.

·:

GENERAL
ANDCLINICAL

Underthegeneral
editorship
of
Anatoliy
V. KUBYSHKIN
Professor D.Sc.f
~M,O,} Pt1.D.~
Headof the Pathophysio!ogy
Department,
CrimeaStateMedicalUniversity

Vinnytsia
NovaKnyha·Publishers
2011
UDC 616-092:616. 1/.9(075.8)
BBC 52.52j!73
G 36

Recommended by the MinistJy of Health of Ukraine as a textbook for

students of higher educational institutions of JV level of accreditation.
letter of27.J0 .2010 No 01.01-47/2409

REVIEWERS

Nikolay V. Krishtal, Professor, M.D., Ph.D. , D.Sc., Head of the

Pathophysiology Department, 0. 0. National Bogomolets Medical Unive r-
sity, Kyiv
Nila K. Kazimirko, Professo r, M .D ., Ph.D., D.Sc ., Head of the
Pathophys iology Department, Lugansk State Medical University

General and Clinical Pathophysiology / Edited by

G 36 Anatoliy V.Kubyshkin- Vinnytsia: Nova KnyhaPublishers - 201 l. - 656p.
ISBN 978-966-382-346-l
The proposed textbook on pathophysiology for English studying students contains
the infonnation selected according to the pathological physiology program for the stu-
dents of med ical uni vcrsities approved by the Ministry of Health of Ukraine. The manual
is written to help students in their independent studies on pathophysiology and to un-
derstand the mater ial on pathological processes development. The material provided in
the textbook is adapted to the credit-module system of training and will help to increase ·
knowl edge of the mechanisms of typical patho logical processes at the molecular, organ
and systemic levels. There are new materials of nationa l and foreign pathological physi-
ology in the book. The textbook is recommended for training medical students of all
medical university facu lties. It can also be offered for use in preparing doctors, interns,
aspirants, postgraduate students, and may be useful to physicians of all specia lties al any
stage of postgraduate education.
UDC 616-092:616.1/.9(075.8)
BBC 52.52si73

© Anatoly V. Kubyshkin, Viktor N. Jelski,

Anatoly 1.Gozhenko, Yuriy M. Kolesnik et al.,
2011
ISBN 978-966-382-346- I © Nova Knyha Publishers, 2011

J '
 REVIEWERS
Nikola
y V. Krishtal NilaK. Kazimirk
o
Professor,M.D., Ph.D., D.Sc., Professor,M.D., Ph.D.,D.Sc.,
Headof the PathophysiologyDepartment, Headof the Pathophysiology Department
,
Bogomolets NationalMedicalUniversity,Kiev LuganskStateMedicalUniversity

AUTHORS
Anatoly
V. Kubyshkin NikolayA. Klimenko
Professor, M.D., Ph.D., D.Sc., Professor. M.0 .. Ph.D., D.Sc.,
Headof the Pathophysiology Department, the Pathophysiology Department ,
CrimeaStateMedicalUniversity KharkivNational MedicalUniversity
(Chapters1-32) (Chapter 8)
·- Viktor N. Jelski Vladimir Z. Kharchenko
Professor,M.D.,Ph.D., D.Sc., Professor
, M.D.. Ph.D.,O.Sc.,
Headof the PathophysiologyDepartment
, the PathophysiologyDepartment,
DonetskNationalMedicalUniversity CrimeaStateMedicalUniversity
(Chapters9,10,13,30) (Chapters1.4,23, 32)
Anatoly
I. Gozhenko MariaR. Khara
Professor, M.D., Ph.D., D.Sc., Professor, M.D.,Ph.D.,D.Sc.,
Headof the Pathophysiology Department, Headof the Pathophysiology Department,
OdessaNationalMedical University TernopilStateMedica l University
(Chapters1. 3, 12, 14, 15, 16, 28, 29) (Chapter17)
YuriyM. Kolesnik Andrey
V. Abramov
Professor,M.D., Ph.D., O.Sc., Professor, M.D., Ph.D., D.Sc.,
Headof the Pathophysiolo gy Department
, the Pathophysio logy Department,
Zaporozhye StateMedical University Zaporozhye State MedicalUniversity
(Chapters5, 6, 9, 10, 13, 30) (Chapters5,6,9,10,13,30)
VitaliyA. Kostenko VeronikaV. Flegontova
Professor. M.D.,Ph.D., O.Sc., Professor, M.D., Ph.D., D.Sc.,
Headof the PathophysiologyDepartment, Headof the Pathophysiology Departmen
t,
UkrainianMedicalStomatological LuganskState MedicalUniversity
Academy,Poltava (Chapters 4, 23, 24)
(Chapters 2, 11, 18, 19,20, 21)
SvetlanaV. Kolesn ikova LeonidL. Aliev
AssistantProfessor,M.D., Ph.D., Assistant Professor
, M.D., Ph.D.,
thePathophysiology Department, the Pathophysiology Department,
Donetsk NationalMedicalUniversity CrimeaStateMedicalUniversity
(Chapters9,10,13,30) (Chapters 2, 32)

InnaP. Gurkalova ViktorV. Sherbak

AssistantProfessor,M.D., Ph.D., AssistantProfessor
, M.D., Ph.D.,
the Pathophysio logy Department , the PathophysiologyDepartment,
OdessaNationalMedicalUniversity CrimeaStateMedicalUniversity
(Chapters 1, 3, 12, 14. 15, 16, 28,29) (Chapter26)

OlgaV. Melnikova VladimirA. Kubyshk in

AssistantProfessor,M.D., Ph.D.,
AssistantProfessor, M.D., Ph.D.,
RadiologyDepartment ,
the Pathophysiology Department ,
CrimeaStateMedicalUniversity
Zaporozhye StateMedicalUniversity (Chapter7)
(Chapters5,6,9,10,13,30)
SvetlanaV. Litvinova
YulianaI. Shramko AssistantProfessor,M.D., Ph.D.,
Assistant Professor, M.D.,Ph.D., PathophysiologyDepartment,
Pathophysio logy Department, CrimeaStateMedicalUniversity
CrimeaStateMedicalUniversity (Chapter16)
(Chapters4, 8, 22)
VladimirA. Makeev
lrynaI. Fomochkina the Pathophysiology
Department,
AssistantProfessor , M.D., Ph.D., CrimeaStateMedicalUniversity
(Illustrations)
the Pathophysiology Department ,
CrimeaStateMedicalUniversity Ky6MWKiHA.B.
(Chapters3, 8, 25, 31, 32) A,MeA .H.,npocpecop,38BiAy
BaY
Ka<peAp11 narocpi3iOJlOfii
Kp11MCbK0f0
PavelF. Semenets AepJKaBH0ro MeA11YH0f0yHisepci,,rery
AssistantProfessor , M.D.,Ph.D., iM.C. I. reopriE:BCbK0f0
the Pathophysiology Department,
8.M.
€nbCKM14
CrimeaStateMedicalUniversity
(Chapters 1, 8, 16,24) A.MeA.H.,
npocpecop
, 3asiAysaYKa<peAp11
narocpiJionorri
AoHe4bKoro Ha4ioHaJ1bH0ro
ArmenM. Petrosyan MeA11YHoroyHise
pc11rery
Assistantprofessor,M.D., Ph.D.,
the PathophysiologyDepartment ,
A.I.
ro>KeHKO
A.MeA.H,,
.
npocpecop, JaBiAy
BaYKaqJ8AP11
CrimeaStateMedicalUnivers ity (Chapter7) naro<piJionorii'
OA8CbK0ro AepJKaBHoro
M8Al1YHoroyHieepc11rery
LudmilaV. Anisimova
AssistantProfessor
, M.D.,Ph.D., KoneCHMKIO.M.
PathophysiologyDepartment, A,MeA,H,,
npoqiecop,
JaBiAyBaY
Ka<pe,QpM
CrimeaStateMedicalUniversity naro¢iJionorri
3anopi3bKoro
.QepJKaeH
oro
(Chapters24, 25,27,28) Me.Q11YHoro
yHisepc11rery
KocTeHKO B.O. <l>OM04KiHa
I.I.
.Q.Me.Q
.H., npocpecop,
aaai.Qyaa4 Kacf)e.Qp11 K.Me.Q.H.,
A01.18HTKacf>eApH
narocpi3ionori'i
naroq>iaionori'i
nomaacbKo ·i ,QeplKaBH0'i KpHMCbK0ro ,QeplKaBH0rO
M8AH4H0ro
CTOMaTOnOri4H0°i aKa,Q8Mii yHisepc11rery
Kr11,1MeHKO M.O., CeMeHe4b n.<l>.
A.MeA.H,,npocpecop, 3aBiAyBa4 K.Me,Q
.H., A01.18HT
Kacpe.Qpvi
narocpi3ionori'i
Kaq:>eApl-1
narocpi3ionorff XapKiBCbKoro KpHMCbK0ro ,QeplKaBH0ro
M8,QH4H0ro
HaL1i0H8JlbH0fO
M8Al-14H0f0 yHiBepc1-1re
ry yHisepc11rery
<l>nerOHToea B. B., neTpOCffH A.M.
A,MeA.H., npocpecop Kaq:>eApl-1 K.Me,Q.H
., ac11creHT
Kaq:>e.QpH
narocpi3ionor
fi
narocpi3ionorff.nyraHCbKoroAep>KaBHoro
KpHMCbKOro ,Qep>KaBH0ro
M8,Ql14H0ro
MeAl-14H0ro yHieepc1-1rery yHiaepc11rery
Xap-.eHKOB.3. AHiciMoea n .B .
.Q.Me.Q
.H., npocpecop Kacf)e.Qp11
narocpiaionorii K.Me.Q
.H., ac11creHT
Kacpe,Qp11
narocpi3iono
ri'i
Kp11MCbK0r0 ,QeplKaBH0r0
M8,Q114H0r0 Kp11MCbK0ro ,QepJKaBH0ro
M8,Q114H0ro
yHiBepc11rery iM. C.IJeopri£BCbK0ro yHisepc11rery
Xapa M.P. Ani ca n.n.
.Q.Me.Q.H.
, npocpecop
, 3aai,Qysa4
Kacpe,Qp11 K.Me.Q
.H., arncreHTKaq:>e,Qpvi
narocp
i3ionori'i
TepHononbCK0'i
narocf>i3ionorii ,Qep)KaBH0'i KpHMCbK0r0 ,Qep>KaBH0fO
M8AH4H0ro
M8,Q114Ho'i
aKa,QeMii yHisepc11rery
A6paMOBA.B.
IJ.tep6aKB.B.
A,Me.Q
.H., npocpecopKaq:>e.Qp11
nar ocpi3ionori'i
aCHCTeHT
Kacpe,QpH
narocpia
ionori'i KpHMCbKOro
3anopi3bK0ro ,QeplKaBH0ro
M8,Ql14H0ro
,Qep>KaeHoro
M8AH4H0royHisepc11
rery
yHisepc11rery
KonecHiKoeaC.B. Ky6HWKiHB.A .

K.Me.Q.H.,
A01.18HT
Kaq:>e,Qp11
narocpiaionori'i aCHCTeHTKa<pe.Qpl-1
M8,QH4H0
°i pa,Qionor
ii
,D,OH81.1bK0r0
Ha1.1ioHanbH0ro
M8,Ql14H0ro KpHMCbK0ro,Q
ep>KaBH0ro
Me,Q114H0ro
yHisepc11rery yHiaepc11rery

fypKanoea 1.n . flHTBHHoeaC.B.

K.Me.Q.H.
, A0l.leHT
Kaq:>e.QpH
narocpi3ionori
i acvicreH
TKa<pe.Qp11
narocpi3ionori'i
Kp11MCbK0
ro
O,Q8CbKOro
,QepJKaBH0ro
M8,Q114H0ro ,Qep>KaBHoro
M8,QH4Horo
yHiaepc11rery
yHiaepc11rery MaK&&e8.0.
MenbHiKoeaO.B. imocrpa1.1ii
K.Me.Q.H
., .Q0l.leHT
Kaq:>e.QpH
narocp
iaionori'i
3anopi3bKOro,QeplKaBH0ro
M8,QH4H0rO
yHiaepc11rery
WpaMKOl0.1.
K.Me.Q.H.
, A01.18HT
Kacf)e.QpH
narocpiaionorii
Kp11MCbKoroA8P)l(8BH0ro
Me.QH
4Horo
yHisepc11re
ry
CONTENTS

Preface........ . ... . ............ .. ....... . .............. .. . 9

PARTI. GENERAL
PATHOPHYSIOLOGY
. .... . . . . . .. . .... . ..... ... 11
UNITI. GENERAL NOSOLOGY
, ETIOLOGY
ANDPATHOGEN
ESIS............ . 12
r 1. Foundation
Chapte Conceptsof Pathophysiology.HealthandDisease.......... 12
r 2. Pathogenic
Chapte Actionof EnvironmentalFactors. . .............. . ... . .. .29
Chapter3. TheRoleof HeredityandConstitution(Somatotypes) in Pathology. ... .. .86

UNITII. MECHA
NISMSOFTISSUEANDCELLULAR
INJURY.. ............. 105
Chapter4. TypicalDisordersof the Peripheral
BloodFlow... ...... ............ 105
Chapter5. Hypoxia..... . .. . ............... .............. . . . .... .. .... 121
Chapter6. CellPathophysiology ......................................... 134
Chapter7. Pathophysiologyof TissueGrowth.Neoplasia ...... . . . ..... . ..... . .166

INFLAMMATION
UNIT111. AND IMMUNEDISORDERS
............ . .. . . .. . 184
Chapter8. Pathophysiologyof Inflammation.................. . ... . . . ...... 184
Chapter9. ReactivityandResistance. ImmuneResponse.... . .. . ..... . ...... .209
Chapter10. Pathophysiologyof the ImmuneSystem............. . .... . . . ... .226
Chapter11. Pathophysiologyof Thermoregulation. Fever . . ....... . ... . ....... 257

UNITIV. PATHO
PHYSIOLOGY
OFMETABOLIS
M . . .... . .. . . . ............ 281
Chapter12. Pathophysiology of EnergyandProteinMetabo!ism.
Starva tion ....... 281
Chapter13. Alterationsin Carbohydrate
Metabolism.DiabetesMellitus. . ... . ..... 294
Chapter14. Pathophysiology
of LipidMetabolism
. Atheroscleros is . . ... ... . . .... 322
Chapter15. Pathophysiology
of WaterandSaltMetabolism. .. .... . . .......... 333
'
r 16. Pathophysiology
Chapte of Acid-BaseBalance............. . . .. .. . ...... 343
Chapter17. Pathophysiology
of CalciumandPhosphate
Homeostasis.... . ...... 348
 J. 7

PARTII. PATHOPHYSIOLOGY
OFORGANS
ANDSYSTEMS
........... 361

UNITV. PATHOPHYSIOLOGY
OFHEMATOPOIETIC
FUNCTION
. . .... . . ... .. 362
er 18. Disordersof TotalBloodVolumeandHematocrit. ... ..... . ......
Chapt .. 362
Chapter19. RedBloodCellDisorders.. .... ... ... ..... ............ .. .... . .371
Chapter20. WhiteBloodCellDisorders..... . ............................ .410
Chapter 21. Neoplast
ic Disordersof Hematopoietic Function.................. .421
Chapter 22. Pathophysiology
of BloodCoagulation... ....... . . .... . . .. . .... .444

UNITVI. PATHOPHYSIOLOGY
OFCARDIOVASCULAR
ANDRESPIRATORYSYSTEM....... . ................. . ............. 460
Chapter23. Disordersof CardiacFunction. HeartFailure. ...... ....... ..... . .. 460
Chapter24. Disordersof BloodPressureRegulation........ . ....... . ..... . .. 478
er 25. CardiacConduction
Chapt andRhythmDisorders .. .. ....... .. .. . .... .. .489
Chapter26. Pathophysiologyof the Respiratory
System ....... . ... .... ....... 500

UNITVII. PATHOPHYSIOLOGY OFGASTROINTESTINAL

ANDRENA L FUNCTION.... ... .... .. .... .. ........... . ........... . 520
27. Pathophysiology
Chapter of the Digestive
System ... ................. .. .. 520
Chapter 28. Pathophys
iology of Hepatobiliary
Function.......... ..... . . . .. . . .546
29. RenalPathophysiol
Chapter ogy ............. . . . .................... . .566

UNITVIII. PATHOPHY.SIOLOGY
OFENDOCR
INE ANONEURAL
FUNCTION
.... 588
Chapter30. Pathophy
siologyof the Endocrine
System ...... .. ...... . .... .... 588
Chapter31. Pathophys
iologyof the NervousSystem............. ... .. ....... 627

UNITIX. PATHOPHYSYOLOGY
OFEXTREME
CONDITIONS
........ ... ..... 641
32. Pathophysiotogy
Chapter of ShockandExtremeMedicalConditions....... . .. 641
 PREFACE
You havethe first edition of "Generaland ClinicalPathophysiology" in
your hands. This book was written with the purposeto help studentsin
their independentpreparationfor classesin pathophysiology.But alsothis
book may be usedby 4-6 yearstudentsof education,graduatesfrom uni-
versitiesand doctors for the increaseof their knowledgein etiologyand
pathogenesisunderstanding.
Pathophysiology is not simply a subject matter.Pathophysiology is an
approachto understanding mechanismsof pathologicalprocessesdevelop-
ment, the basisof clinicalthinking of a futuredoctor.Pathophysiology is one
of the mostintensivelydevelopingsciences.
Whenpreparingthis book,we usedsomeprincipalapproaches .
First, this book not only attemptsto translatethe nationaltextbookfor
pathophysiology teaching.Preparingthis book,we drewonthe bestexperi-
encewhic in teachingpathophysio logy in Russiaand Ukraine,as well as
in severalforeign countries.In this regard,we attemptedto basethe pre-
sentationof the materialon the principle"from generalto specific".In our
opinion,this is oneof the basicandfundamentaldistinguishingfeaturesof
our book.
Secondly , we clearlydividedthepresentation of the materialintotwo parts.
Thefirst part includescommonpathophysiology or description of localand
systemicpathologicalprocesses.Thesecondpart describesthe mostcom-
mon pathological processesof organsandsystems. In this part description
of pathologicalprocessesis followedby describingtheir clinicalmanifesta-
tions,that is actuallyfor the clinicalpathophysiology.
Thirdly, it is first attemptto systematize the materialon the pathophysiol-
ogy of visionby the Ukrainianpathophysiologists. Thebookwaspreparedby
the leadinglecturersandhighlyqualifiedstaffof the Pathophysiology Depart-
mentsof the Crimea,Odessa,Donetsk , Zaporozhye, Ternopi, Kharkiv, Lu-
ganskMedicalUniversities andUkrainianStomatological Academy(Poltava).
Wehopethatthis experience will .besuccessfulandif the bookgainsits high
reputationamongstudentsanddoctors,the groupof the authorsfurtherwill
extendits contents,will try to fill the bookwith additionalillustrativematerial.
 I 9

Wehopethatthe represented booknot onlywill promotegoodmastering

of the materialon pathophysiology by3-yearstudents , butwill alsobecomea
realhelpfor studentsin studyingclinicaldisciplineson the seniorrates.
Wedo not havemuchexperiences in presentationa vastamountof infor-
mationin Englishandinaccuracies or omissionsmayhaveoccurred . Readers
areencouraged to contactusaboutsucherrors. Suchfeedbackis essentialto
the futherdevelopment of the book.
E-mailfor contacts: [email protected]
'/~
;, GENERAL
PATHOPHYSIOLOGY

A littlestoryasan epigraph

WhenI wasa little boy,

mymotherandfatheralwaystold me:
"Son, you muststudy English!"
AndwhenI was7 yearsold, they
ledmeto schoolN9 with depthstudyof
subjectsin English.

SoI dedicatethisbookto myparents

VladimirandElenaKubyshkin
 GE NERAL NOSOLOG Y,
Unit I ETIOLOGY A ND
F")ATHOGENESIS

Chapter 1. FoundationConcepts of
Pathophysiology. Healthand Disease
Pathophysiology is the scienceaboutvital activity in a diseasedorganism,
the main mechanismsof the developmentand outcomesof the disease.
Pathophysiologists try to find the generalpointsof differentgroupsof dis-
eases. Thefinal aim is to discoverthe hypothesisof diseasedeveloprT)ent.
It studiesthe basic patternsof occurrence , developmentand outcomeof
diseases.
Theterm pathophysiology also may be definedas the physiologyof al-
teredhealthstate.Theterm combinesthe wordspathologyandphysiology.
Pathology(fromthe Greekpathos,meaning"disease")dealswith the study
of the structuralandfunctionalchangesin cells,tissues,andorgansof the
bodythat causeor are causedby diseases.Physiologydealswith the func-
tions of the humanbody. Thus, pathophysiologydealsnot only with the
cellularandorganchangesthat occurwith disease,but with the effectsthat
thesechangeshaveon total bodyfunction. Pathophysiology also focuses
on the mechanismsof the underlyingdiseaseandprovidesthe background
for preventiveas well as therapeutichealthcaremeasuresand practices.
Pathologicalphysiologyas an ~ducationaldiscipline providesthe forma-
tion of theoreticbasisfor deepunderstanding of etiology,pathogenesis, clini-
cal manifestations, and principlesof prevention and treatmentof diseases.
Thispurposedeterminesthe exactpositionof pathophysiology in the system
Generalnosology, etiologyand pathogenesis Unit I I 13

Surgery Therapy Gynecology

Biology Biochemistry

Anatomy Chemistry

Genetics Histology

Physiolo
gy

Fig. 1. Connection
between
pathophysiology
andothe
r disciplines

of anyspecialtydoctorstrainingandrequiresdetailedintegrationwith other
educational disciplines.Suchintegrationhasto be realized at leastin four
directions(Fig.1)
Thefirst of themenvelopsthe connections with disciplines studying pro-
pertiesof environmental factorswhichcan causethe diseasedevelopment.
Theseare such theoreticalsubjectsas physics, non-organicand organic
chemistry , biology,microbiology,sociology . Thesesciencesgive students
knowledge whichis necessary for learningof etiologyof diseases .
 14 I Part I Generalpathophysiology

Thesubjectswhichgiveto the studentsunderstanding of organismprop-

ertiesandlawsof its activityin normalconditions (anatomy,histology,nor-
mal physiology,biochemistry , immunology,genetics)constitutethe second
group of educationaldisciplines.Thesesciencesare basisfor learningof
pathogenesis of diseases.
Pathophysiology is closelyconnectedwith biologyand normalphysiol-
ogy. Buttheyare not beingsame.Differentdisturbances of cell activityhave
no prototypein the healthyorganism(A. D. Ado).Thediseaseisn't a com-
binationof normalprocesses,it's a newconditionof the organism.This is
the maindifferenceof pathophysiology from normalphysiology.Theaim of
pathophisiology is to learnall the manifestations
of the disease , to find the
lawsof its development (N. N.Zayko).
Thestudentsstudythe third groupof the subjects(pathological anatomy,
pharmacology)simultaneouslywith pathologicalphysiology.Connections
with thesedisciplinespromoteformationof integralideaaboutdiseasesna-
tureandtheir possibleinfluences.
Pathophysiology has a deep connectionwith pathoanatomy. The func-
tionalchangesarecloseto the morphologicalones.Butthe functioncan be
unchangedin consequence of compensatory processes. We can investigate
theseprocessesonthelivingbeingonly.So,pathophysio logyis distinguished
from pathoanatomy by usingof experimentalmethods.
Andfinally, the mainpositionin medicalhighereducationalsystemoccu-
piesthe clinicaldisciplinesin whichpathologicalphysiologyplaysthe roleof
theoretical basisbecauseit is foundationstoneof medicalscienceideology
of a doctor.

The course of pathophysiology is divided into three

parts: ·

1. Generalnosology , a doctrineaboutinternaland externalreasonsand

conditionsof diseasesappearance .
Nosology (Greek:nosos- illness+ logos- science)is generalscience
aboutdiseasesincludingthe basicconceptsandcategories of pathology,
Generalnosology, etiologyand pathogenesis Unit I I 15

classificationandnomenclature of diseases, socialaspectsof pathology.

Butalsodoctorsin theireveryday practice mustanswertwo mainques-
tions: what is the reasonof diseasedevelopment(etiology)and what
arethe mechanisms of diseasedevelopment (pathogenesis ).
Etiology (Greek:aetia- the reason+ logos- science)is a scienceabout
reasonsandconditionsof occurrence of diseases. Etiologystudies:gen-
eralpropertiesof pathogenic factors, basiccategories of pathogenic fac-
tors, significanceof conditionsin occurrenceof diseases , principlesof
etiotropicprophylaxisandetiotropictherapy. Thecauseof disease may
beintrinsic(genetic) , extrinsic(environmental) or multifactorial.Inheri-
tance, age, gender, infectious agents, or behaviors(suchas inactivity,
smoking, or abusingillegaldrugs)canall causedisease.Diseasesthat
haveno knowncausearecalledidiopathic.
Pathogenesis (Greek : pathos- disease+ genesis- origin) is the sci-
enceaboutmechan isms of development , courseand outcome of dis-
eases . It includes:mechanisms of stabilityof the organismto theaction
of pathogenic factors, generalmechanismsof development of diseases,
mechanisms of recovery , mechanisms of dying, principlesof pathoge-
neticprophylaxis andpathogenetic therapy.
2. Generalpathophysiology - the doctrineabout typicalpathological
processes (allergy, typicallocalbloodcirculationdisturbances , inflam-
mation, tumor growth, typicalmetabolismdisturbances , edema,fever,
hypoxiaetc.).
3. Pathological physiology of organsand systems- the part of disci-
pline which studiesgeneralregularitiesof pathologicalprocessesand
pathological conditionsdevelopment in separatefunctionalsystemsand
organs.

The main tasks of pathophysiology are :

• Essenceof main notionsof generalnosologysuch as disease , patho-

logicalprocess,typicalpathological
process
, pathologicalreaction,eti-
ology,pathogenesis.
 16 I Part I Generalpathophysiology

• Causes , mechanisms of development andmanifestation of pathological

processes;
• Causes andmechanism of development oftypicaldisorders of metabolism.
• Generalregularitiesof pathologicalprocessesdevelopment in organs
andsystemsof organs,conceptof theirfunctionalinsufficiency.
• Contemporary ideasaboutetiologyandpathogenesis of the mostwide-
spreadhumandiseases .
• Etiologicaland pathogenetic principlesof classificationof pathological
processes anddiseases.
, Experimentalproceduresfor decisionof etiologyand pathogenesis
problems .
• Mechanisms of development of basicclinicalmanifestations of patho-
logicalprocesses andthe mostwidespread diseases.

Pathophysiology is the basisof clinicalthinking.By this reasonpatho-

physiologyis connectedwith the clinic, as it hasthe sameaim:to learnthe
disease , andto cureit effectively.Butthey havedifferentmethodsandsub-
jects.Clinica l scienceslearnthe diseasedpeopleandpathophysiology learns
the processes , commonfor all diseasesor for somegroupsof diseases.So,
pathophysiology has its own specific method- the methodof pathophysi-
ologicexperiment.It consistsof two stages:a) the formationof pathologic
processin the animal; b) its investigationduring its development with the
helpof contemporary analyses(N. N.Zayko).Themeaningof experimentis:
the observationof pathologicprocessdevelopment from its beginningto the
end; experimentallowsus to take actionswhich are impossiblein clinics;
test newmedicineson the animals . Themodelis usuallysimplerthanthe
diseasein people . That'swhythe investigator candivideit into partsandthen
reconstructit conformably to people.Butthe modelwill neverbeequalto the
humandisease(N. N.Zayko).
Developmentof clinicalscienceandr:iewmethodsof researches , whichis
applied in clinicalpractice, allowsto get necessary informationfor the study
of etiologyand pathogenesis of 'diseasesdirectlyin a clinic at the patient
examination. Functionalresearches , suchasthe ultrasoundexamination, ·er,
MRI, allowto understandmechanisms of functionalchangesin the patho-
 Generalnosology,etiologyand pathogenesis Unit I 17

logicalorgans,andmodernmethodsof ELISA,PCR,geneticandbiochemical
researchesto getinformationaboutthe mechanisms
of developmentof path-
ologicalprocesses.Bythis connection,
thetermssuchasclinicalexperiment
andclinicalpathophysio/ogy, havebeenusedmoreoften.

The general etiology and pathogenesis

Etiologyis thestudyaboutthecausesandconditionsof the diseaseoccur-
renceanddevelopment. Thecauseof the diseaseis a factorwhichprovokes
the diseaseand determinesits specificfeatures.It is the influencewithout
whichthe diseaseis absent.Thecauseof the diseasecouldbe:externaland
internal.Theexternalcausesare mechanical,physical,chemical,biological
andsocialones(Table1). Theinternalare- hereditary, age,constitution,sex.
Theformationof internalcauseswasmadein closeinteractionwith the envi-
- ronmentduringevolution.Theterm''internalcauses''meansthatthe disease

Table1. Typesof etiolological

factors

3lld:::1m:ri1iug0Joo;ie
Microorgaoic$ms _.•. '.Bacteria,virus~s,
fungt,
.protozoa,
vectors
-
exposwij$i•··
.
, < ·.c: :ii ·
..·•·•. .
·· · ··(e.g.,lns~cts
.
•
andanimals),
• ••
allergens
. .
•
. .
:~, • ::.
.
•• :: ••~· • •• :.>•• ,:: : ••
.
••
. . .. . . . . . .

habitsandlifestyle
Personal physical
Smoking, exercise,
dietaryintake
.· .. •.;; . . . . . . . . . . . . . . ~ ·. .
'· ·... · .. · .-··

substances:
Chemical ·•·
•
. ,
• .;,. '❖
, .
pollutants,
_·Toxln:s, medications,
solvents ~~. .

environment
Physical Climate,radiation,
physical
trauma,geographical
location(e.g.,sunexposure, community
altitude),
(e.g,waterandfoodsupplies)
milieu· : -.·
Psychosocial' ·-•Familystatus(e.g.,bereavement,
loss,status,
. ~ ; ',,...
·_change).-stress, socialisolation,
copingskill.s,
-. ethnicandracialcusto·ms1 custom.a
re-lioi-ous_ _
 18 I Part I Generalpathophysiology

developedin patientwithout obviousinfluencesof the environment.Forex-

ample, hereditaryorigin; deafnessanddumbness , or constitutionanomalyas
diathesis,whena child reactsto a normalagentby hemorrhagicreactionetc.
Thefactorswhichinfluencethe development of the diseasearecalledthe
conditions of the disease . Theyaren'tobligatory.Therearethe conditions
which predisposeto the diseaseand the conditionswhich preventthe dis-
ease.Theseconditionsareexternalandinternal.
The internalconditions , which predisposeto the disease , are: congenital
predisposition, pathologicconstitution(diathesis), earlychildhoodandoldage.
Theexternalconditions,predisposing to thediseaseare:foodmalnutrition,
overexhaustion, neurosis , badcarefor the patients.
The internalconditions , preventingfrom the diseaseare: congenitaland
constitutionalfactors.Theexternalconditions aregoodfeeding,appropriate
workingconditions,physical training.
Theterm "pathogenesis " describesthe studyof mechanisms of a disease
onset, development and outcome.It refersto the sequenceof eventsin re-
sponseof the cellsor tissuesto anetiological agent, from the initialsignsof
disorderto the ultimateexpressionof the disease.Therearethreevariantsof
connectionbetweenthe causeand pathogenes is.
1. The causeinitiatesthe pathologicprocessand after that disappears ,
so the pathologic process(or disease)develops without any etiologi-
cal factor (crushtraumaticsyndrome,ionizingradiationdisease,burn
disease) .
2. The causecontinuesits actionthroughoutall the period of the develop-
mentof disease(infectiousdisease),as a consequence, the etiological
factorpenetrates andinfluencesthe pathogenesis all the time.
3. The causeof the diseaseis delayedin the organism(after infectious
diseasesthe personbecomesa healthybacilli carrier).Thepersistence
of the etiologicalfactor.

The mechanismof the developmentof the diseasedepends,on the one

hand, on the etiologicalfactor,and on the other hand,on the organism,its
immunologicreactivityand regulatorysystems( the endocrineandnervous
systems). Systemicpathologyin organsandtissuedependon structureand

,!- .,' .'

Generalnosology,etiologyand pathogenesis Unit I I 19

Hypo
tension

(
Accumulation-
of. Hypoxia
vasodilatation
J~ctors

Fig.2. "Vicious circle"undershock

morphologickindsof appropriateorgans.Forexample,inflammationin the

cortexof thekidneyis characterized byprominentalterationresponsewithout
exudationanda standardproliferationreaction(A.Gozhenko . 2006).
In pathogenesis of manydiseasesit is necessary to know"the mainstage"
in the formation of a"viciouscircle"(lat.- circulusvitiosus).The mainstage
of pathogenesis is theprocess , whichinitiatesthedevelopment of others.The
time of eliminationof the mainstageis the time of eliminationof the whole
process(disease). Thesearethe mainprinciplesof the treatmentof disease.
Forexample,the mainstagein diabetesmellitusis insulin insufficiency.Its
elimination(introductionof the hormone)leadsto the disappearance of hy-
perglycemia, glucosuria, polydipsia, ketoacidosisetc.
Causesand consequences can constantlyswaptheir places.The cause
(theetiologicalfactor)bringsaboutthe pathologicalprocessor diseaseand
due to feed backcan stimulateand intensifyillness.So, a "vicious circle"
is formedin pathogenes is. For example,undershock,arterialpressureis
decreased, it causeshypoxiaandthenvasomotorcenterdepressed(Fig.2).
This leadsto a prolongeddecreaseof arterialpressureandthe formationof
a"viciouscircle". If one normalizes(stimulates)increasingof arterialpres-
sure,otherpartsof this circledisappear .
Thereare localand generalkindsin pathogenesis which interconnected.
So, inflammation , neoplasms , burns- are local (redness,pain,tumor) and
 20 I Part I Generalpathophysiology

systemic involvements(fever, leucocytosis , cachexia).Thatis why, a local

processcannotoccur separetely;everylocal processcan be transformed
to the generalpathologicalprocess(disease)and vice versa- everygen-
eral pathologicalprocesshas local kinds. For example , in diabetesmellitus
(systemicdisease)presentthe local processes- furuncles , blindnessetc.
Pneumonia(a systemicdisease)hasa localinflamedfocus in the lung. Lo-
cal burn can leadto toxemia, sepsis,burn shock.So, eachdiseaseand its
pathogenesisincludethe complexof complicatedspecificand nonspecific,
systemicand local, morphologicalandfunctionalchangesof the organism.
Pathogenes is of the diseasealwayshastwo opposite processes - injurious,
damagingpathologicalprocessproperand defensive , protective , adjusting
responsewhichis directedat the restorationof the homeostasis .
A compensatoryreactioneliminatesthe pathologicalprocessdueto the
restorationof the homeostasis . It is stimulatedto eliminateconsequences of
the injuriousprocess.
Adaptatio n - it is the statein whichthe organismis adapted(adjusted)to
the constantlychanging environment.
The main differencebetweenadaptat ion and a compensatory reactionis
basedonthefactthatadaptation develops when thereis anincreased intensity
of the environmental factors,but withoutpathological changesandthe main
parameters of the homeostasis arenormal.Compensation is characterized by
pathologicchangesof the mainlyparameters of the homeostasis . Thereare
specificand nonspecificprocessesand mechanismsin pathogenesis. Spe-
cific kindsdependon the etiological (pathogenmaybe phlogogen , oncogen,
pyrogenetc.)factor.Hereditary and regulatorycompositionof the organism
bringaboutnonspecif ic response(parabios , pathologicdominanta,neurodys-
trophicdisorders,stress,alterationof the cortico-vegetative interconnection).
The conceptionaboutthe role of the organismresistanceis of greatim-
portance(A.A. Bogomolets). Theorganismis the basis of suchinteraction ,
as it is a reactivesystemable to perceiveandmakea responseto the external
irritation.So,the etiologyof the diseaseis the resultof interactionof external
andinternalfactors.Thedisease ' asa consequence isn't a resultof the exter-
nal influenceand"organism'scorrelations", but it is a specificinterpretation
of the externalandinternalinfluences.
 Generalnosology,etiologyand pathogenesis Unit I I 21

Restoration after diseaseis anotherprocesswithout the pathological

processproperand was describedin 1960- 1970 by S. Pavlenkoas sano-
genesis.
Sanogenesis is characterizedby compensatory-adaptational reactionsof
the organismin the periodof reconvalescence , whena "vicious circle" and
pathological cascadeof the injuriesarehealing(disappear). To fulfill restora-
tion, a long periodof time is sometimesnecessary(e.g., after myocardial
infarction, ga$troectomia, nephroectomia) for the activation and rehabilita-
tion of variouscompensatory and adjustingmechanismsof the organism
(A. Gozhenko , 2006).

The g en eral information about the healt h

and dise ase
. Diseaseand healtharethe mainforms of living process.They canturn into
eachothermanytimesduringanimalandhumanlife. It is necessary to deter-
minewhatis normalhealthylife, to beabletounderstand the essenceof the
disease. It's difficult to differthe diseasefrom the healthstateandthat's why
we mustgivetotalcharacteristics of healthandlearnfeaturesof the disease.
Forthis reasonwe mustfind out qualitativedifferencesof thediseaseandthe
mechan ismsof specificchanges .

Th e normal cond ition of th e org a nism is ch a ra ct e r-

ized by :

• the balanceof the organismandenvironment

;
• organismintegrity;
• abilityto work.

Thesefeatures can be maintainedevenunderthe influenceof extreme

stimuli and very intensive organism activity. So, the organismhas great
adaptability.
 22 I Part I Generalpathophysiology

The health- " the state of completephysical,mental,and socialwell-

being,but not onlythe absenceof the diseaseandphysicaldefects". (World
HealthOrganization,1948).A favorablecondition,good spirit and ability
to work are typicalfor the humanhealth(P. D. Gorizontov).Healthis the
life of the human, ableto work andadaptedto the changesof environment
(I. P. Petrov).
By N. N. Zayko- health is the normalconditionof the organism,its struc-
ture andfunctions correspondto eachotherand its regulatorysystemsare
ableto supportthe homeostasis. Theadequatereactionsappearin response
to daily stimuli. Thesereactionscorrespondto the majorityof peopleby their
character , time andduration.
As for the human, the norm of healthis an existencewith the mostvalu-
ableparticipationin socialandworkinglife. By Mar, the workingpoweris a
complexof physicalandspiritualabilitiesof a socialperson.
Thusthe norm is the biologicoptimumof functioningand developingof
the organism.
A diseasehas beendefinedas any deviationfrom or interruptionof the
normalstructureor functionof a part, organ, or systemof the bodyt~at is
manifestedby a character istic setof symptomsor signs; the etiology,pathol-
ogy, and prognosismay be knownor unknown.
By I. R. Petrov,"a diseaseis a disturbanceof humanlife-activity. It is char-
acterizedbythe limitationandreductionof the abilityto work underthe influ-
enceof harmfulfactors". ByA. D. Ado, "a diseaseis a damageto organism's
life with the compensations of disturbedfunctions. A diseasedecreases the
humanabilityto work". ByN. N. Zayko,"a diseaseis a disturbanceof normal
organismactivityunderthe influenceof damagingagents.As a result,the
humanadaptabilityand ability to work are decreased". Theessenceof this
determinationis equal. .
Thediseaseis a newcomplicatedprocessin the organism.That'swhy we
cannotgive a short and absolutedete.rmination of this process.However ,
theselimitationsareof little impQrtance for the essenceof the disease.
Afterthe analysisof thesedefinitions,the generalconceptionis revealed:
a normallife is a result of constantorganismadaptabilityto the changing
environment.Consequently , health is mainly determinedby adaptability.
Generalnosology,etiologyand pathogenesis Unit I f 23

If the adaptabi lity is reduced,the "extremefactors"·provokehomeostatic

disturbances.But duringa diseasethe compensatoryprocessesaren't ex-
haustedcompletely. Twooppositeprocesses alwaystakeplacein a disease.
Thefirst is namedby Pavlov(1) "the measureagainstthe disease",andthe
secondone- (2)" the pathologicprocessproper" . Theseprocessesdon't
exist separately. Theyare unitedin dialectics.No unity- no disease.So, a
diseaseis a unity of opposites , whichmakesthe diseasecertainlyfocused.
Usuallywecannotdeterminewhattheproperdiseaseandprotectionare.The
doctormustfind outthe properpathologicprocessandstimulateprotection
againstit.
Besidesusualfactors(chemical,physicalandbiological) , socialfactorsare
of greatimportancefor humanlife. That'swhy humandiseasehas its own
features.Thestructureof morbidityis changedin consequence of (1) urban-
izationand(2) prolongation of life span.Therateof the cardio-vascular, ner-
vousdiseases(cardiacinfarction , bronchialasthmaand so on) is increased
as a result of industrialmodernization. A socialsideof the diseasedisturbs
humanworkingactivityand can causea materialdamageto the society.A
humandiseaseis characterized by the unityof biologicalandsocialaspects.
Lately,weoftenfindthejunctionof socialandbiologicalaspectsboth"inside"
the humanandin his surroundings.
Socialenvironmentis not onlyan environmental factor:1) it actsnot only
uponthe human;2) humansocialactivity influencesthe nature.Thenegative
consequences of such influence(naturalpollution, oxygenand cleanwater
deficit)arealsothe causesof a disease.
Social-economical andmedicalmeasures areorganizedto improvehealth.
Thesemeasures are basedon the constantindustrialgrowthof materialand
culturallevelof life.Theyareaddedbythe widespread activityof the system
of healthprotection.
Statemeasuresdirectedat the preservationand increaseof naturalre-
sourcesmakepreconditions to removethe unfavorable influenceof ecology
uponthe human.
A diseasecanmanifestitselfthroughsignsandsymptoms.A symptomis
a subjectivecomplaint,such as pain or dizziness; a sign is an observable
manifestation, suchas an elevatedtemperatureor a reddenedsore throat.
 24 I Part I Generalpathophysiology

A syndromeis a compilationof signsandsymptomsthatarecharacteristic of

a specificdiseasestate.
Theclinicalcourseof a diseasedescribesits evolution.It canbeacute(rela-
tivelysevere,but self-limiting) , chronic (continuousor episodic,but taking
placeovera longperiod), or subacute(notassevereasacuteor asprolonged
as chronic).Withinthe diseasespectrum,a diseasecanbe designatedpre-
clinical, or not clinicallyevident; subclinical, not clinically apparentand
not destinedto becomeclinically apparent;or clinical, characterized by
signsandsymptoms.
The distinctive featuresof the disease , whichdifferentiateit from health
are: low organismadaptability to the environment ; thedisturbances of life-ac-
tivity; a low humanabilityto work; the diseasedevelopsasa resultof extreme
(pathogenic) stimulus.The mainof the differences that differentiatedisease
from the healthis a reductionof the ability to work.So, a diseasedhumanis
of leastimportancefor the societyas he is badlyadaptedin consequence of
influenceof extremefactors.Thesepoints arethe basisof the diseasenotion
(I. P. Pirogov).
Consequently , a diseaseandthe healthhavesimilaritiesand differences.
Similaritiesarefound in someseparatemanifestations, buttheycannotbethe
reasonof a diseaseandhealth identity.
Separatediseasesalso havetheir similaritiesanddifferences . As we have
alreadyknown, diagnosisof differentdiseasesis basedon theirspecificreac-
tions.We canunderstandthe meaning of suchmanifestations only afterthe
dialecticanalysis of interactions : (1) of specificand(2) nonspecificmanifes-
tations.Theetiologicfactoris of greatimportancefor the specificfeaturesof
the disease.But it is not the only cause.Theremustbe certainconditionsin
whichthe stimulusactsandthe organismresiststo the development of the
disease.
Patholog ic stimuliactmainlyuponthespecializedreceptorsandpathogen-
ic factorshavea differentinfluence(thedamageof cellsandtissues,the irri-
tationanddamageof receptors , n~rvesandnervouscenters) . In consequence
of tissuedamage , differentBASandtoxinsareformed.Besides , pathogenetic
stimuli influenceuponcertainreceptorswhichactivateprotectiveandspecific
andnonspecificreactionsof adaptation.
Generalnosology,etiologyand pathogenesis Unit I I 25

The localizationof the processis of greatimportancetoo. For example,

atheroscleroticchangesof the sameetiology,locatedin the coronaryarter-
ies, brainvessels,aorta,havedifferentsymptomologic and nosologicunits.
So,the qualitativefeaturesof the diseaseare determinedby: 1) the causes;
2) the localizationof changesand 3) the correlationsof pathologicchanges
andreactionsof adaptation.
So, the qualitativedifferencesof the diseasefrom healthandfeaturesof
differentdiseasesarefound out in a formulatedform on the levelwith the
wholeorganismandchangedlife conditions.Weshouldrememberthat the
diseaseis not a complexof differentreactions of adaptationand pathologic
processes, butit is a newcondition,whichis preparedby differentchangesin
thecells,tissues, organsandsystems.

There are some criteria at the basis of the disease

classification:

• etiologicalcriterion(infectiousandnoninfectiousdiseases) ;
• topographo-anatomical criterion- it is the most convenientclassifica-
tion (heartdiseases , kidneydiseasesandso on);
• ageandsex(children'sdiseases, diseasesof old age);
• ecologicalfactor- the conditionsof human life; theyare:geographical
pathology, diseasesof "civilization" determinedby the intensetown life,
hypodynamia, excessunbalanced food (diabetes,obesity);
• hereditaryfactor;
• community of mechanisms (allergicdiseases,collagenoses,
hypoxidoses).

InternationalClassification
of Diseases (ICD-10)include21 classesof dis-
eases(WHO,1990).
A diseaseconsistsof: a) pathologic process;b) pathologiccondition.
Thepathologicprocessis a combinationof pathologicand protective-ad-
aptativereactionsin the affectedorgansor the organism.Thesimplestform
of the pathologicprocessis calledpathologicreaction(e.g.,stabledilatation
of the arterioles,mucusdischargeonthe pathogenic stimulation).
 26 I Part I General pathophysiology

Pathologicalconditionis also the pathologicalprocessdeveloping slow-

ly (e.g.,cicatrisation).However , the oppositedirectionsof the processare
possible.Thepresenceof the pathologicalprocessor pathological condition
doesn't meanthe diseaseof the wholeorganism.But it canturn intothe dis-
easeunderthe influenceof additiona l stimuli.
Oftendifferentpathologicalprocessesandseparatepathological reactions
arefoundout as usualcombinations in humanandanimals.Theyarecalled
typicalpathologicprocesses(inflammation , fever, edema , tumor, dystrophy
etc.). All theseprocesses areformedduringevolution.
Everydiseaseinflictsdamageon the wholeorganism , hencethe damage
spreads.It hasits own featuresas for the interconnection of localand sys-
temic aspects . Everydiseaseconsistsof separatestagesand has its own
cycle from the beginningof pathogenicactiontill the end of the disease.
Sometimeswe cannotfind the borderbetweenthesestagesandsometimes
the bordersarewell expressed .

Typ ic a lly, dis ea ses progress through these stages:

1. Exposureor injury - target tissue is exposedto causativeagentac-

tion.
2. Latent (initial; incubation- for the infectious disease);the periodfrom
exposureof the etiologicalfactor to the first symptoms of the dis-
ease.
3. Prodromal- the period of diseaseprecursors ; the periodfrom the first
diseasesigns (usually- nonspecific)to the typicalsymptomsof the
disease.
4. Manifestation- appearing of typical diseasesymptoms .
5. Periodof the outcomeof the disease:

.
Favorable outcom e s:

1. Recovering
:
Generalnosology,etiologyand pathogenesis Unit I I 27

• complete-absolute functionandstructurerestored ;
• incomplete - differentafter-effectsretained.
• remission- temporarywellnessandthe mainsymptomsdisappearing ;
but minimal morpho-functional signsstill exist.
2. Recurrence - re-appearance of a disease.
3. Complication - appearance of new pathological · processesor condi-
tions.

Unf a vor a ble out c om e s:

1. Preagonal state- theterminalstateof the organism'sliving,occursas a

resultof stronginjuryor a severedisease ;
2. Agonalstate-moredeepbreathi ng, circulatoryandnervousdisturbances;
3. Clinicaldeath- completecirculatoryandbreathingarrest;
4. Biologicaldeath- deathof the braincortex.

Thelatentperiodis an intervalbetweenthe beginningof pathogenicaction

andthe occurrence of the disease . This periodis of greatimportancetor the
prophylaxis.
Theprodromalperiod- is a periodfrom thefirst manifestationsto the full
development of symptoms.Sometimes this periodis undetermined and in
othercasesit is typicalfor the disease .
Theperiodof expressed manifestat ions. Its durationis from somedays to
manyyears(tuberculosis,syphilis).However , thesemanifestations are ex-
presseddifferentlyanddependon theorganismresistance .
Theoutcomeof the disease . Thereare severaloutcomes:recovery(com-
pleteandincomplete) , turningto the pathologicconditionanddeath.
Recoveryis the processleadingto the eliminationof damagesandto the
restorationof organism normalinteraction with the environment , the res-
toration of humanabilityto work.Thewholerecoveryis a turn to the initial
conditions. But we must alwaysrememberthat the diseaseleavesbehind
somechanges . Whenthereis an incomplete recoverythe consequences of
the diseaselastfor a longtime or forever.
 28 I Part I Generalpathophysiology

The following processes are of great importance for

the recovery:

1. protective-adaptationalmechanisms beforethedisease(homeostasis),
2. reserveabilitiesof separateorgans.Thenervousandendocrinesystems
are of greatimportancetoo. Theoutcomeof the diseaseis determined
duringall stagesof its development.Protectiveelementsarenon-sepa-
ratepartsof pathogenesis.

Accordingto the clinicalcourse,diseasesare dividedinto (1) acuteand

(2) chronicones.An acutediseaseis characterized by a quickincreaseand
disappearance of symptoms.Anacutediseasedevelopsduringa limitedtime,
andall manifestations of thediseasedisappear afterthecourseof thedisease.
It is the maindifferencebetweenanacutediseaseanda chronicone.A chron-
ic diseaseis prolongedandcharacterized bythe alterationof attenuation and
relapsesor exacerbation.
Complications arethejoiningof someadditionalchanges to themainman-
ifestations.Thecausesof thesechangesaren'timmediately connected · with
thecauseof the disease.Therelapseis a returnto thediseaseaftertheperiod
of attenuation.
Deathis oneof outcomes.It consistsof somestages(terminalconditions):
preagony,agony,clinicaldeathand_ biologicaldeath.
The preagonalstateis characterized by disturbancesof vitallyimportant
organsafter strong injury or a severedisease - thereare no reflexes , loss
of consciousness, dyspnoe,periodicalbreathingappears(Cheyne-Stokes,
Biot's or Kussmaultype).
Theagonalstateis accompanied by deeperdisturbances of the breathing,
hallutinosis,hypotension, capillarystasis,severearrhythmias.
Clinicaldeathis observedundera completecirculatoryand breathingar-
restandcanbe reversible(it lasts5-7 min).
Biologicaldeathis characterized bythedeathof the brain cortex.Thisstate
is irreversible.
Generalnosology,etiologyand pathogenesis Unit I I 29

Chapter 2. Pathogenic Action

of EnvironmentalFactors

Peopleareoftenconfusedaboutthe magnitudeof the detrimentalhealthef-

fectsof various agentsof theexternalenvironment - physical
, chemical , bio-
logicalandpsychic.Thepathogenicity of thesefactorsvariesanddependson
the extentof.the adaptationovershootof the organism and I or its reactivity.

Pathogen ic p hysic al factors

Mechanical Factors. Mechanical traumais an injuryof thetissuewith a rigid
bodyor explosionwave.It includesinjurieswhichvaryin character , duration,
intensityand pointof application . Mechanical factorsmay be both of exog-
enousandendoge nous origin, for example , pressureof a hematomaor tumor
on thesurroundingtissues.
A woundis the term givento an interruption in the continuityof tissue
by mechanical force. Thereare woundscausedby stabbing,blunt trauma
(punching , kicking,beating, etc.), strangling, biting, shooting, fallingfrom a
height,beinghit by a vehicle,andblasttraumafrom explosives.

There are several morphologic types of such dis-

ruptive lesions, for which distinctive terms are used :

• abrasionis a superficialinjury, commonlyknown as a "graze" or

"scratch". Thistypeof wounddamagesonlythe epidermis (uppermost
skinlayer),andshouldnotthereforebleed.However , abrasionsdo usu-
allyextendintothe dermiscausingslightbleeding;
• lacerationis a split or tearandrepresents theeffectof excessive stretch-
ingof tissue.Theforceof anexternalimpactmaylacerateinternal struc-
tureswithoutdamage to theskin orsubcutaneous tissue(e.g.,ligaments ,
muscles,or bloodvesselsmaybelacerated byexcessive stretchingwith
 30 I Part I Generalpathophysiology

or without a superficialinjury; compressionof fluid or gas in hollow

visceramaycauselacerationandperforationof theirwalls);
• contusionor bruiseis an injuryin whichtheforceof an impactis trans-
mittedthroughthe skinto the underlyingtissueswith sufficientintensity
to disruptthewallsof smallbloodvesselsandto causeinterstitialbleed-
ing withoutdisruptionof the epidermis;
• incisedwound(or cut) is one producedby the pressureand friction
againstskin or othertissuesby an instrumenthavinga sharpedge;
• penetratinginjury is a deepand relativelysmalldiameterlesionof the
skin and/orsubcutaneous tissueresultingfrom the impactof an appro-
priatelyshapedresistantobject;
• fractureis a mechanicallyproduceddisruptionin the continuityof bone.
Suchosseousdefectsvaryfrom a simplelinearbreak,causedby exces-
sive bending,to an explosivecomminutioncausedby the impactof a
high-velocityprojectile.A relativelyminorstressmaycausepathologic
fracturesof diseasedbones.
A mechanical traumais characterized by localandgeneralpathologicphe-
nomena.
Localsequelaeof mechanical injury.Themechanicalinjuryof livingtis-
sues is attendedand followedby variouslocal disturbances , the natureof
whichdependsin part on the siteandseverityof the lesionandin partonthe
organism'sreactivity.

The most typical local sequelae of mechanical injury

are thr following.

1. Hemorrhage is an immediateandinevitablesequelto mechanicalinjury

of livingvascularized tissue.Bloodcontinuesto flow from the damaged
vesselsuntil preventedfrom doingso by thrombosis,vasoconstriction,
or equalization of intravascuJarandextravascular pressures.
2. Asepticinflammation. Theintensityof the inflammationdependson the
extentandnatureof the injury andthe reactivepropertiesof the organ-
ism.
Generalnosology,etiologyand pathogenesis Unit I I 31

3. Other local circulatorydisturbances(inappropriateregionalvascular

spasmwith secondaryischemicnecrosis,propagationof a thrombus
from the siteof a disruptivevascularinjury, etc.).
4. Localinfection.Anyinjurythat disturbsthe continuity of the protective
and especiallyadaptedlayerof cellsthat separatesthe organismfrom
its externalenvironment , whetherit is the integumentor the mucous
membranelining an internalpassage , may createa portalof entryfor
infection.Eventhoughprimarywoundinfectiondoesnot takeplace, a
locusof diminishedresistancemaybeestablished. Delayedinfectionof
theinjuredtissuebythe bloodstream mayoccurbecauseof thecreation
of conditionsfavorableto bacterialgrowthat the woundsite.

The general effects of m ec hanic a l injury are :

• generaladaptationsyndrome, or stress;
• traumaticshock- is anextremestateof theorganismproducedneurore-
·flexively by theactionof anextraordinary stimulusandmanifestedin an
acutecirculatorydisturbance with an acutedrop in bloodpressureand
depression of all importantvital functions:nervousfunction, bloodcircu-
lation,respiration, metabolism, etc.; traumaticshockmayresultin death;
• hemorrhagic shock,
• crush syndromeis the systemicmanifestationof rhabdomyolysis
causedby prolongedcontinuouspressureon muscletissue.It hasbeen
describedmostcommonlyafternaturaldisasterssuchas earthquakes,
in war, andafterbuildingshavecollapsedas a resultof explosion.The
mechanism behindthecrushsyndromeis theleakinessof thesarcolem-
mal membranecausedby pressureor stretching.As the sarcolemmal
membrane is stretched, sodium, calciumandwaterleakintothe sarco-
plasm,trappingextracellular fluid insidethe musclecells.In additionto
the influxof theseelementsintothecell,thecell releasespotassiumand
othertoxicsubstances suchas myoglobin,phosphate andurateintothe
circulation. Theresultof theseeventsis hypovole mic shock, hyperkale-
mia, metabolic acidosis,compartment syndrome , andacuterenalfailure.
 32 I Part I Generalpathophysiology

Theacuterenalfailureis causedby a combinationof hypovolemiawith

subsequentrenalvasoconstriction,
metabolicacidosisandthe insultof
nephrotoxicsubstancessuchas myoglobin,urateandphosphate .

Table2. Peripheral
coldinjuries

• Tabovefreezing • TissueT < o °C causingice crystals/ cellular

• Repeatexposures architectural
disruption
• Microvascular bloodstasisandthrombosis
Chilblain(pemio) Superficial
frostbite
t MildneuronalI endothelial • Injuryof superficialepidermis/dermis
injury • Notissueloss
• Dryconditions Deepfrostbite
• Hands/ feet in patientsof • Injury involves deeper subcutaneous and
Raynaud phenomenon musculoskeletal elements
• Repeatvascularspasticity • Deepfrostbitegradedlikeburns
/ inflammation- nodules, Firstdegree(GradeI)
ulcers,plaques • Mostcommonlyinvolvesexposedareasof the
face, fingers,andtoes
Trenchfoot • Erythema andanesthesia
• Immersionfoot injury • Rewarding generallyreversesprocess
• Wetenvironments Second degree(GradeII)
• Constant vasoconstriction • Cutaneous vesiculation,edema,anderythema
-+ ischemia, bullae,ulcers, • Thefrozenepidermisis whiteandwaxy
pain,Lfunction,gangrene Thirddegree(GradeIll)
• Hemorrhagic vesiculation
secondary
to micro-
vascularinjuryandthrombosis
Fourthdegree(GradeIV)
• Sublacentmusculature,connectivetissue,
andboneinjury
'
: From A.Nixdo
Source rf-Miller
, et al. Hypothermia
andHyperthermiaMedicolegal
Investigation
of Morbid
ity and
Mortali
ty From Exposu re to Environmental
Temperatu
re Extremes/
/ Arch. Path.Lab. Med.- 2006. -Vol.
130, No.9.-P .1297-1304.
Generalnosology,etiologyand pathogenesis Unit I I 33

ThermalFacto rs. Humansarehomeothermic endotherms , inthatwemain-

taina uniformbodytemperature by internalgenerationof heat.A stablebody
temperature resultsfrom a balancebetweeninternalheatproductionandheat
lossto theenvironment. TheCNSprocesses inputfrom peripheral andcentral
thermalsensorsandregulatesbodytemperature by maintainingthis balance.
Cellularinjury or deathoccursif tissuetemperatureis maintainedat a level
morethan5 °c aboveor morethan15°Cbelowthatwhichis normalfor the
blood.Theseverityof injurycausedat anygiventemperature tendsto bepro-
portionalto the durationof the hypothermal or hyperthermal episode.
Effectsof Cold. Variousperiods of exposureto extremecold may result
in differentforms of cold injury or illnesses.Thereare basicallytwo kinds
of cold injuries- local cold-inducedtissue injury and generalovercooling
(hypothermia) . Thelattermaybeassociated with tissueinjuryandviceversa.
Local cold-inducedtissue injurymaybe mild to seriousin the affected
regionsbut usuallyis notfatal.Clinicalmanifestations of peripheralandcuta-
neous cold exposureinclude both nonfreezingand freezinginjuries (Table2).
Frostbite. Exceptin rareinstancesfrostbite is restrictedto the extremities
of the bodyor to areassuch as the tip of the nose,the chin, cheeks,ears,
fingers, toes,hands,andfeet.

Th ere ar e 3 ph a se s in its pa thog e nes is:

1. Coolingand frost effects. Whenexposedto cold, the organismre-

spondsby a peripheralvasoconstriction. This vasoconstrictioncauses
a decreasein the capillaryperfusiongradientand the developmentof
local stagnationphenomena,hyperviscosity , hypoxiaand acidosis.
Frostis limitedto the extracellularspacefirst. In this area,the growing
of icecrystalscausesan increaseof osmolarity,and thenan intracel-
lulardehydrationby passivediffusion of waterthroughthe membrane.
Thecauseof cellulardeathdependson the rapidityof development of
the lesions.Oftendue to the mechanicalaggressionof extracellular
crystals,it can be causedby the ultimateeffects of the dehydration
mechanism.As the skin temperaturefalls below+7 °C the subjects
 34 I Part I Generalpathophysiology

havelost their sensoryfunctions,andthusdo not recognizethe devel-

opingfrostbite.
2. Thawingand progressivenecrosis.During rewarming,arteriolarva-
soconstrictionis replacedby a reactivehyperemiawhich facilitates
the movementof fluids to the interstitium, andcausesan increasein
the bloodviscosityfollowedby a slowingdown of the microcircula-
tory flow. The desquamation of endothelialcells and the alterationof
the basalmembraneprovokean activationandadhesionof leukocytes.
The activationof the arachidonicacid cascadein plateletscausesthe
releaseof thromboxaneA2. Thisreperfusioninjury endsin a total inter-
ruptionof the microcirculationwithina few hours.
3. Permanentlesions.This is the richestphasein clinical manifestation
dueto the progressivevascularnecrosis(edema,blisters,necrosis),it
begins.
4. Hoursafterrewarming . Thelesionsarethenirreversibleandif thetreat-
ment is begunonly at this stage, the results are disappointing.
Generalovercooling (hypothermia).Systemicovercooling(hypothermia)
is a disturbancein the heatbalanceaccompaniedby an unintentional
drop in
a corebodytemperature to lessthan35 °C.

It may be the result of:

1. increasedheatlossdueto the effectof coldon the body;

2. considerably
decreased heatproduction;
3. combinationof boththe abovefactors.

Evenmild hypothermiais a medicalemergencybecauseof the rapidfail-

ure of thermoregulation
and incrementaldeclineof the neuropsychological
awareness.
Unlikesecondaryhypothermia,which resultsfrom diseasesdisrupting
hypothalamicthermoregulation, hypothermiafrom exposureto low environ-
mentaltemperature(primaryaccidentalhypothermia) supervenes whencom-
pensatoryprocessesareinsufficientto maintaineuthermia.
 Generalnosology, etiologyand pathogenesis Unit I I 35

Riskfor hypothermiais particularlygreatduring prolongedexposureto

subfreezing (0 °C) ambienttemperatures. Hypotherm ia mayresultfrom pro-
longed exposureto a temperatureevenonly 10-15 °C belownormalbody
temperat ure.Thewind chill indexcalculatedby aplyingthesefactors, ambi-
enttemperature, windvelocity,andthermalradiation , is anaccepted,reliable
measureof conditions contributingto coldstress.At above-freez ingtempera-
tures, anoverridingwindchillfactorcan hastenhypothermia . Forexample, at
5 °C in windand rain, andat 15 °C in hurricaneconditions,individualshave
experience d hypothermiaclinically.Increasedheatlossand diminishedheat
productionlowerthe organism 's resistanceto cold.
A varietyof commonlyprescribeddrugs, whichincludeantidepressants ,
barbiturates,opioids, benzodiazepines , phenothiazines , and reserpine,
adverselyaffect the body's ability to sensecold. Ethyl alcohol prompts
rapid coolingby effectingcontinuousperipheralvasodilationand inhibit-
ing heatproductionby shivering.Alcohol, whoseintoxicatingeffectscloud
· appropriatedecision makingin cold environments , is the chemicalmost
commonly detectedin the bloodof victimssuccumbingto primaryhypo-
thermia.
Theelderlyandthe veryyoungareespeciallysusceptible to fatalcold ex-
posure.

Multiple mechanisms of action put the aged a t risk

for hypothermia :

1. Reduce d heat production becauseof loss of physiologicreservesin

chronicdisease ;
2. Increasedheat loss from malnutrition and diminishedsubcutaneous
muscle and fat;
3. Impairedthermoregulation primarilyfrom primaryor secondarypathol-
ogiesof thecentral nervoussystem;
4. Inactivity relatedto senescence
; increasedbodysurfacearea, bodymass
indexcoexistswith underdeveloped thermoregulatory
mechanismsin
infants.
 36 I Part I Generalpathophysiology

Bodyresponses tocold.Therearetwo stagesin the overcooling: compen-

satory(bodytemperatureis not altered)anddecompensatory.
Thefirst(compensatory) stageis characterizedbythe development of two
pathwaysin adaptiveandcompensatory reactions.
Reactionsdirectedto the heatretention(limitationof conductive,convec-
tive, radiationandevaporative heatloss.
Conductive heatloss(conduction) describesa directtransferof heatenergy
bycontactbetween two bodiesof differenttemperature(e.g.,skinandobjects).
Convectiveheatloss (convection)is definedas the heat loss by contact
betweenthe surface(skin)anda movingmedium(air or water).
Radiativeheatloss(radiation)is a transferof heatenergybetween2 sepa-
rateobjectsat differenttemperature.Heatenergyis transferredvia electro-
magneticwaves(photons).Thisheattransferdoesnot requirea medium,and
the temperature of any interveningmediumis immaterial.
Evaporative heatloss is definedas the heatloss by evaporation from the
body surfaceor lungs.
Peripheralvasoconstriction. Whencutaneousblood vesselsare cooled,
theybecomemoresensitiveto catecholamines andthe arteriolesandyenules
constrict.Thisact lowersskintemperature , andtherebyreducesthe conduc-
tive-convective heatlossthat is determinedbythetemperature gradientfrom
the skin surfaceto the environment.Cutaneous vasoconstriction directsthe
peripheralvenousbloodbackto the bodycorethrough the deepveinsand
the commitantveins.Theseveinsarelocatedaroundthe arterieswith warm
blood,so that the venousblood receivespart of the heatenergyfrom the
arterialblood- so-calledcountercurrentheatexchange.Thearterio-venous
shuntsof the handsandfeetare closed,so the bloodflow to the limbs is a
nutritiveminimum.
Decrease in sweating(hypohidrosis).
Behavioral mechanisms usedto reduceof openbodysurfacearea(assum-
ing a fetalposition,warmerclothingor environment, etc.).
Piloerection-increasingin beat-insulating
qualitiesof animal's hairor coat
dueto the contractionsof arrectorpili muscles(humanshavepreservedonly
rudimentaryreaction- goose-fleshor goosebumps).
Reactionsdirectedto the heatproductionincreasingare the following.
 Generalnosology,etiologyand pathogenesis Unit I I 37

Increasein shiveringthermogenesis which is an involuntaryreflexmyo-

genicresponseto coldwith asynchronous or balancedmusclecontractions
elicitedfromthe hypothalamus viacutaneous receptors.Theactivityin stimu-
lationandinhibitionof musclesbalance , so thereis noexternalwork.Without
outsidework, all energyis liberatedas metabolicheatenergy.The primary
motorareafor shiveringis a smallareain the posteriorhypothalamus, which
triggersshiveringwhencore temperaturefalls fractionallybelowa critical
value.Maximalshiveringcanincreaseheatproductionby somefour to five
timesnormal.
Increasein voluntarymuscleactivity(foot stampingand dancingup and
downon a coldday).
Increasein non-shiveringthermogenesis, whichis the productionof heat
withoutmuscularactivity(shivering or exercise) , primarilyby the production
of heatthroughtherisingin oxidativemetabolism anduncouplingof oxidative
phosphorylation. Heatproductionis increased bythyroidglandactivityandby
• releaseof catecholamines from theadrenalmedulla . Miceareunableto make
norepinephrine andepinephrine because theirdopaminep-hydroxylase gene
is inactivated(doesnot toleratecold);they havedeficientvasoconstriction
and are unableto increasethermoge nesis in brownadiposetissuethrough
a 32-kDauncouplingprotein(UCP1) causinguncouplingof oxidationand
generation of ATP.
A sourceof considerable heat,particularlyin infants,is brownfat, which
makesup a small percentag e of total bodyfat. This fat has a high rate of
metabolism: stimulationof the sympathetic innervationto brownfat releases
norepinephrine , whichactsvia p3-adrenergicreceptorsto increaselipolysis,
and increasedfatty acidoxidationand uncoupledoxidativephosphorylation
in the mitochondriawhichall leadto the increaseof heatproduction.The
thermogenic functionof the brownfat is likened .to that of anelectricblanket.
Thesecond(decompensatory) stageis markedby loweringof the body
temperature.Progress ive whole body pathophysiologic alterations,which
mayarise, correspondto ascendinggrades(mild, moderate , or severe)of.
hypothermia.
Hypothermia, likehypocapnia andalkalosis,shiftsthe oxyhemoglobin-d is-
sociationcurveto the left, resultingin decreased oxygenreleasefrom hemo-
 38 I Part I Generalpathophysiology

globinintothetissuesat a lowerpartialpressureof oxygen.Vasoconstriction ,

ventilation-perfusion mismatch,andincreasedbloodviscosityareadditional
impediments to tissueoxygenation. Metaboliccausesof acidosisincludelac-
tate generationfrom shiveringanddecreased tissueperfusion,coupledwith
impairedhepaticmetabolismand impairedacid excretion.Dehydrationand
fluid sequestration arecommonaftera long-termexposureto the cold.The
hematocritincreases2 percentper 1 °C declinein temperature.
Prolongedhypothermiasuccessivelyinducessomnolence,diminished
respiration,a certainfall in bloodpressure , unconsciousness and,lastly,pa-
ralysisof the nervouscenters.
The ensuingperipheralvasodilationresultsin a suddenrush of warmer
bloodto theextremities.Thisexaggerated heat sensation,as perceivedby the
mentallyconfused,severelyhypothermicindividual,"paradoxically" leadsto
the rarevolitionalact of undressingprior to comaanddeath.
The most devastatingeffect of hypothermiaoccurswhenthe core tem-
peraturedrops below24 °C. Belowthis temperature,ventricularfibrillation
generallywill occur, andas the coretemperaturefalls below20 °C asystole
will occur.
Long-term coldadaptation.It is foundamongAustralianaboriginesand
Inuitsin Greenland.
The Australianaborigines,for instance , can sleepnearlynakedin tem-
peraturesas low as 4 °C andwith a skintemperaturedownto 27 °C without
shivering.Someadaptationto cold can take placeby improvingthe usual
generalized vasoconstrictionin a processcalledinsulativehypothermicac-
climatization.
Inuits(Eskimos)haverelativelymore sweatglandsin the faceandlesson
the body.Inuitshavea basalmetabolicrate50% higherthanpersonslivingin a
temperate climate.Thethresholdfor shiveringis shiftedtowardstheleftin cold-
adaptedpersons,but theymaintainnormalfunctionat the newset point.Very
old peoplemayshowthe samephenomenon, andlivewith a coretemperature
of 35 °C withoutshivering.Onviously,cold adaptationimpliesnon-shivering
thermogenesis, whichis economicmetabo lic heatliberation(P.-E.Paulev).
Artificiallyinducedhypothermia (artificialhibernation) . In naturallyhi-
bernatingmammals,bodytemperaturedropsto low levelswithoutcausing
Generalnosology,etiologyand pathogenesis Unit I I 39

anyill effectsthat aredemonstrable uponsubsequent arousal.Thisobserva-

tion ledto experiments on inducedhypothermia. If careis takento preventthe
formationof ice crystalsin the tissues,the bodytemperatureof the non-hi-
bernatingexperimental animalscanbeloweredto subfreezing levelswithout
producingany damagethat is detectableafter subsequentrewarming.Hu-
manstoleratebodytemperatures of 21-24 °C withoutpermanentill effects,
and inducedhypothermiahasbeenusedin brain-and heart-surgery, where
the usualfunctionof the heat-regulating centeris inactivatedby generalan-
esthesia.All thesephenomena lowerthe organism'ssensitivity to the action
of pathogenic stimuliandareconducive to a slowingof the bloodcirculation,
whichmakesit possiblefor a certainperiodto isolatethe heartfromtheblood
circulationandto performthe necessary operationson it.
Effectsof Heat.An exposureto hightemperatureprovideslocal (burns)
and general(burndisease, generaloverheating) damagingactionon an or-
ganism.
Burns.Beginn ing at about50 °Cthethermalfactor(hotwater, heatedmet-
al or glass,fire, etc.)causesinjuryto thesurfaceof the body(burn).Contact
with hot objectsproducesa greatereffectthanthat of hot air of the same
temperature.
Longrepeatedactionof relativelyhightemperatures on the oral mucosa,
for example,frequentconsumptionof hot food,reducesthe sensitivityof the
mucosato heatandresultsin a thickeningof its epitheliallayer.

Several degrees of burns are distinguished:

A. Partial-thickness burns
Firstdegreeburn.is characterized
by hyperemiaand mild inflammationof
the injuredpart(erythemaandedemalimitedto the epidermis).It is charac-
terizedby heat,pain, moisteningand reddeningof the burnt surface.First
degreeburnsoften healin 3-7 daysand seldomscar.Typicalfirst degree
burnsincludesunburnandminorscalds.
Seconddegreeburninvolvesinflammation of anexudative characterextend-
ing intothe dermislayerwith formationof the blisterson the skinor mucous
 40 I Part I Generalpathophysiology

membrane. It cancausedamageto sweatglandsandhairfolliclesandis ex-

tremelypainful,oftenwithintenseswelling.Aninjuriedsurfaceis moist, redand
weepy.Mostof themhealsin 1Oto 21 days,but leavesa changein skincolor
andpigmentation . Deeplesionscanbeivoryor pearlywhitein colorandmayre-
quirea processknownasdebridement andadditionalskingraftingtreatments .

8. Fu/I-thickness burns
Thirddegreeburnis accompanied byescharextendingbelowhairfollicles
and sweatglandsto subcutaneous (fat) tissue.At this degreeof burn,the
skin and mucousmembranesbecomecharredand leatheryand often ap-
peardepressedrelativeto surroundingtissue.The skin can be bright red,
waxywhite, tan or brown;thereareno blisters; andthird degreeburnsmay
causemassiveswelling. Perhapssurprisingly,third degreeburnsareusually
not painfulbecausethe injuryhasdestroyednerveendings.Skingraftingor
otherreplacement optionsare requiredfor treatmentof a third degreeburn.
Fourthdegreeburn results in carbonizationinvolvingmuscle, bone, ten-
donand/orligament.Theseburnsareoftenlife threateningand mayrequire
amputation. .
Thegeneralchangesin the organismresulting from burnsdependon the
degreeof the burnandthe sizeof the burntarea.
Thegreaterthe burntsurfaceof the bodyandthe longerthe actionof the
thermalstimulus,the moreseriousthe consequence. Thefunctionalstateof
the organism is alsoveryimportant.
Observations and experimentshaveshownthat the organismperishesif
one-thirdof the bodysurfaceis damaged(in seconddegreeburns)andeven
less (in third and fourth degreeburns).In casesof vast and severeburns
deathoccursinstantaneously or within2-3 days.
Systemic disturbances causedbyburns(burndisease).Thecomplexof
typicalchangesin the humanbodydevelopingdueto the deepand severe
burns, is knownas burndisease.
Therearethe followingstagesof burndisease : burnshock, burntoxemia,
burninfection,burnemaciation , outcome .
Burnshock. In the development of primaryor neurogenic shockwith rapid
peripheralcirculatorycollapseleadingto syncopeor evena deathpaintac-
Generalnosology, etiologyand pathogenesis Unit I I 41

tor playsthe dominantrole. This mayexplain the long-termnonprogressive

(erectile,excitatory)phaseof the shock.
Withburnsof morethan20 % of thebodysurface,thereis a rapidshift of
bodyfluidsintothe interstitialcompartments . Patientswith third-andfourth-
degreeburnsexperience an averagewaterlossof 0.35ml/cm2 of burntarea
perdayduringthefirst week.Theprogressive loss of plasmafrom the burnt
surfaceor into the damagedtissue beneathit may result in hemoconcen-
tration and secondary{hypovolemic ) shock.The mechanismsinclude an
increasein local interstitialosmoticpressure{from releaseof osmotically
activeconstituents of dyingcells)andbothneurogenic andmediator-induced
increasesin vascularpermeability .
Burntoxemiais relatedto accumulation in the organismof toxic products
of tissuedecomposition and systemicexpressionof multipleinflammatory
mediators(systemicinflammatoryresponsesyndrome).
Burninfection. Theburnsiteis idealfor growthof microorgan isms. Further-
more, cellularandhumoraldefenses againstinfectionsarecompromised (both
lymphocyte andphagocyte functionsareimpaired).Directbacteremic spread
andreleaseof toxicsubstances suchasendotoxinfrom the localsite exertdi-
rectconsequences. Pneumonia or septicshockwith renalfailureandtheacute
respiratory distresssyndromearethemostcommonserioussequelae.
Burnemaciation (or burndystrophy)is characterized by the development
of a hypermetabolic statewith excessheatloss and an increasedneedfor
nutritionalsupport. It is estimatedthat when morethan 40 % of the body
surfaceis burnt,the resting metabolicratemayapproachtwicethe normal.
Theconseque nce is breakdownof tissue, which may result in loss of es-
sentialproteinstores,reachinglethalproportionscomparableto starvation
within severalweeks. The developmentof progressivecachexia,edemas ,
anemia,dystrophicalterationsin viscera,complications(pneumonia,glo-
merulonephritis) , adrenocortical insufficiencyis usuallyobserved . Thereis a
50 % rise in metabolic rateof nonthyroidal origin, and someburnt patients
develophemolyticanemia . Because of thesecomplications,plusthe severity
of the shockandthe problemsof sepsisand kidneydamage , the mortality
ratewhenthird-andfourth-degree burnscovermorethan75 % of the body
is still closeto 100%.
 42 I Part I Generalpathophysiology

Duringthe recoverythetotal rejectionof necrotictissues,filling of the de-

fect with granulationtissue,scarringandepithelization occur.
Generaloverheating, or hyperthermia, is a resultof heatretentionin the
organismdueto disturbedthermoregulation andimpededheatdissipation.
Overheating is favoredby the followingfactors.
Exogenousfactors:humidity(in high ambienttemperatures , evaporation
is the mostefficientmechanismfor mediatingheatloss,yet it is ineffective
with humiditylevelsof morethan 75 %); diminishedmovementof the air,
moisture-proofclothing,factorsconduciveto decreased perspiration. Social
andenvironmental factors,suchas bedconfinement, livingonthetop floor of
an apartmentbuilding,lack of accessto air conditioning,andsocialisolation
with the inabilityfor self-care,all predispose to preventable,yet oftendeadly,
hyperthermia.
£endogenous conditions:impairedthermoregulation, well-developed sub-
cutaneous tissue,fatigue,emaciation, effectsof pastdiseases,overwork,etc.
Elderly,e very young, and chronicalcoholicsare less likelyto mount a
proper thermoregulatoryresponseto excessiveheat. Underlyingmedical
conditionssuchas hyperthyroidism, obesity,andburnscomplicatethe usual
liberationof heatbecauseof the increasedmetabolismanduncoupledmito-
chondrialoxidationand phosphorylation, decreased activity,increasedsub-
cutaneousfat, or inabilityto sweatproperly(hypo-or anhidrosis). .
Variousclassesof licitandillicitdrugs,amongwhichareanticholinergics, an-
tihistamines , antidepressants (monoamine oxidaseinhibitors,tricyclics),anti-
parkinsonian, antipsychotics (phenothiazines,
butyrophenones, thioxanthenes),
alcohol,amphetamines , cocaine,andlysergicaciddiethylamide, can raisethe
metabolicrateandcausehypohidrosis resultingin increased heatproduction .
Bodyresponses to heat.Excessive heatretentionresultsin hyperthermia
or heatillnessof varyingdegreesof severity.
At rest, the basalmetabolicrate (BMR,it is a standardizedestimateof
metabolism)generates100kcal/kgper hour.Withoutproperdissipationof
heat,the increasedheatproductioncan resultin bodytemperatureincrease
at a rateof 1.1 °C/h. '
Unacclimatized individuals undergoing strenuousactivitygenerateandre-
tain heatenergyupto 1000kcal/kgperhour,whichmayresultin severeheat
Generalnosology, etiologyand pathogenesis Unit I I 43

illnessesor death.Thereare two stagesin the overheating: compensatory

(bodytemperature is not altered)anddecompensatory ones.
Thefirst (compensatory) stageis character ized by the developmentof
adaptiveand compensatory reactionson the part of physicalthermoregula-
tion for the purposeof the heatlossincreasing.
Dilatingof theperipheralvessels-anintrinsiclevelofthe heatlossthrough
the infraredradiationto the environment , conduction , convection(if environ-
mentis coolerthanbodytemperature ). This resultsin increasedcardiacout-
put.Thearterio-venousanastomoses in the handsandfeetareopen,andthe
bloodflow canriseup to at least10 folds.Theskincoveringis limited, when
a nakedpersonis in warmair. Theskinbloodflow, mainlyin the extremities,
determinesthe amountof heatenergy,which is carriedfrom the bodycore
to be lost on the surface.Theheatenergyis transportedfrom the largebody
coreto the skin by convectionin the blood. A substantialpart of the heaten-
ergyis lost throughthe superficialveins of the extremitiesactingas cooling
mechanism. Thebloodof the superficialveinsis thus arterialized , whenthe
personis warm.
Increasein evaporation throughsweating(hyperhidrosis)and panting(in
animals)- an extrinsicpathwayof heat-dissipation (if environmentis warmer
than bodytemperature).Sweatingis vaporizationof wateron the skin and
mucousmembranes of the mouthandrespiratorypassages.Vaporizationof
1 g of waterremovesabout0.6 kcalof heat;
Behavioracts concernedwith extensionof the open surfacearea (de-
creasedactivity,coolerclothingor environment , fans, andso forth).
Thesecond(decompensatory) stageis markedby elevationof the body
temperature andexcitement- restlessness, accelerated andshallowrespira-
tion, accelerated pulse (130-140 beatsper minute),excessivemetabolism ,
particularly,increasedexcretionof nitrogenin the urine, intensifiedreflexac-
tivity, andsometimesconvulsive twitchings.Onfurtherheatingtheexcitement
is replacedby diminishedvegetative functions(shallowrespirationand low
bloodpressure),disappearance of reflexesanda comatosestate,i.e., uncon-
scious stateresemblingsleep,whichmaybeaccompanied by clonicspasm.
Overheati ng is characterized by hemoconcentration (dueto lossof water},
disturbancesin electrolytebalance(dueto loss of chlorides),that overbur-
 44 I Part I Generalpathophysiology

Table3. Classification
of heatillness

Heatillness Signsand~ms .. '

:-.•·.}'f •~~'
'ti!:2~f~1;
Heatedema - Swollen
hands,feet,andankleswithprolonged sittingor
standing
in hotweather
Healrash(miliaria - Pruriticvesicu
lar rashresulting
fromsweatforcedthroughductal
rubria, lichentropicus,wallsintosurrounding tissuesinsteadof intraductal
pathway
from
or prickly heat) glandto skinsurface
Heatcrampsandheat - Fluidandelectrolyte
lossfromprofusesweating without
syncope adequate hydration
- AspHchanges, tetanyandpainfulmuscular spasms arjse
- Heatsyncope: a vasovagalresponse
to intravascularvolume
depletionaridperipheral
vasodilation
- Respond wellto promptrehydration
Heatexhaustion - Significantfluidandelectrolyte
depletion
withdecreased cardiac
outputandmassive peripheral
vasodilatation
- Flu-likesymptoms includeheadache,blurredvision,fatigue,
nausea, vomiting,chestpain,anxiety,
andconfusion
- CorebodyT > 38 °C
- Promptfluid andelectrolytetreatmentdetersprogression to heat
stroke
heatstroke - Elder
Classical ly or chronically
ill passively
affectedin heatwavesituations
- Symptom triad:hyperthermia,anhidrosis,
andmentalstatus
changes
ional heatstroke - Occursin unacclimated
Exert youngpeopleinvolved invigorous
physicalactivityin hotweather
- Second mostcommon causeof deathin highschoolathletes
- Tachycardia,tachypnea , hypotension,
andmentalstatus
alterations '
- Pers
istentsweating in 50 % victims
- Elevatedmuscleandliverenzymes andcreatininesecondaryto
rhabdomyoly,sis, hepaticandrenalinjury
Source:
FromA.Nixdorf-Miller,et al. Hypotherm
ia andHyperthermia
Medicolegal
Investigation
of Morbidity
and
MortalityFromExposu reto EnvironmentalTemperature
Extremes//
Arch.Path.Lab. Med.- 2006. -Vol.
130, No. 9. -P. 1297- 1304.
 Generalnosology,etiologyand pathogenesis Unit I I 45

densthe hemopo ietic apparatusand mayleadto the developmentof heart

failure.
Heatillnessis classifiedaccordingto increasing degreesof severity(Ta-
ble 3). Mild heatillnessesare generallynot life threatening.Heatexhaus-
tion and heatstrokeare moreseriousmanifesta tions of heatillnesses.Heat
stroke, subclassified aseitherclassicalor exertionaltype, is a life-threatening
illnesscharacterized by corebodytemperaturemorethan40 °C. If the core
bodytemperature is not rapidlyreducedin eithertypeof heatstroke, signifi-
cantmorbidityandmortality occursin 30 % to 80% of affectedpeople.Death
occursin respiratoryarrest during exhalationand cessationof the heart's
actionin the systole.
Sunstroke. A sunstrokeoccursas a resultof exposureof the headdirectly
to the broilingsun. It is characterized
primarilyby phenomena of ultraviolet
radiation-de pendentmassivereleaseof cytokinesand prostaglandins(espe-
cially in the meningealand cerebralblood)and extremestimulationof the
_ centralnervoussystem.Sunstrokeis manifested asgeneralexcitement, often
mentalandnervousdisturbances, andsometimesconvulsions.Mildercases
are markedonly by intenseheadaches , irritability, restlessness and cardiac
weakness.

Effects of Electric Energy . The organism experiences

the harmful influence of electric energy in the event of:

• anexposureto discharges
of atmospheric electricity(lightnings);
• a contactwith man-madeelectriccurrent(e.g., from high-or low-volt-
agelines).

Theconsequencesresultingfromcontactwith electriccurrentdependon a
numberof conditions,the mostimportantof whicharethefollowing.
Type of current(director alternating).Directcurrent (DC)actsfasterthan
alternati
ngcurrent (AC),butthe latteris moredangerous thantheformerat a
relativelylowtensionandlowfrequencybecause tissuesofferlessresistance
to ACthanto DC. AC of 100-150 V producesa strong effectandsometimes
 46 I Part I Generalpathophysiology

provesfatal.Upto 500V ACis moredangerous thanDCof the samevoltage.

Above500V DCbecomesmoredangerousthanAC.
Electromotiveforce (voltage).It usuallycausesdamageproportionate to
its magnitude.Thehigherthevoltage,in general,the moreseverethedamage
seen.High-voltage(>500to 1000V) currentstendto causedeepburns,and
low-voltageto causefreezingto the currentsource;
Frequencyof alternatingcurrent.Somealternatingfrequenciesare more
dangerousthan others.AC at 50 or 60 Hz (householdcurrent) produces
muscletetany,often freezingthe handto the current'ssource;prolonged
exposuremayresultin severeburnsif the voltageis high.ACwithforegoing
frequencyis the mostdangerousto life becauseit lies in the frequencyrange
that is particularlydisturbingto the respiratorycentersof the brainandto the
heartwhereit caninducefibrillation.Increasein thefrequencydiminishesthe
harmfuleffectsof the current.High-frequency currentsare not dangerous
andareevenusedfor therapeuticpurposes(e.g.,d'Arsonvalcurrent).
Currentstrength(ampere).At the sametensionthe strengthis the great-
er, the lowerthe resistanceof the tissues.Low amperagemaycauseonly a
tinglingsensation , while higheramperages will causepainand oftensevere
burns.In addition,amperagecan be relatedto bodyreactionsproportionate
to its magnitude.Themaximumamperagethat can causethe flexorsof the
armto contractbutthatallowsa personto releasehis handfromthecurrent's
sourceis termedthe let-gocurrent.ForDC,the let-gocurrentis about75 mA
for a 70-kgman;for AC,it is about15 mA, varyingwith musclemass.
Amount of resistanceoffered by the tissuesin the path of the current.
Eachtissuehasa differentresistancerelatedto its watercontentand den-
sity. Theseare the least resistants(nerves,bloodvessels, muscles,skin)
and most resistant(fat, tendon, bone)tissues or organs.The resistance
of the skin, too, varieswith its densityand watercontent,so that the skin
of mucousmembranesand of the innerarm and thigh offers the leastre-
sistanceandthe callousedsole and palm offer the most. Electricalcurrent
tendsto flow throughthe tissueswith the lowestresistanceoncethe skin
hasbeenburntthrough. As a result, oftena largeamountof muscle,nerve,
and blood vesseldamageoccurs underthe surfaceof the skin that may
not be apparentfrom the surfaceinitially.The harmfulinfluenceof current
 Generalnosology, etiology and pathogenesis Unit I I 47

will be muchgreaterwhenexertedon moist skin (with resistanceof about

500-1.500 ohms/cm2).
Surfaceareaof contact.It playsan importantpartin the resistance to elec-
tric current.Small-surface areacontactis moredangerous thanwide-surface
contact.Bipolarcontactwith potentialsourceis moredangerous thanunipo-
lar contact(in whichelectricitydischarges intofield).
,, Durationof currentflow.Theseverityof thedisturbance causedbytheflow
of a givenamountof currentbetweensimilarexternalcontactsis proportional
to the durationof flow (currentevenof highvoltageandgreatstrengthis not
fatalif it actslessthan0.1 second);
Pathwayof currentthroughthe body.It determinesthe natureof injury.
Dipolesbetweenhandsmeetsthe heart,causingcardiacarrhythmia,ven-
tricularfibrillationandthen cardiacarrestin thediastole.Passage throughthe
handsandcontralateral foot meetsthe heart, whiledipolespassingthrought
the headmeetcerebralcenters,causinggeneralized seizures , intraventricular
- hemorrhage, respiratoryarrest, ventricularfibrillationor asystole . Passage
throughthefeetis not dangerous(localconvulsions);
Physiological stateof theorganism.Predisposing factorsarefatigue, pro-
fuse sweating,fever, emotionaltension, cardiopathies,alcoholism , status
thymicolymphaticus, diabetesandhysterics . Themore excitablethe nervous
system,the moreintenseits reactionduringthe passageof current.Toler-
ancedevelopsin electricians andexperimental animalmodels.
Thegeneraleffectsof electric currenton the organisminclude(depending
on its strength)headache , nausea,a riseandsubsequent slightdropin blood
pressure,paralysisof nervesandmuscles , edema.Cardiovasc ular effectsin-
cludearrest,multipletypesof arrhythmias,coronaryvesselspasmor damage
leadingto a myocardialinfarction-like picture, blocks,andsymptomsof car-
diac ischemiaincludingconstrictingchestpainand palpitations.Pulmonary
hemorrhage andcontusionhavebeenreported.Hypotension , fluid andelec-
trolytedisturbances , andseveremyoglobinuria maycauseacuterenalfailure.
Thelocalactionof electricshockon the bodysurfaceusuallyproducesa
burnwhichis not infrequentlyshapedlikethe conductorwhich madecon-
tact with the body.Woundsresemblingthoseresultingfrom a gunshotare
formedat thesitesof entranceandexitof thecurrent.In somecasesnecrosis
 48 I Part I Generalpathophysiology

of the affectedportionsof theskinandunderlyingtissueis observed;it devel-

opssometime afterthe actionof the electriccurrent.

Effec ts of Altered Atmospheric Pressure

,t

Effects of Lowered Atmospheric Pressure . Altitude

sickness is developed as a result of lowered atmospheric
pressure. It affects:

Table4. Resting
ventilation
andarterialbloodgasvalues,
measured
duringa simulated
40-dayascentof Mt.Everest
ina chamber
insevensubjects
("Operation
Everest
II")*

Altitude Baro-
(m)

0 760 150 11,0 ± 7.43± 33.9± 99.3± 97.6±

1.0 0.04 3.5 9.3 0.1
4,580 429 80 14.6 ± 7.46 ± 25.0 ± 52.4 ± 84.8 ±
2.7 0.02 2.2 4.0 4.0
7,000 347 63 20.9 ± 7.50± 20.0± 41.1 ± 75.2±
6.3 0.04 2.8 3.3 6.0
8,100 282 49 36.6± 7.53 ± 12.5± 36.6 ± 67.8±
7.9 0.03 1.1 2.2 5.0
8,848 240 43 42.3 ± 7.56± 11.2 ± 30.3± 58.0±
7.7 0.03 1.7 2.1 4.5

• Valuesare mean± standard

deviation.

Source:
ModifiedfromJ.R.Sutton, et al.Operation
Everest II:Oxygen
transportduringexerc
iseat extreme
simulated
altitude//J. Appl.Phys
iol. - 1988.- Vol.64.- P.1309.
Generalnosology,etiologyand pathogenesis Unit I I 49

• personsclimbinghigh mountains(mountainsickness,or soroche,or

puna, or mareo);
• pilots flyingat highaltitudeswithout oxygenmasks.

Loweredatmosphericpressureis injuriousto the organismbecauseof

hypobarichypoxiadevelopment. It is characterized by two effects.
Loweringof thebarometricpressure . The gradualfall in ambientpressure
during ascentis calledas decompression . It is manifestedby earacheand
painfulsensationsin frontalbonysinusesasa resultof rapidexpansionof the
gas, floodinginto cavities,meteorism,nasalbleeding(epistaxis)due to the
ruptureof smallbloodvessels.
Loweringof thepartialoxygenpressurein the inhaledair. It is a causeof
hypoxichypoxiadevelopment. The humanorganism toleratesa decreasein
atmosphericpressureworsethan an increaseof equalmagnitude . Thus the
atmosphericpressureof the humanenvironment canbetripledwithoutharm,
butyeta loweringof the pressureby aslittleas50 % incidentto elevationto an
altitudeof 6,000 m resultsin severesystemichypoxiaandmaycausedeath.
Thedecrease in barometricpressureresultsin a reductionin thepartialpres-
sureof oxygenin the inspiredair (Table4). Thisinitiatesa sequenceof patho-
geneticeventsleading to a reductionin arterialoxygenpressure(PaO 2
) and
saturation.About20 % of personsascendingabove2,000 m for lessthan 1
day(without acclimatization) developsomeform of altitudesickness.
Fastascentduringflight rarelycausesproblemsat altitudesbelow10 km.
At altitudesabove20 km (wherethe ambientpressureis lessthan47 mmHg)
the blood of a spacetravelerwith normalbodytemperaturewill boil, if the
pressurewithin his suit is lost. This is becausethe partialpressureof satu-
ratedwatervaporat bodytemperatureis 47 mmHg.
Abruptexposureto high altitude(e.g., depressurization of aircraft, balloon
ascent)causesdecompression syndromedevelopment with acuteseverehy-
poxiaand lossof consciousness .
Themechanisms that protectoxygendeliveryand otherphysiologicfunc-
tions developwith time at highaltitude.Thetypesand degreesof adaptation
dependon manyfactors, includingdurationof exposure,level of physical
activity, age,and generalphysicalcondition of the organism(its endurance ,
 so I Part I General pathophysiology

typologicalcharacteristicsof the nervoussystem,rateof adjustment, etc.).

Personswith limitedcardiorespiratory reservemayexperience acute moun-
tain sicknessat altitudesas low as 1,500 m abovesealevel.

There is a number of neuroendocrine responses

d e sign e d to compensate for the reduced arterial
oxygen content:

• a direct effect of hypoxia on stimulating adrenal medullaryreleaseof

epinephrine;
• an increasein wholebodyandtissuespecificsympatheticnerveactivity;
• a transientincreasein circulatingcortisollevels;
• anenhancement of erythropoietinincretion.

An ~immediate benefit from these adaptations in-

cludes :

• an increasein ventilation(helpingwith oxygenation of arterial blood);

• increasedcardiacoutput(helping with deliveryof oxygenatedbloodto
tissues);
• redistribution of blood flow (ensuringcritical tissuesand organsget
adequateoxygen);
• contractionof the spleenand stimulationof the hematopoietic appara-
tus, whichis accompanied by increasein the erythrocytesof the blood
andof its oxygencapacity;
• changesin substrate selection , monopolization of the mitochondrialre-
spiratorychainwith succinate(economicaluse of oxygen).

Bystimulatingrespirationhypoxiacausesrespiratoryalkalosis,which con-
tributesto symptomsuntil loss of HC03 in urinepartiallycompensates.
Thebasicpathophysiology of altitude sicknessis disturbanceof water and
electrolytebalance.Capillarypermeabilityis increased,allowingfluid to ac-
Generalnosology,etiologyand pathogenesis Unit I I 51

cumulatein variouslocations;the causeis thoughtto bevascularendothelial

damage . In susceptiblepersons, increasedADHsecretionresults in tissue
fluid retention
, and plasmavolumeis decreased , simulatingan increasein
hematocrit.
Rapiddevelopmentof hypoxiais followedby strong peripheralvasocon-
strictionwith consequentshiftingof a largeportionof the bloodvolumeto
the pulmonarycircuit. This hemodynamicdisturbanceleadsto pulmonary
arterialhypertens ion associated with hypoxicdamageto pulmonarycapillary
endotheliumandalveolarpneumocytes. Theresultof the combinedactionof
thesetwo responsesto the abnormalphysicalenvironmentis the so-called
high-altitudepulmonaryedemaandhigh-altitudecerebral edema.
Acutemountain sickness (AMS).Thisform is the mostcommonandmay
developat altitudesas low as2,000 m. It is characterized by headache , weak-
ness,vertigo,tinnitus, nausea,dyspnea,palpitations,andsleepdisturbance.
In both the brainand the lungs, hypoxiaelicits neurohumoraland hemody-
namicresponses that resultin overperfusion of microvascu lar beds, elevated
hydrostaticcapillarypressure , capillaryleakage , andconsequentedema.The
hypoxia-induced cerebralvasodilatationor its effectors, such as nitric ox-
ide, mostlikely producethe headache , perhapsthroughthe activationof the
trigeminovascular system.The headacheitself can causeother symptoms,
suchas nauseaand malaise , andtherebyaccountfor mild AMS. An alterna-
tive hypothesisis that earlyAMSis dueto mild cerebraledema.
AMS usuallysubsidesin 24 to 48 h but occasionallyevolvesinto high-
altitudepulmonaryedema , high-altitudecerebraledema,or both.
High-altitude pulmonary edema(HAPE ) is a noncardiogenic pulmonary
edemaassociatedwith pulmonaryhypertension andelevatedcapillarypres-
sure.Theusualpulmonaryhypertension on ascentto highaltitudeis excessive
in thosewith HAPE , as a resultof exaggerated hypoxicpulmonaryvasocon-
striction.Themechanisms for this responseincludesympathet ic overactivity,
endothelial dysfunction , andgreaterhypoxemiaresultingfrom a poorventila-
tory responseto hypoxia.In addition,the increasedsympatheticactivityprob-
ablyraisescapillarypressureasa resultof pulmonaryvenousconstriction.
High-altitude cerebraledemais more malignantform of AMS. It is a
potentiallyfatal neurologicsyndromethat developsover hours or days in
 52 I Part I Generalpathophysiology

personswith AMSor HAPE.This high-altitudeillnesstypically presentswith

alteredmentalstatus,hallucinations, irritability,ataxia,altered consciousness
andprogressiveneurologicdeterioration. Hemodynamic factorssuchas sus-
tainedvasodilatation, cerebralautoregulation, andeleva ted cerebralcapillary
pressuremostlikelycontribute to theformationof edemabut cannotentirely
explainthe process.Hypoxia-inducedbiochemicalalterationof the blood-
brain barriermayalso be important.Possible mediators,sometriggeredby
endothelialactivation,includevascularendothelialgrowth factor, inducible
nitric oxidesynthase,andbradykinin.
Chronic mounta in sickness (Mange 's disease) . This uncommo n disorder
affectslongtimehigh-altituderesidents;it is characterized by fatigue, dys-
pnea,achesand pains,excessivepolycythemia, andthromboembo lism.The
disorderresemblesalveolarhypoventilation;both are thoughtto be caused
by an inadequately sensitiverespiratorycenter.Thepatientshoulddescend
to sealevel.
Effects ofelevatedatmospheric pressure . Elevated atmosphericpressure
alsoproducespathologicphenomena in the organism(e.g.,in deep-seaand
scubadivingor caissonwork). .
Directeffectsof pressure.As externalpressureon the bodyincreaseswith
depth,so doesthe pressureof gas in the lungsand airways.Normally the
middleear,sinuses, andlungsall ventto ambientpressurevia a contiguous
respiratorytract. Localpathology(i.e.,mucousplugging,blocked eustachian
tube)cansubjectthesespacesto volumechangesin accordance with fluctua-
tions in ambientpressure.Establishment of modera te pressure gradientson
eitherascentor descentbetweenthesespacesand·the externalenvironment
canresultin barotrauma . If the diveris unableto equilibrateon descent,the
resultingcompressive forcestendto "squeeze"the bodycompartments. On
ascent,if the expandinggas is trapped,the localanatomywill be distorted,
producingan overpressurization injury (aerosinusitis, aero-otitis mediawith
ruptureof the tympanum , dentalbarotrauma,pulmonarybarotrauma).
Dentalbarotrauma(or aerod~ntalgia). Expandinggas within the enamel
confinesof thetooth canleadto fracture on ascent.
Pulmonaryoverpressu rizationsyndrome,or pulmonarybarotrauma. If a
diverinspiresevena singlebreathof air or othergasat depthanddoesnot let
Generalnosology, etiologyand pathogenesis Unit I I 53

it escapefreelyduringascent, the expandinggas may overinflatethe lungs.

Possibleconsequences includepneumothorax , mediastinaland subcutane-
ous emphysema, and air embolism.Fatalair embolismhasoccurredduring
rapidascentfrom as shallowa depthas5 m.
Indirecteffectsof pressurearecausedby changesin the partialpressures
andsolubilitiesof differentgases.As a resultof the increasein atmospheric
pressurethe partialpressureof oxygenandothergasesforming part of the
atmosphericair rises.Signsof the pathogenic effectof elevatedatmospheric
pressuremayappearalreadyaftera few hoursstay undera pressureof 2-3
atm,i.e., at a depthof 10-20 m underwater.
In a gas-liquidsystem,thesolubilityof gasis directlyproportionalto its par-
tial pressure(Henry'slaw).Sincethe humanbodyis largelycomposedof wa-
ter, it followsthatmoregaswill enterthefluid compartment asdepthincreases.
Thedissolvedgasesthatmostaffectthediverarenitrogenandoxygen.
Nitrogennarcosisappearsat 40 m when breathingcompressedair. Eu-
phoriawith behaviorsimilarto alcoholicintoxication (i.e., lackof judgment
and concentration,incoordination,anxiety)has affordedthis syndromethe
nicknameraptureof the deep. At a depth of 90 m or morea typical narcotic
conditiondevelops(anesthesia and unconsciousness). Thusthe problemof
nitrogennarcosiscanbeavoidedby breathingmixturesof 0 2 andhelium, and
deeperdivescanbe made.
High-pressurenervous syndrome(HPNS)developsduringdeepdiveswith
breathingmixturesof 0 2 andinertgas.It is characterized bytremors, drowsi-
ness, anda depressionof the a activityin the EEG.Unlikenitrogennarcosis,
intellectualfunctionsare not severelyaffectedbut manualdexterityis im-
paired.Thecauseof HPNS is not settled, but it is worth notingthat a variety
of gasesthatarephysiologicallyinertat atmosphericpressureareanesthetics
at increasedpressure .
Inert (inactive)gasesare lipid-solubleand dissolveeasilyin fatty tissues,
cell membranes andintracellular structures
, wheretheybindto activesites or
receptors. Thegasesmodifyneuronalactivityandnerveconductionvelocityas
wellas ionictransportacrosscell membranes. Argonhasa largernarcoticef-
fectthannitrogen(largerlipid-solubility, largerenergycontentor VanderWaals
chemica l bonds),andnitrogenis a muchstronger anesthetic than helium.
 54 I Part I Generalpathophysiology

Oxygentoxicity. Extendedexposureto a P02 > 0.5 atm (equivalentto

50 % 02 at surfaceor 25 % 02 at 10 m) canresultin pulmonaryoxygentoxic-
ity. CNSoxygentoxicity,occurringprimarilyduring diving,may causesei-
zuresit the P02 approachesor exceeds2 atm (e.g., 100 % 02 at 10 m or
50 % 02 at 30 m) or evenis as low as 1.6 atm(e.g.,100 % 02 at 6 m).
Decompression sickness.In casesof returnfrom elevatedto normal at-
mosphericpressure(whichcausesdecompression) the gasesdissolvedin
the blood,mainlynitrogen,whichmakesupfour fifths of the inspiredair, dif-
fusefrom thetissuesintothe lungsalongthe partialpressuregradient.If the
decompression is gradual,no harmfuleffectsareobserved;but if the ascent
is rapid,N2 escapesfrom solutionin the form of bubblesandoftenobstructs
smallvessels(gasembolism)causingthe symptomsof decompression sick-
ness(alsoknownas dysbarism,caissondisease,the bends,the staggers,or
the chokes).
Thenatureandseverityof decompression sicknessaredeterminedby the
rateandlocationof nitrogenrelease . Symptomsandsignscanbe presentin
all tissuesof the body.Bubblesin the tissuescauseseverepains,particularly
in the musclesand in the joints (the bends),and neurologicsymptomsthat
includeparesthesias anditching. ·
The main problemsare causedby bubblesblockingthe blood supply.
Bubbles in the bloodstream , whichoccurin moreseverecases,obstruct the
arteriesto the brainandspinalcord.Thecentralnervoussystem'ssymptoms
andsignsarevertigo,paralysis,collapseandunconsciousness.
Disabilityanddeathmaysupervenewithin minutesor hoursafterdecom-
pression.Life-threatening bubblesmayblockthepulmonarycapillaries,which
triggersthoracicpainandalarmingdyspneathat diverscalled"the chokes"
with pulmonaryedemaandoftendeath.Bubblesin the coronaryarteriesmay
causemyocardialdamage . .
Subacuteor chroniceffectsof decompression arecharacterizedby lower
limb, bladder,andrectalparalysisfrom demyelinationof the dorsalandlat-
eralcolumnsof the inferiorthoracicspinalcord ratherthan the uppercord
or brain. ln divers with a history of the bendsand persistentjoint symp-
toms, foci of asepticnecrosishave usuallydevelopedin bones. Venous
gas embolismwith resultantvascularobstructionis the most likely basis
Generalnosology,etiologyand pathogenesis Unit I I 55

for the localizedareasof osseousdestruction.Becauseof the solubilityof

nitrogenin fat, obesitypredisposesto the developmentof decompression
sickness.
Theascentfrom deepdivesmustbeslowandsystematically in stages.Any
saturationdiveto lessthan1Omallowsascentwithoutdecompression signs
(Haldane'srule).
A very rapidchangefrom normalto subnormalpressure,as may occur
duringrapidascentin supersonicaircraft,may also causedecompression
sickness.
Explosivedecompression occurswhenthe externalpressureis suddenly
reducedfrom atmospheric to subatmospheric. It canappeardueto a breach
in the fuselageof a pressurizedaircraft or spaceship(depressurization},
failureof cabinair compressionsystems , or an unrestrainedascent.Acute
hypoxemiarapidlyensuesbecauseof reducedPa02. This occurrencelimits
subjectsto a periodof a few minutesto a few seconds , the "time of use-
ful consciousness ," to remedythe situationbeforehypoxicsyncopeensues.
Practicalremediesconsistin breathing02 from a containedsourceand rapid
descentto loweraltitudeandhigherbarometricpressure.
Substantial explosivedecompressi on consequences arethe resultsof the
expansionof gaseswithinbodycavities.
Lungs.Owingto a rapidexpansion of the gasesthelungsbecomeover-ex-
pandedby the excessively high intrapulmonicpressure,causingactualtear-
ing and ruptureof the lungtissuesandcapillaries.Thetrappedair is forced
throughthe lungsintothe thoraciccage,andair canbe injecteddirectlyinto
the generalcirculationby way of the rupturedbloodvessels , with massive
air bubblesmoving(air embolism)throughoutthe bodyand lodgingin vital
organssuchas the heartandbrain.
Gastrointestinaltract. Thediaphragmis displacedupwardby the expan-
sion of trappedgasesin the stomach,which can inhibit respiratorymove-
ments.Distentionof abdominalorgansmay also stimulatethe abdominal
branchesof the vagusnerve, resultingin cardiovascular depression,and if
severeenough,causesa reductionin bloodpressure,unconsciousness, and
shock.Usually,abdominaldistresscanbe relievedaftera rapiddecompres-
sionbythe passageof excessgas.
 56 J Part I Generalpathophysiology

In rareinstancesinstantaneous deathoccursdueto bloodboilingandful-

minanthypoxia.Theboilingof the blooddenatures the lipoproteincomplexes ,
renderingthe lipidsinsolubleandcausingfat embolism.
Hyperbaric Oxygenation. The use of increasedatmospherepressurefor
medicaltherapyhasintriguedmanyphysicians, scientists,andlaypersonsfor
hundredsof years.Vagueaccountsof increased atmosphere pressures usedon
humansdateto thefifth centuryBC.Henshaw , a Britishclergyman, builtthefirst
sealedchamber , termedthe Domicilium,in 1662. Thischambercompressed air
(21 % oxygen)for numerousailmentssuchas inflammation, scurvy,arthritis,
andricketsbut likelyhadtoo littlecompression to do anyphysicalgood.
Mechan isms of hyperbaricoxygeneffects.The mechanismof action of
hyperbaricoxygenat ion (HBO)is attributedto the immediatedirectphysical
effectsof oxygen(hyperoxygenation) andothergasesunderpressureandto
thedelayedsecondaryphysiologicandbiochemical effects(vasoconstriction ,
angiogenesis,fibroblastproliferation,leukocyteoxidativekilling,toxin inhibi-
tion) thatareset into motionwith eachhyperbarictreatment.
Oxygentoxicity.Elementa l oxygenis requiredto maintaincellularrespi-
rationand to allow for normalcellularproteinproduction.Toxiceffectsof
oxygenare observedat extremelyhigh dosesover prolongedperiods: HBO
treatmentincreasesthe relativedose of oxygen;thus susceptiblepatients
needto be recognized andmodificationsmadeto preventthe manifestations
of oxygentoxicity.
Damaging or toxiceffectsof oxygentherapyarelikelyrelatedto theunbridled
formationandreleaseof reactiveoxygenspecies,suchassuperoxide, hydroxyl
radical, andhydrogenperoxide.Antioxidantenzymes(superoxide dismutase,
catalase,glutathioneperoxidase , andglutathionereductase)keepthe forma-
tion of theseradicalsin checkuntil the oxygenloadoverwhelms the enzymes,
leadingto the detrimentalaffectson cell membranes, .proteins, andenzymes.
Otherantioxidants usedby the bodyincludevitaminsCandE, andglutathione .
Lavoisierfirst observedthe detrimentaleffects of hyperoxygenation in
1789.In 1878,Paul Bert demonstratedthat HBO inducedseizures.This
becameknownas the "Paul Bert effect" or oxygen-induced seizures.This
neurologiceffectmay be relatedto the free radical-induced peroxidationof
neuronsandglial cellsuponinteraction with iron.Alternatively , a decreasein
Generalnosology,etiologyand pathogenesis Unit I I 57

thegammaaminobutyric acid(GABA)levelsinducedby hyperbaricpressures

andincrease d oxygenmaybeimportantin seizureinduction.
The most importantfactorthat maydecreasethe potentialpredispos ition
to oxygentoxicityis intermittentexposureto roomair. Givesusceptiblepa-
tients"air breaks"at somepointduringthe treatment.Duringthis time, the
patientis breathingroomair that is pipedinto the chamber . A 1a-minuteair
breakmaybeall that is requiredto preventthe symptomsof oxygentoxicity.
Otherpotentialcounteractive measuresto decreaseoxygentoxicity include
inducinghypothermia or administeri ng vitamin E, disulfiram, glutathione,
phenobarbital, diazepam,or adrenergic blockers.

Effec ts of Radiant Energy

Theorganismmaybe exposedto the actionof variousforms of radianten-
ergy. All of them are potentially injuriousto living organisms.
Radiationinvolvesthe emission, propagation,and absorptionof radiant
energy.With respectto propagation , radiation hasbeenclassified as electro-
magneticor particulate(alphaandbetaparticles , neutrons, protons).
Electromagnetic radiationis propagated by meansof wavemotionand is
subclassifiedon the basisof the lengthandfrequencyof thewaves.Thepen-
etratingpowervariesgreatlydependingon thewave-length. Electromagnetic
radiationformsa continuousspectrumcoveringa wide rangeof wavelengths
andfrequencies. Microwaves and radiowavesexhibitlong wavelengths(up
to severalmiles),but the numberof wavesemittedper unit of time is small.
At the otherendof the spectrumarecosmic, gamma,and roentgen(X) rays,
whichexhibitshortwavelengths andhighfrequencies. Intermediate between
theseextremesareultraviolet,visiblelight, andinfraredrays.

Nonion izing Rad iation

Infraredrays. The infraredrays of the solar spectrumand otherssources
(fire, lamps, infraredlasers, etc.) possessonly a thermaleffect.Theaction
 58 I Part I Generalpathophysiology

of the thermalrays is from the very outsetaccompanied by local (thermal

burns,acquiredcataract)andgeneralhyperthermia(heatstroke,sunstroke).
Owingto this, the skin becomes , as it were, an ultrafilterbarely permeable
to ultravioletrays.
Ultraviolet (UV)radiation.It is definedasthatportionoftheelectromagnet-
ic spectrumbetweenX raysandvisiblelight, i.e., between40 and400 nm.The
UVspectrumis dividedintoVacuumUV(40-190 nm),FarUV(190-220nm),
UVC(220-290 nm), UVB(290-320), and UVA(320-400 nm). The sun is
our primarynaturalsourceof UV radiation . Artificial sourcesincludetanning
booths, blacklights, curinglamps, germicidallamps, mercuryvaporlamps,
halogenlights, high-intensitydischargelamps,fluorescentandincandescent
sources,andsometypesof lasers(excimerlasers,nitrogenlasers,etc.).
Uniquehazardsapplyto the differentsourcesdepending onthe wavelength
rangeof the emittedUVradiation.UVCis almostneverobservedin naturebe-
causeit is absorbedcompletelyin theatmosphere , asareFarUVandVacuum
UV.Germicidallampsaredesignedto emitUVCradiationbecauseof its ability
to kill- bacteria.In humans,UVCis absorbedin the outerdeadlayersof the
epidermis.Accidentaloverexposure to UVCcan causecornealburns,com-
monlytermedwelders'flash, and snow blindness , a severesunburn·to the
face.While UVCinjury usuallyclearsup in a dayor two, it can beextremely
painful.
UVBis typicallythe most destructiveform of UV radiationbecauseit has
enoughenergyto causephotochemicaldamageto cellular DNA, yet not
enoughto be completelyabsorbedby the atmosphere . UVBis neededby
humansfor synthesisof vitaminD; however , harmfuleffectscanincludeery-
thema (sunburn),cataracts , anddevelopment of skincancer,suppressionof
the immunesystem.Individualsworkingoutdoorsare at the greatestrisk
of UVBeffects. Mostsolar UVBis blockedby ozon~in the atmosphere , and
thereis a hypothes is that reductionsin atmospheric ozonecouldincreasethe
prevalence of skincancer.
UVAis the most commonly ~ncounteredtypeof UV light. UVAexposure
hasan initial pigment-darkeningeffect(tanning)followedby erythemaif the
exposureis excessive.Atmosphericozoneabsorbsvery little of this part of
the UVspectrum.UVAis neededby humansfor synthesisof vitaminD; how-
General nosology, etiologyand pathogenesis Unit I I 59

ever, overexposure to UVA hasbeenassociatedwith tougheningof the skin,

suppression of theimmunesystem,andcataractformation.UVAlight is often
calledblacklight. Most phototherapy
andtanningboothsuse UVAlamps.

Pathogenesis. Ultraviolet rays producethe following

effects.

1. Thermaleffect.
2. Photochemical effect.Theex behavioralcited moleculeis lesselectro-
philicandso it maybemoreeasilyoxidized , producingredoxreactionsor
freeradicals(e.g., throughphotodynamic effectmediatedby photosensi-
tizers(Seebelow)).UVCarespecifically absorbedbythearomaticgroups
in nucleobases leadingto dimerformationbetweenconsecutive thymine
residuesin DNAandbyaromaticgroupsin aromaticaminoacids.
3. A verymild ionizing (or radicalizing)effect.

Thelocal actionof ultravioletrays is limitedwith the skin and the eyes

becauseof the low penetratingpropertiesof UVradiationin humantissues.
Thepenetrationinto the skin is lessthan 1 mm and ultravioletraysare ab-
sorbedby oculartissues(mainlythe corneaandthe lens)beforethey reache
the retina.

The normal and pathologic responses of the skin to

UV radiation can be divided into two groups:

• acuteeffect (sunburn, tanningand vitaminD production), which is of

rapid onsetandgenerallyof shortduration.
• chroniceffect(photo-ageing, skin cancer,etc.)producedby prolonged
or repeatedUVradiationexposure.

Sunburn. The extentof reddeningof the skin (erythema)followingexpo-

sureto a particulardoseof ultravioletradiationis dependent
on skinsensitivi-
 60 I Part I Generalpathophysiology

of exposure(250-290 nm beingthe mosterythemogenic)

ty, wavelength and
skin pigmentation(fair skin burnsmoreeasilythan dark).Erythemaoccurs
3-5 hoursafter UV exposure,reachesa maximumbetween8 and 24 hours
andthenfadesover3 days. In its mostsevereform, erythemais followedby
inflammation,blisteringandpeelingof the skin.Histologically, sunburnis as-
sociatedwith vasodilationof the capillaryvesselswithinthe papillarydermis,
dyskeratotickeratinocytes (sunburncells), perivenularedema,andpresence
of dermalneutrophils.Blistersshowelevatedlevelsof prostaglandins, while
keratinocytesexposedto UV releasecytokinesand tumor necrosis factor-
alpha,potentmediatorsof inflammation . Thereis evidenceof DNAdamageat
suberythemal as wellas erythemaldosesof UVradiation.
In additionto erythemaandtanning,thickening (hyperplasia) of theepider-
mis is a significantcomponentof a mild sunburnreaction.A singlemoderate
exposureto UVBcan result in up to a three-foldthickeningof the stratum
corneumwithinoneto threeweeks,andmultipleexposureseveryoneto two
daysfor up to sevenweekswill thickenthe stratumcorneumby aboutthree-
to five-fold.Skinthicknessreturnsto normalaboutoneto two monthsafter
ceasingirradiation.
Thickening of the skin,especiallyof the stratumcorneum,aftersun·expo-
surecan leadto a significantincreasein protectionagainstUVradiationby a
factorof five or evenhigher.In Caucasians skin thickening is probablymore
importantthantanningin providingendogenous photoprotection, althoughin
darklypigmentedracesit is likelythat skin pigmentationis the most impor-
tant meansof protectionagainstsolarUVradiation.
Photo-aging . The clinicalsigns of a photo-agedskin are dryness,deep
wrinkles,accentuated skin furrows, sagging,loss of elasticity, mottled pig-
mentationandtelangiectasia. Thesecharacteristics reflectprofoundstructur-
al changesin theskin (changesin dermalelastinandcollagen,impairedkera-
tinization,etc.). It hasbeenspeculated(Leyden,1990)that perhapsas much
as 80 % of solar UV-inducedphoto-agingoccurswithin the first 20 years
of life, with the exceptionof thosewhoseoccupationor life style resultsin
extensiveexposureas adults. '
Resultsfrom recentanimalstudieshaveshownthatchronicUVBandUVA
irradiationin hairlessmouseskin both result in histological,physicaland
 Generalnosology,etiologyand pathogenesis Unit I I 61

visiblechangestypicalfor photo-aging. UVBradiationwasonly20-50 times

moreefficientthan UVA; this is in markedcontrastto sunburn,suntanand
skincancerwhereUVBis about1000timesmoreeffectivethanUVA.
It shouldberemembered thatsolarradiationincludesnotonlyUVradiation
but also visibleand infraredradiation.Visiblelight is thoughtto be unim-
portantin photo-aging but studieshaveconfirmedthat·infraredradiationcan
certainlydamagethe dermalmatrix.
Photo-aged skinhasthecapacityto repairUVradiation-induced connective
tissuedamageand it hasbeenshownthat topicalretinoicacidcanenhance
this processandimprovehealingin photo-aged skin.
Skincancer. It is the mostcommonhumancancerandthereis little dis-
putethatchronicexposureto solarultravioletradiationis the most important
causeof non-melanoma skin cancers(NMSC ). Thetwo commontypes of
NMSCarebasalcellcarcinomaandsquamouscellcarcinoma.Geneticfactors
associatedwith a tendencyto developskin cancerare light eyes,fair com-
- plexion,light hair color,tendencyto sunburnandpoorabilityto tan.
Cutaneous malignant melanoma . Thereis little doubtfrom the epidemio-
logicliteraturethat UVradiationplaysanimportantrolein thedevelopment of
malignantmelanoma. Evidence includes:a positiveassociationbetweenmel-
anomaincidenceandresidenceat lowerlatitudes;a decreasedrisk of mela-
nomain thosewhomigratedin childhood,fromanareaof low UVradiationto
an area of highUVradiation(compare d to thoseborn in the areaof high UV
radiationandstill residentthere);a bodysitedistributionwhichmirrorsthose
areasof thebodyusuallyexposedto sunlight;a correlationwith frecklingand
development of melanocyticnevi; a correlation with otherevidenceof solar
skindamage(wrinkling,solarkeratoses) ; theverylow incidenceof melanoma
in peoplewith blackskin,andan increasedrisk with a historyof intermittent
sunexposureandsunburn.
Effectsonthecornea . Ambientlevelsof solarUVradiationaresuchthatthis
acutephototoxiccornealdisorderis largelyconfinedto snowfieldsanddeserts.
Approximately 2 hourexposureoutdoorsaroundnoonon snow-covered ter-
rainis sufficientto inducephotokeratitis, andthat an exposureof 6-8 h may
beneededin sandyterrain. Outdoorworkerswith highsolarexposurehavean
approximate three-fold riskof developing pterygium (afleshygrowthon a nor-
 62 I Part I Generalpathophysiology

mallyclearcornea)anda six-foldriskof havingclimaticdropletkeratopathy (a

depositionof alteredproteinsonthesuperficial cornealeadingto opacification).
Effectsonthelens.Thedevelopment of certaintypesof cataract(opacity
of the lens)is associated with ocularUVBexposure.A doublingof cumulative
exposureincreases the riskof corticalcataractbya factorof 1.6.Noevidence
wasfoundfor a thresholdlevelof sunexposureeitherin termsof irradiance,
durationof exposureor age.Alsono associationwasfoundbetweennuclear
cataractsandUVBexposure,nor betweeneithercorticalor nuclearopacities
andUVAexposure.
Effectsontheretina.Thenaturalcrystallinelensabsorbsall incidentUVB
and almost all UVAradiationand concernhas beenexpressedthat some
typesof implantedthin plasticintraocularlensesmaynot provide adequate
UVprotectionto the retina.Neverthe lessthereis a strongtemporalrelation-
ship betweenthe intensesolarexposureandthe retinopathy.Mostcasesof
acutesolar retinopathyrecovertheir visionloss overweeksor months, but
a few will go on to permanentvisualimpairment,usuallya centralscotoma.
Thereis circumstantialevidenceof a link betweenexcessUV exposureand
acutemaculardegeneration.
Immuneeffects . Thereis increasingevidencethat UV radiation(mostly
UVB,lessUVA)in sunlighthasbothlocalandsystemiceffectsoncell-mediat-
ed immunity.Locallyan importanteffectof UVradiation is to turn off immune
responsesto abnormalcellsthat in turn allowthe development of skin can-
cers.However,systemiceffectson the cell-mediated immunesystem,princi-
pallythroughsuppressionof theT helpercelltype1(Th-1)immuneresponse,
havebeendemonstrated, particularlyas relatesto turningoff of the immune
responseto "self immuneresponse"whichmay be relatedto the develop-
mentof autoimmunedisorders.

Ultraviolet radiation suppresses the immune system

in several ways: ·

1. Inhibition of the antigenpresentation.

Higherdosesof UVinduceapop-
totic deathof Langerhans cells (majorantigenpresentingcells in the
Generalnosology,etiologyand pathogenesis Unit I I 63

skin).In addition,UVradiationsuppresses the expressionof majorhis-

tocompatibility(MHC)classII surfacemoleculesandadenosinetriphos-
phatase(ATPase) activityin Langerhans cells.Bothmarkers,in particu-
lar MHCclassII, areusedto identifyLangerhans cellsin the epidermis.
Furthermore, uponUVexposureLangerhans cells are impairedin their
capacityto presentantigens;
2. Inductionof the releaseof immunosuppressive cytokines (interleu-
kin-10,interleukin
-4, tumor necrosisfactor-a,etc.);
3. Inductionof the regulatory T cells with suppressoractivity.After UV
exposurethesecells, whichproducedhighamountsof IL-4, suppressed
upontransferof specificantigendelayed-type hypersensitivityrespons-
es andantitumoralimmunityagainsthighly immunogenicUV induced
skintumorsin recipientmice;
4. Inductionof the apoptosisof T-lymphocytes.

Thereis evidenceof the activationof latentvirus infection(herpeslabialis,

papillomavirus) in immunosuppressed patientsexposedto sunlight.
Photosensitization. The photochemical effectsof UV radiationcan be ex-
acerbatedby exogenousand endogenousphotosensitizingsubstances,or
photosensitizers, i.e.their exposureto sunlightleadsto a cutaneousreaction
with rash, erythema,itching, scalingand edema.Photosensitivityreactions
canbecausedby injected,oral, or topicallyappliedchemicalphotosensitizers
Photosensitivity reactionscould be inducedby a non-limitedrangeof the
electro-ma gnetic radiationspectrumthatincludesUVradiation(200-400nm)
andvisiblelight (400-800nm). Photosensitivity reactionscanoccurin expo-
sureto bothUVAandUVB, but aremorelikelyto occurin the UVArange.
The forms of photosensitivity are phototoxicity and photoallergy.Photo-
toxic disordershavea high incidence , whereasphotoallergicreactionsare
muchlessfrequentin humanpopulation.
Phototoxicityis a form of photosensitivity that is not dependedon an im-
munologicresponse.In phototoxicreactionthe photoactivatedchemicals
causedirectcellulardamage;no sensitization periodis required,andmecha-
nism is non-immunologic, so it can manifestduringan initialexposure.The
reactiondependsupontheamountof thecompound , levelof activatingradia-
 64 I Part I Generalpathophysiology

tion, andthequantityof otherchromophores in theskin.Absorptionof UVra-

diationproduceschemicalor metabolitein anexcitedstate,whichmayin turn
followoneof two pathwaysthat leadto photosensitization. Thefirst pathway
proceedsthroughthe generationof a free radicalandthe secondpathwayis
throughthe generationof singletoxygen,whichin turn resultsin the oxida-
tion of biomolecules, damagingcriticalcellularcomponents andinitiatingthe
releaseof proinflammatory mediators.
Photoa!lergicreactionmay not be predicted.They are immunologically
mediatedand determinedby eitherdelayedhypersensitivity responsesor,
morerarely, immediatehypersensitive reactionsdueto lgE responseto UV
radiation.An incubationperiodfor the immunologicmemoryto developafter
the first contactwith the photosensitizeris required,so thereis no reaction
on first exposure.On subsequentexposures , the elicitationof responseis
shorter. Thedelayedtype of photoallergyis morefrequent.Thepathogenetic
mechanisms of photoallergicreactionsarequitesimilarto allergicdermatitis:
the photoantigen(hapten)is presentedby epidermalLangerhans cellsto T
lymphocyteswith all the subsequentfeaturesof delayedskin hypersensitiv-
ity responseof lymphocyticinfiltration,releaseof lymphokines, activationof
mastcells,andinc·reasedcytokineexpression.
Microwave radiation.Electromagnetic radiationin the 1 mmto 1 m wave-
lengthrange(300MHzto 300 GHz)is referredto as microwaveradiation,and
is a partof what is knownas radiofrequency (RF)radiation.Thelattercovers
the 0.5 MHzto 300GHzrangeand is consideredin the contextof adverse
biologicaleffects.
Potentialsourcesof exposureto microwaves includemicrowaveovensand
the high-output radardevicesusedin navigationandweathersystemsas well
asburglaralarms.Thefrequencyof microwave radiationusedto carryinforma-
tion betweenmobilephonesandtransmissiontowersis 900MHz(GSM-900).
RFradiationis nonionizingradiation.This meansthat, in general,it does
not havesufficientenergyto kick an electronoff an atom thus producing
chargedparticlein a bodyand causingbiologicaldamage.Theonly proven
harmfuleffectfrom exposureto microwave(or RF)radiationis thermal.Ex-
posureto high levelsof microwavescancausea burn.
RFradiationcanenterdeepinto the bodyandheathumanorgans.
Generalnosology,etiologyand pathogenesis Unit I I 65

Thus , the d e pth of pe ne tration a nd th e le v e l a bsorp-

tion of radi a tion in the body are re le v a nt :

• above10 GHz(3 cm wavelengthor less)heatingoccursmainlyin the

outerskinsurface;
• from 3 GHzto 10GHz (10 cm to 3 cm) the penetrationis deeperand
heatinghigher;
• from150MHzto about1GHz(200cmto 25cmwavelength), penetration
is
evendeeperandbecauseof highabsorption
, deepbodyheatingcanoccur.

Anypartof the bodythat cannotdissipateheatefficientlyor is heatsensi-

tive maybedamagedby microwaveradiationof sufficientpower.Thelensof
theeyeis particularlysensitiveto intenseheat, andexposureto highlevelsof
microwaves cancausecataract.Likewise,testesareverysensitiveto changes
in temperature. Accidentalexposureto high levelsof microwaveenergycan
alteror kill sperm,producingtemporarysterility.
Non-thermal adverseeffectsof microwaveradiation.Animalexperiments
haveshownthat behav ioral disorders , hematologic, endocrine, and possibly
geneticeffectscanbecausedby microwaveradiation.Thereis noevidenceof
a co-promoting(cocarcinogenic) effectof exposureto GSM-90,signalsus-
ing a carcinogen(7,12-dimethylbenz(a)anthracene) femaleSprague-Dawley
rat model.Research is still continuingin this areaas wellas in the areaof RF
radiationeffectson immuneandcentralnervoussystem.
IonizingRadiation . Particularlyimportantfor the organismis the effect
of ionizingradiationwhichcharacterized by shortwavelengths and highfre-
quencies,carriessufficientenergyto causeionizationin the materialsthat
absorbthem. In otherwords,it producesions on passagethroughmatter.
Because of the high penetrabi lity of the electromagneticwaves, gammaand
X-rayscanresultin whole-bodyexposure.
Furtherto electromagnetic wavesionizingradiationincludesparticulatera-
diationcausedbythemovementof subatomicparticlesof thefollowingtypes.
Alphaparticles , or nucleiof helium,aremassive,chargedparticles(4 times
the massof a neutron).Because of theirsize, alphaparticlescannottravelfar
and arefully stoppedby the deadlayersof the skin or by a uniform.Alpha
 66 I Part I Generalpathophysiology

particlesarea negligibleexternalhazard,but whenthey areemittedfrom an

internalized radionuclide source,theycancausesignificantcellulardamagein
the regionimmediatelyadjacentto their physicallocation.
Betaparticles,or electrons,arevery light,chargedparticlesthat arefound
primarilyin fallout radiation.Theseparticlescan travela short distancein
tissue; if largequantitiesareinvolved,theycanproducedamageto the basal
stratumof the skin.Thelesionproduced,a "betaburn,"canappearsimilarto
a thermalburn.
Neutrons , like gammarays, are uncharged , are emittedonly during the
nucleardetonation,and are not a fallout hazard . However , neutronshave
significantmassand interactwith the nucleiof atoms,severelydisrupting
atomic structures.Comparedto gammarays,they can cause20 times as
muchdamageto tissue.
Radioisotopes areunstable formsof elementsthatemitradiation.Eachhas
a characteristic rate of decaydescribedby its half-life,a uniquearrayof radio-
activeemissions,andphysiologicpropertiesdefinedby its elementalnature.
Commonlyusedunitsof measurement arethe roentgen,gray,andsievert.
Theroentgen(R) is theamountof X or gammaraysin air.Thegray(Gy)is the
amountof energyabsorbedbya tissueor substance andappliesto all typesof
radiation.TheRandthe centigray(cGy)areessentiallyequivalent. Thesievert
(Sv) equalsthe Gy adjustedby a qualityfactor to accountfor the biologic
effect.It is usedbecausedifferenttypesof radiationhavedifferentbiologic
effectsfor a givenamountof energy;e.g., neutronshavea greatereffect.The
GyandSvhavereplacedthe radandrem(Gy= 100rad; Sv= 100rem)in non-
systemnomenclature. Thequantityof any radioisotope is measuredin curies
1
(Ci),a unit representing 3.7 x 10 radioactive disintegrations persecond.
Radiosensitive tissuesare thosewith the greatestmitoticactivityandthe
leastdegreeof differentiation.This phenomenonis basedon the Bergonie
andTribondeaulaw (1906)that anycellsthat are immature,undifferentiated
andactivelydividingaremoreradiosensitive ; cellsthataremature,differenti-
atedandnot activelydividingaremoreradioresistant. A cellthat is radiosen-
sitivewouldbe moreinclinedfo die afterexposureto ionizing radiationthan
a radioresistantcell. Thus, cells undergoingactivemitosisare more likely
to be affectedby ionizingradiation , and stemcells (bonemarrow, stomach
Generalnosology, etiologyand pathogenesis Unit I I 67

mucosa,germlayerof the skin)or low differentiated tumor's cellsare much

moreradiosensitive thanneurons.whicheitherneverreplicateor do so very
slowly, or highdifferentiate d tumor's cells.
Radiationinteractionswith cells.Theinteractionof radiationwith cells is
a probabilityfunction.Because cellularrepairusuallytakesplace, permanent
damagewill not necessarilyresultfrom an interactionof ionizingradiation
with livingtissue.Energydepositionto a cell occurs very quickly, in some
10- 18 s, with the energybeingdepositedin the cell in a randomfashion. All
interactionshappenon a cellularlevel, which in turn may affectthe organ
andtheentiresystem.In addition,thereis no uniquecellulardamageassoci-
atedwith radiation.Anydamageto a celldueto radiationexposuremayalso
happendueto chemical , heat,or otherdamage . Afterradiationexposureto a
cell, thereis a latentperiodbeforeanyobservable response.Thelatentperiod
couldbedecades for low radiationdoses,but onlyminutesor hoursfor high
radiationexposure .

There are really only 2 possibiliti e s when ionizing ra -

diation inter a cts w ith a c e ll:

1. Directinteraction . In directinteraction , cellularmacromolecules (pro-

teins or DNA)are hit by the ionizingradiation , which affectsthe cell
as a whole,eitherkillingthe cell or mutatingthe ONA. Thereare many
targetandcellsurvivalstudiesthatshowthat it is harderto permanently
destroyor breakdouble-stranded DNAthan single-stranded DNA. Al-
thoughhumanshave2 pairsof double-stranded chromosomes , some
cellsreactas if theycontainsingle-stranded, nonpairedchromosomes
andare moreradiosensitive. Manydifferenttypesof directhits canoc-
cur, andthe typeof damagethat occursdetermineswhetheror not the
cellcanrepair itself.Generally , if a directhit causesa completebreakin
the DNA or someotherpermanent damage,thecell diesimmediatelyor
will dieeventually.
However , humanshaveanabundance of cellsandso-
maticcellular reproduction(mitosis)is alwaysoccurringto replacecells
that die. Therefore,it is only whenthis systemof replacingcells fails
 68 I Part I Generalpathophysiology

that radiationeffectsareseen.This occursat higherdosesof radiation.

In M phaseof mitosis(in whichcellsdividein 2) the chromosomes are
condensedand paired. So it is the most radiosensitive. More DNAis
presentin oneareaat this pointin the cycle,whichis why it is theorized
thatthis is the mostradiosensitive
time.It is alsothoughtthatincreased
chromatinin cancercellsis why thesecells,which haveunusuallyhigh
mitoticrates, aremoreradiosensitive thannormalcells.
2. Indirectinteraction.It occurs when radiationenergyis depositedin
the cell, andthe radiationinteractswith cellularwaterratherthanwith
macromolecules withinthe cell.
The reactionthat occurs is radiolysisof the water molecule(Fig. 3),
resultingin a hydrogenmoleculeand hydroxylradicalmolecule . If the
2 hydroxylmoleculesrecombine,they form hydrogenperoxide,which
is highlyunstablein the cell.This will form a peroxidehydroxyl, which
readily combineswith someorganiccompound , whichthencombinesin
the cellto form anorganichydrogenperoxidemolecule,whichis stable.

Freeradicaloxidationproductsformingin irradiatedtissuesof the organ-

ismsarecalledradiotoxins. ·
In the pathogenesis of radiationdamagelipid radiotoxins(lipid hydroper-
oxides,epoxides , aldehydes,ketones)areconsideredto be of the greatsig-
nificance.Beingintermediateand final productsof lipid peroxidation , they
accumulatein the cell membranesimpairingtheir barrierfunctions.
Moreover, in the cells exposedto radiation so called quinoidradiotoxins
areformedfrom certainaminoacids(tyrosine, tryptophan).Theseradiotox-
ins are characterized as chemicalmutagens , andsuppressorsof the activity
of numerousenzymes.
This may resultin the loss of an essentialenzymein the cell,whichcould
leadto celldeathor a futuremutationof the cell.An.tioxidantsblockhydroxyl
radicalrecombination into hydrogenperoxide , preventing stableorganichy-
drogenperoxidecompoundsfrom occurring.This is oneway in which the
bodycandefenditselffrom indirectradiationinteractionson a cellularlevel,
andis onereasonwhy antioxidantshavereceivedso muchattentionrecently
as radioprotectors andcancerpreventionagents.
Generalnosology,etiologyand pathogenesis Unit I f 69

Ionizing
Radia
/ H,O

"excited
" water H20+- - -

Hydrogen
radical

H' f,
2

Fig.3. Exposure of cellsto ionizingradiation

induceshigh-energyradioly sis of H2O water
moleculesintoH+andOH-radicals, whicharethemselves reactiv
e.Theseinturnrecombine
to produceavarietyofhighlyreactive radicals
suchashydrogen superoxide (HO)andhydro -
genperoxide (H2O2) that produceoxidativedamag e withinthecell(after Aren
a).

Cellular injury. There are 3 ways for cellular injury to

occur after ioniz ing radi ation exposure.

1. Divisiondelay, with dose-dependentdelayin cell division. Mitotic divi-

sion is delayed
. This is seenin dosesgreaterthan 0.5 Gy (50 rads)up
to approximately 3 Gy(300rads).Thisis the first observableeffectfrom
 70 I Part I Generalpathophysiology

ionizingradiationexposure.At morethan 3 Gy (300rads),the mitotic

ratedoes not recoverand the divisionmay neverhappen,thus killing
the cell.
2. Reproductive failure,whencellsfail to completemitosiseitherimmedi-
atelyor afteroneor moregenerations. It dependson the dose.At levels
at or below1.5 Gy (150rads), reproductive failureis randomand non-
linear.At dosesabove1.5 Gy(150rads),it is linearandnonrandom. As
doseincreases , so doesreproductive death.
3. lnterphasedeath,a relativelysuddendeathcausedby the apoptosis
mechanism.Celldeathcan occurmanygenerations from the initialra-
diationexposure.It is thoughtthat this is eithera naturalprocessof
programmedcell death(apoptosis),or that a criticalmechanism of cell
replicationhasbeenaltered.It dependson the typeof cellaffectedand
the doseto the cell. Generally,rapidly dividing,undifferentiatedcells
exhibitinterphasedeathat lowerdosesthannondividing,differentiated
cells.

Anyof thesetypesof cellularinjurycanhappenas a resultof eitherdirect

or indirectcellularinteractionswith radiation.

Types of radiation injury. Radiation injury may result

from two circumstances.

1. Exposure(whole-body , or local)to a largeradioactivesourceor radia-

tion field;
2. Contamination, eitherinternally or externally
, causedbythepresence of ra-
dioactive gas,liquid, or particulate materialwithinor onthebody.Radioac-
tivematerialmaygainentrance to thebody(internalcontamination) byway
of inhalation(e.g.,duringa fire or explosion), ingestion(i.e.,oralintakeof
accidental, therapeutic, Oi suicidalorigin),andabsorption throughanopen
wound,a burn,or a puncturewound.Internalcontamination shouldelicit
prompttherapeuticmeasuresto preventpermanent depositionwithina
criticalorgan,wherethis elementaccumulated moreintensively .
Generalnosology,etiologyand pathogenesis Unit I I 71

Dose-effect relationship. The connectionbetweenthe effectsof radiation

exposureanddose(i.e.,dose-response relationship)is classifiedinto 2 cat-
egories,deterministic andstochastic .
Deterministic,also referredto as non-stochasticeffects, are specificto
eachexposedindividual.Theseeffectsare very predictableand rangefrom
bloodandchromosome aberrationsto radiationsicknessanddeath, depend-
ing on the dose, doserate, age, immunecapacityof an individual,andtypeof
radiation exposure.

Data on deterministic health effects are collect e d

from observation of:

• sideeffectsof radiotherapy;
• effectson the early radiologists;
• effectsamong survivorsof the atomicbombsat Hiroshimaand Naga-
sakiin Japan(1945);
• consequences of severeaccidents(Table5)

Table5. Health effects after severenuclearaccidents(by the dataof the interna-

tionalAtomic EnergyAgency)

134casesof acuteradiation
sickness
amongresponders(firefightersandrecovery
operatio
n workers):
28diedin 1986froma combinationof highexternal
dosesofy-exposure (2.2-16Gy)and
skinburnsdueto b-emitters
17diedin 1987-2004fromvarious
causes,
notalllinkedto radiation
 72 I Part I Generalpathophysiology

Deterministiceffectsarecharacterized by thefollowingfeatures.
A certainminimumdosemust be exceededbeforethe particulareffectis
observed . Becauseof this minimumdose,the deterministiceffectsarealso
calledthresholdeffects.Thethresholdmaydifferfrom individualto individual.
Theseverityof theeffectis greaterfor a higherdosereceivedbytheindividual.
Thereis clearrelationshipbetweenexposureto radiationandthe observed
effecton the individual.
Stochasticeffectsareradiation-induced healtheffects, wherebythe prob-
ability of their occurrence,but not their severityis a function of the dose
withoutthe existenceof a thresholdvalue.
Themainstochasticeffectsaremalignantgrowthandgeneticdefects.Ac-
cordingto currentknowledge, a neoplasmis initiatedby damaginggenomein
a somaticcell.Geneticdefectsarecausedby damageto geneticmaterialin a
germcell(spermor ovum). Thereis noknownexistingthresholdfor stochastic
effects.Onesinglephotonor electroncanproducetheeffect.Forthis reason,a
stochasticeffectis calleda linearor zero-threshold dose-response effect.
Theprobability thatstochasticradiationdamage will occurdifferswidelyforthe
irradiatedindividualorgansor tissues.The International Commission on Radio-
logicalProtection indicates
a valueof 5 % per sievertfor whole-body irradiation.
The risk coefficientfor seriousinheritabledamageamountsfor the first
two successorgenerations to 0.4x 10-2 persievertgonaddose,for all follow-
ing generations1 x 10-2 persievert.
Stochasticeffectscanalso be causedby manyotherfactors,not only by
radiation.Sinceeverybodyis exposedto naturalradiation,andto otherfac-
tors, stochasticeffectscan arisein all of us regardlessof the type of work
(workingwith radiationor not). Whetheror not an individualdevelopsthe
effectis simplya questionof chance.
As far as canceris concerned,it is extremelydifficult to say whethera
particularcanceris attributableto a specificexposurebecausemostcancers
havea 20-yearslatency periodfrom exposureto manifestation. Therefore,
chroniclow-doseradiationexposureeffectsareseenas stochasticin nature.
Acuteradiationeffects.A singleaccidentalexposureto a high doseof
radiationduring a short periodof time is referredto as an acuteexposure,
and may producebiologicaleffectswithin a short periodafter exposure.At
Generalnosology,etiologyand pathogenesis Unit I I 73

or aboveapproximately 0.5 Gy (50 rads), acuteeffectsare predictable(i.e.,

deterministic)andfollowa linearpath.Somechromosomeaberrationsmay
be seenundera microscopeat or below0.5 Gy (50 rads), but no clinical
symptomshavebeenfoundto manifestfrom this observation.However,this
canbe usedas a bioassaytechniqueyearsafteran acuteexposure . Table6
showsthegenerallyacceptedacuteeffectsandsymptomsthesedoseranges
canbeexpected to manifest.
Acuteradiationsicknessis a conditionresultingfrom short-term(several
minutesto 1- 3 days)exposureof over 1 Gy of ionizingradiation(gamma
rays,neutronsflux). This is commonlyassociatedwith external irradiation ,
but maybe causedby internalinflowof certainquickand uniformdistribut-
ableradioactive substancesin the organismas well (e.g., tritium, etc.).
In thecountriesof theformerUSSRacuteradiationsicknessis convention-
allyclassifiedinto4 clinicalformsdepend ing on the radiation doselevel: me-
dullarform (1-10 Gy), intestinalform (10-20 Gy), toxemicform (20- 80 Gy),
cerebralform (over80 Gy). Fourperiodsare distinguishedin the develop-
mentof the medullarform of acuteradiationsickness .
Thefirst, initialperiod(orprodromal phase , orprimaryreactionperiod )
(1-2 days)beginsa few hoursafterirradiation.Signsincludeoverexcitation
of the nervoussystem(asa resultof stimulationof the nervousreceptorsby
productsof radiolysisandtissuedisintegration) , elevatedtemperature,and
decrease in the lymphocytes of theblood(lymphopenia ), NVD(nausea , vom-
iting,anddiarrhea),hair lossandskinerythemaabove3 Gy.
Thesecondperiod(latentphase)lastingup to 1-2 weeksbegins.The
initialpathologicphenomena areabsent.Onlylymphopenia andthrombocy-
topeniamaydevelopandthe reticulocytes maydiminish. In severecasesof
the radiationsicknessthe secondperiodmaynottakeplaceat all.
Thethirdperiod (manifestphase ): NVDreturns, hematologicsyndrome ,
gastrointestinal syndrome, CNSsyndromesignsandsymptomsreturnto pro-
dromallevelsorworse.Hematopoiesis is depressed , theleukocyte countsharp-
ly decreases (leukopenia),
thrombocytopenia is engendered (resultingin hem-
orrhage) , agranulocytosissometimes occurs,progressive anemiadevelops .
Thefourthperiod(recovery phase ) - gradualrestorationof the functions
impairedbythesickness.It beginswithin2-3 weeks.Althoughirritabilityand
Table6. Summaryof acuteclinicaleffectsof ionizingradiation* -..J
~

'·
..
Subcllni~I
Range.
Therapeutic
Range · LethalRange -
-0
0)
;:i
Acuteradiatio
n 0-1 Sv 1-2 Sv 2-6Sv 6-10 Sv 10-50Sv > 50 Sv
exposurein
sieverts
Treatment re- Reassurance Reassurance Bloodtransfus ion Considerbone Maintenance of Sedatives
quired andhematologicandantibiot
ics marrowtrans- electrolyte
bal-
surve
illance plant ance
. -~ ,,,
'
. - . ~,..... .SUbclin
lcat·
'nanij~.....
,
' ::fbJrcs
p, util Ratlg~·- j~ ;{_;; . ·_.·~\
~-- ~' - .i
<:·:<:,
.-.~
. .:J-Let.ttaUtange
..
- ,..,
.

. . . t'..(
' .

t: . . '·~·. ~. .. ,·. ' . . _., ... 'f, , .

, . "C ' ' "
Overal
l treatment Noneneeded Observation Effective Therapy
promis- Palliat
ive Palliative
plan ing
Incidence
of None 5%at 1 Sv; 100% at 3 Sv 100% 100% 100%
vomiting 50%at 2 Sv
Delaytimeprior N/A 3h 2h 1h 30 min 30min
to vomiting G)
(l)
~
Lead ingorgan None Blood-forming Blood-forming Blood-forming Gastrointest
inal CNS ...
(l)

~
affected tissue tissue tissue tract
Characteristic None Mildleukopenia Severeleukope- Severe leukope- Diarrhea;
fever; Convulsions;
i:::T

sign(s} nia;hemorrhage;nia;infections; electrolyte

lmbal- tremor;ataxia;
.g
;;s-
hairlossabove erythema ance lethargy;
coma ~
3 Sv
er
~
Generalnosology,etiologyandpathogenesis Unit I I 75

C:
fatigabilitypersist,the nervoussystem
~ ~ shows some improvement , the tem-
0 '. ~-g ' peraturedrops and hematopoiesisis
.c ~ 0
,... -e cu
JR ~ cu
co
"'1" § #0 -
-i".2CI>E restored.
,...I :I: C) a: $2 -g In radiationtherapy, acute deter-
•
ministic effects of radiation exposure
~
8 include radiationfibrosis in the lung
-0
rn
rn
<D
0
0
,... i when normallung tissue is exposed.
~ # Othertissuesaffectedare the kidney,
"'1"
,... "5 [
~
J, :I:
0
c3~
C)
brain and spinalcord. Becausetissue
'O
C:
cu
injury is known to occur if a certain
'#. Cl)
C) thresholdis exceeded,there are well-
0 cu
.:r. 'O
Cl)
0
,... ·"Eg establishedguidelinesin radiotherapy
!':
<D
Ecu ck ~-i to avoidexceeding a specificdose.
I ~ 0 (I)
"'1" C!:) co :I: .s
Chronic (or delayed)radiation ef-
'O
C:
n:I fectsareprimarilystochastic.The most
(I)

~ common delayedeffects are various

.:r.
!': '#. -€ 5 forms of malignanttumors (leukemia,
-0 0
-~~
~ bonecancer,thyroidcancer, lungcan-
<O
.J 8
C!:) Cl) -
:J:.E
cer) and genetic defects (malforma-
tions in childrenborn by parentsex-
-C:
JR
Q) Cl)
posedto radiation).
Leukemiahas been associatedas
--
<(
z
(.)

i.ti z0
C:
~ a stochasticeffect of chronic radia-
tion exposurewith doses as low as
50- 100 cGy (50-100 rads). Between
1= 100-500 cGy (100-500 rads),there is
JR
Cl) a linearcorrelationbetweendoseand
~
C:
~ ~-
z z0 leukemiaincidence.Datasuggestthat
incidenceof leukemiaincreasesat a
15
·- ~::,
.__
Q.) 0
Cl. Cl.
V)
V)
·;;;
-g
0
5
i
0
rateof 1-2 casesper million per year
percGy(1 rad)as a resultof exposure.

l ~=
- X 0
.~~ C:
~ In any radiologicalsituationinvolv-
·- "'
u'c ~
Cl.
(.)
.E
Cl)
'O ~ ing the inductionof cancer,there is a
 76 I Part I Generalpathophysiology

certain time periodbetweenthe exposureto radiationandthe onsetof dis-

ease. This is knownas the "latencyperiod" and is an intervalin which no
symptomsof diseasearepresent.Theminimumlatencyperiodfor leukemi a
produced by radiation is 2 yearsandcanbeup to 10 yearsor morefor other
typesof cancer.
Chronic radiationsickness resultsfrom prolongedandrepeated exposure
to small dosesof ionizingradiation . It may be the resultof both external
actionof radiation(X and gammarays)and internaluptakeof radioactive
substances(radium,thorium, radiostrontium,etc.). Deterministic effectsof
chronicradiationsicknessare characterized by dysadaptation disordersof
the functionsof the nervousandcardiovascular systemsand, especially , dis-
turbancesin hematopoiesis (bonemarrowaplasia).
Chernobylexperiencein radiation- inducedchronic radiationeffectsde-
scribed in "Liquidators" and generalpopulation (by the Dataof the Interna-
tional AtomicEnergyAgency).

In "Liquidators":

• Doublingof leukemia morbidityin workerswith D>150 mGy

• Someincreaseof mortality(~5%) causedby solid cancersandcardio-
vasculardiseases
• Increasedcataractfrequency
• Dosesrecordedin the Registries rangeup to about500 mGy, with an
averageof ~ 100 mGy
• In generalpopulation
:
• No increaseof leukemia
• No increaseof solid cancersexceptof thyroid cancerin children and
adolescents
• Effectivedoseduring 1986-2005rangefrom a few mSvto somehun-
dredmSvwith an averagedose10-20 mSv.
'
Effectsof radiationonembryoor fetus.It is well knownthat the embryo
andfetus is moresensitive to the effectsof radiation thanthe adult human.
Generalnosology,etiology and pathogenesis Unit I I 77

If an irradiationoccurs in thefirst two monthsof pregnancy , delayedeffects

mayappearin thechild.Theseincludementalandbehaviorretardation,with
delayperiod of approximately 4 years.
A studyof about1,600childrenexposedin uteroat Hiroshimaand Naga-
sakito various radiationdosesandat variousdevelopmental stagesrevealed
excessmental retardationwasat a maximumbetweenB and 15weekswith
risk 0.05 % per mSv.
Diagnostic X-rayirradiationat lowdosesin uteroincreasesthecancerinci-
denceby a factorof 1.5to 2 duringthefirst 1Oto 15 yearsof life. The maxi-
mumpermissible doseto the fetusduringgestationis 5 mSv.
Effectsof verylow radiationlevels.Exposure to verylow levelsof radiation
is a controversialissue,originatingmanydebatesthroughoutthe scientific
community . Whathappensat very low levelsof radiationexposure?Every-
bodyas is well knownis exposedto a levelof radiationcalledthe naturalra-
diationor backgroundradiation.Also, wasprovedthatthe backgroundlevels
varyon earthby a factorgreaterthan 10.Whathappenswhensomebodyis
exposedto levelsof radiationwithina few percentage of the background , on
top of the dayto daybackground irradiation?
As statedabove,currentknowledgeshowsno evidenceof a thresholdef-
fectfor stochasticeffects.Therefore , anylevelof radiationmaybeconsidered
to causethem. Conversely, somestudiesshowthat low levelsof irradiation
are in fact beneficialto the health(radiationhormesis- the phenomenon
or condition of a substanceor otheragenthavinga beneficialphysiological
effectat low levelsof exposureeventhoughtoxic or otherwiseharmfulat
higher levels).Thisconceptis supportedby studiesshowingincreased activ-
ity of the components of the immunesystem.
It hasbeenalsoshownintroductionof the quinoidradiotoxinsintothe or-
ganismsin ultra-smallconcentrations increases the resistanceof the organ-
ism andactivatesa numberof essentialfunctions.
Howeve r, in theabsenceof clearscientificevidence, the regulatorsadopted
a conservative approachandconsiderall levels of radiationas beingpoten-
tiallydamagingto thehumanbody.
NaturalMechanisms ofAntiradiation Defense.Despitethe fact that bio-
logicalspecies, including man,are exposedto potentiallyharmful levelsof
 78 I Part I Generalpathophysiology

differentradiation, mechanismshaveevolvedto protectcellsand to repair

damagedmolecules.
DNArepair.Thecell componentmostvulnerableto injuryof ionizingand
UV radiationis nuclearDNA. UponsensingONAdamageor stallsin replica-
tion, cell cyclecheckpointsare activatedto arrestcell cycleprogressionto
allow timefor repairbeforethe damageis passedontodaughtercells.In ad-
ditionto checkpointactivation,the ONAdamageresponseleadsto induction
of transcriptionalprograms , enhancement of ONArepairpathways , andwhen
the levelof damageis severe,to initiationof apoptosis.
A numberof differentDNArepairmechanisms havebeenestablished, the
bestknownbeingphotoreactivation, baseandnucleotideexcisionrepair, and
SOSrepair.
Photoreactivation. Thisrepairprocessbeginswith a photoreactivat ing en-
zymebindingto UV-inducedpyrimidinedimersin the dark. If this complex
is exposedto opticalradiationbetweenabout330and 600 nm. the active
enzymeseparates from thedimeranda repairedDNAsegmentresults.
Baseexcisionrepair(BER).It is a multi-step processthat correctsnon-
bulky damageto basesresultingfrom oxidation, or loss of the DNAbase
itself. Thesealterations, althoughsimplein nature,are highly mutagenicand
thereforerepresenta significantthreatto genomefidelityandstability.
Nucleotideexcisionrepair(NER).It is perhapsthe mostflexibleof the ONA
repairpathways considering thediversityof DNAlesionsit actsupon.Themost
significantof theselesionsarepyrimidinedimers(cyclobutane pyrimidinedi-
mersand6-4 photoproducts) causedbythe UVcomponentof sunlight.Other
NERsubstratesincludeDNAintrastrandcrosslinks ; andsomeformsof oxida-
tivedamage . TheNERprocessrequirestheactionof morethan30 proteins in
a stepwisemannerthatincludesdamagerecognition, localopeningof the ONA
dublehelixaroundthe lesion, dualincisionof the damagedDNAstrand,gap
repairsynthesis,andstrandligation.Patientswiththe hereditarydisorder,xe-
rodermapigmentosum, showreducedlevelsof NERwhichmakesthemprone
to the development of multiple'>kincancersfrom childhoodonwards .
SOSrepair.This mechanismof repairis not yet fully understoodbut is
thoughtto includea bypasssystemthat allows growth of the DNAchain
acrossthe damagedsite of the thyminedimer.This is achievedat the cost
 Generalnosology,etiologyand pathogenesis Unit I I 79

of fidelityof replicationanda greatdealof evidencenow indicatesthat SOS

repairis the majorcauseof ultraviolet-induced mutagenesis .
Ionizingradiationcan produceboth single-strandbreaksand double-
strandbreaks in the DNAbackbone.
Single-strand breaks(SSBs)repair.Breaksin a singlestrandof the DNA
moleculearerepairedusingthe sameenzymesystemsthat are usedin base
excisionrepair.
Double-strand breaks(OSBs) repair.Therearetwo mechanisms by which
the cellattemptsto repaira completebreakin a DNAmolecule.
Directjoiningof thebrokenends.This requiresproteinsthat recognize and
bindto the exposedendsand bringthemtogetherfor ligating.Theywould
preferto usesomecomplementary nucleotides but canproceedwithoutthem
so this type of joining is also callednonhomologous end-joining. Errorsin
directjoiningmaybea causeof thevarioustranslocations thatareassociated
with malignantneoplasms(Burkitt'slymphoma,the Philadelphiachroma-
- somein chronicmyelogenous leukemia,8-cellleukemia) .
Homologousrecombination. Herethe brokenendsare repairedusingthe
information(1) on the intactdaughterchromatid(availablein G2afterchro-
mosomeduplication),or (2) on the homologous chromosome(in G1; that is,
beforeeachchromosomehasbeenduplicated) , or (3) on the samechromo-
someif thereareduplicatedcopiesof the geneon the chromosomeoriented
in oppositedirections(head-to -heador back-to-back) . Two of the proteins
usedin homologousrecombination are encodedby the genesBRCA 1 and
BRCA2.Inheritedmutationsin thesegenespredisposewomento breastand
ovariancancers.
Non-emergency cellulargeneticprogramblocking.This allowsto con-
centratethe adaptive resourcesantiradia tion defenseandis usuallyachieved
by increasingin DNA methylation .
Emergency geneticprogramexpression . In damagedcellularnucleithere
is the occurrenceof insertionof emergency geneticprogramexpressionse-
ries, whichcannot bereadoutcompletelyin the normalconditionsor canbe
minimally.They includethe followingtypesof genes.
Genesof heat-shockproteins(HSP).HSP(chaperones, ubiquitins)"res-
cue" damagedproteinsfrom misfolding and denaturation.Chaperones fa-
 80 I Part I Generalpathophysiology

cilitatedegradationof the damagedprotein.This degradative processoften

involvesubiquitins,whichareaddedto the abnormalproteinandmarksit for
degradationby the proteasome complex.
Antioncogenes (e.g., tumor-suppressor genep53).p53accumulates when
DNAis damagedandarreststhe cellcycle(at the G1phase)to allowtimefor
repair.However , if the DNArepairprocessfails,p53triggersapoptosis.When
p53 is mutatedor absent(asit is in certaincancers),it is incapableof induc-
ing apoptosisandit favorscell survival.
Apoptosisregulatorygenes.
Growthpromotinggenes-proto-oncogenes (e.g.,c-fos,c-mycandc-jun).
Antioxidant mechanisms includescavengingof free radicals,donationof
H· ion, boundingto critical biologicaltargets,forming mixeddisulfidefor-
mations).Antioxidantseitherblockthe initiationof free radicalformationor
inactivate(e.g., scavenge) free radicalsandterminateradicaldamage .
Radioprotection. Radioprotectors areknownto besubstances whichhav-
ing been injectedmay preventor reducethe intensity of radiationdamages.
Theygenerallyare classifiedas eithersulfhydrylcompounds,otherantioxi-
dants,or receptor-media ted agents(e.g., cytokinesandgrowthfactors).
Sulfhydrylcompounds. Considering theresultsof investigating greatnumber
of radioprotective compounds , it can be statedthat thosecontainingsulphur
havethe mostprotectiveeffect.Theseareaminothiols, aminodisulfides , thio-
ureaderivatives , thiosulfuricandthiophosphoric acid, dithiocarbamates, thia-
zole, etc.Amongthelargenumberof testedcompounds, themostexamined are
cysteamine derivatives, i.e.compoundsknownasaminothiolradioprotectors.
Radioprotective effectof theseagentsis basedon their abilityto donate
their sulfhydrylgroup.As a result,theyprotecttheir own SH-groups,which
form the compositionof activecentresof numerousenzymes.
Recent ly therearedeveloped inositolsignalingmoJecules (ISMs)drugsfor
radioprotection. Theyarekeycomponents of intracellularsignalingandfigure
prominentlyin the regulationof radiationrepairmechanisms. ISMsregulate
activityof proteinsin radiationresponseandDNArepairpathwaysbyfacilitat-
ing doublestrandbreaksrepair.
Hypothermia , hypoxia and pro-hypoxicagents (e.g., methemoglobin
formedsubstances)havecertainradioprotective peculiarities aswell.
Generalnosology,etiologyand pathogenesis Unit I I 81

Effects of Gravity and Ac celeration

Effects
of SpaceFlightFactors

Physiologically active factors of the space flight (by

V. A. Berezovsky) include:

• Preflighttraining(anechoicroom, orthostaticload,etc.);
• Startingstress(hypergravity, vibration, noise, etc.);
• Microgravity ;
• Hypokinesia;
• Insulatingstress;
• Radiation damage ;
• Toxicpropertiesof the air in thespacecraftcompartments;
• Landingstress.

Startand landingstressesapartfrom mentalcomponentsincludeinflu-

enceof acceleration andhypergravity , vibration, noise.
Acceleration andhypergravity. Accelerationis the time rateof changein
velocity.Hypergravity (overload)- is a forceexertingon the organismin ac-
celeration, whichis higherthanacceleration of gravity.Theeffectof accelera-
tionsdependson theirmagnitude, duration,directionandrateof increase , as
wellas on thefunctionalstate(endurance) of the organism.
Thefollowingaccelerations are distinguished:linear(in changesin veloc-
ity of rectilinearmotion),centripeta l or radial(in curvilinearmotion), angular
(in changesin angularvelocity), andcross-coupled,or Coriolis, accelera tion
(whena physicalbodyis movingin a circlewith equilibriumangularvelocity
with simultaneous approachingor movingoff the centerof rotation).Two
abovementionedformsof acceleration areof greatimportancein the orbital
flightand maybecause of spacesickness(Seebelow).
A linearacceleration maybepositive(craniocaudal) , negative(caudocranial),
ortransverse, i.e.,actingin ananteroposterior direction.Uniformlinearpositive
 82 I Part I Generalpathophysiology

acceleration is bettertoleratedby menevenat high velocities.Acceleration of

2-3 g lastingseveralsecondsdoesnot produceanappreciable effect.
The start accelerationof a spacecraftis approximatelylinear (positive),
andthe astronautis exposedto a tremendoushypergravity-oftencloseto 8
timesthe gravityof the earth(8 g) at the first stageof 3-stageblast-off.The
spaceshuttleimplies3 g startand1.2 g landing.Positiveacceleration of 6-8
g causespoolingof blood in the lower extremities,respiratorydifficulties,
quickeningof the pulse,a critical drop in arterialblood pressurein the up-
per partof the bodywith orthostatichypotensionor collapsedueto reduced
venousreturn,nausea,vomiting,and spatialdisorientation , sometimesloss
of consciousness . Transientreductionof cerebralperfusionmay leadto so-
calledgravitational-force loss of consciousness.
Negativeacceleration (underlanding)affectsthe organismmoreintensely.
Evenat 1-2 g it mayproduceconsiderable congestionin the head,a rise in
bloodpressure,anddisturbancesin visionandin the functionsof the higher
divisionsof the nervoussystem, which maypersistfor a long time afterthe
flight. Greataccelerations maygive rise to cerebralhemorrhages anddevel-
opmentof pulmonaryedema.
Transverse acceleration (even6-8 g) is toleratedbest.Thusthe bodyof the
astronautis locatedtransverseto the axisof acceleration in orderto prevent
redistributionof blood.Theastronautoftenwearsananti-gravitysuit with the
samepurpose.
Trainingincreasesthe organism'stoleranceof accelerations severalfold.
Themainfactorsin the mechanismof the morbideffectof accelerations are
changesoccurringas a resultof stimulationof the nervoussystemanddis-
turbancesin bloodcirculation.Theaccelerations giveriseto disturbancesin
neuromuscular coordinations andvegetative functions,especiallydisturbanc-
es in redistribution of the bloodwith changesin bloodpressure,disordersof
vision dueto stimulationof the nucleiof optic nervesand diminishedblood
supplyto the retina.Theyalsobringaboutcompensatory phenomena: reflex
vascularreactionsfrom the re~on of the carotidsinus andthe aortic arch,
as well as reactionsof the striatedmuscles , manifestedin tensionof the ab-
dominalandleg muscles,whichpreventtheflow of bloodto thevesselsof the
lowerhalfof the bodywhenthe accelerations act in a craniocaudal direction.
Generalnosology, etiologyand pathogenesis Unit I I 83

Oepressurization and explosivedecompression . Spaceflight requires

pressuresuits or cabinsensuringadequateoxygenationand pressurization
to protectagainst hypoxiaand decompression sickness. More than 20 km
out in the stratosphere , the barometricpressureis lessthanthe water vapor
tensionin alveolarair (47 mm Hgor 6.3 kPa), andthe oxygentension is rap-
idly approaching zero. Withoutpressurized cabinsthe bloodof the astronaut
wouldboil.In thestratosphere , depressurization causesa monstrousform of
decompression sickness(explosivedecompression) with air emboliall over
the body. Thebodyvolumeof humansincreasesby a factorof at leastthree
by air expansio n in tissuesandblood.
In theorbitalflight spacepassenger is subjected to theeffectof micrograv -
ity (weightlessness) , hypokinesia , insulatingstress, andsometimesradiation
andtoxic influenceof theair in the spacecra ft compartment s.
Microgravity . Weightlessness , causedby the absenceof gravitational
forces,resultsin the rather pronounced , but reversiblefunctional, structural
and metabolicchangesin muscles , bones, myocardium, and neurosen sory
systemof the humanbody.
Themain adaptivechange s in the humanbodyto microgravityusuallyde-
velopin two stages.
Thefirst, initial phasedevelopsin first 3-6 weeksof the flight. The as-
tronautexperiences spacesickness:vegetative disorders(nausea , vomiting,
salivation, pulseand blood pressure !ability), vertigo, sensitivitydisorders
(disorientation, insubstantialsensations) anddisturbancesin coordinationof
movements. This is associated with the disturbances in analyzerfunctioning
due to mismatchedstimulifrom receptor sites of the vestibularapparatus,
skin, organof vision, proprioceptor s. Initialalterationsin tissuedeformation
andwatermetabolismarealso observed.
Thesecond,adaptivephase , startsin somemonthslatersincethebeginning
of theflightandis characterized byfallingtotalbloodvolume,muscularatrophy,
2
Ca• Lossfromthebones , andobstipation, broughtaboutbythelack of stimuli,
cardiovascular functionalterations , probabledecreaseof immuneresponse.
Theboneloss. Unloadingof weightbearing bonesas inducedby micro-
gravityor hypokinesia hassignificantimpactson the calciumand boneme-
tabolismand is the most likelycausefor spaceosteoporo sis. Duringa 4.5
 84 I Part I Generalpathophysiology

to 6 monthstayin spacemostof the astronautsdevelopa reductionin bone

mineraldensityin spine, femoralneck,trochanter , and pelvisof 1-1.6%.
Osteoporosisitself is definedas the deteriorationof bonetissueleadingto
enhancedbonefragility and to a consequentincreasein fracturerisk. The
bone loss continueslong after the returnto earth, becausestimulationof
boneformationrequiresphysicalactivityin a gravityfield.
Muscular atrophy . Astronautscurrentlyundergoa rigorousfitnessregime
whenin space,but it is still difficultto mimicthe effectsof gravity,andlong-
term spacepassengers facelosingup to 25 % of their bodymuscle.Astro-
nautsrisk losing musclemassand functionbecausetheir musclesare not
bearingenoughweight.
Oeconditioning. It is a changein cardiovascular functionafter prolonged
periodsof weightlessness, probablyrelatedto a shift of a quantityof blood
from the lowerlimbsto thethorax,resulting in reflexdiuresisanda reduction
of bloodvolume.
Disturbances in immuneresponse.Returningastronautsexperienceal-
teredimmunefunctionand increasedvulnerabilityto infectionduringspace
flights. Recentlygravity-dependent genesand pathwaysresultingin lack of
immuneresponsein microgravityhavebeenfound out. Impairedinduction
of early genesregulatedprimarilyby severa l transcriptionfactors (NF-KB,
AP-1,etc.) after cross-linking the T-cell receptorcontributesto T-cell dys-
functionin alteredgravityenvironments.
Radiationdamage.Lethal radiationdoseis rapidly reachedwhenflying
aroundthe earthin the VanAllen radiationbelts,_ consistingof high-energy
level protonsandelectrons.Therefore , commercialflying takeplacesessen-
tially belowthe innerbelt (500km). Startandlandingof long distancespace
flights take placeas closeto the magneticpoles- with minimumradiation
energyexposure- as possible.
It has beenfound out that rats exposuredto radiation(137Ce in a dosage
inducingthe development of radiationsickness)duringthe"Bion-2, biosatel-
lite flight showedno considerabie modificatingeffectof microgravityon the
courseof radiation pathologyandpost-radiationrehabilitation.
Toxicpropertiesof the air in the spacecraft compartments. Recycling
techniqueshavebeendevelopedfor the reuseof 02. Thespacecraft- just as
 Generalnosology, etiologyand pathogenesis Unit I I 85

submarines - mustcarryalongenoughcarbondioxideabsorbentto prevent

deathfrom carbondioxidepoisoning .
Motionsickness (or kinetosis)is a resultof certainkindsof motionand
is inducedduring passivelocomotion in vehicles , generatedby unfamiliar
bodyaccelerations , to whichthe personhasthereforenot adapted , or by an
intersensory conflict betweenvestibularandvisualstimuli.
Strictly speaking,motionsicknessis consideredto be a normalresponse
to an abnormalsituation(i.e.,accelerations , whichthe humanbodyhasnot
adaptedto duringthe evolution).All individuals(humansandanimals)pos-
sessingan intactvestibularapparatuscan be mademotion sick giventhe
rightqualityandquantityof provocative stimulation , althoughtherearewide
andconsistentindividualdifferencesin the degreeof susceptibility .
Thepathogeniceffectof the motionis observedwhentravelingby a ship
(seasickness), airplane(airsickness) , spaceship(spacesickness) , and less
frequentlywhenriding in automobiles(car sickness),high-speedtrains, or
- rockingin swings(swingsickness).
Cardinalsignsof motionsicknessare nausea,vomiting,pallorand cold
sweating.Associatedreactionsincludevertigo,hyperventilation , flatulence,
lossof bodyweight, headache andsomnolence (drowsiness) .
Pathogenesis. All situationswhichprovokemotionsicknessarecharacter-
izedby a conditionof sensoryrearrangement in whichthe motion signals
transmittedby the eyes, the vestibularsystemandthe proprioceptors areat
varianceonewith another,and hencewith whatis expectedon the basisof
previoustransactions withthespatialenvironment. Thepathogenic conflictis
between thepresentsensoryinformationandthatretained fromtheimmediate
past("exposure-history "). Thattheconflict existingwithinthe presentpattern
of sensoryinputsis by itselfinsufficientto causemotionsicknessis evident
from the earlier observationthat continuedinteractionwith the pathogenic
stimulusresults in the eventualdisappearance of symptomseventhoughthe
incongruitybetweenthevarioussourcesof spatialinformationremains.
 86 I Part I Generalpathophysiology

Chapter 3. The Role of Heredityand

Constitution(Somatotypes)in Pathology

Genetics is the studyof heredity-the passingof physical,biochemical and

physiologictraits from biologicalparentsto their children.In this transmis-
sion, disorderscan be transmitted,andmistakesor mutationscan resultin
disabilityor death.
Geneticinformationis carried in genes,which are strung togetheron
the deoxyribonucleicacid (DNA)doublehelix to form chromosomes.Ev-
ery normal humancell (exceptreproductive cells) has 46 chromosomes,
22 pairedchromosomescalled autosomes,and 2 sex chromosomes(a
pair of Xs in femalesandan X anda Yin males). A person's individualset
of chromosomesis called his karyotype.The humangenome(structure
and locationof eachgeneon which chromosome)has beenintensestudy
for only about 15-20 years.

Genet ic components
Eachof the two strandsof DNAin a chromosomeconsistsof thousandsof
combinationsof four nucleotides - adenine(A), thymine(T), cytosine(C),
and guanine(G)- arrangedin complementary triplet pairs(calledcodons),
eachof whichrepresentsa gene.
Thestrandsare looselyheldtogetherby chemicalbondsbetweenadenine
and thymineor cytosineand guanine- for example , a triplet ACGon one
strandis linkedto thetripletTGAonthe other.Thelooseness of the bondsal-
lowsthestrandsto separateeasilyduringcelldivision.Thegenescarrya code
for eachtrait a personinherits,from bloodtypeto eyecolor to bodyshape
anda myriadof othertraits. Structureandfunctionof all cells,systemsand
organsin organismdepended from synthesisof differentproteins(Fig. 4).
Development of the diseasearid its pathogenesis dependsfrom etiologic
externalfactorsandsuchabilityof organismas heredity,constitution , reac-
tivity. Oneof the most importantquestionsis whenand howthe hereditary
Generalnosology,etiologyand pathogenesis Unit I I 87

Gene(DNA)

RNAtemplate

?c CellenZ)!mes
..:

Fig.4. Genes
contro
l ofcellfunction

diseasesappear?Forunderstanding answeron this questionit's needto un-

derstanddifferencesbetweenhereditary(genetic)andcongenitaldisorders.
Congenitaldisorderinvolvesdefectsin or damageto a developingfetus.It
maybethe resultof geneticabnormalities, the intrauterineenvironment, er-
rorsof morphogenesis, or a chromosomal abnormality . Congenital
disorders
varywidelyin causationandabnormalities . Anysubstancethat causesbirth
defectsis knownasa teratogen .
Geneticdisordersor diseasesareall congenital,thoughthey maynot be
expressedor recognized until laterin life. Genetic diseasesmay be divided
into single-genedefects, multiple-gene disorders , or chromosomaldefects.
Single-gene defectsmayarisefrom abnormalities of bothcopiesof an auto-
somalgene(a recess ivedisorder)or of onlyoneof the two copies (a domi-
nantdisorder). Someconditionsresultfrom deletionsor abnormalitiesof a
few geneslocated contiguously on a chromosome.
 88 I Part I Generalpathophysiology

All geneticdiseasesare resultof a mutationin the geneticcode.This may

bea changeof a singlebase-pairof a gene,resultingin functionalchangein
the productprotein(e.g.,thalassaemia) or grossrearrangement of the gene
withina genome(e.g., Down'ssyndrome).
Thesemutationscan be congenital(inheritedat birth) or somatic(arising
during a person'slife). The latter are responsible for the collectivedisease
knownas cancer,andthe principlesunderlyingMendelianinheritanceact in
a similarmannerto dominantand recessivetraits. Bothgrosschromosomal
andpointmutationsoccurin somaticgeneticdisease.
Fromthis casewe maysayabouthereditaryhereditarypredisposition and
hereditarydiseases.
Hereditarypredisposition is connectedwith geneticdamageof regula-
tory apparatus.Theirmanifestations dependon presenceetiologicalfactors.
Withoutinjuryfactorshereditarypredisposition don't turningin disease.For
example , the development of diabetesmellitusdependson the interactionof
geneticfactorsandthe environment.
Hereditary diseases areonlysuchdiseaseswhicharecausedby mutation
of the reproductive cells.Their manifestations doesn'tdependuponexogenic
(etiological)factors.

The spectrum of inherited or genetic disorders can

be classified as:

• chromosomal disorders,
includingmitochondrialchromosomedisor-
ders;
• Mendelianandsex-linkedsingle-gene disorders
;
• non-Mendeliandisorders;
• multifactorial
andpolygenicdisorders
.

1. Abnormalities
of chromosomescanbedividedinto 2 types:
• structuralabnormalities; '
• numericalabnormalities.
Generalnosology, etiologyand pathogenesis Unit I I 89

Abnormal chromosome structures

• Deletions.Deletionsof a portionof a chromosomemay give rise to a
diseasesyndromeif two copiesof the genesin the deletedregionare
necessary , andthe individualwill not be normalwith just the onecopy
remainingonthe non-deleted homologous chromosome. Many deletion
syndromeshavebeenwelldescribed.Forexample,Prader- Williesyn-
dromeis the resultof cytogene tic eventsresultingin deletionof partof
the longarmof chromosome 15 andmicrodeletions in the longarm of
chromosome 22 giveriseto the DiGeorge syndrome.
• Duplications. Duplications occurwhena portionof the chromosomeis
presentonthe chromosome in two copies, so thegenesin thatchromo-
someportionare presentin an extradose.A form of the neuropathy
Charcot-Marie-Tooth diseaseis dueto a smallduplicationof a regionof
chromosome 17.
• Inversion.Inversionsinvolvean end-to-endreversalof a segmentwithin
a chromosome ; e.g., klmnoprstbecomesklmponrst.
• Translocations . Translocations occurwhentwo chromosomeregions
join together,whentheywould not normally.Chromosome transloca-
tions in somaticcells maybe associatedwith tumourogenesis. Trans-
locationscanbeverycomplex, involvingmorethantwo chromosomes ,
but mostaresimpleandfall into oneof two categories.
• Reciprocaltrans/ocations occurwhenanytwo non-homologous chro-
mosomesbreaksimultaneously andrejoin, swappingends. In this case,
the cell still has 46 chromosomesbut two of them are rearranged.
Someonewith a balancedtranslocationis likelyto be normal(unless
a translocationbreakpointinterruptsa gene);but at meiosis,whenthe
chromosomesseparateinto differentdaughtercells, the translocated
chromosomes will enterthe gametesandanyresultingfetusmayinherit
oneabnormalchromosome andhavean unbalanced translocation , with
physicalmanifestations.
• Robertsoniantranslocationsoccur when two acrocentricchromo-
somesjoin and the short arm is lost, leavingonly 45 chromosomes.
This translocationis balancedas no geneticmaterialis lost and the
90 I Part I Generalpathophysiology

individualis healthy. However, any offspringhavea risk of inheriting

an unbalancedarrangement.This risk dependson whichacrocentric
chromosomeis involved. Clinically important is the 14/21Robertso-
nian translocation . A womanwith this karyotypehas a 1 in 8 risk of
deliveringa babywith Down's syndrome(a malecarrier has a 1 in
50 risk). However , they havea 50 % risk of producinga carrier like
themselves, hencethe importanceof geneticfamilystudies. Relatives
should be alerted about the risk of a Down's offspring and should
havetheir chromosomeschecked.
• Ring chromosomeis formedbya breakat boththetelomeric(terminal)
endsof a chromosome followedby deletionof the brokenfragmentand
thenend-to-en d fusion. Ringchromosomes arecompatiblewith life.
• lsochromosome . When centromereratherthan dividingparallelto the
longaxis, insteaddividestransverseto the long axis of chromosome ,
it resultsin eithertwo short arms only or two long arms only called
isochromosomes. The exampleinvolving isochromosomeof X-chromo-
some is seenin somecases(15%) of Turnersyndrome.

Numerical chromosome abnorm alit ies

• Polyploidy . Very rarelythe entirechromosomeset will be presentin
morethantwo copies, so the individualmaybetriploid ratherthandip-
loid and havea chromosomenumberof 69.Triploidy and tetraploidy
(foursets)resultin spontaneousabortion. ·
• Aneuploidy . It is a numberof chromosomes whichis not exact_multi ple
of haploid numbering. hypodiploid (45chromosomes)monosomy , hy-
perdiploid (47 chromosomes) trisomy.
• Nondisjunction. Nondisjunctiionduringmeiosis resultsdifferentgam-
etes- someof it have no chromosomes(nullisomes), othermaybe nor-
mal.Occasiona lly, non-disjunction canoccur during mitosisshortlyaf-
tertwo gameteshavefused. It will thenresultin the formationof two cell
lines, each with a differentchromosome compleme nt.This occursmore
oftenwith the sexchromosome , andresultsin a 'mosaic'individual.
Generalnosology,etiologyand pathogenesis Unit I I 91

Most clinically import a nt syndrom e s th e re a re:

Autosomal disorders
Downsyndromeis the mostfrequentlyoccurringchromosomaldisorder
(1 on 650live births). Causesof Downsyndrome(trisomy21) is produced
usuallyby maternalmeioticnondisjunction(for 95 % of cases), and inci-
denceincreaseswith maternalage. Otherform is connectedwith transloca-
tion betweenchromosome 21 andanotherchromosome (accountsfor 3-5 %
of caseshavingno relationto maternalage).

Clin ic a l ch a ra ct e rist ics:

• Severementalandphysicalretardation
• Largeforehead , broadnasalbridge, wide-spacedeyes, epicanthalfolds,
largefolds, protrudingtongueandsmalllow-setears
• Brushfieldspots
• Short, broadhands,simiancrease,singlepalmarcrease
• Complications:
a. Congenital heartdisease(atrioventricular valvemalformations , arte-
rial andventricularseptaldefects
b. Leukemia (themostoftenlymphoblastic).
c. Immunitydefectdueto suscep tibility to infection.
d. In patientssurvivinginto middle age morphologicchangesinto
brain- senileplaquesandneurofibrillary tanglessimilarto thoseof
Alzheimerdisease .
e. maternalscreening :
• a-fetoprotein - low in Down syndrome
• humanchorionicgonadotropin (HCG)- highrisk
• unconjugated estriol- low risk.

Oneof the most prevalentand dramaticclinicalfeaturesof Down's syn-

drome- premature
onsetof Alzheimer's
disease-isnotevidentuntiladulthood.
 92 I Part I Generalpathophysiology

Althoughfrankdementiais not clinicallydetectable in manyadultswith Down's

syndrome , theincidenceof typicalneuropathologic changes..:.senileplaquesand
neurofibrillary tangles- is nearly100% byage35.Themajorcausesof morbid-
ity in Down'ssyndrome arecongenitalheartdisease
, infections,andetardati.Life
expectancy depends to a largeextentonthepresence of congenital
heartdisease ;
survivalto ages10 and30yearsis approximately 60 % and50 %, respectively,
for individuals withcongenital heartdiseaseandapproximately 85 % and80 %,
respectively, for individuals withoutcongenitalheartdisease.
Cri du chat(5p-, cry of the cat) syndrome - appearswith deletionof
the short arm of chromosome5. Characterized by severementalretarda-
tion, microcephalyand unusualcatlikecry. Furthermanifestedby low birth
weight,roundface,hypertelorism(wide-seteyes),low-setearsandepican-
thal folds.
Edward 's syndrome(trisomy 18) (1 on 3000live births) is markedby
mentalretardation, flexiondeformitiesof thefingers,rockerbottom,feetcon-
genitalheartdisease.
Patau's syndrome (trisomy13) (1 on 5000live births) is manifestedby
mentalretardation , microcephaly, microphtalmia
, brainabnormality,cleft lip
andpalate,polydactyly , rocker-bottomfeetandcongenitalheartdisease.
Di Georgevelocardiofacial syndrome - microdeletionin chromosome
22 (catch22 syndrome).Characterized by cardiacabnormalities,abnormal
facies,T-celldeficitbecauseof thymushypoplasia,cleft palateand hypocal-
cemiabecauseof hypoparathyroidism.

Sex-chromosome disorders
Klinefelter's
syndrome(1 on 1000live birthsmales)is a geneticdisorder
in whichtherearethreesexchromosomes , XXV(1 on 5000live births).

Total number of chromos-omes 47, 48, 49. Affected

individuals are apparently male, but they are:

• Tallandthin
• Smalltestesfailureof normalspermproductionfound.
Generalnosology,etiologyand pathogenesis Unit I I 93

• Azospermia.
• Enlargement of the breasts- gynaecomastia.
Absenceof facialandbody
hair.
• Lessintelligence.
• Insufficientphysicalandgeneticaldevelopment.

Whenthe numberof X-chromosomes morethantwo -three , four- XXXY,

XXXXY- oligofreniamay be present.Whenthe numberof Y-chromosome
morethanone- the possibility of aggressivebehaviorincreases.
XYYsyndrome (1 on 800 live births males)- occurswith aggressively
behavior.
Turner's syndrome (1 on 2500live birthsfemales)is the mostoftenchar-
acterizedby an XOkaryotype(45, X), in which no Barrbodiesare seenon
buccalsmear.The most commoncauseof femalehypogonadism with pri-
maryamenorrea,but usuallyis not complicatedby mentalretardation.

Manifestations of the syndrome :

• Replacement of the ovariesby fibrousstreaks

• Decreasedestrogenproductionand increasedpituitarygonadotropins
lossof feedbackinhibition
• Infantilegenitaliaandpoor breastdevelopment
• Shortstature,webbedneck
• Lymphedema of the extremitiesandneck
• Coarctationof the aortaandothercongenitalmalformations

XXXsyndrome (47,XXX)(1 on 1000live birthsfemales)is characterized

by menstrualirregularities,mild mentalretardation
. Thedegreeof mental re-
tardationappearsto increasewith the numberof additionalX chromosomes.

2. Mendelian
disorders
Autosomaldominantdisorders.
Eachdiploid containstwo copiesof all
theautosomes.
Anautosomaldominantdisorderoccurswhenoneof the two
 94 I Part I Generalpathophysiology

copieshas a mutationand the proteinproducedby the normalform of the

genecannotcompensate. In this casea heterozygote individualwho hastwo
differentforms (or alleles)of the samegenewill manifestthe disease.
Theoffspringof heterozygotes havea 50 % chanceof inheritingthe chro-
mosomecarryingthe diseaseallele,andthereforealsoof havingthe disease.
However,estimationof risk to offspringfor counselingfamiliescan be dif-
ficult becauseof somefactors:
• Thesedisordershavea greatvariabilityin their manifestation. "Incom-
pletepenetrance"mayoccurif patientshavea dominantdisorderbut it
doesnot manifestitself clinicallyin them.This givesthe appearance of
the genehaving"skipped"a generation.
• Newcasesin a previouslyunaffectedfamilymaybethe resultof a new
mutation.If it is a mutation,the risk of a furtheraffectedchild is negli-
gible.Mostcasesof chondroplasia aredueto newmutations.

Theoverallincidence
of autosomal
dominantdisorders
is 7 per1000livebirths.

Most important autosomal dominant diseases there

are:

1. Adultpolycystic kidneydisease- characterized by numerousbilateral

cysts,whichbecomesclinicallymanifestedbetween30 and50yearsof
age,thoughthe geneticdefectis presentat birth; deathusuallyoccurs
at aboutage50.
2. Familialhypercholesterolemia - is connectedwith geneticdefectof
receptorsfor low-densitylipoprotein(LDL),whichresultsin decreased
transportof LDL into cells dueto hyperchlolesterolemia and in earlier
onsetof atherosclerosis.
3. Hereditaryhemorrhagictelangiectasia(Osler-Weber-Rendu syn-
drome)is characterized by,recurrent hemorrhage from theskinandmu-
cousmembranes with localizedtelangiectasesin them.
4. Hereditaryspherocytosis is connectedwithinheriteddefectsof erythrocyte
membrane - associated skeletalproteins,producinghemolyticanemia.
General nosology, etiologyand pathogenesis Unit I I 95

5. Marfan ' s syndrome is a defectof connectivetissue causedby a de-

ficiencyof fibrillin, a glycoprote in substrate of microfibrils.This syn-
dromeis charac terizedby defects:
• In skeletalstructures-the patientsaretall andthin with abnormallylong
legsandarms, spider-likefingers(arachnodactyly) ,.
• In visualorgans- dislocationof the ocularlens (ectopialentis) is fre-
quent.
• In cardiovascular systemcan be aorticdilation with resultantaneurism
of the aorta, aorticvalvularinsufficiency.Lossof connectivetissue sup-
port mayleadto mitralvalveprolapse .
6. Neurofibromatosis (vonReckling-Hausen disease)- characterized by
multipleneurofibromas in skin, bones, nerves.
7. Tuberous sclerosis - is characterized by seizures,mentalretardation
dueto presenceof glial nodulesanddistortedneuronsof the cerebral
cortex.
8. VonHippel-Lindau diseaseconnectedwith defect of the short arm of
chromosome 3. Manifestedin hemangioblastoma or cavernousheman-
giomaof the cerebell um, brainstem or retina; adenomasand cystsof
the liver, kidney,pancreas.

Autosomal recessive disorders . Thesedisordersmanifestthemselves only

whenan individualis homozygous for the diseaseallele; i.e. both chromo-
somescarrythe mutatedgene.In this casethe parentsare generallyunaf-
fectedhealthy carriers (heterozygous for the diseaseallele).Thereis usually
no family history,althoughthe defectivegeneis passedfrom generationto
generation. The offspringof an affectedpersonwill be healthyheterozygotes
unlesstheother parent is alsoa carrier. If carriersmarry,theoffspringhavea 1
in 4 chanceof beinghomozygous andaffected , a 1 in 2 chanceof beinga car-
rier, anda 1 in 4 chanceof being geneticallynormal.Consanguinity increases
the riskof twocarriershavinga childwhohasa 25 % chanceof beingaffected.
Theclinicalfeaturesof autosomalrecessivedisordersare usuallysevere;pa-
tientsoftenpresentin the first fewyearsof lifeandhavea highmortality.
Inthis group maydevelopmentintermediate inheritance diseases . In this
situationthe possessionof a singlerecessivemutantgeneleadsto detectable
 96 I Part I Generalpathophysiology

abnormalities but lessseverethanin homozygotes. Examplesinclude:Sickle-

cell trait,thalassaemia minor,carriersof the phenylketonuria
gene.

The most important autosomal recessive diseases

are the following.

1. Cysticfibrosis- abnormalion transportprotein.

2. Sickle-cellanemia- abnormalhemoglobin.
3. Thalassemias - abnormalhemoglobin.
4. Glycogenosys - enzymedeficiency .
5. Mucopolysaccharidoses - enzymedeficiency.
6. Wilson'sdisease- copperaccumulation.
7. Lysosomal storagedisease- deficiencyof a specificsinglelysosomal
enzyme,resultingin anaccumulat ion of abnorma l metabolicproducts.
8. Tay-Sachs disease(amaurotic familialidiocy)- causedbya deficien-
Gy of hexosaminidase A with consequentis the mostcommonform of
gangliosidosisin neurons ; characterized by CNSdegeneration, severe
mentaland motordeterioration , blindnessanddeathbefore4 yearsof
age.
9. Gaucher disease- disorderof lipid metabolism causedbya deficiency
of glucocerebrosidase, which resultsin an accumulationof glucocer-
ebrosidein cellsof the mononuclear phagocyticsystem.
• TypeI (adultGaucherdisease)characterized by hepatosplenomega ly,
erosionof the femoralheadand of the longbonesand mild anemia.A
normal lifespanis possible.
• TypeII (infantileGaucherdisease)is associatedby severeCNSdisor-
dersandresultsin deathbefore1 yearof age.,
• TypeIll (juvenileform) is characterized by both the brainand viscera
disorders.Onsetis usuallyin earlychildhood.
10. Niemann-Pick disease- causedby deficiencyof sphingomyelinase
with consequentsphingomyelinaccumulationin phagocytes.Such
"foamy histiocytes"proliferatein the liver, spleen,lymph nodesand
skin.Deathoccursby 3 yearsof age.
Generalnosology,etiologyand pathogenesis Unit l I 97

11. Phenylketonuria (PKU)- causedby mutationof the phenylalanine hy-

droxylasegene,dueto highserumconcentrations of phenylalanine de-
velops.Phenylketoneandphenylacetic acidaccumulates . Clinical mani-
festationis characterized by mental retardation,seizures, decreased
pigmentation of hairand eyes(blondand blue- eyedchildren), musty
bodyodorfrom phenylaceticacid in urineandsweat.Canbe success-
fully treatedby a phenylalanine
- freediet.

Sex-linked single-gene disorders.Genescarriedon the X chromosome

aresaidto beX-linkedandcanbedominantor recessivein the samewayas
autosomalgenes.As femaleshavetwo X chromosomesthey will be unaf-
fectedcarriersof X-linkedrecessivediseases.However,since maleshave
just one X chromosome, any deleteriousmutationin an X-linkedgenewill
manifestitselfbecausenosecondcopyof the geneis present.
X-linkeddominant disorders. Theseare rare.Vitamin0-resistantrickets
is the best-knownexample.Femaleswho are heterozygous for the mutant
geneandmaleswhohaveonecopyof the mutant
X-linkedrecessive disorders.Thesedisorderspresentin malesandpres-
ent only in (usuallyrare)homozygous females.X-linkedrecessivediseases
aretransmittedby healthyfemalecarriersor affectedmalesif theysurviveto
reproduce.An exampleof an X-linkedrecessivedisorderis haemophiliaA,
whichis causedby a mutationin the X-likedgenefor the essentialclotting
factor, factor VI11.It hasrecentlybeenshownthat in 50 % of casesthereis
an intrachromosomalrearrangement (inversion)of thetip of the longarm of
the X chromosome(onebreakpoint beingwithinintron22 of the factor VIII
gene).
In the offspringfrom a carrierfemaleanda normalmale:
• 50 % of thegirls will becarriersastheyinherita mutantallelefrom their
motherand the normalallelefrom their father;the other 50 % of the
girls inherittwo normalallelesandarethemselvesnormal
• 50 % of theboyswill havehaemophilia as they inheritthe mutantallele
from their mother(andtheY chromosome from theirfather); the other
50 % of the boyswill be normalas they inheritthe normal allelefrom
theirmother(andtheY chromosome from theirfather).
 98 I Part I Generalpathophysiology

Themaleoffspringof a malewith haemophilia anda norm,.;femalewill not

havethe diseaseas they do not inherit his X chromosome.However,all the
femaleoffspringwill becarriersastheyall inherithis X chromosome.

The most important X-linked recessive diseases are

the following:

1. Hemophilia A - bleedingtendencydueto clottingfactor VIII deficiency .

2. Hemophilia B - bleeding tendencydueto clottingfactorX deficiency.
3. G-6-PDdeficiency- attacks of hemolyticanemiaaftercertaindrugs.
4. Duchenne musculardystrophy - progressivemuscleweaknessdueto
dystrophicdeficiency.
5. X-linked(Bruton)agammaglobulinemia - decreasedgammaglobu-
lins dueto B-cellmaturationfailure.
6. X-linkedichthyosis - permanently thick, scalyskin dueto steroidsul-
phatasedeficiency.

Sex-limitedinheritance.Occasionally a genecan be carried oh an auto-

somebut manifestsitself only in onesex.Forexample, frontalbaldnessis an
autosomaldominantdisorderin malesbut behavesas a recessivedisorder
in females.

3. Non-Mendelian disorders
Althoughdisordersresultingfrom single-genedefectsthat demonstrate
Mendelianinheritanceare perhapsbetterunderstood , it is now clearthat a
significant numberof single-genediseasesalso exhibitdistinctly non-Men-
delianpatternsof inheritance.Amongtheseare such disorders that result
from tripletrepeatexpansions withinor nearspecificgenes(e.g., Huntington
diseaseand fragile-Xsyndrome); a collectionof neurodegenerat ive disor-
ders, such as Leberhereditaryoptic neuropa t hy (LHON), that resultfrom
inheritedmutationsin the mitochondria l DNA; anddiseasesthat result from
mutations in imprintedgenes(e.g., Angelman syndromeand Prader-Will i
syndrome).
 Generalnosology,etiologyand pathogenesis Unit I I 99

Sucha examplefragileX-associated mentalretardation syndrome pro-

ducesa-uniquecombinationof phenotypic featuresthataffectthecentralner-
voussystem,thetestesandthe cranialskeleton.
In some respec ts, fragile X-associatedmentalretardationsyndromeis
similarto othergeneticconditionscausedby X-linkedmutations- affected
areimpaire d moreseverelythanaffectedfemales,andthe conditionis never
transmittedfrom fatherto son.
This artificialpedigreeof the syndromeshowsthe each individualwill
manifestphenotypicfeaturesof the condition(penetrance) . Penetrance in-
creaseswith eachsuccessive generation
owingto the progressive expansion
of a triplet repeatelement.Expansionis dependenton maternalallele;thus,
daughtersof normaltransmittingmalesarenon-penetrant.

4. Multifactorialandpolygenic disorders
Manycongenitalabnormalities , especiallymalformationscannotbe ex-
- plainedon the basisof singlegeneinheritance.It is assumedthat thesede-
fectsariseby virtueof the additiveeffectof multipleminor or 'weak' gene
disturbances.Whetheror not theselinkedblocksof genes(polygenes)are
expresseddependsupon the extentto which they are dilutedby blocksof
normalgenesandthe interplayof environmental factors.Mendelean andsex-
linkedsingle-gene disordersare the resultof mutationsin a proteincoding
sequence.Thesemutationscan havevariouseffectson the expressionof
the gene, but all causea dysfunctionof the proteinproduct.Characteristics
resultingfrom a combinationof geneticand environmental factorsare said
to be multifactorial;thoseinvolving multiplegenescan also be said to be
po/ygenic.Measurements of most biologicaltraits showa variationbetween
individualsin a population.This variabilityis dueto variationin geneticfac-
tors andenvironmental factors.Environmental factorsmayplayanimportant
partin determining somecharacteristics, suchas weight,whilst otherchar-
acteristicssuchas heightmaybelargelygenetically determined.Thisgenetic
componentis thoughtto bedueto the additiveeffectsof a numberof alleles
at a numberof loci, manyof whichcanbe individually identifiedusingmo-
lecularbiologicaltechniques , for examplestudyingidenticaltwinsin different
environments .
 100 I Part I Generalpathophysiology

Onesuch conditionthat has beenstudiedis congenitalpyloric stenosis .

This is most commonin boysbut if it occursin girls the latterhavea larger
numberof affectedrelatives.This differencesuggeststhata largernumberof
the relevantgenesare requiredto producethe diseasein girls than in boys.
Most of the importanthumandiseases,suchas heartdisease , diabetesand
commonmentaldisorders,aremultifactorialtraits (Table7).

Table7. Examples
of disorders
thatmayhavea polygenic
inheritance
,-
•-- ·n<ar
.,
-:a.-_, ,, ,,i;··~:··.- 1
.- .-

Disease ;~(%) 'i •,. ·-

11
• ,_ e '~- r ' -.-~ii:-:,,i
-- -~ '

Hypertension 5 62
Asthma 4 80
.

Schizophrenia 1 85
Congenital
heartdisease 0,5 35
Pyloricstenosis 0,3 75 . ..
Cleftpalate 0,1 76

* Percentage
of thetotalvariation
of a traitwhichcanbeattributed
to geneticfactors.

The role of body co nstitution (somatotype)

in pathology
Theconstitutionor somatotypeis an unifiedcomplexof morphological, func-
tional, psychologicalpeculiaritiesbeingformedonthe hereditarybasisunder
the influenceof the environmental factors.
Absolute constitutionalmarkersare: histocompatabilityantigens,blood
groupandhand'sdominance .
Relativeconstitutional markersare: high nervousactivity type, body
shape.
Generalnosology, etiologyand pathogenesis Unit I I 101
Theconstitution determines the individualreactivity andadaptationa l pos-
sibilityto theenvironment andpathological predisposition to certaindiseases.
Theconstitutionplaya keyrole in pathogenesis of manyvariousdiseases
(for example,tuberculosis,obesity,hypertension, bronchialastmaand oth-
ers).
At first constitutiondescribedHippocrates. Firstclassificationby Hip-
pocrate's includedthreetypes of constitution:Phtysic,Athletic, Apoplec-
tic.
Then Hippocrate 's describedsecondclassificationdue to temperament
andsocialbehavior.Thisclassification includefour types:
A. Choleric
B. Phlegmatic
C. Sanguine
D. Melancholic

Eachinnateconstitutionhasa different mixtureof the four elementsand

four humours.
Whenthereis a predominance of the bilioushumourthis makesthe dry
andhotcholeric temperament.
A predominance of the phlegmatic humourmakesthe moist and cold
phlegma tic temperame nt.
A predominance of the sanguine bloodhumormakesthe hot and moist
sanguinetemperament.
A predomi nanceof the atrabilemakesthe cold anddry melancholic tem-
perament.
Eachof thesefourtemperaments is associatedwith its ownsphereof influ-
encein the constitution.
Thecholeric temperament is associatedwith the liver, gall bladder,diges-
tive andeliminativesystems;
Thephlegmatictemperamentis associated withthe brainfluids,lymphand
genito-urinarysystem; ·
Thesanguinetemperament relatesto the heart, bloodandarteries;
The melancholic temperamentis associatedwith the nerves,lungs and
spleen.
 102 I Part I General pathophysiotogy

Morphological classification by Sigaud- oneof the mostpopular mor-

phologicalconstitutionis beingformedthroughoutall life, butwill bechanged
bythe processof training. Thisclassification
includefour types:
A. Respiratory type
8. Digestive
C. Muscular
D. Cerebral

Classificationby Kretschmer . Basisof theseclassificationnot only mor-

phological peculiaritiesbut specific charactertraits, psychicsand tempera-
mentwith the mentaldiseasemorbidity.Amongthe schizophrenics onecan
meetasthenictypemoreoftenthenothertypes, whileepilepticsencountered
mainly amongindividuals of athletic constitution, pyknictypeis spreadamong
thosepatientswho suffermaniacal-depressive psychosis . Thisclassification
includethreetypes:
A. Asthenic ( Hypostenic)
8. Athletic(Normostenic)
C. Picknic(Hyperstenic )

Classification
by 8ogomolets. A basisof theseclassificationis structural
and functionalpeculiaritiesof the connectivetissueas activemesenchymal
system,whichplaysthe main rolein reactivityof the organism.
A. Asthenic
8. Pastly
C. Fibrotic
D. Lipomatous

ClassificationbyPavlov.Dueto 1-st or 2-nd signal nervous system.Rea-

soning type with prevalence1-st signal n.s.; artistictype is predominated
2-ndsignalsystem. This classification
includethreetypes:
A. Reasoning type '
8. Artistictype
C. Mixtype
Generalnosology,etiologyand pathogenesis Unit I I 103
Classification bythetypeof vegetative nervous system.This classifica-
tion include two types:sympathicotonic andvagotonic .
In peoplewith sympathicotonic type of constitutionprevalencetonus of
sympatheticpart of the vegetativenervoussystem. This type characterized
by pale, dry skin, cold extremities , modulatecoretemperature,predisposing
to tachycardia,weaknessof the sleep-waking cycle(tendencyto drowsiness ,
nightterror), very high levelsensitivityto noise, sun light, electromagnetic
wavesetc.In peoplewith vagotonic(parasympathetic) constitutionhavebeen
seencoldwet skin, hypersalivation, bradycardia, hypotension,asthenia,ten-
dencyto depressionandlossof conciousness.
Thestudyof the mostvulnerablesidesof constitutionmakesit possibleto
prognosistraumaticconsequences , to determinethe diseasepredisposition ,
to prognosisthe diseasecourse,to havean individualapproachto the treat-
mentcourse.
Abnormal , so calleddiathesis
ity of constitution , is characterizedby patho-
logicalreactionson physiologicalagent.
Classification of diathesisincludesometypes:
Hemorrhagic - characterizedby hemorrhagicreactionto physiological
(non-pathogeno us) factors.
Thymico -lymphatic- characterizedby enlargementof lymphatic nodes,
muscularatrophy, individualpale, pastous , predisposingto autoallergicdis-
ease,lymphocytosis , anginaandotherinfectiondiseases.
Neuro -arthritic- predisposingto arthralgia,arthritis, rheumatism,obe-
sity, gout,psychicdisease .
Edematic - characterized byedemareactionto differentenvironment factors.
Asthenic - expressedin hypodynamia , hypotonia.
And the last very importantaspectof the diseasesdevelopment. This is
dependent on the pathology,on the ageof people.At different agesdifferent
diseasesmoreoftendevelop
Frombirth to 14 years moreoftendevelopment congenitaldisorders,aller-
gy, infections,cancer(leukemia,tumor, medulloblastoma, retinoblastoma) ,
accidents , diabetes (juvenile).
From15 to 30 years - allergy (asthma),endocrinepathology,accidents
(suicide),venerealdiseases.
 104 I Part I Generalpathophysiology

From30 to 40 years - ulcer,hypertension, breastcancer,homicide,sui-

cide,complicationsof pregnancy, alcoholism . .
From40 to 60 years - heartdisease(hypertension, rheumatic, infarction),
kidneydisease(glomerulonephritis), liver disease(cirrhosis), cancer(lung,
colon, breast, ovary).
From60 to 80 years - cancer(leukemia,lymphoma,prostate),dementia
(Alzheimer's
, Parkinson's),
osteoporosis , infections,cardiovascular diseases.
 MECH AN ISMS
Unit2 OFTISSUE
AND CELLULAR INJURY

Chapter 4. TypicalDisorders
of the Peripheral Blood Flow

Cardi ovascularSystem.Theleft ventricleof the heartpumpsbloodthrough

the arterialbloodvessels of the systemiccirculation to the peripheral capil-
laries.Thebloodis returnedto the right side of the heartvia the systemic
veinsandis puf!1ped bytherightventricleintothelungs, whenceit is returned
to the left sideof the heart(pulmonary circulation
).
Thetotalbloodvolumeamountsto about4.5-5.5 L (approx.6-8 % of
the bodyweight),of whichroughly80 % arein the systemicveins,the right
sideof the heart, andin the vesselsof the pulmonarycirculation collectively
knownas the low-pressu re system . Lessthan20 % of bloodvolumeare in
the arterial high-pressure system. Cardiac outputis the volumeof blood
ejectedby eachventricleperunitof timeandcanbecalculatedfrom the heart
ratex strokevolume:at restit amountsto (70/minx 0.07 L) = about5 Umin.
Thecardiacoutputcanbe increased to manytimesthis valueby increased
heartrateandstrokevolume.
In the systemiccirculation the bloodleavesthe left ventriclein the aorta
andflows intothe arteries,whichdivideandsubdivideto form the arterioles
via whichthe bloodreachesthe capillaries.Thesereunite to form venules,
from whichthe bloodis passedon to theveinsand reentersthe rightatrium
of the heartviathesuperiorandinferiorvenaecavae.
 106 I Part I Generalpathophysiology

On the way, the mean bloodpressure drops from about 13.3 kPa(100
mmHg)in the aortato about 0.25 to 0.5 kPa (2 to 4 mmHg)in the venae
cavae.This meanpressuredifferencebetweenthe aortaandthe right atrium
(roughly13 kPa)andthe totalperipheralresistance (TPRJin the systemic
circulationdeterminethe flow rateof the blood,that is, the cardiacoutput.
Thearteriolesandsmallarteriestogetheraccount for about50% of the
TPR,so that herethe blood pressureundergoesa steepdrop (resistance
vessels). Changesin the arteriolar resistancewill thus considerably
affectthe
TPR.Thewidthof the individualarterioles,andespeciallyof theirprecapillary
sphincters , alsodeterminesthe bloodflow in the capillary network(the size
of the capillaryexchange area).
Resistancevessels play a centralrole in the regulation of the systemic
bloodpressureand bloodflow in microcirculation.Peripheral resistance is
the centralfactor of the regulation of the systemicbloodpressuretogether
with: cardiacoutputand totalbloodvolume . Atthesametime,sametime
resistancevesselstake part in the regulationof bloodflow in microcircula-
tion.
Microcirculationincludessome groups of vessels.Anatomical classifi-
cation hasa differencesfrom functionalclassification,which is more often

Table8. Compo
nents of microcirculation

Anat,omlcal
cta~ tton
Arterioles Resistance
vessels
Precapillaries.
Precapillary
sphincters
Capil
laries Exchange
vessels
Postcapillaries Reservoir
vessels
Venules · (capacitance
vessels)
Smallveins '
Arteriolovenu
laranastomoses
Lymphatic
ciculatory
system Resorptive
vessels
Mechanismsof tissueand cellularinjury Unit 2 I 107
usedby physiologyand pathophysiology (Table8). Althoughthe radiusof
the capillariesis still smallerthanthat of the arterioles, their total number
is so largethat theycontribute only 27 % to the TPR.Theresulting drop in
bloodpressurealongthecapillariesis largelyresponsible for the bidirectional
exchange offluidbetweenbloodandinterstitialspace.Onaccountof the low
velocityof flow in thecapillaries(0.3 mm/s),theirverylargetotal surfacearea
(about300 m2), and extremelythin and thereforepermeable walls,they are
especiallysuitablefor theexchange of solutesandfluids.

Capillary Exchange. There are 3 main proc es ses in

capillaries:

• filtration;
• diffusion;
• microvesiculartransport.

Filtration . Cell nutrition is effectedvia the blood capillaries.Waterand

substances dissolvedin the plasma(exceptbloodcellsand largeproteins)
canfreelycrossthe thin capillarywallsthroughpores(8 nm diameter).Each
day, a total of roughly20 L of fluid (0.5 % of plasmaflow) are filtered by
the nonrenalcapillariesinto the interstitialspace. About 18 Lid reenterthe
capillariesby resorption-, the remaining2 L/d returnto the bloodstreamvia
the lymph .
Thedrivingforcesforfiltrationandresorption at the capillarywall arethe
differencein hydrostaticpressure(HP)and the differencein oncoticpres-
sure(OP)betweenthe insideand outsideof the capillary (Starlinghypoth-
esis)(Fig. 5). Hydrostaticpressurein capillaryis the force that drivesfluid
throughthe capillarywall into the interstitialspace(hydrostaticpressurein
interstitialtissuenormallyis very low). Oncoticpressurein capillaryis the
forcethattendsto drawfluidfrom interstitialtissueintothe vessels(oncotic
pressurein interstitialtissueis verylow). Oncoticpressureis exertedby pro-
teins presentin plasma . Normal proteinsconcentrationis 60-80 g/L, from
whichdepended oncoticpressure near20-25 mm Hg.
 108 I Part I Generalpathophysiology

Normal A V

HP 35 mmHg 15 mmHg

OP 25 mmHg 25 mmHg

- -- -- -+ Lymphatic
utflow
----- - --- -- -- -

Fig.5.Normalfluid exchange
inmicrocirculation

Thedrivingforce for filtrationamountsto about3.9-4.5 kPa(30-35 mm

Hg)at the arterialendof the capillaries,droppingto roughly 1.9 kPa(15 mm
Hg)at the venousend.This is opposedby the oncoticpressuredifference , of
about2.7-3.3 kPa(20-25 mm Hg) in most organs.The differencebetween
hydrostaticpressureandoncoticpressureat the arterialendof thecapillaries
is 35 minus25 = 10 mm Hg (filtrationoccurshere),whereasat the.venous
endit is 15 minus25 = -1 0 mm Hg (resorptiontakesplace).
Diffusion.Differenceof partialpressures of gasesresultsin gasexchange
betwee n capillariesandtissue.In this way,02 leavesthecirculatingblood, and
CO2 diffuses,in the oppositedirection (Fig.6).

NL
A V

p02 100mmHg 40 mmHg

pC02 40 mmHg 45-50 mmHg

Fig.6. Normalgasesexchangein microcirculation

Mechanismsof tissueand cellularinjury Unit 2 I 109
Microvesicular transport. Microvesiculartransportis activetransportof
macromolecules (i.e.fibrinogen) throughthe endoteliocyte cytoplasm.
Bloodflow throughthe microcirculationdependson differentregulatory
factors.Thisneurogenic and humoralfactorsmayleadto the vasocons tric-
tion or vasodilatationof the resistancevessels(Table9). Vasodilatationand
vasoconstrictionmaydevelopat onthesystemicor locallevel.Fromsystemic
or localconstrictionor dilationtheredependsystemicor localconsequences
of thesereactions(Table10).Sometypicaldisturbances in microcirculation
maydevelop.

Table9. Factorsof resistancevessels(microcirc

ulationbloodflow)regulation.
..
:,'\ }h,'
~~j.~ I '(,-11
~'°J\<'
~~-ii
➔ --~....·~-~ ,--•~"
·
rllti 'l--,s
tt.·.~
..
•

,,
,;': t
,..;.
ilvaiodllabda,ls .· '
- -~ • ~

Basal Contractile
automatism
of
component smooth- muscular
cellsof
(myogenic) vessels
Neurogenlc SympathellcvasoconstrictorsSympathetic
vasodilators
(mediator
-
(mediator
- epinephrine epinephrine
actingonbeta-2receptors)
;
(adrenaline),
norepinephrine
, parasympathetic vasodilatators
actingona/pha-1receptors) (mediator
- ocetylcholine)
Humoral Catecholamines, Kinines
ongiotensin
II,vasopressin; histamine
,
endothelins
- paracrin prostaglandins;
peptides
of endothelium; leucotriens.
someleukotriens.
Vasoactive Carbon dioxide;
products lacticacid;
of a tissue cationsofpotassiumandhydrogen;
exchange productsofATP-ADP hydrolysis,
odenosine;
nitrogenoxide(NO)
.
 110 I Part I Generalpathophysiology

Table1o.Pathological vessels
situationswhichdependonthe resistance

Vasoconstriction Hypertension lschemia

Vasodilatation Hypotension Arterialhyperemia

Hyperemia - an excessamountof bloodin organsandtissues.

Arterialhyperemia (activehyperemia) - localincreasingof bloodinflow
from arterialvesselsto microcirculation.
Congestion (passivehyperemia,venousheperemia) - localor systemic
decreasing of bloodoutflowfrom microcirculation.
lschemia - limitingor completestop of arterialbloodinflowto microcir-
culation.
Stasis- stopof the bloodflow in microcirculation.
Thrombosis - formationof clotson the internalsurfaceof vesselsin living
organism.
Embolism - carry by the bloodvariosforeignbodies(emboli)from the
placeof theirformationto the placeof blockingbloodflow.

Arterial hyperemia
Arterialhyperemiais an activeprocessresultingfrom augmented tissuein-
flow becauseof arteriolardilation, as in skeletalmuscleduringexerciseor at
sitesof inflammation.Theaffectedtissueis redderbecauseof the engorge-
mentof vesselswith oxygenated blood.

Causes:

• Mechanical (friction)
• Physical(t atmosphere
0
, pressure,UVradiation)
Mechanisms
oftissueandcellularinjury Unit 2 I 111

• Chemical(acidsandalkalis)
• Biologica
l (microorganisms)
• Social(emotions)

Types:

1. Physiological
• Organhyperfunction (muscle,intestine
, gland)
• Thermoregulation (skin)
2. Pathologic
• "Basic"
• Inflammation andinfection
• Allergicreaction
• Fever(brain)
3. Adaptive(postischemic)
4. Vacate(cupping-glasses)

Mechanis
ms:

• Neurotonic (stimulationof b-adrenoreceptors

, M-cholinoreceptors)
• Neuroparalytic (blockageof a1-adrenoreceptors)
• Humoral (actionof kinines,histamine,
prostaglandines,
ATP,lactate,e.t.c.)

Howprocessesin capillariesarechangedin arterial hyperemia?

Filtration. Increasedinflowto microcirculationresultsin increasedhydro-
static pressurein botharterialand venousend of capillary . So, force that
drivesfluid throughthe capillarywall intothe interstitial spaceis higherthen
normally.Butfluid isn't accumulated in interstitialtissue,becauseit is drained
by increased lympha tic outflow(Fig.7).
Diffusion . Muchoxygenatedbloodand its fastflow leadsto higherpartial
pressureof oxygen in venousblood.
Microvesicular transport isn't changed.
112 I Part I General
pathophysiok>gy

A V

HP 45 mmHg 25 mmHg
OP 25 mmHg 25 mmHg

i Lymphatic
outflow

Fig.7. Microci
rculatoryfluid exchangein arterial
hyperemia

Clinical features:

• Arteriesdilation, pressureand arterialpulseincreaseFunctioningarter-

iescountincrease
• Bloodflow speedincrease
• Decreasein the arterio-venous oxygendifference(dueto the increaseof
oxygen in venousblood)
• Reddening, enlargement andtemperatureincreaseof the organ
• Increaseof skinturgor
• Lymph-formation acceleration

Consequences:

Favorable
- intensificationof metabolismand organ'sfunction (usefor
treatment- massage,physiotherapy).
Unfavorable
- raptureof the vesselsandhemorrhage.
Mechanismsof tissueand cellularinjury Unit 2 I 113
Congestion
Congestion is a passiveprocessresulting from localor systemicdecreasing
of bloodoutflowfrom microcirculation . Congestionand edemacommonly
occurtogether,primarilysincecapillarybedcongestioncan result in edema
dueto increased fluidtransudation
.

Causes:

1. Externalsqueezing:
• Seam(scar)
• Tumor
• Ligature
• Edema
2. Internalocclusion (thrombus, embolus)
3. Rightventricleinsufficiency
4. Smallcircleof circulationandlungsdysfunction

Howprocesses in capillariesarechangedin congestion?

Filtration.Decreased outflow from microcirculation resultsin increased
hydrostatic pressurein venousend of capillary.So, force that drivesfluid
throughthe capillarywall into the interstitialspaceis positivethere(Fig.8).
Thereis't reabsorption of extrafluid from interstitial tissue.Fluid is not drain-
agedby lymphatic outflowbecauseof reflectorspasmof lymphvesselsin
response to increasedhydrostaticpressurein veins.Fluidaccumulates in in-
terstitialtissuecausing edemaformation.Then, compensatory decreaseof
inflowto microcirculation becauseof arteriolospasm develops.It resultsin
hypoxiaof tissue.
Diffusion. Decreaseoutflowof bloodwith CO2 resultsin decrease of differ-
enceof pC02 in tissueandblood.It leadsto accumulation of carbondioxide
in tissue. Compensatory decreaseof inflow to microcirculatio n becauseof
arteriolospasm resultsin hypoxiaof tissue.
 114 I Part I Generalpathophysiology

A V

HP 35 mmHg 30 mmHg
OP 25 mmHg 25 mmHg

______ i Lymphaticoutflow
-- - -- - -- --- -- - Edema
development

Fig.8. Microcircu
latory fluidexchange
inconges
tion(venous
hyperem
ia)

Microvesicular is changedbecause
transport of ATPdeficitin hypoxiaand
furtherincreasedpermeability
of capillaries.

Features:

• Veinsdilation, winding, pressureincreaseandsubsequent permeability

increaseof the veinwall
• Edema
• Decrease bloodmovementin veins (grosshyperemia)
• Bloodflow speeddecrease
• Increasein thearterio-venous oxygendifference(dueto thedecrease
of
oxygenin venousblood)
• Cyanosis,enlargement andtemperature decreaseof the organ
• Lymphaticvesselssqueezing withthe edema ·
• Stimulatesconnective tissuegrowth(usedin trophicwoundstreatment)

Consequences:

• Dystrophicchanges
Mechanismsof tissueand cellular injury Unit 2 I 115
• Atrophy
• Excessive
growth of the connect
ive tissue,cirrhosis

lschemia

lschemia
- limitingor completestop of arterialbloodinflowto microcir-
culation

Causes of ischemia:

• Sympatheticvasoconstrictors (mediator-epinephrine (adrenaline),

act-
ing on alpha-1receptors)
• lowtemperature
• thrombosis , embolism
• occlusionof thearterial vessels (endarteritis
, atherosclerosis)
• extrinsic compression of a vessel(tumor, edema)

Local changes in ischemia

• decreaseof metabolicprocesses
• decreaseof functionalactivity
• painsyndrome
• atrophyof tissue,organ
• necrosis,infarction

Filtration. Decreased inflowto microcirculation

resultsin decreasein fluid
exchange in capillaries.
Tissues sufferfrom nutrientsdeficit.
Diffusion. Lessoxygena ted bloodcomesto tissue. Tissuesuffer from cir-
culatory hypoxia.
Microvesicular transport is decreased
.
116 I Part I Generalpathophysiology

Consequences:

Dependon the followingfactors.

1. Metabolicactivityof tissues(brain,myocardium).
2. Specificactivityof tissues.
3. Durationandlevelof ischemia.
4. Development of collateralcirculation(vascular
occlusion)
(Fig.9).

Hypoxia

Anaerobic
glycolysis

~ ~
Accumulation
of metabolic
products
• carbondioxide • -kinines
' . •·'
• lacticacid • histamine .
• cationsofpotassiumandhydrogen • prostaglandlils
·''
• Products ofATPADPhydrolysis, • leUC<JtiienS
adenosine
• nitrogenoxide(NO)

Fig.9.Mechan
ismsofcollateralcircu
lationactivation

Vulnerability
tohypoxia dependson metabolicandspecificactivityof tis-
sues.Neuronsundergoirreversibledamageafter3 to 4 minutesof ischemia;
Mechanismsof tissueand cellularinjury Unit 2 I 117
myocardial cellsdieonlyafter20to 30 minutes. In contrast,fibroblastswithin
ischemicmyocardium areviableevenaftermanyhours.
Collateral
circulation(vascularocclusion)have threetypes:
• Absolutelysufficient(muscles , skin)
• Rathersufficient(intestine)
• Absolutelyinsufficient(brain, myocardium)

lschemia-Reperfusion Injury
Whenthe periodof ischemiais of short duration, reperfusion with resupply
of oxygenrestoresthe structuraland functionalstate of the injuredcells.
Whenischemiais of longerduration,thenratherthanrestorationof structure
andfunctionof cell, reperfusionparadoxall y canincrease in damage called
reperfusioninjury.Themainproposedmechanismin ischemia-reperfusion
injury is that upon reoxygenation there is increasedgenerationof oxygen
free radicalsor activatedoxygenspecies(superoxide,hydrogenperoxide,
hydroxylradicals) . Reactive oxygenspeciesin postischemictissuecan be
derivedfrom incompletereductionof oxygenby mitochondriaand produc-
tion of superoxideion by xanthineoxidase(from vascularendothelium).
Alternatively,duringreperfusionactivatedoxygenspeciesmaybegenerated
byadhesionandactivationof circulatingneutrophils . Besides,ischemiaalso
damagesthe cellularantioxidantdefensemechanismfavouringfurther ac-
cumulationfree radicals.If a significantpartof the organismsufferedfrom
ischemiafor long,after reperfusionit canleadto shockdevelopment.

Embolism
Occlusionof a vesselby materialtravellingin the circulationis termed"Em-
bolism ".
An embolus is a substancethatcirculatesfromonelocationin the bodyto
another,throughthebloodstream. Althoughmostemboliarebloodclotsfrom
a thrombus,theymayalsoconsistof piecesoftissue , anair bubble, amniot-
 118 I Part I Generalpathophysiology

icfluid,fat, bacteria
, tumorcells,or a foreignsubstance
. Themostcommon
typeis dueto fragmentsof circulatingthrombus,termedthromboemboli.

There are two main types of thromboembolism:

• pulmonarythromboembolism;
• embolismof systemiccirculation.

Pulmonary thromboembolism
Embolithatoriginatein thevenouscirculation,suchasfrom deepveinthrom-
bosis,travelto the right side of the heartto the pulmonarycirculationand
eventuallylodgein a capillary,causingpulmonaryinfarctionandevendeath.

Embolism of systemic circulation

Most emboliin the arterialsystemoriginatefrom the left side of the heart
from conditionssuchas arrhythmias,valvularheartdisease,myocardialin-
farction,heartfailure,or endocarditis.Arterialembolimaylodgein organs,
suchasthe brain,kidneys,or extremities, causingischemiaor infarction.The
mostcommonpreventable causeof deathin hospitalpatientsis pulmonary
thromboembolism ..
Thetwo mainconsequences of embolization to the pulmonaryarterialtree
areanincreasein pulmonaryarterialpressure(whichputsa strainonthe right
sideof theheart)andischemiaof thelung, withventilatedareasnotbeingper-
fusedby blood.Theclinicalconsequences of pulmonaryembolismdependon
theextentof the pulmonaryvasculature blockageandthetime-scaleinvolved.
If 60% of the pulmonaryvasculature is suddenlyblocked,the heartcannot
pumpbloodthroughthe lungs.Thereis cardiovascular collapse,with electro-
mechanical dissociationof the heartas it continuesto beatbut developsno
output.Thispatternof blockageis knownasmassive pulmonary embolism.
Mechanismsof tissueand cellularinjury Unit 2 I 119
Causingrapiddeath,it accountsfor about5- 12 % of all casesof pulmonary
thromboembolism.
Accountingfor about1O% of all casesof pulmonarythromboembolism ,
majorpulmonary embolism occurswhenthereis blockageof middle-sized
pulmonaryarteries.Patientscommonlyexperiencebreathlessness. Infarc-
tion of lungdevelopsin onlyabout10 % of suchcases.It canleadto hemop-
tysis and, if adjacentto the pleura, pleuriticchestpain.It is not uncommon
for patientsto developa subsequentmassivethromboembolism if untreated.
In about85 % of all casesof pulmonarythromboembolism thereis block-
age of small peripheralvesselsby small emboli(minorpulmonary embo-
lism).Patientsmaybeasymptomatic or mayexperience breathlessness and
pleuriticchestpainas a resultof small infarcts.As with major pulmonary
embolism , it is not uncommonfor patientsto developa subsequent massive
thromboembolism if untreated.

Usual outcomes of tromboembolism:

• 70-80- fragmentation
or fibrinolysisoccurs
• 10-15 %- pulmonaryinfarcts
• 15 % - chronicpulmonaryhypertension
• 8-12% death

Embolismof materialotherthanembolusis lesscommon

• Tumorembolismis the way in which malignanttumors spreadfrom
the site of origin to distantmetastaticsites using the blood stream
route.Themalignanttumorinfiltratesthroughthewall of a bloodvessel
(usuallya venuleor vein)at the primarysite to occupythe lumen, and
clumpsof tumorcellsof varioussizesbreakoff and are carriedin the
venoussystemuntiltheyreacha vesseltoo smallto permitfurtherpas-
sage,thenimpactthereandoftengrowto producea distantmetastasis.
• Fat andbonemarrowembolusmay occurfollowingseverefracture
traumato bones.Fragments of fat released
fromtraumatized adiposities
in the fatty bonemarrowmayenterthe bloodcirculationthroughthin-
 120 I Part I Generalpathophysiology

walledveinstorn bythe fracturetrauma.Theypassthroughthevenous

systemto the rightsideof the heart,andthenvia pulmonaryarteriesto
the lungcapillarieswheresomearetrapped.
• Airembolism is usuallydueto accidentalpumpingof air intothevenous
circulationduringintravenousinjectionor transfusion.If largequantities
of air mixedwith bloodenterthe rightatrium,a bloodyfroth is formed
and the patientmay suffercardiacarrest.In deep-seadivers, inhaled
air maydissolveinto the plasmadueto the increasedpressureat great
depths,only to reforminto bubblesof gaswithinthe circulationif the
divercomesto the surfacetoo quickly.This decompression sickness
(knownto diversas "the bends") andtheembolization of the bubblesof
mainlynitrogengas mayoccludesmallvessels,leadingto widespread
anoxiaof tissues,andevendeath.
• Amnioticfluidembolismmayoccurrarelyduringchildbirth;someof
theamnioticfluid (containing
fetalcellsfromtheskinsurface)mayenter
the maternalcirculationthrough the exposedand bleedingplacentalbed
in the uterus.Thematerialpassesin the venouscirculationto the lung
capillariesandmaycauseacutealveolarwalldamageanddisseminated
intravascularcoagulation

Trombosis
A thrombusis a bloodclot, consistingof platelets,fibrin, and redandwhite
blood cells,that forms anywherewithin the vascularsystem, such as the
arteries,veins,heartchambers,or heartvalves.

Three conditions, known as Virchow's triad,

promote thrombus formation:

1. endothelialinjury, '
2. sluggishbloodflow,
• changesin laminarflow,turbulenceleadsfor arterialthrombosis
• changesto stasisof flow leadsfor venousthrombosis
Mechanismsof tissueand cellularinjury Unit 2 I 121
3. increased
coagulability.

Whena bloodvesselwall is injured,the endothelial liningattractsplatelets

andotherinflammatory mediators , whichmaystimulateclot formation.Slug-
gishor abnormalbloodflow alsopromotesthrombusformationby allowing
platelets
andclottingfactorsto accumulateandadhereto thebloodvesselwalls.
Conditions thatincrease
thecoagulabilityof bloodalsopromoteclotformation.
Theconsequences of thrombusformationincludeocclusionof the blood
vesselor theformationof anembolus(if a portionof a thrombusbreaksloose
andtravelsthroughthecirculatorysystemuntilit lodgesin a smallervessel).

Chapter 5. Hypoxia

Hypoxia(oxygenstarvation)- is a typicalpathologicalprocessthat mayoc-

cur whenthe bodyis deprivedof adequateoxygensupplyor dueto the lack
of oxygenutilizationthat resultsin the disturbanceof energymetabolismin
the organism.
Thereareseveralclassifications of hypoxicconditions.
Accordingto classification of hypoxiabasedon the causesof occurrence
and mechanisms of development all hypoxiacasesare dividedinto two big
groups:hypoxiascausedby exogenous reasonsandhypoxiascausedby en-
dogenous reasons.
Exogenous hypoxiahasanothernamehypoxichypoxia;it is causedby the
decrease of the partialpressureandpercentage of oxygencontentin inhaled
air. It is subdividedinto hypobaricandnormobarictypes.
Endogenous hypoxiais dividedinto 6 types:respiratory, hemic, circula-
tory, histotoxic , substrateandoverloadtypes.
Classification of hypoxiabasedonthetimeofappearance andduration of
hypoxia featuresincludesthefollowingtypes.
1. Fulminant(immediate) - endsup with the deathof organismaftersev-
eralseconds (histotoxichypoxiaduringcyanidepoisoning).
2. Acute- lastsfor severalminutes(cardiacarrest,respiratorystandstill).
 122 I Part I Generalpathophysiology

3. Subacute- lastsfor severalhoursor days(duringextremeconditions

andpathologies thatthreatenlife).
4. Chronic- lastsfor monthsandyears.

Classification
of hypoxiabasedon the prevalence of clinicalsymptoms
defineslocalandgeneralhypoxiaforms.
Classification
of hypoxiabasedon the severityof P.athological process
includes:a) mild;b) moderate;c) severe;d) critical(lethal)hypoxia .
Hypo xichypoxia hypobaric typedevelopsduringthedecrease of baromet-
ric pressurethat .is accompanied with decreaseof P02• Thisconditionleads
to the development of altitudeor mountainsickness.It commonlyoccursat
thealtitudesabovethan2,500 meters.
Mountainsicknessdevelopsafter gettingto high altitudesin mountains.
Thefactors contributingto mountain sicknessdevelopment are: low partial
pressureof oxygen,low barometricpressure , physicalloading, cooling,in-
creasedexposureto UV rays.
Altitudesickness
, also knownas acutemountainsicknessor altitudeill-
nessis a pathologicalconditionwhichis causedby acuteexposureto high
altitudes.It maydevelopin openedaircraftsor afterrapiddepressurization
of
closedaircrafts.Themainpathogenic factorsin this caseare:low barometric
pressureandlow partialpressureof oxygen

Normob a ric typ e of hypoxic hypoxi a occurs

a s a result of 0 2 perc e ntage in a ir d e crease
without ch a ng es of ba rometric a l pr e ssure.
It m a y d e ve lop :

• whenpersonsare situatedin small roomswith badventilation(eleva-

tors, mines, mineshafts);
• in divers,whenthereareproblemswith aqualungfunction;
• incorrectconductionof artificiallungsventilationduringsurgicalopera-
tions.
Mechanismsof tissue and cellularinjury Unit 2 I 123
Theleadingpathogen ic mechanisms of exogenoushypoxia(in spite of its
cause)are:low amountof oxygen and carbondioxidein the blood, distur-
bancesof acid-basebalance(ABB), lowABP.
Thestartingpoint of exogenoushypoxiais the decreasingof bloodoxy-
genconcentration.It resultsin low oxygensaturationof the hemoglobinand
disturbancesof gaseousexchange andmetabolicprocessesin thetissuesof
the organism.
Carbondioxideconcentration in the blood(hypocapnia) is reduceddueto
compensatory hyperventilation in the lungs.Hypocapnialeads to ABBdis-
turbancesthat manifestsas gaseousalkalosis. Lowcarbondioxideconcen-
trationin the bloodalso resultsin compensatory constrictionof brainand
heart bloodvesselsthat onlyworsensbrainandheartbloodsupplyand can
result in the disturbance s of vital functions,such as fainting of myocardial
ischemia.
Resp iratoryhypoxiarisesas a result of respiratory insufficiencydue to:
alveolar hypoven tilation, disturbances of lungsbloodsupply, disturbances of
gasesdiffusionin lungs.
Alveolarhypoventilat ion is a state in which there is a reducedamount
of air enteringthe pulmonaryalveoli. This mayoccuras a result of impaired
lungsfunctiondueto obstructiveand restrictiveviolationsof lungsventila-
tion.
Thereasonsof obstructiveviolationsare: edema , tumorsor foreign bodies
in the lumenof bronchiandbronchioles .
Thereasonof restrictiveviolationsis decreasedlungstissueelasticitydue
to chronicinflammatoryor sclerotic processesin the lungsand in the chest.
Alveolarhypoventilat ion mayalso be causedby the disturbancesof res-
piratoryregulation(toxic substances poisoning, brain traumaandothers).
Disturbances of lungsbloodsupplymayoccur as a resultof heartfailure,
decreased circulatingbloodvolume (afterbloodloss).
Disturbances of gasesdiffusionin lungs is observedin non-specific
chronicinflamma tory diseasesof the lungs, lungs edema .
Thedevelopment of respiratoryhypoxiais accompan ied by hypoxemia and
decreased hemoglobinsaturationwith oxygen.Bloodlevelof carbondioxide
is increase d - hypercapnia,pHof the bloodis low- acidosis.
 124 I Part I Generalpathophysiology

Circulatory hypoxia(or cardio-vascular

hypoxia)arisesduringthe distur-
banceof bloodcirculationdue to heartand vesselspathologythat leadto
insufficientbloodsupplyof organsandtissues.

The decrease of blood quantity that flows through

tissues per time unit can be caused by:

• decreaseof heart activity (infarction,cardiosclerosis,

myocarditis-
theseareall causesthat decrease thecardiacoutput);
• hypovolaemia - abnormallylow intravascular volumewith a decreased
volumeof circulatingbloodin the body(severebloodloss,dehydration
of the organismafterburns, cholera,vomiting,etc.);
• vasculardisordersthat manifestas low vascular tone(shock, collapse,
aldosteronedeficiency).

Circulatoryhypoxiamay be localdue to insufficientbloodsupplyof the

organor tissue(ischemia)or thedifficultyof venousoutflow(venoushyper-
emia,stasis)or systemic(causedbytheabovementionedreasons)
Thecharacteristicsof bloodgascontent arethefollowing:normal02 pres-
sureandits contentin arterialblood,the decrease of theseindicesin venous
blood.Usuallynon-gaseous acidosisdevelops asa resultof circulatory hypoxia .
Hemichypoxia(bloodhypoxia)maybe connectedwith hemoglobin(Hb)
quantityor inhibitionof its functions.It is observedduringanemiaof different
genesis(anemictype)andalsoduringpoisoningwith carbonmonoxide , ni-
trates,sulfadrugsandothersubstances. In this casewewill observeinactiva-
tiontypeof hemichypoxiawiththeacquiredhemoglobinopathies development.
Acquiredhemoglob inopathiesarecharacterized by formationof carboxy-
hemoglobinandmethemoglobin. Carboxyhemoglobin is a complexof hemo-
globinwith carbonmonoxide.Hemoglobin has200 timesgreateraffinityfor
COthanfor oxygen.Thegasis especiallydangerousbecauseit is not easily
detectedby humansenses.Carboxyhemoglobin is incapable of carryingoxy-
gen.Earlysymptomsof carbonmonoxidepoisoningincludedrowsiness and
headache, followedby unconsciousness, respiratoryfailure, anddeath.Sys-
Mechanismsof tissueand cellularinjury Unit 2 I 125
temichypoxiadevelopswhenthe hemoglobinis 20% to 30% saturatedwith
CO,andunconsciousness anddeathare likelywith 60% to 70% saturation.
Methemoglobin(MetHb)is hemoglobinhavingferric ion (Fe..•) instead
of ferrousion (Fe* ) and is incapableof carryingoxygen.Thereare a lot of
substances capableof iron oxidation:nitrites, nitrates, quinones , drugs (sul-
fanilamides,acetaminophen) , free oxygenspecies , andothers.Formationof
MetHbis reversible.Severityof hypoxiadependson percentage of MetHband
rangesfrom asymptomat ic (levelsof MetHbareabout5 % to 15%) to lethal
(levelsof metHbare about70% to 75%). Vulnerabilityto abovementioned
agentsdependsto a greatextenton the activityof enzymesfavoringconver-
sion of methemoglobin to hemoglobin.The most importantenzymeof this
groupis methemoglobin reductaseandit maybe hereditarydeficient.
Expressed symptomsof hypoxiain anemicpatientsdeveloponly during
considerable absolutemassdecreaseof erythrocytesor acutedecreaseof Hb
content in erythrocytes . Suchanemiasariseduringthe exhaustionof bone
marrowon the basis of chronic bleedings(tuberculosis,stomachulcer),
erythrocyteshemolysis(during hemolytic toxine poisoning, severeburns,
malaria), duringerythropoiesisdepressionby toxic factors (lead,radiation,
deficiencyof ironandvitamin 812), etc.
The indicesof gasesin the bloodarethe following:arterialand venous
hypoxemia,non-gaseous acidosis.
Histotoxic hypoxia is the inabilityof cellsto takeup or utilizeoxygenfrom
the bloodstream , despitephysiologicallynormaldeliveryof oxygento such
cellsandtissues.Histotoxichypoxiaresultsfrom tissuepoisoning, such as
that causedby alcohol, narcotics,cyanide (which acts by inhibiting cyto-
chromeoxidase),andcertainotherpoisons.
Thedecreased effectiveness of oxygenutilizationby the cellsusuallyis the
resultof inhibitionof biologicaloxidationenzymesactivity. the disturbance
of theirsynthesisor the damageof membranestructuresof the cell.Cyanide
poisoningcan be a typicalexampleof histotoxic hypoxiacausedby specific
inhibitorsof tissueenzymes .
Cyanideions bind to the iron atom of the enzymecytochromeC oxidase
in the mitochondrial membraneof cells.This deactivates the enzymeandthe
finaltransportof electronsfrom cytochromeC oxidaseto oxygencan not be
 126 I Part I Generalpathophysiology

completed.As a result, theelectrontransportchainis disrupted,meaningthat

the cell can no longerproduceATPfor energy.Tissues that mainlydepend
on aerobicrespiration , suchas the centralnervoussystemandthe heart,are
particularlyaffected.
Oneof the causesof histotoxichypoxiacanbethe disturbanceof respira-
tory enzymessynthesisas a result of certainvitaminsdeficiency(thiamin,
riboflavin, pantothenicacid).
Thedisturbanceof oxidationprocessesoccursbecauseof the damageof
mitochond rial membranes andothercellularelements,whichis observeddur-
ing radiationinjury, over-heating,intoxication
, infection,cachexia , uremia,etc.
Duringhistotoxichypoxiaconnected withthetissuesinabilityto utilize02, the
pressure , saturationandcontentof 02 in bloodcanstaynormalfor sometime.
A peculiarvariantof histotoxichypoxiarisesduringacutedissociationof
processesof oxidationand phosphorylation in respiratory chain. Consump-
tion of 02 by tissuescan increase,but the significantpart of energyis dis-
persedin the form of heat, which leadsto energetic"depreciation"of tissue
respiration.Relativeinsufficiencyof biologicoxidationarises,whenATPre-
synthesisdoesnot covertissueneedsfor energy, despise high intensityof
respiratorychainfunctioning.Theagentsthat dissociateprocessesof oxida-
tion and phosphorylation are wide rangeof substancesof exogenousand
endogenous origin:hormonesof thyroidgland, excessof Ca,toxins, etc. In a
healthyorganism,thyroidhormones- thyroxineandtriiodthyronine- carry
out the functionof physiologicregulatorof the associat ion of oxidationand
phosphorylation degree,togetherwith otherfunctions.
Overloadhypoxiaarisesduringexcessive ly strainedactivity of certainor-
ganor tissue, whenfunctionalreservesof transportsystemor utilizationof
02 or substratesare insufficientto supplyacutelyincreaseddemands , even
without any pathologicchangesin thesesystems.· Significantoxygendebt,
venoushypoxemiaandhypercapnia aretypicalfor overloadhypoxia .
Thisform of hypoxiahasits practicalmeaningas appliedto heavyloadsof
muscularorgans:skeletonmusc~sandmyocardiu m. If the loadis excessive,
the relativecoronaryinsufficiency,localhearthypoxiaandsecondarygeneral
circulatoryhypoxiaarise. If muscular work is excessive , skeletonmuscles
hypoxiais accompanied with the increasedbloodflow in the muscles.These
Mechanismsof tissueand cellularinjury Unit 2 I 127
eventsleadto ischemiaof othertissuesand developmentof the widelydis-
tributedhypoxia.
Substrate hypoxia. In absolutemajorityof caseshypoxiais connectedwith
the insufficienttransportor the disturbanceof 02 utilization.In normalcon-
ditionsthe substratereserveis big enoughand exceedsthe 02 reservevery
much.But in somecases, whenoxygensupplyis normal, the stateof mem-
braneandenzymesystemsis normal;the primarysubstratedeficiencyleads
to the disturbanceof biologicaloxidation.Suchhypoxiais usuallyconnected
with glucosedeficiencyin tissues.Thus, the cessationof glucosesupplyof
the brainleadsto the deathof the mostsensitivenervouscells in 5-8 minutes.
Carbohydrate starvationandhypoxiaof insulin-dependenttissuesoftenoccur
duringdiabetesmellitus andotherdisturbancesof carbohydrate exchange.
Combined hypoxia is observedmostfrequentlyand presentsa combina-
tion of 2 and more maintypes of hypoxia.In somecasesthe hypoxicfac-
tor itselfaffectsseverallinks of 02 transportationsystemand utilization.For
example,COactivelybindsto Fe2• of hemoglobin , but increasedconcentra
-
tions of it alsocausedirecttoxic effectuponthe cell, inhibitingcytochrome
oxydasefunctioning.Nitrites can also dissociateoxidation-phosphorylation
processesalongwith met-hemoglobin formation.
In somecasesprimarilyarising hypoxicconditioninevitablycausesthe
disturbanceof differentorgansand systemsfunctions that participatein 02
supplyand utilization. Duringseverehypoxiacausedby the insufficiencyof
externalrespirationthe functionof nervouscentersregulatingvesselstone
andconductingsystemof the heartis disturbed. It resultsin decreasedheart
contractionsand increasedvesselspermeability . Thus, respiratoryhypoxia
is exacerbated with additionalcirculatoryhypoxia.Practicallyeverysevere
hypoxicconditionhascombinedcharacter .

The d isturba nc es in orga nism d urin g hyp oxia

Theseverity of organismvital activityviolationsis dependenton the type of
hypoxia,the degreeof its severity, the previousstate of organismreactivity
andon the speedof hypoxiadevelopment.
 128 I Part I Generalpathophysiology

Fulminantor acutehypoxiausuallyresultsin deepviolationsof vital func-

tions of the organismandsubsequentdeath.Chronichypoxiaof constantor
intermittentcharacteris accompanied by the adaptationto hypoxia.
Thevarietiesof the disturbancesof the organsandtissuesfunctionsthat
are manifestedin hypoxicconditionsdependon the degreeof tissueresist-
anceto hypoxia.Thetissueof bones,cartilages , tendonsis the mostresistant
to hypoxia.Theskeletalmusclesproducemorphologicalchangesin about2
hoursof acutehypoxia.Myocardialcellsandparenchymal organsshowsigns
of injuryin 20-30 minutesof hypoxia.Nervoustissueis lessresistantto hy-
poxia.Themostsensitiveto oxygendeprivationarethe neuronsof cerebral
cortex- 2-3 minutesof hypoxiaresultin their morphologicalandfunctional
changes.Anoxiaof braincancauseunconsciousness in 15seconds,irrevers-
iblecell damagein about2 minutes,andcell deathin 4 to 5 minutes.Lesser
degreesof hypoxia,as in heartfailureor chronicpulmonarydisease,maybe
manifestedclinicallyby confusion,disorientation , andbizarrebehavior.
Cyanosis occurswhendesoxygenated Hb in the capillariesexceeds50 g/1.
Sinceit hasa darkcolor,nailbeds,lips,earlobes, andareaswherethe skin is
thin takeon a duskypurplishcoloration. Becausedevelopmentof cyanosis
dependson the absoluteconcentrationof desoxygenated Hb, hypoxiamay
be severewithout cyanosis(as in anemia) , and cyanosismaybe seenwith-
out significanthypoxia(as in polycythemia). In the lattercase,polycythemia
mightbean adaptiveresponseto, for example,a previoushypoxichypoxia.
Theclinicalmanifestation of the organsphysiological functionsarethe fol-
lowing:
Nervoussystem- behavioraldisturbances(euphoriawith emotionaland
motion excitation,then depressionof mentalactivity)and disturbancesof
movementscoordination.In 8-12 minutesof acutehypoxiaviolationsof me-
dullafunctionoccur,resultingin arrestof heartactivity, periodic breathdevel-
opment(Cheyne-Stokes' type), loss of consciousness.
The heartandvessels- signsof ischemic heartdisease,the decreaseof
heartstrokevolume,arrhythmiasdevelopment. All theseeventsresultin car-
diacfailure with the subsequentinsufficiencyof bloodcirculation.
Respiratorysystem- in the beginning of hypoxiahyperventilation occurs
but then hypoventilationof the lungsdevelops . The disturbancesof lungs
Mechanismsof tissueand cellularinjury Unit 2 I 129
perfusion , diffusionandventilation -perfusionratiofinallyresultin respiratory
failure.
In the kidneys- variabledisturbances of diuresisare observed . In severe
casesof hypoxiaacuterenalfailuredevelops .
Liverfunctiondisturbances are usuallyobservedin the casesof chronic
hypoxia . Theyincludedisturbances of all substancesmetabolism(carbohy-
drates, lipids,proteinsandvitamins), decreased antitoxic activityof the liver
andinhibitionof varioussubstan ces synthesis(clotting factors, bile acids).
Thedisturbances of GIT organsincludeviolationof appetite,inhibitionof
peristalsis andsecretionin the stomachandintestines, developme nt of ero-
sionsandulcers.
Chronichypoxicstatesare alsoaccompanied by the decreased activityof
theimmune system,which manifestsas low functional activity of the immune
cells,loweffectiveness of the innateimmunityfactors(complement , interfer-
ons, naturalkillers).

Protec tive ada pt ive and comp e nsa tory reactions

unde r hyp oxia
Adaptive reactionsthat occurduringhypoxiadevelopment may be directed
to adaptationto acuteshort-timehypoxia (urgentor protective-adaptive reac-
tions)and reactionsthat provideconstantadaptationto lessexpressedbut
durableor repeatinghypoxicconditions- chronic hypoxia- (permanentad-
aptationor compensatory reactions).Bothurgentandpermanent adaptivere-
actionsareformedat all stagesof 02-transportandutilizationin theorganism .
Thefollowingorgansandorganssystemstakepartin this process : the lungs,
theheartandvessels,bloodandtissue's systemsof biologicaloxidation.
Thereactionsof urgentadaptation usuallyariseimmediatelyor soonafter
the beginningof acute hypoxia.
Permanent -adaptivereactionsare formedgradually duringlong-term or
repeatinghypoxiceffects.Thereareno existingmechanisms in the organism
for adaptatio
n to long-termhypoxia ; there are only geneticallydetermined
preconditions that providegradualformationof adaptationmechanisms.
 130 I Part I General pathophysiology

The urgentadaptationto acutedevelopsduringshort periodsof hypoxia .

The reasonwhichcausesthe onsetof the abovementionedreactionsis the
lackof biologicaloxidationthat resultsin the decreaseof ATPamountin the
organismcausingthe lackof energysupply.
Reactionsof the vrespiratorysystemto hypoxiaare manifestedas the in-
creaseof alveolarventilation.They arecausedby the changesof bloodoxy-
genand carbondioxideamountwhich influencethe chemoreceptors of the
vesselsand brain.The activationof chemoreceptors resultsin the increase
of the frequencyand depthof breathingandalso in mobilization(including
into respiratorymetabolism)of non-functioningalveoli.On the interaction
betweenalveolarventilationand deadspaceventilationthe type of adaptive
reactionsof the respiratorysystemis dependent.Whenalveolarventilation
increases , we may sayaboutthe compensatory type. In pathogenictype -
alveolarventilationdecrease.Themechanism of adaptivereactionsin the res-
piratorysystemis shownin table11.

Table11.Typesof reactionin respiratory

function
.
~ .,~·'

Typeof Breath Tidal Total Deadspac;eAlveolar,.·

-ventilation -~
reaction rate volume ventilation
. -:, ...-..,.
· ·"' .

0.171/1
Normal 15 0.5L 7.5L 5L
2.5L

Compensatory 22 0.5L 11.0L 3.7L 7.3L

'
Pathogenic 30 0.25L 7.5L 5.0L 2.5L

Urgentadaptationof bloodcirculationsystemto acutehypoxiaincludesthe

increasingof the frequencyandstrengthof the heartcontractions.It becomes
Mechanismsof tissueand cellularinjury Unit 2 I 131
possibledueto the activationof the sympatheticadrenal system.The index
of minutebloodvolumeis increasedtoo. Normallyminuteblood volumeis
about4-5 L, whereasin acutehypoxiait may reach30-40 L. In the circula-
tion systemtherealsomaydevelopthe compensatory and pathogenictypeof
adaptivereactions,which dependson the interactionbetweenthe heartrate
andcardiacoutput.If the heartratebecamemorethan 160-180 per minute,
the strokevolumeandcardiacoutputdecreaseand pathogenictypeof adap-
tive reactiondevelopment.
The centralizationof blood flow is also observedin acute hypoxia.This
effectis manifestedas the dilationof the arteriolesof the vitally important
organs- the brainand the heart- and simultaneousconstrictionof the ar-
teriolesin othertissuesand organs.This effecthelpsto preventthe hypoxic
damageof thoseorgansthat areverysensitiveto the lackof oxygen.
The reactionsof bloodsystemmanifestthemselvesin the increaseof the
bloodoxygencapacitydueto theactivationof erythrocytesexitfrom the bone
marrowandblooddepot(liver,spleen).Theaffinit y of hemoglobinto oxygen
andthe degreeof oxyhemoglobin dissociationin the tissuesare increased.It
helpsfully utilizeincoming oxygen.
Thefunctionof the tissuessystemsof biologicaloxidationis changedin
thefollowingway:anaerobicglycolysisis activated in tissues, theactivationof
oxidationandphosphorilation is observed,respiratoryenzymesareactivated.
Chronichypoxicconditionswill result in permanentcompensatoryreac-
tions development.It is realizedat all the levelsof the organism's function.
Thedifferencebetweenurgentadaptationand permanentcompensationlies
in the following.Urgentreactionsare primarilydirectedat the activationof
the oxygentransportto the tissues.Permanentcompensationis determined
by the activationof biologicaloxidationin the cells. Organsand physiological
systemsthat are transportingoxygenbeginto function on the new levelof
capacityandeffectiveness that is providedwith their structuralchanges.
In the lungs we can observethe signs of hypertrophydue to increased
surfaceof alveoli,increasednumberof capillariesin the lungs tissues.The
diffusion of gasesthroughalveoli to vesselsis increasedtoo. We can also
observethehypertrophyandincreasedcapacityof the musclesthataretaking
part in respiratorymovements .
 132 I Part I Generalpathophysiology

Thesignsof hypertrophyarepresentin the hearttoo:the numberof myo-

cardialfibers, capillariesand nervesis increased.Thus, the contractionsof
the heartbecomemoreeffective.It manifestsitselfas increasedheartstroke
volumeandminutevolumeof the blood.
Thenumberof the vesselsin all organsandtissuesis increased to provide
betterbloodsupplyof the tissues.
Thepermanentadaptationto hypoxiaresultsin the increaseof bloodcells
quantitydueto increased erythropoiesis.
Themechanism of this is thefollow-
ing: chroniclackof oxygencausesthe activationof erythropoietinsynthesis
in the kidneys.

Metabolic processes in the tissue of the organism

which is adapted to hypoxia are characterized by
the following features:

• decrease of metabolismintensiveness;
• highefficiencyof anaerobicglycolisis;
• prevalence of anabolicprocessesin the cells.

Clinical app lication of adaptation to hypoxia

Thetreatmentwith the medicinesis the main methodof differentdiseases
therapy.But the progressof pharmacologyis accompanied by the list of
negativeconsequences: the frequencyof allergicdiseasesis increasedand
the useof drugsthemselvescan resultin diseasesdevelopment. Sothe aim
of modernmedicineis to createthe newmethods-of diseasetreatmentand
prophylaxiswithoutdrugs.It is knownthat hypoxiais oneof the mainlinks
of diseasesoccurrenceanddevelopment. Butthe stateof mild hypoxiahelps
to normalizethe homeostasis ofthe humanorganism.It is a well established
fact that peopleliving in the mountainshavethe higherindicesof cardio-
circulatoryand pulmonarysystemfunctions.Thefrequencyof somaticand
infectiousdiseasesin this groupis lowerin comparisonwith otherpeople.
Mechanismsof tissue and cellularinjury Unit 2 I 133
The changesthat developin the organismduring adaptationto chronic
hypoxiamay be usedwith the medicalpurposein order to strengthenthe
work capacityof the organsandsystemsthat take part in oxygentransport.
Intermittenthypoxiais usedin this case.
Intermittenthypoxiais definedas repeatedepisodesof hypoxiainter-
spersedwith normoxicperiods. Hypoxicepisodesmaybe createdby expo-
sureto naturalhighaltitude, sojournsin hypobaricchambersor by breathing
hypoxicgas mixturesin normobaricconditions.Suchrepeatedshort-term
hypoxiawith normoxicperiodsis also knownas IntervalHypoxicTraining.
Thepreventivehypoxictrainingcourseconsistsof 10-20 sessions.
Onthe onehand, the mainreasonfor the clinicaluseof intermittenthypox-
ia is that resistance to hypoxiaresultingfrom hypoxictrainingsis not specific
andfirst of all improvesthe functionof the mainregulatorysystemsof the
organism:nervous,immuneandendocrine.Generally, adaptationto hypoxia
activatesparasympathetic activity of the vegetativenervoussystem.It is also
characterized by the increasedexpressionof stressproteinsandantioxidant
systemswhich is an adaptiveconsequence of hypoxiaprovidingprotection
againstthe generalized stressof disease.
Onthe otherhand,adaptation to chronichypoxiais characterized by a pro-
gressiveincrease in ventilation, adaptations of the cardiocirculatoryandhaema-
tologicalsystemsto enhance oxygendeliveryto thetissues.Arterialbloodpres-
sureandheartratearedecreased asa resultof adaptation to hypoxia.It reflects
the increased resistance of the nervousandcirculatorysystemto hypoxia.This
manifestation is moreexpressed in thepatientswithhypertonic disease.Adapta-
tion to hypoxia alsoinfluenceslipidmetabolismby decreasing cholesteroland
lowdensitylipoprote ins levelwhichcanpreventor inhibitatherosc lerosisdevel-
opment.Adaptat ionto chronichypoxiaisaccompanied bythechangesmanifest-
edatthetissuelevelin orderto optimizetheutilizationof oxygen- improvement
of microcirculation. This effectcan be usedin pepticulcerdiseasetreatment.
Adaptation to hypoxiaalsoresultsin increased bodyresistance to variouspatho-
genicfactors(acutehypoxia,hypothermia, overheating, physicaloverstrain) , it
increases immuneresponsefor anantigenandimmunoglobulin level.
IntervalHypoxicTraining is a methodof adaptationmedicinewhichis used
for preventio n, rehabilitationand treatmentof differentdiseases.The wide
 134 f Part I Generalpathophysiology

list of diseasescanbetreatedwith IntervalHypoxicTraining. Theyare: bron-

chial asthma,chronicobstructivepulmonarydiseases,coronary heartdis-
ease,arterial hypertension,neurocirculatoryasthenia,neurode rmitis,allergic
dermatitis,diabetesmellitus II type, disfunctionaluterine bleeding,anemia,
climactericsyndrome,gestoses,etc.
This methodis effectivein preparat ion for plannedsurgeriesandanesthe-
sia, in postoperativerehabilitation,during rehabilitationafter cardiovasc ular
diseases,to increasephysicaland mentalworkingcapacity,in preparation
for long flights, mountainclimbing,diving,for training and conditioning of
athletes.Thecontra-indications are:all acutesomatic andinfectiousdiseases,
the chronicfailureof the lungs,kidneys,liveretc.
Theeffectof intervalhypoxictrainingdependson the previousstateof the
patientandthe levelof his adaptiveabilities:the higher is the adaptiveability,
the more expressedeffectof trainingwill beforeseen.
In spiteof wideclinicalapplicationof hypoxia,the investigation of its thera-
peutic role is beingcontinued.

Chapter 6. Cell Pathophysiology

A cell is an elementaryself-regulatingstructurallyfunctional unit of tissues

andorgans. Processesunderlying energyandplastic maintenanceof varied
structuresandfunctioninglevel of tissuesandorgansproceedin it.
Sincemost pathologicalprocessesoriginateat the cellular level, an un-
derstandingof cell structureandfunctions, as well as their impairment,is a
crucial pointfor understanding of all the pathologicalphysiology.

The basic concepts of cellular biology are arranged

into cell theory inciuding the following issues :

• All free-living organismsarecomposedof cellsandtheir products.

• All cellsarebasicallysimilar in their chemicalconstruction.
 Mechanismsof tissue and cellularinjury Unit 2 I 135
• Newcellsareformedfrom preexistingcellsby celldivision.
• Theactivityof an organismis the sum of activities and interactionsof
its cells.

Basicallyall the cellsconsistof two principalparts: the cytoplasmwith

organelles andcellmembrane.
Thecellmembrane maybeeithersmoothor foldedandconsistsof phos-
pholipids , cholesterol
, andotherlipids. The hydrophobicportionsof the lipid
moleculesarearrangedin a doublelayerfacingoneanother,the hydrophilic
portionsjutting out into the waterysurroundings . Proteins
, manyof them
mobile,areincorporated intothe membrane , someextendingthroughits en-
tire thicknessandservingas carriersor poresthroughwhich polar(hydro-
philic)substances canpass.
Someof the functionsof the cell membrane arethe protectionof the inte-
rior of thecellfrom its surroundings,transport, the recognitionof hormones
- and other BAS, and the adhesionof cells to one another.
Thenucleus containsa fluid knownasthekaryolymph , aswellasthechro-
matinnetworkandthe nucleolus . Chromatincontainsthe desoxyribonucleic
acids(DNA)that arethe carriersof the geneticinformation . Two strandsof
DNA(doublehelix)aretwistedandfoldedto form the chromosomes.
Theroughendoplasmic reticulum (RER) consistsof flat vesicleswhich
are connectedto form a network of channelsthroughout the cell.The ribo-
somesareattachedto the outsideof the RER(thus roughER)or arefound
freein the protoplasm . Theycontaintranscripts (RNA)of the nuclearDNA.
ERwithoutribosomesis calledsmoothERandis chieflyengagedin the syn-
thesisof lipids(lipoproteins).
The mitochondriaare the powerstation of the cell. They containen-
zymesof the citric acid (Krebs)cycleand of the respiratorypath.way. They
are the principal site for oxidativereactionsthat generateenergy. The en-
ergythus producedis storedprimarilyin chemicalform in the adenosine
triphosphate(ATP) molecule . Synthesisof ATPprovidesalmostall of the
immediatelyaccessibleenergystores of the body; breakdownof ATP by
variousenzymes (phosphatases, ATPases)liberatesenergyfor utilizationin
cellularreactions .
 136 I Part I Generalpathophysiology

Lysosomes areenzyme -containingvesicles , arisingin most casesfrom the

ERand the Golgiapparatus(primarylysosomes).Theyare also involvedin
proteintransportand the breakdownof substancestakenup in the cell by
phagocytosisor by pinocytosis(phagolysosomes andsecondary lysosomes).
Cell signaling . Whencells communicatewith eachother, the one that
sendsthe signalis referredto as the signalingcell andthe cell receivingthe
signalis the targetcell. Transmission of the information mayoccur eitherby
the secretionor presentationof signalingmolecules , which contactrecep-
torson the targetcell membrane(or intracellular ly).
Accordingto the distancebetweenthe signalingcellandthetargetcell,the
humoralpathwayof regulation canbegradedlikethis.
1. Endocrine - regulatorysubstances(in this casecalledhormones)are
producedby the specialized tissue,secretedto the blood,anddelivered
to the remotetargetcellsthroughoutthe body(eg ~(beta)-cells of the
isletsof Langerhans produceinsulinthat regulatesglucoseabsorption
by the majorityof the cellsin the wholeorganism).
2. Paracrine - regulatory substancesproducedby somecell act only on
the nearlylocalized cells (e.g.,histamineelaboratedby the mastcells
causesvasodilationand increasesvascularpermeabilityonly in the
nearestvessels).
3. Autocrine - regulatorysubstances act onthe cellwhich producesthem,
cellregulatesitselfby meansof biological activesubstances (BAS)pro-
duction(eginterleukin-2producedby T-cellinducesits proliferation).

Normally, the cell acceptsthe informationthrough receptors of a mem-

brane, the receptorsreactwith biologically activesubstances(BAS),hor-
mones,enzymesetc (primarymessenger) (Fig.10). If closelyto a cellthere
arethesesubstances , the cell reactsto them,the receptorsareactivatedand
the informationis transferred inside of the cell to the secondary messen-
gers. Eachsecondarymessengeractivatesa specificenzyme(proteinkinase
or other), transmitsa signalto the executivesystemsof cell and regulated
differentreactions,for examplephosphorylat ion of protein, metabolism of
an arachidonicacid, synthesis of hormonesor enzymes.Themostimportant
secondary (or tertiary)messengers thereare:cyclicadenosinemonophos-
Mechanismsof tissueand cellularinjury Unit 2 I 137
phate(cAMP),cyclic guanosinemonophosphate (cGMP) , Ca2·-calmodulin
,
proteinkinaseC, inositoltrisphosphate
, diacylglycerol.

~
(Primary messenger)

i
~···········~ -
~ a
y
G Protein
(Transducer)
-
· AmpllfterEnzyme
AdenytylCyclase
GunytylCyclase
·

Phosphollpase C

;-~Precursors ' . Second.messengers

ATP cAMP
GTP cGMP
Phosphotldylin
osltol Inositol1,4,S•triphosphote
4,5-blsphosphote and diocylgtycerol

. ___...l ......
. ......
_
Intracellulareffects

1 Cell response
I - ·- -

Fig.10.Cellsignaling and secon

darymessengers

In manycells, onehormoneinitiatesthe inflowof Ca2+ • whileanotherhor-

monetriggersthe formationof cAMP. Thetwo secondarymessengers then
exerteitheran antagonisticor a synergisticeffecton cellularmetabolism.
Theantagonisticeffectmightpartlybe dueto the Ca2•-calmodulincomplex
activatingtheenzymephosphodiesterase , whichis responsiblefor the break-
downof cAMP.
Diacylglycerol
remainsattached to theinnerleafletof theplasmamembrane ,
andwith theassistance 2
of Ca·, activates
theenzyme proteinkinaseC(C-kinase).
 138 I Part I Generalpathophysiology

C-kinase, inturn,initiatesa phosphorylation cascade, whoseendresultisthe ac-

tivationof generegulatory proteinsthatinitiatetranscriptionof specific genes.
As a rulesecondary messengers activated or inhibitedreactions
whichmore
typicallyfor thistypeof cells.Forexample in themusclecellthisis contractionor
relaxation, in thesecretorycell - increaseor decrease secretion
andsoon.Sever-
al stagesarepresentin information sendingandreceivingandeachof them can
bedamaged resultingintopathology development.Thesestagesareasfollows.
1. Signalization- production of signalmoleculesandtheir delivery.
2. Reception - recognition of signalmoleculeby the target cell by means
of specificstructurecalledreceptorwhichis localizedeitheron the cell
membraneor insidethe cell.
3. Intracellular informationtransfer - activationofthe cascadeof intracel-
lular regulatorymolecules(cAMP, Ca++ etc) calledsecondary messen-
gerscontraryto firstmessengers thatact on the cellfromthe outside.
4. Realizationofresponse to stimuli- changesin cellularactivitythatare
specificfor everystimulusandbasedon programscodedby DNA.

Cell injury can be of two types

1. Infringementof informationmaintenanceof a cell.
2. Damageof the executive(structural)deviceof a cell.

Therearefollowingkindsof infringementof information

maintenance of a cell.
a. Pathologyof the signalization.
b. Infringementof the reception.
c. Infringementof functionof the secondarymessengers .
d. Defectsof the cellsprogramsat a stageof r~alization
of a finaleffect.

A. Patho logy of the signai'isation

Thereareplentyof substancesthatcanserveasfirst messengers: hormones,
cytokines,neurotransmitters,
otherbiologicalactivesubstances(BAL). Both
 Mechanismsof tissueand cellularinjury Unit 2 1139

excessandlackof signalsmayleadto cellinjury.Excessof hormonescauses

suchdiseasesas Cushingdisease(excessof adrenocorticotropic hormone)
or Cushingsyndrome(primaryexcessof glucocorticoids).Excessivepro-
ductionof cytokinessuchas inflammatorymediatorscanleadto the shock
development. Exces s of neurotransmitters (acetylcholine)developsat or-
ganophosphorous compounds(usedas insecticides)poisoningsincethey
are acetylcholine esteraseblockers.Deficiencyof insulin leadsto diabetes
mellitus(typeJ) development. Deficiencyof cytokinesproducedby CD4+-
leukocytes leadsto immunodeficiency in AIDS. ·
Thereis alsoa specifictypeof pathologyof signalizationcalledmimicry
of thesignal.In certaincasesa moleculecanbe mistakenfor anotherone.
Wrongmoleculehavingphysicochemical andbiologicalpropertiesdifferent
from normalligandcaneitherblock receptoror causeits overstimulation.
lmmunoglobulinsare the principalmoleculesthat can substitutefor an-
other one sincethey havevariabledomainin their structure.Blockadeof
- receptor-ligand interactionis involvedin the developmentof myasthenia
gravis.In this diseasethe N-cholinoreceptors of a motorendplatebecome
blockedwith antibodiesand signalconductingfrom motoneuronto mus-
cle get impairedwhichleadsto muscularweakness.Whileantibodiescan
stimulatereceptorsas it happensin Grave'sdisease.This stateis character-
izedby productionof antibodiesagainstthyroidstimulatinghormone(TSH)
receptorsof thyrocytes.Antibodies bind to receptorand causeprolonged
stimulationof thyrocytesleadingto hyperfunctioningand hyperplasiaof
thyroidgland.

B. Infringement of the reception

Cellcanonly recognizesignalif it hasa specificreceptorcomplementary
to the signalmoleculestructure.Therearetwo primarytypesof receptors:
membra ne-bound- localizedon the plasmamembraneand intracellular -
localizedinsidethecell.The latterare usedby steroidhormonesandthyroid
hormones , whereasthe formerare usedby the vast varietyof signalmol-
eculessuchas peptides , derivatesof aminoacids,andso forth.
 140 I Part I Generalpathophysiology

Althoughsignalscan be present the cell cannotrecognizethem if spe-

cific receptorsareabsentor their structureis modified.This is quitea fre-
quent pathologicalsituation.For instance, the inabilityof cells to recog-
nize insulin due to changesor absenceof insulin receptorsleadsto the
developmentof diabetesmellitustype II; atherosclerosisoften develops
againstthe backgroundof absenceor decreasednumberof receptorsfor
apoproteinB of low densitylipoproteinsthat leadsto hyperlipidemiadue
to decreasedlow densitylipoproteinsabsorptionand infiltrationof vessel
wallswith lipids.

C. Pathology of secondary messengers

Receptorsbound to the plasmamembraneneedcertain mechan isms to
conductreceivedto the intracellularexecutivestructures.Thereare some
mechanismsinvolved.Sometimestheremaydevelopdeficiencyof second-
ary messengers. Anothervariantis whenthere is inhibitedproductionof
onesecondarymessengerand activatedanother.Forexample:a receptor
can be coupledwith the G-protein , with the ion channel,and it canhavein-
tracellulardomainwith enzymicactivity(commonlytyrosinekinase).Those
that coupledwith G-proteinsproducesmall moleculescalled secondary
messengerfrom precursorsthat resideeitherin cytoplasmor in the plasma
membrane.All G-proteinsconsistof threesubunitsa(alpha),P(beta),and
y(gamma).Beta and gammasubunitsform stable, noncovalentty-linked
dimmer,alphasubunitcabbindandhydrolyzeGTP(it hasGTPase activity).
Whenalphasubunit binds GDP, it associateswith betaand gammasub-
unitsto form a trimerthat caninteractwith cytoplasmicdomainof receptor.
Changesof the receptorconformationoccurupon ligandbindingandthese
allow the alphasubunitof G-proteinto replaceGDPby GTP.This replace-
ment causesalphasubunit to dissociatefrom beta and gammasubunits
andassociatewith effectormoleculesuchasadenylyl cyclaseor phospholi-
paseC and preventingproductionof cAMP.AlphasubunithydrolysesGTP
to GDP, detachesfrom effectormoleculeandassociateswith beta-gamma
subunits.Thenthe cyclecan repeat.
Mechanisms
of tissueandcellularinjury Unit 2 I 14 1
D. Defects of the cells pro gram s at the stage of
reallzation of a final effect
Thisinfringement, whicharisesat normalworkof receptorsandmessengers,
whenin the cell thereare no factorsnecessaryfor performanceof specific
functions(enzymes, vitamins, ions,etc.).

Damage of the execut ive (structural) device of a cel l

Whenconfronte d with stressesthat endangerits normalstructureandfunc-
tion, thecellundergoes adaptivechanges thatpermitsurvivalandmaintenance
of function.If stressesare not severe,the celltendsto maintainthe normal
homeostasis by adjustingits physiological properties,whichresultsin cell's
adaptation. Whenthestressis overwhelming or adaptation is ineffective,
then
cellinjuryanddeathoccur.Thereactionof cellto variousstimuliis dependent
notonlyonthe natureandseverityof the stress,butalsoonthe vulnerability,
differentiation,bloodsupply,nutrition,andpreviousstateof the cell.
Celldamagecanoccurin manyways.Suchcausescan resultin cell ad-
aptationsand cell injury:physical agents, chemicals, hypox ia, biological
agents , nutritionalimbalances .
Injuryfromphysical agents.Physicalagentsresponsible for cell andtis-
sue injury includemechanicalforces, extremesof temperature , electrical
forces,ionizingandultravioletradiation.
Injuryor traumadueto mechanical forcesoccursasthe resultof bodyim-
pactwith anotherobject.Thesetypesof injuriessplit andteartissue,fracture
bones,injurebloodvessels,anddisruptbloodflow.
Extremes of Temperature. Extremes of heatandcoldcausedamageto the
cell,its organelles, andits enzymesystems.Exposureto heat(43° to 46°C),
suchas in the caseof burnsand severeheatstroke,causescell injury by
inducingvascularinjury, accelerating cell metabolism, inactivatingtempera-
ture-sensitiveenzymes , anddisruptingthe cell membrane .
Exposure to cold increasesbloodviscosityand inducesvasoconstriction
by directactionon bloodvesselsandthroughreflexactivityof thesympathet-
 142 I Part I Generalpathophysiology

ic nervoussystem.Injuryfrom freezingprobablyresultsfrom a combination

of icecrystalformationandvasoconstriction. Thedecreased bloodflow leads
to capillarystasisandarteriolarandcapillarythrombosis.
ElectricalInjuries.Electricalinjuriescanaffectthe bodythroughextensive
tissueinjuryanddisruptionof neuralandcardiacimpulses.Theeffectof elec-
tricity onthe bodyis mainlydeterminedby its voltage,thetypeof current(i.e.,
director alternating),its amperage,the resistanceof the interveningtissue,
the pathwayof the current, andthe durationof exposure.
IonizingRadiation.Ionizingradiationaffectscellsby causingionizationof
moleculesandatomsin the cell, by directhittingthe targetmoleculesin the
cell, or by producingfree radicalsthat interactwith criticalcell components.
It can immediatelykill cells, interruptcell replication,or causea varietyof
geneticmutations,whichmayor maynot belethal.
UltravioletRadiation.Ultravioletradiationcausessunburnand increases
the risk for skin cancers.Thedegreeof risk dependson the typeof UV rays,
the intensityof exposure,andthe amountof protectivemelaninpigmentin
the skin. Skin damageinducedby UV radiationis thoughtto be causedby
reactiveoxygenspeciesand by damageto melanin-producing processesin
the skin.
ChemicalInjury.Anychemicalagentor drug maybethe reasonof cell in-
jury. Chemicalagentscaninjurethe cell membrane andothercellstructures,
blockenzymaticpathways,coagulatecell proteins, and disruptthe osmotic
andionic balanceof the cell. Corrosivesubstances suchas strongacidsand
basesdestroycellsasthe substancescomeinto contactwith the body.Other
chemicalsmayinjurecellsin the processof metabolismor elimination.
Hypoxicinjury.Hypoxia,an extremelyimportantand commoncauseof
cell injuryandcell death,impingeson aerobicoxidativerespiration.

Hypoxic states results from:

• loss of bloodsupply(ischemia)whenthe arterialflow or the venous

drainageis impededby vasculardiseaseor thrombi; this is the most
commoncauseof hypoxia;
Mechanismsof tissue and cellularinjury Unit 2 f 143

• inadequate oxygenationof the bloodowingto cardiorespiratoryfailure;

• loss of the oxygen-carryingcapacityof blood, as in anemiaor carbon
monoxidepoisoning (producinga stablecarbonmon-oxyhemoglobin
that blocksoxygentransport).

Injuryfrombiologicalagents . Theseagentsrangefrom submicroscopic

virusesto the largerparasites.Biologicagentsinjurecellsby diversemecha-
nisms.Virusesenterthecellandbecomeincorporatedinto its DNAsynthesis.
Certainbacteria elaborateexotoxinsthat interferewith cellularproductionof
ATP. Otherbacteriareleaseendotoxinsthat causecell injury and increased
capillarypermeability .
Injuryfromnutritionalimbalances . Nutritionalexcessesand nutritional
deficiencies predispose cellsto injury.Obesityanddietshighin saturate d fats
are thoughtto predisposepersonsto atherosclerosis.Dietarydeficienci es
canoccurin the form of starvation , in whichthereis a deficiencyof all nutri-
entsandvitamins, or becauseof a selectivedeficiencyof a singlenutrientor
vitamin.Theprotein andcaloriedeficiencies that occurwith starvationcause
widespread tissuedamage .
Cellinjuryis a disturbanceof homeostasis typicalfor this cell,accompa-
nied by limitationof its adaptationto the environmentand shorteningof its
normal life duration.
Thereare acute(underthe effectof strongirritants),and chroniccellular
injuries, which,in their turn, can be reversibleand irreversible.Theexample
of reversibleinjury can be the injury of myocardialcells duringstenocardia
attack,causedby reflexischemiaof myocardium , or the injury of intestinal
epithelium underthe effectof microbialendotoxins.After cessationof dam-
agingfactor effectthe homeostasis of the cell is completelyrestored.
In caseof stronganddurableeffectthe cellularinjurybecomesirreversible
andresultsin the deathof the cell.Irreversiblecellularinjuriescanbe caused
by durableischemiaof myocardium,intoxication , etc. Whenthe disturbance
of homeostasisin an injuredcell reachesthe critical level, the deathof the
cell occurs,that is characterized by cessationof all livingprocessesin it. The
deathof the cell is usuallyfollowedby autolysis.
Themanifes tation of cell injury canbespecific andnon-specif ic.
 144 I Part I Generalpathophysiology

The exampleof specificfeaturesof injury,which is typicalfor only one

certainpathogenicagent, is immunehemolys is of erythrocytes as the result
of anti-RSCantibodiessynthesisin the organism.
Non-specific changes of lifeactivitycanalsobeobserved in injuredcells.They
arecommonfor the effectof differentdamagingagents . Theexampleof non-
specificfeaturesof cellulinjuryis the depression of enzymes' function,cellular
pumps, the disturbance of energymetabolism , waterandelectrolytes metabo-
lism, ABBdisorders , changesof intracellular organelles structureandfunction.
In practicalmedicinethe indicesof cell injuryareusedfor the diagnosing
of differentdiseases,determiningthe functionalconditionof the injuredtis-
sue,evaluatingthe degreeof viabilityof tissues,subjectedto conservation
andtransplantation .
Cellinjurycanbecharacter izedbyvariousmorphological andfunctional signs.
Morphological signsof injurymanifestasswellingor shrinkingof thecell,
the disturbanceof contactwith adjoiningcellsandsupportingstructures.The
breakingof tubes, vesiclesandcisternsof endoplasmic reticulum,decrease
of quantityof ribosomelocatedon its membrane, accompany cellularinjury.
Theswelling of mitochondrionmaybe observed,whichis accompanied by
the lossof double-structureof externalmitochondrial membrane, its damage,
andthen- by completedestruction of mitochondrion . Nuclearandlysosome
membranedamagecan be observedtoo. Lysosomalenzymesreleaseinto
cytoplasmleadsto additionalinjuryof intracellularstructures.
Dueto all theseprocessesin the cell, changesof cell size(enlargement or
decrease) , shape,colorandcell organellesoccur.
Intracellularaccumulat ion of substancesin abnormalamountscan occur
withinthecytoplasmor nucleusof thecell. Suchsubstances canbeaccumulat-
ed:constituents of normalcellmetabol ism (lipids, proteinsetc.), abnormalsub-
stancesas a resultof metabolismdisorders(glycoge ·n in glycogenoses) , and
pigments.Intracellu lar accumu lationof thesubstance canindicatecellinjury.

Functional signs of cellular injury:

1. Decrease
of cell mobility(diagnosing
test uponspermsmobility).
Mechanisms
of tissueandcellularinjury Unit 2 I 145
2. Disturbance or interruptionof cellulardivision(it is manifestedas the
development of atrophicprocessesin tissues).
3. Change of cellularmembrane permeability to macromolecules (proteins,
colloid stains),compoundswith low molecularweight (amino-acids ,
glucose),andions(is valuatedby the abilityof cellsto be stainedwith
vitalstainsor neutralstains)
4. Appearance of cytoplasmicenzymesin bloodas a resultof roughinju-
riesof cellularmembranes. Forexample,duringthe injuryof livercells
the releaseof aspartataminotransp herase(AST)into bloodoccurs,dur-
ing injuryof heartmusclecells- creatinphosphokynase (CPhK)andlac-
tatdehydrogenase (LOG),whichis widelyusedfor diagnosingof myo-
cardialinfarctionandits severity.
5. Injuryis sometimescharacterized by appearance of new, qualitatively
differentfunctions, whichare not typicalfor non-injuredcell. For ex-
ample,mastcellsand macrophages release leukotriensduringallergic
alteration.Leukotriens causecontractionof smoothmusclesof bronchi;
leukocytes underthe effectof bacterialendotoxinsreleaseendogenous
pyrogens,whichcausethedevelopment of feverreaction.
6. Changesof biochemicalprocessesin injured cells with releaseof
suboxidized andtoxic productsof metabolisminto blood.

GeneralPrinciplesof Cell InjuryCell responsedependson kind, se-

verity, and durationof injury. Thesefactorswill determinethe type of cell
injury.
Clinicaleffectsof cell injury dependon what kind of cell is affected
, its
priorstateof health,andwhatsort of adaptivemechanisms areavailableto it
(Fig.11). It maymanifestitselfat variouslevelsof functionaldisturbances of
organ/tissue or whenthe cellcannotadaptitselfto them.The consequences
of it maybefatalfor the wholetissueor organ.
Thecell components whichare most sensitiveto injuryare:maintenance
of cellmembra ne integrity,aerobicrespiratio
n, proteinsynthesis,geneticin-
tegrity.
Cellularmechanisms areall interdependent, so no matterwhatkind of in-
juryfirst occurs,manycellsystemsareaffected.
 146 I Part I Generalpathophysiofogy

Adaptation Morphologicchangesbe-
comeapparentvisuallyafter
30% theyoccur,with cell swelling
70%
beingevidentwithin minutes
but deeperstructuralchang-
es - genetic dysfunction,
chromatinclumping,taking
30%
70% longerto observe.
/ Themainprocesses of cell
Cell ( injuryincludethe following.
~ 1.DecreasedATP produc-
Paranecrosis-. Necrobiosis tion becauseof decreased
Hypoxic cellular respirationis often
caused by various stimuli
Freeradical
either ischemia or toxins.
Thedecreasein ATPamount
Necrosis starts a cascadeof otheref-
fects whichdo further injury
includingfailureto maintain
'>,'. , <
normalNaandCagradients.
10 %
2.Toxic oxygenradicals are
formednormallyduring res-
Fig.11.Generally mechanismsof cellular injury piration,but unlessthey can
(~ 30% usingpotentialof cell in normalcondition, bescavenged effectively,
they
whichincreasein adaptation up to 70- 80% and maycausecellularinjury.
decrease more lessthan10 % in paranec rosis ) 3. Calciumregulationwithin
the cell plays an important
role in cell homeostasis.Normalintracellularcalciumin the cytosolis
less than 0.1 µmol and 1.3 mmol outsidethe cell or in the mitochon-
dria and endoplasmicreticulum.Gradientsare maintainedby ATPase
pumps.Influxof calciumintocytosolactivatesphospholipases, proteas-
es,ATPases andendonucleases whichthenactto furthercellularinjury.
4. Mitochondrialinjury: injuryto mitochondr ial membraneresultsin for-
mationof nonselectiveinner membranechannelthat disruptsnormal
Mechanismsof tissue and cellularinjury Unit 2 I 147
protongradient.Mitochondrialpermeabilitytransitionmaybecomeper-
manentwhich indicatesimpendingcell death.CytochromeC mayalso
bereleasedintothe cytosolplayinga rolein triggeringapoptosis.

Mechanisms of cell injury

Themostcommonforms of cell injuryare causedby low oxygensupplyto
the cell as a resultof ischemia(interruptionof bloodsupply)and hypoxia
(impairedoxygensupplyto the tissues).Oxygen,however , playsa central
role in cell injury. Lackof oxygenunderlies the hypoxiccell injury. On the
otherhandactivatedoxygenspeciesare importantmediatorsof cell deathin
manypathologicconditions.The other commonmechanismsof cell injury
areinjury inducedbyfreeradicals,andcertainforms of chemicalinjury.
Hypoxic (ischemic)injurycanbe reversibleandirreversible.
Reversible injury. If oxygendeprivationis of shortdurationthe effectsof
hypoxiaare reversibleon rapidrestorationof circulation(e.g. ischemicheart
diseaseresultingfrom coronaryarteryocclusion).

The sequence of event is as follows:

1. Decreased oxidativephosphorylation by mitochondriaandgenerationof

ATP(adenosine triphosphate). ATPis neededfor almostall cellularfunc-
tionssuchas synthesisof proteinsandlipids, membrane transport.The
decrease of ATPhaswidespread effectson manysystemswithinthecell.
2. Damageto plasmamembranesodiumpump.Thelackof ATPresultsin
the decreased activityof the cell membraneadenosine -triphosphatase
(ATPase),causingfailureof the activemembrane"sodiumpump". The
consequence of this eventis intracellularaccumulation of sodium,and
diffusionof potassiumout of the cell.This processis accompanied by
aniso-osmoticgainof water,whichresultsin acutecellularswelling.
3. Reduced intracellularpH.Thedecrease in cellularATPandassociated in-
creasein adenosi nemonophosphate (AMP) result in anincreasedrateof
 148 I Part I Generalpathophysiology

anaerobicglycolysis
. Limitedglycogencell'sstoreis thusrapidlydeplet-
edandlacticacidis accumulated in thecell loweringthe intracellular
pH.
4. Reduced proteinsynthesis.Thisphenomenon occursdueto detachment
of ribosomesfrom the granularendoplasmic reticulumanddissociation
of polysomesinto monosomesas a resultof continuedhypoxia.If hy-
poxiacontinues,functionalconsequences and ultrastructuralchanges
mayoccur.

All the abovedisturbances are reversibleif oxygenationis restored.How-

ever,if ischemiapersists, irreversibleinjuryoccurs.
Irreversibleinjury.Theactualtime necessary to produceirreversiblecell
damagedependson the degreeof oxygendeprivationand the metabolic
needsof the cell.Well-differentiated cells,suchas thosein the heart, brain,
andkidneys,requirelargeamountsof oxygento provideenergyfor theirspe-
cial functions.Braincells beginto undergopermanentdamageafter4 to 6
minutesof oxygendeprivation.

Two essential phenomena always distinguish irre-

versible cell injury from reversible one:

• inabilityof the cell to reversemitochondrialdysfunctionuponreperfu-

sion or reoxygenation ;
• profounddisturbancein cell membranefunction.

Mitochondrial dysfunction. Irreversibleinjury is associatedmorphologi-

cally with severevacuolization of the mitochondria , including theircristaeand
depositsof amorphouscalciumsalts in the mitochondrialmatrix.
Disturbance in cellmembrane functionis a centralfactorin thepathogen-
esisof irreversible cell injury. The mechan isms underlyingmembranedam-
agearethe following.
1. Damageby products of free radicaloxidationof lipids. Freeradi-
calscandamagecellularmembranes by lipid peroxidation, whichis the
destructionof polyunsaturated lipids (the sameprocessby whichfats
Mechanismsof tissue and cellularinjury Unit 2 I 149
becomerancid).Peroxidation involvesthe reactionof oxygen -derived
freeradicals , suchasfreehydroxylgroups(OH).andlipidsto form free-
radical intermediatesand moderatelystableperoxides . Theseactions
canleadto chainreactions, causingautooxidation of the fatty-acidcon-
tent of lipidsin cellularmembranes.
2. Damageof lipidsandproteinsof a membraneby proteinases and
phospholypases . Theseenzymesareactivatedat a hypoxia,acidosis,
damageof lysosomes.The proteinasesdamage proteinesof a mem-
brane(receptors,ion channels).Phospholipase reacton fatty acidsof
a membrane, thereforethe membraneis damagedand the activesub-
stanses- eikosanoids are formed, to which concernprostaglandins ,
prostacycl ins, tromboxansandleukotriens.In plentiesthesesubstanses
resultin suchinfringements , as anedema , bronchospasm , clottageetc.
3. Amphiphylis damageof a cell membrane. To amphiphylsbelongthe
chemicalsubstances whichhavehydrophobicand hydrophylicfieldsin
composition of the molecule , for examplefatty acids,but not normal
components of the membrane. Thefatty acids are built in a membrane
of the cellandmodifyits specific frame.Thusthe functionof the mem-
braneis broken.
4. Accelerated degradation of membranephospholipids . Oxygenstar-
vationis knownto releasecalciumsequesteredin mitochondriaand
endoplasmicreticulum, thus raisingcytosoliccalciumwhich activate
endogenousphospholipases. The latter progressivelydegrademem-
branephospholipids whichare the main constituentof the lipid bilayer
membrane
5. Cytoskeletal damage.In the presen ce of cellswelling, whichoccursin
ischemia, injury of thecytoskeleton mayresultin detachment of the cell
membrane from the cytoskeleton , rendering the membranesusceptible
to stretching andrupture. A potential mechanismin cytoskeletal protein
degradation is theactivationof intracellularproteases,possiblyinduced
by increase d cytosoliccalciumor by physicaleffectof cellswelling.
6. Toxicoxygen radicals.Partiallyreducedoxygenspeciesarehighlytoxic
molecules, which causeinjury to cell membranesand other cell con-
stituents. Such oxygenradicalsare increasedin ischemictissuesupon
 150 I Part I Generalpathophysiology

restorationof bloodflow andmaybethe causeof the so-calledreperfu-

sion injury.
7. Lipid breakdown products.Thesecatabolicproductsaccumulatein
ischemiccellsasa resultof phospholipiddegradation
andcausefurther
damageto membranes.

Thereis also continuedloss of proteins, essentialcoenzymes, and ribo-

nucleicacidsfrom the hyperpermeable membranes, conversely,entryof ex-
tracellularmacromolecules from the interstitialspaceinto the cell occur.The
cellsmayalsoleakmetabolites, whicharevitalfor the reconstitutionof ATP,
thuscell'senergystorewill befurtherdepleted.
The falling pH leadsto injury to the lysosomalmembranes, followedby
leakageof theirenzymesintothe cytoplasmandenzymaticdigestionof cyto-
plasmicandnuclearcomponents.
Finally,the deadcell maybecomereplacedby largemasses,composedof
phospholipids. Thesearetheneitherphagocytosed byothercellsor degraded
further.into fatty acids.

Reperfus ion injury:

Muchof the injury from ischemiaor hypoxiaoccurson the restorationof
circulation:reperfusioncan help restorehealthto reversiblydamagedcells,
but canalsoleadto cell death.
Depending uponthe duration of ischemia (hypoxia)reperfusionmayresult
in the followingconsequences .
1. Whenthe periodof ischemiais of short durationreperfusionrestores
the structuralandfunctionalstateof injuredcell.
2. Whenischemiais for longerdurationreperfusiondeterioratesthe al-
readyinjuredcell.Thefollowingmechanisms underliefurthercell injury:
• circulationbrings neutrophilsto·re-perfusedtissuesthat releasetoxic
oxygenradicalsthat do inJuryto membranes; damagedcells mayex-
presscytokinesthat attractmore neutrophilesto them and causein-
flammationwith additionalinjury;
Mechanismsof tissueand cellularinjury Unit 2 I 151
• reperfusion bringsa massiveinfluxof calciumwhichleadsto activationof
phospholipases , endonucleases,proteases,
andDNAases; theresultofabove
mentioned enzymes actionis progressive
destruction
of all cellstructures.
3. Longerperiodof ischemiamay produceirreversiblecell injury during
ischemiaitself withoutany roleof reperfusion

Injury by free radicals

Oneof importantmechanisms of cell injuryis injuryinducedby free radicals,
particularlyby activatedoxygenspecies.Freeradicalinjury is emergingas a
final commonpathwayof tissueinjury in suchvariedprocessesas chemical
and radiationinjury,oxygenand other gaseoustoxicity, cellularaging, mi-
crobialkilling by phagocyticcells,inflammatoryinjury,tumor destructionby
macrophages, andothers.
In mostatoms, the electronorbitalsare filled with pairedelectronsspin-
ning in oppositedirections,thus cancellingeachother's physicochemical re-
activity.A freeradicalis a chemicalspeciesthathasa singleunpairedelectron
in an outerorbital.
In this state,the radicalis highlyunstableandcanenterthe reactionswith
cellularconstituents,particularlykey moleculesin cell membranesand nu-
cleicacids.Moreover , free radicalscanestablishchainreactions , sometimes
thousandsof eventslong,as the moleculesthey reactwith in their turn form
free radicals.Chainreactionsmaybranch,causingevengreaterdamage .

Free radicals may be gen e rat e d in th e following w a ys:

1. Byabsorbingradiantenergy(UVrays,x-rays).
2. Freeradicalformation is a byproductof manynormalcellularreactionsin
the body, includingenergygeneration , breakdownof lipidsandproteins,
andinflammatoryprocesses . Forexample,free radicalgenerationis the
mainmechan ism for killingmicrobesby phagocyticwhitebloodcells.
3. As partof the metabolism of drugsandpoisons.
 152 I Part I Generalpathophysiology

Th e most important fre e radicals are three partial-

ly r e duc e d inte rmed iate species between 0 2 and
H 20 :

• superoxide(C\)anionmaybe generatedby direct autooxidationof 02

duringmitochondrialelectrontransportreaction
, or it canbe produced
enzymaticallyby xanthineoxidaseandcytochromeP450 ;
• hydroxylradical(OH·)is formedby two waysin biologicprocesses:by
radiolysisof waterand by reactionof hydrogenperoxidewith ferrous
ions;
• hydrogenperoxide(H202} is reducedto waterenzymatically by catalase
andglutathioneperoxidase .

Theeffectsof thesereactivespeciesarewide-ranging,but four reactions

areparticularlyrelevantto cell injury.
1. Lipid peroxidationof membranes.Free radicalsin the presence of
oxygenmay causeperoxidationof polyunsaturated fatty acidsin cell
membranes.Suchfatty acids possessdoublebondsbetweensome
of the carbon atoms. Such bonds are vulnerableto attack by free
radicals.The lipid-radicalinteractionsyield lipid peroxides,whichare
themselvesunstableandreactivetoo, thenchainreactionof oxidation
starts,which resultsin extensivemembrane,organellar,and cellular
injury.
2. Nonperoxidative mitochondrialinjury.This effectis not dependenton
lipid peroxidationandresultsin lossof mitochond rial function,mimick-
ing the effectsof hypoxiaon mitochondria .
3. Lesionsin deoxyribonucleic acid (DNA). Freeradicalscausebreaksin
the singlestrandsof the DNA.SuchDNAinjuryr:naybethe causeof cells
deathandtheir malignanttransformat ion.
4. Oxidationof proteins.Oxygen -derivedfree radicalscause cell injury by
oxidation of proteinmacro,molecules,crosslinking of suchlabileamino
acidsasmethionine , histidine,cystine,andlysine.Theendresultis deg-
radation of cytosolice11.,ymesandcell destruction.
Mechanismsof tissueand cellularinjury Unit 2 I 153
Theeffectof free radicalsuponthe organismdependson the degreeof
their initiationand their elimination.Stress,aging, pollutedair, cigarette
smokeandexcessiveUVradiationcanaddto the numberof free radicals in
the body.Someof the free radicalsmayspontaneously decay.Superoxide ,
for example,is unstableanddecaysautomatically into oxygenandhydrogen
peroxide . In othercasesfree radicalsareneutralizedby specificsubstances,
namedantioxidants . Thus cells are more or less vulnerableto free radical
injury,dependingon the presenceandquantity of antioxidantsthat serveas
protectivemechanisms.

Antioxidants
are the substancesthat preventor slow the breakdownof
anothersubstanceby oxygen.Antioxidative
substancesaredividedinto enzy-
maticandnon-enzymatic ones.

Enzymatic antioxid a nts include:

• Thethioredoxin system , includingthioredoxinand thioredoxinreduc-

tase.In its activestate,thioredoxinactsas an efficientreducingagent,
scavengi ng reactiveoxygenspeciesand maintainingproteinsin their
reducedstate.Afterbeingoxidized,theactivethioredoxinis regenerated
by theaction of thioredoxinreductase.
• Theg/utathione system , includingglutathione, glutathione
reductase
, and
glutathione peroxidase. Glutathione peroxidase catalyzethebreakdown of
hydrogenperoxideandprotectslipidsin cellwallsfrom peroxidation.
• Superoxide dismutase (SOD},a classof closelyrelatedproteins found
in almostall livingcellsandin extracellularfluids.Superoxidedismutase
protectscellsby catalysingthe breakdownof the highly reactivesuper-
oxide anionintooxygenandhydrogenperoxide.
• Catalase , catalysesthe conversionof hydrogenperoxideto waterand
oxygenat ratesof up to 6,000,000 moleculesper minute.Catalasehas
a secondaryrole oxidisingtoxins including formaldehyde, formic acid
andalcohols.
 154 f Part I Generalpathophysiology

Theleading rolein non-enzymatic anti-oxidationis playedbyvitamins.

• VitaminA (Retinal),also synthesized by the bodyfrom beta-carotene ,
protectsdarkgreen,yellowandorangevegetables andfruits from solar
radiationinjury, andis thoughtto playa similarrolein the human body.
Carrots,broccoli,sweetpotatoes,tomatoes , kale, peaches andapricots
are particularlyrich sourcesof beta-carotene.
• VitaminC (Ascorbicacid)is a water-soluble compound that fulfills sev-
eralrolesin livingsystems.Importantsourcesincludecitrus fruits (such
as oranges , sweetlime, etc.), greenpeppers , broccoli, greenleafyveg-
etables, strawberries , blueberries
, rawcabbageandtomatoes .
• VitaminE is fat solubleandprotectslipids from oxidation.Sourcesin-
cludewheatgerm, nuts, seeds,wholegrains, green leafyvegetables,
vegetableoil, andfish-liveroil.

Anothergroup of non-enzymaticantioxidantsincludevitamincofactors
andminerals
• Coenzyme 010 is an antioxidantwhichis bothwaterandlipid soluble.It
is notclassifiedasa vitaminin humansasit canbemanufactured bythe
body, but quantitiesdecreasewith ageto levelsthat maybe lessthan
optimal,and levelsin the diet are generallylow. Supplementation with
CoQ10 hasbeenclinicallyprovento improvethe healthof gums.
• Seleniummust be taken in measuredamountsbecauselargedosesof
the elementcanbetoxic. Goodfood sourcesincludefish, shellfish, red
meat, grains, eggs,sunflowerseeds,chicken,turkey,garlic.
• Zincmaysafeguardred bloodcell membranes againstoxidativeeffects
of othermineralssuch as copper or iron.

Antioxidativepropertiesarealsopeculiarto carotenoids andbioflavonoids.

Carotenoids (Lycopene , Lutein, Alpha-carotene, Beta-carotene)areorgan-
ic pigmentsthat are naturallyoccurring in plants. In photosynthet ic organ-
isms, carotenoids playa vital rolein the photosynthetic reactioncentre.They
eitherparticipatein the energy- transfer process,or protectthe reactioncen-
ter from auto-oxidation.In non-photosyntheticorganisms , carotenoidshave
beenlinkedto oxidation-preventing mechanisms.
Mechanismsof tissueand cellularinjury Unit 2 I 155
, a subsetof polyphenolantioxidants
Bioflavonoids , are presentin many
darkberries,aswell as in certaintypesof coffeeandtea,especiallygreentea.

Chemicals induc e ce ll injury by one of two mechani sm s:

1. Directcytotoxic effect.Somechemicalscan act directlyby combining

with componentsof the cell and producecytotoxocitywithout requir-
ing metabolicactivation.The cytotoxicdamageis usuallythe greatest
to cells whichare involvedin the metabolismof such chemicals . For
example , in mercuricchloridepoisoning,mercuryproducesthe greatest
damageto thecellsof alimentarytractandkidney.Cyanideaffectthe cell
by blockingcytochromeoxidaseand breakingoxidativephosphoryla-
tion. Manyantineoplastic chemotherapeutic agentsandantibioticdrugs
alsoinducecell injuryby directcytotoxiceffects.
2. Conversion to reactivetoxicmetabolites. Most other toxic chemicals
are not biologicallyactivebut can be convertedto reactivetoxic me-
tabolites.Althoughthesemetabolitesmightcausemembraneinjuryand
cell injury by direct bindingto membraneproteinand lipids,the most
importan t mechanismof cell injury involvesthe formationof reactive
freeradicalsandsubsequentlipid peroxidation.

Theabovementioned mechanisms of cellinjurycan producesublethal andre-

versiblecellulardamage or lead to irreversi
ble injurywithcelldestructionor death.
Cellsdeathcanalso occurwithoutthe influenceof injuringfactorseither
whentheyhavecompleteda fixednumberof divisioncycles(around 60, the
Hayflicklimit) or at someearlierstagewhenprogrammed to do so.

Gener al mechanisms of cellular injury

Cell destructionand removalcan involve one of two mechanisms:pro-
grammedcell-death,whichis designedto removeinjuredor worn-outcells,
or necrosis,whichoccursin irreversiblydamagedcells.
 156 I Part I Generalpathophysiology

Programmed cell-deathis deathof a cell in anyform, mediatedby an intra-

cellularprogram.Theconceptof programmed deathassumesthatcertaincells
aredetermined to dieat specificstagesandspecificsitesduringdevelopment.
Therearetwo typesof programmedcell-deathdescribed:
1. Apoptosis or type I programmed cell-death;
2. Autophagy or type II programmedcell-death.
Apoptosis is a programmedcell deathas signalled by the nucleiin nor-
mallyfunctioninghumanandanimalcellswhenthe ageor stateof cell health
andcondition dictates. It is an activeprocessrequiringmetabolicactivityby
the dyingcell.
Apoptosisis thought to be responsiblefor severalnormal physiologic
processes , including programmeddestructionof cells during embryonic
development , hormone-dependentinvolutionof tissues,deathof immune
cells, cell deathinduced by cytotoxicT cells,and cell deathin proliferating
cell populations.During embryogenesis, in the developmentof a number
of organssuchas the heart, which beginsas a singlepulsatingtubeand is
graduallymodifiedto becomea four-chambered pump,apoptoticcell death
allowsthe next stageof organdevelopment.It also separates the webbed
fingers andtoes of the developingembryo. Apoptoticcell deathoccurs in
the hormone-dependent involution of endometrialcellsduringthe menstrual
cycleandin the regressionof breasttissueafter weaningfrom breast-feed-
ing. Thecontrolof immunecell numbersand destructionof autoreactiveT
cells in the thymushavebeencreditedto apoptosis.CytotoxicT cells and
naturalkiller cells are thoughtto destroytargetcells by inducingapoptotic
cell death.
Apoptosisappearsto be linkedto severalpathologicprocesses.Pathol-
ogycal processesmay developmentin situationwhen apoptosisincrease
(Fig.12)andalsowhenapoptosisreduce(Fig.13). Forexample,suppression
of apoptosismaybea determinantin the growthof cancers.Apoptosisis also
thoughtto beinvolvedin the celldeathassociated with certainviralinfections,
suchas hepatitisB andC, andui cell deathcausedby a varietyof injurious
agents,suchas mild thermal injuryandradiationinjury.
The characteristicmorphologicchangesof the cell in apoptosisare the
following.
Mechanismsof tissue and cellularinjury Unit 2 I 157
External Internal
factors factors

~
-poisons
- infections
-radiation
/4 geneticdefects
'schemia
unediseases

Aplastic Diabetes Immune Liver Neurona

l
anemia mellitus deficiency failure degeneration

Fig.12.Pathological
situations
with activation
of apopto
tic cell death

External Internal
factors factors

- genet
ic defects
- endocrine
disorders

Autoimmune Persistent
diseases infections

Fig.13.Pathological
situations
withinhibition
of apoptotic
celldeath
158 I Part I Generalpathophysiology

1. Involvementof singlecells or small clustersof the cells in the back-

groundof viablecells.
2. Shrinkageof the cell with densecytoplasmandalmostnormalorgan-
elles.
3. Formationof apopticbodies(membrane-bound near-spherical bodies
containingcompactedorganelles).
4. Condensation of chromatinaroundthe peripheryof nucleus.
5. Inflammatoryresponsearoundapoptosisis absent.
6. Phagocytosis of apopticbodiesby macrophages.

Therearetwo pathwaysof apoptosisinitiation:extrinsicandintrinsic.

1. Apoptosis triggered by internal signals. Internal signaling is gone
through BCL-2proteinexpression . The genecodingthis proteinwas
discoveredin a B-cellleukemia(hencethe name).Bcl-2is locatedin the
membranes of the endoplasmic reticulum(ER),nuclearenvelope,andin
the outermembranes of the mitochondria .
The intrinsicor mitochondrialpathwayincludesformationof the apopto-
some. Apoptosomeis the complexof cytochromeC (that is releasedfrom
damagedmitochondria) , Apaf-1(apoptoticproteaseactivatingfactor-1), cas-
pase9 (type of proteasethat cleaveproteins)and ATP.The actionof this
complexresultsin digestionof structuralproteinsin the cytoplasm , degrada-
tion of chromosomalDNA,andphagocytosis of thecell.
2. Apoptosistriggeredby externalsignals.Theextrinsicor deathreceptor
pathwayuses Fasand the TNFcell surfacereceptors.Bindingof the
complementary deathactivator(Fasl andTNFrespectively) transmitsa
signalto the cytoplasmthat resultsin initiationof a cascadeof caspase
activationleadingto phagocytosis of the cell.

Theearlystepsin apoptosisarereversible.In somecases,finaldestruction

of the cell is guaranteed onlywith its engulfmentby a phagocyte .
Autophagy, is an evolutionarilyconserved
, geneticallycontrolledcell sur-
vival pathwayinvolvingthe degradationof cytoplasmicconstituents,andthe
recyclingof ATPand essentialbuildingblocksfor the maintenance of cel-
lular biosynthesisduring nutrientdeprivationor metabolicstress.This eel-
 Mechanismsof tissue and cellularinjury Unit 2 I 159
lular self-consumptionprocess is
characterizedby sequestrationof
bulk cytoplasm , long-livedproteins
and cellular organellesin double-
membranevesicles,calledautopha-
gosomes,which are ultimatelyde-
liveredto and degradedin the lyso-
somes. Autophagyplays a critical A B
rolein cellularhomeostasis by elim-
inatingexcessive, damagedor long- Fig.14.The morphologyof apoptosis
lived proteinsand organelles , thus (A) andnecro
sis(B)
preservingthe quality of essential
cellularcomponents . Autophagyis intricately implicatedin both healthand
disease.Theprocesswhentheautophagyleadto the destructionof the main
cell structuresnamedas autophagicprogrammedcell death (also known
· as cytoplasmiccell death).In this processan importantrole playlysosomes
and lysosomalenzymes.Autophagydefectstake part in the pathogenesis of
diversediseases , includingmyopathyneuronaldegeneration , microbialinfec-
tion, inflammatoryboweldisease,agingandcancer.
Necrosis is definedas a focal deathalongwith degradationof tissue by
hydrolyticenzymesreleasedby the cells. Necrosisdiffers from apoptosis
in that it involvesunregulatedenzymaticdigestionof cell components , loss
of cell membrane integritywith uncontrolledreleaseof the productsof cell
deathinto the intracellularspace, andinitiationof the inflammatoryresponse
(Fig.14). In contrastto apoptosis,whichfunctionsin removingcells so that
newcells can replacethem, necrosisoften interfereswith cell replacement
andtissueregene ration.
Necrosiscanbecausedbyvarietyof agents- hypoxia,physicalandchemi-
cal agents,microbialagentsetc. With necroticcell death,there are marked
changesin the appearance of the cytoplasmiccontentsandthe nucleus.The
nuclearchangesincludecondensation of nuclearchromatin(pyknosis)which
may either undergo dissolution (karyolysis)or fragmentationinto many
granularclamps(karyorrhexis). Cellsandtheir organelles swell(becausethe
ability of the plasmamembraneto controlthe passageof ions and water is
 160 I Part I Generalpathophysiology

disrupted);the cellcontentsleakout, leadingto inflammationof surrounding

tissues.Therearefive majortypesof necrosis : coagulative, liquefactive(col-
liquative), caseous, fat andfibrinoidnecrosis.
Coagulative necrosis is the mostcommontypeof necrosis.Duringcoagu-
lationnecrosis,acidosisdevelopsanddenatures the enzymatic andstructural
proteinsof the cell.Thistypeof necrosisis characteristic of hypoxicinjury (in
infarcted areas) andlessoftenfrom chemicalagents(acids).
Liquefactionor colliquativenecrosisoccursdueto degradationof tissue
by the actionof powerfulhydrolyticenzymes . An exampleof liquefaction
necrosis is the softeningof the centerof an abscesswith dischargeof its
contents.
Gaseousnecrosiscombinesfeaturesof both coagulativeand liquefactive
necrosis. It is most commonlyfound in the centerof tuberculosisgranulo-
mas, andis thoughtto resultfrom immunemechanisms
Fatnecrosisis a term for necrosisin fat, causedeitherby releaseof pan-
creatic enzymesfrom the pancreas(acutepancreasnecrosis)or bytraumato
fat, either by a physical blow or by surgery(traumaticfat necrosis).
Fibrinoidnecrosisis characterized bydepositionof fibrin-likematerialusu-
ally as a resultof immunologictissue injury. The sameprocessoccursin
arteriolesin hypertension , in pepticulcer development etc.

Mech anisms of cell adapt ation du ring c ellular injury

As it wasconcernedearlier,cellsmustconstantlyadapt, evenundernormal
conditions, to changesin their environment. Thesephysiologicadaptations
usually representresponsesof cells to normalstimulationby hormonesor
endogenous chemical substances. Forexample,as in the enlargement of the
breastandinductionof lactation , by pregnancy.Pathologicadaptatiansmay
sharethe sameunderlyingmechan isms, but they providethe cellswith the
abilityto modulatetheir envircAment andperhapsescapeinjury. Cellularad-
aptation,then, is a statethat liesintermediatebetweenthe normal, unstressed
cell andthe injured, overstressed cell.
Mechanisms of tissueand cellular injury Unit 2 I 161
Cellular adaptation is provided both with intracellu-
lar and intercellular mechanisms of cellular adapta-
tions . The most important of them provide:

• compensation of energymetabolism disturbancewith decreaseof cell's

functional activity;
• protectionof cellsmembranes ;
• compensation of water-ion misbalance;
• repairof cellgenome .

Co m pe nsation of en ergy m et ab olism d istur banc e

Cell injury is usually accompanied with mitochon-
drial dysfunction and decrease in ATP production .
These changes start the following compensatory
processes:

• increased ATPproduction by the means of glycolysis;

• increaseof enzymes activitywhicharetaking partin reduction-oxidation
reactions;
• activationof ATPtransport andincrease ATPuse effectiveness in thecell;
• decrease of cell's functionalactivity anddecreaseof anabolic processes
in the cell.

Protection of c ells m embranes

Protection of cells membranes is realized with acti-

vation of:

• antioxidantsaction - enzymaticand non-enzymatic antioxidantsinacti-

vatefreeradicalpreventingtheir pathogen
ic effects;
 162 I Part I General pathophysiology

• cells buffer systemactivation- leadsto neutralization of intracellular

acidosis,whichoccursdueto highactivityof enzymes;
• endoplasmicreticulumenzymesactivation- it increasesinactivation of
toxic substanceswhichwereformedin the cell;
• activationof cellularstructuresreparationwhich helpto repair mem-
branesof the cell andcellularorganelles
.

Compensation of water-ion imbalance is provided with

• activationof ion "pumps"energysupply;

• increaseof ion-transport ing enzymesactivity;
• activationof cell's buffersystem.

-- - -- Normal -- -----,!
Change
incellsizeof Change
in celltype
number

Atrophy

Displasia
Hypertrophy

Hyperplasia Metaplasia

Fig.15.Thetypes ofcellularresponse
Mechanismsof tissueand cellularinjury Unit 2 1163

Re pair of cell g e nom e is provid e d with th e followin g

m e chanisms:

• revealingandelimination of damagedDNAfragment;
• replacement of damagedDNAfragments;
• eliminationof DNAruptures;
• normalization of DNAtranscription andtranslation.

Cellsalso may adaptby undergoingchangesin their size, number,and

type.Thesechanges , occurringsinglyor in combination, mayleadto atrophy,
hypertrophy, hyperplasia, metaplasia , anddysplasia (Fig.15).
Atrophy.Whenconfrontedwith a decreasein work demandsor adverse
environmenta l conditions,mostcellsareableto revertto a smallersizeand
a lowerand moreefficientlevelof functioningthat is compatiblewith sur-
vival.Thisdecreasein cell sizeis calledatrophy.Cellsthat are atrophiedre-
-duce their oxygenconsumptionand other cellularfunctionsby decreasing
the numberandsizeof theirorganelles andotherstructures.Therearefewer
mitochon dria, myofilaments , andendoplasmicreticulumstructures.Whena
sufficient numberof cellsareinvolved , the entiretissueor muscleatrophies.
Thegeneralcausesof atrophyare:decreased workload,loss of innervation,
diminishedbloodsupply(ischemia),inadequatenutrition, loss of endocrine
stimulation andaging.
Agingisa physiologic causeofatrophythatisatrophyisa normalprocess of ag-
inginsometissueswhichcouldbedueto lossof endocrine stimulationor arterio-
sclerosis.Forexample atrophyof lymphoid tissueinthymusandlymphatic nodes.
Others stimuli are clearly pathologic . The decreasedworkloaduponthe
skeletalmusclesresultsin disuseatrophy. An extremeexampleof it maybe
seenin the musclesof extremitiesthat havebeenencasedin plastercasts.
Because atrophyis adaptiveand reversible, musclesizeis restoredafterthe
cast is removed.Denervat ion atrophyoccursin the musclesof paralyzed
limbs. lschemicatrophyoccurswhenthereis gradualdiminishmentof blood
supplydueto atherosclerosis ; it may resultin shrinkageof affectedorgan
(e.g.atrophyof brainin cerebralatherosclerosis) . In the caseof inadequate
nutritionor evenstarvationcellsdecrease their sizeandenergyrequirements
 164 I Part I Generalpathophysiology

as a meansof survival.Lossof endocrineregulatorymechanismsresultsin

reducedmetabolicactivityof the tissueand henceits atrophy.Forexample,
in women, the lossof estrogenstimulationduringmenopause resultsin atro-
phicchangesin the reproductiveorgans.
Hypertrophy refersto anincreasein thesizeof cellsand,with suchchange,
an increasein the sizeof the organ.It is usuallyseenin musclesbecause this
typeof tissueis not capableof mitoticactivity.Hypertrophy canbecausedby
increased functionaldemandor byspecifichormonalstimulationandmayoc-
cur underbothphysiologicandpathologicconditions.Theincreasein muscle
massassociatedwith exerciseis an exampleof physiologichypertrophy. An-
otherexampleof physiologichypertrophyaffectedby hormonalstimulation
is enlargedsizeof the uterusin pregnancy. Thecellularhypertrophyis stimu-
latedby estrogenthroughsmoothmuscleestrogenreceptors.
Pathologichypertrophyoccursas the resultof diseaseconditionsandmay
beadaptiveor compensatory. Exampleof adaptivehypertrophyis the myocar-
dialhypertrophy thatresultsfromvalvularheartdiseaseor hypertension. Com-
pensatoryhypertrophyis the enlargement of a remainingorganor tissueafter
a portionhasbeensurgicallyremovedor renderedinactive.Forinstance , if one
kidneyis removed,the remaining kidneyenlargesto compensate for the loss.
Hypertrophy eventuallyreachesa limit beyondwhichenlargement of mus-
cle massis no longerableto compensateincreasedworkload,and cardiac
failure, for example,ensues.At this stagea numberof "degenerative" chang-
es occursin the myocardialfibers.The limitingfactors for continuedhyper-
trophy aredueto limitationof the vascularsupplyto the enlargedfibers,to
diminishedoxidativecapabilitiesof mitochondria,or to alterationsin protein
synthesis anddegradation.
Hyperplasia is an increasein the numberof cellsof a tissueor organ.It oc-
cursin tissueswherecellsarecapableof mitoticdivisipnsuchastheepidermis,
intestinalepithelium, andglandulartissue.Hyperplasia is a controlledresponse
to anappropriatestimulusandceasesoncethestimulushasbeenremoved.
The stimuli that induce hyperplasiamay be physiologicor pathologic.
Therearetwo commontypesof physiologichyperplasia : hormonalandcom-
pensatory.Breastanduterineenlargement duringpregnancy areexamplesof
a physiologichyperplasia that resultsfrom estrogenstimulation.The regen-
Mechanismsof tissue and cellularinjury Unit 2 1165

erationof the liverthat occursafter partialhepatectomy(i.e., partialremoval

of the liver) is an exampleof compensatory hyperplasia.Hyperplasiais also
an importantresponseof connectivetissuein woundhealing, duringwhich
proliferatingfibroblastsandbloodvesselscontributeto woundrepair.
Mostformsof pathologichyperplasia aredueto excessivehormonalstim-
ulationor the effectsof growth factors on target tissues. Excess ive estro-
genproductioncan causeendometrialhyperplasiaand abnormalmenstrual
bleeding.Skinwartsarean exampleof hyperplasiacausedby growthfactors
producedby certainviruses,suchasthe papillomaviruses.
Metaplasia is a reversiblechangein whichoneadultcelltype (epithelialor
mesenchymal) is replacedby anotheradultcell type.Metaplasia is thoughtto
involvethe reprogramming of undifferentiatedstem cellsthat are presentin
the tissueundergoing the metaplasticchanges.Metaplas ia usuallyoccursin
responseto chronicirritationandinflammation. Metaplasiais bestseenin the
form of squamouschangethat occursin the respiratorytract in the habitual
cigarettesmoker.The normal columnarciliatedepithelialcells of the trachea
and bronchiare replacedfocallyor widelyby stratifiedsquamousepithelial
cells. Stonesin the excretoryducts of the salivaryglands, pancreas , or bile
ductsmaycausereplaceme nt of the normalsecretorycolumnarepitheliumby
nonfunctioning stratified squamous epithelium. A deficiencyof vitaminA induc-
es squamousmetaplasia in the respiratoryepithelium.In all theseexamples,
squamo usepitheliumis moreableto surviveundercircumstances in whichthe
morefragilespecialized epitheliummostlikelywouldhavesuccumbed.
Dysplasia is characterized by derangedcell growthof a specifictissuethat
resultsin cells that vary in size, shape, and organization.Minor degreesof
dysplasiaareassociated withchronicirritationor inflammation.Thepatternis
mostfrequentlyencountered in areasof metaplasticsquamousepitheliumof
the respiratorytract anduterinecervix.Althoughdysplasiais abnormal,it is
adaptivein thatit is potentiallyreversibleafterthe irritatingcausehasbeenre-
moved. Dysplasiais stronglyimplicatedas a precursor of cancer.In cancers
of the respiratorytract andthe uterinecervix,dysplasticchangeshavebeen
foundadjacentto thefoci of canceroustransformation.However , dysplasiais
an adaptiveprocessanddoesnot necessa rily leadto cancer.In manycases,
the dysplasticcellsrevertto theirformerstructureandfunction.
 166 I Part I Generalpathophysiology

Chapter 7. Pathophysiology of
Tissue Growth. Neoplasia

Neoplasia is a typicalpathologicprocesscharacterizedby unregulatedlimit-

lessgrowthof thetissue, which is not connected with thegeneralstructureof
the impairedorganandits functions.
Neoplas ia causesabout 13% of all humandeathsand havestable2-4
placeof deathscausein differentcountries.Accordingto the AmericanCan-
cer Society, 7.6 million peopledied from neoplasticdiseasesin the world
during2007year.Theincreaseof the quantityof deathsdependson the fol-
lowingtwo mostimportantfactors.
1. Pollutionof an environmental factors
2. Increasesof life termsof the population
Neoplasia mayaffectpeople at all ages,evenfetuses, but the riskfor most
vari~etlesincreaseswith age.The numberof reportedcasesof malignancy
increasesmarkedlyafterthe ageof 50.

Terminology of neoplastic diseases

Forthenameofabnormal growthsoftissuessomeclosely relatedtermsareused.
Firstly,it is tumor. Veryoftenthis term is alsousdfor abnormalswelling,
lumpor mass.However,the wordtumorhasbecomesynonymo uswith neo-
plasm, specificallysolid neoplasm.
Neoplasm is theterm which is moreoftenusedto describean abnormal
proliferation of genetically
alteredcells.Neoplasmscanbebenignor malignant.
Malignant neoplasm ormalignant tumoris synonymous to cancer.
Thenamecancerderivedfromthe Latin word for "a crab",assuch tumors
were perceivedto seizeuponadjacenttissueswith pincer-likeoutgrowths.
Cancer(malignantneoplasm)is a classof diseasesin whicha groupof cells
displayuncontrolledgrowth(divisionbeyondthe normallimits), invasion(in-
trusion on and destructionof adjacenttissues), and sometimesmetastasis
(spreadto otherlocationsin the bodyvia lymph or blood).
Mechanismsof tissue and cellularinjury Unit 2 1167

Benignneoplasm or benigntumoris a tumor (solidneoplasm)that have

onlylocalgrowth,doesnotinvadeothertissuesanddoesnotform metastases.

Class ificat ion of neo plasia

Cancersareclassifiedby thetypeof cellthat resemblesthetumor(histologi-
cal characteristic)and,therefore,the tissuepresumedto bethe originof the
tumor(locationof thetumor).
Bythis characteristicsall neoplasias aredividedinto somegroups.
Carcinoma is themalignanttumorderivedfrom epithelialcells.Thisgroup
represents themostcommoncancers,includingthecommonformsof breast,
prostate, lungandcoloncancer.
Sarcoma is the malignanttumorderivedfrom connectivetissue, or mes-
enchymalcells.
Lymphoma and leukemiat are malignancies derivedfrom hematopoietic
(blood-forming)cells.
Mesothelioma is the tumor derivedfrom the mesothelialcells liningthe
peritoneum andthe pleura.
Gliomais thetumorderivedfrom braincells.
Germcelltumors whicharederivedfromtotipotentcells.In adults is most
oftenfoundin the testicleandovary.
Choriocarcinoma is the malignanttumorderivedfrom the placenta.
Blastictumoror blastoma (usuallymalignant)resembles an immatureor
embryonictissue.Manyof thesetumorsaremostcommonin children.
Malignanttumors(cancers)are usuallynamedusing-carcinoma , -sarco-
maor -blastomaasa suffix,withthe Latinor Greekwordfor the organof ori-
gin asthe root.Forinstance , a cancerof the liveris calledhepatocarcinoma;
a cancerof thefat cells is calledliposarcoma.
Benign tumors (which are not cancers)are namedusing -oma as a
suffixwith the organ nameas the root,for e.>5ample myomaor fibroma.Un-
fortunately, somecancersalsousethe -omasuffix, for examplemelanoma.
Exceptuncontrolledgrowth, invasionandmetastasis formationtheremany
otherdifferences betweenbenignandmalignanttumors(Table12).
 168 I Part I Generalpathophysiology

Table12.Differencebetweenbenignand malignant tumors

Benign '
~ :-.:\~0ifi:;:~
,.:·:
1 Growth
rate Slow Rapid

2 Mitosis Few Many

3 Nuclear
chromatin Normal Increased
4 Differentiation Good Poor
5 Localgrowth Expansive Invasive
6 Encapsulation Present Absent .
7 Vesse
l invasion None Frequent
8 Metastasis None Frequent

9 Effectof host Ofteninsignification Significant

-cachexy,
death.

Benigntumorsgenerallyhavea verygoodprognosisandleadonly rarelyto

death.In contrast, malignanttumorsarea majorcauseof mortality.

Etio logy of tumors

Historyof etiologyunderstand ing
• In 1775,in Englandchimneycleanercancerwasdescribedfor thefirst time
• lshikava& Yamigavain Japanon the beginningof 20-th century pro-
ducedexperimentalcancerof skin in rabbitsby usingcoal powderfor a
long term contactwith earof the rabbit ----
• Ellerman& Bangin 1908 producedexperimentalleukemiain hensby
usingdamagedleucocytesfrom henswith leukemia
• In 1910 Rausproducedsarcomain hens(Raussarcoma)
• In 1936Bittner describedmilkfactor asa riskfactorfor tumordevelopment
• In 1940 Zilberdescribedvirusestheoryof tumor development
• Investigationsof the propertiesof X-ray radiationleadsto understand-
ing the roleof physicalfactors in tumor development
Mechanismsof tissueand cellularinjury Unit 2 1169

Theseinvestigationshaveleadto understanding etiologyof tumorsandnow

weknowthatcancerpathogenesis istraceable backto DNAmutationsthatimpact
cellgrowthandmetastasis.SubstancesthatcauseDNA mutations areknownas
mutagens, and mutagensthat causecance rs are known as carcinogens . Car-
cinogenic
substances have3 typesof origin: chemical, physicaland biological.

Chemical carcinogens may c a use development of neo-

plasia either directly or indirectly. They can be grouped
into three classes according to the mechanism by
which they stimulate development of ne oplasia:

• Genotoxic: causedirectdamage to DNAbyformingchemicalDNAadducts.

• Mitogenic: bindto receptorson or in cellsand stimulatecell division
withoutcausingdirectDNA damage.
: producetissuedamageand leadto hyperplasiawith cyclesof
• Cytotoxic
tissueregene rationanddamage .
• Chemicalcarcinogens canbefurtherdividedinto two groups:
• Directacting : theagentis capableof directlycausingneoplasia.
• Procarcinogens : theagentrequiresconversion to anactivecarcinogen.
Thisconversionoftentakesplaceby normal metabolicpathways .

Themainsourceof humanexposuresto carcinogens todayis man-made

chemica l compounds. Development of civilizationleads for the increase
quantityof chemicalsubstances , medicines
, andotherwith differentchemical
structures.Thevastmajorityof industrialchemicalshaveneverbeentested
for theirpotential to causeor promotecancer.

The main groups of chemical cancirogens by struc-

ture are as follows:

• Polycyclichydrocarbons, foundin tars, are amongthe potentagentsin

cigarettesmokethat causelung cancer.
 170 I Part I Generalpathophysiology

• Aromaticaminesare mainlyencountered throughindustrialexposure

(e.g. rubberor dyeindustry)andareconvertedto activeagentsin theliver.
• Nitrosamines havebeenshownto be potent carcinogensin animals,
andin humansthereis a pathwayfor conversionof dietarynitritesand
nitratesto nitrosaminesby gut bacteria.
• Alkylating agentscanbinddirectlyto DNAandaredirectlymutagenic . They
arerarein theenvironment,butexamples areusedincancerchemotherapy.

Decades of researchhavedemonstrated the link betweentobaccouseand

cancerin the lung, larynxand manyotherorgans.Tobaccosmokecontains
overfifty knowncarcinogens, includingnitrosamines andpolycyclicaromatic
hydrocarbons. Tobaccois responsiblefor aboutone in three of all cancer
deathsin the developedcountriesof the world.

Phys ica l carcinogens (irradiation)

There are two main effects of DNA damage through

irradiation:

• Formationof DNAbreaks.
• Development of DNAinstability.

Exposureto radioactivematerialin the environmentis a morecomplexis-

sueasthetypeof tumor is relatedto the typeof exposyre.

For example:

• Inhalationof radioactivedust or gas (e.g.radon)increasesthe risk of

carcinomaof the lung.
• Ingestionof radioactive
iodineincreases the riskof carcinoma
of the thy-
roid.
 Mechanismsof tissueand cellularinjury Unit 2 I 171
of radioactive
• Incorporation metalsinto boneincreasesthe risk of tu-
morsof bonemarrowandbone.

A frequentlyoverlookedsourceof radiation , which is a major causeof

neoplasia
, is UVlightin sunlight.Thisis knownto increasethe risk of devel-
opmentof manytypesof malignantskintumor.

Biologic al ca rcinogens
Manycancersoriginatefroma viralinfection.Thisis especially
truein animals
suchas birds,miceetc.Butonly12% of humancancerscanbeattributedto
a viralinfection(Table13).

· Table13. Virusesimplicatedin human neoplasia

· Burkitfslymphoma
·Nasopharyngea l carcinoma
Other8-celllymphomas andsomecasesof
Hodgkin's disease
Hepati
tis Bvirus(HBV) DNA Hepatocellul
ar carcinoma
Humanpapillorn;ivirus. DNA Cervical
'carcinoma
(HPV) . :, . ,, ..: ,.. Someformsof carcinomaof theskin
Humanherpesvirus
-8 DNA Kaposisarcoma
{HHV-8)
Human T-ce11
'1eukemia
·· · · RNA _T-cell\eukemia/lymphoma
virus(HTLV-1i ._:·

Main virusesthatareknownto causecancersuchasHPV (cervicalcancer),

HepatitisB (livercancer),andEBV(atypeof lymphoma),areall DNAviruses.
 172 I Part I Generalpathophysiology

It is thoughtthat whenthe virus infectsa cell,it insertsa partof its own DNA
nearthe cell growthgenes,causingcell division.Thegroupof changedcells
thatareformedfromthefirst celldividingall havethesameviralDNAnearthe
cellgrowthgenes.Thegroupof changedcellsarenowspecialbecauseoneof
the normalcontrolsof growthhasbeenlost.
Onlyone RNAvirus HTLV-1havespecificenzymereversetranscriptase
thattranscribessingle-stranded RNAintosingle-stranded DNA.Thisalsomay
causecelldivision.
The mode of virally-inducedtumors can be dividedinto two, acutely-
transformingor slowly-transforming. In the acutely-transformingviruses,
the virus carriesan overactiveoncogenecalledviral-oncogene (v-onc), and
the infectedcell is transformedas soonas v-oncis expressed . In contrast,
in the slowly-transforming viruses,the virus genomeis insertsneara pro-
to-oncogenein the host genome . The viral promoteror othertranscription
regulationelementsthencauseoverexpression of that proto-oncogene. This
inducesuncontrolledcelldivision.Because thesiteof insertionis not specific
to proto-oncogenes andthe chanceof insertionnearany proto-oncogene is
low, the slowly-transforming viruseswill causetumors much longerafter
infection thanthe acutely-transforming viruses.

Internal factors of carcinogenesis and heredity

Also in the organismsomesubstancesare presentthat havepropertiesof
procancirogens andnamedendogeniccarcinogens.

The main endogenic carcinogens are the following:

• Somehormones canactina similarmannerto non-mutagenic carcinogens

in thattheymaystimulateexcessive cellgrowth;a well-estab
lishedexam-
pleis the roleof hyperestrogenicstatesin promotingendometrialcancer.
• Derivatives of the aminoacidthryptofan- indol.
• Bileacidsandcholesterol(frombileacids).
Mechanismsof tissueand cellularinjury Unit 2 I 17 3
• Freeradicalsandperoxide.

Someforms of cancerare sporadic, meaningthat there is no inherited

causeof the cancer.Thereare,however,a numberof recognisedsyndromes
wherethereis an inheritedpredisposition
to cancer,oftendueto a defectin a
genethatprotectsagainsttumorformation.Forexamplecertaininheritedmu-
tationsin the genesBRCA 1 andBRCA2areassociated with an elevatedrisk of
breastcancerand ovariancancer; familial adenomatous polyposisan inher-
ited mutationof the APCgenethat leadsto earlyonsetof colon carcinoma.
Furthermore , Downsyndromepatients,who havean extrachromosome21,
areknownto developmalignancies suchas leukemiaandtesticularcancer.

Pathogenes is of tumors (carcinogenesis)

Historyof pathogenes is understand
ing
• Temin& Baltimorin the 1970's found enzymein virusesRNA(reverse
transcriptase) , whichcontrolsynthesisof DNA
• B.Amesatthesametimechecked upcarcinogenic
substancesonmutagenic-
ity effectsandfoundoutthedependence of mutagenicity
oncarcinogenicity.
• In1979,Wainberg producedtumorsbyusingpartsof DNAfromtumorcells.

This investigationsleadsfor the conclusionthat developmentof tumors

dependfrom the specificchangesin DNA-mutations.
Canceris fundamentally a diseaseof regulationof tissuegrowth.In orderfor
a normalcellto transforminto a cancercell,functionof geneswhichregulate
cell growthanddifferentiation mustbe change.Geneticchangescanoccurat
manylevels, from gainor loss of entirechromosomes to a mutationaffect-
ing a singleDNAnucleotide. Therearetwo broadcategoriesof geneswhich
are affectedby thesechanges.Oncogenes may be normalgeneswhich are
expressedat inappropriately high levels,or alteredgeneswhich havenovel
properties.In eithercase,expressionof thesegenespromotesthe malignant
phenoty peof cancercells.Tumorsuppressor genesaregeneswhichinhibitcell
division,survival,or otherpropertiesof cancercells. Tumorsuppressorgenes
 174 I Part I General pathophysiology

Stimuluscauses
geneticalteration
to cell

Normal
cells ~ +
1
.~1~1~
~-~[~J Altered
I
genesfor:
• growthfactor
• growthfactorreceptors
• signaltransduction
Transformed
cells • transcription
regulation
• DNArepair
~ • cellsurvival
r·-1-;. .r;-r:-i
1
• -- J transformed
-- cellsprolifer-
- ------ ~ -

atewithpoorregulation
of growthasa resultof
Neoplasm geneticchanges andde-
velopsmutation

Fig. 16.Pathophysiolog
y of tissuegrowth
andtransformation

areoftendisabledby cancer-promoting geneticchanges.T1pica lly, changesin

manygenesarerequired to transform a normalcell into a cancer cell (Fig. 16).

The genetic reasons for .neoplastic transformation

are variable : ,

• Point mutationsin oncogenecausing production of abnormally func-

tioning product or lossof a suppressor.
Mechanismsof tissueand cellularinjury Unit 2 f 175

• Geneamplificationcausingexcessive productionof oncoprotein product.

• Chromosomal rearrangements wherebyan oncogeneis activatedinap-
propriatelyby anotherpromoterregion.
Thereis nowmuchevidenceto suggestthatthis geneticdamageis a mul-
tistepdevelopment,requiringthe interactionof severalprocesses , oftenover
a periodof manyyears.
Thefollowingthreestepshavebeendefinedin carcinogenesis .
Initiation:inductionof geneticchangesin cells.In experimental chemical
carcinogenesis in the skin, the Harveyrasgenehasbeenidentifiedas being
frequentlymutated.Thisgeneis involvedin epidermalproliferationandwhen
it becomesabnormalepidermalcellsarelessresponsive to signalsthat nor-
mallycauseterminaldifferentiation.
Promotion : inductionof cell proliferation.Inthisphaseof carcinogenes is a pro-
motingagen t, eithera mitogenor a cytotoxicagent,bringsaboutincreased cell
proliferation.Promotionis initially reversible if thepromotingagentis withdrawn.
Progression: If thereis persistentcell proliferation then initiatedcellsac-
quiresecondarygeneticabnormalities in oncogenes whichfirst leadto dys-
regulationandeventually to autonomouscellgrowth.Theultimateend-point
of progressionis the development of an invasiveneoplasm .
Whilemanyenvironmental agentsfit into the categoriesof initiatingand
promotingagents,somefactorscanactas bothinitiatorandpromoter(com-
pletecarcinogens).

The following four main genetic mechanisms are

thought to have a role in th e development of most
human neoplasms:

• Expression of genes resultingin inappropriateactivity of products

which, undernormalcircumstances , stimulategrowth. Suchgenesare
termedoncogenes andact in a dominantfashion.
• Lossof activity of geneswhich,under normalcircumstances,produce
productsthat inhibitcell growth.Suchgenesaretermedtumorsuppres-
sor genes or anti-oncogenes .
 176 I Part I Generalpathophysiology

• Over-expression of geneswhich,undernormalcircumstances, produce

productsthat preventnormalcell death. Failureto eliminategenetically
damagedcellsallowscontinuedgrowthof tumors.
• Lossof activityof geneproductswhich,undernormalcircumstances,
would repairdamagedDNA.Lossof activity leadsto a stateof DNA
instability with the developmentof somaticmutationsin oncogenesor
tumorsuppressorgenes.

Role of oncogenes
Oncogenes maypromotecellgrowththrougha differentpathways . Somecan
producehormones,a chemicalmessengers betweencells whichencourage
mitosis.Whena hormonereceptoron a recipientcell is stimulated,the signal
is conductedfrom the surfaceof the cell to the cell nucleusto effectsome
changein genetranscriptionregulationat the nuclearlevel.Someoncogenes
arepartof thesignaltransductionsystemitself, or the signalreceptorsin cells
andtissuesthemselves, thuscontrollingthe sensitivityto suchhormones.
Mutations in proto-oncogenes , which are the normallyquiescentcoun-
terpartsof oncogenes, can modifytheir expressionandfunction,increasing
the amountor activityof the productprotein. Whenthis happens,the proto-
oncogenes becomeoncogenes, andthis transitionupsetsthe normalbalance
of cell cycleregulationin the cell,makinguncontrolledgrowthpossible.
Exampleof typicaloncogenes in cancerresearchis the rasoncogene.Mu-
tationsin the Rasfamilyof proto-oncogenes (H-Ras,N-Ras,K-Ras)arevery
common, beingfoundin 20% to 30% of all humantumours.

Role of tumor suppressor genes

Manytumor suppressorgenes,effect signaltransductionpathwayswhich
regulateapoptosis.Tumorsuppressorgenescodefor anti-proliferation sig-
nals and proteinsthat suppressmitosisand cell growth. Generally,tumor
suppressorsaretranscriptionfactorsthat are activatedby cellularstressor
Mechanismsof tissueand cellularinjury Unit 2 I 177
DNAdamage. Thep53protein, oneof the mostimportantstudiedtumorsup-
pressorgenes,is a transcriptionfactoractivatedby manycellularstressors
including hypoxiaand ultraviolet radiationdamage.OftenDNAdamagewill
causethe presenceof free-floatinggeneticmaterialas well as other signs,
andwill triggerenzymesandpathwayswhichleadto the activationof tumor
suppressorgenes.
In differentinvestigations showedthat nearlyhalf of all cancerspossibly
involvingalterationsin p53.p53clearlyhastwo functions:onea nuclearrole
as a transcriptionfactor, and the othera cytoplasmicrole in regulatingthe
cellcycle, celldivision,andapoptosis.Otherinheritedtumorsuppressorgene
syndromesincludeRb mutations , linkedto retinoblastoma , and APCgene
mutations,linkedto adenopolyposis coloncancer.
Alsoit's possibleto say aboutepigeneticshypothesisof carcinogenesis.
Epigenetics is thestudyof the regulationof geneexpression throughchemi-
cal, non-mutational changesin DNAstructure.Thetheoryof epigeneticsin
cancerpathogenesis is that non-mutational changesto DNAcan leadto al-
terationsin geneexpression . Normally, oncogenesare silent, for example,
because of DNAmethylation. Lossof thatmethylationcaninducetheaberrant
expression of oncogenes, leadingto cancerpathogenesis.

Mechanisms of organism antitumor protection

Understanding of main mechanismsof the tumor development allowedto
dividedall factorsof the antitumordefenseof organismon three groups:
anticarcinogenic,antitransformative
andanticellular(Fig.17).
Anticarcinogenic mechanisms protectcellsfrom the influenceof the car-
cinogens.

This factors may include:

• CytochromeP450oxygenase systemwhichplaysan importantrole in

conversionof carcinogenic
factorsintothe noncarcinogenic
 178 I Part I Generalpathophysiology

Physical ..•.......

Chemical ·••·••·••·

Biological •-••••••••

Fig.17. Levels ofantitumor protectivemechanisms

• Normalexcretionof urine, fecesandbile whichdecreaseaccumulation

of pro-carcinogensin organsandtissues
• Freeradicalinhibitionwhichleadsto thedecrease
activation
offreeradicals
• Antiviral
activityoftheorganismwhichblockstheactionofoncogenicviruses.

Antitranstormative
mechan
isms includethe actionof the factorswhich
blockthe processof transformation of normalcellsto tumor.
• Antimutagen icityfactorsincludespecificenzymes fromwhichdepended
control of replicationof DNAand RNA.This enzymesincludereverse
transcriptase, endonucleases, polymerases .
• Antioncogenicmechanismsincludethe action of tumor suppressor
genes.Themostfamousof this genesare:
• suppressorgenep53which is locatedon chromosome 17andon which
the activation of apoptoticpathwaysdepends;
Mechanismsof tissueand cellularinjury Unit 2 I 179
• suppressorgenewhich is locatedon chromosome13 and is termed
Rb. Themainfunctionof Rbis the suppression
of protein synthesison
which celldivision depends.

Anticellular mechanismsof antitumordefenseincludeactionof factors

whoseactivationleadsto thedestructionof transformative cells.Thismecha-
nismscanbe immuneandnonimmune.
Immune or specific mechanism in whichtakepart T-lymphocy tes
• COBT cells, upon beingpresentedwith antigenby MHCclass I, can
directlykill the cancerous
cell by secretionof specificprotein- perforin.
• CD4T cells were not involved directly in antitumour immunity, but
rather functionedsimply in the priming of CD8T cells, throughthe
activationof antigenpresentingcells(APCs)andincreasedantigenpre-
sentationon MHC classI, as well as secretionof excitatory cytokines
suchas IL-2.

Nonimmune or nonspecific mechanism which de-

pends on the action of som e factors:

• TNF-alpha inducesapoptoticcelldeathandinhibitscarcinogenesis.
• Properdininducesalternativepathwayfor the complementactivation
anddestructionof thetumorcellmembrane .
• Interferonsare antiviralagentsandcanfight tumorsby the activationof
somecomponentsof the immunesystem
• Naturalkillersplaya majorrole in the rejectionof tumorsand cells in-
fectedbyviruses;thecellsarekilledby releasingperforin andgranzyme
that causethetargetcellto die by apoptosis.

Symptoms of cancerdependon the locationof the tumor. Cancersymp-

tomscanbedividedinto threegroups.
Localsymptoms : unusuallumpsor swelling(tumor), hemorrhage (bleed-
ing), pain and/or ulceration. Compressionof surrounding tissuesmaycause
specificsymptomswhichdependon theorgan.
 180 I Part I Generalpathophysiology

Systemicsymptoms: weight loss, poor appetite,fatigue and cachexia

(wasting),excessivesweating(nightsweats),anemiaandspecificparaneo-
plasticphenomena (dependon the specificfunctionalactivityof the tissues).
Symptoms of metastasis (spreading):enlargedlymphnodes, coughand
hemoptysis,hepatomegaly , bonepain,fractureof affectedbonesandneuro-
logicalsymptoms.
All the symptomsdependon the changesin the tissuestructureandfunc-
tion whenthe tumor develops.Mostimportantchangesthis is tumorsatypia
or anaplasia.
Anaplasiais the abnormallackof differentiationin cells.It is characteristic
of malignanttumorsandusuallyrefersto a reversalin cell differentiation.
Manytissuesin the humanbodycontainstemcellswhichareundifferenti-
atedand can self-renewthroughcell division.Being undifferen tiatedmeans
that stemcells are multipotentor multidifferential; they can becomeone of
severalcelltypesdependinguponthe needsof the body.Forexample,stem
cellsin the bonemarrowareableto differentiateintoall the differenttypesof
bloodcells.
Anaplasiaoccurswhendifferentiatedbodycells returnto an undifferen ti-
atedstate,oftenforminga tumor.Cellsundergoinganaplasia alsooftenshow
an increasedability to multiply.Stemcellsthat fail to differentiateproperly
canalsobethe sourceof canceroustumors.
Anaplasia follow changesin cell division,biochemicalandphysico-chemi-
cal metabolicchanges,functionalandantigenicatypia.
Abnormalityof cell divisionis characterized by lack of Heyfliklimit. The
Hayflicklimit is the numberof timesa normalcell populationwill dividebe-
fore it stops.TheHayflicklimit wasdiscoveredby LeonardHayflickin 1961,
whenhedemonstrated thata populationof normalhumanfetalcellsin a cell
culture dividebetween40 and60 times. Onlyabnormalcellswith predomi-
nant cancercell properties are immortal.Thesecells producethe enzyme
telomerasethat keepsthe telomeresfrom shortening.Telomerase activation
is one of the most prevalentaberrationsin pre-cancerous lesions.For this
reasoncellsin cellculturesfrom tumorsmaydividedwithoutanylimit.
Biochemicaland physico-chemical changesin the tumor cells leadsto
somespecificmetabolicpathwaysandaccumulation of metabolicproducts.
Mechanismsof tissueand cellularinjury Unit 2 I 181
• Bythe Warburghypothesis, the use of glycolysisfor energyto sustain
cancergrowthis preferential.In this case, in tumor cellsthe intensifi-
cationof anaerobicglycolysisin aerobicconditionsdevelopsand this
phenomenon is namedas oneof variantsof negativePasteureffect. In
theregulationof theshiftfrom respiratoryto theglycolyticpathwayp53
protein takespart.
• Phenomenon of substrate"traps"for glycose,nitrogenandcholesterol.
Theseare substratesfor energy productionand thesesubstratesare
veryintensivelycaught by thetumorcellsfrom the blood.Becausepro-
ductionof energyby glycolyticpathwayis nearly20 times less than
normal,cancercellsuseveryhighquantityof substrates . This leadsfor
cachexiadevelopment.
• Glycolyticpathwayof metabolismleadsto the accumulationin tumor
tissuesacidproducts andacidosisdevelopment.
• Intensivesynthesisof oncoproteins(tumoralproteins)and formation
of embryonicproteins,for examplea -phetoprotein , whichsynthesized
only by fetus hepatocytesand is neverproducedby maturehepato-
cytes.

Thesynthesisof this specificproteinis also namedtumor markersused

for the diagnosticof tumors.Tumor markersare substancesfound in the
blood, urineor bodytissuesthatcanbeelevatedin cancer.An elevatedlevel
of a tumor markercanindicatecancer,howevertherecanoftenalsobeother
causesof theelevation.
Tumormarkerscanbe classifiedin two groups:cancer-specificmarkers
andtissue-specific markers.
Cancer-specific markers are relatedto the presenceof canceroustissue.
Becausethere is a largeoverlapbetweenthe manydifferenttumor types,
thesemarkersaremoreoftenused in follow-upof treatedpatientsto describe
progressof the diseasebeforeanyfurther massescan befoundclinicallyor
by imaging . A few examplesof thesemarkersare CEA,CA19-9,CA125.An
exampleof a cancer-specific marker,CEA,or carcinoem
bryonicantigen , is a
blood-borne protein,first notedto beproducedby tumorsof the gastrointes-
tinalsystem .
 182 I Part I Generalpathophysiology

Tissue-specific markersarerelatedto specifictissueswhichhavedeveloped

cancer.Thesesubstances arenot specificallyrelatedto thetumor,andmaybe
presentat elevatedlevelswhenno canceris present.But unlikethe previous
group,elevatedlevelspointto a specifictissuebeingatfault.Examples include
PSA(prostatespecificantigen),beta-HCG (Humanchorionicgonadotropin),
AFP(Alpha-fetoprotein), AFP-L3(a lectin-reactiveAFP)andthyroglobulin.
Functionalatypiaincludechangesin functionalactivityof malignantcells.
Threemainsituationsmaydevelopment.
In the first case, tumor cells beginthe synthesisof unusualsubstances
which are not synthesizedby normalcells. .Forexample,hormonesof the
pituitaryglandmaybe synthesizedin lung canceror thyroxinis revealedin
the malignanttumorof renalorigin.
In the secondcase,the development of cancerleadsto the decreased syn-
thesisof specificsubstances. Forexample,bileformationis oftendecreased
in cancerof the liver or secretionof the gastricjuice in stomachcanceralso
maybe suppressed.
In the third case,the development of cancerleadsto the increaseof pro-
ductionof somespecificsubstances, primarilyhormonesin tumorsof endo-
crineglands.This is a morecommonsituationin the development of endo-
crineglandscancer.
The antigenicstructureof cancercells receptorsis also changedand
changesin HLAclassI as well as HLAclassII antigenshavebeenidentified
in malignantlesions.Thesechangesare believedto playa majorrole in the
clinicalcourseof the diseasesincebothHLAclassI andclassII antigensare
criticalto the interactionbetweentumorcellsandcomponents of boththe in-
nateandadaptiveimmunesystem.Abnormalitiesin ~LAantigenexpression
in malignantcells, whichrangein frequencyfrom 0-90 %, arecausedby dis-
tinct mechanisms. Theyincludedefectsin ~2-microglobulinsynthesis,loss
of the genesencodingHLAantigenheavychains,mutations,which inhibit
HLAantigenheavychaintranscriptionor translation,defectsin the regulatory
mechanisms, whichcontrolHLA,antigen expression andabnormalities in one
or moreof the antigenprocessing.
Severaldifferentsystemsareusedfor rankingcancersby stagein the pro-
cessof diagnosticand treatment.Stagingcancersis important,becauseit
Mechanismsof tissueand cellularinjury Unit 2 I 1a3
allowsa doctorto assessa cancerand usestandardized terminologyto de-
scribeit. Stagesarerankedin orderof severity,with slowor non-aggressive
cancersat the bottomof the scale, and fast-moving,severecancersat the
top. Verycommonsystemfor stagingcancersrunsfrom zeroto four, with a
stagezerocancerbeingthe leastsevere,while four is the mostaggressive .
VerypopularTNMsystemto stagecancers , whichranksa cancerwith three
separateparameters: tumor size, lymph nodeinvolvement,and metastas is.
Forexample , someonecould havea T2, NO, M1 cancer,meaningthat the
tumorwasmedium-siz ed, no lymphnodesareinvolved,andthe cancerhas
begunto metastasize slightly.
 INFLAMMA TION
Unit 3 AN O IM M UNE
DISORDER S

Chapter a. Pathophysiologyof
Inflammation

Inflammation is definedas the local responseof living mammaliantissues

to injurydueto any agent.It is a typicalpathologicalprocessor bodylocal
defensereactionin orderto eliminateor limit the spreadof injuriousagentas
wellasto removethe consequent necroticcellsandtissues.
Depending uponthe defensecapacityof the hostanddurationof response,
inflammationcanbeclassifiedas acuteandchronic.
Acuteinflammationis the processwith shortduration,represents the early
bodyreactionandis usuallyfollowedby repair.
Chronicinflammation is the processwith longerdurationandoccurseither
afterthe causativeagentof acuteinflammationpersistsfor a long time, or
whenthe stimuluswhich induceschronicinflammationhas influencefrom
the beginning. ,

The agents causing inflammation are named phlog-

ogenic factors and divided into some groups:
'
• Physicalagentslike heat,cold,radiation,mechanical
trauma.
• Chemicalagentslikeorganicandinorganicpoisons.
Inflammationand immunedisorders Unit 3 I 1as
• Infectiveagentslikebacteria,virusesandtheirtoxins.
• Immunologicalagentslike cell-mediatedand antigen-antibodyreac-
tions.

Bythe prevalence of thecausingfactor, inflammationcanbeclassifiedac-

cordingto thefollowingtypes.
1. lnfectional- causedby inflectionalfactors(bacteria, virusesetc.)
2. Noninfectional- causedby noninfectional factors(chemicalsubstances
etc.)
3. Immune- inflammationas a componentof primaryinjuriesof the im-
munesystem(for example,allergy).
4. Nonimmune- inflammationplays an importantrole in a wide vari-
ety of humandiseasesthat are not primarydisordersof the immune
system (for examplecancer, atherosclerosis,ischemicheartdisease
etc).

Accordingto thedegreeof immuneresponse , inflammation

canbedivided
into normoergic, hypoergicandhyperergic.

Acute inflammation

Th e Roman writer Celsus in 1st c e ntury A. D . na med

the famous four cardinal signs of infla mmation a s :

• rubor(redness);
• tumor(swelling);
• calor(heat);
• dolor(pain).

Thefifth signfunctiolaesa(lossof function)was lateraddedto first four

by Virchow.
 186 I Part I General pathophysio
logy

Acute inflammation has three major components:

• Alterations in thetissuestructureandvascularcaliber thatleadto injury

andincreasein bloodflow
• Microcirculatory diserdersand exudation. Structural changesin the
microvascula ture that permit the plasmaproteins and leukocytesto
leavethe circulationto producean inflammatory exuda te and emigra-
tion of the leukocytesfrom the microcirculation with their accumulation
in the focusof injury
• Cellularproliferation (repairing of the tissues)

In differentinflammato ry reactionstheremaybepredominan t one of these

processesandinflamma t ion canbedividedinto alternative,exudativeor pro-
liferative.All of thesecomponents of inflammationhavedifferentmechanisms
of development with verystrongcooperationandinteraction.

Alterat ion
Primaryalteration - destructionof cells and tissuesby a cause factor. Pri-
maryalterationleadsto necrosisanddystrophyof cells.
Secondaryalteration- destructionof cellsand tissuesby factors, which
are releasedand activatedin the organismin the primaryalteration.These
factorsarecalled inflammatory mediators . Theycanbe subdividedinto two
groups:humoral andcellular mediators.

Humora l med iators of inflammat ion

There are three interrelated plasma-derived media-

tors that play key roles in inflammatory responses:

• Complemen
t system
 Inflammationand immunedisorders Unit 3 1187

• Kininsystem
• Clottingfactorsystem

Complement system
Activationof complement functionsin hostdefenseagainstmicrobial agents
culminatesin the assemblyof the membrane attackcomplex(MAC)and
lysis of the offendingagent.In this process,complementcomponentsare
generated thatcauseincreased vascularpermeability, chemotaxis, andopso-
nization(Fig. 18). Moreactivecomponentsof the complementsystemthere
arethefollowing.
C5ais anextremelystronganaphylatox in, it releaseshistaminefrom mas-
tocytesandbasophils , increasespermeab ility of endothelium of postcapillary
- venules;it is a chemoattractant for neutrophils , basophils, eosinophils,and
macrophages , inhibitorof macrophage migration , stimulatorof pllagocyteIi-

Classic pathway Lectin pathway Alternative pathway

Ab-Ag: CRP MBL Microbes °'

c:•
.~ - ~~ ~ ~B
~"-' i

~ ~ I
~l
C,

½bBb ---·-· ·····-·--·-···---·J

c.1>?a~ I/
~- -Properclin
C~b C3b

MAC
l ~~
+C.

Fig.18. Complementsystemactivation
. Ab-Ag- antibody-ant
igencomplex, CRP
- C-reac-
tive protein
, MBL- mannos
e-bindin
g lectin, MAC- membrane attackcomplex
 188 I Part I Generalpathophysiology

poxygenase, spasmof smoothmuscles,stimulationof leukocyteadhesion , in-

creasesthe releaseof IL-1 (interleukin-1)
andPAF(plateletactivationfactor).
C3a- anaphylatoxin of a mediumpower,its effectsaresimilarto thoseof
C5a,a chemoattractant actionis very weak,and it doesnot activatelipoxy-
genase.
C2a- a vasoactivepeptide,dilatesmicrocirculatory vesselsandincreases
vascularpermeability, effectorof hereditaryangioneurotic edema.
C3b,C4b- marginationof leukocytes, synthesisof prostaglandins, op-
sonizationof cells,stimulationof exocytosisandphagocytosis.
C5b,6, 7- hemoattractant for leukocytes.
Theactivationof complementoccursvia two generalmechanisms.
The classicpathwayinitiatedby antigen-antibodycomplexes.Whenthe
complementis activatedby this pathway,MACformationtakesplaceon the
membranesof the cellswhich haveantigenin thier structure.Specificlysis
onlyof thesemembranes anddestructiononlyof thesescellsdevelop.
Thealternatecomplementpathwayis activatedby endotoxin,complexpol-
ysaccharides, andaggregated globulins.In this case,the formationof MAC
havenot specificinteractionwith presenceof antigenandthis type of com-
plementactivationleadsto the alterationsof differentcellsmembranes in the
focusof inflammation.

Kinin sys tem

Thekininsystemgeneratesvasoactivepeptidesfrom plasmaproteinscalled
kininogensby specificproteasescalledkallikreins,ultimatelyresultingin the
productionof bradykinin(Fig. 19). Thesurfaceactivationof Hageman factor
(factorXII) producesclottingfactorXlla, whichconvertsplasmaprekallikrein
into kallikrein.Kallikreinactivetedhigh-molecular-weight kininogento brady-
kinin, most importantcomponentof kininsfamily.Kallikreinin an autocata-
lytic loop is a potentactivatorof Hagemanfactor, haschemotacticactivity,
andcausesneutrophilaggregation. Thus,kallikreincan,byfeedback,activate
Hageman factor, resultingin profoundamplificationof theeffectsof the initial
contact.
Inflammationand immunedisorders Unit 3 1189

t
Prekallikrein-- - Kallikrein

/
--➔ Bradykinin
Kaninogen
Effects:vasodilatation.
increase
permeability.
pain

Fig.19. Kallikrein-kinin system

activation

Kininsleadto the increaseof vascularpermeability,pain, spasmof smooth

musclecells of venules, bronchi, uterus, intestine, and dilationof arterioles
(vasodilators).Moreover,kininsactivatechemotaxisof leukocytes , stimulate
migrationand mitogenesisof lymphocytes , stimulateproliferation of fibro-
. blastsanddegranulationof tissue basophils (mastocytes),inhibiteneutrophil
migration,stimulatecyclooxygenase in variouscells, whichleadsto hypoten-
sion, stimulationof heartactivity, diureticeffect.
Theactivationof the blood clottingsystemleadsto the cell aggregation ,
thrombosis andlocalchangesin microcirculation .
Cellularpro-inflammatory mediatorsare subdividedinto some groups.
Most of them performtheir biologicactivity by binding initiallyto specific
receptorson targetcells, althoughsomehavedirectenzymaticactivity(e.g.,
proteases) , and othersmediateoxidativedamage(e.g.,oxygenmetabolites).
By activation of receptorsone mediatorcan stimulate the releaseof other
mediators by the targetcells.

Biogenic Amines
Histamine is synthesized
andsecretedfrom tissuebasophils , thrombocytes ,
endothelium, smoothmusclecells. Actionon H1 + H2-receptorsleadsto pain,
itch, mucushypersecretion,heartfibrillation.Activationof H1-receptorsleads
to bronchospasm, activationof chemotaxisand lymphocytotoxicity , genera-
 190 I Part I Generalpathophysiology

tion of lipid mediators,increasevesselspermeability,suppression of pace-

makerof heartrhythm.Action on H2-recepto rs leadsto bronchodilatation
,
dilation of arterioles,inhibition of chemotaxis
, degranulation,exocytosis,
lymphocytotoxicity, stimulationof suppressiveaction of lymphocytes,ar-
rhythmogenic effect.
Serotonin is secretedby enterochromaffin cells, thrombocytes,and eo-
sinophils.Serotoninactivatesthe aggregationof thrombocytes , which leads
to bronchospasm,dilation of arterioles,increasein vascularpermeability,
spasmof damagedvessels,stimulationof steroidogenesis.
Adrenalineand noradrenaline from thrombocytesleadsto vasoconstric-
tion, reductionof permeabilityandthrombocyteaggregation.

Cell-mediat ed factors of inflammation

Cytokines are proteins produced principally by ac-

tivated lymphocytes and macrophages that modu-
late the function of other cell types. Cytokines are
divided into:

• Monokines - cytokinesgeneratedby mononuclear phagocytes.

• Lymphokines - cytokinesgeneratedby activatedlymphocytes.
• Colony-stimulating factors- cytokines producedby monocytesand
macrophages that stimulatethe growthof immatureleukocytesin the
bonemarrow.
• Interleukins
- broadfamilyof cytokinesthat are regulatedinter~ction
s
betweenleuckocytes andact primarilyon leukocytes.
• Chemokines - cytokinesthat share the ability to stimulateleukocyte
movement(chemokinesis)and directed movement(chemotaxis)and
areparticularlyimportantin inflammation.

Ontheotherside,cytokinescanbegroupedintofiveclasses,dependingon
their majorfunctionor on the natureof thetargetcell.
Inflammationand immunedisorders Unit 3 I 191
Cytokines thatregulatelymphocytefunction- regulatelymphocyteactiva-
tion, growth, anddifferentiation (e.g.,IL-2and IL-4 whichfavor lymphocyte
growth; IL-10andthe transforminggrowthfactorwhichare negativeregula-
tors of immuneresponses ).
Cytokinesinvolvedwith naturalimmunity- includethe pro-inflammatory
cytokines(e.g., TNF-aandll-1) , interferons(IFN), andIL-6.
Cytokinesthatactivate inflammatorycells- activatemacrophages during
cell-mediatedimmuneresponses(e.g., IFN, TNF --a, IL-5, IL-10, and IL-12).
Chemokines-characterized by chemotact ic activityfor variousleukocytes
(e.g., IL-8)
Cytokinesthat stimulatehematopoiesis - mediateimmature leukocyte
growthanddifferentiation(e.g., IL-3, IL-7, granulocyte-macrophage colony
stimulatingfactor [GM-CSF].macrophage-CSF [M-CSFJ,granulocyte-CSF
[G-CSF],andstemcellfactor).
Cytokines havemanydifferentproperties whichmaybedescribed asfollows.
• Cytokinesproducedduring immuneand inflammatoryresponses , and
secretionof thesemediatorsis transientandcloselyregulated.
• Manycelltypesproducemultiplecytokines.
• Cytokineeffectsare often redundant , and theseproteins can influence
the synthesisor actionof othercytokines.
• Cytokinesare multifunctionalin that an individualcytokinemay have
bothpositiveandnegativeregulatoryactions.
• Cytokinesmediatetheireffectsby bindingto specificreceptorson target
cells, and the expressionof cytokine receptorscan be regulatedby a
varietyof exogenous andendogeno us signals.

The most importantcytokineswith pro-inflammatorypropertiesare the

following.
Interleukin-I(IL-I) is producedby macrophages , endothelium,keratino-
cytes, microglia, 8-lymphocytes,fibroblasts, dendritic cells. On IL-I there
dependpro-inflammatoryeffects, inductionof adhesive molecules,endopy-
rogenicactivity,reasonof prodromalsyndrome,triggerof the reactionof an
acutephaseof inflammation , the mainmediator of the immunereactionto
aliensubstances , stimulatorof stress.
 192 I Part I Generalpathophysiology

lnterleukin-6(IL-6) is producedby T and B cells, macrophages , fibro-

blasts, endothelium , thymusepithelium. On IL-6 theredependpro-inflam-
matory effects, induction of the reactionof an acute phase, endopyrogenic
activity, stimulation of antibodyproduction.
Interleukin-a(IL-8) is producedbyfibroblasts,monocytes,macrophages.
IL-8 leadsto the initiationof inflammation and reactionof anacutephase,act
such as hemoattractant andactivatorof degranulatio n of granulocytes andT
lymphocytes , factorof lymphocytegrowth.
TNF(tumornecrosis factor) alphaandbetais producedby macrophages ,
mastocyte s, lymphocytes,astrocytes. TNF - endogenicpyrogen, stimulator
of an acutephasereaction,inductor of IL-1, IL- 6, stimulator of cytotoxicity ,
granulocytes, apoptosisof tumoralandothercells.Takes partin thedevelop -
ment of cachexia , hyperca tabolism, contrinsulin action, induction of colla-
genase , procoagulants , FTA(factorof thrombocytes activation),fibrogenesis ,
granuloma tosis, angoigenesis.
Interferonalpha,beta, gammasecretedby macrophages, Th1, NK-cells, fi-
broblasts.All interferonsshareseveralcommoneffects;theyareantiviraland
antitumoralagents. Also interferonsmay leadto activationof macrophages ,
inhibitionof cytokines synthesis,stimulation of endopyrogenic and antipro-
liferative effects.

Lipid media tors

Thegroupof lipid mediatorswhich includes productsof prostagla ndin (eico-

sanoid)system activation.Activationof this systembegins from arachidonic
acid - cellularmembranecomponent.Metabolism of arachidonicacid has
two pathways:cycloxygenase and lipoxygenase(Fig. 20).
The cycloxygenas e pathwayof activationleads to the prostaglandinpro-
duction.
Prostaglandins leadsto the.expansionof vesselsandincrease of perme-
ability (PgE1, PgD2), narrowingof skin vessels, suppressionof emigration
(F2a),spasmof smooth musclesof bronchi(PgD2,PgG2, PgH2), potentia-
tion of painfuleffectsof kininesand histamine(PgE2),activationof phago-
Inflammationand immunedisorders Unit 3 I 193

i +-- Cyclo-oxygenaze
pathway

Prostaglandins

i PgG2 i
PgE2 PgE2o

A, B, C, D, E, F, . , TxAz Pg1i,

Fig.20. Eicosanoid
system
activation

cytes, stimulationof adhesionandphagocytosis , chemotaxisof neutrophils ,

adhesionandreaction of releasing of thrombocytes(PgG2, PgH2),
Tromboxanes which producein thrombocytes , endothelium,macrophages
leads to vasoconstriction, chemotaxisandmarginationof neutrophils, adhe-
sion,aggregationof thrombocytes , bronchospasm .
Prostacyclines whichareproduced in endotheliumleadto vasodilatation,
stimulationof collateralbloodflow, antithrombotic , antiadhesive, anticoagu-
lativeaction,stimulationof fibrinolysis, antiatherogen ic effect.
Thelipoxygenase pathwayof activationleadsto the leukotriensproduction.
Leukotriens are producedby various cells, especiallyneutrophils , mast
cells and leadto vasoconstriction and increaseof permeab ility, bronchos-
pasm,chemotaxis , margination of neutrophils , macrophages , chemotaxis
and inhibitionof lymphocyteproliferation, chemotaxisof eosinophils,de-
granulation of basophiles.
FTA(factorof thrombocytes activation)is producedin basophiles, neu-
trophiles,macrophages , mastocytes , eosinophils, endothelium. FTAstronger
stimulator of adhesion, aggregationand reactionof thrombocyterelease,
activator of granulocytes, vaso- and bronchoconstric tor, promotesproduc-
 194 I Part I Generalpathophysiology

tion of eicosanoids,in small concentrationsexpandsvessels,synergistof

thromboxanes, stimulatesemigrationof neutrophiles
andbasophiles,
a pow-
erful agentraisingvascularpermeability(in 10,000times moreactivethan
histamine).

Lysosomal constituents of leukocytes

Neutroph ils andmonocytescontainlysosomalgranules,whichwhenreleased
maycontributeto the inflammatoryresponseandto tissueinjury.
Enzymesof lysosomes- proteases,Iipases,glycosidases, phosphatases
lead to the destructionof collagen,elastin, basal membranes,glycopro-
teins, componentsof intercellularsubstance,lipids, etc., and stimulated
activationof polypeptidecascademediatorysystems(kallikrein-kininsys-
tem, coagulationsystem, complementsystem, fibrinolytic system),acti-
vation of eukosanoidformationand other derivativesof arachidonicacid
cascade.
Lysosomalconstituentscan potentiatefurther increasesin vascularper-
meabilityandchemotaxisandcausetissuedamage.Theseharmfulproteas-
es,however,areheldin checkby a systemof antiproteases in the serumand
tissuefluids.

Oxygen-Derived free rad ica ls

Oxygen-derived free radicalsare metabolitesthat may be release~extracel-
lularlyfrom leukocytesafter exposureto chemotacticagents, immunecom-
plexes,or a phagocyticchallenge.Theseinclude02·., H20 2, andhydroxylradi-
cal (OHt andthesemetabolitescancombinewith nitric oxideto form other
reactivenitrogenintermediates , whichcause:
• Endothelialcell damagewhich leadsto the increasedvascularperme-
ability
• Inactivation of antiproteases,thus leadingto unopposedprotease
activity
• Injury to a varietyof celltypes.
Inflammationand immunedisorders Unit 3 1195

Nitr ic oxide
Alsoknownas endothelium-derived relaxationfactor, nitric oxide(NO)acts
in a paracrinemannerandcausesvasodilation. NOinhibitsplateletaggrega-
tion and adhesion,mayact as a free radical, becomingcytotoxicto certain
microbes , tumor cells, and also possiblyothertissue cells. Nitric oxide is
synthesized fromarginine,molecularoxygen,NADPH, andothercofactorsby
theenzymenitricoxidesynthase(NOS) .
Nitric oxideactsin the host responseto infection.Interactionsoccurbe-
tweennitric oxideand reactiveoxygenspecies,leadingto the formationof
multipleantimicrobialmetabolites.Eachreactiveform is distinct, but they
sharethe abilityto damagemicrobes,at the potentialcost of inflammatory
damageto hostcellsandtissues.

Anti -inflammatory med iator s

Therearemanyanti-inflammatory factors,whichprotectorganismfrom the

systemicactivationof pro-inflammatory agents.Anti-inflammatory mediators
includethe followingtypes.
Polysaccharide mediators(glycosaminoglycans) include heparinwhich
producedby mastocytes , eosinophils, basophiles, macrophages, fibroblasts.
Heparinbindsbiogenicamines,inhibitscomplement , coagulation, adhesion,
aggregation, reduceskininsystemactivity, servesas a structuralcomponent
of the intercellularsubstanceof the connective tissue, participatesin regen-
erativeprocesses.Heparin- sulfates.chondroitin-sulfates, dermatin-sulfate
s
havea similarto heparinaction.
Inhibitors of proteases(alpha-1-antitrypsin, alpha-2-macroglobulin,
antiplasmin,antithrombin-III,inhibitors of complement,and some oth-
ers) suppressthe activity of lysosomalhydrolasesand a guard contact
blood polysystem , reducealterationand eliminateconsequencesof exo-
cytosis.
Antiphospholipases (macrocortin , renocortin
, lipomodulin)inhibitthe pro-
ductionof eicosanoids.
 196 I Part I Generalpathophysiology

Antioxidants(ceruloplasmin,haptoglobin, hemopexin,transcoba lamine,

peroxidase , superoxiddismutase, beta-2-microglobulin, amyloid-A,C-reac-
tive protein)playan activerole in the inactivationof activeoxygenradicals
andlipoperoxides.

Enzyme system of inactivators of inflammatory me-

diators:

• arylsulphatase - inactiva
tion of leukotrienes;
• histaminase - inactivationof histamine;
• kininase- inactivationof kinins, etc.

Polyamines(cadaverine, putrescine,spermine,spermidine)inhibit exuda-

tion andstimulateregeneration.
Somecytokineshaveanti-inflammatory properties.For example,IL-1Ois
an inhibitorof cytokineproductionwhichblocksfunctionsof T-helpers.

Microcircu latory disorders and exudation

Changes in microcirculation begin to develop due to

the action of the phlogogenic factor and are divided
into four stages:

1. transient
vasoconstriction
of arterioles;
2. progressive
vasodilatation
, causingan increasedflow;
3. slowingofthebloodflow;
4. stasis. ,

Theprocessesthattakepartin the pathogenesis

of localvascularreactions
at the site of inflammationarethe following.
Inflammationand immunedisorders Unit 3 I 197
1. Respectiveof the type of injury, immediatevascularresponseis of
transient vasoconstriction of arterioles.Witha mild form of injury,the
bloodflow maybereestablished in 3-5 secondswhilewith severerinjury
the vasoconstriction maylast for about5 minutes. Transientvasocon-
strictionis the resultof sympathetic neverfiber'slocalactivationandis
rapidlyremovedby mooaminooxydase and vasodilativeinflammatory
media t ors.
2. Persistent progressive vasodilatation which involvesmainlythe ar-
terioles, but to a lesserextent, affectsother componentsof the mi-
crocirculationlike venulesand capillaries.This changeis obvious
within half an hourof injury.Vasodilatation resultsin increasedblood
volumein microcirculation in the inflammatoryarea, which is respon-
siblefor rednessandwarmthat thesiteof acuteinflammation. Oftenthis
stagenamedas arterialhyperemia.
3. Progressive vasodilatation withtheslowingofthebloodflow, in turn,
mayelevatethe localhydrostaticpressure result ing in transudationof
fluid into the extracellularspace.Thisis responsible for swellingat the
localsite of acuteinflammation. This stageoftennamedas venoushy-
peremia,butthe mechanism of disordersin bloodflow havedifference
from the typicalpassivehyperemia. Thedeer-ease of bloodflow in this
stageof microcirculatory changesin inflammation dependson :
• agregation andadhessionof the cells;
• increasevesselspermeabi lity;
• increasebloodcoagulation;
• raisedbloodviscosity.
4. Slowingor stasisof microcirculationoccursnext. Slowingis attrib-
utedto increasedpermeabilityof microvasculature that resultsin the
increase d concentrationof redcells,andthus, raisedbloodviscosity.

Exudation
Exudation
followsmicrocirculatorydisordersand beginsto developduring
thesecondstageof vascular reactionsof inflammation.
 198 I Part I Generalpathophysiology

Exudation. Theescapeof fluid, proteins,andbloodcellsfromthe vascular

systeminto the interstitialtissueor bodycavities.
Edema . Denotesan excessof fluid in the interstitialtissueor serouscavi-
ties; it can beeitheran exudateor a transudate.
Transudate . A fluid with low proteincontentanda specificgravityof less
than 1.012.It is essentiallyan ultrafiltrateof bloodplasmaandresultsfrom
hydrostaticandoncoticpressureimbalance acrossthevascularendothelium.
Exudate. An inflammatoryextravascular fluid that hasa highproteincon-
tent, specificgravity(1.012)and manycells.The most importantfactor of
the exudatesdevelops , beingdependenton the increase endothelialperme-
ability.

There are six possible mechanisms of increased

endothelial permeability:

• endothelialcell contractionin venules;

• endothelialretraction;
• increasedtranscytosis;
• leakagefrom regenerating capillaries
;
• directendothelialinjury;
• leukocyte-mediated endothelial injury.

Typ es of exudat ion

The appearance of escapedplasmadeterminesthe morphologictype of in-
flammation.Thesetypesarethe following. ·
• Serous , whenthe fluid exudat~resemblesserumor is watery(pleural
effusionin tuberculosis,blisterformation in burns).Characterized by
the presenceof smallproteinandcellsquantities.
• Catarrhal , when the surfaceinflammat ion of epitheliumproducesin-
creasedsecretionof mucus.Hasthe samecharacte risticssuchas se-
rousones.
Inflammationand immunedisorders Unit 3 f 199

• Fibrinous , whenthe fibrin contentof thefluid exudateis high (in pneu-

mococcalandrheumaticpericarditis,diphtheria)
• Purulent orsuppurative exudate istheformationof creamypusasseen
in infectionwith pyogenicbacteria(abscess,acuteappendicitis).In this
case,verymanycells, primarilyneutrophils , areaccumulated in the fo-
cus of inflammation.After sometime, the destructionof neutrophiles
developsand in exudatesthere accumulateinternalleukocyticfactors
with alterativeproperties
.
• Haemorrhagic , whenthere is a very strong vasculardamage(acute
haemorrhagic pneumonia in influenza).

Cellular extravasation and phagocytosis

.A criticalfunctionof inflammationis thedeliveryof leukocytesto the site of
injury.Thesequenceof eventsin this journey,calledextravasation, can be
dividedintothe followingstages:
• Margination,rolling,andadhesion of leukocytesin the lumen
• Oiapedesis or transmigr ationacrosstheendothelium
• Migrationin interstitialtissuestowarda chemotacticstimulus
• Chemotaxis andleukocyteactivation

Theescapeof leukocytes from the lumenof microvascu latureto the inter-

stitialtissueis themostimportantfeature of inflammatoryresponse.In acute
inflamma tion, polymorphonuclear
neutrophils(PMNs)comprisethe first line
of bodydefence,followedlaterby monocytes andmacrophages.

The processe leading to the migration of leukocytes

are as follows : ·

1. In theearly stageof inflammation , the rateof flow of bloodis increased

due to vasodilatation. But after sometime there developsslowing or
stasisof bloodstream. Slowingof the bloodflow leadsto changesin
200 I Part I Generalpathophysiology

the normalmicrocircula tion. The normalaxialflow consistsof central

streamof cells comprisedby leukocytesand RBCsandthe peripheral
cell-freelayerof plasmaclose to the vesselwall. Dueto slowingand
stasis, thecentralstreamof cellswidensandtheperipheralplasmazone
becomes narrowerbecauseof loss of plasmaby exudation.This phe-
nomenonis knownas margination . Theneutrophilsof the centralcol-
umncomecloseto the vesselwall.
2. Peripherall y marginatedneutrophilsstick brieflyto the endothelialcells
lining the vesselwall or roll over it. Injury leadsto neutralisationof
the normalnegativechargeon leukocytesand endothelialcells so as
to causeadhesion. Thephenomenon of looseandtransient adhesions
betweenendothelialcells and leukocytesis dependenton 4 types of
distinctadhesionmolecules .
• Selectinsthat takepart in rolling of PMNsoverthe endothelialsurface.
Theseconsistof P-selectin(preformedand storedin endothelialcells
and platelets), E-selectin(synthes isedby cytokine-activated endothelial
cells)andL-selectin (expressed onthe surtaceof lymphocytes andneu-
trophils).
• Address insexpressed onthe surfaceof leukocytes andendothe liumand
regulatethe localisationof subpopulation of leukocytes.
• lntegrinsbringaboutfirm adhesionbetweenleukocyteandendothelium.
• lmmunoglobu lin superfamilyadhesion moleculesuch as intercellular
adhesionmoleculehelpin localisingleukocytesto the site of tissuein-
jury andthus helpin transmigrationof PMNs.
3. After sticking of neutrophils to endothelium , the former movealong
the endothelial surfacetill a suitablesite betweenthe endothelialcells
is found wherethe neutrophils throw out cytopfasmicpseudopods .
Subsequently,the neutrophilslodgedbetweenthe endothelialcells
and basementmembranecross the basementmembraneby damag-
ing it locallywith secretedcollagenases and escapeout into the ex-
travascularspace.This stageis namedas emigration . Importantthat
neutrophilsare the dominantcells in acuteinflammatoryexudatein
the first 24 hours, and monocyte-macrophages appearin the next
24-48 hours.However,in the normaltissuesmonocytesand macro-
Inflammationand immunedisorders Unit 3 I 201
phagesare prevalenton which normal defencereactions are depen-
dent.
4. The chemotac tic factor-mediatedtransmigrationof leukocytesafter
crossingseveralbarriers (endothelium,basementmembrane , peri-
vascular myofibroblastsand matrix) to reachthe interstitialtissues
are called chemotaxis . Theconceptof chemotaxisis well illustrated
by Boyden 's chamberexperiment.In this, a milliporefilter separates
the suspensionof leukocytesfrom the test solution in tissue culture
chamber.If the test solution containschemotacticagent, the leuko-
cytes migratethrough the pores of filter towards the chemotactic
agent.

The agents acting as potent chemotactic substanc-

es for different leukocytes called chemokynes are
- as follows:

• Leukotriene B4
• Plateletfactor4
• Compone nts of the complemen t system
• Cytokines
• Solublebacterialproducts
• Monocytechemoattrac tant protein
• Exotoxinchemotact ic for eosynophils.

Chemotactic agents also cause leukocyte activa-

tion that leads to the ability of leukocytes to phago-
cytosis, and are characterized by:

• Degranulation andsecretionof enzymes

• Activationof an"oxidativeburst"
• Productionof arachidonicacidmetabolites
• Modulationof leukocyteadhesionmolecules.
 202 I Part I Generalpathophysiotogy

Phagocytosls
Phagocytosis and the releaseof enzymesby neutrophilsand macrophages
constitutetwo of the majorbenefitsderivedfrom the accumulation
of leuko-
cytesat the inflammatory focus.

Phagocytosis involves three steps:

• Recognition
andattachment oftheparticleto beingestedbytheleukocyte
• Engulfmentby pseudopods encirclingthe phagocytosed particle,with
the subsequent
formationof a phagocytic vacuoleor phagosome.
• Killinganddegradationof bacteria.

There are two types of bactericidal mechanisms of

phagocytosis:

• Oxygen-dependent
mechanisms
• Oxygen
-independent
mechanisms

Oxygen-dependent mechanisms. Bacterialkillingis accomplished largely

by oxygen-dependent mechanisms. Thisis triggeredby activationof nicotin-
amide-aden ine dinucleotidephosphate(reducedform) (NADPH)oxidase,in
the processof reducingoxygen(02) to superoxideanion(02-) andhenceto
hydrogenperoxide(H202). Myeloperoxidase (MPO)from lysosomalgranules
then convertsH202, in the presenceof a halidesuchas Cl· , to the highly
bactericidal HalideOxideCytotoxic Complex(HOCK).Althoughthe H202-
MPO-halide systemis the mostefficientbactericidalmechan ism,the reactive
oxygenspeciesproducedduringan oxidativeburstcankill bacteriadirectly.
Oxygen-independent mechaQisms. Theseinclude bactericidalperme-
ability increasingprotein, lysozyme,lactoferrin,major basicproteinof eo-
sinophils,andarginine-rich defensins. Killedorganismsarethendegradedby
hydrolasesandotherenzymesin lysosomesandphagolysosomes.
Inflammationand immunedisorders Unit 3 I203
Leukocyte-induced tissue injury
Duringphagocytosis,
leukocytesreleaseproductsnot only within the pha-
golysosome,
butalsopotentiallyintothe extracellular
space.

These released products include:

• lysosomal enzymeswhicharereleasedbyexocytosis andcytotoxicrelease

;
• oxygen-derivedactivemetabolites;
• productsof arachidonic
acidmetabolism , includingprostaglandinsand
leukotrienes.

Theseproductsare powerfulmediatorsof tissuedamageandamplify the

effectsof the initialinflammatorystimulus.Theactionof thesefactorsleads
tothe increaseof alterationreactionsin the focus of inflammation.

Proliferation and outcome of ac ute inflammation

Injuryof tissue mayresultin cell deathandtissuedestruction. Healing, on
the otherhand,is the bodyresponse to injury in anattemptto restorenormal
structureandfunction.

The process of healing involves 2 distinct processes:

• Regene rationwhenhealingtakesplacebytheproliferation of parenchymal

cellsandusuallyresults in completerestorationof theoriginaltissues.
• Repairwhenthe healingtakesplaceby proliferationof connectivetissue
elementsresultingin fibrosisandscarring.

Onthe otherhand, the processof acuteinflammationoutcomeis depen-

denton the natureand intensity of the injury,the site and tissueaffected
,
 204 f Part I Generalpathophysiology

andresponsiveness of the host,andis generallydescribedbyfour outcomes

variants:
• Complete resolution , with the regeneration of nativecellsandrestora-
tion of the site of acute inflamma tion to normal
• Abscess formation , particularly in infectionswith pyogenic organisms
• Healing by connective tissuereplacement (fibrosis)and scarring,
whichoccursafter substantialtissuedestruction , whenthe inflamma-
tion occursin tissuesthat do not regenerate or whenthereis abundant
fibrin exudation
• Progression tochronicinflammation , as is outlinedin moredetailsub-
sequently .

Theprocessof proliferationis regulatedby the actionof growthfactors.

Growth fa ctors include som e groups of regulators

of prolifer a tion such as :

• Growth factorsfrom macrophages , lymphocytes , fibroblasts,thrombo-

cyteswhichstimulateproliferationandrestrictionof apoptosis ;
• Keilons- glycoproteintissue-specificinhibitorsof growth
• Adhesiveglycoprote ins of intercellular substance
• Fibronectin- chemoattractant of fibroblasts
• Laminin- the main adhesiveproteinof basementmembranes
• Syndecan - integral proteoglycan of cellular membranes , attachescol-
lagen,fibronectinandthrombospondin
• Thrombospondin is a glycoprotein , whichforms complexeswith syn-
decan,collagenandheparinandplaysan essentialrole in the assembly
of the bonetissue.

Chronicinflammationis definedas prolongedprocessin whichtissuede-

structionandinflammat
ion occurat the sametime.
Inflammationand immunedisorders Unit 3 f 2os

Chronic inflammation can be caused by one of the

following 3 ways:

• Chronicinflammationfollowingacuteinflammation.Developswhenthe
tissue destructionis extensive, or the bacteriasurviveand persist in
smallnumbersat the siteof acuteinflammation(in osteomyelitis,pneu-
moniaterminatingin lungabscess ).
• Recurrentattacksof acuteinflammation.Development when repeated
boutsof acuteinflammationculminatein chronicprocess(in recurrent
urinarytract infectionleadingto chronicpyelonephritis , repeatedacute
infection of the gall bladderleading to chroniccholecystitis).
• Chronicinflammationstartingde novo. Development when the infec-
tion with organismsof low pathogenicity is chronicfrom the beginning
(infection with Mycobacterium tuberculosis) .

Thoughtheremaybedifferences in chronicinflammatoryresponsedepend-
ing uponthe tissueinvolvedandcausative organisms , thereare somebasic
similaritiesamongstvarioustypesof chronicinflammation. Thesegeneralfea-
turescharacterize anychronicinflammation andincludethefollowingones.
Mononuclear cellinfiltrationbymononuclear inflammatorycellslikephago-
cytesand lymphoid cells.Phagocytes are representedby circulatingmono-
cytes, tissuemacrophages , epithelioid cells and sometimes , multinucleated
giantcells.The macrophages comprisethe most importantcells in chronic
inflammation.Otherchronicinflammatorycellsincludelymphocytes , plasma
cells,eosinophilsandmastcells.In chronicinflammation,lymphocytesand
macrophages influenceeachotherandreleasemediatorsof inflammation.
Tissuedestructionand necrosisarecommonin manychronicinflamma-
tory lesionsanddependon the releaseof a varietyof biologicallyactivesub-
stancesbyactivatedmacrophages.
Proliferat
ionthatdevelopsasa resultof necrosis.Theproliferationof small
bloodvesselsand fibroblasts is stimulatedresultingin the formationof in-
flammatorygranulationtissue. Eventually,healingby fibrosis and collagen
layingtakeplace.
 2061 Part I Generalpathophysiology

Themorphologicvariationin inflammation
dependsupona numberof fac-
tors andprocesses.
Thesefactorsincludethosedependent
andnon-depend-
enton the organism.

Factors dependent on the organism:

1) generalhealthof the host;

2) immunestateof the host;
3) presence of leucopenia;
4) siteor typeof tissueinvolved;.
5) localhostfactors.
6) Factorsnon-depended on the organism:
7) typeof injuryor infection;
8) virulenceof infection;
9) doseof phlogogenic factor;
10) portalof entry.

Systemic effects of inflammation

The major systemicmanifestations of acuteinflammationinvolvea wide
rangeof endocrine,autonomic , andbehavioralresponses whichincludethe
followingones.
1. Endocrine andmetabolic
• Secretionof acute-phaseproteinsbythe liver(incluqingC-reactive pro-
tein, serumamyloidA, complement, andcoagulationproteins,proteo-
lytic inhibitors).
• Leukocytosis (elevationin thetotalwhitebloodcellcount)is a common
featureof inflammatoryreactions,especiallythoseinducedby bacte-
rial infection.Extremeelevations arereferredto as leukemoidreactions.
The leukocytosisoccursbecauseof the proliferationof precursorsin
the bonemarrowand the accelerated releaseof cells from the bone
marrow.
 Inflammationand immunedisorders Unit 3 I 207
2. Autonomic
• A redirectionin bloodflow from cutaneousto deepvascularbeds, to
minimizeheatlossthroughthe skin;
• Fever(elevationof bodytemperature , usuallyby 1 to 4 °C);
• Increasedpulseandbloodpressure ;
• Decreased sweating

3. Behavioral
:
• Rigors (shivering)
, chills (searchfor warmth), anorexia, somnolence
,
andmalaise.

The princip als of the anti-inflammatory treatment

_Thereare two possiblemethodsof the inflammatoryprocesstreatment:
ethyotropicandpathogenetic
treatmen
t.

Ethyotropic treatment of the inflammation includes:

• Destroyingof the ethyologicalfactor- usingof antibacterial,

antiviral,
antifungal,antiparasiticdrugs.
• Limitingor stoppingof the ethyological
factor's influence- neutraliza-
tion of biologicalactivechemicalsubstances
, removingof the necrotic
andtumortissues.

Oftenethyological
factorsareuncertain
orcompletely unknown andethyotropic
measures arenotenough to successful
resolutionof acuteandchronicinflamma-
toryprocess.Inthiscase,pathogenic
treatment of theinflammation
is applying.

Pathogenetic treatment includes:

1. Physicalmethods:
2oa I Part 1 Generalpathophysiology

• coolingon the beginningof inflammationfor stops of the metabolic

burstandhyperemia;
• semi-spirituouscompresseswhich leadsto convertingstatic hyper-
emia into arterial,mediatorsand toxins resolutionand destroyingof
bacteria.

2. Anti-inflammatory medicines:
• Nonsteroidanti-inflammatorydrugs which are usedin the typicalin-
flammation(salycilates). Thesemedicineslimit exudative andprolifera-
tive phasesof the acuteinflammation.The main mechanismof they
actionis an inhibitionof cyclooxygenases andprostaglandins synthesis
andthis leadsto paindiminishing,feverdecreasing andvasoconstric-
tion.
• Steroidanti-inflammatory medicineswhichincludessyntheticanalogs
of the naturalglucocorticoids(prednisolon).Glucocorticoids suppress
all phasesof the inflammation.Inhibition of the alterativephasein-
c1ude :
• stabilizationcellular and lysosomic membranes,preventingthe
phlogogenicinjury;
• decreaseliberationof lysosomicenzymesandsuppressfreeradicals
synthesis
• Inhibitionof the exudation , hyperemiaandedemadevelopmentin the
inflammatoryfocusanddepressionof proliferationinclude:
• decreaseleukocytes adhesiaandemigrationwhichresultin the de-
creasingof enzymesandmonokinesliberation;
• preventphospholypase A2 activationby stimulationof its inhibitor
andby stabilization of the cell membranes; '
• decreasesynthesisof prostaglandins, mucopolysaccarides, mono-
kines,lymphokynes andcollagenase;
• blockageFe-receptorsin the macrophages.
• Long-term anti- inflammatorymedicines(chinidinederivates).These
drugs cannottreat an ordinaryinflammation , but they are especially
activein autoimmune causes.Theymechanisms of treatmentare con-
nectedwith an inhibitionof I_L-1 andsomelymphokynesliberation.
Inflammationand immunedisorders Unit 3 I209
• Cytostatics. Theybreaksynthesis of proteins(especially in high-mitotic
cells).That is whythis groupis ableto suppressT-lymphocytes division
andtheir conversionin T-helpersor suppressors.
• lmmunomodulators. Their action needsfuture investigation
.

Chapter 9. Reactivityand
Resistance. ImmuneResponse.

Reactivity is the ability of the organism to react to the

influence of internal and external fa cto rs by c hanges of
vital activity .

• Thedevelopment of reactivityhadpassedseveralstagesin theevolution

of livingcreatures :
• reaction- the response of the wholeorganism or its partto externalor
internalinfluence ;
• sensitivity- the ability to accept and definetype, localization , force
(strength)andperiodic ity of thefactorinfluence;
• irritability-the abilityof theorganismto accepttheinfluenceof externa l
andinternalfactorsandrespondto themwith genera l, low-differentiated
reaction(changesof metabolism , shapeandsize, etc.);
• resistance - anti-action : resistanceof the organismor its partsto the
influenceof variousfactors.

The reactivity level can be:

• normal(normergia) - a qualitatively
andquantitativelyadequatereaction
to differentfactors.
• increas ed(hypererg ia)- a moreintensivereactionsuch asin anaphylac-
tic shock develops asthe result of antigenaction;
 210 I Part I Generalpathophysiology

• low (hyporergia)can be illustratedwith suchan example:peoplewith

immunedeficiencyhavean ineffectiveimmuneresponseto antigens.
• finally, reactivitycanbeabsentcompletely- suchavariantis calledanergy.
• The manifestation of reactivity can be observedat all the levelsof bio-
logicalsystemsorganization : molecular, cellular, organ, systemicand
thosebelongingto organism.

Types of rea ctivity

Speciesreactivityis the ability to respondto differentirritants that can be
possesse d by severalspeciesonly. Forexample , atherosclerosis
is oftenob-
servedin humans, but it is neverobservedin rabbits.If rabbitsare infected
with treponemapallidum,they do not manifest syphilis. Anotherexample of
differentspeciesreactivityis the abilityto hibernateduringwinter.
Groupreactivityis divided into reactivitydeterminedwith age, sex and
body constitution.
Age-relatedreactivity- childrenare more susceptibleto infectiousdis-
easesthen adult persons, becausetheir immunesystemis not completely
developed.
Sex-related reactivity - men havemorehigh resistanceto physicalover-
load,womenhavemorehighresistanceto bloodloss.
Constitution-relatedreactivity - peoplewith asthenic constitution are less
resistant to physicalandpsychica l overloadthennormostenicpeople.
Resistance is thestabilityof the organismto theactionof unfavorablefac-
tors. Resistance and reactivityare linkedand reflectthe abilityof the organ-
ism to accommodate to changesof internalandexternal conditions.

In a healthy organism there are direct interrelations

between them. But there can be irregular interrelation :

• mincreasedreactivity- reducedresistanceis observedin allergicstates;

• reduced
reactivity- increased
resistance
is observed
in hibernatinganimals.
 Inflammationand immunedisorders Unit 3 I 211
There are following types of resistance :

• Passiveresistanceis determinedby barriersystemsof the organism

(skin,mucouscovers,acidityof gastricjuiceetc).
• Activeresistance is determinedbythe protectiveadaptationmechanism
andby the formationof compensatory mechanismsin responseto the
actionof unfavorable factors.
• Cross-resistance: whentheincreased stabilityto onefactor(for example
,
hypoxia)is formed, thesameextentof stabilityto otherfactors(cooling,
physicalloading)is formedat thesametime.This fact givesus the pos-
sibilityto usethis phenomenon in prophylaxisand non-med icamental
correctionof somediseases .

Thelevelof reactivityandresistance dependson variousfactors- heredi-

taryandacquired(sex,age,condition of the nervous,immuneandendocrine
· systems , the environment ). That's why we can influencereactivity . Thera-
peuticandprophylacticeffectsof physicaltraining, hypoxictraining,climate
sanatoriums, etcarebasedon this fact.
Alsoveryoftenreactivityis dividedinto nonspecif ic andspecific.
Nonspecific (initial, simple) reactivityis displayedat the actionof vari-
ousfactorson the organism.At its basisaregeneticallyprogrammedstan-
dard reactionsto the actionof high and low temperatures , oxygenstarva-
tion, etc.
Specificis referredto immunologic reactivity(immunity ), that is the
abilityof the organismto reactto the actionof agentsby formingantibod-
ies and by a complexof cellularreactionsspecificin relationto the given
antigen.
Therearetwo kindsof immunity:unspecific , inbornimmunityand spe-
cific, acquired(adaptive)immunity(Fig.21). Acquiredimmunityis divided
into activeandpassive.Activeimmunitymaydevelopduringlifeafterdisease
or aftervaccination.
Theimmune systemis responsiblefor safeguarding the bodyfrom dis-
ease-causing microorganisms . It is part of a complexsystemof host de-
fenses.
 212 I Part I Generalpathophysiology

Innate·

Fig.21.Types of immuno
logical reactivity

Immune system funct ion

The immunesystemis madeup of all the mechanismsthroughwhich a
multicellularorganismdefendsitselffrom internalinvaderssuchas bacteria,
virusesor parasites.But the main functionof the immunesystemduring
humanlife-timeis the maintenance of genetichomogeneity of the organism.
It is well knownthat the numberof mutationsin humanorganismreaches
1O millions in everymomentof life. It meansthat the probabilityto meet
mutatedcell is severaltimesmorethanto meetalienone.Theconsequences
of mutatedcell maturationand divisionmaybe fatalfor the organism.So,
everymutatedcell mustbedestroyedandeliminatedbythe immunesystem.
In other words, the main function of the immuneS1/Stem is to recognize
"self" cell and "non-self" cell. Non-selfcell maybe of alienorigin or it may
bechangedself cell.
Howcanthe immunesystemrecognizeself cell?All bodycellscarrymo-
lecularmarkerson their surfacethat enablethemto be identifiedas"self" by
immunesystemcells.The most importantself-markingmoleculesare en-
codedbya groupof genesknownasthe majorhistocompatibility complex,or
MHC.Thereis onegroupof proteinsin the MHCwhicharecarriedby almost
Inflammationand immunedisorders Unit 3 I 213
all bodycells,calledclassI MHCantigens, whichare alteredwhenthe cell
is infectedby a virus or it hadundergone cancermutation.Thesemolecules
serveto alertkillerT-cells to the presence of malignantbodycells.
A secondgroupof MHCproteins, classII antigens,are found only on B
cells, macrophages , and othercells responsible for presentingforeignanti-
gento helperT-cells. ClassII MHCproteinscombinewith particlesof foreign
antigenand, by the resultingshape, direct the actionsof the T-cells. In hu-
mansMHCmoleculesare namedHLA- humanleukocytesantigen, because
theywerefirst foundonthe surfaceof leukocytes.
Theimmune systemconsistsof central andperipheralorgansandimmunecells.
Centralorgansof the immunesystem(bonemarrowandthymus) produce
immunecellsand providetheir differentiat ion that is not dependenton the
antigenstimulation. Lymphocytes , monocytes and granulocytesderivefrom
precursorstem cells in the bonemarrow . B-lympho cytes migratedirectly
from marrowto the peripherallymphoidtissue, whereasT-lymphocytesun-
dergofurthermaturationin thethymus.The bonemarrowandthymus arein-
volvedin generatingprecursorlymphocytes ratherthanimmuneresponses .
Thethymusplaysan importantrole in the developmentof the immune
systemin earlylife, and its cellsform a part of the body'snormalimmune
system.It is most activebeforepuberty,after which it shrinksin sizeand
activityin mostindividuals, andis replacedwith fat.
Thekey function of the thymusis theselectionof theT-cell whichthe im-
munesystemusesto combatinfections. This involvesselectionof T-cells
thatarefunctional(positiveselection) , andeliminationof T-cellsthat areau-
toreactive(negativeselection) . Positively-selectedcellswill betakencareof
by specialized nursecells.
Peripheralorgansof the immunesystem(lienandlymphatic nodesin dif-
ferentorgans,Peyer'spatches , theappendix andtonsils ) provideantigen-
dependentimmunecells differentiation givingthe opportunityfor effective
interactionof immunecells.
Immunecellsincludelymphocytes, phagocytes andnaturalkillercells.
Lymphocytes havereceptors for antigenanddetermine specificityon an im-
muneresponse. Lymphocytes expressreceptors withdifferentaffinityfor thean-
tigen.Affinityinthissituationmeanstheattractionbetween antigenandreceptor.
 214 I Part I Generalpathophysiology

Thecell with the highestaffinityfor the mostabundantantigenwill have

growthadvantage andwill generateprogenyof it. Thisprocessis calledclonal
expansionandis drivenby antigen.
All lymphocytesare dividedinto T- and B-lymphocytes . Youcan not find
the differencebetweenthesecells underthe microscope.T-cellsare chiefly
responsiblefor cell-mediatedimmunity whereasB-cellsare primarily re-
sponsiblefor humoralimmunity(relatingto antibodies).Nowmoreoftenuse
classification,whichdividedall bloodcellson the CDclassesby the specific
membranereceptors .
T-cells arenamedsuchbecausetheselymphocytes maturein the thymus.
T-cellscirculatein blood, wheretheycomprise60 to 70%of peripherallym-
phocytes.Theydo not produceantibodymoleculesandarethe effectorsof
cellularimmunity.EachT-cellis geneticallyprogrammed to recognizea spe-
cific cell-boundantigenby meansof an antigenspecificT cell receptor.
Whena T-cellencounters an invadingvirusit beginsto divide,formingfour
differenttypesof T-cell,eachwith a differentfunction.
KillerT-cells(C0-8) destroycellsthat havebecomeinfectedwith thevirus
by lysis.HelperT-cells(CD-4)activatemorekillerT-cellsandalsostimulate
8-cellsby the meansof cytokinesto beginantibodyproduction.Suppressor
T-cellsstop specificimmunereactions from occurringand protecthealthy
cellsfrom viral attack.MemoryT-cellspersistin the bloodstreamto guard
againstre-infection.
8-lymphocytes (CD-19;CD-20)constitute10 to 29% of the circulating
peripherallymphocytepopulation.B-cellsare namedfor the bursaof Fabri-
ciusin whichtheymaturein bird species.In humanstheymaturein the bone
marrow.B-lymphocytes produceantibodiesandareresponsible for humoral
immunitydevelopment. WhenB-lymphocytecontactswith the antigenit is
transformedintothe blastcellwith the helpof T-lymphocytes . Thisprocessis
realizedin lymphatic nodes.Blastcellsthenaredifferentiated into plasmatic
cellsthatcanproducespecificantibodies.Aswith T-cellseach8-cellreceptor
hasa uniqueantigenspecifity.
Phagocytes take part practicallyin all immune reactions . Their main
function is phagocytosis,but thesecells also can act as antigenpresent-
ing cells for lymphocytes.Monocytesand macrophages are key members
Inflammationand immunedisorders Unit 3 I 215
of the mononuclear phagocyticsystem.Themonocytesmigratefrom blood
to varioustissueswherethey matureinto the majortissuephagocytes , the
macrophages. Thetissuemacrophages are scatteredin connectivetissueor
clusteredin organssuchasthe lung(alveola r macrophages), liver(Kupffer's
cells),spleen,lymphnodes,peritoneum, centralnervous$ystem(microglial
cells)andotherareas(Fig. 22.). Veryimportantpropertiesof macrophages
their rolesuchas antigen-presenting cells(CD-14) whichleadsfor activation
of T- and8-lymphocytes .
Approximately 1Oto 15% of the peripheralbloodlymphocytescannot be
distinguishedlikeT-cellor 8-cells.Thesecellsare naturalkiller(NK)cells.
Naturalkiller cellsconstitutea majorcomponentof the innateimmunesys-
tem, andaredistinctivein following- NKcellsattacktumor cells,virallyin-
fectedcells.Theywerenamednaturalkillersbecauseof the initial notionthat
theydo not require activationin order to kill cellswhichare not recognized
as owncells.

Bonrmarrow Blood Tissues Microg

lia(CNS)
KupfferOiver)
Alveolar
macropages(lung)
Osteoclasts
(booeJ

-"'.._ ...__ ._...,.

L Activated
macropage

Fig.22. Mon
onuc
learphagocytes
 216 I Part I Generalpathophysiology

NK cellsare cytotoxicand containspecialproteinssuchas perforinand

proteasesknownas granzymes.Uponreleasein closeproximityof a cell to
bekilled (targetcell), perforinformsporesin the cell membrane
of thetarget
cellthroughwhichthe granzymes andassociated moleculescanenter,where
theyinduceapoptosis.Killingcell by apoptosisis veryimportantin immunol-
ogy.If a virus-infected cellweredestructedby necrosiswithsubsequent lysis
it wouldonly releasethe virions. Apoptosisleadsto destructionof the virus
insidemakingit unableto releasefrom the cell.

The immune defense of the organism can be divid-

ed into two main branches:

• Theinnateor non-specificimmuneresponseconsistingof physical and

chemicalbarrierssuchas skin, gastricacid,mucusor tearsas well as
cellsandactivemechanisms suchasphagocytes,naturalkillercellsand
the complement system
• Theadaptiveimmuneresponse , with antigen-specific
activitybyT-cells
(cellularresponse)andspecificantibodyproductionby B cells(humoral
response).

This divisionis usefulfor categorizing

the differentcomponents of the im-
munesystem,but it is importantto recognize that in the immuneresponseis
continuousinterplaybetweenmembersof bothbranches .

Innate non -spec ific mechanisms '.

The innatesystemis comprisedof all the mechanismsthat defendan or-
ganismin non-specificform, against'an invader,respondingin the same
fashion, regardle
ss of what it is~ It constitutesolderdefensemechanisms
,
someof these beingfound in primitivemulticellularforms, in plantsand
fungi.
Inflammationand immunedisorders Unit 3 I 217
Physical Barriers
• Theskin is the first and main line of defense.Thesurfaceis madeup
of deadskin cellsrich in keratin,whichimpedesmicroorganisms from
enteringthe body.Lightlyacidicand lipidic secretions from sebaceous
glandandsweatglandscreatea hostilecutaneousenvironmentimped-
ing the excessive growthof bacteria.
• Gastricacid is a powerfuldefenseagainstinvadingbacteriafrom the
intestines.Fewspeciesare ableto survivethe low pH and destructive
enzymes that existin the stomach.
• Salivaandtearscontainantibacterial enzymes , suchas lysozyme , which
destroythe cellularwallsof bacteria.
• In the intestines,the bacterialfloracompeteswith oneanotherandnon-
commensalpathogensfor food andspace,diminishingthe probability
of pathogenic bacteriamultiplyingin sufficientnumbersto causeillness.
Forthis reasontheexcessive ingestionof oralantibioticscanleadto the
depletionof benignbacteriain the intestine . Uponendingtreatment,
dangerous speciescanmultiplywithoutanycompetition , therebycaus-
ing manyillnesses.
• Mucusis anotherdefense , coatingthe mucousmembranes. It catches
andimmobilizes invadingbodies;its compositionis deadlyto manymi-
croorganisms. It alsocontainslgA antibodies(whichare a component
of theadaptiveimmunesystem).

Phagocytes and their role in immunity

Phagocytes are cells,suchas neutrophilsand macrophages, that havethe
capacityto directionallyextendcellularportions(pseudopod), engulfingand
overtakinga foreignparticleor microorganism. This microorganismis con-
tainedinsidea vacuolewhichis thenmergedwith lysosomes, vacuolesrichin
enzymesandacids,whichdigestthe particleor organism.Phagocytes react
to cytokinesproducedby lymphocytes, butalsopatrolthebodyautonomous-
ly, withoutstimulus,but in a lessefficientmanner.Thisform of defenseis im-
 1
.

218 I Part I Generalpathophysiology

portantagainstbacterialinfections,asvirusestypicallyhavetheirownmeans
of enteringhost cellsandthe majority of para~ itestoo largeto beconsumed.
Phagocytosisis also an importantpart of the cleaningprocessafter cellu-
lar destructionfollowing infectionor anyotherprocessthat leadsto cellular
death.Manyphagocytes dieafterphagocytosis , bothphagocytes andbacteria
canbetrappedin a pastyliquidrich in stucturalproteins,knownas pus.
Somebacteria,suchas Mycobacterium tuberculosiswhichcausestuber-
culosis, havedefensemechanisms againstdigestionafterphagocytosis , and
survivewithinthe phagocyteundetectable by lymphocytes.
Neutrophil granulocyte: themostabundanttypeof phagocyte andis always
thefirst to arriveat the sceneof infection.Alongwith its lysosomalenzymes,
it destroysforeignsubstancesor kills pathogens with its "respiratoryburst."
Theneutroph il respiratoryburst is a chainof reactionsthat produceshydro-
genperoxide,whichalmostimmediatelyreleasesits oxygenion to form hy-
pochloriteby combiningwith surroundingchlorideions.Hydrogenperoxide ,
with its release of oxygenion, and hypoc~lorite,are strong oxidizingagents
which accomplishdestructionof foreignsubstances andpathogens . Forthis
respiratoryburst,the neutrophilincreasesits oxygenuptakea hundredfold.
Macrophages : a giganticcell, the matureform of a monocyte,has the
capacityto consumemanymorebacteriathana neutrophil.Differentiation is
stimulatedthroughcytokine.It is moreefficientin destroyingbacteriathan
neutrophils,but lives for a shorteramountof time, havingto be reformed
throughmonocytesduring eachinfection. It has its own respiratoryburst,
releasingnitric oxidefrom arginine.Nitric oxideandchemicalsthatarisefrom
it, particularlyperoxynitrite,can kill viruses,bacteria, fungi, protozoa , some
helminths,andtumor cells.With this powerfulmechanism,the only reason
sicknessstill occursis becauseit couldnot functionf.ully.
Basophilgranulocyte andMastCells:consuming verylittle,thesecellsrelease
histamineandare importantin someallergicreactions(suchas asthma)and
alsodefending againstparasites.
TheyaremobilizedbytheantibodytypelgE.
Eosinophil granulocyte:a non-consuming cell relatedto the neutrophil.It
is an important partof defenseagainstparasites.
Neutrophils,eosinophilsand basophilsare also knownas polymorpho-
nuclearleukocytes (dueto their lobednuclei)or granulocytes.
Inflammationand immunedisorders Unit 3 I 219
Complement system and ther role in the immunity
Thecomplementsystemis a biochemicalcascadeof proteinsthat helpsto
clear pathogensfrom an organism.It is derivedfrom manysmall plasma
proteinsworkingtogetherto form the primaryendresultof cytolysisby dis-
ruptingthe targetcell's plasmamembrane. The proteinsare synthesizedin
the liver,mainlyby hepatocytes .
In bloodit is usuallyin a passivestate.In a classicalwaycomplementis
activatedby antigen-antibody complex;thenit disintegrates
, its fragments are
biologically activeandinfluenceimmuneandallergicreactions.

The results of compl e m e nt a ctiv a tion a re:

• destructionof antigen-antibody complex;

• increasedvesselspermeab ility causedbytheactivationof coagulantand
kininsystems;
• releaseof histaminefrom mastcells;
• dilatationof capillaries;
• contractionof smoothmuscles , etc.
Complement takespartin alienproteins,microbesandvirusesinactivation,
rejectionof transplants
, eliminationof tumorandmutatedcells.

Specific or adaptive immune response

Thebasisof specificimmunitylies in the capacityof immunecellsto distin-
guishbetweenself antigens(thoseof the originalorganism),and proteins
producedby invadersor cellsundercontrolof a virus ("non-self"antigenor
whatis not recognized asthe originalorganism).Thisdistinctionis madevia
T-CellReceptors (TCR)or 8-CellReceptors(BCR).
Specific immuneresponsecanberealizedeitherwith humoralor with cel-
lularmechanism. It also canbeprimary(antigenis metfirst) andsecondary
(antigenwasmetearlier).
 220 I Part I Generalpathophysiology

Antigensare recognizedby receptorson immune cells and by protein

called antibodiesor immunoglobulins,which are generatedin response to
the antigen. Antigens include bacteria, viruses, protozoans , and parasitic
worms. Antigensalso can includesubstancessuchas pollen, insectvenom,
and transplantedorgans. Most antigensare macromolecules such as pro-
teins and polysaccharides . Smallersubstances(molecularmasses< 10 000
daltons) usually are unableto stimulatean immuneresponseby themselves.
Whentheselow-molecular -weightcompounds , knownas haptens , combine
with largerproteinmolecules , theyfunctionas antigen.
Humoral mechanism oftheprimaryimmuneresponse requirescoopera-
tion of phagocyte , 8-lymphocyteandT-lymphocyte(Fig. 23).
Themainobjectsof the humoralimmunereactionarealienproteins.When
the antigen gets to the organismit is capturedand processedby phago-
cyte.The resultof the processingis the presentat ion of antigenstructureon

cellularimmunity humoralimmunity

Antigen B Cell
IL-2IL-4
IFNy IFNy Antibodies

Antigen
preseting
cell

Phagocyte
NKCell
Complement

Fig. 23.Cellularandhumora
l immunity
Inflammationand immunedisorders Unit 3 I 221
phagocytemembrane. T-lymphocytes-helpers identifythis antigenwith T-cell
receptorandstimulate8-lymphocyteswith lymphokines.Antigenbindsonly
with thoseB lymphocytes whichhavespecificreceptorto it. ThenB-lympho-
cytesaretransformedinto the blastsand proliferateinto the plasmaticcells
that canproducespecificantibodiesinto blood.
An antibodyor immunoglobulinis a largeY-shapedproteinusedby the
immunesystemto identifyand neutralizeforeignobjects like bacteriaand
viruses.It consistsof two heavyandtwo lightchainsandhasantigen-binding
fragment(Fab)and Fefragmentcrystallizablefragment.Eachantibodyhas
uniqueFabaffinespecificto only onespecificalien(or own) antigen.When
antibodybinds to antigenit becomesactivated,taggingor neutralizingits
target.
Therearefive typesof antibodiesor immunoglobulins (lg): lgA, lgD, lgE,
lgG, andlgM.
lgA representsabout15% to 20% of immunoglobulins in blood, although
it is primarilysecretedacrossthe mucosaltract into the stomachand intes-
tines.This preventsmicrobesfrom bindingto epithelialcells in the digestive
andrespiratorytracts. This immunoglobuli n helpsto fight againstpathogens
that contactthe bodysurface,areingested , or are inhaled.
lgDmakesupabout1% of proteinsin the plasmamembranes of immature
B-lymphocytes. lg D's functionis currentlyunknown.
lgEis anantibodysubclassfoundonlyin mammals.It playsleadingrolein
allergicreactionof the first type.
lgG has four subclassesand is the most abundantimmunoglobulinand
provideslong term defensefrom antigens.This is the only lg that can pass
throughthe placenta , therebyprovidingprotectionto the fetus in its first
weeksof life beforeits ownimmunesystemhasdeveloped.
lgM is the largestantibodyin the circulation.It providesdefensefrom in-
fectiousagentduringa primaryimmuneresponse.lgM antibodiesare also
responsible for the agglutinationof redbloodcellsif the recipientof a blood
transfusionreceivesbloodthat is not compatiblewith his/herbloodtype.
lg Mand lg Ghelpto eliminatethe alienantigenby its opsonization. Opso-
nizationrefersto thecoatingof antigenwith antibodythatresultsin enhanced
uptake of the antigenthat can be further destroyedby phagocytesand NK
 2221 Part I Generalpathophysiology

cell. Alsotheseantibodiesare knownto activatecomplementsystem, which

provide complement-dependent antigenlysis.
The primaryhumoralimmuneresponsewhichdevelopsafterthe antigen
wasfirstly met by the organismresultsin lgM secretion.The secondaryim-
muneresponse(whenthe antigenis metfor the secondtime) resultsin lgG
secretion.Later, whenthe concentrationof immunoglobulins is rising in the
organism,their production is limitedby T-lymphocytes-suppressors.

Cellular mechani sm of primary immune resp on se

The mainobjectsof cellularimmunereactionarealiencells(transplantation),
bacteria,cells affectedwith viruses, tumor cells,or own cellsdestructedby
differentinfluencesso thattheir antigenstructureis changed.
T cells recognizeantigenin a differentwayto B cells. Theyrecognizepep-
tide fragmentsof antigencombined with cell surfaceMHCproteins.
Antigencanbe identifiedby the directcooperationof aliencell andT-lym-
phocyteor with the helpof phagocyte . T-helpersstimulatethe proliferationof
T-killers that have membranous T cell receptorto specific antigen. Sensitized
T-lymphocytesproducelymphokines,whichmediatethe development of in-
flammatoryreaction in the placeof antigeninvasion.
Someimmunecellsactivatedduringthe primary immuneresponsedo not
proliferateintoplasmocytes andsensitized T-cells.Theyarestoppedin G1mi-
totic phase.Thesecellsarethe cellsofimmune memory . When the organism
meetsantigenfor the secondtime thesecells are activated.Thesecondary
immuneresponseis realizedfasterthanthe primaryoneandis moreeffective
(the levelof specificantibodiesandthe amountof sen.sitizedT-cellsis more).

Cytokines and their rqle in the immunity

It is well known that the inductionand regulationof the immuneresponses
involvemultiple interactions amongimmunecells. Manysuchinteractionsare
dependent on cell-to-cellcontact.In severalinstancescellinteractions areme-
Inflammation
and immunedisorders Unit 3 I223
diatedby solublemediators . Dependingon the source, mediatorsare called
lymphokines(lymphocyte-derived , suchas the T cell-derived factor interleu-
kin-2or monokines(monocyte -derived, suchas tumor necrosisfactor).Now
thesepolypeptidemediatorsaregroupedunderthe singlenameof cytokines.
Cytokinesincludeinterpherons , interleukins,tumor necrosisfactor (TNF).
Interferonsarea classof naturalproteinsproducedby the cellsof the im-
munesystemsin responseto foreignagentssuchas viruses,bacteria,para-
sitesandtumorcells.Therearethreemajorclassesof interferons:alpha(a),
beta(P), andgamma(y). Theygenerallyhaveseveraleffects:antiviralandan-
tioncogenicproperties,macrophage andnaturalkillerlymphocyteactivation.
Interleukinsarea groupof cytokinesthat werefirst seento be expressed
by leukocytes.Nowit hasbeenfoundthat interleukins(IL) areproducedby a
widevarietyof bodycells.Thefunctionof the immunesystemdependsin a
largeparton interleukinsinfluence.
. TNFis a pro-inflammatory cytokinethat is producedby white bloodcells
(monocytesand macrophages) ; has an antineoplasticeffectbut causesin-
flammation(as in rheumatoidarthritis)

By the effects on the immune system all cytokines

can be divided into four groups:

1. Cytokinesthat mediatenaturalimmunity:IL-1, IL-6 and IL-8, TNF-a,

a-interferons. Certainof these cytokines(e.g., interferons)protect
againstviral infections,whileothers(e.g., IL-1, TNF-a,IL-8) initiatenon-
specificinflammatoryresponses.
2. Cytokinesthat regulatelymphocytegrowth, activation,and differentia-
tion: IL-2, IL-4, and transforminggrowth factor-(TGF). Transforming
growthfactor(TGF)cancauseoncogenictransformationin cells.While
IL-2 and IL-4 usuallyfavor lymphocytegrowthanddifferentiation , TGF
is a powerfuldown-regulator of immuneresponses .
3. Cytokinesthat activateinflammatorycells:y-interferon,TNF-a , lympho-
toxin,migrationinhibitoryfactor,andIL-5.Mostof thesecytokinesderived
fromT cellsserveto activatethefunctionsof phagocytes , naturalkillercells.
 224 I Part I Generalpathophysiology

4. Cytokinesthat stimulate haematopoiesis:granulocyte-macrophage

(GM)stimulatingandgranulocytestimulating.

It shouldbe notedthat somecytokinessuch as IL-I and TNF-ahavea

plentyof effects.

Cytokines mediate their effects by binding to spe-

cific high-affinity receptors on their target cells and
can induce their effects in three ways:

1. They act on the same cell that producesthem (autocrineeffect),

as occurs when IL-2 producedby activatedT cells promotesT-cell
growth.
2. Theyaffectothercellsin their neighboring(paracrineeffect),as occurs
when IL-I producedby antigen-presentingcells affectsT cells duringthe
inductionof an immuneresponse. _
3. Theyaffectmanycellssystemically(endocrineeffect),the bestexam-
ples in this categorybeingIL-I and TNF-a,which producethe acute-
phaseresponseduringinflammation.

Immunological tolerance
In certaincircumstancesimmunecell do not reactto the specificantigen
while reactivityto other antigensis normal.Suchstate is calledimmuno-
logicaltolerance.Toleranceis a statein whichthe .immunesystemfails to
respondto a givenantigen.Thismechanism evolvedfrom a needfor the body
to preventits tissuesbeingattackedby its own defensenetwork.On occa-
sionswhentolerancefails or is incomplete,autoimmunitycanresult.
Immunological toleranceis dividedinto naturalandinducedtypes.
Naturalimmunological toleranceis presentin all organismsand is mani-
festedas the absenceof reactivity to own antigens.Naturalimmunological
toleranceis formedduringembryogenesis. The mechanisms of naturalim-
Inflammationand immunedisorders Unit 3 I225
munological toleranceformationare realizedin the centralorgansof the im-
munesystem.Thesemechanisms are:selectionand eliminationof the im-
munecellsthat reactto the ownantigens.
Inducedimmunological tolerancecan be provokedwith the following
methods.
1. Administrat ion of a foreignantigenintothe embryo.
2. Administration of foreignlymphocytes intothe embryo.
In suchcases,immunological tolerancewill beinducedwiththemechanisms
similarto themechanisms of naturalimmunological toleranceformation.
3. Administration of a foreignantigento the organismin big doses.

Thisconditionis called immunologicalparalysis. Themechan ism of its for-

mationis the blockingof the immunecellspecificreceptorsto the alienanti-
genwithanexcessive amountof antigen.It shouldbenotedthatimmunologi -
caltolerancediffersfrom immunologicaldeficiency asfollowing: in thecaseof
immunological toleranceimmuneresponseis absenttowardssomespecific
antigen,whilereactivityto otherantigensis normal.Immunodefic iencystate
meansthata depressed immuneresponseis observedtowardsall antigens.

Transplantation and immunity

Tissuetypingfor organgraftingrequiresHLAtyping.TheHLAantigenstruc-
ture shouldbe as closeas possible , as this increasesgraft survival. When
cells with foreign MHC antigensare transplanted,the recipient'simmune
systemattemptsto eliminatethe donorcells, a processreferredto as host-
versus -graftdisease(HVGD).Conversely, the cellularimmunesystemof the
transplanted tissuecanattackunrelatedrecipienttissue, causinga graft-ver-
sus-host disease(GVHD).
In HVGO , the immunecellsof thetransplantrecipientattackthedonorcells
of the transplantedorgan.HVGDusuallyis limitedto allogeneicorgantrans-
plants,although evenHLA-identicalsiblingsmaydiffer in someminor HLA
loci, whichcan evoke slow rejection.Rejectiondue to HVGDis a complex
processthat involves cell-mediatedandcirculatingantibodies.Although many
 226 I Part I Generalpathophysiology

cellsmay participatein the processof acutetransplantrejection,onlythe T-

lymphocytesseemto be absolutelyrequired.Theactivationof CD8cytotoxic
T-cellsandCD4helperT-cellsis triggeredin responseto thedonor'sHLAan-
tigens.Activationof CD4helpercellsleadsto proliferationof B-cell-mediated
antibodyproductionanddelayed-type hypersensitivity
reaction.Theinitialtar-
getof the recipientantibodiesis graftvasculature. Theantibodiescanproduce
injuryto thetransplanted organby complement-mediated cytotoxicity,gener-
ationof antigen-antibody complexes , or throughantibody-mediated cytolysis.
Threebasicrequirementsare necessaryfor GVHD to develop:the trans-
plantmusthavea functionalcellular immunecomponent;the recipienttissue
must bearantigensforeignto the donortissue;andthe recipientimmunity
must be compromisedto the point that it cannotdestroythe transplanted
cells.Theprimaryagentsof GVHDareT-cells, andthe antigensthey recog-
nizeandattackareHLA. The pathogenesis of acuteGVHDis initiatedin three
stages:recognitionand presentationby donor T-cellsof foreign recipient
antigens , activationof T-cellsthroughcytokines,and multiplicationof acti-
vatedT-cells.The actualtissuepathology_ observedwith GVHDis produced
directly by the actionof cytotoxicT-cellsor indirectlythroughthe release
of inflammatorymediatorssuch as tumor necrosisfactor, interleukins, and
complement.If GVHDoccurs,the primarytargetsof the acuteillnessarethe
skin,liver,intestine,andcellsof the immunesystem.Moreoftenthis typeof
diseasedevelopsin bonemarrowtransplantation.

Chapter 10. Pathophysiology

of the Immune System

Disorders of the human immune system are divided

into two broad categories:

• Weakenedimmuneresponse.This categoryincludescongenital(in-
born)andacquiredformsof immunodeficiency
.
Inflammationand immunedisorders Unit 3 I 227
• Overzealous
immuneresponse. Thiscategoryincludesautoimmunedis-
ordersandhypersensitivity
reactions
.

Immunodeficiency disorders are a group of disordersin which part of

the immunesystemis missingor defective . Defectscanoccurin anycom-
ponentof the immunesystemor in morethanone component(combined
immunodeficiency). Differentimmunodeficiency diseasesinvolvedifferent
componentsof the immunesystem.The defectscan be inheritedand/or
presentat birth (congenital)or acquired.Congenitalimmunodeficiency is
causedby geneticdefects,which generallyoccurwhile the fetus is devel-
oping in the womb.Thesedefectsaffectthe developmentand/orfunction
of one or moreof the immunesystemcomponents.Acquiredimmunode-
ficiencyis the resultof a diseaseprocessor injuringfactorsinfluence, and
it occurslaterin life.
Congenital immunodeficiency disorders are also calledprimaryimmu-
nodeficiencies. Eventhoughmorethan70 differenttypesof congenitalim-
munodeficiency disordershavebeenidentified,they rarelyoccur.Congenital
immunodeficiencies may occuras a resultof defectsin 8-lymphocytes , T-
lymphocytes , or both.They alsocanoccurin the innateimmunesystem.
Bruton 's agammaglobulinemia , also known as X-linkedagammaglobu-
linemiais a congenitalimmunodeficiency disorderwhichaffectshumoralim-
munity. It is seenonly in malesbecauseit is causedby a geneticdefecton
the X chromosome. Womenmay passthe defectivegeneon to their male
children.
It usuallydoesnot becomeapparentuntil aboutsix monthsof age,when
maternalimmunoglobulins are depleted.In suchpatientsB cellsare absent
or remarkably decreased in thecirculation, andtheserumlevelsof all classes
of immunoglobu lins are decreased whereaspre-8cellsarefound in normal
numbersin bonemarrow. Plasmatic cellsthroughoutthebodyareabsentand
germinalcenters(centersof cellsdivision)of lymphnodes, Peyer'spatches ,
theappendix, andtonsils areunderdeveloped or rudimentary .
If thereis an abnormalityin eitherthe developmentor functionof B lym-
phocytes , theabilityto makeantibodieswill beimpaired.This allowsthe body
to be suscep t ible to recurrentinfections.In most cases,recurrentbacterial
 22a I Part 1 Generalpathophysiology

infectionssuchas acuteand chronicpharyngit is, sinusitis,otitis media, bron-

chitis, and pneumoniacall attentionto the underlying immunedefect.Most
viral, fungal, and protozoa!infectionsarehandled normally by cell-mediated
mechanisms .
Anotherexampleof humoralimmunitycongenitaldisorderare selective
immunoglobulin deficiency syndromes.The most commontype of immu-
noglobulindeficiencyis selectivelgA deficiency . The amountsof the other
antibodytypesarenormal.Somepatientswith selectivelgAdeficiencyexpe-
rienceno symptoms,whileothershaveoccasionallung infections and diar-
rhea.In anotherimmunoglobulindisorder,lgGand lgA antibodiesare defi-
cientandthereis increasedlgM production . Peoplewith this disordertend to
get severebacterialinfections.
Themostcommondisorderof cell-mediated immunity is DiGeorge 's syn-
drome . This disorderresultsfrom a lackof thymicinfluenceon the immune
system.Thethymusis usuallyrudimentaryandT cellsaredeficientor absent
in the circulation.Thus, infantswith this defectare extremelyvulnerableto
viral, fungal, and protozoa!infections.Susceptibilityto intracellular bacteria
is alsoincreased,becausephagocyticcellsthateliminatethem requireT cell-
derivedsignalsfor activation . TheB-cellsystemandserumimmunoglobulins
areentirelyunaffected.
DiGeorge ' s syndrome results from a congenitalmalformationaffect-
ing the third and fourth pharyngealpouches.Thesestructuresgive rise to
the thymus, parathyroidglands, and portionsof lips, ears, and the aortic
arch. Hence,in addition to thymic hypoplasiathe parathyroid glandsare
also eitherhypoplasticor totally absent,often leadingto tetany(condition
characterizedby periodicpainful muscularspasmsandtremors) resulting
from hypocalcemia.Most of these infants haveadditionaldevelopmental
defectsaffectingthe face,ears, heart,andgreatvessels. Forexample, they
may havelow-setears, a small recedingjawbone,and wide-spacedeyes.
Transplantationof thymus tissue has beensuccessful in some of these
infants. In others (with partia! defects) immunity may improvespontane-
ouslywith age.
Sometypesof immunode f iciencydisorders affectbothB lymphocytesand
T lymphocytes.For example,severecombined immunodeficiency disease
Inflammationand immune disorders Unit 3 I229
(SCIO)or (Swiss-TypeAgammaglobulinemia) severecombinedimmunodefi-
ciencyrepresents a constellationof syndromesall havingin commonvariable
defectsin both humoralandcell-mediatedimmuneresponses.Severalvari-
ants havebeenidentified , all quiterare.Mostaffectedpersonshavemarked
lymphopeniawith a deficiencyof both T and B cells. Othershavenormal
numbersof 8 cells,which are nonfunctionalowingto lackof T-cell help.In
all cases, however , the thymusis hypoplasticandfetal in type, or it may be
absent.Lymphnodesaredifficultto find, markedlyreducedin size.Thelym-
phoidtissuesof the tonsils, gut, andappendixarealsomarkedlyhypoplastic .
Infantswith thesesevereimmunehandicapsare vulnerableto all forms
of viral, fungal, and bacterialinfections, and most die duringthe first year
of life.
Disorders of innateimmunityaffectphagocytesor the complementsys-
tem. Thesedisordersalsoresultin recurrentinfections.Forexample , chronic
. granulomatosis is a disorderof the phagocytesin whichthey ingestbacteria
normallybut fail to kill themdueto absenceof proteolyticenzymes;disease
is usuallyfataldueto overwhelming bacterialinfection.
Chediak-Higashi syndromeis characterized with impairedleukocytefunc-
tion dueto failureof phagolysosome formation(impairedlysosomedegranu-
lationwith phagosomes) . The diseaseis characterised by poor bactericidal
functionleading susceptibilityto infections, abnormalitiesin nuclearstruc-
ture of leukocytes, anaemia,hepatomegaly.
Acquired immunodeficiency disorders.Acquiredimmunodeficiency dis-
ordersaremorecommonthancongenitalimmunodeficiency.

Aquired immunod e ficiencies ar e caused with a n in-

fluence of various ethiological factors :

• viral infectionsincludeAIDS, measles , hepatitis8 andC, epidemicpar-

otitisandothers;
• bacterialinfections- lepra, tuberculosis , luesandothers;
• digestiondisturbances-obesity,malnutrition,deficiencyof vitamins,iron
(depression of T-cells), copper (lymphopenia, depressionof T-helpers);
 230 I Part I General pathophysiology

• surgicaloperations andanesthesia(depression of lymphocytes function

remainsfor about30 days);
• hypoproteinemias;
• intoxication,ionizingradiation
, tumorschemotherapy andmalignanttu-
morsthemselves;
• medications(particularly the use of anti-cancer drugs, corticostero
ids,
andantibiotics);
• endocrinediseases(diabetes,thyrotoxicosis,Kushing 's syndrome).

Many factors can also contribute to the general

w e akening of the immune system :

• Alcoholanddrugsabuse,cigarettesmoking
• Stressand/or depression(psychologicalstresscan greatlyincrease
susceptibilityto viral diseases
, namelythroughan increasein serum
corticosteroidlevels
• Age(abilityof the immunesystemto respondis decreased at earlyand
old age)
• Lackof exerciseas wellasexcessive exerciseresulting in physiological
stress.

Acquiredimmunodeficiencyoften occurs as a complicationof other

conditionsand diseases.For example,the most commoncausesof ac-
quired immunodefic iency are malnutrition,some types of cancer,and
infections.Peoplewho weighlessthan 70% of the averageweightof per-
sons of the same age and genderare consideredto be malnourished.
Examplesof types of infections that can lead to immunodeficiency are
chickenpox , cytomegalovirus.measles , tuberculosis, infectious mono-
nucleosis(Epstein-Barrvirus), chronichepatitis,lupus,and bacterialand
fungalinfections.
Sometimes , acquiredimmunodeficiency is broughton by drugsusedto
treat anothercondition.For example,patientswho havean organtrans-
plantare givendrugsto suppressthe immunesystemso the bodywill not
Inflammationand immunedisorders Unit 3 I 231
rejectthe organ.Also, somechemotherapy drugs,whichare givento treat
cancer,havethe side effectof killing cells of the immunesystem.During
the periodof time that thesedrugs are beingtaken, the risk of infection
increases.It usuallyreturnsto normalafter the personstops taking the
drugs.
Generalsymptoms of immunedeficiency . Peoplewith an immunode-
ficiencydisordertendto becomeinfectedby organismsthat don't usually
causediseasein healthypersons.Themajorsymptomsof most immuno-
deficiencydisordersare repeatedinfectionsthat healslowly.Thesechronic
infectionscausesymptomsthat persist for long periodsof time. People
with chronicinfectiontendto be paleandthin. Theymayhaveskin rashes.
Theirlymphnodestendto be largerthan normalandtheir liver andspleen
alsomaybeenlarged.Brokenbloodvessels, especiallynearthe surfaceof
the skin, maybeseen.This can resultin black-and-bluemarksin the skin.
.Thepersonmaylosehairfrom their head. Sometimes , a red inflammation
of the lining of the eye(conjunctivitis)is present.Theymay havea crusty
appearance in andon the nosefrom chronicnasaldripping.
Usually, the first sign that a personmight havean immunodeficiency
disorder is that they don't improverapidlywhen given antibioticsto treat
an infection.Strongindicatorthat an immunodeficiency disordermay be
presentis whenrarediseasesoccuror the patientgets ill from organisms
that don't normallycausediseases,especiallyif the patientgetsrepeatedly
infected.If this happensin very young childrenit is an indication that a
geneticdefectmay be causingan immunodeficiency disorder. Whenthis
situationoccurs in older childrenor young adults, their medicalhistory
will be reviewedto determineif childhooddiseasesmay havecausedan
immunodeficiency disorder.
AIDSor acquiredimmunodeficiency syndrome is a diseasecausedby
a rapidlymutatingretrovirusthat primarily attacksthe immunesystem.It
was first recognizedas a diseasein 1981. Thevirus was isolatedin 1983
and was ultimatelynamedthe humanimmunodeficiency virus (HIV). In a
processstill imperfectlyunderstood , HIV infectsthe T-helpercells of the
body'simmunesystem, cellsthat are necessaryto activate8-lymphocytes
and inducethe productionof antibodies.
 2321 Part I Generalpathophysio
logy

Somepeopledevelopflu-like symptomsshortly after infection,but many

haveno symptoms.It may be a few monthsor manyyearsbefore serious
symptomsdevelopin adults;symptomsusuallydevelopwithin the first two
years of life in infantsinfectedin thewomb or at birth. Beforeserioussymp-
toms occur,an infectedpersonmayexperience fever, weightloss, diarrhea,
fatigue, skin rashes, herpeszosteraffectionof nervousganglions. Infants
mayfail to developnormally.
HIVis not transmittedby casualcontact;transmissionrequires a directex-
changeof bodyfluids, suchas bloodor bloodproducts,breastmilk, semen,
or vaginal secretions , most commonlyas a result of sexualactivity or the
sharing of needlesamongdrug users.Sucha transmission mayalsooccur
from motherto babyduring pregnancyor at birth. Saliva, tears, urine, feces,
andsweatdo not appearto transmitthe virus.
Therearetwo maintargetsof HIV: the immune systemandthe centralner-
voussystem.Profoundimmunosuppression thatprimarilyaffectscell-mediated
immunity is the hallmarkof AIDS.It resultsfrom a severelossof CD4 T-cells
(T-helpers), because CD4moleculeis a highaffinityreceptorfor HIV. HIV causes
thelysis of CD4T-cells. In additionto thelossof CD4T-cellsinfections of mono-
cytes andmacrophages arealsoimportan t for thepathogenesisof HIV infection.

The major abnormalities of the immune function in

AIDS are:

• Lymphopenia;
• Decreased T-cellfunctionthat resultsin suscept ibility to opportunistic
infectionsandneoplasms;decreased delayedtypehypersens itivity;
• ImpairedB-cells function that results in hypergammaglobuliemia and
high levelof circulatingimmune-complexes ;
• Alteredmacrophage funct10n(decreased chemotaxis).

Thereis noadequate treatment for immunodeficiency

disorders.Therapy
is aimedat controlling infectionsand,for somedisorders,replacing defective
or absentcomponen ts.
Inflammationand immunedisorders Unit 3 I233
Patientswith Bruton'sagammaglobulinemia mustbe givenperiodicinjec-
tions of a substancecalledgammaglobulinthroughouttheir livesto make up
for their decreased abilityto makeantibodies.The gammaglobulinprepara-
tion containsantibodiesagainstcommoninvadingbacteria.If left untreated ,
the diseaseusuallyis fatal.
In somecases,no treatmentis requiredfor DiGeorgesyndromebecause
T-lymphocyteproductionimproveson its own. Eitheran underdeveloped
thymusbeginsto producemoreT lymphocytes or organ sitesotherthanthe
thymuscompensate by producingmoreT lymphocytes. In someseverecases,
a bonemarrowtransplantor thymustransplantcan be doneto correctthe
problem.
For patientswith SCIO, bone marrowtransplantationis necessary.The
bonemarrowof the personreceivingthe transplantis destroyed , and is then
replacedwith marrowfrom the donor.
In mostcases,immunodeficiency causedby malnutritionis reversible.The
healthof the immunesystemis directlylinkedto the nutritionalstatusof the
patient.Amongthe essentialnutrientsrequiredby the immunesystemare
proteins,vitamins,iron,andzinc.
For peoplebeingtreatedfor cancer, periodic relief from chemotherapy
drugscanrestorethe functionof the immunesystem.
Patients withimmunodeficiency disordersshouldavoidbeingnearpeoplewho
haveinfectious diseasesbecause theycaneasilyacquirenewinfections. Forthe
samereason, theyshouldpracticegoodpersonalhygiene, especiallydentalcare.
Despitehigh hopes, there are no medicationsthat directly increasethe
activityof the immunesystem.Variousforms of medicationthat activatethe
immunesystemmaycauseautoimmu ne disorders.

A llergy
Anotherbig groupof immunesystemdisordersis describedwith the over-
zealousimmuneresponse.It can manifestas hypersensitivityreactionsor
autoimmunedisorders.Hypersensitivity
reactionsare also termed allergic
reactions.
 2341 Part I Generalpathophysiology

An allergycan referto severalkinds of immune reactions in which a per-

son's body is hypersensitized to some substances . Thesesubstancesare
knownas allergens.The word allergyderivesfrom the Greekwords allos
meaning"otller" andergonmeaning"work".
Theterm and conceptof "allergy" was coinedby a Viennesepediatrician
namedClemensvon Pirquetin 1906.Heobservedthatthesymptomsof some
of his patientsmighthavebeena responseto outsideallergenssuchas dust,
pollen, or certain foods.For a long time all hypersensitivities
werethought
to stemfrom the improperactionof lgE, howeverit soonbecameclearthat
severaldifferentmechanismswereresponsiblefor the disorderspreviously
classifiedas "allergies". A new four-class(now five) classificationscheme
wasdesignedby P. G. H. GellandR. R. A. Coombsin 1968.

1. Anaphylactic reactionsor Type I Hypersensitivity: atopic bronchial

asthma, pollinosis,anaphylaxis shock.
2. Cytotoxic reactions or Type II Hypersensitivity: autoimmunehemolytic
anemia,agranulocytosis.
3. Reactions mediatedbyimmunecomplexes or TypeIll Hypersensitiv-
ity: serumsickness , Arthusreaction.
4. Cell mediatedreactionsor Type IV Hypersensitivity : allergiccontact
dermatitis,transplantrejections,infectious-allerg ic illnesses(tuberculo-
sis, lepra, brucellosis,syphilis)
5. Stimulating allergicreactions or TypeV Hyperse nsitivity:autoimmune
thyroiditis.This type is not presentin all classifications , moreoften in
the clinic classificationis usedwhichincludesonlyfour types.

An allergenis anysubstance(antigen), mostofteneatenor inhaled

, thatis
recognizedby the immunesystemandcausesanallergicreaction.
Dust,pollenandpet dandruffareall commonallergens,but it is possible
to be allergicto anythingfrom chlorineto perfume. Foodallergiesare not
as commonas food sensitivity,but some foods such as peanuts(really
a legume), nuts, seafoodand shellfishare the causeof seriousallergies
in many people.A few peoplehaveeven beenrecordedto be allergicto
certainchemicalsfound in almostall water.Othercommon causesof seri-
Inflammationand immunedisorders Unit 3 I235
ous allergyare wasp,ant and beestings, penicillin,and latex.In addition
to foreign proteins found in foreignserum(from blood transfusions)and
vaccinesallergensinclude:
• plantpollens(Hayfever)-ryegrass,ragweed, timothygrass,birchtrees;
• moldspores (fungi spores);
• drugs(penicillins,sulfonamides, salicylates(alsofoundnaturallyin nu-
merousfruits), localanaesthetics- novocaine, dicaine;
• foods(foodallergy)- nuts, sesame , seafood , egg (typicallyalbumen ),
peas, beans , peanuts
, soybeansand otherlegumes , soy, milk, wheat;
• insectstings- bee stingvenom,waspstingvenom;
• animal and birds products(animal allergy) - animalhair and dander,
birdsfluffs;
• insectproducts- cockroachcalyx, dust miteexcretion .

The gen eral m echa nism of allerg ic react io ns

develo pm ent
Thegeneralmechanism of allergicreactionsdevelopmentcanbe explaimed
with thefollowingexample.Will you imaginethe groupof peopleworking at
batteryfarm,wherehens are grown.Hen's fluff is a powerfulallergen.Re-
searchingstudiesshowthatabout75to 90 % of theworkershaveantibodies
to this allergen,butonly1Oto15% of themwill havemanifestation of allergy.
In orderto understand generalmechanisms of allergicreactionsdevelopment
we needto definesimilaranddifferentfeaturesbetweenimmuneandallergic
reactions.Bothimmunereactionsandallergiconesareaimedto protectthe
organismfrom geneticallyforeign antigens.Theyalso havesimilar mecha-
nisms of reactionsand both of themare mediatedwith the sameimmune
cells.
But allergicreactionsdifferfrom immuneoneswith increasedreactivity ,
transformedcharacterof an immuneanswerand tissuesinjury is always
present.
Thetype of reaction(immuneor allergic) dependson antigen's quality,
quantityandpeculiarities of individual'sreactivity.
 2361 Part I Generalpathophysiology

One of the allergy main risk factor is hereditary pre-

disposition, which can be realized at the following
stages:

• at the stageof allergencoming into the organismdueto increasedper-

meability of skin and mucuscover;it leadsto the filtering of antigens
into the organism, which in normalstate don't enter organismor its
entranceis limited;
• at the immunological stageof allergicreactiondueto the highfunctional
activityof T-helpers,increasedproductionof specificlgE;
• at the stageof allergicmediatorsreleasedueto the increasedsynthesis
of differentmediators(complement, cytokines);
• at the stageof tissuereactionon mediators(hyperreactivity of bronchi,
skin etc.) and inactivationof this mediators(decreaseof hystamyno-
pexicpropertiesof plasma).

All this constitutionalfeaturesof individual'simmunesystemcan be in-

heritedand resultin the development of atopicallergicreactions(hereditary
predisposed) .
Thedevelopment of everyallergicreactionincludesthreestages:immuno-
logicalstage,biochemical stageand the pathophysiological stage(stageof
clinicalmanifestation).

Immunological stageor thestageof sensitization is characterized

with
thefollowingevents:
• revealing of theallergenby immunecells;
• presentationof the allergenby the phagocytes t.o lymphocytes;
• synthesisof specificantibodiesby plasmaticcells;
• maturationof immunememorycells;
• fixationof the antibodiesard sensitizedlymphocytes(wemeanhereT-
killers) in the site of allergenlocalizationor in blood.

The stage of sensitizationor immunologicalstage of allergic reaction

does not haveany clinical manifestation.This state may last from several
Inflammationand immunedisorders Unit 3 I237
daysto severalmonthsor evenseveralyears.But we can establishsensi-
tizationstatewith specificallergictests, which revealantibodiesleveland
sensitizedT lymphocytes.
Sensitizationfollowing immunologicalstageof allergicreactionsmay be
active and passive. We are speakingabout acute sens'itizationwhen the
mechanismsdescribedaboveare startedin the organismafter the direct
contact with allergen. Passivesensitizationstate may be achievedwith
transfusion of immunoglobulines(antibodies)or lymphocytessensitized
to specificantigenfrom the animalwith active sensitizationto the intact
animal.
Pathochemical (biochemical) stagedevelopsafterthe secondcontact of
the immunesystemwith allergen.At this stage allergen forms complexes
with specificantibodiesor sensitize d lymphocytes.In someallergicreactions
complementis involvedto the formationof this complex.
Immune complexesfixate at the site of the highestallergen ' s and anti-
body'sconcentration (it is true to localallergicreactions suchas Arthusphe-
nomena).If allergic reactionis generalized (anaphylactic shock), thesecom-
plexesarefoundthroughoutthe bodyand also in bloodor lymph.
Theabove-mentioned complexescausereleaseor synthesisof biologically
activesubstances - mediatorsof allergy.Everytypeof allergic reactionshas
its own mediators .
Thestageof clinicalmanifestation (pathophysiological stage)is devel-
opedunderthe influenceof allergymediator s andis characterized with both
localandgeneraldisturbancesof organism'sfunctions.
Local pathologicalprocessesincludedevelopmentof inflammation,in-
crease d permeability of vessels walls, disturbancesof regionalbloodflow,
thrombosisof microcirculatory vessels.

The following general signs of allergy m a y b e

observed:

• Nose: swellingof the nasal mucosa(allergicrhinitis)

• Eyes:rednessanditching of the conjunctiva (allergic conjunctivitis)
 2381 Part I Generalpathophysiology

• Airways:bronchoconstriction, wheezingand dyspnoea , sometimesat-

tacksof asthma
• Ears:feelingof fullness,possiblypain,andimpairedhearingdueto the
lackof eustachian tubedrainage
• Skin:variousrashes,suchas eczema,hives(urticaria)andcontactder-
matitis.

A systemicallergicresponseis alsocalledanaphylaxis.Depending on the

rateof severity,it can causecutaneousreactions,bronchoconst
riction,ede-
ma,hypotension , comaandevendeath.
The mechanismsof differenttypes of allergic reactionsdue to Gell and
Coombsclassificationarethe following.

Type1 allergic(lgE-mediated) reactionis a rapidlyoccurringallergicre-

action.Theexamplesof diseaseswhichdevelopwith type 1 allergicreaction
are: hay fever, includingallergicasthma,conjunctivitisand allergicrhinitis,
anaphylaxis , angioedema, urticaria(hives). Thistypeof reactionalsomaybe
namedthe reaginictype,becauselgEhavethe secondname- reaginesand
anaphylactic type (Fig. 24).
Immunologicalstageof anaphylacticreactionstartswith the first contact
of allergenwith immunecells.This processresults in B-lympocy tes transfor-
mationto plasmaticcellswhichbeginto synthesizeimmunoglobulines. Type

Immunological Pathochemical Pathophysiological

stage stage stage
: -!> !> \·.' ·.·:: ::: ;, .
'
>----~ ii,'\: Release ·oiallerg ic mediators : Cellular
infiltrations All .
---► )II ~ • -~ ':,:,:: ~ (histamine . proteases , leucot- : ~ byeosinophiles__,. ergic_
Antigens .+. ..f · : rtens04, B,. CJ : andneutrophiles Inflammation
, Mastceff : I '
atation 't
• Vaso<i,1
lg£antibod'y • Increasedvascular perme ability
• Smooth muscule contraction
• Hypersecretion

Fig.24.Anaphylact
ic type of allerg
ic react
ion
 Inflammationand immunedisorders Unit 3 1239

1 reactionsin humansare mediatedby lgEantibodies(alsocalledreaginican-

tibodies),in othercaseslgGcanmediateanaphylactic reactions.This process
requiresthe assistanceof helperT cellsandis underthe regulatoryinfluence
of suppressorT cells. The lgE is stronglycytophylicfor mastcells and ba-
sophils, whichpossesshigh-affinityreceptorsfor the Feportionof lgE.Mast
cells are producedin the bonemarrowand are found predominantlynear
bloodvesselsand nervesand in subepitheliansites.The granulesin mast
cells containbiologicallyactivemediators.Linkingof lgE receptorson their
surfaceactivatesmastcellsand basophils.Mastcellsalso may be activated
by complementcomponentsC5aand C3A, macrophage -derivedcytokines
(IL-8), somedrugssuchas codeinand morphinand physicalstimuli (heat,
cold, sunlight).If lgE is boundto the surfaceof mastcells an individualis
primedto developtype1 reaction.
Pathochemical stageof anaphy/actic reactions.The next exposureto the
· sameantigenresultsin fixing of the antigento mast cell-boundlgE. This
processleadsto mast cell degranulation with the dischargeof preformed
or primarymediators(histamine,heparine, serotonineetc.)andsynthesis of
secondarymediators(prostaglandins , leukotrinsand cytokines).One of the
mostimportantprimary mediatorsis histamine.
Histam ineis a biogenicamineinvolvedin localimmuneresponsesaswell
as regulatingphysiological functionin the gut andactingasa neurotransmit-
ter. Most tissue histamineis found in granulesin mast cells or basophils.
Non-mast cell histamineis found in severaltissues, includingthe brain,
whereit functionsas a neurotransmitter.
Histamineexertsits actionsby combiningwith specificcellularreceptors
locatedon cells.Thethreetypesof histaminereceptorshavebeendiscovered.
H, histaminereceptorsare found on smoothmuscle, endothelium , and
centralnervoussystemtissue.Theactivationof it causesvasodilation,bron-
choconst riction, smooth muscleactivation , and separationof endothelial
cells (responsiblefor hives),and painand itching due to insectstings; the
primaryreceptorsinvolvedin allergicrhinitissymptomsandmotionsickness.
In stomach,it stimulatessecretionof gastricacid.
H2 histaminereceptorsare locatedon parietalcells,which primarilyregu-
lategastricacidsecretion
 240 I Part I Generalpathophysiology

H3 histaminereceptoractivation decreaseneurotransmitte r release:hista-

mine, acetylcholine,
norepinephrine,serotonin .
Anotherwell-knownmediator of allergy is serotonin. It is knownto cause
increasedvascularpermeabili ty, vasodilatation, increasetone of smooth
muscle cellsandincreasedsecretionof mucus.
Otherprimarymediatorsarechemotaxins for neutrophilsandeosinophils,
heparin,neutralproteasesandinflammatoryfactorof anaphylaxis.
Secondarymediato rs includetwo classesof compoun d: lipid mediators
and cytokines.Lipid mediatorsare generatedby sequentia l reactions in the
mastcells membranesthat leadto the activationof phospholipase A2 - an
enzymethat causesmembranephospholipids to yieldarachidonicacid.Ara-
chidonic acidis processed to prostaglandinsandleukotrienes .
Leukotrienesarevasoactive,spasmogenic , and hemotacticfactors. Pros-
taglandinscausebronchospasm andincreasemucus secretion.Anothersec-
ondarymediatoris the platelet-activating
factorthatcausesplateletaggrega-
tion andreleaseof histamineandbronchospasm.
Mastcells can producea varietyof cytokines , includingTNF-a,IL-1, IL-5
andIL-6.
Pathophysio/ogicalstage.A varietyof chemotactic , vasoactiveandspas-
mogeniccompounds mediateclinicalmanifestatio n of type1 reactions. Type
1 reaction mayoccuras a systemicdisorderor as a localreaction.
Clinicalmanifestat
ions at the pathophysiolo gical stage dependon the
place,whereallergenhavecontactwith the lg E andmastcells(Table14).

Table14.Placeof contact allergen- lgEandtypeof disease

PlaceofcontactaJfeFgen
- lgE·
Mucous
membrane
of noseandeyes·, Allergicrhinitis
Allergicrhino-conjunctivitis
Pollenoses
Hayfever
Skin Urticaria
Inflammationand immune disorders Unit 3 I 241
: . ;.,.
Pi~ e oft.oirtadt
,.,...:~, :
~tiWr ge
•.):;<~&~·s,
,... ¼,$~~,d<
if'!.:1gE
.,
: ·? •
;(.f·Jf ·... '· . ....
~ . ·'
!'•
·01sease
: •• .,
~·
. ;· ·,; .
4:
...
. . _., . .• ..

&act..
Gastrointestinal Foodallergy
Undercutaneous
injectionor bite Ouincke
edema
Mucous
membraneofbronchi Bronch
ialasthma
Intravenous injection Anaphylactic
shock

Systemic(parente ral) administrationof proteinantigen(such as antisera)

anddrugs(suchas penicillin) resultsin systemic anaphylaxis. However, ex-
posureby ingestion,inhalation,or skincontactcanalsocauseanaphylaxis.
Anaphylaxisis a rapidlyprogressingallergicreactionwhich lead to the
anaphylactic shock.It may beginwithin minutesor evensecondsof expo-
sure,and rapidlyprogressto causeairwayconstriction, skin and intestinal
irritation, andalteredheartrhythms.In severecases, it canresultin complete
airwayobstruction,shock,anddeath.
Symptoms of systemic anaphylaxismayinclude:urticaria(hives), swellingand
irritationof thetongueor mouth,difficultyin breathingupto shortbreath,vomit-
ing,or diarrhea , anxietyor confusion
, palpitations
andlossof consciousness .

The reasons of patient's death in anaphylactic shock

are the following:

• acuteheartandvesselsfailure;
• asphyxiadueto bronchialspasmandswellingof the larynx;
• thrombosisof brain andheartvessels.

Localreactionsgenerallyoccur on theskinor mucosa!surfaceswhenthey

arethe sitesof antigenicexposure.Thesusceptibi lity to localizedtype1 reac-
tionsappearsto begeneticallycontrolled.Atopyis an inheritedpredisposition
which causesa tendencyto sufferfrom oneor moreof the following"atopic
diseases": allergicasthma,allergic rhino-conjunctivitis andatopic dermatitis.
 242 I Part I Generalpathophysiology

Type2 allergic(cytotoxic) reactions

are also called antibody-dependent
cytotoxicity.Thefollowingdiseasesoccurin suchway autoimmune haemo-
lytic anaemia,perniciousanemia,immunethrombocytope nia,transfusion re-
actions, Hashimoto's thyroiditis.
In immunologicalstageof type 2 allergic reactionsthe antigensof own
cell of the humanbodyaretransformedto "non-self" antigen.Thevarietyof
chemicalsor medicinescanstartthis process.

Self cell can transform to non-self cell by the follow-

ing ways:

• chemicals cantransformthe structureof cell membra

ne;
• chemicals candamagecell membrane;
• chemicalcan bindto cell membrane.

In all thesecasesantigenstructureof thecell surfacewill bechangedand

this cell becomesa targetcellfor the immunesystem. ThenlgGand lgM are
formedagainstthis targetcells.Whenthe amount of lgGand lgM reaches
sufficientlevelbiochemicalstagebegins.
Pathochemicalstage.Three different , the antibody-dependent mecha-
nismsof cell damageareknown.

1. Complement-mediated cytotoxicity. Antibody(lgG) reactswith a cell

surfaceantigen.lgGin its turn hasreceptorfor thecomplementsystem.
Thatleadsto the fixationof complementonthe targetcell. Complement
proteins are activatedwith a cascadereaction. Activatedcomponents
of the complementdestroythe membrane of targetcell and cause its
lysis.
2. Thesecondmechanismis activationof phagocytosis by lgGantibodies.
'
Targetcellscoatedwith antibodiesandcomplementbecomesusceptibleto
phagocyt
osis. This phenomena is knownas opsonisat
ion.
Inflammationand immunedisorders Unit 3 I243
Blood cells are most commonly damag e d by the se
two mechanisms. Clinically , it occurs in the following
situations:

• Transfusionreactions,in which red cells from an incompatibledonor

aredestroyedafterbeingcoatedwith antibodiesnormallypresentin the
recipient.Suchantibodiesaredirectedagainstbloodgroupantigens.
• Rhesusincompatibility, in whichanRh-negative motheris sensitizedby
red cellsfrom an Rh-positivebaby.Antibodies(lgG) againstRh factor
areformed.The peculiarfeatureof lgG is their abilityto cross placenta.
WhilematernalRhantibodiescrossthe placentatheycausethe destruc-
tion of Rh-positivefetal redcells.
• Somepersonsdevelop antibodies againsttheirown bloodelements.It re-
sultsinautoimmune hemolyticanemia , agranulocytosis,thrombocytopenia.
3. Antibody-dependent cell-mediated cytotoxicity.This is thethird possible
mechanism involvedin type 2 reactions.Manytypes of cell (macrophages.
neutrophils , eosinophils,naturalkillers) that bearreceptorsfor the Feportion
of lgG causethe lysis of targetcellscoatedwith lgG antibodies.Thelysis of
the targetcell requirescontactbut doesnot involvethe phagocytosisor the
fixationof complement. Thosecellsdestroy targetcellswith specificproteins
perforinsand granzymes(NK cells), neutrophils, eosinophilsuse the sub-
stancesin their granules(Fig.25).
In somecases, antibodiesdirectedagainstthe cell surfacereceptorsde-
regulatethefunctionwithoutcausingcellinjuryor inflammation.Forexample,
antibody-mediated stimulationof the cell functionis noted in autoimmune
thyroiditis . In this disorder, antibodiesagainstthe thyroid-stimulatinghor-
mone(TRH)receptoron thyroidepithelialcellsstimulatethe cells, resulting
in their hyperplasia andexcessivesecretionof thyroidhormones.
At presentthis mechanismof antibody-mediatedcellular stimulationis
consideredto betype5 allergicreactions (stimulating reactions)
.
Pathophysiological stage.Clinicalfeaturesof type II hypersensitivity disor-
dersarebasedon effectsof activatedcomplementandactivatedphagocytes ,
causingdestructionor inactivationof the cells bearingantigen. In somedis-
orders,antibodies interact with antigenson cellsandcauseeitherstimulation
 2441 Part I Generalpathophysiology

Immunological Pathochemical Pathophysiological

stage
stage stage
Hapten
(semihapten) Comp/
e-:
. 2i Antigen fixation Lysis
membrane
i
->-~
~\\-~.- me~t :
,._.. ·· ,, activa- , :§-;;;- Erythrocyt
e ------➔ Anemia
.,• tion : ~~
~
M ·~!:~
oa>
Granulocyte ------➔ Agranu
lation

t
Redbloodcell
~;s..
::,

~
cc
Thromboe
yte ------➔ Trombocytope
nia

lgMorlgG t'l6~e-,s Clomerulonephri

tis

~
antibod
ies Basal memb
rane
Goodpastur
e's
syndrome

Fig.25. Cyto
toxic typeofallergic reaction

or inhi/Jitionof the functions of that cell rathethan cell death. It is the altered
cellular functionthat causesdisease
; the cell itself may or may not show
signsof injury.

Clinical examples of type II hypersensitivity reaction

include the following reactions.:

1. Transfusionreaction,in whichtransfusionof a mismatchedbloodtype

resultsin an immediateantibodyreactionto nonselfblood-groupanti-
gens,with resultantintravascular hemolysis.
2. Autoimmunehemolyticanemiain whichpatient~produceantibodiesto
their own red cellantigens,with resultantintravascular
hemolysis .
3. Certaindrug reactions,in whichthe bindingof certaindrugsto the sur-
faceof red or white bloodcells elicitsan antibodyand complementre-
sponsethat lysesthe drug-coatedcell. It canproducetransientanemia,
leukopenia , or thrombocytopenia .
4. StimulationreactionsThe exampleis Graves'disease(primaryhyper-
thyroidism). In this desease, autoantibodies which reactwith the thy-
Inflammationand immunedisorders Unit 3 I245
raid-stimulatinghormonereceptors of thyroid epitheliumstimulatethe
cells to increasedfunctionand proliferationby activatingof adenylate
cyclase.
5. InhibitionreactionsInhibitoryantibodiesplaya key role in myasthenia
gravis,a disordercharacterized by failureof neuromusculartransmis-
sion, with resultingmotor weakness. The diseaseis due to lgG anti-
bodiesdirectedagainstacetylcholine receptors.Theantibodiesinterfere
with the action of acetylcholine , therebyblockingtransmissionof the
nerveimpulse.
6. GlomerulardiseasesNow it is well knownthat antigen-antibody deposi-
tion in the glomerulus(type 111 hypersensitivity) is a major pathwayof
glomerularinjury. However , thereis experimentalevidencethat cyto-
toxicantibodiesdirectedagainstglomerularcellcomponentsmaycause
glomerularinjury. In additionto producingimmunedeposits, antibodies
directedto glomerularcell antigensmay causedirect cell injury, often
without deposits.Antibodiesto mesang ial cell antigens, for example
,
causemesangiolysis followedbymesangialcell proliferation;antibodies
to endothelialcellsurfaceproteinscauseendothelialinjury; andantibod-
ies to certainvisceralepithelialcell glycoproteinscauseproteinuriain
experimental animals.

Type3 allergic(immunecomplex)reactions are mediatedby antigen-

antibody(immune)complexesthat initiatean acuteinflamma tory reactionin
tissues.Theexamplesof diseasesare: immunecomplexglomerulonephritis,
rheumatoidarthritis, serumsickness , subacutebacterialendocarditis, sys-
temiclupuserythematosus andArthusreaction(Fig.26).
Immunological stagelastsfrom allergenenteringthe bodyto theformation
of immunecomplexes , whichconsistof antigenandimmunoglobulines (lgG
and lgM). The list of substancesthat can participatein immunecomplexes
formationis verylongandincludemedicines(penicilline , sulfonamides) , an-
titoxicserum(antitetanus),gamma -globulines,food, bacterialandviral anti-
gensandothers.
Pathochemical stageOnly complementfixing antibodieslgGand lgM are
involvedin type3 reactions. Activationof the complementandthe accumula-
 2461 Part I General pathophysiology

Immunological Pathochemical. Pathophysiological

stage
stage stage
;• Fixation'
;
1
• Thrombos
is
. Immunecomplex
: Complement \ : 1-1xat1on
• 1
. ' .
: act,vat,on,
'
~: ~
pace PathO!ogy
Kidneys __.., Clomerulooepmlis
•
)<t •>- : ~ ~ :
•• J..
Antigens ,-
~ .,..
~
:
~embrane:
·rdestruction:
Joints __.., Arthritis

lgMorlgG Antigen-l MAC . ~ ! Local __.., Arth!IS

reactions
antibodies antibody; ~
complex: : . Systemic__.., Serumsickness
l i Inflammation
: Endothelium
basalmembrane:

Fig.26. Immun
e - complex
typeofallergicreacti
on

tion of polymorphonuclearleukocytesarethe importantcomponents of the

immune-complex mediated tissue injury.

Pathogenic immune-complexes may cause two

types of immune-complex disease:

1. Systemicimmune-complex disease- immune-complexes are formed

in circulating blood andthen are deposited in tissues (serum sickness
type).
2. Localimmune-com plex disease- immune-complexesare formed at ex-
travascula r siteswhereantigenmayhavebeenplanted (ArthusReac tion).

The pathogenesis of the systemic immune-complex

disease can be divided into three phases:
'

1) formation of antigen-antibody complexesin circulation;

2) deposition of the immunecomplexesin various tissues;
3) inflammatory reactionat various sites of the body.
Inflammationand immunedisorders Unit 3 I 247
Serumsicknessis causedby the administrationof largeamountof alien
serum(horseantitetanusserum)usedfor passiveimmunisation. A weekafter
seruminjectionantibodiesagainstserumcomponentsare produced.They
reactwith the antigenstill presentin circulationto form antigen-antibody
complexes. Undernormalconditionsimmunecomplexes arerapidlyremoved
from the bloodstreamby macrophages in the spleenand Kuptfercellsin the
liver. In somecircumstances , however,immunecomplexescontinueto cir-
culate.

It happens when :

1) theamountof antigenmustbelargeenoughto form immunecomplexes ;

2) the sizeof the complexesmust be intermediateor small; largecom-
plexesarerapidlyremovedfrom circulationby monocytes;
3) the dysfunctionor overloading
of the phagocyte's
system.

Thefavoritesitesof the immunecomplexdepositionarethe kidneys,the

joints,skin,the heart, serosalsurfaceandsmallvesselsprobablydueto re-
ceptorsto the components of the immunecomplexeson theirsurface.When
complexes aredepositedin tissuestheyinitiateacuteinflammatoryreactions .
Clinicalfeaturesof serumdiseaseappearduringthis phase(10-12 daysafter
antigenadministration). Theyarefever,urticaria,artralgias , lymphnodeen-
largement andproteinuruia .
Themainmechanism of tissueinjuryis thefixationof thecomplement bythe
complexes andtherelease of its biologically
activecomponents, whichincrease
vascular permeabilityandattract phagocytes (chemotactic factors).Phagocyto-
sisof theimmunecomplexes resultsinthereleaseof lysosomal enzymes,which
candamagebasement membrane, collagen,
elastinandcartilage.Freeoxygen
radicalsproducedby activated phagocytes mayalsomediatetissuedamage.
Immunecomplexesmaybeformedat bodysurfaces,notablyin the lungs
followingrepeatedinhalationof antigenicmaterialfrom moulds, plantsor
animals.Thisis exemplifiedin Farmer'slungandPigeonfancier'slung,where
thereare circulatingantibodiesto the actinomycete fungi found in mouldy
 2481 Part I Generalpathophysiology

hay, or to pigeonantigens.Bothdiseasesareformsof extrinsicallergic alveo-

litis andthey onlyoccurafterrepeatedexposureto the antigen.
Immunecomplexdiseaseis a frequentcomplicationof autoimmunedis-
easewherethe continuedproductionof antibodiesto a self-antigenleadsto
prolongedimmunecomplexformation.Themononuclear phagocytes,eryth-
rocytes, and complementsystems(which are responsiblefor the removal
of complexes)becomeoverloaded andthe complexesaredepositedin body
tissues.as it occursin systemiclupuserythematosus.
Pathophisiological stage Immunecomplexesformed in the circulation
producedamagewhenthey come in contactwith the vessellining or are
depositedin tissues, includingthe renalglomerulus , skin venules,the lung,
andjoint synovium.
Immunecomplexdiseasemay be systemic, causedby circulatingcom-
plexes(asin serumsickness)or localized , dueto formationof immunecom-
plexesat the site of entryof antigen(as in the Arthusreaction).
In the Arthus-typereaction,tissuenecrosisoccursat the site of entry of
the antigen.This phenomenon is seenin the skin after repeatedinjectionof
antigen(e.g., in rabies vaccination,in which multipleinjectionsof vaccine
are given).Repeated exposureto an antigenleadsto the formationof large
antigen-antibodycomplexes , whichprecipitatelocally in smallbloodvessels,
wheretheyactivatecomplementandproducea severelocalacuteinflamma-
tory reactionwith hemorrhage andnecrosis.
Acuteserumsicknessis the prototypeof a systemicimmunecomplexdis-
ease.Serumsicknessis a syndromeconsistingof rash, lymphadenopathy , ar-
thralgias , andoccasionally neurnlogicdisorders,whichappear7 or moredays
afterexposureto a largedoseof antigen,suchas foreignserumprotein,anti-
biotics(especiallypenicillin),variousfoods,insectvenoms,andviralandother
microbialantigens . In thesereactionimmunecomplexes formedin the blood
passthroughthe endothelial poresof small vesselsto bedepositedin theves-
sel wall,wherethey activatecomplement andresultin complement-mediated
necrosisandacuteinflammation of the vesselwall (necrotizingvasculitis).
Type Ill reactionsare responsiblefor the acuteglomerulonephritis (GN)
thatfollowsa strepotococcal infectionandthe manifestations of autoimmune
disorderssuchas systemiclupuserythematos us (SLE).
Inflammationand immunedisorders Unit 3 I249
Acuteglomerulonephritis
Type111
reactionsunderliemorethan80% of GN.

Two forms of antibody-assosiated injury are involved

in pathogenesis of the disease:

1) injury resultingfrom depositionof solublecirculatingantigen-antibody

complexesin the glomerulus , and
2) injury by antibidiesreactingin situwithinthe glomerulus.

CirculatoryimmunecomplexesnephritisThe antigenin this form of in-

jury is not glomerulaeorigin. It may be endogenousas in glomerulopathy
associatedwith SLE, or it may be exogenous , as is in glomerulonephrit is
thatfollowsa strepotococcal infection.Whateverthe antigenmaybeantigen-
antibodycomplexes areformedin the circulatuinandaretrappedin the glom-
eruli, wheretheyproduceinjury by activatingcomplement.
Immunecomplexes nephritisin situ In this form of injury, antibodiesreact
directlywith fixedor plantedantigenin the glomerulus.Thebest-established
modelis nephritis producedby antibodiesthataredirectedagainstfixedanti-
genin glonerularbasenement membrane(GBM), the so-calledcalassicanti-
GBMnephritis. It has its experimental counterpartin nephritisproducedby
injectingratswith anti-GMBantibodiesproducedby immunizationof rabbits
with rat kidneyso-calledMasuginephritisor nephrotoxicserum nephritis.
Anotherexampleis a rare type of glomerulonephritis, Goodpasture 's syn-
drome, in whichautoantibodies to the basementmembraneof the glomeru-
lar and pulmonarycapillariesdevelop.Theautoantibodies bind to the inner
surfaceof the basementmembrane , and complementactivationoccurs to
produceinflammatorylesionin the glomeruliandlung.

Type4 (cell-mediated) allergicreactionsor delayedhypersensit ivity re-

actionsaremediatedby T-cells.Theclassicalexampleof a delayedhypersen -
sitivity reactionis a positiveMantouxreaction(tuberculin test)in an individual
alreadysensitizedto thetuberculebacille. In the site of intracutaneo us tuber-
culineinjection a localareaof erythemaandinduration appears(Fig.27).
 250 I Part I Generalpathophysiology

Immunolog
ical • Pathophysiological
Pathochemical stage
'
stage stage ·
• )'( ~- ~ CD-4• '- '
·-..--.
, T-cell ~ • Cellurar infiltrations lissue
;, --::::. ------- ;.... bymacro phages ~ lnflam- ~
/ Cytokines : and monosytes matlon injury
.)'ti.·,C0·8•
' -~ T-cell :
''
Macrophages
(antigen
presentingcell) '

Fig.27.Cell-mediated(delayed) typeof allergic reac

tion

Immunologicalstageconsistsof the productionof antigen-specificT-cells

andthe conversionof nativeT-cellsto effectorscells(CD8andCD4cells).In
this ty~ereaction,anantigenthatstimulatesnativeT-cellsto bedifferentiated
into effectorscellsis oftencellularantigen(autoimmunity).
Pathochemical stageAt the sametime as T-cells areseeingantigen,they
receive additionalsignalsfrom microbesor from innatedefensereactionsto
the microbes.In responseto thesestimuli, the antigen-specific
T-cellsbegin
to secretecytokines . Cytokinesarea largegroupof proteinsthatfunction as
mediators of immunityandinflammation .

They include:

1. lnterleukin-2 (IL-2). IL-2 is producedby CD4T,-cellsaftertheir activa-

tion by anantigen.Themainactionof IL-2 is to stimulateproliferationof
T-cells, the samecellsfrom whichit is produced.For this reasonIL-2 is
calledT-cell growthfactor.,
2. lnterferon-y(IFN-y). IFN-y is producesby Th-1 cellsthat arethe subset
of CD4+T-cells.IFN, is responsible for the inhibitionof viral infection.
It alsostimulatesphagocy te-mediatedingestion andkilling of microbes,
the keycomponentof cell-mediated immunity.
Inflammation and immunedisorders Unit 3 I 251
3. Th-1cellsalsoproduce :
• lnterleukin-4 (IL-4) which stimulates the production of lgE
antibodies,
• lnterleukin-5(IL-5)whichactivateseosinophiles
.

Therefore , Th-1cellsstimulatephagocyte-independent , eosinophil-mediat-

ed immunity, whichis especiallyeffectiveagainsthelminticparasites .
4. lnterleukin-12(IL-12). IL-12 is producedby macrophages and it is re-
sponsiblefor activationof macrophages to kill the microbes.

If thesummarizethemaineffectsof cytokines , it possibleto describethem

as follows.
1. Regulationof immuneresponseandorganization of inflammationin the
placewhereantigenis foundout (by attractionof phagocytes).
2. Destruction of foreigncells(by perforation of its membranes, induction
of apoptosis).

At the site whereantigenis implantedforeign cells are destructedand

digestedby phagocytes.The accumulatedmacrophagesoften undergo
morphologicaltransformat ion into epithelial
-like cells. The aggregationof
thesecellssurroundedby lymphocytes is referredto as a granuloma.Such
granulomato us inflammationis a typicalfeatureof cell-mediated allergicre-
actions.

Mechanisms of tissue injury in type 4 allergic reac-

tions are:

1. Directcytotoxic actionof T-cellson foreigncells(targetcells);

2. Lympho kine-mediatedcytotoxicactionof T-cells;
3. Phagocytosis of targetcells anddamageof own cells with lysosomal
enzymes;
4. Granulomatous inflammationdevelopment,which is accompaniedby
macrophagesandlymphocytes aggregation.
 2521 Part I Generalpathophysiology

Pathophisiological stage Delayedhypersensitivityoccurs in infectious

causedby facultativeintracellularorganisms,e.g.,mycobacterium andfungi.
Thereactionmaybeof the tuberculinor granulomatous type.
Theclassicexampleof delayedtype hypersensitivity is the reaction to the
tuberculintest in whicha solubleproteinantigen(tuberculin)is injectedinto
the skin. In a previouslysensitizedindividual,rednessand indurationof the
area developwithin 8 to 12 hours, reachinga peak in 24 to 72 hours. A
positivetuberculintest indicatesthat a personhashadsufficientexposureto
mycobacter iumtuberculosisantigento provokea hypersensitivity reaction.It
doesnot meanthat the personhastuberculosis.
Granulomatous hypersensitivity is clinicallythe most significantform of
type IV reactions.Hypersensitivity resultsfrom the presenceof a persistent
antigenwithin macrophages. Certaintypesof antigens(large,insoluble, and
difficultto eliminate)inducecell-mediated immunitywith a pronouncedmac-
rophageresponse.Theaccumulated macrophages areoftentransformedinto
so-calledepithelioidcells. An aggregationof thesecells, which usuallyare
surroundedby a layerof lymphocytes , is calleda granuloma,and inflamma-
tion that is characterized by this type of reactionis calledgranulomatous.
Sarcoidosisis an exampleof granulomatous hypersensitivity.
Autoimmunediseasessuch as Hashimoto 's thyroiditis or transplantant
rejection, as well as an eradicationof virus-infectedcells involvethe third
mechanismof type IV hypersensitivity - directT-cell-mediated cytotoxicity.
In this reactioncytotoxicT-cells(CDScells)kill by disruptingionicflux in tar-
get cells (antigen-bearingcells).In Hashimoto'sthyroiditisandautoimmune
gastritisassociatedwith perniciousanemiadirect T-cellsresponseagainst
antigenson the host cells (thyroid epithelialcells and gastricparietalcells)
leadsto progressivedestructionof thesecells.
Allergic contactdermatitisis anotherexampleof type IV hypersensitiv-
ity. An antigenin directcontactwith the skin inducesT-mediatedcytotoxic-
ity with well-circumscribed lesi:}flS, the site of whichcorrespondsprecisely
to the area of contact (e.g., back of a watch, bracelet).Common antigens
includedyes in clothing cosmetics,hair dyes, metals.Contactdermatitis
usually consists of erythematosusmacules,papules , and vesicules(i.e.,
blisters).
Inflammationand immunedisorders Unit 3 I253
Pseudoallergic react ions
Amongthe generalpublic, the distinctionis rarelymadebetweenallergiesand
pseudoallergies. Pseudoallergies
havesymptomsvery similarto "true" aller-
gies.But pseudoallergiesarenot developed with the immunesystem.Unlike
"true" allergies,pseudoal
lergiesdo not havea sensitization
phase.Symptoms
occurevenat the first exposureto an antigen.Trueallergysymptomsdon't
dependon the doseof the allergen.Thesymptomsof pseudoallergy directly
dependon the doseof the substance- the moreis the dose, the moreex-
pressedclinical manifestation
is observed.

Pseudoallergy can be realized through the following

mechanisms.

1. Actionof histamine- liberatingsubstances. Theyare roentgen-contrast

medicines , somesortsof cheeseandredwine, cocoaproducts , tomatoes ,
fish(tunaandsardines). Thesesubstances actdirectlyon mastcellsandin-
creasetheirrelease of histaminewiththedevelopment of clinicalsymptoms;
2. The alternativepathwayof complementactivation(without action of
specificlgG and M antibodies).Somepreservatives that are addedto
food productscancauseactivationof the complementby the alterna-
tive pathway.Activatedcomponentsof the complementproducetissue
injurywith the subsequent clinicalsigns;
3. Disturbances of arachidonicacidmetabolism. Thesedisturbancesresult
in aspirinasthmadevelopment. Thisdiseaseis characterized by the de-
velopmentof asthmaattacksafterthe intakeof non-steroidanti-inflam-
matorydrugssuchas aspirin,ibuprofenandothers.

Auto immune disease s

Althoughthe immune system has an elaboratesystem of checksand bal-
ances to ensure self tolerance, occasiona
lly this system breaks down.
 254 f Part I Generalpathophysiology

Whenthe immunesystem attacksself cells componentscausingpatho-

logicalchange, this is calledautoimmunity . Autoimmunediseasesform a
spectrumrangingfrom organ-specificconditionsin which oneorganonly
is affectedto systemicdiseasesin whichthe pathologyis diffusedthrough-
out the body.
Autoimmunediseasesaremediatedwith antibodiesor sensitizedlympho-
cytesto tissueantigensof the own organism.In normalorganismimmune
responseagainstownantigensis absent,becauseself-tolerance exists.Self-
toleranceis developedduring embryonicontogenesisperiod.The mecha-
nismsof self reactivitypreventionarethe following.
1. Selectionanddeletionof self-reactive
T-cellsandB-cellsandtheirclones
in the thymusduringtheir maturation.
2. Peripheralsuppression byT suppressorcells, whichlastsallthelife time.

Normally,thedevelopmentof autoantibodies
andtheactivationof autolog-
ic lymphocytesdo not occur.Duringthe periodof embryogenesis all clones
immunecells which reactedwith antigenesof own tissuesare eliminated
or supressed.Therefore,in postembriogenesisthe answersto the ownanti-
genesareabsent.
Autoimmunediseasescanoccureitherin individualswith normalimmune
system, or with primarydamageof the immunesystem. In thefirst case,it is
the responseof immunesystemto "unknown" antigens.

It can take place in the following situations:

1. Damageof physiologicalbarrierswhich existsover nervoussystem, a

crystallinelens, colloidof a thyroid glandand·othertissues.Normally
thereis no self-toleranceto thesetissues,becauseimmunesystemhas
no contactwith them while self-toleranceis beingformed.It is espe-
ciallyimportantin the case' of autoimmunedamageof pair organssince
oneof them is damaged(usuallyaftertrauma).Theexampleis sympa-
theticophtalmia- autoimmuneinflammationof a healthyeyeafterthe
development of inflammatoryprocessin an injuredeye.
Inflammationand immunedisorders Unit 3 I2ss
2. Normallyorganismcells (exceptimmunecells) do not expressMHC
2 classmolecules.In the casewhencells beginto expressthe named
molecules , they becomea targetfor the immunesystem.For exam-
ple,diabetesandautoimmunehepatitismaybecausedbythis mecha-
nism.
3. Alteringof self-antigens,for exampleafter burn denaturation
, influence
of medicalproducts.
4. Whenbacterial antigenshavethe antigenstructure, that is similar to
that of self-antigens.Suchsimilarityof antigensis establishedin the
streptococcusand myocardialand kidneystissue components.This
fact explainsthe development of heartandkidneysaffectionafteracute
streptococcal infection.
5. In other casesautoimmuneprocessescanarisein individuals with pri-
marychangesof immunesystem.

Therearethreegeneral mechanisms of autoimmunepathology:

• Directantibodymediatedeffects
• T cell mediatedeffects
• Immunecomplexmediatedeffects.

Autoimmunediseasesoften havehereditarypredisposition.The clinical

manifestationof autoimmunediseasesis characterized
by chronic current
with the tendencyto the diseaseprogress.

Allergy diagnostics
If a patientwantsto knowwhatallergensareaffectinghim - allergytesting
haveto be performed.Furthermore , testingis necessaryif the patientwishes
to startimmunotherapy.
Theskinprickor scratchtestisthe mostcommonandreliabletestfor most
allergies.A small needleor plasticdeviceis usedto lightly prick or scratch
your backor forearmwith a tiny amountof allergen.After15-20 minutes, you
will be ableto interpretthe resultsby examiningeachspot whereallergens
 256 f Part I Generalpathophysiology

werescratchedor prickedinto yourskin.Thespotswhereyouareallergicwill

becomeredandswollen,andthe others will remainnormal.
Theintradermaltestis donewhenthe skin prickor scratchtest results are
unclear.It is similarto the prickor scratchtest, but involvesinjectinga small
amountof allergenunderthe skin usinga needle.
Reactionsto skin testingshouldclearup quickly.Becauseskin testing in-
volvesthe injection of allergensunderthe skin,thereis a small risk of ana-
phylaxis. Forthis reason,allergyskin testingshouldonly be performedin a
medicalsetting,with accessto emergency treatment.
The blood test measuresthe levelsof reaginicantibody, lgE, produced
whenpatientsblood is mixedwith a seriesof allergensin a laboratory.If a
patientis allergicto a substance,the lgE levelsmay increasein the blood
sample.
To confirm a foodor drugallergyaftera skinor bloodtestresultis positive,
a challengetest may be performed . Forthe challengetest, the patientswal-
lowsa very smallamountof the suspectedallergen(e.g.,milk or antibiotic).
If thereis no reaction,the dosegraduallyrisesuntil a reactionis noted.Due
to the risk of a severeallergicreaction like anaphylaxis , challengetests are
donein a clinicalsettingandareonly performedwhenabsolutelynecessary.

Specific imm un otherapy or hyposensitization

Hyposen sitizationis a form of immunotherapy whenthe patientis gradually
vaccinated againstprogressively largerdosesof theallergenin question.This
caneitherreducethe severityof allergicprocessor eliminatehypersensitivity
altogether. It relieson the progressiveproductionof lgG("the blockinganti-
. body"), as opposedto the excessivelgE productionseenin hypersensitivity
type I cases. .
WhenlgGcirculatein the bloodplasmaandtissuefluids in largeamounts,
they bind to allergensand reducethe abilityof lgEto detectthe presenceof
the allergens . Thus, the inflammation,mucus hypersecretion,andtissueal-
terationsthat takeplacein untreatedallergicdiseasedecreasewith immuno-
therapy.Therelativeincreaseof the lgGto lgEratioleadsto bettertolerance
Inflammationand immunedisorders Unit 3 1257

to the allergen.By givingsmall but increasingamountsof allergenat regu-

lar intervals,toleranceincreases.Theendresultis that the personbecomes
"immune"to the allergens , so that theycan toleratethem with fewer or no
symptoms.This processis also knownas specificimmunotherapy , because
is trying to turn off oneor morespecific allergicresponses.The higherthe
dosetoleratedwithout significantside-effects,the more likely is treatment
successful.
Hyposensitization is effectivein mostpeoplewith hayfeverandoftenhelps
thosewithasthma.lmmunother apyis alsoanessentialpartof managingpeo-
ple with dangerousallergicreactions(anaphylaxis) to beeand waspstings.
Medicinesmayhelpyouto livewithallergiesbut will not curetheseproblems.
Furthermore, it is not alwayspossibleto avoidallergictriggers, suchas grass
pollens.Theonlywayto preventtypeanaph ylacticallergicreactionsis hypo-
sensitization.

Chapter 11. Pathophysiology of

Thermoregulation.Fever.
Fever(Lat.febris), orpyrexia(Gk. puretos,fever), is a typicalpathologicpro-
cesswhichconsistsin a regulated elevationof bodytemperature thatexceeds
the normaldailyvariationandoccursin conjunctionwith an increasein the
hypothalamic set point.
It is perhapsthe oldestandmostuniversallyknownhallmarkof a disease.
Feveris a nearlyuniversalsymptomof infection;it is alsoassociatedwith cer-
tain allergies
, asepticinflammations, traumas, specificimmuneresponses ,
cancers,andotherorganicillnesses.Feverswhosecausesare unknownare
calledfevers of unknownorigin.
The first experimentalapproachto the natureof the stimulus respon-
sible for fever was madeat the middle of the nineteenthcentury, when
severalGermanscientistsproducedfever in experimentalanimalsby the
injectionof pus and blood from other infected animals.In 1875, Von Li-
ebermeisterconcludedthat in feverthe bodytemperaturewas regulatedat
an abnormallyhigh level,but that the temperature-regulating mechanism
 2sa I Part 1 Generalpathophysiology

remainedintact and efficient.This hypothesishas beensubstantiatedby

numerousresearches .
Whenfever occurs,the thermoregulatorymechanismsbehaveas if they
were adjustedto maintainbody core temperatureat a higherthan normal
level, i.e., "as if the thermostathad beenreset" to a newpoint above38 °C.
This shift of the set point from "normothermic"to febrile levelsvery much
resemblesthe resettingof the householdthermostatto a higher level in
order to raisethe ambienttemperaturein a room.

Phylogenesis
Feverhasappearedrather late in phylogenyas this responserequiresthe
occurrencein an animalof the followings:(1) ability to centralthermoreg-
ulation, and (2) ability to producecytokines.Therefore,a febrile response
is enorganicfor higherwarm-blooded(homoiotherma l) animals.
Nevertheless,the possibility in using of the own body's heatingin cer-
tain pathologicalconditionsdevelopedhundredmillions yearsago. Ecto-
thermic, or poikilothermic, organisms (e.g., reptiles, amphibia,and fish)
havea markedlydecreasedsurvivalwhen blockedfrom their normalheat-
seekingbehaviorafter introductionof a pathogenicagent.
A verygood reasonto acceptthe usefulnessof a responseis whenevolu-
tion has selecteda mechanism(only behavioralin the caseof ectotherms)
that remainsin the phylogenyovermillionsof years.Experimental datashow
thatthe higher body temperaturedefendedin fever is extremelyprotective
againstinfectionand usefulto the phylathat inheritedit. Alreadyin arthro-
podsincreasedtemperatureis usefulandsaveslives.Risein body'stemper-
atureremainsprotectiveagainstinfectionin otherphylaincludingmammals.
A study with febrile mice indicatedthat fever iQcreasesthe rate of an-
tibody synthesis.Work with tissue cultures showedthat increasedtem-
peraturesstimulatethe activities of T cells and increasethe effectiveness
of interferon.Artificially infect~drabbitsand pigs allowedto remainfebrile
surviveat a higherratethanthosegivensuppressantdrugs.Feverappears
to enhancephagocytosisof staphylococciby neutrophilsin guinea pigs
and humans.Thus, parallelwith harmful effects, fever has essentialben-
efits for the survivalof a species.
Inflammationand immunedisorders Unit 3 I259
Ontogenesis
Veryyoung or old patientsmay not mounta febrile response.With young
patientsthis may be due to an immaturetemperature-regulating mecha-
nisms(especiallyconnectedwith heatloss limitation)and immunesystem.
In 3-4-monthbabiespneumoniaproceedsunderthe subfebriletemperature
or evenwithoutrisingin temperature.
Olderpatientswith severediseasesmaynot be febrile.Studiesin animals
suggestthat this maybe dueto poor nutritionalstatusratherthanto senes-
cenceof the immunesystem.

Etio logy of Fever

Thetermpyrogen(Gk.pyr, fire+ gennan
, to produce)is usedto describeany
substancethat causesfever.Theycanbesubdivideinto 2 categories.

1. Primary pyrogens arepyrogenswhichcannotactdirectlyon thethermo-

regulatorycenterof the brain. Thereis a delayof 1 hour or so between
theinjectionof a primarypyrogenandthe onsetof fever, whichsuggests
that the actionof the pyrogenon thermoregulation is indirect.Primary
pyrogenscausefeverby inducingreleaseof secondarypyrogens ;
2. Secondary pyrogens(or so-calledendogenouspyrogeniccytokines)
are polypeptidesproducedby varioushost cells,especiallymonocyte-
macrophages. Othercellsthat producefever-inducing cytokinesinclude
keratinocytes and endotheliocytes, B-lymphocytes , mesangial , epithe-
lial, andglialcells.

Secondary pyrogens, suchas interleukinsIL-1, IL-8, macrophage-inflam-

matoryprotein-1p (MIP-1p),tumornecrosisfactor(TNF),the interferons,and
the gp 130receptor-activating family(IL-6, IL-11, leukemia inhibitoryfactor,
ciliaryneurotropicfactor, and oncostatinM), causefeverby initiatingmeta-
bolicchangesin the hypothalamic thermoregulatory center.
Primarypyrogens are describedasexogenous(comingfrom outsidethe
body)or endogenous (originatinginternally).
 260 I Part I Generalpathophysiology

Exogenous pyrogens arebothinfectious(productsof infectiousagentssuch

asbacteria,
fungi,rickettsia
, viruses,andprotozoa)
andnoninfectious(Table15).

Table15. Infectious
andnoninfectious
primarypyrogens
.

Infectious .Noninfectious . :-~"":·~•'\~.

'·; . .. .
;

·.

"' Endotoxins comprisedof toxic lipo- • Immunecomplexes

polysaccharidecomponents of the • Incompat iblebloodandbloodprod-
outermembrane of Gram-negative ucts(transfusion-inducedfever)
bacteria • Foreignproteins(e.g.,globulinum
"' Exotoxinsreleasedfrom some antitetanicum-antitoxic
fractionof
Gram-positivebacteria(staphylo- horseserum)
coccal,streptococcal,
diphtheritic, • Tissuedestructionproducts
tetanic) • Syntheticpolynucleotides
"' Pathogenic productsof • Steroidhormonesmetabolites (i.e.,
., Fungi androgenbreakdownproduct- etio-
f, Rickettsia cholanone)
~ Viruses
,, Protozoa

The classicexampleof an exogenouspyrogenis the lipopolysacchari de

(LPS)endotoxinproducedby all Gram-negative bacteria
. Purifiedendotoxin
appearsas largeaggregates. Themolecularcomplexcanbedividedintothree
regions:(1) the a-specificchains,whichconsistof a varietyof repeatingoli-
gosaccharide residues,(2) the core polysaccharide that formsthe backbone
of the macromolecule , and (3) lipid A, composedu·suallyof a glucosamine
disaccharidewith attachedlong-cha in fatty acidsand phosphate.The poly-
saccharideportionsareresponsiblefor antigenicdiversity, whereasthe lipid
A moietyis responsible for pyro-genicityandtoxicity.
Anothergroupof potentbacterialpyrogensis producedby Gram-positive
organismsandincludesthe enterotoxinsof Staphylococcus aureusandthe
groupA and B streptococcaltoxins, also calledsuperantigens.Onestaph-
ylococcaltoxin of clinical importanceis the toxic shock syndrometoxin
 Inflammationand immunedisorders Unit 3 I 261
associated with isolates of S. aureusfrom patientswith toxic shock syn-
drome.Likethe endotoxins of Gram-negative bacteria, the toxins produced
by staphylococciand streptococcicause fever in experimentalanimals
wheninjectedintravenouslyat concentrationsof <1 µg/kg of bodyweight.
Thereare artificialinfectiouspyrogens.Thus, purifiedlipopolysaccharide
extractsof endotoxin -producingmicroorganisms (Pseudomonas aeruginosa,
Salmonellaabortusequi, etc.) are commonlyusedfor pyretotherapy(See
belowunderPossibleBenefitsof Fever ). Theyareverystableon storageand
resistautoclaving,but they can be destroyedby prolongedexposureto very
hightempera t ures.Theirubiquityand stabilityare constantsources of anxi-
ety to thoseinvolvedin the preparationand useof anymaterialfor parenteral
administration.
Saltfeveris an exampleof noninfectiousfever. It is producedby injection
. of hypertonicsodium chloride solutions;it is apparently the resultof osmotic
disturbances , destructivechangesin leukocytes , macrophages , and endo-
theliocyteswith consequentpassageot pyrogenicsubstancesinto the blood.
Moreover , Na+is directlyableto increasein the hypothalamicset point.

Endogenous primary pyrogens are derived from in-

side the patient. This group includes:

• primaryand secondaryalterationproductsformed in inflammatoryfo-

cus;
• products arrived from local necrosis
·foci (e.g., in pulmonary,cerebral,
or myocardial infarction,and rhabdomyolysis) ;
• steroidhormonesmetabolites;
• immunecomplexes.

Pathogenesis of Fever
1. Induction
of cytokines productionandtheirrelease. Fever is the result
of communication betweenthe peripheralimmunesystemandthe brain.
2621 Part I Generalpathophysiology

After contactwith a primarypyrogen,macrophages and otherimmune

cellsareactivatedto releasecytokines.Therearetwo typesof cytokines
responsible for thegeneration of fever.Secondary pyrogensarecytokines
that inducefeverandincludeinterleukinsIL-1, IL-6, IL-8, macrophage-
inflammatoryprotein-1p(MIP-1p),and interferon-y(IFN-y).The other
typesof cytokinesare endogenous antipyretics,whichlimit the magni-
tude and durationof fever and includesuch substancesas IL-10, ar-
gininevasopressin (AVP),a-melanocyte-stimulating hormone(a-MSH),
andglucocorticoids. AlthoughAVP,a-MSH,andglucocorticoids arenot
true cytokines,they still possessendogenousantipyreticproperties.
Othersubstances, such as tumor necrosisfactor-a(TNF-a),havebeen
shownto havepyrogenicand antipyreticproperties , dependingon the
conditions.Ultimately,it is the sum of the interactionsof pyrogenicand
antipyreticcytokinesthat is responsible for the heightanddurationof a
fever response.Thesecytokineinteractionsaredependenton a variety
of factors, including the species,thekind of infection,andthe strength
of the fever-inducingstimulus.Figure28 providesa generalpathwayof
feverregulationinvolvingsecondarypyrogensandantipyretics.
2. Cytokines influenceon thermoregulatory centerand its reset. Re-
leasedcytokinesaretransportedby blood.Theyarepolypeptides, andit
is unlikelythatcirculatingcytokinespenetrate the brain.Instead,thereis
evidencethat theyact on the organum vasculosumof the laminatermi-
nalis (supraopticcrest).It is oneof the circumventricular organs, which
havefenestratedcapillaries , and becauseof their permeabilitythey are
saidto be"outsidethe blood-brainbarrier."Thuscytokinescanactivate
the preopticareaof the hypothalamus. Cytokinesarealsoproducedby
cells in the CNSwhenthesearestimulatedby infection,andthesemay
act directlyon the thermoregulatory centers.
Centrally,IL-1, andperhapsotherpeptides , actas calcium-dependent
thermostimulators. Its me_chanism of actionappearsto involveinduc-
tion of phospholipases, which in turn causethe releaseof arachidonic
acidsfrom membranephospholipids.As a result,prostaglandinlevels
rise, particularlylevels of prostaglandinE (PGE).lntrahypothalamic
injectionof prostaglandins producesfever.In addition,the antipyretic
Inflammationand immunedisorders Unit 3 1263

i
Monocytes
, Macropages
,
Kupffercells

i
Endogenous Antipyretics
Secondary Pyrogens
(e.g.IL-10,AVP,
TNF-a, a-MSH,
(e.g.lL-1, -6, -8, MIP-1~. IFN-y)
glucocorticoids)

i
Preoptic
Areaof Hypothalamus

Prostaglandins

Raisetemperature
setpoint

Initiation
of effectormechanisms

Fever

Fig.28. Gener
al pathway
offeverdevelopment

effect of aspirin is exerteddirectlyon the hypothalamus

, and aspirin
inhibitsprostaglandin synthesis.
 2641 Part I Generalpathophysiology

PGE 2
is one of the prostaglandins that causesfever.It acts on four
subtypesof prostaglandinreceptors - EP1, EP2, EP3, and EP4 - and
knockoutof the EP3 receptorimpairs thefebrileresponseto prostaglan-
din E2 , IL-1p,andbacteriallipopolysaccharide.
These prostaglandinsthen increase neuronal cyclic adenosine
monophosphate (cAMP)which raisethe set point in the hypothalamic
structures.A set point is an informationinputthat may be determined
byan externalsignalto whichthe regulatedvariableis comparedor may
be determinedby the structuralcharacteristics of thesystemitself. In
the caseof temperatureregulation , the actualinternal temperatureis
comparedwith the set point "wanted" by the organism.Theactivating
signal for the regulatoryresponses, the "error signal,"is the difference
betweenthe actualtemperature andthe set point.Whenan errorsignal
is detected , the organismproducesthe availablecorrectiveresponses .
Sensitivitythresholdsof "cold" and"warm"thermosensors in the pre-
optichypothalamus arechanged,andthe blood'stemperature is detected
by the hypothalamus as coolerthanthe set pointof the thermostatand
mechanisms for increasingthe bodytemperature arebroughtinto play.
3. Initiationof effectormechanisms and temperature rise. Oncethe
hypothalamicthermalset point has beenelevated , thermoregu latory
mechanismsare broughtinto playto raisethe bodytemperatureto the
levelof the newset point.Autonomic efferentsleadto heatconversion
through cutaneousvasoconstrictionand cessationof sweating.This
createsa sensationof cold, and the arrectorpili musclesin the skin
causegoose-flesh(or goosebumps) to form.

Somaticnervesare responsiblefor increasing.heat production via in-

creasedskeletalmuscletone or shivering(shiveringthermogenesis); how-
ever, shiveringis not requiredif heatconservationmechanismsraiseblood
temperaturesufficiently.The :Ayalgiasthat accompanymanyfebrilestates
mayin part be causedby this increasedmuscletone. Rigor,whichis a dra-
maticprecursorof somefever spikes, is nothingmorethanan exaggerated
form of shiveringthat rapidlyelevatesbodytemperaturein responseto an
increasedhypothalamic thermalset point.
Inflammationand immunedisorders Unit 3 I2ss
Heatproductionfrom the liver,splanchnicorgans, and the brainalso in-
creases(non-shiveringthermogenes is).
However , thenatureof the responsedependson theambienttemperature .
Thetemperature risein experimentalanimalsinjectedwith a pyrogenis due
mostly to increasedheatproductionif they are in a cold environmentand
mostlyto decreased heatlossif theyare in a warmenvironment.
In humans,behavioral mechanisms (e.g., puttingon moreclothingor bed-
ding,drinkingof hotfluids)helpraisebodytemperature.
Heatconservation andproduction continueuntilthetemperature of theblood
bathingthe hypothalamic neuronsreaches the newsetting.Thehypothalamus
thenmaintains thenewfebriletemperature.Resetting thehypothalamic setpoint
downwardinitiatestheprocessof heatlossthroughsweatingandvasodilation.

-Stage s of Fever
Threeperiodsor stagesmaybedistinguished
in fever(Fig.29).

These are:

1)thestageof elevationof the bodytemperature(stadiumincrementi);

2) thestagein whichthetemperature is at its acme(stadiumfastigii);
3) thestageof decreasing
temperatureordefervescence (stadiumdecrementi)
.

Thesethreestagesarecharacterized by a certaindisturbancein the inter-

relationbetweenheatproductionandheatloss,anddisordersof the different
formsof metabolism , etc.
Stadiumincrementi. Thefirst, usuallyshort stageis characterized by a
rapidor gradualelevationof bodytemperature. Theratioof heatproduction
to heatlossincreases.
It is thoughtthatinthis periodthethermoregulatorycenteris resetting.The
impulsesfrom the sympathetic compartment of the thermoregulatorycenter
thataresentbysympathetic fibersto thewholeorganismareoperatingin this
 2661 Part I Generalpathophysiology

44 - - - - - Settingof thethermostat
-- Actualbodytemperature
43

G 42
g__ Setpoit Crisis
....
Q) suddenly raised
-:::,
r....
Q)
a.
o
41 / to highvalue

40 I···· ····· ····· ··· ············· ·:..,·

·----;
E
-
Q)

>,
-0
0
39
Va~il~tion
SWtlalif!Q
'• ·')'

co
. .
38 1.Vasoconstrictlon Setpoltsu!filenly
2. Piloerection loWvaWe
recfuced16
3. Epinephrinesecretion
37 4. Shivering

36
2 3 4 5

Fig. 29. Stagesof fever developmen

t

stage.In cutaneousandsubcutaneous vessels, theycausevasoconstriction,

thustheydecrease the heatloss. The individual first noticesvasoconstriction
in the handsandfeet.Therearealsocontractionsof arrectorpili muscles(in
animals- piloerection,in humans- goose-flesh or goosebumps).
Onthe otherhand,underthe influenceof sympathetic compartment there
is increasingin shiveringandnon-shivering thermoge nesis.
The disparitybetweenheatproductionand heatloss in casesof rapidly
rising temperaturebeingaccompanied by chills - a sensationof cold and
shivering,pallorof the skinandappearance of gooseflesh.Thechillsaredue
to stimulationof the nerveendiogsin the skin as a resultof the drop in its
temperature causedby spasmof the superficialvessels.
Thefasterfeverdevelops,the greaterthe disparitybetweenphysicaland
chemicalthermoregulation, andthe morestronglypronounced the chills. In
thesecasesheatproductionalwaysexceedshe~tloss.
Inflammationand immunedisorders Unit 3 1267

Thermogenesis participatesin this processthroughthyroxinandtriiodo-

thyronine.In consequence of thyroxin-dependent thermogenesisand the
activationof sympatheticnervoussystem, the effectof cardiovascular and
respiratorysystemsincreasestogetherwith the basalmetabolism.These
changesmaybemeasured by increased utilizationof oxygenin the organism.
Stadiumfastigii.Thesecondstageis characterized by establishment of
the ratio of heatproductionto heatlossat a definite level.It is theculmination
of fever, whichmeansa newset pointis reached.
Thecenteris washedby bloodthathasthetemperature originallyadjusted.
Because of this, theactivationof sympatheticcompartments stops.However ,
the parasympathetic compartmentof the thermoregulatory centeris activat-
ed. Subsequently, the impulsescausevasodilatation of skin vesselsand the
decreasein peripheralvascularresistance. Thesechangesarethe reasonof
decreasedbloodpressureand increasedpressurein the pulmonaryartery.
Thepressurein the pulmonaryarteryincreasesbecauseof vasoconstriction
of pulmonaryarterioles.Thepatienthaswarmand red skin; he sweats, and
loosesheatby conduction , radiation, andevaporation .
Compared with the first stageheatproductionmaydecrease , sometimes
evento normal, but the balancebetweenheatproductionand heatloss is
established at a higherlevelthanin healthypeople.
Stadiumdecrement i. Thethird stage- the stageof fallingtemperatureor
defervescence (Lat. defervescere - to stopboiling, cool off) is characterized
by increase d heatloss and its predominance over heatproduction , which
mayrelativelyevenincrease . Thisusuallyoccurswhenprimarypyrogensare
exhausted,or production of secondarypyrogensis stopped,or underthe
influenceof naturalor iatrogenicantipyretics.
Heatloss increasesas a resultof excessive perspiration(sometimesvery
profuse)and considerable dilatationof the peripheralvessels.The ratio of
heatproductionto heatloss is the reverseof that observedduringthe first
stageof fever.Thenheatproduction,heatlossand bodytemperature return
to normal.At this stagethetemperature is oftenunstable .
Thedefervescence maybegradual(lysis)or rapid(crisis).Criticaldecrease
meansthesituationwhenthefeverdecreases to normaltemperature in 1 or 2
hours.Withthedefervescence , alsothe frequencyof pulseandrespirationis
 2681 Part I General pathophysiology

decreased . Suddendecreaseespeciallyof long-lastingfevermaycause tem-

perature crisis. Expressive defervesce nce, decreasedpulse, and decrease in
peripheralvascularresistancemaycausethefailure of circulation(collapse).
This is especiallydangerous for personswith cardiovasculardiseaseand for
old persons.
Thecourseof the differentstagesof thefebrile processis determined, not
only by the etiologicfactor, but also by the generalstateof the organism, its
reactivity
, metabolismandintensityof the oxidativeprocesses.

Types of Temperature Cu rve s

A number of pathologicprocesseshavetypicaltemperature curvescharacter -
izingthe manifestationsof fever.
Thetypeof tempera turecurvesdepends onthe doseandthecycleof pyrogen
production , vital activityof causativeagents, therapy, and individualreactivity.
Feveris definedas a temperatureof 38 °C or greater, or greaterthan2 °C
abovebaselinetemperaturein certaindiseasestates(e.g.,renal failure).The
humanbodyclosely maintainsa normaltemperatureof 36 to 37 °C. During
a 24-h period, temperature varies from lowest levels in the earlymorning to
highestin lateafternoon.Theamplitudeof this dailyvariation,the circadian
temperature rhythm,is about0.6 °c.
The following forms of elevatedtemperatureare distinguished: subfe-
brile(not above 38 °C), moderate (up to 39 °C), high(39-41 °C), hyperpy-
retic(41 °Candhigher).Feversof 41 °Candaboveareverydangerous, but
they are rareandare usuallydueto organicdisease, not infectiousagents.

Th e following main forms of fever are distinguished ,

a ccording to the charact e r of the temperature curves :

1. Ephemeral fever(febrisephemera) is feverspersistingor lasting only

a day or two with an indefinite or irregular course(considerablediurnal
variations in bodytemperature) . Thisform of temperaturecurveis char-
Inflammationand immunedisorders Unit 3 I2sg
acteristicof mild pseudotuberculos is, milk fever (which said to attend
the establishment of lactationafterdelivery);
2. Continuous fever(febris continua , Figure30 A) in which the elevated
temperaturefor sometime persistsat a high level, the differencebe-
tweenthe morningand eveningtemperaturenot exceeding1 °C. The
fevermayendabruptly(crisis)or gradually(lysis).This form includes
typhoidfeverearlyin the courseof the disease , the fever in croupous
pneumonia, typhusandcertainotherinfectiousdiseases ;
3. Remlttent fever(febrisremittens,Figure30 B) in whichthe differencebe-
tweenthemorningandevening temperature exceeds 1 °C,butthetempera-
tureneverfallsto a normallevel.It includesthetemperature curvesobserved
duringthelatecourseof typhoidfever,sepsisandcatarrhalpneumonia;
4. Intermittent fever(febrisintermittens , Figure30 C) whichis character-
izedby regularalternationof briefattacksof fever(paroxysms)with fe-
verlessperiods(apyrexia).Hightemperature persists for severalhours,
dropsto normalandthenrisesagain.Thelengthof the feverlessperiods
mayvary.This form of temperature curveis characteristic of malaria.At-
tacksof fevermayoccureverythird day (febrisquartana) , everysecond
day (febris tertiana)or everyday(febrisquotidiana) ;
5. Recurrent fever(febrisrecurrens , Figure30 D), which is characterized
by longerperiodsof pyrexiathanin intermittentfever (5-8 days). The
durationof theseperiodscorrespondsto that of the periodsof normal
temperature. Sucha curveis characteristic of variousdiseases,includ-
ing borreliosis(relapsingfever), treponematoses, tularemia,meningo-
coccemia,malaria,andrat-bitefever.
6. Hecticfever(febrishectica,Figure30 E)is feverin whichthe swingsare
3 to 5 °C.It occursin sepsis,severetuberculosis,andmalignanttumors.
7. Inversefever(febris inversa,Figure30 F) is fever with a perverted
course,for example , an elevationof temperaturein the morningand a
drop in the evening(in someformsof sepsisandtuberculosis).

Therearefevers, whichat first runthe courseof febriscontinuaandthen

changeto febrisremittens(e.g.,in typhoidfever).
Theaforement ionedtypesof temperature curvesdo notexhausttheirvariety.
 270 I Part I Generalpathophysiology

Dueto the anti-infectiouschemotherapy

and antipyretics
, conventional
temperature curveshavebecomeuncommonandhavelosttheir pastsignifi-
cancefor differentialdiagnostics.
A. D.
Davs 1 2 3 4 5 6 7 8 9 10 11 2 3 14 Davs 1 2 3 4 5 6 7 8 9 10 11h2h3 14
me m e n e me m em e e e m e me e me n e men em e 1n e en e e rn e In e n e
·~ 11 mem
Ctn

41° 41°
40° 40°
~ ~
39° J \I 39°
38°
I,<
38° ,' ~
~

~ ~ ~ ~

37° 37°
,
36° I, LoII, j ~
350 1, ~ L,I
~

35° 35°
8. E.
Davs 1 2 3 4 5 6 7 8 910 11~2 3 14 Davs 1 2 3 4 5 6 7891 011 h2h31i4
me ene e melm e me m e:n em e me e•• e me me ,. e me em e m e e It e men e e e e
41° 41°
40° I 40°
I
39° II 39°
38° ~
~
38° •
~
37° 37° u
,,
36° ' " 36° 1, II,

35° 35°
C. F.
Davs 1 2 3 4 5 6 7 8 9 10 11Ii2M314 Davs 1 2 3 4 5 6 78 910 11h2h3h4
me me en e me m .~ e e I Im e m eh e 111 em e meme m e~ e me m em e eln m e me e e e
41° 41°
40° 40° '
39° 39° I\

38° 38° 1,IJ \iJ

37° . 37°
'
36° J ~
JO ~

~
7
, ... '~I/ 36° "'
~

35° 35°

Fig.30. Typesoftempe
raturecurves
Inflammationand immunedisorders Unit 3 I 271
Metabolism in Fever
Metabolicdisturban
cesin feverarecausedby variousfactors.

The main factors are:

• etiologicalpeculiarities,mostfrequentlyof the infectiousagent;

• systemicinflammatoryresponsesyndrome , which generallyaccom-
paniesinfectiousand non-infectiousfeversand is seenas a systemic
expressionof multipleinflammat ory mediators(cytokinestogetherwith
oxygenfree radicals, coagulationfactors, etc.);
• elevationof bodytemperature ;
• starvation
, which in somemeasureaccompan ies feversince, owingto
lossof appetiteanddigestivedisturbances , the organismconsumesand
assimilateslessfoodthanusual.

In mostcasesbasalmetabolism is increased , this increaseunderlyingthe

greaterheatproduction . Forevery1° Cincreaseover37° C, basalmetabolism
increases 10-12%, andoxygenconsumption-13%.This stimulatesincreased
requirement in nutrients.Asa patienthasnoappetite , the organismconsumes
the energyof endogenous sources,andthe patientloseshis/herweight.
Oxidativeprocessesspeedup duringthe feverwhatmaybe demonstrated
by the increasedutilizationof oxygen.However , theremay be a discrepancy
betweenthe amountof oxygenconsumedby the organismand heat gain
with accumulation of underoxidized metabolitesand, in connectionwith it, a
decreasein the respiratoryquotient.
Carbohydrate metabolism is increased; this canbeseenfrom the decrease
in glycogenin the liverandthe possibledevelopmentof hyperglycemia.
Lipidmetabolism is appreciablyincreasedmainlyin lingeringfeversof in-
fectiousorigin.Theincreasedexpenditure of fats is duenot only to the fever,
but also to the concurrentstarvationand, in a certainmeasure,perhapsto
intoxication.Ketonemiaandketonuriaaresometimesobservedas a resultof
carbohy dratedeficiencyanddecreasedoxidationof fats.
 2721 Part I Generalpathophysiology

Proteinmetabolism may be disturbed.The catabolismof proteinswith

negativenitrogenbalanceincreasesleadingto the lossesof proteinthat may
reach300 to 400 g per day. Decreased diuresisassociatedwith increased
proteincatabolismoftenleadsto the rise in metabolicacidosis.Thesemeta-
bolicchangesmaybe improvedin the phaseof polyuriathat startsafterthe
decreaseof fever.
The loss of valuableproteinsby the feverishorganismmay be in some
measurecompensated by consumptionof carbohydrates, fats andproteins.
In severefevers,someinvestigatorshaveobservedan increasedspecificdy-
namiceffect of protein,which also explainsthe increasedloss of nitrogen
with the urinein highfever.
The problemof metabolismin fever is very importantfor the choiceof
diet for feverishpatients.It is difficult completelyto eliminatethe lossesof
tissueproteinsin fever,especiallyinfectiousfever involvinghigh tempera-
ture. In severeinfections,it is necessary to strivefor a possiblelimitationof
proteinexpenditureby a plentifuladministrationof carbohydrates. Forthis
purposepatientsareintravenously administeredglucosewhichis moreeas-
ily oxidizedandis in a certainmeasurecapableof makingup for the caloric
deficiencyandthe excessiveexpenditureof protein, the latterimperilingthe
feverishorganismwhich is fighting the active,in most casesinfectious,
agent.
Waterandsaltmetabolism is moreor lessaltered.Asa resultof increased
metabolismand accumulationof underoxidized productsthe tissuesretain
water.The dysfunctionof the renal filter dueto intoxicationand the rise in
temperatureis alsoof someimportance.
At the first stageof feverprofounddiuresisdueto the increasingin blood
pressureis observed.Thesecondstageis accompariied by decreased excre-
tion of urine resultingfrom the retentionof sodiumand water due to the
accelerated synthesisof the.aldosterone. Theretentionof wateris noticeable
alreadyat the heightof pyrexia.Butduringthethird stageincreasedexcretion
of waterby the kidneysis observedin additionto the sharpincreasein heat
loss andexcessiveperspiration.
Asfor the saltmetabolism,the disturbedwatermetabolism involvesreten-
tion of chlorides;duringthe third period, whenthe excretionof urinebegins
 Inflammationand immunedisorders Unit 3 I 273
to increase
, morechloridesareeliminated.Morephosphates
and potassium
saltsareexcretedas a resultof tissuedisintegrati
on.

Changes in Functions of Internal Organs and

Systems in Fever
Infever,importantchanges occurinthefunctionof internalorgansandsystems.
Cardiovascular system.As a directconsequence of fever,tachycardiais
observed.Usuallya 1° risein temperature is accompanied by an increaseof
8-1 Obeatsin the heartrate (VonLiebermeister 's rule). In feverthe cardiac
rhythmis acceleratedasa resultof thesinoatrialnodewarmingandexcitation
of the sympathetic nervoussystem.
Excepttachycardia, extrasystoles mayalsooccurduringfever.Thesemay
· havetoxicor infectiousoriginor maybethe signof myocardialdegeneration
at long-term fever.
Thechangesin the stateof the vesselsare connectedwith disturbances
in physicalheatregulation;for example , chillsareaccompanied by spasmof
the peripheralvesselsanda rushof bloodto the internalorgans;duringthe
secondand, especially, the third stagesof feverthevesselsaredilated.
In thebeginningof feverthe bloodpressureis somewhatelevatedbecause
of the increased actionof the heartandexcitationof the vasomotorcenters;
duringthe laststage,however , the bloodpressuredropsas a resultof weak-
enedheartactionand dilatationof the vessels.The drop in blood pressure
maysometimesleadto collapse.
Respiratory system.In fever it is acceleratedsimultaneously, with the
quickeni ng of the pulseand elevationof the body temperature.Feveralso
involvesa rise in the temperatureof the bloodand acidosisdevelopedas
a resultof accumulation of acid metabolites. Respira tion participatesin the
physicalregulationof heatalongwith the vascularsystemand the sweat
glands.A change in respirationis thus one of the mechanismsof physical
thermoregulatio n in fever.
Digestive system. Thefunctionof thedigestiveapparatusis alteredmainly
dueto thesystemiceffectof cytokinesand non-thermogenic effectof bacte-
 Generalpathophysiology
2741 Part I

rialtoxins.Thesecretionof digestivejuicesandbileis decreased. Hyposaliva-

tion is the part of decreasedsecretoryfunctionof the gastrointestinal tract.
In hyposalivationinflammationof buccalmucosaand the tongueis pres-
ent as well. Thereare motor disordersand the disturbancein absorption.
Somecasesare accompaniedby constipationwith increasedputrefaction ,
accumulation of gasesanddevelopment of meteorism . In general, the patient
losesappetitewhatis causedby directactivityof TNF-a butalsobyfunctional
changesin the digestivetract.
Kidneys . The function of the kidneysis also altered. Renalfiltration is
particularlyaffectedby cytokinesand toxins in infectiousfevers (for ex-
ample, scarlet fever, septic diseases).At the height of fever the amount
of urine perceptiblydiminishes. The water is retainedby the tissues.The
contentof nitrogenoussubstancesin the urineis increased.Theamountof
urine appreciablyincreasesduring the third stageof fever whenthe body
temperaturebeginsto fall. Duringthe fever, or after its finish, pathologi-
cal components- proteins, hyaline casts,andcreatinineare presentin the
urine.Theamountof excretedproteinmainlydependson the characterand
severityof renalaffection.Herean importantpart is playednot so muchby
hyperthermia,as by the infectionand intoxicationwhich have initiatedthe
febrileprocess.
Nervoussystem.Disturbances underlyingthe disordersof thermoregula-
tion arisein the nervoussystem.Moreover , phenomena dueto changesin
bodytemperature , "cytokinestorm" (cytokineselevatingin the bloodstream)
andintoxicationareobserved . Hyperthermia mayof itself (in so-calledasep-
tic fevers), dependingon its intensity, stimulateandsubsequently inhibitthe
central nervoussystem.Infectiousfeversare not infrequentlyaccompanied
by a sensationof heavinessin the head, generalindisposition, cloudedcon-
sciousness , delirium, hallucinations
, etc.
Childrenreactto pyrexiaby greater·excitementthan do adults.In emaci-
atedpatientsfever is usuallyattendedwith phenomena of depressionof the
nervoussystem.
Changesin mentalcondition are presentin veryyoungandvery old per-
sons.Theymaybe very mild or maydevelopinto deliriant state.Expressive
changesin mentalconditionmaybesometimesobservedin alcohol drinkers,
Inflammationand immune disorders Unit 3 I 27 5
cardiovascular patients
, andsenilepersons. TNF-aandIL-1 causethe release
of ~-endorphins in thebrainthatmayparticipateon changedmentalcondition.
As regardstheautonomicnervoussystem,thefunctionsof its sympathetic
division predominateat the first stage of fever,and parasympathetic
divi-
sion- at the secondstage.

Possible Benef its of Fever

Feveris presumablybeneficial , becauseit has evolvedand persistedas
a responseto infectionsand other diseases.The febrile increaseof body
temperatureis regardedas a componentof the complexhost responseto
infectionor inflamma t ion that accompaniesthe activationof the immune
system.
· 1. Manymicroorgani sms growbestwithina relativelynarrowtemperature
range,anda risein temperatureinhibitstheir growth.Thus, feverinhib-
its multiplicationof suchtemperature-sensitive microorganisms as the
poliovirus, cold viruses,herpeszostervirus, systemicand subcutane-
ous fungalpathogens , Mycobacterium species, andthe syphilis spiro-
chete(Treponema pallidum).
2. Feverimpedes the nutrition of bacteriaby reducingthe availabilityof
iron, zinc,andcopper.It hasbeendemonstrated that duringfever, the
macrophagesstop releasingtheir iron stores, and this could retard
severa l enzymaticreactionsneededfor bacterialgrowth. Fever is also
markedby a metabolicshift awayfrom glucose,an excellentsubstrate
for bacteria, to fat andprotein as energysources.
3. Feverslightlyincreasesimmunereactions, hematopo iesis,and speeds
up chemotactic,phagocytic , and bactericidal activity of polymorpho-
nuclearleukocytes.Up to certainvalue, it stimulates the processesof
antibodyproduction.Hightemperature causesdestructionof lysosomes
and the whole cells. This is a way by which the body defendsitself
againstmicrobesbut alsoagainstreplicationof viruses. Theincreased
productionof interferonsalsoactsagainst viruses.
4. Feveralsoslowsthe growthof sometumors.
 2761 Part I Generalpathophysiology

Pyretotherapy(Gk.pyretos,fever+ therapeia,to treat medically),or py-

rotherapy , is treatmentof a diseaseby injectingpyrogensor applyingheat
(artificialfever).
The history of pyretotherapy beganwith the observationscarriedout by
A.S. Rosenbluem (Odessa,Ukraine , 1876), who noticedthe ameliorationin
the stateof healthin the patientswith syphilishadinfectedthemwith relaps-
ing fever(borreliosis).
Forthe elaborationof pyretotherapy of syphilisby malariainoculationJu-
lius Wagner-Jauregg (Denmark)wasawardedTheNobelPrizein Physiology
or Medicine(1927).In 1917, hecommenced to put into practicehis proposal
madein theyear1887,andinjectedninecasesof advancedsyphilis(progres-
siveparalysis)with tertianmalaria.Six of theseninecasesshowedan exten-
siveremission,andin threeof thesecasesthe remissionprovedenduring.
Currentlysomefever-producing vaccines(e.g., TBAvaccine- typhoidand
paratyphoid), artificialpyrogens(SeeaboveunderEtiologyof Fever)andpy-
rogeniccytokinesareappliedas pyretotherapeutic means.
Beforethe adventof antibiotics,feverswere artificiallyinducedfor the
treatmentof neurosyphilis andprovedto be beneficial.
Hyperthermiabenefitsindividualsinfectedwith anthrax, pneumococcal
pneumonia,leprosy,andvariousfungal,rickettsial,and viral diseases . Pyr-
etotherapyhas beeneffectivein treatingthe cutaneouslesionsof sporotri-
chosis,paracoccidioidomycosis , andleishmaniasis.
Pyretotherapy is beingusedto treat noninfectious diseasesas well as to
accelerate reparativeprocessesin traumaticor burninjuries, to resolvescars
andadhesionsthat refersto theabilityof pyrogeniccytokinesto stimulatethe
collagenase activityandto promotethe scartissueresorption .
Pyretotherapy is a usefulprocedurein someneuropsychic diseases(e.g.,
psychoses , West'ssyndrome), whicharefoundto beresistantto the classical
treatment.
It is beinginvestigated for a possiblerolein treatingmalignancies. Antican-
cer effectresidesin suchendogenouspyrogeniccytokineas tumor necrosis
factor(TNF).However , in this regardadjunctiveregionalhyperthermia is more
commonlyused, whichoftenimprovesthe rateof responsewhencompared
with radiotherapyor chemotherapy alone;superficialtumors respondmost
Inflammationand immunedisorders Unit 3 I 277
favorably,but betterresponses
maybeobtainedwith internalmalignancies as
techniques for deepheatingareimproved.
In general,feveris consideredto be a pathologicalprocess.However , it
hasimportantrolesin defensemechanisms. Infectiousdiseasewithoutfever
meansa prognostically badmedicalfinding.

Harmf ul Effec ts of Fever

Theymay comeinto consideration at high temperatures, if fever lasts too
long, and especiallyif the patientsare sufferingfrom an additionaldisease,
too. Increasedbasalmetabolism , minuteheartvolume,and waterand salt
lossmaycomplica te otherbasicillnesses.Veryhightemperature suppresses
immunemechanisms.
Long-termfevercausesdysfunctionsof parenchymal organs. It is so in
hyperpyretic fever, febrilespasms,seizures , andcardiacproblems.
Elevatedbodytemperatures are most harmfulto the veryyoungand the
very old. Because feverincreases oxygenconsumption,it imposescircula-
tory demandsthatmayprecipitateischemia , arrhythmias , or congestiveheart
failurein patientswith cardiovascular disease . The fast decrease of fevermay
endanger the patientby fastloweringof the bloodpressure(collapse) .
Whenthe rectaltemperatureis over41 °cfor prolongedperiods,some
permanent braindamageresults.Whenit is over43 °C, heatstrokedevelops
anddeathis common.
Febrileseizuresare a risk in childrenbetween6 monthsand 6 yearsof
age. Althoughfebrileconvulsions aregenerallybenign,theyarealarming,and
it is alwaysnecessary to excludeunderlyingneurologicillnesses, including
meningitis . Febrileseizuresdo not occurin adults, but feveroftenresultsin
decreased concentration andsleepiness; high temperatures commonlypro-
duceanalteredsensorium , includingstupor anddelirium.
Increasedbodytemperaturemayactivatelatentvirus of herpessimplex.
Fromunclea r reasons , it oftenoccursin pyogenicbacterialinfections(pneu-
mococcal,streptococcal,meningococcal), in malaria , and in rickettsioses.
Herpeslabialisto a certain extentis a signof suppressed cellular immunity.
 2781 Part I Generalpathophysiology

Feverduring pregnancydoesnot appearto causefetal death,but during

the first trimester,fevermayincreasethe risk of congenitalheartdisease.
Antipyretictreatment.With this revisedperspectiveon fever, whether
to suppressit or not can be a difficult decision.Someadvocatesfeel that a
slightto moderatefeverin an otherwisehealthypersonshouldbeallowedto
run its course,in light of its potentialbenefitsandminimalsideeffects.Oth-
ers believethatthe possiblebenefitsof feverdo not outweighits discomfort
and potentialharm. All medicalexpertsdo agreethat high and prolonged
fevers,or feversin patientswith cardiovascular disease
, seizures,andrespi-
ratoryailments,are riskyandmustbetreatedimmediatelywith suppressant
drugs.The classictherapyof fever are antipyretic agentssuchas nonste-
roidal anti-inflammatorydrugs (e.g., aspirin, indometacin,acetaminophen)
that lowersthe set point of the hypothalamiccenterand restoresnormal
temperature .
Themechanismof their actionis associatedwith cyclooxygenase-2 (COX-
2) inhibitionandthe reductionin producingprostaglandins in the hypotha-
lamicthermalcontrolcenter.
Glucocorticoidswork antipyreticallyby inhibitingthe productionof IL-1
and TNF-a, and by inhibitingthe metabolicprocessesof arachidonicacid
(by meansof phospholipaseA 2 inhibition). But they should not be used
expresslyfor this purposebecauseof their other effects on the immune
system.
Theclinicalapplicationof antipyretic'cytokines requiresin-depthstudy.
Anyphysicaltechniquethat increasesheatloss (e.g., coldwateror alcohol
rub-downs)canalsohelpreducethe coretemperature.

Fever versus Hyperthermia

Feveris considerednot to be a thermoregulation disorder,but a resettingof
the biologicalthermostatto a highervalue,i.e.the organismitself keepshigh
temperature. Whenan animalburningwith feveris subjectedto coolingoff,
theanimal'sbodetemperature will still behigh.Thus,thecoretemperature of
feverishsubjectsis independe nt of ambient temperature.
Inflammationand immunedisorders Unit 3 I279
Hyperthermia hasno relation to the effectof pyrogens.In this casethe
thermoreg ulationdisturbancesareobserved . Thebodytemperatureincreas-
es in spiteof theorganism's attemptsto thermalhomeostasis. Theset point
of thethermoregulatorycenter is unchanged.Whenananimalwith hyperther-
miais beingcooled,so dueto the abruptincreasingof the heatlossthe body
temperature startslowering.
Fever-like states.Therearea numberof endogenous hyperthermias , re-
semblingfever, but, howeverbeingnotassociated withtheeffectof pyrogens.

Neurogenic hyperth e rmia is due to :

• injuriesandcontusionsof the brain, heatpuncture , tumorsof the dien-

cephalon , hemorrhages into thethird ventricle;
• disturbances in highernervousactivity, mentalstress("stressfever").
Sometimesit maybedeveloped owingto hypnoticsuggestion ;
• reflexstimulationof the heat-regulatingcenter(in renalor hepatic colic,
urethracatheterization,etc.).

Habitualhyperthermia (37-38 °C) is detectedin childrenandyoungwom-

en. It is associated with the signs of psychoneurosis, asthenia,complete
weakness , andinsomnia.Theyoftenhavedifferentunpleasant subjectivefeel-
ingsthatforcethemto thinkabouttheirhightemperature.
Neurogenichyperthe rmia developmentis associatedwith the formation
of a generatorof pathologically enhanced excitationin the thermoregulatory
centeror direct thermogenesis increasingandheatlossdecreasing underthe
influenceof sympathoadrenal system.
Endocr inehyperthermia is constantlyobserved in certainendocrinopathies ,
for example, in hyperthyroidism. Hormones of thyroidglandessentially
increase
non-shiveringthermogenesis dueto uncoupling of oxidativephosphorylation.
Drugortoxicant -induced hyperthermia resultsfrom introductionof some
drugs or toxicants (e.g., adrenalin,thyroxin, cocaine,ecstasy,dinitrophe-
nol, pentachlorophenol, nicotine, caffeine).Thesesubstanceshavedifferent
mechanisms of action.Someof themare sympathicotropic and excitethe
 280 I Part I Generalpathophysiology

heat-regulatingcenter;others(thyroxin,dinitropheno l) directlyinfluenceen-
ergymetabolismand uncoupleof mitochondrialoxidationandgenerationof
ATPcausing excessiveheatproduction.
Malignanthyperthermia is a pharmacogenetic hypermetabolic state of
skeletalmuscleinducedin susceptibleindividuals by inhalatio nal anesthetics
and/or succinylcholine (andmaybeby stressor exercise).Theterm pharma-
cogeneticrefersto the fact that, in almostall cases, two essentialelements
arerequiredto inducethe hypermetabolic stateof skeletalmusclereferredto
as malignanthyperthermia .
In orderfor this stateto occur in an individual, that individualmust have
inheritedthe appropriateabnormalgene(s)in malignanthyperthermia , vari-
ous mutationsof the genecodingfor the ryanodinereceptor leadto excess
Ca2• releaseduringmusclecontractiontriggeredby stress.This in turn leads
to contracturesof the muscles, increasedmusclemetabolism , and a great
increasein heatproductionin muscle.Theincreasedheatproductioncauses
a markedrise in bodytemperature that ls fatal if not treated.

An apy rexi a

Theword anapyrexia(Gk.anaback+ puretos,fever)wascoinedto describe

the humansyndromeof lower core temperaturewith lower thresholdsfor
shivering,vasodilatation, and sweatingthat takes placewith intensewarm
discomfortin several situationssuchas during menopausal hotflashes,al-
cohol intoxication,and spontaneous episodicbouts.Sucha syndromemay
be summarizedasdueto a loweredset pointfor temperatureregulationbe-
causeheat-lossresponsesare activated while cold·defenseresponses are
inhibited.
 Pl--,\'HO Ph'l ' c·1r"'·
,_) ,_JL.or.:\J

Unit4 I '

OF ME:TABCJL.JSM
,}\.,_,,
l

....

Chapter 12. Pathophysiologyof Energy

and Protein Metabolism. Starvation.
All the metabolicprocessesin the organismthereincludetwo main phases:
anabolismandcatabolism .
• Anabolismis the phaseof metabolicstorageand synthesisof cell con-
stituents. Anabolismdoesnot provideenergyfor the body; it requires
energy.
• Catabolisminvolvesthe breakdownof complexmoleculesinto sub-
stancesthat canbe usedin the productionof energy (Fig. 31).

Nutritionalstatusdescribesthe conditionof the body relatedto the avail-

abilityanduseof nutrients.

Nutrients provide the e ne rgy and mat e ria ls nec e s-

sary for performing :

• the activitiesof dailyliving;

• for maintaininghealthyskin, muscles,and otherbodytissues;
• for replacingandhealingtissues;
• for the effectivefunctioningof all bodysystems, including the immune
andrespiratorysystems.
 2a2 I Part I Generalpathophysiology

Catabolism Anabolism
i
Kreb
's cycle - ---
I
ATP _ _ ,., Mechanical
work(muscles)

HEAT

Fig.31. Principa
l orga
nizationof metabol
ic processes
inorga
nism

Nutrients are derivedfrom the digestivetract through the ingestionof

foods.
Once insidethe body, nutrientsare usedfor energyor as the building
blocksfor tissuegrowthandrepair. Whenexcessnutrientsareavailable,they
frequentlyarestoredfor future use. If the requirednutrientsare unavailable
,
the bodyadaptsby conservingandusingits nutrientstores.
Metabolismin the organismis determinedby hereditaryfactorsandregu-
latedby the nervousand endocrinesystems.Therefore , thesedisturbances
of metabolismmayhavethe hereditary natureor appearin the processof the
life as a resultof disturbanceof the regulatorysystems.Thedisturbances of
metabolism can be manifestedon all levelsof biologicalorganizationfrom
the cellulomolecularto the organism.The leadingrole is carryingout self-
regulationbelongsto geneticinformationat the cellularlevel.The majority
of hereditarydefectsof metabolismis stimulatedby mutationof the genes
encodingthe synthesisof ferments- hereditaryenzymopathies. Theessence
of enzymopathy is that enzymeproteinisn't synthesizedor synthesizedwith
a changed structurethat alters1tsactivity. Accumulation of unmetabolised
substrateor fallingout of the intermediateproductof metabolismis possible
in decreaseof enzymeactivity.
Enzymopathies maybehereditaryandacquired.
Pathophysiologyof metabolism Unit 4 I283
For the acquired enzymopathies ther e m a y lb e
some causes the main of which a re:

• disturbancesin enzymesynthesis
;
• co-enzymesdeficiency;
• increaseinhibitorsactivity.

Consequences of enzymopathies in the organism- developmentof meta-

bolicblockades.
Metabolicblockades are dividedinto four groups by the main conse-
quences , whichdependson the mechanismof its development(Fig. 32).
1. Decreaseof secondary productsof metabolism(hypothyreosis,albi-
nism).
2. Increaseof primeryproductsof metabolism(glycogenosis).
3. Increaseof alternativepathwayactivity(adrenogenital
syndrom).
4. Activationof pathologicalpathway(phenylketonuria).

The Increaseof enzymeactivity leadsto the accumulationof final prod-

ucts of metabolism.The constantinflux of information, which is carried
out by the nervoussystemmediatorsand hormones,is necessaryfor the
coordinationof metabolismin the cells. Thereare specific receptorson

lE 1

)( ), B l 90%

C i 10 %

Fig. 32. Types

of metabo
licblockades
 284 f Part I Generalpathophysiology

the membranein the cell for the perceptionof this information. Pathology
of the receptorscan be one of the mechanismsof the pathologic process
development , for example, in diabetesmellitusanddiabetesinsipidus.To-
getherwith intracellularmechanismsof self-regulation , the organism has
got the more complicatedmechanisms- neurohumoralmechanismsof
regulation.The nervoussystem controls the tissue metabolismwith the
help of mediators;the neurodystrophicprocessdevelopson disturbance
of this function.
Disturbance of metabolismat a higherlevel of organization
- organand or-
ganism- dependson the stateof the neuroendocrine regulationto a greater
degree.So, the emotionalstimulationis accompanied by the changeof the
corticalregulationof heat production,carbohydratemetabolism,etc. Many
disturbancesof metabolismare stimulatedby lesionof the diencephalons.
The role of hypothalamusis especiallyimportant,which exert influenceof
metabolismwith the help of releasing- factorsthroughthe pituitarybody.
Disturbances of the vegetativenervoussystemalso provokethe changesof
metabolism.Thus, there is a closeconnectionbetweenintracellular mecha-
nisms of self-regulationconnectedwith geneticinformationand neurohu-
moral regulationof the metabolism. And the disturbanceof any of them is
accompanied by the development of pathology.

Energ y metabolism and its d isturbances.

Energyis measuredin heat units calledcalories . A calorie, spelledwith a
small c and also calleda gram calorie,is the amountof heator energyre-
quiredto raisethetemperatureof 1 g of water by 1 °C.
A kilocalorie(kcal),or largecalorie,is the amountof energyneededto
raisethe temperatureof 1 kg of water-by 1°C. Because a calorieis so small,
kilocaloriesoftenareusedin nutritionalandphysiologicstudies.
Theoxidationof proteinsprovides4 kcal/g; fats- 9 kcal/g; carbohyd rates-
4 kcal/g, andalcohol- 7 kcal/g.
Most of the energyrequirements are satisfied by carbohydratesandfats,
whichare largelyinterchangeable. Theenergycontributionof carbohydrates
Pathophysiologyof metabolism Unit 4 I2as
(starch, sugar,glycogen) , normally60 % of the total, canfall to 10 % before
metabolicdisturbances appear.
Fatsare providedby a supplyof essentialfatty acids (e.g., linoleic)and
of fat-solublevitamins(A, D, E, K). On average , dietaryfat providesabout
25-30% of the energy(onethird as essentialfatty acids).
Thedisturbanceof energymetabolismlies at the baseof the majorityof
functionalandorganicdisturbancesof organsand tissues. Theycanariseof
all stagesof energytransformations asa resultof absenceor deficiencyof a
substrate,changeof enzymeactivity, dueto geneticdefects, actionof inhibi-
tors of enzymes,insufficiententranceof indispensable aminoacids,fat ac-
ids, vitamins,traceelementsand othersubstances , which are necessaryfor
carryingout metabolicprocessesor as a resultof damageof the regulatory
systems.Normalcourseof metabolismis stimulatedby dynamiccooperation
of catabolismandanabolismprocessesat the molecularlevel.
Oxidationof metabolicproductsin Kreb's cycle is the most effectivein
energyrespect.Degreeof conjugation of respirationand phosphorylation
in the cells is a regulatedprocess,which is connectedwith the state of mi-
tochondria.In someconditions, whichare connectedwith the necessityto
maintainits own temperature underthe influenceof cold, the organismis
in needof urgent mobilizationof heat, which happensby estrangementof
oxidativephosphorylationand increaseof free oxidation. Parathyrine , pro-
gesterone , growth hormone, and vasopressinare relatedto the estranged
factors. Oxidativephosphorylationis essentiallydisturbed in avitamino-
sis, especiallyof B group, as many vitaminsof this group are present in
the compositionof Kreb'scycle coferements.Deepdisturbanceappearin
diabetesmellitus, when the productionof macroergiccompoundsis de-
creaseddue to the disturbanceof inhibitors of enzymes, insufficient res-
piratory chain, stipulatedby the limitation of the capacityof the Kreb's
cycle.
Forthe investigationof energymetabolismthey usethe basalmetabolic
rate(BMR). Basalmetabolicrateis the amountof energyexpendedwhile at
restin a neutrallytemperateenvironment, in the post-absorptive state(mean-
ingthatthe digestivesystemis inactive,whichrequiresabouttwelvehoursof
fastingin humans).Thereleaseof energyin this stateis sufficientonlyfor the
 2861 Part I Generalpathophysiology

functioningof the vital organs, suchas the heart,lungs,brainandthe restof

the nervoussystem, liver, kidneys,sexorgans,musclesandskin.
Thedisturbance ofbasalmetabolism is closelydependent on the hormo-
nalstatusof organism.
Thyroxinis oneof the basicregulators,it increases the permeabilityof mi-
tochondria,influenceson the oxidationand phosphorylation processesand
intensityof energyprocesses.Increaseof the basalmetabolismby 20% and
moreis a diagnosticsign of thyrotoxicosis,and its decreaseindicateshypo-
functionof the thyroidgland.
Thehormoneof the pituitarybody- somatotropin- stimulatesfreeoxida-
tion anddueto this increasethe heatproduction.That'swhy the intensifica-
tion of energyprocessesoccursin tumorsof the pituitarybody.
Adrenalinestimulatesthe basalmetabolism,especiallyin coldconditions.
Insulinhasthe oppositeinfluence;it reducesmusculartremblingandheat
productionincreasingthe estrangement of oxidationandphosphorylation.
Sexhormones- testosteroneand progesterone - activatefree oxidation
andpromoteenergyrelease .

The d isturbances of prote in metabo lism

The minimumproteinintakeis about0.5 g protein/kgweight.This intake
is necessaryto balancethe outputof endogenous proteinlost as a resultof
degradative reactions.However, for normalactivity,abouttwicethis valueis
needed(functionalminimum), of whichhalf shouldbe in the form of animal
proteinsto furnishthe essentialaminoacids.
In humans, the essentialaminoacids are: histidine,isoleucine,leucine,
lysine,methionine.phenylalanine, threonine,tryptophan,andvaline.
Theproteinsoccupya centralplacein carryingoutvitalfunctionprocesses
of the organism,andthereforethe disturbanceof proteinmetabolismis im-
portantcomponentof all pathologicprocesseswithout exception.Thedepot
of proteinsis practicallyabsentin the organismandthe food is the source
of aminoacids.Not only aminoacidsbut alsothe normalfunctioningof the
systemof synthesisandits encodinggeneticstructuresarenecessary for the
Pathophysiologyof metabolism Unit 4 I 2a7
normalsynthesisof aminoacids.The disturbanceof proteinproductioncan
be acquiredand hereditary.It is expressedin changeof quantityof synthe-
sizedmoleculesor appearance of moleculeswith changedstructure.
Thedisturbance of transamination and oxidativedesamination . Trans-
aminationleadsto the formationof amino acids,desamination - to their de-
struction.The disturbancesof transaminationcan arise in insufficiencyof
pyridoxine(pregnancy , suppressionof theintestinalflora by sulfamideprepa-
rations).Decreaseof transaminase activity takes placein the limitation of
proteinsynthesis(starvation,diseasesof the liver).
Thetissuetransaminases enterbloodin the destructionof cells (myocar-
dial infarction,pancreatitis
, hepatitis,etc.). Andthe increaseof their activityin
this pathologyis oneof the diagnosticcriteria. Thedisturbanceof correlation
betweensubstratesof reaction,andalsohormones,especiallyof glucocorti-
coidsand hormonesof the thyroidglandstimulating this process, is impor-
·tant in the changeof the transamination reactionrate.
Suppression of oxidativedesamination canprovokesan increaseof amino
acids concentration in bloodhyperaminoacidemia andaminoaciduria.
The disturbance of decarboxilatio n. Decarboxilationis carriedout with
formationof CO2 andbiogenicamines.Someaminoacidsareexposedto this
process:histidin- with formationof histamine , glutaminicacid, aminobu-
tyric acid, 5-hydraoxytryptophan - serotonin.Biogenic amineshavea specific
biologicalactivity and increaseof their quantitycan provokea numberof
pathologicchangesin the organism.Theappearance of a great quantityof
biogenicaminesin tissues(especiallyhistamineand serotonin)can provoke
the considerable disturbancesof localbloodcirculation,increaseof the vas-
cularpermeability,damagesomepartsof the nervoussystem.
Hereditarydisturbances of enzymesynthesisleadto that that properamine
acidsdon't participatein metabolism , and accumulatein the organism, ap-
pearin biologicalmedia:urine, sweat,cerebralfluid. The clinical pictureis
manifestedat first by the appearance of too much quantityof the substance
which must by metabolized in participationof the blockedferment, and sec-
ond1y by the deficiencyof the substancewhich must be formed.Thereare
manysuchdisturbances of amineacidsmetabolism.All of themareinherited
recessively.
 2aa I Part 1 General pathophysiology

Mal nut rition an d starvat ion

Malnutritionandstarvationareconditionsin whicha persondoesnot receive
or is unableto use an adequateamountof caloriesand nutrientsfor body
function.Amongthe manycausesof starvation , somearewillful, suchas the
personwith anorexianervosa who doesnot consumeenoughfoodto main-
tain weightand health,and someare medical,suchas personswith Crohn 's
diseasewho are unableto absorbtheir food. Most casesof fooddeprivation
resultin semistarvationwith proteinandcaloriemalnutrition
.

Starvati o n
Starvationimpliesthe lack of food intake.Dependingon the prestarvation
state, the metaboliceventsof starvationpermitlife to continuefor months
withoutcaloricintake.In healthy, normallyfed persons,thereis fuel enough
to last for morethan80 days, assumingprevioususeof 2000kcal/day;ap-
proximately85 % of thesecaloriesare stored in fat tissue, 14 % in body
proteins, and 1 % in storedcarbohydratesources.
Nowstarvationis consideredasa stateof prolongedstressconnectedwith
anadaptiveactivationof biosynthesisof the adrenalglandshormones.These
hormonesexertthe direct(activated)and indirect(savinginfluenceon vitally
importantenzymesystemsof the organism).
Starvationmay be physiologicaland pathologic . Hibernationof some
mammalsis an exampleof physiologicalstarvation. The complete, incom-
plete(quantitativemalnutrition)and partial(qualitative)starvation are dis-
tinguished.Completestarvationwithoutwateris namedabsolutestarvation.

The co m p lete sta rvation

Causesof completestarvation as of othertypes,may be externaland inter-
nal. Externalcauseis absenceof the food. Internalcausesare the children
development defects,diseaseof the digestivesystemorgans,infectious pro-
Pathophysiologyof metabolism Unit 4 I2a9
cesses,anorexia. The durationof starvationandlife of smallmammalsis less
thanof big ones.Smallsizeof the bodyand less perfectregulationof me-
tabolismandheatexchange explainthe quickdeathof new-bornchildrenin
starvation.Ageddecrease of the levelof basalmetabolism9eterminesgreater
durationof starvationof the old personsandanimals. Besidesthesefactors,
the durationof starvationis determinedby individualpeculiarities connected
withthe characterof the neurohumoral regulationandby the reactivityof the
individual.

Periods of starvation.
The deepernotionaboutpeculiaritiesof differentperiodsof the starvation
givesthe pathophysiological
description , taking into accountthe state of
metabolismandexchange of energy.

Starvation may be divided into three periods on the

ground of this description:

• uneconomical energyexpendituremaximumadaptat
ion;
• tissuedecay ;
• intoxicationanddeath(terminalperiod).

Thedurationof thefirst periodin a humanis 2-4 days.Thesecondperiod

determines practicallythe periodof starvationandcancontinue40-50 days,
thethird 3-5 days.
Manifestations . Oneof the earliestand moreseriousmani-
of starvation
festationsof starvationis a sensationof hungerstipulatedby excitationof the
food centre.Thesensationof hungerin completestarvationmaydisappear
someday later afterbeginningof starvation . And the followingsuppression
of the food centremaybe so deepthat specialmeasuresare necessaryfor
its excitation.In incompletestarvation,the excitationof the food centreis
maintained all thetimeandthe sensation of hungeris renewedperiodically.
 290 I Part I Generalpathophysiology

The massof differentorgansis decreasedunequally.Theadiposetissue

loss massthe mostintensively(97%),andlessintensively-heart (3.6%)and
nervoustissue(3.9 %). The quantityof the nitroussubstances- albumins
and globulinsis increasedin a gastricjuice on the 6-8 day of starvation.
Proteinsareabsorbedfrom bloodandusedfor the constructionof the vitally
importantorgans.This processis a resultof engagingof adaptationmecha-
nism providingthe repeatedusageof proteinsfor the syntheticprocesses.
Metabolism in starvation . Thefirst periodof starvationcharacterized by
increasedexpenditureof carbohydrates . Respiratorycoefficientincreased
dueto this approaching one.
Glucoselevelin blood decreaseless than 3 mmol/L, secretionof insulin
decreaseand glucagonsincrease.Thefunctionof the cortexof the adrenal
glandsis stimulatedand catabolismof proteinsand glycogenesis increase.
Thecontent of glycogen(in the liver)decreases quicklybut it doesnot disap-
pear,it is formedas a resultof the glyconeogenesis process.Theeffective-
nessof the creb's cycleweaknessas a resultof depressionof insulinsecre-
tion. Thelevelof oxygenatephosphorilation decreases andsucha resultwe
canseeanenergymetabolismof the cells.
At the beginningof thefirst periodthe basalmetabolismmaybe increased
a little. At the endof this periodin transitionto economicalenergyexpendi-
ture, it is decreasedby 10-20 % ·and remainson this level in the second
period. Decrease of the basal metabolismin starvationreflectsa deepreor-
ganizationof metabolicprocessesdirectedat on economicalexpenditureof
energyrecourses.In this processan importantroleis playedby the suppres-
sionof the thyroidglandfunction.
Thenitrogenexcretionin urineis decreased on the 2nd-3rddayof starva-
tion. Thenthe reservesof carbohydrates areexhausted andon the 5th - 6th
dayof starvationbeginactivatedmetabolismof fats.
In the second,the longest,periodof starvation,. the respiratorycoefficient
is decreased to 0.7 that reflects
' the primaryoxidationof fats. About80 % of
energythe organismreceivesas a resultof oxidationof fats, 3 % - by oxida-
tion of glucose, 13 % - by oxidationof proteins.In this periodall reserves
of glycogenwhichareusedfor energyneedsof the organismareexhausted.
Thenthe activationof metabolismis registeredin adiposetissue.
Pathophysiologyof metabolism Unit 4 I 291
As a resultof the low levelof insulin,the transportof glucoseto the lipo-
cytesdecreasesandthe deficiencyof glycerinefor the synthesisof the tri-
glyceridesoccurs.The dominantactionof glucagonsand cathecholamines
activatesthe adenilat-cyclase systemand makesthe lipolysisstronger.The
freefat acidscomeintothe blood(lipemia) andotherorgans.Thelevelof free
fat acidsincreasesin the liverandmuscles , andtheirtransportis stimulated
throughthe mitochondria1membranes whereoxygenationtakesplace.The
lipogenesis andsynthesisof fat acidsin theliveris inhibited, but the retention
of-thetriglyceridesin the liveranddevelopment of fat infiltrationoccursin the
deficiencyof proteinsandinsufficientformationof lipoproteids.
In exhaustionof glycogeneand decreaseof enteringof acetyl-koafrom
glycolyticway and decreaseof the levelof melanin-koa , the productionof
ketonebodiesbegins.Thethreeketonebodiesareacetone , acetoaceticacid,
_and beta-hydroxybutyric acid.The increaseof ketogenesiscan leadto the
ketoacidosis .
An intensiveglyconeogenesis registeredin the kidneys.Everyday kidneys
produced80gof glucoseanda halfof this quantityformedfrom aminoacids
(proteincatabolism)andglycerin(catabolismof fats).
Thethird terminalperiod of starvationis characterized by increasedusing
of proteinsasthe energymaterial.Therespiratorycoefficientis equalto 0.8.
Theexcretionof nitrogen,potassium , phosphoruswith urineis increased.Ac-
cumulationof chlorides,the increaseof the tissueosmoticconcentration and
decreaseof the oncoticbloodpressureleadsfor the increasewaterretention
anddevelopment cachecticedema.

Organs and systems in sta rvation

At the beginningof starvation
, the functionof the thyroidglandandhypophy-
sis increases.
Thesecretionof adrenocorticotropichormoneincreasesand
the adrena1 glandsare stimulated.In the secondperiodof starvationthe
functionof the mainendocrineglandsis depressed.The deficiencyof es-
sentialaminoacidsandvitaminsleadsto development symptomsof pellagra
andbery-bery.
 292 I Part I Generalpathophysiology

Heat productionis maintainedduringall the starvationat a minimallevel

anddecreased in the endof the third period.Themainfunctionsof the organ-
ism are kept within physiologicallimits during the first and secondperiod
of starvation.Specialdisturbancesare absentin the blood circulation and
respiration.Activityof the digestivesystemis inhibited.
Therestorationof all functionsof the organismis total evenat the begin-
ning of the last periodof starvation.It is evidentthat completestarvation
doesn'tprovokeirreversiblechanges.Restorationoccursduring2 weeksin
situationwith loss of 40-59 % of bodymassduring 1 month.Appetiteap-
pears, oxidativeprocessesare intensified,processof assimilationis stimu-
lated,andpositivenitrousbalanceis established. However , in all situationsof
starvation,it is necessaryto carryout fatteningcarefully.
Completestarvationwithoutwaterhasthe samemechanismof develop-
mentsuchas starvationwith water,but it is severerandshorter.Metabolic
processesleadto moreproductionof oxidativewaterandmoreintensiveac-
cumulationof metabolicproducts.

Incomp lete starvat ion

Incompletestarvationis registeredmorefrequentlythan completeone. In-
completestarvationappearswhenthe organismdoesn'tchronicallyreceive
the necessaryquantityof food for energyproduction.If starvationis pro-
longedmore,then the adaptationmechanismsbeginto develop,the basal
metabolismis decreasedconsiderably. Alsothe bodymassdecreases, but
sometimesthis processis maskedby the retentionof water.At the sametime
the degenerative
processesdevelopedin the tissues,.Deathmaycomein the
lossabout40% of the bodymass.

Part ia l starvation
Partialstarvationmayby carbohydratic in the deficiencyof carbohydrates
in
food,fatty if the deficiencyintakeof fats andalbuminouswhenthe intakeof
Pathophysiolo
gy of metabolism Unit 4 f 293

proteins and the formation of albumindecrease.Albuminousstarvationis

moreserious.
Mostof the literatureon malnutrition andstarvationhasdealtwith infants
andchildrenin underdeveloped countries.Malnutritionin this populationcom-
monlyis dividedinto two distinctconditions: marasmus andkwashiorkor .
Protein-caloriemalnutrition,also referredto as marasmus, is charac-
terizedby the loss of muscle and fat stores.Marasmusis characterized by
progressivewastingfrom inadequate food intakethat is equallydeficientin
caloriesand protein.The personappearsemaciated , with sparse, dry, and
dull hair and depressedheartrate, bloodpressure , and bodytemperature.
Thechildwith marasmushasa wastedappearance , with stuntedgrowthand
lossof subcutaneous fat, but with relativelynormalskin, hair, liverfunction,
andaffect.
Kwashiorkor is causedby protein deficiency.Theterm Kwashiorkorcomes
·from the Africanword meaning"the diseasesufferedby the displacedchild,"
because the conditiondevelopssoonaftera childis displacedfrom the breast
after the arrivalof a new infantand placedon a starchygruel feeding. The
child with kwashiorkoris characterized by edema, desquamatingskin, dis-
coloredhair, enlargedabdomen , anorexia, and extremeapathy.The serum
albuminlevelis lessthat30 g/L, andthereis pittingedemaof the extremities .
Also oneof the forms of qualitative(partial)starvationthereare vitamin
deficiency . It mayby exogenous(absentor low contentof vitaminsin food)
andendogenous (dysfunctionof vitamins metabolismin organism).

The most important diseases which develop in vita -

min deficiency are:

• Scurvy(vitaminC deficiency)
• Rickets(VitaminD deficiency)
• Beriberi(Thiamine (Vitamin81) deficiency)
• Pellagra (Niacin (Vitamin83) deficiency)
• Perniciousanemia(Vitamin812 deficiency)
• Xerophthalmia (VitaminA, but not uniqueto vitaminA deficiency)
 2941 Part I Generalpathophysiology

Vitamindeficiencies canleadto otherconditions,suchas dermatitis,anae-

mia,cheilosis,atheroscleros
is, andmooddisorders,whicharenot uniqueto
peoplesufferingto vitamindeficiencies.

The rapeut ic starvation (fasting )

Now fastingis usedas non-spe cific methodof treatmentof somediseasesin-
cludingallergic,cardiovascula r, cutaneous , obesities,anddiseases of thejoints.
Dosedstarvationincreases the processof excretionof metabolicproductsand
toxins. In the deficiencyof exogenous sourcesof foodorganismbeginsmore
intensiveuseof it's own fats, carbohydrates and proteins.At the sametime,
the restorativeprocessesincrease , that leadsto renovationof the organism .
Themedicinalstarvationhasthe sameperiodsas pathologic , howeverthe last
concludingperiodis a periodof compensation. In this periodusuallygeneral
conditionimproves , the weakness disappears , andappetiteappears.

Chapter 13. Alterationsin Carbohydrate

Metabolism. Diabetes Mellitus
Dietarycarbohydrates arethe majorpart polymersof hexoses,of whichthe
mostimportantaregalactose , fructose, andglucose.Theprincipalproductof
carbohydrate digestionandthe principalcirculatingsugaris glucose.
Thenormalfastinglevel of glucose in peripheralvenousbloodis 70-100
mg/di (3.3-5 .6 mmol/1).In arterialblood, the glucoselevelis 15-30 mg/di
higherthanin venousblood.
Glucoseis an efficientfuel that, whenmetabolizedin the presenceof oxy-
gen, breaksdownto form carbondioxideandwater.Althoughmanytissues
and organsare ableto use other forms of fuel, such as fatty acidsand ke-
tones,the brainandnervoussystemdependalmostexclusivelyon glucoseto
generateenergy. Thebraincannotsynthesize glucoseandstoresonly a few
minutes' supplyas glycogenandthereforerequiresa continuoussupplyfrom
circulation.As the plasmaglucoseconcentration falls belowthe physiologic
Pathophysiology<?fmetabolism Unit 4 I295
range, blood-to-brainglucosetransportbecomesinsufficientfor adequate
brain energymetabolismand functioning.Severeand prolongedhypogly-
cemiacancausebraindeath,andevenmoderatehypoglycemia can resultin
braindysfunction .
Plasmaglucoselevelis maintainedwithin a narrowrangeandat anygiven
time it is determinedby the balancebetweenthe amountof glucoseentering
the bloodstream andthe amountleavingit.

Theprincipledeterminants aretherefore:
1) the dietaryintake;
2) the rateof entry into the cells of muscle, adiposetissue,and otheror-
gans,and
3) the glucostaticactivityof the liver.

Abnormalities in c a rbohydr a t e m e t a boli s m c a n be

divid e d into:

1) disordersof digestionandabsorptionof carbohydrates

in the intestine;
2) disordersof carbohydratemetabolismin the liver;
3) disorderof hormonalregulationof carbohydratemetabolism

Digestion andabsorption of carbohydr

ates
Theaverageintakeof carbohydrates is about250to 300g perdaythat repre-
sentsabouthalfthe dailyintakeof calories.Digestionof dietarypolysaccha -
ridesbeginsin the mouthbysalivaryamylase , andit is completedin the small
intestineby pancreaticamylase.Thenthe productsproducedby bothamylas-
es, the disacchar
ide maltose,alongwith ingestedsucrose(tablesugar)and
lactose(milk sugar),are brokendowninto monosaccharides - glucose,ga-
lactose,andfructose- by enzymeslocatedon the luminalmembranes of the
smallintestineepithelialcell (brushborder).Most of the glucosemolecules
that areformedentermucosalcellssecondaryto Na· transport,transported
acrossthe intestinalepitheliumintothe portalcirculation,andgo throughthe
liverbeforetheygainaccessto the circulatorysystem.
 Generalpathophysiology
2961 Part I

Disorders of digestion
andabsorption ofcarbohydrates in the intestine
Alterationsin carbohydratedigestionand absorptioncan resultfrom enzy-
maticdefectsin carbohydrate metabolism.Theyareasfollows.

1. Insufficiency of amylo/yticenzymesof the gastrointestinal

tract(pancre-
atic amylaseand others)leadsto disordersof hydrolysisof poly-and
disaccharides into monosaccharides with resultantcarbohydrates mal-
absorption.
2. Deficiency of oneor moredisaccharidases maycausediarrhea,bloating,
and flatulenceafter ingestionof carbohydrates. Lactaseis of interest
becausein most mammals,intestinal lactaseactivity is high at birth,
declinesto low levelsduringchildhood,andremainslow in adulthood.
The low lactaselevelsare associatedwith intoleranceto milk (lactose
intolerance). Thediarrheais dueto the increasednumberof osmotically
activeoligosaccharide molecules that remainin the intestinallumen
causingthe volumeof the intestinalcontents to increase.The bloating
andflatulencearedueto productionof gas(CO2 andHz)from disaccha-
ride residuesin the lowersmallintestineandcolon.
3. Disordersof carbohydrate absorptioncan resultfrom impairedactivity
of enzymehexokinase.Insufficiencyof hexokinasethat leadsto dis-
ordersof glucosephosphorilationin the intestinalmucosacan result
in the impairedreleaseof glucoseinto the bloodstream.Hexokinase
defectmay be causedby inflammatoryprocessin the intestineor by
poisoningwith drugsthat depresshexokinase(phlorhizinor monoio-
dacetate).

Alterationsin carbohydrate
digestionandabsorptionresultin carbohydrate
starvation.

Glucostatic function
ofthe m,er
Bodytissuesobtainglucosefrom the blood. Onceit entersthe cells,glucose
immediat ely combineswith a phosphateradicalto form g/ucose
-6-phosphate
(G-6-P).This phosphorilation is promotedmainlyby the enzymeglucokinase
in the liver andby hexokinase in mostothertissues.Thephosphorilationof
Pathophysiologyof metabolism Unit 4 I 297
glucoseis almostcompletelyirreversibleexceptin the liver cells, the renal
tubularepithelialcellsandthe intestinalepithelialcells.In thesecells,another
enzymeglucosephosphatase is alsoavailable
, andwhenthis is activated,it
canreversethe reaction.In mosttissuesof the body, phosphorilation serves
to captureglucosein the cell.Thatis, becauseG-6-Pis unableto leavethe
cell,sincethe plasmamembraneis impermeable to phosphaticacidesters.
Theexceptionis specialcells,especiallyliver cells that havephosphatase.
Therefore, G-6-Pcanbedegraded to glucoseandphosphate , andthe glucose
canthenbetransportedthroughthe livercell membranebackinto the blood.
Afterabsorptioninto a cell, glucosecan be usedimmediatelyfor release
of energyto the cell, or it canbe storedin the form of glycogen.Glycogen ,
the storageform of glucose,is presentin most bodytissues,but the major
suppliesare in the liverandskeletalmuscle . Theliverfunctionsas a sort of
:·glucostaf'maintaininga constantcirculatingglucoselevel.

It re gulates blood glucose through thr ee pro ce sses:

1) glycogensynthesis(glycogenesis);
2) glycogenbreakdown (glycogenolysis)
;
3) synthesisof glucosefrom nonsaccharide
sources(gluconeogenesis)
.

Althoughthe diet is normallya majorsourceof glucose, betweenmeals

or duringfasting,plasmaglucoselevelis maintainedprimarilyby the break-
downof glycogenand gluconeogenesis. Whenbloodglucoselevelrises, it is
removedfrom the bloodandconvertedto glycogen.
Alterations in glucostatic functionof the livercan be dividedinto two
categories.
1. Decrease in glycogencontentsin the liver which can resultfrom the
followingthings.
a. Decrease d entryof glucosefromthe intestine(starvation)
.
b. Impairedconversionof dietarymonosaccharides (galactose,fruc-
tose)into glucosethat occursin hereditaryenzymopaties - galacto-
semiaandfructosemia.
 2981 Part I Generalpathophysiology

In galactosemia , thereis a congenitaldeficiencyof phosphogalactose uri-

dyl transferase , the enzymeresponsiblefor the conversionof galactoseinto
glucose.This resultsin accumulation of ingestedgalactosein the circulation
causingseriousdisturbances of growthanddevelopment.
In hereditaryfructoseintolerancethereis a defectof fructose-1-phospha-
tasealdolase.Thebreakdownof fructose(fruit, saccharose) is blocked,and
fructose-1-phosphateaccumulatesthat inhibits phosphorilasein the liver
causinghepatogenic hypoglycemia,acute liverfailure, or cirrhosis.
It diagnosed , earlybothgalactosemia andfructosemiacanbeimprovedby
the treatmentwith galactose-or fructose-freediets.
a. Disorderof synthesisof glycogenfrom glucosecausedbya decrease
in activityof enzymesinvolved .
b. Deficiencyof ATP(hypoxia).

2. Decreased releaseof glucosefrom glycogenwith resultantdecreased lib-

erationof glucoseinto the circulation from the liver. This disorderunderlines
conditionscalledglycogenoses . In glycogenoses, breakdownof glycogenis
blocked, glycogenoverloadingand hypoglycemiaresult.This is caused by
enzymedeficienc ies,suchas glucose-6-phosphatase deficiency(von Gierke
disease); phosphorilase deficiency(Hersdisease),lysosomala-glycosidase
deficiency(Pompedisease)andothers.

Hormon al regulation of carbohydrate metabolism

Glucostaticfunction of the liver is not automatic,glucoseuptakeandglucose
dischargeareaffectedby the actionsof numeroushormones.
Thehormonalcontrolof bloodglucoseresideslargely with the endocrine
pancreas . •
Thepancreas consistsof two majortissuetypes,namelytheacini,whichse-
cretedigestivejuices into the duodenum , andthe isletsof Langerhans,
which
secreteinsulin and glucagoninto the bloodstream.Eachislet is composed
p-cells,whichconstituteabout60-80 % of the islet cellsandsecreteinsulin,
a-cellswhichsecreteglucagon,ando-cellswhichsecretesomatostatin.
Pathophysiologyof metabolism Unit 4 I299
Insulin
Althoughseveralhormonesare knownto increasebloodglucoselevels, in-
sulin is the only hormoneknownto havea direct effect in loweringblood
glucoselevel.Thereleaseof insulinfrom the pancreaticp-cellsis regulatedby
a feedbackeffectof the bloodglucoseleveldirectlyon the pancreas.

Mechanism of action of insulin

Theactionsof insulinaremediated by specificreceptorslocatedon the plas-·
mamembrane of thetarget cells. Theinsulin receptoris a combinationof four
subunits,two a-subunitsandtwo p-subunits,whichare linkedcovalentlyto
eachother by disulphidebridges. The a-subunitsare extracellularand in-
volvedin insulin binding.The p-subunits spanthe membrane , and contain
a tyrosinekinaseenzymethat becomesactivatedduringinsulin binding.Ac-
tivationof the tyrosinekinaseenzymeproducesautophosphorilation of the
p-subunitson tyrosineresidues , whichin turn activatessomeenzymesand
inactivates otherstherebydirectingthe desiredintracellulareffectof insulin
on glucose,fat, andproteinmetabolism .
The numberand affinity of insulin receptorsare affectedby insulin and
other hormones,exercise,food, and otherfactors. Exposureto increased
amountsof insulin, obesity, acromegaly,and excessof glucocorticoids
decreasereceptorconcentrationand their affinity. Exposureto decreased
amountsof insulin, starvation , andadrenalinsufficiencyincreasethe number
andaffinityof insulinreceptors .
Insulineffects . Whenglucoseentersthe circulation(througha meal), in-
sulinis releasedimmediately from the pancreas. All effectsof insulinleadfor
the decreaseglucoselevelin the blood (Fig.33). Insulin removesglucose
from the circulationand promotesits conversionto glycogenand lipids. In-
sulinpromotesthe conversionof fattyacidsto lipidsandthe uptakeof amino
acidsinto liverandskeletalmusclewhere theyareelaboratedinto protein.In-
sulinis thus ananabolic hormone.Hypoglycemic actionof insulinis the best
known. Insulinfacilitatesthe entryof glucoseinto cells of muscle, fat, anda
 300 I Part I General pathophys
iology

variety of othertissuesby increasingthe number of glucosetransporters in

the cell membranes .

The mechanism by which insulin causes glucose up-

take and storag e in the liver includes several steps :

1. Insulininactivatesliver phosphorilase, thereforeit preventsbreakdown

of the glycogenthat hasbeenstored in the liver cells.

Glycogen

IN t glycogenesis
glycolysis

Glucose Cell

IN t lipolisis
Fats,
Acety
l-CoA • )( Prqteins
Fattyacids
/ipogenesis glyconeogenesis

, Kreb'
s cycle·

Fig.33. Roleof theinsulin in the metabolic

pathways
(IN - insulin activatedj or inhibited
J metabolic pathway)
Pathophysiologyof metabolism Unit 4 I 301
2. Insulincausesenhancedliver uptakeof glucosefrom the blood by in-
creasingthe activity of glucokinase , the enzymewhich initiatesphos-
phorilationof glucoseafter it diffusesinto the liver cells.
3. Insulinpromotesglycogensynthesisby increasingthe activity of gly-
cogensynthase,the enzymewhich is responsiblefor polymerization
of the monosaccharide units to form the glycogenmolecules.

Glucagon.Glucagonhasthe oppositeeffectsto thoseexertedby insulin.

Unlikeinsulin, it producesan increasein blood glucose.Glucagonis es-
sentialfor maintainingblood glucosebetweenmealsand during periodsof
fasting.In the liver glucagonpromotesthe breakdownof glycogen(glyco-
genolyticeffect), and increasesthe transportof aminoacids into the liver
and stimulatestheir conversioninto glucose(gluconeogeniceffect).
· Somatostatin.Somatostatinaffectsthe releaseof insulin and glucagon
by the pancreas.It also decreasesgastrointestinalactivity after ingestion
of food and thereforeit extendsthe time during which food is absorbed
into the blood.
Manyhormonesin additionto insulin,glucagon, and somatostatinhave
importantrolesin the regulationof carbohydratemetabolism.Theyinclude
catecholamines , thyroid hormones, glucocorticoids,and growth hormone.
Catecholamines . Catecholamines (epinephrineand norepinephrine)help
to maintainblood glucoselevelsduring periodsof stress. Epinephrinein-
hibits insulin releaseand promotesglycogenolysis.
In the liver, epinephrineactivatesphosphorilasevia p-adrenergicrecep-
tors that increasesintracellularcyclic AMP and intracellularCa2+ with re-
sultant increasein hepaticglucoseoutput.
In muscle, the phosphorilaseis also activatedvia cyclic AMP and pre-
sumablyvia Ca2•, but the G-6-Pformedcanonly be catabolizedto pyruvate
becauseof the absenceof G-6-P-ase . Pyruvateis thenconvertedto lactate
which diffuses from the muscle into the circulation, moves to the liver
whereit is convertedto glycogen.
Catecholamines alsoincreaselipaseactivity andtherebyincreasemobili-
zationof fattyacids,a processthat conservesglucosefor useby the brainand
nervoussystemthat dependalmostexclusivelyon glucoseas a fuel source.
 1

3021 Part I Generalpathophysiology

Adrenalmedullarytumor (pheochromocytoma) that secretesepineph-

rine causeshyperglycemia,glucosuria, and an elevatedmetabolicrate.
However,the hyperglycemiceffectof epinephrine is generallytoo transient
to producepermanentdiabete,and the metabolicdisordersdisappearas
soon as the tumor is removed.
Thyroid hormones.Thyroid hormonescase hyperglycemic(diabeto-
genic) effect via an increasein absorptionof glucosefrom the intestine.
The hormonesalso cause(probably by patentingthe effects of catechol-
amines) some degreeof hepaticglycogendepletion.Thyroid hormones
may also acceleratethe degradationof insulin. All these actions havea
hyperglycemiceffectand may leadto p-cellexhaustion.
Adrenalglucocorticoids . Glucocorticoidsfrom the adrenalcortexelevate
bloodglucoseandproducea diabetictypeof glucosetolerancecurve.They
stimulategluconeogenesis by the liver, sometimesproducing a 6- to 10-
fold increasein hepaticglucoseproduction.

This results mainly from two effects of cortisol:

1) cortisol increasesthe enzymesinvolved in conversionof aminoacids

into glucoseby the livercells;
2) cortisol causes mobilizationof aminoacidsfrom the extrahepatic
tis-
sues,mainlyfrom muscle.

Cortisolalso causesa moderatedecreasein the rate of glucoseutiliza-

tion by most cells in the body. Boththe increasedr.ateof gluconeogenesis
andthe reductionin glucoseutilizationby the cellscausethe bloodglucose
concentrationto raisethat in turn stimulatessecretionof insulin.The in-
creasedplasmalevelsof insulin.howeverare not as effectivein maintaining
plasmaglucoseas they are under normalconditions.Excessivelevelsof
glucocorticoidsreducethe affinity of insulinreceptorsin manytissues, es-
peciallyin skeletalmuscleandadiposetissuethat in turn decreasescellular
uptakeand utilizationof glucose.In predisposedpersons,the prolonged
elevationof glucocorticoidhormonescan leadto hyperglycemiaand the
Pathophysiologyof metabolism Unit 4 1303

developmentof adrenaldiabetes.Glucosetoleranceis reducedin 80 % of

patientswith Cushing's syndrome, and 20 % of thesepatientshavefrank
diabetes .
Growthhormoneantagonizes the effectsof insulin. It decreasescellular
uptakeand use of glucose, therebyincreasing the levelof blood glucose.
Growthhormonemobilizesfreefatty acidsfrom adiposetissue, thusfavoring
ketogenesis. It decreasesglucoseuptakeintosometissues,increaseshepatic
glucoseoutput, andmaydecreasetissuebindingof insulin.Growthhormone
alsodecreases the numberof insulinreceptorsanddecreases glucoseutiliza-
tion by inhibitingglucosephosphorilat ion. Growthhormonedoesnot stimu-
late insulinsecretion, but hyperglycemia it producedsecondarilystimulates
the pancreasandmayexhaustthe B-cells.
Chronichypersecretion of growthhormone,as occursin acromegal y, can
leadto glucoseintoleranceandthe developmentof diabetes.

Alterationsin hormonalcontrolof bloodglucose can resultseither hy-

perglycemiaor hypoglycemia. Insulinexcessleadsto hypoglycemi
a. Insulin
deficiencyas well as an excessof counter-regulatoryhormone(catechol-
amines, glucocorticoids
, thyroidhormones, andgrowthhormone)causehy-
perglycemia.
Hyperglycemia is definedas a plasmaglucoselevelsexceedingthoseof
normal.

Two princip a l mech a nisms involv e d in hyp e rglyc e -

mia de velopm e nt ar e:

1) reducedentryof glucoseinto cells (decreasedperipheralutilization);

2) increasedliberationof glucoseinto the circulationfrom the liver (in-
creasedhepaticglucogenesis).

Themostcommoncauseof hyperglycemia is absoluteor relativelackof

insulinthatoccursin diabetesmellitus.
 3041 Part I Generalpathophysiology

Diabetes me llitus
The constellationof abnormalitiescausedby insulin deficiencyis called
diabetesmellitus (OM). The term diabetesderivesfrom the Greekword
meaning"going through" and me/litusfrom the Latin word for "honey"
or "sweet". The disorder was first describedin the first century AD as
a chronic affectioncharacterizedby intensethirst and a large volumeof
honey-sweeturine. Diabetesmellitus is commonin humans,althoughit
can occur in other species.Strainsof mice, rats, guineapigs, miniature
swine,and monkeysthat havea high incidenceof spontaneousdiabetes
mellitus havebeendescribed.
In humans, insulindeficiencyis a commonandseriouspathologiccondi-
tion. The worldwideprevalenceof OM has risendramaticallyoverthe past
two decadesandnowit occursin morethan5% of the population.Themeta-
bolic disregulationand hyperglycemia associatedwith OMcausesecondary
pathophysiologic changesin multiplyorgansystemsof whichthe mostcom-
mon are proliferativescarringof the retina(diabeticretinopathy),renaldis-
ease(diabeticnephropathy) , lossof nervefunction(diabeticneuropathy),and
acceleratedatherosclerosis. The atherosclerosisleadsto circulatoryinsuffi-
ciencyin the legs,with chroniculcerationandgangrene,andto an increased
incidenceof strokeand myocardialinfarction.With an increasingincidence
worldwide,diabetesmellituswill bea leadingcauseof morbidityandmortal-
ity for the foreseeable
future.

Defin ition and c lass ification

Diabetesmellitusis a syndromeof impairedcarbohydrate, protein, andfat
metabolism resultingfrom eitherlackof insulinsecretionor decreased sensi-
tivity of the tissuesto insulin. '
Chronichighbloodglucoselevel,or hyperglycemia, is the hallmarkof dia-
betesmellitus.The hyperglycemia of OM resultsfrom etherthe insufficient
secretionof insulinby p-cells of the isletsof Langerhans or the inabilityof
secretedinsulinto stimulatethe cellularuptakeof glucosefrom the blood.
Pathophysiologyof metabolism Unit 4 13 05

Althoughdiabetesmellitus clearly is a disorderof insulin availabilityit

probablyis not a singledisease.Diabetesmellitusis classifiedon the basis
of the pathogenicprocessthat leadsto hyperglycemia into two broadcatego-
ries:type 1 andtype2 diabetes .
Type1 OMresultsfrom pancreaticp-celldestructionwhich leadsto ab-
solute insulin deficiency.Type1 diabetesusuallydevelopsbeforeage 40,
althoughit can occur at any age,and it is characterizedby loss the ability
to secreteof insulin with eventualabsenceof insulin in the circulation.
Hence,it is also calledjuvenilediabetes,and insulin-dependentdiabetes
mellitus(/DOM).
Type2 OMresultsfrom insulinresistance(i.e.reducedsensitivityof target
tissuesto the metaboliceffectof insulin)causingrelativeinsulin deficiency
Type2 diabetesis far morecommonthantype 1, accountingfor about90 %
of all casesof diabetesmellitus.It usuallydevelopsafter age40 and is not
associated with absoluteinsulin deficiency.Therefore
, this syndromeis often
referredto as maturity-onsetdiabetes,and non-insulin-d ependeddiabetes
mellitus(NIOO M).
Thereis table16 belowthat includesmaindifferentialcriteriaof type 1 and
type2 diabetesmellitus.

Table16. Criteriaof type1 andtype2 diabetes

mellitus
.
,

,
-:... e~,. ,--
.~--.
No
,
. Tjpe1 . ~· ·-Type2
·. , ·,
2 Pathogenesis
• Autoimmune destruc - • Notassociated withauto-
tionof p-cells immuneprocesses
• Notassociated withpri- • Primaryinsulin resistance
maryinsulinresistance • Relative
insulindeficiency
• Absolute insulindefi-
ciency
3 Plasmainsu
lin • ln~ulin is virtuallyab- • Oftennormalor elevated
levels sent • Rare decreased
4 Metabolic • Commonly complicated • Lowriskof ketoacidosis
disorders byketosis andacidosis
 3061 Part I Generalpathophysiology

Table16. Criteria of type1 and type2 diabetesmellitus.

.. ' .,
,. /~ .,,·◄~•t; •;;·.\,,,IY
No Type1 'Type2 '
..
:- V•
, .. ., ' .
. ·- _.

1 Etiology • Geneticpredisposition• Stronggenetic predisposi-

+ environmental factors tion (concordancerate is
(triggeringevent) 90-100 %)
♦ Associated withHLA • Notlinkedto HLAantigens
markers • Over80 % of type2 diabet-
• Occursin youngper- icsareobese(triggering
sons . .. event)
• Develops afterage40

Type 1 d iabetes

Etiologyof type 1 diabetes

Type 1 diabetesmellitusdevelopsas a result of synergeticeffectsof genetic,
environmental , andimmunological factorsthat ultimatelydestroythe pancre-
atic p-cells. In type 1 OM, the concordance rateis about50%, indicatingthat
an environmental factoras well as a geneticpredispositionis involved.Cer-
tain inherited humanleukocyte antigens (HLA-OR4 and/or DR3) arestrongly
associatedwith the development of type1 diabetes .Environmentalfactorsin-
cludehypothetically viruses(coxsackie andrubellamostprominently)bovine
milk proteins,andnitrosoureacompounds . .
In animals, insulindeficiencycanbeproducedby the administrationof al-
loxan, streptozocin , or othertoxinsthat in appropriatedosescauseselective
destructionof the p-cells of the,pancreaticislets, by drugsthat inhibitinsulin
secretion,andby administrationof anti-insulinantibodies.

Pathogenesisof type 1 diabetes

It now appearsthat in individualswho havegeneticpredispositionindi-
catedby the HLApattern, a triggeringeventthat is environmental
, initiates
 Pathophysiologyof metabolism Unit 4 f 307

formationof antibodiesagainstisletcells,andthe resultinginfiltrationof the

isletswith lymphocytes("insulitis")leadsovera periodof yearsto the loss of
p-cellsandfrankdiabetes.
Thelackof insulindecreases the entryof glucoseinto various"peripheral"
tissuesand increasesthe liberationof glucoseinto the circulationfrom the
liverthat resultsin hyperglycemia. Thehigh bloodglucosecausesmoreglu-
coseto filter into the renaltubulesthancan be reabsorbed , and the excess
glucosespills into the urinecausingglucosuria.Therenalthresholdfor glu-
cose, i.e.the plasmalevelat whichglucosefirst appearsin the urinein more
thanthe normalminuteamounts,is about200mg/diof arterialplasma,which
correspondsto a venouslevelof about180 mg/di. Whenthe blood glucose
level risesto 300 to 500 mg/di - commonvaluesin peoplewith untreated
diabetes- 100 or moregramsof glucosecanbe lost into the urineeachday.
· Theveryhighlevelsof bloodglucose(sometimesas highas 8 to 10 times
normal)cancauseseverecell dehydratation throughthe bodybecauseof the
increasesosmoticpressurein the extracellular fluids. In additionto this, the
loss of glucosein the urinecausesosmoticdiuresisresultingin extracellular
dehydratation.
Thus, po/yuria(excessiveurine excretion) , intracellularand extracellular
dehydratation, and polydipsia(increasedthirsts) are classicsymptomsof
diabetes.
Type1 diabetesis a catabolicdisorderin whichcirculatinginsulin is virtu-
ally absent; glucagonlevelis elevated , and pancreaticp-cellsfail to respond
to insulinproducingstimuli. Oneof the actionsof insulinis the inhibitionof
lipolysis(i.e., fat breakdown)and releaseof free fatty acids (FFA)from fat
cells.In the absenceof insulin,theseFFAare releasedfrom the fat cellsand
convertedto ketoacidsin the liver.Theshiftfrom carbohydrate to fat metabo-
lism in diabetesincreasesthe releaseof the keto acids, suchas acetoacetic
acidandp-hydroxybutyric acid,intotheplasmamorerapidlythantheycanbe
takenup andoxidizedby thetissuecells.As a result, the patientsdevelopse-
veremetabolicacidosisfrom the excessketo acids(ketoacidosis).Kussmaul
respiration(i.e., rapid and deepbreathing)that occursas a compensatury
responseto the acidosis,and a fruity odoron the patient'sbreathcausedby
increasedacetoneareclassicsingsof the disorder.
 Generalpathophysiology
3081 Part I

Ketoacidosis in associationwith dehydratation

causedby excessiveurine
formationcanleadrapidlyto diabeticcomaanddeathunlessthe conditionis
treatedimmediatelywith largeamountof insulin.
Failurein the useof glucosefor energyleadsto increasedutilizationand
decreasedstorageof proteinas well as fat. Therefore
, the patientswith un-
treatedOMhaverapid weightloss and asthenia(lackof energy)in spite of
increasedappetiteandeatinglargeamountsof food (polyphagia).

Type 2 diabetes
Etiologyof type2 diabetes
Type2 diabetesmellitushasa stronggenetic,or at leastfamilial,component.
Whenone identicaltwin developstype 2 diabetesthe other almostinvari-
ablydnes(i.e. the concordance rateis closeto 100%). Insulinresistance, as
demonstrated by reducedglucoseutilizationin skeletalmuscle,is presentin
manynondiabetic, firs-degreerelativesof individualswith type2 OM.In con-
trast to type 1 diabetes,type 2 diabetesis not associatedwith HLAmarkers
or autoantibodies. Majorgenesthat predisposeto this disorderhaveyet to
be identified,but it is nowclearthat the diseaseis polygenicandmultifacto-
rial. Environmental factorssuch as nutritionand physicalactivitymodulate
phenotypicexpressionof the disease.Almostall patientswith type2 diabetes
areoverweight,andthe presenceof obesityis importantconsideration in the
development of this form of the disease.

Pathogenesis of type2 diabetes

Type 2 OM describesa conditionof fasting hyperglycemiathat occurs
despitethe availabilityof insulin.In contrastto type 1, type 2 diabetesmel-
litus, is associatedwith increasedplasmainsulinconcentration , i.e. hyper-
insulinemia.This occursas a co'mpensatoryresponseby pancreatic~-cells
for diminishedsensitivityof targettissuesto the metaboliceffectsof insulin,
a conditionreferredas to insulin resistance.Insulin resistanceimpairsthe
peripheralglucoseutilizationandstorage,raisingbloodglucoseandstimu-
latinga compensatoryincreasein insulinsecretionwith resultanthyperin-
 Pathophysiologyof metabolism Unit 4 f 309

sulinemia.In time, the insulin responseby the p-cells declines becauseof

exhaustion.
The development of insulinresistance andimpairedcarbohydratemetabo-
lism begins with excessweight gain and obesity,the most important risk
factorfor type2 diabetes.The mechanisms that link obesitywith insulin re-
sistancearestill uncertain . Somestudiessuggestthat obesepatientshavea
reduced numberof insulinreceptors , especiallyin the skeletalmuscle, liver,
andadiposetissue,andthe numberof insulinreceptorsincreaseswith weight
reduction,aswellastheirglucosetoleranceis restoredto or towardnormalif
theyreduce.Therefore, it hasbeenhypothesized that individualswhodevelop
type 2 diabetesovereat,with consequentincreasedstimulationof insulin
secretion,and the elevatedplasma insulinlevelscause down regulation on
the receptors.In addition, adipocytessecretea numberof biologicproducts
. (leptin,TNF-a, FFA,and others)that modulateinsulin secretion,insulinac-
tion, andbodyweight,andmaycontribute to the insulin resistance .
Thus, the decreased abilityof insulinto act effectivelyon peripheraltarget
tissues(especially muscleandliver)is a prominentfeatureof type 2 OMand
resultsfrom a combinationof geneticsusceptibilityandobesity.Insulinresis-
tanceimpairsglucoseutilizationby peripheraltissuesand increaseshepatic
glucoseoutput, botheffectscontributeto the hyperglycemia. Becausepeople
with type2 diabetesdo not havean absoluteinsulindeficiency, they are less
proneto ketoacidosisthanthe peoplewith type 1 diabetes .
Therealso is evidenceto suggestthat insulinresistancenot only contrib-
utesto the hyperglycemia in personswith type2 diabetes , but also mayplay
a rolein othermetabolicabnormalities. Insulin resistanceis partof a cascade
of disordersthat is oftencalledthe "metabolic syndrome " or"syndrome X".

Th is includes:

1) obesity,especiallyvisceralor central (asevidenced

bythehip-waistratio);
2) insulinresistance;
3) fasting hyperglycemia;
4) lipid abnormalitiessuchas highlevelsof plasmatriglycerides;
310 I Part I Generalpathophysiology

5) hypertension;
6) coronaryheartdisease;
7) abnormalfibrinolysis.

So to s um up th e clinic a l signs of OM a re:

• hyperg lycemia - increaseglucosein blood

• glucosuria - excretionof glucoseexcessfrom the organismwith urine
(if glucoselevelin bloodincreasemorethan9 mmol/L)
• polyuria- increasequantityof excretedurine
• polydipsia - increaseliquidconsumption(thirst)
• hyperphagia - increasefoodconsumption(polyphag ia)
• hyperl actatac idemia- increaselacticacidandotheracidic metabolites
in blood
• hyperketonemia - increaseketonicbodies(productsof disturbedlipid
metabolism)
• ketonuri a - excretionof ketonicbodieswith urine
• hyperlipidemia - increaselipidslevelin blood
• hyperazotem ia - increaselevel of nitrogenin blood
• hyper azoturia- excretionof nitrogenexcesswith urine
• changeof bodymass.

Generalcharacteristics
of types1 and2 OMdemonstrated
in table 17.

Metabolic d isorders in diabetes mellitus

Metabolicdisordersin type1 andtype2 diabetesmellitus havemanygeneral
features.This is becausethe causeof OMis alwaysa deficiencyof the action
of insulinon peripheraltargettissue(absolute insulin deficiencyin type1 and
relativeinsulindeficiencyin type 2 OM). Thedisorderof insulinavailability
leadsto thefundamental defectsto whichmostof the biochemical abnormali -
ties can betraced,whichare (1)reducedentryof glucoseinto peripheraltis-
 -0

Table17. General
characteristics
of types1 and 2 diabetesmellitus ~
0
-0
=r
-<
(/)
a·
0
<O
< 30 yr
Mostcommonly -<

Associated
obesity No Ver/common
--
0

3
~
Propensity
to ketoacidosis Yes No O"
Q.
v;·
development 3

us insulin I Extremely
Plasmalevelsof endogeno lowto undetec
table Variable:
maybelow,norma l, orelevated
depending onthedegreeof insulin
resistance
andinsulinsecretory defect

Associated
withspecificMHC I Yes No
proteins
Isletcellantibodies
at diagnosis Yes No
Isletpathology lnsulitis,
selective
lossof mostbeta Smaller
, norma
l-appear
ingislets
cells
Proneto developdiabetic Yes IYes C
complications (retinopathy, ::::J
nephropathy, neuropathy, r-T

.t,..
atherosclerotic
disease)
cardiovascu
lar
- u)
Treatment Insulininjections I Oralantihyperglycemic
drugs I I .....
.....
 312 I Part I Generalpathophysiotogy

suesand(2) increasedliberationof glucoseintothecirculationfrom the liver.

This is thereforean extracellular glucoseexcess(i. e., hyperglycemia) and, in
manycells,an intracellularglucosedeficiency,a situationthathasbeencalled
"starvation in the midstof plenty".
Themechanisms of hyperglycemia development in diabetesarethefollow-
ing. things.
1. Decreased peripheral utilizationof glucosewhichis basedonthefollow-
ing things.
a. Reduced entryof glucoseintocell.Insulincontrolstheentryof glucose
intoinsulin-sensitivetissuesbycausingtranslocation of glucosetrans-
porter GluT4 in the cell membranes. Therefore,in insulin deficiency,
theentry of glucoseintoskeletal , cardiac
, andsmoothmuscle(in both
type1 and type2 DM)andintofat (in type1 DM)tissuesis decreased.
b. Reducedsynthesisof glycogenin the liverandsceletalmuscle.This
is becausethat insulin deficiencyleadsto a decreasein activityof
glucokinase(hexokinase) with the resultant decreasein G-6-P syn-
thesis as well as to inhibitionof glycogensynthaseactivity.·
c. Decreasedactivity of glycolysis(Embden-Meyerhofpathway)and
hexosemonophosphate shunt( directoxidativepathway) .This is due
to inhibitionof activity of key enzymesinvolved as well as due to
deficiencyof G-6-Pwhichresultfrom insulindeficiency.
d. Decreased activityof Krebscycleenzymesin the liver and skeletal
muscle;
2. Increasedliberationof glucoseinto the circulation from the liver.

Derangement of the glucostaticfunction of the liver is the majorcauseof

hyperglycemia in diabetes.Thelivertakesup glucosefrom bloodstreamand
stores it as glycogen, but becausethe.liver containsenzymeglucosephos-
phataseit also dischargesglucoseinto bloodstream . Insulindoesnot affect
the movementof glucoseacrossthe membranes of hepaticcellsdirectly, but
it facilitatesglycogensynthesisand inhibits hepaticglucoseoutput. Insu-
lin suppressesthe synthesisof keygluconeogenic enzymesand inducesthe
synthesisof keyglycolyticenzymessuchas glucokinase. Glycogensynthase
activityis alsoincreased.Theseeffectsaremissingin diabetes .
 Pathophysiology of metabolism Unit 4 I 313
Glucagonalsocontributesto glucoseoutputby the liver by increasingthe
activityof enzymesinvolvedin gluconeogenesis as well as it suppliesthe
synthesisof glucose"de nova" with substratesby activatinglipolysisand
inhibiting proteinsynthesis.
Effectsof hyperglycemia . Hyperglycemia by itself can causesymptomes
thatresultfrom the hyperosmolarity of the blood.In addition, thereis glucos-
uriabecause the renalcapacityfor glucosereabsorptionis exceeded . Glucos-
uriain turn entailsthe lossof largeamountsof water(i.e., osmoticdiuresis)
andan appreciab le urinarylossof sodiumandpotassiumas well. Theresult
is dehydrationleadingto polydipsia , hypovolemia,hypotension , and shock
development.
Glucosebeginsto beusedfor the synthesisof somesubstanceswhichare
normallyproducedin smallquantities . Thereare activatedalternative path-
~ ways of metabolismfor synthesiscomponentsof the groundsubstanceof
the connectivetissues, such as sorbitol, hyaluronicacid and glycoproteins.
Excessquantityof this componentsaccumulated in the intimaof smallves-
selsandin futureleadsto the development microangiopathyas (Fig.34).
Whenplasmaglucoseis episodicallyelevatedovera periodof time, small
amountsof hemoglobinare nonenzymatically glycosylated.Controlof OM
with insulinreducesthis level,thereforethe concentration of glycosylatedHb
is measuredclinicallyas an integratedindexof diabeticcontrol for the 4-6
weekperiodbeforethe measurement.
The plethoraof glucoseoutsidethe cells in diabetescontrastswith the
intracellular deficit. Glucosecatabolismis normallya major sourceof en-

..----- -• Sorbitol(CNS,
lens} Manifestations:
• microangiopathies

i Glucose

.__ __
Hyaluronic
(aorta
acid
, kidneys,
... Glucoproteines
retina
)
• neuropathies
• nephropathies
• retinopathies
(capilaries,retina
} • cataract

Fig.34. Carboh
ydrate
meta
bolismchanges
indiabetes
mellitus
 314 I Part I Generalpathophysiology

ergy for cellularprocesses . Becauseof intracellular glucosedeficiency,in

diabetesenergyrequirementscan be met only by drawingon protein and
fat reserves.Mechanismsareactivatedthat greatlyincreasethe catabolism
of protein andfat, and one of conseguences of increasedfat catabolism is
ketosis. Glycogendepletionis a common consequence of intracellular glu-
cose deficit, andthe glycogencontentof liverandskeletalmusclein diabetic
animalsis reduced .
Changesin fat metabolism.Principa l abnormalitiesof fat metabolism
in diabetesare accelerat ion of lipid catabolism, accumulationof acetyl-CoA
whichbeginsto be usedfor the excesssynthesisof ketone bodiesand cho-
lesterol (Fig. 35). Themanifestationsof the disorderedlipid metabolismare
so prominentthat diabeteshas beencalled"morea diseaseof lipid than of
carbohydratemetabol ism". If 30-40 % of an ingestedglucoseload is nor-
mallyconvertedto fat in the fat depots,in insulindeficiencylessthan5 % is
done. Therefore , glucoseis accumulated in the bloodstream and spills over
into the urine.
Insulin inhibitsadiposecell lipase, and, in the absenceof this hormone ,
the plasmalevelof freefatty acids is increased.Theincreasedglucagon also

Cholesterol
Lipogene
sis .----- - (Atherosclerosis)
Marcoangiopathi es
Fats, Fattyacids Acetyl-CoA
Lipolysis
Ketoneacid
.__ __ _,. Oxibutyric acid
Acetone
Manifestations:
(Ketoacido sis)
• hyperlipemia K_
reb's cycle
• hypercholesterolemi
a
• hyperglycemia
• ketonemia
• ketonuria

Fig.35. Lipidmetabolism
changes
in diabetes
mellitus
Pathophysiologyof metabolism Unit 4 I 315
contributesto the mobilizationof FFA.In the liverandothertissues, the fatty
acidsare catabolized to acetyl-CoA. Someof the acetyl-CQAis burnedalong
with aminoacidsto CO2 andH20 in thecitric acidcycle.However,the supply
exceedsthe capacityof the tissuesto catabolizethe acetyl-CoA . Theexcess
acetyl-CoA is convertedto ketonebodies. In uncontrolleddiabetes,thereis
an increasein the plasmaconcentration of triglyceridesandchylomicronsas
well as FFA,and the plasmais oftenlipemic. In the absenceof insulin, the
riseof theseconstituentsis duemainlyto decreased removalof triglycerides
into fat depots. Thedecreased activityof lipoproteinlipasecontributesto this
decreased removal.
In diabetes , the plasmacholesterollevelis usuallyelevated, andthis plays
a rolein theaccelerated developmentof the arterioscleroticvasculardisease
that is a majorlong-termcomplication of OM.The risein plasmacholesterol
levelis dueto an increase in the plasmaconcentrationof very low density
lipoproteins(VLDL) andlow densitylipoproteins(LDL), whichmaybedueto
increas edhepatic productionof VLDLor decreased removalof VLDLandLDL
from thecirculation.
Changes in proteinmetabolism. Whensufficientglucoseand insulinare
present,proteinbreakdownis minimalbecausethe bodyis ableto useglu-
coseandfattyacidsasfuel source.Insulinincreases activetransportof ami-
noacidsintocellsandincreases proteinsynthesisby increasingtranscription
of messengerRNAandacceleratingprotein synthesis by ribosomalRNA. It
alsodecreasesproteinbreakdownbyenhancingthe useof glucoseandfatty
acidsas fuel. In diabetes, these effectsare missing.Thereis thereforehype-
raminoacidemia, negativenitrogenbalance , and increasedureaexcretion.In
diabetes, accelerated proteincatabolism to CO2 and H20 and to glucoseas
well as diminishedproteinsynthesisleadto proteindepletionand wasting.
Proteindepletionis associa ted with poor resistanceto infections, and the
sugar-rich fluids are undoubted ly goodculturemedia for microorganisms.
This is probablywhy diabetics are particularlyproneto bacterialinfections .
In diabetes, the increasein proteincatabolism is accompanied by the release
of potassiumandotherintracellular electrolytes intothe bloodwith theircon-
sequentloss in urine. The processis especiallymarkedin skeletalmuscle
causingmyasthenia.
 316 I Part I Generalpathophysiology

Acute comp licat ions of d iabetes mel litus

Thethreemajoracutecomplicationsof diabetesmellitusare diabeticketo-
acidosis (OKA),hyperglycemic hyperosmolar state(HHS)andhypoglycemia .
OKAmostcommonlyoccursin personswithtype1 diabetes; HHSis primarily
seenin individuals withtype2 OM.Bothdisordersareassociated withabsolute
or relativeinsulindeficiency , volumedepletion,andacid-base abnormal ities.
Diabetic ketoacidosis is characterized by hyperglycemia (bloodglucose
level> 250 mg/di (13.9 mmol/1),ketosis, and metabolicacidosis(pH < 7.3;
low bicarbonate). Hyperglycemia leadsto glucosuria,volume depletion, and
tachycardia. Hypotension canoccurbecauseof volumedepletionin combina-
tion with periphera l vasodilatation . Mostof the hydrogenions liberatedfrom
ketoneacids are buffered, but severemetabolicacidosis still develops.The
low plasmapH stimulatesthe respiratorycenter,producingthe rapid, deep
respirationdescribedby Kussmaulas "air hunger" andnamed,for him, Kuss-
maul breathing . Finally, the acidosisand dehydratation depressconscious-
nessto the point of coma,namedketoacetonemic coma.OKAis the com-
monestcauseof earlydeathin clinicaldiabetes.
Hyperg/ycemic hyperosmolar state is characterizedby hyperglycemia
(bloodglucose> 600 mg/di (33.3 mmol/1),hyperosmolarity (plasmaosmo-
larity > 31O mOsm/1),dehydratation , andabsenceof ketoacidosis . It is seen
mostfrequentlyin personswith type 2 OM.A relativeinsulindeficiencyand
excessivecarbohydrateintakeare underlyingcausesof hyperglycemia that
precipitatesthe condition. Insulindeficiencyincreaseshepaticglucose pro-
duction(via gluconeogenesis and glycogenolysis) and impairsglucoseuti-
lizationin skeletalmuscle.Hyperglycemia inducesan osmoticdieresis that
leadsto intravascularvolumedepletion.The blood g·lucosecan be eleva ted
to sucha degreethat independent on plasmapH, the hyperosmo larity of the
plasmacausesconsciousness.This is· becausethat the increasedosmotic
pressurein the extracellular fluids causesosmotic transferof waterout of the
cells, includingbrain cells.The resultant intracellulardehydratationin turn
leadsto mentalconfusion,lethargy,or coma,namedhyperosmolaric coma.
Hypoglycemia , sometimesreferredto as an insulin reaction,occurs from
a relativeexcessof insulinin the bloodandis characterized by below-normal
Pathophysiologyof metabolism Unit 4 I 317
bloodglucoselevels.Hypoglycemiaoccursmostcommonlyin peopletreated
with insulin injection,but it also can result from some oral hypoglycemic
agents(i.e.,~-cells stimulators),alcohol,insuloma,andothers.
Becausethe brainrelieson bloodglucoseas its essentialenergysource,
hypoglycemia producedbehaviorsrelatedto alteredcerebralfunction.Al-
though insulin is not necess ary for the use of glucoseby the brain, high
levelsof insulincausesbloodglucoseto fall to low valuethat metabolismof
the centralnervoussystembecomesdepressed . Hypoglycemiausuallyhasa
rapidonsetandprogressivesymptoms.
At the onsetof the hypoglycemicepisode, activationof the parasympa-
thetic nervoussystemoftencauseshunger, sweating , and paresthesia. The
initialparasympathetic responseis followedby activationof the sympathetic
nervoussystem;this causespalpitations, tremor, anxiety, andconstrictionof
the skinvessels (i.e., the skin is pale, coolandclammy).
Apartfrom causingautonomicresponse s, hypoglycemia is responsiblefor
neuroglycopenic symptomsthat are a direct result of centralnervoussys-
tem neuronalglucosedeprivation.Theseincludefatigue, headache , difficulty
in problemsolving, disturbedor alteredbehavior , seizure,and coma.If the
hypoglycemia is prolonged , irreversiblechanges develop, and deathresults
from depressionof the respiratorycenter.
Sometimes , it is difficult by simpleclinicalobservationto distinguishbe-
tween diabetic(ketoacetonemic) and hypoglycemic coma. The acetone
breath andKussmaul 's respirationof diabeticcomaare not presentin coma
due to hypoglycemia.The most effectivetreatmentof an insulin reaction
is the immediateingestion of a concentrated carbohydrate source, such as
sugar,honey,candyor administrationof concentratedsolutionof glucose
intravenouslywhenthe personhavingthe reactionis unconscious or unable
to swallow.
Comasarethe mostseverecomplications of diabetesmellitus.There are
differenttypesof comas: 1) hyperglycemic; 2) hypoglycemic ; 3) hyperosmo-
lar; 4) hyperlactata cidemic.
Hyperglycemic comausedto be a causeof death 70% of patientswith
diabetesmellitusin pre-insulin era.Insulin insufficiencyplays the mainrole
in its pathogenesis . It is characterized by expressedhyperglycemia(>20
 318 I Part I Generalpathophysiology

rnmol/1). progressivedehydrationof the organism(waterloss up to 10% of

bodymass), ketoacidosis with a typicalsmellof acetonefrom the mouth. In
responseto thedisturbanceof thehomeostasis, thehypothalamo-hypophysi -
al-adrenocortical systemis activatedandthe secretionof catecholamines and
glucocorticoidsis intensified, which only aggravateshyperglycemia and ke-
toacidosis.Patientsdevelopinhibitionof CNStill completelossof conscious-
nessand depressionof reflexes.Kussmaul 's respirationis observedwhich
is consideredto be a sign of the last possibilityto compensate metabolic
acidosis.But it only increasesaggravatedehydrationof the organismbe-
causeof waterlosswith exhaledair; arterialpressuredecreases. Tachycardia
accompanied by disturbanceof myocardi al excitability(extra-systolia)rises.
Microcirculation is disturbed in .differentorganswhich may leadto anuria.
Principlesof pharmacological correctionconsistin insulininjectionsfor nor-
malizationof metabolicprocessesandwater-salineexchange, eliminationof
toxicosis,dehydration , metabolicacidosis.
Hypoglycemic comais the mostcommoncomplicationof insulintherapy.
It may developif the glucoseintakedoesnot matchthe treatment.The pa-
tient maybecomeagitated,sweaty,andhavemanysymptomsof sympathetic
activationof the autonomicnervoussystemresultingin feelingssimilarto
dreadand immobilizedpanic.Consciousness can bealtered,or evenlost, in
extremecases, leadingto comaand/or seizuresor evenbraindamageand
death. In patients with diabetesthis can be causedby severalfactors, such
as too much or incorrectlytimed insulin,too much exerciseor incorrectly
timedexercise(whichdecreases insulinrequirements) or not enoughfood or
insufficientamountof carbohydrates in food. In mostcases, hypoglycemia is
treatedwith sweetdrinksor food. In severecases,an injectionof glucagon
(a hormonewith the oppositeeffectsof insulin)or an intraveno us infusionof
glucoseis usedfor treatment,but usuallyonly if the diabeticis unconscious.
Hyperosmolar comais observedduring decompensative currentof dia-
betesmellitus.It is characterized by high concentrationof glucose,Na, Cl,
bicarbonates , urea, ammoniain blood;the levelof ketonicbodies is usually
normal.Clinics:the disturbanceof consciousness; the absenceof acetone
smell from the mouth; frequentsuperficialbreath,short breath;tachycar-
diaandheartratedisturbances. Theprinciplesof pharmacological correction
Pathophysiologyof metabolism Unit 4 I 319
consistin re-hydration , restoring water-salinebalancein the organism, the
decreaseof hyperglycemia .
Hyperlactatacidemic comais a rare complicationof diabetesmellitus
andis observedin elderlypeoplesufferingsevereaccompanying diseasesof
the liver, kidneys,heartandlungs.As a resultof predominance of anaerobic
oxidationof glucosein tissuesof thesepatients,the concentrationof lactic
acidin bloodincreases , the reservealkalinityof blooddecreases.Thepatient
developsexpressedacidicconditionwith lossof consciousness , Kussmaul 's
respiration , dehydration, hypotonia,oligo-andanuria.Principlesof pharma-
cologicalcorrectionconsistin obligatoryinjectionof alkalinesolutionsintra-
venouslyfor the restorationof pHof blood.In severecaseshaemodialy sis is
necessary.

C hroni c comp lications of diab ete s me llitus

Chronicelevationof bloodglucoselevel leadsto damageof bloodvessels. In
diabetes , the resultantproblemsaregroupedunder"microvascular disease"
(dueto damageto smallbloodvessels)and"macrovascular disease"(dueto
damageto the arteries).
Thedamageto smallbloodvesselsleadsto microangiopathy whichcauses
thefollowingorgan-related problems.
• Diabeticretinopathy,growthof friable and poor-qualitynewbloodves-
selsin the retina, whichcanleadto severevisionlossor blindness.Reti-
nal damage(from microangiopathy) makesit the mostcommoncause
of blindnessamongnon-elderlyadults.
• Diabeticneuropathy,abnormaland decreasedsensation , usuallyin a
stockingdistributionstartingat the feet but potentiallyin othernerves.
Whencombinedwith damagedbloodvesselsthis can leadto diabetic
foot. Otherforms of diabeticneuropathymaybe presentas mononeuri-
tis or autonomicneuropathy .
• Diabeticnephropathy, damageto the kidneywhichcan leadto chronic
renalfailure,eventuallyrequiringdialysis.Diabetesmellitusis the most
commoncauseof adultkidneyfailureworldwide.
 320 I Part I Generalpathophysiology

Macrovascular disease leads to cardiovascular dis-

ease, mainly by accelerating atherosclerosis:

• Coronaryartery disease,leadingto myocardia l infarction("heart at-

tack") or angina
• Stroke(mainlyischemic type)
• Peripheralvasculardiseasewhichcontributesto diabeticfoot.

Diabeticfoot, oftendueto an overlapbetweenneuropathyandarterial dis-

ease, maycausenecrosis, infectionand gangrene.It is alsothe mostcom-
moncauseof the amputation,usuallyof toesandfeet.
Diabeticcardiomyopathy is thoughtto resultfrom manyfactors,includ-
ing epicardialatherosclerosis , hypertension andleft ventricularhypertrophy ,
microvasculardisease , endothel ial andautonomicdysfunction , obesity, and
metabolicdisturbances . Patientsdevelopheartfailuredueto the impairment
in leftventricularsystolicanddiastolicfunctionandaremorelikely to develop
heart failureafterMl.
Infection: Diabeticsareproneto bacterialandfungalinfectionsbecauseof
adverseeffectsof hyperglycemia on granulocyte
andT-cellfunction.Themost
commonaremucocutaneous fungalinfections(e.g, oral andvaginalcandidia-
sis) andbacterialfoot infections(includingosteomyelitis) , whicharetypically
exacerbated by lowerextremityvascularinsufficiency anddiabeticneuropathy.

Ot he r sp eci fic typ es of diabet es .

Thereis a categoryof other specific types of diab.etes, formely knownas
secondarydiabetes,in whichhyperglycemia occurs secondaryto othercon-
ditions(e.g.,Cushing'ssyndrome , pancreatitis,andacromegaly).Endocrine
disordersthat producehyperglycemia do so by increasingthe hepaticpro-
ductionof glucoseor decreasingthe cellularuseof glucose,but theyare not
primarilyassociatedwith insulindeficiency.
Gestationaldiabetesmellitus(GDM)refersto glucoseintolerancethat is
detectedfirst during pregnancy.In pregnancy , the fetoplacenta
l unit induc-
Pathophysiologyof metabolism Unit 4 I 321
es majormetabolicchanges,the purposeof which is to shunt glucoseand
aminoacidsto the fetus while the mother uses ketonesand triglycerides
to fuel her metabolicneeds.Thesemetabolic changes are accompanied
by materialinsulin resistance, causedin part by placentalproductionof
counteregulatoryhormones(e.g., steroids, growth hormonevariant) that
in turn increasesinsulin requirementsand may leadto impairedglucose
tolerance.

Ge neral princ iples of phar m aco logica l correction

and prev ention of diabetes mellitus.
Treatmentof OM involvescontrol of hyperglycemia to improvesymptoms
.andpreventcomplications whileminimizinghypoglycem ic episodes
.
Keyelementsfor all patientsare patienteducation, dietaryand exercise
counseling,and monitoringof glucosecontrol.All type 1 diabeticsrequire
insulin. Type2 diabeticswith mildlyelevatedplasmaglucoseshouldbe pre-
scribeda trial of diet andexercise followedby a single oral antihyperglyce-
mic drug if lifestylechangesareinsufficient , additionaloral drugsas needed
(combinationtherapy),andinsulinwhenmorethantwo drugsareineffective
for meetingrecommended goals.
No treatmentsdefinitelypreventthe onsetor progressionof type 1 OM.
Earlytype 1 OMin somepatientsmaybe preventedby suppressionof auto-
immunebetacell destruction.
Type2 OMusuallycanbeprevented with lifestylemodification.Weightloss
of as little as7 % of baselinebodyweight, combinedwith moderate-intensity
physicalactivity(e.g.,walking30 min/day), mayreducethe incidenceof OM
in high-riskindividualsby > 50 %.
Patientswith impairedglucoseregulationshouldreceivecounselingad-
dressingtheir risk of developing OMand the importanceof lifestylechang-
es for preventingOM. Theyshould be monitoredcloselyfor the develop-
ment of OMsymptomsor elevatedplasmaglucose;idealfollow-up inter-
vals havenot beendetermined , but annual or biannualchecksare probably
appropriate .
 322 I Part I General pathophysiology

Chapter 14. Pathophysiology

of Lipid Metabolism. Atherosclerosis

Fatplays a very importantrole in the organism. Fatis a sourceof reserve

energy,its suppliesare 10 %. Also fat is a source of endogenous metabolic
water.Fatparticipatesin heatproductionandheatsaving.
Humanfat tissuecontainsabout87 % lipids. Thereare three chemical
substancescomposedof long-chainhydrocarbonfatty acids (triglycerides,
phospholipids, and cholestero l), which are classified as lipids, most impor-
tant for the development of dyslipidemias in a humanbody.
Becausecholesterolandtriglycerideare insoluble in plasma,they areen-
capsulatedby special fat-carryingproteinscalledlipoproteins for transport
in the..blood.Therearefive typesof lipoproteins classifiedby their densities
as measuredby ultracentrifugation: chylomicrons (ChM),very-low-density
lipoprotein(VLDL), intermediate-density lipoprotein(IDL), low-density lipo-
protein (LDL), andhighdensitylipoprotein(HDL).
Eachtype of lipoproteinconsistsof a large molecular complexof lipids
combinedwith proteinscalledapoproteins . Thereare four majorclassesof
apoproteins:A (A-I, A-11,andA-IV), B (B-48, 8-100), C (C-I, C-II, andC-III),
and E. The apoproteinscontrolthe interactions.and ultimatemetabolic fate
of the lipoproteins.The majorapoprote in in LDLis B-100. HDLis associated
with A-I andA-II.
Researchfindingssuggestthat geneticdefectsin apoproteinsmaybe in-
volvedin hyperlipidemiaandacceleratedatheroscl~rosis . LDL,sometimes
calledthe badcholesterol , is the maincarrier of cholesterol.HDL is synthe-
sizedin the liver and often is referred_to as the good cholesterol. HDL par-
ticipatesin the reversetransport of cholesterol, that is, carryingcholesterol
from the peripheraltissuesbackto the liver. Epidemiolog ic studiesshow
an inverserelationbetweenHDLlevelsandthe developmentof atheroscle-
rosis.
 Pathophysiology of metabolism Unit 4 1323

Main disorders of the lipid metabolism may be di-

vided into the following groups:

1) hyperlipidemias;
2) atherosclerosis, arteriosclerosis
;
3) obesity;
4) fatty infiltrationanddystrophy(liverandsomeotherorgans), fatty de-
generation.

Hyperlipidem ias and hyperch o les tero lemia .

Normalycholesterolparticipatesin constructionof the cellularmembrane
- andconsequently in its permeability;beingthe dielectricit providesthe con-
ductionof impulsesin the definitedirection(structuralcomponentof myelin
in nervossystem);the corticosteroids , sex hormones , bile acids, vitaminD
areformedfrom cholesterol.
Whenhigh levelsof cholesterolare presentin the blood, hypercholester-
olemiadevelops.It is not a diseasebuta metabolicderangement that canbe
secondaryto manydiseasesand cancontributeto manyforms of disease ,
mostnotablycardiovascular disease.
Hypercholesterolemia canbeclassifiedas primaryor secondaryhypercho -
lesterolemia.
Primaryhypercholesterolemia describeselevatedcholesterollevelsthat
developindependen tly of otherhealthproblemsor lifestylebehaviors .
Secondary hypercho/esterolemia is associatedwith otherhealth problems
andbehaviors.
Manytypes of primaryhypercholesterolemia havea geneticbasis. There
maybea defectivesynthesisof theapoproteins,a lackof receptors,defective
receptors, or defectsin the handling of cholesterolin the cellthat are geneti-
callydetermined.
Forexample, the LDLreceptoris deficientor defectivein the geneticdisor-
derknownas familial hypercholesterolemia (typeIIA). This autosomaldomi-
 324 I Part I Generalpathophysiology

nant typeof hyperlipoproteinemia resultsfrom a mutation in thegenespecify-

ing the receptorfor LDL.
Causesof secondaryhyperlipoproteinemia includeobesitywith high-calo-
rie intakeanddiabetesmellitus. High-caloriedietsincreasethe production of
VLDL, with triglycerideelevationand highconversionof VLDLto LDL.
Hypercholesterolemias are classifiedwith hyperlipidemiasaccordingto
the Fredricksonclassificationwhich is basedon the patternof lipoproteins
on electrophoresis or ultracentrifugation.It was lateradoptedby the World
HealthOrganization (Table18).

Table18. Fredrickson
classification of hyperlipidemia
s

Typeof Synonyms
hypeFlipidemia
.
TypeI (rare) Buerger
-Gruetzsyndrome, Decreased lipoprotein Chylomicrons
Primaryhyperlipoproteinaemia,
lipase(LPL)or altered '
or Familial ApoC2
hyperchylomicronemia
TypeIla Polygenic LDLreceptor LDL
hypercholesterolaem
ia or deficiency
Familialhypercholesterolemia
Typellb Combined
hyperlipidemia Decreased LDL LDLandVLDL
receptorandincreased
ApoB
TypeIll (rare) Familial
dysbetalipoproteinemia
DefectinApoE2 IDL
synthesis
Type
IV Familial
hyperlipemia Increased
VLDL . VLDL
' and
production
Decreasedelimination
TypeV (rare) Endogenous Increased
VLDL VLDLand
hypertriglyceridemia production
and Chylomicrons
DecreasedLPL
 Pathophysiologyof metabolism Unit 4 1325

Arteriosclerosis is a chronicdiseaseof the arterialsystemcharacterized

by abnormal thickeningand hardeningof the vesselwalls. Smoothmuscle
cellsandcollagenfibersmigrateintothetunicaintimacausingit to stiffenand
thicken;this decrea sesthe artery's abilityto changelumensize.
Atherosclerosis is a type of arteriosclerosis or hardeningof the arteries.
Thetermatherosclerosis, whichcomesfrom the Greekwordsatheros(mean-
ing "gruel" or "paste") and sclerosis(meaning "hardness "), denotesthe for-
mationof fibro-fattylesionsin the intimal lining of the largeand medium-
sizedarteriessuchas the aortaand its branches , the coronaryarteries, and
the largevesselsthat supplythe brain.Ofthese, the coronariesarethe most
commonlyaffectedarteries
Atherosclerosis cantakeseveralformsdependingon the anatomicvessel
location,the individual 's age, geneticand physiologicstatus, and the risk
~ factorsto whicheachindividualmayhavebeenexposed . It is the leadingcon-
tributorto coronaryarteryandcerebrovascular disease.Lipiddepositionis an
earlyeventin atherogenesis andoccurs with excessiveinfluxanddeposition
of macrophages containingoxidizedlow-densitylipoproteins(LDL)into the
arterial wall.This eventoccurssubsequently to endothelialinjury.Thelesions
of atherosclerosis occur primarilywithinthe tunicaintimaor the innermost
layer.Theselesionsincludethe fatty streak,fibrous plaque, andcomplicated
lesion.Theearly fattystreakis a flat, yellow, lipid-filled smoothmusclecell
thatcauseslittle or no obstructionof the affected vessel.
Fibrousplaqueis the characteristic lesionof advancingatherosclerosis and
consistsof lipid-ladensmoothmusclecells surroundedby a fibrous matrix.
Thelesionis elevatedandprotrude s into the lumenof the artery.Thecoreof
the fibrousplaqueconsistsof lipidsanddebrisfrom cellularnecrosiscaused
byinsufficientbloodsupply.If the lesionprogresses sufficiently, it occludesthe
arteriallumenat arterialbifurcation,curves,or regionswherethearteriestaper.
Complicated lesionsoccur as the fibrous plaque s are alteredby hemor-
rhage, calcification, cellularnecrosis , andbloodclots throughoutthe intimal
layer.Asthe alteredcomplexstructure becomesrigid, it causesexJensive vas-
cularocclusion.Highblood pressuredevelopsif arteriosclerosiselevatessys-
temicvascularresistance . Cerebralor myocard ial ischemiais a life-threatening
manifesta tionof atheroscleros is thatoccursin thevesselsof the brain or heart.
 3261 Part I Generalpathophysiology

Etiology.As it is well-knownthereare manyvariousrisk factorswhich

predisposeto atherosclerosis.

Th e m a in of t he m are th e follow ing:

1. Age. Cholesterolis a productwhich is difficult to metabolize. A lot of

cholesterolis containedin 8-lipoproteins(70-75 %),and 8-lipoproteins
areincreasedin elderlypersons.
2. Hereditarypredisposition.Theseare the dataaboutfamilialhypercho-
lesterinemiawith high levelLDL and VLDL("atherogenous", "worse"
cholesterol)
3. Hypodinam ia and hypoxiapredisposeto atherosclerosis becausethey
decrease the oxidationof lipidsandpromotetheiraccumulation with the
consequent events- infiltration, proliferation,degeneration
with calcifi-
cation,cellularnecrosisandprogressingscleroticprocesses .
4. Stress. It is provedthat neuro-emotional overtensionmayleadto disor-
derstrophycityof the wall of the vesselsdueto decreaseresistanceto
injuriousfactor.
5. Overeating especiallywith usingfattyanimal's origin.
6. Intoxicationby alcohol,smoking,microbes,chemicalmaterials.
7. Hormonaldisturbancesas hypothyroidism,hypogonadism, Cushing's
syndrome.
8. Pathologyof the liver.
9. Diabetesmellitus.
10. Gout,obesity, xanthomatosis , hereditaryformsof hyperlipoproteinemia
andhypercholesterinemia.

Pathogene sis is basedon lhe metabo lism disturbanceswhich lead to

hyperlipemia,hypercho lesterinemiaand hyperbetalipoproteinemia.HDL is
a-lipoproteids containinga lot of proteinand few lipids, and possessesthe
antiatherogenous influence.Theyprovokea reversetransportof cholesterol
fromthe cells,vessels,liverandpromoteits excretionfromthe organismin a
form of biliaryacids.
 Pathophysiologyof metabolism Unit 4 1327

LDL- VLDL- are lipoproteinswith low and very low densitycontaina

few proteinsanda lot of lipids. LDLPandVLDLParethe atherogenous, they
promotethe accumulation of cholesterolin thewall of thevessel.
Hypertension, inflammatory processes inthevascularwall,formationof LP-
lgGautoimmune complexes promotethesclerosisof thevascularwall.It leads
to thedisturbance of receptor-mediated captureof LDLPandtransformation of
macrophages intothefoamycells,which arethe baseof lipidspots.Thenthe
fibrouspatchesareformed, calcification andthrombogenesis arein progress.
Atherosclerosis is a reactionof the connectivestructures of the aortaand
largearterieson fallingout of cholesterolin to the subendotheliun. Athero-
sclerosisdoesn't happenwithoutcholesterol.Pathogenesis may be divided
into somestages.
I stageis thedepositionof lipidswhichleadsto the irritationandprolifera-
- tion of the histiocytes.
II stageis xanthomatosis with activationof histiocytes, than captureof
lipids and irritation of fibroblastswhichleadsfor thickeningof the suben-
dothelium , deformationof the elastictissueandconsolidationof theconnec-
tivefibers.
111 stage- patches,nutrientmaterialis receivedby histiocyteswith dif-
ficulty, necrosis.
IV stageis atheromatosis , formation of ulcers, whichcan perforateand
thrombimayformed.
Theclinicalmanifestations of atherosclerosis dependon the vesselsin-
volvedandtheextentof vesselobstruction.

Atherosclerotic lesions produce their effects

through :

• narrowingof the vesselandproductionof ischemia

;
• suddenvesselobstructiondueto plaquehemorrhage or rupture;
• thrombosisandformationof emboliresultingfrom damageto the ves-
selendothelium;
• aneurysmformationdueto weakening of the vesselwall.
 Generalpathophysiology
3281 Part I

Obes ity and overwe ight

Obesityis definedas a conditioncharacterized by excessbodyfat. Obesity
resultsfrom an imbalancebetweenenergyintakeandenergyconsumption.
Because fat is the mainstorageform of energy,obesityrepresents
anexcess
of bodyfat.

Overweightand obesityare determinedby measurements of bodymass

index(BMI;weight[kg)/height[m2]) andwaistcircumference.
A BMI of 25 to 29.9is consideredoverweight;
A BMIof 30 or greateris regardedas obese;
A BMIgreaterthan40 is regardedas very greator morbidlyobese.

Causes of obesity
Althoughfactorsthat leadto the development of obesityarenot understood,
they are thoughtto involvethe interactionof genotypeand environmental
factors, which includesocial,behavioral,cultural,with the physiology,me-
tabolism, andgeneticsof the individual.Obesityis moreoftenmetin women
in the age groups older than 50 years old. In the economicallydeveloped
countries,obesityamongtheadultpopulationis.metin 30-60%andthe body
massby 20%exceedsthe norm.
Twotypesof obesitybasedon the distributionof fat havebeendescribed:
upperbodyandlowerbodyobesity .
Upperbodyobesityis alsoreferredto as central , abdominal, or maleobe-
sity. Lowerbody obesityis knownas peripheral,gluteal-femoral, or female
obesity. Theobesitytype is determinedby dividingthe waistby the hip cir-
cumference.
In general,menhavemoreintra-abdominal fat andwomenmoresubcu-
taneousfat. As menage,the proportionof intra-abdominal fat to subcutane-
ous fat increases.After menopause , womentendto acquiremorecentralfat
distribution.Increasing weight gain, alcohol,and low levelsof activityare
associatedwith upperbodyobesity.
Pathophysiology
of metabolism Unit 4 1329

Etiology . Obesityis the resultof disorderof homeostasisof energyex-

change . Internalfactors,whichchangethe behaviorof menasto the nourish-
ment, takepart in its appearance . Thesefactorsaredeterminedby genetical ,
constitutionalpeculiaritiesof the person,andalsoby the influenceof the en-
vironment.Thelatterincludesmother's nutritionin pregnancy , child'sfeeding
in baby'sageandearlychildhood,typesof unconditionedreflexesconnected
with nutrition;family and nationaltraditions, the levelof well-off and avail-
abilityof food; motor activity.Increasedconsumptionof food is one of the
basiccausesof obesity. Primarydisturbances of neurohormonalregulation ,
changesof adipocyticmetabolismor geneticfactorsare rarelythe causeof
obesity.The primary(constitutional)- 55-65 %, secondary(symptomatic)
and cerebral(16-20 %) obesityare distinguishedby etiology.The role of
heredityin obesityis important.The structureand functionof the systems,
which regulatethe alimentarybehavior,peculiaritiesof adipocyticand myo-
cytic metabolismcan be inherited.It is observedthat obesitydevelopsin
somegenerations of the samefamily.
Pathogenesis. Threebasicpathogenetic factorsareimportantin tile devel-
opmentof obesity:increasedintakeof foodwhichdoesn't correspondto the
energyexpenditures; insufficientmobilizationof fat from the depots; surplus
formationof fat from carbohydrates.
Thesurplusconsumptionof food,whichis provokedby increasedappetite,
can be stipulatedby increasedexcitabilityof the "nutritionalcenter" which
is situatedin the anteriolateralnucleiof the posteriorhypothalamicregion.
The changes , to which the nutritionalcenteris reacting, can be the cause
of prolongednutritionalexcitationandas a resultof alimentaryobesity.So,
all stateswhichdecreasethe levelof glucosein blood (for example , some
increaseof the functionof the pancreaticislands)are accompaniedby the
feelingof hunger,whichstipulatesthe possibilityof overeating.Thesignals
from the receptorsof the alimentarytractarealsoimportantin activityof the
nutritionalcenter.A definitedegreeof extensionof the stomachinhibitsthe
activityof the nutritionalcenter.In the decreaseof sensitivityof the nervous
endingsin the wall of the stomach, the inhibitiondevelopsonly in exces-
siveextensionof the stomach,diet alsocreatespreconditionsto overeating
andobesity. Disbalance of energyis possiblein transitionfrom the physical
 330 I Part I Generalpathophysiology

labourto thewayof lifewithoutphysicalloadingif theformerdegreeof excit-

ability of the nutritionalcenteris preserved.Obesitycan be connectedwith
the disturbanceof fat mobilizationfrom fat depotsas a sourceof energyin
normalfunctionof die nutritionalcenter.
The regulationof processof mobilizationanddepositionof fat is accom-
plishedby the nervousandendocrinesystems.So,the decreaseof thetonus
of the sympatheticnervoussystemcanprovokethe delayof mobilizationand
goingout of fat from the adiposetissue.Disturbanceof mobilizedfat influ-
enceof hormonesis observedin pathologyof the pituitary,thyroidgland, ad-
renalandsexualglands.Obesity,whichis characterized by hyperinsulinism,
resistanceto insulinand hyperglycemia, can be observed.It is considered
thatbasicdamagesareat the levelof targetcells.Theyareconnectedwith de-
creaseof quantityof receptorsfor insulin stipulatingthe resistance to insulin
andcompensatory hyperinsulinism.
Nowthepeculiaritiesof theadiposetissue,quantityandsizeof fattycells -
adipocytesaretakeninto accountin pathogenesis of obesity.Thequantityof
the adiposecells is geneticallystipulatedfactorandtlleir sizedependon the
age,sex, influenceof the regulatoryand metabolicfactors.Quantityof the
adiposecells is relativelyconstantand doesn't changewith age.It is more
in womenthan in men.Thequantityof the adiposecells in youngpeopleis
3x1010, contentsof fat in the adipocyteare 0.6 mcg,total quantityof fat in
the organismis about18 kg.Therearecasesof obesitywith total quantity of
fat morethan 70 kg, in normalquantityof adipocytes,howeverthe massof
onecell is 1.6 mcg. In othercases,the massof adipocytesremainsnormal
andtheir quantityreaches9 x 1010 . Totalquantityof fat canbeequalto 100
kg andmore.
Bythis criterionpathogenetical classificationof obesityis describedwhich
is basedon theconnectionbetweensizeandquantityof adipocytes. Thisclas-
sificationincludestwo typesof obesity:hypertrophicandhyperplastic.
Hypertrophicobesitydependson the quantityof fat in eachadipocytethat
is connectedwith increasedconcentrationof insulin,hyperlipemiaand de-
creaseof the toleranceto glucose.Not infrequentlythis form of obesityis
complicatedby the development of atherosclerosis and diabetesmellitusat
youngage.
Pathophysiologyof metabolism Unit 4 I 331
Hyperplastic obesityis connectedwith the increaseof quantityof adipo-
cytes, whichdependson the geneticfactorsor the environmentregulating
themorphogenesis of theadiposetissuein theembryonicperiodandat early
age.
Overwe ight and obesityhavebecomenationalhealthproblemsin many
countries,increasingthe risk of hypertension, hyperlipidemia , type 2 diabe-
tes, coronaryheartdisease , andmanyotherhealthproblems.
Thenegativeinfluenceof obesityis manifestedin less degreeat young
age,whenadaptational possibilitiesare expressedbetter.And the quantity
of complicationsconnectedwith obesityincreaseswith age.The mortality
of peoplewith obesityat 20-24 yearsold 30 % higherthanin personswith
normalbodymass,and it is by 50% higherin personsof 40-55 yearsold.
Theprolongedobesityprovokesa numberof functionalchangesin thevitally
tmportantorgansandalsothedisturbanceof metabolismin connectionwith
depositionof largequantityof fat and increaseof the loadingon most of
vitallyimportantorgans. Firstof all the metabolismin the adiposetissueis
disturbed , wherethe speedof synthesisof triglyceridesand lipoproteins is
increased, abilityto mobilizationof theadiposereservesis disturbed,hyper-
lipemia, increaseof freefatty acid level, hypercholesterinemia is observed .
Disturbances in carbohydrate metabolismaremanifestedin the limitation of
glucosemetabolism,increaseof glycogencontentin the liver. Utilizationof
glucoseis impaired in the musculartissuein spiteof hyperinsulinism . Res-
piratorycoefficient,equalto 0.7-0.74, is evidencethat fatty acidsare used
as a sourceof energy.
Deposition of fat in the myocardium decreases significantlythe contractile
functionof the heart.Obesityis oftenaccompanied by atherosclerosis, in-
creaseof thearterialpressure , bloodcoagulation anddevelopment of throm-
bosis.Thepulmonaryventilationis deteriorated , vital capacityis decreased
andpredisposition to the congestionanddevelopment of chronicinflamma-
tion in the respiratorytractsappear.Dyspnoearisesevenin small physical
loading.Thecirculatoryandrespiratoryhypoxiasappear.
Combination of obesitywith diabetesmellitusarisesin the caseof insulin
resistance connected with decrease of the numberof receptorsto insulinon
thesurfaceof the adiposecells.
 332 I Part I General pathophysio
logy

Compensatory hypertrophy andhyperplasia of the pancreatic islands pro-

viding the increasedsecretionof insulin (hyperinsulinism)for overcoming
resistance,is followedby exhaus tion. In this caseit is supposedthat obesity
is the etiologicalfactorof diabetesmellitus.
A moreactivelifestyletogetherwith a low-fat diet (< 30% of calories)is
seenas the strategyfor prevention obesity.Toolsneededto achievethis goal
includepromotionof regular meals, avoidanceof snacking , substituting wa-
ter for calorie-containingbeverages , decreased televisionviewingtime, a low-
fat diet, andincreasedactivity. Otherexpertstargetthe high-riskperiodfrom
25 to 35 years, menopa use,andthe yearaftersuccessfulweightloss.

Fatty infiltration and dyst rophy of liver

Th e cause of fatty degeneration of the liver can be

a ny disturbance which disintegrates the exchange
a nd synth e sis of lipids in the liver:

1) increasedhepaticlipogenes is;
2) decreaseof oxidation of fatty acids;
3) increasedlipolysisof the adiposetissue; .
4) delayof secretionof lipoproteins(VLDLP)of verylow density.

Combinationof lipid andproteinsynthesisis necessary for the production

of VLDLPin the liver andtheir disturbanceleadto the accumulationof fat in
the liver. Insufficientnourishmentanddeficiencyot aminoacidsdisturb the
synthesis of apolipoproteidsand decreasethe productionof lipoproteids.
Thesameresultis observedin the adiposetissue in the starvationor diabe-
tes mellit us. Disturbanceof theformationof phospholipidsalsoveryimpor-
tant in the pathogenesis of adiposeinfiltration.Sufficient contentsof them
in the liver securethe thin dispersion of fat and helpsin its excretion from
the liver. Phospholipidsarepresentin the compositionof ~-lipoproteinsand
maketheir goingout from the hepaticcellseasy. Some of fatty acidspartici-
Pathophysiologyof metabolism Unit 4 1333

patein theformationof phospholipidsandleavethe liverwith them.Besides ,

the fatty acidsare oxidatedbetterin a moleculeof phospholipids.Choline
and methionine , whichgivetheir methylicgroupsfor the formationof cho-
line, are the necessarycomponentsof basichepaticphospholipid-lecithin.
So the deficiencyof choline,methionineand other lipotropicsubstancesin
fool leadsto the developmentof the adiposeinfiltration of the liver. The
deficiencyof endogenouslipotropicfactor - lipocaine- leadsto the same
result.Lipocaineactivatesthe formationof phospholipids in the liver,oxida-
tion of fatty acidsin it andpreservesthe liverfrom obesity.Theinsufficiency
of the factor is importantin the pathogenesis of hepaticobesityin diabetes
mellitus.

Chapter 15. Pathophysiology

of Water and Salt Metabolism
Without water,life on Earthcouldnot exist.Thecellsof all multicellular ani-
malsnot onlycontainwaterbut arealsosurroundedby fluid, the internalen-
vironment.Thisfluid environmentis the connectinglink betweenthe external
worldandthe innerspaceof the cell; it carriesnutrients, disposesof wastes,
andcarrieshumoralmessages.
Thewatercontentof the bodyis normallyveryexactlyregulatedandis the
result of the waterbalance:that is, waterlossesmust continuouslybe bal-
ancedto matchwaterintakeandproduction .
The averagewater intake(2.5 Lid) consistsof drinks (roughly 1.1 Ud);
water in solid food (0.9 Ud); water of oxidationarising from metabolism
(0.5 Ud). In the mean,this is exactlybalancedby the water losses(also
2.5 Ud), whichon anaverageconsistof: the urine(1.5 Ud); waterlost in the
expiredair andfrom the skin (0.8 Lid); watercontainedin the feces0.2 Lid).
A waterdeficit resultsin thirst; this mechanismis underthe controlof the
thirst centerin the hypothalamus . Thirst is elicitedby an elevatedosmolality
of the bodyfluidsandby an increasedangiotens in II concentration
.
With an averagetotal water content of about 60 % (body weight =
100 %), roughly3/5 (40 % of body weight) of this water is in the cells
 3341 Part I Generalpathophysiology

(intracellularfluid,/CF)and2/5 (20 % of bodyweight)in the extracellular

space( extracellularfluid, ECF). Extracellularfluid containinginterstitial
water(15 %) and intravascularwater(5-7 %), andthe so-calledtranscel-
lular fluid. Plasmadiffers from the rest of the ECFchieflyon the account
of its proteincontent;the ICFdiffers considerablyin its ionic composition
from the ECF.

The intracellular fluid is presented in three condi-

tions:

1. Waterof the protoplasmaboundwith hydrophilicstructures.

2. Waterof attractionon the surfaceof the colloidstructures.
3. Capillarywater- in lacunasof the protoplasma - the mostmobile, rela-
tivelyfreewaterof the cells.

The intravascular fluid is bloodplasma.Oneof its importantfunctionsis

the formationof mediumfor normalvital activityof the cellularelementsof
blood.Thevolumeof bloodplasmacomposes3.5-6 % of the bodymassand
93 % of it is purewater.
The interstitialor intercellularfluid is the fluid of the extracellularandex-
travascularspace.It washesthe cellsdirectlyandby ion andmolecularcon-
tents it is closeto blood plasma(exceptproteincontents).This fluid is in
constantexchange with bloodplasmaso that approximately 20 litresof fluid
withthe dissolved substances comeintothe tissuesfromthe vesselsperday
and the sameamountreturnsinto the generalbloodflow and 3 litres of it
returnthroughthe lymphaticvessels.
The transcellularfluid is a specialfluid of the organism.It is relatedto
the digestivejuices, the content-ofthe tubulesof the kidney,cerebrospinal
fluids, etc.
In normalconditionsexchangebetweenbloodand interstitialwaterde-
pendsonly on interactionsbetweenhydrostatic(HP)andoncotic(OP)pres-
sure.Exchange betweenall volumesin pathological situationsdependsfrom
the changesin osmolality.
Pathophysiologyof metabolism Unit 4 1335

Th er e ar e two m a in rules of t he w a t e r e xch a ng e be-

tween th ree ma in sp a c e s :

1) changesin water-saltmetabolismbeginfrom bloodvolume;

2) watermovingin volume, whereconcentrationof salts morehigher.

If one usestheserules, it's veryeasyto understandthat if concentrations

of salts in the blood beginto increase, the water beginsto movefrom the
interstitialspaceto the blood and then from the intracellular spaceto the
interstitialvolume.If concentrationsof salts decrease,the water beginsto
movefrom blood to the interstitialspaceand when concentrationsof salts
decreasehere,the watercomesto the intracellularvolume.

Salt and water hor m o na l c on tro l

Withrareexceptions, the ICFandECFof the bodyhaveanosmolalityof around
290 mosm/kg H2O. However , the electrolytecompositionof the extracellular
fluids differs from that of the intracellularones.The cellularfluids contain
more ions of potassium(K·), magnesium(Mg2• ) , phosphates(HPO/ ) and
the extracellular fluids containmoreionsof sodium(Na•), chlorine(Cl· ), cal-
2
cium (Ca+), bicarbonates (HCO 3
").Theintakeof NaClor loss of watercauses
a rise in the osmolalityof the ECF.The oss of NaClcausesa decrea se of
osmolalityof the ECF .
TheosmolalityoftheECFhasto bestrictlycontrolled.Thisfunctionis shared
byosmoreceptors (mainlyin the hypothalamus), the hormoneadiuretin(ADH,
vasopressin), andthe kidneys,the targetorgans(Fig.36 andFig.37).
In stimulationof theosmoreceptors of the hypothalamus area(in increased
bloodosmolarity)as wellasvolumoreceptors of the left atrium(in decreased
bloodvolume),the releaseof vasopressin(ADH)by suproopticaland para-
ventricularhypothalamus nucleiincreases.Vasopressinintensifiesreabsorp-
tion of waterin the tubulesof the nephrons.
The stimulationof the receptorsof the adductingrenalarteriole(in the
reductionof the renalbloodflow andbloodloss)andsodiumreceptorsof the
 336 I Part I Generalpathophysiology

waterdeficit I
I

t Plasma
i
osmolarity J,Atrial
i I
I
I
I

pressure~ ..-: •_Thirst tAtrialpressure !Plasmaosmolarily

l '-------...::;.____,.
_ '"it:
;;~t,;,
t,.!Jtt·,.
_,;, . ,,y:
'
J
i,..-~--~----..J J

tWater
reabsorptiont
.~-◄-11--------J
"
' --------------
Urinevolume Urinevolume
reduced increased
(Ant
idiuresis) (Diuresis)

Fig.36.Water defic
it andwaterexcess
regu
lations

Saltexcess Saltctt,ftcit

t Plasmavolume
i i
Anglotensin
II
r ►
1
Renin,../ ..................
.,'
,.t
:' iI

: ,·
' I
:.l(..:,
______
,.,..
.......................
...........
........... ) I
~ I
x:1:
., ' iti . ~•'°
~- ....J:~
Saltexcretio
increases
n
I
a
I
Saltexcretion
I decreases
I

Fig.37. Saltexcess
andsalt deficit regulations
Pathophysiology
of metabolism Unit 4 1337

thick spot (maculadensa)of the juxtaglomerular complexof the kidneys(in

sodiumdeficiency)intensifiessynthesisand release,of renin.Theactivation
of the rennin-angiotensin systemleadsto proteolyticreleaseof angiotensinI
(AT I) andangiotensin II (ATII) (Fig. 38.).AngiotensinII hastwo maineffects.
1. AT II is the mostpotentvasoconstrictor substancein the organismand
actsdirectlyonthe arterioles . Theresultis a risein bloodpressure.
2. ATII stimulates therelease of aldosteroneintheadrenalcortex(secondary
aldosteronism) . Aldosterone increases Na+resorptionin thedistaltubule.

ol
Restoration
plasmavolume or
- -- - .ofblood,pressure

I Apettite
' forsalt

GFRandRBF
t Thirst secreted
Systemic
vasoconstriction

Saltandwater retention

Saltandwateruptake
increased

Fig.38. Roleoftherenin-angiotensin
system
inwater-salt
metabolism
regu
lations
 3381 Part I Generalpathophysiology

Thereductionof the extracellular fluid volumeandangiotensinstimulates

the centerof thirst situatedin the lateralportionof the hypothalamus.
Antidiureticand antinatriureticmechanisms are opposedby diureticand
natriureticones.The mainfactorsof thesemechanisms are: renomedullar
,
renalprostaglandins andatrial(fromthe heart)natriureticfactor(ANF,atrio-
peptide).ANFis producedin the cells of the atriumand it is peptideof 28
aminoacids.
It increasesdiuresisand natriuresis , relaxes the smoothmusclesof the
vesselsanddecreases the arterialpressure . Theamoutof ANFin the atrium
and its secretioninto the bloodincreasesunderthe influenceof the intake
of an excessiveamountof waterand commonsalt, distension of the atria,
increasedblood pressureas well as stimulationof a-adrenoreceptors and
receptorsof vasopressin.

Disturb ances in salt and water ho me os tasis

Disturbances in salt and water homeostasis may be

due to errors in:

• the waterandsalt balance(imbalancebetweenintakeandlosses);

• thedistributionbetweenplasma,interstitium,andintracellular
waterand
salt balance
;
• hormonalregulation .

It is acceptedto dividedisturbanceof water-electrolyte

metabolisminto
hypohydration(dehydration) and hyperhydration (retentionof water in the
organism).Dependingon the changeof osmoticconcentration(waterand
ratio),de-and hyperhydrationaresubdividedinto threekinds:isoosmolar ic,
hydroosmola ric andhyperosmol aric (Table19).
Pathophysiologyof metabolism Unit 4 1339

Table19. Classification
of disturbancesin salt andwaterhomeosta
sis
-,.,., ,,..
~

<, " • I· -.- ,. • :,, ·. u~

. J/lcr.'
li-Gh'
" ,it
[t~Ji;J~_r~;;,
I '
',
.._t;
-::.·
;.::\;.-,
i -~
..::•": .,,
'
. ·Hypohydration
' . . ·.

lsoosmotic
excess lsoosmotic
loss
(edemas)
Saltexcess(hyperosmotic) Waterdeficit
(hyperosmotic
)
Waterexcess(hypoosmotic) Saltdeficit
(hypoosmotic)

lsoosmotic hyperhydration (isoosmoticexcess)developsin clinicalsitu-

ationsthat lead to the activationof mineralocorticoids in the adrenalgland.
Moreoften,thereare heartfailure, nephrosis,acuteglomerulonephritis, de-
compensated cirrhosis.In all this pathologysecondaryaldosteronismdevel-
ops. In diseasesof the heartandkidneyssecondaryaldosteronismdevelopst
as a resultof rennin-angiotensinsystemactivation. In liver pathology,sec-
ondaryaldosteronismdevelopsbecauseof the decreaseof the degradation
of aldosteronin the hepatocytes . In isoosmoticexcess, osmolalitydoesnot
changeandECFaccumulate . Asaconsequence edemasdevelop,in heartdis-
eases- on the lowerextremities , in kidneysdiseases- on the face.
Edemais a typical pathologic process, which is characterizedby the in-
creasedamount of waterin the extracellu lar space.It is basedon water ex-
changedisturbancebetweenbloodplasmaandperivascular fluid.
Theclassificationof edemasby the origindividesedemason congestive ,
inflammatory, allergic, toxic, neurogenic,endocrine,edemain cachexia , etc.
Pathologicaccumulationof fluid in the serouscavitiesof the organism is
calledhydrops(ascites- in the abdominalcavity, hydrothorax- in the pleural
cavity, hydropericard ium- in the pericardium).
Severalprincipalpathogenicfactors of edemaare distinguished , they are
the following.
1. Positivewater balance(dysfunction of the kidneys, intake of large
amountof osmoticallyactivesubstances).
 340 I Part I Generalpathophysiology

2. Increasedhydrostaticpressuremainlyin thevenouspartof thevascular

flow (localvenoushyperemiaor systemiccongestionin cardiacinsuf-
ficiencyoccurmostcommonlyin congestiveheartfailureaffectingright
ventricularcardiacfunction).
3. Decrease of oncotic(colloid-osmotic) bloodpressure(hypoproteinemia,
hypoalbuminemia, hyperproteinuria in fasting,nephroticsyndrome,he-
paticinsufficiency) .
4. Increaseof colloid-osmoticpressurein the tissuedueto accumulation
of osmoticallyactivesubstances: electrolytes,proteins,productsof me-
tabol!sm(in inflammation,allergyandhypoxia).
5. Disturbance of waterexchangebetweenthe capillariesandtissues(was
describedin pathologyof microcirculation) .
6. Increasedpermeability of the capillaryvessels:
a) underthe influenceof the humoralfactors (histamine,serotonin,
. kinines, prostaglandins) ;
b) in dystrophyof the wallsof thecapillaryvessels(neurotrophic distur-
bances,fasting, hypoxia).
7. Disturbanceof lymphoutflow (mechanicor dynamiclymphaticinsuf-
ficiency).
8. Disturbance of the nervousandhumoralregulationof water-electrolyte
metabolism (disordersin the regulatorysystems) .

Hypoosmolaric hyperhydration (waterexcess)developsin acute renal

failure(in the stageof anuria),Parkhansyndrome(as a resultof ejectionof
the largeamountof vasopressininto the blood),excessiveADHsecretion,
infusionof glucosesolutions.It is characterizedby the increasedamountof
waterin the organismand decreasedosmoticpressurein the extracellular
sector, the waterbeginsto enterthe cells.Thesodium-potassium balanceis
chargedon eitherside of the membrane.Sodiumpassesinto the cellsand
henceits amountin the bloodplasmadecreases. K+goesout of the cellsinto
the extracellularsector. The persondevelops . headache , nausea
, vomiting,
convulsions,comaand,at last, death.
A morecommonsituationfor the development of the hypoosmolaric hy-
perhydrationanuricstageof acuterenalfailure.In this pathologywaterand
Pathophysiologyof metabolism Unit 4 I 341
salts in samequantitiesno excretedwith urineandbeginaccumulatedin the
organism.Butaftersometimewaterbeginprevalence on salts.Thisdevelops
becausein the tissuesnearhalf litter perday of metabolicwateris produced
andthe patientmaydrinksomequantityof watere. After 2-3 daysthereap-
pearsthe hypoosmolality state.Thefluid beginsto moveinto the cells and
a moredangero us consequences in this situationis cerebralswelling,which
mayleadto death.
Hyperosmolaric hyperhydration (salt excess) developsrarelyin drinking
salt (sea)water in extremesituations, infusion of hypertonicsaline,adre-
nal hyperactivityor steroidtherapy.As a result, the osmoticpressurein the
extracellularmediumincreasesand the fluid passesfrom the cells into the
intercellular space.Dehydration of the cellsdevelops.Butgraduallythe adap-
tationto saltwatermayappearandtheremaybe no seriousdisturbancesof
water-electrolyte metabolism. Sometimeshypervolemia appears.
Hypohydration (dehydration,hypohydria,exicosis)developsin the cases
whenoutputof waterexceedsits inputinto the oranism(negativewaterbal-
ance).It maydevelopin disturbanceof waterinput into the organisn(water
starvation , dysphagia , atresiaof the esophagus, comatouscondition, etc.) or
in its increasedloss (diarrhea,vomiting, blood loss, loss of fluid with exu-
date- burn, etc), aswell as in combinationof thesecombinations.In dehy-
dration, the extracellular fluid andsodiumionsare lost.
Dehydrationresultsin severeconsequences connectedwith a decrease
of the circulatingbloodvolume(hypovolemia) anda increaseof its viscosity
that maycauseseveredisturbanceof bloodcirculationandmicrocirculation ,
collapse.Theterm of the development of hypovolemia whichdependson the
abilityof bloodvolumecompensation is the criteriaof clinicalsituation hard-
ness.Forthis reason,a moreserioussituationis hypoosmolarichypohydra-
tion in whichwateroutcomesfrom the bloodandthe bloodvolumeis really
not compensated. In isoosmotichypohydrationcompensationit's possible
only by transcellutar fluid (neartwo bloodvolumes)and hard hypovolemia
may developmentafter 2-3 days of pathologydevelopment.A more com-
pensativesituationof hypohydrationis the hyperosmoticstatein which the
compensation of the bloodvolumemay developby the use of transcellular
andintracellularfluid. These two fluid volumesmaycompensatenearly5-6
 342 I Part I Generalpathophysiology

bloodvolumesandfor this reasonseverehypovolemia usuallydevelopsonly

after5-7 days.
Disturbanceof bloodcirculationresultsin the development of tissuehy-
poxiaandthe centralnervoussystemsuffersfrom it. It maybemanifestedby
the lossof consciousness, hallucinations, comatouscondition.Thefunctions
of the nervouscentres, respiratoryrhythmbecomedisturbedandbodytem-
peratureincreases . Alsothe decreaseof the arterialpressuremaybeaccom-
paniedby the impairmentof filtrationin thetubulesof the nephrons,oliguria,
hyperasotemia andnon-gasacidosis.
Compensatory reactionsariseas a responseto the developeddisturbanc-
es.So,hypovolemia andreductionof renalbloodflow promotehyperproduc-
tion of vasopressinand aldosterone.Reabsorbtion of waterand sodiumin
tubulesof the nephronsis intensifiedunderthe influenceof thesehormones.
/soosmolaric hypohydration (isoosmoticloss) is a rarevariantof distur-
bances , whicharebasedon proportiona l volumedecreaseof fluids andelec-
trolytes.This situationmaydevelopin acuterenalfailure(stageof poliuria),
vomiting,diarrhea,diuretictherapy,blood loss, burns,drainageof ~scites.
More commonpathologywhich may leadto isoosmotic loss is the second
poliuricstageof acuterenalfailure. In poliuria,the waterwith electrolytes
is excretedfrom the organismin high quantities(morethen 5 L/day). Be-
causethe loss of equalquantitiesof waterandsaltsdevelops,isoosmiaand
compensation maydevelopby the useonlyof interstitialfluid. Severehypov-
olemiamaydevelopafter2-3 days.
Hypoosmolaric hypohydration (saltdeficit)developsdueto diarrhea(most
importantdiarrheain cholera) , vomiting,sweating,adrenalinsufficiency,hy-
pokalemia, CNSlesions,salt-losingnephritis.
For example,in choleraloss of salts in diarrheamoreintensivethan wa-
ter. In this caseobservedsecondarymovementof the fluid in the organ-
ism: somepart of it comesinto the intracellularsectorthat is the osmotic
pressurein the extracellularmed,umdecreases. It is very importantthat real
compensation of bloodvolumeis not possibleI~mayleadto the increaseof
the degreeof the extracellularhypohydrationin the simultaneousdevelop-
mentof the intracellularedema.Hypovolemia maydevelopveryquicklydur-
ing somehours.
Pathophysiologyof metabolism Unit 4 1343

Hyperosmolaric hypohydration (waterdeficit)developsdueto the loss of

the fluid whichlackselectrolytes.Hyperosmolaric hypohydrationmaydevel-
op in diabetesinsipidus,livingfor a longtime withoutdrinkingwater, sweat-
ing, hyperventilation
, osmoticdiuresisin the chronicrenaldisease.
The increaseof osmotic pressurein the extracellularfluid involvesthe
movementof waterfrom the cells into the extracellularsector.Forthis rea-
son, the compensationof the bloodvolumeis very goodand severehypo-
volemiadevelopsonly after 5-6 days.Buttotal hypohydrationof the organ-
ism develops.Theelevationof osmoticpressureof the extracellular fluid and
dehydrationof the cells causesthirst, intensificationof proteinlysis, fever,
hallucinations,lossof consciousness , coma.

Chapter 16. Pathophysiology

of Acid-Base Balance
ThepHvalueis a logarithmicmeasureof the "effective"H· ion concentration
or H· activity,wherepH= - LoG[H]. ThepHvalueof the bloodaveragesabout
7.4. Exceptfor localdeviations(gastricjuice, urine),the pH is similar in all
fluids.A constantpH is of vital importancefor the organism;the molecular
form of the proteins,for example , andthus the normalstructureof the cell
constituentsis pH-dependent. Consequently, largerdeviationsfrom the nor-
mal leadto disturbancesin metabolism,in the permeabilityof membranes,
in electrolytedistribution, and so on. BloodpH valuesoutsidethe rangeof
6.8-7 .8 areincompatible with life.
Theconstancyof the pHvalueis maintainedby bufferswhichact by par-
tially neutralizing
the acidsandbases.
Themainbufferof the bodyfluids is the system

ForanygivenpHvaluein a solution,the concentration ratiofor eachbuffer

"base" to the correspon
ding buffer "acid" is fixed (Henderson-Hasselbalch
equation).
344 I Part I Generalpathophysiology

Four main bioch e mical buffer systems are present

in th e organism.

1. Hydrocarbonate buffersystemH2CO3 / NaHCO 3

= 1/20 maintainscon-
stantlypH in the plasmaof bloodandinterstitial fluid.
2. PhosphatebuffersystemNaH2PO4 / Na2HPO4 = 1/4. Participatesin the
regulationof theacid-baseconditionin the kidneys.
3. Haemog lobin bufferactsin erythrocytes .
The relatively acid HbO2 takesup less H+ ions (HbO 2 H-►H bO 2 + H+)and
gives up moreof them thanthe less acid desoxy-genated form of Hb.
Thus if Hb is oxygenated in the lungsto HbO2, H~ionsaresetfree.They
partially compensate for the rise in pH causedhereby the remova l of
respiratoryCO2.
4. ProteinbufferregulatesintracellularpH.

Also in re gulations of a cid - ba se b a lance physiologi-

cal buff e r systems take p a rt.

1. Respiratory systemis regulatedpH by the CO2 concentration. CO2 is pro-

ducedcontinuallyasanendproductof metabo lism, andits concentration
or partialpressure(pCO 2
) in thebloodis principally
controlledbythelungs.
2. Cardiovascular systemcontrolled pH by the regulationof bloodflow in
tissues.
3. Kidneysregulatedacid-baseballansby the excretionof NaH2PO4 (ac-
idogenesis),excretionof NH/ (ammoniogenesi~) , reabsorptionof bi-
carbonates(HCO 3
'). Most importanturinarybuffer is NH/ NHt This is
becausethe synthesisof NH/ NH/ (ammoniogenesis) in the tubulecells
is controlledby the acid-basestatusof the body. Acidosisstimulates
NH/ -productionfrom renalglutamate, whereasalkalosisstimulateshe-
paticureaproductionfrom hepatic glutamate.
4. Gastrointest inal tract regulatedpH by the secretionof acid and base
ions. In the stomachprevalence productionof acid ions andin the inte-
stinumbaseions.
Pathophysiologyof metabolism Unit 4 1345

Th e pH of pl a sm a a nd re d ce ll, a nd thu s of th e blo o d ,

ca n b e changed by a va rie ty of f ac tors :

• H+ions can be directly addedfrom metabolism(hydrochloricacid,

lacticacid,ketoacids,sulfuricacid)or they canbe removedfrom the
blood (by H• excretion by the kidneys, H• loss by vomiting);
• OH·ionscanbeaddedwiththe(basic)saltsof weakacids(vegetab lediet);
• the concentrationof CO2 canbe changedby a changein CO2 produc-
tion in metabolismor in CO2 expirationin the lungs. If the CO2 con-
centrationincreases,the pHvaluedrops.
• the bicarbonateconcentration[HCO3·] can changeprimarily due to
the excretionof HCO 3
· by the kidneys or HCQ
3
· lossesdueto diarrhea.
A rise in [HCO3· ] resultsin a drop in pH.

Classifications of disorders in ac id-base balance

Acidosis(acidaemia) is definedas a disorderwith pH in the arterialbloodless
than 7.35, and alkalosis(alkalaemiaor baseosis)is definedas a condition
with a pH largerthan7.45.
Eachof thesetwo disordershasrespiratoryand nonrespiratoryforms. The
nonrespiratoryform of acidosisis subdividedinto metabolicand excretory,
andthe metaboliconeis subdividedon lactoacidosisandketoacidosis.
Bythe levelof pHchangesacidosisandalkalosisdividedon compensative,
subcompensative,and decompensative (Table 20)

Table20. Classificationsof acid-basebalancedisorders

.
' -. ' ' --.~ ' ."'
...... ·.~
' ·~ . •'
~- ", - ' ' '

AcldllJI.,::.;. ..:,.,~•~
"."'
·~~-~, '.Ip
L.:s.:.
<I: .... ~
. .... ·
f,.i.• - • _i.;,;_j· .Alkalosls
7.35 Compensative 7.45
7.34-7.20 Subcompensative 7.46-7.55
7.19-6.80 Decompensative 7.56-7.80
 346 I Part I Generalpathophysiology

Humanscansufferfrom 4 mainacid-basedisorders:respiratoryacidosis,
nonrespiratoryacidosis,respiratoryalkaosis,nonrespiratory alkosis.
Respiratoryacid-basedisordersarecausedby primarychangesof pCO 2,
andcompensated by alteredrenalexcretionof acidin a matterof days.
Nonrespiratoryacid-basedisordersare causedby primary changesin
metabolicprocesses,and compensated partiallyby the lungsin a matterof
hours.Thefinal correctionof metabolicdisordersis alwaysrenalandtakes
severaldays.

1. RespiratoryAcidosis
Is causedby hypoventilation(or breathingof CO2 containingair). Hypoven-
tilationis associatedwith an impairedabilityto eliminateCO2, wherebypCO2
increasesandthe accumulated CO2 reducesthe arterialpH.
For eachmol of bicarbonateproduced , one mol of non-carbonicbuffer
baseis eliminated.
Any primaryrespiratorydisorderis compensated by the kidneysoverdays.
This is because the highintracellular[H+]increasesthe glutaminase synthesis
andactivity,therenalammoniaproduction, theurinaryH+-excretion (mainlyNH/
butalsoH2PO4-l, witha virtuallycompletereabsorption of filteredbicarbonate.

2. Nonrespiratory Acidosis
Nonrespiratory acidosisis causedby accumulation of strongacidsin the
extracellularvolume.Strongacidsaccumulate, becauseof excessproduction
(in metabolicacidosis)or impairedH+-excretion(in excretoryacidosis).
The lactictype of metabolicacidosisis causedby increasedlacticacid
productionduringexercise,shock,anoxiaor followir.gcardiacarrest.Another
type of lacticacidosisis causedby decreasedhepaticlactatemetabolism -
oftendrug-induced .
Ketotype of metabolicacidosisis causedby accumulationof ketoacids
in diabetesmellitus.In this situationactivation of alternativemetabolismof
acetyl-KoAleadsfor the excessproductionof the ketonebodies(acetone,
acetoacetic acid,andbeta-hydroxybutyric acid).
Sometimes high proteinintakewith increasedproductionof hydrochloric
andsulphuricacidmaycausea specificraretypeof metabolicacidosis.
Pathophysiologyof metabolism Unit 4 13 4 7

The excretorytype of acidosismay developin two situations.Impaired

renalH+excretionis relatedto increasedlossof bicarbonate in the urine(due
to renalfailure).Diarrheacausesacidosisby the lossof bicarbonate with the
faeces.Anylossof bicarbonate in the urineor faecesis equivalentto anaddi-
tion of H+to theextracellular
fluid.
Renaltubularacidosis is a damageof tubularcells causedby drugs or
immunologicalreactions,or sometimes it may be inherited.The impaired
H+secretionreducesthe tubularbicarbonatereabsorption.Kidneydisease
with the destructionof a large numberof nephronsreducesthe tubular
capacityto excreteH• and NH/ in the urine. Acid ions accumulatein the
blood.
The patientwith nonrespiratory (metabolic)acidosissuffersfrom dysp-
noea(deepand frequentKussmaul!respiration).This hyperventilation is a
respiratorycompensation whichdevelopsoverhoursas a reductionin pCO2 .
Thiscompensation is causedby the chemoreceptors, whichare surrounded
bytheextended extracellular
fluidandstimulatedby its hydrogenion concen-
trationto reactwith hyperventilation.
A patientwith metabolicacidosismaybetreatedwith bicarbonate infusion.
Thecorrectionof theprimarydisease(insulinto diabeticketoacidosis) mayin
itselfcuretheacidosisby combustionof ketoacidsto bicarbonate.

3. RespiratoryAlkalosis
Is causedby hyperventilation. The hyperventilation is disproportionately
high comparedto the CO2 production , wherebythe pCO2 falls and the pH
increases . Whenthe alveolarventilationis doubled , the pCO2 is halved.This
is a typicalreactionto high altitude.As the atmosphericpressurefalls with
increasing altitude,thepO2 eventually falls below55 mmHg,whichstimulates
the chemoreceptors to hyperventilation (CO2 -wash-out).
Othertypicalcasesarethe anxiouspatientduringan attackof asthmaor
the hystericalhyperventilation in neuroticpatients.Thesepatientsoftenexpe-
riencetetaniccramps.
Acuterespiratoryalkalosisis compensated by increasedrenalexcretion
of bicarbonate, which is the resultof decreasedtubularH• -secretion. This
is becausethe low pCO 2 reduces the tubularH•-secretion , andthe alkalosis
 3481 Part I Generalpathophysiology

inhibitsthe formationand secretionof NH/ . The renalmechanisms

takes
daysto becomeeffective.

4. MetabolicAlkalosis
Is causedrarelybya primaryaccumulation of strongbasesin the extracel-
lularvolume.
Vomiting(lossof gastricacid),increasedmetabolismof lactateandcitrate
(turns into bicarbonateand water),and excessiveintakeof basestowards
gastriculcercan causethis form of alkalosis.A long-termuse of thiazides
and loop diuretics,K·-deficiency,and excesssecretionof mineralocorticoid
increasethe H+-secretionin exchangefor Na• in the distaltubules.This in-
creasesrenalbicarbonatereabsorptionandalso mayleadsto metabolical-
kalosis.
Thehypoventilatory compensation reducespH,but raisespC02 . Thecom-
pensati.on is nevertotal. Thedelayedrenalcorrectionincreasesbicarbonate
excretionby reducingits reabsorption. Thefinal renalcorrectionof metabolic
disorderstakesseveraldays.

Chapter 17. Pathophysiologyof

Calcium and Phosphate Homeostasis
Calcium(Ca)and phosphorus(Ph) belongto the mostwidespread elements
of our organism.Calcium(above98 % ) and phosphorus(about86 %) are
mainlyfixedin bonesandteeth,from wheretheseelementscanbe mobilized
in caseof immediateorganismneeds.Metabolisms of calciumandphospho-
rus arecloselyconnected . ·
The role of calciumin the organismconsistsin the participationin bone
construction , transmissionof nervousstimulation , bloodclotting, regulation
of membranespermiability,interactionof actineand myosineof muscular
cells, enzymesactivation(actin-myosine-APTase, lecitinase,succynatde-
gidrogenase) andin the modulationof hormonesaction. Calciumplaysa criti-
cal rolein the regulationof cell functions.ThetotalCa2 • concentration in the
serumis normally2.3-2.7 mmol/L.
Pathophysiologyof metabolism Unit 4 1349

Phosphorus mainfunctionsareassociated with the growthand supportof

the integrityof bonesandteeth, Phrefersto highlyenergeticsubstances (ATP,
creatinephosphate) andphosphorilated intermediateproductsof carbohydrate
metabolism , it takespartin DNA,RNAandphospholipids construction,Phis the
componentof phosphate buffer. Thedailyintakeof phosphate is about1.4g, of
which0.9g areabsorbed and,onanaverage , alsoexcretedagainviathekidneys.
Normally , theserumphosphate concentration amountsto 0.8-1.4mmol/L.
Calciumphosphatehasa lowsolubility.If the productof the Ca2+ concentra-
tion andthe phosphateconcentration exceedsa certainvalue (solubility prod-
uct), calciumphosphate precipitates outof thesolution;in the livingorganism,
calciumphosphateis mainlydepositedin the bonesbut, in extremecases,in
otherpartsof the bodyaswell. If a patientis givenan infusionof a phosphate
solution,the Ca2+ concentration in the serumis loweredsincecalcium phos-
.phateis depositedin the bones(or evenin otherorgans)dueto the solubility
producthavingbeenexceeded.Conversely , a drop in the serumphosphate
concen trationleadsto hypercalcemia dueto releaseof Ca2• from the bones.
Calcium balanceis regulatedby three hormones : parathyrin(parathyroid
hormone, PTH), calcitonin(CT),and O-hormone(vitaminD, calcitriol).They
act mainlyon threeorgans:the intestine,the kidneys,andthe bones.General
mechanisms of calciumbalanceregulationshowedon figure39.
PTHis a peptidehormonewhich is formedin the parathyroidglands.The
parathyroidglandsare small endocrineglandswhosesole function is the
secretionof parathormon.Synthesisand releaseof the hormoneare regu-
latedby the concentration of ionizedCa2 • in the plasma. If it dropsbelowthe
normalvalue(hypocalcemia) more, PTHis releasedinto the blood,whereasa
risehasexactlythe reverse effect.

Parathyroid hormone serves to incr e ase blood con-

centrations of calcium . PH mobilizes blood calcium
by several major eff e cts:

• Stimulatesproductionof the biologically

-activeform of vitaminD within
the kidney.
 350 I Part I Generalpathophysiology

0.25-0.5 g. 0.25-o .5 g. M
0.1- 0.2 g.
ECF

1-2 g.
02~ .5g. ill
\i I

Intestine
6-10 g. 5.9-9.7 g. Bone

i Filtration Reabsorption
0.35-1 g.

Excretion

Kidney 0.15-0 .3 g.

Fig.39. Pathways
of calcium
metaboli
smregulation

• Facilitates mobilization of calciumandphosphatefrom bone.To prevent

detrimental increases in phosphate , parathyroidhormonealso hasa po-
tent effecton the kidneyto eliminatephosphate (phosphaturiceffect).
• Maximizestubularreabsorption of calciumwithi.n the kidney.Thisactiv-
ity results in minimallossesof calcium in urine.In addition, PTHinhibits
phosphat e reabsorption. Theresul.tinghypophosphatemia stimulatesCa2•
release fromthebonetissu~andpreventsthedeposition of Caphosphate.

CT, likePTH, is a peptide hormoneandis mainlysynthesizedin theparafol-

licularor Ccellsof thethyroidgland. In hypercalce
mia, theplasmaconcentra-
tion of CTis increasedmanytimesaboveits normalvalue, whereasat Ca2 +
concentrationsbelow 2 mmol/L CTis no longer detectable .
Pathophysiologyof metabolism Unit 4 I 351
Calcitoninis a hormonethat functionsto reducebloodcalciumlevels.

It is secreted in response to hypercalcemia and has

at least two effects:

• Suppression of renaltubularreabsorptionof calciumor maysay that

calcitoninenhances excretionof calciuminto urine.
• Inhibitionof boneresorption, whichwould minimizefluxesof calcium
from boneinto blood.

0-hormone (calcitriol,vitaminD) is a groupof fat-solubleprohormones ,

the two majorforms of whicharevitaminD2 (ergocalciferol) andvitamin03
-(cholecalc
iferol). VitaminD obtainedfrom sun exposure,food, and supple-
ments,is biologicallyinertandmust undergotwo hydroxylation reactionsto
be activatedin the body.

This transformation occurs in two steps:

• Within the liver,cholecalcifera

l is hydroxylated
to 25-hydroxycholecal-
ciferolby the enzyme25-hydroxylase.
• Withinthe kidney, 25-hydroxycholecalciferolservesas a substratefor
1-alpha-hydroxylase, yielding 1,25-dihydroxycholecalc
iferol, the bio-
logicallyactiveform.

Eachof theformsof vitaminDis hydrophobic , andis transportedin blood

boundto carrier proteins.The majorcarrieris calledvitaminD-bindingpro-
tein.
Calcitriolincreasebloodconcentrations of calciumandplaysan importan t
rolein the maintenance of severalorgansystems.However , its majorrole is
to increasethe flow of calciuminto the bloodstream, by promotingabsorp-
tion of calciumandphosphorus from foodin the intestines, andreabsorption
of calciumin the kidneys ; enablingnormalmineralization of boneand pre-
 352 I Part I Generalpathophysiology

ventinghypocalcemictetany.It is also necessaryfor bonegrowth and bone

remodeling by osteoblastsandosteoclasts.

Calci um and phosphorus metabolism d isorders

Themaincausesare infringementof synthesisparathormone , vitamin03 and
calcitonin. Thefunctional activity of parathyroidglandscan be increased(hy-
perparathyreosis) or decreased(hypoparathyreosis).
Hypoparathyroidism. When the parathyroid glandsdo not secretesuf-
ficient parathyroid hormone, the osteocyticreabsorptionof exchangeable
calciumdecreasesand the osteoclastsbecomealmosttotally inactive. As a
result, calciumreabsorptionfrom the bonesis so depressedthat the level of
calciumin the bodyfluids decreases . Yet, becausecalciumand phosphates
arenot beingabsorbedfrom the bone, the boneusuallyremainsstrong.
Whenthe parathyroidglandsare suddenlyremoved, the calcium level in
the bloodfalls within 2- 3 daysand the blood phosphateconcentrationmay
double.Whenthis low calcium level is reached , the usual signs of tetany
develop.Among the musclesof the bodyespeciallysensitiveto titanic spasm
are the laryngealmuscles.Spasmof these musclesobstructs respiration,
which is the usualcauseof deathin tetanyunless appropriatetreatmentis
applied.
Hyperparathyroidism. The causeof hyperparathyroidism ordinarily is a
tumor of one of the parathyroidglands; such tumors occur much morefre-
quently in womenthan in men or children, manly becausepregnancyand
lactationstimulate the parathyroidglandsand therefore predisposeto the
developmentof such a tumor.
Hyperparathyroidismcausesextremeactivity in the bones.This elevates
the calciumion concentrationin-the extracellularfluid whileusuallydepress-
ing the concentrationof phosphateions becauseof increasedrenalexcretion
of phosphate;over longerperiodsof time this can leadto calcification(kid-
neys)and, if [Ca2+] > 3.5 mmol/L, to comaanddisturbances in cardiacrhythm.
Very often calciumand phosphorushomeostasisdisorderare causedby
the violationof vitaminD metabolism .
Pathophysiologyof metabolism Unit 4 1353

Hypovitaminosis D mayappeardueto its insufficientreceiptfrom outside

or insufficient calciferoleformationin the organism.In vitamin D deficiency
causedby inadequate intakeor absorption(impairedfat digestion),by lackof
UVlight, or by a reductionin the synthesisof calcitriol(renalinsufficiency),
demineralization of the skeletonoccurs (osteomalacia; rickets in children).
Themainreasonfor this is the continuedexcessivereleaseof PTHdueto the
chronichypocalcemia(compensatory hyperparathyroidism).
It's knowntoday, that over 90% of serum25-oxyvitamin03 circulating
in bloodis synthesized in the skin dueto ultra-violet irradiationandonly its
insignificantpartcomeswith food. So, the mainrisk factorcausingvitaminD
insufficiencyis the insufficiencyof ultra-violetirradiation.Hypovitaminosis D
can be commonfor peoplewho prefervegetariandiet.VitaminD sourcesin
foodarethe productsof animalorigin- fat fish (herring,salmon,pilchards,
tunny), enrichedmargarine,milky mixturesfor children,eggsand liver. Vi-
tamin 03 insufficiencyis commonfor the pathologyof thoseorgans which
takepartin its metabolism , specificallyat variousliver pathology, diseasesof
gastric-intestinaltrackandkidneys.
Vitamin03 canaccumulatein the organismin excessandcausehypervita-
minosisD. Sometimes that happensat uncontrolledandsurplusconsumtion
of vitamin03, with the aim of prophylaxyof calcium-phosphoric metabolism
violations,especiallyin earlychildage.
Calcitoninsecretiondisordersare mostly common for patients with
medullarcarcinomathat developsfrom parafollicularcells of the thyroid
gland.The following pathologicstatesare the basicviolationsof calcium
and phosphorus metabolism: hypocalcemia , hypophosphatemia,hyper-
phosphatemia.
Hypocalcemia is the statewhenthe generalcalciumbloodconcentration
is lessthan2.3 mmol/1.Hypocalcemia oftenarisesin the n~wbornperiodbut
it is temporalandis caused by cessationof calciumincominginto the child
organismfrom mother. This phenomeno n can be complicatedby lowering
of organs-targets sensitiveness of a newbornto parathormone . Hyperphos-
phatemiacanbethe reasonof hypocalcaemia, whichcan be easilyprovoked
in childrenwho are fed with cow milk. This statecan also arisedue to the
development of hypoparathyreosis. Dueto the insufficiencyof parathormone.
 3541 Part I Generalpathophysiology

the absorptionof calciumin intestineand its mobilizationfrom bonessec-

ondlydiminishes.phosphorusreabsorptionsimultaneously increasesin ne-
phriticcanals.
Thatcauseshyperphosphatemia andthe decreaseof ionizedcalciumblood
leveldueto the formationof hardlysolublephosphoricsalts.Othercauses
of hypocalcemia areas follows:organs-targetsinsensibilityto parathormone
(pseudohypoparathyreoris) , violations of calcium absorptionin intestine
bowelsat D hypovitaminosis, digestivesystemdiseaseswith diarrheaand
steatorrhea, hyperproduction of calcitoninat the medularcancerof thyroid,
chronicnephriticinsufficiency,at whichcalciumloss is observedand bones
insensibilityto parathormone develops.
Hypocalcemia is displayedwith tetany, ricketsandosteodistrophy. Tetany
is the resultof ionizedcalciumconcentration in extracellularspacedecrease ,
which causesthe increaseof neuro-muscularstimulationand tetanysyn-
drome. It's characterized with memoryloss, orientationdisorders, convul-
sions, hard breathing , carpopedalspasmand bronchispasm ; laryngospasm
can develop,which causesasphyxiaanddeathin children.Therewereeven
casesof coronalarteries spasmwhichprovokedstenocardia attacksandces-
sationof heartactivity(so calledcardiotetany).In the patogenesis of tetany
the mainrole belongsto the drop of nervouscells membranesstability.The
posttetanicpotentiationconductionphenomenon weakensandthe impulse
on the reflexarc becomeseasierin motoneurons andin the systemof spinal
cord intermedialneurons.This leadsto the considerablerise of reflexmus-
clescontractionsin responseto mechanical andotherstimulations.
Rickets. History showsthe neanderthalpeople sufferedfrom it evidently
dueto insolationinsufficiency,limitedaccessof food sourcesof vitaminD.
Then the antirachiticsubstance(vitamin D) had beendiscoveredand the
medics developedspecial arrangementswhich quickly lowered morbid-
ity with endemicrickets. Hov~ever , ricketsdoesn'tvanish, constantare its
formswhichareresistantto the improvement of environment.Now we know
that ricketsetiologyis associatedwith genepathologytoo. All calciumand
phosphorusmetabolicdisorderforms knowntoday in childrenare caused
by hereditarydefectsgatheredin such unitednotionas hereditaryrickets-
osteomalacia.
 Pathophysiologyof metabolism Unit 4 1355

Osteomalacia is the bonesconditionwhen mineralsubstancescan't be

quicklyaccumulatedin recentlyformed proteinmatrix of intraossealbone
allotments,whichare beingreconstructed. At rickets,which is a pediatrics
equivalentof osteomalacia, the violationof mineralization takesplacein bone
andcartilages, whichgrowth.
Therearetwotypesof rickets:phosphopenic (it's the resultof primaryvio-
lationsof phosphorusmetabolism)and calcipenic(it's the resultof vitamin
D homeostasisviolations).Secondtypes of calcipenicrickets/osteoma lacia
aredescribedandnaimly: autosomic-recessive dependence on vitaminDfirst
type (calcipenicricketsfirst type) and vitamin 0-dependentricketssecond
type (calcipenicricketssecondtype).Thefirst type doesnot dependon ad-
equateintroductionof vitaminD in organism.Thisricketsbeginsin the ageof
two yearsmostlywithin first six monthsof life. It's characterized by the hy-
- potonia,convulsions , hypocalcemia , andhypophosphatemia. Themaincause
of this diseaseis hereditarydefectof 1,25 (OH)203 synthesisin the kidneys.
Secondtype beginsin the ageof oneyearof life andis characterized by the
hard clinicalmanifestat ion, the decreaseof calciumand phosphorusblood
level,violationsof calciumabsorptionin the intestine.Themainreasonof this
type ricketsis the resistanceof organs-targets to 1,25(0H)2D3.
Osteodistrophy (it is the pathologicalprocessesin the bones)is character-
izedby osteomalacia, osteoporosisand osteofibrosis.Hypocalcemiais the
mainreasonof dystrophicprocesses , which developin bones.It is caused
by vitaminD insufficiency(for example:chronickidneysdiseases,intestine
pathologysuchasa syndromeof malabsorption , stomachor intestineresec-
tion), hypoparathyreosis , pseudohypoparathyreosis , by thyroiddiseasesand
sexualglandsinsufficiency.
The functionalstateof osseoustissuedependson two basic processes
suchas formationanddestruction . Normallythey are balancedand provide
skeletonconstructionandreconstruction . 2-4 % of bonesare reconstructed
annuallyand within 10-12 yearsthe half of bonesrestores.The hormones
controlcalciumlevelin blood. An insignificantdecreaseof its bloodconcen-
trationis eliminateddueto depotof calciumactivation,which is the bones,
thus, bonesdestructionprocessstrengthens.Bonesresorption is the result
of the highosteoclastsactivity,whichdissolvecalciumandphosphorussalts
 3561 Part I Generalpathophysiology

of bones.Osteoklasts promotethe accumulation of organicacidsandlysoso-

mal fermentsandthis causesthe bonecollagensplitting.Calciumgoesout
intothe extracellu lar liquid.
Bonesresorptiondisplays in osseousbeamsrefiningand deformation .
Osteomalaciais the bonessofteningas the resultof insolublecalcium salts
synthesizeviolation.The main complicationsare the skeletondeformation
andtheviolationsof the differentorgansfunctions.
Osteoporo sis is the bonesatrophy. In the resultfracturesmayoccurseven
dueto insignificanttrauma, amongwhichthe mostdangerousarecompres-
sion fracturesof vertebraebodiesand fracturesof femoralcervixand the
excessive flexibilityandskeletoninabilityto executethe functionof hardsup-
portfor the body. This leadsto the development of deepdisablement.
Hypercal cemiais an organismstatewhengeneralcalciumbloodlevelex-
ceeds2.7 mmol/1.Themainreasonsare primaryhyperparathyreosis, hyper-
vitaminosisD, whencalciumabsorptionin intestineincreases . Hypercalcemia
often accompaniesdifficult fracturesor malignanttumors of bones.Numer-
ous fracturesviolatethe equilibriumbetweenboneconstructionprocesses,
whichsharplydecreases , andthe resorption , whichcontinueswith previous
speed.In the resultof this processcalciumis mobilizedfrom bonescausing
hypercalcemia. Hypercalcemia can be complicatedwith osteodistrophy , cal-
cinosisandcalciphylaxy .
Reklinghausen describeddevelopmentof osteodistrophy as the result of
bonesdecalcinosisat the continuoushyperparathyreos is. This diseaseis
characterizedby gradualdilutionandsofteningof bones.Theskeletonviola-
tion at hyperparathyreosis is the resultof all componentsbone resorption,
andnot only its demineralization becauseamountandmetabolicosteoclasts
activityincreasesdueto the actionof parathormone. Parathormone increas-
es glucosemetabolism , lacticand otherorganic acidssynthesis.Citric acid
forms easy-solublesubstanceswith calcium; lysosomalfermentssplit os-
seouscollagento peptides.Generallythe extra secretion of parathormone
causesthe reinforced resorptionof osseous tissue.Osteoporosis(the 1st
stageof osteodisrophy) develops.In caseof the processprogressing the loss
of bonesmatrixoccursandthe bonebecomessoft. Resorption allotmentsare
replacedwith connectivetissueandzonesof osteoidsubstanceareformed.
Pathophysiologyof metabolism Unit 4 1357

Thedissolvedbonesarereplacedwith organicmatrix. Theprocrastinations of

mineralsubstances arebroken,andosteofibrosisdevelops.
Calcinosis (calcification) is characterized by the accumulationof insoluble
calcium salts in soft tissues. This processis promotedby changesof col-
loid stateproteins,localphosphatase activationandtissuesalkalosis.There
is cellularandextracellularcalcinosis. Mitochondria andcell lysosomes , gli-
cosaminoglicans of the basicsubstance,collagenand elasticfibres can be
calcinosismatrixes.
Dependingon the dominanceof generalor localfactors,thereare such
typesof calcinosisas metastatic , dystrophicandmetabolic.Theprocesscan
be eithera general(spreadcalcinosis)or a local.Themetastaticoccursdue
to the inforcedcalciumcomingout of the depot.Thiskindof calcinosisdevel-
opsdueto the destructionof bones(pluralfractures, myelomaillness. tumor
metastases into bones), osteomalacia andparathyroidosteodystrophhy , due
to the intestineinjure, kidneysdiseases(polycystosis.chronicnephrite)and
D hypervitaminosis.
Saltscalciumsedimentmostlyin the lungs,stomachmucousmembrane ,
in myocardium,kidneys,and arterialwalls. Acid productsare excretedin
the lungs, stomachandkidneys.Veryhigh pH of thesetissuesbecomesthe
physiologicalprecondition to calcinosis.The deposition of calciumsalts in
myocardiumandarterialwallsis promotedby washingof thesetissueswith
arterialbloodpoor in CO2. In calciummetastasescalcium salts encrustthe
parenchyma cells, fibresandbasicsubstanceof connective tissue.In the kid-
neysand myacardiumphosphate and calciumsalts hearthsare localizedin
mitochondrias andphagolysosomes , in vascu"lar
wallson membranes motion
andfibredstructures.
Dystrophic calcification (petrofication)is the depositionof calciumsalts.in
necroticor dystrophictissues. In dystrophic calcification,calcifiedconglom-
eratesof stone density anddifferentsizes, calledpetrificatesdevelopin tis-
sues.Theyaregenerated in tubercularcaseosae cavernof lung, rubbersand
infarctionsareas,in deadcells,in the areaof chronicinflammation . In exu-
dates calcinosis,whichis generatedon the pleura, the so-calledtestaceous
lungsappear,andthe development of this processon the pericardiumcauses
the testaceousheartappearance. Thecalcinosisof nephronecanalscells in
 358 f Part I Generalpathophysiology

the resultof theirdeathor excessive excretionof calciumcausesnephrocalci-

nosis. Thesameprocessdevelopsin heartvalves,in atherosclerotic plaques,
in cartilage,in transplantants , in deadfoetusat extra-uterinepregnancy.
The pathogenesis of metaboliccalcinosisis not studiedcompletelybut in-
stabilityof buffersystemsandhighsensitiveness to calciumplaysan impor-
tant role. Metaboliccalcinosiscan be localandsystem.Limestonedeposits
in the skin, in hypodermicfatty cellulose , in the directionof fasciasand of
aponeurosis, in muscles,nervesandvessels.Theconsequences of calcinosis
for the organismaredeterminedby the mechanisms of its developmen t, cal-
cinosisdissemination. lnterstitionalcalcinosisis a complicatedprogress ing
diseasebut the limestonemetastases don't haveclinicalsigns. Dystrophic
calcificationof the arterywall at atherosclerosis causesfunctionalviolations
andcomplications(thrombosis).Limedepositionin the caseosaltubercular
hearth, on the contrary,testifiesit's healing.
Calciphylaxy is a state of increased organismsensitiveness to calcium.
Twophenomena takeplacein thedevelopment of calcifilaxy:sensibilizingand
unleashing.Thesensibilizingfactorsare hyperparathyreosis , hypervitamino-
sis 0), total nephrectomy. The unleashingfactorsare saltsof iron, chrome,
manganese , aluminum, glair, dextrine,serotonine , mechanfcal damages . In
this caseagentcausinghypercalcemia operatesasgeneraltissuesensibilizer,
andthe unleashing factorsarenecessary in orderto localizereactionin sepa-
rateallotments .
Hypophosphatemia is the statewhenphosphorusbloodlevel loweris than
normal.The main reasonsof hypophosphatemia are surplus phosphorus
loss by the kidneysat the kidneysinsufficiency,cystinosis,and primaryor
secondaryhyperparathyreosis , malnutrition , unrestrained vomit,malabsorp-
tion syndrome , violationof phosphorusintestinesabsorptionas a result of
vitamin03 deficiensy , liver pathology.The hypophosphatemia can be as the
resultof diabeticketoacidosis'treatment, when the reinforcedphosphorus
absorptionfrom extracell ular spacetakesplacein organismfor guaranteeing
the activeprocessof glucosephosphorilationby cells.Chronicloweringis
followedby the development of phosphopenic ricketsor osteomalacia.
Thereare four phosphopenic types of rickets:hypophosphatemia-con-
nectedwith X-chromosoma , autosomal-dominative hypophosphatemia bone
 Pathophysiology
of metabolism Unit 4 f 359

affection,autosomal-dominat ive hypophosphatemition ricketsand Fanconi 's

syndromes.All of themarehereditary,arecharacterized by the bonespathol-
ogy, but the reasonsand pathogenesis of them is unknown.Besidesviola-
tions in bonesystem,chronichypophosphatemia is accompanied with lower-
ingof appetite,giddiness , weaknessin proximalmuscles,bonepain, liverand
heartfunction disorders, thrombocyto-and leucocytopenia , inclimationto
infections,andcomacanoccur.Thesesymptomsarethe resultof oxydative
phosphorilation processesviolations,energydeficiencyandtissueshypoxia.
Hyperphosphatemia is sucha statewhenPh bloodslevelmorethan 1.4
mmol/1.The maincausesof hyperphosphatemia are factorswhich provoke
the reinforcedphosphoruscaptureby the kidneysand parathyroidglands
insufficiency,hypothyreosis; factors promotingthe developmentof hyper-
phosphatemia dueto the activationof phosphorusexitfrom bones(fastbone
-growth, healingof fractures, neoplasmin bonesandit's massivedisintegra-
tion); hypophysisgiantismbecausesomatotropichormonehas an ability
to stimulatephosphorusreabsorbtionin nephriticcanals; states when rein-
forcedphosphorusabsorptiontakesplacein gastric-intestinal track (hyper-
vitaminosisD, sharp intestinalimpassability);diseaseswhich havehyper-
phosphatemia as a symptomand is causedby the exceededdestructionof
cellularelements(hemolyticanemia , leucosis).Hyperphosphatemia doesn't
haveindepen dentimportancebecauseundercertainconditionsit causesthe
formationof insolublephosphoriccalciumsaltsin bloodandthe loweringof
bloodconcentrationof this element.So, the symptomsthatdevelopat hyper-
phosphatemia are, really,the resultof hypocalcaemia.
 ..
.
PATHOPHYSIOLOGY
PA~T2 OF ORGANS AND
SYSTEMS
 PAT~10PHYSIOLOGY
Unit5 OF HEMATOPOIETIC
FUNCTION

Chapter 18. Disordersof Total

Blood Volume and Hematocrit

Thefunctionalbloodsystemincludesperipheralblood(circulatingbloodpool
andreservoirbloodpooldepotedin theorgansandtissues),blood-producing
(hemopoietic) organs, blood-destroying (hemodieretic) organs,aswellasthe
regulatoryneurohumoral apparatus.
Mechanismsregulatingthe amountof blood cells and their qualityare
closelyconnectedwith the bloodpooling processes , changesin bloodcircu-
latingrate, in vasculartone,hemopoietic andhemodieretic volumes.
Highmitoticactivityof hemopoietictissuedeterminesits high sensitivity
to the affectingfactors, while geneticdeterminacyof reproductionand dif-
ferentiationof bloodcells, their structureandmetabo lic processescreatethe
necessary prerequisitesfor the structuralanddysre,gulatorydisordersof the
geneticapparatus.
Morespecifically,the pathological .changesof bloodresultfrom boththe
impairmentsof its somecomp,onentsand disjunctionsof otherorgansand
systemsof the organism.
Any disease , pathologicalprocessas well as a number of physiological
shifts (especiallyduring the developmentin childhood)may in someway
effectthe quantitative andqualitativecharacteristics
of circulatingbloodcom-
position. Therefore , muchattentionshouldbepaidto the "bloodmirrorof the
Pathophysiologyof hematopoieticfunction Unit 5 I 363
organism" and to the ascerta
ining the regularitiesof bloodchanges under
differentdiseases.

Tot al bloo d volume and hematocrit their d isorders

The total blood volume includescirculatingblood pool and reservoir blood
pool depotedin thevesselsof theabdominalcavity, lungs, andother tissues.
Thecirculatingbloodvolumeof a full-termnewbornfor thefirst daysof liveis
anaverage85 ml/kg, whilein anadultit equals65-80 ml/kg.A moreconsid-
erablerelativebloodvolume of babiesprovidesthe higherrateof metabolism
in theirorganisms.
Hematocrit (Hct),or packedcell volume(PCV)- the ratioof the blood
corpusclesvolumeto the plasma volume. Hematocritof newbornsby birth
makesup about55 %, that is somehigherthen in adults(36-48 %). This
is conditionedby the larger amountof erythrocytesand the largeraverage
volumeof certainerythrocytes in newborns.
Whensomediseasesor pathologicalprocessesalreadypresent the total
bloodvolumeas well as the proportionof blood corpusclesand bloodcor-
pusclesmayvary(Table 21).

Table21. Typical forms of changes

in totalbloodvolume

Normovolemia
:
Oligocythemi
c Plasma
prevail
s Decre
ased
Poty
cythemic Bloodcellsprevail Increased

Normocythemic
(simple) Normalproportion Nochanges
 364 I Part 2 Pathophysiologyof organsand systems

Typeof changes Proportionof blood .

corpU&Clesand..... ...' . - , /,~·
~ . . :.~ ... v_ <~·.
l',_.., ·:'..
::
Oligocythemic Plasma
prevails
Polycythemic
(plethora):
Hypervolemia
Normocythemic
(simple) Normalproport;on Nochai:iges
Oligocythemic Plasma
prevails Decreased
Polycythemic Bloodcellsprevail Increased

Normovolemic (L. norma+ OldFr. volume+ Gk.haima- blood)disorders

- the conditionscharacterized bythe normaltotal bloodvolume, but the pro-
portionof bloodcellsandplasmais changed.
In oligocythemic normovolemiathe totalbloodvolumehasnochanges while
theamountof bloodcells,erythrocytes in particular,decreases resultingin the
fall of the hematocritvaluebelow the norm.It usuallyoccurs·as a result of
massivehemolysis of erythrocytes
, inhibitionof hemopoiesis (especially
eryth-
ropoiesis) , and blood lossas well (whenthe bloodvolumehasbeenrecom-
pensedbytissuefluid,theamountof erythrocytes hasnotimeto renewitself).
Signsof this conditiondependon the level of RBCcountreducing(anemia,
hypoxia), rarely- onthedecreasing of plateletcount(hemorrhagic syndrome)
andWBCcount(loweringof anti-infectionresistance of the organism).
Polycythemic normovolemiais characterized with the normaltotal blood
volumewhilethe numberof bloodcorpusclesis increased , whichleadsto the
riseof the hematocritvalueabovethe norm.This maybe dueto the transfu-
sion of someportionsof bloodcorpuscularfractions(erythrocytic,leuko-
cytic,or thrombocyticmass},chronichypoxiaresultingfromtheactivationof
erythropoiesis andthe development of erythrocytosis.
Polycythemic normovolemiamaybe distinguishedby the bloodmicrocir-
culationdisturbances concernedwith the increaseof blooddense,bloodvis-
Pathophysiologyof hematopoieticfunction Unit 5 I 365
cosityandformationof platelets,that is accompanied by the loweringof the
intensity of transcapillary
circulation.
Hypovolemic disorders (Gk.Hypo+ OldFr. volume)the conditionschar-
acterizedby a decrease of thetotal bloodvolume
Normocythemic, or simplehypovolemia is definedby the loweringof total
bloodvolumeor itscirculating part,whilethehematocritvalueis usuallynormal.
This is observeddirectly after acutehemorrhages (until the massof cir-
culatingbloodis compensated by an inflowof bloodfrom the blooddepots
andtissuefluid), aftershockconditions. In thesecasesthe development of
normocythemic hypovolemia is determinedby the poolinga largeamountof
bloodvolumein veins and by a considerable decreaseof circulatingblood
volume,whichhematocritvaluehasnotyet beenchanged.
Oligocythemic hypovolemia- a diminishedvolumeof blood mainlybe-
-causeof a decreasednumberof erythrocytes,the hematocritvalue is de-
creasedaswell.It is observedafteracutehemorrhages in casesof increased
passageof fluid from tissues into the vascularsystemand in certain forms
of anemia , for example , perniciousanemia , relatingto massivehemolysis of
erythrocytes or inhibitionof theirformationin the bonemarrow.
Polycythemic hypovolemia is a conditionwith a decreased amountof plas-
mausuallycharacterized by appreciable concentration andincreasedviscos-
ity of the blood.Thehematocritvalueis abovenormal.
Thisconditionis observedin connectionwith considerab le loss of water
by theorganism , as in diarrhea , intractable vomiting,hyperventilation, shock
(throughthe inflowof fluid into thetissuesbecauseof markedvascular per-
meability) , andextensiveburnsinvolvinglossof a greatdealof fluid with the
exudateandevaporation from burnedsurfaces.Polycythemic hypovolemia is
distinguishedaccordingto the signsof a principalpathology(hyperthermia,
shock, diabetesinsipidus,etc), as well as to the disturbancesof tissueand
organbloodsupply.
Hypervolemia (Gk.hyper+OldFr. volume)conditionsarecharacterized by
anexcessof thetotalvolumeof bloodin the body.
Normocythemic , or simple hypervolemia with a normalplasma-erythro-
cyteratio(hematoc rit valueis usuallynormal)occursveryrarely. It mayarise
for a shorttimefollowingtransfusionof largeamountsof blood, ejectionof
 366 I Part 2 Pathophysiologyof organsand systems

bloodfrom the blooddepotsin the beginningof strenuouswork, or under

highexternaltemperature.
Oligocythemic hypervolemia (hydremicplethora,hemodilution) with anex-
cessof plasma(hematocritvalueis decreased)maybe dueto the retention
of waterin the bloodstreamas a result of excessive fluid inflowin the organ-
isms ( e.g., pathologicalthirst, introducingof blood plasmasubstitutesor
bloodplasmainto the bloodstream).Thisconditionmaybealsodetermined
by the water retentionresultingfrom the failureof renalexcretoryfunction,
hyperproduction of antidiuretichormone.
Polycythemic hypervolemia (with an increasednumberof erythrocytes)-
the increasein the numberof the bloodcorpuscles(essentially of erythro-
cytes).Thehematocritvalueis abovenormal.
This conditionis alsoknownas trueplethoraor truepolyemiaandis char-
acterizedby increasedhematopoiesis whosesignsareusuallyeasilyobserved
in the bonemarrow, spleenandotherhematopoietic organs.It is supposed
that the increasedhematopoietic functionof the bonemarrowis stimulated
by somesubstanceformedin the processof disturbedmetabolism .
Hypervolemia is often characterized by tegumentaryhyperemia,elevated
blood pressure,hypertrophyof the left ventriclewhich with eachsystole
drivesmorebloodinto the aorta.Underan isochronicincreaseof hematocr it
(polycythemichypervolemia) the bloodviscosityincreasesas well that may
leadto the microcirculatory disordersandthrombosis.

Posthemorrhag ic Process
Blood loss. Bloodlossis a pathologicalprocessresultingfrom an escape
of bloodfrom the vesselsinto the env~ronmentandcharacterized
by a wide
rangeof pathologicaldisorders,, adaptive,compensatory
and protectivere-
sponsesof the organism.

Typesofbloodloss
According to the bleedingvesselsor cardiacchambers,
blood loss is
distinguishedas arterial,venous,capillaryandmixed.
Pathophysiologyof hematopoieticfunction Unit 5 I 367
Acco rding to their volume, bloodlossmay be mild (the loss of 20-25
percentsof circulatingblood), moderate(25-30 percent), andsevere(more
than35-40 percent).
Bloodloss may be externalor internal,depending arr whetherthe blood
exudesto theexterioror insideanorganor cavityas wellas feto-maternal
and
feto-fetalduringtheantenatalandperinatalperiods.

Etiology

Etiologic a l fa cto rs re sulting in blo o d loss includ e:

1) traumascausingexternalor internalhemorrhages ;
2) wall rupturesof vesselsdamagedby pathologicalprocesses(ulcerative
diseases, aneurism, hemangiomableeding, etc)
3) hemorrhagic disordersof coagulationandthrombocyte-vascularhemo-
stasis;
4) dysfunctionaluterinebleeding
.

Theresultsof acutebloodlossvary greatly.Theydependon the age, sex,

the massof bloodlost, the rateof the bloodflow, the conditionof hemostasis,
the organismresponsiveness.
A fetusis considered to bemoreresistantto bloodlossthatan infant, how-
ever, someremarkableincidencesprovethe babieshavinglost morethan a
halfof circulatingbloodvolumeduringthe prenatalperiod, showno singsof
hemorrhagic chockat birth that usuallydevelopsin newbornshavinglost at
about10-15 percentof circulatingblood.
An outflowof about20-25 percentof circulatingbloodvolumein infants
afterthe 1st yearof lifeandin adultsis usuallyconsideredto benot life-threat-
eningandis compensated by engagement of urgentadaptivefunctionsof the
organism.The loss of 25-25 per cent of circulatingblood is accompan ied
with markeddisordersof hemodynamics. For a healthyorganisma single
lossof SD-60percentof the total amountof bloodis fatal.
In comparisonwithadults, the infantsof 12 monthsandolderaremorere-
sistantto the hemorrhages dueto sympathicotonia andthey usuallydevelop
 368 I Part 2 Pathophysiology
of organsandsystems

the signsof hemorrhagicshockat the loss of 25-25 per centof circulating

blood.
Therateof the bloodflow,the massof bloodlostdeterminetheseverityof
vitalfunctiondisorderssincesometimeis neededto develop certainadaptive
andcompensatory responses . Forinstance,the lossof evena halfof circulat-
ing bloodfor severaldaysmaynot alwaysresultin death.
Pathogenesis. A decrease of circulatingbloodpoolis considered to trigger
differentchangesin the organismin bloodloss.Thisresultsin the develop-
mentof simplehypovolemia , circulatoryhypoxia(a decreasein heartminute
volume, a decrease of the rateof oxygen-carrying capacity)andhemichypox-
ia (a decreasein hemoglobinconcentration , a decreasein oxygentransport
capacityof blood).
Simultaneously with the disordersof a numberof vitally importantfunc-
tionshemorrhages leadto mobilizationof the urgentadaptiveandcompensa-
tory mechanisms by meansof whichit is possibleto restorethe bloodpres-
sure, as well as the volume and function of the blood.

These mechanisms include the following processes:

1. Narrowingof volumetricandresistivevesselsin the siteof damagedue

to theactionof localvasoconstrictor factorsandactivationof the hemo-
stasissystem.
2. Bloodredistributionin orderto maintainbloodcirculationthroughthe
vital organs(centralizationof bloodcirculation) dueto the reflexstimu-
lationof the vasomotorcenterwith a resultantincreasein vasculartone
andspasmof the peripheralvessels(skin,muscles,stomach,kidneys)
aswellasthe hemostasis activation
. Thisoccursby meansof the stimu-
lation of carotidsinus, ao!la and cardiopulmonary areas, acceleration
of the sympathoadrenal systemand hypercatecholaminemia. Dilatation
of cerebralandcardiacvesselsrefersto the rapidandconsiderable ac-
cumulationwithinthemlocalvasodilatorssuchas nitricoxide,adenos-
ine, prostacyclin
, kininsandunderoxidized metabolicproductslowering
arteriolatone.
Pathophysiologyof hematopoieticfunction Unit 5 I 369
3. Neuroreflectory increaseof heartbeatrate(mainlydueto the activation
of thesympathoadrenal system;
4. Neuroreflectory hyperfunctionof externalrespirationpreventingthe de-
velopmentof oxygendeficiency in the organism.
5. Accelerationof oxygenutilizationin bloodvolumeunit (shiftof thecurve
of oxyhemoglobin dissociationat the"arterypoint" to the leftanddown-
ward).
6. Increasein the massof thecirculatingbloodthroughan inflowof blood
from the blooddepotsandtissuefluid.

Theseprocessesdirectat the changeover of circulatoryhypoxiainto and

hemichypoxiawhichis notso life-threatening andeasierto becompensated.
Whenthe outcomesof blood losssurpassthe adaptiveabilitiesof theses
- responses(at the loss of 30-40 per cent or moreof circulatingblood)the
bloodpressuresequentiallydrops.At the loss of 45 per cent of circulating
bloodit lowsdowntoo mmHg.Therefore, above-mentioned adaptivemecha-
nismsareunable to compensate massivebloodloss.
Othernon-urgentcompensatory mechanisms of an acutebloodloss are
engagedinto theadjustmentof bloodvolumeat the laterstageof posthemor-
rhagicprocessandaimto restoreof bloodvolumeandbloodcomposition.
Compensatory responses directingto increaseof the volumeof circulating
bloodundera hemorrhage mobilizetheirabilitiesfor theintervalvaryingfrom
somehoursto severaldaysand relateto the enhancement of sodiumand
waterion reabsorpt ion in the kidneys.
Initialfactors drivingtheseresponsesare afferentinflow from numer-
ous baroreceptors due to the drop of arterialpressure.This resultsin the
triggeringof renin-angiotensin-aldosterone cascade.Reninas a proteolytic
enzymeconvertsangiotensinogen to angiotensinI. In the lungsangiotensin
I is convertedto angiotensinII and 111 by the effectof angiotensinconvert-
ing enzyme.Therearepowerfulvasoconstriction agentsthat alsofacilitatea
fast releaseof noradrenaline (norepinephrine) from the sympatheticnerve
terminals.Vasoconstriction aimsto increasethe bloodpressure . Angiotensin
II increases the releaseof aldosterone with the resultingretentionof sodium
andwater.
 370 I Part 2 Pathophysiologyof organsand systems

As a responseto hyperosmiawhichis developingandto stimuli of blood-

streamosmoreceptors thesynthesisand secretionof vasopressin (antidiuret-
ic hormone)increases . This hormoneeffectson epitheliumV2-receptorsof
renaldistalconvolutedtubulesandcollectingducts, thereafterthe facultative
water reabsorpt ion in renal tubules(osmoreflex)is accelerating. Loweringthe
bloodvolumeby 1Opercentof its volumeis a strongstimulusfor the release
of vasopressin.
Theincreaseof angiotensinandvasopressin concentration in the bloodis a
powerfulstimulusof thehypotha lamicthirstcenter.It is thethirstasa oneof prin-
cipal compensatory mechanisms reaches its maximumin hemorrhagic shock.
Thus, this is the mainpointof "hydremiccompensation" of the circulating
bloodpooldecreased dueto the bloodloss. At this stageof posthemorrhagic
processoligocythemicnormovolemia or hypovolemia develop .
Compensatory responsesaiming to diminish hypoproteinemia resulting
from bloodloss may be noticeablein severalhoursafter bloodlossandlast
for the following1.5 - 3 weeks.Plasmaproteincompositionis restoredby
meansof extravascular proteinreservesandequallyby albuminsandglobu-
lins ("proteincompensation "). Evenat the loss of 15 per cent of circulating
bloodthe albuminsynthesisin a liver increasesup to 75 percentas well as
globulinsflow into the bloodat the sametime.
Compensatoryresponses resultingin the renewalof peripheralblood
compositionafter blood loss developfor severaldaysor 1-3 weeks. Renal
hypoxiatriggersthis process, hencethe largeamountof erythropoietinpro-
ducedby renalperitubularendothelialcellsflows in the bloodstream.These
renalperitubularendothelialcellseffecton the bonemarrowcellspromoting
erythropoiesis that leadsto increasedinflowof youngregenerative forms of
erythrocytesin the peripheralblood("bonemarrowcompensation ").

Posthemorrhagic changes reflecting the disorders

of physiological functions are the following:

• disturbancesin systemichemodynamics (loweringof the circulating

bloodvolume,arterial andvenouspressure, myocardialform of cardiac
Pathophysiologyof hematopoieticfunction Unit 5 I 371

insufficiency
, bradycardia , decreasein cardiacoutput and venousre-
turn) and regionalcirculation(microcirculation}, alteration of rheologi-
cal propertiesof the blood,impairmentof organandtissueperfusion;
• hematologicaldisorders- posthemorrhagicanemia,accelerationof
thrombocyte-vascular hemostasis , microthrombosis , disseminatedin-
travascularcoagulation(DIC-syndrome); and hypoxicsyndrome- the
development of mixedhypoxia(circulatoryand hemichypoxiabecome
aggravated by respiratoryandtissueones);
• nongaseous acidosiscausedby hypoxiaand inflow of underoxidized
metabolicproducts in the blood (when the loss of blood is about
30-40 ml/ kg the concentrationof lactic and pyruvic acids grows in
1.5- 2 times);
• dysfunctionsof internalorgans:the lungs(bradypnea , respiratorydis-
tresssyndrome),kidneys(renalfailure, decreaseof glomerularfiltration
intensityunderthe drop of arterialpressure)./iv er (disturbances in en-
zymeproduction , inhibitionof macrophagephagocyticactivity, meta-
bolic disordersof all types, loweringof plasmapr otein reservewhich
mayresultin completeexhaustionof proteinsystemsin the organism).

After a profuseblood loss, there is an emergencystate namedhemor-

rhagicshockmaydevelop .

Chapter 19. Red Blood Cell

Disorders
The erythrocytes, or red blood cells (RBC), are the most numerousof the
formedelements.Theyare small,biconcavediscswith a largesurfacearea
andcaneasilydeformin small capillaries.Theycontainthe oxygen-carrying
protein, hemoglob in, that functions in the transportof oxygen.Hemoglobin
alsobindssomecarbondioxideandcarriesit from the tissuesto the lungs.
Theerythrocytesarederivedfrom the myeloidor bonemarrowstemcell and
live approxima
tely 120 days in the circulation.The processof proliferation
andmaturationof red bloodcells stimulatedby erytropoetin , whichsynthe-
 372 f Part 2 Pathophysiologyof organsand systems

tise in the kidneys, and duringthis processstem cells transfermto baso-

philic, polychromatophilic, and acidophilicnormoblasts,than reticulocytes,
andmatureerythrocytes.In basophilicerythrocytescytoplasmreactto base
stainings,in polychromatophilic - bothacidandbasestainings,andin acido-
philic- acidstainingsstainedby Romanowsky-Giemsa. Themostimportant
processesin maturationof erythrocytes arethe accumulation of hemoglobin
in cytoplasmanddisappearance of the nuclearon whichchangesin staining
of erythroblasts depend.Reticulocytes maybedetectedin the bloodsmearby
supravitalstainingwith cresylviolet.
AgedRBCareremovedfrom the bloodin sinusesof the spleenandarede-
graded.Thefragmentsarebrokendownby macrophages in themononuclear
phagocytoticsystem(alsocalledreticuloendothelial system)of the spleen,
liver, bone marrow,and so on. Whenthe membraneof the RBCruptures
(hemolysis) , Hb is setfreeandis metabolized to globinandbilirubin.
In adults,the numberof redbloodcellsis 4-5x10 12/L of the bloodin males
and 3.5--4.5>< 1012/L in females. The hemoglobinconcentrationin malesis
130-160 g/L,whilein females120- 140 g/L.

There are two possible types of changes in erythro-

cyte and hemoglobin number in the peripheric blood
caused by pathological conditions:

1) erythrocytosis(polycythemia,erythrocythemia)
- an increasednumber
of erythrocytesandhemoglob in;
2) anemia- a reductionin erythrocytesandhemogJobin.

Quantitative change~ in erythrocytes may be:

• absolute,relatedto the changeof absoluteerythrocyteamountin the

blooddueto the bloodlossor imbalancebetween theerythrocyteforma-
tion (erythropoiesis)
andthe erythrocytedestroying(erythrodieresis);
Pathophysiologyof hematopoieticfunction Unit 5 I 373
• relative,are observedin a volumeunit of the bloodwithout changesof
the total massof erythrocytesin the organismdueto the redistribution
of their circulating anddepotfractionsresultingfrom changedplasma
volume(in water loss, hemodilution).

Qualitativechangesin red blood cells includeregenerativeformsof

, cells of pathological
erythrocytes regeneration, degenerative
changesin
erythrocytes.

Qualitative changes in erythrocytes may be caused by :

• disturbancesin erythrocytematurationresultingfrom erythropoietic

disorders;
• accelerated outputof so-calledregenerativeforms of erythrocytes(re-
ticulocytes,polychromatophilicerythrocytes,acidophilic,polychro-
matophilic, and basophilicnormoblasts)- young immature cells with
the lowcontentof hemogl obin (asa resultof the increasedpermeabil
ity
of the marrowybarrier);
• changeof the hemopoietictypefrom erythroblasticto megaloblastic
accompaniedby producingcells of pathologicalregeneration-meg-
aloblasts (extremelylarge nucleatedcells (diameter- 12-15 µm)
containingbasophilic,polychromic,or acidophilic cytoplasmwith
a large off-center nucleuswhich has delicatechromatin network),
megalocytes(akaryocytesdevelopingunderthe maturation of meg-
aloblasts. Diameter> 9.5 µm. They are intensivelycolored, oval-
shaped,having no clarificationsin their central part, particularto
erythrocytes);
• productionof degenerative(defective)formsof red bloodcells.

Degenerativechanges are the qualitativechangesin erythrocytescon-

firmingthestructuralandfunctionaldefectivenessof thecells.
 374 I Part 2 Pathophysiologyof organsand systems

These changes are characterized by the following

phenomena

a. Anisocytosis - the presenceof differentlysizedcells: normocytes

(diameter=7.0-8.0 µm, MCV= 75-100 fl), microcytes-diameter
< 6.9 µm (MCV< 75 fl), macrocytes - diameter>8.1 µm (MCV>
100 fl) .
MCV- meancorpuscularvolume:the averagevolumeof a red bloodcell,
expressed in femtoliters- fl (1 fl= 1 µm3 = 10-15 L); MCV= (Hctx110) / RBC.
b. Poikilocytosis - the presenceof abnormallyshapederythrocytes
(poikilocytes)(Fig. 40): almost spherica l in shape(spherocytes),
oval or cigar shaped(el/iptocytes) , with slit-like, rectangular or
mouthlikearea(stomatocytes) , with a darkcentralcolor spot in the
areaof pallor and a peripheralring of hemoglobin,separatedby a
pale unstainedring containingless hemoglobin, resembling a tar-
get (codocytes),helmet-like (chistocytes),sickle (drepanocytes),
shapedlike a teardrop(dacryocytes) , appearingto havea bite of
cytoplasmremoved( "bite cells" or degmacytes), urchin-like with
multiplesmall projectionsevenlyspacedover the cell circumfer-
ence(echinocytes , crenocytes),with finger-like(thorny)projections
(acanthocytes).
The presence/absence of spherocytesindicatedby the erythrocyticindex
MCHC(Meancorpuscularhemoglobinconcentration) : the averageconcen-
trationof hemoglobinin a givenvolumeof packedredbloodcells,expressed
in percentage(%); MCHC= Hb (g/dl)/Hctx 100. Norm- 32.4-34.8 %. In
spherocytosishemoglobinis housedinsidethe lesscapacityof erythrocyte,
so MCHCincreases( > 36 %). ·
Pyropoikilocytosis - presencein the blood of numerousbizarre-shaped
heat-sensitivepoikilocytes.
c. Anisochromia - a differentamountof hemoglobinin erythrocytes .
Therearehyperchromic (intensivelycolored- MCH> 35 pg)andhy-
pochromic(slightlycolored- MCH< 27-30 pg), annulocytes, having
coloredanonly peripheralring-shapedsitewhichcontainshemoglo-
bin, whilein its centralpartthereis a clarification;
 Pathophysiologyof hematopoieticfunction Unit 5 I 375

• 1
.9 ◄"
••• 2
(J
3
Alli
~

~· ,~,c ~
4 5

f.st
6 7 8 9 10

Fig.40. Pathologicformsof erythrocytes :

• 1 - spherocyte
, 2 - elliptocyt
e,3 - stomatocyte,
4a- codocyte (targetcell,Mexica n hatcell),4b- scheme ofcodocyte "halfface",
5 - schistocyte
(helmet cell), 6 - drep;mocyte (sickle cell),7 - dacryocyte (teardropcell),
8 - degmacyte (bitecell),9 - echinocyte, 10 - acanthocyte (spur cell).

1 3 4

b
7

Fig.41. Pathologicerythrocyte inclusio ns:

1 - Howell
-Jollybodies, 2 - Cabot 's ringbodies,3 - Pappenheimerbodies,
4 - basophilic
pointing, 5 - Heinz -Ehr1ich bodies, 6 a,b - HbCcrystals,
7 - babesial
inclusions, 8 a,b,c - plasmodial inclusions.
 376 I Part 2 Pathophysiofogy
of organsand systems

MCH- meancorpuscularhemoglobin : the averagecontent(mass)of he-

moglobinper red blood cell, expressedin picograms- pg (1 pg = 10-12 g);
MCH= Hb(g/L)/RBC.
d. Pathologic inclusions(Fig.41):
• Howell-Jollybodies(smooth,roundpurplestainingremnantsof nuclear
chromatindueto incompletenucleusexpulsionseenin erythrocytes);
• Cabot's ring bodies(lines in the form of loops or figuresof 8, possibly
remnantsof the nuclear membraneor mitotic spindle, seenin stained
erythrocytesin severeanemias);
• Pappenheimer bodies(veryfine darkviolet staining(basophilic), sepa-
ratedor connectedgranulespresentin the cytoplasmof the erythrocyte,
particularlyoften nearthe peripheryof the red cell; probablytheseare
the equivalentto nonhemeiron granulesof siderocytes);
• basophilicpointing- disseminatedgranulesrelatingto ribosomepre-
cipitationthat displaystoxic affectionof bonemarrow;
• Heinz-Ehrlichbodies or granules(coccoid inclusion bodies resulting
from oxidativeinjury to and precipitation of hemoglobin, seen in the
presenceof abnormalhemoglobinssuch as Hb H, Hb Kain, etc. and in
erythrocyteswith enzymedeficiencies;retractilein fresh bloodsmears,
they are not visible when stainedwith Romanowsky -Giemsadyes but
maybe stainedsupravitallywith crystalviolet as darkinclusions);
• HbCcrystalsunderC- hemoglobinopatlly;
• parasiticinclusions(babesialand plasmodial).

Polycythemia (erythrocytosis, erythrocythemia):

an increasein the total
redcell massof the blood, hemoglobin and hematocri~.
Accordingto their origin, polycythemias may be absolute(due to the ac-
celeratederythropoies is) and relative(dueto plasmadiminishing).
Absolutepolycythemia: an increasein RBCmass(> 36 ml/kg in the male
or> 32 ml/kg in the female, measuredwith 51Crassay)causedbya sustained
overactivityof the erythroid componentof the bone marrow. This is often
followedwith an increasedoutput of the erythrocyte regenerative forms (a
numberof reticulocytesincreasesto 2-2.8%). Absolutepolycythemiamay
be primaryor secondary(erythropoietin -dependent).
Pathophysiologyof hematopoietic function Unit 5 I 377

Primary (erythropoietin-independent) absolute polycythemiaresultsfrom

the primarydefectof earlygenerat ionsof erythroid lineage , thatallowseryth-
rocyteprecursorsto divide andto maturebeingunexposed to normalregula-
tory influences. Thisis the characteristicsign of erythremia.
Erythremia(polycythemiavera, or Vaquez -Oslerdisease)is a neoplastic
diseaseby its nature(a myeloproliferative form of chronicleukemia) , accom-
paniedby the activationof all hemopoieticlineagesandthe increaseof both
packedcell volumeand hemoglob in level,and as well as leukocyteamount.
Theerythropoietinlevelis usuallylowered.1.5 to 15 per cent of erythremia
casestransformto acuteleukemia.
Secondary (erythropoietin-dependent)absolutepolycythemiaresultsfrom
the accelerated proliferationof erythroid cells under the influenceof exog-
enousirritantsandthe growthof erythropoietinproduction.Therearephysi-
ologicaland pathologicalsecondaryabsoluteerythrocytoses.Physiological
forms are consideredto be the manifestationsof long-lasting hypoxia(in
mountain-dwellers,in mountain-climbersduringtheacclimatization at a great
height,underthe useof dosatednormo-or hypobarichypoxiato train ath-
letesor in the therapyof certaincardiovascular , respiratorydisorders, etc.).
Thisform of erythrocytosisoccurs in caseswhenerythropoietinis adminis-
teredintothe organismas a dope or a medicine(e.g., as a component of pre-
operativeroutineto prevent the developmentof severeanemiawhich may
resultfrom a profuseblood loss- the so called"autodonation ").

Pa thological secondary a bsolut e polycyth e mi as

m a y be du e to :

• the totaloxygendeficiencyleading to the enhancement of erythropo ietin

incretion,andasa result to the accelerat
ion of erythropoiesis that is ob-
servedin cyanotic congenital heartdiseases , chronicpulmonarydisor-
ders,sleepapneasyndrome,chroniccarbonmonoxidepoisoning, inher-
itedabnormalities of hemoglobin anderythrocytes decreasing oxygenca-
pacityof blood. Theseabnormalitiesaregeneticallydeterminedby globin
defectsinthemoleculeof hemoglobin and/or bydeficiencyof erythrocyte
 378 I Part 2 Pathophysiologyof organsand systems

2,3-diphosphoglycerate (dueto thedeficiencyof diphosphoglycerate mu-

tase),whichregulatesoxygenation anddysoxidating of hemoglobin. And
at the sametime the contingencyof hemoglobinandoxygenincreases
(oxyhemoglobin-dissociation curveshiftsto the left) whileits output to
the tissueslowers.Hypoxiais observedas well as erythropoieti n pro-
ductionis stimulatedthat resultsin the enhancement of erythropoiesis;
• regionalrenalhypoxia(ischemia) as a resultof the excessiveproduction of
erythropoietin
inthekidneys( especially
in renalcystsand/orhydronephrosis) ;
• the presenceof erythropoietin-producing tumors;
• underthe elevatedconcentrationof hormonesin the bloodwhich pro-
mote erythropoietinproduction(thyroid hormones,glucocorticoids,
androgens , catecholamines). This is usuallyobservedundercertainen-
docrinepathologiesor under the hormonetherapy.

Togetherwith the growthof a numberof erythrocytes , hemoglobin

, and
hematocrit, in the caseof absoluteerythrocytosesthe circulatingbloodpool
may increase(polycythemichypervolemia) , the blood viscosity becomes
higher,but the rateof the bloodflow slowsdownandcardiacfunctionsmay
be impaired.This conditionis characterized by the increasedarterialpres-
sure,plethoraof internalorgans, hyperemiaof the skin and mucousmem-
branes,enhancedbloodclotting.
Relativeerythrocytosis maybe physiologicaldueto the bloodredistribu-
tion (outletof the bloodform blooddepots)or maydevelopduringtheemer-
gencyadaptation responseto hypoxia(e.g., in casesof the rapidmountain
climbingwhenthereis no time for preliminaryacclimatization).

Th e common e st c a uses of p athological relative

e rythrocytos es ar e : ,

• thedecreasein thevolumeof thebloodplasma(hemoconcentration) which

is connectedwith considerablelossof waterby the organism(asin diar-
rhea, plasmorrheain extensiveburns, lymphorrhagia,
diuretic therapy)
;
• bloodredistribution(as in shock).
Pathophysiologyof hematopoieticfunction Unit 5 I 379
Thecharacte risticsignsof relativeerythrocytoses aremainlydetermined by
thehemoconcentration withthedevelopment of normo-or hypervolemic polycy-
themiaandthe riseof the hematocrit value.Thisresultsin t~eworsening of the
bloodrheologica l properties
, microcirculatory disordersandthrombosisaswell.
A numberof regenerative formsof erythrocytes (reticulocytes)
is still normal.
Anemia(an- negation+ Gk.haima- blood)is a conditionwith hemoglobin
reduction in bloodbelowthenormalreference rangerelevantto thegivenperson
according to thesex,age,externalconditionsof lifeandimportantcircumstanc -
esin theorganismin thegivensituation . Reduced concentration of erythrocytes
andhematocrit valuearefrequen tly accompanied withdecreased hemoglobin.
Accordingto World HefalthOrganization criteria, anemiais diagnosedin
maleswhenHbis< 130g/L and Hct is< 39 %; in females,whenHb is< 120
g/L andHct is < 36 %.
If the changesof watercontentor its shift in the organismarenot involved,
the hemoglobinlevelcorrelateswiththe hematocritvalue(duringdehydration
evenin ananemicpatientarenormalhemoglobinanderythrocytevaluesdue
to the plasmavolumedecrease).
Theprincipalandobligatoryphenomenon accompanying the development
of anemiais a reductionof the hemoglobinconcentrationper unit of blood.
It followsthat the essenceand importanceof this stateof the organismare
primarily determinedby the diminishingof the oxygenconcentrationof the
blood, resultingin hemichypoxemia , which in its turn conditionsthe com-
monsignsof clinicalpresentation of variousanemias.At the sametime,the
peculiar ities of their etiologyand pathogenesis determineseriesof specific
syndromeswhich are inherentin certainanemia(e.g., B,2-deficient anemia
is characterized by neurologicaland digestivedisorders, while jaundiceis a
particularfeatureof hemolyticanemia).
Anemias canbesubdividedinto2 groupsonthebasisof whetherthechange
in redcell mass(RCM) is absoluteor relative.In absoluteanemia,thereis a
true decreasein RCM.In relativeanemia,thereis a fluid shift from the ex-
travascularto the intravascular compartment , expandingthe plasmavolume
anddilutingthe RCM.This is usuallyseenin associationwith pregnancyand
hyperproteinemia. Thus, accordingto their pathogenesis relativeanemiasare
diluting.Theclassification of absoluteanemiasis represented in the table22.
 380 I Part 2 Pathophysiologyof organsand systems

Table22. Classification
of anemias
(abso
lute)
- ,., ' ·. ;( ' ,: , :t~\;;.:;.,;.,.~, . "·
..~.r...-M't»-fe•
.,.,~!':··-
Criteria Types
.ofanemias ,. ,' ,. :.:;:;t~~~:::t
/~!~~{
'
;
. ".

Byetiology Hereditary,
acquired

Bypathogenesis Posthemorrhagic,
hemolytic,
dueto erythropoiesis
disturbance

Bytypeof hemopoiesis Erythroblastic,

megaloblastic

Byabilitiesof thebone Regenerative

(1.5-5%reticulocytes,
reticulocyteindex1-2),
marrow toregenera
tion ( > 5%reticulocytes,
hyperregenerative index> 2),
reticulocyte
( < 1.5%reticulocytes,
hyporegenerative reticulocyteindex< 1),
aregenerative
(0reticu
locytes)

Bycoloi:index(Cl),orMCHCNormochromic(Cl=0.85-1;MCHC = 33-36g/dl),
(Cl> 1; MCHC
hyperchromic > 36 g/dl), hypochromic
(Cl< 0.85;MCHC < 32 g/dl)
Bysizeoferythrocytes
, or Normocytic(0 =7.0-8.0mm;MCV= 75-100fl), microcytic
MCV (0 < 6.9 mm;MCV< 75 fl), macrocytic
(0 > 8.1 mm;
MCV> 100fl)

Byclinical
course Acute,
chronic

Reticulocyte index = reticulocytes (%) x patient's Hct / normal Hct.

Posthemorrhagic anem ias

Posthemorrhagic anemias arise.asa resultof the lossof largebloodvolume.
Accordingto the characterof bloodloss,anemiasaredividedinto acuteand
chronicposthemorrhagic anemias .
Acuteposthemorrhagic anemiasarise after a single severehemorrhage
(morethan10 percentof circulatingbloodpool).
Pathophysiologyof hematopoietic function Unit 5 I 381

Peripheral blood shows the st a ge char a cter in

changes of hematological indic e s :

1. Soonafter hemorrhage(for first severalhours)a steadydiminishing

of total corpuscular volumeand proportion of blood plasma(normo-
cythemichypovolemia) is usuallyobserved.Hence , hematocritvalue, a
numberof erythrocytesandhemoglobinconcentrationper volumeunit
of bloodare still normal.Onlythe indexof circulatingerythrocytevol-
umeis decreased .
2. Duringtheperiodof severalhoursor severaldaysafteracutebloodloss
the following changesas the reduction of hemoglobin concentration ,a
numberof erythrocytes, andthe diminishingof hematocritvalue(oligo-
cythemic hypo-or normovolem ia) aremarked.All thesechangesresult
from dilution(hydremic)compensation of acutebloodloss (Seeabove
under"Blood loss").The color index remainsunchangeable (erythro-
cyticnormochromia), asthe matureerythrocyteshavingbeenpresentin
the bloodstreamprior to a bloodlosscirculate in the blood.
3. Duringtheperiodof 4-5 daysto 1-2 weeks afteracutebloodloss due
to the mechanisms of its marrowycompensation a dramaticincreasein
a numberof regenerative erythrocyticforms occurs(a numberof reticu-
locytesexceeds15 %, reticulocyteindexis morethan 1), that indicates
the regene rativecharacterof anemia. The color indexis usually lower
than 0.85 (erythrocytichypochromia),as the rate of hemoglobinsyn-
thesisremainsbehindthe rateof the erythrocyteprecursorproliferation.

Chronicposthemorrhagic anemiadevelopsafterrepeatedevenslightblood
lossesand relatedto the increasingiron deficiencyof the organism.This is
a variant of iron-deficientanemias(Seebelowunder"Deficiencyanemias ").

Hemol yt ic anem ias

Hemolyt ic anemiasaredue to the increasederythrocytedestruction (hemoly-
sis), that resultsin the shorteningof erythrocytelife-span.
 382 I Part 2 Pathophysiology
of organsand systems

Classification
1. Accordingto the origin:a) hereditary
; b) acquired.
2. Accordingto the causeof hemolysis: a) intrinsic (intracorpuscular)
abnormalities of red cells; b)extrinsic(extracorpuscular)abnormali-
ties;
3. Accordingto the mechanismsof hemolysis:a) anemiaswith mainlyin-
tracellular(extravascular)hemolysis;b) anemiaswith mainlyintravas-
cularhemolysis;
4. Accordingto theclinicalcourse:a)acute;b) chronic.

Generalmechanisms of hemolyticprocess.In hemolyticanemia,the

destruction of erythrocytesmaydevelopboth intracellularly(dueto the in-
gestionanddigestionof erythrocytesby macrophages) as it usuallyoccurs
within1henorm, anddirectlyinsidethe vessels.
Theintracellularhemolysis(extravascular) hemolysisis usuallydueto the
following factors.
a. Theappearance of abnormalerythrocyteshavingreducedflexibility
and elasticity which can not rapidly changetheir shapeand, hence
can not passthrough interendothelial spacesof narrow,slitlikeve-
nous passagesin the spleen.Damagederythrocytesare held up in
the redpulpanddigestedby macro·phages.
b. The desializationof the erythrocytic membranesglycoproteins(
the so called antigenof aging cell belongsto them) and the de-
masking of terminal residuaof certain carbohydrates(e.g., ga-
lactose),that triggers the mechanismof phagocytosisunderthe
influenceof reactiveoxygenspecies, underthe changeof cellular
volumeandosmoticenvironment,aging,certainpathologicalpro-
cesses; ,
c. Opsonization of erythrocytes
with immunoglobulins whichcaninter-
act with macrophage receptorsin a specialway.
d. Hypersplenism - an increaseof phagocyticactivity of macrophages
in the spleen.
Pathophysiologyof hematopoieticfunction Unit 5 I 383
Enhanced phagocytosis may lead to the following
changes:

• productionof a largeamountof indirect bilirubin (unconjugatedwith

glucuronicacid)resultingform hememetabolism,that maygiverise to
hemolyticjaundice;
• proliferationof macrophages, leadingto the enlargementof the spleen
(splenomegaly).

Moreover , when intracellular hemolysis is turning

into chronic, this may give rise to:

• production of hemosiderin,an iron-containingpigment,as a result of

hemoglobinbreakdownin macrophages (hemosiderosis);
• formationof gall-stonedueto long-term bilirubinemia(cholelithiasis)
.

Intracellularhemolysisarisesin casesof damagingerythrocytesdirectly

within the bloodvesselsby mechanical , complement-determined influence
,
exogenous hemolyticfactors(ionizingradiation,ultrasoundwaves, hemolytic
poisoning , microorganisms and/ or theirtoxins).

lntravascular hemolysis is manifested by :

• hemoglobinemia -the presenceof freehemoglobinin the bloodplasma

in the concentration > 0.04 g/L;
• hypohaptoglobinemia - is a significantfall of plasmatichaptoglobin
level,which boundsfree hemoglobinin plasma;when the haptoglobin
is depleted, free hemoglobinis prone to oxidationto methemoglobin,
whichis unableto carryoxygen;
• hemoglobinuria , and methemoglobinuria (someof the filtered hemo-
globinand methemoglobin passesout with the urine,impartinga red-
browncolor);
 384 I Part 2 Pathophysiologyof organs and systems

• hemosiderinuria - the presenceof hemosiderinin the urine which is

appearedin the cellsof tubularepithelium whenthe hemoglobi
n breaks
down;
• hemolyticjaundicedue to hyperbilirubinemia owing to unconjugated
bilirubin.

Hemopoiesis in hemolytic anemias.As a responseto the shorteningof

erythrocytelife-spanin the peripheralblooderythropoiesisincreases . When
stimulating healthybonemarrowits productivity becomes6- 8 timeshigher.
At the sametime, the life-spanof erythrocytesmay reduceto 15-20 days
without anymarkeddevelopment of anemia.
Endoerythrocytic hemolytic anemias , accordingto themechanisms of the
development , are divided into three groupswhich are relatedto the distur-
bancesof:
1) erythrocytic membranestructure(membranopathy);
2) erythrocytic enzymeactivity (enzymopathy);
3) structureor rateof hemoglobinsynthesis(hemoglobinopathy).

Membranopathies arecharacter
izedby disorders of proteinor lipid com-
ponentsof the erythrocyticmembranestructure.

So , two typ e s of m e mb ranopathies may be dist in-

gui she d :

1. Membranopaties
causedby the disordersof proteinstructure(protein-
dependent): a) hereditaryspherocytosis (Minkowski-Chauffard disease);
b) hereditaryelliptocytosis(ovalocytosis); c) hereditary pyropoikilocyto-
sis; d) hereditaryandacquiredstomatocytosis.
2. Membranopathies causedby the disordersof lipid structure (Jipid-
dependent):a) hereditaryabetalipo proteinemia (hereditaryacantho-
cytosis - Bassen-Kornzweig syndrome);b) hereditarydeficiency of
phosphatidylcholine -cholesterol-acyltransferase activity; c) hereditary
growthof phosphatidylcholi ne (lecithin)in anerythrocytemembrane ; d)
Pathophysiologyof hematopoietic function Unit 5 I 385
paroxysmal nocturnal hemoglobinuria (Marchiafava-Micheli disease);
e) secondary(in E vitamindeficiency
, acutehepatitis, hepatocirrhosis,
prematurity
, hypothyroidism, etc).

Protein-dependent membranopaties . Hereditaryspherocytosis(HS,

Minkowski-Chauffard disease)is a heterogenous groupof genocopies caused
by genemutation, whichcodemembranes of erythrocyticcytoskeletalpro-
teins(ankyrin, p-spectrin , band3 protein, a-spectrin,andprotein4.2).
In approximately two thirds of HSpatients,inheritanceis autosomaldomi-
nant.In this groupof "typical"HSpatients, ankyrinmutationsare the most
common causeof HS, followedby mutationsin band3 andp-spectrin. Cases
with autosomalrecessive inheritance aredue to defectsin eithera-spectrinor
protein 4.2, as wellas de novamutationsin the HSgenes.
· Erythrocytemembranesfrom HS patients most commonlycombined
spectrinandankyrin deficiency, followed by band3 deficiency , isolatedspec-
trin deficiency
, and protein4.2 deficiency. As a result, the abilityof spectrin
to polymerizedecreases , as well as erythrocyte s lose their ability to keep
biconcav e shape.
An increasedpenetrationof sodiumionsand calciumions into an eryth-
rocyteresultsin an increasedutilization of ATP, which is required for the
functioningof Na+/K•-ATP-ase,glycolysisactivation,andcorrespondingly for
the lacticacid accumulation and pH reductionas the acidoticmechan isms
triggeringthe erythrocytedamage . Under the condition of the developing
bioenergyinsufficiencysodiumions stay within the cell too long initiating
electrolytic-osmotic mechanism of its damage.Erythrocytes becomespheric
in shapeandexpressanantigenof agingcells.
Thespleenis involvedimmediately in the developmentof the disease.The
spheric shapeof erythrocytesimpedes themto transform passing through
the narrowpassagesof bloodstream(e.g.,throughthe endothelialfissures
whosediameter is 2-3 µm whentransferringfrom inter-sinusspaceinto the
sinuses).This results in the long-periodrestrainingof erythrocytesin the red
pulp, theirbeing"cracked"and"bitten" by macrophages of the spleen.
Whensomepartsof the plasmalemma do breakoff the erythrocyteturns
into the smallsizesherocyte(microspherocyte) undergoingthe osmoticly-
 386 I Part 2 Pathophysioiogyof organsand systems

sis and phagocytosis(intracellularhemolysis)in 2-3 passagesthroughthe

spleen.Therefore , the life-spanof microspherocytesis considerably reduced.
It lasts8-15 days, i.e. 1otimesshorterthanin normalerythrocytes.
In the severecourseof inheritedmicrospherocytosis the procedureof the
removalof the spleen, wherethe erythrocytessequestration occurs most
intensively , maybetheonlywayof the effectivetreatmentandis pathogeneti-
callyjustified.Whenthe operationhavingbeenperformedon, hemolyticane-
miadisappears, but morphological abnormalities
of erythrocytesstill remain.
In inheritedelliptocytosisthe abnormalitiesof cytoskeletonare localized
on the sitesof cytoplasmicproteins'interaction , speciallybetweena- andp-
spectrinas well as betweenthe spectrinandprotein4.1.This producesoval-
shapedor ellipticerythrocytes(theirnumbermayreachmorethan25-27 %
of thetotal numberof erythrocytes) havingreducedlife-span.Theinheritance
is usuallyof the autosomal-dominant type;moreover,the majorityof the pa-
tients areasymptomaticor sufferfrom moderateanemiaor splenomegalia.
The severe form of inherited elliptocytosis is inherited pyropoikilocytosis,
characterized by the autosomal-recessive
typeof inheritance, the presenceof
fragmentederythrocytes . microspherocytes, andelliptocytes.
Someraredefectsinheritedby theautosomal-dominant typeandrelatedto
the cationpermeabilityor completeabsenceof the structuralproteins in the
erythrocyticmembrane whichcarryRh-antigen (Rhnullsyndrome)mayiniti-
atethe transformationof the cell'sshapeaccordingto thetypeof stomatocy-
tosis.Casesof acquiredstomatocytosis resultingfrom alcoholism,malignant
tumors, vasculardiseasesanddiseasesof biliaryducts,as adversereaction
of somemedicinesareknownas well.
Lipid-dependent membranopathies. Alterationsin quantitativeandquali-
tativecompositionof the plasmalipidsmayprovokedisordersin thechemical
compositionof erythrocyticmembranes, in the correlationbetweenthe area
andvolume.in the osmoticsta~ility.Passive changein lipid contentsof the
membraneof erythrocyteslowerstheir toleranceto autooxidation,andthis
promoteshemolysisof erythrocytes(oxidativeerythrocytolysis).
Hereditaryabetalipoproteinemia (hereditaryacanthocytosis,or Bassen-
Kornzweigsyndrome)- is an autosomal-recessive diseasecharacterized by
p-lipoproteindeficiency.Acanthocyte(Gk.<<acanthus» -thorn , barb),or spur
Pathophysiologyof hematopoieticfunction Unit 5 I 387
cells,mayoccuras a resultof acquireddisturbancesin lipoproteinmetabo-
lism (severeliverimpairment , E hypovitaminosis, starvation,certainresorp-
tive disorders,in patientswith the removedspleen).In uremiaerythrocytes
with prominentedgedsurfaceare present.Theyare calledechinocytes(Gk.
«echinos » - urchin).
Inheritedlipid-dependent membranopathies may also be relatedto the
insufficiencyof phosphatidylcholine-cholesterol-acyltransferase activity(au-
tosomalrecessive inheritance)andthe increaseof phosphatidylcholine (leci-
thin)in erythrocyticmembrane (autosomal dominant inheritance).In this case,
the lecithinaccumulation in the erythrocytesof the patientsresultsfrom the
disturbances in the transmissionof plasma phosphatides through phospha-
tidylethanolamine. This promotesthe increasedmembranepermeabilityto
cationsandthe shift in sodiumandpotassiumratioof 1:1 (the normalratio
is of 2: 3) dueto the increasingof Na•/K•-ATP-aseactivityin 4 times.These
factorsleadto the shorteningof the life-spanof erythrocyteswith their pre-
dominant sequestration in the.liver(intracellularhemolysis).
Paroxysmal nocturnalhemoglob inuria(PNH,Marchiafava-Micheli disease)
is anacquireddiseaserelatedto the somaticmutationwhenthe cloneof he-
mopoieticcellsis unableto synthesize glycosylphosphatidylinositol (GPI) - a
specializedphospholipid,neededfor bindingpowerful serumcomplement
inhibitors(GPl-linkedproteins)with anerythrocyticmembrane.
Threeproteinsareknownto producethedevelopment of PNHbythe defec-
tivebindingwiththem:thesearea decay-accelerating factor(OAF) , or CD55;a
membrane inhibitorof reactivelysis(MIRL), or CD59;anda C8 bindingprotein.
Thelargestpartinthedevelopment of PNHbelongsto CD59thatis determined
by its crucial rolein the limitationof spontaneous activationof the alternative
complement pathwayresultingfromthe rapidinactivationof C3 convertase.
Owingto the ability of hypercapnia and acidosisdevelopingduring the
sleepto provokethe complement activation,the attacksof hemolysisoccur
at night (in 25 per cent of cases), and in the morningthe peculiarsigns of
intravascular hemolysis(hemoglobinuria, hemoglobinemia, hemosiderinuria)
appear.Sometimes theseattacksareaccompanied with backaches. Butin the
majorityof PNHpatients, chronichemolysiswithoutconsiderablehemoglo-
binuriais usuallyobserved .
 388 I Part 2 Pathophysiologyof organsand systems

As the defectdevelopsat the levelof pluripotentsteamcells, erythrocytes

as wellas leukocytes , thrombocytes aresubjectedto complement-dependent
lysis.PNHmaybeaggravated bythe development of aplasticanemiaor acute
leukemia.
Enzymopathies are characterized by the deficiencyand /or the decrease
of activityof erythrocyticenzymeswhich participatein the energysupply or
antioxidantprotectionof erythrocytes.
1. Embden-Meyerhof pathway(anaerobicg/ycolysis)defects , that is con-
sideredto be virtuallya significantway in ATPresynthesis. Thetrait is
autosomalrecessive.The commonestdefectis the deficiencyof pyru-
vatekinase. Insufficien t energy of ATPinfluencesnegativelyon the Na•/
K·-ATP-aseactivity, resultingin the loss of potassium ions, hyperhy-
drationand edemaof the cells, so a largenumberof erythrocytesare
expanded(macrocytes).Onthe surfaceof the cellsthe antigenof aging
cells expresses,that leadsto their sequestration and phagocytosisby
macrophages of the spleen(intracellularhemolysis).
2. Hexosemonophosphate shunt defects.The commonestenzymopathy
is relatedto glucose-6-phosphate dehydrogenase (G6PD)deficiency ,
and more than 200 millions peopleworldwideare reportedto suffer
from the disease . The deficiencyis determinedby recessivecoupled
with X-chromosomeinheritanceof one of numerousabnormalalleles
of the generesponsible for G6PDmoleculesynthesis . Thus, thedisease
relatedto the defectof the enzymeis morefrequent amongthe males.

There are two genetic variants of the disease con-

sider e d to be the commonest :

a. the variantA·, occurringin blacksis milder (dueto the singlemuta-

tion of the geneof this enzymeanddamageof aged erythrocytes);
b. the varianta-(Mediterranean) , occurringin the regionof Mediter-
ranean Sea)is a conditionwith very low values of G6PD, reaching
only 5 % of normalvalues (relatedto two mutationsanddamaging
of erythrocytesof all the agegroups).
Pathophysiologyof hematopoieticfunction Unit 5 I 389
G6PDinsufficiencyresults in the reducedproductionof NADPHin an
erythrocyte(owing to the defectof hexosemonophosphate shunt,whichkey
enzymeis G6PD ) and therefore,considerablylessensability to resist free-
radicalprocessesdueto the deficiencyof reducedglutathione.
Oxidativestressin erythrocytesmaybe inducedmorethan 60 drugs (an-
timalarials , sulfonamides , nitrofurantoins, etc.), plants (frequen tly - fava
beans, bilberry, malefern, etc.), certain infections(microplasmous,viral,
etc.). Exceptional hypersensitivity to the drugs and fava beans(Viciafaba)
or evento their pollen(favism)are peculiarto the Mediterranean variant of
G6PDdeficientanemia(occurringin the regionof the Mediterranean Sea).
Theoxidationof unprotectedSH-groupsof the hemoglobinresultsin its
denaturation with furtherprecipitationin theform of Heinzbodiesandforma-
tion of disulfide"bridges"with the cellularmembraneof erythrocytes.Later
on the damagedcellsareeliminatedby macrophages of the spleen(intracel-
lularhemolysis).In the peripheralblood, the so calledbitecells(degmacytes)
maybe observed.Theirappearance resultsfrom the removalby phagocytes
the segmentsof cellscontaininghemoglobinprecipitates.
In the variantof G6PDA insufficiency the hemolysis mayoccurin 48-96
hoursafterthedrugadministering andis knownto be self-limiting .
In G6PDs-deficiency , the hemolysismaybe severe, intravascular,result-
ing in indirecthyperbilirubinemia andanemiawith high reticulocytosis aswell
as in hemoglobinemia , hemoglobinuria , thrombosis, etc.
3. Inheriteddefectsof theglutathionesystem(glutathionesynthetase,glu-
tathionereductase , glutathioneperoxidase)promotethe implementa-
tion of the oxidationand osmoticmechanismsof the erythrolysiswith
the followingphagocytosis of damagedcells.
4. Inheriteddetectsof ATP utilizationferments(protein componentsof
Na•/K•-ATP-ase ) result in the increaseof sodiumion concentrationin
cellsandthefunctioningof the osmoticmechanisms by meansof which
defectiveerythrocytes areeliminatedby macrophages of the spleen.

Hemoglobinopath ies are inherited abnormalitiesin the humanhemoglo-

binsynthesis.Qualitative
hemoglobinopathies referto disturbancesof the pri-
marystructureof hemoglobinmolecules(hemoglobinoses) and quantitative
 390 I Part 2 Pathophysiology
of organsand systems

hemoglobinopathiescharacterizedbythe quantitative
fall of productionor by
completeabsenceof normalglobinchainwith the unalteredprimarystruc-
ture (thalassemias).
Theintracellularhemolysisis peculiarto all thetypesof
hemoglobinopathies.

The following types of hemoglobinoses are distin-

guished. They are related to the following things.:

1. Thecarriageof hemoglobinchangingits structurein hypoxia(S hemo-

globinopathyor sicklecellanemia(drepanocytosis)). This conditionis
a singlebasemutationof DNAmoleculeleadingto the substitutionof
valinefor glutamic acidin 6th positionof the '3-chainof globin.
Deoxygenated HbS is 50 times less solublecomparingwith HbA,
thereforeif the HbSis lesssaturatedwith oxygenits moleculesundergo
aggregation and polymerization . With continueddeoxygenation , aggre-
gatedHbSmoleculesassembleinto long needle-like fibers within red
cells,producinga distortedsickleor holly-leafshape(drepanocytes).
They hardlypassthroughthe narrowcapillariesand interendothelial
spacesof venoussinusesof the spleen,that maycausethe occlusion
in the microcirculation.This explainsthe intensityof the phagocytos is
of sickle-shaped erythrocytes by macrophages (intracellularhemolysis)
andmarkedtrophicalterationsin thetissues, eventhrombosesandne-
croses.The severeform of this anemiaoccursin only homozygous by
HbSgenecarriers.
2. Thecarriageof abnormalstabilehemoglobin _s (C,D, E hemoglobinopa-
thies).Thesediseasesdeclarethemselves in the homozygous condition
only.
3. Thecarriageof abnorm~Iunstablehemoglobins. In contrastto the sub-
stitutionof aminoacidseffectingthe polarityof theexternalsurfaceof a
hemoglobinmoleculeamongthe stabilehemoglobins, the substitution
in the unstablehemoglobins occursinsidethecavity(or "socket")of the
hemein a - or p-polypeptide chains.Thesubstitutionin this siteof heme
attachmentresultsin the abruptinstabilityof the moleculeand hemo-
Pathophysiologyof hematopoieticfunction Unit 5 I 391

globinprecipitationcausinghemolyticanemiain heterozygous
persons
carryingthe pathologicgene.

The precipitatedhemoglobinbindingwith the membraneof erythrocytes

evokesthe hemoglobin'sdestroying.Suchchronichemolyticprocessesare
character izedbytheappearanceof Heinzbodiesin erythrocytes aswellasthe
excretionof umberurinewhichcontainsdipyrrolcompounds.Theanemias
areinheritedby the autosomal -dominanttype.As a rule nearlyall the typeof
the diseaseis givena nameof the city whereit wasfoundout firstly.
Thalassemias (Gr. thalassa- sea (this was firstly observedamongthe
Mediterraneans) + haima- blood) are hereditarydetermined(autosomal-
recessive hereditarytype)hypochromic hemolyticanemiasrelatingto thede-
fect in the synthesisrateof hemoglobin chainsandas a resultthe formation
of a- andp-chainsis unbalanced. Thisgivesriseto the disturbances of het-
eropolymerization («pairing»)of hemoglobin chainscausingHbA(a2P2) de-
ficiency.Erythroidcellsof the diseasedpersonsproducehemoglobins which
arepartiallyto completelylacking in of a- andp-chains,so at a- thalassemias
andp- thalassemias aredistinguished.
Thedevelopment of p-thalassemias is concernedwith mutationswhich
blockcertainstagesof the geneexpressioninvolvingthe transcription , pro-
cessing,and translation.The mutationsin the promotorsite restrainthe
mRNAtranscriptionor disturbmRNAsplicing, andtherefore , reducethe rate
of p-chainsynthes is (p+-thalassemia). At the sametime the nonsensemuta-
tionsof exonsor stop signappearingresultin the untimely arrestof p-chain
synthes is, and,respectively , theircompletefailure(p0- thalassemia).
Thesigns of the reductionor arrestin the formationof the certainhe-
moglobinchain are concernednot onlyto the low levelof the intracellular
hemoglobin(hypochromatism) , but alsoto the relativelyacceleratedsyn-
thesisof certainotherchains.So,p-thalassemia is characterized by the ac-
celeratedsynthesisof a-chains, whichaggregateinto dissolubleinclusions
in erythrocytesand their precursors.This provokesprematured€stroying
of the cells of erythroidlineagein the bonemarrow(ineffectivehemopoi-
esis) and the intracellularhemolysisof matureerythrocytesin the spleen
as well.
 392 I Part 2 Pathophysiologyof organsand systems

Whena patientis a heterozygous individualandoneof allelesmaintainsthe

abilityto producep-chain(p+),the decreased numberof HbAunderthe com-
pensatoryincreasednumbersof bothHbF(a2y2) andHbA2 (a282) is observed
in the peripheralblood.This manifestationis peculiarto thalassemiaminor.
Whena patientis a homozygous individualby the alleleof p0-thalassemia,p-
chainsarenot produced , so thalassemia major(Cooley'sanemia)develops.It
usuallystartsduringthefirst yearof the life.Theconsiderable amount(upto
80-90 percent)of HbFin the bloodaswellasthe simultaneous HbA2 increas-
ing maybe detected.HbFis of increasedoxygenaffinity,·andas a resultthe
tissuehypoxiadevelops,the growthof the childis impaired.
a-thalassemia occurswhenoneor moreof four identicalcopiesof a-chain
globin geneof the 16th chromosomeare lost (in about80-85 per cent of
cases)or nonfunctional. Thesevereformsof hemolyticanemiadevelopwhen
three or four a-globin genesare lost or nonfunctional.In this case,HbA,
HbA2, and HbFare not produced.Insteadof a-chainsas a compensatory
response , the ~- andy-chainsaresynthesized.
The defectof three genescodinga-chains results in the productionof
unstableHbA(P4 ) , which easilyprecipitates.This causesthe development
of ineffectivehemopoiesisand intracellularhemolysis.Moreover, p-tetra-
mers are less proneto intraerythrocyticaggregation,that is why this type
of thalassemiais taking the relativelymild coursein comparisonwith its
p-type.
In the case of homozygousa-thalassemia,when all the four a-globin
genesare damaged , the productionof functionalhemoglobindiscontinues.
This hemoglobinis replacedwith y-chainsproducingHbBart(y4 ) in the pre-
natalperiod.HbBart(y4 ) is characterized with the highoxygenaffinity,which
is not releasedin the tissuesof the fetusthat resultsin the intrauterinefetal
deathor early neonataldeathdueto the developmentof severetissue hy-
poxia,congestiveheartfailure,oydropsfetalis.
The peripheric bloodof thalassem ic patientsrevealshypochromicmicro-
cyticanemia,poikilocytosis(codocytesanddacryocytes), regenerativeforms
of erythrocytes.Osmoticresistanceof the erythrocytesis high.
Exoerythrocytic hemolyticanemiasmay be immune-dependent (are
characterized with intracellularhemolysis,markedsignsof extravascular he-
Pathophysiologyof hematopoieticfunction Unit 5 I 393
molysismayalsobepresent ) andimmune-independent
(intracellularhemo-
lysisusuallypredominates).

Immune-dependent hemolytic anemias develop du e

to the immune mechanisms and, according to the
causative agents are divided into four groups:

• autoimmune- arecharacterized by antibodiesagainstthe ownerythro-

cytes;
• alloimmune (isoimmune)-causedbytheinfluxof antibodies fromoutside
againsttheownerythrocytic antigens(hemolyticdiseaseof newborns), or
bytheinfluxof erythrocytes containing antigensagainsttheownantibod-
ies (transfusion of incompatib le ABO, RHblood, etc.);- heteroimmune-
dueto theattachment of foreignantigens(haptens}, andmoreparticularly
drugs(antibio tics,sulfonamide), virusesto thesurfaceof erythrocytes;
• transimmune - developswhenantibodiesof a mothersufferingfrom
autoimmune hemolyticanemiapassthroughplacentato thefetus(these
antibodiesarepointedtowardanantigenof erythrocytes mutualfor both
- a motheranda fetus).

Such mechanisms contribute to the development of

hemolytic anemias:

1. Complement-dependent erythrocytecytolysisby binding erythrocytic

autoantigens with antibodiesand then later on with complementpro-
teins.
2. Antibody-dependent phagocytosisof erythrocytesdueto the bindingof
bindingerythrocyticautoantigens or beingadsorbedon the red blood
cellswithantibodies - opsoninswithfurthersplittingout of phagocytized
erythrocytes.
3. The"innocent"harmlesstype- complement-dependent erythrocytely-
sis dueto the adsorptionof immunecomplexeswith non-erythrocytic
 ·•.l

394 I Part 2 Pathophysiologyof organs and systems

antigenson it. This type of hemolysisoccursfollowing sulfonamide-,

phenothiazine- , quinine-andisoniazid-treatment.
• 4. Erythrocytic cytolysisresulting from the antibodyactionagainstfor-
eignantigen(haptens)dueto its absorptionon redbloodcells.
• 5. Mechani sms of "chemicalcomplex-formation" concernedwith non-
specificadsorptionof plasmproteins,includingimmunoglobulinsand
complement , on the erythrocytesby meansof a chemica l agentthat is
not an antigen(hapten).

Antibodieswhichare responsible for immunehemolysis, maybe grouped

asfollow:
Warm antibodies (generallylgG) - they show their maximumactivityat
37° Ctemperatureof a humanbody. Theyareincomplete , thereforetheydo not
stimulateerythrocytic agglutination,but makethemopsonic. Theantibodiesin-
teractwith earlycomponents of the complementaswell, buttheyareunableto
activatethewholecomplementary cascade (i.e.to inducethesuccessiverelease
of theproductswith hemolyticactivity).Thisresultsin thedevelopmentof intra-
cellularhemolysis, mediatedbydestroying of erythrocytes opsonized by macro-
phagesof thespleenandotherorgans.Andatthe sametimetheredbloodcells
becomespherocyte -like by their shape.Theseantibodiesmayarisespontane-
ously, in association with certaindiseases(autoimmune diseases, lymphomas ,
chroniclymphaticleukemia s), or afterstimulation by a drug(e.g., methyldopa,
levodopa). They mayalsooccur as partof a transienthaptenemechanism with
drugssuchas high-dosepenicillinor cephalosporins, in whichthe antibodyis
directedagainsttheantibiotic- RSC-membranecomplex.
Coldantibodies(generallylgM) are boundwith erythrocytesat the tem-
perature up 4° C to about 30 to 32° C. This temperature(30to 32° C) occurs
in acralparts of organismduring exposureto moderatecold. Theyaggluti-
nateerythrocytesandat high antibodytiter activatethe complementsystem
throughC1-component,resulting in the intravascular hemolysis.At low tem-
perature reactinglgM antibodiesmay be producedin organismduringthe
infectiousmononucleosis , cytomegaloviral or Epstein-Barrvirus infections
and mycoplasma l pneumoniaor during protozoa!infections. The produced
antibodiesmaysurvivein organismdaysandweeks.
Pathophysiologyof hematopoieticfunction Unit 5 I 395
D. Donath-Landsteiner antibodies- lgG:theyshowbetterresponseat low
temperature, areableto activatethecomplement , evokingthe intracellularhe-
molysis,anddeterminethe development of paroxysmalcold hemoglobinu ria,
whichmaybeprimary, but commonlyoccursdueto infections(congenitalor
acquiredsyphilis,infectiousparotiditis,measles , etc.).
Hemolytic diseaseofnewborns - is a diseaseresultingfrom the erythrol-
ysisof a fetusanda newborncausedby maternalantibodies,i.e.this disease
is consideredto be alloimmunehemolyticanemia.As antibodiesbelongto
lgG,they easilypenetratethe placentalbarrierandthen bind with the eryth-
rocytesof the fetus,that resultsin their destroyingin the spleen(intracellular
hemolysis).
As a rulethis pathologyis relatedto the immunefeta-maternalincompat-
ibilitydueto Dantigen(rarely- CandE) of Rhsystem,antigensof ABOblood
groups.
Rh-conflictmay developduringthe pregnancy(is morecommonduring
the consecutivepregnancy when an Rh-negativewoman is pregnantwith an
Rh-positivefetus. At first a motherbecomesimmunizedwith D antibodyof
fetalerythrocytes whichmaygetintothe maternalcirculationduringthe preg-
nancywhenthe placentalmembranethat separatedthe maternalbloodfrom
the fetal bloodmaybe broken,or duringthe childbirth. Immunizationduring
the childbirth is regardedto bethe mostlikely, thereforethe Rh-conflictusu-
allyoccursduringthe pregnancy with a secondRh-positivefetus.Rh-negative
womenmaybeimmunizedby Rh-positivebloodtransfusion(intramuscularly
or intravenously) aswellasdueto the inducedor spontaneous abortion,ecto-
pic pregnancy. As a responseto the inflowof Rh-positiveerythrocytesin the
maternalorganismthe antibodiessynthesizeagainst0-antigen. .
ABO- conflictcommonlyoccurswhena motheris a personwith 0(1)blood
type,whileafetusiswithA(II) or B(III). Norma l isoagglutinins
of ABOsystembe-
longto lgM.Theseantibodies do not penetrate the placentalmembrane, there-
forecannotevokeABO-conflict. Nevertheless, 10 % of healthypersonswithtype
0(1)bloodhaveantibodies againstA andBagglutinogens,belongto lgG.
Thepresenceof suchantibodiesdoesnot dependon the previousimmuni-
zation. lgGagglutininspenetratethe placentalmembraneand maycausethe
erythrolysisof a fetuswith typeA(II) or B(III) blood.
 396 I Part 2 Pathophysiologyof organsand systems

To overcomethe considerableerythrocyteloss in hemolyticdiseaseof

newbornsimmaturecellsof erythroidlineagecontainingnucleibegin appear
and accumulatein the peripheralblood(so, anotherterm for the disease-
erythroblastosisfetalis).
Certaincases, causedby physicalhemolyticimpacts(mechanica l injuries
of erythrocytes,ionizingand UV radiationexposure,microwavefields),he-
molytictoxic substances, infectious agentsdestroyingerythrocytes,maybe
classifiedas non-immune-dependent exoerythrocyt
ic hemolytic anemias.
Traumatic hemolyticanemiasare relatedto thedevelopment of intravascu-
lar hemolysisdueto the traumaticfragmentation of erythrocytes.

Tr a um a may origin at e from:

• outsidethe vessel(in Marathonrunnersandduringor afterlong-lasting

marches- marchhemoglobinuria , or from karateor bongoplaying);
• withinthe heart, as in calcificaorticstenosisor with plasticvalvepros-
theses;
• in arterioles,as in disseminated intravascular coagulation
, thrombotic
thrombocytopenic purpura,hemolyticuremicsyndrome,in severe (es-
peciallymalignant)hypertensionand in transplantrejection(microan-
giopathichemolyticanemia).

In the peripheralblood, fragmentederythrocytes,or schistocytes(Gk.

schistos,schizo- to split out)areobserved.
Toxichemolyticanemiasdevelopdueto the effectof substancesdamaging
erythrocyticmembranethat resultsin the acuteintracellulardamageof red
bloodcells.

Such anemias may be due to:

• exogenouschemical agents:benzene (benzol,carbonoil), toluene,dini-

trobenzene
, chloroform,copper, lead,etc.;
Pathophysiology
of hematopoieticfunction Unit 5 I 397
• endogenous chemicalagents:bileacids, phosphatidylcholine (lecithin),
productsresultingfrom burndisease,uremia;
• biopoisons(spiders,snakevenom,etc.).

Theoccurrenceof infectioushemolyticanemiasmayoriginatefrom inva-

sion and destruction of the RBCby the microorganism(e.g., Plasmodium ,
Babesia,or Bartone/la)or dueto the actionof toxins-hemolysins(e.g.,from
Clostridiumperfringens, or hemolytic streptococci,
or meningococci).

Anemias due to the erythropoi etic disorders

Anemias due to the erythropoietic disorders may

originate from:

• thedisordersof theearlygenerations of hemopoietic cells- hypop/astlc

(aplastic);
• the reductionof erythropoieticbasesdueto the infiltrationof the bone
marrowwithtumorouscells(bothlocalandmetastatic),granulomasor
replacement of hemopoieticcallswith the connective tissues(myelofi-
brosis)- mye/ophthisic (Gk. myelos- marrow,phthisis- exhaustion);
• the deficiencyof microelements , vitamins, proteins, porphyrinneeded
for the normalhemopoiesis - deliciency;
• thedisordersof segmentation andmaturationof erythropoiet ic progeni-
tor cells(ineffective
erythropoiesis)- dyserythropoielic ;
• the disordersin the humoralregulationof erythropoiesis - dysregula-
tory.

Hypoplastic (aplastic)anemiasarecharacterizedby the inhibitionof he-

mopoiesisin the bonemarrowand bythe insufficientproductionof erythro-
cytes, granulocytes
, thrombocytes(pancytopenia)
or just only erythrocytes
(partialhypoplasticanemia).
Hypoplasticanemiasmaybehereditary andacquired .
 398 I Part 2 Pathophysiologyof organs and systems

Hereditary hypoplasticanemiasarecharacterized by the presenceof gen-

eralized(Fanconianemia)or partial(Diamond-Blackfan anemia)bonemarrow
insufficiency.
Fanconianemia-·is a typeof familialhypoplasticanemia(autosomal-reces-
siveinheritance)with congenitaldefectsof bones,hypoplasiaof the kidneys,
spleen,gonads,vulvardefects,hypopigmented macules.In 30 % of casesthe
patientshaveno physicalabnormalities(Estren-Dameshek anemia).
Themainpointof the defectis the disturbances of DNA(y-endonuclease)
reparationsystem.Dueto the disturbances th-e irreversibledamagesof DNA
undertheinfluenceof UVradiationandchemicalseasilyoccur.It is considered
thatthe defectof hemopoiesisis localizedin the levelof a stemcell,though
theconcentration of humoralhemopoietic factorsis usuallydecreased. Hemo-
poieticcellsrequireadditionaltimefor the maturation,enhancement of apop-
tosis.Thelife spanof erythrocytesis considerably reduced(in 2.5-3 times).
Diamond-Blackfan anemiaresults from the geneticdefectof erythrocyte
precursors . In mostcasesis developssporadically,throughthe autosomal-
recessive and autosomal-dominant inheritance.The normal cellularityof
bonemarrowwith isolatederythroidhypoplasiais usuallyobserved,the pe-
ripheralblood shows macrocyticor normocyticanemia,reticulocytopenia,
the amountof leukocy tes andplateletsshowsno changes.
Acquired hypoplastic anemiasmaybecausedby physicalimpacts(ioniz-
ing radiation),chemicals(alkylagents,lead,arsenic,glycolethers,trinitrotol-
uene,benzol,organicsolvents,etc.), medicines(cytostaticagents,antibiot-
ics, non-steroidanti-inflammatorydrugs, anticonvulsants), biologicalfactors
(Epstein- Barrvirus,hepatitisEvirus,HIV,parvovirus819).
The so calledidiopathicform with unclearetiologyis regardedto be ac-
quiredas well.
The developmentof hypoplasticanemiamay be relatedto the direct ef-
fect on the stem cells andtheir microenvironment - stromalcells influenc-
ing greatly(theyproducehemoµoieticfactors)uponthe processesof blood
cell multiplicationand maturation.Nevertheless , in morethan70% casesof
the diseasethe processis determinedby immunemechanisms: hemopoietic
cellswith alteredgenestructure(dueto the effectof medicines,ecotoxicants,
viruses,etc.)areattackedby cytotoxicT-lymphocytes.
Pathophysiologyof hematopoieticfunction Unit 5 I 399
Thecytotoxic T-lymphocytesproducea seriesof antiproliferativecytokines
(interferon-y, tumor necrosisfactor-a) that in turn inhibits the hemopoiesis
byinducingapoptosisin hemopoietic target-cells.Thismayexplainthe futility
of the syngeneic bonemarrow(syngene ic donoris an identicaltwin without
hypoplastic anemia)andtheeffectiveness of immunosuppressivetherapyap-
plyinganti-thymic antibodies .
In the majorityof cases of hypoplast ic anemia,the erythropoietin levelin
the bloodis increasedor normalbut its effectuponthe bonemarrowis re-
duced.
Whenhypoplastic anemiais present,a numberof erythropoieticprogenitor
cellsdecrea sesin the bonemarrow.
Pancytopenia is observedin the peripheral blood, the colorindexis normal.
A blood smearshowsno reactivatedforms of erythrocytes(reticulocytes ,
polychromatophiles). The reducedproductionof thrombocytesresultsin the
·developmentof hemorrhagicsyndrome,whilethe reductionin granulocyte
(especiallyneutrophiles) formationmayleadto the loweringof the resistance
to infectious agentsandto the development of inflammatorydiseases(pneu-
monias, otitis, pyelitis).

Deficiency 88emias
Thedevelopmen t of deficiencyanemiasis concernedwith the disturbance s
or completestoppingof erythropoiesisresult from the deficiencyof certain
substances requiredfor the normalerythropoiesis: microelements (iron, cop-
per, cobalt), vitamins(812, folic acid, 81, 82 , 86 , PP, A, C, E), proteins, por-
phyrins.

Iron-deficiency anem ias (IDA) ar e due to th e follow-

ing factors.

1. Increasediron loss (1 ml bloodcontains0.5 mg iron (!); so, evena

small, chronicbleedingcancauseiron deficiency):
400 I Part 2 Pathophysiology
of organsand systems

• gastrointestinal bleeding(fromhemorrhoids , gastriculcer,diverticulitis

,
neoplasm , or unknownsite);
• excessivemenstrualflow (menorrhagia) - mostcommoncauseof IDA
in females;
• acute.bloodloss (e.g., massivetrauma).
2. Decreased iron intake:
• dietarydeficiency(rarelythesolecauseof IDA);theneedis 5-1 0 mg/day
(females)or 7-20 mg/day(males);iron in meatis absorbedbetterthan
iron in veggies .
• decreased absorption- achlorhydria(theneedof gastricacidto absorb
ironfrom food), gastricsurgery.
3. Increased iron requirement (e.g., pregnancy,
lactation)

Pathogenesis. The enhanced loss of iron results in

the development of compensatory processes in-
cluding the following ones.:

1. Theemploymentfor erythropoiesis. The Festorageform represented

with iron-containing
proteinssuchasferritinandhemosiderin (in mac-
rophages andparenchymatous cellsoftheliver,bonemarrow, spleen,
lungs,muscles). Ferritinconcentrationusuallylowers(<30 ng/ml);
2. Increasein adsorptionof alimentaryFeand its bondingwith transport
plasmaticproteintransferrin,whoseconcentration increases.Inherited
transferrindeficiency(atransferrinemia)or presenceof its defective
form aggravates thecourseof iron-deficiency
anemia.

The exhaustionof the tissueFestoragedeterminesits decreasein bone

marrowprogenitorcellsof erythropoiesis. Thisblocksthehemesynthesis,its
bindingwith hemoglobin , and, thereafter
, thehemoglobinproduction.Distur-
bancesof erythropoiesisareobservedwhenthelevelof serum Feis lessthan
9 µmol/Landiron saturation of transferrinis lessthan16 %.
Moreover,the disturbances in synthesisof iron-containing
compoundsin
differentcells are observed. Thedeficiencyin productionof aconitase, cy-
Pathophysiologyof hematopoieticfunction Unit 5 I 401
tochromes , FeSproteinsgivesrise to the development of bioenergyinsuf-
ficiencyand primarytissuehypoxia;the deficiencyof peroxidase, catalase,
glutathioneperoxidase leadsto theloweringof cellularantioxidantprotection ,
the lackof myoglobinmaycausethe drop of cellularadaptiveresponsesto
hypoxia.
Disturbances in synthesisof catalaseand glutathioneperoxidasein an
erythrocytecausethe decreased resistanceto the negativeactionof pro-ox-
idants, the increased hemolysisandthe shorteningof erythrocytelife-span.
Inthebonemarrow,thenormoblastic hemopoiesis remains , whilethecon-
tent of sideroblastsandsiderocytes(erythroblasts and normocytescontain-
ingtheiron granules)makingup20-40 % in the normalconditiondecreases.
At the sametime, the numberof basophileand polychromatophile forms of
RBCsprecursorsis growing whilethe oxyphileformsarediminishing(a sign
.of inhibitionof the cell maturation).
Theperipheralbloodshowshypochromic ( thecolor indexmaydropto 0.6
andmore),microcyticanemia,anisocytosis(manymicrocytes),poikilocyto-
sis (elliptocytesmaybeseen).Thenumberof reticulocytes maybeincreased
(at the earlystagesof anemia) , normalor reduced(at the long-term course
of anemia).
Togetherwith hematologic manifestations disturbances in iron-containing
enzymesin tissuesresultin the appearance of certainspecificsymptoms:
pica or geophagy(patientscraveandoftenreallyeatdirt, cardboard) , pago-
phagia(excessive ingestionof ice, ice-cream) , olfactoryperversions(some
patientslike smelling of kerosene ), koilonychia( the so calledspoon nail)
and bluecolor of eyewhites.Iron-deficiency in the non-erythroidtissuesis
considered to bethe causeof glossitis, angularstomatitisandesophagitis .
Vitamin812 deficiency anemias.Onlyanimalfood(meat,liver, milk, eggs)
is rich in vitamin B12 (cobalamin,extrinsicfactor). In the stomach, it binds
with R-proteinof saliva(othernames- cobalophilin , haptocorrin)prevent -
ing the vitaminbreakdownandcarryingit to the duodenum . In the duode-
num, cobalami n combineswith anotherglycoprotein- intrinsicfactor(IF)or
Castle's intrinsicfactor, whichis secretedby parietalcellsof the stomachand
thentransporte d by themto the distalpart of the ileumwhereadsorbedby
meansof membrane -boundreceptors.Havingflowedinto the bloodstream,
 402 I Part 2 Pathophysiologyof organsand systems

vitamin812 bindswith a transportprotein- transcobalamin II by the mecha-

2
nismof receptor-mediatedCa· - endocytosis.
Thecausesof vitamin812 anemiasmaybe inheritedandacquired.Among
the inheritedanemiasthere are the inheritedsorptiondeficiency- IF and
its receptoron the erythrocytesknownas lmerslund-Graesback syndrome,
transportdefects(insufficiencyof transcobalamins)andvitamin812 metabo-
lism (all thesedeficiencies
areautosomal-recessiveinherited).

Among the acquired B 12 anemias there are:

• alimentarycobalamindeficiencydueto keepingon the long-termveg-

etariandietexcludingthe uptakeof animalfood;
• the defectsin vitamin 812 adsorptionin the terminalpart of the ileum
(celiacdisease, localileitis,gastricresection,ileectomy
, excessivecon-
sumptionof cobalaminby parasitessuchas broadtapeworm(Diphyl-
lobothrium latum),lamblia(Giardialamblia), as well as bacterialover-
growthof bowelin the blindloopsyndrome ;
• IF deficiencydueto the autoimmunedisordercharacterized by the at-
rophyof parietalcells of the stomach(perniciousanemiaor Addison-
Biermeranemia) ;
• increasedutilization of vitamin812 undermalignantneoplasms , hypo-
thyroidism.

Pathogenesis. Cobalamin deficiency in the organ-

ism results in the disturbance of two metabolic reac-
tions in which vitamin B 12 coenzyme forms as meth-
ylcobalamin and adenosylcobalamin participate:
'

1. In the cytoplasm - methylationof homocysteine to methionine,which

requiresmethylcobalamin as an essentialcofactorfor methioninesynthase.
In the reaction,methylcobalaminyieldsa methylgroupandis regenerated
from 5-methyl-tetrahydrofolicacid(5-methylFH4 ), the principalform of folic
Pathophysiologyof hematopoieticfunction Unit 5 I 403
acid in plasma.In the samereaction, 5-methylFH4 is convertedto tetrahy-
drofolicacid (FH4}. FH4 is crucial, sinceit is required(throughits derivative
5,10-methylene FH4 } for conversionof deoxyuridinemonophosphate to de-
oxythymidinemonophosphate , an immediateprecursorof DNA.
Cobalamin deficiencyresultsin the blockagethis way,"internal"(or func-
tional)deficiencyof the activeform of folic acidandthenin the disturbances
in 5-deoxythymidine monophosphate forming.AccordinglyONAsynthesisof
erythropoieticprogenitorcells and otherintensivelydivisiblecells becomes
impaired.This leadsto the slowercelldivisiontime (prolongationof S-phase)
at the normal maturationrate of cytoplasmicstructures(RNA synthesisis
unimpaired). Theoutcomeof suchnuclear/cytoplasmic asynchronyis the for-
mationof big cellswith immaturenucleusbut maturecytoplasmandchang-
ing of erythroblastichemopoiesisinto pathologicalmegaloblastic type of he-
mopoiesis.
Whenvitamin812 deficiencyis presentthe erythropoiesisis ineffective , i.e.
erythropoieticprogenitorcells show reducedmitotic activity, low resistance,
and short life-span.Theirconsiderablepart (up to 50%, while normallyat
about20 %) is destroyedin the bonemarrow.Thereby,the numberof eryth-
rocytesin the peripheralbloodsignificantlydecreases andthe cellsof patho-
logical regenerationanderythrocyteswith markeddegenerative impairments
appear.
Erythropoiesis as well as granule-andmegakaryocytopoiesis areexposed
to the detrimentaleffects.The majorityof giantmyeloidcellsentersthe phase
of DNAsynthesisbut dueto its abnormalcourse,the cellsaccumulatein the
post-synthesis period(G2) that resultsin theirdeath.
Anemiabeingmainlyof hyperchrom ic type (color indexis abovethe nor-
mal at about1.1 - 1.5 and more),anisocytosis(macrocytes,megalocytes) ,
poikilocytosis, Howell-Jollyand Cabot'sring bodies, basophilicstipplingof
erythrocytesis usuallyobservedin the peripheralblood.A numberof reticu-
locytesis generallyreduced(hyporegenerative condition),and rarelyis nor-
mal.As a rule leukopenia(owingto neutrophils)which conjugateswith the
presenceof hypersegmented giant neutrophils(a numberof segmentsis 5
andevenmoreupto 16), thrombocytopeniais observed.Dueto the increased
erythrolysis(mainlyin the bonemarrow)bilirubinemiaoccurs.
 .I

404 I Part 2 Pathophysiology

of organsand systems

Thedisturbances of DNAsynthesisandcorresponding lythedisturbances in

thecelldivisionandmaturationdetermine theformationof giantcellsof theal-
imentarycanalepitheliumwhicharepoorlyresistantto theactionof damaging
agents.Thisbringson thedevelopment of inflammatory-atrophic processes in
the mucouscoatmanifested bysocalledHunter's glossitiswith «bald»tongue
(dueto the atrophyof its papillae), stomatitis, achylicgastritis,andenteritis,
thataggravates the courseof the diseaseandrelatedto the subsidiarydistur-
bancesin vitamin812sorptionandinsertionthe "viciouscircle"mechanism.
2. In mitochondria - isomerization of methylmalonyl coenzyme A to suc-
cinyl coenzymeA, which requiresadenosylcobalamin as a prostheticgroup
on theenzymemethylmalonyl -coenzyme A mutase.
Thedisturbancesin this reactionleadto increasingin methylmalonic and
propionicacidsresulting in fattyacidsalterationsanddisturbance of neuronal
lipids.Havingbeenincludedinto lipidsof neuronsandSchwanncells, these
substancesprovokethe disordersin myelinization andlipid dystrophyof the
cells. Degeneration of myelinin the dorsaland lateraltracts of the spinal
cord (funicularmyelosis)occurs,andthereforecranialandperipheralnerves
becomeaffected.

Folic acid deficiency anemias. The causes resulting in

the development of folic acid deficiency anemias may
be genetic (congenital disorders of folate adsorption
and metabolism) and acquired resulting from:

• decreasedintakeof folateswith food (reducedconsumptionof green

vegetablessuch as lettuce, spinach,asparagus , and broccoli,eggs,
meat;boiling,steaming,or fryingof foodsfor 5 to 1Ominutesdestroys
up to 95 % of the folatecontentaswell;
• defectsin folateadsorptionand methylationin the smallintestine(ce-
liac disease,kwashiorkor,exudative enteropathy)includingthe cases
evokedby the drugtherapy(anticonvulsants);
• increasedrequirements of folatesby rapidlydividingcells(pregnancy,
infancy, acute and chronic hemolysis, exfoliativedermatitis , rapidly
Pathophysiology
of hematopoieticfunction Unit 5 I 405
progressingmalignanttumors), as wellas applyingof certainfolic acid
antagonists(methotrexate and other metabolites
, sulfonamides , nitro-
furans, pyrimethamine (chloridinum)
, antituberculousdrugs), or when
a patientis subjectedto hemodialysisaccompan ied with considerable
folic acidloss.

In all thesecircumstances , the demandsof activeDNAsynthesisrender

normalintakeinadequatly .
Certaininheritedforms of megaloblastosis areknownto becausedby im-
pairedfolatetransformation intoa metabolicactivederivative- tetrahydrofo-
late(whenthedihydrofolate reductase activity reduces), andby thefunctional
folatedeficiencyoccurringagainstthe backgroundof the deficiencyin me-
thyltetrahydrofolate transferase activity.
Pathogenes is. Folicacid insufficiencycausesthe impairmentsof DNA
synthesisandDNAstructureasthis acidactingin its metabolicactiveform -
tetrahydrofolic acid- is required for 5-deoxythymidilate monophosphate syn-
thesis(seeabove),andfor the inclusionof uridineandoroticacidinto a DNA
molecule.Thisis accompanied bytransformingof normoblastichemopoiesis
into megaloblastic typewith all theensuingconsequences (seePathogenesis
of vitamin812 deficiencyanemias).
Themanifestation of this anemiaarethesameasthatcausedbyvitamin 812
deficiency. However , theneurologicchangesseenin vitamin812 deficiencydo
not occur.At the sametime it shouldbestressedthat folic acidis important
for the nervesystemdevelopment in the fetal and neonatalperiods.Insuf-
ficientfolateintakeduringthe pregnancygivesrise to the developmentof
severeneurological impairments in a fetus.
Folicaciddeficiencyanemiaaccompanied with vitaminC deficiencywhich
participates in the renewingof tetrahydrofolic acid.
Protein deficiency anemias areaccompanied with kwashiorkor - a proteic
-caloriestarvationdiseasewhich is observedin the countriesof Asia and
South-Eastern Asia.Pathogenesis of this anemiais relatedto the reduced
productionof erythropoietinby the kidneyswith the followingdecreaseof
erythropoiesis. Proteindeficiencyalso effectsthe activity of enzymespar-
ticipatingin the intestinaladsorptionof iron andvitamins.Thereforeprotein
 'I
I

406 I Part 2 Pathophysiologyof organsand systems

deficiencyanemiashavethe samecharacteristics as that causedby vitamin

812 or folic acid deficiency.
Porphyrin deficiency(ironrefractory) anemiasdevelopdueto the distur-
bancesin iron inclusionintoa heme(theironcontentin boththe bloodplasm
and cells is therefore increased ) and, as a rule, determinedbythe loweringin
activityof enzymesparticipatingin porphyrinsynthesis . In a hememolecule
iron is boundwith protoporphyrin- a certainform of porphyrins.Porphy-
rins aresynthesized in all the cells of the humanbody, but their abundance
is producedby erythropoieticprogenitorcellsand the liver. Porphyrinsare
required componentsof iron-containingenzymeslike catalase, peroxidase ,
cytochromes , andhemo-andmyoglobinsaswell.
By the originporphyrindeficiencyanemiasaredistinguishedas inherited
and acquired.
Inheritediron refractoryanemiasareinheritedbeingrecessively linkedwith
X-chromosome or autosomeandrelatedto the disturbancesin the synthesis
of one or more enzymes participatingin porphyrin production . Thecommonly
observedis the defectof keyenzymeof the 1st stageof porphyrinsynthesis
- 5-aminolevulinic- acid synthetase , or congenitalmetabolicdisorderof its
co-factor - pyridoxal 5'- phosphate.

Among the causes of inherited iron refractory ane-

mias there may be:

• lead poisoning , which is able to block sulfhydricgroupsof enzymes

participatingin hemesynthesis ;
• alimentaryvitamin86 deficiency;
• excessivealcoholconsumption_and long-termmedicineintake(e.g.
isoniazid, sulfonamides)inducing disturbanceof pyridoxine metabo-
lism. '

Acquirediron refractory anemiasmayalso developdueto the clonaldis-

ordersof stemcellsandbe regardedasa sigtsof myelodysplastic syndrome
consideredto be preleukemic stageof acutemyeloblastleukosis
.
Pathophysiologyof hematopoieticfunction Unit 5 I 407
Pathogenesis. Disturbances in any stageof porphyrinsynthesisresults
in inabilityin iron bindingandforming of a hememolecule.This evokesthe
ineffectiveerythropoiesis with intramedullary deathof ABCprecursorsand
the development of hypochromic anemia.
Unclaimedfor hemesynthesisferriphosphate complexesare accumulated
in mitochondr iaor cytoplasmof erythroidcells(sideroblasts) in thebonemar-
row.Therefore,porphyrindeficiencyanemiamayalsobe namedby the term
sideroblastic or sideroachrestic (deficientin iron, form Gk.achrestos- futile).
In thebonemarrowmicronormoblast hyperplasiaappears . A largenumber
of sideroblasts - erythropoieticprogenitorcellscontainingincreasednumber
of iron granulesis usually observed.Thegranules,as a rule, surroundsthe
nucleusand store betweenthe mitochondrialcristaewherenormally heme
synthesisunderthe participationof iron andporphyrinoccurs.
A periphericbloodsmearshowshypochromicanemia , anisocytos is (mi-
crocytosis),poikilocytosis , the presenceof targetcells.Reticulocyte countis
either normal or slightly lowered.Iron serum concentrationis considerably
increased.
Ferriphosphate
complexesmayaccumulatein anyinternalorganscausing
thesecondaryconnective
tissueenlargement
(hemosiderosis).

Dyserythropoietic anemias
Primarydyserythropoietic anemiasare associatedwith the dysfunctionin
the mechanism providingtimelystoppageof nuclearfissionduringthe hemo-
globinization of erythropoieticprogenitorcells.Thisconditionis accompanied
with insufficient productionof matureerythrocytesdue to the disturbances
in mitosisand surfaceglycoproteinbiosynthesis(defectsin certain surface
proteins , especiallyin protein4.2, band3 protein, disturbances in its glyco-
sylationby lactosaminoglu cansas wellas the deficiencyin an enzymeof N-
acetyl-glycosaminyl-transferase 11whichshouldfunctionunderthesecircum-
stances)in erythroidcellsduringtheerythropoiesis andtheirexcessdeath.
In the bonemarrowthe markedhyperplasia of erythroidprecursorsis ob-
served- no morethan10-15 % of multinucleate cells.Manydestroyedcells
 408 I Part 2 Pathophysiologyof organsand systems

havesignsof apoptosis.Thereductionof ironinclusionintoerythrocytes(up

to 25-50 % in comparisonwith that of normalindividuals)is alsoobserved.
Thisindicatesthe enhanced destroyingof erythroidcellsin the bonemarrow.
Theperiphericbloodshowsnormochromic anemia,sometimes reticulocyte-
mia,anisocytosis , basophilic stipplingof erythrocytes,
thepresence of fragmen-
tationcells.Theincreased levelof bothiron (upto 60-70 µmol/L)andindirect
bilirubin(thesignof accelerated erythrolysis)is revealed
in the bloodserum.
Externalmanifestations usuallyappeartoo late,whena child livesan age
of 10 yearsold. The manifestations includejaundice , certainchangein the
skeleton(oxycephaly , high palate, etc.),splenomegaly, sometimes- biliary
calculusformation(cholelithiasis). Severeformsof thediseaseareaccompa-
niedwith hemosiderosis - iron overloadof the body.
Ineffective erythropoiesisis associatednot only with inheriteddyseryth-
ropoieticanemias , but with someotherblooddiseasesaswell, e.g.:vitamin
B12 deficiency anemia , thalassemia,myelodysplastic syndromes(mainlyin
retractor sideroblastanemia).

Dysregulat ory anem ias

Dysregulatory anemiasresultform the disturbancesin humoralregulation
of erythropoiesis, mainlyunderthe impairmentsin erythropoietin formation
and its releaseinto the circulation,and/orunderthe changing of correlation
betweenerythropoiesis (andits synergists)anderythropoieticinhibitors(Ta-
ble 23). This mechanismis considered to be peculiarto anemiasdeveloping
underthevariousdiseasesof innerorgans(i.e., seco.ndaryanemias):

Table23. Cytokines-synergists
an~antagonists
of erythropoietin

• lnterleukin-6
- activateshemopo~ • Interleukin
- 1
eticcells
Pathophysiologyof hematopoieticfunction Unit 5 I 409

• lnterleukin-6 - activateshemopoi- • Tumornecrosisfactor- inhibitsearly

eticcells erythroidprogenitor
s, reduceseryth-
• lnterleukin-9 - maintainsburst- ropoietinproduction
formingcellsin the bonemarrow
• lnterleukin-3- stimulatesgenera-
tion and differentiationof erythroid
cells
• Stemcell factor- stimulatesery-
throidprecursors

Anemiasof chronicdiseasemaydevelopin patientswith chronicinfec-

tious or inflammatoryprocesseslasting more than 2 months, malignant
neoplasms , autoimmunedisorders.Theyare characterized
by relativelylow
erythropoietinleveland reducedresponseof the bonemarrow to erythropoi-
etin, that is consideredto be associatedwith the effectof certaincytokines
(interleukin-1p, tumor necrosis-afactor, interferon-p , etc.)producedby ac-
tivatedmacrophages. The macrophages also retainiron, takenfrom phago-
cytizederythrocytes and makeit inaccessible for the hemoglobinsynthesis .
Normochromic , normocyticanemia(usually);maybe hypochromic , micro-
cytic(MCVrarelybelow72fl). Minimalanisocytosis andpoikilocytosis.
Anemiaof chronicrenaldiseasedevelopsdueto the advanceddestruc-
tion of the kidneysand inadequate synthesisof erythropoietin.It may be
complicatedby iron deficiencyanemia(secondary to hemodialysis) , anemia
of chronic disease(secondary to concurrentchronicinfectionor inflamma-
tion), or microangiopathic hemolyticanemia(secondary to changesin renal
microvasculature). Normocytic, normochromicanemia.Minimalaniso-and
poikilocytosis; someechinocytescanbeseen("burr" cells).
The impairment in erythropoietinproductionmay be also observedin
protein-deficiency anemias(Seeabove).Anemiascausedby disturbances
betweenthe hemopoietic factorswhichare producedandtheir inhibitorsef-
fectingtheearlygenerations of hemopoiet ic cellsarerepresented in thegroup
of hypoplastic anemias.
 410 I Part 2 Pathophysiologyof organsand systems

Chapter 20. White Blood Cell

Disorders

Theleukocyres,or whitebloodcells(WBC), constituteonly 1 % of the total

bloodvolume.Theyoriginatein the bonemarrowandcirculatethroughout
the lymphoidtissuesof the body. Normalconcentration
of leukocytesin per-
9
iferalblood4-9 x 10 / L.

Th e re are two g roup s of le ukocyt es:

• agranulocytes(includelymfocytesandmonocytes)
• granulocytes
(includeeosinophiles, basophiles
andneutrophiles).

Leukocytes takepartin defencereactionsof theorganismandin thedevel-

opmingof inflammatory andimmuneprocesses .
Quantitative changes in leukocytesmay consistin increasing(leukocy -
tosis)or decreasing(leukopenia) any of theirtypes.Thesechangesmaybe
absolute(an increaseor decrease in a numberof a certaintypeof leukocytes
pera bloodcubicunit) or relative(characterized by parentage
changingin a
certaintypeof leukocytes)(Table 24).
Increasingor decreasing in percentage doesnotalwayscorrespondto the
realquantitativechangesin the leukocytes. Forinstance,whenthe leukocytic
percentsdrop to 15 percent,andthe differentialbloodcountis 12 x 109/L,
thenthe absolutenumberof lymphocytesper 1 L of bloodis 1.8 x 109, i.e.
normal.This is consideredto be relativelymphopenia. Thesameas the in-
creaseof relativeindicesin decreased leukocytecountper 1L of blooddoes
not meanactualgrowthin their number.
Qualitative changes in l_eukocytesarestudiedbytestingperipheralblood
smears.In the presenceof a'certainpathologythe followingdegenerative
changesin leukocytesmay progress:pyknosisof a nucleusand its hy-
persegmentation, the appearance of toxic granularity(azurophil, or kappa,
granules)in the cytoplasm,inclusionslike Amato-Dahlebodies(basophil-
like stainednubbinsof cytoplasm), vacuolization . Degenerative forms of
Pathophysiologyof hematopoieticfunction Unit 5 I 411
leukocytesare representedby anisocytesand cells destroyedowing to
leukolysis. The degenerativechangesare the commonestin neutrophilic
granulocytesand monocytes , and accordingto their causesmay be inher-
ited or acquired.

Table24.Whitebloodcellscountandcharacteristics.
'_.,•}•'.' v~.'~ •••-~., ...., , • ,. ,. "'-•· .• •.· .
·Pa~(Pete
rs. ;,~ .~~ ~ocytas ._,
: ;(:,..:t-l ..:. <
.
'
Granulocytes Agranulocytes
Baso- Eosino-Neutrophiles Lympho- Mono-
philes philes cytes cytes

Myelo- Meta- Bands Segs

cytes myelo -
cytes
(young)
Percentage 0-1 0.5- - 0-1 1-6 47-72 19-37 3-11
5.0
Absolute 0- 0.02- - 0- 0.04- 2.0- 1.2-3.0 0.09-0.6
quantity 0.065 0.03 0.065 0.3 5.5
(109/L)
Size(µm) 8-10 10-12 12-20 10-12 10-12 10-12 7-9 12-20

Someabnormalitiesin leukocyteswhich are inheritedby the autosomal-

dominanttype,are asymptomatic:inherited hypersegmentation and granu-
locytehypersegmentation. At the sametime,a numberof metabolicdefects
is accompanied with disordersof phagocytosisand increasedsensitivityot
infectionsdespitethe propernumberof leukocytesin the peripheralblood
(insufficiencyof NADP-oxydase , myeloperoxidase,glucose6-phosphatede-
hydrogenase, etc.)Therealsoexistcertainisolateddisordersin the abilityof
chemotaxiscausedby abnormalities of cellularcytoskeleton(lazyleukocytes
syndrome).
 412 I Part 2 Pathophysiologyof organsand systems

Acquiredstructuralleukocyticabnorma litiesresultfromthe damagingleu-

kocytesin hemopoieticorgansand in the bloodunderthe influenceof vari-
ous pathogenicagents(bacteria, viruses, antibodies , physicaland chemical
changesandparaneoplasticprocesse 's).

Leuko cyt ose s

Leukocytosis (Gk.leuk- white+kutos- cell+ osis- pathology,disease)-is
the leucocytecountelevation(or theirforms)overthe upperlimit.
• By the causalagentsleukocytoses are distinguishedas physiological
andpathological;
• by pathogenesis - pure,redistributive
, andhemoconcentration (anhy-
dremic);
• by whitebloodcellforms,whichconcentration is increasedsuchtypes
as neutrophilic(neutrophilia),eosinophilic(eosinophilia), basophilic
(basophilia)
, lymphocytic(lymphocytosis),monocytic(monocytosis)
aredistinguished;
• by a changeof absoluteWBCper a bloodcubic unit - absoluteand
relative.

Absoluteleukocytosisis characterizedby the increasein the total number

of any form of leukocytesin the blood. Relativeleukocytosisis said to be
developingwhenthereis an increasein the proportionof anyvarietyof leu-
kocytesof the blood,withoutthe increaseof thetotal numberof leukocytes.
Physiological leukocytosisis consideredto be a normalresponseof the
organismto certainconditions.

In its turn physiological leukocytosis is divided into:

• leukocy
tosis in newborns;
• alimentary-usuallydevelopsin 2-3 hoursaftermeal;
• myogenic- mayby causedbythe strenuousphysicalexertion;
Pathophysiologyof hematopoieticfunction Unit 5 I 413

• emotiongenic - dueto the mentalstress;

• acclimatization-whenthetime zoneor climaticzoneis beingchanged;
• static- whenthe recumbentpositionis changed into the plantigrade
position;
• leukocytosisin pregnant(5-6 monthsof gestation) and recentlycon-
finedwomen(2-3 weeksaftertheact of delivery).

Alimentary, myogenic , emotiogenic , and staticleukocytosisreflectthe al-

terationsin previouslyformedleukocytes in bothcirculating andvascularen-
dotheliumpools, i.e. areredistributive,andbythetypeof involvedleukocytes
they are neutrophilic.Theseleukocytosesare transient(with a short-term
course)andretainnormalproportionof the variousforms of leukocytes(dif-
ferentialbloodcountis unchanged) .
Leukocytoses in newborns , pregnantand confinedwomenare suggested
to bemixedby the pathogenesis , andengagebothredistributivemechanism
and enhanci ng of leukopoiesis, and the leucocytereleasefrom the marrow
storagepoolintothecirculation.
Accordingto their pathogenesis , pathological leukocytose s maybetrue,
redistributive,
andhemoconcentration (anhydremic).

True le ukocytos e s may be influ e nc e d by th e follow-

ing fa ctors :

• mobilizationof leukocytesof reservepool from the bonemarrowinto

thecirculationdueto theactionof antiinflammatory cytokines(interleu-
kin-1, tumornecrosisfactor,etc),whichelevatepermeability of marrow
bloodvesselwalls(in acuteinfectiousdiseases , endotoxemia, hypoxia,
increased concentration of glucocorticoids);
• enhance of leukocyte proliferationin theredbonemarrow,whichmaybe
reactive- polyclona l, referringto the productionof increasedamounts
of colony-stimulatingfactorsunderthe influenceof cytokines(interleu-
kin-1, tumornecrosisfactor-a. , etc.)in chronicinfectionsandleukemic
(or subleukemic)formsof leukemias .
 414 I Part 2 Pathophysiology of organsand systems

Redistributivemechanismalso participatesin the pathogenes is of patho-

logicalleukemias andmayrefersto thedemargination of leukocytes, i.e.tran-
sition of the parietal pool into blood circulatingpool (in acuteinfections,or
activationof sympathoadrenal system).This mechanism mayresult from the
decreased marginationof leukocytes(extravasation, diapedesis)into tissues
(under the increasedglucocorticoidconcentrat ion), throughthe leukocyte
circulationratein the bloodgrows.
Hemoconcentrat ion leukocytosis develops dueto the bodyhypohydration
of diverseorigins(diarrhea,reversevomiting,polyuria).Underthesecircum-
stances,notonlyleukocytesbutotherbloodcellsareobservedto beelevated.
Neutrophilic /eukocytosis (neutrophilia) is regardedto bea salientfeature
of localizedor generalized forms of suppurativeinfectionsas well as certain
non-infectious inflammatoryprocesses , severehypoxias , endogeno us intoxi-
cations(uremia).In thesecases,boththe total WBCandrelative neutroph ile
numbeFincrease.Depending on the proportionbetweenthe matureandpre-
matureforms of neutrophilestwo typesof the nuclearshiftmaybe distin-
guished:to the left, whenthereis an elevatedcontentof immatureforms of
neutrophilicgranulocytes (myelocytes , metamye locytes, bands)in the blood,
and to the right, whenthe matureneutrophiles with a largenumberof seg-
ments (5- 6) prevail against a background of youngercellsdisappearing .

The nucl ea r shift (Table 25) may be subdivided into:

• regenerativeshift - developsagainstthe backgroundof mild general

leukocytosis,accompanied with elevatedcontent.of bandsandmetamy-
elocytes, sporadicmyelocytesmaybe seen. This shift resultsfrom the
reactivegranulocytopoiesis activationand is commonin suppurative-
septicprocesses ;
'
• hyperregenerative shift is characterized by the appearance in differential
WBCmuchmoreyoungerformsof leukocytes (myelocytes andevensome
promyelocytes andmyeloblasts} , whileeosinophiles areoftencompletely
absent(aneosinophilia).Thisshift is considered to be prognostically un-
favorablesignin a courseof infectiousandsuppurative-septic diseases ;
Pathophysiologyof hematopoieticfunction Unit 5 I 415
• degenerative shift-is characterized by increasingin band'snumberand
appearance of a largenumberof destructivechangedsegmentedforms
(nuclearpyknosis , toxic granularityand cytoplasmvacuolization , etc.).
This indicates the inhibition of granulocytopoiesis andmayoccurin the
severe courseof infectiousdiseases , in endogenous intoxication
, etc.;
• regenerative-degenerative shift- againstthe backgroundof total leuko-
cytosisthe numberof bandgranulocytes , metamyelocytes,and myelo-
cyteswith the manifestations of degeneration increases.The hyperpro-
ductionof pathologicall y changedleukocytesand impairmentin their
maturationin the bonemarrowis commonlyobserved.

Table25. Leftnucleardeviation

Type ?!Jl : cause

':¢~:t ~,. ' .·.-yl~§!:\;:~
. ;\~
•--i't:,"f~i-
,;,· ti;·,· . ' .-
,, · ·N~trophileschanges
Myelo- Metamyelo- Bands Segs
cytes cytes(young) (Stab)
Normal - 0-1 1-6 47-72
Regenerative Reactive
activation
of 0-1 1-4 3-8 50-75
leucopoiesis
Hyper
- Leukaemoid
reactions 1-4 2-6 5-15 50-80
regenerative Sepsis
Degenerative Chronic
andspecific - 0-1 8-16 45-70
inflammation

Nuclearshift to therightwiththefollowingappearance of hypersegmented

neutrophiles occursin radiationsickness,812-deficiencyanemias , but in cer-
tain casesit maybe presentin the healthyindividuals.
Eosinophilic leukocytosis (eosinophilia) is observedin diseasescaused
by infestationwith helminthsandotherparasites(ascaridiasis, echinococco-
sis, opisthorchiasis, lambliasis(giardiasis),etc.),variousallergicconditions
with anaphylactic type of allergicreactions(bronchialasthma,dermatoses,
eosinophilicinfiltrations),diffusediseasesof the connectivetissues(rheuma-
 416 I Part 2 Pathophysiologyof organsand systems

tism, periarteritisnodosa),intakeof certaindrugs(antibiotics,sulfonamides),

systemicblood diseases(chronicmyeloleukemia , lymphogranu lomatosis),
malignantneoplasms , burn diseaseandfrostbites, certainendocrinopathies
(hypophysialcachexia , myxedema) , infectiousdiseases(scarletfever, TB,
syphilis),heredofamilial(etiology is unclear) abnormalities.Moderateeo-
sinophiliamayalsodevelopduringthe recoveryperiodafterviral infections.
Eosinophiliasdevelopingin parasitic,allergic,and oncologicaldiseases ,
as well as in leukemias , are caused,as a rule, enhancedproductionof cer-
tain cytokines(interleukin-5,interleukin-3,granulocytic-macrophage colony-
stimulatingfactor), underthe effectof immunecomplexesor factors, excret-
ing by the tumoroustissue.
Redistributive componentin the pathogenesis of eosinophilicleukocytosis
is associatedwith the productionby mucosa!cells of eotaxins- mediator-
chemokines engagingeosinophilesinto the zoneof allergicinflammation.
Basophilic /eukocy tosis(basophilia ) appearsin patientswithlymphogran ulo-
matosis,polycythemia , hemophilia , chronicmyeloleukemia , thyroidhypofunction.
Physiological lymphocytic leukemia (lymphocytosis) is typicalfor thechildren
of first 5 years,andalso mayoccurin vegetarians andjust afterphysicalexer-
tions (myogenic).Pathologica l reactive lymphocytosis developsunderthe cir-
cumstances of certaininfectiousdiseases (whooping cough,mumps,typhoidfe-
ver,malaria, brucellosis , infectiousmononucleosis , tuberculosis , syphilis,etc.),
as wellas underalimentary dystrophy , bronchialasthma , andcertainendocrine
disorders (eunuchism , thyroidhypofunction), "graft versushost" disease.
Monoc ytic leukocytosis (monocytosis ) is associatedwith chronic infec-
tions (tuberculosis,brucellosis,systemicmycoses , bacterialendocarditis) ,
infectiousmononucleosis, andsomeotherinfection _s causedby rickettsiaand
protozoa(louse-bornetyphus, malaria).
limphocytic leukocytos is (lymph,ocytosis ) is associatedwith virus infec-
tions, chronicinflamma t ions, lympholeucosis andinfectiousmononucleosis .
Infectious mononucleosis is a self-limiting lymphoproliferative disorder
causedby the Epstein-Barr virus (EBV).
The virus undergoesa replicativecycle in the oropharyngeal epithelium
and then invadesthe bloodby selectivelyinfectingB cells,a cell population
that hasspecificsurfacereceptorsfor the virus.
Pathophysiology of hematopoieticfunction Unit 5 I 417
Infectious mononucleosis is characterized byfever, genera lized lymphade-
nopathy,and sorethroat.The hallmarkof infectiousmononucleosisis the
appearance in the bloodof atypicallymphocytes that are primarilyactivated
cytotoxic(CD8)T cellsandnaturalkiller cells.
Lymphadenopathy affects90% of patients, who havesymmetrically en-
largedandoftentenderlymphnodes.Theperipheralbloodusuallyshowsan
increasein the numberof leukocytes, with a whitebloodcell countbetween
12-18x 10/ L, 95%of whicharelymphocytes.
9

Leukopenias
Leukopenia (fromleukocyte+Gk.-penia- poverty, necessity)-is a decrease
in WBC(or certainleukocyticforms) below the lower limits. Leukopeniais
mostfrequentlyobservedin certaindiseases . It shouldbe mentionedthere
are certainnosologicunitsin whichleukopenia is consideredto be a salient
manifestation of diseasesanddetermines
their clinicalcourse.
Bythe etiologyleukopen iasaregroupedinto inheritedandacquired.

By the pathogenesis there are the following groups

of leukopenias:

1) causedby disturbances in leukopo iesisin the bonemarrow;

2) causedbytheslowreleaseof leukocytes fromthe bonemarrow intothe
circulation;
3) causedby the time reductionof leukocytestaying in the peripheric
blood;
4) associated with the redistributionof leukocytes insidevascularbed.

Accordingto the leukocyticformswhoseconcentratio n is decreasedthere

arethefollowingtypesof the conditionas lymphopenia, neutropenia
, eosino-
penia,monocytopenia, agranulocytosis( a drasticdropof granulocytes
in the
peripher
ic bloodupto theircompletedisappearing ).
 418 I Part 2 Pathophysiologyof organsand systems

Depending onthe alterationin total leukocyte numberper bloodcubic

unit leukopenia maybeabsoluteandrelative.
Neutropenias. Absoluteneutropeniais evaluatedby decreasingof abso-
luteneutrophilenumber(lowerthan1.5 x 109 ) . Theabsoluteneutrophilcount
(ANC)is calculatedby takingthe leukocytes andmultiplyingit bythe percent-
ageof matureneutrophilsplusbandcellsdividedby 100.
Neutrophilic withinthelimitsof0.5--1.0
concentration x 109/L leads totheincreased
risk in thedeveloping of mucosal andcutaneous covering infections (furuncu losis,
9
gingivitis, stomatitis Whentheindicesarelowerthan0.5 x 10/L the
, periproctitis).
riskinthedeveloping of severe
infections (including
septicemia) is ratherhigh.
A highfrequencyin thedevelopment of neutropenia amongnewbornsmay
beexplainedby the presenceof a less numberof granulocytopoietic precur-
sor cells, insufficiencyof neutrophilicbonemarrowstoragepoolandits rapid
depletionin infectiousdiseases.Neonatalneotropenias giveriseto the occur
of purulentdermal infections,umbilicalcord lesionsas well as the impair-
mentsof respiratoryorgansandbacteriemia.
Neutropenias causedby the disturbances of leukopoiesis in the bone
marrowmayoccuras signsof generalized disturbanceof bonemarrowhe-
mopoiesis(e.g.,in aplasticanemia , whichwas alsotermedas hemorrhagic
aleukia) or as isolatedneutropenias , whichin their turn aredistinguishedas
inheritedandacquired.

Inherited neutropenias may be subdivided into :

• cyclicneutropeniais of autosomal -dominantor recessiveinheritance,

characte rizedby periodicappearance of neutro.penia(usuallyin intervals
of 14-45 days),fever,mucosaland subcutaneous coveringinfections;
disturbances areevidentto developon the stemcells'level(disturbanc-
es in erythro-andthromoocytopoiesis maybe possible,but areof little
clinicalsignificancebecause of long life-spanof theseelements) ;
• chronicbenignneutropeniamay also be of both autosomal -dominant
or recessiveinheritance,usuallyasymptomaticor manifestedby ''trite
infectionscausingdiscomfort" (furuncles,stomatitis);
Pathophysiologyof hematopoietic function Unit 5 I 419

• infantilelethal agranulocytosis(congenitalneutropenia,Kostmann's
syndrome)is inheritedby autosomal-recessive type; startingfrom the
1st monthof life, severe,sometimesmortalsuppurativeinfectious of
the skin andair passages develop; in the bonemarrow the retardation
of maturationon the stageof a promyelocyte or a youngmyelocyteis
foundout, neutrophilicleukocytesin the bloodaremainlyabsent.

Neutropenia is associated with a numberof inheritedmetabolicdisorders

or disturbances in the connectivetissuestructure, namely,idiopathichyper-
glycinemia , propionicacidemiaand isovalericacidemia(sweatyfeet syn-
drome}, Shwachman-Diamond syndrome(metaph yseal chondrodysplasia ,
dwarfism,insufficientexocrinepancreas secretion, andneutropenia).
The development of acquiredneutropenias andagranulocytosis , causedby
the leukopoietic disturbances in the bonemarrow, maybedeterminedby the
followingmechanisms:
• cytolytic,whichis relatedto thedamagingdose-dependent effectof ion-
izingradiation , heavymetals(andtheirsalts),viruses(grippe,hepatitis,
respiratorysyncytialvirus, roseola , chicken-pox , Epstein-Barr), myco-
toxins (trichothecenes) , benzenederivatives , cytostatics,immunefac-
tors (antibodies, T-lymphocytes) on the hemopoieticcells;
• antimetabolic-is associated with thesubstances , effectingthe metabo-
lism of purineand pyrimidinebasesand disturbingthe processesof
stemcelldivision(antineo plasm drugs, antibiotics(chloramphenicol));
• dysregulatory - due to the deficiencyof cytokines,impedingthe de-
velopmentof hemopoieticcells' (interleukin-3 , stem cell factor for the
youngestapoptosishemopoietic cells,granulocytic-macrophage colony-
stimulatingfactor, interleukin-10 for the myeloidcells)apoptosiswhen
thecellsproducingthemaredamaged(especially bonemarrowstroma);
• deficiencyof substancesrequiredtor /eukopoiesis(vitamin B12. folic
acid, pyridoxine , iron,protein, etc.);
• idiosyncrasyto certainmedicines(sulfonamides , syntheticpenicillins,
antithyroiddrugsand phenothiazines), and there is no correlationbe-
tweenthe probability of neutropenic developmentandthe dosage , and
durationof medicineeffectas well;
 420 I Part 2 Pathophysiologyof organsand systems

• mye/ophthisis, when the hemopoiet

ic tissue is replacedby leukemia
cells,tumorousmetastases, etc.

Neutropenias causedby retardedoutflowof leukocytes fromthe bone

marrowintotheblood,maybeassociatedwith geneticdefectsof leukocytes,
effectingtheir locomotivefunctions(lazyleukocytessyndrome,incidentalor
YemeniteJews neutropenia).Neutrophilicactivity is limited by the waste
productsof virulentmicroorganisms, viruses,as well as certaindrugs(cy-
toskeletonactioninhibitors, suchas colchicine , vincristine,vinblastine
, etc.),
andunder the insufficientstorageof energyresource(glycogen)in cells.
Neutropenias causedby the reducedtime of leukocyte floatingin the
peripheralbloodmaydevelopdueto:
• shorteningof granulocytes' life-spandeterminedbytheir morphological
of functionaldisorders(vitaminB12 deficiencyanemia,Chediak-Higashi
syndrome);
• immunologically determinedleukocytic destructionin systemicautoim-
munediseases(systemiclupuserythematosus, atrophicarthritis), neo-
plasms(lymphomas), viralinfection,drugtherapy(haptenmechanism) ;
• leukocytic destructionby antineutrophilicantibodies,inheritedfrom a
motherto a fetus (e.g., whena motheris sensibilizedto fetal neutro-
philicantigens,andin maternalautosomalpathologyas well);
• sequestration of neutrophiles in hypersplenism (increasinginthe phago-
cytic activityof macrophages in the spleen);
• enhancedutilizationof leukocyteswith the previousincreasedneutro-
philicoutflowfrom the vascularcanalin diffuseinflammatoryprocess-
peritonitis,pneumonia , extensivemechan icali~jureof tissues;
• increasedleukocyticloss, especiallyin plasma-and lymphorrhagia,
burns,chronicsuppurativeproc.esses(osteomyelitis,endometritis),in
the presenceof fistulasof lymphaticvessels,coughwith sputum.
'

Neutropeniasrelatedto the redistributionof leukocyteswithin the blood

streamdevelopdueto the temporaryreducingof circulatingpoolcells(with-
out the changingin their total number)in the stateof shock(anaphylactic,
traumatic,hemotransfusion), hyperthermia,massiveinflammatoryprocess-
Pathophysiologyof hematopoieticfunction Unit 5 I 421

es, afterintensivemuscular work (dueto the whitebloodcell concentration

in the capillariesof muscles,intestine, liver, lungs, andthe loweringof white
bloodcell number in the otherpartsof the body).
Eos inopenias developdueto the inhibitionof the synthesisof certaincyto-
kines(mainly,interleukins-5 , -3, granulocytic-macrophage colony-stimulating
factor)in viraldiseases, septicconditions,myelotoxic form of agranulocytosis.
Decreasing inthenumberof eosinophiles is observed undertheelevated produc-
tion of glucocorticoids (hypercort icism,stress)owingto the abilityof the hor-
monesto evokehomingof eosinophils in tissueswiththefollowingapoptosis.
Monocytopenias usuallyoccurin the rathergravedisturbances of thebone
marrowhemopoiesis.
Lymphopenias are typicalfor a numberof primarycombinedand T-cell
immunodeficiencies , andmayresultfrom:
• the reducingof lymphopoiesis (bonemarrowinsufficiency,radiationle-
sions, intakeof immunosuppressive agents,starvationanddietarypro-
teindeficiency , lymphogra nulomatosis);
• the activityof lymphotropicviruses(measles , poliomyelitis, humanim-
munodeficiency virus, etc.),invokingtheaccelerated lymphocyticloss;
• the disturbancesin leukocytemigrationin stressand hypercorticism
dueto the homingof the cellsin tissues(andtheir apoptosis)because
of the high glucocorticoid concentrations;
• the proteinCD95(Fas-receptor) expressionon the surfaceof lympho-
cytes,that indicatesthe readinessof the cell to induce apoptosiswith
thefollowingcelllossin diversimmunopatholog ical processes (atrophic
arthritis,systemiclupuserythematosus, disseminated sclerosis , etc.).

Chapter 21. Neoplastic Disorders

of Hematopoietic Function
Hemoblastoses (Gk.haima- blood,blast - growth,enlargement+ osis -
pathology,diseases)- refer to neoplasticclonaldiseases
, arisingfrom he-
mopoietic organs. Depending on whetherthe bonemarrowis primarilydam-·
aged,hemoblastosesare classifiedinto two largegroups:leukemiasand
 422 I Part 2 Pathophysiologyof organsand systems

lymphomas . In lymphomas , the neoplasticclonesprimarilyappearout of

the bonemarrow,often in lymph nodesand may graduallyspreadinto the
periphericbloodandotherorgans(includingbonemarrow).
Accordingto the up-to-dateliteraturehemoblastoses encompassthe fol-
lowing diseasesas:
• myeloproliferative , in whichthe pronouncedability of abnormalbone
marrowhemopoieticcells to differentiateis still preserved.This type
includeschronicmyeloleukemia, polycythem ia vera(erythremia,Vaquez
disease,Osier's disease , Osler-Vaquez disease) , essentialthrombocyto
-
penia, idiopathic myelofibrosis, paroxysma l nocturnalhemoglobinuria
(Marchiafava-Micheli syndrome};
• myelodysplastic syndromes , belongingto the groupof clonal disorders
of stemcellsanddeclarethemselvesby defectsof maturation, whichin
turn resultin the ineffectivehemopoiesisandthe increasedrisk of the
development of acutemyeloblastic leukemia,i.e. theyareconsideredto
be preleukemic stageof its formation;
• histocytoses - neoplasticclonaldiseases , arisingfrom the localmacro-
phagesof hemopoieticorgans.

Leu kemi as
Leukemias (Gk.leuk,from leukos,white, relatedto leukocytes+ aimia, from
haima,blood)are malignantneoplasms,arisingfrom hemopoiet ic cellsand
primary affecting red bonemarrow.The diseasesmakeup the largestper-
centage(25- 30 %) amongthe childhoodmalignancies.
Classificationofleukemias. At the endof 19th centuryleukemias
wererec-
ognized:acuteand chronic,that wasa·n attemptto reflectthe clinicalcourse
of the disease:the life expectancyof individualswith acuteleukemiaswas
usuallyshort-term, while in thosewith chronicleukemiait was somewhat
longer.Butthis characteristic shouldnotconsideredto beabsolute:thereare
well-knownfacts of lingeringclinicalcoursesof acuteleukemias(especia lly
underthe cytostatictherapy),andviceversachronicleukemiasmaybeof the
impetuouscourse.
Pathophysiologyof hematopoieticfunction Unit 5 I 423
Nowadays theclassificationof leukemiasintoacuteandchronicis no long-
er basedonthe duration of the courseof the disease , but mainlydependson
the degreeof thecelldifferentiation.
Thecharacteristicfeatureof acuteleukemias is that neoplasticcellsbeing
ableto unlimitedand uncontrolledproliferationlosetheir ability to mature,
i.e. to differentiateinto the followingforms.Sometimesjust onlythe partial
differentiation intointermediate forms maybepossible.
At the sametime, in chronic leukemias malignantcellsparallelwith their
abilityto unlimitedgrowthcanmaturateandproducethe consequent forms.
Thus, in acute leukemias clonedifferentiationbecomescompletelyblocked,
whilein chronic leukemias just onlydepression of this processis present.Tak-
ing this into account,acute leukemiasreferto hemobl astoseswith the more
_markedstageof tumorousprogression, i.e.theyare moremaligna nt in com-
parisonwith chronicleukemias.Andthis determinesthe turningof chronic
leukemias intoacuteonesasthe progression increases, andnotthe reverse.

Besides of leukemia classification into acute and

chronic , according to the dominant typ e of involv e d
into tumorous process c e lls leuk e mias are subtyp e d
into :

• lymphoid(affectinglymphoidprogenitor cells);
• non-lymphoid (affectingall non-lymphoidlineages(erythroid,granulo-
cytic, monocytic
, andmegakaryoc ytic)).

A rudimentary classification of more common le uk e -

mias divides leukemias into four typ e s:

• acutelymphocytic(lymphoblastic
) leukemia(ALL);
• chronic lymphocyticleukemia(CLL);
• acutemyelocytic(myeloblastic)
leukemia(AML);
• chronicmyelocyticleukemia(CML).
 424 I Part 2 Pathophysiologyof organsand systems

Differentleukemiasmoreoftendevelopment in differentperiodsof life.

ALLis the mostcommonleukemia in childhood , comprising80 % to 85 %
of leukemiacases.Thepeakincidenceoccursbetween2 and4 yearsof age.
CLLaffectsolderpersons.
AML is seenmostoftenbetweenthe agesof 13 and39 years.
CMLmostcommonbetweenthe agesof 30 and50 years.
Accordingto the numberof leukocytesin the peripheralbloodtherearethe
followinggroupsof leukemiasare distinguished:leukemic(hyperleukocyto-
sis - morethan 50 x 109/L), subleukemic(leukocytosisup to 50 x 109/L),
aleukemic(thenumberof leukocytesis unchanged), leukopenic(thenumber
of leukocytesis lower).

The evidences adducing the tumorous nature of

leukemias are concerned with the commonality of
principal features in pathogenesis of both these dis-
eases and malignant tumors, namely as:

• growthatypism(unlimitedandunregulatedcell division),and differen-

tiation(partialor completesuppressionof cell maturation);
• clonalcharacterof the disease(allthe leukemiacellsas well as cellsof
anyothermalignanttumorsoriginatefrom the onlyonecell;
• multi-stagepathogenesis , that involvesthe stageof initiation(whichis
inducedby variouscarcinogens),the stageof promotion(whichleads
to the appearance of neoplasticcells),andthe stageof progression(as
time goesbythe cellsaregainingmoreandmor~ malignantproperties);
• the presenceof certaintypesof anaplasias.

Etiologyof leukemias. Thee~ologyof leukemiasis not quiteclearas yet.

Nevertheless, amongthe factors resultingin the developmentof leukemias
aswell as anyothertumorstherearecarcinogens(leukemogens) of physical
(ionizingradiation),chemicalandbiological(oncogenicviruses)nature.
Radiation-induced leukemogenesis has been experimentallyverifiedon
mice and rats (underthe single exposureto high-doseionizingradiation ,
Pathophysiologyof hematopoieticfunction Unit 5 I 425
chronicinfluenceof smalldosesandradioactivenuclide incorporation),and
hasbeenalsoprovedonthegroundsof increasedrateof leukemiaincidences
in personswhosurvivedafter atomicbombingof HiroshimaandNagasakiin
1945or thosewho wereexposedto radiationdueto the man-causedacci-
dents(Chernobyl'nuclearpoweraccident , andothers),or duringthe profes-
sionalactivity(amongthe radiologists,roentgenologists) , or due to the ra-
diotherapy,includingchildren,exposedto radiationin utero.In all the cases,
the regulardose-dependent increasein the risk of leukemiashas beenreg-
istered.Discussingof iatrogenicfactorsfurtheredthe reasonablelimitation
of roentgen-diagnostic procedures , withdrawalof radiophosphorus, certain
restrictionsin radiotherapy applyingamongthe non-oncological patients.
Chemicalleukemogenesis hasalsobeenprovedexperimentally by induc-
ingleukemias in animals(mice, rats, hens)by meansof chemicalcarcinogens
(polycyclicaromatichydrocarbons , N-nitroso-compounds) , andasa resultof
revealingthe correlationof leukemiadevelopmentin individualswho for a
longtime contactedwith benzolor its derivatives , or took certainmedicines
- alkylatingcytostaticagents(cyclophosphamide , busultan(myelosanum ),
chloraminophene (chlorbutinum), chloramphenicol, phenylbutazone).
Nowadays therearestrongevidencesof viraletiologyof a numberof leu-
kemiasandotherhemoblastoses in animalsand certain forms of leukemias
in humans.As far backas in 1908EllermanandBangwerethefirst to dem-
onstratethat a filterableextractcould transmitleukemiaamongchickens .
In 1910, PeytonRousidentifieda transmissibleavian tumor virus. He was
eventually vindicatedandhis discoveryearnedhima NobelPrizein 1966.
In 1946, Burmester foundout virus of chickenlymphomatosis , andat the
earlyfifties of the last centuryGrossdescribedinfectiousleukemiain mice,
transmittedto newbornC3Hmice by inoculationof leukemiatissuefiltrate
takenfrom AK2mice,that provesthe infectiousnatureof the disease .
Leukemiavirusesexist in proviralform in a cell genome(endogenous
oncoviruses) and in the form of infectiousvirusesexogenousoncoviruses) .
Accordingto oncogenicproperties , virusescausingleukemia in speciesof
animals(birds,mice,rats,cats,monkeys)aredividedintotwo maingroups.
1. Quick-transforming , or virusesof acuteleukemia- causethe tumorde-
velopment followingaftera shotlatentperiod, andcontainoncogenes in
 426 I Part 2 Pathophysiology
of organsand systems

their structure.Theviruseslost their abilityto multiply, andin orderto

reproducetheyrequireexpressionof helperviruses,with whichthe on-
cogenicvirus replicatesby setting-upthe viral particles.Theseviruses
referto slow-transforming viruses.
2. Slow-transforming, or virusesof chronicleukemia - areregarded asfull-
valueviruses(i.e.capableto self-procreation). Theycausethe develop-
mentof the neoplasms after a long-term latentperiod, lastingfor several
daysor months.A genomeof all thesevirusescontainsno oncogens.

Themajorityof leukemiavirusesof animalsbelongsto thevirusescontain-

ing RNA-retroviruses.
At presentsomevirusesare known to causehemoblastoses in humans:
• Epstein-Barrvirus- is a DNA-containing virus of herpesvirusfamily,
that givesriseto the development of Burkitt'slymphomain childrenof
2-14 yearsold in somecountriesof CentralAfrica;
• retrovirusHTLV-1, giving rise to the development of adultT-celllym-
phoma/ leukemia;the diseaseoccursin Japan,WestAfrica, the Carib-
bean,SouthAmerica , Alaska,is transmittedby sexualway,throughthe
placenta,by bloodtransfusionor bloodproducttransfusion.

The leukemogenic role of retrovirusHTLV-11 is also foreknownbecause

therearesomeindirectfactsprovingthe correlationof the agentwith certain
T-cellforms of hairycell leukemia(a typeof chroniclymphaticleukemia).
Theroleof virusesin the etiologyof hemoblastoses in human ·s is of lesser
importancebecauseof exceptionalstabilityof a humancell genomein con-
trastto theothermammalsandbirds. Themostneces .saryconditionsprovok-
ingthe appearance of hemoblastoses aregeneticpeculiarities of theorganism
reactivity(geneticfactor) andthe decr~ase of anti-neoplasticresistance.
Theroleof geneticfactoris suggestedto betrue becauseof the following
observations. '
1. Thepresenceof "leukemicfamilies",whichmemberssufferedfrom leu-
kemiasacrossthe generations. It hasbeenfoundout thatwhenan only
family memberhas leukemia , his/hersibling or hetero-ovular twin is
likelyto haveleukemiain morethan4 timesin comparison withthe total
Pathophysiologyof hematopoietic function Unit 5 I 427
population.Amongthe monozygotictwins, the concordance is usually
observedin 20-25% of cases,andthe secondtwin developsleukemia
somemonthslatersincethefirst twin got thedisease;
2. The high frequencyof leukemiain individualswith chromosomalab-
normalities(breakage, disorderin varianceof somaticor sex chromo-
somes).Downsyndrome(trisomy21) is associatedwith an increased
incidenceof childhoodleukemia 20-30 times.Sucha regularityis ob-
servedin the patientswith Klinefelter 's andTurner's syndromesas well
as in thosehavinggeneticabnormalitiesin the systemsof DNArepa-
ration ("genomicinstability" syndromes- Bloomsyndrome , Fanconi
anemia,and ataxiatelangiectasia) . Theyare at increasedrisk for the
development of leukemias
(especiallymyeloblastic).
3. Thehighfrequencyof cytogenetic abnormalities in leukemiacells,which
consistnot only in changingof chromosomenumber(hyperdiploidy
and hypodiploidy),but in variousdisordersof their integrity(deletion,
translocation.inversion).Suchdisordersare typicalfor eachforms of
leukemia , andin non-lymphoblast leukemias arecommonly observedin
8,21pair, in acutelymphoblast ic leukemia - in 411or 1,19pairsof chro-
mosomes.In somecases, chromosomal aberrationsmaybeof certain
importance in theprocessof neoplasm transformation, for example,for-
mationof Philadelphiachromosome(Ph ) is relatedto the appearance
1

of activecelloncogendueto the hybridizationof c-aBLand bcr genes.

But morecommonlycytogenetic abnormalities arethe consequence of
thegeneticapparatusinstability underleukemias.
4. Purestrainsof laboratoryanimalsareknownto showhighrateof leukemia
incidences (e.g.,AKRmicelinewith spontaneous lymphaticleukemia) .

The probabilityof leukemiaand lymphomaincidencesconsiderablyin-

creasesin immunereactivitydisorders- primaryand secondaryT-cellim-
munodeficiencies and mixedimmunodeficiencies , as well as inducedby cy-
tostaticadministration
, or in certainautoimmunediseases(for example , in
dermatomyositis).
Pathogenesis . Numerousepidemiological investigations and dataon ex-
perimentalcarcinogenesis in vitro andin vivoallowto suggestthattheevolu-
 428 I Part 2 Pathophysiologyof organsand systems

tion of a normal cell into a leukemiaoneis a multi-stageprocess,havinglike

any other neoplasticprocessthreemainstages : initiation,promotion,and
progression.
It is supposedthat eachstageof leukemogenesis reflectsthe processof
mutation, resultingin the activationof primarycell oncogen;then activated
oncogensstart "working" together, inducinga completeneoplasticcell phe-
notype. The necessarycondition promotingtumorousproliferationof cells
in hemopoietictissuesconsistsin the loweringof antioncogene activity.The
antioncogenes actsas agentsin anti-mutativemechanisms of anti-neop lastic
protection. These genesprovide either "blockage " of activatingcellularonco-
genes, or their detectionandtheneliminationby meansof enzymesystems
of DNAreparation .
According to the lawsof monoclonalgrowth,an onlymutanthemopoietic
cellsgivesriseto theformationof tumorousclonein the bonemarrow.Leu-
kemianeoplasticcells (alsoknownas "blasts" in hematology)demonstrate
decrea sing in colony-formingability, asynchronismin the processesof pro-
liferationanddifferentiat ion, andcompleteblockingof differentiation (in acute
leukemias).Theelongationof mitoticcycleandcells' life-spanis usuallyob-
served. In the leukemiablast, clonethe presenceof two cell populationsof
"growing" and "dormant" cells (78-90 %) is seen. Having beendivided, an
only mutativecell producesthe abundanceof cells (1012 cells in 3 months)
weightingup to 1 kg and givesrise to the developmentof clinicalfeatures.
This processis rathercomplicated , it assumescompetitivefightingbetween
normalandneoplasticcellsas a basis, triggersthe mechanisms of neoplastic
progression .

Th e sa lie nt f ea tur e s of th e progress ion

of he mobl a stos es includ e:

• transformat ion of hemoblastoses from monoclonal(relativelybenign

tumors)into polyclonal(malignant);
• inhibitingof normalhemopoieticlineagesby the developmentof pancy-
topenia- anemia,thrombocytopenia , leukopenia;
Pathophysiologyof hematopoieticfunction Unit 5 I 429
• leukemia transformingfrom thealeukemicform into the leukemicone;
• dissemination of lymphomasintothe bonemarrow- the so calledtheir
"leukemization"·
'
• dissemination of leukemiacellsinto extramedullary hemopoietictissue
andoutsideof hemopoietic organswith the followingformingof leuke-
mic infiltrations(in the skin,kidneys, braintunic);
• increas ing in a numberof relativelydifferentiatedneoplasticcells and
increasingin theirundifferentiated forms;
• decreasing (loss)of enzymatic(biochemical) andantigenspecificityof
leukemiacells;
• intensificationin thefeaturesof cellatypism;
• developmentof resistance(adiaphoria)to the effectof anti-neoplastic
(especially cytostatic)drugs- hemoblastoses "escaping"from thether-
apy.

Acuteleukemias . Theyapproximately constitute 97% of all childhoodleu-

kemicdiseases.Having beenuntreated , acuteleukemiasbringto lethalter-
minationin severalweeksor months.Whenacuteleukemiais undergonethe
aggressive therapy,theprognosisfor thediseaseis oftenfavorable.Leukemia
cells, beingprecursorelementsof oneor morehemopoieticlineages(blasts
or earliergenerations of hemopoieticcells)are consideredto be pathomor-
phologicalsubstratumof thetumors.

According to the cytomorphological pictur e and data

of cytochemical reactions acute leukemias may be
classified as follows (FAS-classification - French-
American-British classification):

1) non-lymphoblastic myelogenous (myeloid)leukemias- there are 8

subtypesdistinguished by the lossof the abilityto differentiate(varying
fromthe considerable levelto its completeloss)andby thecharacterof
proliferatingleukemia"blasts");
2) lymphoblastic ;
 430 I Part 2 Pathophysiologyof organs and systems

3) myelopoietic
dysplasias
or myelodysplastic
syndrome
(pre-leukemic
conditions).

Non-lymphoblastic acute leukemias include:

M0 - acuteundifferentiated
leukemia(primitivecellshavingno certaincy-
tologicalor cytochemical markers,howevertheyexpressantigenstypicalfor
the cellsof myeloidlineage(Table26);

Table26.Histochemical , immunophenotypic
andchromosomal
characteristics
of
leukemia
cells in acuteleukemi
as

Su~ Histochemistry
Myelo- NE
· Pero.,r:idase '

·orSudan
MO CD34,33,13
M1 +!- +!- CD33,13 t(8,21)
M2 +++ +!- CD33,15,13 t(8,21)

M3 +++ + +!- CD33,

13,HLA-DR t(15,17)
M4 +!- +++ .
C011b,14,13,15,33 inv16
M5 +++ +!- CD11b,14 t (9,11),(1
1,23)
or del(11
)(q23)
M6 +/- +++ Glycophorin
A 5q-,7q-
M7 +/- ++ CD13,33,41
L1 -hH- Seetable5 t{9,22)
L2 +++ t(4,11)
L3 +++ Seetable5 t(8,14), rarely
t(2,14),(22,14)
Pathophysiologyof hematopoieticfunction Unit 5 I 431

Chromosomal
abnormalities

L2 +++ t(4,11)
L3 +++ See table5 t(8,14), rarely
t(2,14),(22,14)

Note-.NE- non-specificesterase(reactionwith a-naphthylacetate) , PAS- reactionwith

periodicacid(Schiff'sreagent)for the detectionof glycogen.Symbolsapplyingin chromo-
somenomenclature: t- translocation
(from... chromosomalpairinto ... pair),inv- inversion,
del- deletion
, q - longarm, q- - shorteningof chromosomallongarm.

M1 - acutemyeloblasticleukemiahaving signs of cell immaturation(per-

oxidase-positiveblastcell);
M2 - acutemyeloblasticleukemiahavingsigns of cell maturation (mor-
phologicalandcytochemical characteristicsof blastcellsaresimilarof those
of M1 blastcell mature into promyelocytes and more matureforms, typical
cytogeneticanomalyt (8,21));
M3 - acutepromyelocyticleukemia(blast cells with plentiful basophilic
granulosity,positivereaction to peroxidase,typical cytogeneticanomalyt
(15,17);
M4 - acute myelomonoblasticleukemia(blastcells possess morpho-
cytochemicalcharacteristicsof both myelo-and monoblasts,aberration
inv16;
M5 - acutemonoblasticleukemia(grainlessblastcellshavingmonocytoid
nuclei,peroxidase is absent,non-specificesterasesuppressionby fluoride,
variouschromosomalaberrationsin 11th pair;
M6 - acute erythroleukemia(erythromyelosis , Di Guglielmo's disease),
blastcellsarerepresented by earlyforms of erythroidlineage.
M7 - acutemegakaryoblastic leukemia.
 432 I Part 2 Pathophysiologyof organs and systems

Acute lymphoblastic leukemias are grouped into 3

types according to cytological characteristic of leu-
kemia cells:

L, - acutemicrolymphoblastic leukemia,smalllymphoidcells,sometimes
havingno nucleolus and immunologicalmarkers , prevail;this form is diag-
nosedin 65 % of childrenandin 5-1O% of adults.
L2 - acutelymphoblasticleukemiawith typicallymphoblastscommonly
occursin adults.
L3 - acutemacro-or 8-cell leukemiais characterized by the presenceof
verylargecells.
In additionto the cytomorphological classification,the immunological
classificationof acutelymphoblasticleukemiaexistsaswell,whichis based
on leukemiaimmunophenotyping (Table27), i.e.detectingcertainsuperficial
antigensby usingtaggedmonoclonalantibodies.Amongthe markersbeing
frequentlyidentified,clustersdesignation(CD)is present:
CD2- expressedon all T-lymphocytes(thymicand peripheric)and on
naturalkillers(NK-killers);
CD3- expressed on peripher ic T-lymphocytes andnaturalkillers(superfi-
cialexpressionrequiresco-expression of T-cellreceptor);
CDS-expressedon all T-lymphocytes;
CD7- expressed on all T-lymphocytes andmyeloidcell precursors;
CD10(antigenCALLA- commonacutelymphocyticleukemiaantigen)
- expressedon generations of 8-lymphocyte earlyprecursors ;
CD19i CD20- expressed on pre-8-cellsof the bonemarrowandon ma-
ture 8-lymphocytes (exceptfro plasmaticcells); ·
CD22- expressed on activatedmature8-lymphocytes ;
CD33-expressed on cellprecursors ·of myeloidlineageandon monocytes;
CD34- expressed on the earliesthemopoietic cell precursors.
Acute/ymphoblastic leukemiasare consideredto be the commonestin
childhood.The diseasemakesup nearly76% of total leukemiaincidences.
Theincidenceof acutelymphoblastic leukemiahighestat aboutthe ageof 4,
andis slightlymorefrequent(1.2-1.3times)in boysthanin girls.
Pathophysiologyof hematopoieticfunction Unit 5 I 433
Table27. Immun
ological classification of acute lymphoblasticleukemia.

Veryearly 5-10% L1 (L2)

pre-B
+ +

Early 50- L1 (L2)

+ .+ + 60%
pre-B
Pre-B + + + + 20% L1 (L2)

- MatureB Upto L3
* + + 1%

Tlineage 15- L2 (L1)

+ +/-* + + 20%

Note: TdT- terminaldeoxytransferase

, Cµ- cytoplasmicheavychainsof lgM, slg - super-
ficialimmunoglobulins.
• MoleculeCO2(receptorsto sheeperythrocytes)expressedjust on matureT-lymphocytes
andis atypicalfor pre-T-cellleukemias.

Thebloodpicturein acutelymphoblastic leukemiamaystart with aleuke-

mic or leukemicforms.Thepresenceof neoplasticlymphoblasts,anemias,
thrombocytopenia, granulocytopeniais typicalfor the disease.A myelogram
showsthe depressionof erythro- andthrombocytopo iesisand the overbal-
anceof blastelements. Clinicallyhemorrhagic, hypoxic, andinfectious-septic
syndromesare manifested.Besidesof the abovementioned , paraneoplastic
syndromerelatedto the productionof variouscytokinesby immuneand leu-
kemiacellsoccurs (determininganorexia,cachexy,osteoporosis , etc.)
Acutenon-lymphoblastic leukemias constitute about20 % of childhood
leukemias . The mostcasesoccur in teenageindividuals, especiallyin those
 434 I Part 2 Pathophysiologyof organsand systems

who havesyndromesof chromosomalinstability (Fanconianemia, Bloom

syndrome).
The blood picturein acutemyeloblasticleukemiamay include moderate
signsof markedanemiaof the normo-or slightly hyperchromic type.Throm-
bocytopenia is usuallyobserved .
WBCshowsthe prevalenceof young undifferentia ted cells, myeloblasts,
oftencontainingazurophilgranulesand clearlydiscerniblein light andelec-
tron microscopesAuerrods(abnormalrod-likeformsof azurophil granules),
that is prognostically favorablecharacteristic.
Typicalsymptomsof acutemyeloblastleukemiaincludethe presenceof hi-
atusJeukemicus of Naegeli(L. hiatus- gates,dip, absence , + Gk. leukemia),
consisting in, on the onehand,the appearance of blastandyoungleukemia
cells(of neutrophile lineage , asa rule), and, onthe otherhand, theabsenceof
oneor moretransitionalforms,for instance,myelocytes, promyelocytes (that
is why the term indicating"dip, absence " is regardedto beproper). This phe-
nomenonis relatedto the processof blockingthe leukemiacell maturation .
An accumulationof neoplast ic "blast"cells in the bone marrowsuppresses
normalerythro- andthrombocytopoiesis.
Thebloodpicturein acuteerythroleukemia (acuteerythromyelosis) shows
the signsof severeprogressinganemias , the appearance of immature nucle-
us-containing cellsof erythroidlineage,thrombocytopenia , granulocytopenia
in the periphericblood.An excess ive numberof changederythroblastsaccu-
mulatesin the bonemarrow.Theerythroblasts arethecellsof irregularshape,
multinuclear,containinggiantformswith abundantnucleoliin the nucleus.
Chronicleukemias. Unfortunately , chronicleukemiasmaytransforminto
acuteleukemias (blastcrisis),thatconsiderablyaggravates theprognosisfor the
condition.In chronicleukemias leukemia cellspartlymatureandaremoreactive
functionallyin comparison with neoplasticcells("blasts") in acute leukemias.
Classifica
tion of chronicleuket17ias is basedon the prevale nce of a certain
typeof cellsin the populationof leukemiacells.The nameof leukemiapoints
out the affectedhemopoietic lineage.
Thereare the followingtypes of chronic leukemias: chronicmyelocytic
leukemia(chronicmyeloleukemia), chroniclymphocyticleukemia(chronic
lymphaticleukemia),chronicmonocyticleukemia , chronicerythromyelosis.
Pathophysiologyof hematopoieticfunction Unit 5 I 435
At the sametime the lymphocytic , monocytic, and erythroidprecursors
becomeaffected respec tively.All the chronicleukemiasin childrenbelong to
non-lymphocytic leukemias.
Chronicmye/oleukemia refersto clonal myeloproliferativediseasewith
elevatedproliferationand suppressionof differentiationof myeloid precur-
sors. In accordanceto recentstudiesthis form of leukemiais regardedto be
a chronic myeloproliferative disease(seeit above).

Two types of chronic myeloleukemia are

distinguished:

• adulttypeis rathercommonthenjuvenile; the myeloidclonearisesfrom

a transformedstemcell: neoplasticcells includePhiladelphiachromo-
some(Ph1);the overallmediansurvivalis morethan2 years;
• juvenile type occursin infantsbefore2-3 yearsof age, is slightly com-
mon in boys, and characterized by proliferationof cells of monocytic
andgranulocyticorigin;cellscontainno Ph1-chromosome ; this subtype
of chronicmyeloleukemia morerapidlyleadsto the fatal outcome(the
overallmediansurvivalis 9 months).

Bloodpicturein chronicmyeloleukemia. A numberof leukocytesmayvary

from aleukemic , subleukemic indicesto hyperleukocytosis. Anemiais mainly
normochromicof variousexpressiveness. WBCshowsthe shift of granu-
locytopoiesisto the metamyelocytes , myelocytes, promyelocytes,and my-
eloblasts.Thereare all the transitionalforms of granulocytelineage(hiatus
leukemicus is absent).TheCommonincreasein the numberof of basophiles
andeosinophiles(basophile-eosinophile association)is often observed,and
is oneof diagnosticfeaturesof chronicmyeloleukemia.
Bonemarrowhyperplasiadevelopsdue to the predominanceof young
forms of granulocyticlineage.Erythroidandmegakaryocytic precursorsmay
be suppressed to a variable extent.
Thejuveniletypeis characterized by hemoglobinfetalization, thrombocyto-
penia,monocytosis,monocyticinfiltrationof the organsandtissues.
 436 I Part 2 Pathophysiology
of organsand systems

Chronic lymphocytic leukemiais diagnosedmainlyin the patientsat ages

over 50 (medianage 60). Thediseasenearlyalwaysarisesfrom the clone
of 8-cells, morethan3% of the incidencesareassociated with the clones of
T-lymphocytes or NK-cells. A salientfeatureof 8-clonesin chronic lympho-
cytic leukemiaconsistsin their inabilityto transferinto plasmocytes under
the retainingother signsof maturation.Leukem ia cells havechromosomal
abnormalities(often trisomy on 12 chromosome
th , defectsof 11th and 14th
chromosomes (dueto thehypogammaglobulinemia) andautoimmune condi-
tions.
Atypiclymphocytesare undetermined towardsapoptosis , a part of them
proliferates.All this resultsin the developmentof leukemic forms of leuke-
mias:in the peripheralblooda numberof leukocytessometimes increases
up to 300-600x109/L of the blood.WBCshowsthe prevalence of leukocytes
(from80to 90%), but prolymphocytes andlymphocytes. Thediseaseis char-
acterizedwith the appearance of the so calledsmudge,basketor shadow
cells (Botkin-Gumprecht-Kleinshadows). Theyare reddish-purplenuclear
remnantof a rupturedimmature leukocyteof any type that has undergone
partialbreakdown duringthe preparation of a stainedsmearor tissue section,
becauseof its greaterfragility.
Typically,the bonemarrowcontainsa considerablyincreasednumberof
leukocytesup to total lymphoidmetaplasia. Fewlymphoblasts maybefound
out aswell.Erythroid andmegakaryocytic precursorsareto a variable degree.

Clinical features of leukemias may be divided into

three groups:

1. Hematological syndromes relatedto myelophthisis:

• pancytopenia - a decreasein a numberof all the bloodcells;this is sig-
nificantlypronouncedin acuteleukemias;
• anemia-dueto the erythropoietic impairment,aswellas in certaincas-
es of leukemias,immuneerythrolysis(for example,in casesof chronic
lymphocyticleukemia) , or dueto the bloodloss resultingfrom the de-
velopmentof hemorrhagic syndrome;
Pathophysiologyof hematopoieticfunction Unit 5 I 437
• hemorrhagicsyndromearisingfrom thrombocytopenia and formation
of leukemicinfiltrationsin the bloodvesselwalls;
• loweringof thebodyresistance to infectionsasa resultof leukopenia (in
acuteleukemias andchronicmyeloidleukemias ) or functionalinferiority
of leukemiacells.

2. Paraneoplastic syndromes determined bysignalandmetabolic inter-

relationoftheleukemic clone,theimmunesystem , andthe organism :
• feveris experienced by morethan 2/3 patientswith leukemiasmainly
developingdue to the releasingsecondarypyrogenes- interleukin-1
and6, andthetumornecrosisfactor-aby neoplasticandimmunecells;
• intoxicationand systemiceffectof bioactivesubstance;manycompo-
nentsof destroyedcellhavea toxiceffectonthecentralnervoussystem
causingthe neurological problemsas fatigue, general weakness,nau-
sea,etc.; thesemanifestations may be also causedby bioactivesub-
stances(themajorityof cytokines)beingproducedby leukemiacells or
cellsof the immunesystem;
• increasedconcentration of uricacidin theblood(hyperuricemia) devel-
ops dueto the breakdown of purinesreleasingfrom neoplasticcells,
whichare destroyed , in acuteleukemias; uric acid may settlein renal
tubulesandresultin renalinsufficiency,
• autoimmune processesassociated with the appearance of the so called
forbiddenlymphocyticclones,productionof antibodiesor their frag-
ments(e.g.,light chains)of autoreactive specificity(e.g.,to owneryth-
rocytesandthrombocytes) by neoplasticclones((in 8-celllymphocytic
leukemia,8-lymphomas) .

3. Syndromes associated withthe dissemination of leukemiccellsand

thedevelopment of leukemic infiltrations
intheorgansandtissues:
• hyperplastic syndromemanifestedby the enlargement of lymphnodes
(/ymphoadenopathy), liver, spleen(hepato-andsplenomega/y), rarely-
by the enlargementof tonsilsand mediastinum lymphnodes;
• compression syndrome.crowdingof neoplasticcellsin theanteriorme-
diastinummayformanextensional newgrowthwhichin turn mayevoke
 .,
1,
438 I Part 2 Pathophysiologyof organsand systems

hypoxiabecauseof respiratoryobstructionandthe development of su-

perior venacavasyndrome ;
• cutaneoussyndromedueto leukemicinfiltrationsin theform of reddish
andbluishplaques;
• ulcerative-necrotic lesions of mucosa(ulcerative-necrotic stomatitis,
tonsillitis,enteropathies);
• osteoarticularsyndromecharacterized by pain in bonesand joints re-
sultingfrom the medullarycavityinfiltrationor compactboneresolution
dueto the leukemiacellactivity;
• neuroleukemiasyndromecharacterizedby meningealsyndrome,in-
creasedintracranialpressure, variousneurologicalcomplications:pa-
reses, paralyses,paresthesias; the syndromearisesfrom the leukemic
infiltrationof the nerveroots,nervetrunks,gangliaof autonomicplex-
uses, meninges,medullarysubstances;
• unilateralor bilateralaffectionof testes:usuallydueto the leukemiacell
infiltration is characterized by the hypertrophyof testiclesdispropor-
tionalto the stageof pubescence (oftenin boyswith acutemyeloblastic
leukemia);
• leukemicpneumonitis : leukemicinfiltratesimpairpulmonaryrespiratory
functionresultingto the upperrespirationfailure;
• cardiacinsufficiencydueto the leukemiacell proliferationinto the myo-
cardium.

Patho p hysiol o g ica l pr inciples of therapy of

leuk em ias:
Cytostatictherapyaimedat the maximal .eliminationof neoplasticcellsis con-
sideredto bethe keypointin theJeukemia treatment.
Currentstate in the therapy of acuteleukemiasincludesapplying of
the special programsworked out in accordanceto pathomorphological
forms, and peculiaritiesof the courseof the disease.The programsallow
to bring 80-95 % of children and 60-80 % of adult patientsinto remis-
sion.
Pathophysiologyof hematopoieticfunction Unit 5 I 439
Combined cytostatic ther a py includes the following
stag e s:

1) inductionof theremission- consistsin the carryingout of the courseof

cytostatictherapyin accordance to effectiveprograms;
2) consolidation(fixation)of the remissiondirectedto the eliminationof
remaining leukemiacellsandthe preventionof neuroleukemia (through
theadministration of drugspenetrating hematoencephalicbarrier, endo-
lumbar(intrathecal)introductionof cytostaticagentsandgamma(-ray)
teletherapy;
3) supportingtherapy(non-stoplow-dosesupportingtherapyand/ or peri-
odiccoursesof re-induction)in orderto providefurthermaximalreduc-
tion of leukemiacells.

Thetherapeutic
resultsmaybeimprovedby autogenous
or allogeneicbone
marrowtransplantation.Havingbeingcarriedout during the 1st remissionand
in about55%thereis achievedlong-term remission.
Currenttechniquesof al/ogenicbonemarrowtransplantationrequiresan
idealdonorlikesibs,whois identicalby antigensof the maincomplexof his-
tocompatibility.Up-to-datestudiesare focusingon the possibilitiesof non-
sibstransplantation whenthe histocompatibility is observedas well as mini-
maldifferences of its antigensor undertheconditionsof immunodepression.
Autogenoustransplantationis carriedout to a patientjust after the pa-
tient'sbonemarrowpurification, thebonemarrowshouldbetakenonlyin the
remissionperiod, andthen it shouldbetreatedwith monoclonalantibodies ,
immunocytotoxins (e.g., ricin)andpharmacologicalpreparations, whereupon
introducedintothe patient.
In thetherapyof adult,chronicmyeloidleukemiainterferonis usedto sup-
pressthe proliferationof cellscontainingPh1-chromosome. Manypresentre-
searches aredevotedto theeffectiveness of drugsinhibitingtheactivityof Ph1-
chromosom e genes(c-alb/bcrhybridfragments,tyrosinekinaseinhibitors).
Anti-leukemia therapyis usually accompanied with measuresaimedto re-
placethe lost bloodvolume(erythrocytes , thrombocytes) , to treatinfectious
complications, to correctacid-basebalance,hyperuricemia, increasedblood
 440 I Part 2 Pathophysiologyof organsand systems

viscosityin leukemicformsof leukemia(replacement

transfusion,leukopher-
esis), compressionsyndrome .

Leuk emoid reac tions

Leukemoid reactions(leukemia+ Gk. -id, aidos- similar,resembling)are
characterized by a considerable increasein a numberof variousimmature
leukocyti c forms (upto normal, non-tumorousblastcells)andasa rule(but
not always)by an increasednumberof leukocytesin the periphericblood.
The term "leukemoid reactions" pointsout that the conditionis consid-
ered not to be a disease , but a reactiveconditionof the organism,certain
changesin the bloodand hemopoieticorganswhich are similar to leuke-
miasand otherneoplasmsof hemopoieticsystem.Thesereactionsreferto
self-limitedprocessesanddo not transformin hemoblastoses, thoughthey
resemblehemoblastoses by their hemolyticcharacteristics.
Two types of leukemoidreactionsare distinguished : myeloid(pseudo-
blastic,neutrophilic,eosinophilic)and monocytic-lymphocytic (monocytic ,
lymphocyt ic, andplasmocytic).Lymphocyticleukemoidreactionsare more
commonin children.
Etiology . Pseudoblast ic leukemoidreactionsoccur in newbornsunder
the rhesusincompatibility , or whencomingout from immuneor myelotoxic
agranulocytosis . Theyareaccompanied by the appearance of true blastcells
whichhaveno leukemiamarkers.Amongthe causative factorsof neutrophilic
leukemoidreactions(whichresembles the clinicalpictureof chronic myeloid
leukemia)thereareseveresepticprocesses , toxic infections in combination
with blood loss, exogenousintoxications (gas poisoning,drug poisoning,
mercurypoisoning,ethyleneglycol poisoning, etc.), radiationinjury, any
typesof shock, the development of acutehemolyticprocess,wasteproducts
of malignantneoplasms , productionof granulocytopoietic stimulantsby cer-
tain tumors (e.g.,by hypernephroma (renalcell carcinoma)).
Eosinophilic leukemoid reactions (alsoknownasextremeeosinophilias or hy-
pereosinophilias) makeup in children80%of all casesagainstthe background
of helminthias is, especiallywhenparasites areintimatelyin contactwithtissues
Pathophysiologyof hematopoieticfunction Unit 5 I 441

(trichinosis,filariasis).Eosinophilic reactionsalsooccurinassociation withallergic

diseases, diffusediseases of connective
tissue,tumorsreleasing cytokines,which
stimulateeosinoph ile production(for instance, in lymphogranulomatosis, T-call
lymphomas, cancers of thedigestive systemorgans,thyroid, osteosarcoma).
Thedevelopmen t of lymphocyticandp/asmocyticleukemoidreactionsare
determinedby weakimmunologiccompetenceof lymphocytesin children
with constitutional abnormalities (exudative diathesis,lymphohypoplastic di-
athesis) . Just in thechildrensufferingfromtheevenslightdiseasesimmuno-
blastinfiltration of lymphnodesor ratherpotentantigenstimulation (during
the vaccination,infectious diseases)of lymphocytesin the periphericblood,
whichtransformintothe blasts, usuallyoccurs.Themostmarkedleukemoid
reactionsof monocytic- lymphatictypeswith certainmorphologica l changes
in lymphocytes areobservedin diseases,causedby DNA-containing viruses
pf herpesv irusfamily(in infectiona l mononucleosis, chickenpox),whileother
viral infectionsprovokethe reactionsof lessintensity.
Pathogenesis of leukemoidreactionsconsistsin the polyclonalreactive
focal hyperplasia of various normallineagesof leukopoiesisand mobiliza-
tion of a considerable numberof immatureleukocytes, includingtheir blastic
forms, from the hemopoietictissueintothe circulation . Thephenomenon, on
the onehand,is determinedby an increasedactivityor increasedconcentra -
tion of leukopoiet ic factors in the hemopoietic tissuesand/ or a decreaseof a
number of antigenssuppressing the divisionandstimulatingthe maturation
of the cells,chalonesin particular .

Clinical features .

Leukemoid reactions can be diagnosed by the fol-

lowing changes in the peripheric blood and in th e
bone marrow :

1. Shift of WBC to the left with a significantnumberof bandneutrophilic

myelocytes(neutrophilicreactions).
 442 I Part 2 Pathophysiologyof organsand systems

2. Elevatednumberof eosinophiles(more than 20 %) in the peripheral

bloodand the bonemarrowaccompanied by increasingin the number
of eosinophilicmetamyelocytes, myelocytes,or promyelocytes (eosino-
philicreactions)
.
3. Elevationof monocytes(more than 15 %) with the presenceof pro-
monocytesin the periphericblood(monocyticreactions).
4. Increasingin a numberof lymphocytesup to 70 % in the peripheric
bloodandevenmorein the bonemarrow, accompanied with lymphoad-
enopathyandsplenomegaly (lymphocyticreactions)
.
5. Elevatednumberof plasmaticcellsin the myelogramandtheir appear-
ance(at about2 %) in the periphericblood(p/asmocytic reactions).

Respectively , eachtype of leukemoidreactionmay be accompaniedby

generalleukocytosis(> 10-15 x 109/L). Reactivethrombocytoses anderyth-
rocytosesmayoccuras well.Thebonemarrowhemopoiesis in all incidences
is accompaniedwith hemopoieticactivation , and a bone marrow punctate
showsan increasednumberof myelopoieticprogenitorcells.
Leukemoidreactionsof the lymphocytictype are manifestedmainly by
immunoblastic lymphoadeno pathy. Lymphocytesbeing blast-transformed
underthe effectof an antigen(allergen)areconsideredto be morphological
substratumresultingin theenlargement of lymphnodes.In infectionalmono-
nucleosissucha stimulationis producedby a causativeagent- Epstein-Barr
virus, whichmaypenetratelymphnodes, the liver, spleen,and resultin their
hyperplasia,infiltration with large blast-transformed cells (immunoblasts-
mononuclearleukocytes ).
In all the incidencesof leukemoidreactions , reactivehyperplasia vanishes
completelytogether with its causativefactor.

Co mmon and distinct features in leukemoid

reactions and leukemia s
Distinguishing featuresof leukemoidreactionsandleukemiasareratherhelp-
ful in the diagnosisof thesedisorders.As appearsfrom the abovethe com-
Pathophysiologyof hematopoieticfunction Unit 5 I 443
mancharacteristic of theconditionsliesin the similarityof the hematological
picture(considerable elevationin a numberof immatureleukocyticforms up
to the blasticcellsin the periphericblood, rejuvenation of the bonemarrow
cellularcomposition,and in bothdiseasesgeneralleukocytosis,sometimes
hyperleukocytosis maydevelop.
Distinctions
between thedisorders aredeterminedbysufficiently differentna-
turesof leukemoid reactions andleukemias : leukemoid
reactions referto there-
active,self-limited
polyclonal processes , whileleukemias
areneoplastic diseases,
causedby uncontrollable proliferation
of a monocloneof atypicalleukemia cells.

H en c e :

~ • pathogenesis of leukemoidreactionsis associated with the activationin

the proliferationof normal(at least, havingno signsof atypism)cellsof
leukocyticlineage , whilethe pathogenesis of leukemiasincludesmecha-
nismsof thetransformation of a normalhemopoietic bonemarrowcells
intoa neoplasticcell;
• leukemoidreactionsare characterized by the absence(in contrastto
leukemias) of antigenmarkersof neoplasticcells;
• genetic,especiallychromosomalabnormalitiesin the cells (e.g., Ph1-
chromosome is typicalfor the adulttypeof chronicmyeloleukemia) are
notattachedto leukemoidreactions ;
• in the bonemarrowfocalhyperplasiaof normalleukopoietic cellsis ob-
servedunderthe developingof leukemoidreactions , whereasin leuke-
miasgeneralized neoplastichyperplasia of hemopoietic tissueis seen;
• myeloblasts oftenprevailin the periphericbloodpicturein acutemyelo-
blasticleukemias, whereasonlyfew myeloblasts arepresentin pseudo-
blasticleukemoidreactions;
• hiatusleukaemicus is typicalfor acutemyeloblastic leukemia , whereasit
is atypicalfor the leukemoidreactionsof the myeloidtype;
• chronicmyeloleukemiais characterized by the presenceof "basophilic-
eosinophilicassociat ion", whilethis is atypicalfor the leukemoid reac-
tionsof myeloidtype;
 Part 2 Pathophysiology
of organsandsystems
444

• a largenumberof leukocytes
with toxic granulosityis usuallyobserved
in theleukemoid
reactions,
whilethecellsareabsentor fewin leukemias.

Chapter 22. Pathophysiology

of Blood Coagulation
The hemostatis basedon the complexof. plasmafactors,thrombocytes
(platelets),andthevesselwall.

Hemostasis is divided into five stages:

• vesselspasm;
• thrombocytesactivation;
• formationoftheplatelet
plug;
• bloodcoagulationor the development
of an insolublefibrin clot, clot
retraction;
• clotdissolution.

Vessel spasm
A vesselspasmis initiatedby endothelialinjuryandcausedby localandhu-
moralmechanisms. A spasmconstrictsthevesselandreducesbloodflow. It
isa transient
eventthatusually lastslessthan1 minute.

Thrombocytes activation
Platelets,
alsocalledthrombocytes,
arelargefragmentsfrom the cytoplasm
of bonemarrowcellscalledmega_karyocytes.
Theyareenclosed in a mem-
branebuthavenonucleus andcannot
reproduce.Theircytoplasmicgranules
release
mediators forhemostasis.
Pathophysiologyof hematopoieticfunction Unit 5 I 445
Thelifespan of a plateletis only8 to 9 days.Thenormalquantityin peripher-
al bloodis 180-320x 109/l. Plateletproductionis controlledbya proteincalled
thrombopoietin thatcausesproliferationandmaturationof megakaryocytes .
Plateletsactivationleadsto a shapechangefrom a disc to a sphereand
they obtain propertiesfor adhesionand aggregation . Factorswhich take
placein thrombocytes activationarereleased from theircytoplasmicgranules
and includeADP, serotonin,platelet-derived growth factor, plateletfactor 4
andotherfactors.
Centralto normal plateletfunction is plateletprostaglandinsynthesis,
whichis inducedby plateletactivationand leadsto the formationof TxA2 in
platelets.Thromboxane (T~) is a powerfulvasoconstrictorandalso lowers
cyclicAMPlevelsandinitiatesthe plateletreleasereaction.
Thromboxane A2 , releasedfrom the plateletsandcells, andothermediators
contributeto vasoconstriction. Prostacyclin(Pg 12) , a prostaglandinreleased
from the vesselendothelium,producesvasodilatationand inhibits platelet
aggregation.

Format ion of the platelet plug

Theplateletplug,the secondline of defense , is initiatedas plateletscomein
contact with the vesselwall.
Plateletplug formationinvolvesadhesionand aggregationof platelets.It
also requires a proteinmoleculecalledvonWillebrand factor(vWF). This
factoris producedby the endothelialcellsof bloodvesselsand circulatesin
the bloodasa carrierproteinfor coagulationfactorVIII.
Plateletadhesionto collagenis dependenton platemembranereceptors
(glycoproteins). Followingadhesionplatelets spreadalongthe subendothe-
lium andreleasethe contentsof their cytoplasmicgranules(containingADP
and serotonin)and X-granules(containingplatelet-derivedgrowth factor,
plateletfactor4, thromboglobulin, fibrinogen,vWFandotherfactors).
Thereleaseof ADPleadsto a conformational changeof the fibrinogenre-
ceptor.Fibrinogenbindsplateletsinto activatedaggregates (plateletaggrega-
tion) andfurtherplateletreleaseoccurs.Furtherplateletmembranereceptors
 Part 2 Pathophysiology
of organsandsystems
446

are execsduringaggregation,providinga surfacefor the interactionof co-

agulationfactors;this plateletactivityis referredplateletfactor3 (PF-3).The
presenceof themencourages fusionof platelets,andfibrin formalreinforces
thestability
oftheplatelet plug.

Blood coagulation and clot retraction

Thecoagulationcascadeinvolvesa seriesof enzymaticreactionsleadingto
the conversionof solubleplasmafibrinogento fibrin clot. Romannumerals
areusedfor mostof the factors,but I, II andIll are referredto asfibrinogen,
prothrombinandtissuefactorrespectively; VI is redundant.Theactiveforms
are denotedby "a". Thecoagulationfactorsare primarilysynthesized in the
liverandareeitherenzymeprecursors(factorsXII, XI, X, IX andthrombin)or
cofactors(V andVIII). Most reactionsin the coagulationcascadehavepro-
teolyticorigin.Therearethreemanestagesin the bloodcoagulation cascade
(Fig.42).
1. Formation ofthethromboplastine complex.
2. Transformationprothrombine to thrombine.
3. Transformationfibrinogen
to fibrine.

Coagulation pathways
Coagulation cascadewasdividedinto "extrinsic"and"intrinsic"pathways.
Extrinsicpathwayof coagulationis initiatedby the tissuefactor,which is
expressed onthe surfaceof perivascular endothelialc8lls,comingintocontact
withplasmaafteraninjury.Thecomplex_ of activated
factorVII andtissuefactor
(TF:VIla) doesactivatefactorX but its mainrolein vivois to activatefactorIX.
'
Intrinsicpathwayof coagulationbeginfrom factor XII (Hagemanfactor)
which is activatedby "contact"with the injuredsurface(endoteliocytes and
collagen)or prekallikrein- kallikreinproteolyticmechanism. ThenHageman
factorinitiates
a seriesof reactions beginning withactivation offactorXI,then
IX,VI11andalsoleadsto theactivation offactorX.
Pathophysiologyof hematopoieticfunction Unit 5 I 447
XII Xlla
XI t ,. Xia
IX !
Ca2• t
Ill
IXa Ca2+
PF-3 VIia-- VII
Ca2•
VIII

X /
xa
Common Ca2•
pathway PF-3
V
+ VIII
Prothrombin
(factor II)
~
,. Thrombin i
VIiia

Stablefibrinpolymer

Fig.42. Blood coagu

lationcascad
e

Theactivationof X factor by both pathwaysleadsto the formationof the

thromboplastine complexwhich includesphospholipide(3rd thrombocyte
factor), activeX andV factorsandCa2•. Thepresenceof the 3rd thrombocyte
factorin the thromboplastine complexis very importantbecausethis factor
playsthe roleof "matrix"for thefuturedevelopment of the coagulationcas-
cade.
 448 I Part 2 Pathophysiologyof organsand systems

Theformationof the thromboplastine complexwith the activefactorX in-

ducesthe conversionof prothrombinto thrombin(secondstep). Thrombin
hydrolysesthe peptidebondsof fibrinogen, releasingfibrinopeptidesA and
B, and allowingpolymerization betweenfibrinogenmoleculesto form fibrin
(third step).At the sametime, thrombin,in the presenceof calciumions,
activatesfactorXIII, whichstabilizesthe fibrin clot by cross-linkingadjacent
fibrin molecules(clot retraction).
Limitationofcoagulation. Coagulation is limitedto the siteof injurybythe
removalof activatedcoagulationfactorsby rapidbloodflow at the periphery
of the damagedarea,by plasmainhibitorsof activatedcoagulationfactors,
andby fibrinolysis.
Antithrombins. Regulationof thrombinactivationis the most common
mechanismof the inhibitoractionon the systemof coagulation.Antithrom-
binsincludesomecomponents with antithrombinactivity:heparin,fibrin and
productsof it's degradation, andantithrombin-111 (AT-Ill). Heparinproduced
by somecellsincludemastcellsandinhibited somestepsof bloodcoagula-
tion cascadeincludethrombinactivation.Fibrinandproductsof it's degrada-
tion working by negativefeed-backmechanism , whereaccumulation of fibrin
leadsto inhibit ion of thrombin.Antithrombin-111 - specific proteinaseinhibi-
tor, a memberof the serpinsuperfam ily, is a potentinhibitorof coagulation .
It inactivates
the serineproteases(includethrombin)byformingstablecom-
plexeswith them, andits actionis greatlypotentiatedby heparin.
ActivatedproteinC. This is generatedfrom its vitaminK-dependent pre-
cursorbythe actionof thrombin;thrombinactivationof proteinC is enhanced
whenthrombinis boundto thrombomodulin, whichis an endothelialcell re-
ceptor.The activatedproteinC destroysfactor V and factor VIII, reducing
furtherthrombingeneration.
Clotdissolution or fibrinolysis.Fibrinolysis- processwhich helpsto re-
storevesselpotency,also occucsin responseto vasculardamage . In the fi-
brinolyticsystem,whichalsoa typicalproteolyticsystem,an inactiveplasma
protein- plasminogen - is convertedto plasminby plasminogen activators
derivedfrom the plasmaor bloodcells(intrinsicactivation)or thetissues(ex-
trinsicactivation).
Themostimportantintrinsicactivators-tissueplasminogen
activator,plasmakallikrein,andextrinsicactivator- urokinase, streptokinase.
Pathophysiologyof hematopoieticfunction Unit 5 I 449
Plasminis a serineproteasewhichbreaksdown fibrinogenand fibrin into
fragmentsX, Y, D and E, collectivelyknownas fibrin (andfibrinogen)deg-
radationproducts(FDPs). Thedegradation of cross-linkedfibrin alsoyields
0-dimerand0-dimer-Efragments. Plasmin is alsocapable of breakingdown
coagulationfactors such as factors V andVIII.
Thefibrinolyticsystemis activatedby the presenceof fibrin. Fibrinin this
situation playsthe roleof "matrix". Forthis reason,theaccumulation of fibrin
leadsto the moreintensiveactivationof fibrinolysis. lnactivators of plasmin
(suchasa2-antiplasm in) arealsopresentin the plasmaandcontributeto the
regulation of fibrinolysis.
Investigation ofbleedingdisorders arebasedon laboratory tests,butalso
muchinformationmaybe obtainedfrom the historyand physical examina-
tion. Thereare3 most importantquestions.Is the haemostatic defectlocalor
·systemic.Is this defect inheritedor acquired?Whichdefectprevails- vascu-
lar/plate let or coagulation?
Laboratory investigations . Thebloodcount andfilm showthe numberand
morpholo gy of plateletsandanyblooddisordersuchas leukaemia.
Bleedingtime measuresplateletplugformation in vivo, normallybetween
3 and1Ominutes.Prolongedbleedingtimes arefoundin patientswith platelet
function defects andthereis a progres siveprolongationwith plateletcounts
9
lessthan80x 10 /L. Thebleedingtimeshouldnot beperformedat low plate-
let counts.
Coagulation testsare performedusing bloodcollectedinto citrate, which
neutralizescalcium ions andpreventsclotting.
The prothrombin time (PT)is measuredby addingtissuethrombopla stin
in the form of animal brainextractandcalcium to the patient's plasma.The
normalPT is 16-18 s, andit is prolongedwith abnormalitiesof factorsVII, X,
V or II, liver disease , or if the patient is on anticoagulant
treatment.
Thepartialthromboplas tin time with kaolin(PTTK)is also knownas the
APTT(activatedPTT). It is performedby addinga surfaceactivator, kaolin,
phospholipids(as plateletsubstitute) and calciumto the patient's plasma.
Thenormal PTTK is 30-40 s, depend ing on the exactmethodology,and it is
prolongedwith deficiencies or inhibitorsto oneor moreof thefollowingfac-
tors: XII, XI, IX.VIII, X, V, II or I (but notfactorVII).
 450 I Part 2 Pathophysiologyof organsand systems

Thethrombintime (TT) is performedby addingthrombinto the patient's

plasma.ThenormalTT is about12 s, andit is prolongedwith fibrinogende-
ficiency,dysfibrinogenaemia (normallevelof fibrinogenbut abnormalfunc-
tion) or inhibitorssuchas heparinor FOPs.
Correctiontests can be usedto differentiateprolongedtimes in the PT,
PTTKandTT dueto variouscoagulationfactordeficiencies andinhibitorsof
coagulation.ProlongedPT,PTTKor TTdueto coagulation factordeficiencies
arecorrectedby additionof normalplasmato the patient'splasma;nocorrec-
tion of anabnormalresultaftertheadditionof normalplasmais suggestivein
the presenceof an inhibitorof coagulation.
Factorassaysare usedto confirmcoagulationdefects,especiallywherea
singleinheriteddisorderis suspected.
Specialtests of coagulationwill often be requiredto confirmthe precise
haemostaticdefect.Suchtests include estimationof fibrinogen and FDPs,
plateletfunctiontestssuchas plateletaggregation andtestsof thefibrinolytic
pathwaywhich include the euglobulinclot lysis time (ELT)and assaysof
plasminogen,tissueplasminogenactivators.Theeuglobulinis clottedwith
thrombinandthetime takenfor lysisof thefibrin clot is a measureof fibrino-
lytic activity; the normalrangeis 60-270 minutes.

Bleeding disorders
Hemorrhage refersto theextravasation of bloodbecause of vesselrupture.Ac-
cordingto theirsize,hemorrhages areroughlygroupedin thefollowingway.:
Petechiae: Minute1-to 2- mmhemorrhages in skin, mucousmembranes, or
serosalsurfaces.Petechiae occurwithincreased intravascular pressure
, lowplate·
letcounts(thrombocytopen ia), efective
plateletfunction,andclottingfactordeficits.
Purpura : Larger(> 3 mm) hemorrhages. Purpuriclesionsareassociated
with similarpathologiesas well as trauma,localvascularinflammation(vas-
culitis),andincreasedvascularfragility
Ecchymoses: Larger(> 1 to 2 cm) subcutaneous hematomas(commonly
calledbruises).Ecchymoses typicallyfollow traumabut maybe exacerbated
by anyof the aforementioned conditions.
Pathophysiologyof hematopoieticfunction Unit 5 I 451

Largeaccumulationsof bloodin bodycavitiesare calledhemothorax , he-

mopericardium, hemoperitoneum , or hemarthrosis
, dependingon the loca-
tion.

Vascular disorder s
Thevasculardisorders , sometimespreviouslyclassified as non-thrombocy-
topenicpurpuras , are characterized
by easybruisingand bleedinginto the
skin. Bleedingfrom mucousmembranessometimesoccursbut the bleed-
ing is rarelysevere.Laboratoryinvestigations
includingthe bleedingtimeare
normal.Thevasculardisordersincludethe following.
Hereditary haemorrhagic teleangiectasiais a raredisorderwith autoso-
mal dominantinheritance. Dilatationof capillariesand small arteriolespro-
ducescharacteristicsmallredspotsthat blanchon pressurein the skin and
mucous membranes
, particularly the nose and gastrointestinaltract. Recur-
rent epistaxisand chronicgastrointestinal bleeding are the majorproblems
andmaycausechroniciron deficiencyanemia.
Easybruisingsyndromeis a benign disorderoccurringin otherwise
healthywomen.It is characterized by bruiseson the arms, legsand trunk
with minortrauma, possibly dueto skinvesselfragility. It maygiveriseto the
suspicionof a seriousbleedingdisorder.
Senilepurpura andpurpuradueto steroidsarebothdueto atrophyof the
vascularsupportingtissue. Purpuradue to infectionsis mainlycausedby
damageto thevascularendothelium .
Henoch-Schiinlein purpuraoccursmainlyin children.It is a type Ill hyper-
sensitivityreactionthat is oftenprecededby an acuteupperrespiratorytract
infection.Purpurais mainlyseenon the legsand buttocks.Abdominal pain,
arthritis,haematuriaandnephritisalsooccur.Recoveryis usuallyspontane -
ous, but somepatientsdeveloprenalfailure.
Episodes of inexplicablebleedingor bruisingmay representabuse; ei-
ther self-inflicted or caused by others, thesevariousforms of artificialor
factitiouspurpurasare expressionsof severeemotional or psychiatricdis-
turbances .
 452 I Part 2 Pathophysiologyof organsand systems

Plate let d isorders

Bleedingdueto thrombocytopenia or abnormalplateletfunctionis character-
izedby purpuraandbleedingfrom mucousmembranes. Bleedingis uncom-
monwith plateletcountsabove50 x 10 /L, andseverespontaneous
9
bleeding
9
is unusualwith plateletcountsabove20 x 10 /L.
Thrombocytopenia. This is causedby reducedplateletproductionin the
bonemarrowor excessiveperipheraldestructionof platelets.??? Thebone
marrowaspirateto assesswhetherthe numbersof megakaryocytes are re-
ducedor normal/increased is an essentialpartof the investigation.
Autoimmune (idiopathic)thrombocytopenic purpura(AITP).Thrombo-
cytopeniais dueto immunedestructionof platelets.Thesensitizedplatelets
areremovedby the reticuloendothelial system.Therearetwo distinctclinical
syndromes.
Acute-AITP is usuallyseenin children, oftenfollowinga viral infection.It
has beensuggestedthat the thrombocytopenia is dueto the depositionof
immunecomplexeson platelets , but the acutedevelopment of plateletauto-
antibodiesis probablyresponsible for the shortenedplateletsurvival.
ChronicAITPis characteristically seenin adultwomen.It is usuallyidio-
pathicbut mayoccurin associationwith otherautoimmunedisorderssuch
as thyroid diseaseandautoimmunehaemolyticanemia (Evans ' syndrome),
in patientswith chroniclymphocyticleukaemia andsolidtumours,andafter
viral infectionswithvirusessuchas HIV.Plateletautoantibodies aredetected
in about60-70 % of patients , andare presumedto be present,althoughnot
detectable, in the remainingpatients;the antibodiesoftenhavespecificityfor
plateletmembraneglycoproteins. .
Major hemorrhages are rare and are seenonly in patientswith severe
thrombocytopenia. Easybruising,purpura, epistaxisand menorrhagiaare
common.Physicalexamination , is normalexceptfor evidenceof bleeding.
The only blood count abnormalityis thrombocytopenia. Normalor in-
creasednumbersof megakaryocytes arefoundin the bonemarrow,whichis
otherwisenormal.Thedetectionof plateletautoantibodies is not essentialfor
the confirmationof the diagnosis,whichoftendependson the exclusionof
othercausesof excessive destructionof platelets .
Pathophysiolo
gy of hematopoieticfunction Unit 5 I 453
Acute AITP in childrenusually remits spontaneously. Treatmentin the
acutephasewith steroids or high-doseintravenousimmunoglobulinis re-
quiredonlywhenthe plateletcountis < 20 x 109/L andthereis bleeding.In
chronicAITPspontaneous remissionsare rare.
Otherimmunethrombocytopenias arecausedbydrugs. Immunethrombo-
cytopeniaoftendevelopsbythe samemechanisms as drug-inducedimmune
haemolyticanemia.Thesamedrugsmayberesponsible for immunehaemo-
lytic anemia
, thrombocytopen ia or neutropeniain differentpatients. It is not
knownwhatdetermines thetargetcell in eachcase.
Platelet functiondisorders(trombocytopathias). These are usually
associatedwith excessivebruising and bleedingand, in some of the ac-
quiredforms, with thrombosis. The plateletcount is normalor increased
and the bleedingtime is prolonged.The rare inheriteddefectsof platelet
functionrequiremoredetailedinvestigationssuchas plateletaggregation
studiesand factor Vlll :C and vWFassays, if von Willebrand's diseaseis
suspected.

Inher ite d ty pes of platelet dysf unct ion

Glanzmann 's thrombasthenia - the lackof the plateletmembraneglycopro-
tein lib/Illa complexresultingin defectivefibrinogenbinding
Bernard- Souliersyndrome- the lackof plateletmembraneglycoprotein
lb/IX, the bindingsitefor factorvWF
Storagepooldisease- the lackof platelet granulescausingpoor platelet
aggregation.

Acqu ired types of plat elet dy sf un c t ion

Myeloproliferative
disorders
Uraemiaandliverdisease
Paraproteinaemias
Drug-induce
d, suchas by aspirin or dipyridamole.
 454 I Part 2 iologyof organsand systems
Pathophys

Coagu lation defects

The impairmentof bloodcoagulationcan resultfrom deficiencies of oneor
moreof the knownclottingfactors.Deficiencies canarisebecauseof defec-
tivesynthesis,inheriteddisease,or the increased
consumptionof the clotting
factors.Coagulationdisordersmay be inheritedor acquired.The inherited
disordersare uncommonand usually involvedeficiencyof onefactor only.
Theacquireddisordersoccurmorefrequentlyandalmostalwaysinvolvesev-
eralcoagulationfactors.

Inher ited coagulation disorders

In inheritedcoagulationdisorders,deficienciesof all factorshavebeende-
scribed.Thoseleadingto abnormalbleedingarerare, apartfrom haemophilia
A (factorVIII deficiency),haemophiliaB (factorIX deficiency)andvan Wil-
lebrand'sdisease.
Haemophilia A. In haemophilia A, the levelof factorVlll:C is reducedbut
the levelof factorvWFis normal. Theprevalence of haemophilia A is about
1 in 5000of the malepopulation . It is inheritedas an X-linkeddisorder.If a
femalecarrierhasa son,he hasa 50%chanceof havinghaemophilia, anda
daughterhasa 50 % chanceof beinga carrier.All daughtersof haemophiliacs
arecarriersandthe sonsarenormal.
ThehumanfactorVI11geneis enormous,constitutingabout0.1 % of the X
chromosome. Variousgeneticdefectshavebeenfound, includingdeletions ,
duplications,frameshiftmutationsandinsertions.ln approximately 50 % of
familieswith severedisease,the defectis an inversion . Thereis a highmuta-
tion rate,with one-thirdof casesbeingapparentlysporadicwith no family
historyof haemophilia. ,
Theclinicalfeaturesdependon the levelof factorVIII. Levelsof lessthan
1 % areassociated with frequentspontaneous bleedingfrom earlylife. Hae-
marthrosesarecommonand mayleadto joint deformityandcripplingif ad-
equatetreatmentis not given.Bleedsinto musclesare also common,and
intramuscular injectionsshouldbeavoided.
Pathophysiologyof hematopoieticfunction Unit 5 I 455
Levelsof lessthan5% areassociated with severebleedingfollowinginjury
andoccasional spontaneous episodes.
Levelsabove5% producemild disease,usuallywith bleedingonly after
injuryor surgery.It shouldbe notedthat patientswith mild haemophilia can
still bleedbadlyoncehaemostasis hasfailed.Diagnosisin this groupis often
delayeduntil quitelatein life.
Themostfrequentcauseof deathin patientswith severehaemophilia used
to becerebralhaemorrhage , but is nowAIDS. HIVwastransmittedto many
patientscoagulation factorconcentrates between1979and 1985.

Haemophilia B (Christmas disease)

Haemophilia B is causedby a deficiencyof factor IX.Theinheritanceand
clinicalfeaturesareidenticalto haemophilia A, but theincidenceis onlyabout
1 in 30 000 males. It is treatedwith factorIX concentrates.

VonWillebrand's disease(vWO)
In vWD, there is defectiveplateletfunctionas well as factor Vlll:C defi-
ciencyand botharedueto a deficiencyor abnormalityof vWF.vWFplaysa
role in plateletadhesionto damagedsubendothelium as well as stabilizing
factorVlll:C in plasma.
ThevWFgeneis locatedon chromosome12 and numerousmutationsof
the genehavebeenidentified . vWDhasbeenclassifiedintothreetypes:
Type1 is characterized by a mild reductionin vWFand is inheritedas an
autosomaldominant.
Type2 is due to a decreasein the proportionof high-molecular-weight
multimers,andit too is inheritedas anautosomaldominant.
Type3 is recessively inheritedand patientshavebarelydetectablelevels
of factorVlll:vWF(andthereforefactorVlll :C).Theirparentsareoftenpheno-
typicallynormal.
Theclinicalfeaturesof vWDarevariable.Type1 andtype2 patientsusu-
ally havemild clinicalfeatures. Bleedingfollows minor traumaor surgery
and epistaxisand menorrhagia often occur.Type3 patientshavemore se-
verebleeding but rarely experience the joint andmusclebleedsseenin hae-
mophiliaA.
 456 I Part 2 Pathophysiotogy
of organsandsystems

Acqu ired coagulation disorders

VitaminK deficiency. VitaminK is necessaryfor thecarboxylation
of glutam-
ic acidresidueson factorsII, VII, IXandX andon proteinsCandS. Without
it, thesefactorscannotbindcalciumandform complexeswith PF-3to carry
out their normalfunctions.

Deficiency of vitamin K may be due to:

• inadequate stores,as in haemorrhagic diseaseof the newbornandpro-

tein-energymalnutrition;
• malabsorption of vitaminK, a fat-solublevitamin, which occursin cho-
lestaticjaundicedueto the lackof intraluminalbilesalts;
• oralanticoagulant drugs,whicharevitaminK antagonists.

Liverdisease.Liverdiseasemayresultin a numberof defectsin haemo-

stasis.Exceptvitamin K deficiency,they mayleadto the reducedsynthesis
factorsof coagulation.Thereducedsynthesisof coagulationfactorsmaybe
the resultof severehepatoce
llulardamage.

Hypercoagulabi lity states

Thrombosis.A thrombusis definedasa solid massformedin the circulation
from the constituentsof the bloodduringlife.Fragments of thrombi(emboli)
maybreakoff andblockvesselsdownstream . Thrombosisandthromboem-
bolicdiseaseis muchmorecommonthanabnormalbleeding.
A thrombusresultsfrom a complexseriesof eventsinvolvingcoagulation
factors,platelets,redbloodcellsandvesselwall.
Arterialthrombosis. It usuallyoccursin association
withatheroma,which
tendsto form in the areasof turbulentbloodflow suchas the bifurcationof
arteries.The risk factorsfor arterialthrombosisare relatedto the develop-
ment of atherosclerosis. Arterialthrombi may form in the heart, as mural
Pathophysiologyof hematopoieticfunction Unit 5 I 457
thrombiin the left ventricleafter myocardialinfarction,in the left atrium in
mitralvalvedisease , or on thesurfac~sof prostheticvalves.
Venous thrombosis. Unlikearterialthrombosis, venousthrombosisoften
occursin normalvessels.Importantcausesarestasisandhypercoagulability.
Themajority of venousthrombioccurin the deepveinsof the leg, originating
aroundthe valvesas "redthrombi" consistingmainlyof red cellsandfibrin.
Thepropagating thrombusis formedof fibrin andplateletsandis particularly
liableto embolize. Chronicvenousobstructionfollowingthrombosisin the
deepveinsof the leg frequentlyresultsin a permanentlyswollenlimb and
mayleadto ulceration(post-phlebiticsyndrome).
Therearetwo generalforms of hypercoagulab ility states: conditions that
createincreasedplateletfunctionand conditionsthat causeaccelerated ac-
tivity of the coagulationsystem.Increasedplateletfunctiondevelopmentin
-atherosclerosis , diabetesmellitus, smoking, elevatedbloodlipid andcholes-
terol levels, increasedplateletlevels. Theaccelerated activityof the clotting
systemtakepartin pregnancy andthepuerperium, useof oralcontraceptives,
postsurgical state,immobility,congestiveheartfailure, malignantdiseases .
Thrombophilia is a term describinginheritedor acquireddefectsof hae-
mostasisleadingto the predisposit ion to venousor arterialthrombosis.

It should be considered in p ati e nts with :

• recurrentvenousthrombosis ;
• venousthrombosisfor thefirst time underthe ageof 40 years.

Anticoagulants in pregnancy carriesa riskof fatalmaternalbleeding

, which
mayequalthe risk of deathdueto postpartumthrombosis,andthe fetus is
alsoat risk of complicationsfrom the useof oralanticoagulants .
Antithrombindeficiency . Thisdeficiencycanbe inheritedas an autosomal
dominant.Manyvariationshavebeendescribedthat leadto a conformational
changein theprotein.It canbeacquire d followingtrauma,with majorsurgery
andwith thecontraceptive pill. Lowlevelsarealsoseenin severeproteinuria
(e.g.,the nephroticsyndromecausingthromboticepisodes).
 458 I Part 2 Pathophysiologyof organsandsystems

Dissemina ted intravascu lar coagu lation (DIC)

Thereis widespread generation of fibrin withinbloodvessels,owingto activa-
tion of the coagulationcascadeby the releaseof coagulantmaterial,and by
diffuseendothelialdamageor generalized plateletaggregation.
Theactivation
of leucocytes,particularlymonocytescausingthe releaseof the tissuefactor
andcytokines,mayplaya rolein the developmentof DIG.
Thereis the consumptionof plateletsandcoagulation factorsandsecond-
ary activation of fibrinolysisleading to the productionof fibrin degradation
products(FDPs),whichmaycontributeto the coagulation defectbyinhibiting
fibrin polymerization.

Causes of DIC include:

• malignantdisease;
• septicaemia(e.g.,Gram-negative andmeningococcal);
• haemolytictransfusion reactions;
• obstetriccauses(e.g.,abruptio placentae,
amnioticfluid embolism);
• trauma,burns, surgery.

Pathophysiology. Underhomeostaticconditions,the body is maintained

in a finelytunedbalanceof coagulation andfibrinolysis.Theactivationof the
coagulationcascadeyieldsthrombin that convertsfibrinogento fibrin; the
stablefibrin clot beingthefinal productof hemostasis.
In DIC,the processesof coagulationandfibrinolysislosecontrol,andthe
resultis widespreadclottingwith resultantbleeding.'Regardless of the trig-
geringeventof DIC,onceinitiated,the pathophysiology of DICis similarin
all conditions.Onecriticalmediatorof DICis the releaseof a transmembrane
glycoproteincalledtissuefactor\TF).TF is presenton the surfaceof many
cell types(includingendothelialcells,macrophages, and monocytes)and is
not normallyin contactwith the generalcirculation,but is exposedto the
circulationaftervasculardamage.Forexample,TFis releasedin responseto
exposureto cytokines(interleukin1), tumornecrosisfactor,andendotoxin.
Pathophysiologyof hematopoieticfunction Unit 5 I 459
Mostimportant,that injuryof endothelium andreleaseof activatorsin this
pathological conditionsbeginin manyregionsof microcirculation.For this
reasontherebeginsa veryintensiveprocess of using factorsof coagulation in
the coagulation cascade.Excess circulatingthrombin results from theexcess
activationof the coagulationcascade . Theexcessthrombincleavesfibrino-
gen, which ultimatelyleavesbehindmultiplefibrin clots in the circulation.
Theseexcessclotstrapplateletsto becomelargerclots, whichleadsto micro-
vascularandmacrovascular thrombosis. Thislodgingof clotsin the microcir-
culation,in thelargevessels , andin the organsis whatleadsto the ischemia,
impairedorganperfusion , and end-organdamagethat occurswith DIC.
Coagulation inhibitorsarealsoconsumedin this process. Decreased inhibi-
tor levelswill permitmoreclottingso thata feedback systemdevelops in which
increased clottingleadsto moreclotting.Atthesametime, thrombocytopenia oc-
-cursbecause of theentrapment andconsum ptionof platelets
. Clottingfactorsare
consumed in thedevelopment of multipleclots,whichcontributes to thebleeding
seenwith DIC.Clottingfactorsare consumedso quickly that the liver has not
enoughtimeto producenewclottingfactors. Massivehemorrhagesmaybegin.
Simultaneously, excesscirculating thrombinassistsin the conversionof
plasminogen to plasmin, resultingin fibrinolysis.The breakdownof clots re-
sults in excessamountsof FDPs , which havepowerfulanticoagulantprop-
erties, contributingto hemorrhage. The excessplasmin also activates the
complement andkinin systems.Activationof thesesystemsleadsto manyof
theclinicalsymptomsthat patients experiencing DICexhibit, suchas shock,
hypotensio n, and increasedvascular permeability. Theacute form of DICis
consideredan extremeexpress ion of the intravascular coagulationprocess
with a completebreakdownof the normalhomeostaticboundaries.DICis
associatedwith a poorprognos is anda high mortality rate.
Theonlyeffective treatment is thereversal of theunderlyingcause.Theprima-
ry pathogenic mechanism of development DICis themassiveactivation of blood
coagu lation. Forthisreasonpathoge nictreatment include
s anticoagulantsfor the
interrupted coagula tioncascade andto blocktheconsumpt ionof clottingfactors.
Thenplateletsmaybetransfused if thecountsarelessthan5,000-10,000/mm3
andmassive hemorrhage is occurring , andfreshfrozenplasmamaybeadminis-
teredin anattemp t to replenish coagulationfactorsandanti-thrombotic factors.
 PATHOPHYSIOLOGY OF

Unit6 CARDIOVASCULAR AND

RESPIRATORY SYSTEM

Chapter 23 . Disordersof
Cardiac Function. Heart Failure

The mainfunctionof the circulatorysystem,whichconsistsof the heartand

bloodvessels,is transport.Thecirculatorysystemdeliversoxygenandnutri-
entsneeded for metabolicprocessesto thetissues,carrieswasteproductsfrom
cellularmetabolism to the kidneysandotherexcretoryorgansfor elimination,
andcirculateselectrolytes andhormonesneededto regulatebodyfunction.
Thecirculatorysystemcanbedividedinto two parts:the pulmonary circu-
lation, whichmovesbloodthroughthe lungsandcreatesa link with the gas
exchangefunctionof the respiratorysystem,and the systemic circulation
,
whichsuppliesall the other tissuesof the body(Fig.43). Thebloodthat is in
the heartandpulmonarycirculationis sometimesreferredto asthe centralcir-
culation , andthatoutsidethe central circulationasthe• peripheral
circulation
.

Regulation of cardiac performance

'

The efficiencyof the heartas a pump oftenis measuredin terms of cardiac

outputor the amountof blood the heartpumps eachminute. The cardiac
output(CO)is the product of the strokevolume(SV)andthe heartrate(HR)
andcanbe expressedbythe equation:CO= SVx HR.
Pathophysiologyof cardiovascular and respiratorysystem Unit 6 I 461

Systemic
Circulation Pulmonary
Circulation
Systemic
capillaries Pulmonary
capillaries

Pulmonary
veins

Pulmonary
artery

Inferior
venacava

Fig.43.Systemic
andpulmonary
circulation

The averagecardiacoutput in normaladultsrangesfrom 3.5 to 8.0 L/

minute.
Thecardiacreserverefersto the maximumpercentage of the increasein
cardiacoutputthat canbe achievedabovethe normal resting level.The nor-
malyoungadult hasa cardiacreserveof approximately300%to 400%.

The heart's ability to increase its output according

to body needs mainly depends on four factors:

• thepreload, or ventricularfilling;
 462 I Part 2 Pathophysiologyof organsand systems

• the afterload,or resistanceto ejection of bloodfrom the heart;

• cardiaccontractility,
• the heartrate.

The preloadrepresentsthe volumework of the heart.Preload represen ts

the amountof bloodthat the heartmustpumpwith eachbeatandis largely
determinedby the venousreturnto the heartandthe accompanying stretch
of the musclefibers.
Themaximumforceof contractionandcardiacoutputis achievedwhenve-
nousreturnproducesan increasein left ventricularend-diasto lic filling (i.e.,
preload)such that the musclefibers are stretchedapproximatelytwo and
one-halftimestheir normalrestinglength
Theincreased forceof contractionthataccompanies anincreasein theven-
tricularend-diastolic volumeis referredto as the Frank-Starlingmechanism
or Starling'slaw of the heart(heterometr ic mechanism ). The Frank-Starling
mechanismallows the heartto adjust its pumpingability to accommodate
variouslevelsof venous return.
Theafterloadis the pressureor tensionwork of the heart(homeomet ric
mechanism ).
Thesystemicarterialbloodpressureis the mainsourceof afterloadwork
on the left heartand the pulmonaryarterial pressureis the mainsourceof
afterloadwork for the right heart. For example,in the late stagesof aortic
stenosis,the left ventriclemayneedto generatesystolicpressuresup to 300
mm Hgto movebloodthroughthe diseasedvalve.
Cardiaccontractility refersto the abilityof the heartto changeits forceof
contraction withoutchangingits resting(i.e., diastolic)length.Thecontractile
stateof the myocardialmuscleis determinedby biochemicalandbiophysical
propertiesthat governthe actin and myosin interactions in the myocardia l
cells.An inotropic influenceis o,rethat modifiesthe contractilestateof the
myocardiumindependent of the Frank-Sta rling mechanism .
The heartratedeterminesthe frequencywith whichbloodis ejected from
the heart.At a heartrateof 75 beatsper minute,onecardiaccyclelasts 0.8
second;of whichapproximately 0.3 secondis spentin systoleandapproxi-
mately0.5 secondin diastole. As the heart rate increases,the time spent
Pathophysiologyof cardiovascular and respiratory system Unit 6 I 463
in systoleremainsapproximatelythe same, whereasthat spent in diastole
decreases.
This leadsto a decreasein stroke volume;at highheartrates, it maycause
a decrease in cardiacoutput.

Heart Failure
The term heartfailuredenotesthefailureof the heartas a pump.
The physiologyof heartfailureinvolvesan interplaybetweentwo factors:
theinabilityof thefailingheart to maintainsufficientcardiacoutputto support
bodyfunctionsandthe recruitmentof compensatory mechanisms designed
to maintain the cardiacreserve .

Classifications of t he heart failure

Heartfailure at first divided on acutewheninsufficiencyof the heartdevel-

ops quickly(in myocard ial infarction,arrhythmiasetc.) andchronic whenthe
symptomsappearsduringlong time (ischemicheartdisease , dilatedcardio-
myopathy , valvularheartdisease,hypertens ion).
Heartfailure can be dividedinto compensative when manifestations de-
veloponlyin situations with physica l activityof the patientsand decompen-
sativewhenmanifestations arepresent at rest.
Heart failuremay by systolicand diastolic . Both systolicand diastolic
heartfailureresultin a decrease in strokevolume. Thisleadsto the activation
of peripheralandcentralbaroreflexes andchemoreflexe s that are capableof
elicitingmarkedincreasesin sympatheticnervetraffic. Theensuing elevation
in plasmanorepinephrine directly correlateswith the degreeof cardiac dys-
functionand hassignificantprognosticimplications. Norepinephrine , while
directlytoxic to cardiacmyocytes , is alsoresponsiblefor a varietyof signal-
transductio n abnorma lities, suchas downregu lation of beta1-adrenergic re-
ceptors, uncouplingof beta2-adrenergicreceptors , andan increasedactivity
of inhibitoryG-protein.Changes in beta1-adrenergicreceptorsresult in over-
 464 I Part 2 Pathophysiologyof organsand systems

expressionandmaybeoneof thefactorsof myocardialhypertrophy develop-

ment.Also heartfailuremayaffectthe left, right or bothsidesof the heart.

Right-Sided Heart Failure

Theright heartpumpsdeoxygenated bloodfromthe systemiccirculationinto
the pulmonarycirculation.Consequently , whenthe right heartfails, thereis
accumulation or dammingbackof bloodin the systemicvenoussystem.
A majoreffectof right-sidedheartfailureis the development of peripheral
edema , hepatomegaly andascites.
In severeright-sidedfailure, the externaljugularveinsbecomedistended
andcanbevisualizedwhenthe personis sittingup or standing.
Thecausesof right-sidedheartfailureincludeconditionsthat restrictblood
flow into the lungs. Stenosisor regurgitation of the tricuspidor pulmonic
valves, right ventricularinfarction,cardiomyopathy, andpersistentleft-sided
failure are commoncauses.Acuteor chronicpulmonarydisease , suchas
severepneumonia , pulmonaryembolus, or pulmonaryhypertens ion, canalso
causeright heartfailure.

Left- Sided Hea rt Fa ilure

Theleft sideof the heartpumpsbloodfrom the low-pressure pulmonarycir-
culationinto the high-pressure arterialside of the systemiccirculation.With
the impairmentof left heartfunction,thereis a decrease in cardiacoutput; an
increasein left atrialandleftventricularend-diastolic pressures;andconges-
tion in the pulmonarycirculation.
Whenthe pulmonarycapillaryfiltrationpressure(normallyapproximately
1Omm Hg) exceedsthe capillaryosmoticpressure(normallyapproximately
25 mm Hg), thereis a shift of intravascular fluid into the interstitiumof the
lunganddevelopment of pulmonaryedema.
The mostcommoncausesof left-sidedheartfailureareacutemyocardial
infarctionandcardiomyopathy.
Pathophysiologyof cardiovascularand respiratorysystem Unit 6 I 465
Stenosisor regurgitationof the aortic or mitral valvesalso createsthe
levelof left-sidedbackflowthat resultsin pulmonarycongestion . Pulmonary
edemaalsomaydevelopduringrapidinfusionof intravenous fluids or blood
transfusionsin an elderlypersonor in a personwith limitedcardiacreserve.

Symptom s of he art failure

Symptoms of heart failure may begin suddenly, es-

pecially if the cause is a heart attack. The most com-
mon symptoms are:

• Cyanosis
• Fluidretentionandedema
• Respiratorymanifestations
(tachypnoe)
• Tachycardia
• Fatigueandlimitedexercisetolerance
• Myocardialhypertrophy

Right-sidedheart failure and left-sided heart failure producedifferent

symptoms.Althoughbothtypesof heartfailuremaybe present, the symp-
toms of failureof one side often predominate. Also left-sided heartfailure
causesright-sidedfailure.
Themainsymptomsof right-sidedheartfailurearefluid accumulation and
swelling(edema)in thefeet,ankles,legs, liver, andabdomen(Fig.44).Where
thefluid accumulates dependson the amountof excessfluid andthe effects
of gravity. If a personis standing , fluid accumulates in the legsand feet. If
a personis lying down,fluid usuallyaccumulatesin the lower back. If the
amountof fluid is large, fluid alsoaccumulates in theabdomen .
Left-sidedheartfailure leadsto fluid accumulationin the lungs, which
causesshortnessof breath.At first, shortnessof breathoccursonly during
exertion,but as heartfailureprogresses , it occurswith lessandlessexertion
andeventuallyoccursevenat rest.P-eople with severeleft-sidedheartfailure
466 I Part 2 Pathophysiologyof organsand systems

Increasein veniuspressure

i i
Arterioles,
precapillaries
efectivehydrodynamic pres- Venules,
postcapillaries
sure(EH P)i effective
oncotic EHP> EORF
resorptiveforce(EORF)!
I
• Impaired of
resOf'l)tion
Increased filtrationof
fluidintotheinter- fluid fromtheinterstitlum
stitium

Edema

Fig.44. Mechan
ismofedema
forma
tioninheartinsuffici
ency

maybe short of breathwhenlying down (a conditioncalledorthopnea),be-

causegravitycausesmorefluid to moveinto the lungs.
Comparisonof manifestationsin heartfailurewith adaptivemechanisms
showedthat the most importantsymptomsare the resultof compensatory
mechanismdevelopment (Table.28).

Table28. The comparative characteristic of manifestations and compensatory

mechanisms in heartfailure

Tachypnoe Increase
breath
ing rate
Pathophysiologyof cardiovascularand respiratorysystem Unit 6 I 467
., --
Com~ mechanisms k • • • • _

Tachycardia Increase
heartrate
FluidRetention
andEdema Renin
-Angiotensin
mechanism
activation
Myocardial
Hypertrophy Frank
Starling
mechanism,
activatio
nof
neurohumoral
mechanisms
, myocardial
remodeling

Pathogenesis and compensatory m ech anisms in

hea rt failure
Thebodyhasseveralmechanisms to compensate for heartfailure.Thebody's
first responseto stress, includingthat due to heartfailure.is to releasethe
fight-or-flight hormones , epinephrine(adrenaline)and norepinephrine(nor-
adrenaline). Forexample , thesehormonesmaybe released immediatelyafter
a heartattackdamagesthe heart. The increaseof the sympatheticnervous
systemactivityleadsto systemicvasoconstriction , stimulationof heartrate,
cardiac contractility andcardiacmetabolism.
Epinephrine and norepinephrinecausethe heartto pumpfasterand more
forcefully.Theyhelpthe heartincreasethe amountof bloodpumpedout (car-
diac output), sometimesto a normalamount, thus initiallyhelp compensate
for the heart's impairedpumping ability.Onthe otherside,anothersyte, the
releaseof epinephrineand norepinephrine , along with the vasoactivesub-
stancesendothelin- 1 (ET-1)andvasopressin , causesvasoconstriction , which
increasesafterload,and, via an increasein cyclicadenosinemonophosphate
(cAMP),causesan increasein cytosoliccalciumentry.Theincreasedcalcium
entryinto the myocytesaugmentsmyocardialcontractilityand impairsmyo-
cardialrelaxa t ion.
The reductionof cardiac output following myocardialinjury sets into
motiona cascadeof hemodynamicand neurohormonalderangement s that
provokeactivationof renin-angiotensin-aldosterone system (RAAS). The
 468 I Part 2 Pathophysiology
of organsand systems

activationof the RAAS~eadsto salt and water retention, resultingin an

increasedpreloadandfurther increasesin myocardialenergyexpenditure .
Increasesin renin, mediatedby decreasedstretch of the glomerularaf-
ferent arteriole,reduceddeliveryof chlorideto the maculadensaand in-
creasedbeta1-adrenergic activity is a responseto decreasedcardiacout-
put. This results in an increasein angiotensinII and aldosteronelevels.
Angiotensine II, along with ET-1, is crucial in maintainingthe effective
intravascularhomeostasismediatedby vasoconstrictionandaldosterone-
inducedsalt and water retention.Retainingsalt and water insteadof ex-
creting it into urineincreasesthe yolumeof blood in the bloodstreamand
helpsmaintainblood pressure. However, the largervolumeof bloodalso
stretchesthe heartmuscle, enlargingthe heartchambers,particularlythe
ventricles.
AngiotensineII also may mediatemyocardialcellularhypertrophyand
promoteprogressiveloss of myocardialfunction. Theneurohumora l factors
aboveleadto myocytehypertrophyand interstitial fibrosis,resulting in in-
creasedmyocardialvolumeandincreasedmyocardialmass,aswell as myo-
cyteloss.As a result, the cardiacarchitecture changes , whichin turn leadsto
furtherincreasein myocardialvolumeandmass.
As heartfailureadvances , thereis a relativedecline in the counterregula -
tory effectsof endogenous vasodilators , includingnitric oxide(NO),prosta-
glandins(PGs),bradykin in (BK), atrial natriureticpeptide(ANP),andB-type
natriureticpeptide(BNP).This occurssimultaneously with the increasein
vasoconstr ictor substancesfrom the RAASand adrenergicsystems. This
fostersfurtherincreasesin vasoconstr ictionandthus preloadandafterload,
leadingto cellularproliferation,adversemyocardial -remodeling,and antin-
atriuresiswith total bodyfluid excessandworseningcongestive heartfailure
symptoms.
ANPandBNPareendogenously generatedpeptidesactivatedin response
to atrial and ventricularvolume/pressure expansion. ANPand BNPare re-
leasedfrom the atriaandventricles andbothpromotevasodilation andnatri-
uresis.Theirhemodynamic effectsare mediatedby decreasesin ventricular
filling pressures , owingto reductionsin cardiacpreloadandafterload.BNP,
in particular, producesselectiveafferentarteriolarvasodilationand inhibits
Pathophysiologyof cardiovascularand respiratorysystem Unit 6 I 469
sodiumreabsorptionin the proximalconvolutedtubule.BNPinhibits renin
and aldosteronereleaseand,therefore,adrenergicactivationas well. Both
ANPandBNPareelevatedin chronicheartfailure.
Inthepathogenesis of heartfailure,othervasoactive systemswhichinclude
theendothelinreceptorsystem,adenosine receptorsystem,vasopressin, and
tumor necrosis factor-alpha(TNF-alpha) , playrole. Endothelin
, a substance
producedby the vascularendothelium,maycontributeto the regulationof
myocardial function,vasculartone, andperipheralresistancein heartfailure.
Elevated levels of endothelin-1closelycorrelatewith theseverityof heartfail-
ure. ET-1is a potentvasoconstrictor and has exaggerated vasoconstrictor
effectsin the renalvasculature , reducingrenalplasmabloodflow, glomerular
filtrationrate,andsodiumexcretion.
TNF-alpha has beenimplicatedin responseto variousinfectiousand in-
-flammatoryconditions.Elevations in TNF-alpha levelshavebeenconsistently
observedin heartfailureandseemto correlatewith the degreeof myocardial
dysfunction.Experimental studiessuggestthat localproductionof TNF-al pha
mayhavetoxiceffectsonthe myocardium , thusdecrease myocardialsystolic
anddiastolic function.
Enlargementof the muscular walls of the ventricles(myocadial hyper-
trophy) is alsoan importantcompensatorymechanismof the heart.When
the heartmust work harder, the heart's walls enlargeand thicken.At first,
the thickenedheartwallscancontractmoreforcefully. However , the thick-
enedheart walls eventuallybecomestiff, causing or worseningdiastolic
dysfunction.

Myocardial Hypertr o phy

Myocardialhypertrophyis a long-termcompensatorymechanism.Cardiac
muscle,like skeletal muscle, respondsto an increasein work demandsby
undergoinghypertrophy.Hypertrophyincreasesthe numberof contractile
elementsin myocardial cellsasa meansof increasingtheircontractileperfor-
mance.Theprocessof progressive cardiacenlargement and hypertrophyis
calledmyoca rdiumremodeling .
 470 I Part 2 Pathophysiology
of organsand systems

The types of hypertrophy that develops in persons

with heart failure are:

• symmetricincreasein musclelengthandwidth namedconcentric hy-

pertrophy;
• disproportionate
increasein musclelength,as occursin personswith
dilatedcardiomyopathies
namedeccentric hypertrophy.

Alsoit's possibleto sayaboutphysiologic andpathologic hypertrophy.

On physiologichypertrophy,the accumulationof actomyosinandgrowth
of apparatusof cardiomyocyte's energeticandplasticprovisionareequal.In
this case, the adaptabilityof the heartis increased.
On pathologichypertrophy , the weightof the hypertrophied myocardium
mostlyconsistsof contractileprotein- actomyosin.Onpathologichypertro-
phy,actomyosinis accumulated muchquickerthenthe apparatusof cardio-
myocyte 's energeticandplasticprovision(vessels,nerves,mitochondria, ribo-
some, andlysosomes).In this case,myocardiodystrophy developsverysoon.
Myocard ial hypertrophymaydevelopment with or withoutcardiacchamber
dilatation,in whichthe massof contractile tissueis augmented. Cardiacdilation
havetwo mechanisms of development: tonogenic and myogenic dilation. At
first theredeveloptonogeniccardiacchamberdilation(Frank-Starling mecha-
nism).Whenthe heartbecomesoverfilledto the extentthat actinandmyosin
filamentscannotproduceaneffectivecontraction myogenicdilationtakesplace.

Molecular mechanisms of hypoxic and

degenerat ive myocard ial injury
In the failing heart,increasedmyocardialvolumeis characterizedby larger
myocytesapproachingthe end of their life cycle.As more myocytesdrop
out, an increasedload is placedon the remainingmyocardiumand this
unfavorableenvironmentis transmittedto the progenitorcells respon-
sible for replacinglost myocytes.Progenitorcells becomeprogressively
less effectiveas the underlyingpathologicprocessworsensand myocar-
Pathophysiologyof cardiovascularand respiratorysystem Unit 6 I 471

dial failure accelerates

. Thesefeatures, namelythe increasedmyocardial
volumeand mass,along with a net loss of myocytes,are the hallmark
of myocardialremodeling.This remodelingprocessleadsto early adap-
tive mechanisms , such as augmentationof strokevolume(Frank-Starling
mechanism)and decreasedwall stress (Laplacemechanism),and later,
maladaptivemechanismssuch as increasedmyocardialoxygendemand,
myocardialischemia,impairedcontractility,and arrhythmogenesis.
lschemiais the most commonmechanismof myocardialinjury (Fig.45).
Myocardialischemialeadsto two most importantconsequences which de-
pendon the activation of anaerobicmetabolism.Thereare energydeficiency
and acidosis.Energydeficiencydevelopsin the stagesof productionATP,
transportation of energyby creatin-phospate and usingof energyin the pro-
cessof contraction.As moreimportantconsequences of energydeficiency,
i onsimbalance develops. Acidosisresultsin theactivationof freeradicalpro-
cessesandleadsto the cellularmembranedestruction .
The calcium overload may also induce arrhythmiasand lead to sudden
death.Theincreasein afterloadand myocardialcontractility(knownas inot-
ropy)andthe impairmentin myocardialrelaxation(knownas lusitropy)lead

.------
Hypo
xia

~
t ATP Acydosis

t -
-tCreatin-phosphate ✓ ~
Phospholypases Freeradicals

i
i ATP ~ /
Membranedestruction

Contractilityt
t
K-Napump'f FreeCa2·t

~/~
Ionsimbalan
ce Troponint

Fig. 45. Hypoxia,

membrane
destruction
andionimbalance
in cardiomyocites
dysfunction
 472 I Part 2 Pathophysiologyof organsand systems

to an increasein myocardialenergyexpenditureand a further decreasein

cardiacoutput.Theincreasein myocardialenergyexpenditure leadsto myo-
cardialcell apoptoticdeath, whichresultsin heartfailureandfurtherreduc-
tion in cardiacoutput, perpetuating
a cycleof furtherincreased neurohumoral
stimulationandfurtheradversehemodynamic andmyocardialresponses.
An importantprocessin the development of heartfailureis the generation
of arrhythmias.Whilelife-threatening rhythmsaremorecommonin ischemic
versusnonischemic cardiomyopathy, arrhythmiaimpartsa significantburden
in all forms of heartfailure. Somearrhythmiasevenperpetuateheartfail-
ure.Themost significantof all rhythmsassociatedwith heartfailurearethe
life-threateningventriculararrhythmias.Structuralsubstratesfor ventricular
arrhythmiascommonin heartfailure,regardlessof the underlyingcausein-
cludeventriculardilatation,myocardialhypertrophy , andmyocardialfibrosis.
At the cellularlevel,myocytesmaybeexposedto increased stretch,wallten-
sion,catecholamines, ischemia,andelectrolyteimbalance . Thecombination
of thesefactorscontributesto an increased incidenceof arrhythmogenic sud-
dencardiacdeathin patientswith heartfailure.

lschemic Heart Disease

Myocardialischemiaoccurswhentheabilityof thecoronaryarteriesto supply
bloodis inadequate to meetthe metabolicdemandsof the heart.Limitations
in coronarybloodflow mostcommonlyarethe resultof atherosclerosis , with
vasospasm andthrombosisas contributingfactors.Themetabo _licdemands
of the heartareincreasedwith the every-dayactivitie~suchas mentalstress,
exercise, andexposureto cold.Coronaryheartdiseaseis commonlydivided
into two types of disorders
: chronici_schemicheartdiseaseand the acute
coronarysyndromes. Therearethreetypesof chronicischemicheartdisease :
chronicstableangina, variant or vasospasticangina, and silentmyocardial
ischemia.Theacutecoronarysyndromesrepresentthe spectrumof ischemic
coronarydiseaserangingfrom unstableanginathroughmyocardialinfarction.
Anginapectoris is a symptomaticparoxysmalchestpainor pressuresen-
sationassociatedwith transient myocardialischemia ,. Chronicstableangina
Pathophysiologyof cardiovascularand respiratorysystem Unit 6 I473
is associatedwith a fixed coronaryobstructionthat producesa disparity
betweencoronarybloodflow and metabolicdemandsof the myocardium.
Anginapectorisusuallyis precipitatedby situationsthat increasethe work
demandsof the heart, suchas physicalexertion,exposureto cold, andemo-
tionalstress.The paintypicallyis describedas a constricting,squeezing , or
suffocatingsensation.It usuallyis steady,increasingin intensityonly at the
onsetand end of the attack.The pain of anginacommonlyis locatedin the
precordialor substernalareaof the chest;it is similarto myocardialinfarction
in that it mayradiateto the left shoulder,jaw, arm,or otherareasof the chest.
Anginathat occursat rest, is of newonset,or is increasingin intensityor
durationdenotesan increasedrisk for acutemyocardialinfarction(AMI) and
shouldbeevaluatedusingthe criteriafor acutecoronarysyndromes.

The pathogenesis of AMI can include:

Occlusive intracoronary thrombus - a thrombus overlying an plaque

causes75 % of myocardialinfarctions,with superficialplaqueerosionpres-
ent in the remaining25 %.
Vasospasm - with or without coronaryatherosclerosisand possibleas-
sociationwith plateletaggregation.It shouldbe notedthat vasoconstriction
in AMI developmentoften has relativecharacter.Predominatingin coronal
vesselsbeta-adrenergic receptorscan resultin their dilationin actionof cat-
echolamine 's. Butthe samelevelof catecholamine in bloodleadsto the more
intensiveincreasesof the myocardiummetabolismwith oxygenusethanthe
increasesof bloodcoronaryflow (Fig.46) If atherosclerosis takesplacein a
coronalvessel,a more intensivedisproportionbetweenan increasedblood
flow andmetabolismdevelopst.
Emboli-fromleft sidedmuralthrombosis,vegetativeendocarditis,or par-
adoxicembolifrom the right sideof the heartthrougha patentforamenovale.
Hypoxia, acidosis,andincreaseof extracellularconcentrationof K+ions in
the myocardiumare consequences of coronaryinsufficiency.The molecular
eventsduring,AMI relateto the initial ischemicevent,reperfusion,and sub-
sequentinflammatoryresponse.Up to 6 hoursfollowingthe initial ischemic
 474 I Part 2 Pathophysiology
of organsandsystems

Epinephrine
effects: Coronary02 use
- Systemicvasodilatation
Coronary blood flow
- Stimulation of heart rate
- Stimulationcardiaccontractility
- Stimulation cardiacmetabolism

t
Epinephrine

Fig.46.Action
of hyperca
techo
lemiaon cardio
myocites andcoro
narycirculation

event, most cell lossesoccur via apoptosis.After that, necrosispredomi-

nates.lsch~micendothelial cellsexpressadhesionmoleculesthatattractneu-
trophifsthatsubsequently migrateinto damaged myocardium.
Amongthecomplicationsof AMIaresuddendeath,heart failureandcardio-
genicshock, pericarditisandDressler's syndrome,thromboemboli, ruptureof
the heart, andventricularaneurysms.Depending on its severity, myocardial
infarctionhasthe potentialfor compromisingthe pumping actionof the heart.
Heartfailureandcardiogenic shock aredreadedcomplicationsof AMI.

Cardiogenic shock
Cardiogenic shock(pumpfailure)is an extremetypeof cardiacfailurewith a
highmortalityof approximately 90 %. Its mostcommoncauseis myocardia l
infarction andit complicatesup to 10% of AMI. Othercausesareacutemas-
sive pulmonaryembolus,pericardia! -tamponade and sudden-onsetvalvular
regurgitation. Cardiogenicshockis diagnosed whenthe critical impairmentof
tissueperfusionoccursdespite an adequateor elevatedpulmonarycapillary
wedgepressure and in the absenceof mechanicalcirculatoryobstruction.
An essential elementin this diagnosis is the measurement of the pulmonary
capillarywedgepressure. In cardiogenicshockthe wedgepressureis nor-
malor elevated.The mortalityratein cardiogenicshockis high,estimatedat
Pathophysiologyof cardiovascularand respiratorysystem Unit 6 I475
80%, becauseof the viciousdownwardspiralthat occurs:hypotension due
to pump failureresultsin a reduction of coronaryflow, which resultsin the
furtherimpairmentof pumpfunction,andso on.
Pathogenic medicalcare: initial therapyfor acuteMl is directedtoward
restorationof perfusionin orderto salvageas muchof the jeopardized myo-
cardiumas possible.Thismaybeaccomplished throughmedicalor mechani-
cal means, suchasangioplastyor coronaryarterybypassgrafting.

The further treatment is based on:

1) restorationof the balancebetweenthe oxygensupply and demandto

preventfurtherischemia ,
2) painrelief,
3) preventionandtreatmentof anycomplicationsthat mayarise.

Cardiomyopathy , definedby WHOas "heartmusclediseaseof unknown

cause",generallyreferredto as primaryor idiopathiccardiomyopathy . Car-
diomyopathy frequently causesprofoundand oftenfatal heartfailure.Three
typesof cardiomyopathy aredistinguished:

• Dilated(90 %)
• Hypertrophic
• Restrictive

The term ischemiccardiomyopathy is often used clinicallyto describe

chronicischemic heartdisease .
Dilatedcardiomyopathy is the most commontype of the diseaseand af-
fectsthe heart's ventriclesandatria. Thediseaseoftenstartsin the left ven-
tricle.Theheartmusclebeginsto dilate(stretchand becomethinner).When
the chambersdilate,the heartmuscledoesn't contractnormally.Overtime,
the heartbecomesweakerandheartfailurecanoccur.
Hypertrophic cardiomyopathy whenthewallsof theventricles(usuallythe
leftventricle)thicken.Despite this thickening,theventriclesizeoftenremains
 'l

476 I Part 2 logy of organsand systems

Pathophysio

normal.Hypertrophiccardiomyopathy mayblock blood flow out of the ven-

tricle. Whenthis happens , the condition is calledobstructivehypertrophic
cardiomyopathy.
In restrictive cardiomyopathyventriclesbecomestiff andrigid. This is due
to abnormal tissue, such as scar tissue, replacingthe normalheart muscle.
As a result,theventriclescan't relaxnormallyandfill with blood, and the atria
becomeenlarged.Overtime, bloodflow in the heartis reduced . This canlead
to problemssuch as heart failureor arrhythmias.

Valvular Heart Disease

Dysfunction of the heart valves can result from a num-

be r of disorders , including :

• congenitaldefects,
• trauma,
• ischemicdamage ,
• degenerativechanges,
• inflammation

Mitral Valve Stenos is

Mitral valvestenosisrepresents theincomplete openingof the mit ral valvedur-
ing diastolewith leftatrialdistentionandimpairedfilling of the leftventricle.
Mitral valvestenosismostcommonly is the result of rheumaticfever.
The normalmitral valve area is 4 to 5 cm2. Narrowingof the valveareato
lessthan2.5 cm2 mustoccurbeforesymptomsbeginto develop .
As the resistance to flow through the valve increases , the left atrium be-
comesdilated andleft atrialpressure rises.
The increasedleft atrial pressureeventuallyis transmittedto the pulmo-
naryvenous system,causing pulmonaryconges tion.
Pathophysiologyof cardiovascularand respiratorysystem Unit 6 I 477
Pulmonaryvenouspressureremainsstablefor a long time, that depends
on workof 2 compensatory mechanisms
• 1-st- constrictionof pulmonaryarteries
• 2-nd- openingof bronchialshunts

Constriction of pulmon ary arteries (Kitaev's reflex) decreasebloodflow

from arteriesto viens(compensative pathway) , but leadsto the pulmonary
vascularresistanceincreaseswith the development of pulmonaryhyperten-
sion(pathological pathway) .
This increasesthe pressureagainstwhichthe right heartmust pumpand
eventuallyleadsto cor pulmona le (hypertrophyof right ventricle)and right-
sidedheartfailure.
Manifestations of decompensat ive right-sidedheartfailureare peripheral
edema,hepatomega ly andascites.
Open ingof bronchi al shunts . Compensation - Bloodshuntfrom the pul-
monaryto tile systemiccirculation
Pathology- fluids and cells comesto the bronchialspace. Wheneryth-
rocytescometo the bronchi, theyare phagocytized by macrophages and in
sputumthereareaccumulatedsiderophages (cellsof valvedysfunction) .
As the conditionprogresses , symptomsof decreased cardiacoutputoc-
cur duringextremeexertionor other situationsthat causetachycardiaand
therebyreduce diastolicfillingtime.

Mitral Valve Regurgitation

Mitralvalveregurgitationis characterized by incompleteclosureof the mi-
tral valve, with the left ventricularstrokevolumebeingdivided betweenthe
forwardstrokevolumethat movesinto the aortaandthe regurgitantstroke
volume that movesbackintothe left atriumduringsystole.
Thedegreeof leftventricularenlargement reflectstheseverityof regurgita-
tion.As the disorderprogresses,left ventricularfunctionbecomesimpaired,
the forward (aortic)strokevolumedecreases , andthe left atrialpressurein-
creases,with the subsequentdevelopment of pulmonarycongestion.
 Pathophysiologyof organsand systems
4781 Part 2

Aort ic Valve Stenosis

Aorticstenosisis characterized by increased
resistance to theejectionof blood
from the leftventricleinto the aorta.Becauseof the increasedresistance, the
work demandson the left ventricleare increased,andthe volumeof blood
ejectedintothe systemiccirculationis decreased . Themostcommoncauses
of aorticstenosisarerheumaticfeverandcongeni tal valvemalformations.

Aortic Valve Regurgitation

Aortic regurgitationis the resultof an incompetentaorticvalvethat allows
bloodto flow backto the left ventricleduringdiastole.As a result,the left
ventriclemustincreaseits strokevolumeto includebloodenteringfrom the
lungsaswell asthat leakingbackthroughthe regurgitantvalve.

Chapter 24. Disordersof

Blood PressureRegulation
Bloodpressure(BP)is a forceexertedbycirculating bloodonthewallsof blood
vessels , andis oneof the most importantvital signs. Duringeachheartbeat,
BPvariesbetweena maximum(systolic)anda minimum(diastolic)pressure.
Bloodpressure(BP)canbeviewedasthe productof the cardiacoutput(CO)
andthetotalperipheral resistance(TPR)andcanberepresented bytheequa-
tion, BP= COx TPR. Thebloodvolumealsoplaysan importantrole.
Thetermbloodpressureusuallyrefersto the pressuremeasured at a per-
son's upperarm. It is measuredon the insideof an elbowat the brachia!
artery, whichis the upperarm's majorbloodvesselthat carriesbloodaway
from the heart. A person'sBP is usuallyexpressedin terms of the systolic
pressureanddiastolicpressure.In healthyadults, the pressureat the height
of the pressurepulse, calledthe systolic
pressure, normallyis approximately
120 mm Hg, and the lowestpressure,calledthe diastolicpressure , is ap-
proximately 80mmHg.Thedifferencebetweenthesystolicanddiastolicpres-
Pathophysiologyof cardiovascularand respiratory system Unit 6 1479

sure(approximately 40 mm Hg) is calledthe pulsepressure. Theregulation

of arterialbloodpressure includesshort-term andlong-termmechanisms.

Short-Term regulat ion

Neuralmechanisms. Theneuralcontrolof bloodpressureis mediatedby the
autonomicnervoussystem(ANS)throughcontrolmechanisms thatincludein-
trinsiccirculatoryreflexes
, extrinsicreflexes
, andhigherneuralcontrolcenters.
Humoral mechanisms . A numberof hormonesandhumoralmechanisms
contributeto bloodpressureregulation,includingthe renin-angiotensin-aldo-
steronemechanism and vasopressin .

Long-Term regulation
Renal-Body fluidsystem
Whenthe bodycontainstoo muchextracellular fluid, the arterial pressure
increases; when too littlefluid is present,the bloodpressuredecreases.
Circadian variations of bloodpressure (Dippersvs. Nondippers).
Bloodpressuretendsto the highestvaluesin the early morning,shortly
afterarisingfrom sleep,thendecreases graduallythroughoutthe day,reach-
ing its lowestpointat approximately 2 to 5 am.
Thetermdippersis usedto referto personswith a normalcircadianblood
pressureprofilein whichbloodpressurefalls duringthe night, and nondip-
persfor personswhose24-hourbloodpressureprofileis flattened.

Hypertens ion
Hypertension,
or highbloodpressure, is probablythemostcommonof all health
problems
inadultsandis theleadingriskfactorfor cardiovascular
disorders.
Hypertensioncommonly is dividedintothe categoriesof primaryandsec-
ondaryhypertension.In primaryhypertension, oftencalledessentialhyper-
 480 I Part 2 of organsandsystems
Pathophysiology

tension
, the chronicelevationin blood pressureoccurswithoutevidenceof
other disease.In secondaryhypertension,
the elevatio
n of blood pressure
resultsfrom someotherdisorders.

Blood pr e ssure levels :

• systolicpressureof lessthan 120 mm Hg and diastolicpressureless

than80 mm Hgis optimal;
• systolicpressurelessthan130 mm Hganddiastolicpressurelessthan
80 mm Hg is normal;
• systolicpressureof 130to 139mm Hganddiastolicpressureof 85 to
89 mm Hgis high-normal.

A diagnosisof hypertension is madeif the systolic bloodpressureis 140

mm Hgor higheranddiastolicbloodpressureis 90 mm Hgor higher.
Hypertensionis furtherdividedinto stages1, 2, and 3 basedon systolic
anddiastolicbloodpressuremeasurements.
Hyper-, hypo-and eukinetictypes of hypertensions depend on cardiac
output changes. Ancreaseof blood pressureat the normallevelof COis
namedthe eukinetictype. In situationswith an increasedCO,the hyperki-
netictypedevelop, and in situationswith a decreased CO- the hypokinetic
type.

Contributing Factors
Althoughthecauseor causesof essentialhypertensionarelargelyunknown,
severalfactorshavebeenimplicatedascontributingto its development.

Th e se risk factors include:

• familyhistoryof hypertension;
• race;
• age-relatedincreasesin bloodpressure
.
Pathophysiology
of cardiovascularand respiratorysystem Unit 6 I 481
Lifestylefactorscan contributeto the developmentof hypertensionby
interactingwiththe riskfactors.

These lifestyle factors include:

• highsodium intake;
• excessive calorieintakeandobesity;
• physica l inactivity;
• excessive alcoholconsumption;
• low intakeof potassium ;
• stress.

Oralcontraceptive
drugs alsomayincreasebloodpressurein predisposed
women.

Hyperinsulinemia.
Insulin resistance and an accompany ing compensatoryhyperinsulinemia
havebeensuggestedas possibleetiologiclinksto the developmentof hyper-
tensionandassociatedmetabolicdisturbances such as hyperlipidemiaand
obesity.Hyperten sion, insulin resistance, dyslipidemia,andobesityoftenoc-
cur concomitan tly. Associated abnormalities includemicroalbuminuria, high
uric acid levels, hypercoagulability , and acceleratedatherosclerosis. This
cosegregat ionof abnormalities , referredto astheinsulinresistance syndrome
or the metabolicsyndrome,increasescardiovascular diseaserisk.

Pathogenic pathways of hypertension

Manypathophysio logic factorshavebeenimplicatedin the genesis of essential
hypertension:increased sympatheticnervoussystemactivity,perhapsrelatedto
heightenedexposure or responseto psychosocialstress;overproduction of so-
dium-retaininghormones andvasoconstrictors;
long-termhighsodiumintake ;
inadequatedietaryintakeof potassium andcalcium;increased or inappropriate
 4821 Part 2 Pathophysiology
of organsand systems

reninsecretionwith resultantincreasedproductionof angiotensin II andaldo-

sterone;deficiencies of vasodilators, suchasprostacyclin, nitricoxide(NO),and
the natriureticpeptides; alterationsin expression of thekallikrein- kinin system
thataffectvasculartoneandrenalsalthandling;abnormalities of resistanceves-
sels, includingselectivelesionsin therenalmicrovasculature; diabetesmellitus;
insulinresistance; obesity;the increased activityof vasculargrowthfactors;al-
terationsin adrenergic receptorsthatinfluencethe heartrate,inotropicproper-
tiesof the heart,andvasculartone;andalteredcellulariontransport. Thenovel
conceptsareincludedin pathogenesis of hypertension structuralandfunctiona l
abnormaiities in thevasculature suchas endothelial dysfunction, increased oxi-
dativestress,vascularremodeling, anddecreased compliance.
In mostcases,hypertension resultsfrom a complexinteractionof genetic,
environmental,and demographicfactors. Improvedtechniques of genetic
analysis,especiallygenome-widelinkageanalysis,haveenableda search
for genesthat contributeto the development of primaryhypertensionin the
population.Applicationof thesetechniqueshasfoundstatisticallysignificant
linkageof bloodpressureto severalchromosomalregions,includingregions
linkedto familialcombinedhyperlipidemia . Thesefindingssuggestthatthere
aremanygeneticloci,eachwith smalleffectson bloodpressurein the general
population.Overall,however,identifiablesingle-genecausesof hypertension
areuncommon, consistentwith a multifactorial causeof primaryhypertension.
Cardiovascular riskfactors,includinghypertension, tendto cosegregate more
commonlythanwouldbeexpectedby chance.Approximately 40% of persons
with essentialhypertension also havehypercholesterolemia. Geneticstudies
haveestablisheda clearassociationbetweenhypertension and dyslipidemia.
Hypertension andtype2 diabetesmellitusalsotendto coexist.Hypertens ion is
approximately twiceascommonin personswith diabetes asin personswithout
diabetes. Since35%to 75%of thecardiovascular complications of diabetes are
attributableto hypertension, diabeticpatientsneedaggressive antihypertensive
treatment,aswellas treatmentof dyslipidemia andglucosecontrol.
Increased sympathetic nervoussystemactivityincreases bloodpressureand
contributes to thedevelopment andmaintenance of hypertension throughstim-
ulationof the heart,peripheral vasculature, andkidneys,causingincreased car-
diacoutput,increasedvascularresistance , andfluid retention.In addition,au-
Pathophysiology of cardiovascularand respiratorysystem Unit 6 1483

tonomicimbalance (increasedsympathetic toneaccompanied by reducedpara-

sympathetic tone) hasbeenassociated with manymetabol ic, hemodynamic,
trophic,andrheologic abnormalities.
Themechanisms of increased sympathetic
nervoussystemactivityin hypertension arecomplexandinvolvealterationsin
baroreflex andchemoreflex pathways at bothperipheral andcentrallevels.
Peripheralvascularresistanceis characteristically elevatedin hyperten-
sion becauseof alterationsin structure,mechanicalproperties , and func-
tion of smallarteries.Remodeling of thesevesselscontributesto high blood
pressureand its associatedtargetorgandamage.The elevatedresistance
in hypertensive patientsis relatedto the rarefaction(decreasein numberof
parallel-connected vessels)andnarrowingof the lumenof resistance vessels.
Theexamination of glutealskinbiopsyspecimens obtainedfrom patientswith
untreated essentialhypertension hasuniformlyrevealedreducedlumenareas
andincreased media-lumenratioswithoutan increasein medialareain resis-
tancevessels(inward,eutropicremodeling ).
Systolicbloodpressureand pulsepressureincreasewith age mainlybe-
causeof reducedelasticity(increasedstiffness)of the largeconduitarter-
ies. Arteriosclerosis in thesearteriesresultsfrom collagendepositionand
smooth-muscle cell hypertrophy , as wellas thinning, fragmenting,andfrac-
ture of elastinfibersin the media.In additionto thesestructuralabnormali-
ties,endothelial dysfunction,whichdevelopsovertimefrom bothagingand
hypertension, contributesfunctionallyto increasedarterialrigidity in elderly
personswith isolatedsystolichypertension. ReducedNOsynthesisor release
in this setting,perhapsrelatedto the loss of endothelialfunctionand reduc-
tion in endothelialNOsynthase,contributesto increasedwall thicknessof
conduitvessels.Thefunctional importanceof NOdeficiencyin isolatedsys-
tolic hypertension is supportedby the abilityof NOdonors,suchas nitrates
or derivatives , to increasearterialcomplianceand distensibilityand reduce
systolicbloodpressurewithoutdecreasingdiastolicbloodpressure.
Nitricoxideis a potentvasodilator, inhibitorof plateletadhesionandaggre-
gation,andsuppressor of migrationandproliferation of vascularsmooth-mus-
clecells.Nitricoxideis released bynormalendothel ial cellsin response to vari-
ous stimuli,includingchangesin bloodpressure , shearstress,and pulsatile
stretch,andplaysan importantrolein bloodpressureregulation , thrombosis ,
 484 f Part 2 Pathophysiologyof organsand systems

andatherosclerosis. Thecardiovascular systemin healthypersonsis exposed

to continuousNO-dependent vasodilatortone,but NO-related vascularrelax-
ationis diminishedin hypertensive persons.Theobservation thatin vivodeliv-
eryof superoxidedismutase(anenzymethatreducessuperoxide to hydrogen
peroxide)reducesbloodpressureandrestoresNObioactivityprovidesfurther
evidencethat oxidantstresscontributesto the inactivationof NOandthe de-
velopmentof endothelial dysfunctionin hypertensive models.It hasbeensug-
gestedthat angiotensinII enhancesthe formationof the oxidantsuperoxide
at concentrations that affectbloodpressureminimally.An increasedoxidant
stressandendothelial dysfunctionmaythus predispose to hypertension.
Endothelinis a potentvasoactive peptideproducedby endothelial cellsthat
has both vasoconstrictorand vasodilatorproperties.Endothelinis secreted
in anabluminaldirectionby endothelialcellsandactson underlyingsmooth-
musclecells to causevasoconstriction and elevateblood pressurewithout
necessarilyreachingincreasedlevelsin the systemiccirculation.Endothelin
receptorantagonistsreduceblood pressureand peripheralvascularresis-
tancein both normotensive personsand patientswith mild to moderatees-
sentialhypertension, supportingthe interpretation thatendothelinplaysa role
in the pathogenesis of hypertension.
An importantrole is also playedby the activationof renin-angiotensin-
aldosteronsystem.AngiotensinII increasesbloodpressureby variousmech-
anisms,includingconstrictingresistancevessels, stimulatingaldosterone
synthesisand release,renaltubularsodiumreabsorption,stimulatingthirst
and releaseof antidiuretic hormone.AngiotensinII alsoinducescardiacand
vascularcell hypertrophyandhyperplasia directlyby activatingthe angioten-
sin II type 1 (AT1) receptorand indirectlyby stimulatingreleaseof several
growthfactorsand cytokines.Theactivationof the AT1 receptorstimulates
varioustyrosinekinases , whichin turn phosphorylate thetyrosineresiduesin
severalproteins,leadingto vasoconstriction, cell growth,andcell prolifera-
tion. Activationof the AT2 receptor stimulatesa phosphatase that inactivates
mitogen-activated proteinkinase,a keyenzymeinvolved in transducingsig-
nalsfrom the AT1 receptor.Thus,activationof the AT2 receptoropposesthe
biologicaleffectsof AT1 receptoractivation,leadingto vasodilation,growth
inhibition,andcell differentiation.
Pathophysiologyof cardiovascularand respiratorysystem Unit 6 1485

Secondary hypertan sion

Only5 % to 10% of hypertensive casesareclassifiedas secondaryhyperten-
sion (i.e., hypertension
dueto anotherdiseasecondition).
Amongthe most commoncausesof secondaryhypertension are kidney
disease(i.e., renovascular hypertension),adrenalcorticaldisorders,pheo-
chromocytoma, coarctationof theaortaandsomeothers.

Renalhypertension
Renovascular hypertensionrefersto hypertension causedby a reducedrenal
bloodflow and the activationof the renin-angiotensin-aldosterone mecha-
nism.It is the most commoncauseof secondaryhypertension,accounting
for 1 % to 2 % of all casesof hypertension. The reducedrenalbloodflow
that occurs with renovasculardiseasecausesthe affectedkidneysto release
excessive amounts of renin,increasingcirculatinglevelsof angiotensin II.

Disorders ofadrenocorticosteroid hormones

Increasedlevelsof adrenocorticosteroid hormonesalso can give riseto hy-
pertension.Primaryhyperaldosteronism excessproductionof aldosteronedue
to adrenocortical
hyperplasia or adenomaandexcesslevelsof glucocorticoid
(Cushing's diseaseor syndrome)tendto raisethe bloodpressure.Thesehor-
monesfacilitatesalt andwaterretentionbythekidney;thehypertension thatac-
companies excessive levelsof eitherhormoneprobablyis relatedto thisfactor.

Pheochromocytoma
Likeadrenal medullarycells,thetumorcellsof a pheochromocytomaproduce
andsecretethecatecholamines epinephrine
andnorepinephrine.Thehyperten-
sionthatdevelopsresults fromthe massivereleaseof thesecatecholamines.

Coarctation of theaorta
Coarctation represen ts a narrowingof the aorta.In the adult form of coarc-
tation, the narrowingmost commonlyoccurs just distal to the origin of the
subclavian arteries.Because of the narrowing,bloodflow to the lowerparts
of the bodyandkidneysis reduced.
 4861 Part 2 Pathophysiologyof organsand systems

An increasein cardiacoutput may resultfrom the renalcompensatory

mechanisms. Theejectionof a largestrokevolumeintoa narrowedaortawith
a limited abilityto acceptthe runoff resultsin an increasein systolicblood
pressureandbloodflow to the upperpartof the body.

Target-Organ damagein hypertension

Target-organ disease- the cardiac, cerebrovascular, peripheralvascular, re-
nal,andretinalcomplications associated with hypertension.
Hypertension is a majorrisk factorfor atheroscleros is; it predisposesto
all major atheroscleroticcardiovascular disorders , includingheartfailure,
stroke, coronaryarterydisease , andperipheralarterydisease.
Astheworkloadof theheartincreases, theleftventricular wallhypertrophies
Despite its adaptiveadvantage , left ventricularhypertrophyis a major risk
factorfor ischemicheartdisease , cardiac dysrhythmias , suddendeath,and
congestiveheartfailure.
Hypertension alsocan leadto nephrosclerosis , a commoncauseof renal
insufficiency.

Pulmon ary hyperten sion and Co r pulmon ale

Pulmonaryhypertension (PH)is a condition in which bloodpressurein the
arteriesof the lungs (the pulmonaryarteries)is abnormallyhigh. Thepres-
sure in a normalpulmonaryarteryis about15 mmHgat rest. In hyperten -
sion, bloodpressureincreasesup to 25-30 mmHgand in somecasesmay
increaseup to 100-120 mmHg.
Theclassificationof pulmonaryhypertension is basedonthemainunderly-
ing causeof pulmonaryhypertension ..

This system classifies the pulmonary hypertension

on 5 groups:

• PHdependent
on left sidedheartdisease
;
Pathophysiologyof cardiovascularand respiratorysystem Unit 6 1487

• PHdependent on lungdisease ;
• PHdependent onbloodclotsformation(tromboembolism morecommon);
• PHoependent on constrictionof arteriesdueto anyreasons(including
primarypulmonaryhypertension) ;
• PHdependent on obstructionfrom the outsideof the bloodvessel(for
example, fromdiseasesof thechestwallcompressing thebloodvessels).

Theconstrictionof pulmonaryarteries(Kitaevreflex)is mainmechanism

which leadsto pulmonaryhypertensiondependenton left sided heartdis-
ease.This reflexis activatedas the compensatory mechanismwhenthe ve-
nousbloodpressureis increased in pulmonaryveins.The constrictionof the
pulmonaryresistancevesselsincreasespulmonaryvascularresistanceand
decreases bloodflow from arteriesto veins(compensation).
· Lung disorderscan also lead to pulmonaryhypertension.One of the
most commonconditionsis chronicobstructivepulmonarydisease.When
the lungsare impaired by a disorder, moreeffort is neededto pumpblood
throughthem. But a more importantmechanismis the constrictionof the
arterialvesselsin pulmonarycirculation(Eiler-Lilestrand's reflex).This reflex
is activatedwhendecreasepartial pressureof oxygenin the alveolarair and
leadsto the normalization of ventilation-perfusion ratio. Theincreaseof the
peripheralresistance leadsto pulmonaryhypertension.
A causeof suddenpulmonaryhypertension is pulmonaryembolism,a con-
ditionin whichbloodclotsbecomelodgedin the arteriesof the lung.
Thedevelopment of thepulmonaryhypertension resultsin morehardwork
of the rightsideof the heartto pushthe bloodthroughthe pulmonaryarteries
intothelungs.Overtime,the rightventricle becomesthickenedandenlarged.
Theenlargement of the rightventricleof the heartis namedCorpulmon a/e.
Carpulmonaleis causedby anyfactorswhichcausepulmonaryhyperten-
sion.Massivepulmonaryembolization is the mainreasonof acutecor pulmo-
naledevelopment. Chronicheartandlungdiseasesarethe mainmechanisms
of chroniccar pulmonaledevelopment.
Themainconsequences of car pulmonaledecompensation dependon the
congestionin veinsof systemiccirculation.Bloodbacksup into thesystemic
venoussystem,includingthe hepaticvein. Chroniccongestionin the cen-
 4881 Part 2 Pathophysiology
of organsand systems

trilobularregionof the liverleadsto hypoxiaandfatty changesof morepe-

ripheralhepatocytes, leadingto situationnamednutmegliver.Congestionat
first leadsto the development of legsedema,than liverenlargement,
portal
hypertension andascites.

Hypo ten sion

If the bloodpressurein theorganismbecomeslowerthanthe normallevel, it
is calledlowbloodpressure or hypotension.
Bloodpressureis continuouslyregulatedby the autonomicnervoussys-
tem, usingan elaboratenetworkof receptors , nerves, and hormonesto bal-
ancethe effectsof the sympatheticnervoussystem, whichtends to raise
bloodpressure,andthe parasympathetic nervoussystem,whichlowersit.
Forthis reason,low bloodpressurecausescanbedueto hormonalchang-
es,wideningof bloodvessels,medicinesideeffects,anemia,heartandendo-
crineproblems.
Reducedbloodvolume, calledhypovolemia, is the mostcommonmecha-
nismwhichleadsto hypotension . This canresultfrom hemorrages, or blood
loss;insufficientfluid intake, as in starvation;or excessive fluid lossesfrom
diarrheaor vomiting.Hypovolemia is often inducedby excessiveuseof di-
uretics.
Anotherreasonof hypotensiondecreased cardiacoutputdespitenormal
bloodvolume,dueto severecongestiveheartfailure, myocardialinfarction, ·
or bradicardia. Thissituationoftencanrapidlyprogressto cardiogen ic shock.
Excess ive vasodilation, or insufficientconstrictionof the resistance blood
vessels , alsocauseshypotension . Thiscanbedueto decreased sympathetic
nervoussystemoutputor to increasedparasympathetic activityoccurringas
a consequence of injuryto thebr.ainor spinalcord.Excessive vasodilation can
alsoresultfrom someextrememedica l conditions , sepsis,acidosis.
Hypotension mayhavesomespecificforms. Orthostatichypotension , also
called"posturalhypotension",is a commonform of low bloodpressure . It
occursafter a changein bodyposition, typicallywhena personstandsup
from eithera seatedor lying position. Simplebloodpressureandheartrate
Pathophysiologyof cardiovascularand respiratorysystem Unit 6 I489
measurementswhilelying,seated , andstanding (with a two-minutedelayin
betweeneachpositionchange)canconfirm the presence of orthostatichypo-
tension.Orthostatichypotensionis indicatedif thereis a dropin 20 mmHgof
systolic pressure(anda 10 mmHgdrop in diastolicpressurein somefacili-
ties)anda 20 bpmincreasein heartrate. It is usually transientandrepresents
a delayin the normalcompensatory abilityof theautonomic nervoussystem.
Collapse is a suddenandoftenunannounced loss of vasculartone, often
but not necessarily accompan ied by a loss of consciousness. If the episode
is accompanied by a loss of consciousness, the term syncopeis used. The
maincausesarecardiac(e.g. dueto irregular heartbeat, low bloodpressure),
seizuresor a psychologicalcause.
Neurocard iogenicsyncopeis a form of dysautonomia character izedby an
inappropriatedrop in blood pressure while in the upright position. Neuro-
cardiogenicsyncopeis relatedto vasovaga l syncopein that both occuras a
resultof increasedactivityof the vagusnerve, the mainstayof the parasym-
patheticnervoussystem.
Thecardinalsymptomof hypotensionis lightheadedness or dizziness.The
pathogenic treatmentof hypotensiondependson its cause. Maneprincipals
of treatmentincludebloodvolumeresuscita t ion, bloodpressuresupport, en-
sureadequate tissueperfusion , treatmentof the underlyingproblem.

Chapter 25. Cardiac Conduction

and RhythmDisorders
Thenormalelectrica l conductionof the heartallowsefficientcontractionof
all four chambersof the heart, therebyallowing selective blood perfusion
throughboththe lungsand systemiccirculation. Time orderedstimulation
of the myocardiumallowssignalsarisingin the SAnodestimulatethe atria
to contract(Fig.47). In parallel, actionpotentialstravelto the AV nodevia
internodalpathways . After a delay, the stimulusis conductedthroughthe
bundle of Histo the bundle branchesandthento the purkinjefibersandthe
endocardium at the apexof the heart,thenfinallyto the ventricularmyocar-
dium.
 490 I Part 2 Pathophysiologyof organsand systems

SAnode AV Bundle
node of His Left
posterior
fascicle
Left
anterior
fascicle
B Purkinje
fibers

C
Leftbundle
branch

Fig.47. Cond
uctionsystr.
m of the heart

Forthe diagnosticthe electricalactivityof the heartin exquisitedetailthe

electrocardiogram (ECG)is used. A typicalECGtracingof the cardiaccycle
(heartbeat)consistsof a P wave,a ORScomplex,a T wave,anda U wave
whichis normallyvisiblein 50 to 75 % of ECGs.(Fig.48).
Abnormalitiesof excitablecardiactissuecanleadto abnormalities of hear
rhythmwhicharecalledarrhythmias or disrhythmias.
Arrhythmia is anycardiacrhythmdifferentfrom the normalsinusrhythm.
Sinusrhythmis the automaticityelicitedfrom the noFmalcardiacpacemaker ,
the sinus node.Thesinus nodedepolarisesspontaneously with a frequency
between60 and100 beatsper min (bpm)at rest.Normally,the parasympa-
thetictonepredominates,wherebythe heartrateis reducedfrom 100to 60-
70 bpmat rest.Any reductionin parasympathetic toneor increasein sympa-
thetictone results in tachycardia(ventricularpumpingfrequencyabove100
bpm).Reductionin sympathetic toneor increaseof the parasympathetic tone
leadsto bradycardia(ventricularpumping ratebelow60 bpm).
Pathophysiologyof cardiovascularand respiratorysystem Unit 6 I 491

D&1ayio
AVllode

,-~.J1
•LJ _
.. : ..Pfl.Sewmlln!
.....: ... ;if~~gmer'l .L... , ......-.., ..
+·r , :t+:J':J-
.··:
y::F·::
~:-~·::·
::~-
+~~: . :;
. : : ;

Oepolarizatioo
of atria
Q
S Repotarizatio11
of ventricles
.l~
-0:
-1
~~TlH+l
.1.
......
il[:~~
:
L., l .;. .J...
:..,.,i•
ar ,~oterv .,.:
.L_,.;
..
:..-::l••
j ••r-r-""1 i ....: !-..;
:.~$.P.u.{~t/9.llk-
--t-••
~•••1! I

Depolarization 0 02 0.4 0.6

of ventricles Second

Fig.48. NormalECG

Cardiac arrhythmias are divided into two groups:

I. Pacemaker abnormalities
II. Conduction
abnormalities
(cardiacblock).

Causes:

1. lschemia
2. Inflammation
3. Degenerationchanges
4. Toxicdefeat

I. Pacemaker abnormalitiesarise in the sinus node (sinus tachycardia,

sinusbradycardia or sinusarrhythmia)or outsidethe node(ectopicbeats,
tachycardia,andfibrillationandshiftingpacemaker) . Thesearrhythmiasare
disordersof rhythmogenesis .
 4921 Part 2 Pathophysiology
of organsandsystems

Sinusnodediseaseis a mixtureof conditionswithinsufficientdischargeof

signalsfrom the sinusnode. Thesicksinussyndromeis causedby damageof
the nodaltissue.Sinuspausesleadto sinusbradycardia, tachycardia,tachy-
brady-cardiasyndrome , ectopicbeatsor atrialarrest(sinusarrest)(Fig.49).

'

Fig.49. Elect
rocard
iograp
hic variants
ofsinusnoderhythms.A) Normal
sinusrhythm
(60-
100 bpm ); B) Sinus bradyca
rdia(~ 60 bpm); C)Sinustachycar
dia(~100bpm); D)Respira
-
torysinusdysrhythmia
Pathophysiotogyof cardiovascularand respiratory system Unit 6 I493
Sinustachycardia (heartrateabove100 bpm)is causedby psychological
(panic,anxiety)or physicalstress(anemia, hypoxia, exercise
, fever, intoxica-
tion,shock).Anyconditionwithanincreased sympathetict-0neresults in tach-
ycardia. Adrenergicj3-blockers
areeffectivein slowingdownthe heartrate.

Ree ntry m ech anism

Themostcommonmechanismof tachyarrhythmias is reentry.Reentryis an
abnormal ity of impulse propagationwherean impulsereturnsto tissuethat
wasalreadyexcitedand reexcitesit, causingthe electricalwavefront to be-
comea continuousloopor circuit.Thethreereentrantcircuitare:
1) a barrieraroundwhichthe circuittravels;
2) a regionof unidirectionalblockwherethe impulsecantravelin onedi-
rectionbut not in the other;
3) a regionof slowconductionto allowthepailsof the reentrantloopto re-
coverexcitabilitybeforethe reentrantwavefront passesthat wayagain.

Sinusbradycardia (heartrate below60 bpm) is a normalphenomenon

in well-trainedpeopleand in elderlypersons . Athletesat rest havea high
stroke volumeanda low pulse, becausetheyaredominatedby vagaltonein
this condition.All personsreactwith sinusbradycardia , duringhypothermia ,
hypothyroidism , jaundice,increasedintracranialpressure,treatmentwith di-
goxinor j3-blockers , andin sinusnodedisease.
Sinusarrhythmia is a normalphenomenon. Thereis a rise in heartrate
duringinspiration followedby a fall duringexpiration.Duringinspiration,the
low intrathoracicpressureimprovesthe venousreturn, which- with a delay
throughthe pulmonarycirculation- increasesthe stroke volumeof the left
ventricle. The resultingincreasein aortic intravascularpressurecombined
with the low intrathoracicpressurearoundthe aorta leadsto an increased
transmuralpressureoverthe aorticwall andthus to a strongstimulationof
the aorticbaroreceptors. This is why the vagaltonefalls andthe sinusnode
dischargequickens.Thereflexand circulationdelay explainswhy the fall in
heartratemanifestsitselfduringexpiration andnot duringinspiration.
 4941 Part 2 Pathophysiologyof organsand systems

Ectopicbeatsoriginatein pacemakercells outsidethe sinus node.The

abnormalpacemaker tissueis triggeredby ischemia,mechanical or chemical
stimuli. Cardiaccatheterisation can trigger ectopicbeats.Ectopicbeatsare
eitherof atrialor ventricularorigin.
1. Atrialectopic beatsappearas early(premature extrasystoles) andabnor-
malP-waves intheECG ; theyareusuallyfollowedbynormalORS-complex-
es. Followingthe premature beatthereis oftena compensatory interval.A
prematurebeatin the leftventricleis weakbecause of inadequate venous
return,butafterthelongcompensatory interval,thepost-extrasystolic con-
traction(followinga longvenousreturnperiod)is strongduetheStarling's
lawof theheart.Adrenergic p-blockers aresometimes necessary.
2. Ventricular ectopicbeats(extrasystoles) are recognized in the ECGby
theirwideORS-complex (above0.12s), sincetheyoriginatein the ven-
triculartissueand slowlyspreadthroughoutthe two ventricleswithout
passingthe Purkinjesystem.Theventricularectopicbeatis recognized by
a doubleR-wave. Theclassicaltraditionof simultaneous cardiacausculta-
tionandradialarterypulsepalpationeasesthe diagnosis.Nowandthena
pulsationis notfelt, andanearlyfrustraneous beatis heardtogetherwith
a prolongedinterval.A beatinitiatedin thevulnerableperiod mayrelease
lethalventriculartachycardia , sincethetissueis no longerrefractory.

Aftera periodwith high cardiacfrequencyfrom activityof an ectopicfocus

(overdrive),
thereoftenfollowsa periodwitha remarkablefall in frequency
(over-
drivesuppression).Duringthe overdrive,
theNa+-K•-pumpis extremely activein
orderto extrudeNa+fromthemyocardial cells.Hereby
, thecellbecomes hyperpo-
larisedintheend,whichmaystopthehighfrequency andturnit intosuppression.

Tachycardia occurs Jn paroxysms and is either of

atrial or ventricular origin.

1. Atrialtachycardiais elicitedin the atrialtissueoutsidetheSNas anatri-

al frequencyaround200 bpm.Oftenonly everysecondimpulse passes
the AV-nodeto the ventricles.
Pathophysiologyof cardiovascularand respiratorysystem Unit 6 1495

2. Ventricular tachycardia is elicitedfrom onefocus in the ventriculartis-

suewith a frequencyaround200 bpm (morethan 120 bpm)andabnor-
mal intraventricular
impulseconduction(disturbedORScomplexes).Of
course,thereare no P-wavesin the ECG,and the ORS-complexes are
broadandirregular.

Fibrillation is either atr ial o r ven tric ular in or igin

1. Atrial fibrillationis a conditionin whichthe sinusnodeno longercon-
trols the rhythmandthe atrialmusclefibresundergoa tumultuousrapid
twitching.A total irregularityof ventricularcontractionscharacterisethe
fibrillation.Anexcitationwavewith400-6 00 cyclespermin,coursescon-
tinuouslythroughtheatrialwallovera circularpathwayaboutthe originof
thegreatveins(thecircusmotiontheory).Thereis a continuousactivation
with morethan400 P-wavesper min, whereregularatrialcontractionis
impossible.It is difficultto seeandcountthe P-wavesof tl1eECG.Because
of the refractoriness of theAV-bundle , onlysomeof the excitationwaves
resultin ventricularbeats.Thepulseof the patientis thereforeirregularas
the occurrenceof ORS-complexes in the ECG.The manyP-waves(also
calledf-wavesfor fluctuations)arecharacteristic for atrialfibrillation. Un-
treatedatrialfibrillationhasa ORS-frequency of 150-180 bpm.
Mostcardiacdisorderscanleadto atrialfibrillationor flutter (Fig.50).
Atrialflutteris relatedto atrialfibrillation, but the atrialfrequency- count-
ed from the P-waves- is much lowerthan 400 bpm - usuallyaround300
bpmandtheAV-conduction is moreregular.Theconsequences to the patient
dependuponthe numberof impulsesconductedfrom the atria throughthe
AV-nodeto the ventricles(recordedas ORS-complexes). Ofteneverysecond
impulsereachesthe ventricles , so the ratio of AV-blocksis 2:1, but the ratio
canalsobe3:1, 4:1 etc.Atrialflutter is recognized in the ECGassawtooth-like
P-waves.
2. Ventricular fibrillationis a tumultuoustwitching of ventricularmus-
cle fibres, which are ineffectualin expellingblood. The condition is
lethal without effective resuscitation . The irregular ventricular rate
 4961 Part 2 Pathophysiologyof organsand systems

is 200-600 twitches/min.Withoutcontractileco-ordinationthe forceis

usedfrustraneously. Actually,the heartdoesnot pumpblood, so within
5 s unconsciousness occurs,becauseof lackof bloodto the brain. In
patientswith coronaryarterydisease,ventricularfibrillationis a cause
of suddendeath.Thetriggeris anoxia(withan ineffectiveNa+-K+-pump)
andthe impulsesarisefrom severalfoci in the ventriculartissue. There
is no regularpatternin the ECG.Ventricularfibrillationis initiatedwhen
a prematuresignalarrivesduring the downslopeof the T-wave(vul-
nerableperiod).Electricalshock(electrocution) alsotriggersventricular
fibrillation(Fig.51).
Ventricularfibrillationis the most serious cardiacarrhythmia . It must be
convertedto sinusrhythmat oncebytheapplicationof a largeelectrical shock
to the heart(ventriculardefibrillation)or the patientwill die. Alternatingcur-
rentis appliedfor 100 ms or 1000voltsdirectcurrent is appliedfor a few mil-
liseconds.The vulnerable periodis dangerous , becausean electricalshock,
whengiven duringthis period, will causein itself ventricular fibrillation.
Heresinusrhythmandoneectopic beatfollowedbyventricular fibrillationare
shown. Theonly•effective treatmentis rapidinstitutionof electrical
defibrillation.
Shiftingpacemaker is a conditionwherethe impulseoriginatesin shifting
locationsinsidethe SN,or the pacemaker shiftsfrom the SNto the AV-node .
In thefirst case,the P-wavechangessizefrom beatto beat, andin thesecond
casethe P-waveis foundeitherin front of the ORS-complex or behind.

II. Conductionabnormalities
1) sino-atrial block,
2) atrioventricular block,
3) bundlebranchblock,
4) WPW-syndrome ,
5) the longQT-syndrome . ,

1. Sino-atrialblock(SNdisease)is characterized
by longintervalsbetween
consecutiveP-waves , andcausedby blockageof the formationor con-
ductionof the stimulus from the SNto the atrialtissue(ischaemiaor
infarctionof the SN).
Pathophysiologyof cardiovascularand respiratorysystem Unit 6 1497

.r ~ c:- r ..."' ,..."'' !

I
r I
! '
i : I
; i
t' ,... I>
•1 I I t I ' !
,_ - ... ,_ ,_ - .. '
!
- L. ~ !
i

..-•
~

i 11..l
i ! i 1

I l ! I ! \
'
' i I '
' I 1 I

." : . -
l I l i '
• .' !
' ··-l
I I I I
I.!:It:fl, , .,. .. I
~
~
~~
I f ! I
l I

t I
......._
_.__,_ J._J ...............:.

. I \ 1,
l n, !<..H b lJ 'i: ..J 1~ I.J 1;:i\., t'lll
I (
p p
iI ;, F I It Ii

1
'
- • - ,. . ! r
i !
l
i i !1. 1 i :
Normalsinusrhythm OnsetPAT

--m ~ A,r. ! i
l j !
Fig.51. Electrocardiographic variants of
{ \. Pl 0 \.'r 0 L..I
"' ! ventricular dysrllyt
hmias.A) Prematu re
I j !
' ventricularcontract
ions(PVC);B)ventric-
'
-• :·'
1"
.,
- ""'"'
r 'I II'
i..
, r-n
ular tachycardia
; C)ventricularfibrillation
I : ! f

Fig. 50. Electrocard iographic variants of

atrial dysrllythmias
. A) Atria
l flutter
; B) Atrial
fibrillation; C) Paroxysmal atrial tachycar -
dia (PA1); D) Premature atrial contractions
(PAC)
 Pathophysiologyof organsand systems
4981 Part 2

2. Atrioventricu/arblock is block-
ageof the conductionfrom the
A atriato the AV-node(Fig.52).

Thefirst-degree AV blockis a
prolongationof the PO (PR)-inter -
· om · i lo 1~ I
' .. ·--~ --- 1
val (above0.2 s) implyinga delay
.
f--t--¼- b.,.,"
If i ..... ~ .. - ~ Q··
I!'T
e l J ,..J
... of theconduction- not a realblock.
B
I
I ".
·r
--~-I
· .
r, .. All beatsareconducted , so thereis
! a ORS-complex following each P-
wave, althoughwith delay.
The second -degreeAV block
occurswhensomesignalsare not
C conductedto theAV-node,so some
of the P-wavesare not followedby
ORS-complexes. Theventriclesac-
tually drop some beats.A typical
Fig. 52. Electrocardiograp hic variants of exampleis Mobitztype I block or
atrioventricular (AV)nodeconductionaltera- Wenchebach block,whichis a pre-
tions. A) AVblock1st degree; B) AVblock dictivelossof a ORS-complex.The
2nddegree; C) AVblock3rd degree PO-interval is increasedprogres-
sivelyuntila P-waveis notfollowed
by a ORS-complex. Mobitztype 11
blockoccurswithoutwarning. Suddenly , a ORS-complexfalls out.
ThethirddegreeAVblock(completeAV-block)is a totalblockof the con-
ductionbetweenthe SN and the ventricles . Also bJo
·ckedHiss bundlecon-
duction resultsin an AV-block. An AV-or ventricularpacemakermaintains
life with a spontaneous escaperhythmaround40-50 bpm,or cardiacarrest
occurswith the faintingparoxysmsof Adam-Stokessyndrome.
TheAdam-Stokes synd romeis a clinicaldisordercausedby a partialAV-
block,with a longP-Qintervalanda wideORScomplexin the ECG,suddenly
becoming a total bundleblock.Thecondition resultsin unconscious nessand
crampscausedby brain hypoxiaandsometimesresulting in universa l cramps
(grandma~dueto violentactivityin the motorcortex.Thekeyholeis the AV
Pathophysiologyof cardiovascularand respiratorysystem Unit 6 1499

nodeandthe bundleof His. Diseaseprocesseshereelicit the Adam-Stokes

syndrome.Therap y is to provokesinusrhythmbya fewforcefulstrokesin the
precardialareaof the thorax,accompaniedby mouth-to-nose-resuscitation
andexternalheartmassage.
3. Bundlebranchblockis a blockof the right or the left bundlebranches .
The signal is conductedfirst throughthe healthybranchandthen it is
distributedto the damagedside.This distributiontakesmoretime than
usual,so the ORS-complex is widerthannormal(morethan0.12s).
In rightbundlebranchblock,the right ventricleis activatedlate,which is
shownbya tall doubleR-wavein V1 (thesecondlateR-waveis from the right
side),anda deepwideS-wavein leadsI andV6.
Theleftbundlebranchblockis characterized by a lateactivationof the left
ventriclefromapextowardsbasis.Thisresultsin a solidR-wavein the left pre-
cardialleads(VSandV6),whereasthereis a deepbroadS-wavein V1 andIll.
4. WPW-syndrome or Wolf-Parkinson-White blockis not a directblockof
the conductionthroughthe Hissbundleand branches . but is causedby
a short cut throughan extraconductionpathwayfrom the atria to the
ventricles. Thisabnormalconductionpathwayis congenitalandcalledthe
bundleof KentDueto this short-cut.theslowconductionthroughtheAV-
nodeis bypassed andthe ventriclesare depolarised fasterthan normal.
TheWPW-syndrome is recognized in mostECGleadsasa shortPO(PR)-
intervalfollowedby a wideORS-complex with a deltawave. Thepatients
oftenhaveparoxysmal tachycardia or theymaydevelopatrialfibrillation.
5. ThelongOT-syndrome . This is frequentlya geneticcondition, where
fast repolarisedcells are restimulatedby cells that havenot repolar-
ised.Whenacquired,the conditionis causedby myocardialischaemia,
by drugsor by a low serum [ Ca2+J - below2 mM. Normally,the QT-
intervalis lessthan 50 % of the precedingRR-interval.The long OT-
interval symbolisesa long ventricularsystole.Actually, the ST-interval
is simultaneouswith the phase2 plateauof the ventricularmembrane
actionpotential.Here,the slowCa2•-Na+-channels remainopenfor more
2
than300 ms as normally.The net influxof Ca• and Na· is almostbal-
ancedbya netoutfluxof K•. Hereb y, a longphase2 plateauor isoelectric
segmentis formed.
 500 I Part 2 Pathophysiologyof organsand systems

Chapter 26. Pathophysiology

of the RespiratorySystem

Externalrespirationis a set of processesoccurringin the lungsandprovid-

ing normal contentsof oxygenand carbondioxidein blood.Threeprimary
processestake placein the lungs:ventilationof alveoli,diffusionof oxygen
andCO2 throughthe alveolar-capillary membrane,andperfusion(passingof
appropriateamountsof bloodthroughthe lung capillaries).Strict intercon-
nectionof all theseprocessesensuresnormalgascompositionof blood.
Air passesthroughthe noseandmouthfurtherintotheairways,whereit is
warmed,humidifiedandfiltered.Fromthe tracheato the alveoli,thereare23
branchinggenerationsof airways.Thefirst 16 (asan average)constitutethe
conductingzone,whichis ananatomicdeadspace,becauseno gasexchange
takesplace.The 17-23 generations form the respiratoryzone.Eachgenera-
tion of branchingincreasesthe total cross-sectional areaof the airways,but
reducesthe radius of eachairwayandthe velocityof air flowingthroughthat
airway.
Theexchange effectiverespiratoryzonecomprisesof the respiratorybron-
chioles,alveolarductsandalveolarsacs. At this deadendof theairways,there
areapproximately 300 millionalveoli.Eachcapillaryis in contactwith several
alveoli, so the capillariespresenta sheetof bloodto the alveolarair for gas
exchange. Thetotal areabetweenpulmonarycapillarybloodandalveolarair
rangesfrom 70-140 m2 in adulthumans(increasedduringexercise)through
recruitmentof newcapillariesin particularin the apica.1partsof the lungs.

The alveolar walls (or alveolar septa) consists, from

blood to air, of the following microscopic structures:

• Thecapillaryendotheliumliningthe intertwiningnetworkof anastomos-

ing capillaries.
• A basementmembrane andsurroundinginterstitialtissueseparatingthe
endothelialcellsfromthealveolarliningepithelialcells.Inthin portionsof
Pathophysiologyof cardiovascularand respiratorysystem Unit 6 I 501
the alveolarseptum,the basementmembranes of epitheliumandendo-
theliumarefused,whereasin thickerportions,theyaresepara ted by an
interstitial space(pulmonaryinterstitium)containing fine elasticfibers,
smallbundlesof collagen , a few fibroblast-likeinterstitialcells,smooth
musclecells,mastcells, and,rarely,lymphocytes andmonocytes.
• Alveolarepithelium,which containsa continuouslayer of two princi-
pal celltypes:flattened , platelike type I pneumocytes (or membranous
pneumocytes) covering95 % of thealveolarsurfaceandroundedtypeII
pneumocytes. -TypeII cellsare importantfor at leasttwo reasons : they
arethe source of pulmonarysurfactant , containedin osmiophiliclamel-
lar bodiesseenwith electronmicroscopy, andtheyarethe maincelltype
involvedin the repairof the alveolarepitheliumafterthe destructionof
typeI cells.

The pressures of oxygen and carbon dioxide in ar-

terial blood are closely controlled . In a typical nor-
mal adult at rest:

• The pulmonaryblood flow of 5 Umin carries11 mmol/min (250 mU

min)of oxygenfrom the lungsto thetissues.
• Ventilationat about6 Umincarries9 mmol/min(200 ml/min) of carbon
dioxideout of the body.
• Alveolarventilation is at about4 Umin
• The normalpressureof oxygenin arterialblood(Pa02) is between12
and13 kPa(90 and98 mm Hg).
• Thenormalpressureof carbondioxidein arterial blood(PaC02) is 4.8-
6.0 kPa(36-45 mm Hg).

Anydiseasedeveloping in the respiratorysystemmayleadto disturbances

of oneof theseprocesses, decrease in theefficacyof respira
tionanddevelop-
mentof respiratory failure.
Concept ofexternalrespiratory failure. Respiratoryfailureis a pathologi-
cal processresulting from impairment of gasexchange betweenambientair
 so2 I Part 2 Pathophysio
logy of organsand systems

and circulatingbloodandleadingto the inequality of bloodgascomposit ion

to an organismoxygendemandat restor in physicalloads.
Impaired intrapulmonarygasexchangeusually resultsin primarilyhypox -
emia(decreasedp02 in arterial bloodat normal levelsof 90- 100 mm Hg),
becausethe diffusing capacity of CO2 is approximately 25 timesgreater than
thatof 02 andbecauseregionalzonesof hypoventilation (inadequate alveolar
ventilation)with poorCO2 remova l can becompensated bythe increased ven-
tilationof normallung units. The processof movinggasesin and out of the
lungsmay be inadequate (globalor generalize d hypoventilation),producing
primarily hypercapnia (increasedpC02 in arterial blood at normallevels of 45
mm Hg), althoughhypoxemiaoccursas well. Many pathologicalprocesses
causesimultaneousfailure of both of thesefunctionsandthe developmentof
totalrespiratory failure, but selective or disproportionateimpairment only of
oxygenleadsto the developmentof partialrespiratory failure.
Therearesomeclassifications of respiratoryfailure.
The first classificationdividedrespiratory failure on total and partial. In
totalrespiratory failurethe partial pressureof bothgases(oxygen and car-
bon dioxide)in the arterialblood gangedhypoxemiadevelopstogether with
hypercapnia . In partialrespiratory failure- hypoxemia in arterialblood de-
velopswithouthypercapnia.
The secondclassification dividesrespiratoryfailuresinto compensative
anddecompensative . In compensative respiratory failure, clinicalmanifes-
tationsappearonly in situationswith physical activity. In decompensative
respiratory failure, all manifestationsmaybefoundin patientsat rest.
Thethird classificationdividesrespiratoryfailuresinto acuteand chronic.
Byacuterespiratory insufficiency one understandsthe statewhenthis
syndromedevelopsfast,withinminutes, hoursor daysandhasthe property
to progressimpetuous ly. Therefastaccruesarterial hypoxemia , hypercapnia,
developsacidosis,therearedisorElersof the centralnervoussystem.All this
canbecompletedwith comaanddeath.
Chronic respiratory insufficiency is characterized by a slowerincreaseof
hypoxemia andhypercapnia, andtheydo not reach suchdegreeasfor wantof
acuteinsufficiencydueto the expenseof inclusion of compensatory mecha-
nisms.
 Pathophysiologyof cardiovascularand respiratorysystem Unit 6 Iso3
Theclinicalsymptoms andsignsof respiratoryfailurearenonspecific. The
primaryphysicalsignsof ventilatoryfatigueare vigoroususeof accessory
ventilatorymuscles,tachypnea , tachycardia, declining tidalvolume,irregular
or gaspingbreathingpatterns,andparadoxal abdomina l motion.
Acutehypoxemia maycause•diverseproblems , includingcardiacarrhyth-
miaandcoma. Somealterationof consciousness is typical, andconfusionis
common.Chronicreductionin p02 }s generallywelltoleratedby patientswith
adequatecardiovascu lar reserve . However , alveolarhypoxiacaninducepul-
monaryarteriolarvasoconstriction and increasepulmonaryvascularresist-
ance(Eiler-Lilestrand'sreflex),leadingoverweeksto months,to pulmonary
hypertensio n, right ventricular hypertrophy(cor pulmonale),and eventual
rightventricular failure.
Hypercapnia may produceacidemia.Suddenincreases in pC02 occur
· muchfasterthancompensatory increasesin extracellularbufferbase.Acute
decreases in cerebralpH increaseventilatorydrive.Theeffectsof acutehy-
percapniaare muchlesswell tolerated than thoseof chronichypercapnia .
Acutehypercapnia maycausechangesin sensoriumrangingfromsubtleper-
sonalitychangesand headache to markedconfusionand narcosis(coma).
Hypercapnia alsocausescerebralvasodilationand increasedcerebrosp inal
fluid pressure.AcuteCO2 retentioncausesacidemia , whichwhensevere(pH
< 7.3), contributesto pulmonaryarterialvasoconstriction, systemicvascular
dilatation,reducedmyocardialcontractility,hyperkalemia, hypotension,and
cardiacirritability, with the potential for life-threatening arrhythmias.
Sincetheefficientgasexchange betweenatmospheric air andbloodis pro-
videdbythreeprocesses - diffusion , perfusion andventilation , disordersof
eitherof themmayleadto respiratoryfailuredevelopment.
Diffusionis gasexchange acrossthealveolar-capillarymembrane.

The alveolar-capillary barrier consists of six zones:

1) a fluid layercontainingsurfactant,
2) thealveolarepithelium;
3) a fluid-filled interstitialspace;
 5041 Part 2 Pathophysiologyof organsand systems

4) the capillaryendothelium
with basementmembrane;
5) the bloodplasma;
6) the erythrocytemembrane. Thesix zonesform an almostidealgasex·
changerfor oxygenandcarbondioxidediffusion.

Disorders of diffusion

Etiology of diffusion disorders include:

1. Increasea thickness
of thealveolar-capillary
membrane
(normal7-9 mcm)
• in chroniclung disease(sclerosis,fibrosis);
• edemaof alveolar-capillary membrane(pneumonia,congestion);
• adultandnewbornrespiratorydistresssyndrome(shock,embolus,DIC·
syndrome).
2. Decreaseof the alveolar-capillary membranearea (emphysema,ab·
scess,lung resection).

Pathogenesis. Thediffusionof oxygenthroughthealveolar·capillarymem·

braneis 20-25 times worsethanthat of CO2. If the thicknessof the mem-
braneincreases, the diffusionof 02 decreases,
but the diffusionof CO2 does
not change.Theredevelopspartialrespiratory failure.Compensation in this
statedevelopsby hyperventilation.

Disorders of perfusion
Perfusion is the lung bloodflow d€1ivering venousbloodto alveoliandarte-
rial bloodto the left heart.The right ventriclepumps,on average,the same
amountof bloodthroughthe lungs as the left ventriclesendsthroughthe
entiresystemiccirculation.Ignoring the smallamountof bloodreachingthe
lungsvia the bronchialarteries,the meanpulmonarybloodflow or perfusion
equalsthe cardiacoutput(5 Umin at rest).
 Pathophysiologyof cardiovascularand respiratorysystem Unit 6 Isos
Hyperperfusion
andhypoperfusio
n leadsto the decreasegasexchangein
the lungs.

Hyperpertusion
.

Etiology:

1) asphyxia
, stress(totalhyperperfusion);
2) inflammation,atelectasis(localhyperperfusion).

Pathogenesis. Fornormal 02 exchange erythrocytesneedfrom 0.3 to 0.5

. secfor moving throughthe alveolarcapillary.If the speedof blood increase,
erythrocytes
havenot enoughtimefor normalgasexchange. Theredevelops
hypoxemia. Because the diffusionof CO2 is 20- 25 times better,hypercapnia
does not develop (partial respiratoryfailure). In clinics, this pathological
situation is namedfunctional
shunt.Compensation
by hyperventilation
takes
placein this situation.

Hypo
perfusion

Etiology:

1) pathologyof the heart(heartfailure,shock,valvesdisfunction,myocar-

dial infarction,myocardites)
2) pathologyof the vessels(atherosclerosis,
tromboembolism, stenosisof
lungartery).

Pathogenesis has three different variants.

1. Decreaseminute volume and hypotensionbecauseheartfailure devel-

opment.
sos I Part 2 Pathophysiologyof organsand systems

2. Openingof shuntsbetweenarterialsandveinsof pulmonarycirculation.

In this case,bloodquickercomesto the left ventricleandcompensates
the strokevolume, but hasnot normaloxygenation. Thisis a morecom-
mon situationof hypoperfusion development.In clinicsthis pathology
namedanatomical shunt.
3. If the bloodflow blockspulmonarycirculationin somevessels(embo-
lism, sclerosis, ), there developspulmonaryhypertensionand an in-
creasedbloodflow in workingvessels.In thesevessels , theredevelops
hyperperfussion.

All threecasesleadto partialrespiratoryfailure.

If patientsare givensomeair with a highconcentration of oxygen, in hy-
perperfussion with functionalshunthypoxemiadecreases or disappeasr, but
in hypqperfussion with anatomical shunthypoxemiadoesnot change . This
is usedfor the differentialdiagnosticsbetweenanatomical(in hypoperfusion)
andfunctional(in hyperperfusion) shuntsin clinic.

Disorders of ventilat ion

Ventilationprovidesthe optimalcompositionof the alveolarair necessary for
the maintenance of gas partialpressuregradientsbetweenthe alveolarand
venousblood.In a healthyperson,alveolarventilationis typicallyabout4 lit-
ers/minute,andcardiacoutputaveragesabout5 liters/minute,for an overall
ventilation-perfusionratio(VPR)of 0.8.
Disturbancesof correlation"ventilation / perfusion".Thegascomposition
of the bloodandits saturationby oxygendependsnot onlyfrom absoluteal-
veolarventilation,but also from levelof lungperfusion. Theamountof blood
whichproceedsthroughthe lungsfor 1 minuteis equalto 4.5-5.0 L that is
approximately corresponds to thevalueof cardiacoutput.Butevenin healthy
personsthis bloodis distributedin lungtissuenon-uniformly:somealveoli
perfusioningmore,others- less.Andthereforeit is important,thataninhaled
air wasdistributedadequately, that is accordingto the intensityof the blood
flow, as underalveolarventilationis understoodnot anyventilation,but per-
Pathophysiologyof cardiovascularand respiratorysystem Unit 6 I so7
fusionof the alveolionly.Thatvolumeof an inhaledair whichis distributed
in thealveoli,wherebloodflow is absentor is sharplyreduced , doesnottake
partin gasexchange betweenthealveolarair andthe bloodof the lungcapil-
lariesanddoesnot supportthe gascompositionof the blood.
Theoptimalr~tioof alveolarventilation andperfusionof thelungmakes4:5.
It canbechangedtowardsan increaseor towardsa decrease. Theincreaseof
correlationventilation/ perfusionis characterized by the effectof deadspace.
Thepredominance of perfusionaboveventilationis characterized by theeffect
of vein-arterialshunt.In bothcases,the normalgascomposition of the blood
supplyis impossible.If the ventilationprevails , the tensionof oxygenin the
bloodflow from the alveoliwill besufficient, but too muchcarbonicacidwill
be removedfrom the blood.As the consequence thereariseshypocapnia.It
.theventilationlagsbehindperfusion , thereariseshypoxemia andhypercapnia.
If VPRis lessthan0.8- hypoventilation , if VPRis morethan0.8- hyper-
ventilation.

Hypoventi lation

Etiology of hypov e ntila tion includ es :

• pathologyof lungs(obstructiveandrestrictivedisorders
)
• pathologyof respiratorycenter
• pathologyof chest

Pathologyof the respiratorycenterand pathologyof the chestare also

thoughtto belongto one group: central,neuromuscularand thoracodia-
phragmaldisturbances of ventilation,whichinclude:
• Disordersof functionsof the respiratorycenter.
• Dysfunctions of motoneurons of the spinalcord.
• Dysfunctions of thr neuromuscular apparatus.
• Disordersof thethoraxmotility.
• Damageof the integrityof thethoraxandpleuralcavity.
 sos I Part 2 Pathophysiologyof organsand systems

Pathogenesis:

In hypoventilationdisorders,there developstotal respiratoryfailure.The

partial pressureof both gaseschangesin the arterial blood and hypox-
emia and hypercapniatake place.Gasacidosisfollows hypercapnia.The
low partialpressureof oxygenin the alveolarair leadsto the constriction
of arterialvesselsin pulmonarycirculation(Eiler-Lilestrand'sreflex). In-
creasedperipheralresistanceleadsto pulmonaryhypertension,then right
ventricularhypertrophy(corpu/monale) , and eventuallyright ventricular
failure.
Corpulmonaleis a heart condition secondaryto pulmonarydisorder
with the loss of pulmonaryvesselsand increasedpulmonaryresistance.
The lung diseasecausespulmonaryhypertension,increasedwork load
of the right heart, right ventricular hypertrophy,and finally right heart
failure.

Hypervent ilatio n

Etiology:

• stimulationof the respiratorycenter;

• compensation in hemodynamic disorders.

Pathogenesis:

In hyperventilation disorders,there developsnormoxemia(becausethe

saturationof the bloodby 02 in normalconditionsis not possiblemorethan
100 mm Hg)andhypocapn ia. FromdependsTheappearance of gasalkalosis
dependsuponthe levelof hypocapnia.
Pathophysiologyof cardiovascularand respiratorysystem Unit 6 Isos
Bas ic clinical manifestations of external
respiratory fa ilure
Oyspnea is an unpleasant sensationof difficultyin breathing
.
Hyperpnea is an increasein the depthandfrequencyof respiratorymove-
ments.It maydevelop as an adaptivereaction,for example,to exercise. In
somecases,it mayleadto alveolarhypoventilation.
Bradypnea is a decreasein frequencyof respiratorymoveme nts. It may
be physiologica l in trainedsportsmen.In caseof very infrequentrespiration,
alveolarhypoventilatio n may develop. In patientswith obstructivediseas,
bradypnea maybea preferable type of respiration.
Tachypnea is a frequentandshallowrespiration.

Against the background of the exited re spiratory

center, the depth of respiration may d e cr e ase , if pe -
ripheral mechanisms confining the volum e of inspi-
ration take parting the followinf ways:

1) an increasein the sensitivityof receptorsreactingto the stretchingof the

lungparenchyma - the premature inductionof theHering-Breuer'sreflexat
inflammation,acidosisofthelungparenchyma (tachypneain pneumonias);
2) painat inhalation(traumaof the chestandthe abdomen,pleuritis).

Mechanicallimitationin the thoraxmotility also may leadto the develop-

mentof tachypnea.
A decreasein the depthof respirationat the maintenance ???ofor evenan
increasein its frequencycan be the manifestation of inceptiveexhaustion of
the respiratorycenter.
Accordinglyto the structure of anact of respiration,it is possibleto distin-
guishtwo typesof dyspnea:expiratory(difficultiesin exhalation)andinspira-
tory (difficulties in inhalation)ones.
lnspiratory dyspnea is observedin caseof the excitementof the respira-
tory center and restrictivedisordersof ventilation.
 510 I Part 2 Pathophysiologyof organsand systems

Expiratory dyspnea
is characteristic
for obstructivedisorders.

P ath o logic a l typ e s of res piration:

1. Periodicalrespiration(Cheyne-Stokes'respirationand Biot's respira-

tion) is characterizedbythe interchange of the stopof breathing(apnea)
with the resumingof the respiratoryactivity.
In caseof the Cheyne -Stokes'respiration, the ceaseof respirationis pre-
cededby the gradualdecreasein the amplitudeof respiratorymovements.
Whenrespiratorymovementsresume,their amplitudegraduallyincreases.
The basic mechanismof Cheyne-Stokes breathing.The basiccauseof
Cheyne-Stokes breathingis the following:Whena personoverbreathes , thus
blowingoff too much carbondioxidefrom the pulmonaryblood and also
increasingthe blood oxygen,it takesseveralsecondsbeforethe changed
pulmonarybloodcan be transportedto the brainand inhibitexcessventila-
tion. By this time, the personalreadyis overventilated for a few seconds.
Therefore , whenthe respiratorycenterdoeseventuallyrespond , it becomes
depressedtoo much becauseof the overventilation, and now the opposite
cyclebegins.Thatis, carbondioxidebuildsup andoxygendecreases in the
pulmonaryblood.Then, againit takesa few secondsbeforethe brain can
respondto newchanges.Whenthe braindoesrespond,the personbreathes
hardonceagain. Thecyclerepeatsitselfagainandagain.
Periodsof apneainterchanging with periodsof resumingof breathingwith-
out significantchangesin the amplitudeof respiratorymovementsarechar-
acteristicfor Biot's respiration.
2. Kussmaul 's respiration("big", "noisy" respiration)is characterized by
vigorousinhalationandactiveexhalationwith forcedcontractionof ex-
piratorymuscles. ,
Thesemanifestations are underlain by the extremeexcitationof the res-
piratorycenterdue to high concentrations of CO2, hydrogenions (e.g.,di-
abeticketoacidosis) , and ammoniumcompounds(e.g.,severeuremiaand
azotemia).
3. Stenoticrespiration andgasping respiration ;
Pathophysiologyof cardiovascularand respiratorysystem Unit 6 I 511
4. Dissociated respiration(Grocco'srespiration)manifestsitself with
non-synchronous contractionsof differentgroupsof respiratorymus-
cles (e.g., intracostalmusclesconstrictand the diaphragmrelaxes).
Sucha conditiontestifiesto severedamageof the respiratorycenter
with disordersin synchronization of excitationandinhibitionin different
groupsof neurons.

Amountsof inspired andexpiredair arereferredto as lungvolumes . Lung

volumesaremeasuredby spirometry.
Theresidualvolume(RV)represents the volumeof air left in the lungsafter
a maximalexpiration.Thevital capacity(VC)is the maximumvolumeof air
that can be exhaledafter a maximalinspiration.VC has threecomponents .
The first is the inspiratoryreservevolume (IRV), which is the quantityof
-air that can be inhaledfrom a normalend inspiratoryposition.The second
componentof VCis the tidal volume(Vrr,whichis the volumeof air inspired
and expiredwith eachbreath(about0.5 Lat rest). Thethird componentof VC
is the expiratoryreservevolume(ERV),which is the amountof air that can
be exhaledfrom the lungsfrom a normalend-tidalexpiratorypositionthat is
characterized by a relaxedexpiratorypause. This is the easiestpositionto re-
produce , andthe lungvolumein this positionis calledfunctionalresidualca-
pacity(FRC= ERV+RV).Thetotal lung capacity(TLC)is the total volumeof
air in the lungs,whentheyaremaximallyinflated(RV+ VC)- near6 L of air.
Whenthe personexhaleswith a maximaleffort,the forcedexpiratoryvol-
umein one-second(FEV 1
) maybe recorded by spirometry.

Diffuse pulmonary diseases can be classified in two

categories:

1) obstructivedisease(airwaydisease) , characte
rizedby the limitationof
airflowusuallyresulting from an increasein resistancedueto partialor
completeobstructionat anylevel;
2) restrictive
disease , characterizedby the reducedexpansionof the lung
parenchyma accompanied by the decreasedtotal lungcapacity.
 512 I Part 2 of organsand systems
Pathophysiology

Themajorobstruct ive disorders (excludingtumorsor inhalationof foreign

bodies)are asthma, emphysema, chronicbronchitis,bronchiectasis, cystic
fibrosis,and bronchiolotis.In patientswith thesediseases, the total lungca-
pacityandforcedvital capacity(FVC)areeithernormalor increased,but the
hallmarkis a decreased expiratoryflow rate, usuallymeasuredby forcedex-
piratoryvolumeat 1 second(FEVJThusthe ratioof FEV1 andFVCis charac-
teristicallydecreased. Expiratoryobstructionmayresulteitherfrom anatomic
airwaynarrowing,classicallyobservedin asthma,or from the loss of elastic
recoil, characteristic
of emphysema.
In contrast,in restrictivediseases , FVCis reducedandtheexpiratoryflow
rateis normalor reducedproportionately. Hencethe ratioof FEV1
andFVCis
nearnormal.

Th e res tri ct ive d ef e ct occurs in two general condi -

tion s:

1) extrapulmonarydisordersthataffecttheabilityof thechestwallactasa
bellows(severeobesityor neuromuscular disorders);
2) acuteandchronicinterstitial lungdiseases.

Theclassicacuterestrictivediseaseis acuterespiratorydistresssyndrome
(ARDS).Chronicrestrictivediseasesincludepneumoconiosis , sarcoidosis,
andidiopathic pulmonaryfibrosis.

Obstructive airway disorders

Obstructiveairwaydisordersarecausedby disordersthat limit expiratoryair
flow.
Chronicobstructivepulmonarydisease(COPD) denotesa groupof respira-
tory disorderscharacterized
bychronicandrecurrentobstructionof air flow in
the pulmonaryairways.COPDcanbecausedby a varietyof airwaydiseases ,
includingchronicbronchitis,emphysema, bronchiectasis,
andcysticfibrosis.
Pathophysiologyof cardiovascularand respiratorysystem Unit 6 I 513
Theterm chronicobstructivepulmonarydiseaseencompasses two types
of obstructiveairwaydisease : emphysema , with enlargementof air spaces
anddestruction of lungtissue, and chronicobstructivebronchitis, with ob-
structionof smallairways.Themechanisms involvedin the pathogenes is of
COPDusuallyaremultipleandincludeinflammation andfibrosisof the bron-
chialwall, hypertrophyof the submucosalglandsandhypersecretion of mu-
cus, andthe lossof elasticlungfibersandalveolartissue. Inflammationand
fibrosisof the bronchialwall, alongwith excessmucussecretion,obstruct
airflowandcausemismatchingof ventilationand perfusion.The destruction
of alveolartissuedecreases the surfaceareafor gasexchange , and the loss
of elasticfibersleadsto airwaycollapse.

-chronic Pulmon ary Em physema

The term pulmonaryemphysemaliterally meansexcessair in the lungs.
However , when one speaksof chronicpulmonaryemphysema , a complex
obstructiveanddestructiveprocessof the lungsgenerallyis meant, andthe
mostinstanceit is a consequence of a long-termsmoking.It resultsfrom the
following majorpathophysiological eventsin the lung.
1. Chronicinfectioncausedby inhalingsmokeor other substancesthat
irritatethebronchiandbronchioles. Theprinciplereasonfor the chronic
infectionis that the irritant seriouslyderangesthe normal protective
mechanisms of theairways,includingthe partialparalysisof the cilia of
the respiratoryepitheliumby theeffectsof nicotine,so that mucuscan-
not be movedeasilyfrom the passageways;stimulationof the excess
mucussecretion , whichfurtherexacerbates the condition; andthe inhi-
bitionof thealveolarmacrophages , so thattheybecomelesseffective in
combatinginfection.
2. Theinfection,excessmucus, andinflammatoryedemaof the bronchio-
lar epitheliumtogethercausechronicobstructionof manyof thesmaller
airways.
3. Theobstructionof theairwaysmakesit especially difficultto expire,thus
causingthe entrapmentof air in the alveoliand overstretchingthem.
 514 I Part 2 Pathophysiologyof organsand systems

This, combinedwith the lung infection,causesthe markeddestruction

of as muchas 50 to 80 % of alveolarwalls.
4. Smokingandprotease-antiprotease mechanisms of emphysema. Smok-
ing inhibitsantielastaseand favorsthe recruitmentof leukocytesand
releaseof elastase,with elastictissuedestructionin the lunganddevel-
opmentof emphysema (Fig.53.).
The physiologicaleffectof the chronicemphysema are extremelyvaried,
dependingon the severityof the diseaseandthe relativedegreeof the bron-
chiolarobstructionverseslungparenchymal destruction.Amongthedifferent
abnormalities arethefollowing:

Smoking

Decreasinga 1- Attraction
of
antitrypsin
activity · inflammatorycells

i
Release
of elestase

i
Inheriteda1- ActionInhibited
by
antitryp~in
deficiency a1-alititrypsin

i
Destructionelastic
fibersin lung

i
Emphysema

Fig.53. Pathogen
ic pathways
ofemphysema
development
Pathophysiologyof cardiovascularand respiratorysystem Unit 6 I 515
• Thebronchiolarobstructiongreatlyincreasesairwayresistanceand re-
sults in the greatlyincreased work of breathing.It is especiallydifficult
for the personto moveair throughthe bronchiolesduring expiration
because thecompressive forceonthe outsideof thelungnot onlycom-
pressesthe alveolibut alsocompresses the bronchioles , whichfurther
increase s their resistance
duringexpiration.
• The markedlossof alveolarwallsgreatlydecreases thediffusingcapac-
ity of the lung,whichreducesthe abilityof the lungsto oxygenatethe
bloodandremovecarbondioxide.
• Theobstructiveprocess is frequently muchworsein somepart of the
lungsthan in other parts, so that someportionsof the lungsare well
ventilated,whereasother portions are poorly ventilated.This often
causesextremelyabnormalventilation-perfusion ratios, with a verylow
VPRin someparts(physiologicshunt), resultingin the pooraerationof
the blood, anda veryhighVPRin someparts(physiologicdeadspace),
resultingin wastedventilation,both effectsoccurring in the samelungs.
• Thelossof largeportionsof the alveolarwallsalsodecreases the num-
berof pulmonarycapillariesthroughwhichbloodcanpass.As a result,
the pulmonaryvascularresistanceincreasesmarkedly , causingpulmo-
naryhypertension. Thisin turn overloadsthe rightsideof the heartand
frequentlycausesrightsidedheartfailure.

Chronicemphysema usuallyprogresses overmanyyears.Thepersonde-

velopshypoxiaand hypercapn ia becauseof hypoventilation of manyalveoli
and becauseof the loss of alveolarwalls.The net resultof all theseeffects
is severe, prolonged, devastating air hungerthat canlast for yearsuntil the
hypoxiaand hypercapn ia causedeath- a highpenaltyto payfor smoking
Pneumonia . Theterm pneumonia includesany inflammatoryconditionof
thelung in whichsomeor all of thealveoliarefilledwithfluidandbloodcells.A
commontypeof pneumon iais bacterialpneumonia , causedmostfrequentlyby
pneumococci. This diseasebeginswith infectionin the alveoli;the pulmonary
membrane becomesinflamedandhighlyporousso thatfluidandevenredand
whitebloodcellspassoutof thebloodintothealveoli.Thus, theinfectedalveo-
li becomes progressively filled withfluidandcells, andtheinfectionspreadsby
 516 I Part 2 Pathophysiologyof organs and systems

extensionof bacteriafromanalveolusto analveolus.Eventually, largeareasof

thelungs, sometimesthewholelobeor eventhewholelung,become"consoli-
dated'', whichmeansthattheyarefilledwith fluid andcellulardebris.
In pneumonia,the pulmonaryfunction of the lungs changesin different
stagesof the disease.In the earlystages,the pneumoniaprocessmightwell
be localizedto only one lung,with alveolarventilationreduced,while blood
flow throughthe lungscontinuesnormally.Thisresultsin 2 majorpulmonary
abnormalities: reductionin the total availablesurfaceareaof the respira-
tory membraneanda decreased ventilationperfusionratio.Boththeseeffects
causediffusingcapacitywhich resultsin hypoxemia(low bloodoxygen)and
hypercapnia ( high bloodcarbondioxide).
Bronchial Asthma.Bronchialasthmarepresentsa reversibleform of air-
way diseasecausedby the narrowingof airwaysdueto bronchospasm, in-
flammation,andincreasedairwaysecretions.It occursin 3 to 5 % of all peo-
ple at sometime in life.Theusualcauseis hypersensitivity of the bronchioles
to foreignsubstancein the air. In youngerpatients,underage30 years,the
asthmais about70% is causedby allergichypersensitivity , especiallyto plant
pollens.In otherpeople,the causeis almostalwayshypersensitivity to non-
allergictypesof irritantsin the air, suchas irritantsin smog.
Theallergicreactionthat occursin the allergictype of asthmais believed
to occurin the followingways:the typicallyallergicpersonhasa tendencyto
form abnormallylargeamountsof lgEantibodies , andthis antibodiescauses
allergicreactionswhen they reactwith their specific antigens.In asthma,
theseantibodiesaremainlyattachedto mastcellsthat lie in the lung interstit-
ium mainlyin closeassociationwith the bronchiolesandsmallbronchi.When
a personbreathesin pollensto whichheor sheis sensitive( that is, to which
the personhas developedlgE antibodies), the pollen reactswith mastcell
attachedantibodiesand causesthesecells to releaseseveraldifferent sub-
stances.Amongthemarehistamine,slowreactingsubstancesof anaphylaxis
(whichis a mixtureof leucotrines), the eosinophilicchemotacticfactor and
bradykinin . Thecombinedeffectsof all thesefactors,especiallyof the leucot-
riens, areto producelocalizededemain the wallsof the smallbronchiolesas
well asthe secretionof thick mucusintothe bronchiolarlumenandspasmof
the bronchiolar smoothmuscles.Airwayresistanceincreasesgreatly.
Pathophysiologyof cardiovascular and respiratory system Unit 6 I 517
Interstitial Lung Diseases and Restric tive
Respira tory Failure
Lowlungvolumes,measuredasa reducedtotal lungcapacity(TLC)andvital
capacity (VC), characteriserestrictivelung diseases . Also the TLCis small,
andall volumesareoften proportionallydecreased. Theairflow velocityand
relative forcedexpiratoryvolumein 1 s is typicallynormal.Oneway or an-
kther, the normalexpansionof the lungsis restrictedor the pulmonarycom-
plianceis decreased .
The diffuseinterstitiallung diseasesarea diversegroupof lung disorders
that producesimilarinflammatoryandtibrotic changesin the interstitiumor
interalveolarseptaof the lung. They include sarcoidosis, the occupational
lungdiseases , hypersensitivity pneumonitis , andlungdiseasescausedby ex-
posureto toxic drugs(amiodarone) andradiation.
Incontrastto theobstructive lungdiseases,whichprimarilyinvolvetheair-
waysof the lung, the interstitiallung disordersexertllleir effectson the col-
lagenandelasticconnectivetissuefoundbetweenthe airwaysandthe blood
vesselsof the lung. Many of thesediseasesalsoinvolvethe airways, arteries,
andveins.In general , theselung diseasessharea patternof lungdysfunction
that includesdiminishedlungvolumes,the reduced diffusingcapacityof the
lung, and varyingdegrees of hypoxemia.
Acuterespiratory distress syndrome (ARDS),first describedin 1967, is a
devastating syndromeof acutelunginjury. Initially calledthe adultrespiratory
distresssyndrome , it is now calledthe acute respiratorydistresssyndrome
because it also affectschildren.The disorder is the final commonpathway
throughwhich many·seriouslocalizedand systemicdisorders producedif-
fuseinjuryto the alveolar-capillarymembrane .
ARDSmayresult froma number of conditions,includingaspirationof gastric
contents, majortrauma(with or withoutfat emboli), sepsissecondaryto pul-
monaryor nonpulmonaryinfections,acutepancreatitis , hematologicdisorders ,
metabolicevents,and reactionsto drugsand toxins. Pathogenesisof ARDS
includeactivationof neutrophi ls anddecreasesurfactantactivity. Neutrophil s
cansynthesize andreleas e products thatarecapable of tissueinjury, including
proteolyticenzymes , toxicoxygenspecies,andphospholipid products.
 518 I Part 2 Pathophysiology
of organsand systems

Lackof Surfactant. It is pointedout thatthesubstance surfactantis secreted

by specialalveolarepithelialcellsintofluid that linesthealveoli2- to 10- folds,
which playsa majorrolein preventing alveolarcollapse.However , in a number
of conditions , suchas in respiratory distresssyndrome, synthesis andsecretion
of surfactantdecrease. Forexample,in newbornprematu re babies,the quantity
of surfactant secretedbythealveoliis greatlydepressed. Asa result,thesurface
tensionof thealveolarfluid is increased so muchthatit causesa serioustendency
for thelungsof thesebabiesto collapseor become filledwithfluid,manyof these
infantsdieof suffocat ion as increasingportionof thelungbecomes atelectatic.
Althougha numberof conditionsmay lead to ARDS, they all produce
similarpathologiclungchangesthat includediffuseepithelialcell injurywith
increasedpermeabilityof the alveolar-capillary membrane.The increased
permeabilitypermitsfluid, protein,and bloodcells to moveout of the vas-
cularcompartmentinto the interstitiumandalveoliof the lung.Theresultant
pulmonaryedemaleadsto intrapulmonaryshuntingof blood,impairedgas
exchange , and profoundhypoxia.Gasexchangeis further compromisedby
alveolarcollapseresultingfrom abnormalities in surfactantproduction.Asthe
diseaseprogresses , the work of breathingbecomesgreatlyincreasedas the
lung stiffensandbecomesmoredifficultto inflate.Wheninjuryto the alveolar
epitheliumis severe,disorganized epithelialrepairmayleadto fibrosis.
Clinically,the syndromeconsistsof progressiverespiratorydistress,an
increasein the respiratoryrate,andsignsof respiratoryfailure.
Asphyxia is a sharplydevelopingexternalrespiratoryfailure, whichreach-
esthe stagewhenthe alveolarair losescontactwith atmosphericoAe·andgas
exchangebetweenthe alveoliandblooddramaticallyceases.
Asphyxiamayresultfromtheobstructionof theupperairwaysor largebron-
chi dueto compression fromtheoutside,inhalationof foreignbodies,edemaof
mucosa,fibrinogenous exudates withth.eformationof membranes in diphtheria,
mechanical traumaof the neck,bleedingwith clotformation , aspirationof food
in caseof disordersof esophagus motility,CNSinjury,alcoholicintoxication etc.
Thedevelopment of clinicalpresentations of asphyxiamaybe dividedinto
severalstages.
Thefirststageis characterized by markedinspiratory dyspnea . Thehigh
tonus of the respiratorycenter,causedby increasinghypercapnia , resultin
Pathophysiologyof cardiovascularand respiratory system Unit 6 I 519
increasingstrengthof respiratorymusclescontraction.However, anobstacle
in airwayspreventsair from quicklyfilling thelungsandexpanding them. The
time of Hering-Breuer 's reflex(reactionto expansionof lung parenchyma )
increasesandinspirationbecomeslonger.Stenoticrespiration , characterized
by tenseandprolongedinhalati on, develops.
Thesecondstageis characterized by prolongationand reinforcementof
exhalationanddevelopment of expiratory dyspnea . Theobstaclein airways
preventingcompleteexhalationleadsto delayof air in the lungs and their
blowing.Thealveolibecomemoreand moreexpandedand time neededfor
achievingthe criticalpoint.
Thethirdstageis characterized by the stop of breathing,which leadsto
the deathof the patient.

Nonrespiratory functions of the lung s

Besidesthe main respiratoryfunction, the lungstakepart in metabolicand
regulatoryfunctions,whichnamednonrespiratoryfunctionsof the lungs.The
mostimportantnonrespiratory lungfunctionstherearethefollowing.
1. The lungs are the filter for biologicalactive substances , which are
haemodynamic regulatoryfactors. The lungsactivateangiotensin-1 and
inactivateserotonin,bradykinineand prostaglandins . Also the lungs
synthetizeheparin andtromboplastin.
2. Thelungscontainmacrophages, neutrophyles andproteolyticenzymes
inhibitors.In shock,there are disturbancesof biologicalactive sub-
stancesinactivation , heparindefficiency , tromboplastinabcenceand
activationof proteolyticenzymes. Thisconditionleadsto dessiminative
intravascularcoagulation syndromedevelopment.
3. Thelungsperformsurfactant synthesis (disturbance
- distress-syndrome).
4. Thelungsmaintainthetemperature bywatervaporization. In fever, there
maybehypohydration.
5. Alsothe lungsregulatetheacid-base balanceby CO2 exchanging. In case
of hypoventilation
, respiratoryacidosisis possible,in hyperventilation-
respiratoryalkalosis.
 r::iA-IH OFJHY SIOI_OG Y

Unit7 OF GASTRO INTESTINA L

A N O REN ,A L FLJ!\JC1 ION

Unit 27. Pathophysiologyof the

DigestiveSystem

In the gastrointestinal
(GI)system, whichis the boundarybetweenthe exter-
nalandthe internalenvironments, foodis preparedfor passage to the internal
environment.Nutrientsare propelledand mixedby the musculatureof the
GI tract and brokendown into smallerunits (digestion) that are absorbed
throughthe intestinaltract mucosa(absorption) into the lymph or portal
blood.Theabsorptionprocesstakesplaceby diffusion,carriertransport,or
endocytosis.
Digestion beginsin the mouth,wherethe largefood particlesare reduced
in size, mixedwith saliva, and convertedto a semifluidmass.Swallowing
transfersthe chewedfood to the esophagus.The.food passesthroughthe
esophagusto the stomach,whereit is mixedwith gastricjuiceandliquefied
bythe contractionsof the "distal"stomach.
Theliquefiedfood is nowcalledchymuswhichpassesthroughthe pyloric
sphincterinto the duodenum.Exocrinesecretionsof the intestinalcellsand
'
digestivejuicesfrom the pancreas andgall bladderareaddedto the intestinal
contentsin theduodenum.Bileproducedbythe liveraidsthe digestionof fats
aswell asthe removalof bilirubin,toxins,etc.Apartfrom this, the liver plays
a keyrolein the metabolismof carbohydrates, fats, proteins,andhormones .
Thepancreascontributesbicarbonate anddigestiveenzymes,besidesbeing
Pathophysiologyof gastrointestinal and renalfunction Unit 7 I 521
an importantendocrineorgan. A numberof gastrointestinal hormones that
contributeto the regulationof digestion are primarily producedin the upper
partof the smallintestine, the lowerstomach,and in the pancreas.Most of
the absorptionof the digestedfood,as well as of the fluids secretedby the
salivaryglands,the stomach,etc., takesplacein the smallintestine(duode-
num, jejunum, and ileum). In the largeintestine,final absorption of electro-
lytesand watertakesplace. Thecontentsof the end of the largeintestine,
feces, consistchieflyof unabsorbable vegetablematter, desquamated cells
and bacteria , and a minimumof water. Theyare storedin the rectum until
they arevoluntarilyeliminated(defecation).
In all partsof the gastrointestinal
tract highquantitiesof differentsecrets
areproduced , on whichdepended process of digestion (Table29).

Table29.Volume
andpHof secretsin differentparts of gastrointestinal
tract.
ii/
-~ ·:AI,1. ·. , ,
""•; ; . I
,,.,'?t'-i'
••'~,
jt-iif{4-
'-:
..
Dailyvolume·(ml) pH
-i ,, _ ~- ~ ...-

Saliva 1000 6.0-7.0

Gastric
secretion 1500 1.0-3.5
Pancreatic
secretion 1000 8.0-8.3
Bile 1000 7.8
Smallintestinesecretion 1800 7.5-8.0
Brunner's
glandsecretion 200 8.0-8.9
Largeintestinal
secretion 200 7.5-8.0
Total
: 6700

Gastro intestinal system regu lation

Theregulationof the gastrointest
inalsystemdepends on the autonomic ner-
voussystemandlocal factorsof regulation.
 s22 I Part 2 Pathophysiologyof organsand systems

Theautonomicnervoussystemstimulates(parasympathetic) andinhibits
(sympathetic) secretionandmotilityin all partsof thegastrointestinal
system.
Gastrointestinal hormonesregulatesomepartsof the gastrointestinal sys-
tem.
Gastrointestinal hormonesare peptidessecretedby the gastrointestinal
mucosa,and controllingall gastrointestinal functionstogetherwith other
hormonesandtransmitters.As an example,insulinworkstogetherwith ace-
tylcholineand parasympathomimetics to stimulatesecretionand motility,
whereascatecholamines, sympatomimetics and parasympatolytics, suchas
atropine,inhibitgastrointestinalsecretionandmotility.
Peptidehormonefamiliesare groups of regulatorypeptidesthat ex-
hibit sequencehomology(theypossessa commonaminoacid sequence).
Thegastrin-familyandthe secretin-glucagon familyarethe most impor-
tant.
Thegastrinfamilyconsistsof gastrinandcholecystokinin (CCK)in three
different forms. Gastrinand CCKreleasepancreaticglucagonfrom the islet
cells.Therearetwo majorforms of gastrinin the plasma,normalgastrinor
G-17and big gastrinor G-34.Theyare 17 and34 aminoacid polypeptides,
respectively . Gastrinis producedby G-cellsof the gastricantrumandduode-
num.TheduodenalBrunnerglandssecretehalfof the G-34.
Gastrinis the strongeststimulatorof gastricacid secretionand motility.
Gastrinalsoimposestropic(growth-stimulating) actionson the parietalcells,
the mucosaof thesmallandlargeintestineandpossiblythe pancreas . Gastrin
stimulatesthe pepsinsecretionfrom pepticcells,andthe glucagonsecretion
from the a-cellsof the pancreaticislets. Whenstimulatinggastricacidity,
gastrinrelaxesthe gastricmuscles,thus retardingthe,passageof chymeinto
the duodenum.
Cholecystokinin, CCK,accordingto its functionandstructure,belongsto
the gastrinfamily.Cholecystokini_n emptiesthe gall bladderasthe nameim-
plies,and stimulatespancreaticsecretionof an enzymerich juice.However,
CCKhasa higheraffinityfor receptorsstimulatinggallbladder contractionand
pancreaticenzymesecretion.CCKhasa maximaleffectonly in the presence
of secretin(potentiation)and normalvagalinfluence.Bothgastrinand CCK
releaseglucagonfrom thea-cellsof the pancreaticislets.Themostimportant
 Pathophysiologyof gastrointestinaland renalfunction Unit 7 1523

stimulusfor CCKliberationis aminoacidsandfatty acids, which reachthe

duodenalmucosa. Bileis ejectedintothe duodenum,wherefat is emulgated
to easeits absorption.CCKalso acts as an enterogastrone - an intestinal
hormonethat inhibitsgastricactivityandemptying . Thisleavesmoretimefor
the bileto emulgatefat.
Thesecretin•g/ucagon family. Secretinexhibitssequence homologywith
pancreaticglucagon, vasoactiveintestinalpeptide(VIP),growth hormone-
releasinghormone(GHRH)andgastricinhibitorypolypeptide(GIP).Secretin
is secretedby S-cellsin the mucosaof the uppersmallintestine,when acid
chyme(pH below4.5) arrivesto the first part of the duodenum . Fattyacids
from fat digestionalsocontributeto secretinrelease .
Secretinstimulatesthe secretion of bicarbonateand water by pancre-
atic duct cells, and of bicarbonate -rich aqueousbile. Secretinpotentiates
· the action of CCKincludingan enterogastroneeffect (gastric inhibiting
effect). Secretinantagonisesgastrin- and potentiatesCCK.Secretinis an
enterogastrone that is releasedby H· to stimulatepancreaticjuice secre-
tion.
Gastricinhibitory polypept ide (GIPor Glucose-dependent insulin releas-
ing peptide)works as the two namesimply:GIPinhibitsthe gastricmucosa
andreleases insulinfromthe a·cellsof the pancreaticislets.
G/ucagon is actuallytwo differentmolecules:Intestinalglucagon(glicen-
tin) andpancreaticglucagon.Bothare hepaticinsulin-antagonists. Glucagon
stimulateglycogenolysis, gluconeogenesis , andketogenesis.

The function of some other most import a nt gastro -

intestinal hormones th e re ar e:

• Ouokrinin- stimulatesduodenalsecretion.
• Endogenous (enkephalins) andexogenous opiates- inhibitganglion-
arytransmission.
• Enterokrinin
- stimulatessecretionin thesmallintestine.
• Gastrinreleasingpeptide(GRP)andbombesin - releasegastrinfrom
G-cells.
524 I Part 2 Pathophysiologyof organsand systems

• Glicentin(intestinalglucagon)- stimulatesinsulinsecretio n as other

incretins.
• Motilin - stimulatesgastrointest inalmotility
• Neuropeptide Y andneurotensin - stimulateneurotransm ission.
• PancreaticPolypep tide (PP) from the PP-cells- inhibits pancreatic
and biliary secretion , which delaysthe absorptionof nutrients. PP is
releasedby meals.
• Pancreotonin- inhibitsthe pancreaticexocrinesecretion .
• Somatostatin (Growth hormone-inh ibiting hormone, GHIH) - is a
strong,universalinhibitor- both blood-bornandparacrine.
• SubstanceP (11aminoacidresidues)- stimulatessmoothmusclecon-
traction andthusthe gastrointestinalmotility.
• Vasoactive intestin al peptide(VIP; vesselwall andbrainneurons)- is
a vasodilatatorin linewith adenosine , ATP, andNO.Theincreasedblood
flow increasesintestinalsecretion.
• Villikrinin - stimulatesthe rhythmic movementof villi in the intes-
tine.
• Nitric oxide(NO)- is a possibleneurotransmitter betweenthe pregan-
glionicandthe NANCpostgangl ionic neurons .

All regulatorypeptidesworking togetherfor the regulationof functions

of differentparts of the gastrointestinaltract. For example, in the stom-
ach gastrin leadsto the strongeststimulationof gastric acid secretionand
motility.Whengastricacid,fats, andhyperosmolarsolutionshaveentered
and distendedthe duodenum , GIP and other enterogastrones (somatosta-
tin, CCK,andsecretin) are releasedandsuppressgastricacid secretionand
motility of the stomachandincreasesecretionandmotilityin the duodenum
(Fig. 54.)
Conceptof insufficiency of ~igestion.The main function of digestion
is supplying of the organismby main food stuffs , water, salts through
olygomers disintegrationand monomersabsorption. Disordersof this main
function-insufficiencyof digestion-malnutrition.
Pathophysiologyof gastrointestinaland renal function Unit 7 Is2s

Food

i
motillity Instomach Gastrin
secretion Stomach secretion

t
Enterogastron
i i
t Seoretln
secretion
Duodenum Instomach motillity
secretion

i i
t motilllty InDuodenum
secretion

Fig. 54. Gastrointestinal

hormons
in regulation
ofgastric
secretion
andmotility

Cl a ss ific at ion :

1) primarymalnutrition- missingfrom the diet of one or all of the main

components;
2) secondary malnutrition- thesupplyof nutrientsis adequate,
but malnu-
trition mayresultfrom nutrientmalabsorbtion, impairednutrientuseor
storage,excessnutrientloss,or increasedneedtor nutrients

Etiology:

1) inheritance;
2) dietproblems;
3) infections;
4) disturbancesof neuralandhumoralregulation.
 5261 Part 2 Pathophysiologyof organsand systems

Appetite disorders
Anorexianervosais self-inducedstarvation,resultingin markedweightloss.
Theclinicalsymptomsof anorexianervosais similarto thosein typicalstar-
vation.In addition,effectson the endocrynesystemareprominent:amenor-
rhea,hypothyroidism. A majorcomplications of anorexianervosais cardiac
arrhythmiaandsuddendeath, resultingfrom hypokaliemia.
Bulimiais a conditionwhenpatientbingeson foodandtheninducesvom-
iting. Hugeamountof food, principallycarbohydrates, are ingested , only to
be followedby inducedvomiting.The majorcomplicationsare: electrolyte
imbalances(hypokaliemia) , pulmonaryaspirationsof gastriccontentsand
esophageal andcardiacrupture.Weightandgonadotropin levelsarenormal.
Vomitingor emesisis initiatedby the feelingof nausea,and an arrayof
sympathetic andparasympathetic responses.Sympathetic responses include
sweating,pallor,increasedrespirationandheartrateanddilatationof pupils.
Parasympathetic responsesinclude profusesalivation,pronouncedmotility
of the oesophagus, stomach,and duodenum , relaxationof the oesophageal
sphincters.Duodenalcontentscan be forcedinto the stomachby anti-peri-
stalsis. Duringthe expulsionof gastriccontents,the persontakesa deep
breath,the pylorusis closed,the glottis is closedso respirationstops,and
thestomachis squeezed between the diaphragmandtheabdominalmuscles,
causingrapid emptying.Vomitingis co-ordinatedby the vomitingcentrein
the medulla.
Vomitingis the meansby whichthe uppergastrointestinal tractridesitself
of its contentswhenalmostanypartof the uppertract becomesexcessively
irritated, over distended,or evenoverexcitable. Excessivedistentionor ir-
ritationof the duodenumprovidesan especiallystrongstimulusfor vomit-
ing. Impulsesare transmitted,both vagaland sympatheticafferentsto the
bi-lateralvomitingcentreof the Q7edulla, whichliesnearthetractussolitarius
at the level of dorsalmotornucleusof thevagus.Appropriateautomaticmo-
tor reactionsaretheninstitutedto causethe vomitingact.Themotorimpuls-
es that causethe actualvomitingare transmittedfrom the vomitingcentre
throughthe5th , 7th,91h,10th and12th cranialnervesto the uppergastrointestinal
tractandthroughthe spinalnervesto thediaphragmandabdominalmuscles.
 Pathophysiologyof gastrointestinaland renal function Unit 7 I s27
Salivaglandsdisorders . Theprincipalglandsof salivationarethe parotid,
submandi bular,andsublingualglands; in additionthereare manysmallbuc-
cal glands.Thedaily secretionof saliva normally rangesbetweenabout800
and1500 ml.
Salivacontainstwo majortypesof proteinsecretion:(1) a serous secretion
that containsptyalin(amylase),which is an enzymefor digestingstarches ,
and(2) mucoussecretionthat containsmucinfor lubricatingandfor surface
protectivepurpose. Theparotidglandsecreteis entirelyof the seroustype,
andthe submandibular and sublingualglandsecreteis both of the serous
typeandmucus.The buccalglandsecreteonlymucus.SalivahaspHbetween
6.0 and7.0,a favorablerangefor the digestiveactionof ptyalin.
Under basal conditions
, 0.5ml of saliva,almost entirely of the mucous
type,is secretedeachminuteall the time exceptduringsleep, whenthe se-
~ cretionbecomesvery little. This secretionplaysan exceedinglyimportant
rolein maintaininghealthyoraltissues.Themouthis loadedwith pathogenic
bacteriathat can easilydestroytissue and cause dental caries.

Saliva helps prevent the deteriorative processes in

several ways:

• theflow of salivaitselfhelpswashawaythe pathogenicbacteriaas well

asthefoodparticlesthat providetheir metabolicsupport;
• salivacontainsseveralfactors that destroybacteria;one of theseis
thiocyanateionsand anotheris severalproteolyticenzymes(the most
importantis lysozyme)that attackthe bacteria,aid thethiocyanat
e ions
in enteringthe bacteria, wherethey in turn becomebactericidal
, digest
food particles, thus helpingfurther to removethe bacterialmetabolic
support.
• salivaoftencontainsignificant amountsof proteinantibodiesthat de-
stroyoral bacteria, includingthosethatcausedentalcaries.

Therefore, in absenceof salivation

, theoral tissuesbecomesulceratedand
otherwiseinfected,andcariesof theteethbecomesrampant.
 5281 Part 2 Pathophysiology
of organsand systems

Hypersalivation is causedby parasympathetic activation,pregnansy toxi-

cosis.Consequences are:stomatitis,hypohydration.
Hyposalivation reasonsare:emotions,pain,feverandothercasesof sym-
patheticstimulations.Patientswith a rareautoimmune disorder(theSjogren
syndrome)sufferfrom dry mouth(xerostomia), dry eyes(xerophtalmia) and
rheumatoidarthritis.In patientslackingfunctionalsalivaryglands,xerosto-
mia,infectionsof the buccalmucosaanddentalcariesareprevalent.In most
casesof xerostomia theconditionis therapy-resistant
andunexplained. Some
casesarecausedby dehydration or by antidepressants.
Gastro-esophageal refluxdisease.Gastroesophageal refluxwithesopha-
gitis is causedby an incompleteclosureof the loweresophageal sphincter.
Gastriccontentswith acid reactionthen refluxinto the esophaguscausing
inflammation, erosionandbleeding.
This disorderis also calledrefluxesophagitis.It resultsfrom the regur-
gitationof gastriccontents(with HCIand pepsin)into the loweresophagus
causinglong lastingdamageof its mucosa.Thewall becomeshyperaemic,
andwhitepatchesareseenon the epithelium(leucoplakias). Thedysphagia
mostoftenpresentsas heartburn . As dysphagiaprogressit is likelythat an
oesophageal strictureis developing.If thesquamousepitheliumof the lower
oesophagus is replacedbycolumnarepithelium,asa response to longlasting
injury,thereis an increasedrisk of transformationof the epitheliuminto an
adenocarcinoma.

Stomach disorders
Functional stomachdisordersaredividedon hyper-andhyposecretion. Hep-
er-or hyposecretionstatesmayhaveprimaryor secondary origin.Secondary
statesfollowdifferentdiseasesof the stomach.
Hypersecretion.Reasonsof hypersecretion maybe:hyperacidic gastritis,
diet problems,somedrugs(insulin,corticosteroids), hightone of n. vagus
andsomeothers.In hyperacidicstatesthe followingconsequences develop
in the stomachandin intestine.In the stomach,thereincreasesecretionand
motility,whichleadsto pyloricstenosisandgastricacidregurgitation.In the
Pathophysiologyof gastrointestinaland renalfunction Unit 7 f s29

intestinethere is activatedsecretionof intestineand pancreaticjuice, bile

hypersecretion occurs,whichleadsto theincreaseof fooddigestionandcon-
stipationdevelopment (Fig.55).
Hyposecretion appearsdue to chronicatrophicgastritis,stomachcan-
cer,vitamin812 anemia , hypohydration.
In hypoacidicstates, consequences
alsodevelopment in the stomachand in the intestine. In the stomach,there
decreasesecretionand motility,which leadsto a long stay of food in the
stomachand bacterialfermentationof food. Forthis reason, fool-smelling
regurgitation,nauseaandvomitingas clinicalmanifestations develop.In the
intestine,theredecreasesecretionand bill production , which leadsto the
decrease of fooddigestionanddiarrheadevelopment (Fig.56).

Intheintestinum
ChaQgis

i
Hyperacldity Gastric
secretion
increasing

i i
Peristalsis
increasing Pancreas
activati
on

i i
Pyloricstenosis Bile hypersecretio
n

i i
Foodretention Increasing
offooddigestion

i
Gastric
acidregurgitation Peristalsis
inhibition

Constipation

Fig.55. Pathogenes
is ofhypersecre
tion
 530 I Part 2 Pathophysiologyof organsand systems

in.thestomach
Changes

i
Hyperacidity Gastric
secretion
decreasing

i
Peristalsis
decrease Pancreatic
Inhibition

i
Bileinhibition
Motilitydecrease

i Decrease
of fooddigestion
Bacte
rialfermention
of food

i
Full.-smelling
regurgitation, Diarrhea
nausea,vomiting

Fig.56. Pathoge
nesisofhypos
ecre
tion

Gastritis
Gastritismeansinflammation of the gastricmucosa.Mildto moderatechron-
ic gastritisis exceedingly
commonin populationasa whole,especiallyin the
lateryearsof adultlife.
Theinflammation of gastritis canbeonlysuperficialandthereforenotvery
harmful,or it canpenetratedeeplyintothegastricmucosaandin manylong-
standingcasescausealmostcompleteatrophyof gastricmucosa.In a few
cases,gastritiscan be acuteand severe,with ulcerativeexcoriationof the
stomachmucosaby thestomach'sownpepticsecretion.
Researchsuggeststhat muchgastritisis causedby chronicbacterialin-
fectionof the gastricmucosa.This oftencan be treatedsuccessfullyby an
intensiveregimenof an antibacter ial therapy.
Pathophysiologyof gastrointestinaland renalfunction Unit 7 I 531
In addition, certain ingestedirritant substancescan be damagingto the
protectivegastricmucosa barrier- that is to the mucousglandandthe tight
epithelialjunctionsbetweenthe gastriclining cells- oftenleading to severe
acuteor chronic gastritis. Twoof the mostcommonof thesesubstances are
alcoholandaspirin.
Gastritis occurs as at leasttwo typicalmanifestations: acute, erosivegas-
tritis andchronic,non-erosive gastritis.
Focalinflammatorylesionsof the mucosacharacter ise acute gastritis.
Sometimestheerosionsextendintothedeeperlayersof thewall (beyondthe
laminapropria) to form acuteulcers. Acute gastritisis producedby alcohol,
drugs(corticosteroids , ASAandNSAIDs)or infectionswith Helicobacterpy-
lori or virus.Afterseverestressthe gastritismaydevelopintoa life-threaten-
ing condition with stressulcersand haemorrhage . Thestressconditionsare
severeburns, trauma, shock, andsepsis.
Chronicgastritisis a long-lasting inflammationof the gastricwall.Thesu-
periiciallayersare infiltratedwith lymphocytesand plasmacells. Atrophia
developswith the loss of both parietaland chief cells. Helicobacterpylori
are the chief causeof chronicgastritisin the antrum.The loss of parietal
cellsleadsto achlorhydria(absentHCIproduction ), and to the deficiencyof
intrinsic factor.
Thegastricbarrierandits penetration in gastritis. Absorptionfrom the
stomachis normallyslight.This low levelof absorptionis mainlycausedby
two specificfeatures of the gastricmucosa: it is linedwith highlyresistant
mucouscellsthat secretea viscidandadherentmucusand it hastight junc-
tion betweenthe adjacentepithelialcells.Thesetwo togetherplusother im-
pedimentsto gastricabsorptionarecalled"gastricbarrier". This barriernor-
mallyis resistantto diffusionthateven the highlyconcentratedhydrogenions
of the gastricjuice, averagingabout100,000 timesthe concentration of the
hydrogenion in plasma,seldomdiffuseevento the slightestextentthrough
the lining mucusasfar astheepithelia l membrane itself. In gastritis,this bar-
rierpermeabilityis greatlyincreased.Thehydrogenionsdothediffuseintothe
stomachepithelium, creatingadditionalhavocandleadingto a viciouscycleof
progressive stomach mucosa!damageandatrophy.It alsomakesthemucosa
susceptible to pepticdigestion, thus frequentlyresultingin gastric ulcer.
 5321 Part 2 Pathophysiologyof organsand systems

Gastricatrophy . In manypeoplewho havechronicgastritis, the mucosa

graduallybecomesatrophicuntillittleor no gastricglandactivityremains. It is
alsobelieved thatsomepeopledevelopautoimmunity againstthegastricmuco-
sa, thisalsoleadingeventually to gastricatrophy.Thelossof stomachsecretion
in gastricatrophyleadsto achlorhydria andoccasionally pernicious anemia.
Achlorhydria (andhypochlorhydria). Achlorhydriameanssimplythat the
stomachfails to secretehydrochloricacidand its is diagnosewhenthe pH
of thegastricsecretionfailsto decrease below6.5aftermaximalstimulation.
Hypochlorhydria meansdiminishedacidsecretion.Whenacidis not secreted,
pepsinalsousuallyis notsecreted;evenwhenit is, thelackof acidpreventsit
from functioningbecausepepsinrequiresanacidmediumfor activity.
Althoughachlorhyd ria is associated withdepressed or evenno digestiveca-
pabilitybythestomach,theoveralldigestionoffoodin theentiregastrointest inal
tractis still almostnormal.Thisis because trypsin anQotherenzymesecreted
bythepancreas arecapableof digestingvirtuallyauthe proteinin thediet.
Perniciousanemiain gastricatrophy . Pernicious anemiais a commonac-
companiment of achlorhydriaandgastricatrophy . Thenormalgastricsecretion
containsglycoproteincalledthe intrinsicfactor, whichis secretedby thesame
parietalcellsthatsecretes thehydrochloric acid; intrinsicfactormust bepresent
for adequate absorptionof vitamin B12 fromthe ileum.Theinstrinsicfactoris
combined with vitaminB12 in thestomachandthereafter protectsit from being
digestedand destroyedas it passesthroughthe gastrointestina l tract.Then,
whentheintrinsicfactor-vitam in B12 complexreaches theterminalileum,thein-
trinsicfactorbindswithreceptors ontheilealepithelial surface
. Intheabsence of
theintrinsicfactor,onlyabout1/50of thevitaminB12 is absorbed. Therefore, an
adequate amountof vitaminB12 is notmadeavailabl ·efromthefoods.Asa result,
maturation failureoccurs in thebonemarrow , resultingin perniciousanemia .

Peptic ulcer disea se ,

Pepticulcers extendbeyondthe laminapropria,whereaserosions are super-
ficial.Pepticulcerdiseaseis a mucusalulcerin anacid-producingzonein the
distalstomachor the proximalduodenum.
Pathophysiologyof gastrointestinaland renalfunction Unit 7 f s33

Thenormalstomachproducesenoughmucusand alkalinejuice to protect

thegastricandduodenalmucosaagainstHCI.Themucinemoleculesswelland
form a non-stirredlayercoveringthe mucosa.In the duodenumthe pancreatic
bicarbonate createsa pH of 7.5 at the luminalmembraneof the mucosa.
Basiccauseof pepticulceration . The usualcauseof pepticulcerationis
an imbalancebetweenthe rateof the secretionof gastricjuiceandthe degree
of protectionaffordedby the gastroduodenal mucosa!barrieras well as the
neutralizationof the gastricacid by the duodenaljuices. It will be recalled
thatall areasnormallyexposedto gastricjuicearewell suppliedwith mucous
glands,beginningwith the compoundmucousglands of the loweresophagus
and includingthe mucouscell coatingof the stomachmucosa, the mucous
neckcellsof the gastricgland,the deeppyloric glandthat secretemainly mu-
cous, and, finally,theglandof Brunnerof the upperduodenum , whichsecrete
a highlyalkalinemucus.
In additionto themmucusprotectionof the mucosa,the duodenumis pro-
tectedby the alkalinityof the small intestinalsecretion.Especiallyimportant
is pancreaticsecretion,whichcontainsa largequantityof sodiumbicarbon-
atethat neutralizethe hydrochloricacid of the gastricjuice,thus inactivating
the pepsinto preventdigestionof the mucosa.In addition,largeamountsof
bicarbonateions are provided in the secretionsof the largeBrunner's glands
in the first few inchesof the duodenalwall and in the bile comingfrom liver.

Fina lly, two fe edback control m e ch a nisms e nsur e

that this neutr a lization of gastric juic e is c ompl e t e .

1. Whenexcessacid entersthe duodenum,it reflexlyinl1ibitsgastricse-

cretionand peristalsisin the stomach, both nervouslyand hormonally,
therebydecreasingthe rateof gastricemptying.
2. The presenceof acid in small intestineliberatessecretion from the in-
testinal mucosa,whichthenpassesby wayof the bloodto the pancreas
to promotethe rapid secretionof pancreaticjuice that containsa high
concentrationof sodiumbicarbonate , thus makingmoresodiumbicar-
bonateavailablefor neutralizationof the acid.
 Pathophysiology
of organsand systems
5341 Part 2

Therefore, a peptic ulcer can be caused in either of

two ways:

• excesssecretionof acidandpepsinby the gastricmucosa;

• diminishedability of the gastroduodenalmucosabarrier to protect
againstthe digestivepropertiesof the acid-pepsincomplex.

Bacterialinfection byHelicobacter Pylori.Epidemiological occurrence can

beexplained bythe prevalence of He/icobacter pyloriinfectionof the stomach
andthe colonisationof the terminalportionof gastricmucosaandinitialpor-
tionsof theduodenalmucosawiththis bacterium.Helicobacte r pyloriinfection
destroysthe protectivesystem,and at the sametime provokesexcessacid
secretion. Oncethis infectionbegins, it can last for a last time unlessit is
eradicatedbyantibacterial therapy.Furthermore, thebacteriais capableof pen-
etratingthe mucosa!barrierbothby virtueof its physicalcapabilityto burrow
throughthe barrierandby releasingdigestiveenzymes that liquefythe barrier.
Asa result,thestrongacidicdigestivejuicesof thestomachsecretioncanpen-
etrateintothe underlyingepitheliumandliterallydigestthe epithelialcells- in
fact,in severecases,eventhe sublyingtissues.Thisleadsto pepticulceration.
An increased secretionof acid-pepticjuicescancontributeto ulceration.In
mostpeoplewho havepepticulcerin the initial portionof the duodenum,the
rateof gastricacid secretionis greaterthan normal,sometimesas muchas
twice normal.Althoughpartof this increasedsecretionmaybestimulatedby
the bacterialinfection,experiments in animals,plusevidenceof excessneural
stimulationof gastricacidsecretionin humanbeingwith pepticulcersuggest
thatanexcesssecretionof gastricjuicesfor anyreasoo( for instance,in psy-
chicdisturbances) is oftena primarycauseof pepticulcer.
In additionto bacterialinfection,an excesssecretionof gastricjuices,oth-
er factorsthat predisposeto ulcersinclude:smoking,presumablybecause
of increasednervousstimulation 'of the stomachsecretoryglands;alcohol,
becauseit tendsto breakdown the mucosalbarrier;andaspirin,whichalsoas
a strongpropensityfor breakingdownthis barrier.
Riskfactorsfor pepticulcer diseaseare drugs (ASA,NSAIDsand corti-
coids),hyperparathyroidism (the high Ca2+ levelstimulatesgastricacid se-
Pathophysiologyof gastrointestinal and renalfunction Unit 7 f 535

cretion),and gastrin-producing tumoursof the pancreas(Zollinger-Ellisons

syndrome).Othercontributingfactors are increasedpepsinogenfrom the
chiefcells,increasedparietalcell mass,reducedsomatostatinsecretionfrom
the antralD cells,anddamageof the mucosa.Acetylsalicylicacidand other
non-steroidanti-inflammatorydrugsdepletethe gastric mucosafor prosta-
glandins,which leadsto mucosa!damage.Strongalcoholicbeveragesalso
damagethe gastric mucosa!barrierand stimulateacid secretion. Caffeine
stimulatesgastricacidsecretion.
Geneticfactorsmust be considered , since personswho do not secrete
bloodgroupOantigenintothe salivaandgastricjuice,havean increasedrisk
of developingduodenalulcers.
Bleedingfrom ulcerscanbefatal.Uppergastrointestinal tract bleedingim-
pliesa significantloss of bloodinto the lumenof the foregut.Haemateme-
sis and melaenademonstratesucha bleeding.Haematemesis is definedas
vomitingof whole bloodor blood clots. Me/aenais definedas passageof
darktarry stools (coal-black, shiny, sticky, andfoul smelling).
Pathophysiology background of treatment.Sincediscoveryof the infec-
tious basisfor much if not most of pepticulceration , therapyhas changed
immensely.Initial reportsare that almostall patientswith pepticulceration
can be treatedeffectivelyby two measures : the useof antibioticandthe ad-
ministration of an acid-suppressant drug (Fig.57).

The therapeutic strategies which are used in the

treatment of peptic ulcer disease include:

1. Eradication of Helicobacterpylori with antibioticsis the treatmentof

choicefor mostcasesof pepticulcerdisease , sinceit seemsto curethe
patient.Clarithromycinis a macrolidethat bindsto andpreventstrans-
locationon Helicobacter pylori- ribosomes , whichis an effectivebasic
therapyof pepticulcers.
2. HistamineactsthroughH2 receptorson the basolateral membraneof the
parietalcells.Thesecondmessengerfor histamineis cAMP.All other
cellscontain H1 receptors.Accordingly, H2 receptorantagonists(cimeti-
 5361 Part 2 Pathophysiology
of organsand systems

Vagus

t
Gastrocepin
Ml-R ACH
Omeprasote
~ tJJ
Atro
pin

ACH t ~CH-R
!~:~f:1i-
G-R . :"
G-cell
H2-R )I,

gastrin
Parietal
cell
Ranitidin
Famotidin

Mastcell

Fig.57.Reg
ulation of parietal cellhypersecretion

dine,ranitidine,famotidine,andnizatidine)inhibitacid secretionbecause
theyfit the H2 receptorsspecifica lly. TheH2 receptorantagonists
prevent
histaminefrom bindingto theH2 receptorsonthebasolateral membrane
of the parietal cells,thus reducinggastricacidsecretionby 70-80 %.
3. Inhibitionof the gastricprotonpumpin the luminalmembraneof the
parietalcells. Omeprazole is a protonpump inhibitor, which relieves
symptomsandcuresmostduodenalulcerswithinfour weeks- oftenin
combinat ion with antibiotics.Omeprazoleandsimilarantagonists to the
gastricprotonpumpare especiallyeffectivein the treatmentof persis-
tent HCl-secretion causedbytheZollinger-Ellisonsyndrome .

All treatmentprocedures,whichwork by inhibitionof gastricacid secre-

tion, havea commondrawback:To the extentthat gastric acidsecretionis
reducedthereis no inhibitionof the gastrinreleasefrom the antralG cells.
Accordingly , the bloodgastrinincreases
, andduringtreatmentof the patients
this concentrationis constantlyincreased.The high gastrinlevelcounter-
actsthe expectedeffecton the acid production.Sincegastrinis a trophical
 Pathophysiologyof gastrointestinaland renalfunction Unit 7 1537

hormonefor the gastricmucosa , long-termtreatmentwith acidsuppression

might result in mucosa!hypertrophywith a further rise in acid production
andin cellularmodifications.Thesecomplicationsare probablyrelatedto the
ratherhigh ulcer recurrencerate of most treatmentprocedures.Obviously,
the only rationalstrategyis to eliminatethe causeof the pepticulcerdisease.
Futurestrategiesincludefindingandinvestigationof gastrininhibitiondrugs.

Pancreas disorders
Pancreatic secretioncontainsenzymesfor digesting all threemajortypesof
food: proteins,carbohydrates, and fats. It also containslargequantitiesof
bicarbonate ions, whichplayan importantrolein neutralizingthe acidchyme
_ emptiedby the stomach into the duodenum .
Themoreimportantof the proteolyticenzymesare trypsin, chymotrypsin.
andcarboxypolypeotidase . Lessimportantareseveralelastases andnucleas-
es.Byfar the mostabundantof theseis trypsin.Thetrypsinandchymotryp-
sin split wholeand partiallydigestedproteinsinto peptidesof varioussizes
but do not causethe releaseof individualaminoacids.Carboxypolypeptidase
splitssomepeptidesinto individualaminoacids,thus completingthe diges-
tion of muchof the proteinsall the wayto the aminoacidsstate.
The pancreaticdigestiveenzymefor carbohydrates is pancreaticamylase,
which hydrolyzestarches,glycogen,and most othercarbohydrates(except
cellulose)to form disacchar idesanda fewtrisaccharides .
Themainenzymesfor fat digestionarepancreaticlipase,which is capable
of hydrolyzingneutralfat intofatty acidsandmonoglycerides: cholesteroles-
terase,whichcausehydrolysisof the cholesterolesters;andphospholipase ,
whichsplit fatty acidsfrom phospholip ids.
Whensynthesizedin the pancreaticcells,the proteolyticenzymesare in
the inactiveforms of trypsinogen,chymotrypsinogen, and procarboxypoly-
peptidase , whichare all enzymatically inactive.They becomeactivatedonly
aftertheyaresecretedinto the intestinaltract.Trypsinogenis activatedby an
enzymecalledenterokinase , whichis secretedbythe intestinalmucosawhen
chymecomesin contactwiththe mucosa.Also, trypsinogencanbeautocata-
 5381 Part 2 Pathophysiologyof organs and systems

lyticallyactivatedby trypsinthat hasalreadybeenformedfrom trypsinogen.

Chymotrypsinogen is activatedby trypsinto form chymotrypsin, andprocar-
boxypolypeptidase is activatedin similar manner.
It is importantthat the proteolytic enzymesof the pancreaticjuice not be-
comeactivateduntil they havebeensecretedinto the intestinebecausethe
trypsinand otherenzymeswoulddigestthe pancreasitself. Thesamecells
that secretethe proteolyticenzymesinto the acini of the pancreassecrete
simultaneouslyanothersubstancecalled trypsin inhibitors. This substance
is stored in the cytoplasmof the glandularcells that surround the enzyme
granules , and it preventsactivationof trypsin both insidethe secretorycell
and in theaciniandductsof the pancreas.Becauseit is trypsinthatactivates
the otherpancreaticproteolyticenzymes , trypsin inhibitor preventsthe sub-
sequent activationof theothersaswell.Whenthe pancreasbecomesseverely
damagedor when a duct becomesblocked, large quantitie s of pancreatic
secretionbecomepooledin the damagedareasof the pancreas.Underthere
conditions.theeffectof trypsininhibitoris sometimesoverwhelmed, in which
casethe pancreaticsecretionrapidlybecomeactivatedandliterallydigestthe
entire pancreaswithin a few hours, givingrise to the condition calledacute
pancreatitis.This oftenis lethalbecauseof accompanying shock;evenif not
lethal, it usuallyleadsto a lifetimeof pancreaticinsufficiency.

Diso rders of secr etory funct ions of pancrea s

Pancreatic hyposecretion or pancreaticexocrineinsufficiencymayoccurs as
a resultof long-standingobstructionof the pancrea _tic duct, actionof toxins,
severeacutepancreatitisandfollowednecrosis(fibrosis).Secondarycases
of pancreaticexocrineinsufficiencymaybe inducedby gastrichyposecretion
and bile evacuationproblems.The main clinical manifestationsare malab-
sorbtion, steatorrhea(non digestivefats in the faces),amylorrhea(non di-
gestivecarbohydrates in the faces), creatorrhea(nondigestivemusclefibers
and proteinsin the faces). Weight loss and hypoalbuminemic edemafrom
malabsorbtionmay point towardthe condition.In seriouscasespancreatic
failuredevelopment.
Pathophysiologyof gastrointestinaland renal function Unit 7 1539

Pancreatitis. Pancreatitis
meanstheinflammation of thepancreasandthis
canoccurin theform of eitheracutepancreatitisor chronicpancreatitis.The
mostcommoncauseof pancreatitis is alcoholandthe secondmostcommon
causeis the blockageof papillaof Vaterby a gallstone; the two togetherac-
countfor morethan90 % of all cases.

Pathogen etic va ria nt s of pa nc rea tit is de v e lo pm en t

m a y be the following :

1. Pancreatic duct obstruction(cholelithiasis

, ampullaryobstruction,duc-
tal concretions).Obstructionleadsto edemaandischemia,whichcause
acinalcellsinjuryandactivationof pancreatic enzymes .
2. Acinalcellinjury(alcohol,drugs, trauma,viruses).Directinjuryreleases
intracellularproteolyticenzymesandinitiatesinflammation andedema.
3. Defectiveintracellulartransport(duct obstruction.alcohol).It leadsto
the intracellular
activationof enzymesandpancreatic cellsinjury.

Morecommonmechanism beginsfromtheactivation of pancreaticenzymes .

Thepancreatic enzymes aredammed upintheductandacini of pancreas . Eventu-
ally, somuchtrypsinogen accumulate thatit overcomes thetrypsininhibitor in the
secretionsanda small quantity of trypsinogenbecome is activatedto formtrypsin.
Oncethis happens , thetrypsinactivates still moretrypsinogen aswellas chymo-
trypsinogenandcarboxypolypeptidase , resultinginaviciouscycleuntilthemostof
theproteolyticenzyme in thepancreatic ductandacinibecome activated.Thisen-
zymesrapidlydigestlargeportionof thepancreas of itself, sometimescompletely
andpermanently destroying theabilityofthepancreas to secretdigestive enzymes.
Theprocess maybecome sosevere thatit leadsto deathwithindaysof evenhours.

Malabsorbtion syndrome
Malabsorbtion is a defeGt
iveabsorbtionof fats, vitamins,proteins, carbohy-
drates,electrolytes,mineralsandwater.
 540 I Part 2 Pathophysiology of organsand systems

Malabsorbtion is a result of disturbance of at least

one of these normal digestive functions:

1) intraluminal digestion(pancreaticinsufficiency, Zollinger-E

llison syn-
drome, resectionsof intestine;)
2) terminal digestion (enzymesdefficiency
, disbacteriosis);
3) transepithelial
transport (abetalipoproteinemia
, bileacidmalabsorbtion).

Occasionally, nutrientsare not adequately absorbedfrom the small intes-

tine eventhoughthe food is well digested. Severaldiseasescancausea de-
creasedabsorptionby the mucosa ; they are oftenclassifiedtogether under
the generalheadingof "sprue" . Malabsorption also can occur when large
portionsof the smallintestine havebeenremoved.
Non-tropical sprue. Onetype of spruecalledvariouslyidiopathicsprue,
celiacdisease (in children) and glutenenteropathy, resultsfrom the toxic ef-
fectsof glutenpresentin r.ertaintypesof grain, especially wheatandrye. Only
somepeoplesusceptibleto this effect but in this people, gluten hasa direct
destructiveeffectin the intestinalenterocytesor perhapsas the resultof an
immunological or allergicreaction.In milderforms of the disease , the micro-
villi of theabsorbingenterocytes of thevilli aredestroyed , thusdecreas ing the
absorptivesurfaceareaas muchas two fold. In the moresevereforms, the
villi themselvesbecomebluntedor disappea r altogether, thusstill furtherre-
ducingthe absorptiveareaof the gut.Theremovalof the wheatand ryeflour
from the dietfrequentlyresults in a miraculouscurewithinweeks, especially
in childrenwith this disease .
Tropicalsprue.A differenttype of spruecalledtropicalspruefrequently
occursin the tropic andcan oftenbe treatedwith antibacterialagents. Even
thoughno specificbacteriumhasbeenimplicatedasthe cause,it is believed
thatthis varietyof sprueis usuallycausedby the inflammationof the intesti-
nal mucosaresultingfrom an unidentifiedinfectious agents.
Malabsorption in sprue.In the earlystagesof sprue,the absorptionof
fats is more impairedthan the absorptionof other digestiveproducts. The
fat that appearsin the stools is almostentirelyin the form of salts of fatty
acids rather than undigestedneutralfats, demonstrating that the problemis
Pathophysiologyof gastrointestinal and renalfunction Unit 7 I 541
oneof absorptionand not of digestion.In this stageof sprue,the condition
is frequentlycalledidiopathicsteatorrhea
, whichmeanssimplyexcessfats in
thestoolsas a result of unknowncauses.
In moreseverecasesof sprue, the absorptionof proteins,carbohydrates,
calcium,Vitamin K,folicacidandVitamin B12 aswellasmanyotherimportant
substances becomegreatlyimpaired.

As a result , th e pe rson suff e rs :

1) severenutritionaldeficiency
, oftendevelopinga severeweightloss of
the body;
2) osteomalacia (demineralization
of thebonesbecauseof lackof calcium);
3) inadequate bloodcoagulation causedby lackof VitaminK
4) macrocyticanemiaof the perniciousanemiatype, becausediminished
Vitamin812 andfolic acidabsorption.

Theconsequences of malabsorbtion affectmanyorgansystem:diarrhea ,

flatus, abdominalpain, weightloss, vitaminsdefficiency;anemia ; osteopenia
,
tetanus;amenorrhea, infertility;purpura,petechiae; peripheralneuropathy.
Themostwell-knownmalabsorbtive diseasesareceliacdiseaseanddisac-
charidase defficiency
.
Celiacdisease(celiacsprue, gluten-sensit ive enteropathy)is a chronic
disease,in whichthereis a characteristic mucosa!lesionof the smallintes-
tine and impairednutrientabsorbtion , whichimproveson the withdrawalof
wheatgliadins and relatedgrainproteinsfrom the diet. Thehallmarkof this
diseaseis a T-cellmediatedchronicautoimmune inflammation. Inflammation
leads to diffuseenteritisandvilli atrophy.Theclassicsymptomsare:diarrhea ,
flatulence, weightloss,andfatigue.
Oisaccharidase defticiency. Anincomplete breakdown of thedisaccharide
lactoseinto its monosacchar ideglucoseandgalactoseleadsto osmoticdiar-
rhea.Bacterialfermentation of the unabsorbed sugarsleadsto meteorism .
Disbacteriosis or bacterialovergrowt h syndromeis a saprophytemi-
crobesbalancedisturban ce. In normin largeintestinethereis a prevaluation
 542 I Part 2 Pathophysiologyof organsand systems

of anaerobicbacteria, byphido-andlactobacteria. In disbacteriosis

is typical
multiplying of pathogenicforms of bacteria and decreasing of saprophytes
amount.
The reasonsof disbacteriosis maybe: immunedefficiency, antibioticther-
apy, chronicpathologyof gastro-intestinal tract.
A moreimportantmechanism of localinflammatoryprocesses(enteritis)
develops.In decompensation , diarrhea, anemia, loss of weight, abdominal
painaretypical.
Diarrhea.Thisterm is usually usedfor an increasedstool frequencyand
impliesa largerthannormalstoolweight.Diarrhearesultsfrom rapidmove-
mentof fecalmatterto the largeintestine.

Diarrhea may have different origin:

1. Bacterial or secretorydiarrheais causedby an increasedCl· - secretion

and reduced Na• - reabsor ption.Enterotoxins from bacteriaon the mi-
crovillussurfaceaffectthe toxin receptors , whichincreasesthe cAMP
levelin the cell.This in turn activatesthe chloride-channeland inhibits
the NaClreabsorption process.
2. Inflammatorydiarrheais causedby mucosa!destructionwith the out-
flow of fluid andbloodsuchas in ulcerativecolitis.
3. Osmotic active substancesin the gut lumencauseosmoticdiarrhea.
Thesesubstancesare normalnutrientsin caseof malabsorption , or
non-absorbable substancestakenfor somereasonor other.
4. Diarrhea followingileal resection.Bile acidsare normallyreabsorbed
in the terminal ileum.Followingileal resectionthe bile acidsenterthe
colon. Bile acidsaretoxicto the colonicmucosaandstimulatecolonic
secretionof largevolumes.
5. Psychogen ic diarrhea.Everyone is familiarwiththediarrheathataccom-
paniesperiods of nervoustension, suchas duringexamination time or
whena soldier is aboutto go into battle. This type of diarrheacalled
psychogenic emotionaldiarrheacauseby excessivestimulation of the
parasympathet ic nervoussystem,whichgreatlyexcitesbothmotilityand
Pathophysiologyof gastrointestinaland renalfunction Unit 7 1543

secretionof mucousin the distalcolon.Thistwo effectsaddedtogether

cancausemarkeddiarrhea.

Severalcausesof diarrheawith importantpathophysiolagical mechanisms

arethe following.
Enteritis.Enteritis meansinfectioncausedby eithera virus or by bacteria
in the intestinaltract. In the usualinfectiousdiarrhea,the infectionis most
extensivein the entirelarge intestineandthe distal endof the ileum.Every-
wherethe infectionis present,the mucosabecomesextensivelyirritated,and
its rate of secretionbecomesgreatlyenhanced.In addition,the motility of
the intestinalwall usuallyincreasesmanyfolds.As a result, largequantities
of fluid aremadeavailablefor washingthe infectious agenttowardstheanus,
andat the sametime strongpropulsivemovementspropelthis fluid forward.
This is an importantmechanismfor riding the intestinaltract of the debili-
tating infections.Of specialinterestis the diarrheacausedby cholera(and
sometimesby otherbacteriasuchas somepathogenic colonbacilli).Cholera
toxin directlystimulatesexcessivesecretionof electrolytesandfluids in the
distal ileumandcolon.Theamountcan be 10-12 L per day, andthe colon
canusuallybe reabsorbed a maximumof only6 L perday.Thelossof water
andelectrolytesleadsto acid-basedisturbances. Therefore,the lossof fluids
and electrolytescan be so debilitatingwithina day or so that deathensues.
Therefore , themostimportantphysiological diseaseof therapyis replacefluid
andelectrolytesas rapidlyastheyarelost, mainlyby givingthe patientintra-
venoussalineandglucosesolution.
Ulcerative colitis.Ulcerativecolitis is a diseasein whichextensiveareas
of walls of the largeintestinebecomeinflamedand ulcerated.The motility
of ulceratedcolon is oftenso greatthat massmovementoccursmostof the
time,ratherthanthe usual10-30minsperday.Also, thecolonsecretionsare
greatlyenhanced.As a result,the patienthasrepeateddiarrhealbowelmove-
ments. The causeof ulcerativecolitis is unknown . Somecliniciansbelieve
that it resultsfrom an allergicor immune destructiveeffect, but it alsocould
resultfrom a chronic bacterialinfectionnot yet understood.Whateverthe
cause, there is a strong hereditary tendencyfor susceptibilityto ulcerative
colitis.Oncethe conditionhasprogressed veryfar, the ulcersareperpetuated
 Pathophysiologyof organsand systems
5441 Part 2

by superimposedbacterialinfectionand seldomwill healuntil ileostomyis

performedto allowthe intestinalcontentsto drainto the exteriorratherthan
to flow throughthecolon.Eventhenthe ulcerssometimesfail to heal, andthe
onlysolutionis removalof the entirecolon.
Constipation meansslowmovementof fecesthroughthe largeintestine;it
is oftenassociatedwith largequantitiesof dry, hardfecesin the descending
colonthat accumulates becauseof the longtime availablefor the absorption
of fluid. The etiologyof constipationincludes: dietaryproblems,intestine
abnormalities,hypovitaminoses, hypothyroidism , muscularhypotones , hy-
pohydration, fever,intestineobstructions,spinaltrauma.
Any pathologyof the intestinesthat obstructsmovementof the intestinal
contentssuchastumors,adhesionsthat constrictthe intestinesandulcers,
can causeconstipation.A frequentfunctionalcauseof constipationis ir-
regularbowel habitsthat havedevelopedthrough a lifetime of inhibition
of the normaldefecationreflexes.Infantsare seldomconstipatedbut part
of their training in the earlyyearsof life requiresthat they learnto control
defecation,andthis control is effectedby inhibiting the naturaldefecation
reflexes.Clinicalexperienceshowsthat if one fails to allow defecationto
occurwhenthe defecationreflexesare excitedor if oneoveruseslaxatives
to take the placeof the naturalbowelfunctions,the reflexesthemselves
becomeprogressivelyless strongover a periodof time and the colon be-
comesatonic.Forthis reasonsif a personestablishesregularbowelhabits
early in life, usually defecatingin the morning after breakfastwhen the
gastrocolicand duodenalcolicreflexescausemassmovementin the large
intestine,the developmentof constipationin the later life can generallybe
prevented.
Constipationcan also resultfrom spasmof a small segmentof the sig-
moidcolon.It shouldbe recalledthat the motility,evennormally,is weakin
the largeintestineso that evena slight degreeof spasmis oftencapableof
causingseriousconstipation. Afterthe constipationhascontinuedfor several
daysandexcessive feceshaveaccumulated abovethe spasticsigmoidcolon,
excessivecolonicsecretionsoftenleadto a dayor so of diarrhea . Afterthis,
the cyclebeginsagain,with repeatedboutsof alternatingconstipationand
diarrhea. ·
Pathophysiologyof gastrointestinal and renalfunction Unit 7 1545

Gastrointestinal Obstruction
Thegastrointestinal tractcanbeobstructedat anypointalongits cause, some
commoncausesof obstructionarecancer,fibroticconstrictionresultingfrom
ulcerationor from peritonealadhesions,spasmsor a segmentof the gut, or
paralysisof a segmentof the gut.
Theabnormalconsequences of obstructiondependonthe point in thegas-
trointestinaltract that becomesobstructed.If the obstructionoccursat the
pylorus,whichresultsoftenfrom fibroticconstrictionafterpepticulceration ,
persistentvomitingof stomachcontentsoccurs.Thisdepressesbodilynutri-
tion; it alsocausestheexcessive lossof hydrogenions fromthe bodyandcan
resultin variousdegressof alkalosis.
If the obstructionis beyondthe stomach,antiperistalticrefluxfrom the
smallintestine causesintestinal juicesto flow backwardinto the stomach,
and thesejuicesare vomitedalongwith the stomachsecretion.In this in-
stance,the personlooseslargeamountof waterandelectrolytes , so that he
becomesseverelydehydrated,but the loss of acidsand basesmaybeap-
proximatelyequal, so that little changein acid-basebalanceoccurs. If the
obstructionis nearthe lowerendof smallintestine,thenit is possibleto vomit
morebasicthanacidicsubstanc~s; in this case,acidosismayresult. In addi-
tion, thevomitus, aftera few daysof obstructionbecomesfecalin character.
Also importantin obstructionof the smallintestineis markeddistention
of the intestineproximalto the obstructedpoint. Large quantitiesof fluids
and electrolytescontinueto be secretedinto the lumen of small intestine;
evenlargeamountsof proteinsarelostfrom the bloodstream,partlyintothe
intestinelumenandpartlyinto the gut wall, whichbecomesedematous as a
resultof theexcessive distention . Theplasmavolumediminishesbecauseof
the proteinloss,andseverecirculatoryshockoftenensues.
If theobstructionis nearthe distalendof the largeintestine,fecescanac-
cumulatein thecolonfor severalweeks.Thepatientsdevelopan intensefeel-
ing of constipation, but in the first stagesof the obstructionvomiting is not
severe.Prolongedobstructionof the largeintestinewill finallycauserupture
of the intestineitself or dehydrat ion and circulatoryshockresultingfrom the
severevomiting.
 5461 Part 2 Pathophysiology
of organsand systems

Chapter 28. Pathophysiology

of HepatobiliaryFunction

Theli1.1eris the mostimportantglandularorganprovidingthe constancyof the

organism("a big chemicallaboratory " by Ludwing).In the organism , the liber
workstogetherwiththe bileproductionsystemandfor this reasontheyoften
usethe termthe hepatobiliary system(Fig.58).
Parenchyma of the liver is organizedinto platesof hepatocyteslying in
a cageof supportingcellstermedreticuloendothelial cells (REC). Individual
platesareseparatedfrom eachotherby vascularspacescalledsinusoids.It
is in these sinusoidsthat bloodfrom the hepaticarteryis mixedwith blood
from the portalveinon the wayto the centralvein.
TheREC,meshworkin whichthe hepatocytes reside,includesdiversecell
types:endothelialcells, specializedmacrophages termed Kupffercells an-
choredin the sinusoidspace; and lipocytes,which lie betweenthe hepato-
cytesandthe endothelialcells.

LeftHepatic
Duct

Liver Pancreas

Stom
ach
Gallbladder

CysticDuct

Pancre
aticDuct

Fig. 58.Hepatobil
iarysystem
Pathophysiologyof gastrointestinaland renalfunction Unit 7 1547

Approximately 30% of all cellsin the liverare REC , andaboutonethird of

theseareKupffer cells.
Hepatocytes platesare organizedaroundindividualcentralveinsto form
hexagons with portaltriads- a portalvenule,hepaticarteriole,andbilecana-
liculus.
Liverbloodsupply.The liver is uniqueamongthe abdominalorgansin
havinga dualbloodsupply- the hepaticarteryandthe portalvein.Approxi-
mately300ml of bloodperminuteenterstheliverthroughthe hepaticartery;
another1050 ml/minuteentersby way of the valvelessportalvein, which
carriesbloodfrom the stomach , the smallandthe largeintestines , the pan-
creas, andthe spleen.Alsoflowinginto the portalveinpriorto its entryinto
the liveris the pancreaticvenousdrainage , rich in pancreatichormones(in-
sulin, glucagon , somatostatinand pancreaticpolypeptide). Theportalveins
form a capillarybedthat allowsindividualhepatocytes to be batheddirectly
in portalblood dueto the liveris a primesitefor metastaticspreadof cancer,
especially from the GIT, breastandlung.
Capacity forregeneration . Whilethenormallivercontainsveryfewcellsin
mitosis,whenhepatocytes arelost,poorlyunderstood mechanisms stimulate
the proliferationof the remaininghepatocytes. After massivehepatocellular
death, if the patientsurvivesthe acuteperiodof hepatic dysfunctionusually
with medicaltherapy,recoverywill becomplete.Similarly,surgicalresection
of livertissueis followedby the proliferationof the remaininghepatocytes
dueto hyperplasia.

The liver is one of the most active org a ns in th e body

and has many functions:

1. Functionof detoxication
• thedetoxication of toxic productscomingfromthe gastrointestinaltract
andconvertstheminto substances essentialto the body;
• takepartin reactionsof decarboxilation
, oxidation, deamination;
• changesammoniaproducedby the deamination of aminoacidsto urea.
synthesisof creatinine;
 Pathophysiologyof organsand systems
5481 Part 2

• the destructionof somemicroorganisms, bacterial andothertoxins

2. Metabolicfunction
• proteinmetabolism(synthesisof proteins,albuminandclottingfactors)
• carbohydratemetabolism(synthesisof glycogenefrom monosacc ha-
rides;synthesisglucosefrom aminoacids,lacticacid,andglycerol;
• lipid metabolism(oxidationof fatty acids,theformation of acetoneand
ketonebodies;synthesisof lipoproteins).
3. Digestivefunction
• the creationof bilepigmentssynthesisof cholesterol, synthesisandse-
cretionof bile.
4. Storagefunction
• storageof glycogen;
• metabolismand storageof vitamins(A, B, K), the depositionof iron,
copper,zincions.
5. Regulatory function
• metabolismof hormones(degradation of glucocorticoids,aldosterone,
testosterone);
• depositionof plasmaof blood,the regulationof a totalamountof blood.
• hemopoiesis in thefetus.

Methods of experimental studying of liver

funct ions
Eee'sfistula.Tyingof v. portaebelowthe liverandmakingthefistulabetween
v.v. portaeandcavaleadsto changingof the circulation:bloodescapesthe
liveranddirectlycomesinthe bloodflow. Afterthat,·it thedietof experimental
animalcontainsplentyof proteins, the animaldiesfrom intoxication. If the
dietdoesn'tcontaina lot of proteins,·theanimalcanlive.
Reverse fee's fistula.If weHeanimal'sv.cavainferior,bloodflow will come
throughv. portae.Gradually,portocavalanastomoses developmentoccurs
andliverextirpationbecomespossible.Justafterthis extirpationthe animal
dyesat first from hypoglycemia, thenfrom a severehemorrhage syndrome
andonlyafterthat from intoxication.
 Pathophysiologyof gastrointestinaland renalfunction Unit 7 1549

Bile production and bilirubin elimination

Thesecretion of bile is essentialfor digestionof dietaryfatsandabsorptionof
fatsandfat-solublevitaminsfrom the intestine.
The liver producesapproximately600 to 1200 mL of yellow-greenbile
daily. Bilecontainswater,bile salts, bilirubin, cholesterol , and certainprod-
uctsof organicmetabolism . Ofthese, onlybile salts,whichareformedfrom
cholesterol , areimportantin digestion .
Bilirubinis the substance that givesbileits color. It is formedfrom senes-
centred bloodcells.In the processof degradation the hemoglobinfrom the
redbloodcellis brokendownto form biliverdin,whichis rapidlyconvertedto
free(unconjugated)bilirubin.Thelevelof unconjugated bilirubindependson
theintensityof hemolysisof erythrocytes . Freebilirubin, whichis insolublein
_ plasma,transportedin the bloodattachedto plasmaalbumin.Freebilirubinis
toxicand isn't filteredin the glomeruliof the kidneysand is absentin urine,
evenif i's levelexceedsthe norm.
Hepatocytes catchactivelythe unconjugated bilirubin.Insidethe hepato-
cytes, this type of bilirubin is convertedto conjugatedbilirubin, makingit
solublein bile.Conjugated bilirubinis secretedas a constituentof bile,and
in this form it passesthroughthe bileducts into the smallintestine.Conju-
gatedbilirubinis turnedinto urobilinogen in the bileductsandin thesuperior
partof the smallintestine excretingin a compositionof bile, andturnedinto
stercobilinogenby the intestinalflora. Most of the stercobilinogen excreted
in thefeces.
Urobilinogenis eitherabsorbedinto the portalcirculationor excretedin
thefeces.Mostof the urobilinogen that is absorbedis returnedto the liverto
be reexcretedinto the bile. A smallamountof urobilinogen , approximately
5 %, is absorbedinto the generalcirculationand thenexcretedby the kid-
neys.
Usually , onlya smallamountof bilirubinis foundin the blood; the normal
levelof totalserumbilirubinis 1 to 12 mg/L(< 20.5mcM/L). Laboratorymea-
surementsof bilirubin usuallymeasurethe freeandthe conjugatedbilirubin
as well as the total bilirubin.Theseare reportedas the direct(conjugated )
bilirubinandthe indirect(unconjugated orfree) bilirubin.

J-
 550 I Part 2 Pathophysiologyof organsand systems

Ja undic e
Jaundice(icterus)is a syndromewhich appearsin an increaseof bilirubin
contentin bloodandis characterized by yellow coloringof theskin, mucous
membranes , scleraas a result of depositof the bile pigmentsin them in
disturbancebreachof billegenesisand excretionof bile.Jaundicebecomes
evidentwhentheserumbilirubinlevelsriseabove20 to 25 mg/L.
Because normalskinhasayellowcast, theearlysignsof jaundiceoftenare
difficultto detect,especiallyin personswith darkskin.Bilirubinhasa special
affinityfor elastictissue. Thesclera of the eye,whichcontainsconsiderable
elasticfibers, usuallyis oneof the first structuresin whichjaundicecan be
detected .

Classific ation
Thefour majorcauses of jaundiceare excessivedestructionof red blood
cells,impaired uptakeof bilirubinbythe livercells, decreased conjugationof
bilirubin, andobstructionof bileflow in thecanaliculiof thehepaticlobulesor
in the intrahepaticor extrahepatic bile ducts. Froman anatomicstandpoint ,
jaundicecanbe categorized as prehepatic (hemolitic),intrahepatic (hepa-
togenous , hepatocellular)
, andposthepatic (mechanical, cholestatic)
.

Prehep at ic (hemolytic) jaun dice.

Thecauseof the appearance of hemolyticjaundiceis excessivedestruction
of erythrocytes,seethe increaseof. unconjugated bilirubinin the blood is
observedbesidesanemiaandpemoglobinemia. It is a resultof the excessive
formationof unconjugated bilirubinfrom the hemoglobin, anda result of the
inability of normalhepaticcellsto catchandtransformthe unconjugated bili-
rubinewhichis presentin theflowingbloodin excess.
Hypoxiaalso promotesthis. Hypoxiadevelopsas a result of hemolysis
of erythrocytesand limits the activity of fermentsof hepatocytes, including
 Pathophysiology
of gastrointestinalandrenalfunction Unit 7 I 551
participat
ion in deglucuronizatonof unconjugated bilirubin.Excessof uncon-
jugatedbilirubinin a bloodconditionsthe coloringof the skin and mucous
membranes,the increaseexcretionof stercobilinand urobilinwith the fac-
es and urine. However , the cholemicsyndrome(bile acidsdon't come into
blood)and digestivedisturbancein the intestines(acholicsyndromeis ab-
sentin otherjaundices)areabsent.Hepatocellular jaundicecan becombined
with hemolyticone, if there hepatocytes are damagedsimultaneouslywith
hemolysis;andmechanical jaundiceas a resultof occlusionof the biliferous
canalsby bilethrombiandstonesfrom bilirubin, cholesterinandcalcium.
In prehepaticjaundice,thereis mildjaundice,the unconjugated bilirubinis
elevated,the stoolsareof normalcolor, andthereis no bilirubinin the urine.

_ Posthepatic (cholestatic) jaundice

Posthepaticor mechanicaljaundice,also calledcholestaticand obstructive
jaundice,occurswhenbileflow is obstructedbetweenthe liverandthe intes-
tine, withthe obstructionlocatedat anypoint betweenthejunctionof the right
or left hepaticductandthe pointwherethe bileduct opensintothe intestine.
Thecauseof its developmentis a steadydisturbanceof bilificationfrom
the bile capillaries,gallbladderor its duct into a lumenof the duodenum. It
is stipulatedby narrowingor total closingof their lumen(the sfonesin the
biliferoustracts,inflammatoryprocessin them, presenceof parasitesin the
gallbladder,dyskinesiaof the biliferousetracts, tumors).Thedisturbanceof
bileoutflowis accompanied by an increaseof its pressurein the bilecapillar-
ies,theirwallsandreversediffusionof manycomponentsof bilein the blood
capillaries.The ruptureof the bile capillariesis possiblein casesof acute
total obturationof the biliferoustracts. Bile, coming into contactwith the
hepatictissue,provokesits damageandthe development of the inflammatory
processthat is calledbilaryhepatitis.Thedevelopment of two syndromesis
typicalfor obstructivejaundice:cholemiaandacholia.
Cholemiais a complexof disturbanceswhichare conditionedby the ap-
pearanceof bile componentsin bloodand mainlyof bile acids,glycocholic
andtaurocholicin particular.Yellowcoloringof the skin,sklerasis provoked
 5521 Part 2 Pathophysiologyof organsand systems

by an increaseof the levelof conjugatedbilirubinin blood.Conjugated bili-

rubinappearsin urinein combinationwith bileacids(cholaluria)thatgivesa
specificcolor to urine. The levelof cholesterinis increasedin blood(hyper-
cholesterinemia), that leadsto the appearance of xanthomas(frequentlyin
the epidermisof the skinof eyelids).
The skin pruritus, which is provokedby irritationof nervousendingsby
bileacids, is observedin cholemia . Cholemiais characterized bya decrease of
theinhibitoryactivityof neuronsof the cerebralcortexthatis accompanied by
heightenedirritabilityandexcitability.Laterthe othercentersof the brainand
spinalcord are inhibited.Depression,disturbanceof daily rhythm of sleep
andawaking,slightfatiguability , a decreaseof tendonreflexareobserved.
Acholiasyndromeis characterized bydisturbances at first of cavitarydiges-
tion. It arisesas a resultof the absenceof bile in the intestines.Thedistur-
banceof lypolysisandfat-solublevitaminssplitting;presenceof fat in feces
(steatorrhea); thediscolorationof fecesbecauseof the absenceof stercobilin-
ogenin it; dysbacteriosis , whichis combinedwith aggravation of putrefaction
processes andfermentationin the intestinesand, as a result,meteorism;the
decreaseof the tone and depressionof intestinalperistalsis,which leadsto
constipation, alternatedwith diarrheas ; hypovitaminosis of K, the disturbance
of synthesisof proteins, includingprocoagulants ; an increaseof the perme-
ability of the microvascular wallsthat stipulatesthe development of hemor-
rhagicalsyndromein combinationwith hypocoagulation - areregisteredby it.
In this typeof jaundice,conjugatedbilirubinlevelsusuallyareelevated ; the
stoolsareclaycoloredbecauseof the lack of bilirubinin the bile; the urine is
dark; the levelsof serumalkalinephosphatase aremarkedlyelevated;andthe
aminotransferase levelsareslightlyincreased. ·
Oneof the mostimportantcausesof mechanical jaundicecholelithiasis or
gallstone diseaseis definedas a conditionwith gallstoneswithinthe lumen
of the gallbladder , whethersymptomsoccuror not.
Morethan70 % arecholestetolstones;the remainderis a so-calledbrown
pigmentgallstonecomposedof Ca2+ saltsof bilirubin,carbonate,cholesterol
andphosphate.
The incidenceof cholestero l stonesamongfemalesis threetimes higher
thanamongmales.
Pathophysiotogy
of gastrointestinaland renal function Unit 7 1553

lntrahepatic (hepatoce llular) jaundice

lntrahepatic or hepatocellu lar jaundiceis causedby disordersthat directly
affectthe abilityof the liverto removebilirubinfrom the bloodor conjugate it
so it canbeeliminatedin the bile.
Liverdiseases suchashepatitisandcirrhosisarethe mostcommoncauses
of intrahepaticjaundice.
Hepatocellular (parenchymatous)andenzymopathic varietiesof jaundices
are relatedto hepatogenous jaundice.
Parenchymatousjaundiceappearsas a resultof a directlesionof the he-
patictissuebyagentsof infections- parasitogenic (viruses, bacteriaandtheir
toxins,malariaplasmod iums andothers)and non-infectiousorigin (organic
and inorganic poisons, for example , tetrachloridehydrocarbon , high doses
of alcohol; hepatotrophic antibodiesandsensitizedlymphocytes;tumorsand
others).The type and manifestation of disturbancesof hepaticfunctionsde-
pendon the degree andof damageandmassof impairedhepatocytes. Dam-
age, beginningfrom the changeof the structureof the cellularmembranes
and(or) suppressionof activitiesof ferments,is increasedandmaybe com-
pleted bythe destruction of the hepaticcellsin manycases.The bile-synthetic
andbile-secretory functionsof the hepatocytes aredisturbedin thezoneof le-
sionalmostbyanyvariantof damageof the liver.However , definitepeculiari-
ties of the disturbanceof pigmentalmetabolismaretypicalof variousstages
of the development of pathologicprocess. Earlyspecificsigns of lesionof the
hepatocytes in the first stage (preicteric) arethe appearance of urobilinogen
in bloodandurine(thecauseof this is the damageof fermentalmechanisms
andcatching and oxidationof this pigment); high levelof hepatictransami-
nases in blood(alanine,aminotranspherase, aspartataminotranspherase and
others),which penetrate easilyby throughthe damagedcellularmembrane .
Theprocessof conjugationof unconjugatedbilirubinwith glucuronicacid
is disturbedin the secondstage(icteric) in connectionwith a decreaseof the
activityof glucoronyltransferase. Thequantityof forming bilirubindiglucuro-
nide(conjugatedbilirubin)is decreased as resultof this. The damagedhepa-
tocytes startto secretthe synthesisbile not onlyin bilecapillaries,but alsoin
bloodcapillariesparallelto this. It stipulatesthe appearanceof freebileacids
 5541 Part 2 Pathophysiologyof organs and systems

in blood,increaseof the levelof total bilirubin in it owingto conjugated , and

alsoappearance of it in urine.Besides , crashingof bilecapillariesby damaged
edematichepatocytes hampertheevacuation of bilefromthemandcreatethe
conditionsfor an increaseof its resorptionin thebloodcapillariesof theliver.
Thecomingof bileintothe intestinesis disturbeddueto the manifestation of
cholemiais observed.
Thetotal lessof the abilityof hepatocytes to catchandtransformthe un-
conjugatedbilirubinin conjugatedoneoccursin the first stagein the caseof
seriouslesionof the liver(stageof precoma).Thelevelof unconjugated bili-
rubin beginsto increasein bloodin connection with this the contentsof the
conjugatedbilirubinin bloodbeginto decreaseand, as a rule, urobilinogen
disappearsbackground.Thedisturbanceof the barrierand otherfunctions
of the liver, appearanceof toxic forms of bilirubinand othermetabolitesin
bloodleadto the essentialdisturbanceof the homeostasis of the organism
andthreatof thedevelopmentof hepatic coma.
Enzymopathic jaundices areconditionedbythedisturbances of intrahepa-
tocyticmetabolism of bilirubin.In this cases,wespeakabout a partialformof
hepaticinsufficiency, whichis connected with thedecrease of the impossibil -
ity of synthesisof numberof fermentswhichtakepartin pigmentalmetabo-
lism. By originthis jaundicesare mainlyhereditary.At the sametime, some
forms are registeredafter havingearlierdiseases of the liver. The forms of
jaundicearedistinguished dependingon the mechanisms of development.
lntrahepaticor hepatocellular jaundiceusuallyinterfereswith all phasesof
bilirubinmetabolism- uptake, conjugation , andexcretion. Boththe conju-
gatedandunconjugated bilirubinareelevated , theurineoftenis darkbecause
of bilirubin in the urine,andthealkalinephosphatase is slightlyelevated .
Gilbert'ssyndrome.It's jaundicewhich is basedon the developmentof
the disturbanceof activecatchingandtransportof the unconjugated biliru-
bin from bloodinto the hepaticcells·. Thecauseof it is a geneticdefectof
synthesisof properferments.The increaseof the levelof the total bilirubin
is stipulatedbythe increaseof contentsof free(unconjugated)bilirubinin it.
Crigler- Nagarsyndrome.Thisvariantof enzymopathic jaundicedevelops
as a resultof the deficiencyof glucoronyltransferase - the key fermentof the
transformation of thefreebilirubinintothe conjugatedone.
 Pathophysiologyof gastrointestinaland renalfunction Unit 7 Isss
Dubin-Johnson syndrome. This variantof jaundiceappearsas a resultof
the defectof ferments,whichparticipatein the excretionof bilirubinglucuro-
nidethroughthemembrane of thehepaticcellsin bilecapillaries.
Asa resultof
this,directbilirubincomesnotonlyintothebilecapillaries,butalsoin blood.
Variousliver diseasesare mainlycausedby such pathologic processes
as inflammation, the disturbance of peripheralbloodcirculation,metabolism
andtumors. Inflammator y affectionsof the liverarecalledhepatitis, primary
changesin the metabolismof hepatocytes followed by dystrophyare called
hepatosis andmetabolicliverdiseasesanddiffusegrowthof the connective
tissueon the background of dystrophyor parenchyme necrosisis calledcir·
rhosisof the liver.

_ Hepatitis
Hepatitisimpliesinjuryto the livercharacterized
hy the presence of inflamma-
tory cellsin thetissueof theorgan.Theconditioncanbeself-limiting,healing
on its own,or canprogressto thescarringof the liver.Hepatitisis acutewhen
it lasts lessthan six monthsand chronicwhenit persistslonger. A group
of virusesknownas the hepatitisvirusescausemost casesof liverdamage
worldwide.Hepatitiscanalsobedueto toxins(includealcohol), otherinfec-
tionsor from autoimmuneprocess .

The causes of acute hepatitis are th e following :

• viral hepatitis:HepatitisA throughE (morethan95 % of viral cause),

Herpessimplex,Cytomegalovirus, Epstein-Barr
, adenoviruses;
• non-viralinfection:toxoplasma, leptospira;
• toxins:Amanitatoxin in mushrooms,carbontetrachloride , alcohol;
• drugs: Paracetamol, amoxycillin , antituberculosis
medicines, minocy-
clineandmanyothers;
• ischemichepatitis (circulatoryinsufficiency;
• autoimmuneconditions(SystemicLupusErythematosus).
 556 f Part 2 Pathophysiologyof organsandsystems

The causes of chronic hepatitis are the following:

• viral hepatitis:Hepatitis 8 with or withouthepatitisD, hepatitisC ;

• autoimmunehepatitis;
• alcohol;
• drugs:methyldopa, nitrofurantoin, isoniazid, ketoconazole;
• heredity: Wilson's disease , alpha1-antitrypsin deficiency;
• primarybiliarycirrhosis.

Theknownhepatotropicvirusesincludehepatitis A virus (HAV),hepatitis

B virus (HBV), the hepatitis8-associateddeltavirus (HOV), hepatitis C virus
(HCV),andhepatitis E virus(HEV).
Thereare two mechan isms of liver injury in viral hepatitis: directcellular
injuryandinductionof immune responses againstthe viralantigens.

The clinical course of viral hepatitis involves a num-

ber of syndromes, including:

• asymptomaticinfection with only serologicevidenceof disease ;

• acutehepatitis;
• thecarrier statewithoutclinicallyapparentdiseaseor with chronichepa-
titis;
• chronichepatitiswith or without progressionto cirrhosis;
• fulminating disease(>1% to 3%) with a rapidonsetof liver failure.

Cirrhosis

Cirrhosisrepresentsthe endstageof chronic liverdiseasein which muchof

the functionallivertissuehasbeenreplacedby fibrous tissue.It is character-
ized bydiffusefibrosisandconversionof normalliver architectureinto struc-
turally abnormalnodules . The disruptionof vascularchannelspredisposes
to portalhypertension and its complications; obstructionof biliarychannels
 Pathophysiologyof gastrointestinaland renalfunction Unit 7 I ss7
andexposureto the destructiveeffectsof bile stasis;and loss of liver cells,
leadingto liverfailure.
Thelatemanifestations of cirrhosisare relatedto portalhypertensionand
livercell failure. Splenomegaly, ascites,andportosystemicshunts(esopha-
gealvarices,anorectalvarices,andcaputmedusae)resultfrom portalhyper-
tension.Othercomplications includebleedingdueto decreased clottingfac-
tors,thrombocytopenia dueto splenomegaly , gynecomastia anda feminizing
patternof pubichairdistributionin menbecauseof testicularatrophy.

Portal Hypertension
Is characterizedby increasedresistanceto flow in the portalvenoussystem
_ andsustainedportalveinpressureabove12mmHg(normal,5 to 1Omm Hg).
Portalhypertension canbecausedby a varietyof conditionsthat increase
resistanceto hepaticbloodflow, includingpre-hepatic, posthepatic
, and in-
trahepaticobstructions .
The major complicationsof the increasedportal vein pressureand the
openingof collateralchannelsareascites,splenomegaly, andthe formation
of portosystemic shuntswith bleedingfrom esophageal varices.
Ascites.Ascitesoccurwhentheamountof fluid in the peritonealcavityis
increased, andis a late-stagemanifestationof cirrhosisandportalhyperten-
sion.

Alcoho lic liver disease

Chronic alcohol consumption leads to three main

pathological changings. :

1. Hepaticsteatosis(fattyliver)-shuntingof normalsubstratesawayfrom
catabolism andtowardlipidbiosynthesis; theimpairmentof lipoproteins
secretion,increasingof peripheralcatabolismof fat.
 ssa I Part 2 Pathophysiologyof organsand systems

2. Alcoholichepatitis-dueto the directandindirectalcoholicinjuryof he-

patocytes
3. Cirrhosis-dueto theactivationof fibroblasts.

The main symptomsare: hepatomegaly, malaise,anorexia,the loss of

weightand appetite;sometimesjaundiceand ascites.Themain reasonsof
deathare:hepaticcoma, a massivegastrointestinal
hemorrhage,an intercur-
rentinfections,hepatorenal
syndromeandhepatocellular carcinoma.

Liver Failure
Althoughthe liver is amongthe organsmostfrequentlydamaged,only ap-
proximately1O % of hepatictissueis requiredfor the liverto remainfunc-
tional.But manycauses mayleadto the criticaldecrease of functionalhepa-
tocytesanddevelopment of the liverinsufficiency
.
Byetiology,all sortsof the liveraffectionsaresubdividedintoinheritedand
acquiredones.Theetiologicalfactorscausingthe liverfailureandsyndromes
are thefollowing.
1. Infectious- virusesandbacteria(virusesof viralhepatitis , pathogene of
tuberculosisandothers).
2. Toxicsubstances - exogenous(alcohol, medicines- sulphanilamides,
chlortetracycline , tetracycline,cytostatics;industrialpoisons- carbon
tetrachloride
, arsenic,insecticides;vegetablepoisons- aphlotoxine,
muscarine)andendogenous (theproductsof thetissuedecomposition
in burn,necrosis,toxicosisof pregnancy) . _
3. Physicalfactors- ionizingradiation(x-rayhepatitis);mechanical trau-
ma.
4. Alimentaryfactors- protein,vitamindeficiencyin theorganism,fat food.
5. Allergicreactions- duringthe injectionof vaccines,serums,food and
medicineallergens.
6. Thedisturbanceof bloodcirculationin the liver of the local(ischemia,
passivehyperemia,thrombosis,embolism)and generalcharacter(in
cardio-vascula r insufficiency)
Pathophysiologyof gastrointestinaland renalfunction Unit 7 Issg
7. Endocrineand metabolicdisturbancesin the organism(diabetesmel-
litus, hypothyreosis, adiposalsyndrome).
8. Tumors - primary(hepatocarcinoma) and metastatic(in cancerof the
stomach, lungs, mammarygland,leucosalinfiltrates).
9. Hereditarydefectsof metabolism(hereditaryenzymopathy), inbornde-
fectsof the liverstructureasa resultof the intratubaldevelopment.

While considering the pathogenesis of the liver af-

fections of various etiology one should distinguish
two kinds of pathologic reactions:

1. A directdamageof the liver by the etiologicalfactor (viruses, chemical

substances, the disturbanceof bloodcirculation)which manifestthem-
selvesby dystrophic changesof the liverincludingnecrosis.
2. Autoimmunedamageof the liveras a resultof the formationof the au-
toantigens(pathologically changedcomponentsof hepatocytes emerg-
ing in directaffectionof the liver) and the developmentof autoallergic
reactionsof humoraland cellulartypes.Thesereactionsintensifythe
liverdamagedueto microcirculardisturbances(in the influenceof BAS,
which areactivatedduringthe reactionantigen-antibody) and immune
cytolysiswith the participationof T-killers.

As a rule, inflammatoryhepatitisand metabolic- dystrophicalhepatitis

affectionsof the liverresultin the development of cirrhosis.A highfrequency
of combineddisturbancesof the liver and organsof the digestivesystem,
spleen(hepatolienal syndrome),kidneys(hepatorenal syndrome)as a result
of anatomicalandfunctionalconnectionsbetweentheseorgansis typicalof
the liver pathology.However,not only pathologicstructureand functional
disturbancesbut also compensatoryreactionsintendedto stop pathologi-
cal processin the organand characteristicof the liver pathology . Theseare
the followingreactions:the intensificationof the metabolicprocessesin the
liver (energy, desintoxicational}, phagocytosis,the increaseof the excretion
of toxic substances;the redistributionof blood;the developmentof anasta-
 560 I Part 2 Pathophysiologyof organs and systems

mosis.Theliveris capableof regeneration whichcanbeevidentboth during

resectionandin diffuseaffectionof the livertissue(regenerational hypertro-
phy of the liver).In the liver insufficiencyone(several)or all liver functions
get lowerthat the levelwhichis necessary to providea normallife activityof
the organism .

The liver insufficiency is subdivided into various

kinds according to the following signs:

1. By the numberof dysfunctions. therecanbe distinguishedpartialand

total insufficiency.
2. By the causeof the disease,the liver insufficiencycan be acuteand
chronic.
3. Bythetermination,the diseasecanbe lethalandnon-lethal.

Depending on principal pathogenic mechanisms of

the liver , insuffic iency can be:

1) hepatocellular(in the dystrophicandnecroticdisturbances of the hepa-

tocytes);
2) excretoryor cholestatic(as a resultof the disturbanceof bile forming
andbileexcretoryfunction of the liver);
3) vascular(in the disturbance of bloodcirculationin the liver).

As a rule the combinatio n of severalmechanisms in the development of

functionalinferiority of the liver can be observed.Cholestasis - the distur-
banceof the bile outflowfollowedby the accumulat ion of its componen ts in
the liver and bloodas a resultof the weakeningof the excretoryfunction of
hepatocytes (a primarycholestasis)or someobstacle to bile outflow in bile
ducts(a secondary cholestasis).
Thegeneralpathogenesis of hepatic insufficiency canbe presented asthe
followingchainof changes.
Pathophysiologyof gastrointestinal and renalfunction Unit 7 I 561
1. Changeof moleculararchitectonics of hepatocytemembranes.
2. Intensificationof freeradicalperoxicfraction of lipids.
3. Partialor completedestructionof membranes , an increaseof their per-
meability.
4. Release of hydrolasesfrom theirlysosomesandfollowingthe intensifi-
cationof damageof the cellmembranes.
5. Rrelease of the necrosogenicfactorandinterleukinof damagedmacro-
phagesand promotingthe development of inflammatory and immune
reactionsin the liver.
6. A formation of autoantibodies andautosensibilizedT-killers,that evoke
functionalautoallergicdamageof hepatocyt es.

Everyenumerated pathogeniclink is a certainstageof the development

of
hepaticinsufficiencycan become a predominant oneandthis circumstance
mustbetakenintoconsideration whilechoosinga typeof treatment.

Signsof hepaticinsufficiency andmechanisms of itsdevelopment .

A disturbanceof participationof the liver carbohydrate metabolismcon-
sists in the decreaseof the abilitiesof hepatocytesto convertglucoseinto
glycogenandsplit glycogento glucose.Thesecausesis a characteristic sign
of hepatic insufficiency- unconstantof the looseof blood.Aftermealhyper-
glycemiadevelops andon anemptystomach- hypoglycemia.
A reductionof gfycogenin the pathologically-alteratedliver resultsin the
weakeningof its desintoxcication function, whereglycogentakespart, con-
vertinginto glycoronacid.

A disturbance of participation of the liver in lipid me-

tabolism is characterized by the decrease of the
abilities of hepatocytes:

a. to converta more aterogenicform of cholesterol(freecholestero

l)
intoa lessaterogeniccholesterol
- ester;
b. to form phospholipid
s with anantiaterogenic
effect.
 5621 Part 2 Pathophysiologyof organsand systems

Boththesechangesleadto the increaseof the levelof freecholesteroland

to the decreaseof antiaterogenic
phospholipids of blood,thus promoting the
depositionof cholesterolon the wallsof vessels anddevelopment of athero-
sclerosis.

The disturbance of participation of the liver in pro-

tein metabolism consists of three types of changes:

a. reductionof synthesisof albuminsof hepatocytes, that leadsto hy-

poalbuminemia andhypoonkia , andat the stageof the development
of portalhypertension promotesthe development of ascites;
b. decrease of biosynthesisof fermentsandproteins- protocoagulants
(prothrombin,proconvertin), thatcausesthe development of coagu-
lopathieswith an inclinationto bleeding;The decreaseof intestinal
absorptionof fat-dissolvedvitaminK promotesthat too, be cause
hepaticinsufficiencycombinedwith the disturbanceof bile-forming
andbileexcretingfunctionsof the liver;
c. reductionof the intensivityo the desaminationof aminoacidsand
synthesisof ureafrom aminogroupsandammonia , that leadsto de-
creaseof ureain blood.

A disturbanceof biosynthesisof enzymesby hepatocytes consistsin the

reductionof secretionof enzymesof hepatocytes that they produce(cholin-
esterase, ANDP,NAO).Besides,the damageof hepatocytes is accompanied
bythe increaseof theirgoingout of intracellular
fermentsinto blood:alkaline -
transaminase andglutamate-transaminase. ·

A disorder of vitamin metabolism consists in:

a. reductionof theinternalabsorptionof fat-dissolved

vitaminsA, D, E, K;
b. decreaseof the abilityof hepatocytes to convertprovitaminsinto ac-
tive vitamins(e.g. caroteneinto vitaminA);
Pathophysiologyof gastrointestinaland renalfunction Unit 7 1563

c. disturbanceof the processof the formationof cofactorsfrom vita-

mins (e.g.acetyl-cofactor
A from lactopinacid, pirovateof co-car-
boxilasefrom vitaminB).

All enumerated changesleadto the development of endogenous(hepatic)

hypovitaminosis.
A disturbanceof antitoxic("barrier'; functionof the liver is characterized
by a decreaseof desintoxication by the liver:internalpoisons- phenol,indol,
skatol;poisoningmetabolites:low - molecularfat acids (valeric, capronic),
sulphur-conta iningacids(cystine,methionin);exogenicpoisons(fungic,mi-
crobic, parasitic
, chemical , etc.). Theinactivationof colloidparticlesand mi-
croorganisms with a Cupfercellsis alsodecreased.
A disturbanceof theformationandsecretionof bilebythe liverleadsto the
development of jaundice.
The manifestationsof liver failure reflectvariousfunctionsof the liver,
includinghematologicdisorders,endocrinedisorders.skin disorders,hepa-
torenalsyndrome , andhepaticencephalopathy.
Fetorhepaticusrefersto a characteristicmusty, sweetishodor of the
breathin the patientin advancedliver failure,resultingfrom the metabolic
byproductsof the intestinalbacteria.
Hematologic Disorders . Liverfailurecan causeanemia,thrombocytope-
nia,coagulationdefects,andleukopenia.
Endocrine Disorders . Theliver metabolizes the sex hormones.Endocrine
disorders,particularlydisturbancain gonadalfunction, arecommonaccom-
panimentsof cirrhosisandliver failure.Womenmayhavemenstrualirregu-
larities(usuallyamenorrhea) , the lossof libido, andsterility.In men, testos-
teronelevelsusuallyfall, the testaatrophy,andthe lossof libido,impotence,
andgynecomastia occur. Thedecreasemetabolizes of aldosteronein the liver
leadsto the accumulationof this hormone in the bloodandformationof sec-
ondaryaldosteronism.
SkinDisorders. Liver failurebringson numerousskindisorders.Thesele-
sions,called variouslyvascularspidentelangiectases , spiderangiomas,and
spidernevi,are seenmostoftenin the upperhalfof the body.Theyconsistof
a centralpulsating arteriolefrom whichsmallervesselsradiate.
 5641 Part 2 Pathophysio
logy of organsand systems

Palmarerythemais rednessof the palms,probablycausedby increased

bloodflowfrom highercardiacoutput.Clubbingof thefingersmaybeseenin
personswith cirrhosis.Jaundiceusuallyis a latemanifestationof liverfailure.
Hepatorenal Syndrome . The hepatorenal syndromerefersto a functional
stateof renalfailuresometimesseenduring the terminalstagesof liverfail-
urewith ascites.lt is characterized by progressive azotemia , increasedserum
creatininelevels,andoliguria. Ultimately,whenrenalfailureis superimposed
on liver failure,azotem ia and elevatedlevelsof bloodammoniaoccur; this
conditionis thoughtto contributeto hepaticencephalopathy andcoma.
HepaticEncephalopathy. Hepaticencephalopathy refersto the totality of
centralnervoussystemmanifestations of liverfailure. It is charac terizedby
neuraldisturbancesrangingfrom a lack of mentalalertnessto confusion,
coma, andconvulsions. A veryearlysignof hepaticencephalopathy is a flap-
pingtremorcalledasterixis.
Hepaticcomais one of the complicationsof the hepaticfailure.At the
beginningof the coma, hepaticencephalopathy develops.If intoxicationbe-
comesgreater , theremaybeconfusion , stupor andunconsciousness .
Thereare distinguishedtwo variantsof the development of hepaticcoma:
shuntand hepatic-cellular.
Shunthepaticcoma._This varietyof comaarisesas a consequence of the
severeaffectionof the liverof a sclerotic(cirrhotic)character.
Cirrhosis of the liver can be an outcomeof acuteand chronic hepatitis ,
chronicvenous-stagnativehypoxiaof the liver, and may be accompanied
by the development of portal hypertens ion. Long-lasting steadyportal hy-
pertens ion leads to the development of porto-cavalanastamosis (througha
hemorrhoidal , esophageal , umbilical viens), by which some part of blood,
sometimesa considerable one, is "thrownout" intothegenera l bloodstream
passingthe liver.It causesthe intoxicationof the organismwith productsof
metabolism , which normally areinactivated in theliver.Thisvariantof hepatic
comahasits ownpeculiarities:firsts, comacanarisein a relativelysmalldis-
ordersof gall-forming(biligenesis)and gall-excretion (bilif ication)functions
of the liver (jaundice is absentat all or is poorlymanifested) . Secondary , its
arising is muchconnectedwith functionalconditionof intestinal digestion
and with a characterof consumedfood. Foodrich in proteinincreasethe
 Pathophysiologyof gastrointestinaland renalfunction Unit 7 1565

abilityof comadevelopment becauseof the absorptionof toxicalproductsof

proteindisintegration , cominginto a generalbloodstream, for example , am-
monia,carbaminoxydated ammonium,cadaverin , methionin.
Hepatocel/u/ar coma.Hepatocellular comaappearsin massivenecrosisof
the hepaticparenchyma , whenits homeostaticandbarrierfunctionsare de-
creasedessentially.
Theseveralinterconn ectedpathogenicmechanisms areat the baseof the
development of coma.
Hypoglycemia is oneof them. It wasdemonstrated in the experiment , that
anextirpationof the liverin animalsleadsto theirdeathin 5-8 hoursbecause
of acutehypoglycemia. Theterm of their life is prolongedtill 20-40 hoursby
the artificialsupportingof the normallevelof glucose.
Severeacidosisis anotheressentialmechanismof the developmentof
_ coma.It wasdemonstrated thatthecorrection of acid-baseallowsprolonging
the life of animalstill 2-3 days.
Theintoxicationof the organismis an importantpathogenicpart of coma.
It is conditione
d by the appearance andincreaseof the level of substan ces in
blood, whichexertthe generaltoxicand, especially , cerebrotoxicinfluence.
Thedisturbanceof aminoacid ic andalbuminousmetabolisms is important
in the mechanismof comadevelopment.
The impairedliver isn't able to supportthe properquantityand correla-
tion of separateaminoacidsandfractionsof proteinin blood.The excessof
oneanddeficiencyof otheraminoacidsmakethe normalmetabolismof pro-
teins impossiblein the tissuesof the organism.Theincreaseof aminoacids
in bloodandtheir appearance in urineis a manifestation of this. Thelevelof
freeammoniais increasedin blood.It is conditionedbythe disturbanceof its
transformationinto ureain the ornithinecycleof hepatocytes. Besides , the
partof urea, whichis excretedby mucousmembraneof the intestine,is split
in it by ureasiswith the formationof ammonia , whichis suckedin blood.The
excessof ammoniadamagesthe cellsof the organsandtissues, suppresses
the fermentative reactionsin them.
Many damagedhepatocytes areexposedto the destruction.Thesubstanc -
es, whichare in them, get into bloodand exertthe pathogenicinfluenceon
the cellsof the organsandtissues, includingthe cellsof the nervoussystem.
 Pathophysiologyof organsand systems
5661 Part 2

Bilepigmentstakepart in intoxicationof the organismtoo: the levelof free

(unconjugated) bilirubinis increasedin blood.
It influencestoxicallythe cellularmembranes.
Thequantityof highlytoxic productsof the decayof aromaticaminoacids
(indole,skatole,phenol)andalsoof albuminousputrefaction(putrescine, ca-
daverin)in bloodis increased.
Systemichemodynamics is disturbeddueto generalintoxication:the car-
diac ejectionis decreased, arterialhypotensiondevelops,the volumeof the
circulatingbloodis reduced.Disturbances in the systemof bloodcoagulation
(deficiencyof prothrombin,fibrinogenandothers)arethe causesof the de-
velopmentof bleedings,hemorrhages in the microvessels of the organsand
tissues.Progressinggeneralhypoxiaappears.

. . _,, Chapter 29. Renal

Pathophysiology
Thekidneysareveryimportantorgansfor supportingsomefunctionsof the
organism.
Homeostatic function of the kidneysincludessupportof the homeostasis
( the constancyof the internalmediumof the organism),providingthe con-
stancyof thefluid volume(isovolemia)andosmoticconcentration (isotonia),
ion composition(isoionia),regulationof acid-basebalanceby the concentra-
tion of hydrogenions (isohydria).
Excretoryfunction of the kidneysis alsoimportantfor the excretionof the
endproductsof nitrousmetabolism(urea,uric acid,.creatinine)anddifferent
foreignsubstances(xenobiotics)from the organism.Thedisturbanceof ex-
cretionis oneof the significantmanifestationsof renalinsufficiency.
Metabolicfunction of the kidneysincludeactivemetabolicpathways(ar-
ginineformation,gluconeogene'sis, peptidehydrolysis)andsynthesisof the
hormones(angiotensinII, erythropoietin,□-hormone, prostaglandins).
Regulatory functionof the kidneystake part in the r~gulationof blood
pressure(renninsynthesis),erythropoesis (erythropoietin
synthesis),coagu-
lation(urokinasesyntesis).
Pathophysiologyof gastrointestinaland renal function Unit 7 1567

Thekidneysarecharacterized by intensivebloodsupply,high levelof en-

ergymetabolismwhichdefinestheirincreased sensitivityto thedisturbances
of bloodcirculation.
Thefunctionalunitof thekidneyis thenephron ; 1.2 millionnephronsmake
up eachhumankidney. Structuralcomponentsof the nephroninclude:the
renalcorpuscle which is situatedin the renalcortexandis madeup of Bow-
man'scapsuleandthe glomerulus ; theproximaltubule ; theloopof Henle;
thedistaltubule(Fig.59).

Bowman's
capsule
Glomerulus Afferent
arteriole
Efferent
arteriole

~
Cortex
Meauna-- -------- Torenal
Efferent vein
arteriole

Fig.59. Nephron
structure
 ssa I Part 2 Pathophysiologyof organs and systems

In the glomerulus , the bloodis filtered:proteinsand cells are retained

,
whereaswaterand all smallerdissolvedsubstancespassinto the tubule,
whencethe greaterpart of this ultratiltrateis transportedacrossthe tubule
wallandreentersthe blood(resorption , reabsorption).
Thefractionthat is not resorbedremainsin the tubuleandappearsin the
terminalurine(excretion).Someurinarysolventsenterthe nephronlumen
from tubulecellsby secretion.

Th e main param e ters of the renal activity are the

following.

1. Urinevolume.Healthadult has1.5-2 I/day; morethan2 I/day-polyuria,

lessthan800 ml/day-olygouria;the absenceof urinelessthan 100 ml/
day)- anuria(Table30).
2. Specific gravityofurine.Normally - from 1,001 to 1,030.Theabsence
of specific gravity's daily deviations is calledisostenuria;high gravity-
hyperstenuria , low gravity- hypostenuria .
3. Urinarysedimentproteinuria-proteinsin the urine; cylindruria-casts
in the urine; hematuria- erythrocytesin the urine;leukocyturia - leu-
kocytesin the urine.Selectiveproteinuria- it is the ability of damaging
glomerulusto let proteinmoleculespassthroughin accordingof their
molecularweight.In selectiveproteinuria, glomerulilet only low-weight
proteinsto pass.It is typicalfor the nephroticsyndrome.Nonselected
proteinuriais typicalfor a moresevereglomerularinjury.

Funct ional tests fo r the study of renal disorders

1. Kakovsky-Addis urine sedimentcount- countingof sedimentsin the
daily urinevolume.Normally , in the dailyurinethereare1 x 106 erythro-
6
cytes, 2 x 10 leukocytesand2 x 104 casts.
2. Zymnitsky 's test (24-hoursurinespecimentest)-the estimationof dis-
tal tubulesfunctions. To do this test,the dailyurineis collectedeach3 h
Pathophysiologyof gastrointestinaland renalfunction Unit 7 1569

Table30. Quantitative
andqualitative
disorders of urine.
. .. . - ,. i t-~: •-i '.... •

~ -of - --- -:-u~. 111ecause ,

Charac~ anda sequence
1. Oliguria
and/or Gtomerulonephritis.Reduced Decreased and/orstopeddiuresis.
anuria bloodvolume(dehydration). Asresult maybe:
Tubular necrosis(nephritic, Azotemia
lipoidor amyloidsyndromes). Disturbances
of water-electrolytes
homeostasis
Acid-basedysbalance
2. Polyuria Psychogenic origin(neuroses). Increa
sedamountof urine(from2
Diabetes mellitus. upto 10 Uday)
Pituitary
diabetes.
3. Polacuria Cystitis Urinary
frequency
4. Nocturia CNSpathology, Characterized bypredominantly
cardiacinsufficiency
, diuresisat night
kidneydisease.
5. Proteinuria Psychicalandchemical Excreted proteinin urine
changes in basalmembrane. {somet imesnotonlyalbumins,
but
Mayoccurin hardwork, a- , ~-. y-globulins).
in overloading,
circulatory Asa result:
insufficiency,
thyrotoxicosis, hypooncia, edema .
infectious
disease andsome
. toxicconditions
.
6. Hematuria Poststreptococcal Isaccompanied bycomingoutof
glomerulonephritis,
tuberculos
is erythrocytesas1 shadows.
of thekidney
, malignant
tumor Asresultof formation of redcells
of thekidney
. castswhichcandegenerate and
become pigmented granularcasts
- thepatient's "smokybrown
urine".Aftertraumaor inflammation
of the uretertherearelargeamount
of fresherythrocytesin urine
(extrarenalorigin
).
570 I Part 2 Pathophysiologyof organsand systems

-. ~ 1' ,••

Kindof disordersThecause Characterisfjcanda.._.,

.
.., ,..
! .• t

7. Pyuria Inflammation
of theureter Largenumbers
of neutrophils
in
urine.

8. Bacter
iuria Urinespecimens
byexternal Definedas morethan105/ ml
flora. organi
smsin urine.

9. Glucosuria Diabetes
mellitus Characterizedby impaired
reabsorption
of glucosein renal
tubular apparatus.

10.Lipiduria Liverdisorders
(cholestero
luria)

11. Cystinuria Dystrophicandnecrot izing

processesin tubularapparatus
of thekidney.

and specific gravityandvolumearedetermined in eachportion. Thetest

is usedfor the diagnosticsof chronicrenal failure, whenhyposten uria
is foundin the urine, isostenuria , nocturia( the samequantitiesof the
urinein thedayandat night, for whichreasonit is neededto getup dur-
ing the nightin orderto urinate).
3. In clinic,thereis used thedetermination of theclearance index.It shows
theamountof plasmaor bloodserum(in milliliters)whichis completely
clearedfrom the exogenic and endogenicsubstanceswhile passing
throughthe kidneysper 1 minute.
Clearance is counted bythe,formula :
C= U x V/P, where:
C- clearance of the investigatedsubstance(ml/min);
U - concentration of the investigatedsubstancein urine(mg/ml);
V - diuresis(ml/min);
P - concentrat ion of the investigatedsubstancein plasma(mg/ml).
Pathophysiologyof gastrointestinaland renalfunction Unit 7 f 571

Todeterminetheamountof glomerulus 's filtrationthereareused exogenic

(polysaccharide inulin), as well as endogenic(creatinine)substances, which
are filtratedin the glomeruli andare not reabsorbed and secretedin the tu-
bules.In the norm, creatininevarieswithin 180-90 ml/min. It meansthat
130-90mlof plasmais clearedform creatinineby the healthykidneysper
min.andthesameamountof initialurineis formed.

Main mechanisms of re gul ation hom e ost a tic func-

tion of kidney s :

• Filtration
• Reabsorption
• Secretion
• Concentration
anddilutionin the kidneys

Pa thology of filtr a tion

In the kidneys150-180L /dayarefiltrated

Glomerular filtrationrate(GFR)is the volume/timethat is filteredby all
glomeruli.An averageof onefifth or 20 % of the renalplasmaflow (RPF)is
filteredat the glomerulus.This ratio, GFR / RPF, is calledfiltrationfraction
(FF).

Filtration depends on:

• Quantityof functionalnephrons
• Characteristics of renalbloodflow
• Levelof filtrationpressure(FP)

FP=HP- (OP+ ITP) =75 mmHg- (25 mmHg+ 10 mmHg)= 40 mm Hg

where: HP- hydrostaticpressurein theglomerulararteries;
 572 I Part 2 Pathophysiologyof organsand systems

OP- oncoticpressure
ITP- intratubularpressure(dependson the resistance
outflowof the
urine).

Disturba nc e of filtrat ion

Disturbancesof diuresis may be first of all, promotedby changesof the
amountof the glomerulus'sfiltration (in norm 100-140ml /min). Thereare
renal andextrarenalmechanisms of filtrationdisturbance .
Thedecrease of filtrationmaybein thefollowingcases.
1. In the decreaseof the hydrostaticpressureon the capillarywalls.It is
connectedwith the decreaseof the arterial pressureto/or less80 mm
Hg due to shockand collapseof differentgenesis, blood circulation
insufficiencyand decreaseof the volumeof the circulatingblood.
2. In the elevation of the blood oncotic pressureabove25-30 mm Hg
dueto hemoconcentration becauseof the dehydratationof the organ-
ism.
3. In the increasedpressurein the capsuleof the glomeruliabove25 mm
Hgwhichis observedin thedelayedreabsorption of fluid in the proximal
part of the tubulesof the nephrons , in the occlusionof the tubules lu-
menby cylinders, necrotic massesandin the obstructionof the ureter
(necrosis , clots, calculi andtumors).
4. In the changeof the condition of the glomerularfilter, there is the
reductionof the numberof the functioningglomeruli(2 min in the
norm), totalfiltrationsurface(about1.5 sm2 in.the norm),the number,
squareanddiameterof the pores(up to 5 nm in the norm), thickening
of the glomerularmembrane(80-120 nm in the norm)and it's physi-
cal and chemicalproperti~s.Suchdisturbancesare observed,first of
all, in inflammatoryprocessaffectingthe glomerularmembrane(glo-
merulonephritis, etc.).
5. IncreaseITP(intratubularpressure)in situationswhenthe blockedout-
flow of urinefrom the kidneys(nephrolithiasis , tumors, anyother cases
of urinarytract obstruction)
Pathophysiologyof gastrointestinaland renalfunction Unit 7 I s73
The damageof the renalfilter anddecreaseof the glomerularfiltrationand
diuresisresultingfrom it maybeobservedin the dystrophyof theglomerular
membranedue to disturbances of bloodsupplyof the kidneys,hypoxiaor
differenttoxic influences
.

Thefollowing factorsinfluence theincrease offiltration

:
1. Increaseof the hydrostaticpressureonthewall of the glomerularcapil-
larieswhich is observedin the increasedvolumeof the intravascular
fluid;
2. Decrease of the oncoticbloodpressure(hypoalbuminemia);
3. Situationswhichleadto theincreased catecholamine level(fever, stress,
hypothermia) . In this case,the increasedconcentrationof catechol-
aminesin the bloodleads to the moreintensiveconstrictionof effer-
entarteriole(vasefferens)thanafferent arteriole(vasafferens)because
efferentarterioleare more sensitiveto catecholamines. This leadsto
the increaseof hydrostaticpressurein the glomerulusand increased
filtration.

The increa se of th e perm eability of th e g lomerul ar

membrane
Thesignof theincreased permeability
of theglomerularmembrane is protein-
uria-th e excretionof plasmaproteinswith the urineabovetheamountpres-
ent in the physiologicalconditions(30-100mg/day)as wellas the presence
of proteinswith a largerelativemolecularmass(above70000)in the urine.
The mechanismof proteinuriacausedby the increasedpermeabilityof
the glomeruli is due physicaland chemicalchangesin the basal mem-
brane.Suchchangesin the glomerularmembranemayoccurin hardwork,
in fluid loss in babiesand in overcooling
. Proteinin urinemayappearafter
havingmealwith a large amountof proteins,especiallyin children(alimen-
tary proteinuria).
Organicproteinuria (in acuteand chronicglomerulonephritis , nephrotic
syndromeandotherorganicimpairments of the kidneys) is characteristic
of
 574 I Part 2 Pathophysiologyof organsand systems

presenceof plasmaproteinswith a high relativemolecularmassof 70000-

820000in urine.
An itermediatepositionis takenby proteinuriain circulatoryinsufficiency,
in infectious diseaseandsometoxicconditions,in thyrotoxicosis,mechanic
andparenchymatous jaundice,enterocolitis
, intestinalobstructionandburns.
When proteinuriais not connectedwith renal impairmentbut brought
aboutby the inflammatoryprocessin the ureteris calledextrarenalor false
proteinuria(proteinis usualnot morethan1 g/I).
The injuryof the glomerularmembranemaybe accompanied by coming
out of erythrocytesinto the glomerularlumenandtheir appearance in urine
(renalglomerularhematuria)as "shadows" (lixiviatederythrocytes).
Renalhematuriashouldbe differentiatedfrom extrarenalone, brought
aboutof traumaor inflammationof the ureter.Thereis a large amountof
fresherythrocytesin it.

Distu rbance of substance excre tion.

Dysfunction of theglomeruliis manifested bythedelayof excretionof nitrous
metabolismproductsand their increasedconcentration(residualnitrogen)
in blood- azotemia.It is causedby accumulation of urea,uricacid,creatine,
creatinine,ergothylanine andammoniain bloodaswellasto lessextentami-
noacids,toxic productsresultedfrom the decayin the intestines- indican,
fenol, indoleandskatole.
The levelof azotemiamay be different- from the slightlyexceed ing the
upper limit of the normal quantityof residualnitrogen(35.7mmol/I) to
142.8-357mmol /l. Themainfactoris the decrease of theamountof the glo-
merularfiltration.
As a resultof excretorydysfunctionof the glomeruli,thereis the delayof
the excretionof phosphates, sulfatesand organicacidsandtheir increased
concentrationin blood- hyperphosphatemia , hypersulfatemia, hyperacide-
mia.Anionsof thesesubstancespushout hydrocarbonates in the extracel-
lularfluid anddecrease the alkalinereserveof the blood(to 18-13.5mmol /l,
25-31mmol/I in the norm)that resultsin acidosis(renalazotemicacidosis).
Pathophysiologyof gastrointestinaland renalfunction Unit 7 1575

Thereis theaccumulationof ionsof magnesium andpotassiumin theextra-

cellularspaceandblood(hyperkaliemia, hypermagniemia)
withdecreased con-
centrationof sodium(hyponatriemia) andchlorine(hypochlore
mia) in blood
plasma.

Pathology of reabsorption and secretiondevelopmentin situations

,
wherein tubulusofkidneys functional
orstructural
disorders
takeplace:
• Epithelium destruction
• Pathologyof regulation
• Enzymopathias (K+-Na+pump)
• Energydefficiency
• Tubulopathias

Pathology
of Nametabolism
Na cumulation
• Decreasefiltration
• Increasereabsorption
(hyperaldosteronism)

consequences
• oligouria
• hyperhydration
• edema
• hypervolemia,
increaseof BP

Na loss
• hypoaldosteronism
• Enzymopathias (K- Napump)
• Epithelium destruction
• activation of aldosteroneantagonists(progesteron)

consequences
• polyuria
• hypohydration
• hypovolemia, decrease
BP
 5761 Part 2 Pathophysiologyof organsandsystems

Pathology of H2 0 metabolism
• In the kidneysnear180 L of H20 perdayarefiltratedand99 % reab-
sorbed

Cumulation of water
• hypoproteinemia
• renin-angiotensin-aldosteronsystemactivation
• hypernatriemia
• lossof filtration
• increaseof reabsorbtion (aldosteroneandADHexcess)
consequences:
• waterexcessandedemasformation

Lossof water
• Increasefiltration
• Decrease reabsorption
• Tubulopathias
consequences
• polyuria
• hypohydrat ion

Concentration anddilutionin thekidneys

Thekidneyis ableto concentrateurinebecauseof the creationof a hyper-
osmoticmedullaryinterstitiumandthe presence of recepto
rs on the collect-
ingductsfor antidiuretichormone(ADH).In the presenceof ADH, thereis an
increasein the numberof proteinwaterchannelsexpressed on the luminal
membrane , andwatermovesintothecelldownits concentration gradient.

Pathologyof concentration anddilutionfunction ofthekidneys :

Theincreaseof the quantity
' of dilutedurinedevelopsin situationsof de-
creasedADHconcentration anddecreased reabsorption of water.
Thredecrease of the quantityof concent ratedurinedevelops in situations
of increased
ADHconcentration andincreased the reabsorptionof water.
Pathophysiologyof gastrointestinaland renalfunction Unit 7 1577

For the diagnostics of this situationthey use 24 hour urine specimen

test..

Pathology
of K• metabolism
.

K• cumulation
• decrease•filtration
• decrease secretion(tubulopathias)
• acuterenal failure
• chronicrenalfailure
consequences
• increaseK• (diagnostictesttor dialysis)
• convulsions
• arithmias

K• loss
• decreasereabsorpt ion
• hyperaldosteronism
• potassiumsparing diuretics
consequences
• musclehypotonus
• weakness
• atrioventric
ulareblockade

Renal disorders of acid-base balance

Hydrogeni um is secretedin tubulesas H+andammonium.Theprocessof H•
ions excretion dependson acidogenesis andammoniogenes is. Hydrogenium
retention may occur as a resultof renalfailure and aldosterondefficiency .
Hydrogenium loss is resulted by primaryor secondaryhyperaldosteronism.
The inhibitionof acidogenesisandammoniogenes is in the leadsit excretory
acidosis development.
 5781 Part 2 Pathophysiologyof organsand systems

Glo meru lonephritis

Glomerulonephritis
is a bilateraldiseaseof the kidneysof the inflammatory
origin.Thereareacuteandchronic(diffuse)glomerulonephritis.

Acute{diffuse)glomerulonephritis
Experimental models.In 1901V.K. Lindemanobservedthe main mani-
festationsof nephritisin the rabbit in the intravenousintroduction of nephro-
toxicserumof the guineapigimmunizedwith suspensionof the rabbitkidney.
In 1933 by usingthe sameschemeof experiment,the Japanesescientist
Masugi reproducedthe clinical pictureof nephritisin rabbitsby introducing
serumsof the duckbloodimmunizedwith thetissueof the rabbit's kidneys.
The late Masugireceivedanothervariantof nephritismodelin the scheme
rat-rabbit-rat.
At present,therearetwo phasesof pathogenesis of the experimental glo-
merulonephritis: heterologicconditionedby the fixationof the nephrotoxic
antibodies(lgG, lgM) on the basalmembraneof the glomeruliof the neph-
ronsandautologicconnectedwiththe productionof complement-fixing anti-
bodiesfor nephrotoxicglobulin.
Etiology.Acute glomerulonephritis arises in (or after) some infection,
mostly of streptococcus nature.It is considered that hemolyticstreptococcus
of groupA is a specific"nephritogenic " strain.Otherinfectionsplaya definite
role, includingviruses,parasites. Glomerulonephritismayarise in cooling,
diffuselesionsof the connectivetissue(lupuserythematosis, rheumatoid ar-
thritis, nodularperiartter
itis), heterologicserumusedin therapy, burns.
Pathogenesis. Thereare two main mechanisms of damageof the glom-
eruli. ·
1. Affectionof the basalmembraneof the glomeruliof the nephronsby
antibodiesis antigens - nephrotoxicglomerulonephritis (it has a quick
progressive course).Glycoproteinas a carrierof antigenicproteins of
the basalmembrane.
2. Development of the inflammatoryprocessin the glomerulydueto the
fixationof the immunecomplexeson the basalmembrane- immuno-
complexglomerulonephritis.
Pathophysiologyof gastrointestinal and renalfunction Unit 7 1579

Themechanismis characterized by eitherexogenic(of infectiousor non-

infectiousorigin)or endogenic (tissueprotein,DNA)antigen.
• Exogenous antigens(e.g.,bacterial)-forexampie,a nephritogenicLance-
fieldgroupA(~-haemolyticStreptococcus )cancause glomerulonephritisin
previouslyhealthyindividuals
• Endogenous antigens- for example, patients with systemic lupus
erythematosus (SLE)mayform antibodiesto host DNA, leadingto glo-
merulonephritis.

The formedantibodies(lgG, lgM) beginto interactwith the mentioned

antigensin bloodserumandthenas immunecomplexes(antigen-antibody-
complement) entertheglomeruliaccumulating
ontheirbasalmembrane . The
impairmentof the immunecomplexes andnephrotoxicantibodiesis realized
by inductionof the immune inflammation.

The secondary m e chanisms of glomerular injury are:

• complement activation
• fibrin deposition
• plateletaggregation
• inflammation with neutrophil-dependent
mechanisms
• activationof kininsystems.

Resultingin an increaseof capillarypermeability

andglomerulardamage.
Glomerulonephritis developing afterthestreptococcal infection,in system-
ic lupuserythematosus, serumdiseaseandothersis relatedto the immune
complexes.
Clinicaland pathophysiological manifestationsof acuteglomerulonephri-
tis reflectchangesof the renal, mainlyglomerularand extrarenalfunctions.
Theclassicalcourseof the disease is characterizedby violentonset,oliguria,
proteinuria,hematuria,azotemia , arterialhypertension, edemaswhich de-
velopsdueto the retention of sodium, hypoproteinemia , hypervolemia, and
increased permeability
of capillariesanddisturbanceof the nervoussystem.
 580 I Part 2 Pathophysiologyof organs and systems

Chronic(diffuse)glomerulonephritis
Etiology . Chronicglomerulonephritismayresultfrom acuteone, but more
often it developsprimarily.Thereare the followingforms of the acute glo-
merulonephritis .
1. Of infectiousorigin (poststreptococcal, in malaria,syphilis,tuberculo-
sis).
2. Non-infectious (serum,vaccine,medicamentous, in intoxicationby dif-
ferentpoisons,traumatic,in thrombosisof the renalveins).
3. In diffusediseasesof the connectivetissue(rheumatoid arthritis, lupus
erythromatosus, hemorrhagic vasculites,etc.)
4. Special(radiation,hereditaryetc.)

Pathogenesis. Hypersensitivityof the delayedtype playsa certainrole.

Thefollowingforms are distinguishedclinicallyin the functionalcompensa-
tory phase.
1. Latent(65 % of all caseswith chronic glomerulonephritis) form is mani-
festedbyan isolatedurinesyndrome- moderateproteinuria , hematuria.
Somepatients (20-25 %) are observedto haveedemasand transitory
hypertension.
2. Hypertensive (32 % of patients)form is characterize d bystableincrease
of the arterialpressure.1/3 of patientshaveedemas,2/3 - hematuria,
all patientshaveproteinuria , and halfof them havecylinduria and leu-
cocyturia.
3. Nephrotic(2-4 % of patients)form is distinguishedby the edematous
syndrome(2/3 of patients) markedproteinuriaandcylinduria(in all pa-
tients)andcharacterist ic changesin blood(hypoproteinemia andhyper-
lipidemia). ·
4. Mixed of nephrotichypertensive (2.4 % of patients)form is charac ter-
izedby edemasandhypertens ion (in all patients).
'
Glomerulonephritis
may be a resultof the prevalence
of acute nephritic
syndromeor nephroticsyndrome.
Pathophysiologyof gastrointestinal and renalfunction Unit 7 I 581
Nephritic syndrome
In acute nephritic syndrom e the most important
clinical manif e stations are:

• haemat uria (macroscopicor microscopic)- red cell castsare typically

seenon urinemicroscopy
• proteinuria
• oliguria
• uraemia
• arterialhypertension
• edema(periorbital,leg or sacral)
• anemiaandhemorrhages

Renalarterialhypertension is connectedwith a highlevelof angiotensinII

andaldosterone. Angiotens in II causesvasoconst riction directly, aldosterone
leadsto salt retention, which resultscirculatorybloodvolumeelevatingand
hypertension.
Anemiaandhemorrhages developin kidney diseasesdue to the deffi-
ciencyof specificstimulatorsof erythro- andtrombocytopoesis .

Nephrotic syndrome
Nephroticsyndromeincludesvariousaffectionsof the kidneysandotheror-
ganswhicharecharacterized by markedproteinuria, hypoalbuminaemia , hy-
povolemia, dysproteinemia, hyperlipidemiaand edematous syndrome.
Etiology.By origin,the nephroticsyndromeis dividedinto primaryand
secondary.
Theprimary nephroticsyndromeis not connectedwith the kidneysdis-
ease.Frequently, its developme
nt is basedon geneticallyconditioneddefects
of metabolism (lipoid nephrosis)or transplacental
transfer of specificantire-
nalantibodiesfrom the motherto the fetus (congenital familynephrosis).
 sa2 I Part 2 Pathophysiologyof organsand systems

TheSecondarynephroticsyndromemay be causedby somediseasesof

the kidneys(glomerulonephritis) or otherorgans(nephropathy of the preg-
nant women, diabetesmellitus, amyloidosis , lupus erythema tosus, serum
disease,staphylococcal sepsis,etc.).It maybe observedin intoxication with
saltsof heavymetals,in vastburns, radiationaffectionin rejectionof the renal
transplant, in usingsomemedicines(sulfa drags,penicillin,corticosteroids)
andin the disturbance of bloodsupply of the kidneys.
Pathogenesis. Most of nephroticconditionsare causedby immunologi-
cal mechanisms , mostly by the sensitivityof the delayedtype. Exogenic
factors may be the sources of antigens:bacterial,virally, parasitic,medi-
camentous , food, compoundsof heavy metals, etc. DNA,denaturatednu-
cleoproteins , proteinsof tumoral origin and thyroglobulin may serve as
exogenic antigens.Antibodiesproducedin responseto theseantigensare
mostlyof lgM class.
Thedamageof the glomeruliof the renalis connectedwith the depositof
amyloid, glyco-and lipoproteins , fibrinogenwith the activationof humoral
andcellularlinks of the inflammatoryreactionon the surfaceor in the basal
membraneof the capillaries.As a result, the structuralintegrityof the basal
membraneis lost, its compositionand physicalandchemicalpropertiesare
changesandits permeability for plasmaproteinsis sharplyincreased.
For those forms of nephroticsyndromewhereimmunologicalmecha-
nismsarenot proved,the mostsuitablearemetabolicandphysico-chemical
mechanisms. So, nephroticproteinuriais explainedby the decreaseof the
constantelectric chargeof the well of the capillarynet; disappearance of
sialoproteinfrom it, whichcoversthe endotheliumand its processesin the
thin layerin the norm. In the placesof the maximalloss of ionsandsialopro-
teins, polymorphno-nuc lear leucocytesare accumulated whoselysosomal
fermentsexertdirectdamageeffecton the basalmembraneof the capillary
vessels.In its turn, proteinurjacausesthe secondarychangesof thetubules
of the nephronsand renalstromaas well as numberof generalchanges
in the organismhypoprotein uria of generalchangesin the organism hypo-
proteinemiaanddysproteinemia (hypoalbuminemiahyper-n2-globulinem ia),
edematoussyndrome.Besideshypoproteinemia and an increasedperme-
ability of the membranes , the latter is causedby secondaryaldosteronism
Pathophysiologyof gastrointestinaland renalfunction Unit 7 Isa3
whichdevelopsdueto hypovolemia(thecauseof whichis "leakage " of fluid
into the tissues), decreaseof the renalbloodflow andincreasedproduction
of renin.
Hyperlipidemia, which is characteristic of the nephroticsyndrome , is
broughtabout, mainly, by thriglycerides , cholesteroland pathogeneticallyit
is connec ted with protein metabolismand the suppressionof the lipolytic
activity of bloodplasma.

Pyelonephritis
Pyelonephritis is the infectiousinflammatorydiseaseof the mucousmem-
braneof the urinarytract and renalparenchyma(simultaneousor subse-
quent)with the predominant affectionof the intestinaltissue.
Etiology andpathogenesis. The disease arisedueto the penetrationof
the causativeagent of the infectioninto the kidneysby the hematogenicway
or by spreadingit up the wardsby the urinarytract.Thecausativeagentsare
mostly colon bacillus, cocci.
The developmentof the diseaseand transitionof acute pyelonephritis
into the chronic oneis promotedby differentconditionscausingurinecon-
gestion (constriction, occlusionof the ureter, adenomaof the prostate),
dystrophyof the urinarytracts, generaldiseasesreducing the reactivityof
the organism(diabetesmellitus,atherosclerosis, obesity,chronic intoxica-
tion, etc.)
Thetypical symptomsof the acutecase:painin the costovertebra l angle,
bladderandurethral irritation,pyuria, leukocytecasts. In the chronicpyelone-
phritistubulointest inalinflammationandrenalscarringaretypical.All symp-
tomsof acutecaseare associatedwith hypertension , polyuria.

Renal Insufficiency
Renalinsufficiencyis a clinicalcondition, wherethe glomerularfiltration rate
is inadequate
to clearthe bloodof nitrogenoussubstances classified as non-
 5841 Part 2 Pathophysiologyof organsand systems

proteinnitrogen(urea, uric acid, creatinine

, and creatine).The retentionof
nonproteinnitrogenin the plasmais calledazotemia. Thenumberof filtrating
nephronsfalls below1/3 of normal, as determined by the measurement of a
GFRbelow40 ml/min.

Acute re nal failure

Acuterenalinsufficiency(ARI) is characterized by acutedisturbanceof the
stabilityof the internalmediumof theorganismdueto considerable andquick
decreaseof the rateof the glomerularfiltration (in the norm 120ml/min, in
oligo-andanuria-1-10ml/min).
Acuterenalfailureis causedby theconditionsthat producean acuteshut-
downin renalfunction.

The causes of acute renal failure may divided into 3

groups of factors:

1. Prerenal(55-60 %)
2. Intrinsic(renal)(35-40 %)
3. Postrenal( ~ 5 %)

Prerenal factors of ARI are : ·

'
1. Blood loss, burns, incontrollable
vomiting, profusediarrhea
, the use of
diureticsresultingin sharpdecreaseof the volumeof the intravascular
andextracellularfluids. ·
2. Vascularforms of shock?septic,anaphylactic) , accompanied by the re-
ductionof the arterialpressure.
3. Acute (myocardialinfarction,embolismof the pulmonaryartery)and
chronic cardiacinsufficiency.
Pathophysiologyof gastrointestinaland renalfunction Unit 7 f sas

Renal factors of ARI :

1. Localdisturbances of microcirculation in the kidneys(thrombosis,em-

bolismof kidney'sarteria, DYCsyndrome,prerenal ischemia ;
2. Acuteandchronicglomerulonephritis , vasculitis, nephriticand nephrot-
ic syndromes,lupusnephropathy ;
3. Nephrotox ic influencesin the kidneys - antibiotics,heavymetals,taxi-
cosesof the pregnancy woman,diabeticcoma, snake poison,anaerobic
infection, sepsis,peritonitis, liverinsufficiency.

Po strenal factors a re :

1. Obstructionof the ureter (calculi,tumors).

2. Retentionof the urine at the levelof the bladder outlet(adenomaof the
prostate)
.

Pathogenesis. The main mechanism of ARI development is temporary

ischemiaof the kidneysconditionedby hypovolemia , spasmof the afferent
arterioles,disseminatedintravascularbloodcoagulationwith microthrombo-
sis or directdamageof the renalvessels.In consequence thereare marked
decreaseof the filtrationpressureand tubularfiltration, switchingoff of a
definitenumberof the nephrons.
Undertheinfluenceof thenephrotoxic factors(toxic,infectious)alongwith
disturbanceof the corticalbloodflow, direct damageof the glomerularand
tubular structuresbecomes important.The rateof the glomerularfiltration
maybe decreased for the secondtimedueto the obstructionof the tubular
lumenby necroticmassesor dueto theleakage of thefiltratethrough thewall
of the damagetubulesintothe interstice.
The increased pressurein the capsuleof Shumlyansky-Bowme n or in the
interstice resultsin a decrease of effectivefiltrationpressure.
In damageof the cells of the proximaltubule, 5he reabsorption of Na+is
disturbed.Its increasedconcentration in the distaltubulesis takenby mas-
culadense that resultsin theactivation of renin-angiotensin system.
 5861 Part 2 Pathophysiologyof organsand systems

Th ere a re four st a g es in th e clinical course of ARI:

1) initial;
2) oligo-, anuria;
3) polyuria;
4) recovery .

Themostcharacteristic andmarkeddisturbances areobservedin thestage

of oligo-, anuria.Along with sharpdecreaseof diuresisup to its complete
stop, thereare hyperazotemia, the disturbanceof water-electrolyte homeo-
stasis (hypoosmotichyperhydration) and acid-baseequilibrium(excretory
acidosis). Themainclinicalmanifestations of this stagearethe brainedema
(becauseintracellularaccumulation of fluid), interstitial lungedema, theclini-
cal pictureof waterintoxicationof the organism,the severedisturbances of
circulation - the decreaseof contractile functionof the heart, arrhythmiaas
extrasystole, bradycardia
, blockade,hypotension with transformation intohy-
pertension , dyspnoeby Kussmaultype (a sign of acidosis),severedysfunc-
tions of the nervoussystem- headache , vomiting,loss of consciousness ,
convulsions , coma, anemia.
A highpercentag e of patientssufferingfrom acuterenalinsufficiencydie.
In providingeffectivetherapeutical measures thereis transitionintothe stage
of diuresisrestoration and polyuriain 5-10 days.Thedevelopment of poly-
uriais a goodprognosticsign. Butfirst beginstheworkof a smallquantityof
nephrons.Forthis reason,azotemiaandacidosisare savedfor a longtime,
andtheredevelophypokaliemia andisoosmotichypohydration.

Ch ronic renal insuff iciency. Uremia

Etiology.Theetiologicalfactorsof chronicrenalinsufficiency(CRI)arechron-
ic progressing diseasesof thekidneysof inflammatory (chronicglomerulone -
phritis, chronicpyelonephritis, etc.),vascular( hypertens
ion,stenosisof the
renalartery)and metabolic(diabeticglomerulosclerosis, amyloidosis, gout)
origin.
Pathophysiologyof gastrointestinaland renal function Unit 7 I sa7
Pathogenesis. CRI develops asa resultof a simultaneous
or subsequentde-
creaseof themassof theactingnephrons andreductionof the renalfunctions.

On this depends th e stage of chronic ren a l failur e :

1. Polyuria
2. Oliguria
3. Uremia

Theinitial signsof CRIappearin the reductionof the massof acting neph-

rons (MAN)to 50- 70 % of the originalamountof the nephrons , clinically
markedpicturedevelopsin reductionof MANto 30-10 %. Furtherreduction
of MANandglomerularfiltration(below10 % of the norm)leadsto thetermi-
nalstageof renalinsufficiency- uremia.The mainmanifestations of CRIare
conditioned , first of all, by azotemia.
Inthepolyuriastage,theappearance of urinesymptoms , whicharediagnosed
by24hoursurinespecimen test,is mostimportantfor diagnostic. Thedecrease
of theconcentrated functionof thekidneys , isoosmotic andhypoosmotic urine,
nocturiafind in the urine.In the bloodazotemia anduremiadevelop. Ureabe-
gins to outcomefrom the organismthroughthe skin, gastrointestinal tract,
lungsandfor this reasondermatitis , gastritisandpneumonia oftendevelop
In oliguriastageazotemiaanduremiaincrease . Appearance hyperkaliemia ,
hypocalcaemia (becau se decreasesynthesisof vitamin0), acidosis , hyper-
tension, anemia.
In the uremic stage,over200 toxicsubstanceswererevealed . Theholeac-
cumulationin bloodin CRIdeterminetheorganismintoxicationandassociated
symptoms.Theyareanorexia(lossof appetite) , dyspepticsigns(vomiting, di-
arrhea ), reductionof thebodymass,generalweakness , headache , apathy,dis-
ordersof taste, hearing , tormentingitching,dyspnoe , progress ive anemia , ure-
micpericarditis , myocardi tis,pleurisy, arthritis,convulsions andcoma. Uremic
comais a resultof brainintoxication by productsof proteinsbreakingdown.
Thetreatmentof CRIin this stageincludeshemodialysis, peritonealdialy-
sis, kidneytransplantation .
 PATHOPf-iYSIOLOGY
Unit8 OF ENDOCRINE
AND NEURAL FUNCTION

Chapter 30. Pathophysiology

of the Endocrine System

Theendocrinesystempresentsan importantcommunicative systemthat is

responsible for regulation, integrat
ion,andcoordination of a varietyof physi-
ologicalprocess , includinggrowth, sex differentiation, metabolism,and ad-
aptationto an ever-changingenvironment.Theendocrineglandssecretetheir
products , whichare biologicallyactivemoleculescalledhormones,into the
blood.The bloodcarrieshormonesto targetcellsthatcontain specificreceptor
proteinsfor thehormonesandwhichcanrespondin a specificfashionto them.
Along with hormones,othertypesor chemicalmessenger systemsinteract
with oneotherto maintain homeostasis.

They include:

1) neurotransmitters , whicharereleased byaxon terminalsof neuronsinto

the synapticjunctions (e.g.,acetylcholine,norepinephrine);
2) cytokines, whichare secretedby cells into the extracellular
fluid (e.g.,
interleukins);
3) cicosanoids , whichare derivedfrom arachidonicacid (prostaglandin s
andleukotriens) ;
Pathophysiologyof endocrineand neuralfunction Unit 8 Isag
4) "Secondmessengers"(e.g.,cAMP,cGMP,Ca2 * ions),whichact inside
the cell helpingsome hormonesand neurotransmitters
to exert their
effects.

Althoughthesemessengers arenot producedby endocrineglands,nor se-

creteddirectlyintothe bloodstream
, theyarehighlypotentandplayimportant
rolesin cell-to-cellcommunication;
hence,theysometimesarecalled"tissue
hormones".

According to terms of the cells they target

hormones and hormone-like substances
can be classified the following ways:

1. Endocrine hormonesinfluencethe functionof cellsat distantlocationin

the body(e.g.,thyroidhormoneor corticosteroids);
2. Autocrinesaffectthe functionof the samecellsthat producedthem by
bindingto cell surfacereceptors;
3. Paracrines affectneighboringcellsof a differenttype(e.g., insulinwhich
is secretedby ~-cells in the pancreasaffectsthe secretionof glucagon
by the neighboringa-cells, alsoin the pancreas).

Structural classification
Hormonesusuallyaredividedinto threeclassesaccordingto their chemi-
calstructure.
1. Proteinsandpolypeptides, includinghormonessecretedbythe anterior
and posteriorpituitary, the pancreas(insulinand glucagon)and many
others.
2. Steroidssecretedby the adrenalcortex (cortisolandaldosterone),the
ovaries(estrogenandprogesterone) , the testis (testosterone
), andthe
placenta(estrogenandprogesterone).
3. Derivationof theaminoacidtyrosinesecretedbythe thyroidgland(thy-
roxinand triiodtironine),andthe adrenalmedulla(epinephrine andnor-
epinephri ne).
 590 I Part 2 Pathophysiologyof organsand systems

Disturbances of endocrinefunction
Disturbancesof endocrinefunctioncanbedividedintotwo categories:hy-
perfunctionandhypo/unction. Bothhyper-andhypofunction of theendocrine
glandcanbeprimary, secondaryandtertiary.
Primarydefectsin endocrinefunctionoriginatein the targetgland(e. g.,
primarydeficiencyof corticosteroidhormonescausedbyadrena lectomy).
In secondarydisordersof endocrinefunction, the target glandis essen -
tially normalbut its functionis alteredby a defectivelevelof stimulating
hormonesfrom the anteriorpituitary(e.g., a decreasein the productionof
corticosteroids bytheadrenalcortexcausedbythe removalor destructionof
the pituitarygland).
Tertiarydisordersresultfrom hypothalamic dysfunctionwhenboth the pi-
tuitaryandtargetorganareunder- or hyperstimulated.

Feedback controlofhormone secretion

The activity of the most of endocrineglandsis regulatedby feedback
mechanisms that involvethe hypothalamic-pituitary -targetcellsystemand
ensurea properlevelof hormoneactivityat thetargettissue.
In positivefeedback(rare)the stimulusis amplifiedby the signal.This
resultsin a largersubsequent response , whichfeedsbackto produceaneven
greaterstimulus.
In negativefeedback , the stimulusis decreasedby the response.Like
mostotherregulatorymechanisms in theorganism,hormonal action is most-
ly subjectto negativefeedback. _
Disorders ofnegative feedback mechanism in thehypothalamic -pituitary-
targetglandsystemsplayan importantrolein thedevelopment of endocrine
pathology.
Forexample , a deficiencyof iodinein drinking waterorfoodleadstoa decreased
synthesis of thyroidhormone . According to theprincipleof thenegativefeedba ck
mechanisma it resultsin anincrease in TRHandTSHsecretion. Hyperproduction
of TSHin turncauseshyperplasia of thethyroidgland,the so-calledstruma.
The otherexampleis that the administrationof corticosteroid hormones
causessuppressionof the hypothalamic-pituitary-adrenal cortexaxis result-
ing in a decreased productionof owncorticosteroi ds by the adrenalcortex.
Pathophysiologyof endocrineand neuralfunction Unit 8 I 591
In epycasewhenthetreatmentwith corticosteroid
drug is stoppedsuddenly
,
the syndromeof abolitionmay occur. This is manifestedby symptoms of
acuteadrenalfailure.

Transportofhormones
Hormonesthat are releasedinto the bloodstreamcirculatefree, unbound
or attachedto transport carriers.Peptidehormonesand proteinhormones
usuallycirculateunboundin the blood.Steroidhormonesand thyroid hor-
monesare carriedby specificcarrierproteinssynthesizedin the liver. It is
important,that onlyfreeformsof hormonesarebiologicallyactive.

Disturbances of the transport of hormon e s may

manifest themselves by two types of disord e rs of
endocrine function:

1) an increasein bindingof a hormonewith transportcarriersleadsto a

decrease in theamountof theactive unboundhormoneandasa conse-
quenceto hypofunctionof the givengland.
2) a decreasein bindingof a hormonewith transportcarriers(e.g., in ne-
phriticsyndromeor cirrhosisthat areassociated with hypoproteinema)
causesan increasein the concentration of an activeunboundform of
hormonein the bloodthat, in its turn, leadsto hyperfunctionof the ap-
propriategland.

Drugsthatcompetewith a hormonefor bindingwithtransportcarriermol-

eculesincreasehormoneactionby increasing theabilityof the activeunbound
hormone.For example,aspirincompeteswith thyroidhormomefor bindingto
transportproteins. Whenaspirinis administrated
to personswithexcessive levels
of circulatingthyroidhormone(suchasthyroidcrisis),seriouseffectmayoccur.

Metabolismandelimination
In somecases, hormonesare eliminatedin the intactform. But most of
hormonesmust be inactivatedto prevent their accumulation.Some hor-
 5921 Part 2 Pathophysiologyof organsand systems

monesare enzimat ically inactivatedat receptorsiteswheretheyexerttheir

action.Thus, catecholamines are degradedby monoamineoxydase(MAO)
and catechol-0 -methyltransferase(COMT).Thedegradation of proteinand
peptidehormonesoccursin theliverundertheactionof enzymespeptidases.
Adrenaland gonadalsteroidalhormoneslikeas thyroidhormoneare inacti-
vatedin the liver by way of conjugationwith glucuronicacidsand thenex-
cretedin the bileor urine.In a human65-95 % inactivatedmetabolites of all
hormonesexcretefrom theorganismwith urine.
Disturbances in metabolism ofhormones maycausethedevelopment of
peripheraldisordersof endocrine function.

They are as follows:

1) impairmentof the inactivationof hormonesleadsto an increasein the

amountof hormonesin the bloodthat is accompanied by appropriate
hyperfunction;
2) increasedtransformationof hormonesinto their inactiveforms ac-
companiedwith the development of endocrinehypofunct
ion (e.g., an
increasedactivityof insulinase
, the enzymethat breaksdown insulin,
cancausediabetesmellitus2 type).

Mechanisms ofaction
Hormonesproducetheir effectsthroughinteractio n with high-affinityrecep-
tors locatedeitheror on the surfaceor insidethetargetcells. Thefunctionof
thesereceptorsis to recognize a specifichormoneapdtranslatethe hormonal
signalintoa cellular response.
Theresponseof a target cellto a hormonedependson
1) the numberof receptorspresent ;
2) the affinityof thesereceplorsfor hormonebinding.

Thereareapproximately
from 2000to 100000hormonereceptorspercell.
Thenumberof hormonereceptorson a cell maybealteredfor anyof several
reasons
.
Pathophysiologyof endocrineand neuralfunction Unit 8 1593

They are as follows:

1) a destroyor blockof the receptorproteinsby antibodies;

2) alteredlevelsof hormonethat influencethe activityof the geneswhich
are responsiblefor receptorsynthesis.

Decreased hormonelevelsproducean increasein receptornumbers;the

processis calledup-regulation. Excessivehormonelevelsproducea decrease
in receptornumbersby down-regulation.
Theaffinityof receptorsfor bindinghormonesis alsoaffectedby a number
of conditions.Forexample,pH is very importantin the affinityof insulinre-
ceptors.In ketoacidosis,insulinbindingis decreased.

There are two types of hormone-receptor interac-

tions:

1) surfacereceptor;
2) intercellularreceptorinteractions.

Surface receptorinteraction
Peptidehormones andcatecholamines interactwith surfacereceptors.It is be-
causetheyhavelow solubilityin the lipid layerof cell membranes andcannot
crossthem. Theinteraction of thesehormones withsurfacereceptorleadsto the
generationof anintercellular
signalthatis termedthesecondmessenger, andthe
hormone is consideredto bethefirstmessenger. Thesecondmessenger activates
enzymes or otherproteinsinsidethecellandquickbiochemical effectsoccur.

There are the following second messengers:

1) cyclicadenosinemonophosphate
(cAMP)that is the most widelydis-
tributed;
2) cyclicguaninmonophosphate
(cGMP)
 594 I Part 2 Pathophysiologyof organsand systems

Bindingof hormonesor neurotransmi tters to surfacereceptors may also

actdirectlyto openionchannelsin thecellmembrane , andoftentherearecal-
cium channels . In this case,the influxof ionsservesasan intracellular signal
to conveythe hormonalmessage to thecellinterior.Theincreasing cytoplas-
micconcentration of calciumresultsin thedirectactivationof calcium-depen-
dentenzymesor calcium-calmod ulin complexes withtheirattendanteffects.

Intracellularreceptor
interaction
Steroid andthyroid hormonesact insidethe cell.Theyare lipid solubleand
passfreelythrow the cell membrane.Thentheyare attachedto intracellular
receptorsandform a hormone- receptorcomplexthat travelsto the cell nu-
cleus. Thehormone-messenger complexthenactivatesor suppressesgene
activitywith a subsequentproductionor inhibitionof proteinsynthesis
.

The following proteins may be produced :

• enzymes ;
• transportproteins;
• receptors;
• structuralproteins.

Disturbancesin the interactionof hormoneswith peripheral

targetcells are
mainlymediatedby abnormalities of cellreceptors
.

They are as follows:

1. a decreasein the amountof receptors or in the affinityof the receptors

for hormonebinding(i.e.,desensitization);
in this case, hypofun ction of
the endocrineglandoccursdespitethe fact that the level of hormonein
the bloodis normalor evenincreased.
2. an increasein the numberof receptors(i.e.,sensitization) is usuallyas-
sociatedwith the developmentof endocrinehyperfunction.
Pathophysiologyof endocrineand neural function Unit 8 Isss
Alter ations in Pituitary functi o n
Normalanatomyandfunction.The pituitary gland is situatedin the sella
turcica, and it is dividedinto an anterior lobe (the adenohypophysis) and a
posteriorlobe(the neurohypophysis). Theanteriorpituitaryandposteriorpi-
tuitary are moreor lessseparateendocrineorgans.Theadenohypophysis is
embriologycallyoriginatedfrom glandulartissue, and it is connecte d with
the hypothalamus by bloodflow in the hypophyseal portalsystem.It repre-
sentsapproximately 90 % of the pituitarygland.Stimulatedby hypothalamic
hormones , the anteriorpituitaryproducestropic hormonesthat affect the
endocrinetargetglands(thyroid,adrenal,andgonads),growth, andlactation.
In addition,theanteriorlobeof the pituitarysecretesp-lipotropin(p-LPH)that
affectslipid metabolism , andmelanocyte -stimulatinghormone(MSH) which
controlsskincoloration.
Thesynthesisandreleaseof anteriorpituitaryhormonesarelargelyregulat-
edbytheactionof hormonesfrom thehypothalamus whichis thecoordinating
centerof the brainfor endocrine,behavioral, andautonomicnervoussystem
function.Thehypothalamus integratesincomingneuralsignalsinitiatedfrom
the bodyandthe environment , and it secretesvariousreleasingor inhibiting
factorsthatevokespecifichormonalresponses from the pituitarygland.

Th e most important hypoth a lam ic hormon es that

regulate the s e cretion of ant e rior pituit a ry hormon es
include :

1. Thyrotropin-releasing hormone(TRH), which stimulates the pituitary

releaseof thyrotropin;
2. Corticotropin-releasing hormone(CRH), whichstimulatesthe pituitary
releaseof adrenocorticotropin;
3. Prolactine-inhibitingfactor(PIF), or dopamine,whichsignalsthe pitu-
itaryto haltthe releaseof prolactine;
4. Growth-hormone-releasing hormone(GHRH), whichstimulatesthe pi-
tuitaryreleaseof growthhormone.
 5961 Part 2 Pathophysiologyof organs and systems

Theprincipalhormonesof theanteriorpituitaryareshownin table31.

Table31. Hormone
s of theanteriorpituitaryglandandtherefunctions
.

.N"!! Name .
'
,•,
. ,, '·· .. ' ,
Prlndpatactioil·.
. :K1 f. :, . .i'•
~!¾
~~
..
·~·/.
_;: y
,.
J. ... .
~,,,,;,N,,:"
~-
;~}~a~~,(
.. ~~-- •

1 Thyroid-stimulating
hormone
(TSH, Stimulates thyroidsecretion
andgrowthof
thyrotropin) thyroid gland
2 Adrenocorticotropic
hormone
(ACTH
, Stimulates
secretion
andgrowthof zone
corticotropin) fasciculate
andzonereticularis
of adrenal
cortex
3 Growth
hormone
(GH,somatotropin
, Acceleratesbodygrowthandcontrols
STH
) metabolism
4 P-lipotropin
(P-LPH) Stimulatesmobilization of fat fromadipose
tissueand useof it in energymetabolism
5 Melanocyte-stimulating
hormone
(MSH
) Controls
pigmentation
of thes~n
6 Follicle-stimulating
hormone
(FSH) Stimulates
ovarian
folliclegrowthinfemale
.___
andspermatogenesis
in male
7 (J)
Cl) Luteinizing
hormone
(LH) Stimulates ovulation
andluteinization
C
0
E
(development of corpuslutein
) of ovarian
,.__
0
..c
folliclesin femaleandtestosterone
(.)
·a. secretion in male
8 -e
0
'O
ro
C
Prolactine
LTH
(luteotropic
, luteotrop
hormo
in, lactogen
ic
ne, Stimulates
breastgrowthaswellasmilk
production
aildmaternal
behavior
C
(!:) hormone, mammotropin)

'
The neurohypophysisis embriologycallyoriginatedfrom neuraltissue, and
it is connected
withthe hypothalamus by the nerveaxonsfrom hypothalami c
thesupraoptic andparaventricularnuclei.In contrastto thehormone-produc-
inganteriorlobe,theposteriorpituitarystoresandreleases two hypothalamic
hormones, oxytocin,whichstimulatesuterinecontractionsandinitiates
 Pathophysiologyof endocrineand neuralfunction Unit 8 1597

lactation,andvasopressin(antidiuretic hormone(ADH)) whichregulatesthe

maintenance of serumosmolality.
Both oxytocinand ADH are producedby neuronsin the nuclei of the
hypothalamusthat haveaxonswhich terminateon the capillarynetwork
in the posterior lobe, where they dischargehormonesinto the systemic
circulation.

Alteration in pituitary function can be divided into:

1) hypofunction
, or hypopituitarism
2) hyperfunction,
or hyperpituitarism.

Hypopituitarism is characterized
by a decreased secretionof a single(par-
- tial hypopituitarism),
several(subtotal hypopituitarism), or all (total hypopi-
tuitarism)pituitaryhormones.
Theanteriorpituitaryhasa largereserve.Typically , 70 % to 90 % of the
adenohypophysis must be destroyedbeforehypopituitar ism becomesclini-
callyevident.The causemaybecongenitalor resultfrom a varietyof acquired
abnormalities.

Hypopituitarism may result from:

1. Primarypituitarylesionsincluding
• pituitarytumor, eithera primaryadenomathat compresses the restof a
normalglandor metastasis to the pituitary;
• pituitaryinfarction,especiallyin the peripartumperiod;
• pituitaryradiationtherapyor surgery;
• geneticdiseases- rarecongenitaldefectsof oneor morepituitaryhor-
mones;
2. Secondary defects:
• hypothalamic disorders- tumorsandmasslesions(e.g.,hypothalamic
radiation,tumor,trauma, infections).
 5981 Part 2 Pathophysiofogyof organs andsystems

Total hypo p ituitar ism

Althoughisolated pituitaryhormonedeficiencies can occur, total hypopitu-
itarism(panhypopit uitarism)from a destructive pituitary lesionis morecom-
mon.Becauseof decreases or depletionof pituitarytropic hormonesandthe
resultantnonstimulationof targetendocrineorgans,affectedpatientsshow
symptomsof hypothyroidism (cold intolerance, lethargy),hypogonadism(in-
fertility},andhypoadrenalism (susceptibilityto infection, stressintolerance).
In children,dwarfism alsoresults becauseof a lack of GH.

Ex a mples of panpituitarism includ e :

1) pituitarycachexia(Simmond 's disease)that is characterize

d by a severe
cachexiaandatrophy of the thyroid,adrenal , andsexualglands;
2) pituitarynecrosis(Sheehan's syndrome)that resultfrom the infarction
of the pituitarygland.

Sheehan 's Syndrome , also knownas postpartumpituitarynecrosis, is a

raresyndromethatoccursmostcommonlyin thethird trimesterof pregnancy
whenthe anteriorpituitary suffers ischemicnecrosisprecipitatedby obstetri-
cal hemorrhage or shock.Thesyndrome canoccurin menand non-pregnant
womenassocia ted with disseminated intravasc
ular coagulationsyndromor
trauma. Pregnantwomenare moresusceptible due to the pituitary enlarge-
mentthat occursin pregnancy.Patientsusuallypresentearlywith inability to
lactatebut canalsopresentyears later with multiple hormonedeficiencies.

Part ia l hyp opit uitar ism

Isolatedpituitarytropin deficienciesoccurrare,andtheyareoftendueto hy-

pothalamic(secondaryhypopitui tarism)rather than pituitary(primaryhypo-
pituitarism)disorders.Forexample, an appreciable numbers of patientswith
partialTSHdeficiencyshowanincreasein TSHsecretionwhenTRHis injected.
 Pathophysiologyof endocrine and neuralfunction Unit 8 Isss
The most common clinical syndromes a ssoci at e d
with the hypoproduction of a single pituitary hor-
mone include:

1) pituitarydwarfism(nanism),which resultsfrom a decreasedsecretion

of GH.
2) pituitaryhypogonadism , whichoccursdueto an impairedsecretionof
gonadotropichormones.
3) pituitaryhypocorticism
, whichis dueto a decreased
productionof ACTH
resultingin secondaryadrenalfailure.

Growthhormonedeficiencycan be primary(e.g.,due to a pituitarytu-

mor or agenesisof the pituitary)or secondary(due to a lack of hypotha-
lamicGHRH).In children, GHdeficiencyinterfereswith linearbonegrowth,
- resultingin short statureor dwarfism.In adults,GH deficiencyleadsto an
increasedcardiovascular mortality(endothelial
dysfunction, atherosclerosis).
The GHdeficiencysyndromeis associatedwith a clusterof cardiovascular
risk factors,includingcentraladiposity,increasedvisceralfat, insulinresis-
tance,anddyslipidemia, the so-calledmetabolicsyndrome(syndromeX).

Posterior p ituitary hypofunction

Deficiencyof vasopressinsecretionleadsto diabet es insipidus.
Diabetes insipidus (DI) is a diseasecharacterizedbythe excretion of large
amountsof severelydilutedurine,whichcannotbe reducedwhenfluid intake
is reduced.It denotesthe inabilityof the kidneyto concentrate urine. DI is di-
videdinto:centralDIwhichis causedby a deficiencyof antidiuretic hormone
(ADH)secretiondueto pituitarytrauma,strokeor infection,andnephrogenic
DIdueto theinabilityof thekidneyto respondnormallyto ADHwhichmayoc-
cur asa hereditaryor acquireddefect(medications effect,polycystickidney).
Theonly symptomsin primaryDI are polydipsiaand polyuria.Enormous
quantitiesof fluid maybe ingested,andlargevolumes(3 to 30 Uday)of very
diluteurineare excreted.Nocturia is almostalwayspresentin DI andin NOi.
 600 I Part 2 Pathophysiologyof organsand systems

Dehydrationand hypovolemia maydeveloprapidlyif urinarylossesare not

continuouslyreplaced.Symptomsof diabetesinsipidusare quitesimilarto
thoseof untreateddiabetesmellitus,with the distinction thatthe urine is not
sweetandthereis no hyperglycemia.

Hyperpituitarism
Hyperpituitarism
is characterized
by an increasedsecretionof pituitary
hormones.

Anter ior pituitary hype rfunc tion

Intrinsichypersecretionof an anteriorpituitarytropic hormonealmostal-
waysis the resultof a neoplasm(usuallyan adenoma) . Althoughfunction-
ing adenomasoccasionally causemultihormoneproduction,the threemost
commonclinicalsyndromesare associa ted with overprod uction of a single
hormone(partial hyperpituitarism).

They include:

1) growthhormoneoverproduction
;
2) hyperprolactinemia;
3) hypercort
icism.

Growth ho rmon e over production '

Themaincauseof excessive GHsecretionbytheanteriorpituitaryis anacido-
phil cell (eosinophilic)pituitaiy adenoma . The effectsvarywith the patient's
age.GHhypersecretion in a childleadsto gigantismandin an adultto acro-
mega/y.
Rarely,GHhypersecretion beginsin childhood, beforeclosureof theepiph-
yses, and leadsto the exaggerate d skeletalgrowthtermedpituitarygigan-
 Pathophysiologyof endocrineand neuralfunction Unit 8 I 601
tism. In children, growthvelocity is increasedbut with little bonydeformity.
However,soft tissueswellingoccursandthe peripheralnervesareenlarged.
Delayedpubertyor hypogonadotropic hypogonadism is alsofrequentlypres-
ent, resultingin a eunuchoidhabitus.WhenGHhypersecretion beginsafter
epiphysealclosure, the earliestclinical manifestationis coarseningof the
facialfeaturesand soft tissueswelling of the handsand feet.The patient's
appearancechanges , andlargerrings, gloves,andshoesare needed . Photo-
graphsof the patientare importantin delineatingthe courseof the disease.
Theincreasein the dimension of theacralparts(belongingto the extremities
or peripheralbody parts)hasledto the term acromegaly.
Acromegaly occurs in the adult when the epiphysesare closed, linear
growthis no longerpossible,andGHproducesthe patternof boneandsoft
tissuedeformities.Thereis anenlargement of the handsandfeet(acralparts;
. hencethe term acromegaly)and a protrusionof the lowerjaw called prog-
nathism.Overgrowthof the malar, frontal, and basal bones combines with
prognathismto producethe coarsefacialfeaturescalledacromegalic facies.
In adultswith acromegaly , otherchangesalso occur.Coarsebody hair
increases, andthe skinthickens andfrequentlydarkens.Thesizeandfunction
of sebaceousandsweatglandsincrease.suchthat patientsfrequentl y com-
plain of excessiveperspirationandanoffensivebodyodor.Theovergrowthof
the mandibleleadsto the protrusionof the jaw (prognathism) and malocclu-
sion of teeth.Cartilaginous proliferationof the larynxleadsto a deep, husky
voice. Thetongueis frequentlyenlarged.In long-standing acromegaly,
costal
growthleadsto a barrel chest.Articularcartilaginousproliferationoccursear-
ly in responseto GHexcess , with the articularcartilagepossiblyundergoing
necrosisanderosion.Joint symptomsarecommon,and degenerat ivearthri-
tis may occur. The heart, liver, kidneys, spleen,thyroid, parathyroidglands,
and pancreasarealsolargerthannormal.GHincreasestubularreabsorption
of phosphateandleadsto mild hyperphosphatemia .
About50 % of patientshaveabnormalglucosetolerancetest thatis a result
of GH-induced insulin resistance.GHexertsmultiple effectson carbohydrate
metabolism,includingdecrease d glucoseuptakeby tissuessuchas skeletal
muscleand adipose tissue, and increased glucoseproductionby the liver.
Each of thesechangesresultsin GH-induced insulin resistancewhichstimu-
 6021 Part 2 Pathophysiology
of organsand systems

latesthe p-cellsof the pancreasto produceadditionalinsulin. Thelong-term

overstimulationof the p-cellscanresultin GH-induced diabetesmellitus, but
clinicallysignificantdiabetesmellitus occursin onlyabout10% of patients.

Hyperprolactinemia
The main cause of elevatedserum prolactinelevel is a pituitaryadenoma
producingprolactine.In female,hyperprolactinemia is associated
with a sus-
tained milk secretion from the breast(galactorrhea) andsecondaryamenor-
rhea,the so-calledamenorrhea -galactorrhea syndrome.Hyperprolactinemia
in male is associatedwith the loss of libido,and impotence, and rarelywith
gynecomastia .

Hypercorticism
Pituitaryhypercorticismis dueto the overproduction of adrenocorticotropic
hormoneresultingin adrenocorticalhyperfunction.Adrenocorticalhyper-
function that resultsfrom an excessiveglucocorticoidproductionby the
adrenalcortex (primaryhypercorticism) is called Cushing'ssyndrome . By
convention , whenthis symptomcomplexis dueto ACTHhypersecretion by
the pituitaryglang, it is calledCushing'sdisease.Pituitaryhypersecretion of
ACTHmaybe causedby the hypothalamicoverproductionof CRH(tertiary
hypercorticism)or by a tumorof the pituitarygland(secondaryhypersecre-
tion). Excessive ACTHlevelsmayalsodueto ectopicACTHproductionby a
nonendocrine tumor (especiallysmall-celllungcarcinoma).
Posteriorpituitaryhyperfunction developsvery rarelyand is usuallyre-
lated to the syndromeof inappropriate antidiuretic hormone (SIADH).The
syndromeof inappropriateADHsecretionis characterized by high levelsof
ADHin the absenceof normalphysiologicstimuli for its release .
Themainfeaturesof SIADHarewaterretentionor increasesin total body
H20; soluteloss, particularlyNa;osmotic inactivationof cellularsolutes.
SIADHrequiresthe followingsigns:serumhypoosmolality andhyponatre-
mia, urine hypersomoalarit y (the osmolalityof the urinein somepatientsis
greaterthan expectedfor the concomitantserumosmolality),urine sodium
excretionthat matchessodium intakeandimprovement in hyponatremia with
waterrestriction.
Pathophysiologyof endocrineand neuralfunction Unit 8 1603

Alteration in Adrenal function

Normalanatomy andfunction. Theadrenalglandsaresmall, bilateralstruc-
turesthat weighapproximately 5 g eachand lie retroperltoneally
at the apex
of eachkidney.The adrenalglandis actuallydividedintoanatomical andfunc-
tionalgroundsintotwo separateendocrineorgans:theadrenalcortexwhich
secretesthe steroidhormones ; andthe adrenalmedullawhichis a modified
ganglionandsecretesthe catecholamines . Adrenalmedullaryhormonesare
not essentialfor life becausethe sympathe t ic nervoussystemalsosecretes
epinephrineand norepinephrine , but they help to preparethe individualto
dealwith emergencies .
Onthe otherhand, the adrenalcortexis essentialfor life. It secretesglu-
cocorticoidswhichaffectthe metabolismof carbohydrate and protein, min-
eralocorticoidsessentialto the maintenance of sodiumbalanceandextracel-
lularfluidvolume,andsexhormonesthatexertminoreffectson reproductive
function.Of these, the mineralocorticoidsandglucocorticoids are necessary
for survival.

Hormones
ofAdrenalcortex

The adrenal cortex has thr ee zones , all of which

produce steroid hormones:

• the outermostzonaglomerulozaproducesmineralocorticoids , princi-

pallya/dosterone-,
• the intermediate
zonafasticulataproducesglucocorticoids
, principally
cortisot,
• the innermostzonareticularisproducesandrogens
.

Thesecretionof theglucocorticoids andtheadrenalandrogens is controlled

bytheACTHsecretedby theanteriorpituitarygland. Thesecretionof the min-
eralocorticoids
is controlledbycirculatoryfactors,of whichthemostimportant
is angiotensin
II that is in turn dependent
onthe renin secretedbythe kidney.
 6041 Part 2 Pathophysiology of organsand systems

Transport , metabolism, andmechanism ofaction.Theglucocorticoids ,

like other steroid hormones, are poorly soluble in aqueous media,and
they circulateboundto plasmaproteins, largelyto corticosteroid-binding
globulin (CBG)and to a lesserextent to albumin. The mineralocortic oids
bind mostlyto albuminfor transportin the circulatorysystem.Oncebond,
the steroid is physiologically inert. Thefree or unboundfraction (< 10 %)
of the total plasmaconcentrationis the biologicallyactiveform. Steroids
that are free in the blooddiffuse throughthe plasmamembranesof target
cells;onceinside,they bind to cytoplasmic receptorproteins, resultingin
the formation of hormone-receptor complex, which translocatesinto the
nucleus.Thesecomplexesthen bindto targetsiteson the DNAthat affects
geneactivitywith subsequent productionof messenger RNAand protein
synthesis.
The main site for metabolismof theadrenalcortical hormonesis the liver,
wherethey are metabolized , conjugatedand madewater soluble. They are
eliminatedin eitherbileor urine.
Effectsof the glucocorticoidscanbe dividedinto physiological
andpatho-
logical.

Physiological effects of the glucocorticoids are as

follows:

Metaboliceffect.Cortisolincreasesthesynthesisof a numberof enzymes

whichplay keyrolesin hepaticgluconeogenesis (ananabolicaction of corti-
sol). In adiposetissueandskeletal muscle,however ,.cortisolis catabolic,i.e.,
it causesa breakdownof bodytissuein orderto mobilize energy. As body
proteinsare brokendown,aminoacidsare mobilized andtransportedto the
liver,wherethey are usedin the productionof glucose(i.e., gluconeogen-
esis). Thebreakdown of triglyceridesandmobilizationof fattyacidsconverts
cellmetabolism fromthe useof glucosefor ATPproductionto the useof fatty
acids.Asglucose productionby the liver increasesand peripheral glucose
usedecreases,moderateglucoseintolerancedevelops . In personswho are
predisposed to diabetesit resultsin hyperglycemia.
Pathophysiologyof endocrineand neuralfunction Unit 8 f sos

Psychological effect.Theglucocorticoidhormonesappearto be involved

directlyor indirectlyin emotionalbehavior,andthey maycontributeto emo-
tionalinstability.
Permissive effecs.Theglucocorticoids facilitatethe responseof the tissues
to humoralandneural influences , suchas that of the catecholamines during
traumaandextremestress.
Pharmacological effectsof the glucocorticoidsincludeimmunologicand
anti-inflammatory ones.The glucocorticoidshavelittle influenceon the im-
munesystemunderphysiologicalconditions.However,whenadministered
in largedosesovera prolongedperiodtheycansuppressantibodyformation
anddecreasethe development of cell- mediatedimmunity.Immature T-cells
in the thymusandimmature8-cellsandT-cellsin lymphnodescanbe killed
by exposureto highconcentration of the glucocorticoids , causinglymphope-
niaandatrophyof lymphoidtissue.
Theanti-inflammatoryactionof the glucocorticoidsis basedmainlyon
their ability to inhibitthe activityof phospholipase A2, reducingthe amount
of arachidonicacid availablefor conversionto prostaglandinsand leucot-
rienes.
A highly significant aspect of long-term therapy with pharmacologic
preparationsof the adrenalcortical hormonesis adrenalinsufficiencyon
withdrawalof the drugs. Prolongedtreatmentwith the glucocorticoids
drives down ACTHrelease;thereforeendogenouscortisol production is
extremelylow. Chronic suppressioncausesthe atrophy of the adrenal
gland,and the abrupt withdrawalof drugs can causeacuteadrenal insuf-
ficiency.Thus, patientshaveto be weanedoff the glucocorticoidsslowly
to allow the rise of plasmacortisol to normal levels.Recoveryto a state
of normal adrenalfunction may be prolonged, requiring 12 months or
more.
Effectsof the mineralocorticoids. The mineralocorticoids stimulatethe
activetransportof sodiumthroughthe epithelialcell wall. In commonwith
the othersteroidhormones,aldosterone stimulatesde novosynthesisof pro-
teins,whichenhancesodiumtransportin the epithelialcell of the distalcon-
volutedtubule of the kidney.
 6061 Part 2 Pathophysiology
of organsand systems

There are three main mechanisms of aldosterone

a ction :

1) it increasesthe numberof sodium channelsin theapicalmembrane;

2) it increasesthe numberof Na+-K+-ATP-ase
molecules;
3) it increasesATPmoleculenumberwithinthecell.

Disorders ofadrenalcorticalfunction canbedividedintotwovariants:hy-

pofunctionandhyperfunction. Usuallyhypofunctiondevelopsasa totalinsuffi-
ciencyof theadrenalglandandhyperfunction haspartialcharacteristics. From
this case,all disordersof theadrenalcortexmaybeclassifiedint ofourgroups.
1. Hypofunction of adrenalcortex(adrenocorticalinsufficiency).
2. Hyperfunct ion of thezonafasticulata(hypercortisolism).
3. Hyperfunction of the zonaglomeruloza (hyperaldos teronism).
4. Dysfunct ion of the adrenalcortex(adrenogenital syndrome) .

Adrenocortical insufficiency
Adrenocortical insufficiency maybecausedby the destructionof the adrenal
cortex(primaryadrenalinsufficiency), low pituitaryACTHsecretion(second -
ary adrenalinsufficiency ), or deficienthypothalamic releaseof CRH(tertiary
adrenalinsufficiency).
Primaryadrenalinsufficiency or Addison 's diseaseresultsfrom the de-
struction of the adrena l cortexby microorganisms or autoimmunedisease .
Beforeeffectivecontrol of tuberculosis, bilaterala9renaldestructionby tu-
berculos is wasthe mostcommoncauseof the disease.Today,autoimmune
destructionaccountsfor 70 % to 90 % of all cases,with the remainderthe
resultingfrom infection, cancer,or adrenalhemorrhage . Antibodiesinvolved
in autoimmuneadrenalitisdevelopment are mainlydirectedto the steroido-
genicenzymes.Geneticsusceptibilityto autoimmune adrena l insufficiencyis
strongly linkedwith the HLA.
In primaryadrena l insufficiency,all threezonesof the adrenalcortexare
usuallyinvolved.The result is the inadequate secretionof glucocorticoids ,
Pathophysiologyof endocrine and neuralfunction Unit 8 1607

mineralocorticoids and androgens.The adrenalcortex has a large reserve

capaci ty, andthe manifestations of adrenalinsufficiencyare not usuallyde-
tecteduntil 90 % of the glandhas beendestroyed.
Mineralocort icoid deficiencyresultsin an increase d excretionof Na and
decreased excretionof K,chieflyinthe urine,whichis isotonic, and alsoin the
sweat, saliva,and GI tract. Blooodanalysiswill show low bloodconcentra-
tions of NaandCl anda high concentration of serumK. Theinabilityto con-
centrate the urine, combinedwith changesin electrolytebalance,produces
severedehydration , plasmahypertonicity , acidosis, decreasedcirculatory
volume, hypotension , andcirculatorycollapse.
Cortisoldeficienc y contributes to hypotensionandproducesdisturbances
in carbohydrate , fat, and proteinmetabolismand severeinsulinsensitivity.
In the absenceof cortisol,insufficientcarbohydrate is formedfrom protein;
hypoglycemia and diminishedliver glycogenresult.Weaknessfollows, due
in part to deficientneuromuscular function.Resistance to infection,trauma,
and other stress is diminishedbecaus e of reducedadrenaloutput.Myocar-
dialweaknessanddehydrationcausereduced cardiacoutput, andcirculatory
failurecanoccur.Decreased cortisolbloodlevelsresultin hyperpigmentation
of the skin and mucousmembraneswhich is a characteristicof Addison's
disease.The increasein pigmentation developsas a result of increase d Me-
lanocyteStimulationHormoneproduction( an intermediate lobeof the pitu-
itarygland), whichoccursat the sametimewith the increasedpituitaryACTH
production.
Clinicalmanifestation : weakness, fatigue, andorthostatichypotensionare
earlysymptomsof Addison's disease.Pigmentat ion is usuallyincreasedex-
cept in adrenalinsufficiencysecondaryto pituitaryfailure.An increasedpig-
mentationis character ized by diffusetanningof both exposedandunexposed
portionsof the body.
Anorexia , nausea , vomiting, and diarrheaoftenoccur.A decreased toler-
anceto cold, with hypometabo lism, may be noted. Dizzinessand syncope
mayoccur.ECGmayshowdecreased voltageandprolongedPRand OTin-
tervals.
Weightloss, dehydration , hypotension , andsmallheartsizearecharacter-
istic of the laterstagesof Addison's disease.
 6081 Part 2 Pathophysiology of organsand systems

In somecases,Addison's symptomsmaypresentrapidly.This"acute ad-

renal failure" is knownas an Addisonianor adrenalcrisis. Thereasonsof it
are: traumaof bothadrenalglands,adrenalbilateralhemorrhage (overdoseof
heparine, acuteor fulminantsepsis).

An adrenal crisis is characterized by:

• acutehypotension - dueto low cardiacoutput, lowvasculartoneanda

decreased bloodcirculatingvolume;
• dehydration of the organism- the lackof aldosteroneresultsin water
andsodium loss, plusvomiting(especially in acuteinfections);
• insufficiencyof bloodflowon all the levels- centralcirculation,tissues
and organscirculation andmicrocirculation;the causesof it are: acute
cardiacfailure,decreaseof the arteriolestone,a decreaseof the blood
circulatingvolume.

Thecauseof the patient'sdeathin adrenalcrisis is acutefailureof blood

circulation.

Ac ute ad renal insufficiency (adrenal c risis)

Acuteadrenalinsufficiencyis a life-threatening situation. It is a rapidlypro-
gressivedisorder(overhoursor days)presentingclinicallyasshock. Suchan
illnessmayoccurin septicemia , especially menin_gococcemia, adrenaltrau-
ma, anticoagulanttherapyor adrenalveinthrombosisas a resultof massive
bilateraladrenalhemorrhage.

Hyperc o rtiso lism. Cus hing 's syndr o m e

Hyperfunctionof the zonafasticulataof the adrenalcortexis characterized
by an increasedsecretionof the glucocorticoids
by theadrenalgland(hyper-
Pathophysiologyof endocrineand neuralfunction Unit 8 Isog
cortiso/ism).The term Cushing'ssyndromerefers to the manifestationsof
hypercortisolismfrom anycause. Theyinclude:
1) adrenalconditionsresultingfrom adenomaor carcinomaof the adrenal
cortex(primaryhypercortisolism);
2) pituitaryconditionsresultingfrom hypersecretion
of ACTH,causingbi-
lateraladrenocortical
hyperplasia(oftencalledCushing's disease);
3) ectopicACTHsyndromeresultingfrom thesecretionof ACTHby nonen-
docrinetumors. usuallysmall-cellcarcinomaof the lung;
4) Iatrogenicconditionsresultingfrom the administrationof excessive
dosesof corticosteroidsor ACTH.

The majormanifestat ions of Cushing'ssyndromerepresentan exagge ra-

tion of manyactionsof cortisol.
Chronicallyincreasedplasmaglucose(hyperglycemia) stimulatesexcess
insulin secretionwith consequentthe ~-cellsexhaustionand diabetesmel-
litus,alsocalledsteroid diabetes, development. Thekidneyshaveto eliminate
excessglucosethat resultsin polyuriaandpolydipsia.
Alteredfat metabolismcausestruncalobesityand redistributionof trun-
cal fat, with a characteristic"buffalohump", and a round, plethoric"moon
face". BothACTHand glucocorticoidsare lipolyticin normalfat stores,and
the excessinsulinmaybe lipogenicin the face, upperbackand in the supra-
clavicularfat pads.
Thecataboliceffectof glucocorticoidson proteincausesnegativenitrogen
balance,with musclewasting,weakness , andthinningof the extremities.The
loss of the boneproteinmatrix resultsin osteoporosis,causingbackpain,
compressionfracturesof the vertebrae,andrib fractures.
The glucocorticoidspossessmineralocorticoids properties;this causes
hypokaliemia as a resultof excessivepotassiumexcretionand hypertension
resultingfrom sodiumretention.
Theglucocorticoidssuppressthe immunesystemby atrophyinglymphoid
tissueand inhibiting lymphocytefunction,resultingin increasedsusceptibil-
ity to infection.
Excesslevelsof the glucocorticoidsmay give rise to extremeemotional
!ability,ranging from middleeuphoriato grosslypsychoticbehavior.
 610 I Part 2 Pathophysiologyof organsand systems

Hyp eraldo ster o nism

Hyperfunction of thezonaglomeruloza of theadrenalcortexis characterized
by an increasedsecretionof the mineralocorticoids (hyperaldosteronism).
Hyperaldosteronism maybe dividedinto primaryandsecondaryones.
Primary hyperaldosteronism(Conn'ssyndrome)is due to a lesion of
the adrenalglandandaccountsfor approximatelyone-thirdof all casesof
adrenocorticalhyperfunction.Themostcommonlesionis an aldosterone-
producing adrenaladenoma.The aldosteroneexcessproducessodium
retention,increasedtotal plasmavolume,increasedrenalarterypressure,
and inhibition of renin secretion.Most patientswith primary hyperaldo-
steronismare womenaged30 to 50 who presentwith hypertensionand
hypokalemic alkalosisthat result from increasedurinarylossesof potas-
sium.
Secondaryhyperaldosteronism is dueto extraadrenal causes, and relates
to reninhypersecretion . An importantstimulusfor the releaseof aldosterone
is angiotensin11
, whichis formedin increasedamountsvia the renln-angio-
tensin systemwhenthe renalperfusionpressureis reduced.For example,
if the pumpingactionof the heartis reduced(heartfailure)or in peripher-
al vasodilatation(e.g., in sepsisor liver failure), the bloodpressurecan be
maintainedonly by massiveactivationof the sympatheticnervoussystem,
resultingin renalvasoconstriction , renin release
, and hyperaldosteronism.
Also secondaryhyperaldosteronism maydevelopin patients with diseases
of the liverwhenhepatocytes do not normallyinactivatealdosteronandtyis
hormoneis accumulated in the blood.

Ad ren oge nital syndr o me

Adrenogenital syndromeis a state of the dysfunctionof the adrenalcortex
causedby inbornenzymedefectsthat inhibit cortisolsynthesis . The result
is a feedbackoverproduction of ACTHcausingadrenalhyperplasia and the
overproduction of the adrenalhormonesthat arenot affectedby the enzyme
deficiency, i.e.androgens.
 Pathophysiologyof endocrineand neuralfunction Unit 8 I 611
In males
, theconditionis seldomdiagnosed , in femalesanincreasein adrenal
androgensadrenal androgensresultsin virilizationwith hirsutism (abnormally
abundantanddistributedbodyhair),baldingandclitoral enlargement. Thesefea-
turesareusually apparent at birth, butin someformsdo not developuntillater.

Disorders of adrenal medull a fun ction

Hormones of theadrenalmedulla
Theadrenalmedullalies withinthe cortexand originatesfrom the neural
crest.Thecatecholamines , epinephrineand norepinephrine , are synthesized
by the chromaffincellsof the adrenalmedulla .
Effectsof catecholamines . Epineph rineandnorepinephrin e produce wide-
- spreadeffectson the cardiovas cular system, muscular system, and carbo-
hydrateand lipid metabolism in the liver, muscleandadiposetissues.Most
cellsof the bodyhavereceptorsfor catecholamines and, thus, aretheir target
cells(Table32).

Table32.Actionsof epinephrine.

N!?
-
. ~-
r ·
•'Jt1,, '' '·ReceptorEffect
flssu'e
;:,;:·~:, ' '! ~ ·;
'
.

1 Heart P1 Acceleration
in heartrateandforceof contract
ion
2 Bloodvessels UI Vasoconstriction
in the skin
P2 Dilatation
of coronaryandskeleta
l musc
le vessels
3 Respiratory
system P2 Bronchodilatation
4 Gastrointestin
al al Sphincters
contract
tract a2 Smoothmusclerelaxes
5 Metabolism a2 Decreased Insulin release
~2 Increasedglucagonrelease
= increaseinbloodglucose level
 612 I Part 2 Pathophysiologyof organsand systems

Stressorscausean immediatereleaseof catecholamines, which prepare

the bodyfor extraordinary physicalandmentalexertion;henceepinephrine is
calledthe hormoneof "flight or fight".
Disordersof adrenalmedullafunction occur rarely.The most common
clinicalsyndromeis associatedwith overproductionof catecholamines by
chromaffincell tumor(pheochromocytoma).
Themostprominentfeatureis hypertension , whichmaybe paroxysmal or
persistent.The hypertensionis dueto secretionof oneor moreof the cate-
cholaminehormonesor precursors:norepinephrine, epinephrine, dopamine ,
or dopa.Commonsymptomsandsignsaretachycardia, diaphoresis , postural
hypotensio n, tachypnea , flushing, cold and clammyskin, severeheadache ,
angina,palpitation , nausea , vomiting, epigastricpain, visual disturbances,
dyspnea , paresthesias , constipation.Paroxysmalattacksmay be provoked
by the palpation of the tumor, postural changes , abdominalcompress ion or
massage,inductionof anesthesia, emotionaltrauma.

Alte ration in thyroid function

Normalanatomy andfunction. Thenormalthyroidweighsapproximately 25

g andis situatedcloseto the trachea . Thefollicleis the functiona l unit of the
thyroid. It is composedof an epithelium-linedsac filed with colloid, which
storesthe thyroidhormonesin the form of thyroglobulin.Thethyroidfollicle
producesand secretestwo thyroid hormones : thyroxin(T4) and triiodthyro-
nine (T3). Thyroxinand triiodthyronineare iodinatedderivatesof the amino
acidtyrosine.Thethyroidis remarkablyefficientin its useof iodide.The follicle
cellshavein their basementmembrane an iodide-trapping mechanism which
pumpsdietaryiodideintothe cellagainsta concentration gradient.Asa result,
the cell concentrates iodideto 20-50'timesits concentrat ion in the plasma.
Inside the cell, iodideis oxioizedby the enzymethyroid peroxidase to the
more reactiveiodine,which immediatelyreacts with tyrosineresidueson
thyroglobulinto form monoiodotyrosine andthen diiodotyrosine . Two diio-
dotyrosine residuesare coupledto form T4 , or a monoiodotyrosineand a
diiodotyrosinearecoupledto form T3.
 Pathophysiologyof endocrineand neuralfunction Unit 8 I 613
Triiodthyronineand thyroxin are re- inhibition
Hypothalamus
leasedinto the circulation, wherethey are
bound to plasmaproteins, includingthy-
roxine-bindingglobulin(TBG).Morethan
i
Anteriorpituitary
TAH

99 % of T4 andT3 are carriedin the bound

form andthereforephysiologicallyinactive,
i
Thyroid gland
TSH

whileonlythe freefractionis active.

Thesecretionof thyroidhormoneis regu- i
Targertissues
latedby the hypothalamic-pituitary-thyroid
feedbacksystem (Fig. 60). Normally, hy-
pothalamicthyrotropin-releas ing hormone Fig.60. The hypothalamic -pitu-
(TRH)stimulatesthyrotropin(TSH)release itary -thyro
id feedbacksystem
from the anteriorpituitary. TSHthenstimu-
-. latesthyroid hormonerelease,whichfeeds
backto the pituitaryto limit TSHrelease.
Effectsof thyroid hormone . Thereis evidencethat T3 is the activeform of
the hormoneandthat T4 is convertedto T3 beforeit canact physiologically.

Thyroid hormone has two m ajor fun ction s :

1) it increasesmetabolismandproteinsynthesis ;
2) it playskeyrolesin the regulationof bodydevelopment,
includingmen-
tal developmentandsexualmaturity.

Thyroid hormone actions

Thesecanbeclassifiedas nuclear(on nuclearreceptor)and non-nuclear (on
plasmamembraneand mitochondria).
At the membrane , the hormonestimulatesthe Na•-K+-ATP
-ase pump, re-
sultingin increaseduptakeof aminoacidsandglucose.
Combiningwith specificreceptorson mitochondriaT3 causesan increase
in mitichondrialoxygenconsumption(calorigenicaction),and productionof
adenosinetriphosphate(ATP)whichis requiredfor the sodiumpump, which
usesup to 40 % of the total energysupplyof the body. A greaterrate of
 614 I Part 2 Pathophysiologyof organsand systems

oxidativephosphorilation resultsin greater heatproduction

. Old theory,that
thyroid hormoneproducedheatby uncouplingoxidationof substrate from
phosphorilation in the mitochondriahasnow beendisproved.
In the nucleiwhicharethe maintargetsfor the thyroidhormones,T3 binds
to receptorsresultingin an increasedexpressionof specificgenes.The re-
sultantmessenger RNAstriggerthe productionof variousenzymesthat alter
cellfunction.

Th ese e nzym e s includ e:

• Na•-K+-ATP-aseof plasmaticmembrane ;
• enzymesof mitochondrias;
• proteincomponentsof p-adrenergicreceptors.

All biologicaleffectsof thyroidhormonecanbe dividedinto threegroups:

metabolic,anabolic , andpermissive.
Metabolic effects Most of the widespreadeffects of thyroid hormone
in the body are secondaryto stimulationof 02 consumption(calorigenic
action). T3 increasesthe 0 2 consumptionof almost all metabolicallyac-
tive tissues,exceptthe brain, spleen, testes,and anterior pituitary. As a
result of this higher metabolism,the rate of glucose,fat, and proteinuse
increases.

Thyroid hormone is c a tabolic :

1) stimulatingintestinalabsorption of glucose;
2) stimulatinghepaticglycagenolysis;
3) stimulatinginsulinbreakdown;
4) potentiatingthe glycogenolyticactionof epinephrine;
5) stimulatinglipolysis;
6) permittingthe lipolyticactionsof other hormones, suchas glucocorti-
coids,glucagon,growthhormoneandepinephrine.
 Pathophysiologyof endocrineand neuralfunction Unit 8 I 615
Thesemetaboliceffectsof thyroidhormoneare high-dose ; thereforethey
becomeevidentat hyperthyroidism.
Anaboliceffects.Thyroid hormoneis essentialfor the growth and dif-
ferentiationof bodytissues.Theseeffectsare low-doseandoccurin physi-
ologicalconditions.Theabsenceor a decreaseof anaboliceffectsbecomes
evidentat hypothyroidismandmanifestsitself by slowedbonegrowthand
delayedepiphysealclosure,as well as by muscleatrophyand weakness ,
weightloss, and negativenitrogenbalance.
Permissiveeffectsrepresentthe ability of thyroid hormoneto increase
the responsiveness of tissuesto catecholamines andother hormonessuch
as estrogensor steroids. Thyroidhormoneincreasesthe numberand af-
finity of p-adrenoreceptors in the heart and possibly in some other tis-
sues, and the effectsof thyroid hormoneon the heart resemblethose of
- p-adrenergicstimulation(i.e., chronotropicand inotropic effects of cat-
echolamines).
Disordersof thyroid functioncan representa hypofunclionalor hyper-
functional state. They may be causedby a congenitaldefect in thyroid
development , or they may developlater in life. Disordersof the thyroid
glandresultprimarily from autoimmuneprocessesthat eitherstimulatethe
overproductionof the thyroid hormone(thyrotoxicosis)or causeglandular
destructionand hormonedeficiency(hypothyroidism).Three major thy-
roid antigenshavebeendocumented:thyroglobulin(Tg), thyroid peroxi-
dase(TPO)andTSH-receptor(TSH-R).Bothhypothyroidand hyperthyroid
states, as well as euthyroidone, may be accompaniedby thyroid gland
enlargement,the so-calledgoiter.

Hypothyroid ism
Hypothyroidismrepresentsa decreasein thyroid function resultingfrom
destructionor dysfunctionof the thyroid gland(primaryhypothyroidism
),
or impairedhypothalamicor pituitary function (secondaryhypothyroid-
ism).
Primaryhypothyroidism is muchmorecommonthansecondaryone.
 616 I Part 2 Pathophysiologyof organs and systems

It may result from:

• insufficientsynthesisof thyroidhormonesdueto the destruction of the

thyroidglandin autoimmunethyroiditis(Hashimoto 's thyroiditis);
• surgicalor radiation"overkill"in removingthyroidtissue;
• dietarylackof iodine(endemicgoiter);
• congenitallackof thyroidtissue(hypo-or aplasiaof the thyroidgland,
or enzymopathies) ;
• use of somedrugsor foodsthat interferewith thyroid hormonessyn-
thesis(e.g., iodine-containing drugs,radiographiccontrastmedia and
other).

Congenital hypothyroidism
Congenitalhypothyroidismis a commoncauseof preventable mentalre-
tardation. Thyroid hormone is essentialfor normal brain development
and growth. Childrenwho are hypothyroidfrom birth are called cretins.
They are dwarfedand mentally retarded. and haveenlarged,protruding
tongues and potbellies.Hypothyroidismin the infant can be causedby
a congenitallack of the thyroid gland, abnormalbiosynthesis of thyroid
hormone,or impairedreleaseof TSH. Beforethe use of ionizedsalt be-
camewidespread, the most common causeof cretinism was maternal
iodinedeficiency.
T4 crossesthe placenta,and unlessthe motheris hypothyroid,the infant
with congenitallackof thyroidglandappear~normalandfunctionsnormally.
However,replacement thyroid hormonetherapymust be startedsoonafter
birth if mentalretardation(cretinism)is to be prevented.

Acquiredhypothyroidism .
The syndromeof adult hypo!hyroid ism is generallycalled myxedema , al-
thoughthe term is also usedto referspecificallyto the skin changesin this
syndrome.
The skin normallycontainsa varietyof proteincombinedwith polysac-
charides,hyaluronic acid,and chondroitin sulfuric acid. In hypothyroidism,
thesecomplexesaccumulatein the connectivetissuesthroughoutthe body,
 Pathophysiologyof endocrineand neural function Unit 8 I 617
promoting waterretentionandthe characteristicpuffinessof the skin (myx-
edema).As a resultof myxedematous fluid accumulation , the facetakeson
a characteristicpuffy look,especiallyaroundthe eyes,the tonguebecomes
enlarged, andthevoicehuskyandslow.Thesecharacteristic changesof voice
arethe basisof the aphorismthat "myxedema is the onediseasethat canbe
diagnosedoverthetelephone ".
Theotherclinicalmanifestationsof hypothyroidismare relatedto the hy-
pometabolic stateresulting from thyroidhormonedeficiency . Thehypometa-
bolicstateis characterized by a decreasein the basalmetabolicrate(BMR),
a tendencyto gainweight,andcoldintolerance. Asthe conditionprogresses,
the skin becomesdry and roughandacquiresa paleyellowishcolourresult-
ing from carotenedeposition.This is becausethat the thyroid hormoneis
necessary for hepaticconversionof caroteneto vitaminA, andthe accumu-
- lation of carotenein the blood-stream(carotenemia)in hypothyroidism is
responsible for theyellowishtint of the skin.
Thyroid hormonedeficiencycausesa decreasein numberandaffinity of
p-adrenoreceptorsin the heartwith resultantbradycardia , decreased cardiac
output,andhypotension .
Gastrointestinalmotility is decreased , producingconstipation , flatulence,
andabnormaldistension.
Nervoussysteminvolvementis manifestedin mentaldullness, lethargy,
and impairedmemory.In somepatientsthereareseverementalsymptoms
("myxedemamadness ").
Themajorcauseof acquiredhypothyroidism is anautoimmune disorderin
whichthe thyroidglandmaybetotallydestroyedbyan immunologicprocess
(Hashimoto'sthyroiditis).
Iodinedeficiencyis alsoa commoncauseof hypothyroidism.Iodinedefi-
ciencyis responsiblefor endemic goiterandcretinismbut is an uncommon
causeof adult hypothyroidismunlessthe iodineintakeis very low. Iodine
deficiencyis prevalentin manymountainousregionsand in centralAfrica,
centralSouthAmerica,and northernAsiawherethereis an increasedprev-
alenceof goiter.Beforethe practiceof addingiodideto tablesalt became
widespread, the conditionwascommonin theseareas, andiodinedeficiency
1 goiteroccurredin up to 50 % of the population .
.,
~

I
 618 I Part 2 Pathophysiologyof organsand systems

Themechanism for the development of the largeendemicgoitersis thefol-

lowing.A lackof iodinepreventsproductionof boththyroxinandtriiodothyro-
ninebut doesnot stoptheformationof thyroglobulin. As a result,no hormone
is availableto inhibitproductionof TSHbytheanteriorpituitary;this allowsthe
pituitaryto secreteexcessively largequantities of TSH.TheTSHthencausesthe
thyroidcellsto secretetremendous amountsof thyroglobulin (colloid)intofolli-
cles,andtheglandgrowslargerandlarger.Butbecause of lackof iodine,thyrox-
in andtriiodothyronine productionstill doesnot occurwithinthethyroglobulin
andthereforedoesnot causethenormalsuppression of TSHproductionbythe
anteriorpituitary.Thefolliclesbecometremendous in size, andthe thyroidgland
mayincrease. Thisenlargement is dueto anincrease in follicular cellheightand
number,i.e., hyperplasia , andit is theexampleof feedback regulation .

Hyperthyroidism
Hyperthyroidism , or thyrotoxicosis, resultsfrom the excessivedeliveryof
thyroid hormoneto the peripheraltissues.The most commoncauseof hy-
perthyroidismis Graves ' disease, whichis accompanied by ophthalmopathy
(bulgingof the eyeballs)andgoiter.

Oth e r c a us es of hyperthyroidism include:

• functioningthyroid adenomas or carcinomas;

• pituitarytumorsthatsecretthyrotropin(secondary
hyperthyroidism);
and
• ingestionof excessivethyroidhormone(rarely).

Clinic a l manif e st ations of hyp e rthyroidism are relat-

e d largely to two factors :

1) hypermetabolic stateassociated with the increasein oxygenconsump-

tion (calorigenicactionof thyroidhormone)anduseof metabolicfuels;
 Pathophysiologyof endocrineand neuralfunction Unit 8 I 619
2) the increasein sympatheticnervoussystemactivity(permissiveaction
of thyroidhormone).

With the hypermetabolic state,therearefrequentcomplaintsof nervous-

ness,irritability, andfatigability, as well as weightloss despitea largeappe-
tite; andan increasein the BMRandheatintolerance.
Thyroid hormoneexcessleadsto an increasein numberand affinity of
~-adrenorecepto rs that enhancesthe effectsof catecholamines causingthe
cardiovascular effects(tachycardia,increasedpulsepressure) , shortnessof
breath, excessivesweating,anda fine tremorof the outstretchedfingers.

Graver's disease{diffusetoxicgoiter )
Graver's diseaseis a state of hyperthyroidismwhich is accompaniedby a
- protrusionof the eyeballs(exophthalmu s) anda symmetricalenlargementof
the thyroid gland(goitef1 . Thediseaseis associatedwith humanleukocyte
antigen(HLA),anda familialtendencyis evident.Diffusetoxic goiteroccurs
five timesmorefrequentlyin womenthanin man.
Graver'sdiseaseis an autoimmunediseasein whichT-lymphocytesacti-
vatedby antigensin the thyroid glandstimulate8-lymphocytesto produce
circulatingantibodiesagainstcomponentsof the TSHreceptors.Thesean-
tibodies,which are calledthyroid-stimulatingimmunoglobulins(TSI), react
with normalTSHreceptorsandstimulatethyroidhormoneproduction.There
is markedstimulationof the secretionof thyroidhormonesandthe high cir-
culatoryT4 andT3 levelsinhibitTSHsecretion , so the circulatingTSHlevelis
decreased .
Theexophthalmus in Graver
's diseaseis dueto swellingof the tissue. par-
ticularlythe extraocularmuscles,withinthe rigid bonywallsof the orbit.This
pushesthe eyeballsforward.Theexophthalmus, whichoccursin as manyas
onethird of affectedpersons,is thought, dueto the depositionof thyroglobu-
lin-antithyroglobulinandotherthyroidimmunecomplexesin the extraocular
muscles,with the production of an immune-complex inflammatoryreaction.
Alternatively, it maybean autoimmunediseaseof the orbitalmuscles.
Thyrotoxicosisplacesa considerableloadon the cardiovascular system.
Tachycardia, oftenwith arrhythmiaand palpitationcanbe mostor evenall of
 620 I Part 2 Pathophysiologyof organsand systems

the symptomsin somepatientswith hyperthyroidism. High-outputcardiac

failurecandevelopin patientswith thyrotoxicosisbecauseof the drop in pe-
ripheral resistancecausedby cutaneousvasodilatation andopeningof a large
arteriovenou s fistuladespitethe cardiacoutput is elevated.

Alteration in endocrin e regulation of calcium

Calciumis essentialfor manyphysiologicprocesses.It is a vital secondmes-
sengerandis necessary for bonegrowth, bloodcoagulation, musclecontrac-
tion, and nervefunction. Threehormonesare primarily concernedwith the
regulationof calciummetabolism.
1. Parathyroidhormone (PTH), which is secretedby the parathyroid
glands, maintainsthe calciumconcentration of the extracellular
fluids. It
performsthis functionby:
• promotingthe releaseof calciumfrom bone;
• stimulatingcalciumconservationby the kidneywhile increasingphos-
phateexcretion.
2. Ca/citonin, which is secretedby the parafollicularcells of the thyroid,
inhibitsboneresorption ; henceit is a calcium-lowering hormone.
3. 1,25-Dihydroxy -vitamin03 , whichis formedfrom vitaminD in the liver
and kidney, increasescirculatingCa2• ions as a meansof enhancing
intestinalabsorptionof calcium.

Parathyroid hormone disorders

Parathyroid hormone , alsocalledparathormone, is a major regulatorof serum
calciumandphosphate. Thedominantregulatorof PTH secretionis changes
in serumcalcium levels,andthereis.an inverse relationshipbetween plasma
Ca2• andPTH.
Hypoparathyroid ism reflectsdeficientPTHsecretionresulting in hypocal-
cemia.The causesof hypothyroidismusuallyare iatrogenicconsequences
of thyroidsurgery,radioiodinetherapy, as well as a mechanicalinjuryto the
neck, as in a motorcar accident, and, morerarely, a congenitalabsenceof all
of the parathyroidglands,suchas occursin Di Georgesyndrome.
 Pathophysiologyof endocrineand neuralfunction Unit 8 I 621
Decreasein parathyroidfunctioncan resultnot only from a deficiencyof
PTHbut alsofrom a failureof targetorgans(bonesand kidneys)to respond
to PTH, a conditioncalledpseudohypoparathyroidism.
Manifestationsof hypoparathyroidism arerelatedto hypocalcemiaandare
chieflyneurologic:anxiety, depression , functionalpsychoses, andneuromus-
cular irritability. Severehypocalcemiacausestetanywith musclecramps,
carpopedalspasm,and convulsions.Patientshavehypocalcemia and hyper-
phosphatemia.
Hyperparathyroidism is causedbythehypersecretion of theparathyroid hor-
moneresultingin hypercalcemia. Hyperparathyroidism canmanifestsasa pri-
marydisordercausedbyadenoma, carcinoma , or hyperplasiaof theparathyroid
glands,or asa secondary disorder associated with avitaminosis D, resulting in
chronicallydecreased serumcalcium,whichin turnstimulatesPTHrelease.
Manifestations of primaryhyperparothyroidism are relatedto hypercalce-
- mia and includementalconfusion, headache , polyuria, polydipsia, hypercal-
curia, calcified corneaand renaland gallstoneproblems. includinglithiasis
(kidneyand gallstonestones),and pancreatitis,which is associatedwith
gallstones.Chronicboneresorptionmay producediffusedemineralization ,
pathologicfractures,andcysticbonelesions.
Secondaryhyperparathyroidism involveshyperplasiaof the parathyroid
glandsand occurs primarilyin personswith renalfailurewhich cannotsyn-
thesizeactivevitamin D, and therefore,hypocalcemia develops. The bone
diseaseis seenin personswith secondaryhyperparathyroidism causedby
renalfailureknownas renalosteodystrophy.

Alterat ions in endocr ine fu nct ion of the gonads

The testesare the male gonads, and their primaryfunctionsare the pro-
ductionof malesex androgenes(i.e., male sex hormones), mainlytestos-
terone,and spermatozoa(i.e., mail germcells). Testosteroneis produced
and secretedby the interstitialcells, the so-calledLeydig cells. and it ex-
erts a variety of biologocaleffects in the male. In the male embryo,tes-
tosteroneis essentialfor the appropriatedifferentiationof the internaland

l
 622 I Part 2 Pathophysiologyof organsand systems

externalgenitalia,and it is necessaryfor descentof the testesin the fetus.

Duringpuberty, testosteronepromotessomaticgrowth and the develop-
mentof the malesecondarysex characteristics.In the adult,testosterone
is responsiblefor spermatogenesis and stimulation of libido and normal
sexualfunction.
All or almostall of the actionsof testosterone andotherandrogensresult
from increasedproteinsynthesisin targettissues.Androgensincreasethe
synthesisand decreasethe breakdownof protein, leadingto an increasein
the rateof growth.
The hypothalamus and the anteriorpituitary glandplayan essentialrole
in promotingspermatogenic activity in the testesand maintainingthe en-
docrinefunctionof the testesby meansof gonadotropichormones.The hy-
pothalamussendsepisodicpulses(approximate ly onceevery90 minutes)
of gonadotropine-releasing hormone(GnRH)to the anteriorpituitarywhich
secretesfollicle-stimulatinghormone(FSH)and luteinizing hormone(LH).
Thesecretionof testosteroneis underthe controlof LH,andthe mechanism
bywhichLHstimulatesthe Leydigcellsinvolvesincreased formationof cyclic
AMP.Circulatinglevelsof the gonadotropic hormonesarein turn regulatedin
a negativefeedbackmannerby testosterone.
Malehypogonadism Hypogonadism is thefailureof thetestesto function,
that is, to producetestosteroneand spermatozoa .The causesof testicular
deficiencyincludehypothalamic and pituitarydiseaseas well as a varietyof
primarytesticularand chromosomaldisorders.Primaryhypogonadism re-
fers to abnonmalitieswithin the gonad, for example,Leydigcells agenesis
(non-development), or failureof Leydingcellsin adultlife (alsocalleda male
climactericphase).Leydigcells failurecan occursafter mumps.Secondary
hypogonadism refersto gonadotropindefector failureto secreteGnRH,and
is alsocalledgonadotropichypogonadism.
Theclinic pictureof malehypogonadism dependsuponwhethertesticular
deficiencydevelopsbeforeor a'fterpubertyandwhetherthe gametogenic or
the endocrinefunctionis compromised. The loss or failureof maturationof
the gametogenic functioncausessterility.If the endocrinefunctionis lost in
adulthood,the secondarysexcharacteristics regressslowlybecauseit takes
very little androgento maintainthem oncethey are established .Whenthe
Pathophysiologyof endocrineand neural function Unit 8 1623

Leydigcell deficiencydatesfrom childhood,the clinicalpictureis that of eu-

nuchoidism.Eunucho id individualsover the age of 20 are characteristically
tall, althoughnot so tall as hyperpituitarygiants, becausetheir epiphyses
remainopenandsomegrowth continuespastthe normalageof puberty.They
havenarrowshouldersandsmallmuscles.A bodyconfigurationresembling
that of the adultfemale.The genitaliaaresmallandthe voiceis high-pitched.
Male hypergonadism Hypergonadism meansthe excessactivity of the
testes, whichcan be virilizingdueto androgen-secreting Leydigcell tumors
or feminizing,due to estrogen-secreting Leydigcell tumors.This is primary
hypergonadism whereasthat producedviaexcessGnRHand/orgonadotropin
production is secondaryhypergonadism.
Thereproductive systemof thefemale,unlikethatof themale,showsregu-
lar cyclicchangesthat maybe regardedas periodicpreparations for fertiliza-
tion and pregnancy,the so-calledmenstrualcycle.The ovaries,the female
gonads,produceestrogens , progesterone , andovariantestosterone. Thees-
trogensfacilitatethe maintenance of fertility. Duringfetal development.the
estrogensare neededfor sexualdifferentiat ion of the brain.Duringpuberty,
theystimulatethe development of breaststromaandducts, andof the uterus
endometrium,myometriumand vagina.In the adult female,the estrogens
maintainthe menstrualcycleandfemalesexualbehavior . Theestrogenshave
importantmetaboliceffects. Theyinhibitboneresorption.an actionof which
becomesapparentafterthe menopause (i.e.,the cessationof naturalfemale
reproductivelife) when the estrogenswane. In menopause , bone resorp-
tion occurswith the attendantdangerof fractures. Theestrogensaffectliver
functionby stimulatinsproteinsynthesis . Theyhaveimportanteffectson the
bloodby increasingthechangesof coagulationvia thestimulationof produc-
tion of factorsII, VII, IX, X, andtheydecreasecholesterollevels.
Femalehypogonadism Hypogonadism is thefailureof the ovariesto func-
tion, that is, to produceestrogens , progesterone , and ovariantestosterone.
If hypogonadismoccursbeforethe puberty, it causesthe so-calledovarian
eunuchoidismcharacterized by a poor developmentof femalesex charac-
teristics, amenorrhea , and a tall height.If the endocrinefunctionis lost in
adulthood,it leadsto menstrualabnormalities, sterility, and prematurecli-
macteric.
 624 f Part 2 Pathophysiologyof organsand systems

General adaptation syndrome and stress

Adrenalglandsaretakingpart in the processof mammalsorganism adapta-
tion to variousexternalandinternalfactors. Eachdemandmadeonthe bodyis
uniquein thatthereis a definiteresponse: whenwe arecold,we shiver;when
wearehotwe perspire ; a greatmusculareffortincreasesthedemandsuponthe
heartandvascularsystem.However,whateverthe specificresponse , thereis
alsoactivateda non-specific response whichis independentof thecause.
The term stresswas definedby Dr. HansSelye(a Canadiandoctorwho
won the NobelPrizefor his studieson stress)as the non-specificresponse
of the bodyto any demandsmadeuponit. As it wasestablishedby Selye's
researchwork the mainrole of stressis to enhancethe adaptiveabilitiesof
the organismand by the meansof the stresshumanorganismobtainthe
resistanceto factorsactinguponit.
Stressis a normalthingin everyday life.Somestressis goodfor humanor-
ganism - it keepspersonalertandprotectsintimesof dangeror whenit is need-
edto actor thinkquickly.Thistypeof stressis named"eustress". Prolongedand
unwanted stress,termed"distress", however , mayleadto mentalandphysical
healthproblems.Nowadays peoplearestandingvariousstressfactorsresulting
from the scientificandtechnicalprogress:urbanization, low physicalactivity,
increased emotionaltension,smoking,eatinglotsof fattyfoodsandothers.

S e lye w a s th e first scientist to notice that various

str es sors a ff e ct th e org a nism with the manifesta-
tion of th e sam e non-sp e cific sig!1s :

• increasedmassof the adrenalglandscorticallayer;

• acuteinvolutionof thymus, spleenandlymphaticnodes(shrinking);
• bleeding stomachandduodenumulcers.

Theclinicalmanifestationof anystress- physicalillnesssuchas infection

or injury, or stressdueto psychological
factors- is termedgeneraladapta-
tion syndrome.
Pathophysiologyof endocrineand neuralfunction Unit 8 1625

Generaladaptat ion syndrome(GAS)is a conceptdevisedby the basisof

which is the wayan organismreactsto stress. This reactionoccursin three
phases:alarm, resistance andexhaustion.
Firstphase:Alarmreaction . The bodyreactsto acutestressby increas-
ing the production of hormonesbythe adrenalgland in orderto mobilizethe
physicalenergyneededto combatthestress.Theresistanceof the organism
at thefirst stageis decreased . It meansthat if the forceof an irritantwill ex-
cessthe limitsof the organism'sadaptiveabilitiesthedeathmayoccur.If the
reactionis strongenoughto overcomeandremovethe stress, the organism
regainsits balance andreturnsto its normalhomeostatic condition.Themain
signsof thefirst stressstageare:highbloodconcentration of glucocortico ids
andcatecholamines, concentrationof blood, the prevalenceof catabolicpro-
cessesin the tissues.
Second phase:Thephaseof adaptation orresistance . If the stressis not
overcome , the secondphasecommences . Theorganismtries to dealwith
the stressby producingand activatingcorticostero id hormonesin the ad-
renalglandthat work as anti-inflammatory agents.This mechanismcreates
hypertrophyof the glands.Nevertheless,this processof adaptationresults
in a consumptionof the organism'senergyreserves . Thesecondphasecan
continuefor a longperiod of time, graduallyweakening the organism.
Thirdphase:Phaseof exhaustion . This is the GASphasewheredeple-
tion is so highthat the patientlosestheabilityto adaptto the stress.It is the
phasewhen medicalinterventionis requestedfor a numberof symptoms,
whichare sometimesdifficultto define. Theorganismhasexhausted its en-
ergy reservestryingto containthestressandstartsto self-destruct. Thetypi-
calsymptomof theexhaustion phaseis chronicfatiguewhichis probablythe
mostwidespread symptomin our society.

Stress and body functions

Glucocorticoids
and catecholamines lead to the functional and metabolic
changesin organism(Fig.61). Theyincreasebloodglucoseconcentration by
themeansof glycogenreservesandgluconeogenesis . Glucocorticoids
stimu-
 626 I Part 2 Pathophysiologyof organsand systems

Stressor

l
Hypothalamus

Sympathetic
CRF nervous
system

Catecholamine
ACTH release

- Increasedbloodpressure
Aldosterone Cartisol - Increa
sedbloodglucose
- Increas
ed fat/ proteinmetabolism
- Skeletal
musclehyperemi a

l
- Na·/1\0 relention - Increas
l
edheartI respiration
rate
- H· loss - Increased
bloodpressure
- Increased
bloodglucose

Fig.61. Mechan
ismsofstress
deve
lopment

lateproteinandlipid catabolismandnegativenitrogenous balance.Aminoac-

ids and freefatty acidsare usedas energysources in stressreaction.This
mayresultin bodyweightloss.
The excessof glucocorticoidsproducedin stressincreasesheartstroke
volumeandarterialbloodpressure.Increased heartworkespecially with high
NaCldiet may result in heartpathologywith the development of myocar-
Pathophysiology
of endocrineand neuralfunction Unit 8 f 627

dial necrosisand atherosclerosis. Themechanism of ulcersdevelopment in

stomachand duodenumincludesincreasedhydrochlo ric acidsecretion, due
toincreasedvagaltoneanddecreased resistance of gastricmucosa!barrier re-
sultingfrom glucocorticoidsaction.
Immunesystemactivityis decreased as a resultof stressinfluence.This
is manifestedas low resistanceto viral and bacterialinfections , increased
frequencyof tumordevelopment.
Thechangesin bloodcountare manifested as high neutrophilsquantity,
low eosinophilsandlymphocytes quantity.
The role of stress is established
in manypathologicalprocessesand dis-
ease ·s development. Stressis responsible to the development and worsen-
ing of pepticulcerdisease , hypertonicillness,secondaryimmunodeficiency,
ischemicheartdisease

Chapter 31. Pathophysiology

of the NervousSystem

The structural o rganization of the nervous system

The nervous systemis a complex,sophisticatedsystemthat regulatesand
coordinates
bodyactivities.

The nervous system is divided into two parts:

• the centralnervoussystem(CMS), consistingof the brain and spinal

cord,whicharelocatedin the skullandspinalcolumn,
• theperipheralnervoussystem, whichis locatedoutsidethesestructures.

Thenervoussystemcontainstwo majortypesof cells: neurons,whichare

functioningcellsof the nervoussystem, andsupporting
cells, whichprotect
the nervoussystemandsupplymetabolicsupport.
 6281 Part 2 Pathophysiologyof organsand systems

The neuronsconsistof a cell bodywith cytoplasm -filled processes,the

dendrites,andtheaxons.Therearetwo typesof neurons:afferentneurons or
sensoryneurons , whichcarryinformationto theCNS,andefferentneuronsor
motoneurons, whichcarryinformationfrom theCNSto theeffectororgans.

The Autonomic Nervous System (ANS)

TheANSfunctionsat thesubconscious levelandis responsible for maintain-
ing homeostatic
functionsof the body.
TheANShastwo divisions:thesympathetic andparasympathetic systems.
Althoughthe two divisionsfunctionin concert,they aregenerallyviewedas
havingoppositeandantagonistic actions.
Thesympatheticdivisionfunctionsin maintainingvital functionsand re-
spondingwhenthereis a criticalthreatto the integrityof the individual
- the
"fight-or-flight" response
.
Theparasympathetic nervoussystemis concernedwith the conservation
of energy,resourcereplenishment,andmaintenanceof organfunctionduring
periodsof minimalactivity.

Etiology of the nervous system pathology

Thestructuralandfunctionalorganization of_the nervoussystemis the most
difficultin a comparisonwith other systemsof the organism.An intensive
studyof physiological functions,providingdifferentaspectsof the nervous
regulationof organismactivity,doesn'tlead to the understandi ng of many
mechanisms of the nervoussystemphysiology.In this connection , thestudy
of pathogenicmechanisms of nervoussystemdisordersis also verydifficult.
Butthe samefundament al mechanisms of cellsfunctionsallowto study pa-
thologyof the nervoussystemfrom the positionsof generalbiology.In this
case,it's possibleto estimatethedevelopment of the nervoussystempathol-
ogy as the influenceof variousexogenousand endogenous factors,which
leadto metabolic , structuralandfunctionalchangesof the nervouscells.
 Pathophysiologyof endocrineand neuralfunction Unit 8 f 629

Therearea few classifications of the nervoussystemactivitydisorders.

According to the anatomicprinciple,theydifferentiate pathologyof the pe-
ripheraland centralnervoussystem.By the origin, they differentiatethe in-
heritedandacquirednervous systempathology . Theacquiredcanbeprimary
andsecondary.Primarydisorders appearby the directactionof pathogenic
factorson the nervoussystem.Thedevelopment of secondarydisordersde-
pendsonchangesof thehomeostasis (hypoxia, hypoglycemia) , immunefac-
tors, disordersof the cerebralcirculation.It is especiallynecessary to select
the hypoxicdamageof the nervoussystem,because the cellsof the nervous
systemareverysensitiveto hypoxia .
The brainconsumesabout20% of oxygenenteringthe organism.At a
suddenterminationof oxygensupplyof the brain(inhalationof oxygen-free
gaseousmixtures, disturbance of cellularcirculation),lossof consciousness
.. comesin 6-7 seconds , in 15 secondsnormalbioelectricactivityof the brain
stops.Fulllrestorationof the brainfunctionin suchcasesis possiblewhen
the standstillof circulationdoesnot exceed5-6 minutes. If ischemiaof the
braincontinues,longermemoryandintellectwill beirreversiblydisturbed.

By the cellular principl e, th e y diff e renti at e th e fol-

lowings typ e s of ne urons function disord e rs:

• Disordersof electrophysiological
processes
• Disordersof neurochemical(mediatordepended)
processes
• Disordersof axonaltransport

Depending on th e type of the broken functions ,

they differentiat e th e following ne rvous system dis -
orders :

• Disordersof sensoryfunctions
• Disordersof effectorsfunctions(motor,vegetative
, trophic)
• Disordersof integrativefunctions.
 630 I Part 2 Pathophys
iologyof organsandsystems

Disorders of se nso ry fun ctions of the nervous

syst em
Thesomatosensory systemrelaysinformationaboutfour majormodalities:
touch, temperature , pain, andbodyposition.
Thesystemis organized segmentallyinto dermatomes, with eachsegment
suppliedbya singledorsalroot ganglion that containsthe neuronalcell bod-
iesfor thesensoryunitsof the segment.
Somatosensory informationis sequentiallytransmittedover threetypes
of neurons:first-order neurons , whichtransmitinformationfrom sensory
receptorsto dorsalhorn neurons ; second-order CMSassociation neurons,
which communicate with variousreflexcircuitsandtransmitinformationto
the thalamus ; andthird-orderneurons , whichforward the informationfrom
thethalamusto the sensorycortex.
The tactile systemrelaysthe sensationsof touch, pressure, and vibra-
tion. It usestwo anatomicallyseparatepathwaysto relaytouch informa-
tion to the oppositesideof the forebrain:the dorsalcolumndiscriminative
pathwayand the anterolateralpathway.A delicatetouch, vibration, posi-
tion, and movementsensationsuse the discriminativepathwayto reach
the thalamus, wherethird-order relay occursto the primarysomatosen-
sory strip of the parietalcortex. A crudetactilesensationis carriedby the
bilateralslow-conductinganterolateralpathway.Temperaturesensations
of warm-hot and cool-coldare the resultof stimulationto thermalrecep-
tors of sensoryunits projectingto the thalamusand cortexthrough the
anterolateralsystemon the oppositesideof the body.

Disorders of sensory functions of the nervous sys-

tem include :

1. Anesthesia
- completelossof sensation.
2. Hypoesthesia-
hyposensitivity
.
3. Hyperesthesia-
hypersensitivity.
4. Dysesthesia-perversion
of sensation(insteadcoldpatientfeels hot).
Pathophysiologyof endocrineand neuralfunction Unit 8 I 631
5. Hyperpatia- disturbance of sensation(in responseto light stimulation
,
the patientfeelsa sharppain).
6. Paresthesia- sensationof creeping, nembness or tingling.
7. Polyesthesia-singlestimulationis felt as mult iply Oi7e.

Dysesthesia and polyesthesiaare usuallyobservedin damagingof the

spinalcord, thalamus or sensorycortexinjury.Sensitivepathway'sinjury is
accompanied by sensoryinjury belowthe placeof damaging.
A completetransversedamagingof the spinalcord leadsto all kindsof
sensitivity loss belowinjury. Lateralcolumnsinjury is accompaniedby a
superficialsensitivity loss of the oppositeside; posteriorcolumnsdamag-
ing causesmuscularsensationlossbelowinjury.In posteriorhorns, injury
proprioceptionis intact, whereasexteroceptive sensationis lost lost. In the
caseof posteriorradices, involvingall typesof sensation , becomeabnor-
mal.
Brown-Secar'ssyndrome : damagingof the half of the spinal cord. On
damagingpart of the bodyspasticparalysis,muscular -articularsenseab-
sence,andsense of discriminationlossaretypical.Spinalshock:temporary
areflexiaand commonparaplegiawith anesthesia just after spinaltrauma.
Spinalshockis causedby theabsenceof the regulatoryinfluencesof higher
parts of CNS. In humans,spinal shocklastsmonths.Posterior central girus
damagingis manifestedby numbnessandparasthesias in the oppositeside
of the body.

Pain
Painis an ''unpleasant sensoryandemotionalexperience associatedwith ac-
tual and potential tissuedamage,or describedin termsof suchdamage."
Attention, motivation,past experience, and the meaningof the situation
caninfluencethe individual's reactionto pain.Thus, paininvolvesanatomic
structures, physiologic behaviors,as well as psychological,
social,cultural,
andcognitive factors.
 6321 Part 2 Pathophysiologyof organs and systems

Types of Pain
Paincan be classified accordingto the location(cutaneous or deepandvis-
ceral), site of referral,andduration.
Cutaneous painis a sharp,burningpainthat hasits originin the skin or
subcutaneous tissues.
Deep painis a morediffuseandthrobbingpainthat originatesin structures
suchas themuscles , bones
, andtendonsandradiatesto thesurrounding
tissues.
Visceralpainis a diffuseand poorlydefinedpain that resultsfrom stretch-
ing, distention , or ischemiaof tissuesin a bodyorgan.
Referredpain is painthat originatesat a visceralsite but is perceivedas
originatingin partof the bodywallthatis innervatedby neuronsenteringthe
samesegmentof the nervoussystem.

Acute pain a nd chronic pain

Acutepain oftenresultsfrom injury, surgery,or invasivemedicalprocedures.

It alsocanbea presentingsymptomfor someinfections(pharyngitis, appen-
dicitis, andotitis media).
Chronic pain canbe symptomaticof a widerangeof healthproblems(ar-
thritis, backinjury, or cancer).In recentepidemiologic
surveys,approximate-
ly 46 % of adultsreportedhavingchronicpain(Table33).

Pain can be either nocicept ive o r neuropat hic in origin

Whennociceptors(pain receptors).areactivated in responseto actualor im-
pendingtissueinjury, nociceptivepainis the consequence.
Neuropathic pain, on the otherhand, arisesfrom directinjury to nerves.
Tissueand nerveinjury can result in a wide rangeof symptoms . Thesein-
cludepainfrom noninjuriousstimulito the skin (allodynia)
, extremesensitiv-
ity to pain(hyperalgesia)
, andtheabsenceof painfrom stimuli that normally
wouldbe painful (analgesia).
Pathophysiologyof endocrineand neuralfunction Unit 8 1633

Table33. Paincharacteristic
' ~!t -:t: ..
t~Af:~.~;
'il~f~1!'tf:··. }'' . ;','
iv,/ ~ i

.1(/--.:';;~ ,.,·c:."'~· AculePaln

. 'i}~ -. -'.} ,""li~ . . 4 • .
Pain
Chronic

1 Onset Recent Continuousor

intermittent

2 Duration Shortduration 6 monthsor more

(<6 months )

3 Autonomic Consistentwithsympathetic fight-or- Absenceof autono

mic
responses flightresponse* respon
ses
Increased heartrate
Increased strokevolume
Increased bloodpressure
. ' Increased pupillarydilation
Increased muscletension
Decreased gutmotility
Decreased salivaryflow(drymouth)

4 Psychological Associated
anxiety Increas
ed irritability
component Somatic
preoccupation Associateddepression
Withdrawal
fromoutsideinterests
Decreased
strengthof relationships

5 Othertypesof Decreased sleep

response Decreased libido
Appetitechanges

Neuralgiais characterizedby severe,brief, oftenrepetitiously occurringat-

tacksof lightning-like or throbbing painthatoccursalongthe distribution of
a spinalor cranial nerveandusuallyis precipitated by the stimulationof the
cutaneousregion suppliedby that nerve.
Trigeminal neuralgia, or tic douloureux, is oneof the mostcommon and
severen_euralgias. It is manifestedby facial tics or grimaces.
 6341 Part 2 Pathophysiologyof organsand systems

Postherpetic neuralgiais a chronicpainthat canoccuraftershingles,an

infectionof thedorsalrootgangliaandcorresponding areasof innervationby
the herpeszostervirus.Thecomplexregionalpainsyndromeis an extremely
painfulconditionthat mayfollowa suddenandtraumaticdeformationof pe-
ripheralnerves.Phantomlimb pain, a neurologicpain,can occurafterthe
amputationof a limbor partof a limb.
Painmayoccurwith or withoutan adequate stimulus
, or it maybeabsentin
thepresence of anadequate stimulus-eitherof whichdescribes a paindisorder
.

There may be:

• analgesia (absenceof pain);

• hyperalgesia (increased
sensitivityto pain);
• hypoalgesia (a decreasedsensitivityto painfulstimuli);
• hyperpathia(anunpleasant andprolongedresponseto pain);
• hyperesthesia (anabnormalincreasein sensitivityto sensation);
• hypoesthesia (anabnormaldecreasein sensitivityto sensations);
• paresthesia(abnormal touch sensationsuch as tingling or "pins and
needles"in theabsenceof externalstimuli);
• allodynia(painproducedby stimulithatdo not normallycausepain).

Pain theo ries and m ec han ism s

Traditionally,two theorieshavebeenofferedto explainthe physiologicbasis
for the painexperience.
Thefirst, specificitytheory, regardspainas a separatesensorymodality
evokedby the activityof specific receptorsthattransmitinformationto pain
centersor regionsin the forebrainwherepainis experienced.
Thesecondtheoryincludesa groupof theoriescollectively referredto aspat-
terntheory.It proposes thatpainreceptorsshareendingsor pathways withother
sensorymodalities, butthatdifferentpatternsof activity(i.e.,spatialor temporal)
of thesameneuronscanbeusedto signalpainfulandnonpainful stimuli.
Pathophysiologyof endocrineand neuralfunction Unit 8 f 635

Painusuallyis viewedin thecontextof tissueinjury.Theterm nociception ,

which means"painsense,"comesfrom the Latin word nocere("to injure").
Nociceptivestimuli are objectivelydefinedas stimuli of such intensitythat
they causeor arecloseto causingtissue damage .
The mechanisms of painarenumerousandcomplex.As with otherforms
of somatosensation , thepathways arecomposedof first-, second-,andthird-
orderneurons.
The first-order neuronsand their receptive endingsdetectstimuli that
threatenthe integrityof innervated tissues.
Thesecond-order neuronsare locatedin the spinalcordand processno-
ciceptiveinformation .
Thethird-orderneuronsprojectpaininformation to the brain.
Thethalamusandcortexintegrateand modulatepainas well as the per-
son'ssubjectivereactionto the pain experience.

Stimulat ion of noc iceptors

Unlikeother sensoryreceptors,nociceptorsrespondto severalforms of
stimulation, includingmechanical, thermal,and chemical.Somereceptors
respondto a singletypeof stimuli(mechanical or thermal)andothers,called
polymodalreceptors , respondto all threetypesof stimuli(mechanical,
ther-
mal, andchemical).
Chemicalstimuli arisefroma numberof sources,includingtissuetrauma,
ischemia , andinflammat ion.

A wide range of chemical mediators are released

from injured and inflamed tissues, including:

• prostaglandins
; • acetylcholine
;
• leukotrienes
; • serotonin;
• histamine; • hydrogenandpo-
• bradykinin; tassiumions.
 6361 Part 2 Pathophysiologyof organsand systems

Bradykinin , histamine
, serotonin , andpotassiumactivateandalsosensitize
nociceptors .
Adenosine triphosphate , acetylcholine,
andplateletsact aloneor in concert
to sensitizenociceptorsthroughotherchemicalagentssuchasprostaglandins .
Aspirinand othernonsteroidal analgesicdrugsareeffectivein controlling
pain becausetheyblockthe enzymecyclooxygenase neededfor prostaglan-
din synthesis .

Endoge nou s Analgesic Mechan isms

Thereis evidencethat the endogenous opioidpeptides,morphine-likesub-
stancessynthesized in manyregions of the CNS,modulatepainin the CNS.
Three familiesof opioidpeptideshavebeenidentified-the enkephalins , en-
dorph·ins, anddynorphins .
Although the endogenousopioid peptidesappear to function as neu-
rotransmitters,their full significancein pain controland other physiologic
functionsis not completel y understood .

Disorders of motor functions of the nervous system

Motor systemsrequire uppermotoneurons (UMNs)thatprojectfromthemotor
cortexto the brainstemor spinalcord, where.theydirectlyor indirectlyinner-
vatethe lowermotone urons (LMNs) of thecontractingmuscles; sensoryfeed-
backfrom the involvedmusclesthatis continuously relayedto thecerebellum ,
basalganglia, and sensorycortex; anda functioningneuromuscular junction
thatlinksnervoussystemactivitywithmuscle contraction.Muscletoneis main-
tainedthroughthe combinedfunctionof the musclespindlesystemandthe
extrapyramidal systemthatmonitorsandbuffersUMNinnervation of theLMNs
Alterationsin musculoskeletalfunctionincludeweaknessresultingfrom
lesions of voluntaryUMNpathwaysof the corticobulbarand corticospinal
tractsand the LMNsof the peripheralnerves . The two main responsesof
peripheralnerveto injury are basedon the targetof the insult. Diseases
Pathophysiologyof endocrineand neuralfunction Unit 8 1637

that affectprimarilythe Schwanncell leadto a loss of myelin,referredto a

segmenta l demyelinisation. Primaryinvolveme nt of the neuronand its axon
leadsto axonaldegeneration. Demyelisation maybea resultof immunedys-
functionof Schwanncells(Guillian- Barresyndrome) or differenthereditary
neuropathies (Charcot-Mariedisease).
Hypotoniais a conditionof less-than-normalmuscletone,and hypertonia
or spasticityis a conditionof excessive tone.
Myasthenia is a groupof diseasesof the neuromuscu lar junction.There
aretwo well-knownforms-myasthenia gravisandLambert-Eaton myasthenic
syndrome.
Myasthenia gravisis a diseasecausedbytheimmune -mediatedlossof ace-
tylcholinereceptors . Themainsymptomis muscularweakness ; at first-extra-
ocular(causedptosisanddiplopia), at thefinalstage-respiratory muscles.
Lambert -Eatonmyasthenicsyndromeis a paraneoplastic process,most
commonlyin the lungs. Thetypicalsymptomis also weaknesswith auto-
nomicdysfunction.
Paralysis andparesis- the absenceor decreasing of muscularstrength
in limbs, whichresultedin movement's impossibility.They maybecentralor
peripheral. Centralparalysiscausedbycentralmotorneuroninjury.Peripher-
al paresismayresultsin peripheral motoneuron damaging.Thesymptomsof
central{spastic)paralysis- muscularhypertonus,proprioreceptivereflexes
increase, absenceof atrophy.In peripheral (atonic)paresisarecommonmus-
cularatrophyand areflexy.Movementdisordersin paralysesand paresises
maybe in a singlelimb (monoplegia or monoparesis), both upperor lower
extremities{upperparaparesis/ paraplegiaor lowerparaparesis/ paraplegia) ,
in a halfof the body{hemiparesis andhemiplegia) andparalysisof lowerand
upperextremities{tetraparesis or tetraplegia).
Paresisrefersto weaknessin musclefunction, and paralysisrefersto a
lossof musclemovement.UMNlesionsproducespasticparalysis,and LMN
lesionsproduceflaccid paralysis.
Themainsymptomsof cerebellum disordersare:atonia,astasia,ataxia,adiad-
ohokynesis anddisequlibration . Inbasalnucleidisorders , typicalarethefollowing
symptoms: in pallidarareadisorders - hypokynesises andmuscular hypertonus;
in thestriatumareainvolving- hyperkynesises andmuscular hypertonus .
 638 f Part 2 Pathophysiology
of organsandsystems

Manyof theagentsthatcausebraindamagedo so throughcommonpath-

ways, includinghypoxiaor ischemia, accumulationof excitatoryneurotrans-
mitters,increasedICP, andcerebral edema.Thedeprivationof oxygen(i.e.,
hypoxia) or bloodflow (i.e., ischemia
, hemorrhage)
canhavedeleterious ef-
fectson the brainstructures. lschemiacanbe focal, as in stroke
, or global.
Globalischemiaoccurswhenbloodflow is inadeq uateto meetthe metabolic
needsof the brain,as in cardiacarrest.

Stroke/Brain Attack
Stroke is an acutefocal neurologicdeficitfrom an interruptionof bloodflow
in a cerebralvessel(ischemicstroke, the mostcommontype)dueto thrombi
or embolior to bleeding intothe braintissue(hemorrhag ic stroke).
A brainattackoccurswhena bloodvesselbringingoxygenand nutrients
to the brainburstsor is clogged bya bloodclot or someotherparticle.When
thebraindoesn't gettheneededbloodflow, because of a ruptureor blockage
,
it is deprivedof oxygen.Thus, nervecellscannotproperlyfunctionand die
within minutes.And whennervecellscannotfunction, the part of the body
controlledby thesecells cannotfunctioneither.The devastatingeffectsof
strokeareoftenpermanentbecausedeadbraincellsarenot replaced .
Whenbraincellsdie, functionof thebodypartstheycontrolbecomesdam-
agedor destroyed.This may includeparalysis , speechproblems , memory
and reasoningdeficits, coma, andpossibly death.

Disorders of integrative functions ofthe nervous

system
'
Integrative functionsof the nervoussystemincludethe ability of personfor
thought,memory,speech,emotions,functioningof sleep -wakecycles.Oneof
the mostimportantintegrative functionsthereis thepresence
of consciousness
in the patient. Consciousnessin medicineis assessedby observinga patient's
alertnessandresponsiveness. Deficitsof consciousness
arecausedby lesions,
Pathophysiologyof endocrineand neuralfunction Unit 8 I639
stroke,injury,or surgerythatdisruptthenormalfunctioning of humansenses and
cognition. Lossof consciousness in clinicis dividedintosomelevels(Table34).

Table34. Descending
levelsof consciousne
ss

Mi ?;
{' -,iftif~i~ Characteristics
r

' :, ,;:

1 Confusion Disturbance ofconsciousness characterizedbyimpaired

abilityto thinkclearly,
andto perceive , respondto, and
remember currentstimuli;alsodisorientation

2 Delirium Stateof disturbedconsciousness withmotor

restlessness, transienthallucinations
, disorientation
. and
sometimesdelusions

3 Obttindation Disorder
of decreased with associated
alertness
psychomotor
retardation

4 Stupor A stateinwhichthepersonis notunconscious

but
exhibitslittle or nospontaneous
activity

5 Coma A stateof beingunarousable andunresponsive

to
externalstimulior internal
needs

A comais a profoundstate of unconsciousness.

Coma may result from a variety of conditions:

1. Comas , causedby braininjury(centralnervoussystemdiseases, acute

neurologicinjuriessuchas stroke, head andbraintrauma).
2. Comas , causedby endocrinedisease(diabetic,hypoglycemic, hypergly-
cemic, adrenal, thyrotoxic)
.
 640 I Part 2 Pathophysiologyof organsandsystems

3. Comas, causedby endogenicintoxication (uremicr hepatic,infection,

pancreatic)and exogenicintoxication(alcoholicpoisoning, barbiturate
poisoning,phosphorganic, inducedby pharmaceutical agents).
4. Comas,causedby variouskindsof hypoxia .
5. Comas,causedby metabolicabnormalit ies (loss of electrolytesand
energeticsubstances)
.

Pathogenesis of comas has different pathogenic

pathways.

1. Decrease brainoxygenation andhypoxialeadto theATPdeficiency.En-

ergyis not enoughfor normallybraincellsfunction.
2. Infringementof synaptictransmissionin theCNSby somepathways:
a. infringement of synthes
is, transportandsecretionof neuromediators;
b. replacement of neuromediators by pseudomediators;
c. inhibitionof post synapticreceptors(this mechanismimportantin
the developmentof hepatic,uremicandtoxiccomas).
3. Infringementof electrolytebalancewith changesof cellularpotentials
andprocessof polarization of neuronsmembranes.

Outcomesof comasrangefrom recoveryto death.Comasgenerallylasta

fewdaysto a fewweeks.Butsomecomashavelastedaslongasseveralyears.
Afterthis time,somepatientsgraduallycomeoutof thecoma,someprogress
to a vegetativestate. Conditionin whichan individuallosesthehighercerebral
powersof the brain,but maintainssleep-wake cycleswith full or partialauto-
nomicfunctionsis nameda persistentvegetative state(PVS).Studiescom-
paringPVSwith healthy , awakesubjectsconsistentlydemonstrate animpaired
connectivitybetweenthedeepe~ (brainstemandthalamic)andthe upper(cor-
tical)areasof the brain.At present, hypotheses aboutlossof consciousness
are basedon the two variantsof the cerebraldisorders:the destructionof
a widespread corticalnetwork,includingparticularlythe frontal,parietaland
temporalcortices, or the destruction of cooperationbetweenthe deeplayers
of the brain,especiallythethalamus , andthe upperlayers,the cortex.
 PATHOPHYSYC)LOGY
Unit9 OF EXTREME
CONDITIONS

Chapter 32. Pathophysiologyof Shock

and Extreme Medical Conditions

Extremeconditionin medicine- an extremedegreeof pathologywhichre-

quiresthe supportof the vital functionsand organsto savethe life of the
organism.
Oneof the mostimportant extrememedicalconditionsis shock.Shockis a
stateof acuteinadequacyof the bloodsupplyto thevital organsof the body,
leadingto acutehypoxiaor anoxia.
Shockis not a diseasebut rathera clinicalsyndromeor systemictypical
pathologicalprocessleadingto reducedperfusionof tissuesandorgansand,
eventually,organdysfunctionandfailure.Evenwith treatment,shockhasa
highmortalityrateoncethe body's compensatory mechanisms fail.
Shockhasdifferentclassifications.

Types of shock dep e ndent on cause factors :

• Traumaticshock
• Hypovolemic
• Hemorragic
• Neurogenic
642 I Part 2 Pathophysiologyof organsand systems

• Septic
• Anaphylactic
• Cardiogenic
• Burning
• Repertussion

Shock can be classified into three major categories

based on the precipitating factors:

• distributive(neurogenic, septic, andanaphylac tic). in thistypeof shock,

problemsof thethe vascularesystemprevail;
• cardiogenic , in whichwith heartproblemsaremostimportantt;
• hypovolemic shock, in whichthe lossof thecirculatoryvolumeprevails.

Shock is often described as a circulatory shock (be-

cause the main mechanism is the disintegration of
circulation):

• circulatoryshockmaydevelopbecause thereis notenoughbloodin the

circulatorysystem(i.e., hypovolemic
shock),
• bloodflow or venousreturn is obstructed(i.e.,obstructiveshock);
• or the tissuesare unableto useoxygen . and nutrients(i.e.,distributive
shock).

Three types of shock share the basic circulatory

pattern of distributive shock:
'

• neurogenicshock;
• anaphylactic
shock;
• septicshock.
Pathophysyology
of extremeconditions Unit 9 1643

Septicshock,whichis the mostcommonof thesethreetypes, is associ-

ated with a severe, overwhelming
infection and hasa mortality rateof ap-
proximately40 %.

Th e usual caus e of shock is a de c rea se d c a rdi a c

output , which may be du e to:

1) heartfailure(cardiogenic shock);
2) too little venousreturn.

The reasons for th e se cond vari a nt a re:

c. reductionin bloodvolume(hypovolemic shock)followingthe lossof

blood(hemorrhag ic shock)or the loss of fluid ( in connectionwith
burns, severevomiting, prolongeddiarrhea , andso on);
d. peripheralvasodilatation
, andhencetoo muchbloodin theperiphery.

Stages of sho c k. Funct ional and struct ural

d isord ers in various stages of shock
The well-known RussiansurgeonN.I. Pirogovhas describedtwo classical
stagesof shockdevelopmentin patientswith traumatic shock:
• erectile phase;
• torpidphase.

In theerectile phase,painfulimpulsesreachCNS,theopticalareaandbrain
cortex. This stage is characterizedby extremeemotional , significantimpel-
lent, movingand speechexcitation.The behaviorof the victim cannotcor-
respondto the severity of damage,the estimationof conditionsfrequently
happensinadequately optimistically
. In the torpid stage, decompensation in
CNSleadsto deep oppression. Thepatientis motionless , doesnot comeinto
 644 I Part 2 Pathophysiologyof organsandsystems

contact, doesnot answer questionsor answersvery silentlyand with long

timeof delay,slowcogitativeactivity. Reflexes areloweredor absence.Pain-
ful sensitivityis alsolowered .
Nowin pathophysio logy of shock, they describethreebasicstagescom-
monto eachtypeof shock.

Basic stages of shock there are:

• compensatory;
• progressive .
• irreversibleor refractory.

Compensatory stag e
When arterial pressureand tissue perfusionare reduced , compensatory
mechanisms are activatedto maintainperfusionto the heartand brain. As
the baroreceptors in the carotidsinusandaorticarchsensea dropin blood
pressure,epinephrine andnorepinephrine aresecretedto increaseperipheral
resistance,bloodpressure , andmyocardial contractility
.
A reducedblood flow to the kidneyactivates the renin-angiotensin-al -
dosteronesystem, causingvasoconstrictionand sodiumand waterreten-
tion, leadingto an increasedbloodvolumeand venousreturn. As a result
of these compensatorymechanisms , cardiacoutput and tissue perfusion
are maintained.Also, these hormonescausethe vasoconstrictionof the
kidneys,gastrointestinal tract, andotherorgansto. divertbloodto the heart,
lungsandbrain. Thelackof bloodto the renalsystemcausesthe character-
istic low urine production.
Thecompensatory stageis characterized
, by highcontentsof stressfulhor-
monesin blood: catecholamines , thyrotropin,thyroxin,glucocorticoids
, aldo-
sterone,angiotensin II. Increaselevelof glucocorticoids andthyroxinleadsto
thestimulation of the oxygen-depended metabolicprocesses.
Both,theperipheralvasoconstriction andstimulationof oxygen-dependent
metabolismleadto hypoperfusion . A hypoperfusional statecauseshypoxia,
Pathophysyologyof extremeconditions Unit 9 f 645

leadingto the mitochondriabeingunableto produceadenosine triphosphate

(ATP).Dueto this lackof oxygen,thecell membranes becomedamaged, they
becomeleakyto extra-cellularfluid, andthe cellsperformanaerobicrespira-
tion. This causesa build-upof lacticand pyruvicacid which results in sys-
temicmetabolicacidosis.

Progressive stage
This stageof shock beginsas compensatory mechanisms fail to maintain
cardiacoutput.Tissuesbecomehypoxicbecauseof poorperfusion.As cells
switchto anaerobicmetabolism , lacticacid builds up, producingmetabol ic
acidosis.This acidoticstatedepressesmyocardialfunction.Tissuehypoxia
also promotesthe releaseof endothelialmediators.Endothelialmediators,
suchas histamine,bradykinin , prostaglandins andsomeother produceva-
sodilationand endothelialabnormalities, leadingto venouspoolingand in-
creasedcapillarypermeability.Sluggishbloodflow increases the risk of dis-
seminatedintravascular coagulation.

Irreversible (refractory) stag e.

As the shocksyndromeprogresses , permanentorgandamageoccursas
compensatory mechanisms canno longermaintaincardiacoutput.Reduced
perfusiondamagescell membranes, lysosomalenzymesare released,and
energystoresaredepleted , possiblyleadingto celldeath.Ascellsuseanaero-
bic metabolism, lacticacidaccumulates, increasing capillarypermeability
and
the movementof fluid out of' the vascularspace.This loss of intravascular
fluid furthercontributesto hypotension. Perfusionto thecoronaryarteriesis
reduced,causingmyocardialdepressionand a further reductionin cardiac
output.Eventually,circulatoryand respiratoryfailureoccur. Braindamage
andcelldeathhaveoccurred.Deathis inevitable.
 6461 Part 2 Pathophysiology
of organsandsystems

Blood pressure compensa tio n in sh oc k

pathog enesi s
The centralization of circulationis an importantcompensatory mechanism
in shockdevelopment. In the beginningof shock, the fallingbloodpressure
reducesthe activityof pressurereceptorsin the arterialsystem,whichleads
to the activationof pressorareasin the CNSand to elevatedsympathetic
tonus.Arterialvasoconstriction in the peripheralorgansandtissues,where
a-adrenoreceptors prevalence , accompanied by withdrawalof blood(not in
shockdueto vasodilatation) from the skin (pallor),the abdominalspace,the
kidneys,andsoonto increase cardiacoutputto thevitalorgans(coronaryarter-
ies,brain,lungs).Invesselsof this organsthereprevailthep-adrenoreceptors
andtherestimulationleadsto thevasodilatation. Bloodis accumulatedin the
vesselsof centralorgansand this effectis namedthe centralization of the
circuration(dependson differences in epinephrinereceptors).
Also, thevasoconstriction of the venouscapacityvesselsincreases cardiac
filling.Theaccompanying tachycardia helpsraisetheloweredcardiacoutputre-
sultingfromthedecreased strokevolume.Theseneurallymediated mechanisms
aresupplemented bythereleaseof catecholamines fromtheadrenalmedulla.
Thecostof centralization of circulation, whichorganismmustpayfor this
compensa tory mechanism , is the progressionof hypoperfusion and hypoxia
in peripheraltissuesand organs.A morelongerand moreintensiveperiod
of hypoxiaresultsin peripheralvasodilatation anda dropof peripheralresis-
tanceandbloodpressure.

Diff e rent pathog e nic reactions and mechanisms of

shock d e velopment m~y be describ e d by the fol-
lowing vicious circles :
'

Bloodvolumel - vasoconstriction - disturbance of tissuemetabolism -

vesseldamage- rvasodilatation
andfiltrationintointerstitium- bloodvolume!
and low BP- bloodflow velocityl - bloodviscosity
Vasoconstriction
r- resistance
r - bloodflow1. ·
Pathophysyology of extremeconditions Unit 9 1647

BP!- --+ 02 deficiencyandacidosis--+ damageof myocardium --+ cardiac

output! --+ BP! ...
BP ! --+ tissue metabolism! --+ vesseldamage
r - bloodclottingj - clot-
ting factors! - bloodloss - BP! ...

Signs and symptoms of shock

In the comp e nsatory st a ge of shock , s ign s and
symptoms may include:

• tachycardia andboundingpulsedueto sympathetic stimulation;

• restlessness andirritabilityrelatedto cerebralhypoxia;
• tachypnea to compensatefor hypoxia;
• reducedurinaryoutputsecondary to vasoconstriction;
• cool,pale skinassociated with vasoconstriction; warm, dry skin in sep-
tic shock dueto vasodilation.

In the progres sive st a ge of sh oc k , signs a nd symp-

toms may includ e :

• hypotension as compensatorymechanisms beginto fail;

• narrowedpulsepressureassociated with reducedstrokevolume;
• weak,rapid, threadypuisecausedby decreased cardiacoutput;
• shallowrespirationsasthe patientweakens ;
• reducedurinaryoutputas poorrenalperiusioncontinues ;
• cold,clammyskincausedby vasoconstriction;
• cyanosisrelatedto hypoxia.

In the irreversible st a ge , clinic a l findings m ay includ e:

• unconsciousness andabsentreflexescausedby reducedcerebralperfu-

sion, acid-baseimbalance,
or electrolyteabnormalites;
 6481 Part 2 Pathophysiology
of organs and systems

• rapidlyfallingbloodpressureas decompensat ion occurs;

• weakpulsecausedby reducedcardiacoutput;
• slow, shallowor Cheyne-Stokes respirations secondaryto respiratory
centerdepression
• anuriarelatedto renalfailure..

Co mplic ation s of sho c k

M a ny body syst e ms are wrecked by severe shock.
Th e fiv e major complications of severe shock are:

• shocklungsor acuterespiratorydistresssyndrom(ARDS);
• acuterenalfailure;
• -gastrointestinal
ulceration;
• disseminatedintravascularcoagulation(DIC);
• multipleorgandysfunctionsyndrome(MODS);
Complicationsof shockareseriousandoftenfatal.

MultipleOrganDysfunction Syndrome ("shockorgans ")

Themultipleorgandysfunctionsyndrome(MODS)representsthe pres-
enceof alteredorganfunction in anacutelyill patientsuchthatthehomeosta-
sis cannotbe maintainedwithoutintervention . As the nameimplies,MODS
commonlyaffectsmultipleorgansystems,includingthe kidneys , lungs, liver,
brain,andheart.

AcuteRespiratory DistressSyndrome
Acuterespiratorydistresssyndrome(ARDS)is a potentiallylethalform of
respiratoryfailurethat canfollowsevereshock.
Themostimportantmechanisms of ARDSare:
• Accumulation andactivationof neutrophils
• Abnormalities in theproduction
, compositionandfunctionsof surfactant
• Athelectasisleadsto respiratoryfailure
Pathophysyologyof extremeconditions Unit 9 1649

RenalFailure
• Therenaltubulesareparticularlyvulnerable
to ischemia
• Blockof glomerulasbythetoxic products(myoglobin)

Gastrointestinalcomplications
• Gastrointestinal
ischemiamayleadto gastrointestinal bleedingand in-
creasedpermeabilityto theintestinalbacteria,
whichcausefurthersepsis
• Bleedingis a commonsymptomof gastrointestinal ulceration

Disseminated lntravascu/arCoagulation {DIC}

• DICischaracterizedbythermationofsmallclotsinthecirculat
ion. Itisthought
to becausedbythe inappropr iate activation
of thecoagulationcascade be-
causeof toxinsor otherproductsreleasedasa resultoftheshockstate.
• Adhessionandaggregation of cells

Specific mechanisms of some shock types

Hypovo/emic shock
Thisis the mostcommontypeof shock.It's development is basedon insuffi-
cientcirculatingvolume.Theprimarycauseof this shocktypeis a lossof fluid
from the circulation(mostoften"hemorrhagic shock"). Causesmayinclude
internalbleeding, traumaticbleeding,highoutputfistulaeor severeburns.

Cardiogenic shock
This type of shockis causedby the failureof the heartto pumpeffectively.
This canbedueto damageto the heartmuscle,mostoftenfroma largemyo-
cardial infarction. Othercausesof cardiogenicshockincludearrhythmias,
cardiomyopathy, congestiveheartfailure(CHF), contusiocordis,or cardiac
valveproblems.

Distributiveshock
As in hypovolaemic shockthere is an insufficientintravascular volumeof
blood.This form of "relative"hypovolaemia
is the resultof dilation of blood
 650 I Part 2 Pathophysiologyof organsandsystems

vessels whichdiminishessystemicvascularresistance.
Thisform of shock
maydevelopin differentvariants.

Septicshock
Causedbysystemicinfectionresultingin vasodilation
leadingto hypotension.
Septicshockcanbecausedbysometypesof bacteriawhichreleaseanendo-
toxin which producesadversebiochemical , immunologicalandoccasionally
neurologicaleffectswhichareharmfulto thebody.Septicshockalsoincludes
someelementsof cardiogenic shockbecausedepressionactionof toxinson
the myocardium takesplace.

Anaphy/actic
shock
Causedby a anaphylactic type of allergicreactionto an allergen,antigen,
drugor foreignproteincausingthe systemicreleaseof histamine.Histamine
causeswidespread vasodilation
, leadingto hypotension andincreased capil-
larypermeability
.

Neurogenic shock
Neurogenic shockis the rarestform of shock. It is causedby traumato the
spinalcordresultingin the suddenlossof autonomicandmotor reflexesbe-
low the injurylevel.Withoutstimulationby sympatheticnervoussystemthe
vesselw~llsrelaxuncontrollably , resultingin a suddendecrease in peripheral
vascularresistance, leadingto vasodilation andhypotension.

Crashsyndrome or ischemia-reperfusion injury

In this syndrome , the longcompression of peripheraltissues(oftencompres-
sionof handor legafterearthquake) leadsto theischemic necrosis development.
In ischemictissuesaccumulated high_quantitiesof biologicalactivesubstances
(bradykinin,serotonin, histamin,
,etc.)andmetabolites (piruvat,lactate,CO2, myo-
globinetc.) withvasodilatation
properties
. Afterdecomp ression, highquantitiesof
thisproducts cometothesystemic circulationandleadto thedilationof resistance
vesse ls anddropof peripheralresistance.Systemicbloodpressure is reduced.
Nowin pathophysiology togetherwith shockoftendescribe the systemic
inflammatoryresponsesyndrome.Systemicinflammatoryresponsesyn-
Pathophysyologyof extremeconditions Unit 9 I 651
drome(SIRS)is an inflammatory stateaffectingthe wholebody.Thecauses
of SIRSare broadlyclassifiedas infectiousor noninfectious.
As above,when
SIRSis dueto an infection,it is consideredsepsis.Noninfectiouscausesof
SIRSincludetrauma, burns,pancreatitis,ischemia , and hemorrhage.Some
investigators
describeSIRSSi.JCh as chainof shockconditions.
SIRSis a seriousconditionrelatedto systemicinflammation, organdys-
function,andorganfailure.It is a subsetof "cytokinestorm",in whichthere
is abnormalregulation of variouscytokines.
Pathogenic prophylaxis andtreatmentof shockbasedonsomeprinci-
pleswhichdependontheshocktype.

Pathogenic treatm e nt include :

• Identificationandtreatmentof the underlyingcause

• Maintaininga patentairway
• Supplementaloxygen
• Continuous cardiacmonitoring
• Intravenous fluids, crystalloids
, colloidsor bloodproducts
• Proteinase inhibitorsandantioxidants
 Y nponoHOBaH OMY 11i.apy'IHIIKY "J naTOcpi·JioJJorii' JlJ1JI cryncHTiB, llKi Ha8'1 8IOTl,C JI aHrniHCl,KOIO
MOBOIO, BIIKJ18llCHi OCHOBHi POJJ1im1 naTOJJOfi'IHO'i' cpi1ionorii' ei .anoBiJI HO no ylf60BOInporpaMH Jl)lll
CTY.llCHTiB BIHUHX MC.llH'IHHX H384aJlbHH X )aKJ1a11iB, JaTBCp11)1(CHOIOMiHiCTCpCTB-OM oxopoH H 311opoB' JI
Y1<pai'rn1. ninpy4Hl1K HanwcaHO 3 MCTOIO 11on0Morm CTy11CHTaMy CaMOCTiHHiH ni.arOTOBUi 110 Ja HJITb
1 narncj>iJionorii' TO BHB'ICHHi MaTcpiany 1 po JBlfTKY naTOnori'IHHX npouccis. H ana HHH y ninpY1.fHHKY
MaTcpia n ananToBaHlfll 110 KpC.llllTOBO· MO.llYJlbHOi" CHCTCMH HaB'laHHJI Ta 6ync cnpH ll TH p03WHpCHHIO
'lHUHI, npo MCXaHiJMM p03BHTKY nmOBHX naTonori4HHX npouccis Ha MoneKynllpHOMY, opraH HOMY Ta
CIICTCMHOMY piBHSIX. y ni npy' IHII KY npcncrasncHO HOBi 110CSlfHCHHll JIK siTlfH3HJIHOi', TaK i 3apy6i)l(H0i'
naTOJlOfi'IHOi' q>iJiOJlOrii'.
ni apr 1HHK pCKOMCH.llYC1'bCSI.llJlll ninroTOBKH CTy11C
HTiB -MC11HKiB Ha ycix <j)aKyJlbTCTax BHIUHX
MC!ll-14HHX H8848 JlbHHX 3aKna11is. TaKO)K aiH MO>KC 6yr11 BHKOpHCTaHHH .llJlll ni.nroroeui niKapie
i HTCpHiB, OpL!HH3TOpie, acnipaHTiB , r a 6yr11 KOpHCHHM JliKapllM ycix cneuianbHOCTCH Ha 6y11b-JIKOMY
crani n iC,'lll.llHUJlOMHOi' oceiTH .

HaelfORbHe euoaHnfl

AHaTonii:i Bonon11M1-tpos114Ky6 mmdu , BiKTop M1-tKona.110B11'i

€J1bCKHii,
AHa·ronii:i Isattos114ro;KeHKO, IOpii:i Is aHOBH'-1
KoJ1ecHHK Ta iH.

3araJihHaTa KJiiui11uanaT04>i1ioJioriH
fli.n.py'-I
HMK(attrn. MOBOIO)

Pe.naKTOp MaplfyK 0. B.
KopeKTop lJJymoea JI. JI..
Kol\m'io Teptta sepcTKa: flapcjJeHIOK0. C.

Tii,nnucatto.no,npy1<y18.05.11. <l>opMaT
60x84/l 6. Ilanip oq>ceTHHH.
rapHirypa TawMc.)lpyx OQ)CeTHHH.YM . i:xpyK. ap1<.38,27.
T11pa)I(1000 npHM.3aM. N~542.

nn "Hoea KH«ra"
21029,M. BiHHHUR , Byn. KBRTeKa,20
Cei.nouTBOnpo BHeceHHR L{0.nep)l(aBH0f0peecrpy Bli,/laBUiB,
BlffOTiBHHKiBi p03TTOBCIO,A~Bat.JiB BH,Aa_BHH40i'
nponyKui'i
)lK N2 2646 Bi,nI 1.10.2006p.
Ten. (0432) 52-34-80, 52-34-82. <l>a1<c
52-34-81
E-mail: [email protected]
, wv.rw.novaknyha.com.ua

Bi-1APYK083HO 3 roTOBHXAiano3Hrneie
Y KH"1lKKOBii1APYK8pHi..Kono"
(CBiA04reo cepii AK N9 498 BiA 20.06 .2001 pot<y)
eyn. 6opi-1cnascbKa , 8, M. Aporo61o14,
YKpaiHa,82100,
ren. +380 3244 29060 , 3 -87-32; en. nowra: [email protected]