic a cid levels ca n pr ovide clu es t o t h e
pr esen ce of H GP S. Im a gin g st u dies m a y be n eeded
t o det er m in e t h e ext en t of bon e a n d blood vessel
in volvem en t .
TREATMENT
Th er e is n o a ppr oved t h er a py for H GP S. H owever,
r esea r ch is u n der wa y t o det er m in e t h e effect iven ess
of gen e t h er a py (elim in a t in g t h e pr odu ct ion of m u -
t a n t LMNA) a s well a s ph a r m a cologic t h er a py, su ch
a s wit h r a pa m ycin (a n a n t ibiot ic), wh ich h a ve been
sh own t o im pa ct a ge-r ela t ed cellu la r pa t h wa ys. Ca r e
for t h ose wit h H GP S in volves t h er a pies t o im pr ove
feedin g a n d n u t r it ion a l in t a ke, a ct ivit y a n d join t m o-
bilit y, m on it or in g of va scu la r disea se, a n d pr ovidin g
fa m ily su ppor t .
Osteoporosis
Ost eopor osis is t h e m ost com m on t ype of bon e dis-
ea se a ffect in g older a du lt s. An n u a lly, 1.5 m illion
people a r e dia gn osed wit h a fr a ct u r e r ela t ed t o os-
t eopor osis. Ost eopor osis a ffect s bot h gen der s, wit h a
gr ea t er pr eva len ce a m on g wom en , in wh ich it occu r s
eigh t t im es m or e fr equ en t ly.
PATHOPHYSIOLOGY
Ost eopor osis occu r s beca u se of a n im ba la n ce in t h e
bon e r em odelin g pr ocess; bon e r esor pt ion by ost eo-
cla st s is fa vor ed over bon e for m a t ion by ost eobla st s,
r esu lt in g in loss of bon e m a ss (Fig. 19.7). Fa ct or s
con t r ibu t in g t o ost eopor osis r isk in clu de:
● Gen et ic pr edisposit ion
■ Fa m ily h ist or y of fir st -degr ee r ela t ive wit h
ost eopor osis
● Pea k bon e m a ss
■ Redu ced m a xim a l a m ou n t of bon e in a given
per son
■ Body m a ss in dex less t h a n 25%
● Loss of est r ogen
● Agin g
● In a dequ a t e ca lciu m a n d vit a m in D in t a ke
● Ciga r et t e sm okin g
500 C h a p t e r 19: Degen er a t ive Ch a n ges in Agin g

Ine ffe ctive or pr odu ced in r espon se t o su n ligh t , pr om ot es t h e

a bs orption of in t est in a l a bsor pt ion of ca lciu m a n d ph osph a t e. Th e
ca lcium by
inte s tine s
pr ocess of bon e for m a t ion is en h a n ced by m ech a n i-
Incre a s e d ca lcium ca l st r ess a n d t h e h or m on e ca lcit on in , in h ibit in g t h e
re s orption from a ct iva t ion of ost eocla st s a n d pr om ot in g t h e deposi-
bone t ion of ca lciu m a n d ph osph a t e in t o bon e. Alt h ou gh
a va r iet y of t issu es pr odu ce ca lcit on in , t h e m a jor
sou r ce of ca lcit on in is t h e pa r a follicu la r cells of t h e
t h yr oid gla n d. P TH opposes ca lcit on in , a ct iva t in g
ost eocla st s a n d pr om ot in g r em ova l of ca lciu m a n d
ph osph a t e fr om bon e, wh ich r esu lt s in bon e r esor p-
t ion . Tu bu le r ea bsor pt ion in t h e kidn eys m in im izes
excr et ion of bot h ca lciu m a n d ph osph or u s in t h e
u r in e (Fig. 19.8).

Stop and Consider

What influence does geographic location have on
Figure 19.7. Osteoporosis in aging. Impaired intestinal vitamin D production?
calcium absorption and increased osteoclastic activity
relative to osteoblastic activity contribute to age-related CLINICAL MANIFESTATIONS
osteoporosis.
Oft en kn own a s t h e “silen t disea se,” ost eopor osis is
n ot m a n ifest ed u n t il fr a ct u r e, spin a l defor m it y, or
● E xcessive a lcoh ol
loss of h eigh t occu r s. Beca u se of t h e h igh qu a n t it y
● Seden t a r y lifest yle
of ca n cellou s bon e in t h e ver t ebr a e, spin a l fr a ct u r es
Secon da r y ost eopor osis, a less com m on for m , r e- r epr esen t sign ifica n t sequ ela e of ost eopor osis. Pa t h o-
su lt s fr om secon da r y ca u ses, in clu din g h or m on a l or logic fin din gs a ssocia t ed wit h ost eopor osis in clu de
gen et ic disea ses (Ta ble 19.1). Redu ced ost eobla st loss of coa r se ca n cellou s bon e a n d t h in n in g of t h e
fu n ct ion ch a r a ct er izes t h is for m of ost eopor osis. cor t ex. Th e t r a becu la e in t h e coa r se ca n cellou s bon e
Ca lciu m a n d ph osph a t e pr om ot e bon e ca lcifica - becom e st r u ct u r a lly im pa ir ed, a n d cor t ica l bon e be-
t ion , a n d t h eir m et a bolism is t igh t ly r egu la t ed t o com es t h in a n d por ou s, in cr ea sin g fr a ct u r e r isk.
m a in t a in n or m a l ext r a cellu la r levels. Met a bolic Com pa r ed t o wom en , m en h a ve fewer spin e a n d
a lt er a t ion s ca n r esu lt in , or ca u se, excessive or in - h ip fr a ct u r es beca u se of in cr ea sed bon e m a ss a n d
a dequ a t e levels of t h ese m in er a ls, wh ich a r e t h e st r en gt h . Redu ced bon e size a n d loss ca u sed by cor-
bu ildin g blocks of bon e. Vit a m in D, t a ken in by diet t ica l a n d t r a becu la r t h in n in g ch a r a ct er izes t h e de-
velopm en t of bon e fr a gilit y in
m en . In cr ea sed bon e r em odelin g
Ta b le 19.1 Con dit ion s Lea din g t o Secon da r y Ost eopor osis in elder ly m en is oft en ca u sed by
secon da r y h yper pa r a t h yr oidism ,
C o n d it io n E t io lo g y E ect ca lciu m m a la bsor pt ion , a n d vi-
Cor t icost er oid Im pa ir ed vit a m in -D- In h ibit ion of t a m in D deficien cy.
a dm in ist r a t ion depen den t in t est in a l ca lciu m ost eobla st ic a ct ivit y
a bsor pt ion lea din g t o in -
cr ea sed P TH secr et ion DIAGNOSIS
H yper pa r a t h yr oidism In cr ea sed P TH secr et ion In cr ea sed ost eocla st Ost eopor osis ca n be iden t ified by
a ct ivit y
t h e pr esen ce of a n u n expla in ed
H yper t h yr oidism In cr ea sed t h yr oid h or m on e In cr ea sed ost eocla st
fr a ct u r e. Th e goa l of dia gn osis is
secr et ion a ct ivit y
t o iden t ify ea r ly bon e loss befor e
H ypogon a dism
sign ifica n t r isk develops. Risk for
Wom en E st r ogen deficien cy st im u la t es In cr ea sed ost eocla st ost eopor osis ca n be det er m in ed
est r ogen -sen sit ive cyt okin es a ct ivit y
by t est s of bon e den sit y a n d bon e
Men Deficien cy of a n a bolic
qu a lit y. Th e du a l-en er gy X-r a y
a n dr ogen s
a bsor pt iom et r y (DE XA) is a spe-
H em a t ologic Ost eocla st a ct iva t in g fa ct or In cr ea sed ost eocla st
m a lign a n ciesOst eocla st secr et ed fr om pla sm a cells a ct ivit y
cia lized, low-level r a diogr a ph ic
a ct iva t in g fa ct or se- t ech n iqu e u sed t o m ea su r e bon e
P TH -r ela t ed pr ot ein secr et ion
cr et ed fr om pla sm a cells fr om t u m or den sit y. Den sit y of bot h t h e t r a -
becu la r a n d cor t ica l bon es ca n
 C lin ic a l Mo d e ls 501

Po s tme no paus al
↑
(type 1) 1,25 (OH)2 D
o s te o po ro s is ↑
Re na l S e nile
↑ ↑ 1 α -hydroxyla s e (type 2)
Es troge ns, Ca a bs orption o s te o po ro s is
ge ne tic, e ndocrine , a nd
e nvironme nta l fa ctors ↑ P la s ma ↑
Ca 2+ P la s ma Ca 2+

Aging
↑ P TH

S e cre tion of
bone re s orptive ↑ Bone re s orption
cytokine s
(IL-1, IL-6, TNF) ↑
Bone forma tion
Os te o po ro s is

Figure 19.8. Bone remodeling in osteoporosis. Vitamin D promotes the intestinal absorption of calcium. Vitamin D is
converted to its active form (1,25(OH) 2D) by the renal enzyme 1-alpha-hydroxylase. Age-related decrease in kidney func-
tion limits the availability of 1-alpha-hydroxylase. Decreased 1-alpha-hydroxylase stimulation by PTH and an age-related
blunted response of the renal tubules to PTH contribute to the development of an imbalance of bone remodeling, favoring
resorption. TNF, tumor necrosis factor. (From Rubin E, Farber JL. Pathology. 4th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2005.)

be det er m in ed in a sin gle t est , a n d ch a n ges in bon e F in din gs of a dequ a t e bon e qu a lit y in t h e per iph er a l
den sit y ca n be det er m in ed if t h e DE XA is don e se- bon e of t h e h eel m a y n ot r epr esen t sim ila r fin din gs
r ia lly, u su a lly a n n u a lly or bia n n u a lly. Resu lt s of in t h e cen t r a l loca t ion s of t h e h ip a n d spin e, r edu c-
DE XA t est in g a r e r epor t ed a s a T scor e, ba sed on t h e in g t h e a bilit y t o gen er a lize fin din gs fr om on e sit e t o
followin g gu idelin es issu ed by t h e WH O: t h e ot h er.
● Nor m a l bon e den sit y
■ Bon e m a ss gr ea t er t h a n 833 m g/cm 2 TREATMENT
■ T scor e m or e t h a n − 1.0
P r even t ion of ost eopor osis is t h e idea l t r ea t m en t .
● Ost eopen ia
Recom m en da t ion s for pr om ot in g bon e h ea lt h
■ Bon e m a ss bet ween 833 a n d 648 m g/cm 2
in clu de:
■ T scor e − 1.0 t o − 2.5
● Ost eopor osis 1. Get you r da ily r ecom m en ded a m ou n t s of ca lciu m
■ Bon e m a ss less t h a n 648 m g/cm 2 a n d Vit a m in D.
■ T scor e less t h a n − 2.5 2. E n ga ge in r egu la r weigh t -bea r in g exer cise.
3. Avoid sm okin g a n d excessive a lcoh ol.
A com pa r ison of a n in dividu a l T scor e t o per son s
4. Ta lk t o you r doct or a bou t bon e h ea lt h .
in t h e popu la t ion of t h e sa m e a ge a n d gen der is doc-
5. H a ve a bon e den sit y t est a n d t a ke m edica t ion
u m en t ed u sin g a Z scor e. Repor t of a Z scor e of less
wh en a ppr opr ia t e.
t h a n −1.5 su ggest s a secon da r y, r a t h er t h a n pr im a r y,
ca u se for ost eopor osis. Ca lciu m in t a ke r ecom m en da t ion s in clu de
Bon e qu a lit y ca n be det er m in ed by t h e u se of 1,200 m g/d for post m en opa u sa l wom en a n d elder ly
qu a n t it a t ive u lt r a sou n d (QUS). Mea su r em en t of t h e m en in divided doses for best a bsor pt ion . Vit a m in D
pa ssa ge of a n u lt r a sou n d bea m t h r ou gh t h e t r a bec- (400 t o 600 IU/d) sh ou ld be in clu ded t o pr om ot e ca l-
u la r bon e in t h e h eel por t ion of t h e foot det er m in es ciu m a bsor pt ion a n d m et a bolism . Weigh t -bea r in g is
bon e st r u ct u r e, st r en gt h ,
a n d degr ee of ela st icit y.
Alt h ou gh u sin g a n u lt r a - F R O M T H E L AB
sou n d m ea su r em en t of
bon e qu a lit y h a s m a n y There are no consistent guidelines for laboratory testing to determine causes of secondary
ben efit s, in clu din g cost , osteoporosis. Tests to determine underlying causes of osteoporosis may include a complete
t im e, a n d con ven ien ce, blood count, blood chemistry tests (calcium, phosphorus, total protein, liver enzymes, al-
su ch m ea su r em en t s kaline phosphatase, electrolytes), urinary studies (calcium excretion), and hormonal testing
m a y n ot be a s a ccu - (serum thyrotropin, vitamin D, PTH, cortisol).
r a t e a s DE XA sca n n in g.
502 C h a p t e r 19: Degen er a t ive Ch a n ges in Agin g
im por t a n t in t h e st im u la t ion of ost eobla st ic a ct ivit y
a n d bon e ca lcifica t ion . E ven im m obile in dividu a ls
sh ou ld h a ve a r egim en design ed t o pr om ot e bon e
h ea lt h or, a t a m in im u m , decr ea se bon e loss.
Most current pha rmacologic trea tments of osteopo-
rosis are limited to the use of drugs tha t inhibit or re-
duce bone resorption, a lso known a s a n t ir e sor p t ive
medications (Ta ble 19.2). The effectiveness of these
medications is caused by the attenuation of the resorp-
tive process with no effect on the formation process,
thereby altering the bala nce in favor of bone formation.
Trea tments, including ca lcium, vita min D, ca lcitonin,
a nd bisphosphona tes, have been shown to be effective
in in dividua ls with bone loss ca used by corticosteroid
use and in postmenopa usal women. Bisphosphonates
(a lendronate a nd risedrona te), calcitonin, estrogens,
PTH, and raloxifen e are drugs currently a pproved by
the U.S. Food a nd Drug Administration (FDA) for use
to prevent or treat osteoporosis. Teriparatide (Forteo),
a form of PTH, is a n a na bolic agent representing the
first trea tment for osteoporosis that works by increas-
ing the forma tion of bone. Teripa ratide, when given in
a small da ily dose, promotes stimula tion of new tra -
becular and cortical bone.
Alzheimer Disease
Alzheimer disease (AD) is the most common neuro-
degenerative disorder and most frequent ca use of de-
mentia in the elderly, affecting more tha n 5 million
people in the United States. It interferes with cogni-
tive a nd social functioning, has a long a nd progressive
Ta b le 19.2 P h a r m a cologic P r even t ion a n d Tr ea t m en t of Ost eopor osis
Tr e a t m e n t C la s s I n d ic a t io n
E st r ogen H or m on e P r even t ion
Alen dr on a t e (Fosa m a x) Bisph osph on a t e P r even t ion
Tr ea t m en t
Risedr on a t e (Act on el) Bisph osph on a t e P r even t ion
Tr ea t m en t
Ra loxifen e (E vist a ) Select ive est r ogen P r even t ion
r ecept or m odu la t or Tr ea t m en t
(SE RM)
Ca lcit on in (Mica lcin ) H or m on e Tr ea t m en t
Ter ipa r a t ide H or m on e Tr ea t m en t
course, a nd ha s no known cure. Although not a nor-
ma l pa rt of a ging, AD can look very much like cogni-
tive cha nges tha t occur with age. For example, in one
study, the neuropathologist incorrectly identified 76%
of cognitively intact elderly pa tients a s having AD.2
PATHOPHYSIOLOGY
Sen ile pla qu es a n d n eu r ofibr illa r y t a n gles a r e t h eo-
r ized t o pla y a n im por t a n t r ole in t h e developm en t of
AD (Fig. 19.9). P la qu es a r e den se deposit s of pr ot ein
ou t side of n eu r on s. Th ey a r e com pr ised of bet a -a m -
yloid (Ab), a pr ot ein fr a gm en t of a m yloid pr ecu r-
sor pr ot ein (AP P ). Ab pr ot ein a ccu m u la t es t o for m
pla qu es begin n in g in sm a ll clu st er s (oligom er s), fol-
lowed by for m a t ion in t o ch a in s (fibr ils), a n d t h en
fin a lly in t o fiber s or ga n ized a s bet a -sh eet s. In AD,
pla qu es for m in t h e h ippoca m pu s a n d cer ebr a l cor-
t ex a n d im pa ct m em or y a n d decision -m a kin g.
H ea lt h y n eu r on s n eed m icr ot u bu les t o br in g n u -
t r ien t s t o t h e en ds of t h e a xon s a n d ba ck. Ta u , a
u n iqu e pr ot ein , bin ds t o m icr ot u bu les a n d pr ovides
st a bilit y, like a ba ckbon e. In AD, t a u becom es “st icky”
a n d t a n gles t oget h er wit h ot h er t a u t h r ea ds for m -
in g n e u r o ib r illa r y t a n g le s . Th ese n eu r ofibr illa r y
t a n gles a ccu m u la t e in it ia lly in t h e t em por a l lobe,
a n d t h en becom e den sely con cen t r a t ed in t h e m edia l
t em por a l lobe a n d h ippoca m pu s, im por t a n t loca t ion s
for m em or y for m a t ion . Th e m icr ot u bu le ca n n o lon -
ger per for m it s r ole of t r a n spor t in g n u t r ien t s t o t h e
n eu r on . Th e n eu r on ca n n o lon ger fu n ct ion , is u n a ble
t o com m u n ica t e wit h ot h er n eu r on s, a n d even t u a lly
dies. Dest r u ct ion of t h ese n eu r on s a n d t h e ch olin er gic
E ect Com m en t s
In cr ea sed bon e den sit y Risk of en dom et r ia l h yper-
pla sia wh en u t er u s is pr esen t
a n d u n opposed by pr ogest in ,
deep vein t h r om bosis, br ea st
ca n cer
In cr ea sed bon e den sit y Upper GI dist r ess, m ya lgia s,
a r t h r a lgia s
Redu ct ion in ver t ebr a l
a n d h ip fr a ct u r e
In cr ea sed bon e den sit y Upper GI dist r ess, m ya lgia s,
a r t h r a lgia s
Redu ct ion in h ip fr a ct u r e
In cr ea sed bon e den sit y H ot fla sh es, DVT
Redu ct ion in ver t ebr a l
fr a ct u r e
Redu ct ion in ver t ebr a l Rh in or r h ea
fr a ct u r e
In cr ea sed bon e for m a t ion Dizzin ess, leg cr a m ps
 C lin ic a l Mo d e ls 503

s AP P
Be ta a myloid

AP P

Ce ll me mbra ne

Be ta -s e cre ta s e

A Ga mma -s e cre ta s e Alpha -s e cre ta s e B Ga mma -s e cre ta s e

He a lthy S eve re
S ta bilizing Bra in Alzhe ime r’s
ta u mole cule s

He a lthy
ne uron
Microtubule s ubunits
fa ll a pa rt
Microtubule s Ta ngle d clumps
Dis inte gra ting of ta u prote ins
Dis e a s e d microtubule
ne uron

Dis inte gra ting

C microtubule s D

Figure 19.9. Selected pathophysiologic processes in Alzheimer disease. A: Amyloid precursor protein (APP) is embedded
in the neuron’s cell membrane. B: Enzymes beta-secretase and gamma-secretase sever soluble amyloid precursor protein
beta (sAPPβ ), releasing a fragment that becomes beta-amyloid. C: Neurofibrillary tangles of tau proteins in microtubules
form. D: As microtubules disintegrate and more and more neurons die, the brain atrophies (note differences in the healthy
and Alzheimer disease-affected brain). (Images courtesy of the Alzheimer’s Disease Education and Referral Center,
a service of the National Institute on Aging.)

syst em ca u ses m em or y fa ilu r e, in a bilit y t o per for m
a ct ivit ies of da ily livin g, a n d per son a lit y ch a n ges.
Neu r ofibr illa r y t a n gles con t in u e t o for m , pr ogr essin g
t o r egion s t h r ou gh ou t t h e cor t ex a n d im pa ct in g exec-
u t ive, m ot or, a n d sen sor y fu n ct ion . Th e r ela t ion sh ip
bet ween n eu r ofibr illa r y t a n gles a n d a m eloid (sen ile
pla qu e) deposit s is n ot clea r ly u n der st ood. H owever,
dem en t ia sever it y a ppea r s t o cor r ela t e wit h t h e
n u m ber a n d loca t ion of n eu r ofibr illa r y t a n gles.
AD occu r s a s a r esu lt of gen et ic a n d en vir on m en -
t a l fa ct or s. Spor a dic, la t e-on set AD is m ost com m on
a n d wit h a bou t 20% of ca ses clu st er in g in fa m ilies.
Th e followin g gen es h a ve been defin it ively a ssoci-
a t ed wit h AD, a n d m a n y ot h er s wit h a pr oba ble r ole
h a ve been iden t ified:
● Am yloid pr ecu r sor pr ot ein (AP P ) gen e
● P r esen ilin -1 (P S 1) gen e
● P r esen ilin -2 (P S 2) gen e
Mu t a t ion s in t h ese gen es r esu lt in pr ot ein s t h a t
h a ve n eu r ot oxic pr oper t ies a n d pr om ot e n eu r on a l
dea t h , syn a pse loss, a n d t h e for m a t ion of n eu r ofibr il-
la r y t a n gles a n d sen ile pla qu es. Sever a l r isk fa ct or s
h a ve been iden t ified in clu din g la t er a ge, fa m ily
h ist or y, obesit y, dyslipidem ia , h yper t en sion , Down
syn dr om e, h ist or y of t r a u m a t ic br a in in ju r y, lea d ex-
posu r e, a n d h ist or y of depr ession .
CLINICAL MANIFESTATIONS
AD is ch a r a ct er ized by a globa l cogn it ive declin e,
ch a n ges in beh a vior, a n d even t u a l com plet e loss of
fu n ct ion . In it ia l sym pt om s m im ic pr ocesses of n a t u -
r a l a gin g a n d in clu de:
● Mem or y loss
● Con fu sion
504 C h a p t e r 19: Degen er a t ive Ch a n ges in Agin g

S ta ge s I a nd II S ta ge s III a nd IV S ta ge s V a nd VI
A B C

Figure 19.10. The spread of neurofibrillary tangles in Alzheimer disease. A: Preclinical. B: Initial clinical symptoms.
C: Fully developed Alzheimer disease. (Adapted from Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in
different age categories. Neurobiol Aging. 1997;18(4):351–357.)

● Rest lessn ess ■ Wor sen in g m em or y

● Mood swin gs ■ Loss of a wa r en ess of su r r ou n din gs a n d r e-
● Difficu lt y in in t er pr et in g visu a l in for m a t ion cen t exper ien ces
■ Occa sion a l loss of m em or y of spou se’s/
AD pr ogr esses t h r ou gh seven st a ges, wit h gr ea t er
pr im a r y ca r egiver ’s n a m e
br a in in volvem en t a s t h e pa t ien t m oves t h r ou gh
■ Disr u pt ed sleep/wa ke cycle
ea ch st a ge (Fig. 19.10):
■ Assist a n ce n eeded wit h t oilet in g det a ils
● St a ge 1 ■ In cr ea sin g episodes of in con t in en ce
■ Min im a l cogn it ive im pa ir m en t ■ Sense of paranoia, delusions, hallu cinations
● St a ge 2 ■ Ma y wa n der or becom e lost
■ Mild cogn it ive im pa ir m en t (eviden t on ly t o self) ● St a ge 7
■ Mem or y la pse ■ Ver y sever e cogn it ive declin e
■ For get fu ln ess of fa m ilia r wor ds ■ Loss of a bilit y t o r espon d t o t h e en vir on -
■ Alt er ed m em or y of loca t ion of ever yda y m en t , in clu din g speech a n d m ovem en t
object s ■ Loss of com m u n ica t ion a bilit y
● St a ge 3 ■ Requ ir es in cr ea sin g a ssist a n ce wit h ea t in g a n d
■ Mild cogn it ive im pa ir m en t (eviden t a m on g t oilet in g
fr ien ds, fa m ily, cowor ker s) ■ Im pa ir ed swa llowin g, posit ion in g, a n d r eflex
■ Difficu lt y wit h wor d or n a m e fin din g r espon se
■ Decr ea sed per for m a n ce a t wor k or h om e
■ Difficu lt y wit h r ea din g r et en t ion
DIAGNOSIS
■ Mispla cin g va lu a ble object s
■ Im pa ir ed or ga n iza t ion or pla n n in g A defin it ive dia gn osis of AD ca n be m a de on ly wit h
● St a ge 4 a n a u t opsy wh en t ypica l ch a r a ct er ist ics of pla qu es
■ Moder a t e cogn it ive declin e (eviden t by a n d t a n gles ca n be seen . Ot h er t est in g ca n be don e
exa m in er ) t h a t , wh en com bin ed wit h clin ica l pr esen t a t ion a n d
■ Declin e in kn owledge of cu r r en t even t s or h ist or y, m a y su ppor t a dia gn osis of AD. A t h or ou gh
occa sion s n eu r ologic eva lu a t ion sh ou ld be com plet ed, wh ich
■ Im pa ir ed m a t h em a t ica l a bilit y in clu des a m en t a l st a t u s exa m in a t ion t o det er m in e
■ Im pa ir ed per for m a n ce of com plex t a sks (e.g., sen se of t im e a n d pla ce, com m u n ica t ion a bilit y, m em -
bill pa yin g, pla n n in g m ea ls) or y, com pr eh en sion , a n d a bilit y t o com plet e sim ple
■ Difficu lt y r em em ber in g per son a l h ist or y m a t h pr oblem s. E va lu a t ion of r ea son in g a bilit y, ba l-
■ Ch a n ge in per son a lit y (su bdu ed or a n ce, a n d visu a l/m ot or coor din a t ion sh ou ld a lso be
wit h dr a wn ) com plet ed. A br a in sca n , MRI, or CT sca n m a y be
● St a ge 5 don e t o r u le ou t ot h er pa t h ology.
■ Moder a t ely sever e cogn it ive declin e
■ E xh ibit s m a jor m em or y a n d cogn it ive
TREATMENT
deficit s
■ Requ ir es a ssist a n ce in da y-t o-da y a ct ivit ies Tr ea t m en t of AD in clu des su ppor t ive ca r e for t h e in -
● St a ge 6 dividu a ls a n d t h eir fa m ilies. Focu s on m a xim izin g
■ Sever e cogn it ive declin e qu a lit y of life a n d gen er a l h ea lt h is t h e cor n er st on e
■ Sign ifica n t per son a lit y ch a n ges of ca r e. Th e m a in st a y of ph a r m a cologic t h er a py for
■ In cr ea sed n eed for h elp in a ct ivit ies of da ily pa t ien t s is t h e u se of cen t r a lly a ct in g ch olin est er a se
livin g in h ibit or s t o a t t em pt t o com pen sa t e for t h e
 C h a p t e r 19: Degen er a t ive Ch a n ges in Agin g
deplet ion of a cet ylch olin e (ACh ) in t h e cer ebr a l cor-
t ex a n d h ippoca m pu s. Va r iou s ot h er m edica t ion s a r e
u sed for t r ea t m en t depen din g u pon t h e pr esen ce of
secon da r y sym pt om s of AD, in clu din g a n t idepr es-
sa n t s, a n t i-a n xiet y a gen t s, a n d a n t ipsych ot ic a gen t s.
To see a video on dementia , visit ht tp://
t hePoin t.lww.com
S U MMAR Y
● Aging is a normal condition that can be complicated
by degenerative changes affecting hea lth status.
● Th e cellu la r ba sis of a gin g r eflect s t h e in flu en ces
of gen et ics a n d cu m u la t ive effect s of da m a ge over
t im e. Th is m u lt ifa ct or ia l pr ocess con t r ibu t es t o
t h e t ypica l m a n ifest a t ion s of a gin g.
● Ma n ifest a t ion s of a gin g r eflect ph ysiologic
ch a n ges ch a r a ct er ist ic of h u m a n pa t t er n s of de-
velopm en t . Ch a n ges in t h e soft t issu es of t h e skin
a n d h a ir con t r ibu t e t o t h e t ypica l ou t wa r d a p-
pea r a n ce of a gin g.
● Alt er ed st r u ct u r e a n d fu n ct ion r esu lt in g fr om de-
gen er a t ive a gin g ch a n ges m a y lea d t o fu n ct ion a l
im pa ir m en t or m a y be exa cer ba t ed by ch r on ic
pa t h ologic con dit ion s.
● Alt er a t ion s in flu id a n d elect r olyt e ba la n ce, im -
m u n e r espon ses, cellu la r pr olifer a t ion , n eu r ologic
fu n ct ion , m obilit y, per fu sion , n u t r it ion , elim in a -
t ion , a n d m et a bolic pr ocesses r epr esen t a r ea s of
pot en t ia l pa t h ologic sequ ela e r ela t ed t o body sys-
t em ch a n ges in a gin g.
● Alt h ou gh t h er e is n o wa y t o h a lt t h e a gin g pr o-
cess, h ea lt h pr om ot ion a cr oss t h e life spa n m a y
im pr ove qu a lit y of life a n d a t t en u a t e m a n y
a ge-a ssocia t ed degen er a t ive ch a n ges.
C AS E S T U D Y 19.1
A.Z., a 65-yea r-old wom a n , wa s h a vin g a follow-u p
visit wit h h er ph ysicia n . Sh e wa s con cer n ed a bou t
a ch a n ge in h er sleepin g h a bit s, in clu din g t a kin g a t
lea st 30 m in u t es t o fa ll a sleep. Sh e woke u p a ft er
on ly a bou t 5 t o 6 h ou r s of sleep a n d fou n d h er self u n -
a ble t o fa ll a sleep a ga in . Sh e con sequ en t ly got sleepy
in t h e a ft er n oon a n d t ook fr equ en t n a ps.
1. Wh a t a r e som e ca u ses of a ge-a ssocia t ed sleep
disor der s?
2. Wh a t a r e t h e t ypica l ch a n ges in sleep pa t t er n s
t h a t occu r in r espon se t o a ge?
3. Wh a t ca u ses a ge-r ela t ed ch a n ges in sleep
pa t t er n s?
4. Wh a t a r e t h e r isks r ela t ed t o t h e u se of ph a r m a -
cologic sleepin g a ids in t h e elder ly?
5. Wh a t n on ph a r m a cologic st r a t egies ca n be u sed t o
h elp pr om ot e sleep?
505
Log on t o t h e In t er n et . Sea r ch for a r eleva n t jou r-
n a l a r t icle or Web sit e, su ch a s h t t p://em edicin e
.m edsca pe.com /a r t icle/291573-over view, t h a t det a ils
sleep disor der s in t h e elder ly t o con fir m you r
pr edict ion s.
P R AC T I C E E XAM Q U E S T I O N S
1. Gen et ic in flu en ces a s t h e m a jor det er m in a n t s
of a gin g a r e t h e focu s of wh ich of t h e followin g
t h eor ies?
a . Developm en t a l t h eor y
b. St och a st ic t h eor y
c. F r ee r a dica l t h eor y
d. E r r or t h eor y
2. Typica l ch a n ges in t ot a l body wa t er in t h e elder ly
in clu de:
a . In cr ea sed t ot a l body wa t er ca u sed by in cr ea se
in m u scle m a ss
b. In cr ea sed t ot a l body wa t er ca u sed by
in cr ea sed fa t m a ss
c. Decr ea sed t ot a l body wa t er ca u sed by decr ea se
in m u scle m a ss
d. Decr ea sed t ot a l body wa t er ca u sed by
decr ea sed fa t m a ss
3. Im m u n e sen escen ce is ch a r a ct er ized by:
a . In cr ea sed a n t igen ic im m u n e r espon se
b. E n h a n ced T-cell fu n ct ion
c. E n h a n ced IgE -m edia t ed h yper sen sit ivit y
d. E n h a n ced a u t oim m u n e r espon se
4. Age-r ela t ed ch a n ges a ffect in g n eu r ologic fu n c-
t ion in clu de:
a . In cr ea sed m yelin
b. Decr ea sed n u m ber of n eu r on s
c. E n h a n ced n er ve con du ct ion
d. Im pr oved a xon a l r epa ir m ech a n ism s
5. An im ba la n ce in bon e r em odelin g ch a r a ct er ist ic
of ost eopor osis is ca u sed by:
a . E n h a n ced bon e for m a t ion ca u sed by in cr ea sed
a ct ivit y of ost eocla st s
b. E n h a n ced bon e for m a t ion ca u sed by in cr ea sed
a ct ivit y of ost eobla st s
c. In cr ea sed bon e r esor pt ion ca u sed by in cr ea sed
a ct ivit y of ost eocla st s
d. In cr ea sed bon e r esor pt ion ca u sed by in cr ea sed
a ct ivit y of ost eobla st s
6. Age-r ela t ed ch a n ges con t r ibu t in g t o im pa ir ed
h ea lin g in clu de:
a . In cr ea sed skin ela st icit y
b. E n h a n ced su bcu t a n eou s fa t
c. Decr ea sed su per ficia l ca pilla r y per fu sion
d. At r oph ied ca pilla r y su ppor t t o der m is
506 C h a p t e r 19: Degen er a t ive Ch a n ges in Agin g

7. Ost eopor osis is t h e r esu lt of a n im ba la n ce fa vor- 5. Wh a t a r e t h e h u m a n differ en ces t h a t a ffect t h e

in g in cr ea sed et iology, r isk, or cou r se of degen er a t ive ch a n ges
a . Ost eobla st ic a ct ivit y in a gin g?
b. Ost eocla st ic a ct ivit y 6. Wh a t clin ica l m a n ifest a t ion s a r e expect ed in t h e
c. Vit a m in D a bsor pt ion cou r se of degen er a t ive ch a n ges in a gin g?
d. Ca lciu m a bsor pt ion 7. Wh a t specia l dia gn ost ic t est s a r e u sefu l in det er-
m in in g t h e dia gn osis a n d cou r se of degen er a t ive
8. Mor t a lit y for pa t ien t s wit h pr oger ia is m ost com - ch a n ges in a gin g?
m on ly a r esu lt of: 8. Wh a t a r e t h e goa ls of ca r e for in dividu a ls wit h
a . Ra pid a gin g degen er a t ive ch a n ges in a gin g?
b. At h er oscler osis 9. H ow does t h e con cept of degen er a t ive ch a n ges in
c. Scler oder m a a gin g bu ild on wh a t I h a ve lea r n ed in t h e pr evi-
d. P sych osis ou s ch a pt er a n d in t h e pr eviou s cou r ses?
10. H ow ca n I u se wh a t I h a ve lea r n ed?
9. Wh ich of t h e followin g is a ch a r a ct er ist ic fin din g
in pr oger ia ?
a . H igh levels of h ya lu r on ic a cid
b. Low levels of ca lcit on in R E SOUR CE S
c. H igh levels of t h yr ot oxicin e
d. Low levels of 1-dioxyglu t a m in e Alzh eim er Associa t ion :
h t t p://www.a lz.or g
10. Mem or y loss in Alzh eim er disea se r esu lt s fr om Na t ion a l Cen t er for Ch r on ic Disea se P r even t ion a n d
im pa ir ed n eu r a l con du ct ion in t h e H ea lt h P r om ot ion : H ea lt h y Agin g
a . F r on t a l lobe h t t p://www.cdc.gov/a gin g/in dex.h t m
b. Ba sa l ga n glia
c. Lim bic syst em Na t ion a l In st it u t e on Agin g:
d. H ippoca m pu s h t t p://www.gr c.n ia .n ih .gov
Na t ion a l Ost eopor osis Fou n da t ion :
h t t p://n of.or g
D I S C U S S I O N AN D
AP P L I C AT I O N P r oger ia Resea r ch Fou n da t ion :
h t t p://www.pr oger ia r esea r ch .or g/
1. Wh a t did I kn ow a bou t degen er a t ive ch a n ges in
a gin g befor e t oda y?
2. Wh a t body pr ocesses a r e a ffect ed by degen er- R e er en ces
a t ive ch a n ges in a gin g? H ow do degen er a t ive 1. Lu der s E , Ch er bu in N, Ku r t h F. For ever you n g(er ):
ch a n ges in a gin g a ffect t h ose pr ocesses? pot en t ia l a ge-defyin g effect s of lon g-t er m m edit a t ion
3. Wh a t a r e t h e pot en t ia l et iologies for degen er- on gr a y m a t t er a t r oph y. Fr on t P sych ol. 2015;5:1551.
a t ive ch a n ges in a gin g? H ow do degen er a t ive doi:10.3389/fpsyg.2014.01551.
2. Br a yn e C, Rich a r dson K, Ma t t h ews F E , et a l. Neu r o-
ch a n ges in a gin g develop? pa t h ologica l cor r ela t es of dem en t ia in over-80-yea r-old
4. Wh o is m ost a t r isk for developin g com plica t ion s br a in don or s fr om t h e popu la t ion -ba sed Ca m br idge
r ela t ed t o degen er a t ive ch a n ges in a gin g? H ow cit y over-75s coh or t (CC75C) st u dy. J Alzh eim ers Dis.
ca n t h ese a lt er a t ion s be pr even t ed? 2009;18(3):645–658.

F in d a d d ition a l r esou r ces for th is ch a pter a t h ttp:th ePoin t.lww.com

 Ch a pt er

20
In t egr a t ed
Pa t h oph ysiologic
Con cept s

L E AR N I N G O U T C O ME S
1. Defin e a n d u se t h e key t er m s list ed in t h is ch a pt er.
2. Recogn ize t h e effect s of com bin in g pa t h oph ysiologic con cept s on t h e h ea lt h
of t h e in dividu a l.
3. Iden t ify h ow pr eviou s con cept s wit h in t h is t ext r ela t e t o dia bet es m ellit u s.
4. Differ en t ia t e t ype 1, t ype 2, a n d gest a t ion a l dia bet es.
5. Iden t ify com m on clin ica l m a n ifest a t ion s of dia bet es.
6. Recogn ize sh or t -t er m a n d lon g-t er m com plica t ion s of dia bet es.
7. Descr ibe dia gn ost ic t est s a n d t r ea t m en t st r a t egies a ppr opr ia t e for
dia bet es.

INTR ODUCTION
Th e h u m a n body is h igh ly com plex. We h a ve a t t em pt ed t o dist in gu ish fu n c-
t ion a l a lt er a t ion s in h u m a n h ea lt h by in t r odu cin g you t o con cept s of pa t h o-
ph ysiology. Wh a t you h a ve pr oba bly figu r ed ou t by n ow is t h a t ver y few h ea lt h
con dit ion s fit pu r ely in t o on e or t wo con cept u a l ca t egor ies. For exa m ple, m yo-
ca r dia l in fa r ct ion (MI) is a pr oblem of per fu sion . MI a lso h a s r oot s in a lt er ed
n u tr ition , gen etics, a n d t h e en vir on m en t. MI r esu lt s in m yoca r dia l in fla m m a -
tion a n d in du ces a str ess r espon se. H or m on es, su ch a s cor t isol, a r e r elea sed
du r in g st r essfu l sit u a t ion s t o a id in r eest a blish in g h om eost a sis. Th e in effec-
t ive m yoca r diu m is less a ble t o m ove flu ids t h r ou gh t h e cir cu la t ion , r esu lt in g
in a lt er ed flu id ba la n ce. P u lm on a r y con gest ion m a y r esu lt , lea din g t o a lt er ed
ven tila tion a n d d iffu sion . Th e goa l of t h is ch a pt er is t o illu st r a t e t h e im pa ct of
com bin in g com plex pa t h oph ysiologic con cept s u sin g dia bet es m ellit u s a s t h e
select clin ica l m odel.

Glucose, Insulin, Energy, and the Pancreas

E n er gy, in t h e for m of glu cose, is essen t ia l for opt im a l h u m a n fu n ct ion in g. Glu -
cose is a m on osa cch a r ide, wh ich is der ived fr om diet a r y ca r boh ydr a t es. E xcess
glu cose is st or ed a s glycogen in t h e liver. Glu cose in t h e blood t r igger s t h e
r elea se of in su lin . I n s u lin is a n a n a bolic h or m on e r equ ir ed for t h e u pt a ke of
glu cose by t h e m a n y cells, pa r t icu la r ly t h ose of t h e liver, m u scle, a n d a dipose
cells. In su lin is n ot r equ ir ed for glu cose u pt a ke in t h e br a in , r ed blood cells,
kidn ey, a n d len s of t h e eye.

507
508 C h a p t e r 20: In t egr a t ed Pa t h oph ysiologic Con cept s

Stop and Consider Pa ncre a tic a cini Alpha ce ll

In the absence of insulin, glucose is still able to Be ta ce ll
move into cells of the brain, blood, kidney, and De lta ce ll
lens. This seems a beneficial property. What do
you think is the drawback of inadequate insu-
lin, resulting in excessive circulating glucose to
these cells?

An a bolic h or m on es, in clu din g in su lin , a r e r espon -

sible for bu ildin g com plex com pou n ds in t h e body,
su ch a s bu ildin g pr ot ein s fr om a m in o a cids. In su lin
h a s sever a l key fu n ct ion s:
● P r om ot in g glu cose u sa ge, t h er eby decr ea sin g
blood glu cose levels
● P r om ot in g pr ot ein syn t h esis
● P r om ot in g t h e for m a t ion a n d st or a ge of lipids
● Fa cilit a t in g t r a n spor t of pot a ssiu m , ph osph a t e,
a n d m a gn esiu m in t o t h e cells
In su lin pr odu ct ion a n d a va ila bilit y a r e closely
con n ect ed t o t h e pa n cr ea s. Th e pa n cr ea s is loca t ed
beh in d t h e lower por t ion of t h e st om a ch a n d is in -
n er va t ed by t h e a u t on om ic n er vou s syst em . Th e
pa n cr ea s h a s bot h en docr in e a n d exocr in e fu n c-
t ion s. Th e e n d o c r in e p a n c r e a s secr et es h or m on es,
su ch a s in su lin a n d glu ca gon . Th e a cin i cells of t h e
e x o c r in e p a n c r e a s secr et e digest ive en zym es a n d
a lka lin e flu ids t h r ou gh t h e pa n cr ea t ic du ct in t o
t h e du oden u m . Ch a pt er 15 wa s con cer n ed wit h t h e
r ole of t h e pa n cr ea s a s a digest ive a ccessor y or ga n .
Th is ch a pt er is con cer n ed wit h t h e en docr in e, or
h or m on e-secr et in g, fu n ct ion of t h e pa n cr ea s.
Th r ou gh ou t t h e pa n cr ea s a r e clu st er s of cells
ca lled t h e is le t s o L a n g e r h a n s (Fig. 20.1). Th e is-
let s of La n ger h a n s con t a in t h r ee m a jor t ypes of h or-
m on e-secr et in g cells:
● Alph a cells secr et e glu ca gon , wh ich m obilizes gly-
cogen fr om t h e liver a n d su ppr esses in su lin se-
cr et ion ; glu ca gon is cr it ica l in m a in t a in in g blood
glu cose levels bet ween m ea ls.
● Beta cells secr et e in su lin , wh ich pr om ot es glu cose
u t iliza t ion .
● Delta cells secr et e som a t ost a t in a n d ga st r in ,
wh ich r egu la t es a lph a a n d bet a cell fu n ct ion by
su ppr essin g t h e r elea se of in su lin , glu ca gon , a n d
pa n cr ea t ic polypept ides.
The pancreas also contains F cells, which are located
primarily at the periphery of the islets, although a few
F cells are scattered throughout the ducts and acini.
F cells secrete pancreatic polypeptides, which suppress
digestive enzyme release from the exocrine pancreas.
Stop and Consider
If you skipped breakfast and had a really low
blood glucose level, which cells of the islets of
Langerhans would you expect to be stimulated?
Is le t of Re d blood ce lls
La nge rha ns
Ca pilla ry
Figure 20.1. Islets of Langerhans in the pancreas.
Th e h or m on es secr et ed fr om t h e islet s of La n g-
er h a n s a r e im por t a n t con t r ollin g devices of ca r-
boh ydr a t e, pr ot ein , a n d fa t m et a bolism . As wit h
ot h er h or m on es, feedba ck syst em s a r e cr it ica l t o
m a in t a in in g h om eost a sis. Wit h in su lin , secr et ion is
in cr ea sed wh en t h er e a r e eleva t ion s in (1) blood glu -
cose; (2) a m in o a cids; (3) pot a ssiu m , ph osph a t e, a n d
m a gn esiu m ; a n d (4) glu ca gon a n d ga st r in . In su lin is
n eeded t o pr om ot e glu cose u pt a ke a n d m et a bolism
of n u t r ien t s. Cer t a in sit u a t ion s a lso pr om ot e a d e-
cr ea se in in su lin secr et ion , su ch a s low blood glu cose,
h igh levels of in su lin (t h r ou gh n ega t ive feedba ck
m ech a n ism s), a n d t h e st im u la t ion of a lph a cells. In
t h ese ca ses, in su lin is n ot n eeded beca u se it wou ld
exa cer ba t e t h e st a t e of h ypoglycem ia .
Stop and Consider
How does eating a large meal or skipping a meal
affect insulin levels in the body?
Diabetes Mellitus
D ia b e t e s m e llit u s is a gr ou p of disor der s, ch a r a c-
t er ized by t h e in a bilit y t o r egu la t e t h e a m ou n t of
glu cose in t h e body, lea din g t o t h e in a dequ a t e m et a b-
olism of pr ot ein , fa t s, a n d ca r boh ydr a t es. Th e differ-
en t t ypes of dia bet es a r e su m m a r ized in Ta ble 20.1
a n d expla in ed in det a il in t h is ch a pt er. Dia bet es
 C h a p t e r 20: In t egr a t ed Pa t h oph ysiologic Con cept s 509

TAB L E 20.1 Com pa r ison of Types of Dia bet es Mellit u s

On set
Type 1 P u ber t y or ch ildh ood (pea k
a t 10–14 yea r s); a lt h ou gh in -
cr ea sin g in a du lt h ood
Type 2 Adu lt yea r s (pea k a t a ge 45
yea r s); a lt h ou gh in cr ea sin g in
t h ose u n der a ge 45 yea r s
Gest a t ion a l P r egn a n cy (pea k a t fift h or
sixt h m on t h gest a t ion )
Ca u se
In su lin deficit
In su lin r esist a n ce or im pa ir ed a bilit y
of t h e t issu es t o u se in su lin ; in su ffi-
cien t in su lin in r ela t ion t o t h e n eeds
of t h e body
In su lin r esist a n ce du r in g pr egn a n cy
a s a r esu lt of t oo m u ch h or m on e pr o-
du ct ion in t h e body (for t h e pla cen t a );
in a bilit y t o m a ke t h e a ddit ion a l in su -
lin t h a t is n eeded du r in g pr egn a n cy
Tr e a t m e n t
In su lin r epla cem en t ba l-
a n ced wit h exer cise a n d
diet
Diet , exer cise, or a l gly-
cem ic a gen t s, possibly
in su lin
Diet , exer cise, som et im es
in su lin , deliver y of ba by

in sipidu s, a con dit ion of in a dequ a t e a n t idiu r et ic
h or m on e, wa s discu ssed in Ch a pt er 13. Ma n y ot h er
secon da r y con dit ion s ca n lea d t o dia bet es; t h ese a r e
su m m a r ized in Box 20.1.
On e or a com bin a t ion of t h e followin g ch a r a ct er-
izes t h e ba sic pa t h oph ysiology in t h e va r iou s t ypes
of dia bet es:
1. A com plet e dest r u ct ion of pa n cr ea t ic bet a cells
lea din g t o a la ck of in su lin secr et ion
2. Redu ced in su lin secr et ion fr om im pa ir ed bet a cell
fu n ct ion in r espon se t o glu cose st im u la t ion
3. A per iph er a l r esist a n ce t o in su lin
Th e a bsen ce, deficit , or r esist a n ce t o in su lin lea ds
t o a st a t e of h y p e r g ly c e m ia , wh ich is a sign ifica n t
eleva t ion in blood glu cose level, cou pled wit h t h e
in a bilit y t o t r a n spor t glu cose a n d a m in o a cids in t o
t h ose cells t h a t r equ ir e in su lin for t r a n spor t . Liver,
m u scle, a n d a dipose cells becom e depr ived of glu -
cose a s a n en er gy sou r ce a n d m u st t u r n t o ot h er less
Box 20.1 S e c o n d a r y C o n d it io n s T h a t
C a n L e a d t o I n s u lin D e ic it o r
R e s is t a n c e
● Disea ses of t h e pa n cr ea s t h a t dest r oy pa n cr ea t ic bet a
cells
● Pa n cr ea t it is
● Cyst ic fibr osis
● Pa n cr ea t ic ca n cer
● H or m on a l syn dr om es t h a t in t er fer e wit h in su lin se-
cr et ion or ca u se per iph er a l in su lin r esist a n ce
● P h eoch r om ocyt om a
● Acr om ega ly
● Cu sh in g syn dr om e
● St r ess, su ch a s occu r s wit h sever e m edica l illn ess
or su r ger y, beca u se in cr ea ses in glu ca gon , ca t ech ol-
a m in es, cor t isol, a n d gr owt h h or m on e levels a n t a go-
n ize t h e secr et ion or effect s of in su lin
● Cer t a in m edica t ion s
● P h en yt oin
● Glu cocor t icoids
● E st r ogen s
efficien t sou r ces, su ch a s body fa t s or even pr ot ein s,
for en er gy. To see a video on h or m on a l con t r ol of
blood su ga r, visit h t t p://t h ePoin t .lww
.com .
INSULIN DEFICIT: TYPE 1 DIABETES MELLITUS
Type 1 dia bet es is a ch r on ic pr oblem of ca r boh y-
dr a t e, fa t , a n d pr ot ein m et a bolism . Th e body is u n -
a ble t o m et a bolize n u t r ien t s beca u se of a n a bsolu t e
or sign ifica n t deficien cy of in su lin . Appr oxim a t ely
10% of in dividu a ls wit h dia bet es a r e ca t egor ized a s
t ype 1. Th is t ype of dia bet es wa s pr eviou sly kn own
a s in su lin -depen den t dia bet es m ellit u s (IDDM) or
ju ven ile-on set dia bet es t o r eflect t h e m ost com m on
t r ea t m en t m oda lit y (in su lin r epla cem en t ) a n d a ge
a t dia gn osis (a ppr oxim a t ely 10 t o 14 yea r s of a ge).
H owever, t ype 1 dia bet es is becom in g in cr ea sin gly
com m on in a du lt s.
Pathophysiology
Th e et iology of t ype 1 dia bet es is m u lt ifa ct or ia l a n d
in clu des bot h gen et ic a n d en vir on m en t a l in flu en ces
lea din g t o a u t oim m u n e dest r u ct ion of bet a cells. Th e
im por t a n ce of gen et ic su scept ibilit y h a s been dem on -
st r a t ed in st u dies of iden t ica l t win s (25% t o 50%
gr ea t er r isk in secon d t win if on e t win is dia gn osed)
a n d t h e pr esen ce of cer t a in a n t igen s expr essed on
t h e m a jor h ist ocom pa t ibilit y com plex (MH C; see
Ch a pt er 4) in t h ose wit h t ype 1 dia bet es. E xposu r e
t o a t r igger in t h e en vir on m en t , su ch a s a vir u s or
t oxin , st im u la t es cell-m edia t ed dest r u ct ion a n d a
pr ocess of a u t oim m u n it y t h a t pr om ot es dest r u ct ion
of t h e bet a cells. Most bet a islet cell a n t ibodies a r e
dir ect ed a ga in st glu t a m ic a cid deca r boxyla se (GAD),
a ch em ica l wit h in t h e bet a cells. E xa m ples of t r ig-
ger in g en vir on m en t a l a gen t s in clu de in fect ion wit h
m u m ps, gr ou p-B coxsa ckie vir u ses, or in t r a u t er in e
r u bella exposu r e.
Cell-m edia t ed im m u n e m ech a n ism s (m or e spe-
cifica lly, t h e pr esen ce of cyt ot oxic T lym ph ocyt es)
510 C h a p t e r 20: In t egr a t ed Pa t h oph ysiologic Con cept s

dest r oy bet a cells. Au t oim m u n e dest r u ct ion t r igger s Clinical Manifestations

a ch r on ic in fla m m a t or y r espon se. In fla m m a t ion
con t r ibu t es t o fu r t h er dest r u ct ion of bet a cells a n d
im pa ir ed in su lin secr et ion . In t h e ea r ly st a ges of
t h is cell-m edia t ed im m u n e dest r u ct ion , a n t ibodies
a ga in st bet a cells a r e cir cu la t in g, bu t h yper glyce-
m ia is n ot yet pr esen t . Th is is con sider ed a st a t e of
“pr edia bet es” a n d ca n la st for sever a l yea r s. Clin ica l
m a n ifest a t ion s a n d det ect ion of dia bet es u su a lly oc-
cu r wh en a u t oim m u n e pr ocesses dest r oy 80% t o 90%
or m or e of t h e bet a cells of t h e pa n cr ea s. Over t im e,
t h e exocr in e pa n cr ea s becom es fibr ot ic wit h t h e su b-
sequ en t a t r oph y of a cin a r cells.
Type 1 dia bet es a lso a ffect s a lph a cell fu n ct ion ,
r esu lt in g in in cr ea sed levels of glu ca gon . Reca ll
t h a t glu ca gon su ppr esses in su lin pr odu ct ion . Th is,
cou pled wit h bet a cell dest r u ct ion , lea ds t o a st a t e
of h yper glycem ia a n d h yper ket on em ia . H yper gly-
cem ia is a r esu lt of a ccu m u la t ion s of cir cu la t in g
blood glu cose u n m a t ch ed by in su lin for u se in t h e
cell. Th e body is st a r vin g for en er gy a n d t u r n s t o fa t
st or es a n d pr ot ein for en er gy. In su lin in h ibit s lip-
olysis (fa t br ea kdown ). Th er efor e, t h e r edu ct ion or
a bsen ce of in su lin a llows t h e u n r egu la t ed m obiliza -
t ion of fa t s for en er gy. As a r esu lt , fa t oxida t ion pr o-
du ces h y p e r k e t o n e m ia (excess cir cu la t in g ket on e
bodies), com posed of a cet oa cet ic a cid, a cet on e, a n d
β -h ydr oxybu t yr ic a cid, lea din g t o a st a t e of m et a -
bolic k e t o a c id o s is .
H yper glycem ia , even wh en n ot a ssocia t ed wit h
ket oa cidosis, is pr oblem a t ic a n d ca n lea d t o osm ot ic
diu r esis. Osm ot ic diu r esis is a con dit ion in wh ich ex-
cess glu cose pr om ot es t h e a t t r a ct ion of wa t er in t o t h e
kidn eys, t h er eby elim in a t in g glu cose, elect r olyt es,
a n d wa t er t h r ou gh t h e u r in e. Th is ca n lea d t o sever e
deh ydr a t ion . H yper glycem ia a lso u n der m in es wh it e
blood cell fu n ct ion , pr om ot es in fect ion , a n d im pa ir s
wou n d h ea lin g.
Stop and Consider
How does an insulin deficit compare to marasmus
as described in Chapter 17?
Th e clin ica l m a n ifest a t ion s of t ype 1 dia bet es m el-
lit u s a r e r ela t ed t o sever e h yper glycem ia a n d h y-
per ket on em ia , a s well a s t o in a dequ a t e en er gy a n d
n u t r ien t m et a bolism (Fig. 20.2). Th ese m a n ifest a -
t ion s oft en a ppea r a br u pt ly despit e m on t h s or even
yea r s of bet a cell dest r u ct ion . Th e clin ica l m a n ifes-
t a t ion s m ost com m on ly a ssocia t ed wit h t ype 1 dia -
bet es in clu de:
● P o ly d ip s ia —excessive t h ir st
● P o ly u r ia —excessive u r in a t ion
● P o ly p h a g ia —excessive h u n ger
Ot h er sym pt om s in clu de n o c t u r ia (u r in a t ion a t
n igh t ), fa t igu e, let h a r gy, u n expla in ed weigh t loss,
a n d blu r r ed vision . Th e clin ica l m a n ifest a t ion s,
a lon g wit h t h e pa t h oph ysiologic or igin s, a r e ou t lin ed
in Ta ble 20.2.
Diagnostic Criteria
Th e dia gn osis of t ype 1 dia bet es m ellit u s is ba sed
on a t h or ou gh pa t ien t h ist or y a n d ph ysica l exa m -
in a t ion , in clu din g specific la bor a t or y a n d dia gn ost ic
t est s. Th e pr esen ce of polyu r ia , polydipsia , polyph a -
gia , weigh t loss, a n d fa t igu e, a lon g wit h a n eleva t ion
in t h e fa st in g blood glu cose a bove 126 m g/dL or t h e
r a n dom blood glu cose level a bove 200 m g/dL, is u su -
a lly su fficien t for dia gn osis. Ch eckin g u r in e for ke-
t on es ca n a lso pr ovide in for m a t ion on t h e pr esen ce
of h yper ket on em ia ; u r in e ket on e levels a r e pr opor-
t ion a l t o blood ket on e levels. Islet cell a u t oa n t ibodies
ca n be det ect ed in t h e ea r ly st a ges of t ype 1 dia bet es
a s well a s a u t oa n t ibodies a ga in st GAD, a n en zym e
pr odu ced by pa n cr ea t ic islet cells, wh ich per sist over
t im e. Ta ble 20.3 pr ovides a gu ide t o la bor a t or y t est s
u sefu l in t h e dia gn osis of t ype 1 dia bet es.
Treatment
Tr ea t m en t of dia bet es m ellit u s r equ ir es a ba la n ce of
t h e followin g:

1. Glycem ic con t r ol
2. E xer cise
F R O M T H E L AB 3. In su lin r epla cem en t
t h er a py
Glycosylated hemoglobin (HbA1c) is a blood test that depicts hemoglobin and red blood cell
exposure to glucose over the previous 3 to 4 months. In prolonged hyperglycemia, found in Th e goa l of t r ea t m en t is
both type 1 and type 2 diabetes, the hemoglobin that travels on the red blood cell becomes t o st a bilize blood glu cose
irreversibly combined with glucose, a situation termed glycosylation, for the life of that levels wit h in t h e expect ed
red blood cell (120 days). HbA1c is therefore a useful determinant of “average” exposure of r a n ge (70 t o 120 m g/dL).
red blood cells to glucose over that period. The higher the HbA1c, the more hyperglycemic, Blood glu cose levels a r e
or uncontrolled, the diabetes has been. The goal for those with diabetes should be 7% or m ea su r ed fr equ en t ly
below. Persons with elevations in HbA1c are at greater risk for long-term complications, u sin g self-blood glu -
including cardiovascular disease and death. cose m on it or in g syst em s
(F ig. 20.3). F ood in t a ke
 C h a p t e r 20: In t egr a t ed Pa t h oph ysiologic Con cept s 511

Ins ulin de fic ie nc y

(and g luc ag o n exc e s s )

De cre a s e d glucos e upta ke Lipolys is

Glyce rol

P rote in bre a kdown We ight los s

Glycoge n
Amino a cids
Hunge r
We ight los s Glucone oge ne s is Ke tone s Fa tty a cids

Polypha gia
Hunge r Glucos e Hype rke to ne mia

Polypha gia Hype rg lyc e mia Me ta bolic

Kus s ma ul
a cidos is
re s pira tions

Glucos uria Os motic CNS de pre s s ion

diure s is
Kidney

Wa te r, Coma
e le ctrolyte los s
(polyuria )

De hydra tion
(polydips ia )

Circula tory
fa ilure

Figure 20.2. Concept map. Mechanisms of hyperglycemia and hyperketonemia. CNS, central nervous system. (Modified
from Porth CM. Essentials of Pathophysiology: Concepts of Altered Health States. Philadelphia, PA: Lippincott Williams &
Wilkins; 2003.)

in cr ea ses blood glu cose levels. Th er efor e, food in - d es t r oyed in t h e ga s t r oin t es t in a l t r a ct if t a k en

t a ke m u st equ a l t h e a va ila ble in su lin a n d m et a bolic
n eeds of t h e body. Th e diet sh ou ld in clu de com plex
ca r boh ydr a t es, pr ot ein , a n d u n sa t u r a t ed fa t sou r ces
wh ile lim it in g sim ple su ga r s, ch olest er ol, a n d sa t u -
r a t ed fa t s. Typica lly, t h e ca r boh ydr a t e t o in su lin r a -
t io n eeded is a r ou n d 10 t o 15 gr a m s of ca r boh ydr a t e
t o 1 u n it of r a pid-a ct in g in su lin . E xer cise decr ea ses
blood glu cose levels t h r ou gh in cr ea sed glu cose u s-
a ge by m u scle t issu e. In cr ea ses in exer cise m u st be
m a t ch ed wit h r edu ct ion s in in su lin or in cr ea ses in
food in t a ke.
I n s u lin r epla cem en t t h er a py is in t egr a l t o t h e
t r ea t m en t pla n for t yp e 1 dia bet es . I n s u lin is
or a lly, s o it m u s t be in ject ed s u bcu t a n eou s ly via
in t er m it t en t in ject ion s or wit h a n in s u lin in fu -
s ion p u m p. Th e on s et , p ea k , a n d d u r a t ion of a c-
t ion ca n va r y a m on g differ en t t yp es of in s u lin a n d
in clu d e:
1. Ra pid on set , sh or t a ct in g (a lso ca lled r egu la r )
2. In t er m edia t e a ct in g
3. Slow on set , lon g a ct in g
Ta ble 20.4 dist in gu ish es t h e differ en t for m s of in -
su lin ba sed on on set , pea k, a n d du r a t ion of a ct ion .
Th e goa l is t o coor din a t e food in t a ke wit h in su lin
a va ila bilit y in t h e body. In ject in g in su lin wit h ou t
512 C h a p t e r 20: In t egr a t ed Pa t h oph ysiologic Con cept s

TAB L E 20.2 Clin ica l Ma n ifest a t ion s a n d Cor r espon din g Pa t h oph ysiologic P r ocess in Type 1 Dia bet es
Mellit u s
C lin ic a l Ma n i e s t a t io n P a t h o p h y s io lo g ic P r o c e s s P o t e n t ia l C o m p lic a t io n s
Polyu r ia H yper glycem ia osm ot ica lly dr a ws flu ids in t o t h e in t r a - Deh ydr a t ion
Noct u r ia va scu la r spa ce; glu cose a lso a ct s a s a diu r et ic; t h is lea ds
t o la r ge volu m es of u r in e bein g filt er ed by t h e kidn eys
Glu cosu r ia (excess glu cose a n d excr et ed; a lso, t h e r en a l t h r esh old for glu cose is ex-
in t h e u r in e) ceeded; t h e kidn eys a llow t h is excess glu cose t o spill ou t
in t o t h e u r in e
Polydipsia H yper glycem ia osm ot ica lly dr a ws flu ids fr om t h e Deh ydr a t ion
Dr y m ou t h cells in t o t h e in t r ava scu la r spa ce; t h is lea ds t o cellu -
la r deh ydr a t ion a n d t h e st im u la t ion of t h ir st by t h e
h ypot h a la m u s
Polyph a gia In su lin deficit disa llows u se of glu cose for en er gy; st or- St a r va t ion , com a , dea t h
Weigh t loss a ge of fa t s, pr ot ein s, a n d ca r boh ydr a t es begin t o deplet e;
cells a r e in a st a t e of st a r va t ion beca u se of la ck of n u t r i-
Fa t igu e en t s, t h er eby in du cin g h u n ger
Blu r r ed vision Len s a n d r et in a a r e exposed t o h yper osm ola r flu ids Vision im pa ir m en t , blin dn ess

TAB L E 20.3 Com pa r ison of La bor a t or y Test s for Type 1 Dia bet es Mellit u s
D ia g n o s t ic Te s t
Ra n dom blood glu cose
Fa st in g blood glu cose
Glu cose t oler a n ce t est :
in dividu a l is given 50–100 g
of glu cose dissolved in wa t er ;
blood glu cose is m ea su r ed a t
1, 2, a n d 3 h ou r s
Glycosyla t ed h em oglobin (A1c)
Ur in a lysis
S ig n i ic a n t F in d in g s (Va lu e s Ar e
E x p e c t e d Va lu e s Ap p r o x im a t e a n d Ma y Va r y b y S o u r c e )
70–120 m g/dL >200 m g/dL a lon g wit h clin ica l m a n ifest a t ion s
70–120 m g/dL >126 m g/dL on t wo occa sion s a ft er fa st in g
120–160 m g/dL a t 1 h ou r >190 m g/dL a ft er 1 h ou r >165 m g/dL a ft er 2 h ou r s
70–120 m g/dL a t 2 h ou r s
2%–6% 8% a n d gr ea t er sign ifies pr olon ged h yper glycem ia
(see F r om t h e La b)
Nega t ive for glu cose Glu cose >15 m g/dL
Nega t ive for ket on es Ket on es pr esen t

a dequ a t e diet a r y in t a ke in du ces h y p o g ly c e m ia , or

Figure 20.3. The child uses an automatic lancet to get
blood sample ( left) and blood glucose monitor to deter-
mine blood glucose level ( right) .
low blood glu cose levels.
In su lin in fu sion pu m ps a r e a n a lt er n a t ive t o
da ily in ject ion s. An in su lin pu m p looks like a pa ger
a n d ca n be wor n in con spicu ou sly on a belt , in a
pocket , or on a n ela st ic ba n d wr a pped a r ou n d a n
a r m or leg. Th e in su lin is deliver ed t h r ou gh a pla st ic
ca t h et er in t o su bcu t a n eou s t issu e of t h e a bdom en .
An in su lin pu m p is a ble t o sim u la t e t h e pa n cr ea s’
deliver y of in su lin m or e closely t h a n in su lin in jec-
t ion s. Most people on t h e pu m p fin d t h a t t h ey a r e
a ble t o a ch ieve bet t er con t r ol of t h eir blood glu cose
levels beca u se t h e in su lin is deliver ed con t in u ou sly
(a t a ba sa l r a t e) a n d in a bolu s for m ea lt im es or
t im es of ph ysica l a ct ivit y. Wh en a n in su lin pu m p
is u sed, blood glu cose levels m u st be ch ecked m or e
fr equ en t ly.
 C h a p t e r 20: In t egr a t ed Pa t h oph ysiologic Con cept s 513

TAB L E 20.4 Com pa r ison of Types of In su lin

S h o r t -a c t in g
R a p id -a c t in g (i.e . R e g u la r , I n t e r m e d ia t e - L o n g -a c t in g Oth er
I n s u lin (i.e ., L is p r o ) H u m u lin R ) a c t in g (i.e ., N P H ) (i.e ., U lt r a le n t e ) (i.e ., G la r g in e )
On set of a ct ion 15 m in u t es 30 m in u t es 2–4 h ou r s 6–10 h ou r s 2–4 h ou r s
Pea k (in h ou r s) 1 2–3 4–12 8–12 Pea kless
Du r a t ion 2–4 3–6 12–20 20–26 Up t o 24
(in h ou r s)
Wh en t o Im m edia t ely Th r ou gh ou t Th r ou gh ou t Nigh t t im e Nigh t t im e
Adm in ist er befor e a m ea l t h e da y t h e da y

NP H , n eu t r a l pr ot a m in e H a gedor n (H a gedor n discover ed in 1936 t h a t wh en pr ot a m in e wa s a dded t o in su lin , it pr olon ged t h e effect s).

INSULIN RESISTANCE
AND REDUCTION:
TYPE 2 DIABETES R E S E AR C H N O T E S
Type 2 dia bet es m elli- Diabetic neuropathy is a common and problematic complication of diabetes. A recent study
t u s is a pr oblem of in su - compared nerve excitability testing in patients who performed daily insulin injections com-
lin r esist a n ce (r edu ced pared with patients using a continuous subcutaneous insulin infusion pump. Results demon-
t issu e sen sit ivit y t o in - strated significant differences in nerve axon function between the daily injections and those
su lin ) a n d a r edu ct ion using a continuous pump. Axonal function remained normal in those on continuous insulin in-
in a dequ a t e in su lin se- fusions, whereas function was impaired with those on daily injections. Researchers concluded
cr et ion . Most (90%) in - that continuous infusion likely has a neuroprotective effect for patients with type 1 diabetes. 1
dividu a ls wit h dia bet es
a r e est im a t ed t o h a ve
t ype 2 dia bet es. Th is for m u n a ble t o com pen sa t e by in cr ea sin g bet a cell pr o-
wa s pr eviou sly r efer r ed t o a s n on –in su lin -depen den t du ct ion of in su lin go on t o develop t ype 2 dia bet es.
dia bet es or a du lt -on set dia bet es, a lt h ou gh som e in - Ot h er r isk fa ct or s in clu de a ge over 30 yea r s, a fa m ily
dividu a ls wit h t ype 2 dia bet es m a y r equ ir e in su lin h ist or y of t ype 2 dia bet es, a n d Na t ive Am er ica n , H is-
r epla cem en t , a n d t h e in ciden ce is in cr ea sin g in ch il- pa n ic, or Bla ck r a ce.
dr en . Ma t u r it y-on set dia bet es of t h e you n g (MODY) Un like t ype 1 dia bet es, t h er e is n o a u t oim m u n e
is a r a r e for m of t ype 2 dia bet es t h a t h a s a st r on g ge- dest r u ct ion of t h e pa n cr ea s. Ra t h er, in su lin r esis-
n et ic com pon en t (a u t osom a l dom in a n t in h er it a n ce) ta n ce, or a decr ea sed sen sit ivit y t o in su lin in m et a -
a n d is fou n d t o a ffect in dividu a ls you n ger t h a n 25 bolic t issu es, su ch a s t h e liver, skelet a l m u scle, a n d
yea r s of a ge. Th e m et a bolic syn dr om e is a con dit ion a dipose t issu e, r esu lt s in in su fficien t in su lin u sa ge
t h a t in clu des in su lin r esist a n ce a n d a con st ella t ion (Fig. 20.4). Obesit y pr om ot es per iph er a l in su lin r e-
of ot h er m et a bolic pr oblem s, in clu din g obesit y, h igh sist a n ce by r elea sin g fr ee fa t t y a cids a n d cyt okin es
t r iglycer ide levels, low h igh -den sit y lipopr ot ein fr om a dipose cells. Th ese ch em ica ls in t er fer e wit h in -
levels, h yper t en sion , a n d cor on a r y h ea r t disea se. su lin sign a ls, disr u pt in su lin r ecept or s on t h e t a r get
In dividu a ls dia gn osed wit h t ype 2 dia bet es m u st cell pla sm a m em br a n es, a n d pr oh ibit in su lin fr om
a lso be eva lu a t ed for m et a bolic syn dr om e t o det er- fa cilit a t in g t h e en t r y of glu cose in t o liver, m u scle,
m in e t h e fu ll r a n ge of m et a bolic a lt er a t ion s. Gest a - a n d a dipose t issu es. In dividu a ls wit h t ype 2 dia bet es
t ion a l dia bet es (discu ssed la t er ) is a lso con sider ed a a lso exh ibit r edu ced in su lin secr et ion in r espon se t o
for m of t ype 2 dia bet es t h a t pr esen t s du r in g glu cose exposu r e. In t ype 2 dia bet es, su ba dequ a t e
pr egn a n cy. levels of in su lin a n d per iph er a l r esist a n ce t o in su lin
u pt a ke lea ds t o t h e followin g:
Pathophysiology
1. Bet a cells do n ot a dequ a t ely r espon d t o cir cu la t -
Sim ila r t o t ype 1 dia bet es, t h e exa ct ca u se of t ype in g blood glu cose levels.
2 dia bet es is u n kn own ; h owever, gen et ic a n d en vi- 2. Th e r elea se of glycogen fr om t h e liver cou pled
r on m en t a l fa ct or s a ppea r t o con t r ibu t e t o it s devel- wit h t h e su ppr ession of in su lin by glu ca gon pr o-
opm en t . Th e m ost sign ifica n t r isk fa ct or is obesit y, m ot es excessive cir cu la t in g glu cose.
wh ich r esu lt s fr om bot h gen et ic a n d en vir on m en t a l 3. Th e in su lin r ecept or s in t h e liver, skelet a l m u s-
in flu en ces. Appr oxim a t ely 90% of t h ose wh o develop cle, a n d a dipose t issu e a r e u n r espon sive, t h er eby
t ype 2 dia bet es a r e obese. All over weigh t in dividu - m a kin g t h e t issu es u n a ble, or r esist a n t t o, u sin g
a ls h a ve in su lin r esist a n ce, bu t on ly t h ose wh o a r e t h e in su lin .
514 C h a p t e r 20: In t egr a t ed Pa t h oph ysiologic Con cept s

polyph a gia , a n d polydipsia ) m a y be pr esen t . Most

Ge ne tic Environme nta l of t h e t im e, h owever, clin ica l m a n ifest a t ion s t h a t
pre dis pos ition fa ctors a ppea r a r e r ela t ed t o lon g-t er m com plica t ion s t h a t
m a y a r ise wit h dia bet es, su ch a s visu a l ch a n ges,
ch a n ges in kidn ey fu n ct ion , cor on a r y a r t er y disea se,
per iph er a l va scu la r disea se, r ecu r r en t in fect ion s, or
Ins ulin Obe s ity n eu r opa t h y. Th e pr esen ce of obesit y a n d h yper lipid-
re s is ta nce
em ia sh ou ld h eigh t en su spicion t h a t t ype 2 dia bet es
Impa ire d ins ulin
re le a s e is pr esen t .

Diagnostic Criteria
Th ose iden t ified wit h in t h e r isk ca t egor ies for t ype
De cre a s e d glucos e
upta ke
2 dia bet es sh ou ld be eva lu a t ed by r a n dom or fa st -
in g blood glu cose m ea su r em en t s. Ma n y in dividu -
a ls wit h t ype 2 dia bet es a r e a sym pt om a t ic a n d t h e
disea se goes u n dia gn osed for m a n y yea r s. As wit h
Incre a s e d Hype rglyce mia in dividu a ls wh o h a ve t ype 1 dia bet es, t h ose in divid-
he pa tic glucos e u a ls wit h clin ica l m a n ifest a t ion s (i.e., polyu r ia , poly-
output
dipsia , polyph a gia , n oct u r ia , a n d weigh t loss) a n d
Type 2 dia be te s r a n dom pla sm a glu cose levels a bove 200 m g/dL a r e
ea sily dia gn osed a s h a vin g dia bet es. A m a jor dia g-
n ost ic ch a llen ge is differ en t ia t in g t ype 1 fr om t ype
Figure 20.4. Pathogenesis of type 2 diabetes. (Modified
2 dia bet es. Mor e oft en , in dividu a ls wit h t ype 2 dia -
from Porth CM. Essentials of Pathophysiology: Concepts
bet es a r e over weigh t a du lt s, bu t t h is is n ot a lwa ys
of Altered Health States. Philadelphia, PA: Lippincott
t h e ca se. Upon dia gn osis, it is n ot u n u su a l for blood
Williams & Wilkins; 2003.)
glu cose levels t o be less t h a n t h a t fou n d wit h t ype 1
dia bet es beca u se in su lin is st ill a va ila ble. If dia be-
Glu ca gon secr et ion is sign ifica n t ly in cr ea sed. Reca ll t es is su spect ed, t wo sepa r a t e fa st in g blood glu cose
t h a t glu ca gon m obilizes glycogen fr om t h e liver a n d m ea su r em en t s a r e wa r r a n t ed. If bot h a r e a bove 126
su ppr esses in su lin secr et ion . Alt h ou gh t h er e is n o m g/dL, t ype 2 dia bet es m a y be su ggest ed. A fa st in g
r edu ct ion in bet a cells, h igh ser u m lipid levels, a s pla sm a glu cose bet ween 110 a n d 125 m g/dL in di-
m a y occu r wit h obesit y, a llows fa t t o deposit in t h e ca t es “im pa ir ed fa st in g glu cose” a n d r equ ir es close
pa n cr ea s, wh ich m a y lea d t o scler osis a n d fu r t h er m on it or in g beca u se t h er e is a h igh r isk of develop-
im pa ir pa n cr ea t ic fu n ct ion . Ult im a t ely, t h is r esu lt s in g dia bet es over t im e. Th e pr esen ce of a n t ibodies
in t h e im pa ir ed m et a bolism of ca r boh ydr a t es, fa t s, a ga in st t h e islet cells or GAD wou ld in dica t e t h a t
a n d pr ot ein s. t h is per son does n ot h a ve t ype 2 dia bet es, bu t r a t h er
h a s t ype 1.
Clinical Manifestations
Treatment
Th e clin ica l m a n ifest a t ion s for t ype 2 dia bet es a r e
oft en in sidiou s a n d n on specific. In som e ca ses, t h e Tr ea t m en t of t ype 2 dia bet es begin s wit h weigh t con -
cla ssic sym pt om s for t ype 1 dia bet es (polyu r ia , t r ol t h r ou gh a n in dividu a lized n u t r it ion a n d exer cise
pla n a n d ca n in clu de or a l
glycem ic a gen t s or in su lin
r epla cem en t t h er a py. Th e
goa l of t r ea t m en t for t ype
R E S E AR C H N O T E S 2 dia bet es is t h e sa m e a s
Multiple studies are identifying links between lifestyle factors and the onset of type 2 diabe- t h a t of t ype 1: t o m a in t a in
tes. One such study systematically reviewed associations between consumption of beverages opt im a l blood glu cose lev-
sweetened with sugar, artificial sweeteners, and fruit juice in over 38,000 patients. Higher els. P h ysica l a ct ivit y is
consumption of sugar was associated with the onset of type 2 diabetes independent of body a dva n t a geou s beca u se it
fat at diagnosis. Results for artificial sweeteners were unclear and there was not a signif- in cr ea ses t h e u pt a ke of
icant association determined with consumption of fruit juice, although it was determined glu cose by t h e m u scles
unlikely that fruit juice would serve as a healthy alternative to sugar-sweetened beverages. wit h ou t in cr ea sin g in su -
Researchers estimated that 1.8 million cases of type 2 diabetes could be attributed to con- lin n eeds. E xer cise a lso
sumption of sugar-sweetened beverages in the United States. 2 im pr oves in su lin sen si-
t ivit y. Th e ot h er posit ive
 C h a p t e r 20: In t egr a t ed Pa t h oph ysiologic Con cept s 515

TAB L E 20.5 Or a l Glycem ic Agen t s Used t o Tr ea t Type 2 Dia bet es Mellit u s

O r a l G ly c e m ic Ag e n t (E x a m p le s o
G e n e r ic N a m e s ) P r im a r y S it e o Ac t io n Me t h o d o Ac t io n
Alph a -glu cosida se in h ibit or s (a ca r bose, m iglit ol) In t est in es Slows ca r boh ydr a t e digest ion
Bigu a n ides (m et for m in ) Liver P r even t s excessive glu cose r elea se
fr om t h e liver ; m a kes per iph er a l
t issu es m or e sen sit ive t o in su lin
Meglit in ides (r epa glin ide) Pa n cr ea s St im u la t es m or e secr et ion of in su lin
fr om t h e pa n cr ea s; sh or t -a ct in g
Su lfon ylu r ea s (t olbu t a m ide, glipizide, glybu r ide, Pa n cr ea s St im u la t es m or e secr et ion of in su lin
glim epir ide) fr om t h e pa n cr ea s
Th ia zolidin edion es (r osiglit a zon e, pioglit a zon e) Mu scle cells In cr ea ses sen sit ivit y of t issu es (fa t ,
m u scle, liver ) t o in su lin

ou t com es of ph ysica l a c-
t ivit y, su ch a s decr ea sed F R O M T H E L AB
body fa t , in cr ea se in
en dor ph in s, im pr oved Annual screening for albumin ( protein) in the urine is recommended in all patients with
ca r diova scu la r h ea lt h , diabetes, especially those with type 2 diabetes to detect early renal damage and is a risk
a n d weigh t con t r ol, a lso factor for heart disease. Performing an albumin-to-creatinine ratio is the best way to start.
lower t h e r isk for som e of If abnormal (i.e., > 30 mg/ g), a 24-hour urine specimen should be performed to determine
t h e lon g-t er m com plica - albumin excretion. Normal urine albumin excretion is defined as less than 30 mg/ d. Microal-
t ion s of dia bet es. buminuria is defined as 30–300 mg/ d (20–200 mcg/ min). At least 2 of 3 samples over 3 to
If diet a n d exer cise a r e 6 months are needed to confirm the presence of albumin in the urine.
in a dequ a t e t o pr odu ce
a dequ a t e glycem ic con -
t r ol, in dividu a ls wit h t ype 2 dia bet es m a y a lso r e- la r ge-for-da t e ba by. Th is con dit ion occu r s in u p t o
qu ir e or a l m edica t ion s a lon g wit h con t in u ed diet a r y 15% of pr egn a n cies a n d is u su a lly dia gn osed in t h e
m odifica t ion s a n d exer cise. Glycem ic a gen t s a ct t o fift h or sixt h m on t h . Tr ea t m en t s for gest a t ion a l dia -
in cr ea se in su lin r elea se by t h e bet a cells, in cr ea se bet es in clu de diet m odifica t ion , exer cise, a n d possi-
glu cose pr odu ct ion by t h e liver, or in cr ea se t h e u p- bly in su lin . Tigh t con t r ol of blood glu cose is n eeded
t a ke of in su lin . Ta ble 20.5 descr ibes com m on or a l t o pr even t over st im u la t ion of t h e fet a l pa n cr ea s
glycem ic a gen t s a n d t h eir m ech a n ism for a ct ion in du r in g pr egn a n cy. Or a l glycem ic a gen t s a r e n ot r ec-
t r ea t in g t ype 2 dia bet es. In su lin t h er a py m a y a lso om m en ded beca u se of t h eir pot en t ia lly t er a t ogen ic
be in it ia t ed if in su lin r epla cem en t is wa r r a n t ed. Th e effect s. If u n t r ea t ed, gest a t ion a l dia bet es, or even
for m s of in su lin a r e illu st r a t ed in Ta ble 20.4. poor ly con t r olled t ype 1 or t ype 2 dia bet es in a pr eg-
n a n t wom a n , ca n lea d t o:
Stop and Consider ● Fet a l m a cr osom ia (a bn or m a lly la r ge body size)
Why is it not recommended to use oral glycemic ● H ypoglycem ia fr om pa n cr ea t ic h yper pla sia a n d
agents to treat those with type 1 diabetes? excess in su lin secr et ion in t h e n ewbor n
● H ypoca lcem ia
● H yper bilir u bin em ia
GESTATIONAL DIABETES ● A 5 t o 10% in ciden ce of m a jor developm en t a l
Gest a t ion a l dia bet es is defin ed a s a n y degr ee of a n om a lies, su ch a s spin a bifida or h ea r t defect s.
glu cose in t oler a n ce t h a t occu r s du r in g pr egn a n cy. Addit ion a l com plica t ion s for t h e m ot h er in clu de
Th is for m of dia bet es is u su a lly t em por a r y, bu t in a gr ea t er r isk for ch r on ic h yper t en sion a n d cesa r-
som e ca ses, t h e wom a n m a y go on t o develop t ype 2 ea n deliver y. Gest a t ion a l dia bet es does in cr ea se a
dia bet es. Gest a t ion a l dia bet es occu r s beca u se of in - wom a n ’s r isk for developin g t ype 2 dia bet es even a f-
su lin r esist a n ce t h a t occu r s du r in g pr egn a n cy a n d t er t h e pr egn a n cy a n d deliver y is com plet e.
beca u se of a n in a bilit y of t h e pa n cr ea s t o m a ke t h e
a ddit ion a l in su lin t h a t is n eeded du r in g t h e pr eg-
Acute Complications of Diabetes Mellitus
n a n cy t o su ppor t t h e pla cen t a . Risk fa ct or s for t h is
t ype of dia bet es in clu de fa m ily h ist or y of dia bet es, Acu t e com plica t ion s of dia bet es m ellit u s a r e r ela t ed
five or m or e pr eviou s pr egn a n cies, a n d a pr eviou s t o eit h er h ypoglycem ia or sign ifica n t h yper glycem ia .
516 C h a p t e r 20: In t egr a t ed Pa t h oph ysiologic Con cept s

Acu t e com plica t ion s h a ve a r a pid on set a n d oft en
h a ve sign ifica n t m a n ifest a t ion s of a lt er ed n eu r on a l
fu n ct ion . Pa r t icu la r ly in t h ose wit h t ype 1 dia bet es,
t h e r egu la t ion of glycem ic con t r ol ca n be ch a llen g-
in g. Th e Som ogyi effect a n d da wn ph en om en on illu s-
t r a t e a cu t e com plica t ion s of dia bet es r ela t ed t o t h e
a t t em pt ed r egu la t ion of glycem ic con t r ol.
HYPOGLYCEMIA
H ypoglycem ia is a st a t e of sign ifica n t ly low blood
glu cose t h a t r esu lt s in dem on st r a ble clin ica l m a n i-
fest a t ion s, su ch a s wea kn ess, pa llor, or cool/cla m m y
skin . Alt h ou gh in dividu a l va r ia t ion s exist , m a n ifes-
t a t ion s t ypica lly pr esen t wh en t h e ser u m glu cose be-
com es less t h a n 50 m g/dL (F ig. 20.5). Th is ca n occu r
in sit u a t ion s su ch a s:
● H yper in su lin em ia (h igh cir cu la t in g in su lin lev-
els) a s ca n occu r wit h t h e a dm in ist r a t ion of exog-
en ou s in su lin t o t r ea t dia bet es
● In a dequ a t e food in t a ke or vom it in g, in wh ich t h e
pr esen ce of glu cose in t h e body is r edu ced
● F r equ en t sim ple ca r boh ydr a t e in t a ke
● St r en u ou s exer cise or in fect ion , du r in g wh ich t h e
u se of glu cose is excessive
H ypoglycem ia is m ost com m on ly fou n d in in dividu -
a ls wit h t ype 1 dia bet es wh o a r e u n der goin g in su lin
r epla cem en t t h er a py. In su lin r epla cem en t t h er a py
r equ ir es t h e ca r efu l in t a ke of a dequ a t e n u t r ien t s t o
m a t ch t h e in ject ed in su lin . Th is st ep is pa r t icu la r ly
cr it ica l wit h t h e in su lin pu m p beca u se t h e pu m p a d-
m in ist er s a ba sa l dose of in su lin t h r ou gh ou t t h e da y.
Th er efor e, t h e pr esen ce of in su lin , cou pled wit h skip-
pin g a m ea l a n d exer cisin g, ca n lea d t o blood glu cose
levels a s low a s 40 t o 50 m g/dL. H ypoglycem ia is
pa r t icu la r ly pr oblem a t ic for t h e br a in , wh ich h a s a n
en er gy dem a n d t wice t h a t of ot h er cells in t h e body.
Neu r on s a r e in a con st a n t st a t e of m et a bolic a ct ivit y,
even du r in g sleep. Men t a l con cen t r a t ion a n d ot h er
for m s of bioelect r ica l com m u n ica t ion t h r ou gh ou t t h e
n er vou s syst em r equ ir e glu cose. A la ck of glu cose
h a s been fou n d t o im pede t h e syn t h esis of a cet ylch o-
lin e, a m a jor br a in n eu r ot r a n sm it t er.
In t er est in gly, t h e in gest ion of sim ple ca r boh y-
dr a t es, a s opposed t o com plex ca r boh ydr a t es, ca n
a lso pr om ot e a st a t e of n eu r on a l h ypoglycem ia .
Com plex ca r boh ydr a t es a r e gr a du a lly br oken down ,
st or ed in t h e liver, a n d r elea sed gr a du a lly in t o t h e
blood in t h e for m of glu cose. Th er efor e, t h e pr o-
cess of in t a ke, st or a ge, a n d r elea se of glu cose fr om

100

Ins ulin pro duc tio n de c re as e s

80

Epine phrine and g luc ag o n

pro duc tio n inc re as e s
Growth ho rmo ne pro duc tio n inc re as e s
l
d
/
g
Co rtis o l pro duc tio n inc re as e s
m
60
,
]
e
Adre ne rg ic
s
o
s ympto ms
c
u
Ne uro g lyc o pe nia be g in:
l
g
s ympto ms be g in:
d
anxie ty
o
he adac he
o
palpitatio n
l
40
B
c o nfus io n
[
tre mo r
s lurre d s pe e c h s we ating
s e izure s
c o ma
de ath
20

Figure 20.5. How the body responds to hypoglycemia.

 C h a p t e r 20: In t egr a t ed Pa t h oph ysiologic Con cept s
com plex ca r boh ydr a t es is idea l for br a in fu n ct ion .
Sim ple ca r boh ydr a t es, su ch a s t h a t fou n d in su g-
a r y foods like syr u p, fr u it ju ice, or h on ey, en t er t h e
blood a n d r a pidly r a ise t h e blood su ga r. Th is st im u -
la t es t h e r a pid r elea se of in su lin . Th e in su lin pu lls
t h is excess glu cose in t o cells of t h e body a n d a ct u -
a lly depr ives t h e br a in of glu cose. Reca ll t h a t n eu -
r on s do n ot r equ ir e in su lin for glu cose u pt a ke a n d
a r e u n a ble t o st or e glu cose. E ven t h ou gh ot h er cells
in t h e body h a ve st or ed glu cose, t h e br a in becom es
h ypoglycem ic.
Clin ica l m a n ifest a t ion s of h ypoglycem ia ca n va r y
a m on g in dividu a ls bu t a r e m ost n ot a bly r ela t ed t o
n eu r on a l depr iva t ion of glu cose. Pot en t ia l sign s a n d
sym pt om s in clu de poor con cen t r a t ion , ext r em e h u n -
ger, cla m m y/cool skin , blu r r ed vision , dizzin ess a n d
con fu sion , difficu lt y wit h speech , la ck of coor din a -
t ion , st a gger in g ga it , a n d h ea da ch e. Th e h ypoglyce-
m ic st a t e a ct iva t es t h e sym pa t h et ic n er vou s syst em ,
wh ich ca u ses a n in cr ea se in t h e pu lse, a lon g wit h
pa lpit a t ion s, swea t in g, a n xiet y, a n d t r em or s. Loss of
con sciou sn ess, seizu r es, com a , a n d dea t h ca n occu r if
h ypoglycem ia is n ot t r ea t ed.
P r even t ion of h ypoglycem ia in volves ca lcu la t in g
a n d a dm in ist er in g in su lin dosa ges wit h r ega r d t o
n u t r it ion a l in t a ke a n d ph ysica l a ct ivit y. Th e t r ea t -
m en t of h ypoglycem ia r equ ir es a dm in ist r a t ion of
15 t o 20 gr a m s of glu cose. Th e m et h od of a dm in is-
t r a t ion depen ds on t h e level of con sciou sn ess of t h e
per son . If t h e per son is fa ir ly con sciou s a n d a ble t o
swa llow, a con cen t r a t ed ca r boh ydr a t e, su ch a s sweet -
en ed fr u it ju ice, h on ey, or ca n dy, is su fficien t . If t h e
sym pt om s do n ot im pr ove wit h in a few m in u t es, t h e
dose ca n be r epea t ed. If t h e per son is u n con sciou s
a n d ca n n ot swa llow, glu ca gon m u st be a dm in ist er ed
pa r en t er a lly, in t r a m u scu la r ly, or su bcu t a n eou sly.
DIABETIC KETOACIDOSIS
Dia bet ic ket oa cidosis (DKA) is a pr oblem of deficien t
in su lin a n d sever e h yper glycem ia lea din g t o a st a t e
of m et a bolic a cidosis a n d sever e osm ot ic diu r esis. It
occu r s m ost com m on ly in t h ose wit h t ype 1 dia be-
t es. DKA t ypica lly develops over a few da ys a n d is
t r igger ed by a n in cr ea sed dem a n d for in su lin , su ch
a s occu r s wit h sever e st r ess, in fect ion , over con su m p-
t ion of food, pr egn a n cy, or in a dequ a t e in su lin a dm in -
ist r a t ion . Th e on set of DKA m a y be t h e even t t h a t
m a kes t h e in dividu a l a wa r e t h a t h e or sh e h a s t ype
1 dia bet es. Blood glu cose levels ca n r ea ch a s h igh a s
1000 m g/dL.
Th e la ck of in su lin ca u ses m obiliza t ion of fa t t y
a cids for en er gy, lea din g t o a n in cr ea sed pr odu ct ion
of ket on es. Th e kidn eys a r e u n a ble t o excr et e t h e ke-
t on es a n d t h e cells a r e u n a ble t o u se t h ese bypr od-
u ct s, a llowin g ket on es t o a ccu m u la t e in t h e blood.
Reca ll t h a t opt im a l cell fu n ct ion occu r s wit h in a
517
n a r r ow pH r a n ge. Acidosis (pH less t h a n 7.3) lea ds
t o widespr ea d cellu la r in ju r y. H yper glycem ia pr o-
m ot es osm ot ic diu r esis, loss of elect r olyt es, a n d de-
h ydr a t ion (Fig. 20.6).
Th e sign s a n d sym pt om s of DKA a r e con sist en t
wit h sever e h yper glycem ia , m et a bolic a cidosis, a n d
deh ydr a t ion . Ma n ifest a t ion s pr ecedin g DKA in clu de
t h ose of t ype 1 dia bet es: polyu r ia , polydipsia , po-
lyph a gia , n oct u r ia , weigh t loss, a n d fa t igu e. Abdom -
in a l pa in a n d vom it in g a r e com m on . Wit h t h e on set
of a cidosis, bu ffer syst em s a r e t a xed a n d com pen sa -
t or y ch a n ges occu r in a n effor t t o im pr ove t h e a cid–
ba se ba la n ce in t h e body. Ku s s m a u l r e s p ir a t io n s
a r e deep, r a pid r espir a t ion s t h a t r elea se excess a c-
ids t h r ou gh t h e lu n gs. Th e br ea t h a lso h a s a sweet ,
fr u it y odor ca u sed by t h e r elea se of a cet on e, a vola -
t ile for m of ket on es. Th e decr ea sed cir cu la t in g blood
volu m e pr om ot es t a ch yca r dia a n d h ypot en sion . Ac-
idosis t r igger s a decr ea sed level of con sciou sn ess,
wh ich ca n pr ogr ess t o com a a n d even dea t h .
Tr ea t m en t of DKA focu ses on st a bilizin g blood
glu cose levels, cor r ect in g a cidosis, r epla cin g flu ids
a n d elect r olyt es, a n d im pr ovin g t issu e per fu sion .
Th ese goa ls a r e a ccom plish ed t h r ou gh in t r a ven ou s
a dm in ist r a t ion of in su lin , flu id, a n d elect r olyt e solu -
t ion s. An y t r igger in g ca u ses, su ch a s in fect ion , m u st
a lso be a ddr essed. Aft er t h e in dividu a l’s blood glu -
cose a n d flu id ba la n ce a r e st a bilized, t r ea t m en t in -
volves in it ia t in g or r esu m in g st r a t egies t o m a n a ge
t h e dia bet es effect ively a n d t o pr even t fu r t h er occu r-
r en ces of DKA over t im e.
Stop and Consider
You arrive on a scene and see that someone
with diabetes is unconscious. How do you know
if the person is experiencing hypoglycemia or
hyperglycemia?
HYPERGLYCEMIC HYPEROSMOLAR
NONKETOTIC SYNDROME
H yper glycem ic h yper osm ola r n on ket ot ic syn dr om e
(H H NK) is pr im a r ily a pr oblem of t ype 2 dia bet es in
older a du lt s t h a t is ch a r a ct er ized by:
● H yper glycem ia , oft en a bove 600 m g/dL
● H igh pla sm a osm ola r it y
● Deh ydr a t ion
● La ck of (or m ild) ket osis
● Ch a n ges in t h e level of con sciou sn ess
In H H NK, sever e h yper glycem ia r esu lt s fr om in -
cr ea sed in su lin r esist a n ce a n d excessive ca r boh y-
dr a t e in t a ke. H yper osm ola r it y fr om excessive glu cose
a n d in a dequ a t e flu id in t a ke r esu lt s in wa t er sh ift in g
fr om in t r a cellu la r t o ext r a cellu la r spa ces, lea din g t o
cellu la r deh ydr a t ion a n d cell dea t h . Th e pr esen ce of
518 C h a p t e r 20: In t egr a t ed Pa t h oph ysiologic Con cept s

S e ve re
In s u lin De fic ie n c y
(Abs olute or re la tive )

Glucos e upta ke P rote in ca ta bolis m Lipolys is

Amino Nitroge n Glyce rol Fre e

a cids los s fa tty a cids

Hype rglyce mia Glucone oge ne s is Ke toge ne s is

Ke tone mia

Os motic diure s is Urina ry e le ctrolyte Ke tonuria

los s

Hypotonic los s e s

Hype ros mola lity Volume de ple tion Ke toa cidos is

Coma S hock Me ta bolic a cidos is

Figure 20.6. Diabetic ketoacidosis (DKA) is characterized by three major pathophysiologic disruptions: coma, shock, and
metabolic acidosis.

glu cose in t h e u r in e im pa ir s t h e a bilit y of t h e kidn ey fu r t h er occu r r en ces of H H NK t h r ou gh t h e on goin g

t o con cen t r a t e u r in e a n d pr om ot es osm ot ic diu r esis.
Th is exa cer ba t es wa t er losses.
Th e on set is oft en gr a du a l a n d pr esen t s over a
per iod of da ys t o weeks. H yper glycem ia a n d solu t e
diu r esis lea ds t o polyu r ia , polydipsia , polyph a gia ,
weigh t loss, wea kn ess, a n d sign s of deh ydr a t ion ,
su ch a s leg cr a m ps, poor t issu e t u r gor, cool ext r em i-
t ies, a n d t a ch yca r dia . Th e in dividu a l m a y a lso pr es-
en t wit h r en a l im pa ir m en t a n d n eu r ologic ch a n ges,
su ch a s seizu r es, h a llu cin a t ion s, wea kn ess, pa r a lysis,
m u scle t r em or s, a n d visu a l ch a n ges. Appr oxim a t ely
on e ou t of fou r of in dividu a ls in H H NK pr esen t in
a st a t e of com a . In som e ca ses, t h e in dividu a l is n ot
kn own t o h a ve dia bet es befor e t h e on set of H H NK.
Glu cose is pr esen t in t h e u r in e a n d ket on es a r e t yp-
ica lly a bsen t or m in im a l. Tr ea t m en t in volves ca r e-
fu l flu id r epla cem en t wit h a t on icit y m a t ch ed t o
t h e level of h yper osm ola r it y, a lon g wit h pot a ssiu m ,
m a gn esiu m , a n d ph osph a t e r epla cem en t , a n d st a -
biliza t ion of blood glu cose levels. Aft er t h e in divid-
u a l is st a bilized, on goin g ca r e is r equ ir ed t o pr even t
m a n a gem en t of t ype 2 dia bet es.
THE SOMOGYI EFFECT AND
DAWN PHENOMENON
Th e S o m o g y i e e c t is t h e pr esen ce of r ebou n d
h yper glycem ia a s a r ea ct ion t o in su lin -in du ced h y-
poglycem ia . In su lin -in du ced h ypoglycem ia t r igger s
com pen sa t or y in cr ea ses in ca t ech ola m in es, glu ca -
gon , cor t isol, a n d gr owt h h or m on e in a n effor t t o
pr om ot e in su lin r esist a n ce a n d in cr ea se cir cu la t -
in g blood glu cose levels. H ypoglycem ia , wh ich of-
t en occu r s du r in g t h e n igh t , is m et wit h m or n in g
or da yt im e h yper glycem ia . Th is pr om pt s t h e in -
cr ea sed exogen ou s a dm in ist r a t ion of in su lin , wh ich
fu r t h er per pet u a t es t h e Som ogyi effect a n d poses
a m a jor ch a llen ge t o t igh t con t r ol of glu cose levels.
In dividu a ls wit h m or n in g h yper glycem ia n eed t o
t est t h eir blood glu cose levels in t h e m iddle of t h e
n igh t t o det er m in e t h e pr esen ce of t h e Som ogyi ef-
fect . If t h e in dividu a l is h ypoglycem ic, a dju st m en t s
 C h a p t e r 20: In t egr a t ed Pa t h oph ysiologic Con cept s 519

in t h e even in g sn a ck or in su lin t ype or dose m a y be

r equ ir ed.
Th e d a w n p h e n o m e n o n is a sit u a t ion in wh ich
Ca ta ra cts
a n in dividu a l’s blood glu cose level u pon wa kin g
is h igh er t h a n t h e level befor e goin g t o bed in t h e P rolife ra tive
re tinopa thy
even in g. Beca u se t h er e is n o food in t a ke du r in g
t h e n igh t , t h is fin din g su ggest s t h a t blood glu cose
sh ou ld decr ea se du r in g t h e n igh t . Th e da wn ph e-
n om en on , sim ila r t o t h e Som ogyi effect , is r ela t ed
t o t h e r elea se of h or m on es (gr owt h h or m on e, cor t i-
sol, glu ca gon , a n d ca t ech ola m in es), u su a lly bet ween
4 AM a n d 9 AM , wh ich t r igger s in su lin r esist a n ce
a n d t h e r elea se of glu cose fr om t h e liver. Th e da wn Corona ry
ph en om en on differ s fr om t h e Som ogyi effect in t h a t a the ros cle ros is
h yper glycem ia is n ot t r igger ed by over n igh t h ypo-
glycem ia . Blood glu cose levels st ea dily r ise t h r ou gh
t h e n igh t . Ma n a gem en t of t h e da wn ph en om en on
r equ ir es lim it in g or r egu la t in g even in g sn a cks or
possibly in cr ea sin g or a l glycem ic a gen t s (in t ype 2 Glome rulos cle ros is
dia bet es) or ba sa l in su lin doses (in t ype 1 dia bet es). Autonomic
dys function
(dia rrhe a )
CHRONIC COMPLICATIONS
OF DIABETES MELLITUS
Th e pr esen ce of dia bet es im m edia t ely in cr ea ses t h e
r isk of developin g ir r ever sible clin ica l com plica t ion s
beca u se of degen er a t ive ch a n ges t h r ou gh ou t t h e
body. Ch r on ic com plica t ion s of dia bet es develop pr i-
m a r ily in t issu es t h a t a r e a ffect ed by t h e h igh levels
of glu cose cir cu la t in g in t h e blood. In t h ose t issu es
t h a t r equ ir e in su lin for t r a n spor t of glu cose, h yper-
glycem ia ca u ses degen er a t ive ch a n ges by t h icken in g
t h e ba sem en t m em br a n e, pr om ot in g coa gu la t ion , ob-
st r u ct in g per fu sion , in du cin g h ypoxia , a n d pr odu cin g Occlus ive
t issu e n ecr osis. In t h ose t issu es t h a t do n ot r equ ir e a the ros cle ros is
in su lin for glu cose t r a n spor t (e.g., r ed blood cells,
len s, kidn ey, a n d n er ves), t h e excess glu cose ca u ses Foca l
de mye lina tion
flu id t o osm ot ica lly sh ift in t o t h ese cells a n d ca u ses
t h e cells t o r u pt u r e. Com plica t ion s, illu st r a t ed in
F igu r e 20.7, a r e fr equ en t ly cla ssified a s:
1. Micr ova scu la r (r ela t in g t o sm a ll vessels)
2. Ma cr ova scu la r (r ela t in g t o la r ge vessels)
3. Neu r opa t h ies
An in dividu a l is less likely t o develop ch r on ic Chronic ulce rs Ga ngre ne
com plica t ion s of dia bet es if blood glu cose levels a r e
kept in t igh t con t r ol (70 t o 120 m g/dL). Figure 20.7. Chronic complications of diabetes.

Microvascular Complications
Degen er a t ive ch a n ges in sm a ll vessels occu r m ost n o-
t a bly in t h e r et in a s, a con dit ion ca lled r e t in o p a t h y ,
a n d in t h e kidn eys, r efer r ed t o a s n e p h r o p a t h y .
On e m ech a n ism for t h e developm en t of com plica -
t ion s is t h e pr esen ce of excess glu cose, wh ich bin ds
t o colla gen a n d pr ot ein s in t h e blood vessel wa lls.
Th is pr ocess is r efer r ed t o a s glycosyla t ion . Th e r a t e
of glycosyla t ion is pr opor t ion a t e t o t h e level of h y-
per glycem ia . Glycosyla t ion per m a n en t ly a lt er s t h e
st r u ct u r e of colla gen a n d pr ot ein s in t h e blood ves-
sel wa lls. Th is a lt er a t ion lea ds t o t h e h a r den in g a n d
t h icken in g of t h e ca pilla r y ba sem en t m em br a n e, r e-
su lt in g in obst r u ct ion or r u pt u r e of t h e ca pilla r ies.
Ult im a t ely, t h is developm en t lea ds t o n ecr osis a n d
520 C h a p t e r 20: In t egr a t ed Pa t h oph ysiologic Con cept s

loss of fu n ct ion in t h ose t issu es bein g su pplied by

t h e sm a ll vessels. In r et in opa t h y, r et in a l isch em ia
r ela t ed t o obst r u ct ion a n d r u pt u r e of ca pilla r ies ca n
lea d t o blin dn ess. Th e developm en t of com plica t ion s
m a y a lso be r ela t ed t o a n a ccu m u la t ion of sor bit ol, a
su ga r a lcoh ol, der ived fr om t h e m et a bolism of exces-
sive glu cose by a ldose r edu ct a se (a n en zym e) in t is-
su es t h a t do n ot r equ ir e in su lin . Sor bit ol is t h eor ized
t o pr om ot e t h e osm osis of flu id in t o t h e len s of t h e
eye a n d m a y a lso be dir ect ly t oxic t o cells. Rea ct ive
oxygen species (fr ee r a dica ls) m a y a lso be in volved
in t h e developm en t of dia bet es com plica t ion s du e t o
r elea se of fr ee r a dica ls a s a r esu lt of t issu e in ju r y
fr om excessive glu cose exposu r e.
Ba sed on t h ese pot en t ia l m ech a n ism s, t h e devel-
opm en t of n eph r opa t h y is a con sequ en ce of: Figure 20.8. Peripheral ulcerations related to vascular and
1. P r ot ein br ea kdown ca u sed by h igh glu cose levels neurologic impairment. (From Marks R. Skin Disease in Old
a n d in a dequ a t e in su lin Age. Philadelphia, PA: J. B. Lippincott; 1987.)
2. E xcessive osm ot ic diu r esis a n d glu cosu r ia t h a t oc-
cu r s wit h h yper glycem ia low con cen t r a t ion s. P la t elet s a dh er e t o t h e da m a ged
3. In t r a glom er u la r h yper t en sion , wh ich is wor sen ed en dot h elia l cells in t h e in t im a . La r ge vessels becom e
in t h e pr esen ce of syst em ic h yper t en sion scler ot ic a n d obst r u ct ed. Th ese com plica t ion s lea d t o
h ypoxia a n d even t u a lly a n oxia , wh ich lea d t o n ecr o-
Wit h n eph r opa t h y, ch a n ges in t h e glom er u la r ca p-
sis of per iph er a l t issu es (F ig. 20.8). Depen din g on t h e
illa r ies in cr ea se t h e in t r a glom er u la r pr essu r e, ca u s-
loca t ion , pla qu e for m a t ion ca n r esu lt in t h e cor on a r y
in g h yper t en sion wit h in t h e kidn ey. Ch r on ic r en a l
a r t er ies, lea din g t o MI; in t h e cer ebr a l a r t er ies, lea d-
h yper t en sion con t r ibu t es t o glom er u la r scler osis,
in g t o st r oke; or in t h e per iph er a l a r t er ies, lea din g
h ypoxia , a n d, u lt im a t ely, ch r on ic r en a l fa ilu r e. Ne-
t o per iph er a l va scu la r disea se, ga n gr en e, a n d m a y
ph r opa t h y in in dividu a ls wit h dia bet es is t h e lea d-
r equ ir e a m pu t a t ion .
in g ca u se of en d-st a ge r en a l disea se, a ccou n t in g for
Th e pr esen ce of m a cr ova scu la r com plica t ion s in
a lm ost h a lf of n ew ca ses of r en a l fa ilu r e. Th e pr es-
in dividu a ls wit h dia bet es is st a gger in g. Mor e t h a n
en ce of con t in u ou s pr ot ein u r ia is a key m a n ifest a -
h a lf of people wit h dia bet es will die of h ea r t disea se
t ion of dia bet ic n eph r opa t h y a n d pr ogr essive r en a l
or st r oke; t h ose wit h dia bet es a r e t wo t o fou r t im es
disea se. P r ot ein r est r ict ion , dia lysis, or r en a l t r a n s-
m or e likely t o h a ve h ea r t disea se or su ffer fr om a
pla n t m a y be in dica t ed for t h ose wh o develop ch r on ic
st r oke t h a n t h ose wit h ou t dia bet es. 3 On e of ever y
r en a l fa ilu r e secon da r y t o dia bet ic n eph r opa t h y. E s-
t h r ee pa t ien t s wit h dia bet es wh o a r e older t h a n
sen t ia l t o t h e a voida n ce of m icr ova scu la r com plica -
50 yea r s is est im a t ed t o h a ve per iph er a l va scu la r
t ion s a r e st r ict blood glu cose con t r ol, m a in t en a n ce of
disea se a n d in t e r m it t e n t c la u d ic a t io n , a con -
H bA1c levels below 7%, t r ea t m en t of h yper t en sion ,
dit ion of fa t igu e or a ch in g in t h e leg m u scles even
a n d a voida n ce of sm okin g.
wh en wa lkin g sh or t dist a n ces. Th e r isk of a leg a m -
pu t a t ion is 15 t o 40 t im es gr ea t er for a per son wit h
Macrovascular Complications dia bet es a n d m or t a lit y r a t es a r e sign ifica n t ly h igh er
for t h ose r equ ir in g a m pu t a t ion .3 At dia gn osis, a n es-
Ma cr ova scu la r disea ses in volve la r ge vessels a n d in -
t im a t ed 50% of t h ose wit h t ype 2 dia bet es pr esen t
clu de cor on a r y a r t er y disea se, cer ebr ova scu la r dis-
wit h m a cr ova scu la r or m icr ova scu la r com plica t ion s.
ea se (st r oke), a n d per iph er a l va scu la r disea se. Th e
m a jor m ech a n ism s for t h e developm en t of m a cr ova s-
Neuropathies
cu la r com plica t ion s a r e r ela t ed t o t h e r ole of dia bet es
in t h e developm en t of a t h er oscler osis. H yper glyce- N e u r o p a t h y is n er ve degen er a t ion t h a t r esu lt s
m ia , h yper lipidem ia , a n d h yper t en sion con t r ibu t e t o in dela yed n er ve con du ct ion a n d im pa ir ed sen sor y
t h e developm en t of a t h er oscler ot ic pla qu es by in ju r- fu n ct ion . Neu r opa t h ies ca n occu r in som a t ic, pe-
in g t h e in t im a . Lipids a r e deposit ed in t h e wa lls of r iph er a l, a n d a u t on om ic n er ve cells. Neu r opa t h ies
la r ge vessels. Low-den sit y lipopr ot ein s a r e t ypica lly a r e a r esu lt of (1) t h icken in g, scler osis, obst r u ct ion ,
fou n d in h igh con cen t r a t ion s in t h ose wit h dia bet es, a n d isch em ia of t h e vessels t h a t su pply n er ve fiber s
pa r t icu la r ly t ype 2. H igh -den sit y lipopr ot ein s, con - a n d (2) dem yelin iza t ion ca u sed by im pa ir ed m et a b-
sider ed a pr ot ect ive for m of ch olest er ol, a r e fou n d in olism . Th ese degen er a t ion s a r e oft en dist in gu ish ed
 C h a p t e r 20: In t egr a t ed Pa t h oph ysiologic Con cept s
a s som a t ic ver su s a u t on om ic. Som a t ic n er ve degen -
er a t ion a n d dela yed con du ct ion lea d t o decr ea sed
sen sa t ion , n u m bn ess, t in glin g, wea kn ess, m u scle
wa st in g, a n d pa in . Au t on om ic n eu r opa t h ies lea d t o
bla dder in con t in en ce, im pot en ce, dia r r h ea , er ect ile
dysfu n ct ion , a n d post u r a l h ypot en sion . Th e pr eva -
len ce of a u t on om ic n eu r opa t h y in cr ea ses wit h a ge,
du r a t ion of dia bet es, a n d in cr ea sed h em oglobin A1c.
Infection
Individu a ls wit h dia bet es a r e a lso a t in cr ea sed r isk
for t he developm ent of infect ion. Th is is r ela t ed t o
sever a l a spect s of h yper glycem ia r ela t ed t o m icr ova s-
cu la r, m a cr ova scu la r, a nd n eur opa t hic com plica t ions:
● E xcess glu cose in blood pr ovides a n opt im a l en -
vir on m en t for som e pa t h ogen s, a llowin g r a pid
pr olifer a t ion .
● Tissu e isch em ia fr om m icr ova scu la r a n d m a cr o-
va scu la r degen er a t ion da m a ges t issu e in t egr it y
a n d a llows r ea dy a ccess t o pa t h ogen s.
● Red blood cell dest r u ct ion a n d h igh levels of gly-
cosyla t ed h em oglobin pr even t r elea se of oxygen t o
t h e t issu es.
● Wh it e blood cells a r e im pa ir ed wit h ou t a dequ a t e
glu cose t r a n spor t a n d a r e u n a ble t o en gu lf a n d r e-
m ove pa t h ogen s.
● Neu r opa t h ies pr even t t h e in dividu a l fr om bein g
a ble t o sen se br ea ks in t h e skin in t egr it y, a llowin g
pa t h ogen s ea sy a ccess.
● Ret in opa t h y m a y pr even t t h e in dividu a l fr om be-
in g a ble t o a dequ a t ely in spect for m a n ifest a t ion s
of in fect ion a n d will dela y t r ea t m en t . To see a
video on dia bet es, visit h t t p://t h ePoin t
.lww.com .
C L I N I C AL P R AC T I C E
As wit h a ll com plica t ion s of dia bet es, t igh t gly-
cem ic con t r ol is key in pr even t ion . Ot h er pr e-
ven t ion st r a t egies in clu de sm okin g cessa t ion ,
m a n a gem en t of h yper t en sion , weigh t loss, a n d
lower in g of lipids. E du ca t ion on pr even t in g com -
plica t ion s ca n follow t h e a lph a bet :4
● A = a dvice t o follow diet , weigh t loss, exer cise
pr ogr a m , a n d lifest yle m odifica t ion s
● B = blood pr essu r e r edu ct ion
● C = ch olest er ol r edu ct ion
● D = dia bet es h yper glycem ia con t r ol
● E = eye scr een in g
● F = foot ca r e
521
S U MMAR Y
● Th is ch a pt er illu st r a t es t h e in t egr a t ion of con -
cept s fr om a ll pr eviou s ch a pt er s t o a ppr ecia t e t h e
com plexit ies of h u m a n disea se. Dia bet es is pr e-
sen t ed a s t h e pr im a r y clin ica l m odel.
● In su lin is n eeded t o pr om ot e glu cose u pt a ke a n d
m et a bolism of n u t r ien t s.
● Dia bet es r esu lt s fr om eit h er (1) a la ck of in su -
lin secr et ion by t h e bet a cells of t h e pa n cr ea s or
(2) a r esist a n ce t o in su lin . Th is lea ds t o a st a t e of
h yper glycem ia .
● In su lin a bsen ce or r esist a n ce pr oh ibit s u sin g in -
su lin t o t r a n spor t glu cose a n d a m in o a cids in t o
t h ose cells t h a t r equ ir e in su lin for t r a n spor t .
● Th e t h r ee m a in t ypes of dia bet es (t ype 1, t ype 2,
a n d gest a t ion a l) differ in t h e wa y t h a t t h e body
pr odu ces or r espon ds t o in su lin .
● Type 1 dia bet es exh ibit s a n a bsolu t e or sign ifica n t
deficit of in su lin ; t h e ca u se is m u lt ifa ct or ia l a n d
in clu des bot h gen et ic a n d en vir on m en t a l in flu -
en ces t h a t lea d t o a u t oim m u n e dest r u ct ion of bet a
cells. Com m on clin ica l m a n ifest a t ion s in clu de
polyu r ia , polydipsia , a n d polyph a gia . Tr ea t m en t
of t ype 1 dia bet es m ellit u s r equ ir es a ba la n ce of
ca r boh ydr a t e/diet a r y in t a ke, exer cise, a n d in su lin
r epla cem en t t h er a py.
● Type 2 dia bet es is a pr oblem of insulin r esist a nce
or subopt im a l insulin pr esence in the body. The ex-
a ct ca use is unknown; however, genetic a nd envi-
r onment a l fa ctor s, pa r ticula rly obesit y, a ppea r t o
contr ibute to it s developm ent. The clinica l m a nifes-
t a tions for t ype 2 dia bet es a r e oft en insidious a nd
nonspecific. Tr ea tm ent involves weight ma na ge-
m ent, nut rit ion monit or ing, a nd (possibly) or a l gly-
cemic a gents or, in som e ca ses, insulin r epla cement .
● Gest a t ion a l dia bet es is defin ed a s a n y degr ee of
glu cose in t oler a n ce t h a t occu r s du r in g pr egn a n cy.
Th is for m of dia bet es is u su a lly t em por a r y, bu t in
som e ca ses, wom en m a y go on t o develop t ype 2
dia bet es. Gest a t ion a l dia bet es occu r s beca u se of
in su lin r esist a n ce t h a t occu r s du r in g pr egn a n cy
a n d beca u se t h e pa n cr ea s is u n a ble t o m a ke t h e
a ddit ion a l in su lin n eeded du r in g t h e pr egn a n cy
t o su ppor t t h e pla cen t a .
● Acu t e com plica t ion s ca n occu r in a ll t ypes of di-
a bet es a n d in clu de dia bet ic ket oa cidosis a n d
h ypoglycem ia . Th e Som ogyi effect a n d da wn ph e-
n om en on a r e a cu t e com plica t ion s r ela t ed t o t h e
t r ea t m en t a n d m a n a gem en t of dia bet es, pa r t ic-
u la r ly in t h ose in dividu a ls wh o r equ ir e in su lin
r epla cem en t .
● H yper glycem ia h yper osm ola r n on ket ot ic syn -
dr om e is a n a cu t e com plica t ion of t ype 2 dia bet es.
It pr im a r ily occu r s in older a du lt s a n d is m a r ked
522 C h a p t e r 20: In t egr a t ed Pa t h oph ysiologic Con cept s
by h yper glycem ia , h yper osm ola r it y, glu cosu r ia ,
a n d deh ydr a t ion wit h ou t t h e pr esen ce of ket osis.
● Ch r on ic com plica t ion s in volve m icr ova scu la r,
m a cr ova scu la r, a n d n eu r opa t h ic degen er a t ion .
Th e com plica t ion s of dia bet es ca n be m in im ized
wit h con t r ol of blood glu cose levels.
C AS E S T U D Y 20.1
P.K. is a 73-yea r-old m a n wit h lon g-st a n din g dia be-
t es. Today, h e pr esen t s t o t h e em er gen cy depa r t m en t
in a com a . You r eview h is h ist or y a n d n ot e t h a t h e
wa s dia gn osed wit h t ype 2 dia bet es a ppr oxim a t ely 12
yea r s a go. H e exper ien ced a st r oke a yea r a go a n d h a s
been livin g in a lon g-t er m ca r e fa cilit y sin ce t h en . H is
ca r e pr ovider s in dica t e t h a t h is blood glu cose levels
a r e m on it or ed da ily. Th e levels a r e t ypica lly a r ou n d
160 t o 200 m g/dL, bu t t h ese h ave been st ea dily clim b-
in g over t h e pa st 2 weeks. H e is on a n or a l glycem ic
a gen t . H e does n ot exer cise beca u se of r esidu a l wea k-
n ess fr om t h e st r oke, a n d h e does h ave fr equ en t vis-
it or s wh o like t o br in g h im h a r d ca n dies. H e h a d a n
a ppoin t m en t sch edu led t h is week t o m eet wit h h is
pr im a r y ca r e ph ysicia n t o eva lu a t e a leg u lcer t h a t
is possibly in fect ed. Th e ca r e pr ovider s in dica t e t h a t
h is u r in e ou t pu t h a s in cr ea sed over t h e pa st 2 weeks.
Th ey a r e n ot su r e if h is flu id in t a ke h a s in cr ea sed.
Wh en t h ey wen t in t o h is r oom t h is m or n in g, h e wa s
u n r espon sive. H is cu r r en t blood glu cose level is 721
m g/dL. H is u r in e is posit ive for glu cose a n d n ega t ive
for ket on es. Ba sed on t h e in for m a t ion pr ovided:
1. Wh a t is t h e m ost likely ca u se for t h e a lt er ed level
of con sciou sn ess?
2. Wh a t r isk fa ct or s a r e pr esen t in t h is pa t ien t t h a t
lea d t o you r con clu sion in qu est ion 1?
3. Wh a t is h a ppen in g in t h is pa t ien t ’s body?
4. Wh a t a r e t h e pot en t ia l ca u ses for t h e on set of t h is
con dit ion ?
5. Wh a t t r ea t m en t st r a t egies wou ld you a n t icipa t e?
C AS E S T U D Y 20.2
G.H ., a 12-yea r-old wit h t ype 1 dia bet es, is a t a
bir t h da y pa r t y a ft er sch ool. At a r ou n d 4 P M , pizza ,
ice cr ea m , a n d ca ke a r e ser ved. G.H . h a s on e slice of
pizza beca u se sh e kn ows sh e ca n n ot h a ve t oo m u ch
su ga r. At a r ou n d 4:30 P M , G.H .’s fr ien ds decide t o
pla y a ga m e of soccer. G.H . pla ys for a bou t 30 m in -
u t es a n d t h en n eeds t o lea ve for gym n a st ics pr a ct ice
fr om 5:15 t o 6:30 P M . On t h e wa y h om e fr om pr a ct ice,
G.H .’s m om a sks h ow h er da y wa s, a n d G.H . ca n n ot
r em em ber wh er e sh e wa s ea r lier t h a t da y. Sh e be-
gin s t o com bin e wor ds t oget h er a n d slu r h er speech .
G.H . a lso r epor t s a h ea da ch e.
1. Wh a t is h a ppen in g t o G.H .?
2. Wh a t wer e t h e a ct u a l or pot en t ia l con t r ibu t in g
fa ct or s?
3. Wh a t sh ou ld G.H .’s m om do?
4. Wh a t cou ld h a ppen if n o a ct ion is t a ken ?
C AS E S T U D Y 20.3
TJ is a 6-yea r-old boy wh o wa s r u sh ed t o t h e em er-
gen cy r oom in a st a t e of disor ien t a t ion . H is pa r en t s
r epor t t h a t h e h a s been r ea lly t h ir st y over t h e pa st
few weeks; h e h a s been wa kin g u p 2 t o 3 t im es per
n igh t a skin g for wa t er. H e h a s a lso st a r t ed wet t in g
t h e bed a ga in , som et h in g h e h a sn ’t don e for a bou t
6 m on t h s. H e h a s a lso been r ea lly t ir ed despit e ea t -
in g a lot m or e t h a n h is fr ien ds a n d h is pa n t s a r e
becom in g loose. H is blood glu cose is m ea su r ed a t
413 m g/dL. H is u r in e is posit ive for ket on es. H e is
dia gn osed wit h dia bet es.
1. Wh a t t ype of dia bet es does TJ m ost likely h a ve
given h is pr esen t a t ion ?
2. Wh a t is t h e ca u se of h is dia bet es?
3. Descr ibe t h e pa t h oph ysiologic ch a n ges t h a t h a ve
occu r r ed over t h e pa st weeks/m on t h s/yea r s.
4. Wh a t is t h e sign ifica n ce of ket on es in h is u r in e?
5. Wh a t is t h e sign ifica n ce of h yper glycem ia ?
6. H ow do t h e pr esen t in g clin ica l m a n ifest a t ion s r e-
la t e t o bet a cell dest r u ct ion ?
7. Wh a t key elem en t s wou ld you a n t icipa t e t o be a
pa r t of h is t r ea t m en t pla n ?
8. Wh a t wou ld be t h e goa l of h is t r ea t m en t a n d h ow
wou ld you kn ow h e is m eet in g t h is goa l?
P R AC T I C E E XAM Q U E S T I O N S
1. Wh ich of t h e followin g is ca u sed by t h e r elea se
of in su lin ?
a . Decr ea sed blood glu cose level
b. In cr ea sed blood glu cose level
c. In cr ea sed lipid br ea kdown
d. In cr ea sed pr ot ein br ea kdown
2. Which of the following is not true of type 1 diabetes?
a . Ca n be t r ea t ed wit h or a l glycem ic a gen t s
b. Pancreas is completely unable to produce insulin
c. Acu t e on set
d. Defin it e gen et ic lin k
3. Wh ich of t h e followin g is n ot t r u e a bou t t ype 2
dia bet es?
a . Accou n t s for u p t o 95% of dia bet ics
b. Gr a du a l on set
c. Sign ifica n t weigh t loss occu r s a s a sym pt om
d. Risk fa ct or s a r e h yper t en sion , fa m ily h ist or y,
a n d obesit y
 C h a p t e r 20: In t egr a t ed Pa t h oph ysiologic Con cept s
4. Wh ich of t h e followin g is n ot a sign of DKA?
a . Ku ssm a u l r espir a t ion s
b. Deh ydr a t ion
c. Ket on u r ia
d. Low blood glu cose level
5. Which la bor a t or y t est is t he best pr edictor of blood
glucose cont r ol over t he pr evious few m ont hs?
a . H bA1c
b. Fa st in g blood glu cose
c. Ur in a lysis
d. Fea st in g (post pr a n dia l) blood glu cose
6. Neu r opa t h ies a r e a pot en t ia l com plica t ion of di-
a bet es. Wh y do t h ese occu r ?
a . In fect ion in t h e n er ves
b. Th icken in g a n d isch em ia of t h e vessels t h a t
su pply t h e n er ve fiber s
c. In a bilit y t o pr ovide con t in u ou s glu cose t o t h e
br a in a n d spin a l cor d
d. E xcessive glu cose exposu r e t o t h e br a in a n d
spin a l cor d
7. Wh a t is t h e m a jor differ en ce bet ween t h e So-
m oygi effect a n d t h e da wn ph en om en on ?
a . One is caused by the relea se of certa in hormones
b. On e occu r s bet ween 4a m a n d 9a m
c. On e t r igger s in su lin r esist a n ce a n d t h e r e-
lea se of glu cose fr om t h e liver
d. On e is ch a r a ct er ized by h yper glycem ia t h a t is
n ot t r igger ed by over n igh t h ypoglycem ia
8. Wh a t wou ld h a ppen if you r pa t ien t did n ot h a ve
a lph a cells of t h e pa n cr ea s?
a . Th ey wou ld n ot be a ble t o secr et e in su lin
b. Th ey wou ld n ot be a ble t o secr et e som a t ost a -
t in a n d ga st r in
c. Th ey wou ld n ot be a ble t o secr et e glu ca gon
d. Th ey wou ld n ot be a ble t o secr et e pa n cr ea t ic
polypept ides
9. Wh a t wou ld be a n u n u su a l sign in a ch ild t h a t
m a y a ler t t h e pa r en t t o t h e pr esen ce of dia bet es?
a . Bedwet t in g in a ch ild t h a t wa s pr eviou sly dr y
t h r ou gh t h e n igh t
b. Ir r it a bilit y
c. Askin g for wa t er t o dr in k in t h e m iddle of
t h e n igh t
d. All of t h ese
10. Wh a t is you r expla n a t ion t o t h e pa r en t s wh o do
n ot wa n t t o give t h eir ch ild in su lin in ject ion s t o
t r ea t t ype 1 dia bet es beca u se t h ey h a ve h ea r d
t h a t pills ca n be u sed t o t r ea t t h is con dit ion ?
a . In su lin is dest r oyed in t h e ga st r oin t est in a l
t r a ct if t a ken or a lly, so it m u st be in ject ed
su bcu t a n eou sly
523
b. Th e ch ild ca n go a h ea d a n d t a ke t h e or a l m ed-
ica t ion beca u se h e does h a ve t ype 1 dia bet es
c. Th e ch ild ca n n ot t a ke t h e pills beca u se we
ca n ’t be su r e t h a t h e wou ld t a ke t h e en t ir e
dose
d. Th e pills a r e r eser ved for t h ose over t h e a ge
of 12
11. Wh en in cr ea sed blood glu cose levels st im u la t e
in cr ea sed secr et ion of in su lin , t h is is a n exa m ple
of con t r ol by:
a . Relea sin g h or m on es
b. E ct opic h or m on es
c. Nega t ive feedba ck
d. Posit ive feedba ck
12. A m a jor d iffer en ce bet ween Bobby (t ype 1 dia be-
t es) a n d h is fa t h er (t ype 2 dia bet es) is:
a . H ow t h e con dit ion is dia gn osed bet ween t ype
1 a n d t ype 2
b. H ow t h e con dit ion is t r ea t ed bet ween t ype 1
a n d t ype 2
c. Th e pot en t ia l lon g-t er m com plica t ion s
d. Th e over a ll goa l of t r ea t m en t bet ween t ype 1
a n d t ype 2
13. Bobby’s fa t h er (wit h t ype 2 dia bet es) h a s been
en cou r a ged t o in cr ea se h is exer cise level. E xer-
cise is en cou r a ged in t ype 2 dia bet es beca u se:
a . E xer cise decr ea ses st r ess
b. Skelet a l m u scles ca n u se glu cose wit h ou t a
pr opor t ion a t e in su lin a m ou n t
c. E xer cise decr ea ses ca r diova scu la r effect s of
excessive glu cose
d. All of t h ese
14. Bobby’s fa t h er h a s been pr escr ibed a n or a l h ypo-
glycem ic dr u g. Su ch dr u gs a ct :
a . As a n in su lin r epla cem en t
b. To decr ea se t h e body’s n eed for glu cose in
body cells
c. To pr even t t h e for m a t ion of glu cose
d. To r edu ce in su lin r esist a n ce
15. Bobby com es in t o t h e clin ic a ft er 6 m on t h s for a
follow-u p visit . H e in dica t es t h a t h is blood su g-
a r s h a ve been a r ou n d 100 t o 120 m g/dL a n d h e
h a s been fu lly pa r t icipa t in g in t h e ot h er a spect s
of h is dia bet es m a n a gem en t pla n . Wh ich wou ld
lea d you t o believe t h a t h e h a s n ot been in t igh t
con t r ol of h is dia bet es?
a . A r edu ced glycosyla t ed h em oglobin level
b. An eleva t ed glycosyla t ed h em oglobin level
c. A r a n dom blood su ga r of 150 m g/dL per for m ed
in t h e clin ic
d. Th er e is n o m et h od t o det er m in e wh et h er or
n ot h e is in t igh t con t r ol
524 C h a p t e r 20: In t egr a t ed Pa t h oph ysiologic Con cept s
D I S C U S S I O N AN D
AP P L I C AT I O N
1. Wh a t did I kn ow a bou t dia bet es pr ior t o t oda y?
2. Wh a t body pr ocesses a r e a ffect ed by dia bet es?
Wh a t a r e t h e expect ed fu n ct ion s of t h ose pr o-
cesses? H ow does dia bet es a ffect t h ose pr ocesses?
3. Wh a t a r e t h e pot en t ia l et iologies for dia bet es?
H ow does dia bet es develop?
4. Wh o is m ost a t r isk for developin g dia bet es?
H ow does t h is differ wit h t h e t h r ee t ypes of dia -
bet es (t ype 1, t ype 2, a n d gest a t ion a l)?
5. Wh a t a r e t h e h u m a n differ en ces t h a t a ffect t h e
et iology, r isk, or cou r se of dia bet es?
6. Wh a t clin ica l m a n ifest a t ion s a r e expect ed in t h e
cou r se of dia bet es?
7. Wh a t specia l dia gn ost ic t est s a r e u sefu l in det er-
m in in g t h e dia gn osis of dia bet es?
8. Wh a t a r e t h e goa ls of ca r e for in dividu a ls wit h
dia bet es?
9. H ow does t h e con cept of dia bet es br in g t oget h er
wh a t I h a ve lea r n ed in t h e pr eviou s ch a pt er s
a n d in pr eviou s cou r ses?
10. H ow ca n I u se wh a t I h a ve lea r n ed?
R E SOUR CE S
Get u pda t ed n ews a n d cu r r en t r esea r ch on dia bet es
a s well a s gen er a l in for m a t ion :
h t t p://www.dia bet es.or g
F in d a d d ition a l r esou r ces for th is ch a pter a t h ttp:th ePoin t.lww.com
A com plet e su m m a r y of dia bet es a n d in for m a t ion for
dia bet es m a n a gem en t :
h t t p://dia bet es.n iddk .n ih .gov/dm /pu bs/t ype1a n d2/
wh a t .h t m
Upda t ed r esea r ch in t h e wor ld of dia bet es:
h t t p://www.n lm .n ih .gov/m edlin eplu s/dia bet es.h t m l
R e er en ces
1. Kwa i N, Ar n old R, Poyn t en A, et a l. Con t in u ou s su bcu -
t a n eou s in fect ion in fu sion pr eser ves a xon a l fu n ct ion
in t ype 1 dia bet es m ellit u s. Dia betes Meta b Res Rev.
2015;31(2):175–182. doi:10.1002/dm r r.2583.
2. F u m ia ki I, O’Con n or L, Ye Z, et a l. Con su m pt ion of su ga r
sweet en ed bever a ges, a r t ificia lly sweet en ed bever a ges,
a n d fr u it ju ice a n d in ciden ce of t ype 2 dia bet es: syst em -
a t ic r eview m et a -a n a lysis, a n d est im a t ion of popu la t ion
a t t r ibu t a ble fr a ct ion . BMJ . 2015;351:h 3576.
3. Kh a r dor i R, Gr iffin g G. Type 2 dia bet es m ellit u s. h t t p://
em edicin e.m edsca pe.com /a r t icle/117853-over view.
Accessed Novem ber 30, 2015.
4. Met oo D. Clin ica l skills: em power in g people wit h
dia bet es t o m in im ize com plica t ion s. Br J Nu r s.
2004;13:644–650.
 Glossa r y
1, 25-d ih y d r o x y c h o le c a lc i e r o l: a ct iva t ed for m
of vit a m in D; pr om ot es ca lciu m a bsor pt ion in t h e
in t est in e
a b s c e s s : a pocket of pu r u len t exu da t e
a b s o r p t io n : a com plex pr ocess of t a kin g in
n u t r ien t s a n d m ovin g t h ese t o t h e cir cu la t ion t o
be u sed by cells
a c c o m m o d a t e : a bilit y of t h e len s t o ch a n ge it s
sh a pe
a c c u m u la t e d m u t a t io n s t h e o r y : developm en t a l
t h eor y of a gin g su ggest in g t h a t gen es t h a t
det er m in e su r viva l a t you n ger a ges h a ve gr ea t er
in flu en ce t h a n gen es expr essed a t older a ges
a c id : su bst a n ce t h a t don a t es h ydr ogen ion s
a c o u s t ic r e le x m e a s u r e m e n t : t est t o det er m in e
m ovem en t of t h e t ym pa n ic m em br a n e in
r espon se t o sou n d
a c r o m e g a ly : con dit ion of h yper pla sia pr om pt ed by
h or m on e st im u la t ion of excessive gr owt h a ft er
closu r e of t h e epiph ysea l gr owt h pla t es of t h e
lon g bon es
a c t io n p o t e n t ia l: elect r ica l even t s t h a t t r a vel
a lon g a n en t ir e n eu r on by a llowin g ch a r ged ion s
t o flood t h r ou gh ch a n n els in t h e sem iper m ea ble
m em br a n e a r ou n d t h e n er ve cell
a c t iv e t r a n s p o r t : en er gy-depen den t t r a n spor t
of pa r t icles a cr oss t h e cell m em br a n e a ga in st a
gr a dien t
a c t iv it ie s o d a ily liv in g (AD L s ): per for m a n ce
of u su a l fu n ct ion s of ever yda y life (e.g., ea t in g,
dr essin g)
a c u it y : cla r it y; a bilit y t o loca t e t h e sit e of t h e
in it ia t ion of a st im u lu s
a c u t e : descr ibes m a n ifest a t ion s or illn esses t h a t
a r e u su a lly a br u pt in on set a n d la st a few da ys
t o a few m on t h s
a c u t e r e s p ir a t o r y d is t r e s s s y n d r o m e (AR D S ):
a con dit ion of sever e a cu t e in fla m m a t ion a n d
pu lm on a r y edem a wit h ou t eviden ce of flu id
over loa d or im pa ir ed ca r dia c fu n ct ion
a c u t e t u b u la r n e c r o s is : con dit ion of t h e kidn ey
ch a r a ct er ized by slou gh in g of t u bu la r cells
a d a p t a t io n : a lt er a t ion in fu n ct ion t h a t a llows
cells, t issu es, a n d or ga n s t o a dju st t o n ew
con dit ion s; su r viva l du e t o t h e ca pa cit y t o a dju st
t o a n a dver se en vir on m en t
a d a p t iv e im m u n it y : cell-m edia t ed a n d h u m or a l
im m u n it y; specific im m u n e r espon se occu r r in g
du r in g a lifet im e
Ad d is o n d is e a s e : a con dit ion of a dr en a l cor t ica l
in su fficien cy m ost com m on ly ca u sed by t h e
a u t oim m u n e dest r u ct ion of t h e a dr en a l cor t ex
a d e n o c a r c in o m a : a m a lign a n t t u m or of epit h elia l
cells
a d e n o id h y p e r t r o p h y : en la r gem en t of
lym ph oepit h elia l a den oid t issu e in t h e ba ck of
t h e n a sa l a r ea
a d e n o m a : ben ign t u m or of gla n du la r epit h elia l
or igin
a d e n o s in e t r ip h o s p h a t e (AT P ): pr in cipa l sou r ce
of cellu la r en er gy; pr odu ct of a ch em ica l r ea ct ion
bet ween oxygen a n d n u t r ien t pr odu ct s su ch a s
glu cose, fa t t y a cids, a m in o a cids, a n d en zym es
a d h e r e n c e : t h e a t t r a ct ion a n d bin din g of cells t o a
specific loca t ion t o pr om ot e h ea lin g
a d h e s io n s : fibr ou s con n ect ion s bet ween ser ou s
ca vit ies a n d n ea r by t issu es t h a t do n ot a llow t h e
su r r ou n din g t issu es t o m ove fr eely
a d ju v a n t : su bst a n ce t h a t in cr ea se im m u n e
r espon se t o a n t igen s
a d v e n t it io u s : r efer s t o a n a lt er a t ion in lu n g
sou n ds, a s wit h wh eezin g or cr a ckles
a e r o b ic b a c t e r ia : m icr oor ga n ism s t h a t r equ ir e
oxygen for gr owt h
a e c t iv e d is o r d e r : con dit ion in volvin g m ood,
em ot ion a l feelin g, a n d t on e r ela t ed t o t h ou gh t ;
in clu des ext er n a l m a n ifest a t ion s
a e r e n t n e u r o n s : n eu r on s t h a t ca r r y im pu lses
fr om r ecept or s t o t h e dist a n t t a r get s of t h e br a in
a n d spin a l cor d; a lso kn own a s sen sor y n eu r on s
a t e r lo a d : t h e a m ou n t of pr essu r e in t h e ven t r icle
t owa r d t h e en d of t h e ca r dia c con t r a ct ion
a ir t r a p p in g : decr ea sed effect ive O 2 in t a ke a n d
especia lly CO 2 r elea se by r et a in in g a ir wit h in t h e
a lveoli beca u se of loss of ela st icit y
a k in e s ia : in a bilit y t o m ove
a lle le : a ser ies of t wo or m or e differ en t gen es
occu pyin g t h e sa m e loca t ion on a specific
ch r om osom e
a lle r g e n : pr ot ein pr om ot in g a lt er ed r ea ct ivit y
r espon ses by t h e im m u n e syst em
a llo a n t ib o d ie s : a n t ibodies pr odu ced a ga in st
a lloa n t igen s
a llo a n t ig e n s : pr ot ein s t h a t va r y bet ween
in dividu a ls
a llo g r a t : gr a ft bet ween u n r ela t ed in dividu a ls
a lt e r n a t iv e s p lic in g : differ en t wa ys of a ssem blin g
exon s t o pr odu ce a va r iet y of m a t u r e m RNAs
525
526 Glossa r y
a m b ly o p ia : a con dit ion r esu lt in g fr om a m u scle
im ba la n ce; com m on ly kn own a s “la zy eye”
a m e n o r r h e a : t h e a bsen ce of m en st r u a t ion
a m n io c e n t e s is : in ser t ion of a n eedle in t o t h e
u t er in e ca vit y t o obt a in a sa m ple of a m n iot ic
flu id
a m p h o t e r ic : a ble t o fu n ct ion a s eit h er a cid or ba se
a m y lo id h y p o t h e s is : t h eor y su ggest in g t h a t fla ws
in t h e a ccu m u la t ion , pr odu ct ion , or disposa l
of Aβ a r e r espon sible for t h e pa t h ogen esis of
Alzh eim er disea se, in clu din g developm en t of
t a n gles, pla qu es, a n d n eu r on a l dea t h
a m y lo id p r e c u r s o r p r o t e in (AP P ): la r ge pr ot ein
pr odu ced by t h e bet a -a m yloid gen e
a n a e r o b ic b a c t e r ia : ba ct er ia t h a t do n ot r equ ir e
oxygen for gr owt h
a n a p h y la c t ic s h o c k : a con dit ion of im pa ir ed
t issu e per fu sion fr om sh ock beca u se of a
m a ssive im m u n e (t ype 1 or IgE -m edia t ed)
h yper sen sit ivit y r espon se
a n a p h y la x is : ext r em e m a n ifest a t ion t o for eign
pr ot ein or ot h er su bst a n ce
a n a p la s ia : a n eopla sm ’s loss of differ en t ia t ion
a n e m ia : t h e r edu ct ion in t h e m a ss of cir cu la t in g
blood cells a n d su bsequ en t ly r edu ced h em oglobin
levels
a n e u p lo id y : a bn or m a l ch r om osom e n u m ber
a n e u r y s m : loca l ou t pou ch in g ca u sed by wea kn ess
in t h e vessel wa ll
a n g in a p e c t o r is : ch est pa in or pr essu r e t h a t is
in t er m it t en t a n d a ssocia t ed wit h m yoca r dia l
isch em ia , a r edu ct ion in blood flow t o t h e
cor on a r y a r t er ies ca u sed by a t h er oscler osis oft en
a ccom pa n ied by va sospa sm
a n g io e d e m a : su dden su bcu t a n eou s edem a
a n g io g e n e s is : t h e gen er a t ion of n ew blood vessels
a n h e d o n ia : loss of in t er est or plea su r e in n or m a lly
en joya ble a ct ivit ies
a n io n e x c h a n g e : t r a n spor t of on e n ega t ively
ch a r ged ion for a n ot h er in opposit e dir ect ion s
a cr oss t h e cell m em br a n e
a n io n g a p : ca lcu la t ion of t h e m a jor m ea su r ed
ca t ion s a n d a n ion s in t h e pla sm a ; pr ovides a n
in dica t ion of elect r olyt e a n d a cid–ba se ba la n ce
a n io n s : ion s wit h a n ega t ive ch a r ge
a n k y lo s is : a debilit a t in g fixa t ion of a join t fr om
ext en sive fibr osis
a n o r e x ia : loss of a ppet it e
a n o r e x ia n e r v o s a (AN ): a n ea t in g disor der
ch a r a ct er ized by a r efu sa l t o m a in t a in a
m in im a lly h ea lt h y body weigh t , a n in t en se fea r
of ga in in g weigh t , body im a ge dist or t ion , a n d
a m en or r h ea
a n o v u la t io n : t h e a bsen ce of ovu la t ion
a n o x ia : t h e a bsolu t e depr iva t ion of oxygen
a n t a g o n is t ic p le io t r o p y t h e o r y : developm en t a l
t h eor y of a gin g su ggest in g t h a t gen es m a y h a ve
ben eficia l effect s du r in g ea r ly life, bu t h a r m fu l
effect s a s t h e in dividu a l a ges
a n t e r o la t e r a l p a t h w a y : n eu r ologic pa t h wa y
in volvin g bot h t h e a n t er ior a n d la t er a l
spin ot h a la m ic pa t h wa ys; ch a r a ct er ized by
m u lt iple syn a pses a n d slow con du ct ion ;
t r a n sm it s t h e sen sa t ion s of pa in , t em per a t u r e,
cr u de t ou ch , a n d pr essu r e n ot r equ ir in g t h e
specific loca t ion of t h e or igin of t h e st im u lu s
Ar t h u s r e a c t io n : com plex-m edia t ed im m u n e
r espon se in t h e skin r esu lt in g in a n a r ea of
loca lized t issu e n ecr osis
a n t ib o d ie s : im m u n oglobu lin s t h a t r ea ct wit h a n
a n t igen in a specific wa y; pr odu ced by a ct iva t ed
pla sm a cells
a n t ig e n : a su bst a n ce t h a t in du ces a st a t e of
sen sit ivit y or a n im m u n e r espon se
a n t ig e n -p r e s e n t in g c e lls : cells t h a t pr ocess a n d
pr esen t a n t igen for r ecogn it ion by im m u n e cells
a n t ig e n v a r ia t io n : a lt er a t ion of pa t h ogen pr ot ein
pa r t icles t o eva de r ecogn it ion a n d st im u la t ion of
m em or y in t h e im m u n e syst em
a n t ig e n ic v a r ia b ilit y : a pr ocess of elu din g t h e
h u m a n h ost defen ses; oft en a r esu lt of a lt er in g
t h e a n t igen s pr esen t wit h in or on t h e su r fa ce of
t h e m icr oor ga n ism
a n t ig e n ic it y : t h e level t o wh ich a pa t h ogen is
viewed by t h e h ost im m u n e syst em a s for eign
a n t ip o r t : syst em of su bst a n ces t r a n spor t ed in t h e
opposit e dir ect ion
a n t ir e sor p t ive : tendency to slow or block absorption
a n t ir e s o r p t iv e m e d ic a t io n : dr u gs t h a t in h ibit or
r edu ce bon e r esor pt ion ; u sed t o t r ea t ost eopor osis
a n u r ia : a bsen t u r in e ou t pu t
a n x ie t y d is o r d e r s : a gr ou p of ch r on ic psych ia t r ic
con dit ion s ch a r a ct er ized by over wh elm in g a n d
ir r a t ion a l feelin gs of fea r or wor r y
a p o p t o s is : pr ogr a m m ed cell dea t h t h a t is
pr om pt ed by a gen et ic sign a l a n d design ed
t o r epla ce old cells wit h n ew; a lso kn own a s
“cellu la r su icide”
a q u a p o r in s : ch a n n els in t h e cell m em br a n e; a llow
wa t er m ovem en t bet ween com pa r t m en t s
a q u e o u s h u m o r : n u t r it ive, wa t er y flu id pr odu ced
by t h e cilia r y body
a r a c h id o n ic a c id : a pla sm a m em br a n e–der ived
su bst a n ce t h a t gen er a t es va r iou s ch em ica l
m edia t or s t h r ou gh a com plex ch em ica l
con ver sion
a r t e r io v e n o u s (AV) is t u la : su r gica l a t t a ch m en t
of a n a r t er y t o a vein ; u sed t o obt a in a ccess t o
cir cu la t ion for h em odia lysis
a r t e r io v e n o u s s h u n t : su r gica l pr ocedu r e
con n ect in g t h e a r t er y t o t h e vein u sin g a
syn t h et ic t u be
a r t h r it is : a gen er ic t er m for degen er a t ion or
in fla m m a t ion of t h e join t s

a s c e n d in g : t h e u pwa r d m ovem en t of a n in fect ion
a scit e s: accumulation of fluid in the peritoneal cavity
a s p ir a t io n : a pr oblem of in h a lin g a for eign
su bst a n ce in t o t h e lu n gs
a s t h m a : a ch r on ic in fla m m a t or y disor der of
t h e a ir wa ys r esu lt in g in in t er m it t en t or
per sist en t a ir wa y obst r u ct ion ca u sed by
br on ch ia l h yper r espon siven ess, in fla m m a t ion ,
br on ch ocon st r ict ion , a n d excess m u cou s
pr odu ct ion
a s t ig m a t is m : ir r egu la r cu r va t u r e of t h e cor n ea or
len s pr even t in g t h e focu sin g of im a ges; blu r r in g
vision
a s t r o g lio s is : for m a t ion of a glia l sca r ca u sed by
pr olifer a t ion of a st r ocyt es in r espon se t o loca l
t issu e in ju r y
a s y m p t o m a t ic : t h e a bsen ce of a n y n ot icea ble
sym pt om s, even t h ou gh la bor a t or y or ot h er
dia gn ost ic t est s m a y in dica t e t h a t a disea se is
pr esen t
a t a x ic : in a bilit y t o con t r ol ba la n ce
a t e le c t a s is : a con dit ion of colla pse a n d
n on a er a t ion of t h e a lveoli
a t h e r o s c le r o s is : a con dit ion of ir r egu la r ly
dist r ibu t ed lipid deposit s in t h e in n er lin in g, or
in t im a , of la r ge or m ediu m a r t er ies
a t h e t o id : in a bilit y t o con t r ol m u scle m ovem en t
a t o p ic : descr ibes in dividu a ls h a vin g a gen et ic
pr edisposit ion t o developin g h yper sen sit ivit ies
a t o p y : t h e pr ocess by wh ich IgE r espon ses a r e
st im u la t ed fr om exposu r e t o t ypica lly ben ign
su bst a n ces
a t r e t ic : is a decr ea se in cell size (a t r oph ic)
a t r io v e n t r ic u la r (AV) n o d e : con n ect s t h e
con du ct ion of im pu lses bet ween t h e a t r ia a n d
ven t r icles
a t r o p h ic m a c u la r d e g e n e r a t io n : r et in a l
det er ior a t ion r esu lt in g fr om deposit ion of
dr u sen , u n der t h e m a cu la n ext t o t h e ba sem en t
m em br a n e of t h e r et in a l pigm en t epit h eliu m ;
a lso kn own a s dr y m a cu la r degen er a t ion
a t r o p h y : decr ea se in t h e size of t h e cell
a t t e n t io n : a cu lt u r a lly in flu en ced pr ocess of
select ively con cen t r a t in g on in for m a t ion
a t t e n t io n -d e ic it h y p e r a c t iv it y d is o r d e r
(AD H D ): a n eu r odevelopm en t a l disor der of
cogn it ive fu n ct ion s, ca u sin g a t t en t ion deficit ,
h yper a ct ivit y, a n d im pu lsiven ess
a t t e n u a t e d : wea ken ed; r edu ced a bilit y t o ca u se
disea se
Au e r b a c h p le x u s : pa r t of t h e en t er ic n er vou s
syst em ; fou n d bet ween t h e lon git u din a l a n d
cir cu la r m u scle la yer s of t h e la r ge in t est in e; a lso
kn own a s t h e m yen t er ic plexu s
a u s c u lt a t io n : t o list en wit h a st et h oscope
a u t o c la v e : a device t h a t u ses st ea m h ea t a t h igh
pr essu r es t o st er ilize object s
Glossa r y 527
a u t o g r a t : gr a ft s fr om differ en t sit es on t h e sa m e
per son
a u t o im m u n e : im m u n e r espon ses dir ect ed a t a n
in dividu a l’s own t issu es
a u t o n o m ic n e r v o u s s y s t e m (AN S ): com pon en t
of t h e per iph er a l n er vou s syst em ; in clu des t h e
sym pa t h et ic n er vou s syst em (SNS) a n d t h e
pa r a sym pa t h et ic n er vou s syst em (P NS); con t r ols
in volu n t a r y fu n ct ion of or ga n s
a u t o n o m y : t h e u n r egu la t ed cell gr owt h of
n eopla sm s
a u t o r e c e p t o r s : r ecept or s in volved in det ect ion of
ch em ica ls t o r egu la t e t h e cell’s own fu n ct ion
a u t o s o m e s : ch r om osom es ot h er t h a n a sex
ch r om osom e; t ot a ls 44 ch r om osom es in ea ch body
cell
a x o n : n eu r on a l st r u ct u r e t h a t ca r r ies im pu lses
a wa y fr om t h e cell body
a x o n h illo c k : poin t a t wh ich t h e a xon join s t h e cell
body
b a c t e r e m ia : a st a t e in wh ich ba ct er ia ga in a ccess
t o t h e blood
b a c t e r ia : sin gle-celled m icr oor ga n ism s t h a t ca n
r epr odu ce ou t side of h ost cells
b a r o r e c e p t o r s : loca t ed t h r ou gh ou t t h e blood
vessels a n d t h e h ea r t ; sen se pr essu r e ch a n ges in
t h e a r t er ies a n d a ler t t h e ca r dia c con t r ol cen t er
in t h e br a in st em
b a r o t r a u m a : in ju r y r esu lt in g fr om t h e in a bilit y of
t h e ea r t o equ a lize pr essu r e
b a s a l g a n g lia : st r u ct u r e of t h e br a in (ADD)
wit h a m a jor r ole in coor din a t ed m u scle
m ovem en t s
b a s e : su bst a n ce t h a t a ccept s h ydr ogen ion s
b a s e d e ic it : a m ou n t of ba se n eeded t o a ch ieve a
pH of 7.4 in t h e blood sa m ple
b a s e e x c e s s : a m ou n t of fixed a cid n eeded t o
a ch ieve a pH of 7.4 in t h e blood sa m ple
b a s e p a ir s : n it r ogen ba se com bin a t ion s; DNA ba se
pa ir s in clu de cyt osin e a n d gu a n in e, a n d a den in e
a n d t h ym in e
b a s e m e n t m e m b r a n e : t h e ou t er m em br a n e of t h e
vessels t h a t sepa r a t es t h e vessel fr om t h e t issu es
of t h e body
b a s o p h il: gr a n u locyt e t h a t com plem en t s t h e
a ct ion s of m a st cells; im por t a n t in est a blish in g
a ller gic r ea ct ion s
B -c e ll r e c e p t o r : r ecept or bou n d t o t h e cell
m em br a n e of t h e B cell; a ssocia t ion wit h a n t igen
a ct iva t es pla sm a cells t o pr odu ce a n d secr et e
a n t ibodies
B e c k w it h –Wie d e m a n n s y n d r o m e : con dit ion
of pedia t r ic over gr owt h a n d pr edisposit ion t o
t u m or gr owt h , lin ked t o gen et ic a n d epigen et ic
a lt er a t ion s
b e h a v io r : h ow people r espon d a n d a ct in a given
sit u a t ion
528 Glossa r y
b e n ig n : descr ibes a t u m or t h a t r em a in s loca lized
a n d closely r esem bles t h e t issu e of or igin
b e t a -a m y lo id p r o t e in : a ccu m u la t ion s lea din g t o
t h e pr odu ct ion of sen ile pla qu es, ch a r a ct er ist ic of
Alzh eim er disea se; a lso kn own a s a m yloid or A
b i u r c a t io n s : r egion s wh er ein a vessel br a n ch es
b ila y e r : t wo in t er con n ect ed la yer s of t h e pla sm a
m em br a n e; t h e lipid (fa t -solu ble) la yer con t a in s
ph osph olipid a n d glycolipid
b ilir u b in : yellow, lipid-solu ble bypr odu ct of
h em oglobin ; eleva t ed levels r esu lt in ja u n dice
b io a v a ila b ilit y : r efer s t o a m in er a l t h a t is
u n bou n d a n d m u st r em a in u n bou n d (a lso ca lled
a n ion ic st a t e) t o be a bsor bed
b io m e d ic in e : a syst em a t ic scien t ific st u dy of
biologic pr ocesses wit h in t h e fr a m ewor k of
West er n m edicin e
b in d in g a in it y : t igh t n ess or st r en gt h of liga n d/
r ecept or in t er a ct ion
b ip o la r a e c t iv e d is o r d e r : a con dit ion
ch a r a ct er ized by per iods of m a n ia a n d depr ession
b la d d e r : m u scu la r or ga n ser vin g a s a r eser voir
for u r in e; lin ed wit h t r a n sit ion a l epit h eliu m a n d
in n er va t ed by t h e pelvic n er ves
b la d d e r t r a in in g : pr ocess of lea r n in g t o h old
u r in e for in cr ea sin g in t er va ls a s a m a n a gem en t
st r a t egy for in con t in en ce
b la s t c e ll: a n y im m a t u r e cell
b la s t o m e r e : ea r ly em br yo
b lo o d –b r a in b a r r ie r (B B B ): r edu ced per m ea bilit y
of ca pilla r ies in t h e br a in t o pr ot ect a ga in st
exposu r e t o pot en t ia lly h a za r dou s su bst a n ces
b lo o d p r e s s u r e : t h e pr essu r e or t en sion of t h e
blood wit h in t h e syst em ic a r t er ies
b lo o d t r a n s u s io n : t h e m ost com m on for m of
t issu e t r a n spla n t ; in fu sion of don or blood in t o
r ecipien t
b lo o d t y p in g : t h e pr ocess by wh ich t h e r ecipien t ’s
blood t ype is det er m in ed
b lu n t o r c e in ju r y : in ju r y t h a t occu r s wh en t h e
h ea d st r ikes a h a r d su r fa ce or is st r u ck by a
r a pidly m ovin g object
B ly m p h o c y t e s : lym ph ocyt es t h a t differ en t ia t e
in t o pla sm a cells in t h e bon e m a r r ow; pr odu ce
a n d secr et e a n t ibodies a ft er con t a ct wit h a n
a n t igen
b o d y m a s s in d e x (B MI ): a m ea su r e of body fa t
ca lcu la t ed by m ea su r in g weigh t in kilogr a m s a n d
dividin g t h is by h eigh t in m et er s squ a r ed
(BMI = kg/m 2 )
b o d y -s e l n e u r o m a t r ix : n eu r a l n et wor k in t h e
br a in con t a in in g som a t osen sor y, lim bic, a n d
t h a la m ocor t ica l com pon en t s; in t egr a t es m u lt iple
sou r ces of in pu t r esu lt in g in t h e cogn it ive,
a ffect ive, a n d sen sor y per cept ion s of pa in
b o w e l r e s e c t io n : su r gica l pr ocedu r e in volvin g t h e
r em ova l of in t est in e
b r a c h ia l p le x u s p a ls y : t r a u m a t o t h e br a ch ia l
n er ve plexu s r esu lt in g in fla ccid pa r a lysis of t h e
a ffect ed a r m
b r a d y k in e s ia : decr ea sed spon t a n eit y of
m ovem en t ; slowed m ovem en t a ssocia t ed wit h
in it ia t ion of m ovem en t or su dden h a lt in g of
m ovem en t
b r o n c h ie c t a s is : t h e ir r ever sible dila t ion a n d
dest r u ct ion of t h e br on ch ia l t r ee m ost oft en
ca u sed by ch r on ic obst r u ct ion or in fect ion
b r o n c h o p u lm o n a r y d y s p la s ia (B P D ): con dit ion
in wh ich cellu la r a lt er a t ion s lea d t o ch r on ic,
ir r ever sible t issu e ch a n ges in t h e r espir a t or y
t r ee of t h e lu n gs
b r o n c h o s p a s m : con t r a ct ion of t h e sm oot h m u scle
in t h e br on ch i a n d br on ch ioles of t h e lu n gs,
decr ea sin g a ir wa y size
B r u d zin s k i s ig n : a t est of m en in gea l ir r it a t ion
wh er e t h e pa t ien t is su pin e a n d t h e n eck is
qu ickly flexed; t h is a ct ivit y elicit s pa in a lon g
wit h in volu n t a r y flexion of t h e h ips a n d kn ees
b u e r s y s t e m : m ixin g of a cid a n d ba se t o r esist
pH ch a n ge; syst em for t r a din g st r on ger a cids a n d
ba ses for wea ker va r iet ies t o a ch ieve a cid–ba se
ba la n ce
c a c h e x ia : a syn dr om e of u n expla in ed weigh t loss
a n d t issu e wa st in g r ela t ed t o t h e st im u la t ion
of in fla m m a t or y m edia t or s, a lon g wit h excess
en er gy u se, by t h e pr olifer a t in g n eopla st ic cells
c a lc it o n in : h or m on e pr om ot in g t h e deposit ion
of ca lciu m a n d ph osph a t e in bon e; pr odu ced
pr im a r ily by t h e pa r a follicu la r cells of t h e
t h yr oid gla n d, wit h ot h er sou r ces in clu din g t h e
pa r a t h yr oid a n d t h ym u s gla n ds
c a lo r ic t e s t : t est t h a t u ses wa r m a n d cool wa t er or
a ir ir r iga t ion t o in du ce n yst a gm u s; dia gn ost ic of
Mén ièr e disea se
c a lp a in : t ype of pr ot eolyt ic en zym e
c a n c e r : a t er m u sed t o descr ibe h igh ly in va sive
a n d dest r u ct ive n eopla sm s
c a p a c it o r : st r u ct u r e t h a t st or es cu r r en t
c a r c in o g e n : a kn own ca n cer-ca u sin g a gen t
c a r c in o g e n e s is : a t er m u sed t o descr ibe t h e
or igin , pr om ot ion , or developm en t of ca n cer ou s
n eopla sm s
c a r c in o m a in s it u : a u n iqu e t er m u sed t o descr ibe
ca r cin om a s t h a t a r e con fin ed t o t h e epit h eliu m
a n d h a ve n ot yet pen et r a t ed t h e ba sem en t
m em br a n e
c a r d ia c c o n t r a c t ilit y : t h e a bilit y of t h e h ea r t
t o in cr ea se t h e for ce of con t r a ct ion wit h ou t
ch a n gin g t h e dia st olic (r est in g) pr essu r e
c a r d ia c c y c le : r efer s t o on e con t r a ct ion a n d on e
r ela xa t ion ph a se of t h e h ea r t
c a r d ia c d y s r h y t h m ia s : a ca t egor y of pr oblem s
wit h m a in t a in in g a n efficien t h ea r t r h yt h m ,
su ch a s im pa ir m en t s of t h e sin oa t r ia l (SA) n ode,

a t r ioven t r icu la r (AV) n ode, ca r dia c cells t h a t join
t h e SA a n d AV n odes, or con du ct ion syst em s in
t h e a t r ia or ven t r icles
c a r d ia c h y p e r t r o p h y : a disea se of ca r dia c
m u scle t h a t r esu lt s fr om excessive wor kloa d a n d
fu n ct ion a l dem a n d
c a r d ia c o u t p u t (C O ): t h e volu m e of blood pu m ped
fr om t h e ven t r icles in 1 m in u t e
c a r d in a l s ig n s : t h e loca l m a n ifest a t ion s of a cu t e
in fla m m a t ion ; in clu de r edn ess, h ea t , swellin g,
pa in , a n d loss of fu n ct ion
c a r d io g e n ic s h o c k : t h e r esu lt of in a dequ a t e or
in effect ive ca r dia c pu m pin g
c a r r ie r s : h et er ozygou s for a r ecessive gen et ic
m u t a t ion ; a ble t o t r a n sm it t h e gen et ic m u t a t ion
t o su bsequ en t gen er a t ion s in t h e a bsen ce of a
disea se ph en ot ype
c a s e o u s n e c r o s is : a dist in ct ive, yellow, pa st y,
ch eese-like n ecr osis of t u ber cu losis
c a s t s : st r u ct u r es fou n d in u r in e con sist in g of a
pr ot ein m esh wor k of en t r a pped cells for m ed in
t h e dist a l collect in g t u bu les a n d collect in g du ct s
c a t a r a c t s : clou din g of t h e len s in t h e eye; ca u ses
blu r r ed vision by sca t t er in g in com in g ligh t
c a t io n s : ion s wit h a posit ive ch a r ge
c a t io n e x c h a n g e : t r a n spor t of on e posit ively
ch a r ged ion for a n ot h er in opposit e dir ect ion s
a cr oss t h e cell m em br a n e
c a u d a e q u in a : ext en sion of n er ves in t h e spin a l
cor d ext en din g below t h e sa cr a l level t h r ou gh t h e
exit of t h e ver t ebr a l colu m n
c a v it a t io n : a r ea of n ecr osis t h a t er ode su r r ou n din g
st r u ct u r es of t h e lu n gs, in clu din g t h e br on ch ioles,
br on ch i, a n d su r r ou n din g blood vessels
C D 4 T ly m p h o c y t e s : su bt ype of h elper T
lym ph ocyt e t h a t expr esses t h e m olecu le CD4 on
it s cell su r fa ce
C D 8 T ly m p h o c y t e s : su bt ype of cyt ot oxic T
lym ph ocyt e t h a t expr esses t h e m olecu le CD8 on
it s cell su r fa ce
c e lia c d is e a s e : a lso ca lled glu t en -sen sit ive
en t er opa t h y; a disor der of glu t en m a la bsor pt ion
ca u sed by a T-cell-m edia t ed h yper sen sit ivit y
t o glu t en in per son s wh o a r e gen et ica lly
pr edisposed t o developin g t h is con dit ion
c e ll: sm a llest com pon en t of t h e livin g in dividu a l
c e ll b o d y : cell st r u ct u r e con t a in in g cyt opla sm
a n d or ga n elles r espon sible for t h e specia lized
fu n ct ion of t h e cell; a lso kn own a s a som a
c e ll-m e d ia t e d im m u n it y : a com pon en t of
a da pt ive im m u n it y; cyt ot oxic T-cell-m edia t ed
dest r u ct ion of pa t h ogen a n d in fect ed h ost cell
c e llu la r c a s t s : com pa cted collection of pr ot ein, cells,
a nd debr is t ha t a r e for m ed in kidney t ubules
c e llu la r r e s p o n s e : t h e r ole of in fla m m a t ion in
a ler t in g t h e pr odu ct s of h ea lin g t o a t t en d t o t h e
sit e of in ju r y
Glossa r y 529
c e llu la r s e n e s c e n c e : developm en t a l t h eor y
su ggest in g t h a t a gin g is ca u sed by a n in t r in sic
loss of t h e ca pa cit y of t h e cell t o pr olifer a t e,
t r igger ed by a cr it ica l loss of t elom er e
c e n t r a l a u d it o r y p r o c e s s in g d is o r d e r : disor der
in volvin g a n a lt er a t ion in a u dit or y sign a l
pr ocessin g in t h e br a in
c e n t r a l n e r v o u s s y s t e m (C N S ): com pon en t of t h e
n er vou s syst em com pr isin g t h e br a in a n d spin a l
cor d
c e n t r o m e r e : st r u ct u r e lin kin g t h e ch r om osom e
pa ir s of t h e som a t ic cells of t h e body; divides t h e
ch r om osom e in t o t wo a r m s; con st a n t posit ion for
ea ch ch r om osom e
c e r e b r a l a q u e d u c t : con n ect in g poin t of t h e
t h ir d a n d fou r t h ven t r icles; a lso kn own a s t h e
a qu edu ct of Sylviu s
c e r e b r a l a t r o p h y : decr ea se in n eu r on a l cell
size a n d n u m ber lea din g t o im pa ir ed n eu r on a l
com m u n ica t ion a n d r edu ced br a in t issu e m a ss
c e r e b r o s p in a l lu id (C S F ): flu id ba t h in g t h e
su r fa ce of t h e cen t r a l n er vou s syst em st r u ct u r es
of t h e br a in a n d spin a l cor d; flows t h r ou gh fou r
flu id-filled in t er con n ect in g ven t r icles in t h e
br a in
c e r u m e n : secr et ion by gla n ds in t h e ea r
c h e ilit is : a pr oblem wit h fissu r e developm en t in
t h e cor n er s of t h e m ou t h oft en a ssocia t ed wit h
r ibofla vin deficien cy
c h e m ic a l in ju r y : in ju r y t o cells ca u sed by da m a ge
fr om t oxin s
c h e m ic a l m e d ia t o r s : pot en t su bst a n ces t h a t
fa cilit a t e t h e pr ocess of widen in g a n d loosen in g
t h e blood vessels a t t h e sit e of in ju r y; a r e a ct ive
in a ll ph a ses of t h e in fla m m a t or y r espon se
c h e m ic a l s y n a p s e : t r a n sm it im pu lses a cr oss
a sm a ll ga p bet ween cells via st im u la t ion of
n eu r ot r a n sm it t er s
c h e m o t a c t ic a c t o r s : su bst a n ces t h a t a t t r a ct
specific t ypes of cells
c h e m o t a x is : t h e ca llin g for t h of in fla m m a t or y cells
t o t h e in ju r ed sit e
c h o n d r o c a lc in o s is : ca lcifica t ion of ca r t ila ge
c h o n d r o m a : ben ign t u m or t h a t st em s fr om
ch on dr ocyt es
c h o n d r o s a r c o m a : a m a lign a n t t u m or of
ch on dr ocyt es
c h o r e a : ir r egu la r, in volu n t a r y m ovem en t s of
ext r em it ies or fa cia l m u scles
c h o r o id p le x u s : st r u ct u r e loca t ed in t h e t wo
la t er a l a n d sin gle t h ir d a n d fou r t h ven t r icles
of t h e br a in ; r espon sible for pr odu ct ion of
cer ebr ospin a l flu id
c h o r o id a l n e o v a s c u la r iza t io n : for m a t ion of
n ew blood vessels u n der t h e r et in a a n d m a cu la ;
a ssocia t ed wit h wet (exu da t ive) m a cu la r
degen er a t ion
530 Glossa r y
c h r o m a t in : n u clea r gen et ic m a t er ia l m a de of DNA;
con den ses in t o ch r om osom es du r in g m it osis
c h r o m a t o ly s is : swellin g of a n eu r on beca u se of
in ju r y
c h r o m o s o m e s : dou ble-st r a n ded DNA con t a in in g
t h r ea dlike sect ion s of gen es t h a t for m a n
in dividu a l’s gen et ic code; m ost com m on ly fou n d
in t h e cell n u cleu s; r espon sible for r epr odu ct ion
of ph ysica l a n d ch em ica l st r u ct u r es; h u m a n
som a t ic cells con t a in 46 ch r om osom es: 22 pa ir ed
a u t osom es a n d 1 pa ir of sex ch r om osom es
c h r o n ic : descr ibes m a n ifest a t ion s or illn esses
t h a t a r e oft en m or e in sidiou s a n d gen er a lly
la st 6 m on t h s or lon ger c h r o n ic b r o n c h it is :
t h e pr esen ce of a per sist en t , pr odu ct ive cou gh
t h a t la st s for 3 m on t h s or lon ger for 2 or m or e
con secu t ive yea r s
c h r o n ic o b s t r u c t iv e p u lm o n a r y d is e a s e
(C O P D ): a gen er ic t er m t h a t descr ibes a ll
ch r on ic obst r u ct ive lu n g pr oblem s in clu din g
a st h m a , em ph ysem a , a n d ch r on ic br on ch it is,
sepa r a t ely or in com bin a t ion
c ilia r y b o d y : ocu la r st r u ct u r e pr odu cin g t h e
a qu eou s h u m or
c ilia r y m u s c le : r egu la t es len s sh a pe t o focu s a n
object a t close r a n ge
c ir r h o s is : a n en d-st a ge liver disea se m a r ked
by in t er fer en ce of blood flow t o t h e liver a n d
widespr ea d h epa t ocyt e da m a ge
c lim a c t e r ic : gr a du a l t r a n sit ion bet ween n or m a l
r epr odu ct ive cycles a n d m en opa u se; a lso kn own
a s per im en opa u se
c lin ic a l m a n i e s t a t io n s : t h e pr esen t in g sign s a n d
sym pt om s of a n illn ess
c lo n a l e x p a n s io n : t h e pr olifer a t ion of B a n d T
lym ph ocyt es a ct iva t ed by clon a l select ion t o
pr odu ce a clon e of iden t ica l cells; en a bles t h e
body t o h a ve su fficien t n u m ber s of a n t igen -
specific lym ph ocyt es t o m ou n t a n effect ive
im m u n e r espon se
c lo n a l s e le c t io n : t h e select ion a n d a ct iva t ion of
specific B lym ph ocyt es a n d T lym ph ocyt es by t h e
bin din g of epit opes t o B- or T-cell r ecept or s wit h
a cor r espon din g fit
c lo n ic : r a pid su ccession s of a lt er n a t in g m u scle
con t r a ct ion a n d r ela xa t ion
c lo s e d h e a d in ju r y : in ju r y t o t h e h ea d t h a t ca u ses
t issu e da m a ge wit h ou t exposin g t issu e t o t h e
ext er n a l en vir on m en t
c lo t t in g s y s t e m : pr om ot es coa gu la t ion t h r ou gh
t h e a ct iva t ion of clot t in g fa ct or s in a ca sca de
sequ en ce a n d su ppr esses coa gu la t ion t h r ou gh
t h e r elea se of a n t icoa gu la t ion fa ct or s
c lu b b in g : a pa in less en la r gem en t a n d fla t t en in g of
t h e t ips of fin ger s or t oes du e t o ch r on ic h ypoxia
c lu s t e r s o d i e r e n t ia t io n : det er m in e specific
fu n ct ion s a n d r espon ses of T-cell su bt ypes
c o c h le a : bon y st r u ct u r e loca t ed in t h e in n er ea r ;
im por t a n t for h ea r in g
c o c h le a r im p la n t : a r t ificia l devices su r gica lly
pla ced beh in d t h e ea r t o en h a n ce h ea r in g
c o d o n : sequ en ce of t h r ee for m s of n it r ogen ba ses
for m s; n u cleot ide t r iplet ; fu n da m en t a l t r iplet
code n ecessa r y for pr ot ein syn t h esis; ba sic
com pou n ds pr odu ced a r e a m in o a cids
c o g w h e e l: m u scle r igidit y (jer kin g) in r espon se t o
lim b flexion a t t em pt
c o in e c t io n : a ph en om en on of h ost in g t wo or m or e
pa t h ogen s sim u lt a n eou sly
c o lla g e n : a lso kn own a s sca r t issu e; a su bst a n ce
m a n u fa ct u r ed by fibr obla st s t h a t fills in t h e ga ps
left a ft er t h e r em ova l of ext en sively da m a ged
t issu es or t h ose t issu es m a de u p of cells t h a t a r e
u n a ble t o r egen er a t e
c o lo n o s c o p y : a pr ocedu r e u sin g a n en doscope t o
per for m dir ect visu a liza t ion of t h e colon
c o lo s t o m y : est a blish m en t of a n a r t ificia l open in g
of t h e la r ge in t est in e ext er n a lly on t h e a bdom en
c o lu m n a r e p it h e liu m : sin gle la yer of epit h elia l
cells t a ller t h a n t h ey a r e wide
c o m m u n ic a b le d is e a s e s : disea ses t h a t a r e spr ea d
fr om per son t o per son , oft en t h r ou gh con t a ct
wit h in fect ed blood a n d body flu ids
c o m m u n ic a t in g h y d r o c e p h a lu s : in cr ea sed
ven t r icu la r a ccu m u la t ion of cer ebr ospin a l flu id
du e t o im pa ir ed cer ebr ospin a l flu id a bsor pt ion
c o m p le m e n t s y s t e m : a key sou r ce of ch em ica l
m edia t or s wit h in t h e pla sm a ; h a s m a n y r oles,
pa r t icu la r ly a s it r ela t es t o in fla m m a t ion ,
im m u n it y, a n d t h e r esolu t ion of in fect ion
c o m p lia n c e : t h e expect ed dist en sibilit y, or
expa n da bilit y, of t h e lu n g t issu e a n d ch est wa ll
c o m p lic a t io n s : n ega t ive sequ ela e fr om a disea se
c o n c e n t r a t io n g r a d ie n t : m ech a n ism of pa ssive
t r a n spor t t h a t pr om ot es t h e m ovem en t
of pa r t icles fr om a n a r ea of h igh t o lower
con cen t r a t ion
c o n c e p t : a n a bst r a ct idea gen er a lized fr om
pa r t icu la r in st a n ces
c o n d u c t iv e h e a r in g lo s s : h ea r in g loss loca lized
t o t h e ou t er or m iddle ea r ; m a y be t em por a r y or
per m a n en t
c o n e : ph ot or ecept or loca t ed in t h e r et in a ; essen t ia l
for sh a r p a n d color vision
c o n g e n it a l d e e c t s : da m a ge t o a developin g fet u s
c o n g e s t iv e h e a r t a ilu r e : occu r s wh en t h e
left ven t r icle of t h e h ea r t is in effect ive a n d
blood ba cks u p in t o t h e pu lm on a r y vein a n d
su bsequ en t ly in t o t h e lu n g t issu es; r esu lt s in
pu lm on a r y edem a ; a lso ca lled left h ea r t fa ilu r e
c o n ju g a t e d v a c c in e : a n t igen s t h a t pr om ot e
a ct iva t ion of m or e t h a n on e cell t ype
c o n ju n c t iv it is : in fla m m a t ion of t h e m u cou s
m em br a n e lin in g t h e eye

c o n s o lid a t io n : a solid m a ss in t h e lu n g t issu e
c o n s t a n t r e g io n : st r u ct u r e for m in g t h e ba se of t h e
Y-sh a ped a n t ibody; t h e m ost st a ble com pon en t
c o n s t ip a t io n : a bsen t or in com plet e bowel
m ovem en t ; m a y r epr esen t a con sequ en ce of
im pa ir ed ga st r oin t est in a l m obilit y or obst r u ct ion
c o n t r a c t u r e s : a r ea s of t h ick, sh or t en ed, a n d r igid
t issu e fr om a loss of ela st icit y
c o n t r a la t e r a l: r efer r in g t o t h e opposit e side of t h e
body
c o r p u lm o n a le : a n a lt er a t ion in t h e st r u ct u r e
a n d fu n ct ion of t h e r igh t ven t r icle ca u sed by a
pr im a r y disor der of t h e r espir a t or y syst em
c o r n e a : clea r, t r a n spa r en t st r u ct u r e cover in g t h e
ext er ior wa ll of t h e eye
c o r p u s c a llo s u m : n er ve fiber bu n dles pr om ot in g
com m u n ica t ion bet ween t h e r igh t a n d left
h em isph er es of t h e br a in
c o r t is o l: is a m a jor glu cocor t icoid secr et ed fr om
t h e a dr en a l cor t ex t h a t r egu la t es m et a bolism ,
in fla m m a t or y/im m u n e pr ocesses, a n d t h e st r ess
r espon se
c o s t o v e r t e b r a l a n g le (C VA): a n a t om ic a r ea
in clu din g t h e lower a bdom en a n t er ior ly a n d
post er ior ly; sit e of a ssocia t ed der m a t om es of t h e
kidn ey
c o t r a n s p o r t : su bst a n ces t r a n spor t ed t oget h er in
t h e sa m e dir ect ion
c o u n t e r c u r r e n t e x c h a n g e r : flow of blood in
t h e va sa r ect a ca pilla r ies a lign ed wit h filt r a t e
flow in t h e loop of H en le; slow descen din g blood
flow a llows wa t er t r a n spor t fr om t h e m edu lla r y
in t er st it iu m in t o t h e ca pilla r y blood, a n d slow
a scen din g blood flow a llows solu t e t r a n spor t
fr om t h e va sa r ect a in t o t h e in t er st it iu m ,
pr eser vin g m edu lla r y gr a dien t a n d pr even t in g
wa sh ou t of in t er st it ia l solu t es
c o u n t e r c u r r e n t m e c h a n is m : pr ocess of filt r a t e
con cen t r a t ion in t h e loop of H en le in t h e m edu lla
of t h e kidn ey; in clu des t h e cou n t er cu r r en t
m u lt iplier a n d t h e cou n t er cu r r en t exch a n ger
c o u n t e r c u r r e n t m u lt ip lie r : pr ocess of wa t er a n d
solu t e t r a n spor t in t h e loop of H en le m a in t a in in g
t h e ver t ica l m edu lla r y gr a dien t
c o u n t e r t r a n s p o r t : su bst a n ces t r a n spor t ed in t h e
opposit e dir ect ion
c r e t in is m : a con dit ion of m en t a l r et a r da t ion
a n d im pa ir ed gr owt h fr om a con gen it a l la ck of
t h yr oid h or m on e pr odu ct ion a n d secr et ion
c r o s s m a t c h in g : t h e pr ocess by wh ich a n t ibody
com pa t ibilit y bet ween don or a n d r ecipien t blood
is det er m in ed
c r y p t o r c h id is m : a con gen it a l con dit ion of on e or
t wo u n descen ded t est es
c r y p t s : m u cosa l epit h elia l depr ession s of t h e colon
Cu sh in g d ise a se : a condition of hypercortisolism
specifically related to pituitary corticotrope tumors
Glossa r y 531
C u s h in g s y n d r o m e : a con dit ion of excess
glu cocor t icoid secr et ion fr om t h e a dr en a l cor t ex
c y a n o s is : a r esu lt of a gr ea t er pr opor t ion of
desa t u r a t ed h em oglobin in t h e blood, wh ich gives
t h e blood a blu ish h u e
c y t o c h r o m e o x id a s e (C O X): en zym e im por t a n t
in ca t a lyzin g oxida t ion –r edu ct ion m it och on dr ia l
r ea ct ion s in cellu la r r espir a t ion
c y t o k in e : a h or m on e-like cell pr ot ein t h a t
r egu la t es t h e a ct ivit y of m a n y ot h er ch em ica l
m edia t or s in a n effor t t o t r igger, en h a n ce, a n d
t h en discon t in u e t h e in fla m m a t or y r espon se
c y t o p la s m : colloid su bst a n ce su r r ou n din g t h e
cell n u cleu s com posed of wa t er, pr ot ein s, fa t s,
elect r olyt es, glycogen , a n d pigm en t s
c y t o s k e le t o n : t u bu le a n d fila m en t st r u ct u r es,
con t r ibu t in g t o cell sh a pe, m ovem en t , a n d
in t r a cellu la r t r a n spor t ; com posed of m icr ot u bu les
a n d t h in , in t er m edia t e, a n d t h ick m icr ofila m en t s
c y t o s o l: t h e cyt opla sm of ba ct er ia t h a t con t a in s
ext en sive r ibosom es, pr ot ein s, a n d ca r boh ydr a t es,
bu t does n ot con t a in m it och on dr ia , en dopla sm ic
r et icu lu m , or ot h er m em br a n ou s com pon en t s
c y t o t o x ic T ly m p h o c y t e : su bset of T lym ph ocyt e
t h a t dir ect s dest r u ct ion of t h e a n t igen or cells
ca r r yin g t h e a n t igen
d a w n p h e n o m e n o n : a sit u a t ion in wh ich a n
in dividu a l’s blood glu cose level u pon wa kin g
is h igh er t h a n t h a t befor e goin g t o bed in t h e
even in g
d e a d s p a c e : a n a r ea wh er e ga s exch a n ge ca n n ot
t a ke pla ce
d e a t h : cessa t ion of life; cessa t ion of t h e in t egr a t ion
of cellu la r, t issu e, a n d or ga n fu n ct ion s
d e c e r e b r a t e p o s t u r in g : in cr ea sed ext en sor
m u scle excit a bilit y ca u sed by n eu r ologic in ju r y
d e c ib e ls (d B ): t h e u n it of m ea su r em en t of
in t en sit y or lou dn ess of t h e sou n d
d e c o r t ic a t e p o s t u r in g : in cr ea sed flexor m u scle
excit a bilit y ca u sed by n eu r ologic in ju r y
d e b r id e m e n t : a pr ocess of m ech a n ica lly r em ovin g
debr is, in clu din g n ecr ot ic t issu e, fr om a wou n d
d e e p b r a in s t im u la t io n (D B S ): r ever sible
pr ocedu r e design ed t o a lt er a bn or m a l fu n ct ion
of t h e br a in t issu e; n eu r ost im u la t or deliver s
elect r ica l sign a ls t o a t a r get ed a r ea of t h e br a in ,
blockin g a bn or m a l n er ve sign a ls a n d r esu lt in g in
t r em or a n d ot h er Pa r kin son disea se sym pt om s
d e e p p a r t ia l-t h ic k n e s s b u r n s : for m er ly kn own
a s secon d-degr ee bu r n s; bu r n s t h a t da m a ge
epider m a l skin la yer s a n d pen et r a t e som e
der m a l skin la yer s
d e e c a t io n : t h e pr ocess of st ool elim in a t ion
d e ic it in ju r y : da m a ge ca u sed by depr iva t ion of
oxygen a t ion , h ydr a t ion , a n d n u t r it ion
d e g r a n u la t io n : t h e r elea se of ch em ica l m edia t or s
in t h e for m of ext r a cellu la r gr a n u les
532 Glossa r y
d e h is c e n c e : a pr oblem of deficien t sca r for m a t ion
in wh ich t h e wou n d split s or bu r st s open , oft en
a t a su t u r e lin e
d e la y e d h y p e r s e n s it iv it y r e a c t io n : r ea ct ion
a ft er a ller gen con t a ct t h a t is slow in on set a n d
pea ks a ft er 36 t o 48 h ou r s; a ssocia t ed wit h a t ype
IV cell–m edia t ed h yper sen sit ivit y r ea ct ion
d e m y e lin a t io n : degr a da t ion of m yelin
d e n d r it e s : br a n ch in g pr ot opla sm ic pr ocesses of t h e
n er ve cell
d e n d r it ic c e lls : pr ocess a n d displa y of a n t igen s t o
T lym ph ocyt es; t a ke u p a n t igen s wh en t h ey a r e
en cou n t er ed in t h e cir cu la t ion
d e o x y r ib o n u c le ic a c id (D N A): t ype of n u cleic
a cid con t a in in g a su ga r (deoxyr ibose); u su a lly
fou n d in t h e cell n u cleu s a n d m it och on dr ia ;
r espon sible for t h e st or a ge of gen et ic
in for m a t ion ; m a de u p of fou r n it r ogen ou s ba ses,
in clu din g a den in e (A) a n d gu a n in e (G), cyt osin e
(C) a n d t h ym in e (T)
d e p o la r iza t io n : r esu lt of r a pid m ovem en t of
sodiu m in t o t h e cell t h r ou gh sodiu m ch a n n els in
t h e cell m em br a n e
d e r m a t o m e s : body r egion s t o wh ich spin a l n er ves
t r a n sm it im pu lses
d e r m a t o p h y t e in e c t io n s : fu n ga l in fect ion s of t h e
skin , h a ir, a n d n a ils
d e t r u s o r m u s c le : t issu e com pr isin g t h e body of
t h e bla dder ; con t r a ct ion a ssist s wit h bla dder
em pt yin g a n d elim in a t ion of u r in e
d e v e lo p m e n t a l t h e o r y : t h eor y im plica t in g t h e
in flu en ce of gen et ics a s t h e m a jor det er m in a n t of
a gin g
d ia b e t e s in s ip id u s (D I ): a con dit ion of in su fficien t
a n t idiu r et ic h or m on e r esu lt in g in t h e in a bilit y of
t h e body t o con cen t r a t e or r et a in wa t er
d ia b e t e s m e llit u s : a disor der of t h e body’s
m et a bolism of pr ot ein , fa t s, a n d ca r boh ydr a t es
beca u se of a n a bsolu t e la ck of in su lin or in su lin
r esist a n ce
d ia g n o s is : a la bel for t h e a lt er ed h ea lt h
con dit ion
d ia p e d e s is : a pr ocess t h a t a llows leu kocyt es t o
m ove bet ween a n d t h r ou gh en dot h elia l cells in
or der t o en gu lf a n d dest r oy t h e offen din g a gen t
a n d r em ove dea d t issu e
d ia r r h e a : loose, wa t er y st ools
d ia s t o le : t h e r ela xa t ion of t h e h ea r t t h a t a llows
blood t o fill t h e ven t r icles
d ia s t o lic b lo o d p r e s s u r e : t h e a m ou n t of pr essu r e
t h a t r em a in s in t h e a or t a du r in g t h e r est in g
ph a se of t h e ca r dia c cycle
d ia s t o lic a ilu r e : fa ilu r e t h a t occu r s wit h
st iffn ess of t h e ven t r icle a n d loss of r ela xa t ion
a bilit y, wh ich im pa ir s t h e h ea r t ’s a bilit y t o
opt im a lly fill wit h blood bet ween ca r dia c
con t r a ct ion s
d i e r e n t ia t io n : a pr ocess of ch a n gin g t h e ph ysica l
a n d fu n ct ion a l pr oper t ies of a cell t o a llow
gr ea t er specificit y a n d fu n ct ion a lit y t o t h a t cell
d i u s in g c a p a c it y : a m ea su r em en t of ca r bon
m on oxide (CO), oxygen , or n it r ic oxide t r a n sfer
fr om in spir ed ga s t o pu lm on a r y ca pilla r y blood;
is r eflect ive of t h e volu m e of a ga s t h a t diffu ses
t h r ou gh t h e a lveola r ca pilla r y m em br a n e ea ch
m in u t e
d i u s io n : m ovem en t of pa r t icles fr om a n a r ea of
h igh t o lower con cen t r a t ion
d ig e s t io n : t h e pr ocess by wh ich food is br oken
down m ech a n ica lly a n d ch em ica lly in t h e
ga st r oin t est in a l t r a ct a n d con ver t ed in t o
a bsor ba ble com pon en t s
d ip le g ia : in volvin g bot h legs
d ip lo id : t h e n u m ber of ch r om osom es a h u m a n
body cell con t a in s; 23 pa ir s of ch r om osom es, or a
t ot a l of 46
d ip lo p ia : r esu lt in g fr om a la ck of coor din a t ion of
t h e ext r a ocu la r m u scles; m a y r esu lt in dou ble
vision
d ir e c t e x t e n s io n : a pr ocess of t u m or cells m ovin g
in t o a dja cen t t issu es a n d or ga n s
d is c o id : r ed, r a ised, r ou n d r a sh
d is c r im in a t iv e p a t h w a y : n eu r ologic pa t h wa y
com m u n ica t in g sen sor y in for m a t ion , in clu din g
discr im in a t ive t ou ch a n d spa t ia l or ien t a t ion
d is e a s e : a n im pa ir m en t of cell, t issu e, or ga n , or
syst em fu n ct ion in g
d is s e m in a t e d in t r a v a s c u la r c o a g u la t io n
(D I C ): a con dit ion of u n con t r olled a ct iva t ion of
clot t in g fa ct or s r esu lt in g in widespr ea d t h r om bi
for m a t ion followed by deplet ion of coa gu la t ion
fa ct or s a n d pla t elet s; lea ds t o m a ssive
h em or r h a ge
d is t a l a x o n o p a t h y : a xon a l in ju r y of n eu r on s in
dist a l a r ea s of t h e body, su ch a s h a n ds a n d feet
d iu r e t ic s : dr u gs t h a t in cr ea se u r in e pr odu ct ion
d iv e r t ic u la : m or e t h a n on e diver t icu lu m
d iv e r t ic u lit is : in fect ion of t h e diver t icu la
d iv e r t ic u lo s is : con dit ion ch a r a ct er ized by t h e
pr esen ce of diver t icu la
d iv e r t ic u lu m : sm a ll sa c or ou t pou ch in g a lon g t h e
wa ll of t h e colon ; plu r a l diver t icu la
d o m in a n t : a n a llele possessed by on e of t h e
pa r en t s of a h ybr id t h a t is expr essed in t h e
la t t er t o t h e exclu sion of con t r a st in g a llele (t h e
r ecessive) fr om t h e ot h er pa r en t
d o r s a l h o r n s : post er ior ext en sion s of t h e spin a l
cor d con t a in in g sen sor y n eu r on s; r eceive a ffer en t
im pu lses via t h e dor sa l r oot s a n d ot h er n eu r on s
d r u s e n : sm a ll, yellow deposit s; deposit ion u n der
t h e m a cu la is ch a r a ct er ist ic of dr y (a t r oph ic)
m a cu la r degen er a t ion
d r y (a t r o p h ic ) MD : r et in a l det er ior a t ion r esu lt in g
fr om deposit ion of dr u sen , u n der t h e m a cu la

n ext t o t h e ba sem en t m em br a n e of t h e r et in a l
pigm en t epit h eliu m ; a lso kn own a s a t r oph ic
m a cu la r degen er a t ion
d u a l e n e r g y X-r a y a b s o r p t io m e t r y (D E XA):
specia lized, low-level r a diogr a ph ic t ech n iqu e
u sed t o m ea su r e bon e den sit y
d y s k in e s ia : difficu lt y in per for m in g volu n t a r y
m ovem en t s
d y s k in e t ic : in a bilit y t o con t r ol m u scle m ovem en t
d y s m e n o r r h e a : pa in wit h m en st r u a l per iods
d y s p a r e u n ia : pa in fu l in t er cou r se
d y s p e p s ia : a va gu e epiga st r ic discom for t
a ssocia t ed wit h n a u sea a n d h ea r t bu r n
d y s p la s ia : a ct u a l ch a n ge in cell size, sh a pe,
u n ifor m it y, a r r a n gem en t , a n d st r u ct u r e
d y s p n e a : t h e su bject ive feelin g of sh or t n ess of
br ea t h or t h e in a bilit y t o get en ou gh a ir
d y s t o n ia : a bn or m a l t on e
d y s u r ia : pa in wit h u r in a t ion
e c c h y m o s e s : br u ises fr om su per ficia l bleedin g in t o
t h e skin
e c t o c e r v ix : ou t side of t h e cer vix lin ed wit h
squ a m ou s epit h eliu m
e c t o p ic : r efer s t o h or m on e secr et ion fr om a sit e
ou t side of a n en docr in e gla n d
e d e m a : t h e pr esen ce of excessive wa t er y flu id t h a t
a ccu m u la t es in t h e t issu es
e e r e n t n e u r o n s : n eu r on s t h a t ca r r y im pu lses
fr om cen t r a l n er vou s syst em t o t h e per iph er y
e la s t in : a su bst a n ce t h a t a llows st r et ch in g a n d
r ecoil of t issu e
e le c t r ic a l s y n a p s e s : t r a n sm it im pu lses via
pa ssa ge of cu r r en t -ca r r yin g ion s t h r ou gh sm a ll
open in gs or ga ps
e le c t r o ly t e s : ion iza ble su bst a n ces in solu t ion ;
con du ct elect r icit y in solu t ion
e le c t r o n y s t a g m o g r a p h y (E N G ): gr ou p of t est s
t h a t det er m in e vest ibu la r fu n ct ion ba sed on eye
m ovem en t
e le m e n t a l b o d y : t h e m et a bolica lly in a ct ive st a ge
in t h e life cycle of ch la m ydia e in wh ich t h e
m icr oor ga n ism a t t a ch es t o a n d in t er n a lizes t h e
h ost cell
e lic it a t io n p h a s e : secon d ph a se of dela yed
h yper sen sit ivit y r ea ct ion ; m em or y cells in
t h e der m is a r e st im u la t ed a ft er pr esen t a t ion
wit h a n t igen by La n ger h a n s cells, pr om pt in g
a ct iva t ion of m em or y T cells a n d st im u la t ion of
cell-m edia t ed r espon ses
e m b o lu s : a n y plu g of m a t er ia l, su ch a s t h r om bi,
a ir, n eopla sm s, m icr oor ga n ism s, or a m n iot ic
flu id, t h a t t r a vels in t h e cir cu la t ion a n d ca n
obst r u ct t h e lu m en of a vessel
e m b r y o n ic c a r c in o m a s : r esem ble pr im it ive
u n differ en t ia t ed em br yon ic t issu e
e m p h y s e m a : a n ir r ever sible en la r gem en t of t h e
a ir spa ces beyon d t h e t er m in a l br on ch ioles, m ost
Glossa r y 533
n ot a bly in t h e a lveoli, r esu lt in g in dest r u ct ion of
t h e a lveola r wa lls a n d obst r u ct ion of a ir flow
e n c e p h a lo p a t h y : br a in disor der
e n c o p r e s is : a con dit ion of feca l in con t in en ce
ch a r a ct er ized by in a ppr opr ia t e feca l soilin g;
fr equ en t ly seen in t h e pedia t r ic popu la t ion ; a lso
kn own a s fu n ct ion a l n on r et en t ive soilin g
e n d e m ic : a con dit ion in wh ich t h e in ciden ce a n d
pr eva len ce a r e st a ble a n d pr edict a ble
e n d o c a r d iu m : t h e in n er lin in g of t h e h ea r t t h a t
for m s a con t in u ou s la yer of en dot h eliu m t h a t
join s t h e a r t er ies a n d vein s t o t h e h ea r t , for m in g
a closed cir cu la t or y syst em
e n d o c e r v ic a l c a n a l: a r ea bet ween t h e ext er n a l
a n d in t er n a l cer vica l os; lin ed wit h colu m n a r
epit h eliu m
e n d o c r in e : h or m on e secr et ion wit h syst em ic
effect s
e n d o c r in e p a n c r e a s : a n or ga n t h a t secr et es
h or m on es, su ch a s in su lin a n d glu ca gon
e n d o c r in e s y s t e m : a collect ive gr ou p of t issu es
t h a t a r e ca pa ble of secr et in g h or m on es
e n d o c y t o s is : t r a n spor t m ech a n ism in volvin g
vesicu la r en closu r e of pa r t icles fr om t h e
ext r a cellu la r en vir on m en t in t o t h e cyt opla sm for
u se by t h e cell
e n d o g e n o u s : fr om wit h in t h e body syst em
e n d o ly m p h : flu id fillin g t h e coch lea
e n d o m e t r io s is : a con dit ion in volvin g en dom et r ia l
t issu e t h a t is loca t ed ou t side of t h e u t er u s
e n d o p la s m ic r e t ic u lu m : cellu la r or ga n elle
com posed of a com plex n et wor k of t u bu les;
im por t a n t in t h e pr odu ct ion of pr ot ein s a n d fa t s
a n d ion r egu la t ion ; su bt ypes in clu de r ou gh a n d
sm oot h
e n d o t h e lia l c e lls : cells t h a t for m a t igh t ju n ct ion
wit h in t h e in n er lin in g of t h e blood a n d
lym ph a t ic vessels a n d t h e h ea r t
e n d o t o x in : a com plex of ph osph olipid–
polysa cch a r ide m olecu les t h a t for m t h e
st r u ct u r a l com pon en t of t h e gr a m -n ega t ive cell
wa ll a n d ca u ses in fla m m a t or y m edia t or s t o be
r elea sed, lea din g t o a m a ssive in fla m m a t or y
r espon se
e n e r g y : t h e ca pa cit y t o do wor k
e n t e r ic n e r v o u s s y s t e m : su bdivision of t h e
per iph er a l n er vou s syst em ; pr ovides in n er va t ion
t o t h e m u scle of fiber s of t h e in t est in e via t h e
m yen t er ic (Au er ba ch ) a n d Meissn er plexu s,
con t r ollin g ga st r oin t est in a l m ovem en t a n d
sen sa t ion
e n u r e s is : u r in a r y in con t in en ce; in a bilit y t o
volu n t a r ily pr even t t h e disch a r ge of u r in e
e o s in o p h ils : gr a n u locyt e wit h gr ea t est pr ot ect ion
a ga in st pa r a sit es
e p id e m ic : a dr a m a t ic in cr ea se in t h e in ciden ce of a
h ea lt h con dit ion in a popu la t ion
534 Glossa r y
e p id e m io lo g y : t h e st u dy of disea se in popu la t ion s
e p ig e n e t ic : r egu la t ion of t h e expr ession of gen e
a ct ivit y wit h ou t a lt er a t ion of gen et ic st r u ct u r e
e p ip h y s e a l: lon g bon e ossifica t ion sit e
e p is t a x is : episodes of n ose bleeds
e p it h e lio id c e lls : ph a gocyt es t h a t ga t h er a n d
con t a in sm a ller su bst a n ces by for m in g a wa ll, or
fibr ot ic gr a n u lom a , a r ou n d t h e a ffect ed a r ea
e p it h e lio m a : a ben ign t u m or of t h e squ a m ou s
epit h eliu m
e r e c t ile d y s u n c t io n (E D ): t h e in a bilit y t o
a ch ieve or m a in t a in a n er ect ion su fficien t for
sa t isfa ct or y sexu a l per for m a n ce
e r y t h e m a : r edn ess ca u sed by in cr ea sed blood flow
t o t h e t issu es
e r y t h r o c y t e s e d im e n t a t io n r a t e : a lso r efer r ed
t o a s a sed r a t e, or E SR; a n on specific m et h od of
t est in g for in fla m m a t ion
e r y t h r o c y t e s : r ed blood cells (RBCs); com pr ise a
la r ge pr opor t ion of t h e blood a n d a r e n eeded t o
pr ovide t issu e oxygen a t ion
e r y t h r o p o ie s is : t h e for m a t ion of n ew r ed blood
cells
e r y t h r o p o ie t in : a pr ot ein t h a t st im u la t es t h e
for m a t ion of r ed blood cells for gr owt h
e s c h a r : a t h ick, coa gu la t ed cr u st t h a t develops
a ft er a t h er m a l or ch em ica l bu r n t h a t ca u t er izes
t h e skin
e s o t r o p ia : su ppr ession of on e visu a l im a ges by t h e
br a in , pr eser vin g n or m a l vision
e s s e n t ia l a t : a lipid r equ ir ed for ph ysiologic
fu n ct ion in g
e s s e n t ia l n u t r ie n t s : t h ose t h a t m u st be con su m ed
r egu la r ly in t h e diet , beca u se t h e body is u n a ble
t o syn t h esize t h e n u t r ien t in qu a n t it ies su fficien t
t o m eet it s n eeds
e t io lo g y : t h e ca u se of t h e disea se
e v o lu t io n t h e o r y : developm en t a l t h eor y
su ggest in g t h a t a gin g is t h e r esu lt of t h e for ces
of n a t u r a l select ion
e x a c e r b a t io n : a per iod in wh ich sym pt om s fla r e
a n d ca n be sever e
e x o c r in e p a n c r e a s : a n or ga n t h a t con t a in s a cin i
cells, wh ich secr et e digest ive en zym es a n d
a lka lin e flu ids t h r ou gh t h e pa n cr ea t ic du ct in t o
t h e du oden u m
e x o c y t o s is : t h e pr ocess of m ovem en t of gr a n u les or
pa r t icles ou t of t h e cell; fu sion of t h e m em br a n e
su r r ou n din g t h e gr a n u le wit h t h e cell m em br a n e,
followed by r u pt u r e a n d r elea se of con t en t s
e x o g e n o u s : fr om t h e ext er n a l en vir on m en t
e x o n : segm en t of DNA coded for pr ot ein pr odu ct ion
e x o p h t h a lm o s : a pr ot r u sion of t h e eyeba lls t h a t
som et im es occu r s wit h h yper t h yr oidism
e x o t o x in s : pot en t su bst a n ces pr odu ced by m a n y
ba ct er ia , wh ich r esu lt in h ost cell dysfu n ct ion or
lysis
e x p e c t o r a t e : t o spit ou t t h e m u cu s t h a t is eject ed
du r in g a cou gh
e x p ir a t io n : t h e pr ocess of r em ovin g ca r bon dioxide
ou t of t h e body t h r ou gh t h e lu n gs
e x p r e s s iv it y : t h e eviden ce of t h e gen e in t h e
ph en ot ype
e x t e r n a l a n a l s p h in c t e r : skelet a l m u scle
su r r ou n din g t h e in t er n a l r ect a l sph in ct er ;
in n er va t ed by t h e pu den da l n er ve of t h e som a t ic
n er vou s syst em ; pr ovidin g volu n t a r y con t r ol of
defeca t ion
e x t e r n a l a u d it o r y m e a t u s : open in g of t h e ea r
ca n a l
e x t e r n a l u r e t h r a l s p h in c t e r : skelet a l m u scle of
t h e bla dder n eck; a llows for volu n t a r y r elea se of
u r in e; in n er va t ed by t h e pu den da l n er ve
e x t r a c e llu la r c o m p a r t m e n t : body flu id in t h e
in t er st it ia l t issu e a n d pla sm a ou t side t h e cells;
con t a in s t wo-t h ir ds of t h e body wa t er ; a ccou n t s
for 40% of body weigh t
e x t r a c e llu la r m a t r ix : (E CM) t h e la yer s of
a r ch it ect u r a l st r u ct u r es t h a t su ppor t t h e cells
e x t r a c o r p o r e a l s h o c k w a v e lit h o t r ip s y (E S WL ):
pr ocedu r e of r en a l ca lcu li r em ova l in volvin g
a cou st ic sh ock wa ves t o br ea k u p t h e st on e;
t h e m ost com m on pr ocedu r e for kidn ey st on e
r em ova l
e x t r a p y r a m id a l d is o r d e r s : m ovem en t disor der s
a ffect in g t h e st r u ct u r es of t h e ba sa l ga n glia ,
su bst a n t ia n igr a , a n d su bt h a la m ic n u cleu s
e x t r a p y r a m id a l s y s t e m : n er vou s syst em ou t side
of t h e pyr a m ida l n er vou s syst em ; a t t en u a t ed
er r a t ic m ot ion s; m a in t a in s m u scle t on e a n d
t r u n k st a bilit y; com posed of t h e su bcor t ica l
n u clei of t h e ba sa l ga n glia
e x u d a t e : t h e wa t er y flu id wit h a h igh pr ot ein a n d
leu kocyt e con cen t r a t ion t h a t a ccu m u la t es a t t h e
sit e of in ju r y
e x u d a t iv e m a c u la r d e g e n e r a t io n : m a cu la r
degen er a t ion ch a r a ct er ized by t h e for m a t ion of
n ew blood vessels u n der t h e r et in a a n d m a cu la ,
kn own a s ch or oida l n eova scu la r iza t ion ; m a cu la r
da m a ge ca u sed by lea ka ge of flu id a n d bleedin g
fr om n ew vessels, a lt er in g t h e sh a pe of t h e
m a cu la a n d dist or t in g cen t r a l vision ; a lso kn own
a s wet m a cu la r degen er a t ion
a c ilit a t e d d i u s io n : a ssist ed m ovem en t of
su bst a n ces a cr oss t h e cell m em br a n e; n ot en er gy
depen den t
a c u lt a t iv e p a r a s it e s : m icr oor ga n ism s t h a t
m a y live on t h e h ost bu t ca n a lso su r vive
in depen den t ly
a m ilia l t e n d e n c y : pr opa ga t ion of a con dit ion
a m on g fa m ily m em ber s
e e d b a c k m e c h a n is m : r egu la t or y m ech a n ism ;
r espon se of in pu t t o a syst em by gen er a t ion of
ou t pu t in a given syst em

e t a l a lc o h o l s y n d r o m e (F AS ): con dit ion
r esu lt in g fr om exposu r e of a fet u s t o a lcoh ol;
ch a r a ct er ized by m en t a l h a n dica p, gr owt h deficit ,
a n d ph ysica l disa bilit y
ib r illa t io n : a pr oblem of t h e h ea r t ch a m ber
vibr a t in g in st ea d of effect ively pu m pin g
ib r in o ly s is : t h e dissolu t ion of blood clot s
ib r o b la s t s : cells t h a t pr odu ce a n d r epla ce
t h e con n ect ive t issu e la yer t o su ppor t t h e
con st r u ct ive ph a se of wou n d h ea lin g
ilt r a t io n p r e s s u r e : t h e for ce t h a t pr om ot es
m ovem en t of flu id a cr oss a pr essu r e gr a dien t
is t u la : a n a bn or m a l t r a ck or pa ssa ge t h a t
for m s bet ween t wo segm en t s of bowel or ot h er
epit h elia l t issu e
la c c id : r ela xed, wit h ou t t on e
o r c e d e x p ir a t o r y v o lu m e in 1 s e c o n d (F E V1):
t h e m a xim a l a m ou n t of a ir expir ed fr om t h e
lu n gs in 1 secon d
o r c e d v it a l c a p a c it y (F VC ): t h e m a xim a l
a m ou n t of a ir t h a t is exh a led fr om t h e lu n gs
du r in g a for ced exh a la t ion
o v e a : a r ea in t h e cen t er of t h e m a cu la wit h t h e
h igh est den sit y of con es
r a n k : visible blood in t h e st ool
r e e r a d ic a l in ju r y : da m a ge t o cells r esu lt in g
fr om r ea ct ive oxygen species
r e e r a d ic a l t h e o r y : st och a st ic t h eor y of a gin g
su ggest in g t h a t in t r a cellu la r pr odu ct ion of
r ea ct ive oxygen species (ROS) con t r ibu t es t o t h e
fin a l det er m in a t ion of life spa n
r ia b ilit y : a st a t e wh er e t issu e r ea dily bleeds
u ll-t h ic k n e s s b u r n s : for m er ly kn own a s t h ir d-
degr ee bu r n s; bu r n s t h a t da m a ge t h e epider m is,
der m is, a n d ca n pen et r a t e su bcu t a n eou s la yer s
a s well
u lly s a t u r a t e d : a st a t e in wh ich a ll of t h e
a va ila ble sea t s for h em oglobin m olecu les a r e
occu pied on t h e r ed blood cell
u lm in a n t h e p a t it is : liver fa ilu r e fr om sever e
a cu t e h epa t it is
u n c t io n : t h e a ct ion or wor kin gs of t h e va r iou s
pr oper t ies of t h e body
u n c t io n a l e le c t r ic a l s t im u la t io n (F E S ):
t ech n iqu e u sed t o gen er a t e a r t ificia l a u t on om ic
r eflexes t o pr om ot e m ech a n ism s r egu la t in g
bowel a n d bla dder fu n ct ion
u n c t io n a l in c o n t in e n c e : u n in t en t ion a l loss of
u r in e; ch a r a ct er ized by n or m a l bla dder con t r ol
cou pled wit h a n im pa ir ed a bilit y t o t r a n spor t t o
t oilet fa cilit ies
u n c t io n a l n o n r e t e n t iv e s o ilin g : volu n t a r y or
in volu n t a r y eva cu a t ion of st ool; occu r s in t h e
a bsen ce of a n a ppr opr ia t e t oilet in g sit u a t ion ;
oft en r esu lt s fr om r esist a n t beh a vior s in t h e
ch ild or in effect ive t oilet -t r a in in g m a n a gem en t
st r a t egies
Glossa r y 535
g a m e t e : ova a n d sper m ; con t a in s on ly on e of
t h e ch r om osom e pa ir s, kn own a s t h e h a ploid
n u m ber
g a n g lio n : collect ion of n er ve cell bodies in t h e
per iph er a l n er vou s syst em
g a p ju n c t io n : in t er cellu la r ju n ct ion s wit h 2-n m
ga ps ch a r a ct er ized by en h a n ced cell-t o-cell
com m u n ica t ion
g a s t r it is : a n in fla m m a t or y con dit ion of t h e ga st r ic
m u cosa of t h e st om a ch
g a t e c o n t r o l t h e o r y : m odifica t ion of t h e
specificit y t h eor y; st im u la t ion of t h e la r ge t ype A
bet a a n d a lph a in h ibit or y fiber s “close t h e ga t e,”
pr even t in g cr ossover a n d in h ibit in g pa in im pu lse
con du ct ion a lon g t ype A delt a a n d t ype C fiber s,
dim in ish in g pa in per cept ion
g e n e a m p li ic a t io n : a pr ocess of a lt er in g
ch r om osom es by a cceler a t in g t h e r eplica t ion a n d
n u m ber of copies of a gen e
g e n e r a l a d a p t a t io n s y n d r o m e : a t er m u sed
t o descr ibe t h e n eu r oen docr in e r espon se t o
a st r essor a n d t h e cor r espon din g ph ysiologic
ch a n ges
g e n e r a lize d a n x ie t y d is o r d e r (G AD ):
a con dit ion ch a r a ct er ized by excessive,
u n con t r olla ble, a n d ir r a t ion a l wor r y la st in g
gr ea t er t h a n 6 m on t h s
g e n e s : in dividu a l u n it s of in h er it a n ce loca t ed
on t h e ch r om osom es; det er m in e cell pr ot ein
ch a r a ct er ist ics
g e n e t ic c o d e : h er edit a r y u n it s con t a in in g
in for m a t ion for t h e pr odu ct ion of pr ot ein s
g e n o m ic im p r in t in g : a n epigen et ic ph en om en on ;
m ech a n ism t h a t con t r ols expr ession of gen es
ba sed on pa r en t a l or igin
g e n o m ic s : st u dy of t h e h u m a n gen om e; in clu des
t h e fu n ct ion s a n d in t er a ct ion s of a ll gen es
com pr isin g a n in dividu a l
g e n o t y p e : gen et ic m a keu p of a n in dividu a l
G h o n c o m p le x : a com bin a t ion of t h e Gh on focu s
a n d a ddit ion a l gr a n u lom a s t h a t develop t h r ou gh
t h e lym ph ch a n n els in t h e lu n gs
G h o n o c u s : t h e for m a t ion of a gr a n u lom a , or
wa lled-off a r ea of ba ct er ia , wh ich is con sider ed
t h e pr im a r y lu n g lesion in t u ber cu losis
g ia n t c e lls : ph a gocyt es t h a t ca n en gu lf pa r t icles
m u ch la r ger t h a n t h e t ypica l m a cr oph a ge
g ig a n t is m : con dit ion of h yper pla sia ch a r a ct er ized
by excessive gr owt h ; gr owt h h or m on e excess
befor e t h e closu r e of t h e epiph ysea l gr owt h
pla t es of t h e lon g bon es
g lia : n eu r a l su ppor t cells in t h e br a in ; pr ovide
su ppor t a n d n u t r it ion , m a in t a in h om eost a sis,
a n d for m m yelin
g lo b a l is c h e m ia : con sequ en ces of in a dequ a t e
blood su pply t o m eet t h e n eeds of t h e br a in
t issu e; r esu lt s in h ypoxia
536 Glossa r y
g lo m e r u lu s : ca pilla r y n et wor k of t h e n eph r on ;
loca t ed in t h e r en a l cor t ex; pr odu ces ea r ly
u r in a r y filt r a t e
g lu t a m a t e : excit a t or y n eu r ot r a n sm it t er
g lu t e n s : specific pr ot ein s fou n d in wh ea t , r ye, a n d
ba r ley
g ly c o lip id : su ga r bou n d t o lipid h ea ds of t h e
pla sm a m em br a n e
g ly c o p r o t e in s : r egu la t e cell m ovem en t a cr oss
t h e m a t r ix, pr ovide a pla ce for a t t a ch m en t of
t h e cells t o t h e m a t r ix, a n d pr om pt t h e cells t o
fu n ct ion
g ly c o s y la t e d h e m o g lo b in (H b A 1c ): a blood
t est t h a t depict s h em oglobin a n d r ed blood cell
exposu r e t o glu cose over t h e pr eviou s 3 t o 4
m on t h s
g o it e r : a n en la r gem en t of t h e t h yr oid gla n d
ca u sed by follicu la r epit h elia l h yper pla sia fr om
excessive t h yr oid h or m on e exposu r e
G o lg i a p p a r a t u s : cellu la r or ga n elle wit h a
m em br a n ou s st r u ct u r e; pr epa r es su bst a n ces by
t h e en dopla sm ic r et icu lu m for secr et ion ou t of
t h e cell
g r a d in g : a pr ocess of differ en t ia t in g t h e level of
a n a pla sia depict ed by t h e t u m or
g r a t v e r s u s h o s t d is e a s e (G VH D ): a con dit ion in
wh ich t r a n spla n t ed don or T lym ph ocyt es m ou n t
a n im m u n e r espon se a ga in st t h e h ost
g r a m -n e g a t iv e : ba ct er ia wit h cell wa lls t h a t
do n ot r et a in a da r k blu e color wh en Gr a m
st a in is a pplied a n d in st ea d t u r n r ed wh en
cou n t er st a in ed in t h e la bor a t or y
g r a m -p o s it iv e : ba ct er ia wit h cell wa lls t h a t
pr eser ve t h e Gr a m st a in a n d t u r n da r k blu e in
t h e la bor a t or y
g r a n u la t io n t is s u e : con n ect ive t issu e
ch a r a ct er ized by ext en sive m a cr oph a ges a n d
fibr obla st s a n d t h e pr om ot ion of a n giogen esis
g r a n u lo c y t e s : ph a gocyt ic cells n a m ed for t h e
cyt opla sm ic gr a n u les com m on t o a ll t ypes;
polym or ph on u clea r leu kocyt es, in clu din g
n eu t r oph ils, eosin oph ils, a n d ba soph ils
g r a n u lo m a s : n odu la r in fla m m a t or y lesion s t h a t
en ca se h a r m fu l su bst a n ces
G r a v e s d is e a s e : a n a u t oim m u n e con dit ion t h a t
ca u ses excessive st im u la t ion of t h e t h yr oid gla n d
g r a y m a t t e r : t issu e of t h e cen t r a l n er vou s syst em
com posed pr im a r ily of cell bodies; con t a in s
syn a pses bet ween sen sor y n eu r on s, m ot or
n eu r on s, a n d in t er n eu r on s
g u s t a t io n : t h e sen sa t ion of t a st e
g ly c e r o l t e s t : dia gn ost ic t est u sed t o iden t ify in n er
ea r volu m e excess t ypica lly seen in Mén ièr e
disea se
g y r i: ir r egu la r con volu t ion s on t h e br a in su r fa ce
h a p lo id : cells con t a in in g sin gle ch r om osom es,
r a t h er t h a n pa ir s; ch r om osom e n u m ber t ot a ls 23
(22 a u t osom es, 1 sex ch r om osom e); ch a r a ct er ist ic
of ga m et es
h a u s t r a : pou ch es bet ween t a en ia coli in t h e la r ge
in t est in e
h e a lt h : t h e con dit ion of bein g sou n d in body, m in d,
a n d spir it
h e a r t b lo c k : t h e obst r u ct ion of ca r dia c con du ct ion ,
oft en a t t h e a t r ioven t r icu la r n ode, lea din g t o
h ea r t dysr h yt h m ia s
h e a r t a ilu r e : r eflect s a n in a dequ a cy of h ea r t
pu m pin g so t h a t t h e h ea r t fa ils t o m a in t a in t h e
cir cu la t ion of blood
h e a r t r a t e : t h e n u m ber of h ea r t bea t s t h a t occu r in
1 m in u t e
h e lp e r T ly m p h o c y t e : su bset of T lym ph ocyt e
t h a t en h a n ce h u m or a l a n d cell-m edia t ed
r espon ses of t h e im m u n e syst em
h e m a t o m a : la r ger a ccu m u la t ion s of blood in t h e
t issu e
h e m a t u r ia : blood in t h e u r in e
h e m ip le g ia : in volvin g on e a r m a n d on e leg on t h e
sa m e side of t h e body
h e m o d ia ly s is : t r ea t m en t u sin g specia l filt er s t o
r em ove wa st es t h a t t h e kidn eys n o lon ger ca n
do on t h eir own t h r ou gh t h e m ech a n ism s of
diffu sion , osm osis, a n d u lt r a filt r a t ion
h e m o g lo b in A (H b A): a du lt for m of h em oglobin
h e m o g lo b in F (H b F ): fet a l for m of h em oglobin
h e m o g lo b in S (H b S ): sickled for m of h em oglobin
h e m o ly s is : br ea kdown of r ed blood cells
h e m o ly t ic : dest r u ct ion of blood cells
h e m o p t y s is : cou gh in g u p blood fr om t h e
r espir a t or y t r a ct ; defin ed by t h e pr esen ce of r ed
blood cells in t h e spu t u m
h e m or r h a ge : the loss of blood through the vessel wall
h e p a t ic s t e a t o s is : fa t t y liver
h e p a t o m e g a ly : en la r ged liver
h e p a t o r e n a l s y n d r o m e : r en a l fa ilu r e ca u sed by
sever e r en a l va socon st r ict ion in pa t ien t s wit h
liver disea se
h e r e d it y : pa ssa ge of ch a r a ct er ist ics fr om pa r en t t o
offspr in g
H e r t z (H z): u n it m ea su r em en t of fr equ en cy;
equ iva len t t o on e cycle per secon d
h e t e r o zy g o u s : differ en t a lleles on ea ch
ch r om osom e
h e t e r o p la s m y : r a n dom dist r ibu t ion of gen es
lea din g t o a va r ia ble dist r ibu t ion in t issu es
h ir s u t is m : a con dit ion of excessive body a n d fa cia l
h a ir
h is t o lo g y : a br a n ch of a n a t om y t h a t dea ls wit h t h e
m in u t e st r u ct u r e of cells a n d t issu es, wh ich a r e
discer n ible wit h a m icr oscope
H o d g k in ly m p h o m a : a m a lign a n t disor der of
t h e lym ph oid t issu e oft en ch a r a ct er ized by t h e
pa in less, pr ogr essive en la r gem en t of cer vica l
(n eck) lym ph n odes

H o m a n s s ig n : a t est of foot dor siflexion , wh ich ,
in t h e pr esen ce of deep vein t h r om bosis, ca u ses
pa in in t h e ba ck of t h e lower leg
h o m e o s t a s is : a dyn a m ic st ea dy st a t e m a r ked by
a ppr opr ia t e r egu la t or y r espon ses in t h e body
h o m o zy g o u s : iden t ica l a lleles on ea ch
ch r om osom e
h o r m o n e s : ch em ica l su bst a n ces, for m ed in a
t issu e or or ga n a n d ca r r ied in t h e blood, t h a t
st im u la t e or in h ibit t h e gr owt h or fu n ct ion of
ot h er t issu es or or ga n s
h o s t : t h e in dividu a l wh o is exposed t o a n d
con t r a ct s a n in fect ion
h u m a n im m u n o d e ic ie n c y v ir u s (H I V):
en veloped r et r ovir u s t h a t in fect s CD4 T
cells, den dr it ic cells, a n d m a cr oph a ges; vir u s
a ssocia t ed wit h t h e secon da r y im m u n odeficien cy,
a cqu ir ed im m u n odeficien cy syn dr om e (AIDS)
h u m a n le u k o c y t e a n t ig e n s (H L As ): t h e m a jor
h ist ocom pa t ibilit y com plex pr ot ein s in h u m a n s;
H LA gen es en code a n t igen specificit y; im por t a n t
in t r a n spla n t r eject ion
h u m a n p a p illo m a v ir u s (H P V): DNA vir u s;
specific vir a l st r a in s ca u se cu t a n eou s a n d gen it a l
wa r t s a n d sever e cer vica l in t r a epit h elia l lesion s
h u m o r a l im m u n it y : a da pt ive im m u n it y in volvin g
a n t ibodies
H u t c h in s o n –G il o r d p r o g e r ia : syn dr om e
com m on ly ch a r a ct er ized by a cceler a t ed a gin g;
r esu lt s fr om da m a ge t o t h e LMNA gen e t h a t
codes for t h e pr ot ein la m in A
h y d r o p h ilic : possessin g a ffin it y t o wa t er
h y d r o p h o b ic : la ckin g a ffin it y t o wa t er
h y d r o s t a t ic o r c e s : for ce pr om ot in g flu id
m ovem en t bet ween ext r a cellu la r com pa r t m en t s;
pr om ot es m ovem en t of flu id ba sed on t h e
pr essu r e gr a dien t ; a lso kn own a s filt r a t ion
pr essu r e
h y d r o u r e t e r : a ccu m u la t ion of flu id in t h e u r in a r y
u r et er ; r epr esen t s a con sequ en ce of com plet e
u r et er a l obst r u ct ion
h y g r o m a : cyst ic st r u ct u r e con t a in in g ser ou s flu id
h y p e r a c u t e g r a t r e je c t io n : r a pid r eject ion of
gr a ft s
h y p e r c a lc e m ia : blood ca lciu m levels gr ea t er t h a n
10.5 m g/dL
h y p e r c a p n ia : a st a t e of in cr ea sed ca r bon dioxide
in t h e blood
h y p e r c h lo r e m ia : blood ch lor ide levels gr ea t er
t h a n 108 m E q/L
h y p e r g ly c e m ia : a n eleva t ion in t h e blood glu cose
level
h y p e r k a le m ia : pot a ssiu m blood levels gr ea t er
t h a n 5 m E q/L
h y p e r k e t o n e m ia : a con dit ion of eleva t ed
cir cu la t in g ket on es t h a t r esu lt s fr om a loss of
in su lin , wh ich is a n in h ibit or of lipolysis
Glossa r y 537
h y p e r la c t a t e m ia : eleva t ion of la ct ic a cid in t h e
blood
h y p e r m a g n e s e m ia : m a gn esiu m levels gr ea t er
t h a n 2.5 m E q/L
h y p e r n a t r e m ia : gr ea t er t h a n 145 m E q/L of
sodiu m in t h e blood
h y p e r o p ia : er r or in r efr a ct ion com m on ly r efer r ed
t o a s fa r sigh t edn ess
h y p e r p h o s p h a t e m ia : blood ph osph a t e levels
gr ea t er t h a n 4.5 m g/dL
h y p e r p it u it a r is m : a gen er ic t er m in dica t in g t h e
in cr ea sed secr et ion of on e or m or e pit u it a r y
h or m on es
h y p e r p la s ia : in cr ea se in t h e n u m ber of cells
h y p e r p o la r iza t io n : wh en t h e r est in g m em br a n e
pot en t ia l is less n ega t ive t h a n n or m a l
h yp e r t e n sion : an elevation in blood pressure
commonly defined by a systolic pressure above
140 mm Hg or a diastolic pressure above 90 mm Hg
h y p e r t h y r o id is m : a st a t e of excessive t h yr oid
h or m on e a s a r esu lt of excessive st im u la t ion of
t h e t h yr oid gla n d, disea ses of t h e t h yr oid gla n d,
or excess pr odu ct ion of t h yr oid-st im u la t in g
h or m on e by a pit u it a r y a den om a
h y p e r t o n ic : solu t ion s h a vin g a gr ea t er osm ola lit y
t h a n t h e in t r a cellu la r flu id
h y p e r t r o p h y : in cr ea se in cell size
h y p e r v o le m ia : excessive in cr ea se of flu id in t h e
ext r a cellu la r com pa r t m en t
h y p h a e : t u bu la r br a n ch es for m ed by m old colon ies
h y p o c a lc e m ia : ca lciu m blood levels of less t h a n
8.5 m g/dL
h y p o c h lo r e m ia : blood ch lor ide levels of less t h a n
98 m E q/L
h y p o c h r o m ic : in dica t es pa le r ed blood cells on
m icr oscopic exa m in a t ion
h y p o g ly c e m ia : low blood glu cose levels
h y p o k a le m ia : pot a ssiu m blood levels of less t h a n
3.5 m E q/L
h y p o m a g n e s e m ia : m a gn esiu m blood levels of less
t h a n 1.5 m E q/L
h y p o m a n ia : st a t e wh er e people a r e en er get ic,
excit a ble, a n d h yper a ct ive, a n d m a y be h igh ly
pr odu ct ive
h y p o n a t r e m ia : less t h a n 135 m E q/L of sodiu m in
t h e blood
h y p o p a r a t h y r o id is m : less t h a n 10 pg/dL
pa r a t h yr oid h or m on e in t h e blood
h y p o p h o s p h a t e m ia : blood ph osph a t e levels less
t h a n 2.5 m g/dL
h y p o p it u it a r is m : a gen er ic t er m in dica t in g t h e
decr ea sed secr et ion of on e or m or e pit u it a r y
h or m on es
h y p o p o la r iza t io n : wh en t h e r est in g m em br a n e
pot en t ia l is m or e n ega t ive t h a n n or m a l
h y p o t e n s io n : a con dit ion of r edu ced blood
pr essu r e
538 Glossa r y
h y p o t h a la m ic –p it u it a r y a x is : t h e n eu r on a l
syst em t h a t r egu la t es h or m on e secr et ion a n d
in h ibit ion
h y p o t h y r o id is m : a st a t e of deficien t t h yr oid
h or m on e
h y p o t o n ic : solu t ion s h a vin g a lower osm ola lit y
t h a n t h e in t er cellu la r flu id
h y p o v o le m ia : decr ea sed va scu la r volu m e
h y p o v o le m ic s h o c k : t h e r esu lt of in a dequ a t e
blood/pla sm a volu m e
h y p o x e m ia : decr ea sed oxygen in t h e a r t er ia l blood
lea din g t o a decr ea se in t h e pa r t ia l pr essu r e of
oxygen (Pa O 2 )
h y p o x ia : cellu la r depr iva t ion of oxygen
ia t r o g e n ic : t h e t er m u sed t o descr ibe illn esses t h a t
a r e t h e in a dver t en t r esu lt of m edica l t r ea t m en t
ic t e r ic p h a s e : a st a ge of liver disea se m a r ked by
ja u n dice
id io p a t h ic : descr ibes a con dit ion t h a t does n ot
h a ve a clea r et iology
illn e s s : a st a t e t h a t r esu lt s in su ffer in g or dist r ess
im m u n e r e s p o n s e : t h e t h ir d lin e of defen se, wh ich
wa ges a specific defen se m ech a n ism t a r get ed a t
cer t a in h a r m fu l in va der s in t h e body
im m u n e s e n e s c e n c e : pr ogr essive dysfu n ct ion
of t h e im m u n e syst em a ssocia t ed wit h a gin g;
ch a r a ct er ized by bot h dim in ish ed a n d en h a n ced
im m u n e r espon ses
im m u n it y : pr ocess con fer r in g pr ot ect ion a ga in st
disea se; in clu des a ct ive a n d pa ssive
im m u n o d e ic ie n c y : con dit ion r esu lt in g fr om a n
in a dequ a t e im m u n e defen se; m a y be pr im a r y
(dir ect ly ca u sed by a n a lt er a t ion in im m u n it y)
or secon da r y (a con sequ en ce of a n ot h er disea se
pr ocess)
im m u n o g lo b u lin s (I g ): a gr ou p of st r u ct u r a lly
r ela t ed pr ot ein s im por t a n t in im m u n e fu n ct ion ;
com posed of a va r ia ble r egion pr om ot in g a n t igen
specificit y a n d a con st a n t r egion ; cla ssifica t ion s
in clu de IgG, IgA, IgM, IgD, a n d IgE
im m u n o lo g ic m e m o r y : pr ocess by wh ich m em or y
cells r espon d m u ch m or e r a pidly wh en r eexposed
t o t h e sa m e a n t igen ; dr a m a t ica lly sh or t en s a n d
in t en sifies t h e im m u n ologic r espon se
im m u n o lo g ic t h e o r y o a g in g : developm en t a l
t h eor y of a gin g a ssocia t ed wit h r edu ced
r esist a n ce t o disea se secon da r y t o r edu ced
T-cell fu n ct ion a n d en h a n ced a u t oim m u n e
r espon ses
im m u n o lo g y : st u dy of t h e st r u ct u r e a n d fu n ct ion
of t h e im m u n e syst em a s well a s t h e ph en om en a
of im m u n it y-in du ced sen sit ivit y a n d a ller gy
im m u n o t h e r a p y : u se of va ccin es t o st im u la t e t h e
im m u n e syst em t o a t t a ck a n t igen s a ssocia t ed
wit h disea se
in c id e n c e : t h e r a t e of occu r r en ce of a h ea lt h
con dit ion a t a n y given t im e
in c u s : on e of t h e t h r ee bon es com pr isin g t h e ossicle
of t h e ea r ; a lso kn own a s t h e a n vil
in a r c t : a n a r ea of n ecr osis r esu lt in g fr om a
su dden in su fficien cy of a r t er ia l or ven ou s blood
su pply
in a r c t io n : t h e pr ocess of obst r u ct in g a blood
vessel
in e c t io u s d is e a s e : a lso ca lled in fect ion ; a st a t e
of t issu e dest r u ct ion r esu lt in g fr om in va sion by
m icr oor ga n ism s
in e c t iv it y : t h e pr opor t ion of exposu r es n eeded
t o ca u se in fect ion in a n in dividu a l ba sed on
t h e pa t h ogen s’ a bilit y t o en t er, su r vive in , a n d
m u lt iply in t h e h ost
in e r t ilit y : t h e in a bilit y t o a ch ieve pr egn a n cy a ft er
1 yea r of u n pr ot ect ed in t er cou r se
in la m m a t o r y r e s p o n s e : t h e secon d lin e
of defen se, wh ich is a n on specific defen se
m ech a n ism t o pr ot ect fr om h a r m fu l in va der s a n d
t o pr epa r e a n in ju r y sit e for h ea lin g
in g e s t : pa r t icle en t r y in t o t h e cyt opla sm t h r ou gh
in cor por a t ion in t o a vesicle via a por t ion of t h e
cell m em br a n e
in h ib in : a h or m on e t h a t a ler t s t h e pit u it a r y gla n d
t o su ppr ess t h e secr et ion of gon a dot r opin s
in it ia t in g e v e n t : a sit u a t ion t h a t ca u ses a
m u t a t ion in a cell
in ju r y : a n y for m of da m a ge, h a r m , or loss t o t h e
cell, t issu e, or ga n , or or ga n syst em
in n a t e im m u n it y : r espon sible for ea r ly, r a pid
r espon se t o pa t h ogen s wit h ou t pr ior exposu r e
in s id io u s : gr a du a l in on set
in s p ir a t io n : t h e pr ocess of br ea t h in g in t o a cqu ir e
oxygen
in s u lin : a n a n a bolic h or m on e r equ ir ed for t h e
u pt a ke of glu cose by t h e m a n y cells, pa r t icu la r ly
t h ose of t h e liver, m u scle, a n d a dipose cells
in s u lin -lik e g r o w t h a c t o r 1 (I G F -1): h or m on e
secr et ed by t h e liver ; pr om ot es gr owt h in bon es,
ca r t ila ge, soft t issu es, a n d or ga n s
in t e g r a l p r o t e in : for m of t r a n sm em br a n e pr ot ein ;
for m s a ch a n n el in t h e pla sm a m em br a n e for
t r a n spor t of ion s
in t e r m it t e n t c la u d ic a t io n : a con dit ion of fa t igu e
or a ch in g in t h e leg m u scles even wh en wa lkin g
sh or t dist a n ces
in t e r n a l r e c t a l s p h in c t e r : t h ick la yer of sm oot h
m u scle a t t h e dist a l en d of t h e r ect u m ; pr ovides
t on ic con st r ict ion u n der sym pa t h et ic con t r ol
in t e r n a l u r e t h r a l s p h in c t e r : r in g of cir cu la r
sm oot h m u scle com pr isin g t h e bla dder n eck;
r ela xa t ion pr om ot es r elea se of u r in e fr om t h e
bla dder
in t e r n e u r o n : n eu r on s con n ect in g m ot or a n d
sen sor y n eu r on s; t r a n sm it sign a ls bet ween
a ffer en t a n d effer en t n eu r on s; m ost a bu n da n t
n eu r on t ype

in t e r v e n t r ic u la r o r a m e n : a r ea of pa ssa ge of t h e
cer ebr ospin a l flu id bet ween t h e la t er a l t o t h e
t h ir d ven t r icle; a lso kn own a s t h e for a m en of
Mon r o
in t r a c e llu la r c o m p a r t m e n t : flu id in side t h e cells;
con t a in s t wo-t h ir ds of t h e body wa t er, a ccou n t in g
for 40% of body weigh t
in t r a n e u r o n a l in c lu s io n s : dist in ct ive st r u ct u r es
for m ed in t h e n u cleu s or cyt opla sm
in t r in s ic e n t e r ic n e r v o u s s y s t e m : sou r ce of
in n er va t ion t o t h e ga st r oin t est in a l n er vou s
syst em
in t r o n : segm en t of DNA n ot in volved in pr ot ein
expr ession
in volu t ion : decrease in the size of tissues and organs
io n s : elect r ica lly ch a r ged pa r t icles r esu lt in g fr om
ga in or loss of on e or m or e elect r on s; n ega t ively
ch a r ged pa r t icles kn own a s a n ion s; posit ively
ch a r ged pa r t icles kn own a s ca t ion s
ir is : color ed pa r t of t h e eye
ir o n -d e ic ie n c y a n e m ia : a pr oblem of h em oglobin
a n d r ed blood cell developm en t ca u sed by
in a dequ a t e ir on st or es
ir r ig a t io n : pr ocess of r in sin g a n a r ea wit h flu id or
a ir
is c h e m ia : loca l r espon se t o decr ea se in blood
su pply
is le t s o L a n g e r h a n s : clu st er s of cells, loca t ed
t h r ou gh ou t t h e pa n cr ea s, t h a t a r e r espon sible for
t h e secr et ion of h or m on es
is o la v o n e : n on st er oida l est r ogen fou n d in h igh
con cen t r a t ion s in soy pr odu ct s; a lso kn own a s
ph yt oest r ogen s
is o la t e d s y s t o lic h y p e r t e n s io n : a n eleva t ion in
syst olic blood pr essu r e wit h ou t a n eleva t ion in
t h e dia st olic blood pr essu r e
is o t o n ic : solu t ion s wit h sa m e osm ola lit y a s t h e
in t r a cellu la r flu id
ja u n d ic e : t h e yellow-t in ged color of t h e skin a n d
scler a of t h e eyes in t h ose wit h liver disea se
k a r y o t y p e : pict u r e of a r r a n ged, pa ir ed, like
ch r om osom es in or der fr om la r gest t o sm a llest
k e lo id s : h yper t r oph ic sca r s t h a t r esu lt fr om
excessive colla gen pr odu ct ion a t t h e sit e of in ju r y
Ke r n ig s ig n : a t est u sed t o elicit m en in gea l pa in ;
t h e pa t ien t is pla ced su pin e wit h t h e kn ees
ben t a n d h ips flexed, on e kn ee is lift ed u pwa r d,
t h er eby elicit in g pa in
k e t o a c id o s is : a st a t e of m et a bolic a cidosis,
wh ich sign ifies t h a t t h e body is a ccessin g fa t
a n d pr ot ein sou r ces for en er gy a n d is r elea sin g
ket on es, wh ich a r e h igh ly a cidic, in t h e pr ocess
k in in s y s t e m : a ser ies of pot en t va soa ct ive
ch em ica l m edia t or s, su ch a s br a dykin in , t h a t
pla y a r ole in va sodila t ion , va socon st r ict ion , cell
m igr a t ion , t h e pa in r espon se, a n d t h e a ct iva t ion
of ot h er cells a ct ive in t h e in fla m m a t or y r espon se
Glossa r y 539
Ku p e r c e lls : ph a gocyt es h ou sed in t h e liver
Ku s s m a u l r e s p ir a t io n s : deep, r a pid r espir a t ion s
t h a t pr esen t a s a com pen sa t or y m ea su r e t o
r elea se excess a cids t h r ou gh t h e lu n gs a n d in t o
t h e a t m osph er e
k w a s h io r k o r : pr ot ein depr iva t ion in per son s
con su m in g a dequ a t e ca r boh ydr a t es
k y p h o s is : exa gger a t ed a n t er ior con ca ve cu r va t u r e
of t h e t h or a cic spin e a ssocia t ed wit h ost eopor osis
la b ile c e lls : t h ose t h a t con st a n t ly r egen er a t e
t h r ou gh m it osis, pa r t icu la r ly epit h elia l cells
of t h e skin , ga st r oin t est in a l t r a ct , a n d u r in a r y
t r a ct , a n d blood cells in t h e bon e m a r r ow
la b y r in t h it is : in fla m m a t ion of t h e la byr in t h of
t h e in n er ea r ; pr ecipit a t ion of sever e ver t igo a n d
sen sor in eu r a l h ea r in g loss
la c r im a l g la n d s : pr im a r y pr odu cer s of t ea r s
la c t e a l: lym ph a t ic ch a n n el wit h in ea ch sm a ll
in t est in a l villu s cr it ica l for t h e a bsor pt ion of fa t s
la c t ic a c id e m ia : eleva t ion of la ct ic a cid in t h e
blood
la c t ic a c id o s is : pH less t h a n 7.35 beca u se of
eleva t ion in la ct ic a cid in t h e blood
L a n g e r h a n s c e lls : im m a t u r e den dr it ic cells in t h e
skin ; ca r r y su r fa ce r ecept or s for im m u n oglobu lin
a n d com plem en t , im por t a n t in t h e im m u n e
r espon se
la n u g o : a fin e down y h a ir t h a t cover s t h e body in
som e pa t ien t s wit h a n or exia n er vosa
la r g e in t e s t in e /c o lo n : or ga n of t h e
ga st r oin t est in a l syst em ; com posed of t h e
cecu m , a ppen dix, colon , r ect u m , a n d a n a l ca n a l;
fu r t h er divided in t o t h e a scen din g t r a n sver se,
descen din g, a n d sigm oid por t ion s
la s e r -a s s is t e d in s it u k e r a t o m ile u s is (L AS I K):
su r gica l pr ocedu r e u sed t o t r ea t m yopia ,
h yper opia , a n d a st igm a t ism
la t e n c y : a per iod of dor m a n cy
le io m y o m a s : fibr ou s t u m or s of t h e u t er u s
le n s : eye st r u ct u r e r espon sible for fin e-t u n in g of
focu s
le u k o c y t e s : wh it e blood cells; a gr ou p of
cells a ct ive in defen din g t h e body a ga in st
m icr oor ga n ism s a n d in pr om ot in g a n im m u n e
r espon se
le u k o c y t o s is : a n eleva t ion in t h e wh it e blood cell,
or leu kocyt e, wit h a cou n t u su a lly a bove 10,000/
mm3
L e w y b o d y : pr ot ein a ggr ega t ion s com posed of
t h e pr ot ein a lph a -syn u clein loca t ed pr im a r ily
in t h e cells of t h e su bst a n t ia n igr a ; a ssocia t ed
wit h n eu r odegen er a t ive disea se, pa r t icu la r ly
Pa r kin son disea se
li e e x p e c t a n c y : t h e a ge a t wh ich 50% of a given
popu la t ion is expect ed t o su r vive
lig a n d s : m olecu les t h a t bin d t o specific r ecept or s;
in volved in sign a l t r a n sdu ct ion
540 Glossa r y
lim b ic s y s t e m : cir cu it s t h a t con n ect on e’s
cogn it ive a ct ivit y, expr ession of em ot ion s, a n d
beh a vior
lip id s : a gr ou p of su bst a n ces t h a t a r e r ich in
en er gy a n d in solu ble in wa t er
lip id b ila y e r : a n or ga n ized st r u ct u r e of t wo
in t er con n ect ed la yer s com posed of n on pola r
h ydr oph obic lipid t a ils con n ect ed t o pola r
h ydr oph ilic h ea ds
lip o u s c in : fa t t y br own lipid pigm en t ; in t r a cellu la r
deposit ion ca u ses st iffen in g or r igidit y of cellu la r
st r u ct u r e
lo c a l: r efer s t o t h ose m a n ifest a t ion s t h a t a r e
dir ect ly a t t h e sit e of illn ess, in ju r y, or in fect ion
a n d a r e con fin ed t o a specific a r ea
lo c a l m e d ia t o r s : su bst a n ces in volved in cellu la r
r espon ses in t h e im m edia t e a r ea
lo c a l s p r e a d : t h e pr olifer a t ion of t h e n eopla sm
wit h in t h e t issu e of or igin
lo o p d iu r e t ic s : dr u gs t h a t in cr ea se u r in e
pr odu ct ion t h r ou gh r edu ced r ea bsor pt ion of
sodiu m in t h e t h ick a scen din g loop of H en le,
ca u sin g a decr ea sed osm ola lit y in t h e in t er st it ia l
flu id of t h e collect in g du ct s a n d im pa ir in g t h e
a bilit y t o con cen t r a t e u r in e a t t h e loop
ly m p h lu id : filt r a t ion pr odu ct of ext r a cellu la r
flu id fr om t issu es
ly m p h n o d e : join ed segm en t of lym ph a t ic vessels
ly m p h a d e n it is : t h e en la r gem en t a n d
in fla m m a t ion of t h e n ea r by lym ph n odes, wh ich
ca n occu r a s a fu n ct ion of filt er in g or dr a in in g
h a r m fu l su bst a n ces a t t h e in ju r y sit e
ly m p h a d e n o p a t h y : swellin g or en la r gem en t of
t h e lym ph n odes
ly m p h a t ic s y s t e m : cir cu la t es lym ph ocyt es in
lym ph flu id; wor k in con cer t wit h t h e blood
vessels t o pr om ot e a n effect ive im m u n e r espon se
ly m p h e d e m a : obst r u ct ed lym ph flow wit h
m ovem en t of flu id in t o t h e in t er st it iu m
ly m p h o c y t e ig n o r a n c e : t h e pr ocess of con ver t in g
lym ph ocyt es fr om n on r espon sive t o self-r ea ct ive
ly m p h o id p r o g e n it o r : cellu la r or igin of n a t u r a l
killer cells, T a n d B lym ph ocyt es
ly s is : t h e br ea kdown a n d r em ova l of cells
ly s o s o m e s : cellu la r or ga n elle com posed of sm a ll
sa cs su r r ou n ded by m em br a n e; r espon sible for
h ydr olyt ic digest ion of cellu la r debr is
m a c e r a t io n : t h e soft en in g a n d br ea kin g down of
t issu e
m a c r o n u t r ie n t s : pr ot ein s, ca r boh ydr a t es, a n d fa t s
m a c r o p h a g e : la r ge, lon g-lived ph a gocyt ic
leu kocyt e fou n d wit h in body t issu es a ssocia t ed
wit h a pr olon ged in fla m m a t or y r espon se
m a c r o s c o p ic a n a ly s is : visu a l det er m in a t ion of
color a n d cla r it y
m a c u la : a r ea of t h e r et in a r espon sible for cen t r a l
vision , color vision , a n d fin e det a il
m a in s t r e a m s m o k e : a ct ive exposu r e t o sm oke
m a jo r d e p r e s s iv e d is o r d e r (MD D ): a con dit ion
ch a r a ct er ized by a per va sive a n d per sist en t low
m ood
m a jo r h is t o c o m p a t ib ilit y c o m p le x (MH C ):
m olecu les pr om ot in g r ecogn it ion of t h e body’s
“self” a n t igen s fr om for eign “n on self ” a n t igen s;
t r a p a n a n t igen wit h in t h e cell a n d t h en
t r a n spor t it t o t h e cell su r fa ce wh er e it ca n be
displa yed t o T cells; su bset s in clu de MH C cla ss I
a n d cla ss II m olecu les
m a jo r h is t o c o m p a t ib ilit y c o m p le x c la s s I
(MH C I ): su bset of MH C m olecu les r ecogn ized
by CD8 cyt ot oxic T cells
m a jo r h is t o c o m p a t ib ilit y c o m p le x c la s s I I
(MH C I I ): su bset of MH C m olecu les r ecogn ized
by CD4 h elper (T H 1 a n d T H 2) T cells
m a la b s o r p t io n : in dica t es a la ck of m ovem en t of
specific n u t r ien t s a cr oss t h e ga st r oin t est in a l
m u cosa
m a la b s o r p t io n s y n d r o m e : a con dit ion in wh ich
sever a l n u t r ien t s a r e n ot a dequ a t ely a bsor bed
m a la r : rash over cheeks; cha racteristic manifesta tion
of systemic lupus erythematosus (SLE)
m a lig n a n c y : in va sive a n d dest r u ct ive cellu la r
gr owt h , a s in ca n cer
m a lig n a n t : descr ibes t u m or s t h a t a r e in va sive,
dest r u ct ive, spr ea d t o ot h er sit es, a n d do n ot
r esem ble t h e t issu e of or igin
m a lle u s : on e of t h e t h r ee bon es com pr isin g t h e
ossicle of t h e ea r ; a lso kn own a s t h e h a m m er
m a ln u t r it io n : a st a t e of in a dequ a t e or excessive
exposu r e t o n u t r ien t s
m a n ia : a con dit ion wh er e a per son displa ys
er r a t ic a n d im pu lsive beh avior, r esu lt in g in poor
decision s, a n d r equ ir es ver y lit t le, if a n y, sleep
m a r a s m u s : a con dit ion of st a r va t ion r ela t ed t o
depr iva t ion of a ll food
m a s s m o v e m e n t s : st r on g per ist a lt ic m ovem en t s,
occu r r in g t h r ee t o fou r t im es a da y; pr om ot es t h e
pr opu lsion of st ool
m a s t c e lls : leu kocyt es t h a t a r e h ou sed t h r ou gh ou t
t h e body wit h in con n ect ive t issu e a n d n ea r a ll
blood vessels; t h ey a r e r espon sible for pr odu ct ion
a n d im m edia t e r elea se of ch em ica l m edia t or s
m a s t o id it is : ba ct er ia l in fect ion a n d in fla m m a t ion
of t h e a ir cells of t h e m a st oid bon e
m a t r ilin e a l: t r a n sm it t ed t h r ou gh fem a le or
m a t er n a l lin es
m e a n a r t e r ia l p r e s s u r e : a n a dequ a t e m ea su r e of
system ic: t issu e per fu sion ; is ca lcu la t ed a s on e-
t h ir d t h e pu lse pr essu r e plu s dia st olic pr essu r e
m e c h a n ic a l in ju r y : da m a ge ca u sed by im pa ct of a
body pa r t
Me c k e l d iv e r t ic u lu m : r a r e con gen it a l con dit ion
ch a r a ct er ized by t h e pr esen ce of a blin d pou ch in
t h e colon

m e c o n iu m : in fa n t ’s fir st st ool; r epr esen t s t h e
digest ion of a m n iot ic flu id a n d is st er ile, bla ck,
st icky, a n d odor less
m e io s is : pr ocess of sex cell (ga m et e) division ; cell
division r esu lt in g in ga m et ocyt es con t a in in g h a lf
(h a ploid) t h e n u m ber of ch r om osom es fou n d in a
som a t ic cell
Me is s n e r p le x u s : pa r t of t h e en t er ic n er vou s
syst em , loca t ed in t h e su bm u cosa of t h e la r ge
in t est in e; t r a n sm it s sen sor y im pu lses t h r ou gh
st r et ch r ecept or s
m e le n a : bla ck st ool in dica t ive of u pper
ga st r oin t est in a l bleedin g
m e m b r a n e a t t a c k c o m p le x (MAC ): a ca sca de of
even t s in t h e in fla m m a t or y pr ocess t h a t lea ds t o
cell lysis
m e m b r a n e p o r e : m em br a n e pa ssa ge bet ween t h e
ext r a cellu la r a n d in t r a cellu la r en vir on m en t
m e m b r a n e p o t e n t ia l: differ en ce in elect r ica l
ch a r ge bet ween t h e in side a n d ou t side of t h e cell
m e m o r y c e lls : differ en t ia t ed B cells ca pa ble of
r espon din g m u ch m or e r a pidly wh en r e-exposed
t o t h e sa m e a n t igen ; dr a m a t ica lly sh or t en in g
a n d in t en sifyin g t h e im m u n ologic r espon se
m e n a r c h e : t h e t im e of t h e fir st m en st r u a l per iod
Me n d e lia n p a t t e r n o in h e r it a n c e : pr edict a ble
t r a it t r a n sm ission ba sed on a u t osom a l dom in a n t
or r ecessive gen ot ypes
Mé n iè r e d is e a s e : con dit ion a ssocia t ed wit h
sever e ver t igo, sen sor in eu r a l h ea r in g loss, a n d
t in n it u s; r ela t ed t o over pr odu ct ion or decr ea sed
a bsor pt ion of en dolym ph
m e n in g e s : m em br a n es su r r ou n din g t h e br a in
a n d spin a l cor d of t h e cen t r a l n er vou s syst em ;
con t a in s cer ebr ospin a l flu id; in clu des t h e pia ,
a r a ch n oid, a n d du r a m a t er
m e n o m e t r o r r h a g ia : sh or t en ed m en st r u a l
in t er va l, h ea vy bleedin g
m e n o p a u s a l b o n e lo s s : r a pid ph a se of bon e loss
in wom en a ft er m en opa u se
m e n o p a u s e : per m a n en t cessa t ion of m en ses for a
12-m on t h per iod
m e n o r r h a g ia : excessive flow or pr olon ged
du r a t ion of m en ses wit h r egu la r m en st r u a l
in t er va l
m e s s e n g e r R N A (m R N A): t em pla t e for pr ot ein
syn t h esis; depen ds on a codon sequ en ce ba sed
on t h a t of t h e com plem en t a r y st r a n d of DNA
(cDNA); cyt opla sm ic a r ea wh er e pr ot ein is m a de
in a m in o a cid sequ en ces
m e t a b o lic a c id o s is : a lt er a t ion in a cid–ba se
ba la n ce ch a r a ct er ized by r edu ct ion of H CO 3 ,
pr om pt in g a n in cr ea se in pH
m e t a b o lic a lk a lo s is : a lt er a t ion in a cid–ba se
ba la n ce ch a r a ct er ized by in cr ea sed levels of
H CO 3 r esu lt in g in a decr ea se of pH
m e t a p la s ia : ch a n gin g of on e cell t ype t o a n ot h er
Glossa r y 541
m e t a s t a s e s : pr ocess t h a t occu r s wh en n eopla sm s
a r e spr ea d t o dist a n t sit es oft en by wa y of t h e
lym ph a t ics or blood vessels
m e t r o r r h a g ia : ir r egu la r m en st r u a l in t er va ls
m ic r o b io lo g y : a sect ion of biology dea lin g
specifica lly wit h t h e st u dy of m icr oscopic for m s
of life
m ic r o c y t ic : cells a r e sm a ll; t h e t er m m icr ocyt ic
is oft en u sed t o descr ibe sm a ll r ed blood cells in
cer t a in t ypes of a n em ia
m ic r o g lia l n o d u le s : st r u ct u r e for m ed by t h e
u n ion of m icr oglia a n d a st r ocyt es
m ic r o n u t r ie n t s : vit a m in s a n d m in er a ls
m ic r o s c o p ic a n a ly s is : a n a lysis of u r in e
com pon en t s u n der m a gn ifica t ion ; low-power
m a gn ifica t ion m a y det ect cr yst a ls, ca st s,
squ a m ou s cells, a n d ot h er la r ge com pon en t s;
wh it e a n d r ed blood cells a n d ba ct er ia l for m s
m a y be det ect ed wit h h igh -power m a gn ifica t ion
m ic r o s t im u la t io n : elect r ica l st im u la t ion t o
pr ega n glion ic n eu r on s a n d in t er n eu r on s
con t r ollin g bla dder fu n ct ion
m ic t u r it io n : pr ocess of u r in e elim in a t ion
m in e r a ls : in or ga n ic su bst a n ces cr it ica l t o t h e
r egu la t ion of h u n dr eds of cellu la r pr ocesses;
m in er a ls con st it u t e bon e, h em oglobin , en zym es,
h or m on es, a n d ch em ica l m edia t or s; ch a r ged
(ion ic) m in er a ls m edia t e im pu lse con du ct ion
wit h in t h e n er vou s syst em ; m in er a ls m a in t a in
wa t er ba la n ce, a cid–ba se ba la n ce, a n d osm ot ic
pr essu r e a n d a r e cr it ica l for m u scle con t r a ct ion
a n d for m t h e st r u ct u r a l com pon en t s of bon es a n d
t eet h
m it o c h o n d r ia : cellu la r or ga n elle con t a in in g
en zym es in volved in cit r ic a cid cycle, fa t t y
a cid oxida t ion , a n d oxida t ive ph osph or yla t ion ;
pr in cipa l pr odu cer of t h e cellu la r en er gy sou r ce
a den osin e t r iph osph a t e
m it o s is : pr ocess of r epr odu ct ion of n u clea r
ch r om osom es in som a t ic cells; r epr odu ct ive
ph a ses in clu de pr oph a se, pr om et a ph a se,
m et a ph a se, a n a ph a se, a n d t eloph a se; r esu lt s
in t h e cr ea t ion of da u gh t er cells wit h t h e sa m e
ch r om osom e n u m ber a n d gen et ic m a keu p a s t h e
cell of or igin
m ix e d h e a r in g lo s s : com bin a t ion of bot h
sen sor in eu r a l a n d con du ct ive h ea r in g loss
m o le c u la r m im ic r y : close r esem bla n ce bet ween
for eign a n t igen a n d self-a n t igen
m o ld : a m u lt icellu la r for m of fu n gu s
m o n o a m in e s : cla ss of n eu r ot r a n sm it t er s,
in clu din g n or epin eph r in e, dopa m in e, a n d
ser ot on in
m o n o c lo n a l o r ig in : t h e pr ocess of st a r t in g wit h a
sin gle m u t a t ed cell a n d developin g in t o ca n cer
m o n o c y t e : la r ge, m on on u clea r leu kocyt es
r epr esen t in g 3% t o 7% of t h e t ot a l n u m ber
542 Glossa r y
of cir cu la t in g leu kocyt es a ssocia t ed wit h a
pr olon ged in fla m m a t or y r espon se
m o n o n e u r o p a t h y : n er ve da m a ge lim it ed t o a
sin gle a r ea
m o n o s o m y : on e copy of a ch r om osom e, in pla ce of
t h e n or m a l pa ir ; t h e r esu lt of n on disju n ct u r e
m o o d : a n in t er n a l, su bject ive psych ologica l st a t e,
wh ich dir ect s h ow a per son feels a n d per ceives
t h e wor ld
m o r b id it y : a poor qu a lit y of life r esu lt in g fr om a
disea se
m o r p h o lo g y : a br a n ch of biology t h a t dea ls wit h
t h e for m a n d st r u ct u r e of a n im a ls a n d pla n t s;
looks m or e specifica lly a t h ow cells a n d t issu es
ch a n ge in for m a ft er en cou n t er in g disea se
m o r t a lit y : t h e dea t h r a t e r esu lt in g fr om a disea se
m o s a ic is m : com bin a t ion of cell lin es wit h r egu la r
a n d a lt er ed n u m ber s of ch r om osom es
m o t o r n e u r o n s : ca r r y im pu lses fr om t h e cen t r a l
n er vou s syst em t o a n effect or m u scle
m u lt i a c t o r ia l: h a vin g a n u m ber of even t s t h a t led
t o t h e developm en t of t h e con dit ion
m u t a t ion : cha nge in genes or sequ ence of ba se pa ir s
t ha t m a ke u p t he chr om osomes; genet ic a lt er a t ion
per pet ua t ed in subsequent cellula r divisions
m u t a t o r g e n e s : gen es t h a t r epa ir m u t a t ed DNA
a n d pr ot ect t h e gen om e
m y c e liu m : a clu st er of h yph a e for m ed fr om m old
colon ies
m y c o s e s : in fect ion s wit h fu n gi a s t h e pa t h ogen
m y e lo id p r o g e n it o r : or igin of im m u n e syst em
cells, in clu din g m on ocyt es, den dr it ic cells,
gr a n u locyt es, a n d m a st cells
m y e n t e r ic (Au e r b a c h ): p le x u s : pa r t of t h e
en t er ic n er vou s syst em ; fou n d bet ween t h e
lon git u din a l a n d cir cu la r m u scle la yer s of t h e
la r ge in t est in e; pr ovides in cr ea sed t on ic a n d
r h yt h m ic con t r a ct ion s
m y o c a r d ia l in a r c t io n : t h e t ot a l occlu sion of on e
or m or e cor on a r y a r t er ies r esu lt in g in isch em ia
a n d dea t h of m yoca r dia l t issu es
m y o c a r d iu m : t h e t h ick m u scu la r la yer of t h e
h ea r t
m y o a s c ia : ou t er m em br a n e of m u scle t issu e
m y o p ia : er r or in r efr a ct ion ; com m on ly kn own a s
n ea r sigh t edn ess
m y r in g o t o m y : in cision of t h e t ym pa n ic m em br a n e
t o dr a in flu id
m y x e d e m a : a con dit ion of h ypot h yr oidism m a r ked
by t h e a ccu m u la t ion of boggy, n on pit t in g
edem a t ou s t issu e, especia lly of t h e fa ce, m u cou s
m em br a n es, h a n ds, a n d feet , fr om pr ot ein –
ca r boh ydr a t e com plexes t h a t a ccu m u la t e in t h e
ext r a cellu la r m a t r ix a n d a t t r a ct flu id in t o t h e
t issu es
n a iv e ly m p h o c y t e s : lym ph ocyt es t h a t h a ve n ot
yet en cou n t er ed a n a n t igen
n a t u r a l k ille r c e lls : la r ge, gr a n u la r lym ph ocyt es;
n on specific cyt ot oxic cells
n e c r o s is : disor der ly pr ocess of cell dea t h
a ssocia t ed wit h in fla m m a t ion
n e g a t iv e e e d b a c k lo o p : a syst em of h or m on e
r egu la t ion in wh ich low levels of h or m on e
st im u la t e a ddit ion a l r elea se a n d h igh levels of
h or m on e in h ibit fu r t h er r elea se
n e o p la s ia : t h e ir r ever sible devia n t developm en t of
cells r esu lt in g in t h e for m a t ion of n eopla sm s
n e p h r o n : fu n ct ion a l u n it of t h e kidn ey; com posed
of t h e glom er u lu s, pr oxim a l t u bu le, loop of H en le,
dist a l t u bu le, a n d collect in g du ct ; r espon sible for
filt er in g wa t er-solu ble su bst a n ces fr om t h e blood,
r ea bsor pt ion of filt er ed n u t r ien t s, wa t er, a n d
elect r olyt es, a n d secr et ion of wa st e
n e p h r o p a t h y : a pr oblem of degen er a t ive ch a n ges
in sm a ll vessels in t h e kidn eys
n e u r o ib r illa r y t a n g le s : t wist ed, h elica l st r u ct u r e
of a ccu m u la t ed pr ot ein s, pr im a r ily in clu din g t a u ;
com m on ly a ssocia t ed wit h Alzh eim er disea se
n e u r o e n d o c r in e t h e o r y : developm en t a l t h eor y
of a gin g su ggest in g t h a t t h e in t er r ela t ion sh ip
bet ween n eu r on s a n d a ssocia t ed h or m on es
ser ves a s t h e st im u lu s for a gin g
n e u r o g e n ic : pa in or igin a t in g wit h in t h e n er vou s
syst em
n e u r o g e n ic s h o c k : a r esu lt of br a in or spin a l cor d
in ju r y in wh ich a lt er ed n eu r on a l t r a n sm ission
lea ds t o a loss of t en sion in t h e blood vessels,
a llowin g u n r egu la t ed va sodila t ion , decr ea sed
per iph er a l va scu la r r esist a n ce, a n d r edu ced
blood pr essu r e; oxygen a t ed blood is n ot: sh u n t ed
t o vit a l or ga n s, a n d per fu sion t o vit a l or ga n s is
r edu ced
n e u r o m a t r ix t h e o r y : m odifica t ion of t h e pa t t er n
t h eor y; a widely dist r ibu t ed n eu r a l n et wor k in
t h e br a in (body-self n eu r om a t r ix) con t a in in g
som a t osen sor y, lim bic, a n d t h a la m ocor t ica l
com pon en t s in t egr a t es m u lt iple sou r ces of in pu t
r esu lt in g in t h e cogn it ive, a ffect ive, a n d sen sor y
per cept ion s of pa in
n e u r o m o d u la t o r : ch em ica l r elea sed fr om a xon
t er m in a ls, wh ich in h ibit s, pot en t ia t es, or
pr olon gs effect s of n eu r ot r a n sm it t er
n e u r o n : n er ve cell; fu n da m en t a l u n it of t h e
n er vou s syst em ; com posed of a cell body, on e
a xon , a n d a va r ia ble n u m ber of den dr it es
n e u r o p a t h y : a pr oblem of n er ve degen er a t ion t o
da m a ge t o cell body r esu lt in g in dela yed n er ve
con du ct ion a n d im pa ir ed sen sor y fu n ct ion
n e u r o p a t h ic : pa in or igin a t in g wit h in t h e n er vou s
syst em
n e u r o p h a g ia : ph a gocyt osis a n d in fla m m a t or y
r espon ses ca u sed by a dea d n eu r on da m a gin g
n e u r o s t im u la t io n : elect r ica l st im u la t ion of
effer en t n er ves

n e u r o t r a n s m it t e r : ch em ica l a gen t a ffect in g t h e
fu n ct ion of a n ot h er n ea r by cell or cells
n e u t r a liza t io n : m a kin g in effect ive a n y a ct ion ,
pr ocess, or pot en t ia l
n e u t r o p h il: gr a n u locyt e pr esen t in t h e gr ea t est
n u m ber ; m ost im por t a n t in t h e r a pid r espon se
t o ba ct er ia l in fect ion ; ph a gocyt ic; t h e fir st
r espon der s in t h e in fla m m a t or y r espon se
N :-m e t h y l-D -a s p a r t a t e (N MD A) r e c e p t o r :
r ecept or wit h a ffin it y for glu t a m a t e
n o c ic e p t iv e : or igin a t ion of pa in ou t side of t h e
n er vou s syst em
n o c ic e p t o r : r ecept or gen er a t in g a pa in im pu lse
n o c t u r ia : fr equ en t u r in a t ion a t n igh t
n o d e s o R a n v ie r : in t er r u pt ion s in t h e m yelin
sh ea t h s su r r ou n din g a xon s in t h e per iph er a l
n er vou s syst em ; r ich in sodiu m ch a n n els t o
pr om ot e m ovem en t of n er ve im pu lses over lon g
dist a n ces
n o n d is ju n c t io n : fa ilu r e of ch r om osom e sepa r a t ion
du r in g m eiosis or m it osis; r esu lt s in a n u n equ a l
n u m ber of ch r om osom es
n o n c o m m u n ic a t in g h y d r o c e p h a lu s : in cr ea sed
ven t r icu la r a ccu m u la t ion of cer ebr ospin a l flu id
ca u sed by obst r u ct ed cer ebr ospin a l flu id flow
n on -H od gk in lym p h om a (NH L): a generic
classification ma de up of a broad range of B-cell
a nd T-cell malignancies within the immune system
n o n p o la r : com pou n d la ckin g posit ive or n ega t ive
ch a r ge
n o n s e l : pa r t icles t h a t a r e n ot pa r t of t h e
in dividu a l
n o n v o la t ile a c id : cir cu la t in g fixed a cid t h a t is
u n a ble t o be excr et ed by t h e lu n gs; r equ ir e
bu ffer in g a n d excr et ion by t h e kidn eys
n o s o c o m ia l: descr ibes illn esses t h a t a r e ca u sed by
exposu r e t o t h e h ea lt h ca r e en vir on m en t
n u c h a l r ig id it y : a h yper ext en ded st iff n eck
r ela t ed t o m en in gea l ir r it a t ion
n u c h a l t r a n s lu c e n c y : u lt r a sou n d det er m in a t ion
of t h ickn ess of t h e n a pe of t h e n eck
n u c le u s : r ou n ded m a ss of pr ot opla sm wit h in t h e
cyt opla sm of a cell; su r r ou n ded by a n u clea r
en velope en closin g st r u ct u r es r espon sible for
m it osis du r in g cell division
n u r s in g d ia g n o s e s : la bels dist in gu ish ed by a
focu s on t h e h u m a n r espon se t o t h e con dit ion
n u t r ie n t : a food or liqu id t h a t su pplies t h e body
wit h t h e ch em ica ls n eeded for m et a bolism
n u t r it io n : t h e pr ocess of in gest ion a n d u se of
n u t r ien t s for en er gy
n y s t a g m u s : in volu n t a r y, ir r egu la r oscilla t ion s of
t h e eye
o b e s it y : a st a t e of excessive body fa t in wh ich t h e
body m a ss in dex is gr ea t er t h a n 30 kg/m 2
o b lig a t e p a r a s it e s : pa r a sit es t h a t r equ ir e t h e h ost
for m et a bolism a n d r epr odu ct ion
Glossa r y 543
o c c lu s io n : blocka ge
o c c u lt : h idden blood in t h e st ool t h a t is n ot visible
o l a c t io n : sen se of sm ell
o lig o d e n d r o c y t e s : n eu r a l su ppor t cells
r espon sible for t h e pr odu ct ion of m yelin a r ou n d
t h e a xon s of t h e cen t r a l n er vou s syst em
o lig o m e n o r r h e a : decr ea sed fr equ en cy of
m en st r u a t ion
o lig u r ia : r edu ced u r in e ou t pu t
o n c o g e n e s : gen es t h a t code for pr ot ein s in volved
in cell gr owt h or r egu la t ion
o n c o g e n ic : ca n cer ca u sin g
o p e n t r a u m a t ic in ju r y : exposu r e of br a in
st r u ct u r es t o t h e en vir on m en t beca u se of in ju r y
o p p o r t u n is t ic p a t h o g e n s : t h ose t h a t ca u se
disea se on ly in a h ost wit h a com pr om ised
im m u n e syst em
o p s o n iza t io n : a pr ocess of r en der in g ba ct er ia
vu ln er a ble t o ph a gocyt osis
o r g a n : fu lly differ en t ia t ed body pa r t wit h
specia lized fu n ct ion s
o r g a n o C o r t i: sen sor y r ecept or in t h e coch lea
con t a in in g h a ir cells
o r g a n e lle s : st r u ct u r es wit h in a cell t h a t per for m a
dist in ct fu n ct ion
o r g a n o g e n e s is : em br yologic per iod of or ga n
developm en t
o r t h o p n e a : t h e ph ysica l n eed t o sit in a n u pr igh t
or st a n din g posit ion t o r edu ce r espir a t or y effor t
o s m o le : u n it of m ea su r e r eflect in g t h e osm ot ic
a ct ivit y t h a t n on diffu sible pa r t icles exer t in
pu llin g wa t er fr om on e side of t h e sem iper m ea ble
m em br a n e t o t h e ot h er
o s m o la lit y : osm ola r con cen t r a t ion in 1 kg of wa t er
(m Osm /kg of H 2 O); u sed t o descr ibe flu ids wit h in
t h e body
o s m o la r it y : osm ola r con cen t r a t ion in 1 L of
solu t ion (m Osm /L); u sed wh en r efer r in g t o flu ids
ou t side t h e body
o s m o r e c e p t o r s : sen sor y n eu r on s in t h e
h ypot h a la m u s t h a t pr om ot e t h ir st
o s m o s is : m ovem en t of wa t er a cr oss a con cen t r a t ion
gr a dien t ; wa t er m ovem en t t o a n a r ea of
h igh er con cen t r a t ion of pa r t icles (less wa t er
con t en t ) fr om a n a r ea of lower con cen t r a t ion of
pa r t icles (m or e wa t er con t en t ); r egu la t ed by t h e
con cen t r a t ion of pa r t icles t h a t do n ot diffu se
a cr oss t h e sem iper m ea ble m em br a n e
o s m o t ic p r e s s u r e : for ce gen er a t ed a s wa t er m oves
t h r ou gh t h e m em br a n e by osm osis
o s s ic le s : bon es of t h e m iddle ea r ; in clu de t h e
m a lleu s, in cu s, a n d st a pes
o s t e o m a : t u m or t h a t a r ises fr om bon e cells
o s t e o p e n ia : r edu ced ca lcifica t ion or skelet a l bon e
m a ss; pr ecu r sor t o ost eopor osis
o s t e o p o r o s is : con dit ion ch a r a ct er ized by
decr ea sed bon e m a ss a n d det er ior a t ion of bon e
544 Glossa r y
t issu e; a ssocia t ed wit h in cr ea sed bon e fr a gilit y
a n d su scept ibilit y t o fr a ct u r e
o t it is e x t e r n a : in fla m m a t ion of t h e skin of t h e
ext er n a l ea r ; com m on ly kn own a s “swim m er ’s
ea r ”
o t it is m e d ia : in fect ion of t h e m iddle ea r
o t o a c o u s t ic e m is s io n (O AE ): t est s u sed t o
eva lu a t e ou t er h a ir cell fu n ct ion
o t o s c le r o s is : a n a u t osom a l dom in a n t con dit ion
ca u sin g t h e m ost com m on ca u se of ch r on ic,
pr ogr essive, con du ct ive h ea r in g loss;
ch a r a ct er ized by im pa ir in g t h e con du ct ion of
vibr a t ion
o v a l w in d o w : m a r ks t h e bou n da r y bet ween t h e
m iddle ea r a n d t h e begin n in g poin t of t h e in n er
ea r
o v e r a c t iv e b la d d e r : in volu n t a r y lea ka ge of u r in e
t h a t is a ccom pa n ied or im m edia t ely pr eceded
by a st r on g u r ge t o void; a lso kn own a s u r ge
in con t in en ce
o v e r lo w in c o n t in e n c e : in con t in en ce r esu lt in g
fr om u r in e volu m es exceedin g bla dder ca pa cit y
o v e r n u t r it io n : a st a t e of excessive exposu r e t o
n u t r ien t s
o v e r w e ig h t : defin ed a s a body m a ss in dex bet ween
25 a n d 30 kg/m 2
o x id a t iv e s t r e s s : pot en t ia l sou r ce of cellu la r
da m a ge by exposu r e t o r ea ct ive oxygen species
o x y g e n r e e r a d ic a ls : a n oxygen a t om ca r r yin g a n
u n pa ir ed elect r on a n d n o ch a r ge
o x y g e n s a t u r a t io n (S a O 2 ): t h e a m ou n t
of oxyh em oglobin ; t h a t is, t h e a m ou n t of
h em oglobin t h a t is com bin ed, or sa t u r a t ed, wit h
oxygen
o x y h e m o g lo b in (H b O 2 ): t h e oxygen –h em oglobin
com bin a t ion wit h in r ed blood cells
P a C O 2 : t h e sym bol for t h e pa r t ia l pr essu r e of ca r bon
dioxide
P a O 2 : t h e sym bol for t h e pa r t ia l pr essu r e of oxygen
p a llia t iv e c a r e : u sed t o descr ibe t r ea t in g
sym pt om s, su ch a s pa in , wit h ou t cu r in g t h e
ca n cer
p a llid o t o m y : ir r ever sible pr ocedu r e in volvin g
dest r u ct ion of t h e globu s pa llidu s; design ed
t o decr ea se excit a t or y n er ve fir in g in t h e
da m a ged t issu e; em ployed in t h e m a n a gem en t of
Pa r kin son disea se
p a n c r e a t it is : in fla m m a t ion of t h e pa n cr ea s,
r esu lt in g in dest r u ct ion of t h e pa n cr ea s by
pa n cr ea t ic en zym es
p a n d e m ic : wh en a n epidem ic spr ea ds a cr oss
con t in en t s
p a n h y p o p it u it a r is m : a deficien cy of a ll a n t er ior
pit u it a r y h or m on es
p a n n u s : gr a n u la t ion t issu e t h a t for m s over t h e
in fla m ed syn oviu m a n d ca r t ila ge
p a p ille d e m a : edem a of t h e opt ic disc
p a p illo m a : a n epit h eliom a t h a t pr esen t s a s
fin ger like pr oject ion s
p a r a c e n t e s is : in ser t ion of a ca n n u la in t o t h e
per it on ea l ca vit y for r em ova l of a scit ic flu id
p a r a c r in e : h or m on e effect s r est r ict ed t o t h e loca l
en vir on m en t
p a r a n e o p la s t ic s y n d r o m e : h or m on a l, n eu r ologic,
h em a t ologic, a n d ch em ica l dist u r ba n ces in t h e
body n ot dir ect ly r ela t ed t o in va sion by t h e
pr im a r y t u m or or m et a st a sis
p a r a ly t ic ile u s : in a ct ive in t est in a l m u scles
pr odu cin g blocka ge or obst r u ct ion of t h e
in t est in e
p a r a s y m p a t h e t ic n e r v o u s s y s t e m (P N S ):
com pon en t of t h e a u t on om ic n er vou s syst em
p a r a t h y r o id h o r m o n e (P T H ): pr om ot es r em ova l
of ca lciu m a n d ph osph a t e fr om bon e; opposes t h e
effect s of ca lcit on in
p a r e n c h y m a l: t issu es wit h a specific fu n ct ion ,
su ch a s t issu es for m ed of n eu r on s, m yoca r dia l
cells, a n d epit h elia l cells
p a r e n t e r a l n u t r it io n : su pplem en t a l n u t r it ion
t h a t bypa sses t ypica l pr ocesses of ea t in g a n d
digest ion
p a r e s t h e s ia : a bn or m a l sen sa t ion , su ch a s bu r n in g,
pr ickin g, t icklin g, or t in glin g
p a r t ia l p r e s s u r e : t h e for ce exer t ed by ga s
m olecu les wit h in a cer t a in volu m e
p a s s iv e d i u s io n : a pr ocess of a bsor pt ion in
wh ich n u t r ien t s r a n dom ly m igr a t e a cr oss
t h e m u cosa fr om a r ea s of h igh er t o lower
con cen t r a t ion or pr essu r e
p a s s iv e s m o k e : en vir on m en t a l bypr odu ct fr om
t oba cco pr odu ct s u sed by ot h er s; a lso kn own a s
secon dh a n d sm oke
p a t h o g e n : a disea se-ca u sin g or ga n ism , su ch a s a
vir u s
p a t h o g e n e s is : t h e or igin a t ion a n d developm en t of
disea se or illn ess
p a t h o g e n ic d e e n s e m e c h a n is m s : t h e wa ys
in wh ich m a n y pa t h ogen s h a ve developed
wa ys t o a void dest r u ct ion by t h e h ost , su ch a s
t h r ou gh t h ick pr ot ect ive ca psu les, wh ich pr even t
ph a gocyt osis
p a t h o g e n ic it y : a bilit y of a pa t h ogen t o pr odu ce
a n in fect iou s disea se; in volve m u lt iple fa ct or s,
in clu din g t h e pa t h ogen ’s pot en cy, in va siven ess,
a bilit y t o eva de t h e im m u n e syst em , speed of
r eplica t ion , pr odu ct ion of t oxin s, a dh er en ce t o
t h e h u m a n h ost cell, a n d degr ee of t issu e da m a ge
t h a t is elicit ed
p a t h o lo g y : t h e st u dy of t h e st r u ct u r a l a n d
fu n ct ion a l ch a n ges in cells a n d t issu es a s a
r esu lt of in ju r y
p a t h op h ysiology: the physiology of altered health
states; specifically, the functional changes that
accompany a particular injury, syndrome, or disease

p a t t e r n t h e o r y : a gr ou p of t h eor ies t h a t su ggest
t h a t n on specific r ecept or s t r a n sm it specific
pa t t er n s in flu en ced by du r a t ion of pa in
sen sa t ion , qu a n t it y of t issu e in volved, a n d
su m m a t ion of im pu lses
p e n e t r a n c e : a bilit y of a gen e t o expr ess a
m u t a t ion ; in flu en ces t h e effect s of m u t a t ion s
p e r c u t a n e o u s n e p h r o lit h o t o m y : su r gica l
pr ocedu r e u sed for r em ova l of la r ge r en a l ca lcu li;
in volves loca t ion a n d r em ova l of st on e wit h a
n eph r oscope
p e r u s io n : t h e pr ocess of for cin g blood or ot h er
flu id t o flow t h r ou gh a vessel a n d in t o t h e
va scu la r bed of a t issu e for t h e pu r poses of
pr ovidin g oxygen a n d ot h er n u t r ien t s
p e r ic a r d it is : infla m ma tion of th e linin g of t he hea r t
p e r ic a r d iu m : t he ou t er coverin g of t he hea r t ,
which h olds t he h ea r t in pla ce in t he ch est cavit y,
cont a in s r ecept or s t ha t a ssist wit h th e r egula t ion
of blood pr essur e a nd hea r t r a t e, a nd for m s a fir st
lin e of defense a ga inst infect ion a nd infla m ma tion
p e r ily m p h : flu id fillin g t h e coch lea
p e r im e n o p a u s e : gr a du a l t r a n sit ion bet ween
n or m a l r epr odu ct ive cycles a n d m en opa u se; a lso
kn own a s clim a ct er ic
p e r ip h e r a l n e u r o p a t h y : disea se in volvin g t h e
n er ves of t h e per iph er a l n er vou s syst em
p e r ip h e r a l n e r v o u s s y s t e m : com pon en t of t h e
n er vou s syst em com pr isin g t h e som a t ic a n d
a u t on om ic n er vou s syst em
p e r ip h e r a l o r g a n s : sit es for m a in t en a n ce of t h e
lym ph ocyt es; a r e t h e or ga n s in wh ich im m u n e
r espon ses a r e oft en in it ia t ed; or ga n s in clu de
t h e spleen , lym ph n odes, a n d ot h er lym ph oid
m u cosa l t issu e, su ch a s t on sils a n d t h e a ppen dix
p e r ip h e r a l p r o t e in s : pla sm a m em br a n e
pr ot ein s ext en din g in t o t h e in t r a cellu la r or t h e
ext r a cellu la r en vir on m en t
p e r is t a ls is : r h yt h m ic con t r a ct ion s of cir cu la r
m u scle fiber s in h ollow or ga n s; pr om ot es for wa r d
m ovem en t of con t en t s
p e r it o n e a l d ia ly s is : pr ocess of wa st e a n d excess
wa t er r em ova l u sin g t h e per it on ea l m em br a n e a s
t h e sem iper m ea ble “filt er ”; wa st e m oves a cr oss
t h e per it on eu m u sin g t h e t r a n spor t m ech a n ism s
of diffu sion , osm osis, a n d u lt r a filt r a t ion
p e r it o n it is : in fla m m a t ion of t h e per it on ea l
m em br a n e
p e r m a n e n t c e lls : cells su ch a s n eu r on s, ca r dia c
m yocyt es, a n d t h e len s of t h e eye t h a t do n ot
u n der go m it osis a n d a r e u n a ble t o r egen er a t e
p e r m e a b le : a st a t e wh er e ju n ct ion s a r e open ed
bet ween t h e en dot h elia l cells, a llowin g flu id t o
m ove in t o t h e in ju r ed t issu e
p e r o x is o m e s : cellu la r or ga n elle m a de u p of sm a ll
m em br a n e-en closed sa cs; pr om ot e cell su r viva l
by oxida t ion of oxygen fr ee r a dica ls
Glossa r y 545
p e t e c h ia e : pin poin t h em or r h a ges of t h e skin or
m u cou s m em br a n es
p H : clin ica l m ea su r em en t of a cid–ba se ba la n ce
p h a g o c y t o s is : in gest in g la r ge pa r t icles su ch a s
cells, ba ct er ia , a n d da m a ged cellu la r
com pon en t s
p h e n o t y p e : gen et ic t r a it s t h a t a r e a ppa r en t or
obser va ble
P h ila d e lp h ia c h r o m o s o m e : fou n d in
a ppr oxim a t ely 95% of t h ose wit h ch r on ic
m yelogen ou s leu kem ia (CML) a n d r epr esen t s
a ch r om osom e 9 a n d 22 t r a n sloca t ion , wh ich
a ct iva t es on cogen es
p h le g m : la r ge a m ou n t s of spu t u m expect or a t ed
fr om t h e or oph a r yn x
p h o s p h o lip id : ph osph a t e [P O 4 ] bou n d t o lipid
h ea ds of t h e pla sm a m em br a n e
p h o t o p h o b ia : a con dit ion in wh ich t h e eyes a r e
ext r em ely sen sit ive t o ligh t
p h o t o r e c e p t o r : r ecept or sen sit ive t o ligh t fou n d in
t h e eye; r ods a n d con es
p h o t o s e n s it iv it y : skin sen sit ivit y t o t h e su n
r esu lt in g in r a sh
p h y s ic a l in ju r y : cellu la r da m a ge fr om m ech a n ica l,
t h er m a l, or ch em ica l sou r ces
p h y t o e s t r o g e n : n on st er oida l est r ogen s fou n d in
h igh con cen t r a t ion s in soy pr odu ct s; a lso kn own
a s isofla von es
p ic a : (pa goph a gia ) t h e com pu lsion t o ea t ice or
n on food su bst a n ces, su ch a s dir t or cla y; a n ot h er
m a n ifest a t ion of ir on -deficien t a n em ia t h a t is n ot
clea r ly u n der st ood
p in n a : t issu e of t h e ou t er ea r
p in o c y t o s is : a den osin e t r iph osph a t e
(ATP )-r equ ir in g pr ocess of in gest in g ver y sm a ll
vesicles
p it t in g e d e m a : edem a t h a t leaves a n im pr ession
wh en pr essu r e is pla ced
p la c e n t a : specia lized or ga n developed du r in g
pr egn a n cy; su st a in s t h e fet u s by pr ovidin g
r espir a t ion , n u t r it ion , a n d excr et ion fu n ct ion s
p la s m a m e m b r a n e : a n or ga n ized st r u ct u r e
com posed of lipids, ca r boh ydr a t es, a n d pr ot ein s
a r r a n ged in a bila yer ; pr ot ect s t h e cell by
cr ea t in g a ba r r ier a ga in st t h e pot en t ia lly h ost ile
en vir on m en t su r r ou n din g it
p la t e le t s : ir r egu la r ly sh a ped cyt opla sm ic
fr a gm en t s t h a t r elea se ch em ica l m edia t or s a n d
a r e essen t ia l for clot t in g, or coa gu la t ion
p le t h o r a : a con dit ion of h yper volem ia in wh ich
t h e blood becom es in cr ea sin gly viscou s,
lea din g t o pr u r it u s (it ch in g), h yper t en sion , a n d
in t er r u pt ion s of cir cu la t ion
p le u r it is : in fla m m a t ion of t h e lin in g of t h e lu n gs
or pleu r a l ca vit y
p le x u s : for m a t ion of a n in t er con n ect ion of spin a l
fiber s
546 Glossa r y
p n e u m o n ia : in fla m m a t ion of t h e lu n gs occu r r in g
com m on ly in t h e br on ch ioles, in t er st it ia l lu n g
t issu e, or t h e a lveoli
p n e u m o t h o r a x : t h e pr esen ce of a ir in t h e pleu r a l
spa ce t h a t ca u ses t h e lu n g t o colla pse
p o ik ilo c y t o s is : t h e ir r egu la r sh a pe of r ed blood
cells t h a t a r e ir on deficien t
p o la r : ca r r yin g a dist r ibu t ion of elect r on s t h a t
r epels wa t er
p o la r ize : a con dit ion in t h e excit a ble cell wh en t h e
in t r a cellu la r com pa r t m en t is m or e n ega t ive t h a n
t h e ext r a cellu la r spa ce
p o ly c y s t ic k id n e y d is e a s e (P KD ): a con dit ion
ch a r a ct er ized by gr owt h of flu id-filled cyst s in
kidn ey t issu e bila t er a lly; oft en lea ds t o ch r on ic
r en a l fa ilu r e
p o ly c y s t ic o v a r y s y n d r o m e (P C O S ): a con dit ion
of excess a n dr ogen pr odu ct ion fr om t h e ova r ies
p o ly d ip s ia : a st a t e of excessive t h ir st
p o ly g e n ic : con t a in in g sever a l m a jor
h ist ocom pa t ibilit y com plex (MH C) cla ss I a n d II
gen es; in t er a ct ion of sever a l gen es in flu en ced by
en vir on m en t a l fa ct or s
p o ly m e n o r r h e a : sh or t en ed m en st r u a l in t er va l
p o ly m o r p h ic : descr ibes som et h in g t h a t occu r s in
m or e t h a n on e for m
p o ly m o r p h is m : occu r r in g in m or e t h a n on e for m
p o ly m o r p h o n u c le a r le u k o c y t e s : gr a n u locyt es,
in clu din g n eu t r oph ils, eosin oph ils, a n d ba soph ils
p o ly n e u r o p a t h y : per iph er a l n er ve da m a ge
in volvin g m u lt iple a xon s
p o ly p h a g ia : a st a t e of excessive h u n ger
p o ly u r ia : fr equ en t , la r ge volu m e u r in a t ion
p o r t a l c ir c u la t io n : a blood bypa ss t h r ou gh wh ich
deoxygen a t ed blood fr om t h e ga st r oin t est in a l
(GI) t r a ct , spleen , a n d pa n cr ea s t r a vel t o t h e
liver by wa y of t h e por t a l vein befor e m ovin g on
t o t h e ven a ca va a n d h ea r t
p o r t a l h y p e r t e n s io n : eleva t ion in t h e h epa t ic
pr essu r e of t h e liver
p o s it iv e e e d b a c k lo o p : a syst em in wh ich t h e
pr esen ce of h or m on e st im u la t es a n in cr ea sed
pr odu ct ion of h or m on e u n t il t h er e is a n
in t er r u pt ion in t h e cycle
p o s t g a n g lio n ic n e u r o n s : a xon fiber s pr oject in g
fr om a n a u t on om ic gr ou p of n er ve cell bodies t o a
t a r get or ga n
p o s t ic t a l: ph ysica l st a t e a ft er r ecover y fr om
seizu r e; m a n ifest ed by ext r em e fa t igu e,
h ea da ch e, m u scle pa in , a n d wea kn ess
p o s t t r a u m a t ic s t r e s s d is o r d e r (P T S D ): a n
a n xiet y disor der ca u sed by ext r em e t r a u m a t ic
even t s, com m on ly a ffect in g t h ose wh o h a ve
exper ien ced m ilit a r y com ba t , vict im s of n a t u r a l
disa st er s, con cen t r a t ion ca m p su r vivor s, a n d
vict im s of violen t cr im e
p r e c ip it a t in g a c t o r s : t r igger s t h a t lea d t o t h e
on set of disea se
p r e g a n g lio n ic n e u r o n s : a xon fiber s ext en din g
fr om cell bodies in t h e br a in or spin a l cor d t o a
gr ou p of n er ve cell bodies
p r e im p la n t a t io n g e n e t ic d ia g n o s is :
iden t ifica t ion of gen et ic a bn or m a lit ies befor e
im pla n t a t ion of t h e bla st ocyst in t h e m a t er n a l
u t er in e lin in g, t h e decidu a
p r e lo a d : t h e wor k im posed on t h e h ea r t ju st pr ior
t o con t r a ct ion
p r e s b y o p ia : con dit ion of fa r sigh t edn ess a ssocia t ed
wit h a gin g; r esu lt s fr om t h e in a bilit y of t h e
cilia r y m u scle a n d len s t o a ccom m oda t e for n ea r
vision
p r e s b y c u s is : sen sor in eu r a l h ea r in g loss con sist en t
wit h a gin g; a ssocia t ed wit h t in n it u s
p r e v a le n c e : t h e per cen t a ge of a popu la t ion t h a t is
a ffect ed by a pa r t icu la r disea se a t a given t im e
p r im a r y a c t iv e t r a n s p o r t : a ct ive t r a n spor t
pr ocess r equ ir in g t h e dir ect u se of en er gy in t h e
for m of a den osin e t r iph osph a t e
p r im a r y in t e n t io n : a for m of h ea lin g in wh ich
t h e wou n d is a ppr oxim a t ed wit h a ll a r ea s of t h e
wou n d, con n ect in g a n d h ea lin g sim u lt a n eou sly
p r im a r y p r e v e n t io n : a ct ion s or a ct ivit ies t h a t
pr oh ibit a disea se con dit ion fr om occu r r in g
p r io n s : pr ot ein pa r t icles t h a t la ck DNA or RNA,
wh ich h a ve been fou n d t o ca u se in fect iou s
disea se in h u m a n s
p r o g n o s is : t h e for eca st or pr edict ion of h ow a n
in dividu a l will pr oceed t h r ou gh t h e h ea lt h
con dit ion
p r o g r a m m e d s e n e s c e n c e t h e o r y : developm en t a l
t h eor y t h a t lin ks t h e a gin g pr ocess wit h
a lt er a t ion s in t h e t elom er e por t ion of
ch r om osom es
p r o g r e s s io n : a n ext en sion of t h e pr om ot ion ph a se
wit h on e except ion : n ow t h e ca n cer ou s gr owt h
n o lon ger depen ds on con t in u ed exposu r e t o t h e
pr om ot er
p r o li e r a t io n : t h e r a pid gen er a t ion of n ew
da u gh t er cells divided fr om pr ogen it or (pa r en t )
cells
p r o m o t in g e v e n t : a n expa n sion of a m u t a t ed cell’s
gr owt h a n d r epr odu ct ion ; t h e con t in u ed gr owt h
of t h e cell depen ds on con t in u ed exposu r e t o t h e
pr om ot er
p r o t e a s e : a n y of n u m er ou s en zym es t h a t cu t or
splice pr ot ein s in t o t h eir sm a ller pept ide u n it s;
a lso kn own a s pr ot eolyt ic en zym es
p r o t e in a s e s : en zym es t h a t dest r oy ela st in a n d
ot h er t issu e com pon en t s
p r o t e in u r ia : pr ot ein in t h e u r in e
p r o t e o ly s is : t h e pr ocess of cu t t in g or splicin g
pr ot ein s in t o t h eir sm a ller pept ide u n it s

p r o t e o s o m e : la r ge cellu la r or ga n elle t h a t
r ecogn izes a bn or m a lly folded or for m ed pr ot ein s;
in volved in pr ot eolysis
p r o t o o n c o g e n e s : “n or m a l” gen es in t h e body wit h
a vit a l r ole in r egu la t in g cell fu n ct ion ; pr ecu r sor s
t o t h e developm en t of on cogen es
p r o v is io n a l m a t r ix : a t em por a r y su ppor t
st r u ct u r e t h a t pr om ot es h ea lin g by decr ea sin g
blood a n d flu id loss a t t h e sit e, a n d a t t r a ct in g
a n d su ppor t in g fibr obla st s, en dot h elia l cells, a n d
epider m a l (skin ) cells
p s e u d o b u lb a r a e c t : u n con t r olla ble la u gh in g or
cr yin g beca u se of a lt er ed con t r ol of em ot ion a l
r espon siven ess
p s e u d o h y p h a e : elon ga t ed ch a in s for m ed by yea st
t h r ou gh bu ddin g
p s y c h o s is : a st a t e of com plet e m en t a l a n d
em ot ion a l loss of t ou ch wit h r ea lit y
p u ls e o x im e t r y : a n on in va sive m et h od of
det er m in in g h ypoxem ia even befor e clin ica l sign s
a n d sym pt om s a r e n ot ed
p u ls e p r e s s u r e : t h e differ en ce bet ween t h e
syst olic a n d dia st olic blood pr essu r e
p u p il: open in g in t h e ir is; con t r ols t h e a m ou n t of
ligh t t h a t en t er s t h e eye
p u r e t o n e b o n e c o n d u c t io n : u sed t o eva lu a t e t h e
in n er ea r fu n ct ion , in depen den t of m iddle a n d
ou t er ea r fu n ct ion
p u r in e : pa r en t com pou n d of t h e n it r ogen ou s ba ses
a den in e (A) a n d gu a n in e (G)
p u r p u r a : t h e pr esen ce of diffu se h em or r h a ges of
t h e skin or m u cou s m em br a n es
p u r s e d lip b r e a t h in g : a pr ocess of h oldin g t h e
lips pu cker ed t igh t ly t oget h er wh ile slowly
exh a lin g t o m a in t a in posit ive a ir wa y pr essu r e
in t h e a lveoli; t h is m in im izes a ir t r a ppin g a n d
pr om ot es expir a t ion of ca r bon dioxide
p u r u le n t : exu da t e t h a t con t a in s pu s
p y e lo n e p h r it is : in fect ion a n d su bsequ en t
in fla m m a t ion of t h e kidn eys
p y o g e n ic : pa t h ogen s t h a t in du ce fever
p y r a m id a l m o t o r s y s t e m : com posed of t h e
cor t icospin a l a n d cor t icobu lba r t r a ct s, pr ovidin g
con t r ol of volu n t a r y m ovem en t
p y r e x ia : a lso ca lled fever, a n eleva t ed cor e body
t em per a t u r e is a r esu lt of ch em ica l m edia t or s
a ct in g dir ect ly on t h e h ypot h a la m u s
p y r im id in e : pa r en t com pou n d of t h e n it r ogen ou s
ba ses cyt osin e (C) a n d t h ym in e (T)
p y u r ia : pu r u len t exu da t e (pu s) in t h e u r in e
q u a d r ip le g ia : pa r a lysis of a ll fou r ext r em it ies
q u a d r u p le t e s t : pr en a t a l scr een in g t est ;
m ea su r em en t of m a t er n a l ser u m a lph a -
fet opr ot ein , u n con ju ga t ed est r a diol, h u m a n
ch or ion ic gon a dot r opin h or m on e, a n d in h ibin A
q u ie s c e n c e : dor m a n cy; t em por a r y r est in g
Glossa r y 547
r e a c t iv e o x y g e n s p e c ie s (R O S ): t oxic oxygen
m olecu les or r a dica ls t h a t a r e for m ed by t h e
r ea ct ion bet ween oxygen (O 2 ) a n d wa t er (H 2 O)
du r in g m it och on dr ia l r espir a t ion
r e a s s o r t m e n t : a pr ocess of ch a n gin g gen et ic
com posit ion du r in g r eplica t ion in t h e h u m a n
h ost cell lea din g t o vir a l offspr in g wit h a lt er ed
a n t igen ic pr oper t ies
r e c e p t o r : a cyt opla sm ic or cell su r fa ce pr ot ein
m olecu le st r u ct u r ed t o bin d specific fa ct or s
r e c e s s iv e : t r a it ca u sed by a pa r t icu la r a llele t h a t
does n ot m a n ifest it self in t h e pr esen ce of ot h er
a lleles t h a t gen er a t e t r a it s dom in a n t t o it
r e c o m b in a n t v a c c in e : su bu n it va ccin es wit h
h igh ly a n t igen ic com pon en t s of a pa t h ogen
r e c o m b in a n t v ir u s : vir u s cr ea t ed t o in clu de
gen et ic m a t er ia l t h a t expr ess a desir ed a n t igen
r e c t a l r e le x : n eu r om u scu la r st im u la t ion for
defeca t ion ; defeca t ion st im u la t ed by m ovem en t
of st ool in t o t h e r ect u m , a lso kn own a s t h e
defeca t ion r eflex
R e e d –S t e r n b e r g c e ll: or igin a t es in t h e cell
com pon en t s of lym ph n odes followin g a
B-lym ph ocyt e lin ea ge; is t h e n eopla st ic cell t h a t
is dia gn ost ic for H odgkin lym ph om a
r e -e p it h e lia liza t io n : t h e m ovem en t of epit h elia l
cells t o for m a cover in g over a wou n d
r e le x a r c : ba sic fu n ct ion a l pa t h wa y of t h e
n er vou s syst em ; a pr ocess by wh ich st im u li a r e
r eceived a n d in t er pr et ed, a n d t h en st im u la t e a
r espon se
r e g e n e r a t io n : a pr ocess of r efor m a t ion of
pa r en ch ym a l t issu es, wh ich ca n on ly occu r in
t h ose cells t h a t u n der go m it ot ic division
r e g u la t o r y T c e lls : su ppr ess a u t or ea ct ive
lym ph ocyt es a n d r egu la t e t h e im m u n e r espon se;
a lso kn own a s su ppr essor T cells
r e g u r g it a t io n : a pr oblem of in com pet en ce of
t h e va lve; t h e va lve is u n a ble t o pr oper ly close,
a llowin g r eflu x of blood
r e m is s io n : a sym pt om -fr ee per iod
r e p o la r iza t io n : r esu lt of m ovem en t of pot a ssiu m
ion s ou t of t h e cell
r e p r o d u c t io n : pr ocess by wh ich cells r eplica t e
r e s id e n t lo r a : m icr oor ga n ism s t h a t live on or
wit h in t h e body in n on st er ile a r ea s wit h ou t
ca u sin g h a r m
r e s id u a l v o lu m e (R V): t h e volu m e of a ir t h a t
r em a in s in t h e lu n gs a ft er m a xim a l expir a t ion
r e s o lu t io n : h ea lin g in r espon se t o m ild in ju r y wit h
m in im a l disr u pt ion t o cells, su ch a s wit h a sm a ll
su per ficia l scr a t ch or m ild su n bu r n
r e s p ir a t io n : t h e pr ocess of oxygen u se a s a
sou r ce of en er gy for pr odu ct ion of a den osin e
t r iph osph a t e (ATP ) a n d r elea se of m et a bolic
pr odu ct s fr om cells
548 Glossa r y
r e s p ir a t o r y a ilu r e : a life-t h r ea t en in g con dit ion
t h a t ca n r esu lt fr om a n y pr oblem t h a t sever ely
a ffect s ven t ila t ion , ven t ila t ion –per fu sion
m a t ch in g, or diffu sion
r e s t in g m e m b r a n e p o t e n t ia l (R MP ): m em br a n e
pot en t ia l of a cell a t r est
r e t e n t iv e in c o n t in e n c e : wit h h oldin g of feces fr om
fea r of pa in on defeca t ion ; r esu lt s in con st ipa t ion
a n d over flow soilin g
r e t ic u la t e b o d y : t h e m et a bolica lly a ct ive st a ge
of t h e life cycle of ch la m ydia e, wh er e t h e
m icr oor ga n ism t a kes over t h e h ost cell
r e t in a : ocu la r st r u ct u r e loca t ed over t h e post er ior
t wo-t h ir ds of t h e eye; con t a in s ph ot or ecept or
cells
r e t in o p a t h y : a pr oblem of degen er a t ive ch a n ges in
sm a ll vessels of t h e r et in a s (eyes)
r e t r a c t io n s : t h e pu llin g in of a ccessor y m u scles
u su a lly in t h e in t er cost a l, su bst er n a l, a n d
su pr a cla vicu la r spa ces t o pr om ot e m or e effect ive
in spir a t ion
r h e u m a t o id a c t o r (R F ): a su bst a n ce t h a t ca n be
fou n d in t h e blood a n d syn ovia l flu id; sign ifies
t h a t a n t ibodies (IgM, IgG, or IgA) a r e a ct in g
a ga in st ot h er a n t ibodies (m a in ly IgG)
r h o d o p s in : ph ot opigm en t pr odu ced by t h e r ods of
t h e r et in a
r ib o n u c le ic a c id (R N A): n u cleic a cid t h a t
con t a in s a su ga r (r ibose); r espon sible for t h e
con t r ol of pr ot ein syn t h esis; m a de u p of t h e fou r
n it r ogen ou s ba ses, in clu din g a den in e (A) a n d
gu a n in e (G), cyt osin e (C) a n d u r a cil (U)
r ib o s o m a l R N A (r R N A): for m of RNA of
r ibosom es; a ssocia t ed wit h m RNA in t h e
t r a n sla t ion of t h e gen et ic code
R in g e r la c t a t e : cr yst a lloid in t r a ven ou s flu id
con t a in in g sodiu m , ch lor ide, pot a ssiu m , ca lciu m ,
a n d la ct a t e
r is k a c t o r s : vu ln er a bilit ies t h a t , wh en pr esen t ,
in cr ea se t h e ch a n ces t h a t a disea se m a y occu r
r o d s : ph ot or ecept or cells of t h e r et in a ; pr odu ce t h e
ph ot opigm en t r h odopsin , a llowin g vision in dim
ligh t
s a lt a t o r y c o n d u c t io n : pa t t er n of n er ve im pu lse
over lon g dist a n ces wh er e t h e im pu lse m oves
down t h e a xon fr om n ode t o n ode in a st epwise
fa sh ion
s a c c u le : st r u ct u r a l com pon en t of t h e sem icir cu la r
ca n a l
s a r c o p e n ia : loss of skelet a l m u scle a ssocia t ed wit h
a gin g
s a t ie t y : a feelin g of ga st r ic fu lln ess, u su a lly
a ssocia t ed wit h ea t in g
s a t u r a t e d a t t y a c id s : fa t t y a cids t h a t h a ve n o
dou ble bon ds a n d eleva t e blood ch olest er ol levels,
a r e fou n d in a n im a l sou r ces, a n d a r e solid a t
r oom t em per a t u r e
s c h izo p h r e n ia : a psych ot ic m en t a l h ea lt h disor der
ch a r a ct er ized by h a llu cin a t ion s, delu sion s,
fixed fa lse beliefs, a n d disor ga n ized speech a n d
beh a vior
S c h w a n n c e lls : n eu r a l su ppor t cells r espon sible
for t h e pr odu ct ion of m yelin on lon g, sin gle a xon s
of t h e per iph er a l n er vou s syst em
s e c o n d a r y a c t iv e t r a n s p o r t : a ct ive t r a n spor t
m ech a n ism in volvin g m ovem en t of a secon d
su bst a n ce; depen den t on en er gy der ived fr om t h e
a ct ive t r a n spor t of t h e pr im a r y su bst a n ce
s e c o n d a r y in t e n t io n : a for m of h ea lin g
ch a r a ct er ist ic of la r ge, open , cr a t er like wou n ds
in wh ich t h e wou n ds h ea l fr om t h e bot t om u p,
posin g a gr ea t er r isk for in fect ion a n d sca r r in g
s e c o n d a r y p r e v e n t io n : ea r ly det ect ion a n d
t r ea t m en t of disea se t h r ou gh scr een in g
s e c r e t e : t h e pr ocess of t h e r elea se of m et a bolic
pr odu ct s fr om cells
s e e d in g : a for m of dir ect ext en sion wh er e
n eopla st ic pr olifer a t ion occu r s wit h in per it on ea l
a n d pleu r a l ca vit ies su r r ou n din g t h e a ffect ed
t issu e or or ga n
s e g m e n t a l m o v e m e n t : cir cu la r fiber con t r a ct ion
a n d r ela xa t ion occu r r in g a t differ en t loca t ion s,
pr odu cin g t h e ch a r a ct er ist ic con t r a ct ion s
a ssocia t ed wit h per ist a lsis
s e l -lim it in g : descr ibes a n in fect ion t h a t cea ses
a ft er a defin it e per iod of t im e wit h ou t a n y
specific t r ea t m en t
s e m ic ir c u la r c a n a l: in n er ea r st r u ct u r es
r egu la t in g ba la n ce; com posed of t h e u t r icle a n d
t h e sa ccu le
s e n e s c e n c e : post m a t u r a t ion a l pr ocesses t h a t
lea d t o dim in ish ed h om eost a sis a n d in cr ea sed
vu ln er a bilit y; u sed in t er ch a n gea bly wit h a gin g
s e n e s c e n t b o n e lo s s : slower loss ph a se t h a t
a ffect s bot h m en a n d wom en ; a ssocia t ed wit h
a gin g
s e n ile p la q u e : a ccu m u la t ion s of pr ot ein s
su r r ou n din g deposit s of β-a m yloid pr ot ein
s e n s it iza t io n p h a s e : in it ia l ph a se of dela yed
h yper sen sit ivit y r ea ct ion ; st im u la t ed by en t r y of
a n t igen via t h e skin a n d pr esen t a t ion of a n t igen
by La n ger h a n s cells, st im u la t in g im m u n e
r espon ses
s e n s it ize d : developm en t of a n im m u n e r espon se t o
a n a n t igen by pr eviou s exposu r e
s e n s o r in e u r a l h e a r in g lo s s : per m a n en t h ea r in g
loss, r esu lt in g fr om disea se, t r a u m a , or gen et ic
in h er it a n ce of a defect in t h e coch lea n er ve cells
s e n s o r y n e u r o n s : n eu r on s t h a t ca r r y im pu lses
fr om r ecept or s t o t h e dist a n t t a r get s of t h e br a in
a n d spin a l cor d; a lso kn own a s a ffer en t n eu r on s
s e p s is : a ba ct er ia l in fect ion of t h e blood
s e p t ic s h o c k : a con dit ion of a lt er ed per fu sion by
sh ock a s t h e r esu lt of over wh elm in g syst em ic

in fect ion , oft en wit h gr a m -n ega t ive ba ct er ia (t h e
en dot oxin com pon en t ) lea din g t o in a dequ a t e
per fu sion of vit a l or ga n s
s e p t ic e m ia : a pr oblem of m icr oor ga n ism s ga in in g
a ccess t o t h e blood a n d cir cu la t in g t h r ou gh ou t
t h e body
s e r o c o n v e r s io n : developm en t of a n t ibodies t o a
pa r t icu la r a n t igen
s e r o u s e x u d a t e : a clea r flu id t h a t seeps ou t of t h e
t issu es
s e x c h r o m o s o m e : kn own a s X a n d Y; t h e gen et ic
det er m in a n t s of t h e sex of a n in dividu a l
s e x -lin k e d : ch a r a ct er ist ics pa ssed on by sex
ch r om osom es; m ost oft en r ecessive t r a it s; oft en
lin ked t o t h e X ch r om osom e
s h o c k : a st a t e of in a dequ a t e blood flow t o
per iph er a l t issu es
s h o r t t a n d e m r e p e a t s (S T R ): u n iqu e len gt h s of
DNA st r et ch es in a n in dividu a l
s h u n t in g : t h e m ovem en t of blood a cr oss t h e a t r ia
or ven t r icles of t h e h ea r t
s ic k le c e ll a n e m ia : sin gle gen e disor der r esu lt in g
fr om a m u t a t ion of t h e sickle bet a globin gen e;
ch a r a ct er ized by sickled h em oglobin (H bS);
a u t osom a l r ecessive
s ic k le c e ll t r a it : h et er ozygou s for a m u t a t ion
of t h e sickle bet a globin gen e; ca r r ier of t h e
a u t osom a l r ecessive t r a it
s id e s t r e a m s m o k e : pa ssive or secon dh a n d sm oke
s ig n a l t r a n s d u c t io n p a t h w a y : m ech a n ism of
cellu la r com m u n ica t ion ; in it ia t ed by bin din g
of liga n d t o r ecept or a n d r esu lt in g in a n a ct ion
t h r ou gh su bsequ en t com m u n ica t ion even t s
s ig n s : r ela t in g t o disea se, t h e obser va ble or
m ea su r a ble expr ession of t h e a lt er ed h ea lt h
con dit ion
s in g le g e n e t r a it : ch a r a ct er ist ics pa ssed on by t h e
t r a n sm ission of a sin gle gen e
s in o a t r ia l (S A) n o d e : t h e pa cem a ker of t h e h ea r t ,
wh ich gen er a t es a r h yt h m ic im pu lse in t h e a t r ia
s in u s it is : sym pt om a t ic in fla m m a t ion of t h e
pa r a n a sa l sin u ses a n d n a sa l ca vit y
s o m a : a lso kn own a s a cell body; com pon en t of
cell com posed of cyt opla sm a n d or ga n elles
r espon sible for specia lized fu n ct ion s of t h e cell
s o m a t ic : r ela t in g t o t h e som a , or body
s o m a t ic m u t a t io n : a m u t a t ion occu r r in g in body
cells, r a t h er t h a n ga m et es; n ot t r a n sm it t a ble t o
su bsequ en t gen er a t ion s
s o m a t ic m u t a t io n t h e o r y : st och a st ic t h eor y of
a gin g su ggest in g t h a t t h e a gin g pr ocess is ca u sed
by im pa ir ed DNA r epa ir, a n t ioxida n t defen se, or
er r or s in pr ot ein expr ession
s o m a t ic n e r v o u s s y s t e m : volu n t a r y n er vou s
con t r ol in skelet a l m u scles
s o m a t o s e n s o r y m o d a lit y : specific n a t u r e of t h e
per cept ion of va r iou s st im u li
Glossa r y 549
S o m o g y i e e c t : t h e pr esen ce of r ebou n d
h yper glycem ia a s a r ea ct ion t o in su lin -in du ced
h ypoglycem ia
s p a s t ic : in cr ea sed m u scle t on e wit h exa gger a t ed
t en don r eflexes
s p e c i ic it y t h e o r y : t h eor y of pa in su ggest in g
t h a t sen sa t ion s of t ou ch , wa r m t h , cold, a n d pa in
in volve specific r ecept or s a n d pa t h wa ys
s p e r m a t o g o n ia : a pr im it ive sper m cell
s p in a l m u s c u la r a t r o p h y : con dit ion t h a t
r esu lt s fr om disu se beca u se of im pa ir ed n eu r a l
in n er va t ion t o m u scle t issu e
s p u t u m : expect or a t ed m a t er ia l
s q u a m o c o lu m n a r ju n c t io n : a r ea of t h e m er ger of
squ a m ou s a n d colu m n a r epit h eliu m ; a lso kn own
a s t h e t r a n sfor m a t ion zon e of t h e cer vix
s q u a m o u s e p it h e liu m : epit h eliu m con sist in g of a
sin gle fla t t en ed la yer of cells
s t a b le c e lls : cells t h a t st op r egen er a t in g wh en
gr owt h is com plet e bu t ca n r esu m e r egen er a t ion
if in ju r ed
s t a g in g : a pr ocess of cla ssifyin g t h e ext en t or
spr ea d of t h e disea se fr om t h e sit e of or igin
s t a p e s : on e of t h r ee bon es com pr isin g t h e ossicle of
t h e ea r ; a lso kn own a s t h e st ir r u p
s t a t u s a s t h m a t ic u s : a st a t e of br on ch ospa sm t h a t
is n ot r ever sed by t h e pa t ien t ’s m edica t ion s or
ot h er m ea su r es
s t e a t o r r h e a : st ool con t a in in g la r ge a m ou n t s of
fa t ; m a y be ca u sed by a bsen ce of bile a cids or
ga st r oin t est in a l m a la bsor pt ion
s t e m c e lls : h igh ly u n differ en t ia t ed u n it s t h a t h a ve
t h e pot en t ia l t o divide in t o da u gh t er st em cells,
wh ich ca n t h en m a t u r e in t o m or e differ en t ia t ed
u n it s wit h a specific fu n ct ion
s t e n o s is : a pr oblem in wh ich n a r r owin g of t h e va lve
occu r s, m a kin g it u n a ble t o open a dequ a t ely
s t e r c o b ilin : bile pigm en t ; pr ovides t h e
ch a r a ct er ist ic br own color of st ool
s t o c h a s t ic t h e o r y : t h eor y posit in g t h a t a gin g is
t h e r esu lt of cu m u la t ive cellu la r da m a ge
s t o r a g e a t : a dipose t h a t a ccu m u la t es u n der t h e
skin a n d a r ou n d in t er n a l or ga n s a n d is n ot
r equ ir ed for ph ysiologic fu n ct ion in g
s t r a b is m u s : la ck of coor din a t ion of ext r in sic eye
m u scles; r esu lt s in a con dit ion kn own a s “cr oss-
eyed”
s t r e s s : t h e r ea ct ion s of t h e body t o for ces of a
delet er iou s n a t u r e t h a t dist u r b h om eost a sis
s t r e s s in c o n t in e n c e : in volu n t a r y loss of u r in e via
a n exer t ion a l st im u lu s; m a y be a ssocia t ed wit h
im pa ir ed sph in ct er con t r ol
s t r e s s o r : a n y en dogen ou s or exogen ou s for ce t h a t
ca u ses st r ess
s t r o k e : a n y clin ica l even t , su ch a s sh ock, cer ebr a l
h em or r h a ge, isch em ia , or in fa r ct ion , t h a t lea ds t o
t h e im pa ir m en t of cer ebr a l cir cu la t ion
550 Glossa r y
s t r o k e v o lu m e : t h e a m ou n t of blood pu m ped ou t of
on e ven t r icle of t h e h ea r t in a sin gle bea t
s t r o m a l t is s u e : a lso ca lled in t er st it ia l t issu e; t h e
con n ect ive t issu e la yer com posed pr im a r ily of
colla gen , ela st in , a n d glycopr ot ein s
s t r u c t u r e : t h e for m a t ion of t h e pa r t s in t h e body;
t h a t is, h ow t h e body is pu t t oget h er
s t r u v it e : m a gn esiu m a m m on iu m ph osph a t e;
com m on com pon en t of r en a l ca lcu li
s u b a c u t e : som ewh er e in du r a t ion a n d sever it y
bet ween a cu t e a n d ch r on ic
s u b s t a n t ia g e la t in o s a : gr a y m a t t er ext en din g
t h r ou gh ou t t h e post er ior h or n of t h e spin a l cor d
t o t h e m edu lla oblon ga t a
s u b t h r e s h o ld : m em br a n e pot en t ia l less t h a n
t h a t n ecessa r y for com m it m en t t o a n a ct ion
pot en t ia l
s u lc i: fissu r es in t h e br a in t h a t pr ovides a n a t om ic
division s
s u p e r ic ia l p a r t ia l-t h ic k n e s s b u r n s : for m er ly
kn own a s fir st -degr ee bu r n s, t h ese bu r n s da m a ge
t h e epider m is
s u p e r in e c t io n : wh en a n ew in fect ion a r ises in
a ddit ion t o on e t h a t is a lr ea dy pr esen t
s u p p r e s s o r T ly m p h o c y t e s : su bset of T
lym ph ocyt e t h a t in h ibit s h u m or a l a n d cell-
m edia t ed r espon ses
s u p r a p h y s io lo g ic : blood levels of su bst a n ces
m u ch h igh er t h a n wou ld n or m a lly be expect ed
s u r a c t a n t : a lipopr ot ein lu br ica n t t h a t coa t s t h e
in n er por t ion of t h e a lveolu s a n d pr om ot es ea se
of expa n sion a n d r epels flu id a ccu m u la t ion
s y m p a t h e t ic n e r v o u s s y s t e m (S N S ): com pon en t
of t h e a u t on om ic n er vou s syst em ; a lso kn own a s
t h e t h or a colu m ba r n er vou s syst em
s y m p o r t : syst em of su bst a n ces t r a n spor t ed in t h e
opposit e dir ect ion
s y m p t o m : a n in dica t or t h a t is r epor t ed by a n ill
in dividu a l a n d is oft en con sider ed a “su bject ive”
m a n ifest a t ion
s y n a p s e : sm a ll ga p or ju n ct ion sepa r a t in g cells
s y n c o p e : loss of con sciou sn ess; fa in t in g
s y n d a c t y ly : fu sion or in com plet e sepa r a t ion of
digit soft t issu e
s y n d r o m e : a clu st er of clin ica l m a n ifest a t ion s a n d
la bor a t or y a n d ot h er dia gn ost ic t est s t h a t fit a
r ecogn iza ble, pr edict a ble pa t t er n
s y n d r o m e o in a p p r o p r ia t e s e c r e t io n o
a n t id iu r e t ic h o r m o n e (S I AD H ): a con dit ion of
excessive pr odu ct ion a n d r elea se of ADH despit e
ch a n ges in ser u m osm ola lit y a n d blood volu m e
s y n e r g is t ic : gr ea t er effect pr odu ced t h r ou gh t wo
or m or e su bst a n ces a ct in g in con cer t t h a n a n y
on e su bst a n ce a lon e
s y n g e n e ic : gr a ft fr om gen et ica lly iden t ica l
in dividu a ls (e.g., m on ozygot ic t win s)
s y s t e m ic : descr ibes m a n ifest a t ion s t h a t pr esen t
t h r ou gh ou t t h e body a n d a r e n ot con fin ed t o a
loca l a r ea
s y s t o le : a h ea r t con t r a ct ion t h a t for cefu lly m oves
blood ou t of t h e ven t r icles
s y s t o lic b lo o d p r e s s u r e : t h e a m ou n t of pr essu r e
exer t ed du r in g con t r a ct ion of t h e left ven t r icle
a n d eject ion of blood in t o t h e a or t a
s y s t o lic a ilu r e : h ea r t fa ilu r e ca u sed by a loss of
con t r a ct ile a bilit y of t h e h ea r t
T-c e ll r e c e p t o r : r ecept or on T lym ph ocyt es t h a t
bin d t o a n t igen s, pr om ot in g a ch a r a ct er ist ica lly
r a pid im m u n e r espon se
T ly m p h o c y t e s : t ype of wh it e blood cell
r espon sible for cell-m edia t ed im m u n it y;
cla ssified by fu n ct ion — h elper, cyt ot oxic, a n d
su ppr essor
t e lo m e r a s e : a n en zym e t h a t a dds len gt h t o t h e
t elom er e, t h e ch r om osom a l “t im e clock”
t e n ia e c o li: lon git u din a l segm en t s of sm oot h
m u scle in t h e la r ge in t est in e; con t r a ct ion s
pr odu ce h a u st r a
t e r a t o c a r c in o m a s : a com bin a t ion of em br yon ic
ca r cin om a s a n d u n differ en t ia t ed som a t ic (e.g.,
skin , m u scle, bon e, gla n ds) t issu es
t e r a t o g e n : su bst a n ces ca u sin g da m a ge t o a
developin g em br yo or fet u s
t e r a t om a s: benign tumors tha t arise from germ cells
t e r t ia r y p r e v e n t io n : r eh a bilit a t ion of t h e pa t ien t
a ft er det ect ion of disea se
T H 1: cla ss of CD4 h elper T lym ph ocyt es; a ct iva t e
m a cr oph a ges, secr et e ch em okin es a n d cyt okin es
t o a t t r a ct m a cr oph a ges; pr om ot e fu sion of
lysosom es wit h vesicles con t a in in g ba ct er ia ; a n d
st im u la t e ph a gocyt osis
T H 2: cla ss of CD4 h elper T lym ph ocyt es; a ct iva t e B
cells t o pr odu ce a n t ibodies
t h e r m a l in ju r y : da m a ge ca u sed by ext r em es of
t em per a t u r e
t h e r m o r e c e p t o r : r ecept or t h a t r ecogn izes t h er m a l
sen sa t ion
t h ia zid e d iu r e t ic : dr u g t h a t in cr ea ses u r in e
ou t pu t t h r ou gh pr even t ion of Na Cl r ea bsor pt ion
in t h e dist a l con volu t ed t u bu le
t h o r a c o lu m b a r n e r v o u s s y s t e m : com pon en t of
t h e a u t on om ic n er vou s syst em ; a lso kn own a s
t h e sym pa t h et ic n er vou s syst em
t h r e s h o ld p o t e n t ia l: in t r a cellu la r elect r ica l
pot en t ia l st im u la t in g a n a ct ion pot en t ia l
t h r o m b o c y t h e m ia : a con dit ion of excess pla t elet s
in t h e blood
t h r o m b o c y t o p e n ia : a bn or m a lly low n u m ber of
pla t elet s
t h r o m b o e m b o lu s : a sit u a t ion in wh ich a
t h r om bu s br ea ks off wit h in a vessel a n d t r a vels
t o a n ot h er loca t ion in t h e body; see a lso em bolu s

t h r o m b o s is : t h e for m a t ion of a blood clot
t h r o m b u s : a pr ot ect ive sca b t h a t is for m ed fr om
dr ied exu da t e a t t h e sit e of in ju r y
t h y r o t o x ic c r is is : a su dden , sever e wor sen in g of
h yper t h yr oidism t h a t m a y r esu lt in dea t h ; a lso
ca lled a t h yr oid st or m
t h y r o t o x ic o s is : t h e pr esen ce of excessive
cir cu la t in g t h yr oid h or m on e
t ic : h a bit u a l r epea t ed con t r a ct ion of cer t a in m u scles
t id a l v o lu m e (T V): t h e a m ou n t of a ir t h a t is
exh a led a ft er pa ssive in spir a t ion ; t h is is t h e
volu m e of a ir goin g in a n d ou t of t h e lu n gs a t r est ;
in a du lt s, t h is volu m e is a ppr oxim a t ely 500 m L
t in n it u s : r in gin g or wh ist lin g in t h e ea r s
t is s u e : gr ou ps of sim ila r cell t ypes t h a t com bin e
t o for m a specific fu n ct ion ; t h e fou r m a jor t issu e
t ypes in t h e body in clu de epit h eliu m (skin ),
con n ect ive t issu e (in clu din g blood, bon e, a n d
ca r t ila ge), m u scle, a n d n er ve
t o n ic : st a t e of con t in u ou s m u scle con t r a ct ion
t o t a l lu n g c a p a c it y (T L C ): t h e t ot a l a m ou n t
of a ir in t h e lu n gs wh en t h ey a r e m a xim a lly
expa n ded; is t h e su m of t h e vit a l ca pa cit y a n d
r esidu a l volu m e
t o x ig e n ic it y : t h e a bilit y of a pa t h ogen t o pr odu ce
h a r m fu l t oxin s t h a t in cr ea se h ost cell a n d t issu e
da m a ge
t r a b e c u la r n e t w o r k : t h e m esh like ocu la r
st r u ct u r e r espon sible for t h e r ea bsor pt ion of
a qu eou s h u m or
t r a n s illu m in a t io n : t ech n iqu e u sin g a sh in in g
ligh t t o view a ccu m u la t ion s of flu id
t r a n s c r ip t io n : t r a n sfer of t h e gen et ic code fr om
on e t ype of r ibon u cleic a cid t o a n ot h er ; ba sed
on t h e n u cleot ide sequ en ce of a com plem en t a r y
DNA t em pla t e
t r a n s e r R N A (t R N A): in volved in t h e
pr odu ct ion of pr ot ein s wit h specific a m in o a cid
a r r a n gem en t s t h r ou gh in t er a ct ion wit h m RNA
t r a n s o r m a t io n zo n e : a r ea of t h e m er ger of
squ a m ou s a n d colu m n a r epit h eliu m ; a lso kn own
a s t h e squ a m ocolu m n a r ju n ct ion of t h e cer vix
t r a n s ie n t is c h e m ic a t t a c k (T I A): a br ief per iod
of in a dequ a t e cer ebr a l per fu sion ca u sin g a
su dden foca l loss of n eu r ologic fu n ct ion ; fu ll
r ecover y of fu n ct ion u su a lly occu r s wit h in
24 h ou r s
t r a n s la t io n : pr ocess in volved in t h e pr odu ct ion of
pr ot ein fr om a m in o a cids
t r a n s lo c a t io n : exch a n ge of a sect ion of
ch r om osom e fr om on e t o a n ot h er ; oft en occu r s
du r in g m eiosis; a ble t o be t r a n sfer r ed t o
su bsequ en t gen er a t ion s
t r a n s m e m b r a n e p r o t e in : pr ot ein ext en din g
t h r ou gh t h e pla sm a m em br a n e, con t a ct in g bot h
t h e in t r a cellu la r a n d ext r a cellu la r com pon en t s
Glossa r y 551
t r e m o r : r epet it ive, oft en r egu la r, oscilla t or y
m ovem en t s
t r ig o n e : t r ia n gu la r sm oot h a r ea a t t h e ba se of t h e
bla dder bet ween t h e open in gs of t h e t wo u r et er s
a n d t h e u r et h r a ; ser ves a s a fu n ct ion a l sph in ct er
t h a t pr even t s u r in e fr om m ovin g in a r et r ogr a de
m a n n er ba ck in t o t h e u r et er fr om t h e bla dder
t r is o m y : pr esen ce of t h r ee copies of a ch r om osom e
in pla ce of t h e n or m a l pa ir ; t h e r esu lt of
n on disju n ct u r e
t r o p h ic : r ela t ed t o gr owt h
t r o p is m : a t er m u sed t o descr ibe t h e a ffin it y of a
pr im a r y t u m or t o a specific dist a n t sit e
t r u n c a t e d : sh or t en ed
t u b e r c u lo s is (T B ): a n in fect iou s disea se ca u sed
by a n a er obic, r od-sh a ped ba ct er iu m (ba cillu s)
ca lled Mycoba cter iu m tu ber cu losis
t u m o r m a r k e r s : su bst a n ces t h a t m a y be det ect ed
in cells or body flu ids a n d ca n pr ovide clu es t o
t h e pr esen ce, ext en t , a n d t r ea t m en t r espon se of
cer t a in n eopla sm s
t u m o r s u p p r e s s o r g e n e s : gen es t h a t pr oh ibit
over pr olifer a t ion of cells a n d r egu la t e a popt osis
t u r g o r : fu lln ess; eva lu a t ion m a de on skin t o
det er m in e h ydr a t ion st a t u s
t w o -p o in t d is c r im in a t io n : discr im in a t ive
pa t h wa y a llowin g t h e iden t ifica t ion of a n object
ba sed on t ou ch or t h e loca t ion of skin t ou ch in
t wo differ en t a r ea s
t y m p a n ic m e m b r a n e : loca t ed a t t h e en d of t h e
ea r ca n a l opposit e t h e ext er n a l a u dit or y m ea t u s;
st r u ct u r e m a r kin g t h e bou n da r y of t h e m iddle
ea r ; com m on ly kn own a s t h e “ea r dr u m ”
t y m p a n o m e t r y : m ea su r es t h e degr ee of m ovem en t
of t h e t ym pa n ic m em br a n e t o iden t ify m iddle ea r
flu id, per for a t ion , or cer u m en blocka ge of t h e ea r
ca n a l
u lc e r : cir cu m scr ibed, open , cr a t er like lesion of t h e
skin or m u cou s m em br a n es
u n d e r n u t r it io n : a la ck of in t a ke of n u t r ien t s m ost
oft en r ela t ed t o in a dequ a t e ca lor ie con su m pt ion ,
in a dequ a t e in t a ke of essen t ia l vit a m in s a n d
m in er a ls, or pr oblem s wit h digest ion , a bsor pt ion ,
or dist r ibu t ion of n u t r ien t s in t h e body
u n iv e r s a l p r e c a u t io n s : a st a n da r d of h ea lt h
ca r e t h a t r ecogn izes a ll blood a n d body flu id a s
pot en t ia lly in fect ed
u n s a t u r a t e d a t t y a c id s : h a ve on e or m or e
dou ble bon d a n d a r e n ot kn own t o eleva t e
blood ch olest er ol levels, a r e u su a lly fou n d in
pla n t sou r ces, a n d a r e oft en liqu id a t r oom
t em per a t u r e
u r g e in c o n t in e n c e : in volu n t a r y lea ka ge of u r in e
t h a t is a ccom pa n ied or im m edia t ely pr eceded by
a st r on g u r ge t o void; a lso kn own a s over a ct ive
bla dder
552 Glossa r y
u r g e n c y : t h e n eed t o u r in a t e im m edia t ely
u r e t e r o s c o p ic s t o n e r e m o v a l: pr ocedu r e u sed
wh en ca lcu li a r e loca t ed in t h e m id or dist a l
por t ion s of t h e u r et er s; ca lcu li loca liza t ion a n d
r em ova l is a ccom plish ed t h r ou gh a u r et er oscope
u r in e : clea r yellow flu id com posed pr im a r ily of
wa t er, wh ich con t a in s a va r iet y of wa t er-solu ble
wa st e pr odu ct s
u r in e d ip s t ic k : t ool u sed t o per for m bioch em ica l
a n a lyses of u r in e
u r in e s p e c i ic g r a v it y : m ea su r em en t of t h e
con cen t r a t ion of pa r t icles in t h e u r in e, com pa r in g
t h e weigh t of u r in e t o t h e weigh t of wa t er
u r t ic a r ia : sen sa t ion of it ch in g
u t r ic le : st r u ct u r a l com pon en t of t h e sem icir cu la r
ca n a l
u v e a l-s c le r a l o u t lo w p a t h w a y : r ou t e of
r ea bsor pt ion of a sm a ll qu a n t it y of a qu eou s
h u m or
v a c c in e : su bst a n ce st im u la t in g im m u n it y t h r ou gh
exposu r e t o a n a n t igen
Va ls a lv a m a n e u v e r s : t h e gen er a t ion of in t r a -
a bdom in a l pr essu r e t h r ou gh in h a la t ion , for cin g
t h e dia ph r a gm a n d ch est m u scles a ga in st t h e
glot t is; pr ovides st im u la t ion of t h e va gu s n er ve
v a r ia b le r e g io n : st r u ct u r e of a n t ibody t h a t a llows
bin din g t o specific a n t igen s
v a s c u la r r e s p o n s e : t h e r ole of in fla m m a t ion in
in cr ea sin g blood flow t o t h e sit e of a n in ju r y
v a s o d ila t e : t o widen t h e blood vessel, pr im a r ily a t
t h e ca pilla r y a r t er iole, a llowin g a n in cr ea se in
blood flow t o t h e sit e
v e c t o r : a veh icle t h a t h a r bor s a pa t h ogen a n d
ca r r ies it t o a h ost
v e n o u s s t a s is : st a gn a t ion of blood in t h e vein s
wit h r edu ced ven ou s r et u r n
v e n t ila t io n : t h e m ovem en t of a ir in t o a n d ou t of
t h e t r a ch ea , br on ch i, a n d lu n gs
v e n t ila t io n –p e r u s io n r a t io : t h e r ela t ion sh ip
bet ween in spir ed oxygen a n d t h e pu lm on a r y
cir cu la t ion , wh ich is r espon sible for t r a n spor t in g
t h e oxygen t o t h e h ea r t t o be pu m ped t o t h e r est
of t h e body; t h is is expr essed a s a r a t io a n d is
t ypica lly 0.8 t o 0.9, wh er e t h e r a t e of ven t ila t ion
is u su a lly sligh t ly less t h a n t h e r a t e of per fu sion
v e n t r a l h o r n s : a n t er ior ext en sion s of t h e spin a l
cor d t h a t con t a in effer en t m ot or n eu r on s
v e n t r ic le s : fou r flu id-filled in t er con n ect in g ca vit ies
in t h e br a in ; sit e of cer ebr ospin a l flu id st or a ge
a n d pr odu ct ion
Vir c h o w t r ia d : t h r ee m a jor fa ct or s r espon sible
for t h r om bu s for m a t ion : vessel wa ll da m a ge,
excessive clot t in g, a n d a lt er a t ion s in blood flow,
su ch a s t u r bu len ce or slu ggish blood m ovem en t
v ir io n s : pa r t icles r elea sed by cells in fect ed by
vir u ses, wh ich ca n en t er a n d in fect ot h er n ea r by
cells
v ir u le n c e : t h e pot en cy of a pa t h ogen in dica t ed by
t h e r a t io of t h e n u m ber of ca ses of disea se in a
popu la t ion com pa r ed wit h t h e n u m ber of people
exposed t o t h e m icr oor ga n ism
v ir u s e s : obliga t e in t r a cellu la r pa r a sit es
v is c o s it y : con cen t r a t ion or t h ickn ess
v is u a l p r o c e s s in g : coor din a t ion of visu a l im a ges
in t h e br a in du r in g t h e sequ en ce of st eps fr om
visu a l r ecept or sign a lin g t o cogn it ive r ecogn it ion
v it a l c a p a c it y (VC ): t h e m a xim a l a m ou n t of a ir
t h a t ca n be m oved in a n d ou t of t h e lu n gs wit h
for ced in h a la t ion a n d exh a la t ion
v it a m in s : m icr on u t r ien t or ga n ic su bst a n ces t h a t
t h e body is u n a ble t o m a n u fa ct u r e a n d t h er efor e
m u st con su m e; oft en cla ssified a ccor din g t o
solu bilit y (fa t or wa t er solu ble) or by m et a bolic
fu n ct ion
v o la t ile : t en den cy for a su bst a n ce t o va por ize; for m
of su bst a n ce excr et ed by t h e lu n gs
Wa lle r ia n d e g e n e r a t io n : degen er a t ion of a xon s
ca u sed by cr u sh in g in ju r y
w e t (e x u d a t iv e ) MD : m a cu la r degen er a t ion
ch a r a ct er ized by t h e for m a t ion of n ew blood
vessels u n der t h e r et in a a n d m a cu la , kn own a s
ch or oida l n eova scu la r iza t ion ; m a cu la r da m a ge
ca u sed by lea ka ge of flu id a n d bleedin g fr om
n ew vessels, a lt er in g t h e sh a pe of t h e m a cu la
a n d dist or t in g cen t r a l vision ; a lso kn own a s
exu da t ive m a cu la r degen er a t ion
w h it e m a t t e r : t issu e of t h e cen t r a l n er vou s syst em
com posed m a in ly of a xon s a n d den dr it es
y e a s t s : u n icellu la r for m s of fu n gi t h a t r epr odu ce by
bu ddin g
 In dex

Pa ge n u m ber s in it a lics den ot e figu r es; t h ose followed by a t den ot e t a bles; t h ose followed by a b den ot e boxes.
A Acou st ic r eflex m ea su r em en t , 304 pa t h oph ysiology of, 61–62
AAT. S ee Alph a 1 -a n t it r ypsin (AAT) Acqu ir ed im m u n e deficien cy syn dr om e t r ea t m en t of, 62
ABA. S ee Am er ica n Bu r n Associa t ion (AIDS), 89–92 Acu t e pyelon eph r it is, 127
(ABA) clin ica l m a n ifest a t ion s of, 90, 90 clin ica l m a n ifest a t ion s of, 126
Abdom in a l t en der n ess, 486 dia gn ost ic cr it er ia , 97 dia gn ost ic cr it er ia , 126
Abdom in a l wa ll h er n ia , 477t pa t h oph ysiology of, 89–90 pa t h oph ysiology of, 126
Abdu cen s n er ves, 243t, 295 t r ea t m en t of, 91 t r ea t m en t of, 126
ABG a n a lysis. S ee Ar t er ia l blood ga s ACR. S ee Am er ica n College of Acu t e r espir a t or y dist r ess syn dr om e
(ABG) Rh eu m a t ology (ACR) (ARDS), 389–391
a BS. S ee An t en a t a l Ba r t t er syn dr om e Acr om ega ly, 23–26, 24, 25 clin ica l m a n ifest a t ion s of, 391
(a BS) wit h a r t h r it is, 24, 25 dia gn osis of, 391
Abscess, 64 wit h ca r pa l t u n n el syn dr om e, 24, 25 pa t h oph ysiology of, 389, 391
in t est in a l, 65 clin ica l m a n ifest a t ion s of, 24 ph a ses of, 390
lu n g, 380, 388 dia gn osis of, 24–25 t r ea t m en t of, 391
t u boova r ia n , 350 pa t h oph ysiology of, 23–24 Acu t e sin u sit is
Absen t br ea t h sou n ds, 376b t r ea t m en t of, 25–26 clin ica l m a n ifest a t ion s of, 50
Absor pt ion , 438, 439–440 ACTH . S ee Adr en ocor t icot r opic dia gn ost ic cr it er ia , 50
a m in o a cid, 440–441 h or m on e (ACTH ) pa t h oph ysiology of, 50
fa t t y a cid, 441 Act ion pot en t ia l, 230, 231 t r ea t m en t of, 50–51
fr u ct ose, 438, 440 Act iva t ed pa r t ia l t h r om bopla st in t im e Acu t e t r ea t m en t , 308
glu cose, 438, 440 (a P TT), 424 Acu t e t u bu la r n ecr osis, 465, 466
glycer ol, 441 Act ive t r a n spor t , 12–13, 12, 438, 440 AD. S ee Alzh eim er disea se (AD)
sm a ll pept ide, 440–441 Act ivit ies of da ily livin g (ADL), 249 Ada pt ive im m u n it y, 76–78, 77
Accu m u la t ed m u t a t ion s t h eor y, 491 Acu it y, defin ed, 289 a ct iva t ion of, 79
ACE inhibitors. See Angiotensin- Acu pu n ct u r e, 294b Addison disea se
converting enzyme (ACE) inhibitors Acu t e disea se, defin ed, 3 clin ica l m a n ifest a t ion s of, 337, 337t
Acet oa cet ic a cid, 510 Acu t e ga st r it is, 59–60 dia gn osis of, 337
Acet on e, 510 clin ica l m a n ifest a t ion s of, 60 pa t h oph ysiology of, 336
Acet ylch olin e, 268t, 291, 516 dia gn ost ic cr it er ia , 60 t r ea t m en t of, 337
Acid–ba se ba la n ce pa t h oph ysiology of, 59 Aden in e, 136, 138
a lt er ed, 221, 224–225 t r ea t m en t of, 60 Aden oca r cin om a , 179
con cept m a p for, 222 Acu t e in fla m m a t ion , 36–41 cer vica l, 29
m et a bolic a cidosis in pa r en t er a l blood t est s in , 41t colon , 186, 187
n u t r it ion , 225–226 cellu la r r espon se t o, 38–39, 39, 40t lu n g, 185, 185
Acid–ba se im ba la n ce vs. ch r on ic, 48t ser ou s, 353
bu ffer syst em s, 219–221, 220 gen er a l m a n ifest a t ion s of, 39–40, 40t Aden oid h yper t r oph y, 16
bica r bon a t e, 220, 220 r esolu t ion of, 41 Aden om a , 179
ch lor ide–bicar bon at e exch an ge, 221 t r ea t m en t of, 40–41, 41t pit u it a r y, 24, 25–26, 25
pla sm a , 219–220 vascular response to, 36–38, 36, 37, 38t Aden osin e t r iph osph a t e (ATP ), 11, 12,
pot a ssiu m –h ydr ogen exch a n ge, Acu t e lym ph ocyt ic leu kem ia (ALL), 13, 204, 423, 438
220, 221 190–191, 191 Aden ovir u s, 111t
r en a l, 220–221 clin ica l m a n ifest a t ion s of, 190–191 ADH . S ee An t idiu r et ic h or m on e (ADH )
r espir a t or y, 220 dia gn osis, 191 Adh esion s, 48
t u bu la r, 221 pa t h oph ysiology of, 190 Adipocyt es, 435, 453
Acidosis, 517 t r ea t m en t of, 191 ADL. S ee Activities of daily living (ADL)
H AART-a ssocia t ed, 222–223 Acu t e m yelogen ou s leu kem ia (AML) Adr en a l cor t ex
clin ica l m a n ifest a t ion s of, 223 clin ica l m a n ifest a t ion s of, 192 h or m on e secr et ion of, 334
dia gn osis, 223 dia gn osis, 192 st er oid h or m on es secr et ed fr om ,
pa t h oph ysiology of, 223 pa t h oph ysiology of, 191–192 ca t egor ies of, 335t
t r ea t m en t of, 223 t r ea t m en t of, 192 Adr en a l h or m on e, 334
h yper ch lor em ic, 221 Acu t e ot it is m edia (AOM), 308. S ee Adr en a l m edu lla , h or m on e secr et ion
la ct ic, 223 a lso Ot it is m edia of, 334
m et a bolic, 221–222 Acu t e pa n cr ea t it is Adr en ocor t icot r opic h or m on e (ACTH ),
Acids, r egu la t ion of, 219 clin ica l m a n ifest a t ion s of, 62 320t, 326, 326, 328, 335
Acou st ic n er ve, 243t dia gn ost ic cr it er ia , 62 deficien cy, 336
553
554 In dex
Adu lt disea se, developm en t a l or igin s
of, 150
Adu lt -on set dia bet es, 513
Adven t it iou s, br ea t h sou n ds, 375
Aer obic ba ct er ia , 105
Aer obic r espir a t ion , 13–14
Affect , pseu dobu lba r, 253
Aft er loa d, 401b
Aga m m a globu lin em ia , 80t
Agin g
a n d a ppea r a n ce, 493
cellu la r ch a n ges in , 492–493
ch a r a ct er ist ic of, 492–498, 492–493,
495, 497
con cept m a p of, 492
defin it ion of, 491
degen er a t ive ch a n ges in , 490–505
flu id a n d elect r olyt e ba la n ce, 493
fr ee r a dica l t h eor y of, 492
a n d im m u n e r espon ses, 493
im m u n ologic t h eor y of, 491
a n d kidn ey, 497–498
n eu r ologic fu n ct ion in , 494
pr olifer a t ive ch a n ges, 493–494
som a t ic m u t a t ion t h eor y of, 492
t h eor ies, 491–492
AIDS. S ee Acqu ir ed im m u n e deficien cy
syn dr om e (AIDS)
Air pollu t ion . S ee a lso E n vir on m en t a l
t oxin s
ca r diova scu la r disea se a n d, 29–31
Air t r a ppin g, 381, 382
Air bor n e t r a n sm ission , 114
Air wa ys, a n a t om y of, 366
Ala n in e, 137t
Alcoh ol
ca n cer r isk fr om , 184, 186
er ect ile dysfu n ct ion a n d, 357
ga st r it is fr om , 60
gen et ic defect s fr om , 149
h yper t en sion a n d, 411, 412
h ypom a gn esem ia r isk fr om , 200
a s liver t oxin , 18
ost eopor osis a n d, 500
Aldose r edu ct a se, 520
Aldost er on e, 205, 207, 335t
Alen dr on a t e, 502t
Alka losis, m et a bolic, 222, 224
Alleles, 141
Aller gen s, 81, 93
Aller gies, 80t, 81
con ju n ct ivit is fr om , 298
food, 81
pen icillin , 81
t r ea t m en t , 92, 94
Alloa n t ibodies, 87
Alloa n t igen s, 87
Allogr a ft , 87
Alloim m u n it y, 87
Alph a cells, 508, 508
Alph a 1 -a n t it r ypsin (AAT), 380
Alt er ed h ea lt h , fu n ct ion a l con cept s
of, 6, 6b
Alt er ed im m u n it y
clin ica l m odels, 89–99
im m u n e r espon se m a n ipu la t ion ,
87–89
in t r odu ct ion , 71
lea r n in g ou t com es, 71
pr ocess of a lt er in g im m u n e fu n ct ion ,
78–87
r eview of im m u n e fu n ct ion , 72–78
Alt er n a t ive splicin g, 137
Alzh eim er disea se (AD), 502–505, 503,
504
clin ica l m a n ifest a t ion s of, 503–504
dia gn osis of, 504
pa t h oph ysiology of, 502–503
t r ea t m en t of, 504–505
Am blyopia , 297
Am en or r h ea , 347, 348
Am er ica n Bu r n Associa t ion (ABA), 55t
Am er ica n College of Rh eu m a t ology
(ACR), 95
Am er ica n Ur ologica l Associa t ion
(AUA) Sym pt om s In dex, 357
Am in o a cids, 137, 137t, 232
a bsor pt ion of, 440–441
Am in opept ida ses, 437t
AML. S ee Acu t e m yelogen ou s leu kem ia
(AML)
Am n iocen t esis, 98, 160
Am ph ot er ic pr ot ein , 220
Am pu lla of Va t er, 475
Am pu lla r y ca n cer, 475
Am sler ch a r t eva lu a t ion , for m a cu la r
degen er a t ion (MD), 311
Am ygda la , 235t, 266
Am yloid pr ecu r sor pr ot ein (AP P ), 502,
503
AN. S ee An or exia n er vosa (AN)
An a bolic h or m on es, 507, 508
An a er obic ba ct er ia , 105–106
An a er obic r espir a t ion , 13
An a ph yla ct ic sh ock, 414
An a ph yla xis, 83, 92–94
clin ica l m a n ifest a t ion s of, 92
dia gn ost ic cr it er ia , 92
pa t h oph ysiology of, 92, 93
t r ea t m en t of, 92, 94
An dr ogen -depr iva t ion h or m on e
t h er a py, 360
An dr ogen s, 320t, 335t, 337t, 344
An em ia
dia gn osis of, 449
ir on -deficien cy, 448–449, 449, 449t
clin ica l m a n ifest a t ion s of, 448
dia gn osis of, 448–449
pa t h oph ysiology of, 448
t r ea t m en t of, 449
per n iciou s, 61
An eu ploidy, 151
An eu r ysm s, a or t ic, 30, 405
An gelm a n syn dr om e (AS), 148
An gin a pect or is, 417
An gioedem a , 92
An giogen esis, 44
An giot en sin , 203
An giot en sin -con ver t in g en zym e (ACE )
in h ibit or s, 412
An giot en sin -con ver t in g en zym e
in h ibit or (ACE -I), 413t, 483
An giot en sin I, 404
An giot en sin II, 404
An giot en sin II r ecept or blocker s
(ARB), 413t
An giot en sin r ecept or blocker (ARB),
483
An gu la r ch eilit is, 447
An h edon ia , 274
An ion exch a n ge, 198
An ion ga p, 219, 219
An ion s, 198
An kylosis, 57
An or exia , 476
An or exia n er vosa (AN), 449–451
clin ica l m a n ifest a t ion s of, 450–451
dia gn ost ic cr it er ia , 451
pa t h oph ysiology of, 450, 450
t r ea t m en t of, 451
An ovu la t ion , 347
ANS. S ee Au t on om ic n er vou s syst em
(ANS)
An t a gon ist ic pleiot r opy t h eor y, 491
An t en a t a l Ba r t t er syn dr om e (a BS),
224
An t er ior cin gu la t e cor t ex, 266
An t er ola t er a l pa t h wa y, 289
An t ibodies, 76–77, 77
An t idepr essa n t a gen t s, m ech a n ism of
a ct ion of, 275
An t idiu r et ic h or m on e (ADH ), 205,
320t, 321, 329t, 330, 404
r egu la t ion of ext r a cellu la r flu id
volu m e, 330
An t igen -pr esen t in g cells (AP C), 76
An t igen ic va r ia t ion , 78, 105
An t igen s, 73
An t ih ist a m in es, 92
An t in u clea r a n t ibody (ANA), 58, 95
An t ioxida n t s, 19, 19
An t ipor t , 13
An t ir et r ovir a l t h er a py (ART), 90
An u r ia , 199
An xiet y disor der, gen er a lized
clin ica l m a n ifest a t ion s of, 272
defin ed, 270
dia gn osis of, 272
dia gn ost ic decision t r ee for, 271
pa t h oph ysiology of, 272
t r ea t m en t of, 272
AOM. S ee Acu t e ot it is m edia (AOM)
Aor t ic a n eu r ysm , 30
AP C. S ee An t igen -pr esen t in g cells
(AP C)
Apn ea , 371t
Apopt osis, 18, 491
APP. See Amyloid precursor protein (APP)
Appea r a n ce, a gin g a n d, 493
Appen dicit is, 473, 474
AP TT. S ee Act iva t ed pa r t ia l
t h r om bopla st in t im e (a P TT)
Aqu a por in s, 202
Aqu eou s h u m or, 297, 297
Ar a ch idon ic a cid, 38, 41t
ARDS. S ee Acu t e r espir a t or y dist r ess
syn dr om e (ARDS)
Ar gin in e, 137t
Ar t er ia l a n eu r ysm s, 405, 405
Ar t er ia l blood ga s (ABG) a n a lysis, 221
Ar t er ioven ou s (AV) fist u la , 483, 484
Ar t er ioven ou s sh u n t , 483, 484
Ar t h r it is, 56–58
a cr om ega ly wit h , 24, 25
defin it ion of, 56
over gr owt h of bon e a n d, 24
r h eu m a t oid, 56–57, 58

SLE a n d, 94, 95
t r ea t m en t of, 58
Ar t h u s r ea ct ion , 84
AS. S ee An gelm a n syn dr om e (AS)
Ascit es, 210, 211
Ascor bic a cid, 433t. S ee a lso Vit a m in C
ASCUS. S ee At ypica l squ a m ou s cells
of u n det er m in ed sign ifica n ce
(ASC-US)
ASD. S ee At r ia l sept a l defect (ASD)
Aspa r a gin e, 137t
Aspa r t ic a cid, 137t
Aspir a t ion , 374
Aspir in
in in fla m m a t ion , 40–41, 41t
in m yoca r dia l in fa r ct ion , 416, 417
Ast h m a , 2b
ca se st u dy on , 100
cla ssifica t ion gu ides for, 386b
clin ica l m a n ifest a t ion s of, 386
dia gn osis of, 386
pa t h oph ysiology of, 384, 385
t r ea t m en t of, 386–387, 386b
Ast igm a t ism , 297
Asym pt om a t ic disea se, defin ed, 3
At a xia , 249b
t ela n giect a sia , 80t
At a xic br ea t h in g, 372t
At elect a sis, ca u ses of, 391b
At h er oscler osis, 405, 405, 495
sm okin g a n d, 30
At h et osis, 249b
At opic a ller gen s, 83
At opy, 83, 92
ATP. S ee Aden osin e t r iph osph a t e
(ATP )
At r ia l sept a l defect (ASD), 408
At r ioven t r icu la r (AV) n ode, 400
At r oph y, 15–16, 15, 233
At t en t ion -deficit h yper a ct ivit y disor der
(ADH D)
clin ica l m a n ifest a t ion s of, 278
defin it ion of, 277–278
dia gn osis of, 278
m a n ifest a t ion s of, 278t
pa t h oph ysiology of, 278
t r ea t m en t for, 278–279
At t en t ion
defin ed, 267
t ypes of, 268
At t en u a t ed va ccin es, 89
At ypica l squ a m ou s cells of
u n det er m in ed sign ifica n ce
(ASC-US), 28
AUA. S ee Am er ica n Ur ologica l
Associa t ion (AUA) Sym pt om s
In dex
Au ba gio, in m u lt iple scler osis, 255t
Au er ba ch plexu s, 471
Au r a , 307, 308
Au scu lt a t ion , 208, 375, 382, 420, 475
Au t ism , defin it ion of, 279
Au t ism spect r u m disor der s
a bn or m a lit ies of, 280
clin ica l m a n ifest a t ion s of, 279–281
dia gn osis of, 281
pa t h oph ysiology of, 279
t r ea t m en t for, 281
Au t ocla ve, 114
Au t ocr in e pa t h wa y, 324, 324
Au t ogr a ft , 87
Au t oim m u n it y, 38, 85–86, 86
Au t on om ic n er vou s syst em (ANS),
244–246, 326, 367, 396
Au t osom a l dom in a n t disor der s,
143–144, 144, 152–154. S ee a lso
H u n t in gt on disea se (H D)
Au t osom a l r ecessive disor der s, 144–
145, 144, 154–156. S ee a lso Sickle
cell a n em ia
Au t osom es, 138
AV. S ee At r ioven t r icu la r (AV) n ode
AV fist u la . S ee Ar t er ioven ou s (AV)
fist u la
Avon ex, in m u lt iple scler osis, 255t
Axon , 229. S ee a lso Neu r on s
Aza t h iopr in e, 88, 96t
B Biot in , 433t
B-cell r ecept or (BCR), 74, 76
B lym ph ocyt es, 72t, 73, 74, 76
Ba ct er em ia , 116
Ba ct er ia , 105–107, 106
ca psu les of, 106
in fect ion , sit es of, 108
pa t h ogen icit y of, st r u ct u r a l
pr oper t ies in , 105–107
st r u ct u r e of, 106, 106
t est for, 109
Ba ct er ia l con ju n ct ivit is, 298
Ba ct er ia l m en in git is
br a in a n d spin a l cor d, 128
clin ica l m a n ifest a t ion s, 127–129
dia gn ost ic cr it er ia , 129
pa t h oph ysiology of, 127
t r ea t m en t of, 129
t ypes of, 128t
Ba ct er u r ia , 468t
Ba la n ced t r a n sloca t ion , 151
Ba llism u s, 249b
Ba r iu m en em a , 476
Ba r or ecept or s, 403–404
Ba r ot r a u m a , 302
Ba r r el ch est , 375, 376
Ba r t h olin gla n ds, 341, 341
Ba sa l ga n glia , 234, 235t, 237
Ba se pa ir s, 136, 138
Ba sem en t m em br a n e, of blood vessels,
36
Ba ses, r egu la t ion of, 219
Ba soph ils, 37, 41t, 74
BBB. S ee Blood-br a in ba r r ier (BBB)
BCL-2 gen e, 174
BCR. S ee B-cell r ecept or (BCR)
Beckwit h –Wiedem a n n syn dr om e
clin ica l m a n ifest a t ion s of, 163–164
dia gn osis of, 164
pa t h oph ysiology of, 163
t r ea t m en t of, 164
Beh avior, defin ed, 269
Ben ign pr ost a t ic h yper pla sia (BP H ),
357–358
clin ica l m a n ifest a t ion s of, 357
dia gn osis of, 357–358
digit a l r ect a l exa m in a t ion of
pr ost a t e, 358
pa t h oph ysiology of, 357
t r ea t m en t of, 358
In dex 555
Bet a -a m yloid pr ot ein , 502, 503
Bet a blocker s, 313
Bet a cells, 508, 508, 513
Bet a -h ydr oxybu t yr ic a cid, 510
Bet a 2 -a dr en er gic a gon ist s, for a st h m a ,
387
Bet a h ist in e, 310
Bet a ser on , in m u lt iple scler osis, 255t
Bet h esda syst em , 28–29
Bica r bon a t e, 463t
Bica r bon a t e bu ffer syst em , 220, 220
Bifidoba ct er iu m bifidu m , 473
Bifu r ca t ion s, 405, 405
Bila yer, 10
Bile a cids, 475
Bilir u bin , 97, 119, 155
Bin din g a ffin it y, 14
Bioa va ila bilit y, 441
Biopsy, 29
Biot in ida se deficien cy, 141t
Bipola r a ffect ive disor der
clin ica l m a n ifest a t ion s of, 277
defin it ion of, 276
dia gn osis of, 277
pa t h oph ysiology of, 276–277
t r ea t m en t for, 277
Bla ck st ool, 475
Bla dder, 462, 464
ca t h et er iza t ion , 464
st r ess t est , 480
t r a in in g, 480
Bla st om er e, 151
Blood-br a in ba r r ier (BBB), 237
Blood cir cu la t ion , 398–404
in bu r n in ju r ies, 54, 54
in h ea r t , 398
Blood glu cose levels, 510–511
exer cise a n d, 511
m on it or in g of, 512
Blood pr essu r e, 401–402
m ea su r em en t of, 401
n eu r on a l con t r ol of, 402–404
r egu la t ion m ech a n ism of, 403
Blood t est s, in a cu t e in fla m m a t ion ,
41t
Blood t r a n sfu sion , 87
Blood t ypin g, 83, 87
Blood u r ea n it r ogen (BUN), 207, 412
Blood vessels, a n a t om y of, 37
Blood volu m e, 401b
Blu n t for ce in ju r y, 238
Body defen se m ech a n ism s, 34–35
Body flu id com pa r t m en t s, 202, 202
Body m a ss in dex (BMI), 455, 455
Body weigh t , m ea su r em en t s, 208
Bon e dem in er a liza t ion , du r in g
m en opa u se, 355
Bon e m a r r ow, 74, 74t
t r a n spla n t , 88
Bor on , 434t
Bovin e spon gifor m en ceph a lopa t h y,
109b
Bowel elim in a t ion , a lt er a t ion in ,
472–477
clin ica l m a n ifest a t ion s of, 475–476
dia gn osis of, 476
m ot ilit y, 472–473
n eu r om u scu la r fu n ct ion , 473
556 In dex

Bowel elim in a t ion , a lt er a t ion in CAH . S ee Con gen it a l a dr en a l a ir pollu t ion a n d, 29–31
(con tin u ed ) h yper pla sia (CAH ) en vir on m en t a l t oxin s a n d, 29–31
pa t en cy, 473 Ca lcit on in , 496, 502t clin ica l m a n ifest a t ion s of, 30
per fu sion , 473 Ca lciu m , 201t, 434t, 463t, 477, 496, dia gn osis, 30
t r ea t m en t of, 476–477 501–502 pa t h oph ysiology of, 30
Bowel r esect ion , 486 ba la n ce, a lt er ed, 200, 214–215 t r ea t m en t of, 30–31
Bowm a n ca psu le, 461 deficien cy of, 446t du r in g m en opa u se, 355
BP D. S ee Br on ch opu lm on a r y dyspla sia Ca lciu m ch a n n el blocker s (CCB), 413t sm okin g a n d, 30
(BP D) cAMP. S ee Cyclic a den osin e Ca r pa l t u n n el syn dr om e
BP H . S ee Ben ign pr ost a t ic h yper pla sia m on oph osph a t e (cAMP ) a cr om ega ly wit h , 24, 25
(BP H ) Ca n cer over gr owt h of bon e a n d, 24
Br a dykin esia , 249b ben ign , 178, 178, 180t Ca r r ier s, 144
Br a dypn ea , 372t ca r cin ogen s, 174–176, 175 Ca r t ila ge, 56
Br a in , 233–234, 234 ch ildr en a n d, 184 Ca seou s n ecr osis, 123
fu n ct ion s, 233–234 defin ed, 171 Ca st s, 465
h em isph er es, 234 dia gn osis of, 182–183 Ca t a r a ct s, 30, 298, 299
lobes, 233–234 gr a din g, 180 Ca t ion exch a n ge, 198
m en in git is of, 128 m a lign a n t , 178, 178, 179, 180t Ca t ion s, 198
st r u ct u r e, 234 m a n ifest a t ion s, 181–182 Ca u da equ in a , 235
Br a in ca n cer, 189 n om en cla t u r e, 179–180, 180t Ca vit a t ion s, 124
dia gn osis of, 189–190 pr even t ion of, 184 CBC. S ee Com plet e blood cou n t s (CBC)
m a n ifest a t ion s of, 189 pr ogn osis of, 180 CBS. S ee Cla ssic Ba r t t er syn dr om e
pa t h oph ysiology of, 188–189 spr ea d of, 178–179 (cBS)
t r ea t m en t of, 190 st a gin g, 180, 180 CCP D. S ee Con t in u ou s cycler-a ssist ed
Br a in r egion s, a ssocia t ed wit h P TSD, t r ea t m en t of, 183–184, 183t per it on ea l dia lysis (CCP D)
273 Ca n d id a , 90 CD4 T lym ph ocyt es, 78, 79
Br a in st r u ct u r e a n d fu n ct ion , a lbica n s, 378 CD4/CD8, 78, 79
a lt er a t ion s in , 269 Ca n didia sis, 90, 91, 112, 112 CD8 T lym ph ocyt es, 78, 79
BRCA1 gen e, 353 CAP D. S ee Con t in u ou s a m bu la t or y Celia c disea se, 451–452, 452
BRCA2 gen e, 353 per it on ea l dia lysis (CAP D) Cell body, 229. S ee a lso Neu r on s
Br ea st t issu e a da pt a t ion , t o t r oph ic Ca pilla r ies Cell-m edia t ed im m u n it y, 77–78, 79
sign a ls, 16, 16 h ydr ost a t ic pr essu r e of, 202, 205 Cell r ecept or s, da m a ge t o, 328
Br ea t h sou n ds, 376b m ech a n ism s of edem a in , 209 Cell-t o-cell com m u n ica t ion , h or m on a l
Br ea t h in g pa t t er n s, a da pt a t ion s in , Ca r boh ydr a t es, 432 m ech a n ism of, 324, 324
371–372t, 375 a bsor pt ion , 438, 439 Cells
Br it ish Men opa u se Societ y a n d m a la bsor pt ion , 444, 446 a da pt a t ion of, 14–17, 15
Wom en ’s H ea lt h Con cer n , 355 t ypes, 431 a lph a , 508, 508
Br on ch opu lm on a r y dyspla sia (BP D), Ca r bon dioxide, 220 bet a , 508, 508, 513
17 diffu sion of, 369–370 ca u ses of, 18–20
Br on ch ospa sm , 92 t r a n spor t of, 369–370 ch ief, 437
Br on ch u s a ssocia t ed lym ph oid t issu e, Ca r bon ic a cid (H 2 CO 3 ), 220, 221 of ch r on ic in fla m m a t ion , 48
75 Ca r boxypept ida se, 437t com pon en t s of, 10–11
Br u dzin ski sign , 129 Ca r cin ogen esis, 172 dea t h of, 17–20, 491
Br u t on disea se, 80t Ca r cin ogen s, 174–176. S ee a lso Ca n cer ca u ses of, 18–20
Bu bble boy disea se. S ee Ca r cin om a in sit u , 179–180 m ech a n ism s of, 18
X-lin ked sever e com bin ed Ca r dia c a r r h yt h m ia , 200 defin ed, 9
im m u n odeficien cy (XSCID) Ca r dia c ca t h et er iza t ion , 409t delt a , 508, 508
Bu dd–Ch ia r i syn dr om e, 210 Ca r dia c cells, 400 differ en t ia t ion , 171, 171, 171–176
BUN. S ee Blood u r ea n it r ogen (BUN) Ca r dia c con t r a ct ilit y, 401b epit h elia l, 437
Bu pr opion , 31 Ca r dia c cycle, 399 F, 508
Bu r ch pr ocedu r e, 481 a ct ion pot en t ia ls t ypes, 400 fu n ct ion s of, 11
Bu r n s, 52–56 Ca r dia c dysr h yt h m ia s, 408 com m u n ica t ion , 14
cla ssifica t ion of, 52–53, 53 Ca r dia c h yper t r oph y, 21–23, 22 in gest ion , 13
clin ica l m a n ifest a t ion s of, 54–55 clin ica l m a n ifest a t ion s of, 22 r epr odu ct ion , 14
dia gn ost ic cr it er ia , 55, 55, 55t dia gn osis, 22–23 r espir a t ion , 13–14
gr a din g of, 55t pa t h oph ysiology of, 21–22 secr et ion , 13
h em odyn a m ic ch a n ges in , 54, 54 t r ea t m en t of, 23 t r a n spor t a t ion , 11–13
pa t h oph ysiology of, 53–54 Ca r dia c n u clea r sca n n in g, 409t G, 437
r u le of n in es, 55, 55 Ca r dia c ou t pu t (CO), 401 ga st r ic epit h elia l, 437
t r ea t m en t of, 55–56 fa ct or s a ffect in g, 401b of im m u n e syst em , 73–75
Bu t t er fly r a sh , 94, 95 im pa ir ed ven t r icu la r pu m pin g, 407 in fla m m a t or y m edia t or s wit h in ,
in a dequ a t e of, 406–408 37–38
C Ca r din a l sign s, 39 in ju r y, 18–20
C-r ea ct ive pr ot ein (CRP ), 41t, 415–416 Ca r diogen ic sh ock, 413 lym ph oid pr ogen it or, 73
Ca ber golin e (Dost in ex), 26 Ca r diom ega ly, 25 lysis of, 38t, 81t, 110
Ca ch exia , 181, 181 Ca r diova scu la r a da pt a t ion , 402–404 m em br a n e of, 10
CAG. S ee Cyt osin e-a den in e-gu a n in e Ca r diova scu la r disea se (CVD), 401 m et a bolism , 199
(CAG) expa n sion m u t a t ion a cr om ega ly a n d, 24 m u cou s, 436
 In dex 557

m yeloid pr ogen it or, 73, 74–75 (CIN), 29 Ch r om osom es, 11, 138–139, 139
pa r iet a l, 436–437 Cer vicit is, 350 Ch r on ic br on ch it is, 383–384, 383
pr olifer a t ion , 171–176 CF. S ee Cyst ic fibr osis (CF ) clin ica l m a n ifest a t ion s of, 384
size, effect of t on icit y on , 205–206, CF TCR. S ee Cyst ic fibr osis dia gn osis of, 384
207 t r a n sm em br a n e con du ct a n ce pa t h oph ysiology of, 383–384
st r u ct u r e, 10–11 r egu la t or (CF TCR) t r ea t m en t of, 384
a n d t issu es, a lt er ed Ch a in of in fect ion , 113–115, 113 Ch r on ic con st ipa t ion , 477t
a da pt a t ion a n d r espon se t o st r ess, h ost fa ct or s, 114–115 Ch r on ic cou gh , 374, 375
14–17 m ode of t r a n sm ission , 114 Ch r on ic disea se, defin ed, 3
clin ica l m odels, 20–31 por t a l of en t r y, 114 Ch r on ic ga st r it is, 60–61
in ju r y a n d dea t h , 17–20 por t a l of exit , 114 a u t oim m u n e pr ocesses
in t r odu ct ion of, 9 r eser voir, 114 clin ica l m a n ifest a t ion s of, 61
lea r n in g ou t com es, 9 Ch a n n el pr ot ein s, 10 dia gn ost ic cr it er ia , 61
st r u ct u r e a n d fu n ct ion , 10–14 CH D. S ee Cor on a r y h ea r t disea se pa t h oph ysiology of, 61
t r a n spor t m ech a n ism s of, 11–13, 12 (CH D) t r ea t m en t of, 61
Cellu la r a dh er en ce, 39 Ch em ica l syn a pses, 231 H elicoba cter P ylor i in fect ion , 60–61
Cellu la r ca st s, 95 Ch em ica ls, a n d ca n cer, 175–176 clin ica l m a n ifest a t ion s of, 60
Cellu la r ch a n ges, in a gin g, 492–493 Ch em or ecept or s, 304, 403–404 dia gn ost ic cr it er ia , 60–61
Cellu la r m igr a t ion , 39 Ch em ot a ct ic fa ct or s, 39 pa t h oph ysiology of, 60, 60
Cellu la r r espon se, 36, 38–39, 39, 40t Ch em ot a xis, 39 t r ea t m en t of, 61
Cellu la r sen escen ce, 491 Ch em ot h er a py, for t est icu la r ca n cer, Ch r on ic gr a n u lom a t ou s disea se, 80t
Cellu la r swellin g, 208 361 Ch r on ic in fla m m a t ion , 48–49
Cen t er s for Disea se Con t r ol a n d Ch est ph ysiot h er a py, for pn eu m on ia , a cu t e vs., 48t
P r even t ion (CDC), 97 380 cells of, 48
Cen t r a l a u dit or y pr ocessin g disor der, Ch est r a diogr a ph , 379, 409t gen er a l m a n ifest a t ion s of, 48
303 Ch eyn e-St okes, 372t gr a n u lom a for m a t ion , 48–49, 49
Cen t r a l n er vou s syst em (CNS), 326, Ch ief cells, 437 t r ea t m en t of, 48–49
411, 412 Ch ildr en . S ee a lso Newbor n s Ch r on ic m yelopr olifer a t ive disor der s,
br a in , 233–234, 234 a u t osom a l r ecessive disor der s in , 493–494
fu n ct ion s, 233–234, 235t 144, 144 Ch r on ic obst r u ct ive pu lm on a r y disea se
h em isph er es, 234 bu r n s a n d, 55 (COP D), 380
lobes, 233–234 a n d ca n cer, 184 Ch r on ic pa n cr ea t it is
st r u ct u r e, 234, 235t ch r om osom es in , 140 clin ica l m a n ifest a t ion s of, 63
in ju r y t o, 238–242 deh ydr a t ion in , 212 dia gn ost ic cr it er ia , 63
excit a t ion , 241 wit h Down syn dr om e, 146–147, 158 pa t h oph ysiology of, 63
isch em ic, 239–241 food a ller gies a n d, 78, 81 t r ea t m en t of, 63
t r a u m a t ic, 238–239 giga n t ism a n d, 24 Ch r on ic r en a l fa ilu r e, 483, 483
n eu r ocir cu la t or y syst em , 237–238 h ea r in g loss in , 304 Ch r on ic sin u sit is
BBB, 237 ot it is m edia in , 308, 309 clin ica l m a n ifest a t ion s of, 51–52
cer ebr ospin a l flu id, 237–238, 238 wit h pr oger ia , 498, 499, 499 dia gn ost ic cr it er ia , 52
cer ebr ova scu la r cir cu la t ion , 237 ROP a n d. S ee Ret in opa t h y of pa t h oph ysiology of, 51
spin a l cor d, 234–237, 236 pr em a t u r it y (ROP ) t r ea t m en t of, 52
dor sa l h or n s, 236 sickle cell a n em ia in , 155 Ch ylom icr on s, 441
ven t r a l h or n s, 236 Ch la m yd ia tr a ch om a tis, 349 Ch ym ot r ypsin , 437t
su ppor t in g cells of, 229–230, 230t Ch la m ydia e, 110, 111 Cilia r y m u scles, 294
Cen t r om er e, 138 Ch lor ide, 201t, 463t CIN. S ee Cer vica l in t r a epit h elia l
Ceph a lospor in , 81 ba la n ce, a lt er ed, 200 n eopla sia (CIN)
Cer ebella r st r oke, 423 Ch lor ide-bica r bon a t e exch a n ge, 221 Cin gu la t e gyr u s, 267
Cer ebellu m , 235t Ch olecyst okin in , 435, 438 Cir cu la t ion
Cer ebr a l a t r oph y, 20–21, 20 Ch olest er ol, 119, 122 of blood, 398–404
clin ica l m a n ifest a t ion s of, 21 Ch on dr oca lcin osis, 495 cor on a r y, 397–398, 398
dia gn osis, 21 Ch on dr om a s, 179 im pa ir ed, 404–406
pa t h oph ysiology of, 20–21 Ch on dr osa r com a , 179 for per fu sion , 397–398
t r ea t m en t of, 21 Ch or ea , 249b pu lm on a r y, 397
Cer ebr a l cor t ex, 234, 235t, 237, 238– Ch or oid plexu s, 237 syst em ic, 397
239, 241, 326 Ch or oida l n eova scu la r iza t ion , 311 Cir r h osis, 121, 210–212
Cer ebr a l pa lsy (CP ) Ch r om a t in , 27 clin ica l m a n ifest a t ion s of, 211
clin ica l m a n ifest a t ion s of, 250–251 Ch r om a t olysis, 233 dia gn osis, 211
dia gn ost ic cr it er ia of, 251–252 Ch r om iu m , 434t pa t h oph ysiology of, 210–211
pa t h oph ysiology of, 249–250 Ch r om osom a l a lt er a t ion s, in h er it a n ce t r ea t m en t of, 211
t r ea t m en t of, 252 of, 146–147, 146, 147 Cla ssic Ba r t t er syn dr om e (cBS), 224
Cer ebr ospin a l flu id (CSF ), 237–238, in ch r om osom e n u m ber, 146–147, Clea n -ca t ch , u r in e collect ion , 464
238, 367 157–160, 162 Clin ica l m a n ifest a t ion s, defin ed, 2
ba ct er ia l m en in git is in , 127 in st r u ct u r e, 147 Clit or is, 341, 341
Cer vica l ca n cer, 29 Ch r om osom a l r eplica t ion , 139, 140 Clon a l expa n sion , 77
Pa p t est for, 28 Ch r om osom e n u m ber, a lt er a t ion , Clon a l select ion , 77
Cer vica l dyspla sia , 26–29, 27, 28t 146–147, 157–160. S ee a lso Down Closed h ea d in ju r y, 238
Cer vica l in t r a epit h elia l n eopla sia syn dr om e; Tu r n er syn dr om e (TS) Clostr id iu m d ifficile, 109
558 In dex

Clot t in g, 36, 36 pu lm on a r y disea se (COP D) Cyt och r om e oxida se (COX), 157

Clu bbin g, 376
Clu st er s of differ en t ia t ion (CD), 78
CNS. S ee Cen t r a l n er vou s syst em
(CNS)
CO. S ee Ca r dia c ou t pu t (CO)
Coa gu la se t est , 109
Coba la m in , 433t
Coba lt , 434t
Coch lea , 301
Coch lea r im pla n t s, 304
Codon s, 137, 137t
Cogwh eel, 249b
Coin fect ion , 105
Colit is, u lcer a t ive, 65–67, 66
Colla gen , 43, 43, 46, 47
Colon , 469
obst r u ct ion s, 474
Colon ca n cer, 186–188
a cr om ega ly a n d, 24
dia gn osis of, 187–188
in fla m m a t or y bowel disea se a n d,
65–67
m a n ifest a t ion s of, 187
pa t h oph ysiology of, 186–187
t r ea t m en t of, 188
Colon oscopy, 476
Color vision , 295
Colost om y, 486
Colposcopy, 29
Colu m n a r epit h eliu m , 27, 27
Com m on va r ia ble im m u n e deficien cy
(CVID), 80t
Com m u n ica ble disea ses, 113–115
ch a in of in fect ion , 113–115, 113
Com m u n ica t ion , in cells, 14
Com plem en t syst em , 41t
Com plem en t a r y st r a n d of DNA
(cDNA), 137
Com plet e blood cou n t s (CBC), 156
Com plex pa r t ia l seizu r es, 251
Com plia n ce, 368
Com pr ession , of a lveoli, 391b
Con cen t r a t ion gr a dien t , 11–12
Con cept , defin ed, 6
Con du ct ion of im pu lses, 399–401, 400
Con du ct ive h ea r in g loss, 303
Con es, in r et in a , 295
Con foca l la ser opt ica l coh er en ce, 313
Con gen it a l a dr en a l h yper pla sia (CAH ),
141t
Con gen it a l disor der s, 148–150, 149
Con gest ive h ea r t fa ilu r e, 418, 419
Con ju ga t ed va ccin es, 89
Con ju n ct iva , 295
Con ju n ct ivit is, 298
Con n ect ive t issu e layer s, 43–44, 43
Con st a n t r egion , of im m u n oglobu lin s,
76
Con st ipa t ion , 475, 477, 485, 486
Con t in u ou s a m bu la t or y per it on ea l
dia lysis (CAP D), 485
Con t in u ou s cycler-a ssist ed per it on ea l
dia lysis (CCP D), 485
Con t r a ct u r es, 54
Con va lescen ce, 116
Copa xon e, in m u lt iple scler osis, 255t
COP D. S ee Ch r on ic obst r u ct ive
Copper, 434t, 446t
Cor pu lm on a le, 419
Cor n ea , 294
Cor on a r y a r t er y disea se
r eva scu la r iza t ion of, 418
r isk fa ct or s for, 2b
Cor on a r y cir cu la t ion , 397–398, 398
Cor on a r y h ea r t disea se (CH D), 415
Cor on a vir u s, 111t
Cor pu s ca llosu m , 234
Cor t ica l ca t a r a ct s, 299
Cor t icost er oids, 38
for Cu sh in g syn dr om e, 335
Cor t icot r opin -r elea sin g h or m on e
(CRH ), 319, 320t
Cor t isol, 88, 335t
Cost over t ebr a l a n gle (CVA), 468
Cot in in e, 30
Cot r a n spor t , 13
Cou n t er cu r r en t m ech a n ism , 461, 463
Cou n t er t r a n spor t , 13
Cowper gla n ds, 345
COX. S ee Cyt och r om e oxida se (COX)
Cr a ckles, a s br ea t h sou n ds, 376b
Cr a n ia l n er ves, 242, 243t
Cr et in ism , 333
Cr eu t zfeldt -J a kob disea se, 109b
CRH . S ee Cor t icot r opin -r elea sin g
h or m on e (CRH )
Cr oh n disea se
clin ica l m a n ifest a t ion s of, 65
dia gn ost ic cr it er ia , 65
fea t u r es of, 65, 65
pa t h oph ysiology of, 64–65
t r ea t m en t of, 65
u lcer a t ive colit is vs., 67t
Cr oss m a t ch in g, 83, 87
CRP. S ee C-r ea ct ive pr ot ein (CRP )
Cr ypt or ch idism , 360
Cr ypt ospor idiosis, 90
CSF. S ee Cer ebr ospin a l flu id (CSF )
Cu sh in g syn dr om e, 334–336
clin ica l m a n ifest a t ion s of, 335–336
dia gn osis of, 336
dom in a n t fea t u r es of, 336
pa t h oph ysiology of, 335
t r ea t m en t of, 336
CVA. S ee Cost over t ebr a l a n gle (CVA)
CVD. S ee Ca r diova scu la r disea se
(CVD)
Cya n osis, 376
Cyclic a den osin e m on oph osph a t e
(cAMP ), 387
Cycloph osph a m ide, 96t
Cyst ein e, 137t
Cyst ic fibr osis (CF ), 387–389
clin ica l m a n ifest a t ion s of, 388–389
dia gn osis of, 389
pa t h oph ysiology of, 387–388, 388
t r ea t m en t of, 389
Cyst ic fibr osis t r a n sm em br a n e
con du ct a n ce r egu la t or (CF TCR),
387
Cyst om et r ogr a m , 480
Cyst om et r y, 480
Cyst oscopy, 480
Cyst s, 481–482
Cyt okin es, 37
Cyt om ega lovir u s (CMV), 90, 97
Cyt opla sm , 10–11
Cyt osin e, 136, 138
Cyt osin e-a den in e-gu a n in e (CAG)
expa n sion m u t a t ion , 153
Cyt oskelet on , 11
Cyt osol, 106
Cyt ot oxic T lym ph ocyt es, 73, 78
D
D(Rh o) a n t igen , 97
D-dim er t est , 424
Dawn ph en om en on , 519
Debr idem en t , 55
Decibels (dB), 303
Deep pa r t ia l-t h ickn ess bu r n s, 53, 53
Deep t en don r eflexes (DTRs), 208
Defeca t ion , 471
volu n t a r y con t r ol of, 471
Deficit in ju r y, 18
Degr a n u la t ion , 37
Deh iscen ce, 47
Deh ydr a t ion , 208, 212–214, 379
cla ssifica t ion of, 212–213, 213t
clin ica l m a n ifest a t ion s of, 212–213
dia gn osis, 213
h yper n a t r em ic, 212, 213t
ison a t r em ic, 213t
m ild, 212
pa t h oph ysiology of, 212
t r ea t m en t of, 213–214
Dela yed h yper sen sit ivit y r ea ct ion s, 84
Delet ion , 143, 143
Delt a cells, 508, 508
Dem en t ia , H IV-r ela t ed, 91
Den dr it es, 229. S ee a lso Neu r on s
Den dr it ic cells, 72t, 75
Deoxyr ibon u cleic a cid (DNA), 11, 136,
138, 139
m it och on dr ia l, 157–158
r eplica t ion of, 139, 140
sh or t t a n dem r epea t s, 146
Depola r iza t ion , 400
of a ct ion pot en t ia l, 230, 231
Depr ession
a r ea s of br a in a ffect ed by, 265
in dia st olic blood pr essu r e, 402
Der m a t om es, 242, 244
Der m a t oph yt e in fect ion , 129
Dest r u ct ion , of a lveoli, 391b
Det r u sor m u scle, 464, 464
Developm en t a l disor der s, 148–150
gen et ics a n d, 135–166
m a n a gem en t of, 151–152
Developm en t a l t h eor ies of a gin g,
491–492
DE XA. S ee Du a l en er gy X-r a y
a bsor pt iom et r y (DE XA)
DI. S ee Dia bet es in sipidu s (DI)
Dia bet es in sipidu s (DI), 508–509
clin ica l m a n ifest a t ion s of, 331
dia gn osis of, 331–332
m ech a n ism of, 331
pa t h oph ysiology of, 331
t r ea t m en t of, 332
Dia bet es m ellit u s

a cr om ega ly a n d, 24
a cu t e com plica t ion s of, 515–516
ch r on ic com plica t ion s of, 519–521
in fect ion , 521
m a cr ova scu la r disea ses, 520
m icr ova scu la r disea ses, 519–520
n eu r opa t h y, 520–521
gest a t ion a l, 509t, 515–516
t ype 1, 509–512, 509t
clin ica l m a n ifest a t ion s of, 510,
512t
com pa r ison of la bor a t or y t est s for,
512t
dia gn osis of, 510
pa t h oph ysiology of, 509–510
t r ea t m en t of, 510–512
t ype 2, 509t, 513–515
clin ica l m a n ifest a t ion s of, 514
pa t h oph ysiology of, 513–514, 514
t r ea t m en t of, 514–515, 515t
Dia bet ic ket oa cidosis (DKA), 517
Dia gn osis, defin ed, 3
Dia pedesis, 39
Dia r r h ea , 212
Dia st olic blood pr essu r e, 402, 402
depr ession in , 402
Dia st olic fa ilu r e, 418
DIC. S ee Dissem in a t ed in t r a va scu la r
coa gu la t ion (DIC)
Diet , elim in a t ion , 82
Differ en t ia t ion , of cells, 14
Diffu sin g ca pa cit y, 370
Diffu sion , 11–12, 12, 365, 374
of ca r bon dioxide, 369–370
fa cilit a t ed, 438
im pa ir ed, 372–373
dia gn ost ic t est s for, 376–377, 377t
effect s of, 373
gen er a l m a n ifest a t ion s of, 373–
376
la bor a t or y t est s for, 376–377, 377t
t r ea t m en t of, 377, 377–378t
over view, 368–369
of oxygen , 369
pa r t ia l pr essu r e du r in g, 369
sim ple, 438
DiGeor ge a n om a ly, 80t
Digest ion , 435–438, 436, 437t, 439
Dih ydr ot est ost er on e (DTH ), 357
1,25-dih ydr oxych oleca lcifer ol, 496
Dim in ish ed br ea t h sou n ds, 376b
Dipept ida ses, 437t
Diploid n u m ber of ch r om osom es, 138
Diplopia , 298
Dir ect cell-m edia t ed t oxicit y, 84
Dir ect con t a ct t r a n sm ission , 114
Discoid r a sh , 95
Discr im in a t ive pa t h wa y, 289
t wo-poin t discr im in a t ion , 289
Disea se
defin ed, 1–2
pr even t ion , 5
Disea se-m odifyin g a n t i-r h eu m a t oid
dr u gs (DMARD), 96
Dissem in a t ed in t r a va scu la r
coa gu la t ion (DIC), 407
clin ica l m a n ifest a t ion s of, 424
dia gn osis of, 424
In dex 559
pa t h oph ysiology of, 423 m iddle, 300, 301
t r ea t m en t of, 424 a lt er a t ion , 302
Dist a l a xon opa t h y, 247 eva lu a t ion of, 303–304
Diu r et ics, 211 E a r dr u m . S ee Tym pa n ic m em br a n e
defin ed, 205 E bola vir u s, 120
loop, 205, 208 E cch ym oses, 409
pot a ssiu m -spa r in g, 205 E CG. S ee E lect r oca r diogr a m (E CG)
t h ia zide, 205 E ch oca r diogr a ph y (ca r dia c
Diver t icu la , 485 u lt r a sou n d), 409t
Diver t icu la r disea se, 477t, 485–486 E ct ocer vix, 27
clin ica l m a n ifest a t ion s of, 486 E ct opic h or m on e, 182
dia gn osis, 486 E D. S ee E r ect ile dysfu n ct ion (E D)
pa t h oph ysiology of, 485 E dem a , 40t, 208, 208–209, 473
t r ea t m en t of, 486 E dem a t ou s t issu es, 208
Diver t icu lit is, 485, 486 E ffect or cells, 76
Diver t icu losis, 485 E IA. S ee E xer cise-in du ced a st h m a
Diver t icu lu m , 485 (E IA)
DKA. S ee Dia bet ic ket oa cidosis (DKA) E la st in , 43
DMARD. S ee Disea se-m odifyin g a n t i- E lder ly, 492–498, 492–493, 495, 497
r h eu m a t oid dr u gs (DMARD) a gin g t h eor ies a n d, 491–492, 499
DNA. S ee Deoxyr ibon u cleic a cid (DNA) H u t ch in son –Gilfor d P r oger ia
DNA fin ger pr in t in g, 146 Syn dr om e (H GP S), 498–499
DNA m et h yla t ion , 174 m a n a gin g degen er a t ive ch a n ges in ,
Dom in a n t disor der s, a u t osom a l, 143– 498
144, 144 n u t r it ion in , 496–498, 497
Dom in a n t gen es, 142 ost eopor osis in , 494, 499–502
Dopa m in e, 268t, 319 E lect r ica l syn a pses, 231
Doppler u lt r a son ogr a ph y, 409t E lect r oca r diogr a m (E CG), 400, 409t
Dor sa l r oot ga n glia fiber s, 287–288 E lect r ocon vu lsive t h er a py (E CT),
Down syn dr om e, 146–147, 157–160 276
clin ica l m a n ifest a t ion s of, 158–159, E lect r olyt es
159 ba la n ce
dia gn osis of, 159–160 a gin g a n d, 493
pa t h oph ysiology of, 158 a lt er ed, 198–201, 199, 201t
pr eva len ce of, 4 con cept m a p for, 222
t r ea t m en t of, 160 r en a l r egu la t ion of, 203
Dr oplet t r a n sm ission , 114 defin ed, 198
Dr u g a ller gies, 81 im ba la n ce, 198–201, 198, 201t
DTH . S ee Dih ydr ot est ost er on e (DTH ) t r a n spor t , 198
DTRs. S ee Deep t en don r eflexes E licit a t ion ph a se, in delayed
(DTRs) h yper sen sit ivit y r ea ct ion s, 84
Du a l en er gy X-r a y a bsor pt iom et r y E m bolu s, 406
(DE XA), 500–501 E m br yon ic ca r cin om a s, 360
Du ch en n e m u scu la r dyst r oph y, 14 E m ph ysem a , 380–383
Du plica t ion , 143, 143 a ir t r a ppin g of, 381, 382
Dyskin esia , ea r ly sign s of, 153 clin ica l m a n ifest a t ion s of, 382
Dysm en or r h ea , 347 dia gn osis of, 382
Dyspa r eu n ia , 347, 354 pa t h oph ysiology of, 381–382
Dyspepsia , 60 t r ea t m en t of, 382–383
Dyspla sia , 15, 17, 17 t ypes of, 381
cer vica l, 26–29, 27, 28t E m u lsifica t ion , 441
clin ica l m a n ifest a t ion s of, 27–28 E n copr esis. S ee F u n ct ion a l feca l
dia gn osis, 28–29, 28t in con t in en ce
pa t h oph ysiology of, 26–27 E n dem ic disea se, defin ed, 4
t r ea t m en t of, 29 E n doca r diu m , 399
Dyspn ea , 375, 496 E n docer vica l ca n a l, 27
Dyst on ia , 249b E n docr in e gla n ds, da m a ge t o, 328
Dysu r ia , 125 E n docr in e pa n cr ea s, 508
E n docr in e pa t h way, 324, 324
E E n docr in e sign a lin g, 14
E a r (s). S ee a lso H ea r in g E n docr in e syst em , 319
a n a t om y of, 300–301, 300 or ga n s of, 321
ca n a l, 300 E n docyt osis, 13, 13
ext er n a l, 300, 300 E n dogen ou s t oxin s, 18
a lt er a t ion , 302 E n dom et r ia l gr owt h , 344, 344
in n er, 301 ph a ses of, 344
a lt er a t ion , 303 E n dom et r iosis, 347, 348
eva lu a t ion of, 304 E n dopla sm ic r et icu lu m , 11
560 In dex
E n dot h elia l cells
of blood vessels, 36
in fla m m a t or y m edia t or s in , 38
E n dot oxin , 106, 107
E n t er ic n er vou s syst em , 471
E n u r esis, defin it ion of, 479. S ee a lso
Ur in a r y in con t in en ce
E n vir on m en t a l t oxin s, a n d
ca r diova scu la r disea se, 29–31
E n zym es, 454
E osin oph ils, 41t, 74
E pidem ic disea se, defin ed, 4
E pidem iology, defin ed, 4
E pididym is, 344, 345
E pigen et ic in h er it a n ce, 147
E pigen et ic in h er it a n ce: Beckwit h –
Wiedem a n n syn dr om e, 163–164
E pin eph r in e, 320t
E piph ysea l, 23
E pit h elia l cells, 437
E pit h elia l t u m or s, 353
E pit h elioid cells, 48
E pit h eliom a , 179
E pst ein -Ba r r vir u s, 120
E r ect ile dysfu n ct ion (E D), 356–357
clin ica l m a n ifest a t ion s of, 356–357
dia gn osis of, 357
pa t h oph ysiology of, 356
t r ea t m en t of, 357
E r yt h em a , 39
E r yt h r obla st osis fet a lis, 97
E r yt h r ocyt e sedim en t a t ion r a t e, 41t
E r yt h r opoiesis, 120
E sch a r, 54
E sch er ich ia coli, 109, 125, 473
E ssen t ia l n u t r ien t s, 429
E st r ogen s, 320t, 341, 344, 354, 454,
502t
E SWL. S ee E xt r a cor por ea l sh ockwa ve
lit h ot r ipsy (E SWL)
E t iology, defin ed, 2
E u pn ea , 371t
E viden ce-ba sed pr a ct ice, 5
E xa cer ba t ion s, 3
E xcit a t ion in ju r y, 241
E xer cise, a n d blood glu cose levels, 511
E xer cise-in du ced a st h m a (E IA), 384
E xocr in e pa n cr ea s, 508
E xocyt osis, 13, 13
E xogen ou s t oxin s, 18
E xon s, 137, 139
E xoph t h a lm os, 333
E xpect or a t e, 375
E xpir a t ion , 368
E xpr essivit y, of m u t a t ion , 142
E xt avia , in m u lt iple scler osis, 255t
E xt er n a l a n a l sph in ct er, 471
E xt er n a l ea r, 300, 300
a lt er a t ion in , 302
E xt er n a l gen it a lia , fea t u r es of, 341
E xt er n a l u r et h r a l sph in ct er, 464
E xt r a cellu la r com pa r t m en t , body flu id,
202, 202
E xt r a cellu la r m a t r ix (E CM), 43–44, 43
E xt r a cor por ea l sh ockwa ve lit h ot r ipsy
(E SWL), 479
E xt r a pyr a m ida l syst em , 237
E xu da t e, 36
E ye(s). S ee a lso Visu a l im pa ir m en t
a n a t om y of, 294–295, 294, 296
color of, 142
ext r a ocu la r m u scles, 295, 296
fu n ct ion , 297t
m ovem en t of, 295
a lt er a t ion s in , 297–298
pr ot ect ive st r u ct u r es, 295–297
a lt er a t ion s in , 298–299
r et in a in . S ee Ret in a
E yelids, 295
F Food a ller gy, 78, 446–447
F cells, 508
Fa cia l n er ve, 243t
Fa cilit a t ed diffu sion , 12, 12, 438
Fa cu lt a t ive pa r a sit es, 105
Fa llopia n t u bes, cr oss-sect ion of, 343
Fa m ilia l t en den cy, of a u t oim m u n it y, 85
FAS. S ee Fet a l a lcoh ol syn dr om e (FAS)
Fa t -solu ble vit a m in s, 432
Fa t t y a cids
a bsor pt ion of, 441
sa t u r a t ed, 430
sh or t -ch a in , 444, 446
u n sa t u r a t ed, 430
Feca l in con t in en ce, 498
Feedba ck m ech a n ism s, 14
for h or m on es, 321–322, 323
da m a ge t o, 328
Fem a le pelvis, a n t er opost er ior
r a diogr a ph of, 349
Fem a le r epr odu ct ive h or m on e, fu n ct ion
of, 341–344
Fem a le r epr odu ct ive or ga n , st r u ct u r es
of, 342
Fer r it in , 449t
F E T. S ee For ced expir a t or y t im e (F E T)
Fet a l a lcoh ol syn dr om e (FAS), 149
F E V1 . S ee For ced expir a t or y volu m e in
1 secon d (F E V1 )
Fiber s, 431
of dor sa l r oot ga n glia , 287–288
Fibr illa t ion , 408
Fibr in ogen , 41t
Fibr in olysis, 423
Fibr obla st s, 43, 48
Fibr om ya lgia
clin ica l m a n ifest a t ion s of, 306
defin ed, 305
dia gn ost ic cr it er ia of, 306
pa t h oph ysiology of, 305–306
t r ea t m en t of, 306–307
Fibr osis, of a lveoli, 391b
Filt r a t ion pr essu r e, 202, 203
Fist u la , 64
F lu id(s)
ba la n ce, 202–205, 203, 206
a gin g a n d, 493
a lt er ed, 206–209, 210–212, 211,
213
excr et ion
m ech a n ism s t o pr om ot e, 206
im ba la n ce, 202–209
r egu la t ion , 203, 205
cycle, 206
r eh ydr a t ion , 213–214
r en a l r egu la t ion of, 203, 203
r epla cem en t , 207–208
t r a n spor t m ech a n ism s, 204t
F lu or escein a n giogr a ph y, for m a cu la r
degen er a t ion (MD), 311
F lu or ide, 434t
F MR1 gen e t est , 162
F MRP. S ee F r a gile X m en t a l
r et a r da t ion pr ot ein (F MRP )
Foca l isch em ia , 239
Fola t e, 433t, 445t, 449t
Follicle-st im u la t in g h or m on e (F SH ),
320t, 322, 341, 355
a lt er ed n u t r it ion
clin ica l m a n ifest a t ion s of, 447
dia gn osis r ela t ed t o, 447
t r ea t m en t r ela t ed t o, 447
For ced expir a t or y t im e (F E T), 382
For ced expir a t or y volu m e in 1 secon d
(F E V1 ), 368
For ced vit a l ca pa cit y (F VC), 368
Fovea , 295
F r a gile X-a ssocia t ed t r em or /a t a xia
syn dr om e (F XTAS), 163
F r a gile X m en t a l r et a r da t ion pr ot ein
(F MRP ), 162
F r a gile X syn dr om e (F XS), 148,
161–163
clin ica l m a n ifest a t ion s of, 162–163
dia gn osis of, 163
t r ea t m en t of, 163
F r ee r a dica l in ju r y, 19
F r ee r a dica l t h eor y of a gin g, 492
F r ia bilit y, 66
F r u ct ose, a bsor pt ion , 438, 440
F SH . S ee Follicle-st im u la t in g h or m on e
(F SH )
F u ll-t h ickn ess bu r n s, 54
F u lm in a n t h epa t it is, 121
F u n ct ion , defin ed, 1
F u n ct ion a l con cept s of a lt er ed h ea lt h ,
5–6
F u n ct ion a l feca l in con t in en ce, 486–487
clin ica l m a n ifest a t ion s of, 486–487
dia gn osis, 487
pa t h oph ysiology, 486
t r ea t m en t of, 487
F u n ct ion a l in con t in en ce, 480
F u n gi, 110–112, 112
F VC. S ee For ced vit a l ca pa cit y (F VC)
F XS. S ee Fr a gile X syn dr om e (F XS)
F XTAS. S ee F r a gile X-a ssocia t ed
t r em or /a t a xia syn dr om e (F XTAS)
G
G-6-P D. S ee Glu cose-6-ph osph a t e
deh ydr ogen a se (G-6-P D)
G cells, 437
GAD. S ee Glu t a m ic a cid deca r boxyla se
(GAD)
Ga la ct osem ia , 141t
Ga llst on es, 450
Ga m et es, 138
Ga m m a -a m in obu t yr ic a cid (GABA),
268t
Ga st r ic epit h elia l cells, 437
Ga st r ic lin in g, 58, 59
Ga st r ic per for a t ion , 59, 59

Ga st r ic su r ger y, 455
Ga st r in , 437–438
Ga st r it is, 58–59
a cu t e, 59–60
ch r on ic, 61
Ga st r oen t er it is, 111t
Ga st r oin t est in a l (GI) t r a ct , 437
Gen e t h er a py, 163
Gen e va r ia n t s a n d epigen et ics, r ole of,
174
Gen er a l a da pt a t ion syn dr om e, 327
Gen er a lized seizu r es, 251
Gen es, 11, 136–138, 137t, 138, 139. S ee
a lso Gen et ics
Gen et ic code, 136
Gen et ic disor der s, in h er it a n ce of,
140–148
Gen et ic m u t a t ion s, 143, 143, 172–174
Gen et ic r eplica t ion , 139–140, 140
Gen et ic t r a it s, t r a n sm ission a n d
expr ession of, 141–142
Gen et ics, 454
ca n cer a n d, 142
con gen it a l disor der s a n d, 148–150
developm en t a l disor der s a n d,
135–166
m a n a gem en t of, 151–152
disea se in h er it a n ce a n d, 140–148,
141t, 142–147, 143t
r epr odu ct ive cou n selin g a n d, 151–
152
scr een in g t est s a n d, 151–152
Gen om ics, 140
im pr in t in g, 148
Gen ot ype, 141
Ger m cell t u m or s, 353, 360
cla ssifica t ion of, 361
Gest a t ion a l dia bet es, 509t, 515–516
GF R. S ee Glom er u la r filt r a t ion r a t e
(GF R)
GH . S ee Gr owt h h or m on e (GH )
Gh on com plex, 123, 123
Gh on focu s, 123
Gh r elin h or m on e, 454
GH RH . S ee Gr owt h h or m on e-r elea sin g
h or m on e (GH RH )
GI t r a ct . S ee Ga st r oin t est in a l (GI)
t r a ct
Gia n t cells, 48
Giem sa , 147
Giga n t ism , 24
Gilen va , in m u lt iple scler osis, 255t
Git elm a n syn dr om e (GS), 224
Gla u com a , 312–313, 312, 313
clin ica l m a n ifest a t ion s of, 312
defin ed, 312
dia gn ost ic cr it er ia of, 313
pa t h oph ysiology of, 312
t r ea t m en t of, 313
Glisson ca psu le, 119
Globa l isch em ia , 239, 240
Glom er u la r filt r a t ion r a t e (GF R), 467
Glom er u lu s, 461
Glossoph a r yn gea l n er ve, 243t
Glu ca gon , 320t, 508, 510, 514
Glu cocor t icoids, 96t, 320t, 329t, 337t
in a cu t e in fla m m a t ion , 41t
Glu cose, 431, 432, 463t, 507–508
a bsor pt ion , 438, 440
Glu cose-6-ph osph a t e deh ydr ogen a se
(G-6-P D), 336
Glu cosu r ia , 468t
Glu t a m a t e, 241, 268t
Glu t a m ic a cid, 137t
Glu t a m ic a cid deca r boxyla se (GAD),
509
Glu t a m in e, 137t
Glu t en -sen sit ive en t er opa t h y, 451–452
Glu t en s, 451
Glycem ic a gen t s, or a l. S ee Or a l
glycem ic a gen t s
Glycer ol, a bsor pt ion of, 441
Glycin e, 137t
Glycolipids, 10
Glycolysis, 14
Glycopr ot ein s, 44
Glycosyla t ed h em oglobin (H bA1c ), 510
Glycosyla t ion , 519
GM2 ga n gliosides, 442
Gn RH . S ee Gon a dot r opin -r elea sin g
h or m on e (Gn RH )
Goit er, 333
Golgi a ppa r a t u s, 11
Gon a dot r opin -r elea sin g h or m on e
(Gn RH ), 319, 320t, 341
Gr a ft vs. h ost disea se (GVH D), 87
Gr a ft s r eject ion , 87
Gr a n u la t ion t issu e, 44, 44
Gr a n u locyt es, 74
Gr a n u lom a for m a t ion , 48–49, 49
Gr aves disea se, 333
dia gn osis of, 333
m a jor clin ica l m a n ifest a t ion s of, 333
Gr ay m a t t er, 234. S ee a lso Cen t r a l
n er vou s syst em (CNS)
Gr owt h h or m on e (GH ), 319, 320t, 329t
Gr owt h h or m on e-r elea sin g h or m on e
(GH RH ), 319, 320t
GS. S ee Git elm a n syn dr om e (GS)
Gu a ia c t est , 476
Gu a n in e, 136, 138
Gu t h r ie ba ct er ia l in h ibit ion a ssay, 142
GVH D. S ee Gr a ft vs. h ost disea se
(GVH D)
H H epa t it is A, 120t
H 2 CO 3 . S ee Ca r bon ic a cid (H 2 CO 3 )
H AART. S ee H igh ly a ct ive
a n t ir et r ovir a l t h er a py (H AART)
H a em oph ilu s in flu en za e, 378
H a ir, a ge-r ela t ed ch a n ges t o, 493
H a ir cells, 301, 301
H a n d-foot -m ou t h disea se, 111t
H a ploid n u m ber of ch r om osom es, 138
H a sh im ot o t h yr oidit is, 333
H a u st r a s, 471
H bA. S ee H em oglobin A (H bA)
H bA1c. S ee Glycosyla t ed h em oglobin
(H bA1c )
H bF. S ee H em oglobin F (H bF )
H bO 2 . S ee Oxyh em oglobin (H bO 2 )
H bS. S ee H em oglobin S (H bS )
H CG. S ee H u m a n ch or ion ic
gon a dot r opin (h CG )
H CO 3 2 . S ee H ydr ogen bica r bon a t e
(H CO 3 2 )
In dex 561
HDL. See High-density lipoprotein (HDL)
H ea d, lipid st r u ct u r e, 10
H ea lt h
defin ed, 4
of popu la t ion , 4–5
H ea r in g. S ee a lso E a r (s)
loss, 302
eva lu a t ion of, 303–304
m a n ifest a t ion s of, 303
t r ea t m en t of, 304
pr ocess, 301
H ea r t
con du ct ion syst em of, 399–401, 400
m ovem en t of blood t h r ou gh a r t er ies,
398, 398
st r u ct u r a l defect s of, 407–408, 407
su per ior view of, 399
H ea r t block, 408
H ea r t fa ilu r e
clin ica l m a n ifest a t ion s of, 420–421
com pen sa t or y m ech a n ism s in , 420
dia gn ost ic cr it er ia of, 421
over view, 418
pa t h oph ysiology of, 418–420
t r ea t m en t of, 421–422
H ea r t r a t e, 401, 401b
H elicoba cter pylor i, 60, 109, 176
H elper T lym ph ocyt es, 74
H em a t om a , 409
H em a t opoiet ic st em cells, 87
H em a t u r ia , 125, 468, 468t, 478
H em odia lysis, 483, 484
H em oglobin A (H bA), 154
H em oglobin elect r oph or esis, 155
H em oglobin F (H bF ), 156
H em oglobin S (H bS), 154, 155
H em olysis, 155
H em olyt ic a n em ia , 97
H em olyt ic disea se, of fet u s a n d
n ewbor n , 96–99
H em oph ilia , 145
H em opt ysis, 124, 375
H em or r h a ge, 207–208, 404
H em or r h oids, 475, 477t
H epa t ic st ea t osis, 223
H epa t it is, 119–120
vir a l, 120–122, 120t
H epa t it is B, 109, 120t, 121, 184
pr even t ion of, 121–122
H epa t it is C, 120t
H epa t it is D, 120t
H epa t it is E , 120t
H epa t om ega ly, 223
H epa t or en a l syn dr om e, 211
H er edit a r y pr ost a t e ca n cer (H P C1),
358
H er edit y, 135
H er pes sim plex vir u s, la t en cy in , 109
H er pes zost er vir u s, la t en cy in , 110
H er t z (H z), 303
H et er opla sm y, 145
H et er ozygou s a lleles, 142
H GSIL. S ee H igh -gr a de squ a m ou s
in t r a epit h elia l lesion (H GSIL)
H H NK. S ee H yper glycem ic
h yper osm ola r n on ket ot ic
syn dr om e (H H NK)
562 In dex

H igh -den sit y lipopr ot ein (H DL), 355, H u m a n ch or ion ic gon a dot r opin (h CG), H yper pla sia , 15, 16
412 341 H yper pn ea (Ku ssm a u l r espir a t ion s)
H igh -gr a de squ a m ou s in t r a epit h elia l H u m a n gen om e m a ppin g, 146 h yper ven t ila t ion , 372t
lesion (H GSIL), 28 H u m a n Gen om e P r oject , 140 H yper pr ost a gla n din -E syn dr om e
H igh ly a ct ive a n t ir et r ovir a l t h er a py H u m a n im m u n odeficien cy vir u s (H IV), (H P S), 224
(H AART), 222–223 89 H yper sen sit ivit y r ea ct ion , 81–85
clin ica l m a n ifest a t ion s, 223 H u m a n leu kocyt e a n t igen s (H LA), 78 t ype I im m edia t e, 82–83, 82
dia gn osis, 223 H u m a n pa pillom a vir u s (H P V), 27–29 t ype II a n t ibody-m edia t ed, 83, 83
pa t h oph ysiology, 223 ca n cer a n d, 176 t ype III im m u n e com plex-m edia t ed,
t r ea t m en t of, 223 H u m a n pa r vovir u s B19, 111t 83–84, 84
H ippoca m pa l for m a t ion , 267 H u m or a l im m u n it y, 76–77, 77 t ype IV cell-m edia t ed, 84–85
H ippoca m pu s, 235t, 241, 266 H u n ger, 435 t ypes of, 82t
H ir su t ism , 336 H u n tin gtin gen e, 153, 154 H yper t en sion
H ist idin e, 137t H u n t in gt on disea se (H D), 152–154 a ffect s ca r diova scu la r syst em , 411
H ist on es, 138 clin ica l m a n ifest a t ion s of, 153 clin ica l m a n ifest a t ion s of, 411–412
m odifica t ion , 174 dia gn osis of, 153–154 dia gn osis of, 412
H IV. S ee H u m a n im m u n odeficien cy pa t h oph ysiology of, 152–153 pa t h oph ysiology of, 410–411
vir u s (H IV) t r ea t m en t of, 154 r isk fa ct or s for, 411
H LA. S ee H u m a n leu kocyt e a n t igen s H u t ch in son –Gilfor d P r oger ia t r ea t m en t of, 412–413
(H LA) Syn dr om e (H GP S) H yper t h yr oidism , 332–333, 496
H odgkin lym ph om a in a gin g, 498–499 clin ica l m a n ifest a t ion s of, 332–333
descr ipt ion of, 192 clin ica l m a n ifest a t ion s of, 499, 499 dia gn osis of, 333
dia gn osis of, 193 dia gn osis of, 499 pa t h oph ysiology of, 332
m a n ifest a t ion s of, 193 pa t h oph ysiology of, 498–499 t r ea t m en t of, 333
pa t h oph ysiology of, 192–193 t r ea t m en t of, 499 H yper t on ic solu t ion s, 205, 208
t r ea t m en t of, 193 H ydr a t ion , for DI, 332 H yper t r oph ic obesit y, 453
H om a n s sign , 408 H ydr oceph a lu s H yper t r oph y, 15, 16
H om eost a sis, 325 clin ica l m a n ifest a t ion s of, 255, 256 H yper volem ia , ca u ses of, 208
defin ed, 4 descr ipt ion of, 254 H yph a e, 111
H om ocyst ein e, 416 dia gn ost ic cr it er ia of, 256 H ypoca lcem ia , 200, 201t
H om ocyst in u r ia , 141t pa t h oph ysiology of, 254 H ypoch lor em ia , 200, 201t
H om ozygou s a lleles, 142 t r ea t m en t of, 256 H ypoch r om ic a n em ia , 448, 448
H or m on e-r ecept or in t er a ct ion s, 324 H ydr ogen , 463t H ypoga m m a globu lin em ia , 80t
H or m on e r epla cem en t t h er a py (H RT), H ydr ogen bica r bon a t e (H CO32), 220 H ypoglossa l n er ve, 243t
355 ba se deficit of, 221 H ypoglycem ia , 516–517
H or m on es, 14, 454 H ydr ogen ion s, 219 clin ica l m a n ifest a t ion s of, 517
a n d ca n cer, 175 elim in a t ion , 220–221 pr even t ion of, 517
defin ed, 319 H ydr on eph r osis, 467, 478 H ypogon a dism , 356, 357
elim in a t ion of, 322 H ydr oph ilic h ea d, 10 H ypoka lem ia , 199
da m a ge t o, 328 H ydr oph obic t a il, 10 H ypokin esia , 249b
feedba ck m ech a n ism s, 321–322, H ydr ost a t ic for ces, 202 H ypom a gn esem ia , 200, 201t
323 H ydr ou r et er, 466 H ypom a n ia , 276
fu n ct ion s of, 320t, 327–329, 327b, H ydr oxych lor oqu in e, 96t H ypon a t r em ia , 199, 493
329t H ygr om a , 161 H ypon a t r em ic deh ydr a t ion , 212, 213t
dia gn osis of, 329 H yper a cu t e gr a ft r eject ion , 87 H ypopa r a t h yr oidism
gen er a l m a n ifest a t ion s of, 328– H yper ca lcem ia , 200, 201t clin ica l m a n ifest a t ion s of, 215
329, 329t H yper ca pn ia , 373 dia gn osis, 215
t r ea t m en t of, 329 H yper cellu la r obesit y, 453 pa t h oph ysiology of, 214–215
m edia t in g cell-t o-cell H yper ch lor em ia , 200, 201t t r ea t m en t of, 215
com m u n ica t ion , 324, 324 H yper ch lor em ic a cidosis, 221 H ypoper fu sion , 213
m et a bolism of, 322 H yper coa gu la bilit y, 406 H ypoph osph a t em ia , 201, 201t
da m a ge t o, 328 H yper glycem ia , 509, 510 H ypopit u it a r ism , 327
r ecept or bin din g in , 322–323, 324 con cept m a p, 511 H ypot en sion , 200, 201t, 413
r egu la t ion of, 319 r ebou n d, 518 H ypot h a la m ic-pit u it a r y a xis, 319, 492
r elea ses fr om h ypot h a la m u s t o H yper glycem ic h yper osm ola r da m a ge t o, 327–328
a n t er ior pit u it a r y, 321b n on ket ot ic syn dr om e (H H NK), r egu la t es r elea se of h or m on es, 322
r espon se t o st r ess, 326, 326 517–518 H ypot h a la m u s, 40, 235t, 266, 319, 326,
secr et ion of, 322 H yper h om ocyst ein em ia , 416 435
H ost defen se fa ilu r e, 78 H yper in su lin em ia , 516 H ypot h yr oidism , 141t, 496
H ost , defin ed, 78 H yper ka lem ia , 199–200, 201t clin ica l m a n ifest a t ion s of, 334
H P C-1, 144. S ee a lso H er edit a r y H yper ket on em ia , 510 dia gn osis of, 334
pr ost a t e ca n cer (H P C1) con cept m a p, 511 m a jor clin ica l m a n ifest a t ion s of, 334
H P S. S ee H yper pr ost a gla n din -E H yper kin esis, 249b pa t h oph ysiology of, 333–334
syn dr om e (H P S) H yper la ct a t em ia , 223 t r ea t m en t of, 334
H P V. S ee H u m a n pa pillom a vir u s H yper m a gn esem ia , 200, 201t H ypot on ic h ypovolem ia , 208
(H P V) H yper n a t r em ia , 199, 201t, 493 H ypot on ic solu t ion s, 205
H RT. S ee H or m on e r epla cem en t H yper opia , 297, 298 H ypovolem ia , 206–207
t h er a py (H RT) H yper ph osph a t em ia , 201, 201t ca u ses of, 207
 In dex 563

clin ica l m a n ifest a t ion s of, 207 t est for, 116, 117t In su lin r epla cem en t t h er a py, 511
H ypovolem ic sh ock, 413 t r a n sm ission of, 114 In t egr a l pr ot ein s, 10
H ypoxem ia , 373, 382 t r ea t m en t of, 116–117 In t egr a se st r a n d t r a n sfer in h ibit or s
H ypoxia , 373 In fect ivit y, 105 (INSTIs), 91
In fer t ilit y, in fem a les, ca u ses of, 347 In t egr a t ed pa t h oph ysiologic con cept s,
I In fla m m a t ion , 34–69 507–522
Ia t r ogen ic disea se, defin ed, 2 a cu t e, 36–41 In t er m it t en t cla u dica t ion , 520
IBD. S ee In fla m m a t or y bowel disea se cellu la r r espon se t o, 38–39, 39, 40t In t er n a l r ect a l sph in ct er, 471
(IBD) ch r on ic, 48–49 In t er n a l u r et h r a l sph in ct er, 464, 464
ICF. S ee In t r a cellu la r flu id (ICF ) clin ica l m odels, 49–67 In t est in a l flor a , 470
Ict er ic ph a se, 121 a n d t issu e r epa ir In t est in a l lipa se, 437t
IDDM. S ee In su lin -depen den t dia bet es a cu t e in fla m m a t ion , 35–41 In t r a cellu la r com pa r t m en t , body flu id,
m ellit u s (IDDM) a pplied pa t h oph ysiology clin ica l 202, 202
Idiopa t h ic disea se, defin ed, 2 m odels, 49–67 In t r a cellu la r flu id (ICF ), 198
IGF -1. S ee In su lin -like gr owt h fa ct or 1 ch r on ic in fla m m a t ion , 48–49 In t r a cr a n ia l pr essu r e (ICP ), 240, 242
(IGF -1) h ea lin g a n d t issu e r epa ir, 42–47 In t r a der m a l skin t est , 81
Ileoceca l va lve, 469 in t r odu ct ion of, 34–35 In t r a ven ou s a lbu m in , 211
Illn ess, defin ed, 4 lea r n in g ou t com es, 34 In t r a ven ou s pyelogr a m (IVP ), 469
Im m u n e defen se va scu la r r espon se t o, 36–38, 36, 37, In t r on s, 137, 139
cellu la r com pon en t s of, 73 38t In ver sion , 143, 143
com pon en t s, fu n ct ion of, 72t In fla m m a t or y bowel disea se (IBD), In volu t ion , 15
Im m u n e r espon ses, 35 63–67 Iodin e, 434t
a gin g a n d, 493 Cr oh n disea se, 64–65, 66 Ion ch a n n els, ca t egor ies of, 12
in disea se m a n a gem en t , 88–89 u lcer a t ive colit is, 65–67, 66, 67t Ion s, 198
m a la da pt ive, 89–99 In fla m m a t or y m edia t or s, 36–38 dist r ibu t ion of, in t r a cellu la r a n d
t r ea t m en t of, 88 in cells, 37–38 ext r a cellu la r, 198
m a n ipu la t ion , 87–89 in en dot h elia l/in ju r ed t issu e cells, 38 h ydr ogen , 219
in pr even t ion of disea se, 89 in pla sm a , 38, 38t elim in a t ion , 220–221
Im m u n e sen escen ce, 493 in pla t elet s, 37–38 st r on g, 219
Im m u n e syst em r ole, 37 Ir on , 434t
cells of, 73–75 in wh it e blood cells, 37 deficien cy of, 448–449, 449, 449t
pr ocesses, 76–78 In flu en za Ir r it a ble bowel syn dr om e, 477t
Im m u n it y, 71–100 clin ica l m a n ifest a t ion s of, 117–118 Isch em ia , 15
a da pt ive, 76–78, 77, 79 descr ipt ion , 117 Isch em ic in ju r y, 239–241
a lt er a t ion in , 78–87 dia gn ost ic cr it er ia , 118 Islet s of La n ger h a n s, 508, 508
clin ica l m odels, 89–99 pa t h oph ysiology of, 117 Isola t ed dia st olic h yper t en sion , 410–
cell-m edia t ed, 77, 79 t r ea t m en t of, 118 411
cellu la r com pon en t s of, 73–75 In gest ion , in cells, 13 Isola t ed syst olic h yper t en sion , 410
h u m or a l, 76–78, 77 In h er it a n ce of gen et ic disor der s, Isoleu cin e, 137t
in n a t e, 76 140–148 Ison a t r em ic deh ydr a t ion , 213t
Im m u n odeficien cy, 80, 80t In it ia t ion -pr om ot ion -pr ogr ession Isot on ic solu t ion , 205–206, 214
Im m u n oglobu lin (Ig), 74, 74t, 76 t h eor y, for ca n cer, 176–177, 176 IVP. S ee In t r a ven ou s pyelogr a m (IVP )
Im m u n oglobu lin A (IgA), 74, 74t, 76 In ju r ed t issu e cells, in fla m m a t or y
Im m u n oglobu lin D (IgD), 74, 74t, 76 m edia t or s in , 38 J
Im m u n oglobu lin E (IgE ), 74, 74t, 76, In ju r y, defin ed, 36 J a u n dice, 120, 120
82, 82t In n a t e im m u n it y, 75 J u ven ile-on set dia bet es, 509
Immu n oglobu lin G (IgG), 74, 74t, 76, 82t In n er ea r. S ee a lso E a r (s)
Immunoglobulin M (IgM), 74, 74t, 76, 82t a lt er a t ion , 303 K
Im m u n ologic m em or y, 77 eva lu a t ion of, 304 Ka posi sa r com a , 90, 91
Im m u n ologic t h eor y of a gin g, 491 In n er m u cosa , 437 Ka r yot ype, 146, 146, 161
Im m u n ology, 72 In ser t ion , 143, 143 Keloids, 47, 47
Im pa ir ed fa st in g glu cose, 514 In spir a t ion , 368 Ker n ig sign , 129
In bor n er r or s of m et a bolism , 442 In su lin , 320t, 454 Ket oa cidosis, dia bet ic, 510, 517
In ciden ce, defin ed, 4 deficit , 509–512, 509b Ket on es, 443
In cu ba t ion , 116, 120 clin ica l m a n ifest a t ion s of, 510, Ket on u r ia , 468t
In cu s, 300 512t Kidn ey st on es, 477–479
In dividu a l h ea lt h , 4 dia gn osis of, 510 clin ica l m a n ifest a t ion of, 478
pa t h oph ysiology in , 4, 4 pa t h oph ysiology of, 509–510 dia gn osis of, 478–479
In dom et h a cin , 225 t r ea t m en t of, 510–512 pa t h oph ysiology of, 477–478
In fa r ct , 406 glu cose a n d, 507–508 t r ea t m en t of, 479
In fect ion , 18, 103–131, 104, 521 in fu sion pu m ps, 512 t ypes of, 478–479, 478
ch a in of, 113–115, 113 r ecept or s, 513 Kidn eys
clin ica l m a n ifest a t ion s, 116 r esist a n ce, 509b, 513–515 a gin g a n d, 497–498
clin ica l m odels, 117–131 t ypes of, 511, 513t a n a t om y of, 462
com plica t ion s of, 116 In su lin -depen den t dia bet es m ellit u s bu ffer syst em , 220
oppor t u n ist ic, 110–112 (IDDM), 509 fu n ct ion of, 126
pa t h ogen icit y of, 105 In su lin -like gr owt h fa ct or 1 (IGF -1), h ydr on eph r ot ic, 467
ph a ses of, 115–116, 115 23, 24 polycyst ic, 482
564 In dex

Klin efelt er syn dr om e (KS), 161, 162 Loop of H en le, 205, 224, 461, 462, 463 Ma le r epr odu ct ive h or m on e, fu n ct ion
KS. S ee Klin efelt er syn dr om e (KS) Low-den sit y lipopr ot ein (LDL), 355, of, 344–346
Ku pffer cells, 119–120 405 Ma lleu s, 300
Ku ssm a u l r espir a t ion s, 517 Low-gr a de squ a m ou s in t r a epit h elia l Ma ln u t r it ive pr ocess, 447
Kwa sh ior kor, 443, 444 lesion (LGSIL), 28 Ma lt a se, 437t
Kyph osis, 495 Lower m ot or n eu r on s (LMN), 236 Ma n ga n ese, 434t
Lu br ica n t s, 477 Ma ple syr u p u r in e disea se, 141t
L Lu n g ca n cer Ma r a sm u s, 443
La bia m a jor a , 341, 341 dia gn osis of, 185–186 Ma r fa n syn dr om e, 381
La bia m in or a , 341, 341 m a n ifest a t ion s of, 185 Ma r sh a ll-Ma r ch et t i-Kr a n t z (MMK)
La bile cells, 45 pa t h oph ysiology of, 185 pr ocedu r e, 481
La byr in t h it is, 303 st a gin g of, 186 Ma ss m ovem en t s, 471
La cr im a l gla n ds, 296 t r ea t m en t of, 186 Ma st cell, 37
La ct a se, 437t Lu n gs, h ist ologic ch a n ges in , 379 Ma st oidit is, 302
La ct ea ls, 438 Lu t ein izin g h or m on e (LH ), 320t, 341 Ma t er n a l sen sit iza t ion , 97, 98
La ct ic a cidem ia , 223 Lym ph flu id, 75 Ma t er n a l ser u m a lph a -fet opr ot ein
La ct ic a cidosis, 223 Lym ph n odes, 72t, 75 (MSAF P ), 165
La ct ic a cidosis syn dr om e (LAS), 223 Lym ph a den it is, 39 Ma t u r it y-on set dia bet es of t h e you n g
La ct oba cillu s a cidoph ilu s, 473 Lym ph a den opa t h y, 90 (MODY), 513
La m in A, 498 Lym ph a t ic syst em , st r u ct u r es of, 75, 75 Ma xilla r y sin u sit is, 51
La n ger h a n s cells, 75 Lym ph a t ics, 75–78 MCA P SV. S ee Middle cer ebr a l a r t er y
La n u go, 451 Lym ph edem a , 197, 208 pea k syst olic velocit y (MCA P SV)
La pa r oscopy, 348 Lym ph ocyt e ign or a n ce, 85 MCH C. S ee Mea n cor pu scu la r
La r ge in t est in e, 469 Lym ph ocyt es, 41t h em oglobin con cen t r a t ion
fu n ct ion of, 65 Lym ph oid m u cosa l t issu e, 72t, 75 (MCH C)
LAS. S ee La ct ic a cidosis syn dr om e Lym ph oid pr ogen it or cells, 73 MCV. S ee Mea n cor pu scu la r volu m e
(LAS) Lym ph om a s (MCV)
La ser-a ssist ed in sit u ker a t om ileu sis H odgkin lym ph om a , 192–193 Mea n a r t er ia l pr essu r e, 402
(LASIK), 299 NH L, 193–194 Mea n cor pu scu la r h em oglobin
LASIK. S ee La ser-a ssist ed in sit u Lysin e, 137t con cen t r a t ion (MCH C), 448
ker a t om ileu sis (LASIK) Lysosom e, 11 Mea n cor pu scu la r volu m e (MCV), 448
La t en cy Mea sles, 111t
defin ed, 78, 80 M Mech a n ica l in ju r y, 18
in vir a l in fect ion , 110 Ma cer a t ion , 112 Mech a n or ecept or s, 287, 288, 288t
LDL. S ee Low-den sit y lipopr ot ein Ma cr olides, for pn eu m on ia , 380 Mediu m -ch a in a cyl-CoA
(LDL) Ma cr om in er a ls, 433 deh ydr ogen a se -deficien cy, 141t
Left h ea r t fa ilu r e, 418, 421 Ma cr on u t r ien t s, 429–431 Medu lla oblon ga t a , 235t
Leigh syn dr om e, 145 Ma cr oph a ges, 72t, 74 Meiosis, 138, 171
Leiom yom a s, 346 Ma cr oscopic a n a lysis, of u r in e, 465 Meissn er plexu s, 471
Lem t r a da , in m u lt iple scler osis, 255t Ma cu la , 295 Mela n ocor t in h or m on e, 454
Lept in , 454 Ma cu la r degen er a t ion (MD), 310–312, Melen a , 475
Leu cin e, 137t 311 Mem br a n e por e, 12
Leu kem ia s, 190–192 clin ica l m a n ifest a t ion s of, 311 Mem br a n e pot en t ia l, 12, 230
ALL, 190–191, 191 defin ed, 310 Mem or y cells, 77
cla ssifica t ion of, 190 dia gn ost ic cr it er ia of, 311 Men a r ch e, 354
CLL, 191–192 pa t h oph ysiology of, 311 Men delia n pa t t er n , 142
CML, 191–192 t r ea t m en t of, 311–312 Mén ièr e disea se, 303
Leu kocyt osis, 40 Ma d cow disea se, 109b clin ica l m a n ifest a t ion s of, 310
Leydig cells, 344 Ma gn esiu m , 201t, 463t defin ed, 310
LGSIL. S ee Low-gr a de squ a m ou s ba la n ce, a lt er ed, 200 dia gn ost ic cr it er ia of, 310
in t r a epit h elia l lesion (LGSIL) Ma in st r ea m sm oke, 30 pa t h oph ysiology of, 310
LH . S ee Lu t ein izin g h or m on e (LH ) Ma jor depr essive disor der (MDD) t r ea t m en t of, 310
Life expect a n cy, 491 clin ica l m a n ifest a t ion s of, 276 Men in ges, of CNS, 237
Liga n ds, 14 defin ed, 274 Men in git is
Ligh t -color ed st ools, 475 dia gn osis of, 276 defin ed, 126
Lim bic syst em , 267, 326 pa t h oph ysiology of, 274–276 fu n ct ion of, 127
Lipids, 429–431 t r ea t m en t for, 276 Men in gocele, 164, 165
bila yer s, 10 Ma jor h ist ocom pa t ibilit y com plex Men opa u sa l bon e loss, 494–495
ca t egor ies of, 430 (MH C), 77 Men opa u se, 16, 492
Lipofu scin , 493 Ma la bsor pt ion , 443–444, 446, 447 clin ica l m a n ifest a t ion s of, 354–355
Lipopr ot ein lipa se, 453 Ma la bsor pt ion syn dr om e, 443 dia gn osis of, 355
Liver Ma la r, 95, 95 pa t h oph ysiology of, 354
fa ilu r e, 122 Ma la r ia ph ysiologic ch a n ges of, 355
fu n ct ion of, 119–120 blood sm ea r, 131 t r ea t m en t of, 355–356
LMN. S ee Lower m ot or n eu r on s (LMN) clin ica l m a n ifest a t ion s, 131 Messen ger RNA (m RNA), 137, 139
Loca l m a n ifest a t ion s, defin ed, 3 dia gn ost ic cr it er ia , 131 Met a bolic a cidosis, 221–222
Loca l m edia t or s, 14 pa t h oph ysiology, 131 clin ica l m a n ifest a t ion s of, 225
Loop diu r et ics, 205, 208 t r ea t m en t , 131 dia gn osis, 225

pa t h oph ysiology of, 225
t r ea t m en t of, 226
Met a bolic a lka losis, 222, 224
Met a bolic disor der s, 442, 442
Met a bolic pr ocesses, 496
Met a bolic syn dr om e, 513
Met a bolism
cells, 199
in bor n er r or s of, 442
Met a pla sia , 15, 16, 17
Met for m in , 352
Met h ion in e, 137t
Met h ot r exa t e, 96t
Met h yla t ion -specific polym er a se ch a in
r ea ct ion (MSP CR), 148
MH C. S ee Ma jor h ist ocom pa t ibilit y
com plex (MH C)
MH C cla ss I m olecu le, 78, 79
MH C cla ss II m olecu le, 78, 79
MI. S ee Myoca r dia l in fa r ct ion (MI)
Micr obes, 104–112
Micr ocyt ic a n em ia , 448, 449
Micr om in er a ls, 433–434
Micr on u t r ien t s, 429, 431–434
Mict u r it ion , 464, 464b
Middle cer ebr a l a r t er y pea k syst olic
velocit y (MCA P SV), 98
Middle ea r, 300, 301. S ee a lso E a r (s)
a lt er a t ion in , 302
eva lu a t ion of, 303–304
Migr a in es
ch a r a ct er ist ics of, 307
clin ica l m a n ifest a t ion s of, 307
defin ed, 307
dia gn ost ic cr it er ia of, 308
pa t h oph ysiology of, 307
t r ea t m en t of, 308
Mild deh ydr a t ion , 212
Min er a locor t icoids, 329t, 337t
Min er a locor t icost er oids, 320t
Min er a ls, 432–434, 434t
deficien cies of, 442–443, 445–446t
Mit och on dr ia , 11, 492
Mit och on dr ia l DNA (m t DNA), 145, 156
Mit och on dr ia l en ceph a lom yopa t h y,
la ct ic -a cidosis, a n d st r oke
(ME LAS), 156–157
clin ica l m a n ifest a t ion s of, 157
dia gn osis of, 157
pa t h oph ysiology of, 156–157
t r ea t m en t of, 157
Mit och on dr ia l gen e disor der s, 145,
156–157
Mit osis, 138, 171
Mixed h ea r in g loss, 303
Mixed syst olic/dia st olic h yper t en sion ,
411
MMD. S ee Myot on ic m u scu la r
dyst r oph y (MMD)
MMK pr ocedu r e. S ee Ma r sh a ll-
Ma r ch et t i-Kr a n t z (MMK)
pr ocedu r e
Mobilit y, 494–495
MODY. S ee Ma t u r it y-on set dia bet es of
t h e you n g (MODY)
Molds, 111, 112
Molecu la r m im icr y, 85
Molybden u m , 434t
Mon oa m in e oxida se in h ibit or s
(MAOIs), 276
Mon oa m in es, 232
Mon ocyt es, 41t, 74
Mon osa cch a r ides, 438
Mon osom y, 146
Mon s pu bis, 341, 341
Mood, a t t en t ion , a n d beh a vior
a lt er a t ion s in
dia gn osin g, 270
r ecogn izin g, 269–270
t r ea t in g, 270
r egu la t ion of, 266–269
Mood, defin ed, 266
Mor bidit y, defin ed, 3
Mor t a lit y, defin ed, 3
Mosa icism , 146
Mot ilin , 437–438
Movem en t disor der s, 248–249, 249b
H IV-r ela t ed, 91
MRNA. S ee Messen ger RNA (m RNA)
MSAF P. S ee Ma t er n a l ser u m a lph a -
fet opr ot ein (MSAF P )
MSP CR. S ee Met h yla t ion -specific
polym er a se ch a in r ea ct ion
(MSP CR)
Mt DNA. S ee Mit och on dr ia l DNA
(m t DNA)
Mu cou s cells, 436
Mu lt ifa ct or ia l et iology, defin ed, 2
Mu lt iple scler osis (MS)
clin ica l m a n ifest a t ion s of, 253
descr ipt ion of, 252, 253
dia gn ost ic cr it er ia of, 253–254
pa t h oph ysiology of, 252–253
t r ea t m en t of, 254, 255t
Mu scles, pelvic, 481
Mu scu la r is la yer, 437
Mu t a t ion s, 17, 141
Myceliu m , 111
Mycoba ct er iu m , 91
Mycoba cter iu m tu ber cu losis, 48, 80,
123
Mycopla sm a pn eu m on ia e, 378
Mycopla sm a s, 110
Mycoses, 111
Myelin , 229–230
Myeloid pr ogen it or cells, 73, 74–75
Myelom en in gocele, 165, 165
Myen t er ic plexu s, 471
Myoca r dia l h yper t r oph y, 420
Myoca r dia l in fa r ct ion (MI), 406, 415–
418, 416
clin ica l m a n ifest a t ion s of, 416–417
dia gn osis of, 417
pa t h oph ysiology of, 415–416
t r ea t m en t of, 417–418
Myoca r diu m , 398, 399
Myoclon ic seizu r es, 251
Myofa scia , 306
Myopia , 297, 298
Myot on ic m u scu la r dyst r oph y (MMD),
148
Myxedem a , 334
N h em oglobin in , 449
N-m et h yl-D-a spa r t a t e (NMDA)
r ecept or, 241
In dex 565
Na ive lym ph ocyt es, 75
Na t ion a l Down Syn dr om e Societ y, 158
Na t ion a l H u m a n Gen om e Resea r ch
In st it u t e (NH GRI), 144
Na t ion a l In st it u t es of Dia bet es a n d
Digest ive a n d Kidn ey Disea ses
(NIDDK), 477
Na t u r a l killer (NK) cells, 73
Necr osis, 18, 18, 491
Nega t ive feedba ck loop, 321, 323
Neisser ia gon or r h oea e, 109, 349
Neisser ia m en in gitid is, 127
Neopla sia , 352
Neopla sm s. S ee a lso Ca n cer
a n a pla sia , 177
a u t on om y, 177
ch a r a ct er ist ics, 177
gr owt h fa ct or s, 177–178
pr olifer a t ion , 178–179
Neph r on , 46
Neph r opa t h y, 520–521
Ner vou s syst em
CNS. S ee Cen t r a l n er vou s syst em
(CNS)
per iph er a l n er vou s syst em . S ee
Per iph er a l n er vou s syst em
Neu r a l t u be defect s (NTD), 164–165
clin ica l m a n ifest a t ion s of, 164–165,
165
dia gn osis of, 165
pa t h oph ysiology of, 164
t r ea t m en t of, 165
Neu r oen docr in e pa t h wa y, 324, 324
Neu r ofibr illa r y t a n gles, 502–503, 503
in Alzh eim er disea se, 504
Neu r ogen ic pa in , 290
Neu r ogen ic sh ock, 414
Neu r ologic fu n ct ion , a gin g in , 494
Neu r ologic m ech a n ism s, 454
Neu r om odu la t or s, 233
Neu r om u scu la r fu n ct ion , a lt er a t ion in
bowel elim in a t ion a n d, 473
u r in a r y elim in a t ion a n d, 465–466
Neu r on oph a gia , 233
Neu r on s. S ee a lso Cen t r a l n er vou s
syst em (CNS); Per iph er a l n er vou s
syst em
a ct ion pot en t ia ls of, 230, 231
a gin g of, 233
com m u n ica t ion bet ween , 231–233
com pon en t s of, 229, 229
in ju r ies t o, 233
su ppor t in g cells of, 229–230, 230t
syn a pses of, 229, 231–233
Neu r opa t h ic pa in . S ee Neu r ogen ic pa in
Neu r ot r a n sm it t er s, 231–233, 319
r egu la t in g m ood, a t t en t ion , a n d
beh a vior, 268t
t ypes of, 232
Neu t r a liza t ion , 77
Neu t r oph ils, 41t, 72t, 75
Newbor n s
br on ch opu lm on a r y dyspla sia in , 17
cyst ic fibr osis in , 389
defeca t ion by, 472
h em olyt ic disea se in , 96
h epa t it is B in , 109
566 In dex
Newbor n s (con tin u ed )
h ypot h yr oidism in , 333
ja u n dice of, 120
pa in in , 293–294b
scr een in g t est s for, 140–141, 141t
NH GRI. S ee Na t ion a l H u m a n Gen om e
Resea r ch In st it u t e (NH GRI)
NHL. See Non-Hodgkin lymphoma (NHL)
Nia cin , 433t, 445t
NIDDK. S ee Na t ion a l In st it u t es of
Dia bet es a n d Digest ive a n d
Kidn ey Disea ses (NIDDK)
Nit r ogen ba la n ce, 429
NK. S ee Na t u r a l killer (NK) cells
Nocicept ion . S ee Pa in
Noct u r ia , 510
Nodes of Ra n vier, 230
Non -H odgkin lym ph om a (NH L)
dia gn osis of, 194
H IV-r ela t ed, 91
m a n ifest a t ion s of, 194
pa t h oph ysiology of, 193–194
t r ea t m en t of, 194
Non -in su lin -depen den t dia bet es, 513
Non disju n ct ion , ch r om osom a l,
146–147, 147
Non n u cleot ide r ever se t r a n scr ipt a se
in h ibit or s (NNRTIs), 91
Non pola r t a il, 10
Non sem in om a s, 360
Non st er oida l a n t i-in fla m m a t or y dr u gs
(NSAID)
in a cu t e in fla m m a t ion , 41t
for SLE , 96, 96t
Nor epin eph r in e, 268t, 320t
Nor epin eph r in e a n d dopa m in e
r eu pt a ke in h ibit or s (NDRI), 276
Nosocom ia l disea se, defin ed, 2
Nosocom ia l pn eu m on ia s, 378
NRTI. S ee Nu cleoside-a n a log r ever se
t r a n scr ipt a se in h ibit or s (NRTI)
NSAID. S ee Non st er oida l a n t i-
in fla m m a t or y dr u gs (NSAID)
NT. S ee Nu ch a l t r a n slu cen cy (NT)
NTD. S ee Neu r a l t u be defect s (NTD)
Nu ch a l r igidit y, 129
Nu ch a l t r a n slu cen cy (NT), 158–159
Nu clea r ca t a r a ct s, 298
Nu cleot ide-a n a log r ever se
t r a n scr ipt a se in h ibit or s (NRTIs),
91, 222–223
Nu cleu s, of cells, 11
Nu r sin g dia gn oses, defin ed, 3
Nu t r it ion , 429–455, 430–432, 435–436,
439–440
a bsor pt ion , 438–441, 439–440
a lt er a t ion in , 441–447, 442, 445–446t
clin ica l m a n ifest a t ion s of, 447
clin ica l m odels, 448–455
defin it ion of, 429
dia gn ost ic t est s for, 447
digest ion , 435–438, 436, 437t, 439
in elder ly, 496–498, 497
in t a ke a n d st or a ge of, 435–438
RDAs a n d, 434
Nu t r it ion a l in t a ke r equ ir em en t s,
434–435
Nyst a gm u s, 298
O t r ea t m en t of, 309
OAE . S ee Ot oa cou st ic em ission (OAE ) Ot it is m edia wit h effu sion (OME ),
Obesit y, 430, 443, 453–455, 454, 455, 308–309, 309
513 Ot oa cou st ic em ission (OAE ), 304
clin ica l m a n ifest a t ion s, 454, 454 Ot oscler osis, 302
dia gn osis of, 455 Ova r ia n ca n cer
h yper cellu la r, 453 clin ica l m a n ifest a t ion s of, 354
h yper t r oph ic, 453 dia gn osis of, 354
lifest yle fa ct or s ca u sin g, 454 pa t h oph ysiology of, 352–353, 353
pa t h oph ysiology of, 453–454 t r ea t m en t of, 354
t r ea t m en t of, 455 Ova r y
Obliga t e pa r a sit es, 105 cr oss-sect ion of, 343
Obst r u ct ion , of a lveoli, 391b fu n ct ion of, 343
Obst r u ct ive br ea t h in g, 372t polycyst ic disea se of, 352
Occlu ded vessels, 85, 87 Over a ct ive bla dder, 480
Occu lt , 65, 476 Over flow in con t in en ce, 480
Ocu lom ot or n er ve, 243t Over n u t r it ion , 443, 445–446t
Olfa ct or y n er ve, 243t, 305 Ovu la t ion , 342
Oligoden dr ocyt es, 230, 230t Ovu la t or y cycle, of en dom et r iu m , 344,
Oligu r ia , 199 344
OME . S ee Ot it is m edia wit h effu sion Oxida t ive st r ess, 19, 19
(OME ) Oxygen
On cogen es, 172–173 diffu sion of, 369
Open -a n gle gla u com a , 312, 312, 313. fr ee r a dica ls, 11
S ee a lso Gla u com a sa t u r a t ion of, 370
Open t r a u m a t ic in ju r y, 239 t r a n spor t of, 367, 369
Oph t h a lm oscopy, 313 Oxygen sa t u r a t ion (Sa O 2 ), 369
Oppor t u n ist ic pa t h ogen s, 112 Oxyh em oglobin (H bO 2 ), 369
Opsin , 295 Oxyt ocin , 320t, 321–322, 341
Opson iza t ion , 38t, 77
Opt ic cr a n ia l n er ve, 243t P
Opt ica l coh er en ce t om ogr a ph y, for P 53 gen e, 173
m a cu la r degen er a t ion (MD), 311 Pa in , 292b, 293, 476, 486
Or a l ca n didia sis, 112, 112 a lt er ed u r in a r y fu n ct ion a n d, 468
Or a l glycem ic a gen t s, t ype 2 dia bet es ch a r a ct er iza t ion of, 289–290
m ellit u s a n d, t r ea t m en t of, 514– cla ssifica t ion s of, 292b
515, 515t con t r ol m et h ods, 293–294b
Or a l r eh ydr a t ion , 213–214 fibr om ya lgia . S ee F ibr om ya lgia
Or ga n of Cor t i, 301 m a n a gem en t , 292
Or ga n elles, 10–11 t h eor ies
Or ga n ogen esis, 149, 149 ga t e con t r ol t h eor y, 291
Or ga n s, defin ed, 9 in t en sit y t h eor y, 291–292
Or t h opn ea , 375 n eu r om a t r ix t h eor y, 292
Osm ola lit y, 202 pa t t er n t h eor y, 290
Osm ola r it y, 202 specificit y t h eor y, 290–291
Osm ole, 202 t r ea t m en t , 292–293
Osm or ecept or s, 205 Pa n cr ea s
Osm osis, 12, 12, 202 en docr in e, 508
Osm ot ic diu r esis, 510 exocr in e, 508
Osm ot ic pr essu r e, 12, 202–203, 205 fu n ct ion s of, 61
Osm ot ic swellin g, 199 islet s of La n ger h a n s, 508, 508
Ossicles, 300 Pa n cr ea t ic a m yla se, 437t, 438
Ost eom a s, 179 Pa n cr ea t ic lipa ses, 437t, 441
Ost eopen ia , 494, 501 Pa n cr ea t it is, 61
Ost eopor osis Pa n dem ic disea se, defin ed, 4–5
in a gin g, 499–502, 500 Pa n h ypopit u it a r ism , 327
clin ica l m a n ifest a t ion s of, 500 Pa n n u s, 57, 57
dia gn osis of, 500–501 Pa n t ot h en ic a cid, 433t
pa t h oph ysiology of, 499–500, 500t Pa pa n icola ou (Pa p) sm ea r, 28–29
t r ea t m en t of, 501–502, 502t Pa pillom a , 179
bon e r em odelin g in , 501 PAP P -A. S ee P r egn a n cy a ssocia t ed
m en opa u sa l in , 494 pla sm a pr ot ein - A (PAP P -A)
Ot it is ext er n a , 302 Pa r a cen t esis, 211, 213
Ot it is m edia , 302 Pa r a cr in e pa t h wa y, 324, 324
clin ica l m a n ifest a t ion s of, 309, 309 Pa r a cr in e sign a lin g, 14
defin ed, 308 Pa r a lyt ic ileu s, 486
dia gn ost ic cr it er ia of, 309 Pa r a m yxovir u s, 111t
pa t h oph ysiology of, 308–309 Pa r a n eopla st ic syn dr om es, 182
 In dex 567

Pa r a sym pa t h et ic n er vou s syst em dia gn osis of, 409, 409t P in ocyt osis, 13
(P NS), 245, 246 excessive dem a n ds of, 408 P it t in g edem a , 208
Pa r a t h yr oid h or m on e (P TH ), 320t, gen er a l m a n ifest a t ion s of, 408– P it u it a r y gla n d, 319
329t, 496 409 P KD. S ee Polycyst ic kidn ey disea se
Pa r en t er a l n u t r it ion , 225 t r ea t m en t of, 409, 410t (P KD)
Pa r est h esia , 201, 239, 240 bowel, a lt er a t ion in , 473 P KU. S ee P h en ylket on u r ia (P KU)
Pa r iet a l cells, 436–437 defin ed, 396 P la cen t a , 97
Pa r kin son disea se over view, 395 P la qu en il, 96
clin ica l m a n ifest a t ion s of, 259–260, wit h oxygen a t ed blood, 396 P la sm a
261 r equ ir em en t s for, 396 bu ffer syst em s, 219–220
descr ipt ion of, 257–259 u r in a r y, a lt er a t ion in , 466 in fla m m a t or y m edia t or s in , 38, 38t
dia gn osis of, 260–261 ven t ila t ion a n d, 495–496 m em br a n e, 10, 10
fa cia l fea t u r es of, 261 Per ica r dit is, 95 P la sm od iu m , 130
m obilit y deficit s in , 261 Per ica r diu m , 398 P la sm od iu m fa lcipa r u m , 131
pa t h oph ysiology of, 259, 261 Per im en opa u se, 354 P la t elet -a ct iva t in g fa ct or, 38
t r ea t m en t of, 262 Per iph er a l n er vou s syst em , 242–246 P la t elet s, in fla m m a t or y m edia t or s in ,
Pa r t ia l pr essu r e, du r in g diffu sion , 369 ANS, 244–246, 245, 246 37–38
Pa ssive diffu sion , 438, 440 cr a n ia l n er ves, 242, 243t P leu r it is, 95
Pa ssive t r a n spor t , 11–12 in ju r y t o, 247–248 P lexu s, 242
Pa t h ogen esis, defin ed, 2 m ot or dysfu n ct ion , 248–249, 249b P n eu m ocystis ca r in ii, 378
Pa t h ogen ic defen se m ech a n ism s, 105 P NS, 245, 246 P n eu m ocystis jir oveci, 90
Pa t h ogen icit y, 105 SNS, 244–245, 245 P n eu m on ia
Pa t h ogen s, 105–112 som a t ic n er vou s syst em , 243 clin ica l m a n ifest a t ion s of, 380
defin ed, 2 spin a l n er ves, 242, 243t, 244 dia gn osis of, 380
fa ct or s a ffect in g, 105 Per iph er a l or ga n s, of lym ph a t ic pa t h oph ysiology of, 378–380
t ypes of, 105 syst em , 75 t r ea t m en t of, 380
Pa t h ology, defin ed, 1 Per ist a lsis, 471, 472 P n eu m ot h or a x, 386
Pa t h oph ysiology Per it on ea l dia lysis, 484–485 P NS. S ee Pa r a sym pa t h et ic n er vou s
a pplyin g, 4–5 Per it on it is, 485 syst em (P NS)
con cept m a p, 3 Per m a n en t cells, 44 Poikilocyt osis, 448
con cept u a l a ppr oa ch in , 6 Per n iciou s a n em ia , 61 Pola r h ea d, 10
defin ed, 1 Per oxisom es, 11 Polycyst ic kidn ey disea se (P KD), 481–
eviden ce-ba sed pr a ct ice, 5–6 Pet ech ia e, 409 485, 481–484
u n der st a n din g of, 1–3 Peyer ’s pa t ch es, 72t, 437 ca t egor ies of, 481–482
Pa t t er n t h eor y, of pa in , 290 pH , 219 dia gn osis, 482
P CI. S ee Per cu t a n eou s cor on a r y bu ffer syst em s for, 219, 220 pa t h oph ysiology of, 481–482
in t er ven t ion (P CI) r en a l r egu la t ion of, 220 sym pt om s of, 482
P COS. S ee Polycyst ic ova r y syn dr om e P h a gocyt osis, 13, 36 t r ea t m en t of, 482–485
(P COS) P h a r m a cologic t h er a py, for Polycyst ic ova r y syn dr om e (P COS),
P D. S ee Pa r kin son disea se (P D) h yper t en sion , 412–413 350–352, 351, 352
Pea k expir a t or y flow r a t e (P E F R), 386 P h en ot ype, 141 clin ica l m a n ifest a t ion s wit h , 352
Pedigr ees, 151 P h en yla la n in e, 137t dia gn osis of, 352
P E E P. S ee Posit ive en d-expir a t or y P h en yla la n in e h ydr oxyla se (PAH ) h ir su t ism , 350, 351
pr essu r e (P E E P ) en zym e, 452, 453 pa t h oph ysiology of, 351–352
P E F R. S ee Pea k expir a t or y flow r a t e P h en ylket on u r ia (P KU), 141t, 442, 442, t r ea t m en t of, 352
(P E F R) 452–453, 453 Polydipsia , 510
Pelvic in fla m m a t or y disea se (P ID), clin ica l m a n ifest a t ion s of, 453 Polygen ic disor der s, in h er it a n ce of,
349–350 dia gn osis of, 453 145–146
clin ica l m a n ifest a t ion s of, 349, 350 pa t h oph ysiology of, 452 Polygen ic MH C m olecu le, 87
dia gn osis of, 350 t r ea t m en t of, 453 Polygen ic t r a it s, 141
pa t h oph ysiology of, 349 P h legm , 375 Polym or ph ic MH C m olecu le, 87
t r ea t m en t of, 350 P h osph a t e, 201t, 463t, 496 Polym or ph ism , 142
Pelvic m u scles, 481 ba la n ce, a lt er ed, 200–201 Polym or ph on u clea r (P MN) leu kocyt es,
Pen et r a n ce, 142 P h osph olipids, 10 74
Pen icillin , a ller gies t o, 81 P h osph or u s, 434t, 446t Polyn eu r opa t h y, 248
Pen icillin pr oph yla xis, 156 P h ot oph obia , 127–129 Polyph a gia , 510
Pen ile er ect ion , a n a t om ic depict ion of, P h ot or ecept or s, 288t, 295 Polyu r ia , 331, 510
356 P h ot osen sit ivit y, 95 Pon s, 235t
Pen is, 344, 345 P h ysica l in ju r y, 18 Por t a l cir cu la t ion , 119, 119
Pepsin , 436, 437, 437t P h ysiology, defin ed, 2 Por t a l h yper t en sion , 211
Pept ides, 232 P ica , 448 Por t a l of en t r y, 114
Per cu t a n eou s cor on a r y in t er ven t ion P ID. S ee Pelvic in fla m m a t or y disea se Por t a l of exit , 114
(P CI), 417 (P ID) Posit ive en d-expir a t or y pr essu r e
Per cu t a n eou s n eph r olit h ot om y, 479 P igm en t ed n eu r on s of, su bst a n t ia (P E E P ), 391
Per cu t a n eou s t r a n slu m in a l cor on a r y n igr a , 260 Posit ive feedba ck loop, 321, 323
a n giopla st y (P TCA), 417 P IN. S ee P r ost a t ic in t r a epit h elia l Post r esidu a l volu m e (P RV), 480
Per fu sion , 46, 365 n eopla sia (P IN) Post er ior su bsca pu la r ca t a r a ct s, 299
a lt er a t ion of, 404–410, 405, 409t P in n a , 300 Post n a t a l scr een in g, 152
568 In dex

Post t r a u m a t ic st r ess disor der (P TSD)
clin ica l m a n ifest a t ion s of, 274
defin ed, 272
dia gn osis of, 274
pa t h oph ysiology of, 273
t r ea t m en t for, 274
Pot a ssiu m , 201t, 463t
ba la n ce, a lt er ed, 199–200
Pot a ssiu m –h ydr ogen exch a n ge, 220
Pot a ssiu m -spa r in g diu r et ics, 205
P r a der-Willi syn dr om e (P WS), 148
P r ecipit a t in g fa ct or s
defin ed, 2
exa m ples of, 2b
P r edia bet es, 510
P r edn ison e, 88
P r efr on t a l cor t ex
la t er a l, 266
or bit ofr on t a l, 266
ven t r om edia l, 266
P r egn a n cy-a ssocia t ed pla sm a
pr ot ein -A (PAP P -A), 158
P r eh yper t en sion , 412
P r eim pla n t a t ion gen et ic dia gn osis,
151
P r eloa d, 401b
P r en a t a l scr een in g, 151–152
P r esbyopia , 297
P r essu r e m ea su r em en t s, 409t
P r eva len ce, defin ed, 5
P r im a r y a ct ive t r a n spor t , 13
P r im a r y in t en t ion , h ea lin g by, 45, 47
P r im a r y pr even t ion , disea se, 5
P r odr om e, 116, 121
P r oger ia , 498–499, 499
P r ogest er on e, 320t, 342, 352
P r ogn osis, defin ed, 3
P r olifer a t ion , of cells, 14, 23
P r olifer a t ive in fla m m a t or y a t r oph y,
359
P r olin e, 137t
P r ost a t e, 344, 345
P r ost a t e ca n cer, 358–360, 359
clin ica l m a n ifest a t ion s of, 359
dia gn osis of, 359–360
in ciden ce of, 144
pa t h oph ysiology of, 358–359
t r ea t m en t of, 360
P r ost a t e epit h elia l cells, m a lign a n t
t r a n sfor m a t ion of, 358
P r ost a t e-specific a n t igen (P SA), 357
P r ost a t ic in t r a epit h elia l n eopla sia
(P IN), 359, 359
P r ot ea som es, 11
P r ot ein (s), 463t
bu ffer syst em , 220
digest ion , 429
P r ot ein -en er gy m a ln u t r it ion , 443
P r ot ein a ses, 48
P r ot ein u r ia , 95, 468t
P r ot eolysis, 11
P r ot eolyt ic en zym es, 440
P r ot h r om bin t im e (P T), 424
P r ot oon cogen es, 172
P r ot ozoa , 112
P r ovision a l m a t r ix, 44
P RV. S ee Post r esidu a l volu m e (P RV)
P SA. S ee P r ost a t e-specific a n t igen
(P SA)
P seu dobu lba r a ffect , 253
P seu doh yph a e, 111
P seu d om on a s a er u gin osa , 378, 389
P sych osis, 276
P T. S ee P r ot h r om bin t im e (P T)
P TCA. S ee Per cu t a n eou s t r a n slu m in a l
cor on a r y a n giopla st y (P TCA)
P TH . S ee Pa r a t h yr oid h or m on e (P TH )
P TSD. S ee Post t r a u m a t ic st r ess
disor der
P u lm on a r y cir cu la t ion , 367, 397
P u lm on a r y syst em , defen se
m ech a n ism for, 367
P u lm on a r y t u ber cu losis, 90
P u lse pr essu r e, 402
P u pil, 294
P u r e t on e bon e con du ct ion , 304
P u r in es, 136, 138
P u r kin je fiber s, 401
P u r pu r a , 409
P u r sed lip br ea t h in g, 375
P u s, 116
P WS. S ee P r a der-Willi syn dr om e
(P WS)
P yelon eph r it is, 126, 465, 466
P yogen ic ba ct er ia , 106
P yr a m ida l m ot or syst em , 236–237
P yr exia , 40
P yr idoxin e, 433t
P yr im idin es, 136, 138
P yu r ia , 125, 468t
Q m a le, 344–346
Qu a dr iplegia , 239
Qu a dr u ple t est , 158
R Resolu t ion , in wou n d h ea lin g, 44
RAAS. S ee Ren in -a n giot en sin -
a ldost er on e syst em (RAAS)
Ra dia t ion t h er a py
for ova r ia n ca n cer, 354
for pr ost a t e ca n cer, 360
for t est icu la r ca n cer, 361
Ra les, a s br ea t h sou n ds, 376b
Ra loxifen e, 502t
RAS. S ee Ret icu la r a ct iva t in g syst em
(RAS)
RBC. S ee Red blood cells (RBC)
RDAs. S ee Recom m en ded Da ily
Allowa n ces (RDAs)
Re-epit h elia liza t ion , 43
Rea bsor pt ion , 202–203
Rea ct ive oxygen species (ROS), 19, 492
Rea ssor t m en t , 117
Rebif, in m u lt iple scler osis, 255t
Recept or s, 14
Recessive disor der s, a u t osom a l, 144–
145, 144
Recessive gen es, 142
Recom m en ded Da ily Allowa n ces
(RDAs), 434
Rect a l r eflex, 471, 472b
Red blood cells (RBC), 369, 521
in sickle cell a n em ia , 155
Reflex a r cs, 246–247, 247
Refr a ct ion , er r or s in , 297, 298
Regen er a t ion , in wou n d h ea lin g,
44–45, 45
Regu la t ion of a t t en t ion , 267–269
Regu la t ion of beh avior, 269
Regu la t ion of m ood, 266–267
Regu la t or y T cells, 85
Regu r git a t ion , 408
Rem ission s, 3
Ren a l a n giogr a m , 469
Ren a l bu ffer syst em , 220–221
Ren a l t u bu lopa t h y
clin ica l m a n ifest a t ion s, 224
dia gn osis, 224
pa t h oph ysiology, 224
t r ea t m en t of, 224–225
Ren a l u lt r a sou n d, 469
Ren in , 203, 404
Ren in -a n giot en sin -a ldost er on e syst em
(RAAS), 207, 461
Repla cem en t , in wou n d h ea lin g, 44, 44
Repola r iza t ion , 400
of a ct ion pot en t ia l, 230, 231
Repr odu ct ion , of cells, 14
Repr odu ct ive fu n ct ion
dia gn osis of, 347–349
gen er a l m a n ifest a t ion s of, 347
h or m on a l im ba la n ce, 346
im m u n e pr oblem s in , 346
m ot ilit y of, 346
over view, 340
t r ea t m en t of, 347–349
Repr odu ct ive h or m on e
fem a le, 341–344
Reser voir, for m icr oor ga n ism , 114
Residen t flor a , 104
Residu a l volu m e (RV), 368
Respir a t ion , 365
in cells, 13–14
Respir a t or y bu ffer syst em s, 220
Respir a t or y fa ilu r e, 379, 379b
Respir a t or y syn cyt ia l vir u s (RSV), 111t
Respir a t or y syst em , 366
Rest in g m em br a n e pot en t ia l (RMP ),
230, 231
Ret icu la r a ct iva t in g syst em (RAS),
235t, 267, 268, 326
Ret icu locyt e cou n t , 449t
Ret in a , 295
con es, 295
fovea , 295
m a cu la , 295
r ods, 295
Ret in en e, 295
Ret in obla st om a (Rb) gen e, 173
Ret in opa t h y, 519, 521
Ret in opa t h y of pr em a t u r it y (ROP ),
314–315
clin ica l m a n ifest a t ion s of, 314
defin ed, 314
dia gn osis, 314
pa t h oph ysiology of, 314
t r ea t m en t of, 314–315
Ret r a ct ion s, 375
Rh im m u n oglobin (Rh Ig), 99
 In dex 569

Rh isoim m u n iza t ion , 96–99 (SE RM), 356 fu n ct ion s of t h e sin u ses, 50
clin ica l m a n ifest a t ion s of, 97 Select ive n or epin eph r in e r eu pt a ke SIRS. S ee Syst em ic in fla m m a t or y
dia gn ost ic cr it er ia , 97–98 in h ibit or s (SNRI), 276 r espon se syn dr om e (SIRS)
pa t h oph ysiology of, 97 Select ive ser ot on in r eu pt a ke in h ibit or s Sken e gla n ds, 341, 341
t r ea t m en t of, 98–99 (SSRI), 276 Skin , fu n ct ion of, 52
Rh eu m a t oid a r t h r it is (RA), 56–57 Selen iu m , 434t Skin gr a ft in g, 56
clin ica l m a n ifest a t ion s of, 57 Sem in a l vesicles, 344, 345 Skin pa t ch t est , 82
dia gn ost ic cr it er ia , 57–58, 58 Sem in om a s, 360 Skin t u r gor, 207
pa t h oph ysiology of, 56–57 Sen escen ce, 491 SLE . S ee Syst em ic lu pu s
t r ea t m en t of, 58 Sen escen t bon e loss, 494–495 er yt h em a t osu s (SLE )
Rh eu m a t oid fa ct or (RF ), 56 Sen ile pla qu es, 502 SLTs. S ee Sa lt -losin g t u bu lopa t h ies
Rh Ig. S ee Rh im m u n oglobin (Rh Ig) Sen sit iza t ion ph a se, in dela yed (SLTs)
Rh in ovir u s, 111t h yper sen sit ivit y r ea ct ion s, 84 Sm a ll in t est in e, 438
Rh odopsin , 295 Sen sor in eu r a l dea fn ess (SND), 224 fu n ct ion of, 64, 64
Rh on ch i, a s br ea t h sou n ds, 376b Sen sor in eu r a l h ea r in g loss, 303, 304 Sm a ll pept ide, a bsor pt ion of, 440–441
Ribofla vin , 433t Sepsis, 54 Sm ell, 304–305
Ribon u cleic a cid (RNA), 137, 138 Sept ic sh ock, 116, 413 Sm okin g, a n d ca r diova scu la r disea se,
Ribosom a l RNA (r RNA), 137 Sept icem ia , 116, 127 30
Ribosom es, 137 Ser in e, 137t SND. S ee Sen sor in eu r a l dea fn ess
Ricket t sia e, 110 SE RM. S ee Select ive est r ogen r ecept or (SND)
Righ t h ea r t fa ilu r e, 418–420, 421 m odu la t or s (SE RM) SNS. S ee Sym pa t h et ic n er vou s syst em
Rin ger la ct a t e, 208, 214 Ser ocon ver sion , 90 (SNS)
Rin gwor m , 130 Ser osa , 437 Sodiu m , 463t
Risedr on a t e (Act on el), 502t Ser ot on in , 268t Sodiu m ba la n ce, a lt er ed, 199, 199,
RMP. S ee Rest in g m em br a n e pot en t ia l Ser ou s exu da t e, 54 201t, 212–214, 213t
(RMP ) Ser t oli cells, 345 Sodiu m -pot a ssiu m pu m p, 199
RNA in t er fer en ce, 174 Ser u m ir on , 449t Som a t ic m u t a t ion , 142
Rods, in r et in a , 295 Ser u m sickn ess, 84 t h eor y of a gin g, 492
Rom e III cr it er ia , 486 Sever e a cu t e r espir a t or y syn dr om e Som a t ic n er vou s syst em , 243
ROP. S ee Ret in opa t h y of pr em a t u r it y (SARS), 111t Som a t osen sor y m oda lit ies, 289, 290.
(ROP ) Sex ch r om osom es, 138 S ee a lso Som a t osen sor y syst em
ROS. S ee Rea ct ive oxygen species Sex cor d t u m or s, 353 Som a t osen sor y syst em
(ROS) Sex-lin ked ch r om osom es, 143 n eu r on s of, 287–289, 287t, 288
Rot a vir u s, 111t Sex-lin ked disor der s, 144, 145, 161– t r a n sm ission , 287–289
RRNA. S ee Ribosom a l RNA (r RNA) 163. S ee a lso F r a gile X syn dr om e r ecept or s of, 287, 289
Ru le of n in es, 55, 55 (F XS) Som ogyi effect , 518–519
RV. S ee Residu a l volu m e (RV) Sh in gles, 110 Sor bit ol, 520
Sh ock Sper m a t ogen esis, 345
S in bu r n in ju r y, 54 Sper m a t ogon ia , 360
SA. S ee Sin oa t r ia l (SA) n ode clin ica l m a n ifest a t ion s of, 414 Sper m a t ozoa , 345
Sa licyla t es, 96t dia gn ost ic cr it er ia of, 414 st r u ct u r e of, 346
Sa liva r y a m yla se, 436, 437t pa t h oph ysiology of, 413–414 Spin a bifida , va r ia t ion s of, 164–165,
Sa lt -losin g t u bu lopa t h ies (SLTs), t r ea t m en t of, 414–415 165
224–225 Sh or t -ch a in fa t t y a cids, 444, 446 Spin a bifida occu lt a , 164, 165
Sa lt a t or y con du ct ion , 230 Sh or t t a n dem r epea t s (STR), 146 Spin a l a ccessor y n er ve, 243t
Sa O 2 . S ee Oxygen sa t u r a t ion (Sa O 2 ) Sh u n t in g, 408 Spin a l cor d, 234–237, 236
Sa r copen ia , 495 SIADH . S ee Syn dr om e of in a ppr opr ia t e dor sa l h or n s, 236
Sa t iet y, 435 a n t idiu r et ic h or m on e (SIADH ) ven t r a l h or n s, 236
Sa t u r a t ed fa t t y a cids, 430 Sickle cell a n em ia , 141t, 154–156, 155 Spin a l cor d in ju r y (SCI), 239, 240t
Sch izoph r en ia clin ica l m a n ifest a t ion s of, 155 ca t egor ies of, 259t
clin ica l m a n ifest a t ion s of, 281–282 dia gn osis of, 155–156 clin ica l m a n ifest a t ion s of, 257
defin it ion of, 281 pa t h oph ysiology of, 154–155 descr ipt ion of, 256–257
dia gn osis of, 282 t r ea t m en t of, 156 dia gn ost ic cr it er ia of, 257
fa m ilia l n a t u r e of, 282 Sickle cell t r a it , 155 pa t h oph ysiology of, 257, 258
pa t h oph ysiology of, 281 Sidest r ea m sm oke, 30 t r ea t m en t of, 257
t r ea t m en t for, 282 Sigm oidoscopy, 476 Spin a l m u scu la r a t r oph y, 16
t win s discor da n t for, 282 Sign a l t r a n sdu ct ion , 14 Spin a l n er ves, 242, 243t, 244
Sch wa n n cells, 230 Sign a ls, 16 Spleen , 72t, 75
SCI. S ee Spin a l cor d in ju r y (SCI) Sign s of disea se, defin ed, 2 Spu t u m , 375
Scr a t ch skin t est , 81 Sim ple diffu sion , 438 Squ a m ocolu m n a r ju n ct ion , 27
SDH . S ee Su ccin a t e deh ydr ogen a se Sim ple pa r t ia l seizu r es, 251 Squ a m ou s epit h eliu m , 26, 27
(SDH ) Sin gle gen e disor der s, in h er it a n ce of, St a ble cells, 44
Secon da r y a ct ive t r a n spor t , 13 142–145, 143t St a pes, 300
Secon da r y in t en t ion , h ea lin g by, 45, 47 Sin gle gen e t r a it s, 142 S ta ph ylococcu s a u r eu s, 109, 378
Secon da r y pr even t ion , disea se, 5 Sin oa t r ia l (SA) n ode, 400 St a r va t ion , 443, 451
Secr et ion , in cells, 13 Sin u sit is St a t u s a st h m a t icu s, 387
Segm en t a l m ovem en t , 471 a cu t e, 50–51 St ea t or r h ea , 475
Select ive est r ogen r ecept or m odu la t or s defin it ion of, 49 St em cells, 171
570 In dex

St en osis, 408 Syst em ic lu pu s er yt h em a t osu s (SLE ), Th yr oid-st im u la t in g h or m on e (TSH ),

St er cobilin , 472 94–96 319, 320t
St er ocilia , 301 clin ica l m a n ifest a t ion s of, 94–95 Th yr ot oxic cr isis, 332
St im u la n t s, 477 com plica t ion s of, 94 Th yr ot oxicosis, 332
St och a st ic t h eor ies of a gin g, 492 dia gn ost ic cr it er ia , 95 Th yr ot r opin -r elea sin g h or m on e (TRH ),
St om a ch pa t h oph ysiology of, 94, 95 319, 320t
fu n ct ion of, 58–59 t r ea t m en t of, 96, 96t TIA. S ee Tr a n sien t isch em ic a t t a ck
secr et or y cells, 436–437 Syst em ic m a n ifest a t ion s, defin ed, 3 (TIA)
St ool, 469–472 Syst olic blood pr essu r e, 401, 402 Tic, 249b
bla ck, 475 Syst olic fa ilu r e, 418 Tida l volu m e (TV), 368
ch a r a ct er ist ics, 471–472 Tin ea
eva cu a t ion , 471 T clin ica l m a n ifest a t ion s of, 130, 130
la bor a t or y a n a lysis of, 472 T-cell r ecept or (TCR), 74 dia gn ost ic cr it er ia , 130
ligh t -color ed, 475 T lym ph ocyt es, 72t, 74, 88 pa t h oph ysiology of, 129–130
pr odu ct ion , 469–470 Ta ch ypn ea , 371t t r ea t m en t of, 130
STR. S ee Sh or t t a n dem r epea t s (STR) Ta ct ile st im u la t ion , 292 Tin n it u s, 303
St r a bism u s, 297 Ta ct ile st im u li, t r a n sm ission of, 289, TIP S, cell in ju r y a n d dea t h , 18–19
S tr eptococcu s pn eu m on ia e, 109, 378 290 Tissu e
St r ess, 325 Ta il, lipid st r u ct u r e, 10 defin ed, 9
h or m on a l r espon se t o, 326, 326 Ta st e, 304 isch em ia , 521
in con t in en ce, 480 Ta u pr ot ein , 502 r epa ir, 34–69
n eu r ologic r espon se t o, 326 Ta y-Sa ch s disea se, 442 h ea lin g a n d. S ee Wou n d h ea lin g
pa t h wa ys for, 325 TB. S ee Tu ber cu losis (TB) TLC. S ee Tot a l lu n g ca pa cit y (TLC)
r espon se t o, 18–20, 19 Tea r s, 296 Toba cco, a n d ca n cer, 176
t est , 409t Tecfider a , in m u lt iple scler osis, 255t Ton ic-clon ic seizu r es, 251
St r idor, a s br ea t h sou n ds, 376b Tect u m , 235t Ton icit y, 205–206, 207
St r oke Tegm en t u m , 235t Ton om et r y, 313
clin ica l m a n ifest a t ion s of, 423 Telom er es, 138, 491, 491 Ton sils, 72t, 75
defin ed, 422 Tem per a m en t , 266 TORCH , 149
dia gn osis of, 423 Ten ia e coli, 471 Tot a l lu n g ca pa cit y (TLC), 368
pa t h oph ysiology of, 422–423 Ter a t oca r cin om a s, 360 Toxigen icit y, 105
t r ea t m en t of, 423 Ter a t ogen s, 149 Toxin s, 18
volu m e, 401 Ter a t om a s, 179 Toxopla sm osis, 91
St r u vit e, 477 Ter ipa r a t ide, 502, 502t Tr a n scr a n ia l m a gn et ic st im u la t ion
Su ba cu t e disea se, defin ed, 3 Ter t ia r y pr even t ion , disea se, 5 (TMS), 276
Su bm u cosa , 437 Test es, 344, 345 Tr a n scr ipt ion , 88, 139
Su ccin a t e deh ydr ogen a se (SDH ), 157 Test icu la r ca n cer, 360–361 Tr a n sfer RNA (t RNA), 137, 139
Su cr a se, 437t clin ica l m a n ifest a t ion s of, 361 Tr a n sfor m a t ion zon e, 27, 27
Su per ficia l pa r t ia l-t h ickn ess dia gn ost ic cr it er ia of, 361 Tr a n sien t isch em ic a t t a ck (TIA), 422
bu r n s, 53 pa t h oph ysiology of, 360–361 Tr a n sla t ion , 137, 139
Su per in fect ion , 105 t r ea t m en t of, 361 Tr a n sloca t ion , 143, 143, 147
Su ppr essor T lym ph ocyt es, 74 Test ost er on e, effect s of, 345 Tr a n sm em br a n e pr ot ein s, 10
Su pr a ph ysiologic doses, 88 T H 1 cells, 78 Tr a n sm ission , m ode of, 114
Su pr a pu bic a spir a t ion , 464 Th a la m u s, 235t, 326 Tr a n spor t , cellu la r m ech a n ism s of,
Su r fa ct a n t , 369 Th er m a l in ju r y, 18 11–13, 12
Swellin g Th er m or ecept or s, 289 Tr a n su r et h r a l r esect ion of t h e pr ost a t e
cellu la r, 208 Th ia m in , 433t, 445t (TURP ), 358
osm ot ic, 199 Th ia zide diu r et ics, 205, 413t Tr a u m a t ic br a in in ju r y, 238–239
Sym pa t h et ic n er vou s syst em (SNS), Th ir d spa ce, flu id com pa r t m en t , Tr em or, 249b
244–245, 245 202 TRH . S ee Th yr ot r opin -r elea sin g
Sym por t , 13 Th ir st , 203, 208 h or m on e (TRH )
Syn a pses, of n eu r on s, 229, 231–233 Th or a colu m ba r n er vou s syst em . S ee Tr icyclic a n t idepr essa n t s (TCA), 276,
Syn a pt ic pa t h way, 324, 324 Sym pa t h et ic n er vou s syst em 307
Syn cope, 22 (SNS) Tr igem in a l n er ve, 243t
Syn da ct yly, 18 Th r eon in e, 137t Tr iglycer ides, 430
Syn dr om e of in a ppr opr ia t e a n t idiu r et ic Th r om bocyt h em ia , 406 Tr igon e, 462, 464, 464
h or m on e (SIADH ), 330–331 Th r om bocyt open ia , 95 Tr isom y, 146, 157
clin ica l m a n ifest a t ion s of, 330 Th r om boem bolu s, 406 TRNA. S ee Tr a n sfer RNA (t RNA)
dia gn ost ic cr it er ia of, 330 Th r om bosis, 404 Tr och lea r n er ve, 243t
pa t h oph ysiology of, 330 Th r om bu s, 42 Tr oph ic sign a ls, 16, 16
t r ea t m en t of, 330–331 for m a t ion , pot en t ia l ou t com es of, Tr ypsin , 437t
Syn dr om es, defin ed, 2 406, 406 Tr ypt oph a n , 137t
Syn gen eic gr a ft s, 87 Th ym in e, 136, 138 TS. S ee Tu r n er syn dr om e (TS)
Syn ovia l join t s, fu n ct ion of, 56 Th ym u s, 72t, 73 TSH . S ee Th yr oid-st im u la t in g
Syst em ic cir cu la t ion , 397 Th yr oid h or m on e, 329t, 454 h or m on e (TSH )
Syst em ic in fla m m a t or y r espon se fu n ct ion s of, 332 clin ica l m a n ifest a t ion s of, 124
syn dr om e (SIRS), 389 Th yr oid h or m on es (TH ), 320t dia gn ost ic cr it er ia , 124–125
 In dex 571

pa t h ogen esis of, 124 Ur in a t ion , 461–465, 463, 464 Vir ch ow t r ia d, 404
pa t h oph ysiology of, 122–124 a lt er a t ion in , 465–469, 468t, 477 Vir ion s, 109, 110
t r ea t m en t of, 125 clin ica l m a n ifest a t ion s of, Vir u len ce, 105
Tu ber cu losis (TB), 375 467–468, 468t Vir u ses, 107–110, 110, 111t
Tu bu la r bu ffer syst em s, 221 dia gn osis of, 468–469 Visu a l field t est in g, 313
Tu bu la r t r a n spor t , 462, 463t t r ea t m en t of, 469 Visu a l im pa ir m en t . S ee a lso E ye(s)
Tu m or su ppr essor gen es, 172, 173–174 Ur in e a m blyopia , 297
BCL-2, 174 a n a lysis, 465 ca t a r a ct s, 298
p53, 173 ch a r a ct er ist ics of, 464 con ju n ct ivit is, 298
r et in obla st om a (Rb), 173 pr odu ct ion of, 461–462, 463, 463t diplopia , 298
Tu r n er syn dr om e (TS), 160–161 r em ova l, 462, 464 eva lu a t ion of, 299
clinical manifestations of, 160–161, 162 Ur in e dipst ick, 465 gla u com a , 312–313, 312, 313
dia gn osis of, 161 Ur odyn a m ic t est in g, 480 m a n ifest a t ion s of, 299
pa t h oph ysiology of, 160 Ur olit h ia sis. S ee Kidn ey st on es n yst a gm u s, 298
t r ea t m en t of, 161 Ur t ica r ia , 92 st r a bism u s, 297
TURP. S ee Tr a n su r et h r a l r esect ion of Ut er u s t r ea t m en t of, 299
t h e pr ost a t e (TURP ) cr oss-sect ion of, 343 Vit a l ca pa cit y (VC), 368
TV. S ee Tida l volu m e (TV) en dom et r ia l ca n cer of, 352 Vit a m in A, 433t
Tym pa n ic m em br a n e, 300 deficien cy of, 444t
Tym pa n om et r y, 303–304 V Vit a m in B 1 , 433t
Type 2 dia bet es, TS a n d, 161 Va ccin es, 89 Vit a m in B 12 , 433t, 449t
Type I im m edia t e h yper sen sit ivit y Va gin a , cr oss-sect ion of, 343 deficien cy of, 445t
r ea ct ion , 82–83, 82 Va gu s n er ve, 243t Vit a m in B 2 , 433t
Type II a n t ibody-m edia t ed Va lin e, 137t Vit a m in B 6 , 433t
h yper sen sit ivit y r ea ct ion , 83, 83 Va lsa lva m a n eu ver s, 471 Vit a m in C, 433t
Type III im m u n e com plex-m edia t ed Va r ia ble r egion s, 76 deficien cy of, 445t
h yper sen sit ivit y r ea ct ion , 83–84, Va s defer en s, 344, 345 Vit a m in D, 433t
84 Va scu la r r espon se, t o in fla m m a t ion , ca lciu m r egu la t ion , 496, 497
Type IV cell-m edia t ed h yper sen sit ivit y 36–38, 36, 37, 38t deficien cy of, 445t
r ea ct ion , 84–85 Va sopr essin , 205 Vit a m in E , 433t
Tyr osin e, 137t, 442, 452 VC. S ee Vit a l ca pa cit y (VC) Vit a m in K, 433t
Tysa br i, in m u lt iple scler osis, 255t VCUG. S ee Voidin g cyst ou r et h r ogr a m Vit a m in s, 431–432
(VCUG) deficien cies of, 442–443, 445–446t
U Vect or, for pr ot ozoa , 112 ph ysiologic fu n ct ion s, 433t
Ulcer a t ive colit is, 65–67, 66 Vect or t r a n sm ission , 114 Voidin g cyst ou r et h r ogr a m (VCUG),
clin ica l m a n ifest a t ion s of, 66 Ven ou s st a sis, 405 469
Cr oh n disea se vs., 67t Ven t ila t ion , 365, 374 VSD. S ee Ven t r icu la r sept a l defect
dia gn ost ic cr it er ia , 66–67 im pa ir ed, 371–378, 372–373t, 376b, (VSD)
pa t h oph ysiology of, 65–66 377–378t, 377t Vu lvova gin a l ca n didia sis, 112
t r ea t m en t of, 67 dia gn ost ic t est s for, 376–377,
Ulcer s, 47, 95 377t W
UMN. S ee Upper m ot or n eu r on s effect s of, 373 Wa ller ia n degen er a t ion , 247
(UMN) gen er a l m a n ifest a t ion s of, Wa t er, 429
Un der n u t r it ion , 442–443 373–376 ch em ica l a lt er a t ion of, 220
pr ot ein en er gy m a ln u t r it ion , 443 la bor a t or y t est s for, 376–377, in t oxica t ion , 208
vit a m in a n d m in er a l deficien cies, 377t Wa t er-solu ble vit a m in s, 432
442–443 t r ea t m en t of, 377, 377–378t WBC. S ee Wh it e blood cells (WBC)
Un sa t u r a t ed fa t t y a cids, 430 m ea su r em en t of, 368 Wh eezin g, 376b, 382
Upper m ot or n eu r on s (UMN), 236 per fu sion a n d, 495–496 Wh it e blood cells (WBC), 41t, 378,
Ur a cil, 137, 138 pr ocess of, 367 521
Ur ea , 463t Ven t ila t ion –per fu sion m a t ch in g (V/Q), in im m u n it y, 73, 74
Ur et er oscopic st on e r em ova l, 479 372 in fla m m a t or y m edia t or s in , 37
Ur et er s, 462, 462 Ven t ila t ion –per fu sion m ism a t ch in g, Wh it e m a t t er. S ee a lso Cen t r a l n er vou s
Ur ge in con t in en ce, 480 404 syst em (CNS)
Ur ic a cid, 463t Ven t ila t ion –per fu sion r a t io, 396–397, Wh it e m a t t er, 234
Ur in a r y in con t in en ce, 479–481 496 WH O. S ee Wor ld H ea lt h Or ga n iza t ion
clin ica l m a n ifest a t ion s of, 480 Ven t r icu la r sept a l defect (VSD), (WH O)
defin it ion of, 479 408 Wilm s t u m or, 147, 184
dia gn osis of, 480 Vest ibu le, 341, 341 Wiskot t -Aldr ich syn dr om e, 80t
pa t h oph ysiology of, 480 Videon yst a gm ogr a ph y (VNG), Wor ld H ea lt h Or ga n iza t ion
t r ea t m en t of, 480–481 310 (WH O), 5
Ur in a r y t r a ct in fect ion s (UTI), 483 Vir a l con ju n ct ivit is, 298 CNS t u m or gr a din g of, 189, 190t
clin ica l m a n ifest a t ion s of, 125 Vir a l h epa t it is on deh ydr a t ion , 212
dia gn ost ic cr it er ia , 125 clin ica l m a n ifest a t ion s of, 121 on H IV in fect ion s, 89
pa t h oph ysiology of, 125 dia gn ost ic cr it er ia , 121 on obesit y, 455
t r ea t m en t of, 125–126 pa t h oph ysiology of, 120–121 ost eopor osis dia gn osis a n d, 501
Ur in a r y u r gen cy, 125 t r ea t m en t , 121–122 Wou n d deh iscen ce, 47
572 In dex

Wou n d h ea lin g
clea r in g, 42
com plica t ion s, 46–47
con dit ion s pr om ot in g, 45
cover in g, 42
by in t en t ion , 45
ph a ses of, 42, 42
restoring functional integrity in, 44–45
restoring structural integrity in, 43–44
a n d t issu e r epa ir, 42–47
X Y
X-lin ked a ga m m a globu lin em ia , 80t Yea st s, 110–111
X-lin ked dia bet es in sipidu s, 331 Yolk sa c t u m or, 360, 361
X-lin ked h yper-IgM syn dr om e, 80t
X-lin ked sever e com bin ed Z
im m u n odeficien cy (XSCID), Z scor e, 501
145 Zin c, 434t, 446t
XSCID. S ee X-lin ked sever e com bin ed
im m u n odeficien cy (XSCID)