N.K.

Simeonova

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Corresponding Member o f the National

Academy o f Medical Sciences o f Ukraine,
Professor VA. Mikhnev

A p p ro v e d
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 CONTENTS

PREFACE...........................................................................................................................................................................10

Part 1
GENERAL PATHOPHYSIOLOGY
( 'hapter 1. Subejct, Method and Aim of Pathophysiology. Concept of Disease. Etiology and
P athogenesis............................................................................................................................................................. 11
Experiment as the Basic M ethod o f Pathophysiology.............................................................................. 12
Concept o f Disease.................................................................................................................................................12
Concept o f E tiology.............................................................................................................................................. 15
Concept o f P athogenesis..................................................................................................................................... 16
Principles o f Treatm ent........................................................................................................................................18
Tests and Tasks........................................................................................................................................................ 19

t 'Impter 2. Pathogenic Effect of Environmental Factors..................................................................................... 21

Pathogenic Effect o f Low Temperature (H ypotherm ia)...........................................................................21
Pathogenic Effect o f High Temperature (Hyperthermia. B u m )............................................................22
Pathogenic Effect o f Ionizing Radiation. Radiation Disease .............................................................. 24
Pathogenic Effect o f Barometric (Atmospheric) Pressure Changes (Barotrauma).......................... 34
Electrotrauma...........................................................................................................................................................37
Pathogenic Effect o f Space Flight F actors....................................................................................................39
Tests and Tasks........................................................................................................................................................ 40

( hapter 3. Role of Heredity and Constitution in Pathology..............................................................................44

Molecular G enetic Hereditary Diseases ........................................................................................................47
Hereditary Predisposition....................................................................................................................................51
Chromosomal Diseases......................................................................................................................................... 51
Congenital Diseases............................................................................................................................................... 54
G enetic Examination.............................................................................................................................................54
Principles o f Hereditary Disease Prevention and Treatm ent..................................................................57
Role o f Constitution in Pathology....................................................................................................................57
D iathesis.............................................................................................................................................................. 60
Tests and Tasks........................................................................................................................................................61

< hapter 4. Organism Reactivity and R esistance....................................................................................................65

Concept o f Reactivity........................................................................................................................................... 65
( oncept o f Resistance.......................................................................................................................................... 66
Mechanisms o f R eactivity...................................................................................................................................66
Role o f Connective Tissue in Reactivity.........................................................................................................67
Biological Barriers..................................................................................................................................................67
Phagocytosis.............................................................................................................................................................68
Role o f BAS in Reactivity...................................................................................................................................70
BAS Effect C on trol............................................................................................................................................... 73
Tests and Tasks........................................................................................................................................................74

< 'hapter 5. IiiiiuunoloKical Reactivity and Its Pathology.....................................................................................76

Mechanisms o f Immune Response...................................................................................................................77
Immunological Tolerance....................................................................................................................................80
Im m unodepression................................................................................................................................................ 81
Im m unodeficiency..................................................................................................................................................82
DUordet* o f Systems Functionally Connected with Immune System ................................................ 83
tests tind Tasks ...................................................................................................................................... 84

з
Ik

<> Allergy .......................................................................................................................................................... 87

t’lgy in Initially Healthy Organism..............................................................................................................87
f i му in Organism with Immune System P athology.............................................................................. 88
o lo g y ..................................................................................................................................................................... 89
mediate Allergy..................................................................................................................................................92
laved Allergy.......................................................................................................................................................95
loullergv............................................................................................................................................................... 96
in iplrs ol Prevention and Treatment o f Allergy. D esensitization................................................... 99
its and Tasks........................................................................................................................................................100

TYPICAL PATHOLOGICAL PRO CESSES

7 Pulliopliysiology o f Peripheral Blood Circulation............................................................................105

« Ii ll H yperem ia................................................................................................................................................ 105
m m H yperem ia................................................................................................................................................ 107
In-mi.i ........................................................................................................................................................108
sis ......................................................................................................................................................................... 110
rombosis .............................................................................................................................................................Ill
iholism ......................................................................................................................................................... 112
t.s and Tanks....................................................................................................................................................... 113

к Inflammation ....................................................................................................................120
•im.il Signs o f Inllnm m ation....................................................................................................................... 120
>l«*n ............................................................................................................................................... 121
honenesis ....................................................................................................................................................121
Alteration ...................................................................................................................... 121
Intbimimitory ( ells ...................................................................................................................... 121
H \ s Kole in Inflammation. Inllammation M ediators........................................................................ 123
MkitH'Irculilllon Disorder............................................................................................................................ 123
I 4iul.ni.4i, I migration, and Phagocytosis.............................................................................................. 125
Pmhi. мной iiiul Regeneration....................................................................................................................126
I Jisnnlri of MrtabollNin ...........................................................................................................................127
iiiiinuitIon .uni Organism Reactivity..........................................................................................................127
I' inU ( hange-. in Inflammation................................................................................................................. 128
niti« . i m o l Inllammation ..........................................................................................................................128
is and I a sks ...................................................................................................................... 128

9 I evn ..................................................................................................................................... 131

>logv .............................................................................................................................................131
hogeiU'Mf» ................................................................................................................................................. 132
Mechanisms ol I ndogenous (Secondary) Pyrogens Formation.......................................................132
h o lt * Hvr Value o f F ev er............ .................................................................................................................134
Metabolic < hangcs ..........................................................................................................................135
i ilium Changes ...................................................................................................................................... 135
»■'. <«| I l \( l ................................................................................................................................. 136
v i lie a lm en t.. ....................................................................................................................................138
m i l o im s o l Hyperthermia........................................................................................................................... 139
ts ami I a sks .................................................................................................................................................. 140

I!) Nnipliishi ....................................................................................................................... 142

illnal Sings o f N eop lasia...............................................................................................................................142
•logy ............................................................................................................................................. 143
: heinkul < am em g en s............................................................................................................................... 144
lliologleal < ancerogens..........!.............................................. ......................................................................144
iingeiieMi (CnncerogencNU)....... ..................................................................................................................145
iplasili I lanslomiltion ...... . 146
Ulinrillis ol I и т о г ( iiow th 149
iplasia Man 11illation s 150
 C ontents

A naplasia............................................................................................................................................................. 150
Systemic M anifestations o f N eop lasia...................................................................................................... 153
Malingnant Tumor and Organism Reactivity...............................................................................................153
M echanisms o f Protection against Tum or..................................................................................................... 153
I umor Influence on Organism Clinical M anifestations o f N eop lasia.................................................155
Tests and Tasks........................................................................................................................................................ 155

< 'hapter 11. Hypoxia....................................................................................................................................................... 160

F tiology......................................................................................................................................................................160
P athogenesis............................................................................................................................................................. 162
Immediate Compensatory R eactions.........................................................................................................162
Pathological Changes.......................................................................................................................................166
Resistance and Sensitivity to H ypoxia........,.............................................................................................168
Principles o f Hypoxic State Treatment........................................................................................................... 169
Tests and Tasks ........................................................................................................................................................ 169

< hapter 12. Starvation................................................................................................................................................... 174

( Complete Starvation without Water Deprivation.........................................................................................175
Medical Starvation (F asting).............................................................................................................................. 181
Complete Starvation and Water Deprivation (A bsolute)..........................................................................182
Incomplete Starvation...........................................................................................................................................182
Tests and Tasks ........................................................................................................................................................ 185

TYPICAL DISO RDER S OF M ETABOLISM

< hapter 13. Pathology of Energy Balance and Basal M etabolism ..................................................................187
I >isorders o f M etabolism R egulation...............................................................................................................188
I nergy Production Increase............................................................................................................................... 191
Energy Production D ecrease..............................................................................................................................193
Pathology o f Basal M etabolism ......................................................................................................................... 195
Tests and Tasks........................................................................................................................................................ 197

' hapter 14. Pathology of Carbohydrate M etabolism ...........................................................................................200

Disorders o f Carbohydrate Metabolism Regulation................................................................................... 202
Insulin Insufficiency.............................................................................................................................................. 207
C auses and Pathogenesis Absolute (Pancreatic) Insulin Insufficiency.......................................... 207
Causes and Pathogenesis Relative (Extrapancreatic) Insulin Insufficiency..................................208
Insulin Insufficiency M anifestations..........................................................................................................208
Metabolic D isorders........................................................................................................................................208
Pathophysiological Disorders........................................................................................................................211
Diabetes M cliitus.................................................................................................................................................... 212
I tio lo g y ................................................................................................................................................................212
P athogenesis....................................................................................................................................................... 213
Diabetic C o m a .................................................................................................................................................. 216
DM Classification.............................................................................................................................................216
tests and Tasks ........................................................................................................................................................ 219

* Iwplcr 15. Pathology of Lipid M etabolism ........................................................................................................... 223

I Msordcrs o f Lipid Digestion and Absorption...............................................................................................223
I Miordcrs o f Lipid Transport in B lood ........................................................................................................... 223
I borders o f Lipid Synthesis............................................................................................................................... 224
Disorders o f Intermediate Lipid M etabolism................................................................................................225
I )iM>rdeiN o f I ipid Accumulation and D ep osition ......................................................................................225
( )hcNity........................................................................................................................................................................ 226
I Ipoid Degeneration ..................................................................................................................................... 231
tests and Tasks .......................................................................................................................................231

t iuiplci Н» Putholojty of Protein Metabolism ................................. 234

...
Ills

Imogen Balance D isorders............................................................................................................................... 235

lood Protein Content D isorder...................................................................................................................... 236
Hwirders o f Protein Entry, Digestion and Absorption............................................................................. 236
it it r in Anabolism (Synthesis) Disorder........................................................................................................ 237
Acquired Disorders o f Protein Synthesis................................................................................................. 237
I Icredltary Disorder o f Protein Synthesis................................................................................................237
rotein Catabolism D isorder..............................................................................................................................238
Proteolysis Disorders.......................................................................................................................................238
Intermediate Am ino Acid Metabolism Disorders................................................................................. 239
I kvrcditary Am ino Acid Metabolism D isorders.....................................................................................240
JUoidfis o f the Formation and Elimination o f Final Protein Metabolism Products...................241
i v/.v and Tasks........................................................................................................................................................243

с г I / Pathology of Acid-Base B alance.........................................................................................................244

orms o f Acid-Base Im balance.........................................................................................................................247
't'vA ami Tasks........................................................................................................................................................250

u i IS Pathology of Water and Electrolyte Balance.................................................................................. 252

Vuter Balance Regulation- M echanism s.........................................................................................................252
lyperhydration.......................................................................................................................................................255
Local E dem a..................................................................................................................................................... 256
Systemic E dem a............................................................................................................................................... 257
Ivpohydration (Dehydration)........................................................................................................................... 259
In irolyte Imbalance........................................................................................................................................... 261
ГеШ and Tasks........................................................................................................................................................263

Part 2
SPECIAL (SY STEM IC) PATHOPHYSIOLOGY

>||||>ч1о1оцу of Blood S y stem ............................................................................................................................... 266

let 19. Hloori Volume Disorders. H em orrhage.................................................................................... 266

t *Hiil blood volum e disorders................................................................................................................ 267
I lontorrhup.c...............................................................................................................................................268
I t'sfs and Tasks................................................................................... ..................................................... 274

Him Л 1 Pathology of Erythrocytes. A n e m ia .......................................................................................... 276

Um m tltative ( 'hanges o f E ry th ro c y te s .................................................................................................. 276
Qua I ii alive ( M orp h ological) Changes o f Eryth ro cytes....................................................................... 277
Anem ia ..................................................................................................................................................... 278
PonI hemorrhagic A n e m ia .................................................................................................................. 278
I h molytii' A nem ia... ........................................................................................................................................................................280
I mm'iyihropoietic A n e m ia ................................................................................................................. 286
l iy t h r o i ytoms........................................................................................................................................... 291
li sts and Tasks......................................................................................................................................... 293

h<m ’ I Pathology » f Leukocytes. Leukocytosis and U*ukopenia....................................................... 297

LeukopoieHis I b o r d e r s ....................................................................................................- ................................................................... 298
O im utiiailve I )lwmiers o f Leukocytes ...................................................................................................................... ................ 299
Q ualitative < luinges o f Leuko cytes....................................................................................................... 302
i •ukot yioMk ...... ........ ............................................................................................................................ 302
I eu ko p etiia.............. ............. '........................................................................................ ........................... M*’
Irsis and Tasks.... .................. .......................... .................................... .......................................... 308

Him } ) 14’ iik ('iiilu 'II

frws and Tasks .. ,, ......... ........................................... „ т и т . . ....................... .................... 320
 Contents

< iMplcr 23, Pathology of H em ostasis........................................................................................................................322

H ypocoagulation.....................................................................................................................................................325
H ypercoagulation................................................................................................................................................... 330
Disseminated Intravascular Coagulation (D IC S yn d rom e).....................................................................332
Tests and Tasks........................................................................................................................................................ 334

* 'hapter 24. Pathophysiology of H e a r t..................................................................................................................... 338

( ompensatory M echanisms o f the Heart...................................................................................................... 338
( ardiac Insufficiency Caused by Heart Overload...................................................................................... 339
Myocardial Insufficiency.................................................................................................................................... 344
Coronarogenic M yocardium Damage (Ischem ic Heart D ise a se ).................................................. 345
N on-Coronarogenic Myocardium D am age........................................................................................... 347
Cardiac Rhythm Disorders (Arrhythmia)..................................................................................................... 348
< ardiac Insufficiency M anifestations............................................................................................................ 351
Tests and Tasks....................................................................................................................................................... 354

« hapter 25. Pathophysiology of Vessels....................................................................................................................364

Plastic-Type Vessel Pathology........................................................................................................................... 365
Atherosclerosis.................................................................................................................................................. 365
Etiology.............................................................................................................................................................. 365
Pathogenesis......................................................................................................................................................366
Morphological and Functional o f Vascular Wall Disorders............................................................. 371
Systemic Atherosclerosis M anifestations................................................................................................ 371
Muscle-Type (Resistance) Vessel Pathology................................................................................................. 372
Arterial H ypertension.................................................................................................................................... 377
Etiology.............................................................................................................................................................. 378
Neurogenic Hypertension.............................................................................................................................379
Salt(Na+, K+, Ca2+)-D ependent H ypertension.....................................................................................380
Renal Hypertension........................................................................................................................................382
Secondary (Symptomatic) H ypertension................................................................................................ 382
M anifestations.................................................................................................................................................. 384
Pulmonary Hypertension..................................................................................................................................... 385
Arterial H ypotension............................................................................................................................................. 385
Capacitance Vessel Pathology. Venous Insufficiency................................................................................386
Tests and Tasks........................................................................................................................................................ 387

* h>i|»ter 26. Pathophysiology of Respiratory S y stem ........................................................................................... 391

F tiology.....................................................................................................................................................................392
Pathogenesis............................................................................................................................................................392
Ventilative Respiratory Insufficiency........................................................................................................392
Disregulative Ventilative Insufficiency............................................................................................ 393
Obstructive Ventilative Insufficiency................................................................................................ 394
Restrictive Ventilative Insufficiency................................................................................................. 395
Diffusive Respiratory Insufficiency........................................................................................................... 398
Perfusive Respiratory Insufficiency........................................................................................................... 399
Disorders o f Ventilation-Perfusion Ratio in Lung D iseases............................................................400
Respiratory Pathology M anifestations........................................................................................................... 401
Asphyxia......................................................................................................................................................405
Impairment o f Non-Respiratory Functions o f Lungs.............................................................................. 406
t ests and Tasks........................................................................................................................................................ 407

* I» »|»ler 27, Pathophysiology o f Digestive S y stem ................................................................................................ 411

iHjn siivr Disorders in Oral C avity...................................................................................................................411
( aries and Parodontitis................................................................................................................................ 412
Мошне It Pathology.................................................................................................................................................413
Gastritis.............................................................................................................................................................. 417
U ln i Disease of Stomach and D uodenum ...........................................................................................419
Pancreas Pathology ............................................................................................ 422
 iU ii I*

Digestive Disorders Connected with Impairment o f Bile and Pancreatic Juice S ecretion ..........425
Intestinal Digestion Disorders........................................................................................................................... 425
I urge Intestine D isorders....................................................................................................................................428
Intestinal Impassabillty.........................................................................................................................................428
Impairment o f Ineretory (Hormonal) Function o f Digestive System ..................................................430
Tests and Tasks........................................................................................................................................................430
tpter 2H, Pathophysiology of Liver........................................................................................................................434
(tio lt)g y ..................................................................................................................................................................... 436
I’lit In g e n e s is ............................................................................................................................................................ 437
Cholestatic Hepatic Insufficiency..................................................................................................................... 438
Acholic (H ypocholic) Syndrom e....................................................................................................... 439
C holem ic Syndrome (C h o le m ia )...................................................................................................... 440
Mechanical (Posthepatic) Jaundice.................................................................................................. 441
Hepatocellular (Parenchymatous) Hepatic Insufficiency.................................................................. 442
Metabolic Syndrom e..............................................................................................................................443
Syndrome o f Antitoxic Function Impairment.............................................................................. 446
liepatic C om a..........................................................................................................................................447
Parenchymatous Hepatic Jaundice....................................................................................................449
Iiepatovascular Insufficiency...................................................................................................................... 450
Syndrome o f Portal H ypertension.....................................................................................................451
Jaundice...................................................................................................................................................................452
Hemolytic Jaundice....................................................................................................................................... 453
Tests and Tasks...................................................................................................................................................... 454

laptei 24, Pathophysiology «f Kidneys...................................................................................................................459

E tiology.....................................................................................................................................................................461
Pathogenesis............................................................................................................................................................ 462
llole o f Allergy................................................................................................................................................462
Role o f G enetic Factors............................................................................................................................... 462
Role ol M edicines..........................................................................................................................................463
( Jlomerular Insufficiency.....................................................................................................................................463
I ubular Insufficiency............................................................................................................................................ 466
Disorders of Ineretory (N on-D iuretic) Renal Functions..........................................................................468
Manifestations o f Renal Disoders..................................................................................................................... 468
I Itinary Syndrom e........................................................................................................................................... 468
Systemic Clinical Syndromes........................................................................................................................470
t Jlort lerulo nephritis................................................................................................................................................471
Nephrotic Syndrom e............................................................................................................................................ 474
Pyelonephritis..........................................................................................................................................................476
Syndrome o f Acute Renal Insufficiency.........................................................................................................476
Syndrome ol Chronic Renal Insufficiency....................................................................................................478
U rem ia........... .............................................................................................................................................479
tvsts and Tasks....................................................................................................................................................... 480

Iniplei 40 Pathophysiology of Endocrine System ...............................................................................................484

Picghutdular Dysregulatory Endocrine Disorders....................................................................................... 488
Glandular Endocrine Disorders.........................................................................................................................489
Pusiglandulai Endocrine Disorders. Disorders ofPeripheral Hormone A ction............................... 490
( oinpciiMitory Adaptive M echanisms in Endocrine S y stem .................................................................. 490
Pathology o f Pituitary Gland..............................................................................................................................491
Adenopituitary Gland H yperfunction....................................................................................................... 491
Adenopituitary Gland H ypofunction.........................................................................................................492
Neuropituitary Gland P athology................................................................................................................493
Pathology o f Thyroid Glahd............................................................................. .493
Hypeifunction (Hyperthyroidism )................................................. 494
Husedow'a Disease ...................................... 494
Ifypofttnetion (H ypothyroldlim )............................................... 495
Myxedema 4%
■..»it«?r............... .............................................. ...................................................... . №6

i
 C ontents

Pathology o f Parathyroid G lan d....................................................................................................................... 497

Pathology o f Adrenal G lan d...............................................................................................................................500
Adrenal Cortex H yperfunction....................................................................................................................500
Adrenal Cortex H ypofun ction..................................................................................................................... 503
Problems o f G lucocorticoid Therapy A buse...........................................................................................505
Adrenal M edulla Disorders........................................................................................................................... 505
Concept o f Stress................................................................................................................................................... 506
Tests and Tasks........................................................................................................................................................509

Chapter 31. Pathophysiology of Nervous System ...................................................................................................512

E tiology......................................................................................................................................................................512
Pathogenesis............................................................................................................................................................. 514
H ypoxia................................................................................................................................................................514
Cerebral Hemorrhage (Hemorrhagic S trok e)......................... ............................................................... 517
Typical Metabolic Disorders......................................................................................................................... 517
Inflammation......................................................................................................................................................518
E dem a.................................................................................................................................................................. 518
Tumor................................................................................................................................................................... 519
G enetic Disorders.............................................................................................................................................519
Starvation and Electrolyte Disorders.........................................................................................................520
Molecular, Subcellular, Cellular and Tissue Disorders....................................................................... 520
Sensitivity Disorders.............................................................................................................................................. 522
P ain......................................................................................................................................................................523
Antinociceptive S y stem ................................................................................................................................ 525
Disorders o f M otor Function o f Nervous S y stem ...................................................................................... 527
Disorders o f Autonom ic (Vegetative) Function o f Nervous System .................................................... 527
Nervous Trophicity and Neurodystrophic P rocess.....................................................................................528
Higher Nervous Activity Pathology................................................................................................................. 531
N eurosis............................................................................................................................................................. 532
Tests and Tasks........................................................................................................................................................ 533

ANSWERS TO TESTS AND T A S K S..................................................................................................................... 536

INDEX 538
 К К FACE

I In* Pathophysiology D epartm ent o f O.O. Bohom olets N ational Medi~

il University is forem ost in its field in U kraine. F ounded by em inent scientists
,V Pod vysotsky, E.A. T atarinov, V.P. K om issarenko, N .N . Sirotinin and
I N, Zayko, it established the fundam ental patterns used in pathophysiology

■m. hiiiy,. The pathophysiology textbook for U krainian- and R ussian-speaking

iiilciiIs (edited by professors N .N . Zayko and Yu.V. Byts, 2008) is in general
si- and has been awarded the State Prize o f Ukraine. Its authors are professors
1 N. Zayko, I Ya. Danilova, Yu.V. Byts,V.A. M ikhnev,G . M . B utenko, L.A. Popova,
II Ke/nikov, V.A. H orban, O .I. Sukmansky, N.V. Krishtal, V.E. D osenko, and
andidate o f M edical Science diplom a holders - 1.1. Pototskaya, N .K . Sim eonova,
,P Saiarnaya and A.G. Repetskaya.
I he au th o r o f this version o f textbook for foreign English-speaking students is
1 К Sim eonova, a State Prize w inner and a senior lecturer.
I he co n tent and structure o f this textbook have been worked out in accordance
Hli tin* new Pathophysiology Educational Program (2006) and Educational Plan,
iimplied on the basis o f the credit-m odule Bologna system o f training process
igaiii/ation.
I aeh chapter ends with exam ples o f tests and tasks for self-control. E ach test
ml task is based on the text o f the chapter. In the end o f the textbook there are
inli*\ o f right answers. Individual work with the tests and tasks will help students
» pu-pare lor the licensed integrated exam ination «Krok-1. G eneral m edical train-
Ш *.
 Part 1
GENERAL PATHOPHYSIOLOGY

( h ap te r I
SUBJECT, METHOD AND AIM OF PATHOPHYSIOLOGY.
CO N C EPT OF DISEASE. ETIOLOGY AND PATHOGENESIS

SUBJECT, M ETHOD AND AIM OF PATHOPHYSIOLOGY

M edical education is organized in such a way, th at at first students study

those disciplines, which deal with the structure and function o f a norm al organism
(anatom y, histology, biochem istry and physiology). L ater students start studying
ili« disciplines (pathological physiology and pathological anatom y) dealing with
iIn structure and function o f a sick organism , w hich prepares students for clinical
*11 iplines study. In its turn, clinic raises problem s for pathophysiology to solve.
Any scientific discipline has its subject and method. T he problem s investigated
In .( scientific discipline are its subject.
Pathophysiology is a science about the most general laws governing the begin­
n in g , development and outcome of a disease.
Pathological physiology is a basic theoretical m edical discipline called a p h i­
losophy o f m edicine.

TWO PARTS OF PATHOPHYSIOLOGY

Pathophysiology originates from the medical discipline term ed General Patho­

logy, which deals with the pathologic basis o f disease. In English-speaking countries
ihr, medical discipline is taught in such a form in m ost m edical universities. The
*\ nlcsprcad textbook «Pathologic Basis o f Disease» by Stanley L. Robbins and Ram/.i
% < on.in dwells both on the structural basis and functional laws o f pathology. It
was em inent U krainian pathologist O.O. Bohom olets, who singled out Pathological
f'hvslobxy from this m edical discipline. Pathological physiology deals with functional
• hinges, m echanism s and dynam ics o f disease developm ent, as opposed to Patho
logical \natomy, which predom inately deals with m orphological signs o f disease.
In its turn, pathophysiology, as a m edical discipline, consists o f two parts
< и nei.il Pathophysiology and Special (System ic) Pathophysiology.
General pathophysiology deals with:
• < ieneral nosology:
• concept o f disease;
• concept o f etiology and pathogenesis (causes and m echanism s o f disease
developm ent);
* role ol heredity and constitution in pathology;
* role o f organism reactivity (resistance) in pathology.
Purl I Piiiliopliysiologv

• Typical pathophysiological processes (inllam -

m alion, neoplasia, hypoxia, fever, etc.).
• Typical pathology o f m etabolism .
Special (systemic) pathophysiology deals with
the most general objective laws o f pathology o f or-
у. in*, and physiological systems (cardiovascular, re­
spiratory, digestive, endocrine, nervous, etc.) and
tin' main pathophysiological syndromes.

EXPERIMENT AS TH E BASIC M ETH O D OF

PATHOPHYSIOLOGY

Method o f any scientific discipline is the way o f

studying I he problem s it proclaim s. The m ain m eth ­
od o f pathophysiology is experiment. Som etim es dis­
ease m echanism s are hidden, and investigation is O .O . B o h o m o le ts
possible only by m odeling the pathology in experi-
m ental anim als. Il becom es possible to study diseases w ith the help o f contem porary
m orphological and biochem ical m ethods.
Organ extirpation, irritation, injection o f different substances (horm ones, en ­
zymes, antibodies, toxins, etc.) are widely used in pathophysiology. Different types
«•I anim als are involved in experim ents. Sim plification o f the pathological process
has some prevalence. Therefore frogs, rats and even isolated organs and cells m ay
he used. Experim enting helps to establish disease m echanism s at different levels of
oiyam sm organization and to observe it from the beginning up to the end.
Pathophysiological experim ents are divided into acute and chronic ones. An
acute experim ent exam ines acute disorders in the organism (shock, collapse, acute
ien il insufficiency, etc.). A chronic experim ent is a prolonged one and shows dis-
ease dynam ics. It is used for investigation o f chronic diseases (diabetes, atheroscle-
n»sis, arterial hypertension, ulcerous disease, etc.).
All m ethods o f treatm ent are experim entally tested (experim ental therapy) and
*o n eet the knowledge about the essence and m echanism s o f diseases.
In addition to experim ents conducted on anim als, clinical pathophysiological
Investijsitions on patients are possible due to contem porary scientific m ethods.

CONCEPT OF DISEASE

I he teaching about disease, o r General nosology (from G reek nos os — disease),

belongs to the ancient problem s o f medicine. It is im portant for a physician to have
eilteria o f distinguishing health and disease unm istakably. F o r this, it is necessary
to determ ine what health m eans to understand the essence o f disease.
N orm al state of the h um an organism is characterized by its balance with the
environm ent, the ability to adapt to it, hom eostatic m aintenance by p ro p e r regu­
lation and the ability to preserve the m ain social function o f a m an working
ability

12
 t 'lljiH r i I Subject, M ethod and Aim of Pathophysiology. C oncept o f DKenNC. l-Uolo^y and .

I he World H ealth O rganization accepted the following definition o f health.

Health is a state of total physical, mental and social welfare of a man, and not
«inly the absence of diseases or physical defects.
I his definition is rather general and characterizes a situation to be sought.
Norm al life proceeds in perm anent adaptation o f the organism to the environ
im ill. which is constantly changing. If this ability reduces, the m ain social fune-
iиmi o f a m an — working ability — is lim ited. Therefore, the following definition of
•Iim iisc may be suggested.
I>isease is a disorder of physical and mental welfare of a man caused by a harmful
effect, which results in limited adaptive capacity and working ability of the organism
increasing the probability of death.
Л physician has to treat patients with certain diseases. T he am ount o f known
diseases is very large and changes in the course o f tim e. Som e diseases disappear,
oihei appear. F o r exam ple, radiation disease was not evident before X-rays cam e
mi.» 11 si* Space m edicine did not exist before space flights becam e a reality. Several
thousands o f diseases are known now, and each o f them has its own nam e.
Iii*lore studying certain diseases, it is necessary to study their com m on features.
И 1ми iUi be em phasized th at in pathophysiology a disease is understood not as a
•«....Пирс unit (the nam e o f a certain disease), not as a disease o f a certain patient
(whit h has an individual variation o f duration), but as an abstraction, a phenom
■mm which differs from health (fig. 1).

General Characteristics of Disease

1)isease is a unity o f two opposite tendencies — dam age and defense, which are
in <onstant coordination and confrontation.
All physiological patterns m ay be changed in the course o f any disease. How-
• Vi i. disease is not a sum o f quantitative changes, but a qualitatively new pheno­
menon,
I >isease reveals a new understanding o f the optim al level o f physiological func-
i и иг. I or exam ple, in the course o f in­
i' <non l he optim al body tem perature I ) is ease a s =
IV a phylosophical generidization
i ihove 37°C (3 8 -3 9 °C and m ore),
i-ui i lie body tem perature o f 36.6°C
/
и not optim al. During inflam m ation D isease as a typical
r; III
fin Increased am ount o f leukocytes in pathological process
ih* blood (up to 15—20 G /l instead o f
7ПТП
I У ( i/I) is optim al. D uring hypoxia D i s e a s e a s a n o 'I " 1
in im leased respiratory rate and an in-
1 1 eased num ber o f erythrocytes are o p ­
timal Analyzing the patient’s q uantita­ Disease in a patient
diagnosis
tive patterns, a physician must com pare
iln in not only with the physiological
Mumlaidfl, but also with the ones con /•>>:. I Levels of a disease (IV I)
s id e red optim al for this disease. .iiul relation ol abstract and concrete
Part I <»iiic n il I ' iiIIio | i IivsIo Iok.v

Disease has two quite opposite processes. They are:

I Pathological process proper with functional, m orphological, and biochem i­
cal disorders.
2. A m easure against disease, which m eans developm ent o f defense reactions.
So, disease is a dialectic unity o f opposites. A physician m ust fight the p ath o ­
logical process proper and stim ulate the protective processes. Disease com ponents
include pathological reaction, pathological process, pathological state, and typical
pathological process.
Pathological reaction is organism reaction to the effect o f the pathological fac-
toi (hyperem ia, ischem ia).
Pathological process is a com bination o f pathological and protective reactions
in the affected organs o r organism . It has a certain dynam ics and stages.
Pathological state is a pathological process, which has lost its dynam ics and is
lixcd (for example, the condition after foot am putation, stom ach resection).
I\p ica l pathological process is the process with com m on features and laws o f
developm ent regardless o f the localization, nature o f injuring agent and evolution-
■ii V organization o f the organism . The following processes are typical pathological
ones inflam m ation, neoplasia, fever, hypoxia, starvation, hyperem ia, throm bosis,
em bolism , ischem ia, and typical m etabolic disturbances.
Any disease has etiology (causes), pathogenesis (m echanism s o f developm ent),
periods and manifestations.

Classification of Diseases

l or practical purposes it is necessary to divide all the diseases into large

IIroups.
C lassification may follow various principles: cause, localization, m echanism s
*1 developm ent, age (diseases o f children o r elderly people), sex (fem ale and male
I r .c .is e s ) , dysbolism type, professional aspects, etc.
( linical classification o f diseases is based on the clinical forms, localization,
linical duration (acute and chronic).
I'.tlologlcal classification is based on causes. A ccording to this classification,
I r .r n s e s an* traumatic, toxic, infectious, as well as acquired and inherited.
Io|»ographic anatomical classification o f diseases corresponds to the m ain
rhysiological systems and m odern specialization o f m edical care. It is rather practi-
al (cardiac, pulmonary, nervous diseases, etc.).
Pathophysiological classification is based on the conception o f typical patho-
ugk il processes. It divides diseases into inflammatory, allergic, neoplastic, and
netaholic ones. C onsequently, before studying inflam m atory diseases (tonsillitis,
nyocardltie, hepatitis, pleuritis, etc.) it is necessary to study inflam m ation as a
ypical pathological process. Before studying such diseases as cancer, m elanom a, or
•sieoma it is necessary tb study neoplasia as a typical pathological process. Uefore
ludylng allergic diseases (bronchial asthm a, rheum atoid polyarthritis) it is neces-
u у to study alleigy.
 < lliip ln I N tibji'rt, M H lind mid Aim o f I'lilhopliysloloKy. ( o n c i'p t of D lncaw . I'Uology and ...

Periods of Disease

M any diseases (infectious and som e others) develop in such four periods:
I Latent (has no clinical signs).
Л Prodromal (there appear first clinical sym ptom s, which are com m on in
m any diseases).
\ Г/w period o f pronounced manifestations and expressed clinical signs (which
aie specific o f this disease).
•I ()utcome.
I Ins four-staged periodization o f diseases was suggested in the past for acute
lull i lious diseases, hut m any diseases (cardiovascular, endocrine, allergic) are gov^
• 1 1 it'd by o th er laws, and the m entioned periodization is not applicable to them .
I h e s e diseases develop in three periods:
I beginning.
) Гhe st age o f disease proper.
I Outcome.
I Msease outcom e depends on the force o f the harm ful factor, organism reac-
1 1 vи\ and the ability to develop self-protective reactions. There are three types of
*11 • r.r o u tc o m e : recovery (c o m p le te , in c o m p le te), tra n sfo rm a tio n into a chro n ic
Ii*iih 01 pathological state, d e a th w ith p reagony, agony, clinical a n d th e n biological
death,
Pievalence o f defense reactions leads to recovery. Incom plete com pensation
leads to disease turning into a chronic form. Exhaustion o f adaptive reactions leads
lo death.
Г m m the pathophysiological point o f view m any diseases undergo two peri
ltd*
I Stage o f compensation (ability to work is preserved);
) Stage o f decompensation (ability to work is lost).

Manifestations of Disease

I m li disease is m anifested by subjective (p atien t’s com plaints) and objective

apiis, which in turn are visible (rash, paleness, edem a, discoordination o f m ove-
in* in .) .11 ill invisible. T he latter are morphological, physicochemical, biochemical and
funhophyslological (functional), which are revealed by special investigations.

CONCEPT OF ETIOLOGY

Hlology is a teaching about causes and conditions of a disease.

Л certain pathogenic factor is called an etiological factor.

Classification of Etiological Factors

I Hologlcal factors are divided into exogenous (external) and endogenous (inter
n il) as well as acquired and congenital ones,
 I ( iriH’l 111 Ги|1|о||1п ч1«»1оц>

D epending on their nature, etiological factors arc divided into physical (m e-

nical, therm al, electrical, radiation, barom etric pressure changes, etc.), chemical
emical poisons, toxic m etabolites, drug side effects) and biological (m icrobes,
iscs, parasites). Besides, there are psychoem otional influences. For m en, social
ses o f disease are distinguished.
(icnctic and immune causes refer to endogenous biological factors.

Role of Conditions in Disease Development

Го analyze etiology, one should consider the conditions o f etiological factor

uence, which are divided into prom oting and preventing a lesion (schem e 1).
ns, analyzing the effect o f high or low environm ent tem perature, it is necessary
ake into account the local or system ic m ode o f its influence. To analyze a radia-
ii injury, one should take into account both the dose and the channel o f its entry
о the organism (o u ter radiation or penetration o f ionized particles).

lifme I. Correlation be­ E T IO L O G Y

en Causa and Conditio in
ology
E tiological f a c t o r ______ C on dition s
(Latin causa) (Latin conditio)
s 4.
Exogenous Endogenous Promoting Preventing
I____________ I disease disease
developm ent developm ent
Physical (risk factors)
Chemical
Biological

I xogcnous and endogenous conditions, w hich can modify etiological factor

ci I in id prom ote disease developm ent, are po o r nutrition, overcooling, overheat-
i, oxygen deficiency, old age, early childhood.
Kish factors are those, which increase m orbidity. F or exam ple, arterial hy-
itension, obesity, hypodynam ia, hereditary factors, stress are the risk factors for
ii m sclcm sis developm ent. Risk factors m ay play the role o f a cause, condition
link of pathogenesis.
( )verestim ation o r underestim ation o f either etiological factors or conditions are
M akes (causalism is overestim ation o f the role o f etiological factors and underesti-
atlon o f the role o f conditions; conditionalism, on the contrary, is overestim ation
* oiiditions value). Only adequate estim ation o f the role o f both etiological factors
id conditions leads to a correct analysis o f disease etiology.

CONCEPT OF PATHOGENESIS

Pathogenesis is mechanisms of disease development ami outcome after etiological

ctor action.
 \ nnjiiov I Minjcci, ivhmiioii tiiki лип oi |'й1Н0р||уя101(щ. i onci'pt oi Disease, i.tioiogy and ...

There are two variants o f Scheme 2. Variants of Cause-and-Effect Rela­

i ausc(etiology)-pathogenesis rela­ tions
tionship.
Etiological factor
1. T he etiological factor initi­
ates a pathologic process and then
disappears, so pathogenesis develops
in the absence o f the etiological fac­
I Infection

tor (traum a, radiation).

2. The cause continues its ac ­
tion throughout all the periods of
disease developm ent (infectious dis­
ease); so, the etiological factor р е­ I )
Chronic non-infectious
disease

ш и ates pathogenesis and influences

l(.
Etiological factor
There are som e general laws in
pathogenesis o f any disease.
• All events observed in any
disease pathogenesis are called links
<>f pathogenesis. The o rder o f events
is called cause-and-effect relations.
I here are three variants o f such rela­
tions (schem e 2), w hich have practi­
cal im portance.
• If pathogenetic links are connected directly (like in infection), self recove­
ry is possible.
• In case o f a «vicious circle» the subsequent pathogenetic link stim ulates
the effect o f the previous one. T he process can not finish w ithout help
and becom es endless, like a circle. F o r exam ple, in shock, w hen arterial
blood pressure decreases, it causes hypoxia, then the vasom otor center
becom es depressed, and it leads to a prolonged decrease o f arterial blood
pressure. Figures 30 and 31 show cause-and-effect relations with m any
«vicious circles» in hem orrhage shock and tissue hypoxia. Such disease
course is characteristic o f m any chronic non-infectious diseases — arterial
hypertension, bronchial asthm a, atherosclerosis, rheum atism . Figure 58
shows a «vicious circle» in endocrine pathology.
• If pathogenesis develops as chain branching reactions (radiation disease),
help is necessary at the initial stage o f pathogenesis. Prophylaxis is the best
measure.
• T here is a so-called leading (m ain) link in pathogenesis. It is a process nece-
ssary for the developm ent o f all others. T reating o f the m ain link is essential for
treatm ent. Thus, in diabetes m ellitus insulin deficiency is the m ain pathogenetic
link Its elim ination (by horm one injection ) results in disappearance o f o th er sings
(hyperglycem ia, glucosuria, polydipsia, ketonem ia, and com as).
• In any disease th e organism resists injuries by developing defense (protective,
adaptive, compensatory) reactions They may be immediate and delayed.

17
I'.it I I (ieiieral Pathophysiology

• Stage o f compensation is such a disease stage, when com pensatory reac-

iions prevail, hom eostasis and norm al vital activity are m aintained. C om pensatory
(defense) reactions are divided into immediate (urgent) and delayed (non-urgent,
which provide long-term adaptation). Im m ediate protective reactions are a m obili­
zation o f physiological hyperfunction m echanism s. Long-term com pensation may
he achieved by organ hypertrophy (m yocardium pathology). Adaptation is such a
state o f com pensation, w hen in spite o f constant action o f the etiological factor,
the ability to work is supported com pletely. Stage o f decompensation is such a dis­
ease stage, w hen (a) com pensatory m echanism s are not adequate, (b) adaptation
reserves are depleted, (c) hom eostasis alters.
• In any disease pathogenesis it is necessary to identify local and systemic
derangem ents. Som etim es the local ones develop originally and lead to systemic
changes. F or exam ple, inflam m ation develops predom inantly locally, but the whole
organism becom es involved. Som etim es a systemic derangem ent develops at first
and is m anifested by local changes. F or exam ple, in diabetes m ellitus (a systemic
disease) local processes (furuncles, neuritis, renal dysfunction) develop secondarily.
I ipid disbolism causes atherosclerosis, w hich m anifests itself as heart attack or gan-
grene o f the lower extrem ities.
• In any disease pathogenesis structural and functional disorders are identi­
fied. A physician is m ainly interested in functional disturbances. N aturally, certain
structural and biochem ical changes underlie the dysfunction. However, in m any
cases m edical science can not identify them (for exam ple, in m ental diseases, see
pp. 58, 514).
• In any disease pathogenesis there are specific and nonspecific signs. The for­
m er characterize certain diseases and underlie diagnostics (for exam ple, the charac­
ter o f pain in case o f stenocardia). T he latter characterize m any or even all diseases
(m echanism s o f a standard response to any pathogenic factor like stress).
• It is necessary to study the pathogenesis o f any disease at different levels o f
biological organization — m olecular, cellular, at the level o f organs, physiological
systems and organism as a whole. Investigation at the level o f population discloses
additional laws (population genetics, investigation o f inflam m ation in evolution by
M echnikov).
• The course o f any disease depends not only on the force o f the etiological
factor, but also on organism reactivity (resistance) and ability to develop defense
reactions.
• The course o f any disease depends not only on the etiological factor, but also
on the genetic and constitutional peculiarities o f the organism .
f rom all these positions it is necessary to analyze the pathogenesis o f any dis­
ease.

PRINCIPLES O F TREATMENT

I Isually a physician records p atien t’s com plaints, subjective and objective m ani­
festations o f a disease, which are called sym ptom s. A physician may treat a certain

IM
 ( ImpkT I Subject, M ethod and Aim of l*ttlhophy>tology« C oncept o f Disease. ICtlology in u l.

vm ptom (pain) and alleviate the patient’s suffering. This is symptomatic therapy,
the worst type o f treatm ent.
I lie real cure is elim ination o f the disease cause (for exam ple, infection treat
M i l lit with antibiotics). This is etiological therapy. However, som etim es elim ina

nun o f etiological factors is im possible and attention m ust be paid to conditions.

* и at ion o f favorable conditions and avoidance o f risk factors underlie etiological
therapy as well.
It is possible to block im portant m echanism s o f disease developm ent. Naturally,
tin* knowledge o f m olecular, cellular and biochem ical m echanism s o f pathogenesis
i necessary. This type o f therapy is effective and is called pathogenetic.

Questions for Self-Control

I What is the difference between norm al and pathological physiology?

' What is the difference betw een pathological physiology and pathological
m orphology?
' What are the advantages o f pathological physiology?
H What are the advantages o f pathophysiological experim ent?
'• < »ive the pathophysiological classification o f diseases.
I» Is ,i disease a quantitative or qualitative disorder? G ive an explanation.
/ What is the difference betw een pathological state and pathological process?
к What is a typical pathological process? G ive definition and examples.
') What is the role o f conditions in etiology?
in What is eausalism and conditionalism ? W hat are the harm ful effects o f such a
disease m isunderstanding?
II What arc risk factors? W hat is their role in disease developm ent?
I What is the role o f the leading pathogenetic link?
Ii What is the significance o f understanding the cause-and-effect relations in
pathogenesis?
II What is the difference betw een the stages o f com pensation and decom pensation
in pathogenesis?
I '> What is a «vicious circle»? W hat is physician’s approach if a disease takes such
a t ours©?
What levels o f biological organization is disease pathogenesis studied on?
I/ What is the best m ode o f therapy - etiological, pathogenetic or sym ptom atic?
Which is the worst one?
IN What can etiological therapy do if a physician can not influence the etiological
factor?
I'» What is physician’s approach if a disease takes a course o f chain branching
reactions?
Part I ( .n i e n il I’iillmplivsioloK.y

Tests for Self-Control

1. A patient has pulm onary tuberculosis and is infected. K och’s bacillus has
been revealed in the mucus. W hat is the role o f K och’s bacillus in disease
developm ent? It plays the role of:
A. C ondition.
B. Pathogenesis.
C. M ain link o f pathogenesis.
I). Etiological factor.
II. G enetic factor.

2 . The m ain pharm aceutical agent for radiation disease treatm ent is the use
o f antioxidants against active form s o f oxygen, w hich determ ine the m ain
pathophysiological changes and clinical m anifestations. W hat is the role of
active forms o f oxygen? They are:
A. Etiological factor.
B. C ondition.
C. Main link o f pathogenesis.
I). C om pensatory reaction.
I’. M anifestation.

3. A clinical exam ination o f a 47-year-old m an revealed dark-red gum s of

l he upper jaw, suppuration in the gingival pockets, loosening o f the teeth.
Established diagnosis: parodontosis. W hat period o f the disease is it?
A. Preillness.
B. Latent.
C. Period o f pronounced m anifestations.
I). Prodrom al.
E. O utcom e.

4. A stom atologist has found som e carious teeth in a 32-year-old w om an. W hat is
the proper nosological term to determ ine this state?
A. Pathological reaction.
B. Pathological process.
C\ Remission.
I). Illness.
I . C om pensatory reaction.

> C om pile a schem e o f viral influenza etiology taking the schem e I from this
ch ap ter as a rpodel,
i h u p ter 2
l*V! IKKJKNIС EFFECT OF ENVIRONMENTAL FACTORS

I nvironm ent is a sourcc o f various pathological factors th at causc pathology

H iht'ii force exceeds adaptive potentialities o f the organism or organism reactivity
din leases,
I In term environmental disease applies to a disease not transm itted by genes or
inli i lion. All o f th em are theoretically preventable.

PATHOGENIC EFFECT OF LOW TEMPERATURE (HYPOTHERMIA)

I Ivpotherm ia is a decrease o f body tem perature as a result o f exposure o f the

h Ih »lrbody to a low am bient tem perature.
I Oology. Etiological factor is a cold, to which the w hole body is exposed. The
I* ПЦН 1 .1ture o f com fort is 18°C. T he tem perature, which is below the indicated
i* vH leqtiires w earing clothes.
Pjilhogenesis. H ypotherm ia develops in two stages - com pensation and de
- om pensation.

Y/ujft* of ( ompensation

I he stage o f com pensation is a period o f hypotherm ia, w hen defense reactions

I'M \ .ill, and norm al body tem perature is m aintained.
V. .1 hom eotherm al organism , m an can tolerate am bient tem perature fluctua­
tion
< om pensation develops as a response and excitation o f the cutaneous tlier-
uiotiH eptors and therm oregulation center. As a result, com pensatory reactions de­
velop.
< ompensatory reactions consist in heat em ission lim itation and heat production
Motivation.
Ileal em ission dim inishes by m eans o f perspiration (evaporation) decrease and
|u iiplietal derm al vessels contraction (angiospasm ).
Hr,it production (therm ogenesis) intensifies, and additional heat calories are
Iи oi It и ed. M etabolism is activated, glycogen splitting in the liver and muscles takes
i*l:M i ( ilueose blood level rises. Oxygen transport activates and oxygen consum p
..... . mi reuses. The organism , which is adapted to cold, has a m ore powerful mito
» i m mi r l n ! s y s t e m .
I ipid m etabolism is activated.
M etabolism is not only activated, but reorganized. A dditional therm al energy
t M in ed due to uncoupling o f oxidation and phosphorylation.
I liennoregulation reorganization is controlled by neurohum oral m echanism s
I ими the cutaneous therm oreceptors through the allerenl nervous ways impulses
и «и Ii ili»- center o f therm oregulation in the hypothalam us, from which in the op
Purl I ( i m oral I’afhophysioloKy

posite direction signals reach the organs and systems, w hich participate in body
tem perature m aintenance. Along the m otor nerves im pulses reach the muscles;
therm oregulatory m uscle tone rises and m uscle trem bling develops. Along the sym ­
pathetic nerves im pulses reach the adrenal m edulla. A drenaline secretion increases
(adrenaline effects the vessels, m obilizes glycogen from the liver and muscles, stim u­
lates oxidation). The pituitary gland stim ulates (by tropic horm ones) the thyroid
gland (thyroxin intensifies m etabolism , activates m itochondria biogenesis) and the
adrenal cortex (glucocorticoids stim ulate form ation o f carbohydrates from n oncar­
bohydrate products and form the condition o f stress).

Stage o f Decompensation

T he stage o f decom pensation is a period o f hypotherm ia, w hen com pensatory

leactions are exhausted and body tem perature lowers. R eduction o f m etabolism and
oxygen consum ption is observed. Vitally im portant functions fail. Im pairm ent of
respiration and hem odynam ics leads to hypoxia.
In the state o f hypotherm ia the organism becom es less sensitive to other injur­
ing factors (intoxication, infection, harm ful effect o f electric current and ionizing
radiation, hypoxia).
If the action o f cold does not cease, death com es.

PATHOGENIC EFFECT OF HIGH TEMPERATURE

(HYPERTHERMIA. BURN)

Hyperthermia is an increase of body temperature as a result of exposure of the

whole body to a high ambient temperature.
Etiology. Etiological factor is a heat, to w hich the whole body is exposed. It
happens in industrial conditions. Nowadays, when clim ate changes, overheating
happens under the tem perature o f surroundings, w hich is above body tem perature
(36°C and higher). T his problem arises all over the world.
Pathogenesis. H ypertherm ia develops in two stages - com pensation and de­
com pensation.

Stage o f Compensation

The stage o f com pensation is a period o f hypertherm ia, when defense reactions
prevail, and norm al body tem perature is m aintained.
Compensatory reactions consist in heat em ission increase by activation o f c o n ­
vection, radiation, perspiration and evaporation. T he peripheral vessels are dilated.
If the tem perature o f the environm ent is above 30°C, convection is inhibited. U nder
the condition o f high air hum idity evaporation is lim ited as well.

Stage o f Decompensation

The stage o f decom pensation is a period o f hypertherm ia, when com pensatory
reactions are exhausted and body tem perature rises
 C h a p te r 2 Pathogenic Effect of Environment ill Iju lo rs

H ypertherm ia m anifests itself by central nervous system excitation and tachy­

pnea I lie cardiovascular system is overloaded. Tachycardia is a sym ptom o f over
h* ating. Later, generalized vasodilatation occurs with sequestration o f a large vol­
ume o f blood and effective circulating volum e reduction.
At the beginning o f hypertherm ia, oxygen intake and m etabolism rise as a result
«-I nervous excitation and body tem perature rise. Protein disintegration is intensi
in-»! A surplus o f final nitrous products is observed. The acid-base balance changes
inwards acidosis. A ctivation o f perspiration has negative consequences — dehydra
non develops (liquid loss can reach 3.5 I per hour). Electrolytic im balance consists
in i he loss o f sodium and chlorides. D isorder o f the intracellular sodium pum p leads
i" potassium redistribution in the extracellular fluid and blood. Hyperkaliem ia thus
*h vclops. Increased blood viscosity creates additional load on blood circulation and
и nils in cardiac insufficiency.
Acute overheating and a rapid body tem perature increase are called therm al
shock (heal stroke). If the action o f the etiological factor does not cease, convul
i"n develop and death occurs because o f disordered respiration and circulation.

Local Hyperthermia (Thermal Burn)

Hum develops as a result o f the local effect o f high tem perature and is m ani
I* .led by skin destruction and systemic disorders in the organism .
I S pen d in g on the intensity o f local dam age, the following degrees o f burn are
distinguished:
I redness o f the skin (erythem a), a weak inflam m atory reaction w ithout skin
И* i ruction;
II acute exudative inflam m ation o f the skin, form ation o f blisters, and epi
ili mils scaling;
III partial skin necrosis and ulceration;
IV transcpiderm al necrosis.
In extensive burns system ic disorders predom inate over local ones. It goes
•Iмин Imiin disease.
< Tinical m anifestations o f burn disease are connected with the developm ent o
h«H I. toxem ia, infection, and dehydration.
Hum shock is the m ost severe post-burn effect. It is a result o f pain and exccs
- • iilleient im p u ta tio n to the central nervous system. T he regulation o f vascular
«••in inspiration and heart contraction is im paired. T he circulating blood volume
di i »• .ises. dehydratation and acute renal insufficiency develop.
Intoxication significantly contributes to the developm ent o f shock. Endotoxins
и- fin nicd as a result o f disbolism ; a large quantity o f toxins is liberated in the /o n e
"• damage C ritical disorders in protein m etabolism are noted; total protein disiti
и jiifitiou is observed D enatured proteins and toxic products o f their en/.yrnal lysis
мн. i ihe blood A critical disorder o f nitrogen m etabolism takes place.
Infection is a constant com plication o f burn disease and aggravates intoxiea
Пин I In* source ol infection is the dam aged surface and bowels (autoinlection).
f J*«i only llie bum area ilsell is colonized by bacteria but the entire skin surface ol

IX
Г.ill 1. ( . r u n a l I’al l i u fi l n s i o l o t ’v

I In* patient. Increased perm eability o f blood vessel walls leads to massive infection
and bacteriem ia. Sepsis resulting from burn w ound infection is the m ost im portant
cause o f death in seriously burned patients. U nder the effect o f proteolytic enzymes,
which are liberated from the dam aged cells, proteins m ay change, and antigens
becom e the reason for autoim m une aggression.
Dehydration is a severe com plication o f burn. It relates to the massive o u t­
pouring o f exudate. T he burn area becom es reddened as sm all blood vessels dilate,
a norwards one observes increased capillary perm eability with protein-rich fluid exu­
dation. Burn implies an open w ound, from which an enorm ous am ount o f plasm a
proteins may be lost through the dam aged surface. T he loss o f liquid induces hypo­
volemia and hem oconcentration. Increased blood viscosity disrupts blood circula­
tion and heart function. The w ater-m ineral balance breaks down. T he dam aged
tissues retain sodium (cellular hyperhydration develops) and lose potassium (the
blood co n ten t o f potassium increases, hyperkaliem ia develops).
Exhaustion (cachexia) is the final stage o f the disease. T he following p ath o ­
logical disorders are observed — edem a, anem ia, dystrophic changes in the organs,
pneum onia, glom erulonephritis, and adrenal glands insufficiency. All these disor­
ders equally with pulm onary transudation striking and pulm onary edem a becom e
the cause o f death.
If burn disease takes a favorable course, recovery begins. D efects are filled with
granulation; w ounds are epithelized.
Thus, severely burned patients confront not only local injury repair but, even
m ore im portantly, its serious systemic consequences.

PATHOGENIC EFFECT OF IONIZING RADIATION

RADIATION DISEASE

Etiology

I tiologieal factors o f radiation disease are various forms o f ionizing high-energy

radiation ( a , [}-, y-rays, X -radiation, etc.). T heir general property is the ability to
pencirate into biological m edia and ionize atom s and molecules.
I he intensity and d u ration o f injury depend o n the form o f radiation, dose,
lime factor and the type o f m olecular or supram olecular target, through which ra ­
th ai mu passes (table 1).
Ihere is no strict correlation between radiation dose and affection severity.
A direct dose-effect correlation appears for large and average doses. As to small
doses, i lie correlation is different. The so-called radiobiological paradox is evident. It
m eans that the clinical effect can be drastic even in case o f insignificant quantity o f
absorbed energy, because the primary physical and chem ical effects are aggravated
by biological m echanisms.
I here are such doses o f radiation that substantially d o n ’t change m orbidity in
population. However, even one quantum o f energy can bo sufficient for m utation
with tragic consequences. So, any radiation dose shouldn't bo appreciated as abso
liiielv harmless for people,
 ( Impii't Pathogenic Effect of liivimiiimiitiil l*'nctorN

M h I
Biological Effect of a Single Whole-Body Exposure to Various Doses
of Ionizing Radiation on Man
Imm (Koeiitgens) Biological Effect
10 No detectable somatic effects. Detectable morphologic and func
tional alterations in specific subpopulations of lymphocytes; prob
able chromosomal abnormalities
100 Mild form of the disease in some persons with nausea, vomiting and
transient leukopenia
1000 Affection of the bone marrow with leukopenia, thrombocytopenia
and anemia; necrosis of the gastrointestinal mucosa; severe radiation
disease; death within 30 days
10000 Death within hours
100000 Death of most types of mammalian cells

4 11 im portant condition that substantially m odifies the type o f radiation disease

■ Ни pathway o f irradiation (distant, contact, inhaled or oral). We talk about ел-
Iriadiation when its source is located outside the organism . Internal (incor-
fmniftut) irradiation takes place when radioactive m aterials get inside. T he latter is
• mii chim 'd m ore dangerous. C om bined radiation is also possible.

Pathogenesis

l*i (пни у M olecular (Physicochem ical) Disorders

I hr energy o f ionizing radiation exceeds the energy o f intram olecular and intra
iinniu bonds. A bsorbed by a m acrom olecule, it may m igrate in th e cell realizing
hi ih« mosi vuln erable places. It results in io n izatio n , excitatio n a n d break o f
ь v> .(able b o n d s, tearin g of!' radicals, w hich are called free.
So, I lie initial links o f pathogenesis consist in ionization and excitation o f atom s
нм I molecules. C hem ical transform ation o f substances and form ation o f active in-
н mi. «lull- products caused by radiation are called radiolysis. Radiation dam age is
• ««пи.»led with direct and indirect action o n im portant biological molecules.
Direct effect o f radiation energy is a dam age o f m acrom olecules by radiation
и * И I veutually, intram olecular changes take place. Any type o f m olecules may be
а пни, i organic m acrom olecules such as DNA , lipids, phospholipids, enzymes,
pi*и* ms, vitam ins, hem oprotein, etc.
Indirect action is a dam age o f m acrom olecules by water radiolysis products.
\S h. i m olecu le io n izatio n is th e m ost sig n ifican t o f all p rim ary rad io c h em ical
i ю н .i«nm illions, I he first products are ionized water m olecules 11,0' and 11,0
Пн и lнм- hydrogen and hydroxyl radicals are form ed (II, O H ), which initiate a
• H uh i »l flirt he i reactions and new products are formed (hydrogen peroxide 11,0,,
h .impt ioside 1И),, atom ic oxygen O, etc.). W ater radiolysis products biochem i
t nilч ui‘ very active and cause extensive nonen/ym alie o x id atio n .
Purl I ( h' iuthI pHlltophysioloK.v

Biochemical Disorders

Later, the oxidizers attack organic m olecules, and new active radicals are
formed. C hem ical and biochem ical reactions rapidly increase, acquiring the nature
o f branching reactions. Such reactions develop m ore aggressively in a lipid m edium
and peroxide oxidation o f lipids is initiated.
fu rth e rm o re, radiotoxins are form ed. U n s a tu ra te d fatty ac id s a n d p h e n o ls
n r o x id ized re su ltin g in th e fo rm a tio n o f lipid (lipid peroxides, epoxides, a l­
d ehyd es) a n d q u in o n e ra d io to x in s (precursors o f quinone radiotoxins are tyrosine,
tryptophan, serotonin, catecholam ines). R ad io to x in s in h ib it n u cleic ac id s y n th e ­
sis, in flu en ce D N A as c h e m ic a l m u ta g e n s, c h a n g e en zy m e activ ity , d am ag e
In tra c e llu la r m e m b ra n e s.
Enzymes are damaged directly (as a target) and indirectly (by w ater radiolysis
products and radiotoxins). Thiolic enzymes (they contain SH groups) have increased
radiosensitivity and are oxidized easily. Some enzymes, on the contrary, are activated,
particularly the ones released from dam aged lysosomes. Subsequently enzymal reac­
tions are intensively intensifying — disintegration o f proteins and nucleic acids is acti­
vated, synthesis is reduced, phosphorylation and antioxidant activity are damaged.
N itrogen balance becom es negative. G lobin synthesis is reduced. A ntibody
synthesis is suppressed.
It is necessary to pay a special attention to the dam age o f a unique D N A m ol­
ecule. Its intram olecular bonds are the m ost vulnerable target for direct and indirect
radiation effect. F ree radicals an d peroxides dam age th e ch em ical stru ctu re o f
D N A . P y rim idine o x id atio n an d p u rin e bases d e a m in a tio n are observed in n u -
clcic acids so lu tio n s a fte r ra d ia tio n influence. T he change o f th e D N A structure
is called m utation, thus ionizing radiation relates to physical m utagens.
Thereby, p rim ary ra d io c h e m ic a l re a c tio n s co n sist o f d ire c t an d in d ire c t
injury o f th e m o st im p o rta n t b io c h e m ic a l cell c o m p o n e n ts — nu cleic acids,
p ro tein s, an d enzym es. L ate r o n , en zy m al re a c tio n s are v io le n tly c h a n g e d —
en zy m al lysis o f p ro te in s an d n u c le ic ac id s is a c tiv a te d , D N A sy n th esis is
in h ib ite d , b io sy n th esis o f p ro te in s a n d en z y m e s is su p p ressed .

Disorders a t the Cellular Level

Any cellular structure may becom e a target for radiation energy, active oxidiz­
er., radiotoxins and activated enzymes. T h e above m en tio n ed physical, chem ical
and bio ch em ical ch an g es d istu rb all m a n ife sta tio n s o f c e llu la r vital activity.
I herefore, all biological processes in cells m ay be dam aged.
The signs o f radiation injury o f the nucleus (swelling, pycnosis, lysis) are c o n ­
firmed histologically. O ne can see signs o f ra d ia tio n in ju ries o f th e n u c le u s
u n d e r th e e le c tro n ic a n d light m icro sco p e s. C hrom osom al a b e rra tio n s (breaks,
d e le tio n , fra g m e n ta tio n ) an d m o re su b tle d iso rd e rs o f th e g e n e tic a p p a ra tu s
(yeno m u tatio n s) may change the synthesis o f D N A , specific p ro tein s and sub­
sequently hereditary properties of cells.
All othei cell organoids are dam aged too.
 C h a p in ’ Ри Н ю д си к' Krrecl of Environmental Factors

Phospholipids o f in trac ellu la r biomembranes (o f th e n u cleu s, m ito c h o n d ria ,

i <» an d cn d o p la sm a tic re tic u lu m ) becom e a target for free radicals.
I )amage o f the fysosome m em brane results in the release o f proteolytic enzymes
n ilu .iu k le a s e , d eso x irib o n u clease a n d ca th c p sin s) into the cytoplasm having an
mini toil', effect o n n u cleic acid s, cy to p lasm ic an d n u c le a r p roteins.
Im pairm ent o f o x id a tiv e phosphorylation and electron transport in mitochon-
thin leads to energy deficit. C ellu la r energy disbolism is o n e o f th e m ost pro b ab le
«и .< . ol th e in h ib ite d sy n th esis o f n u c le ic acid s, n u c le ic p ro te in s a n d m itosis.
... i u liation in ju ry o f th e n u cleu s is c o n n e c te d n o t o n ly w ith th e d irect effect
• i i- mii/m g ra d ia tio n on D N A an d c h ro m o s o m e s b u t also w ith p a th o lo g y o f
mi! h i o rg anelles.
I hiring m itosis cells becom e m ore vulnerable to radiation. C ell division is
m ini.ih (l C ells m ay be d e s tru c te d at th e m o m e n t o f d iv isio n as w ell as in the
If111 iphase.
II ,i <ell with genetic errors is not elim inated, it becom es a carrier o f changed
h- и tluv Som atic cells m ay becom e m alignant. M utation in germ cells may cause
h* iи ! lini v diseases in descendants.

Мй(н tiers л! the Tissue Level

hi | mi« o f the fact that radiosensitivity o f the nucleus is not higher than that
III itllii i nijr.moids, its dam age is m ore evidently m anifested in the vital activity of
I I'll-:
I !m i. lore, it is not hard to understand the relative radiosensitivity o f tissues. In
|h m Ml и lies are sensitive to radiation energy in direct proportion to m itotic ae-
iM lv iin I 111 inverse proportion to the level o f differentiation. Thus, the tissues with
к ЫН» i-»ie o f cellular renovation dem onstrate the greatest radiosensitivity: these
ан Ии hm p h o id , hem opoietic, epithelial tissues (particularly the epithelium o f the
I и » aiul sex glands) and endothelium o f vessels. T he fibrous, bone, m uscular,
itiiH и* n o u s t ells are less radiosensitive. T he nervous cells are destructed under the
ф Пон oi high overdose radiation (interphase destruction).

t Ими «hr, hi the W h ole-O rgan ism Level

In . o f lethal and superlcthal radiation doses interphase cell destruction pre

ш \ uni <it nh com es within som e hours (m inutes) after exposure to radiation. In
!'<»"» oi пн di.in radiation doses life is possible, but in all physiological systems pat ho-
|нрь il * !mh}*< . lake place depending on the com parative radiosensitivity o f tissues.
Hi tin whole organism level, the pathogenesis o f radiation injury consists in
whih (Miiliophvsiological syndrom es (syndrom e is a com plex o f sym ptom s, which
$ \f ппмм| hv a com m on pathogenesis).

lit т пьФ щ к Syndrome

lln m.. .I t liaraeteristie o f all form s o f radiation injury is ;i disorder o f the

h. (Норма н* .ни) blood system, H em atologie syndrom e is e h a ia e le n /e d by changes
I*urt 1. (ien c ru ! I’athopliysioloKy

iii I he peripheral blood, progressive atrophy o f the lym ph nodes, bone m arrow
and spleen. A decreased quantity o f all types o f blood cells and depression o f
their function are observed. Lym phocytes are the m ost vulnerable ones. Therefore
lym phopenia develops from the very beginning. Lym phocytes break down in the
lymph nodes and blood. Later, throm bocytopenia, granulocytopenia and eventually
anem ia develop.

Hemorrhage Syndrome

A typical and obligatory sign o f radiation disease is hem orrhage syndrom e

(predisposition to bleeding). It em braces hem orrhages into the skin (petechiae,
ecchym oses, epistaxis), m ucous m em branes (gingival bleeding), internal organs,
bleeding from the nose, bowels, bladder.
T here are several m echanism s o f hem orrhage syndrom e developm ent.
• Throm bocyte deficiency (th ro m b o cy to p e n ia ) in the peripheral blood results in a
decrease o f biological factors o f blood co a g u latio n . T h e causes are:
•• suppression o f platelet precursors division in the bone m arrow;
•• d iso rd er o f throm bocyte m aturation in the bone m arrow;
•• th ro m b o cy te d estru ctio n in th e blood;
•• th ro m b o cy te loss w ith hem orrhage.
• Im pairm ent o f th e adhesive ability o f throm bocytes. T his dysfunction is o f
great significance, because biological factors o f blood coagulation release in the
course o f throm bocyte aggregation. This disorder is co nnected w ith changes o f
their m em brane ultrastructure.
• R eduction o f procoagulant synthesis in the liver.
• C hanges in the m olecular structure o f fibrinogen and fibrin underlie the reduc­
tion o f fibrin fiber contractile ability and blood clot retraction.
• A nticoagulant system activation. A nticoagulants appear in the blood (for ex­
am ple, heparin is released in the course o f tissue basophile degranulation).
• Fibrinolytic system activation.
• D erangem ent o f p latelet’s function in endothelium trophicity (throm bocytes
take part in m aintaining vascular wall integrity, elasticity and m echanical resis­
tance).

Immunodepressive Syndrome

Im m une reactivity decreases. Im m unosuppressive syndrom e is m anifested by

phagocytosis depression. A ntibody form ation is inhibited or com pletely suppressed.
I or this very reason, infection is the earliest and severest com plication o f irradia­
tion.
Not only environm ent but also the internal m edium becom es a source o f infec-;
lion (autoinfection).
I he oral cavity is severely inflam ed. Tonsillitis becomes necrotic. P neum onia
is a frequent cause o f p atient’s death. Infection violently develops in the intestine
and bowels
 C h a p te r 2. Р а И т ц а и г KfTcct of ln v lro n m rn tiil l iu lo rs

1 *11. ulut Syndrome

I In s . . .t h (m ainly sm all) are seriously dam aged in radiation disease. There

и. .п т mi l h.misms o f its developm ent.
I In nnlothellum is a possible target for the direct action o f radiation.
I it* - mint helium is dam aged by oxidizers (water radiolysis products) and radiotox
itu
* V* I lio ph lcity significantly suffers in platelet deficiency.
i
I In pathologically changed e n do th elium loses the ability to produce polysaccha
nil. p m triii c o m p le x e s to c o n s tru c t basal m e m b ra n e s,
ih* p r m a s c u lu r connective tissue, w hich is a m echanical base o f the vessels, un
1)1 destructive changes.
I In m im ed tissues release biologically active substances (proteolytic en zy m es from
Hi* m|mi*d lysosom es, kinins, h y a lu ro n id a s e ), w h ich aggravate th e d a m a g e o f
ih. tit** nl.и wall in creasing its perm eability.
* I In I iiih a n d resistance o f th e vessels are disturbed.
I »• im. (Ion o f the vascular wall leads to function al insufficiency o f th e ves
«*1 .и.I m u rocircu lation disorder. It has a negative effect o n m etabo lism (tissue
MH|»|lH IIV)
IMl И III vessel lesion significantly contributes to hem orrhage predisposition.

i ЫшемЫЫ Syndrome

‘ »* im m irstin al syndrom e is a com plex o f sym ptom s in the digestive system,

WHh li U iiiJ lo nourishm ent disorders and intoxication. T here are som e m echanism s
nl н ill v. lupmont.
Н и - . i mil indirect d a m a g e o f the e p ith e liu m o f the digestive tract m u c o sa by
i HlltlllMII
* ^ и i i nl m itotic division a n d regeneration o f the digestive canal epithelium .
! l «• ui ili. protective properties (barrier function) o f the m ucous m em brane.
- И м . i.»|мн.-nl ol infection in the intestine (autoinfection).
M* ni|iii,in ol toxic substances o f bacterial and intestinal origin into the blood.
* Mu*. i in.I Indirec t dam age o f the digestive glands.
* **ml i и \ Injury d u e to in fla m m a tio n a n d n e c ro tic tonsillitis.
^ Н и т к о й disorder.
М и im hm and diarrhea. Fluid loss.
H ilh
I *it и* im u ol die organism .
I »i|H им h a d pathology is one o f the causes o f death.

* r n f 't t il S y n d ro m e

ими и mil i hanges ol the nervous cells occur in case o f higher radiation doses.
Him* vi i inn dual changes do not always correspond to the functional ones.
• i *• hi ill syndrom e confirm s nervous system sensitivity to any influenced, in
imimij i.нищItin Nervous receptors le a d to mdiolysis products almost immcdi
h u t I (ii'i tem l rullio|tliysioluK,v

ately. Changes o f the bioeleetrieal activity o f the brain can be registered within first
minutes. At first excitation is recorded. So, neuroreflectory activity is observed b e­
fore o th e r typical sym ptom s o f radiation disease appear.
T he lethal dose o f ionizing radiation provokes th e cerebral form o f acute disease
(see below) due to direct dam age o f the nervous tissue.

indocrlne Insufficiency Syndrome

I he endocrine gland epithelium can be dam aged by direct and indirect radia­
tion. In addition to this, the endocrine system is affected by stress.
All signs o f stress are obvious (hyperfunction o f the pituitary gland and adrenal
cortex, lym phopenia). In the endocrine system organs, the initial signs o f increased
activity are replaced by endocrine gland inhibition. Eventually, the endocrine sys­
tem is exhausted.
Special atten tio n m ust be paid to radioisotopes. Thus, radioactive iodine affects
the thyroid gland most o f all.

Internal (Incorporated) Irradiation

Internal (incorporated) irradiation is the result o f inhaled or oral entrance o f

radionuclides into the body.
T he fate o f radionuclides in the organism is connected with the size o f radio-
active particles, solubility, half-life period, m etabolic specificity, and the ability o f
the organism to remove them . O rganotropism is characteristic o f all o f them . Thus,
strontium isotopes replace calcium in the bones, cesium isotopes replace potassium ,
iodine isotopes are accum ulated in the thyroid gland. O steotropic, hepatotropic, and
thyrotropic radionuclides are distinguished. They create very high radiation dosage
locally, and in the places o f their accum ulation radiation dam age is violent.

Defense Reactions

As any o th er pathological process and disease, radiation disease includes the

developm ent o f com pensatory reactions. They develop at all levels o f organism or­
ganization.
At the m olecular level, pathological changes are com pensated by natural anti-
oxidant systems. They consist o f free radical acceptors, peroxide inactivators, donors
ol SI I groups, thiolic com pounds (glutathione), m etalloenzym es (catalase, super­
ox tde dism utase, glutathione peroxidase), and vitam ins (С , PP, E, D 2). The ability
ol cells to restore DNA ( DNA repair enzyme system) is one o f the m ain m echanism s
that determ ine organism resistance to ionizing radiation.
Inactivation o f HAS (biologically active substances) is also under control.
C hem ical and biochem ical substances, which neutralize w ater radiolysis p ro d ­
ucts and radiotoxins, are called natural radioprotectors.
M utant cells may be annihilated by the m echanism s o f immunological reacti-
vlty.

30
 C h a p te r Л P iH liogeiilc Mffecl o f I .iiv iro n m c n lu l F a c to r*

i .и п . . i o n l y the radiation dose, but also organism reactivity determ ine I lie
н ниI d tn aiio n ol radiation disease. In schem e 3 the m echanism s o f DNA
* и*.I и p a n a iv sum m arized.

i m , , hani не. ol loni/ing Radiation-induced DNA Damage and Repair Factors,

i. I...ins ^ ik! Restore Damage

Radiation-induced DNA damage factors

i Mieii action Indirect action

X rays, Water Primary Activated

Y*quant a, radiolysis radiotoxins, D N A ase
и \S pm t iclcs products peroxides

I In III|< 1)1
*ih'|iMlll4 lo i'

UVi f«i| 1ИК

ИMHvwmt

Иг1|||м)нмц
|**i * III ШИ

iHtihnliini
они iiitv

i ii yin» \ which Natural

«Um«u Ii dmmiued DNA radioprotectors - Radiotoxin
lltlgHH’UlN polymcuiHc radical interceptors
interceptors

Repait factors

II
I1 art I (iimiitn! Pathophysiology

ACU TE RAD IATION D IS E A SE

All m entioned disorders o f hem opoiesis, function o f the nervous and alim en­
tary system s are m arked in all form s o f radiation disease. But the degree o f injury,
developm ent rate and prognosis depend on the absorbed dose o f total radiation.
T hree clinical forms o f acute radiation disease are distinguished — m edullary, |
gastrointestinal and cerebral.

Medullary Form

T he m edullary form o f acute radiation disease develops if the absorbed dose

makes 0 .8 -1 0 G r and proceeds in four clinical periods.
Initial period is con n ected with direct and indirect effect o f radiation on the pe­
ripheral and central nervous system. It lasts from several hours to 1—3 days. Clinical
m anifestations are: nervous excitation, headache, instability o f vegetative functions,
lability o f vasom otor reactions (arterial blood pressure and pulse), nausea. Im pair­
m ent o f alim entary canal m otility is m anifested through vom iting and diarrhea.
Body tem perature rises as a result o f central therm oregulation disorder. Short-term
redistributive neutrophilic leukocytosis (neutrophilia) is accom panied by absolute
lymphocytopenia. T he hypophyseal-adrenal system is activated. R adiation shock is
possible in severe cases.
Latent period lasts from 10 days to 3 weeks. It is a period o f false sense of
well-being. Nervous sym ptom s and dyspeptic disorders have disappeared, but the
m ain pathophysiological syndrom es are still absent. N evertheless, lym phopenia is in
progress, the am ount o f granulocytes and throm bocytes is reduced, as well as some
signs o f the disease: arterial pressure instability, pulse liability.
Period o f m a rked clinical manifestations lasts 2—5 weeks. T he m ain pathophysio­
logical syndrom es m entioned above develop. Leukopenia and throm bocytopenia
are in progress. The bone m arrow is depleted. A nem ia and infectious com plications
develop.
Disease Outcome. M axim al lethality is observed in the period o f acute granu­
locytopenia and throm bocytopenia. T here are inevitable infectious com plications,
which are the main cause o f p atien t’s suffering. D evelopm ent o f autoinfection in
the oral cavity is typical o f this period. Inflam m ation o f the tongue and gum s, ne-:
crotic tonsillitis are observed. Food intake becom es difficult. Radiation disease may
be com plicated by pneum onia, w hich is very severe due to im m unodepression and
eventuates in p atien t’s death.
T he p atien t’s appearance is quite typical — the skin is covered with num er­
ous hem orrhages. There is blood in the urine, feces and sputum . H em orrhages and
infection are the m ain reasons o f death.
Recovery is possible. W ell-being and blood cell content increase are the evi
dence o f recovery. Young (regenerative) blood cells appear.
However, the residual signs may persist for a long time (up to \ m onths). They
are divided into somatic (asthenia, fatigue, weakness, instability o f hemopoiesis,
endocrine and sexual dysfunction, sterility, im m unological Insufficiency, cataract,
 C h ap ter Л Pathogenic Effect o f Environm ental Factor*

> I'i.M. « !•m i . neoplasia, prem ature aging) and genetic (instability o f hereditary
<i r " Нм ,u » um tilation o f gene dam ages, leukem ia, diseases o f posterity).

i m iHiintt siliuil Form

l in j M.iiom tcstinal form o f acute radiation disease develops if the dose makes
i" n cm as I и iilt o f extensive destruction o f the intestinal epithelium . The
m i ... mi Hi. iniesimal mucosa becom es dam aged and prom otes infection penetra
Mi in
Ни disease m anifests itself through nausea, vom iting, pain in the bowels,
Mood м leaked stool and diarrhea. The loss o f fluids and electrolytes leads to dehy
Й о то й i. dm non in circulating blood volum e, vascular collapse. There develops
i n .1 п. ..h iruction o f the intestines and peritonitis due to the im paired barrier
Мни Ион ol the intestinal wall.
Mi*и I i possible tlue to the effect o f toxic substances o f m icrobial and tissue
mMiMh пи- toxemic form is observed in 20—80 G r radiation). M itotic division o f the
imi i HI ни I epithelium stops. Massive interphase destruction o f the digestive tract
* t M iik* plii* e I oss o f proteins and electrolytes, increased body tem perature and
г mm im Hi* intestines m ust be added.
I и nil »nun's w ithin X 12 days (or earlier). Lethality is 100 %.

I f l t l t l t i l I 'o i III

I h« . * и Inal form o f acute radiation disease develops if th e dose is over 80 G r

i i о ult oM he direct effect o f a large radiation dose on the nervous tissue. Severe
in*l in* s* i ihle structural changes o f the brain cortex, hypothalam us and pituitary
* I m .. i mi nh’-eived Ihe endothelium and vascular tonus are severely dam aged.
Mu ш ин. fill iimn is disturbed. C onvulsive-paralytic syndrom e and com a develop.
n*> ili*i и * Is always fatal. D eath com es w ithin 1—2 hours.
Пн и» т . .i form o f radiation disease is observed w ithin m inutes (hours) as a
о ими м! ptoh mi denaturation.

C H R O N IC RAD IATION D ISEA SE

» Июни hull.и ion disease is a consequence o f the repeated action o f sm all ra

i(M<hh *ii» I he pathogenesis and clinical m anifestations are the same as in acute
♦ими и* u i ill.'ii v, the dynam ics and intensity o f the disease differ. T hree degrees o f
Hh* iMi» ф * м. distinguished.
Hh fn\i f/eiyrv ol the disease proceeds in the form o f reversible functional
i" mi ili< most sensitive systems. Som etim es the patient feels quite well, how
И м hioi.ii nimh ieveals unstable leukopenia and throm bocytopenia.
iHt \ t «oml ih'ftrce ol the disease is characterized by m ore significant changes in
м.. to n «м. >11 id hem opoietic s y s t e m s , Leukopenia and lym phopenia becom e stable,
i hi мм .I мм \ \i i «и He lit is reduced, H em orrhage syndrom e and inim unodepression
lit | И 1- | | и )
ГаИ I bene гаI I’alliopliYslolou.Y

The third degree o f the disease m anifests itself through deep dystrophy o f tissues
and irreversible organ changes. The function o f the pituitary gland and suprarenal
glands is exhausted. Hem opoiesis is suppressed, vessel tone is lowered, vessel per­
m eability is increased. N ecrotic defects o f the m ucous m em branes are observed.
Infection and inflam m ation take a necrotic course.
C h ronic radiation disease o f any form underlies late pathological alterations.
G ene disorders might cause neoplasia. The organism that has undergone small ir­
radiation doses grows old prem aturely.

RADIATION LESION CORRECTION

There is a special group of preparations for antiradiation chem ical protection

These are substances blocking the developm ent o f chain radiochem ical reactions.
C hem ical drugs for radiation lesion correction are called radioprotectors. They are
interceptors o f active radicals, antioxidants, m etals with variable valence, hypo­
xia-causing substances (m ethem oglobin form ers), protectors o f protein SH -groups,
stim ulators o f cell repair.
If radioprotectors are injected before irradiation, they decrease the dam age,
block radiolysis and convert tissues to the state o f radioresistant m etabolism .
Radiation injury correction includes a num ber o f m easures directed at the
prevention o f infection, intoxication and hem orrhage signs. S ym ptom atic drug
treatm en t corrects endocrine glands dysfunction, nervous and alim entary system
disorders. H em opoiesis restoration is o f special im portance. In this respect bone
m arrow tran sp lan tatio n is the m ost effective m easure. H ypotherm ia and hypoxia
increase radiostability o f experim ental animals.

PATHOGENIC EFFECT OF BAROMETRIC (ATM OSPHERIC)

PRESSURE CHANGES (BAROTRAUMA)

Etiology. Etiological factor o f barotraum a is barom etric pressure if its para­

m eters are changed in com parison with standard ones. The gravity o f barotraum a
depends on the extent and rate o f com pression and decom pression.
Pathogenesis. Physical characteristics o f gas and liquid — solubility o f oxygen
■uni o th er gases o f the inspired air in the blood (saturation, desaturation), gas volu­
me in the organism cavities and the boiling point o f liquids — depend on the level
o f barom etric pressure.

Negative Effect of Decreased Barometric Pressure (Hypobaria, Decompression)

Man is exposed to decreased barom etric (atm ospheric) pressure at high altitude
(in the m ountains, on a nonherm etic aircraft and during a spacecraft crash, when
barom etric pressure equals zero). U nder laboratory conditions, hypobaria is m od­
eled m ;i special test low-pressure (hyperbaric) cham ber.
I lie pathological changes that develop in the situation o f reduced barometric
pressure are caused by two etiological factors: a) low partial oxygen pressure (pO,)

.14
 ( Iw ip lc i <’ 1*н<li<>K 4*iili' IC JTecI o f E n v i r o n m e n t a l I ' a c t o r s

in ilf inspired a n hypoxic hypoxia (c h a p tc r II «H ypoxia^ p. 160) and b) atm o

nh' «к pit'v.uii* re du c tion (hypobaria).
Ни u n g e o f p h e n o m e n a , c o n n e c te d with atm ospheric pressure decrease, is
.1 decompression syndrome.
I h* m anifestations o f d e c o m p re ss io n d e p e n d o n its velocity and degree.
II \ pubai la results in gas e x p a n sio n in th e in te rn a l cavities (sinuses, pleural and
im i и*пи *tl * ivitics, bowels). In th e c o u rs e o f d e c o m p r e s s io n , m a n feels p a in in the
it 11и I Imntal sinuses, in the a b d o m e n a n d joints. Nasal b leeding o cc u rs as a result
•i .III.n inn and ru p tu re o f small vessels.
M.m should n o t be elevated at 19000 m altitude w ith o u t a h e rm e tic cabin. In
. ..I . iiiastrophic d epressurization in a spacecraft, a tm o s p h e ric pressure reduces
* -i'"' И \ . that it is te rm e d explosive decompression. It causes in sta n ta n e o u s death.
I In и in г observed:
* lliHliitK »>l th e b lo o d a n d o t h e r liquids at b od y tem p erature.
* I uni.* Im n a t i o n (because o f q u ick p u lm o n a ry pressure increase).
* I ....... .. solubility o f gas in the b lo o d a n d liquid m ed ia. Free gas bubbles may
• ♦ и I» i.ed into th e blood a n d act as em boli (gas embolism).
i Mn|*inio o f the lung alveoli a n d vessels b ecause gas bubb les get into th e circula
i " n vMom.
* 1 1<iiiniii o f th e heart a n d large m ediastinal vessels d u e to ab ru p t lung expansion.
* S. nh lo n n o f hypoxia.

Negative Effect of Increased Barometric Pressure (Hyperbaria)

M m Is exposed to increased b a ro m e tric pressure in w ate r du rin g diving and

. n, ..и wmk O n e c a n feel pain in the ears because o f pressure o n the ty m p a n ic
in* i nl *i н и I In- alveoli m a y rup tu re if b a ro m e tric pressure increase is rapid.
Иш i inoie im p o rta n t fact is that in hyperbaria m a n must breath e air o r gas
mii"»i h i i iiih U i increased pressure. U n d e r su c h c o n d itio n s additional q u a n tity o f gas
i .h olvi .1 in the blood and tissues o f the o rg a n ism (saturation).
Nmoyyn has th e m o s t negative effect if o n e is b r e a th in g com p re sse d air. For
» l«my (inn ii was co nsidered that nitrogen, as an inert gas, has no biological effect.
* ini, mult ivvatei m e d ic in e prov ed th e op posite. N itrogen causes the sy n d ro m e o f
*1» i Hi* i Illinoi s in people working u n d e r increased pressure.
I Mu n> Hie close affinity o f nitrogen with lipids (n itrogen is liposoluble), the
in i • 'hi h ,nc is mostly affected. T h e first m a n ife sta tio n is nervous e xcitem ent that
.......... ... e u p h o ria , th e n th ere takes place intoxication, w hich resembles narcosis
ii.tl'h 'i In avoid such disorders, nitrogen is substituted by helium in inspired gas
Hi» П и т i l e v , soluble th a n nitrogen).
I h.i inils n itrog e n is toxic at in creased pressure. S u rp lu s o f oxygen ( hyperoxi
Iнм .i | мi .иiv« o ile d only at the beginning by im proving oxidatio n (this p h e n o m e n o n
» и «и! in hvpeilm iia tre a tm e n t). At the stage q f compensation so m e adaptive reac
»*-и .1- u lop I hey ire d irected at the m a in te n a n c e o f optim al oxygen regime in
ihf in nn 11ill Unutution o f th e excessive inc re a se o f oxygen c o n c e n tr a tio n in it. It is
и* hit vi <1 I•s lowering blood c h e m o re c o p lo r excitability, As .i result, rcspiratoiy rale
Part I G eneral I'atliophysioloK)

and pulse slow dow n, circulating blood volume decreases, as well as erythrocyte and
hem oglobin content (due to blood depositing), the brain vessels contract.
U n d er increased pressure oxygen acts toxically, but its toxic effect is realize*
later, at the stage o f decompensation. The condition o f tissue asphyxia develops. Ii
has the following explanation: tissues use oxygen that is physically dissolved in the
plasma, but not the one connected with hem oglobin (oxyhemoglobin). At increase!
pressure, the content o f oxygen dissolved in the blood increases. I f the quantity d
dissolved oxygen corresponds to the norm al consum ption o f oxygen by tissues, oxy
hem oglobin does not dissociate. In o th er words, hem oglobin becom es blocked hi
oxygen (hem oglobin is in the form o f oxyhem oglobin not only in the arterial but
also in the venous blood) and loses the ability to transport carbon dioxide ( C 0 2)
Since oxyhem oglobin is a stronger acid than the restored one, acidosis develops. I
U nder increased pressure, oxygen acts as a strong oxidizer causing oxidatior
o f lipids, proteins, nucleic acids. T he toxic effect o f high oxygen concentration ii
sim ilar to th at o f radiation. In both cases form ation o f free radicals and peroxide
with strong oxidative abilities causes affection o f D N A and tissue enzymes.
Sensitivity o f the organism to toxic action o f oxygen is determ ined by the levd
o f tissue antioxidants (tocopherols, glutathione, etc.). They can be used for th e treatj
m ent an d prophylaxis o f oxygen action on th e organism u n d er high pressure.

Table 2
Symptoms o f Nervous D isorder in M an Depending on Immersion Depth

Immersion Depth, m Symptoms

30 -6 0 Euphoria
60-75 Causeless smile and first symptoms of hysteria. Decreased 1
ability to concentrate. Mistakes in performance of simple
professional and mental tasks. Underestimation of safety
100 Depression and inability to think clearly. Motor incoordi- 1
nation
115 Loss of consciousness

To prevent the toxic effect o f oxygen and nitrogen, a gas m ixture with a lovJ
co n ten t o f oxygen an d nitrogen m ust be supplied into the underw ater breathin
apparatus. The optim al concentration o f oxygen in the inspired air is calculated fo
every im m ersion depth. For example, oxygen concentration in the gas m ixture ■
about 2 % while diving at 100 m depth. N itrogen is substituted with helium .
W hile returning from depth to the norm al atm ospheric conditions a new val
riety o f decompression syndrome is observed. An excessive quantity o f dissolved gal
is released through the blood and lungs (desaturation). D ecom pression m ust bJ
perform ed slowly. If it is not so (rapid ascent), the rate o f gas bubble formation!
exceeds the ability o f the lungs to release them . Bubbles o f air occlude blood veal
sels, press on cells and irritate receptors (gas embolism). C linical m anifestations ard
determ ined by bubble localization (subcutaneous em physem a, pain in the joints!
itch). In serious cases such m anifestations are possible impalrH«*nt and loss o f vi

36
 C h a p te r Pathogenic Effect o f I'.nvlroiiiiii'iiiul Factors

tit » j* Mdl\ -1 m en tal disorders, loss o f conscio usn ess a n d o th e r sings o f brain and
( mhI ■им I Injury (even c o m a ). Placing the patient into a c o m p re ssio n c h a m b e r,
iftiM 14 ibhli", ,м c c o m pletely dissolved, p ro m p tly relieves th e se sym ptom s.

ELECTROTRAUMA

Etiology

I i . . т . .il * мi rent d am ages the o rg anism d ep e n d in g o n its physical p ara m e te rs

il«H * i)Mii|и iap e), tensio n (voltage), n atu re, as well as exposure d u r a tio n , tissue
и i i ми • iми I i lif passage o f c u rre n t th ro u g h th e body.
i i> mim mi ol НИ) mA is fatally d ang erou s. Its basic d a n g e r consists in «chain
<•! * poison lo the electric object. A lte rn a tin g c u rr e n t is m o re d a n g e ro u s th an
И'минннн <u n c u t o f the sa m e am perage. T h e frequency o f alternating c u rre n t is
MttliH mmjmи i.int Alternating current o f 1,000,000 Hz a n d m o re isn’t pathogenic,
pii »* * Ни mi ll ollect a n d is used for treatm ent.
И м е н и и ol electric c u rre n t passing th ro u g h the h u m a n bo dy is o f conse
* Wo ми mi the vitally im p o rta n t o rgans (heart, nervous tissue), w h ich o c
||< «|ы i mim ui pathway. Ascending direct cu rrent (anode is lower, ca th o d e is higher)
I il**и « iUii^.eious th a n the d e scend in g o n e (opposite lo calization o f electrodes).
With ....* inline* i in rent through the h eart, th e sinus node is u n d e r exciting influence
til * («Мин!* mhI ilie apex is u n d e r suppressing influence o f an o d e.
л.,*.ih. i im p o rta n t factor, w hich plays a role, is tissue resistance. T h e electri
Ml hv "I ihe organism is hetero geneo us. Full resistance o f th e h u m a n body
$li tfiif im iimii» i n iie n t is the called im p e d a n c e . Liquids are goo d c on duc tors. T he
fttHH i t i t .mi in electric, current is the external epiderm al layer o f the tissue (up to
| шиммн 1 м н и | h e te nd ons, bones, nerves, m uscles follow it. T h e least resistant
t# Нн * - и i •i «*.| >11iaI fluid. G e n e r a l resistance o f the h u m a n body is from 1,000 to
i мим ими I im | he dry skin is m ore resistant th a n the wet skin. If th e skin is d a m -
H l f l : ill* InhIv behaves as purely o h m ic resistance.
I'll*-- bn lo r . a n d c o n d itio n s m odify th e effect o f the etiological factor and
й и 11m| MMIIIHI CKlent

Pathogenesis

Ни Ih II.ivmm)' events underlie the injury electrical en ergy tran sfo rm atio n into
it!(il i Ihmm n hi t null, m e c ha n ic al a n d che m ic a l).
I Im ми и \ ju .laii/es a to m s a n d m olecules, changes o rie n ta tio n o f particles an d
Ц Н м ) # iIn И iiiovement. T h u s electrical energy tran sfo rm s into the th e rm a l one
H pfftifi/ »/m /) Skin b u tn m ay occur.
I I и. ш р и м с and ho ne fractures are m anifestations ol the m echanical effect,
A i» • Hi. it i и mi o f electricity is called electrolysis (electrochemical effect). Posi
i Ihiitfi 'I ions пн id reaction) are c o n c e n tr a te d near c a th o d e , negatively charged
llltii mH Him и и n o n ) n e a r a n o d e . In biological m e d ia , electrolysis ciiusos ion
ИИЙЫНЬмМпм . Ii.mini's biological potentials a n d the state o f voltage d e p e n d e n t ion

17
1*1111 I. (tODOrttl I’ullmpliysiolony

channels, causes cellular m em brane depolarization and appearance o f action poten-I

tials in excitable tissues. As a consequence, the functional state o f cells changes.
Excitable structures (nervous, m uscular) are o f the highest sensitivity. C urrent I
excites the nervous receptors and conductors, sm ooth and skeletal muscles. Muscle]
spasms develop.
In addition, it is necessary to em phasize that electric current changes the state]
o f biocolloids. Coagulative o r colliquative necrosis results from colloid m ovem ent and!
swelling. C ellular protoplasm m ay coagulate.

Manifestations

E lectrotraum a causes local and system ic changes in the organism .

Local effects are current marks and bums. The form er appear on the skin if the]
tem perature o f the site does not exceed 120°C. They are small form ations o f white-]
gray color o f hard consistency (parchm ent skin). W hen the tem perature is higher
than 120°C, bum s arise.
E xcitem ent o f the nervous system causes hypersecretion o f catecholam ines
(adrenaline, noradrenaline) with som atic and visceral functional changes. Muscle
spasms and tonic convulsions may cause fractures, respiratory im pairm ent, blood I
pressure rise, involuntary urination and defecation.
The passage o f electric current through the heart is the m ost dangerous for
man. Electrolysis in the cardiac syncytium may shorten the refractor phase and]
change the cardiac rhythm. V entricular heart fibrillation is fatal. C ardiac rhythm
disturbance (tachy- and bradycardia, extrasystole and blockade) m ay develop even!
in such a case w hen electric current does not penetrate the heart (by reflex). Cardiac]
arrest may arise due to:
• ventricular fibrillation,
• spasm o f the coronary vessels,
• injury o f the vasom otor center,
• increase o f the n. vagus tone.
Respiratory im pairm ent and arrest have both central and peripheral origin, j
Respiratory arrest may depend on:
• injury (paralysis) o f the respiratory center,
• im pairm ent o f the respiratory ce n te r as an interoreceptor reflex,
• spasm o f the vertebral arteries, which bring blood to the respiratory center, j
• spasm o f the respiratory muscles,
• laryngospasm .
I lectrotraum a causes pain shock. M uscle contractions cause loss o f conscious-
ness, cardiac and respiratory im pairm ent. T he patient feels vertigo, headache,
photophobia, nausea. C linical death m ay com e. Im m ediate death is caused by
respiratory standstill an d cardiac arrest.
I he severity o f electrotraum a depends on the initial state o f the organism . For
exam ple, electrotraum a is less severe under anesthesia, in case o f sleeping, overcool
ing, hypothyroidism . On the contrary, fatigue, attention deficit, slight or m oderale
alcohol intoxication, hypoxia, overheating aggravate the lesion < ordiovascular in-
sufficiency, exhaustion and blood loss decrease resistance to rift tiotiaum a
 C h ap ter 2 Huthogcnlc Effect o f Environmental Factors

I ' M N O G IONIC EFFECT OF SPACE FLIGHT FACTORS

Mi i<h imi . ol space Might (such as overloading, weightlessness) belong to the

ми mmi I мм iiuse the human organism was not exposed to them in the process
I I i h Ihi иmi ни! adaptation is limited.

H u i Im.mIImm

• i - •h i‘* a force, w hich acts o n th e organism in the process o f accelerate

jfljib nit mi ihiiHif spacecraft la u n c h in g a n d landing. It refers to kinetosis.
I in hi iih path o g e n e tic link is d isp la c e m e n t o f organs a n d liquids in the direc-
Hmh Hr in ilu m oving direction . T h e re fo re, during la u n c h in g a n d landing the
р Н п н м imi in „ и is o rie n te d in s u c h a way, th a t th e ve c tor o f overloading d o es not
енНн lil* vva 11 1110 longitudinal axis o f th e body. Pathological c hang es are m anifested
I|hhmi-i> miii*iiifii u spiration, p u lm o n a ry blo od circulation a n d gas exchange. T he
ИНН1' i »i и*-.м. . a n d liquids gets increased. D isplac e m e n t o f the internal organs,
ни» п и п r p t o r irritation a n d significant afferent im p ulsatio n c o n trib u te to
Hn il.HM^'

\ \ . ij iii I. mu«ns is a c o n d i tio n o f loss o f grav itatio n. W eightlessness sig n ific an t­

,.
ly 1 1* h i . ih. system o f b lo o d c irc u la tio n . D im in is h e d h y d ro sta tic c o m p o n e n t o f
M§it.<l |M. мне и s u i t s in re distrib utio n o f b lo o d sup ply w ith its increase in the
1 l»»»»l\ p a i l s S tim u la tio n o f the v o lu m o r e c e p to r s , in h ib itio n o f vasopress
|H || »b!i 1 1 . и me 1*\ i ‘letio n result in th e loss o f s o d iu m a n d w a ter, low circ u la tin g
NniHl vhIh hh and load on the h eart. M uscle to n e a n d en erg y e x p e n d itu re are
*i N t 11 s г n itro ge n b a la n c e a n d loss o f w a te r c o n tr ib u te to b o d y m ass d e -
н м > I м "I » a k ium a n d p h o s p h o ru s , d e c re a se d mass o f th e b o n e s a n d skeletal
i n f ill. 1 with h yp ok in esia result in significant c h a n g e s o f the lo c o m o to r
ФН'И.ИЧ*
liHpaih il n rm iu s tm phidty is o f great significance in the pathogenesis o f the
B to t l t H in ih. slate ol weightlessness. A d eq u a te afferent im pulsation is a neces
ttiin 1 .................. . ol the trophic reflex (see p. 530 a b o u t nerv ou s trophicity a n d the
l»>b ol м. 1 on a lle re n ta tio n a n d d eafferentatio n). Its deficiency is observed in
м Hf|Mii nvIkisc lu n e lio n in g d e p e n d s 011 the gravity force (lo c o m o tio n a n d oto
и| *l ы 111111s , 1 г и helium , vascular walls). C o n c o m ita n tly , these o rgans are in
«Hi 1ФИ1 и! him lioiial d ealferentatio n. It m e a n s that n o t o nly atro p h ic , but also
Н н |н Н Ы ( н |||и < al c h a n g es develop in these org a n s during prolo ng ed weightlessness
I И ► 4m » t»nova)
I'ti.Mi) 1 1mi. t flight, p ath o g e n ic factors act not in isolation but in different
IfUfltiiHHiuiHs I' h a s been sho w n (N .K . S im e o n o v a ), th a t ov e rloading considerably
i fisiHtu < Ни r.m nil reactivity o f the o rgan ism , a n d the a c tio n o f additio nal influ
| • " чi.i heal, cold, intoxication, m e d ic in a l agents) differs from w hat was
Part 1, General PathophyiloloBy_________________________ 1

T he new level o f functioning m entioned above is adequate for weightlessness,

but it is unfavorable for E arth life, to which a cosm onaut m ust return. After com ing
back, insufficiency o f the systems th at oppose gravity is observed.

Questions for Self-Control

1. W hat are environm ental diseases?

2. W hat types o f therm oregulation do you know?
3. W hat is an im portant condition o f the harm ful effect o f low and high ambient
tem peratures?
4. H ow does therm oregulation change at the first stage o f hypotherm ia?
5. H ow does therm oregulation change at the first stage o f hypertherm ia?
6. W hat defense reactions develop under the effect o f low am bient tem perature?
7. W hat defense reactions develop under the effect o f high am bient tem perature?
8. By w hat m echanism do defense reactions develop under the effect o f high and
low am bient tem peratures?
9. W hat is the principal condition o f the harm ful effect o f ionizing radiation? i
10. W hat are direct and indirect effects o f ionizing radiation?
11. W hat is w ater radiolysis?
12. N am e w ater radiolysis products.
13. W hat are radiotoxins?
14. W hat is the m echanism o f biom em brane dam age under the effect o f ionizin
radiation?
15. W hy is the bone m arrow dam aged m ost o f all under the effect o f ionizing j
radiation?
16. W hat is the pathogenesis o f hem orrhage syndrom e in radiation disease?
17. W hat defense reactions develop in radiation disease?
18. W hat are radioprotectors?
19. W hy does gas em bolism develop in decom pression syndrom e?
20. In w hat way does the increased pressure o f oxygen act?
21. W hat is electrochem ical effect?

Tests and a Task for Self-Control

(give correct answers and find m istakes in the statem ents)

1. Give the com parison characteristics o f radiosensitivity o f different tissues.

1. Radiosensitivity o f the bone m arrow is m ore than that o f the epithelium , i
2. Radiosensitivity o f the gland epithelium is m ore than th at o f the lym ph oij
tissue.
3. Radiosensitivity o f the derm al epithelium is m ore than that o f the musel(
tissue.
4. Radiosensitivity o f the gland epithelium is m ore than that o f the vasculul
endothelium .
5. Radiosensitivity o f the muscle tissue is more than that of the lymph
glands.

ia
 Chapin Л I'ailioKcnic I^fToct o f Environmental Factors

i* M i«h«>*.rnsitivily o f the bone tissue is less than that o f the derm al epithe
Hum
t M иlii» r ir.it ivity o f the hem opoietic system is the highest.

♦ Ми И», characteristics o f the first period o f acute radiation disease in the

и»* «biliary form.
I N ervous system c o n d itio n is norm al.
It is accompanied by:
I * tvihropoiesis in hibition in the b o n e m arrow,
* anem ia,
\ leukocytosis,
‘ lym phopenia,
f« eoiist Ipntion,
* vomiting,
ft vegetative function instability,
'» l*«il мIttу o f arterial blood pressure,
In Inn body tem perature.

A mmh who worked in a thick uniform in sum m er, m anifested body tem perature
о * •i■. pne.i tachycardia, dizziness, cram ps. T hen he lost consciousness. What
i** Hi. . .him ot this serious state?
\ I ......... heat pro duction .
H Im. tea I icd heat prod uctio n.
• lniritMflcd heat emission.
I * И н к aseil heat emission.
i il- a em ission equals heat production.

1 1 »« i- 1 1 1 1 hitiiic stim ulates activity o f the therm oregulation m echanism s. What

н о . 11 .«1 1 1 . 111 m o s t clliciently limits heat em ission?
v Mi iilypnen
M I »• m i,i I vessel c o n tra c tio n (angiospasm ).
♦ Ihiulveimlln.
II Vrt «MtihH.it ion o f the skin.
I In. и r ed sweating.

Mm Iup h.initiation o f C hornobyl catastrophe consequences, a worker received

a i'oliiiMihi «In.» ot S ( it. lie com plains o f headache, nausea, dizziness. What
H h»I >»l • Iimmh.cs o f the leukocyte formula will take place in 10 h?
N I MHinophllla,
M I vniphocytosls,
) I i nkopettlit.
I* i mnlocvtosls.
I ' utiophllla
I’hiI I GcihthI I'ulliophvsioloKy

0. A m an was ad m itted to the hospital in 3 days after exposure to an ionizing

radiation dose o f 3 G r. W hat physiological system is dam aged most o f all in
such a case?
A. Digestive.
B. Cardiovascular.
C. Nervous.
D. Blood.
E. Endocrine.

7. As a result o f an accident at a nuclear pow er station a w orker received a dos<

o f ionizing radiation o f 4 G r. W hat changes in the blood o f the victim are]
observed on the first day?
A. T hrom bocytopenia.
B. Leukopenia.
C. Anemia.
D. Lym phopenia.
E. N eutropenia.

N. After diving at a depth o f 60 m, a diver developed such sym ptom s o f CNS

dysfunction: excitem ent, euphoria, attention deficit, m aking professional
mistakes. W hich substance caused this toxic influence on the neurons?
A. Lactic acid.
B. Oxygen.
C. C arbon dioxide.
D. Am m onia.
E. N itrogen.

4 While clim bing a m ountain for several days at an altitude o f 3,500 m a m ountain-
clim ber had tachypnea, tachycardia, headache and dizziness. W hat are these
sym ptom s caused by?
A. D ecrease o f barom etric air pressure.
B. D ecrease o f the fractional pressure o f oxygen in the air.
C. Hypoventilation.
D. G as em bolism.
E. Decrease o f atm ospheric tem perature.

10. As a result o f rapid ascent a diver developed convulsions and unconsciousness.

What is the basic pathogenic m echanism o f such sym ptoms?
A. H ypercapnia.
B. Hypoxia.
C. Toxic effect o f oxygen.
I ). Toxic effect o f nitrogen.
I G as embolism.

42
 ( Iwipin Гниющ ий- K ffi'd of MiivlronmonlHl Kmctors

M A ■« • w u ik n l ill a d ep th o f 40 m for a long tim e. D urin g d e c o m p re ss io n he

d e n tn|H .1 i iiiv.nu disease. W hat kind o f e m b o lism is its un derlying cause?
Л IIN li
и Air
1 I Illly
i ‘ I lim m b n e m b o lism .
I Ими

A h »l* * i »I» inn i .iMiully to u c h e d a b a re d electricity cable with both han ds and
ihi .i VVIiiii was the* cause o f d e a th ?
а ч т и luadycardia.
И >ммi tin hycaidia.
* I il *i 11Lit It in ol the heart.
I • ‘ <niipli u heart blockade.
I i ti.li.H tam ponade.

(I I ni im.I ihI Ion disease tre a tm e n t a physician m ust know th e pathog en esis o f the
... ни . luiii al sy ndrom es discovered by m o d e rn scientific researches.
Pathogenesis o f hemorrhage syndrome is:
I l linim hni yle m a tu ra tio n in the b o n e m arrow is inhibited.
’ Им ability o f th ro m b o c y te s to aggregate is n o t im paired.
i l ii alii* *1у sis activity is not ch an ged .
I I|н л hi Ih . o f p ro coagu lan t p ro tein s in the liver is decreased.
is

1 I In a m o u n t ol h ep a rin is elevated d u e to its release fro m neutrophils.

< i In ability ol fibrin fibers to c o n tra c t is not im paired.
Hi* vast ulai e n d o th e liu m is n o t dam aged .
t he /unctions o f the organism are impaired in such a way:
! 11* m opolesis is inhibited,
ч hiiilu* i ю н ol antibo dies is inhibited.
Ml Im m u no lo gical reactivity is stim ulated,
i I ritajMH у Uis is activity is increased.
I M l * iiHMiliage syn d ro m e develops as a result o f hypercoagulation.
И I Ih ih ivoiis system is not dam ag ed .

(4 I Mu* a • hr in* o n radiation disease patho gen esis in th e form o f c h a in b ra n c h

Ui*i и >н 11*MIN,

43
( hapter 3
ROLE OF HEREDITY AND CONSTITUTION
IN PATHOLOGY

to g eth er with environm ental pathogenic factors, the genetic ones play a sig­
nificant role in the developm ent o f diseases.
Hie diseases caused by genetic factors are called genetically determ ined. T heir
liansm ission to d escendants m ay be lim ited in case o f im paired reproductive
capacity o f the patient. I f diseases are tran sm itted to next generations, they are
ta ile d hereditary. A close n o tio n is congenital diseases. Such diseases declare
them selves right after birth. T hose diseases, w hich are caused by environm ental
lactors and have a clinical picture sim ilar to know n h ereditary diseases, are called
phenocopies.

M UTATION

M utatio n is a jumping stable change o f the genetic a p p a ra tu s (no t c onnected with

cell division o r usual chrom osom al recom bination) and a m aterial basis o f genetically
determined diseases.
M utation is a p rom oter o f evolution. Biological species com plication and ob­
taining o f useful properties, w hich are fixed in the genetic apparatus, occur due
to m utations. T hough, there is a paym ent for it - genetic diseases. C onsequently,
m utations m ay be useful and harm ful. W e will dwell o n harm ful m utations.

( '«uses

I liological factors, which cause m utations, are term ed mutagens. They are di­
vided into physical, chem ical and biological as well as exogenous and endogenous.
A m ong physical mutagens ionizing radiation is the strongest. It dam ages the
fc n etic apparatus directly o r by radiolysis products. M utation m ay be caused by
io n i/in g radiation in such a m inim al dose, w hich does n o t cause radiation dis­
ease.
I he most potent chem ical mutagens are the analogs o f purine and pyrim idine
ba-.cs Hie chem ical com pounds o f carbon (polycyclic arom atic hydrocarbons) and
m hogcii (nitrosam ines) refer to mutagens.
/liological mutagens are D N A - and R N A -containing viruses. They som etim es
behave as m utagens in patients with measles, chickenpox, m um ps, infectious m ono­
nucleosis. Rubella infection in pregnant w om en is associated with congenital infan­
tile m alform ations. The products o f the vital activity o f som e fungi (e.g. aflatoxin)
also belong to m utagens. Oncoviruses are the strongest biological mutagens.
Ix o genous m utagens can induce endogenous mutagens (a< live forms o f oxygen,
free tadu ills, nulioloxins, etc.). Such m utagens may be induced in disbolism.
 ( luipliT R o lf o f l lc m llty and C o n stitu tio n in Pathology

i i jh

r Ini п и т .не divided into useful and harm ful, spontaneous and induced. The
Hhim. и* \ 1*1 spontaneous m utations is low in com parison with th e induced ones.
Swimth im itations (in som atic cells) disappear from the population after the
|и i *!• iih and arc not transm itted from generation to generation. G erm m uta-
|И>н пи г- пн cells) affect heredity o f descendants.
I »r prill liny, on the degree o f destruction, m utations are divided into gene and
Н и н и н xniil ones.
tu mutation is a change o f the structure o f only one gene, nam ely, the spe-
I(ti. tuiiri 1 1 | purine and pyrim idine bases in the D N A m olecule (the so-called point
' -и 11 u snlts in a change o f the order o f am ino acids in the protein m olecule.
Ih* »....... i»l possible gene m utations is enorm ous (both in structural and regu-
|§H - i* n* s) In germ cells gene m utations m ay happen in any gene (dom inant,
f§*§ 0 1 sex-linked).
i htomosomal mutation is a m ore vast destruction o f the hereditary apparatus
liml * * hiiim t n i/ed by changes o f the chrom osom e structure (break, deletion, in-
H ttin n . hiinslocation and fragm entation) or quantity (increased or decreased). The
tfiMniM iii%. i hnnges o f chrom osom es result from nondisjunction o f hom ologous
i. |н и 111 *»%•111 h’s during gam etogenesis o r at the early stage o f zygote splitting.

M m titiitkius of Defense against Mutation

I h. • fig.mism controls its genetic hom eostasis. A lot o f checking m echanism s

pin « Nnme <>1 them control som atic cells, o th er — reproductive (germ ) ones.
inthnidant biochemical system prevents m utation, neutralizes active form s of
m n 11 In- h belong to endogenous m utagens.
* <* и» m unitions can be restored w ithout any harm ful consequences in t
MijfHHi t,i I veiv cell has a DNA repair enzyme system (fig. 2), w hich restores u p to
| l it of sponlaneous gene m utations.

Exonuclease
--------------------- /-Ч —
и 111,1" 0 -~ (г--------------------- 4. Further cleavage

I lvndonuclease
_____ - v — P°lymerase
Ik itM U i >11 ) N A ...........................................................5. Synthesis --------------------- VWWA
of normal DNA

I ximuelcase I Ligase
l||ii|lt i( ii --------- f - B m d i n g o l a n e w --------------------------------------
—--------------------------------- D N A liagm cnl

In : R epair o l u d a m a g ed D N A c h a in by repair e n z y m e s
I'in I I G eneral Pathophysiology

The im m une system has im portant defense m echanism s. A nom alous proteins
and m utant som atic cells m ay be elim inated by hum oral and cellular im m une reac­
tions. B-lym phocytes produce im m une globulins for the elim ination o f anom alous
proteins and cytotoxic antibodies, which destroy m utant cells by cytolysis (with the
aid o f a com plem ent). T-killers can destroy m utant cells with the aid o f lym phok-
mes Phagocytosis participates in im m une response.
Mechanisms of Germ Cells Protection. It is unknow n w hether m utant germ
cells are controlled by the antioxidant system and im m une m echanism s. They may
lose the im pregnation ability. If im pregnated, m utant genes are inherited by M en­
d el’s genetic laws, some o f w hich prevent clinical m anifestation or gene spread in
population.
Recessive m utant genes are expressed only in the hom ozygous state (the re­
cessive type o f inheritance) and are n o t m anifested in the heterozygous one. In the
latter case the m utant gene carrier is clinically healthy (however, it is a conductor
o f m utant genes in population).
Sex-linked m utant genes are inherited depending on the sex o f the host. About
60 pathological signs are connected with the X -chrom osom e, and m ost o f them arc
recessive ones. It m eans th at w om en, carriers o f such gene, are healthy, becausc
a norm al X -chrom osom e com pensates the presence o f an X -chrom osom e with a
dam aged gene (X -chrom osom e pathology in m en is not com pensated).
Most physiological patterns (arterial pressure, blood glucose level, im m unolo­
gical reactivity, etc.) are determ ined n o t by one, but several genes (the polygenic type
o f inheritance). M anifestation o f the m utant gene o f these gene systems depends on
tin- environm ent (the so-called multifactorial diseases).
Such phenom ena as penetrance (the probability o f th e phenotypic m anifesta­
tion o f a m utant gene) and expressiveness (the degree o f clinical m anifestation) arc
an im portant m echanism o f protection. P enetrance never reaches 100 %.
I )o m inant m utant genes are transm itted directly from parents to th eir children
and are m anifested in the first generation (the dom inant type o f inheritance). But
in this case protection shows at the level o f population as natural selection. The
carriers o f chrom osom al anom alies and dangerous dom inant genes do not survive
(because o f problem s in the em bryo) o r lose reproductive capacity.
In addition, it should be added that m any m utations o f germ cells have no con
sequences. C hildbirth is not so frequent during life. In spite o f m utation frequency
increase with age, the reproductive function is depressed and reproductive cells arc
rarely im pregnated.

GENETIC PATHOLOGY CLASSIFICATION

M utation underlies all types o f genetic pathology, but pathogenesis, realization

and clinical m anifestations are different as will be seen later.
Not all the diseases caused by genetic pathology arc hereditary in the literal
m eaning o f this word. Som e patients with genetic pathology are horn by healthy
parents. Some patients with genetic pathology do not transm it И because o f inferti
lily.
 C h a p te r • Role of l l u i d i l v and C o n stitu tio n in Pathology

i h M ilita ry disease is such a disease, which is determined by mutation in the

к и т *i lls of parents and may be transmitted in generations.
• 1 1 . .ilu aiion o f genetically d e te rm in e d pa thology m ay be based o n sever
}H|||t Iplev
I >< pending o n th e degree o f genetic defect (a gene is sm aller th a n a c h r o m o -
и, ihe c o n se q u e n c e s o f gen e a n d c h r o m o s o m a l m u ta tio n s are diffe
><<*♦л i .не divided into molecular genetic a n d chromosomal. T h e fo rm e r in th eir
Ним hi divided into monogenic a n d polygenic. M o n o g e n ic diseases are subdivided
iihh dominant, recessive a n d sex-associated.
I I gun system classification (diseases o f the b lood, lungs, kidneys, etc.) re-
H» » • p ie d o tn in a n t disorders o f a certain physiological system. T h e disbolism -based
»I » ilh oi и hi is also useful for m edical practice (diseases o f p ro tein , carb oh ydrate,
Hphl inliiei.il, p ig m en t m etabolism , etc.).

MOLECULAR GENETIC HEREDITARY DISEASES

\ r in m u ta tio n c arrier usually preserves th e re productive fun ctio n. T herefore,

pul* ■ni ii genetic diseases m ay be transferred in g e n e ra tio n s a n d are hereditary in
ill* III* lal m ea n in g o f this word.
MiH\e МЮ0 M e nde lia n disorders are identified, a n d n ot all o f th e m are h a rm -
tiH ....... "I th e m have a protective value in the heterozygous state (e.g. H bS pro-
le iIh iu r a n is m against m alaria). It is estim a te d th a t every individual is a carrier
1 H h i i mful recessive genes, w hich are d a n g e ro u s in th e h o m o z y g o u s state.

Etiology

I iinlnj/h al factors are physical, c h e m ic a l, a n d biological mutagens , w h ich are

$ ||M h h lo i hange the g enetic a p p a ra tu s o f g erm cells.
I tiiilngv ol hereditary diseases has s u c h a peculiarity that causes o f diseases and
ЙН№<1 i k iliemselvcs are separated in g enerations: the da m a g e o f the genetic app a ra -
N** hv miiiagens lakes place in o n e p erson, a n d diseases d evelop in d e scendants.

PATHOGENESIS

I In initial p a th o g e n e tic link o f he reditary diseases is a germ m u ta tio n in o n e o f

Hit» i*4i* mi li the m u ta n t cell is im p re g n a te d , su c h events take place — in heritance
nt (to mutant gene by the child, disease d e v e lo p m e n t, its transm ission to th e fol­
io# m*. у fil iations
lh .« a .i pathogenesis d e p e n d s o n th e fu n c tio n o f th e gene, which is broken.
jpHtHli ills d e te r m in e d pathology has the e n d in g -pathy.

NlmlHMih ul Disorders

Him Ih iii Iu i ! c h a n g e s d e p e n d o n the fun ctio n o f p ro te in , whose synthesis is

iiHprth» *1
Г.I l l I (iiMHiul rallio|iliysiolo)>v

l.nzynwpathy is a genetically determ ined enzym e disorder. It is manifested

through errors o f m etabolism . Enzym e synthesis may be decreased o r stopped. In
hibitor surplus o r activator deficiency have the sam e effect.
The quantity o f an enzym e m ay be norm al, but its catalytic activity is low 01
absent. Blocking o f a certain m etabolic pathw ay results in the accum ulation ol
substrate precursor and a lack o f final products (som e clinical examples see on
pp. 2 4 0 -2 4 1 ).
I nzym atic activity m ay be increased due to inhibition blockade. Uncontrolled
synthesis o f final products m ay take place. These are the so-called diseases o f ac­
cumulation (glycogenosis, hypercholesterolem ia, m ucopolysaccharidosis, m ucovis­
cidosis, gout).
D eficiency o f the D N A repair enzym e system eventuates in increased organism
sensitivity to m utagens (this m echanism underlies m alignant growth and prem ature
aging). Som etim es enzym opathy is m anifested only after loading by food or drugs.
Hemoglobinopathy is a genetically determ ined globin disorder. It results from
the m utation o f genes responsible for globin synthesis. H em oglobinopathy ami
erythrocytopathy underlie som e forms o f hem olytic anem ia (sickle-cell anemia,
thalassem ia).
Coagulopathy is a genetically determ ined disorder o f proteins, which are ne­
cessary for blood coagulation. C oagulopathy and throm bocytopathy underlie some
lorm s o f hem orrhage syndrom e (hem ophilia).
( ienetically determ ined deficiency o f transport proteins or peptide hormones
(endocrinopathy) is also possible.

( Vllular Disorders

At the cellular level, hereditary diseases are m anifested by changes in cell func­
tion an d form (sickle, spheroidal and target-like erythrocytes, which are typical of
lieieditary hem olytic anem ia). M embranopathy is a genetic defect o f the cellular
m em brane. As a variant o f m em branopathy it is a pathology o f membrane recep­
tors l.rythrocytopathy is also a variety o f m em branopathy (spectrin deficiency in the
erythrocyte m em brane results in the im pairm ent o f m em brane elasticity, and eryth-
rocytcs are deform ed as in hem olytic m icrospherocytic anem ia). Trombocytopathy
is .1 genetically determ ined throm bocyte dysfunction. Lymphopathy is a genetically
determ ined disorder o f lym phocyte m aturation and functional activity w hich leads
to Immunopathy (immunodeficiency).

Disorders in the Whole Organism

At the level o f the whole organism the pathogenesis o f hereditary diseases de­
pends on the nature o f disbolism and the type, structure and function o f im paired
cells Som etim es the genetic defect limits the reproductive ability. T he carrier o f the
most dangerous m utation dies in the wom b (as an em bryo).
M any patients with hereditary pathology survive and lepm duee posterity. Il
leads to m utant gene accum ulation at the level o f population
 C hapter ' Holt* o f Heredity and C onstituition in Pathology

I о <i (o i > Adaptive Reactions

i ..... и* и itory-adaptive reactio ns m ay be observed in th e p a th o g e n e s is o f he

1и1Н-1П dN'ilNCN.
hm. . partial activity o f a n e n z y m e is sufficient fo r its n o r m a l function.
Цщ, iMMiiinn-. m the o rganism are p rovided by different metabcolic ways, and
n -iiu hi is possible.
N-H . . i\ alteration in th e prim ary stru c tu re o f p ro tein leads to clin ic a l m ani-
рНйНмп | .и exam ple, m o re t h a n 300 h e m o g lo b in varieties are id e n tifie d , but only
цнн* ' 111' in declare them selves as a n e m ia w hile m ost o f th e m p r e s e n t no clinical
ii
I h* .нашими as a whole may co m p e n sa te insufficiency o f o n e sy ste m by hyper-
Йии Нин Ml a not h r i o n e (circulation activation in a patient with h e re d ita ry anem ia).

Manifestations of Hereditary Diseases

I <i In.inch o f m ed icine (cardiology, h e m a to lo g y , n e p h ro lo g y , e n d o c rin o -

Цн mu i i . o n c e rn e d with a lot o f diseases, in th e d e v e lo p m e n t o f w h ic h genetics
Ни m am role, a n d every disease has its clinical m a n ife s ta tio n s studied by a
ими •...iinr university d e p a rtm e n t. In this te x tb o o k som e h e re d ita ry diseases are
■piM nii. .1 us exam ples (im m u n o d e fic ie n c y , h e m o p h ilia , diabetes, etc.). In every
fik ) i the role o f genetic factors will be p o in te d , a n d reference to this c h a p te r
v iH и ii >liil
II»* * liiiie.il m a nifestations o f hereditary diseases d e p e n d o n 1) th e fu n c tio n
| lltk id nipied gene, 2) the type o f p ro te in , w hose synthesis is a ffe c ted , 3) the
и hii laintlu disorders, 4) the type o f inh e rita n c e if th e disease is m o n o g e n ic ,
B f j f H i n i m i . ntal factors if the disease is p olygenic, a n d 6) sex. C o n c e r n i n g the
f p ^ #il . Imn ,il m anifestations, h ered itary diseases m ay be c o n g e n ita l o r manifest
mb*--* b» i" the co u ise o f life. S o m e tim e s diseases declare th e m se lv es im m e dia te ly
i I II I h 11111it oviscidosis, polydactylia), s o m e tim e s later (gout d e c lare s itself in
(Mil» IllN).

Им hi .. . i a.erious genetic a n o m a lie s disturb th e ca rrie r’s re p ro d u c tiv e ability.

IttlHHiHo . ih. »arriei dies as an em bryo.
|lh inainlesiations «>1 M endcliau diseases depend on the type o f transm ission.
p^iitnH iinn ne given below.

Itomlfitint Disorders

I It и 'И и им is m o nogenic a n d th e pathologic gene is d o m in a n t, o nly those a n o n i-

gtyps *la* h -I.- not allect viability a n d d o n ot prevent m ultiplication, are trails
HffM ........in i at ions Skeletal anom alies (polydactylia (fig. 3), brachydactylia, teeth
anomaly), long sightedness a n d short-sightedness, astigm atism , otosclerosis,
((Hi*1* '..........к I.миг. ol m uscular atrop hy arc exam ples o f su c h pathology. T h e Ini
.Ii • i • aie inherited m such a way achondroplasia (a form o f dwarfism),
l l p P t H dlM’iine (congenital hypcrhilirubineinia), H u n tin g to n ’s disease (neurologi
Pari I (ммита! PalhophvsioloK.v

cal disorder), polycystic kidncj

colon polyposis, sickle-cell aneti
(hem oglobinopathy), Willebrami
disease (hem orrhage diathci
spherocytosis (hem olytic anemlj
thalassem ia (red cell disorder).

Autosomal Recessive Disorders

M ost hereditary diseases

inherited recessively. It m eans
j H ftg Щ a disease develops w hen a chi
gets pathologic genes from

^ • sf~. 1*
Fig. 3. Polydactylia crinopathy), agammaglobulinei
(im m unodeficiency), glyct
storage disease, galactosem ia, phenylketonuria, and m uscular dystrophy.

Sex-L in ked Disorders

M orbidity o f carriers o f m utant genes in the X - or Y -chrom osom e depea

on the p atien t’s sex. Alm ost all sex-linked disorders are X -linked, and almost
o f them are recessive. X -liked pathologic conditions include B ruton’s agarmfj
globulinem ia (im m unodeficiency), diabetes insipidus (pituitary disorder), G 6 |
deficiency (hem olytic anem ia), hem ophilia A and В (hem orrhage syndrom e), и
thyosis (skin disease), m ucopolysaccharidosis (lysosom al storage disease), museij
lar dystrophy, color-blindness (daltonism ), juvenile glaucom a, hypophosphatetl
rachitis. A heterozygous female w ith an X -linked recessive m u tan t gene is hea
because o f the norm al paired allele.

Polygenic Disorders

The role o f genetic factors in the pathogenesis o f such diseases as diabelj

mellitus, arterial hypertension, bronchial asthm a, allergic diseases, cancer, stoma
ulcer is confirm ed statistically. N o t one but several genes determ ine them . Equt«|
with genetic factors, living conditions are o f great significance (multifactorial d
eases). F or each o f them a specific lim iting environm ental factor is estim ated (<
or sugar consum ption, cholesterol content in food, stress, hypoxia). A variety
clinical forms and individual m anifestations is typical ol these diseases.
 C h a p in l Hole o f l l r m l l t y anil C onst Million in P athology

in к к о п а к у p k i c d i s p o s i t i o n

■и > * • и • di h im ined exclusively by environm ental factors (radiation

S i t i Нин 'И it m .) oilier disorders by genetic ones (D o w n ’s disease). There
iii.it-.. ill i hi whose developm ent is determ ined by both genetic and exo
Ни Its tin Ill .nth eases we speak about hereditary predisposition.
gpHj It i им i■■ mil polygenic types o f inheritance underlie hereditary predisposi
^ ||щ р i i:
j | i H ilMai \ pH d isp o sitio n is a g e n e tic a lly d e te r m in e d s t a t e o f in c r e a s e d p ro b a b i-
I iMbtin «Имчие d e v e lo p m e n t u n d er c e r ta in e n v ir o n m e n ta l c o n d itio n s.
» ip i *| *11ii i.i .11 lei ial hypertension, atherosclerosis (i.e. the m ain thera
Иннин*. i и hi. i li .niM s) are inherited in such a way.
I * fi*iиi » ih|m nnir, i,к tors may cause different diseases in patients with differ
Min» 1 1.и * sam ple, m ental overload and negative em otions m ay provoke
|»|§|м н hi (hvmliixieosis depending on heredity).
|(Mh............IIii11 m anilestations depend both on genetic factors and conditions
(мини I........ . .1 ltd load on the insular apparatus).
Iи ........ . , .mdied by im m unogenetics (term ed im m unodeficiency) are an
i in11 *и 111 1* <-i in irditary predisposition. D eficiency o f im m unoglobulins, В
■и \ i > , 1 1Пек-псу o f phagocytic activity o f leukocytes are inherited.
h i m

ttiiHi ih. ih 1 . 1 i\ .iif m anifested by predisposition to infection, allergy, auto-

i\* Mlon
Uup ж. i lUth in has individual peculiarities and harm ful side effects o f m edi-

£ *»* u i 11 и .«Нм m il I nzym opathy underlies an increased sensitivity to m edi-

|H

I U*- .........pt ol Инк laetors is im portant in medical practice. Thus, m etabolism

( М Ы i“ •» м'Л l.и ini loi a heterozygous enzym opathy carrier. An infection is a
j | | | ftti но Iи i ........im uinodeflcient patient. R adiation and m utagens are risk fac-
pH'ilt i| мi к и in oncological diseases (depending on the heredity they cause
hi

h i huktHllltf)
Щ $ Р Hi- n .\ 0 \H\ ol Ih e s e diseases depends on the interaction o f genetic and
HpiiidMm tii'ii iiilhii i h rs Bv changing living conditions and avoiding risk factors it
р р м ы * ь» ни h( the developm ent o f m ultifactorial diseases.

CHROM OSOM AL DISEASES

:i iм»иtм- . «мi,11 mm.ii mu dam ages a greater part o f the genetic apparatus and
итт. i и ui-, disorder than gene m utation. C hrom osom al aberrations may
Ц ШшHimI I hit ,il-. deletion, inversion, translocation, fragm entation) and quanti
Ш я i* ml' *'| iioiulisjunclion o f hom ologous chrom osom es).
ItiH i p.iih иг ап- оПсп stciile and therefore do not transfer the disease to de
I h« iHiMrnt' parents are healthy.
hut I ( hihdiI hilhophvslologv

Chromosomal disease is such a disease, which develops as a result of chromo­

somal mutations in the germ cell of one of the parents.
T hus, chrom osom al diseases relate to genetically determ ined disorders, and not
to inherited ones. C hrom osom al anom alies are not accum ulated in population.

Etiology

Etiological factors are m utagens o f physical, chem ical and biological origin.
T he peculiarities o f chrom osom al disease etiology are the following:
• An etiological factor affects parents, but disease develops in a descendant.
• l)e novo a chrom osom al m utation in a germ cell takes place in a healthy adultj
person, and if this cell is not im pregnated, m utation has no consequences.
• fam ily predisposition to chrom osom e nondisjunction has been revealed.
• The disorders o f gam etogenesis and chrom osom e nondisjunction are m ore fre-]
quent in elderly people, but their germ cells are im pregnated less frequently.

Pathogenesis

T he initial pathogenetic link is chrom osom al m utation in the sex cell o f one
parent. The vitality o f this cell is seriously im paired. It usually dies o r loses im preg­
nation ability. If it is im pregnated, the em bryo could die. C hrom osom al anom alies
cause 40 % o f spontaneous abortions and about 6 % o f stillbirths. If chrom osom al)
im balance is com patible with life, the host is seriously ill or dies in the immediate]
postnatal period. Som atic and m ental developm ent is deranged, the reproductive'
ability is lost. After the d eath o f such a patient the m utation disappears from popu­
lation. If the reproductive function is preserved (in 3—5 % cases), posterity inherits]
the chrom osom al anom aly.

Manifestations and Clinical Syndromes

The m anifestations o f chrom osom al diseases depend on the type o f the ch ro ­

m osom e, which is subjected to m utation. A bout 300 chrom osom al anom alies have
been discovered.
Some chrom osom al diseases are caused by qualitative (structural) changes o f
chrom osom es, which have m ore severe consequences in com parison with the quan-
lnative ones. T he patients require constant m edical assistance because o f serious
physical handicaps and m ental retardation. Most children die young. Predisposition
to the developm ent o f immunodeficiency (p. 82), allergy (p. 89), neoplasia (p. 148)
and leukemia (p. 313) is detected.
As to autosom al m utations in germ cells, they have m ore severe consequences.
Autosom c deficiency is m ore harm ful than autosom e excess (m onosom ia in living
people has not been revealed). Trisom ia o f large autosom cs has not been described
(presum ably, it is lethal). Trisom ia o f small autosom cs is very often lethal, but if it
is com patible with life, it results in plural physical handicaps and i high lethality in
early childhood.

52
 C h u p tc t ' Hole of llc m lily and C onstitution in ГиНиИоку

M utation in the 23rd (sex) pair o f chrom osom es affects the carrier’s viability
К л I o f all. T he quantitative changes o f this pair o f chrom osom es frequently d o not
Iи« w in ch ild ’s life. Clinical syndrom es are well described. T he patients have very
■nous physical and m ental disorders. T he karyotype 45,YO is lethal.
Hi-low we give som e exam ples o f chrom osom al diseases, w hen the carrier sur-
v Iv c n ,

Multi X Syndrome

In m ulti-X syndrom e a female has the 4 7 ,XXX karyotype. M ost patients are
•i. olutely norm al. Som etim es triple-X fem ales do not have any evident clinical
inninlestations and som e o f them have children. But m ore frequently, this syn­
t o n i c declares itself through hypogonadism , am enorrhea or o th er m enstrual ir-
*» Mul.irities. Affected w om en have two or m ore B arr’s bodies (sex chrom atin) in the
Hituiilc cells.

M int'filter's Syndrome

К lincfelter’s syndrom e (trisom ia 47,XXY) declares itself in m en through a large

Mitihie. hypogonadism (testicular atrophy and azoosperm ia, eunuchoid state, gyne-
«MimiNiia), sterility, m ental retardation. Som etim es such m en have norm al sexual
•!« vrlopm cnt and even high fertility. T heir intellect is norm al or average. The ten-
ilnu v towards aggressive behavior is noted. The typical karyotype is 47,XXY, but
tin u id ic s 48,XXXY and 49,XXXXY have been revealed. Sex chrom atin (B arr’s
in ills i is present in the som atic cells.

ho m i \ Syndrome

In lu m c r’s syndrom e girls have the 4 5 ,XO chrom atin-negative karyotype.

1Mils * 1 1 o f fetuses survive and are b o m , frequently they are aborted. If children
ilhvivr, Ihey show prim ary am enorrhea, infertility, lym phostasis and lym phedem a,
■" , ih ином o f aorta, predisposition to H ashim oto’s thyroiditis. M icroscopy shows
мм « ч chrom atin in the nuclei o f the som atic cells (oral m ucosa cells).

Очи n \ Syndrome

i .и i и-is o f trisom ia 21 are the most viable am ong all carriers o f autosom al tri-
...... in I lie lotal num ber o f chrom osom es equals to 47, XY, 21+. There is a variety
wiili If» » hrom osom es if one 2 Iм chrom osom e is fused via its centrom ere with an-
Milii i .и m ccntric chrom osom e. This abnorm al chrom osom e is called R obertsonian
n.»i,.i<it ill Ion and can som etim es be inherited.
In th r typical form o f the disease m en are sterile, w om en may have children.
Им h u m * o! the dom inant type o f inheritance, 50 % o f children are healthy, but half
•«I i In in have the sam e disease.
Part I G eneral Pathophysiology

The disease is m anifested by developm ent delay, grow th inhibition and m ental
ictardation, prem ature aging, neuralgic disorders, cataract, increased purine synthe­
sis, am yloidosis, on co p rotein production, a high frequency o f leukem ia, activation
ol free-radical oxidation. The visible signs are characteristic facial and dysm or­
phic features such as brachycephaly, epicanthal folds, small ears, transverse palm ar
creases. Inhibition o f vertical grow th is m oderate, and m ost adults with D ow n’s
syndrom e are shorter th an the m ajority other people. In contrast to this, patients
with D ow n’s syndrom e gain m ore weight com pared to other population, and most;
adults with D ow n’s syndrom e are overweight. A pproxim ately 50 % o f affected chil-j
dren have congenital heart diseases th at declare them selves in the early perinatal
period because o f cardiorespiratory problems.
Im m une problem s are typical in the form o f im m unodeficiency. Laboratory
abnorm alities can be detected in both hum oral and cellular im m unity. A ntithyroid:
antibodies predispose to disturbance o f gam etogenesis and nondisjunction o f the
21 1 pair o f chrom osom es. C onsequently, the hypofunction o f the thyroid gland is
a risk factor. Increased susceptibility to infections is a com m on clinical feature at!
all ages.
There is a considerable range in the degree o f m ental retardation in adults w ith
D ow n’s syndrom e, and m any affected individuals can live sem i-independently.
W om en older than 35—39 years and m en older th a n 55 years have a higher risk
o f giving birth to a child with D ow n’s syndrom e.

CONGENITAL D ISEASES

Congenital disease is such a disease, which manifests itself right after birth.
C ongenital diseases are som etim es connected w ith genetic apparatus p ath o ­
logy.
C ongenital diseases m ay result from pathological pregnancies, intrauterine in-l
loci ion. Examples o f such congenital diseases are toxoplasm osis and congenital !
syphilis. They are not genetically determ ined and, naturally, are n o t inherited.
I he diseases caused by environm ental factors w ith a clinical picture sim ilar to
known hereditary diseases are called phenocopies.
If hereditary diseases declare them selves im m ediately after birth (polydactylia),
(hey are also term ed congenital.

GENETIC EXAMINATION

Significance

I о provide appropriate treatm ent one should know the cause o f a disease. Th
role o f genetic and environm ental factors must be established.
M any acqu ired diseases arc clinically sim ilar to the hereditary ones. F o r e x ­
am ple, hyp othy ro id ism , w h ich is caused by iodine deficiency in the e n v iro n m e n t, is
clinically sim ilar to the genetically d e te rm in e d lack o f thyroid h o im o n e , but treat
men! and prognoses arc different (p h e n o c o p ie s are not i n h n i l r d )
 | hiiplei t Hole of H eredity and C o n stitu tio n in Pathology

If a sick child is born by a healthy w om an (a m utation happened during preg­

nancy), it is unlikely that this disease will repeat again.
A w om an, a carrier o f the hem ophilia A gene, is clinically healthy, but she
must know, that half o f her sons will be ill with hem ophilia. I f both parents are ill
with the same disease, their children have an increased predisposition to it. A d o c­
t o r o f any specialty observes the phenom enon o f hereditary predisposition. G enetic
-* muscling may help a family with a genetic pathology to find the probability o f its
i «petition in posterity.

Q u a n t i t a t i v e changes of c h r o m o s o m e s

в s '* * "

li ft H ii Si К П П O & q fr

№
и а и и ия м дt 6-12
4-5
1

h и и и u u и
6 7 8 9 10 11 12
А* М Ai XX ЛХ II
ш ш
П -15 16 17 18 ~1зУ)5

II АД ЯД
16 17 18
20 21 22 XXXYY Ш
19-20 21-22 XXX

tto I ( hromosomal mutations л f. 1Ч

I btii votvpc (XXXYY, o f a sick man Q u a l i t a t i v e ( s t r u c t u r a l )
tl< (им i< Hi t s syndrome); в karyotype (XXX) changes of c h r o m o s o m e s
uf nil l woinnn (X-trisomy); С - 1) deletion,
M >Imнии,nine associate, 3) ring-shaped
С
1
НЮШывшпв _ ___ ___

=4
ill I I ( H'ticnil I'silliopliysioluKy

Ictliods

M cl hot Is o f genetic exam ination are num erous and are constantly improved.
Statistical m ethod consists in the com parison o f disease incidence in a family
ltd hum an p opulation (according to m edical statistics). This m ethod m akes it pos-
hlc | о establish the genetic n atu re o f a fam ily disease. I f the type o f inheritance is
nown (from literature), a physician m ay prognosticate morbidity.
Genealogical method reveals the type o f inheritance. It enables a physician to
i.tblish the probability o f disease repetition in the following generations.
biochem ical m ethod d etects enzym opathy (for exam ple, phenylketonuria) even
i a new born baby. F o r ex am ination it is enough to take the urine o r a drop o f
lood.
Morphological (cytological) method is investigation o f the p atien t’s karyotype,
nine diseases are karyotype-dletectable. C hrom osom es are visible under the light
ticroscope in the m ultiplying cells (at the stage o f m etaphase). It is possible to
hscrve quantitative and stru ctural m utations o f chrom osom es (fig. 4).
S ex Chromatin (B a rr’s Body) Analysis. Sex chrom atin is a spiral X -chrom o-
>me present in the interphase nuclei if there are two o f them in the chrom o-
imc set. N aturally, healthy w om en have sex chrom atin. If a cell contains several
chrom osom es, the quantity o f Barr’s bodies equals the quantity o f X -chrom o-
jtncs m inus one. B arr’s bodies can be easily detected in the oral m ucosa cells.
Genetic analysis uses co n tem porary m ethods o f m olecule D N A study.
th e twin m ethod (exam ination o f identical and fraternal twins) gives a possibili-
/ lo distinguish the role o f heredity and environm ent (table 3).

We 3
Disease Incidence of Another Twin in a Pair of Twins

Disease Incidence
Disease of Another Twin, %
In Identical Twins In Fraternal Twins
1uherculosis 66.7 23
tlincy, imbecility, debility 97 37
Manic depressive psychosis 96 19
Schizophrenia 69 10
piicpsy 56 10
»uthcies mellitus 65 18
L’ongcnitiil pylorostenosis 67 3
H i Up 33 5
Uilemic goiter 71 70

By tlu* n i c l l t o d o f u ltra so u n d m o r p h o l o g i c a l d e f e c t s o h m e m b r y n ( m i c r o c e p h a
tydrocephaly) may be detected.
 ( hiiplri 1 Mnlr of Heredity and C onstitution in Pathology

i \ p e r intent a! modeling o f genetic diseases in anim als is possible. (Sub)popula

tinn*. ol anim als with a high o r low frequency o f cancer, leukem ia, arterial hyper-
i- iiMon and atherosclerosis are created under laboratory conditions.

PRINCIPLES O F HEREDITARY DISEASE PREVENTION AND TREATMENT

Etiological therapy and prophylaxis consist in prevention o f m utagen entrance

Hiio the organism . N eutralization o f endogenous m utagens with artificial antioxi-
>i m i, is possible.
Pathogenetic Therapy. As m utations are the initial link in the pathogenesis
*>i h u a litu ry diseases, genetic engineering (m anipulations w ith genetic m aterial)
Hi* o p tically is possible in scientific laboratories, but not yet in everyday m edical
pnu'tiee,
Substitutive Therapy. Injecting hem ophilia A patients w ith antihem ophilic
*?!•»!hi|in increases their lifetim e and m akes it possible to lead a norm al life. G am -
iiMpiobulin, horm ones (insulin, thyroxine), enzym es and m etabolites m ay be added.
Mi* iooinanism s synthesizing useful proteins (interferon, horm ones and enzymes)
им * rented in laboratories by genetic engineering.
Uioehemical disbolism correction has m any possibilities. Inactivation o f toxic
tи»m|iH is may be achieved. The dangerous com ponents o f food, w hich are not m e-
laboh/ed com pletely, m ust be avoided.
Symptomatic Therapy. Psychotropic drugs are used to treat m ental disorders. In-
I* * Ниц о Гsex horm ones to girls with T u rn er’s syndrom e and to boys with K linefelter’s
n ihIiohu- som etim es prom otes the developm ent o f the secondary sexual characters,
i'M aiivrlv influences the m ental condition o f patients. Im m unom odulator injection
mi ни . о inanism ’s own im m une m echanism s o f protection. Surgical treatm ent o f
m.Mjiiiologieal defects can be very successful.
* и Iu i wise, the treatm ent o f hereditary diseases is lim ited. O ne should b
it i и %оц to prophylaxis. All the substances used by people m ust be checked for
ним ф щ icily. T he knowledge o f risk factors helps to provide polygenic disease
jm *'plivlaxis,

ROLE OF CONSTITUTION IN PATHOLOGY

< niisMlulion is a unique complex of morphological and functional (including ps

i liiflnuit al and mental) features of the organism , which determ ines its individual re-
iH M lh (adaptation capacity and pathological predisposition) and is formed on the
1н !и!Мии basis under the innuenee of the environment.
li in im portant to see the interaction between inherited and acquired peculiari
т ч '*( ih,' organism in its constitution. T he inherited features can be defined as
hI(hhii ih potentialities.
io the environm ent, it is a condition o f constitutional realization and
hvlib lorm atlon o f new features having constitutional significance. It is obvious
Hint ini*»iю н, intoxication, avitam inosis and radiation can considerably change
♦Ih t mh (me o f the body, its reactivity and resistance. Pathological influences are
I’,ill I. (ic n m il Piitliophyslology

especially harmful in childhood. Beyond doubt, social and hygienic factors, such
as everyday conditions, food habits etc. have a great significance. T he teaching o f
constitution confirm s the law that the course o f any disease, its prognosis and trea t­
ment depend not only on the character and severity o f the pathogenic factor, but
a ls o on the individual peculiarities o f the patient.

( '(institution Classification

Hippocrates offered one o f the first constitution classifications. H e focused his

attention on the differences in tem peram ent and social behavior o f people. The
scholar differentiated choleric, sanguine, phlegm atic and m elancholic tem peram ent
types and this term inology is still used. A choleric person is excited, his workability
is high, but not stable. A sattguinic person is sociable, vivacious, active and em o-
lional, but predisposed to apoplexy and diabetes mellitus. A phlegm atic person is
calm , apathetic and sluggish, but stable. A melancholic person is a weak introvert,
depressed and hesitating. H ippocrates explained the constitutional variations by a
d i(Теrent proportion o f «humors» (blood, phlegm , choler or yellow bile, m elancholy
or black bile) in the h u m an organism . C ontem porary scientists also focus th eir a t­
tention on the role o f hum oral factors — blood, horm ones and biologically active
substances - in organism reactivity.
Sigaud offered a m orphological classification. On the basis o f the pronounced
developm ent o f a certain physiological system, he differentiated the following four
constitutional types: respiratory, digestive, muscular and cerebral (fig. 5). Sigaud be­
lieved that constitution is form ing throughout life, but predom inantly in childhood
.md in the process o f physical training.
Kretschmer distinguished three constitutional types: asthenic, athletic and picnic
(hi*. (>). Psychiatrist by profession, K retschm er attem pted to connect person’s m or­
phological features not only with psyche and tem peram ent, but also with predispo-
sition to m ental diseases. The asthenic constitution type is m ainly observed am ong
schizophrenia patients. P atients suffer­
ing from m anic-depressive psychosis
are usually o f the picnic type. Patients
with epilepsy have the athletic type of
constitution.
In clinical practice, М. V. Cher-
no ru tsky’s classification has taken ac ­
know ledgem ent. M.V. C hernorutsky
focused his attention on body organi­
sation, correlation betw een vertical and
horizontal dim ensions. Each co n stitu ­
a b с d tional type was characterized from the
liy 5. SignuiTs classification of constitu­ standpoint o f the m ain physiological
tional types functions and m etabolism Thus, in
a irspliutory, <liMt*HJve, c muscular, com parison with a normosthenic pcr-
iff!
 C h ap ter 3. Кок* of H iT n llly iinil C o n stitu tio n in I’atlioloKy

a b
I ig. 6. K r e tsc h m e r ’s c la s sific a tio n o f c o n stitu tio n a l ty p es
</ asthenic, b — athletic, с — picnic

son, a hyposthenic one suffers from arterial hypotension, reduced intestinal absorp­
tion, and elevated m etabolism . P atients o f th e hypersthenic type have the following
peculiarities: a higher level o f arterial pressure, slow m etabolic processes, reduced
carbohydrate to lerance, predisposition to ischem ic heart disease, m yocardial in ­
farction, obesity and diabetes mellitus.
William Sheldon based his classification on the developm ent o f the ectoderm ,
endoderm and m esoderm .
0 .0 . Bohomolets studied the role o f the connective tissue in the structural and
functional peculiarities o f the hum an body. H e presented a point o f view th at the
connective tissue unites the organism as a whole and form s the basis for constitu­
tion. H ence, he based his classification on the peculiarities o f the active m esenchy-
ma. The scholar differentiated the following types — asthenic, fibrous, lipom atous,
and pastose. The asthenic type is characterized by predom inantly thin and tender
connective tissue. The fibrous type has denser connective tissue. T he lipomatous
type has ab u n d an t adipose tissue; the m esenchym al elem ents are predisposed to
latty infiltration and lipoid decom position (atherosclerosis). The pastose type has
edem atous connective tissue.
1.P. Pavlov considered that it is the nervous system, w hich unites the organism
■is a whole and ensures its reactivity and balance with th e environm ent. The charac­
teristics o f higher nervous activity (force o f excitation and inhibition, th eir mobility
and balance) were taken as the basis o f classification. These types are sim ilar to
H ippocrates’ ones. The strong, mobile and unbalanced type (with the prevalence of
excitem ent) is choleric; the strong , mobile and balanced type is sanguine; the strong
hut slow type (inertia o f the m ain nervous processes) is phlegm atic; the weak type
(weakness o f both nervous excitem ent and inhibition with a relative prevalence of
Inhibition) is m elancholic.
G erm an hom eopathist Hahnemann classified patient types depending on their
sensitivity to m edicines. This idea is quite practical and underlies the use o f small
doses o f m edicines.
Studying the constitutional types m akes it evident that only som e people can
he referred to pure types, and most o f them are mixed ones.
Г hi I ( k i u t u I Pathophysiology

Significance o f Constitution

Significance o f constitution was well understood by ancient physicians. It was

obvious to them that pathological predisposition is reflected by constitution. They
« nm atcd the strong and weak features o f each constitutional type, predisposition
to certain diseases, and gave recom m endations as to rational behavior and life style,
I hey saw that a sanguine person is predisposed to apoplexy and recom m ended
bloodletting, which was very popular. T he physicians discovered th at a short per­
son is predisposed to apoplexy, while a tall person is predisposed to respiratory
diseases. In tuberculosis prim ary infection is independent o f constitution, but in
a-sthenic people the course o f the disease is m ore severe and lethal outcom e occur,
more often. A therosclerosis and coronary disease are directly related to the picnic
constitution. G astric ulcer, arterial hypertension, neurasthenia are characteristic ol
people with an excitable type o f the nervous system. It has been also noticed I hat
llit specificity o f neurotic sym ptom s is connected w ith constitution. F or example,
hysteria and depression are m ore com m on am ong the athletic and picnic types,
while fear and anxiety are m ore com m on for asthenic people.
Now the aim o f science is to study the nature o f the established connections,
which are probably genetically determ ined. M ost o f evidence favors the view that
the same group o f genes sim ultaneously controls a group o f features, w hich are
m orphological, functional and psychic.
Analysis o f the most vulnerable points o f constitution makes it possible to
prognosticate the disease course, determ ine pathological predisposition, provide an
individual approach to treatm ent.

Diathesis

H ie concept o f constitution is closely related to the idea o f diathesis, which

m anifests itself in childhood.
Diathesis is an abnormal state, which is characterized by inadequate reaction of
the organism to the environment.
Diathesis reflects the type o f reactivity bordering upon pathology.

/ vii da rive-Catarrhal Diathesis

I he child looks norm al or pastose. Inflam m atory processes develop easily with
exudate form ation and a tendency to a hyperergic course. The following atopic
leatures o f im m unological reactivity are revealed — a tendency to excessive IgE and
IgC i production, increased kinin system activity. T he im m ediate (anaphylactic) type
ol allergy develops easily, sensitivity to serotonin and histam ine is increased. T heir
are eosinophils in the blood. Clinical m anifestations include bronchial asthm a,
hives, Q uincke’s edem a, croup, and anaphylactic shock.

I ymphohypoplastic Diathesis

l)clayed involution o f the thvinus and epinephriin dellclency underlie tin*

diathesis On the one hand, hypeiplasia o f the tonsil lymph nodes and spleen I*
 C h a p te r 3. Koli* o f H c n r c d i t y and C o n stitu tio n in Pathology

>'■ , и» <1 On the o th er hand, there is hypoplasia o f t l he adrenal, thyroid and sexual
11 Hi.i . early exhaustion o f the reparative properties . o f the m esenchym a. Som atic
h i «I mental infantilism , pastosity, paleness, and weaWkly developed m uscles charac-

I» и . siu'h a child. Angina and pharyngitis arise frequiiently. Adrenal gland dysfunc
п««и i iv.ociated with a decreased resistance to stress s. Sudden death may be caused
In in insignificant reason.

\r u t oar t/iritic Diathesis

N»-11 m arthritic diathesis is characterized by inte.ensive purine m etabolism and

in* •« i *<1 form ation o f endogenous urates. T he urate e effect is sim ilar to that o f caf-
Imhi ami forms a strong unbalanced type o f co n stitu u tio n , nervous excitability, veg
i <»n r and em otional lability. A tendency tow ard theie following diseases is noted
м» hi ii)*ia, migraine, noninfectious diseases o f the jo o in ts , uro- or chololith forma
iMm ищи, diabetes m ellitus, rheum atism .
11 i . im portant to em phasize that diathesis is n o o t a disease, but a tendency
и Г ии ill', arc in the condition o f m inim al resistanoce and m axim al risk o f disease
i!* u lupm ent.

Questions for Self-Conti:roI

i < in m utation m ay be useful?

What is the difference betw een genetically d ete e rm in e d , hereditary, congenital
Неи-ases and phenocopies?
< an a disease be sim ultaneously genetically dete erm ined and congenital?
« an a disease be genetically determ ined but not»t congenital?
< m ,i disease be congenital but not genetically determ ined?
« h i a disease be genetically determ ined but noT«t hereditary?
VVIiai a ir biological m utagens?
VVh.M the polygenetic type o f inheritance?
is

i мs« a classification o f genetic pathology.

« и •. i hr characteristics o f defense reactions in genetic pathology.
Wliai «l<> f’cnetic pathology m anifestations d e p e e n d on?
Wli.il nr e polygenetic disorders?
I и i»i >s .ible to m odel genetic pathology e x p e rim e n ta lly ?
f <иiin the principles o f hum an constitution c la s s ific a tio n .
WIimi r. th r significance o f hum an constitution*.?

ihmk a/ some points fo r comparison and fill in a c o m p a riso n table o f the common
(Viihttes and differences between molecular genethic and chromosomal diseases
Гимн nl C o m p a r is o n M olecular G enetic D i s e a s e s C hrom osom al Diseases
i'.n l I ( ioili‘m l I ’iilhopliysioloKv

T ests and Tasks for Self-Control

(give correct answers and find mistakes in the statem ents)

I C haracterize the significance o f m utation.

1. M utation is an etiological factor o f inherited diseases.
2. M utation is the m ain link o f inherited diseases pathogenesis.
3. A virus may be a m utagene.
4 . M utation may result in the synthesis o f an anom alous protein form.
5. M utation may result in biochem ical processes disorder.
6. M utation is always harm ful.
7. All germ cell m utations are transm itted to the next generation.
X. M utations in the som atic cells m ay be transm itted to the next generation.
G ene m utation underlies D ow n’s syndrom e.

2. C haracterize the consequences o f m utations.

1. M utation always leads to errors in m etabolism .
2. T here is no defense m echanism against gene disorders.
3. T here are enzym al systems for the repair o f dam aged D N A m olecules.
4. T he reproductive function o f a gene m utation carrier may be preserved.
5. All congenital diseases are genetically determ ined.
6. M utation m ay result in a deficiency o f an im portant protein.
7. M utations are always harm ful.
8. Most m utations have no harm ful consequences for the organism .
l). M utations declare them selves right after birth o f a child.
10. C onsequences o f gene m utations do not depend on th e age o f the
patient.

I N am e the m echanism s, w hich prevent harm ful effects o f m utations.

1. The enzym atic systems o f dam aged D N A reparation are present in cells.
2. The im m une system neutralizes free radicals.
3. Antioxidant systems neutralize the active form s o f oxygen.
4. Recessive genes are m ore strictly controlled by natural selection.
5. Polygenetic diseases are controlled by the environm ent.
6. The hom ozygous condition o f the recessive pathological gene prevents
pathology m anifestation.
7. I killers destroy cell m utants by lym phokines.

I Explain m anifestations o f m utations.

I. Clinical m anifestations o f m utations depend on the type o f inheritance il
a disease is m onogenetic.
1. M utation o f the genes, which control the D N A repair enzym es, leads to
an increased sensitivity to radiation.
$, Enzym opathy is a genetically determ ined disorder o f enzym e am ount or
activity.
1 C l i ni c a l m a n i f e s t a t i o n s o f m u t a t i o n s nevei d e p e n d o n the p a t i e n t ’s sex.
S. C o a g u l o p a t h y is a gene t i c a l l y d e t e r m i n e d c o a g u l a t i o n l u e t o r def i c i enc y.
 C h a p te r 3. Roll* o f Н т ч Ш у and C o n stitu tio n in Pulliology

(» I lie intensity o f the clinical m anifestation o f a genetic disease is called

penetrance.
7 . I he probability o f the phenotypical m anifestation o f a m utant gene is
called expressiveness.

I xplain possible disease m echanism if a hereditary predisposition to this disease

\н suspected.
I, It is determ ined only by genetic factors.
Л Exogenous factors have no influence on the disease developm ent.
< It is not possible to change m anifestations o f this disease by environm ent
changes.
I Л certain etiological factor m ay cause different diseases depending on h e­
reditary predisposition.
Hereditary predisposition may be based on:
v D om inant type o f inheritance.
6. IEnzymopathy.
7 . Polygenetic type o f inheritance.

I xplain the aim o f every m ethod o f genetic exam ination.

I , Statistical m ethod establishes the genetic nature o f the disease.
Л Statistical m ethod establishes the type o f inheritance,
i. Statistical m ethod establishes the probability (in %) o f pathology repetition
in the next generations.
4. G enealogical m ethod establishes the type o f inheritance,
v G enealogical m ethod com pares disease incidence in a family and popula­
tion.
(\. Biochem ical m ethod studies the karyotype.
7 . Biochem ical m ethod m ay establish enzym opathy.
N The twin m ethod gives a possibility to distinguish the role o f genetic and
environm ental factors.
Cytological m ethod m ay localize a genetically determ ined pathology in the
genetic apparatus.
10. Pathological genes are studied m icroscopically.

л doctor consulted a w om an with physical and sexual m aldevelopm ents. Oral

mucosa m icroscopy showed no sex chrom atin in the nuclei. W hat kind o f
«lirom osomal pathology does it characterize?
Л T u rn er’s syndrom e.
В D ow n’s syndrom e.
< K linefelter’s syndrom e.
И Ilem op h ilia A.
I X~trisomia.

What m ethod should be used to diagnose T u rn er’s syndrom e?

A G enealogical.
Ii Statistical.
 C. Sex chrom atin identification.
D. Twin.
E. Derm atoglyphics.

l) A 42-year-old w om an had am niocentesis perform ed. The fetal karyotype is *1 \

XV, 21+. W hat genetic pathology is it?
A. Sickle-cell anem ia.
B. K linefelter’s syndrom e.
C. T u rn er’s syndrom e.
I). Phenylketonuria.
E. D ow n’s syndrom e.

10 During an inspection an 8-year-old boy was diagnosed with daltonism Ии

parents are healthy, their color vision is norm al. The m aternal grandfather iuul
the same anom aly. W hat type o f inheritance corresponds to this pathology?
A. A utosom al recessive.
B. A utosom al dom inant.
C. Polygenic.
D. Recessive, sex-linked.
E. D om inant, sex-linked.

11 In the population o f Ukraine heterozygotes with phenylketonuria genom e muki

3 %. W hat m ethod o f genetic investigation is used for early phenylketom iiw
detection in a newborn?
A. Cytological.
B. Statistical.
C. Genealogical.
D. Biochemical.
E. Derm atoglyphics.

I ?. A wom an with signs o f m ental retardation gave birth to a child (girl). A genet i*
pathology and its possible transm ission is supposed. W hat concepts must gui<U»
a physician? How m ust the child be exam ined?
Such diseases are sex-linked:
1. D ow n’s syndrom e.
2. Enzym opathy.
If the karyotype is examined, such characteristics
are typical o f certain syndromes:
3. A patient with K linefelter’s syndrom e is a girl.
4. A patient with T u rn er’s syndrom e is a boy.
5. I he am ount o f chrom osom es in a patient with D ow n’s syndrom e is 45,
6. T he am ount o f chrom osom es in a patient with T u rn er’s syndrom e is 45,
7. D ow n’s syndrom e - XO.
8. Turner's syndrom e - XXX.
Sex chrom atin (B arr's body) is absent in pat n u ts with Turner's л и-
drom e.
10 A patient with uuilti X syndrom e has no \« s <hiom ittln (B a n ’s body).
i hapter 4
OUCiANISM REACTIVITY AND RESISTANCE

C O N C E PT O F REACTIVITY

I Ih* course o f any disease depends not only on the force o f the etiological fac-
i■и hnl also on organism reactivity. In practical m edicine, the notion o f reactivity
h. ip in evaluate the adaptive potentialities o f the organism.
Reactivity is an ability o f the organism to change its activity and develop reac-
iions (mainly adaptive) in response to normal and pathogenic influences.
Reactivity m echanism s m anifest them selves at different levels o f biological or-
iniii/ation:
• Molecular (enzym e-substrate reaction, reaction o f hem oglobin to gas com po­
sition in the blood, transform ation o f biologically active substances, etc.).
■ Cellular (phagocytosis, reaction o f B- and T -lym phocytes to antigens, mast
cell degranulation).
• Tissue (connective tissue reaction in inflam m ation).
• Organ (activation o f heart pulsation in response to overload).
• Physiological systems (arterial blood pressure rise in response to pain, hy­
poxia, etc.).
• Organism as a whole.
• Population (form ation o f passive im m unity in children during the first year
o f life by transm ission o f im m une antibodies from m others to new borns via
the placenta and breast milk).
I he following systems significantly contribute to reactivity — genetic (constitu-
M*hi), nervous (central and vegetative), endocrine, connective tissue (which forms
biological barriers and provides im m une m echanism s).
Reactivity depends on sex and age. Low reactivity is typical o f early childhood
•in. hi underdevelopm ent o f the nervous, endocrine and im m une systems, im per-
I* • i к mi o f the external and internal barriers. T he highest reactivity is noted in adults,
lliiiiln.tlly descending to the old age.
D erangem ent o f reactivity is an im portant link in the pathogenesis o f every
•It • • . Reactivity disorder reduces the adaptive capacity o f the organism . At the
мин nine, any pathological process changes organism reactivity.

Types o f Reactivity

Reactivity is divided into prim ary (specific or biological) and secondary (ac-
(I under pathological influences o f the environm ent or developed in the
ими e oi a disease), group and individual. In addition, it is subdivided into norm al
inmmrrgy), increased (hyperergy), decreased (hypoergy) and qualitatively changed.
Physiological reactivity em braces reactions o f a healthy organism under favorable
In 11 ih conditions. Pathological reactivity m anifests itself uiulei the effect o f pat ho-
Pill! I (icm -nil I’alliophvsiolo^y

nenic factors (reactivity o f a sick person). The latter can manifest itself through
uncom m on reactions (allergy, shock).
Depending on its m echanism s, reactivity m ay be divided into nonspecific and
tpcclflc.
Nonspecific reactivity em braces reactions, which are not strictly dependent
>n a certain etiological factor and m ay occur in a variety o f conditions. All the
lelense reactions m entioned above (changes o f heat production and em ission in
»sponse to low and high am bient tem perature, vasodilatation, tachycardia and
typerventilation) relate to nonspecific reactivity. N onspecific defense reactions are
universal and econom ical. N onspecific organism reactions to infection (phagocy
o .i , form ation o f biologically active substances) should be also referred to this
m m o f reactivity
Specific reactivity em braces reactions, which are strictly dependent o n a certain
•liological factor. Only im m unological reactivity satisfies this requirem ent, when a
Id mite im m une antibody is form ed in response to a definite m icroorganism (an
ij'vn). Specific reactivity provides resistance to infection and form ation o f specific
m m unity. Specific defense reactions are m ore energy-dependent and are easily
lamagcd by unfavorable influences on the organism .

C O N C E P T O F R ESISTA N C E

I he concept o f resistance is closely connected with the concept o f reactivity.

Resistance is an ability o f the organism to withstand pathogenic factors.
Resistance is determ ined by reactivity, therefore resistance is one o f the main
laniTestations o f reactivity.
Resistance can be prim ary w hich is determ ined by genetic factors and second
ry, which is acquired.
Resistance is divided into passive and active. The passive one is based on ana
•mical structures (biological barriers). Active resistance is based on active defense
in lions, which develop at various levels o f biological organization.
I Isually reactivity and resistance change in the sam e direction, but o th er cor
•lailons are also possible. Thus, in hibernation reactivity o f anim als falls but resis
nice (passive) increases.
Reactivity is closely connected with sensitivity. Increased sensitivity determ ines
и n - . i s e d reactivity. An opposite example w ould be increased (but passive) resis
nee under anesthesia and hypotherm ia.
Abnorm al increased sensitivity (hypersensitivity) is called sensibilization as in
lergy.

M E C H A N IS M S O F REACTIVITY

The nervous and endocrine systems as well as connective tissue significantIv

m tribule to reactivity.
 C h a p te r 4 O r g a n is m R e a c tiv ity a n d R e s is ta n c e

ROLE O F NERVOUS AND ENDOCRINE SYSTEM S IN REACTIVITY

Hiylo and ontogenesis dem onstrate th at organism reactivity form ation is con»
и* • iril with the level o f nervous and endocrine system developm ent.
I he functional state o f the central and autonom ic (vegetative) nervous systems
•l»in mines decreased reactivity in narcosis and shock. D ystrophy develops after
‘ » non o f the som atic and vegetative nerves.
II vpei function o f the thyroid gland stim ulates reactivity while hypofunction
м л и is it. Diabetes m ellitus is associated w ith reactivity decrease. A drenaline and
MMikotropin (adenohypophyseal horm one) prom ote adaptive reactions. Adrenal
• in lex horm ones also influence reactivity. Thus, glucocorticoids inhibit inflam m a-
i"i\ leactions, an d m ineralocorticoids stim ulate inflam m ation.

ROLE OF CONNECTIVE T ISSU E IN REACTIVITY

I ikrainian scientist O.O. B ohom olets developed the concept o f the physiologi-
• >1 system o f the connective tissue, which plays an im portant role in reactivity and
n i.i.mce. T ogether with support and plastic functions, it accom plishes the fol-
Ihwiiih ones — trophic, defense (form ation o f barriers, phagocytosis and im m une
inn hanism s), reparative.
I he connective tissue system includes: biological barriers, bone m arrow , lym-
phiu vies and lym ph nodes, m icro- and m acrophages (neutrophils, m onocytes, his-
Hih vU's o f the connective tissue), reticular cells o f the liver, spleen, kidneys, lungs.
In perform its functions the connective tissue uses non-specific (barriers, phagocy-
Im h) and specific (form ation o f im m une response) m echanism s.
I or connective tissue stim ulation 0 . 0 . Bohom olets offered to use a serum
M in i antireticular cytotoxic serum (ACS). It contains antibodies against co n n e c­
t s tissue elem ents. This serum is produced by injecting elem ents o f the hum an
1 1 inflective tissue to anim als. A small dose o f ACS stim ulates functions o f the con-

im liv e tissue and organism reactivity; a large dose suppresses them .

Biological Barriers

Biological barriers are an im portant m echanism o f resistance and relate to pas-

i" unes. They are special structures, w hich protect the organism from pathogenic
!m inis and support hom eostasis. They are form ed in the process o f evolution, and
i" Hjile possess them from birth.
I here are two types o f biological barriers — external and internal.
External barriers include the skin, m ucosa o f the respiratory, digestive and
ни.|ч niial tracts, which contain bactericidal factors (leukocytes, lysozyme and se-
• *. in i\ l)',A antibodies) on the surface.
Internal barriers prevent penetration o f foreign and poisonous m aterials from
Ih* blood into organs and tissues. Internal barriers perform regulative, trophic and
*1* I* u s e functions. T hey regulate the process o f necessary substances getting from
IIfi hh mil into organs, support the optim al com position o f organ m edium , m aintain
И I (ieIKirul l\llllupllYNlol<>K.Y

llular hom eostasis and protcct organs from infection. I lie main structural ole
с ills o f internal barriers are the blood capillaries — endothelium , basal m em brane
id perivascular connective tissue.
Barrier perm eability may be changed under the influence o f m any factors,
ii leased perm eability is obtained under the effect o f ionizing radiation, acetyl-
inline, histam ine, kinins, hyaluronidase. T he opposite effect is produced by cate
lolam ines, salts o f calcium , vitam in PP. Barrier perm eability is changed undei
e m lluence o f different pathologic processes, such as traum a, inflam m ation, viral
loci ion. Barrier perm eability makes an organ m ore sensitive to infection, poisons
id intoxication.
I ach tissue has its own m edium and barrier. The com m on term for such bar
is is histo/icmatic.
I ach histohem atic barrier has its selective perm eability. In som e organs il
-.1lengthened by additional structures and receives a new nam e. These are the
ailed specialized barriers. It is a particular group o f barriers, w hich defend or
ins with weak local im m unity m echanism s (antibody form ation and phagocytosis),
нч lalized barriers arc hematoencephalic, hematoophthalmic, hematolabyrinthic, he
atotesticular, hematothyroid, and placenta.
The hem atoencephalic barrier (blood-brain barrier) has the m ost com plex or
m i/at ion. Besides the endothelium and basal m em brane, it has also argyroplnl
uilenal and astrocytes. M icroorganism s, toxins and antibodies do not penetrate
ito the brain under physiological conditions (the m orphology o f the hem atoen
•phalic barrier and its role in pathology are described o n p. 518 in chapter 31
’athophysiology o f nervous system»). As to m etabolites, horm ones and biological
active substances, the barrier acts selectively regulating the penetration o f these
laterials into the brain cells.
Hie placental barrier is vitally im portant for fetal developm ent as it protects
ie Ictus during pregnancy. Barrier perm eability im pairm ent harm fully influences
nbryonic developm ent and results in different types o f postnatal pathology.
Specialized barriers protect organs from infection and large m olecules, which
e circulating in the blood. But, on the o th er hand, these very organs are isolated
nin the im m une system in the em bryo, and physiological im m unological tolerance
> them (see below) is not form ed. Specialized barrier injury leads to autoim m une
egression against these organs.

Phagocytosis

Phagocytosis is an im portant but nonspecific reactivity m echanism .

Phagocytosis is a process o f capture and intracellular destruction o f foreign par
eles (m icrobes, distorted tissues) by special cells o f the connective tissue, which are
tilt'd phagocytes.
Phagocytes are leukocytes: neutrophils (m icrophages), m onocytes (m acrophag
i) and the tissue type o f m acrophages (star cclls in the liver, alveolar, pleural and
 C h a p te r 4 . O r g a n is m R e a c tiv ity a n d R e s is ta n c e

Phagocytosis is regulated by m any factors. Antibodies, im m une com plexes,

i Minplenients and horm ones (adrenaline, thyroxin, m ineralocorticoids, sex h o r­
m ones) activate phagocytosis; besides, phagocytosis is activated during fever. Bio-
Iиjiu .illy active substances (BAS) activate all stages o f phagocytosis. G lucocorticoids
«ml .icctylcholine inhibit it.

Siufffs and Mechanisms

Phagocytosis proceeds in four stages.

1. С hemotaxis (approaching) o f a phagocyte to an object after its recognition.
»>n I heir surface phagocytes have receptors to chem otactic substances (m icrobial
{Moilucts belong to them ).
2. Adhesion (attachm ent) o f phagocytes to objects. A dhesion is provided by
polysaccharides, which are located on the leukocyte surface. Electrostatic interac-
llon between the negative leukocyte charge and the positive charge o f the inflam -
iiuiory locus contributes to adhesion.
I Capture o f foreign particles by phagocytes (endocytosis) and phagosom e
(urination.
/. Intracellular digestion o f phagosom e co n ten t by lysosomal proteolytic e n ­
g in es.
Phagocytosis requires A TP energy. Leukocytes are know n to have uncom m on
rHut Ions with oxygen - m itochondria are absent in phagocytes, and ATP is form ed
l»V Hveolysis. Phagocytes use oxygen for the production o f bactericidal factors. Oxi-
tll fi is (hydrogen peroxide and active forms o f oxygen) are form ed inside phagocytes
in mi m olecular oxygen by a special enzym e system (the key enzym es are N A D PH
iiHiilase, superoxide dism utase and m yeloperoxidase). Glycolysis activation results
III ai i um ulation o f acids (acidosis), w hich act as a bactericidal factor. Lysozyme,
I t. lolcrrin and non-enzym e cation proteins also refer to bactericidal factors.

IHwrders

Phagocytosis fails if phagocyte quantity reduces (leukopenia) or their func-

iimiu I activity is disturbed.
I'.tlology. Etiological factors are physical (ionizing radiation), chem ical (poi-
" n ,i and biological (including genetic) factors o f external and internal origin,
"in. h suppress leukocyte form ation in the bone m arrow or disturb their functional
tHtlvlty.
Pathogenesis. Phagocytosis disorders are divided into acquired and genetically
H« h i m ined. M echanism s are the following:
• I )ecrease o f the quantity o f phagocytes (leukopenia) is the m ost frequent
о « нм lor suppressed phagocytosis. H em opoiesis in the bone m arrow is depressed
in i filiation disease, intoxication, autoim m une injury, avitam inosis o r leukopoietin
tM iclcncy.
• I \cessivc glucocorticoid secretion suppresses phagocytosis. T he same effect
Iм pioiluccd by the influence o f glycolytic poisons (they dim inish energy form ation

- .— — - .........— .... **
I'illI I ( i H l f r u l l'ullio|»liysioloK >

in leukocytes), inhibitors o f D N A synthesis and other laetots, which disorder cell

division.
• G enetically determ ined disorders m ay result from enzym opathy (deficiency
«>1 m yeloperoxidase and N A D PH oxidase, lysosomal proteolytic enzym es and gly­
colytic enzym es), lack o f lysosomes in phagocytes or deficiency o f receptors on
their surface.
• Acquired and genetically determ ined pathology o f BAS form ation, lack ol
opsonizing, com plem ent and o th er factors, w hich are functionally connected with
phagocytosis.
• Phagocytosis suppression u n d er stress, thyroid hypofunction, sex gland insuf
fieiency (during clim ax). Leukem ia is accom panied by reduced enzym e activity in
leukocytes.

Manifestations

Disordered phagocytosis m anifests itself as incom plete. At the level o f the

whole organism , phagocytosis disorder declares itself by disorders o f organism re­
activity and resistance to infection. Predisposition to infectious diseases is obvious.
I ven saprophytic infection (autoinfection) may cause problem s. Inflam m ation, a s
a defense reaction, takes a chronic course.

Role o f BAS in Reactivity

HAS perform a lot o f functions under physiological and pathological condi

lions, contributing to organism reactivity and resistance. They are form ed in a small
concentration in tissues and in the blood plasm a. BAS regulate m icrocirculation,
vessel tone and perm eability, blood coagulation, activate phagocytosis and im ­
m unity m echanism s, stim ulate leukocyte form ation and liberation from the bone
m arrow, have an enzym atic effect and destroy m em branes o f m icrobes and foreign
cells T hey cause fever and have growth factor characteristics.
U nder pathological conditions, BAS are produced in a large quantity and be
com e a harm ful factor (there develops inflam m ation, allergy, edem a, spasm , pain,
hock, etc.). M any drugs, which are used to treat inflam m ation and allergy, are
di ice ted against BAS. T herefore a physician needs to know BAS origin, synthesis,
inhibition, physiological and pathological effects.

HAS o f Cellular Origin

Biologically active substances may be form ed in almost all cells. C onnective

tissue cells are especially active in this respect. Som e BAS are already present in
cells, and som e are form ed after cell stim ulation (activation) I he process o f BAS
secretion needs energy, therefore energy form ation blocking stops BAS release. Cy
chc nucleotides o f cells (cA M P and cCiM P) take part in tin pioce . .

70
 C h a p te r 4. <)гци1|1м11 R eactivity and Resistance*

HAS arc form ed by m eans o f som e m echanism s: a) release (secretion) from

ih. n a n u le s o f neutrophils, eosinophils, basophiles and m ast cells; b) synthesis (as
Ivmphokincs in T -lym phocytes, in terleu k in -1 in m onocytes); c) form ation from
m. mhrane phospholipids; d) appearance after cell dam age (proteolytic enzym es
ни leleased from destructed tissues as cathepsins and hyaluronidase; histam ine and
I» с urn are released from destructed throm bocytes and m ast cells).
Below we give inform ation about B A S-producing cells in short (it is studied in
Hi lulls in the course o f biochem istry).
Must cells release histam ine, heparin, serotonin, neutrophil and eosinophil
• in inoiaxic factor, enzym es, which are already present in cells and are released after
«i'll d ep a n u la tio n . A slow -reacting substance (SR S), w hich is produced from m em -
Iи .и n com ponents during degranulation, m ust be added. Histamine acts through
»*• i plors located on the som atic cells sensitive to it. There are two types o f recep-
imi 11( and H2. Stim ulation o f H ,-receptors prom otes contraction o f the sm ooth
mu ,» les, endothelial cells and postcapillary part o f m icrocirculation. Stim ulation
"i 11 receptors causes the opposite effect. Serotonin causes vessel spasm. Heparin
* ■h.iracterized by antithrom botic and anticom plem ent activity, inhibits phagocyte
»In motaxis.
Neutrophils liberate proteolytic lysosomal enzymes from th eir granules.
leukocytes, fibroblasts and lymphocytes produce interferon (a class o f pro-
i< m .) in response to viral infections. It inhibits the replication o f both D N A - and
НМЛ containing viruses. In viral infection interferon appears even before B- or
I • ell im m une responses are identified.
An im portant group o f BAS (o f lipid origin) is form ed from m em brane phos-
|tlmhpids after activation o f the enzym e (phospholipase A2), which releases arachi-
ilciiu acid. It is a group o f eicosanoids (arachidonic acid m etabolites, products o f its
i" ioxidation). A rachidonic acid m etabolism may be cyclo- and lipooxygenic. In the
hi i i ase (under the influence o f cyclooxygenase) m etabolism results in the form a-
ii--и и [prostaglandins, to which thromboxanes (from thrombocytes) and prostacyclin
Mmm endothelium) refer. In the second case (under the influence o f lipoxygenase)
m. taholism leads to the form ation o f leukotrienes, to w hich the m ast cell SRS refers.
I «ykntrienes increase m ucus secretion, stim ulate phagocyte chem otaxis.
Monocytes are a rich source o f BAS — esterase, protease, lysosome hydrolase,
Hdlaycnasc, elastase, interferon, m onokines, transferrin, com plem ent, growth fac-
Imi throm boxane, prostaglandin E, etc. Am ong them interleukin-1 ( IL-1) is very
Impnitant. It is a horm one-like protein, w hich plays an im portant role in im m u-
ииЦчса! reactivity. All cells, which are responsible for im m unity, have receptors
........ neilcukin 1 and are sensitive to it. It effects B- and T-lym phocytes functions
h cum ulating their division, antibody synthesis and lym phokine form ation. II I
MmiMhutes to fever developm ent. H epatocytes, fibroblasts, myocytes and nervous
i . |K их с as targets for IL-1 (fig. 7).
/ lymphocytes after their activation produce a group o f lymphokines (interleu
which govern the functions o f others leukocytes. Interleukins involve all
vies in im m une response. T-killers release perforin, w hich destroys mem
linnies of m icrobes o r foreign cells.

71
Г , III I ( iC IllM U l 1’|Н1ю|>||уч1о1оКУ

Itlood proteins

Fibroblast
proliferation

b p ith e lio c y te
o f the liver

Antibodies

Lym phokins

A ctive T -lym phocyte

Fig. 7. I n t e r l e u k i n - 1 ( I L - 1 ) a n d its ta rg e ts
In the cen ter o f the figure th ere is a m acrophage, w hich produces IL-1 after
activation. IL-1 influences its targets: cells o f the bone m arrow , liver, hypothalam us,
lym phocytes, fibroblasts

Thrombocyte activating factor (TAF) is secreted by basophiles, lym phocytes,

throm bocytes and endothelial cells. T A F acts on the target cells via corresponding
leeeptors in some ways. It causes aggregation o f throm bocytes and release o f hist;i
mine and serotonin, prom otes phagocyte chem otaxis, activates BAS secretion from
eosinophils and neutrophils, causes spasms o f the sm ooth muscles, and increases
perm eability o f vessels.

It tS o f Plasma Origin

I his type o f BAS consists o f a com plem ent system and proteolytic enzymes,
which are found in the blood plasm a in the inactive form.
The complement system consists o f som e protein com ponents (denoted C l,
( ' СЧ, C5, C 6, C7, C8, C 9), which are in the blood serum in the inactive state
An activated com plem ent has a lot o f regulative and enzymal properties — proper
h e . of esterase and protease — activates phagocytosis and various BAS, provides
bacteric idal action o f the blood, destroys m icrobes by perforating their m em brane
I his system is activated (as a cascade) after the beginning o f im m une reaction (by
uitibodies and im m une com plexes) and takes part in infection elim ination. T he ae
:ive com plem ent destroys the im m une com plex and thus finish* antigen inactiva
Ion C om plem ent system disorder may be acquired and mh* h i * <1 Blockade o f the

n
 C h a p t e r 4. O rg an ism R eactiv ity and R e sista n ce

vhi in -,is o f any com plem ent com ponent m ay be caused in pathology. Loss o f the
l> н I* in ulal action o f the blood, im m unity depression and developm ent o f serious
«И * r.rs arc the consequences.
\i tlvated //axeman factor stim ulates blood coagulation, activates the com ple-
mh hi s y s t e m and proteolytic blood enzymes.
I'hitcolytic blood enzymes are present in the blood in the form o f plasm inogen
м.. I l .1 111 к rei nogen. They are activated by o th er BAS (H agem an factor, com ple-
Hhini microbes and im m une com plexes. Kallikrein (activated kallikreinogen) is
...........in enzym e o f the kallikrein-kinin system. K inins are form ed from the blood
I'Imт . i protein (kininogen, which is a globulin).
I he kallikrein-kinin system is engaged in vasoactive substance (kinin) produ
IIhii *In»* to a cascade o f biochem ical reactions, w hich begins with H agem an factor
№ и v it ion (schem e 4). Bradykinin and kallidin refer to this system.
Ml m echanism s o f BAS form ation activate each other.
Scheme 4. System of Plasma Kinins
H agem an factor

T ripsin
K allikrein
F ibrinolysin

1
A ctivation o f
J
A ctivation o f A ctivation o f the
coagulation prekallikrein fibrinolytic system
I
Fibrin F ibrinolysin
Prekallikrein ► K allikrein

K ininogen K inin (bradykinin)

K ininase
I
Inactivated peptides

H is i fleet ( ontrol

I lie biochem ical system o f BAS form ation is u n d er control.

II f.S disintegration is provided by enzym es o f proper specificity — histam inase,
itMHt i г urylsulfatase (eicosanoid annihilation enzym e). Superoxide dism utase and
§i Milnpl.ismin destroy active forms o f oxygen.
// I S inhibition is provided by a 2-m acroglobulin o f the blood (inhibitor o f kinins
HmI pintrolytic enzym es o f Iysosomes), antitrypsin, antithrom bin (com plem ent in-
hlhlioi), lipom odulin (inhibitor o f the eicosanoid, w hich suppresses phospholipase
\ • 111 .1 .mime inhibits T -lym phocyte activity and lym phokine secretion by H 2-
jи **|Mni Activation.
II IS secretion arrest is insured by cA M P (inhibits mast cell degranulation) a
Ими nle (suppresses lysosotne activation).
h i l l I ( ИМИ*I 111 P ullio|)liysioloK y

Protection o f target-cells from HAS influence is realized by corlisole and adrena

line.
A special role in the regulation o f BAS activity belongs to eosinophilic granulo­
cytes, which co n tain m any protective substances (histam inase, arylsulfatase).
f inally, it is necessary to m ention that phagocytosis and BAS are function
.illy connected with im m unological reactivity (see the next chapter, p. 83). They
stim ulate and regulate it. Im m une antibodies react specifically with antigens but the
etlectivencss o f antigen binding and destruction depends on the activity o f these
systems. Pathology o f phagocytosis, com plem ent system and BAS may underlie im
m unity pathology, dim inish the effect o f im m une response and organism resistance
to infection.

Q u estion s for S elf-C o n tro l

I What is specific and non-specific reactivity?

2. What is active and passive resistance?
V W hat is the role o f connective tissue in reactivity?
4. W ho studied the role o f connective tissue in reactivity?
V Do you know the way o f connective tissue stim ulation?
() What specialized internal barriers do you know?
7. (live the characteristics o f the blood-brain barrier.
K. What are the consequences o f phagocytosis disorders?
l) May a phagocytosis disorder be genetically determ ined?
10. Сiive a classification o f BAS.
11. What are the ways o f cellular BAS appearance?
12. Do lym phocytes produce BAS?
IV In what way is the BAS action controlled?

T asks for S elf-C o n tro l

(give correct answers and find m istakes in the statem ents)

I Reactivity and resistance are not synonym s. Analyze th eir relations filling the
table and finding proper examples for each situation
Situation Examples
1 T reactivity leads to T resistance A —hibernation
2. t reactivity leads to i resistance В —training in a pressure chamber
V 1 reactivity leads to T resistance С —sensibilization (allergy)
4. 1 reactivity leads to I resistance D —chronic diseases

2. (iive the characteristics o f BAS effect control m echanisms:

1. A special role in BAS activity regulation belongs to eosinophilic granulo­
cytes.
2. I osinophilic granulocytes contain arylsulfatase

1A
 C liaptci I < >i ;■.1111 111 R e a c tiv ity a n d R e s is ta n c e

i I osinophilic granulocytes contain histam inase.

I. N eutrophils contain arylsulfatase.
v l~suppressors stim ulate im m une reactions
(> cA M P accelerates m ast cell degranulation.
7. C ortisole protects target cells from BAS effect.
K. BAS secretion and inactivation depend on genetics.

Pharm acologists propose different drugs for the treatm ent o f inflam m atory and
allergic diseases. This therapy is based on BAS inactivation. W hat knowledge
about BAS should guide pharm acologists?
Blood kallikrein-kinin system activation is accompanied by formation
o f such BAS:
1. histam ine,
2. serotonin,
3. prostaglandins,
4. bradykinin,
5. eicosanoids,
6. heparin,
7. leukotrienes.
The following BAS are o f cellular origin:
8. com plem ent,
9. proteolytic enzym es from neutrophil lysosomes.
Such BAS are released from tissue basophiles:
10. histam in,
11. heparin,
12. serotonin,
13. kinins,
14. kallidin.
( liaptcr 5
IMMUNOLOGICAL REACTIVITY AND ITS PATHOLOGY

I he term immunity has broad and narrow interpretations. 1.1. M echnikov in

terpreted it broadly as organism resistance to infection, independently o f its pri
nmry o r repeated developm ent. A ccording to his interpretation organism resistance
i . bused on such nonspecific m echanism s as barriers (including the skin and mu
cons m em branes) an d especially phagocytosis, whose discovery m ade Mechnikov
.1 Nobel Prize w inner. As to infectiologists, they give a narrow interpretation ol

im m unity it is defined as resistance to a repeated entry o f the sam e infection

People, who have had a contagious disease and becam e unsusceptible to it, arc
called im m une.
M odern im m unologists interpret im m unological reactivity as exclusively spe
с ilie im m une m echanism s, as the function o f the thym us, B- and T-lym phocytes,
is resistance to any genetically foreign inform ation but not only infectious. In this
chap ter the latter conception o f im m unological reactivity is accepted.
Resistance to infections is determ ined by som e m echanism s. They are passive
(biological barriers), active (phagocytosis, im m une cell activity), nonspecific (bar
не is, phagocytosis, interferon and other BAS), specific (antibody form ation anil
i ooperation o f B- an d T-lym phocytes).
The study o f im m unological reactivity pathology is based on the following
knowledge received earlier.
• C oncept o f antigen as genetically foreign inform ation, w hich m ust be rejected
by the im m une system.
• Structure o f the im m une system, which consists o f central and peripheral
organs. The thym us and bone m arrow are central. Peripheral organs are the spleen,
lymph nodes, tonsils. M ovable elem ents o f the im m une system are B- and T-lym
phocytes. M onocytes represent antigens to lym phocytes.
• В and T -lym phocyte genesis (origin, m aturation, differentiation), which
includes the following processes:
• В and T-lym phocytes originate from com m on cells. T heir further m ature
tion and differentiation are dissimilar.
• В lym phocytes m ature in the bone m arrow o f adults.
• I lym phocytes m ature in the thym us and differentiate into som e sub­
populations — T -helpers, T-suppressors, T-effectors (which transform into
I killers after activation), m em ory cells. There are natural killers (N K ),
which use antigens o f the m ajor histocom patibility com plex as receptors.
• I he difference between the functions o f B- and T-lym phocytes consists in
the following:
• В lym phocytes provide humoral immune mechanisms A lter activation by
an antigen they arc transform ed into plasm acytes and produce hum oral
factors of im m une response (im m unoglobulins) l r lu v ly circulate in the
organism liquids (blood and intracellular liquids) and can get into mucus

76
 С h a p t c r 5. Iiiiiiiiiii€il<>|jili‘iil R e a c tiv ity a n d I ts P a th o lo g y

and secrets. I hey can be absorbed by som e cells (m ast cells, epithelium ,
sm ooth muscles).
■ Г-lym phocytes provide cellular mechanisms o f immunity. They ruin patho
logical cells by lym phokines and perforin (elim inate b o d y ’s own m utant
cells and foreign cells), provide cooperation betw een all the cells o f the
im m une system.
* li lym phocytes do not distinguish body’s own proteins from the foreign
ones (are not tolerant to body’s own antigens).
• I lym phocytes distinguish body’s own proteins from the foreign ones (are
tolerant to body’s own antigens).
• Im m unoglobulin varieties are A, D , G , M , E (they are called im m une ant
1мн|)гч) T heir peculiarities are the following: IgE and IgG en ter tissues and m ay be
ih m bed by the som atic cells, IgG and IgM have precipitating properties, IgA arc
h! n id o ry type, IgD penetrate the placenta.
- Im m une response may be prim ary (after the first entry o f an antigen; the im
tmnir system m em orizes the results) and secondary. The latter is accom plished after
и | и иotl entrance o f the sam e antigen and proceeds m ore quickly and actively.
I lie m odern definition o f im m unological reactivity is the following.
hiiinuiiological reactivity is a com plex o f hum oral and cellular reac tio n s o f the
•<4 iiiKiii in response to antigens and specific to them .
So, the basic function o f im m unological reactivity is controlling the antigen
M.mposition o f the organism and m aintaining its antigen hom eostasis. B- and
\ hm phocytes (with the aid o f other systems) fulfil this function.

C lassification o f A ntigens

Antigens are m acrom olecular agents, m ainly o f protein nature. They are di-
■nl. t! mto infectious and noninfectious, natural and artificial, molecular and cellular,
complete and incomplete (haptens).
11tuler natural conditions antigens are m icroorganism s (bacteria, viruses, fungi).
I iиIt*i pathological conditions there w ork o th er types o f antigens (artificial, incom -
|il> i< non-protein, w hich will be discussed in chapter 6 while studying allergy).
In analyze im m unity m echanism s and im m une response disturbances it is
hii|M»ii;mt to keep in m ind that som e antigens (like cocci and m icrobial toxins) cir-
*ul ih in the blood, but others do not (viruses and fungi are located inside cells).

M E C H A N IS M S O F IM M U N E R E S P O N S E

M echanism s o f im m une response depend on the type o f antigens, th eir dose,

И tii1 1 ueI o f entry, w hether antigens circulate in the blood o r persist inside cells.
Ih* * conditions determ ine the type o f im m une response (by hum oral antibodies
h i • ellular m echanism s).
I In- first cells, w hich confront infection (antigen), are m onocytes. Together
Mirи I* phagocytizing capacity, they (by m ediator IL -1 ) im plicate specific im m uno
nm petent cells (B - and I lym phocytes) in im m une response (fig. (>).

77
Hurt I (id io m I I’iillmphvsioloKv

Hum oral M ech an ism s

• H um oral m echanism s develop if an antigen is a m icroorganism or its toxins,

which circulate in the blood.
• Antibodies also circulate in the blood and organism liquids (hum oral antibod
ies).
• I lum oral m echanism s are connected with the function o f B-lym phocytes.
• H lym phocytes react to an antigen and transform (in the spleen and lymph
nodes) into plasm acytes, w hich in a couple o f days (3—5) produce im m unoglobu
tins (A, I), ( i, M, E). The latter en ter the blood and liquid m edium and spread
ihm ughout the organism (IgE can fix to som e cells including m ast cells).
• After hum oral antibody production, an im m une com plex (antigen+antibody)
is formed. It is the initial stage o f antigen destruction. Im m une com plexes activate
I he com plem ent, phagocytes, BAS, w hich accelerate antigen destruction involving
the whole organism into im m une response and increasing body tem perature.
• I -helpers and T-suppressors regulate these processes. Cells o f im m unological
m em ory rem em ber this situation. Active natural immunity forms (the organism is
im m unized).
• If the same antigen (m icrobe) enters again, the organism , w hich is im mu
m /ed, elaborates antibodies very quickly because im m unological m em ory cells are
quickly transform ed into plasm acytes and antibody form ation begins.

СVllular M echanisms

C ellular m echanism s o f im m unity are activated if the hum oral ones are not
siillieient. The type o f antigen also m atters. C ellular m echanism s have the following
characteristics.
• Antigens do not circulate in the blood.
• U nm oral antibodies (im m unoglobulins) are no t formed.
• C ellular m echanism s develop:
• for elim ination o f body’s own m utant cells;
• in case o f intracellular localization o f a foreign antigen (virus, m ycobacterium
o f tuberculosis, T reponem a pallidum in lues, brucella, histoplasma, etc.);
• as a response to incom plete antigen.
• M acrophages represent antigens to T-effectors, which transform into T-kill
ere.
• I killers react with antigens directly. Lym phocytes infiltrate the locus with
antigens. I killers destruct the cells by cytolysis with the aid o f lym phokines and
perforin.
• Phagocytosis and BAS are involved in im m une reactions.
• I helpers and T-suppressors take part in the process as well.

Im mune R esponse R egulation

All variants o f im m une response are regulated. It m eans balancing the stimuli!
tlon and inhibition m echanism s. Its relevance m atter, in itniininologica! disorders,
which have a disregullitivc character (allergy).
 ( l u i p l c r S. lniiiiiiiioloK ic;il K e a c tiv ily a n d Its P a th o lo g y

Regulatory m echanism s develop both in the im m une system proper (autoregu-

liition) and outside it.
Some m echanism s are genetically determ ined and provided by products o f the
1 1 1 iii«>i histocom patibility com plex.

I he organism is capable to react to a large num ber o f antigens due to m utations

hi | иi-cursor cells an d polyvalency o f variable im m unoglobulin parts. A high rcli
•btlity o f im m une response is provided by sim ultaneous developm ent o f cellular and
humoral im m une reactions as well as by production o f m any antibody m olecules
с» ! one antigen m olecule.
I helpers help B- and T -lym phocytes react to antigens. Intolerant B-lym pho-
* \ u can not react w ithout the help o f tolerant T-lym phocytes. The suppressive
hi net ion o f T-lym phocytes is a potent m echanism o f intersystem regulation o f im ­
mune reactions.
I he effectiveness o f antigen destruction depends o n the systems, w hich are
h in d tonally connected with the im m une system — phagocytosis, com plem ent and
HAS
MAS form ation and activity are regulated by biochem ical m echanism s o f their
inhibition and destruction as well as participation o f blood cells (eosinophils) and
Ни endocrine system.
Participation o f the nervous and endocrine systems in im m une response reali-
Itttion has been proved by experim ents and clinical practice.
W eakening o f the nervous system due to overstrain significantly decreases re-
•iiiivity to bacterial toxins, antigens and m icrobes. Shock o f any origin inhibits
tiuu tivity to infection. N arcosis aggravates the course o f strepto- and pneum ococcal
- p i*, in experim ental anim als and increases the frequency o f fatal outcom e. Stress
inhibits cytokine form ation.
H orm ones also participate in the regulation o f im m une response. Thyroxin,
м1 и n.iline, sex and som atotropic horm ones stim ulate it. Increased A C TH secretion
bom the pituitary gland increases resistance to infection. A drenalectom y decreases
и i i.nice to bacterial toxins. A drenal cortex extract stim ulates antibody form ation
( upposedly due to aldosterone) but large doses o f glucocorticoids inhibit the for-
m т о п o f antibodies and cytokines. Im m unity decrease in diabetes m ellitus results
in iиi4Imposition to purulent infection an d tuberculosis.

I4 " <>f Immunity

Im m unity is divided into natural and artificial (form ed for the purpose of
piHphylaxis and treatm ent). In their turn, each type is subdivided into active and
t«i r.lve.
Natural active im m unity appears after an infectious disease.
Natural passive im m unity form s by antibody transm ission from a m other to her
bub\ with the m o th er’s milk and through the placenta.
Artificial active im m unity (active immunization) is form ed by injection o f vac-
\ in* , containing weak or dead m icroorganism s.
I'.ill I ( i n ie r a l I’lillioplivsloloKy

Artificial passive im m unity (passive immunization) is formed by injection of

an im m une serum , which contains specific antibodies against a certain infection.
Im m une sera arc produced by injecting antigens (m icrobes) to anim als or people
volunteers. Using an im m une serum for prophylaxis or treatm ent a physician musl
keep in m ind that the im m une serum was prepared with foreign (to the patient)
protein m aterial and its repeated injection is dangerous (causes the so-called serum
disease, ch ap ter 6 «Allergy», p. 94).

IM M U N O L O G IC A L TOLERA N CE

Im m unological tolerance is the absence o f im m une reaction to som e antigens

with preserved reactivity to other antigens.
Im m unological tolerance differs from im m unodepression (see below) by its
specificity.
Physiological immunological tolerance is the absence o f im m une reaction to 0 1
nanism 's own proteins. U n d er pathological conditions the im m une system begins to
react with organism ’s ow n proteins (the loss o f physiological im m unological toler
ancc and autoim m une aggression is described in chapter 6).
I he organs, w hich are located beyond the specialized barriers (the brain,
e v e s , and ear labyrinth), obtain an exclusive position in the organism , because
they are isolated from the im m une system in an em bryo and later in postnatal
cMsience. T hese organs avoid infection if the barriers are unaffected. If the barri
e i are broken, these organs becom e an object o f au to im m u n e aggression because
lh< im m une system is not «acquainted» with these organs and thus is n o t tolerant
to them .
An exclusive role belongs to an em bryo. In spite o f the fact that it is h alf for
11 genetic inform ation for a pregnant w om an, it is not rejected by the w o m an ’s
im m une system.
Pathological immunological tolerance m ay be m odeled experim entally by injec -
non o f a large quantity o f an antigen causing im m unological paralysis (high-dose
im m unological tolerance) or injection o f an antigen to an embryo.
A kind o f pathological im m unological tolerance develops tow ards em bryo-like
ualignant cells (see ch ap ter 10 «Neoplasia», p. 155).
l o r the purpose o f successful transplantation o f foreign organs physicians
brm an artificial state o f the organism opposite to im m unological reactivity — the
ihsence o f im m une response to foreign tissues. It is artificial immunological toler
wee,

IM M U N O L O G IC A L REACTIVITY PATHOLOGY

Disorders o f the im m une system may manifest them selves as hyper/unction and
iypo/unction. As to the participation o f the gene m echanism s, im m unological reac
iv itv pathology is divided into acquired and hereditary
Classification o f im m unological reactivity pathology is given in schem e 5.

0
 ( liiiplci S. IiniiK iiiolo^ical K ra c tiv ity a n d U s P a th o lo g y

Scheme 5. Types o f Im m unological Reactivity Pathology

IM M U N O D E P R E S S IO N

hiiiitiinodcpression is an acquired d e crease o f im m unological reactivity.

1 1й40|ку

Im inunodepression causes are such etiological factors, which inhibit m ultipli-

mimm. i and differentiation o f lym phocytes o r disturb their functional activity. They
♦it! ......./m g radiation, m utagens, cytostatics, carcinogens, various toxins (including
»lnses o f drugs), infectious agents (A ID S virus). M alnutrition and avitam inosis
Iff ih< conditions prom oting im m unodepression. Em otional stress m ay depress
iHmitnu' response.

Nilm genesis

I <• analyze im m unodepression pathogenesis the following argum ents should be

into consideration.
• Im m unocom petent tissue belongs to the tissues o f the m itotic type. H ence, it
ftp t liiK.li sensitivity to all the factors disturbing cell m ultiplication. This peculiar­
ity ill*i« i mines the developm ent o f various pathological processes in the im m une
•Hi • in ilne to the effect o f the inhibitors o f cell division and D N A synthesis and
pillil ini’ radiation (p. 28).
• Somatic m utations in the im m une system eventuate in the appearance o f im -
flHHHH vies with im paired functional activity.
• l-Hcessivc synthesis o f glucocorticoids (they suppress protein synthesis and
IfII iniiHiplication) decreases im m une response (clinical examples are stress and
lltb elieel s of horm onal glucocorticoid therapy).
• A utoim m une aggression against im m une system cells and im m unoglobulins
Инн i like place.
• Pathology o f the systems, which are functionally connected with the im m une
him (phagocytosis, the com plem ent system ), eventuates in im m unodepression.
• Many diseases accom panied by intoxication (renal and hepatic insufficiency,
i .1.1 ) and systemic disorders o f m etabolism (diabetes meUitus, avitam inoses)
It! • 'im plicated by im m unodepression.
• Aging is accom panied by a reduction o f im m unological reactivity.

uI
Г.u I I <.m o r a l P iillin p liysloloi'v

M anifestations

Im m unodepression always m anifests itself by a reduction o f organism res is

lance to infection. Saprophytic infection becom es a problem . T he best exam ple ol
im m unodepression is radiation disease.
A cquired im m une deficiency syndrom e (A ID S) refers to acquired forms o f ini
nuinosuppression. It is a severe infectious disease. A lym photropic RNA-containiii}'
virus (hum an im m unodeficiency virus - HIV) is the etiological factor. This virus
a fleets the m em brane o f T -helpers and o th er cells (brain and spinal cord cells). The
virus destroys cells by m ultiplying in them . There develops com plete paralysis of all
the m echanism s o f im m unological reactivity (both hum oral and cellular).
Clinical m anifestations o f A ID S are: lym phadenopathy, weight loss, recurrent
lever, autoinfection activation (pneum onia, diarrhea), pulm onary infiltrates, neuro
logical abnorm alities with dem entia at late stages (deficient m em ory and decrease I
interest in the environm ent).
Social and hygienic factors are im portant for A ID S prevention.

IM M U N O D E F IC IE N C Y

Immunodeficiency is a genetically determined decrease o f immunological reactivi

ty (ininiiinopathy).
Im m unodeficiency diseases refer to hereditary ones. They are called primary
.is opposed to secondary disorders o f the im m une system , w hich develop as com
plications o f oth er diseases. Up to date about 20 form s o f this pathology have been
investigated. They arc studied in the course o f pediatrics. C arriers o f genetic defects
m the im m une system are ill from early childhood.
Ktiology. There is a close interrelationship betw een im m une com petence and
genotype. The cause o f im m unodeficiency is m utation o f genes, w hich are respon
s ib le for the form ation o f im m unocytes and im m une response. Physical, chemical
and biological m utagens are the etiological factors.

Pathogenesis and Clinical M anifestations

G enetic defects may concern any stage o f the form ation and m aturation ol
И and Г lymphocytes. In m any cases im m unopathy is based on enzymopathy
(ien e and especially chrom osom al anom alies in the organism predispose to immu
nodefliciency and consequently to allergy (p. 89), neoplasia (p. 148) and leukemia
Ф 4.1) Hie pathogenesis and clinical m anifestations o f im m unodeficiency depend
on the type o f lymphocytes, whose function is im paired most o f all. There are three
forms ol immunodeficiency: B-lym phocytic, T-lym phocytic and the com bined type

It I viiiplioeytie Im m unodeficiency

li lym phocytic im m unodeficiency can be underlain by genetically determ ined

disorders o f the following processes:

H2
 C h a p t e r 5. Im m u n o lo g ic a l Reactivity a n d Its P a th o lo g y

• form ation and differentiation o f B -lym phocytes;

• It lym phocyte transform ation into plasm acytes;
• im m unoglobulin form ation.
A lack o f B-lym phocytes results in the hum oral type o f im m une reactions
■iiuirder.
( linical manifestation is low resistance to infection, m ainly o f purulent type,
t litUliси are constantly sick with tonsillitis or pneum onia. IgA lack leads to de-
• и list’d protective ability o f m ucous m em branes. Viral infections occur m ore rarely,
s - 1uiical exam ple is B ruton’s agam m aglobulinem ia.

I I viuphocytic Immunodeficiency

I lym phocytic im m unodeficiency can develop from genetically determ ined

ill niders of: a) form ation o f the thym us in an em bryo (thym us hypoplasia); b) dif-
Im nliation and m ultiplication o f T-lym phocytes.
I lym phocytes lack results in disorders of: a) the cellular type o f im m une reac­
tion., b) control over all im m une reactions (disturbance o f regulative and coopc
i Hive functions o f T-lym phocytes). Besides, it eventuates in loss o f physiological
im munological tolerance to body’s ow n proteins.
( linical manifestation is low resistance to viral and fungal infections, predispo-
и и m to chronic m ycotic affection, allergy and autoim m une aggression. This type
h| im m unodeficiency predisposes to prem ature aging. T ransplant rejection is sup-
jiM'v.ed. A clinical exam ple is D iG eorge syndrom e connected with hypoplasia o f
ilu lliymus in an em bryo.

< iHtiMiicd Immunodeficiency

In most cases im m unodeficiency is o f com bined type. Insufficiency o f T - and

И lymphocytic im m une reactions underlies this pathology. T he thym us develops
»н.«m eetly. The quantity o f lym phocytes and gam m a globulins is reduced (lym -
l<!in|>em.i, hypogam m aglobulinem ia). Im m unological reactivity is significantly ге­
й м * i * d i i n i l qualitatively changed.

( linical manifestations are severe. All the m echanism s o f im m unity are limited.
I и n the vaccines used for im m unization may provoke diseases and death. Predis-
|in ,iiinn to allergy and neoplasia is observed. C linical exam ples are W iskott-A ldrich
nvndrome, L ouis-B ar syndrom e (with skin telangiectasia) and Swiss-type agamma-
tti"hullnemia.

D ISO R D E R S O F S Y S T E M S FU N C TIO N A LLY C O N N E C T E D WITH

IM M U N E SY S T E M

Phagocytosis, BAS, and com plem ent are functionally connected with the im
imme system. I heir disorders essentially decrease the effectiveness o f im m une rear
i m mi . imd, first o f all, resistance to infections.
Purl I <»enenil Pathophysiology

Phagocytosis disorders have been analyzed in every detail in ch ap ter 4 (p. 69),
Phagocytosis is supposed to be the main m echanism o f resistance to saprophytiJ
infections. So, all the reasons, which decrease the am o u n t o f leukocytes (ionizing
radiation, cell division inhibitors, etc.) or disturb their functions (genetic reasons,
neoplastic transform ation in leukem ia, intoxication, horm onal disorders, avitamm
osis), result in disorder o f im m unological reactivity.
All the BAS m entioned and analyzed in ch ap ter 4 (p. 70) influence the activ­
ity o f im m unocytes, their division and m aturation. Im m unocytes perform then
functions with the aid o f m onokines, lym phokines, etc. So, genetic and acquired
problem s in the BAS system essentially im pair im m unological reactivity.
A special role in im m unological reactivity belongs to the com plem ent sys
tern, which is activated by antibodies and im m une com plexes. Active comple
m ent possesses a lot o f regulative and enzym atic properties. It has esterase nntl
protease properties, provides bactericidal action o f the blood, ruins the microbial
m em brane, com pletes antigen elim ination by im m une com plex proteolysis, activa
lion o f phagocytosis and o th er BAS. Some grave clinical situations (genetic anal
acquired) take place w hen the synthesis o f one o r an o th er com plem ent com ponent
(C l, C2, C3, C 5, C6, C7, C8 deficiency) is im paired. It leads to serious clinical
derangem ents: predisposition to m icrobial and viral infections, developm ent o f dift
fuse diseases o f the connective tissue (collagenoses), autoim m une diseases (chronii
glom erulonephritis, autoim m une joint dam age), repeated infections o f the respiru
lory system. Most o f them m anifest them selves in early childhood. It is a com m on
cause o f early death.
Not only decreased, but also pathologically increased com plem ent activity may
cause a disease. A deficiency o f com plem ent inhibitors underlies it. An example in
angioneurotic Q uincke’s edem a caused by genetic deficiency o f C l inhibitor, which
leads to pathological activation o f the com plem ent system.
Since many diseases proceed with or due to decreased im m unological reactivity
n is an actual problem o f m odern m edicine finding possibilities to effect it positive
!v l or this purpose the so-called im m unom odulators are devised by pharm acolo
j'is ts In this connection attention should be paid to a natural process, which works
.is ,i stim ulator o f im m unological reactivity. It goes about fever (will be described
m ch ap ter 9, p. 134).
Im m une system hypofunction, as well as im m unodepression and immunodefl*
i iencу have been discussed in this chapter. As to its hyperfunction, the next chaplcr
(«•Allergy») dwells on it.

Q uestions for Self-C ontrol

I ( iive a definition o f im m unological reactivity.

2. Why docs im m unological reactivity refer to a specific type o f reactivity?
V N am e the types o f im m unity.
I What is the difference between hum oral and cellular im m une reactions?
s, What is the difference between В and T-lym phoeyte participation in im mune
response?

84
 ( h a u le r \ I iiiiiiu iio Iok Ich I K v u ctlv ity am i Its P a th o lo g y

f» What can you say about BAS role in im m une response?

What can you say about com plem ent role in im m une response?
N What can you say about phagocytosis role in im m une response?
'» In what way do glucocorticoids influence im m unological reactivity?
M' Wh.it is the relation between im m unological reactivity and im m unological
lolcrunce?
II In what body’s ow n tissues and why is the im m une system not tolerant?
I ' What consequences might a dam age o f the internal specialized barriers have?
II What is the difference between im m unodepression and im m unodeficiency?
H What is the difference between B- and T -im m unodeficiency?

T ests and a Task for Self-C ontrol

(give correct answers and find m istakes in the statem ents)

I \ girl, 8 years old, began to walk late. At 1 year she was ill w ith a serious
Ini m o f pneum onia. Later telangiectasia appeared on the skin and conjunctiva.
IgA are absent, the am ount o f T-lym phocytes is reduced. W hat type o f
im m unodeficiency is present?
A. DiGeorge.
H. W iskott-A ldrich.
< B ruton’s agam m aglobulinem ia.
I ). Swiss-type com bined.
I Louis-Bar.

J \« iivity o f the im m une system o f H IV -infected patients is depressed. What

i \ pi* o f cell deficiency causes the state o f im m unodeficiency?
A l-helpers.
И l -suppressors.
( Plasmacytes.
D И-lym phocytes.
I Г-killers.

i Л research o f the im m une system o f a patient with a chronic m ycotic skin

altcction revealed cellular im m unodeficiency. W hat param eter decrease is the
most typical in such a case?
A, IgA.
И IgG.
< Г-lym phocytes.
I) IM ym phocytes.
I Plasmacytes.

I I Ini m onotherapy is necessary for autoim m une reaction depression after organ
11 nr,plantation. W hat horm ones are used in such a case?
A Som atotropin.
H M ineralocorticoids.

' - i l i l i T ' ........ ... hhh ........................................... _ ................... .......................... .............

1 1 I (iiM icrul P a th o p h y sio lo g y

C. Sex horm ones.

I). Epinephrine.
I G lucocorticoids.

A 2-year-old child has thym ic hypoplasia diagnosed. W hat is typical o f this

im m unodeficiency?
A. D eficiency o f IgM.
B. Deficiency o f T-lym phocytcs.
С . Deficiency o f T - and B-lym phocytes.
I). Absence o f plasmacytes.
I Deficiency o f B-lym phocytes.

» Pharm acologists devise m edical drugs for the treatm ent o f im m unological
system disorders. W hat scientific knowledge should guide them ?
Lymphokines have the following properties:
1. T hey are released from T-lym phocytes after contacting an antigen.
2. T hey regulate the function o f all lym phocyte populations.
3. T hey do not influence granulocytes.
Antibodies are characterized by the following features:
4. They get into the organism from the outside.
5. T hey are form ed from album ins.
6. Antibodies are im m unoglobulins.
7. T hey provide the hum oral m echanism o f im m unity.
8. They freely circulate in the blood and organism liquids.
Immunoglobulins have the following types and properties:
9. lgE can be absorbed by tissue basophiles.
10. T here are 3 classes o f im m unoglobulins.
11. T hey inhibit com plem ent activity.
12. Im m unoglobulins can pass through the placenta and form active natural
im m unity in the newborn.
13. IgE can pass through the placenta.
( hapter 6
ALLERGY

Allergic diseases are an actual problem o f m edicine. They are widespread am ong
people, and there are m any reasons prom oting allergy expansion in population.
Allergy is a disorder o f immunological reactivity in the form o f increased and
i|iialilatively changed immune response, which dam ages the organism by immune
mechanisms.
A question arises, why in some cases im m une reactions result in health and
im m unity (im m unization), but in o th er cases the sam e im m une reactions result in
pathology in the form o f allergy (sensitization, o r allergization) and even death.
Why does allergy co n tin ue to expand in population?

C O M P A R IS O N O F IM M U N IT Y AND ALLERGY

IM M U N ITY

C ellular im m unological reactions are created in the process o f evolution for

elim ination o f bo d y ’s ow n m utant som atic cells, w hich are changed in their ge­
nome. It is a function o f T-lym phocytes.
H um oral and cellular im m unological m echanism s are created in the process o f
i volution as a response to antigens o f natural origin. Only m icroorganism s, such as
lorcign protein, en ter the organism under norm al conditions. An im portant fact is
that an antigen enters the organism not in a large but in a small dose. C onsequently,
ili< am ount o f BAS is sm all, and the natural system o f BAS control is sufficient for
MAS regulation. A reliable control o f im m une response is created in the process o f
evolution. As a result, infection is elim inated and active im m unity is created (im ­
m unization).
U nder norm al conditions the im m une system is tolerant to body’s own proteins
(physiological im m unological tolerance).

M J l ’RGY

The sam e im m unological reactions (hum oral and cellular) underlie allergy, but
*auses, conditions and final effects are entirely different.
I here are two principal ways o f allergy developm ent:
* In an initially healthy organism.
* In an organism with im m une system pathology.

\llergy in Initially Healthy Organism

I he cause o f this type o f allergy is located outside the organism and is d ete
mined by peculiarities o f the antigen (its origin, dose, frequency and interval o f
' lit IV).
«iit I (iciieral l^iihophyilology

hi o u r tim e an enorm ous quantity o f proteins o f unnatural origin m ay enter

к organism in the form o f foreign sera, vaccines, transplants and m edicines,
Inch correspond to the concept o f antigen. Im m une response develops, but it is
uantitatively and qualitatively perverted and dam ages the organism . It has been
4|H'hmcntally proved by injecting a foreign serum parenterally to a healthy anim al
vice (with a two-week interval).
I he dose o f antigen does m atter. It is always large. Even natural antigens (in-
■i lions) injected in a large dose cause allergy in a healthy experim ental anim al,
i such cases form ation o f im m une com plexes is excessive, overloads the im m une
Mein an d results in superfluous BAS form ation (exceeds the potentiality o f their
(activation).
I hus, this form o f allergy is not a problem o f the organism , but a problem of
ic environm ent.

Истцу in Organism with Immune System Pathology

I he cause o f this type o f allergy is inside the organism . The causes m ay be

quired o r genetically determ ined. T he latter (im m unopathy) are m ore often. In
1 11 cases we speak about predisposition to allergy.

tie o f Genetic Factors in Allergy

I he role o f genetic factors in allergy developm ent has been confirm ed statist!-
Uy.
I lie structure and properties o f im m unocytes are genetically determ ined as
II a s the system o f BAS control. M ore often hereditary predisposition to allergy
delerm ined polygenetically.
I he following reasons and m echanism s are possible.
I In* m ost com m on cause o f allergy is T -lym phocytic o r com bined im m unodefi­
ciency. In T-suppressive m echanism deficiency the function o f lym phocytes be­
c o m e s unregulated and excessive. This deficiency m ay lead to the loss o f physio­
logical im m unological tolerance and autoallergy developm ent.
Piedisposition to IgE form ation (w hich are cytophilic and fixed on the m ast
cells) may be genetically determ ined. A healthy organism has a m echanism
inhibiting IgE synthesis. This balance is genetically determ ined and m ay be dis-
u ranged. Г-suppressor deficiency and high IgE tite r are noted in m ost allergic
lisenses.
HAS inhibitor deficiency, which regulates pathochem ical events in allergy, may
>o genetically determ ined.
Deficiency o r excessive activity o f com plem ent underlie m any forms o f allergic
llieases.
)isorders o f the barrier function o f the respiratory and gastrointestinal tract m u ­
ons m em branes may be genetically determ ined and provide the entry o f foreign
m itcins (allergens) inside the organism .
• ЛИ chrom osom al syndrom es (see ch ap ter 5) are associated with serious distur­
bances o f im m unological reactivity, predisposition to im m unodeficiency (p. 54)
and allergy.
• Diatheses are exam ples o f hereditary im m unological pathology.

Acquired Causes o f Allergy

Besides reasons o f genetic nature, allergy m ay be caused by acquired pathology

o f the im m une system. T he following causes have been identified.
• Experim ental thym ectom y provokes allergy developm ent.
• C hronic infection m ay induce an excessive quantity o f infectious antigens. D e­
pressed resistance to infection m ay lead to organism sensitization instead o f im ­
m unization.
• Som atic m utations in the im m une system are possible, and in such a case im m u-
nocytes m ay identify body’s own proteins as foreign antigens or lose the ability
to govern im m une reactions.
• Neoplasia in the im m unocom petent tissue, as it is in leukem ia, m ay deprive
m alignant im m unocytes o f control over im m une m echanism s.
• H orm onal insufficiency (glucocorticoid and corticotropin deficiency) m ay turn
im m une response into an aggressive form.
• IgE-binding factor glycolization (in diabetes m ellitus) leads to IgE accum ulation
and predisposes to allergy.
• Acquired pathology o f the gastrointestinal m ucous m em brane allows foreign p ro ­
teins (m ilk, egg, fish) entry into the blood w ithout prelim inary proteolysis. The
same situation is possible due to im pairm ent o f the respiratory tract m ucous bar­
rier.
T he com parative analysis o f im m unity and allergy, given above, helps to u n ­
derstand the reasons for allergy expansion in population. They are: a) appearance o f
new allergens in the environm ent; b) an increasing quantity o f patients with genetic
pathology.
It is possible to confirm that allergy is a disease o f civilization.

ETIOLOGY

Etiological factors o f allergy are antigens (they got the nam e allergens) th a t lead
Iо sensitization (allergization) o f the organism instead o f im m unization.

A llerg en C la ssific a tio n

Allergens are divided into exogenous and endogenous (autoallergens).

I Exogenous allergens get into the organism from the outside while endoallergens
.m* form ed inside the organism . T here are several classifications o f allergens in ac ­
cordance with their chem ical structure, origin, source, way o f entry and biological
organization (m olecular or ce llu lar/
T he classification is given in schem e 6.
I III I ( ii'iii'n il P a th o p h y sio lo g y

ix ogenous Allergens

Exogenous allergens are divided into infectious and noninfectious. Infectious

antigens (bacterial, fungous, viral) behave as allergens only in an organism with
im m unological reactivity pathology.
M ore often allergens are noninfectious.
A ccording to the chemical structure allergens m ay be o f protein (foreign sera,
transplants) and nonprotein nature; the latter being sim ilar to true antigens (m acro-
m oieeular polysaccharides and lipopolysaccharides).
I he concept o f incom plete antigens (haptens) helps to understand why allergy
develops under the effect o f sim ple chem ical substances (brom ine, iodine, ch ro ­
m ium , nickel) and m edicines. After binding with organism proteins, they form a
com plex antigen and induce antibody form ation.
As to the source, allergens are divided into everyday (dom estic dust, cosm etics, ;
synthetic fabrics, detergents, decay products o f co tto n ), industrial (rubber, glue,
plastic, metals and th eir salts, latex, cellulose, w oodw ork), vegetable (pollen and es­
sential oils), epidermal (scurf, wool, feather, scale). Food is a widespread source o f
allergens (fish, milk, eggs, w heat, beans, tom atoes, citrus fruits and chem ical sub­
stances added to food products such as coloring agents, antioxidants, flavoring and
o ther substances). Drugs m ay becom e allergens (antibiotics, vitam ins, sulfonam ides,
enzym es). Fungi are widespread allergens. M any nonpathogenic fungi while en ter- j
ing the organism m ay cause sensitization and allergic diseases (bronchial asthm a).
Such fungi are contained in the atm ospheric air, dwellings, dom estic dust and food
products. As to the way o f entry allergens are divided into inhaled, injected, enteral,
and epidermal.

I ndogenous Allergens

Endogenous allergens are body’s ow n proteins, w hich a) have changed the an - |

iiyi n structure under the action o f injuring factors; b) are located beyond the d am ­
aged specialized biological barriers (brain, eyes, ear labyrinth); c) belong to th e sick

Srheme 6. Classification o f Allergens (adapted from A. A do, 1970)

A llerg e n s

E x o g en ous E ndogenous

V egetable [ Im m une N atural A cquired

B acteria Food sera, B rain, crystalline
Fungi I ) o m e siic vaccines lens, sex glands,
V iruses thyroid gland
Sim ple Noninrectiouw | Infectious
chem ical P roducts form ed c o m plex
substances under ellc* i ol cold I >•“ ie • m icrobe
and rndinllon. In I hhh iKiue*toxin
 C h a p t e r (>. Allergy

organism , which has lost physiological im m unological tolerance. Both exogenous

imd endogenous allergens are divided into molecular and cellular.
Physical environm ental factors (cold, heat, ionizing irradiation), which are not
antigens them selves, m ay initiate allergy by inducing antigen form ation from m ole-
« nles o f the organism (by disclosure o f hidden antigen determ inants or form ation of
new ones as a result o f protein m olecule denaturation).

P A T H O G E N E S IS

C om m only used allergy classification is based on its pathogenesis.

T Y PE S O F ALLERGY

T here are differentiated immediate and delayed types o f allergy depending on

Ihe rate o f developm ent (several m inutes in the first case and several days in the
w cond one). In their tu rn , these types are subdivided depending o n th eir pathogene-
i . Thus, five types o f allergy are distinguished (according to C oom bs and G ell’s
classification).
The im m ediate type o f allergy is subdivided into three variants:
/. Anaphylactic
2. Cytotoxic
3. Immune complex
The im m ediate type o f allergy is based o n by hum oral im m unological reactions.
Antigens (allergens) circulate in the blood. T he m ain role in pathogenesis belongs
lo И lymphocytes. H um oral antibodies are form ed.
Delayed-type hypersensitivity is accom plished w hen cells serve as antigens
in.insplant o r dam aged body’s own cells). H um oral antibodies are not formed.
I he m ain role in pathogenesis belongs to T-killers (a clinical exam ple is transplant
rejection).
Stimulating reactions are considered a separate type o f allergy though their
m echanism s are hum oral (cytotoxic type). Antibodies react with those cell recep­
tors. which are intended for horm ones and are stim ulated by them . Thus, som e
hum s o f hyper- and hypofunction o f the thyroid gland are connected with this
mechanism. This co n cerns thyrotropic horm one (T T H ) receptors located on thyro-
■\ies Antibodies to these receptors (an ti-T T H -recep to r antibodies) com pete with
luum ones in T T H -rec ep to r binding, and antibody-receptor bonds are m uch stron-
i" i and longer than bonds with T T H . T he effect depends on antibody titer. A
mudl dose m ay stim ulate the gland function (hyperfunction, or Basedow’s disease).
I м cssive am ounts o f antibodies against these receptors m ay cause th eir block and
hypothyroidism (on the background o f an increased concentration o f TTH and
hspothalam ic liberins). Such im m unopathies are receptor diseases. They are n u m er­
ous I luis, autoantibodies to insulin receptors underlie som e forms o f insulin rcsis
tniit diabetes mcllitus. Som e forms o f m egaloblastic anem ia with atrophic gastritis
Inivo the same nature (autoantibodies to gastrin receptors o f accessory stom ach
»ells) D opam ine receptor antibodies may cause schizophrenia il they are stimula
кНИ I ( i m m i l I ’lilliuplivsiologv

ivi and parkinsonism if they arc blocking. A drenoreceptoi antibodies have been
Iso discovered.
M any allergic diseases are com bined as to their m echanism s.
W hen antigens are o f endogenous origin (autoantigens, autoallergens), we speak
bout autoallergy (autoimmune aggression).
In addition, allergy (sensibilization) is divided into active and passive.
ictive sensibilization develops under experim ental conditions after injecting an
Kens lo Ilie organism. Antibodies and im m une lym phocytes are form ed inside the
iganism.
Passive sensibilization develops under experim ental conditions after injectinr
nm unr antibodies o r sensibilized lym phocytes (injecting the blood plasma or lym
hold cc 1Is o f an actively sensitized d o n o r to an intact recipient).

STA G ES O F ALLERGY

All allergic reactions have com m on pathogenetic m echanism s and proceed in

ice stages.
I Im m u n o lo g ical stage (sensibilization form ation) starts at the m om ent o f th e
.1 entry o f an allergen into the organism . It em braces form ation o f antibodies or

nsiti/ed lym phocytes and is finished by form ation o f im m une com plexes a fte r a
pealed entry o f the allergen.
2. P u llio c h cm ica l stage consists o f BAS form ation.
I. P ath o p h y sio lo g ic a l stage appears as m orphological and functional distni
m vs, which underlie clinical m anifestations.
Various types o f allergy have special features o f pathogenesis.

IM M E D IA T E ALLERGY

Anaphylactic Allergy

Ii r. convenient to analyze anaphylactic allergy dynam ics using as an illu stn

n experim ental parenteral injection o f a heteroserum to a healthy anim al (twice
h a two-week interval).
Immunological stage begins after the first entry o f an allergen into the organ
i .iiul covers all changes in the im m une system. B -lym phocytes transform into
Iu.u vles, which produce antibodies (in some days, predom inantly in the form
Iи I > and im m unological m em ory cells. IgE can fix on the m em brane o f tissue
ophiles (m ast cells), whose granules contain a large quantity o f BAS. From tins
inent the organism is sensitized. If the same antigen is introduced repeatedly
•I earlier than in two weeks), im m une com plexes (antigen+antibody) are form ed
tin mast cell m em brane and degranulation is caused im m ediately. A large quan
ol HAS is released. This event starts the next stage o f allergy.
Pathochemical stage em braces BAS form ation aftei mast cell dcgranulation.
. stage dillers from the one in im m une response by: ,i) л 1шцс quantity o f HAS.
eh are being formed; b) cascade like involvement ol all systems o! HAS lot
 ( Ii m pi с i (>. A llergy

н м iи)1 1 . c) insufficient control over BAS form ation and destruction. H istam ine,
in p.nin, and serotonin are released from mast cell granules and stim ulate eico-
tiMHHtl form ation (prostaglandins, leukotrienes, SRS) from m em brane lipids. T hen,
•I» n i ascade, all systems o f BAS form ation are activated — the kallikrein-kinin
м ...„I system (form ation o f bradykinin and other BAS), proteolytic blood enzym es
HiY|eanogen, profibrinolysin) and com plem ent (schem e 7).
I I - physiological system o f BAS inhibition and destruction does not work in
k

•Ii* situation. BAS involve the entire organism and initiate the next stage o f al-
Ьчцу.
/ *athophysiological stage is m anifested by local and general (system ic) chang-
• Vasodilatation, local reddening, skin eruption, itch, burning, pain are local
m anifestations representing an acute inflam m ation. Acute and chronic local allergic
f<l> ms arc a result o f increased perm eability o f vessels. Since eosinophils are a rich
мни c o f BAS inhibitors (histam inase, arylsulfatase as eicosanoid annihilation en-
fvme) I heir increased co u n t is observed in allergic diseases (eosinophilic leukocytosis,
I* U)4).
( icneral m anifestations o f allergy are m ore dangerous. Spasms o f the sm ooth
ишsi Ies o f the internal organs are clinically m anifested by bronchospasm (cough,
• 4 "' 't‘>ry breathlessness), spasm o f the gastrointestinal tract m uscles (spasm odic
p un m the abdom en, nausea, vom iting, diarrhea), spasm o f the uterus in w om en.
NpiHtic phenom ena are aggravated by edem a o f the m ucous, which covers the inter-
Vi h>me 7. Formation of BAS in Allergic Reactions

SRS
u i I (io itm il I’jHliophysioloKy

.«I organs. Larynx edem a manifests itself as asphyxia. Hem ostasis disorder consists
i sim ultaneous activation o f coagulation, anticoagulation and fibrinolysis. C lini-
illy il is m anifested by hypocoagulation in the aorta and large arteries (hemorrhage
ndrome), and hypercoagulation (thrombosis) in the capillaries. A rterial blood pres-
irc decrease, loss o f consciousness are the gravest m anifestations o f allergy. There
•v e lo p s shock, which is called anaphylactic.

m ini D isease

Scrum disease is a clinical exam ple o f anaphylactic allergy. This disease arises
hen an im m une serum containing antibodies against a certain infectious agent is
»ed lor passive im m unization o f a patient (see artificial passive immunity on p. 80).
iw ether with a therapeutic or preventive effect, the serum itself sensitizes a patient,
ul a repeated injection o f the same serum is very dangerous; it m ust be injected
small repeated doses (specific desensitization, p. 99). If it is injected w ithout pre-
ninary desensitization, acute renal insufficiency with anuria develops due to renal
ter dam age by im m une com plexes (p. 472).
A nother clinical exam ple o f anaphylactic allergy is the so-called pollinosis
.ilients suffer from itch and burning sensation in the eyes, lacrim ation, nasal
scharge).

C ytotoxic Allergy

( ytotoxic reactions refer to im m ediate allergy. They are called cytotoxic be-
use antibodies cause lysis o f cells.
Immunological Stage. T he pathogenic effect o f chem ical substances (usually
dicines, e.g. pyram idone), viruses and m icrobes plays a role. These etiological
tors m ay change body’s own antigen structure o f cellular m em branes. A ntibodies
formed against foreign o r body’s own cells (if they acquire autoallergen proper-
s). Antibodies belong to IgG and IgM and are called cytotoxic.
Pathochemical Stage. It em braces BAS activation. The m ain m ediators arc
m plcm ent and activated enzymes. BAS activate phagocytosis and N-killers.
Pathophysiological Stage. Cell lysis is provided by activated com plem ent and
k i l l e r s together with phagocytosis o f the cells covered with antibodies.
( finical Manifestations. A clinical exam ple is hem olysis o f d o n o r’s erythrocytes
e i m ism atched hem otransfusion (including rhesus incom patibility). The eryth-
v i e s undergo im m ediate cytolysis. A nother exam ple is autoim m une aggression
inisi body’s own blood cells (erythrocytes, leukocytes or throm bocytes) if th eir
linen properties are changed after dam age by m icrobes or m edicines (hemolytic
rmiu, leukopenia and thrombocytopenia). Cytotoxic im m une sera are widely used
experim ents for selective dam age o f certain cells and pathology m odeling. If cy-
ohic antibodies are form ed against the dam aged basal m em brane ol renal glom e-
rs, it causes acute glomerulonephritis.
 C hap ter 6. Allergy

Immune Complex Allergy

Im m une com plex diseases develop if im m une com plexes form insoluble m i­
croprecipitates.
Immunological Stage. M any dissolved allergens (exogenous and endogenous,
com plete and incom plete) after binding with antibodies form insoluble im m une
com plexes in the form o f m icroprecipitates. Here belong drugs (penicillin, sulfa-
nilam ides), vaccines, food products (m ilk, eggs), inhaled allergens (dom estic dust,
fungi). In such cases IgG and IgM (with precipitate properties) are produced. Im ­
m une com plexes form m icroprecipitates in the tissues or in the blood and attach to
the basal m em branes.
Pathochemical Stage. U nder the effect o f im m une com plexes the following
m ediators are form ed — com plem ent, lysosomal factors o f leukocytes, kinins, su-
peroxide radicals.
Pathophysiological Stage. Im m une com plexes are usually attached to the basal
m em branes o f vessels. M icrocirculation is dam aged by BAS. An inflam m ation with
alteration, exudation and proliferation develops. Phagocytosis is activated. Leuko­
cytic infiltration results in allergic productive inflam m ation. Throm bosis occurs in
the vessels. Inflam m ation m ay lead to ulceration and hem orrhages.
Clinical manifestations depend on the place o f im m une com plex fixation and
the kind o f the dam aged tissue. If im m une com plexes are fixed in the vessels,
hem orrhagic vasculitis develops. In case o f th eir localization in the kidneys (basal
mem branes o f glom erules), acute glom erulonephritis develops (80 % o f all form s o f
glom erulonephritis). Allergic derm atitis is an exam ple o f im m une com plex allergy
on the skin. If m icroprecipitates are located in the lungs, alveolitis arises. Some
autoallergic diseases (rheum atoid arthritis, system ic lupus erythem atosus) as well as
dom estic and food allergies are o f this type. In case o f massive com plem ent activa­
tion anaphylactic shock and bronchial asthma may develop.

DELAYED ALLERGY

Delayed allergy develops in response to antigens, which are cells (foreign trans­
plant o r dam aged body’s ow n cells). These reactions are realized n o t by hum oral
antibodies, but by cellular im m une reactions.

t ransplant Rejection Reaction

Transplant rejection reaction is an exam ple o f delayed allergy.

Immunological stage begins with foreign cellular antigen recognition by T-
iM uphocytes, whose receptors include th e m ajor histocom patibility com plex an ti-
re n v A fter activation by the antigen, T -effectors transform into T -killers, w hich
have IgM as receptors. T hen lym phoid infiltration and a direct co n tact o f lym ­
phocytes with foreign cells take place. T -killers exert a cytotoxic effect on foreign
colls.
I*ui( I (к 'п с г и ! l ’atlio p liy sio ln j(y

Pathochemical stage consists in BAS liberation from activated I -lym phocytes

lym phokincs and perforin. They involve the entire organism into im m une response,
activate ;ill subpopulations o f lym phocytes, m icro- and m acrophages and initiate
the pathophysiological stage.
Pathophysiological stage consists in accum ulation o f m acrophages, granulocyte**
ami lym phocytes around the foreign tissue, its infiltration, derangem ent o f vessel
perm eability, developm ent o f edem a, inflam m ation and destruction o f the trails
plant

( ontact Dermatitis

C o n tact derm atitis also belongs to the delayed type o f allergy. It is a result ol
dei ina dam age after contacting everyday, industrial, m edical and other substances,
which play the role o f hapten and form com plex antigens w ith derm a proteins
M acrophages represent (by IL-1) the dam aged cells to T -helpers, which involve
I killers into skin damage.

AUTOALLERGY

Autoallergy is a damage o f body’s own proteins or cells by immune m echanism .

(autoimmune aggression).
A utoim m unization m ay be provided by various im m une m echanism s and re
laies both to im m ediate and delayed types o f allergy.

Etiology

I very protein, cell and tissue o f the organism may serve as an antigen (autoan
liy.ens, autoallergens) and may becom e an object o f autoim m une aggression.

Pathogenesis

I here are several pathogenic m echanism s o f autoim m unization.

• I oss o f physiological im m unological tolerance (underlies autoim m unization
u the m ajority o f cases). In its turn, this pathology m ay be genetically determ ined
Im m unodeficiency) and acquired. T-suppressor deficiency underlies the situation,
vhen intolerant B-lym phocytes produce antibodies against body’s own proteins.
• Sim ilarity between exogenous (m icrobial) and endogenous (own) antigens
• Inability o f the pathologically changed im m une system to distinguish foreign
intigens from body’s own ones, which m ay be sim ilar, but are nevertheless diflei
ni As a consequence, production o f autoantibodies against proper proteins ami
ells may be initiated.
• Im m unodeficiency (T -suppressor deficiency), genetic predisposition to 1ц1
ynlhesis contribute to the developm ent o f autoallergy
• Som atic m utations in im m unocom petent tissues may underlie the acquired
ypo ol autoallergy. M utant im m unocytes may perc eive HOI null tissues as antigen’*
 C h a p te r (>. A llerg y

• I )rugs may play the role o f haptens and form com plex antigens with b o d y ’s
own proteins. A utoantibodies belong to IgG and IgM and dam age cells by cy-
inly.is I killers are involved into cell dam age. T he factors o f physical nature
и old, high tem perature, ionizing radiation) are capable o f changing pro p er antigen
.mu lilies by disclosure o f hidden and form ation o f new antigenic determ inants.
\< iivated com plem ent, phagocytic enzym es and superoxide radicals are the m ain
m ed iators.
• I )amage o f specialized biological barriers creates a situation, w hen the tissues,
which arc located beyond, becom e an object o f autoim m une aggression (this situ a­
t i o n was discussed on p. 68).

M anifestations

A utoim m une diseases m anifest them selves depending on the protein or cells
dam aged by im m une aggression. An inflam m ation o f the native tissues develops
under an effect o f BAS.
A utoim m une aggression may concern any tissue, but most o f all the connective
и Iи* (basal m em branes, blood cells and joints). As clinical exam ples, glom erulone-
i»i11 ms, autoim m une version o f hem olytic anem ia, leukopenia and throm bocytope-
iii.i, allergic vasculitis, and rheum atoid arthritis m ust be noted. Im m unocom petent
i i- мu s ( I -lym phocytes, im m unoglobulins, lym ph nodes and b one m arrow) m ay
I- an object o f autoim m une aggression as well. F orm ation o f antibodies against
j*anmia globulin in patients with rheum atoid arthritis m ay also be m entioned as an
- чample. A utoim m une thyroiditis is an exam ple o f such pathology. C ardiopathy in
H iМЧlow’s disease is caused by anti-cardiac autoantibodies. D iabetes m ellitus o f the
in .1 type is referred to autoim m une diseases.
Л large group o f dem yelinating nervous system diseases (p. 521) are a u to ­
im mune (dissem inated sclerosis am ong them ). In postvaccinal and postinfectious
- if ■phalom yelitis im m unoglobulin, cellular and im m une com plex autoim m une re-
......... to C N S antigens (m yelin in particular) have been revealed. They are pro-
'••Ь «I by viral and bacterial infections in predisposed (to allergy) patients.
I hr pathogenesis o f m any autoim m unopathies is underlain by receptor d am -
4 " t receptor diseases have been m entioned on p. 91 — som e forms o f hyper- and

hvpolunction o f the thyroid gland, insulin resistant diabetes m ellitus, m egaloblastic

iiih nua. etc.).
A utoim m une pathology is m ore often observed in w om en, because the genes,
“ In. h control im m unocom petent tissue form ation, are located in the X -chrom o-
• ми» Since wom en have two X -chrom osom es, m utation o f these genes arises in
*oiiu*n m ore often than in men.

IN F E C T IO U S-A L L E R G IC D ISE A SE

Infectious-allergic d isease is such a d isease, w hose initial fa c to r is an infection,

Imii |uitlioKCiicsis includes allergic m echanism s in p atien ts with allergic predisposi­
tion,
a it I ( i f ii o r a I PallinphysioloKy

Etiology

Exogenous etiological factors are m icrobes with antigen determ inants sim ilar
> hum an. There are a lot o f such exam ples (som e m icrobes and connective tis-
u*. streptococcus and sarcolem m a o f cardiom yocytes, album ins o f cow ’s m ilk and
isylin, etc.). Due to parallel evolution, m any m icrobes have obtained m olecular
m ilarity with m olecules o f m acroorganism s.
More often this situation occurs if a-hem olytic streptococcus is the etiological
ii to r Its polysaccharide antigens are sim ilar to glycoproteids o f the connective tis-
le, cardiac valves, and basal m em branes (o f nephrons). Viruses may cause allergy
. well Fungi, which are present in the inhaled air, are widespread allergens. Vac-
nes (dead or attenuated m icroorganism s) may also be an initial factor.

P atho g en esis

U nder experim ental conditions it is possible to sensitize the organism by an

lections antigen introduced in a large dose overloading the im m une system. A
nilar situation may arise in patients with chronic infection w hen excessive infec-
>us antigens sensitize the organism.
Infectious-allergic diseases refer to autoallergy. Im m unodeficiency, genetic
(•disposition to IgE synthesis and adrenal cortex hypofunction predispose to the
velopm cnt o f this kind o f diseases. The pathologically changed im m une system
it always can differentiate antigens and targets for its action.
I here is a phenom enon o f antigen crossing and heteroallergy, when antibodies
iborated against one antigen (m ore often bacteria or th eir toxins) react with other
t sim ilar antigens (body’s own). It determ ines the autoreactive effect o f antibod-
produced for foreign antigens, activates autoreactive lym phocytes, stim ulates
lym phocyte response to autoantigens, provokes rheum atoid factors production,
oss antigen reactions may increase the concentration o f autoantigen up to the
el, which allows activation o f T -helpers and th eir affinity with antigen-presenting
lls,
Viruses may provoke cellular autoim m une response against C N S antigens in
disposed people. In virus-induced autoim m unopathy autoim m une response may
directed against the genom e o f the cells contacting with the virus. A utoantibodies
unst antiviral im m unoglobulins m ay determ ine th eir autoorientation.
In short, antigen sim ilarity between m icrobes and body’s own tissue m ay lead

• D im inished im m une response to infection.

• I ransition o f infection into the chronic form.
• -M istaken» recognition o f antigen by the im m une system.
• Initiation o f autoim m une reactions against body’s own tissue.
• Acute and chronic allergic inflam m ation.
 C h a p t e r (). Allergy

M anifestations

Such allergic diseases appear as a com plication o f the infectious ones. Clinical
m anifestations depend on the type o f tissue, w hich gets dam aged by autoim m une
aggression.
R heum atoid carditis, rheum atoid vasculitis and glom erulonephritis m ay arise as
a com plication o f p u rulent tonsillitis and scarlet fever caused by hem olytic strepto­
coccus. A utoim m une dam age o f the nervous system (both central and peripheral)
may develop in predisposed to allergy patients as a com plication o f viral infections
and vaccination (postvaccinal and postinfectious encephalom yelitis).

P R IN C IP L E S O F P R E V E N T IO N AND T R E A T M E N T O F ALLERGY. D E S E N S IT IZ A T IO N

The knowledge o f allergy etiology and pathogenesis provides the base for its
prevention and therapy.
Etiological therapy (prophylaxis) is prevention o f potential allergen entrance
into the organism.
Pathogenetic therapy is directed tow ard im m unological o r pathochem ical
m echanism s o f allergy. H orm onotherapy (injection o f im m unodepressants, gluco­
corticoids — hydrocortisone and prednisolone) blocks antibody and BAS form a­
tion and is used for (auto)im m une reaction depression. G lucocorticoids have an
anti-inflam m atory effect stim ulating lipocortin production in tissues - it suppresses
the activity o f phospholipase A ^ therefore prostaglandins and leukotrienes are not
formed.
BAS inhibitors are used to alleviate pathochem ical reactions (antihistam ine
drugs).
If a disease appears to be o f the infectious-allergic type and is accom panied by
inllam m ation, together with antibacterial drugs im m unodepressants are used.
Desensitization is divided into specific and nonspecific.
Specific desensitization is carried out w ith the aid o f the sam e allergen, which
has caused sensitization. F or this purpose the allergen is introduced in small fre-
<|uent doses. The effect is achieved by form ation o f sm aller portions o f im m une
*omplexes. U n d er these conditions the pow er o f BAS inhibitors proves to be suf­
ficient to alleviate pathochem ical and pathophysiological m anifestations. If after a
prophylactic injection o f an im m une serum its repeated injection is necessary, the
serum might be introduced by fractional sm all doses. T he same approach is used as
a sensitivity test before any serum usage.
Nonspecific desensitization is achieved by m edicines, w hich m inim ize the influ­
ence o f BAS.
Symptomatic therapy consists in the usage o f m edicines, which decrease such
sym ptom s as spasm, pain, itch, edem a.
Г.ill I (ic n c rill I'lltllophysloloK.y

PSEU DOALLERGY

I here are m any diseases with clinical sym ptom s sim ilar to the allergic ones
irtklening o f the skin, eruption, itch, dyspnea and the state sim ilar to anaphylactic
•.hock However, there are no im m unological m echanism s, which underlie any true
allergy,
Such diseases m ay be caused by the following external factors - cosm etic and
everyday substances, detergents, industrial products (rubber, glue, plastic, wood),
Inod (m ilk, eggs, berries, tom atoes, citrus fruits), pollen and m edicines.
Som etim es such m orbid co n d itio n s are interpreted as allergy, but it is true
only in the cases, w hen im m unological events are detected - participation o f T
lym phocytes, form ation o f antibodies, an increased level o f IgE, a decreased level
o f co m p lem en t, a possibility o f specific desensitization. V irtually, the m entioned
substances may behave as allergens (haptens) w ith com plex antigen form ation
with organism proteins. But in th e cases, w hen im m unological events are absent,
и is not an allergy. Such diseases m ust be interpreted as individual intolerance
to a substance (it is not a synonym o f allergy). T he term pseudoallergy»is suitable
and may be used.
U nderstanding o f this problem is im portant for the treatm ent and prophylaxis
ol Mich diseases. N one o f the m ethods m entioned above is effective — neither im
m unodepression nor specific desensitization by fractional repeated doses o f the
•..une substance. A single m easure is avoidance o f the substance causing the morbid
condition and sym ptom atic therapy.
Pseudoallergy has the following m echanism s o f pathogenesis.
• I hese substances m ay dam age tissues and activate the sam e BAS, w hich are
form ed in true allergy. They are called histamine liberators (cause degranulation
of mast cells). T he clinical m anifestations are sim ilar to the allergic ones.
* 11 factors, which cause a disease, are foodstuffs (m ore often these are exotic prod
nets), enzym opathy m ay underlie individual intolerance.
• II m edicines cause a disease, it is necessary to take into consideration that drug
m etabolism is individual and genetically determ ined. T he products o f drug me
labolism may be a reason for BAS form ation.
* Some patients have such derm al m ast cells, w hich are easily dam aged by natu
tal environm ental factors (sun rays, cold, clothes friction). Local sym ptom s are
sim ilar to allergic inflam m ation.

Q uestions for Self-C ontrol

I What is the co n n ectio n between im m unological reactivity and allergy?

What is com m on between im m unity and allergy?
I Why does allergy continue to expand in population?
•I Is a true allergic reaction possible in a healthy person?
V In what cases does antigen entry into a healthy organism cause not Im m unization
but sensibilization?
 C h a p te r ft. Allergy

f» C om pare im m unization and sensibilization.

7 W hat genetic reasons are responsible for predisposition to allergy?
Mow does the anaphylactic type o f allergy differ from the cytotoxic one?
W hat are allergic reactions o f th e stim ulating type?
10. W hat is the m echanism o f transplant rejection?
W hat are the pathogenetic m echanism s o f autoim m unization?
I) Why may an infectious agent cause the allergic process?
I l W hat organism cells and tissues m ay be an object o f autoim m une aggression?
II What are the principles o f allergy prophylaxis and treatm ent?
I v What is pseudoallergy?

T ests and Tasks for Self-C ontrol

(give correct answers and find m istakes in the statem ents)

1 Give the characteristics o f the 1st stage o f the im m ediate type o f allergy.
1. It is a pathochem ical stage.
2. It is a stage o f BAS form ation.
3. Sensibilization o f the organism is form ed during this stage.
4. O ne antibody m olecule is form ed on one m olecule o f the antigen.
5. This stage begins after the second dose o f the antigen.
6. It is finished after im m une com plex (antigen+ antibody) form ation.
7. Sensibilization o f the organism may be active only.
8. Sensibilization consists in distribution o f hum oral antibodies in the organ­
ism and th eir fixation on tissue basophils and other som atic cells.
9. The period o f antibody form ation is 3—5 days.
10. The period o f sensitization form ation is 1—2 weeks.

2 Give the characteristics o f autoallergy.

1. It is autoim m une aggression.
2. It is a loss o f physiological im m unological tolerance.
3. It is form ation o f antibodies against body’s own antigens.
4. Every body’s own dissolved protein, but not the cells, m ay becom e an
object o f autoim m une aggression.
5. It is always genetically determ ined.
6. M ay not be acquired.
Its pathogenetic mechanisms include:
7. D em asking o f body’s own antigens after a dam age o f the specialized his-
tohem atic barriers.
8. M utation o f im m unocytes.
9. D eficiency o f T-suppressors.
10. Drugs can n o t provoke autoallergy developm ent.

i I here are m any autoim m une (autoallergic) diseases. They are based on the loss
o f physiological im m unological tolerance and form ation o f antibodies against
body’s own tissues.
ini I ( . r m r a l I'lHliuplivM oloKv

Autoantibody formation is possible against body л own:

I cardiom yocytes,
2. hepatocytes;
3. pancreatic islands and (3-cells;
4. brain;
5. erythrocytes.
Autoantibody formation is impossible against body's own:
(>. y-globulin;
7. connective tissue;
S. lym phocytes;
9. horm ones;
10. collagen;
11. throm bocytes.

•I A 32-year-old w om an suffers from itch and burning sensation in the eyes,

lacrim ation, and nasal discharge. The sym ptom s appeared in sum m er aftei a
trip to the countryside. The diagnosis is pollinosis. W hat type o f allergy has
developed?
A. Anaphylactic.
B. Cytotoxic.
C. Im m une com plex.
I). D elayed-type hypersensitivity.
I Stim ulating.

' Before antitetanic serum injection a high sensitivity o f the patent to this serum
was discovered. W hat substance is used for specific desensibilization?
A. An allowed dose o f antitetanic serum .
B. G lucocorticoids.
С\ Small doses o f antitetanic serum.
I). A ntihistam ine drugs.
I Im m unodepressants.

() A patient had leukopenia after treatm ent with pyram idon. Antileukocytic
antibodies have been found. W hat type o f allergic response according to
( oom bs and G ell’s classification takes place in such a case?
A. Anaphylactic.
И Cytotoxic.
C. Stim ulating.
I) D elayed-type hypersensitivity.
I Im m une complex.

7, А И year old patient used eye drops with penicillin In a couple o f mi nut e*
skin Itch, edem a o f the lips and eyelids, cough appeared, arterial pressure began
to decrease What type o f im m unoglobulins lake pan m the developm ent <»|
this allergic response?
 C h a p t e r ft. ЛПсгку

A. IgE and IgG.

B. IgM and IgG.
C. IgA and IgM.
D. IgM and IgD.
E. IgG and IgD.

8. A 14-year-old girl with congenital heart and thyroid gland defects suffers from
viral and fungal diseases. Im m unological investigation revealed T -lym phocytes
decrease. W hat disease o f the im m une system arises in such a case?
A. C om bined im m unodeficiency.
B. B ru to n ’s agam m aglobulinem ia.
C. Hypoplasia o f the thym us gland.
D. T u rn er’s syndrom e.
E. Inherited com plem ent deficiency.

9. A 7-year-old boy, like his grandfather, suffers from pneum onias and purulent
skin diseases. Significant decrease o f B-lym phocytes num ber has been revealed.
W hat type o f im m unological pathology takes place?
A. Inherited deficiency o f the com plem ent system.
B. H ypoplasia o f the thym us gland.
C. C om bined im m unodeficiency.
D. T u rn er’s syndrom e.
E. B ruton’s agam m aglobulinem ia.

10. An injection o f a large dose o f antibodies against the basal m em brane o f the
renal glom eruli o f an experim ental anim al leads to acute glom erulonephritis
developm ent. W hat type o f allergic response according to C oom bs and C e ll’s
classification provokes this pathology?
A. Anaphylactic.
B. Cytotoxic.
C. Im m une com plex.
D. D elayed-type hypersensitivity.
E. Stim ulating.

11. A patient with proteinuria, hem aturia, edem as and arterial hypertension was di
agnosed with acute glom erulonephritis. W hat type o f allergic response accord
ing to C oom bs and G ell’s classification is the cause o f a glom erulonephritis in
80 % o f cases?
A. A naphylactic.
B. Cytotoxic.
C. Im m une com plex.
D. D elayed-type hypersensitivity.
E. Stim ulating.
Pan I (intend Г)1 (||0 |)||уч|0 |»К.У

12 Allergic diseases are widespread am ong people .md Ihen num ber is constanllv
increasing. A physician must know that there h illeiHie predisposition, which
is determ ined genetically.
1. Allergic predisposition is inherited as a dom inate type.
2. Allergic predisposition is inherited as a polygenetic type.
The mechanisms o f allergic predisposition m ay he the following:
3 I im m unodeficiency.
4. Increased perm eability o f the m ucous m em branes for foreign proteins.
5. Surplus o f T-suppressors.
6 I suppressors deficit.
7. Predisposition to IgE production.
К Deficiency o f BAS inhibitors production.
9. Adrenal cortex hyperfunction and surplus o f glucocorticoids production.

I V I very physician m eets in his m edical practice a lot o f patients with allergic
diseases. W hat are the m ethods o f th eir prevention and treatm ent?
1. Isolation o f the organism from potential allergens is the best prophylactic
measure.
Use o f remedies with the following effect:
2. BAS inactivators, w hich block the first stage o f allergy.
3. Im m unodepressants, w hich block th e second stage o f allergy.
4. Drugs with antihistam inic effect.
5. Stim ulators o f T -lym phocyte production (im m unom odulators).
Glucocorticoids, which are commonly used to treat such patients,
have the following effects:
6. Inhibition o f antibody production.
7. Protection o f target cells from the effect o f BAS.

I I C om pare im m unity and allergy. Find points o f com parison reflecting com m on
features and differences. C om pile a com parison table.

Comparison o f Im m unity and Allergy

Points of Comparison Immunity Allergy
1.
2.
i ommon features
3.

1.
2.
Differences
3.
 TYPICAL PATHOLOGICAL PROCESSES

Typical pathological processes are those, w hich have com m on features and
laws o f developm ent regardless o f the localization, nature o f th e causative factor
and organism evolutionary organization. T he following processes refer to them
inicrocirculation disorders, inflam m ation, fever, neoplasia, hypoxia, and starvation
i\s well as typical pathology o f m etabolism .

( hapter 7
PATHOPHYSIOLOGY OF PERIPHERAL BLOOD
CIRCULATION

Peripheral blood circulation (in arterioles, precapillaries, capillaries, postcapil-

lary venules and sm all veins, arteriovenous anastam oses) provides balance o f nu tri­
ent substrates, gases, m etabolites, electrolytes and w ater in the system blood-tissue-
Hlood.
Typical local m icrocirculation disorders are arterial and venous hyperem ia,
ischemia, stasis, throm bosis, and em bolism.

ARTERIAL H Y PE R E M IA

The term hyperemia m eans an increased blood volum e in a tissue or an organ.

Arterial hyperemia is an active increase o f organ or tissue blood filling due to
rvcessive blood inflow by arterial vessels.
Active hyperem ia occurs w hen artery dilatation results in increased inflow o f
the blood into capillary beds with opening inactive capillaries. It is caused by neu­
rogenic m echanism s o r vasoactive substances.
Types. Arterial hyperem ia is divided into physiological (working) and pathologi­
st! In its turn, pathological arterial hyperem ia is subdivided into neurogenic and
metabolic. In its tu rn , neurogenic arterial hyperem ia is subdivided into neurotonic
hhI neuroparalytic.
Etiology. Etiological factors are physical (m echanical, heat, ultraviolet radia
non), chemical an d biological (infectious, im m une, em otional), w hich lead to arte
Hal vessel dilatation.
Pathogenesis. Neurotonic arterial hyperemia develops due to neurotonic m ech­
anism activation. C laude Bernard was the first to reproduce it by stim ulation o f the
• horda tym pani (a b ranch o f the facial nerve), containing parasym pathetic vasodi
luting libers (fig. 8).
In the vessels, w hich have no parasym pathetic stim ulation, hyperem ia is caused
hv the sym pathetic system (cholinergic, histam inergic and p-adrenergic m edia
nisms). Sym pathetic cholinergic nerves dilate the small arteries and arterioles o f the
keletal muscles, facial muscles, m ucosa o f the cheeks and intestine. Acetylcholine
I’h i I I I’ltllio p h v slo lo g y

is a m ediator. A clinical example o f neurotonic hypeienua is reddening and sensa­

tion o f heat in the skin in the region o f neuralgia.
Neuroparalytic arterial hyperemia may be m odeled in experim ental anim als by
rutting o f I lie vasoconstrictive fibers and nerves (sym pathetic a-adrenergic ones).
N orepinephrine is a m ediator. C laude Bernard observed hyperem ia and hyper-
ihorm ia ol the skin o n a rabbit’s head (ear) on the side o f the removed cervical
node o f the sym pathetic trunk (ganglionary sym pathectom y). T heir m ediator is
norepinephrine.
Metabolic arterial hyperemia is caused by BAS o f different origin (cellular and
plasm atic). ATP, A D P , adenosine, nonorganic ions, p 0 2 reduction and p C 0 2 in-
cicasc in the blood and tissues have the sam e effect. In som e cases prostaglandins
I and A, which have a vasodilative effect on arterioles, m etarterioles, precapillaries
and venules, cause hyperem ia.
M anifestations. Arterial hyperem ia m anifestations are m orphological (m icro­
scop ical), biochem ical (m etabolic), functional, and clinical. T he hydrodynam ic
pressure in arterioles, capillaries and veins is increased (fig. 9). Arterial hyperem ia
is always accom panied by swelling (tum or), but never edem a.
T he following visible clinical signs m anifest arterial hyperem ia:
• redness o f the affected part;
• enlargem ent o f an organ or tissue due to swelling (tum or);
• increased tissue turgor;
• local hypertherm ia.
Subjective unpleasant sensations are:
• pulsation;
• swelling;
• pain.

Fig. 8. C laude B ernard’s experim ent (on the right -

the cervical node o f the sym pathetic tru n k has
been rem oved)
Fig. 9. Blood pressure dynam ics in different parts
o f the vascular bed in the norm al state an d in arte­
rial hyperem ia
 C h a p te r 7. P a th o p h y s io lo g y o f I V r lp l u t ii t H lood C ir c u la tio n

The microscopic picture is characterized by:

• dilatation o f sm all arteries, arterioles, veins, capillaries;
• increased n u m b er o f functioning vessels;
• blood flow acceleration;
• opening o f inactive capillaries;
• division o f blood flow into two parts — central flow o f the blood cells and
peripheral flow o f the plasma.
Metabolism intensifies locally due to increased supply o f oxygen and sub­
strates.

Significance

In the m ajority o f cases arterial hyperem ia is accom panied by intensification of

m etabolism and organ functioning. However, unfavorable outcom e is also possible.
Thus, sclerotic vessel dilatation m ay result in rapture and hem orrhage. It is espe­
cially dangerous in the brain (see hem orrhage stroke, p. 517). A rterial hyperem ia is
o f great significance in the course o f inflam m ation.

V E N O U S H Y PE R E M IA

Venous hyperemia is an increase o f organ or tissue blood filling due to limitation

of blood outflow by venous vessels.
C ontrary to arterial hyperem ia, w hich is active, venous hyperem ia (congestion
or passive hyperem ia) results from im paired venous drainage.

Etiology

Etiological factors o f venous hyperem ia are those, w hich narrow the lum en or
decrease the tonus o f veins. T hey m ay be exogenous and endogenous. They are:
• obstruction o f veins with a throm bus or an em bolus;
• com pression o f veins by a tum or, enlarged internal organ (for exam ple, uterus),
exudate in the region o f inflam m ation;
• com pression o f veins by exudative pleuritis, hem othorax, pneum osclerosis, em ­
physem a;
• cardiac left- o r right-ventricular failure;
• professional overloading (m aintaining vertical position for a long tim e);
• genetic predisposition to venous congestion (weakness o f the venous elastic ap ­
paratus, low to n u s o f the sm ooth m uscle elem ents o f the vascular wall).

Pathogenesis

T he disorders are caused by a local lack o f oxygen (hem oglobin deoxygenation,

tissue hypoxia) and substrates. It leads to tissue disbolism. As a result, atrophic and
dystrophic changes develop.
Blood viscosity increases as well as perm eability o f capillaries. Transudate is
form ed due to high hydrostatic blood pressure. C ongestion in the capillary bed is
1*1111 I (it'iicn tl P ltlllop llvM olojy

closely related to edem a developm ent. Therefore, congestion and edem a com m only
o ccur together (venous edema). C ongestion leads to introvascular throm bosis.
Prolonged venous congestion results in the excessive growth o f the connective
tissue, which substitutes the parenchym a (so-called cirrhosis).

M anifestations

Venous hyperem ia m anifestations are m orphological (m icroscopical), bio­

chem ical (m etabolic), functional, and clinical.
T he following visible clinical signs m anifest venous hyperem ia:
• enlargem ent o f organs or tissues due to swelling (tum or);
• cyanosis as a result o f hypoxia and accum ulation o f non-oxygenated h em o ­
globin;
• edem a caused by high hydrostatic pressure and increasing perm eability of
vessel walls due to non-oxygenated condition;
• local hypotherm ia;
• subjective unpleasant sensations o f swelling and pain.
The microscopic picture is characterized by:
• dilatation o f small arteries, arterioles, veins, capillaries;
• blood flow deceleration due to increased blood viscosity;
• transudate form ation;
• throm bosis;
• atrophic and dystrophic changes in the tissue;
• excessive growth o f the connective tissue;
• sclerosis.
Metabolic disorders in venous hyperem ia develop as a result o f local circulatory
and tissue hypoxia. Interm ediate products o f incom plete oxygenation are accum u-
l.ilcd. Local m etabolic acidosis develops.

Significance

In most cases venous hyperem ia has a negative effect. It leads to tissue dis-
holism and causes atrophic and dystrophic changes. Organ functioning is disordered
due to hypoxia, dystrophy, and cirrhosis.
However, during inflam m ation venous hyperem ia is o f great significance pro ­
viding leukocyte em igration (see ch ap ter 8 «Inflam m ation», p. 125).

ISC H E M IA

Ischemia is a decrease o f organ or tissue blood filling due to limitation or com ­

plete slop of arterial blood inflow.
Types

Ischem ia is divided into com pressive, obstructive and angiospastic. Every type
ol im henna lias its own etiology and pathogenesis.
 C h a p te r 7 . P athophysiology o f P e rip h era l Blood C ircu la tio n

Compressive ischemia is a result o f m echanical influence on arteries (tum or,

foreign body, ligature, etc.).
Obstructive ischemia is a result o f vessel lum en narrow ing by a throm bus, an
em bolus o r atherosclerotic process.
Angiospastic ischemia is a functional disorder, which consists in derangem ent of
the m o to r (vasoconstrictive) apparatus o f the vessels.

Etiology

Various agents can cause ischem ia. Angiospastic ischem ia develops as a re­
sult o f stim ulation o f the vasoconstrictor apparatus o f vessels o r their reflex spasm
caused by: a) physical factors (cold, m echanical and o th er injuries); b) chemical
agents; c) biological factors (bacterial toxins); d) emotional factors (fear, pain, rage)
and pathologic reflexes.
The duration and consequences o f ischem ia depend on such conditions, which
can m odify the effect o f etiological factors: a) tim e o f harm ful effect; b) type of
ischem ia; c) localization; d) condition o f collateral circulation; e) functional state
o f the organ or tissue.
Pathogenesis

T he m echanism o f angiospastic ischem ia depends on the perm eability o f sm ooth

muscle cell m em branes for N a +, C a2+, K+ and Cl" ions. N eurogenous a-adrenergic,
histam inergic, serotoninergic, dopam inergic m echanism s also m atter. A ngiotensin
II is on e o f the m ost potent vasoconstrictors. It effects sm ooth m uscle cells directly
causing depolarization as a result o f increased N a+ perm eability. W hen N a+ ions
accum ulate in the m uscle fibers o f vessels, th eir sensitivity to vasoconstrictors (cate­
cholam ines, vasopressin and angiotensin) increases.
E ndothelium injury results in its inability to produce relaxing factors (N O ).
This leads to spastic reactions.
Angiospastic ischem ia m ay have a conditioned reflex nature.
Ischem ia leads to oxygen deficiency (hypoxia).

M anifestations

Local visible m anifestations o f ischem ia are:

• paleness o f the ischem ic region;
• dim inution in the organ’s size;
• local hypotherm ia;
• organ o r tissue dysfunction.
The microscopic picture shows:
• blood flow deceleration;
• dystrophic tissue changes;
• necrosis (infarction).
Ischem ia produces certain bad subjective sensations. They are:
• pain (ischem ic pain is very strong);
• paresthesia (sensitivity disorder, tingling);
’nit I (iiM im il riillio p liv sio lo gv

•organ function failure.

I lie gravest outcom e o f ischem ia is necrosis (infarction is a synonym ). It is
isually caused by vessel occlusion.

Significance

( icnerally, angiospasm is a nonspecific short-term reaction o f vessels to differ-

- nl injuring factors. Prolonged ischem ia has a negative effect. Ischem ia o f the brain
uul heart has severe clinical consequences. T he skeletal m uscles and especially the
m nnectiv e tissue are m ore resistant to ischem ia due to th eir high anaerobic m e-
hibolism.
ST A SIS

Stasis is deceleration or com plete stop o f blood flow in capillaries, small arteries
and veins.
I he following types o f stasis are distinguished: true (capillary), ischemic (co m ­
plete stop o f blood inflow), and venous.

True Stasis

I rue stasis develops as a result o f pathological changes in capillaries o r ab­

norm ality o f rheological properties o f the blood. In capillaries and small veins the
blood becom es stagnant and hom ogenized. Erythrocytes swell and lose m ost of
i Ihmi pigm ent. Together with the released hem oglobin, the plasm a escapes from the
vessel. In the focus o f stasis the tissues show signs o f dystrophy.
I ’tiology. Etiological factors o f true stasis are physical (cold, burn), chemical
(poisons, turpentine, m ustard oil), and biological (m icrobial toxins).
Pathogenesis. The m echanism o f true stasis developm ent is based on the intra-
vaseular aggregation o f erythrocytes (adherence) and form ation o f conglom erates,
which ham per blood flow. It also causes an increase o f peripheral resistance.
Iry th ro cy tes aggregate as a result o f alteration o f the physical properties of
»ryihrocyte plasm olem m a under the direct effect o f the factors entering the capil-
l.iry Hie surface o f erythrocytes, w hich is sm ooth under norm al conditions, be­
com es furry. Erythrocytes aggregate as a result.
A significant role in true stasis pathogenesis belongs to hem oconcentration
.uul increased perm eability o f the capillary walls. T he etiological factor itself and
m etabolites, produced in tissues, prom ote it. An im portant role in stasis genesis b e­
l o n g s to HAS (serotonin, bradykinin, histam ine), local acidosis and changes in the
colloidal state o f the blood. It results in increased vessel perm eability and dilatation
leading to hcm ocoagulation, blood flow deceleration, erythrocyte aggregation and,
consequently, to stasis. It should be noted that stasis alone does not induce th ro m ­
bosis Stasis o f poorly oxygenated blood causes chronic local tissue hypoxia.
Significance. In most cases true stasis has a negative elleet Organ functioning is
Im paired due lo dystrophic changes. However, during inflam m alion. siasis provides
leukocyte em igration (see chapter N «Inflam m ation*, p I 'M
 C h a p t e r 7. P athophysiology of P e rip h era l Blood C ircu la tio n

Ischem ic and Venous Stasis

Ischem ic and venous stasis is a consequence o f blood flow deceleration and

arrest. These conditions are caused by the sam e factors as venous hyperem ia and
ischem ia. Ischem ic stasis is a consequence o f artery spasm, com pression o r occlu ­
sion. Venous stasis is a result o f vein com pression or occlusion with a throm bus
or an em bolus. E lim ination o f the cause leads to restoration o f norm al circulation.
However, the progress o f ischem ic and venous stasis prom otes the developm ent o f
true stasis.
T H R O M B O S IS

Thrombosis is lifetime formation o f a m ass containing blood elem ents (cells and
coagulated proteins) on the internal surface o f vessels.
T he final mass is term ed thrombus.
D epending on the com ponents, throm bi can be white (form ed o f platelets,
leukocytes and a sm all am ount o f plasm a proteins), red (contain erythrocytes), and
mixed (have alternating white and red layers).

Etiology

T he conditions, w hich predispose to throm bosis, are know n as V irchow ’s tri­

ad:
1. Injury o f th e vessel wall (endothelium ).
2. Im balance betw een coagulative, anticoagulative and fibrinolytic blood sys­
tem s (hypercoagulability).
3. Blood flow deceleration.
It explains why throm bosis o f veins occurs m ore often than that o f arteries.
All the factors creating these conditions are etiological factors o f throm bosis.
They are exogenous and endogenous. T he exogenous ones are physical (traum a,
electric current), chemical (tobacco sm oking, side effects o f som e drugs) and bio­
logical (infectious, im m une) agents, which dam age the blood vessels o r change the
rheological properties o f the blood. Atherosclerosis, arterial hypertension and al­
lergy m ay cause an injury o f the vessel wall and predispose to throm bosis. Diabetes
m ellitus and obesity change coagulation and predispose to throm bosis (see schem e
13, p. 230).

Pathogenesis

T he course o f throm bosis can be divided into two stages:

(1) cellular (reaction o f platelets);
(2) plasm atic (coagulative).
Cellular Stage. T his stage o f throm bogenesis begins after 2—3 m inutes from
the m om ent o f vessel injury and consists in platelet adherence (adhesion) on the
endothelium . It results from the changes o f both the vascular wall (its potential,
decrease o f prostacycline production) and platelets (which release throm boxane
I'.и I I (.e iie n il I'udm phvslolo^y

(P G ). Platelet adhesion is followed by th eir aggiegni Ion I'hen platelet destruction

follows.
I here are various platelet-aggregating stim ulators (throm bin, serotonin, epi­
nephrine, norepinephrine, P G D 2, P G H 2, PG 1,-prostacyclin). A shift o f the
AI P/A D P ratio to the A D P content provides platelet adherence and aggregation.
Aggregated platelets lose th eir internal structure and release granules rich in a
variety o f products.
Plasmatic Stage. Substances, derived from activated platelets, prom ote coagu­
lation. F orm ation o f BAS and various coagulation factors triggers the coagulative
system o f the blood and begins the second stage o f throm bosis. Fibrin is form ed,
constituting the strom a o f throm bi, which contain (besides throm bocytes) a small
am ount o f erythrocytes.
A throm bus m akes blood circulation difficult. It dim inishes or obstructs vascu­
lar How, causing an ischem ic injury o f tissue, and m ay give rise to em bolism .
In the course o f tim e a throm bus may be changed by: a) aseptic (enzym atic,
fibrinolytic) lysis; b) organization and substitution by the connective tissue; c) re-
canalization; d) septic (purulent) disintegration.
T he septic outcom e is especially dangerous because it m ay cause septicopyem ia
and num erous abscesses in various organs. N ecrosis developm ent (infarction, gan­
grene) is possible at the term inal stage o f throm bosis.
A throm bus m ust be differentiated from a blood clot. The latter is form ed by
i o a g illation o f extravasal blood. T hrom bi, on the contrary, are form ed intravascu-
larly in the circulation (on the internal surface o f vessels).
I hose throm bi, w hich are form ed in the rapidly m oving arterial circulation, are
com posed predom inantly o f fibrin and platelets w ith only a few trapped red cells.
I luis, a throm bus bears a little resem blance to a blood clot. However, in a very
sluggish venous flow throm bi may closely resem ble blood clots.

Significance

I hrom bosis is created in the process o f evolution as a defense reaction arresting

bleeding and blood loss after m echanical traum as and vessel ruptures.
In o th er cases throm bosis plays a negative role if it causes ischemia.
Infarction is an area o f ischem ic tissue necrosis and is the gravest outcom e of
ihm m bosis. Infarction o f the heart, lung and brain collectively account for more
deaths than all forms o f cancer and infections diseases taken together. It is usually
caused by throm botic (o r throm boem bolic) occlusion o f vessels.
I hrom bosis o f veins has a chronic course causing venous congestion and in ­
flam m ation (throm bophlebitis).

E M B O L IS M

I niholisni is formalion and carrying along the blood How o f a mass, which is not
typical of normal hlood com position.

112
 C h a p te r 7. P a t h o p h y s i o l o g y o f P e r i p h e r a l B lood C i r c u l a t i o n

This mass is called embolus. The blood carries it to a site distant from its point
o f origin.
An em bolus m ay be solid, liquid o r gaseous.
A bout 99 % o f all em boli originate from throm bi. Indeed, throm bosis and em
holism are closely interrelated (throm boem bolism ).
Rare forms o f em boli are: a) foreign bodies such as bullets; b) droplets o f fat
(in case o f bone fracture); c) bits o f tum or; d) fragm ents o f bones or bone m arrow:
e) bubbles o f air (gas em bolism in caisson disease, p. 36), nitrogen or an o th er gas.
Inevitably, em boli get stuck in vessels too small to perm it th eir further passage.
It results in com plete vessel occlusion. Emboli m ay slow dow n and stop anywhere
within the cardiovascular system producing different clinical effects.
Significance. Em bolism always has a negative effect. T oday throm boem bolism
and infarctions constitute the m ain clinical problem s. Throm boem bolism o f the
pulm onary artery (the clinical picture: dyspnea, acute pain in th e chest, cyanosis,
swelling o f the cervical veins) is a frequent cause o f death in hospitalized patients.
Heart disease (m yocardial infarction, rheum atic heart disease, arrhythm ia) increase
the risk o f em bolism.

Q uestions for Self-C ontrol

1. W hat types o f peripheral blood circulation disorders do you know?

2. G ive correct definitions o f every type o f peripheral blood circulation
disorders.
У W hat is com m on between arterial and venous hyperem ia?
4. W hat is the difference betw een arterial and venous hyperem ia?
5. W hat is the difference in the m icroscopic picture o f arterial and venous
hyperem ia?
(>. W hat pathogenetic variants o f arterial hyperem ia do you know?
7. Give examples o f a negative effect o f arterial hyperem ia.
S. Give examples o f a positive effect o f venous hyperem ia.
l). W hat is the pathogenesis o f venous edem a?
10. W hat pathogenetic variants o f ischem ia do you know?
11. W hat is Virchow ’s triad?
12. Give the characteristics o f the double m eaning o f throm bosis.
13. Give the characteristics o f the cellular stage o f throm bosis.
14. W hat is the role o f prostaglandins in throm bosis?
15. W hat is throm boem bolism ?
К». Why is pulm onary artery em bolism life-threatening?

T ests and Tasks for Self-Control

(give correct answers and find mistakes in the statem ents)

I A 38-year-old m an com plains o f pain in the heart, which arises after negative
em otions. A d o cto r diagnosed ischem ic illness (stenocardia). What m echanism
o f ischem ia is the most probable?
P a ri I. ( t e n e r u l P a t h o p h y s i o l o g y

Л. A ngiospastic.
B. Obturative.
C. Compressive.
I). M echanical.
E. Occlusive.

2. Л p atient with a closed fracture o f the hum eral bone had a plaster bandage
applied. The next day the hand swelled, becam e cyanotic and cold. W hat kind
o f pathology o f peripheral circulation took place?
A. G as em bolism.
B. Air em bolism.
C. Ischemia.
D. Venous hyperem ia.
E. Arterial hyperem ia.

After exercising a patient with throm bophlebitis o f the lower extrem ities has
dyspnea, acute pain in the chest, cyanosis, swelling o f the cervical veins. W hat
kind o f circulation pathology took place?
A. Throm boem bolism o f the m esenteric vessels.
B. T hrom boem bolism o f the coronary vessels.
C. T hrom boem bolism o f the brain vessels.
1). Throm boem bolism o f the pulm onary artery.
E. Throm boem bolism o f the v. porta.

4. A patient with obliterating endarteritis had ganglionary sym pathectom y per­

formed. T he positive m edical effect o f this operation is connected w ith arterial
hyperem ia developm ent. W hat type o f hyperem ia is it?
A. Reactive.
B. N eurotonic.
C. M etabolic.
D. Working.
E. N europaralytic.

5. A small N aC l crystal was placed near the m esenteric vein o f a frog during an
experim ent. This operation leaded to the form ation o f a blood clot. W hat is the
initial point in throm bogenesis?
A. Blood flow deceleration.
B. Activation o f coagulation.
( ’. A ctivation o f throm bocyte adhesion.
I). D am age o f the vascular wall.
I D ecreased activity o f anticoagulants.

(>. I inbolism o f the small circle o f circulation occurred «Пег a fem ur fracture.
What kind o f em bolism took place?
A. I at.
И I h m m bonnbolism
 С h iip lc i / P a t h o p h ysio lo g y o f P e r i p h e r a l Hlood C i r c u l a t i o n

C. Cellular.
D. Gas.
E. Air.

7. A 27-year-old w om an with neuralgia com plains o f reddening in the right

part o f the face and neck, derm al hypersensitivity and pain in the region of
n. trigem ini. W hat kind o f arterial hyperem ia explains these sym ptom s?
A. M etabolic.
B. N europaralytic.
C. N eurotonic.
D. W orking.
E. Reactive.

К Explain arterial hyperem ia pathogenesis.

1. N eurotonic arterial hyperem ia develops due to activation o f neurotonic
parasym pathetic vasodilative m echanism s.
2. A TP, A D P, adenosine, nonorganic ions, reduction o f p 0 2 and increase o f
p C 0 2 in the blood and tissues cause neurotonic arterial hyperem ia.
3. N orepinephrine is a m ediator o f neurotonic arterial hyperem ia.
4. A cetylcholine is a m ediator o f neuroparalytic arterial hyperem ia.
5. M etabolic arterial hyperem ia is caused by BAS o f different origin (cellular
and plasm atic).
6. Claude B ernard observed neurotonic arterial hyperem ia and hypertherm ia
o f the skin o n the rabbit’s head (ear) o n the side w here the cervical node
o f the sym pathetic trunk is cut (ganglionary sym pathectom y).
7. C laude Bernard reproduced neuroparalytic arterial hyperem ia stim ulating
the chorda tym pani (a branch o f the facial nerve), w hich contains para­
sym pathetic vasodilating fibers.

Give the characteristics o f arterial hyperem ia m anifestations.

The microscopic picture is characterized by:
1. D ilatation o f small arteries, arterioles, veins, capillaries.
2. Decreased blood flow rate.
3. C losure o f inactive capillaries.
4. Division o f blood flow into tw o parts — central flow o f the blood cells and
peripheral flow o f the plasma.
The clinical signs are:
5. Redness o f th e affected part.
6. Enlargem ent o f an organ or tissue due to swelling.
7. Local hypotherm ia.
8. Painlessness.
9. It is accom panied with edem a because the hydrodynam ic pressure in arte
rioles, capillaries and veins gets increased.

10 W hat is the significance o f arterial hyperem ia?

I. In the m ajority o f cases arterial hyperem ia is accom panied with intensifi
cation o f m etabolism and organ functioning.
I'.ill I, ( i n i r n i l I *i«l li«»|iliysiol<»KV

2. Its role is always positive.

3. Unfavorable outcom e o f arterial hyperem ia is not possible.
4. Arterial hyperem ia is o f great significance in the course o f inflam m ation.
5. D ilation o f sclerotic vessels can result in rapture and hem orrhage.
(>. It is especially useful in the brain.

11 ( iive the characteristics o f venous hyperem ia.

1. It is an increase o f organ o r tissue blood filling due to lim itation o f venous
outflow.
2. C ontrary to arterial hyperem ia, w hich is passive, venous hyperem ia is ac­
tive and is a result o f im paired venous drainage.
Causes o f venous hyperemia:
3. I’hey narrow the lum en or decrease the tone o f veins.
4. O bstruction o f veins with a throm bus o r an em bolus.
5. C om pression o f veins w ith a tum or, inflam m atory exudate.
6. C ardiac failure.
7. Professional overload (staying in a vertical position for a long tim e).
X. G enetic predisposition to venous congestion (lack o f elasticity o f veins,
high tone o f the sm ooth m uscle elem ents o f the vascular wall).

12 ( iive the characteristics o f venous hyperem ia m anifestations.

1. M etabolic disorders develop due to tissue hypoxia.
2. Viscosity o f the blood is increased.
The microscopic picture is characterized by:
3. D ilatation o f small arteries, arterioles, veins, capillaries.
4. Blood flow acceleration.
5. Thrombosis developm ent.
(>. Excessive growth o f the connective tissue.
The clinical signs o f venous hyperemia:
7 Enlargem ent o f an organ or tissue due to swelling.
К Redness due to dilatation o f small arteries, arterioles, veins, capillaries.

I V Explain ischem ia pathogenesis.

I . Сienerally, angiospasm is a nonspecific short-term reaction o f vessels to
different injuring factors.
2 rhe m echanism o f angiospastic ischem ia depends on the perm eability of
the sm ooth muscle cell m em branes for N a+, C a2+, K" and Cl" ions.
3. N eurogenous a-adrenergic, H -histam inergic, serotoninergic, dopam inei
gic m echanism s play a role.
4 When N a' ions accum ulate in the m uscle fibers o f vessels, th eir sensl*
tivity to vasoconstrictors (catecholam ines, vasopressin and angiotensin)
decreases.
5 Angiotensin II is one o f the most potent vasodilator.
() Angiotensin II elTects the sm ooth m uscle cell m em brane directly causing
depolarization as a result o f increased Na p» rnn ability.
____ ______________________________ C h a p te r 7. P athophysiology o f P e rip h e ra l Blood Circulation

7. Injury o f the endothelium results in the activation o f its ability to produce

relaxation factors (N O ). It leads to spastic reactions.
8. Angiospastic ischem ia m ay have a conditioned reflex nature.

14. Give the characteristics o f ischem ia m anifestations.

The microscopic picture is:
1. Blood flow acceleration.
2. Necrosis.
The clinical manifestations:
3. C yanosis o f the ischem ic region.
4. D im inishing o f the organ size.
5. Local hypertherm ia.
6. Infarction is usually caused by venous vessel occlusion.
The patient feels:
7. Pain (ischem ic pain is very strong).
8. Organ dysfunction.

15. G ive the definition and characteristics o f throm bosis.

1. Throm bosis is form ation o f a mass, which consists o f blood elem ents (cells
and coagulated proteins).
2. It may cause arterial hyperem ia.
3. It m ay cause ischem ic tissue injury.
4. It may give rise to em bolism.
5. T hrom bosis always plays a negative role.
6. Throm bosis o f arteries occurs m ore often than that o f veins.
7. C onditions, w hich predispose to throm bosis, are known as Virchow’s tri­
ad.
16. Explain throm bosis pathogenesis.
1. The process o f throm bosis is divided into three stages.
2. T he first stage is coagulative.
3. T he second stage is platelet reaction.
4. T he cellular stage is distinguished.
5. T he plasm atic stage is distinguished.
6. T hrom bosis starts in 2—3 m inutes after the m om ent o f vessel injury.
7. A dam aged vascular wall releases throm boxane (P G ).

17. G ive the characteristics o f the first stage o f throm bosis.

1. It is a reaction o f platelets.
2. It is the plasm atic stage o f throm bosis.
3. It is a result o f changes both in the vascular wall (its potential) and plate­
lets.
4. Shift o f the A T P /A D P ratio to the A TP content provides adherence and
aggregation o f platelets.
5. Platelets arc destroyed after aggregation.
6. D am aged platelets release throm boxane (P G ).
7 I he dam aged vaseiilai wall releases PG prostacyclin
h u t I ( i r i i m i l Pathophysiology

IS Explain the participation o f platelets in throm bosis,

1. They participate in the first stage.
2. They participate in the cellular stage.
3. They react to vessel injury in 2—3 minutes.
4. After vessel injury, at first platelet aggregation occurs, then th eir adher­
ence (adhesion) on the endothelium .
5. Aggregated platelets lose th eir internal structure and release granules rich
in a variety o f products.
After their damage:
6. Platelets release throm boxane (P G ).
7. Platelets release P G -prostacyclin.
8. T he substances derived from activated platelets start the second stage of
throm bosis.

I(J Explain the participation o f the endothelium in throm bosis.

1. It participates in the first stage.
2. It participates in the cellular stage.
3. It participates only in the plasm atic stage.
4. It reacts to vessel injury in 2—3 m inutes.
After its damage:
5 It releases throm boxane (P G ).
6. It releases PG -prostacyclin.
7 It stops producing P G -prostacyclin.

20. ( ilobal warm ing prom otes exacerbation o f som e diseases. W hen air tem perature
was 34°C, a 42-year-old healthy patient had a heat stroke. His body tem pera­
ture is 39°C, consciousness is dim m ed, the face is red, respiration is labored.
T he reason is arterial hyperem ia o f the brain. Give th e characteristics o f arterial
hyperem ia, which developed in this case.
1. The term hyperem ia m eans increased blood volum e in the affected tissue
o r organ.
2. Arterial hyperem ia o f the brain developed due to increased arterial in­
flow.
3. As to pathogenesis, it is working.
4. It is characterized by local hypotherm ia.
5. It is always accom panied with organ swelling.
6. Pulsation is unpleasant subjective sensation.
7. It is always accom panied with brain edem a.
8. Arterial hyperem ia is especially useful for the brain.
The microscopic picture is characterized by:
9. Hlood flow acceleration.
10. Opening o f inactive capillaries.

I A 4 V year old patient suffers from ischem ic heart disease' I |e has severe attacks
of heart pain, Give the characteristics o f p atien t’s pathology
 C h a p te r 7. P a th o p h y s io lo g y o f P e r ip h e r a l Itlo o d C ir c u la tio n

1. Ischem ia is a decrease o f organ o r tissue blood filling due to lim itation or

com plete stop o f arterial inflow.
2. T here are som e types o f ischem ia and all o f them have the sam e causes
and m echanism s o f developm ent.
3. Com pressive ischem ia is a result o f vessel lum en narrow ing with a th ro m ­
bus, an em bolus, or atherosclerotic process.
4. Obstructive ischem ia is a result o f m echanical influence on the arteries
(tum or, foreign body, ligature, etc.).
5. Angiospastic ischem ia is a functional disorder.
6. The essence o f angiospastic ischem ia is derangem ent o f the m otor (vaso­
constrictive) apparatus o f the vessels.
The microscopic picture in the region o f ischemia is:
7. Blood flow deceleration.
8. D ystrophic changes o f tissue.
9. N ecrosis is impossible.
The clinical manifestations:
10. Organ in the region o f ischem ia is swelling.
11. Organ in the region o f ischem ia is hot.
12. T he gravest outcom e o f ischem ia is infarction.

22. In a 58-year-old patient with obesity (body weight 105 kg), atherosclerosis of
vessels and arterial hypertension, m yocardial infarction developed. Throm bosis
o f the coronary vessels was a causative factor. Explain the reasons and m echa­
nism s o f p atien t’s state developm ent.
1. Throm bosis is a lifetime form ation o f a mass containing blood elem ents
(cells and coagulated proteins) on the internal surface o f the vessels.
2. The etiological factors o f throm bosis m ay be endogenous and never exo­
genous.
3. Infarction is the term inal stage o f throm bosis.
4. T he plasm atic stage is the first.
5. T he cellular stage is the second.
6. A therosclerosis predisposes to throm bosis.
7. Obesity increases predisposition to throm bosis, and arterial hypertension
prevents it because arterial pressure increase accelerates blood flow.
8. Obesity increases predisposition to throm bosis because heparin inhibits
lipolysis.
9. Throm bosis in this case has a defensive character.

Tin(I points o f comparison and compile a comparison table o f common features and
differences between arterial and venous hyperemia
4 )in ts o f C o m p a r is o n A rteria l H yperem ia Venous H yperem ia
С hapter 8
INFLAM M ATION

In llam m atio n is the most widespread pathological process. Inflam m atory diseases
arc the largest group o f diseases (gastritis, myocarditis, tonsillitis, hepatitis, etc.).
Inflam m ation is a typical pathological process, which is characterized by a com ­
plex o f m orphological, biochemical and functional changes, a reaction o f microcircu-
lation and conn ective tissue in response to tissue damage.

Cardinal Signs o f Inflammation

C elsus a n d G alenus described the local signs o f inflam m ation in ancient times.
Inflam m ation is a predom inantly local process, but the whole organism becom es
Involved.
I.oral signs o f inflam m ation are the following (fig. 10):
• Tumor (swelling).
• Rubor (redness).
• Calor (h e at).
• Do lor (p ain ).
• Funrtio teasa (functional disorder).
System ic signs o f inflam m ation are fever, leukocytosis, stim ulation o f the bone
m arrow , im m unological reactivity, hepatic function (synthesis o f new proteins),
la*ling sick (h ead ach e, insom nia, loss o f appetite and working capacity).

Tii• Id C ardinal sings o f Inllam m ation according («* < <bn uul Clnlcnus
 C h a p t e r 8. In fla m m a tio n

ETIO LO G Y

Etiological factors o f inflam m ation are called flogogens. They are exogenous
and endogenous.
Exogenous flogogens are divided into physical (m echanical and therm al traum as,
electrical injury, ionizing and ultraviolet radiation), chemical (acids, alkalis, chem i­
cal poisons) and biological (bacteria, viruses, fungi).
Endogenous flogogens are form ed in the organism as a result o f o th er diseases
(throm bosis, em bolism , allergy, form ation o f biliary and urinary calculi). Im m une
com plexes are the m ost potent endogenous flogogens and cause allergic inflam m a­
tion.
P A T H O G E N E SIS

Stages o f Inflammation

Inflam m ation proceeds in three stages (fig. 11):

1) alteration;
2) disorder o f m icrocirculation, exudation, em igration o f leukocytes into the
focus o f inflam m ation, and phagocytosis;
3) proliferation and regeneration.

Action o f the ALTERA TION

flogogen
E xudation The term alteration m eans dam -
P roliferation age j w0 types o f alteration are dis­
tinguished in the focus o f inflam m a­
tion — prim ary and secondary.
Prim ary alteration is tissue dam -
Ei'H II. Diagrammatic representation of the or- a8e by the etiological factor itself.
i 'i and level of inflammation stages. It is shown This effect m ay be very short-term .
Hint every new stage arises in the previous one but the local dam age o f tissue is not
finished.
Secondary alteration is an additional tissue dam age by num erous factors of
endogenous origin. These factors are the following:
• inflam m atory cells;
• BAS (m ediators o f inflam m ation);
• m icrocirculatory disorders;
• hypoxia;
• local increase o f osm otic and oncotic pressure;
• local acidosis;
• products o f tissue decay.

Inflammatory Cells

In the focus o f inflam m ation it is possible to see a lot o f cells. Some o f them
• migrate from the blood (neutrophils, m onocytes, eosinophils, throm bocytes and
P u rl I (il'IU 'IJll Pillho|lllVslol<>Ky

lym phocytes), som e o f them have a local origin (tissue basophiles or m ast cells,
tissue m acrophages, fibroblasts). So, inflam m atory c ells are o f histiogenic and he­
m atogenic origin. They perform im portant functions in the focus o f inflam m ation.
Hie defensive function is the most im portant one (phagocytosis, BAS form ation).
I lie most im portant role belongs to neutrophils and m onocytes (table 4). At the
same tim e, they are the factors o f secondary alteration.

ТаЫе 4
In fla m m a to ry C e lls

Cells BAS Participation in Inflammation

Lysosomal enzymes, leukotrienes,
Neutrophilic Chemotaxis, phagocytosis, cy­
thrombocyte activation factor, anti­
grunulocytes totoxic effect
bacterial factors
Phagocytosis, cooperation with
Interleukin-1, enzymes, interferon,
other cells, influence on fibro­
Monocytes complement components, prosta­
blasts, lymphocytes, epithelio-
glandins, protease inhibitors
cytes, hepatocytes, neurons
Histamine, heparin, eosinophil
1issue basophiles
chemotactic factor, thrombocyte ac­ BAS formation
(masi cells)
tivation factor, SRS (leukotrienes)
1osinophilic Destruction of histamine and
Histaminase, arylsulfatase
granulocytes leukotrienes
Prostaglandins, thromboxane, leu­
Aggregation, blood coagula­
l hrombocytes kotrienes, thrombocytic growth fac­
tion, thrombosis
tor, serotonin, histamine, adrenaline
В and T-lym­ Lymphokines, interleukin-2, immu­
phocytes Immune response
noglobulins
Proliferation, restoration of tis­
fibroblasts Glycosaminoglycans, collagen
sue after inflammation

Neutrophils get into the focus o f inflam m ation from the blood and move to
he cen ter o f inflam m ation. Phagocytosis is th eir m ain function. M any neutrophils
lie liberating active hydrolytic enzym es from lysosomes. These enzym es are so n u ­
nc m us (about 60 — protease, amylase, lipase, phosphatase, collagenase, elastase,
IN A ase, DNAase, m yeloperoxidase, lactoferrin, lysosomal) th at neutrophils are
netaphoricaliy called a «mobile laboratory». BAS from neutrophils play an im -
lorianl role in the purification o f the inflam ed focus and at the .same tim e they
re harmful factors. Like o ther BAS, they can activate all o th er systems o f BAS
Munition.
Monocytes are a source o f a large quantity o f BAS (com plem ent, collagenase,
lastase, m onokines, interferon, transferrin, prostaglandins, throm boxane, leuko
icucs). One o f them is interleukin-1, which is liberated .il the very beginning of
illum ination It produces many effects (see fig. 7 on p. 7)), скрегinlly in the acute
 Chapter 8. Inflammation

phase of inflammation. All systems, which are responsible for inflammation, are
sensitive to interleukin-1. The bone marrow is activated, an additional quantity
of’ leukocytes appears in the blood. Many cells have interleukin-1 receptors and
are its target — hepatocytes, fibroblasts, endotheliocytes, synoviocytes, nerve cells.
Ilepatocytes synthesize new proteins, including ceruloplasmin, S-reactive protein,
and fibrinogen. The synthesis of albumins and globulins for the blood is activated,
fibroblasts provide proliferation by collagen synthesis. Interleukin-1 influences
(he endothelium of capillaries and provides leukocyte adhesion. Endotheliocytes
form prostaglandins and coagulation factors. Collagenase production is increased
m chondrocytes (cartilage destruction and pain in the joints are noted). Proteolysis
is activated in the muscles (pain in the muscles). One of IL-1 effects is influence
on the hypothalamus and fever development. Loss of appetite, disturbance of the
central nervous system also refer to IL-1 effects.
, ,
Mast cells eosinophils thrombocytes and lymphocytes participate in inflamma­
tion and are a source of BAS. From cellular membrane prostaglandins are formed.
I hey cause numerous and various manifestations of inflammation.

BA S Role in Inflammation. Inflammation Mediators

The BAS, which play a role in inflammation, are called mediators o f inflam m a­
tion. They provide all the manifestations of inflammation (beginning from alteration
up to proliferation and reparation). All biologically active substances are common
for the normal reactivity (see pp. 70—73 and scheme 4 on p. 73) as well as for the
mechanisms of immunity, allergy and inflammation. However, there are some dif-
lerences. Lymphocytes play the main role in immunological reactions (p. 76), mast
cells — in allergy. As to inflammation, neutrophilic granulocytes and monocytes, as
phagocytes, are the main source of BAS together with other cells, which participate
in inflammation.
The BAS, which are formed in the first place, activate, as a cascade, all systems
of BAS formation, which are responsible for secondary alteration, microcirculation
disturbance, vascular permeability increase, edema, leukocyte migration, phagocy­
tosis, proliferation. BAS involve the whole organism into inflammation, stimulate
the bone marrow, activate protein synthesis in the liver, increase body tempera
lure. There are no phenomena in inflammation, to which BAS would not have a
relation. Antipyretic medicines (e.g. aspirin) are directed against BAS, especially
prostaglandins. Table 5 gives all kinds of BAS, their origin and effects in the focus
of inflammation.

M ICRO CIRCULATIO N D ISO RD ER

Local vascular reaction begins immediately after flogogen action and leads I о
I he development of the second stage of inflammation.
Cohnheim discovered the dynamics of local vascular reactions. It is easy to
observe it on the frog mesentery after its damage (fig. 12).
Local vascular reaction proceeds in four stages:
I. Short term spasm of arterial vessels.
*lUl I (•Climil Ги11|0|>1ил1о||>Ц)

labl* 5
Inflammation Mcdiaton»

Mediators Source Effect

Cellular
1ysosomal enzymes Granulocytes, macrophages Second alteration, chemotaxis

llUlutninc Local vasodilatation, increased

Granules of mast cells
vascular permeability
Serotonin Granules of thrombocytes The same
Arachidonic acid from the cel­
Increased vascular permeability,
Pimiaglandins lular membranes of damaged
edema, chemotaxis
cells
Aggregation of thrombocytes, an­
1hromboxane Thrombocytes
giospasm, activation of hemostasis
Disaggregation of thrombocytes,
Prostacyclin Endotheliocytes
vasodilatation
Chemotaxis, spasms of smooth-
1cukotriencs Leukocytes
muscle fibers, edema
Humoral
Kinins (bradykinin, Vasodilatation, increase of perme­
a2-globulins of blood
kallldin) ability, pain, itch
Chemotaxis, cytolysis, activation
<'implement sys-
Blood plasma of leukocytes, release of inflam­
lem
mation mediators
Activates kinin and complement
Нацетап factor Blood plasma
systems, effect on hemostasis

2. Arterial hyperemia.
У Venous hyperemia.
4. Stasis.
I lu* named four forms of microcirculation disorder correspond to those de-
nhcd in chapter 7 «Pathophysiology of Peripheral Blood Circulation». However,
u*\ have some peculiarities. In particular, all of them have features of defense.

Iiort Term Spasm

A short -term spasm of arterial vessels is an angiospastic reaction of reflex na-

in 11 is an unspecific initial reaction of vessels to any damage and has protective
iluc due lo limitation of pathologic substances entering the organism from the
imaged focus. Sometimes in clinical practice a physician applies cold at the very
'ginning of inflammation in order to stop the process. Sometimes it is really use-
il But usually this stage is short-term and substituted by more significant changes
i microcirculation.
 С hapter К. Inflammation

Arterial Hyperemia

Arterial hyperemia determines

Tig. 12. Inflammation of the frog mesenterium:
/ emigrated leukocytes; 2 -leukocyte emigration;
f erythrocytes in the tissue
those signs of inflammation, which
Celsius described as rubor (redness),
tumor (swelling) and calor (heat). Ar­
terial hyperemia supplies the focus of
inflammation with an additional vol
ume of oxygen and substrates.
Virchow attached great impor­
tance to arterial hyperemia claiming
that the inflamed tissue requires in­
creased nourishment ( Virchow’s nutri­
tional theory o f inflam m ation). Mech­
nikov considered arterial hyperemia
a way 0f supplying the focus of in-
flammation with additional quantity
0f leu co cytes ( Mechnikov \sphagocytic
theory o f inflam m ation).

Venous Hyperemia

Venous hyperemia inevitably follows the arterial one. The bloodstream decelera­
tes, and leukocytes occupy the boundary position near the vascular wall. It means that
chemotactic substances, which are formed in the center of inflammation, influence
the leukocytes located in the bloodstream. Adhesive proteins, which are formed in the
endothelium, make the surface of endotheliocytes and leukocytes more sticky.

Stasis

Stasis (stop of blood flow in the capillaries) provides leukocyte release from
vessels into the center of inflammation. Vascular permeability to plasma proteins
and leukocytes considerably rises. Without blood flow deceleration, boundary posi­
tion of leukocytes and permeability increase, the leukocyte emigration and further
phagocytosis are impossible.

EXUDATION, EM IGRATION , AND PHAGOCYTOSIS

Departure of plasma proteins (albumins, globulins, fibrinogen, etc.) into the

center of inflammation is accompanied by water discharge. This process is called
exudation.
Departure of leukocytes from the blood into the center of inflammation is
• tiled emigration. Leukocytes actively move to the center of inflammation through
the capillary wall between the endothelial cells and through the basal membrane.
A certain order of leukocyte emigration has been noted - neutrophils, monocytes,
lymphocytes.
Phagocytosis (stages, mechanisms, disorders on pp. 68-70) is the main function
of leukocytes in the center of inflammation and has the following peculiarities:
Г.и I I (•('ihm i i I I'nlliopliysioloKy

• A large quantity of phagocytes in tin* centei ol inflammation is provided by

active vascular reactions.
• C'hemotactic substanses, which arc formal in the center of inflammation,
effect even the leukocytes located inside vessels.
• Phagocytosis is intensified.
• Phagocytosis is provided with additional energy and oxygen.
• Phagocytosis is intensified due to body temperature increase.
• Phagocytosis is activated by the effect of mineralocorticoids.
Purulent inflammatory exudate is formed in the center of inflammation (fig,
И ) Then the pus leaves the focus of inflammation.
In/lammatory edema is local. It is re-
dist rihution of water from vessels into tis­
sues in accordance with Starling’s laws.
I lu* following mechanisms of inflammato­
ry edema pathogenesis are of importance:
.i) an increase of hydrodynamic (venous)
pressure of the blood; b) an increase of vas-
i ular permeability and release of proteins
from the blood into the center of inflam­
mation, which leads to increased oncotic
pressure in the center of inflammation; c)
hydrophilia of colloids due to pH reduction Fig. 13. Inflammation of the rabbit’s eye.
(local acidosis) in the inflamed tissue. On the bottom of the anterior chainin'i
purulent exudate is present
Purulent Exudate Morphology

A microscopic study of purulent exudate reveals its essential part — the so

railed pyocytes. They are active leukocytes, which have performed the function
ol phagocytosis (organoids are not distinguished). In addition, it is possible to see
intact micro and macrophages, microorganisms, damaged tissue debris, fragments
ol t ell decay, coagulated fibrin, admixture of blood. An analysis of purulent exudate
composition makes it possible to characterize organism reactivity. Pyocyte prevn
lence is ;i positive sign. Prevalence of intact micro- and macrophages is a negative
sign testifying to decreased reactivity.

PRO LIFERATIO N AND REGENERATION

I hiring the third stage the center of inflammation becomes free from microor­
ganisms, necrotized tissues, foreign and toxic substances.
In the damaged tissue proliferation (multiplication) of the viable cells begins
I lie degree of reparation depends on regeneration ability. The cells of the cornice
live tissue, epidermis, and mucosal epithelium have the best regenerative ability
I he cells of the liver and kidneys possess smaller regeneration capability. The cells
ol the muscular and nerve tissues possess weak regeneration capability.
II ihe quantity of viable cells in the parenchyma is Insignificant, an organ is
restored by the connective tissue, f ibroblasts mulliplv and produce collagen, which
forms a scai m the /one of inlliuniuatioii
 Chapter 8. Inflammation

Studying the stages of inflammation, it is important to understand that their

outer is superimposed, and in the focus of inflammation it is possible to observe
simultaneously all manifestations with some of them being predominant.

Forms of Inflammation

Classification of inflammation is based on the predominance of alteration, exu-

•I.it ion or proliferation. Thus, three forms of inflammation are distinguished.
Alterative inflammation is characterized by the predominance of the first phase
•I.image, dystrophy and necrosis. It is mainly observed in the parenchymatous organs
m case of infectious diseases (caseous necrosis of the lungs of tuberculous origin).
Mlcrgic inflammation proceeds with formation of aphthae, erosions and ulcers.
Exudative inflammation is characterized by a significant increase of vascular
permeability. Exudation and edema accompany allergy. Inflammation of the mu-
»ous membranes may have such a course (catarrhal inflammation).
Proliferative (productive) inflammation is characterized by the predominance of
hlstiogenic or hematogenic cell multiplication. Cellular infiltration is formed in the
loi us of inflammation. Rheumatoid arthritis (allergic disease) has such a character.
II formation of new connective tissue predominates, sclerosis and cirrhosis develop.
In addition, inflammation is divided into acute and chronic.

D ISO R D ER OF M ET A B O LISM

l ocal changes of metabolism are characterized by three metaphoric expres-

•lonv The expression «the fire o f metabolism» characterizes its intensity. An in-
•и .isc of the local temperature (calor) takes place. The expression «leukocytes are
о mobile laboratory» reflects accumulation of a large quantity of enzymes and BAS
••I leukocyte origin, which actively move towards the center of inflammation. The
»spu ssion «oxygen explosion» reflects the exclusive role of oxygen in inflamma-
llou increased formation of energy in the form of heat calories and especially in
Hi* form of A TP (p. 191) and also active forms of oxygen. The latter play a role in
*ondary alteration and bactericidity.
Physicochemical Changes. The products of incomplete oxidation are accumu-
11I 1 4 I. Since all of them are acids, local acidosis develops, pH is lowered to 5.3-6.0
in acute and 6.0—7.5 in chronic inflammation. Osmotic and oncotic pressure is
in* leased in the center of inflammation as a result of accumulation of ions, proteins
mil products of their incomplete disintegration.

INFLAM M ATION AND O RGAN ISM REACTIVITY

Ilya Mechnikov, a great scientist and Nobel Prize winner, studied inflamma
ii"ii in animals of different organization. He revealed that inflammation develops in
Hi« process of evolution and has more simple forms. Frogs (heterothermal animals)
il« nionsirate vascular reactions and phagocytosis during inflammation, but do not
hrtvi .my increase of local and general temperature. Investigating inflammation in
M ilr.li (an invertebrate without the vascular system), Mechnikov discovered the
pin nomcnon of phagocytosis without vascular reactions. So, Mechnikov made a
•п т In мои that phagocytosis is the earliest and most principal event in inllammation
htH I. (ii'iicrul Pathophysiology

It is known that duration of any pathological process depends not only on the
lorce of the etiological factor, but also on organism reactivity. This law refers to in­
flammation as well. Children and newborns demonstrate a violent (badly regulated)
and sometimes dangerous course of inflammation. Elderly persons have inactive
inflammation.
Depending on individual reactivity, inflammation may be divided into normer-
Hie (proceeds optimally), hypoergic (weak), and hyperergic (excessive).
Reactivity decrease (hypothermia, narcosis, effect of immunodepresants, ad­
vanced age) diminishes manifestations of inflammation, which may take on a
chronic form without essential fever.
Allergic inflammation has some grave forms - acute erosive, acute exudative,
acute edematous, chronic productive (rheumatism).

S Y ST EM IC CHANGES IN INFLAM M ATION

The whole organism is involved in inflammation. Manifestations are the fol­

lowing:
• Increase in body temperature (fever) is one of the most prominent systemic
manifestations, especially when inflammation is associated with bacteremia.
• Endocrine system activation.
• Hypothalamus involvement in fever development, adenopituitary and adrenal
cortex activation.
• Mineralocorticoids stimulate inflammation, and glucocorticoids inhibit it.
• Hematological syndrome is characterized with neuptrophilic leukocytosis (p. 303),
which is a common feature of inflammatory reactions, especially those induced
by bacterial infection. The leukocyte count usually climbs to 10 G/l and more.
Leukoformula shows a regenerative left-side nuclear shift (p. 300)
• Increased number of neutrophils in leukoformula and appearance of their im­
mature forms are an evidence of hemopoiesis activation in the bone marrow.
• Hlood sedimentation rate (B S R ) is accelerated.
• Immune system activation.
• Nervous disturbances, insomnia.
So, inflammation, immunity and fever are tightly connected.

SIG N IFIC AN C E OF INFLAM M ATION

Analysis of the clinical significance of inflammation helps to estimate its dialec­

tics. This process has both positive and negative features. On the one hand, it is a
fundamental protective response, a defense reaction, which contributes to damaged
tissue restoration and organism survival. On the other hand, patients suffer, their
ability to work is impaired, they are ill. It is potentially harmful. Some cells, tissues
and organs may perish. An overactive inflammatory response may be lethal.

Questions for Self-Control

I What is a typical pathological process?

1 What are the systemic signs of inflammation?
. .

What is the time correlation between inflammation singes?

 Chapter К. Inflammation

4. What are the peculiarities of allergic inflammation?

5. What are the mechanisms of secondary alteration?
6. What are inflammation mediators?
7. What is the pathogenesis of inflammatory edema?
8. Give the characteristics of metabolic disorders in the focus of inflammation.
9. What is the significance of organism reactivity in the course of inflammation?
What terms are in use?
10. What theories of inflammation do you know? What did the authors base their
theories on?
11. What are Konheim’s investigations?
12. What are Mechnikov’s investigations?
13. What is the practical importance of the theories?

Tests for Self-Control

(give correct answers)

1. An intradermal tuberculin injection was given to an animal sensibilized by

tuberculin. In 24 hours in the place of injection venous hyperemia and edema
formed. A histological analysis of the skin showed a lot of lymphocytes and
monocytes. What kind of inflammation took place?
A. Purulent.
B. Serous.
C. Allergic.
D. Fibrinous.
E. Aseptic.
2. A patient had a skin abscess. A microscopic examination of the punctate from
the focus of inflammation showed plenty of different blood cells. What type of
leukocytes are first to get from vessels into tissues?
A. Lymphocytes.
B. Monocytes.
C. Basophiles.
D. Eosinophils.
E. Neutrophils.

3. A 4-year-old child had a hyperergic inflammation of the upper respiratory

tract. Later the beginning of a serious respiratory pathology forced to apply an
anti-inflammatory hormone. What hormone has anti-inflammatory action?
A. Epinephrine.
B. Hydrocortisone.
C. Somatotropin.
D. Testosterone.
E. Insulin.
I Reproduction of inflammation of the frog’s mesentery demonstrates peripheral
orientation of leukocytes inside the vessels and their migration through tin*
vascular wall. What factors predetermine this process?
A. Decrease of oncotic pressure in vessels.
B. Increase of oncotic pressure in the focus of inflammation.
t I (.ilH'lill rallinplnsioloKy

С Local acidosis.
I) Influence of chcmotactic substances.
I Decrease of hydrostatic pressure in vessels.

A patient suffers from pleuritis. Pleural cavity puncture showed exudate. What
is the initial mechanism of exudation?
A. Increase of vessel permeability.
B. Increase of blood pressure.
C. Hypoproteinemia.
I ). Aggregation of erythrocytes.
I Decrease of oncotic pressure in tissues.

Reproduction of inflammation of the inferior extremity of an animal is associated

with a high body temperature, increased quantity of antibodies, leukocytes.
What substances provoked the development of these systemicl reactions of the
organism?
A. Histamin.
B. Glucocorticoids.
C’. IVlineralocorticoids.
1). Interleukins.
Г. Somatomedins.

A lot of leukocytes are accumulated in the focus of inflammation. What is the

order of emigration of different types of leukocytes into the inflammation zone
according to Mechnikov?
A. Neutrophils, lymphocytes, monocytes.
B. Lymphocytes, neutrophils, monocytes.
( '. Monocytes, neutrophils, lymphocytes.
I). Monocytes, lymphocytes, neutrophils.
I Neutrophils, monocytes, lymphocytes.

An experimental model of inflammation was reproduced with turpentine. A

lethal dose of tetanine was injected into the abscess cavity, but the animal
stayed alive. What is the probable cause of such a result of the experiment?
A. Activation of antibody synthesis.
B. Formation of a barrier around the focus of inflammation.
( . Stimulation of leukopoiesis.
I ). Intensification of vascularization of the focus of inflammation.
I Activation of desintoxicating functions of phagocytes.

In some hours after burn in the site of hyperemia and edema a focus of necrosis
appeared. What is the main mechanism, which intensified destructive processes
in the focus of inflammation?
A. Emigration of lymphocytes.
B. Primary alteration.
С\ Secondary alteration.
I) I migration ofcrythrocytes.
I Proliferation of fibroblasts.
Chapter 9
FEVER

There are several terms close in meaning, which define the phenomenon of
increased body temperature. However, the cause, pathogenesis and significance are
completely different in each case.
Hyperthermia is the most common term for body temperature rise.
Overheating is a rise of body temperature due to a high ambient temperature
(this process was studied earlier, described on p. 22, pay special attention to defen­
sive changes in thermoregulation).
Fever (from Latin febris) has a special place. It formed in the process of evolu­
tion as an organism reaction to infection. The present chapter deals with this very
phenomenon.
Fever is a typical pathological process characterized by thermoregulation reorga­
nization and an increase of body temperature in response to pyrogens.
Under clinical conditions (in an infected patient) it is impossible to assess fe
ver and distinguish it from infectious intoxication. One gets a mistaken impression
that a patient suffers from elevation of body temperature and wants to bring the
temperature down. Only under experimental conditions it is possible to model pure
fever and study it.
There are several methods of experimental modeling of pure fever, for example,
by injecting pure pyrogens. Hypothalamus perfusion with blood of different tempera­
ture allows achieving an increase of body temperature of any degree. Such experi­
ments made it possible to get information about fever etiology and pathogenesis.

ETIOLOGY

Etiological factors, which cause fever, are termed pyrogens.

Pyrogens are divided into
• Infectious and noninfectious.
• Exogenous and endogenous.
• Prim ary (inductive) and secondary (true).
Exogenous pyrogens are comiected with microorganisms. In scientific studies
it is possible to differentiate microbial pyrogens from toxins and study them sc pa
lately.
Microbial exo- and endotoxins are proteins. Immune antibodies are formed
against them. Microbial pyrogens are not proteins; they are biopolymer molecules
of lipopolysaccharides. No antibodies are formed against them and they are not
destroyed by proteolytic enzymes. The pyrogenic effect is connected with the li
pid part of these macromolecules (lipoid A). It causes fever in the concentration
u.OOOl g/kg.
Nevertheless, microbial pyrogens are not true, because they do not cause fevei
when injected into the hypothalamus. Formation of the so-called secondary (endo
hut I (liiim il ralliophvsioloKv

Kenous) pyrogens is necessary for fever development. Consequently, microbial (pri­

mary, exogenous) pyrogens are the factors of etiology, but endogenous (secondary)
pyrogens are the factors of pathogenesis.

PA TH O G ENESIS

Mechanisms of Endogenous (Secondary) Pyrogens Formation

I he formation of endogenous pyrogens follows the penetration of the microbial

ones They are not damaged tissue products, but the products of endogenous pro­
lan synthesis. Endogenous pyrogen production is called pyrogenesis. It is realized by
healthy leukocytes — macrophages (fixed and free monocytes), lymphocytes and neu-
trophils after their activation. Pyrogenesis is not realized in damaged leukocytes. If
energy formation in leukocytes is damaged (under experimental conditions), as well
•is after protein synthesis blockade (by puromycin), pyrogenesis does not occur.
Among different endogenous pyrogens interleukin-1 is the most potent. It is
a hormone-like protein, which is produced in macrophages and causes fever to­
rn her with various other effects (see fig. 7 on p. 72). IL-1 plays an important role
m inflammation (p. 123). IL-1 is produced in monocytes in vitro after microbial
pyrogens are added. All the systems, which are responsible for immunity and in­
flammation, are sensitive to IL-1. Fever, immunity and inflammation are a triad,
which determines organism reaction to infection. The connection between them is
so close that they do not exist without each other.
It has been shown experimentally that IL-1 does not pass through the hemato-
eneephalic barrier and does not reach the hypothalamus. At the level of the cerebral
intenes and capillaries prostaglandins E, and E 2are formed, reach the hypothalamus
and influence its function. So, the hypothalamus is a target of endogenous pyrogens.
14 i I produce experimental fever after being injected into the cerebral ventricle.
II cnee, the order of events is the following: microbe -> leukocytes (monocytes
and lymphocytes) -> IL-1 -> P G E -> hypothalamus.

Changes in Hypothalamus

I hernial homeostatic control is one of hypothalamus functions. The organism

w o rk sas a biological thermostat, and the regulator (thermoregulatory center) is
lot aied in the hypothalamus. The function of the thermoregulatory center consists
in the maintenance of temperature homeostasis, balancing the processes of heat
production and heat emission. This is based on the mechanism of establishing in the
hypothalamus of the so-called fixed point, according to which body temperature is
regulated. The normal fixed point in man is about 36-37°C.
I >ue to endogenous pyrogens the fixed point rises, and the hypothalamus regu­
lates body temperature on another, more useful (fora new situation) level. Different
type» of infection have developed their fixed points in the process of evolution. It
In veiy important to understand that a change of the lived point is not a disorder of
herniostatic control but its regulation on another level

132 .. » i
____________________________________________________________________ Chapter 9. Fever

After the fixed point reaches an adequate level, the hypothalamus sends regula­
tory impulses to proper organs, and additional heat is formed for body warming.

Mechanisms of Heat Accumulation

There are three mechanisms of heat accumulation during fever.

/. Lim itation o f heat emission is the main mechanism. Spasms of the peripheral
vessels, pale skin, decreased sweating and evaporation are noted. These mechanisms
are effective and economical since they require no energy. At this moment direct
and indirect calorimetry shows different indices: direct calorimetry shows decreased
parameters in comparison both with the initial level and patterns of indirect calo­
rimetry.
Only under the condition of diminished heat emission two other mechanisms
are effective and convenient.
2. Activation o f heat production (thermogenesis) is an additional mechanism
Intensification of metabolism actually takes place, but to a less degree — about 35-
45 % . It may be established by the method of indirect calorimetry (oxygen con
sumption). For comparison, it is useful to indicate that intensive physical work is
accompanied by more significant oxygen consumption (sometimes up to 500 % ),
hut overheating does not occur (heat emission increases proportionally). Contractile
and noncontractile thermogenesis is actually intensified in fever, but insignificantly.
Muscular tremor takes place. Glycogen is split off in the muscles and liver.
3. Disconnection (uncoupling) o f oxidation and phosphorylation allows to receive ad­
ditional quantity of heat calories without additional consumption of oxygen (this possi­
bility is explained on pp. 191—192 and in scheme 9 on p. 192). The energy of electrons
ind protons moving along the respiratory enzymal chain is not accumulated in ATP
but dissipates as free heat (free oxygenation). ATP formation is temporarily and insig­
nificantly diminished. Some microorganisms have an effect of disconnection.
After achieving the optimal level of body temperature, the latter is regulated
lor a while. During what time? Up to antibody formation and infection elimina­
tion. Within several days antibodies are formed resulting in the cessation of pyrogen
formation (microbial and IL-1). The fixed point in hypothalamus returns to the
physiological level, and body temperature normalizes.

Stages of Fever

Fever develops in three stages:

(1) body temperature increase (stadium incrementi);
(2) maintenance of high body temperature (stadium fascigii) with some fluctua
lions in the morning and evening;
(3) body temperature reduction (normalization) ( stadium decrementi).
The relationship between heat production and heat emission is different at
these stages. At the first stage heat emission is less than heat production. At the
.econd stage heat emission and heat production are equal. At the third stage heat
emission considerably rises; vasodilatation, intense sweating and loss of water are
noted.

IU
Г.ill I (iciicml I'iilhoiiiivsioloKv

Body temperature decrease (nor-

mali/alion) may be gradual, lytic (take
some days) or fast, critical (fig. 14). In
llu* latter case, extensive vasodilatation
may happen and, when it is accompa­
nied by intoxication, leads to collapse
development.

PROTECTIVE VALUE OF FEV ER

Very important events take place

during the second stage of fever. In the
process of evolution fever formed as a
delense reaction against infection.
Immunological reactivity is acti-
vated in fever. Cellular and humoral
mechanisms of immunity, inflammation
and lever are uniform.
Phagocytosis is activated (optimum
temperature for phagocytosis is 38°C) as
well as the rate of antibody and inter- Hours Days
leron formation, function of B- and T- Fig. 14. Critical (A ) and lytic ( B ) decrease of
Ivmphocytes, leukopoiesis. body temperature at the third stage of fever
Vitality and multiplication of mi-
<robes are impeded by temperature rising up to 40°C. The sensitivity of microor-
ramsms to medicines rises.
I ever activates other systems with their defensive functions — antitoxic func­
tion of the liver, filtration in the kidneys, secretion of hormones.
II antipyretic drugs are injected into experimental animals simultaneously with
mlectious agents, the course of infection may worsen.
( linical practice confirms the protective value of fever. Clinical findings are as
Follows.
- Patients recover more quickly and completely if fever develops.
• A more persistent and prolonged active immunity is formed if patients are fever­
ish.
Weak and elderly patients do not develop active fever and that is why infection
frequently takes a chronic course in them.
Antipyretic medicines sometimes worsen the course of infectious diseases.
We may summarize that fever in its essence is a protective phenomenon and
namtains organism vitality during infection.
In fact, such a course of fever is observed under experimental conditions with
Hire pyrogens free from infectious intoxication. Under clinical conditions dur-
ny. severe infections intoxication may damage the hypothalamus and consequently
nipait defense mechanisms So. in fever, like in any othei Ivpieal pathological
•ior ess, defense and haiinlul effects are interconnected

.14
 Chapter 9. F e w

M ETABO LIC CHANGES

The data on metabolic changes in pure fever without infectious intoxication

have been obtained under experimental conditions.
Basal Metabolism. It is necessary to understand that any protective reaction
requires additional energy. It concerns fever as well. Metabolism activation occurs.
Basal metabolism increases by 35—45 % . Oxygen consumption increase is the same.
Carbohydrate Metabolism. The blood glucose level rises. Glycogenolysis is ac­
tivated. The glycogen content in the liver and muscles is slightly reduced. The
intermediate metabolism of carbohydrates is not impaired. The respiratory quotient
equals 1, which indicates preferable utilization of carbohydrates.
Lip id Metabolism. The synthesis of phospholipids in the nervous tissue is in­
creased. Lipolysis is activated but intermediate lipid metabolism is not impaired
in the course of short-term fever. In prolonged fever, ketone bodies appear in the
blood and urine. Introduction of carbohydrates moderates these changes.
Protein Metabolism. The protein-synthetic function of the liver is activated
The formation of S-reactive protein, fibrinogen, ceruloplasmin is intensified. The
synthesis of y-globulin is also activated. In infectious diseases a negative nitrogen
balance is established and an increased content of urea in the urine is noted, but
there is no connection with the level of fever but infectious intoxication.
Acid-base balance moves to the state of compensated metabolic acidosis. The
quantity of blood bicarbonates is slightly reduced.
W ater-M ineral Balance. At the first stage of fever diuresis is increased (as a re­
sult of arterial blood pressure rise). At the second stage, retention of sodium, chlo­
rides and water is detected, diuresis decreases (as a result of increased aldosterone
secretion). At the third stage (patients sweat intensively) a negative water balance
may be established (patients need to drink additional fluid), sodium and chloride
excretion increases.

ORGAN CHANGES

In the course of infectious fever clinical symptoms are numerous, but there is
no strict correlation between them and the fever degree. The symptoms depend on
infectious intoxication, pyrogen effect and IL-1.
Experiments with pure pyrogens show changes in the organs, connected with
body temperature increase. They are milder than in infectious diseases and have
mainly protective value.
Stim ulation o f immunological reactivity (see above).
Blood circulation is activated. Pulse is accelerated (as a result of the local
warming of the cardiac pacemaker and activated sympathetic nervous influences).
Systolic and cardiac output increase. Arterial blood pressure (at the first stage) may
rise. Vasoconstriction is characteristic of the first stage, and vasodilatation of the
\eeond and third ones. If body temperature is reduced critically (at the third stage),
collapse may develop with vasodilatation in the background. Loss of water and hy­
povolemia may develop. Significant changes of systemic blood circulation, which
are observed in infectious diseases result from intoxication, not fever.
Рим I, (li’IUTIll I’ullinphvsloloHv

Respiratory System. Lung ventilation does not change essentially because in

spile of the accelerated rhythm respiration depth becomes shallower. Tachypnea is
observed in case of brain temperature increase.
Gastrointestinal Tract. The patient’s appetite is slightly suppressed (due to IL-1
ellecl on the brain). Salivation decreases as well as of gastric juice acidity (the pa­
tient's feeding must be reduced too). More evident changes result not from fever,
but from infectious intoxication.
Liver. The liver functions of protein synthesis and antitoxicity are activated.
VHne form ation may be activated.
Endocrine system is activated. Fever is a kind of stress and results in activation of the
pituitary gland and adrenal cortex. On the other hand, the endocrine system influences
lever development. Hormones can induce the synthesis of endogenous pyrogens in
macrophages (thus, in women in the ovulation period body temperature rises by 0.4—
0 l)“( ’ under the influence of progesterone). Thyroxin contributes to fever develop­
ment, possesses the effect of disconnection between oxidation and phosphoryla­
tion I ever development is depressed in hypothyroidism and pituitary insufficiency.
<ilucocorticoids inhibit the development of fever due to suppression of leukocyte
maturation and endogenous pyrogen production.
Nervous System. The following subjective clinical symptoms are noted in the
clinical picture - insomnia, tiredness, and headache. The study of these symptoms
in experimental animals is limited. Probably, these symptoms result from intoxica­
tion, not fever.
Figure 15 illustrates changes of some functions, which were detected in the
omse of experimental investigation of
Hire fever. Days
of disease 1 2 3 4 5 6 7 8 9 10
Stages
of fever I П III
T Y PES OF FEVER
У 41
| 40
Depending on the temperature rise
2 39
he following fever types are distin­
§■ 38
guished: I 37
• subfebrile - 37-38°C; •ё* 36
• moderate - 38-39°C; S 35
• high 39—41eC;
• hyperpyretic - above 41 °C. Pulse
( lassification of fever according to
rganism reactivity is of great clinical Respiraiion ------ ^ ---- -----
ignilkancc. From this point of view
Diuresis / \ /-- V
ie following types of fever are distin-
uUhcd: Muscle
tremor mm
• normergic (body temperature
corresponds to the optimum of a Fig. 15. Chungcs <»t temperature, pulse, res-
ccrtain inlcction); piration, and dnm r. ,ii dlllerent stages of
fever
 Chapter 9. l ever

• hypoergic (body temperature is below the optimal level);

• hyperergic (body temperature is above the optimal level).
The physician’s skill consists in evaluation of these parameters. In infants fever
develops rapidly and to a higher level. In elderly people fever develops slowly and
to a lower level.
Before the time of antibiotics and medicine abuse, general practitioners ob­
served a dependence of fever dynamics on biological rhythms. Clinical practice
established typical forms of fever in accordance with the biorhythmic dynamics. It
was discovered that in most cases infectious fever is not constant: increase is fol­
lowed by decline.
Depending on the biorhythmic dynamics the following types of fever curves
are distinguished.
Febris continua is a constant one. At the beginning, body temperature sharply
increases keeping at the maximum level during 7—9 days with morning-night fluc­
tuations of not more than 1°C, then it sharply decreases (fig. 16). It is typical of
pneumonia.
Febris intermittens is intermittent fever. The cyclicity of bacteria develop
ment in the blood is reflected on the curve. Malaria is an example. Attacks
may occur daily or every other day. During an attack, body temperature sharply

Fig. 16. Curves of body temperature, pulse and respiration in febris conti
nua (croupous pneumonia)
I’ll 11 I ( | 1‘|10Г в 1 l * i ll ll O | » li y s l o l o ^ V

increuses keeping at the high level for 30-60

minutes or 2—3 hours, then returns to the
normal level or below (fig. 17).
I'ehris remittens develops in many bacte­
rial infections. The morning-night tempera-
l in i' fluctuation is 1.5—2.0°C without return­
ing to the normal level.
I'ehris reccurens is recurrent. Relapsing
levei is an example. An attack lasts for several
days (6 8), followed by a critical decrease of
body temperature and a period of apyrexia
lasting for several days (fig. 18).
I'ehris hectica is exhausting. Fluctuation
ol body temperature is 2—3°C and more. Sep-
sis and wound infection are clinical examples.
Sometimes it is characterized by several rises
and falls of body temperature during a day.
Analysis of temperature curves gives in­
formation about the functional state of a pa- Fig. 17. Dynamics of body tempera-
tient, prognosis, and is important for differ- ture curve in a malaria patient
rutial diagnostics.
As a result of antibiotic and antipyretic
abuse, temperature curves lose their typical features.
I ever in patients with chronic infectious diseases is characterized by a low (37.5—
IK.()“( ’) increase of body temperature for a short period of time with unstable
morning night fluctuations.

FEV ER TREATM ENT

I ever usually accompanies infectious or other inflammatory diseases and there

is no special aim of its treatment. The treatment of the underlying disease has the
principal significance. Nevertheless, a lot of antipyretics are offered to influence
fever proper.
II fever is normergic, a physician assesses the patient’s reactivity as normal.
I In* patient gets better himself. The physician’s help is necessary but it does not
concern the fever.
II fever is hypoergic, a physician assesses the patient’s reactivity as depressed.
I lie help is necessary and concerns immunological reactivity stimulation. Immuno-
inodulators improve the course of infection and adequate fever development.
II lover is hyperergic, a physician assesses the patient’s reactivity as inadequate
1 1 id qualitatively changed. Infants are very reactive. Children frequently develop a

ilghci fever than it is adequate for a certain infection. If a child endures fever badly,
mdy temperature must be brought down. There are many antipyretic medicines,
'lit the truth is that physicians sometimes abuse them, clumping normal reactivity
uto a decreased one.

138
 C h a p te r Fever

I'ig. 18. Dynamics of body temperature and pulse curves in a recurrent typhus patient

Artificial fever can be used to treat some diseases because of its ability to stimu­
late immunological reactivity. Pure pyrogens (pyrogenal is of bacterial origin) are
used in case of lues, gonorrhea, osteotuberculosis and arterial hypertension (of renal
genesis, when vasodilatation is achieved and renal blood supply is improved). They
cause body temperature rise for 6—9 hours. Nowadays, IL-1 and other cytokines are
used in the clinical practice for this purpose. Their advantage in comparison with
pyrogens of bacterial origin consists in the absence of side effects.

Other Forms of Hyperthermia

In addition to fever, there are other forms of body temperature rise, which are
not as beneficial for the organism as fever.
Blood transfusion, injection of proteins and lipids for the purpose of parenteral
feeding may cause elevation of body temperature.
Primary pyrogens may be produced inside the organism independently from
infectious agents (in bone fractures, myocardial infarction, hemolytic crisis). These
substances are produced as a result of body’s own tissue destruction and influence
the organism as exogenous pyrogens.
Hyperthermia caused by overheating significantly differs from fever. The final
irsult is the same — body temperature increase, but the etiology, pathogenesis and
significance are different. The etiological factor is of physical origin (high ambient

«штшшш ............ ^ ............

Part I <«питн1 slolo^y

temperature). Compensation is directed at heat emission activation. Thus, high

body temperature manifests decompensation and exhaustion ol the thermoregula­
tion function. Such a state is harmful. Hyperthermia develops at the first stage of
acute radiation disease due to thermoregulation disorder.
A variant of hyperthermia is observed in intoxication with some chemical
.i)H'nts ((x-dinitrophenol), which damage mitochondria and produce an effect of
uncoupling of oxidation and phosphorylation (p. 190).
Attacks of hyperthermia are noted in workers involved in quinine (quinic hy­
perthermia) and iodine (exhaustive hyperthermia or iodism) production. There has
1нси described ‘salt’ hyperthermia. Some plants (Aconitum, Baptisia tinctoria, Bel­
ladonna, Dulcamara) cause hyperthermia in sensitive persons. Some pharmaceuti-
<nl preparations (caffeine, ephedrine, strychnine, adrenaline, atropine, benzedrine,
..ilv.usiin, sulphasan) have hyperthermia as a side effect. Malignant hyperthermia
with body temperature increase up to 44°C has been described as a consequence of
the use of muscle relaxants and some medicinal substances for anesthesia.
l ever-like states have been described without any influence of environmental
lactors. Endogenous hyperthermia is described as neurogenic (in brain damage),
psychogenic (in neurosis, emotional stress), reflexogenic (in cholelithiasis), and
endocrine (in hyperthyreosis, under the influence of progesterone).

Questions for Self-Control

I What terms are used to denote body temperature increase?

) What is pure fever?
< May antibodies form against microbial pyrogens?
I What are secondary pyrogens and in what way are they produced?
*> What is the role of BAS in fever development?
ft What is the fixed point in the hypothalamus?
7. Name the three main mechanisms of heat accumulation in fever.
N Mow can you prove that thermoregulation is not disordered but actively
reorganized in fever?
4), What arc the proofs of the defensive role of fever?
10. What about the biorhythmic dynamics in fever? What does it manifest?
11 What metabolic changes develop in fever?
IЛ What changes in different organs develop in fever?
I\ What types of fever are distinguished in connection with organism reactivity?
What terms arc used to describe them?
14 Wliat chemical substances can cause attacks of hyperthermia?
15 What is common and different between fever and other types of hypert­
hermia?
Hi What is the approach to antipyretics use?
 Chapter ‘) l-Vver

Tests for Self-Control

(give correct answers)

1 A woman fell ill with acute pneumonia. There is fever up to 39°C, general
weakness, dry cough appeared. What inflammation mediator has the properties
of an endogenous pyrogen?
A. Thromboxane
B. Interleukin-1.
C. Histamine.
D. Serotonin.
E. Bradykinin.

2. A patient has a fever. Body temperature rises and keeps high from 1 till 3 a.m.
and then decreases to the normal level. Such fever is observed every fourth day.
What type of temperature curve is it?
A. Febris intermittens.
B. Febris continua.
C. Febris reccurens.
D. Febris hectica.
E. Febris remittens.

3. After overcooling the patient’s body temperature increased to 39.7°C and rose
from 39°C to 39.8°C in 3 days. What type of temperature curve is it?
A. Febris hectica.
B. Febris reccurens.
C. Febris continua.
D. Febris intermittens.
E. Febris remittens.

I'ind points o f comparison and compile a comparison table o f common features and
differences between fever and overheating due to high ambient temperature

Points of Comparison Fever O verheating

1
2.
1
4.

141
Chapter 10
NEOPLASIA

Neoplasia refers to pathology of growth. Tumor may be benign and malignant.

l ilts chapter deals with malignant tumors. Neoplasia is a process of malignant tu­
mor formation. The term neoplasm is frequently used as a synonym of malignant
tumor; like the term cancer.
Neoplasia is a typical pathological process, which is characterized by an unlimi­
ted (uncontrolled, independent and endless) increase of tissue growth, which does not
correspond to the normal structure and function of the organism.

CARDINAL SIN G S OF NEOPLASIA

I o distinguish one typical pathological process from another one should note
their cardinal sings. For neoplasia they are:
• endless growth (absence of the so-called limit of division, immortality);
• independence o fgrowth, autocrine (own) regulation (tumor grows from itself,
from one single transformed cell) infiltrating healthy tissues;
• unaplasia, reversion to a simpler, less differentiated form (like embryonic
state);
• metastatic expansion.
CLASSIFICATION

According to the clinical course and outcome, it is accustomed to divide tu­

mor. into benign (usually do not substantially impair the vital activity of the organ­
ism) and malignant (very often lethal). The former are characterized by expansive
'towth, when surrounding tissues are moved apart. The latter have an infiltrative
growth pattern. Malignant tumors may be prim ary and metastatic.
According to the histological structure, tumors customarily get the name of the
illected tissue with the suffix -oma: carcinoma, osteoma, myoma, neuroma, etc.

E X PER IM EN T A L STUDY OF NEOPLASIA

II is difficult to estimate the etiology and pathogenesis of malignant growth in

ilieady affected patients. For this purpose experiments are conducted — neoplasia
nodding in animals (experimental oncology). Experimental oncology gives a possi­
bility to study the value of the dose, intensity and duration of cancerogen effect, the
vay of cancerogen entry, the role of the immune system and genetic factors, condi-
mns, which promote or prevent neoplasia. High- and low cancerous populations
•I annuals are created in laboratories. Experimental oncology gives a possibility to
nvcstigate antitumor drugs.
I here are three methods of experimental neoplasia modeling induction,
nnmplantation and explantation.
 Chapter 10. Neoplasia

Induction

Induction is tumor reproduction by applying different physical, chemical and

biological factors. This method gives a possibility to prove or deny cancerogenic
properties of the investigated influences and substances. Using chemical substances,
il is possible to distinguish cancerogenic chemical substances from noncancerogenic
ones. In such cases, when a viral origin of a malignant tumor is assumed, the scien
tific proof lies in malignant tumor induction in an animal using noncellular filtrate
of this tumor or a certain virus strain.

Transplantation

This method consists in transplanting a tumor from a sick animal to a healthy

one.
The method of transplantation revealed the following facts:
• Homotransplantation of malignant tumors is possible while that of normal tissues
does not succeed without immunodepression.
• Heterotransplantation of malignant tumors (to other animal species) does not
succeed. It creates difficulties in modeling human tumors.
• The growth of malignant cells is endless. Malignant cells are maintained in labo­
ratories for many years (100 and more). Experimental animals die from neopla­
sia, but transplanted cells live infinitely (it is called immortality).

Implantation

Explantation consists in cultivating malignant cells outside the organism (in

vitro). This method gives a possibility to induce neoplasia by cancerogenic chemical
substances and oncoviruses in healthy cells out of the organism. This method is of
л particular value because it gives a possibility to study human malignant cells. This
method also confirms immortality of malignant cells. This method allows investi
Hating the effect of drugs on the cellular level.

E T IO LO G Y

Etiological factors, which cause malignant tumors, are called cancerogens. The
agents intensifying the effect of cancerogens but not causing tumors themselves are
i ailed cocancerogens. Cancerogens, which have all these effects, are called syncan
4 ‘rogens.
Cancerogens may be exogenous (physical, chemical and biological) and en
dogcnous.

Physical Factors

The physical factors are ionizing and ultraviolet radiation, radioactive isotopes
d»l iodine, radium) and ultrasound. They may cause neoplasia in such small doses,
which do not cause radiation disease.
'nil I («t'licml Pathophysiology

hemieal Cancerogens

( hemieal cancerogens are compounds of carbon (polycyclic aromatic hydro-

aihons PA IIs) and nitrogen (nitrosamines or aminonitrocompounds).
M Beuzopyrene, 9,10-dimethyl-l,2-benzantrazen refer to PAHs. PAHs are
vulcly spread. They are products of incomplete burning and form at 400—500°C
I hf lemperature of tobacco burning in a cigarette). They are found in smoke, over-
urd oil, exhaust gases, smoked food, oil and coal.
Polycyclic aromatic hydrocarbons have a predominantly local effect (cause
iimors in the place of entry or greatest accumulation). When applied on the skin,
hev cause cancer, in subcutaneous introduction they cause sarcoma. They may
ause tumor in the organs, in which they are accumulated: a mammary gland tu-
nor is formed when chemical cancerogens are excreted in milk, kidney tumors may
levclop when cancerogens are excreted in the urine.
Aminonitrocompounds have an organotropic effect irrespective of the way of
•ni i \ I )imethylaminoasobensol causes cancer of the liver in 80 % of cases regard-
css of the place of introduction, |3-naphthylamine causes cancer of the urine blad-
Iri Nitrosamines are also organotropic. Diethylnitrosamine causes cancer of the
ivt*i and esophagus. Methylnitrosurea causes tumor of the brain.
Non~organic carcinogenic substances are chromium, arsenic, cobalt, lead,
ilckel, etc.

lilologlcal Cancerogens

Biological cancerogens are viruses called oncoviruses.

Only experiments may prove the role of viruses in neoplasia, when tumor re-
Moduction is possible with noncellular filtrate of malignant tumor.
I here is an essential difference between infectious and oncological viruses. An
nlet tious virus multiplies in cells and leads to cell death, and an oncovirus masks
и .1 cell and initiates endless cell multiplication. Oncoviruses are not rejected by
mmime mechanisms; vaccination is not possible.
I spending on the type of the nucleic acid, oncoviruses are divided into DNA-
ind RNA-genome viruses.
A I >NA genome virus can penetrate into the genome of a healthy cell and
i.iiisloim it into a malignant one. Epstein—Barr virus causing Burkitt’s lymphoma
и men belongs to this group.
An RNA-genome virus (called oncornavirus or retrovirus) does not have this
lhilily, nevertheless it influences the genome of a cell by transmitting the genetic
nlormal ion from the viral RN A to the D N A of a cell. An RNA-genome virus has
i gene of enzyme revertase (RNA-dependent DNA- polymerase), which performs
.uch transmission and helps to synthesize DNA-copies on the RN A gene of the
arue.
Such human tumors are supposed to be caused by oncoviruses:
• Bin kilt s lymphoma, which is spread as an epidemit among children in the
countries of ( ’ent rnl Africa,
 Chapter 10. Neoplasia

• T-cell lympholeukemia of adults. The patients have antibodies against virus

proteins.
• Tumors in A ID S patients are supposed to be caused by the virus H T LV -III.
The proofs are:
• tumors (Kaposi’s sarcoma) concomitant with A ID S;
• it is spread with A ID S.
The genome of an RNA-containing oncovirus is rather simple, it has 4—6 genes,
and only one of them ( oncogen) can transform a normal cell into a malignant one.
Investigations show that oncogens are similar to the human genes of growth fac­
tors (thrombocytic, epidermal) as well as of other regulators of cell division — their
membrane receptors, intracellular messengers. Penetrating into a healthy somatic
cell, such viruses initiate the formation of the so-called oncoproteins, stimulators
of cell division.
The similarity between oncoviruses and the organism is one of the reasons for
a problem of oncovirus rejection (elimination). It is considered that viral oncogens
are components of the normal human genome (they are called protooncogens), but
under physiological conditions they are repressed.
The virus-genetic theory of neoplasia etiology is the most acceptable. It suggests
that physical and chemical factors cause neoplastic transformation by activating
viral oncogenesis.
Except viruses, some other biological objects can cause neoplasia. Among them
there is the fungus Aspergillus flavus, which synthesizes aflatoxin — a substance
causing tumors of the liver. This fungus multiplies well in most environments. It
may affect rice, peanuts, powdered milk, eggs and corn.

Endogenous Cancerogens

Endogenous cancerogens are steroid hormones (folliculin), bilic acids, choles­

terol, free radicals, peroxides, derivatives of the amino acid tryptophan (indole).
Studying the etiology of tumors, it is necessary to take into consideration the
law, according to which the presence of etiological factors is not sufficient for the
development of the pathologic process, and additional conditions are necessary.
I he necessary condition for neoplasia development consists in additional stimula
lion of cellular proliferation. It is known that neoplasm is frequently formed in the
*enter of chronic proliferative inflammation.
The knowledge of tumor etiology (etiological factors and conditions) is of
practical importance for neoplasia prevention. These factors and conditions must
In* avoided.

PA T H O G E N E S IS (C A N C E R O G E N E S IS )

Pathogenesis of neoplasia proceeds in three stages:

1. Neoplastic transformation.
2. Neoplastic promotion.
3. Neoplastic progression.
РнИ I (н'ИСГН! I’ntllophvsloloKy

N EO PLASTIC TRANSFORMATION

Neoplastic initiation ( malignization) is a process of transformation of a normal

cell into a malignant one and transmission of new properties to descendant cells (a
malignant cell produces only malignant ones).
I Ik* mechanisms of neoplastic transformation have not been completely stud­
ied yet. Nevertheless, the idea that malignization results from a stable change in
the cellular genome has been generally assumed. There are some theories of malig­
nancy, which are given below.

Theory of Mutative Cancerogenesis

I his theory is proved by the fact that all the etiological factors are mutagens.
I Ih* essence of this theory consists in the assumption that mutation (damage of the
genes responsible for cellular division) is a cause of malignization. The process of
cellular division loses inhibition and becomes endless. Since mutation is irrever­
sible, neoplasia is also irreversible. Mutation of the gene P53leads to apoptosis block
and thus cells avoid death.

Theory of Epigenomic Cancerogenesis

According to this conception, cancerogens do not destroy the structure of the

somatic cell genetic apparatus (mutation does not occur). This is proved by rare
cases of malignant cells returning into the normal state. It is assumed that the ge­
net ic apparatus is dysregulated under the effect of the factors, which do not belong
to the genome. These factors are located in the micro- and macromedia (cyto­
plasm, organism as a whole). The nature of these factors has not been established
yet. A protein, which is produced with oncovirus participation and inhibits the
gene-repressor of cell division, may be such a factor.

Theory of Protooncogen Effect

The normal human genome has been proved to have genes similar to viral
oncogens (the scientific term for these genes is protooncogens). The real function
o! these genes is participation in embryogenesis regulating cellular sensitivity to
growth factors. During a normal postembryonic period these genes are inactive
(repressed).
I he essence of this theory is the assumption that these genes can become ex-
* essively active, and different etiological factors (including physical and chemical
mutagens) play a role in this activation. DNA-copies of oncoviruses may play the
promotor role. An activated protooncogen is called active cellular oncogen. It is that
which leads to neoplastic cell transformation.
Active cellular protooncogen expression leads to increased oncoprotein (tumor
protein) synthesis. It is supposed that:
• oncoproteins act as growth factors;
• o n c o p r o t e i n s b in d with c e llu la r g r o w th fa c t o r t n r p i n r . and g e n e ra te signals
lo r cell division;
 Chapter 10. Neoplnsiu

• oncoproteins increase the sensitivity of growth factor receptors or decrease

sensitivity to growth inhibitors;
• oncoproteins play the role of cellular protein kinase, which starts cellular
division.

( )ncogerminative Theory of Cancerogenesis

Cohnheim was the first to pay attention to the similarity between malignant
and embryonic cells and offered an oncogenesis theory named the theory o f em­
bryonic rests. According to it, neoplasm develops as an atypical embryo in atypical
place. Thus, malignization is embryonalization and oncogenesis is blocked embryo-
genesis. Nowadays this conception received further development.
The similarity between malignant and embryonic cells consists in the follow­
ing.
• Common m arkers (markers are substances, which provide the growth, de­
velopment and function of tissue - hormones, enzymes, activators, inhibitors, as
well as immunoregulatory, transport, receptor and structural proteins). In fact, all
cancer markers are found in the embryonic tissue. It determines common biological
properties — implantation ability, invasive growth, autocrine regulation.
• Im m unological tolerance to the presence in the organism of foreign genetic
information. Due to these mechanisms in a pregnant woman a half-foreign embryo
is not rejected but preserved («protection of something foreign within the organ­
ism»). The mechanisms are the following — masking of foreign antigens, blocking of
lymphocytic aggression by antibodies, activation of T-suppressors (markers possess­
ing suppressive activity). The same mechanisms are found in the organism with a
neoplasm. On the one hand, neoplastic antigens are immunogenic for the organism
itself; on the other hand, an oncospheroid can escape from immune supervision.
I he causes of escape are low immunogenicity of malignant cells, adsorption of
blocking antibodies on their surface and their defense against the cytotoxic effect
of macrophages and T-lymphocytes. It is supposed, that the trigger role belongs to
antigens, which are common for a neoplasm and an embryo.
• Parthenogenetic division and multiplication of one single fertilized egg and
one signal malignant cell after transformation. Neoplasm is not a group of simple
copies of a primary transformed cell; it is a heterogenic population of cells. Similar
lo blastocyst formation, an oncospheroid has three germ layers with their own spe-
eilic functions — differentiated somatic cells (determine various histological types
of tumors - melanoma, neuroma, sarcoma, etc.), oncotrophoblastic and germ cells
(oncogerminative). Then, similarly to blastocyst, an oncospheroid provides further
development. In an embryonic anlage every germinal layer harmoniously develops
according to its function. Contrary to this, a tumor anlage has abortive embryonal
development. So, oncogenesis is a blocked embryogenesis. An oncospheroid de
vclops in the direction of a progressive decrease of the quantity of differentiated
•His, which are substituted by germ and trophoblastic cells (neoplastic progression,
see below).
I'liil I. ( n i i m i l I ’lilliopliyslolou.v

• Im m ortality is another common properly of malignant and embryonal cells

(malignant cells are endlessly transplanted in new hosts under experimental condi­
tions). Similarly to the infinite line of germ cells of multicellular organisms, ma-
lignant cells are endless. It is supposed that this property is genetically determined.
I Jiuler normal conditions a group of genes are believed to function only in germ
cells (in somatic cells they are repressed) providing the genetic program of immor-
lality. This very group of genes is considered derepressed in one somatic cell in the
course of neoplastic transformation and it is the main link of oncogenesis.

N EOPLASTIC PROM OTION

Neoplastic promotion is the second stage of cancerogenesis. A transformed cell

may he in the latent state for a long time, but begins to multiply under additional
efleet of promotors. It is a preclinical stage of neoplasia, when multiplication of
malignant cells has already begun, but clinical manifestations are still absent. Dif-
leient factors can play the role of promotors (cocancerogens), but the majority of
cancerogens cause simultaneous transformation and promotion. The growth factors,
which are elaborated during inflammation, may play this role.

NEO PLASTIC PRO G RESSIO N

Neoplastic progression is the third stage of cancerogenesis. Its essence is a

stable qualitative change of neoplasm in the direction of constant (progressive) ag­
gravation of malignant properties.
I he supposed mechanisms of neoplastic progression are the following:
• constant selection of the most viable malignant cells;
• escape of malignant cells from immune supervision;
• increase of oncogerminative cells quantity and replacement with them of
other oncospheroid cells;
• additional spontaneous mutations of malignant cells;
• additional action of cancerogens on the genome of malignant cells;
• superinfection by infectious and oncoviruses.
New cells differ more and more from those primarily transformed. Anaplasia
aggravates. Clinical manifestations appear.

ROLE OF G EN ETIC FACTORS IN NEO PLASIA

At the cellular level, malignant properties are inherited dominantly (dominant

somatic inheritance). It is observed both in vivo and in vitro as well as during tumor
transplantation. Malignant cells, being multiplied, produce only malignant cells. It
is supposed that in the course of malignization there takes place derepression of the
genes connected with endless division and immortality ol germ cells.
At the level of the whole organism, predisposition to neoplasia is inherited
polvgenetically. It means that both genetic and environmental factors are impor
I.mt in the development of a malignant tumoi ( iene and «specially chromosome

148
anomalies predispose to neoplasia development (this predisposition was noted in
chapter 1, p. 52) as well as immunodeficiency (this predisposition was noted on
p. 82).
Hereditary predisposition is proved statistically. The phenomenon of «canccr
families» has been described. High- and low-cancer lines of experimental animals,
which have increased or decreased resistance to cancerogens, are created under
experimental conditions.
Genetic factors determine the mechanisms of organism reaction to cancero­
gens and defense against tumors. The genetically determined disturbance in the
immune system considerably increases the frequency of neoplasia. T-lymphocytic
and combined immunodeficiency increases the risk of neoplasia.
Men are more frequently affected with stomach cancer while women more
frequently have tumors of the sexual and mammary glands.

PE C U LIA R IT IE S OF TU M O R GROWTH

The phenomenon of im m ortality of neoplastic cells, both in vivo and in vitro,

is a cardinal sign of neoplasia. Hayflick limit is lost (the upper limit of the n u n i
her of cell divisions; normally there are about 50 divisions, after which cells die).
Transformed cells develop in the direction to the embryonic state. Their growth
is independent. Tumor is originated from a single transformed cell having its own
growth stimulators. New cells transmit their peculiarities as a dominant sign of
somatic inheritance.
The endless growth of malignant cells is another cardinal sign of neoplasia. In­
hibition and limitation of cell division are lost. Membrane receptors become more
sensitive to growth factors.
Intercellular contacts are weakened. It is a matter of membrane receptors and
eytoskeleton disorder (radicals of neuraminic acid and glycoproteids are active).
I he cells become too mobile. Cell multiplication is chaotic and tissue structure is
violated. The growth is characterized by infiltration and invasion of the neoplasm
into the normal tissue.
Malignant cells synthesize enzyme collagenase, activator of plasminogen (pro
hhrinolysin) and other proteolytic enzymes, which destroy the connective tissue.
I hey involve mast cells and phagocytes into the destruction of the surrounding
normal tissue.
Malignant cells induce capillary formation (by synthesis of angiogcnin and
oilier growth factors) providing blood supply of the tumor tissue with substrates,
glucose, and amino acids. Heparin intensifies angiogenin effect and growth of the
vessels into the tumor tissue.
Malignant cells dissolve the collagen of the vessel basal membrane and get into
the blood and lymph promoting infiltration and metastasis. In this way they spread
throughout the organism. In a new place they induce development of the same
tumor.
Metastasis is spreading of a malignant tumor to other organs. Metastasis pre
serves the properties of the primary tumor.

liiO
Г . Ill I . ( • 4*tl(* I'll I I'lld lo p llY sln lo K V

I he order of events in metastasis is the following .1 ) tearing off of malignant

cells from the tumor; b) dissolution of the connective tissue of blood and lymphatic
vessels; c) spreading in the organism by the blood and lymph; d) adhesion to the
vascular wall at a new place; e) growing into the new tissue, fixation and formation
of a new malignant node.
In a new place malignant cells also demonstrate their cardinal properties — in-
lilt rat ion and invasion of a new tissue, endless growth, immortality.

N E O P L A S IA M A N IFEST A T IO N S

Neoplasia manifestations are local and systemic.

Local manifestations are qualitative changes in malignant cells (anaplasia).
Systemic manifestations are the signs of interrelation between the organism and
malignant tumor (influence of the organism on the tumor and vice versa).

ANAPLASIA

Qualitative changes in malignant cells are characterized by such terms — ana-

plasia , metaplasia or atypism.
Anaplasia is dedifferentiation (simplification, immaturity, return to the embry­
onic state). Actually, malignant cells resemble the embryonic ones. However, there
is an essential difference — embryonic cells are normal and have differentiation
potentiality. In spite of similarity to embryonic cells, malignant cells are patho­
logical. They don’t have differentiation potentiality, have a changed morphology,
metabolism, antigen structure. Therefore, such terms are used to describe malignant
transformed cells — metaplasia and atypism.
Such types of anaplasia are distinguished — morphological, energetic, bio­
chemical, physicochemical, immunological, functional. From all these points of
view malignant cells are simplified and similar to embryonic cells.

Morphological Anaplasia

Morphological anaplasia is morphological signs of simplification and immatu-

iilv of malignant cells. Microscopic investigation reveals similarity between malig­
nant and embryonic cells.
The signs of morphological anaplasia are the following.
• Partial or total loss of maturity.
• Increased mitosis.
• Disorder of the mitotic process. Incomplete mitosis is nuclear division without
cytoplasm division. It is possible to see malignant cells with two nuclei and cell
division into unequal parts. Cellular polymorphism is obtained.
• Presence of a nucleoli in the nucleus of a malignant cell.
• A large nucleus with multiple vacuoles.
• I he nuclcocytoplasmic relation is changed: the nucleir. occupies a larger part of
a cell

ISO
 ( h a p lc i I" Neoplasia

• The cell shape becomes round.

• Phenomenon of cytoplasm budding (the surface tension of the membrane is low
ered).
• Mitochondria pathology — changes of the number (decrease), size and shape.
• The Golgi apparatus structure changes.
• The cytoplasm becomes basophilic (due to R N A presence in the granular cyto­
plasmic reticulum).
• Hyperchromia of cells (they are more intensively dyed).

Biochemical Anaplasia (Metabolic Disorder)

Energetic anaplasia is a change of the energy formation type as in embryonic

cells.
For their constant growth and energy formation, malignant tumors require
more glucose (a malignant tumor is a «trap» for glucose). The blood, which flows
out of the malignant tumor, does not contain glucose.
Similarly to embryonic cells the malignant ones form energy by glycolysis. The
linal products are pyruvate and lactate (glycolysis, which accomplishes in the pres
once of oxygen, is called aerobic). The quantity of mitochondria is decreased, and the
activity of oxidative enzymes is depressed. Glycolysis is intensified. There is a nega­
tive Pasteur effect (it means that glycolysis is not replaced by oxidation in the pres­
ence of oxygen). As a result, lactic acid is accumulated in a large concentration.
Biochemical anaplasia consists in enzymatic decomposition, which is similar
to the embryonic state. The quantity of enzymes, which provide differentiation and
specific function, decreases. The quantity of enzymes, which stimulate cellular di­
vision, increases. The change of enzymatic composition results from repression of
some genes and derepression of other ones.
If an RNA-virus is an etiological factor, revertase appears in malignant cells.
The synthesis of nucleic acids and proteins is considerably intensified. The
pentose phosphate pathway of metabolism, which leads to an increased formation
of pentose (for nucleic acid synthesis), is activated. Protein synthesis for the mitotic
apparatus is considerably increased.
Malignant cells require more amino acids for constant division, multiplication
and synthesis of proteins. Therefore, a malignant tumor is a «trap» not only for
glucose but also for nitrogen and cholesterol of the blood. All substrates are used
lor energy production.
The synthesis of histones (suppressors of D N A synthesis; without histones pro
ii in synthesis changes qualitatively and quantitatively) is decreased.
c-AM P is reduced (normally c-AM P depresses division). It underlies the acti
vation of cell division. c-G M P is elevated.
Intensive synthesis of oncoproteins (tumor proteins) from protooncogens is
characteristic.
Embryonic a-fetoprotein is synthesized. There is physiological immunological
tolerance to this protein and the organism doesn’t form antibodies against il (the
presence of embryonic a-fetoprotein in the blood usually confirms the diagnosis ol
liver cancer).

151
Purl I PlKlloploNiolo^V

Somciimcs malignant tumor synthesizes such proteins, which arc not typical of
tissues before their transformation (for example, hormones).

Physicochemical Anaplasia

Some physical and chemical indices are changed in malignant tumors towards
the embryonic state.
• Quantity of water is increased.
• ( ilycolysis activation together with an increased amount of K +leads to lactic acid
accumulation and intracellular acidosis development (cell pH is reduced to 6.4).
Hut in the blood alkalosis develops due to compensatory mechanisms.
• ( outent of potassium is increased.
• ( outent of calcium and magnesium is reduced.
• I leetrical conductivity increases.
• I'he surface tension of the cellular membrane is reduced (due to a decreased
amount of Ca2+). Intracellular adhesion is reduced, and malignant cells easily
move into the surrounding normal tissues in invasive growth.
• ( olloid viscosity is reduced.
• Malignant cells have a negative charge. Due to the negative charge of leukocytes,
the latter do not approach malignant cells.
I lie dilfusion of metabolic substances into cells and of their products — outside
cells is stimulated.
Malignant cells are intensively dyed.

inmiinological (Antigen) Anaplasia

I he antigenic composition of tumor cells is changed. Some antigens disappear

antigenic simplification), some new antigens appear.
Normal tissue specific and individual antigens are lost completely. Species-
peeilie antigens (to which a tolerance exists) remain. It explains the fact that
nm<(transplantation of a malignant tumor is possible while heterotransplantation
i not.
On the other hand, antigen complication of malignant cells takes place. Anti-
•ns, which are produced by a viral oncogene, are found in a malignant tumor. The
nthesis of embryonic (fetal) antigens is derepressed; embryonic proteins are pro-
lu ed Fetal a protein is found in hepatoma. Tumor of the liver may be diagnosed
у the presence of this protein in the blood before any clinical manifestations. Ac-
deutal antigens may appear as a result of additional mutations of malignant cells
ulci the cffcct of cancerogens.

inelioual Anaplasia

I he division of malignant cells is changcd. During initial neoplasia stages the

pe id division is parthenogenesis and later mitosis.

2
 Chapter 10. Neoplasia

The functions of malignant cells are simplified. Malignant cells lose those spe
cific functions (secretion, formation of mediators and hormones, excitability, etc.)
that were typical to them before transformation. Secretion of the gastric juice in
■.loinach cancer (achylia) and bile formation in liver cancer are suppressed. Tumor
of the pancreas cells causes hyperglycemic conditions and even coma.
In addition, functional metaplasia may consist in production of substances,
which are unusual for this organ. For example, malignant tumor of the pancreas
sometimes synthesizes gastrin; thyroxin was revealed in a malignant tumor of renal
origin; synthesis of a thyroid gland hormone (calcitonin) was revealed in breast
«.mcer; hormones of the pituitary gland (A D H , A C T H ) are synthesized in lung
i .nicer. Uncontrollable synthesis of hormones (hormone-producing tumors) may
occur.
S Y ST EM IC M ANIFESTATIONS OF NEOPLASIA

Neoplasm is a local manifestation of a systemic disease. More frequently it is

lethal. However, the organism influences tumors by developing defense reactions.
Only in the organism with depressed reactivity the development of malignant tu­
mors is possible.

MALIGNANT T U M O R AND O RGAN ISM REACTIVITY.

INI LUENCE OF ORGANISM ON TUM OR

The law, according to which the course of any pathological process depends
not only on the etiological factor, but also on organism reactivity, refers to neopla­
sia as well.
Examining the patient it is possible to see reactivity depression, however, it
is difficult to assess defense reactions. An experiment allows conducting such an
Investigation.
The method of transplantation shows that transplanted malignant cells do not
always multiply. A small quantity of malignant cells cannot be transplanted.
Successful transplantation requires sterility. If inflammation develops in the
place of transplantation, the transplant can die. Even after providing all necessary
conditions (sufficient mass of malignant cells, sterility) transplantation may not be
successful in 100 % cases.

Mcchanisms of Protection against Tumor

The method of transplantation consists in transferring malignant cells into

healthy animals; many defense reactions have been discovered in such a way.
Defense reactions are divided into nonimmune (including genetic) and im
inunc.
Hie nonimmune mechanisms of protection are metabolic (elimination of can
MMogeus, inactivation of peroxides and free radicals, antioxidant protection), en
ynui/ic (damaged DNA repair), cellular (phagocytosis, the effect of leukocytic
hilt I (.«iicial I'ullioplivsioloKy

lysosomal factors), genetic (a gene-repressor of a viral oncogen). O.O. Bohomolets

described the cancerolytic property of a healthy blood serum
I he method of explantation shows that after mixing a small quantity of normal
and malignant cells the latter sometimes grow as normal ones and are capable of
accepting inhibitory signals from normal cells.

Mechanisms of Immune Protection

Appearance of tumor cells in the organism does not necessarily result in the
development of a tumor process. The immune tissue controls antigen homeostasis
m I lie organism (a clone of cells with any antigenic differences is eliminated by
immunological reactions). It refers to tumor cell clones. The immune system is the
main system of protection against tumors.
II is a function of T-killers to eliminate mutant somatic cells involving phago­
cytosis and complement. This mechanism is also extended onto mutant malignant
t ells. Isolated malignant cell-mutants are as a rule recognized and eliminated by
I killers, cytolysis and phagocytosis mechanisms. Since malignant cells have some
new antigens (viral), B-lymphocytes can form antibodies. Interferon is an inhibitor
of nucleic acids of viral origin.
These mechanisms of immune protection against malignant tumors have been
well studied under experimental conditions in healthy animals, to which malignant
cells were transplanted.
().(). Bohomolets proclaimed that the development of a malignant tumor is
theoretically impossible if the connective tissue is healthy. The transformed cells
aie destroyed in such a case, and therefore clinical manifestations of tumors are
noted less frequently than neoplasia occurrence. Consequently, malignant tumor
development is possible only against the background of reduced immunological
reactivity.
Investigation of patients with malignant tumors shows that their immune reac-
tions are depressed.
Causes o f immunodepression are: a) effect of etiological factors (all cancerogens
suppress immune reactions); b) overload of the immune system with a tumor of a
large mass.
Malignant tumors have their own mechanisms o f escaping from immune supervi­
sion. They arc:
• antigen simplification of malignant tumor;
•appearance of fetal antigens, to which the organism has immunological toler
anee;
• masking of tumor antigens (for example, chorionepithelioma cells have a
neutral polysaccharide capsule);
• a negative charge of tumors and leukocytes.
A surprising phenomenon was described in an experiment Antibodies, which
.ue formed in response lo tumor antigens, do not destroy .1 minor, but, on the con­
trary, protect il. I hey are fixed on malignant cells and him к tin cytotoxic effect of
I killers ami macrophages. In some tumors there are sevcml antigen determinants,

I— 111 ............ * _ ...............

 Chapter 10. Neoplasia

which stimulate T-suppressors. It is pathological immunological tolerance (this notion

was given on p. 80). It is supposed that the same mechanisms underlie both physio
logical immunological tolerance to an embryo (fetus) and to malignant cells.

IH M O R IN FLU EN C E ON ORGANISM . C LIN IC A L M ANIFESTATION S OF NEO PLASIA

Neoplasia is a disease of the entire organism.

As to its clinical manifestations, they depend on the form of the tumor and its
localization (details are studied at clinical departments).
Independently from localization, malignant tumor leads to extreme exhaus
lion, which is called cancer cachexia. It is caused by retention of glucose, carbon,
nitrogen, amino acids by a tumor. All reserves are depleted.
Neoplasm development is accompanied with intoxication by tissue decay prod
nets. Malignant cells produce substances (peptides), which activate apoptosis ol
healthy cells (for example, erythropoietic, resulting in diserythropoietic anemia).
Anemia develops irrespective of the localization of malignant tumors. This anemia
together with leukopenia appears to be the hematological syndrome, which accom
panies neoplasia.
Immunological depression provokes infectious diseases.
In neoplasia pathogenesis, the state of the endocrine system matters. At old
age the risk of neoplasia development rises. Uncontrolled synthesis of hormones
sometimes occurs. Hormones themselves may become cancerogens.
Patients lose weight. Lethal outcome is frequent.

Questions for Self-Control

I Why is it difficult to study the etiology and pathogenesis of neoplasia under

clinical conditions?
' What is the connection between neoplasia etiology and human growth
factors?
\ Explain the difference between DNA- and RNA-dependant viruses.
I Explain the terms — oncovirus, oncogen, oncornavirus, retrovirus, oncoprotein,
protooncogen.
S What are the local and organotropic effects of cancerogens?
(* What facts has the method of transplantation revealed?
/ What theories of neoplastic transformation do you know?
К What types of anaplasia are determined in neoplasia?
{) What are the defense reactions of the organism against neoplasia?
10. What are immune protective mechanisms against neoplasia?
11 What does the polygenetic type of neoplasia inheritance mean?
I’ What are the causes of immunodepression in neoplasia?

155
'. I l l I. ( i i 'I H T H l P m l i o p l i v s i o l o K )

Tests and Tasks for Self-Control

(give correct answers and find mistakes in the statements)

1 <iive the characteristics of neoplasia.

1. It is a typical pathological process.
2 . It is a controlled growth of tissue, which does not correspond to the gene­
ral structure and function of the organism.
3. Tumors may be benign (usually lethal) and m alignant (usually do not sub­
stantially impair the vital activity of the organism).
4. The term neoplasm is not a synonym of malignant tumor.
5 . There is no so-called limit of division in neoplasm.
6. Growth of transformed cells infiltrates the healthy tissue.
7. Dedifferentiation and return to the embryonic state are noted in neo­
plasm.
8. Partial or total immaturity of malignant cells is proved.
9. Neoplasm has no own growth stimulators.

2 Experimental study of neoplasia.

1. Experimental oncology gives no possibility to study the value of genetic
factors in neoplasia development.
2 . Induction is reproduction of tumor by applying different oncogenic fac­
tors.
3. The viral origin of malignant tumors is scientifically proved by malignant
tumor induction under experimental conditions by a noncellular filtrate of
this tumor.
4 The method of explantation consists in malignant cells cultivation outside
the organism (in vitro).
5. High-cancerous populations of animals can not be created in laborato­
ries.
6. Homotransplantation of malignant tumors is impossible.
7 Heterotransplantation of malignant tumors does not succeed.
8. Transplantation of human tumors on animals is successful.
9. Hie method of transplantation does not prove neoplastic cell immorta­
lity.

l (iive (he characteristics of neoplasia etiology.

I T he etiological factors, which cause malignant tumors, are called cancero­
gens.
2. ( 'ancerogens may be exogenous (physical, chemical and biological) but
not endogenous.
3 The presence of an etiological factor is sufficient lor the development of
neoplasia without any additional conditions.
I, Neoplasm is often formed in the center of chronic proliferative inflamma
(ion,
 Chapter 10, Neoplasia

Chemical cancerogens:
5. They are compounds of carbon (polycyclic aromatic hydrocarbons
PAHs) and nitrogen (nitrosamines).
6. There are no PAH in the environment.
7. PA H have a predominantly organotropic effect.
8. Nitrosamines have a local effect.
Endogenous cancerogens are:
9. Bilic acids.
10. Steroid hormones (folliculin) never act as cancerogens.

4. Pathogenesis of neoplasia.
1. Neoplasia pathogenesis proceeds in three stages.
2. Neoplastic progression is the first stage.
3. Neoplastic promotion is the second stage.
4. Neoplastic transformation is the third stage.
5. The malignant cell genome remains stable during malignization.
6. A transformed cell begins to multiply under the additional effect of pro
motors.
7. A malignant cell may produce only malignant cells.
8. A malignant cell does not transmit new properties to descendant cells.
9. The process of cellular division loses intercellular contact inhibition and
becomes endless.

5. A clinical examination of a patient allowed giving a preliminary diagnosis: liver

cancer. The presence of what type of protein in the blood will confirm the
diagnosis?
A. y-Globulin.
B. Properdin.
C. Paraprotein.
D. C-reactive protein.
E. a-Fetoprotein.

(». Experimental animals received sodium nitrite with food. In 80 % of cases

tumors developed. What type of cancerogens does this substance belong to?
A. Nitrosamines.
B. Aminonitrocompounds.
C. Polycyclic aromatic hydrocarbons.
D. Simple chemicals.
E. Hormones.

/, A man has been working for a long time in the petroleum-refining industry.
What classes of carcinogenic agents did he contact?
A. Nitrosamines.
B. Aminonitrocompounds.
C. Polycyclic aromatic hydrocarbons.
Г .111 I (.meritI I'jiIIioiiIivsIoIoky

I). Carcinogenic agents of biological nature.

I Simple chemicals.

8. A 62-year-old patient suffers from nausea, bloody vomiting, pain in the

abdomen, fatigue, loss of appetite and weight, sleeplessness. The tissue of the
gastric mucosa was investigated by biopsy. Carcinoma of the stomach with
metastases was diagnosed.
Give the characteristics o f neoplastic growth:
1. Malignant growth is characterized by infiltration of malignant cells into
the normal tissue.
2. Malignant cells have strong intercellular connections.
3. Malignant cells spread throughout the organism.
4. In a new place malignant cells cause the development of another tumor.
5. Metastasis is the development of the same malignant tumor in other or­
gans.
The metastasis mechanisms are the following:
6. Plasminogen activator synthesis (the enzyme which destroys the connec­
tive tissue and vessels).
7. Synthesis of collagenase, which destroys the vascular wall collagen.
8. Angiogenin and other growth factors of the vessels are synthesized by a
tumor providing blood supply of the tumor tissue.
9. Loss of cellular contact inhibition.

9, A diagnosis of gastric carcinoma was given to a 63-year-old patient. There have

been two cases of malignant tumor in this family. Give the characteristics of
the role of genetic factors in neoplasia development.
1. Hereditary predisposition is not proved statistically.
2. In the development of malignant tumor genetic factors are important
while the environmental ones are not.
3. Genetic factors determine the mechanisms of defense against the tumor
and organism reaction to cancerogens.
4. Genetically determined disturbances in the immune system considerably
decrease the frequency of neoplasia.
V Men are more frequently affected by stomach cancer while women more
frequently have tumors of the sexual and mammary glands.
6. Iligh-cancerous lines of experimental animals are created under experi­
mental conditions.
7. High-cancerous lines of experimental animals have an increased resis­
tance to cancerogens.
8. I -lymphocytic and combined immunodeficiency increases the risk of
neoplasia.
9. I he existence of cancer families is a statistical proof of genetic factors
role.
10 Predisposition of the organism to neoplasia is inhniUHl reecssively,
 Chapter 10. Neoplasia

10. Anemia and a malignant tumor of the uterus were diagnosed in a 58-year-old
woman, who suffers from pain in the abdomen and uterine hemorrhage. What
are the systemic manifestations of neoplasia?
1. Neoplasm is a local manifestation of a systemic disease.
2. At old age the risk of neoplasia diminishes.
3. Uncontrolled synthesis of hormones sometimes occurs.
4. Independently from the localization of malignant tumors, anemia deve
lops.
5. Systemic manifestations of neoplasia are a peculiarity of growth and quali­
tative changes in malignant cells (anaplasia).
6. Systemic manifestations of neoplasia result from interrelation between the
organism and a malignant tumor (influence of the organism on the tumor
and vice versa).
7. The organism does not influence tumors.
8. There are no defense reactions of the organism against malignant tu­
mors.
9. Only in the organism with depressed reactivity the development of malig
nant tumors is possible.
C hapter I I
HYPOXIA

Hypoxia is one of the most widespread pathological processes. All the diseases
from birth till death have a hypoxic component.
Hypoxia is a typical pathological process developing due to insufficient oxygen
supply to tissues or impaired oxygen use resulting in energy (in the form of A TP)
production disorder.
Lack of oxygen and energy (A T P) leads to disorders of metabolism and energy-
linked functions of the organism.

CLASSIFICATION

According to localization, hypoxia is divided into local and systemic. According

to clinical course, it may be acute and chronic. According to causes and mecha­
nisms of development, it is classified as hypoxic ( exogenous), respiratory, hemic,
circulatory , histic and combined.

ET IO LO G Y

Hypoxia refers to the so-called polietiological pathologies. All the reasons,

which cause insufficiency of the systems of oxygen transport and utilization (the
lungs, vascular system, blood), cause hypoxia.
Etiological factors are physical, chemical and biological. Their common property
is disturbing oxygen entry into the organism, its spread in the organism or utilization.
Mechanical traumas of the chest disturb breathing. Narcotics damage the respiratory
center. Chemical poisons inhibit respiratory enzymes. Microbes (pneumococcus)
cause pulmonary inflammation. The list of such examples may be continued.
For practical purposes one should know the causes of every type of hypoxia. 1

Hypoxic Hypoxia

Hypoxic hypoxia develops under conditions of low partial oxygen pressure

(p 0 2) in the inspired air. A typical example is mountain disease and other examples
of hypobaria (see p. 34). Industrial accidents with impaired oxygen supply are an- ;
other example. Under laboratory conditions, this type of hypoxia is modeled in a
pressure chamber (it gives a possibility to investigate pure hypoxia, which is not
underlain by physiological system disorders).

Respiratory Hypoxia

Respiratory hypoxia is caused by the factors, which disturb lung ventila-1

lion, perfusion (blood supply) or gas diffusion described In every detail in chap-1
 ( -hapter 11■Hypoxia

u*r 26 «Pathophysiology of Respiratory System». Respiratory hypoxia is the main

pathophysiological manifestation of respiratory insufficiency (p. 401).

Ilemic Hypoxia

Hemic hypoxia is caused by the factors, which impair oxygen capacity of the
blood. Hemic hypoxia is subdivided into anemic hypoxia and hypoxia caused by
hemoglobin inactivation.
Anemia as a cause of hypoxia is discussed in chapter 20 «Pathophysiology of
I rythrocytes. Anemia». It has hemic hypoxia as the main pathophysiological mani
Irstation (p. 278). Hemorrhage as a cause of hemic hypoxia is discussed in chapter
19 devoted to blood loss (p. 269).
As to hemoglobin inactivation, in pathologic conditions such hemoglobin com­
pounds are formed, which are not able to perform the respiratory function. It is
airboxyhemoglobin, formed from hemoglobin and CO (carbon monoxide, whose
affinity for hemoglobin is 300 times more than for oxygen); this kind of hemoglobin
ran not bind oxygen; the iron-containing enzymes are also inactivated. Methemo
globin is formed during poisoning with nitrates and some drugs with an oxidizing
capacity. In this form of hemoglobin trivalent iron does not bind oxygen.

Circulatory Hypoxia

Circulatory hypoxia is caused by the factors, which disturb local or systemic

blood circulation. Local circulatory hypoxia is subdivided into ischemic and con­
gestive forms (see information on ischemia, thrombosis, embolism, and stasis in
chapter 7 «Pathophysiology of Peripheral Blood Circulation»). Chapters 24 and 25
deal with problems of acute and chronic insufficiency of the heart and systemic
blood circulation.
If a disorder occurs in the system of greater circulation, blood oxygenation
can be unchanged, but there are some disorders in oxygen transfer into tissues. If
changes occur in pulmonary blood circulation (lesser circulation), blood oxygen­
ation is impaired.
Circulatory hypoxia may develop not only in absolute but also in relative insuf­
ficiency of blood circulation, when the tissue need for oxygen exceeds normal blood
supply. Microcirculatory disorders also lead to hypoxia of the same type.

Ilistic Hypoxia

Histic hypoxia is caused by the factors, which disturb oxygen utilization and
energy (in the form of A T P) formation. Oxygen supply to tissues may be sufficient,
but biological oxidation is impaired.
A classical example of histic hypoxia is poisoning with cyanides (they inaeti
vate cytochrome oxidase). Large doses of alcohol, narcotics and some drugs inhibit
dehydrogenases of the Krebs cycle. The antibiotic oligomycin damages the enzyme

Ii lU fiM . 161
I ’,ill I ( . e n n u i Ги11|ор||уч1о1оцу

Л I Раке. Respiratory enzyme synthesis dccieases in him ol dclieit of vitamins,

which are respiratory enzyme components (ribollnvin. mcotlim acid).
Uncoupling o f oxidation and phosphorylation results in the same disorders, which
arc characteristic of lack of oxygen. It disturbs efficiency of biological oxidation and
Л I P formation. Energy becomes dispersed as free heat. Macroergs resynthesis is
inhibited. The factors, which activate peroxidation of lipids and other ways of free
radical formation, damage the mitochondrial membranes. Ionizing radiation causes
14)1 activation. A deficit of natural antioxidants (catalase, cholesterol, some steroid
hormones, serotonin), which reduce free radicals and destroy hydrogen peroxide,
has the same consequences.

Combined Hypoxia

Hypoxia of the mentioned above types is not frequently observed. In clinical

pi .idice ;i combination of them — combined hypoxia — takes place. For example,
pneumonia (inflammation of the lungs) leads to hypoxia development and includes
respiratory, vascular and tissue components. Every case of chronic hypoxia (regard
less of the initial cause) refers to this type because of the damage of respiratory
enzymes.
Hypoxia o f overloading develops against the background of sufficient or even in
cicased oxygen supply to tissues. But an increased functional activity of the organ-
г.m or a certain organ and their increased need in oxygen leads to inadequate oxy­
gen supply and development of metabolic disorders typical of true oxygen deficit.

PA T H O G E N ESIS

I here are two stages of hypoxia development — compensation and decompensa­

tion,
At the stage of compensation, normal oxygen supply to tissues is maintained
due to compensatory reactions. The stage of decompensation develops when adap
I at ion is exhausted and oxygen deficit takes place.
As hypoxia causes are too numerous and this pathological process is too widely
spread, a lot of defense reactions have developed in the process of evolution and
embrace almost all physiological systems, fist of all, the systems of transport and
utilization of oxygen.
( 'ompensatory reactions are divided into immediate (urgent) and delayed (non
urgent, but long-term).

IM M ED IA TE COM PENSATORY REACTIONS

Immediate compensatory reactions are connected with the physiological

mechanism of hyperfunction and are preferably realized in the systems of oxygen
transport. All of them consists in the «fight for oxygen».
An increase ol lung ventilation is realized by reflex excitation of the respiratory
center by impulses from vascular chemoreccptors. (These leceptors react to changes
 Chapter 11 Hypoxia

in I he chemical composition of the blood, in particular, accumulation of C 0 2, de­

creased 0 2 content and increased H +concentration.)
Lung hyperventilation is a positive organism reaction. However, it has some
negative consequences: development of hypocapnia and respiratory (gaseous) a l
kalosis as a result of C 0 2 loss in the organism (p. 249). Taking into consideration
l I k * role of C 0 2 in the cerebral and coronary blood circulation, the regulation of
icspiratory and vasomotor centers tonus, hemoglobin dissociation and maintenance
of the acid-base balance, it is easy to realize the importance of carbon dioxide loss.
All these functions become impaired. Thus, in the pathogenesis of mountain disease
(and other types of hypoxic hypoxia), hypocapnia plays the same role as hypoxia.
Activation of blood circulation (heart hyperfunction, increase of the blood
speed, opening of reserve capillaries) is intended to mobilize oxygen transport. The
i irculating blood is redistributed to supply the most important organs (the lungs,
heart and brain) at the expense of decreased blood circulation in the skin, spleen,
muscles, and intestines. Reflex and humoral mechanisms (N O production among
ihem) and tissue decay products, which can dilate vessels, regulate the mentioned
changes.
An increase of erythrocyte and hemoglobin content in the blood supports oxy
gen capacity of the blood. Redistribution of erythrocytes from depots provides a
short-term compensation of hypoxia. During more prolonged hypoxia, erythrocyte
production is increased in the bone marrow. Young forms of erythrocytes (reticu­
locytes, polychromatophils) appear in the peripheral blood (information about this
kind of cells is given on p. 277).
Oxyhemoglobin dissociation is significantly changed and may be analyzed with
I he aid of corresponding curves (fig. 19). In hypoxia, the ability of hemoglobin to
hind oxygen in the lungs and supply it to tissues is increased. The left displace
ment of the upper curve inflexion testifies to an increased ability of hemoglobin to
absorb oxygen in the lungs from the inhaled air; i.e. the arterial blood is saturated
with oxygen better than usually. The right displacement of the lower curve inflexion

hy, 19. Changes of the oxyhemoglobin dissociation curve {a, b, c) in the process ofnigtin
ism adaptation i<
>hypoxia
Г.i l l I ( i f i in u l Ги11н1||||)ч1о1ою

AlPase. Respiratory enzyme synthesis d c u e .i.i . hi him ol deficit of vitam ins,

wlm li arc respiratory enzyme components (iilx illa v iii. nicotinic acid).
Uncoupling o f oxidation and phosphorylation results in the same disorders, which
.lie characteristic of lack of oxygen. It disturbs efficiency ol biological oxidation and
Al l * formation. Energy becomes dispersed as free heat. Macroergs resynthesis is
inhibited. I he factors, which activate peroxidation of lipids and other ways of free
ladical formation, damage the mitochondrial membranes. Ionizing radiation causes
l*<>1 activation. A deficit of natural antioxidants (catalase, cholesterol, some steroid
hormones, serotonin), which reduce free radicals and destroy hydrogen peroxide.
I i . i s the same consequences.

( oniliiiieil Hypoxia

Hypoxia of the mentioned above types is not frequently observed. In clinical

piactice a combination of them — combined hypoxia — takes place. For example,
pneumonia (inflammation of the lungs) leads to hypoxia development and includes
respiratory, vascular and tissue components. Every case of chronic hypoxia (regard
less of the initial cause) refers to this type because of the damage of respiratory
en/ymes.
Hypoxia o f overloading develops against the background of sufficient or even in
i leased oxygen supply to tissues. But an increased functional activity of the organ
ism 0 1 a certain organ and their increased need in oxygen leads to inadequate oxy­
gen supply and development of metabolic disorders typical of true oxygen deficit.

PATHOGENESIS

I here are two stages of hypoxia development — compensation and decompensu

lion
At the stage of compensation, normal oxygen supply to tissues is maintained
due to compensatory reactions. The stage of decompensation develops when adap
t.il ion is exhausted and oxygen deficit takes place.
As hypoxia causes are too numerous and this pathological process is too widely
spread, a lot of defense reactions have developed in the process of evolution and
em hiacc almost all physiological systems, fist of all, the systems of transport and
utili/alion of oxygen.
( ompensatory reactions are divided into immediate (urgent) and delayed (non
urgent, hut long-term).

IM M ED IA T E COM PENSATORY REACTIONS

Immediate compensatory reactions are connected with the physiological

mechanism of hyperfunction and are preferably realized in the systems of oxygen
transport All of them consists in the «light for oxygen».
An increase ol lung ventilation is realized by reflex excitation of the respiratory
t enlei by impulses from vascular chemoreceptors. (These receptors react to changes
 t'haplci II 11>|м>\1и

hi the chemical composition of the blood, in particular, accumulation of C O „ dc

i leased 0 2 content and increased H +concentration.)

Lung hyperventilation is a positive organism reaction. However, it has some
negative consequences: development of hypocapnia and respiratory (gaseous) ol
i nlosis as a result of C 0 2 loss in the organism (p. 249). Taking into consideration
iIn* role of C 0 2 in the cerebral and coronary blood circulation, the regulation ol
u .piratory and vasomotor centers tonus, hemoglobin dissociation and maintenance
"I the acid-base balance, it is easy to realize the importance of carbon dioxide loss
Ml these functions become impaired. Thus, in the pathogenesis of mountain disease
land other types of hypoxic hypoxia), hypocapnia plays the same role as hypoxia.
Activation of blood circulation (heart hyperfunction, increase of the blood
i " cd, opening of reserve capillaries) is intended to mobilize oxygen transport. The
11 rculating blood is redistributed to supply the most important organs (the lungs.
In-art and brain) at the expense of decreased blood circulation in the skin, spleen,
muscles, and intestines. Reflex and humoral mechanisms (N O production among
them) and tissue decay products, which can dilate vessels, regulate the mentioned
i lianges.
An increase of erythrocyte and hemoglobin content in the blood supports oxy
цеп capacity of the blood. Redistribution of erythrocytes from depots provides a
hort-term compensation of hypoxia. During more prolonged hypoxia, erythrocyte
I'induction is increased in the bone marrow. Young forms of erythrocytes (reticu
locytes, polychromatophils) appear in the peripheral blood (information about this
kind of cells is given on p. 277).
Oxyhemoglobin dissociation is significantly changed and may be analyzed with
ilie aid of corresponding curves (fig. 19). In hypoxia, the ability of hemoglobin to
bind oxygen in the lungs and supply it to tissues is increased. The left displace
ment of the upper curve inflexion testifies to an increased ability of hemoglobin to
absorb oxygen in the lungs from the inhaled air; i.e. the arterial blood is saturated
with oxygen better than usually. The right displacement of the lower curve inflexion

lift ll> Changes o f I he oxyhemoglobin dissociation curve ( a , h, <-) in the process ol oiyan
ism adaptation to hypoxia
I ’i i i I I ( • r u n ill 1'и1Ьо||||уч||||<1к>

u-.tilies to a decreased affinity of hemoglobin for oxygen in tissues; so, tissues get
more oxygen.

IX)NG-TERM ADAPTATION REACTIONS

Immediate hyperfunction of external respiration and blood circulation cannot

pmvide steady and long-term adaptation to hypoxia as they require more oxygen,
пи I organs are working more intensively. This situation is reflected by the formula
I I Vi lT/w ( IF S is the intensity of structure functioning, A is work, and m is organ
mass) Immediate compensation is accompanied with an increased protein decay.
I oi long term hypcrfunction, these
organs need a structural (plastic) Norm Adaptation
Mi|>|N)it to perform their functions Capillaries
m i I he course of long-term hypoxia.

Ii in realized by their mass increase.

I I 11.is been established that all the
lystems responsible for oxygen
liansfer undergo hypertrophy and
hyperplasia (fig. 20). The mass of
lln respiratory muscles, lung alveoli Mitochondria tV J w fl i <Pi1% <ETA
uitl myocardium increases. Capil-
iiu s are hypertrophied as well (in-
letiscd in number due to the effect Myoglobin — 0 -
> 1 thrombocytic and endothelial
powth factors - angiogenin and Fig. 20. Tissue mechanisms of adaptation to
>rostucyclin). So, these organs be- hypoxia
omo better supplied with the blood.
Ч Л normalizes (IF S =A\/m\).
I In adrenal cortex, hypothalamus and even neurons of the respiratory center be-
«*nit- hypertrophied as well. The bone marrow undergoes hyperplasia. Erythrocy-
o .i in detected. Lrythropoiesis is intensifled under the influence of renal erythro-
Htu-liiiN and erythrocyte destruction products. Young erythrocytes (reticulocytes),
Jiu Ii appear in the peripheral blood, stimulate erythropoiesis (p. 271). Fetal he-
tmrlohin ( IIb F is more related to oxygen) appears.
I In myofflohin content in the muscles is increased. It is an additional oxygen
apuuty, a stimulator of oxygen diffusion into the tissue possessing antioxidant
ctivity.
(hy/fen utilization system has the following adaptive mechanisms:
I issue enzymes (due to hypertrophy of the mitochondria) utilize oxygen better,
aippoit a proper level of oxidizing processes and realize normal A TP synthesis in
spite of hypoxemia.
I itcrgy In used more effectively during oxidizing processes.
Additional energy is produced during glycolysis.
Iniym c\ (hat participate in oxidation and energy loiiiuilion are changed during
liiptation to hypoxia. I hey are activated due to increase in content and molecular
 С'haplci II llypoxia

conformation. It refers to cytochrome oxidase (the final enzyme of the respiratory

chain) and Krebs cycle enzymes. It is adaptation at the molecular level. At the cel
lular level, it goes about mitochondria, which are hypertrophied.
Below the order of events, which lead to sufficient energy production in spite
of oxygen deficit, is represented.
An initial link in the pathogenesis of these events is inhibition of oxidation and
oxidizing resynthesis of A T P in oxygen deficiency. As a result, the number of tissue
macroergs is reduced and tissue decay products are accumulated. The correlation
AD P x P/ATP, marked as the phosphorylation potential, increases. It is a stimulus
lor the cellular genetic apparatus, which leads to an increased synthesis of nucleic
acid and proteins in mitochondria and other cellular structures. The mitochondrial
mass increases. Tighter coupling of phosphorylation and oxygenation takes place in
mitochondria in the brain (such possibility is described on p. 190). Thus, cells can
produce A T P in spite of oxygen deficiency in the blood.
It is clear that the main link in the development of compensation in hypoxia is
energy production decrease. For a long time it was not understood in what way the
genetic apparatus is activated in hypoxia. Ultimately a specific factor was detected.
It is the HIF-factor (hypoxia-inducible factor), which is a regulator of the genes
responsible for mitochondrial energetic metabolism, vasomotor control, erythro-
poiesis, angiogenesis, hypertrophy and hyperplasia (scheme 8). So, adaptation to
hypoxia is genetically determined.
The described processes mainly take place in the organs responsible for oxy­
gen transport (the lungs, heart, respiratory muscles, vessels) and in the organs,
which suffer from oxygen deficit most of all. The synthesis of structural proteins
is increased in these organs and leads to their hypertrophy and hyperplasia. So,
prolonged hyperfunction of the transport and utilization systems gets a plastic and
energy provision.
The adaptive reactions mentioned above are the strategy of «fight for oxygen*.
In prolonged hypoxia there is another strategy — activation of glycolysis (A T P for­
mation without oxygen). A T P splitting products activate glycolysis enzymes.

Scheme 8. Mechanisms of Adaptation to Hypoxia

 II I <.ru n «I Гн|||о||||>л|||||1к\

Increased production ol antiaxidant system еи/уше. (i .ilnliisc, |>eroxydase, sn

M'oxidc dismutase) is of a great importance.
I'ndocrine system supports prolonged adaptation by additional secretion of the
» called adaptive hormones (glucocorticoids), which provide tissue resistance to
/poxia.
I he described reactions, which are developed at the molecular and cellulai
vels, provide not only survival in hypoxia but also working capacity. It is already
i>t only a compensation of hypoxia but also an adaptation - a stable, economical,
mg term accommodation. It is an increase of systemic nonspecific resistance.
In various types of hypoxia, correlation between the noted adaptive reactions
lay be different. The adaptive reactions mentioned above are determined by the
ulily of a tissue to provide hypertrophy and hyperplasia, which is determined by the
metie apparatus. This potentiality is more essential in the bone marrow than in more
illercntiated cells of the nervous tissue, where compensation gets exhausted earlier.

PATHOLOGICAL CHANGES

If adaptive mechanisms are insufficient or exhausted, decompensation takes

laee with pathological disorders in the organism. They develop at all levels of bio
igical organization — molecular, cellular, organs and organism as a whole.

H«orders of Metabolism

In brief, such metabolic disorders take place:

I nergy formation deficiency.
Accumulation of intermediate metabolic products.
Negative nitrogen balance.
Metabolic acidosis.
I’<>1 activation.
Лее ii uiul.it ion of toxic products.
I he following metabolic processes are inhibited (all of them are energy-depen
hint):
Protein synthesis.
( omplex lipid synthesis (content of lipids in the blood is decreased).
Neuromediator synthesis.
Hormone synthesis.
I lectrolyte transport.
Itnergy formation gets reduced especially in the form of phosphorus compounds
outlining macroergic bonds (A T P). In hypoxia, the number of these compounds
s deeTeased, flius, oxygen deficiency leads to energy deficit in tissues (p. 194). All
ithei disorders are based on it.
In oxygen deficiency, metabolism is disturbed and toxic products of incomplete
ixidation are accumulated. Glycogen content in the livei and muscles is rcduccd.
rlueose is not oxidi/cd completely. Accumulated lache acid leads to mctuholic aei
loxls (p .’47)
 Chapter II llypoxi»

I he intermediate products of lipid metabolism (acetone, acetoacetic and

i hvdroxybutyric acids) are toxic for membranes. PO L activation is an important
1 1 . mi of hypoxic injury of cells. The products of lipid peroxide oxidation appear.

i 'iiclcr (heir influence, hemoglobin is transformed into metHb and membranes arc
Mili/cd. The intermediate products of protein metabolism are accumulated. The
in.unity of ammonia increases, of glutamine — decreases. The negative nitrous hul-
imu- is established.
rhosphoprotein and phospholipid metabolism becomes disturbed. Their synthesis
in the liver gets reduced.
As the membrane canals are an important A T P consumer, the active transport
.</ ions through the biological membranes gets disturbed. The content of intraccl
ini.и potassium is decreased. Calcium accumulation in the cytoplasm is one of the
Iumc links in the pathogenesis of the hypoxic damage of cells (p. 262).
Synthesis of neuromediators and hormones is reduced. It leads to nervous and
mlocrine regulatory mechanism impairment.

Morphological Changes

I lie observed biochemical disorders in the cell cause the structural ones.
At the cellular level, an ultrastructure lesion is marked as hyperchromatosis and
■it ' (imposition of the nucleus, swelling and degradation of mitochondria.
Increased acidity, membrane destruction and energy deficit lead to lysosome
л,image. Active proteolytic enzymes are released and damage the cellular structure.
Cell division gets suppressed.

I >i'.orders in Organs and Physiological Systems

I lie sensitivity of different tissues to hypoxia depends on the following factors:

• intensity of tissue’s own metabolism;
• capacity of the tissue glycolytic system;
• energy reserves in the form of macroergic substances (A T P);
• the ability of the genetic apparatus to provide hypertrophy and hyperplasia
From all these points of view the nervous system is in the most unfavorable
i nmlitions.
Hie first symptoms of oxygen deficiency manifest themselves in the nervous
wstcm At first, euphoria occurs. It is characterized by emotional and motor excilc
ment, the feeling of one’s own power or, on the contrary, the absence of interest in
ih- .urroundings, inadequate behavior. A disorder of the so-called internal nervous
Inhibition underlies these symptoms, it is more sensitive to oxygen deficiency be
iuse metabolic intensity (see p. 515).
In prolonged hypoxia metabolic and functional changes in the nervous svs
I. in are severer. Inhibition develops. Reflex activity is disturbed, the regulation ol
I'n tilling and blood circulation is also impaired. Loss of consciousness and convul
•nous are symptoms of deep hypoxia.
Г .и I I t . i m i III Г ц | | | 0 | | | | > II \

Disorders in other organs are correlated uiili Impaired nervous regulation,

energy deficiency and accumulation of toxic mdabolu products
As to sensitivity to oxygen deficiency, the cardiac muscle ranks second aliei
Ihe nervous system. The conductive system is more stable than the contractile one
I achycardia and arrhythmia arc the clinical manifestations of disturbed excitability,
conductivity and contractility of the myocardium. I lie main role in such impaii
mcnt belongs to calcium (p. 262) and peroxide mechanisms. Cardiac insulficieiu \
iiikI reduced arterial blood pressure lead to systemic disorders of blood circulation
I he latter complicates the course of all other pathologic processes.
I )isordcrs of the external respiration consist in disorders of lung ventilation. IV
iiodic Cheyne—Stokes respiration appears (see fig. 49 on p. 404). Blood congestion
hi i lie lungs leads to the thickening of the alveolocapillary membrane and decreased

diffusion of oxygen from the alveolar air to the blood.

In the digestive system the following pathologic signs are observed — inhibition
i»l secretion in the stomach (decreased acidity), peristalsis and intestines and pan
creas functions.
I lie system of microsomal oxidation in the liver is inhibited. Production ol the
cytochrome P-450 gets suppressed (p. 446). The antitoxic function of the liver fails
I aking into consideration the role of the cytochrome P-450 in drug metabolism н
is easy to understand the problem of using medicines in the treatment for all hv
poxic diseases (heart and respiratory insufficiency).
Primary polyuria is followed by renal dysfunction.
Body temperature decrease is obtained at the stage of decompensation.
tdrenal cortex exhaustion is of consequence in decompensation development
Discussing the compensatory reaction and pathological changes in hypoxia
it is necessary to state that protection and impairment are closely related. Som e
pathologic sings can be simultaneously interpreted as adaptive ones. Thus, the nci
« h i s system is very sensitive to oxygen deficiency, and the inhibition, which deve

lops, is protective; as a result, the nervous system becomes less sensitive to oxygen
Hiciency I he decrease of body temperature may be interpreted in the same wav
II is a damage that induces compensatory adaptation. Thus, it is a decrease ol
>(),, in the blood that initiates chemoreceptor stimulation and mobilization ol ex
eiiial respiration and blood circulation. It is A T P deficit that induces mitochondna
nogenesis,

RESISTAN C E AND SEN SIT IV IT Y TO HYPOXIA

I lie resistance of the entire organism to hypoxia depends on several paranu

erv
I nst, the role of age mast be mentioned. In newborns, the automatism ol ili<
cspiratory center in hypoxia can be supported by the primitive form of carbohy
Irate metabolism (anaerobic). The blood of newborns contains more letal hemo
flohin, which can reali/e the respiratory function in the condition of a lowei partial
xessure of oxygen in the blood. Hut the most important lad is poor development
il I he newborn’s central nervous system.
 Chapter II. Hypoxia

I here are some individual differences in sensitivity to hypoxia. Markers of in

11 ised sensitivity to hypoxia are hyperglycemia, hyperlipidemia, acidemia, lowei
. •intent of insulin in the blood, increased content of thyroxin, more intensive mcta
i ilism, hyperparathyroidism, sympathotonia, a high level of peroxide metabolism, a
i ■« level of such an antioxidant erythrocyte enzyme as superoxide dismutasc. Mark
11 til higher resistance to hypoxia are hypoglycemia, hypolipidemia, an increased
i •! of insulin, a decreased level of thyroxin and somatotropin, vagotonia.
Some conditions, characterized by a deep inhibition of the central nervous sys
i m and metabolism (sleep, narcosis, hypothermia), provide reduction of organism
•nsitivity to hypoxia.

P R IN C IP L E S OF H YPOXIC STATE TREATM ENT

It is possible to raise resistance to hypoxia by:

• improving adaptive reactions (by training in a pressure chamber);
• decreasing the organism requirement of oxygen.
If oxygen utilization is normal, it may be added.
It is possible to correct metabolic disorders with the help of specific antihyp» л к
in. parations. They stimulate the transport of electrons in the respiratory chain (cyto
■Inome) and inhibit free radical oxidation (antioxidants). The following preparation
im in use — phosphorylated carbohydrates, blockers of calcium canals as well as the
Mibstances increasing glycolysis and reducing organism requirement of oxygen.

U S E OF HYPOXIA IN M E D IC IN E

Paradoxically, hypoxia is used in clinical practice for treatment. For this pin
ри л pressure chambers are used. While training in hypoxic conditions, the organ
i in becomes more resistant to various unfavorable factors, in particular, physi» il
load, infection, poisoning and ionizing radiation. Immune reactions are activated
It is used in the treatment for bronchial asthma, anemia and other chronic disease,
in whose pathogenesis hypoxia is a leading mechanism.
In some diseases, oxygen under an increased pressure is used (hyperoxi;») Ii
■trales oxygen reserves in the blood and tissues. It is used in poisoning with carbon
monoxide and operations on the «dry» heart (without blood supply).

Questions for Self-Control

I May hypoxia be local?

' May hypoxia be caused by infection?
I What is pure hypoxia?
I What forms of hypoxia do you know with oxygen transport insufficiency?
' What type of hypoxia occurs more often?
<
> Can the organism adapt to hypoxia immediately?
I ( an the organism provide long-term adaptation to hypoxia immediately?
N Use the indice II S to charactcri/e adaptation to hypoxia.
'.til I ( im c iiil Ги11||1||||>\1о||1К У

4 III what w ay docs the system ol oxygen nlih/ali«mi adapt lo hypoxia?

0. In wlial way is hypoxia used in medicine?

Tests and Tasks for Self ( onlrol

(give correct answers and find mistakes in the statements)

1 An unconscious man was taken to the hospital alter poisoning with carbon
monoxide. Appearance of what substance in the blood provokes hypoxia?
A. Carboxyhemoglobin.
H Met hemoglobin.
C. Carbohemoglobin.
I). Oxyhemoglobin,
li. Lactate.

2 A blocker of cytochrome oxidase was injected to an experimental animal. I he

animal died immediately. What substance caused death of the animal?
A. Potassium oxalate.
H. Potassium nitrite.
C. Potassium sulphate.
I). Potassium phosphate.
I Potassium cyanide.

\ At a height of 6000 m above the sea level a mountain climber experiences

euphoria, inadequate assessment of the situation, hallucinations. What is the
main cause of the development of these mountain sickness symptoms?
A. Dilating of the air in the frontal sinuses.
И Snow ophthalmia.
< I >ecrease of pO, in the air.
I > I )ecrease of pCO, in the air.
I I xercise stress.

I A S0-year old man was taken from a closed room full of smoke from a fire. I Ic
was unconscious. What kind of hypoxia did the victim develop?
A. Hypoxic.
M Respiratory.
C. Hemic.
I). 11istic.
I . Circulatory.

5 A sportsman was climbing a mountain for several hours. At a height of 4X00 in

he suffered from dyspnea, palpitation, bursting headache. What is the cause <>l
such signs?
A I )ecrease of barometric air pressure.
R Decrease of p(), in the air.
C. Lack of ventilation.
I> (ias embolism.
I Decrease of air temperature.
 Chapter I I 11у|м»\1й

<
> Л patient demonstrates a decreased amount of erythrocytes and hemoglobin
in the blood, reduced color index, low concentration of iron in the serum,
microanisocytosis, poikilocytosis. These changes are accompanied by hypoxia
development. What kind of hypoxia is observed in this case?
Л. Exogenous.
B. Hypoxic.
C. Circulatory.
D. Hemic.
E. Respiratory.

Potassium cyanide solution was injected to an animal. What type of hypoxia

developed in this case?
A. Hemic.
B. Respiratory.
C. Hypoxic.
D. Histic.
E. Circulatory.

s Л patient had a lung surgery. The heart stopped. Its regular contractions were
restored only in 10 minutes. What organ suffered from hypoxia most of all?
A. Spleen.
B. Heart.
C. Liver.
D. Kidneys.
E. Brain cortex.

‘I A 40-year-old man complains of fever, general sickness, headache, cough,

dyspnea. After a clinical inspection a diagnosis of bronchopneumonia was
given. What form of hypoxia is it?
A. Hemic.
B. Circulatory.
C. Respiratory.
I). Histic.
E. Hypoxic.

HI I'liree experimental animals — a snake, a frog and a rat — were put into .1
pressure chamber to study hypoxia. After decompression a difference between
1hem was noted. What is the difference and how is it explained?
The following immediate compensatory reactions are necessary
fo r survival in acute hypoxia development:
1. Acceleration of heart rate.
2. Development of additional capillaries in organs.
3. Stimulation of erythropoiesis in the bone marrow.
4. Activation of glycolysis.
5. Myocardial hypertrophy.
(>. Hyperplasia of the bone marrow.
I'tirl I (irlHTMl Рй1||0|>||)ч|0|»К>

7. Hyperventilation.
S. Decrease of arterial blood pressure.
Results o f the experiment are the following:
9. The snake dies the first.
10. The frog has the best active resistance.
11. The rat lives the longest time.
Resistance o f the organism to acute hypoxia may be increased by:
12. Decrease of body temperature.
13. Increase of body temperature.
14. Narcotic substances.
15. Caffeine.
16. Antioxidants.
11 A chronic inflammation of the lungs (chronic pneumonia) was diagnosed in .i
patient of 59 years old. He suffers from sickness, cough, dyspnea (respiratory
insufficiency). During a year his body temperature periodically rises to 37.2'(
I he leukocyte content in the blood is not increased.
What is the patient’s organism reactivity?
1. Normal.
2. Increased.
3. Decreased.
What compensatory reactions are characteristic
to chronic hypoxia o f respiratory type?
4 Hyperventilation.
5. Tachycardia.
(>. Hyperplasia of the bone marrow.
7. Increase of the respiratory capacity of the lungs.
X. Erythrocytes leaving the depot.
W lial disorders o f metabolism are typical o f chronic hypoxia?
9. Activation of the basal metabolism.
10. Inhibition of synthetic processes.
II Inhibition of oxidation.
12. PO L activation.
IV Positive nitrogen balance.
14. Increase of the glycogen content in the muscles.
1 Myocardial infarction was diagnosed in a 44-year-old patient. He was с а т Ы
to the hospital in a grave state.
What type o f hypoxia developed in the patient?
1. Acute.
2. Chronic.
3. Hypoxic.
4 Circulatory.
5. Hemic.
<
> Respiratory.
7. Tissue.
К ( Dinbini'il
 ( hapU'i 1 1 . II.Y |H > \iu

What compensatory reactions are characteristic to hypoxia caused

by cardiac insufficiency in this case?
9. Hyperplasia of the bone marrow.
10. Increase of arterial blood pressure.
11. Hyperventilation.
12. Increase of the minute volume of the heart.
13. Increase of the systolic volume of the heart.

I i To study hypoxia pathogenesis a scientist modeled a toxic damage of the bone

marrow of an experimental animal and investigated the sensitivity of different
organs to hypoxia.
W hat type o f hypoxia was modeled in the anim al?
1. Hypoxic.
2. Hemic.
3. Circulatory.
4. Local.
5. Systemic.
Which compensatory reactions are characteristic to this type o f hypoxia?
6. Hyperplasia of the bone marrow.
7. Hyperventilation.
8. Blood leaving the depot.
9. Tachycardia.
10. Increase of mitosis in normoblasts.
W hat is the explanation o f the high sensitivity o f the brain to hypoxia?
11. Presence of developed collaterals.
12. Intensive metabolism.
13. Active glycolysis.
14. Intensive energetic metabolism.

14 A 45-year-old woman suffers from uterine hemorrhage caused by menstrual

cycle disorders. Chronic anemia developed as a result.
W hat biochemical disorders develop in hypoxia?
1. Positive nitrogen balance.
2. Metabolic acidosis.
3. Deficit of macroergic substances.
4. Glycolysis activation.
5. Calcium accumulation in the cellular cytoplasm.
6. Increase of intracellular potassium content.
What kind o f defense reactions in the system o f oxygen utilization are
characteristic to hypoxia?
7. Hyperventilation.
8. Increase of heart rate.
9. Increase of the amount of capillaries in the lungs.
10. Increase of the amount of mitochondria.
11. Increased coupling of oxidation and phosphorylation in the brain.
12. Myocardial hypertrophy.
I ’ait I (•«■until l'iilllo|ihyslol»K>

2. Txcitation (connected with sensiition «>i luingei nnd active hunting for
lood).
.1 Suppression (the most prolonged period).
4. Terminal, or the period of paralysis and death (3-4 days).
Restoration comes if starvation is stopped before the terminal period and nour­
ishment is restored.
In people fasting deliberately with a serious motivation, excitation and suppres-
II >n may not take place.
Pathophysiological Periods. Three pathophysiological periods of complete star­
vation are distinguished on the basis of changes of metabolism and energy con-
.umption. fhe respiratory quotient is used as an index. They are:
/. Uneconomical use of energy (2—4 days in man, respiratory quotient increases
to I ).
2. Maximal adaptation (40—50 days in man, respiratory quotient decrease to
0.7).
f. Tissue decay, intoxication and death (3—5 days, respiratory quotient equals
O.K).
Pathophysiological periods of complete starvation correspond to those of stress
(sec chapter 30 «Pathophysiology of Endocrine System», p. 506).

PA TH O G EN ESIS

Starvation is constantly observed in nature (under natural circumstances ani­

m al. starve frequently). So, in the course of evolution many adaptive reactions have
developed, which sustain survival.
Starvation proceeds in two stages — compensation and decompensation.
Hie stage o f compensation is such a stage when adaptive reactions prevail and
homeostasis is maintained.
I he stage o f decompensation is such a stage, when defense reactions are ex­
hausted and homeostasis fails. Pathological changes prevail.
Adaptive reactions are created in the process of evolution of adaptation to the
absence of food and serve to maintain homeostasis and physiological functions
mulct unusual life circumstances. They maintain: a) body temperature; b) blood
glucose level; c) Wood pH; d) A TP formation; e) function of the organs that work
I.....lancntly heart, organs of respiration, renal filtration, hormone production,
etc.
IX'tense reactions arc active and passive. The first are directed at active food
■ <king, but they are uneconomical (need additional energy) and short-term. The
passive ones develop at the level of metabolism and are directed at decreasing the
need for and expenditure of energy making metabolism more economical.
Adaptive reactions have some dynamics according to the periods of starvation
corresponding to the dynamics of stress, which is a non specific mechanism of
adaptation m extreme situations (p. 507). Realization ol sttcss is provided by the
nctiviition ol the hypophysis adrenal cortex system biosynthesis of adaptive hot
 _________________________________________________________________ Chapter 12. Starvation

mones increases. These hormones have an activating and preserving influence on

the enzymal systems.
More detailed information about the pathogenesis of complete starvation is
riven below in accordance with the periods of this process.

IIR S T PERIO D

The first period is a realization of the hunger instinct. It is an active stage,

which provides an active search for food and preserves life. The duration of this
period is 3—4 days.
Adaptation is directed at the realization of instinct. Sensation of hunger acti­
vates behavior in the absence of food. According to Hans Selye (the author of the
roncept of stress), it is an alarm reaction in extreme situations. It provides nervous
excitement, adaptation and survival. It is active defense, which needs additional
energy.

( hanges in Metabolism

Metabolism is activated. It is a period of uneconomical energy and substance

expenditure.
Basal metabolism increases as well as oxygen consumption.
The respiratory quotient increases to 1. It means that oxidation and energy
formation are provided by increased carbohydrate expenditure. It is carbohydrates
that are utilized predominantly.
The blood glucose level is normal or temporarily increased.
The reserve of glycogen (in the liver), which is used for energy formation,
decreases quickly, during 6 hours of starvation. However, it does not disappear
because it is formed as a result of glyconeogenesis.
The glucocorticoidal function of the adrenal cortex is stimulated.
Insulin secretion decreases, the activity of pancreatic а -cells increases with
glucagon secretion.
The excretion of nitrogen in the urine decreases (from 12-14 g to 10 g daily)
on the 2nd-3rd day of starvation. The negative nitrogen balance establishes.

( hanges in Organs and Systems

The earliest manifestation of starvation is nervous excitement and sensation <il

hunger caused by excitation of the alimentary center.
All physiological systems are activated and serve for realization of the hun^ei
instinct and stress for homeostasis regulation and metabolism reorganization in the
absence of energy resources.
Motor activity is promoted.
Arterial blood pressure slightly rises.
The pituitary-adrenal cortex system is activated. Hormones of adaptation
(ACTH and glucocorticoids) are secreted. Tropic pituitary hormones activate the
I'.llt I (iCIHTUl l*UlllO|lliysiol<IK>

fUnction of the peripheral endocrine glands. Ihyrolropln secretion activates the

function of the thyroid gland. Corticotropin secretion stimulates the adrenal coi
tex.
Hotly weight decreases significantly due to wasteful use of energy.
In some days (3—4) sensation of hunger disappears. The next stage of adapta
lion comes.

S H ONI) PERIO D

I lie second period is the most prolonged one. Together with the first period, it
is а Маце o f compensation but regulated by other mechanisms. The second stage is a
si age of maximal adaptation. It is a period of economical utilization of substances
.iiul energy. The second period determines practically the whole course of starva
lion. Its duration depends on many factors mentioned above. In men it is 30-4(1
days and more.
Adaptation is provided at the level of metabolism. Adaptive reactions are real
i/.ed by: a) more economical use of nutrients; b) use of lipids as nutrition reserves;
c) basal metabolism reduction; d) changes in the enzyme activity and isoenzyme
systems I hey are given below with more details.

( hanges in Metabolism

I In- second period is the longest period of starvation.

Metabolism demonstrates maximal adaptation and deep reorganization direct
i ll .it economical expenditure of energy resources.
Basal metabolism decreases by 10—20 % and remains at this level.
Reseives of carbohydrates in the form of glycogen are exhausted after 5—6 days
.mil metabolism is switching over to fat metabolism. Lipids are utilized predomi
uantly Ii is demonstrated by respiratory quotient decrease to 0.7. The organism
m rives about XO % of energy as a result of fat oxidation, 3 % — from glucose
oxidation, 13 % — from protein oxidation.
I ipolysis is activated in the liver while lipogenesis is inhibited. Transport lipemiu
is observed. Free fatty acids come into the blood and other organs. In the liver and
muscles fatty acids are transported through the mitochondrial membranes to the
places of oxygenation.
In glycogen exhaustion, ketone bodies production begins. Intensification ol
|) oxygenation is marked in increased ketone body concentration in the blood. In
IX 72 h of starvation the level of ketone bodies is 3 mmol/1.
As to the blood glucose level, it is nevertheless maintained normal in spite of the
absence of food for many days and carbohydrate reserve exhaustion. It is provided
by glyconcogcncsis activation, which is registered in the kidneys and liver. XO g ol
glucose is produced every day and half of this quantity is formed from glycerin (fat
ciitiibolism) and amino acids (protein catabolism).
I lie level ol insulin decreases resulting in the inhibition of hexokinase and
Krebs cycle ctlicicncy Л dec reuse ol glucose enleiinu the cells occurs in those (is
 < h iip tri 12 SlarvN lion

m in which the transport of glucose through the cellular membranes depends on

<ii Iiii (myocardium, skeletal muscles and adipose tissue). It is these organs where
li|nil utilization increases. The brain gets a normal quantity of glucose.
( alabolism is directed at provision of metabolism and function of the vitally
>ni|»«>rtant organs, especially of the brain, which needs 1.600—1.800 kcal/day pro
•i' il by splitting of 100—150 g of glucose.
It is very important to note that blood pH is maintained normal in spite of
.... rased ketogenesis. Regulatory mechanisms join this process for ketoacidosis
•iii|>cnsation. Ammonia, which is released by desamination, binds ketone bodies.
'•Uni mechanisms of acid-base regulation (acidogenesis and ammoniogenesis in
•ii. kulneys) are activated. Non-respiratory (m etabolic) acidosis (p. 247) develops as
• " ult of this, but it is compensated up to the terminal period of starvation. The
.... nut of blood bicarbonates is decreased. The excretion of ammoniacal salts in
Ии urine increases.
I he amount of oxidative water increases.
As to proteins, they are generally preserved at this stage of complete starva-
... . without water deprivation. Nitrogen excretion in the urine decreases to 7—
I г inflecting the economical expenditure of proteins. Nevertheless, the nitrous
1'iihince is negative as a result of increased deamination and use of amino acids for
I I ■ oncogenesis and maintenance of the blood sugar level. At the same time, the
i sibility of protein synthesis for vitally important organs is preserved at the ex-
i i’ii .с of protein splitting in other organs. It is provided by the so-called endogenous
nshment as an exclusive mechanism of adaptation in complete starvation.
Indofienous Nourishment. Scientific research has shown that the organism is
..... ished during complete starvation. The quantity of albumin and globulin ele-
viiii ■ . in the gastric juice on the 6th—8,h day and digestive enzymes are present in
tin Intestine during complete starvation up to its end. Proteins split in the intestine
tiliey are fermented) with the formation of amino acids, which are absorbed into
'i" Mood and are used repeatedly for protein synthesis in the vitally important
•и ms Thus, protein substances are redistributed in the organism. A new unique
и гnlaiion of protein balance between the organs provides the vitally important con-
i inilv working organs with plastic materials by a repeated use of amino acids.
It has been discovered that the weight of the heart and nervous tissue is reduced
Ii than that of other organs.

<hiuiiies in Organs and Systems

llody temperature is maintained at the normal level. Heat production is main-

i ilnrd at the minimum level. Heat emission is somewhat reduced.
<> 1her functions of the organism are kept within physiological limits. Any spe-
•i ll disturbances are absent in the system of blood circulation and respiration. Arte
Uul blood pressure, the circulating blood volume and heart activity are maintained
>'lllnn physiological standards.
I lie activity of the digestive system is inhibited but it participates m endo
Minions nutrition.

i in
1‘iiH I (•rncrul Гй11ш||||уч1о||>к>

I he mctabolic function of the liver is activated (lipolysis and glyconeogenesis

air provided).
Production of urine (filtration, reabsorption, and secretion) is maintained in
the kidneys.
I lie function of the endocrine system is principally reorganized. The function
ol i nost endocrine glands (thyroid, adrenal medulla, pancreatic, sex) is suppressed
Decreased neurosecretion in the hypothalamus nuclei is the main mechanism. An
exception is the function of the adrenal cortex as an organ of profound adaptation
(.li icocorticoid secretion is maintained due to adrenal cortex hypertrophy.
It is of principal importance that mental activity is preserved in complete star
vai io n without water deprivation.
As I о body mass, there is observed such a peculiarity. It continues to decrease
but more slowly than during the first period because of economical use of materials
am 1 basal metabolism decrease. An interesting fact is that a decrease of the mass
ol various organs is different. The adipose tissue loses mass the most intensively
wh ile the heart and nervous tissue — less intensively. Moreover, it has been shown
experimentally with young animals (which are in the period of growth) that their
bi.i i ii continues to grow during complete starvation without water deprivation. This
dvi lamics is shown in figure 21.
Finally, it must be noted that in complete starvation without water deprivation
и* • dystrophic changes are registered, only atrophic ones.

I l l 11<I) ( II ' KM INAL) PERIO D

I lie third period is a period of decompensation, the terminal one. Its duration is
■и ne days (about 3—5 days). It is a period of tissue decay, intoxication and death

<Ii.nines in Metabolism
Fat depots 97 %
I'lie respiratory quotient in­ Spleen 60 %
i ' reuses in comparison with the Liver 53.7 %
previous period and equals 0.8. It Testis 40 %
m eans that proteins are used as a Muscles 30.7 %
source o f energy. There is an in­ Blood 26 %
creased lysis not only of the pro- Kidneys 25.9 %
lei ms that are easily mobilized Skin 20.6 %
(blo o d proteins) but also of the Intestine 18 %
slitblc proteins of the muscles. The Lungs 17.7 %
Pancreas 17 %
decrease of body mass is acceler­
Bones 13.9%
ated again reflecting the destruc­
Nervous tissue 3.9
tiv e processes.
Heart 3.6 °«
Ihere appear destructive
changes in (he mitochondria. The 0 20 40 60 80 100%
le ve l ol oxidative phosphorylation 21 l lio ileiiu-c ol mass loss by organs and tis
decreases hi cells, A disorder ol the s,,cs complete starvation
 Chapter 12. Starvation

i nzymal systems, which are destructed in the process of starvation, provokes deep
ilisbolism.
The blood glucose level is less than 3 mmol/1.
Excretion of nitrogen, potassium and phosphorus in the urine increases. Their
ialio in the urine is the same as in the protoplasm.
Metabolic acidosis becomes decompensated (p. 246).

Changes in Organs and Systems

A deep disorder of physiological functions takes place due to exhaustion of

energy and regulative functions of the endocrine system.
A disorder of all vital functions is the same as in any terminal state — arte-
i ial blood pressure decrease, disorders of respiration, renal filtration, etc. Paralyses
develop.
Body temperature reduces. Heat production collapses.
Peculiar is the fact that pathomorphological changes are insignificant (pre
dominantly atrophic but not dystrophic ones) even in those who died after complete
starvation.

RESTORATION

There are two outcomes of complete starvation — lethal or restoration if nour

ishment is resumed.
Restoration is possible even at the beginning of the last period of starvation.
All organism functions may recover completely. It testifies to the fact that complete
starvation does not provoke irreversible changes. Restoration is very quick. Thus,
a loss of 40-50 % of body mass during one month is restored during two weeks.
Appetite appears, oxidative processes are intensified, the process of assimilation is
stimulated, and a positive nitrous balance is established. However, taking into ac­
count the state of the digestive system, fattening should be carried out carefully.
Finally, it must be noted once more that in complete starvation without water
deprivation no dystrophic changes have been registered but only atrophic ones that
are rather quickly and completely restored when starvation stops.

M ED IC A L STARVATION (FASTING)

The regularities observed in the course of the scientific study of complete star
vation without water deprivation serve as approval of its therapeutic use as fasting. It
is based on the idea that such starvation does not cause dystrophy but only atrophy,
which can be completely restored.
Nowadays fasting is used as a non-specific method of some diseases treatment
including allergic, cardiovascular, digestive, dermal, diseases of the joints, obesity
and even mental ones. Dosed fasting (from 1—7 to 15—35 days but before the tlnul
|x*riod starts) increases the processes of dissimilation and promotes discharge of ex
ccssive metabolic waste. During the so-called endogenous nourishment the organism
uses its own pathological and dystrophic tissues and proteins fat depots, metabolie
I'lllt I < l'nllio|ilivsloliiK>

products, pathologic proteins, infiltration anil indiiiiiilon ol I Ih- connective tissue,

scars. Restorative processes lead to renovation ol the whole organism. The general
slate of the organism improves, weakness disappears, and appetite appears.
An important condition of a successful result of lasting is a serious motivation
of a patient.

CO M P LE T E STARVATION AND WATER DEPRIVATION (ABSO LU TE)

Complete starvation with water deprivation has the same periods as complete
starvation without water deprivation, but it is severer and shorter (3—6 days).
II water does not come from the outside, it is taken from the tissues. It is oxida
live water. The largest quantity of water is produced by fat oxidation — 100 g lipids
r ive 112 g of water, protein and carbohydrate oxidation provides half that quantity.
I lu- metabolic products, which are formed, require more water for their excretion
and thus a vicious circle is formed, which approximates death. Catabolic processes
.не excessively activated, tissue decay products are accumulated, and intoxication
develops.
IN C O M P L E T E STARVATIO N

( Contrary to complete starvation, which happens not often, incomplete starva

lion is frequently observed. Many pathological states, especially connected with
dysfunction of the digestive organs, are accompanied with starvation. It may be also
caused by social troubles.
Incomplete starvation may be quantitative and qualitative. Their etiology and
pathogenesis are different as well as clinical manifestations. Very often they are
combined.
QUANTITATIVE IN C O M PLET E STARVATION

I his type of starvation is undernourishment. It takes place when the organism

chronically does not receive with food the necessary quantity of materials for energy
production (2000-1500 kcal and less instead of 2500-3500 kcal).

Etiology

Г liological factors are those, which cause partial limitation of food intake by
i lie organism or difficulties in its utilization. They can be exogenous and endo
notions.
lyogenous causes are: a) insufficient amount of food, b) the factors, which
damage the digestive tract resulting in the limitation of food intake by the organism,
с ) the factors, which cause diseases of the digestive tract with a disturbance o f food
utilization. Etiological factors are physical (trauma), chemical (poisoning, which
causes constant vomiting), biological (infectious, psychogenic factors, which cause
anorexia) and social (undernourishment in poverty unci unemployment).
r.ndoRcnous causes are diseases of the digestive system, which limit food intake
by the organism (morphological delects), or diseases, which make it difficult to
 Chapter 12. SltirvMlioii

utilize food (inflammation, tumor, disbacteriosis, endogenous avitaminosis, genetic

causes as in enzymopathy, which hamper food absorption).

Pathogenesis

Incomplete starvation is a chronic situation, which may last for a long time.
In food deficit, the organism spends energy resources very economically. Body
mass decreases more slowly than in complete starvation, but it is often masked by
edema.
Basal metabolism decreases considerably, more significantly than in complete
starvation without water deprivation (by 30-35 % instead of 10—20 % ). The respi­
ratory quotient decreases insignificantly.
Contrary to complete starvation, when no dystrophy is observed, incomplete
starvation shows severe signs of dystrophy. Degenerative processes develop in tis­
sues. They are graver than in complete starvation because of a longer duration.
As a result of plastic material (protein) deficit synthetic processes are sup­
pressed. Oncotic blood pressure decreases due to a decrease of the content of pro­
teins in the blood. Osmotic pressure in tissues rises due to chloride accumulation.
As a result water retention is observed.
Starvation may cause many diseases (in some chapters of this textbook it is
mentioned as an etiological factor).

Manifestations

Inhibition of synthetic processes underlies most pathophysiological and clinical

manifestations of incomplete starvation.
Hemopoiesis is suppressed and blood cell deficit takes place. Dyserythropoietic
anemia often develops. Leukocyte content decrease (leukopenia and lymphopenia)
results in immunodepression.
The protein-synthetic function of the liver is impaired as well. The production
of albumins and globulins (immunoglobulins) is suppressed. The organism becomes
predisposed to infections.
Hormone synthesis is insufficient.
Healing of wounds and bone fractures is slow.
A typical manifestation of prolonged starvation is cachexial edema. This edema
is systemic. Hypoproteinemia underlies it.
In incomplete starvation alimentary center excitation is maintained all the time
and sensation of hunger is periodically renewed.
In the system of blood circulation bradycardia (heart rate decrease) and arterial
hlood pressure decrease are observed. Respiration is decelerated and weakened. The
sex instinct is suppressed.
Workability is decreased.
Death comes in the loss of about 40 % of body mass.
I*.и I I (•fiic ru l I'nlliophvsioloio

QUALITATIVE (PARTIAL) l \ < m i n i l l s | \l<\ U i n N

Qualitative starvation develops when Ihc conlenl ol one oi some nutrient com
ponents (proteins, lipids, carbohydrates, minerals, vitamins, and electrolytes) in
food is insufficient. The energy value o f food is normal. Qualitative starvation is
often com bined with the quantitative one.
Clinical manifestations are specific and depend on insufficient intake o f certain
substances.
In carbohydrate deficiency the liver becom es poor in glycogen resulting in ke
logeiiesis due to lipid transport into the liver.
I)eliciency o f fats in food is easily compensated by carohydrates and proteins
used as a source o f energy. However, to provide the plastic function o f lipids, the
organism should be necessarily supplied with indispensable fatty acids — arachi
donic, linoleic and linolenic. It is also important to take into consideration th.ii
absorption o f vitamins A, D, К is connected with lipids (liposoluble vitamins) and
avitaminosis develops in fat starvation.
Protein starvation is the most serious. Prolonged malnutrition with a primaiv
deficit o f proteins in food leads to protein calorie deficiency. It causes severe ah
uicntary dystrophy. In children it develops quicker than in adults as they have an
increased need in proteins (Kwashiorkor disease). It harmfully influences the de
vclopincnt o f the nervous system in early childhood, when the nervous cells grow
intensively. Depression o f the synthesis o f nucleoproteids, proteins and decreased
си /у iibil activity accompany prolonged protein insufficiency. The quantity o f cells is
diminished and atrophic processes develop in organs. The growth and development
o l bones is suppressed. Avitaminosis develops. It is a basis for anemia developmeni
H.14.1I metabolism is decreased. Hepatic lipid degeneration occurs. The pancrens
u u d e ig o e s hyalinosis and fibrosis. Dystrophic changes o f the heart and kidneys take
place. Ii often leads to death. Only rational nourishment can save a child.
Mineral starvation manifests itself through a deficit o f important ions — polas
nun (nervous and muscle excitability is depressed), calcium (osteoporosis and teta
in.i develop), iron (hypochromic anemia develops), cobalt (hem opoiesis disorder),
iodine (endemic goiter and hypothyroidism), fluorine (bone formation disorder).
I itamin insufficiency (avitaminosis and hypovitaminosis) can be exogenous (as
.1 lesuli o f the absence or a low content o f vitamins in food) or endogenous. Vila
iniiis B,, Bh, Bl2 and PP are important for the nervous system, vitamins Bh, B^ and
I lor the endocrine system, vitamin Bl2 — for hemopoiesis, vitamins B, and PP
lot the digestive system.
Here are some example o f avitaminosis:
• Beriberi (deficit o f vitamin B, is manifested as polyneuritis and dystrophic chany
es in Ihe nervous fibers and myelin layers).
• Pellagra (deficit o f vitamin PI* is manifested a s dermatitis, damage o f the mucous
membranes ol the digestive tract with diarrhea).
• Rachitis (deficit o f vitamin I), is manifested as a tlinordei ol the absorption •>)
calcium and phosphorus in Ihc small intestine and lentil tubules with a disordn
ol hone mine rail/at Ion).
 ( h u p te i 12. .M arvulion

• Scurvy (deficit o f ascorbic acid is manifested as a disorder o f oxidative processes,

iollagen synthesis, due to which the vessels lose solidity and easily break resulting
in hemorrhage syndrome).

Questions for Self-Control

I What is the difference between starvation duration in animals and human

beings?
' What conditions determine the duration o f starvation?
i Compare the clinical and pathophysiological periods o f starvation.
•I Why a healthy organism may adapt to starvation sufficiently?
' In what way is metabolism changed in different periods o f starvation?
(' In what way are reserves used in starvation?
I In what way does the endocrine system participate in adaptation to star­
vation?
What is endogenous nutrition?
') Why do some oigans (what namely) lose little mass in starvation? How is it
provided?
10 In what way does restoration after starvation proceed?
11 What is the difference between starvation and fasting?

Tests for Self-Control

(give correct answers)

I A 3-year-old child was diagnosed with Kwashiorkor disease. Such symptoms

are observed: keratinization and desquamation o f the skin, hepatic adipose
infiltration. What type o f starvation is observed in this case?
A. Carbohydrate.
B. Protein.
C. Mineral.
D. Vitamin.
E. Fatty.

I lie basal metabolism o f a rat after 48 h o f starvation without water deprivat ion
has decreased by 20 %. The respiratory quotient is 0.7; there is lipemia, nega
live nitrous balance. What period o f com plete starvation is it (according to the
pathogenetic classification)?
A. Uneconom ical energy expenditure.
Ii. Maximal adaptation.
C. Terminal.
I). Indifference.
Ii. Excitement.

I After 10 days o f experimental starvation without water deprivation the btnly

mass (o f a rat) and basic metabolism have decreased by 40 'V , the respiratory
I'llll I (• n ir iiil Г и 1 1 м 1 |» ||> ч |о 1 о к у

quotient is O.X, there is acidosis, edemas, kctoncima Wlial period o f complete

starvation is it (according to the pathogenctie classification)?
Л. Uneconom ical energy expenditure.
B. Maximal adaptation.
C. Terminal.
D. Indifference.
E. Excitement.

4. After 10 h o f starvation without water deprivation the basal metabolism o f a rat

increased, the respiratory quotient is 1 .0, there is a high level o f glucocorticoids
and catecholamines in the blood. The content o f nitrogen in the urine is high.
What period o f complete starvation are such symptoms typical o f (according to
the pathogenetic classification)?
A. Uneconom ical energy expenditure.
B. Maximal adaptation.
C. Terminal.
D. Indifference.
E. Inhibition.

5. During starvation the mass o f organs and tissues as a rule decreases. What or
gan loses more mass?
A. Brain.
B. Kidneys.
C. Liver.
D. Heart.
E. Muscles.

6. A group o f animals starved for 10 h. The concentration o f glucose in the blood

remained normal. What mechanism can explain this?
A. Activation o f glycogenolysis.
B. Activation o f glycogenesis.
C. Activation o f glycolysis.
I). Depression o f glycogenesis.
Г. Depression o f glyconeogenesis.
 TYPICAL DISORDERS OF METABOLISM

Chapters 13—18 deal with typical disorders o f metabolism (energy balance,

ми tabolism o f carbohydrates, lipids and proteins as well as water, acid-base and
• Icctrolyte balance). Some clinical examples (diabetes mellitus, obesity, edem a) are
idditionally mentioned.

(hapter 13
PATHOLOGY OF ENERGY BALANCE AND BASAL
METABOLISM

Metabolism performs the energetic (energy formation) and plastic (synthesis o f

in i essary products) functions.
livery disease is based on disorders o f metabolism. N o pathogenesis can be truly
understood without a deep penetration into metabolism changes. It is metabolism
■Ii orders that underlie the development o f all pathological processes (inflammation.
Hit rgy, neoplasia, hypoxia, etc.) interpreted at the molecular level. Failure o f any
physiological system includes specific features o f disbolism, which are discussed in
tin- corresponding chapters o f this textbook.
The dynamics o f metabolism is provided by:
• I ntry o f simple and complex substances (proteins, carbohydrates, lipids, vita
mins, electrolytes) with food into the digestive tract.
• Primary splitting o f the substances into simpler products with the aid o f digestive
enzymes.
• Absorption o f them into the blood.
• I ransport o f the substances with the blood to organs and tissues.
• ( atabolism (intracellular splitting o f substances by intracellular enzymes).
• f ormation o f intermediate products, which in their turn serve as substrates lot
various metabolic pathways.
• Anabolism (synthesis o f substances for organs).
• Deposition o f reserves.
• I inal product formation.
• I'inal product excretion.
Disorders are possible at any stage o f metabolic transformation o f substances,
"huh is provided with the help o f enzymes. The reaction substratc-cnzyme is i
l м .is o f metabolism.
So, metabolism consists in two opposite processes — anabolism and catabolism,
«Inch are connected dynamically. Metabolism disturbances are divided into m
i/Hired and hereditary as well as increase and decrease.
I’illl I < I ( ' l l r r u l l * l l l l l o |t l l > 4 l o l o |> >

D IS O R D E R S O l M E I AIM II IS M Н М Л I \ I ION

Metabolism is determined by genetic factors and is regulated by the nervous

and endocrine systems. Therefore its derangement may have a hereditary nature or
he acquired as a result o f regulatory system disorders.
Disturbances o f metabolism manifest themselves at all levels o f biological orgii
m /ation - molecular, cellular and the organism as a whole.
At the cellular level the leading role in metabolism self-regulation belongs in
genetic mechanisms. The majority o f hereditary defects o f metabolism are caused
by mutations o f the genes encoding enzymes ( enzymopathy, a concept is given on
P IX). G enetically determined enzymopathy results in depressed or altered syndic
s i s o f substances.
I lormonal regulation o f intracellular metabolism is provided by the influence
on the genetic apparatus resulting in enzyme synthesis induction. In addition, hoi
inones activate existing non-active forms o f enzymes (adrenaline activates phospho
rylase, insulin — hexokinase). Hormones may influence the permeability o f cellulai
membranes for substrates (glucose, amino acids, ions, etc.).
Information constantly brought by neuromediators and hormones is necessary
for Ihe coordination o f cellular metabolism. These regulatory influences are realized
with the help o f specific receptors to them, which are located on the cellular mem
bianes Pathology o f the receptors may underlie pathogenesis o f diseases. Disordei
may be genetically determined (p. 48 and p. 369 as it is in «family* hypercholes
tcrolcmia) and acquired (relative insulin insufficiency (p. 208) and type 2 diabetes
mellitus (p. 218).
Depressed enzyme activity leads to incomplete metabolism and accumulation
o f noil-metabolized substrates and intermediate products (diseases o f accumulation.
p. 4X), as it is in glycogenosis (p. 201). Increased enzymal activity leads to accunni
l it ion o f final metabolism products.
Together with intracellular self-regulation mechanisms, the organism has moie
complicated ones — neurohumoral mechanisms, which influence metabolism («> a
greater degree.
In understand the mechanisms o f regulation, it is necessary to distinguish the
iiK'chanisms o f catabolic and anabolic effects.
Catabolic regulatory effect is activation o f substance splitting. They are: synipn
llietic nervous influences and hormones with catabolic effect. Anabolic regulatory
effect is activation o f synthetic and plastic processes, reserve formation.
I lius, emotional irritation may cause heat production impairment, hyperglyee
iniii. hyperlipemia, overeating and obesity. Many disorders o f metabolism, thermo
regulation, physical and sex maturation are caused by diencephalon lesion. Hypo
thalamus influences metabolism by releasing factors through the pituitary gland oi
parapituitary pathways.
Hie vegetative nervous system actively influences metabolism. Thus, its sym
pathetic part activates lipolysis, tlie n. vagus activities insulin secretion. Disorders ol
the vegetative nervous system may provoke metabolism changes. Some diseases a i e
connected willi damage ol the sympathetic nodes
 C h ap let I ' I *:i I In »l<>>■> o f Кпсгку IM -iim Mini ll u s i a l M t l a l m t i in

I he nervous system provides the so-called neurotrophic function and controls

i ими- metabolism with the help o f mediators and axoplasmic flow. The neurodystro
plui process develops due to impairment o f this function (will be described in detail
in i hapter 31, p. 528).
Any hormone effects metabolism by its specific influence on certain metabolic
i и hways. As to the direction o f the effect, they are o f catabolic and anabolic ac
lion.
He low there are given hormone characteristics as to their influence on energy
uni basal metabolism.
Adrenaline provides all types o f organism activity, stimulates basal metabolism,
и и lies lipolysis, causes hyperglycemia and provides the organism with calorigcnic
materials.
thyroxin is a catabolic hormone. It stimulates metabolism and is one o f the
in нм regulators, stimulates oxidation, phosphorylation and energy formation in the
im hi o f calories.
Hormones o f the pituitary gland influence metabolism, and somatotropin
iш" w i l l hormone) has the strongest influence. It stimulates free oxidation and heat
production.
(ilucocorticoids refer to catabolic hormones as they stimulate protein disintegra-
....... but at the same time promote glycogen synthesis and obesity.
Sex hormones (testosterone and progesterone) refer to anabolics. At the same
i iin< Ih ey activate free oxidation and promote energy release.
Insulin is the main trophotropic hormone. It increases formation o f glycogen,
i it hi fat depots and proteins in muscles. It ensures glucose utilization by cells.
Involves lipids and proteins into the production o f a freely used energy source in
ill* lorm o f glucose, provides reserve depositions in the form o f glycogen and fat. It
■ii .urcs ATP formation by coupling o f oxidation and phosphorylation.
I'lius, there is a close connection between intracellular mechanisms o f m e­
tabolism self-regulation, which are genetically determined, and their neurohumor.il
irgiilution. Disorder o f any o f them results in disbolism, cellular pathology and
им ам dysfunction.

PATHOLOGY OF ENERGY BALANCE

I very kind o f work needs energy. Every defense reaction and hyperfunction
tn i ils energy as well.
A macrooiganism is a system, which produces energy for itself. Probably we do
n u t know all types o f biological energy, nevertheless, it is known that dehydrogena
imii (detachment o f H ') is a mechanism o f energy release (like proton fuel). Ii is
pioiluccd with the aid o f oxygen as an acceptor o f electrons. G lucose, fatly acids,
пиши) acids serve as substrates for energy production. In brief, for energy produc
linn t h e cells need substrates, enzym es and as a rule oxygen. Then Ihc energy takes
two forms:
• thermal energy in the form o f heal calorics;
• biological energy in the form o f high-energy phosphate bonds (AI I'l.
 ■
I'llll I I . r u n ill l'u(llo|ilivsiiil<iKV

The first form o f energy is needed to maintain normal body temperature. The
second form is needed for all biological energy-dependent processes — contraction,
secretion, ion channel functioning, substance synthesis, cell division, etc. ATP is
a specific form o f biological energy, which is accumulated in the organism in this
reserved form. There are two main metabolic processes o f energy production — oxi­
dation and phosphorylation.
The hypothalamus regulates the balance o f thermal energy. Mitochondria arc
the place o f energy production. Oxidation (with participation o f 0 2) is a more effec-
live way o f energy production in the form o f ATP than glycolysis (different variants
o f oxygen deficiency form different types o f hypoxia, chapter 11, pp. 160—162).
Energy imbalance underlies most functional and organic disorders in organs
and tissues. It may develop at all stages o f energy transformation due to a) absence
oi lack o f substrates; b) oxygen deficit; c) change in the amount or activity o f en­
zymes (o f respiratory chains, Krebs cycle, glycolysis); d) damage o f the regulatory
systems; e) genetic defects.
The respiratory quotient reflects preferred oxidation o f certain substrates. The
normal respiratory quotient is 0.9. It rises to 1.0 if carbohydrates are oxidized
predominantly; it decreases to 0.7 if lipids are mainly oxidized. The respiratory
quotient equals 0.8 if proteins are used for energy production. (It helps to distin
guish the pathophysiological periods o f com plete starvation on the basis o f energy
consumption as it was described on p. 176).
Two processes are tightly connected (coupled) in mitochondria — oxidation and
phosphorylation. They are regulated and depend on the state o f mitochondria anil
hormonal regulation. The organism manipulates with this connection. If the or
ganism needs additional heat, these processes may be uncoupled, free oxidation
predominates, ATP formation is temporarily limited. If the organism needs an ad
ditional amount o f ATP (hyperfunction) then oxidation and phosphorylation may
be coupled more tightly.
Contemporary methods o f investigation make it possible to determine the
amount o f ATP and estimate the state o f mitochondria. Their swelling results in
Ihc spatial removal o f the enzymes transporting electrons via the respiratory chain
from the enzymes o f the phosphorylation system. It leads to uncoupling o f oxida
(ion and phosphorylation. ATP formation decreases, energy becom es dispersed as
free heat, the specific functions o f cells are impaired (it is described as a variant
of histic hypoxia on p. 161). Many factors, which have the effect o f uncoupling,
are o f clinical interest because o f phosphorylation disorder. Some microorganism',
produce this effect. Diphtheria toxin as well as live and dead aurococcus cultures
produce it. Poisoning with some chemical agents (a-dinitrophenol, which damages
mitochondria) uncouples oxidation and phosphorylation resulting in hyperthermia,
which has no defense value (p. 140).
As to thyroxin, this hormone together with adrenaline is the most potent regu
lator o f energy production. It increases the permeability o f mitochondria, stimulates
oxidation, phosphorylation and energy formation Energy production in the form
ol heat increases. Its calorigcnic effect is nol explained by uncoupling o f oxidation
and phosphorylation because mitochondria are not swollen Imt enlarged Oxidative
 ( li.ipl ci I ■ I ’ .iiliiiln;’ v o f K i w r g y Balancr iintl l . i il Metabolism

<ii/ymes and ATPase are activated. A simultaneous stimulation o f both anabolic

uul catabolic processes takes place but thermal energy gets dispersed increasing
body temperature.
Most viral infections are connected with bioeneigetic process disorders. Viruses
н е certain substrates (ATP, AM P, acetyl-CoA, RNA, free nucleotides, etc.) for
ilu ir growth. Deficit o f free nucleotides leads to insufficient formation o f N A D and
N A D P ; ribonucleic acid deficit — to disorders o f cellular protein synthesis, spccifi
illy o f cellular enzymes.
Vitamins, especially o f В group, are rather important in energy production,
1 .1 hey are compounds o f coenzym es o f the Krebs cycle and respiratory chains o f
Icctron transport. Thus, vitamins PP and B2 are com pounds o f nicotinamide and
llnvinic dehydrogenases.
The disturbance o f energy metabolism underlies the majority o f functional and
•>i^anic impairments o f organs and tissues as well as insufficiency o f physiological
systems.
Analyzing energy imbalance one should keep in mind the following aspects for
nvmg its characteristics:
• increase and decrease;
• significance — defense or disorder,;
• oxidation and phosphorylation proportion (heat and ATP production);
• hereditary and acquired mechanisms;
• systemic and local development.
According to this, a lot o f situations are distinguished.

ENERGY PRODUCTION INCREASE

The mechanisms o f energy production increase are created in the process o f

evolution and provide not only physiological activity but also adaptation under
Imi liological conditions. Besides its activation as a defense reaction it may be a
i' nit o f metabolism regulation disorder. The difference between these mechanisms
lies in the fact that the former have a positive meaning and are very well regulated.
I lie latter are a disorder and have a negative meaning (scheme 9).

Energy Production Increase as a Defense Reaction

Ih at Calories

Systemic increase o f heat production occurs under the influence o f low ambi
• nl temperature (for the maintenance o f normal body temperature) and in fever
Ilor organism warming and body temperature increase). In these cases the defense
ir.ictions are very well regulated. The thermoreceptors and a special nervous ccnlcr,
which is located in the hypothalamus (the center o f thermoregulation), control the
thermal balance.
It is important to understand the strategy o f biological adaptive mechanisms in
i i <h situations because it differs from that in non biological objects. In the lattei
I ’. l l l I «.I III I .11 I 'l l l l l l i p l l N M I l l l i p

Si'lieme У. Causes, Mechanisms and Consequences ol liuergy Production Increase

•is E nergy pro d u ctio n

As a defense As a result o f
reaction m etabolism
JL d iso rd er
H eat
calories ^A T P l 'f ' C atabolic
Л --- .------- horm one
I M echanism s |-
Thermo­ T O xidation secretion
regulation /f' O xidation and T oxic effect
-| M echanism s
phosphorylation o f uncoupling
activation
coupling substances
I 4O xidation
4 / H eat em ission
i-l'l4 H eat production
O xidation and - T H eat em ission
p hosphorylation R esults |- E xhaustion o f
uncoupling
nervous and
endocrine system s
M aintenance
o f body /T> Plastic
tem perature processes
on exposure -| R esults |-
to cold Pregnancy

"t4o f body Prolonged

tem perature
in fever

ones (machines) energy is produced according to the physical laws o f thermodyna

mics - the more fuel, the more energy. In biological objects the laws are different
they allow receiving thermal energy by mechanisms, which do not need more sub
stratcs and oxygen. It is heat emission limitation and uncoupling o f oxydation and
phosphorylation. These mechanisms were described in every detail on p. 21 regard
ing overcooling and on p. 133 regarding fever. At the first stage o f overcooling re
servation o f heat is provided partially by increasing heat production (oxidation) and
especially by limitation o f heat loss. In accumulation o f heat and organism warm my
in fever the heat production by oxidation increases not so intensively in comparison
with the limitation o f heat emission and the uncoupling effect.
These reactions have a positive meaning.

ATP

Activation o f energy production in the form o f ATP is necessary for growth

and pregnancy as well as for every kind o f hypcrfunction and defense reactions (im
munity, inflammation, cardiac hyperfunction, el с ) During Ihc development o f am
pathological process (in ihc stage o f com pensation) il goes about additional Al l '
production. И is provided by:
• activation o f oxidation!
 C h a p te r 13. 1‘atholoK) o f Energy B alance .uul lia \a l M etabolism

• tighter coupling o f oxidation and phosphorylation;

• hypertrophy o f mitochondria.
At the stage o f compensation (even if it is hypoxia) energy production increases
lor adaptive reactions development. Immediate compensatory reactions are more
energy-dependent and require more energy expenditure. An increase o f oxygen
consumption and oxidation are detected.
There is a quick biological adaptive reaction directed at increased ATP produc­
tion without an increase o f substrates and oxygen consumption. It goes about tighter
nnipling o f oxidation and phosphorylation (as it is in the brain in oxygen deficiency,
p. 165) directed at normal ATP production in spite o f a lack o f oxygen.
If physiological and particularly pathological hyperfunction lasts for a lon-
ксг time, an increased production o f energy in the form o f ATP is provided by
mitochondria hypertrophy and increased amount o f respiratory chains. As it was
explained in chapter 11 «Hypoxia» (p. 165), it is ATP amount decrease (with the
iid o f HIF-factor, schem e 8) that stimulates the genetic apparatus resulting in in­
creased synthesis o f mitochondria structures.
These reactions have a positive meaning. Hormones o f the catabolic effect
provide it.
A local increase o f energy production is observed in the focus o f inflamma-
iton («oxygen explosion», p. 127). An increase o f both heat and ATP production is
ulaptive and facilitates active defense reactions — leukocytes emigration, phagocy-
losis, proliferation and regeneration.

Energy Production Increase as a Result o f Metabolism Regulation Disorder

Energy production increase is obtained in pathology not only as an adaptive

reaction but also as a pathological change.
A pathological increase o f heat production not connected with the organism
needs in energy occurs in hypersecretion o f hormones with catabolic effect (thy-
toxin, parathyrine, progesterone, somatotropin, vasopressin). Catabolism activates.
Oxidation activates but excessive energy is dispersed as heat. It leads to body over
lii iiting and exhaustion o f the nervous and endocrine systems. It happens in tumors
ol the endocrine glands, which produce these hormones. The most widespread
i linical example is thyrotoxicosis with goiter and increased thyroxin secretion. Tu
mors o f the pituitary gland (eosinophilic adenoma) with an increased secretion ol
Mimatotropin have the same effect on the energy balance.

ENERGY PRODUCTION DECREASE

Energy production decrease (both in the form o f heat and ATP) always has .i
negative meaning (schem e 10). It may occur at all stages o f energy production and
may result from:
• deficit o f substrates;
• deficit o f oxygen;
• deficit or damage o f enzymes;
• damage o f mitochondria;
Г.и I I (•ciK ia l I’alhnplnMoloK)

• disorder o f regulation in the form o f reduction o f the content o f hormones

with catabolic effect.
Reduction o f energy production takes place in starvation (deficit o f the sub­
strates entering the organism). In spite o f adaptation by a more econom ical ex­
penditure o f energy, the negative nitrous balance gets established at the stage o f
com pensation (p. 179) and energy production decreases significantly with lowering
o f body temperature at the third stage (p. 181).
All forms o f hypoxia lead to energy deficiency (p. 166). It underlies all func­
tional and morphological changes, which accompany all diseases o f the hypoxic
type (cardiac and respiratory insufficiency, anemia, etc.). Glycolysis activation to a
certain extent compensates oxygen deficit. A disorder o f glycolytic processes has a
negative effect on the organism ability to adapt to hypoxia.
Deficit o f enzymes, which participate in energy production, or changes in their
activity are an important cause o f energy deficit. It goes about the enzymes o f Krebs
cycle and enzyme com ponents o f the electron transport in the respiratory chain (it
was described as histic hypoxia, p. 161). In case o f citric acid cycle blocking energy
formation diminishes by about two thirds. Lack o f enzym es is divided into geneti­
cally determined (enzymopathy) and acquired.
Expressive disorders o f energy production are observed in case o f a disorder of
mechanisms o f coupling o f oxidation and phosphorylation. Mitochondria damage
underlies energy deficit in a lot o f cases. When the contractile ability o f mitochon
dria is damaged, they remain swollen for a long time. This causes phosphorylation
disorders and release o f the factors, which stimulate the glycolytic type o f metabo
lism in cells.
A disorder o f energetic metabolism is observed in endocrine pathology. Hypo
thyreosis is the best example. A deep disorder o f energy metabolism is observed in

Scheme 10. Causes, Mechanisms and Consequences of Energy Production Decrease

 C h a p te r 13. l*iithitl»K> of Кпсгцу liului" <- anil IIhmiI MrlulHilisin

insulin deficiency (diabetes mellitus) when production o f macroergic compounds

(ATP) is essentially decreased due to the limitation o f the poverty o f three carbon
acid cycle and respiratory chain (p. 209). Lack o f sex hormones (climacteric disor­
ders) accompanies metabolic disorders and energy production deficit.
Hypo- and avitaminosis may cause diseases leading to energy production d e­
crease. Oxidative phosphorylation is essentially disturbed in B-avitaminosis, as
many vitamins o f this group are present in the com position o f Krebs cycle cocn-
/ymes. In B,-hypovitaminosis the Krebs cycle is disordered and thus the amount
of substrate material for the respiratory chain is decreased. Convulsions and psy­
chosis, which are observed in this avitaminosis, are the clinical symptoms o f a
disorder o f biological oxidation in the brain. Disorders in the respiratory chain
are characteristic o f lack o f nicotinamide and flavinic dehydrogenases in PP- and
0,-hypovitaminosis.
Deficit o f some microelements may result in energy deficiency. Fe ions deficit
leads to Hb content decrease and development o f anemia, which cause oxygen de­
ficiency. The role o f J-deficit in hyporhyreosis is widely known.
Consequences o f energy deficit are numerous.
Calorie deficit results in adaptation to cold impairment. The development o f fe­
ver, when it is necessary in case o f infection, is problematic. We observe it in patients
with hypothyreosis, starvation, hypoxic diseases (anemia, heart insufficiency, etc.).
Deficit o f ATP results in suppression o f plastic and regenerative processes
(healing o f wounds, fractures, and ulcers), impossibility to develop compensatory
hypertrophy, decrease o f immunological reactivity.
Energy deficit leads to impaired reproduction o f important substances (en
zymes, hormones), which are necessary for metabolism.
Local lack o f energy production occurs in tissues as a result o f disturbance ot
peripheral blood circulation when tissue supply with substrates and oxygen is re­
duced. A local decrease o f energy metabolism is observed in malignant tumors. I( is
the so-called energy anaplasia (see chapter 10, p. 151). As it was discussed in that
chapter, suppression o f the genes o f redox system enzymes and changes in mito
chondria underlie it.

PATHOLOGY OF BASAL METABOLISM

Energy balance is an important characteristic o f the organism, both healthy

and sick. So, determination o f energy balance at the level o f the whole organism i
particularly important for assessment o f the patient’s state and studying o f disc r.<
pathogenesis. Historically, for this purpose, determination o f such an integral index
is the so-called basal metabolism is used.
Basal metabolism is a quantity of energy produced in the organism utidri
stan d ard conditions (at rest, on an empty stomach, at the ambient temperature ol
IH C ).
It is the minimal energy necessary for the organs and systems, whose I'iiik Ih m i
c. permanent: respiratory, hlood circulation, urine formation, production ol Inn
mones, HAS, etc.
Г;п1 I ( •cnt-rul I'.■111<>|>11\ siul(i)’\

I lie standard level o f basal m etabolism is 1200-1500 k cal/m 2 o f body surface

daily.
U nder the physiological conditions the level o f basal m etabolism depends on
the age (children have a higher basal m etabolic rate than adults; in old persons it is
reduced), sex (m en have a higher basal m etabolic rate than w om en), clim ate, living
conditions, m ode o f nourishm ent. Basal m etabolism is increased in pregnancy.
U nder pathological conditions changes o f basal m etabolism are m ore expres­
sive.
Basal m etabolism is under neurohorm onal control. Thyroxin, som atotropin,
adrenalin, and sex horm ones stim ulate it. Insulin has an opposite effect. M any dis­
eases and pathologic processes are accom panied by changes o f basal m etabolism .
There are tw o m ethods o f basal m etabolism m easurem ent — direct and indirect
calorim etry. The first m ethod determ ines heat calories, w hich are released by the
organism , and requires a special apparatus (calorim eter), w hich is w arm ed by a
patient (or an experim ental anim al) located inside. The second m ethod is based on
oxygen consum ption determ ination and calculation o f energy in calories according
to the law o f therm odynam ics. B oth m ethods deal with therm al energy.
In a healthy organism indices o f both m ethods coincide.
In pathological situations they often m ism atch and do not correspond to the
real energy balance.
I hus, if heat em ission is lim ited (the first stage o f fever), the direct calorim etry
Index is masked, lowered and less th an that o f the indirect one. W hen the organism
m anipulates with proportion o f oxidation and phosphorylation and the uncoupling
Hlci I occurs, oxygen consum ption (indirect calorim etry) does not reflect real ener
gy production (A TP am ount is not m easured) and it is less th an the direct one.
I or a deeper study o f the energy balance the m odern m ethods investigate the
am ount o f A TP in the tissues and the state o f m itochondria.
In spite o f the fact that basal m etabolism is not an absolutely correct index, н
is used m scientific and clinical research because o f its convenience.

Basal Metabolism Increase

Basal m etabolism increase reflects energy production activation. T he exam

pies are the sam e as given above. It is growth and pregnancy, physiological ami
pathophysiological hyperfunction, influence o f cold (but it is m asked by heat cmix
sion decrease), fever (but sim ultaneous heat em ission decrease and uncoupling ol
oxidation and phosphorylation m ask it).
All diseases arc accom panied by the developm ent o f com pensatory reactions,
which need additional energy. So, any pathological process in any system at Ilie
stage o f com pensation is accom panied by basal m etabolism increase. It rises in in
Icction, inllam m ation, anem ia, disturbances ol (lie respiratory and circulatory svx
irm s (hypoxia, pneum onia, m yocardial infarction, etc.). Al (lie beginning o f lieail
m siilliciency basal m etabolism increase makes III Ml % Palients lose weight anti
grow tInn. Stress increases basal m etabolism as wrll
 _____________________________ C h a p te r 13. Pathology o f E nergy B alance and Itasal M etabolism

Basal m etabolism is increased with hypersecretion o f horm ones with a catabolic

f ile d - thyroxin, parathyrine, progesterone, som atotropin, vasopressin. A drenaline
.timulates basal m etabolism , especially in case o f cooling (insulin suppresses trem
bling).
Basal m etabolism is increased in tum ors o f the endocrine glands with hyper
i ret ion o f horm ones with a catabolic effect. Basal m etabolism increase by 20 %
nul m ore is an im portant diagnostic indicator o f thyrotoxic goiter as well as o f
' nsinophilic adenom a o f the pituitary gland.

Basal Metabolism Decrease

Basal m etabolism decrease reflects energy production decline. Aging and hi

i'filiation are the exam ples as well as the state o f nervous system inhibition (shock,
t om a).
Basal m etabolism reduction accom panies:
• starvation (at the second stage) due to reorganization o f m etabolism for a
m ore econom ical use o f energy;
• hypoxia at the stage o f decom pensation.
In patients with endocrine diseases accom panied with hyposecretion o f hor
Mittnes o f a catabolic effect the level o f basal m etabolism is decreased. The exam ples
iif the following:
• hypothyroidism ;
• hypofunction o f the pituitary gland accom panied with a decreased p ro d u c­
tion o f thyrotropin and corticotropin (A C T H );
• hypofunction o f the sex glands (castration, clim ax);
• bilateral lesion o f the suprarenal glands (m ore often o f tuberculosis genesis
as it is in A ddison’s disease);
• obesity.

Questions for Self-Control

I (iive exam ples o f energy balance disorder in case o f nervous system

im pairm ent.
(iive exam ples o f energy balance disorder in case o f endocrine system
im pairm ent.
i What are the consequences o f uncoupling o f phosphorylation and oxidation?
I ( iive exam ples o f energy production increase as a defense reaction.
■ May energy production increase have a negative value?
fi W hen docs energy production increase o cc u r in the form o f heat calories?
’ W hen does energy production increase occu r in the form o f ATP?
N May energy production decrease have a positive value?
'I W hen does energy production decrease o ccu r in the form o f heat calories?
HI W hen does energy production decrease occu r in the form o f ATP?
11 What m ethods o f basal m etabolism m easurem ent do you know?
I ' W hen d o indices o f direct and indirect calorim etry m ism atch?
I’a it I (it'tic ia l I’ulhitphysioliiK)

Tasks for Sc*lf-< 'oniiol

(give correct answers and find m istakes in the statem ents)

1. A 32-year-old w om an com plains o f palpitation, sensation o f heat, trem bling of

extrem ities. A diagnosis o f Basedow’s disease was put (thyrotoxic goiter). What
energy balance disorders accom pany thyrotoxicosis and what is th eir pathogen­
esis?
1. Basal m etabolism is increased.
2. Oxygen consum ption is decreased.
3. The organism loses energy in the form o f heat.
4. Heat production is decreased.
5. The degree o f oxidation and phosphorylation coupling is dim inished.
6. Swelling o f m itochondria is noted.
7. The share o f non-phosphorylating oxidation is increased.
8. Plastic processes are activated.

2. A 44-year-old patient was exam ined in an endocrine clinic. Basal m etabolism

was determ ined. Give the characteristics o f basal m etabolism .
1. It is a quantity o f energy, which is necessary to sustain life at rest, at the
am bient tem perature o f lS 'C , on an em pty stom ach, e.g. 24 hours after
food intake.
2. It is determ ined at the am bient tem perature o f 18°C, as it does not depend
on the clim atic conditions and tem perature o f the habitat.
3. In adult persons o f average height and body mass it is about 1600—
1700 kcal/h.
•1 It is lower in children th an in adults.
5. It is higher in w om en th an in men.
(>. The ch aracter o f nutrition does not influence basal m etabolism as it is
determ ined on an em pty stom ach.
7. Basal m etabolism and specific body surface are in direct proportion in
concordance with R ubner’s isodynam ic law.

V Mow may basal m etabolism change in different pathological conditions?

1. Il is decreased in thyroid gland hypofunction.
2. A drenaline increases basal m etabolism .
3. In sex gland hypofunction (for exam ple, in castration) basal m etabolism
is decreased and accom panied w ith obesity.
4 II is increased at the initial stage o f cardiac dysfunction.
5. It is decreased in starvation due to transition to econom ical energy ex
penditure.

■t. Biological oxidation dccrcasc

takes p la tr in
1 Deficit ol oxidation substrates.
2 Deficit ol respiratory chain en/yniCN anil Kichs cycle enzymes
 C h a p te r 13. Pathology of Energy B alance and Kasai M etabolism

3. Deficit o f В group vitamins, which results in Krebs cycle disorder and

transportation o f electrons via the respiratory chain.
4. Uncoupling o f oxidation and phosphorylation.
5. Mitochondria swelling, which results in the spatial removal o f the en
zymes transporting electrons via the respiratory chain from the enzymes
o f the phosphorylation system;
manifests itself through:
6. Increase o f ATP quantity.
7. Decrease o f specific functions o f cells.
8. Activation o f plastic processes.
9. Disorder o f energy production.

What are the consequences o f oxidation and phosphorylation uncoupling?

1. The share o f non-phosphorylating free oxidation increases.
2. Less energy is spent on the production o f macroergic compounds.
3. Heat production is decreased.
4. Specific functions o f cells are inhibited.
5. Plastic processes are activated.
Chapter 14
PATHOLOGY OF CARBOHYI)RATIO Ml l AROLISM

Carbohydrates are an important energy source lor cells, and for some o f them
(nervous) carbohydrates are essential.
Го master the pathology o f carbohydrate metabolism one should know several
lernis:
• glyccmia — blood glucose level, an integral index o f carbohydrate metabolism,
,i standard measure is 3.3—5.5 mmol/1;
• hyperglycemia and hypoglycemia - increased and decreased blood glucose
levels;
• glycolysis — anaerobic glucose oxidation to pyruvate;
• glycogenesis — glycogen formation from glucose;
• glycogenolysis — splitting o f glycogen into glucose;
• glyconeogenesis — carbohydrate formation from non-carbohydrate products
amino acids - under the effect o f glucocorticoids o f the adrenal cortex and from
I'ally acids;
• glycogenosis - pathological storage o f glycogen in the liver and muscles;
• glycosuria - presence o f glucose in the urine.
Carrier proteins that transport glucose into cells are termed GLUT (G LU T-4
is Ihe insulin-regulated glucose transporter found in the adipose tissues and striated
muscles (skeletal and cardiac); G L U T -2 is the Na-dependent transmembrane car
m i protein that enables passive glucose movement across cell membranes into Ihc
cells o f the digestive tract and kidneys).
Pathology o f carbohydrate metabolism consists in disorders o f anabolism and
catabolism.
Disorders o f carbohydrate metabolism may take place at any point o f carbo
hydialc balance — digestion and absorption, maintenance o f the blood sugar level,
intermediate metabolism, formation o f reserves in the form o f glycogen, correlation
with other types o f metabolism.
I he main indices, which characterize carbohydrate metabolism, are the follow
imk blood sugar level and tolerance to carbohydrates. In pathology there are several
additional indices: the amount o f glucose in the urine, the amount o f intermediate
products o f carbohydrate metabolism (ketone bodies, other products).
I he main disease, which is connected with carbohydrate metabolism disordei,
is diabetes mcllitus.

DISORD ERS O F С ARBOHYDRATE DIGESTION AND ABSORPTION

Carbohydrates are digested and absorbed in the stomach and intestine. Disoi
dcrs o f carbohydrate digestion and absorption may be acquired and congenital.
Amylolytic enzyme deficit in the alimentary Irad is observed in case o f in
(lamination o f the intestinal mucosa. Nevertheless, .uquired enzymal splitting ol
 ( li.iplfi 1-4 l'iilli» l» K > o f < a r h o l i y t l r i i l c M c I u I h iI is iii

nhohydrates in th e sm all intestine is rather rarely im paired, since the salivary,

i■mu rcatic and intestinal glands produce amylase. In case o f achylia (decreased
i i l ie acidity) the amylase effect o f saliva is preserved in the stom ach.
M ore often enzym e deficit is congenital (enzym opathy), therefore digestion
ili orders arc observed in childhood. It goes about a deficit o f a specific disacchari
11 - or a deficiency o f the m onosaccharide transport system. In congenital deficit
■I hcxokinase, phosphatase and lactase, disorders o f m onosaccharide absorption
' iki place. Hexokinase deficit underlies a disorder o f glucose phosphorylation in
llit intestinal m ucosa.
W hen infants o f the first year o f life have problem s with m ilk suction, lactase
irlk it underlies it. D i- and polysaccharides are not split into m onosaccharides, and
llii ir absorption is reduced. C arbohydrates are accum ulated in the intestine lum en,
intestinal juice osm olarity increases involving w ater. A child suffers from pain, me
i' orism, and diarrhea. G row th and m aturation are retarded.
C ongenital deficit o f G L U T -2 results in glucose absorption disturbance with
tli.in hea, loss o f fluids (dehydration) and exhaustion.

D ISORD ERS O F GLYCOGEN SYNTHESIS AND SPLITTING

(ilycogen is a form o f carbohydrate reserves, which is accum ulated in the

muscles and particularly in the liver. Insulin provides form ation and accum ula
i и hi o f glycogen as a reserve. A drenaline, glucagon, thyroxin, corticotropin and
• iinatotropin provide glycogen splitting and use (in the form o f glucose) for energy
1 'ioiluction and o th er types o f m etabolism .
I )isorders o f glycogen synthesis and splitting m ay be in the form of:
• inhibition o f glycogenesis (glycogen synthesis);
• activation o f glycogenolysis (glycogen splitting);
• decreased glycogen splitting (glycogenosis).
Inhibition o f glycogen synthesis occurs in case o f a severe dam age o f the hepatic
■rlls (hepatitis, phosphorus poisoning, hypoxia) as well as in insulin deficiency. In
Hlvi ogen deficit energy production is based on lipid and protein oxidative m etabo
11 -■111 In this case, energy form ation requires m ore oxygen. Lack o f oxygen, in its
Ih i n . leads to tissue hypoxia, accum ulation o f ketone bodies and intoxication.
Activation o f glycogenolysis in the liver occurs under excitation o f the central
i i f i vt m is system and is connected with activation o f the influence o f the sym pathetic
ih ivt>us system. Glycogenolysis is intensified u n d er increased production o f such
lioiinoncs: som atotropic (S T H ), adrenaline, glucagon and thyroxin.

(tlvi'i»genosis

< ilycogen splitting decrease underlies glycogenosis. Excessive glycogen rcten

пип in the liver (also in the m uscles, kidneys, leukocytes, erythrocytes) is observed
li 1 1 *It*is to storage diseases (diseases o f accum ulation, p. 4X> and is congenital
I ii/vm opathy underlies glycogen splitting decrease. It goes about deficit o f the cn
\ mi s participating in glycogen splitting — glucose-6-phosphatase, phosphorylnse,
I’.III I (•t'licrul Г.Н 1н>|||цч| 1||о ц \

am ylo-1,6-glucosidase. In congenital deficit ol' glycosidasc in lysosomes, glycogen

is accum ulated and destroys them .
I he most widespread form o f glycogenosis is hcpatoncphrom cgaly o r G ierk e’s
disease. Il is based on the congenital deficit o f the enzym e glucose-6-phosphatase
in the liver and kidneys. This enzym e splits free glucose from glucose-6-phosphate
and prom otes transm em brane transfer o f glucose from the liver and kidney cells
into the blood. In deficit o f this enzym e, glycogen is not split and accum ulates in
Ihe liver and kidney cells. Hypoglycem ia develops. Sensitivity to insulin increases.
A patient needs m ore food. The form ation o f lactic acid from glucose-6-phosphate
is activated. Its co n ten t in the blood increases. M etabolic acidosis develops. The
pathology becom es obvious in infants and is accom panied w ith physical and mental
retardation. Life span gets lim ited.

DISORDERS OF CARBOHYDRATE METABOLISM REGULATION

Regulation o f carbohydrate balance is provided by nervous and horm onal

m echanism s as well as by carrier proteins transporting glucose (G L U T ) into cells
via the cellular m em brane.
It is im portant to understand that hypeiglycem ia accom panies all adaptive
reactions as glucose is an im portant source o f energy. Therefore, the num ber of
m echanism s, w hich increase the blood glucose level, exceeds that o f its decrease.

Nervous Mechanisms

T he nervous regulation o f carbohydrate m etabolism has been show n under

experim ental m odeling o f hyperglycem ia by puncturing the fourth ventricle bottom
(( laudc B ernard), stim ulating the basal nuclei o f the great brain, gray tu b er o f the
hypothalam us, lentiform nuclei and striate body.
M ental overstrain, intensive em otions, pain and attacks o f epilepsy cause hy-
pcrglyccmia as well.
I here is an o th er way o f central nervous system influence on carbohydrate
m etabolism . It is an effect o f the parasym pathetic fibers, w hich innervate the pan
creatic gland.

Hormonal Mechanisms

I he following horm ones provide the horm onal control o f carbohydrate m e­

tabolism and elevate the blood glucose level by different m echanism s — adrenaline,
glucagon, thyroxin, corticotropin and som atotropin. T hey stim ulate eith er glyco
gcnolysis or glyconeogenesis.
Adrenaline causes short-term hyperglycem ia by stim ulating glycogenolysis in
the liver.
(HucoKon activates glycogenolysis, inhibits actsim ulation o f glycogen in the
liver, lias glyconcogcnctic, lipolytic and insulin stim ulating effects.
 C h a p te r 14. 1‘alholoK.v <>( < '» rb o h y d r* te M ctiiliolisni

Thyroxin stim ulates glucose absorption in the intestines, activates liver phos
pliorylase and lim its organism tolerance to carbohydrates. H yperfunction o f the
ihvroid glands is characterized by a decreased tolerance to carbohydrates.
(Hucocorticoids (horm ones o f the zona fasciculata o f the adrenal cortex) raise
tin blood glucose level by glyconeogenesis activation (glucose synthesis from am ino
к id s). T hey induce the synthesis o f m atrix R N A , w hich is responsible for the
• n/ym es o f glyconeogenesis form ation. They decrease the cellular m em brane pei
ми ability for glucose and inhibit the rate o f hexokinase reaction and hexose-6
phosphate form ation.
Corticotropin acts similarly to glucocorticoids because it stim ulates th eir secre
non. It activates glyconeogenesis and inhibits hexokinase activity.
Somatotropin (the horm one o f grow th produced in the adenopituitary gland)
impairs tolerance to carbohydrates, causes hyperglycem ia, ensures hyperplasia o f
iIn- u-cells o f th e pancreatic islets, stim ulates glucagon synthesis, activates liver
iir.ulinase, lipolysis and glyconeogenesis (from fatty acids).
11 is only insulin (secreted by pancreatic p-cells) that decreases the blood glu-
i use level and provides balance.
Such dissim ilarity o f horm onal participation in blood sugar level regulation has
(wo consequences: (a) the first line o f horm ones is called contrainsulin although
ili< и physiological action is synergic to insulin, (b) insulin deficiency significantly
■illn is the blood sugar level, raises it (fig. 22).

Insulin Effect Mechanisms

Го m aster the m aterial o f this chapter one should know in detail the m echa
nr m s o f insulin effect.

Glycemia
5 .5 5

1. a-Endocrinocytes o f the pancrcalic islands

2. Adrenal cortex
3. Adrenal medulla
4. Adenohypophysis

hr Norm al regulation o f carbohydrate m etabolism and its possible disord eis hi him "i
h i altered correlation betw een insulin and h orm on e antagonists
Pllfl I < H 'l l r l ill l 'u l l l < l |l l i y s i o l o K .V

Ih c m ain с fleet o f insulin consists in lowerti i# the 1>1<нн1 \ицчг level It is achieved
by increasing glucose utilization by target cells and acciunulaliiiK carbohydrate re­
serves. Insulin provides the m em brane transport o f glucose, am ino acids and certain
ions. So, insulin is the main anabolic (trophotropic) horm one in the organism .
Insulin realizes these effects by such m echanism s:
• Raises target cell perm eability for glucose by increasing in the cell m em branes
the am ount o f glucose carriers (G L U T -4 ) and the rate o f hexokinase reaction
resulting in increased form ation o f gIucose-6-phosphate as the m ain m etabolic
substrate for interm ediate glucose m etabolism .
• Activates the Krebs cycle (the enzym e citrate synthase).
• Activates glycogenesis, prom otes glycogen storage in the liver and muscles.
• Inhibits glycogenolysis by stopping phosphorylase activity.
• Activates lipogenesis (conversion o f 10 % glucose into lipids).
• Induces synthesis o f protein, R N A and DNA.
• Regulates such intracellular indices: adenylate cyclase (w hich regulates the intra
cellular cA M P level), guanylate cyclase and c G M P production, N a-K -A M P ase
activity, sodium -calcium flux.
• Provides penetration o f potassium into cells.
• Inhibits glyconeogenesis.
• Has m itotic activity (sim ilar to grow th factors).
• Influences the genetic apparatus o f target cells and induces the corresponding
enzymes.
T he effect o f insulin on target cells depends on the am ount and affinity o f
insulin receptors. T hey have been identified on fat cells, hepatocytes, fibroblasts,
m onocytes, thym ic lym phocytes.
A com parison between the effect o f insulin and contra-insulin horm ones 0 1 1
carbohydrate m etabolism is given in schem e 11.

HYPOGLYCEMIA

Hypoglycemia is a reduction o f the blood glucose level below 3.3 m m ol/1. Ii

develops as a result o f insufficient content o f glucose in the blood.

( iiusos

I lie causes o f hypoglycem ia are:

• carbohydrate starvation (alim entary hypoglycem ia);
• m alabsorption o f carbohydrates in the intestine;
• increased insulin production in hyperfunction o f the pancreatic insulin a p ­
paratus (hyperplasia, insulinom a);
• insulin overdose in the course o f treatm ent for diabetes mcllitus;
• insufficient production o f contrainsulin horm ones (thyroxin, adrenaline,
glucocorticoids);
• decreased glycogen splitting in glycogenosis (Ini exam ple, G ierk e’s disease)
• damage ol the hepatic cells (acute and c I ih m iu hepatitis);
 C h a p te r 14. I'a lh o lo x y o f ('jirh o h y d riile M e tab o lism

• renal diabetes caused by im pairm ent o f glucose reabsorption in the renal

tubules and loss o f glucose in the urine.

M anifestations

I he central nervous system is especially sensitive to glucose deficit, because

i imDsc is its only source o f energy. Oxygen consum ption by the brain is decreased
mi hypoglycemia. Irreversible changes take place in the nervous cells in prolonged

h\|H>glycemia.
lachycardia develops due to adrenaline hyperproduction. H unger (excitation
■■I the ventrolateral nuclei o f the hypothalam us), trem or, weakness, irritability and
li и are the clinical sym ptom s. C onvulsions develop. If the glucose level is below
1 1 m m ol/1 hypoglycemic coma develops.

HYPERGLYCEMIA

Hyperglycemia is an increase o f the blood glucose level. It results from in

■и used glucose production (glycogenolysis, glyconeogenesis), its decreased ti.nr.
i"'II into tissues and utilization.
I lyperglycem ia can be alim entary (after consum ing a large quantity o f easily di
i * .ted carbohydrates). G lucose is quickly absorbed into the blood from the intestine
1 1 1 >im>ting the ability o f the liver, m uscles and o th er organs to assim ilate it.

Ilypcrglycem ia is observed in an excessive am ount o f such contra-insulin hor

....... as glucagon, adrenaline, glucocorticoids, corticotropin, som atotropin and
ihsroxin. Insulin deficit and contra-insulin horm one prevalence are accom panied
in hvpcrglycemia.

INTERMEDIATE CARBOHYDRATE METABOLISM DISORDER

Interm ediate carbohydrate m etabolism disorder consists in glucose non-split

iniy it» linal products ( C 0 2and H 20 ) . Interm ediate products (lactate, pyruvate) are
■ * mutilated. It leads to acetyl-C oA accum ulation. M etabolic acidosis develops.
I he causes are:
• Hypoxia (respiratory and vascular insufficiency, anem ia). T he anaerobic phase
■il carbohydrate catabolism prevails over the aerobic one. T he blood lactate level
rises.
• I ivei dysfunction (it is known that lactic acid is partially resynthesized into glu
i use and glycogen under physiological conditions).
• Vitamin B, (thiam in) hypovitam inosis. D ecarboxylation o f keto acids is disturbed
Im-cause this vitam in is part o f cocarboxylase. T he synthesis o f acetyl-С оЛ from
pyruvate is suppressed. Acetylcholine synthesis is decreased, and transm ission ol
nervous impulses is disordered. T he function o f the nervous system fails.
• Insulin insufficiency (see details below).
I’ilH I (iriH 'IM l I'UlllopllVsiolllKV

Scheme II. Intluence ol Insulin and Its A ntagonists o n (ilu c o sc M e­

tabolism in u Cell
C ellu lar m em branes perm eability

H exokinase reaction rate

Insulin
Insulin ► G lycolysis enzym es synthesis 4 antagonists

G lyconeogenesis enzym es synthesis

* G lucose-6-phosphate form ation

Activation Suppression

RENAL TH R ESH O LD O F GLUCOSE

It is known that all the blood glucose is filtered in the renal glomerules into
Ihc primary urine. Then glucose is com pletely reabsorbed into the blood from the
primary urine via the epithelium o f the proximal tubules. Carrier proteins (N a-de-
pendent G L U T -2) and enzymes (hexokinase) provide glucose reabsorption. Energy
and proper N a-K pump regulation are necessary for it.
I hc renal threshold is the maximal level o f glycemia (normally 8.8 mmol/1),
which is not accompanied by appearance o f glucose in the final urine.
II blood glucose concentration is high (hyperglycemia), some glucose is ex­
a c te d m Ihc urine (glycosuria).
In some cases glycosuria develops without hyperglycemia, i.e. when transport
\ .(cms in (he kidneys are impaired. Acquired and hereditary pathology o f the
proximal lubules as well as Na-balance disorder have the same result. In these cases
one- speaks about renal threshold decrease and the so-called renal diabetes.

TOLERANCE TO CARBOHYDRATES

lolcrance to carbohydrates means the organism ability to utilize a certain

.h i munit o f carbohydrates at a certain speed without any glucose appearing in the
urine.
Normally, the maximal amount o f glucose, which is utilized without glycosu-
n.i is 160 1X0 g consumed on an empty stomach. Normally glycosuria develops
when the blood glucose level is above the renal threshold (8.8 m m ol/1).
In clinical practice tolerance to carbohydrates is determined by the glucose
tolerance test with sugar taken on an empty stomach and dynamics o f alimentary
hv|>eiglycemia (fig. 23). Normally, the blood sugar level must be normalized during
a certain time.
I In is, tolerance to carbohydrates reflects carbohydrate metabolism regulation
•iiiil is determined by:
• ability o f the organism to release an adequate amount o f insulin in response
to hyperglycemia and return the blood glucose level to normal in time;
• function o f insulin receptors on target t ells.
• condition ol the glucose transport systems lit tin kidneys (renal threshold).
 C h a p te r 14. РаПмИоку of <'a rb o h y d ra lr M clalm lism

Increased tolerance to carbohydrates

is observed in pancreatic (3-ccll hyper
| 15.5() function.
Decreased carbohydrate tolerance is
observed in hormonal insufficiency (ac­
I 1-'30 romegalia, Itsenko—Cushing’s syndrome,
and insulin deficiency).
1 11.10
IN SU LIN INSUFFICIENCY
X.X8
Since insulin plays an extraordinary
6.66 role in the regulation o f carbohydrate
metabolism, the main pathophysiological
4.44
syndrome connected with carbohydralc
disbolism is insulin insufficiency.
3 Hours Insulin insufficiency is metabolic and
hr 23. Curves reflecting the results o f glu- pathophysiological disorders in the organ-
. . . . loading in a healthy penson (A), in ism caused by insulin amount or function
. im! o f decreased tolerance to glucose (B), disorders,
uul in case o f diabetes mellitus (C)
TYPES

Depending on the reason and degree o f problems with insulin, its insufficiency
i . divided into two forms — absolute and relative. Depending on cause localization,
it is divided into pancreatic and extrapancreatic. These two classifications actually
<omcide.
Absolute (pancreatic) insulin insufficiency is a result o f decreased insulin biosyn
ih.ms or secretion.
Relative (extrapancreatic) insulin insufficiency refers to the situation, when in
м11111 production is normal, but metabolic disturbances and clinical picture are l lie
пне as in absolute insulin deficit.
I he causes and pathogenesis o f these two forms are different.

t AtlSKS AND PATHOGENESIS O F ABSOLUTE (PANCREATIC) INSULIN INSUFFICIENCY

I he pancreatic deficit o f insulin is caused by acquired and hereditary disordeis

и any stage o f its formation and secretion.
I he following mechanisms are possible:
• Impairment o f the glycoreceptor system on the pancreatic (J-cell membrane,
which receives an insulinogenic stimulus o f the blood glucose. As a result, insulin
.ecretion in response to glucose is suppressed.
• I )isorders o f intracellular messengers, which transfer signals from glycorcccptois
io the |i-cell genetic apparatus. A disorder o f the ion C V entering (i-cells has the
Mime result.
• Disorders o f proinsulin transformation into insulin.
1*1111 I 1
<a«'IM'llll Г и | |»||||у% |о|о |0
• Disorders o f insulin secretion from |l cells (inipiopei insulin secretory re
spouse).
• Cytotoxic damage o f (i-cells by (i-cytotropic chemicals (including drugs).
• I)amage o f |l-cells by р-cytotropic viruses (Coxsackie virus).
• Immune damage (formation o f antibodies against insulin or p-cells).
• Destructive changes in the pancreas — tumors, cirrhotic and inflammatory pro
cesses, vessel sclerosis.

CAUSES AND PATHOGENESIS O F RELATIVE (EXTRAPANCREATIC)

IN SULIN INSUFFICIENCY

Relative insulin insufficiency is a situation, when insulin production is normal

I lowever, metabolic derangement is similar to absolute insulin deficit. Causes origi
ua l e out o f the pancreas.
I he following causes are possible:
• Excessive production o f contra-insulin hormones.
• I )isorders o f insulin transport in the blood.
• Activation o f the factors accelerating insulin destruction (insulin antagonists,
insulinase and other proteolytic enzymes).
• Peripheral effect o f insulin disorders is the main cause o f this type o f insulin
insufficiency. A decrease o f target cell sensitivity to insulin is called insulin resis­
tance, which may be prereceptor, receptor, and postreceptor. Receptor resistance
is connected with:
• lack o f receptors;
• altered receptor affinity to insulin;
• autoimmune aggression against receptors;
• genetic pathology o f receptors.
I'ostreceptor changes are connected with glucose transport disorders by the
i arnei CiLUT-4 in the adipose tissue, which results in carbohydrate intolerance in
obesity.
Relative insulin insufficiency connected with insulin resistance can be compli
■ iied with the absolute one due to activation o f insulin production by p-cells (to
overcome resistance) and p-cell overload.

INSULIN INSUFFICIENCY MANIFESTATIONS

Manifestations o f insulin insufficiency are metabolic and pathophysiological. All

types o f metabolism are deranged because o f insulin insufficiency.

Metabolic Disorders

( :uImlivdrale Metabolism Disorder

Carbohydrate metabolism is impaired most ol all. which manifests itself through

disorders ol intermediate glucose metabolism, hvi>ei|i!vcrmia and glycosuria.
 C h a p te r 14. P ath o lo g y o f ( a rtio liy d ra tc M e tab o lism

Intermediate Glucose Metabolism Disorder

Interm ediate glucose m etabolism is im paired in all possible ways, nam ely:
• G -6 -P form ation decrease as well as its participation in glycolysis, pentose
phosphate cycle and glycogen synthesis;
• inhibition o f m etabolic capacity o f the Krebs cycle;
• accum ulation o f interm ediate acid m etabolites and m etabolic acidosis devc
lopm ent;
• A TP form ation decrease;
• glycogenesis suppression;
• glycogenolysis activation;
• glyconeogenesis activation;
• glycogen reserve depletion in the liver and muscles;
• suppression o f glucose conversion into lipids.
As a result, such an integration pattern as tolerance to carbohydrates fails.

Hyperglycemia

Hyperglycem ia som etim es reaches 25 mmol/1 and m ore. Hyperglycem ia pailio

yenesis is the following:
• difficulty in glucose passage into cells from the blood due to reduced perme­
ability o f the target cell m em brane for glucose;
• activation o f glycogen splitting into blood glucose;
• activation o f carbohydrate form ation from fatty acids, am ino acids, lactate
and pyruvate;
• inhibition o f glucose conversion into liver glycogen;
• inhibition o f glucose conversion into lipids.
In spite o f th e fact that glucose is not a toxic product, constant hyperglycemia
h i', negative consequences, w hich consist in:
• osm otic blood pressure increase;
• blood protein glycolization (non-enzym e dam age o f protein m olecules);
• form ation o f glyco- and m ucoproteids, w hich are accum ulated in the con
nective tissue contributing to hyaline form ation and dam age o f the vascular
wall.
(Hycosuria (appearance o f glucose in the urine) develops if the blood glucose
l< vel rises above the renal threshold.

I Ipid Metabolism Disorders

I ipid m etabolism is critically involved in m etabolic disorders in insulin instil

ll« lency. The changes are the following:
• l.ipolysis activation (m obilization o f fatty acids from the adipose tissue) and
lipogenesis inhibition (glucose conversion into lipids, triglyceride resynthesis from
I.illy acids).
• Transport hyperlipemia.
I’.II t I ( ir llr llll I’ulllllllliyslolllKy

• Increased cholesterol synthesis (hypercholestermemla) Iroin acetyl-CoA, which

is not introduced into the Krebs cycle. Together wiili an increased synthesis o f high
density lipoproteins it results in atherosclerosis development.
• Obesity development in case o f insulin resistance (see p. 22X).
• Lipoid degeneration o f the liver and other parenchymatous organs (p. 231)
(An increased quantity o f fatty acids com es into the liver. Some o f them are con
verted into triglycerides, which are a precondition for liver lipoid infiltration. Some
o f them are transformed into acetyl-CoA by p-oxidation and a great amount ol
a». ntyl-CoA is produced. There may be no lipoid infiltration o f the liver, if the pan
creas produces lipocaine.)
• Accumulation o f incompletely oxidized products o f lipid metabolism (ketone
bodies — acetone, acetoacetic and p-oxibutyric acids). Under normal conditions
ketone bodies are formed in the liver, then get into the blood, lungs, muscles, anil
kidneys, where they are oxidized to C 0 2 and H20 . In insulin deficiency they are
accumulated in the blood. The state is called hyperketonemia and ketoacidosis based
on the following mechanisms:
• reduced activity o f the Krebs cycle (hence, acetyl-CoA transformation
into citrate is inhibited);
• delay o f fatty acid resynthesis from acetyl-CoA as a result o f N A D PII,
deficiency (reduced speed o f the pentosophosphate cycle);
• intensified decom position o f fatty acids from fat depots and their accelc
rated oxidation to acetyl-CoA;
• decreased activity o f acetyl-CoA carboxylase, which participates in tlu-
synthesis o f fatty acids through malonyl-CoA.
Ketone bodies inactivate insulin aggravating insulin insufficiency. A smell ol
acetone from the mouth and presence o f acetone in the urine are observed in pa
lients. Kctonemia underlies comatose state.

Protein Metabolism Disorder

Protein metabolism disorders are the following.

• Intensification o f protein catabolism.
• Increased use o f deaminated amino acids for glyconeogenesis.
• Ammonia release after amino acid deamination. (It is compensated by urea for
ination and combination o f ammonia with P-ketoglutaric acid o f the Krebs cycle
\i the same time, such compensation has a negative feature — p-ketoglutaric acid
deficit results in Krebs cycle inhibition, ketone body accumulation, as well as .1
decrease o f ATP formation.)
• I)epression o f protein synthesis in the liver in ATP deficit and weakened stimu
laiiiig influence o f insulin on protein synthesis enzymes.
• Suppression o f RNA and D N A synthesis.
• Negative nitrogen balance.
• Damage o f proteins by glycolization; synthesis nl glyco and mucoproteids with
hyaline formation.
• Decrease o f immune antibody formation as a u siill ol protein deficit
 C h a p te r 14. I’allioloKv of < la rb o h y d ra te M e tab o lism

\i lil-Base Balance Disorder

Acid-base balance disorders consist in:

• accumulation o f incompletely oxidized products o f metabolism, all o f which
are acids (lactate, ketone bodies);
• decrease in bicarbonate blood reserve;
• development o f metabolic acidosis and ketoacidosis.
At the stage o f compensation it is possible to obtain compensatory reactions
m\olvcment o f the buffering systems, increased excretion o f acids and ammonia
ills in the urine, hyperventilation. Participation o f the lungs, kidneys and adre
nil cortex (aldosterone) in acidosis compensation is presented on p. 244 and in
hemes 17, 18, 19 on pp. 245—246. If com pensation is insufficient (diseases o f
Ни sc organs) or exhausted acidotic coma develops.

Wи Ii t and Mineral Balance Disorders

(ilycosuria induces osmotic diuresis and thus polyuria, causing a loss not only
■•I water but also electrolytes (N a, K, Mg, P). In addition, insulin insufficiency
ntuates in limitation o f membrane transport o f certain ions and increased pen
• l nil ion o f sodium into the cells. Disorders o f water balance result in:
• dehydration due to increased loss o f water in the urine;
• elevation o f blood osmotic pressure.

Pathophysiological Disorders

Pathophysiological derangement, which is observed in insulin insufficiency, is л

..... sequence o f metabolism disorder. It is necessary to distinguish (a) pathophysm
i ru.il consequences o f insulin insufficiency and (b) pathophysiological const-
щи nces o f prolonged and incomplete compensation o f insulin insufficiency wiili
ii" .iid o f drugs that takes place in clinical practice.
I’alhophysiological disorders are the following.
• Metabolic acidosis may be decompensated and results in coma develop
ment.
• Ketonemia and ketoacidosis cause intoxication and may result in com a <l<
vclopment.
• High blood glucose level increases osm otic blood pressure and may c a u se
comatose state.
Nowadays com atose state rarely develops due to modern medical aid (si.ii<
i i'Tiams provide patients with drugs). Disease becom es chronic and lasts for in.im
us So, another group o f pathophysiological changes must be added Ihc t li.mr
■. c onnected with prolonged medical care o f patients with insulin insulin um \
M'Klern drugs prolong life, however, compensation is incomplete. Palhophysioloni
• il disorders progressively increase and are aggravated with lime. So. the h i ol
i' и In (physiological disorders may be continued.
Г .ill I ( i r n t T i i l Г |||||о |> ||у ч 1 о 1 » к у

• C onstant loss o f glucose in the urine overloads .ill horm onal m echanism s
o f blood sugar level support (secretion o f glucocorticoids and o th er contra
insulin horm ones). O verloading o f horm onal m echanism s leads to their ex
haustion.
• Atherosclerosis acquires a generalized form.
• Excessive synthesis o f glyco- and m ucoproteids leads to the developm ent ol
vessel hyalinosis, w hich is accom panied by autoim m une inflam m ation and
aggravates atherosclerotic dam age. Vascular pathology (angiopathy) is the
m ain reason for invalidity and death.
• I ipid infiltration o f the parenchym atous organs (liver, m yocardium ) lead-,
to failure o f these organs and aggravates pathophysiological disorders with
various clinical sym ptom s.
• (ilycosuria prom otes osm otic diuresis, which can reach 1 0 -1 2 1/day. Loss
o f w ater leads to dehydration. A lthough patients com pensate it by drinking,
electrolytes (N a, K, M g, P) are lost in the urine. Loss o f w ater results in
hyperosm olarity and thirst.
• G lycolization o f various proteins (H b, enzym es, collagen, etc.) has different
consequences depending on the type o f dam aged proteins.
• f orm ation o f im m une antibodies is suppressed. It results in decreased resis
lance o f the organism to infection (im m unodepression).
• Regenerative and plastic processes are suppressed resulting in decreased
wound healing. Any traum a is accom panied by incapability o f regeneration
and frequently results in form ation o f the so-called trophic ulcers, whose
developm ent is prom oted by atherosclerosis.
• G row th retardation is observed in children.

DIABETES MELLITUS

Diabetes m ellitus (D M ) is a clinical exam ple based on insulin insufficiency.

It is a cause o f high m ortality due to plural com plications and refers to relevant
medical problem s. DM is diagnosed in 1—4 % population and 30 % elderly people
I he num ber o f diabetics in the world doubles every 15 years. This phenom enon is
■\pl.lined by a significant role o f genetic factors in D M developm ent. Successful
treatm ent and survival o f patients results in the accum ulation o f genetic disorder,
in population.
Diabetes mellitus is a disease, which is characterized by chronic hyperglycemia
resulting from absolute or relative insulin insufficiency.

E TIO LO G Y

I liological factors, causing D M , are physical, chem ical and biological, whose
general property is the ability to cause insulin insufficiency. D epending on genet it
m echanism participation, DM is divided into acquired and genetically determ ined
 C lu ip tc r 14. I’alholuKV of < a rb o h y d ra tc M i-laliulisin

ll< rrditary insufficiency o f the pancreatic islets can be detected under the effect of
pmvoking exogenous etiological factors.
Physical factors are not very relevant. They are traumas o f the pancreas (in
• liulmg surgical) and ionizing radiation. Environmental influences raise the risk o f
ii,ise development (if predisposition is present).
Chemical factors are р-cytotropic chem ical substances (alloxan, dithizone,
irrptozotocin and nitrosamines are p-cell cytotoxic agents inducing a diabetes
lik«- condition in experimental animals). Some pharmacological agents (diurct
и ■ oral contraceptives, p-adrenergic drugs) inhibit insulin secretion in man and
m induce the disease. The mode o f nutrition matters a lot. The factors, which
иii rease the load on the insulin apparatus (overeating, excessive consumption o f
iibohydrates and fats) provoke DM manifestations in patients with genetic pre-
•lr position.
Biological factors are o f infectious, immune and psychogenic origin.
Infectious factors are р-cytotropic viruses (Coxsackie, agents o f whooping
ищцИ, measles, German measles, hepatitis, influenza), agents o f scarlet fever, lues
•iiiil tuberculosis.
I he value o f immune factors is confirmed by the possibility o f experinien-
i it DM reproduction by injection o f heterogeneous antibodies against insulin or
|t cells.
Emotional overstrain can provoke the development o f DM (if genetic predis
I i t ion exists). Stress aggravates the diabetic condition and acts through steroid-
tuiluced glyconeogenesis or increased catecholamine secretion.
Pregnancy plays a role o f a biological factor. Predisposition is often importani
Thus, genetic predisposition is the main endogenous cause o f DM .

P A T H O G E N E S IS

I he main pathogenesis link o f DM is absolute or relative insulin insufficiency

(ti f the essence, reasons, and pathogenesis above).
ЛИ typical pathological processes (infectious and allergic inflammation, tumoi
thrombosis, necrosis and sclerosis) in the pancreas and other organs, which provide
tiiMilin effects, play a role in DM pathogenesis.

Role of Genetic M echanism s

Hereditary factors significantly contribute to DM development. Their role i

<on firmed by the existence o f «family» diabetes, when the disease is recorded in
м vrral members o f one family (sometimes in 3—4 generations), and high concm
........ in monozygotic twins (4 times higher than in dizygotic ones), Ilxaininalion
■I lust degree relatives o f diabetics confirms this idea. The concordance rale .i|>
си ii hcs 90—100 % in twins having N ID D M (non-insulin-dcpcndcnt DM мч
In low) and 50 % in ID D M (insulin-dependent DM ).
I he risk o f a disease in women is two times higher than in men (il allow. i
miming that the pathologic genes are connected with the X-chrom osom e) < o n
Г.i l l I ( •rilrtlll Г х 11| 0 ||||у л | 0|ику

ncclion o f the disease with the ABO system antigens has been noted (patients with
the A blood group are alTccted more often).
Mutation o f the genes, which participate in the functioning o f the insulin ap
p;i ml us and peripheral effect o f insulin, underlie hereditary predisposition to DM
Several mutant genes, which determine DM development, have been revealed
( ienetic defects o f p-cell membranes, insulin synthesis and secretion, insulin an
tagonist content, and insulin receptor structure may be inherited.
Types o f inheritance include autosomal dominant, autosomal recessive and
polygenetic ones. DM reference to the category o f multifactorial diseases reflecis
the value o f genetic factors together with the role o f the environment.
(ien etic predisposition is the basis, on which causative exogenous etiological
lactors (chemical, immune, infectious, psychic, overeating, etc.) lead to the devel
opnicnt o f DM . They unmask hereditary predisposition.
Secondary diabetes can develop in chromosomal syndromes (Klinefelter’s.
D own’s).
Thus, the disease depends on the interplay o f genetic and environmental influ­
ences.

Role of Immune Mechanisms

Autoimmune aggression against the insular apparatus consists in the formation

o f autoantibodies against insulin, p-cells and insulin receptors as well as leukocytii
helper activation and suppressor inhibition. DM is frequently combined with othci
autoimmune diseases (autoimmune thyroiditis).
Specific leukocyte antigens o f the HLA system serve as genetic markers o f DM
predisposition. Close association between the gene governing histocompatibility
antigens and IR (immune response) genes is noted, because HLA system genes
are localized in the 6,h chromosome near the focus o f immune response control. It
determines a specific immune status o f the organism. Som e viruses with p-tropic
properties can induce autoimmune process in the pancreas provoking realization of
hereditary predisposition to DM .
I hus, DM pathogenesis includes genetic, immune mechanisms and environ
mental factors, however, the relationship between them differs in various types ol
I >M (see details below).

DIABETES M ELLITUS MANIFESTATIONS

DM manifestations are metabolic and pathophysiological (described above in

detail as insulin insufficiency manifestations).

M etabolic Changes

I hc metabolic changes concern all pathways <>l metabolism as it has been dis
cussed above. In spite o f essential limitation o lsu gai use with food, a patient has a
liiK-h blood glucose level because o f glyconeogenesis Intermediate glucose mctnho
 C h a p te r 14. I'alholoK ) of C a rb o h y d ra te M e tab o lism

ii in is disordered. So, insulin, as a drug, is used no t only to reduce the blood sugar
level, but mostly to correct interm ediate m etabolic pathways.
I he m etabolic m anifestations o f D M are detected by laboratory investigations.
• lunges in laboratory indices are: hyperglycem ia, acetonem ia, ketonem ia, lactaci
•innia, hyperlipem ia, hypercholesterolem ia and glycosuria.
Hyperglycemia som etim es reaches 25 m m o l/1 , glycosuria — up to 555 666
niinol/1 (100—120 g /d ay and m ore), the level o f lactic acid (lactocidem ia) exceeds
IIК m m ol/1 (N 0.033—0.078 m m o l/1 ), hyperlipem ia — up to 50—100 g /l (N 3.5
n к/ I ) , ketonem ia (by determ ination o f ketone bodies) — up to 5200 m c m o l/l
(N < 517 m c m o l/l).
Clinical Manifestations

Renal, vascular, neurological and o th er long-term effects o f DM are the fol­

lowing.
Polyuria is increased diuresis. An increase o f osm otic pressure o f the urine and
• decrease o f w ater reabsorption underlie it. Diuresis m ay reach 1 0 -1 2 1 daily.
Polydipsia is thirst accom panied by dryness in the m outh and on the skin.
Polyphagia is increased appetite as a result o f carbohydrate starvation o f tis-
IIJCK.
Muscle and general weakness is a consequence o f energy tissue starvation.
Atherosclerosis is a com m on com plication o f D M . A therosclerosis is a big prob-
i in o f m odem m edicine and m ore often is based on D M . C onsequences o f vessel
itliciosclerosis cause death.
Angiopathy (m acro- and m icroangiopathy) is a pathology o f large and small
w ‘.sc Is, which develops as a result o f atherosclerosis and hyalinosis. C hronic vas
nl.и syndrom e includes pathology o f the cerebral, coronary, renal, retinal and
nilerial vessels o f the lower extrem ities. It is not difficult to understand the wide
ilinger o f pathology that m ay develop - stroke, m yocardial infarction, am putation
til extrem ities, blindness.
irterial hypertension is an increase o f arterial blood pressure.
Nephropathy is renal dysfunction, w hich m anifests itself through m any renal
uni systemic sym ptom s including the developm ent o f the renal type o f arten.il
li\l*citcnsion.
Immunodepression m anifests itself through increased sensitivity to infection Л1
..... . all patients suffer from furunculosis. M any diabetics are ill with tuberculosis
Neuropathy is a disorder o f the m orphology and function o f the pcriphci.il
hi ivcs (sensitive, m o tor and vegetative ones).
Partial or complete loss o f sight is retinopathy. It is a result o f eye vessel uii|>.in
ни nl and cataract (crystalline sclerosis).
Depression of regenerative processes (as a result o f depressed protein syndic ,m
i m anifested by problem s with w ound reparation and trophic ulcer developm ent.
Hody mass alterations are emaciation (a result o f lipolysis activation) or obe\iii
и i result o f insulin resistance.
I hits, a DM patient visits doctors o f different specialties cndociinolofi i
lliciapeutists, ophthalm ologists, neuropathologists, surgeons, etc.
I ’l l ll I (•«'IM'lul l*Ulh»|lll\4lolll|(y

Diabolic Ciми.i

I lie most violent com plication o f DM is com atose slate. I lie m anifestations
o f com a are th e following: loss o f consciousness, arterial hypotension, Kussm aul’n
disorder o f respiration, a smell o f acetone from the m outh.
Ih ere are several types o f diabetic com a. They are:
Acidotic (lactacidemic), w hich is a result o f lactic acid accum ulation and blond
p ll reduction.
Ketonemic, w hich is a result o f the toxic effect o f ketone bodies.
Hyperosmolar, which is a result o f high hyperglycem ia.
Hypoglycemic, w hich is a com m on result o f insulin overdose.
I hc clinical and m etabolic m anifestations o f DM m entioned above as well as
the etiology and pathogenesis vary in different types o f D M m entioned below.

D M C L A SS IFIC A T IO N

According to clinical classification DM is divided into primary ( idiopathic) and

secondary (symptomatic as a com plication o f an o th er disease). In its tu rn , primal \
(idiopathic) DM is subdivided into two types depending on the form o f insulin
insufficiency (pathogenic classification) — insulin-dependent (type 1, ID D M ) and
non-insulin-dependent (type 2, N ID D M ). Type 3 diabetes mellitus is connected
with pregnancy (gestational DM).
Ih c role o f genetic and im m une m echanism s together with the role o f the en
vironm cnt in DM developm ent has been discussed above. T he relationship between
them as well as clinical sym ptom s are different in diabetes o f different types.

IN S U L IN -D E P E N D E N T D M
(type 1; juvenile-onset; ID D M )

ID D M accounts for about 5 - 1 0 % o f diabetics. This form o f D M is observed

in young persons - this is the juvenile-onset type.
Absolute insulin insufficiency (see above) underlies this type o f D M , which is
characterized by insulinopenia. C onsequently, it is also nam ed pancreatic and pri
тагу.
It is assum ed that the main link o f ID D M pathogenesis is connected with ,i
special im m une status o f the organism (leukocyte antigens o f the HLA system are
genetic markers) resulting in autoim m une aggression against body’s own insular
apparatus. Antibodies against insulin and p-cells are determ ined. The correlation
between com m on children’s viral infections (m um ps, measles, influenza, G erm an
measles, hepatitis, parotitis) and ID D M onset has been established. In such patients,
vital infections are characterized by increased p-tropism and appear to localize spe
i llieaIly within the pancreatic islets. Young persons, who are IILA-positive, have a
high level o f antibody titers to the vims. T he im m une response induced by direct
vital dam age o f p cells provokes an autoim m une process in the insular apparatus
I hits, viruses are exogenous etiological factors, which realize predisposition lo
type I I )M (schem e 12).
 C h a p te r 14. PalholoK ) o l ( u ib o h y d ru tf M etab o lism

Scheme 12. Etiology and Pathogenesis of IDDM

G enetic predisposition con n ected w ith
________ H L A system antigens________

Р-T ropic viruses

ft-Tropic chem ical substances |

D am age o f p-cells,
change o f th eir antigen properties

M acrophages | T -helpers | T -effectors | NK. | ft-Lym phocytes

IL-1 | A ntibodies | L ym phokins (factor o f necrosis) y-Interferon | PCI

A utoim m une aggression

against ()-cells
Р-C ell destruction
A bsolute insulin insufficiency

G enetic factors, as etiological ones, are im portant in 30 % cases. C oncordance

in m onozygotic twins m akes about 50 %.
I'he pancreas contains little o r no extractable insulin and is ch aracteri/cd hv
overall reduction in the size o f the pancreatic islets and P-cell mass. Islel infillia
linn with lym phocytes, m onocytes and eosinophils is observed (insulinitis). Some
iMiients with ID D M have p-cell-sensitized cytolytic lym phocytes. A ntibodies i<»
liMilin receptors are determ ined.
T he plasm a insulin level is low and responds poorly, if at all, to injection ol
i incose o r o ther stim ulators o f insulin secretion. These patients therefore rc»|ini<
i uigenous insulin injection; hence it is an insulin-dependent variant o f DM
M etabolic disorders are essential and m ay be life-threatening or even fatal
I'he clinical duration o f this form o f DM is aggravated with ketoacidosis uul
iliabetic com a. The body mass decreases (D M o f thin persons).
I he basic treatm ent is insulin injection.

NO N -IN SU LIN -D EPEN D EN T DM

(type 2; adult-onset; N IDD M )

N ID D M represents 9 0 -9 5 % o f all diabetic patients.

N ID D M is not connected with a reduction in p-cell mass or insulin dcli« it
lUhnive insulin insufficiency (see above) is the basis o f this type ol DM In .iilm
I’iii I I (ii'iK 'iul 1“н ( ||о ||||\\|( ||о щ

production is normal. Consequently, tins Ibrni ol dlnbeti « is nuined extrapancreatic

or insulin-independent.
I hc m ain link o f N ID D M pathogenesis is connectcd with insulin resistance.
Overeating and obesity provoke it. 70-X 0 °'< cases ol I Ins form o f DM are com bined
with obesity. P atients are significantly overweight (D M o f thick persons).
I here are two m echanism s o f insulin resistance in obesity:
• dim inished quantity o f insulin receptors on target cells;
• post-receptor changes (G L U T and o ther m echanism s), which result in prob
lems with intracellular transport o f glucose or its intracellular m etabolism .
So, the co nnection between D M and obesity is reciprocal: obesity leads to DM
(type 2) and vice versa (see p. 230)
Antibodies against insulin receptors are som etim es determ ined. How ever, anti
bodies against insulin and p-cells are absent.
An increased production o f insulin (hyperinsulinem ia) occurs for overcom
ing o f insulin resistance at the stage o f com pensation. M etabolic derangem ent is
m inim al. K etoacidosis and com atose state develop rarely. T he clinical duration is
less severe.
In spite o f the absence o f genetic m arkers in leukocyte antigens, genetic factois
arc m ore im portant in N ID D M induction than in ID D M induction. This form ol
DM has expressed hereditary predisposition. C oncordance in m onozygotic twins
icaches 9 0 -1 0 0 %.
T he disease m anifests itself in the second half o f life (after 40 years).
Insulin therapy is useless.

Secondary (Symptomatic) DM

Secondary DM em braces a heterogeneous group o f disorders.

This type o f diabetes is associated with the presence o f o ther endocrine di
eases (acrom egaly, hyperthyroidism , pheochrom ocytom a, C ushing’s syndrom e),
when the production o f contra-insulin horm ones prevails (metasteroid diabetes, see
p. 4‘)l).
Sym ptom atic DM may be observed as a result o f side effects o f m edicines (di
un ties, oral contraceptives, p-adrenergics, corticotropin). E pinephrine secretion oi
exogenously adm inistered corticosteroids tend to induce carbohydrate intolerance.
Increased need for endogenous insulin is associated w ith stress, obesity and
pregnancy.
Gestational DM

Pregnancy itself induces no significant alteration in carbohydrate m etabolism

Nevertheless, som e pregnant w om en dem onstrate signs o f DM .
I here arc several m echanism s.
I lie em bryo needs more glucose and therefore the Mood glucose level rises in
the m aternal organism . Hut it rises not by the activation o f adrenaline o r thyroxin
secretion but m ainly by tem poral relative insulin deficiency and insulin resistance
 C h a p te r 14. I’llllloUtKV o f < 'a rb o h y d ra tc M c I uIkiIImii

I he substances, w hich tem porarily cause insulin resistance in pregnant w om en,

mi< formed in the placenta. Placental insulin antagonists are produced (estrogens,
iM'Wcstogens, o r lactogen). H ence, a pregnant w om an has to produce an additional
•in.intity o f insulin for herself to overcom e insulin resistance. Thus, pregnancy over
i "ills the m aternal pancreatic islets.
Those w om en, w ho are not capable o f m obilizing an additional quantity of
insulin for them selves, have D M sym ptom s. M ost o f them have a genetic prcdispo
it ion to D M , and pregnancy significantly aggravates glucose intolerance.

Questions for Self-Control

I C om pare insulin and its antagonist effects on glucose m etabolism in a cell.

’ What is tolerance to carbohydrates?
< W hat is insulin resistance?
I What is the difference betw een absolute and relative insulin insufficiency?
■ In what way is D M inherited?
<i What is the role o f the im m une system in DM pathogenesis?
/ N am e the m ain clinical m anifestations o f D M .
N N am e and explain the varieties o f diabetic com atose states.

Tests and Tasks for Self-Control

(give correct answers and find m istakes in the statem ents)

I M atch the term s, w hich are used in the study o f carbohydrate m etabolism p a ­
thology, and th eir definitions.

Term Definition

1 (ilycemia A. Carrier proteins that transport glucose into cells.

} Hyperglycemia B. Appearance of glucose in the urine.
\ Hypoglycemia C. Increased blood glucose level.
1 (ilycolysis D. Decreased blood glucose level.
'< (ilycogenesis E. Pathological storage of glycogen in the liver and muscles.
(• ( ilycogenolysis F. Splitting of glycogen into glucose.
’ Glyconeogenesis G. Glycogen formation from glucose.
N (ilycogenosis H. Glucose blood level, integral index of carbohydrate metabolism
4 (ilycosuria I. Carbohydrate formation from non-carbohydrate products
0 GLUT amino acids - under the effect of glucocorticoids of the adrenal
cortex and from fatty acids.
J. Anaerobic glucose oxidation to pyruvate.

1 (iiv e the characteristics o f the peripheral effect o f insulin and its disorders.
I. It is the m ain cause o f absolute insulin insufficiency.
I'iiil I <ie n rr a l I‘mIIi<i|)Ii >\I<iIok >

2. Il is connected with the condition nl Insulin in c p io is , which determine

the sensitivity o f target cells to insulin
3. T olerance to carbohydrates gels increased.
4. C auses originate in the pancreas.
Such reasons are possible:
5. G en etic pathology o f receptors.
6. A utoim m une aggression against receptors.
7. Activation o f the factors inhibiting insulin o r accelerating its catabolism
(insulin antagonists, insulinase and o th er proteolytic enzym es).
X. Dam age o f (3-cells by р-cytotropic viruses (C oxsackie virus).
9. Lack o f insulin receptors on target cells.
10. G en etic problem s o f p-cells.
11. D isorder o f proinsulin transform ation into insulin.

3. Ciive the characteristics o f D M etiology.

1. It m ay be acquired but never genetically determ ined.
2. Infectious factors are a-cy to tro p ic viruses.
3. Such р -cytotropic substances (alloxan and dithizone, nitrosam ines, which
can induce diabetes-like condition in anim als) are biological etiological
factors.
4. Pharm acological agents (diuretics, oral contraceptives, corticotropin.
P-adrenergic drugs inhibit insulin secretion in m an) are biological etio
logical factors.
5. Etiological factors m ay unm ask genetic predisposition.
f>. The m ode o f nutrition plays no role in diabetes developm ent.
7. The value o f im m une factors is confirm ed by the possibility o f experinien
tal reproduction o f D M by injection o f heterogeneous antibodies against
insulin o r p-cells.
8. External factors, w hich overload pancreatic а -cells (overeating, excessive
consum ption o f carbohydrates and fats), are risk factors.
9. L m otional overstrain can provoke DM developm ent if genetic predisposi
lion exists.
10. Stress aggravates the diabetic condition and acts through steroid-induco.l
glycogenesis.

•I A DM patient was taken to a hospital unconscious. T here is observed K uss

m aul’s respiration, arterial pressure o f 80/50 m m H g, a smell o f acetone from
the m outh. A ccum ulation o f w hat substances provoked such a state?
A. K etone bodies.
B. p-Lipoproteins.
C. Lactate.
I). lilood glucose.
E. Cholesterole.
■
C h a p te r 14. PatholoK y o f ( urtH ihvilralv M e tab o lism

A 48-year-old m an is ill with diabetes. He was hospitalized in unconscious state

il'ter significant physical load. R espiration is superficial, arterial pressure
K0/40 m m H g, glycem ia - 1.88 mmol/1. W hat kind o f com a has developed?
Л. Lactacidem ic.
B. H yperketonem ic.
C. Hypoglycemic.
D. Hyperosm olar.
E. H ypoosm olar.

(i Л 12-year-old teenager grew thin. The level o f glucose in the blood w;is
50 mmol/1. Later com a developed. W hat was the m ain m echanism o f com a?
A. Ketonem ic.
B. Hypoglycemic.
C. H yperosm olar.
D. Lactacidem ic.
E. Hypoxic.

A patient with type 1 diabetes was injected insulin. Later he suffered from
sickness, irritability, sweating. W hat is the basic m echanism o f hypoglycem ia,
which developed?
A. Intensifying o f ketogenesis.
B. Intensifying o f glycogenolysis.
C. C arbohydrate starvation o f the brain.
D. Intensifying o f lipogenesis.
E. Depressing o f glyconeogenesis.

N A patient is ill w ith diabetes. Regenerative processes are reduced, w ounds do

not heal for a long tim e. W hat is the cause o f such changes?
A. Acidosis.
B. A ccum ulation o f ketone bodies.
C. Depressed synthesis o f proteins.
I). D ecreased co n ten t o f glucose in cells.
E. Lipid disbolism.

ч A child was b o m in a family with a history o f som e DM cases. At the age o f K,

insulin injections were prescribed. W hat about the role o f genetic m echanism s
in DM developm ent?
1. G enetic defects o f p-cell m em branes, insulin synthesis and secretion, m
sulin antagonist co n ten t, and insulin receptor structure may be inherited
2. T he disease depends on genetic but not environm ental influences.
3. T he type o f inheritance m ay be polygenetic.
4. M utant genes, which determ ine DM developm ent, have not been re
vealed.
I'a rt I b r n c r a l I’allioiiliysiolttKy

5. The reference o f DM to the category <•! niiiliilactoi i;il diseases reflects the
value o f genetic factors together with the role ol pathogenic influences ol
the environment.
6. G enetic predisposition is a basis, on which different etiological factors
may cause DM .
Proofs o f the role o f genetic mechanisms are the following:
7. Existence o f «family» diabetes, when the disease is recorded in several
members o f one family.
8. The concordance rate in ID D M is about 50 % and approaching 100 % for
twins having N ID D M .

Compile a comparison table o f the normal influence o f insulin on the blood sugar
level and its disorder in insulin insufficiency
Normal Influence of Insulin Disorder of Blood Sugar Level
on Blood Sugar Level in Insulin Insufficiency
(not less than 10 mechanisms) (pathogenesis of hyperglycemia)

1.
2.
3.

I 'ind points o f comparison and compile a comparison table o f differences between type
I and type 2 DM
Points of Comparison Type 1 DM Type 2 DM
1.
2.
3.
4.
<luipter 15
PATHOLOGY OF LIPID METABOLISM

I ipids perform energetic and plastic functions.

I ipids are the m ost im portant source o f energy: their calorific value is higher
Hum th at o f carbohydrates and proteins. Lipids are light and therefore are the most
"iiivenient form o f energy accum ulation. Besides, they are a source o f oxidative
' .iicr. Lipids and carbohydrates are converted into each o th er (lipogenesis from
nhohydrates with the aid o f insulin; glyconeogenesis from fatty acids with the ;iid
•I glucocorticoids).
The plastic function o f lipids consists in form ation o f phospholipids and lipo­
proteins for m em branes, steroid horm ones and nerve tissue.

Disorders o f Lipid Digestion and Absorption

Ihere are anim als (rabbits, horses) that do not get fats with food, but develop
......ilim entary deficit o f lipids. 10 % o f carbohydrates are converted into lipids tin
•In physiological conditions with the aid o f insulin.
As to lipid absorption in the bowels, there are som e causes o f disorder:
• lack o f bile (liver insufficiency, calculous cholecystitis), which emulsifies
lipids by bile acids and exposes them to pancreatic lipase;
• inflam m ation o f the bowel m ucosa;
• pancreatic insufficiency (the pancreas is the m ain source o f lipase in the
bowels).
II lipids are not absorbed in the bowels, they appear in feces (steatorrhea).
Absorption o f fat-soluble vitam ins (A, D, К , E) is connected with lipid absorp
...... C orresponding clinical m anifestations o f a- and hypovitam inosis (bleeding,
i n Intis. vision and endocrine system im pairm ent) develop in case o f insufficient
.ii • ni pt ion o f lipids and vitam ins.

Disorders o f Lipid Transport in Blood

An excessive co n ten t o f lipids in the blood is called hyperlipemia, lowered

Hi I'olipemia.
U nder pathological conditions it is im portant to estim ate not only the quiin
ills o f lipids in the blood, but also their form (chylom icrons, which contain m
*lv* ciidcs, lipoproteins o f different density, fatty acids absorbed on album ins .uni
I' lipoproteins, phospholipids and cholesterol entering the com position o f lipopm
li'lns). An excessive co ntent o f cholesterol and ji-lipoprotcins in the blood is .1 n .l
i и loi o f atherosclerosis developm ent and lipid degeneration ol the p a ie iic h v iiu in n ,
Hiltons.
Г.n l I G e n era l Pathophysiology

Disorders of Lipid Synthesis

C om pound lipids (lipoproteins, phospholipids) and cholesterol arc synthesized

in the organism and are soluble. Fatty acids are better oxidized in the form o f com
p ound lipids.
Lipoproteins are com pounds o f lipids with proteins. This com bination prevent
pathological fat accum ulation. The proportion o f lipids and proteins in lipoprotein
m olecules determ ines their high o r low density (a- o r р-lipoproteins). The enzyme
lipoprotein-lipase lyses this form o f lipids. This enzym e is located in the endothelium
and enters the blood under heparin influence. The latter in such a case avoids pat
ticipation in hem ocoagulation and predisposition to throm bosis develops.
Insufficient nourishm ent and am ino acid deficit decrease lipoprotein produc­
tion.
T he sam e result is observed in increased lipolysis in the adipose tissue in star
vation o r D M , when lipid and protein predecessors participate in carbohydrate but
not in lipoprotein synthesis.
N icotinic acid removes m ethylic groups and increases the quantity o f lipopro
tcins.
Phospholipids are com pounds o f lipid with phosphorus. T heir sufficient content
in the liver secures fine dispersion o f fats and their excretion from the liver. Phos­
pholipids are present in the com position o f р-lipoproteins and ease their release
from the hepatic cells. Fatty acids are better oxidized in the form o f phospholt
pids.
Lecithin is the m ain phospholipid in the liver (the optim al cholesterol-lecithin
ratio is less th an 1). Choline and methionine (am ino acid as a resource o f methyln
groups) are necessary com ponents o f its form ation. Deficit o f cyanocobalam in,
folic and pantothenic acids disturbs choline synthesis. C holine and m ethionine
deficiency leads to the developm ent o f lipoid infiltration o f the liver.
T he substances, w hich provide the best m etabolism o f lipids and prevent then
pathologic accum ulation, are called lipotropic. They include som e lipotropic food
products, w hich form lecithin; m ilk and a cottage cheese am ong them . T he en
dogenous lipotropic factor lipocaine (from the pancreas) leads to the sam e result
Lipocaine activates phospholipid form ation in the liver, fatty acid oxidation and
protects the liver from lipid infiltration. Deficit o f this factor occurs in DM .
M ore cholesterol is synthesized in the oi^anism than obtained with food. Its
ethers are soluble. C holesterol is used for plastic function. It is a part o f membrane
structure, is necessary for bile and steroid horm one synthesis.
In pathology, excessive cholesterol and P-lipoprotein content is the m ain link
in atherosclerosis pathogenesis.
Thyroxin increases cholesterol decom position. Mg ions provide cholesterol
splitting. В group vitamins improve its metabolism. Rutin decreases permeability
for cholesterol. Introduction o f small doses o f vitamins activates mast cells and
thereby the lipolytic activity o f the vasculat wall, stimulates thyroid hormone syn­
thesis.
 Chapter 15. 1‘atluiloKy o f l ipid M W iiliolisin

S our clotted milk, m ineral w ater, laxatives intensify cholesterol excretion from
the intestine. Physical training prevents accum ulation o f endogenous cholesterol.
The m edicines, w hich block endogenous cholesterol synthesis at the level o f
и i tic acid, have been created. How ever, they block steroid horm one synthesis.

Disorders of Intermediate Lipid Metabolism

Linder physiological conditions, ketone bodies (w hich are form ed in the pro-
• oss o f p-oxidation o f fatty acids) provide the organism with energy, com peting
with glucose.
Ketogenesis intensification is a serious disorder o f interm ediate lipid m etabo­
lism. In glucose deficiency o r im possibility o f its utilization as a source o f energy,
iipolysis and ketoacidosis get increased. U n d er pathological conditions, w hen lipo
lysis in the adipose tissue gets intensified, the liver does not utilize all fatty acids for
m^lyceride synthesis, and part o f them are included into p-oxidation and ketogcne
м It is th e m echanism o f ketoacidosis in starvation (p. 178) and D M (m ore details
••ii p. 210). Significant accum ulation o f ketone bodies in the blood (m ore than 0.1
and up to 20 m cm ol/1) is
dangerous for life resulting
in metabolic acidosis.

Disorders of Lipid
Accumulation and
Deposition

Lipids m ay be ac­
cum ulated in a specific
ndipose tissue and in o th er
ones. T he first variant is
tailed obesity. The second
is lipoid degeneration (in-
llltration, decom position).
N curohum oral regulation
ol lipid deposition and
mobilization is represent­
ed in figure 24.

I ik 24. Neurohumoral regu-

liitlon of lipid metabolism:
Im tors, which stimulate de­
position (Л) and mobilization
(II) of lipids
1*111( I <>гп«'ги1 I’litlm plivsiolom

OBESITY

Specialized cells o f the connective tissue (adipocytes) can contain alm ost un- I
limited quantity o f fat drops.
Obesity is an excessive accumulation of lipids in the adipose tissue.
Obesity is an actual m odem problem not from the point o f view o f esthetics,
but as a risk factor o f the developm ent o f such pathological processes as D M , athc- I
rosclerosis, arterial hypertension and throm bosis. It becom es clear that obesity is
related to m any diseases and prem ature aging.

TYPES

As to etiology, obesity is divided into acquired and constitutional. As to patho- |

genesis, it is divided into alimentary, endocrine and cerebral (hypothalamic).
The pathom orphological classification is based on the size and quantity ol
adipocytes. A ccording to this classification, two types o f obesity are distinguished 1
hypertrophic and hyperplastic.
Besides, primary (constitutional) and secondary (sym ptom atic) obesity is dis
tinguished.
The etiology and pathogenesis o f obesity depend on its type.

ETIOLOGY

Etiological factors, which cause obesity, are divided into exogenous and endo- I
genous, as well as acquired and genetic.
An exogenous factor is overeating. Increased consum ption o f food is one o f the
m ain causes o f obesity. The latter includes m o th er’s nutrition during pregnancy, I
child feeding in early childhood, family and national traditions, way o f life, pros I
perity and food accessibility. C ertain diets predispose to overeating and obesity, j
Overeating causes alimentary obesity. W hat kind o f food leads to obesity most of
all? It is carbohydrates. Patients should be recom m ended to limit consum ption of
farinaceous food, potato and sweet.
C hronic stress usually changes eating habits o f people and provokes overeal
ing.
H ypodynam ia is an o th er exogenous factor. If sensitivity o f the alim entary cen
ter and constitution are norm al, energy im balance is created by the way o f lilt*
without m o to r activity.
T he endogenous factors o f obesity are nervous and endocrine system d is o rd e r
as well as the pathological constitution. M any patients com plain that in spite ol
norm al appetite and lim itation o f high-calorie product consum ption, their weiglii
increases and they are obese. Suppressed catabolism underlies such a situation.
G en etic factors (m etabolism peculiarities, enzym e activity) also refer to Ih e ,
endogenous ones. A peculiarity o f obesity etiology consists in the fact that Ih e j
lipomatous constitution (according b) O.O. Rohoinolcls, p. 59) plays Ihe role o f «
decisive condition.
 Chapter I S. Pathology o f I jp id M etabolism

PATHOGENESIS

( )besity is a result o f im balance betw een energy production and use.

Three basic pathogenetic m echanism s are im portant in obesity pathogenesis:
• increased intake o f food, w hich does not correspond to energy expenditure;
• decreased m obilization o f fat from the depots as a source o f energy;
• excessive fat form ation from carbohydrates.

Molt* of Genetic Factors

I lie role o f genetic factors and constitution has been confirm ed statistically. It
ii i been observed th at obesity develops in som e generations o f one family (consti­
tutional obesity). However, this inform ation is not a direct evidence o f the role ol
h a rd ily , as one can not exclude the influence o f the sam e environm ent, the same
luibits concerning the kinds o f food and the way o f life.
More convincing inform ation has been received under experim ental condi
lions.
Л subpopulation o f m ice with congenital obesity has been artificially created in
i laboratory. The pathology is inherited as an autosom al recessive trait.
The role o f constitution in obesity is obvious. O.O. B ohom olets distinguished
ih.- lipom atous type o f constitution together with fibrous, pastose and asthenic (the
i .1 1 . 1 has no obesity in any case).
Prim ary (constitutional) obesity is observed in 55—65 % o f all cases. T he gene
"I obesity and its product leptin are being investigated.
The structure and function o f the systems, w hich regulate alim entary behavior
.nil lipid m etabolism peculiarities can be inherited — adipose tissue peculiarities,
. lipocyte quantity and size. All these factors m ust be taken into account in obesity
1 'iiliogenesis. In general, obesity is inherited polygenetically. In m eans that il is

il« iri m ined by genetic, environm ental factors and acquired diseases.

Molt* of Nervous System

Prim ary cerebral (hypothalamic) obesity is observed in 16—20 % o f all cases.

Excessive consum ption o f food, w hich is provoked by increased appetite, can
i. nil from increased excitability o f the alim entary center, which is situated in I hr
null lolateral nuclei o f the posterior hypothalam ic region. All the reasons affect
in»' Ih r alim entary cen ter can be a cause o f prolonged alim entary excitation and
iillnirntary obesity as a result. C hronic stress, which is often accom panied with
им iratin g , is an exam ple.
C erebral (hypothalam ic) obesity may be m odeled under experim ental condi
H o n s by dam aging the ventrom edial nuclei o f the hypothalam us. Hyperphagia.
"Int li is obtained in an experim ental anim al, results in obesity, which is sim ilar to
hnnian hypothalam ic obesity.
H ypotonia o f th e sym pathetic nervous system prolongs fat m obilization front
ill. adipose tissue*.
Г .п I I < |П К 'Г и 1 Г и 1 1 н 1 ||||> ч н Н о щ

B arraq u er-S im o n s disease is an exam ple ol progressive lipodystrophy con

nected with a lesion o f the centers o f diencephalon, spinal cord and sym pathcti
trunk nodes. It is characterized by fat deposition in the lower part o f the body and
fat disappearance in the upper part.
Signals from the alim entary tract receptors are im portant in the activity o f the
alim entary center. A definite degree o f stom ach extension after eating inhibits the
activity o f the alim entary center. In case o f decreased sensitivity o f the stom ach
wall receptors, alim entary ce n te r inhibition develops only in excessive stom ach
extension.

Role of Endocrine System

T ogether w ith the nervous system the endocrine one accom plishes regulation of
fat m obilization and deposition. A drenaline and insulin have the m ost potent influ
ence but in the opposite direction. A drenaline stim ulates lipolysis. Insulin stimu
lates lipogenesis by the synthesis o f neutral fats from glucose and fatty acids, inhibit
lipolysis, decreases the blood sugar level, stim ulates appetite. Figure 25 represent
the role o f insulin and adrenaline in lipid m etabolism in the lipocytes and correla
tion o f lipogenesis and lipolysis.
All conditions, w hich decrease the blood glucose level, stim ulate pancreatic
island function and are accom panied by hunger provoking overeating.
T here is a variant o f obesity, w hich is characterized by hyperinsulinism , insulin
resistance and hyperglycem ia. T he basic dam ages are at the level o f target cells. Л
decreased quantity o f insulin receptors on the surface o f adipose cells leads to in ­
sulin resistance and com pensatory hyperinsulinism . Obesity com bines with D M in

Adrenaline В Adrenaline

I iK 25 I hc influence o f insulin and adrenaline o n Ьроцспомч and lipolysis in lipocytcs mi

Ihc normal stale (A ) and in obesity (B):
I I Л tree laity acids. PA tally acids; Tr Iryglyi eitdev Ulu ulticosc, Oly (tlyceiiu, X lipo
Kenesis, Y lipolysis
 C h a p te r I S. P a th o lo g y o f U p id M e tab o lism

isc o f insulin resistance (see p. 218). C om pensatory hypertrophy and hyperplasia

I the pancreatic islands providing an increased secretion o f insulin for overcom ing
resistance is followed by exhaustion. In this case it is supposed that obesity is an
• liological factor o f DM .
T he sam e form o f obesity and decreased fat m obilization is observed in hy
I'olunction o f the pituitary, thyroid, adrenal and sex glands (endocrine obesity).
»>bcsity is m ore often observed in w om en older than 50 (clim acteric obesity is an
example).
METABOLIC D ISORD ERS IN OBESITY

T here are two principal pathogenic m echanism s o f m etabolic disorders: a) in

MilTicient m obilization o f fat from the depots and b) surplus form ation o f fat from
i ubohydrates.
M etabolism in th e adipose tissue is disturbed in the first place. T he rate o f
11 glyceride and lipoprotein synthesis is increased, the ability to mobilize adipose
tс serves is disturbed, and hence hyperlipem ia, increased free fatty acid level and
hypercholesterolem ia are observed.
C arbohydrate m etabolism disorders m anifest them selves through lim itation o f
rlucose m etabolism and increased glycogen co n ten t in the liver. U tilization o f
i lucose is im paired in the m uscular tissue in spite o f hyperinsulinism . T he respira
lory quotient equals 0.7—0.74. It testifies to the fact that fatty acids are used as a
source o f energy. Surplus form ation o f fat from carbohydrates takes place due to
livperinsulinism.
Individual peculiarities o f the adipose tissue, adipocyte quantity and size arc
i iken into account in obesity pathogenesis. T he quantity o f adipose cells is a geneti
i illy determ ined factor and th eir size depends o n the p atien t’s age, sex, regulatory
uul m etabolic factors. The quantity o f adipose cells is larger in w om en than in
men.
According to th e quantity and size o f adipocytes, obesity is divided into hyper
trophic and hyperplastic.
Hypertrophic obesity depends o n the quantity o f fat in each adipocyte that is
■onnected with increased insulin concentration, hyperlipem ia, and decreased tolci
mice to glucose. F requently this form o f obesity is com plicated by the developm ent
■■I .itherosclerosis and D M at young age.
Hyperplastic obesity is connected with an increase o f adipocyte quantity, which
•if pends on genetic o r environm ental factors regulating adipose tissue m orphogcnt
Iin the em bryo and at early age.
A ccum ulation o f fats in nonadipose tissues (parenchym atous organs - the livn
uul m yocardium ) is called lipid decomposition (degeneration).

MANIFESTATIONS AND COM PLICATIONS

In econom ically developed countries adult obesity is observed in 30 <>o '•

« iscs and body mass exceeds the norm by 20 %.
P art I. (ic n c ra l P athophysiology

The negative influence o f obesity is manifested to a lesser degree at young age,

when adaptive possibilities are expressed better. The quantity o f com plications con ­
nected with obesity increases with age. The mortality o f obese people at the ago
o f 20—24 years is 30 % higher than in persons with normal body mass. It is 50 %
higher in persons aged 4 0 -5 5 years.
Obesity influences the organism unfavorably.
There are cases o f obesity with the total quantity o f fat exceeding 70 kg. Body
mass can be increased by 100 kg and more. It overloads the physiological systems -
motor, cardiac, and respiratory.
Pulmonary ventilation is deteriorated, vital capacity is decreased, and predis
position to congestion and development o f chronic inflammation in the respiratory
tract appears. Dyspnea arises even at small physical load. Circulatory and respira­
tory hypoxia develops.
Obesity is tightly connected with such widely spread diseases as DM and ar­
terial hypertension as well as atherosclerosis and thrombosis. These relations arc
represented in scheme 13.
Blood hypercoagulability is an obvious com plication. Deficit o f heparin as an
anticoagulant is created because o f its participation in lipase activation. Predisposi­
tion to thrombosis and infarction has been noted in patients.

Scheme 13. Relation between obesity, DM, atherosclerosis, arterial hypertension, thrombosis
and myocardial infarction
G enetic predisposition (not connected w ith HLA system antigens)

D isorder o f enkephalin, endorphins, PG,

digestion horm ones secretion

H eparin
deficiency

D ecrease o f insulin
receptor am ount

Relative insulin
insufficiency

I
P-Cell
dysfunction

|| 1 . 1 1 A b s o lu te in su lin
---------------- -------------------
e x h a u s t io n iiwullU itncy
 C h a p te r IS. Га11|»1»ю o f Lipid M e tab o lism

LIPOID DEGENERATION

Accumulation o f fat in nonadipose tissues (all parenchymatous organs) is called

lipoid decomposition ( infiltration, degeneration).
Any disorder o f lipid m etabolism may cause fatty degeneration o f the liver.
‘>uch disorders include:
• increased lipolysis in the adipose tissue;
• decreased oxidation o f fatty acids;
• increased lipogenesis;
• changed type o f lipoproteins, prevalence o f P-Iipoproteins;
• deficit o f lipotropic substances (choline, m ethionine, lipocaine, lecithin);
• avitam inosis.
Insufficient form ation o f phospholipids disturbs fat dispersion and its ability
in be excreted from the liver. D isorder o f lecithin production in the liver leads to
ui cum ulation o f fat in the liver. Insufficient nourishm ent, am ino acid deficiency,
mil starvation eventuate in decreased production o f lipoproteins. T he connection
between DM and lipoid liver degeneration was m entioned on p. 210.
Adipose dystrophy and degeneration o f the parenchym atous organs (livct.
Iii irt) im pair th eir functions and add corresponding clinical sym ptom s to obesity
Ihus, deposition o f fat in the m yocardium significantly decreases the contractile
function o f the heart.

Questions for Self-Control

I N am e co m pound lipids and explain their role in pathology.

' In what way is fat absorption violated if bile does not enter into the duodc
num?
I (iive a classification o f obesity.
I What is the role o f genetic factors in obesity pathogenesis?
V What type o f constitution is predisposed to obesity m ost o f all?
II What is the role o f the nervous system in obesity pathogenesis?
7. What is the role o f the endocrine system in obesity pathogenesis?
К What are the negative consequences o f obesity?
') Explain why obesity predisposes to DM developm ent.
Hi Why does obesity predispose to m yocardial infarction?
11 Why does obesity predispose to arterial hypertension developm ent?
I J What is the con n ection betw een obesity and throm bosis?
I I What is the con n ection betw een obesity and atherosclerosis?

Tests and Tasks for Self-Control

(give correct answers and find m istakes in the statem ents)

I What is correct about cholesterol?

I C holesterol is absent in the bile in norm .
2. C holesterol is toxic.
Part I. G e n e ra l Pathophysiology

3. It has no function in norm .

4. T he liver is a single organ o f cholesterol synthesis.
5. C holesterol is form ed from lipids, proteins, and carbohydrates — from ac­
tive acetyl-C oA .
6. C holesterol transform s into bile acids in hepatocytes.
7. E therification o f cholesterol is its connection with proteins, w hich pro
vides easier catabolism .
8. C holesterol is not form ed from acetyl-C oA u n d er Krebs cycle inhibi
tion.
9. C holesterol provides bile properties as o f a digestion participant.
10. C holesterol causes jaundice.

2. Сiive the characteristics o f phospholipids and their participation in liver func­

tioning.
1. T he m ain phospholipid o f the liver is m ethionine.
2. The m ain phospholipid o f the liver is lecithin.
3. Phospholipids are com pounds o f lipids with phosphorus.
4. Phospholipids secure fine dispersion o f fat (including cholesterol) and as
sure th eir excretion from the liver preventing fatty liver degeneration.
5. Phospholipids are present in the com position o f р-lipoproteins and ease
th eir release from hepatic cells.
6. The cholesterol-lecithin ratio exceeds 1 in norm and provides the bc-sl
solubility o f cholesterol.
7. Fatty acids are oxidised worse in the form o f phospholipids.
8. Lecithin is not a bile com ponent in norm .
9. Pancreatic lipocaine activates phospholipid form ation in the liver and
prevents fatty liver degeneration.
10. Lecithin provides bile properties as o f intestinal digestion secret.
11. C yanocobalam in provides lecithin synthesis.

\ A group o f m ice have hereditary obesity. Hyperglycem ia and a decreased level

o f insulin receptors in lipocytes have been found. W hat is the initial pathoge­
netic m echanism s o f intensified lipogenesis?
A. H ypertrophy o f lipocytes.
B. Hypoinsulinism .
C. Ilyperinsulinem ia.
I). D ecreased tolerance to glucose.
E. D ecreased m obilization o f lipids.

4. D uring the second period o f com plete starvation w ithout w ater deprivation Ihc
level o f lipids in the blood o f an experim ental anim al has increased. Wlial form
o f hyperlipem ia is observed in this case?
A. Transport.
B. N utritional
 ( lu p in I' Г ;Н ||(||оц\ o f I .ipid M cliiliolisin

D. Productional.
E. Combined.

' Give the characteristics o f lipid disbolism in insulin insufficiency.

1. Lipolysis is inhibited due to glycogen deficit in the liver.
2. Transport lipemia is observed.
3. Mobilization o f fatty acids from the fatty tissue is inhibited.
4. Synthesis o f cholesterol (hypercholesterinemia) from AcCoA is activated.
5. Obesity accompanies insulin insufficiency in case o f insulin resistance.
6. Hyperketonemia and ketoacidosis develop.
7. Ketone bodies inactivate insulin aggravating insulin insufficiency.
8. Fatty degeneration o f the liver may take place

ii A 52-year-old woman has a body weight o f 98 kg. She complains o f dyspnea,

palpitations, climacteric disorders, heart rhythm disorders, edemas. Her appe­
tite is increased. Glycem ia has been about 12 mmol/1 during two years. Arterial
blood pressure is 160/100 mmHg. The veins on the shins are dilated and pain
ful. What is the explanation o f all these symptoms?
1. They developed due to obesity.
2. They developed due to arterial hypertension which is a complication ol
obesity.
3. Type 1 DM is a complication o f obesity.
4. Increased production o f sex hormones.
Probable metabolic disorders are the following:
5. Absolute insulin insufficiency.
6. Increased tolerance to carbohydrates.
7. Insulin resistance results in appetite stimulation.
8. Overeating takes place.
Probable disorders in the cardiovascular system are the following:
9. Atherosclerosis.
10. Cardiosclerosis.
11. Thrombosis o f the shin veins due to hypocoagulation.
Chapter 16
PATHOLOGY OF PROTEIN METABOLISM

P roteins play a central role in the vital activity o f the organism . They determ ine
the structure and function o f any organ. Each organ has its specific proteins
structural proteins, enzym es, receptors, transport proteins, etc.
F or this very reason protein m etabolism pathology is an im portant com ponent
o f the pathogenesis o f all pathologic processes w ithout exception. The pathogenesi
o f any pathology at the m olecular level includes dam age o f the protein m olecules
T here are no reserves o f proteins in the organism , and only food is a source ol
am ino acids. T he dynam ics o f protein balance has the following order:
• entry o f proteins with food;
• digestion o f proteins in the digestive tract into am ino acids;
• absorption o f am ino acids into the blood;
• intracellular anabolism and catabolism ;
• excretion o f final products.
Disorders o f the protein balance m ay occur at every stage o f the transform ation
o f proteins received with food.
Regulation of Protein M etabolism . Anabolism and catabolism o f proteins an
regulated by horm ones. T he latter serve as a signal for the activating o r inhibti
ing effect on the processes o f transcription in the genom e. T hen, w ith the aid ol
enzym es, m any functional proteins (the structural and receptor proteins, etc.) аи-
synthesized. So, it is a classical schem e: horm one — gene — enzym e.
Anabolic effect o f horm ones consists in activation o f the processes o f protein
synthesis in com parison with their disintegration. T he following horm ones have
such an effect.
Somatotropic hormone is a horm one o f growth. It activates protein synthesis
It activates lipid oxygenation and neutral lipid m obilization and thus leads to stil
ficicnt release o f energy, which is necessary for protein synthesis.
Insulin provides transm ission o f am ino acids through the cellular m em brane
into cells and thus provides protein synthesis and inhibits gluconeogenesis. Lack ol
insulin leads to protein synthesis decrease.
Sex hormones (testosterone, progesterone) refer to anabolics and activate protein
synthesis.
Catabolic effect o f horm ones consists in activation o f protein disintegration in
com parison w ith protein synthesis. T he following horm ones have such an effect.
Thyroxin increases the am ount o f active sulfhydric groups in the structure ol
som e enzymes. Tissue cathepsins are activated and th eir proteolytic effect gets in
creased. It increases the activity o f som e am inooxydases thus desam ination ol
som e am ino acids is increased.
Glucocorticoids (cortisol) activate protein disintegration Protein expenditure in
creases gluconeogenesis. Protein synthesis is deccleialed
 C h a p te r l(>. Га11к||»к> o f I’ro lcin M etabolism

Classification of Protein Disbolism. T he causes, pathogenesis and m anifesta

• . o f protein disbolism are diverse and num erous. It is possible to divide them
hiid the following large groups:
/. Systemic (protein im balance in the whole organism ) and local (in tissues).
2. Hereditary and acquired.
.?. Disorder o f anabolism and catabolism (synthesis and disintegration).
Systemic increase o f protein content in the organism takes place only under
physiological conditions (grow th, pregnancy). U n d er pathological conditions an
increase o f protein co n tent can be only local as hypertrophy (tissue enlargem ent
uiscd by enlargem ent o f every m orphological unit having a positive value in com
i"■iisation), hyperplasia (tissue enlargem ent caused by an increase in the quantity o f
•Its som etim es has a positive m eaning in com pensation), tumor (tissue enlargem ent
uul excessive grow th, w hich is not connected with organism functioning, always
i n . a negative m eaning).
Decrease o f protein content in the organism occurs m ore often. T he m ain rea­
lm s are:
• low er entry o f proteins into the organism ;
• disorder o f protein digestion and absorption;
• increased loss o f proteins;
• increased disintegration o f proteins;
• decreased protein synthesis.
The causes m ay be acquired and genetically determ ined. E nzym opathy under-
lii s it m ore often.
U nder pathological conditions not only the co n ten t but also the functional
i.iic o f proteins m atter. A utoim m une destruction o f proteins by antibodies (every
protein m ay be an object o f autoim m une aggression, p. 96) o r dam age o f proteins
hy llieir glycolization under hyperglycem ia effect (p. 210) are the exam ples, which
luivc different consequences depending on the type o f dam aged proteins.
The integral patterns of systemic protein balance are:
• N itrogen balance.
Blood protein level.
Protein com position o f the blood.

NITROGEN BALANCE DISORDER

O ne may get a general idea o f protein m etabolism disorder by studying the

nitrogen balance betw een the organism and the environm ent. It is an integral index
■■I protein balance.
Positive nitrogen balance reflects intensification o f protein synthesis (prevalence
"I protein anabolism over catabolism ). Besides physiological processes (growth and
pn'gnancy), intensive nourishm ent after starvation o r wasting diseases can be an
- sim ple. It is such a state, w hen less nitrogen is excreted from the organism lli.ni
■burned with food. It is observed in case o f curative injection o f anabolic horm one'.
iM iinatoptropin, androgen).
I’art I. (iriH T al Pullmpli.vsioluKV

Negative nitrogen balancc reflects intensification ol protein disintegration (ca

tabolism ) o r loss. Starvation, infection, protein loss in the urine (proteinuria in
renal pathology), loss w ith exudate in bum s, with intestine content (diarrhea)
thyreotoxicosis, and fever are examples. Excessive secretion o r curative injection of
catabolic horm ones (thyroxin, cortisole) are also examples.

BLOOD PROTEIN CONTENT D ISORD ER

Q uantitative and qualitative disorders o f blood protein com position reflect van
ous pathologic processes. T hey are m anifested by changes in the organism durii,u
infection, neoplasia, allergy, inflam m ation, etc.
Hyperproteinemia is always relative, caused by hem oconcentration. Its absolut
variety is observed in some types o f leukem ia with form ation o f anom alous proteii
(paraproteins).
Hypoproteinemia is, as a rule, absolute and occurs during starvation, neoplasi
diseases o f the liver (decreased production o f proteins) and kidneys (increased pro
tein loss in the urine), disorder o f protein absorption in the digestive tract.
Dysproteinemia is a im balance betw een the co n ten t o f album ins, globulins and
o th er proteins in the blood.

DISORD ER O F PROTEIN ENTRY, DIGESTION AND ABSORPTION

T he entry o f proteins into the organism is im paired in com plete o r partial (pro
tein) starvation (see chapter 10, p. 184).
Im paired protein digestion in the digestive tract into am ino acids happens in
case o f a decrease o r absence o f digestive proteolytic enzym es (pepsin from th
stom ach, tripsin and hem otripsin from the pancreas). In decreased gastric acidi
ty, the activity o f peptidases (pepsin, chem osin) m ay be disordered. A complci
arrest o f pepsin secretion in the gastric juice does not affect the degree o f protein
splitting in the intestine but essentially influences its rate. In achylia o r subtotal
stom ach resection the form ation o f tyrosine and tryptophan is disordered. In chonic
pancreatitis (inflam m atory and dystropic pathology o f the pancreas) digestion gel
disordered.
T here are acquired and genetic varieties o f protein balance disorder.
A m ino acids are absorbed on the microvilli o f the intestinal m ucosa with ih>
aid o f proteolytic enzym es and then en ter the portal vein system. A lack o f the.
enzym es is m ore often o f genetic origin. D isorder o f am ino acid absorption ma
appear due to pathological changes o f the intestinal wall, for exam ple, in its inflam
m ation, dystrophy and edem a.
Deficit o f even one essential amino acid hampers the process o f protein bio
synthesis and creates a relative surplus o f other am ino acids with accumulation о
intermediate products o f the metabolism o f these amino acids.
The genetic deficit o f intestinal proteolytic eii/.ynics can lead to the situation
when proteins can be absorbed into the blood without preliminary proteolysis aiu
sensitize the organism (lactase deficit is connct led with milk intolerance).
 C h a p te r l(>. Pathology o f P ro te in M etabolism

Iii decreased transformation o f proteins in the digestive tract a deficit o f plastic

materials for the synthesis o f body’s own proteins is created in the organism.

PROTEIN ANABOLISM (SY N TH ESIS) D ISORD ER

Amino acids, absorbed into the blood, are used by tissues for synthesis o f
i "«ly's own proteins as well as for other organs and blood.
As to etiology, protein synthesis disorder may be acquired and hereditary (ge
helically determined).
Acquired Disorders o f Protein Synthesis

Protein synthesis may be disordered under the influence o f various external and
internal harmful factors.
Protein synthesis disorder may be connected with a lack o f amino acids, which
hie protein precursors (tyrosine for thyroxin, tryptophan for oxidizing enzymes).
Protein synthesis may be stopped by the absence in a cell o f even one essential
imino acid. The need for essential amino acids is connected with their participa
Hun in the synthesis o f hormones, mediators and BAS. Essential amino acids are
11 \ ptophan (its deficit leads to decreased plasma protein concentration), arginine
11 uls to spermatogenesis suppression), histidine (decreased hemoglobin concentra
n u n ) , methionine (fatty liver degeneration as a result o f a deficit o f labile methyl
rumps necessary for lecitin synthesis), valine (growth retardation, body weight loss,
ki-iutoses development), lysine, leucine.
I)isorder o f 7-globulin synthesis is o f especial importance. It leads to a decrease
I immunoglobulin (antibody) synthesis and immunological reactivity disorder.
Blocking o f protein catabolism enzym es leads to protein synthesis disorder.
Since the organism has no protein reserves, starvation (exogenous and endo
ye nous) causes alimentary protein deficiency.
Disorder o f the ratio o f anabolic and catabolic factors, which regulate protein
metabolism, leads to protein synthesis disorder. Hormonal derangements, namely,
imbalance between hormones with anabolic (insulin, somatotropic and sex hor
nioncs) and catabolic (thyroxin, adrenaline, hydrocortisone) mechanisms, signifi
■ mtly influence protein metabolism. A lack o f somatotropin leads to a decrease
•I protein synthesis. A lack o f insulin has the same effect and leads to metabolism
"m utation at increased glucose production (glyconeogenesis).
A lack o f microelements can also impair protein synthesis (thyroxin needs
Iodine).
Hepatic insufficiency and disorder o f its protein synthesis function arc also a
и ison for decreased protein synthesis or production o f anomalous proteins (para
piolcins).

Hereditary Disorder of Protein Synthesis

I ach protein is encoded by a gene, and any code (gene) can hr disrupted
(Quantitative changes o f normal proteins or synthesis o f anomalous ones wit Ii a
I'ilrt 1 (•(‘lU-riil PulliopliVNioloK)

changed structure manifest this. Mutation may lead to upprar.mcc ol pathological

structural genes and absence o f normal regulative and structural genes.
T he genetic forms o f protein disbolism arc so num erous that it is impossible to
enum erate all o f them . T he nam es o f genetically determ ined pathology usually end
with -pathy. Such concepts as enzym opathy, im m unopathy, hem oglobinopathy,
coagulopathy, erythrocytopathy, throm bocytopathy, m em branopathy, endocrino
pathy have already been given (chapter 3 «Role o f H eredity and C onstitution in
Pathology», p. 48). Any hereditary and chrom osom al disease includes protein dis
bolism.
A lm ost all problem s with genetic disorders o f protein production are underlain
by enzym opathy.
As a result o f protein synthesis disorder, cells do not produce proteins foe
them selves, o th er organs, blood proteins, protein horm ones, protein receptors.
T he role o f genetic factors is usually studied to m aster pathogenesis o f any
pathology. It goes about protein disbolism , w hich is typical for this very case. In
the previous chapters o f this textbook the role o f heredity in im munodeficiencx
allergy, neoplasia, diabetes m ellitus has been m entioned. T he sam e inform ation will
be given in th e following chapters.

P R O T E IN CA TA BO LISM D IS O R D E R

Intracellular protein disintegration is as im portant function o f cells as protein

synthesis.
P rotein catabolism disorder includes im pairm ent of:
• proteolysis;
• interm ediate m etabolism o f am ino acids;
• production and elim ination o f the final products.

Proteolysis Disorder

D isintegration o f proteins (proteolysis) is determ ined by specific proteolyn*

enzym es (proteases) located in lysosomes. Proteolysis pathology m ay be increased
(activated) and decreased, local and systemic, acquired and inherited. Pathology mav
be caused by
• lysosome dam age;
• changes o f enzym e quantity o r activity.
Active proteolytic enzym es, w hich are revealed from dam aged lysosomes, afl'e*. i
cells. It is an im portant m echanism o f cellular death.
An example o f systemic lysosome damage is their damage under the action ol
ionizing radiation and chemical toxins. Thyroxin activates tissue cathepsins whoso
proteolytic effect increases. The focus o f inflammation is an example o f local lyso
some damage resulting in local cell damage.
Massive disintegration o f proteins is observed h i malignant tumor that leads In
cancer cachexia.
 C h a p te r 16. P athology o f P ro te in M etabolism

Hereditary reasons usually lead to a deficit o f specific proteolytic enzymes

I litis, genetically determined pathology o f macrophagal lysosomes and a deficit o f
lysosomal proteolytic enzymes make phagocytosis incomplete.
Decreased intracellular proteolysis leads to protein aggregation in cells and
impairment o f cellular functions.

Intermediate Amino Acid Metabolism Disorders

Arrest o f the synthesis o f the enzymes, which regulate protein and amino acid
iuinform ation, leads to a disorder o f intermediate amino acid metabolism due to
lunsamination, deamination and decarboxylation (scheme 14).

transamination and Deamination Disorders

Transamination leads to formation o f amino acids, deamination — to their de

miction. Transamination disorders may result from pyridoxine deficit (pregnancy
suppression o f the intestinal flora by sulfonamide drugs). Transaminase activity is
сIn teased in starvation and liver diseases.
Tissue transaminase enters the blood after cell destruction (myocardial infarc
lion, pancreatitis, hepatitis, etc.). An increased level o f this enzyme in the blood r.
in- o f the diagnostic criteria. Glucocorticoids and hormones o f the thyroid gland
annulate transamination.
Suppression o f oxidative deamination leads to an increased amino acid con
in itiation in the blood (hyperaminoacidemia and aminoaciduria) and acidosis
Thyroxin increases the activity o f some aminooxydases and thus deamination
nl some amino acids.

IWarboxylation Disorder

Decarboxylation is carried out with formation o f C 0 2 and biogenic amine-

i HAS). Thus, histamine formation is associated with decarboxylation o f histidim
serotonin formation wllli
decarboxylation o f 5-hydm
Si heme 14. Amino Acid Transformation Disorder
xytryptophan. Biogenic ашпн
- - » Г соГ have a high biological adlv
K eto acids ity in small doses. An incre i
l>elimination
Г*Й ГГ h 2o ~ o f their quantity causes tn.iin
Hypoxia pathologic changes, provok<
considerable impairment nl
A ininoucids local blood circulation, м
cular permeability, nici.iln.li.
Hyperthyrosis changes. Biogcnic amines pin
Hypercorticism
an important role in аНащ
l><;urhoxylulion
________ _____ inflammation, thrombosis, «i<
| A m ines~ K —И NH? ]
I ’. l l l I ( i C I M 'i a l l * U l ll l> |) li y s io l o K y

Hereditary Amino Acid Metabolism Disorders

Inclusion o f am ino acids to certain m ctabolic pathways and tlieir transform a

tion are determ ined and regulated by the am ount and activity o f coresponding en
zymes. T he arrest o f enzym e synthesis leads to interm ediate am ino acid metabolism
disorder.
T here are a lot o f am ino acid m etabolism disorders. E nzym opathy very often
underlies them .
In such a case an am ino acid is not included into m etabolism and is accum u
lated appearing in biological m edia: urine, sweat, and cerebral fluid. T he clinicil
picture in such cases depends on the appearance o f a great quantity o f the sub
stance, w hich m ust be m etabolized, and a deficit o f the substances, w hich must
synthezied. A m ino acid accum ulation in the blood results in acidosis. All disorders
are inherited recessively.

Tyrosine Disbolism

Tyrosine is a precursor o f m elanin. In case o f a hereditary deficit o f tyrosinav

(which transform s tyrosine into m elanin) albinism develops (schem e 15). Albinism
is characterized by discoloration o f the skin and hair (absence o f the pigm ent mela
nin in them ).
Alkaptonuria is an o th er clinical exam ple o f tyrosine disbolism. This disease i
also underlain by enzym opathy. T he p atien t’s urine and tissues becom e black.
Tyrosine is also a precursor o f the horm one thyroxin. In case o f a deficit ol
an enzym e, w hich catalyzes binding o f tyrosine with free iodine, the synthesis ol
thyroid gland horm ones gets disordered (hypothyroidism).

Schem e 15. Synthesis of Melanin and Catecholamine

in Albinism
T y ro sin e
T yrosinase |
In the adrenal cortex In melanocytes

D ihydroxyphenyl- D ihydroxyphenyl-
alan in e (D O P A ) a la n in e (D O P A )i
------------ 1---------
r
D opam ine D opaquinonc

5r
N oradrenaline I >o|>.n.hrumc I

r
A drcnalinc
~ T
IIhtnhm
 C h a p te r 16. PalholoKV o f P ru li'in M etabolism

I'limylalanine Disbolism

Ih ere is a type o f oligophrenia called phenylpyruvic oligophrenia. T he enzym o

i*иhy, w hich is connected with phenylalanine disbolism , underlies it.
U nder norm al conditions phenylalanine is irreversibly oxidized to tyrosine
' i heme 16). In case o f a deficit o f the enzym e phenylalanine hydroxylase phenyl
ilmiine is accum ulated in tissues, blood (m ore than 1.2 mmol/1 instead o f ().()(>
ii I mmol/1), and cerebral fluid.
Phis am ino acid in such concentration and especially its m etabolites (keto acid
i'li. nylpyruvate) are toxic for the nervous system. D uring the first m onths o f life it
1 ills to grave dam age o f the central nervous system. T he nervous cells o f the great
••(пт are destroyed and substituted by microglial elem ents. M icrocephalia is noted.
I mm the very childhood, the following clinical signs are observed — growth retar-
i ii ion, m oderate to severe m ental retardation, nervous excitem ent, activation o f
frllcxcs, increased m uscle tone, signs o f epilepsy, untreated oligophrenia.
Tyrosine disbolism adds neurological sym ptom s connected with disbolism ol
««itccholamine (adrenaline, noradrenaline) as well as sym ptom s o f albinism (disc»)
' i.ition o f the skin and hair) to the clinical picture. The patients die in childhood.
rh e term phenylketonuria denotes an elevated level o f urinary phenylpyruvate
inil phenyllactate. These substances may be easily found in one drop o f the new
1" in ’s urine. Exclusion o f phenylalanine from a diet prevents developm ent o f this
i uivc and incurable m ental disease.

Scheme 16. Blockade of Phenylalanine Metabolism

I he disease m entioned above presents one o f the m ost dram atic exam ples ol
mil i relationship betw een m utations o f one gene, absence o f one enzym e, dism c
lnholism o f one am ino acid, severity o f clinical m anifestations, phenotype depen
i nre on the environm ent, and effective prophylaxis by rather sim ple m easures as
• >ln ion o f som e sim ple products in a diet.

Disorders of the Formation and Elimination of Final Protein Metabolism Products

At the final stages o f protein m etabolism , nitrogen products (urea, creatinine,

miimonia, uric acid and its salts) are formed and excreted in the urine. T he main
I’llll I (ic iu 'ru l I'ulhoplivsioldKV

index o f a disorder o f their form ation and elim ination is the level and com position
o f the so-called residual (non-protein) nitrogen in the blood. Its norm al level о
14.3—21.4 mmol/1. As to com position, it consists o f 50 % urea. 25 % am ino acid*,
and nitrogen products.

Urea Synthesis Disorders

A m m onia is produced in all tissues as a result o f am ino acid m etabolism . Am

m onia is toxic, its accum ulation dam ages the cellular cytoplasm . F or its binding
and neutralization two m echanism s exist — urea is form ed from am m onia in ilii
liver, in o th er tissues am m onia binds with glutam ic acid (am idation) and glutamine
is form ed. Later, glutam ine gives am m onia for the synthesis o f new am ino acids
whose transform ation is com pleted by the form ation o f urea, w hich is excreted in
the urine. 90 % urinary nitrogen falls to the share o f am m onia (there is about <> 'I
am m onia).
U n d er pathological conditions am m onia neutralization and elim ination from
the organism fail. H epatic and renal insufficiency lead to such a disorder. An m
crease o f residual nitrogen in the blood — hyperazotemia — may result from impaired
urea synthesis in the liver (productive hyperazotem ia) o r secretory function o f ilu
kidneys (retention hyperazotem ia). These processes are im portant c o m p o n e n t ot
hepatic and urem ic com a pathogenesis. T he sam e problem with neutralization ol
am m onia with involvem ent o f a-ketoglutaric acid o f the Krebs cycle appears in
insulin insufficiency and was discribed on p. 210 (D M ).
T he activity o f the urea synthesis enzym e is im paired in liver diseases (hepalin
cirrhosis), hypoproteinem ia, oxidizing phosphorylation inhibition as well as due in
genetic reasons. In such cases am m onia is accum ulated in tissues and blood, im<i
intoxication develops.
T he nerve cells are the m ost sensitive to am m onia. T ogether w ith a d iim
dam aging effect o f am m onia on the nerve cells, am m onia binds w ith glutam ic at id
w hich thus is excluded from m etabolism . In accelerated transam ination o f am ....
acids with a-ketoglutaric acid the latter does not e n ter the Krebs cycle. Oxyyrit
consum ption gets decreased. O xidation o f pyruvic and acetic acids gets liniilt »l
Krebs cycle inhibition ham pers acetyl-C oA utilization and results in ketone bodu
form ation.
D isorders m anifest them selves through dystrophic changes in the liver, hypoxlf
These m ay be genetically determ ined defects (synthesis enzym e disorder).

Uric Acid Metabolism Disorders

A final product o f the m etabolism o f purine bases (adenine and guanine, win» It
belong to th e structure o f nucleic acids), is uric acid. D isorder o f its synthesis .mil
excretion leads to hyperuricem ia, which is a rather widespread syndrom e (in мин*
populations up to IX %). An exam ple o f im paired synthesis and excretion o f nil»
acid is gout.
 C h a p te r U>. I ’utholoK) <>l 1’iotc'iii M rliilm lism

Questions for Self-Control

What are the m ain indices o f protein m etabolism ?

W hat horm ones have an anabolic effect?
W hat horm ones have a catabolic effect?
W hen m ay protein synthesis be increased?
What is positive and negative nitrogen balance?
I n w hat way are th e changes o f blood protein co n ten t called?
What are the causes o f urea synthesis disorders?
What is (hyper)azotem ia and w hat are its consequences?
What is gout?

Tests for Self-Control

(give correct answers)

Л 15-year-old boy suffers from alkaptonuria. His urine becom es black aftei
settling. M etabolism o f w hat substance is genetically disturbed?
A. U ric acid.
B. Cysteine.
C. Alanine.
D. Urea.
E. Tyrosine.

In som e m onths after birth a child has a C N S lesion. T he skin and hair bright
encd. A ddition o f a solution o f trichloracetic iron to fresh urine leads to the
appearance o f olive-green coloring. W hat kind o f hereditary disbolism took
place?
A. Tyrosinosis.
B. A lkaptonuria.
C. Fructosuria.
D. Phenylketonuria.
E. Albinism.

I xam ination o f a child w ith oligophrenia showed an increased level o f phenyl

alanine and phenylpyruvate in the blood and neurolym ph. The reaction o f the
urine with trichloracetic iron is positive. W ith deficiency o f what enzym e is the
child’s disease connected?
A. Tyrosinase.
B. Hexokinase.
C. Phenylalanine hydroxylase.
I). D opam ine hydroxylase.
E. Hydroxyphenylpyruvate oxydase.
Chapter 17
PATHOLOGY OF ACID-BASE BALANCE

T he positively charged ion o f hydrogen (H +) is o f great im portance for many

functions o f th e organism . Protein conform ation and consequently condition o f tin
m em branes, channels, receptors, colloids, enzym e activity and m olecules depend
on m edium pH .
Blood pH is one o f the principal constants o f the organism and is strictly con
trolled.
Acid-base balance is maintenance of constant H + concentration (medium pH ).
Different m edia o f the organism have their own pH rates. T he saliva and intcs
linal juice have alkaline reaction. T he gastric juice contains a large am ount o f free
hydrochloric acid (HC1) and has high acidity reaction (pH approaches 1).
Blood pH is 7.35—7.45. The level o f blood pH less than 6.8 o r higher than 7..H
is not com patible with life.
Excessive form ation o f H + ions leads to pH reduction. A decrease o f H* ion
form ation elevates pH.

Mechanisms of Acid-Base Balance Regulation

Since the m ajority o f interm ediates (products o f interm ediate m etabolism ) arc
acids, pH regulation is provided continually. M any m echanism s (in the liquid me
dia, blood and cells) are constantly participating in acid-base balance regulation.
1. Buffer systems neutralize surplus o f acids and alkalis, transferring them into
a form convenient for further secretion by the lungs and kidneys.
• H ydrocarbonate buffer system H 2C 0 j /N a H C 0 3 = 1/20 m aintains pH in
the blood plasm a and interstitial fluid. This buffer has a volatile form о
acid ( C 0 2), which can be easily excreted by the lungs.
• Phosphate buffer system N aH jP O y N ajH P C ), = 1/4 participates in acid
base regulation in the kidneys.
• Hem oglobin buffer functions in erythrocytes.
• Protein buffer regulates intracellular pH .
2. Lungs role consists in constant discharge o f carbon acid in the form o f cai
bon dioxide C O r 1
3. kidneys role consists in acid-base regulation through three m ech an ism .
(schem es 16, 17, 18):
• Acidofienesis is secretion o f H* ions into the renal tubules.
• Ammoniogenesis is form ation and secretion o f am m onia ion (N11,) into the
renal tubules. T hen, N11, reacts with H* to form N ll4'. Afterwards il is
accom panied by anion Cl . N eutral am m onium salt N11,(1 is form ed and
excreted in the urine.
• Rcuhsorplion of hicurhonutc ( N a l K ' ( ), ) ill llic ren al tu b u le s.
 Chapter 17. Га|||и||>к> of Acid-Base Balance

Scheme 17. Acidogenesis in the Kidneys

Blood Renal tubular cells Urine

COj- -- > C02+ HjO
Ф Carbohydrase
H2CO,

H CO r -> HCOJ H * ----- -> tr

Na---- -------- ► Na’------------ ■> Na'

Consequently, urine examination reflects the acid-base state. Two urine indices
.ire of practical use. They are:
• urinary acidity tested by titration;
• ammonium salt content.
4. Aldosterone (hormone of the adrenal cortex) supports acidogenesis in the
kidneys, participates in H +and Na+exchange (H +ion secretion and N a+ion
reabsorption).

ETIOLOGY

Etiological factors of acid-base balance disorder can be exogenous or endo­

genous; physical, chemical and biological.
Exogenous causes are the following:
• mechanical trauma of the chest that impairs gas exchange in the lungs;
• excessive intake of acid or alkaline products (mineral water, different
diets);
• oxygen deficiency in the inhaled air and accumulation of incompletely
oxidized metabolites in the organism;
• surplus of C 0 2 in the inhaled air (submarine accidents);

Scheme 18. Ammoniogenesis in the Kidneys

lilood Renal tubular cells llrine

Glutamin

-NH,
( ilulamin

Glutaininic acid
+Cl N IM I

-NH,
-> N II, + H ‘- •N11,
a-ketoglularic acid
Part I Gmeral I'lilluiphysioloKy

Scheme 19. Hydrocarbonate Reabsorption in the Kidneys

• poisoning that manifests itself through vomiting (loss of acid) and din
rhea (loss of alkalis);
• starvation;
• infection that results in pulmonary or renal insufficiency and in dison
of the main physiological mechanisms of acid-base balance regulation
Endogenous causes are the following:
• disorders in metabolism regulation and accumulation of acid intermed
ates (D M );
• pathology of the organs that participate in acid-base balance regulaii
(inflammation, vascular disorders leading to malfunctioning of the lui
kidneys, and adrenal glands);
• various diseases that manifest themselves through vomiting, diarrhea,
excessive salivation.

PATHOGENESIS

Pathogenesis of a disorder depends on the reason, which has caused it.

The pathogenesis of acid-base balance disorder proceeds in two stages — cot
pensation and decompensation. The cause-and-effect relation frequently acqui
the nature of a vicious circle.
Stage o f compensation manifests itself through normal blood pH in spite of el и
logical factor influence. It is possible due to mechanisms of compensation.
For example, a patient with D M can have normal blood pH for many yetil
However, an examination of the blood and urine shows an acid-base disorder (i
creased blood bicarbonate concentration, increased urinary acidity and ammonin
salts content, hyperventilation). Polyuria, which is typical of D M , leads to loss
potassium.
Stage o f decompensation develops if mechanisms of compensation arc exhan
ed. Dysfunction of the organs, which participate in p ll regulation, provokes d«
ompensation. Thus, if pneumonia occurs in a patient with I >M, the function ol l
lungs fails in a compensatory process. Renal insulin irncy significantly impairs I
 Chapter 17 1’alholoK.v of At'iiMtasc llalancr

и ""i" nsaling possibilities of the organism with any form of acid-base dysfunction.
(It I" 1 ‘>i hypoproduction of aldosterone may also provoke decompensation.
I '( compensation is manifested by a change in blood pH. This state is incom
toiii'l' with life and is called acidic coma. The patient dies without urgent medical
M l'
CLASSIFICATION

I here are several classifications of acid-base balance disorders depending on

||w pilnciple, which is assumed as a basis.
kidosis (decreased pH) and alkalosis (increased pH) are distinguished accord-
li to the direction of acid-base disorder. In their turn, each of them is further
MHllvldcd.
( ompensated and decompensated.
Gaseous and non-gaseous (syn. respiratory and non-respiratory) —connected or
Цн •onnected with volatile acids (carbon dioxide) or organic acids.
I xogenous and endogenous. This classification is based on the origin of the
fHnlityical factor.
Hie endogenous type is subdivided into two types - metabolic (accumulation
|| !■nl metabolites) and excretory disorders (kidney or lung insufficiency).
icuie and chronic disorders reflect the type of clinical duration.
lo a d (pH changes in tissues) and systemic (in the blood).

FORMS OF ACID-BASE IMBALANCE

l iking into account all the aspects, the following four forms of acid-base dis­
pel- i are distinguished (table 6 gives additional characteristics).

Non-Respiratory Acidosis

Non respiratory acidosis develops as a result of organic acid accumulation. It

|l tilnlivided into metabolic and excretory.
Uclaholic non-respiratory acidosis develops as a result of metabolic acid prod-
I* I n b illion. Here are clinical examples:
• Oxygen deficiency (hypoxia) of any genesis leads to accumulation of in
■iiii|iletely oxidized products in hypoxia (p. 166), blood loss (p. 269), hemorrhage
Ним к (li>> 30 on p. 272), anemia (p. 278), cardiac insufficiency.
• DM (p. 212), when endogenous non-respiratory metabolic acidosis may
|k I..... compensated (without comatose state; blood pH is normal) and acute
.........pensated (coma; blood pH 7.2). Manifestations are the following: hyper
Kfjfii ini.i. glycosuria, reduced blood bicarbonate concentration, increased urine
■мини Pulmonary hyperventilation has a compensatory value.
• <omplete starvation (without water deprivation) in the third stage (p. 181).
Mrtabolic acidosis is compensated by respiratory reduction in plasma CO,
imitation. However, the lower the plasma CO, concentration, Ihe less CO,
I ’.il l I ( •t'lU'rul Г й 1 ||< > |||п ч о |о щ

given oil with each breath. Thus, in order to exhale a particular amount of COr hy­
perventilation must be maintained until the plasma 1 1 ( 0 , concentration is again
normal, either through raised renal excretion of acid or through the breakdown of
organic acids. Increased urinary acidity and ammonium salt content are the signs
ol kidney participation in compensation.
In extracellular acidosis cells lose K +. Hyperkalemia develops. Due to Na+up
lake cells arc swelling. Intracellular acidosis inhibits K +channels and has a negative
t*licet 0 1 1 the cardiac muscle. Prolonged intracellular acidosis inhibits cell division
and favors apoptotic cell death.
lixcrelory non-respiratory acidosis is illustrated by the following clinical ex­
amples.
• I )iarrhea, when alkaline intestinal juice loss takes place.
• Renal dysfunction, when acidogenesis, ammoniogenesis and bicarbonate reab­
sorption are depressed.
• Adrenal gland disease accompanied with aldosterone deficiency.
Compensation and disorders are the same as mentioned above. Hyperventila
lion plays the main role.

Respiratory Acidosis

Respiratory acidosis develops when the lungs fail to remove CO r Hypercapnia

develops. It induces dilatation of vessels and relaxation of the bronchial smooth
miisi les, activates n. vagus, enriches hydrocarbonate buffer system, and optimizes
o\yl lb dissociation. (A moderate respiratory acidosis in the stage of compensation
induced by breathing of air with increased pC 03is used for treatment of bronchial
isihrna and other diseases with chronic hypoxia.) Later this acidosis is compensated
by Increased renal excretion of acids (or through forming of H C O J). The increased
plasma I IC O , results in more H C O J being filtered in the glomeruli. The kidneys
iiiiisi therefore continually reabsorb an increased amount of filtered H C O J if renal

loss ol I IC O , is to be avoided. A complete normalization of acid-base imbalance

in I Ins form may be achieved only by normalization of the respiratory function.
Here are some clinical examples of respiratory acidosis.
• Respiratory system diseases, for example, pneumonia.
• Drug abuse (respiratory center depression induced by narcotics, hence acute
dysfunction of pulmonary ventilation).
• Accidents in a closed space, for example, submarine accident (CO , retention).

Non-Respiratory Alkalosis

Non respiratory alkalosis develops in the following situations:

• I \cessive intake of alkaline substances into the organism.
• I oss of acids by the organism.
Il can theoretically be compensated by hyperventilation, hut the need to take
up sufficient <), limits this form of compensation Hypokalemia is a result of al
kalosis because the cells lose less K ‘. Na' is puuipnl out of the cell In addition,
 Chapter 17. I'athol'igy of Лги! Hast- Italamr

more Ca2+ is bound to plasma proteins; there is a fall in the concentration of C a"
in the plasma. Chronic non-gaseous alkalosis influences carbohydrate metabolism
Ii inhibits p-cells, activates а -cells, causes hyperglycemia and decreases tolerance
in glucose.
This disorder may be illustrated by the following clinical examples.
• Abuse of alkaline mineral water (exogenous type of disorder).
• Uncontrollable vomiting and loss of acidic gastric content.
• Different disorders of the adrenal cortex, when excessive aldosterone formation
lakes place (tumor).

Respiratory (Gaseous) Alkalosis

Respiratory (gaseous) alkalosis may take place in case of pulmonary hypei

u-ntilation and increased C 0 2 excretion. A clinical example is mountain climbing
mil hyperventilation as a compensatory reaction (p. 163). This situation with acid
l>asc imbalance is very short as in some days is fully compensated by stimulation
ol crythropoiesis, when hyperventilation stops. Drinking acidic liquids easily helps
ihe situation. In case of prolonged non-defensive hyperventilation connected with
disorder of the respiratory system (see p. 402 about reasons and pathogenesis) hy
l»ncapnia develops. Its effects include raised neuromuscular excitability with cramps,
■onstriction of the cerebral vessels and thus hypoperfusion of the brain, contraction
of the bronchial smooth muscles. It is compensated by decreased reabsorption of
IK 'O J in the kidneys.

hihle 6
Characteristics of Acid-Base Conditions
1 )isorders
of Acid- Clinical
PH н со,
и
О

Etiological Factors
Manifestations
N

Base
Balance
Acute re- Acute respiratory insuf­ Tachycardia, tac­ I T Un­
\|>iratory ficiency, cardiopul­ hypnea, sweating, changed
acidosis monary insufficiency, headache, cyanosis,
trauma of the breast arrhythmia, arterial
bone, asphyxia, CNS hypotension
trauma/tumor, dam­
age of the respiratory
muscles
( hronic Chronic obstructive Dyspnea or tac­ I T Т
nspiratory disease of the lungs hypnea, coma
Hinipen-
Mited aci­
dosis
Г.н I I ( ■ciirrul l*Mlh<i|)hv4ioli>K>

/<//>/<•ft conliniuul
I )isorders
of Acid- Clinical
Etiological Factors PH CO, H CO ,
Base Manifestations
Balance
Metabolic DM, starvation (com­ Kussmaul’s respira­
acidosis plete), shock, heart tion (hyperpnea),
block, respiratory fail­ hypotension,
ure sweating, cold skin,
coma, arrhythmia
Non- Chronic renal insuf­ Weakness 4-less
rcspiratory ficiency than in
excretory the acute
acidosis form
Respira­ Hyperventilation, CNS Dizziness, par­ Un­
tory alka­ damage esthesia changed
losis
Non- Wasting HC1 under Muscle weakness,
rcspiratory vomiting, hyperadre- arrhythmia apathy,
excretory nocorticism (Cushing’s confusion, stupor
alkalosis syndrome), aldostero-
nism

Questions for Self-Control

I What is acid-base balance?

What is the role of the buffer systems in acid-base balance regulation?
I Wlial is the role of the lungs in acid-base balance regulation?
•I What hormone participates in acid-base balance regulation most of all?
V What is the mechanism of aldosterone effect on acid-base balance?
< • I xplain the role of the kidneys in acid-base balance regulation.
7. What processes take place in the kidneys for acid-base balance regulation?
S Explain the terms acidogenesis and ammoniogenesis.
{> What urine indiccs are used to characterize acid-base balance?
Ill Name 7 principles of acid-base balance classification.
11 ( iive the characteristics of the stages of compensation and decompensation in
acid base balance disorders.
12. What is acidosis? Give its types, causes, examples.
I t What is alkalosis? (iive its types, causes, examples.

Tests and Tasks for Sclf-( ontrol

(give correct answers and find mistakes hi the statements)

I While climbing a mountain a climbci lecls activation of breathing, dyspnea,

headache, and palpitation. What type ol at id I hihc unbalance has developed?
 Chapter 17. Pathology of Acid-Нам- HuIiiih c

Л. Respiratory alkalosis.
Ii. Metabolic alkalosis.
C. Non-respiratory alkalosis.
D. Respiratory acidosis.
E. Excretory acidosis.

(iive the characteristics of compensatory reactions directed to maintain acid

base balance in DM .
1. Hydrocarbonate content in the blood gets decreased.
2. Carbon dioxide retains in the organism due to hypoventilation.
3. Acidogenesis increases in the renal glomeruli.
4. Ammoniogenesis gets activated in the renal glomeruli.
5. Aldosterone excretion from the adrenal cortex gets activated; it inhibits
hydrocarbonate absorption from the primary urine into the blood.
6 . Exhaustion of compensatory reactions results in decompensated metabolic
acidosis development.
7. Influenza limits acidosis compensation in DM .
8 . Adrenal cortex insufficiency results in a disorder of acid-basc balance
regulation and rises the probability of coma development.

Inherited chronic hemolytic anemia (decreased amount of erythrocytes) has

been diagnosed in a patient. It causes chronic hypoxia of the hemic type
and accumulation of non-oxidized metabolites. Working capacity is preserved
What type of acid-base imbalance is observed in the patient?
A. Acidosis.
B. Systemic.
C. Exogenous.
D. Compensated.
E. Gaseous.
F. Metabolic.
G. Acute.

What type of acid-base imbalance is observed in sailors who continue to work

during submarine catastrophe?
A. Alkalosis.
B. Systemic.
C. Exogenous.
I). Compensated.
E. Non-gaseous.
F. Metabolic.
G. Acute.
( hapter /<У
PATHOLOGY OF WATER AND ELECTROLYTE BA1ANCE

Water composes 60 % of body mass (from 45 % in thin aged persons to 70 %

in the young). It is one of the most important constants of the organism.
Л person drinks about 1—2 1 of water a day. About 1 1 comes into the organ
i in with food and about 300 ml of water is produced from nutrient oxidation. The
..ime amount of water (about 2.5 1) is excreted from the organism by the kidneys
(I 1.5 1), skin vaporization (0.5—1 1), the lungs (about 400 ml) and also in the feces
(50 2(H) ml).
Water is distributed in the oiganism in the following way.
Water o f the blood (intravascular) composes about 5 % . It is the circulating
blood volume. 93 % of it is pure water. The rest is bound with blood cellular ele
ments.
I his volume must not be changed significantly since it determines heart load
I olumoreceptors of the large vessel wall and atrium of the heart control this vol
ume.
Intracellular water composes 35—45 % . This volume is constantly regulated and
1 1 11 ist not be changed. The intracellular fluid is present in three conditions: a) water
ol the cytoplasm bound with hydrophilic structures; b) water connected with the
ми face of colloid structures; c) water in the cytoplasmic lacunas, which is the most
mobile, relatively free water of cells. In different pathologic conditions the intracel
lulin lluid volume changes at the expense of the mobile water volume.
Extracellular (in terstitial) water composes about 15 % . Only the quantity of this
water may change significantly. The interstitial fluid is close to the blood plasma
(except protein contents) and washes cells with ion and molecular substrates. This
lluid is in constant exchange with the blood plasma so that approximately 2 0 I ol
lluid with dissolved substances comes into tissues from vessels daily and the same
amount returns into the systemic blood flow. 3 1 of the fluid returns through the
lymphatic vessels.
Extracellular (transcellular) water (1—3 % ) forms the digestive juice, cercbro
spinal lluid, and the kidney tubule fluid.
I he intravascular and interstitial fluids are the most mobile, and they are the
In -.1 to change their volume.
I he total body water amount decreases with aging. In old people the extracel
liiliii lluid amount is increased while the content of water in cells is reduced.

Water Balance Regulation Mechanisms

I lie water balance is regulated by many mechanisms. Some o f them act locally
mi tissues; some are systemic for the whole organism
 Chapter IX. Pathology of Water anil Kleetrolyle llalauee

total Mechanisms

I ocal (tissue) mechanisms regulate the water balance between the blood and
ii nos through the capillary walls.
I Starling and other scientists (Vidal, Fisher) studied the factors, which de-
i nnine liquid passing from the blood stream into the intercellular space (llllui
11 <hi) and its return into the vessels. This balance is regulated by physicochemical
tiK'chanisms:
Hydrodynamic pressure difference between the blood and extracellular fluid. I hc
blood moves in the capillaries at a definite speed and under a definite pressure,
л liich results in the formation of hydrodynamic force, which makes water go out
ol the capillaries into the interstitial space. The higher blood pressure and ihc
less tissue fluid pressure, the higher effect of hydrodynamic force. Hydrodynamic
blood pressure in the arterial section of the capillaries is 35—40 mmHg, and in ihc
venous section — 10—15 mmHg (Starling, fig. 26).
• Oncotic pressure (of proteins) difference between the blood and interstitial liquid
An increase of vascular permeability for proteins occurs in a number of pallm
logic processes and essentially influences this parameter (Starling, fig. 26).
• Osmotic pressure difference between the blood and interstitial liquid (Vidal).
Interstitial tissue pH. The hydrophilic nature of colloids depends on H ' con
ccntration and rises in acid media. Then colloids swell and detain more walct
i Fisher).
I he resultant force is called filtration pressure.
Hie ratio of these forces determines the passage of liquid into tissues from the
.nioiial part of the capillaries and its return to the blood in the venous part.

Systemic Mechanisms

Systemic mechanisms regulate the water balance between the organism and
Ihc environment. One should understand that all the organism water cannot be
и ulated by the physicochemical laws mentioned above. It is regulated by biologi
■il (neurohumoral) mechanisms with the participation of such a high-level organ
is ihc hypothalamus.
These mechanisms are the following.

Fig. 26. Mechanism of edema formation hi

case of altered hydrosratic (A) and oncotic
(B) pressure (according to Starling):
1 —arterial part of the capillary vessel (lluul leaves
the vessel); 2 —zone of balance; 3 - venous pail
of the capillary vessel (fluid enters the blood from
the tissue); a — increased hydrostatic pressure,
b — decreased oncotic pressure; normal
levels of hydrostatic and oncotic pressure
7 4
I ’iiiI I <it'iHTuI l*allui|>hvsi»loK .V

• Participation of the volumoreceptors ol the vasiulai wall and the left atrium «»!
the heart, which control the circulating blood volume.
• Participation of osmoreceptors o f the vascular wall (arches of aorta and carotid
sinus), which control blood osmotic pressure.
• Participation of aldosterone of the adrenal cortex, which regulates (increases)
Na reabsorption from the primary urine into the blood (antinatriuretic mechu
nism).
• Participation of the hypothalamus, which reacts both to decreased bloo<l
volume and increased blood osmolarity in response to volumo- and osmoreccptot
iriials. It releases vasopressin (antidiuretic hormone, A D H ) by the supraoptii .il
and paraventricular hypothalamic nuclei. The point of vasopressin action is th«
renal tubule epithelium. Vasopressin increases water reabsorption from the primals
urine and thus regulates diuresis (the primary urine quantity is 180 1/day; the final
urine quantity — 1 —2 1 ).
• Participation of the kidneys with their receptors and renin. Stimulation of tin
adducting renal arteriole volumoreceptors and of the osmoreceptors of the macula
densa of the juxtaglomerular complex intensifies renin synthesis and release. Ли
giotensin II, which is formed under renin influence, increases aldosterone secretion
and stimulates the thirst center located in the lateral part of the hypothalamus.
• Retention of water and Na+ in the organism is opposed by two mechanism-,
of natriurcsis:
• renomcdullar prostaglandins;
• atrial natriuretic factor (A N F, atriopeptide of 28 amino acids).
Antidiuretic and antinatriuretic mechanisms oppose the diuretic and natriurcin
ones Renomcdullar prostaglandins and A N F increase diuresis and natriuresis, re
lax the vessel smooth muscles and decrease arterial blood pressure. The amount ol
AN I in the atrium and its secretion into the blood increases after excessive water oi
i omnion salt intake, blood pressure rise as well as stimulation of p-adrenoreceptor,
oi vasopressin receptors.
All these mechanisms are constantly functioning and provide water-electrolvh
homeostasis restoration in case of blood loss and dehydration, water retention In
tin organism as well as osmotic concentration changes.

WATER IMBALANCE CLASSIFICATION

Water imbalance is divided into two varieties - positive and negative.

Positive water balance (hyperhydration) is water retention in the organism.
Negative water balance (hypohydration) is water loss by the organism.
Depending on osmotic concentration, hypo- and hyperhydration are subdi
vuled into three types: isoosmolar, hypoosmolar and hyperosmolar. (The normal он
niotic concentration of the hlood and intercellular fluid is about 0.3 osmol/l -
tOO inosniol/l.)
In clinical practice it is manifested in the form ol two syndromes hyperhy
ilialio n (edem a) and dchydrotion
 Chapter IX. 1'allioloK.v of Water and Mct-lruMr ItalaniT

H Y PER H Y D R A T IO N

Hyperhydration is a positive water balance.

Hypoosmolar hyperhydration develops in acute renal failure or as a result of
im|i i ting a large dose of vasopressin. It is characterized by an increased amount of
Mriiic t ii) the organism and decreased osmotic pressure in the extracellular space,
w iii i enters cells. The membrane sodium-potassium balance changes. Sodium
■iiicis cells and hence its amount in the blood plasma decreases. K f is released
11 1 nit cells into the extracellular space. The patient suffers from headache, nausea,
limiting, arrhythmia, convulsions, and coma.
Hyperosmolar hyperhydration develops in drinking salt (sea water) in extreme
limit ions. As a result, osmotic pressure in the extracellular medium increases, and
* Mi i is released from cells into the intercellular space. Cell dehydration develops.

EDEMA

Idema is a typical pathological process, which is characterized by a positive

Hater balance and accumulation of water in the interstitial space.
I lie principal pathogenic factors of edema are the following.
• Increased hydrodynamic pressure in the venous part of the vascular flow (lo-
tH'l venous hyperemia, inflammation, and cardiac insufficiency).
• Decreased colloid osmotic blood pressure (in case of a decreased concentra-
.....of plasma proteins — hypoproteinemia, especially of highly hydrophilic albu
... . in fasting, nephritic syndrome, hepatic insufficiency, etc.).
• Increased permeability of the capillary vessels, which occurs:
• under the influence of BAS (histamine, serotonin, kinins, prostaglandins,
etc.);
• in capillary wall dystrophy (fasting, disturbed neurotrophic supply, etc.).
• Increased colloid-osmotic pressure in tissues due to accumulation of osmotic
iml oncotic substances: electrolytes, proteins, metabolic products (in inflammation,
•III гцу).
• Lymph outflow disorders (mechanic or dynamic lymphatic insufficiency).
• Disorders of the nervous and humoral regulation of the water-electrolyte
ti.iliiiice («wrong switching» of the antidiuretic and antinatriuretic systems, as well
и unpaired sensitivity of volumo- and osmoreceptors, secondary aldosteronism,
hypothyroidism).
Types

I dema is divided into local and systemic.

According to pathogenesis (the main pathogenetic factor), edema is divided
mi., hydrodynamic, oncotic, osmotic, membranogenic, and lymphogenic.
( Imical practice divides edema according to localization and causes into in-
IhiHmatory, allergic, toxic, venous, neurogenic, lymphogenic (which are local) and
i m iliac, fasting, nephritic, hepatic, endocrine (which arc systemic).
I lie etioloKY ami pathogenesis o f each type of edema are different.
Г.ii I I <General rulliu|iliysl<ilo)(v

Local lilcimt

l ocal edema is accumulation of liquid in Ihe interstitial space of an organ 01

its part. It is redistribution of water in the blood-tissue direction according to lot .ii
(tissue) mechanisms of water balance regulation.
Ihe water balance between the vessels and tissues performs through the hi
pillary wall. The wall is a biological structure, through which water, electrolyte»,
some organic compounds (urea) are easily transported, but it is not permeable im
proteins. It results in unequal concentration of proteins in the blood plasma <<>(•
SO g / l) and tissue fluid (10—30 g/1).
I wo stages are distinguished in local edema development. At first, excessiu
lluid is accumulated in the interstitial space as if fixed (bound) with gel structuni
(collagen fibers, connective tissue) increasing the mass of nonmobile water. Thai
when this water mass increases by 30 % , the water behaves as mobile (free) (fig. .V»
and manifests itself as a pit when pressed with a finger.

l ocal Hdema Types

Local edema may be inflammatory, allergic, venous, toxic (membranogenn i

neurogenic and lymphogenic.
Inflam m atory and allergic types of edema are studied in corresponding chapter»
It has already been mentioned (chapter 6 «Allergy», P- 93 and chapter 8 «Inflam
->
4■
......i____ l ___ 1___ i___ _________ i___ V
I Ml (17X II 2<1 0 0.26 0.7H
(Чепчик* of cxlraccllulaf lluid. к Pa
I ik 27. Dependence of the volume
ol lift' (I) .uul lixotl (2) extracel-
IiiIiii ihinl on its pressure
mation», p. 126) that the main component in I In
pathogenesis of inflammatory and allergic edenni
is increased vascular permeability under BAS el
feet (histamine, bradykinin, etc.). As a resiili
plasma proteins get into tissues. Blood oncotli
pressure gets reduced. In the center of inflain
mation (this concerns allergic inflammation i
well) colloid osmotic pressure rises. Arterial ami
venous hyperemia, which develop in the foeUk ol
inflammation, lead to hydrodynamic blood pu s
sure increase. Local acidosis contributes to col
loid hydrophia and excessive binding of water
Toxic (membranogenic) edema has a similm
pathogenesis (edema after a bee sting). Pho&gnii
causes a selective increase of pulmonary capll
lary permeability and pulmonary edema tlcvt*
lopment.
Venous edema develops in case of vein иг*
congestion (p. 108), which is accompanied by im
increase in hydrodynamic pressure in the veinm
part of the capillaries and water filtration.
Neurogenic edema develops as a result nl
nervous ilysiviniliilloii til vessel tmphicity (tin
 Chapter 18. Pathology of Water and Klcctrolytc llalant-r

.... icurosis) and increased vessel permeability. Edema of extremities in hemiparesis

i in urogenic as well as edema of face in trigeminal neuralgia. Quincke’s edema has
iin same pathogenesis.
lymphogenic edema develops in the region of lymphostasis and lymph drainage
•list ii dors (in physiological conditions this mechanism compensates accumulation of
ln|ind in the intercellular space).
Noninflammatory fluid accumulated in different cavities and tissues is called
transudate.
Pathologic accumulation of fluid in the serous cavities of the organism is called
ii hops. Its varieties are ascites (in the peritoneal cavity), hydrothorax (in the plcu
i il cavity), hydropericardium (in the pericardium).

Systemic Edema

Systcmic edema may take such forms - cardiac, nephritic, hepatic, endocrine
iih I i ichexial (fasting).

t anlin с Edema

Heart (cardiac) insufficiency is described in chapter 24 «Pathophysiology ol

i Ii .nl». Edema is one of its symptoms (p. 347). It is a systemic retention of water
hi ihc organism and its redistribution into tissues.
I lie hydrodynamic factor is the main in the pathogenesis (increased hydro-
i Mimic pressure in the venous part of the capillaries). Due to a decrease of ик­
ни tactile function of the heart, a systemic increase of venous pressure develops
i M nous congestion). Resorption of liquid from the interstitial space into the blood
h decreased.
A concomitant mechanism in the pathogenesis is hypoproteinemia causcd by
• decrease of protein synthesis in the liver (due to blood congestion). The mem-
i i mogcnic factor may also have some influence (due to circulatory hypoxia and
a* ulosis).
Actually, all these factors are present in heart insufficiency. However, in such
и w.iv il is possible to explain only redistribution of water in the blood-tissuc direc­
tion I hc reason for positive systemic water balance (systemic retention of water) is
..... iccted with other mechanisms - participation of the vascular receptors, hypo
ih.il.imus, adrenal cortex, hormones and renal tubules.
I lie following sequence of events is characteristic of cardiac edema pathogenc

I )ccrease of the contractile capacity of the myocardium -» decrease of sys

lolic blood volume -» reaction of the volumoreceptors of the arch of aorta
> transmission of impulses to the hypothalamus -» liberation of vasoprcs
sin (antidiuretic hormone — A D H ; the point of action is the renal tubule
epithelium) stimulation of water reabsorption from the primary urine hi
the tubules into the blood -» limitation of diuresis -» water retention in the
hlood >hypervolemia -> redistribution of water into Ihc intercellular space
(accordiii|| to Starling's law).
(’.ill I (.<iKi.il Ги|1н1||||>Мо|<>к>

One more mechanism of systemic watei icleution hi the organism joins the
mentioned ones. It is described below.
Disorder of renal blood supply caused by cardiac insufficiency —>renin pro
duction and angiotensin formation -» aldosterone secretion -> stimulation «>1
Na' reabsorption from the primary urine into the blood -» increase of blood
osmotic pressure -» reaction of vascular osmoreceptors -» transmission ol
impulses to the hypothalamus -» vasopressin (A D H ) liberation - »stimulation
of water reabsorption from the primary urine into the blood - » limitation ol
diuresis -+ retention of water in the blood -» hypervolemia -» redistribution
of water into the intercellular space (according to Starling’s law).
This is cardiac edema pathogenesis.
I lie given sequence of events is physiological (it is compensation in case ol
circulating blood volume reduction, for example in blood loss). In case of heart in
sullicicncy this chain of events can be named «an error of adaptation» and becomes
the main pathogenetic factor of systemic edema development.
I Itus, all pathogenic factors participate in cardiac edema and it is their combi
nation and mutual reinforcing effect that provide its pathogenesis.
The understanding of this pathogenesis allows a physician to treat effectively
a patient with cardiac edema. The therapy is directed at heart disease treatment
However, this therapy requires time while quick removal of excessive water is nee
essary, since hypervolemia overloads the sick heart. Therapy is guided not by the
fact of venous congestion, but by the mechanisms, which are responsible for sys
temic water retention. It becomes clear that neither the hypothalamus nor vasculai
receptors are proper targets for the drugs. The effect of contemporary diuretics is
directed a) against angiotensin or aldosterone formation and b) inhibition of then
activity. Salt-free diet must be recommended to the patient.

Nephritic Edema

Renal insufficiency is described in chapter 29 «Pathophysiology of Kidneys».

Systemic edema is one of its symptoms (p. 470).
In kidney inflammation (acute and chronic glomerulonephritis, nephritic syn
drome) protein is lost in the urine. Hypoproteinemia underlies water redistribution
into tissues according to Starling’s law, but positive water balance (systemic watci
letcntion) has another explanation. Renin, which is produced in the inflamed kid
ileys, has two effects: a) arterial blood pressure increase (by angiotensin II forma
tion) and b) aldosterone secretion stimulation.
I he following order of events is similar to the one mentioned above as a result
<il aldosterone secretion.
Increased Na' reabsorption from the primary urine into the blood -»increase
of osmotic blood pressure -» reaction of vessel osmoreceptors involving the
posterior part of the hypothalamus >release of vasopressin (A D H ) * acliva
tion ol water rcabsorption from the primary urine into the blood >decrease
of diuresis ►increase of water quantity hi the hlood (hypervolemia) -» pas
sage of liquid into the intcrccllulai space
 Chapter IS. Pathology of Water anil Kleiirolytr lt.il.onc

I his is nephritic edema pathogenesis.

I here is an additional and even more important component of nephritic edein.i
i* ithogenesis, namely, decreased synthesis of renal prostaglandins, which contribute
i'i Na' removal under physiological conditions.

1141a tic Hdema

Hepatic insufficiency is described in chapter 27 «Pathophysiology of Liver».

• innic edema is one of its symptoms (p. 445). Limitation of protein synthesis
mhI hypoproteinemia underlie the pathogenesis. According to Starling’s law edema
ilrvelops.
In case of portal circulation disturbance (pressure increase in the v. porta)
.... ditions for edema development are created according to Starling’s law. Liquid
I ictained in the peritoneal cavity ( ascites, p. 451).
I here is an additional component of hepatic edema pathogenesis. It is known
iii.it hormones are destroyed in the liver and hepatic insufficiency is accompanied
ith suppression of hormone destruction. This concerns aldosterone, which is nc
iiniuilated (relative hyperaldosteronism). Subsequent events are similar to those
.... itioned above.

I lulm rine Edema

I ndocrine diseases are often accompanied by edema development.

Myxedema is a so-called mucous edema of the skin and subcutaneous cellular
и tie, which develops in thyroid gland hypofunction (p. 496). Colloids are accu­
mulated (collagen, glycosaminoglycans), which are hydrophilic and bind an enor­
mous amount of water. A pit is not formed in the region of edema when pressed
«11 Ii a finger.
Diseases, which are accompanied by increased aldosterone formation (pri
mury or secondary hyperaldosteronism), are characterized by edema (pathogenesis
1 i Icar from explanations given above).
•in hexial Edema

( achexial edema occurs in starvation and exhausting diseases.

It develops during incomplete quantitative and qualitative (protein) starva
Iliui (p. 183). The pathogenetic basis of this form of edema is hypoproteinemia
т . I oncotic blood pressure decrease. According to Starling’s law water leaves the
Vh •ular channel and is accumulated in the interstitial space. During the first and
м. mid periods of complete starvation without water deprivation, edema does not
1I1 velop. On the contrary, removal of excessive water from the organism and edema
•1 ilmlion are observed. During the terminal period edema develops. Edema is more
1 ii mictcristic of chronic incomplete starvation.
HYPOHYDRATION (DEHYDRATION)
Hypohydration (dehydration, hypohydria, exicosis) is a negative water hal
Mine.
P . I ll I ( ir n tT H l Г и 1 ||о р ||> л Ы » К у

Causes

Hypohydration develops when water loss exceeds its intake by the organism
It may develop in water intake limitation (water starvation, dysphagia, esophagc
atresia, comatose state, etc.). An increased water loss (diarrhea, vomiting, blood
loss, loss of fluid with exudate in bum, etc.) has the same effect. A combination о
these conditions may take place.
In dehydration the extracellular fluid and sodium ions are lost first. In the end
cells may lose potassium and the intracellular fluid.

Types

Isoosmolar hypohydration occurs in proportional loss of fluids and electrolyte

predominantly in the extracellular sector. Usually this condition arises immedialel
after acute blood loss. But it is quickly changed and substituted by hypoosniol
normovolemia due to compensatory mechanisms (immediate retention of water)
Hypoosmolar hypohydration develops due to loss of fluid enriched by elec
trolytes. This situation arises in pathology of the kidneys (increased filtration an
decreased electrolyte reabsorption), digestive tract (uncontrollable vomiting, dial
rhea), adrenal gland insufficiency (decreased production of aldosterone). Some «
these conditions are accompanied by polyuria (increased diuresis) and hypoosmola
hypohydration.
Polyuria can lead to extracellular hypoosmolar hypohydration. In case of a sc
vere form of hypoosmolar hypohydration water moves into the intracellular sect»
causing intracellular edema development.
Hyperosmolar hypohydration develops due to loss of fluid poor in electrolytes I
may arise due to polyuria (A D H deficit), diarrhea, profuse sweating, hyperventila
tion, vomiting.
Special attention should be paid to DM as one of the causes of this patholo»
Under the conditions of hypoinsulinism osmotic polyuria develops but the lev
of blood glucose remains high. Osmotic pressure increase in the extracellular tin
involves the movement of water from cells into the extracellular sector. If the can
ative factor keeps on acting, the organism loses fluid. It results in the developme
of total hypohydration of the organism. Increased osmotic pressure of the extraccl
lular fluid and cell dehydration cause thirst, protein lysis, fever, loss of conscion
ness, hyperosmolar diabetic coma. These disorders are based on hypoxia connecw
with hypovolemia and arterial hypotension.

Consequences

Dehydration has severe consequences connected with circulating blood voltn

decrease (hypovolemia) and blood viscosity increase that may cause severe disord
of blood microcirculation. Collapse may eventuate
Disorders of blood circulation result in (issue hypoxia development. The cel
tral nervous system suffers first of all. Il declares ilscll through loss of consciousne
 Chapter IX. Pathology of Walcr ami klcctrulylt- It.il.imc

IihIIih millions, and coma. The functions of the nervous centers and respiratory
tliMlmi become disturbed. Body temperature rises.
A marked decrease of arterial pressure may be accompanied by impairment of
liliiiiiion in the nephrons, oliguria (decreased diuresis), hyperazotemia and non
Iv-pn itory acidosis.
I hsorders of microcirculation, hemoconcentration, blood viscosity increase
m i l i.i m s result in the tissue form of hypoxia. Hypoxia combined with tissue dchy

ih ниш leads to dismetabolism: protein lysis and development of hyperazotemia (ai

ih. ■\|K*nse of ammonium because of kidney dysfunction), urea hyperproduclion
Iklilncy dysfunction). Acidosis (due to sodium and bicarbonates loss) or alkalosis
(ii.i. io potassium and chlorine loss) occur.
( ompensatory reactions may arise in response. So, hypovolemia and renal
l-l... I llow reduction promote hyperproduction of vasopressin and aldosterone. Wa
Ц i иnd sodium reabsorption in the nephron tubules intensifies under the influence
ui ihcsc hormones.

ELERCTOLYTE IMBALANCE

I Icctrolyte imbalance is associated with water imbalance. Sodium (N a ') and

feii.i.sium (K +) have a special value. They are the most potent osmotic ions. I hey
м.\ mi important role in water balance. There are special receptors (osmorecep
||hi ) to check their concentration and a special hormone with the same role (aldo
■цини* which is a mineralocorticoid).
A peculiarity of sodium and potassium ions functioning consists in performing
И* •important roles. Together with participation in osmotic pressure regulation they
pail in membrane potential and excitability provision. Potassium is the main
It......Iltilar ion, and sodium — the main extracellular one. Analyzing electrolyte
Im iI m I nice in pathology one should keep in mind not only electrolyte concentra
1Г ■" m the blood, but also their displacement in the direction from the extracellular
•p... . lo cells and backwards.
Normally depolarization of the muscle cell membrane is triggered on excita-
M 1 1>\ .1 voltage-gated Na+channel that causes the opening of a voltage-gated Ca-'
liiiniirl and a Ca2+channel of the sarcoplasmic reticulum. As a result, intracellular

I и is increased, mediating muscular contraction. Repolarization is achieved by

I 'L l • m illion of the Na+channels, by Cl* influx, and K + efflux. This causes inactive

pun >il ihe Ca2+channels so that the intracellular Ca2+concentration again falls and
||h muscle relaxes.
\n increase of Na+concentration in the blood causes predisposition to edema
M.i i niry into myocytes increases their tone (aldosterone easily provides it). Thus,
■мы. i llular retention of N a+ predisposes to arterial blood pressure increase. I lu*
h i m . . llular position of K + relaxes myocytes, ensures their rest, decreases their ex
Kji.iinlily threshold and prevents blood pressure increase. It is not easy to provide
Ии мши entry into a cell (due to heavy density gradient). The vagus nerve, atn.il

E Ittlmelic factor and renal prostaglandins promote it. Potassium loss from myocytes
ih. blood (hyiH'ikalemia) leads to disorders of myocardial excitability (cardiac
I ’a i l I (it-m-ral Pathophysiology

arrhythmia). Hypokalemia resulting in muscic weakness occurs in prolonged use ol

mineralocorticoids.
Analyzing Ca2+ ion imbalance in pathology one should keep in mind not only
( a ion concentration in the blood, but also their displacement into cells and
backwards and also displacement between intracellular compartments (cytoplasm,
mitochondria, cytoplasmatic reticulum). Ca2+ion transport is active and is provided
with the aid of Ca2+-transport systems (Ca2+-pumps of the plasma membranes and
endoplasmic reticulum, Na+-Ca2+ exchange system, Ca2+-accumulation system ol
mitochondria). In A TP deficit, Na+-K+-pump disorders and decrease of the gradi
enl of Na* ion concentration on both sides of the membrane the release of C a”
from the cellular cytoplasm is hampered and Ca2+ ions remain in it. It leads to
myofibril contractions and loss of their ability to relax. Retention of Ca2+ and Na
h i myocytes makes the vascular wall sensitive to all vasoconstrictive influences (cat

ccholamines, vasopressin, angiotensin). Clinically it results in the loss of the vessel

wall’s ability to dilate and predisposes to arterial blood pressure increase (p. 374),
cardiac insufficiency, arrhythmia. Impairment of the Ca2+-accumulation function of
the mitochondria results in uncoupling of oxidation and phosphorylation and disoi
dcrs of oxidative phosphorylation. Stable increase of Ca2+ ion concentration in the
cytoplasm leads to phospholipase A activation with formation of prostaglandins and
leukotrienes. Steadily contracting myofibrils are destroyed by proteolytic enzymes,
which arc activated by Ca2+ excess. Calcic damage of cells takes place. Especially
и refers to contractile cells - myocardium and smooth muscles of resistance artct
ies (il will be discussed later while studying myocardial hypertrophy (p. 344) and
arterial hypertension (p. 380). So, retention of Ca2+ ions in the cellular cytoplasm
is an important mechanism of cell damage and death. Cytosolic concentration ol
Ca2' are important in apoptosis. The most modem medicines used to treat arterial
hypertension and cardiac arrhythmia are Ca2+-channel blockers.
Additional information about electrolyte imbalance is given in table 7.

lahlc 7
Electrolyte Imbalance

llcctrolyte Excess Deficit

Sodium Hypernatremia > 147 mEq/1. Cell
shrinking may cause CNS irritabi­
lity, tachycardia, dry and flushed
skin, arterial hypertension, thirst,
elevated temperature, weight loss,
oliguria, anuria
Potassium Hyperkalemia > 5.5 mEq/l. Im­
pressed conductivity in the heart,
muscle cramps, paraslhesia, nausea,
diarrhea, metabolic acidosis
Hyponatremia < 135 mEq/l.
Cell swelling may cause cerebral
edema, polyuria, headache, siii|>ui
coma, peripheral edema, absence
of thirst, decreased body tempera
lure, tachycardia, arterial hypotcn
sion, nausea, vomiting
Hypokalemia < 3.5 mEq/l.
( uidiac irritability, dysrhyihnua,
voimliiiK, paralytic ileus, (hirst,
uii'labollc alkalosis, inability to
i out «*iilrule urine
 Chapter IX. Pathology of Water anil Klectrolyle lliilanci-

/w/'/с 7continued

I lectrolyte Excess Deficit

i .lU ium Hypercalcemia > 12 mg/dl. De­
creased neuromuscular excitability,
muscle weakness, CNS depression,
stupor, coma, increased risk of bone
fracture, vomiting, renal calculi
I'husphate Hyperphosphatemia > 4.5 mg/dl.
(See hypokalemia)
Magnesium Hypermagnesemia > 2.5 mEq/l.
Anorexia, muscle weakness, tremor,
seizers, coma, anemia, bleeding,
leukocyte alteration
Hypocalcemia < 8.5 mg/dl. In­
creased neuromuscular excitability,
skeletal muscle cramps, tetany,
laryngospasm, asphyxia, death
Hypophosphatemia < 2 mg/dl.
Skeletal muscle depression, muscle
weakness, arterial hypotension,
bradycardia, respiratory depression
Hypomagnesemia < 1.5 mEq/l.
Hypocalcemia and hypokalemia,
neuromuscular irritability, tetany,
convulsions, tachycardia, arterial
hypertension

Questions for Self-Control

I In what way is water distributed in the organism?

' I xplain the local mechanisms of water balance regulation in tissues.
I Name the local variants of edema.
I What is the role of nervous receptors (which ones exactly) in water balance
regulation in the organism?
'■ What is the role of the adrenal cortex in water balance regulation in the organ­
ism?
<’ What is the role of the hypothalamus in water balance regulation in the organ­
ism?
I What is the role of the kidneys in water balance regulation in the organism?
N What is the role of the heart in water balance regulation in the organism?
'• I xplain the pathogenesis of cardiac edema,
in What is the role of aldosterone in cardiac edema development?
11 What type of edema develops in hepatic pathology?
I 1 What is calciac damage of the cells?

Tests and Tasks for Self-Control

(give correct answers and find mistakes in the statements)

I A 38-year-old patient with a history of hepatitis abused alcohol. Over lime

symptoms of cirrhosis appeared with ascites and edema of the lower extremities
What type of changes in blood composition caused edema development?
A. Hypocholcsterinemia.
li. Hypoglobulinemia.
C. Hypoalhuminemia.
I'nit I (irnrrftl Ги1||11||||уч1о1ок>

I). Hypokalemia.
E. Hypoglycemia.

2. Л girl is 6 years old. After eating an orange she suffered from edemas of the
eyelids, lips and tongue mucosa. Earlier after eating oranges rash and itch ap
peered. What pathogenetic mechanism is the main one in girl edematization?
Л. Decreased oncotic blood pressure.
H. Disorder of lymph drainage.
C. Increased oncotic blood pressure.
I). Increased permeability of the capillaries.
I Increased hydrostatic blood pressure in the capillaries.

l Л patient with third-degree bums had hypoproteinemia and edemas. What is

the basic mechanism of such edemas?
Л. Increase of oncotic blood pressure.
B. Decrease of oncotic blood pressure.
C. Increase of hydrostatic pressure of the venous blood.
I). Decrease of hydrostatic pressure of the arterial blood.
E. Decrease of circulating blood volume.

4. Л person who was stung by bees suffers from edema of the upper extremities
and face. What is the basic pathogenetic mechanism of edema development?
A. Increased permeability of the vessel walls.
B. Increased hydrostatic pressure in the capillaries.
C. Decreased hydrostatic blood pressure.
I). Increased oncotic tissue pressure.
I Decreased oncotic blood pressure.

5 Complete (with water deprivation) nutritional starvation is associated with

generalized edemas. What is the main mechanism of edema development in
such a case?
Л. Decrease of hydrostatic blood pressure.
B. Decrease of oncotic blood pressure.
C. Decrease of osmotic blood pressure.
I). Increased oncotic pressure of the intracellular fluid.
I Increased osmotic pressure of the intracellular fluid.

<i Л patient is ill with pneumosclerosis. Pulmonary hypertension and right veil
tricular heart failure with ascites and edemas have developed. What is the basic
pathogenetic mechanism of edema development?
Л. Increased hydrostatic vein pressure.
B. Increased oncotic tissue pressure.
C. Decreased oncotic blood pressure.
I). Decreased osmotic blood pressure
I Increased permeability of vessels
 Chapter IS. radiology of Water and Klectrolytc Italanee

’ Л dog who was put in a thermostat at a temperature of 40°C showed respiration

rate increase. What kind of water-electrolyte imbalance occurred?
A. Isoosmolar dehydration.
B. Hypoosmolar dehydration.
C. Hyperosmolar dehydration.
D. Positive water balance.
E. Hypoosmolar hyperhydration.

A patient was hospitalized to an infectious diseases hospital with complaints ol

intractable vomiting. What type of water-salt imbalance developed?
A. Hypoosmolar dehydration.
B. Isoosmolar dehydration.
C. Hyperosmolar dehydration.
D. Hypoosmolar hyperhydration.
E. Hyperosmolar hyperhydration.

A patient used mineralocorticoids for a long time. As a result muscle weakness

developed. What has caused the development of such failure?
A. Hyponatremia.
B. Hyperkalemia.
C. Hypernatremia.
D. Hypokalemia.
E. Hypervolemia.

HI A 42-year-old patient has a diagnosis of chronic heart insufficiency. Edemas

of the legs are observed. Proper understanding of cardiac edema pathogenesis
is necessary for the patient’s treatment. One thinks that this edema is a local
one caused by blood congestion in the lower part of the body. Though this
mechanism takes place, it is not the main link of pathogenesis. The leading
pathogenesis link consists in systemic water retention due to neurohumoral
mechanism involvement. What is the order of events in pathogenesis?
1. Heart insufficiency results in cardiac output decrease.
2. Osmoreceptors of the arch of aorta transmit impulses to the hypothala
mus.
3. Liberation of vasopressin (A D H ) from the anterior part of the pituitary
gland.
4. The renal glomerules are the point of vasopressin action.
5. Stimulation of water reabsorption from the primary urine in the tubules
into the blood.
6 . Limitation of diuresis.
7. Retention of water in the blood.
X. Hypovolemia.
9. Redistribution of water into the intercellular space (according to Starling's
law).
 Part 2
SPECIAL (SYSTEMIC) PATHOPHYSIOLOGY

PATHOHYSIOLOGY OF BLOOD SYSTEM

The bl(K)d performs various functions. They are:

transport — transfer of substrates, hormones, electrolytes, cells, fluids, enzymes,
HAS. etc.
Respiratory — transportation of oxygen and C 0 2.
trophic — transfer of nutrients to tissues and removal of metabolic products.
Protective — phagocytosis, bactericidal properties, immune reactions, transportation
ol antibodies and immune lymphocytes.
Hemostatic — maintenance of the liquid state of the blood in norm and its coagula
lion in response to hemorrhage.
The next chapters (19-23) deal with typical pathologies of the blood — volume
pathology, pathology of erythrocytes and leukocytes, and hemostasis pathology.

Chapter 19
BLOOD VOLUME DISORDERS. HEMORRHAGE

GENERAL CHARACTERISTICS OF BLOOD SYSTEM PATHOLOGY

I'he normal state of the blood may be disordered prim arily (due to pathologi
i ill influence on the blood or bone marrow) and secondarily (due to pathological
changes in different organs and systems, which regulate blood functions and sustain
Us morphological, protein, electrolyte and gas homeostasis, e.g. in the lungs, liver,
kidneys, nervous and endocrine systems).
All typical pathological processes can develop in the blood system — inflam
mation and neoplasia of the bone marrow, allergy, hypoxia, dystrophy, typical
sysicmic disorders of metabolism.
Pathologic changes can develop in any part of the blood system — in the he
mopoietic organs (color fig. 28 represents the scheme of normal hemopoiesis), in
tin- blood circulation or deposition in the vessels, and in the organs and tissues, in
which (he blood is destroyed. These parts are tightly interconnected. As a result, a
pathologic process is not, as a rule, strictly isolated. The entire blood system reads
to the pathologic process as a whole.
As to pathophysiological and clinical inanilestalions, they are different depend
iiik on the part of the blood system, which gets primarily disordered. They may In*
localized in the systems of blood production, >In ulillion and destruction as well as
in the whole organism (systemic).
 Chapter 19. ItliNNl Volume Disorders. I l<-inorrha|(<‘

I Msorders in the Blood

Ihese disorders manifest themselves through changes of blood indiccs. These

indices are:
• total blood volume;
• quantity, structure and function of blood cells (erythrocytes, lcukocytcs and
blood platelets in the form of anemia, leukocytosis, leukopenia, leukemia);
• hemostasis indices;
• biochemical indices (content of proteins, electrolytes, metabolites, etc.);
• physical properties of the blood (oncotic, osmotic pressure, viscosity, etc.).
Changes in the blood system are called hematological syndrome. It frequently
•к( oinpanies different diseases (radiation disease was mentioned on p. 27, in ev
•iv inflammatory disease, p. 128, neoplasia, p. 155, myocardial infraction, p. 34(>,
i lomerulonephritis, p. 470, etc.).

Systemic Disorders

Systemic disorders in hematological pathology are:

• disorder of workability;
• hypoxia (circulatory in blood loss and hemic in anemia and hemorrhage);
• immunological reactivity pathology;
• pathology of hemostasis - hemorrhage (p. 325) and thrombophilic (p. 330)
syndromes;
• tissue dystrophy;
• cachexia (in leukemia).

TO TAL BLO O D V O L U M E D IS O R D E R S

Blood volume disorders manifest themselves as hypovolemia and hypervolemia,

«li.it is blood volume decrease or increase in comparison with the norm (norm o­
volemia) constituting 6 - 8 % of body weight or 65—80 ml of blood per 1 kg of body
weight. In their turn, in accordance with hematocrit index, normo-, hypo- and
ii\|H.-rvolemia are subdivided into simple (normocythemic), polycythemic and oligo
. i iliemic ones. It depends on whether there is a normal blood cell-plasma correla
tion (36-52 % of blood volume is formed by blood cells and 48-64 % - by plasma)
■и ihere is a prevalence of cells or plasma; variants are given in fig. 29.
Sim ple hypovolemia (blood volume reduction without hematocrit index chang
1 1 ) arises immediately after acute blood loss and persists until the fluid docs not
<oine from tissues into the blood.
Oligocythemic hypovolemia (blood volume decrease with plasma prevalence) is
i i-rved after acute blood loss till normal blood volume is completely restored by
lissue fluid.
Polycythemic hypovolemia (blood volume reduction due to plasma volume de
i и isc with relative prevalence of erythrocytes) develops in dehydration of the oi
tMiiism (diarrhea, vomiting, increased perspiration and hyperventilation).
I’nil .’ Special (Systemic) l*Mlh»|iliyslnloKv

Sim ple hypervolemia (blood volume in m w r in ».r< ol normal blood cell

plasma correlation) occurs right after transfusion ol .1 large amount ol'blood (undl'i
experimental conditions).
Oligocythemic hypervolemia (blood volume increase al the expense of plasma)
develops in water retention in the organism due to renal disorders or if blood sub
Mitnles are injected.
Polycythem ic hypervolemia is blood volume increase at the expense of an in
creased amount of blood cells. It is observed in hypobaria (atmospheric pressure
leduction) as well as in different diseases connected with oxygen deficiency (head
i nline or emphysema) with compensatory activation of erythropoiesis. Polycythemii
hypervolemia appears in tumorous hyperplasia of the bone marrow and has no de
tense significance (polycythemia rubra and vera, erythremia, leukemia).
Oligocythemic normovolemia occurs in anemia of different types.
Polycythemic normovolemia is observed in transfusion of any amount of red
cells.
HEMORRHAGE

Hemorrhage is a pathological process, which is characterized by a complex ol

pathologic disorders and compensatory reactions as a result of bleeding from ves
sels.
Damage and rupture of .1
blood vessel is an obvious cause ol
hemorrhage.
Hemorrhage syndrome const 1
tutes a group of clinical disorders
having increased bleeding tendency
in common. It was mentioned eai
Her — in radiation disease (p. 28),
as the hereditary sex-linked disease
Normovolemia Hypovolemia Hypervolemia hemophilia (p. 50), in anaphylac­
tic allergy (p. 94) - and will be
.1 simple; b oligocythemic; с — polycythemic
mentioned many times later - us
r I a cause of posthemorrhagic anemia
I Hi hkI cells Plasma (p. 278), in disorder of hemostasia
(p. 325), in liver (p. 446) and kid
Hk Blood volume changes ney (p. 470) pathology.

I IMM.OGY

I liological factors are those, which impair vessel integrity.

Ihe causes of hemorrhage are numerous. They may be exogenous and endo
gcnous.
More often it is vessel rupture due to a mechanical trauma.
I ndogcnous causes include traumas caused l>v diseases that attack Ihe vessel
wall (e g. inflammation, atherosclerosis, iic c io s In, tumor, ulcer, erosive cancer. I.il
 Chapter 19. Hlood Volume Disorders. lleinorrliUKe

i<>pi;in tube rupture in extrauterine pregnancy, etc.). Platelet deficiency and a lack
.•I any clotting factor may cause hemorrhage. Endocrine disturbance may cause
in morrhage as it is in metrorrhagia (uterine bleeding).
Important conditions, which determine the course of hemorrhage, arc:
• size of the damaged vessel;
• volume of blood loss;
• rate of blood escape (speed of bleeding);
• ability of the organism to stop bleeding by thrombosis (coagulative system,
quantity of platelets, etc.);
• localization of hemorrhage;
•whether hemorrhage is external (hemoglobin is lost) or internal (hemoglobin
is reutilized).
The localization of hemorrhage is of critical significance. Even a relatively
small hemorrhage in the brain or pericardial sac may cause death. If the blood
• >apes into the serous cavity, it is called hemothorax, hemopericardium or lictп о р т
i maim. Small hemorrhage into the skin is known as petechia, purpura or ecchymo
tlx Microscopic hemorrhage may be produced by marked blood congestion ihc
phenomenon is called red cell diapedesis (arterial hypertension is worthy of spci ial
mention in this context).
In this chapter hemorrhage is mentioned as blood loss ( bleeding) in connection
with blood volume decrease (hypovolemia).

IV IIIO G EN ESIS

Blood loss pathogenesis consists of two groups of events - pathological changes

and compensatory reactions.

radiological Changes

Pathological changes in bleeding concern not only the blood system but the
whole organism - the cardiovascular and respiratory systems, metabolism, pigment
balance, etc. Pathological changes are:
• decrease of the circulating blood volume (hypovolemia);
• decrease of erythrocyte and hemoglobin content;
• disorder of hemodynamics — decrease of arterial blood pressure, decrease ol
the venous blood entering the heart, decrease of systolic output;
• disorder of microcirculation in tissues;
• deficiency of tissue oxidation and respiratory function of the blood due to
the development of circulatory, hemic and tissue hypoxia;
• disorders of the functions of the vitally important organs (the nervous system
and heart as a result of hypoxia);
• disorders of tissue metabolism;
• acid-base imbalance (non-respiratory metabolic acidosis).
Secondarily blood loss may cause or aggravate arrhythmia, insufficiency of
югопагу blood supply and external respiration, as well as disorders of hemostasis
and renal filtration.
I’utl 2 S |n ‘<'mI (Systemic) I’iilliopliysioloKy

External bleeding causes vital iron loss In <.ts< ol bleeding into a body tis
sue or cavity hemoglobin and iron are reutili/ed In ihe course of this hemoglobin
resorption, an increased amount of bilirubin is formed and may causc transient
laundicc.

( onipensatory Reactions

Compensatory reactions are divided into urgent (immediate) and nonurgeni

(delayed).
I )iflerent physiological systems participate in blood loss compensation. The nei
vous system reacts with the aid of reflexes from volumoreceptors of the arch of aorf.i
and carotid artery, excitation of the sympathetic part of the autonomic (vegetative)
nervous system. The endocrine system participates with the aid of hormones
vasopressin, catecholamines, gluco- and mineralocorticoids. The kidneys react by
the secretion of renin, which after angiotensin formation partially or completely
normalizes blood volume, vessel tonus and other indices of hemodynamics.

Immediate Compensatory Reactions

Immediate compensatory reactions are directed at the renovation of blood

volum e and arterial blood pressure restoring blood supply of the vitally importani
organs (scheme 20). They are:
• spasm of the peripheral blood vessels;
• blood coagulation (thrombosis), which stops hemorrhage;
• rellex acceleration and intensification of cardiac contractions;
• restoration of the circulating blood volume at the expense of blood reserves,
• redistribution of the blood towards increased blood supply of the most im
portant organs (lungs, heart, brain, kidneys) at the expense of decreased
blood circulation in the skin, spleen, muscles and intestines;
• reflex ventilation increase due to acceleration and deepening of respiration
contributing to compensation of oxygen deficiency in the organism;
•erythrocyte quantity restoration at the expense of reserves (in the liver, spleen
and bone marrow);

Acute Blood Loss Scheme 20. Mechanisms ol

Central Blood Circulation
A ilii'iia l gland I lypothalamus

Renin

( кич liolainines
I
Vasopressin Angiolcnsin II
Angiotensin

+ | Constriction of nrtcriolcii
► Opening of'nrtcrio vcnoir. Ik-«I
► Venous c o n s tiu iio n
 Chapter 19. Blood Volume Disorders. Непинiliu^e

• increase of hemoglobin capacity to return oxygen to tissues (activation ol

oxyhemoglobin dissociation);
• decrease of diuresis;
• thirst;
• redistribution of the interstitial fluid in the vessels.

th-tayed Compensatory Reactions

Delayed mechanisms of compensation develop later as:

• increased hemopoiesis;
• restoration of the protein content of the blood (normalized in 8 - 1 0 days
after blood loss due to an increase of protein synthesis in the liver).
On the 5th day young forms of erythrocytes (reticulocytes) appear in the blood
h i sconnected with an increase of the hemopoietic activity of the bone marrow tin
ill i the influence of an increased production of erythropoietins in the kidneys and
(i istric internal Castle’s factor. Reticulocytes, in their turn, contain more enzyme
), I D PG , which is a stimulator of erythropoiesis.
Hemorrhage is divided into acute and chronic.

Acute Hemorrhage

Acute hemorrhage occurs after an injury of a large vessel. In this case the cel
hiliii elements and liquid part of the blood are lost proportionally (simple hypo
vnlcmia).
Acute loss of up to 10 % of blood volume and slow loss of even greater amount
itmy have no grave manifestations. Sudden loss of 25-40 % of the blood is very
iliingcrous. 60 % blood loss is lethal.
I he state of the hemostasis system plays an important role; thus, in its disorder
I... age of even a small vessel may lead to acute blood loss.
In clinical manifestations such changes play a critical role:
• acute disorder of the systemic blood circulation;
• critical decrease of arterial blood pressure;
• decrease of heart filling and systolic output, cardiac insufficiency (decrease
of coronary blood supply);
• development of acute circulatory hypoxia;
• acute renal insufficiency;
• acute posthemorrhagic anemia development;
• hemorrhagic shock may occur if compensation fails and is characterized hy
extreme impairment of all vital functions, loss of consciousness and death il
not treated.
Immediate compensatory reactions mentioned above may save the patient’s
hi- All the reactions are reflex. Hormones (vasopressin, adrenaline) and renin (an
yii iiensin) play an important role.
I ’.нt 2 S p e c i a l ( N v s lc n iic ) r u tl io p liy s io liiK y

II a patient survives, the cell, protein and electrolyte content in the blood is
restored, but up to complete restoration acute anemia lasts with oligocythemia
normovolemia.

Ilemorrhagc (Hypovolemic) Shock

Hemorrhage shock develops in sudden and massive blood loss, when potential
compensatory ability is insufficient for homeostasis normalization. Overstraining’
ol all physiological systems develops, and their activation becomes extreme. It is .1
potentially fatal situation if not properly treated.
In young people 20-40 % (1—2 1) blood loss leads to the development of mod
11 ate shock, loss of more than 40 % (more than 2 1) of the blood — grave shock
Not only the amount but also the rate, intensity and term of blood loss transform
hemorrhage into hemorrhage shock. The initial state of the organism and conconn
taut factors (starvation, overcooling, etc.) play a negative role.
Primary disorders in hemorrhage shock pathogenesis are a decrease of effective
blood volume, arterial pressure, heart filling and systolic output. It causes acute
circulatory hypoxia.
I II hemorrhage shock (as in any other form of shock) compensatory reactions
I.nl to be synchronic, balanced and properly regulated. Then these very reaction.
become additional mechanisms of damage and aggravate the situation. Numeron
vicious circles develop, the process becomes irreversible. The range of defense reac
lions narrows. The specificity of adaptive reactions to causative factors is lost.
I lie suppressed nervous system becomes insensitive to afferent influences from
v, it (receptors. The limbic system avoids regulation and leads to extreme activation

Fig. 30. «Vicious circle» in hy­

povolemic (hemorrhage) slun k
pathogenesis:
1 — i effective volume of circulai
ing blood; 2 — I cardiac output.
3 — acute circulatory Мурома
4 — disorder of central regulation
of hemodynamics and respiration,
5 — release o f hormones, activation
of the sympathoadrenal and hypo
thalamo-pituitary-adrcnal systems
6 —t peripheral vascular resistance.
7 BA S production, «mediator ex
plosion»; 8 — metabolic stress, anil
Inter exhaustion; 9 tissue hy|«i
xia. ID acidosis; 11 clcctmlvte
imbalance; 12 miciocirciilalion
ilisoiilei, I I l) l( nyndrome,
И oiyan ilysltmction
 Chapter 19. Blood Volume Disorders. lleinorrhiiKe

I the sympatho-adrenal and hypothalamo-pituitary-adrenal systems («hormone

\plosion»)- Concentration of most hormones in the blood rises up to a very high
I. \el. Endocrine response becomes too intensive and exhausting for organs.
Hemodynamic disorders, primarily changed by blood loss, get aggravated. Ves
l lose reactivity to regulatory influences, and vasoconstriction becomes too ex
i. usive, generalized and irregular. Disorders of microcirculation and D IC syndrome
must be added.
Concentration of BAS, which are too aggressive, is increased by a hundred
nines. They provide the cardio- and vasodepressive effect. Electrolytes are imba
i meed, especially Ca ion.
All the reasons mentioned above eventuate in severe acidosis and tissue hy­
poxia. A TP production is suppressed.
In some hours, fatal cardiac, respiratory and renal insufficiency develops ag
yi.ivating the situation.
This pathogenesis is an example of a combination of chain branching reactions
mill «vicious circles» (fig. 30). Urgent medical help is required.

Chronic Hemorrhage

Causes of chronic hemorrhage are usually of endogenous origin. They arc

i bleeding stomach or intestinal ulcer, cancer of the stomach or intestine, bron
•Inal hemorrhage with pulmonary tuberculosis, massive menses in women, uterine
lu inorrhages. Chronic blood loss is accompanied by the development of iron deli
•и in massive gastrointestinal bleeding red cell mass is rapidly digested and iron is
«•'utilized. Important pathogenic components in the development of clinical disoi
•Ins in chronic hemorrhage are anemia and hemic hypoxia.
In the pathophysiological and clinical manifestations such events dominate:
• insufficiency of tissue respiration due to the development of hemic and tissue
hypoxia;
• disorders of tissue metabolism;
• acid-base imbalance (non-respiratory acidosis);
• iron deficit;
• bone marrow disorders caused by its chronic suffering from hypoxia;
• development of chronic hyporegenerative anemia (oligocythemic normo
volemia).

BLOOD TRANSFUSION

Blood disorder treatment and bleeding management have traditionally relied on

Hi. iapies involving transfusion of the donor blood and blood products. I'he blood
im sents a riddle, but attempts of its use for treatment remain tempting because ol
...... nber of events it magically effects.
Arguments in favor of hemotransfusion were understood long ago, but only
piolound research of individual characteristics of the blood (types of agglutinino
i" ns and agglutinins) allowed using hemotransfusion in medical practice.
I’urt i S|M4'iul (Systrnm) 1’nllioplivsioloK.v

I he transfused foreign blood contains water, blood colls, proteins, carboliy

dratcs, lipids, electrolytes, antibodies and BAS.
I he eflect of the transfused bkxxi depends on the amount, method and rate ol
hemotransfusion.
Mechanisms of transfused blood action are:
• replacement of the blood lost in the course of bleeding, which threatens (In­
patient's life;
• hemostatic effect;
• nourishing action;
• disintoxication effect;
• stimulation of immunological reactivity;
• stimulation of metabolism.
When it is necessary to transfuse blood during bleeding, the transfused blood
irritates vasoreccptors stimulating vascular system tonus and heart activity togetlu-i
with renovation of the circulating blood volume. The respiratory surface of eryth
rocytes is restored.
I he hemostatic effect is provided due to entering of blood coagulation factor,
and platelets. This effect is most evident in transfusion of fresh blood (used not latei
than after 1—3 days of preservation).
In case of intoxication (poisons or bacterial toxins), the transfused blood pro
vulcs the effect of disintoxication and stimulates urine production.
().(). Bohomolets studied the stimulation of immunological reactivity by lie
motransfusion. Apart from bringing globulins and antibodies, the transfused blood
stimulates functioning of the bone marrow and lymph glands, which participate in
immune correction of the organism.
Transfused blood has a trophic effect due to nourishing substances — proteins,
carbohydrates and lipids.
Intensification of metabolism and oxidative processes also ensue.
Mismatch hemotransfusion causes acute renal insufficiency due to blocking ol
the glomerular filter by agglutinated erythrocytes.

Questions for Self-Control

I What functions does the blood perform?

2. What varieties of total blood volume changes do you know?
< What conditions play an important role in determining the course of hemor
rhage?
•1 (iive the characteristics of urgent compensatory reactions in acute hemor
rhage.
S. (iive the characteristics of delayed compensatory reactions in acute hcmoi
rhage.
(i. ( iive the characteristics of hemorrhagic shock pathogenesis as a vicious circle
7. Wlial arc the mechanisms of transfused blood action?
К Why «lid ().() Bohomolets offer to use licmolniiisluslon in medical practice'’
 Chapter И. I f lo o d V o lu m e D i s o r d e r s . I le in o rrliu K * '

Tests and Tasks for Self-Control

(give correct answers)

A healthy driver had acute massive bleeding as a result of a car crash. In hall
an hour he was hospitalized in the state of posthemorrhagic shock. What is the
slate of his blood volume?
A. Oligocythemic normovolemia.
B. Oligocythemic hypovolemia.
C. Simple hypovolemia.
D. Polycythemic hypovolemia.
E. Oligocythemic hypervolemia

A healthy driver had acute massive bleeding as a result of a car crash but was
hospitalized only in a day. What is the state of his blood volume?
A. Oligocythemic normovolemia.
B. Oligocythemic hypovolemia.
C. Simple hypovolemia.
D. Polycythemic hypovolemia.
E. Oligocythemic hypervolemia.

Fig. 31. «Vicious circle» in the

pathogenesis of tissue hypoxia
in hypovolemic (hemorrhage)
shock. Signs are the same as in
fig. 30

1 I Ise fig. 30, which reflects hemorrhage (hypovolemic) shock pathogenesis as a

vicious circle, and analyze a part of this scheme, represented in fig. 31, which
shows the pathogenesis of histic hypoxia in it.

i I Ise fig. 30 and 31 and compile the pathogenesis of a disorder of

a) nervous activity and
h) myocardium.
( huptor 20
PATHOLOGY OF ERYTHROCYTES. ANEMIA

Го master the material of this chapter one should know the physiological
histological and biochemical aspects of the structure and function of erythrocytes
and bone marrow, types of erythropoiesis (adult normoblastic (erythroblastic) and
embryonal megaloblastic), hemopoietic factors (the role of renal erythropoietin,
iron, vitamin B l2and folic acid), normal indices of the blood.
Pathological changes of erythrocytes may be quantitative and qualitative.

QUANTITATIVE CHANGES OF ERYTHROCYTES

Quantitative indices are the following:

• Quantity of erythrocytes per liter of blood (the norm is 4-5.5 T/l in men anil
3.7-4.7 T/l in women).
• Content of hemoglobin (the norm is 8.4-10.85 mmol/1 or 135—175 g/1 in men
and 7.4-10.3 mmol/1 or 120-160 g/1 in women).
• Color index (the norm is 1 in the range 0.85-1.15).
• Si/.e of erythrocytes (7—8 ц, on average — 7.2 ц).
The changes of erythrocyte quantity are termed erythropenia and erythrocyto\i\
I he changes of the color index are hypochromia and hyperchromia (blood pathology
with a normal color index is called normochromia).
All quantitative changes are divided into absolute and relative.
Absolute and relative changes mean that in a pathological condition any quan
illative indices must be evaluated in connection with other ones.
So, analyzing the content of erythrocytes and hemoglobin in the blood one
should consider changes of the total blood volume. For example, immediately aliei
hlood loss (cells and plasma are lost proportionally), the content of erythrocytes
and hemoglobin in a liter of blood seems normal, which is not so because anemia
develops.
Analyzing the color index one should consider the size (volume) of eryth
rocytes. Only in case of the normal size of erythrocytes (7—8 ц) the color iiule*
rvllccts erythrocyte saturation with hemoglobin. A healthy erythrocyte is saturated
with hemoglobin maximally and this quantity is accepted as 1 (for normal-si/ed
erythrocytes). If erythrocytes are small (5 ц), the color index is less than I even
in case of their normal saturation with hemoglobin. The color index of more than
I indicates an increase (sometimes to a giant size) of erythrocyte volume. Nain
rally, if the color index is more than I in macro- and megalocytes, this does not
indicate higher crythrocytc saturation with hemoglobin, which is, on the contraiv
reduced.
 C'hiiplci ?0. r.ii lioi.\ of KrylhriK'ylf». Aiirinlu

QUALITATIVE (MORPHOLOGICAL) CHANGES OF ERYTHRO CVIES

Morphological changes of erythrocytes are investigated on stained blood smears

!■<>!or fig. 32). They are divided into two groups — regenerative and degenerative

Krucnerative Forms of Erythrocytes

If a patient has a normal type of hemopoiesis (normoblastic, erythroblastic), the

billowing forms of erythrocytes relate to the regenerative ones - reticulocyte (poly-
•hromatophil’) , normoblast and erythroblast. All of them are normal predecessors ol
•Mature erythrocytes (normocytes) and are normally located in the bone marrow. Il
i these forms of erythrocytes that get into the peripheral blood in pathology (reticu
l<к ytes are normally present in the peripheral blood in the content of 0 .2—2 % ).
If a patient has a pathological (megaloblastic) type of hemopoiesis with mega
I", ytes as final products, megaloblasts (cells of pathologic regeneration) are mature
■dl predecessors. Reticulocytes are absent in this type of hemopoiesis.

I »«Ki-nerative Forms of Erythrocytes

In pathological conditions, erythrocytes change their size, form and coloration,

they may also contain pathological inclusions. All these cells are degenerative
..... is of erythrocytes.
A change in size is termed anisocytosis. A normal erythrocyte is called normo-
Mi' and is 7—8 ц in diameter, a microcyte is less than 6.5 ц, a macrocyte is more
Hi,hi X ц, rnegalocyte is a giant erythrocyte sized 10—15 ц and more (the final pro­
duct of megaloblastic hemopoiesis).
A change in form is termed poikilocytosis. Pathological erythrocytes are di-
h’isc - ovalocyte, spherocyte, sickle-shaped, target cell, etc. Some anemias manifest
ilu mselves through appearance of specific pathologic forms of erythrocytes, which
rive as a diagnostic sign.
A change in coloration concerns its intensity and hues. A normal erythrocyte
i normochromic) has a zone of central enlightenment (pallor). It is connected with
ilu normal form of a biconcave disc. The color index equals 1. If an erythrocyte-
.... tains a decreased amount of hemoglobin ( hypochromic erythrocytes, the color
nitlcx is less than 1 ), the zone of central pallor is larger, sometimes only the erytli
им vie membrane is visible ( anulocyte). If an erythrocyte is enlarged (mcgalocytc)
mil us form is changed from a biconcave disc to spherical, the color index exceeds
I uul erythrocyte looks hyperchromic.
I he pathological inclusions in erythrocytes are nucleus remainders because blast
II free themselves from the nuclei not by expulsion but by intracellular destine
linn (karyorrhexis and karyolysis). Jo lly’s bodies, Cabot’s rings and granulosity rclei
In pathological inclusions.
Komanovsky—Giemsa stain is the most commonly used (it is a mixture ol
i f in, which colors the basal substances red, and hematoxylin, which colors acids
Ыне). A normal erythrocyte, which contains nothing but hemoglobin, accepts only
I ’iiiI 1 Special ( S y s l r n i K ') l >ulhopli>sl<>l<>K.V

cosm (nuclcic acids arc absent in mature erythrocytes) II erythrocytes simultanc

ously acccpt eosin and hematoxylin (they look lilac), il means that crythrocytes air
immature and nucleic acids arc present in the cytoplasm. Such erythrocytes .in
called polychmmatophils and are very important for anemia characteristics. For tin
best detection of immature erythrocytes another method of staining is used. It is tin
so called supravital staining with brilliant cresyl blue, which colors all erythrocytes
кгссп and detects RN A (in complex with ribosomes) in young erythrocytes as blue
granules. Such immature erythrocytes got the name reticulocytes, which in fact an
polychromatophil analogs.

ANEMIA

Anemia is an independent disease or a hematological syndrome, which is chai

ucterized by an absolute decrease of the content of hemoglobin and erythrocytes with
morphological changes of erythrocytes.
There are several groups of anemia. All of them have common systemic clinical
manifestations. They are: skin paleness, dyspnea, tachycardia, headache, vertigo and
reduced workability.
I he pathophysiological manifestations of anemia are all signs of hemic hypoxia
and metabolic acidosis.
Ihe hematological manifestations of anemia consist in quantitative and qualita
live changes of erythrocytes. All anemias are characterized by an absolute decrease
ol hemoglobin and morphological changes of erythrocytes. However, each anemia
has hematological peculiarities (for example, erythrocyte content sometimes re
mains normal).
Causes and mechanisms of the development of anemia varieties are different

CLASSIFICATION

A couple of anemia classifications are proposed based on different principles

(table X).
In its turn, every type of anemia has its own classification (see below).
Different anemias have their own etiology and pathogenesis.

POSTHEMORRHAGIC ANEM IA

Posthemorrhagic anemia is a type of anemia that develops as a result of blood

loss (acquired anem ia).
The etiological factors (exogenous and endogenous) of posthemorrhagic anc
ini.i arc those, which cause vessel injury and lead to bleeding. Endogenous reason ,
include tumor and other necrotic processes (atherosclerotic changes, inflammation,
etc.) that destroy vessels (all of them are discussed on p. 2(>X).
The rate of bleeding is a critical condition ol posthemorrhagic anemia develop
nient, which subdivides il into acute and chntnh d elu d in g on ihe amount and rale
ol blood loss.
 _____________ Chapter 20. Pathology of Krylhroiylos. Annuiu

/.!/»/«• S
Classification of Anemia
Principles of Classification Classifications
I linlogy (causes) Traumatic (mechanical destruction of erythro
cytes), toxic, immune
I'.iiticipation of genetic mechanisms Acquired and hereditary
г iihogenesis Posthemorrhagic, hemolytic, dyserythropoietic
I vpc of hemopoiesis Normoblastic (erythroblastic) and megaloblas
tic
M'llity of the bone marrow to regenerate Regenerative, hyporegenerative (hypoplastic),
1 iIns ability is estimated by the quantity
aregenerative (aplastic), hyperregeneralivc
o! n-generative erythrocyte forms)
<olor index Normochromic (0.85—1.15), hypochromic
(< 0.85), hyperchromic (> 1.15)
Si/e of erythrocytes Normocytic (7-8 ц), microcytic (< 7 ц),
macrocytic (> 8 ц), megalocytic ( 1 0 - 1 2 and
more)
1 linical course Acute and chronic

Pathogenesis, clinical picture and hematological indices are different depend

liilt i»n the type of blood loss — acute or chronic.

Vi ute Posthemorrhagic Anemia

Acute posthemorrhagic anemia occurs after acute blood loss in case of Iran
in.is of large blood vessels or inability of the organism to stop bleeding because of
hnnostasis disorder.
Immediately after blood loss and during the first hours the quantitative indices
I (lie peripheral blood are delusively normal because erythrocytes, hemoglobin and
i i i wna are equally reduced (simple hypovolemia, p. 268).
Immediate compensatory reactions directed at the restoration of the total blood
■ilume and arterial blood pressure develop (peripheral blood vessel spasms, resloni
... . of Ihe circulating blood volume due to the reserved blood, decrease of diuresis,
i г p. 270). Then, erythrocyte release from the depots (the liver and spleen) partly
n stores the cellular blood composition.
Alter restoration of the total blood volume (in some hours) a reduction ol
niuhrocyte and hemoglobin concentration is recorded. Delayed mechanisms ol
....ipensation are observed later as increased hemopoiesis. On the 4,h—5"' day alici
i' nic blood loss, proliferation of the erythrocytic stem cells of the bone marrow
т .iv be observed (it is provided by erythropoietin). In this period a microscopic
Mitmination of the cellular composition of the blood shows signs of regeneration
Ilu regenerative forms of erythrocytes (reticulocytes, polychromatophils) appeal
hi the peripheral blood (regenerative anem ia). Their content rellccts the capability
P . i l l 2 S | x i ia l ( S y s lt- i iiit'> l >u lh o |ih > s io lo K v

ol Ihc bone marrow lo regenerate and a possibility ol llit.- patient's recovery. I hr

color index is reduced (hypochromic anem ia) as accclcrulcd regeneration advance*
cell maturation. Acute massive blood loss may lead lo iron deficiency and decreased
hemoglobin synthesis.
rhe degenerative forms of erythrocytes arc usually absent.
In case of extreme blood loss (40 % and more) we speak not about ancinlu
but hemorrhage shock (see pathogenesis in the previous chapter 19, p. 272). Aculi
anemia develops later if a patient gets proper medical care.

( hronic Posthemorrhagic Anemia

Chronic posthemorrhagic anemia develops due to repeated blood loss caused

by a damage of the small blood vessels in some diseases (stomach ulcer, uterine
problems, hemorrhoids, etc.) as well as in hemostasis disorders ( hemorrhage svn
drome, p. 325).
Repeated blood loss is accompanied with iron deficiency in the organism. In
case of hemopoiesis inhibition, such anemia may become hypo- and aregeneratm
with a low content of regenerative erythrocyte forms in the peripheral blood (hy
pun-generative anem ia).

Itlood Picture

I he quantity of erythrocytes and hemoglobin is decreased as well as the colot

Index ( hypochromic anem ia).
Investigation of the blood smear shows the following changes:
• Appearance of regenerative forms of erythrocytes (reticulocytes), which is a dc
lense reaction, but regenerative forms are not as numerous as in case of acute
posthemorrhagic anemia. Single normoblasts may appear.
• Appearance of degenerative forms of erythrocytes — hypochromic erythrocytes,
microcytes with anisocytosis and poikilocytosis.
• rhe ratio of regenerative and degenerative cells content moves in favor of dcgcne
rative ones. The reason lies in the fact that the bone marrow is also affected h\
chronic hypoxia.
H E M O L Y T IC A N EM IA

Hemolysis is erythrocyte destruction inside the organism.

Ilcniolytic anemia is a type of anemia, which develops as a result of erythrocyte
destruction (erytlirodieresis) prevailing over erythropoiesis.
I he systemic clinical manifestations of hemolytic anemia are the same as in
other forms of anemia — skin paleness, dyspnea, tachycardia, headache, vertigo,
reduced workability, an absolute decrease of hemoglobin and erythrocyte content
I here are some disorders, which distinguish hemolytic anemia from other typca
ol anemia and are important diagnostic signs It goes about hemolytic jaundice («Ic
scribed hi detail on p. 453 in chapter 2H -Pathophysiology ol I ivcr*). Ifhemoglo
Inn, which is released into Ihe blood from (Irslnii led erythrocytes, joins haptoglobin
 Chapter 20. PiitholoKy of Erythrocytes. Лмгпна

h« the blood, it does not pass through the renal filter, but transforms into indirect
1'ilirubin in spleen macrophages causing jaundice. In case of massive hemolysis and
i hi oat amount of free hemoglobin in the blood, the latter passes through the renal
hltcr and appears in the urine (hemoglobinuria), which becomes dark.
In case of massive acute hemolysis, body temperature rises (because of II I
pi eduction by activated macrophages). D IC syndrome (p. 332) development is pos
nblc in case of massive production of thromboplastin.

i lussification

Hemolytic anemia has its own classification. According to the participation

nl genetic mechanisms it is divided into acquired and hereditary. According to the
participation of immune mechanisms it is divided into immune and nonimmune. Ac
>aiding to etiological factors it may be m echanical (traum atic), toxic and immune.
According to the localization of erythrocyte destruction, hemolysis is divided
into intravascular (mainly acquired) and intracellular (takes place in spleen mac
•••phages by phagocytosis, mainly genetic).
fach form of hemolytic anemia has its own etiology and pathogenesis.

ACQUIRED HEMOLYTIC ANEMIA

I Oology

litiological factors, which cause erythrocyte destruction, are physical, chemical

imhI biological as well as exogenous and endogenous.
Among physical factors we should mention mechanical injury of erythrocytes,
'Inch occurs after blood vessel and cardiac valve prosthetics. Prolonged marching
•и running on a solid surface (so-called march hemoglobinuria) cause hemolysis as
4 II The latter may develop against the background of erythrocyte predisposition
in destruction. Cold sometimes causes erythrocyte hemolysis (the latter is realized
"till the participation of immune mechanisms).
I he chem ical factors, which cause hemolysis, are called hemolytic poisons (hemo
Iwins). Compounds of arsenic, salts of lead, nitrobenzene, phenylhydrazine, medi
il drugs are among them. Some of them destroy erythrocytes directly (poisoning
In salts of heavy metals), others (medicines) — through immune mechanisms. Il is
mwс hemolytic anemia.
Hiological hemolysins can be of infectious and parasitic origin - hemolytic
Hn ptococcus, anaerobic infection, virus of influenza, malarial plasmodium, Icisli
... niasis. Mushroom, snake and bee poisons cause hemolysis as well as fungi
Immune acquired hemolytic anemia may be induced by transfusing the blood ol
ми incompatible group (sometimes mismatched hemotransfusion does not cause
lirmolytic anemia of the recipient because the donor’s erythrocytes arc hemolysed
in the first place).
Hemolytic anemia may occur due to endogenous reasons. Autoimmune an
lunnlierythrocyte antibodies relate to endogenous factors. Pathology of the liver,
"In -и bile acids enter the blood, results in hemolysis (p. 441). Endogenous loxic
Г,ill 2 S|M'«'iul (Syslcniic) rulliii|ihysiolo|o

products of nitrous metabolism may have the same result. Splenomegaly may Inul
to excessive erythrocyte destruction.
rhe causes of acquired hemolysis may be of genetic origin — somatic mutation
of crythroblasts under the influence of viruses, microorganisms, medicinal prepani
lions with formation of pathologic populations of erythrocytes.

Pathogenesis

There are some mechanisms of acquired hemolysis.

M echanical hemolysis is connected with a direct damage of the erythrocyte
membrane. Oxidative hemolysis is connected with the effect of oxidizers (nitrite ,
arsenic hydride). They produce metabolic and later structural changes in the eryth
rocyte membrane resulting in hemolysis. Many hemolysins (of biological origin)
possess enzymal activity distracting membranous lecithin ( enzymal hemolysis), hn
ти п е-dependant hemolysis is connected with participation of antibodies and com
plcment.
Under the influence of Scheme 21. Disorders Connected with Intravasculai
hemolytic agents pores are Hemolysis
formed in the erythrocyte Hemolysin
membranes. Potassium ions (etiological factor)
and phosphates come out of
i.
cells and sodium ions get in­ Destruction (hemolysis) of erythrocytes
side. Due to electrolyte imba­
lance, water gets into erythro­ Release of free hemoglobin
cytes that become swollen and
spherical. Such spherocytes Hb +
can not go through the inter- haptoglobin
endothclial pores of the splen­
1
ic sinuses and are phagocy- Macrophages ~|— t-rythropoidni |
ti/ed by spleen macrophago­ Kidneys ]
cytes (scheme 21). When the Indirect bilirubin Bone marrow ]
si/e of erythrocytes becomes
larger than normal, hemolysis 4r Hemolvtic Erythropoir*)*
takes place and hemoglobin Hemoglobinuria jaundice stimulation |
comes to the plasma.
In acquired hemolytic anemia hemolysis mainly occurs in the blood (intravu\
cular hemolysis) under the action of hemolysins on the erythrocyte membrane. In
case of a rhesus conflict, hemolysis occurs not only inside the vessels but also in tin'
liver and spleen (intracellular hemolysis).
Products of destroyed erythrocytes stimulate erythropoiesis in the bone mat
row.

Hole of Immune Mechanisms

Пи* role of immune factors in hemolysis t an l»c proven experimentally In

introducing heterogeneous anticrythrocyti» scrum (antibodies) into a healthy ant
 Chapter 20. Pathology of Erythrocytes. Anemia

In cases when antibodies against erythrocytes are found in a patient and the
"inplement content gets lowered, participation of immune reactions in a disease
i beyond doubt. It is an allergy of cytotoxic type (p. 94) or autoimmune aggression
Ip % ). It means that treatment needs to use immunodepressants.
Autoantibodies are formed against body’s own erythrocytes when their antigen
ptopcrties are changed under the influence of microorganisms, viruses, drugs, or
I t result of somatic mutation of immunocytes, when forbidden clones of lym
phocytes appear producing antibodies against normal erythrocytes (in leukemia,
v.temic lupus erythematosus, etc.).
Antibodies against erythrocytes belong to IgG and IgM type. They get con
tm ted with the erythrocyte membrane, and then two mechanisms develop:
I rythrocytes with IgG and IgM on their membrane are phagocytized by mac
tophages of the spleen, liver and bone marrow, which have receptors to these
Immunoglobulins.
IgG and IgM join the complement to the erythrocyte membrane, the formet
causing lysis after its activation (complement-dependent hemolysis).
Cold sometimes causes hemolysis and immune mechanisms participate in tc
ih/ation of this damage. It is connected with the presence of cryoglobulins (im
nmitoglobulins, which change their form under the effect of temperature and react
with body’s own erythrocytes).
Anemia of newborn may result from an immune conflict (rhesus incompati
hlllty) of the mother’s and fetal erythrocyte proteins. Antirhesus agglutinins, which
и1 formed in the organism of a rhesus-negative mother, cause hemolysis of rhesus
pn Hive erythrocytes of the fetus or newborn.

Hole of Drugs

I lie role of drugs in blood cell damage (not only erythrocytes) is a problem. In
pharmacological prescriptions one can see such indications.
Some drugs (quinine, antituberculous medicines, ftivazide) act as oxidizers
пт! directly damage the erythrocyte membrane (this is often underlain by genetic
pn disposition to hemolysis).
I lie role of drugs in the realization of immune mechanisms of hemolysis is
piovtded by the following mechanisms:
• I lie antigen structure of erythrocytes may change under the effect of medicines
uul subsequently antibodies form against erythrocytes.
• Medicines can act as haptens. Binding of medicines with erythrocyte antigens
Ь ids to the formation of the antigen complex, which initiates formation of anti
bodies, which act against body’s own erythrocytes.

blood Picture

Acquired hemolytic anemia is erythroblastic according to the type of hemopoi

91.1 regenerative according to erythropoiesis activation, normo- or hypochromic ac
•Hiding to the color index (or pseudohyperchromic due to absorption of hemoglobin
Г .Ш 2 S |M 4 'U I ( S y s t e m i c ) I ’lilh o p liy s lo lo K .v

on ihc surfacc of erythrocytes). Blood smear ;in;ilvsis t an show cells of physiolonii

regeneration (reticulocytes, some normoblasts), dcgcnerativcly changed erythro
cytes (poikilocytosis, anisocytosis, and fragmented erythrocytes). A great amount
ol normoblasts and even erythroblasts are observed in newborns with hemolytit
disease.
II hemolytic crises are repeated, anemia obtains hyporegenerative or aplastu
character.
HEREDITARY HEMOLYTIC ANEMIA

Genetic predisposition is of great importance in the development of hemolylH

anemias.

Etiology

Etiological factors are mutagens, which damage the genes responsible for crylh
rocyte protein synthesis. If a patient inherits a pathological gene, other physii .il
chemical and biological factors play the role of risk factors, which realize pathologl
cal predisposition.

Pathogenesis

I lie protein composition of erythrocytes includes globin, enzymes, and mem

bi.me proteins (among them spectrin is important).
Depending on the localization of the genetically determined defect, heredit ai\
hemolytic anemia is divided into 3 forms — hemoglobinopathy, enzymopathy mnl
mcmbrunopathy (they were mentioned on p. 48 in chapter 3 «Role of Heredity ami
Constitution in Pathology»).
Hereditary hemolytic anemia is characterized by reduction of osmotic and
mechanical resistance of erythrocytes caused by genetic defects of the membram
structure, enzymes and hemoglobin.
All genetically defective erythrocytes are prematurely destroyed. This form ol
hemolysis occurs in the spleen (extravascular or intracellular hemolysis). The mat
rophage cells of the spleen phagocytize defective erythrocytes and their fragments
I he spleen enlarges in this case (scheme 22, compare mechanisms with those in
inlravascular hemolysis, scheme 2 1 ).

Hemoglobinopathy

Hemoglobinopathy is connected with the synthesis of hemoglobin, which in

abnormal or not characteristic of a given age. A lot of forms of hemoglobinopalln
have been described.
All hemoglobinopathies are divided into a) disorders of the primary Hb shut
turc (replacement of amino acids in a Hb molecule) and b) disorders of the second
ary Hb structure (replacement of a- or |l chains ol Hb). In all cases the properUe*
ol I lb arc impaired and erythrocytes arc destroyed
 Chapter 20. radiology of Krylhroeytos. Анемии

Hemoglobin of healthy Scheme 22. Disorders Connected with Intraeellulai

"hilts has the following Hemolysis
■nurture: HbA, (a ^ ). Fetal
rrythrocytes have fetal hemo-
globin - H bF (a 2y2); its syn-
i Ik’sis begins after the 8,h week
nl embryonal life. Newborn
•rvthrocytes have 70—90 % of
HbF and 10-30 % of HbA,.
Mv the end of the first year of
life and in adults erythrocytes
Hintain 96—98 % of HbA,,
I % of HbAj (<x28 2) and 1 -
/ % of HbF.
As clinical examples, two diseases are mentioned below as hemoglobinopathy
и klo-cell anemia and thalassemia.
Sickle-Cell Anemia. Sickle-cell anemia results from a disorder of the primary
.nocture of hemoglobin molecules, namely, the amino acid composition of the
1 1'bin molecule. HbS is formed when glutamic acid in the p-chain of hemoglobin
1 .ubstituted by valine. In its restored state, Hb precipitates to form crystals and
1 Ruses erythrocyte deformity. HbS molecules are sensitive to deoxygenation. Under
Inpoxic conditions, HbS molecules are polymerized, crystallized, decrease erythro-
■Me plasticity, destroy erythrocytes and give them a shape of a sickle.
Sickle-cell anemia is inherited by incomplete dominance. So, HbS homo/y
(Hites, whose erythrocytes contain only HbS, are ill with a severe form of anemia
II. lerozygotes (their erythrocytes have 22—45 % of HbS and 55—78 % of HbA,)
tiller from mild hemolysis only under hypoxic conditions.
thalassemia is a damage of the secondary structure of hemoglobin molecules,
H.imely the relationship between a-, P-, y- and 6-chains of the globin molecule.
.< ( liain synthesis is disordered in a-thalassemia (P4, y4), synthesis of the (i-chaius
' 1 unpaired in p-thalassemia (a 2y2, a 28 2). There are some other variants — H bll ф ,),
lll’A (a 262), Bart-Hb (P4).

I n:\nwpathy

Enzymopathy is the absence (deficit) of erythrocyte enzymes (enzymes of gly-

1 ulssis, G-6 -PDGase, ATPase, glutathione peroxidase, etc.). Disorders of metabo
Iikiii take place. Metabolic defects predispose to membrane instability and crytliro

1 vie destruction.
I 11 hereditary G-6 -PDGase-deficiency anemia erythrocytes have a reduced
t iniient of restored glutathione (antioxidant). A deficit of the enzyme glutathione
petoxidase, which contains iron, leads to SH-group oxidation, decreased cry thro
. \t. plasticity and membrane damage.
Such erythrocytes are sensitive to oxidizers. These diseases are drug-dcpcndcnt
(medicines with an oxidizing action play a special role). The usage of such medi
Plirt 2 Spccuil (Systemic) Ги1 ||(1 ||||\ч1 о|<>к\

cines as primachin, sulfanilamides, aspirin, phenaluin play ihc role of risk fact oh
and may cause acute intravascular erythrocyte hemolysis

Лlemhrurwpathy

Membranopathy is a genetic defect of erythrocyte membrane proteins. I In

main one is spectrin (due to its contractile properties the erythrocyte membraix
keeps the form of a biconcave disc). If the content of spectrin decreases or 11
polymerization occurs, the erythrocyte cytoskeleton is destroyed. It leads to mem
brane tension decrease and provokes transformation of normal biconcave disks into
pherocytes. Membrane changes predispose erythrocytes to hemolysis. The osniotK
stability of erythrocytes is reduced.
Сienetic deficiency of Ca2+-dependent ATPase and phospholipids in the eryth
rocyte membrane results in increased membrane permeability.
Л clinical example of membranopathy is hereditary microspherocytic hemo
lytic anemia or Minkowski-Chauffard disease. Microspherocytes are visible undo
the microscope.

Itlood Picture

As in other anemias, the content of erythrocytes and hemoglobin is decreased

Proliferation of the erythrocytic stem cells of the bone marrow is activated hut
often crythropoiesis is not effective because the nuclear forms of erythrocytes an
destroyed in the bone marrow. Nevertheless, reticulocytosis, polychromatophilu
and normoblasts may be observed in the peripheral blood. Specific degeneraliv i
forms of erythrocytes are detected — microspherocytes in Minkowski—Chaull ml
disease, sickle-like erythrocytes in corresponding anemia, target cells and erythm
cyles with basophilic granules in thalassemia. These cells are the most important In
diagnostics.
D Y SE R Y T H R O P O IE T IC A N EM IA

Dyserythropoietic anemia is a type of anemia that develops as a result of ervlh

rocyte production (crythropoiesis) disorder.
I his type of anemia may develop as an independent disease (in case of hoi
marrow damage). All typical pathologic processes (inflammation, neoplasia, allcigv
dystrophy, thrombosis) can develop in the bone marrow. It may be an associated
hematological .syndrome in other systemic diseases.

К Oology

I he causes of dyserythropoietic anemia may be exogenous and endogenotii

Myelotoxic anemia may result from diseases of Ihe bone marrow developing midi i
the elfeci of physical, chemical and biological etiological factors, which damage ihi
bone marrow or organs influencing erylhropoiesh
Ionizing radiation is the most potent haimlnl factor lor the bone maim*
Dvseivthiopoiiiii anemia is an inevitable sign ol i.nti.iiion disease. All kind* (
 (l u pi n .’(I I ".I i Inil. ' of Krythrocytcv Ancnila

poisons, including drug abuse, damage the bone marrow and cause anemia. Any
*m’ic pathology in the organism (kidney insufficiency, hepatitis, uremic or hcpatic
•on.i, etc.) is accompanied with formation of toxic products of endogenous origin,
*Inch lead to anemia development. Severe infections and immune causes may be
■Unlogical factors as well. All these situations are accompanied with dyserythropoi
*in anemia as hematologic syndrome.
As to participation of genetic factors, this anemia may be acquired and heredi
birv.

I'xlhogenesis

As to mechanisms of erythropoiesis disorder, dyserythropoietic anemia is di

tiled into the following groups.
Myelotoxic anemia accompanies many diseases — chronic diseases of the kid
ticvs (glomerulonephritis), hypofunction of the pituitary and thyroid glands. In
tlicse and other diseases myelotoxic anemia is an associated syndrome.
Disregulatory anemia is caused by reduced synthesis of erythropoietin or in
I reused synthesis of its inhibitors in the kidneys.
Deficiency anemia arises in deficit of the substances, which are necessary lot
i\ihrocyte production. They are: iron, vitamin B,,, folic acid, amino acids and
pmtcins. Digestive tract diseases often lead to anemia development due to disorders
■■ I hemopoietic factor absorption.
Enzymopathy is a genetically determined impairment of the activity of the en-
>me, which participates in erythropoiesis.
Hypo- and aplastic anemia results from hemopoietic tissue exhaustion in any
«listing chronic disease, which leads to inhibition of hemopoiesis.
Metaplastic anemia develops after replacement of an erythrocytic stem cell of
ilu hone marrow with another tissue, for example, in leukemia.
As to the type of erythropoiesis, dyserythropoietic anemia may be normoblastic
i ■/vihrohlastic) and megaloblastic.
As to clinical course, it may be acute and chronic.
Together with common features, which characterize all types of dyserythro
(miotic anemia, all varieties have their own peculiarities of etiology, pathogenesis.
Hematological and clinical manifestations.

Iron Deficiency Anemia

Iron deficiency anemia is a common type of anemia caused by iron deficiency

in the organism as a result of imbalance between its intake, usage and loss. It is the
.... . frequent type of anemia (80 % ).
Iron is necessary for the formation of hemoglobin, respiratory enzymes con
Mining iron and providing electron transport, catalase and glutathionpcroxida.se in
frvlhrocytes.
Iron reserves are mainly present in the composition of the proteins ferritin (its
depots are in enterocytes and the liver), hemosiderin (in the bone marrow, ш;к
...phagocytes, spleen, Kupffer’s cells) and myoglobin of the skeleton muscles.
I’ ll I 1. S|H4'iitl (Systemic) I’alhopliysioloK)

Etiology

Etiological factors, which cause iron deficiency anemia, are those, which lead
to impaired entering of iron into the organism or disorders of its utilization.
Etiological factors may be exogenous or endogenous, which cause prim ary and
secondary iron deficiency in the organism.
The causes are the following:
• Iron loss in bleeding is the most often cause. It may be a repeated or massive
single blood loss in the uterus, gastrointestinal, renal, pulmonary diseases.
• Impaired entering of iron into the organism occurs in:
• starvation;
• iron deficit in food (if children are fed with cow or goat milk only).
• Impaired iron absorption in digestive tract pathology (hypoacid gastritis,
chronic enteritis) or resection.
• Impaired iron transport (hypotransferrinemia in liver disturbances, genet н
atransferrinemia).
• Disorders of iron utilization from reserves (in infection, intoxication, helmin
thie invasion).
• Disorders of iron deposition (in hepatitis, hepatic cirrhosis).
• Increased needs of the organism for iron and its increased consumption dm
ing:
• pregnancy;
• growth;
• lactation.

Pathogenesis

The main pathogenesis link is insufficient iron for hemoglobin formation. In

its turn, it leads to suppression of the respiratory function of the blood and hemlt
hypoxia development.
Compensatory reactions in the form of iron mobilization from depots and ;u
iivation of its absorption take place, but gradual exhaustion of iron reserves follow»
in chronic diseases.
Anemia develops with the following order of events.
• fhe level of iron in the blood serum gets reduced. Hyposideremia reaches I H
2.7 mcm/1 (instead of 12.5—30.4 mcm/1).
• Ferritin content in the blood decreases to less than 12 mcg/l (normally il к
1 2 - 2 0 0 mcg/l).
• Depiction of iron reserves in the form of hemosiderin in the macrophages of tin
liver and spleen, ferritin content in the liver and enterocytes.
• Production of transferrin is reduced. Transferrin saturation with iron decrease-, i"
less than 20 % (normally it is 30—50 % ). It means a decrease of iron transport I"
the bone marrow.
• Negative iron balance develops.
• Disorders of iron entering into erythrocytes and decreased heme synthesis
• Decreased synthesis of some iron containing en/yincs in erythrocytes (catahisf,
glutathionpcroxidasc) results in increased erythrocyte sensitivity to the hcniolv
/inn clfccl ol oxidizers Ihe erythrocyte lllcllme ieduces to 20 10 days.
 C'liaplci 20. I'ailicilii, » of KryfhriM-yfes. Anemia

Increased erythrocyte hemolysis in the bone marrow and blood.

I rythropoiesis becomes non-effective.
Atrophic, aplastic and dystrophic processes in tissues and organs develop as a
i onsequence of iron-containing enzyme deficit.
Ilem ic and tissue types of hypoxia.
• Atrophic and dystrophic changes in the digestive tract (atrophic glossitis and
gingivitis, dental caries, injury of the esophageal mucosa, atrophic gastritis with
achylia).
• Myocardial dystrophy.
• Alopecia may develop.

Illood Picture

The quantity of hemoglobin is always reduced. The quantity of erythrocytes can

!>
<• lowered or normal, but erythrocytes are always small in size (microcytes) — 5ц
Instead of 7—8 ц ( microcytic anem ia).
The color index is low — 0.6 and less (up to 0.4). Erythrocytes are hypochro­
mic The reason lies in a) Hb synthesis decrease, b) Hb content decrease exceeding
eivthrocyte amount, c) small size of erythrocytes. Hypochromic blood shadows arc
"bscrved in the blood smear. Anisocytosis and poikilocytosis are also observed.
The amount of the regenerative forms of erythrocytes (reticulocytes) depends
пи the regenerative ability of the erythrocytic stem cells of the bone marrow. Their
>|iiantity may be sufficient or decreased.
So, iron deficiency anemia is erythroblastic, hypochromic, regenerative or more
"Псп hypogenerative anemia.

Vitamin B l2and Folate Deficiency Anemia (Megaloblastic, Pernicious)

Vitamin B l2 (cyanocobalamin) and folic acid participate in D N A synthesis and

iHiimal (erythroblastic) hemopoiesis. In their deficit, normal erythropoiesis trails
i'>ims into pathological (megaloblastic). Pernicious (m alignant) Addison—Bienm r's
anemia develops.
B l2 and folate deficiency anemia is a type of anemia, which is connected with
lie orders of nucleic acid synthesis and substitution of erythroblastic hemopoiesis with
i lie megaloblastic one.
I here is enough vitamin B |2 in food, but for its utilization stomach proteins
(internal Castle’s factor, gastromucoprotein, which is secreted by the stomach mu
losa glands) are necessary.
A daily need in vitamin B l2is 3—5 meg, and its depot in the liver is 1000 times
inrgcr, thus, cyanocobalamin reserves in healthy adults are sufficient for approxi
m.itely two years.

I Oology

Ну etiology this anemia may be acquired and hereditary.

Etiological factors, which lead to the development of this anemia, arc the rca
nns for insufficient entering or utilization of the vitamin in the stomach.
Tiiil 2 SjH't wl (Systemic) I'alhoiihysloliiKy

Exogenous vitamin deficit is possible only in t hlldieii arlilicially ted with goal
milk or dry milk mixtures. In adults this anennn develops lor endogenous reason ч
m stomach diseases when gastromucoprotein is not formed.
Deficit of internal Castle’s factor (gastromucoprotein) may be acquired and
inherited. Acquired deficit may result from gastric mucosa damage in case of:
• chronic atrophic gastritis;
• tumor of the stomach;
• destruction of internal Castle’s factor by antibodies against the parietal stom
ach cells or gastromucoprotein;
• autoimmune aggression with antibodies of stimulating type against gastim
receptors of the accessory stomach cells (discussed on p. 91);
• resection of the stomach.
Hereditary defects of internal Castle’s factor formation result from mutations
ol Ihe genes responsible for this protein synthesis by the gastric gland cells. Ii is
inherited as an autosomal recessive trait.
Impaired cyanocobalamin deposition in the liver (vitamin depot) in case «>1 и
diffuse lesion (cirrhosis, hepatitis) as well as increased need for the vitamin (dm me
pregnancy) are also reasons for vitamin deficit.

1'athogencsis
Development of this form of anemia is connected with ineffective erythropoi
esis.
In deficiency of cyanocobalamin (of its coenzyme — methylcobalamin), then*
is no transformation of folic acid into its coenzyme form (tetrahydrofolic acid),
which is necessary for the synthesis of thymidine monophosphate (one of DNA
components). Disorders of D N A synthesis cause disorders of hemopoietic tissm
cell division. Giant cells appear as a result of atypical mitosis. Normal hemopoicsli
(erythroblastic) is replaced by the embryonic one (megaloblastic).
I he final products of this form of hemopoiesis are giant erythrocytes (megalu
cytes). Their lifetime is very short (10-14 days) because of hemolysis.
Regenerative processes in the bone marrow are intensified, but regeneration
t ells are pathological - megaloblasts are produced in a large quantity and appear
in the peripheral hlood.
I eukopoiesis and thrombocytopoiesis are suppressed.
Mitosis disorders are also observed in the cells of the digestive mucosa. Giant
mucous cells appear. Inflammatory and atrophic changes in the digestive mucosa
(Ihe oral cavity, stomach, intestine) are observed as glossitis, stomatitis, esophagi
lis. enteritis. Hydrochloric acid is absent in the stomach (ach ylia). Digestion is
impaired.
As a result of cyanocobalamin lack, methymalonic acid, which is toxic for i Im
nervous cells, is accumulated in the organism. Myclination is disturbed, impulse
conduction is disordered. Signs of nervous tissue degeneration arc present Defi ne
ration ol Ihe posterior and lateral columns ol the spinal cortl develops (lunitulai
myelosis) Ihe cranial and peripheral nerves are allectcd developing multiple nett
rologicul symptoms
 Chapter 20. l’ath»l»Kv of Erythrocytes. Anemia

Without treatment the disease results in death. Therefore this anemia is called
ivnticious (malignant).

Illood Picture

Blood picture is characterize by the following quantitative signs:

• a significant decrease of the amount of erythrocytes (2-3 T/l and less);
• a decrease of hemoglobin content (70—80 g/1 and less);
• an increase of the color index to exceed 1 (1.2—1.4 and more);
• leukopenia (decreased amount of leukocytes);
• thrombocytopenia (decreased amount of thrombocytes).
I'he following morphological disorders of the blood cells (signs of degencra
iiod) are detected in a blood smear:
• Erythrocytes are significantly enlarged (megalocytes with the diameter It)
12 p and more, 20 p has been recorded in some patients).
• Erythrocytes (megalocytes) are hyperchromic, without a zone of central pal
lor due to their large volume and changed form.
• Poikilocytosis, anisocytosis.
• Pathologic inclusions (nucleus remainders) in megalocytes — Jo lly’s bodies
• Cabot’s rings and basophilic granules.
• A large quantity of nuclear forms of erythrocytes (megaloblasts).
• Physiologic regeneration cells (reticulocytes) are absent.
• Leukocytes have a large size and a hypersegmented nucleus (right-side nu­
clear shift in leukoformula is described on p. 301).
So, vitamin B |2 and folate deficiency anemia is megaloblastic and hyperchro
9HIC.
ERYTHROCYTOSIS

frythrocytosis is an increase of erythrocyte content in the blood to more than

i' I/I, of hemoglobin content — to 10.55 mmol/1 (170 g/1) and of packed cell vol-
... . - to more than 0.52.

I liissidcation

According to etiology, erythrocytosis is divided into acquired and Hereditary

In accordance with pathogenesis it is divided into true ( absolute, which is caused
by i iythropoiesis activation in the bone marrow and an increase of circulating
mihrocyte mass) and false — relative and hemoconcentration (results from plasma
•Inmc decrease and thus is not accompanied by an increase of circulating erytli
Им vies mass). Absolute erythrocytosis in its turn is subdivided into prim ary (as an
nil. pendent disease) and secondary ( symptomatic), the latter — into physiological
|compensatory) and pathological.

I Oology

Prim ary absolute erythrocytosis is caused by tumorous transformation of erytli

HmvIic stem cells with intensification of their proliferation independently from
I'.ill 1 S|M4'iul (Systemic) l'u(li<>|ihvsiol<>K>

erythropoietin. It is true polycythemia (erythremia, or Vaquez disease), which is ii

variety of chronic leukemia.
Secondary absolute erythrocytosis (acquired) is caused by an increased prodm
lion of hemopoietic factors. Here are some examples.
• Hypoxic, respiratory, circulatory hypoxia (mountain disease, chronic diseases of
Ihe organs of respiration and blood circulation).
• Local (ischemic) hypoxia of the kidneys (hydronephrosis, stenosis of the renal
arteries) resulting in erythropoietin hyperproduction.
• Overproduction of erythropoietin by some tumors (hypernephroma, liver c.m
cer).
• Neurohumoral regulation disorder with excitation of the sympathetic part of tin
vegetative nervous system.
• Hyperfunction of some endocrine glands, when catecholamines, corticotropin,
thyroid hormones, glucocorticoids, androgens increase the need for oxygen anil
thus contribute to hypoxia development and erythropoietin formation in the knl
neys.
Hereditary absolute erythrocytosis may result from a genetically determined deli
cit of 2,3-diphosphoglycerate (regulator of hemoglobin oxygenation and deoxygeim
lion) in erythrocytes. The affinity of hemoglobin to oxygen increases and its return
to tissues decreases. Tissue hypoxia develops, erythropoietin production increase»,
erythropoiesis activates.
Relative erythrocytosis results from the effect of such factors, which cause:
• organism dehydration and hemoconcentration (increased perspiration, pin
longed vomiting, diarrhea, polycytemic hypovolemia p. 267);
• blood redistribution with polycythemic hypovolemia (shock, burn).

Pathogenesis

Absolute erythrocytosis in hypoxia is physiological and protective (p. 163) Ii

results in intensive erythropoietin synthesis and erythropoiesis activation contribnl
ing to Ihe improvement of tissue supply with oxygen. After stopping the action ol
Ihe etiological factor the quantity of erythrocytes and hemoglobin is normaliml
Absolute erythrocytosis, which is caused by tumorous proliferation of the erytli
ropoietic part of the bone marrow, is pathological and has no protective value. I In
polycythemic hypervolemia results in such pathological changes:
• increased blood viscosity, hemoconcentration and disorders of the rheolnul
cal blood property;
• decrease of the blood flow speed;
• disorder of microcirculation;
• increase of arterial blood pressure;
• hyperemia of the internal organs, skin and mucous membranes;
• impairment of heart function;
• activation of thrombogenesis;
• l)IC syndrome development.
 ______ ___________________________ Chapter 20. 1*а11и>1оц.у of Krytlirocylcs. Anemia

Questions for Self-Control

in what way are quantitative indices analyzed in anemia?

What does hyperchromic anemia mean?
Give 8 classifications of anemia.
Analyze vitamin B 12 and folate deficiency anemia according to all classifica­
tions.
Give a classification of hemolytic anemia.
Explain the immune mechanisms of hemolytic anemia development.
Explain the genetic mechanisms of hemolytic anemia development.
Explain the role of drugs in hemolytic anemia development.
What is erythrocytosis?

Tests and a Task for Self-Control

(give correct answers and find mistakes in the statements)

The scleras and skin of a 20-year-old patient periodically become yellow; the
patient feels sick. Diagnosis: Minkowski—Chauffard disease. What is typical ol
blood investigation in this case?
A. Agranulocytosis.
B. Anulocytosis.
C. Microspherocytosis.
D. Macrocytosis.
E. Thrombocytosis.

A 1.5-year-old child was hospitalized with symptoms of nitrate poisoning: cy­

anosis, dyspnea, convulsions. What form of hemoglobin caused the pathology?
A. Carbohemoglobin.
B. Methemoglobin.
C. Carboxyhemoglobin.
D. Sulfhemoglobin.
E. Oxyhemoglobin.

A 3-year-old child was hospitalized with hemoglobinopathy (sickle-cell anemia)

What acid replaced glutaminic acid in the p-chain of HbS?
A. Arginine.
B. Serine.
C. Tyrosine.
D. Phenylalanine.
E. Valine.

A patient who has arrived from Tunis has a-thalassemia willi erythrocylc
hemolysis and jaundice. Presence of what cells in the blood is typical of this
illness?
A. Target cells.
B. Spheroidal erythrocytes.
C. I’olychromatophilic erythrocytes.
1'inl 2 Sp rcia l (System ic) Ги11ю||||>лК)1оку

I). Normocytes.
E. Reticulocytes.

V A 58-year-old woman complains o f tiredness, sleepiness, dyspnea while walk

ing. Analysis of the blood: erythrocytes — 4 Ю '-’/l, hemoglobin — 92 g/1, the
color index — 0.6, many anulocytes and microcytes. What anemia is it?
A. Thalassemia.
B. Iron deficiency.
C. Hemolytic.
I). Pernicious.
E. Sickle-cell.

(> A patient is ill with iron deficiency anemia. As a consequence there may devc
lop atrophic and dystrophic processes in the digestive tube (glossitis, gingivitis,
caries, esophagitis). What is the cause of such changes associated with this type
of anemia?
A. Decreased activity of glycolysis.
B. Increasing activity of transaminase.
C. Increasing activity of proteases.
I). Decreased activity of iron-containing enzymes.
E. Increasing activity of catalase.

7. A 40-year-old man was given a diagnosis of sickle-cell anemia. What is ihc

mechanism of erythrocyte amount decrease in the blood?
A. Intracellular hemolysis.
B. Intravascular hemolysis.
C. Bleeding.
D. Inhibition of erythropoiesis.
E. Disturbance of D N A synthesis.

8. A clinical observation of a 50-year-old man showed a decreased amount <»l

erythrocytes in the blood and an increased level of free hemoglobin in tli.
blood plasma (hemoglobinemia). The color index is 0.85. What kind of ancmi.i
is most probable in this case?
A. Chronic posthemorrhagic.
B. Acquired hemolytic.
C. Acute posthemorrhagic.
I). Hypoplastic.
E. Metaplastic.

') A patient with chronic diffuse glomerulonephritis suffers from anemia. W lut r.
the pathogenesis of this anemia?
A. Presence of antibodies against peripheral hlood cells.
H. Iron deficiency.
C. Deficiency of internal Castle’s liictoi
D Hemolysis of erythrocytes.
I Dei teased erythropoietin production
 Chapter 20. P;ithol<»K> <>Г Krylhrocyles. Липши

10 . Degenerative and regenerative forms of erythrocytes were found in the periphc

ral blood of a patient with toxic hemolytic anemia. What cells are the regencra
tive forms?
A. Spherocytes.
B. Microcytes.
C. Reticulocytes.
D. Poikilocytes.
E. Hyperchromic erythrocytes.

11. The erythrocytes of a patient with hypochromic anemia contain 45 % HbS and
55 % HbA,. What form of anemia is it?
A. Microspherocytic.
B. a-Thalassemia.
C. Addison—Biermer’s disease.
D. GIucose-6 -phosphate dehydrogenase deficiency.
E. Sickle-cell.

I.’ A 36-year-old patient is ill with a respiratory viral infection. He was treated
with sulphanilamide drugs. Later hyporegenerative normochromic anemia, leu
kopenia, thrombocytopenia were found. In the bone marrow the amount ol
megakaryocytes is decreased. What anemia is it?
A. Posthemorrhagic.
B. Hemolytic.
C. Hypoplastic.
D. Vitamin B 12 and folate deficiency.
E. Iron deficiency.

11 Microcythemia and poikilocytosis were found in the patient’s blood smear. O f

what anemia are these changes characteristic?
A. Microspherocytic.
B. Vitamin B 12 and folate deficiency.
C. Hypoplastic.
D. Sickle-cell anemia.
E. Iron deficiency.

11 A patient had stomach resection performed. Later vitamin B ,2 deficiency ane

mia developed. What color index is characteristic of this anemia?
A. 0.4.
B. 0.5.
C. 0.8.
D. 1.0.
E. 1.4.

I i A woman complains of headache, giddiness, and dyspnea caused by physical

load. During the last 3 years extensive menstrual bleedings were marked. Visual
inspection findings: the patient has a normal body type, the skin is pale and
dry. Analysis of the blood: hemoglobin - 90 g/1, erythrocytes 3.7 10 'y i, the
I’art 1 . Special (Systemic) I’afhuphysioluRy

color index — 0.7, S S E — 20 mm/h, hypochroinia ol crylhrocytes, anisocytosis,

poikilocytosis. What type of anemia is it?
A. Megaloblastic.
B. Hemolytic.
C. Acute posthemorrhagic.
D. Vitamin B 12 and folate deficiency.
E. Chronic posthemorrhagic.

16. A woman is 6 months pregnant. The amount of erythrocytes and hemoglobin is

reduced, the color index is 1.4, there are megalocytes, megaloblasts. What typl
of anemia is it?
A. Iron deficiency.
B. Vitamin B 12 and folate deficiency.
C. Myelotoxic.
D. Aplastic.
E. Metaplastic.

17. A 34-year-old woman is ill with hereditary hemolytic microspherocytic aneniu

(Minkowski-Chauffard disease). What is the cause of erythrocyte hemolysis ’
A. Enzymopathy.
B. Endogenic intoxication.
C. Hemoglobinopathy.
D. Autoimmune process.
E. Membranopathy.

18. A 7-year-old boy has spontaneous hemorrhages. The hemoglobin blood cod
tent is 80 g/1. A diagnosis of chronic posthemorrhagic anemia was put con
nected with hemophilia (biochemical blood investigation showed antihemo
philic globulin deficit). A physician is deciding whether anemia is regeneral m
or not. Blood smear investigation showed a deficit of the regenerative forms n(
erythrocytes and a lot of degenerative ones.
Degenerative forms o f erythrocytes are:
1. Polychromatophils.
2. Poikilocytes.
3. Ovalocytes.
4. Target cells.
5. Macrocytes.
6 . Sickle-like cells.
Regenerative forms are:
7. Hypochromic erythrocytes.
8. Hyperchromic erythrocytes.
9. Reticulocytes
10. Sphcrocytcs.
11. Microcytes.
12. Anisocytosis.
1.3. Mcgalocytcs.
( hup te r 21
PATHOLOGY OF LEUKOCYTES. LEUKOCYTOSIS AND
11 UKOPENIA

I here are five forms of leukocytes — granulocytes (neutrophils, eosinophils, ha

nphiles) and agranulocytes (lymphocytes and monocytes). Formation of leukocytes
ilcukopoiesis) is accomplished in the bone marrow and lymph nodes.
All immature granulocytes (myeloblasts, promyelocytes, myelocytes, metamy
Hocytes, band cells) are located in the bone marrow.
All mature leukocytes are divided into three pools.
The majority of mature leukocytes are located in tissues. This amount cannot
Ik1 calculated. They perform their functions in tissues.
A small quantity of leukocytes is located in the blood. In their turn, these leu
k'K ytes are redistributed into two pools. H alf of them are located near the vascular
.ill ( m arginal pool). They get into the circulating pool after food intake, muscle or
I'liysical overload and nervous excitement (under catecholamine influence) and also
under pathological conditions.
Mature leukocytes are partially located in the peripheral blood, and partially in
Ihc bone marrow as a reserve.
The role of leukocytes in pathology was discussed many times in the previous
■li.ipters. Their function is connected with participation in immunological reactivity
••id pathological processes connected with it (immunodepression, allergy, inflam
million and fever). Its function consists in phagocytosis, formation of immune
itiiihodies and BAS as well as in BAS neutralization.
Neutrophils (microphages) are the main participants in phagocytosis (p. 69).
Ilieir participation in inflammation (p. 125) was described in chapter 8 «Inflam
’H.it ion*. Monocytes are macrophages. Basophiles (mast cells) are the richest source
I HAS (p. 71). Eosinophils contain BAS inhibitors; their participation in allergy
ingether with basophiles (mast cells) was described in chapter 6 «Allergy» (P- 93).
Participation of B- and T-lymphocytes in immunological reactions was described
m chapter 5 «Immunological Reactivity and Its Pathology» (p. 78). The role ol
liiikocytes in secondary pyrogens production was discussed on p. 132 (chapter 9
l ever»). Leukocytes as the cells of inflammation and a source of mediators of
inflammation were represented in tables 4 and 5 (pp. 122. 124).
The proportion between different types ol leukocvies in Ihe peripheral blood
i . called leukocyte form ula (it is obtained by examining a stained blood smear, ex
pirssed in per cent per 10 0 - 2 0 0 cells).
Pathologic changes of leukocytes manifest i I h ih .<Iv ■ thniupli disorders of their
< •нination in the hemopoietic tissue, quantitative ami ipialiiaiivr disorders. Ihese
i hanges occur as a result of a primary' damage ollrukm \i< in ilx 1 к niopoiclic tis
mi<’ and circulating blood under the influence ol ih llrii nl |щшшг I n tois Second
ntv changes of leukocytes are usually a protective . ....... i> pun i<* pathologic
processes in the whole organism.
r.llt i S|H4'lnl (S)slrilllt ) Г.||||1>|||пМ1>|<>ц«

L E U K O I'O IK M S IM SO KIH l<

I here are dilTcrentiated Ihe following 1еик«>р«»1сн1к disturbances:

• increased or decreased leukocyte production mi the hemopoietic tissue;
• impaired leukocyte maturation in the hemopoietic organs;
• production of pathologically changed leukocytes.
Leukopoiesis disorders may be p artial (concern a certain lineage of hemopoi
otic tissue) and total (concern all of them).

Etiology

Etiological factors of such disturbances are exogenous and endogenous. Kiev

arc:
• physical (ionizing radiation, ultraviolet rays);
•chemical (stimulators and inhibitors of cell division);
• biological (bacteria, viruses and protozoa);
• endogenous:
•• genetic defects of leukocyte formation and differentiation;
•• hormonal dysregulation of leukopoiesis;
•• immune factors.

Pathogenesis

Hractive hyperplasia o f the leukopoietic tissue and activation o f leukopoie\i\ \

proliferation of the leukopoietin-sensitive cells of the bone marrow, which result
in leukocytosis. It can be caused by increased production of humoral activatoi
(colony-stimulating factor — C SF, interleukins) or decreased production of then
inhibitors (chalons, prostaglandins, lactoferrin and isoferritin). Infection is the nm
potent stimulator of leukopoiesis.
Reactive activation of leukopoiesis is more often partial. The type of proltli i
.ited leukocytes depends on the etiological factor. Bacterial endotoxins stimul i!
proliferation and differentiation of neutrophilic granulocyte precursors. Eosinophl
precursors get proliferated in response to immune complexes and helminthcs. An
tigens stimulate proliferation of lymphocytes.
Tumorous hyperplasia o f the leukopoietic tissue and neoplastic increase o f teukn
poiesis occur under the influence of cancerogens, which cause mutation of the .......
ies|K>nsible lor multiplication and differentiation of class I I —IV cells. It is obseiu •!
in leukemia (see chapter 2 2 ).
Depression o f leukopoiesis may be partial and total and is caused by:
• ionizing radiation;
• generalized affection of the leukopoietic tissue (intoxication, severe into»
lions);
• (aiito)immune aggression against leukocytes;
• diseases ol Ihe bone marrow or lymph nodes (inllammation, tumor);
• disturbance ol leukocyte production regulation (deficit ot Icukopoictins),
 Chapter 21. Patlml»K> of leukocytes. leukocytosis and I<ruko|K*nia

•deficit of plastic factors (in protein starvation), cyanocobalamin and folic

acid;
• leplacement of normal leukocytes in the bone marrow with tumor mctasla
tscs and leukemic infiltrations;
•drug abuse, which may damage leukocytes in the hemopoietic organs, (side
cUcds of medicines);
• hereditary disturbances of leukopoiesis (hereditary neutropenia).
Disorders o f leukocyte maturation are caused by differentiation blockade at van
•и I. \els of cell development. Genetic regulation and certain metabolites provide
•Min ■ntiation. Sometimes such a disorder is connected with a decrease of leuko
Hi production. Disorders are connected with:
• mutation;
• exo- and endogenous factors (agents of purulent and viral infections, drug
allergens and intoxication);
• tumorous hyperplasia and leukemoid reaction;
• disorders of the bone marrow barrier and its permeability (influence of t SI
glucocorticoids, interleukins, bacterial toxins), when immature leukocytes
leave the bone marrow.
Production o f pathologic leukocytes may arise as a result of:
• (timorous transformation of the lcukopoietic tissue (in leukemia);
• metabolic disturbances in leukocytes;
• genetically determined structural disturbances (dominant hereditary Pelger
anomaly of granulocytes, deficiency of myeloperoxidase and glucose-6 -
phosphate dehydrogenase - G 6 PD ).
All these leukopoiesis disorders manifest themselves as quantitative or qualita-
II lunges of the peripheral blood.

Q U A N TITA TIV E D IS O R D E R S O F LE U K O C Y T E S

(Quantitative disorders of leukocytes are represented by:

• llie total quantity of leukocytes in a liter of blood;
• changes of leukoformula indices (quantity of every form of leukocytcs).
Within the standard the total quantity of leukocytes equals 4—9 G/1. An increase
III tin- total quantity of leukocytes is called leukocytosis, a decrease - leukopenia.

Leukoformula Analysis

Analyzing the leukoformula (scheme 9 on p. 309), it is necessary to focus alien

Unit пи absolute and relative quantitative changes of various forms of leukocytes
II Ihe total quantity of leukocytes in the peripheral blood is normal, il is |>os
to he oriented with their relative (expressed in per cent) quantity in the leuko
mill,i II the total quantity of leukocytes differs from the normal one (il occurs in
n% diseases), one should know the absolute quantity of every form of leukocytes
Ihe peripheral blood.
Pjirt 1 S|N4'IhI (Systemic) I'hIIi<>|>IivsIoIok.v

lii this connection, absolute and relative changes in I lie i|iiantity of leukocyte»
are distinguished.
I'he correlation between mature and immature forms of leukocytes also miit.i
be analyzed in the leukoformula.
In the Shilling leukocyte formula, all types of cells are located horizontal
depending on their maturity. Immature forms of neutrophils (myelocytes, metamy
elocytes, band neutrophilic granulocytes) are placed in the left part of the formula,
and mature forms (segmented neutrophilic granulocytes) — in the right part. Ли
increase of young neutrophil amount in the peripheral blood is called the left-sul#
nuclear shift o f neutrophils. The prevalence of mature forms (with many nucle.n
segments - 5-6 and more) associated with the absence of young cells is called the
right-side nuclear shift o f neutrophils.
An increase of young leukocyte content in the leukoformula associated with ait
increased amount of leukocytes reflexes leukopoiesis activation caused by reactive
01 tumorous hyperplasia.
Absence of young forms of leukocytes in the leukoformula with a decrease <»l
the total amount of leukocytes (leukopenia) reflexes leukopoiesis inhibition.

lift-Side Nuclear Shift of Neutrophils

I lie appearance of immature neutrophils in the peripheral blood under patho

logical conditions is analyzed.
I here are four types of the left-side nuclear shift.

Regenerative

I'he regenerative left-side nuclear shift is an increase of the amount of younn

neutrophils to the appearance of metamyelocytes in the leukoformula. The total
amount of leukocytes is increased (up to 20 T/l). This nuclear shift reflects rcac
live activation of leukopoiesis. It occurs in inflammation (leukoformula on p. 12S»
and immunological reactivity activation. The value of this nuclear shift is always
positive.

Ilyperregenerative

I'he Ilyperregenerative left-side nuclear shift is an increase of the amount ol

Immature neutrophils in the leukoformula to the appearance of myelocytes, pro
myelocytes and myeloblasts. The total number of leukocytes is increased to motr
than 20 T/l.
II is excessive hyperplasia of the hemopoietic tissue with a disorder of cell
maturation, which cannot be named defense.
It may be of tumorous origin under the influence of cancerogens (in leukemia)
besides, it is also observed in some cases ol acute inllammation (the so-called leu
kcnioid reaction, see below).
 Chapter 21. P a t h o l o g y o f l e u k o c y t e s , l e u k o c y t o s i s a n il l e u k o p e n i a

H.11 •iterative-Degenerative

I lie regenerative-degenerative left-side nuclear shift of neutrophils is observed

ih i long-term course of infection (sepsis), when myelopoiesis potentiality is in
iiiMtcd or exhausted. Leukocyte maturation is impaired. The general content of
li nkocytes may be increased (moderate leukocytosis) or not increased. Leukocytes,
im Ii are produced in the bone marrow, are pathologically changed. Young leuko
i \ti s (band neutrophilic granulocytes and metamyelocytes) are hyperproduced and
ii не signs of degeneration.

tKuvnerative

I he degenerative left-nuclear shift of neutrophils is the appearance of a large

■in unity of band neutrophils (with degenerative signs) in the absence of metainy
flncytes. It testifies to a deep disturbance and inhibition of leukopoiesis. The total
.in unity of neutrophils is reduced. It means that bone marrow functioning is sup
гм cd, and neutrophil maturation after band forms is limited. This nucleai slnlt
nlwiiys has a negative value. It is observed in infectious diseases with significant
Intoxication (typhoid fever) as well as in gangrene or sepsis.

Kiilhl-Side Nuclear Shift of Neutrophils

I he right-side nuclear shift of neutrophils is an increased proportion of mature

м i mailed neutrophils in the leukoformula in comparison with their young precur
••in.
It may be of redistributive origin associated with leukocytosis, when reserved
nulure leukocytes enter the circulating blood from the depot (the bone marrow)
ни! marginal pool. This change is of adaptive nature. It occurs in all types of stress
i uni at the first stage of acute radiation disease).
I he right-side nuclear shift associated with a decrease of the total amount
■ I leukocytes (leukopenia) is much more important. It is of degenerative nature.
>ntmg forms (band neutrophils) are absent in the leukoformula. Mature ncutro
(ilnls are degenerative - their nuclei have many segments ( 6—8 and more). Vari
me. degenerative changes are revealed in the cytoplasm of these hypersegnicnlcd
in iitniphils. It testifies to a deep inhibition of leukopoiesis. The right-side nucleai
«lull is observed in megaloblastic and aplastic anemia, aleukia, radiation disease. In
VMison-Biermer’s anemia, giant polysegmented neutrophils (with 8—12 segments
Jtl it» nicin in diameter) appear in the blood as a result of a critical decrease and
•li under of hemopoiesis and atypical mitosis due to vitamin B l2 deficit (p. 290). I lie
tut til ii mount of leukocytes is decreased.
Г .1 Н S|M '«'iul ( S y s t e m i c ) l* ullio|ilivslol< iK y

Q U A LIT A T IV E C H A N G ES IN I I I K« К Y I KS

Qualitative changes in leukocytes arc mostly degenerative. They manifest them

selves through nucleus and cytoplasm disorders (color lig. 33). They are:
• anisocytosis (change in the size of leukocytes);
• poikilocytosis (change in the form of leukocytes);
• absence of normal granulation;
• pathological inclusions in the cytoplasm (toxic granulosity, large azurophilu
granules, basophilic bundles of cytoplasm);
• vacuolization of the nucleus and cytoplasm;
• swelling of the nucleus;
• karyorrhexis;
• hypo- and hypersegmentation of the nucleus;
• cytolysis.
Degenerative changes are caused by the influence of different pathologic fae
tors (chemical toxins, bacteria, viruses and antibodies) that damage leukocytes in
the hemopoietic organs and blood. Leukocyte metabolism disorders lead to strue
tin a I anomalies.
Production of pathologic leukocytes may arise as a result of neoplastic trails
formation of the leukopoietic tissue in leukemia.
Structural disturbances may be genetically conditioned (e.g. hereditary Pelger
11 net anomaly of granulocytes, when neutrophils have round rod-shaped or two
segment nuclei after maturation).
Degenerative leukocytes are produced in non-effective leukopoiesis and ate
characterized by phagocytic activity reduction and shortened life.

LEU K O C Y T O SIS

I cukocytosis is an increase in the total amount of leukocytes in the peripheml

blood to more than 9 G/1.
Morphological (degenerative) changes of leukocytes may accompany the quail
Illative ones.

I here are several classifications of leukocytosis.

I ’hysiolofiical (after food intake, physical and emotional load, in pregnancy)
.uul patholof>ical (in diseases) — according to its value.
Reactive, redistributive and tumorous in accordance with pathogenesis.
Neutrophilic, eosinophilic, basophilic, lymphocytosis, monocytosis are dislin
guishcd depending on the type of leukocytes being increased.
Ibsolutc and relative (it refers to each form ol leukocytosis).
L ___________________ C hapter 2 1 . P a t h o l o g y o f l e u k o c y t e s , l e u k o c y t o s i s a n il I e u k o p c n i a

I llolugy

I nological factors are exogenous and endogenous as well as physical, chemical

itnd biological.
Ionizing radiation causes redistributive leukocytosis during the first day of ra
illation disease.
Toxic chemicals (of exogenous and more often endogenous origin from a ru
itii'il tissue) cause absolute reactive leukocytosis.
Infection is the most potent activator of leukopoiesis and phagocytosis, which
has a protective value.

I'alhogenesis

I here are the following principal mechanisms of leukocytosis pathogenesis.

• Rcactive activation of leukopoiesis, which is more often partial, resulting in
hyperproduction of a certain type of leukocytes. Leukocytosis is absolute It
is caused by an increased production of humoral activators (colony-siimu
lating factor, etc.). Leukocytosis may be accompanied by suppression nl
leukocyte maturation in the bone marrow and, sometimes, by production ol
pathologic forms.
• Tumorous hyperplasia (neoplasia) of the leukopoietic tissue results in pro
duction of pathologic leukocytes (leukemia).
• Acceleration of leukocyte release from the bone marrow into the blood may
result from an increased permeability of the bone marrow barrier.
• Redistribution of leukocytes from the marginal pool into the circulating one
causes relative leukocytosis.
I Afferent types of leukocytosis have peculiarities in their etiology, pathogenesis
mill мцтПсапсе.

St uim philic Leukocytosis

Relative redistributive neutrophilosis (physiological) occurs after food intake,

iti\mc;i1 work, emotional overstrain (fear, fury). In these cases the total quantity of

1 ■iikocytcs in the peripheral blood increases temporarily without young form ap

n и mce (described above as the right-side nuclear shift of neutrophils). In palho

I n»>\ irlalive redistributive neutrophilosis is observed in the first period of acute

*iihaiion disease in the medullary form (p. 32).
Absolute neutrophilosis proceeds with steady total leukocyte quantity increase
up in 20 Cj /I. The quota of neutrophils in the leukoformula is also increased
\|ц|щ' forms of neutrophils (including metamyelocytes) appear in the peripheral
lil* иnl (the regenerative left-side nuclear shift). Reactive activation of leukopoiesis
... li dies the pathogenesis of this form of leukocytosis. It has an adaptive value in
inflammation (phagocytosis). Stimulation of immunological reactivity occurs.
Ihe causes of neutrophilosis are various. The basic etiological factors, which
ih m- hone marrow functioning, appear infectious (strepto- and siaphylococ
uni lungi). They provoke an increased production of C S I', which stimulates
■inflation and differentiation of neutrophilic granulocyte precursors.
Pttll 1 Special (Stslrimcl Ги11|<1||||>л1о||1К>

I he substances, which arc formed in non Inlet tlous Inllammation, also Minm
late neutrophil production. They arc:
• products of tissue dccay and necrosis (myocardial infarction, malignant in
mor decay, products of decay in chronic myeloleukemia), tissue destnu .....
by physical factors (cold, heat);
• products of crythrocyte hemolysis;
• toxic metabolites in uremia and hepatic coma.

/ osinophilic Leukocytosis

Allergy is the most frequent reason for eosinophilic leukocytosis. Activation "i
cosinophilopoiesis and release of eosinophilic granulocytes from the bone maim*
into the blood are observed in allergic diseases connected with an increased ( I
synthesis by lymphocytes after antigenic stimulation. Mast cells produce the eosum
phil chemotactic factor. It is also connected with increased permeability of the ......
marrow to eosinophils under the influence of histamine and other BAS released tin.
to antigen-antibody reaction.
To understand the importance of eosinophilia one must take into account i
function of eosinophils in allergy. Eosinophils contain histaminase and arylsull.ii .i •
in their granules and neutralize BA S in allergy (leukoformula in allergy is герм
se nled 011 p. 93; increased quota of eosinophils in leukoformula is a diagnostic m»hi
ol allergic component in patient’s disease). The amount of eosinophils is elev.iieil
in helminthic invasion (eosinophils release a protein, which damages the membiim.
of helminths).
Eosinophilia is observed in chronic myeloleukemia.

Hasophilic Leukocytosis

Basophilic Icukocytosis as a separate form of leukocytosis occurs rarely. Ii и

observed in chronic myeloleukemia, ulcerative colitis, after splenectomy and м.
myxedema.

l ymphocytic Leukocytosis

Lymphocytic leukocytosis (lymphocytosis) is caused by the agents of ml

miosis and lues as well as viral infections (infectious mononucleosis, hep.iti
measles, whooping cough). The named forms of lymphocytosis have an adapti
value. Lymphocytosis also occurs in allergy.
In chronic lympholeukemia the amount of lymphocytes is significantIv it
creased but has no protective value.

Monocytosis

Monocytosis develops under the influence of viruses, microorganisms (м м I

streptococcal endocarditis), and prolo/on I lie agents of tuberculosis and sypli
are Ihe reasons for monocytosis as well
 is r i
tr.

8
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ЯOil

a
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00 • 2
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00 10 о
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li 1
oo
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Fig 33. Degenerative changes of leukocytes:
1 - toxic granulosity; 2 - vacuolization of the
nucleus and cytoplasm; 3 - Kniazkov’s bodies;
4 - hypcrsegmcntation of the nucleus; 5 - ani­
socytosis

Fig. 34. Blood picture in acute myeloleukemia

(myeloblasts)
Fig. 35. Blood picture in chronic myeloleukemia:
/ - myeloblast; 2 - promyelocyte; 3 - neutrophilic mye­
locyte; 4 - neutrophilic metamyelocyte; 5 - band-form
neu-trophil; 6 - segmented neutrophil granulocyte; 7 -
eosinophilic myelocyte; 8 - eosinophilic granulocyte; 9 -
baso-philic granulocyte; 10- lymphocyte

Fig <0 MI«nhI piduiv in chioiiu lyinpliolciikcniiii

/ lyinphtK'ylc; 2 laiyi'lyinplHH yti I lymphoblast
 Chapter 21. I’atholoK'V o f leu k o cytes, leu ko cyto sis anil leukopenia*

Monocytosis can develop in noninfectious inflammation, since monocytcs arc

и live phagocytes. The value of monocytosis is positive, since phagocytosis is a
pmti ctive reaction.

14ikemoid Reaction

I eukemoid reaction is an acute increase of immature forms of leukocytes in the

I» iipheral blood. It is observed in patients with instable hemopoiesis in response lo
• iiie infections (sepsis) and acute erythrocyte hemolysis.
Ihe blood picture resembles leukemia but differs from it by etiology, pat ho
..... -is and significance. The cause is often known (it is always infection) contrary
*11 leukemia. The pathogenesis is different as well - it is hyperreactive but not neo
1 11.tic hyperplasia of the leukopoietic tissue.
I cukemoid reaction is temporary, reversible and does not turn into leukemia
I here are two types of leukemoid reaction — myeloid and lymphoid depending
нм ihc type of cells, which underwent proliferation.

IUoihI Picture

Hlood picture in leukocytosis is estimated by the total number of leukocytes

ni l leukoformula. It shows whether the quantitative changes of different forms ol
It ukocytes are absolute or relative.
Young forms of neutrophilic leukocytes appear in the peripheral blood - the
... lear shift to the left.
Degenerative changes in leukocytes are registered in the course of blood smear
Investigation.

HlKiilfleance

Ultimately, in most cases leukocytosis has a positive value. It is a sign of

mmated reactivity. Reactive hyperplasia of the leukocytic tissue leads to organ
* hi icsistance increase. The most evident protective role of leukocytosis is seen in
iMllainmation and immune response. Neutrophilic leukocytosis and monocytosis
ii' . parallel participation in phagocytosis. As it has been said, eosinophils play a
i iMii|>ensatory role in allergic reactions. Lymphocytes play a decisive role in im
ките response.
M the same time, under other circumstances, leukocytes may be aggressive
hi.I become a harmful factor. Double and contradictory role of neutrophils in
lull iiumation (factor of secondary alteration) was discussed on p. 122 in chapter
tiiiliiinmation».
Neoplastic hyperplasia of the leukopoietic tissue is always harmful (leukemia).

LE U K O P E N IA

I * ukopcnia is a decrease of the total quantity of leukocytes in the peripheral

hli'iul below 4 G/1.
Pint 2 S|N'i'lul (Systcmlc) I *иIli<ipliуч!<>I»K.V

Leukopenia has been mentioned sevenil imu hi tin- previous chapters. In in

diation disease it is a leading pathogenesis link A decrease of lymphocyte quantity
and functional activity underlies the pathogenesis nl immunodepression and im
munodeficiency.

Types

rhere are several classifications of leukopenia.

Acquired and genetically determined (hereditary) leukopenia is distinguished
depending on the participation of genetic mechanisms.
Neutropenia, eosinopenia, lymphopenia and monocytopenia are distinguished dc
pending on the type of leukocytes being decreased.
Besides, leukopenia may be absolute and relative.

Ktiology

Etiological factors of leukopenia are those of external and internal media

which lead to a decreased formation of leukocytes in the bone marrow and lymph
mules, their increased destruction or redistribution.
Etiological factors are divided into:
• physical (ionizing radiation);
• chemical:
•• poisons, which have a leukodepressive quality;
•• medicines (aspirin, amidopyrine, sulfanilamides, barbiturates, cytostatic*
and glucocorticoid hormonal preparations);
•• vitamin B (2 and folic acid deficiency;
• biological:
•• infectious (severe infections, for example, typhus, viruses of influcn/n,
measles, rickettsia toxin, miliary tuberculosis agent);
•• immune (the effect of antileukocyte antibodies);
•• hormonal (stress, redistributive leukopenia);
•• genetic (mutations).

Pathogenesis

There are some pathogenetic varieties of leukopenia. They are:

I Decreased leukocyte production in the hemopoietic tissue.
2. Increased leukocyte destruction in the blood and hemopoietic tissue.
V Excessive loss of leukocytes.
4. Redistribution of leukocytes in the vessels.
.S. Decelerated leukocyte release from the bone marrow.
decreased production o f Icukocytes is connected with leukopoiesis iinpaiinii nl
under (lie effect of poisons and ionizing radiation, genetic and immune factor, in
Icukopoictin deficit, etc. (mechanisms were discussal in detail at the beginning ol
this chapter).
 Chapter 21. Pathology of I eiikocylt's. I xukoivlosis anil I eiiko|M-niu

Increased destruction o f leukocytes in the blood and hemopoietic tissue can oc

iin in:
• genetic inferiority of leukocytes, which get destroyed prematurely;
• action of immune antileukocyte antibodies, which cause cytolysis or agglu
tination of leukocytes;
• side effects of medicines (drug allergy), which can serve as hapten stimulat
ing antileukocyte antibody formation;
• hypersplenism (increased leukocyte lysis in the spleen macrophages).
ixcessive loss o f leukocytes occurs when much pus is exuded in chronic inflam
itory diseases (in purulent bronchitis, purulent endometritis, purulent processes
in ihc urogenital organs).
Redistribution o f leukocytes in vessels may be a reason for relative leukopenia.
Ii i . observed, for example, in hemotransfusion shock and is characterized by ;in
•lined ratio between the circulating and marginal pools of leukocytes.
accelerated release o f leukocytes from the bone marrow into the blood may lake
pin с in a genetically determined decrease of leukocyte mobility due to membianr
•if In is. It is the so-called syndrome of lazy leukocytes, which move very slowlv
I he named pathogenetic variants refer to all types of leukopenia, which may be
и il and partial, acquired and hereditary. Peculiarities of some of these types must
' .ttlilcd to these general considerations about leukopenia.
Neutropenia develops in the third period of acute radiation disease, in all pc
... I of chronic radiation disease, in the course of severe viral infections (viral
miluenza, infectious mononucleosis, measles, A ID S ), in protein starvation, and as
■iiile effect of drug abuse.
hisinopenia is observed in stress (p. 508), Itsenko—Cushing’s disease, injection
III <oiiicotropin and corticosteroids (cortisone, prednisolone).
I vmphopenia develops form the very beginning of acute radiation disease
ip 'H), in all forms of immunodepression, in hereditary and acquired immuno-
'•In п-псу. Deficit of T-suppressors is the main link in the pathogenesis of allergy
ip NH). Lymphopenia is a side effect of glycocorticoid therapy. It develops in stress
Mini myxedema.
Monocytopenia is observed in all syndromes and diseases connected with mye-
li'i.l .т п cell disorders (radiation disease, severe septic states and agranulocytosis).
I cukopenia is usually combined with functional deficiency of leukocytes.
Ueukia is total leukopenia. It is an aplastic damage of the bone marrow ac
HHiipanied by acute inhibition or complete stop of leukocyte production. The ali
N Hi ii .i i y-toxic form develops if a person eats grains infected with mould. Usually,

vlopenia (aleukia and thrombocytopenia) is observed in such cases.

Mi иifrstations and Significance

I he hematologic manifestations of leukopenia consist in a decrease ol the total

.р. mlily of leukocytes or only of one form of them.
I In- main consequence of leukopenia at the level of the whole organism is
ptfHiusin resistance decrease caused by reduction of phagocytic activity and anti
I'u il 2 S p c t till ( S y s tr iiilc ) Гй1||ор||>л1о1<>ку

body formation. Immunological and inflammatory dcleuse reactions get rediunl

Immunodeficiency is an example of genetically determined reduction of leukoevii
quantity and functional ability.
Such patients suffer from infectious and oncological diseases, especially Hi
hereditary neutropenia and T- and B-lymphocyte deficiency. An example of severe
areactivity is A ID S.
Leukopenia always has a negative value.

Questions for Self-Control

1. Explain the function of every type of leukocytes.

2. Name the types of leukopoiesis disorders.
.V Name the quantitative indices for leukocyte characteristics.
4. (iive a leukoformula scheme.
5. What is absolute and relative quantity of leukocytes in the leukoformula?
(>. Lxplain the significance of absolute and relative quantity measurement nl
leukocytes in the leukoformula.
7. To what cells in the leukoformula does the concept of nuclear shift refer?
S. Name and explain the types of the left-side nuclear shift in the leukoformula
‘J. Explain what the right-side nuclear shift in the leukoformula is.
10. Name degenerative changes in leukocytes.
11 Name the types of leukocytosis.
12. Explain the significance of every type of leukocytosis.
13. What is leukemoid reaction?
14. What are the causes of leukopenia? Give clinical examples.
15. Name the types of leukopenia.
16. What is the significance of leukopenia?

Tests and Task for Self-Control

(give correct answers and find mistakes in the statements)

I A group of nuclear power station workers were delivered to a clinic in au Im h

after a catastrophe. What leukocyte changes are evident?
A. There arc no changes yet.
B. Neutropenia.
C. Lymphocytosis.
D. Absolute leukocytosis.
E. Relative (redistributive) leukocytosis.

2. A 7-year-old child was given a diagnosis of bronchial asthma. What chany<"> of

blood are typical of this disease?
A. Neutrophilic leukocytosis.
H Lymphopenia.
С Losinophilia.
I) Basophilia.
I Anemia
 Neutrophils
Leuko­
Eo­ My­ Lym­
cyte count Baso­ My­ Pro­ Meta­ Seg­ Mono­
sino­ elo­ pho­
(norm philes elo­ myelo­ myelo­ Band men­ cytes
phils cytes cytes
4-9 G/1) blasts cytes cytes ted
Diagnosis

о
о

T
T

С1
Norm, %
1

51-67 20-40

40
OO

Ч O
Norm 06-0 06-0 40- 2040- 800- 160—

•rj 1 о
00 £
^
in 1 mkl 540 6030 3600 720
Pneumonia
Acute tonsillitis
.Appendicitis
Bronchial asthma
Rheumatism
Tuberculosis
| Lues

1
/)
<
Leukemoid reac­
tion
Regenerative
nuclear left shift
Hypenegene-
rathe nuclear left
shift

‘2

i l
* a
v "Si
Chapter 21. I’alholoKy of leukocytcs. leukocytosis anil Lrukopcnla
I ’rnt ) S|M'« litl (S y s ln iilt ) Гя11|ор||уч1о||>кУ

< Л 32-year-old man fell ill with pneumonia Wli.ii elian^es of the blood are lypi< al
of this disease?
Л. Regenerative nuclear shift to the lelt
B. Ilyperregenerative nuclear shift to the left.
C. Degenerative nuclear shift to the left.
E. Nuclear shift to the right.

•I Л 7-year-old child fell ill with acute tonsillitis. There is a significant incie.i •
of leukocyte count in the peripheral blood; young forms of leukocytes have ,ц>
peared (the Ilyperregenerative nuclear shift to the left). It is possible to susp.«t
leukemia. But a doctor decided it was leukemoid reaction. Give the charai t<1
isiics of leukemoid reaction.
1. Leukemoid reaction is an acute increase of immature forms of Icukn
cytes in the peripheral blood.
2. It is observed in patients with instable hemopoiesis in response to ami.
infection.
3. Blood picture resembles leukemia.
4. It differs from leukemia in etiology but not pathogenesis.
5. The cause is often known (it is always infection) contrary to leukemia
6. It is hyperreactive hyperplasia of the leukopoietic tissue.
7. There are two types of leukemoid reaction - myeloid and lymphoid
depending on the type of cells, which underwent proliferation.
8. Leukemoid reaction is temporary and irreversible.
9. It is neoplastic hyperplasia of the leukopoietic tissue.
10. Leukemoid reaction usually turns into leukemia.

5. Draft leukoformulas in % for the cases given in table 9.

< hapter 22
I I UKEMIA

leukemia is a pathology of the hemopoietic tissue of neoplastic nature.

In chapter 10 «Neoplasia» the general laws governing malignant growth as .1
1\pical pathological process were given. This process can develop in any tissue
M the same time, neoplasia has specific features depending on its localization.
• niiscquently, all general considerations concerning neoplasia (definition, etiology,
1' iiliogenesis, manifestations and outcome) relate to leukemia as well. In addition,
1 nU mia, as neoplasia, has its specific features. So, the definition of neoplasia is
unlimited (uncontrolled, independent and endless) increase o f tissue growth, which docs
mil correspond to the normal structure and function o f the organism (p. 142) can In­
i' in red to leukemia as well.
Leukemia belongs to the group of malignant hematopoietic tissue tumors called
hanoblastoses.

C LA SSIFIC A TIO N

( lassification of leukemia is based on such morphological aspects.

• Predominance of specific forms of leukocytes in the leukoformula. Nco
plastic transformation and growth of a single lineage of the bone marrow or
lymphoid tissue (erythroid, myeloid, lymphoid, monocytic, megakaryocytic)
underlies the classification.
• The point of the complete stop of hemopoietic cell differentiation al a cer­
tain intermediate stage, i.e. the level of differentiation.
Leukemia is divided into acute and chronic.
Acute leukemia is subdivided into myeloblastic, lymphoblastic, monohlustic,
....iukuryoblastic, nondifferentiated forms and acute erythromyelosis. The substrate
■I tumor growth is the bone marrow blast cells of the I —IV classes (or precursors ot
bmplwcytes) that proliferate and lose their ability to differentiate. The nondifier
.... . form originates from cells of the II and III classes, which are not identified
...... il к (logically.
( lironic leukemia is divided into myelocytic, lymphocytic, monwytic, mega-
km v<H-ytic and chronic erythromyelosis. Neoplastic transformation occurs in he
... Iioietic cells of the I I —IV classes but they mature up to cells of the V and VI
fliiv.rs, which are determined in the peripheral blood. Chronic lympholcukcmia is
и Ivinphoproliferative process.
I here are also more detailed leukemia classifications based on morphological,
ntm hemical, immunological and moleculogenetic peculiarities of hemoblaslosis.
Mill. Ii may be found in special literature.
I'liit 1 Special (System ic) 1‘athophysioloK.v

КЛОНИЛ'

I tiological factors, which cause leukemia, arc the same as those of neoplasia
All ol them are mutagens (cancerogens). They are divided into physical (ionizing
tadiation), chem ical (cancerogens), biological (DNA- and RNA-containing viruses
and genetic anomalies).

Ionizing Radiation

Ionizing radiation causes radial leukemia. It increases the incidence of IcuKe

mia tit patients, who underwent X-ray or radioactive isotope treatment. Leukemi.t
is .uiioiig the consequences of nuclear weapons usage. There is information about .1
high incidence of leukemia in children exposed to radiation in utero. Radiologist-,
and roentgenologists run a higher risk of falling ill with leukemia.
Ionizing radiation causes radial leukemia in experimental animals.

( hemieal Cancerogens

I he same chemical cancerogens, which cause malignant tumors (p. 144), cause
leukemia as well.
С hemieal cancerogens may cause leukemia in people subjected to occupational
contact with certain substances (benzol, pesticides) or treatment with medicines
having a mutagenic effect (cytostatics, immunodepressants, butadiene, chlorani
phcnicol, cyclophosphamide). Derivatives of tryptophane, tyrosine, and indole in
ducc leukemia under experimental conditions.

Oncogenic Viruses

Under experimental conditions, leukemia is induced by injecting cell-free lil

trates of malignant new growths from a sick animal to a healthy one.
Ihe viruses themselves can induce mutations. The role of oncomavim . .
(p 144) in leukemia development is confirmed by the presence of the enzyme rcvei
tase (reverse transcriptase or RNA-dependent DNA-polymerase) in leukemic cells
In the normal human D N A more than 60 protooncogens, which are homolo
nous to viral oncogens, have been revealed. They are activated under the effect of
different factors and promote leukemia development.
Oncogenic viruses cause leukemia in birds, mice, cats, cattle, monkeys an.I
oihet animals. The vimses can be transmitted through feces, urine, nasal and pint
ryngcal discharge (in visceral lymphomatosis in the chicken spleen).

Role of (ienetic Factors

(ienetic peculiarities of hematopoiesis may also have an etiological role 111

leukemia.
I he most profound proofs are experimental It is possible to create pure Inn
mice with high and low predisposition to leukemia
• fam ily* leukemia (chronic lymphoid leukemia with dominant and recessive
types ol Inheritance), concordance ol the form, 1 Initial and hematological signs ol
i' nl cmia in 1/3—1/4 of monozygotic twins have been found (the same is in olhet
in 11tenant tumors, p. 149).
I he twin method confirms the value of genetic factors in leukemia etiology.
Patients with chromosomal anomalies are predisposed to leukemia develop
m. nl (p. 52). Somatic and sex chromosome mutations and nondisjunction of chro
.... . predispose the organism to neoplasia. Thus, leukemia cases are more lie
•ми nl in patients with Down’s (by 20 times), Klinefelter’s and Turner’s syndromes.
' liioniosome mutations are revealed in 80—90 % patients with acute leukemia, in
mi l)7 % patients with chronic myeloleukemia, and 50 % patients with chronic
i tnpholeukemia. Mutation of the 21я chromosome is detected in patients with
leukemia.
In genetic defects of the immune system (T-lymphocytic and combined im
niimodeficiency) incidence of malignant tumors, including leukemia, increases.
I lie role of genetic factors in leukemia development has been proved by a liinh
Im Idcnce of leukemia in certain ethnic groups.
Chromosome mutations, which are found in leukemia, serve as its gene in
in nkers. Thus, the abnormally short Philadelphia (Ph ) chromosome (which was
•Ii .covered in Philadelphia) is typical of chronic myelocytic leukemia. This chronm
•т. appears as a result of deletion of the 22nd pair of chromosomes and transitu ,i
... . of the separated segment to the 9lh pair. Translocation of the 8,h chromosome
M rincntt0 the 14th pair occurs in Burkitt’s lymphoma most likely under the inllu
. in i of Epstein—Barr virus.
Genetic factors often play the role of conditions. It means that an etiological
11. iiм (ionizing radiation, virus) in some cases causes cancer of some organ, in
nilu i cases — leukemia depending on the genetic predisposition of the organism.

PATHOGENESIS

lii leukemia, the neoplastic process develops in the hemopoietic tissue. As in

inv other type of neoplasia, leukemia pathogenesis proceeds in three stages neo
(•litsltc (leukemic) transformation, promotion, and progression (described in chap
ji)f 10 -Neoplasia»). The first two are preclinical, the third is a terminal stage with
•lluii al manifestations.
Peculiarity of a neoplasm in the hemopoietic tissue lies in the fact that solid
I l l i n o i s are not formed in the bone marrow. Malignant cells (leukocyte predeces
.... ire mobile, leave the bone marrow and appear in the peripheral blood im
т. ilialely after the process starts. They are found and can be calculated in Ihe
l ii и in ’s blood smear at the beginning of the disease. According to peripheral blood
im. ligation, two stages of leukemic pathogenesis are distinguished - monoclonal
.uul polyclonal.

«plastic Transformation

Neoplastic transformation is a transformation of one normal cell of ihe bone

••(•иtow or lymphoid tissue into a malignant one. Primary formation of a neoplastic
Ii ни* lakes place in blood cell precursors in Ihe bone marrow or lymphoid tissue
I ’iiit 2 S p e c ia l ( N o s t r u m ) Га11н>|»||>мо||>ку

As lo the mechanisms of neoplastic trausloruiution. some theories have been

proposed — of mutative or epigenomic canccrogcnesis (details are given in chaplci
10 «Neoplasia», p. 146). In case of leukemia, oncogenic viruses, ionizing radia
tion and chemical substances cause mutation of the genes, which are critical lot
hemopoiesis. The theory of epigenomic cancerogenesis is based on disorders Ы
regulation of hematopoietic cell multiplication and maturation.
Oncoviruses can cause chromosomal translocation that results in .................
ol the oncogens localized in chromosomes to the part of genome, in which they
can be activated.
Penetrating into the cell genome, oncoviruses can activate protooncogeim
coding synthesis of various oncoproteins. Some of oncoproteins serve as growth
(actors (thrombocytic, epidermal, T-lymphocytic, etc.), others serve as receptor
to growth factors or protein kinases catalyzing tyrosine phosphorylation. The abill
ty to transform normal blood cells into neoplastic ones is common for all onco
proteins.
Alter neoplastic transformation, a cell clone appears in the bone marrow, which
is characterized by immortality, unlimited autonomous growth and low ability lo
differentiate.

Neoplastic Promotion

Neoplastic promotion (remember this concept, p. 148) is a period, when mill

liplication of malignant cells of the hemopoietic tissue begins. Neoplastic malig
nant cells appear in the peripheral blood. It is the monoclonal stage of leukemia
development (one clone of a primarily transformed hemopoietic cell appears in tin
blood).
In comparison with normal cells, which after 4-6 divisions start to differential,
into mature cells without mitotic activity, in acute leukemia leukemic cells actively
proliferate without maturation. They are morphologically and cytochemically un
differentiated. At the monoclonal stage all cells have the same geno- and plteno
type, the same antigen, chromosomal and biochemical markers.
Leukemic cells do not need growth stimulators because they have their own
stimulator. Among them there is IL-2 from leukemic lymphocytes, which serves at
a stimulator. Leukemic cells are characterized by autonomous growth.
Normal hemopoietic cells continue to form at this stage of leukemia. There an
no changes in other organs. It is a preclinical stage. Nevertheless, typical chant»'*
in the blood are already taking place.

Neoplastic Progression

Neoplastic progression is characterized by aggravation o f the malignant prop. ■

lies of neoplastic cells.
Ihere are several explanations of neoplastic progression, which are given oil
l> I IX in chapter «Neoplasia*. One ol them lies in the fact that malignant cell,
undergo additional mutations. Instability ol the leukemic cell genome leads lo ap
pearancc ol new mutations, both spontaneous and caused by oncogenic factors Нин
 Chapter 22. I^ukciiiiu

и .nit in the appearance of new tumor clones. The leukemic tissue becomes geneti
•nils and phenotypically heterogeneous.
It is the so-called polyclonal stage of leukemia.
Selection of the most malignant cells takes place. They avoid immune system
.... .. Among the cells, which are subjected to treatment with cytostatics (chcmi
■il hormonal and radioactive), some are destroyed (more mature), but the most
Hiiihgnant cells are resistant to these effects. Only they continue to multiply as a
'Milt of such selection. Therefore, treatment for leukemia with cytostatics, ionizing
i filiation and radioactive substances becomes ineffective at the polyclonal stage.
t ransition of the monoclonal stage into the polyclonal one is an indicator ol
.... plastic progression.
I.eukemic cells may spread throughout the blood system and beyond il (me
•i uses) forming leukemic infiltrates in the lymph nodes, spleen, liver and ollici
HtjIIIIIS.
Accumulation of mature leukocytes in the blood (in chronic lympholcukcmta)
t •\plained not only by their intensive formation but also by apoptosis impairment
when mature cells do not die for a long time.

Ihsorders o f Other Bone M arrow Lineages

In leukemia, hemopoiesis is disturbed first of all in the cells, where neoplastic

Mim formation has occurred. As clones of malignant leukemic cells prevail over
Hoinial hemopoietic cells and are characterized by fast growth, they occupy the
Ihmic marrow and displace all other normal bone marrow lineages.
Malignant cells substitute the bone marrow parenchyma and its normal mi
• nvironment. Differentiation of precursor cells of the normal hemopoietic tissue
11 Inhibited. The neoplastic myeloid tissue displaces the erythroid and thrombocytic
limn marrow lineages. Besides, leukemic cells excrete the factors, which activate
itpupiosis of other cells. Inhibition of normal erythro- and thrombopoiesis results in
vmptoms of anemia and hemorrhage.

MANIFESTATIONS

I lie manifestations of leukemia are local (changes in the malignant cells of the
•«••с marrow and peripheral blood) and systemic (in the whole organism).

\n.i|il.isia and Metaplasia

Anaplasia and metaplasia of leukemic cells are local manifestations.

I he concept of neoplastic anaplasia and metaplasia (see pp. 150-153 in chap
ii i It» «Neoplasia») also refers to leukemic cells. It means that leukemic cells only
tun v.mlly resemble normal leukocyte precursors. A special research has revealed
tin n ilillcrences.
Morphological anaplasia and metaplasia concern morphological peculiarities
nl leukemic cells. There can be various degenerative changes in the nucleus and
Hinplasm of the leukocylcs observed, their vacuolization, morphological and cy
Im In niical atypical nature, making identification ol the cells difficult.
I’.iil 2 S|MTUil (Syslom le) I’ulliophysioloKy

Hiocliemicul anaplasia concerns change's ol then cn/.ymal composition, pH.

chemical and biophysical properties. There arc bio and cytochemical markers ol
leukemic cells. Positive reactions to myeloperoxidase, nonspecific esterase, and acid
phosphatase arc detected.
Immunological anaplasia consists in antigen simplification and obtaining new
embryonic antigens. In leukemic cells the immunological markers of stem cells are
detected. So, not only biochemical but also immunological identification of leuke
mic blasts is possible.
functional anaplasia consists in functional disorders of transformed leukocytes
(immunoglobulin and enzyme synthesis, BAS formation, phagocytosis). Al the
polyclonal stage leukocytes completely lose their functions though at the monoclo
nal stage their function is partially present.

Clinical Manifestations

Clinical manifestations are identical in all types of leukemia. They are fatigue,
weakness, fever, night sweats, decrease in weight, exhaustion of the organism. Seve­
ral pathophysiological syndromes determine the manifestations. They are anemic,
hemorrhage and D IC syndromes, immunological insufficiency, some extramcdul
lary syndromes together with hematological syndrome, which is different in various
types of leukemia.
Acute leukemia leads to death of the patient in several weeks. Cancerous ca
chcxia and secondary infection are the reasons for death.

Anemic Syndrome

Anemia develops in all patients with leukemia. As to its pathogenesis, it is

predominantly dyserythropoietic (hypoplastic and metaplastic, p. 287). It is partially
hemolytic. Autoimmune hemolysis occurs in lympholeukemia. Hemorrhages and
posthemorrhagic anemia are possible.

Hemorrhage Syndrome

Hemorrhage syndrome (predisposition to spontaneous hemorrhages, p. 325) is

determined by a decrease of thrombocyte amount (thrombocytopenia, p. 327). In
addition, there is functional platelet insufficiency in leukemia (thrombocytopalhy
p 32K). Injury of the vessel wall with leukemic infiltrates plays its role. Very o f t e n
hemorrhage is the reason for patient’s death.

/>/( ’ Syndrome

D IC syndrome in leukemia is a consequence of significant disorders of homo

stasis (p. 332). Simultaneous activation of all hemostasis systems may lake place
A lot ol procoagulants arc found due to enoinious destruction of leukemic cells
(thromboplastin, which determines intravasculiu coagulation). Plasminogen may hi
activated All these events provoke thrombosis iiiul latei also hemorrhage.
 Chapter 22. I x' u Iu - i i i I m

Immunological Insufficiency Syndrome

Immunodepression is connected with depression of normal granulo-, mono

to and lymphocytopoiesis, which promote disorders of immune responses of
tit. organism. A disorder of immunological reactivity is an obvious manifestation
..I leukemia. Humoral and cellular immune mechanisms get inhibited. Malignant
i nkocytes do not perform their functions (phagocytosis and antibody formation). Ii
I* ads to immune insufficiency as well as secondary autoinfection development. I lie
г nhology may lead to forbidden cell clones formation, which are able to synthesize
antibodies to body’s own tissues. Autoimmune process is possible.

/ \inim edullary Syndromes

l-xtramedullary syndromes develop in various organs and are manifestations ol

I. tikemia as well. They result from a damage of different organs by:
• leukemic infiltrates;
• appearance of toxic substances, which are released from damaged organs in
laige quantities.
For example, some neurological symptoms (pareses and paralyses) may ap
iи и due to leukemic infiltrates of the meninges, parts of the brain and spinal cord
i inial nerves. Pathology of the skin and mucous membranes (gingivitis, stomatitis
. t. ), diseases of joints and bones, other organs (lungs, heart, kidneys, testicles,
i it ) with corresponding symptoms and signs of their insufficiency also develop.

BLOOD PICTURE (HEMATOLOGICAL SYNDROME)

I lie total quantity of leukocytes in the peripheral blood is often increased.

I >.pending on the degree of this increase leukemia is divided into leukemic (an
.... ease to 50-200-500 G/1 and more) and subleukemic (slightly increased to
Ml ( i/|) forms. But there are also leukopenic (less than 4 G/1) and aleukemic forms
' ith a normal amount of leukocytes in the blood. Since the hemopoietic tissue cells
..... nobile, their malignant forms appear in the peripheral blood and the diagnosis
..I leukemia type is based on the leukoformula.
Ilyperregenerative nuclear shift to the left (p. 300) is always detected. Il means
tli.it a large quantity of immature leukocytes are found in the peripheral blood up
in the appearance of blast cells.
I lie blood picture in various types of leukemia is different and plays a decisive
mil in diagnostics.
Acute Myeloleukemia

In acute myeloleukemia the youngest forms of neutrophils, eosinophils and

tiii .ophiles are present in the leukoformula. Appearance of a large quantity ol blast
..II. in the hlood is typical of acute leukemia. Neoplastic blast cells are identified
"lilt the aid of cytochemical and immune methods.
A special feature ol the leukoformula in this form of leukemia is the fact that
"lily the youngest lorms (myeloblasts) and mature neutrophils (segmented) are
Г.ill 2 S|m tIuI ( SyslcinU ') l'«lliii|ili)«liilii||y

present 111 п. I tie intermediate forms between Must «ill', iiiul mature neutroplulu
granulocytes (promyelocytes, myelocytes, uiclaniyclocvtcs, band cells) are absent
(color lig. 34). This phenomenon is called hiatus Iruknnicus
Hiatus leukemicus reflects a deep disorder ol leukopoiesis in the hemopoietic
organs neoplastic cells lose the ability to differentiate. Neutrophils do not matiue
in the bone marrow. Only myeloblasts multiply and get into the peripheral blood
Maiure neutrophils, which are found in the peripheral blood, are the ones which
were formed earlier, before the beginning of the disease. The lifetime of matiue
neutrophils is short. Consequently, this situation lasts for two weeks and then .1
patient dies.

Chronic Myeloleukemia

In chronic myeloleukemia, a neoplastic clone appears in the cells of the II l\

hemopoiesis classes but a larger part of them mature in the bone marrow. It is .1
tumor, which mostly consists of cells of the V and V I classes. Microscopic ехаин
nation ol the peripheral blood makes it possible to see granulocytes of any maturih
degree. I he picture of the peripheral blood resembles the picture of the bone mai
iow I'he Ilyperregenerative nuclear shift to the left is noted, but the phenomenon
ol hiatus leukemicus is absent (color fig. 35).
An increased number of neutrophilic metamyelocytes, bilobate myelocytes,
promyelocytes and single myeloblasts is typical of chronic leukemia.
I he number of eosinophilic and basophilic granulocytes is increased (eosino
philic and basophilic leukocytosis, p. 304).
I he terminal stage is characterized by the so-called blast crisis. It is sudden
slopping of myeloblast maturation. Blast cells (myeloblasts and nondifferentiaied
blasts) appear in the peripheral blood. It is a manifestation of neoplastic progres
sum appearance of a new clone of the cells.

Lymphoid Leukemia

I ymphoid leukemia is neoplastic transformation of the lymphoid tissue. Chron

ic lymphoid leukemia is characterized by absolute and relative lymphocytosis.
Lymphocytes are mostly mature. The majority of lymphoblasts completely dil
leieniiales ( В lymphocytic leukemia is more common). In the leukocyte formul.i
Ihe proportion of mature lymphocytes reaches 80-90 % (relative and absolut»
lymphocytosis with relative neutropenia). There are single prolymphocytes and
lymphoblasts in the leukoformula (color fig. 36). It is possible to see the so-called
smudge cells (lymphocytes in the state of lysis) in the blood smear.
Absolute neutrophil count may remain normal taking into consideration a siy
nilkanl increase of the total quantity of leukocytes (above 120 C»/l).
I lie course of the disease is chronic and lasts for years. Nevertheless, some
limes complete substitution of all hemopoietic lineages with lymphocytic ones laki
place (lymphoid metaplasia of the myeloid tissue)
 /
.5
LCUaU-
Eo­ My­ Lym­
cyte count Baso­ My­ Pro­ Meta­ Seg­ Mono­
sino­ elo­ pho­
(norm philes elo­ myelo­ myelo­ Band men­ cytes
phils cytes cytes
4-9 G/1) blasts cytes cytes ted
Diagnosis
1

1
9-1

О
Tf

Norm, % 0-1 2-5 51-67 20-40

OO

06-0
40- 2040- 800- 160—

O
Norm
0-90 540 6030 3600 720

° O2
1о
in 1 mkl

Acute myeloleu­
kemia
Chronic myelo­
leukemia
Chronic lym­
phoid leukemia
I ‘.ui 2 S|M4'iul (.System ic) l ’iilho|)h>sioli>K.v

Blast crisis may develop (blast crisis is iai« m ilus lorm of leukemia — in '
•1 % cases). At this moment lymphoblast maturation stops. Many lymphoblasts up
pear in the peripheral blood. Patients can die at this stage of lymphoid lcukctnl.i
development.
Questions for Self-Control

1. What proves the role of genetic mechanisms in leukemia pathogenesis?

2. What arc the monoclonal and polyclonal stages of leukemia pathogenesis'’
3. What is hiatus leukemicus in hematologic syndrome in leukemia?
4 What is the difference between blood pictures of acute and chroni.
myeloleukemia?
5. What is blast crisis?
<
> Why is patient’s life possible in chronic lymphoid leukemia when the lymphocvii
proportion is 80-90 % and neutrophil proportion is less than 20 % ?
7. Name the clinical syndromes of leukemia.
8. Compile leukoformulas for the cases given in table 10.

Tests and Tasks for Self-Control

(give correct answers and find mistakes in the statements)

I (iive the characteristics of leukemia pathogenesis.

1. Differentiation of leukocytes stops at a certain intermediate stage ol In
mopoiesis.
2. It is a malignant tumor, which is localized in the bone marrow or lymph
nodes.
3. More often leukemia is accompanied with an increase of leuko«\i>
amount.
4. Leukemia and leukocytosis are synonyms.
5. It is a limited hemopoietic tissue growth, which does not correspond
the normal structure and function of the organism.
6. It is a disease of the hemopoietic tissue of neoplastic nature.
7. Leukemia belongs to the group of hematopoietic tissue tumors called I"
moblastoses.
8. Chronic leukemia originates from the cells of the II and III hemopol
classes.
4. The neoplastic myeloid tissue displaces the erythroid and thrombi> <
parts of the bone marrow.

2. Characterize the role of genetic factors in leukemia development.

1. Genetic predisposition to leukemia has not been revealed.
2. (ienetic peculiarities of hemopoiesis may play an etiological role in I
kemia.
3. Etiological factors (oncogenic viruses, ioni/ing radiation and them
substances) can cause mutation ol the genes regulating hemopoietl» t
multiplication and maturation
 Chapter 22. 14'ukcniia

4. Mutation can not occur in the genes, which are critical for hemopoiesis.
5. Leukemia has no genetic markers.
6. The Ph-chromosome is a genetic marker of chronic myelocytic leuke­
mia.
7. Malignant leukemic cells are predisposed to additional mutations.
X. Instability of the leukemic cell genome leads to new mutations that result
in the appearance of new tumor clones.

I «sting of the peripheral blood of a 42-year-old patient showed such results: Ik-
moglobin — 80 g/1, erythrocytes — 3.2 T/l, leukocytes — 25 G/1; the leukocytic
lormula: basophiles — 5 % , eosinophils — 9 % , myeloblasts — 3 % , promyclo
i vies — 8 % ; neutrophils: myelocytes — 11%, metamyelocytes — 22 % , band
17 % , segmented — 19 % , lymphocytes — 3 % , monocytes — 3 % . What kind
nl hlood pathology is this?
Л. Leukocytosis.
B. Acute myeloblastic leukemia.
C. Chronic myeloleukemia.
I). Lymphoid leukemia.
Г. Erythromyeloleukemia.

Hlood examination showed leukocytosis (50 G/1), lymphocytosis (80 % ), smudge

i ' lls, anemia. What disease can it be?
A. Inflammation.
B. Chronic lympholeukemia.
( Chronic myeloleukemia.
I ). Acute myeloleukemia.
1 . Tuberculosis.

Л .’X year-old patient has fever. The patient’s body temperature rose to 39°C. 11is
I.lie resembles acute infection. Blood analysis showed leukocytosis 20 G/1. The
laikoformula reveals young forms of leukocytes. Acute myeloid leukemia was
diagnosed. Give the characteristics of acute myeloid leukemia.
I . Neutrophils do not mature in the bone marrow.
2 Myeloblasts multiply and get into the peripheral blood.
< The amount of leukocytes in the peripheral blood is always increased.
4. Mature neutrophils, which are determined in the leukoformula, arc those,
which were formed before the beginning of the disease.
S Hiatus leukemicus in the leukoformula reflects a loss of the ability of nco
plastic cells to differentiate at the stage of myelocytes.
<>. Oncogenic viruses may cause mutation of the genes regulating multiplica
tion and maturation of hematopoietic cells.
Proofs o f the virus role in leukemia development are the following:
7 I xperimental: injection of cell-free filtrate of leukemia tissue from a sick
animal to a healthy one may cause leukemia.
X Biochemical: the presence of reverse transcriptase (K N A depending
DNA-polymcritsc) in leukemic cells.
( liaptcr 2 J
PATHOLOGY OF HEMOSTASIS

I hc term hemostasis (not to be confused with the term homeostasis) means .11
rest of bleeding.
Actually, early scientific investigation of the coagulation system of the hlooil
discovered the role of thrombocytes and blood proteins in thrombosis and arrest ol
bleeding (coagulation and anticoagulation systems). Later a question arose about
the function of these mechanisms in the absence of blood loss. It becomes clear 1li.it
all these systems also participate in maintaining the liquid state of the blood.
Therefore, the old term hemostasis got a new definition. Hemostasis is the or
nanism л function o f m aintaining the liquid state o f the blood and its coagulation in
ease o f need.
Consequently, it is possible to give the following definition of hemostasis p.i
thology.
Hemostasis pathology is a disorder of the maintenance of the liquid state of tin
hlood and its coagulation in response to vessel injury.
Examples of hemostasis pathology were given in the previous chapters — r.idin
tion disease (hemorrhages as a result of thrombocyte deficit and pathology of ili>
vascular wall, p. 28), genetic disorders (coagulopathy, p. 48), anaphylactic shock
(p. 94), thrombosis (p. I l l ) , leukemia (p. 316). In this chapter pathology of tlx
hemostasis system will be discussed in detail.

HEM OSTASIS MECHANISMS

Physiological and biochemical mechanisms of hemostasis are described in »l«

tail in the course of normal biochemistry and normal physiology. Below this inloi
nialion is given in brief for the purpose of mastering the topic.
I he hemostasis system has many components. These are platelets and other
hlood cells, vessel walls, extravascular tissue, BAS, vascular and tissue factors to
tmusic pathway), plasma factors of blood clotting (intrinsic pathway), which m
closely associated with the kallikrein-kinin system.
I here are two mechanisms of hemostasis:
• coagulative hemostasis;
• thrombocytovascular hemostasis.

Coagulative Hemostasis

I he coagulative hemostatic system consists of hlood proteins and is subdiviiM

into three groups of mechanisms.

/. System o f blood coagulation consists ol hlood proteins proconglllaiit*

Blood coagulation proceeds in three stages (lotmillion of the prolhrombiiiase ю т
 Chapter 23. ГяИи>1»к> of HcniosUsiN

i<li ч thrombin and fibrin). Fibrin is the final product of coagulation. Then librin
•Им i retraction takes place (by platelet thrombasthenin). Vitamin К is part of Ihe
■^illative system (participates in the synthesis of the II, IX and X factors).
2. System o f blood anticoagulation consists of anticoagulants. Heparin is an
important substance.
f. System o ffibrinolysis provides dissolution of fibrin fibers by plasmin, which
■ pii-scnt in the blood in the inactive form (plasminogen, or profibrinolysin) and is
i. mated by many factors (see below).

Thrombocytovascular Hemostasis

Plasma factors and their participation in hemostasis attracted attention of sci

■uii-.is at first. Later it became clear that an important role in maintaining the nor
hi il rheological state of the blood belongs to thrombocytes and the vascular wall•.
iitmlcr physiological conditions platelets are situated near the endothelium ami
11111-1act with it). It is they that initiate blood coagulation and thrombogencsis alt»-1
vi .i l injury if there is a threat of blood loss.
I hrombocytovascular hemostasis is subdivided into two groups of mechanisms
ни ntioned below.

t'lutdet Role

Platelets play a central role in hemostasis. Their role is the following.

• \nniotrophic function with respect to the endothelium of the vascular wall,
which promotes maintenance of the liquid state of the blood.
■ lllood coagulation after vessel injury (aggregation, adhesion to the endothelium
uul formation of thromboplastin, which starts blood coagulation).
• 1'ioduction of prostaglandins (thromboxane) as initiators of platelet aggregation
liter vessel injury.
formation of the primary (only by thrombocytes) thrombus after vessel injury.
Production of vasoconstrictive substances (serotonin, adrenaline, noradrenaline),
which promote arrest of bleeding.

W .m'I Kndothelium Role

I lie role of the vessel endothelium in hemostasis consists in two functions

niiiithrombotic (under physiological conditions) and prothrombotic (after vessel
liiiury).
in/ithrombotic function of the endothelium provides the so-called thromboresis
•ми «• prevention of platelet aggregation - and consists in maintaining the liquid
«iiiii of the blood. This function is performed with the aid of several mechanisms
• production of prostacyclin (P G ), which prevents platelet aggregation;
• destruction of the agents, which stimulate thrombocyte aggregation (such as
A D P);
Г.ill 2 S|M4i»l (System ic) I'иIlio|ili>sl<iIiikv

• production of sulfated mucopolysan handt which resembles heparin (ami

coagulant);
• plasminogen activation, which initiates fibrinolysis and prevents formation ««I
intravascular clusters.
Proihrom hotic function of the endothelium provides and initiates blood coagu
lation after vessel injury by starting thrombogenesis. This function is carried out
with the aid of such mechanisms:
• Thromboplastin formation.
• Production of Willebrand factor, which initiates thrombogenesis (activating
factor V III). It is produced in the endothelium but is accumulated in plate
lets and released during their degranulation. A thrombocytic clot can not l> <
formed without it. This factor is necessary for thrombocyte aggregation, il
stimulates adhesion of platelets to vessel wall collagen. Special receptors in
this factor are found on the thrombocyte membrane.
The rheological state of the blood depends on the balance of all the mentioned
systems. Disorders of any of these components lead to hemostasis pathology.

HEM OSTASIS PATHOLOGY CLASSIFICATION

Some classifications of hemostasis disorders have been suggested.

/. Ilypocoagulation and hypercoagulation are distinguished according to disordri
direction.
2. Local (thrombosis, hemorrhage, hematoma) and systemic (blood loss, gcncni
li/.cd D IC syndrome) disorders are distinguished according to localization.
3. Acquired and hereditary (coagulopathy, thrombocytopathy, angiopathy) dr.
orders are distinguished according to the participation of genetic mechanisms.
Hemorrhage syndrome (corresponds to hypocoagulation), thromhophilic мл
drome (corresponds to hypercoagulation) and D IC syndrome (disseminated inlra
vascular coagulation syndrome) are the clinical terms, which determine hemost.i u
disorders.
In addition, disorders may be acute and chronic. Acute disorders refer to enu i
gency medicine: acute hemorrhage, thromboembolism as well as D IC syndromr,
which may lead to death in the absence of immediate medical care. Thrombophlr
hitis of the extremities is an example of a chronic disease.
Sometimes, as it is in anaphylactic shock, hypo- and hypercoagulation occur
al the same time - hypocoagulation in the large vessels and hypercoagulation hi
the microcirculatory bed (p. 94).

ETIOLOGY ANI) PATHOGENESIS

Etiological factors of hemostasis pathology may be exogenous and cndogcnoi

as well as physical (mechanical injury ol platelets, е.ц in the course of heart vnl
prosthetics, ioni/.ing radiation), г/rrmfai/(mcdicines, heparin overdose) and hioli
 ( ll .ip U 'l .M l*Mthol«>K> i>f I I t'lllO N liis is

.// (microorganisms, viruses, immune and genetic factors). The etiology of various
•чI» of hemostasis pathology is different.
I he pathogenesis of numerous clinical and pathophysiological syndromes
ih po and hypercoagulation, hemorrhage, excessive thrombogenesis, D IC syn
i" «не) is different depending on what is the primary disorder (quantitative and
ih.ihiative platelet changes, vessel diseases, liver pathology, disorders of plasma pro
i' in synthesis, etc.). Pathogenesis is absolutely opposite in two main syndromes
11viк) and hypercoagulation.

H YPO C O A G U LA TIO N

llvpocoagulation syndrome (hemorrhage syndrome) is a tendency to hcm»rrhiij>«'

«trilling spontaneously or due to an insignificant injury.
llvpocoagulation may lead to hemorrhage and hematoma.
Hematoma is accumulation of blood in a tissue (in the skin, joints, mucous
m. mbranes, internal organs, etc.). In the site of hematoma morphological and
.... lional changes develop. Cerebral hematoma is especially dangerous. Hypoco
• nl.ition prolongs hemorrhage, leads to acute or chronic posthemorrhagic anemia
iml hemic hypoxia if blood loss is essential.
I’athogenesis of hypocoagulation consists of five groups of mechanisms men
llmied below:
• lack of plasma procoagulants;
• surplus of anticoagulants;
• activation of fibrinolysis;
• deficit of platelets;
• pathology of vessels (hemorrhagic angiopathy).

Lack of Plasma Procoagulants

Causes of procoagulant deficit may be acquired or hereditary.

Acquired procoagulant deficit occurs in the following cases.
• I >iseases of the liver affected by various pathological factors. In the liver all
pit «coagulants (prothrombin, fibrinogen, antihemophilic globulin, etc.) are syn
tlifsi/ed. Any stage of coagulation may be disturbed in disorders of the protein
\nthesis function of the liver.
1 I hypo- and avitaminosis lead to disorders of the second phase of coagulation
lin ause synthesis of the II, V II, IX , X factors is vitamin K-dcpcndent.
• \iiloimmune aggression towards coagulant proteins. Immune antibodies block
nine of them. Production of antibodies against the V III, IX factors is observed
in diffuse autoimmune diseases of the connective tissue.
■ K.uliation disease has in its pathogenesis a disorder of the molecular structure ol
Ilium. As a result, fibrin fibers lose the ability to contract and blood clols to
irtmct.
I'nrt 2 S|Mkrlu l (S y s lrin lc ) I ’uthoplivslnloKv

• Enteritis, resection of the small intestine and dysbacteriosis may lead to II, V,
V II factor synthesis decrease (disorder ol vliamln К absorption). Some medicine*
(streptomycin sulfate) may cause the same elfect
• Increased consumption of procoagulants takes place at the first stage of DIC
syndrome (see below).
ЛИ these causes disturb one or another stage of blood coagulation.
Hereditary deficiency of procoagulants ( coagulopathy) results from mutation
ol the genes responsible for procoagulant synthesis. Hemorrhage occurs in genet и
deficiency of antihemophilic globulin (IX ), V III and X I factor synthesis (in lie
mophilia Л. В, C ) and genetic deficiency of factor V in parahemophilia. Genelu
hypo , afibrinogenemia and fibrin stabilizing factor (X III) deficiency are revealed

Surplus of Anticoagulants

Surplus of anticoagulants occurs in their increased synthesis or activation (ana

phylactic shock) as well as in case of overdose of drugs with anticoagulant ellecl
(usually heparin).
Heparin is an important substance of the anticoagulation system. It is re
leased during mast cell degranulation (inflammation and allergy) and regulates local
thrombogenesis. It is widely used in clinical practice as a medicinal preparation In
case of overdose or increased sensitivity to heparin, disorders of systemic thrombo
genesis and hemorrhage develop.

Fibrinolysis Activation

Disorders of the third stage of hemocoagulation usually result from fibrinolysr.

activation, which ends in hemorrhage. It occurs under the influence of exogenous
and endogenous factors, which activate plasminogen. They are:
• bacterial and tissue fibrinokinase;
• immune complexes;
• 11ageman’s factor;
• complement;
• kallikrein-kinin system components;
• complex of heparin with fibrinogen, profibrinolysin and adrenaline (proud,
non-enzyme fibrinolysis).
The most actual clin ical examples of hemorrhage caused by fibrinolysis achvn
lion are the following:
• «-hemolytic streptococcus infection (rheumatoid endocarditis);
• massive trauma (including parenchymatous organ surgery) of the luiiu'
(p. 407), liver, uterus, pancreatic gland;
• crush syndrome;
• anaphylactic shock;
• trypsinogcn activation in pancreatitis;
• massive burns;
• overdone o f fibrinolytics as drugs.
 Chapter 23. Pathology of Mmmstusls

PLATELET PATHOLOGY

I'.ilhology of platelets, which leads to bleeding, consists in their quantitative

tml qualitative disorders. There are two forms of the pathology, which lead to hy
.......initiation — thrombocytopenia and thrombocytopathy. In both cases hemor
ihiip occurs.

Thrombocytopenia

I hrombocytopenia is a decrease of the quantity of thrombocytes in the periphe

' il hlood (norm is 180—320 G/1). However, spontaneous hemorrhages occur in case
■■I thi'tr number decrease down to 30 G/1.

t lloloio

biological factors, which cause thrombocytopenia, are exogenous and endo

i>
<in mis; physical, chemical and biological. They are:
• mechanical injury of platelets in case of splenomegaly and artificial cardiai
valves;
• ionizing radiation (the effect of aggressive forms of oxygen and radiotoxins,
P. 28);
• toxic chemicals;
• side effects of medicines, which may change the antigen structure of throm­
bocytes (acetylsalicylic acid);
• viral infection, which may change the antigen structure of thrombocytes;
• endogenous metabolites (in uremia, liver cirrhosis);
• Ihrombocytopoietin deficiency;
• deficiency of cyanocobalamin and folic acid;
• hormonal disorders (hypothyroidism).

I nili'igvnesis

I here are the following mechanisms of thrombocytopenia development.

• I ■ ion of the megakaryocytic lineage of the bone marrow.
■ I'' placement of the megakaryocytic lineage of the bone marrow with tumor me
i i i.tscs, leukemic infiltrates (in leukemia, p. 315).
• I lnombocytopoiesis suppression due to pathology of the megakaryocytic lineage
•'I ihe bone marrow, thrombocytopoietin deficiency.
Im teased destruction of platelets in the blood under the effect of external and
Htletnal mechanisms — by bacterial toxins, herpes virus, macrophages as well as
iti i .ise of autoimmune aggression against body’s own thrombocytes (pp. 94, 97)
mi >ise of changes of the antigen structure of thrombocytes affected hy vmiscs,
nirthcincs, incompatibility of thromhocytic antigens of a mother and an cm
hi vo).
Г.и I 1 S|mtiuI (S y s ln iitc ) I*мI l i « чй>l<>к>

• Increased usage of platelets in the course ot generalized intravascular blood со

agulation (D IC syndrome, see below).
As a consequence, it is predisposition to hypocoagulation and a tendency to
ward hemorrhage starting spontaneously or due to an insignificant injury.
In the pathogenesis of bleeding and blood loss the following mechanisms aw
important:
• Disorders of thrombocytovascular hemostasis, decrease of the adhesive and ay
grcgational capacity of platelets.
• Deficit of the thrombocytic factors of blood coagulation.
• I)eficiency of A D P, serotonin, adrenaline, antiheparin factors that leads to insul
ficiency of primary (from the platelets) clot formation. Decreased fibrin retmc
tion as a result of suppressed activity of platelet contractile protein (thrombus
thenin).
• Insufficient trophicity of the endothelium (vessel wall dystrophy), decrease ol
vessel solidity, increased permeability of capillaries to erythrocytes (diapedesis)
and other blood components.
• Decreased ability of vessels to contract due to deficit of serotonin and adrenaline
from platelets.
Thrombocytopathy

In clinical practice one may notice diseases, which manifest themselves throuyli
predisposition to hemorrhage in normal thrombocyte count. It becomes clear that
this is caused by thrombocyte functional disorder, when they do not react propeilv
to vessel injury by initiating coagulation and thrombogenesis. Bleeding arrest is de
celeraled, tissue hematomas form. It is thrombocytopathy.
I lironibocytopathy means qualitative defects and dysfunction of thrombocytes
I lie causes are more often genetically determined.
The following genetic defects of the membrane structure and biochemical com
position of platelets can underlie it:
• enzymopathy (G 6PD H deficiency);
• membranopathy (deficiency of the membrane receptors of the V, V III, \l
factors);
• impairment of platelet contractile protein (thrombasthenin) synthesis;
• deficiency of energy formation in the form of ATP;
• deficiency of A D P, adrenaline, serotonin, thromboxane.
I he factors mentioned above are the reasons for the formation of pathologii il
platelets in the bone marrow.
I lie extrinsic hemostasis pathway is impaired in the same way in tliroiul«i
cytopathy and thrombocytopenia, because it is connected with platelet function
disorder In both cases predisposition to bleeding is observed.
Speaking about pathophysiological disorders and clinical manifestations w«i
must repeat that they have been discussed above All the necessary properties and
functions ol platelets are impaired adhesive and aggregal ional capacity, HAS
 Chapter 23. Pathology of MnnoslusK

vuihesis, primary thrombocytic thrombus formation, and hemocoagulation init ia

..... flic synthesis of thrombocytic coagulation factors, thromboxane, serotonin,
uni contractile protein (thrombasthenin) gets suppressed. Vascular wall trophicity
i disturbed, vessels lose their ability to contract as well as their solidity.
Vs a result, thrombocytovascular hemostasis is impaired. Hemorrhages develop
1 'iiianeously or after insignificant vessel injury.
f unctional disorders of thrombocytes may be acquired. For example, aspirin
•i••i •is known to predispose to bleeding. Inhibition of cyclooxygenase activity by
i.pirin underlies this pathology.

VASCULAR WALL PATHOLOGY. HEMORRHAGIC VASCULOPATHY

In clinical practice one may see predisposition to hemorrhage in patients with

nui neither coagulation system nor thrombocyte pathology. It goes about pathology
"I tin- vascular wall.
Hemorrhagic vasculopathy is a disorder of hemostasis in the form of hcinoi
ilntges as a result of primary vascular wall pathology.

I Oology

biological factors may be exogenous (physical, chemical and biological) or

■mlngenous (immunological, genetic), acquired and genetic.
I lie acquired forms develop as a result of:
• ionizing radiation effect;
• side effects of medicines;
• viral infection;
• action of various factors, which cause vessel inflammation, including im
mune factors (autoimmune aggression against the endothelium);
• action of BAS (allergy);
• nutritious deficiency of vitamin C, which results in reduction of collagen
synthesis;
• vascular trophicity disorder as an effect of thrombocytopenia;
• vascular wall destruction as a secondary effect of leukemic infiltrates;
• disorder of nervous and hormonal regulation of vascular tone.
(icnetic forms of hemorrhage vasculopathy develop as a result of mutations ol
ili. n nes, which are responsible for the synthesis of endothelial proteins (enzymes.
•"Hagen, contractile proteins, etc.) and receptors. Hereditary Willcbrand disease is
км rvatnple. The absence of receptors of this factor underlies this disease.

Inlhogencsis

Iniiiry of vessels under the action of exogenous and endogenous factors ie

nil 111 inflammation and impairment of endothelium participation in hemostasis
iIn inorrhagic vasculitis) I )ystrophy has the same result
I'llll 1 Spcclal (S yslc iiilc ) l’ullio|ihyslolo|ty

ЛИ immune complexes may be absorbed on the endothelium causlnu iiiiH M

immune inflammation (immunocomplex hemorrhage vasculitis was incnlloiinl ИЙ
l> 93).
Hemorrhage syndrome is also observed in the activation of membram |<1ии
pholipid peroxidation. It results in hypcrproduction by the endothelium ol i . i i m h |
inhibitor of platelet aggregation — prostacyclin (P G ).
Л disorder of thrombocytovascular hemostasis takes place. Vessels I*» . il*
ability to contract, the endothelium loses the ability to produce НЛ.Ч <pm.i m-i-ih
dins, procoagulants).
Vessels lose solidity due to impairment of collagen synthesis (collagcn с •
bocytc activator; if collagen is destroyed or its synthesis is impaired, platelet •hIIi#|
sion and conformation are afTected).
Predisposition to bleeding is observed.

HYPERCOAGULATION
TH RO M BO PH IUC SYNDROM К

Syndrome of hypercoagulation, or thrombophilie syndrome, is a tendency

tlirombogenesis arising spontaneously or due to insignificant vessel injury.
Hlood coagulation increase declares itself as local thrombosis 01 .......... *•*♦!
intravascular blood clotting. Thrombophilie disease causes vascular o c c I u m h i i >*im!
is a source of emboli.
In severe cases thrombi can form not only in the veins, where the blood il«
rate is slower (Virchow called it a necessary condition of tlirombogenesis), luii
in the arteries.

Etiology

Mechanical injury is the most common cause of blood coagulation In till >
blood clot (thrombi) formation is a defense reaction and has a positive valm
In pathology, the causes are mainly endogenous. All types of vessel iiiiim \ i
sel inflammation, dystrophy, atherosclerosis, formation of fibrous phu|in . Ии
may lead to excessive clot formation.
(ienetic factors may underlie predisposition to hypcrcoagulation In ми Ii •
all other reasons play a role of conditions. Even a small quantity ol clot ритм
substances can induce intravascular coagulation on the ground of gcnelU i "
position.
More details are given below.

Pathogenesis

In pathology, two principle pathogenic mechanisms underlay hyp*.... .

Iio ii.1 ) blood coagulation system activation 0 1 b ) anticoaKulation system d< li> ‘
As to primary cause localisation, the nicchnnlsins may be connected with pulln
 Chapter 23. I’alholoio of I I ciiion I msI s

I I pi<>icms, thrombocytes or endothelium. In the latter case we speak about

Ии Iii mi thromboresistance decrease.
11" I'.ithogenesis of hypercoagulation includes the following mechanisms.
I m. к i .nl formation of procoagulants due to massive tissue injury (including
....... "iterative trauma and crush syndrome).
i ti. i <.1 production of blood clotting activators.
Im и i «d quantity of thrombocytes (thrombocytosis).
II не<in.m factor (X II) deficiency.
I il i и и il v m s failure (profibrinolysin deficit).

•'•tin. i ion in the quantity of anticoagulants, first of all, heparin and antithrombm
III
А. и ii ton of the prothrombotic function of the endothelium in case of its chron
ilniiiagc, vessel inflammation (allergic and autoimmune), atherosclerosis.

J "•с mi nifiit of the antithrombotic function of the endothelium (decreased quan

i " . "I prostacyclin or sensitivity to it).
||i ttiin оnccntration.

rtl Manifestations

11\ i«'Icoagulation results in blood circulation disorders, local hypoxia, in.il

....ung of the organs, where excessive blood clot formation takes place.
lb lnw the most relevant clinical examples are given, when hypercoagulation
urn •. л problem.
11....ubophlebitis is a widespread surgical disease connected with both chronic
llintiitory vein damage and coagulation system activation. Trophic ulcers and
in i tic frequent outcomes of this disease. Thromboembolism is its another
I'll! Mtlon.
hi .orders of lipid metabolism (its activation) are accompanied with throm
It is connected with relative heparin deficiency (since heparin functions not
i hi anticoagulant, but also as a lipase activator, p. 230). Consequently,
t\ i s accompanied with a tendency toward thrombogenesis and thromboem
м. I lie same situation is observed in lipid metabolism disorder in atherosclc
which is also accompanied with constant vessel injury. DM is complicated
itlii'tosclerosis, hence with thrombosis (see scheme 13 on p. 230).
I limmbosis of microcirculation vessels is noted in allergy.
In mmiic malignant tumors (carcinoma of the mammary glands, lungs) proco
Hi', nitty be* excessively produced.
I'o itoperative thrombosis is connected with excessive formation of procoagn

Si i >1 is accompanied with thrombosis due to impairment of the anticoagulant

и i n . i l nl ilie vascular wall caused by its damage hy bacterial toxins.
I 'iiiI 2 S|M't lul (SysU-mk ) l'Hlli<>|ih>sl<ili>Kv

D IS S E M IN A T E D IN I KAVAM ЧИ.АК
CO AGULATIO N (D IC SY N D R O M E)

Disseminated (generalized) intravascular coagulation (D IC syndrome) is ihe

gravest form of hemostasis pathology. Frequently it is lethal.
D IC syndrome is a disorder of hemostasis, which manifests itself through massive
formation of thrombi and microemboli in the vessels, mainly of the microcirculatorv
bed.

Etiology

DIC syndrome is never inherited but only acquired. The possible causes an
the following:
• massive trauma of tissues, crush syndrome, operative trauma of the parenchyma
(ous organs;
• massive bum;
• obstetrical pathology, premature placenta removal, manual placenta removal,
amniotic fluid embolism;
• acute intravascular erythrocyte hemolysis (p. 282);
• leukemia (destruction of a large amount of neoplastic cells, p. 316);
• (rue erythrocytosis (p. 291);
• uremia (renal insufficiency);
• generalized infections, sepsis;
• all kinds of shock, terminal states;
• acute pancreanecrosis;
• peritonitis;
• side effects of the medicines, which influence hemostasis.

Pathogenesis

D IC syndrome is the heaviest pathology of hemostasis. It is an imbalance «и

.ill hemostasis mechanisms.
I he main pathogenesis link is imbalance between the coagulation, anticoagulu
lion and fibrinolytic systems and their simultaneous activation with further exlunis
lion of all of them.
II occurs when a large quantity of procoagulants and blood clotting activator,
t illers ihe blood in massive trauma, which leads to formation of numerous mu m
i lois hi microcirculation vessels. Later hypocoagulation, thrombocytopenia ami
hemorrhage develop due to coagulation factor lack and increased functional aclivih
ol Ihe anticoagulation system and fibrinolysis.
I he pathogenesis of D IC syndrome proceeds in two stages.
Stage o f hypercouKulation is excessive procoagulanl formation and activation
ol the blood coagulation system. A great amount ol procoagulants enter the blood
(tissue thromboplastin plays the mam role) Inlravnst ular formation ol mimenm.
 ( Im plcr 23. Га11|»1<>к> of I Irniostasli

inieroclots occurs. Blood circulation can stop, which is often incompatible wiili
life.
Microclots stop microcirculation and cause development of heavy dystrophic
•hkI functional disorders in organs (renal, cardiac and pulmonary insufficiency,
luain damage). They are not compatible with life.
Stage o f hypocoagulation starts as a reaction. The systems of anticoagulation
•«rid fibrinolysis get activated. The content of coagulation factors (thrombocytes,
llhrinogen) significantly decreases as a result of their use in the previous phase, l i
hrinolysis activates and this fact aggravates hemorrhage. Severe bleeding is difficult
t«>stop. It is a terminal phase of syndrome. Complete exhaustion of all hemostasis
\ .terns underlies hemorrhage. Necrosis develops in the organs, where blood supply
• unpaired in the form of hemorrhage or thrombosis. In the kidneys, lungs, and
heart it is incompatible with life.
I he situation can become uncontrollable and lead to death. A patient dies ei
ilier from thrombosis or hemorrhage, which cannot be stopped. The situation can
hardly stopped therapeutically.

METHODS OF HEM OSTASIS STUDY

Investigation of hemostasis is of high practical value. Some methods are widely

нм-d in everyday practice; others are used in scientific investigations.
I he thrombocyte count is calculated in a specially stained blood smear.
Ihromboelastogram is a graphical study of different hemostasis indices. In
Hr 37 two types of changes are rep-
icscntcd — hypo- and hypercoagula-
lion The difference is obvious. There
• i method of numerical analysis of
uives and many important hemo-
.1 r.is indices.
With the aid of modern bio-
*40
ln mical and immunological meth-
"I all hemostasis factors may be
ilrtermincd. Thus, in case of hemo-
I'luli.i there are some forms of this
ii '-.ise (А, В, C, parahemophilia)
.... netted with the absence of dif-
!■u ni procoagulants (antihemophi-
lli globulin, plasmatic kallikreino-
i'<и convertin, etc.). It is possible Fig. 37. Thromboclastograms
to determine all of them giving a 0 " norm: h ~ hypercoagula.ion; <
• hypocoagula
lion
•oiiecl diagnosis.
1’iirt 2 S|M'«'inl (S yslcin l* ) Г»|1ю||||у%1о1оку

Questions for Si‘ir-('oiilrol

I What does the term hemostasis mean?

2. Name and classify the physiological mechanisms of hemostasis.
V Explain the role of platelets in hemostasis.
4 What are prothrombotic and antithrombotic functions of the vascul.n
endothelium?
(iive a classification of hemostasis pathology (name the principles ol
classification).
(> What is the role of genetic mechanisms in hemostasis pathology?
7. What is the difference between thrombopenia and thrombopathy?
X What is hemorrhage vasculopathy?
l) (iive the characteristics of thrombophilie syndrome - its definition, etiology,
pathogenesis, clinical manifestations.
10. (iive the characteristics of DIC syndrome - its definition, etiology, pathogenesis,
clinical manifestations.
11. What are the methods of hemostasis pathology study?

Tests and Tasks for Self-Control

(give correct answers and find mistakes in the statements)

1. (iive a correct scientific definition of the term hemostasis.

1. It is bleeding arrest.
2. It is blood coagulation.
3. It is maintenance of the liquid state of the blood.
4. It is a function of the organism, which consists in maintaining the liquid
state of the blood and its coagulation in case of need.
5. Platelets do not participate in maintaining the liquid state of the blood
6. The vascular wall does not participate in maintaining the liquid state <»l
the blood.
7. Blood proteins do not participate in maintaining the liquid state of tin
blood.

2. (iive the characteristics of thrombocytovascular hemostasis and its mech.i

nisms.
I . It is participation of blood proteins in hemostasis.
2. It is participation of platelets in hemostasis.
It is participation of the vessel wall in hemostasis.
4. Il is participation of the vessel endothelium in hemostasis.
5. Il provides arrest of bleeding.
(). It does not provide the maintenance of the liquid state of the blood.
7. It provides thrombosis.
К I lie system ol fibrinolysis belongs lo thrombocytovascular hemostasis
 (h iip lc r 23. I’atholony of llomoslnsts

It is divided into 3 systems:

9. System of blood coagulation.
10. System of blood anticoagulation.
11. System of fibrinolysis.

<iive the characteristics of platelet function in hemostasis.

1. Participate in arrest of bleeding.
2. Participate in maintaining the liquid state of the blood.
3. Provide the trophic function of the vascular wall.
4. After vessel injury such processes take place — aggregation, adhesion ol
thrombocytes, and formation of thromboplastin, which starts blood со
agulation.
5. Release serotonin, which dilates vessels.
Such substances are released from thrombocytes:
6. Thromboplastin.
7. Prostacyclin.
8. Heparin.
9. Thromboxane.
10. Growth factor of the endothelium.
11. Collagen.

How does the endothelium participate in hemostasis?

1. Participates in blood coagulation.
2. Does not participate in maintaining the liquid state of the blood.
3. Participates in bleeding arrest.
4. Does not participate in thrombus formation.
5. Synthesizes thromboxane (P G ).
6. Synthesizes prostacyclin (P G ), which is a potent thrombocyte aggregation
inhibitor.
7. Produces Willebrand factor, which is necessary for platelet adhesion to the
vessel wall.
8. System of fibrinolysis belongs to vasculothrombocytic hemostasis.

<iive (he characteristics of the fibrinolysis system and its pathology.

1. It refers to vasculothrombocytic hemostasis.
2. It presupposes thrombin dissolution.
3. It presupposes fibrin dissolution by plasmin.
4. Plasmin and fibrinolysin are synonyms.
5. Plasmin is present in the blood in the active form (plasminogen, or pro
fibrinolysin.
Its activation leads to:
(>. Hypercoagulation.
7. Hemorrhage.
8. Thrombosis.
I'm I 2. N|M4'inl ( System ic) l*ullio|>hysiuluK.v

The most relevant clin ical situations tire:

9. a-Hemolytic streptococcus infection (rheumatoid endocarditis).
10. Operative trauma (of the parenchymatous organs Ihe lungs, liver, utei
us, pancreatic gland).
11. Appendititis.
12. I rypsinogen activation (in pancreatitis).
13. Burns.
14. Overdose of fibrinolytics as medicinal preparations.

ft I xplain the pathogenesis of hemorrhage vasculopathy.

I Vasculopathy is a vessel pathology resulting in the impairment of on
dothclium participation in hemostasis.
2. Activation of the prothrombotic function of the endothelium.
3. Inhibition of the antithrombotic function of the endothelium.
4. Production in the endothelium of a potent inhibitor of platelet aggregation
— thromboxane.
5. In vasculopathy the endothelium loses the ability to produce BAS (thrum
boxane, thrombasthenin).
ft. Vessels lose solidity due to disorders of collagen synthesis.
7. Lack of production of prostacyclin (P G , a strong inhibitor of platelet ay
gregation) in the endothelium predisposes to hypocoagulation.
X. Immune injury of the vascular wall is imposible.
9. Acquired and inherited disorders of collagen synthesis can underlie va.sui
lopathy.

7 (iive the characteristics of D IC syndrome.

1. It is local blood hypercoagulation.
2. Il is the gravest form of hemostasis pathology.
Causes may be the following:
3. Premature or manual placenta removal.
4. Side effects of the medicines, which influence hemostasis.
5 Operative trauma of the parenchymatous organs.
ft. May be inherited.
Pathogenesis o f D IC syndrome:
7. Ii is an imbalance of all hemostasis mechanisms.
X Proceeds in three stages.
Consequences may include:
9. A patient may die from thrombosis.
ID. A patient may not die from hemorrhage.
11 I’his pathology is well curable.

X Blood examination showed thrombocytopenia as a complication of an autulm

munc process. VVIiat is the cause ol throml>ocylopcnia in tins case?
A Disturbance ol thrombocyiopoiodN irttulniion
 ( Im plcr 23. Pathology of llc iilo s lu s ls

B. Decrease of thrombocyte production.

C. Redistribution of thrombocytes.
D. Destruction of thrombocytes.
E. Increased consumption of thrombocytes.

A 9-year-old boy has spontaneous hemorrhages. The hemoglobin blood con

tent is 72 g/1. A diagnosis of chronic posthemorrhagic anemia connected will)
hypocoagulation has been given. Causes of hypocoagulation may be acquired
and hereditary. What are they?
Hereditary causes are:
1. Radiation disease with thrombocyte deficiency (due to decreased forma
tion of platelets in the bone marrow).
2. Diseases of the liver, when procoagulants (prothromboplastin, prothrom
bin, fibrinogen, antihemophilic globulin, etc.) are synthesized.
Acquired causes are:
3. Appearance of procoagulant inhibitors.
4. Vitamin К hypo- and avitaminosis.
5. Autoimmune aggression towards coagulation proteins.
6. Overdose of the procoagulant heparin.
7. Defect of the genes, which are responsible for procoagulant synthesis.
X. Genetic defects of antihemophilic globulin synthesis in hemophilia.
9. Genetic hypo- and afibrinogenemia.
10. Acquired causes are called coagulopathy.

I )sc as an example the scheme of hemorrhage shock pathogenesis (fig. 30 on

p. 272) and compile a scheme of D IC syndrome pathogenesis in it.
( hapter 24
I’ATIIOPHYSIOLOGY OF HEART

I'he heart, as a pump, performs the function of moving the blood through the
circulatory system.
I lie main indices of heart performance are heart stroke, minute volume and the
speed of Mood circulation. If these indices are within the standard, we speak about
ellcctive heart work. If otherwise, we speak about cardiac insufficiency.
( 'ardiac insufficiency is a pathological process, which is characterized by impair-
iiiciit of heart functioning as a pump to move the blood through the vessels at a proper
speed and inability to supply tissues with the necessary amount of blood at rest and
under physical load.
Cardiac insufficiency develops in discrepancy between the required load on the
In .ui and its ability to perform this work.
logether with cardiac insufficiency we speak about vascular insufficiency (see
I lie next chapter). We often observe combined cardiovascular insufficiency.

CO M PENSATO RY M EC H A N ISM S O F T H E HEART

Both under physiological and pathological conditions the heart has some
mechanisms to activate its function (compensatory hyperfunction). The heart can
;|iiu kly adapt to load increase and, carrying the increased work, compensate pos-
*ihle disturbances of blood circulation.
I here are three adaptive mechanisms, which provide the maintenance of the
icart minute volume and a proper speed of blood flow:
• Enforcement of heart contractions.
• Acceleration of heart contractions (tachycardia).
• Enlargement of heart (hypertrophy).
I ach mechanism has its advantages and disadvantages. They are evaluated
ими the following points of view.
Advantages are:
• urgency of development (immediate reactions), which has an advantage over
delayed reactions;
• long lasting duration of adaptive reactions;
• energy economy.
Disadvantages are:
• slow development;
• short term duration;
• energy dependency.
From these points of view, the named mechanisms of hyperfunction difler in
ic following ways.
I nlorccmciii and acceleration of heart contractions are immediate reactions,
which develop iiist after overloading begins, but they arc short-term and require
additional energy for realization.
 C'hiiplrr 24 l*ullio|iliv4loloKy of llru rl

• Acceleration (tachycardia) is a more energy-dependent reaction than enforce

incnt.
• I nlargement of the heart (hypertrophy) requires a longer time for its develop
mcnt (delayed reaction), but it is less energy-dependent and ensures more lasting
adaptation.
Under physiological conditions these mechanisms provide physical and cmo
iinnal overstrain. The same mechanisms operate in cardiac or vascular pathology as
■uinpensatory reactions.
Deep knowledge of the pathophysiological mechanisms of heart hyperfunction
helps to understand cardiological clinical situations and give prognosis for patients
m iIi cardiovascular pathology.

м nut's of Cardiac Insufficiency

Under increased heart load the disorders are divided into two stages.
Stage o f compensation takes place, when in spite of the harmful effect of the
etiological factor the heart minute volume and blood flow speed are kept at the
normal level.
Stage o f decompensation develops, when the heart minute volume decreases,
■ougestion in the circulatory system develops.

CLASSIFICATION

I he pathophysiological classification of cardiac insufficiency (according to the

mechanisms of development) is of special attention. There are three pathophysio­
logical types of cardiac failure.
1. Cardiac insufficiency due to overload o f the heart occurs, when a healthy heart
l»<ilorms hard work for a long time.
2. M yocardial type of cardiac insufficiency results from prim ary myocardium
pathology. It may be caused by disorders of coronary circulation, autoimmune ag­
gression against the heart, infection, intoxication, hypoxia, avitaminosis, systemic
hormonal and electrolyte imbalance, some hereditary disturbances of metabolism.
M ixed type of cardiac insufficiency develops, when damage of the myocar
ilium is combined with heart overload (for example, in rheumatism, when inflam
m.itory lesion of the heart is combined with disorders of the valve apparatus).
Depending on the clinical course, cardiac disturbances are divided into:
•0 acute and chronic; b) right-side and left-side; c) prim ary and secondary (as an as
mu latcd symptom of other diseases — fever, anemia, hyperthyroidism, etc.).
I lie etiology and pathogenesis of different types of heart insufficiency are dil
ft rent.

CARD IAC IN S U F F IC IE N C Y C A U SED BY H EA R T O VERLO A D

In this case wc mean Ihe situations, when the healthy heart with normal con
inu tile ability is overloaded
I'ii 11 } S|m'«'InI (System ic) l >Hlliii|ihy\li>l<>K>

Types of Heart Overload

I he type of heart overload is of high significance for evaluation of the defensive

.ilnhiy of the heart.
I here arc two types of heart overload. They are:
• volume overload due to an increased amount of blood inflow;
• overload by resistance (pressure) to blood outflow.

ETIO LO G Y

I liological factors are the ones, which increase heart load. Causes may be ex-
Irucardial and intracardial.
Physical overstrain increases blood inflow into the heart (load by volume). Sys-
teiitic or pulmonary arterial blood hypertension also hampers the work of the heart
but by increased resistance (pressure). Generalized atherosclerosis, pneumosclero
i aorta contraction (atherosclerosis, luetic gumma) create resistance overload.
Intracardial morphological defects also create overload to cardiac chamber
x lore ihe defect. There are two intracardial situations connected with: a) narrow-
iik (stenosis) of foramen, which overloads the preceding part of the heart by resis
пн е and b) valve insufficiency (regurgitation), when morphological defect of the
.ilsc impairs its complete closure and causes overload by additional (regurgitant)
volume.
PA TH O G EN ESIS

I lie heart can rapidly adapt to load increase and, carrying the increased load,
onipcnsatc possible disturbances of systemic blood circulation.
Depending on the type and duration of the load, this or that mechanism of
onipcnsation (mentioned above) begins to act.
Enforcement of heart contractions (in its turn, it is subdivided into two types
ieiem and lionieometric).
■Ureleration of heart contractions (tachycardia).
/ nlarxcmenl of the heart (myocardium hypertrophy).
Due to these mechanisms the heart minute volume is supported at the normal
м -I. systemic disturbances of blood circulation are prevented.
As to the effectiveness and duration of compensation, disease outcome and
toyiiosis foi the patient, these mechanisms have different values.

Heart Contraction Enforcement

Increase of heartbeat force is the first immediate compensatory reaction, which

lould he mentioned because of its prevalence over others.
I here arc two different mechanisms of compensatory enhancement depending
n (lie iwo types of heart overload: hetero- and homeometric. They have different
ieehiinism.s ol development, different duration of compensation and decompcnsa
on stages, different outcome and prognosis (ot the patient.
 ('Im p lor 24. I’Hlhoph'NsloloK'Y of Il«*xrt

Volum e Overload

If the heart is overloaded by volume, the mechanism of heart contraction en­

hancement is called heterometric. It means more significant preliminary extension
■'I ihe myocardium before systole.
rhe heterometric type of cardiac hyperfunction is observed in physical work (ii
i hi extracardial situation).

Intracardial situation is observed in morphological defects of the valves (their

in* omplete closure). During diastole a certain cardiac cavity is filled not only wiili
iln hlood inflowing by the normal route, but also with the regurgitant blood return
Iiik due to incomplete closure of the valve during systole. The same is observed in
congenital defects of the heart septum.
Elevated blood filling of the heart cavities during diastole and increased disten
■mu of the muscle fibers result in stronger heart contraction during systole in ac
■«иdance with Frank—Starling’s law. This mechanism is conditioned by myocardial
lil >ci elasticity.
Permissible increase of the linear size of the heart muscle fibers is up to 15
4) V. Such cardiac dilatation may be accompanied by an adequate increase ol
Ii- irtbeat force and is called tonogenic dilatation. However, when the degree of
myocardial fibers stretching exceeds the permissible limit (more than 25 % of their
initial length), contractile force decreases.
Heterometric hyperfunction is less energy-dependent and more favorable for
tin- myocardium in comparison with resistance overload and homeometric type of
hyperftrnction, which is described below.

Ki-sistance Overload

If resistance (pressure) overload occurs, the mechanism of heart contraction

•nh.mcement is called homeometric (without preliminary more significant myocar
di.il dilatation before systole and Frank-Starling’s law). The length of the cardiac
muscle fiber is not additionally increased.
I his mechanism of compensation is connected with a considerable increase
■I svstolic pressure to overcome the increased resistance to outflow. It may be
и lucved by a more significant increase of muscle fiber tension. Enhancement ol
In im contractions gradually develops during some subsequent heart contractions
until il reaches the level, which is necessary to ensure proper heart minute volume
11 needs additional A T P and oxygen. So, this form of compensation is more energy
dependent than the heterometric one.
I he homeometric type of hyperfunction develops in arterial blood hypertension,
iMiieralizcd atherosclerosis, pneumosclerosis and intracardiac foramen stenosis.
Comparative analysis of the hetero- and homeometric types of cardiac hy
I>eifunction (fig. 38) allows understanding the differences in the clinical course ol
unions types of cardiac pathology. Thus, in arterial hypertension and stenosis of the
Intiiicardiac foramens, the phase of compensation is shorter; the stage of dccom
pensation and patient's invalidity starts more rapidly. The pathological processes,
winch an* based on the I milk Stalling mechanism (in extensive physical work, in
Г.Ill ) Nprriat (S yslciiiic) rMllui|ilivsioliiKy

Incomplete valve closure), have a more favorable course. As to physical work, it can
be used lor heart training.

V. W . per inin V, W , per min

A В
liK IS. Dependence between cardiac output (V) and work (W) in heterometric (A) and
lioincomctric (B) compensatory mechanisms (heart rate is constant):
i Ii the lower and upper levels of the volume of the incoming blood and resistance to blood outflow,
ln’vond which there is no compensation

Heart Contraction Acceleration (Tachycardia)

Tachycardia is heart rate increase. This compensatory reaction, as well as in

crease of heart contraction force, is immediate and quickly contributes to the main
tenance of the heart minute volume and a proper speed of blood flow.
Mechanisms of tachycardia may be intracardial and extracardial.
Intracardial regulation belongs to the right atrial pacemaker — the sinoatrial
node that is stimulated by the direct effect of atrium distension.
I xtracardial regulatory effects may be nervous and humoral. The main role
belongs to the sympathetic part of the autonomic (vegetative) nervous system and
its mediator noradrenaline, which is released by the nerve endings. The same effect
belongs to the hormone of the adrenal medulla. These mediators (catecholamines)
internet with l^-adrenoreccptors on the cells of the sinoatrial node.
In sympathetic excitation, the force and rate of heart contractions are con
•iderahly increased, blood outflow from the heart during systole is more complete
(under usual load about half of the blood remains in the ventricles at the end ol
systole).
However, from the point of view of energy need, tachycardia is a less advanta
gcous mechanism of compensation in comparison with enforcement according the
I i.ink Starling mechanism. Its disadvantages arc the following:
• considerable oxygen consumption;
• shortening of the period of myocardium restoration and rest due to considei
able shortening of diastole (fig W);
 Chapter 24. I'lilhophysloloiiy of Heart

• decrease of myocardial contrac­

tility due to diastole shorten­
ing and poor filling of the heart
cavities with the blood. Systole Systole
becomes less effective. The he­
| | Diastole
modynamic characteristics of
the heart worsens.
At 170 beats per minute, the be­
ginning of atria contraction approaches
the end of ventricular systole (atrial oc-
. Iiim o ii). In EC G the P wave overlaps
the I wave.
If heart overload exceeds the
limned compensatory mechanisms (en- 100
Heart rate, bpm
luicement and acceleration), cardiac
insufficiency may develop. If overload Fig. 39. The change of duration of the cardiat
cycle, systole and diastole in different heait
I-. moderate but prolonged and perma-
rates. The atrial systole is shown by haehurcs
iiint, another compensatory reaction
■It sflops. It is compensatory hypertrophy of the myocardium.

Heart Enlargement (Myocardium Hypertrophy)

I lypertrophy of the myocardium is its enlargement due to increase in the size of

■и Ii muscle fiber (but not due to increase in their quantity). Specific metabolic and
11 in tural changes develop in the myocardium leading to increase of heart mass and
•> ikability. This type of compensation is delayed but long-term and economical.
I he IS F index (intensity structure function) is used to characterize the dynam
и <>l myocardial hypertrophy development. IS F = W/m (IF is work, m — mass of
ili< myocardium) reflects load on the functional units of the myocardium, which
1 I s i) must be constant for prolonged and steady heart work. According to the dy
mimics of changes, expressed by IS F , hypertrophy develops in 3 stages.
1. Stage o f emergency (urgent) hyperfunction is characterized by increase in Ihe
i ni < •of heart contractions by homeometric or heterometric type depending on the
i i" of overload. This stage develops immediately after overload beginning, how
I il is short-term and energetically uneconomical. The load on the muscle units
in* iciises (T !S F = tW /m ).
I his stage is characterized by a combination of pathologic changes in Ihe
...... irdium and mobilization of its reserves. It includes glycogen disappearance
*1•im lion of the creatine phosphate level, intracellular potassium decrease and so
ilium content increase, glycolysis mobilization, and lactate accumulation. The dis
nukiiiees of metabolism, which take place, start hypertrophy. The heart enlarges
Пне lo intensified protein synthesis and muscle fiber thickening.
2. Stage o f complete hypertrophy and relatively stable hyperfunction reflects
iIh so called «plastic snppoit- for myocardium hyperfunction till IS F normalizes
{I\l tWyt/w).
I’iiiI 2 Spi'i'inl (S y s lfn iir) I’allmpln м<»1оц>

Al this stage the process of hy­

pertrophy is completed, the myo­
cardium mass may increase by
100 120 % . Oxygen uptake, en­
ergy formation and the content of
macroergic compounds are within
I lie norm. The hcmodynamic indi­
ces are normal. The hypertrophied
heart adjusts to the new load and
compensates it for a long time. All
components of the heart undergo
hypertrophy - myofibrils, capillar­
ies and nerve endings.
Nevertheless, this stage is not
endless. I'he hypertrophied myocar­
dium loses its harmonious propor-
tlons (lig. 40). The mass of myofi-
bi iIs, cellular membranes, nuclei,
<ipillaries and nerve endings in- ftg. 40. Correlation between the cardiac muscle
creasesdisproportionately.Themyo- fibers, capillaries and nerves in a newborn (a, d),
i .iidiuin loses its reserves and dec- a healthy adult (b, e; heart mass is 310 g), and
onipcnsation is inevitable. an adult with hypertrophied myocardium (c, f;
t. Static o f decompensation (de- heart mass is 540 g)
1 rcascd function), gradual exhaus­
tion and progressive cardiosclerosis is the final stage. It is explained by impairment
nl myocardial trophicity, hypoxia, which leads to cardiosclerosis, pathological ac­
cumulation of Ca2+ ions in cardiomyocytes (calcic damage of cells, see p. 262).
I he mass of active cardiomyocytes decreases. IS F increases but on the basis of
decreased mass (T lFS= T W /lm ). Heart decompensation starts. The stage of gradual
L'xhaustion and progressive cardiosclerosis is characterized by profound metabolic
uul structural changes in the myocardium, myogenic dilatation. It is a condition of
1'/ironic cardiac insufficiency.
M YO C A RD IA L IN S U F F IC IE N C Y

Myocardial insufficiency results from prim ary myocardium damage. In this

ise. disorder of myocardium contractile ability and heart insufficiency develop
м и under normal or decreased heart load.
Myocardial heart insufficiency may be acute and chronic and, according to the
involvement of coronary circulation, — coronarogenic and non-coronarogenic.

ETIO LO GY

I liological factors of direct myocardium damage can be physical (passage ol

lei Inc current through the myocardium), chem ical (toxins, smoking), biological
infection, illumine factors, emotional slicss, hereditary dismetabolism, thrombi
uul emboli, electrolytic and hormonal imbalance)
 Chapter 24 1'м11|ор1|>ч1о1ок> <>r llc .u i

Hypertrophy of the myocardium at the third stage of its development is ac

■ompanied with myocardial dystrophy.

PATHOGENESIS

All the pathological processes described in the previous chapters, can develop
in the myocardium - inflammation, allergy, microcirculation disorder, dystrophy,
atherosclerosis, necrosis.
In case of myocardial heart failure, the adaptive reactions which have been
mentioned above develop but there are the following peculiarities:
• Possibility of myocardial contraction enhancement is limited.
• Possibility of myocardial hypertrophy is limited.
• Compensation is mainly induced by tachycardia.
Thus, the stage of decompensation begins earlier.
Depending on the involvement of coronary circulation, myocardial failure is
ilivided into two forms:
• coronarogenic damage of the myocardium;
• non-coronarogenic damage of the myocardium.

Coronarogenic Myocardium Damage (Ischemic Heart Disease)

Diseases and pathological states accompanied by disturbances of myocardial

Mood circulation all refer to a special nosological unit called ischemic heart disease.
It declares itself through functional disturbances and pain syndrome (angina pecto­
ris) or leads to necrotic changes of the myocardium.
M yocardial infarction is a local ischemia and necrosis of the heart occurring due
to limitation of blood supply or when the amount of blood is insufficient to meet
energy requirements.

Etiology

Ischemia (decreased blood filling of the myocardium caused by arterial blood

Inflow limitation or stopping) underlies coronarogenic damage and necrosis of the
imocardium. According to the cause, myocardial ischemia (as any other ischemia.
P I OS) is divided into obstructive, angiospastic and compressive.
I he cause of obstructive ischemia of the myocardium is coronary artery narrow
lug (or occlusion) by thrombi, emboli or arteriosclerotic plaques.
I he cause of angiospastic ischemia of the myocardium is functional disturbances
nl (he vasoconstrictive and vasodilative apparatus of the coronary vessels.
I lie cause of compressive ischemia of the myocardium is coronary artery com
pie .sion by a tumor (for example, by syphilitic gumma).
Atherosclerosis is the most frequent cause of coronary artery wall defects. In
most cases, myocardial infarction develops due to calcification and ulceration ol
iilhcrosclerotic plaques with the lollowmg vessel occlusion by a thrombus.
Mcnosing sclerosis of the coronary vessels limits entering of nutrients into the
•Hiiliac muscle. Even insignificant vast ulai stenosis based 011 an increased need ol
ihe muscle lor oxygen may cause не» losls
I’iii I .’ S p e c ia l (N ystrniU ') l*Mlh«>pli>

Coronary blood circulation is impaired In am ir arterial hypotension (shock,

collapsc, blood loss), bradycardia, cardiac insiittiueiicy ol any genesis, aortic valve
defects (diastolic arterial pressure falls abruptly)
Risk factors leading to infarction include arterial hypertension, excessive physi
eal work, thrombophilie syndrome (p. 330), atherosclerosis (p. 372), hormonal and
electrolytic disturbances, DM , overeating, consumption of a large amount of fats,
smoking, stress, hereditary factors, gout, environmental factors. A tight connection
Ik -tween pathogenesis of myocardial infarction, obesity, atherosclerosis, thrombosis,
and DM is represented in scheme 7 on p. 230.

Pathogenesis

I lie following pathogenic variants of myocardial infarction development arc

possible.
• Occlusion of the vessel promoting coronary blood flow decrease below the criti
cal level (usually 3/4 of the normal vessel lumen).
• Stenosis, which does not declare itself at rest but under little exertion, physical
or mental, resulting in cardiac ischemia.
• Physical exertion or emotional stress, which may cause inadequacy of the need
lor oxygen to the possibility of blood inflow. In this case, intensified secretion of
catecholamines and adrenal hormones plays an important role.
In ischemia, the deficit of oxygen, substrates and A T P in the myocardium takes
place.
I he increased function of the sympathoadrenal system in stress and release of
large doses of catecholamines into the blood frequently accompany ischemic heart
disease in man. It activates the heart, increases the level of free fatty acids in the
blood and increases oxygen consumption (the latter is a reason for relative circula
torv hypoxia, p. 161). In these cases protection of the heart from catecholamines,
for example, by using p,-adrenoblocker, is beneficial.
Absorption of substances from the necrotized myocardium areas into the blood
is accompanied with appearance in the blood of myoglobin and intracellular en
/vines (creatinphosphokinase, aspartataminotransferase, lactate dehydrogenase)
which is named resorption necrotic syndrome. This fact may be used for diagnostic
purposes. Cellular protein resorption is accompanied by fever, increased erythro-
cyte sedimentation rate (E S R ), leukocytosis (hematological syndrome, neutrophilu
leukocytosis, regenerative left-side nuclear shift.
I lie entry of intracellular myocardial proteins into the blood flow may be ac­
companied by autoimmunization with production of anticardiac antibodies and
sensitized (to cardiac antigens) lymphocytes as well as eosinophilia and hypei
Kamniaglobulincmia. I he development of postinfarction syndrome (Dressler’s syn
drome) is associated with it. The syndrome is characterized by inflammation of the
serous membrane of the heart, lungs, and joints.

Manifestations

Myocardial ischemia and infarction may be clinically diagnosed with the help
ol I ( ( i I tiiiuiv. the first minutes allci <initiation disturbance there develop chang
 Chapter 24. I’alhophyNkrfopy <>f Henri

■i in the electrocardiogram such as deviations of the S—T segment, changes of the

i >I<S complex and T wave.
Infarction develops in the area of the myocardium, which is supplied by the
I'I'mhI through damaged vessels.
Morphologically, at first structural impairment of mitochondria is noted. Then
mi. U i swelling or pyknosis occurs. The transverse striation of the muscle fibers dis
ippears. Cardiomyocytes lose glycogen and potassium. H + ions are accumulated.
rhe main consequence of infarction is local coagulative necrosis and myocyte
i' i I here are several zones in the focus of infarction. In the central area the tis
in is irreversibly damaged. In the intermediate zone there are necrotized muscle
lls with signs of calcium accumulation. Dead cells are surrounded by neutrophilic
»ii,imilocytes, which later are substituted by macrophagocytes, lymphocytes and
ri ismacytes. Later on, cardiomyocytes are resorbed and substituted by fibroblasts
uni connective tissue. The main systemic disorder is accumulation of Na4and wa
им in the organism — cardiac edema (p. 257).
I'ain is a typical clinical manifestation of ischemic heart disease and myocai
<lt.il infarction. It is characterized by typical localization in the upper left part ol
Ihc body and behind the breastbone. However, there have been observed painless
iiii.uctions.
Myocardial infarction causes acute cardiac insufficiency that leads to hypoxia,
и idosis, dysfunction of the brain and other organs, and finally to death.
Damaged (by atherosclerosis) coronary arteries may be substituted by normal
scssels with the aid of modern surgical techniques. Blood flow to the heart is thus
' lored (reperfusion). But, the ischemic myocardium, which has functioned under
limited blood flow for a long time, reacts to such sudden and quick recovery of
nxvgen supply by «oxygen explosion», formation of free radicals, damage of DNA
•ml mitochondria and release of cytochrome С and other apoptosis-inducing sub
i.mces. Mitochondria damage results in accumulation of Ca2+ ions in the cyto
pl isin and calcic damage o f cells (see p. 262 — tab. 7). It additionally enlarges ihe
пне of myocardial infarction and aggravates the general condition of the patient.
I lu-sc pathological events are called reperfusion syndrome.

Non-Coronarogenic Myocardium Damage

I here are several experimental models of cardiac muscle necrosis, which are
iiiii connected with cardiac vessel pathology.
Ilypoxic necrosis of the myocardium may be reproduced with the help of dil
I- icnt kinds of hypoxia: hypoxic and hemic. Necrosis development is promoted
li\ fixation of an experimental animal in an uncomfortable position (in this case
>nlicnaline increases the need for oxygen) or providing additional load (running on
*i trainer).
I'lcctrolyte-steroid cardiopathy with necrosis develops (according to Selye’s oh
•ivations), when a large amount of sodium salts combined with some anions (sul
lilies, phosphates) and aldosterone is injected to an experimental animal: Ihere
ilcvelops degcncnitive-nccrotic impairment of the heart.
Pun 1 S|M4'lul <S>sim ile | l‘«llio|>li\slol<>K\

Immune damage of the heart is possible in injection of a heterogenic serum to

an experimental animal with heart protein antibodies (cardiotoxins).
Mixed cardiac insufficiency occurs in different combinations of myocardium
damage and overload. For example, in rheumatism, it is a combination of myocai
diuin inflammation and disorders of the valve apparatus.

CARD IAC RH YTH M D IS O R D E R S (A R R H Y T H M IA )

Cardiac arrhythmia is a disorder of the rhythm of contractions of the whole

heart or its separate parts.
Depending on the localization of the cause, arrhythmia may be cardiac (caused
by heart diseases) and extracardiac (fever, anemia, hyperthyroidism, etc.).
I here is a classification of arrhythmia depending on the impairment of myo­
cardium functions — automatism, excitability, conductivity and contractility.
Ihe etiology and pathogenesis of arrhythmia varieties are different.

Automatism Disorders

Automatism disturbance leads to development of tachycardia , bradycardia and

respiratory arrhythm ia.
I he ability to form impulses automatically is known to depend on the cells
located in the conduction system of the heart (P cells). Spontaneous slow depolari
/ation of the cellular membrane occurs in them during diastole.
Tachycardia is observed under the influence of high body temperature, sympa
tlietic mediator effect, distension of the area of the sinoatrial node, loss of potas
sunn (the role of Na+and K +ions in excitability is described on p. 261).
Under stimulation of the vagus nerve, impulse generation is decelerated as well
.is heart rate — bradycardia develops (retention of potassium has the same effect).
f luctuations of the vagus nerve tone during respiration may cause respiratorv
arrhythm ia (accelerated heartbeats in inspiration and decelerated — in expiration).
Respiratory arrhythmia may be observed in healthy children, rarely in adults.

Excitability Disorders

I xcitability disturbance leads to development of extrasystolic and paroxysmal

tachycardia.
I lie difference of potentials between the neighboring cardiomyocytes may be a
mechanism leading to the appearance of ectopic excitation foci. Extraordinary con
traction of the heart or only its ventricles is called extrasystole. Under the influence
nl ischemia, an ectopic focus of excitation appears promoting extrasystole.
Sinus extrasystole arises due to premature excitation of some part of the sinoa
trial node cells. In EC G it doesn't differ from the normal contraction except foi
the shortening of the diastolic T —P interval I >uc to diastole shortening and reduced
ventricular filling, the pulse wave is decreased in extrasystole.
 ( h.ipU'i .4 Г иIim|iIi\ iuIii” > o f I I i -h i I

A trial extrasystole is observed when there is a focus of ectopic excitation in

ilitlerent areas of the atria. It is characterized by P wave deformation (decreased,
iwo phase, negative) in the preserved Q R ST complex and some lengthening of the
diastolic interval after extrasystole. It is conditioned by the fact that excitation,
coing not in direct but opposite direction, prematurely discharges a normal sinus
impulse, which coincides with ventricular excitation. Such extrasystole has an in
iomplete compensatory pause.
Atrioventricular extrasystole is observed under additional impulse in the atrio
utricular node. The wave of excitation from the upper and middle parts of the
node is spreading in two directions: normal — to the ventricles and reverse to
ilu atria. The negative P wave may precede the Q RS complex or overlap it. The
•h.istolic interval after extrasystole is a little prolonged. Extrasystole may be ac-
oinpanied by simultaneous contraction of the atria and ventricles. If the wave ol
■natation is formed from the lower part of the node, there is a compensatory pause.
' Inch is the same as in the ventricular extrasystole, and the negative P wave follows
ihc Q RS complex.
Ventricular extrasystole is characterized by a complete compensatory pause at
ii i extraordinary contraction. It develops because ventricle excitation is not trails
milled through the atrioventricular node to the atrium, and the following normal
impulse of excitation from the sinoatrial node does not cause contraction of Ihc
tnitrides, which are in the refractory phase. The next ventricle contraction occurs
niily after the next normal impulse. Therefore the duration of the compensatory
cause with the previous interval is equal to the duration of two normal diastolic
pauses.
If there is a group of quickly repeating extrasystoles, which completely inhibit
tin- physiological rhythm, paroxysmal tachycardia develops. Numerous ectopic foci
■■I excitation together with conductivity disturbance create conditions for repeated
•in illation of excitation and paroxysmal tachycardia development. The normal
iliythm of the heart is suddenly interrupted by an attack of contractions at the rate
nl 140-250 beats per minute. Attack duration may be different — from several sec
•mils to a few minutes. Then it suddenly stops and the normal rhythm restores. The
«trial form of paroxysmal tachycardia is most frequently observed.

Conductivity Disorders

Conductivity disturbance leads to the development of Mocks.

A block may be caused by conduction tract impairment, which leads to pro
longation of the refractory period and is accompanied by deceleration or complete
11 sation of impulse conduction. Conductivity disturbances may occur between the
sinoatrial node and atria, inside the atria, between the atria and ventricles, and in
•ню of the pedicles of the atrioventricular bundle. In intraatrial and intraventriculai
Mock heart rate does not change, and the disturbance manifests itself through I ( <«
■hanges. Changes of the heart rhythm and rate may accompany atriovcntriculai
block.
I'nrt 2 S|M4'lul (Syslcm lc) l’;illio|>livsiol<tKy

Atrioventricular or transverse block may be complete and incomplete. In incom­

plete atrioventricular block three degrees are distinguished depending on the degree
of conductivity impairment.
I irst-degree atrioventricular block is characterized by prolongation of impulse
conduction from the atria to the ventricles with extension of the P—Q interval by
more than 0.21 sec. The atria and ventricles contract at the same rate. Second-
dcgrce block is accompanied by more marked impairment of atrioventricular con­
ductivity: one or several impulses from the sinus node cannot be conducted to the
ventricles, and the number of atrium contractions exceeds the number of ventricle
contractions. Conductivity worsens until one contraction is missed (Wenkebach—
Samoilov’s periods). In the third-degree block every 3rd—5lh ventricular contraction
is missing, or only one of 3—6 contractions is transmitted. In complete atrioven-
tricular block the atria and ventricles contract according to different rhythms inde­
pendently of each other. The atria contract at the rate 60—80 per minute, the ven­
tricles, depending on the location of a new pacemaker, contract 20—40 times per
minute (the pacemaker is in the atrioventricular node) or 15—30 times per minute
(the pacemaker is in the ventricle — idioventricular rhythm).
The moment of incomplete block changing into the complete one, when the
atria do not transmit impulses to the ventricles, is of special importance. Slow
diastolic depolarization in potential rhythm drivers occurs only in some time after
there ceases impulse transmission from the sinoatrial node. This period is called
the preautomatic pause, ventricular asystole is observed during this pause. As the
blood doesn’t come to the brain, there is loss of consciousness and convulsions
(Morgagni-Adams-Stokes syndrome). Death is possible, but usually, when ven­
tricular contraction is resumed, these symptoms disappear. The syndrome may
repeat many times.
Contractility Disorders

Contractility disorders manifest themselves through impaired reproduction of

excitation frequency (rhythm transformation, frequency division). Consecutive po­
tentials of action and contraction appear unequal (alteration). Disorders of the
contractile apparatus of the cell, excitation-contraction coupling underlie this ar­
rhythmia. Not all muscle fibers contract in response to an incoming impulse.

Combined Disorders of Cardiac Rhythm

Combined disorders of cardiac rhythm are conditioned by simultaneous distur­

bances of automatism and conductivity (fig. 41).
In numerous ectopic foci of excitation and conductivity disorder flu tter and
fihrillution may occur.
In some cases the rate of atrium contractions reaches 250-400 per minute.
I lie conductive system can not transmit so many impulses, the ventricles are not
able to produce a high rhythm of ihe .itn.i and relative heart block may develop.
I lie ventricles contract at every 2'"1, Vй oi -I"’ contraction of the atria as other
 ( lu p in .’ I l>;illi»|(h>siolo|>> <>I llr .n l

waves of excitation get into the refractory

phase. The ventricles may contract before
they are sufficiently filled with the blood
that results in severe disturbances of cir
culation. This state is called atrial flutter
and may continue for several months and
O O Q O O O years.
t in 41. Movement of the excitation wave When the number of atrial contrac­
tu the myocardium in the normal condi- tions is 400—600 per minute, we speak
non (a) and in myocardial flutter (b) about atria l fib rillation. Only some sepa
rate muscle fibers contract, and the whole
itnum is in the state of incomplete contraction. The atrium no longer participates
m blood pumping.
Not infrequently the ventricles can contract before they are filled with the
blood and contractions are not accompanied by the pulse wave. Therefore, pulse
rule is less than the rate of heart contractions. It is called pulse deficit or cardiu>
fibrillation. It occurs mostly in stenosis of the left atrioventricular foramen, thyro
toxicosis, cardiosclerosis.
Ventricular fib rillation develops under some pathogenetic influences, for ex
imple, electric current passing through the heart, chloroform or cyclopropane an
•slhesia, coronary artery occlusion or other cases of acute hypoxia, heart trauma,
loxic doses of digitalis and calcium. Because of chaotic contraction of separate
muscle fibers, the propulsive force of contraction is practically absent, the patient
loses consciousness and dies.
Passing a single short powerful electric discharge through the heart effectively
livats atrial and ventricular fibrillation. It produces simultaneous depolarization of
.ill myocardial fibers and nonsynchronous excitation of the muscle fibers ceases. To
prevent fibrillation development, physicians resort to correction of the salt content
nl Ihe blood.
CARD IAC IN S U F F IC IE N C Y M A N IFEST A T IO N S

Heart insufficiency manifestations are divided into acute and chronic. Further
nunifestations are divided into local (in the myocardium) and systemic (in Ihc
whole organism). Local manifestations are subdivided into biochemical, morphologi
. nl and functional changes in the myocardium.

Changes in the Myocardium

liiochem ical changes in the myocardium are the following:

• damage of the enzyme composition;
• reduction of oxygen intake (hypoxia);
• disorder of oxidative phosphorylation;
• reduction in the synthesis of macroeigic compounds (A T P);
• loss of glycogen;
• disturbance of protein synthesis;
• electrolytic imbalance (tab. 7 on p. 262):
I’lirt S|H4'ial (S yslc iiiic ) l*iilho|)hysioloK,v

•• accumulation of sodium and calcium ions in cells;

•• loss of potassium from cells;
•• hampered reverse transport of Ca2+ ions from mitochodria into the sarco
plasmic reticulum;
• acidosis in the intracellular media.
Morphological changes in the myocardium include:
• destructive changes in the mitochondria;
• swelling or pyknosis of the nuclei;
• disappearance of transverse striation in the muscle fibers;
• disorders of the nervous apparatus of cells;
• dilatation of the heart cavities;
• substitution of cardiomyocytes by connective tissue (cardiosclerosis);
• cardiomyocyte death.
Functional disturbances of the myocardium are the following:
• cardiac rhythm disorders resulting from disturbance of automatism, excitability,
‘ conductivity, contractility;
• impairment of the process of contraction and relaxation of the cardiac muscl-
fibers;
• reduction of the force and speed of cardiac muscle contraction;
• local contractions of separate cardiomyocytes;
• reduction of the systolic heart volume;
• increase of the residual systolic volume and diastolic pressure;
• changes in EC G .

Systemic Changes in the Organism

Acute Cardiac Insufficiency

If increased heart load is excessive, compensatory mechanisms fail to manag

the overload, and acute cardiac insufficiency develops. It is accompanied by signili
cant changes in blood circulation:
• acute decrease of arterial blood pressure;
• increase of venous pressure;
• significant reduction of the minute blood volume;
• circulatory and tissue hypoxia and systemic metabolic acidosis connected
with it;
• acute pain;
• disorders of breathing;
• ischemia of the brain, loss of consciousness, convulsions;
• severe changes resembling shock.
Together with metabolic there may be structural changes in the cardiac muscle,
so that even under further load reduction heart activity may not be normalized.
Acute cardiac insufficiency can develop in myocardial infarction, myocardilr
ventricular fibrillation, paroxysmal tachycardia, heart tamponade, thrombosis am
embolism of the pulmonary artery
 C liiip lc i .’ I l*iilh»phyMi>l»Ky '»• 11«*иП

<I....lie Cardiac Insufficiency

Some manifestations of chronic cardiac insufficiency have been described in

п.. previous chapters, and the pathogenesis has been discussed in details. They arc
. ih т а , dyspnea, venous congestion, chronic circulatory hypoxia, cyanosis, basal me
hiluilism increase.
Chronic or congestive cardiac insufficiency develops due to metabolic distur
i чин es in the myocardium in prolonged hyperfunction of the heart or different
111ids of myocardium pathology.
I he hemodynamic indices in chronic insufficiency of the heart are the follow
Hilt:
• Minute blood volume of the heart decreases from 5—5.5 to 3—4 1/min.
• Blood flow speed is 2—4 times lower.
• Arterial blood pressure changes a little in spite of cardiac failure (it may be
explained by an increase of the peripheral vessel resistance).
Because of insufficient blood outflow from the heart, blood filling of org;ms is
diminished. At the same time due to inability of the heart to pump the outflowing
blood, venous congestion develops. As the volume of the venous vascular flow i
ippioximately 10 times larger than that of arterial flow, a considerable amount ol
Мши! is accumulated in the veins. Venous pressure is elevated.
I he capillary vessels and postcapillary veins are dilated, blood flow is decelera
■I m them and pressure is increased. Blood flow deceleration in the systemic
■ illation and circulatory disturbance in the lungs leads to an increase of deoxy
lirinoglobin concentration in the blood. It stains the skin and mucous membranes
i hi' cyanosis develops.
I lie tissues suffer from lack of oxygen. Hypoxia is accompanied by accumula­
tion of underoxidated metabolism products and carbon dioxide. Acidosis develops.
At ulosis and hypoxia lead to respiration disorders and dyspnea. To compensate
inpoxia, erythropoiesis is stimulated, the total volume of circulatory blood increases
ii* well as the relative content of blood cells in it that promotes blood viscosity in
i к use and worsens its hemodynamic properties.
Retention of sodium and water in the organism is observed. The mechanisms,
Im h developed evolutionally to provide sufficient content of salts and fluid in the
iMttiinism, become harmful in cardiac insufficiency. In patients with circulatory
in ulficiency the surplus of consumed salt is not excreted by the kidneys as in a
In ill hy person but retains in the organism with water. Cardiac edema develops (ils
puiliogcnesis is described in detail on p. 257).
Prolonged circulation insufficiency leads to profound and irreversible impait
im nt of intracellular metabolism.
In combination with digestive tract dysfunction and progressive circulatory
in ulficiency the patient begins to suffer from severe cachexia called cardiac ca
i hrxia.
II a ventricle is impaired, circulatory insufficiency acquires some specific lea
tun and left-side or right-side insufficiency develops. In the first case, blood con
i‘> lion is observed in the veins of the pulmonary circulation I hat may result hi lung
Plirt 2 Special (Sysli-ttilc) Piillio|iliy\iolu|(y

edema. In the second case, blood congestion is observed in the veins of the systemic
circulation, the liver enlarges, there are edemas on the legs and ascites.

CIRCULATO RY IN SU FFIC IEN C Y IN IM PA IR ED BLO OD IN FLO W TO T H E HEART

This pathology develops in cases when blood inflow to the heart by the veins is
little or when the heart is not able to take all the inflowing blood. It is observed in
hypovolemia (blood loss), acute blood vessel dilatation (collapse), accumulation of
lluid in the pericardial cavity that hampers cavity dilatation during diastole.
Fluid accumulation in the pericardial cavity may be fast and slow. Fast accu­
mulation occurs due to hemorrhage in case of heart trauma or in quickly develop­
ing pericarditis. Because of poor stretching of the pericardium, the pressure in its
cavity increases preventing diastolic dilatation of the heart. It causes acute cardiac
tamponade.

Questions for Self-Control

1. What are the main indices of heart work effectiveness?

2. Name three mechanisms of heart hyperfunction and compare them.
3. What are the mechanisms of heart contraction enforcement?
4. Find points of comparison and compile a comparative table of common and
different features between homeo- and heterometric types of heart contraction
enhancement.
Points Homeometric Type of Heterometric Type of Enforcement
of Comparison Enforcement of Heart Contractions of Heart Contractions
1.
2.
3.

5. What are tachycardia disadvantages?

6. Explain the stages of myocardial hypertrophy with the aid of the IS F index.
7. What are the defects of hypertrophied heart leading to cardiac decompensa­
tion?
X. Can myocardial necrosis develop without coronary blood circulation disor­
ders?
9. Ciive a classification of cardiac rhythm disorders (compile a comparative table
indicating the function of the myocardium, which determines certain arrhyth­
mia).
Function of the Myocardium, Which Underlies Arrhythmia Types of Arrhythmia
1
2.
3.
 Chapter 24. I’athuphysioloto of llc w l

Hi What are the clinical manifestations of acute cardiac insufficiency?

11 What are the clinical manifestations of chronic cardiac insufficiency?
I E x p l a i n the pathogenesis of cardiac edema.

Tests and Tasks for Self-Control

(give correct answers and find mistakes in the statements)

I Give the comparative characteristics of the homeo- and heterometric types of

heart hyperfunction.
1. Heterometric hyperfunction (volume overload) is more energy-depcndenl
in comparison with resistance overload and homeometric hyperfunction.
2. The comparative analysis of hetero- and homeometric types of heart hy
perfunction allows understanding the differences in the clinical duration
of different types of cardiac pathology.
3. More favorable clinical duration of heart disease means a longer phase ol
compensation.
4. More favorable clinical duration of heart disease means a later onset of I lie
phase of decompensation.
5. More favorable clinical duration of heart disease means that patient's in
validity arises more rapidly.
6. In arterial hypertension the phase of compensation is shorter than in
physical overstrain.
7. The stage of decompensation and patient’s invalidity begin more rapidly
in case of cardiac foramens stenosis then in case of valve failure.
8. Those pathologic processes, which are based on the Frank—Starling mech
anism (in case of valve insufficiency as opposed to foramen stenosis), have
a less favorable course.
9. Physical work (volume overload) may be used for heart training.

’ Acute failure of the mitral valve was experimentally reproduced in an animal.

I he heart adapted by activation of the heterometric mechanism. What is the
essence of this mechanism?
A. Compensatory hypertrophy of the myocardium.
B. The law of Frank-Starling.
C. Decreased formation of calcium-troponin complexes.
D. Intensification of protein biosynthesis.
E. Intensification of conductivity.

\ A 41-year-old patient with signs of pulmonary edema and left ventricular heart
failure was given a diagnosis of aortic stenosis. What is the cause of heart failure
development?
A. Increased volume of the vascular bed.
B. Damage of the myocardium.
C. Decreased volume of the circulating blood.
I). Cardiac overload due to increased blood volume.
E. Cardiac overload due to increased blood outflow resistance.
I'a rt 2 S|H'»lnl (N ysU -iiilc) 1‘ullioplivsinloK.v

4. Л 37-year-old man who had suffered from mitral valve failure for many years
developed acute cardiac decompensation. What pathophysiological variant ol
cardiac failure is observed in this case?
Л. Neurogenic heart damage.
B. Hypoxic heart damage.
C\ Coronary heart damage.
I ). Cardiac volume overload.
I Cardiac resistance overload.

5. Л patient has mitral valve regurgitation. As a result, cardiac overload by blood

volume developed. What is the main mechanism of immediate compensation?
Л. Effect of catecholamines.
B. Homeometric.
C. Intensification of protein biosynthesis.
I). Heterometric.
E. Hypertrophy of the myocardium.

(>. Л woman has suffered from arterial hypertension for 15 years. Now dyspnea
and palpitation appeared; systolic pressure decreased a little. What is the basic
mechanism of heart failure in this case?
Л. Disturbance of conductivity.
B. Cardiac overload with increased blood volume.
C. Damage of the myocardium.
I). Cardiac overload due to increased blood outflow resistance.
I Disturbance of cardiac activity regulation.

7. Л patient demonstrates abrupt arterial pressure increase due to changes of the

vascular tone. What compensatory mechanism provides an increased force of
myocardial contraction in this case?
Л. Renin-angiotensin system activation.
B. Influence of the sympathetic nervous system on the heart.
C. Influence of the parasympathetic nervous system on the heart.
D. Homeometric.
E. Hcterometric.

X. Л patient has arterial hypertension. As a consequence of hypertensic crisis,

acute heart failure developed. What is the main mechanism of heart failure
onset in this case?
Л. Absolute coronary failure.
B. Cardiac volume overload.
C. I )amage of the myocardium.
I). Cardiac resistance overload.
E. Relative coronary failure.

A 51-year-old patient complains ol dyspnea, palpitation, pain in the right hy

pochondrium, edema on the legs I (<> shows hypertrophy of both ventricles
 ( ll.ip ll'l .4 P . l l III I | l l l \ lu ll Ilf llt'H rl

and the right atrium. Regurgitation of the tricuspid valve is diagnosed. Wh.ii
pathogenetic variety of heart failure is it?
A. Arrhythmic.
B. Cardiac resistance overload.
C. Initial myocardial failure.
D. Cardiac volume overload.
E. Extramyocardial.

10. In an 18-year-old man mitral valve insufficiency without circulation distur

bance is revealed. What type of adaptive reaction takes place?
A. Homeometric.
B. Heterometric.
C. Myogenic dilatation.
D. Hypertrophy of the heart.
E. Intensification of conductivity.

11 Give the characteristics of myocardial hypertrophy.

1. If overload is moderate but permanent (in valve failure, arterial blood
hypertension), there develops a compensatory reaction in the form ol
myocardial hypertrophy.
2. It is an increase of the myocardium mass due to enlargement of every
myocardial functional unit.
3. It is a compensatory mechanism directed at increased heart work pcrfor
mance after IF S increase.
4. IF S normalizes during the last stage of hypertrophy.
5. It is «plastic support* of heart hyperfunction.
6. Myocardium hypertrophy at the third stage of its development is the most
frequent reason for myocardial insufficiency.
This type o f compensation is:
7. Immediate.
8. Long-term.
9. Economical.

12. In one hour after a ring narrowing the dog’s aorta was applied, the force and
frequency of systoles increased, but the circulating blood volume and thickness
of the left ventricle did not differ from the initial parameters. What stage of
myocardium hypertrophy is observed?
A. Complete hypertrophy.
B. Decompensation.
C. Progressive cardiosclerosis.
D. Relatively stable hyperfunction.
E. Emergency.

It In 1 month after experimental reproduction of arterial hypertension the leli

ventricle of the dog’s heart became 1.7 times thicker. Later the heart mass did
not enlarge, the minute volume normalized. What stage of myocardial hyper
trophy is observed?
I ’u il } S|M4'ial (S y s lrn iK ) l'Hlh<i|>hysioloK>

A. Initial.
B. Emergency.
C. Complete hypertrophy.
I). Progressive cardiosclerosis.
E. Decompensation.

14. An animal with experimental aortal valve insufficiency has left ventricular hy­
pertrophy with local contractions. Accumulation of what substance in cardio-
myocytcs is the cause of contractures?
A. Sodium.
B. Potassium.
C. Lactic acid.
I). Carbon dioxide.
E. Calcium.

15. A 4 1-year-old patient complains of severe pain in the cardiac region. With the
aid of electrocardiography a diagnosis of myocardial infarction was put. Give
the characteristics of coronarogenic myocardial insufficiency.
I . It is a result of limitation or stopping of arterial blood inflow.
2. Atherosclerosis is the most frequent cause of coronary artery wall impair­
ment.
3. Nutrient substrate deficit is created in the myocardium.
4. The content of oxygen in the myocardium is normal.
5. Trophicity of the myocardium is normal.
6. The content of A TP in the myocardium is normal.
7. Local ischemia of the myocardium may lead to its necrosis (infarction).
X. This type of cardiac insufficiency may be reproduced experimentally by
injecting anti-myocardial antibodies.
Examples o f coronarogenic m yocardial insufficiency are the following:
9. Myocardial infarction.
10. Ischemic heart disease.
11. Electrolyte-steroid cardiopathy.
12. Immune cardiopathy.

I(>. Name the types of heart rhythm disorders (arrhythmia).

1. I here is a classification of arrhythmia according to myocardium functions
impairment — automatism, excitability, conductivity and contractility.
2. Extrasystole is a disorder of myocardial automatism.
3. Tachycardia is a disorder of myocardial conductivity.
4. Bradycardia is a disorder of myocardial conductivity.
5. Respiratory arrhythmia is a disorder of myocardial automatism.
(>. flutter is caused by numerous ectopic foci of excitation and disorder ol
coduct ivity.
7. Paroxysmal tachycardia is a disorder of myocardial excitability.
X. Block is a disorder of myocardial excitability.
fibrillation is a combined disordei ol myocardial rhythm.
Depending on ihc cau.sc localization, arrhythm ia is divided into
 ( h.iplor 24 l*:ilh<>pli>si«»l<>K> of llc x il

10. Cardial as an associated symptom of other diseases (fever, anemia, hyper

thyroidism).
11. Extracardial (as a result of heart diseases).

17. A 52-year-old patient complains of pain in the heart after psychoemotional

stress. An ambulance doctor diagnosed ischemic heart disease (stenocardia).
What mechanism of ischemia is the most probable?
A. Angiospastic.
B. Obliterative.
C. Compressive.
D. Obstructive.
E. Hypovolemic.

IS. A patient had myocardial infarction. In 1.5 months Dressler’s syndrome with a
characteristic triad (pericarditis, pleuritis, pneumonia) was diagnosed. What is
the main mechanism of this complication?
A. Decreased organism resistance to infection.
B. Autoimmune lesion.
C. Activation of saprophytic microflora.
D. Intoxication with necrosis products.
E. Myocardial enzymes getting into the blood.

I'). Myocardial ischemia was reproduced in an experimental animal. Activation ol

lipid peroxidation was revealed. An increased concentration of what substances
in the myocardium stimulates this process?
A. Catecholamines.
B. Catalase.
C. Glutathionperoxidase.
D. Superoxide dismutase.
E. Tocopherol.

.’(I. A patient had heart ischemia caused by coronary artery atherosclerosis. Al

ter coronarography thrombosis of the frontal interventricular artery developed.
What is the initial mechanism of this complication development?
A. Increased level of clotting factors.
B. Deceleration of blood flow.
C . Damage of the vascular wall endothelium.
D. Decreased content of anticoagulants in the blood.
E. Decreased activity of the fibrinolytic system.

’I Reperfusion syndrome activates the process of free radical oxidation, which

results in cell membrane impairment and dysfunction of the myocardial cells
Excessive accumulation of ions in the cytoplasm takes place. What ions arc
accumulated?
A. Potassium.
B. Magnesium.
C. Chlorine.
I'« it 2 Spec lei (Syntrm lc) l'ullHi|ihvsi<iliiK>

I). Iron.
E. Calcium.

22. Restoration of the coronary blood flow in a patient with myocardial comit
sclerosis was accompanied by a decrease of the contractile ability of Ilu It**
and aggravation of the general condition of the patient. What is the .......
cardiomyocyte damage under the conditions of reperfusion?
A. Phosphorylation.
B. Dephosphorylation.
C. Inflammation.
D. Free radical damage.
E. Transamination.

2.V Alter one branch of the dog’s coronary artery was ligated, myocardial Inf
tion with resorption necrotic syndrome developed. What is the chanu и i
symptom of this syndrome?
A. Block.
B. Increased level of catecholamines in the blood.
C. Increased level of creatine phosphokinase in the blood.
D. Ventricle fibrillation.
E. Diminished heart minute volume.

24. A patient with acute myocardial infarction developed lung edema. Whul I» •
cause of this complication?
A. Allergic response.
B. Right ventricle failure.
C. Left ventricle failure.
D. Surfactant deficiency.
E. Intoxication with necrosis products.

25. A patient has transmural myocardial infarction complicated with at nit I

ventricle failure. What are the most typical sings of this condition?
A. Ascites.
B. Edema of the extremities.
C. Acrocyanosis.
D. Edema of the lungs.
E. Arterial hypertension.

2(>. A 28-year-old woman with a diagnosis of rheumatic myocarditis has synt|Hfl(

of heart failure. What is the cause of systemic circulation disturbance?
A. Cardiac overload due to increased blood outflow resistance.
B. Decreased circulating blood volume.
C. Cardiac overload due to increased blood volume.
I). Damage of the myocardium.
I Increased resistance in the vessels ol ihe lesser circulation.
 ( Iiapk-t 24 PathophysMoRy of Heart

llb'h intracranial pressure in a patient with cerebral hematoma caused execs

*|и activity of the vagus nerve (vagotonia) and heart rate changes. What kind
nl .iirhythmia is observed in this case?
\ Sinus bradycardia.
И Sinus tachycardia.
< Ventricular extrasystole.
I » Paroxysmal tachycardia.
I Atrioventricular block.

I • t . findings of a patient with idiopathic hypertension: sinus rhythm, pulse

'»' Ihc PQ interval — 0.19 sec, the Q RS complex is not changed. What func
l in n o l the myocardium is impaired?
A Contractility.
II Conductivity,
t I xcitability.
I > Automatism.
I Sensitivity.

И» changes of E C G findings: at first, prolongation of the P- Q interval; then,

ingle Q RS complexes drop out; later, increased quantity of the Q RS com
pit м-s; then auricle and ventricle contraction became different - auricle con-
n и lion rate is 70 per minute, ventricle contraction rate — 35 per minute. What
li иiii of arrhythmia is taking place?
Л I xtrasystole.
II Intraatrial block.
( Intraventricular block.
I > Atrioventricular block.
I Bradycardia.

\n examination of a 16-year-old boy showed heart rate acceleration during

m (Mi llion, deceleration — during expiration. EC G findings: decrease of tlie
lf R interval during inspiration and its increase during expiration. What kind
nl nirhythmia does the patient have?
\ Idioventricular rhythm.
It Alrial fibrillation.
( Sinus tachycardia.
I ) Respiratory arrhythmia.
I Sinus bradycardia.

I I lisl degree atrioventricular block with an increase of the P^Q interval up lo

II .4 sec has been found in a patient. What impairment of heart function caused
iln> condition?
A Automatism.
H Conductivity.
< I xcitability.
I) Contractility.
I Sensitivity.
Рш1 2 S pedal (Syatem k) 1'alliopli.vsloloK.v

32. A 42-year-old patient has such changes in E C G findings: prolonged P Q in­

terval, each second or third Q R S T complex is missed. What type of arrhythmia
is observed?
A. Extrasystole.
B. Fibrillation.
C. First-degree incomplete atrioventricular block.
I). Third-degree incomplete atrioventricular block.
E. Complete atrioventricular block.

33. EC G findings of a woman with ischemic heart disease: pulse 230, the P wave
is deformed, ventricular complexes are without changes. What type of cardiac
arrhythmia is it?
A. Bradycardia.
B. Paroxysmal tachycardia.
C. Extrasystole.
I). Ventricular fibrillation.
E. Complete block.

4. A serious infectious disease resulted in myocarditis accompanied with impair

nient of the conductive system of the heart, periodic syncopes due to develop­
ment of Morgagni-Adams-Stokes syndrome. What kind of pathology devel
oped in the patient?
A. Paroxysmal tachycardia.
B. First-degree incomplete atrioventricular block.
C. Third-degree incomplete atrioventricular block.
D. Complete atrioventricular block.
E. Change of incomplete atrioventricular block into complete.

35. A teenager having an infectious disease developed arrhythmia with a decreased

R - R interval during inspiration and increased during expiration. What is the
cause of this kind of arrhythmia?
A. Disturbance of myocardium excitability.
B. Variation of the vagus nerve tone during respiration.
C. Impairment of the contractile function of the heart.
D. Effect of catecholamines.
E. Disturbance of myocardium conductivity.

36. A 15-year-old teenager complains of air hunger sensation, general sickness,

palpitation. Pulse rate is 130, arterial pressure — 100/60 mmHg. EC G findings:
the Q RS complex is of normal form and duration; the amount of the P waves
and ventricular complexes is the same. What arrhythmia is observed?
A. Sinus extrasystole.
II Sinus tachycardia.
C. Fibrillation.
I). M u t t e r .
E. Paroxysmal tachycardia.
 ( 'huptcr 24. r:ilho|)livsli>liiK.y of llm rt

<7. E C G findings of a patient with cardiac arrhythmia: pulse - 50, irregular sinus
rhythm, the P—Q interval is prolonged; periodically missing Q RS complcx
(Wenkebach-Samoilov’s). What type of arrhythmia is it?
A. Second-degree incomplete atrioventricular block.
B. Complete atrioventricular block.
C. Right bundle branch block.
D. First-degree incomplete atrioventricular block.
E. Syndrome of cardiac pacemaker weakness.

J8. After experimental adrenalectomy an animal demonstrated significant potas

sium retention in the organism caused by hyperkalemia. What type of heart
arrhythmia is the most possible in this animal?
A. Sinus bradycardia.
B. Sinus tachycardia.
C. Respiratory arrhythmia.
D. Ventricular extrasystole.
E. Block.

39. A patient with heart failure developed arrhythmia. E C G data: auricular con
traction rate — 70 per minute, ventricular — 35 per minute. What function of
the cardiac muscle is impaired?
A. Automatism.
B. Excitability.
C. Sensitivity.
D. Conductivity.
E. Contractility.

40. A patient with heart failure developed arrhythmia in the form of ventriculiu
extrasystoles. Impairment of what function of the cardiac muscle is observed in
this case?
A. Automatism.
B. Excitability.
C. Sensitivity.
D. Conductivity.
E. Contractility

41. A 45-year-old patient complains of a dyspnea during slight exercise, edema

of the legs. She has been ill for 2 years. The patient has a history o f frequent
anginas. Circulatory insufficiency is diagnosed. What hemodynamic paramok-i
of heart decompensation is seen in this case?
A. Decrease of venous pressure.
B. Decrease of the total amount of blood.
C. Decrease of the minute volume of the heart.
D. High arterial pressure.
E. Tachycardia.
Chapter 25
PATHOPHYSIOLOGY OF VESSELS

The main function of the vessels is to provide blood supply of organs with
proper volume, rate and pressure of the blood and permeability of the vessels.
Regulation of vessel functions ensures proper circulatory bed for blood volume
Moving the blood through the circulating system the vessels provide exchange
substances and oxygen between the blood and tissues. The main efficiency indices
are minute volume o f the blood, speed o f circulation and blood pressure.
The vascular system consists of four types of vessels. According to their mor­
phology and function such types of vessels are distinguished (fig. 42):
• elastic-type arteries — compensatory vessels;
• muscle-type arteries — resistance vessels;
• capillaries (microcirculation) — exchange vessels;
• veins — capacitance vessels.
Vascular insufficiency is a disorder of blood circulation and blood supply of or­
gans resulting in impairment of substance and oxygen exchange between the blood
and tissues.

------ --- - ■ -

/ \

Pump Vessels of Precapillary

X z tl
Capillaries - Postcapillary Capacitance
the «boiler» resistance exchange resistance vessels
vessels vessels vessels
 Chapter 25. Ги11|1>||1нчМик.У Vessels

Vessels of each type have their own functions, special features of metabolism
and typical pathology.
Disorders of microcirculation (hyperemia, ischemia, stasis, thrombosis, and
embolism) were described in chapter 7 «Pathophysiology of Peripheral Blood Cir
i illation*. Pathology of exchange vessels having permeability as the main function
was discussed in chapter 8 «Inflammation*. In this chapter attention is mainly fo-
i used on the pathology of compensatory and resistance vessels.

ELA ST IC - T Y PE V E S S E L PA TH O LO G Y

AT H ERO SC LER O SIS

Atherosclerosis (A S) is a typical pathology of large elastic arteries (such as the

aorta) and large and medium-sized muscular arteries (e.g. coronary, arteries of the
brain, kidneys and lower extremities), which produces arterial insufficiency.
Global in distribution, it has reached alarming epidemic proportions in eco
nomically developed countries.
Atherosclerosis is a pathological process, which is characterized by infiltrative
proliferative changes of the inner layer of elastic-type arteries with deposition of
lipids, fibrin and calcium accompanied by elasticity impairment and vessel lumen
narrowing.
The main event of this pathology is lipose dysplasia of the vessels.

ETIOLOGY

Etiology of any disease is known to consist of the interaction of etiological

l.ictors, conditions, and risk factors. The etiology of atherosclerosis includes many
causative factors, among which external and internal are distinguished, and factors,
which predispose to atherosclerosis de­
Man ‘ External environment velopment.
Metabolic diseases
Atherosclerosis etiology has tin-
Arterial hyperteasion following special feature — as a rule
Hypodynamia * one separate exogenous factor can not
______________ Stress, cause atherosclerosis. Under expci i
Intoxication _ mental conditions it is possible lo in
Overeating,
Sex.
duce only one model of atherosclero i
by feeding experimental animals did
that raise the plasma cholesterol lew I
or injecting large doses of cholcslcml
to them. Consequently, cholcslcml
in this model may be qualified i .h i
etiological factor. However, such сч
0 10 20 30 40 50 60 70 80 90
Age, years perimenls are successful only in nib
bits that do not consume animal loud
I Ik 43. Dependence o f atherosclerosis inci-
ilcnee nil different I.к tors
Г.mi S|M4-iul ( Syslcm ic) PiilhophysioloKy

I Ins model does not succeed in other animals, which consume animal food and are
resistant to cholesterol.
It is possible to model atherosclerosis in roosters by prolonged introduction of
dicthylstilbestrol (an androgenic hormone), in dogs by thyroidectomy plus choles­
terol overload.
I he level of plasma cholesterol in man is largely determined by overeating
(more lipids and carbohydrates), i.e. by dietary habits. So, studies and clinical
practice reveal relationship between dietary cholesterol or saturated fat, plasma
cholesterol levels, and atherosclerosis.
Besides overeating, alcohol abuse and emotional overstrain are unfavorable in
this aspect. Intoxication by fluorides, mercury and lead salts promotes atheroscle-
iosis . Cigarette smoking (nicotine) plays its role.

Endogenous factors play a more decisive role in atherosclerosis development.

They are:
• pathological heredity (enzymopathy);
• elderly age (hyperlipoproteinemia and hypercholesterolemia are more fre­
quently observed in elderly people);
• hormonal insufficiency (hypothyroidism, D M , hypogonadism, Cushing’s
syndrome);
• arterial blood hypertension («the higher the blood pressure, the greater the
risk»);
• diastolic hypertension is a more important correlate;
• disorders of metabolism (obesity, gout, xanthomatosis, liver pathology).
Risk factors are:
• hypodynamia;
• overeating, alcohol abuse, smoking;
• stress, which may lead to vessel wall trophicity disorder.
Analyzing atherosclerosis etiology, it is possible to see that the same factor in
some cases plays a role of an etiological one, and in other cases — a role of a con­
dition or a risk factor (fig. 43). So, atherosclerosis is multifactorial in origin. Each
individual case is underlain by a specific totality of factors.

PA TH O G EN ESIS

Some concepts of atherosclerosis pathogenesis have been proposed.

1. Concept of primary systemic disorders of lipid metabolism and secondary
damage of the vascular wall.
2. Concept of primary damage of the vascular wall and its secondary lipoidosis
(•reaction to injury» hypothesis).
Erom (he point of view of the main link of atherosclerosis pathogenesis there
are three concepts distinguished:
I Hypercholesterolemic.
2. Thrombogenic.
V <icnctic.
 ( hapter 25. РаИ м м ЬпМ оцу of Vessels

Concept of Primary Systemic Lipid Dismetabolism

The essence of this concept lies in the assumption that typical disorders of lipid
metabolism are primary and lead to lipid infiltration of the vessel wall. It is based
on the following proofs and assumptions.
• Hypercholesterolemia (increased cholesterol level in the blood) is a neces
iry and the most obvious metabolic event in atherosclerosis and correlated with
severity of AS. A generally accepted postulate is that «without cholesterol there is
no atherosclerosis*.
Cholesterol is a physiological substrate, which participates in:
• construction of the cellular membranes and provision of their permeability:
• synthesis of corticosteroids, sex hormones, bile acids, vitamin D;
• providing (as a dielectric) impulse conduction (with myelin) in a definite
direction in the nervous system.
As it was noted above, it is possible to reproduce atherosclerosis under experi
mental conditions by excessive introduction of cholesterol to rabbits. This concept
nmulates people to limit cholesterol consumption. But the fact is that the amount
ui endogenous cholesterol synthesis in man prevails its exogenous entry (see p. 224
about cholesterol function and metabolism). In atherosclerosis pathogenesis the
amount of cholesterol does not matter so much as its modification and chemical
Ixmds with other substances.
• Cholesterol etherification ( cholesteryl esters, combination of cholesterol with
laity acids) plays an important role. This especially concerns the kind of fatty acids
Dietary saturated fatty acids elevate plasma cholesterol levels, whereas polyunsatu
lated fatty acids reduce them. Unsaturated fatty acids (fats of plant origin) contribute
lo the highest solubility of cholesterol. Saturated fatty acids (fats of animal origin) <l<»
not have this property and contribute to atherosclerosis development. It explains tin
Mgnificance of nourishment and diet, as risk factors, in atherosclerosis pathogenesis
• The relationship between the content of cholesterol and lecithin (the mam
hepatic phospholipid with lipotropic effect, pp. 224, 444) in the blood ensim
Ik-Iter solubility of cholesterol and prevents vascular wall infiltration with it il th<
Ifi ithin-cholesterol ratio is above 1. Fatty acids are better oxidized in phosphohpul
molecules. Choline and methionine (which provide methylic groups for cholm*
lormation) are necessary components of lecithin. So, deficiency of choline ami
methionine in food promotes atherosclerosis development. Choline symhe.i. к
Impaired in deficiency of vitamin B 12, folic and pantothenic acids.
• All lipids in the plasma are known to circulate in combination wiili pmtem
(compound lipids lipoproteins (L P ), see p. 224). Plasma lipoproteins can In- <h\ i<l« < 1
Inlo some types depending on their electrophoretic mobility and sedimentation
properties — low-density lipoproteins (L D L ), very low density lipoproteins (V I I »l i
and high-density lipoproteins (H L D ). The type of cholesterol connection with pm
loins has a great significance for its solubility:
• |i lipoproteins (lipoproteins of low and veiv low density (L D I.) toniiiiiiiM»
more lipids than protein) arc а(1югоцеи1» inul promote acctimulallon nl
cholesterol in Ihe vessel wall (they uie Ivpx al <i| men);
I ’.ul S|M4'UI (Svslem n ) rutho|ihvslol<i|>>

• «-lipoproteins (high-density lipoproteins (H D L ) containing more protein

than lipids) have the antiatherogenous effect (they are typical of wom­
en).
I his fact explains sex differences in predisposition to atherosclerosis (men are
more predisposed than women).
• Since lipids are an energy substrate for the skeletal muscles (especially
|t lipoproteins in men), physical work prevents atherosclerosis development, but
hypodynamia (especially in men of athletic constitution) is a risk factor for athero­
sclerosis development.
• Deficiency of the endogenic lipotropic factor lipocaine (see pp. 224, 444
about its pancreatic origin, function in activation of phospholipid formation and
tatty acid oxidation, and obesity pathogenesis) must be added as a mechanism lead
ing to atherosclerosis.
Role of Hormonal Factors. Hormonal deficiency (in hypothyroidism, hypogo­
nadism, DM , Cushing’s syndrome) has a great significance in lipid dismetabolism
and thus in atherosclerosis development.
Estrogens provide H D L synthesis. Thus, women are less predisposed to athero­
sclerosis. In the period of climax, when progesterone activity decreases, the inci­
dence of atherosclerosis in women and men equalizes.
Testosterone is a hormone, which predisposes to L D L synthesis and athero­
sclerosis development (experimental and therapeutic introduction of this hormone
increases the risk of atherosclerosis).
t hyroxin increases splitting of lipids, so, hypothyroidism contributes to athero­
sclerosis development.
Insulin insufficiency is the most significant factor in this aspect. Insulin con­
verts 10 % of carbohydrates into fats and provides complete metabolism of lipids
(p. 203). As it has been explained in chapter 14 «Pathology of Carbohydrate Meta
bolism», insulin insufficiency leads to hypercholesterinemia and generalized athero­
sclerosis (p. 210). It especially matters in prolonged treatment of patients with DM
when compensation is not complete (p. 212). D M has atherosclerosis as a com­
mon complication. Moreover, DM is the most common reason for atherosclerosis
(p. 215). The pathogenesis of DM and atherosclerosis is tightly connected. The
reason for invalidity and mortality of DM patients is connected with atherosclerosis
development.
All the mechanisms mentioned above result in cholesterol accumulation in
vessels and their secondary damage. Cholesterol (C^H ^O ) is a substance, which is
difficult to metabolize. After getting into the subendothelium it provokes reactions
as a heterologous substance (triglycerides have the same property).
I luis, atherosclerosis is a reaction of the connective tissue of the aorta and
laige arteries to cholesterol precipitation in the subendothelium.

( <>1114*111 of Primary Damage of Vascular Wall and Secondary Lipoidosis

According to this concept, the primary factor of atherosclerosis development

is acquired (dystrophic) or gcnclic changes in ihe inner layer ol the arterial vessel
 Chapter 2S I ‘иIli<>pliyni«>1«>к> <»f Усчжгк

w all followed by lipoidosis. AS is initiated as a response to some form of arterial

endothelium injury. Pathogenetic mechanisms are the following:
• Disorders of the receptor system of the vascular wall, which mediate the cho
Icsterole and lipoprotein capture.
• Disorders of the enzyme system of the vascular wall. Physiologically, the cells
can provide themselves with adequate supply of cholesterol at the same time pre
venting its overaccumulation due to lipolytic activity. A special role belongs to the
enzyme p-lipoprotein lipase, which is located in the vessel wall, metabolizes lipids
(|i-lipoproteins) and prevents cholesterol plaque formation (p. 224).
• Introduction of vitamins B ir B l5 — pantothenic acid and rutin - activates
lipolytic activity of the vascular wall and helps atherosclerosis prevention
and treatment.
• Since the activity of this enzyme decreases with age, the role of elderly age
in the development of atherosclerosis becomes clear.
• Constitution, which is called lipomatous, is predisposed to obesity, fatty
infiltration and lipoid decomposition (as it was explained on pp. 59, 227).
Predisposition of this type of constitution to atherosclerosis is likely to be
connected with a low activity of р-lipoprotein lipase.
• Since the activity of this enzyme (as well as of other enzymes) depends on
heredity, it is understandable that this enzymopathy is a factor of heredi
tary predisposition to atherosclerosis.
• Heparin is known to activate lipoprotein lipase and its release from en
dothelium. At the same time it creates relative deficit o f heparin as an
anticoagulant. Its participation in anticoagulation diminishes and resulis
in hypercoagulation and thrombosis. It creates an additional link in ath
erosclerosis pathogenesis, which is noted below.
• Thrombogenesis activation (thrombogenic concept of atherosclerosis). Thrombus
incrustation is a determinant of AS. The smooth muscle cells of a vessel, which react
to it, produce components of the atheromatous plaque: collagen, elastic tissue, and
proteoglycans. Later they accumulate large amounts of cholesterol, cholesteryl esters
and lipoproteins. The pathogenesis is the following:
• Focal sites of endothelium injury permit platelets to adhere to the sub
endothelial connective tissue, aggregate, and release the contents of theii
granules.
• Reaction of platelets, microthrombi formation, release of the platelet
derived growth factor directly stimulate proliferation of the smooth muscle
cells.
• Small thrombi composed of platelets, fibrin, and leukocytes collected over
foci of endothelial injury, and the following organization of such thrombi
resulted in plaque formation.
• Thrombi may become incorporated within the intimal plaque.
• Focal sites of endothelium injury lead to increased vascular permeability
to plasma constituents such as lipoproteins.
1’iirt .’ S|M4.'UI (K ytlem k ') l*»llio|tli>sioUiK.v

• Inflam m ation of the vascular wall. Migration of monocytcs and neutrophils

promote proliferation of the connective tissue. Repeated or chronic inflammatory
vascular injury promotes proliferation of the vascular smooth muscle cells.
• Immune mechanisms of vascular wall damage (cells of the intima and L P be
come autoantigens), LP-lgG autoimmune complex formation.
So, the vessel wall changes mentioned above provoke its dystrophy, thrombo
genesis, formation of fibrous and lipomatous plaques, calcification, and sclerosis. 11
is thought that endothelial injury with associated platelet deposition plays a critical
role in initiating vascular intima proliferation — a prelude to AS. Muscle cell pro
liferation is a consequence of endothelial injury.
Cases of A S without significant accumulation of cholesterol and with relatively
normal L D L prove the given concept. It is postulated that vascular smooth muscle
cell proliferation is a fundamental and early event in the development of AS.
Genetic Concept of Atherosclerosis

AS development in children attracts attention to genetic mechanisms in its

pathogenesis. Genetically determined disorders that cause elevated plasma or tissue
cholesterol levels, such as familial hypercholesterolemia or cholesteryl ester storage
disease, produce fatal atherosclerosis in childhood despite the lack of any other
contributing factors such as hypertension, smoking, or DM .
Genet ic predisposition to atherosclerosis development in adults is confirmetl
statistically. There have been observed hereditary family forms of hyperlipopro­
teinemia and hypercholesterolemia. The male sex critically predisposes to athero
sclerosis.
A number of genetic mutations (including absent or defective L D L receptors)
will result in hypercholesterolemia, increased accumulation of cholesterol in cells,
and predisposition to premature AS. It is a variant of membranopathy.
The fallowing changes can be genetically determined:
• special features of cholesterol metabolism and its disturbances;
• predisposition to р-lipoprotein synthesis;
• deficit o f lipases (enzymopathy);
• deficit o f lipotropic substances (phospholipids, lecithin, lipocaine);
• deficit o f cellular receptors to low-density lipoproteins (L D L );
• predisposition to autoimmune aggression and formation of antibodies against
the «cells of the vessel intima.
It is postulated that only against the background of genetic predisposition dil
fercnt exteirnal and internal factors mentioned above contribute to atherosclerosis
development.
I liiis, as to the research of AS etiology and pathogenesis it appears to be .1
disease of multifactorial origin.
 Chapter 25. I’athoph.vsiology of VVssHs

MORPHOLOGICAL AND FUNCTIONAL OF VASCULAR WALL DISORDERS

Morphological changes in vessels and the dynamics of their atherosclerotic dam

iite proceed in some stages with the following order of events.
/. Infiltration of the vessel intima by native or modified lipoproteins of the
hlood plasma. Lipid deposition is an early event in atherogenesis. Lesions occur
primarily within the tunica intima. Excessive capture of lipids by macrophagcs and
infiltration of the arterial wall with macrophages containing low-density lipopro
loins. Transformation of macrophages into foam cells, which are the base of lipid
tain formation. It leads to endothelial injury. Lipid capture by smooth muscle cells
I ipid-filled smooth muscle cells lose contractility.
2. Proliferation is local irritation and multiplication of histiocytes, fibroblasts
.md smooth muscle cells of vessels, which capture lipids. Connective tissue excres
i once. Consolidation of the connective fibers. Thickening of the subendothelium,
deformation of the elastic tissue. Formation of atherosclerotic fibrous plaques on
llic endothelium, which consists of lipid-laden smooth muscle cells surrounded l>\
a fibrous matrix. If a lesion is in progress, it occludes the arterial lumen.
3. Degeneration and destruction of the intima and vascular wall. Destruction ol
loam cells, their lysis, fragmentation of fibrous structures. Formation of lipid stains
I ormation of ulcers, which can perforate. Progressing atherosclerotic plaques. I lie
■ore of fibrous plaques consists of lipids and debris of cells nccrotized as a result ol
insufficient blood supply.
4. Sclerotization (calcification) of vessels. The lumen of the atherosclerotically
■hanged vessels narrows as a result of atherosclerotic plaque formation. When the
altered complex structure becomes rigid, it causes vascular occlusion.
Atherosclerotic changes in vessels predispose to thrombogenesis. Blood clots
•ire formed in the intima layer. Ischemia (infarction) develops in the region of the
damaged vessels. Fibrous plaques are altered by hemorrhage.
Functional disturbances of vessels consist in:
• disorders of vessel elasticity;
• vessel incapability of dilatation;
• tendency of the damaged vessels toward spasm.
Atherosclerotic damage of vessels results in disorders of blood circulation,
ischemia, local blood congestion and stasis, disturbance of tissue trophicity, and
nccrosis (infarction) in the regions of damaged vessels.

SYSTEM IC ATHEROSCLEROSIS MANIFESTATIONS

In the whole organism atherosclerosis manifestations depend on a) locali/a

non of the process, b) degree of functional disturbance of the organ, whose blood
«irculation is impaired.
Depending on this, atherosclerosis has a variety of complications. Although any
iiftery may be affected, the aorta, arteries of the brain, coronary vessels of the heart,
arteries of the kidneys and extremities are the prime targets.
The most essential clin ical consequences of atherosclerosis are the following
Kelt •’ Special (System ic) I’alhophysloluKy

• I lirombosis and consequent embolism.

• Ischemic heart disease. AS is the main causative factor of coronarogenie cardiac
insufficiency. Myocardial ischemia is a life-threatening manifestation of AS. AS
is the main cause of myocardial infarction.
• С erebral ischemia is another life-threatening manifestation of AS. It is the main
causative factor of cerebrovascular diseases (ischemic encephalopathy). It is
manifested by serious disorders of cerebral blood circulation and corresponding
clinical symptoms (ischemic episodes, stroke, disorders of memory and higher
nervous activity).
• Atherosclerosis is a risk factor of arterial blood hypertension.
• Atherosclerosis increases systemic vascular resistance and overloads the heart by
resistance. It leads to myocardial hypertrophy development.
• Atherosclerosis of the lower extremity vessels frequently leads to necrosis (gan
grene) and amputation.
• Atherosclerosis is a complication of insulin deficiency (p. 212).
Atherosclerosis, thrombosis, obesity, D M and arterial hypertension are so
tightly connected that a complicated picture of organism damage is created (scheme
13 on p. 230). Myocardial infarction and cerebral stroke are the two major consc-
quences of AS.
Vascular insufficiency connected with AS constitutes a significant part of all
organs and systems pathology.

M U SC LE- T Y PE (R E S IS T A N C E ) V E S S E L PA TH O LO G Y

I he main function of muscle-type (resistance) vessels is to maintain arterial

blood pressure at a certain level. It means that the first manifestation of resistance
vessel pathology is arterial pressure deviation from the normal level.
The tone of muscle-type (resistance) vessels consists of two components:
• vasomotor (neurogenic), which is regulated by nervous mechanisms;
• basal (m yogenic), which is partially regulated automatically as a reaction of
the smooth muscles to stretching, partially by BAS and electrolytes (Na, K,
Ca ions).
All mechanisms of the physiological regulation of arterial blood pressure are
divided into two groups — vasoconstrictive (provide arterial blood pressure increase-)
,ind vasodilative (provide arterial blood pressure decrease). The interconnection
between them determines arterial blood pressure.

VASOCONSTRICTIVE M ECHANISM S

Nervous Mechanisms. Scientific investigations of nervous system participation

in vessel tone regulation revealed the following mechanisms.
• I xpcrimcnts on animals confirmed that stimulation of some structures of the
brain (e.g. of the anterior pole of frontal lobe, orbital gyri, motor /one of the cor­
tex, anterior temporal pole, cruciform gyms ol the hippocampus, amygdaloid body)
causes arterial blood pressure increase
 ( lliip lcr 25. I‘ulli<i|ih>slolo)(v of Vessels

• Participation of the nervous system is proved by the influence of emotions on

iiih'iial blood pressure.
• Reticular formation of the brain influences arterial pressure because the he
....dynamic center is part of the reticular formation.
• I he hypothalamus is the highest integrator of vegetative functions and influ
nt cs arterial pressure.
• Sympathetic innervation performs vasoconstrictive function and increases
tii. \asomotor component of the vascular tone. It is achieved with the aid of the
"trvous mediator noradrenaline:
• a-adrenergic receptors increase arteriole resistance to blood flow;
• (i-adrenoreceptor mechanism influences venoconstriction and increases
venous blood return to the heart;
• (i,-adrenoreceptors activate the function of the heart and increase the sys
tolic component of arterial blood pressure;
• Pj-adrenoreceptors provide vasodilatation.
• l-unction of the peripheral baroreceptors of the carotid sinus and aortic arch
i i lusely connected with the action of the central mechanisms of vascular lone
и filiation.
• Exclusion of the inhibiting influence of the baroreceptors of the vasomotoi
■ruler, brainstem reticular formation and hypothalamus (by cutting the depressor
ni'iM s from the aortic arch and carotid sinus) causes increased secretion of ca
i holamines (by the adrenal medulla) and aldosterone (by the adrenal cortex).
Hormonal Mechanisms. The hypothalamo-pituitary and sympatho-adrenal sys
Wilis play the main role in vascular tonus regulation.
• The hypothalamus secrets vasopressin, which increases arterial blood pres
Hire.
• Activation of the adrenal medulla under the effect of sympathetic nervous
mlluences ensures catecholamine entry into the blood. Noradrenaline, which is
nil rid under a-adrenoreceptor excitation, exerts vasoconstrictive influence on
и I i.mce vessels.
• Mineralocorticoids (aldosterone and desoxycorticosterone, which are formed
m die adrenal cortex) produce a vasospastic effect. They cause sodium retention in
ih' organism as a result of increased sodium absorption from the primary urine into
Пи hlood and then retention of water and increase of circulating blood volume.
• Under the influence of aldosterone and sodium retention in the vessel wall
ih' latter becomes more sensitive to different vasoconstrictive influences — nervous
iiih I humoral (catecholamines, vasopressin, angiotensin II).
• Glucocorticoids in large doses (formed in the adrenal cortex) contribute lo
in . formation and arterial blood pressure increase. Cortisol raises responsiveness
in i iii-cholamines and can cause an increase in cardiac output.
• Thyroid hormone raises sensitivity to catecholamines and increases the force
nl heartbeat.
Renal Mechanisms. Participation of the kidneys in arterial blood pressure rcgu
I ninn has been studied in detail in l In- course of normal physiology and bioclie
iiii .lry. Ik-low, il is described hi burl lot understanding of the treatment ol renal
hypertension.
I’.ul 1 Special (S v s Ic iiik ) I'alhiiphysiiilom

I'he juxtaglomerular apparatus of the kidneys is a place of renin formation,

whose secretion depends on blood pressure in the afferent vessels of the renal
glomerules. Renin is a proteolytic enzyme, and a-globulin of the blood plasma
(angiotensinogen) is its substrate. Renin splits the decapeptide angiotensin I from
angiotensinogen (so, angiotensin I is a product of the enzymatic reaction renin >
angiotensinogen). Then another enzyme (the peptidase angiotensin-converting en
zyme, A C E) removes two amino acids from the polypeptide (decapeptide) angio
tensin I and transforms it into angiotensin I I (the latter is an octapeptide, which is
so times more active than its predecessor).
Angiotensin II is the most effective of all known pressor agents, which directly
influences the wall of precapillary vessels (scheme 23). The vasoconstrictive effect
ol angiotensin II depends on a) activation of the sympathetic part of the vegeta
live nervous system; b) increase of aldosterone secretion from the adrenal cortex
and sodium reabsorption in the kidneys. Angiotensin II is destroyed by the enzyme
angiotensinase.

Scheme 23. Mechanisms of Vasopressive Effect of Angiotensin II

Angiotensi nogen

Angiotensin I

Angiotensin II

. ... I
I
Activation
Stimulation Endothelial Activation o f Stimulation
o f pressure Bradykinin
of growth dysfunction sym pathetic o f aldosterone
factors destruction
factors (N O deficiency) effects secretion
(endothelin-1)

Role of Electrolytes. Ions of sodium and calcium influence the basal (myo
genic) tone of resistance vessels elevating it (see p. 261 — table 7 about the propei
lies of these ions).
• Na' influences muscle membrane potential, increasing it. Besides, it retain
water elevating circulating blood volume.
• ( V raises the tonus of contractile fibers.
In addition, retention of these ions in the vascular wall increases vasomotoi
apparatus sensitivity to different pressor effects nervous and humoral. Loss ol
potassium Irom muscle cells is connected wiih и
 < 11.11>(>< Л I'n tlii «physiology (if Vessels

VASOD1LATIVE MECHANISMS

Nervous Mechanisms. Nervous vasodilative mechanisms are connected with:

• vagotonus, i.e. the vasodilative action of parasympathetic fibers and the me
diator acetylcholine (on vessels of the skin, intestine, pelvic organs);
• |i-adrenergic effect of adrenaline on the muscular structures of arterioles,
where parasympathetic innervation is absent;
• baroreceptors of the carotid sinus and arch of the aorta, which are receptors
of depressor nerves.
Hormonal Mechanisms. A trial natriuretic hormone (factor A N F ) opposes vaso
•nnsirictive hormonal mechanisms. This hormone is a polypeptide (28 amino acids)
vnlhesized mostly in the heart atria (p. 254). Its effect consists in:
• antagonism against aldosterone, suppression of aldosterone production;
• antagonism against angiotensin;
• excretion of sodium in the urine (intensifies natriuresis by sodium reabsorp-
tion suppression in the renal tubules);
• removal of water from the organism (intensifies diuresis by suppression of
water reabsorption in the renal tubules);
• increase of glomerular filtration;
• inhibition of Ca2+entry into the smooth muscle cells;
• inhibition of Ca2+ release from the intracellular depot.
Due to these mechanisms, natriuretic atrial hormone promotes marked vaso-
•lil.itivc effect, contributes to antihypertensive effects and decreases arterial blood
im ssure.
Progesterone prevents stable increase of arterial blood pressure.
Renal Mechanisms. The kidneys are known to promote both increase- and
I- M;ise of arterial blood pressure. So, together with hypertensive function, the
t hlneys perform antihypertensive (depressive) function. Experiment shows that the
l hi a function of the kidneys is more important than the hypertensive one because
"I its uniqueness.
Kperiment shows that ischemia of the kidneys (reproduced by partial narrow
•иг of the renal arteries) increases the concentration of renin and angiotensin in the
••Ьчк! only during the first days after operative manipulation. Very quickly arterial
M.'od pressure normalizes. Removal of both kidneys (under experimental condi
....is with use of artificial hemodialysis to avoid uremia) leads to a stable increase
<•1 nterial blood pressure. It is called renoprival hypertension. These facts suggest
ili и .i stable increase of arterial blood pressure can be conditioned by disorders ol
ilu depressive function of the kidneys.
I he function of the kidneys directed to decrease or/and normalize elevated
т . i i.il blood pressure is called antihypertensive (antipressor, depressive) function о/
ihe kidneys.
I lie depressive function of the kidneys controls the effects of renal (renin) and
■siuienal (vasopressin, catecholamines, aldosterone, angiotensin II) vasoconstric­
tive mechanisms.
Ihe depressive role ol (he kidneys is realized by:
Рш1 S|N4‘lul (SyslrniH ) l'ulh<)physioloK.v

Hypokinetic (resistance) hypertension - Q is not changed, R is increased. The

increase of myogenic component of blood pressure (diastolic) prevails. Increased
total peripheral resistance delays stroke volume activation. Ps and Pd are either
both equally increased or (more frequently) Pd exceeds Ps. Pulse pressure decreas
es Resistance hypertension is caused mainly by high peripheral vasoconstriction
(arterioles) or some other narrowing of peripheral vessels, but may also be caused
by increased blood viscosity (increased hematocrit).
In accordance with the main pathogenic link, there are distinguished fotn
forms of arterial hypertension:
• Neurogenic.
• S a ll(calcium)-dependant.
• Renal.
• Hormonal.
I rom the point of view of clinical value and treatment approach, there are
distinguished two forms of hypertension:
• Labile (threshold) hypertension — cases of alternating normal and elevated
levels, when blood pressure may be normalized without drugs;
• Fixed hypertension — blood pressure may not be normalized without drugs.

ETIOLOGY

Similarly to atherosclerosis etiology, the etiology of essential hypertension con

sisis m the interaction of etiological factors, conditions and risk factors. In any
individual case of arterial hypertension, the same factor plays a role of an etiologi
cal or a risk factor, or a condition. Specifically, this gives a possibility to determine
arterial hypertension as a polyetiologic disease.
It is indisputable that higher nervous activity overtension under the influence ol
emotional effects is significant as a cause of primary hypertension. Negative emo
lions are of special importance, in particular the ones, which are not accompanied
wiili motor reactions. In such a case the pathogenic effect of such emotions affects
I lie blood circulation system.
Essential hypertension is «a disease of the autumn of a man’s life, it does not
give him an opportunity to live till winter» (O.O. Bohomolets). So, age plays an
important role in the onset of hypertension. But sometimes, primary hypertension
occurs at young age. It should be noted that men younger than 40 have this disease
more ollen than women, but after 40 the situation is opposite.
Stress determines the activation of the hypophyseal-suprarenal and sympatho
adrenal systems with subsequent development of renin-angiotensin-aldosterone
pressor mechanisms. It is confirmed by frequent development of primary hypertcn
мои in people with stressful professions.
I pidemiological observation has established a close connection between the
level of arterial blood pressure and the quantity of consumed table salt ( table \ah
abuse) Prolonged consumption of more than (>g of table salt a day is supposed lo
promote primary hypertension in people having hereditary predisposition to it. Sue
eessfitl experimental reproduction ol salt hypertension confirms the importance ol
 Chapter 25. I'litliophysioloK) of Vessels

Mblc salt overconsumption. A favorable therapeutic effect of low-salt diet in some

im ms of primary hypertension has been clinically proved.
Risk factors are nerve strain, hypodynamia, smoking, alcohol abuse, elderly
ii ' hormonal (climacteric, hyperthyroidism) disturbances, atherosclerosis, system
и disturbances of metabolism, and common salt overconsumption.
(ienetic factors (predisposition) is an important factor of primary hypertension
th vclopment in man and has been confirmed statistically and by proper methods
. in-illogical, twin and experimental. Special features of the nervous and endocrine
i' rillation of the vascular tone are genetically determined. In some families this
ihscasc develops several times more often than in other people. A high incidence
"I essential hypertension in monovular twins also testifies to genetic factor signift
■nice. Against this background other external and internal factors can contribute to
tin development of arterial hypertension.

PATHOGENESIS

In each individual case of hypertonic disease, the pathogenesis is determined

In the balance of pressor and depressor mechanisms (activation of vasoconstrictive
mechanisms and/or inhibition of the vasodilative ones). In essential hypertension
"i sufficiency o f the vasodilative mechanisms is prim ary. Their stimulation (antidiurclic
hormone, renal prostaglandins, methods of Ca2+ion removal from myocytes) would
i" optimal as the arterial hypertension treatment. But unfortunately these methods
im badly developed. Against this background various vasoconstrictive mechanisms
I'H-vail (neurogenic, renal or salt-dependent, their combination is possible) and
manifest themselves clinically. This allows distinguishing three main forms of arte
n il hypertension — neurogenic, salt(calcium)-dependent and renal. A physician
tins nothing to do but to block the named vasopressive mechanisms. There arc
tinec groups of remedies - adrenoblockers, Ca-channel blockers, and blockers of
.mi'iotcnsin-converting enzyme (A C E ) using as a basis for arterial hypertension
in itment.
Neurogenic Hypertension

I he nervous concept of arterial hypertension is based on the possibility to model

li h i animals by reproducing neurosis.
I he role of the neurogenic factor in essential hypertension pathogenesis undei
lit ihe concept of Russian cardiologists Lang and Myasnikov. They suggested that
iit-rvc strain, the etiological essence of hypertensive disease, causes disorders of the
' rtcbral centers of control over arterial blood pressure. Imbalance between excita
..... and inhibition in the region of the vasomotor center and then impairment ol
и function causes neurotic and higher nervous activity disorders, development ol
'.tiiWc increase of arterial blood pressure.
I'licsc considerations afford ground for using sedatives for the treatment ol
hypertension, which is accompanied with neurosis.
Г.Щ 1 Special (N yslem ii) I'HlliopliysloloKy

I lie function of the baroreceptors of the carotid sinus and aortic arch is closely
connected with the action of the central mechanisms of vascular tonus regula
lion I heir exclusion is accompanied by marked and stable pressor reaction. It is
confirmed by scientific observation: sensitivity of the carotid sinus baroreceptors is
decreased in hypertension in the course of time.
I'he sympathetic part of the vegetative nervous system, which activates the ad
renal medulla and entry of adrenaline and noradrenaline into the blood is of great
significance in the pathogenesis of neurogenic hypertension. Stable excitement of
the hypothalamus (the highest regulator of vegetative functions) activates the sytn-
patho-adrenal system and the vasomotor component of the vascular tonus.
I he role of adrenoreceptors in arterial hypertension is represented in scheme 24.
Activation of |i,-adrenoreceptors of the heart activates heartbeats (tQ — hyperkine-
lic hypertension, [^-adrenoblockers are used for treatment). When the a-adreneigic
elicet of catecholamines on the resistance vessel tonus exceeds the P2-adreneigic
( lied, hypokinetic (T R ) hypertension develops. It allows using a-adrenoblockers
for treatment.
Srheme 24. Role of Adrenoreceptors in Arterial Hypertension

Salt(N a+, K+, Ca2+)-Dependent Hypertension

Ihe sail-dependent concept of arterial hypertension is based on the well-known

lad of hypertension development dependence on table salt abuse.
Ihe pathogenesis is connected with intracellular (in the smooth muscles of
resistance vessels) retention of Na+and Ca2+ and loss of K + ions (electrolyte bal
инее pathology is described on p. 261). Aldosterone plays its role (the aldosterone
incchanism is connected with the influence on the sodium balance, p. 261, tab. 7 on
p ?<>2, p. S O I, lig. 58 on p. 502). A high level of the myogenic component of vasculai
tonus is achieved under such conditions, when the balance of aldosterone and angio
tensm II on the one hand and natriuretic atrial hormone on the other hand is shilled
in favor of the first. Such imbalance arises at early stages of arterial hypertension
Retention of N a1 ions in the organism leads to water retention and edema
development Increase of arterial pressure Is characterised by у elevation (due to
 ( liaplet 24 r.iilm pln i..Ii>r' of Vi-ssrk

•iiiiilating blood volume increase, hypervolemic form of hypertension). Inlracellulai

uii myocytes) retention of Na+ increases their tone due to an increase of excite
mcnt potentiality. Endothelial edema and partial vessel narrowing develop because
n| water retention in the vessel walls.
Potassium loss from myocytes decreases their excitability threshold. They be
•1мне more sensitive to all vasoconstrictive influences (catecholamines, vasopressin,
muiotensin II).
Intracellular (in myocytes) retention of Ca2+ ions results in irreversible myofi
iMil contraction. In addition it causes a severe damage of myocytes (disorder of oxi
dative phosphorylation, formation of prostaglandins and leukotrienes). Contracted
nivofibrils are destroyed by proteolytic enzymes. C alcic damage of cells takes place
(mo p. 262). For patient’s treatment a physician should introduce К preparations
Hid limit salt (N aC l) consumption, which can be achieved easily. As to Ca2+ion
i«Mention, its limitation is achieved by usage of Ca-channel blockers.
Besides, there are cases of primary hypertension without table salt abuse, wlnli
It* limited consumption and Ca-blockers intake promote treatment effectiveness
I Ins may be explained by individual increased sensitivity of some patients to table
ill These are «salt-sensitive* people (it is considered that 1/3 of patients with
primary hypertension refers to this category).
The nature of hypersensitivity to table salt is not completely clear, though it is
■'bvious. The cellular mechanisms of salt sensitivity still await clarification. While the
•Hyanism is well protected against Na+loss (by aldosterone secretion), the patients
with increased salt sensitivity are unprotected against high NaCl intake. Moreover,
N.i retains in their organism under normal and even decreased salt intake (such
patients are even not inclined to add salt to food). There is an obvious peculiarity
in cellular Na+transport. Some theoretical suppositions may be proposed for «sail
'•usitivity* explanation:
• It is possible to suggest that in «salt-sensitive* people there are problems with
iklosterone balance regulation and removal from tissues and the organism. Its re
moval may be inhibited even under normal Na+ intake.
• Increased sensitivity of aldosterone receptors may also be supposed. Const
ini iitly, a diet with low NaCl intake would bring the NaCl balance into aldosterone
li \' Is (or high sensitivity to it) in such patients.
• Increased intracellular Na+concentration decreases the driving force of the
N.i Ca2+ exchange mechanism, as a result of which intracellular Ca24 conccntra
i иhi rises, which in its turn increases the tone of the vasoconstrictor muscles (Ca
i lianncl blockers are useful in treatment).
• Increased responsiveness to catecholamines may be supposed in people sensi
i i''1to NaCl (the connection between NaCl and catecholamine sensitivity).
Among these not thoroughly studied mechanisms the following supposition
sin mid also be mentioned. Increased activity of a certain mechanism may result
In >in decreased activity of another mechanism, which is opposite to it and balances
и I hat is, an increased capacity of Na+ ions to enter cells (myocytes) may he a
i onsequencc of a decreased capacity of myocytes to hold K ' ions inside the cells
iiiul sustain Ihe resting potential and a high excitability threshold of the excitable
I'iiiI S|N'( I dI IS y s lrm li'l Гя11н1|4|.<Ыо1»к>

myocylc membranes against a high gradient ol K ' ion concentration between tin
intracellular and extracellular spaccs.
It is possible to suggest insufficiency of the atrial natriuretic mechanism as well
.is ol the renal prostaglandin mechanism, which refer to N a+ ion balance rcgulu
lion.
t heoretically, the optimal therapeutic method would be stimulation of these
regulative mechanisms or replacement therapy with the mentioned substances (alii
.il natriuretic hormone and renal prostaglandins), but such methods have not been
developed yet. Thus, only one measure is left — salt consumption limitation (even
complete exclusion of table salt from the diet because dietary habits of such patients
do not require much salt). A diet low in N a' can lower (not yet fixed) hypertension
Simultaneous elevated K +supply enhances this effect.
I he next supposition is based on paradoxical clinical observations: consump
tion of any quantity of another sodium salt, namely sodium bicarbonate (in tin
lorm of mineral water), does not lead to blood pressure increase, but oppositely,
results in normalization of blood pressure and increase of diuresis. Participation ol
( I ions in the pathogenesis becomes obvious.

Renal Hypertension

I lie renal concept of arterial hypertension interprets blood pressure increase In

activation of the hypertensive renal mechanisms (excessive formation of renin jind
activation of the renin-angiotensin system) or/and suppression of the depressive
renal mechanisms (prostaglandin synthesis reduction, which results in electrolyte
balance disorder, sec fig. 45). In accordance with the blood renin levels, three forms
ol hypertension are differentiated — hyperreninemic (accounts for 25—30 % of hy
pertension cases), normoreninemic (55-60 % ) and hyporeninemic (10—20 % ).
Methods of antihypcrtensive renal function stimulation (prostaglandin pro
duct ion stimulation) have not been developed yet. The only measure is left - an
gioicnsin II formation blockade by inhibiting the A C E or angiotensin reccptoi
antagonist application.
At the same time, renal hypertension (concerning its pathogenesis), is usually
secondary (symptomatic, sec below), but not primary (essential). Although renin
concentration is not elevated in primary hypertension, blood pressure can be re
diiced even in primary hypertension by inhibiting the A C E or the use of angiotensin
leeeptor antagonists. It means that the renal mechanisms aggravate other forms ol
essentlal hypertension.

Secondary (Symptomatic) Hypertension

Arterial hypertension may be a complication of other diseases of the nervous

.uni endocrine systems (a complication of thyrotoxicosis, adenoma of the hypophv
ms and adrenal glands, sex gland insufficiency, etc.) and especially of the kidneys,
though, according to some authors, the remil and hormonal forms make only about
^ 10 ‘i ol all eases.
 ( liaplci 2S HaHmphyshihiity nf УгччК

Secondary Neuorogenic Hyperten­ Stenosis of the renal aiteiy

sion I nccphalitis, cerebral edemas or
livmorrhages, and brain tumor may Hypertrophy and
hyperplasia of the
153
lend to hypertension development. It juxtaglomerular apparatus
i* connected with stimulation of the
«tinpathetic nervous system. Central Disorder of renal
depressive function Disorder of
ih'ivoun stimulation of cardiac activity
intrarenal
lut ms hyperkinetic heart syndrome. blood How
Renin hypersecretion
Secondary renal hypertension is the
-------^ -----
iimsi common form of secondary hy-
Increased production
|n ill usion. Every renal ischemia leads of angiotensin II
(и renin release in the kidneys, which Aldosterone
••■Mills in elevation of blood pressure hypersecretion
M il by angiotensin II formation and
im leased aldosterone secretion. Angio-
ii tiMiiase activity of the kidneys may be secret,ion
Increase of vessel
•Iineascd in hemodynamics disorders reactivity and
hi both kidneys. In kidney disease with peripheral resistance
й significant reduction of the func­
tioning renal mass, Na+ retention can
llirrefore occur even during normal I lypertension
Nii supply. Glomerulonephritis (see
|i -I/(I), renal failure, and nephropathy Fig. 45. Pathogenesis of renal hypertension
■•I pregnancy are some of the causes
"I n nal hypertension. The disease can also be caused by renin-producing tumor.
Hi. kidneys are also central to other forms of hypertension that do not primarily
•«I luinalc from them (primary hyperaldosteronism, adrenogenital syndrome, Cush
Inn's syndrome).
Methods of antihypertensive renal function stimulation (prostaglandin stimula
...... have not been developed yet. The only measure is left - angiotensin II forma
linn blockade by inhibiting the A C E or angiotensin receptor antagonists.
Secondary Hormonal Hypertension. The endocrine mechanisms of arterial by
lu'iii usion are the following:
• Vlivation of the hypophyseal-suprarenal and sympatho-adrenal systems.
• Vlivation of the adrenal medulla under the effect of sympathetic nervous inllu
i iu es; activation of adrenaline entry into the blood.
• V im (constrictive effect of noradrenaline connected with a-adrenorcceptor exciln
Hon of resistance vessels.
■ Hypersecretion of aldosterone, which leads to sodium retention and potassium
itinoval.
• Ndivalion of the aldosterone-vasopressin system (increased secretion of vaso
piessin).
• Hypersecretion of glucocorticoids (hormones of the adrenal cortex), which has a
permissive effect on catecholamines.
I'lilt S|M-» iiil (S y s li'in ic ) I*ut li<>|»h>si<>l«

• Sex hormone (especially progesterone) deficiency (e.g. climacteric arterial hypci

tension).
I he adrenal glands (both the medulla and cortex) are the most importunt
Under physiological conditions adrenaline (and thyroxin) cause a short-term in
crease of arterial blood pressure. In pathology, when the sensitivity to adrenaline li
increased (connected with adrenoreceptors), blood pressure increase is steadier.
Aldosterone occupies an extraordinary position connected with electrolyte ini
balance (p. 261, hyperaldosteronism in fig. 58 on p. 502).
In primary hyperaldosteronism (Conn’s syndrome) an adrenal cortical tunioi
releases aldosterone without regulation.
In Cushing’s syndrome, an excess of A C TH release (neurogenic causes; hypo
physeal tumor) or an adrenal cortical tumor increase plasma glucocorticoid con
ccntration resulting in enhanced catecholamine affect (cardiac output increase) and
unncralocorticoid action.
In pheochromocytoma (hormone-producing adrenomedullary tumor), i .i
Iccholamines are produced, which results in uncontrolled high epinephrine .iml
norepinephrine levels and thus both hyperdynamic and resistance hypertension.
In adrenogenital syndrome, cortisol formation in the adrenal cortex is blocked,
and thus ACTH release is not inhibited. As a result excessive amounts of mineral) •
corticoid-active precursors of cortisol and aldosterone (1 1-deoxycorticosteronc
I )()(') arc produced and released. This leads to Na+retention, hence to an incrc.i .
hi extracellular volume and thus to hypertension resistance.

MANIFESTATIONS

Clinical manifestations of arterial hypertension are described in every detail In

therapy textbooks.
The first complications are local circulatory disorders, and then insufficient \
of organs and systems. The most widespread clinical forms of complicated hypci
tension are cerebral circulatory insufficiency (including stroke), hypertrophy ol (In
myocardium with cardiac insufficiency, and renal insufficiency (contracted kidney
syndrome).
A brief description of clinical manifestations of arterial hypertension is given
below:
• increase of arterial blood pressure above 140/90 mmHg;
• increase of heart load (resistance load);
• myocardial hypertrophy;
• heart insufficiency;
• disorder of blood circulation in the kidneys;
• disorder of blood circulation in the retina;
• edema;
• hemorrhage;
• disorder of tissue trophicity;
• risk factor of atherosclerosis development;
• risk factor of myocardial infraction;
• risk factor ol hemorrhagic stroke
 C hapter 25. I’ulhoph.vsioloKy of Vessels

PULMONARY HYPERTENSION

Pulmonary hypertension is characterized by increased pulmonary arterial blood

* . лиге to more than 25 mmHg and development of the so-called cor pulmonale
1 1

iм.I /lyjit-side circulatory insufficiency.

Ily its origin pulmonary hypertension can be primary and secondary.
I he development of secondary pulmonary hypertension is caused by diseases
•м.. ting the respiratory tract and alveoli (chronic bronchitis, bronchial asthma,
........ pneumonia, pulmonary emphysema, pneumosclerosis), disorders of chest
......incuts (kyphoscoliosis, pleural fibrosis, chronic neuromyasthenia or poliomyc
..... .11nl also by diseases affecting the pulmonary vessels (periarteritis, thrombosis
.i .in.ill blood vessels, embolism of the pulmonary artery) and the heart (mitral
i. inisis, ventricular septal defect).
Primary pulmonary hypertension is rarer, develops without diseases of the limns
iml heart (pulmonary hypertension of unknown etiology). Sometimes primary pul
miHiary hypertension is congenital.
One of the mechanisms of pulmonary hypertension development is p(), de
....... in the alveolar air. Under high-altitude conditions the influence of this l.и
i..i i more marked. Low partial pressure of oxygen in the alveolar air has a direct
iiiihiencc on the smooth muscular elements of the pulmonary vessels causing a
•inhle increase of their tonus. The smooth muscles of the lungs have 0 2-sensitive К '
..... il Decrease of p02 in the alveolar air leads to closure of these canals, absorp
п. .и ol sodium by vessel myocytes, depolarization of their membranes, excitability
•in. hold decrease, Ca2+ion entry into the hyaloplasm and smooth muscle contrac­
tion vessel spasms.
I lie vasopressive effect of hypoxia is increased in case of acidosis development
т . I physical exertion. On the other hand, hydrogen ions, vasoactive amines (hista
Milne serotonin), and metabolic disorders play a role of the mediator of the pressor
. и .. I of hypoxia on the lung vessels. Alkalosis decreases the vasoconstrictive effect
mi 11 s poxia. Adenosine, A M P, acetylcholine have a vasodilatative effect on the lung
urtiHlci
ARTERIAL HYPOTENSION

Nrterial hypotension is a stable decrease of arterial blood pressure (lower than

|uii i.o mmHg) caused by decreased resistance vessel tone.
\iterial blood hypotension is divided into physiological and pathological, pri
.... uid secondary, acute and chronic.
Physiological arterial hypotonia is not accompanied by painful symptoms. More
Hlii'ii il is observed in people with asthenic constitution.
Pathological hypotonia has a typical symptom complex. It includes decreased
pin i. il development and nutrition, general adynamia, groundless fatigability,
i.n li\. .mlia, dyspnea, vertigo, hcadache, syncope.
I. ulc arterial hypotension develops in shock and collapsc.
Г»г1 S| m-cIhI (SyM rm te) I' mI lit >|>liysi<>l«>
k>

( hronic arterial hypotension is divided into primary (hypotensive neurocircula

lory dystonia) and secondary (symptomatic).
I here are three hemodynamic forms of arterial hypotension: a) connected with
impairment of the contractile function of the heart and decreased systolic blood
volume; b) caused by decreased circulating blood volume; c) caused by decreased
tonus of resistance vessels.
It is believed that the main etiological and pathogenic factor of primary arterial
hypotension is overtension of the main processes of the cerebral cortex (excitation
and inhibition) as in essential hypertension. But unlike primary hypertension, tin
is predomination of inhibition and its spread to the subcortical vegetative forma
lio n s (the vasomotor center). Suppression of vasoconstrictive influences, and at Ihe
same lime prevalence of cholinergic influences over the adrenergic ones (typical ol
Ihe asthenic type of constitution) are the cause of the decreased tonus of resistance
vessels, decreased peripheral vessel resistance and arterial blood pressure.
Symptomatic (secondary) chronic arterial hypotension is a consequence of acnle
and chronic somatic diseases of the heart (myocarditis, myocardial infarction)
blood (anemia), endocrine glands (hypofunction of the adrenal, thyroid and pitu
itary glands), liver (mechanical jaundice), lungs (pneumonia).
Exogenous and endogenous intoxication can promote chronic arterial hy
potension development.

CAPACITANCE V ESSEL PATHOLOGY

VEN O US IN SU FFIC IEN C Y

I he bulk of the blood (70—80 % ) is concentrated in the veins (capacitance ves

els), deposited and redistributed in them before returning to the heart. Because ol
their high compliance and large capacity, the veins serve as a blood store. Venous
insufficiency may develop in any part of the venous bed, but more often in th<
lower extremities veins, which are divided into superficial and deep.
KtioloKy. Job-related fixed standing position for many years leads to vein ills
tension and deformation (varicosis, i.e. formation of varices), especially in the legs,
where the hydrostatic pressure of the column of blood increases the transmiual
pressure. I Iderly age and constitutional peculiarities of the venous vessels (increase.I
distcnsihility of the veins) predispose to venous valve incompetence. Frequently il
develops or worsens during pregnancy or in obesity.
Pathogenesis. The venous valves ensure vertical blood flow against Ihe force ol
gravity. Due to the large mass of blood, peculiarities of blood movement (from l>e
low from Ihe lower extremities — upwards), thinness of the vessel wall (witIi few
muscles) Ihe blood How in the venous part of systemic blood circulation is predis
posed lo congestion. Constant contractions and relaxations of the leg muscles and
joint movement during walking are an essential driving force of venous return via
the deep veins. When the leg muscles are relaxed, Ihe blood Mow from the surface
lo the deep veins ensures and protects the blood (lowing in the opposite direction
when the muscles contract.
 ( 'liaplcr 2.V I*иt li<»|iliуsi«>
l<>k> of Vessels

Pathophysiological events in venous insufficiency are connected with venous

■•ingestion. It leads to venous edema (see p. 256 about pathogenesis). Inflamma
..... often accompanies it (phlebitis) and can lead to chronic venous insufficiency.
Hl<мul Ho w deceleration predisposes to congestion, congestion — to thrombosis. II
• ilnombus forms in the deep leg veins, the blood drains via the superficial veins
.mg their varicosis. Together with inflammation there develops a typical pal ho
i и \ of this part of systemic blood circulation — thrombophlebitis. Thrombosis,
hi its turn, predisposes to embolism (thromboembolism, which develops when a
lluombus detaches from its original site, see p. 113. It is especially dangerous in
■ .|mel to vessels of the heart (causing infarction, which was mentioned on p. 345),
in,im (causing stroke, which will be mentioned on p. 517), and lungs (see p. 113).
Manifestations. In addition to cosmetic problems, sensation of heaviness,
i'innmg, pain, and edema develop in the legs. In long-term chronic venous iusnl
ti. if iicy, edema with protein exudation and deposition of fibrin in the pericapillary
r i. с m the skin, results in fibrosis, dermatosclerosis, tissue hypoxia, and ultimately
hi li-ц ulcers, which is a surgical disease.

Questions for Self-Control

I How and why does pathology of elastic- and muscle-type vessels differ?
' What is the role of genetic factors in atherosclerosis pathogenesis?
I Name and explain the theories of atherosclerosis.
I What is the role of the endocrine system in atherosclerosis pathogenesis?
What are the risk factors of atherosclerosis development?
fi What are atherosclerosis manifestations?
What are the risk factors of arterial hypertension pathogenesis?
N Wliat is the role of genetic factors in arterial hypertension pathogenesis?
'i Wliat is the role of the kidneys in arterial hypertension pathogenesis?
|u | xplain the antihypertensive function of the kidneys.
11 Wliat is the role of Ca2+ and other electrolytes in arterial hypertension pat ho
genesis?
i ' What are arterial hypertension manifestations?
I ' Wliat are the main ways of pathogenetic treatment for arterial hypertension?
i I Wliat are the peculiarities of pulmonary hypertension?
I Wliat are the hemodynamic forms of arterial hypotension?
I»' What are pathogenesis and manifestations of venous insufficiency?

Tests for Self-Control

(give correct answers)

I Л (»0 year-old man has blood vessel atherosclerosis. Excess of what substances
plays a leading role iu Ihe pathogenesis of this disease?
A. Histic lipoprotein lipase.
I< High density li|H»prolcins.
I’uii S|H4-ImI (S v s lm m ) l*Mllio|thvsiolo)o

C. Chylomicrons.
I). Low-density lipoproteins.
I , Fatty acids.

.’ Kahhils were fed with addition of cholesterol. In 5 months atherosclerotii

changes in the aorta were found. What is the main cause of atherogcncsis in
(his case?
Л. Endogenic hypercholesterinemia.
B. Overeating.
C. Inactivation of receptors to low-density lipoproteins.
I). Hypodynamia.
I Exogenous hypercholesterinemia.

< In a patient with persistent arterial hypertension angiography showed athcro

sclerotic lesion of both renal arteries. What is the initial mechanism of arteri.il
hypertension development?
Л. Increased secretion of vasopressin.
B. Increased level of catecholamines.
C. Increased level of hydrocortisone.
I). Increased cardiac outflow.
I Increased production of renin.

4. A patient suffers from hypertensic crisis. An increased level of angiotensin II

was found in the blood. What is the pressure effect of angiotensin associated
with?
A. Activation of biogenic amine synthesis.
B. Contraction of the arteriole muscles.
C. Hyperproduction of prostaglandins.
I). Stimulation of vasopressin formation.
E. Activation of the kallikrein-kinin system.

5. A patient has arterial hypertension caused by renal artery stenosis. Activation

of what system is the main mechanism of this form of hypertension?
A. Sympatho adrenal.
B. Kenin-angiotensin.
C. Parasympathetic.
I). Kallikrein-kinin.
I Hypothalamo-pituitary.

li A patient with idiopathic hypertension revealed increased concentration ol vu

soprcssin h i the blood. The function of what organ does this hormone inllucin t
directly?
A. Liver.
В Kidneys.
 t hap ter 25. I ’hIIioiiIiysIoIok.v o f Vessels

C. Heart.
I). Lungs.
li. Epinephral glands.

A 43-year-old patient suffers from arterial hypertension caused by a moderate

increase of cardiac outflow and general peripheral resistance. What hemody
n.nnic variant of arterial hypertension has developed in this case?
A. Eukinetic.
B. Hyperkinetic.
C. Hypokinetic.
I). Akinetic.
E. Combined.

N A 65-year-old man has been suffering from arterial hypertension for 15 years
Now systolic pressure is decreasing and diastolic pressure remains increased
What hemodynamic type of arterial hypertension is it?
A. Hyperkinetic.
B. Normokinetic.
C. Hypokinetic.
I). Eukinetic.
E. Dyskinetic.

'* Arterial hypertension was reproduced by narrowing the renal arteries in a dog.
Activity of the renin-angiotensin-aldosterone system increased. What compo­
nent of this system has the strongest pressor effect?
A. Renin.
B. Angiotensin II.
C. Angiotensin I.
I). Kinins.
I Aldosterone.

I" A patient with alcoholic cirrhosis of the liver complains of common ailment
dyspnea. Decrease of arterial pressure, ascites, dilatation of the superficial ;ib
dominal veins, and splenomegaly have been revealed. What impairment of
hemodynamics is observed?
A. Failure of the left ventricle.
B. Failure of the right ventricle.
( '. Total heart failure.
I ). Collapse
I Portal hypertension.

li A patient has myocardial infarction. His arterial pressure has decreased to

70/40 mmHg. Wlial is the initial mechanism of arterial hypotension develop
mcnl in this case?
1*11(1 2 S|M4'iiil (Syslom lc) I’alhopliysiolo^v

A. Decrease of the minute volume of the blood.

B. Sodium loss in the organism.
C. Accumulation of potassium in the organism.
I). Generalized vasodilatation.
I Constriction of the peripheral vessels.

12. A patient with rheumatism developed myocarditis with circulatory insufficicn

cy. What disturbance of hemodynamics is typical of this case?
A. Decrease of diastolic arterial pressure.
B. Decrease of systolic arterial pressure.
C. Increase of systolic arterial pressure.
I). Acceleration of blood flow.
E. Decrease of venous pressure.

I V Septic disease was diagnosed in a patient. For 5 days his body temperature
ranged from 39.5°C to 40-40.2°C. On the 6,h day an abrupt decrease in bo«l\
temperature led to collapse. What is the main mechanism of collapse develop
ment in this case?
A. Hyperventilation.
B. Vasodilatation.
C. Vasoconstriction.
I). Tachycardia.
E. Polyuria.
( lu ip te r 26
Г ЛИ IOPHYSIOLOGY OF RESPIRATORY SYSTEM

Respiration is a function of the organism, which consists in maintaining the gas

..... position of the blood, supplying tissues with oxygen (0 2) and releasing carbon
illMMdc (C02).
Respiration is divided into external and internal. Internal (tissue) respiration is
■mcn/.ymal system of oxygen utilization by tissues. Internal respiration disorders are
ill «libed in chapter 11 «Hypoxia».
I \ternal respiration is realized with participation of the central nervous system,
с H|iheral nerves (motor and sensitive, somatic and vegetative), respiratory muscles
i mi г icostal muscles and diaphragm), upper respiratory tract, thorax and lungs,
«rim Ii are necessary for normal ventilation. In case of their disorder respiratory
(inline develops.
I liree main physiological processes take place in the lungs:
• ventilation;
• diffusion of molecular oxygen and carbon dioxide through the alveolar-capil
lary membrane;
•perfusion (flowing of the blood through the pulmonary capillary vessels).
Respiratory insufficiency is a pathologic process, which develops as a result of
>urinal respiration disorder, when the gas content of the blood does not correspond
. requirements at rest and under physical load.
Respiratory failure even at rest may lead to hypoxia, gaseous acidosis and limits
Hi' oiganism ability to perform physical work.

CLASSIFICATION

I'alhology of the respiratory system may be classified according to different

pi im iples.
I tiological classification divides it into acquired and hereditary ( congenital), as
*• II .is infectious and noninfectious (including environmental pathology caused by the
iwtlioycnic effect of environmental factors).
topographic classification divides it into extrapulmonary and pulmonary accord
Him io localization of the initial cause.
Pathogenetic classification divides it into prim ary (pathology begins in the respi
(Nliи\ system) and secondary (complication of other diseases - arterial hyperten
iIihi heart insufficiency, cardiac asthma, etc.) as well as total and p artial (disordci
tn ill oi one physiological process in the lungs). The latter in its turn is subdivided
.... w ntilative , diffusive, perfusive and combined. In its turn, ventilativc pathology
I» Milnlividcd into disregulative, obstructive and restrictive (scheme 25) Depending
II" ili> kind of a typical pathological process it may be divided into inflammatory,
*ll>чц1с, tumorous, and vascular.
<lin ical classification divides il into acute and chronic
Г.ill S|K4'lnl (System ic) ralh»|ihysiol<iK>

Scheme 25. Classification of Respiratory Pathology

ETIO LO G Y

I lie causes of respiratory pathology are numerous. Their general property is the
ability to influence gas composition of the blood and oxygen supply to tissues.
I liological factors are divided into exogenous and endogenous, acquired and
hereditary. Further they are divided into physical, chemical and biological.
Physical factors are mechanical traumas, foreign bodies obstructing the lumen
of the respiratory tract, barotrauma leading to increased or decreased solubility ol
gases in the blood, electrotrauma (if electrical current passes through the respira
tory center).
Chemical factors are poisons (muscarine), which lead to respiratory arrest <>r
lung edema, narcotics, side effects of drugs, smoking, harmful industrial factois
leading to environmental diseases, chemical warfare agents (phosgene), which cause
pulmonary edema when inhaled.
Biological factors are infectious with tropism to the organs of the respiratory
(pneumococcus, tubercle bacillus, adenoviruses) and exogenous immune factors
(vaccines, heterogenous immune serum).
Endogenous factors are autoimmune and genetic.

PA T H O G E N E SIS

I he pathogenesis of different types of respiratory insufficiency is different and

should be discussed separately.

V EN TILA TIVE RESPIRA TO RY IN SU FFIC IEN C Y

Ventilative respiratory insufficiency is divided into disregulative, obstructive

and restrictive.
 Chapter 2<> 1’alhophyslology of Respiratory System

Disregulative Ventilative Insufficiency

All parts of the nervous system relate to respiratory function regulation the
•tebral cortex, hypothalamus, spinal cord, n. vagus, motor and sensitive nerves.
Mveolar ventilation is regulated by neurons of the respiratory center, which arc
i " ited in the medulla oblongata, pons cerebelli, cells of the reticular formation,
•pinal motoneurons, nerve pathways transmitting impulses to the respiratory mils
■I. , and diaphragm. These mechanisms provide certain depth, rate and rhythm ol
i' piration. Disregulative ventilative insufficiency is based on respiratory center dys
11met ion or impaired transmission of efferent influences to the respiratory musclcs
Respiratory Center Dysfunction. The respiratory center is a morphological struc
tuic in the medulla oblongata, which includes inspiratory and expiratory neurons,
as well as apneustic (in the caudal parts of the pons) and pneumotaxic (in the uppei
part of the pons) centers. Partially the respiratory center is regulated directly, pai
nally - by reflexes (the vagus nerve realizes the Hering—Breuer reflex - inhibition
••I inspiration in case of alveolar distention, prevents pulmonary superdistention ami
n ali/es expiration inhibiting inspiration). Dysfunction of the respiratory centcr may
lie caused by a direct effect of different pathogenic factors on the central nervous
vstem or by reflex.
Disorders of the respiratory center may be caused by pathogenic factors, which
directly influence metabolism, structural and functional properties of its neurons,
'•iii li factors may include hypoxia, hypoglycemia, brain trauma, compression of the
puns cerebelli (edema, tumor, hematoma), disorders of brain circulation, intoxica
..... (poisoning by narcotics and muscarine, toxic metabolic products in hepatic
uul renal insufficiency). Inflammation and dystrophy are possible in any part of the
nervous system.
t utting of two vagus nerves under experimental conditions leads to lung col
lapse. Expiration is inhibited, respiration becomes infrequent and deep (vagus respi
i it ion). Hemorrhage into the region of the respiratory center or vagus nerve center
impairs the respiratory act. The function of the respiratory center may be changed
tis reflex with influencing receptors of the vascular bed, respiratory tract and lung
piiienchyma.
In pathology, under the action of reflex, humoral or other factors on the respi
iiilory center, respiration depth, rate and rhythm may be changed. Some of these
■lunges may manifest compensatory reactions directed at supporting gas constancy
m ihe blood. At the same time, some of them manifest impairment of normal
i' filiation of respiration leading to disorders of alveolar ventilation and respiratory
Insufficiency.
Changes of respiration depth and rate lead to alveolar ventilation decrease
I hypoventilation) or increase ( hyperventilation). In nervous regulation disorders such
types of respiration may develop — bradypnea (infrequent breathing), tachypnea
lliei|uent shallow breathing), hyperpnea (deep frequent breathing), apnea, periodic
hiea thing.
Disorders o f impulse transmission to the respiratory muscles may result from:
■ damage of nervous conduction pathways, which connect respiratory center neu
tons with spinal motoneurons.
Г . Ill ’ >|М . I II ( S y s lr m k ') I * ■I li<>||||\ I. .1.\

• inipairmcnt of the function of the spinal motoneurons, which innervate the re­
spiratory muscles (inflammatory and dystrophic processes in the spinal cord);
• damage of the peripheral nerves, which innervate the respiratory muscles (trau
nia, inflammation, avitaminosis);
• damage of nervous impulse transmission to the muscles (myasthenia, injection ol
myorelaxants);
• damage of the phrenic nerve and diaphragm paralysis.
Sometimes, due to disorders of respiratory act regulation, respiratory automa
I ism is lost when only voluntary control over respiration remains.

Obstructive Ventilative Insufficiency

Obstructive ventilative insufficiency is connected with pathology of the respira

tory tract. It is subdivided into compressive, occlusive and spasmodic ones.
Compressive ventilative insufficiency happens in cases if the respiratory ways oi
lungs are pressed from outside by a tumor, inflammatory swelling, retropharyngeal
abscess, enlarged thyroid gland, strangulation, etc.
Occlusive ventilative insufficiency occurs as a result of narrowing of the respira
lory ways from inside and increased resistance to air.
The causes are:
• entrance of foreign bodies into the respiratory ways;
• occlusion by vomit mass, water, blood, pus, transudate;
• thickening of the respiratory tract walls (inflammation, edema, hyperemia, tu
mor);
• hypertrophy and hyperplasia of mucous cells;
• accumulation of phlegm (hypersecretion of mucus, disorders of its Theological
properties, disorders of cough mechanism).
Spusmodic ventilative insufficiency is a widespread and significant mechanism
of bronchial obstruction.
Bronchial spasm has nervous and humoral causes.
Nervous regulation of the bronchial lumen is provided by the vagus and sym
pathetic nerves. The vagus nerve has different types of neurons. Cholinergic mo
toncurons release acetylcholine, which stimulates bronchial contraction. Peptidei
gic neurons release the P substance, which has the same effect. Another type of
neurons release the so-called V IP substance (vasoactive intestinal polypeptide),
which dilates the bronchi. Noradrenaline and adrenaline dilate the bronchi as well
(|l adrenoblockcrs cause cough and bronchospasm).
So, bronchial spasm is determined by:
• increased activity of the cholinergic neurons of the vagus nerve and acetylcholine
release;
• increased activity of the peptidergic neurons of the vagus nerve, which release I ho
P substance;
• deficiency of VIPergic neuron activity.
I here is a large group of lium oral ftn loix (hystamine, serotonin, IcukotrieucK,
kinins, prostaglandins, thromboxanes, etc ), which cause bronchospasm.
 Chapter Hi I'ullHiphysioloio of Ki-spirulory NyMrm

Bronchial asthma is a typical clinical example of bronchospasm (the role ol

ullcigic mechanisms is represented on p. 95).

Restrictive Ventilative Insufficiency

Restrictive ventilative insufficiency is connected with a disorder of lung com

ph.mce. It may occur due to extrapulmonary (connected with pathology of the
■> piratory muscles, thorax and pressure in the pleural cavity) and intrapulmonary
reasons, which are connected with properties of the alveoli. Inflammation, blood
■ongestion and edema in the lung impair its compliance and sufficient expan
Moil.
Disorders of the Surfactant System of the Lungs. Normally, the internal sin
luce of the alveoli is covered with surfactants — surface-active agents of lipoprotein
iigin. Surfactants protect the alveoli from collapse and prevent liquid transudation
imm capillaries into the alveolar lumen. Pneumocytes participate in surfactant syn
thesis and storage of synthesized material. Macrophages remove surfactants.
I'he mechanisms of surfactant system disorders are the following:
• synthesis impairment;
• accelerated removal from the surface of the alveoli;
• destruction.
Below are given typical clinical situations characterized by surfactant system
problems:
• systemic hypoxia and acidosis;
■ lung inflammation;
• disorders of blood circulation in the lungs;
• vomit aspiration;
provision of artificial blood circulation;
• usage of high concentration of oxygen (use of pure oxygen in respiratory insul
liciency may aggravate it);
■ tuberculosis;
• atelectasis in premature babies.
Atelectasis is collapse of the lungs. In this pathologic process alveolar vent da
imn stops and the lung collapses as a result of air resorption. Atelectasis may be
uhsiructive and compressive. The causes are bronchial obstruction, lung compres
мин by exudate or tumor. Surfactant deficiency is also important. Tuberculosis may
i" accompanied with atelectasis.
Emphysema is a condition which is characterized by a reduced area of dillu
......when the alveoli have a large lumen but are also diminished in number. I lie
.ilsi-olar ducts, respiratory bronchioles, terminal alveoli are distended. Lung tissue
lasiicity is lost. A deficiency in proteinase inhibitor (which normally inhibits the
и non of proteinases) very often underlies the pathology. In addition to it, increased
' l i t.isc production (serine elastase from granulocytes, metalloelastasc from alveolai
micro phages, and various proteinases from pathogens) may be a cause of cmpliy
•ina An excess of clast uses in chronic inflammatory diseases leads to destruction
ul elastic libers in the lungs Reduced clastic recoil lias the same elfect as obslriic
Г.I l l J Special (Sys(nnlc) l’ulho|ihv4iiil<>K>

live lung disease. Vital lung capacity is diminished. The loss of alveolar walls leads
to a diminished diffusion area, increased pulmonary artery pressure and vascular
resistance to the heart.
Pncumosclcrosis is fibrosis of the lungs, which results in lung compliance de­
crease. Its reasons are the following:
• chronic toxic damage;
• prolonged inflammation;
• diffuse systemic diseases of the connective tissue;
• ionizing radiation influence;
• smoking.
Pneumosclerosis develops in the end of different diseases of the lungs and most
often of chronic inflammatory diseases (infectious and allergic). Excessive growth of
the fibrous tissue takes place in parenchymatous elements and capillaries.
Kxtrapulmonary reasons are connected with:
• impaired structure and function of the respiratory muscles;
• hampered mobility of the thorax and diaphragm;
• increased pressure in the pleural cavity, accumulation of exudate or transu­
date (hydrothorax).
As a result of these causes, thoracic excursions and lung expansion are impaired
by hypoventilation.
Pathology of the respiratory muscles (intercostal muscles and diaphragm) im­
pairs breathing and causes extrapulmonary restrictive respiratory insufficiency. Dis-
orders of their structure and function, inflammation, and dystrophy may be another
reason. Inflammation (myositis), radiculitis, paralysis, and paresis are possible. The
pain connected with respiratory muscle pathology impairs respiration.
Respiratory arrest or impairment may occur in lim itation o f thorax mobility
(mechanical trauma of the chest).
11'the pleural cavity is damaged and air enters it, negative pleural pressure rises,
transpulmonary pressure gets decreased and the lung collapses. Pneumo-, hydro-,
pyo- and hemathorax is accumulation of air, fluid, pus or blood in the pleural cavi
ly as a result of trauma of the thorax and pleura, perforation of the esophagus,
extension of lung abscess or other infections in the pleura with formation of broil
choplcural fistula, rupture of air-containing cysts or bullae associated with emphy­
sema or other forms of diffuse or local lung disease.
In figure 46, spirograms of some clinical cases with obstructive (b) and restric­
tive (c, d) disorders arc represented. If the lung parenchyma is normal but the rcspi
ratory tract is narrowed, the vital lung capacity (V L C ) may remain normal but the
volumetric air flow rate decreases. In restrictive processes the lungs become more
riK.id and straighten poorly but the function of the respiratory tract is usually not
disordered and thus the speed of air flow is not changed. Though V L C and FEV
(forced expiration volume) are decreased, their ratio remains normal.
Obstructive and restrictive processes are accompanied by increased work of the
respiratory muscles, increased need for energy and oxygen consumption while A TP
formation. Prolonged overload of the respiratory muscles results in their fatigue and
aggravation of respiratory insufficiency
 Chapter ih ГиИшрЬучМоку of Respiratory Sysle

Forced j Maximal
" “ 'T j • ^ orced | pulmonary
expiration i inspiration I ventilation
vmtibiimri

U
P
dя

Fig. 46. Spirograms of a healthy person (a), a pneumosclerosis patient

(b), a bronchial asthma patient (c), and a pulmonary emphysema
patient (d):
T L C — total lung capacity; V LC — vital lung capacity; IR V - inspiratory re
serve volume; l;.RV expiratory reserve volume; RV — residual volume
Г,ill 2 Special (System ic) PalhopliysioloKy

D IFFUSIVE RESPIRATORY INSUFFICIENCY

I he movement of gases through the alveolar membrane is provided by diflu

мои and depends on the diffusion ability of the membrane and the difference ol
gas pressure in both parts of the membrane. The diffusion ability of the membrane
depends on some components, which provide solubility of gas in tissues, the area ol
membrane surface, its thickness, molecular mass and diffusion coefficient.
According to this, disorders of gas diffusion in the alveolar capillary region oc­
cur in case of alveolar capillary barrier impairment and have such mechanisms:
• decrease of the area of the alveolar capillary membrane;
• thickening of the capillary membrane;
• decrease of the transmembrane gradient of partial pressure of gases in tin-
alveoli-blood system;
• decrease of the volume of the capillary blood in the lungs;
• decrease of the speed of reaction between 0 2 and Hb and oxygen capacity ol
the blood;
• decrease of alveolar ventilation;
• decrease of exposition and contact of erythrocytes with the alveolar air.
I he named disorders may be connected with the following pathological pro
cesses and diseases:
• damage of membranes (membranogenic poisoning);
• inflammation and accumulation of inflammatory exudate;
• sclerosis;
• fibrosis;
• edema;
• anemia and Hb inactivation;
• emphysema;
• cardiac insufficiency.
The diffusive surface may decrease as a result of lung resection, alveoli destmc
lion in Ihe course of chronic inflammation, tuberculosis, atelectasis.
Pathological processes may be accompanied by thickening of the alveolar and
capillary walls, increase of the amount of connective tissue in them, liquid in the
alveoli and pulmonary interstitium. It hampers gaseous diffusion in the lungs and
formation of the so-called alveolar capillary block
(lig. 47). Alveolar capillary block may be caused by
such diffusive lung damages as pneumoconiosis of
different etiology, pneumosclerosis, scleroderma,
emphysema, pneumonia.

/ /.*: 47. Causes ol diffusion disorders:

1 normal correlation between capillaries aiul alveoli;
2 alveolus wall thickening; 3 — capillary wall thickcning;
I intiaalvcolar edema; 5 interstitial edema; (> inplllary
dilatation
 C 'liiiplci 2l\ Гй11н>||1пч1<>1<>КУ Respiratory System

Disorders ol gas diffusion mostly refer to oxygen since diffusion of (.'(), is

41 25 times easier provided. Thus, depending on the change of the gaseous con
tent of the blood, hypoxemic and hypercapnic types of respiratory insufficiency are
differentiated.
Pulmonary edema plays an important role in alveolar capillary block. It devcl
•>i>s when a liquid gets filtrated via pulmonary microcirculation more rapidly than
revealed via the lymph vessels. At first, a liquid is accumulated in the interstitiuni
between the capillary endothelium and alveolar epithelium ( interstitial edema). I lien
i larger part of this liquid gets into the interstitium under the pleura and near the
bronchi, and the latter prevents the liquid from getting into the alveoli. Afterwards
die liquid enters the alveoli ( alveolar edema) impairing gas exchange.
Hemodynamic factors may cause edema, which leads to an increase of pres
мне in the capillaries. It is observed in case of left-side heart insufficiency, some
■ongcnital or acquired heart failure (stenosis of the left atrioventricular opening).
Among other causes of lung edema it is necessary to note impairment of the
lung microvascular endothelium resulting in its increased permeability to proteins
It is observed in inspiration of some toxins including high concentration of oxygen
Ii happens also in sepsis when BAS are accumulated (inflammation mediators).
I inbolism of the pulmonary artery may result in lung edema as well.

PERFU SIVE RESPIRATORY INSUFFICIENCY

Disorders of pulmonary blood circulation may be local and caused by systemic

disorders of hemodynamics.
Local disorders are hyperemia, venous congestion, ischemia, thrombosis, and
inbolism. Inflammation (including allergic) impairs pulmonary blood circulation
Systemic disorders of blood circulation secondarily impair pulmonary blood
>Irculation. There is differentiated pulmonary arterial hypertension (p. 385).

Decrease of Pulmonary Blood Circulation

Decrease of lung perfusion may take place in case of:

• systemic disorders of blood circulation (shock, collapse);
• disorders of right ventricle contractility (infarction, myocarditis, cardiosclerosis,
exudative pleuritis);
• disorders of left ventricle contractility;
• blood congestion in the lungs;
• some congenital and acquired cardiac disorders, heart diseases (stenosis or atresia
of the pulmonary artery);
• embolism of the pulmonary artery.
In all these cases the rate of blood flow in the lungs decelerates. Al the same
lime, alveolar ventilation prevails over perfusion and provides sufficient saturation
nl the blood with oxygen and decreased amount of CO , (hypocapnia). But, since
(lie minute hcarl volume and the blood flow rate in the greater circulation decrease
under such circumstances, tissues suffer from hypoxia.
I’ll f t S|H‘cImI (System ic) PutliopliysiuloKy

Disorders of (he Ventilation-Perfusion Ratio in Lung Diseases

Proper ratio between ventilation and perfusion is important for normal g;r.
exchange in the lungs. When ventilation prevails over blood flow, a larger amount
ol CO, is released from the blood than usually ( hypocapnia). If ventilation is slowei
than the blood stream, p C 02 concentration in the alveolar air increases and p(),
concentration in the blood decreases with hypoxemia and hypercapnia.

Hr . 48. Local pulmonary ventilation-perfu-

sion relations and their influence on blood
oxygenation
V4 alveolar ventilation; Q — the amount of blood ()2 ^
(lowing through the pulmonary vessels per minute concentration

For the best gas exchange in the lungs the optimal ventilation-blood supply
ratio must be provided in all alveoli. But even under normal conditions it is not
so In the course of lung diseases pathological ventilation-perfusion inequality joins
(lie physiological one. In well-ventilated alveoli the blood flow may be weak and
Ihe alveoli, which are provided with the blood intensively, may be badly venh
hited.
Figure 48 shows significant changes of the ventilation-perfusion ratio undct
such conditions. We can see that a high ventilation-perfusion ratio only slightIv
increases blood oxygenation while a low one determines its significant decrease and
results in substantially decreased content of oxygen in the blood.
I lie lungs have mechanisms, which maintain the necessary ratio between al
veolar ventilation and their perfusion in case of ratio deviation from the normal
level. O, deficit determines spasms of the vessels of the lesser circulation (hypoxic
vasoconstriction).

COMBINED RESPIRATORY INSUFFICIENCY

Mosi clinical cases of respiratory insufficiency relate to the combined type.

In case of inflammation, ventilation, perfusion and diffusion are disturbed si
niultaneously. The lung parenchyma and interstitium are involved at the same time
As inflammatory diseases are the most frequent pathology, a majority of clinical
examples are essentially combined respiratory insufficiency (pneumonia, bronchitis,
tuberculosis, etc.). Edema of the lungs refers to this category as well.
Disorders of the surfactant system usually joins all types of pathology.
A space flight is an example of a grave disorder of all physiological processes
in the lungs both during dynamic periods ot the llt^lit and in the stale of wcitdit
 Chapter I’lilhiiithvsloloKY of Ki-spiraton System

h .sness. High pressure on the chest limits thoracic excursions. Redistribution ol

iln- hlood in the lungs disorders blood supply of certain parts of the lung. Essential
tnavity changes (substantial increase of gravity while launching and landing and its
ihscnce in the outer space) result in disorders of the ventilation-perfusion ratio in
iIh- lungs.
R ESP IR A T O R Y PA TH O LO G Y M A N IFEST A T IO N S

The manifestations of respiratory pathology are metabolic, pathophysiological

uul clinical.
Metabolic and Pathophysiological Disorders

Respiratory pathology is one of the reasons for hypoxia development (res,;pi-

raiory hypoxia, p. 160). It is a complex of pathological changes (lack of energy,
impairment of physiological functions, nervous disturbances, etc.) and compensa
lory reactions (erythropoiesis activation, changes in tissue mechanisms of oxygen
"iili/ation, etc.), which are typical of every type of hypoxia as a typical pathologic
process (described in chapter 11 «Hypoxia»). Disorders of metabolism are conned
14I with oxygen deficiency and/or changes of carbon dioxide content. Disorders ol
initiative process and metabolic acidosis are the main metabolic changes. In some
•.iscs of hyperventilation respiratory alkalosis develops (p. 249).
Nevertheless, in many disorders of external respiration with impairment of
ventilation and perfusion, respiratory failure may not develop at rest, as gas con-
i<?nl in the blood is maintained normal. Potent compensation is connected wiili
Ihe presence of an excessive amount of functional elements in the lungs (alveoli
mill capillaries), which substantially prevail the organism’s need for oxygen at resl.
In addition, the perfect system of external respiration regulation reacts to minimal
Mmluations of p02 and pC 02 in the blood and, if it is necessary, activates the re
piratory muscles increasing the depth and rate of respiration. Blood circulation is
и nvated in accordance with breathing. It provides constancy of gas content both at
и I ,md in case of respiratory organ pathology. This is the stage o f compensation
Disorders of ventilation, diffusion and perfusion determine activation of Ihe
и inratory muscles at rest, increase of the load on the system of blood circulation,
... -nsification of metabolism. The need for oxygen constantly increases, l-inally.
kin Ii a moment comes (the stage o f decompensation), when at rest it becomes impos
нЫе to maintain the normal gas content in the blood. Then hypoxia, hypercapnia
uul gaseous acidosis become the main link in the development of further disorder.
In the organism.

Clinical Manifestations

Changes of respiration rate, depth and rhythm relate to the clinical symptoms
nl icspiratory failure.
At rest man breathes without any efforts paying no attention to I his process
lliis condition is called ic-.pnatory comfort eupnea Dyspnea, oi shortness ol
Г.ill 1 S|H4'iul (System ic) 1‘iilhopli.vsioloK.v

breath, is a clinical notion, which indicates unpleasant subjective sensations con

nected with breathing. It is a feeling of lack of air and demand of respiration activa
lion connected with it.
Hyperventilation is an increased volume of ventilation. As an adaptive reaction,
it develops in different physiological and pathological situations connected with an
increased load on the organism, for example, muscular work, and intensification
of metabolism (as in overcooling). As a compensatory reaction, hyperventilation
develops in circulatory and hemic hypoxia and improves oxygenation of the blood
It supports the acid-base balance in the organism in all types of metabolic acidosi
by releasing CO, (see p. 244 about lung participation in acid-base balance regulu
lion). Under pathological conditions ventilation is increased under the stimulating
effect of epinephrine and norepinephrine in the blood, histamine, acetylcholine and
prostaglandins in the central nervous system, progesterone, and corticotropin.
Hyperpnea or deep and frequent breathing under physiological conditions de
velops as a response of the respiratory system to make lung ventilation meet tin
requirements of intensified metabolism. It develops due to intensive reflex or Ini
moral stimulation of the respiratory center in case of p 02 reduction or increased
CO, concentration in the blood.
Pathologic hyperpnea with hyperventilation, which is not connected with
adaptation, is of our special attention. It occurs under pathological excitation of tin
respiratory center. In such a case it does not follow blood circulation activation and
results in decreased concentration of p C 02 in the blood (hypocapnia) and respii.i
lory alkalosis development (p. 248). In its turn, it results in decreased blood supph
ol the brain and heart (due to increased blood pressure in them), electrolyte balam •
changes (hypocalcemia, hypokalemia) disorders of oxyHb dissociation, impaited
utilization of oxygen by tissues.
Hypoventilation accompanies respiratory insufficiency and is its basic maniles
tation. Ventilation is reduced by alkalosis, hypocapnia, Ca2+ and Mg2+ increase in
the CN S. Deep hypothermia, ganglion blockers, high concentration of atropine,
cathecholamines, endorphins and glycine in the C N S also diminish ventilation
Hypoventilation itself results in hypoxia, hypercapnia and gaseous acidosis.
Tachypnea (polypnea) is quick breathing. Sometimes it is accompanied by li\
perventNation. If breathing is frequent and shallow, hypoventilation develops, h
some cases polypnea occurs if there is stronger than usual stimulation of the re:
ratory center, on the one hand, and excessive activation of the factors inhibit n
it, on the other hand. Polypnea may be observed in fever, functional impainni n
ol the central nervous system (hysteria), in lung diseases (atelectasis, pneumoin
congestion). Polypnea may develop due to pain locating in the organs taking pan n
the act of respiration (thorax, abdomen, pleura). Pain limits the depth of respiratm
and accelerates it.
Ilradypnea is infrequent breathing. Vagotonus may underlie it. Reflex dec нм
of respiration rate may be observed in increased arterial blood pressure as a relicч
Ihe baroreceptors of the aorta arch and carotid sinus. Respiratory rate decreases и
hyperoxia due to inhibition of «hypoxic drive- о с periodic excitation ofchcmoi
ceplors sensitive to lowering of oxygen hi tin arterial blood). Increased resislanii
 ( lu p k 'i 2(\ riillio|>livsioli>K\ of Kt-spiriilon System

i*> inflow in the upper respiratory tract causes stenotic breathing, deep infrequent
и spi ration, which is a type of convulsive breathing. It occurs with asphyxia (sec
inflow). In this case, inspiration and expiration are slower than usually. Bradypnea
иmy develop as a result of a direct effect of pathogenic factors on the respiratory
■liter, which decrease the excitability of the respiratory neurons.
Apnea is respiratory standstill. It is most often based on pathologic reflexes.
\|>uea may result in impairment of gas exchange in the organism, whose severity
it ponds on apnea duration.
Periodic breathing is a rhythmical periodic change of breathing rhythm both
In rate and in depth. Periods of apnea may interrupt breathing. Respiration
I ( heyne—Stokes’ and Biot’s types is periodic. It is represented in figures 49
nikI 50.
( heyne—Stokes ’ breathing is characterized by a gradual increase of respira
пни amplitude till marked hyperpnea develops and then its diminishing to apnea.
•i»* n the same cycle repeats (fig. 49 A). Breathing of such type may be observed hi
in «Ithy people at a high altitude (especially during sleep) and in premature babies
'Inch is probably connected with imperfection of the nervous centers. In mosl
■i i s Cheyne—Stokes’ respiration is observed in hypoxia, in hypoperfusion ol tin
hmin.
I he pathogenesis of this type of breathing has not been thoroughly studied
<i Some authors interpret it as a disorder of the functional state of the respiratory
■cuter. They suppose that the cells of the brain cortex and subcortical formations
i i i inhibited as a result of hypoxia (due to this respiration stops, p02concentration
iimmishes), but chemoreceptors are still capable to react to gas content changes
"i ihe blood and stimulate the respiratory center to resume respiration. Respiratory
ruler activity is paradoxical indeed (increased amplitude while decreased pCO, in
tin blood and vice versa). The response of respiratory neurons to changes in blood
I’ir.cs is delayed resulting in overshooting reactions. According to this concept, this
i v|h-of breathing has peripheral mechanisms (impulsing from chemoreceptors due
i" <(), accumulation and baroreceptors due to arterial blood pressure reduction
iii.it periodically renew the respiratory center activity). According to this concept,
ihr. type of breathing is pathological.
I here is another concept, which interprets Cheyne—Stokes’ respiration as an
••t.iptive reaction (N . Simeonova, 1962). An experiment showed that this very
lv|v ol respiration caused essential prolongation of life of experimental animals ш
in I'oxic hypoxia. In fig. 49 В it is possible to see periodic deceleration of respira
..... rate (the depth of breathing periodically becomes gradually deeper and then
11 nlually shallower, like a concertino) as well as periodic limitation of both inspira
... . and expiration. Periodic overextensive inspirations are observed. The author
.... iprets it as primary reorganization in the respiratory center itself and secondary
li.mges in the respiratory act. The author assumes that the main role in adaptation
I't'ltnigs to periodic retention of C 0 2. It is this retention that results in compensa
i . m \ accumulation of bicarbonate buffer and optimization of oxyHb dissociation

i .i < ■|> 24S about respiratory acidosis).

Г ui ’ Special (System ic) Pathophysiology

/юкп c

Hr . 49. Cheyne-Stokes’ periodic breathing

Л in a cat after acute blood loss (according to Y. Britvan, 1966); В, С — in rats in experimci
hypoxic hypoxia (according to N. Simeonova, 1962

B io t’s periodic breathing (fig. 50) differs from Cheyne—Stokes’ respiration

respiratory movements, which are characterized by a constant amplitude and |x
riodic stops with periods of apnea. This type of breathing has no such adapli
features as mentioned above. Biot’s respiration is mostly observed in menin^m
encephalitis and other diseases accompanied by impairment of the central nervon
system, especially the medulla oblongata.
Terminal (agonal) respiration has several varieties — apneustic, Kussminil
gasping respiration.
Apneustic respiration is characterized by increased convulsive efforts to inspi
occasionally interrupted by expira­
tion. Apneustic respiration is observed
in experimental animals after cutting ill___ J in _____ mill i _ a
both vagus nerves and the brain stem Tir 50. Hiot’s periodic breathing in an e*
between the pncumotaxic (in the ros peiimcntul animal after the brain stem is h i
tial pons) and apneustic centers (in the al I lif level of the pons (according to Y. lii И
middle and caudal parts of the pons) It Villi. I 'J M t )
 Chapter 2(v l’allmpli>siol<>K\ of Respiratory System

r. believed that the apneustic center has the ability to excite the inspiratory neurons,
which are periodically inhibited by impulses from the vagus nerve and pneumol
isic center. Cutting of these structures leads to constant inspiratory activity of the
ipncustic center.
Extreme excitability of the respiratory center manifests itself as Kussmaul's
breathing. It is an adequate response of the respiratory neurons to metabolic aci
ilosis. Thus, it is mostly observed in patients in diabetic coma. The depth of every
breath is greatly increased but breathing is regular. It is deep noisy accelerated
ixcathing, when deep inspiration is followed by intensive expiration with active
Involvement of the muscles.
Gasping respiration signifies a marked disorder in the regulation of breathing. It
i iare inspirations observed during agony after the pre-terminal pause (respiratory
taudstill).
Cough can be a defense reaction if untypical matter (mucus, foreign bodies)
«.cumulates in the lumen of the respiratory tract. However, there are types ol
•nigh without a defense value. Cough commonly develops under stimulation of the
■ndings of the glossopharyngeal and vagus nerves in the mucous membrane of the
pharynx, larynx, trachea (the most sensitive area is its bifurcation), and bronchi
In addition, it may be caused by stimulation of the sensitive nerves or the pleura
Cough consists of short inspirations followed by immediate closing of the glottis.
I \piratory efforts of the respiratory muscles develop simultaneously. It leads to
piessure increase in the respiratory tract, alveoli and pleural cavity. Then the glottis
••pens and air leaves the respiratory tract at a high speed.
Sneezing can be a defense or a pathologic reaction. Sneezing develops in re-
iponse to stimulation of the endings of the trigeminal nerve located in the nasal
mucosa (especially in the middle turbinate bone and septum). In contrast to cough,
hi sneezing forced expiration occurs (after opening of the glottis) through the nose,
in»t through the mouth.

Asphyxia

Asphyxia develops when respiratory failure occurs acutely or subacutely and

■aches such a degree when oxygen no longer enters the blood and carbon dioxide
i not released from the blood. The most frequently asphyxia occurs in respiratory
Intel compression.
I'hcre are three periods in the course of asphyxia.
Ihe first period of asphyxia is characterized by a rapid increase of the depth
itml rate of respiration. The inspiration phase prevails over the expiration one. It is
I>••sible to observe general excitement, increased tension of the sympathetic part
"I the vegetative nervous system (dilated pupils, tachycardia and blood pressure
•Irvation).
During the second period the respiration rate gradually diminishes under pre
w'tud maximal amplitude of the respiratory movements and the phase of expiration
с t. intensified. It is possible to observe that the tone of the parasympathetic part ol
ih. vegetative nervous system prevails over the sympathetic one (narrowed pupils,
MimkI pressure reduction, bradycardia).
I’.nl 2 S|H'« lul (K y sim ile) Ги1||<1||||уч|о1ок\

During the third period of asphyxia respiration amplitude and rale are decreased
and in the end respiration stops. Arterial Ы(нк1 pressure is considerably decreased
Alter a short-term respiratory standstill there are usually observed several rare spun
modic respiratory movements {gasping breathing mentioned above), which are lol
lowed by paralysis. Convulsions are possible.
At first the effects observed in asphyxia are connected with accumulation
carbon dioxide in the organism. Acting by reflex and via central chemoreccptois m
I I ' ions, carbon dioxide excites the respiratory center making the respiration depth
and rate maximal. Besides, respiration is stimulated by reflex by reduction ol p<»
concentration in the blood. The content of C 0 2in the blood increases. Arterial hi... I
pressure increases. Experiments with inspiration of gas mixtures containing Hi
20 % of C 0 2showed that respiratory intensification is connected with:
• reflex effect of chemoreceptors on the vascular motor center;
• intensified secretion of adrenaline into the blood;
• increased minute blood volume resulting from elevated vein tension .1
increased blood inflow into the heart.
Then, the narcotic action of increased C 0 2 concentration in the blood beynw
lo declare itself, blood pH is reduced to 6.8—6.5. Hypoxemia increases and so d*
hypoxia of the brain. In its turn, it leads to respiration inhibition and arterial bl«
pressure decrease. Finally, respiratory paralysis and cardiac arrest develop.

IM PAIRM ENT OF NON-RESPIRATORY FUNCTIONS OF LUNGS

The lungs perform a protective function. Possessing a large total area (

100 m2) they are the largest surface of the organism that comes into contact w
more and more aggressive environment. The lungs are capable of detaining ham
mechanical and toxic products of the inspired air. The particles, which are dep<
ted in the lungs, are removed from the bronchial wall by the ascending How ol
mucus (mucociliary transport).
The filtratio n function of the lungs consists in the ability to clean the bh
from some mechanical admixtures — drops of fat, small thrombi, bacteria ret.и
in the lungs with further destruction.
The excretory function consists in releasing some volatile metabolites (aceti
ammonia, etc.) or exogenous substances (alcohol) in case of intoxication. The hi
lake pari in detoxication of a number of medicines (aminazine, sulfanilann
etc.).
The absorption function consists in absorption of some lipo- or watei soli
substances, mostly volatile aerosols. It is a base of the inhalation variety ol di
therapy.
I lie lungs fulfill important metabolic functions taking part in protein, l.il
carbohydrate metabolism. The lungs are exclusively rich in lipolytic and proleo
cn/yincs and may be compared with the liver lipid metabolism intensity. Ilu h
regulate (lie amount of fat coming into ihe arterial blood. They partially < 1
and metabolize chylomicrons coming from the intestines via ihe lymph ve
 C h ap in 2<> siol«>K> <4 Kcsplrnlory Sysli'in

I In v may synthesize fatty acids and phospholipids, in particular, dipalmitoyllcci

Him ( (imposing surfactant, whose deficiency causes lung collapse.
I'rotein synthesis also plays a significant role as the structural base of the lungs
|t burned from collagen and elastin. Impairment of their synthesis, intensified de
•пи lion or hyperproduction of these proteins may cause emphysema and pneu
im1 .1 lerosis development.
< arbohydrate metabolism is also very important, especially the production of
ник npolysaccharides composing the bronchial mucus. In their deficiency mucovis
11.1-•is develops.
Metabolism of many substances circulating in the blood takes place in the
liiiiyv A lot of vasoactive substances lose their activity partially or completely hav-
". lussed the pulmonary vessels. Bradykinin is inactivated by 80 % . The lungs are
ill. in.m i organs that liberate the blood from serotonin by means of catching and
il. 1»'<iiing it. There are also enzymes that inactivate prostaglandins E ,, E 2 and I
т . i partially catch (up to 80 % ) noradrenaline and histamine. In the pulmonary
Ищм Is ihe polypeptide angiotensin I transforms into angiotensin II under the influ
im i of the converting enzyme.
I lie lungs participate in hemostasis maintaining the anticoagulant and fibrino
Inn activity of the blood. There are a lot of mast cells containing heparin. Fibrin
nl\ .is activation resulting in hemorrhage occurs in extensive injury of the lungs
... hiding operative, p. 326).
Ihe lungs participate in thermoregulation. Under conditions of low ambient
I*' "i 1.1 ature biological oxidation is activated in the lungs and heat production is
и ased. At the same time there decreases capillary blood flow in the lesser circu-
....... and heat emission via the lungs.
I lie lungs are a reservoir o f the blood due to the ability of the vessels to change
Hull capacity even under conditions of insignificant change of pressure in them.
I lie lungs play a certain role in m aintaining the water balance as water is re-
M'i .i ll with the expired air.
Vpudopathy. The cells, which may produce BAS (amino acid derivatives), relate
In ih. A PU D system. Therefore some cells of the lungs relate to this system. They
.....hu г enkephalin, calcitonin, bombesin, vasointestinal peptide, P substance. The
M i I ) system has many functions; it influences microcirculation, the nervous sys
i. п. . k With age, the lungs gradually lose elasticity, the alveolar ducts dilate
...I i lu- lung parenchyma enlarges. That is why apudopathy can be found in oldei
■ "I'll' and under different chronic lung diseases (emphysema, amyloidosis, chronii
..I. inn live pulmonary diseases, etc.).

Questions for Self-Control

I Wliat arc the main processes taking place in the lungs?

/ i iive a classification of typical disorders ol the respiratory system.
I ( iive the characteristics of disrcgulativc ventilative insufficiency.
4 i iive the characteristics of obstructive ventilative Insufficiency.
^ I xplain the mechanisms of bronchospasm
I'uil ' S|H4-iul (Systemic) I’alhophysiotoRy

(). Give the characteristics of restrictive ventilative insufficiency.

7. What is the surfactant system and what is its role in the development ol
respiratory system pathology?
K. What are the causes of gas diffusion disorders in the lungs?
9. When is pulmonary circulation impaired?
10. Name and explain the periodic types of breathing.
11. Name the terminal (agonic) types of respiration.
12. What non-respiratory functions do the lungs perform?

Tests for Self-Control

(give correct answers)

1. Л 23-year-old patient was hospitalized with a craniocerebral trauma in a sen

ous condition. Respiration is characterized by prolonged convulsive inspiration
and short expiration. What type of respiration is it?
A. Kussmaul’s.
B. Gasping.
C. Apneustic.
D. Cheyne-Stokes’.
E. Biot’s.

2. Cutting of both vagus nerves was reproduced under experimental conditions

What lype of respiration will the experimental animal develop?
A. Frequent and shallow.
B. Frequent and deep.
C. Infrequent and shallow.
D. Infrequent and deep.
E. Periodic.

V 5 ml of air was injected into the pleural cavity of a rat. What type of respiration
failure develops in this case?
A. Restrictive disorder of alveolar ventilation.
B. Obstructive disorder of alveolar ventilation.
C. Perfusive.
I). Diffusive.
E. Disregulatory impairment of alveolar ventilation.

4. A patient has been delivered to a hospital in diabetic coma. Respiration is noiny

and frequent. Forced expiration follows deep inspiration. What type of respii.i
lion is il?
A. Apneustic.
B. Cheyne-Stokes’.
C. Gasping.
I). Stenotic.
I КишпаиГв.
 ('lu p in I *;■I lit si<>li>к> <>f Krspim lory S j sit-in

Л diphtheria patient developed edema of the larynx. In addition, infrequent

and deep respiration with labored inspiration is observed. What is this respira
tion called?
A. Apneustic.
B. Kussmaul's.
C. Cheyne-Stokes’.
D. Stenotic.
E. Gasping.

A 30-year-old man complains of dyspnea, sensation of heaviness in the right

part of the chest, general weakness. Body temperature is 38.9°C. Objectively:
during respiration the right part of the thorax is behind the left one. Exudate
has been found by means of pleurocentesis in the right part of the chest. What
is the main cause of exudation?
A. Decreased resorption of the pleural fluid.
B. Increase of blood pressure.
C. Hyperproteinemia.
D. Aggregation of erythrocytes.
E. Increase of vessel wall permeability.

7 A 12-year-old teenager has developed a serious attack of bronchial asthma

with such symptoms: pronounced expiratory dyspnea, pale skin. What kind of
alveolar ventilation disorder is taking place?
A. Neuromuscular.
B. Restrictive.
C. Perfusive.
D. Central.
E. Obstructive.

n A patient was hospitalized to the otolaryngologic department with a foreign

body in the upper respiratory tract. What kind of pathological respiration is
observed in this case?
A. Frequent, shallow.
B. Frequent, deep.
C. Infrequent.
D. Kussmaul’s.
E. Periodic.

ч An X-ray examination revealed diffuse atelectasis in a newborn. What is ili<

most possible cause of this condition?
A. Bronchopneumonia.
B. Bronchial asthma.
C. Occlusion of the pulmonary artery.
I). Surfactant deficiency.
E. Pulmonary lubcivulouls
1'iirt } Special (System ic) I’athophystuloKy

И). Л 45-year-old woman has been ill with bronchial asthma for a long time.
Sometimes she has attacks of dyspnea. What is the pathogenic mechanism ol
these attacks?
Л. Decreased sensitivity of the respiratory center.
B. Loss of elasticity of the pulmonary tissue.
C. Spasm of the small bronchi.
D. Decrease of thorax motility.
E. Decrease of pulmonary tissue perfusion.

11. Pneumosclerosis accompanied with alveolar ventilation disturbance has been

revealed in a miner. What is the main mechanism of alveolar disturbance?
Л. Failure of the nervous control of respiration.
B. Narrowing of the upper respiratory tract.
C. Decrease of lung compliance.
D. Disturbed motility of the thorax.
E. Bronchial spasm.

12. Л 60-year-old man suffering from diabetes was delivered to a hospital in com.»
Respiration is noisy and accelerated. Deep inspirations alternate with intensi
fied expirations with participation of the expiratory muscles. What form ol
respiration is observed?
A. Kussmaul’s.
B. Stenotic.
C. Tachypnea.
D. Cheyne-Stokes’.
E. Biot’s.

13. Л patient with pulmonary tuberculosis has surfactant deficiency. What patho
logical changes will take place in the pulmonary tissue due to surfactant al*
sence?
A. Emphysema.
B. Atelectasis.
C. Bronchospasm.
I). Edema.
E. Lymphostasis.

14. Epileptic convulsions have been complicated by asphyxia development resuli

mg from dental prosthesis breakage and aspiration. What type of respiratoiv
insufficiency has developed?
A. Diffusive.
B. Ventilative restrictive.
C. Ventilative disregulatory.
I). Perfusive.
I Ventilative obstructive.
( hapter 27
PATHOPHYSIOLOGY OF DIGESTIVE SYSTEM

The digestive system provides intake of food, its transformation into simple ;ib
orbable chemical compounds, which are necessary for life maintenance and supply
u| ihe organism with energy and plastic materials.
Different sections of the digestive system are interconnected by means of the
i*.ist rointestinal tract, common nervous and humoral mechanisms of regulation.
I Ins interconnection is especially evident under pathological conditions: dysfunc
non of one section of the digestive system results in impairment of other ones. The
unity of different organs of the digestive system manifests itself by substitutional
(t ompensatory) possibilities of this system.
Digestive system pathology includes disorders of:
• alimentary tube; in its turn, this impairment is subdivided into disorders of:
•• oral cavity;
•• esophagus;
•• stomach;
•• small intestine;
•• large intestine;
• digestive glands — pancreas and liver.

D IG E S T IV E D IS O R D E R S IN O R A L CAVITY

Digestion impairment in the oral cavity may be connected with pathology and
dysfunction of:
• teeth in case of injury, absence or pathology due to dental caries or parodon
tosis;
• masticatory muscles (disorders of nervous regulation);
• temporomandibular joints;
• salivary glands.
Besides the alimentary function (amylase content), saliva plays a role in wetting
Ilu iceth and oral mucosa providing protective (bactericidal) and trophic clTects
i inder normal conditions 0.5—2 1 of saliva is excreted daily.
Uypersalivation (in pathology the amount of saliva arises up to 6-7 1) is ob
l ived in stomatitis, gingivitis, pulpitis, parodontitis as well as during preparation ol
with a dental drill. Parasympathetic activation (vagotonia) stimulates saliva
lion Pregnancy is also accompanied with hypersalivation.
As a result of saliva hypersecretion the following processes occur:
• Increase of the concentration of Na+ and C1‘ ions and reduction of K ' ion con
ccnlration in saliva;
• increase of the total content of nonorganic components of saliva;
• neutralization of gastric juice by saliva and impairment of stomach digestion;
• systemic dehydmtion due In loss of a large amount of saliva.
Г . mi 1 Special (Systcm ic) I'.i 11 n i | >11s ■.n >I <>:• s

Hyposalivation (reduction of saliva secretion) is connected with sympathetic

nervous activation, injection of parasympathetic inhibitors (atropine), infectious
and feverish processes. Disturbances of saliva secretion and connected microfloi*
multiplication result in inflammation of the mucous membrane and salivary gland
and promote dental calculus formation. It disturbs mastication and swallowing.
Disorders of carbohydrate metabolism may develop due to hyposalivati.m
(amylase deficit). The stomach gland function is impaired.
There is a severe systemic lesion of the salivary and lacrimal glands (Sjogrein
syndrome), which is characterized by dryness of the oral mucosa, eyes and ир|нч
respiratory tract.
Atrophic-inflammatory processes of the oral mucosa, gums and tongue develop
in vitamin B l2 deficiency (in pernicious anemia, p. 290, after gastrectomy).

Caries and Parodontitis

Caries is a destruction of the hard tooth tissues with cavity formation, win. ii
may be complicated by pulpitis and periodontitis. Microbes (especially Streptoax
cus mutans) play a role in disease etiology. Impairment of the defensive function
of saliva on the enamel is significant in the pathogenesis of caries. Organic acid*
(especially lactic) provide demineralization of teeth. Dismetabolism, formation ol
protein hydrolysis products may mobilize Ca2+ from hydroxyapatite crystals from
the enamel and dentine. Hereditary predisposition is assumed. Decrease of imnitt
nological reactivity plays its role. Contrary to people, animals have a possibility to
form secondary dentine by fibroblasts as a compensatory mechanism.
Parodontitis is an inflammatory-destructive process, which is characterized In
damage of the parodentium, which surrounds the tooth root. It manifests itself In
purulent discharge from the gingival pockets, loosening and falling of teeth. Bade
rial infections may cause it. Lack of vitamins with antioxidation activity - ascoih.
acid, bioflavonoids and tocopherol (vitamins С, P and E ) - is very important
Neurogenic dystrophy is supposed to underlie the parodontosis pathogenesis (so#
p. 530) about the concept of neurogenic trophicity and pathogenesis of neurodystn.
phy). In impaired neurotrophicity of the parodont tissue, it gets damaged by saliv*
enzymes (kallikrein, RNAase, etc.) and active leukocyte factors. Peroxidation ,i.
tivation and intensification of eicosanoid (prostaglandins, leukotrienes) syntlioli
provide inflammation. Immune destruction of tissue, the action of bacterial tin.l
leukocytic collagenase play a role in pathogenesis as well as endocrine disonli j l
(hypogonadism, hypothyreosis, hypoinsulinism, hyperparathyroidism, decrease iif
the incretory function of the salivary glands). Emotional stress may play a role ш
the etiology and that is why it refers to diseases of adaptation (see p. 508 about tin
concept of diseases of adaptation).
 Chapter П . 1’й11н>|)||>ч1о1оку of Digestin' System

STO M A C H PA TH O LO G Y

ETIOLOGY

Causative factors of stomach pathology are exogenous and endogenous. In

their turn, they are subdivided into physical, chemical and biological.
Physical factors are trauma (mechanical irritation of the stomach with coarsc
in |юог1у masticated (as a result of teeth absence) food, thermal irritation due to
intake of too hot food, disorders of dietary pattern, irregular nourishment.
Chemical factors are damage by acids or other poisons, abuse of alcohol and
it irettes, damage by medicines, particularly aspirin, nonsteroid anti-inflammatory
lilies, hormonal preparations (corticosteroids).
Biological factors are the following:
• Infectious (viruses are among them). The bacterium Helicobacter pylori (a
gram-negative microorganism) plays an exclusive role in gastric pathology. It
is found in 50 % of the world population, especially in the poorest countries,
where standards of personal hygiene are inadequate. The most likely chan noI
of human-to-human infection is fecal-oral.
• Immune factors (experimental injection of a heterogeneous serum, which
contains antigastric antibodies).
• Psychogenic factors (constant emotional overload, emotional stress and nega
tive emotions) play a significant role (it is reproduced under experimental
conditions by prolonged fixation of animals).
Endogenous factors (may be congenital and acquired) are the following:
• Genetic predisposition, which is associated with congenital prevalence of ag­
gressive factors and insufficiency of defensive ones.
• Nervous and endocrine regulation disorders, which lead to an increase of gas­
tric juice acidity and pepsinogen hypersecretion.
• Autoimmune aggression against the stomach tissues.
• Neoplasia in the stomach (see p. 152 about functional anaplasia of malignant
cells, which leads to achylia as the gravest sign of stomach dysfunction).
• Bile reflux (bile acids entry into the stomach).
• Vitamin B l2 deficiency in pernicious anemia is complicated with achylia (stop
ping of hydrochloric acid production, p. 290).

PA TH O G EN ESIS

Pathology of the stomach may be primary (initially developing in the stomach)

uul secondary (as a result of pathology, which develops in other organs that may
liilliience stomach functions).
All typical pathophysiological processes can develop in the stomach:
• inllammation (gastritis);
• allergy (autoimmune нщ т’хмоп);
Г 111 ' p.m il (S yslt‘iiii« ) Г;||||11|)||>мо|оц>

• tumor (carcinoma);
• dystrophy up to necrosis (stomach ulceration);
• disorders of blood supply;
• hemorrhage;
• genetic disorders (which predispose to gastric pathology).
The pathogenesis of every named pathologic process is aggravated by the c.\is
tcnce in the stomach of specific aggressive factors (pepsin and hydrochloric acid ш
large concentration).
Nervous and endocrine factors in the form of disorders of neurogenic and Ini
moral (endocrine, paracrine, and autocrine) regulation of gastric secretion play it
critical role in stomach pathology. Below their brief description is given.
An important role in neurogenic regulation of gastric functions belongs to tli>
vagus nerve and acetylcholine as a neurotransmitter of the parasympathetic nervous
system. The vagus nerve is the main secretory nerve of the stomach and acts by ace
tylcholine, postganglionic transmitter of vagal parasympathetic fibers (muscarim.
M, receptors) and via neurons stimulating gastrin release by the gastrin-releasinti
peptide. It stimulates production of hydrochloric acid, pepsinogen and gastrin. The
vagus nerve influences blood circulation in the submucous layer of the stomach,
acetylcholine dilates submucous vessels. The sympathetic nervous system influence*
the stomach cells by membrane adrenoreceptors. It promotes contraction of lIn
submucous vessels and smooth muscles of the stomach. Together with the iiillu
cnce on secretion, motor activity (fig. 51) and blood circulation in the stomach, iln
nervous system is connected with trophicity of the gastroduodenal area.
Humoral regulation of gastric secretion includes the influence of hormones of
the endocrine glands and gastrointestinal system.
The pituitary gland stimulates gastric chief and parietal cells by corticotropin
and somatotropin. Noradrenaline influences stomach cells; it promotes contraction
of the vessels and smooth muscles of the stomach submucosa inhibiting secretion
Cilucocorticoids (cortisol, hydrocortisone) influence the gastric mucosa, stimiil.m
gastric chief and parietal cells and intensify production of hydrochloric acid ainl
pepsinogen; they stimulate cholecystokinin and inhibit mucous cell multiplication
and regeneration. Insulin stimulates gastric secretion. Glucagon inhibits it.
Some secretory products (which are present in the intramural autonomic ncivi
terminals) act as chemical messengcu
and modulate normal digestive fum
tions by a combination of endocrine,
paracrine and neurocrine mechanism*
Some of them act as С -cells of the thy
roid gland, chromaffin cells of the .nl
renal medulla, corticotrophs and mdn
notrophs of the pituitary gland.
Gastrin is a so-called gastrointes
tinal hormone, which is produced by
( i cells of the gastric mucosa and 14
stimulated by the vagus nerve. Il is ilir
 Chaplet .’7 rallio|ih>sliilo|(> of I > i k <'s I I m - System

most potent stimulator of gastric secretion (especially of hydrochloric acid) which

in addition has a trophic effect on the gastric mucosa (stimulates multiplication of
ilioir cells).
Histamine (paracrine regulation, acts on H 2receptors) is secreted by the cn-
ii mchromaffin-like and mast cells of the gastric wall, stimulates gastric secretion.
Cholecystokinin (resembles gastrin), which is produced in the intestine, is a
imuilator of gastric secretion.
Acetylcholine, gastrin and histamine are messengers and stimulators of gastric
■notion. In addition, they transmit stimulating impulses to the vagus nerve. Re-
•ptors of gastric parietal and chief cells, having received mechanical and chemical
innuli, stimulate additional messengers (cyclic nucleotides) inducing gastric pari-
■lal cells to produce HC1 and chief cells — to produce pepsinogen.
Secretin (endocrine mechanism) secreted from the small intestine, belongs to
"iliibitors of stomach secretion together with prostaglandins. The latter are pro-
ilm ed in the gastric mucosa, increase mucosal blood flow as well as bicarbonate and
miiicus secretion and stimulate mucosal cell repair and renovation.
Genetic factors are assumed to predispose or prevent gastric pathology develop
mont. Genetic factors determine:
• number of gastric parietal cells;
• individual sensitivity to secretory stimuli (gastrin);
• type of pepsinogen (there are two types of pepsinogen: type I includes five
fractions, type II — two fractions);
• presence or absence of A and В erythrocyte antigens, which resemble the
gastric mucosa and play a role of a protective mechanism (the human organ
ism has genes, which contribute to A or В antigens of erythrocyte entrancc
into the saliva and stomach interacting with the gastric mucosa).
Digestion in the stomach is achieved with the aid of the digestive enzyme
pepsin secreted (in the form of pepsinogen) by gastric chief cells. Pepsinogen is
uiivated by hydrochloric acid. At maximal secretion, the level of hydrogen ion
■oncentration in the stomach is 3 million times greater than that of the blood and
tissues. In hypoxia and cancer, acidogenesis in the stomach is inhibited due to sup
pn ssion of oxidative processes.
All active substances and mechanisms, which act in the stomach, are divided
into stimulating and protective. Below they are represented in brief.
Stim ulative factors (many of them are aggressive, corrosive) arc the following
• active pepsin;
• hydrochloric acid;
• vagal stimulation (and congenital vagotonia);
• acetylcholine;
• catecholamines (adrenaline, noradrenaline);
• glucocorticoids;
• insulin (stimulates gastric chief and parietal cells);
• gastrin and cholecystokinin;
• bile acids (in duodenogastric reflux);
• histamine, bradykinin (in case of inflammation);
Part 2 Spccial (System ic) I ’athiipliysMiloKy

• antigastric antibodies (in pathology);

• Helicobacter pylori (in pathology).
Their intensified action can be aggressive and cause stomach damage. I In
excitable type of gastric secretion is characteristic of gastric function. In pathology
it is observed in:
• disorders of nervous regulation, emotional stress;
• disorders of endocrine functions (hypersecretion of catecholamines, glum
corticoids, thyroxin, parathyrine);
• increased tone of the vagus nerve;
• factors causing angiospasm in the stomach, ischemia and necrosis of the gas
trie mucosa;
• hypersecretion of gastrin (in gastrinoma);
• bile reflux into the stomach and damage of the mucosal barrier of the stom
ach.
Protective factors oppose the aggressive ones (corrosive effects damaging tin
gastric mucosa) and exist together with them. They are the following:
• gastric mucus (gastric mucosal barrier);
• sufficient blood supply of the mucosa;
• intestinal hormones (gastroinhibitory hormone, secretin);
• pancreatic hormone glucagon (inhibits gastric secretion);
• somatostatin;
• PG (prostaglandins);
• bicarbonates;
• genetic factors associated with A and В antigens in erythrocytes;
• neurotrophic function of the gastric nerves;
• high regenerative ability of epithelial cells.
Gastric mucous cells possess high regenerative properties. In a healthy person
the mucosa of the gastrointestinal tract is renewed every 1—5 days. Glucocorticoid
suppress this property.
The secretory process is divided into three phases — cephalic, gastric and in
testinal.
Taste, smell, chewing and swallowing of food initiate the cephalic phase. I hi»
phase is mediated by direct vagal stimulation of parietal cells (it involves vagul
stimulation of gastrin release).
The gastric phase involves stimulation of the mechanical and chemical reccp
tors of the gastric wall. Chemical stimuli, the most important of which are protein
and amino acids, induce gastrin release (fat and glucose do not stimulate gasirk
acid secretion in the stomach).
The intestinal phase is initiated when food containing digested proteins enirn
the small intestine. Hormones, which are secreted (secretin, gastric inhibitory pep
tide) inhibit gastric secretion.
Estimation of gastric juice acidity is resorted to characterize the functional si.iii
of gastric digestion. Stimulation of the stomach by histamine is used for this pur
pose. Dynamics of gastric acidity change is measured after stimulation. Dynamo*
 C'haplci I’alhophysiotoRy of I>in»-4ti\»• System

is expressed in the form of curves, which

tofleet two phases of stomach secretion re­
sponse - neurogenic (induced by vagal in­
fluence) and humoral (induced by gastrin).
Normalization of gastric secretion after
\iimulation is realized by secretin, prosta­
glandins, somatostatin, a high concentra­
tion of H +ions in the gastric lumen (nega­
tive feedback regulatory mechanism).
There are four types of pathological
»astric secretion — excitable, asthenic, in-
crt, and inhibitory. They have the follow­
ing differences (represented in fig. 52):
• Excitable type is characterized by
jastric juice secretion increase under the
influence of both mechanical (neurogenic)
uid chemical (hormonal) stimuli. It has a
predisposition to stomach ulcer develop- Ffg 52 Types of gaStric secretion
nent. It appears due to increased reactivity
"I vagal mechanisms. In this case surgeons
recommend vagotomy. (Vagotomy, surgical division of the vagus nerve, does limit
lereased gastric secretion, but at the same time impairs the neurotrophic function
•I the vagus nerve (p. 530) and thus is harmful).
• Asthenic type is characterized by increased and quick reaction of gastric sccre-
ion under the influence of neurogenic and mechanical stimuli (but this phase is
Oiort) and reduced under the influence of chemical ones.
• Inert type is characterized by reduced gastric secretion under the influence
I vagal stimuli and elevated and prolonged secretion under the influence of the
iiinnoral ones. It is a case of inhibitory regulative mechanism insufficiency.
• Inhibitory type is characterized by depression of both neurogenic and humoral
«limuli.
The ratio of aggressive and protective factors plays a significant role in stomach
pathology.
GASTRITIS

Gastritis is an inflammation of the gastric mucosa.

All the general laws governing inflammation as a typical pathological process
i an be applied to stomach inflammation (alteration, microcirculation disorders,
HAS production, proliferation). At the same time, localization peculiarities are
luitc important. They are connected with:
• presence of specific aggressive factors in the stomach (hydrochloric acid,
pepsin);
• necessity of constant renovation of gastric mucous cells (every 5 days in
norm);
Г.м! 2 Special (System ic) I’a1liophvsiulo)>.v

• correlation of stomach function with other parts of the digestive tract.

The humoral mediators of inflammation (histamine, bradykinin, etc.) are criti
cal damaging factors due to stimulation of hydrochloric acid production and pep
sinogen secretion and activation. Depending on the extent of alteration, gastrli
inflammation is divided into acute and chronic. According to the level of gasin<
acidity, stomach inflammation may be of hyper-, hypo- and anacidity types. Nevci
theless, complete inflammatory reaction is often absent in many cases of gastritis,
therefore the term gastropathy is often used.
Three types of gastritis are differentiated.
/. Erosive and hemorrhagic gastritis develops due to the following causes:
• corrosivc chemicals;
• radiation trauma;
• ischemia (vasculitis);
• alcohol abuse;
• side effects of nonsteroid and anti-inflammatory drugs, which have an inhibitoiy
effect on cyclooxygenase, thus blocking prostaglandin synthesis. If used in ih>
treatment for chronic inflammatory diseases (more frequently of allergic origin I
they cause a systemic block of prostaglandins with their protective effect on iI h
stomach mucosa. In addition, these drugs, introduced orally, damage the mucosa
locally. An acute ulcer may develop in a couple of days or weeks. The inhibit*>i \
action of these drugs on platelet aggregation increases the danger of ulcer bleed
ing
2. Nonerosive chronic gastritis is usually restricted to the antrum and is assoc i
ated with Helicobacter invasion, which not only diminishes mucosal protection, hnl
can also stimulate gastrin liberation and thus gastric juice secretion in the fundus
3. Atrophic gastritis is usually of autoimmune origin. It is most often limited lo
the fundus. In these cases the gastric juice and blood plasma contain autoantibodu
(immunoglobulins G , infiltrates of plasmacytes and В lymphocytes) against parn i.il
cells (their microsomal lipoproteins, gastrin receptors, carboanhydrase, etc.). I'u
rietal cell atrophy ensues and secretion falls markedly (achlorhydria). If antibodies
also block cobalamin binding, there develops pernicious anemia (see p. 289) As ii
variety o f stimulating allergic reactions and receptor diseases (see p. 91) autoantihod
ies to gastrin receptors of accessory stomach cells cause hypertrophy of gaslrni
producing cells and thus more gastrin is liberated. As a consequence of high gastrin
levels, hyperplasia of enterochromaffin-like cells may take place. These cells, c.n
rying gastrin receptors, are responsible for histamine production in the gastric w.ill
I lyperplasia of the named cells can be in progress causing mucosal metapla-.i.i
which, as a precancerous condition, may lead to stomach carcinoma.
Together with aggressivity and effect on the secretive activity of pepsin, ili<
level of gastric acidity influences gastric motor activity. Hyperacidity is associated
with delayed emptying of gastric contents into Ihe duodenum including reflux Ii
may be a cause of gastric ulcer formation. Hypoacidity is associated with accelci
aled emptying of gastric contents resulting in disorders of the normal digestive
(unction of ihe stomach.
 Chaptci 17 I’athophysioloRy of D Irm IIvc System

Disorders of digestion in the stomach

i vcntuate in digestion disturbance in the
lower parts of the digestive tract.

ULCER D ISEASE OF STOMACH

AND DOUDENUM

Ulcer is a recurrent disease character­

ized by areas of destruction in the mucous
membrane under the influence of acti-
iied pepsin, hydrochloric acid and other Fig. 53. The number (% ) of parietal cells
■Kuressive factors. Ulcers have affected in the gastric mucosa:
1 - 100; 2 - 75; 3 - 50; 4 - 0-1
10 % of human population. Peptic ul-
i or is the most common in the antrum
a lion of the stomach, the proximal sec-
llon of the duodenum and sometimes in
ilie inferior part of the esophagus. It is as-
ociated with a number of parietal cells
inoducing hydrochloric acid (fig. 53, 54).

Etiology

Etiological factors of ulcer are divid-

<1into exogenous and endogenous, which
in their turn are subdivided into physical,
•liemical and biological.
Physical factors are chronic mechani-
il injuries of the gastric mucosa in the
i nin of nutrition mode impairment (coarse
I'H>d, eating on the go, poor mastication
■■I food as a result of teeth absence) and
ihernial ones (too hot food). Sometimes,
those factors play a role of conditions (risk
Motors). Fig. 54. Localization of stomach ulcer
Chemical factors cause damage of the
i i .iric mucosa by chemical substances, which include abuse of medicines (used as
therapy: corticosteroids, aspirin, indometacin and other non-steroid anti-inflain
111.1lory drugs). Alcohol abuse and smoking as well as vitamin and microelement
iloliciency must be added.
Biological factors are the following:
• Infectious factors rank first. Special attention must be paid to the etiological
role of Helicobacter pylori in the development of some forms of acid peptic
disease, stomach and duodenal ulcers. It is isolated in 90 % of patients with
duodenal ulcer and in 60—70 % of patients with gastric ulcer.
I’art ’ Spccial (System ic) I’alhophysiotoRy

• Immune factors (injection of a heterogeneous scrum, which contains anti

gastric antibodies, causes gastric ulcer under experimental conditions).
• Emotional stress and negative emotions play a significant role.
Endogenous factors sometimes play a role of etiology, sometimes a role Ы
conditions, and sometimes they are mechanisms of pathogenesis. They arc the lot
lowing:
• Disorders of the gastric secretion regulation, which result in an increase ol
gastric juice acidity and pepsinogen hypersecretion. The corrosive effect **l
acid and pepsin plays a key role in gastric and duodenal ulcers and acut*
erosive gastritis.
• Increase of gastric secretion and acidity in gastrin hyperproduction (in tunioi
of the pancreas, Zollinger-Ellison syndrome with hyperacidic hypersecie
tion).
• Autoimmune aggression.
• Genetic predisposition.
Genetic predisposition has been proved by statistics. The type of pepsinogen г
genetically determined. There has been established a correlation between type I
pepsinogen and ulcer. Patients with the Iй blood group are predisposed to ulcn
development. It is considered that this is connected with the absence of A anil It
antigens in erythrocytes, which have protective value for the gastric mucosa.
In addition, patients with gastric ulcer may have a genetically determined
increased number of gastric parietal cells, high individual sensitivity to secretory
stimuli (gastrin).
The risk factors are drugs, alcohol abuse, smoking, eating pattern disordm,
emotional stress.
As a conclusion, it must be stressed that peptic ulcer disease is multifacton.il
in origin.
Pathogenesis

Ulceration of the gastric mucosa is determined by the following pathogenetic

mechanisms:
• activation of aggressive factors (corrosive effect of acid and pepsin secrcti ■
by the stomach);
• suppression of protective mechanisms;
• disorders of blood circulation in the gastric mucosa (ischemia, stasis);
• inhibition of regenerative ability of the gastric mucous cells.
Imbalance between aggressive and defensive mechanisms is the essence ut
pathogenesis. Usually, it is a combination of mechanisms. So, circulatory disordm,
drug abuse and stress lead to gastric mucosa damage if they are connected with tin
peptic factor (pepsin + hydrochloric acid), decreased regenerative ability ofgastiii
mucous cells or genetic predisposition.
Depending on etiology, the main link o f pathogenesis may be individually .1
sociated with infectious, nervous, humoral or genetic mechanisms.
 C'liuplci 27. I’ulhupliysioloKy <>Г Digestive System

If it is an infectious mechanism (Helicobacter pylori), the most likely media

iiis m of gastric ulceration is diminished mucosal defense due to inflammation as
Helicobacter pylori affects the gastric epithelium. This etiological agent opsonizes
secretory IgA and serum immunoglobulins, acts as a «barrier destroyer». 90 % «>1
infected individuals show signs of inflammation (gastritis or duodenitis) in endo
t opic investigation. Despite of the high rate of association of stomach inflam
mation with Helicobacter pylori infection, the important role of other factors
is indicated by the fact that only about 15 % of infected persons have clinically
significant ulcers. These factors (both genetic and environmental) are pathophysio
logically important.
If the neurogenic mechanisms of the disease are the main, the vagal stimulation
determines them. It promotes peptic aggressive mechanisms. The neurotransmitter
nl the parasympathetic nervous system (acetylcholine) stimulates the production of
peptically aggressive digestive factors — hydrochloric acid, pepsin and gastrin (but
dilates the vessels of the submucous layer). Excitation of the sympathetic nervous
I systems leads to hypersecretion of noradrenaline, which constricts microcirculation
I vessels. This results in spasms of the smooth submucosal and vascular muscles re
.ulting in hypoxia. Hypoxic affection and spasm may be very severe and long-term
so that stasis (circulation arrest) occurs. It leads to hemorrhage in the gastric mu
iosa and erosion. Neurodystrophy aggravates the effect of peptic factors.
If hormonal mechanisms are the reason for stomach ulceration, glucocorti
'<>ids (hypercorticoidism) play the main role. They influence the gastric mucosa,
intensify gastric secretion (production of hydrochloric acid and pepsinogen), in­
hibit mucus secretion and gastric epithelium division, and decrease gastric tissue
legeneration. In addition to glucocorticoids, noradrenaline has a harmful effect on
i istric cells.
Chronic inflammation provokes ulceration development. Allergic inflammation
'silh autoimmune aggression is severer in comparison with ordinary inflammation.
Disorders o f blood circulation in the gastric mucosa provoke ulceration. Mucosal
I ischemia and hypoxia play a significant role. The causes are disorders of the sympa
ilietic or parasympathetic regulation of blood circulation in the stomach.
Disorders o f gastric m otility contribute to the development of gastric ulcer by
nl delayed emptying of gastric contents into the duodenum and mechanical irrita
lion of the gastric mucosa; b) increased gastrin secretion and gastric acid produc
non due to delayed gastric emptying; c) tendency to duodenal reflux in an incom
latent pyloric sphincter. Bile acids in the duodenal reflux material act as an irritant
find may be an important contributor to a diminished mucosal barrier against acid
ntid pepsin.
Due to a combination of pathogenetic mechanisms, stress (maximal overstrain
• и ihe organism) plays a leading role in gastric ulcer pathogenesis. Stress is realized
I !>v the hypothalamus-pituitary-adrenal system (see p. 506 about the concept and
luihogenesis of stress). During stress the amount of noradrenaline in the blood in
i teases. It activates the Hageman factor (X II factor of blood coagulation), which is
mi activator of the kallikrcin kiniti system. Hormones of the adrenal cortex (gluco
Mtnicoids) influence the gastric mucosa — intensify production of hydrochloric acid
ГаИ 1 Special (Sys(cm lc) IIlio|iliV4iol<

and pepsin, inhibit gastric mucocyte division. Glucocorticoids have a perm г..m
effect as to noradrenaline. Dystrophy results from chronic emotional stress.
Genetic mechanisms play a significant role in ulcer disease development Ни »
determine congenital increase of aggressive mechanisms — increased numhei if
parietal cells or their increased sensitivity to gastrin, individual composition ol pop
sinogen, properties of the gastric mucosa, congenital vagotonia.
Medicamentous variety of gastric ulceration is connected with abuse of sti-mM
and nonsteroid anti-inflammatory drugs, which directly damage gastric mucocytd
and inhibit prostaglandin production.
Summarizing the information about gastric ulceration pathogenesis it is posniH
to arrive at a conclusion about the decisive role of decreased regenerative capai ity
of gastric mucocytes. Against this background any aggressive influence eventuate* im
chronic ulcerous process. In comparison, it should be mentioned that experiment!
on healthy animals showed that any damage of the gastric mucosa (mechanit at.
thermal, chemical) results in complete regeneration in some days.

Principles of Pathogenetic Therapy

Therapy of the ulcer disease of the stomach and doudenum should be dim l« il
at:
• inhibition of aggressive factors (anti-Helicobacter drugs);
• antiacid drugs inhibiting H +secretion (blocking the H + pump);
• cholino- and histamine blockers;
• stimulation of protective factors (cytoprotectors).
Neutralization of increased gastric acidity by bicarbonates is palliative and ill
not solve the problem of pathogenetic therapy. Vagoectomy (bilateral section ol t
vagus nerves) is used eventuating in a decrease of gastric secretion, but can di.tm
motility of the stomach and gallbladder and especially the neurotrophic function
the nervous system (p. 530).
PA N C REA S PATH O LO G Y

The pancreas is a source of many digestive enzymes.

Powerful proteolytic enzymes are formed in the pancreas in the inactive stab
trypsinogen and chemotrypsinogen. Only in the intestine they are activated l>\ ■it
terokinase or trypsin (autocatalysis). If they are activated in the tissue of ран» и
it results in necrosis of the gland, and then these active enzymes get into the Mm
which may lead to death of the patient. The reason for death is a decrease ol at1«|
blood pressure and shock.
This situation is possible in pancreatitis.

PAN CREATITIS

Pancreatitis is an inflammation of the pancreas, which may be acute

chronic.
 Chaplet .'7 P;Hlio|ih>si»l<>n.\ of Digestive System

Etiology

Г liological factors of pancreatitis are exogenous and endogenous.

Exogenous factors include trauma and infection. Trauma may occur in surgical
Interventions. Infectious factors are bacterial infection, cocci, viruses (in parotitis
mil hepatitis), and tuberculosis agent.
Risk factors (the conditions aggravating the action of etiological factors) play
■t ntical role in pancreatitis development. They are: overeating and abuse of fat
' iitng food (it causes increased secretion of pancreatic juice), intoxication includ
me drug side effects (immunodepressants, thiazides, corticosteroids, etc.). Alcohol
•Imisc associated with overeating is of great importance in the etiology of pancrea
litis.
Among endogenous etiological factors the following ones are very important:
• disorders of blood circulation in the pancreas (thrombosis, ischemia);
• sclerosis of the pancreatic vessels;
• occlusion of the pancreatic duct by edema, concrements (gallstones), polyps
and tumors;
• entry of bile into the pancreatic duct (bile reflux);
• autoimmune aggression (in chronic forms of pancreatitis).

Pathogenesis

As any other form of inflammation, pancreatitis proceeds in three stages — al-

ution, exudation and proliferation, has local (in the pancreas) and systemic (in
к whole organism) manifestations. The acute form is dangerous for life for it is
*•i ompanied with pancreatic shock development.
Acute inflammation in this organ has the following peculiarities:
\lteration (secondary) predominates over all other stages of inflammation.
Systemic changes in the organism predominate over the local ones.
I inks of pathogenesis rapidly develop like chain branching reactions and vicious
circles.
An etiological factor starts inflammation (primary alteration). In response.
Inch is characteristic of inflammation, microcirculation is impaired. Hyperemia
nl edema lead to pressure increase in the pancreatic duct. Pancreatic secret release
mines difficult. The bile and duodenal chyme (containing enterokinase) may
ui' i the pancreatic duct by reflux. As in any other case of inflammation, BAS are
itined. They activate intraorganic trypsinogen and chemotrypsinogen, which da
ii" the pancreas. Secondary alteration is very severe. Pancreonecrosis develops,
ii ular permeability rises. As a cascade, all systems of BAS formation are activated
•piotcolytic explosion»). Elastase and phospholipase A are prematurely activated
tin ducts and cells of the pancreatic gland under the effect of bile, enterokinase
■ I other BAS. Active trypsin, BAS and toxic products of tissue autolysis enter the
nid Activation of the blood kallikrein-kinin system aggravates the situation. All
i substances arc vasoactive and have a powerful vascular and hypotensive ellect
Itcmc 26).
I’art 2 Special (System ic) l*allHi|ili>stiil<iKy

Scheme 2b. Inflammation of the Pancreas (Acute Pancreatitis)

Pancreonecrosis involves the peritoneum (peritonitis) and causes seve n |иш

The latter together with systemic blood circulation disorder results in sluu f lilft
is called pancreatic shock. Severe disorders of hemodynamics, respiration and ••»*•»
vitally important functions ensue. This may lead to death of the patient il inliihlKj|
of proteolytic enzymes are not injected.
An important role in pancreatitis pathogenesis belongs to imbalance i><tw#(|
proteolytic enzymes and their inhibitors (the latter arc produced by the р.нмкф
itself and other organs - the salivary glands, lungs). It is them that art* пмч! M
acute pancreatitis treatment.
 Chapter 27. >1«>1<>ку of Digestive System

D K iE S T IV E D IS O R D E R S C O N N EC TED W IT H IM P A IR M E N T O F B IL E
AND PA N C REA TIC JU IC E S E C R E T IO N

I he liver forms bile, which is secreted into the duodenum. Bile plays a signili
mu role in intestinal digestion. Bile acids emulgate fats, promote intestinal and
■ ionic motility, have bactericidal effect.
Absence of bile ( acholia) or its insufficient entry into the duodenum (hypocho
(ho happens due to impairment of bile production or secretion (obstruction of the
ii bladder duct by stones). It is accompanied by indigestion and malabsorption ol
ilccreased peristalsis of the bowels and intensified processes of putrifaction and
iiiiciitation in them (details are given in chapter 28 «Pathophysiology of Liver»,
I №).
Serious indigestion is caused by pancreatic secretion changes, as the pancreas
•hluces the main digestive enzymes. The bulk of pancreatic juice proteins (ovei
V ) is proteolytic enzymes: trypsin, chemotrypsin, elastase, carboxypeptidase (A
i Ii) and kallikrein. All these enzymes as well as phospholipase A are produced in
inactive form. The other ones — lipase, amylase, RNAase and DNAase — are
" led in the active form.
I >isturbance of pancreatic juice secretion is observed in occlusion or compres
hi of the pancreatic ducts, cystic fibrosis of the pancreas, acute and chronic
n icatitis or duodenitis, in disturbance of the neurohumoral mechanisms of pan­
tile secretion regulation. The vagus nerve is a secretory nerve of the pancreas,
tiiiitiral regulation is accomplished by secretin (which activates excretion of water
I hydrocarbonates), cholecystokinin (pancreozymin) which stimulates contrac-
ii of the bile bladder and production of pancreatic enzymes.
In pancreatic juice insufficiency, a considerable amount of fat is not digested
I excreted with feces (steatorrhea). Indigestion of proteins arises in insufficient
Mluction of peptidases by the pancreas as well as in their activation disorder,
reused pancreatic secretion impairs food nucleic acids hydrolysis and to a lesser
n o - starch splitting.

IN T E S T IN A L D IG E S T IO N D IS O R D E R S

I he intestine consists of the duodenum, small and large intestines. The intcs
fulfills secretory, motor, absorptive, ineretory and excretory functions.
I lie duodenum is an important section of the intestine, where duodenal gland
" i bile and pancreatic juice are collected. The outlet of acidic mass from the
■ l u ll into the duodenum stimulates production of secretin, which induces bicat
Mie production. Bicarbonates neutralize the acid mass, and pH increases from
f “>to 7.0. It activates proteolytic enzymes (trypsinogen, chemotrypsinogen,
Misypeptidase) and cholecystokinin secretion. In the duodenum, secretin and
llln, which regulate the digestive system, are produced as well as arentcrin and
i i >m u effecting appetite, metabolism and possessing a neurotropic effect.

I he small intestine has digestive glands, which secrete many digestive enzymes
It i their inllucncc, nutrients are digested into final products. Proteins are split
Г.и I 2 S|M4'lal (Syslt'in ic) l>
allii)|ih>siol(iKV

into amino acids and oligopeptides, fats - into latty acids, di- and polysaccharides
into monosaccharides, which are absorbed into the blood.
In the small intestine cavitary and membranous digestion is accomplished
Cavitary digestion takes place in the lumen of the small intestine and consists in
destruction of large molecules. Disorder of cavitary digestion depends, first of all,
on impairment of bile and pancreatic juice production.

Membranous Digestion Disorders

Membranous digestion is accomplished in the small intestine by the enzymes,

which are fixed on the surface of striated border (the latter is formed by microvilli
of columnar cells). Enzymes of membranous digestion (oligosaccharides, oligopep
tides, phosphatase, etc.) are partially synthesized inside columnar cells and partially
absorbed from chyme (pancreatic amylase, lipase, etc.). The main way of enzym<
entry into intestinal juice is rejection and decay of columnar cells (under normnl
conditions the cycle of their renewal is 3 days). The final stages of nutrient hydro
lysis and absorption proceed here.
Membranous digestion is characterized by coupling of the processes of nutrient
fermentation and absorption, a high rate of hydrolysis and sterility conditioned l>\
the small size of the pores between the microvilli (10—20 nm), where microorg.m
isms can’t penetrate.
Disorders of enzyme production by columnar cells play the main role in mem
hranous digestion disorders and may be caused by the following factors:
• damage of the villi and ultrastructure of the columnar cell surface;
• disorders of the enzymal layer of the intestinal surface;
• changes of the absorptive properties of the cellular membranes;
• peristalsis disorder when transportation of substrates from the intestinal cav i
ty to cells is impaired.
Reduction of the digestive intestinal surface as a result of its atrophy and dr
crease of the number of the villi or microvilli is observed in cholera, ileojejunitis, alii i
abuse of some antibiotics (neomycin), gastrojejunostomy and stomach resection. An
example of impairment of the enzymal layer of the intestinal surface is milk intolci
anec in lactase deficiency and saccharose intolerance in glucosidase deficiency.

Impairment of the Absorptive and Excretory Functions of the Intestine

Absorption of nutrients, hydrolyzed to the state of monomers, is mainly .к

complished in the small intestine. During the process of membranous digestion
nutrient hydrolysis and transportation through the cellular membrane are c lo s . U
conjugated. Therefore, all factors causing membranous digestion disturbance lentl
to malabsorption.
Syndrome o f malabsorption may be primary (hereditary) or secondary ( n
quired).
Hereditary syndrome of malabsorption is characterized by selective deliciciu \
ol enzymes. As a result, absorption ol one oi several nutrients is disturbed. I his (ур*
ol malabsorption includes:
 C h ap in 11. Pathophysiology of l>i|(t-4llvr System

• mono- (glucose, fructose, galactose) or disaccharides (lactose, saccharose,

isomaltose) intolerance;
• deficit of peptidases (glutenic disease);
• malabsorption of amino acids (cystinuria, tryptophane malabsorption, methion
me malabsorption);
• malabsorption of vitamins (cyanocobalamin, folic acid deficiency).
Acquired syndrome of malabsorption is observed:
• alter gastrectomy;
• in intestinal diseases (enterocolitis, Crohn’s disease);
• m diseases of the pancreas (pancreatitis);
• in diseases of the liver (acholic syndrome);
• alter prolonged radiation or medicamentous therapy;
• in disorders of blood and lymph circulation in the intestine, which disturbs en
ergy supply of active nutrient transport;
• under the influence of poisons blocking enzyme activity;
• in water-electrolyte imbalance;
• m ATP and sodium ion imbalance (which are of special importance in the active
transport of glucose, amino acids and other compounds).
The disturbance of digestion in the small intestine has a value in allergy de
\clopment. If the barrier properties of the mucous membrane are impaired, the
nbstances of antigenic nature (products of incomplete protein digestion) can be
absorbed into the blood and be a source of organism sensitization (food allergy,
bp. 90, 100).
The excretory function of the intestine is closely connected with the absorp
live one. The final products of hemoglobin and cholesterol metabolism, metal salts,
l.ictic acid, purins, some hormones, phenols, salicylates, sulfanilamides, dyestull
ire excreted in the intestine. In renal insufficiency there is increased compensatory
i xcretion of nitrogen waste (urea, uric acid, etc.) into the intestine.

IM PAIRM ENT OF TH E MOTOR FUNCTION OF THE INTESTINE

Disturbance of the motor function of the intestine manifests itself through peri
i ilsis increase or decrease. Serotonin, P-substance, gastrin, and motilin activate
peristalsis. Contraction of the intestinal muscles is activated by vagus nerve stimula
non. Vasoactive intestinal peptide and glucagon inhibit peristalsis.
Motility increases in:
• inflammation (enteritis, colitis);
• influence of mechanical or chemical stimuli due to consumption of undo
cooked food;
• effect of bacterial toxins;
• disturbance of nervous and humoral regulation.
Increase of peristalsis usually leads to accelerated movement of nutrient masses
in the intestine, disorders of their digestion and absorption.
Spasms of the intestinal muscles manifest themselves through spasmodic pain
I*iill 2 S |M '» 'in l ( S y s l r i H K ) I’utliopliysioloKy

Constipation and diarrhea are clinical symptoms of decreased and increa-.<<i

intestinal motility and arc connected with large bowel dysfunction.
Irritable bowel syndrome is an example of disturbed nervous and humoral куп
lalion of intestinal motility. Negative emotions change the motor and absorplm
functions of the intestine and cause pain and diarrhea, frequently followed by con
si ipat ion.

LARGE IN TESTIN E DISORDERS

In the large intestine feces formation and water absorption take place.
Microflora is found here. It includes anaerobic sporeless Bifidobacteria, anacm
bic colon bacilli, lactobacilli, streptococci, etc. Normal microflora plays a prole»
live role inhibiting the development of pathogenic microorganisms and promoting
natural immunity. Microflora of the bowels synthesizes vitamins.
Inflammation and disbacteriosis development are possible in the large intcsiim
I hey manifest themselves through diarrhea.
Acute forms of diarrhea may be caused by infections, which enter the bowel*
in food poisoning, from the blood or directly into the rectum. Causative facton
my he viral (herpes simplex, H IV ), bacterial (B. coli, rectal syphilis and gonorrlx .1
dysentery and cholera agents), parasitic (salmonella, ameba, spirochete, Chlamydi i
trachomatis), and fungal infections.
Chronic diarrhea is observed in inflammation of the bowels, irritable bowel
syndrome, malabsorption syndrome, and colon cancer.
Disbacteriosis (microflora content impairment) underlies many cases of di.ii
rhea. Therapeutic intervention into bacterial spectrum often has no effect. Unloi
Innately, disbacteriosis is frequently confused with enzymopathy.
Diarrhea may play a protective role promoting excretion of toxic subslantci
from the organism (in food intoxication) or excess of indigested food. Howevoi,
prolonged diarrhea, especially in children, leads to organism dehydratation and l<>i
of electrolytes (N a+, K +). In such cases hypovolemia develops, which may I* к
cause of cardiovascular collapse. Diarrhea may be connected with systemic osnioll*
disturbances — generalized malabsorption of salts, glucose, galactose or fructose
In addition, excretory acidosis develops as a result of a loss of intestinal content*,
which is alkaline (excretory non-respiratory acidosis, p. 248).

INTESTINAL IM PASSABILITY

Intestinal impassability (ileus) may be:

• m echanical (compressive or obstructive);
• dynamic (due to spasms or paralysis of the smooth intestinal muscles).
Obstruction arises due to congenital abnormalities, occlusion by leces oi In I
mint lies. Twisted bowels and knuckle are also examples of obstructive impassabiliu
Spastic disorders may be conncclcd with an increased tone ol the ninsuilii
layei of ihe intestine under ihe influence ol serotonin excess (in carcinoid я
serotonin producing tumor).
 Chaplet . 4 I’utliophvsiiiloKy <»f I>int-sll*e System

Paralytic impassability is frequently conditioned by activation of adrenorecep

lots (which inhibit contraction of the muscular layer), in vagus nerve paralysis,
pnllonitis, as abdominal operation complications.
Intestinal impassability is divided into high and low. In the first case problems
tit vt-lop in the small intestine, in the second — in the large one. In both cases in
ь «1Inal contents absorption into the blood takes place.
I he pathophysiological and clinical manifestations are very different, becausc
•I*, contents of the small and large intestines differ as to toxicity. Active diges
live enzymes with extreme biological activity are the contents of the small intes
line while putrifaction and fermentation products — of the large intestine (which
•м и under physiological conditions are absorbed into the blood in moderate
«mount).
High ileus has a grave clinical course. Pathophysiological changes quickly in
■о .isc and lead to patient’s death if a patient does not get urgent medical help. I lie
pathogenesis includes the following mechanisms:
• Distention of the bowels, compression and irritation of the mesentery cause
severe pain and shock.
• Arterial blood pressure decreases.
• Disorders of blood supply of the bowels (especially in strangulation ileus)
cause their necrosis.
• Damage of the intestinal wall results in disorders of its barrier function in
two opposite directions: intestinal contents get into the blood and the blood
plasma gets into the intestinal space.
• In constant uncontrollable vomiting the patient throws up not only gastric
contents but also pancreatic and intestinal juices as well as the blood plasma,
which gets into the intestinal space and aggravates arterial hypotension.
• Loss of water (sometimes up to 5—7 1) leads to dehydratation, hemoconcen
lration and aggravates arterial hypotension.
• Hypovolemia aggravates disturbance of blood circulation, shock and results
in acute renal insufficiency.
• Absorption into the blood of active intestinal enzymes results in BAS forma
lion in the blood, especially of vasoactive kinins, which aggravate arterial
hypotension.
• Absorption into the blood of activated trypsin and chemotrypsin resembles
pancreatic shock in its main pathophysiological mechanisms and requires
immediate help and injection of trypsin and chemotrypsin inhibitors.
• Decompensated disorder of the acid-base balance is connected with I I ' ion
loss with gastric juice (during uncontrollable vomiting) and hydrocarbon
ates with pancreatic and intestinal contents. If loss of acidic gastric contents
prevails, nongaseous alkalosis develops. Nongaseous acidosis may develop in
excessive loss of pancreatic and intestinal juices.
• Renal insufficiency aggravates acidosis.
• Loss of N a+ ions and chlorides with K* ion imbalance causes acute cardiac
automatism disorder and excitability results in heart arrest in diastole.
I’.m Special (System ic) I *:•th<>|>hysit

• D IC syndrome is a result of entering into the blood of a large quantity of

procoagulants from damaged tissues.
• Peritonitis aggravates all above-mentioned changes.
Low ileus is connected with occlusion of the large intestine. Activation <>l
putrifaction and fermentation, formation of toxic substances (indole, skatolc, c;i
daverine, putrescine) and their absorption into the blood are important. (Under
physiological conditions they are formed and absorbed into the blood in model.ii<
amount and deactivated in the liver.) Chronic constipation (sometimes up to H*
days) is an example of low impassability.

IM PAIRM ENT OF INCRETORY (HORMONAL) FUNCTION

OF DIG ESTIVE SYSTEM

Now it is known that over 20 substances with hormonal activity are produced
by the neuroendocrine cells of the A P U D system of the digestive tract and increial
into the blood. They not only regulate nutrient digestion and absorption but also
influence systemic blood circulation, metabolism, appetite, assimilation, trophicitv
nervous and endocrine functions.
The hormones of the digestive system are connected with the hypothalanm
pituitary system and other endocrine glands. Gastric inhibiting peptide and secrcim
stimulate insulin and glucagon production and participate in the pathogenesis •> 1
obesity and emaciation. Gastrin, cholecystokinin and glucagon stimulate the pro
duction of calcitonin and, therefore, play a definite role in calcium balance impan
ment.
Disorders of hormone production of the digestive tract result in deep distui
bailees of digestion, metabolism and function of various organs. Hormone-prodn.
mg cells of the digestive organs may be liable to cancerogenesis and development
of malignant tumors (Zollinger-Ellison syndrome is increased gastrin production I

Questions for Self-Control

1. What is the role of infection in stomach ulcer disease development?

2. What is the role of genetic factors in stomach ulcer disease development?
3. What is the role of neurogenic mechanisms in stomach ulcer disease develop
ment?
4. What is the role of humoral mechanisms in stomach ulcer disease develop
ment?
5. What is the role of stress in stomach ulcer disease development?
(». What are the peculiarities of acute pancreas inflammation?
7. Characterize disorders of membranous digestion.
К What is intestinal impassability? Name its types.
•V What arc systemic disorders in intestinal impassability?
 < lu p in .’ / I’athophysMojU' of Digestive System

Tests and Tasks for Self-Control

(give correct answers and find mistakes in the statements)

I Caries was reproduced experimentally in rats. What compensatory reactions

developed?
Л. Formation of secondary dentine by fibroblasts.
B. Ncogenesis of the enamel.
C. Hypotrophy of the salivary glands.
D. Inhibition of phagocytosis.
E. Hyperfunction of the parathyroid glands.

With the purpose of stomach ulcer modeling, sclerosis of animal gastric arteries
was reproduced. What is the main mechanism of gastric mucosa damage in this
experiment?
A. Disregulatory.
B. Neurodystrophic.
C. Mechanical.
D. Ischemic.
E. Neurohumoral.

' Л patient has Zollinger-Ellison syndrome (tumor of the pancreas). Elevation ol

gastric secretion and acidity, ulcers in the duodenum and jejunum are observed.
Wliat substance is produced by the tumor and provokes this syndrome?
A. Secretin.
B. Vasoactive intestinal peptide.
C. Pepsin.
D. Trypsin.
E. Gastrin.

i A 20-year-old man, who participated in nuclear accident elimination, suffers

Irom parodontosis. What is the main etiological factor of the development ol
this pathology?
A. Iron deficiency.
B. Emotional stress.
C. Malnutrition.
I). Increased mechanical load on the dentomandibular apparatus.
E. Streptococcus infection of the oral cavity.

A patient suffers from inflammation of the trigeminal nerve and progressive

parodontosis. What is the pathogenesis of parodontosis in this case?
A. Decrease of immunoglobulin concentration in salvia.
B. Decrease of the phagocytic activity of leukocytes.
C. Dystrophic changes in the parodontium.
I). Hypertomis of the vagus nerve.
E. I lypersalivalion.
INirt 2. Special (Systemic) РиИшрЬулМоку

6. A patient came to a doctor with complaints of purulent exudate from the uni
gival pocket and teeth loosening. What is the cause of purulent periodontitis hi
this case?
A. Hypersalivation.
B. Viral infection.
C. Bacterial infection.
D. Local anaphylaxis.
E. Generalized anaphylaxis.

7. A 57-year-old patient was delivered to the gastroenterological department with

Zollinger—Ellison syndrome suspected. What kind of stomach secretory Inin
tion disturbance is the most probable in this case?
A. Hyperacidic hypersecretion.
B. Low level of gastrin in the blood serum.
C. Achylia.
D. Hypoacidic hyposecretion.
E. Hypoacidic hypersecretion.

8. A patient with high mechanical intestinal obstruction complains of abdonnn il

pain, uncontrollable vomiting during the last 3 hours, dyspnea. Objectively]
pulse is 110, arterial pressure — 90/50 mmHg, hematocrit value — 0.52, In
ponatremia. What is the main mechanism of cardiovascular disorder?
A. Alkalosis.
B. Respiratory acidosis.
C. Dehydration, hypovolemia.
D. Intestinal endointoxication.
E. Hypoxia.

9. A patient has been taking glucocorticoids for a long time. Fibrogastrost opy
revealed erosions and ulcers in the stomach and duodenum. What mechaniMii
determines the development of ulcers?
A. Increasing production of PgE.
B. Decreased influence of histamine on the gastric mucus.
C. Increasing tone of the sympathetic nervous system.
D. Deficit of mucous protection factors.
E. Decrease of gastric secretion and acidity.

10. 5 years ago a patient underwent gastrectomy. Now a stomatologist found iiim
phic-inflammatory processes of the mucous membrane of the gums and tonjuit»
What is the cause of these changes?
A. Vitamin С deficiency.
B. Vitamin B l2 deficiency.
C. Vitamin B, deficiency.
D. Malnutrition.
E. Psychocmotional stress.
 C'luipli'i J7 r»lh()physii)li>Ky «f I s i m System

lii a 45-year-old patient intestinal digestion is severely disordered because ol' .1

■in reased amount of bile in the duodenum and small intestine (the reason lies
i cholelithiasis). What disorder developed in the patient?
Manifestations o f digestive disorders:
1. Disorders of fat digestion in the intestine.
2. Presence of fats in the feces.
3. Activation of pancreatic and intestinal enzymes.
4. Meteorism.
General symptoms connected with digestive disorders:
5. Hemorrhage syndrome (due to vitamin К hypovitaminosis).
6. Vitamin С hypovitaminosis.
7. Blood hypercoagulation.
X. Vitamin A, D, E hypovitaminosis with corresponding clinical sings -
dryness of the skin, disorder of sex hormone synthesis, etc.

A patient complains of pain in the abdomen, diarrhea, blood-streaked stool

bacteriological investigation of the feces shows autoinfection development. In
addition, there are hemorrhages. The lymph nodes are enlarged. The hemoglo
I'm content is 90 g/1 (anemia). Leukocytosis is 50 G/1. Lympholeukemia has
i«rn diagnosed. What are the mechanisms of such symptoms in the digestive
•.vslem?
1. Depression of normal granulo-, monocyto- and lymphocytopoiesis pro­
motes impairment of the immune response of the organism.
2. Secondary autoinfection development results from immune supervision
deficiency.
3. Autoimmune process may develop.
4. Humoral and cellular immune responses are disordered.
5. Lymph nodes are obviously enlarged.
(>. Malignant leukocytes do not perform their functions (phagocytosis and
antibody formation).
7. Cancerous cachexia develops.

i ompile a scheme of high impassability pathogenesis including disorders ol

Mood pressure, hemostasis, cardiac insufficiency, electrolyte imbalance and
other patterns.
Chapter 28
PATHOPHYSIOLOGY OF LIV ER

The liver is a compound organ with many functions providing homeostasis in

the organism.
Morphologically the liver consists of three functional parts: hepatic cells (Ii*
patocytes), bile secretory apparatus (bile ducts and gallbladder), and blood cin ni t
tion system (hepatic vein and artery, as well as portal vein). The portal system i* 4
peculiarity of hepatic blood circulation, which collects the blood from the ink .1tit#
and provides neutralization of toxic digestive metabolites and other toxins ciiteiing
the organism.
The functions of the liver are the following.
Excretory function consists of (a) bile formation (cholepoiesis) and (b) I
excretion. Bile is formed by hepatic cells and excreted by the biliary tract. Hi-
gallbladder is a sac for bile accumulation.
The normal bile composition is the following: bile acids (cholic and demy
cholic, which are formed in hepatocytes from cholesterol and determine pn»|i«f
ties of bile as a digestive secret), glycocholic and taurocholic acids conjugated lu
glucuronic acid, bilirubin, lecithin, cholesterol (in the soluble state due to bile ,n id
salts and lecithin), water and mineral salts. Glucagon, secretin, gastrin, cholecynin
kinin, n. vagus activation, food proteins and fats (egg yolk, milk, meat, fats) a c tiv e
bile secretion.
In pathology, toxins, drugs and their metabolites are excreted in bile.
The excretory function of the liver includes bile pigment circulation. Billitt
bin, which is formed in macrophages of the spleen, liver an bone marrow In ни
hemoglobin of destroyed erythrocytes (free bilirubin) is insoluble, but in the hit mg
a soluble bilirubin-albumin complex is formed ( unconjugated ( indirect) bilirubin)
Hepatocytes actively capture this complex, the bond with albumin is split, biliiiiliiti
conjugates to glucuronic acid as soluble bilirubin glucuronide (conjugated (iln n y
bilirubin). Direct bilirubin is excreted into the duodenum with bile. Bile pijuiii ui*
are present in feces (stercobilin) and urine (urobilin).
Digestive function of the liver is participation of bile in nutrient digestion in ili|
intestine (see p. 392). Bile acids emulsify fats and make them accessible to ршн it
atic lipase. Bile provides intestinal peristalsis and bactericidal action.
M etabolic function is participation of the liver in anabolism and catabolm
of:
• proteins - synthesis of proteins (blood plasma proteins, sec p. 236, and рюнИ
agulants), transamination and deamination of amino acids (p. 239), formnllon nf
urea from ammonia (p. 242), formation of creatinine;
• carbohydrates - synthesis of glycogen from monosaccharides and its s p lillln |
into glucose (sec p. 201), glucose oxidation, gluconeogenesis;
• lipids formation of lipoproteins лnil phospholipids (see p. 224 about syni lit.
sis of compound lipids), laity acid oxidation, bile acid formation, syndic*!* щ
 Chapter 28. Patbophysiolog) of liver

liolcsterol (which is necessary for membrane formation and steroid hormone

.vnthesis, see p. 224);
• iiamins - deposition and metabolism of vitamins А, В, K, D; vitamin B l2 de
IN isit;
• к id-base balance regulation;
■ ' I. position of iron, copper, and zinc ions.
Intitoxic Junction is neutralization of toxic substances and xenobiotics, which
••im* from the intestine or enter the organism from outside the body.
Defensive function is phagocytosis, bactericidal properties of bile, and high re-
(•'ncrative properties of hepatocytes.
Hemodynamic function is collection of the blood from the digestive tract
I* - of the minute circulation volume), blood deposition (about 800 ml), influ-
■in г on the total blood volume, participation in vascular tone regulation (synthesis
nl mgiotensin precursor, ferritin, which participates in vasocontriction, and angio-
llii .inase, which has the opposite effect), development of collateral blood circula-
.... and opening of anastamoses (when portal hypertension develops). Bile acids
in* г a hypotensive effect (in pathology).
Hemostatic function is synthesis of all plasma coagulation factors ( I —X II), anti-
HMKiilants and fibrinolytic systems of the blood (antiplasmin, antithrombin, hepa-
lln) (p.305).
Hemopoietic function consists in participation in empryonic hemopoiesis, de-
in. иion in adults of such important hemopoietic factors as cyanocobalamine, folic
*i ul. and iron. Erythrocytes are destroyed by tissue macrophages (stellate cells).
I ndocrine function is participation in hormone (insulin, thyroxin, aldosterone,
(Imocorticoids, sex hormones) destruction.
hiking into account the great number and variety of liver functions, it is pos-
ililr to give the following definition of hepatic insufficiency.
Hepatic insufficiency is a group of syndromes characterized by impaired ability
"I the liver to fulfill its functions, which results in disorders of the organism's vital
•Hlvlty.
CLASSIFICATION

I here are several classifications of hepatic insufficiency.

itiological classification divides it into acquired and hereditary, prim ary (indc
pnulcnt liver diseases) and secondary (hepatic syndromes, which complicate otliei
И 'I' пне diseases).
Pathophysiological classification divides it into:
• Cholestatic (excretory) resulting from impairment of bile formation (cholcpoi
i l l ) and excretion (cholestasis).
• Hepatocellular (parenchymatous) resulting from dystrophic disorders of liepa
im vies.
• Hepatovascular connected with blood circulation disorders.
In addition, hepatic insufficiency may be total (all functions are impaired) anti
in itia l(certain functions arc impaired), absolute (hepatic function impairment) ami
I’art 2. Spccial (System ic) Pathophysiology

relative (discrepancy between liver activity and increased needs of the organMi
for example, increased hemolysis leads to hemolytic jaundice in spite of inci« iwd
bile formation in the liver). Very often a combination of several mechanisms in ilit
development of hepatic pathology can be observed.
C linical classification divides hepatic pathology into acute (lasting for sonu •l.ivi
or weeks) and chronic (lasting for some months or years).

ETIOLOGY

The causes of hepatic pathology are so numerous, that there is a tendcm \ i«

exaggerate them and connect many diseases with liver pathology.
Etiological factors are divided into exogenous and endogenous, hepalu .и-4
extrahepatic, hereditary and acquired, physical, chemical and biological.

Exogenous Factors

Exogenous factors of physical, chemical and biological origin directly iniiMf

the hepatic tissue.
Physical factors are ionizing radiation (radiation hepatitis) and mech.mu^j
trauma.
Chem ical factors are the following:
• noninfectious organic and nonorganic toxic substances and poisons (|>Ihm
gene, carbon tetrachloride, arsenic, insecticides, industrial poisons);
• vegetable poisons (aflatoxin, muscarine);
• side effects of some medicines (sulphanilamides, salicylates, biomycin u in .
cycline, cytostatics);
• alcohol abuse;
• alimentary factors - lack of food (starvation), vitamin deficiency, fallv 1«мц|
abuse.
Biological factors are the following:
• infectious factors may be bacterial and viral, among which a special pmilltli
is occupied by hepatitis viruses (А, В, C, D, E, G ); agents of tuber» ni.n|«
and lues, malaria plasmodium and parasites (lamblia, hclminthes),
• immune factors associated with vaccination, immune serum injection, i "t il
as food and drug allergens.

Endogenous Factors

Endogenous factors are also physical, chemical and biological, hut ol ini< мнЙ
origin. They are the following.
Physical factors are traumas and mechanical occlusion of the bile trail Mu
most common cause is the presence of stones (from bilirubin, cholesterol and <*l<
cium) in the biliary tract and gallbladder llili.iry tract narrowing due lo inllt.....и
tion or tumors must be added.
 Chapter 2K. I'atlm pln smli>K> of liv e r

( hemieal factors are endogenous poisons (metabolites) in uremia, DM (hyper

Ifiniicm ia), pregnancy toxemia, and also products of tissue lysis in case of burn
HhI i rush syndrome.
Hiological factors are:
• autoimmune (hepatotropic autoantibodies, sensitized lymphocytes, T-killers
and BAS during autoimmune reactions);
• tumors both primary (hepatocarcinoma) and metastatic (in cancer of the
stomach, lungs, mammary glands, leukemic infiltrates);
• genetic (enzymopathy) and congenital structural defects of the liver;
• nervous regulation disorders: dyskinesia (spasms) of the bile tracts;
• hlood circulation disorders as a result of ischemia, thrombosis, embolism,
cardiovascular insufficiency, portal blood circulation disorders;
• endocrine and metabolic disorders (D M , obesity).

PATHOGENESIS

Damage of the liver can be primary (by direct action of an etiological factor)
nl secondary (indirect affection of the liver in other pathology - allergy, systemic
khI circulation disorders, heart insufficiency, hypoxia).
All typical pathological processes can occur in the liver.
Inflammation (hepatitis) is caused by infectious and noninfectious agents.
Allergy results from formation of cytotoxic autoantibodies against pathologi-
!l\ changed hepatocytes and development of autoallergic reactions of humoral
I cellular types; then the liver is damaged by immune cytolysis with T-killers
til HAS.
liim ors may be primary and metastatic.
Ilypoxia of different origin creates a relative deficit of microsomal cytochrome
, needed for the antitoxic function of the liver.
Metabolic disorders.
Dystrophy (hepatosis) is a result of primary or secondary metabolic changes in
ipntocytes.
Sclerosis (cirrhosis), i.e. diffuse growth of the connective tissue (as a rule against
ii.ickground of chronic inflammatory or metabolic affection of the liver); alco
it alnise plays a role.
I >ue to anatomical and functional connections between the liver and other or
Hi nl the digestive system as well as with the spleen and kidneys, a high frequency
iinnbined disturbances of the liver and these organs (hepatolienal and hcpato
и il syndromes) is typical of liver pathology.

Compensatory Reactions

As any other pathology, liver pathology consists not only of pathological si rue
i il .ind functional disturbances, but also of compensatory reactions, which ;i i c
n иled to slop the pathological process in the organ.
I here are such defense reactions:
I'.iii 2. Spccial (System ic) I*:■Ih«>|>li.vsi<il<>^>

• phagocytosis of infectious and other harmful agents;

• toxic substance excretion;
• intensification of metabolic detoxication;
• intensification of energy production in the liver;
• blood redistribution, vessel tone changes (as in blood loss);
• development of vascular anastamoses in case of portal circulation disorders;
• regenerative hypertrophy (liver capability of regeneration can be observed dm mg
its partial resection under experimental conditions).
Finally, having outlined general considerations in the etiology and pathogcntH
of hepatic pathology, it should be mentioned that each form of this patholoyv im
peculiarities of its etiology and pathogenesis. Details are given below.

C H O LEST A T IC H EP A T IC IN S U F F IC IE N C Y

Cholestatic hepatic insufficiency is a group of syndromes caused by bile sem i...

disorders (cholestasis).

ETIOLOGY

All the factors (exogenous and endogenous), which cause occlusion of tin ЫЦ
duct lumen, cause bile secretion disorders. Concrement (stone) formation in ib*
biliary ducts and gallbladder ( cholelithiasis) is the most widespread situation llm
presence of parasites in the gallbladder, dyskinesia of the biliferous ducts (gallhlittl
der spasms), tumors (of the head of pancreas), and inflammation have the мнн|
effect occluding the bile ducts.
The degree of bile tract obstruction is a determining factor of cholcstaiit In
patic insufficiency development and manifestations.

PATHOGENESIS

The pathogenesis of this disorder depends on the fact whether bile dud >» •luf
sion is acute and complete or chronic and partial.
Acute complete obstruction of the biliary ducts is accompanied by seven p tIM
which bears the name of hepatic colic. Emergency aid must be rendered i<> thf
patient. Spasmolytics sometimes help. Urgent surgical intervention is so...... t«j
necessary.
Bile outflow obstruction results in pressure elevation in the bile capllliiitfl
Their rupture may occur. Bile acids damage hepatocytes and the reverse li.inimH
of bile into blood capillaries occurs. Bile components appear in systemic until#
tion (a group of signs termed cholem ia). On the other hand, bile normally <lu. i (M#
enter the duodenum and does not participate in digestion (a group ol sign;. t<initif
acholia or hypocholia).
 Chapter 2K. I'alhophysioloto o( I Jv rr

MANIFESTATIONS

( holestatic hepatic insufficiency is manifested by three pathophysiological syn

illumes - acholic (hypocholic) syndrome, cholemic syndrome and m echanical (post
'«га/и) jaundice. All of them have common etiology (narrowing or complete occln
«ion nl die bile ducts), but the pathogenesis and clinical manifestations are different
ilii'iinh they develop simultaneously.

Acholic (Hypocholic) Syndrome

Acholic (hypocholic) syndrome is a group of symptoms connected with complete

и» partial non-entrance of bile components into the duodenum and intestine.

i tlology and Pathogenesis

Acholic (hypocholic) syndrome is a result of biliary tract occlusion by different

in inrs, which hamper bile movement in proper direction into the duodenum. In its
"im. acholia means absence of bile and hypocholia means its lack in the intestine
I he following processes, which are connected with the role of bile in the intes
line (p. 425), are impaired:
> l.il emulsification in the intestine, which is necessary for lipid digestion (with the
ml of pancreatic lipase) and absorption;
• vilamin absorption in the intestine, namely, the group of fat-soluble vitamins ( K,
I A, D, E );
• pigment circulation (direct bilirubin does not enter the intestine and does not
participate in further pigment transformation);
• motility of the small and large intestine;
• luctcricidal activity in the intestine (which is provided by bile acids under normal
i onditions).

Mil infestations

Manifestations depend on the extent of biliary tract occlusion. If occlusion is

""i complete (hypocholia) and some part of bile flows into the intestine, the I'ol
lowing clinical manifestations develop:
• malabsorption — a disturbance of nutrient lipolysis in the digestive tract and, as
a result, a disorder of nutrient absorption;
• disbacteriosis (p. 428);
i activation of intestinal putrefaction and fermentation caused by disbacteriosis
and malfermentation;
• liypocoloration of the feces caused by lack of stercobilin;
< I'u sence of fat in the feces (steatorrhea), which acquire a specific look like
white clay (sticky fecal masses together with hypocoloration);
• depression of intestinal peristalsis; alternating constipation and diarrhea;
• ineleorism;
• abdominal pain (due to meteorism);
I'.n | ' Special (System ic) I ’allm itlitsm lo^

• blood hypocoagulation and hemorrhage syndrome, which is aggravated due hi

K-hypovitaminosis, lack of procoagulants and increased permeability of microv#
ssels;
• hypovitaminosis A, D, E with corresponding clinical signs - skin impairment. IU
dryness, disorders of sex hormone synthesis, etc.
If occlusion is complete (acholia), pain prevails (hepatic colic), the feces .m
discolorated (white), and stercobilin (urobilin) is absent in the urine.

Cholemic Syndrome (Cholemia)

Cholemic syndrome is a group of symptoms connected with bile entry into ilu
blood.
When speaking about cholemic syndrome, it is necessary to take into consul, i
at ion that the most toxic component of bile is bile acids (as well as glycocholu an.l
taurocholic acids). It is the elevation of their rate in the blood (it is termed chain
lem ia) that causes the gravest symptoms of cholemia. Other components of bile tit#
not so toxic. An increase of their content in the blood is called hypercholesterolemia
and hyperbilirubinemia.

Ktiology and Pathogenesis

Cholemic syndrome accompanies the acholic (hypocholic) one and is саимч!

by the same reasons (complete or partial occlusion of the biliary tract). Duo to
elevation of pressure in them bile moves in the reverse direction — into the bloo.l
capillaries and then into systemic blood circulation.
The pathogenesis of this disorder is mostly connected with cholalemia and u
the following:
• C'erebrotoxic effect is the most evident, since the nervous system is the inoM
sensitive to all types of intoxication. It disturbs the functional state of the nervoiMI
system: excitation is followed by inhibition of the centers of the brain and spin*!
cord.
• Vagal irritation by bile acids (vagotonia) results in disregulation of arterial blntnl
pressure, heart activity, respiration and digestion.
• Irritation of the cutaneous nerve receptors is caused by entry of bile acids ntlil
the skin.
• Hemolysis is a result of the destructive effect of bile on the erythrocyte mem
brane.
• Tissues may be damaged by bile acids in inflammation and necrosis.

Manifestations

C holemic syndrome has the following clinical manifestations.

• Cholalemia causes:
•• malaise and neurasthenic symptoms asthenia, disturbance of Ilu* dully
rhythm ol sleep and wakefulness (sleepiness in Ihe daytime and insomuM
 • liaplci 2S rallio|)h>4i(>liiK> of live r

at night), headache, irritability, excitability, depression, fatigability, ten

don reflex decrease;
•• skin itch;
•• arterial hypotension;
•• bradycardia;
•• hemolytic anemia (p. 281);
••peritonitis, acute pancreatitis and necrosis of the liver may develop in sc
vere cases.
Hypercholesterolemia causes cholesterol deposition (xanthoma) in the skin ol
the hands, feet and eyelids.
Hyperbilirubinemia causes mechanical (posthepatic) jaundice.

Mechanical (Posthepatic) Jaundice

Jaundice (icterus) is a syndrome connected with elevation of the bile pigment

iitilirnbin) content in the blood, yellowing of the tissues due to bilirubin deposi
lion.
Ihere are three types of jaundice — suprahepatic, hepatic and posthepatic with
•Mlnent causes and significance.
Mcchanical (posthepatic) jaundice is yellowing of the skin, mucous membranes
«•nl sderae by conjugated bilirubin deposited in them as a result of hyperbilirubinemia
Mused by biliary tract obstruction.
Mechanical jaundice is one of the syndromes of cholestatic hepatic insulli-
t'lnicy together with acholic and cholemic syndromes.
Ktiology. The causes of posthepatic jaundice are similar to those of cholemic
mill acholic syndromes mentioned above (complete or partial occlusion of the hi
llaiy iracts).
Pathogenesis. Disorders of bile outflow and pressure increase in the biliary tracts
ifMilt in hepatic cell damage and reverse transport of bile into the blood. Speaking
til» ail jaundice, we mean entering in the blood of the bile pigment - conjugated
i liicct) bilirubin. Laboratory determination of its presence in the blood allows find
Inn Ihc exact cause of the patient’s grave condition — occlusion of the biliary tracts
i more often by gallstones). This type of bilirubin filters through the membrane of
Ни renal glomeruli, appear in the urine and gives a specific dark color to it.
Manifestations. Direct bilirubin is not very toxic. Yellow discoloration of the
Mu and sclerae does not cause patient’s suffering (this pigment docs not cause
•ms pathological symptoms except for yellow discoloration). In mechanical jaun
tlii <
• yellow discoloration of the skin is never an isolated symptom, it accompanies
Vliolcmic syndrome (nervous disorders, itch, arterial hypotension, destruction ol
H\i|irocytes) and symptoms of acholia (discoloration of feces) mentioned above
I'ani (hepatic colic) is often the reason of urgent surgery.
11 ms. the clinical picture of mechanical jaundice is determined by such mam
li stations of cholestatic hepatic insufficiency: pain (hepatic colic), symptoms ol
i liolemia and acholia.
I’iirt 2. S|M4'ial (Syslcm k-) l*iitli<>|ili> sh>I«ik>

H EPA T O C ELLU LA R (PA R EN C H Y M A T O U S) H EPA T IC IN SU F F IC IE N C Y

Hepatocellular (parenchymatous) hepatic insufficiency is a group of syndrom* *,

which develop as a result of hepatic cell (hepatocyte) damage.

ETIOLOGY

Parenchymatous hepatic insufficiency may be prim ary (direct injury of hcp.i

tocytes by etiological factors) and secondary. Causes may be exogenous and ciuln
genous of physical, chemical and biological nature. They are:
• ionizing radiation;
• poisoning by salts of heavy metals, phosphorus and arsenic, organic and iihm
ganic (tetrachloride hydrocarbon) poisons, high constant doses of alcohol;
• infection (viral);
• hepatotrophic antibodies and sensitized lymphocytes;
• drug abuse;
• endogenous products of metabolism in uremia and nephropathy of pregn.m. \
(secondary lesion of hepatocytes);
• genetic factors - lack of enzymes (enzymopathy) or receptors (which particip.il»
in numerous biochemical reactions in hepatocytes);
• disorders of blood circulation (including problems in the portal system and sett*
ondary lesion of hepatocytes);
• lack of food (starvation), avitaminosis;
• extirpation of the liver in experiment.

PATHOGENESIS

Primary or secondary, all typical pathological processes (inflammation, allciuv,

minors, ischemia, dystrophy, hypoxia, etc.) may develop in hepatic cells. Stnictuni!
and functional disorders in hepatocytes concern their membranes, mitochoiuliiii
nuclei, and lysosomes.
fhe pathogenesis can be presented as the following chain of events:
• impairment of hepatocyte membranes;
• increase of membrane permeability;
• release of hydrolases from lysosomes, which aggravate the damage;
• release of necrogenic factors and interleukins from damaged macrophages .mil
development of inflammation;
• formation of autoantibodies and autosensitized T-killers that promote autoiilli \
gic damage of hepatocytes.
Hepatocyte damage, induced by any pathological process, gets complicated l>>
disorders of bile secretion in the area of lesion and additional damage of them Ц
bile acids. The barrier between the biliary tract. Wood and lymphatic vessels цен
broken, and bile comes into the blood (cholem ia). I he blood level of conjii|Mi< < 1
bilirubin increases, bilirubin appears in the urine. Mile How into the intestine l«
hampered ( hypocholia).
 (h a p lo i ,’ .ч r;illi<>physiol(>K\ of IJvo r

Lesion of hepatic cells results in impairment of all their functions. The con
■iiuences depend on its degree and mass of impaired hepatocytes. The chronic
H>urse of any pathology in hepatocytes results in parenchyma substitution by con
ncctive tissue and sclerosis ( cirrhosis) development (toxic, biliary’ or porta! cirrhosis
depending on the initial cause).

MANIFESTATIONS

The manifestations of parenchymatous hepatic insufficiency are biochemical,

pathophysiological and clinical. They are represented as:
• metabolic syndrome;
• hemorrhage syndrome;
• syndrome of antitoxic function impairment;
• hepatic coma;
• parenchymatous hepatic jaundice;
• cholemic syndrome;
• hypocholic syndrome.
The last two syndromes (cholemic and acholic) have been described above.
I he other ones are given below.

Metabolic Syndrome

The liver is metaphorically called «a big biochemical laboratory of the organ­

ism*. It means liver participation in carbohydrate, lipid and protein metabolism as
u-ll as in acid-base, water, hormone and vitamin balance. General considerations
about disorders of metabolism are represented in corresponding chapters. Below are
'h-scribed the ones, which are connected with hepatocellular insufficiency.

( arbohydrate Dismetabolism

Disorders of carbohydrate metabolism are the following.

• Glycogen synthesis (glycogenesis) suppression and low glycogen content in the liver
the main depot of glucose in the organism. Primary disorder is determined by
enzymopathy (reduced activity of glycogen synthetase), secondary - by hor­
monal disorders (in deficit of insulin, which provides conversion of glucose into
glycogen) and starvation.
• Glycogen splitting (glycogenolysis) suppression. Primary disorder is underlain by
enzymopathy (lack of phosphorylase, glucose-6-phosphatase and other enzymes
of glycogenolysis). Intracellular (in hepatocytes) retention of glycogen (glyco
genosis, disease of accumulation) leads to hepatocyte degeneration. Secondary
disorder is determined by endocrine disturbance (glycogenolysis is controlled by
glucagon, adrenaline and thyroxin).
• Glyconeogenesis disorder (formation of carbohydrates from lipids and proteins
controlled by glucocorticoids).
• Hypoglycemia (on an empty stomach) and hyperglycemia (develops after meals)
I'ii il S|M4'ial (S y s la n k l l ’allm|>li}sioli>n>

• Disorders o f intermediary glucose metabolism (formation of glucose-6-phosphatc,

which participates in the citric acid cycle (C A C ) and pentose-phosphate cycle»
• Non-oxidized metabolite accumulation (metabolic acidosis).
• Glucuronic acid synthesis suppression (which is formed from glycogen and part к i
pates in the antitoxic function of hepatocytes).

Lip id Dismetabolism

Lipid metabolism in the liver is an important source of energy in the org.m

ism (lipid acid oxidation). In addition, it is a place of the synthesis of import.mt
compound lipids - phospholipids, lipoproteins, cholesterol and its ethers (the lallrr
is necessary for fatty acid formation, vitamin D 3 formation, corticosteroid and sex
hormone synthesis).
There is a concept of lipotropic substances (see p. 224), which provide thin <lis
persion of lipids in the blood, their release from hepatocytes and proper oxidation
These lipotropic substances are phospholipids — lecithin of the liver (with cholinc
and methionine of food, whose utilization is necessary for lecithin synthesis) ami
lipocaine (from the pancreas). Deficit of lipotropic substances results in fatty do
generation (decomposition) of the liver.
Lipid metabolism (anabolism and catabolism) is disordered in parenchymaltuis
hepatic insufficiency. Its dynamics is the following.
• Transport hyperlipemia (which develops, when the stock of glycogen — a source
of energy substrate — decreases).
• Lipolysis (lipid disintegration) activation as a mechanism of energy production
(in glycogen deficit in the liver) with accumulation of fatty acids.
• Incomplete oxidation of triglycerides (neutral fats) and fatty acids with accumula
tion of intermediate products in the form of ketone bodies (formed from АсСоЛ
if the Krebs cycle is inhibited), hyperketonemia and ketonuria (ketosis), when
utilization of ketone bodies gets disordered in deficiency of oxidative enzymes 01
carbohydrate.
• Peroxidation activation resulting in accumulation of toxic products.
• Lipoprotein and phospholipid synthesis decrease.
• Hyperlipoproteinemia (increased lipoprotein synthesis from fatty acids), wlm Ii
predisposes to atherosclerosis development.
• Lip id accumulation outside the adipose tissue (in the epithelium and interccllul.n
substance of the liver). It is adipose degeneration and dystrophy of the liver (lam
hepatosis, a combination of lipid infiltration with a disorder of the cytoplasm
structure, see pp. 210, 231).
• Hypocholesterolemia caused by a decrease of cholesterol biosynthesis from
AcCoA. On the other hand, hypercholesterolemia may be a result of (a) decreased
use of plasma cholesterol by hepatocytes, (b) disorder of cholesterol excretion m
bile in cholemic syndrome (in mechanical and parenchymatous jaundice).
• Steroid hormones metabolism disturbance.
• Steatorrhea (fecal excretion of lipids in disorders of lipid absorption in the intei
tine in hypo- and acholic syndromes).
• Bile secretion disturbance and jaundice development.
1 Chapter 2X. l'.Hli.i|>ln\tolnKV nl liv e r

Protein Dismetabolism

Protein metabolism is disordered in parenchymatous hepatic insufficiency and

manifested by the following signs.
• Hypoproteinemia (hypoalbuminemia) develops due to reduction of the protein
synthesis function of the liver. (Normally, all blood albumin and part of a- and
P-globulins are synthesized in the liver.)
• Dysproteinemia is a disorder of the albumin-globulin ratio in the blood.
• Oncotic pressure of the blood decreases ( hypooncia) with a tendency to edema
development ( hepatic edema, p. 259).
• a-Fetoprotein formation in liver cancer.
• Disorders o f intermediate amino acid catabolism (desamination, decarboxilation,
transamination). The impaired liver is not able to provide a proper quantity
and correlation of certain amino acids and protein fractions in the blood. An
increased content of free amino acids in the blood ( hyperaminoacidemia), their
appearance in the urine ( am inoaciduria) and metabolic acidosis are manifestations
of these disorders.
• Urea synthesis from amino groups and ammonia is reduced, ammonia accumula
tion in the blood ( azotemia, pp. 242, 210) is noted.
• Hypocoagulation and a tendency to bleeding (hemorrhage syndrome) due to de­
creased synthesis of procoagulants (prothrombin, fibrinogen, proconvertin).
• Intracellular enzymes are released into the blood from destroyed hepatocytes (al
kaline-transaminase, glutamate-transaminase, aminotransferase, aspartat-amino
transferase), which easily penetrate through the damaged cellular membrane
Transaminase content in the blood elevates in viral hepatitis and cirrhosis. A high
level of hepatic transaminases in the blood is a diagnostic indicator.

Hormonal Im balance

Inactivation of insulin, thyroxin, aldosterone, sex hormones takes place in the

liver under physiological conditions. In parenchymatous hepatic insufficiency hot
monal imbalance develops in the form of relative excess o f hormones (p. 486). I )u<
to suppression of this liver function, these hormones, which might be destroyed in
the liver, are retained in the blood. It results in endocrinopathy of hepatic genesis
with corresponding clinical symptoms (hyperaldosteronism, hyperinsulinism, etc )

Acid-Base Im balance

Acid-base imbalance is manifested by accumulation of incompletely oxidi/eil

products (the majority of them are acids) and development of metabolic acidosis
Hyperaminoacidemia aggravates it.

H ater Im balance

Retention of water in the organism and its redistribution into tissues manilest
water imbalance. Hypoproteinemia and hypooncia underlie it as a result of impan
nient of the protein synthesis function of the liver. The situation is aggravated l>\
I' ll И S|M'iinl (S.vsli'inlc) 1>и11ю|>||>ч1о1ок.у

iclalivc hypcraldostcronisin iluc lo suppressed destruction of this hormone in lie

palic cellular pathology (results in increased sodium reabsorption).
Hepatic edema (p. 259) develops both in the form of systemic and specific cdc
mas (ascites) accumulation of water in the peritoneal cavity. Portal hypertension
(ui cirrhosis) adds a hydrodynamic component to edema development.

I ilam in Imbalance

Vitamin imbalance consists in the development of hypovitaminosis due to Ihe

following reasons:
• inhibited synthesis of vitamins and formation of their active forms (retinol from
carotin, cocn/yme Л from pantothenic acid), impaired formation of the active
lorm of vitamin I),;
• disorder of vitamin B (, and folic acid deposition;
• reduced absorption of fat-soluble vitamins (Л, D, E, K ) from the intestine in
deficit of bile and lipid absorption impairment.

Hemorrhage Syndrome

Hemorrhage syndrome (hypocoagulation) is an inclination to blood loss

spontaneous or due to an insignificant damage of vessels. The deficit of proco
agul.iut synthesis (fibrinogen, prothrombin, proaccelerin, proconvertin, Christmas
I.icloi, otlici plasma factors of coagulation, p. 325) underlies hemostasis disorder. It
is connected with a disorder of the liver function of protein synthesis. Нуросоаци
lation is aggravated by K-hypovitaniinosis connected with impaired bile secretion
uitii the intestine and fat absorption. Absorption of fat-soluble vitamins (including
vitamin K) from Ihe intestine is impaired in cholestatic hepatic insufficiency.
Al the same lime hypercoagulation is possible in case of suppressed synthesis
i»l components of the anticoagulation and fibrinolytic systems (antiplasmin, anti
thrombin, heparin).

Syndrome of Antitoxic Function Impairment

Under physiological conditions, Ihe products of amino acid oxidation in Ihe

intestine (indole, skatolc, phenol, putrcscines) and ammonium (which forms in
ihe course »»l dcsamination and decomposition in the intestine) arc inactivated in
I he liver. Chemical and infectious toxins, drugs are also rendered harmless in the
liver.
Mechanisms of deactivation are the following:
• ющиха/шп wiili paired conjugates glucuronic acid, glycocol, cysteine, sulfuric
acid;
■ initiation ui the system of microsomal oxidation (agranular cytoplasmic rcticu
Inin cytochrome I’ 450 is an important component);
■ synthesis ol urea from ammonia is llie main way of ammonia deactivation in Ihe
orgnniain;
' trdiiclioH is л mechanism ol nitrocompound neutralization;
 ( 'huptcr 2K. 1'ullutiiliysioloK.v of I Jvcr

• hydrolysis is a mechanism of cardiac glycoside neutralization;

• im 'thylation is a mechanism of purine derivative neutralization;
• acetylation.
Causes of antitoxic function impairment are the following: a) a decrease of the
in.in s of actively functioning hepatocytes, b) dystrophic changes of hepatocytes, c)
i nergy dcficit (hypoxia, oxidation disorder resulting in A T P deficit), d) deficit of
ImiIred conjugates, e) enzymopathy — lack or disorder of the activity of enzymes,
" Inch participate in metabolism (aigininosuccinate ligase, carbamoyl phosphate
synthetase, ornithine carbamoyltransferase, aigininosuccinate synthetase).
In parenchymatous hepatic insufficiency the following toxic products are ac-
t umulated in the blood:
• internal poisons from the intestine — phenol, indole, skatole;
• toxic metabolites: low molecular fatty acids (valeric, capronic), sulphur-contain­
ing acids (cystine, methionine);
• microorganism toxins (normally microbes are destroyed by Kupffer cells);
• exogenous chemical poisons;
• products of incomplete drug neutralization.
The outcome of progressive hepatic insufficiency is hepatic coma.

Hepatic Coma

Hepatic coma is the heaviest manifestation of parenchymatous hepatic insuf-

llciency.
Hepatic coma is CN S function impairment resulting from the disturbance of all
liinetions of the liver.
Hepatic coma is a syndrome caused by a toxic lesion of the central nervous
.vstcm with profound disorders of its functions.
Etiology. Causes of hepatic coma are those, which cause parenchymatous he-
pulic insufficiency (mentioned above), if their intensity exceeds protective possibili
in s of the liver.

Pathogenesis

Hepatic coma develops when homeostatic and barrier functions of the liver are
«It <leased essentially. In addition, the substances contained in damaged hepatocytes
cei into the blood and exert pathogenic influence on organs and tissues including
i In cells of the nervous system.
I hc pathogenesis of hepatic coma has a lot of physicochemical, chemical, bio
■hemieal and pathophysiological mechanisms. A simple enumeration of them al
lows understanding how difficult, almost impossible it is to provide medicamcntous
lorrcclion of this severe clinical condition
• Hypoglycemia is the main i.nise ol dentil alter total liver extirpation in ex
pcruncntal animals. I lie niiiinalt died in *> H hours because of acute hypoglycemia.
I lie duration ol life may be prolong'd lo Ml -III hours hy artificial support ol lhe
normal glucose level.
ru n > |M 't lul (N yM nutc) Ги11ш||||>м»1ок>

I lie level of unconjugated bilirubin in the blood is also increased. So, an increase
of direct and indirect bilirubin in the blood is detected.
Manifestations. Jaundice is one but not the gravest symptom of hepatocellular
insufficiency. Systemic intoxication connected with dismetabolism prevails. Acholic
and cholemic syndromes are also observed (but not so evident as in cholestatic he-
patic insufficiency and mechanical jaundice connected with it).
The laboratory signs of this jaundice include elevation of the level of noncon-
jngatcd bilirubin and appearance of direct (conjugated) bilirubin in the blood. The
amount of pigments in the feces decreases, the feces become hypocolored. Direct
bilirubin and urobilin appear in the urine, which determines hypercoloration of the
urine.

I<n/yiiiatic Hcpatic Jaundice

Etiology. The causes of this form of jaundice are endogenous. It is genetically

determined and congenital. Enzymopathy underlies it. Some genes are responsible
for transformations of bilirubin in hepatic cells (capture, conjugation and excre­
tion), and their mutation is possible.
Pathogenesis and Manifestations. Enzymatic hepatic jaundice is an isolated dis­
order of pigment metabolism and is not associated with impairment of other func­
tions of hcpatic cells.
rhe following pathogenetic varieties of intrahepatocytic bilirubin dismetabo-
lism arc possible.
• I )isordcrs of the active capture of indirect bilirubin (bilirubin-albumin complex)
by hepatocytes and its transport from the blood into hepatic cells. An increased
level of bilirubin in the blood is stipulated by the unconjugated one (Gilbert’s
syndrome). The amount of stercobilin in the feces and urine decreases, the feces
are hypocolored.
• I )isordcrs of bilirubin conjugation with glucuronic acid in hepatocytes. This va-
riety of jaundice develops as a result of genetic deficit of glucoronyltransferase
(ihc key enzyme of indirect bilirubin transformation into conjugated). A large
quantity о f free bilirubin appears in the blood. This form of bilirubin (as op­
posed to all other forms - bound to albumin, conjugated with glucuronic acid)
is very toxic and is able to penetrate through the blood-brain barrier. It results in
grave encephalopathy ( nuclear icterus). The content of bilirubin glucuronide in
bile is decreased, which results in a decreased amount of pigments in the feces
(Crigler Najjar syndrome).
• Disorders of bilirubin glucuronide excretion through the membrane of hepatic
cells in the bile capillaries. As a result, direct bilirubin comes not only into the
bile capillaries but also into the blood.

11KPATOVASCUI A lt INSUFFICIENCY

Vascular hepatic insufficiency results from impairment of Ihe heinodyiiaiuic Гипс-

Нон оГ Hie liver, hluud congestion in Ihe portal system of Mood circulation.
 Chapter 2H l’alliii|ili>stiiloK> of liv e r

K tio lo g y

I'he causes, which lead to liver cirrhosis, are the main reasons for vascular
hepatic insufficiency. Liver cirrhosis can ensue from acute and chronic hepatitis.
i hronic toxic damage, alcohol abuse, chronic circulatory hypoxia (venous conges
lion in the liver).
Pathogenesis

Chronic toxic damage of the liver and its chronic inflammation lead to the
development of sclerotic process in the parenchyma and stroma of the liver. As a
irsult, blood passage from the portal system through the liver is hampered. Conges
non develops in the portal system (portal arterial hypertension).
The compensatory reactions, directed at unloading of portal blood circulation,
develop. Portacaval (through the hemorrhoidal, esophageal, umbilical veins) and
i avacaval vascular shunts (anastamoses) form, but this unloading is achieved with
out the liver. The neutralization of toxic products of the digestive tract is limited.
The output of liquid part of the blood into the abdominal cavity occurs. Spe
( ilie edema, which is called ascites, develops.

Manifestations

The complex of clinical manifestations of hepatovascular insufficiency includes.

i»n ihe one hand, signs of systemic and portal blood circulation disorders (syndrome
nl portal hypertension), and on the other hand, all signs of parenchymatous and
i holestatic hepatic insufficiency (acholic and cholemic syndromes, dismetabolism,
i iundice, coma).
Pathology of the kidneys and spleen often accompanies hepatic insufficiency.
Hepatorenal syndrome develops as a result of a decrease of the circulating blood
volume and glomerular filtration rate. Hepatolienal syndrome is manifested by spleen
■nlargement (hypersplenism), phagocytosis activity, anemia, leukopenia, thrombo
i ytopenia.

Syndrome of Portal Hypertension

All manifestations of the impairment of the hemodynamic function of the liver

ire united in a complex, which is called syndrome o f portal hypertension.
Increased blood pressure in the portal system results in development of col
Literal blood circulation and opening of portacaval and cavacaval anastamoses. The
dilated subcutaneous veins are visible on the anterior abdominal wall during exami
nation of the patient (Ihe so-called caput medusae).
Varicose dilatation of Ihe veins of the esophagus and cardiac part of the stomach
develops. It is a place of possible hemorrhage (from the esophagus and stomach).
Ascites is the most representative pathophysiological and clinical manifestation
nl hepatovascular insufficiency Ii in a« i uniiilalion of water in Ihe abdominal cavity
and is a kind of local edema 11••palhoyoiiisis is Ihe following:
• increase of hydrodynamic hlood pn am- in the portal system (passage ol
liquid from Ihe plasma In m ■oidani г with Starling’s law);
 2 S|H'«liil (S v s lfitiU ) I*мIli«>|>liyч1«>l«>10

• decrease of oncotic blood pressure (also according to Starling’s law);

• Na ion retention (due to relative hyperaldosteronism).
I hc outcome of chronic portal hypertension is development of liver cirrhosis,
which is called portal cirrhosis (there is cirrhosis caused by other initial reasons
toxic and biliary).

t I t с
u b
I ix 5.5. Modelling of vascular fistulas:
a vessels before operation; b - direct fistula (Eck’s); с — reversed fistula (Eck—Pavlov’s)

lii addition, it should be mentioned that the disturbance of portal blood cir
illation reproduced under experimental conditions secondarily causes hepatocyte
i-sion l igure 55 represents experimental models.

1'oNthi‘putic (Shunt) Coma

I Ins variety of coma arises as a consequence of severe affection of the liver of

clcmtic (cirrhotic) character.
Hy portacaval anastamoses, which develop in the course of long-term persis
nil portal hypertension, some part of blood, which may be quite substantial, is
thrown- into the general circulation passing the liver. Toxic substances from the
ntcsiinc enter the blood. It causes intoxication of the organism with products of
letaholisin, which normally are inactivated in the liver.
I Ins variety of hepatic coma has some peculiarities. It can arise with moderate
c.oidci of bile production and bile excretion. Jaundice is absent at all or is poorly
laiuleslcd. lls development is closely connected with intestinal digestion and the
fin ol lood. Food rich in protein aggravates the state causing absorption of toxic
loducts of protein disintegration (ammonia, cadaverine, phenols, indole, skatoie,
utiesi h ic k ) coming into systemic blood circulation.

JA U N D IC E

laundicc was mentioned above as a result of hepatic excretory function disor

•I Ii is an expressive clinical symptom, which attracts attention first of all in (lie
uirse ol clinical examination of a palient
 ( iiu p ii'i 2K. Pathophysiology of liver

Jaundice is yellow coloration of the skin, mucous membranes and scleras by bile
pigments deposited in (hem as a result of hyperbilirubinemia.
Although bile pigments (bilirubin, urobilin, stercobilin) are not so toxic as bile
acids, it is the symptom of jaundice that attracts physician’s attention to hepatic
pathology. At the same time, jaundice is not always connected with liver patholo­
gy. Therefore, analysis of jaundice is of great diagnostic significance in clinical
practice.
There are three forms of jaundice - mechanical (posthepatic), parenchymatous
(hepatic), and hemolytic (suprahepatic). Two of them have been described above.
I'he third form is given below.

HEMOLYTIC JAUNDICE

Suprahepatic jaundice is not connected with impairment of liver function,

nevertheless, it is connected with accumulation of bilirubin in the blood. It is
hemolytic jaundice.
Hemolytic jaundice is yellow coloration of the skin, mucous membranes and
scleras by unconjugated bilirubin deposited in them as a result of increased bilirubin
production from hemoglobin due to enhanced erythrocyte destruction.

Etiology

The etiological factors are hemolysins, which cause erythrocyte destruction

(hemolysis). They are of exogenous and endogenous origin and have been described
in detail in chapter 20 «Anemia*. It has been noted that jaundice is an obvious sign
of hemolytic anemia (p. 280).

Pathogenesis

Indirect bilirubin is a bile pigment, which is present in the blood under normal
conditions. Its level depends on the intensity of erythrocyte destruction. It is the
hilirubin-albumin complex that does not filter through the membrane of the renal
i lomeruli and is absent in the urine, even if its level in the blood exceeds the norm.
Excessive destruction of erythrocytes in the spleen results in excessive forma­
tion of bilirubin-albumin complexes from hemoglobin and their entering the blood.
II functioning of the liver is not impaired, indirect bilirubin is converted in the liver
into direct bilirubin, which then enters the bile and intestine. Increased quantity of
tcrcobilin and urobilin is excreted in the feces and urine.
If increased destruction of erythrocytes exceeds the ability of hepatic cells to
i apture indirect bilirubin and transform it into direct bilirubin, then an excess of
iiulirect bilirubin in the blood conditions coloration of the skin and mucous mem­
branes. Indirect bilirubin docs not have toxic properties.
It is a typical variety ol hemolytic jaundice.
In case ol albumin deficit in the blood (in starvation and other pathological
conditions), transport ol bilniihui lioni the spleen to the liver is disturbed and the
I’.iil ! (S yslcm k ) 1‘alliophysioloK.v

so called free bilirubin appears in the blood, which is not connected neither witli
albumin nor glucuronic acid. This form of bilirubin easily penetrates through the
blood brain barrier. It is very toxic for nerve cells and causes the so-called nuclear
u terus I his variety of suprahepatic jaundice develops in hemolytic jaundice of new­
borns against the background of a decreased level of albumins in the blood.

Manifestations

In the clinical picture of typical hemolytic jaundice the signs of hepatic insuffi­
ciency arc absent. Cholemic syndrome is absent (bile acids do not enter the blood).
Acholic syndrome is absent, and bile acids enter the intestine. Digestion is not dis­
united. Stercobilin (which is not toxic) forms excessively and intensively colors the
feces and urine. Biochemical examination of the blood shows an increased content
ol indirect bilirubin; direct bilirubin is absent. It is a typical variety of hemolytic
laundice. Such a patient is called «more yellow than ill». (However, it should be
taken into account that such a patient suffers from anemia.)
Л variant of hemolytic jaundice of newborns — nuclear icterus — was described
above.
I )ilferent types of jaundice may combine.
II hemolytic jaundice is associated with hepatocyte damage or biliary tract ob-
struction, clinical manifestations would be more complete. Parenchymatous jaun­
dice may join the hemolytic one. Although the liver possesses potent bilirubin
conjugation ability, hepatocellular insufficiency may occur in hemolytic anemia be­
cause many hemolytic poisons damage hepatocytes simultaneously with hemolysis.
Besides, hypoxia, which develops due to hemolytic anemia, may limit the activity
ol hepatocyte enzymes participating in bilirubin conjugation.
Mechanical jaundice can be combined with the hemolytic one as a result of
occlusion of the biliary tracts by bile thrombi and stones of bilirubin, cholesterol
and calcium.

Questions for Self-Control

1 Name the functions of the liver.

2 ( five a classification of hepatic insufficiency.
i What are the endogenous causes of hepatic insufficiency?
I I >o compensatory reactions develop in hepatic diseases?
S Wliat is acholic syndrome — its definition, causes, pathogenesis, manifesta­
tions?
<> What is cholemic syndrome — its definition, causes, pathogenesis, manifesta­
tions?
7 What are the causes of hepatic coma?
N I xplain the pathogenesis of hepatic coma.
4 What are the causes of portal hypertension?
Id Wliat are the manifestations of portal hypertension?
 t'h ap lcr .’К Г*П|)1|)||>ч1о1<1к> of liv e r

II In what way is the antitoxic function of the liver impaired in hepatic insuffi­
ciency?
12. What is the pathogenesis of hemorrhage syndrome in hepatic insufficiency?
I V Name the types of jaundice and their causes.
14. In what way is it possible to distinguish jaundices from each other with the aid
of laboratory tests?

Tests and Tasks for Self-Control

(give correct answers and find mistakes in the statements)

I Give the characteristics of the causes and mechanisms of hepatic antitoxic

function disorder.
1. Decrease of the mass of hepatocytes.
2. Hypoxia.
3. Inhibition of mitochondrial oxidation with the aid of the cytochrome
P-450.
4. Disorders of microsomal oxidation.
5. Disorders of glucuronic acid formation from fatty acids.
6. Formation of portacaval anastamoses when the blood enters systemic cir
culation passing the liver.
7. Decrease of ammonia synthesis from urea.
8. Decrease of substance secretion in bile.
9. Decrease of conjugation and paired conjugate formation.

2. Give the characteristics of cholemic syndrome (cholemia).

Etiology and pathogenesis:
1. It results from biliary duct occlusion by different exogenous and endo­
genous factors.
2. It is a group of symptoms connected with non-entrance of bile into the
intestine.
3. It is entry into the blood of the most toxic component of bile - biliru­
bin.
4. Due to pressure decrease in the biliary duct bile moves in the reverse direc­
tion — into the blood capillaries and then into systemic blood circulation.
It is a group o f symptoms with such pathogenesis:
5. Disturbance of the functional state of the nervous system.
6. Inhibition of vagal influence.
7. Vagal irritation by bile acids (results in disregulation of arterial blood pres
sure, heart activity and digestion).
8. Irritation of cutaneous nervous receptors (caused by bilirubin entry into
the skin).
( lin ical manifestations:
9. Asthenia, disiiuhaiu < nl lln daily rhythm of sleep and wakefulness, head
ache, excitation, depression iMllpabllltv, decrease of tendon reflexes due
to cerchrotoxk clli«I
Г,III 2 S | n <ml (SyslcniU ) Ги11|о||||>ч||||ик)

10. Tachycardia (due to vagotonia).

11. Erythrocytosis due to hemolysis.
12. Itch.
13. Arterial hypertension (due to vagotonia).

3. Give the characteristics of biochemical disorders in hepatic coma.

1. Hyperglycemia.
2. Ammonia accumulation in the blood.
3. Entry of toxic products from the intestine into the blood as a result uf
hepatic antitoxic function disorder.
4. Disorder of the neutralization of cadaverine and phenol, which are pro*
duced in the liver and enter the blood.
5. Metabolic alkalosis due to accumulation of non-oxidized metabolites in
the blood.
6. Decompensated metabolic acidosis.
7. Inhibition of the Krebs cycle due to deficit of glucuronic acid, which i
part of the Krebs cycle but is used for ammonium neutralization.
8. Accumulation in the blood of ketone bodies, which are formed fromi
acetyl-CoA due to Krebs cycle inhibition.
9. Disorder of electrolyte balance due to secondary hypoaldosteronism,
which is caused by inhibition of aldosterone destruction in the liver.
10. Loss of sodium.
11. Retention of potassium in cells due to acidosis.

4. A patient complaining of yellowing of the scleras and skin, darkening of the urine
and feces consulted a doctor. Analysis of blood: erythrocytes — 2.5 • lO'-’/l,
hemoglobin —80 g/1, color index —0.9, a lot of reticulocytes. What form ol
jaundice has developed?
A. Mechanical.
B. Parenchymatous.
C. Nuclear.
D. Hemolytic.
E. Shunt.

5. In a 57-year-old woman an attack of hepatic colic was followed by jaundice,]

Ultrasound examination revealed occlusion of the common bile duct with 4
stone. An increased level of what substance in the blood testifies to mechanioil
jaundice?
A. Cholesterole.
B. Bilivcrdin.
E. Stercobilin.
I). Indirect bilirubin.
C. Direct bilirubin.
 Chapter 2H ГяПш рЬуоЫоуу of IJv c r

». Л newborn has hemolytic illness I ncepluilopathy has developed. An increased

level of what substance in the hlood has caused C N S lesion?
A. Free bilirubin.
И Hilirubin-albumin complex.
( Itilirubin-glucuronide complex.
I > Vcrdohcmoglobin.
I Bile acids.

In I hepatocirrhosis patient ascites, splenomegaly, dilatation of the subcutane­

ous veins of the anterior abdominal wall, and peripheral edemas are found.
What pathological syndrome has developed?
A. Hepatocerebral.
II Arterial hypertension.
( Hcpatocardiac.
I). Hepatorenal.
I Portal hypertension.

N \ IS year-old patient developed immune hemolytic anemia. The level of what

nlisiance increases in the blood serum most of all?
A Stercobilirubin.
It Stercobilinogen.
( Direct bilirubin.
I). Indirect bilirubin.
I Protoporphyrin.

'» \ VS year-old woman complains of tiredness, irritability, sleeplessness at night

.uul sleepiness during daytime, skin itch. Pulse — 58, arterial pressure
I IO/(>5 mmHg. The excrements are colorless and contain a lot of fat. The ini
nil diagnosis is cholelithiasis with occlusion of the common bile duct with a
lone. What is the cause of nervous symptoms?
A I ipid absorption disorder.
H Hyperbilirubinemia.
( Hypercholesterinemia.
I ) I)isorder of fat-soluble vitamin absorption.
I Cholcmia.

In \ woman with chronic hepatitis complains of sensitivity to barbiturates, which

'.lie used to tolerate without signs of intoxication. What function of the liver is
tliimHged?
A I xcrelory.
It Antitoxic.
< Hemodynamic.
I* Hemopoietic.
I Digestive.
I'nrt .’ S|H4'lnl (S yslcm k )

11 Ап ultrasound examination of a patient allowed establishing an initial diagno

sis: cancer of the liver. What protein is found in the blood in this case?
A. y-Cilobulin.
Ii. Properdin.
C. Paraprotein.
I). C-reactive protein.
E. a-Fetoprotein.

12 A 58-year-old patient had hepatitis B. Later he developed signs of hepatocir

rhosis with ascites and edema of the inferior extremities. What changes ol
blood composition led to edema development?
A. Mypoalbuminemia.
B. Hypogammaglobulinemia.
C. Hypocholesterinemia.
I). Hypokalemia.
E. Hypoglycemia.

13. In a patient, poisoning with mushrooms was followed by the development ol

yellow coloration of the skin and scleras, the urine became dark. What pigment
colors the urine of the patient with hemolytic jaundice?
A. Free bilirubin.
B. Direct bilirubin.
C. Indirect bilirubin.
I). Stercobilin.
E. Hemoglobin.

14 A 9-year-old child is ill with viral hepatitis. Jaundice has developed. The fece»
are decolorated. In some years after recovery consequences of viral damage ol
the hepatic parenchyma are observed. Give the characteristics of parenchyma­
tous (hepatic) jaundice.
1. Develops in viral hepatitis.
2. Cholemic syndrome develops.
3. Acholic syndrome develops.
4. Hypercoagulation develops.
5. Hypercoloration of the feces is observed.
Such substances are present in the blood:
(>. Bile components.
7. Direct bilinibin.
8. Bile acids.
Such substances are present in the urine:
9. Direct bilirubin.
10 Indirect bilirubin.
< hapter 29
ГЛI HOPHYSIOLOGY Ol KIDNKYS

I lie kidney is a compound parenchymatous organ with numerous functions.

11 ■<insists of nephrons (glomeruli, tubules) and interstitium. Each part has its own
. lions. There are diuretic and non-diuretic functions.
I xcrelory function is performed by nephrons. It is urine formation and elimi
ii и ion I he kidneys deal with the constancy of the volume of water and lluid (iso
in/.w in ), electrolytes (isoionia), osmotic concentration (isotonia), acid-base balance
11 u livilria). The kidneys excrete the end products of nitrogen metabolism (urea,
.......к id, ammonia, creatinine) and amino acids. Under pathological conditions
ilu kidneys excrete foreign and toxic substances.
Incri'tory function of the kidneys consists in production of the substances,
Int h are increted directly into the blood, but not into the urine. They are renin,
I'in'.taglandins, and erythropoietin. The juxtaglomerular apparatus can be consid
m l a small endocrine organ.
Ucmodynamic function is participation of the kidneys in the regulation of arte
i Ml Mood pressure and circulating blood volume.
Hemopoietic (erythropoietic) function of the kidneys consists in the formation
"I the stimulator (erythropoietin) and supposed inhibitor of erythropoiesis.
Hemostatic function is influence on blood coagulation, anticoagulation and
Itlu uiolysis.
I hree physiological processes are accomplished in the kidney parenchyma to
im in the urine: filtration, reabsorption and secretion.
nitration takes place in the glomeruli, which are the vascular-epithelial organs
■I' lulled for blood plasma ultrafiltration. It depends on glomerular filtration pressure
.....(elation between hydrostatic and oncotic blood pressure, as well as intracap
nl.li glomerular pressure). For glomerular filtration estimation the so-called clear
.in, . index is used. It shows the amount of blood (in milliliters), which is completely
■I in (I from exogenous and endogenous substances while passing through the kul
i" \ per minute. Clearance is calculated by the formula C= UV/P, where С — clear
.пи i ol the investigated substance (ml/min), U — concentration of the investigated
ui' i.mcc in the urine (mg/ml), V — diuresis (ml/min), P — concentration of the
in . .tigatcd substance in the plasma (mg/ml). For such determination, exogenous
i|i"lv.accharide inulin) and endogenous (creatinine) substances, which are nitrated
in (In glomeruli, not reabsorbed and secreted in the tubules, are used.
I he renal filter (having a certain number, area and diameter of pores) is located
In ilu glomeruli and consists of capillary endothelial cells, basement membrane and
I'udocytcs. Chemically, the glomerular basement membrane is a complex glycopro
i' in consisting o f collagen like glycopcplidcs and highly acidic sialoglycoprotcins
i ^ In* h cover the epithelium and pievent filtration ol plasma proteins). The primary
tiiine is a noil protein filtrate ot tin blood plasma In the primary urine there arc
I’.iil 2 S|M4'lnl (System ic) I*uIIio|>IiysI»Iok>

i h ) cellular elements of the blood. The quantity of the primary urine is 120—1X0 11

daily.
Renal filtration is very sensitive to blood circulation disorders. A special fea-1
ture of renal blood circulation lies in the fact that it is the place where the double I
capillary network is found, namely, in the region of glomeruli, where filtration is
accomplished, and also in the region of tubules, where reabsoption and secretion I
are achieved.
Reuhsorption of the primary urine components (water, glucose, amino acids, I
phosphates, bicarbonatcs, ions) into the blood takes place in the tubules. Enzymes, I
hormones (aldosterone, vasopressin) and energy (produced by oxidative phospho- I
ryhit ion) are necessary for transmembrane transport and reabsorption. If a little I
amount of low-molecular-weight (to 40,000) plasma proteins is filtrated, they may I
be reabsorbed in the tubules.
Secretion of some products (acidogenesis, ammoniogenesis, see schemes 17 ,1
IS, 19 on pp. 245, 246) occurs in the tubules. Many xenobiotics, toxic products and I
medicines get into the urine in this part of the kidneys.
Hormones provide regulation of the processes taking place in the kidneys. Al i
dost с rone of the adrenal cortex ensures sodium reabsorption, H^and K +secretion; I
vasopressin (antidiuretic hormone) provides water reabsorption.
I he role of the kidneys in the pathogenesis of different pathological processes I
has already been mentioned in the previous chapters — in the development of ’
arterial hypertension, anemia, edema, acidosis (see corresponding chapters for
details).
On the basis of the enumerated renal functions, we can offer the following I
definition of renal insufficiency.
Renal insufficiency is a group of syndromes of homeostasis disorder caused by
renal function failure.

CLASSIFICATION

Etiological classification divides renal pathology into acquired and hereditary as

well as infectious and noninfectious. In clinical practice it is subdivided into trau
m alic, nephrotoxic, metabolic, immunological, and vascular (ischem ic).
Topographic classification divides it into prerenal, renal and postrenal. This clas
sillcation is built on the assumption that the initial reason for kidney pathology is
locali/cd. Division into glom erular, tubular and tubulointerstitial types is based on
ihe morphological principle.
Pathogenetic classification divides renal pathology into prim ary (pathology be
gins in the kidney) and secondary (the kidney is involved in systemic disordcs of the |
organism or as a complication of another disease) as well as total and p artial (all oi
single renal functions are impaired).The latter in its turn is subdivided into filtrative,
rvahsorbtlve, secretory and incretory.
( lin ical classification divides the pathology into acute and chronic.
 ( haptcr 24. I ‘mII io |i Ii >s I<i I<>k \ of Kiilnrys

I I I O I ( МЛ

I liological factors, which cause renal pathology, arc divided into exogenous and
•iiJi h’i'iious, physical, chem ical and biological as well as acquired and hereditary.
/ \ogenous factors are the following:
• Im um atic: mechanical trauma, massive crushing injury, ionizing radiation, cold,
burns.
• /.'W, different chemical nephritogenic poisons. These are salts of heavy metals
(mt icury, lead, bismuth, chromium, cadmium), medicine abuse (of antibacterial
uul hormonal drugs — sulfanilamides, antibiotics, neomycin, penicillin, phcna
i din, corticosteroids, etc.), mushroom, snake poison, pesticides.
■ In/ictious: bacterial, viral (streptococcal, staphylococcal, pneumococcal, menin
I'ocnccal, colon bacillus, agents of syphilis, tuberculosis, malaria, hepatitis Hi,
parasitic. Among them hemolytic streptococcus takes a special place — it is con
uli icd to be especially nephritogenic. Fungi also may be a cause.
• Immune: foreign proteins initiating renal disorder of immune nature (complica
i иins after immune serum use and vaccination); mismatched hemotransfusion
I iidogenous factors are the following:
< Im um atic: occlusion, external compression of the urinary tracts, mechanical
пишу by stones located in them.
• /owe: products of dismetabolism in D M , amyloidosis, hepatic insufficiency,
1» nlonitis, pathological pregnancy, gout.
■ Vascular in systemic (shock, arterial hypertension) and local (ischemia, throm-
i " is, embolism, D IC syndrome) disorders.
• Immune factors are of special significance. Denaturated nucleoproteins, thyro-
11'iluilin, proteins of tumor origin may serve as endogenous antigens. The kidneys
т .is be secondarily damaged in diffuse lesions of the connective tissue (rlieu
inntoid arthritis, systemic lupus erythematosis, nodular periarteritis, hemorrhagic
' .im ulitis, etc.).
• I >iи initiative disturbance of the hormonal (aldosterone, vasopressin) control of
n ii.il functions.
• in nclic causes are genetically conditioned defects of metabolism (lipoid nephro
I'.), enzymopathy, congenital morphological defects.
In addition to the mentioned classification of etiological factors, the follow
нм illusion of initial causes into prerenal, renal and postrenal is useful for clinical
pfNCtlcC.
Prerenal factors arc those, which secondarily involve the kidneys into the fol
Itmhlg pathology:
• '.\ .icmic disorders of blood circulation resulting in a decrease of systemic blood
lиi '.sure and circulating blood volume (blood loss, shock, collapsc, acute cardiac
in .nllicicncy).
' I '<hydratation of the organism and henioconcentration (uncontrollable vomiting,
piolusc diarrhea).
• Iu< reuse of systemic blood pressure (.nlcii.il hypertension).
> \i ulr systemic intoxication (in mnv.lvr * in .li nl tissues including burns).
> M.r.sive hemolysis (mismatched ln'tnotiiiip.hiNion)
Pilrt S|M4'I hI (System ic) I’ullHipliysioloKy

Renal factors яте those, which directly influence the kidneys — toxic (intoxica
lion with ncphritogcnic poisons), bacterial, viral, immune, vascular (local disorders
ol Mood supply).
Postrenal factors are connected with obstruction of the urinary tracts (calculi,
tumors) and urine retention.
Conditions, which aggravate the action of etiological factors and predispose
10 renal pathology, are the following: a) accessibility of the kidneys as organs of
excretion to damaging factors; b) infection entry into the kidneys not only by the
hematogenic route but also by spreading upwards from the urinary tract.

PATHOGENESIS

All typical pathologic processes occur in the kidneys — inflammation (ordi

nary and presumably allergic), hypoxia (presumably local of vascular type), typical
disorders of peripheral blood circulation (thrombosis, embolism), tumor, typical
disorders of metabolism and hemostasis, etc.
I here are some peculiarities in the kidneys, which predispose to their patholo
gy: a) peculiarities of antigen composition of the kidneys, which contributes to
autoalleigy; b) special features of blood circulation in the kidneys - high arterial
blood pressure in the renal artery and a double vascular network in the nephron.

Kolc of Allergy

Allergy is a frequently observed pathologic process, which develops in the kid

iievs. Antibodies against the renal basement membrane are revealed in the blood ol
many patients with kidney pathology. The following mechanisms underlie predis
position of the kidneys to allergic diseases.
• Antigenic similarity between a-hemolytic streptococcus and the basement mem
brane of the renal filter. That is why this infection may initiate (in case of im
munopathy) an autoimmune damage of the renal filter.
• Antigenic similarity between glycoproteins of the renal filter and connective lis
sue I hat is why some diseases of the kidneys are often associated with diflfusc
impairment of the connective tissue.
• Immune complexes may be nonspecifically adsorbed on the renal filter and dam
age it causing an immune inflammation.
Many exogenous and endogenous factors may serve as antigens: bacterial, vi
nil. parasitic, medicamcntous, food, D N A, denaturated nucleoproteins, proteins ol
11hi 101 origin and thyroglobulin. Antibodies produced in response to these antigen-,
are mostly of the IgM class. The kidneys very often get involved into immune re
spouse.

Hole of Genetic Factors

A large quantity of cn/ymes and othci pmtcins participate in renal functions

11 means that genetic problems develop qulle frequently. I ii/ymopathy is one of
 ( hapter l*ulh»pliysiolo|tv нГ kidneys

t!•<in ( icnctic pathology «»• lenal receptors (lo hormones) is also possible. C'ongcni
nl morphological dcfomiulions in the kidneys and urinary tract may be observed.

MhU* of Medicines

11 is widely known that medicines can be factors of kidney damage. There are
■vaal reasons for this.
It is the kidneys that excrete medicines and thus can be damaged by them.
I he damaged tissue of the renal filter can become autoantigenic.
Medicines can serve as haptenes and be converted into complex antigens to
i ■(her with renal filter proteins.
When medicines serve as exogenous antigens, the antibodies, which are pro
im i d in response, are mostly of the IgM class.

G L O M E R U LA R IN S U F F IC IE N C Y

( ilomerular insufficiency is connected with filtration disorders in the glomeruli

uni eventuates from:
• changes of glomerular filtration pressure (the ratio between the blood, intra
capsular glomerular pressure and oncotic blood pressure);
• the amount of functionally active nephrons;
• damage of the renal filter (glomerular capillaries and basement membrane).
I he glomeruli may be injured by a variety of factors in the first place (primari
tv) and in the course of a number of systemic diseases (secondarily). Damage of
ili« renal filter is associated with inflammation of the glomeruli, more often of al
l<n ii origin. Damage of the glomeruli may be connected with deposition of amy
I-ч. I, fibrinogen, glyco- and lipoproteins with activation of humoral and cellular
.... ban isms of the inflammatory reaction in the capillary basement membrane. As
i и nil, the structural integrity of the basement membrane is lost, its composition,
I*11\ и al and chemical properties are changed, especially its permeability. Il means
ili.it the renal filter begins to let through itself the substances that must not pass
iliiough it, namely, proteins and cellular elements of the blood. In such cases, these
nb-,tances and cells are detected in the composition of the urine. At the same time,
th< tiller ceases to filter the substances, which must be filtered, namely, nitrogenous
■i i< urea, uric acid, amino acids, electrolytes. In such cases, these substances are
и >umulated in the blood in high concentration.

GLO M KRUIAR FILTRATION INCREASE

I’renenal causes of increased filtration are the following:

• increase of systemic blood pressure (arterial hypertension);
• increase of blood volume (hypervolemia);
• decrease of oncotic blood pressure (hvpoproteincmia).
Keual causes have significance in a<ulr alliiyu inllammation (acute glomeru
lonrphrilis), when permeability ol tin m im I lllln Is m utely increased
Pitil 1 Special (System ic) l‘ullio|ilivsi(>loK>

Clinical Manifestations

I lie following clinical signs manifest glomerular fitration disorders associated

with increased permeability of the glomerular membrane of the renal filter.

( ilom crular Proteinuria

Proteinuria is the presence of protein in the urine. It is the main sign of in

creased permeability of the glomeruli. In proteinuria plasma proteins are excreted
ш the urine due to physical and chemical changes in the basement membrane,
is characterized by low content of plasma albumines and mostly low-moleculai
weight proteins (to 40,000).

Hem aturia

Hematuria is the presence of erythrocytes in the urine. An injury of the glome

rular membrane may be accompanied by leakage of erythrocytes into the glomeru
I.n lumen and their presence in the urine as «shadows» (lixiviated erythrocytes)
I cukocyturia is also possible.

GLOMERULAR FILTRATION DECREASE

(ilomcrular filtration decrease may have renal and extrarenal mechanisms.

Prerenal causes of filtration decrease take place in the following cases.
Decrease of hydrostatic blood pressure on the glomerular capillary walls, e.
arterial blood pressure (fig. 56). It is connected with systemic blood circulation
insufficiency such as (a) arterial blood pressure decrease to 80 mmHg due to
shock of different genesis, collapse, acute cardiac failure, (b) decrease of tli
circulating blood volume (blood loss). At the same time it must be mentioned
that the kidneys have their own regulatory mechanisms of blood pressure in tli
glomerular capillaries (systemic blood pressure may vary within 70—200 mmll
but in the glomerular capillaries it is
constant — 45 mmHg). RPF, ml/min GFR, ml/nun
Novation of oncotic blood pressure
above 25 10 mmHg due to hemocon-
cc nt rat ion caused by dchydratation of
the organism.
Occlusion of the renal artery (com­
pression, spasm, thrombosis).
Renal causes are the following:
Chronic inflammation alfccting the
Arterial hlixxl pressure, кPa
glomerular membrane (chronic glome­
rulonephritis). It leads to thickening ol I IK 56- Dependence of glomerular liltni
the glomerular membrane and changc linn rate ((il K) and renal plasma tin
(RPP) on arterial blood pressure
 ( lu p in 24. I'allHiphyslitluKy of Kidneys

nl iis physical and chemical properties, decrease of the number, area and dia
meter of (he pores.
• I >vslrophy of the glomerular membrane due to disturbances of blood supply ol
ilu' kidneys, hypoxia, toxic influences.
■ l" duction of the number of functioning nephrons and of the total filtrational
in lace (chronic glomerulonephritis, diabetic nephropathy).
• Im ivase of pressure in the capsule of the glomeruli above 25 mmHg, which is
observed in delayed reabsorption of fluid in the proximal part of the tubules, in
<h elusion of the tubule lumen by cylinders, necrotic masses.
Pastrenal causes are associated with ureter obstruction by calculi or tumor
11и,, i.iic hypertrophy and adenoma).

» Unit al Manifestations

I he following clinical signs manifest glomerular filtration impairment.

I Hiчипа and Anuria

Ii is diuresis decrease. Oliguria is a decrease and anuria — cessation of urine

(•induction.

hmemia

Л/otcmia is an increased content in the blood of nitrous substances (urea, uric

<i id. creatine, creatinine, and ammonia) as well as amino acids (see p. 242). The
i Im' io of azotemia (residual nitrogen level) may be different — from slightly ex-
H <dmy the upper limit of the normal quantity of residual nitrogen (35.7 mmol/1)
In I l.’.X 357 mmol/1. The clearance of endogenic creatitine decreases (110
i и ml/min under normal conditions). Dysfunction of the glomeruli is manifested
I» i delay of excretion not only of nitrous metabolism products, but also accumula
п. и m the blood of toxic products from the intestine (indican, phenol, indole and
i ii. di ). ЛИ of them are very toxic and cause poisoning, being a reason for uremia
ih w Inpment (see below).

Hiu irolyte Im balance

As a result of excretory dysfunction of the glomeruli there is decreased excrc

.........I phosphates, sulfates and their retention in the blood (,hyperphosphatemia.
H\i <i r\ii(/iilem ia). These anions push hydrocarbonates out into the extracellular fluid
ill' ii.i'iiug the alkaline reserve of the blood. I xcret ion of magnesium and potas
•lum is also delayed with their accumulation in the blood (hyperkalem ia, hypermag
hi ,in i,i) As to sodium and chlorine, then excretion is also delayed Mil they are
и <mnulaled not in the blood Mil in the i elK wiih a decrease of their concentration
in iIn blood plasma (hyponatremia and /»»•/*«»i hlotrm la) Il leads to edema develop
Itlrill
Г .ill .’ S | m -c i m I ( S y s t e m i c ) 1*й 1 1 |» ||Н > л 1о 1 » к У

( ilom crular (Azotcm ic) Acidosis

As a result of decreased filtration in the glomeruli there is a delay of excretion

nl organic acids (amino acids) and their retention in the blood — hyperacidemiu
logethcr with phosphates and sulfates they decrease the alkaline reserve of tin
blood (up to IX-13.5 mmol/1, and 25—31 mmol/1 is normal) aggrcvating acidosis
I .iter decompensated acidosis may develop.

T U B U LA R IN S U F F IC IE N C Y

Tubular insufficiency is a disorder of tubular functions resulting in impairment

ol homeostasis in the organism or selective derangement of partial functions of tli«
tubules (tubular syndrome). Acute tubular necrosis is a major cause of acute renal
failure.
Etiology

As to initial causes, tubular insufficiency may be prim ary and secondary, extra
renal and renal.
Direct toxic or infectious actions on the tubules as well as secondary lesion of
them in systemic dismetabolism and other systemic disorders may cause structni.il
changes in the tubules of inflammatory or dystrophic nature. Some hormonal dis
orders in the organism (aldosterone and vasopressin secretion in both directions
increase and decrease) result in dysregulatory tubular disorders.

Pathogenesis

As to pathogenesis, tubular insufficiency may be dysregulatory (functional) iiih I

organic. The tubules are mostly prone to ischemic and toxic damages (while glome
i i i I i inflammation, as it has been explained above, is immunologically mediated)
I Inis, as to mechanisms, tubular insufficiency may be nephrotoxic, infectious
metabolic, vascular (ischemic), immunological, dysregulatory or in the form <•!
rellux nephropathy (in acute and chronic pyelonephritis). There are two main pro
cesses in the tubules — rcabsoption and secretion, which may be disturbed sep.i
lately or together.

t ubular Reuhsorption Disorders

In tubule pathology reverse rcabsorption of the following substances is dr

tiubed glucose, bicarbonates, sodium, potassium, calcium, magnesium, wain,
amino acids. As a result, these substances are present in the final urine or accuiuu
late in the blood.
Rcabsorption is impaired (suppressed or activated) in hormonal disorders. (>lu
cosuria develops in DM (hyperglycemia exceeds the renal threshold li»i glucos< |
Due to osmotic properties of glucose polyuria develops.
 ( haptcr 24 I’ulliophysmloKy »f Kidneys

Increased secretion ol aldosteione icsnlts in increased rcabsorption of bicar

• . into the blood ( tubular alkalosis), excretion of potassium in the urine (wich
IHninolcs tubular epithelium dystrophy) and lack of potassium in the blood ( hy-
rokuh-mla). In aldosterone deficiency, sodium (bicarbonates) and potassium re
mption is disturbed and they are excreted in the urine. This results in tubular
■4itlosis and retention of potassium in the blood (hyperkalem ia).
Deficit of the antidiuretic hormone of the hypophysis (vasopressin) results in
i<> >ol water in the urine (polyuria , which is a symptom of diabetes insipidus, when
....ic than 10 I of water is excreted in the urine) and concomitant hypostenuria.
I ubular disorders mentioned above belong to dysregulatory ones and may be
|initial.
As to organic tubulopathy, it is connected with inflammatory, dystrophic, atro
t in. and necrotic changes of the tubular epithelium, which loses the ability to re
tli orb as well as to concentrate and dilute the urine ( isosthenuria with the density
"i mine making 1010).
Disorders of the rcabsorption of phosphates and Ca ions result in their loss hi
(In urine (phosphaturia, calciu ria) and decreased concentration in the blood (phos
rh,itcm ia, hypocalciem ia) eventuating in demineralization of the bones and rachitis
•It wlopment in children.
As to reverse reabsorption of amino acids, enzyme transport systems are needed
it и ilns. In genetically determined deficit (enzymopathy) of such systems corre-
i"Hilling amino acids are detected in the final urine (am inoaciduria).
tubular proteinuria develops as a result of impaired reabsorption of glomerular
lilt Lite protein as well as of accumulation in the tubules of their own destroyed
•t II In severe forms of tubular apparatus damage and grave dystrophic changes of
1*11«iil.tr cells, proteins of high molecular weight (more than 40,000) are present in
ii" urine. It is accompanied with the presence in the urine of hyaline, epithelial
im! pianular cylinders (cylin d ru ria). The latter are sort of impressions of the renal
mimic lumen, which consist of proteins coagulated in the tubules and exfoliated
iitiiiilar epithelium.
Organic tubulopathy is often combined due to anatomical proximity of the
iми lures and certain biochemical unity (eneigy dependence) of the mechanisms,
-im h determine the processes of reabsorption of different substances.

I tilnilur Secretion Disorders

Mv tubular secretion the kidneys excrete hydrogen (acidogenesis) and ammoni

uni (aiumoniogcncsis). Disorders of these processes result in acid-base imbalance
•«I n ’tory tubular acidosis (p. 24X).
Secretion of uric acid leads to its accumulation in the blood (hyperuricem ia)
••tut gout development.
I u retion of medicines from Ihe oiganisiu is also provided by tubular secrction.
Пн pharmacodynamics of drugs is iinpalicd in lubnlar insufficiency and toxic side
i lit i Is are possible.
ГиП 1 S|M4'lnl (System ic) ruthophysioloKy

Tuliiilointerstitial syndrome is a combination of tubular epithelium atrophia and

stromal sclerosis development resulting in disorders of the main tubular functions

D ISO R D E R S O F IN C R ET O R Y (N O N - D IU R ET IC ) R EN A L FU N C T IO N S

I'he ineretory renal function provides the non-diuretic one. It is connected

with production of renin and prostaglandins (which deal with systemic blood pres
sure regulaion), erythropoietin and supposed inhibitor of erythropoiesis. The role
ol the kidneys in systemic pathology was mentioned in previous chapters while
discussing the pathogenesis of hypertension and anemia.
Ilyperproduction of renin occurs in systemic (blood loss, other cases of hypo­
volemia) and local (inflammation of the kidneys) disorders of blood circulation in
iIns organ, in the latter case it results in arterial hypertension and (by stimulation
ol aldosterone production) systemic edema development.
Incrction of renin gets suppressed in nephrosclerosis (substitution of the renal
tissues by the connective one). At the same time production of renal prostaglandin
is suppressed as well. It results in the development of a very severe form of arterial
hypertension (renal prostaglandins are very potent vasodilatators).
I Erythropoietin deficit results in anemia.

M A N IFEST A T IO N S O F R EN A L D IS O R D E R S

URINARY SYNDROME

I lie so-called common urine analysis plays a central role in the charactens
lies of renal function disorders. It includes estimation of the amount of the urine,
its specific gravity, pathologic admixtures of the urine (biochemical and cellular),
urine acidity, salts and bacteria.
I’he daily amount of urine is called diuresis, which is equal to the difference
between the amount of fluid filtered in the glomeruli and its amount reabsorbed in
the tubules. So, a change of diuresis may result from dysfunction of the glomemll
and tubules.
Polyuria is an increase in the total quantity of urine to more than 2 1.
O liguria is diuresis decrease to less than 500 ml.
Anuria is the absence of urine excretion or diuresis decrease to less than
11)11 ml/day.
Specific gravity of the urine is characterized by the following terms.
Hyposthenuria is a decrease of urine specific gravity to less than 1010 (to 1002)
I Ins specific gravity of the urine confirms the fact that the kidneys are capable
ol diluting the primary urine. Edema development is not typical of such patients
However, as to the ability to concentrate the urine, it is decreased. Consequently,
iiiemia development is possible.
Hypersthenuriu is an increase in the specific gravity of the urine to more Ilian
1011) (to 1040) l liis specific gravity ol (lie urine confirms the fact that the kidney*
are capable of concentrating the primary mine Uremia development is not typical
 ( 'hapter 24 I'uthuph.vsioloK) of Kulnevs

I >iu h patients. However, ilu- ability to dilute the primary urine is reduced. C on
•<|iii-iitly, the development ol systemic edema is possible.
l\o\thenuria is a monotonic specific gravity with a constant index 1010. I Ins
i" * die gravity of the urine confirms the fact that the kidneys arc not capable «>1
neither concentrating nor diluting the primary urine. Consequently, the develop
mu mi of edema and uremia is possible.
radiological admixtures of the urine is the presence of substances or cells,
vsin. Ii arc not typical of the standard urine composition.They are the following.
Proteinuria is the presence of protein in the urine. It is divided into true (pro
i. ins excreted into the urine by the kidneys) and false (proteins are not excreted
in the kidneys but are admixed to the urine in inflammation of the urinary tracts),
•ilonal (transitory, which disappeares after elimination of the cause) and organic
...... rganic lesion of the kidneys — inflammation, nephrotic syndrome), extrarenul
<iiid renal.
Kenal (true) proteinuria is organic (acute and chronic glomerulonephritis,
mi iHirotic syndrome, etc.) and is subdivided into glomerular and tubular, which
li ne been described above. The gomerular one is a cardinal sign of an increased
i-nmeability of the glomerular filter for proteins due to physical and chemical
i ii uiK.es in the basement membrane. Tubular proteinuria is connected with dis
•inlets of protein reabsorption from the primary urine as well as entry of protein
MHileculcs into the urine from destroyed tubular cells. Organic proteinuria is char-
n leii/ed by stableness, a large amount of protein in the urine — from 10-15 up to
I 'О к/I. the presence of fractions of high-molecular-weight plasma proteins.
I unctional proteinuria (false) is nonstable, inconsiderable, not more than I g/1
•м.I disappears after causative factor elimination. Below examples are given:
• hard work (march);
• functional disorders of renal hemodynamics accompanied with increased
secretion of adrenaline and noradrenaline;
• standing position of children (orthostatic);
• overcooling;
• loss of fluid in babies (dehydration);
• after having meals with a large amount of proteins, especially in children
(alimentary proteinuria).
In the following cases the cause of proteinuria is also extrarenal, it is more
•'i.lent but still less than in organic diseases of the kidneys:
• infectious diseases;
• some toxic conditions;
• thyrotoxicosis;
• mechanical and parenchymatous jaundice;
• enterocolitis;
• Intestine impassability (ileus);
• burns;
• inflammatory process in the uieiei (usually proteinuria does not exceed
in/D.
 ■
ГмИ 2 S|M'«'iul (S y sim ile) Г]Н1ш||||)лш1оку

(Hucosuria is the presence of glucose in the urine. It is the main symptom ol

DM
llcm uturia is the presence of erythrocytes in the final urine and is determined
as cellular pathologic admixtures by microscopic examination of the urinary sedi
incut. It is subdivided into renal and extrarenal. Renal hematuria, which is causal
by increased permeability of the glomerular filter for blood cells, has been describcil
above. Extrarenal hematuria is caused by traumas or inflammation of the urinatv
bladder or ureter (if there are stones). It is important to differentiate them in dim
cal practice. In the latter case there is a large amount of fresh erythrocytes in the
urine. In renal hematuria shadows of erythrocytes are found in the urine (lixiviated
erythrocytes).
Lvukm yturia is the presence of leukocytes in the final urine. It may be ol
glomerular, tubular and exrtarenal origin. As a rule, it testifies to inflammation.
Urine acidity reflects disorders of the acid-base balance. Systemic acidosis i\
associated with an increased content of ammonium salts in the urine.
Sails (urates, phosphates, oxalates) are present in the final urine in systeimi
disorders of mineral balance in the organism.
Bacteria appear in the final urine in case of inflammation of the kidneys oi
urinary tract.

SYSTEM IC CLINICAL SYNDROMES

I he role of the kidneys in various pathological processes and systemic disorder,

of the organism has been mentioned many times in previous chapters (allergy, acid
base imbalance, edemas, D M , arterial hypertension, etc.). Below these pathologu ii
conditions are described in brief.
Nephritic edema is described in chapter 18 «Pathology of Water-Electrolvit
Balance» (p. 258). Excessive secretion of renin, aldosterone and vasopressin to
get her with hypoproteinemia and dysproteinemia underlie the pathogenesis of Ihc
nephritic edema.
Arterial hypertension is described in chapter 25 «Pathophysiology of Vessels», 1
I xcessive production of renin and insufficient production of renal prostaglandin*
cause an increase of systemic peripheral resistance and play a leading role (detail*
about the role of the kidneys in the pathogenesis of aterial hypertension see on
pp. 373, 375. 382).
Anemic syndrome is described in chapter 20 «Pathology of Erythrocytes. Лиг
mia- Ihe deficit of erythropoietin together with intoxication of the bone manow
with toxic metabolites, which develop in renal insufficiency, play the leading ml*
in disregulatory and myelotoxic anemia (see p. 287).
Nonrespiratory secretory acidosis is described in chapter 17 «Pathology ol
And Base Balance» (p. 248). In its turn, the disorder is divided into glomemUl
(retention of amino acids in the blond) and tubular (disorder of acido- and am
inoniogcnebis, and also bicarbonate rcabsoplion).
Disorder of hciiiocongiilalion is manifested as I >l(' syndrome in acute or i bin
uic renal ihsiillicicncy.
 ( iliip lei r.itlio p ln ol k id n ey s

Nephrolithiasis is formation <«l concrcments from the components of the urine

(uioliihic disease).
Syndrome of nephrogenic cardiac insufficiency is conncctcd with imbalance ol
t lei Imlytes — sodium, potassium, calcium.
Syndrome of nephrogenic osteodystrophy is connected with imbalance of cal
i nun and its salts. Under physiological conditions, vitamin D3is activated in the
kidneys, which ensures phosphate and CaJ+ reabsorption in the tubules and absorp
ii«.u of Ca2+ in the intestine.

G L O M E R U L O N E P H R IT IS

(iloniiTulonephritis is a bilateral diffusive infectious-allergic kidney disease of

Inflammatory origin with prevailing damage of the glomeruli.
It may be prim ary and secondary (as a complication of other diseases, more
lien of diffuse lesions of the connective tissue), as well as acute and chronic.

Acute Glomerulonephritis

I чи п mental Model

Animal models of acute diffusive glomerulonephritis deserve consideration be

hi < they prove that such type of kidney inflammation cannot be modelled under
•11>inmental conditions by any usual inflammatory agent (even with the aid of
•• hemolytic streptococci), but only by the way of immunological reaction repro-
iIm lion.
I’rofessor of Kyiv University V.K . Linderman observed (in Mechnikov labo-
iiitoiy in Paris in 1901) the main manifestations of nephritis in a rabbit after in
n iw nous introduction of the nephrotoxic serum of a guinea pig immunized with
i 'I I mi kidney suspension. Later, Japanese scientist Masugi, using the same scheme
nl experiment, reproduced the clinical picture of glomerulonephritis in a rabbit by
mi inducing the blood serum of a duck immunized with the rabbit kidney tissue.
I here are two phases of experimental glomerulonephritis development: liclcro
hn:i, conditioned by fixation of nephrotoxic antibodies (IgG , IgM ) on the glome
mini basement membrane, and autologic, connected with production of complc
m e nl fixing antibodies against nephrotoxic globulin.

I Oology

Infection (mostly of streptococcal nature) is the initial factor of acute diffuse

uloiiicniloncphritis. a-Hemolytic streptococcus is considered specifically ncphrilo
г nil Other infections may play a definite role (viral, parasitic). Glomeruloneplui
II» limy arise in supercooling, burns, uftci van mat ion and immune serum applica
llini (ilomemloncphritis may be pmvoked by diffuse diseases of the connective
и ne (rheumatoid arthritis, ct> )
IVi l l } S|i<n;il (.System ic) l**lllo|>liysloloRy

Pathogenesis

I lie allergic nature of acutc glomerulonephritis has been confirmed.

I here are two main mechanisms of glomeruli damage:
/. Immune complex glomerulonephritis develops in the majority of cases (XO '<•)
I >iI.ills about this type of allergy are given on p. 95. In immune complex-mediated
glomerulonephritis antigens are not of renal origin and antibodies are not speciIn
lo the glomeruli. Many exogenic (infectious and noninfectious) or endogenic (iis
не protein, D N A) substances serve as antigens. Antibodies (IgG , IgM ) to them
are formed. Both antigens and antibodies circulate in the blood, where immune
coplexes are formed. The latter enter glomeruli and are absorbed on their basemeni
membrane. Then the complement is activated. Bilateral immune inflammation ol
the glomeruli develops. Cellular proliferation and leukocytic infiltration may he
observed. In these cases the kidneys are the «victims» of their filtrative function and
immune complex fixation.
2. Nephrotoxic glomerulonephritis has a quick progressive course. Glycoprotein
ol the basement membrane serves as an antigen. Antibodies (nephrotoxic) read
directly against glomerular antigens. This type of glomerulonephritis is easily re
produced in experiments of Masugi described above. In clinical practice it is often
triggered by streptococcal infection in 1—2 weeks after recovery from an infectious
disease (acute tonsillitis). The pathogenesis of the so-called infectious-allergic din
eases was discussed in chapter 6 «Allergy» (p. 97). Due to the similarity between l lie
microbial polysaccharide antigen and glycoproteins of the glomerular membranes,
the antibodies react with both of them (cross reactivity, «mistaken» recognition ol
antigen by the immune system, see p. 98) causing allergic inflammation with mono
cytic and neutrophilic infiltration in the glomeruli. Activated complement, enzyme*
released from neutrophilic lysosomes and vasoactive amines (histamine, serotonin)
from basophils serve as mediators. Intraglomerular coagulation plays a significant
role, f ibrin (fibrinogen) may leak into Bowman’s space serving as a stimulus to cell
proliferation.
In the cases, when infection is not detected as an etiological factor, there ate
othei immune mechanisms initiating autoantibody formation and autoallergic in
llamniation of the glomeruli.

Manifestations

I he clinical and pathophysiological manifestations of acute glomerulonephritU

rctlect changes of the renal (mainly glomerular) and extrarenal functions.
Violent onset, oliguria (100—500 ml/day), azotemia, arterial hypertension ch.u
acleri/e ihe classical course of the disease. Urinary syndrome is characterized In
proteinuria, hematuria, leukocyturia. Rdemas develop due to retention of sodium,
hypoproteinemia, hypervolemia and increased capillary permeability. Pain in the
luinhai region and disorders of the nervous system must be added.
Acute glomerulonephritis is one ol ihe causes of acute renal insufficiency find
may lend lo uremia (see below).
 ( Implcr 29. l,ullio|ih>sl<iloK.v of Klilnrys

l*i «Г Therapy

Understanding the pathogenesis of this disease is important for provision of

г iiliogenetic therapy. No anti-inflammatory drug can be effective alone. Immuno
mpim-sive therapy is necessary. Anticoagulants as well as histamine and serotonin
nil,ironists are in use.

Chronic Glomerulonephritis

Chronic glomerulonephritis is a prolonged progressive disease characterized by

•Utilise bilateral injury of the kidneys of inflammatory nature, heterogeneous by origin,
iMtliogenesis and clinical manifestations.

I llnlogv

As to etiology, there are the following forms of chronic glomerulonephritis:

• Infectious (poststreptococcal, in malaria, syphilis, tuberculosis);
• non infectious (traumatic, intoxication by different poisons, after immune scrum
md vaccine use, thrombosis, ischemia, in drug abuse);
•pedal (radiation, hereditary, etc.);
• . (implication of diffuse diseases of the connective tissue (rheumatoid arthritis,
hemorrhagic vasculitis, etc.).

1'nlhogenesis

I he immune concept of chronic glomerulonephritis pathogenesis is commonly

in i cpted. Together with two main mechanisms, which are connected with the
ili u'lopment of acute glomerulonephritis (immune complex-initiated and nephro-
iiiv ii), delayed-type hypersensitivity are rather important.
I he pathogenesis proceeds in two stages - compensation and deconipens;i
Hon.
At the stage of compensation the quantity of functioning nephrons is preserved
hi .lightly decreased in most of patients. Filtration is changed a little. As to the
iiilnili s, excretion of ammonia and H + ions (ammonio- and acidogenesis) get de
■n i fd; reabsorption of N a+ and water gets increased. It leads to edema develop
MU' n l .
Al the stage of decompensation, the connective tissue develops excessively in
tin kidneys leading to nephrosclerosis. The quantity of functioning nephrons sin
nllii nilly decreases resulting in oliguria. This stage is manifested as a syndrome of
•minil renal insuffitiency (see below).

Manifestations

Chronic glomerulonephritis may luivc an acute onset resembling the onset ol

к nii* glomerulonephritis, Mui moir ollen <hionic glomerulonephritis develops in
ilu lust place (primary).
Purl 2 .S|H4'lul (N yslcm ic) P;i II io |>Iivm o I<>k >

rhe following clinical forms arc distinguished in the phase of compensation.

• I lie latent form (65 % of all cases) is manifested by isolated urinary syndrome -
moderate proteinuria and hematuria. Some patients (20—25 % ) have edemas and
transitory hypertension.
• I he hypertensive form (32 % of patients) is characterized by stable increase ol
arterial blood pressure. 1/3 of patients have edemas, 2/3 — hematuria, all pa
tients have proteinuria, and half of them have cylindruria and leukocyturia.
• I lie nephrotic form (2-4 % of patients), which is characterized by edematou .
syndrome (2/3 of patients), marked proteinuria and cylindruria (all patients) and
typical changes in the blood (hyperproteinemia and hyperlipidemia).
• I lie mixed or ncphrohypertensive form (2.4 % of patients), which is characlei
i/cd by edemas and hypertension (all patients). Changes in the urine are similiii
to those observed in the nephrotic form but there are no changes in the blood.

N EP H R O T IC SY N D R O M E

Nephrotic syndrome is a totality of clinical and laboratory symptoms mam

lestcd as massive proteinuria (5 g and more daily), disorders of protein (hypopm
tcincmia, dysproteinemia) and lipid (hyperlipidemia) metabolism as well as watci
electrolyte imbalance, edema development up to the degree of anasarca with serous
sac dropsy.

Etiology

Nephrotic syndrome develops due to various types of kidney affections. It\

origin, il is divided into primary and secondary.
Prim ary nephrotic syndrome is more often not connected with previous diseases
of the kidneys. It develops on the basis of 1) intoxication with salts of heavy met
als, burns, 2) radiation disease, 3) abuse of some drugs, 4) disturbance of renal
blood supply, 5) genetically conditioned defects of metabolism (lipoid nephrosisi,
(>) transplant rejection, 7) specific antirenal antibodies transmission from the moth
ci lo the fetus as in congenital family nephrosis.
It may be caused by some kidney diseases (glomerulonephritis).
In immunologic cases, both exogenous (bacterial, viral and parasitic agen il,
medicines, food products, heavy metals, etc.) and endogenous (D N A , dcnaturalcri
nuclcoproteins, tumor proteins) factors play the role of antigenes.
Secondary nephrotic syndrome may be caused by some systemic diseases (col
lagcnosis, DM , amyloidosis, scrum disease, staphylococcal sepsis, nephropathy of
pregnancy, etc.), chronic purulent diseases (abscess of the lungs, bronchiectasesi,
parasitic (malaria) and viral diseases.

Pulliogcucsis anil Manifestations

I lie pathogenesis of nephrotic syiuhomc is lightly connected with the princip.il

disease. In most cases, nephrotic syndrome development is determined by 111111111110
 <'hunter 24 I’ulhnphysloloK.v <>f kidneys

mechanisms (delayed-type hyiKiscnsitivity) with the antigens mentioned above.

Illinium* complexes or antibodies against the glomerular basement membrane may
•и1observed.
Histologically, pathology of glomerular podocytes, hyaline dystrophy of Ihc
I'lMsimal tubules and the presence of foam cells with lipid deposition is observed.
•.I'Hiu-ruli damage is connected with deposition of amyloid, fibrinogen and gly
• ■ and lipoproteins on the surface or the basement membrane with activation
I humoral and cellular mechanisms of inflammation. The antibodies, which arc
. lined in response to antigens, belong to the IgM class. As a result, the structure
i tin basement membrane, its components and physicochemical properties gel
ii nip d, permeability for blood plasma proteins gets increased.
I or those forms of nephrotic syndrome, where immunological mechanisms arc
imi proved, the most suitable reasons are metabolic and physicochemical media
IllM IIV
Massive proteinuria is the main symptom of nephrotic syndrome. The main
linl m its pathogenesis is a decrease or disappearance of the constant electric
•ii иgo of the capillary wall. It is connected with depletion and disappearance ol
i.iliiprotein. In the places of maximal loss of ions and sialoproteins, polymoi
ell-Hinclcar leukocytes are accumulated, whose lysosomal enzymes provide direct
iiiMii.igc of the basement membrane. As a result, a large amount of high-moleculai
• irin proteins get filtrated, which can not be reabsorbed in the proximal tubules
nl the nephron.
All other manifestations of nephrotic syndrome are secondary to massive pro
i' типа They are: decrease of colloid osmotic pressure of the plasma, decrease of
n mil blood circulation, hypovolemia, increased production of renin, aldosterone
•п. I vasopressin, increased Na+ion reabsorption and edema development. Second-
и aldosteronism can develop due to hypovolemia (whose cause is leakage of fluid
Inin tissues), a decrease of renal blood flow and increased production of renin.

I.ihlr I I
<onsequences of Proteinuria and Dysproteinemia in Nephrotic Syndrome
1vi»«л ill Proteins Which Are in Deficit Consequences of Diminished Amount
in the Blood of Proteins in the Blood
Alliiiiiiin.s Hypooncia, edema
Predisposition to thrombosis and thromboem
Aiiinliiiiiiihin
bolism
1 и li us of blood coagulation Hemorrhage syndrome
l iiiii|ioncnts of complement Decreased resistance to infection
i i iIh Im iIiiis Decreased resistance to infection
11111» Piedisposition lo atherosclerosis
l‘i••(«-ins connected with niicroclcinonls 1b ill li lli v ol l e, Zn, C’u
P m Hi ' I iis ininKporting hormones 1mint Hue tli*.iinliances
I’lllt Sp inal (Nysli-iuic) Pathophysiology

llypcrlipidctnia, which is characteristic ol nephrotic syndrome, is determined

by triglycerides and cholesterol. Pathogenetically it is connected with protein dis
metabolism and suppression of the lipolytic activity of the blood plasma.
In addition to the changes mentioned above, many clinical manifestations an
connected with the lack of important proteins in the blood (dysproteinemia). C'lini
cal consequences are represented in table 11.

P Y E L O N E P H R IT IS

Pyelonephritis is an infectious inflammatory disease of the mucous membrane ol

Ihe urinary tract and renal parenchyma (simultaneous or subsequent) with predomi
naul affection of the interstitial tissue.

Kliology and Pathogenesis

I he disease arises due to infection getting into the kidneys by the hematogenu
route or spreading upwards from the urinary tract. The causative agents are mosil\
colon bacillus and cocci.
I he development of the disease and transition of acute pyelonephritis into ilu
chronic form is promoted by different conditions causing urine retension — con
st net ion and occlusion of the ureter (very often with adenoma of the prostate in
men), dystrophy of the urinary tracts, systemic diseases, which reduce organism
reactivity (D M , atherosclerosis, obesity, chronic intoxication, etc.).
Tubular dysfunction prevails upon glomerular dysfunction. The ability to con
cenlrate the urine decreases. Early and severe tubular acidosis develops due in
suppression of acido- and ammoniogenesis. Salts are lost due to decreased tubulin
irabsorption of Na* and Ca2+. As a result, life-threatening disorders of water-ela
trolyte and acid-base balance may develop.

Manifestations

Pyelonephritis begins as an acute (which more often gets transmitted into ilu
chronic form) or latent disease. In both cases kidney shrinkage and renal instil
licicncy develop.
I'he clinical picture may manifest itself as a heavy infectious disease with into*
ication, arterial hypertension, moderate edema and anemia. Urinary syndrome 1
polyuria, olyguria, hypostenuria, leukocyturia, hematuria, moderate proteinnm
cylindruria. Progression of the named disorders leads to a decrease of the quantity
ol limtional nephrons and transition of tubulointestinal insufficiency into chronic
renal Insufficiency.

SY N D R O M E O F A C U TE REN A L IN SU FFICIEN C Y

Aeule renal insufneieney is an acute homeosliisis disorder caused by a signifa'iinl

uml quick decrease of (lie glomerular fill nil I o i i rule.
 ( 'hupler 24 1’м11|<ф||ук1о1ок> of Kidneys

I his syndrome, associated vmiIi acute suppression of the renal function, is ac

■iiinpanied by glomerular filtration rate reduction to I —10 ml/min compared with
l 'и ml/min under normal conditions.

I ItoloKy

Acute renal insufficiency is caused by three groups of factors: prerenal, renal

mid post renal.
Prerenal factors are:
• hock, collapse accompanied by acute blood hypotension (decrease of arterial
Mood pressure to less than 40 mmHg);
• Hood loss, incontrollable vomiting, profuse diarrhea, diuretic abuse resulting in
m acute decrease of the intravascular and extracellular fluid volume;
• massive hemolysis (mismatched hemotransfusion);
massive trauma of tissues (crush syndrome, large cutaneous burns);
• u utc (myocardial infarction) and chronic (myocardial hypertrophy, myocardio
i lerosis) cardiac insufficiency;
• <nelusion of the renal artery (compression, spasm, thrombosis, embolism).
Renal factors are:
• local disorders of blood circulation (ischemia, thrombosis, D IC syndrome);
intoxication with nephritogenic poisons (salts of heavy metals, arsenic, phospho
ms. mushroom and snake poisons, endogenous intoxication in diabetic coma,
.fpsis, peritonitis, hepatic insufficiency);
• w ere diffuse glomerulonephritis;
• m ite tubular necrosis;
• immune nephrotoxin action;
• m issive infection (pyelonephritis).
Postrenal factors are obstruction of urine flow and retention of the urine at the
i cl of the urinary tract (calculi in the ureter, tumors, hypertrophy and adenoma
nl Ihe prostate).

MlftgM

I our stages of acute renal insufficiency are distinguished in accordance with

tin <linical course.
• I'he initial stage which lasts several hours.
• I he stage of oligo- or anuria (during 5—10 days).
• Polyuria.
• Outcome — recovery (if treatment is effective) or death.

Pathogenesis

I he pathogenesis of acute renal Insufficiency consists in an acute decrease ol

•lb'» live filtration pressure due to the following reasons:
I h i tease of systemic blood presstiic ot temporary ischemia of the kidneys con
tlllloned by a) hypovolemia, hi '.рами ol ilu ulVerent renal arterioles, c) dissemi
iiiiled intravascular blood coagulation with inli intluoinbosis of the renal vessels.
I’iirt ' |H «ial (System ic) l*alho|>liysi<>loKy

• Increased pressure in the Bowman’s capsulc and interstitium.

Under the influence of nephrotoxic factors (toxic, infectious) together with
hlood circulation disorders, direct damage of the glomerular and tubular structure»
becomes important. Prolonged ischemia may lead not only to a decrease of glome­
rular filtration and switching off of a definite number of nephrons, but also to и
reversible structural changes in the glomeruli and tubules.
nitration in the glomeruli may be decreased secondarily due to the followuit<
problems in the tubules:
• Obstruction of the tubular lumen by necrotic masses.
• Leakage of the filtrate through the wall of the damaged tubules into the intersii
tium.
• Increased Na* reabsorption in the tubules (it is accepted by the macula densa and
results in activation of the renin-angiotensin system, spasms of the afferent renfll
arterioles, a decrease of blood circulation and glomerular filtration).
I he most characteristic and marked disorders are observed at the stage of
oligo- and anuria. In addition to an acute decrease of diuresis to its complete stop
there is hyperazotemia, disorders of the water-electrolyte and acid-base balances II
filtration in the nephrons is restored (spontaneously or in response to treatment),
polyuria follows oligo/anuria.

Manifestations

I he main clinical manifestations are determined by disorders of homeostii

sis: nausea, brain edema, interstitial lung edema, severe disorders of circulation,
decreased contractile function of the heart, arrhythmia (extrasystole, bradycarili.i
blockade), arterial hypotension with transformation into arterial hypertension
Kussmaul respiration, severe dysfunctions of the nervous system (headache, vonui
mg, loss of consciousness, convulsions, coma), anemia. Most of these events .in
symptoms of azotemia. Frequently, it is a reason for patient’s death.
If treatment is proper, the stage of restoration is observed in 5—10 days.

SY N D R O M E O F C H R O N IC R EN A L IN S U F F IC IE N C Y

Chronic renal insufficiency is a disorder of homeostasis caused by progress»)

and irreversible loss of the functional parenchyma.
Chronic renal insufficiency is the end result of a variety of renal diseases and t»
the nuyor cause of death from renal pathology. It develops gradually due to scvcrfl
disorders of renal processes and the main renal functions as a result of a decrease nl
the amount of active nephrons, substitution of the parenchyma with the conncclivf
tissue and kidney shrinkage. Its clinical picture is connected with azotemia, water
electrolyte and acid-base imbalance.

Etiology

I lie etiological factors of chronu renal insufficiency arc most frequently intni
iciuil I hey are cluomc progressive diseiiM •. nl ilic kidneys of iiillaiiiinatory (chmnii
 ( lu p in 24. I'HllinplivsiiiloKv »Г k iiln o s

uloincrulonephritis, chronic pycloncphi il is, ctc.), vascular (arterial hypertension)

Hid metabolic (D M , amyloidosis, gout) origin. The connection between chronic re-
mil insufficiency and DM is especially relevant. Diabetics rarely avoid renal pathol-
"i \ It is the term of the disease (during 15—20 years) and not its severity, which
m nit is Half of patients with longstanding diabetes die from diabetic nephropathy
(diabetic glomerulosclerosis).

I'lithogencsis

( hronic renal insufficiency is the final stage of the impairment of all compo-
.... . <>l the kidney (glomeruli, tubules, intestitium, vessels). It is a disorder of all
ilu (unctions and processes taking place in the kidneys (filtration, reabsorption,
к i iiiion, incretion).
Ihe pathogenesis is determined by a decrease of the quantity of functionally
I »• live nephrons and reduction of all renal functions. Nephrosclerosis is in progress
• Ii ionic renal diseases produce scarring of the kidneys that are smaller than nor
im il I he concentration ability is impaired and manifested through isosthenuria. ЛИ
' i'li\ lological systems of the organism are gradually involved, and multiple clinical
«Vni|>loms appear.
Patients require long-term hemodialysis or transplantation.

I here are three clinical stages of chronic renal insufficiency.

• Ihe initial stage develops, when the remainder of active nephrons makes 50-
И1 "i. T his stage is characterized by polyuria. Diuresis increases as a result of
decreased water reabsorption. The specific gravity of the urine approaches 1010.
• Ihe stage of clinical manifestations develops when the remainder of active
nephrons makes 30-10 % . The stage of polyuria passes into the stage of oliguria.
Л/otcmia develops.
1 I he terminal stage develops, when the remainder of active nephrons comprises less
Ilian 10 % . Clinical manifestations: loss of appetite, dyspepsia, emaciation, head
.и lies, skin itch, polyneuritis, anemia, arterial hypertension, convulsions, coma.
I lie terminal stage of renal insufficiency is called uremia.

UREM IA

I iieinia is the end stage of chronic renal insuffitiency. It is characterized by dis

пн liiholism and involvement of all physiological systems with grave disorders. It is
; |tiiii|ilele impairment of the excretory renal function and regulation of homeostasis
! M li the following systemic changes:
• Initixlcalion is connected with retention in the blood of the substances, which
inii'.i be excreted in the urine urea and creatinine (azotemia), phenols, indoles,
iiniuio acids. Furthermore, many new toxic substances are formed over 200
Ionic substances are revealed. Il Is tin > substances that determine organism iu
Invit ation and associated « hint ill syinploni-.
Г.и I ’ Sprcial (System ic) Га(1ю|>||умо1<>ку

• Electrolyte disorders in the blood — decreased amount of Ca2+, increased amoiuil

of phosphorus, porassium.
• Acidosis.
Uremia is not merely biochemical abnormalities mentioned above. There art’
lot of external clinical manifestations. It is serious disorders of all functions.
Development of the following clinical syndromes is necessary for the diagunsl
of uremia:
• Hemorhage syndrome (predisposition to bleeding, disorders of throniboi
aggregation).
• Anemia (as a result of blood loss, uremic hemolysis, suppression of hemopol
esis due to bone marrow intoxication).
• Gastrointestinal syndrome (dyspeptic signs) — anorexia (loss of appetite), dh
orders of taste, vomiting, diarrhea, esophagitis, gastritis, colitis).
• Cardiovascular syndrome (uremic myocarditis and pericarditis, arterial Ii
pertension).
• Neuromuscular syndrome (spasms, paresis, convulsions).
• Respiratory insufficiency (pulmonary congestion, dyspnea, uremic plcurill
Kussmaul breathing).
• Peripheral neuropathy (tormenting itching).
• Encephalopathy (general weakness, apathy, headache, hearing disordt i
coma).
• Endocrine disorders (connected with general intoxication).
• Body weight reduction.
• Arthritis.
Uremic patients must be dialyzed.

Questions for Self-Control

I What are the functions of different parts of the kidneys?

? ( iive a classification of renal pathology,
l What are the endogenous causes of renal pathology?
4. What is the role of immune mechanisms in renal pathology?
5. What is ihe role of medicines in renal pathology?
6. What arc the causes and consequences of decreased glomerular filtration?
7. What are the causes and consequences of renal tubule disorders?
8. What is azotemia, its causes and manifestations?
9. What is proteinuria, its causes and consequences?
10. In what way is the acid-base balance disordered?
11. What is uremia, its causes and manifestations?
12. What is the pathogenesis of nephritic edema?
IV What are the non-diuretic functions of the kidneys?
14. What are the systemic disorders in kidney inflammation?
15. What is the pathogenesis of renal arterial hypertension?
If*. Compare the syndromes of acute and « hionic renal insufficiency.
 Chapter 24 l‘ulhoplivslol<»K> of Kidneys

i n li fo Self-Control
(give correct answers)

l Л year-old patient complains of pain in the lumbar region, baggy lower eye
Iills, sickness. Erythrocytes and proteins were found in the urine of the patient.
Arterial pressure — 160/110 mmHg. What pathology can be most probably
.iiKpccted in this case?
Л. Urethritis.
H. I*yclitis.
Cystitis.
I ). Glomerulonephritis.
I Pyelonephritis.
Л ncphrocytotoxic serum was injected to a rabbit. What pathology of the kid
nrys has been modeled in this experiment?
Л. Acute diffuse glomerulonephritis.
H Nephrotic syndrome.
( '. Acute pyelonephritis.
I ). Chronic renal failure.
I Chronic pyelonephritis.
Mercury dichloride solution in the dose of 5 mg per 1 kg was injected sub-
t utancously to a white rat. In 24 h the concentration of creatinine in the
Mood plasma increased by several times. What is the mechanism of retentional
ii/ntemia in this case?
A Increased glomerular filtration.
B. Increased formation of creatinine in the muscles.
< Increased rcabsorption of creatinine.
I) Decreased glomerular filtration.
I Increased secretion of creatinine in the renal tubules.
i ln .|>cction of a patient showed that the clearance of endogenous creatinine
m.ikes 50 ml/min (normal - 110-150 ml/min). To a decrease of what function
tli »cs it testify?
A Ions excretion from the organism.
И Tubular reabsorption.
< Incretory function of the kidneys.
I > ( ilomcrular filtration.
I Tubular secretion.
' I luring 17 years a man was ill with chronic glomerulonephritis. Pulse X2,
uterial pressure — 190/120 mmlig. What is the initial mechanism of arterial
pressure rise?
A Increased minute volume ol the blood
II Decreased circulating blood volume
( Increased lone of the venous vrv.ds
D Increased systolic blood output
I Increased periphciiil icslsliiim
I’.iH 1 S|N4'ial ( S>s I c i i i k - > Ги(1ш|>||умо1ок>

(i Л 32-ycar-old man has been ill with chronic glomerulonephritis for 4 years. In
sped ion showed edemas on the face, legs and trunk, a high level of protciniin.i
What is the mechanism of edemas?
Л. Decreased oncotic pressure of the blood.
B. Increased hydrostatic pressure of the blood in the capillaries.
C. Increased oncotic pressure of the intracellular lymph.
I ). Lymphatic drainage impairment.
Ii. Increased permeability of the capillaries.

7 Л patient with a hemorrhage into the supraoptic region and periventriculai

nucleus of the hypothalamus suffers from polyuria. The level of vasopressin ш
the blood decreased. What is the main mechanism of polyuria developmcni m
lhis case?
Л. Decreased reabsorbtion of sodium in the tubules.
B. Increased filtration of water in glomeruli.
C. Increased reabsorption of sodium in the tubules.
I). Decreased reabsorption of water in the tubules.
E. Increased excretion of potassium.
К. Л patient has a diagnosis of initial nephrotic syndrome. The level of Ы<ии1
protein makes 40 g/1. What is the cause of hypoproteinemia in this case?
A. Decreased synthesis of protein in the liver.
II. Exudation of protein from vessels into tissues.
C. Proteinuria.
I). Increased proteolysis.
E. Decreased assimilation of protein from the intestine.
У. Л patient has chronic glomerulonephritis. Glomerular filtration reduced (<•
20 % . What is the cause of decreased glomerular filtration in chronic renal
failure?
Л. Obstruction of the urinary tracts.
B. Tubulopathy.
C. Decreased amount of nephrons.
I ). Ischemia of the kidneys.
E. Thrombosis of the renal arteries.
10. Л 30-year-old patient was hospitalized with a diagnosis of acute glomerulonr
phritis. Proteinuria is observed. What is the mechanism of its origin?
Л. Decreased oncotic pressure of the blood.
B. Delayed excretion of the products of nitrogen metabolism.
Increased permeability of the glomerular membrane.
I). Increased hydrostatic pressure in the capillaries.
I Decreased amount of the functioning nephrons.

11 One kidney of an experimental animal was removed and a ligature narrowed

the artery of the second kidney Wliat model of hypertension was reproduced
in lhis саке?
 ( 'Iliip U 'l 24. 1’» |||< > р ||у ч М < 1Ку o f k id n e y *

Л. Ncurogcnic.
H. Renoprival.
C’. Endocrine.
I). Renovascular.
E. Saline.

I ’ A 55-ycar-old female patient is ill with gout. She suffers from pain in the kid
neys. Ultrasonic inspection showed the presence of renal stones. A high level
of what substance is the most probable cause of stone formation in this case?
A. Cholesterin.
B. Urea.
C. Bilirubin.
1). Urates.
E. Cystine.

I ' A patient suffers form diabetes. He had diabetic nephropathy with uremia
development. The glomerular filtration rate is 9 m l/m in. What is a possible
mechanism of decreased glomerular filtration and development of chronic re
nal failure?
A. Lack of functioning nephrons.
B. Decrease of systemic arterial pressure.
C. Occlusion of the renal tubules by hyaline cylinders.
I). Development of metabolic acidosis.
E. Spasm of the afferent arterioles.

И A patient has chronic diffuse glomerulonephritis. A chronic failure of the kid­

neys with oliguria has developed. What is the cause of oliguria?
A. Disseminated intravascular coagulation of the blood.
B. Ischemia of the renal cortex owing to vasospasm.
C. Decreased filtration pressure in the glomeruli.
I). Increased reabsorption of water in the distal tubules.
E. Decreased quantity of the functioning nephrons.

h A patient is ill with chronic glomerulonephritis. Normochromic-normocytic

imcmia has developed. What is the mechanism of its development?
A. Loss of iron.
B. Decreased production of erythropoietin.
C. Decreased secretion of erythropoietin inhibitor.
I ). Streptococcal intoxication.
I Harmful action of immune complexes.

I»' A patient was ill with a serious infection. Later symptoms of diabetes insipidus
appeared - diuresis 10 I. What is the main mechanism of dehydration?
A. Decreased oncotic pressure of ihc plasma.
B. Increasing osmolarity of the ultiiifiltrutc
C. Decreased rcabsorption of wiiloi in the intestine.
I) Decreased rcabsorption ol nodluin in Ihc kidneys.
I Decreased rcabaorption of witln in llx kidneys
( hapter 30
PATHOPHYSIOLOGY OF ENDOCRINE SYSTEM

I lie endocrine system plays an important role in the regulation of basic physi
««logical processes. The specific function of the endocrine glands is realized l>\
hormones. Many endocrine glands can secret not one, but several hormones witli
ill lie rent biological effects.
fhe participation of the endocrine system in the development of various patlui
logical processes and main pathophysiological syndromes was described in previous
chapters.
fhe development of arterial hypertension is associated with catecholamines,
vasopressin, mineralocorticoids, glucocorticoids and thyroid hormone с fled',
(pp. 373, 375, 383). The role of aldosterone and electrolyte imbalance in the dcvel
opincnt of myocardial necroses has also been explicated (electrolyte-steroid non
coronarogenic cardiopathy with necrosis, p. 347). It has been mentioned that in lie
patic insufficiency the destruction of hormones may be depressed, and the clinical
picture of endocrine hyperfunction with a relative excess of hormones is observed
(relative excess of hormones in hepatocellular hepatic insufficiency, p. 435). Renal
insufficiency, as it has been mentioned, is accompanied with arterial hypertension
and edema, in whose development an important role belongs to renin, aldosterone
and vasopressin (antidiuretic hormone).
One should gain understanding of the role of deficit or excess of hormones in
the development of all typical metabolic disorders — insulin and other hormones
in the pathogenesis of D M , aldosterone — in acidosis (p. 245), aldosterone tuul
vasopressin — in the development of edema (p. 254), hormones with catabolic tuul
anabolic effect — in energy imbalance (p. 187). The role of hormones (estrogens,
progesterone, testosterone, thyroxin, and insulin) in atherosclerosis development
was explained on p. 368; the role of thes endocrine system in obesity pathogenesis
on p. 228, thyroxin - in basal metabolism disturbances.
I he role of glucocorticoids and mineralocorticoids in the development of in
llanunation has been discussed (p. 128). Glucocorticoids were mentioned as the key
therapeutic means for allergy pathogenetic treatment.
Ihe value of genetic factors in endocrine pathology has also been mentioned
Most chromosomal diseases manifest themselves through endocrinopathy and sic
iilily (p. 53).
Endocrine Function Regulation. Endocrine system functioning is regulated l>\
nervous and humoral mechanisms. In spite of relative independence, the endocune
glands arc subordinated to the regulatory influences of the nervous system. Nervous
regulation consists in changing the function of an endocrine gland by nerve con
dm lion mechanisms. Such regulation has been proved for the adrenal medulla and
ihe cells of the pancreatic islets. Endocrine gland dysfunctioning in emotional stie ss
confirms the participation of the C N S. limbic system nuclei, reticular formation
 ( hitplci К) I’HlliophysioloKy of ImkIik t I ih - System

'iiul ilicncephalon in endocrinc function regulation. They influence the production

mil secrction of hormones.
I hc autonomic (vegetative) nervous system also participates in the regulation of
physiological and pathological processes in the endocrine system. N. vagus excita
п.-и activates insulin secretion. The sympathetic nerves stimulate adrenaline secrc
11*«и from the adrenal glands (after cutting the sympathetic nerves the reaction ol
'ii .idrcnal cortex to corticotropin stimulation is impaired). Humoral regulation of
iii endocrine functions is achieved by transpituitary and parapituitary mechanisms
l in former are achieved with the aid of the hypothalamus where the main centers
•I endocrine system regulation are located. In its turn, hypothalamus functioning
i ' onnected with the overlying parts of the brain. The hypothalamus regulates the
limclion of the pituitary gland with the aid of releasing factors (stimulating oligo
pi pi ides — liberins and the inhibiting ones — statins). Neuropituitary hormones
i \ ivoprcssin and oxytocin) are formed in the hypothalamus accumulating in the
posterior lobe of the pituitary gland and coming into the blood from there.
I he tropic hormones of the pituitary gland are an important regulation media
iilsin of the peripheral endocrine glands and refer to them.
Interrelations between the central (hypothalamus, pituitary gland) and periphe
■il endocrine glands are characterized by an important peculiarity — the regulating
mechanism of direct and reverse relations. A decreased concentration of the pc
iiplii-ral hormone has a stimulating effect on the hypothalamus and pituitary gland
mi icspcct to this hormone synthesis. An increased concentration of the peripheral

in.imone has an opposite effect. Thus, peripheral endocrine cells are targets for
H.tpic hormone action. The influence of tropic hormones is regulated with the
iM.l of the receptors located on the cellular membrane of the endocrine cells of the
peripheral glands. Intracellular messengers provide transmission of the regulating
itilliK'nces from the receptors to the cellular nucleus.
Parapituitary regulation is substrate regulation (glucose-insulin, calcium-para-
ilivnn) or another humoral factor (cytokins).
Intcrglandular hormonal connections are an important mechanism of regulation.
I mi ci relations between hormones are described as antagonism, synergism and per

"и ive effect. Thus, insulin and contrinsular hormones are antagonists of the blood
".и level, but they are synergists of glucose supply to the tissues. The permissive
•lb 1 1 consists in providing the optimal conditions for the physiological activity of
... hormone by another one. Thus, glucocorticoids have a permissive effect on
на holamine action, insulin — on somatotropin and sex hormones.
I lie synthesis of any hormone requires specific substrates and enzymes and is
■li in mined by genetic mechanisms.
Hormone precursors are transformed into the final hormone in a gland. Hoi
Itmne secretion from the glandular cells is an energy-dependent process.
Mechanisms of the Peripheral KITed of Hormones. Some hormones are trails
pnited to the target somatic cells l»v Ihe hlood with Ihe aid of transport proteins
liilluiuiins for estrogens, transcorlln loi triucocoiticoids). Binding of hormone with
Ии transport protein and its release linni tin-, connection can he disordered.
Г.и I 2 Speelul (S y s lfiiu i) l*alli<iph>si<tl»K>'

I he hormonal effect on a target somatic cell is achieved by participation of the

cellular receptors, which determine cellular sensitivity to the hormone, and partici
palion of intracellular messengers.
Hormones are destroyed in the liver, kidneys, and intestine.
Л brief enumeration of the physiological aspects of endocrine gland functioning
helps us to understand numerous reasons for endocrine pathology.
Insufficiency of the endocrine glands is an acquired and genetically determined
state of the organism, which is connected with disorders of the hormonal control of
the physiological functions of the organism.
The term insufficiency reflects function impairment, which can have the form
ol hyper-, hypo- or dysfunction.
Methods of Experimental Study of Endocrine Disorders. It is the easiest to il
lust rate the role of experiment in pathophysiology and its forms by experimenl.il
study of endocrine pathology.
Method o f removal is extirpation (ectomy) of an endocrine gland.
Method o f overload consists in introduction of hormones or endocrine gland
extract into an animal.
Method o f damage is endocrine gland injury by poisons, radioisotopes, immune
antibodies, inhibitors of energy production (A T P), etc.

CLA SSIFIC A TIO N

Several classifications of endocrine pathology have been suggested based on

different principles.
As to the participation of genetic mechanisms, endocrine pathology is divided
into acquired and hereditary (congenital).
fhe division of endocrine gland insufficiency into prim ary and secondary' re
fleets the sequence of disorders, namely, either it starts in the gland or is a compli
cation of another disease.
Monoglundular endocrine pathology is a lesion of one endocrine gland. Poly
Klandulur endocrine insufficiency is pathology of several endocrine glands.
I here is a division of endocrine pathology into glandular and extraglanduhn
In ils turn, extraglandular pathology is subdivided into preglandular and postglan
dular.
(ilandular endocrine pathology is subdivided into p a rtial and total dcpenduiu
on the extent of hormone synthesis impairment (if the synthesis of all or only оно
hormone of this gland is disrupted).
I ndocrinc insufficiency can be absolute (deficit or surplus in hormone pmdm
lion) and relative (hormone production can be normal, however, dismetabolisni in
the whole organism is similar to the one occurring in absolute hormone deficit ot
surplus caused by increased or decreased hormone destruction, altered bounding lu
ils transport protein or sensitivity of target cells to this hormone).
As to the clinical course, endocrine insufficiency is divided into acute and
chronic.
 < II) I’Hlhitphysioloio of kniltHTliif System

Г ach form of endocrine pathology manifests itself through hyperfunction, hy-

ro/unction or dysfunction. Dysfunction means dilfcrently directed changes in the
inoduction of different hormones in one gland or formation of atypical hormonal
<i impounds.
ETIO LO G Y

Г liological factors, which lead to endocrine insufficiency, are physical, chemi

•al and biological.
Among physical factors mechanical trauma and ionizing radiation arc rather
important.
( hcm ical factors include poisons and medicines, both deficit and surplus of
microelements (iodine, cobalt).
Hiological factors include infectious (Coxsackie and measles viruses, tubcrculo
m bacillus), immune, genetic and psychogenic.
I he endocrine glands can become an object of autoimmune aggression. Ли
m.miibodies against the hormone-releasing factors of the hypothalamus, tropic hoi
mihiics of the hypophysis (somatotropic, thyrotropic, prolactin), vasopressin, insulin

may form. Production of autoantibodies against the endocrine cells and their mem
11 me receptors is also possible. Among allergic reactions there are delayed-type im
шипе reactions, the so-called stimulating ones (see p. 91), when antibodies perform
i '.simulating role concerning receptors of a peripheral endocrine gland similarly to
itopic hormones.
I he role of genetic factors is manifested in the form of genetic and chromo-
....al mutations. The manifestations include enzymopathy, genetic defects of hor-
iiiuiies and receptors, defects of endocrine gland genesis. A ll chromosomal diseases
in. lude pathology of the endocrine system (patients with Turner’s or Klincfclter’s
viidrom.es are sterile).
Psychogenic overload and stress can cause damage (lead to thyrotoxicosis,
l >M, disturbances of the ovarian-menstrual cycle).
Ihe patient’s age has a great significance in endocrine pathology manifesta
.... . Depending on this, endocrine pathology is divided into infantile and juvenile
inlocrinopathy and endocrinopathy of adult or elderly patients. Sex differences are
nl-..» significant in endocrine pathology.

PA TH O G EN ESIS

All typical pathologic processes can develop in the endocrine glands, and also
in i lie organs, whose disease is secondarily manifested by disturbances of the endo
■Пт- gland function. These pathologic processes are the following: inflammation
(including allergic and infectious), neoplasia, thrombosis, atrophy, dystrophy, ge
m ill disorders, dismctabolism.
Г.ill 2 Spccuil (System ic) I’allinpliysiology

Preglandular Dysregulatory Endocrine Disorders

Preglandular dysregulatory endocrine pathology is a disorder of the media

nisins of endocrine system regulation. In such cases pathology develops in (lie
organs (nervous, endocrine), which regulate the endocrine functions. The following
reasons and mechanisms are possible.
• Disorders of higher nervous activity, for example, emotional trauma frequently
leads to endocrine diseases (D M , thyrotoxicosis, amenorrhea). It is the so-called
psychogenic endocrinopathy. Destruction or stimulation of the limbic system, re­
ticular formation, and diencephalon together with irritation or blockade of tin-
central and peripheral mechanisms of autonomic (vegetative) innervation dam
age hormone synthesis or secretion.
• Disorders of the neuroendocrine regulation of the endocrine system is caused
by pathology of the hypothalamus or overlying parts of the brain connected
with it. Hypothalamus pathology usually involves the entire endocrine system
(pluriglandular endocrine insufficiency). These diseases are called neuroendocrine
(hypothalamic syndrome).
• Pathology of the pituitary gland, which secretes tropic regulative hormones lot
the peripheral endocrine glands, causes diverse glandular pathologies, most fre­
quently partial.

IiK 57. Regulation of hormonal balancc in Ihc normal condition (a) and in ease of feedback
mechanism disorders (h — in ease of reduction; с increased hypothalamic excitability) I
I hypothalamus; 2 pituitary gland; I peripheral endocrine gland; II hormone of pcriphef il
gluiul, K ll releasing hormone; TH tropli hoiiiionc ol the pituitary gland
 < ||й|)1|'| К) |,«|||(1||||\л1о1ок.у of I niliH iliic Nyslcm

I >isordcr, of the so-cnllcd reverse connections is an important pathogenetic

mechanism of endocrine instiHiciency (fig. 57). Reduction in hypothalamus sen
itivity to the effect of peripheral hormones leads to a more intensive production
ol releasing factors and tropic hormones. As a result, a peripheral gland at first
и tivates its function and then results in exhaustion and insufficiency. Frequently
a peripheral gland reacts not by function activation, but by tumor formation and
growth (prostate gland adenoma, metrofibroma). If a patient uses some hoi
mones for the purpose of treatment (for example, prednisolone in rheumatism),
i peripheral gland becomes less sensitive to the corresponding tropic adenohypo
physeal hormone. It creates a problem of hormonal therapy withdrawal.
• Ml endocrine glands act as an interrelated system due to interendocrine relations
It leads to a situation, when pathology of one gland causes pathology of anothci
For example, thyroid gland removal leads to lesions of the sex glands and adrenal
cortex.
Disorders of the central regulation of the endocrine system usually leads to
di orders of hormone synthesis and endocrine function.

Glandular Endocrine Disorders

( ilandular hormonal pathology develops as a result of disturbances of any stage

I hormone formation and secretion. Inflammation, infection, autoimmune aggrcs
mhi. vascular disorders (thrombosis), alimentary disturbances and insufficient entry
•и uhstrates and microelements can underlie such disorders.
(ilandular disorders can be total (formation of all hormones of a gland is dis
milted) and partial (formation of one hormone is disrupted) and may be manifested
n hypofunction, hyperfunction and dysfunction.
I he following mechanisms are possible:
disorders of the receptor system on the surface of an endocrine cell, namely,
ciisitivity of these receptors to regulatory signals (as a result, the synthesis of
hormones in response to regulatory nervous and humoral influences stops);
disorders of the intracellular messengers (adenylate cyclase system), which trails
lei signals from the receptors to the genetic apparatus of the endocrine cells
(impairment of Ca2+ ion entry into cells has the same result);
disorders of prohormone transformation into the final hormone;
• deficit of the substrates, microelements and enzymes, which are necessary foi
hormone synthesis;
• disorders of the secretion of the hormone, which is already formed in the glan
dular cells;
• infectious damage to the endocrine glands;
■ damage to the glandular cells by chemical (including drugs) substances;
Immune damage to the endocrine glands (formation of antibodies against hoi
mones and sensitization lymphocytes against endocrine cells);
• neoplastic process in ihe glands (oveipioduclion of hormones by a hormone
luoducing tumor, adenoma);
I'urt 2. S|M4'iitl (S yslrm ii ) l‘ullio|ih>siol(i)(v

• destructive changes of a gland caused hy inllaniinatory and cirrhotic processes,

sclerous changes in the vessels;
• genetic problems of glandular cell functioning;
• blood supply disturbance — thrombosis, embolism.
All variants of glandular endocrine disorders (except hormone-producing in
mors) lead to absolute hormonal insufficiency (see p. 297 about absolute insulin in
sufficiency).

Postglaiulular Endocrine Disorders. Disorders of Peripheral Hormone Action

Poslglandular disturbances of the endocrine function are characterized by inn

m il hormone production, however, changes in the organism are similar to absolute
deficit or surplus of hormones. The clinical picture may correspond to both hypo
and hyperfunction. The causative factor is found outside the endocrine gland. I lie
following reasons are possible:
• impaired formation of secondary mediators, which realize effects of hormones in
cells - cAMP, cG M P, diacylglycerol, inositol triphosphate, calmodulin, protein
kinases;
• disorders of hormone transport in the blood (stronger or weaker binding of a hoi
mone with transport proteins because of an altered quantity of transport protein*
or competitive displacement of hormones with other substances (drugs);
• increased or reduced production of hormone antagonists;
• activated or weakened hormone destruction;
• increased need for hormones (pregnancy);
• genetic pathology of the proteins, which participate in the endocrine function
transport proteins, receptor proteins, antagonists, enzymes that determine Inn
mone binding and release from transport blood proteins;
• pathology of hormone receptors on the somatic target cells, which deterniuu *
their sensitivity to the hormone effect:
•• a decrease of the quantity of receptors;
•• reduction in their affinity to the hormone;
•• formation of antibodies against the receptors;
•• genetic pathology of the receptors.
Most variants of postglandular endocrine disorders lead to relative homioniil
insufficiency. This term is closely connected with the term hormone resistance и
duel ion in the sensitivity of the target cells to the hormone (see p. 20X about retain*
insulin insufficiency and insulin resistance). In the course of aging the quantity unit
sensitivity of receptors usually decreases. The manifestations of hormonal insiilll
cicncy in elderly people are connected with it.

( nmpensatory Adaptive Mechanisms in Kndoerine System

Doth under physiological conditions and in pathology, the endocrine syntofVI

lias adaptive mechanisms, which balance the organism with external and inlninil
media, which constantly change. These met hnuisins are the following:
 < liii|ilri 1(1 l*Mlli<»|>liysiol<»K> <>f I'm lm rlnc System

presence of paired cndociine oik-ihs (the adrenal glands, ovaries, testis);

hypertrophy of a paired organ during a pathological process or removal of one ol
them;
feedback between the peripheral and central organs of the endocrine system;
iI k-synergetic and permissive action of hormones;
liable binding of a hormone with transport proteins;
changes in the quantity of receptors to a hormone on the target cells depend me
on the hormone content in the blood.
Somatic cells are the target of hormone effect. For each hormone they are
■liecific.
C oncluding the common concept about the etiology and pathogenesis of cn
■im tine insufficiency, one should emphasize that the pathophysiological links and
■linical manifestations of endocrine insufficiency depend on the endocrine gland
((■ ntral or peripheral) and the type of target cells, whose function is disrupted.

PA TH O LO G Y O F P IT U IT A R Y GLAND

Adenopituitary hormones are thyrotropic, adrenocorticotropic, gonadotropic

•. well as somatotropin and prolactin. Neuropituitary hormones are formed in the
hypothalamus, but are accumulated by the hypophyseal cells and/or arc released
into the blood through the posterior pituitary. They are vasopressin (syn. antidi
мм he hormone, which influences water retention in the organism and has a vaso
l«ii ssive effect) and oxytocin.
Pituitary pathology may be total (panhypopituitarism) and partial in the form
I .1 separate pathology of the adeno- or neuropituitary gland, hyper- and hypo
function.
Adenopituitary Gland Hyperfunction

Hyperfunction of the adenohypophysis is more frequently partial. The develop

пн nt of a benign tumor (adenoma) from some cells underlies the pathology.
II adenoma develops from eosinophilic cells, hypersecretion of somatotropin
■ ml prolactin takes place.
I lie pathologic influence of an excessive quantity of somatotropin on the or
I'Hinsm is determined by the ability of the hormone to increase the permeability
•I the cell membrane to amino acids and accelerate their inclusion in synthesized
|4i;teins. It stops disintegrative proteolysis.
Somatotropin increases lipolysis and inhibits lipid formation from carbohy-
diates. It activates mobilization of depot fat and thus elevates the content of non
■llicn/.ed fatty acids in the blood. Increased oxidation of lipids in the liver leads to
ketone body formation due to the effect of somatotropin on different links of cai
bohydrate metabolism so that hyperglycemia and diminution of insulin sensitivity
an always observed (metusteroid diabvh's) In inctahypophyscal diabetes lipolysis
11и teases, abundant free fatty acids loiin plenty ol acetyl-CoA thus glyconeo
Кdiesis increases (other types ol metasleiold dlabclcN are noted on p. 21X>.
Г.ill 2 N|M'i'IhI (N yslcm lc) I'ulhophysioloio

I he pathologic effect of somatotropin on the connective tissue, hone and cat

tilage tissue is stipulated by the ability of this hormone to stimulate the pathologic
formation of oxyproline (the most important component of collagen) and chon
droitin sulphate.
I hesc and other effects of somatotropin are explained by the formation ol
special protein factors (somatomedins), which are formed in the liver under the
inllucncc of somatotropin.
Hyperfunction of somatotropin in the human body is exhibited as pituitary gi
gam ism or acromegaly, depending at what age of the patient the pathology begins
riiu iia ry gigantism develops in excessive secretion of somatotropin at young
age, before the epiphyseal cartilages fuse.
In adults, after epiphyseal suture fusion and body growth completion, hormonal
.lulls cause acromegaly. In this disease separate parts of the body are disproportion
ately enlarged, facial features are also enlarged. Simultaneously, splanchnomcgalv
(enlargement of the liver, spleen, heart) develops. These changes are stipulated by
the growth of the soft tissues. In acromegaly the concentration of somatotropin in
the blood can exceed the normal parameters by 100 times and more.
IГ adenoma develops from the adenopituitary basophilic cells, which produce
adrcnocorticotropin, Itsenko—Cushing's disease develops. A consequence of com
cotropin hyperproduction is excessive secretion of glucocorticoids by the adrenal
glands.
Adenopituitary Gland Hypofunction

io ta l hypofunction of the adenopituitary gland (panhypopituitarism) develop*

when all regions of the adenohypophysis are affected. It may be congenital or ai
quired It leads to pluriglandular endocrine insufficiency.
I he most frequently observed acquired causes of this disease are tumors, post
natal necrosis of the pituitary gland, injury of the skull base, inflammation, throni
husis and viral infections. When more than 95 % of the gland mass is destroyed
adult people develop pituitary cachexia (Simmonds disease). It is characterized t»\
severe cachexia and atrophy of the thyroid, adrenal and sex glands, muscle lissm
visceral organs, destruction of the bone tissue, falling out of hair and teeth, hint
lioual disorders of the vegetative nervous system, hypoglycemia, increased scnsitivi
tv to insulin. Most of disorders are connected with cessation of somatotropin iiihI
thyrotropin secretion.
Partial hypofunction is a decreased production of any pituitary hormone.
I ally (including at the embryonic stage) impairment or decrease of the
inatotropic function of the pituitary gland leads to dwarfism (pituitary nanism) \
decrease til protein synthesis rate leads to atrophy of the muscular and connecltvi
tissues, which is externally manifested by skin flabbiness and aging. The sexual «и
gaits remain infantile (hypogenitalism). Decreased functioning of the thyroid glainl
endocrine metabolic disorders and decreased reactivity of the organism are tin
disease manifestations.
 < Im plo UI 1’iilhiiphysloloio of M K ' r i n r System

I’artial gonadotropic itisnlTlcioiicy leads to infantilism: in girls it leads to ah

ii'ncc of menstruation, infertility. In boys il leads to hypoplasia of the testis, incom
pli te physical development and hypogenitalism.

Neuropituitary Gland Pathology

Increased secretion of vasopressin promotes water reabsorption in the renal

tubules and accumulation of liquids in the organism. It plays an important role in
(1и pathogenesis of systemic edema. Reflex anuria in pain shock also results from
im ivased secretion of vasopressin. A relative increase of vasopressin secretion oc
«ms in liver cirrhosis, when inactivation of the hormone is inhibited.
Vasopressin deficiency inhibits water reabsorption in the renal tubules, which
и ults in polyuria and arterial hypotension. The patients excrete 3-8 I of urine
nil a low specific gravity. Sometimes diuresis makes 10—12 1 and more (diabetes
ln\ipidus).

PA TH O LO G Y O F T H Y R O ID GLAND

I he basic hormone of the thyroid gland — thyroxin — actively influences me

inltolism, especially the basal one.
Causes of the pathology may be environmental (physical, chemical, biologi
ill. immune, and genetic. Thyroid pathology may be total (in thyroidectomy) and
inirtial (selective deficit of thyroxin or calcitonin).
All typical pathological processes may develop in the thyroid gland — inflam-
Hi.ition (including allergic), neoplasia, disorders of blood circulation (thrombosis,
littnorrhage).
Tumors may develop from glandular cells (adenoma, cancer). Enlargement of
tin thyroid gland may be diffuse (caused by elevation of TTH secretion as in Base
.low's disease), and local (as a thyroid nodule caused by a benign or malignant neo
iH.ism). A benign tumor may produce hormones (hormone-producing tumor) and
i . ociate with hormone hypoproduction. Goiter is a tumor of the thyroid gland.
Immune mechanisms play an important role in thyroid pathology. The pat ho
• ncsis of some thyroid diseases involves an autoimmune process. The following
ktihstances may serve as antigens — thyroglobulin, thyroid enzymes, receptors. Van
' 'its thyroid antigens sensitize body’s own lymphocytes. As to antibodies, they may
inhibit or stimulate glandular cells. Receptors to thyrotropic hormone (located on
thvrocytes) may accept antibodies as a signal of thyrotropic hormone (effect of
•.mutilation will be a result of this allergic mechanism, see p. 91). Environmental
l.и tors (viral or bacterial infection, high iodine intake) and genetic factors (imnui
nodi liciency) may be responsible for initiating autoimmune thyroid disease.
Pathology of the thyroid gland manifests itself through hyperfunction (hypei
thvroidism, or thyrotoxicosis, caused by .in euess of thyroid hormone) and hypo
liintiion (hypothyroidism caused by a ddu icncv ol thyroid hormone).
Г.и! 2. S|M4-lal (Systcm lc) l*nlli«»|>hysi<»l<>K>

HYPERFUNCTION (IIYPKKTIIYROID1SM)

Mypcrfunction (thyrotoxicosis) combines pathophysiological and clinical sign

ol increased functioning or toxic action of thyroxin and triiodothyronine. Then
absolute or relative increase underlies the pathology.

Etiology and Pathogenesis

I hc causes of thyroid gland hyperfunction are hyperstimulation of the gland l>v

the central endocrine organs (hypothalamus, hypophysis), stimulating antibodu-.,
abuse of hormonal drugs in replacement therapy.
Mypcrfunction of the thyroid gland has several pathogenetic mechanisms. The
main mechanisms of an increased effect of thyroid hormones, which lead to thyro
toxicosis development, are the following:
• thyroid hormone overproduction (absolute excess of the hormone), which result-,
from:
•• stimulation of the thyroid gland by the hypothalamus;
•• stimulation of the thyroid gland by the pituitary gland (pituitary inscnsiti
vity to thyroid hormones);
•• hypersecretion of the hypophyseal thyrotropic hormone (adenoma of tlu-
pituitary gland as a frequent cause);
•• irritation of receptors on the thyrocyte surface by stimulating antibodies,
•• hypertrophy of thyroid glandular cells;
•• inflammation of the gland (lymphocytic or granulomatous thyroiditis);
•• hormone-producing tumor of the thyroid gland (toxic multinodular goitei
follicular adenoma, metastatic follicular thyroid carcinoma);
•• interglandular interaction in germ cell tumors (hormone-producing cho
riocarcinoma, ovarian teratoma);
• relative excess of the hormone as a result of:
•• weakening of bonds between thyroxin and thyroxin-binding globulin;
•• increased sensitivity of the tissues subject to thyroxin influence;
• disorder of thyroid gland hormone destruction.

Basedow's Disease

Basedow’s disease is diffuse toxic goiter.

Etiology and Pathogenesis

The most important etiological factor of thyrotoxicosis in man is mental ti.ni

nia Infection and allergy «ire considered to be predisposing factors.
In excess of thyroxin and triiodothyronine, the number of mitochondria ш
target cells increases, they swell. An increase of the activity of oxidizing en/yniM
(succinate dehydrogenase, cytochrome oxidase, glycerophosphate dehydrogena-.i l
Na\ ATPasc is observed.
 ( liii|itri III I'u llio p liy s lo lo K V ill I'Im Iih tIiic System

Due to the increased sphlluiK ol glycogen in the liver and muscle tissue, hy
1'i iglycemia is marked. Utilisation of glucose in tissues is accelerated, the activity
••I hexokinase is increased.
Abundance of thyroid hormones inhibits transformation of carbohydrates into
tin-, accelerates disintegration of cholesterol and its utilization by tissues, intensi
lii hit oxidation in the liver and increases the sensitivity of the fatty tissue to tlu-
lipolytic effect of adrenaline. Due to this, mobilization of depot lipids rises, which
plains why thyrotoxicosis patients lose weight and why hypercholesterolemia and
ki-ionemia occur.
Negative nitrogen balance testifies to predominance of protein catabolism.

Manifestations

Hasedow’s disease is characterized by a typical syndrome: enlargement of the

Humid gland, exophthalmus, heat production increase, tachycardia, arrhythmia,
in nibling fingers, psychic excitement increase, vibration, basal metabolism in
i n iise, emaciation.
An excess of thyroid hormones disturbs the metabolism of the cardiac muscle
I »\slrophic changes in the myocardium, disorders of atrioventricular conductivity,
им i loading of the left ventricle are revealed. The energetic and plastic maintenance
"I i ardiac activity is disturbed. «Thyrotoxic* heart reacts inadequately to cholin
i ikii and adrenergic influences.

HYPOFUNCTION (HYPOTHYROIDISM)

Hypothyroidism combines pathophysiological and clinical signs of a decreased

Mm lion of thyroxin and triiodothyronine. Their absolute (defects in hormone bio
viithesis) or relative (diminished hormone release or problems of transport and
nsitivity of target cells) decrease underlies the pathology.
Hypofunction of the thyroid gland has several pathogenetic mechanisms. The
иitiin causes and mechanisms of a decreased effect of thyroid hormones are noted
In'low.

I llology and Pathogenesis

I he etiological factors and causes of hypothyroidism are:

• thyroid surgery (including experimental thyroidectomy);
• radioactive iodine excess due to drug overdose (I31 radiation treatment for
hyperthyroidism, external beam radiation therapy for head and neck can
cer);
• damage of the gland by thyroslalic substances;
• infectious agents;
• deficiency of iodine and cobalt in the environment;
In the pathogenesis of hypothyroidism sm h mechanisms arc obvious:
• deficient IT II secretion;
I ’n il 2 S | m-« liil (N vslriim ) I’ulhophysioloKy

• inflammation, which suppresses (ho thyroid function (lymphocytic thyroidi

iis);
• autoimmune aggression against the glandular epithelium;
• tumors with inhibited function of the thyroid gland (Hashimoto’s disease);
• destruction of the gland by a cirrhotic processes, sclerotic change in the vcs
sols, neoplasia;
• congenital causes of the defects of thyroid hormone biosynthesis connccted
with congenital hypoplasia or aplasia of the thyroid gland;
• resistance of target cells to the thyroid hormone.
Hypothyroidism is manifested by basal metabolism reduction, decreased blood
sugar level, a tendency towards atherosclerosis, enhancement of destructive pro
cesses, edemas, arrested child development.
In severe thyroid gland insufficiency, which is congenital or has developed in
early childhood, cretinism develops, in adult people — myxedema.

Myxedema

Myxedema is hypothyreosis accompanied by specific (mucous) edema (see

p. 259).
Myxedema is characterized by a decrease of metabolism and body tempera
lure, obesity, and sluggishness. As a result of increased hydration of the skin and
subcutaneous tissue and high accumulation of hydrophilic mucous substances in
them the face becomes puffy, the nose and lips become thicker. Brittle nails, han
loss and other trophic disorders are marked. The sexual function, intellect, an«l
memory gradually decrease, apathy and sleepiness appear, and ultimately dementia
appears.
GOITER

( ioitcr is an enlargement of the thyroid gland.

I here are 3 types of goiter:
• Thyrotoxic (with increased functioning of the thyroid gland).
• Hypothyroid (with reduced functioning of the thyroid gland).
• Endemic (with normal functioning of the thyroid gland).
rhe first two types have been described above as Basedow’s disease ami
Ilashimoto's thyroiditis.
I ndemic goiter is an enlargement (hyperplasia) of the thyroid gland due in
iodine deficit in the environment (in water and food). In this case thyroxin prodiu
lion may remain normal due to an increase in the mass (compensatory hyperplasia)
ol ihe gland (it does not always restore the function of the gland if it is a deficit ol
iodine in the environment).
I his disease is widespread in the Alps, Carpathians, Himalayas, Andes, when
Ihc soil and water contain a little amount of iodine. Iodine deficiency stipulate*
a decrease of thyroxin and triiodothyronine synthesis, and due to (his thyrotropin
production increases in the pituitary gland In iis turn it leads lo hyperplasia ol tin
thyroid gland, whose mass sometimes tea» lies a couple of kilograms.
 < Intplci И) Ги11|о||||\ч1о1оку of I'ih I ih t Iim' System

CAM I MININ M l KM ION inSOKDKKS

Disorders of calcitonin seeret ion are another example of partial thyroid gland
pathology.
Calcitonin is synthesized in the intrafollicular cells of the thyroid gland. The
main function of calcitonin is to lower the serum calcium level. This hormone is re
i< i ,cd in response to hypercalcemia. Calcitonin receptors are located in the kidneys
mil bones. The interaction between calcitonin and receptors stimulates adenylate
i vclase activity and cAM P generation.
Calcitonin receptors are found on osteoclasts, and calcitonin accomplishes its
■iK'cl acting directly on them. Calcitonin inhibits bone resorption and blocks the
if lease of calcium and phosphate from the bones. The latter effect is apparent within
minutes after calcitonin administration. This effect, along with resorption inhibition,
ultimately decreases the serum level of calcium and phosphate. Calcitonin blocks
•’one resorption induced by a variety of hormones, including the parathyroid hoi
mono and vitamin D. Calcitonin potency depends on the rate of bone resorption
Receptors for calcitonin are localized in the cortical thick ascending limb of I lie
llcnle’s loop. Calcitonin affects the kidneys, which leads to mild phosphaturia

PA TH O LO G Y O F PA RA TH YR O ID GLAND

Pathology of the parathyroid gland is associated with absolute or relative chang

* . of the concentration of the hormone parathyrin in the blood.

Hyperfunction

I linlogy and Pathogenesis

Under experimental conditions hyperparathyrosis is modeled by an injection of

ilu hormone to an animal.
In clinical practice, primary and secondary hyperparathyrosis is observed.
Primary hyperparathyroidism develops due to excessive production of parathy-
1"id hormone (parathyrin) by the parathyroid gland. Under clinical conditions hy-
r iparathyrosis occurs in benign (adenoma, 80—85 % cases) or hormone-producing
malignant (carcinoma, 2—5 % cases) tumors of the gland. Diffuse hyperplasia causes
ilu disease in 10 % cases.
Secondary hyperparathyroidism develops as a complication due to pathology
in other organs (reduced Ca2+absorption in the intestine, skeletal resistance to
lui.iihyrin, chronic renal insufficiency). In most cases of secondary hyperparathy
•oidism, parathyroid hyperplasia regresses substantially correcting the underlying
iilinormality.
An excess of parathyrin leads to
• increased formation and activity nl osteoclasts, which realize hone resorp
lion;
Part 2. Spccial (S vs in n ic) ralliuph.vsioluK)

• inhibition of osteoclast differentiation into osteoblasts, which participate In

the formation of the bone tissue;
• increased reabsorption of phosphate ions in the renal tubules;
• increased absorption of calcium in the intestine;
• increased formation of soluble calcium salts in the bone tissue;
• increased content of insoluble calcium phosphate in different organs, cspr
dally in the kidneys;
• decreased reabsorption of phosphate ions in the renal tubules.

Manifestations

In an animal with experimental chronic parathyrosis osteoporosis is observed

together with accumulation of calcium salts in the kidneys, lungs, heart and otlwf
organs. The vessel walls become thick, and blood pressure increases. The anininl
dies from uremia as a rule.
In patients the so-called generalized fibrous osteodystrophy develops. It is chur
acterized by pain in the muscles, bones, joints, deformation of the skeleton,
teomalacia. The bones lose their mineral components, which are accumulated in
the muscles and internal organs. Nephrocalcinosis, narrowing of the renal tubuM
lumen, or nephrolithiasis, lumen occlusion by calculi, develop. This results in gr;iv*
renal insufficiency. Due to calcareous deposition in the walls of the great vessel»,
hemodynamics and blood supply of the tissues are disturbed.

Hypofunction

Etiology and Pathogenesis

Etiological factors and causes of parathyroid hypofunction may be exogenom

and endogenous.
Under experimental conditions, hypoparathyroidism is reproduced by removal
of the glands in an animal.
In people under clinical conditions hypoparathyroidism occurs most often >tt
a complication of thyroid and parathyroid surgery (after occasional removal of ilif
parathyroid gland by means of thyroidectomy), damage of the parathyroid glniiil
in the course of I31 therapy of Basedow’s disease or thyroid cancer. A tumor к
the parathyroid gland may cause its hypofunction. There are hereditary forms if
hypoparathyroidism (autosomal dominant or recessive and X-linked recessive) Au­
toimmune aggression in case of DiGeorge syndrome (autosomal recessive imniuiHl
deficiency with congenital absence of the parathyroid gland and thymic dysgent'MI
or agenesis) is also a reason.
Relative hypofunction of the gland is marked in accelerated growth, pregmint v
lactation and other conditions when the organism requires more calcium anil III
salts.
The main evidence of hypoparathyroidism is hypocalccmia, which eventual*
in different disorders. Mineral imhiilnncc is conditioned by:
 ( ||й |Н г | III l ’M lhoph.vsioloK .v o f I iii Ii k m i i c S y s t e m

•decreased absoфtion of calcium in Ihe intestine;

• increased reabsorption of phosphates in the renal tubules.
Simultaneously with hypocalcemia, the content of non-organic phosphorus in
Ни hlood is increased. Electrolyte balance is critically disturbed. The correlation
Mwrcn univalent (Na, K ) and bivalent (Ca, Mg) ions changes due to reduction
•i -alcium concentration in the blood from 2.25—2.99 to 1.0-1.25 mmol/l. As a
Mill, neuromuscular excitability increases.
Ihc disintoxicating function of the liver is connected with the parathyroid
function. In hypoparathyroidism it is impaired. Feeding of parathyroectomi/.cd
••••»’ ■with meat intensifies tetanus due to insufficient disintoxication of nitrous me
i lUilism products, in particular, decreased ability of the liver to convert ammonium
lulu urea.

'l,inifi‘stations

In 1-2 days after parathyroidectomy experimental animals become languid.

Mhse to eat, are thirsty, have a low body temperature, dyspnea. The animals dir
liming one of the episodes of convulsions.
Hie pathogenesis and clinical picture of hypoparathyroidism in man are closr
p those observed in experimental animals. Dysfunction of the parathyroid gland
I* nils in the development of parathyroprival tetany. There are multiple fibrillar
ii nMiisions of the body muscles, which are then followed by episodes of clonic
■’iiwilsions. Clonic convulsions transform into the tonic ones, opisthotonus dr
и lnps (the head and heels arch backwards in extreme hyperextension and the
|h»i\ forms a reverse bow). Spastic contractions may spread to the internal organs
||nhiro , laryngo- and bronchospasm). Laryngospasm is very dangerous as it may
. asphyxia and death.
( hildren of the Iя and 2ndyear of life may have spasmophilia — periodic spasms
И ihr muscles, arising in environmental temperature rise and other unfavorable
hilhirnces.
Ik low a list of clinical syndromes is given.
I SvHlemic: weakness, easy fatigue, weight loss, anemia, anorexia, itch.
I Nt uropsychiatry: depression, psychosis, mental retardation, poor concentration,
im nюгу deficits, peripheral sensory neuropathy, paresthesia.
I Neuromuscular motor neuropathy, generalized muscle weakness, peripheral
■ usury neuropathy, muscle cramps, Parkinsonism,
i i h ular: keratopathy, cataract,
i i auliac: changes in QT interval, T wave changes.
!<•n.il ncphrocalcinosis, polyuria, polydipsia, metabolic acidosis.
i I' lrtal: osteopathy, pathologic fractures, tumors of bones, bone pain, gout,
•liuiidrocalcinosis.
• i i r iiointestinal: peptic ulcer disease, pancreatitis, constipation, nausea, vomit
I tutt
I ii nlal: enamel hypoplasia, defective ими formation.
I(i spiratory: laryngospasm, bioin hospnsm
Г.mi ’ S|M4'iul <Syst«*mic-> r,illio|ili\sinlii| \

PA TH O LO G Y O F ADKKNAL (J IA N OS

I here arc two important parts of the adrenal glands — cortex and medulla.
In the adrenal cortex three groups of hormones are produced - glucocorticoid-,
(cortisole, there is a description of glucocorticoid effect in table 12), mineralocoi
iicoids (aldosterone), and sex hormones. Noradrenaline is produced in the adrenal
medulla.
Pathology of the adrenal glands is divided into pathology of the adrenal cortex
uul ol the adrenal medulla, and further into total and p artial as well as hyperfunction
and hypo/unction.

Table 12
Effects of Glucocorticoids
Target Effect Mechanisms
Inhibition of glucose uptake and metabo
Muscle Catabolic lism. Decrease of protein synthesis. In­
crease of amino acids and lactate release
Stimulation of lipolysis. Increase of free
liit Lipolytic-
fatty acids and glycerol release
Increase of glyconeogenesis. Increase of
glycogen synthesis. Increase of glucosc-
l.iver Synthetic
6-phosphatase activity. Increase of the
blood glucose level (hyperglycemia).
Reduction of the number of circulating
lymphocytes, monocytes, eosinophils,
Suppression basophiles. Inhibition of the production
Immune of IL-2 by T-lymphocytes. Decrease of
system antibody and PG production
Decrease of neutrophil, monocyte, lym­
Anti-inflammatory
phocyte migration to the sites of injury
Increase of cardiac output.
( 'ardiovascular Permissive effect on catecholamines, con
1ncrea.se of peripheral vas­
system traction of the peripheral vessels
cular tone
Increase of glomerular fil­
Renal
tration rate. Participation in Na+and water retention
system
water-electrolyte balance
Resistance to stress. Insulin
( Xher Increase of the blood glucose level
antagonism

ADKKNAL CORTEX IIY I’KKI-IJNCTION

Hyperfunction of the adrenal cortcx occurs in bilateral hyperplasia, formation

ol a hormone producing tumor (adenoma), and also in hypcrstimulation ol ili<
adrenal cortcx by the hypothalamus and pituitary gland
 ( 11 11*i • i HI Г м И ш р Ь у л Ы п к у (if E n d o c r i n e S y s t e m

More often it is chronic partial hyperfunction associated with hyperplasia of a

•'parate /one of the adrenal cortex fascicular, glomerular, or reticular. Due to
this hyperfunction is manifested in the form of three syndromes — hypcrcorticism,
hyperaldosteronism and adrenogenital syndrome.

Hypcrcorticism

Hypcrcorticism occurs in bilateral hyperplasia or a hormone-producing tumor

•'I the fascicular zone, ACTH stimulation, and enzyme deficiency. Itsenko—Cushing
\vndrome is a clinical example of a primary affection of the adrenal cortex in case
' 'I a hormone-producing tumor (adenoma) from the fascicular zone cells. Excessive
■i rction of cortisole is the main pathogenetic link, which determines the clinical
picture.
I he etiology of Itsenko—Cushing syndrome and Itsenko—Cushing disease is
different, but the clinical symptoms and pathogenesis are similar.
Manifestations of the syndrome are:
• catabolic effect (negative nitrogen balance, a decrease of protein synthesis);
• hyperglycemia (due to glyconeogenesis activation, antagonism with insulin)
which can assume the form of metasteroid diabetes;
• obesity with prevailing fat deposition on the face («moon face»);
immunodepression (due to lymphopenia and eosinopenia, inhibition of phagocy­
tosis and antibody production as well as cellular immune reactions and decreased
interleukin production);
• increase of arterial blood pressure (contraction of peripheral blood vessels, pci
missive effect of catecholamines, PG inhibition);
• increase in gastric juice acidity and the risk of stomach ulcer formation;
• dystrophic changes in the muscles, bones (osteoporosis), joints;
■ inhibition of regenerative processes;
• hypocoagulation (depressed synthesis of procoagulants and platelets).

11\peraldosteronism

Hyperaldosteronism may be primary and secondary.

Primary hyperaldosteronism (excessive production of aldosterone) is caused by
nt. noma of the glomerular zone cells of the adrenal cortex.
Secondary hyperaldosteronism is observed in many pathologic conditions. The
1 1.>inerular zone cells of the adrenal glands intensify production of aldosterone undei
ih* influence of angiotensin, ACTH (permissive effect), K +excess and Na' deficit
In ihe blood plasma. Atrial natriuretic hormone, dopamine and a high extracellular
i uiiccnlration of Na* inhibit aldosterone secretion. So, in case of decreased renal
liluod supply (acute blood loss, acute arterial hypotension, hypovolemia, acute and
i hmiiic cardiac insufficiency, livei cmlimls, kidney diseases with disorders of renal
i in illation) increased secretion ol u-ihii by luxtaglomcrular cells takes place wilh
I lit* following excessive formation ol ницlot г list n and aldosterone (fig. 5X).
Pltrl } S|M4 lul (Syntonic) rnllio|ilivsHiloK>

liy. 58. Feedback mechanism regulating aldosterone secretion and «vicious circle» formal...
in pathology

Under Ihc influence of excessive aldosterone the following biochcmu.il

pathophysiological and clinical phenomena develop:
• sodium ion retention;
• loss of potassium and chlorine ions;
• arterial hypertension (due to high concentration of sodium ions in the vessel wall
cells that increases their sensitivity to sympathetic mediators and other v&socon
strictivc mechanisms);
• myasthenia and paresis, attacks of skeletal muscle spasms;
• disorders of myocardial contractile function (due to loss of potassium and cltlo
rme ions);
• imngaseous alkalosis;
• water retention.
In spite of water retention, edema does not develop in all cases. Its develop
men! depends on Ihc sensitivity of the renal tubules to vasopressin. If they hetuim
dystrophic, they lose the ability to react to vasopressin. So, polyuria develop*,
which explains ihe absence of edema in primary hyperaldostcronism.
 ( 'huplri «I Ги11|1)|)||уч|||1ок.У of KmliHTim* System

Xilmiogenital Syndrome

Adrenogenital syndrome in children is a clinical manifestation of congenital

hyperplasia of the adrenal cortex.
Development of this syndrome is connected with hereditary blockade of coi
iisol synthesis. It eventuates in counterinhibition of corticotropin secretion, which
in its turn stimulates secretion of androgens in the adrenal glands. The latter have a
M iili/ in g effect (evident masculine appearance and signs) in the intrauterine period.
<onsequences of hormonal disorders may be different — from mild masculinization
и» severe anatomic abnormalities of physical and sexual development.
In boys this pathology causes premature development of the secondary sexual
■ii.iracters. Girls are often born with pseudohermaphroditism. The androgenital
uidrome in children is characterized by a deep disorder of enzymes, which partici
pule in the biosynthesis of steroid hormones and is accompanied by severe walei
rlcctrolyte imbalance (syndrome of salt loss). If hormone synthesis is blocked,
i u cssive desoxicortisone (a steroid with mineralocorticoid properties) is formed As
i consequence, grave arterial hypertension develops. Without substitution therapy
vslih corticosteroids children die at early age.
Adults and children can have hyperestrogenization and hyperandrogeni/ation
"I ihe organism in case of tumor degeneration of the reticular zone of the adrenal
Mtitex. Depending on the character of hormone secretion and the patient’s sex
uilization (in women) and feminization (in men) are observed, or a person has
pu-mature sexual development.

ADRENAL CORTEX HYPOFUNCTION

Cortex hypofunction is more often total. It occurs in bilateral gland destruc­

tion, autoimmune aggression, bacteremia (tuberculosis, meningococcal and other
inlcctions), ischemia, shock, hemorrhage, carcinoma or metastatic tumor (in case
I lung carcinoma). It has two forms — acute (experimental extirpation of the ad
и nal gland) and chronic (as a result of chronic processes (inflammation, tumors),
which destroy the gland).

\nilo Hypofunction

Acute adrenal cortical hypofunction is modeled under experimental conditions

in adrenalectomy. In man it can develop due to a hemorrhage into the adrenal
i'I. i i k Is or necrosis.

I xclusion of corticoid function (glucocorticoids and mineralocorticoids) is

Mini с important because cessation of adrenal medullary hormone (noradrenaline) is
■onipensated by catecholamine formation hy the sympathetic nervous system.
Alter adrenalectomy experimental animals die in some days. Arterial Mood
im ssiirc, blood glucose level and body ii iii|K-i.ilure decrease. Resistance of the oi
v inism I») overcooling decreases
P n r t .’ S |M 4'ln l ( S ) s ( r l l l l l I l ‘ll(llO|llnsi<ll<»f(V

I xclusion of glucocorticoid function lias the following biochemical anil

pathophysiological manifestations.
Hypoglycemia has some mechanisms of development and is connected wilh
exclusion of glucocorticoid function in carbohydrate metabolism. The mechanism ,
are the following:
• reduction of glucose-6-phosphatase activity;
• inhibition of glyconeogenesis;
• reduction of the glycogen depot in the liver and muscles;
• reduction of the glycogenolysis rate in the liver cells;
• reduced insulin sensitivity;
• increased glucose tolerance.
iricria l hypotension is connected with weakening of the vasoconstrictive action
of catecholamines, to which corticosteroids have a permissive effect.
Some disorders are connected with exclusion of aldosterone function. They arc
described below.
A decrease o f the circulating blood volume (hypovolem ia) plays an important
role in the genesis of acute adrenal gland insufficiency and arterial blood pressun-
decrease. It is connected with water-electrolyte imbalance. Under physiological
conditions aldosterone supports the sodium pump, ensures reabsorption of sodium
ions m the distal parts of the renal tubules. After adrenal gland removal sodium ions
.ne excreted in the urine, therefore the content of sodium in the blood plasma is
reduced. At the beginning, there is marked polyuria, but later oliguria, anuria and
watci poisoning develop. Potassium leaves cardiomyocytes. An increase of potas
siuin ion concentration in the plasma causes disorders of bioelectric processes.
Disorders of electrolyte balance and bioelectric processes eventuate in cardiac
insufficiency. Heart rate and force are disordered, which are manifested as arrhyth
niia (up to ciliary arrhythmia). The contractility of the cross-striated muscle tissue
is decreased (the symptom of muscle weakness).
At the terminal stage of acute adrenal insufficiency, urination stops completely
Ilu- patient's pulse and breathing decelerate.

( lironlc 11>|»<li nnet ion

( 'hronic hypofunction occurs in bilateral adrenal gland destruction (autoiin

шипе aggression, tuberculosis).
( hronic hypoadrenocorticism is characterized by cmaciation, rapid psychii
l.itlgability, bad appetite, alimentary canal dysfunction, arterial hypotension, psv
i hical depression, muscle weakness, disorders of the growth and maturation ot
hlldrcn.
In a patient with chronic adrenal hypofunction, different pathogenic influcncr*
.ik h as trauma, infection, hemorrhages and even tooth extraction can cause aeule
nsullkicncy of the adrenal cortex. Organism resistance is suppressed.
In man it is known as Addison's disease (bronze skin disease) Il develops mote
•Men because til tuberculosis of the adrenal glands, atrophy ol the cortical sub
tam e alter severe infectious diseases I'rogiessivc hypcipignientation of the skin is
 I lu p in 10, I'ulhophysiolitto' <>f EnUocrint- System

observed. The mechanism of hyperpigmentation is connected with intensification

ol the melanostimulating activity of the pituitary gland, which is concomitant to an
increase of corticotropin secretion during hypoadrenocorticism.

Problems of Glucocorticoid Therapy Abuse

Problems of glucocorticoid therapy abuse are connected with the phenomenon

nl adrenal cortex hyper- and hypofunction.
Glucocorticoids are used as immunodepressants in the treatment for allergic
diseases (bronchial asthma, rheumatism, etc.). The side effects of this therapy re­
semble the picture of chronic hypercorticism (mentioned above). They are:
• catabolic effect (negative nitrogen balance);
• hyperglycemia (metasteroid diabetes);
• deposition of fats (especially on the face — «moon face»);
• decreased immune resistance to infection;
• arterial hypertension;
• predisposition to hemorrhages;
• increase in gastric acidity and predisposition to stomach ulcers;
• osteoporosis;
• inhibition of cellular division and regenerative processes, wound healing and
fracture union;
• teratogenic action;
• psychotropic effect (psychosis development);
• disorders of the growth and maturation of the children, who have been
treated with corticosteroids for a long time.
Prolonged treatment with corticosteroids and hormone abuse cause hormone
ilqx'ndence. It means that production of body’s own glucocorticoids reduces. Ac-
«idcntal cessation of this hormonal therapy is accompanied by the development of
withdrawal syndrome. The clinical picture is manifested as (sub)acute hypofunction
cl the adrenal cortex with the following clinical signs (mentioned above): hypo
i-lycemia, arterial hypotension, physical depression, muscle weakness, fatigability,
weight loss, decrease of the general resistance of the organism. Any additional
pathogenic influence causes grave complications.

ADRENAL M ED U LLA D ISO R D ERS

Hyperfunction of the adrenal medulla is connected with hypersecretion ol

•ntccholamines. It is observed in hyperplasia (rare) or pheochromocytoma (a tumor
originating from the adrenal medulla), ganglioneuroma, and neuroblastoma.
Its manifestations include paroxysmal or stable arterial hypertension, tachycai
ili.I, acute pain in the epigastrium, profuse sweating. Attacks result from massive
adrenaline and noradrenaline release into the blood under the influence of psychi
t.il and mental load or otlici conditions
I’iiiI l Ч|М'«'1и1 <System ic) l‘ttllHi|tliv<>loloKy

CO N C EP1’ OK S T R E S S

Stress was mentioned in many chapters of this textbook as a reason for disease*
(arterial hypertension, p. 37X, myocardial infarction, p. 346, stomach ulcer, p. I I
DM, p. 213, thyrotoxicosis, etc.).
I he concept of stress is connected with the physiological role and ра(1ю1окл "I
the adrenal cortex. Canadian scientist Hans Selye is the author of this widespn .nl
theory.
Selye noticed under experimental conditions that any harmful inllucncc (или
ina, infection, overcooling, intoxication, muscle overload) causes a complex ol
changes in the thymus, adrenal glands, lymph nodes, blood composition and me
Inbolism. He focused special attention on the changes in the endocrine glands Hi
particular, in the hypothalamic-adrenal cortex system.
He noticed that any harmful influence is accompanied by:
• activation of the adenopituitary gland (the role of ACTH secretion was и
vcalcd);
• hypertrophy of the adrenal cortex;
• increased content of secretory granules in the cells of the adrenal cortex
I he physiological role of glucocorticoids in the activation of organism Iiiim
lions was revealed. It consists in:
• activation of glyconeogenesis;
• increase of the blood glucose level (hyperglycemia);
• reorganization of metabolism;
• increase of energy formation;
• protection of membranes from damage;
• antipyretic effect;
• antiallergic effect;
• support of the catecholamine effect (permissive effect).
Selye interpreted these changes as nonspecific adaptive reactions develop. < 1
.H maximum. He named this group of symptoms systemic (nonspecific) adupilt*
syndrome. Selye drew a conclusion that it is hormones of the adenopituitary (mi
licotropin) and adrenal cortex (corticosteroids) that play a significant role in 1 1*»
development of adaptation. He called them adaptive hormones.
I arlier W. Cannon and L. Orbclly studied the role of the sympathetic pmI "|
the vegetative nervous system in adaptive and trophic reactions. Selye added ilu
concept of an important role of the endocrine system, especially of the role ol pliu
il arv and adrenal hormones in organism adaptation to the influence of patho|>cn№
I.к tors I hus, adaptation is a complex of nonspecific reactions with parlicipiill..... I
Ihe nervous system anil emloerine glands.
Al the same time Selye revealed by experiments that prolonged nonspecific nl ip
live reactions cause a typical complex of nonspecific signs of damage. They aie
• involution ol the thymico-lymphatic apparatus;
• eosinopeuia;
• hemorrhage ulcers in the mucous mcmhninc of Ihe gastrointestinal tract
Selye connected il with Ihe prolonged effect of adrenal cortex hormones II wm
Selye who introduced ihe term stress in medical science.
 ( h iin li i III I'M llinpliY sliiliiK V o f Im liK 'rilK ' S y s t e m

Stress is a nonspecific reactions of adaptation, which is characterized by reorga­

nization of nervous and humoral regulation (developed at maximum) to the action of
<«••> strong influence (stressor), directed at organism resistance increase and capable
lo damage the organism.
St», wc sec the double meaning of stress. On the one hand, it is adaptation
l>ioiuoting life due to release of adaptive hormones. On the other hand (under pro
lunged duration), it is a mechanism of damage.

‘.luges of Stress

Stress manifests itself in three stages (fig. 59). They are: 1) alarm reaction;
'I siage of resistance; 3) stage of exhaustion.
Slii*4sor

Fig. 59. Stages o f stress

and the amount o f adre­
nal cortex hormones

Alarm reaction means immediate mobilization of the organism. It is further

Mil>divided into shock and anti-shock phases. In the shock phase there are muscu
i n .uul arterial hypotension, hypothermia, hypoglycemia, eosinopenia, increased
|H-inicability of the capillaries, prevalence of catabolic processes. The phase of
пип shock is characterized by reverse changes — increased arterial blood pressure,
ним le tone and blood glucose level. An increase of corticotropin and corticoste
иMil blood level occurs due to hormone reserve release.
I he stage o f resistance is a stage of compensation and prevalence of defense
и .и lions. The adrenal cortex is hypertrophied and secretes an additional amount ol
I'ini ocorticoids. Anabolic processes prevail. Glyconeogenesis is intensified. At this
«I ip' there is such a peculiarity — organism resistance is increased not only to the
i и itn causing stress, but also to other factors, even lethal agents. It manifests itsoll
ilnoiigh a decrease of inflammation, prevention of impairment of the heart, kidneys
itnil oilier organs by any pathogenic factors. This state is callcd increased nonspecific
h i nanism resistance.
I he stage o f exhaustion (the Ihiul, final, stage) develops under prolonged cl
lu i of the injurious agent when adaptation is impaired. Transition of the resistance
*Ыце lo I lie* linal one is chaiat Icn/nl In
I'.nl Sprclal (Systemic) l*Mlliii|iliy4ioli)K>

• atrophy of the adrenal cortex;

• depletion of hormonal activity;
• involution of the thymus and lymphoid tissue;
•cosinopcnia;
• negative nitrogen balance;
•decrease of arterial blood pressure;
• activation of proteolysis;
•development of bleeding ulcers in the stomach and duodenum;
•exhaustion of the functional reserves.
After all, stress outcome depends on the ratio between the force and duration ol
ihc stressor effect and potential abilities of the protective reactivity of the organism
I tiscascs of Adaptation

rhe development of adaptation can be disturbed.

On ihe one hand, the ability of the organism to develop adaptive reactions may
Ih-depressed. According to Selye, it is endocrine insufficiency (first of all hypofunc
lion of the pituitary and adrenal cortex) that causes adaptation insufficiency.
A hypcrergic course of inflammation and its chronic forms (rheumatism, al
Irigy (bronchial asthma, dermatosis)) are connected with deficiency of adaptive re
actions underlain by adrenal cortex hypofunction. Lack of glucocorticoids underlies
decreased organism resistance to any injuring environmental factor. Any additional
influence of moderate force (overcooling, overheating, physical overstrain, excessive
intake of salt) significantly aggravates every pathology. It was Selye who proposed to
use adaptive hormones (glucocorticoids) for organism resistance support.
On the other hand, chronic overstraining of adaptation mechanisms and con
coinitant excess of glucocorticoids become a reason for another group of patholn
K ies Then wc speak that chronic stress plays a decisive role in their pathogenesis
I hey are: arterial blood hypertension, stomach ulcer, periodontitis, diabetes, neph
rosclcrosis, hyalinosis.

Significance of Stress Concept

Stress concept had a great influence on modern medicine development.

Гraining of experimental animals with systematic influence of moderate stimuli
(cold, hypoxia and muscular tension) protects the organism from myocardial nr
crosis caused by intravenous injection of proteolytic enzymes.
I he study of stress started the clinical use of adrenal cortex hormones in medi
cal practicc. Selye theoretically grounded the corticosteroid therapy, which is now
used both in acute and chronic clinical situations.
Glucocorticoids arc used as emergency care when the state of a patient is c\
Urinrly grave. They activate* organism resistance and provide survival.
Corticosteroid therapy is used in chronic diseases when the organism reactivlh
is qualitatively changed. The use of glucocorticoids as immunomodulators in allergy
and chronic hyperreactive inflammation is widely spread.
However, a prolonged use of these hormones has side effects, which have been
noted above Impairment ol thr stoniiu li and duodenum, predisposition to arterial
 ( lu p in К) Гя1||»р||уч1м1ок? »f Endocrine System

hypertension together with hormonal dependence appear a problem of corticostei

•ml therapy.

Questions for Self-Control

1 How is endocrine pathology classified?

1. What are the mechanisms of glandular endocrine insufficiency?
I What are the mechanisms of peripheral hormone action disorders?
I What is the role of immune mechanisms in thyroid gland pathology?
V Give the characteristics of compensatory-adaptive mechanisms in endocrine
pathology.
(> What is hypercorticism (mechanisms and manifestations)?
7. What is hyperaldosteronism (mechanisms and manifestations)?
к What are the side effects of glucocorticoid therapy?
ч What is withdrawal syndrome?
10 What is the essence of stress concept?

Tests for Self-Control

(give correct answers)

I Adenoma of the glomerular zone of the adrenal cortex was diagnosed in a

patient. It caused the development of initial hyperaldosteronism (Conn’s syn
drome). The balance of what ion is changed in this case?
A. Calcium.
B. Chlorine.
C. Magnesium.
D. Sodium.
E. Iron.
A patient suffers from chronic failure of the adrenal cortex — Addison’s disease.
A lack of what hormone is observed in this case?
A. Vasopressin.
B. Insulin.
C. Epinephrine.
D. Thyroxin.
E. Aldosterone.
' A 28-year-old patient complains of mental and physical weakness, dyspepsia
The tuberculin test is positive, hypoglycemia, arterial pressure — 90/60 mini Ip.
hyponatremia. The skin is overpigmented. In what pathology of the adrenal
glands arc such phenomena observed?
A. Addison’s disease.
B. Itsenko—Cushing’s syndrome.
C. Acute failure of the adrenal cortex.
I). Adrenogenital syndrome.
E. Conn’s syndrome.
ГиМ ) S |H 'iiu l ( S y N l r m i r ) 1‘и11к1|>||\м<|1оку

•I A 44 year-old woman complains of sickness, obesity of the upper part of (In-

body, appearance of hair on the face, menstruation cessation, and hypcrgly
cemia. Arterial pressure — 165/100 mmllg. Determination of what parametn
will allow distinguishing Itsenko—Cushing’s disease from Itsenko—Cushing's
syndrome caused by adenoma of the adrenal glands?
A Level of androgens in the blood plasma.
B. Level of hydrocortisone in the blood plasma.
Level of 17-oxysteroids in the urine.
I). Level of corticotropin in the blood.
I Amount of eosinophils in the blood.

S A woman had a complicated delivery. In some months after loss of hair and
teelh, body weight decreased, she became very sick. Later arterial pressure,
body temperature, concentration of glucose, somatotropin and corticotropin in
(lie blood reduced. What pathology of the pituitary gland is observed?
A. Diabetes.
B. Pituitary nanism.
C. Acromegaly.
I). Itsenko—Cushing’s disease.
I Panhypopituitarism.

<
> A 10-year-old child has a hyperergic form of rheumatism with extensive pain
syndrome, which can’t be treated with nonsteroid medicines. Therefore il wn
necessary to use an anti-inflammatory hormone. What hormone has an and
inflammatory action?
A. Epinephrine.
B. Hydrocortisone.
C. Somatotropin.
I ). Testosterone.
E. Insulin.

7 A 53-year-old woman is 163 cm tall, her body weight is 92 kg, there is edem.i
ol the face and upper extremities. When pressed, the skin does not form a pH.
(lie skin is dry and yellowish. Arterial pressure — 90/60 mmHg. Pulse V.
Failure of what endocrine gland can such symptoms be connected with?
A. Neurohypophysis.
B. Adrenal cortex.
C. 'I hyroid gland.
I ). Ovaries.
I Parathyroid glands.

К A 50-year-old patient was ill with encephalitis. Later diuresis increased I"
12 11 lie level of blood glucose was 4.1 mmol/l. A lack of what hormone <m
(lie state Ik * connected with?
A. Aldosterone.
B. (Jlucagon.
 < liiijiln III Г и 1 1 |о ||||у ч Ы о к у o f l i u l o t h i m - S y s t e m

C. Insulin.
I). Hydrocortisone.
E. Vasopressin.

4 A patient has increased body temperature, tachycardia, emotional lability, tremoi

I he change of what hormone concentration is this state connected with?
A. Vasopressin.
B. Thyroxin
C. Testosterone.
D. Aldosterone.
E. Insulin.

10. A 44-year-old woman complains of weakness, pain in the heart, weight gain.
Objectively: «moon face», arterial pressure — 165/100 mmHg. Body height
164 cm, body weight 103 kg, obesity of the face, neck, shoulders, abdomen.
What is the cause of the development of these signs?
A. Deficiency of thyroid hormones.
B. Excess of glucocorticoids.
C. Excess of insulin.
D. Deficiency of glucagon.
E. Excess of mineralocorticoids.

11 A 50-year-old patient complains of thirst, polyuria, drinking plenty of water.

Blood glucose — 4.8 mmol/1. In the urine glucose and acetone are absent; the
urine is colorless, relative density is 1002—1004. What has caused polyuria?
A. Thyrotoxicosis.
B. Hypothyroidism.
C. Lack of insulin.
D. Aldosteronism.
E. Lack of vasopressin.

12. A patient with hyperthyroidism complains of weight loss, tachycardia, finger

tremor, fever. Basal metabolism increased by 40 %. What is the cause of basal
metabolism increase?
A. Intensifying of glycogenesis.
B. Activation of glyconeogenesis.
C. Activation of oxidative processes.
D. Intensifying of lipogenesis.
E. Depression of proteolysis.

I ' A woman complains of tachycardia, weight loss, tremor, intensified sweating

Wlial endocrine pathology can cause it?
A. Hypergenitalism.
B. Hypothyroidism
C. Hyperthyroidism.
I). Hypogonadism.
E. Hypoaldostcronism.
( hapter J /
PATHOPHYSIOLOGY OF NERVOUS SYSTEM

I he nervous system performs a function of higher nervous activity (conscious

ness, emotions, memory, psychic constitution formation), regulates motor activity
.uul sensitivity as well as visceral functions (of the respiratory, cardiovascular, diges
live and other systems). Nervous trophicity is one of its functions.
I here are three physiological mechanisms of nervous regulation:
• ncuroimpulsive;
• mediatory (with the aid of neuromediators and neurohormones);
• with the aid of the axoplasmic flow (via nerves) of regulative substances !<•
the innervated organ.
Damage of the nervous system in various pathological processes was men
Honed in all the previous chapters of the textbook. Increased sensitivity of the net
vous system to all environmental factors (barometric pressure and thermal factor.,
electricity, ionizing radiation), genetic problems, systemic and local disorders ol
blood circulation, metabolic disorders was also mentioned above. In its turn, as н
has been mentioned, the functional state of the central and autonomic (vegetative)
nervous systems influences the organism’s sensitivity to any harmful factor and ilu
outcome of the pathological process (hypoxia, p. 137, electrotrauma, p. 38).
I he role of the nervous system, especially of its vegetative part, in the develop
ment of inflammation, fever, starvation, hypoxia, and also its role in cardiac, и
spiratory, vascular, digestive, hepatic, renal, endocrine insufficiency was mentioned
in previous chapters.
I he functional state of the nervous system influences organism reactivity (.< ■
p. (>5) changing the course of pathological processes. Immune response reali/ahon
reactivity to bacterial toxins, antigens and microbes also depend on the fund... ii
stale of Ihe nervous system. Weakening of the nervous system, psychic overslnim
shock of any origin, and narcosis decrease immune response and aggravate lit.
course of infection (sec p. 79).
I he nervous system plays a role in systemic metabolic disorders (dismetahoHsm
of carbohydrates, p. 202, obesity, p. 227).
I Ins chapter deals with general considerations of pathology of the nervoin
system proper.

ETIOLOGY

lliology of neurological disorders consists in etiological factors, which a ll" '

ihe nervous system, and conditions of their action. Etiological factors are cxogcnou*
and endogenous, and also physical, chemical and biological. They may influent i
m etabolism , structure and function o f the nervous cells, receptors, conductors, syn
apses, nervous centers. There is no environmental factor, which does not influent •
Ihe nervous system and can not damage it
 ( |||||Н(‘Г И PnllmphvsloloHy of Nervous System

Ixngcnous Factors

Physical environmental factors are: mechanical trauma (the nervous system is

piotected by the bones; the head is protected from penetrating wounds, which in
uldition to brain damage can predispose to infection), barometric pressure (nervous
.vmptoms in decompression syndrome and hyperbaria, p. 36, tab. 2), ionizing radia
non (nervous symptoms, p. 29, and cerebral form of acute radiation disease, p. 33),
high and low temperature (thermal shock, p. 23), electrical energy (pain shock in
i lcctrotrauma, p. 38), electromagnetic fields, noise, vibration. As a result of its high
•■nsitivity, the nervous system is the first to react to changes in the environment.
Chem ical factors are poisoning by the so-called neurotropic (cerebrotoxic) poi­
nt is of natural and artificial origin — industrial poisons, alcohol, narcotics, psy-
i liotropics. They can selectively disturb bioenergetic processes in the nervous cells,
lot mat ion, transportation, excretion and metabolism of neuromediators, influence
i I k- permeability of ionic channels in neurons. Deficit of necessary elements may
also lead to disorders in the nervous system. For example, vitamin B l2 and folate
deficiency leads to myelination disturbance, nervous tissue degeneration, disorders
"I impulse conduction (for pathogenesis details see p. 290).
Hiological factors are infectious agents mostly of neurotropic action:
• neurotropic viral infection (meningoencephalitis, encephalitis, poliomyelitis);
• meningococcus (purulent meningitis);
• tubercle bacillus;
• I. pallidum;
• IO RCH infections (TOxoplasma, Rubella, Cytomegalovirus, Herpex simplex);
■ lungal infection;
• human immunodeficiency virus (H IV );
• immune factors (with the aid of a heteroimmune serum with antibodies against
proteins or cells of the nervous system it is possible to reproduce neuropathology
under experimental conditions).
Since man has the second signaling system, higher emotions, and developed
«•use organs, a typical sign of the etiology of nervous pathology is the fact that
li,иmini information factors (words, images) may be etiological. With the help of
linages, symbols and notions a model of the surrounding world is created in human
imagination. Harmful psychogenic information influences (which cause emotions)
may be referred to exogenous etiological factors. Functional pathology of higher
m ivous activity and the following visceral pathology can be stipulated by them.
I'' alive and especially negative emotions can cause psychogenic shock, neurosis
uul a lot of psychosomatic visceral disturbances (arterial blood hypertension, thy-
nitoxicosis and other disturbances of endocrine functions).
Since man is a social being, social factors may become a reason for pathology.
W ia l factors are tightly connected with emotions. They occupy an important
plan- among the factors, which cause nervous system disturbances. Prolonged or
lii t|iient conflict situations, which arc conncclcd with peculiarities of a personality,
ilf character of social environment, organization ol society, conditions of work
I'iirt 2 S|M i wl < S)\lrn ik ) I'ulhopli.wtoloK.v

and I lie mode of life may lead to an excessive stimulation of emotional centers atul
disturbances of higher nervous activity of a person.
I‘ ih I o k c iio iis Factors

Physical (mechanical) pressure on the nervous tissue by primary and secondary

(metastatic) tumors, hemorrhage foci, scars.
( 'hcm ical factors are cerebrotoxic substances of endogenous origin (especially
in comas).
Hiological factors are immune, genetic, reflex influences, aging, psychic con
stitution.
Immune antibodies against the nervous tissue (autoimmune aggression) form in
case of hematoencephalic (blood-brain) barrier disorder.
(ienetic failure of higher nervous activity was described in this textbook as he­
reditary and chromosomal diseases. Affection of the nervous system in hereditary
diseases may have a secondary character (e.g. phenylketonuria, p. 241).
Pathological reflex (strong and extraordinary effects of external and internal
receptors) is a peculiarity of neuropathology etiology and a specific cause of a dis
ease, finis, concremcnts in the biliary and urinary tracts, uterine pathology may
In- a source of pathologic reflexes and cause cardiac rhythm disorders; an embolus
moving via the pulmonary artery causes a reflex spasm of the coronary arteries atul
may be a reason for patient’s death.
I he significance of aging for the structure and functions of the nervous system
is beyond doubt. With age neuron atrophy develops, which leads to brain mass de
crease. Neuron mass decreases at different rate in different parts of the brain and
starts at different time.
I he significance of psychic constitution for predisposition to certain types ol
mental diseases (schizophrenia, manic-depressive psychosis, epilepsy) was disco
veied by Kretschmer (see p. 58). Psychic constitution (temperament — choleric,
sanguine, phlegmatic, and melancholic types of persons) is an important condition,
wluch influences predisposition and duration of neuropathology.
As lo conditions, which significantly determine neuropathology, localization ol
the damage (nervous centers, conductors, synapses, receptors) does matter.

PATHOGENESIS

All pathologic processes that affect the somatic organs (infections, vasculni
pathology, local disorders of blood circulation, thrombosis, embolism, ischemia
trauma, neoplasia, starvation, vitamin starvation in particular, as well as immuno
logical, toxic, and metabolic abnormalities) also affect the nervous system in much
ilu- same way. However, there are some peculiarities of the development of these
pathologic processes in Ihe nervous system.

Hypoxia

Ihe pathogenesis and manifestations ol hypoxic damage of the nervous system

are described in chapter II «Hypoxia- on p 167. Hypoxia in the nervous system
 ('hiirH ci II l*H(ho|ihy\loloKV of Nervous System

and especially in its central sections has the gravest course. The brain consumes
about 20 % of oxygen entering the organism. At a sudden stop of oxygen supply to
the brain, loss of consciousness develops in 6—7 min, in 15 min the normal bio
electric activity of the brain stops. Complete recovery of the brain function in such
rases is possible when hypoxia duration does not exceed 5—6 min. If hypoxia ol
Ihe brain lasts longer, the memory and intellect will be irreversibly damaged. When
deprivation of oxygen is inconsiderable, there may be early euphoria followed by
indifference, drowsiness, and apathy. When oxygen deficit is severe and especially
when it is sudden, unconsciousness and convulsions may occur. The patients, who
recover from such situation, are often left with a considerable lesion. They are ol
ion demented, have bilateral spasticity, and some of them are inclined to recurrent
mnvulsions. It should be noted that different parts of the central nervous system
(CNS) are characterized by different sensitivity to oxygen deficiency. Phylogeneti
rally old structures are more resistant to hypoxia. Mechanisms of inhibition are
more vulnerable than those of excitement. Therefore euphoria is the first sign ol
acute hypoxia of any genesis.

( in itiatory Hypoxia

Blood circulation disorders in the brain have very serious consequences. I Ins
pathology is called cerebral stroke. Specifically, the brain is very sensitive to distui
l>ances of local (cerebral) and systemic blood circulation (decrease of arterial blood
pressure).
Circulatory hypoxia may be systemic and local. The reasons include shock,
collapse, thrombosis, embolism, ischemia, angiospasm.
Cerebrovascular diseases are the most prevalent group of CN S disorders. After
heart diseases and cancer it is the third major cause of death among population.
Any process that reduces effective oxygenated perfusion of the brain can result
in hypoxic or anoxic encephalopathy. Systemic hypotension, reduced cardiac out
put, respiratory failure, depletion of oxyhemoglobin due to anemia or intoxication
are the most common causes.
Cerebral infarction is a consequence of decreased blood supply to a certain
area. Infarction is caused by arterial occlusion due to thrombosis (which is most
often caused by atherosclerosis) and embolism. When there is no blood supply to
the brain, as in cardiac arrest, the result is either death or diffuse pathomorphologi
* il changes. Gradual occlusion of a vessel, such as concentric obliteration of the
vascular lumen by an atheroma, does not necessarily produce infarction.
Thrombi, with rare exceptions, are associated with a local damage of the vessel
wall at the site of occlusion. Atherosclerosis and hypertension are the most impoi
taut underlying processes. The sites of atherosclerosis and thrombosis are almost
parallel. Rarely, other forms of vascular injury, such as arteritis or hypcrcoagula
lion, can initiate thrombosis. Wnliiii the CN S thrombosis usually occurs in great
vessels.
Sudden complete occlusion ol a vessel with ail embolus usually results in in
laretion of the tissue in the region ol 1 1•<
- o i»ludeU vessel
I ’.iM S |M 4 'la l ( S y s l e m l i ) Гл11|о|>1|)мо1<>к>

Hie origin of emboli is very variable. I he most common source is a thrombi!'

mi the lelt ventricle or atrium. Less frequently, small bits of atheroma may break o i l
large ulcerated plaques in the aorta or internal carotid artery system. Such emboli
are usually very small and produce a multitude of tiny infarctions, most commonly
in the cerebral cortex. Infected emboli may originate from bacterial or fungal en
ilocarditis. Massive trauma, especially involving the long bones, can result in I.и
emboli, which pass through the lungs to the CNS.
Lmboli, in contrast to thrombi, usually involve small vessels. They arc h.
qucntly found at sites of arterial bifurcation and vessel lumen narrowing. I .mboli,
however, arc rarely found during postmortem examination, presumably be» . him

they have migrated, fragmented or lysed. They can disappear within hours and il
most always within days or weeks following their formation.
Cerebral infarctions due to embolic occlusion often differ from those caused in
thrombi. There is frequently hemorrhage, while thrombotic infarcts are ischeuiit
While the internal carotid artery is the most common site of cerebral thrombi > mv
emboli most frequently occur in the middle cerebral artery. An infarct may •»
ischemic or hemorrhagic. The original mechanism is the same for each type «l«
privation of blood supply to a given area.
Hemorrhagic infarcts are usually located in the cortex and are associated inmi
commonly with an embolus. They are caused by vascular compression. Reperfus...
ol the blood into the infarcted region is responsible for the hemorrhagic сотри
nent. In some situations, collaretal channels and venous stasis may also play a roll
in producing hemorrhagic infarctions.
Clinically, various features help to distinguish cerebral thrombosis from cm
holism. Thromboses usually form over a period of time, and patients frequently
have a stuttering course. Some patients, who develop a thrombotic infarction with
permanent neurological deficits, will have preceding transient attacks of neurolo>>i
cal impairment. The pathologic basis of such attacks is due to ischemia and is iIiim
railed transient ischemic attacks. Most are associated with atherosclerotic Ihrombu
sis, and they almost never precede a huge embolic infarction or cerebral hemoi
rhage. Transient ischemic attacks last from a few seconds to two hours, most be...
.1 lew seconds to 10 minutes in duration. Specific neurological features of Iran .к nl
ischemic attacks last for the same time. Specific neurological features indicate ilu
territory of the brain or the artery involved.
In contrast to thrombosis, emboli induce a sudden onset of focal impairment,
which appears without warning.
Ihe symptoms and signs of brain infarction depend on the si/.c of the lesion
and the structures involved. Loss of consciousness in infarction is generally coito
luted with the part of the brain involved. Convulsions at the onset of an infari tinii
иге uncommon. They arc more frequent in embolism. Convulsions as a late eon
sequence ol infarctions are relatively common, and they can usually be coriclalid
wit Ii old scats in the cerebral cortex.
 ( in i| ilr i И Pulhophysiolony of Nervous System

f rrvb ral Hemorrhage (Hem orrhagic Stroke)

Hemorrhage (intracerebral, subarachnoidal) consists of bleeding into the brain

.pace or subarachnoidal space. Hemorrhage into the brain substances is most com
mtmly caused by hypertensive vascular disease, but trauma, aneurysm rupture, an
Yunnas, bleeding into a tumor also cause intracellular hemorrhage. Atherosclerosis
иlimit hypertension is not a cause. Hypertension is 10 to 20 times more frequent
ilian all other causes. Cerebral hemorrhage happens in significant systolic-diastolic
«levations for several years. Hemorrhage never occurs during sleep. A blood vessel
may hurst within the brain substance in a hypertensive patient.
Hypertensive encephalopathy occurs in hypertensive vascular disease as an
n ute clinical condition in which there is a severe and usually abrupt elevation of
л tolic and diastolic blood pressure, headache, clouding of consciousness, and
i onvulsions, leading to stupor or coma. There are usually retinal changes with
papilledema, exudates, hemorrhage, and renal failure is also present. The patient
may die or recover.
I he pathogenesis is related to an acute, severe increase in intravascular pres
sine. Longstanding hypertension is not necessary for its development, since it can
«к cur in eclampsia and other acute hypertensive episodes. Lowering of blood pres
••me can produce a relief of the signs and symptoms. Functional disorders may kill
ihe patient before any morphological changes.
T h e clinical course of hypertensive hemorrhage is of a sudden onset with col
lapse, but there are some cases in which the onset is less apoplectic, beginning with
I k ulach e and trivial focal signs before the final collapse. Intractable vomiting is
I O lllllio n .
Thus, a neurologist requires a subtle specialization to differentiate the type of
local vascular disorder in a patient (thrombosis, embolism, hemorrhage) and the
и ali/ation of this disorder.

typical Metabolic Disorders

Typical systemic metabolic disorders have manifestations in the nervous system

r. well. The nervous tissue consumes the greatest quantity of glucose. Practically
ill oxygen consumed by the brain is used for glucose oxidation. The brain is very
■usitive lo hypoglycemia (p. 205). Hypoglycemic coma is manifested by loss ol
•"iisciousness. In acute decrease of the blood glucose level brain action currents are
ill. ( led. Prolonged hypoglycemia causes irreversible damages of the brain cortex.
In more marked hypoglycemia the functions regulated by the stem mechanisms get
disturbed.
I ipid metabolism disorders are manifested as atherosclerosis of the cerebral
vi sels, which is a frequent reason for diseases of the organism.
The most severe systemic mctiiholic disorders in the organism, causing grave
disorder*. in Ihe nervous system, develop in comas: acidic (p. 247), diabetic
Ip 2I(>). hepatic (p. 447), and uroinh tp l/'M
1’nrt S|H‘clul (System ic) I’ulliuphystoluKy

Inflammation

Inflammation in the CN S is not so common because the nervous system is

protected from the penetration of infection by the hematoencephalic barrier (see
p (iX). As il was mentioned, the nervous tissue is slow to oppose infection by im­
mune reactions. The role of the hematoencephalic barrier and autoimmune proh
li n t s connected with it was mentioned in chapter 5 «Immunological Reactivity and
Its Pathology» on p. 80 and chapter 6 «Allergy* on p. 97.
I lie hematoencephalic barrier was investigated on experimental animals: an
intravenous injection of trypan blue, which binds to serum albumin, stained all
organs of the body, except for the brain tissue, blue. Ultrastructural studies show
tli at the blood-brain barrier is composed of endothelial cells, a basal membrane
and astrocytes. Endothelial cells, rather than astrocytes, are the structure that is
functionally responsible for protein exclusion from the brain. Endothelial cells are
attached to each other by a continuous series of tight junctions or occluded zones.
I racers arc unable to penetrate through the tight endothelial junctions. In addition,
the transccllular pathway is excluded, since endothelial cells in the CN S are devoid
ol pinocytic vesiclcs.
Infection enters the nervous system through the blood (in blood-brain barrier
destruction), or from penetrating wounds, infected middle ear, sinuses.
As to allergic inflammation, there are some peculiarities of its course in the
nervous system. On the other hand, the presence of the blood-brain barrier makes
ihc nervous system vulnerable. If this barrier is affected, the cells of the nervous
system become an object of autoimmune aggression because there is no physiologi
i al immunological tolerance to the nervous tissue (see p. 80 about immunological
tolerance).

Kdema

( ercbral edema is an abnormal increase of the water content in the central

nervous tissue. If water is accumulated within cells, it is called cytotoxic edema. It is
opposed lo water accumulation in the extracellular space, which is called vasogenic
edema.
In cytotoxic edema the ATP-dependent sodium pump within the cell mem
In.me lails Sodium accumulates within cells, with water content increasing, as well
to maintain osmotic balance. All cellular elements of the brain (neurons, glia, and
endothelial cells) may swell, which results in a decrease of the brain cxtraccllulai
Hind space. Acute hypoosmolarity secondary to water intoxication and cerebral liv
poxia are examples of conditions that can produce cytotoxic cerebral edema.
Vasogenic edema is the most common form of ccrcbral edema. Primary and
melastatic brain tumors, absccsscs, hemorrhages, infarctions, contusions can cause
it and lead to encephalopathy. It results from water and plasma leaking directly into
Ihc CN S through or between the damaged capillary endothelial cclls, which have
lost their barrier function. Fluid collec ts in Ihe cxlraccllular space. I'.dcnia can he
focal or dillusc
 ( lliip trr И l'ullH)|ih>si»li>K.v N it v o iis S y s t e m

Interstitial edema is characterized by an increase of water and sodium content

in the periventricular white substance. It most commonly occurs in association with
obstructive hydrocephalus.
Cerebral edema is an extraordinarily common clinical complication, which
may result in death. Osmotic, metabolic, and traumatic processes may coexist,
leading to an increase in water content both in cells and extracellular space.
Hydrocephalus refers to distention of the cranial cavity (ventricles) with an
increase in the volume of the cerebrospinal fluid. It may result from its overpro
duction or, much more commonly, its decreased absorption due to inability of the
arachnoid villi to transfer it to the venous system or block the pathway to the villi
In children it may be due to many causes including congenital malformations,
infections, trauma, subarachnoid hemorrhage, and tumors together with viruses,
irradiation, and vitamin deficiencies. Signs of increased intracranial pressure umi
ally manifest acute hydrocephalus. Hydrocephalus denotes increased volume of the
cerebrospinal fluid within the cranial cavity (ventricles).
Increased intracranial pressure, cerebral edema, and hydrocephalus are exceed
mgly common pathophysiological conditions, which may complicate almost any
disease involving the CNS. They frequently occur in combination. Trauma, inflatn
matory, vascular, degenerative, and metabolic diseases as well as both genetic and
acquired conditions can lead to one or all of these pathophysiological complica
tions.
Increased intracranial pressure may be due to diverse pathological processes
All cases are associated with some sort of enlargement. It may be either diffuse,
e.g. caused by generalized brain edema, or focal, as may be seen in brain tumors,
abscesses, or subdural hematomas. Regardless of the cause, it is compression of the
vital centers of the brain that leads to life-threatening complications.
Patients with increased intracranial pressure usually show the following cardi
nal clinical manifestations — periodic headache, mental slowness, confusion.
In addition to directly crushing the nervous tissue, brain herniation may also
compress arteries against the surrounding structures, resulting in collapse and oc
elusion of their lumens and secondary infarction of the brain.

lumor

The tumors, which develop in the nerve tissue, may be benign and malignant,
and also primary and metastatic. The clinical picture depends on the localization of
a tumor. A tumor exerts mechanical pressure on the nervous centers, irritates them,
causes their excitement or impairs their functions. Thus, it is necessary lo define
what part of the nervous system is clinically involved before a tumor is examined
morphologically.

(•cnetic Disorders

Chromosomal diseases, dest nhed in »linpter \ on p. 5.1 (Klinelelter's syn

drome. Turner’s syndrome, Down • •vndioine), ate characterized by mental re
I'lirt 1 S|»« i liil (System ic) ГиПшрЬулЫоку

lardation. Huntington’s disease is an autosomal dominant disorder with a delayed

onset of clinical manifestations at the age of 30-40. The enzymopathy, which is
connected with phenylalanine disbolism, is manifested as phenylpyruvic oligophre­
nia (see p. 241).
( icnctic disorders associated with gene and chromosomal abnormalities may
manifest themselves through neural tube defects, spina bifida, failure of closure of
tin posterior vertebra arches, encephalopathy. Fetal alcohol syndrome is associated
with excessive alcohol intake by the mother during pregnancy. Facial abnormalities
and development defects such as microcephaly, atrial septal defect, etc. character­
ize it.

Starvation and Electrolyte Disorders

Starvation, especially deficit of В vitamins, has neurological manifestations.

Electrolyte disorders (changes in the concentration of Na, K, Ca, and hy­
drogen ions in the blood) influence nervous system activity, its excitability and
conductivity.

Molecular, Subcellular, Cellular and Tissue Disorders

I о continue the description of the pathogenesis of nervous system disorders,

we should note that any pathological process disturbs nervous system functions at
the levels of molecular, cellular, tissue organization and also at the whole-organism
level.
A l Ihe m olecular level the disturbances are manifested as disorders of potential
formation and neuromediator and neurohormone production.
I he universal mechanisms of neuron function disturbances are explained be
low.
I oss of the ability to maintain the definite value of membrane potential by the
nervous cell, generation of action potentials and conducting them by the processes
passing excitation from one nervous cell to another one are the mechanisms ol
disorders.
Disturbances of mediator synthesis, excretion and destruction may be an ini
poit.mt link in the pathogenesis of many disorders of nervous system activity. Many
I.ids prove that the activity of the nervous system is defined by substances of pep
tide nature (neuropeptides), which are produced both by nerve and other cells and
perform mediator and non-mediator functions. The opiate system regulated by
endorphins and enkephalins, is the most studied. In the brain of man and animals
dozens of oligopeptides have been discovered: injection of these peptides into Ihe
cerebral ventricles or directly into the nervous centers may cause different cnm
tional states and behavior reactions, influence conditional reflex production, the
ability lo memorize, study, etc. Л lack or excessive formation of neuropeptides, i
change in the sensitivity of nerve cells to them may be important in the patlmpe
nesis of nervous system dysfunction. I )isorders ol mediator transport and deposition
also mallei In Alzheimer's disease Ihe levels ol choline acctyltranslerasc and ace
 ( Imptci M Pelhoghyskilony of NrrvouN Sy*lrm

lylcholinesterase were markedly reduced in the hippocampus, amygdala, neocorlex,

and deep gray nuclei.
At the cellular and tissue levels, lesion of nerve cells, conductors, synapses, .1
decrease of the quantity of intemeuronal contacts are the mechanisms of nervous
system dysfunction. The peripheral nervous system includes the sensory and mo­
tor components of the cranial and spinal nerves as well as the autonomic nervous
system with its sympathetic and parasympathetic divisions.
If a nerve is damaged so much that its connection with the neurocyton is losi,
it degenerates due to blocked axoplasmic flow of nutrient substances.
At the level o f the whole organism nervous system pathology and its clinical
manifestations depend on localization. A prominent peculiarity of nervous system
responses is selective vulnerability of a group of neurons or of a specific region ol
I lie brain or spinal cord leaving the rest of the nervous system virtually intact.

Dystrophy

Dystrophy in the nervous tissue is specifically manifested by demyelinization and

degeneration. They critically disturb the functional activity of the nervous system
Demyelinating diseases are characterized by myelin destruction with relative
preservation of axons. Demyelinating diseases or loss of myelin sheaths are a defect
common to many CN S disorders. Secondary demyelinization (axon lesion with
subsequent loss of its myelin) is distinguished from primary or true demyelinization,
which results from dendroglia damage with relative sparing of the underlying axons.
Ihese diseases include multiple sclerosis, acute disseminated encephalomyelitis,
postinfectious encephalomyelitis, etc. In the peripheral nervous system, primary
demylinating conditions are caused by genetic defects, but inflammatory demyeli
nating peripheral neuropathies are also possible.
Multiple sclerosis is a disease of such kind. It is a chronic, remitting and re
lapsing disorder sometimes leading to total disability. Autoimmune mechanisms
play a role, triggered or accentuated by a viral infection as an etiological factor (see
p. 98 about mechanisms). Adenovirus and measles antibodies have been found as
well as antimyelin antibodies. Immune response may be altered. An elevated level
of polyclonal IgGs have been found in the cerebrospinal fluid. Corticosteroids or
aggressive immunosuppressive therapy may be used. There is genetic predisposition
to this disease.
In contrast to the CNS (which has little if any ability to regenerate), the basic
reactions of the peripheral nervous system include both degeneration and rege
Deration. These widespread hereditary diseases of the nervous system are charac
leri/.ed by a gradual, usually symmetric, progressive atrophy of groups of neurons
Many eventually result in death. Vascular, infectious, metabolic and immunological
mechanisms have not been found. However, there is slow degeneration and disap
pcarance of nerve cells and their processes or simple neuronal atrophy accompanied
by mild gliosis. In addition to neuronal loss, some degenerative diseases show char
acteristic changes in the nerve cell iylnpl rim or nucleus (e.g. Alzheimer's disease
and Parkinson’s disease).
I'ti1 1 } S|m i ml (S \ s trin li) l‘ulliupli>sl<il»Ky

Aii outstanding clinical manifestation ol conical degenerative diseases is de

incnlia. Dementia may he secondary to known causes, such as cerebral infarction,
hydioccphalus, encephalitis, virus infection and metabolic diseases. These demen
n.i . are divided into presenile and senile types. Presenile dementia is defined as
,i progressive mental deterioration leading to dementia before the age of 65. Two
examples of presenile dementia are Alzheimer’s disease and Huntington’s chorea.
Alzheimer's disease is the most important cause of progressive dementia. De
Ui-ni'iativc disorders are characterized by progressive generalized cerebral atrophy,
paiticularly of the temporal and frontal lobes, a decreased number of neurons in
the basal nucleus, granulovascular degeneration with general impairment of higher
intellectual functions or subtle emotional liability in the absence of focal neurologi
nil delects. It progresses steadily over 5 to 10 years to severe dementia and death,
ollen associated with respiratory infection. There is some tendency toward familial
occurrence, although many cases are sporadic. Symptoms are aphasia, agnosia and
.ipraxia; convulsive disorders may be prominent during the course of some patients.
I here are abnormalities of the presynaptic cholinergic system in the cortex of some
patients with Alzheimer’s senile dementia. Presynaptic defects are revealed.
Huntington's chorea is also characterized by progressive dementia. Patients
manifest delusions, paranoia, and neurosis.

M A N IFEST A T IO N S

SENSITIVITY DISORDERS

Sensitivity disturbances arc manifested in the form of the following symptoms

iitu'sihi'siti (sensitivity reduction), hyperesthesia (sensitivity increase), hypoesthesia
(sensitivity decrease).
Depending on the character of sensitivity loss there are distinguished tactile,
pain (analgesia), thermal (thermanesthesia) anesthesia and loss of deep or proprio
ccphvc sensitivity.
II the pathologic process is located in the spinal cord or brain, sensitivity dis
oulei depends on the types of the ascending pathways disturbed.
I here are two afferent systems of sensitivity. One of them is called lemniscus
.uul contains large-diameter nerve fibers, which conduct stimuli from propriorecep
inis ol the muscles, tendons, joints and partially from dermal receptors of touch
.mil pressure (tactile receptors). The fibers of this system enter the spinal cord and
.is p.ui ol the structure of the posterior column get to the medulla oblongata. From
iIn medulla oblongata nuclei the medial lemniscus pathway begins, it passes to tin
opposite side and proceeds to the ventral posterolateral nucleus of the thalamus,
whose neurons transmit the obtained information to the somatosensory zone of the
bruin cortex.
I lie second ascending system is the spinothalamic (anterior and lateral) path
way conducting pain, thermal and partially tactile sensitivity. Its fibers ascend in (hr
si i net lire of the anterior and lateral I'niiu uli ol the spinal cord and terminate mi tin
 ( IliltHei H INUhophynMofy of Nervous System

Typical changes of sensitivity are observed if the right or left half of the spinal
cord is cut (Brown—Sequard syndrome). Deep sensitivity disappears on the side ol
cutting while thermal and pain sensitivity disappears on the opposite side because
(lie conduction pathways relating to the anterolateral system intersect in the spinal
cord. Tactile sensitivity is partially disturbed on both sides.
A disorder of the lemniscus system is possible in case of damage of the peri
pheral nerves (thick myelin fibers) and also in various pathologic processes in llu-
spinal cord (disturbance of blood circulation, trauma and inflammation). An iso
lated damage of the posterior funiculi of the spinal cord is rather rare, but together
with other conductive pathways they can be damaged by a tumor or trauma.
Disturbance of conductivity in the fibers of the medial lemniscus pathway
causes various disorders of sensitivity, whose manifestation depends on the degree
of system damage. Thus, the ability to determine the speed and direction of ext re
mity motion may be lost. The feeling of separate touch in two places simultaneously
and also the ability to feel vibration and evaluate the weight of a lifted object an-
considerably disturt>ed. The patient isn’t able to determine the shape of subjects by
touching them and to identify the letters written on the skin: he feels only mechani
cal touch and is not able to indicate the place and force of tactile sensation exactly
The sensation of pain and temperature sensitivity are preserved.
Removal of the postcentral gyrus of the cortex in experimental animals causes
sensitivity disturbance on the opposite part of the body. The nature of this distin
bance may be understood on the basis of our knowledge about the functions of the
lemniscus system, connecting such an operation with lemniscus denervation on the
opposite side, where elements of the anterolateral system are, however, preserved
Obviously, the disturbance consists in kinesthesia loss. An experimental animal
often stops moving remaining in an inconvenient position for a long time. Tactile,
pain and thermal sensitivity on this side is preserved although its threshold can be
increased. In man an isolated injury of the postcentral gyrus occurs very seldom.
I'or example, sometimes surgeons remove a part of this gyrus to treat a cortical epi
lepsy patient. In this case there develop disorders mentioned above — sensation ol
extremity location in space and the ability to determine the shape of objects, their
size, weight, surface type (smooth, rough, etc.) by touch are lost.

I’AIN

Pain refers to sensitivity disorders. It is a leading symptom of any disease.

Pain is a specific negative sensation and a negative emotional and pathophysio­
logical reaction to it connected with disorders in the organism.
The meaning of pain is double. On the one hand, pain is a defense reaction ol
the organism, a signal about the presence of pathology and a response directed ill
deliverance from the pain factor and disease. On the other hand, pain makes pa
lienls suffer. Pain conditions the development of functional and structural changes
and impairments in the cardiovascular system, inner organs, in the system of mi
crocirculation, vegetative reactions, cndoninc system.
1‘iu l S |H 'c lu l ( S y s t e m i c ) l'ttllio |iliy slo lo K .v

Pain is realized by a special system of pain sensitivity and psychoemotional

sphere. Ihe system of pain perception and conduction is called the nociceptive
(atgic) system. It has its functional antipode — the antinociceptive system, which
controls the activity of the nociceptive system.

Mt'cliunisms of I’ain

Neurochcmical processes at different levels of the nociceptive and antinociccp

live systems realize mechanisms of pain sensitivity.
In the development of pain, pain receptors, nervous centers (in the hypothala
i i i i i s ) and also mediators of pain are important.

Peripheral sources of pain may be tissue receptors (nociceptors) in case ol

llieir intensified stimulation, chronically damaged and regenerating sensitive nerves,
dnnyclinizcd fibers, etc. Damaged nerves are quite sensitive to different humoral
eIVecis and therefore become an ectopic focus of nociceptive stimulation. The pain
associated with nerve damage is called neuropathic.
Neuroma (formation of chaotically grown, interwoven sensitive nerve fibers,
which develops in case of unregulated regeneration) is quite sensitive to different
ellecls, which may provoke pain attacks (causalgia).
Peripheral nociccptors arc activated under the influence of many endogenous
biologically active substances — histamine, serotonin, kinins (bradykinin), prosta
K.landins, etc. Substance P plays an important role in excitability conduction in Ihe
primary nociceptive neuron. It is conditioned to be a pain mediator.
As lo Ihe central mechanisms of pain, some theories have been proposed.

(•ate Control Theory

According to the gate control theory, there is a control mechanism of pass

iiiK nociceptive impulses via the afferent system into the spinal cord. This control
mechanism represents «a gate», which regulates the activity of the relay neurons ol
llic posterior horn (spinal gating mechanism).
11 is known that transmission of nerve impulses from afferent fibers to spinal
neurons (which in their turn transmit signals into the brain) is regulated by the spi
n.il gale neurons of the gelatinous substance, which are able to inhibit transinis
мои ol impulses lo spinal neurons and play a role of a gate in the way of afl'croni
impulses lo them. Pain develops in high-frequency discharges in spinal neurons
When excitement of spinal neurons exceeds the critical level, the gate com ml
mechanism turns on.
I ioni the point of view of this theory pathological pain develops in insul
liciency of the inhibitory mechanisms of gate control, when uninhibited spinal
neurons may be activated by different stimuli from the periphery. A constant How
ol stimuli lioui different sources to spinal neurons with disturbed inhibitory conliol
is a condition of pathological pain.
 ( ill'p ld Ч Ги11|1»|»||уч|о|оцу Ilf Nervous Sysll'lll

theory o f Formation o f a Generator of Pathologically Intensified Excitation

Appearance in the nervous centers of groups of neurons, which begin lo work

independently and produce excessive excitation, is an important link in the patho­
genesis of functional disorders of the central nervous system. It is supposed that it
may play a role in pain development. Such neurons are called a generator o f patho
logically increased excitement (G.N . Kryzhanovsky).
According to this theory, pathological pain is caused by formation of a genera
tor in the nociceptive system. It is a group of hyperactive neurons, which may de­
velop self-sustained activity without any additional stimulation from the periphery.
Significant and stable depolarization of nociceptive neurons may reproduce the
generator. Deficit of these neurons inhibition is an obligatory condition for the for
■nation and activity of the generator in any part of the pain sensitivity system. Then
the generator involves different parts of the pain sensitivity system into a pathologic-
process with formation of a new pathodynamic organization with abnormal activity
producing pathological pain. It is a pathological algic system (PAS), which is a base
of pain syndrome. PAS involves structures of the emotional sphere and vegetalive
nervous system. Stable, ramified, active PAS is a pathophysiological mechanism ol
severe polymorphic pain syndrome.
The nature of the activity of the generator and PAS allows understanding the
peculiarities of pathological pain, in particular, its attacks, persistence and intensifi
cation after induction by a single stimulus, spontaneous pain attack without afferent
stimulation.
At the same time, stimulation from the periphery may intensify the generator.
I'hus, the generator in the posterior horn of the spinal cord and trigeminal nerve
nuclei may be stimulated from the periphery. Under these conditions initially pe­
ripheral pain may acquire the nature of central pain syndrome.
Generator formation may be caused by partial deafferentation, for example,
after cutting the ischiadic nerve or dorsal spinal roots. Epileptiform signals arc-
registered in the deafferented posterior horn and then in the nuclei of the thalamus
and the somatosensory zone of the cortex.
The generator may be formed in the posterior horn of the spinal cord under the
local influence of different convulsants, and their nature is of no importance. In all
cases there is pain syndrome with typical signs.
Under the influence of the primary generator, the functional state of other
parts of the pain sensitivity system may be changed, the excitability of their neurons
increases and there is a tendency to formation of neuron population with prolonged
pathological activity. Secondary generators may be formed in different parts of tIn-
pain sensitivity system.

Antinociceptive System

Antinociceptive system is a physiological system of pain reduction. It plays

л significant role in the mechanisms ol pain prevention. In excessive nociceptive
stimuli, it joins the response and lessens ilu- intensity of pain sensation. I hanks to
it, pain remains under control
I'ш I Spcci.il (Nyslcm ic) l’alh{i|ill)AiiiliiK.v

I hc anlinociccptivc system consists of various nervous formations related lo

Uitfercnl parts and levels of the CNS, from the spinal cord to the brain cortex.
Opioid neuropeptides are rather effective endogenous analgesics. They inhibit
nociceptive neuron transmission and activate the neurons of the antinociceptive
system, changing the activity of the neurons of the brain.
Among classical neuromediators the analgetic effect is characteristic of sero
tonm, noradrenaline, dopamine, G ABA (gamma-aminobutyric acid). Serotonin is
.1 mediator of the antinociceptive system at the spinal level. Noradrenaline is also
,i mediator of the descending antinociceptive system, it inhibits the activity of I hr
nociceptive neurons of the posterior hom of the spinal cord and trigeminal nerve
nuclei ( iAHA takes part in the inhibition of the activity of the nociceptive neurons
.ii ihe spinal level. Substance P may also cause analgesia, activating antinociceptive
structures, for example, the dorsal nucleus of the suture.
I here are four antinociceptive systems in the brain: neural opioid, hormonal
opioid, neural nonopioid, hormonal nonopioid. They either inhibit pain trails
mission via synapses (enkephalins), inhibit the activity of pain sensitivity neurons
(|1 endorphin, a strong analgesic polypeptide), inhibit reflex pain reactions (sero
tonin, noradrenaline), or influence the function of the spinal gating mechanism
(vasopressin).

rrnitnient o f Pain

I reatment of the principal disease, which has caused pain (e.g. inflammation),
is the main principle of pain treatment. If pain acquires pathological self-exciliiik
character, il is necessary to interfere into the mechanisms of pain formation men
Honed above.
I lie two main principles of treatment for pathological pain are:
• inhibition of the hyperactivity of the nociceptive neurons and generator
formed by them and elimination of PAS, which is a base of pain syn
drome;
• stimulation of mechanisms of the antinociceptive system.
As nociceptive and antinociceptive effects are realized at different levels and
hy several mechanisms, it is necessary to apply complex pathogenetic therapy. Ii i
important lo influence psychoemotional, vascular and other vegetative and lisxtir
components of pathological pain.
Generator inhibition by inhibitory mediators leads to pain syndrome disap
P< .11. nice for Ihe time of their action, when they are introduced in the area ol tin
Urnrialoi in microinjection. Correction may be provided with the help of anticon
vulsants, which, inhibiting the generator and induced hyperactive PAS, cause pain
syndrome relief or disappearance.
With ihe help of C’a antagonists, Ca2+ entry into the nociceptive neurons I*
blocked.
As ii usually happens in medicanicntous therapy, suppression and inhibition
woik better than stimulation lu such a case, stimulation of anlinociccplivc systnn
mechanisms would hr Ihe best bill is lalhei difficult lo accomplish
 (,'huptci H 1’nllioplivsioloKV of Nervous System

D IS O R D E R S O F M O TO R FU N C TIO N O F N ER V O U S SY ST E M

Disturbances of the motor function are manifested by pareses, paralyses, spasms,

and convulsions. Myasthenia, spinal shock, disorders of movement coordination and
rigidity also refer to disorders of the motor function of the nervous system.
Contractions of the skeletal muscles and their tone are connected with excite­
ment of the motoneurons of the spinal cord. Motoneurons functioning is regulated
by a variety of impulses coming to them via the conduction tracts of the spinal cord
from the periphery, different parts of the brain stem, cerebellum, basal nuclei and
cortex of cerebrum, providing the highest motor control in the organism. Motor
disorders develop both in impairment of the mentioned parts of the nervous system,
in violated conduction of impulses in motor nerves, and in impulse transfer onto
the muscle.
Paralyses and pareses are a loss or relaxation of movements. Depending on tIn-
pathogenesis, the tone of the damaged muscles may be either lost (flaccid paralysis)
or increased (spastic paralysis). Besides, peripheral (connected with a damage ol
peripheral motoneurons) and central (as a result of a damage of central motoncu
rons) types of paralysis are distinguished.
Myasthenia is one of the disorders of neuromuscular transmission. Antibodies
to acetylcholine receptors are revealed in the blood serum.
Convulsion development is connected with brain cortex disorders. A convulsive
attack may be caused by a tumor or a scar localized in the motor or sensitive area
of the cortex.
Huntington’s chorea is clinically characterized by extrapyramidal involuntary
or choreiform movements. Biochemically, there is a marked decrease in endo­
genous gamma-aminobutyric acid and glutamic acid decarboxylase. There is also a
decrease in choline-acetyltransferase and muscarinic cholinergic receptors. It leads
to deterioration of the filtering ability of the striatum, allowing uncontrolled stimu­
lation of the lower centers by the pale globe, which results in abnormal involuntary
movements and chorea. Motor deficit (bradykinesia, akinesia) joins abnormal act i
vation of the motor system resulting in rigidity.
Parkinsonism (senile paralysis) usually occurs after the age of 50. Parkinson’s
disease is based on substantia nigra lesion. Degeneration of nigral neurons leads to
a loss of dopaminergic inhibition, a relative excess of cholineigic activity, an in
creased muscular tonus, constant tremor of the extremities and body.

D IS O R D E R S O F A U T O N O M IC (V E G E T A T IV E ) FU N C TIO N
O F N ER V O U S S Y S T E M

The peripheral nervous system includes the sensory and motor components ol
cranial and spinal nerves as well as the autonomic nervous system with its sympa
thctic and parasympathetic divisions.
Participation of the autonomic- (vegetative) nervous system in the development
ol all pathophysiological and clinical syndromes was mentioned in all previous
chapters.
1*1111 2 Sp ri lnl (System ic) l*iilhopliyslol»|ty

Disorders of the balance between the sympathetic and parasympathetic paiis

ol the autonomic nervous system are the most important. Vegetative effects are
observed more often if the structures are irritated than in their cessation. Thus, il
sympathetic influences prevail, as it has been noted, cardiovascular disorders de
vclop and blood pressure increases (see p. 380 and tab. 24 about the role of a- and
|l idivnoreceptors in hypertension pathogenesis). Vagotonus was mentioned as the
mam pathogenic mechanism of peptic ulcer development (see p. 421).
II the centers of the autonomic (vegetative) nervous system are constantly in
.1 siale of tension, the visceral organs constantly receive their inhibiting or excit
11if impulses. In a denervated organ functional and structural changes develop
I n-sympathized animals arc less resistant, their thermoregulation is disturbed, the
cardiovascular system loses the ability to adapt to varying need of the organism Ibi
oxygen, resistance to hypoxia decreases, stress may lead to death.
ЛИ the activity of the autonomic (vegetative) nervous system is subject to Ihe
luglu-i centers located in the reticular formation, hypothalamus, thalamus, and
hi.mi cortex. They integrate correlation between different parts of the vegetative
system itself, and also relations between the vegetative, somatic and endocrine
systems.

N KRVO U S T R O P H IC IT Y AND N EU R O D Y ST R O PH IC P R O C E S S

Nervous trophicity is nervous control of metabolism.

Nervous trophicity guides metabolism according to the needs at any given mo
ment. I he trophic action of nerves is closely connected with their other function
(sensitive, motor, secretory) and together with them provides an optimum function
ol each organ.
I he disturbance of nervous trophicity bears the name of neurodystrophic pro
C C .tt
I rench scientist Majandy was the first to prove the nervous influence on tissue
liophicity. In experiments on rabbits he cut the trigeminal nerve and revealed an nl
cer ui the denervated tissues (eye, lip). Trophic disorders develop in any organ il its
innervation is disturbed by an intervention on nerves (afferent, efferent, vegetative)
oi nervous centers. Medical practice can give a number of facts of nerve damage
(trauma, inflammation) causing an ulcer or other disorders in the corresponding
/one (edema, erosion, necrosis).

Mechanisms of Trophic Influence of Nerves

Ii is important to answer the question if there exist special trophic nerves.

I Majandy assumed that besides the sensitive, motor and secretory nerves
then- are also special trophic ones, which regulate tissue nutrition, i.e. nutrition-,
material assimilation.
I P Pavlov in experiments on animals, among the nerves coming to Ihe he.hi
found such a branch, which increases the power of systole without any influence
on blood circulation. Pavlov called this nerve ■reinforcing* and considered it to be
 ( haplri И I'NlhoiihyslitloK.v <>r N rnnns Sysirni

purely trophic. Pavlov assumed that complete and harmonious heart innervation is
provided by a triple nervous control: functional, vasomotor (regulating the supply ol
the blood and nutritious substrates) and trophic nerves (providing the final utili/a
tion of these substances). L. Orbclli was of the same opinion.
The information mentioned above does not mean that trophic nerves have no
other influence on tissues, or that the motor or secretory ones have no influence
on metabolism. As to mechanisms of the trophic influence of nerves, there arc two
points of view.
According to the first view, trophicity is not an independent function of the
nervous system. A.D. Speransky considered that all nerves influence metabolism,
there are no nontrophic nerves — «the nerve is functional just because it is trophic»
A nervous stimulus, which activates an organ (for example, a muscle), changes its
metabolism because the nervous mediator activates enzymes.
According to another point of view, it is impossible to bring trophicity to .in
impulse (mediator) action of a nerve. Nerves also have a function named non ini
pulse. It consists in a flow of axoplasm, i.e. «substance of trophicity», whose nature
is being studied. Humoral substances, which move via neurons, penetrate through
synapses and appear in innervated cells. These substances provide a specific action
on effector cells. When a nerve intended for a red muscle after a surgical operation
grows into a white muscle, the latter shows radical changes in its metabolism.
We may conclude that the trophic action of the nervous system consists of two
mechanisms — impulse and non-impulse.

Biochemical, Structural and Functional Changes in Denervated Tissue

Any damage of the peripheral nerve is always accompanied by metabolic

changes in the corresponding organ. This concerns carbohydrates, fats, proteins,
and nucleic acid imbalance.
Not only quantitative but also qualitative changes are observed. Thus, myosin
in a denervated muscle loses its ATPase properties, and glycogen in its structure
becomes simple. The enzymal process is reorganized. Thus, isoenzyme spectrum
of lactate dehydrogenase changes to LD G 4 and LD G S, i.e. those forms, which are
adapted to anaerobic conditions. The activity of succinate dehydrogenase decreases.
A common tendency is for metabolic changes to become embryonic — glycolysis
begins to predominate over oxidation. The power of the Krebs cycle is weakened;
the output of macroeigs decreases, the energy potential is lowered.
Essential morphological changes are observed in denervated tissues. All stages
of inflammation develop. Prevention of infection and trauma docs not prevent the
dystrophic process but only delays its development. Finally an ulcer appears without
a tendency to heal (fig. 60). Investigation of subcellular structures shows chiinges
of organelles — mitochondria decrease in quantity, their matrix is clarified. Impaii
ment of oxidative phosphorylation and the Ca accumulating ability of mitochondria
together with affected energetic abilities ol cells are connected with this I he ini
lolic activity is reduced in denervated tissues
I ’m l S jM ila l ( S y s l r m l r ) l ’ntlio|>livslol<(K.V

As to functional disorders, de-

ncrvalion consequences depend on the
type of tissue. The salivary gland se­
cretes saliva, hut its properties do not
depend on the kind of food. As to the
myocardial muscle, it contracts even
if all cxtracardial nerves are cut. The
skeletal muscle deprived of sympathetic
or cholinergic nerves reacts to adrena­
line or acetylcholine more intensively
than under normal conditions. Accord- _ „ _ , , ...
,, , .. . * . rig. 60. Trophic ulcer of the cornea, which
mg lo ihe law of denervation, denervated
, . . . . , developed after n. trigemini cutting
structures are characterized by increased
sensitivity. Il is explained by the fact that cholinoreceptors, which are concentrated
in normal muscles only in the area of the myoneural synapses, appear on the entire
membrane surface after myocyte denervation. The denervated structure response
differs not only by an increase but also by abnormality: for example, instead ol
relaxing Ihe vascular muscles contract.

Neurodystrophic Process Pathogenesis

I he significance of the nervous centers in dystrophy development has been

proved by experimental selective damage of the hypothalamus. It is accompanied
by Ihe development of ulcers in various peripheral organs.
I he trophic function is provided by the principle of reflex. So, analyzing the
ncurodystrophic process, it is necessary to evaluate the significance of each link ol
lellcx and its contribution to the mechanism of this process development.
Sensitive (afferent) nerves play a special role. After their cutting ( deafferentu
linn ) ihe following events take place:
• cessation of an information flow from a peripheral organ to the nervous center;
• a Mow of pathological information into the centers from the place of nerve cui
ling;
• centrifugal How of irritation into an organ from the place of nerve cutting;
• cessation of the axoplasmic flow of regulative substances via nerves to an organ
I he role of efferent nerves in dystrophy consists in cessation or perversion ol
IIh'ii functions (motility, secretion), and thus of trophic influence. The impulsive
activity, synthesis of mediators (adrenaline, serotonin, acetylcholine, etc.) cease,
ihe axonal transport of trophic substances is disturbed or stops. Normal functions
di .appeal and pathologic ones develop.
( ienome gets involved into neurodystrophy development. Enzyme synthesis
is unpaired, the output of macroergs decreases, and metabolism becomes moie
primnive I lie membranes and their transport functions are disturbed. A denervated
organ can become an object of autoimmune aggression. The dystrophic process
is complicated by (lie disturbance ol blood and lymph circulation. I lien hypoxia
ensues.
 C ll.ip lr i II Г й 1 1 м ф ||> ч н ||о к у » f N r n i i u s S > s l n n

Thus, we may conclude that the pathogenesis of neurogenic dystrophy is a

complex multifactorial process that develops when the nervous system ceases to
control metabolism in tissues, after what complex disorders of the structure and
function develop.

H IG H E R N ER V O U S A C T IV IT Y PA TH O LO G Y

Higher nervous activity encompasses psychic functions — consciousness, emo

tions, verbal function, and memory. Pathology of higher nervous activity is studied
by a separate branch of medicine — psychiatry.
In spite of the fact that higher nervous activity is more developed in man,
experimental pathophysiology investigates it in animals with the aid of objective
methods of investigation and reproduces pathology, first of all, by the method of
conditioned reflexes.
Pathophysiology studies the mechanisms of the appearance and developmcni
of pathologic deviation from the normal course of higher nervous functions of lIn­
human and animal brain. The theoretical ground is based on Pavlov’s doctrine ol
conditioned reflexes.
Etiology

Etiological factors, which cause higher nervous function pathology, are exo­
genous and endogenous of physical, chem ical and biological origin.
Posttraumatic pathology of higher nervous activity in the form of behavior
disturbances results from a direct action of a pathogenic agent on the brain, for
example, in its injury, or a brain tumor.
Chemical factors are called psychotropic, among which there are narcotics and
medicaments.
A peculiarity of the etiology lies in the biological effect of information factors.
Thanks to the second signaling system functional pathology of higher nervous acti­
vity can be stipulated by verbal action.
The pathological effect of negative emotions refers to biological factors. In
experiments with animals it is possible to model a behavior disorder and even a
siomach ulcer by forced limitation of movement (prolonged fixation), long-term
restriction of visual, auditory, tactile and other stimuli entry into the brain.
Functional changes and behavior disturbances are also studied by acting with
pathogenic agents on internal and external receptors.
Genetic factors, which cause congenital disorders of higher nervous activity,
refer to biological but endogenous ones.

Pathogenesis

Pathology of higher nervous activity may be primary caused by a direct action

of an injuring factor on the brain and by congenital genetic defects, or secondary
as a result of other pathology ol I lie oiguuiMii (more often of a vascular disease).
As a rule, secondary pathology ol liighci unvous activity results from asthcni/ation
1*ш1 S |M 't'lu l ( S .v s t n n l c ) P .H lm jiln чк>|<>щ

ol the nervous system, decrease of its strength in relation lo psychogenic and ot hoi
actions.
I I’ I'avlov singled out the types of higher nervous activity (see p. 59), which
determine individual reactivity, predisposition to diseases and the type of pathology
I he type of higher nervous activity is a congenital peculiarity of the nervous system,
which is reflected in such congenital characteristics as strength, balance, and mobi
lily ol nervous processes. These types are:
I Strong balanced mobile (corresponds to the sanguine type of Hippocrates)
2. Strong unbalanced with predominance of excitation over inhibition (cho
leric).
V Strong unbalanced with predominance of inhibition over excitation (phlcg
matic).
4. Weak, excitation and inhibition are poorly developed (melancholic).
As to the role of negative emotions in the pathogenesis of higher nervous acti
vity disorders, they play a positive biological role as a factor of extreme mobili/a
lion of the organism as counteraction to a pathogenic agent. If they have a long
lagnant duration and arc promoted by a long delay of external manifestation (ilu
so (. ailed untold emotions), they are accompanied by hormonal and other chemical
deviations in the blood. They decrease nervous system resistance to the pathogcnu
agent and thus an independent self-sustained pathological system is formed (a vi
i ious circle), which disorganizes the activity of other systems. Negative emotioir.
luive been named a cause of arterial hypertension, thyreotoxicosis, stomach ulcoi
etc All these examples result from stress with negative emotions.

Manifestations

I he manifestations of functional pathology of higher nervous activity are van

oils but first of all they include psychic functions. We can see weakness of tli<
т .ilylic synthetic activity of the brain, disturbance of long-term and short-lcim
memory, disorders of emotions and motivations.
As the frontal lobe of the brain cortex takes part in the management of con
gfiiital behavioral reactions, concordance of motivations, accumulation of expei i
■и» < we can see such changes in a patient with frontal lobe pathology: absence <>i
motivation, having unpredictable plans and intentions with preservation of intellect
ilu patient becomes rude, tactless, frivolous and irritable.
A frequent manifestation of higher nervous activity pathology is disturbance <>i
l><P waking cycles, impaired regulation of the vegetative and somatic function

the.ut rale, regulation of arterial blood pressure and skin trophicity).

In experimental animals these disturbances are manifested in feeding and schii
al behavior, which is mostly investigated to characterize higher nervous activity.

Neurosis

Neurosis is a typical form of dysfumHoning of the higher nervous system, wlm Ii

lesults from overstrains and breakdown ol lilyliei nervous activity. The pathogenetic
 t'lm p lrr H Г:Н1|о||||\мо1ок> of Nervous System

base of neurosis is disturbance of the main nervous processes such as excitation and
inhibition, namely of their strength and balance. Neuroses have such characteristics
as disturbances of higher nervous activity, vegetative regulation, movements, and
nervous trophicity as well as a decrease of general resistance of the organism.
Neurosis is reproduced in experiment by several methods.
Excitative process overstrain is reproduced by applying a very strong uncondi
tioned stimulus (intensive pain, strong sound), long or repeated action of a stimulus,
simultaneous action of some different, strong or uncommon stimuli (conditioned
and unconditioned). Continuous, inadequate agitation, aggressiveness and anger of
the animal manifest this neurosis.
Inhibitory process overstrain is reproduced by generation of very fine and com
plex differentiations, application of many differentiations in one stereotype, changcs
of the time of dynamic stereotype differentiation. The development of passive protec­
tive reactions, depression and drowsiness of the animal characterize this neurosis.
Overstrain of nervous process mobility is achieved by disturbance of a dynamic-
stereotype (electric current at the moment of eating).
The modern tendencies of developing methods of experimental reproduct ion of
neuroses are directed at maximal approximation of the model to human neuroses
These methods are: limitation of the «reflex of freedom* (forced immobilization
of an animal in an apparatus), disturbances of daily eating pattern, a high level of
behavior motivations (strong feeling of hunger), preliminary asthenization of the
nervous system under the action of chronic noise, ionizing radiation and a large
amount of information by combination of these factors.
As in any other pathology, we can see the development of compensatory reac­
tions — animals ease their condition and stop reacting to one of the signals if there
are several, inhibition develops, which protects the CNS. The phase of protective
inhibition follows the phase of excitation.
Determination of ultrastructural and neurochemical changes in the animal
brain in experimental neurosis suggests that neuroses have a structural basis. The
method of electron microscopy found destructive changes in the neuronal and glial
elements of the neocortex, reversible and irreversible disturbances of the neurome­
diator system. And we can say that any pathology has structural changes, which can
be determined by adequate investigation methods.

Questions for Self-Control

1. What are the peculiarities of the etiology of nervous system disorders?

2. Give the characteristics of blood circulation disorders in the nervous system.
3. What are the peculiarities of the course of inflammation in the nervous
system?
4. (Jive the characteristics of molecular and cellular disorders in nervous system
pathology.
5. What arc the mechanisms of pain?
6. What is nervous trophicity and its mechanisms?
7. What are the mechanisms and mimllcsintlons ol neurodystrophic process?
I'lirt 2 S p rcU l (Syntrm lc) Ги11||1||1|>л1и1<1ку

Tests for SdM'ontrol

(give correct answers)

I A patient suffers from sciatic nerve trauma. In some time trophic skin changcs
developed. What is the mechanism of skin lesion?
A. Phagocytosis of nerve terminations.
Ii. Phantom pain.
C. Cessation of axoplasmic flow.
I) Destruction of the myelin sheath.
E. Damage of vessels.

2. Parathyroid glands were removed in an experimental animal. Clinically it mu

nilcsted through sickness, thirst, neuromuscular excitability. Imbalance ofwlui
ion is this connected with?
A. Calcium.
B. Manganese.
C. Chlorine.
I). Molybdenum.
E. Zinc.

I A man with a closed hip fracture was hospitalized. He was in the excited stai*
What mechanism of traumatic shock demands immediate correction?
A. Hypoxia.
B. Pain.
C. Acidosis.
I). Intoxication.
E. Kcnal failure.

•I A 68-year-old woman had a stroke. She cannot move both right extremitx ■
Muscle tone and reflexes are increased. Pathological reflexes are obseivnl
What kind of paralysis is it?
A. Tetraplegia.
B. Paraplegia.
C. Peripheral.
I). Central.
E. Keflex.

A patient is ill with epilepsy. Specific centers are formed in Ihe brain ilu >
function according to the principle of pathological determinant. Wliat i ilu
mechanism of the formation of these centers?
A. Protective inhibition.
B. Intoxication.
С f ormation of a pathological excitation generator.
I). Hypoxia.
I Paiahiosis.
 C'hupk'i И I’ulhopliysioloKV <»f Nervous System

<
> Neurosis was experimentally modeled by applying a very strong unconditioned
stimulus. What kind of somatopathology can develop as a consequence of ncu
rosis?
A. Pancreatitis.
B. Glomerulonephritis.
C. Duodenal ulcer.
D. Hepatitis.
E. Myocarditis.

1 A woman ill with myasthenia had respiratory impairment, which required ar­
tificial lung ventilation. What respiratory impairment has developed in this
case?
A. Obstructive.
B. Central.
C. Thoracodiaphragmal.
D. Neuromuscular.
E. Destructive.

к The left leg of a 43-year-old patient was amputated after a trauma 4 months
ago. Now he complains of constant strong, sometimes intolerable pain in the
amputated extremity. What kind of pain does the patient have?
A. Phantom.
B. Causalgia.
C. Neuralgia.
D. Thalamic.
E. Reflex.

ч After a road accident a patient was diagnosed with trauma of the brachium and
median nerve. Motor and sensitive functions are impaired. The patient com­
plains of stinging intolerable pain. What kind of pain is it?
A. Somatic.
B. Visceral.
C. Reflected.
D. Phantom.
E. Causalgia.
 ANSWERS TO TKSTS AND TASKS
( Im p It T I Chapter 6 Chapter 9 C hapler 14

I - I) 1- 3 6 8 9 10 I - В 1- 1-H, 2-C,
2- С 2- 12 3 7 8 9 2- A 3-D. 4-J.
3- С 3- 12 3 4 5 3- С 5-G. 6-1.
4 - I) 4- A 7-1 . 8-E,
5- С Chapter 10
Chapler 2 6- В
1 - 15 6 7 8 9—B, 10-A
7- A 2567 9
1 13 4 6 7 X- С 2 -234 7
2 457К9 3 - 14 5 9 579
9- E 4 - 13 6 7 9 A
3- I) 10 - В
4- It 5- E С
II - С 6 A
5- E 12 - 2 34 6 78
-
С
6-1) 7- С С
13 - 14 5 6 7 8 13 5 6 7 8 9
7-1)
-

9 - 3 56 89
с
К- E Chapter 7 10 - 13 4 6 9 13 5 6 7 X
9— D
10 - E 1- A Chapter 11 Chapler 15
11 - E 2- D
12 С 3- I) 1- A 56
13 I 4К9 4- E 2- E 2 3 4 5 9 11
5- I) 3- С С
Chapter 3 6- 4- С
A A
7- В 5- В 24 5 6 7 X
1- 234 5 6- D
2- 346 8 X- 15 1 2 7 X 9 III
9- 14 5 6 7- D
3- 13 5 7 8- E
4 12 3 5 10 - 14 5
II - 13 4 5 6 7 9- С Chapter l(>
5- 46 7 10-1 7 12 14 16
6 14 7 X 9 12 - 12 3 5 6 7 11 - 3 5 6 9 10
12 3 6 8 E
7 Л 13 - II 12
14 - 24 78 I)
X С 12-1 4 II С
9 - E 15 - 34 7 13 - 2 5 7 9 12
10 I) 16 - 4 56 14
17 - 13 5 6 14 - 2 3 4 5 10 Chapter 17
11 - I)
12 69 18 - 1 2 35 6 8 II
1') 12 4 7 A
С liaptcr 4 20 - 12 5 6 9 10 Chapter 12 I 6 7X
21 - 1 5 6 7 8 12 А В I) I
1 I В. 2-C, 22 - 13 6 I - В В С I) Cl
1-Л. 4-1) 2- В
2- I 2 3 7X Chapter 8 3- С
4- A Chapter IN
3 - 4 9 10 II 12 5- С
1 A 6- Л
Chapter 5 2- E 1- С
3- В 2- I)
Chapter 13 3- II
E 4- 1)
A 5- A 1 13 5 6 7 4- A
С 6 1) 2 7 5- II
E 7- E 3 - 12 3 4 5 6- Л
II X- В I 12 3 4 5 7 9 7- С
I 26 7 X 9 9 С % - I 24 X- А
 A n s w e r s l o T e s t s u n it I u s k s

9- D 6 - 169 4- В 9- Е
10 - 1 5 6 7 9 7 - 23 45 79 5- В 10 - В
Chapter 19 8- D 6- В 11 - Е
9 - 345 7- A 12-А
I- С 8- С 13 - D
2- A Chapter 24 9- В 14 - 1 2 3 6 7 8 9
10- Е
I - 2346 79 11 - А
Chapter 20 2- В Chapter 29
12 - В
3- E 13- В
I- С 4- D I - D
2- В 5- D 2- А
Chapter 26
3- E 6- С 3- D
4- A 7- D 4- D
1- С 5- Е
5- В 8- D 2- D
6- D 9- D 3- А
6- А
7- A 10- В 4- Е
7- D
8- В II - 1 2 3 5 6 8 9 8- С
5- D 9- С
9- E 12- E 6- Е
10 - С 10- С
13-C 7- Е II - D
II - E 14 - E 8- С
12 - С 12 - D
15 - 1 2 3 7 9 10 9- D 13 - А
13 - E 10 - С
14 - E 16 - 1 5 6 7 9 14 - Е
17 - A И -С 15 - В
15 - E 12 - А
16 - В 18 - В 16 - Е
19 - A 13 - В
17 - E 14- Е
18 - 234 569 20-С
21 - E Chapter 30
22 - D Chapter 27
Chapter 21 23 - С I - D
24 - С 2- Е
I- А 3- А
I- E 25 - D 2- D
2- С 26 - D 4- D
3- Е 5- Е
3- A 27-A 4- В
4 — 12 3 5 6 7 28 - D 6- В
5- С 7- С
29- D 6- С
30- D 8- Е
Chapter 22 7- А 9- В
31 - В 8- С
32 - D 10 - В
I- 12 3 6 7 9 9- D II - Е
33 - В 10 - В
2- 24678 34 - E 12 - С
3- С II - 1 2 4 5 8 13 - С
35 - В 12 - 1 2 3 4 5 6 7
4- В 36- В
5 - 12 4 6 7 8 37 - A Chapter 31
38-A Chapter 28
Chapter 23 39- D 1- С
40 - В I - 12 4 6 8 9 2 - Л
I- 4 41 - С 2 - I 5 7 9 12 3- В
2- 23457 3- 2 36 8 4-1)
3 - 12 3 4 6 8 9 Chapter 25 4-1) 5- С
10 5 С 6- С
4 - 13 6 7 I- I) 6 Л 7-1)
5 - 3 4 7 9 10 12 2- E 7 I 8- Л
13 14 3- E N I) 9- Е
 IN D K X
л antioxidant system 45
Achylia 290, 413, 439
Ai holiu 425, 439
Ami base imbalance 247
Aculogencsis 244, 460
Acidosis 403
in hypoxia lft(>
in starvation 179, 181
azotemic 466
excretory 248, 428, 467, 470
ketoacidosis 225
in diabetes mellitus 211
hi hepatic coma 448
in lipid metabolism disorder 225
Adaptation (concept) 18
to hypoxia 165, 166
to starvation 177, 178
systemic (nonspecific) adaptive syn­
drome 506
AIDS (acquired immune deficiency syn­
drome) 82
Aldosterone imbalance (see also mineralo­
corticoids)
disorder of regulation 502
hyperaldosteronism 501
role in acid-base imbalance 245
role in arterial hypertension develop­
ment 373
role in edema development 254
Allergens, types and origin 89
Allergy
concept 87
difference Irom immunity 87
role of infection 97
iole m renal pathology 462
Alkalosis 248, 401. 402
Anaplasia 150
Anemia 278
in leukemia 361
in renal pathology 470
Angiopathy (vasopalhy)
in diabetes mellitus 215
in hemostasis pathology 329
Angiotensin 374
in arterial hypertension 382
participation in aldosterone secretion
regulation S02
Antioxidants
in radiation disease 30
in hypoxia 166
Antinociceptive system 525
Anuria 465, 468, 477
Arrhythmia
cardiac 348
periodic breathing 403
Arterial hypertension 377
in atherosclerosis 372
in renal pathology 383, 470
Asphyxia 405
Ascitc 259, 451
Atherosclerosis 365
in diabetes mellitus 215
in obesity 230
Autoallergy 96
in renal pathology 462
Autoimmune aggression 96
in anemia 283
in cardiac pathology 348
in hepatic pathology 437, 442
Avitaminosis 184, 446
Azotemia 242, 445, 448, 463, 465
В
Barriers 67
hematoencephalic 68, 518
role in autoallergy 97
BAS (biologically active substances) 70
control upon BAS effect 73
in allergy 88, 92
in immune reactions 78, 79, X*
in reactivity 70
in inflammation 123
Blast crisis 318
Klockadc (block)
of enzymal activity 240
of myocardial conductivity 349
Bohomolets O.O. 12, 59. 67. IV». } I
378
Bronchial asthma 95, 395
Burn 23
role in autoallergen formation 'Ml
С
<ali ic damage 262, 44, 47, 180
<'anccragcn(n) 144
 Index

Cancerogenesis, theories 146 Huntington’s chorea 520

Caries 412 hypertensive 377
Cerebral syndrome Itsenko-Cushing 492
in hepatic coma 449 Kwashiorkor 184
in radiation disease 29 Minkowski-Chauffard 286
in uremia 480 Parkinson’s 521
Cholemia 440 radiation 24
Cholesterole synthesis disorder 224, 367 receptor 91, 418
Chromosomal anomalies 45, 51 Simmond’s 492
Cirrhosis 43, 452 peptic ulcer 419
Coagulopathy 48 DNA repair system 31, 45
in hemostasis disorders 326 Dysproteinemia 236
Constitution 57 in hepatic pathology 445
role in atherosclerosis development Dystrophy
369 of liver (hepatosis) 437
role in obesity development 226 of kidney 465
Coma(s) of nervous tissue521
acidic 247 Diathesis 60
diabetic (acidotic, lactacidemic, ke- DIC syndrome 332
tonemic, hyperosmolar) 211, 216 in leukemia 316
hepatic 447 in renal pathology 470, 477
hypoglycemic 205, 517
uremic 479 E
Complement (disorders) Exudation 125
connective tissue Edema
role in constitution formation 59 allergic 93, 256
role in inflammation ascite 256, 451
cells of inflammation 121 cachectic 183, 259
role in regeneration 126 cardiac 257, 347
role in reactivity 67 cerebral 448, 518
endocrine 259
D hepatic 259, 445
Decompression (syndrome) 35, 36 inflammatory 93, 256
Dehydration 24, 259, 461 in starvation 183, 259
I )esensitization 99 lymphogenic 257
I )iabetes nephritic 258, 470
insipidus 493 pulmonary 399
mellitus 212 toxic (membranogenic) 256
mctasteroid 218,491 venous 108, 256
Disbacteriosis 428, 439 Electrolyte imbalance 261
I )isease(s) in arterial hypertension pathogenesis
of accumulation 48, (concept, 12) 374
of adaptation 508 in edema development 261
Addison’s 504 in hepatic pathology 448
Addison—Bicrmer’s 289, 412, 418 in renal pathology 467, 480
Alzheimer’s 521 Embolism 112
Basedow’s 494 gaseous 36
bum disease 23 I ndothelium damage
chromosomal 51 in atherosclerosis development 371
congenital 54 in radiation disease 29
hereditary 47 I IK'ikv
|||<1г\

dcficit Gout 242

in hypoxia 166
in starvation 178
imbalance 1X9
in neoplasia 151
I n/ymopathy 48
in anemias 285
I rythro|H>ietin(s)
in renal pathology 459
in anemia 285
I xporiincnt pathophysiological 3
m odeling o f
allergy 89, 92
arterial hypertension 372, 375
atherosclerosis 365
diabetes mellitus 202
endocrine pathology 486
glomerulonephritis 471
lever 131
hcpatic pathology 452
hypoxia 160
inflammation 125
myocardial infarction 347
neoplasia 142
neurodystrophic process 528
neurosis 533
respiratory pathology 404
I xtrasystole 348
I icosanoids 71
F Hyperazotemia 242, 465
I .isling 181. 191
lever 131
artificial 139
in inflammation 120, 128
I ihiillation
of myocardium 38, 350
I logogen(s) 126
I tec radical(s) activation
in hypcroxia 36
in radiation disease 25
(»
( ilucocorticoidl 500
hi arterial hypertension 373
participation in infection 128
participation in allergy 8')
role in sliess 506
( ilucosuiiil .’Ot), 20’), •!<>(»
( ilycogciumls .’01
Goiter 4%
Genetic pathology 44
defense reactions 45
methods of gcnetic examination nl
patients 56
H
Hematuria 464
Hematologic syndrome 267
in radiation disease 27
Hemoglobinopathy 48
in anemias 284
Hemolysis 281
in hepatic pathology 441
in renal pathology 461
Hemorrhage 268
hemorrhage stroke 517
hemorrhage syndrome 268
in ionizing radiation 28
in hemostasis disorders 325
in leukemia 316
in hepatic pathology 446
Hemostasis disorder 322
genetic determination 48
in allergy 94
in hepatic pathology 446
in leukemia 316
in radiation disease 28
role of lungs 326, 407
Hepatic colic 438
Hyperbilirubinemia 449, 453
Hypercholesterolemia 444
in atherosclerosis 366, 367
in diabetes mellitus 210
Hypercoagulation 330
Hyperemia
arterial 105
in inflammation 125
venous 107
in inflammation 125
Hyperglycemia 105, 209
in diabetes mellitus 215
Hyperhydration 255
Hypcrketoncmia 225
in diabetes mellitus 215, 216
in hepatic coma 448
in lipid dismetabolism 225
Hypcroxia 35
llvpeipintcincinia 23(t
Hypertension
 Index

arterial 377 Infarction

portal 451 due to atherosclerosis 345, 372
pulmonary 385, 399 due to ischemia 110
Hyperthermia 22, 131, 139 due to thrombosis 112
Hypertrophy 235 of brain 515
of myocardium in cardiac insufficien­ of myocardium 345
cy 343 Insulin
organs in adaptation to hypoxia 164 insufficiency 207
Hyperthyroidism 494 resistance to it 208, 218
Hypervolemia 267 ISF index
Hypercorticism 501 in hypoxia 164
Hyperkalemia 261 in myocardial hypertrophy 343
in renal insufficiency 467 Ischemia 108
Hyperventilation 402 ischemic heart disease 345
as a cause of alkalosis 249
in hypoxia 162 J
Hypobaria 34 Jaundice 452
Hypoglycemia 204, 447, 517 hemolytic 280, 453
Hypohydration 259 hepatic mechanical 441
Hypoproteinemia 236 hepatic parenchymatous 449
in starvation 183
in nephrotic syndrome 475 К
Hypothyroidism 495 Kinetosis 39
Hypovolemia 267, 269 Kinins 73
Hypoxia 160
in anemia 161, 278 L
in hemorrhage 269 Lecithin 224, 444
in hemorrhage shock 272 Leukemia 311
in hypobaria 34 hiatus leukemicus 318
respiratory 160, 401 leukemoid reaction 305
Leukotrienes 71
I Lipemia (hyper- and hypo-) 223
Immunoglobulins 77 transport hyperlipemia
Immunity 76 in diabetes mellitus 209
mechanisms 77, 78 in starvation 178
types 79 Lipid degeneration 210, 231, 444
Immunodeficiency 82 Lipocaine 224, 444
Immunodepression 81 Lipotropic substances 224, 444
in diabetes mellitus 212 Lymphokines
in leukemia 317 in allergy 96
in neoplasia 154 in immune response 77
in radiation disease 28 in reactivity 71
Inflammation 120 Lysosome pathology
immune in kidneys 462 in hepatic pathology 442
mediators 123 in radiation disease 27
peculiarities in pancreas 422
Inheritance 46 M
Interleukins 71 Malabsorption syndrome 426
interleukin-1 71 Mast cells
in inflammation 123 in reactivity 71
in fever 132 in allergy 92
Index

Mediators of inflammation 123 of radiation disease 34

Membranopathy 4X Phagocytosis disorders 69
in anemias 2X6 in inflammation 125
Mclasiases 142 Phenocopies 44
Mitochondria pathology 190, 193 Phenylketonuria 241
m hypoxia 165 Phospholipids 22, 444
in radiation disease 27 Polygenetic disorders 46
Microcirculation disorders 105 Polyuria
in inllammation 123 in diabetes insipidus 493
Mineralocorticoids (see also aldosterone) in diabetes mellitus 215
role in arterial hypertension develop­ in renal pathology 466, 46X, 479
ment 373, 3X0 Portal hypertension 451
Mutagens 44 POL activation
Mutation 44 in hyperoxia 36
in allergy XX in hepatic pathology 444
in immunodeficiency X2 under ionizing radiation effect 25
in neoplasia 146 Predisposition to diseases 51
in radiation disease 26 Prostaglandin(s)
Myxedema 259, 496 in arterial hypertension 376
in inflammation 124
N in reactivity 71
Neoplasia 142 in renal pathology 468
in leukemia 311 Proteinuria 464, 467, 469, 475
Neurosis 532 Protooncogens 146
role in arterial hypertension develop­ Pseudoallergy 100
ment 379 Pyrogen(s) 131
Nephrotic syndrome 474 Pyrogcncsis 132
Nervous trophicity 52X
disorder in space flight 39 R
Neurodystrophic process 530 Radioprotcctor(s) 34
in vagotomia 422 Kadiotoxin(s) 26
in paradontitis 412 Reactivity
concept 65
() normergy, hyperergy, hypoergy 6'
<Ин-sity 226 in inflammation 128
connection with diabetes mellitus in fever 136
2 ix. 230 specific 66
Oliguria 465, 46X, 472, 474 Renoprive hypertension 375
Oncogenesis 145 Resistance
Oncogcn(s) 143 concept 66
to hypoxia 167
P to insulin 20X
Pain 523 to ionizing radiation (sensitivity) )")
Pancreatitis 422 to neoplasia (protective reaction»)
Puradontitis 412 153, 154
Pathogenetic therapy 14 Risk factors 16, 51. 366
ol allergy 94
ol genetic disorders 57 S
ol glomerulonephritis 473 Sulurat ion 35
of hypoxia 16*) Sensitivity (concept) 66
of pain 526 to hvpoxia 167
 Index

to ionizing radiation 27 Tolerance

Sensibilization 92 immunological 80
Serum disease 94 absence to nervous tissue 518
Shock artificial 80
anaphylactic 94 loss in autoimmune aggression
hypovolemic 272 81, 96
pancreatic 424 to carbohydrates 206
psychogenic 513 to neoplasm 80, 155
SRS (slowly reactive substance) 71, 93 Trauma
Starvation 174 baro- 34
Stasis 110 electro- 37
in inflammation 125 psychogenic 513
Stress Thrombophilic syndrome 330
concept 506 Thrombosis 111
in starvation 176 complication of obesity 230
role in arterial hypertension develop­ role in atherosclerosis development
ment 378 369
role in ulcer disease development role in myocardial infarction develop­
421 ment 345
Surfactant, role in pathology 395 Thrombocytopathy 48, 328
Syndrome(s)
acute renal insufficiency 476 U
adaptive 506 Uncoupling of oxidation and phosphory­
adrenogenital 503 lation
AIDS (acquired immune deficiency concept 190, 192
syndrome) 82 in fever 133
Bruton’s agammaglobulinemia 83 in hypoxia 162
chronic renal insufficiency 478 Uremia 479
Brown—Sequard’s 523 Urine retention 462, 476
DiGeoige 83
Down’s 53 V
Itsenko—Cushing’s 501 Ventilative respiratory insufficiency 392
hepatorenal 451 Venous hyperemia 107, 125
hepatolienal 451 Venous edema 108, 256
Klinefelter’s 53 Viruses DNA- and RNA-containing 44
Louis-Bar 83 blockade by interferon 71
Morgagni-Adams-Stokes 350 in neoplasia 144
neurocerebral 29, 449, 480
nephrotic 474 W
Turner’s 53 Water imbalance 254
Swiss-type agammaglobulinemia 83 Withdrawal syndrome 505
resorption in myocardial infarction
346 Z
Wiskott-Aldrich 83 Zollinger-Ellison syndrome 420
withdrawal 505
Zollinger-Ellison 420

T
Tachycardia 342, 348
paroxysmal 348
Thalassemia 285
 Н авчал ьн с видання

N.K. Simeonova

PATHOPHYSIOLOGY
( англ. мовою )

Пщписано до друку 15.09.2010.

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