PathPhysio BNMU

PREFACE
The Pathophysiology Department of Bogomolets National Medical University is the

foremost in its field in Ukraine. Founded by the eminent scientists E. A. Tatarinov, V. P.
Komissarenko, N. N. Sirotinin and N. N. Zayko, it established the fundamental patterns used in
the teaching of pathophysiology. A textbook of pathological physiology for Ukrainian- and
Russian-speaking students (edited by the professors N.N.Zayko and Yu.V.Bytz) is in general
use and was awarded the State Prize of Ukraine. Its authors are professors N. N. Zayko, L. Ya.
Danilova, Yu. V. Bytz, V. A. Mikhnev, G. M. Butenko, L. A. Popova, A. G. Reznikov, V. A.
Gorban, O. I. Sukmanskiy, and A. V. Ataman; and I. I. Pototskaya and N. K. Simeonova,
holders of the Kandidat of Medical Science diploma. The author of an adapted version for
foreign students using English is N. K. Simeonova, a winner of the State Prize and a Senior
Lecturer.
The content and the structure of this textbook were completely worked out in accordance with
the Program and the Working Plan of the Ministry of Public Health of Ukraine by the teaching
staff of the department.
Content
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PART ONE. GENERAL PATHOLOGY
Chapter 1. SUBJECT, METHOD AND AIM OF PATHOPHYSIOLOGY. THE GENERAL

CONCEPT OF DISEASE, ETIOLOGY AND PATHOGENESIS
Chapter 2. PATHOGENIC EFFECT OF ENVIRONMENTAL FACTORS
Chapter 3. THE ROLE OF HEREDITY AND CONSTITUTION IN PATHOLOGY
Chapter 4. REACTIVITY AND RESISTANCE OF ORGANISM
Chapter 5. IMMUNOLOGICAL REACTIVITY AND ITS PATHOLOGY
Chapter 6. PATHOLOGY OF IMMUNOLOGICAL REACTIVITY (Continuation). ALLERGY
Chapter 7. PATHOPHYSIOLOGY OF THE PERIPHERAL BLOOD CIRCULATION
Chapter 8. INFLAMMATION
Chapter 9. NEOPLASIA
Chapter 10. TYPICAL DISORDERS OF METABOLISM.

PATHOLOGY OF ENERGY BALANCE AND BASAL METABOLISM
Chapter 11. TYPICAL DISORDERS OF METABOLISM (Continuation).

PATHOLOGY OF CARBOHYDRATE METABOLISM

PATHOLOGY OF PROTEIN METABOLISM

PATHOLOGY OF LIPID METABOLISM

PATHOLOGY OF ACID-BASE BALANCE

PATHOLOGY OF WATER-ELECTROLITE BALANCE
Chapter 17. STARVATION
Chapter 18. FEVER
THE SECOND PART. PATHOPHYSIOLOGY OF ORGAN SYSTEMS

Chapter 19. PATHOPHYSIOLOGY OF BLOOD SYSTEM.
DISORDER OF BLOOD VOLUME. HEMORRAGE
Chapter 20. PATHOPHYSIOLOGY OF BLOOD SYSTEM (Continuation).

PATHOLOGY OF ERYTHROCYTES. ANEMIA

PATHOLOGY OF LEUKOCYTES. LEUKOCYTOSIS, LEUKOPENIA

LEUKEMIA
Chapter 23. PATHOLOGY OF BLOOD COAGULATION
Chapter 24. PATHOPHYSIOLOGY OF HEART
Chapter 25. PATHOPHYSIOLOGY OF VESSELS
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Chapter 26. PATHOPHYSIOLOGY OF RESPIRATORY SYSTEM
Chapter 27. HYPOXIA
Chapter 28. PATHOPHYSIOLOGY OF DIGESTIVE SYSTEM
Chapter 29. PATHOPHYSIOLOGY OF THE LIVER
Chapter 30. PATHOPHYSIOLOGY OF THE KIDNEYS
Chapter 31. PATHOPHYSIOLOGY OF THE ENDOCRINE SYSTEM
Chapter 32. PATHOPHYSIOLOGY OF THE NERVOUS SYSTEM
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PREFACE
The Pathophysiology Department of Bogomoletz National Medical University is the
foremost in its field in Ukraine. Founded by the eminent scientists V.V. Podvisoysky, E.
A. Tatarinov, V. P. Komissarenko, N. N. Sirotinin and N. N. Zayko, it established the
fundamental patterns used in the teaching of pathophysiology. A textbook of pathological
physiology for Ukrainian- and Russian-speaking students (edited by the professors
N.N.Zayko and Yu.V.Bytz) is in general use and was awarded the State Prize of Ukraine.
Its authors are professors N. N. Zayko, L. Ya. Danilova, Yu. V. Bytz, V. A. Mikhnev, G.
M. Butenko, L. A. Popova, A. G. Reznikov, V. A. Gorban, O. I. Sukmanskiy, N.V.
Kryshtal, A. V. Ataman; доктор медицинских наук V.E. Dosenko, and I. I. Pototskaya,
N. K. Simeonova, L.P. Sayarnaya and A.G.Repezlaya, holders of the Kandidat of Medical
Science diploma.
The author of an adapted version for foreign students using English is N. K.
Simeonova, a winner of the State Prize and a Senior Lecturer.
The content and the structure of this textbook were completely worked out by the
teaching staff of the department in accordance with the Program and the Working Plan
Учебная программа и Учебный план of the Ministry of Public Health of Ukraine.
PART 1
GENERAL PATHOPHYSIOLOGY
CHAPTER 1
SUBJECT, METHOD AND AIM OF PATHOPHYSIOLOGY.

GENERAL CONCEPT OF DISEASE, ETIOLOGY AND
PATHOGENESIS
SUBJECT, AIM AND METHOD OF PATHOPHYSIOLOGY
Medical education is constructed in such a way, that at first the students

study those disciplines, which deal with the structure and function of normal
organism (anatomy, histology, biochemistry and physiology). Later the
students start studying those disciplines (pathological physiology and
pathological anatomy) that deal with structure and function of a sick
organism, preparing the students for studying clinical disciplines. In turn, a
clinic arises the problems for pathophysiology to solve.
Any scientific discipline has its subject and method. The problems, which
scientific discipline investigates, are its subject.
Pathophysiology is a science about наиболее общие закономерности the
most general? common? laws? governing the beginning, development
and outcome of a disease.
Pathological physiology is the basic theoretical medical discipline and is
called as a philosophy of medicine.
TWO PARTS OF PATHOPHYSIOLOGY
Pathophysiology is originated from medical discipline termed General

Pathology, which deals with the pathologic basis of a disease. В англоязычных
countries this medical discipline is teaching in such a form in majority of
medical universities. The text-book “Pathologic basis of disease” by Stanley
L. Robbins and Ramzi S. Cotran is in general use, in which structural basis
and functional закономерности of pathology излагаются совместно.
It was Ukrainian eminent pathologist A.A.Bogomoletz, who has выделил
from this medical discipline the Pathological Physiology, which deals with
functional changes, mechanisms and dynamics of disease development, on
the contrary to Pathological Anatomy, which deals predominately with
morphological sings of a disease.
______________________________________________________________________
A.A.Bogomoletz (c.19 украинского учебника)
_____________________________________________________________________
In turn, pathophysiology, as a medical discipline, consists of two parts -
General Pathophysiology and Special (Systemic) Pathophysiology.
General Pathophysiology deals with
 General Nosology
  Concept of a disease
  Concept of etiology and pathogenesis (causes and mechanisms of
a disease development)
  Role of inheritance and constitution in pathology
  Role of organism reactivity (resistance) in pathology
 Typical pathophysiological processes (inflammation, neoplasia, hypoxia,
fever and others)
 Typical metabolic derangements
Special (Systemic) Pathophysiology deals with наиболее общие
закономерности of pathology of organs and physiological systems (cardio-
vascular, respiratory, digestive, endocrine, nervous etc) and the main
pathophysiological syndromes.
EXPERIMENT AS A BASIC main? METHOD OF PATHOPHYSIOLOGY
Method of any scientific discipline is a way of studying the problems it

proclaims. The main method of pathophysiology is an experiment. Sometimes
the mechanisms of a disease are hidden, and investigation is possible only by
modeling pathology in experimental animals. Studying of a disease with the
contemporary morphological and biochemical methods becomes possible.
Extirpation of organ, irritation, injection of different substances
(hormones, enzymes, antibodies, toxins etc.) are widely used in
pathophysiology. Different types of animals are involved into experiment.
Simplification of pathological process has some prevalence. That is why
frogs, rats and even isolated organs and cells may be used. An experiment
helps to establish the mechanisms of a disease genesis at different levels of
organism organization and to observe it from the beginning up to the end.
Pathophysiological experiments are divided into acute and chronic ones.
An acute experiment examines acute disorders in organism (shock, collapse,
acute renal insufficiency, etc). A chronic experiment is a prolonged one and
shows disease dynamics. It is used for investigation of chronic diseases
(diabetes, atherosclerosis, arterial hypertension, ulcerous disease, etc).
All methods of treatment are tested in experiment (experimental therapy)
which in turn corrects the knowledge about essence and mechanism of a
disease.
In addition to experiments made on animals, the clinical
pathophysiological investigations on patients are possible with the
contemporary scientific methods.
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CONCEPT OF A DISEASE
A teaching about disease, or General Nosology (nosos in Greece –

disease), belongs to the ancient problems of medicine. It is important for
physician to have criteria to distinguish health and disease without mistakes.
For this, it is necessary to determine what health means to understand the
essence of a disease.
Normal state of organism is characterized by its balance with
environment, an ability to adapt to it, maintenance of homeostasis by proper
regulation and an ability to preserve the main social function of a man –
workability трудоспособность.
The World Health Care Organization accepted the following definition of a
health:
Health is a state of a total physical, mental and social welfare of a
man, but not only an absence of a disease or physical defect. This
definition is rather general and characterizes a situation to be approached to.
Normal life proceeds in a permanent adaptation of organism to the
environment, which is constantly changing. If this ability gets reduced, the
main social function of a man - an ability to work - can be limited.
Therefore, the following definition of a disease may be suggested:
A disease is a disorder of physical and mental welfare of a man caused
by injuring influence, which results in limitation of adaptive capability of
organism and its workability трудоспособность elevating probability of a
death.
A physician has to treat a patient with a certain disease. An amount of
known diseases is very large and changes in course of time. Some diseases
disappear, other appear. For example, radiant disease had not been evident
before X-rays started to be used. Cosmic medicine did not exist before
cosmic flights became a reality. Some thousands of diseases are known now,
and each of them has its own name.
Before studying the certain diseases, it is necessary to study their common
features. It should be emphasized, that in pathophysiology a disease is
understood not as a nosologycal form (the name of a certain disease), not as
the disease of a certain patient (which has an individual variation of duration),
but a disease, as an abstraction, as a phenomenon which differs from a health
(fig.1).
Disease as a phylosophical обобщение

Disease as a typical pathological process
Disease as a nosological form
Disease in a concrete patient (diagnosis)
Fig.1. Relationship between abstractive and concrete in a disease ( Мал.1. с. 27

украинского учебника)
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GENERAL CHARACTERISTICS OF A DISEASE
Disease is a unity of two opposite tendencies – damage and defense, which

are in a constant coordination and fight.
All physiological patterns may be changed in a course of any disease.
However, a disease is not a sum of quantitative changes, but a qualitatively
new phenomenon.
A disease reveals new understanding of an optimal level of physiological
functions. For example, in a course of infection an optimal body temperature
is above 37 (38-39° and more), but the body temperature equal to 36,6° is
not optimal. During an inflammation an increased quantity of leukocytes in
the blood (up to 15-20 G/l instead of 4-9 G/l) is optimal. During hypoxia an
increased frequency of respiration and increased quantity of erythrocytes are
optimal. Analyzing the patient’s quantitative patterns, a physician must
compare them not only with the physiological standards, but those, which are
considered as optimal for this disease.
A disease has two quite opposite processes. They are -
1. “Pathologic process proper” собственно патологическое with functional,
morphological, biochemical disorders,
2. “ A measure against a disease”, which means development of defensive
reactions.
So, a disease is a dialectic unity of противоположностей. A physician must
fight the pathologic process proper and stimulate the protective processes.
The components of a disease include
 Pathological reaction
 Pathological process
 Pathological state
 Typical pathological process
Pathological reaction is a reaction of organism on effect of pathological
factor (hyperemia, ischemia).
Pathological process is a combination of pathologic and protective
reactions in the damaged organs or organism. It has a certain dynamics and
stages.
Pathological state is a pathological process which has lost its dynamics
and is fixated (for example, a condition after amputation of a foot, resection
of a stomach).
Typical pathological process is the one, which has common features and
laws of development regardless from localization, nature of injuring agent
and evolutionary organization of organism. The following processes behave
as the typical pathological ones – inflammation, neoplasia, fever, hypoxia,
starvation, hyperemia, thrombosis, embolism, ischemia, and typical metabolic
disturbances.
Any disease has etiology (a cause), pathogenesis (mechanisms of
development), periods and manifestations.
CLASSIFICATION OF DISEASES
For practical purpose it is necessary to divide all the diseases into larger
groups.
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Classification may follow various principles: cause, localization,
mechanisms of development, age (diseases of children or elderly peoples),
sex (female and male diseases), type of dysmetabolism, professional aspects,
clinic duration and others.
Clinical classification of the diseases is based on the clinical forms,
localization, clinical duration (acute and chronic).
Etiological classification is based on a cause. According to this, the
diseases are traumatic, toxical, infectious as well as acquired and inherited.
Топографоанатомическая classification of the diseases corresponds with
the main physiological systems and modern specialization of medical help. It
is suitable for practice (cardiac, pulmonary, nervous diseases etc.).
Pathophysiological classification is based on conception of typical
pathological processes. It divides diseases into inflammatory, allergic,
neoplastic, metabolic ones. Consequently, before studying the inflammatory
diseases (tonsillitis, myocarditis, hepatitis, pleuritis etc.) it is necessary to
study an inflammation, as a typical pathological process. Before studying
such type of diseases, as a cancer, melanoma, osteoma it is necessary to study
a neoplasia, as a typical pathological process. Before studying the allergic
diseases (bronchial asthma, rheumatoid poliartritis) it is necessary to study
allergy.
PERIODS
Many diseases (infectious and some others) develops in such periods:

 Latent (has not clinical signs),
 Prodromal (first clinical symptoms which are common in many diseases),
 Period of expressed clinical signs (which are specific for this disease),
 Outcome.
This four-staged periodization of a disease was suggested in the past for
acute infectious diseases, but many diseases (cardiovascular, endocrine,
allergic) are governed by another laws, and the mentioned periodization is not
applicable to them. These diseases develop in three stages:
 Beginning
 Stage of a disease proper
 Outcome
Outcome depends on force of a damaging factor, reactivity of organism
and an ability to develop the self-protective reactions. There are three
outcomes of a disease: recovery (complete, incomplete), transformation into
chronic form or pathologic state, death with preagony, agony, clinical and
then biological death.
The prevalence of defensive reactions leads to recovery. Uncompleted
compensation leads to the turning of a disease into chronic form. An
exhaustion of adaptive reactions leads to death.
From pathophysiological point of view many diseases are divided into
two stages:
 Stage of compensation (ability to work is preserved)
 Stage of decompensation (ability to work is lost).
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MANIFESTATIONS
Each disease is manifested by subjective (patient’s complaints) and

objective signs, which in turn are visible (rash, paleness, edema,
discoordination of movements) and invisible. The latter are morphological,
physico-chemical, biochemical and pathophysiological (functional), which
are revealed by special investigations.
CONCEPT OF ETIOLOGY
Etiology is a teaching about causes and conditions of a disease.

A certain pathogenic factor is called an etiological factor.
Classification of Etiological Factors
Etiological factors are divided into exogenous (external) and endogenous

(internal) as well as acquired and congenital ones.
Depending on nature, etiological factors are divided into physical
(mechanical, thermal, electricity, radiation, barometric pressure changes
etc.), chemical (chemical poisons, toxic metabolytes, side-effect of medical
drugs) and biological (microbes, viruses, parasites), psyco-emotional
influences. For men, the social causes of a disease are distinquished.
Genetical and immune causes refer to endogenous biological factors.
Role of Conditions in Development of a Disease
Analyzing etiology, it is necessary to take into consideration the

conditions of etiological factor effect, which are divided into aggravating and
preventing a lesion (scheme 1). Thus, analyzing an effect of high or low
temperature of surroundings, it is necessary to take into account local or
systemic mode of its influence. Analyzing a radiant injury, together with a
dose, it should be considered a pathway of its entry in organism (external
irradiation or entry of ionized particles inside).
Exogenous and endogenous conditions, which can modify an etiological
factor effect and promote disease development, are poor nutrition,
overcooling, overheating, oxygen deficiency, old age, early childhood.
Risk factors are those, which increase morbidity. For example, arterial
hypertension, obesity, hypodynamia, hereditary factors, stress are the risk
factors for atherosclerosis development. Risk factors may play a role of cause,
condition or link of pathogenesis.
Overestimation or underestimation of either etiological factor or
conditions are mistaken (causalism is an overestimation of an etiological
factor role and an underestimation of conditions role; conditionalism, on the
contrary, is an overestimation of conditions value). Only an adequate
estimation of the role both etiological factors and conditions leads to the
correct analysis of a disease etiology.
______________________________________________________________________
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Scheme 1. Correlation between causa and conditio in etiology
ETIOLOGY
Etiological factors Conditions

(Latin - causa)
+ (Latin - conditio)
Exogenous Endogenous Promote a Prevent a

(external) (internal) disease disease
development development
Physical
Chemical
Biological
CONCEPT OF PATHOGENESIS
Pathogenesis is the mechanisms of development and outcome of a

disease after an action of etiological factor.
There are two variants of interconnection of the cause (etiology) and
pathogenesis:
 Etiological factor initiates pathologic process and then disappears, so
pathogenesis develops without presence of etiological factor (trauma,
radiation).
 Cause continues its action throughout all periods of a disease development
(infectious disease); so, an etiological factor penetrates into pathogenesis and
influences it.
Pathogenesis of any disease follows such общие закономерности general
lows:
 All events, which are observed in pathogenesis of any disease, are called
the links of pathogenesis. The order of events is called the причинно-
следственные cause-consequence relations.
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There are three variants of such relations (scheme 2), which have a
practical importance.
 If the links of pathogenesis would be connected directly (like in
infection), a self-regulated recovery is possible.
 In “ circulus vicious ” a consequent последующий link of pathogenesis
stimulates an effect of previous one. Process would not be finished
without а help and becomes endless, like a circus. For example, in
shock, when arterial blood pressure decreases, it causes hypoxia, then the
vaso-motor center would be depressed, and then it leads to the prolonged
decrease of arterial blood pressure. Figure 30 demonstrates cause-
consequence relations with many “ circulus vicious ” in hemorrhage
shock. Such duration is characterized for many chronic non-infectious
diseases – arterial hypertension, bronchial asthma, atherosclerosis,
rheumatism.
 If pathogenesis develops as the branching chain reactions цепные
разветвленные реакции (radiant disease), the help is necessary at the initial
stage of pathogenesis. Prophylactics is the best measure.
_______________________________________________________________________
Scheme 2. Variants of cause-consequence relations
. Infection
Chronic non-infectious disease
Нужно сделать круг из 5-6 стрелок – информация для художника
Etiological factor
8
Radiation disease
Anaphylactic shock
___________________________________________________________________________
 There is a so-called leading (main) link in pathogenesis. It is a process,
which is necessary for development of all others. Liquidation of the main
link is essential for treatment. Thus, in diabetes mellitus the insulin deficiency
is the main link in pathogenesis. Its liquidation (by injection of hormone)
results in disappearance of other sings (hyperglycemia, glucosuria,
polydipsia, ketonemia, and comas).
 In any disease an organism resists an injury by developing of the self-
defensive (protective, adaptive, compensatory) reactions.
 The stage of a compensation is a stage of a disease, when compensatory
reactions prevail, homeostasis and normal жизнедеятельность are maintained.
Compensatory (defensive) reactions are divided into immediate (urgent) and
delayed (non-urgent, which provide the long-term adaptation). Immediate
protective reactions appear a mobilization of existing mechanisms of
physiological hyperfunction. The long-term compensation may be reached by
hypertrophy of organ (pathology of myocardium). Adaptation is such a state
of compensation, when in spite of a constant action of etiological factor, an
ability to work is supported completely. The stage of a decompensation is a
stage of a disease, when (a) compensatory mechanisms are not adequate, (b)
reserves of adaptation are depleted, (c) homeostasis gets altered.
 In pathogenesis of any diseases it is necessary to identify local and
systemic derangements. Sometimes the local ones develop originally and lead
to systemic changes. For example, an inflammation develops predominantly
locally, but the whole organism is involved obviously. Sometimes the
systemic derangement develops originally and can be displayed by the local
changes. For example, in diabetes mellitus (systemic disease) the local
processes (furuncles, neuritis, renal dysfunction) develop secondarily. The
lipid dismetabolism causes atherosclerosis, which displays as heart attack or
gangrene of lower extremities.
 In pathogenesis of any disease structural and functional disorders are
identified. A physician is interested preferably in functional disturbances.
Naturally, certain structural and biochemical changes underlie the
dysfunction. However, in many cases medical science has not still revealed
them (for example, in psychic diseases).
 In pathogenesis of any disease there are specific and nonspecific signs.
The first characterize a certain disease and underlie the diagnostics (for
example, the character of pain in a case of stenocardia). The second
characterize many or even all diseases (mechanisms of a standard answer to
any pathogenic factor like stress).
 It is necessary to study pathogenesis of any disease at different levels of
biological organization - molecular, cellular, at the level of organ,
9
physiological system and organism as a whole. Investigation at the level of
population discloses additional закономерности (популяционная генетика,
investigation of inflammation in evolution by Metchnokov).
 A course of any disease depends not only on a force of etiological factor,
but reactivity (resistance) of organism and ability to develop the defensive
reactions.
 A course of a disease depends not only on an etiological factor, but the
genetical and constitutional peculiarities of organism.
From all these positions it is necessary to analyze pathogenesis of any
disease.
PRINCIPLES OF TREATMENT
Usually a physician records patient’s complains, subjective and objective

manifestations of a disease, which are called symptoms. A physician may
liquidate a separate symptom (pain) and alleviate the patient’s suffering. It is
a symptomatic therapy, the worse type of it.
The real cure is a liquidation of a cause of a disease (for example,
treatment of infection with antibiotics). It is an etiological therapy.
However, sometimes liquidation of etiological factor is unreal, and attention
must be paid to conditions. Creation of favorable conditions and avoidance of
risk factors underlay etiological therapy as well.
It is possible to block the important mechanisms of a disease development.
Naturally, the knowledge of molecular, cellular and biochemical mechanisms
of pathogenesis is necessary. This type of therapy relates to effective one and
is called pathogenetic.
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CHAPTER 2
PATHOGENIC EFFECT OF ENVIRONMENTAL FACTORS
Environment is a source of various pathological factors that cause a disease if their force
exceeds the adaptive potentialities of organism or reactivity of organism gets decreased.
The term environmental diseases applies ultimately to every disease not strictly inherent in
genes. All of them are theoretically preventable.
PATHOGENIC EFFECT OF LOW TEMPERATURE

(HYPOTHERMIA)
Hypothermia is a lowering of body temperature as a result of the whole body exposure

to low ambient temperature.
Etiology
Etiological factor is a cold if a whole body is exposed to. Temperature of comfort is 18 o C.

The temperature, which is below, need cloth.
Pathogenesis
Hypothermia develops in two stages - compensation and decompensation.
Stage of Compensation
The stage of compensation is a period of hypothermia, when the self-defensive reactions

prevail, and normal body temperature is maintained.
As a homeothermic organism, a man can tolerate fluctuation of ambient temperature.
Compensation develops as a response and excitation of the dermal thermoreceptors and the
center of thermoregulation. As a result, the compensatory reactions develop.
Compensatory reactions consist in limitation of heat emission and activation of heat
production.
Heat emission diminishes by decreasing of perspiration (evaporation) and contraction of
peripheral dermal vessels.
The heat production (thermogenesis) intensifies, and additional calories of heat are produced.
Metabolism is activated, splitting of glycogen in liver and muscles takes place. Glucose blood
level rises. Oxygen transport activates and oxygen consumption increases. The organism, which
is adapted to cold, has more powerful mitochondrial system.
Lipid metabolism is activated.
Metabolism is not only activated, but reorganized. An additional thermal energy is formed due
to uncoupling of oxidation and phosphorylation.
1
Reorganization of the thermoregulation is controlled by neurohumoral mechanisms. From the
dermal? cutaneous? thermoreceptors the impulses through the sensitive ways reach the center of
thermoregulation in hypothalamus, from which in opposite direction the signals reach the organs
and systems which participate in maintenance of body temperature. Through По the motor nerves
the impulses reach the muscles; thermoregulatory muscular tonus rises and muscle trembling
develops. По Through sympatic nerves impulses reach the medullar substance of adrenal glands.
Secretion of adrenaline increases (adrenaline effects the vessels, mobilizes glycogen from liver
and muscles, stimulates oxidation). Pituitary gland stimulates (by tropic hormones) the thyroid
gland (thyroxin intensifies metabolism, activates biogenesis of mitochondria) and adrenal cortex
(glucocorticoids stimulate the formation of carbohydrates from noncarbohydrate products and
form the condition of stress).
Stage of Decompensation
The stage of a decompensation is a period of hypothermia, when compensatory reactions are

exhausted, and the body temperature gets diminished. Reduction of metabolism and oxygen
consumption is observed. Vitally important functions fail. Disorder of respiration and
hemodynamics leads to hypoxia.
In a state of hypothermia organism becomes less sensitive to other injuring factors
(intoxication, infection, harmful effect of electric flow and ionizing radiation, hypoxia).
If an action of cold would not ceased, a death comes.
PATHOGENIC EFFECT OF HIGH TEMPERATURE

(HYPERTHERMIA. BURN)
Hyperthermia is an increase of body temperature as a result of the whole body exposure

to elevated ambient temperature.
Etiology
Etiological factor is a heat if the whole body is exposed to. It happens in industrial conditions.
Nowadays, when climate changes, an overheating happens under temperature of surroundings,
which is above body temperature (36o C and above). This problem arises all over the world.
Pathogenesis
Hyperthermia develops in two stages - compensation and decompensation.
Stage of Compensation
The stage of a compensation is a period, when the self-defensive reactions prevail, and the
normal body temperature is maintained.
Compensatory reactions consist in increasing of heat emission by an activation of convection,
radiation, perspiration and evaporation. Peripheral vessels are dilated. If the temperature of
environment is over 30 C, convection is inhibited. Under the condition of high humidity of air,
evaporation is limited as well.
Stage of Decompensation
The stage of a decompensation is a period of hyperthermia, when compensatory reactions are

exhausted, and the body temperature rises.
2
Hyperthermia is manifested by excitation of central nervous system and tachypnoe.
Cardiovascular system is overloaded. Tachycardia is a symptom of overheating. Later, the
generalized vasodilatation occurs with sequestration of large volume of blood and the effective
circulating volume reduction.
At the beginning of hyperthermia, oxygen intake and metabolism rise as a result of nervous
excitation and elevation of body temperature. Disintegration of proteins is intensified. The
surplus of final nitrous products takes place. Acid-base balance moves toward acidosis.
Activation of perspiration has negative consequences - dehydration develops (liquid loss can
reach 3,5 l per hour). Disorder of electrolytic balance consists in loss of sodium and chlorides.
Disorder of the intracellular sodium pump leads to redistribution of potassium into extracellular
fluid and blood. Hyperkaliemia thus develops. Increased blood viscosity creates additional load
on blood circulation and results in cardiac insufficiency.
Acute overheating and a rapid increase of body temperature are called thermal shock (heat
stroke). If the action of etiological factor would not ceased, the convulses develop and the death
occurs because of disorder of respiration and circulation.
Local Hyperthermia (Thermal Burn)
Burn develops as a result of local effect of high temperature and is manifested by destruction
of skin and systemic disorders in organism.
Depending on violence of local damage, the following degrees of burn are distinguished:
I - redness of skin (erythema), weak inflammatory reaction without destruction of a skin;
II – acute exudative inflammation of skin, formation of bubbles, and epidermis scaling;
III - partial necrosis of skin and ulceration;
IV – transepidermal necrosis.
In обширных ожогах the systemic disorders predominate local ones. It goes about burn
disease.
Clinical manifestations of burn disease are connected with development of shock, toxemia,
infection, dehydration.
Burn shock is the most severe post-burn effect. It is as a result of a pain and excessive
afferent impulsation into the central nervous system. The regulation of vascular tonus, respiration
and heart contraction is impaired. The circulating blood volume decreases, dehydratation and
acute renal insufficiency develop.
Intoxication contributes significantly in the development of shock. Endotoxins are formed as
a result of metabolism disorder; majority of toxins is liberated in a zone of damage. Critical
disorders in protein metabolism are noted; the total disintegration of proteins is observed. The
denatured proteins and toxic products of their enzymal lysis enter the blood. Critical disorder of
nitrogen metabolism takes place.
Infection is a constant complication of burn disease and aggravates intoxication. The source
of infection is the damaged surface and bowels (autoinfection). Not only burn area itself is
colonized by bacteria but the entire skin surface of the patient. Increased permeability of blood
vessel wall leads to massive infection and bacteriemia. Sepsis resulting from burn-wound
infection is the most important cause of death in seriously burned patient. Under effect of
proteolytic enzymes, which are liberated from the damaged cells, the proteins may got changed,
and antigens become the reason of autoimmune aggression.
Dehydration is a severe complication of burn. It relates to the massive outpouring of exudate.
Burn area becomes reddened as small blood vessels dilate, followed by increased capillary
permeability with exudation of protein-rich fluid. Burn implies an open wound from which an
enormous amount of plasma proteins may be lost through the damaged surface. The loss of
liquid induces hypovolemia and hemoconcentration. An increased blood viscosity disrupts blood
circulation and function of heart. Water-mineral balance breaks down. The damaged tissues
3
retain sodium (cellular hyperhydration develops) and loose potassium (blood content of
potassium increases, hyperkaliemia develops).
Exhaustion (cachexia) is the final stage of the disease. The following pathological disorders
are observed - edema, anemia, dystrophic changes in organs, pneumonia, glomerulonephritis,
and insufficiency of the adrenal glands. All these disorders equally with striking pulmonary
transudation and pulmonary edema become the reason of death.
If the burn disease acquires favorable current, recovery begins. Defect would be filled up
with granulation. A wound would be epithelized.
Thus, the severely burned patient confronts not only the repair of the local injury but, even
more importantly, its serious systemic consequences.
PATHOGENIC EFFECT OF IONIZING RADIATION

RADIANT DISEASE
ETIOLOGY
Etiological factors of radiant disease are the various forms of ionizing radiation of high
energy (-, -, - rays, X-radiation, etc.). Their general property is an ability to penetrate in
biological medium and ionize atoms and molecules.
Intensity and duration of injury depends on form of radiation, dose, time factor and type of
molecular or supramolecular target, which occurs on the pathway of radiation (table 1).
Table 1. Biologic effect of a single whole-body exposure to various doses of ionizing radiation on a man
Dose (roentgens) Biological effect

10 No detectable somatic effects. Detectable
morphologic and functional alterations in specific
subpopulations of lymphocytes; probable
chromosomal abnormalities.
100 Mild form of a disease in some persons with nausea,
vomiting and transient leukopenia.
1000 Damage of bone marrow with leukopenia,

thrombocytopenia and anemia; necrosis of
gastrointestinal mucosa; severe radiant disease; death
within 30 days.
10000 Death within hours.
100000 Acute гибель of most types of mammalian cells.
There is no strict correlation between dose of radiation and severity of affection. Direct
dose-effect correlation appears for large and average doses. As to small doses, the correlation is
another one. The so-called radiobiological paradox is evident. It means, that clinical effect can
reach catastrophic scales even due to insignificant quantity of absorbed energy, because the
primary physical and chemical effects are aggravated by biological mechanisms.
There are such doses of radiation that substantially don’t change the morbidity in population.
However, even one quantum of energy can be sufficient for the mutation with tragic
consequences. So, any radiant dose shouldn’t be appreciated as absolutely harmless for people.
An important condition that substantially modifies the type of radiant disease is the pathway
of irradiation (distant, contact, inhaled or oral). The external irradiation is such one, when a
source of it is located out of organism. The internal (incorporated) irradiation is the one, when
4
radioactive materials enter inside. The letter is considered to be more dangerous. Combined
radiation is possible.
PATHOGENESIS
PRIMARY MOLECOLAR (PHYSICOCHEMICAL) DISORDER
Energy of ionizing radiation exceeds energy of the intramolecular and intraatom bonds.
Absorbed by macromolecule, it may migrate in the cell realizing in the most vulnerable
places. It results in ionization, excitation and break of less stable bonds, tearing off
radicals, which are called free.
So, the initial links of pathogenesis consist in ionization and excitation of atoms and
molecules. The chemical transformation of substances and the formation of active intermediate
products due to radiation are called radiolysis.
Radiant damage is connected with direct and indirect action on important biological
molecules.
Direct effect of radiant energy is a damage of the macromolecules of organism by radiation
itself. Eventually, intramolecular alterations happen. Any type of molecules may be a target -
organic macromolecules as DNA, lipids, phospholipids, enzymes, proteins, vitamins,
hemoprotein, etc.
Indirect action is a damage of macromolecules by the water radiolysis products.
Ionization of water molecules is the most significant of all primary radiochemical
transformations. The first products are the ionized water molecules Н2O+ and Н2O- . Then free
hydrogen and hydroxyl radicals are formed (H. , OH.), which initiate a chain of father reactions
and new products are formed (peroxide of hydrogen H2O2., hydroperoxide HO2., atomic oxygen
O etc.). The water radiolysis products biochemically are very active and cause extensive
nonenzymatic oxidation.
BIOCHEMICAL DISORDER
Later, the oxidizers attack organic molecules, and new active radicals are formed. Chemical
and biochemical reactions rapidly increase, acquiring a nature of branching reactions. Such
reactions develop more aggressively in lipid medium and the peroxide oxidation of lipids gets
initiated.
Furthermore, radiotoxins are formed. Unsaturated fatty acids and phenols are oxidized
resulting in formation of lipid (lipid peroxides, epoxids, aldehydes) and quinone
radiotoxins (precursors of quinone radiotoxins are tyrosine, tryptophan, serotonin,
catecholamines). Radiotoxins inhibit synthesis of nucleic acids, influences DNA as
chemical mutagens, change enzyme activity, damage intracellular membranes.
Directly (as a target) and indirectly (by water radiolysis products and radiotoxins) enzymes
are damaged. Thiolic enzymes (they contain SH-groups) appear increased radiosensitivity and
are oxidized easily. Some enzymes, on the contrary, are activated, particularly those, which are
liberated from damaged lysosomes. Subsequently the enzymal reactions are stormily
intensifying - disintegration of proteins and nucleic acids get activated, synthesis gets reduced,
phosphorylation and antioxidant activity are damaged.
Nitrogen balance becomes negative. Synthesis of globin is reduced. Synthesis of antibodies is
suppressed.
It is necessary to pay a special attention to damage of unique molecule DNA. Its
intramolerular bonds are the most vulnerable target for direct and indirect effect of radiation.
Free radicals and peroxides damage the chemi cal structure of DNA. The oxidation of
pyrimidine and desamination of purine bases оснований are observed in nucleic acids
5
solutions after an effect of radiation. The change of the DNA structure is called mutation,
and so, the ionizing radiation relates to the physical mutagens.
Thus, primary radiochemical reactions consist of direct and indirect injury of the most
important biochemical cell components — nucleic acids, proteins, and enzymes. Later on,
fermentative reactions are violently changed — enzymal lysis of proteins and nucleic
acids gets activated, synthesis of DNA gets inhibited, biosynthesis of proteins and
enzymes gets suppressed.
DISORDER AT CELLULAR LEVEL
Any cellular structure may become a target for the radiant energy, active oxidizers,
radiotoxins and activated enzymes. The above mentioned physical, chemical and biochemical
changes disturb all manifestations of the cellular vital activity. Therefore, all biological
processes in cells may be damaged.
The signs of radiant injury of nucleus (swelling, pycnosis, lysis) are confirmed
histologically. One can see signs of radiation injuries of the nucleus in the elect ronic and
light microscope. Chromosomal aberrations (breaks, deletion, fragmentation) and more
subtle disorders of the genetic apparatus (gene mutations) may change synthesis of DNA,
the specific proteins and subsequently the hereditary properties of the cells.
All other organoids of cell are damaged too.
The phospholipids of the intracellular biomembranes (of the nucleus, mitochondria,
lysosomas, and endoplasmatic reticulum) become a target for free radicals.
Damage of lysosome membrane results in liberation of proteolytic enzymes (ribonuclease,
desoxiribonuclease and catepsins) into cytoplasm having an injurious effect on nucleic
acids, cytoplasmatic and nuclear proteins.
Disorder of oxidative phosphorylation and electron transport in mitochondria leads to
energy deficit. Disorder of cellular energy metabolism is one of the most probable cause of
inhibition of synthesis of nucleic acids, nucleic proteins and mitosis. So, radiation injury
of the nucleus is connected not only with direct effect of ionizing radiation on DNA and
chromosomes but also with pathology in other organelles.
During mitosis the cells become more vulnerable to radiation. Cell division gets inhibited.
The cell may be destructed at the moment of division as well as in interphase.
If a cell with the genetic errors is not eliminated, it becomes a carrier of the changed heredity.
Somatic cell may become malignant. Mutation in germ cells may cause hereditary disease in
descendants.
DISORDER AT TISSUE LEVEL
In spite of the fact, that radiosensitivity of nucleus is not higher than of other organoids, the
disorder of nucleus is manifested more actually in the vital activity of the cells.
Therefore, it is not hard to understand the relative radiosensitivity of tissues. In general,
tissues are sensitive to radiant energy in the direct proportion to mitotic activity and in inverse
proportion to the level of differentiation. Thus, the tissues with high rate of cellular renovation
demonstrate the greatest radiosensitivity - lymphoid, hemopoetic, epithelial (particularly
epithelium of digestive and sex glands), endothelium of vessels. Fibrous, bone, muscular and
nervous cells are less radiosensitive. The nervous cells get destructed in high over-dose
radiation (interphase destruction).
DISORDER AT THE LEVEL OF A WHOLE ORGANISM
In lethal and superlethal radiant doses interphase destruction of the cells prevails and death
comes within some hours (minutes) after radiation. In median radiation doses the life is
6
possible, but in all physiological systems there are pathologic changes, which depend on
comparative radiosensitivity of the tissues.
At the level of a whole organism, the pathogenesis of radiant injury consists in some
pathophysiological syndromes (syndrome is a complex of symptoms, which are united with
common pathogenesis).
Hematologic Syndrome
The most characteristic for all forms of radiant injury is a disorder of hemopoietic and
blood system. Hematologic syndrome is characterized by changes in peripheral blood,
progressive atrophy of lymph nodes, bone marrow and spleen. The decreased quantity of all
types of blood cells and depression of their function are observed. Lymphocytes are the most
vulnerable ones. That’s why lymphopenia develops from the very beginning. Lymphocytes break
down in lymph nodes and in blood. Later thrombocytopenia, granulocytopenia and eventually
anemia develop.
Hemorrhage Syndrome
The typical and obligatory sign of the radiant disease is hemorrhage syndrome (predisposition
to bleeding). It embraces hemorrhage into the skin (petechiae, ecchymoses, epistaxis), mucous
membranes (gingival bleeding), internal organs, bleeding from nose, bowels, bladder.
There are several mechanisms of hemorrhage syndrome development.
 Deficiency of thrombocytes (thrombocytopenia) in the paripheral blood which results in
decrease of biological factors of blood coagulation. The causes are:
 suppression of pletelets precursors division in the bone marrow,
 disorder of thrombocyte maturation in the bone marrow,
 destruction of thrombocytes in the blood,
 loss of thrombocytes with hemorrhage.
 Impairment of the thrombocyte ability to adhesion. Disorder of this function is of a great
significance, because the biological factors of blood coagulation release while thrombocytes
aggregation. This disorder is connected with the changes of their membrane ultrastructure.
 Reduction of procoagulants synthesis in the liver.
 Change in molecular structure of fibrinogen and fibrin underlay the reduction of fibrin fibers
ability to contractility and blood clot to retraction.
 Activation of anticoagulant system. Anticoagulants appear in the blood (for example, heparin
is liberated while degranulation of tissue basophiles).
 Activation of fibrinolytic system.
 Derangement of platelet’s function as to endothelium trophicity (thrombocytes play a role in
maintaining целостности integrity of the vascular wall, its elasticity and mechanical resistance).
Immunodepressive Syndrome
Immune reactivity decreases. Immunosuppressive syndrome is manifested by depression of

phagocytosis. Formation of antibodies is inhibited or completely suppressed. For this very
reason, infection is the earliest and severe complication of irradiation.
Not only environment but also internal medium becomes a source of infection
(autoinfection).
Oral cavity is severely inflamed. Tonsillitis obtains a necrotic character. Pneumonia is a
frequent cause of the patient's death. Infection violently develops in the intestine and bowels.
Vascular Syndrome
7
The vessels (mainly small) are seriously damaged in radiant disease. There are some
mechanisms.
 Endothelium is a possible target for a direct action of radiation.
 Endothelium is damaged by oxidizers (products of water radiolysis) and radiotoxins.
 Trophicity of vessels significantly suffers in deficiency of platelets.
 Pathologically changed endothelium loses an ability to produce polysaccharide-protein
complexes to construct basal membrane.
 The perivascular connective tissue, which is a mechanical base of the vessels, undergoes
destructive changes.
 The injured tissues release biological active substances (proteolytic enzymes from the injured
lysosomes, kinines, hialuronidase), which aggravate damage of the vascular wall increasing
its permeability.
 Tonus and resistance of the vessels are disturbed.
Destructure of the vascular wall leads to the functional insufficiency of the vessels and the
microcirculation disorder. It has negative effect on metabolism (tissue trophicity).
Lesion of blood vessels contributes significantly to the hemorrhage predisposition.
Gastrointestinal Syndrome
Gastrointestinal syndrome is a complex of symptoms in digestive system, which lead to the

disorder of nourishment and intoxication. There are some mechanisms.
 Direct and indirect damage of epithelium of digestive tract mucous membrane by radiation.
 Stopping of mitotic division and regeneration of digestive channel epithelium.
 Loss of protective properties (barrier function) of mucous membrane.
 Development of infection in the intestine (autoinfection).
 Absorption of the toxic substances of bacterial and intestinal origin into the blood.
 Direct and indirect damage of digestive glands.
 Injury of oral cavity due to inflammation and necrotic tonsillitis.
 Disorder of nutrition.
 Meteorism and diarrhea. Loss of water.
 Pain.
 Exhaustion of the organism.
Pathology of digestive tract is one of the causes of death.
Cerebral Syndrome
Structural changes of the nervous cells occur in higher doses of radiation. However, structural
changes do not always correspond to the functional ones.
Cerebral syndrome confirms the sensitivity of nervous system to any influences, including
radiation. Nervous receptors react on the products of radiolysis almost immediately. The changes
of the bioelectrical activity of the brain can be registered within first minutes. At first an excitation
is recorded. So, neuro-reflective activity is obtained before appearance of other typical
symptoms of radiant disease.
Lethal dose of ionizing radiation causes cerebral form of acute disease (see below) due to
direct damage of nervous tissue.
Syndrome of Endocrine Insufficiency
8
Epithelium of endocrine glands can be damaged by direct and indirect effect of radiation. In
addition to it, endocrine system is affected by stress.
All signs of stress are obvious (hyperfunction of pituitary gland and adrenal cortex,
lymphopenia). In the organs of the endocrine system the initial signs of increased activity are
replaced by the endocrine glands inhibition. Eventually, an exhaustion of endocrine system
comes.
Special attention must be paid to radioisotopes. Thus, radioactive iodine affect thyroid gland
most of all.
Internal (Incorporated) Irradiation
Internal (incorporated) irradiation is a result of inhaled or oral entrance of radionucleides

inside the body.
The fate of radionucleides in the organism is connected with
 Size of radioactive particles,
 Solubility,
 Half-life period,
 Metabolic specificity,
 Ability of organism to remove them.
Organotropism is characteristic for all of them. Thus, isotopes of strontium replace calcium
in bones, isotopes of cesium replace potassium, isotopes of iodine are accumulated in the thyroid
gland. Osteotropic, hepatotropic, thyrotropic radionucleides are distinguished. They create very
high radiation dosage locally, and at the places of their accumulation radiant damage is violent.
Self-Defensive Compensatory Reactions
As any other pathological process and disease, the radiant disease includes the development
of compensatory reactions. They develop at all levels of organism organization.
At the molecular level, pathological changes are compensated by natural antioxidant systems.
They consist of
 Free radicals acceptors,
 Inactivators of peroxides,
 Donors of SH-groups, thiolic bounds (glutathione),
 Metalloenzymes (catalase, superoxidedismutase, glutathione peroxidase),
 Vitamins (C, PP, E, D2).
Ability of cells to restore DNA (DNA repair enzyme system) is one of the main mechanisms
that determine the resistance of organism to ionizing radiation.
Inactivation of BAS (biological active substances) is also under control.
Chemical and biochemical substances which neutralizes the products of water radiolysis and
radiotoxins are called natural radioprotectors.
Mutant cells may be annihilated by mechanisms of immunological reactivity.
Thus, not only radiant dose, but also the reactivity of organism determines the intensity and
duration of radiant disease. In the scheme 3 the mechanisms of the damage and restoration of
DNA are summarized.
Scheme 3. Mechanisms of damage and restoration of DNA during ionizing radiation

Factors, which modify and restore a damage (со с.57 украинского учебника)
9
Factors which damage DNA during irradiation
Direct effect Indirect effect
X-rays products of water radiolysis
-quantums primary radiotoxins
-, -particles peroxydes
activated DNA-ase
Factors, which modify a damage of DNA

Chemical radiopotectors
Active forms of oxygen
Precursors of radiotoxins
Intensivity of metabolism
Cellular radiant effects

Mutations
Chromosomal aberrations
Интерфазная гибель или during division
stopping of development
suppression of synthesis of DNA, RNA, proteins, enzymes
Factors of restoration
Enzymes, which отщепляют damaged участок
DNA-polymerase
Natiral radioprotectors – перехватчики of radicals
Перехватчики of radiotoxins
В центре - DNA
________________________________________________________________________________
ACUTE RADIANT DISEASE
All mentioned disorders of hemopoiesis, function of the nervous and alimentary systems are
marked in all forms of radiant injury. But the degree of injury, development rate and prognosis
depend on the absorbed dose of total radiation.
Three clinical forms of acute radiant disease are distinguished - medullar, gastrointestinal and
cerebral.
Medullar Form
The medullar form of an acute radiant disease develops in absorbed dose 0,8-10 Gr and
proceeds in four clinical periods.
The initial period is connected with direct and indirect effect of radiation on peripheral and
central nervous system. It lasts several hours to 1-3 days. Clinical manifestations are - nervous
excitation, headache, instability of vegetative functions, liability of vasomotor reactions (arterial
blood pressure and pulse), nausea. Disorder of the alimentary canal motility is manifested in
vomiting and diarrhea. The body temperature rises as a result of the central thermoregulation
disorder. The short-term redistributive neutrophilic leukocytosis is accompanied by absolute
lymphocytopenia. Hypophys-adrenal system is activated. Radiant shock is possible in severe
cases.
The latent period lasts 10 days to 3 weeks. It is a period of мнимого благополучия alleged health.
The nervous symptoms and dyspeptic disorders have passed, but the main pathophysiological
syndromes still are absent. Nevertheless, lymphopenia is in progress, a quantity of granulocytes
10
and thrombocytes is reduced, as well as some signs of the disease: instability of arterial pressure,
liability of the pulse.
The period of marked clinical manifestations lasts 2-5 weeks. The main pathophysiological
syndromes mentioned above develop. Leukopenia and thrombocytopenia are in progress. Bone
marrow is depleted. Anemia and infectious complications develop.
The Outcome of the Disease. Maximal lethality is observed in the period of acute
granulocytopenia and thrombocytopenia. There are inevitable infectious complications, which
are the main cause of the patient's sufferings. Development of autoinfection in oral cavity is
typical of this period. Inflammation of the tongue and gums, necrotic tonsillitis is observed.
Nourishment becomes difficult. Radiant disease may be complicated by pneumonia, which is very
severe due to immunodepression and eventuates in the patient's death.
The вид больного is quite typical — the skin is covered with numerous hemorrhages. There is
a blood in urine, feces and sputum. Hemorrhages and infection are the main reasons of death.
Recovery is possible. Improvement of self-sensation and blood cell content are evidence of
recovery. Young (regenerative) blood cells appear.
However, the residual signs may persist for a long time (up to 3 months). They are divided
into somatic (asthenia, fatigue, weakness, instability of hemopoesis, endocrine and sexual
dysfunction, sterility, immunological insufficiency, cataract, nephrosclerosis, neoplasia,
premature aging) and genetic (instability of hereditary apparatus, accumulation of gene damages,
leukemia, diseases of posterity).
Gastrointestinal Form
The gastrointestinal form of acute radiant disease develops in dose 10-20 Gr as a result of the
massive distraction of intestinal epithelium. The surface of the mucous membrane of the
intestines becomes damaged and promotes penetration of infection.
The disease is manifested with nausea, vomiting, pain in bowels, admixture of blood in feces
and diarrhea. The loss of fluids and electrolytes leads to dehydration, reduction in circulating
blood volume, vascular collapse. Paralytic obstruction of the intestines and peritonitis due to
impairment of the barrier function of the intestinal wall, develop.
Shock is possible due to the effect of toxic substances of microbial and tissue origin (toxemic
form is observed in radiation of 20-80 Gy). Mitotic division of the intestinal epithelium stops.
Massive interphase destruction of digestive tract cells takes place. Loss of proteins and
electrolytes, increased body temperature and pain in the intestines must be added.
Death comes within 8-12 days (or earlier). Lethality is 100%.
Cerebral Form
The cerebral form of acute radiant disease develops in dose over 80 Gr as a result of a direct
effect of large radiant dose on nervous tissue. Severe and irreversible structural changes of
brain cortex, hypothalamus and pituitary gland are displayed. Severe damage of endothelium
and vascular tonus occurs. Thermoregulation gets disturbed. Convulsive-paralytic syndrome and
coma develop. The disease is always fatal. Death comes within 1-2 hours.
The acutest form of radiant disease (death “under the ray”) is observed within minutes
(hours) as a result of protein denaturation.
CHRONIC RADIANT DISEASE
Chronic radiant disease is a consequence of the repeated action of small radiant doses.
Pathogenesis and clinical manifestations are the same as in acute form, nevertheless dynamics
and intensity of the disease differ. Three degrees of a disease are distinguished.
11
The first degree of the disease proceeds in form of reversible functional disorders of the most
sensitive systems. Sometimes the self-sensation of patient is satisfactory, however, a study of the
blood reveals unstable leucopenia and thrombocytopenia.
The second degree of the disease displays the more significant changes in nervous and
hemopoietic systems. Leucopenia and lymphopenia become stable, quantity of thrombocytes is
reduced. Hemorrhage syndrome and immunodepression are revealed.
The third degree of the disease manifests itself by deep dystrophia of tissues and irreversible
changes in organs. The function of pituitary gland and suprarenal glands is exhausted.
Hemopoiesis is suppressed, tonus of vessels is lowered, and permeability of vessels is increased.
Necrotic defects of mucous membranes are obtained. Infection and inflammation receive a
necrotic duration.
Chronic radiant disease of any form underlies the late pathological alterations. Gene disorders
might cause neoplasia. Organism that underwent small doses of irradiation grows old
prematurely.
CORRECTION OF RADIANT LESION
There is a special group of preparations for antiradiation chemical protection These are
substances blocking the development of chain radiochemical reactions. Chemical drugs for
radiant lesion correction are called radioprotectors. They are
• Interceptors перехватчики of active radicals,
• Antioxidants,
• Metals with variable valence,
• Substances causing hypoxia (methemoglobin-formers),
• Protectors of protein SH-groups,
• Stimulators of cell repair.
If radioprotectors are injected before irradiation, they decrease the damage, block radiolysis
and convert tissues to the state of radioresistant metabolism.
Correction of radiation injury includes a number of measures directed to prevention of
infection, intoxication and hemorrhagic signs. The medical drugs of symptomatic therapy
include correction of the endocrine glands dysfunction, nervous and alimentary system.
Restoration of hemopoiesis is of a special importance. In its respect transplantation of the bone
marrow is the most effective measure. Hypothermia, hypoxia increases radiostability of the
animals in experiment.
PATHOGENIC EFFECT OF BAROMETRIC (ATMOSPHERIC)

PRESSURE CHANGES
( BAROTRAUMA)
ETIOLOGY
The etiological factor of barotrauma is a barometric pressure if its parameters are changed in
comparison with standard. The gravity of barotrauma depends on extend and rate of compression
and decompression.
PATHOGENESIS
Such physical characteristics of gas and liquid are depended upon the level of barometric
pressure - solubility of oxygen and other gases of inspired air in the blood (saturation,
desaturation), gas volume in cavities of organism and boiling point of liquids.
Negative Effect of Decreased Barometric Pressure

(Hypobaria, or Decompression)
12
A man is exposed to decreased barometric (atmospheric) pressure at high altitude (in
mountains, nonhermetic aircraft and during cosmic catastrophe, when the barometric pressure is
equal to zero). In laboratory, hypobaria is modeled in special chamber (barocamera).
The pathological changes that develop in the situation of reduced barometric pressure are
caused by two etiological factors:
 Lowered oxygen tension pO2 in inspired air - hypoxic hypoxia (observed the chapter
"Hypoxia"),
 Decrease of atmospheric pressure (hypobaria).
Range of phenomena, connected with decrease of atmospheric pressure, is called decompression
syndrome.
The manifestations of decompression depend on its velocity and degree.
Hypobaria results in expansion of gases in internal cavities (sinuses, pleural and peritoneal
cavities, bowels). While decompression, a man feels pain in ears and frontal sinuses, pain in
abdomen and joints. Nasal bleeding occurs as a result of dilation and rupture of small vessels.
A man might not be elevated at 19000-m altitude without hermetic cabin. In the case of
catastrophic dehermetisation in spacecraft, the lowering of atmospheric pressure is so quick, that
it receives the term explosive decompression. Momentary death occurs because of
 Boiling of blood and other liquids at body temperature,
 Rupture of lungs (because of quick increase of pulmonary pressure),
 Decrease of solubility of gas in blood and liquid medium. Free gaseous bubbles may be
released in the blood and act as emboli (gas embolism).
 Rupture of alveoli and vessels of the lungs because gas bubbles penetrate into circula tory
system,
 Trauma of heart and large vessels of mediastinum due to acute expansion of lung,
 Acute form of hypoxia.
Negative Effect of Increased Barometric Pressure (Hyperbaria)
A man is exposed to increased barometric pressure in water during diving and caisson works.
One can feel pain in ears because of pressure on tympanic membrane. Rupture of alveoli could
happen if increase of barometric pressure would be rapid.
But the more important fact is that in hyperbaria a man must breath by air or gas mixture under
increased pressure. In such conditions an additional quantity of gas is dissolved in the blood and
tissues of the organism (saturation).
Nitrogen has the most negative effect if breathing is conducted with compressed air. For a
long time it was considered, that nitrogen, as inert gas, have no biologic effect. Only the
underwater medicine showed another thing. Nitrogen causes syndrome of specific changes in
people, working under increased pressure.
Due to increased affinity of nitrogen with lipids (nitrogen gets dissolved preferably in them),
nervous tissue is mostly affected. The first manifestation is a nervous excitement that resembles
euphoria, then intoxication comes which resembles narcosis (table 2). Gas with helium,
substituted nitrogen, is used for avoiding these disorders (helium is dissolved less than nitrogen).
Not only nitrogen is toxic at increased pressure. Surplus of oxygen (hyperoxia) has positive
effect only at the beginning, improving oxidation (this phenomenon is used for treatment with
hyperbaria). In the stage of compensation some adaptive reactions develop. They are directed
to maintenance of optimal oxygen regime in the brain and limitation of the excessive increase
of oxygen concentration in it. It is achieved by lowering of blood chemoreceptors excitability.
As a result, the respiratory rate and pulse slow down, circulating blood volume is decreasing, as
well as erythrocyte and hemoglobin content (due to депонирования of the blood), brain vessels are
narrowing.
13
Oxygen under increased pressure acts toxically, but its toxic effect realizes later, in the stage
of decompensation. The condition of «tissue asphyxia” develops. It has the following
explanation. Tissues use oxygen that is physically dissolved in plasma, but not that which is
connected with hemoglobin (oxyhemoglobin). At increased pressure, the content of dissolved
oxygen in blood is increased. If the quantity of dissolved oxygen corresponds to normal
consumption of oxygen by tissues, then oxyhemoglobin would not dissociated. In other words,
hemoglobin becomes blocked by oxygen (hemoglobin is in a form of oxyhemoglobin not only
in arterial but in venous blood) and loses ability for carbondioxide (CO 2) transport. Because
oxyhemoglobin is a stronger acid than restored one, acidosis develops.
Under increased pressure, oxygen acts as a strong oxidizer causing oxidation of lipids,
proteins, nucleic acids. Toxic effect of high concentration of oxygen is similar to that one of
radiation. In both cases formation of free radicals and peroxides with strong oxidative abilities
causes affection of DNA and tissue enzymes.
Sensitivity of the organism to toxic action of oxygen is determined by level of tissues
antioxidants (tokopherols, glutathione, and others). They can be used for treatment and
prophylaxis at oxygen action on the organism under high pressure.
Table 2. Symptoms of Nervous Disorder in Men Depending on Depth of Diving
Depth of Diving in Meters Symptoms
30-60 Euphoria
60-75 Causeless smile and first symptoms of hysteria.

Decreased ability to concentrate attention.
Mistakes in performance of simple professional
and mental tasks. Underestimation of safety.
100 Depression and loss of четкого мышления.

Disorder of motor coordination.
115 Loss of consciousness.
For prevention of toxic effect of oxygen and nitrogen, the gas mixture with low oxygen and
nitrogen content must be given into the underwater apparatus. Optimal concentration of oxygen
in inspired air is calculated for every depth of diving. For example, concentration of oxygen in
gas mixture is about 2% while diving at 100 m depth. Nitrogen is substituted by helium.
While return from depth to normal atmospheric condition, a new variant of syndrome of
decompression appears. An excessive quantity of dissolved gas is released through the blood and
the lungs (desaturation). The decompression might be performed slowly. If it is not so, the rate
of gaseous bubble formation would exceed the possibility of lungs to release them. Bubbles of
air cause occlusion of blood vessels, press on cells and irritate receptors (gaseous embolism).
Clinical manifestations are determined by localization of bubbles (подкожная эмфизема, pain in
joints, itch). In serious cases such manifestations are possible - disorder and loss of vision,
14
paralysis, mental disorders, loss of consciousness and other sings of brain and spinal marrow
injury (even coma). Placing the patient into a compression chamber, where the solution of the
bubbles is accomplished, we promptly relieve these symptoms.
ELECTROTRAUMA
Etiology
Electrical current damages organism depending on its physical parameters - force

(amperage), tension (voltage), nature of current, as well as duration of exposure, resistance of the
tissues, pathway of the current passage through the body.
Current of 100 mA is fatally dangerous. Its basic danger is "chaining" of a person to the
electric object. Alternating переменный current is more dangerous than постоянный one of the
same force (amperage). Frequency of alternating переменного current plays a role. Alternating
current of 1,000,000 Hz and more isn't pathogenic, exerts a thermal effect and is used for
treatment.
Direction of electric current passing through the human body plays a role. We mean the
vitally important organs (heart, nervous tissue) which occur on the current pathway. Ascending
direct current (anode is lower, cathode is higher) is more dangerous than descending one (opposite
localization of electrodes). With ascending current through the heart, the sinus node is under
exciting influence of cathode and the apex is under suppressing influence of anode.
Tissue resistance plays a role. The electrical property of organism is heterogeneous. Full
resistance of the human body to alternating current is called impedance. Liquids are good
conductors. The most resistant to electric current is external epidermal layer of the tissue (to
2,000,000 Om). Tendons, bones, nerves, muscles follows it. The least resistant is the
cerebrospinal fluid. General resistance of the human body is from 1,000 to a million Om. The
dry skin is more resistant than the wet skin. If skin is damaged, body behaves, as purely ohmic
resistance.
These factors and conditions modify the effect of etiological factor and extend of the
electrotrauma.
Pathogenesis
The following events underlie the injury - the transformation of electrical energy into other
forms (thermal, mechanical and chemical).
Electricity polarizes atoms and molecules, changes orientation of particles and activates their
movement. Thus electrical energy transforms into thermal one (thermal effect). Burn of the skin
may occur.
Rupture of tissues and bone fractures are the manifestation of the mechanical effect.
A specific action of electricity is called electrolysis (electrochemical effect). Positively
charged ions (acid reaction) are concentrated near cathode, negatively charged ions (alkaline
reaction) – near anode. In biological medium, electrolysis causes a redistribution of ions,
changes biological potentials and a state of потенциал-зависимые ионные каналы, causes
depolarization of cellular membranes and appearance of потенциалов действия в возбудимых
tissues. In consequence, functional state of the cells gets changed.
Excitable structures (nervous, muscular) are of the highest sensitivity. Current causes an
excitement of the nervous receptors and conductors, smooth and skeletal muscles. Muscle
spasms happen.
In addition, it is necessary to emphasize that the electric current changes the state of
biocolloids. Coagulative or colliquative necrosis are a result of moving and swelling of
colloids. Cellular protoplasm may coagulate.
15
Manifestations
Electrotrauma causes local and systemic changes in organism.

Local effects are current marks and burns. The first appear in the skin if a temperature in the
place isn't more than 120°C. They are small formations of white-gray color of hard consistency
("pergament" skin). When the temperature is more than 120 °C, burns arise.
Excitement of the nervous system causes hypersecretion of catecholamines (adrenaline,
noradrenaline) with somatic and visceral functional changes. Muscle spasms and tonic
convulsions may cause fractures, disorder of breathing, elevation of blood pressure, involuntary
urination and defecation.
The passage of the electric current through the heart is the most dangerous for a man.
Electrolysis in the cardiac synticium may shorten the refractor phase and changes cardiac
rhythm. Ventricular heart fibrillation is fatal. Disorder of the cardiac rhythm (tachy- and
bradycardia, extrasystole and blockade) may develop even in such a case, when electric current
does not penetrate the heart (by reflex). Cardiac arrest may arise due to
 Ventricle fibrillation,
 Spasm of the coronary vessels,
 Injury of the vasomotor center,
 Increase of the n. vagus tonus.
Disorder and stopping of respiration have both central and peripheral origin. Respiratory
standstill may depend on
 Injury (paralysis)of respiratory center,
 Disorder of respiratory center as a reflex from interoreceptors,
 Spasm of the vertebral arteries, which bring blood to the respiratory center,
 Spasm of the respiratory muscles,
 Laryngospasm.
A shock while electrotrauma belongs to the group of болевых pains. Cramping muscle
contractions cause loss of consciousness, cardiac and respiratory disorder. Patient feels
vertigo, headache, photophobia, nausea. Clinical death may come. Immediate death is caused
by respiratory standstill and cardiac arrest.
Severeness of electrotrauma depends upon initial state of organism. For example,
electrotrauma is less severe under anesthesia, sleeping, overcooling, hypothyroidism. On the
contrary, tiredness, fatigue, weakening of attention, slight or moderate alcohol intoxication,
hypoxia, overheating aggravate a lesion. Cardiovascular insufficiency, exhaustion and blood
loss decrease resistance to electrotrauma.
EFFECT OF SPACE FLIGHT FACTORS
The factors of space flight (such as overloading, weightlessness) belong to the extreme ones
because a human organism was not exposed to them in evolution, and adaptation is limited.
Overloading
Overloading is a force, which acts while moving with acceleration during the start and landing
of a spacecraft). It refers to kinetosis.
A main link in pathogenesis is a displacement of organs and liquids in the direction, which is
opposite to the moving one. Therefore, the body of cosmonaut is oriented during the start and
landing in such a way, that the vector of overloading would not coincide with the longitudinal
axis of the body. Pathological changes are manifested by disorder of respiration, pulmonary
blood circulation and gas exchange. Weight of tissues and liquids gets increased. Displacement
16
of internal organs, the excessive irritation from interoreceptors and significant afferent
impulsation contribute the damage.
Weightlessness
Weightlessness is a condition of loss of gravitation. Weightlessness significantly changes the

system of blood circulation. Diminished hydrostatic component of arterial pressure results in
redistribution of blood supply with its increase in upper body parts. The stimulation of the
volumoreceptors, inhibition of vasopressin and aldosterone excretion result in loss of sodium and
water, lowering the circulating blood volume and load on the heart. Muscular tonus and energy
expenditure is reduced. Negative nitrogen balance and loss of water contribute the decrease of
body mass. Loss of calcium and phosphorus decreased mass of bones and skeletal muscles
together with hypokinesia result in significant changes in locomotor apparatus.
The disorder in nervous trophicity is of a great significance in the pathogenesis of disorder
while weightlessness. The adequate afferentation is the necessary component of throphic reflex.
The deficit of afferent impulsation occurs in all organs, function of which depends upon the
gravity force (locomotion and otolith apparatus, cerebellum, vascular wall). Concomitantly, the
state of functional deafferentation appears in these organs. It means, that not only atrophic, but
also neurodystrophical changes develop in these organs during prolonged weightlessness
(N.K.Simeonova).
During space flight, the pathogenic factors act not isolately but in different combinations. It
was shown (N.K.Simeonova), that overloading considerably changes the general reactivity of
organism, and additional influences (hypoxia, heat, cool, intoxication, pharmacological medical
drugs) act differently from expected.
The new level of functioning mentioned above is adequate for weightlessness, but it is
unfavorable for Earth life to which a cosmonaut must return. After coming back, the
insufficiency of the systems that oppose the gravity is observed.
17
CHAPTER 3
ROLE OF HEREDITY AND CONSTITUTION IN PATHOLOGY
Together with environmental pathogenic factors, the genetic ones play a

significant role in the development of the diseases.
The diseases, which are caused by genetic factors, are called genetically
determined. Their transmission to descendants may be limited in the case of impaired
reproductive capability of the patient. If diseases are transmitted to the next
generations, they are called hereditary. The close notion is the congenital diseases,
which are manifested just after the birth. Those diseases, which are caused by
environmental factors and have a clinical picture similar to known hereditary diseases,
are called phenocopies.
MUTATION
Mutation is a стойкое скачкообразное change of genetic apparatus (not

connected with cell division or usual recombination of chromosomes) and is a
material basis of genetically determined diseases.
Mutation is a promoter of evolution. Усложнение биологических видов and obtaining
of useful properties, which закрепляются in genetic apparatus, occur due mutations.
But, payment for it - genetical diseases. Consequently, mutations may be useful and
harmful. Below it goes about harmful mutations.
Causes
Etiological factors, which cause a mutation, are termed mutagens. They are
divided into physical, chemical and biological ones as well as exogenous and
endogenous.
Among physical mutagens the ionizing radiation is the most potent. It damages
genetic apparatus directly or due to the products of radiolysis. Mutation may be
caused by ionizing radiation in such minimal dose, which does not cause the radiant
disease.
The most potent chemical mutagens are the analogs of purine and pyrimidine
bases основания. The chemical compounds of carbon (polycyclic aromatic
hydrocarbons) and nitrogen (nitrosamines) relate to mutagens.
Biological mutagens are the DNA-containing and RNA-containing viruses. They
sometimes behave as mutagens in patients with measles, chickenpox, mumps,
infectious mononucleosis. Rubella infection in pregnant women is associated with
congenital malformations in infants. The products of the vital activity of some fungi
(e.g. aflotoxin) belong to mutagens as well. Oncoviruses are the most potent
biological mutagens.
1
Exogenous mutagens can induce endogenous mutagens (active forms of oxygen,
free radicals, radiotoxins, etc.). Such mutagens may be induced in metabolism
disorders.
Types
The mutations are divided into useful and harmful, spontaneous and induced.
The frequency of spontaneous mutations is little in comparison with induced ones.
Somatic mutation (in somatic cells) disappears from the population after death of
the host and is not transmitted in generations. Germ (гаметична) mutation (in germ,
or reproductive cells) affects heredity of descendants.
Depending on a degree of destruction, the mutations are divided into gene and
chromosomal ones.
Gene mutation is a change of a structure of only one signal gene, namely, the
specific order of purine and pyrimidine bases in the DNA molecule (the so-called
point mutation). It results in change of order of aminoacids in protein molecule. The
amount of possible gene mutations is enormous (both in structural and regulative
genes). In the germ cells the gene mutation may happen in any gene (dominant,
recessive or sex-linked).
Chromosomal mutation is a more vast destruction of hereditary apparatus and is
characterized by changes of structure of chromosome (break, deletion, inversion,
translocation and fragmentation) or their quantity (increased or decreased). The
quantitative changes of chromosomes occur, as a result of homologous chromosome
nondisjunction нерасхождение during gametogenesis or at early stage of дробления
зиготы.
Self-Defensive Mechanisms against Mutation
Organism controls its genetic homeostasis. A lot of checking mechanisms exists.

Some of them control somatic cells, some – reproductive (germ) ones.
Antioxidant biochemical system prevents mutation, neutralizes the active forms of
oxygen, which belong to endogenous mutagens.
Gene mutations can be restored without harmful consequences in organism. Every
cell has DNA repair enzyme system (fig. 2), which restore up to 95% of spontaneous
gene mutations.
_______________________________________________________________________________
1. Recognition
2. Crossing перерезывание of damaged DNA endonuclease
3. …расщепление exonuclease
4. Father ….. расщепление exonuclease
5. Syntesis of normal DNA polimerase
6. Соединение of a new DNA fragment ligase
Fig. 2. Restoration of damaged DNA by enzymes of reparation (со с. 60 украинского учебника)
2
________________________________________________________________________________
Immune system is an important mechanism of protection. Anomalous proteins
and mutant somatic cells may be eliminated by humoral and cellular immune
reactions. B-lymphocytes produce immune globulins for elimination of anomalous
proteins and cytotoxic antibodies, which destroy mutants cells by cytolysis (with the
aid of complement). T-killers can destroy mutant cells with the aid of lymphokines.
Phagocytosis participates in immune response.
Mechanisms of Germ Cells Protection. It is unknown whether mutant germ cells
are controlled by antioxidant system and immune mechanisms. They may loose
ability for impregnation. If they would be impregnated, mutant genes are inherited
by Mendelian genetic lows, some of which prevent clinical manifestation or
spreading genes in population.
Recessive mutant genes are expressed only in homozygous state (recessive type of
inheritance) and are not manifested in heterozygous one. In the latter case the carrier
of mutant gene is clinically healthy (however, is a conductor of mutant gene in
population).
Sex-linked mutant genes are inherited depending on sex of the host. About 60
pathological signs are connected with X-chromosome, and majority of them is
recessive ones. It means, that the woman, carrier of such gene, is healthy, because
normal X-chromosome compensates the presence of X-chromosome with damaged
gene (pathology of X-chromosome in men is not compensated).
Majority of physiological patterns (arterial pressure, glucose blood level,
immunological reactivity and other) is determined not by one, but several genes
(polygenic type of inheritance). Manifestation of mutant gene of these gene systems
depends on environment (so-called multifactorial diseases).
Such phenomenon as penetrance (probability of phenotypic manifestation of
mutant gene) and expressiveness (degree of clinical manifestation) are an important
mechanism of protection. Penetrance never riches 100%.
Dominant mutant genes are transmitted directly from the parents to the child and
are manifested in the first generation (dominant type of inheritance). But in this case
protection appears at the level of population as natural selection. The carrier of
chromosomal anomalies and dangerous dominant genes do not survive (by problems
in embryo) or loose reproductive capacity.
In addition to said above, it is possible to add, that many mutations of germ cells
remain without consequences. Childbirth takes place during a life not so often. In
spite of elevation of mutation frequency with age, reproductive function diminishes
and reproductive cells get impregnated rarely.
CLASSIFICATION OF GENETIC PATHOLOGY
Mutation underlies all types of genetic pathology, but pathogenesis, realization

and clinical manifestations are different as will be seen later.
Not all the diseases caused by genetic pathology are hereditary in literal meaning
of this word. Some patients with genetic pathology are born by healthy parents. Some
patients with genetic pathology do not transmit it due to impossibility to reproduce the
posterity.
Hereditary disease is that, which is determined by mutation in the germ cell of
one of the parents and may be transmitted in generations.
3
Classification of genetically determined pathology may be based on several
principles.
Depending on degree of genetic defect (gene is smaller than chromosome, so, the
consequences of gene and chromosomal mutations are different) the diseases are
divided into moleculo-genetic and chromosomal ones. The first in turn are divided
into monogenic and polygenic. Monogenic diseases are subdivided into dominant,
recessive and associated with sex.
Органо-системна classification (diseases of the blood, lungs, kidneys etc.) reflects
predominant disorder of a certain physiological system. Classification based on
dismetabolism is also useful for medical practice (diseases of protein, carbohydrate,
fatty, mineral, pigment metabolism etc.).
MOLECULO-GENETIC (INHERITANT? HEREDITARY? наследственные)

DISEASES
A carrier of a gene mutation usually preserves reproductive function. Therefore,

the moleculo-genetic diseases may be transferred in generations and are hereditary in
the literal meaning of this word.
Above 3000 Mendelian disorders are identified, and not all of them are harmful.
Some of them in heterozygous state have a protective value (e.i. HbS protects
organism against malaria). It is estimated that every individual is a carrier of 5-8
recessive harmful genes, which are dangerous in homozygous state.
ETIOLOGY
Etiological factors are physical, chemical, and biological mutagens, which are
capable to change the genetic apparatus of germ cells.
Etiology of hereditary diseases has such peculiarity, that the cause of the disease
and the disease itself are separated in generations: the damage of genetic apparatus by
mutagens happens in one person, but the disease develops in descendants.
PATHOGENESIS
The initial link in pathogenesis of hereditary diseases is a germ mutation in one of

the parents. If the mutant cell would be impregnated, such events would take place –
inheritance (receiving) of mutant gene by child, development of the disease, its
transmission to the following generations.
The pathogenesis of a disease depends on the function of gene, which is got
broken. The genetically determined disorders are called pathy (at the end of a proper
term).
Biochemical Disorder
Biochemical changes depend on the function of protein, synthesis of which is

deranged.
Enzymopathy is a genetically determined disorder in enzymes. It is displayed by
the errors in metabolism. Synthesis of enzyme may be decreased or stopped. Surplus
of inhibitor or lack of activator has the same effect.
4
A quantity of enzyme may be normal, but its catalytic activity is lowered or
absent. Block of a certain metabolic way results in accumulation of substrate-
precursor and lack of the final products.
An increased activity of enzyme is possible due to blockade of inhibition.
Uncontrolled synthesis of the final products may take place. They are the so-called
diseases of accumulation (glycogenosis, hypercholesterolemia,
mucopolysacharidosis, mucoviscidosis, gout).
Deficit of DNA repair enzyme system eventuates in increased sensitivity of
organism to mutagens (this mechanism underlies malignant growth and premature
aging). Sometimes enzymopathy is manifested only after loading by food or drugs.
Hemoglobinopathy is a genetically determined disorder in globin. It is a result of
mutation of genes responsible for globin synthesis. Hemoglobinopathy and
erythrocytopathy underlie some forms of hemolytic anemia (sickle-cell anemia,
thalassemia).
Coagulopathy is a genetically determined disorder in proteins, which are necessary
for blood coagulation. Coagulopathy and thrombocytopathy underlie some forms of
hemorrhage syndrome (hemophilia).
Genetically determined deficit of transport proteins or peptide hormones
(endocrinopathy) is also possible.
Cellular Disorder
At the cellular level, the hereditary disease is manifested by changes in function

and form of cells (sickle-like, sphere-like and target-like erythrocytes, which are
typical for the hereditary hemolytic anemia). Trombocytopathy is a genetically
determined disturbance of the thrombocyte function. Membranopathy is a genetic
defect of a cellular membrane. Erythrocytopathy is a version of membranopathy
(deficit of spektrin in erythrocyte membrane results in impairment of membrane
elasticity, and erythrocytes are deformed as it is in microspherocytic hemolytic
anemia). Immunopathy (immunodeficiency) is a genetically determined disorder of
maturation and functional activity of lymphocytes.
Disorders in the Whole Organism
At the level of a whole organism the pathogenesis of hereditary disease depends

on the nature of dismetabolism and the type of cells, structure and function of which
are deranged. Sometimes the genetic defect limits the reproductive ability. The carrier
of the most dangerous mutation dies intrauterine (in embryo).
Many patients with the hereditary pathology survive and reproduce posterity. It
leads to accumulation of mutant genes at the level of population.
Compensatory-Adaptive Reactions
Compensatory-adaptive reactions may be observed in the pathogenesis of

hereditary disease.
Sometimes the half-activity of enzyme is sufficient for its normal function. Many
functions in organism are provided by different metabolic ways, and compensation is
possible.
5
Not every alteration in primary structure of protein leads to clinical manifestation.
For example, more then 300 variants of hemoglobin are identified, but only some of
them are manifested as anemia while the most of them are without clinical disorder.
Organism as a whole may compensate insufficiency of one system by
hyperfunction of another (activation of circulation in patient with hereditary anemia).
MANIFESTATIONS OF HEREDITARY DISEASES
Every part of medicine (cardiology, hematology, nephrology, endocrinology etc.)

describes a lot of diseases, in the development of which genetics play a main role, and
every disease has its clinical manifestations studied at a correspondent university
department. In this textbook some hereditary diseases are mentioned as an examples
(immunodeficiency, hemophilia, diabetes etc.). In every next chapter it will be
pointed the role of genetic factors, and reference to this chapter will be useful.
The clinical manifestations of hereditary diseases depend on
• Function of gene, which is disrupted,
• Type of protein, synthesis of which is disrupted,
• Type of metabolic disorders,
• Type of inheritance, if a disease is monogenic,
• Factors of environment, if a disease is polygenic,
• Sex.
Concerning the time of clinical manifestation, the hereditary disease may be
congenital or not. Sometimes disease is manifested immediately after the birth
(mucoviscidosis, polydactilia), sometimes later (gout is manifested in elderly
patients).
The most serious genetic anomalies disturb the reproductive ability of carrier.
Sometimes the death of carrier happens in embryo.
Manifestations of Mendelian diseases depend on the type of transmission.
Autosomal Dominant Disorders
If a disease is monogenic and the pathologic gene is dominant, only those

anomalies, which do not disrupt viability and do not prevent multiplication, are
transferred in generations. Skeletal anomalies (multi-fingered, brachydactilia,
anomaly of teeth structure), long-sightedness and shortsightedness, astigmatism,
otosclerosis, cataract, some forms of muscular atrophy are the examples of such
pathology. The following diseases are inherited in the same type – achonroplasia
(form of dwarfism), Gilbert,s disease (a cause of hyperbilirubinemia), Huntington,s
chorea (neurologic disorder), polycystic kidney disease, polyposis of the colon, sikle-
cell anemia (hemoglobinopathy), von Willebrand,s disease (hemorrhage diathesis),
spherocytosis (hemolytic anemia), thalassemia (red cells disorder).
Autosomal Recessive Disorders
Majority of hereditary diseases is inherited recessively. It means that disease

develops, when a child gains pathologic genes from both parents. It is the largest
group of Mendelian disorders. Enzymopathy, hemoglobinopathy, erythrocytopathy,
coagulopathy and diseases of metabolism are inherited thus. In addition they are –
6
adrenogenital syndrome (endocrinopathy), agammaglobulinemia (immunodeficiency),
glycogen storage disease, galactosemia, phenylketonuria, and muscular dystrophy.
Sex-Linked Disorders
Morbidity of the carriers of mutant genes in X or Υ-chromosome depends on sex

of the patient. Almost all sex-linked disorders are X-linked, and almost all of them
are recessive. The X-liked pathologic conditions are - agammaglobulinemia Bruton’s
type (immunodeficiency), diabetes insipidus (pituitary disorder), G-6-P-D deficiency
(hemolytic anemia), hemophilia A and B (hemorrhage syndrome), ichthyosis (skin
disease), mucopolysaccharidosis (lysosomal storage disease), muscular dystrophy,
color-blindness, youthful glaucoma, hypophosphatemic rachitis. The heterozygous
female with the X-linked recessive mutation does not usually express the full
phenotypic change because of the paired normal allele.
Polygenic Disorders
The role of genetic factors in pathogenesis of such diseases, as diabetes mellitus,

arterial hypertension, bronchial asthma, allergic diseases, cancer, stomach ulcer is
confirmed statistically. Not one but several genes determine them. Equally with
genetic factors, living conditions are of a great significance (multiphactorial
diseases). For each of them the specific limiting factor of environment is estimated
(salt or sugar load, the content of cholesterol in the food, stress, hypoxia). The variety
of clinical forms and individual manifestations is typical for these diseases.
HEREDITARY PREDISPOSITION
Some diseases are determined exclusively by the factors of environment (radiant

and infectious diseases), but others - by genetic ones (Down's disease). There are
many diseases, development of which is determined by both genetic and exogenous
factors. In such cases we speak about hereditary predisposition.
The recessive and polygenic types of inheritance underlie hereditary
predisposition.
Hereditary predisposition is a genetically determined state состояние of
increased probability of a certain disease development under certain
environmental conditions.
Allergy, neoplasia, arterial hypertension, atherosclerosis (e.g. the main therapeutic
noninfectious diseases) are inherited in such a way.
Certain exogenous factor may cause different diseases in patients with different
heredity (for example, mental overload and negative emotions may provoke
hypertension or thyrotoxicosis depending on heredity).
Manifestations of diabetes mellitus depend both upon genetic factors and the
conditions of life (nourishment and the load on insular apparatus).
Processes, which are studied by immunogenetics (termed as immunodeficiency)
are another examples of hereditary predisposition. Deficit of immunoglobulins, B- or
T-lymphocytes, insufficiency of phagocytic activity of leukocytes are inherited.
Clinically these defects are manifested by a predisposition to infection, allergy,
autoimmune aggression.
7
Metabolism of medicines has individual peculiarities and harmful side-affects of
medicines are often observed. Enzymopathy underlies an increased sensitivity to
medicines.
Risk Factors
For medical practice a concept of risk factors is important. In fact, the overloading
of metabolism is a risk factor for heterozygous carrier of enzymopathy. An infection
is a risk factor for patient with immunodeficiency. Radiation and mutagens are the
risk factors for oncopredisposition (depending on heredity, they cause cancer or
leukemia).
So, emergency of these diseases depends on interplay of genetic and
environmental influences. Changing the living conditions and avoiding the risk
factors, it is possible to prevent development of multifactorial diseases.
CHROMOSOMAL DISEASES
Chromosomal mutation damages the greater part of the genetic apparatus and
causes more serious disorder than gene one. Chromosomal aberrations may be
structural (break, deletion, inversion, translocation, fragmentation) and quantitative
(as a result of homologous chromosome nondisjunction).
The patient more often sterile and therefore does not transfer disease to
descendants. His parents are healthy.
Chromosomal disease is a such type of diseases, which develops as a result of
chromosomal mutation in germ cell of one of the parents.
Thus, chromosomal diseases relate to the genetically determined ones, but not to
inheritant ones. Chromosomal anomalies are not accumulated in the population.
Etiology
Etiological factors are the mutagens of physical, chemical and biological origin.
The peculiarities of etiology of chromosomal diseases are the following:
• Etiological factor affects parents, but a disease develops in descendant.
• De novo a chromosomal mutation in germ cell happens in a healthy adult person,
and if this cell would not be impregnated a mutation remains without
consequences.
• Family predisposition to nodisjunction of chromosomes is revealed.
• The disorders of hametogenesis happen more frequently in elderly people but less
frequently germ cells get impregnated.
Pathogenesis
The initial link of pathogenesis is a chromosomal mutation in sex cell of one of

the parents. The vitality of such cell is seriously impaired. It usually perishes or loses
capability for impregnation. If it is impregnated, the embryo could perish.
Chromosomal anomalies cause 40% of spontaneous abortions and about 6% of
stillbirths. If chromosomal disbalance is compatible with life, the host may die while
immediate postnatal period or is seriously ill. Somatic and mental development is
deranged, an ability to reproduce posterity gets lost. After death of this patient the
8
mutation disappears from the population. If reproductive function remains (3-5%),
posterity inherits chromosomal anomaly.
Manifestations and Clinical Syndromes
Manifestations of chromosomal disease depend on the type of chromosome, which

is subjected to mutation. About 300 chromosomal anomalies are discovered.
Some chromosomal diseases are caused by qualitative (structural) alterations of
chromosomes, which have more severe consequences in comparison with quantitative
ones. The patients require a constant medical help because of serious physical
deficiencies and mental backward. Majority of children perishes in the beginning of
life.
As to autosome mutation, it has more severe consequences. The deficit of
autosomes is more harmful than surplus (monosomy in living people is not revealed).
Trisomy of large autosomes is not described (presumably, it is lethal). Trisomy of
small autosomes very often is lethal, but if it is compatible with life, it results in plural
physical defects and high lethality in early childhood.
The mutation in 23-rd (sex) pair of chromosomes deranges the viability of the
carrier least of all. The quantitative changes of this pair of chromosomes frequently do
not prevent the life of a child. Clinical syndromes are well described. The patients
have very serious physical and mental disorders. Karyotype 45,YO is lethal.
Below there are examples of chromosomal diseases, when a carrier survives.
Multy-X Syndrome
In multy-X syndrome female has 47,XXX karyotype. Majority of patients is

entirely normal. Sometimes triple-X females do not have the obvious clinical
manifestations and some of them have children. But more frequently, this syndrome
displays by hypogonadism, amenorrhea or other menstrual irregularities. The woman
has two or more X-chromatin (Barr’s bodies) in somatic cells.
Klinefelter's Syndrome
Klinefelter's syndrome (trisomy 47,XXY) is manifested in men by high stature,

hypogonadism (testicular atrophy and azoospermia, eunochoid bodily habits,
gynecomastia), sterility, mental retardation. Sometimes these men have normal sexual
development and even increased fecundity плодовитость. Intellect is normal or mild. A
tendency toward the aggressive behavior is noted. Typical karyotype is 47,XXY, but
variants 48,XXXY and 49,XXXXY are revealed. Sexual chromatin (Barr’s body) is
present in the somatic cells.
Turner’s Syndrome
In Turner’s syndrome a girl has 45,XO chromatin-negative karyotype. Only 3%

of fetuses survive to birth, frequently they are aborted. If they survive, they show
primary amenorrhea, infertility, lymphostasis and lymphedema, coarctation of aorta,
predisposition to Khoshimoto’s thyroiditis. Sexual chromatin is absent in somatic
cells.
Down's Syndrome
9
The carriers of the 21st pair trisomy are more viable among all carriers of
autosomal trisomy. The total number of chromosomes equals to 47. There is a variant
with 46 chromosomes if one 21st chromosome is fused via its centromere to another
acrocentric chromosome. This abnormal chromosome is called Robertsonian
translocation and can sometimes be inherited.
In typical form of a disease the men are sterile, the women may have children.
Because of dominant type of inheritance, 50% of children are healthy, but half of
them are ill with the same disease.
The disease is manifested by developmental delay, growth and mental retardation,
premature aging, neuralgic disorders, cataract, increased synthesis of purines,
amyloidosis, production of proteins-oncogenes, high frequency of leukemia,
activation of free-radical oxidation. The visible signs are characteristic facial and
dysmorphic features such as brahycephaly, . epicanthal folds, small ears, transverse
palmar creases. Retardation of linear growth is moderate, and most adults with
Down's syndrome have the height shorter than the most of the general population. In
contrast, weight growth in Down's syndrome exhibits a mild proportionate increase
compared with that of the general population, and most adults with Down's syndrome
are overweight for height. Approximately 50% of affected children have congenital
heart defects that come in the immediate perinatal period because of cardiorespiratory
problems.
Immune problems are typical in form of immunodeficiency. Laboratory
abnormalities can be detected in both humoral and cellular immunity. Antithyroid
antibodies predispose to disturbance of gametogenesis (nondisjunction of the 21st
pair of chromosomes). Consequently, the hypofunction of the thyroid gland is a risk
factor. Increased susceptibility to infections is a common clinical feature at all ages.
There is a considerable range in the degree of mental retardation in adults with
Down's syndrome, and many affected individuals can live semi-independently.
The woman older than 35-39 years and the man older than 55 years have higher
risk of giving birth to child with Down's syndrome.
CONGENITAL DISEASE
Congenital disease is such, which is manifested just after the birth.

The congenital diseases can be or not connected with pathology of genetic
apparatus.
The congenital disease may be a result of pathological pregnancy or infection
intrauterine? in embryo? or during labour. The examples of congenital diseases are
toxoplasmosis and congenital syphilis. Such congenital diseases are not genetically
determined and, naturally, are not inherited.
Those diseases, which are caused by environmental factors and have a clinical
picture similar to known hereditary diseases, are called phenocopies.
If hereditary disease is manifested immediately after the birth (polydactilia) it is
also termed congenital.
METHODS OF GENETICAL EXAMINATION OF A PATIENT
Significance
10
For an appropriate treatment it is necessary to know the reason of a disease. The
participation of genetic and environmental factors must be established.
Many acquired diseases are clinically similar to the inherent ones. For example,
hypothyroidism which is caused by iodine deficiency in surroundings, clinically is
similar to the genetically determined lack of thyroid hormone, but treatment and
prognoses are different (phenocopies are not inherited).
If a sick child is born by a healthy woman and a mutation happens during the
pregnancy, the repetition of this disease is of a low probability.
The woman, carrier of the hemophilia A gene, is clinically healthy, but she must
know, that half of her sons will be ill with hemophilia. If both parents are ill with the
same disease, their children have increased predisposition to it. The physician of any
speciality observes the phenomenon of hereditary predisposition. Consultation of
geneticist sometimes is necessary for the family having a genetic pathology. The
question is about a probability of its repetition in posterity.
Methods
Methods of genetic examination are numerous and constantly improved.

Statistic method consists in comparison of a frequency of a certain disease in the
family and human population (according to medical statistics). This method gives a
possibility to establish genetic nature of a disease in the family. If a type of
inheritance is known (from literature) physician may prognosticate the morbidity.
Genealogical method reveals the type of inheritance. It makes it possible to
establish the probability of repetition of the disease in the following generations.
Biochemical method detects enzymopathy even in a newborn baby. For
examination it is enough to take urine or a drop of the blood.
Morphological (Cytological) Method. Investigation of patient’s karyotype. Some
diseases are detectable in the karyotype. Chromosomes become visible with the light
microscope research of multiplying cells (in the stage of metaphase). It is possible to
observe the quantitative and structural alterations of chromosomes (breaks, noncentric
chromosomes, fragments, annular chromosomes, chromosomal associates) (fig. 3).
___________________________________________________________________________________
Fig. 3. Chromosomal mutations (со с.97 украинского учебника)

A - quantitative disorders: a) karyotype (XXXYY) of a sick man (Kleinfelter syndrome); b)
karyotype (XXX) of a sick woman (X-trisomia).
B – structural disorders: 1- deletion, 2- chromosomal ассоциат, 3-circle-lyke chromosome.
___________________________________________________________________________________
Investigation of sex chromatin (Barr’s body). Sex chromatin is the spiraled X-
chromosome and obtains in the interphase nuclei, if chromosomal collection contains
their two. Naturally, healthy women have sex chromatin. If cell contains several X-
chromosomes, a quantity of Barr’s bodies is equal to a quantity of X-chromosomes
minus one. The cells of the mucous membrane of mouth are convenient for detection
of the Barr’s body.
Genetic analysis is possible with the contemporary methods of molecule DNA
studying.
11
Gemellary method (the examination of identical and nonidentical twins) gives the
possibility to distinguish the role of heredity and environment (table 3).
Table 3. Frequency of Disease of Another Twin in the Pair of the Twins
Disease Frequency of Disease of Onother Twin in

the Pair of Twins %
Однояйцовых Двуяйцовых
Tuberculosis 66,7 23
Idiotia, imbecility, debility 97 37
Maniac-depressive psychosis 96 19
Schizophrenia 69 10
Epilepsy 56 10
Diabetes mellitus 65 18
Congenital pilorostenosis 67 3
Расщелина губы (заячья губа) 33 5
Endemic goiter 71 70
By the method of ultrasound echography the morphological defects of embryo

(microcephalia, hydrocephalia) may be detected.
Experimental modeling of genetic diseases in animals is possible. The
(sub)populations of animals with high or low frequency of cancer, leukemia, arterial
hypertension and atherosclerosis are created in the laboratories.
PRINCIPLES OF PREVENTION AND TREATMENT OF HEREDITARY

DISEASES
Etiological therapy and prophylactics consist in prevention of mutagens entrance

in organism. The neutralization of endogenous mutagens with artificial antioxidants is
possible.
Pathogenetic Therapy. Mutations are the initial link in the pathogenesis of
hereditary diseases. Genetic engineering (manipulation with genetic material) is
possible in scientific laboratories, but not yet in everyday medical practice.
Substitutive Therapy. Injection of anti-hemophilic globulin to patients with
hemophilia A increases lifetime and makes them possible to live (sub)normally.
Gammaglobulin, hormones (insulin, thyroxine), enzyme and metabolite may be
added. Microorganisms, which synthesize the proteins useful for a man (interferon,
hormones and enzymes) are created in the laboratories by genetic engineering.
12
The biochemical correction of dismetabolism has many possibilities. Inactivation
of toxic products may be achieved. The dangerous substrates of the nourishment must
be avoided.
Symptomatic Therapy. Psychotropic drugs are useful for the mental disorders.
The injection of sex hormones to the girls with Turner’s syndrome and to boys with
Klinefelter’s syndrome sometimes results in the development of the second sexual
features, positively influences the mental condition of the patient. Injection of
immunomodulators insures the mechanisms of own anti-mutant protection. Surgical
management of morphological anomalies is very successful.
Otherwise, the treatment of hereditary diseases is limited. Prophylaxis has an
advantage. All substances, which are used by people, must be checked for
mutagenicity. The knowledge of the risk factors helps to provide the prophylaxis of
polygenic diseases.
ROLE OF CONSTITUTION IN PATHOLOGY
Constitution is a unique complex of morphological and functional (including

psychological and mental) peculiarities of organism, which determines its
individual reactivity (adaptation capacity and pathological predisposition) and is
formed on the hereditary basis under the influence of environment.
It is important to see in constitution the interaction between the inherited and
acquired peculiarities of organism. The inherited ones can be defined as potentialities
of organism.
As to environment, it is the condition of constitutional realization and may provide
the formation of new features having constitutional significance. It is obvious that
infection, intoxication, avitaminosis and radiation can considerably change the
structure of the body, its reactivity and resistance. Pathological influences are
especially harmful in childhood. Beyond doubt, the social and hygienic factors, as
every day conditions, food habits etc. have a great significance. The teaching of
constitution confirms the low, that the course of any disease, its prognosis and
treatment depend not only on the character and severity of the pathogenic factor, but
also on the individual peculiarities of the patient.
Classification of Constitution
Hippocrate proposed one of the first classification. He focused attention upon the
differences in temperament and social behavior of the people. Choleric, sanguinic,
phlegmatic and melancholic – are the Hippocrate,s terminology, which is in use up to
now. Choleric is excited, his workability is high, but not constant. Sanguinic is
communicable, vivacious, lively, active and emotional, but predisposed to apoplexy
and diabetes mellitus. Phlegmatic is calm, apathetic, unexcitable and sluggish, but
stable. Melancholic is an inverted weak type, depressed and hesitating. Hippocrate
explained the constitutional variations by the different proportion of “humores”
(sanguis, phlegma, cholon, melanos cholon) in human organism. Contemporary
scientists, like Hyppocrate, focus attention on the role of humoral factors – blood,
hormones and biological active substances - in reactivity of organism.
Sigau proposed morphological classification. Basing upon the pronounced
development of a certain physiological system, he differentiated the following four
constitutional types: respiratory, digestive, muscular and cerebral ( fig.4). Sigau
13
believed that constitution is forming throughout the life, but mainly in the childhood
and while training.
_____________________________________________________________________
Fig. 4. Classification of constitution by Sigau (со с. 106 украинского учебника)

a – respiratory, b – digestive, c – muscular, d – cerebral
__________________________________________________________________________________
Kretschmer distinguished three constitutional types - asthenic, athletic and picnic.
Psychiatrist by profession, Kretschmer attempted to connect the morphological
features of a man not only with the psyche and temperament, but also with the
predisposition to mental disease. Asthenic type of constitution is observed mainly
among patients with schizophrenia. Patients suffering maniac-depressive psychosis
are preferably of a picnic type. The patients with epilepsy have predominantly
athletic type of constitution.
__________________________________________________________________________________
Fig. 5. Classification of constitution by Kretschmer (со с. 106 украинского учебника)

a – asthenic, b – athletic, c - picnic
In clinical practice, M. V. Chernorutsky's classification has received

acknowledgement. M. V. Chernorutsky focused attention on body строение,
соотношение между вертикальными и горизонтальными размерами. Each constitutional type
was given a characteristic from the standpoint of the main physiological functions and
metabolism. Thus, in comparison with normosthenic, the hyposthenic suffers arterial
hypotension, depressive sucking ability of bowels, and elevated metabolism. For the
patients of hypersthenic type, the following peculiarities are more typical - higher
level of arterial pressure, retarded metabolic processes, reduction of carbohydrate
tolerance, predisposition to the ischemic heart disease, myocardial infarction, obesity
and the second type of diabetes mellitus.
U. Sheldon placed the predominant development of an ectoderm, endoderm and
mesoderm on the base of classification.
А.А.Bogomoletz investigated the leading significance of the connective tissue in
the structural and functional peculiarities of a human body. He postulated the view
that the connective tissue unites organism as a whole and forms the basis for
constitution. Hence, he put the peculiarities of an active mesenchyma as a basis of
classification. He named the following types - asthenic, fibrous, lipomatous, and
pastous ones. The asthenic type is characterized by predominantly thin and tender
connective tissue. The fibrous type has denser connective tissue. The lipomatous type
has an abundant adipose tissue; the mesenchymal elements are predisposed to fatty
infiltration and decomposition of a lipoid character. The pastous type has an
14
edematous connective tissue.
I. P. Pavlov had leading idea that it is the nervous system, which unites the
organism as a whole and ensures its reactivity and balance with the environment. The
characteristics of higher nervous activity (force of excitation and inhibition, the
mobility and balance of them) were proposed as a base of the classification. These
types are similar to Hippocrate,s ones. Strong, mobile and unbalanced type (with
prevalence of excitement) is the choleric; strong, mobile and balanced type is a
sanguinic; strong but slow type (inertia of the main nervous processes) is a
phlegmatic; weak type (weakness of both nervous excitement and inhibition with a
relative prevalence of inhibition) is a melancholic.
German homeopathist Hahnemann divided the patients depending on sensitivity to
the medicines. This idea is useful for practice and underlies the usage of the small
doses of medicines.
While studying the constitutional types, it becomes evident that minority of the
people can be referred to pure types, but the majority of them present mixed ones.
Significance of Constitution
Significance of constitution was well understood by the ancient physicians. It was

obvious to them that pathological predisposition is reflected by constitution. They
estimated the strong and weak features of every constitution, the predisposition to
certain diseases and gave recommendations as to the rational behavior and life style.
They saw a sanguine personality predisposition to apoplexy and usefulness of
bloodletting, which was so popular. They have discovered that a short stature type has
a predisposition to apoplexy, while a tall type is predisposed to respiratory diseases.
In tuberculosis the primary infection is independent of constitution, but among
asthenics the course of the disease is more severe and lethal outcome occurs more
often. Atherosclerosis and coronary disease are directly related to picnic constitution.
Gastric ulcer, arterial hypertension, neurasthenia are characteristic of people with
excitable type of the nervous system. It has also been noticed that the specificity of
neurotic symptoms is connected with the constitution. For example, hysteria and
depression are more common among the athletic and picnic types, while a fear and
anxiety are more common for asthenics.
Now the aim of science is to study the nature of the established connections, which
are probably genetically determined. Most of evidence favors the view that the same
group of genes controls simultaneously a group of features, which are morphological,
functional and psychic.
The studies of the most vulnerable point of constitution makes it possible to
prognosticate the disease course, to determine the pathological predisposition, to
provide an individual approach to the treatment.
Diathesis
Concept of constitution is closely related to the idea about diathesis, which is

manifested itself in the childhood.
Diathesis is an anomalous constitution, which is characterized by inadequate
reaction of organism to environment.
Diathesis reflects the types of the reactivity bordered upon pathology.
Exudative-Catarrhal Diathesis
15
The view of child is normal or pastous. Inflammatory processes appear easily with
the formation of exudate and a tendency toward the hyperergic duration. The
following atopic features of immunological reactivity are revealed - tendency toward
the excessive production of IgE and IgG, an increased activity of kinin system.
Immediate (anaphylactic) type of allergy appears easily, sensitivity to serotonin and
histamine is increased. Eosinophilia is noted in the blood. Clinical manifestations are
the following - the bronchial asthma, hives, отек Квинке, croup, and anaphylactic
shock.
Lympho-Hypoplastic Diathesis
The delayed involution of thymus and lack of epinephrin hormones underlie this
diathesis. From one side, the hyperplasia of tonsils, lymph nodes and spleen is
observed. From other side, the hypoplasia of the adrenal, thyroid and sexual glands,
the early exhaustion of the reparative properties of mesenchyma are observed.
Somatic and mental infantilism, pastousity, paleness, and weak development of
muscles characterize the habit of child. Angina and pharyngitis are developed
frequently. The dysfunction of the adrenal glands is associated with decreased
resistance to stress. Sudden death from the insignificant reasons may occur.
Neuro-Arthritic Diathesis
Neuro-arthritic diathesis is characterized by intensive purine metabolism and

increased formation of endogenous urates. The effect of urates is similar to coffeine
and forms the strong unbalanced type of constitution, nervous excitability, vegetative
and emotional liability. Tendency toward the following diseases is noted - neuralgia,
migraine, noninfectious diseases of the joints, formation of urolithic or biliar
concrements, gout, diabetes mellitus, rheumatism.
It is important to emphasize that diathesis is not a disease, but a tendency toward it.
Patients are in the condition of minimal resistance and maximal risk of the disease
development.
16
CHAPTER 4
REACTIVITY AND RESISTANCE OF ORGANISM
CONCEPT OF REACTIVITY
The course of any disease depends not only on the force of etiological factor, but
on reactivity of organism. In practical medicine, the notion of reactivity helps to
evaluate the adaptive potentialities of organism.
Reactivity is an ability of organism to change its activity and develop reactions
(mainly adaptive one) in response to normal and pathogenic influences.
Mechanism of reactivity are manifested at different levels of biological
organization:
• Molecular (reaction enzyme-substrate, reaction of hemoglobin to gas composition
in the blood, transformation of biological active substances etc.),
• Cellular (phagocytosis, reaction of B- and T-lymphocytes to antigen,
degranulation of mast cells),
• Tissue (reaction of connective tissue while inflammation),
• Organs (activation of heart pulsation in response to overload),
• Physiological systems (increase of arterial blood pressure in response to pain,
hypoxia etc.),
• Organism as a whole,
• Population (formation of passive immunity in a child during the first year of life
by transmission of immune antibodies from mother to newborn via placenta and with
milk).
The following systems significantly contribute to reactivity – genetic
(constitution), nervous (central and vegetative), endocrine, connective tissue (which
forms biological barriers and provides mechanisms of immunity).
Reactivity depends on sex and age. Low reactivity is typical for early childhood
due to incomplete development of nervous, endocrine and immune systems,
imperfection of the external and internal barriers. The highest reactivity is noted in
adults, gradually descending to the old age.
Derangement of reactivity is an important link in pathogenesis of every disease.
Disorder of reactivity reduces adaptive capacity of organism. At the same time, any
pathological process changes reactivity of organism.
TYPES OF REACTIVITY
Reactivity is divided into primary (видовая or biological) and secondary

(acquired under pathological influences of surrounding or developed in a disease),
group групповая and individual. In addition, it is subdivided into normal (normergia),
increased (hyperergia), decreased (hypoergia) and qualitatively changed.
1
Physiological reactivity embraces reactions of a healthy organism under favorable
conditions of existence. Pathological reactivity manifests itself under an effect of
pathogenic factors (reactivity of a sick person). The letter can be manifested by
uncommon reactions (allergy, shock).
Depending on its mechanisms, reactivity may be divided into nonspecific and
specific.
Nonspecific reactivity embraces reactions, which are not strictly depended upon a
certain etiological factor and may occur in a variety of conditions. All defensive
reactions mentioned above (change of heat production and emission in response to
low and high temperature of surroundings, vasodilatation, tachycardia and
hyperventilation) relate to the nonspecific reactivity. Nonspecific defensive reactions
are universal and economical ones. To this form of reactivity it is necessary to add
nonspecific reactions of organism in response to infection (phagocytosis, the
formation of biological active substances).
Specific reactivity embraces reactions, which are strictly depended upon a certain
etiological factor. Only immunological reactivity satisfies this requirement, when a
definite immune antibody is formed in response to definite microorganism (antigen).
Specific reactivity provides resistance to infection and formation of a specific
immunity. Specific self-protective reactions are more energy-dependent and are
damaged easily by unfavorable influences on organism.
CONCEPT OF A RESISTANCE
Concept of a resistance is closely connected with concept of reactivity.

Resistance is an ability of organism to opposite to pathogenic factors.
Resistance is determined by reactivity, therefore resistance is one of the main
manifestations of reactivity.
Resistance can be primary which is determined by genetic factors and secondary,
which is acquired.
Resistance is divided into passive and active. Passive one is based on anatomical
structures (biological barriers). Active resistance is based on active defensive
reactions, which develop at various levels of biological organization.
Usually reactivity and resistance are changed in the same direction, but other
correlation are possible. Thus, in hibernation (зимняя спячка) reactivity of the animal
falls but resistance (passive) increases.
Reactivity is closely connected with sensitivity. Increased sensitivity determines
increased reactivity. An opposite example – an increased (but passive) resistance
under narcosis and hypothermia.
Abnormal increased sensitivity (hypersensitivity) is called sensibilization as in
allergy.
MECHANISMS OF REACTIVITY
Nervous and endocrine systems, as well as connective tissue significantly

contribute to reactivity.
ROLE OF NERVOUS AND ENDOCRINE SYSTEMS
2
Filo- and ontogenesis demonstrate, that становление of reactivity of organism is
connected with the level of nervous and endocrine systems development.
A functional state of the central and autonomal (vegetative) nervous systems
determines decreased reactivity in narcosis and shock. Dysthrophy develops after
cutting of the somatic and vegetative nerves.
Hyperfunction of a thyroid gland stimulates reactivity while hypofunction restricts
it. Diabetes mellitus is associated with decrease of reactivity. Adrenaline and
corticotropin (hormone of anterior lobe of pituitary gland) promote adaptive
reactions. Adrenal cortex hormones also influences reactivity. Thus, glucocorticoids
inhibit inflammatory reactions, mineralocorticoids stimulate inflammation.
ROLE OF CONNECTIVE TISSUE
Ukrainian scientist A.A. Bogomoletz is a founder of a concept about the

physiological system of connective tissue, which plays an important role in reactivity
and resistance. Together with опорная supportive? and plastic functions, it
accomplishes the following ones - throphycal, defensive (formation of barriers,
phagocytosis and mechanisms of immunity), reparative.
A system of connective tissue includes
• Biological barriers
• Bone marrow
• Lymphocytes and lymphоnodes
• Micro- and macrophages (neutrophills, monocytes, histiocytes of connective tissue)
• Reticular cells of the liver, spleen, kidneys, lungs.
Mechanisms with which the connective tissue performs its functions are non-
specific (barriers, phagocytosis) and specific ones (formation of immune response).
For stimulation of the connective tissue, A.A. Bogomoletz proposed a serum,
which is called antireticular cytotoxic serum (ACS). It contains antibodies against
elements of the connective tissue. This serum is produced by injection of the elements
of human connective tissue to animal. The small dose of this serum stimulates
functions of connective tissue and reactivity of the organism (large dose suppresses
them).
Biological Barriers
Biological barriers are an important mechanism of resistance and relate to the

passive ones. They are the special structures, which protect organism from
pathogenic factors and maintain homeostasis. They are formed in evolution, and a
man possesses them from the birth.
There are two types of the barriers - external and internal.
External barriers are the following - skin, mucous layer of respiratory, digestive
and urogenital tracts, which contain bactericidal factors (leukocytes, lysocim and
antibodies of a secretory type IgA) on the surface.
Internal barriers prevent penetration of the foreign and poisonous materials from
the blood into the organs and tissues. Internal barriers have regulative, throphical and
defensive functions. They regulate entering of the necessary substances from the
blood into the organ, support an optimal composition of its medium, maintain
cellular homeostasis and protect an organ from infection. The main structural
elements of internal barriers are the blood capillaries - endothelium, basal membrane
and perivascular connective tissue.
3
The permeability of a barrier may be changed under many influences. Increased
permeability is obtained under effect of ionizing radiation, acetylcholine, histamine,
kinines, hialuronidase. An opposite effect have catecholamines, salts of calcium,
vitamin PP. Permeability of barriers is changed under different pathologic processes,
such as trauma, inflammation, viral infection. Increase of barrier permeability makes
an organ more sensitive to infection, poisons and intoxication.
Each tissue has its own medium and own barrier. The common term for such
barriers is histohematic ones.
Each histohematic barrier has its selective permeability. In some organs it is
fastened by additional structures and received a new name. They are the so-called
specialized barriers. It is a particular group of barriers, which defend such organs,
which have weak local mechanisms of immunity (antibody formation and
phagocytosis). Specialized barriers are: hematoencephalic, hematoophthalmic,
hematolabirintic, hematotesticular, hematothyroid, placental ones.
Hematoencephalic barrier (blood-brain barrier) has the most compound
organization. Besides endothelium and basal membrane, it has also argirophile
material and neuroglial astrocytes. Microorganisms, toxins and antibodies do not
penetrate into the brain. As to metabolites, hormones and biological active
substances, this barrier acts selectively regulating penetration of these materials into
the cells of the brain.
Particular value for fetus development belongs to placental barrier, which protects
the fetus in pregnancy. Impairment of permeability of this barrier harmfully reflects in
embryonic development and results in different types of postnatal pathology.
The specialized barriers protect organs from infection and large molecules, which
are circulating in the blood. But, from other side, just these organs are isolated from
immune system in embryo, and physiological immunological tolerance (see below) is
not formed towards them. Injury of the specialized barriers leads to the autoimmune
aggression against these organs.
Phagocytosis
Phagocytosis is an important but nonspecific mechanism of reactivity.

Phagocytosis is a process of capture and intracellular destruction of foreign
particles (microbes, distorted tissues) by special cells of the connective tissue,
which are called phagocytes.
Phagocytes are the leukocytes, namely, neutrophiles (microphages), monocytes
(macrophages) and the tissue type of macrophages (star-like cells in the liver,
alveolar, pleural and peritoneal macrophages). Phagocytes are circulating in the
blood while phagocytosis proceeds in the tissues. Consequently, leukocytes must
emigrate from the vessel into the tissue through the wall of capillaries.
Phagocytosis is regulated by many factors. Antibodies, immune complexes,
complement and hormones (adrenaline, thyroxin, mineralocorticoids, sexual) activate
phagocytosis as well as phagocytosis is activated during a fever. BAS activate all
stages of phagocytosis. Glucocorticoids and acetylcholine inhibit it.
4
Stages and Mechanisms
Phagocytosis proceeds in four stages:

1. Chemotaxis (approaching) of phagocyte to the object after its recognition by
phagocyte. Phagocyte has receptors on its surface to the chemotaxins (substances,
which cause chemotaxis). The microbial products act as chemotaxins.
2. Adhesion (attachment) of phagocyte to the object. Adhesion is provided by
polysaccharides, which are located on the surface of leukocytes. Electrostatic
interaction between negative charge of leukocyte and positive one of inflammatory
locus contributes to adhesion.
3. Capture of foreign particle by phagocyte (endocytosis) and formation of
phagosome.
4. Intracellular digestion of phagosome content by lysosomal proteolytic
enzymes.
Phagocytosis requires energy of ATP. It is known, that the leukocytes have
uncommon relations with oxygen - mitochondrias are absent in phagocytes, and ATP
is formed by glycolysis. Phagocytes use oxygen for production of the bactericidal
factors. Oxidizers (peroxide of hydrogen and the active forms of oxygen) are formed
inside phagocyte from molecular oxygen by a special enzymal system (key enzymes
are NADF-oxidase, superoxidedismutase and myeloperoxidase). Activation of
glycolysis results in accumulation of acids (acidosis), which act as a bactericidal
factor. Lysocim, lactoferin and cation nonenzyme proteins refer to the bactericidal
factors as well.
Disorders of Pagocytosis
Phagocytosis fails, if a quantity of phagocytes lowers (leukopenia) or their

functional activity gets disturbed.
Etiology. Etiological factors are physical (ionizing radiation), chemical (poisons)
and biological (including genetic) factors of external and internal origin, which
suppress the formation of leukocytes in the bone marrow or disturb their functional
activity.
Pathogenesis. Disorders of phagocytosis are divided into acquired and genetically
determined. Mechanisms are the following:
• Decrease of the quantity of phagocytes (leukopenia) is the most often reason of
suppressed phagocytosis. Hemopoiesis in the bone marrow is depressed in radiant
disease, intoxication, autoimmune injury, avitaminosis or deficit of leukopoetins.
• Excessive secretion of glucocorticoids suppresses phagocytosis. The same effect
occurs under an effect of glycolytic poisons (they diminish the formation of energy in
leukocyte), inhibitors of DNA synthesis and other factors, which disorder division of
the cells.
• Genetically determined disorder may be a result of enzymopathy (deficit of
myeloperoxidase and NADP-oxidase, proteolytic enzymes of lysosome and enzymes
of glycolysis), lack of lysosomes in phagocytes or deficit of receptors on their
surface.
• Acquired and genetically determined pathology of BAS formation, lack of
opsonizing factors, complement and other factors, which are functionally connected
with phagocytosis.
5
• Suppression of phagocytosis under stress, thyroid hypofunction, sexual gland
insufficiency (while a climax). Leukemia is accompanied by reduction of leukocyte
enzymal activity.
Manifestations
Disordered phagocytosis is manifested as an incomplete незавершенный one. At the

level of a whole organism, the disorder of phagocytosis is manifested by disorder of
reactivity and resistance of organism to infection. Predisposition to infectious diseases
is obvious. Even saprophytic infection (autoinfection) may appear a problem.
Inflammation, as a self-defensive reaction, obtains a chronic duration.
Role of Biological Active Substances (BAS) in Reactivity
Biological active substances (BAS) accomplish a lot of functions under

physiological and pathological conditions, contributing to reactivity and resistance of
organism. They are formed in a small concentration in tissues and in blood plasma.
BAS regulate microcirculation, tonus and permeability of vessels, coagulation of
blood, activate phagocytosis and mechanisms of immunity, stimulate formation of
leukocytes and their liberation from the bone marrow, possess enzymal effect and
destroy the membranes of microbes and foreign cells. They cause a fever and
possess property of the growth factors.
Under pathological conditions, BAS are produced in a large quantity and become a
factor of damage (inflammation, allergy, edema, spasm, pain, shock etc.). Many
medical drugs, which are used for treatment of inflammation and allergy, are directed
against BAS. That is why a physician needs knowledge about BAS origin, synthesis,
inhibition, physiological and pathological effects.
BAS of Cellular Origin
Biological active substances may be formed in almost all cells. The cells of the
connective tissue are especially active in this respect. Some BAS are present in the
cells in a ready form, some are formed after stimulation (activation) of the cells. The
process of BAS secretion needs energy, that is why blocking of energy formation
blocks releasing of BAS. Cyclic nucleotides of the cells (cAMP and cGMP) play a
role in this process.
There are some ways of BAS appearance:
• Liberation (secretion) from cellular granules of neutrophiles, eosinophile,
basophiles and mast cells,
• New synthesis (as lymphokins in T-lymphocytes, interleukin-1 in monocytes) ,
• Formation from membrane phospholipids,
•Appearance after damage of cells (proteolytic enzymes are revealed from the
destructed tissues as catepsines and hyaluranidase; hystamine and heparin are
revealed from destructed thrombocytes and mast cells).
Below is a short reminding about cells, which produce BAS (studied in details in a
course of biochemistry).
Mast cells release histamin, heparin, serotonin, neutrophile and eosinophile
chemotaxic factor, enzymes, which are present in the cells in a ready form and are
released after their degranulation. Slow reactive substance (медленно реагирующая
субстанция) SRS, which is produced from membrane components during
6
degranulation, must be added. Histamine acts through the receptors which are
situated on the somatic cells sensitive to it. Here are two types of receptors – H1, and
H2. Stimulation of H1-receptors promotes contraction of smooth muscles, endothelial
cells and postcapillary part of microcirculation. Stimulation of H2-receptors causes an
opposite effect. Serotonin causes spasm of the vessels. Heparin possesses an
antitrombine and anticomplement activity, inhibits chemotaxis of phagocytes.
Proteolytic lysosomal enzymes are liberated from granules of neutrophiles.
Interferon is a class of proteins produced by leukocytes, fibroblasts and
lymphocytes in response to a viral infection. It inhibits the replication of both DNA-
and RNA-containing viruses. It performs this function itself or by another protein -
viral translation inhibitory protein, which blocks a translative function of viral-
dictated mRNA. In viral infection interferon appears even before B- or T-cell immune
responses can be identified.
An important group of BAS (of lipid origin) is formed from membrane
phospholipids after activation of enzyme (phospholipase A2), which releases
arachidone acid. It is a group of eicosanoides (metabolites of arachidone acid, the
products of its peroxide oxidation). There are two ways of arachidone acid
metabolism - cyclooxygenic and lipooxygenic. The first way (under influence of
cyclooxygenase) leads to formation of prostaglandins, to which tromboxans (from
thrombocytes) and prostacycline (from endotelium) refer. The second way (under
influence of lipooxygenase) leads to the formation of leukotriens, to which the slow
reactive substance (SRS) from mast cells refers. Leukotriens increase secretion of
mucous, stimulate chemotaxis of phagocytes.
Monocytes are the rich resource of BAS – esterase, protease, lisosome hydrolase,
collagenase, elastase, interferon, monokins, transferin, complement, growth factor,
thromboxan, prostaglandin E and other. Among them interleukin-1 (IL-1) is very
important. It is a hormone-like protein, which plays an important role in the
immunological reactivity. All cells, which are responsible for immunity, have
receptors for interleukin-1 and are sensitive to it. It effects B- and T-lymphocytes
functions by stimulating their division, synthesis of antibodies and formation of
lymphokines. IL-1 contributes to the development of a fever. Hepatocytes, fibroblasts,
myocytes and nervous cells serve as a target for IL-1 (fig.6).
_________________________________________________________________________________
Macrophage
Endotheliocyte of the liver → proteins
Hypothalamus cell → fever
T-lymphocyte → IL-2
B-lymphocyte → antibodies
Fibroblast → proliferation
Bone marrow → granulocytosis
Fig.6. Interleukin-1 and its effects (со с. 232 украинского учебника)

In a center of a figure is a macrophage, which after activation produces IL-1.
The letter influences its target-cells – bone marrow, liver,
hypothalamus, lymphocytes, fibroblasts
___________________________________________________________________________________
7
Activated T-lymphocytes produce a group of lymphokins (interleukins), which
govern the functions of others leukocytes. Interleukins, as mediators of cooperation,
involve all leukocytes in immune response. T-killers release perforine, which
destroys membrane of microbes or foreign cells.
Thrombocyte activating factor (TAF) is secreted by basophiles, lymphocytes,
thrombocytes and endothelial cells. TAF acts on target-cells через corresponding
receptors in such a way:
• Causes aggregation of thrombocytes and release of histamine and serotonin,
• Helps chemotaxis of phagocytes,
• Activates secretion of BAS from granules of eosinophiles and neutrophiles,
• Causes spasm of smooth muscles,
• Increases permeability of vessels.
BAS of Plasma Origin
This type of BAS consists in system of complement and proteolytic enzymes,

which are localized in the blood plasma in inactive form.
System of a complement consists in some protein components (they are determed
as C1, C2, C3, C4, C5, C6, C7, C8, C9), which are in the blood serum in an inactive
state. Activated complement has a lot of regulative and enzymal properties – a
property of esterase and protease, activates phagocytosis and various BAS, provides
bactericidity of the blood, destroys microbes by perforation of their membrane. This
system gets activated (as a cascade) after the beginning of immune reaction (by
antibodies and immune complexes) and takes participation in liquidation of infection.
Active complement destroys immune complex and thus finishes inactivation of an
antigen. Disorder of the complement system appears in acquired and inherited forms.
The blockade of synthesis of any component of a complement is possible in
pathology. A loss of blood bactericidity, depression of immunity and development of
serious diseases are the consequences.
Activated Hageman factor stimulates the blood coagulation, activates system of
complement and proteolytic blood enzymes.
Proteolytic blood enzymes are present in the blood in a form of plasminogen and
kallikreinogen. They are activated by other BAS (Hageman factor, complement),
microbes and immune complexes. Kallikrein (activated kallikreinogen) is a main
enzyme of kallikrein-kinin system. Kinins are formed from plasma blood protein
(kininogen which is a globulin).
Kallikrein-kinin system refers to the vasoactive substances (kinins) production
due to cascade of biochemical reactions, which begins with Hageman factor activation
(scheme 4). Bradykinin and kalidin refer to this system.
All mechanisms of BAS formation activate each other.
8
_______________________________________________________________________________
Scheme 4. Scheme of plasmatic kinins (со с. 238 украинского учебника)
Hageman factor
Tripsin
Kalikrein
Fibrinolisin
Activation of Activation of Activation of

coagulation prekalikrein fibrinolytic
system
Fibrin Fibrinolisin
Prekalikrein Kalikrein
Kininogen Kinin
(bradikinin)
Kininase
Activated
peptids
__________________________________________________________________________________
9
Control upon BAS Effects
Biochemical system of BAS formation is under control.

BAS disintegration is provided by enzymes with proper specificity - histaminase,
protease, arylsulfatase (enzyme for eicosanoid annihilation). Superoxidedismutase
and ceruloplasmin annihilate the active forms of oxygen.
BAS inhibition is provided by α2-macroglobulin of the blood (inhibitor of kinins
and proteolytic enzymes of lysosomes), antitrypsin, antithrombin (inhibitor of
complement), lipomodulin (inhibitor of eicosanoides, which inhibits phospholipase
A2). Histamine by activation of H2–receptors inhibits activity of T-lymphocytes and
secretion of lymphokins.
Stopping of BAS secretion is insured by cAMP (inhibits degranulation of mast
cells) and cortisole that suppresses activation of lysosomes.
Protection of the target-cells from BAS effect is realized by cortisole and
adrenaline.
A special role in regulation of BAS activity belongs to eosinophilic granulocytes,
which contain many substances of protection (histaminase, arylsulfatase).
Finally, it is necessary to mention that phagocytosis and BAS are functionally
connected with immunological reactivity (see next chapter). They stimulate and
regulate it. Immune antibodies react specifically with antigens but affectivity of
binding and destruction of antigens depends on activity of these systems. Pathology
of phagocytosis, system of complement and BAS may underlie the pathology of
immunity, diminishes an effect of immune response and resistance of organism to
infection.
10
CHAPTER 5
IMMUNOLOGICAL REACTIVITY AND ITS
PATHOLOGY
As to the term immunity, there is a wide and more narrow its interpretation. I.I.
Mechnikov interpreted it widely as an opposition of organism to infection,
independently of its primer or repeated development. По этой интерпретации this
opposition includes such non-specific mechanisms as barriers (including skin and
mucous membranes) and especially phagocytosis for which discovery Mechnikov
became a Nobel Price Winner. As to инфекционистов they нередко interpret immunity
more узко as a resistance to the repeated entrance of the same infection. Иммунными
называют людей переболевших заразной болезнью и невосприимчивых к повторному
заболеванию. Их использовали на эпидемиях чумы, холеры и для ухода за больными.
Modern immunology interprets immunological reactivity as exclusively specific
immune mechanisms, as a function of thymus, B- and T-lymphocytes, as a resistance
to any genetically foreign information but not only infectious. In this chapter the latter
conception of immunological reactivity is accepted.
A resistance to an infection is determined by some mechanisms. They are
Passive (biological barriers),
Active (phagocytosis, activity of the immune cells),
Nonspecific (barriers, phagocytosis, interferon and other BAS),
Specific (antibody formation and a cooperation of B- and T-lymphocytes).
For mastering the pathology of immunological reactivity it is necessary to
remember the following knowledge received from the disciplines studied earlier.
• Concept about an antigen as a genetically foreign information, which must be
rejected by immune system.
• Structure of immune system which consists of the central and peripheral organs.
Thymus and bone marrow are central ones. Peripheral organs are a spleen, lymph
nodes, tonsils. The movable elements of immune system are B- and T-lymphocytes.
Monocytes represent antigen to lymphocytes.
• Genesis of B- and T-lymphocytes (origination, maturation, differentiation) which
includes the following processes:
B- and T-lymphocytes are originated from the common steam-cells of
the bone marrow. Their father maturation and differentiation are different.
B-lymphocytes maturate in the bone marrow of adults.
T-lymphocytes maturate in the thymus and differentiate into some
subpopulations - T-helpers, T-suppressors, T-effectors (which after their
activation transform into T-killers), memory cells. Существуют natural killers
(NK), which use as receptors the antigens of major histocompatibility
complex.
• The difference between functions of B- and T-lymphocytes is the following –
1
B-lymphocytes provide humoral mechanisms of immunity. After
activation by antigen they gets transformed into plasmatic cells and
produce humoral factors of immune response (immunoglobulins). Ig freely
circulate in the liquids of organism (blood and intracellular liquids) and
can exude into mucous and secretes. They can be absorbed on some cells
(mast cells, epithelium, smooth muscles).
T-lymphocytes provide cellular mechanisms of immunity. They ruin
pathological cells by lymphokins and perforin (liquidate own mutant cells and
foreign cells), perform cooperation between all cells of immune system.
B-lymphocytes do not distinguish the proteins of own organism from
foreign ones (do not tolerant to own antigens).
T-lymphocytes distinguish the proteins of own organism from foreign
ones (are tolerant to own antigens).
• Variants of immunoglobulins are A, D, G, M, E (they are called immune
antibodies). Their peculiarities are the following - IgE and IgG enter tissues and may
be absorbed on the somatic cells, IgG and IgM have precipitate properties, IgA are of
a secretory type, IgD penetrate placenta.
• Immune response may be primary (after the first entrance of antigen; immune
system memorizes the results) and secondary. The latter is accomplished after
repeated entrance of the same antigen and proceeds more quickly and actively.
Modern definition of immunological reactivity is such –
Immunological reactivity is a complex of humoral and cellular reactions of
organism in response to antigen and specific to it.
So, the basic function of immunological reactivity is supervision upon antigen
composition of the organism and maintenance of its antigen homeostasis. B- and T-
lymphocytes (with the aid of other systems) accomplish this function.
Classification of Antigens
Antigens are the macromolecular agents, mainly of protein nature. They are
divided into infectious and noninfectious, natural and artificial, molecular and
cellular, complete and incomplete (haptenes).
Under natural conditions the antigens are microorganisms (bacterias, viruses,
fungi). Under pathological conditions another types of antigens play a role (artificial,
incomplete, non-protein which will be discussed in the chapter 6 while studying
allergy).
Analyzing mechanisms of immunity and disturbances of immune response it is
important to have in mind, that some antigens (like cocci and microbial toxins)
circulate in the blood, but another do not (viruses and fungi are located intracellularly).
MECHANISMS OF IMMUNE RESPONSE
Mechanisms of immune response depend on the type of antigen, dose, way of

entrance, whether or not antigen circulates in the blood or persists inside the cells.
Just these conditions determine a type of immune response (by humoral antibodies or
cellular mechanisms).
2
The first cells, which confront infection (antigen), are monocytes. Together with
capacity to phagocitize it, they implicate antigen (by mediator IL-1) to the specific
immunocompetent cells (B- and T-lymphocytes) (fig. 6).
Humoral Mechanisms
• Humoral mechanisms develop, if antigen is a microorganism or its toxins, which

circulate in the blood.
• Antibodies also circulate in the blood and liquids of organism (humoral antibodies).
• Humoral mechanisms are connected with the function of B-lymphocytes.
• B-lymphocytes react on antigen and get transformed (in spleen and lymph nodes)
into plasmocytes, which in some days produce immunoglobulins (A, D, G, M, E).
The latter enter into the blood and liquid medium and spread throughout organism
(IgE can fix on some cells including mast cells).
• After producing of humoral antibodies, an immune complex (antigen+antibody) is
formed. It is an initial stage of the antigen destruction. Immune complexes activate
complement, phagocytes, BAS, which accelerate antigen destruction involving the
whole organism into immune response and increasing body temperature.
• T-helpers and T-suppressors regulate these processes. Cells of immunological
memory remember this situation. An active natural immunity gets formed (organism
is immunized).
• If the same antigen (microbe) would enter again, the organism, which is immunized,
elaborate antibodies very quickly because the cells of immunological memory gets
quickly transformed into plasmatic cells and formation of antibodies begins.
Cellular Mechanisms
Cellular mechanisms of immunity are activated if the humoral ones are not
sufficient. Type of antigen plays a role.
• Antigens do not circulate in the blood.
• Humoral antibodies (immunoglobulins) are not formed.
• Cellular mechanisms of immunity develop
for elimination of own mutant cells,
in a case of intracellular localization of foreign antigen (virus,
mycobacterium of tuberculosis, pale spirocheta in lues, brucella, histoplasma
etc.),
as a response to incomplete antigen.
• Macrophages represent antigen to T-effectors, which gets transformed into T-killers.
• T-killers react with antigen directly. As the receptors, they have major
histocompatibility complex. Lymphocytes infiltrate the locus with antigen. T-killers
destruct the cells by cytolysis with the aid of lymphokines and perforine.
• Phagocytosis and BAS are involved into immune reactions.
• T-helpers and T-suppressors take part.
Regulation of the Immune Response
3
All variants of immune response are regulated. It means balance of stimulative and
inhibitory mechanisms. Actuality of it is connected with development of
immunological disorders which have disregulative origin (allergy).
Regulative mechanisms are laid both in immune system proper (autoregulation)
and out of it.
Some mechanisms are genetically determined and provided by products of major
histocompatibility complex.
An organism is capable to react to a large number of antigens due to mechanisms
providing mutation (in cells-precursors), variety of variable parts of
immunoglobulins and their potential polyvalency. A high reliability of immune
response is provided by simultaneous development of the cellular and humoral
immune reactions as well as by production of 100000 molecules of antibodies per one
molecule of antigen.
T-helpers assist B- and T-lymphocytes to react on antigens. Intolerant B-
lymphocytes can not react without help of tolerant T-lymphocytes. Suppressive
function of T-lymphocytes is a potent mechanism of внутрисистемной regulation of
immune reactions.
Though antibodies specifically react with antigens, an effectiveness of their
distraction depends from the systems which functionally connected with immune
system – phagocytosis, complement and BAS.
Formation and activity of BAS are regulated by biochemical mechanisms of their
inhibition and destruction as well as participation of blood cells (eosinophiles) and
endocrine system.
Participation of nervous and endocrine systems in realization of immune response
is proved by experiment and in clinic.
Ослабление of nervous system due to overstrain decreases significantly reactivity to
bacterial toxins, antigens and microbes. Shock of any origin inhibits reactivity to
infection. Narcosis ухудшает a course of strepto- and pneumococci sepsis in
experimental animal and it more often ended by death. Stress inhibits formation of
cytokins.
Hormones also participate in regulation of immune response. Thyroxin, adrenaline,
sexual and somatotropic hormone stimulate it. Increased secretion of ACTH from
pituitary gland increases resistance to infection. Adrenalectomia decreases resistance
to bacterial toxins. Extract of adrenal cortex stimulates antibody formation (supposed
due to aldosterone) but large doses of glucocorticoids inhibit formation of antibodies
and cytokins. Decrease of immunity in diabetes mellitus results in predisposition to
purulent infection and tuberculosis.
Types of Immunity
Immunity is divided into natural and artificial (created for the purpose of
prophylactics and treatment). In turn, each of them is subdivided into active and
passive.
Natural active immunity appears after an infectious disease.
Natural passive immunity appears by transmission of antibodies from mother to
baby with the mother’s milk and through placenta.
Artificial active immunity (active immunization) is created by injection of
vaccines, which contain the weakened or убитые microorganisms.
4
Artificial passive immunity (passive immunization) is created by injection of
immune serum, which contains the specific antibodies against a certain infection. An
immune serum is produced by injection of antigen (microbes) to an animal or people-
volunteers. Using an immune serum for prophylactics or treatment, a physician must
have in mind, that immune serum was prepared with the aid of the foreign (to the
patient) protein material and its repeated injection is dangerous (causes so-called
serum disease, see in chapter 6).
IMMUNOLOGICAL TOLERANCE
Immunological tolerance is an absence of an immune reaction to some antigens

while keeping reactivity to others.
Immunological tolerance differs from immunodepression (see below) by its
specificity.
Physiological immunological tolerance is an absence of immune reaction towards
proteins of own organism. Under pathological conditions immune system begins to
react with proteins of own organism (loss of physiological immunological tolerance
and autoimmune aggression are described in chapter 6 while studding allergy).
The organs, which are located beyond the specialized barriers (brain, eye and
labyrinth of ear), obtain an exclusive position in organism, because they are isolated
from immune system in embryo and later in postnatal existence. These organs avoid
infection if the barriers are normal. If barrier would be broken, these organs become
an object of autoimmune aggression because immune system «is not acquainted with
these organs” and thus is not tolerant to them.
Exclusive position in organism belongs to embryon. In spite of the fact that it is
half a foreign genetical information to pregnant woman, it is not rejected by immune
system.
Pathological immunological tolerance may be modeled in experiment by injection
of a large quantity of antigen and reproducing «immunological paralysis” (high-dose
immunological tolerance) or injection of antigen in embryo.
A kind of pathological immunological tolerance develops toward embryo-like
malignant cells (described in the chapter “ Neoplasia”).
For the purpose of successful transplantation of foreign organs the physicians
create artificial state of organism which is opposite to immunological reactivity – an
absence of immune response to foreign tissue. It is an artificial immunological
tolerance.
PATHOLOGY OF IMMUNOLOGICAL REACTIVITY
Disorders of immune system may be manifested as hypofunction and

hyperfunction. As to participation of the gene mechanisms, the pathology of
immunological reactivity is divided into acquired and hereditary inherited?
Classification of immunological reactivity pathology is represented in scheme 5.
5
__________________________________________________________________________________
Scheme 5. Forms of Immunological Reactivity (IR) Pathology
IMMUNOLOGICAL REACTIVITY (IR)
Decreased IR Increased IR
IMMUNODEPRESSION Loss of physiological
(hypofunction) (hyperfunction) immunological
tolerance
Immunodepression Allergy Autoimmune aggression

Immunodeficiency (autoallergy)
IMMUNODEPRESSION
Immunodepression is an acquired decrease of immunological reactivity.
Etiology
The causes of immunodepression are such etiological factors, which inhibit

multiplication and differentiation of lymphocytes or disturb their functional activity.
They are: ionizing radiation, mutagens, cytostatics, carcinogens, various toxins
(including large dose of medical drugs), infectious agents (virus AIDS), cytostatics.
Bad nutrition, avitaminosis play a role of conditions that promote immunodepression.
Emotional stress may depress immune response.
Pathogenesis
Analyzing pathogenesis of immunodepression the following arguments are

important to be taken into consideration:
• Immunocompetent tissue belongs to the tissues of mitotic type. Hence, it has a
high sensitivity to all factors, which disturb cell multiplication. Just this peculiarity
determines the development of various pathological processes in immune system due
to an effect of inhibitors of cell division, inhibitors of DNA synthesis.
• Somatic mutations in immune system eventuate in appearance of immunocytes
with deranged functional activity.
6
• An excessive synthesis of glucocorticoids (they suppress synthesis of protein and
multiplication of cells) decreases immune response (clinical examples – stress and the
side-effect of hormonal therapy with glucocorticoids).
• Autoimmune aggression against the cells of immune system and
immunoglobulins may happen.
• Pathology of systems, which are functionally connected with immune one
(phagocytosis, the system of complement), eventuates in immunodepression.
• Many diseases, accompanied by intoxication (nephritic and hepatic insufficiency,
neoplasia) and systemic disorders of metabolism (diabetes mellitus, avitaminoses)
have immunodepression as a complication.
• Aging is accompanied by reduction of immunological reactivity.
Manifestations
Immunodepression is always manifested by reduction of organism resistance to

infection. Saprophyte infection appears a problem. The best example of
immunodepression is a radiant disease.
Aquired Immune Deficiency Syndrome (AIDS) refers to acquired forms of
immunosuppression. It is a severe infectious disease. The lymphotropic RNA-
containing virus (human immunodeficiency virus HIV) is an etiological factor. This
virus strikes membrane of T-helpers and other cells (brain and spinal cord cells).
Virus destroys cells, being multiplied in them. A complete paralysis of all
mechanisms of immunological reactivity (both humoral and cellular) develops.
Clinical manifestations of AIDS are
• Lymphadenopathy,
• Weight loss,
• Recurrent fever,
• Activation of autoinfection (pneumonia, diarrhea),
• Pulmonary infiltrates,
• Neurological abnormalities with dementia in the late stages (lack of memory and
decreased interest to surroundings).
The social and hygienic factors for prevention of ADS are important.
IMMUNODEFICIENCY
Immunodeficiency is a genetically determined decrease of immunological

reactivity (immunopathy).
Immunodeficient diseases refer to hereditary ones. They are called primary
contrary to secondary disorders of immune system, which develop as a complication
of another diseases. Up to date about 20 forms of this pathology are investigated.
They are studied в курсе педиатрии. The carriers of genetic defects in immune system
are ill from early childhood.
Etiology. There is a close interrelationship between immune competence and
genotype. Cause of immunodeficiency is a mutation of genes, which are responsible
for formation of immunocytes and immune response. Physical, chemical and
biological mutagens are the etiological factors.
Pathogenesis and Clinical Manifestations
7
Genetic defect may concern any stage of formation and maturation of B- and T-
lymphocytes. In many cases immunopathy is underlined by enzymopathy.
Pathogenesis and the clinical manifestations of immunodeficiency depend on the type
of lymphocytes, whose function is disrupted predominantly. There are three forms of
immunodeficiency: B-lymphocytic, T-lymphocytic and combined type.
B-Lymphocytic Immunodeficiency
B-lymphocytic immunodeficiency could be underlined by genetically determined

disorder of the following processes:
• Formation and differentiation of B-lymphocytes,
• B-lymphocyte transformation into plasmatic cells,
• Immunoglobulin formation.
Lack of B-lymphocytes results in humoral type of immune reactions disorder.
Clinical manifestation is a low resistance to infection, mainly of purulent type.
Children are constantly sick with tonsillitis or pneumonia. Lack of IgA eventuates in
decreased protective ability of mucous membranes. Viral infections occur more rarely.
Clinical example is a hypogammaglobuliemia Брутона.
T-Lymphocytic Immunodeficiency
T-lymphocytic immunodeficiency could be underlined by genetically determined

disorder of
• Formation of the thymus in embryo,
• Differentiation and multiplication of T-lymphocytes.
Lack of T-lymphocytes results in disorder of
• Cellular type of immune reactions,
• Control over all immune reactions (disturbance of regulative and cooperative
functions of T-lymphocytes),
• Loss of physiological immunological tolerance to own proteins.
Clinical manifestation is a low resistance to the viral and fungus infections,
predisposition to allergy and autoimmune aggression. This type of immunodeficiency
predisposes to premature aging. The rejection of transplant is suppressed. Clinical
example is a Ди Dжорджи syndrome connected with hypoplasia of thymus in embryo.
Combined Type of Immunodeficiency
Majority of immunodeficiency is of a combined type. Insufficiency of T- and B-

lymphocytic immune reactions underlies this pathology. Thymus develops not
correctly. A quantity of lymphocytes and gammaglobulins is reduced (lymphopenia,
hypogammaglobulinemia). Immunological reactivity is significantly reduced and
qualitatively changed.
Clinical manifestations are severe. Limitation of all mechanisms of immunity takes
place. Even the vaccines, which are used for immunization, may provoke a disease
and death. Predisposition to allergy and neoplasia is observed. Clinical examples -
syndrome Вискотта-Олдриджа and швейцарский тип of immunodeficiency.
8
DISORDER OF THE SYSTEMS, WHICH ARE FUNCTIONALLY
CONNECTED WITH IMMUNE SYSTEM
Phagocytosis, BAS, complement functionally connected with immune system.

Their disorders essentially decreases effectiveness of the immune reactions and, first
of all, resistance to infections.
Disorders of phagocytosis was analyzed in every details in chapter 4. It is
supposed that phagocytosis is the main mechanism of opposition to saprophytic
infections. So, all the reasons which decrease an amount of leukocytes (ionizing
radiation, inhibitors of the cell division etc.) or disturb their functions (genetic reasons,
neoplastic transformation in leukemia, intoxication, hormonal disorders, avitaminosis)
results in disorder of immunological reactivity.
All the BAS, which were mentioned and analyzed in chapter 4, influence an
activity of immunocytes, their division and maturation. In turn, immunocytes
perform their functions with the aid of BAS (monokins, lymphokins and others). So,
the genetical and acquired problems in BAS system essentially disorder
immunological reactivity.
A special role in immunological reactivity belongs to the system of a complement
which gets activated by antibodies and immune complexes. Active complement
possesses a lot of regulative and enzymal properties. It has a property of esterase and
protease, provides the blood bactericidity, ruins the microbial membrane, finishes
завершает liquidation of antigen by proteolysis of immune complex, activation of
phagocytosis and another BAS. Some grave clinical situations (genetic and acquired)
are described when a synthesis of one or another component of the complement
(deficit of the C1, C2, C3, C5, C6, C7, C8) is deranged. It leads to the serious clinical
derangements – predisposition to microbial and viral infections, development of
diffuse diseases of connective tissue (colagenose), autoimmune diseases (chronic
glomerulonephritis, autoimmune damage of the joints), repeated infections of the
respiratory system. Most of them are manifested in early childhood. It is a common
reason of early death.
Not only decrease but pathological increase of complement activity may cause a
disease. Deficit of complement inhibitors underlies it. An example - the angioneurotic
Kvink,s edema due to genetic deficit of C1 inhibitor which lead to pathological
activation of the complement system.
In present chapter a hypofunction of immune system was discussed.

Hyperfunction and loss of immunological tolerance (autoimmune aggression) is
discussed in the chapter 6 «Allergy».
9
10
CHAPTER 6
ALLERGY
Immunodepression and immunodeficiencd, as examples of a decreased immunological reactivitd, were

discussed in chapter 5. Allergd is an example of increased immunological reactivitd.
Allergic diseases are an actual problem of medicine. Thed are widespread among people, and the
reasons, which promote expansion of allergd in population, exist.
Allergy is a disorder of immunological reactivity in form of increased and qualitatively changed
immune resionse, which damages organism by immune mechanisms.
A question arises, whd in some cases immune reactions result in health and immunitd (immunization)
but in other cases the same immune reactions result in pathologd in form of allergd (sensitization, or
allergization) and even death. Whd does allergd continue to expand in population?
COMPARISON OF IMMUNITY AND ALLERGY
IMMUNITY
Cellular immunological reactions are created in evolution for elimination of own mutant somatic cells,
which are changed in their genome. It is a function of T-ldmphocdtes.
Humoral and cellular immunological mechanisms are created in evolution as a response to antigens of
natural origin. Onld microorganisms, as foreign protein, enter organism under normal conditions. An
important fact is such that an antigen enters into organism not in massive but small dose (as while
popping). Consequentld, an amount of BAS is small, and natural sdstem of BAS control is sufficient for
BAS regulation. A reliable control of immune response is created in evolution. As a result, an infection is
liquidated and active immunitd is created (immunization).
Under normal conditions immune sdstem is tolerant to proteins of own organism (phdsiological
immunological tolerance).
ALLERGY
The same immunological reactions (humoral and cellular) underlie allergd, but causes, conditions and
final effect are entireld others.
There are two principal variants of allergd development:
• In initialld healthd organism,
• In organism with pathologd of immune sdstem.
Allergy in Initially Healthy Organism
A cause of this tdpe of allergd is located outside of organism and is determined bd peculiarities of
antigen (its origin, dose, frequencd and interval of entrance).
In our time an enormous quantitd of proteins of unnatural origin mad enter organism in form of
foreign serum, vaccines, transplants and medicines, which correspond to the concept of antigen. Immune
response develops, but it is quantitativeld and qualitativeld perverted and damages organism. It is proved
1
in experiment, when foreign serum is injected parenteralld to healthd animal twice (with the two-week
interval).
Dose of antigen plads a role. It is alwads large. Even natural antigen (infectious) but injected in a large
dose, models an allergd in a healthd experimental animal. Formation of immune complexes would be
excessive, overloads immune sdstem and results in excessive BAS formation (above potentialitd of their
inactivation).
Thus, this form of allergd is not a problem of organism but a problem of environment.
Allergy in Organism with Pathology of Immune System
A cause of this tdpe of allergd is located inside of organism. The causes mad be acquired or geneticalld
determined. The latter (immunopathd) are more often. In such cases we speak about predisposition to
allergd.
Role of Genetic Factors in Allergy
Role of genetic factors in development of allergd is confirmed statisticalld.

Structure and properties of immunocdtes are geneticalld determined as well as a sdstem of BAS control.
More often hereditard predisposition to allergd is determined poldgeneticalld.
The following reasons and mechanisms are possible.
• The most often reason of allergd is T-ldmphocdtic or combined immunodeficiencd. In deficit of T-
suppressive mechanisms, a function of ldmphocdtes becomes unregulated and excessive. This deficit
mad lead to the loss of phdsiological immunological tolerance and autoallergd development.
• Predisposition to IgE formation (which are cdtophilic and are fixed on the mast cells) mad be
geneticalld determined. Healthd organism has a mechanism, which inhibits IgE sdnthesis. This balance is
geneticalld determined and mad be disarranged. Deficit of T-suppressors and increased titer of IgE is noted
in majoritd of allergic diseases.
• Deficiencd of BAS inhibitors, which regulates pathochemical events in allergd, mad be geneticalld
determined.
• Deficiencd or excessive activitd of complement underlie mand forms of allergic diseases.
• Disorder of barrier function of respiratord and gastrointestinal tract mucous membranes mad be
geneticalld determined and provides entrance of foreign proteins (allergens) inside.
• All chromosomal sdndromes are associated with serious disturbances of immunological reactivitd.
• Diatheses are examples of inheritant immunological pathologd.
Acquired Reasons of Allergy
Besides reasons of genetic nature, acquired pathologd of immune sdstem leads to allergd. The
following causes mad take place.
• Experimental thdmectomia provokes allergd development.
• Chronic infection mad induce an excessive mass of infectious antigens. Depressed resistance to
infection mad lead to sensitization of organism instead of immunization.
• Somatic mutation in immune sdstem is possible, and then immunocdtes mad percept own proteins as
foreign antigens or loose an abilitd to govern immune reactions.
• Neoplasia in immunocompetent tissue, as it is in leukemia, mad deprave malignant immunocdtes a
control over immune mechanisms.
• Hormonal insufficiencd (deficit of glucocorticoids and corticotropin) mad pervert immune response
into aggressive form.
• Gldcolization of IgE-binding factor (in diabetes mellitus) leads to accumulation of IgE and
predisposes to allergd.
2
• Acquired pathologd of gastrointestinal mucous membrane allows an entrance of foreign proteins
(milk, egg, fish) into the blood without preliminard proteoldsis The same situation is possible due to
impairment of respiratord tract mucous barrier.
Comparative analdsis of immunitd and allergd, which is above, helps to understand the reasons of
allergd expansion in population. Thed are
• Appearance of new allergens in surroundings
• Increasing quantitd of patients with genetic pathologd.
It is possible to confirm that allergd is a disease of civilization.
ETIOLOGY
Etiological factors of allergd are antigens (thed receive additional name allergens), that lead to
sensitization (allergization) instead of immunization.
Classification of Allergens
Allergens are divided into exogenous and endogenous (autoallergens).

Exogenous allergens come into organism from outside while endoallergens are formed inside
organism. There are several classifications of allergens in accordance with chemical structure, origin,
source, wad of entrd and biological organization (molecular or cellular). The classification is represented in
the scheme 6.
Exogenous Allergens
Exogenous allergens are divided into infectious and noninfectious ones. Infectious antigens (bacterial,
fungous, viral) behave as allergens onld in organism with pathologd of immunological reactivitd.
More often allergens are noninfectious ones.
According to chemical structure thed are of protein nature (foreign serum, transplant) and nonprotein
but similar to the true antigens (macromolecular poldsaccharides and lipopoldsaccharides).
Concept of incomplete antigens (haptens) helps to understand whd allergd develops under effect of
simple chemical substances (bromium, jodum, chromium, nickel) and medicines. After binding with
proteins of organism, thed form a complex antigen and induce antibodd formation.
As to a source, the allergens are divided into everyday (domestic dust, cosmetics, sdnthetic cloth,
washing means, the decad products of cotton), industrial (rubber, glue, plastic, metals and their salt, latex,
cellulose, wood products), vegetable (pollen and essential oils), epidermal products (scurf, wool, birds, fur,
fish, scales). Food is a widespread source of allergens (fish, milk, egg, wheat, beans, tomatoes, citrus fruits
and chemical substances added to food products, as dde-stuffs, antioxidants, aromatic and other
substances). Medical drugs mad become allergens (antibiotics, vitamins, sulfonamides, enzdmes). The
widespread allergens are the fungi. Mand nonpathogenic fungi while entering organism mad cause
sensitization and allergic diseases (bronchial asthma). Such fungi are contained in atmospheric air,
dwellings, domestic dust and food products. As to the way of entry the allergens are divided into inhaled,
injected, enteral, epidermal.
3
Scheme 6. Classification of the allergens (ЀЀ Ѐ. 156 ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ)
Allergens
Exogenous Endogenous
Bacterias Vegetable Natural Aquired
Fungi Brain Non-infectious Infectious

Medical
Food Crdstalline
Viruses lens
Cold antigen Simple Complex
Tissue+microbe
Domestic Sex glands
Burn Tissue+toxin
Simple Thdreoid
chemical gland Radiation
substances
Endogenous Allergens
Endogenous allergens are the own proteins of organism, which

• Have changed antigen structure under effect of injuring factors;
• Located bedond the damaged specialized biological barriers (brain, ede, labdrinth of ear);
• Belong to sick organism, which has lost the phdsiological immunological tolerance.
Both exogenous and endogenous allergens are divided into molecular or cellular.
Phdsical factors of environment (cold, heat, ionizing irradiation) which are not antigens themselves,
mad initiate allergd bd inducing the antigens formation from molecules of organism (bd disclosure of
hidden antigen determinants or formation of new ones as a result of denaturation of protein molecules).
PATHOGENESIS
Commonld used classification of allergd is based on pathogenesis.

TYPES OF ALLERGY
Allergd is divided into immediate and delayed tdpe depending on rate of development (several minutes
in the first case and several dads in the second). In turn, thed are subdivided depending on pathogenesis.
Thus, five tdpes of allergd are distinguished.
Immidiate tdpe of allergd is subdivided into:
1. Anaphylactic
2. Cytotoxic
4
3. Immunocomplex ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ.
Immediate tdpe of allergd is underlined bd humoral tdpe of immunological reactions. Antigen (allergen)
circulates in the blood. The main role in pathogenesis belongs to B-ldmphocdtes. Humoral antibodies are
formed.
4. Reactions of delayed hypersensitivity are accomplished when the cells serve as antigens (transplant
or damaged own cells). Humoral antibodies are not formed. The main role in pathogenesis belongs to T-
killers (clinical example – rejection of transplant).
5. Stimulating type reactions is considered to be a separate tdpe of allergd though mechanisms are
humoral (cdtotoxic tdpe). Antibodies react with those receptors on the cells, which are intended for
hormone and stimulate them. Thus, some forms of hdper- and hdpofunction of thdroid gland are
connected with this mechanism. It goes about receptors to thdrotropic hormone (TTH of pituitard gland)
located on thrdrocdtes. Antibodies to these receptors (anti-TTH-receptor antibodies) ЀЀЀЀЀЀЀЀЀЀЀ with
TTH ЀЀ ЀЀЀЀЀЀЀЀЀЀ with receptors, ЀЀЀ ЀЀЀЀ ЀЀЀЀЀ of antibodies with receptors ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀЀЀ
then ЀЀЀЀЀ with ЀЀH. An affect depends on titer of antigbodies. Small dose mad stimulate a function of a
gland (hdperfunction, or Basedov disease). An excessive amount of antibodies against these receptors
mad cause their blockade and hdpothdreosis (ЀЀ ЀЀЀЀ of increased concentration of ЀЀH and
hdpothalamic liberins). Such immunopathies are disregulative ЀЀЀЀЀЀЀЀЀЀe diseases. Their amount verd
large. Thus, autoantibodies to insulin receptors underlie some forms of insulinoresistant diabetes mellitus.
Some forms of megaloblastic anemia with atrophic gastritis has the same nature (autoantibodies to
ЀЀЀЀЀЀЀЀЀЀЀ receptors and ЀЀЀЀЀЀЀЀЀЀЀ pump of ЀЀЀЀЀЀЀЀЀЀЀ cells of the stomach). Antibodies to
dophamine receptors mad cause ЀЀЀЀЀЀЀЀЀЀ if thed are of stimulative character and ЀЀЀЀЀЀЀЀЀЀЀЀ – if thed
are blocking. Antibodies against adrenoreceptors are discovered also.
Mand allergic diseases are combined as to mechanism of development.
When antigen is of endogenous origin (autoantigens, autoallergens) we speak about autoallergy
(autoimmune aggression).
In addition, allergd (sensibilization) are divided into active and passive ones.
Active sensibilization develops in experiment after injection of antigen into organism. Antibodies
and immune ldmphocdtes are formed inside.
Passive sensibilization develops in experiment after injection of immune antibodies or sensibilized
ldmphocdtes (injection of blood plasma or ldmphoid cells of an activeld sensitized donor into an intact
recipient).
STAGES OF ALLERGY
All allergic reactions have the common pathogenetic mechanisms and proceed in three stages.
1. Immunological stage (sensibilization formation) starts at the moment of the first entrd of allergen
into organism. It embraces formation of antibodies or sensitized ldmphocdtes and is finished bd
formation of immune complexes after repeated entrd of allergen.
2. Pathochemical stage consists of BAS formation.
3. Pathoihysiological stage appears as morphological and functional disturbances, which underlie
clinical manifestations.
Various tdpes of allergd have special features of pathogenesis.
IMMEDIATE TYPE OF ALLERGY
Anaihylactic Tyie
It is convenient to analdze the ddnamics of anaphdlactic tdpe of allergd using, as illustration, the
experimental parenteral injection of a heteroserum to healthd animal (twice with the two-week interval).
Immunological Stage
5
Immunological stage begins after the first penetration of an allergen into the organism and covers all the
changes in immune sdstem. B-ldmphocdtes get transformed into the cells of immunological memord and
plasmocdtes which produce antibodies (in some dads, predominantld in form of IgE). IgE has an abilitd
to be fixed on membrane of tissue basophils (mast cells), granules of which contain a large quantitd of
BAS. From this moment the organism is sensitized. If the same antigen would be introduced repeatedld
(not earlier then in two weeks), immune complexes (antigen+antibodd) are formed on the mast cell
membrane and immediateld leads to degranulation. A large quantitd of BAS is reviled. This event starts
the next stage of allergd.
Pathochemical Stage
Pathochemical stage embraces BAS formation after degranulation of the mast cells. This stage differs
from that in immune response bd
• Large quantitd of BAS which are formed;
• Involving, as a cascade, of all sdstems of BAS formation;
• Insufficiencd of control over formation and destruction of BAS.
Histamine, heparin, serotonin are liberated from the granules of the mast cells and stimulate the
formation of eicosanoides (prostoglandins, leukotrienes, the so-called slowld reacting substance SRS) from
membrane lipids. Then, as a cascade, all sdstems of BAS formation are activated - kallikrein-kinin blood
sdstem (formation of braddkinin and another BAS), the proteoldtic blood enzdmes (trdpsinogen,
profibrinolizin) and complement (scheme 7).
Scheme 7. Formation of the BAS in allergy (ЀЀ Ѐ. 165 ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ)

T-ldmphocdtes+antigen – limphokins
Hageman factor activtion, blood proteoldtic ferments activtion, trdpsin, kalikrein, fibrinolisin, kalidinogen, bradikininogen,
α2-globulin of the blood, bradikinin, kalidin
Complex antigen+antibodd
Complement activation, ldsis of cells and release of intracellular components
Increase of the blood acetilcholin content, phagocdtosis activation and lisosome factors,
Basophilic granulocdtes, thrombocdtes, basophiles degranulation,
Histamine, serotonin, heparin
POL
Lipoxdgenase, cicloxdgenase,
Leukotriens, SRS, prostaglandins, thromboxans
______________________________________________________________________________
Phdsiological sdstem of inhibition and destruction of BAS occurs not proper for such situation. BAS
involve entire organism and initiate the next stage of allergd.
Pathophysiological Stage
Pathophdsiological stage is manifested bd local and general (sdstemic) changes. Vasodilatation, local
reddening, skin eruption, itch, burning, pain, edema (as a result of increased permeabilitd of the vessels)
are the local manifestations, which are an acute inflammation.
The general manifestations of allergd are more dangerous. Spasms of smooth muscles of internal organs
are clinicalld manifested bd bronchospasm (cough, expiratord breathlessness), spasm of gastrointestinal
tract muscles (spastic pain in abdomen, nausea, vomiting, diarrhea), spasm of uterus in women. Spastic
phenomena are aggravated bd edema of mucous, which covers internal organs. Edema of lardnx is
6
manifested as asphdxia. The disorder of hemostasis embraces a simultaneous activation of coagulation,
anticoagulation and fibrinoldsis. Clinicalld it is manifested bd hdpocoagulation in aorta and large arteries,
but hdpercoagulation (thrombosis) in capillaries. Decrease of arterial blood pressure, loss of consciousness
are the gravest manifestations of allergd. It is a shock, which is called anaphdlactic.
Serum Disease
Serum disease is a clinical example of anaphdlactic tdpe of allergd. This disease happens when an
immune serum (containing antibodies against a certain infectious agent) is used for passive immunization
of patient. Together with a therapeutic or preventive effect, this serum in turn sensitizes a patient, and the
repeated injection of the same serum is verd dangerous.
Cytotoxic Tyie
Cdtotoxic tdpe reactions relate to immediate tdpe of allergd. Thed are called cdtotoxic because
antibodies cause damage of cells and their ldsis.
Immunological Stage. Antibodies (thed belong to IgG and IgM and are called cdtotoxic) are formed
against the cells – foreign or own (if thed acquire autoallergen properties). Pathogenic effect of chemical
substances (usualld medicines), viruses and microbes plads a role. These etiological factors mad change an
antigen structure of cell membranes.
Pathochemical stage embraces BAS activation. The main mediators of cdtotoxicitd are complement
and activated enzdmes. BAS activate phagocdtosis and N-killers.
Pathophysiological Stage. Ldsis of the cells is provided bd activated complement and N-killers
together with phagocdtosis of the cells covered with antibodies.
Clinical Manifestations. As a clinical example, a hemoldsis of erdthrocdtes of donor after mismatched
hemotransfusion (including rezus-conflict as a result of rhesus incompatibilitd of mother and fetus) mad be
proposed. The erdthrocdtes undergo immediate cdtoldsis. Another example relates to the autoimmune
aggression against the blood cells of own organism (erdthrocdtes, leukocdtes or thrombocdtes) if their
antigen properties would be changed after damage bd microbes or medicines (hemoldtic anemia,
leukopenia and thrombocdtopenia). Cdtotoxic immune serums are wideld used in experiment for selective
damage of the certain cells and modeling the proper pathologd.
Immunocomilex Tyie
Immunocomplex diseases develop, if immune complexes form nondissolved microprecipitates.

Immunological Stage. Mand dissolved allergens (exogenous and endogenous, true and incomplete)
after binding with antibodies, form nondissolved immune complexes, as a microprecipitates. Among them
there are medical drugs (penicillin, sulfanilamides), vaccines, allogen γ-globulin, food products (milk,
eggs), inhaled allergens (domestic dust, fungi). In such cases IgG and IgM (with precipitate properties) are
produced. Immune complexes form microprecipitates in the tissues or in the blood and fix Ѐn the basal
membranes.
Patochemical Stage. Under effect of immune complexes the following mediators are formed -
complement, ldsosomal factors of leukocdtes, kinines, products of POL (superoxdde radicals).
Pathophysiological Stage. Immune complexes, usualld, are fixed on the basal membranes of the
vessels. Microcirculation gets damaged bd BAS. An inflammation with alteration, exudation and
proliferation develops. Phagocdtosis is activated. Leukocdtic infiltration results in allergic productive
inflammation. Thrombosis occurs in the vessels. Inflammation mad lead to ulceration and hemorrhages.
Clinical Manifestations. Clinical manifestations depend on the place of immune complex fixation and a
kind of a damaged tissue. If thed are fixed in the vessels, hemorrhagic vasculitis develops. In the case of
their localization in the kidneds, glomerulonephritis develops. Allergic dermatitis is an example of
7
immunocomplex allergd in skin. If microprecipitates are placed in the lungs, alveolitis appears. Some
autoallergic diseases (rheumatoid arthritis, sdstemic red lupus erdthematosus) as well as «domestic” and
“food” allergd are of this tdpe. In a case of massive activation of complement anaphdlactic shock,
bronchial asthma mad develop.
DELAYED TYPE OF ALLERGY
Deladed tdpe of allergd develops in response to the antigens, which are the cells (foreign transplant or
own cells, which is damaged). These reactions are realized not bd humoral antibodies, but bd the cellular
immune reactions.
Reaction of a Transilant Rejection
Reaction of a transplant rejection is an example of deladed tdpe of allergd.

Immunological stage starts bd recognition of a foreign cellular antigen bd the T-ldmphocdtes which
receptors include the antigens of major histocompatibilitd complex. After activation bd antigen, T-
effectors get transformed into T-killers, which have IgM as the receptors. Then the ldmphoid infiltration
and a direct contact of ldmphocdtes with the foreign cells take place. T-killers realize cdtotoxic effect on
them.
Pathochemical stage consists in liberation of BAS from activated T-ldmphocdtes - ldmphokines and
perforine. Thed involve the entire organism into immune response, activate all subpopulations of
ldmphocdtes, micro- and macrophages and initiate the pathophdsiological stage.
Pathophysiological stage embraces accumulation of macrophages, granulocdtes and ldmphocdtes
around the foreign tissue, its infiltration, derangement of vessel permeabilitd, development of edema,
inflammation and destruction of transplant.
Contact Dermatitis
Contact dermatitis also belongs to the deladed tdpe of allergd. It is a result of derma damage after
contact with everddad, industrial, medicines and other substances, which plad a role of hapten and form the
complex antigens with proteins of derma. Macrophages represent (bd IL-1) the damaged cells to T-
helpers, which involve T-killers into damage of the skin.
AUTOALLERGY
Autoallergy is a damage of own iroteins or cells by immune mechanisms (autoimmune

aggression).
Autoimmunization mad be provided bd various immune mechanisms and relates both to immediate and
deladed tdpes of allergd.
Etiology
Everd protein, cell and tissue of organism mad serve as antigens (autoantigens, autoallergens) and mad
become an object of autoimmune aggression.
Pathogenesis
There are several pathogenic mechanisms of autoimmunization.

• Loss of phdsiological immunological tolerance (underlies autoimmunization in majoritd of cases). In
turn, this pathologd mad be geneticalld determined (immunodeficiencd) and acquired. Deficit of T-
8
suppressors underlies the situation, when intolerant B-ldmphocdtes produce antibodies against own
proteins.
• Antigene similaritd between exogenous (microbial) and endogenous (own) antigens.
• Inabilitd of pathlogicalld changed immune sdstem to distinguish the foreign antigens from antigens of
organism, which mad be similar but nevertheless different. As a consequence, production of
autoantibodies against proper proteins and cells mad be initiated.
• Immunodeficiencd (deficit of T-suppressors), genetic predisposition to IgE sdnthesis contribute to
development of autoallergd.
• Somatic mutations in the immunocompetent tissue mad underlie an acquired tdpe of autoallergd. The
mutant immunocdtes mad accept normal tissues as antigens.
• Medical drugs mad plad a role of haptens and form the complex antigens with own proteins.
Autoantibodies belong to IgG and IgM and damage the cells bd cdtoldsis. T-killers are involved into the
damage of the cells. The factors of phdsical nature (cold, high temperature while the burns, ionizing
radiation) are capable to change an antigen structure of own cells bd a disclosure of hidden and formation
of new antigenic determinants. Activated complement, enzdmes of phagocdtes and POL products are the
main mediators.
• Damage of the specialized biological barriers creates a situation, when the tissues, which are located
bedond, become an object of autoimmune aggression.
Manifestations
Autoimmune diseases are manifested depending on protein or the cells damaged bd immune aggression.
An inflammation of own tissues develops under an effect of BAS.
Autoimmune aggression mad concern and tissue, but most of all the connective tissue (joints, basal
membranes and blood cells). As clinical examples, rheumatoid arthritis, allergic vasculitis,
glomerulonephritis and autoimmune version of hemoldtic anemia, leukopenia and thrombocdtopenia must
be noted. Immunocompetent tissue (T-ldmphocdtes, immunoglobulins, ldmph nodes and bone marrow)
mad be an object of autoimmune aggression as well. Formation of antibodies against gammaglobulin in
patients with rheumatoid arthritis mad be mentioned as an example. Autoimmune thdroiditis is an example
of such pathologd. Cardiopathd in Basedov disease is caused bd anti-cardiac autoantibodies. Diabetes
mellitus of the first tdpe refers to autoimmune diseases.
A large group of demdelinating nervous diseases are autoimmune (disseminated [multiple] sclerosis among
them). In postvaccinal and poptinfectioup encephalomdelitis the immunoglobulin, cellular and immunocomplex
autoimmune responses against antigenes of CNS (particulard mdelin) detected. It gets provoked bd viral and
bacterial infections in predisposed (to allergd) patients.
Pathogenesis of mand autoimmunopathies is underlied bd damage of receptors (receptor diseases were
noted above - some forms of hdper- and hdpofunction of thdroid gland, insulinoresistant diabetes
mellitus, megaloblastic anemia and oth.).
More often an autoimmune pathologd is observed in women, because the genes, which control the
formation of immunocompetent tissue, are located in X-chromosome. Since women have two X-
chromosomes, a mutation of these genes appears more often in women than in men.
INFECTIOUS-ALLERGIC DISEASES
Infectious-allergic diseases are such, when initial factor is an infection but iathogenesis includes
immune mechanisms in iatients with allergic iredisiosition.
Etiology
9
Exogenous etiological factors are such microbes which have similar antigene determinants with those
of people. There are a lot of such examples (some microbes and connective tissue, streptococcus and
sarcolemma of cardiomdocdtes, albumins of ЀЀЀЀЀЀЀЀЀ milk and insulin and oth.). Due to parallel evolution,
mand microbes obtained molecular similaritd with molecules of macroorganisms.
More often this situation occurs if hemoldtic streptococcus is an etiological factor. His poldsaccharide
antigens are similar to glicoproteids of connective tissue, cardiac valves, basal membranes (of nephrone).
Viruses mad cause allergd as well. Fungi, which are present in inhaled air, everddad dust and food, are the
widespread allergens. Vaccine (killed or weaken microorganisms) mad also be an initial factor.
Pathogenesis
In experiment it is possible to sensitize organism bd infectious antigen introduced in a large dose which
overloads immune sdstem. Similar situation mad arise in patients with chronic infection when excessive
infectious antigen sensitize organism.
Infectious-allergic diseases refer to autoallergd. Immunodeficiencd, genetic predisposition to IgE
sdnthesis and a hdpofunction of adrenal cortex predispose to development of this kind of diseases.
Pathologicalld changed immune sdstem not alwads mad ЀЀЀЀЀЀЀЀЀ antigens and targets for its action.
There is a ЀЀЀЀЀЀЀ of antigene ЀЀЀЀЀЀЀЀЀЀ and heteroallergd, when antigens elaborated against one
antigen (ЀЀЀЀ ЀЀЀЀЀЀЀЀ ЀЀЀ ЀЀ ЀЀЀЀЀЀЀЀ) react with another but similar antigen (own). It determines
autoreactive effect of antibodies produced for foreign antigens, activation of autoreactive ldmphocdtes,
stimulates response of B-ldmphocdtes against autoantigens, provokes production of rheumatoid factors.
ЀЀЀЀЀЀЀcЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀ reactions mad increase concentration of autoantigene up to the level which allows
activation of T-helpers and their affinitd with ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ cells.
Viruses mad provoke cellular autoimmune response against antigens of CNS in predisposed people.
In ЀЀЀЀЀ-ЀЀЀЀЀЀЀЀЀЀЀЀЀЀ autoimmunopathd autoimmune response mad be directed against genome of the
cells contacting with virus. Autoantibodies against antiviral immunoglobulins mad determine their
autoЀЀЀЀЀЀЀЀЀЀЀЀЀЀ.
In short, antigene similaritd between microbes and own tissue mad lead to
• Diminished immune response to infection
• Transition of infection into chronic form
• «Mistake of recognition” of antigene bd immune sdstem
• Initiation of autoimmune reactions against own tissues
• Acute and chronic allergic inflammation as a result.
Manifestations
Such kind of allergic diseases appear as a complication of infectious ones. Clinical manifestations
depend on tdpe of tissue which gets damaged bd autoimmune aggression.
Rheumacarditis, rheumavasculitis and glomerulonephritis mad occur as a complication of purulent
tonsillitis and scarlet fever caused bd hemoldtic streptococcus. Autoimmune damage of nervous sdstem
(both central and peripheral) mad develop in predisposed to allergd patients as a complication of viral
infections and vaccination (ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀЀ).
PRINCIPLES OF PREVENTION AND TREATMENT OF ALLERGY DESENSITIZATION
The knowledge of etiologd and pathogenesis of allergd provides the base for its prevention and therapd.
Etiological therapy (prophylactics) is a prevention of potential allergen entrance into the organism.
Pathogenetic therapy is directed toward immunological or pathochemical mechanisms of allergd.
Injection of immunodepressants, adrenal cortex hormones (hddrocortisone, prednisolone) blocks antibodd
10
and BAS formation. The BAS inhibitors are used for the softening of pathochemical reactions
(antihistamin drugs).
If a disease appears infectious-allergic tdpe and is accompanied bd inflammation, together with
antibacterial drugs immunodepressants are used.
Desensitization (liquidation of sensitization) is divided into specific and nonspecific.
Specific desensitization is carried out with the aid of the same allergen, which caused sensitization. For
this purpose allergen is introduced in small frequent doses. The effect achieves bd formation of smaller
portions of immune complexes. Under these conditions the power of BAS inhibitors proves to be
sufficient for softening of pathochemical and pathophdsiological manifestations. In the case, when after a
prophdlactic injection of an immune serum the repeated injection of it is necessard, the serum might be
introduced bd fractional small doses.
Nonspecific desensitization is achieved bd medicines which minimize influence of BAS.
Symptomatic therapy consists in usage of medicines, which decrease such sdmptoms, as spasm, pain,
itch, edema.
PSEUDOALLERGY
There are mand diseases with clinical sdmptoms, which are similar to the allergic ones - reddening of
the skin, eruption, itch, popping, dispnoe and a state similar to anaphdlactic shock. But the immunological
mechanisms, which compose the essence of a true allergd, are absent.
The diseases mad be caused bd the following external factors - cosmetic and everddad substances,
washing means, industrial products (rubber, glue, plastic, wood), food (milk, egg, berrd, tomatoes, citrus
fruits), pollen and medicines.
Sometimes these situations are interpreted as allergd, but it is true onld in the cases, when
immunological events are detected - participation of T-ldmphocdtes, formation of antibodies, increased
level of IgE, decreased level of complement, possibilitd of specific desensitization. Actualld, these
substances mad behave as allergens (haptenes) with formation of a complex antigen with proteins of
organism. But in a cases, when immunological events are absent, it is not an allergd. Disease must be
interpreted as individual ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ of a substance (it is not a sdnondm of allergd). The term
pseudoallergy is suitable and mad be used.
Understanding of it has a value for treatment and prophdlactics of these diseases. No one of the
methods mentioned above are effective – neither immunodepression nor specific desensitization bd the
fractional repeated doses of the same substance. A single measure is an avoidance of this substance
entering and sdmptomatic therapd.
Pseudoallergd has the following mechanisms of pathogenesis.
• These substances mad damage tissues and activate the same BAS, which are formed in true allergd.
Thed are called the liberators of histamine (cause degranulation of mast cells). Clinical manifestations are
similar to allergic ones.
• If factors, which cause a disease, appear foodstuffs (more often thed are exotic products), the
enzdmopathd mad underlie the individual ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ.
• If medicines are the cause of a disease, it is necessard to take into consideration, that metabolism of
medicines is individual and geneticalld determined. The products of drug metabolism mad be a reason of
BAS formation.
• Some patients have such dermal mast cells, which are easild damaged bd the natural factors of
environment (solar rads, cold, friction of cloth). It is possible to see local sdmptoms, which are similar to
allergic inflammation.
11
TYPICAL PATHOLOGICAL PROCESSES
_____________________________________________________________
CHAPTER 7
PATHOPHYSIOLOGY OF PERIPHERAL BLOOD

CIRCULATION
Peripheral blood circulation (in arterioles, precapillaries, capillaries,

postcapillary venules and small veins, arterio-venous anastamoses) provides
balance of nutrient substrates, gases, metabolites, electrolytes and water in
the system "blood-tissue-blood".
The typical types of the local microcirculation disorders are arterial and
venous hyperemia, ischemia, stasis, thrombosis and embolism.
ARTERIAL HYPEREMIA
The term hyperemia means an increased volume of the blood in an

affected tissue or organ.
Arterial hyperemia is an active increase of organ or tissue blood
filling due to the excessive blood inflow by arterial vessels.
Active hyperemia occurs, when arterial dilatation produces an increased
inflow of the blood into capillary beds with opening of inactive capillaries.
Neurogenic mechanisms or vasoactive substances release brings to it.
Types
Arterial hyperemia is divided into physiological (working) and

pathological. In turn, pathological arterial hyperemia is divided into
neurogenic and metabolic. In turn, neurogenic arterial hyperemia is divided
into neurotonic and neuroparalytic.
Etiology
Etiological factors are physical (mechanical, heat, ultraviolet radiation),

chemical and biological (infectious, immune, emotional) which lead to the
dilation of arterial vessels.
Pathogenesis
1
There are two types of arterial hyperemia according to pathogenesis –
neurogenic (of neurotonic and neuroparalitic type) and caused by local
metabolic (chemical) factors.
Neurotonic arterial hyperemia develops due to activation of neurotonic
mechanisms. At first Claude Bernard reproduced it by stimulation of chorda
tympani (the branch of the facial nerve), containing parasympathetic
vasodilating fibers (fig.7).
__________________________________________________________________________
Fig. 7. Claude Bernard experiment

(in the right – a cervical node of the sympathetic trunk is resected) ЀЀ Ѐ. 199 ЀЀЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ
______________________________________________________________
In the vessels, which don’t have parasympathetic stimulation, hyperemia

is caused by sympathetic system (cholinergic, histaminergic and beta-
adrenergic mechanisms). Sympathetic cholinergic nerves dilate the small
arteries and arterioles of skeletal muscles, facial muscles, mucous membrane
of the cheeks, intestine. Acetylcholine is a mediator.
Neuroparalytic arterial hyperemia may be observed in clinic and
experiment on animals after cutting of the vasoconstrictive fibers and nerves
(sympathetic α-adrenergic ones). Norepinephrine is a mediator. Claude
Bernard observed hyperemia and hyperthermia of the skin on a rabbit's head
(ear) on the side of cutting the cervical node of the sympathetic trunk. Their
mediator is norepinephrine.
Metabolic arterial hyperemia is caused by biological active substances
(BAS) of a different origin (cellular and plasmatic). ATP, ADP, adenosine,
nonorganic ions, reduction of pO2 and increase of pCO2 in the blood and
tissues have the same effect. In some cases prostaglandins E and A, which
have a vasodilative effect upon arterioles, metarterioles, precapillaries and
venules, cause hyperemia.
Manifestations
Manifestations of artherial hyperemia are morphological (microscopical),

biochemical (metabolic), functional, and clinical. The hydrodynamic
pressure in arterioles, capillaries and veins is increased (fig. 8). Arterial
hyperemia is always accompanied with swelling (tumor), but never edema.
__________________________________________________________________________
2
Blood pressure in kPa
Arterial hyperemia
normal
Fig. 8. Blood pressure dynamics in different parts of the vascular bed in norm and in
arterial hyperemia (ЀЀ Ѐ. 197 ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ)
__________________________________________________________________________
The following visible clinical signs manifest arterial hyperemia:

• Redness of the affected part
• Enlargement of organ or tissue due to swelling (tumor)
• Increase of the tissue turgor
• Local hyperthermia
• Intensification of organ function.
Subjective unpleasant sensations are
• Pulsation
• Swelling
• Pain.
Microscopical picture is characterized by
• Dilatation of small arteries, arterioles, veins, capillaries
• Increased number of the ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ vessels
• Acceleration of the blood flow
• Opening of the inactive capillaries
• Division of blood flow into two parts – central flow of the blood cells
and peripheral flow of plasma.
Melabolism intensifies locally due to increased supply with oxygen and
substrates.
Significance
In the majority of cases arterial hyperemia is accompanied with

intensification of metabolism and organ’s function. However, unfavorable
outcome is also possible. Thus, dilation of sclerotic vessels can result in
rapture and hemorrhage. It is especially dangerous in the brain. Arterial
hyperemia is of a great significance in course of inflammation.
VENOUS HYPEREMIA (CONGESTION)
Venous hyperemia is an increase of organ or tissue blood filling due to

limitation of blood outflow by venous vessels.
Contrary to arterial hyperemia which is active, the venous hyperemia
3
(congestion or passive hyperemia) is a result of impaired venous drainage.
Etiology
Etiological factors of venous hyperemia are those, which narrow the

lumen or tonus of veins. They may be exogenous and endogenous. They are
• Obstruction of veins with a thrombus or an embolus
• Compression of veins by tumor, enlarged uterus, in the region of
inflammation by exudate
• Exudative pleuritis, hemothorax, pneumosclerosis, emphysema
• Cardiac left- or right-side ventricle failure
• Professional overloading (vertical position for a long time)
• Genetic predisposition to venous congestion (weakness of venous elastic
apparatus, low tonus of the smooth muscle elements of the vascular wall).
Pathogenesis
The disorders are caused by a local lack of oxygen (deoxygenation of

hemoglobin, tissue hypoxia) and substrates. It leads to the tissue
dismetabolism. As a result, atrophic and dystrophic changes develop.
Viscosity of the blood increases as well as permeability of capillaries.
Transudate is formed due to the high hydrostatic blood pressure. Congestion
in capillary bed is closely related to edema development. Therefore,
congestion and edema commonly occur together (venous edema).
Congestion leads to intravascular thrombosis.
Prolong venous congestion results in excessive growth of the connective
tissue, which substitute the parenchyma (so-called cirrhosis).
Manifestations
Manifestations of venous hyperemia are morphological (microscopical),

biochemical (metabolic), functional, clinical.
The following visible clinical signs manifest venous hyperemia:
• Enlargement of organ or tissue due to swelling (tumor)
• Cyanosis as a result of hypoxia and accumulation of deoxydated
hemoglobin
• Edema, due to high hydrostatic pressure and increasing permeability of
the vessel wall due to unoxygenated condition
• Local hypothermia
• Subjective unpleasant sensations are swelling and pain.
Microscopical picture is characterized by
• Dilatation of small arteries, arterioles, veins, capillaries
• Slowing of the blood flow due to increased viscosity of the blood
• Transudate formation
• Thrombosis
4
• Atrophic and dystrophic changes
• Excessive growth of the connective tissue
• Sclerosis.
Metabolic disorders in venous hyperemia develop as a result of tissue
hypoxia. Intermediate products of uncomplete oxygenation are
accumulated. Local metabolic acidosis develops.
Significance
In majority of the cases venous hyperemia has a negative value. It leads

to disorder of the tissue metabolism and cause atrophic and dystrophic
changes. The function of organ is disordered due to hypoxia, dystrophia,
cirrhosis.
However, during inflammation venous hyperemia is of a great
significance providing emigration of leukocytes (see in the chapter 8 “
Inflammation”).
ISCHEMIA
Ischemia is a decrease of organ or tissue blood filling due to the

limitation or complete stop of arterial blood inflow.
Types
Ischemia is divided into compressive, obstructive and angiospastic types.

Every type of ischemia has its own etiology and pathogenesis.
Compressive ischemia is a result of a mechanical influence on arteries
(tumor, foreign body, ligature, etc).
Obstructive ischemia is a result of narrowing of a vessel lumen by
thrombus, embolus or atherosclerotic process.
Angiospastic ischemia is a functional disorder. The essence of it is a
derangement of motor (vasoconstrictive) apparatus of the vessels.
Etiology
Various agents can cause ischemia. Angiospastic ischemia develops as a

result of stimulation of vasoconstrictor apparatus of vessels or their
ЀЀЀЀЀЀЀЀЀЀЀЀ spasm caused by
• Physical factors (cold, mechanical and another injury),
• Chemical agents,
• Biological factors (bacterial toxins),
• Emotional factors (fear, pain, rage) and pathologic reflex.
Duration and consequences of ischemia depend on such conditions,
which can modify an effect of etiological factors -
• Time of injuring effect,
5
• Type of ischemia,
• Localization,
• Condition of the collateral circulation,
• Functional state of organ or tissue.
Pathogenesis
Mechanism of an angiospastic ischemia depends on permeability of the

smooth muscle cells membranes for Na+, Ca2+, K+ and Cl- ions. Neurogenous
α-adrenergic, H-histaminergic, serotoninergic, dopaminergic mechanisms
play a role. Angiotensin II is one of the most potent vasoconstrictors. It
effects smooth muscle cells directly causing depolarization as a result of
increased Na+ permeability. When Na+ ions accumulate in the muscle fibers
of vessels, their sensitivity to vasoconstrictors (catecholamines, vasopressin
and angiotensin) increases.
Injury of endothelium results in losing of its ability to produce the
relaxative factors (NO). It leads to spastic reactions.
Angiospastic ischemia may have a conditioned reflex nature.
Ischemia leads to the oxygen deficiency (hypoxia).
Manifestations
Local visible manifestations of ischemia are

• Paleness of ischemic region
• Diminishing of organ's size
• Hypothermia
• Disorder of an organ or tissue function
Microscopical picture is
• Slowing down of the blood flow
• Dystrophic changes of tissue
• Necrosis (infarctus)
Ischemia produces certain subjective bad sensations. They are
• Pain (ischemic pain is very strong)
• Paresthesia (disorder of a sensibility, tingling)
• Failure of an organ function
The gravest outcome of ischemia is a necrosis (synonym is infarction). It
is usually caused by occlusion of a vessel.
Significance
Generally, angiospasm is a nonspecific short-term reaction of vessels on

different injuring factors. More prolonged ischemia has negative meaning.
Ischemia of brain and heart has severe clinical consequence. Skeletal
muscles and especially connective tissue are more resistant to ischemia due
to high anaerobic metabolism in them.
6
STASIS
Stasis is a slowing down or complete stop of the blood flow in

capillaries, small arteries and veins.
The following types of stasis are distinguished: true (capillary), ischemic
(total stop of blood inflow) and venous.
True Stasis
True stasis develops as a result of pathological changes in capillaries or

abnormality of reological qualities of the blood. In capillaries and small
veins the blood becomes still and homogenized. Erythrocytes swell and loose
most of their pigment. Together with the released hemoglobin, plasma
escapes from the vessel. In the focus of stasis the tissues show the signs of a
dystrophy.
Etiology
Etiological factors of true stasis are physical (cold, burn), chemical

(poisons, turpentine, mustard oil) and biological (microbial toxins).
Pathogenesis
The mechanism of a true stasis development is based on the intravascular

aggregation of erythrocytes (adherence) and formation of conglomerates,
which make the flow difficult. It also causes increasing of the peripheral
resistance.
Aggregation of erythrocytes occurs as a result of changing of the physical
properties of erythrocyte plasmolemma under direct effect of the factors,
entering the capillary. The surface of erythrocytes, which is smooth under
normal conditions, becomes ЀЀЀЀЀЀЀЀ 'fuzzy". Aggregation of erythrocytes
occurs as a result.
A significant role in pathogenesis of a true stasis belongs to a
hemoconcentration and increased permeability of capillary walls. Etiological
factor itself and metabolites, produced in tissues, promote it. A special
significance in genesis of stasis belongs to the biological active substances
(serotonin, bradykinin, histamine), local acidosis and a change in the blood
colloid state. It results in increasing of vessel permeability and dilatation of
vessels leading to hemocoagulation, slowing of the blood flow, aggregation
of erythrocytes and, consequently, to stasis. It is important to emphasize that
stasis alone does not induce thrombosis. Stasis of poorly oxygenated blood
causes chronic tissue hypoxia.
Significance
7
In majority of cases a true stasis has a negative value. The function of
organ is disordered due to dystrophic changes. However, during
inflammation, stasis provides the emigration of leukocytes (chapter 8
“Inflammation”).
Ischemic and Venous Stasis
Ischemic and venous stasis is a consequence of slowing down and

stopping of the blood circulation. These conditions are caused by the same
factors as venous hyperemia and ischemia. Ischemic stasis is a consequence
of a spasm, compression or occlusion of the arteries. Venous stasis is a result
of compression of veins or their occlusion with thrombus or embolus.
Liquidation of the cause leads to the restoration of the normal circulation.
However the progression of the ischemic and venous stasis promotes the
development of the true stasis.
THROMBOSIS
Thrombosis is a lifetime formation of mass, containing blood

elements (cells and coagulated proteins) on internal surface of the
vessels.
The final mass is termed a thrombus.
Depending on the components, thrombi can be white (which are formed
of platelets, leukocytes and a small amount of plasma proteins), red (contain
erythrocytes) and mixed (have alterating white and red layers).
Etiology
Conditions, which predispose to thrombosis, are known as the Virchow's

triad:
1. Injury of a vessel wall (endothelium)
2. Disbalance between coagulative, anticoagulative and fibrinolytic
systems of the blood (hypercoagolability)
3. Slowing down of the blood flow.
It explains why thrombosis of veins occurs more often than that one of
the arteries.
All factors which create this conditions are the etiological factors of
thrombosis. They are exogenous and endogenous. Exogenous ones are
physical (trauma, electric current), chemical (cigarette smoking, side-effect
of some drugs) and biological (infectious, immune) agents, which damage
the blood vessels or change the reological properties of the blood.
Atherosclerosis, arterial hypertension and allergy may cause the injury of a
vessel wall and predispose to thrombosis.
8
Pathogenesis
The process of thrombosis could be divided into two stages:

(1) cellular (reaction of pletelets)
(2) plasmatic (coagulative).
Cellular stage of thrombosis begins after 2-3 minutes from the moment
of vessel injury and consists of adherence (adhesion) of platelets on
endothelium. It is a result of the changes both a vascular wall (its potential
ЀЀЀЀЀЀЀЀЀ) and the platelets which release thromboxane (PG). The adhesion
of the platelets is followed by their aggregation. Then destruction of platelets
follows.
There are various platelet-aggregating stimulators (thrombin, serotonin,
epinephrine, norepinephrine PGD2, PGH2, PGI2-prostacyclin). Shift of the
ATP/ADP ratio to the ADP content provides adherence and aggregation of
platelets.
Aggregated platelets lose their internal structure and release granules rich
in variety of products.
Plasmatic Stage. Substances, derived from activated platelets, favor
coagulation. The formation of biological active substances and various
coagulant factors trigger coagulative system of the blood and start the second
stage of thrombosis. Fibrin is formed, constituting the stroma of thrombi,
which contain (besides thrombocytes) a little number of erythrocytes.
Thrombus makes blood circulation difficult. It diminishes or obstructs
vascular flow, causing ischemic injury of tissue, and may give rise to
embolism.
In course of time the thrombus may be changed by
• Aseptic (enzymatic, fibrinolytic) lysis
• Organization and substitution by connective tissue
• Recanalization
• Septic (purulent) disintegration
The septic outcome is especially dangerous because it may cause
septicopyemia and numerous abscesses in various organs. Development of
necrosis (infarction, gangrene) is possible terminal stage of thrombosis.
A thrombus must be differentiated from a blood clot. The latter is formed
by coagulation of extravasal blood. Thrombi, in contrast, are formed
intravascularly in the circulation. Those thrombi, which are formed in the
rapidly moving arterial circulation, are composed presumably of fibrin and
platelets with only a few trapped red cells. Thus, thrombus bears little
resemblance to a blood clot. However, in a very sluggish venous flow
thrombi may closely resemble the blood clots.
Significance
Thrombosis is created in evolution as a defensive reaction stopping

bleeding and blood loss after mechanical trauma and rupture of vessel.
In another cases thrombosis plays a negative role if cause an ischemia.
9
Infarction is an area of ischemic necrosis of tissue and is the gravest
outcome of thrombosis. Infarction of the heart, lung and brain collectively
account for more deaths than all forms of cancer and infections diseases
together. It is usually caused by thrombolic (or thromboembolic) occlusion of
the vessels.
Thrombosis of veins have a chronic duration causing venous congestion
and inflammation of veins (thrombophlebitis).
EMBOLISM
Embolism is a formation and caring along the blood flow of mass,

which is not typical for normal blood content.
This mass is called embolus. The blood carries it to a site distant from its
point of origin.
Embolus may be solid, liquid or gaseous.
About 99% of all emboli originated from thrombi. Indeed, thrombosis and
embolism are closely interrelated (thromboembolism).
Rare forms of emboli are
• Foreign bodies such as bullets
• Droplets of fat
• Bits of tumor
• Fragments of bone or bone marrow
• Bubbles of air, nitrogen or another gas
Inevitably emboli lodge in vessels too small to permit their further
passage. It results in complete occlusion of the vessel. Emboli may come to
rest anywhere within the cardiovascular system producing different clinical
effects.
Significance
Embolism always plays a negative role. Thromboembolism and

infarctions constitute the dominating clinical problems today. Thrombotic
occlusion of pulmonary artery is often cause of death in hospitalized
patients. Heart disease (myocardial infarction, rheumatic heart disease,
arrhythmia) increase the risk of embolism.
10
CHAPTER 8
INFLAMMATION
Inflammanion is nhe mosn widespread panhological process. Inflammanory diseases

are nhe largesn group of nhe diseases (gasnrinis, myocardinis, nonsillinis, hepaninis enc).
Inflammation is a typical pathological process, which is characterized by a
complex of morphological, biochemical and functional changes, the reaction of
microcirculation and connective tissue in response to the tissue damage.
CARDINAL SIGNS OF INFLAMMATION
Celsus and Galenus described nhe local signs of inflammanion in annique nimes.
Inflammanion is a predominannly local process, bun nhe whole organism is involved.
Local signs of inflammanion are nhe following (in Lanin)(fig.9):
• Tumor (swelling)
• Rubor (redness)
• Calor (hean)
• Dolor (pain)
• Functio leasa (funcnional disorder)
_______________________________________________________________________________
Fig.9. Cardinal sings of inflammanion by Celsus and Galenus (ЀЀ Ѐ. 228 ЀЀЀЀЀЀЀЀЀЀЀ)
_______________________________________________________________________________
Systemic signs of inflammanion are nhe fever, leukocynosis, snimulanion of

immunological reacniviny and bone marrow, snimulanion of hepanic funcnion
(synnhesis of new proneins), disnurbance of a self-sensanion (headache, insomnia, loss
of appenine and capaciny no work).
ETIOLOGY
1
Eniological facnors of inflammanion are called flogogens. They are exogenous and
endogenous.
Exogenous flogogens are divided inno physical (mechanical and nhermal nrauma,
elecnrical injury, ionizing and ulnraviolen radianion), chemical (acid, alkali, chemical
poisons) and biological (bacneria, viruses, fungi).
Endogenous flogogens are formed in nhe organism as a resuln of anonher diseases
(nhrombosis, embolism, allergy, formanion of bilious or urinary concremenns). The
immune complexes are nhe mosn ponenn endogenous flogogens and cause allergic
inflammanion.
PATHOGENESIS
Stages of Inflammation
Inflammanion proceeds in nhree snages (fig. 10):

1/ Alneranion
2/ Disorder of microcirculanion, exudanion, emigranion of leukocynes inno nhe focus of
inflammanion, and phagocynosis
3/ Proliferanion and regeneranion.
___________________________________________________________________________________
Flogogen agenn acnion

Alneranion
Exudanion
prolifiranion
Fig. 10. Schemanic figure of order and level of nhe snages of nhe inflammanion.
In is shown nhan every new snage as is born in nhe previous one
ALTERATION
The nerm alteration means a damage. Two nypes of alneranion are disninguished in
nhe locus of inflammanion - primary and secondary.
Primary alteration is a damage of nissue by eniological facnor inself. This effecn
may be very shorn-nermed, bun nhe local damage of nissue is non finished.
Secondary alteration is an addinional damage of nissue by numerous facnors of
endogenous origin. These facnors are nhe following:
• Cells of inflammanion,
• BAS (medianors of inflammanion),
• Disorder of microcirculanion,
• Hypoxia,
• Local increase of osmonic and onconic pressure,
• Local acidosis,
2
• Producns of nissue decay.
Cells of Inflammation
In nhe locus of inflammanion in is possible no see a lon of cells. Some of nhem

emigrane from nhe blood (neunrophils, monocynes, eosinophils, nhrombocynes and
lymphocynes), some of nhem have local origin (nissue basophils seu masn cells, nissue
macrophages, fibroblasns). So, nhe cells of inflammanion are of hisniogenic and
hemanogenic origin. They perform impornann funcnions in nhe locus of inflammanion.
The defensive funcnion is nhe mosn impornann one (phagocynosis, formanion of BAS).
An nhe same nime, many cells perish revealing facnors of damage and innoxicanion.
The mosn impornann role belongs no neunrophils and monocynes (nable 4).
Table 4. Cells of Inflammation
3
Cells BAS Participation in
Inflammation
Neunrophilic granulocynes Lysosomal enzymes, Chemonaxis, phagocynosis,

leuconrienes, facnor of cynonoxic effecn
nhrombocyne acnivanion,
annibacnerial facnors
Monocynes Innerleukin-1, enzymes, Phagocynosis, cooperanion

innerferon, componenns of winh onher cells, influence
complemenn, prosnaglandins, on fibroblasns, lymphocynes,
inhibinors of proneases epiheiocynes, hepanocynes,
neurons
Tissue basophils (masn cells) Hisnamin, heparin, facnor of BAS formanion

eosinophils chemonaxis,
facnor of nhrombocynes
acnivanion, nhe slowly
reacning subsnance SRS
(leuconriens)
Eosinophilic granulocynes Hisnaminase, Desnrucnion of hisnamine

Arylsulfanase and leuconrienes
Prosnaglandins,
Thrombocynes Aggreganion, blood
nhromboxane, leuconrienes,
coagulanion, nhrombosis
nhrombocynic grownh facnor,
serononin, hisnamine,
adrenaline
Lymphokines, innerleukin-2,
B-and T-lymphocynes Immune response
immunoglobulins
Glycosaminoglycans,
Fibroblasns Proliferanion, resnoranion of
collagen
nissue afner inflammanion
Neutrophils appear in nhe locus of inflammanion from nhe blood and move no nhe
cenner of inflammanion. Phagocynosis is nheir main funcnion. Many neunrophils perish
liberaning acnive hydrolynic enzymes from lysosomes. These enzymes are so
numerous (aboun 60 - pronease, amylase, lipase, phosphanase, collagenase, elasnase,
RNA-ase, DNA-ase, myeloperoxidase, lacnoferin, lysozymal), nhan nhe neunrophils are
called menaphorically as “mobile laboranory”. BAS from nhe neunrophils play
impornann role in nhe purificanion of nhe inflamed locus and simulnaneously nhey are
nhe facnors of a damage. Like anonher BAS, nhey possess an abiliny no acnivane all onher
sysnems of BAS formanion.
4
Monocytes are a source of a large quanniny of BAS (complemenn, collagenase,
elasnase, monokins, innerferon, nransferin, prosnaglandins, nhromboxane, leuconrienes).
One of nhem is innerleukin-1, which is liberaned an nhe very beginning of
inflammanion. In produces many effecns, especially in acune phase of inflammanion.
All sysnems, which are responsible for inflammanion, are sensinive no innerleukin-1.
The bone marrow is acnivaned, an addinional quanniny of leukocynes appear in nhe
blood. Many cells have recepnors no innerleukin-1 and are a nargen for in - hepanocynes,
fibroblasns, endoneliocynes, sinovicynes, nerve cells. The hepanocynes synnhesize new
proneins, including ceruloplasmin, S-reacnive pronein, fibrinogen. Synnhesis of
albumins and globulins for nhe blood is acnivaned. Fibroblasns provide proliferanion by
synnhesis of collagen. Innerleukin-1 has an influence on nhe endonhelium of capillaries
and provides an adhesion of leukocynes. Endoneliocynes form prosnaglandins and nhe
facnors of coagulanion. The producnion of collagenase is increased in chondriocynes
(desnrucnion of carnilage and pain in joinns are noned). Proneolysis is acnivaned in nhe
muscles (pain in nhe muscles). One of nhe Il-1 effecns is an influence on hyponhalamus
and developmenn of a fever. Loss of appenine, disnurbance of nhe cennral nervous
sysnem refers no nhe effecns of innerleukin-1 as well.
Mast cells, eosinophils, thrombocytes and lymphocytes parnicipane in nhe
inflammanion and are a source of BAS. From nhe lipids of nhe cellular membranes
prosnaglandins are formed. They cause nhe numerous and various manifesnanions of
inflammanion.
Role of Biological Active Substances (BAS) in Inflammation.

Mediators of Inflammation
BAS which play a role in inflammanion are called mediators of inflammation.

They provide all nhe manifesnanions of inflammanion (beginning from alneranion up no
proliferanion and reparanion). All biological acnive subsnances are common for nhe
normal reacniviny as well as for nhe mechanisms of immuniny, allergy and
inflammanion. However, nhere are differences. Lymphocynes play nhe main role in
immunological reacnions, masn cells - in allergy. As no inflammanion, nhe neunrophilic
granulocynes and monocynes, as phagocynes, are nhe main source of BAS nogenher winh
onher cells, which parnicipane in inflammanion.
BAS, which are formed primarily, acnivane, as a cascade, all sysnems of BAS
formanion, which are responsible for nhe secondary alneranion, disnurbance of
microcirculanion, increase of vascular permeabiliny, edema, migranion of leukocynes,
phagocynosis, proliferanion. BAS involve nhe whole organism inno inflammanion,
snimulane bone marrow, acnivane pronein synnhesis in nhe liver, increase a body
nemperanure. There is no phenomena in inflammanion, no which BAS would non have a
relanion. The leading annipyrenic medicines (aspirin), which are proposed, are direcned
againsn BAS, especially prosnaglandins. In nhe nable 5 all kinds of BAS are noned, nheir
origin and effecns in nhe locus of inflammanion.
Table 5. Mediators of Inflammation
5
Mediators Source Effect
Cellular
Lysosomal enzymes Granulocynes, macrophages Second alneranion,

chemonaxis
Hisnamine Granules of nhe masn cells Local vasodilananion,

increase of vascular
permeabiliny
Serononin Granules of nhrombocynes The same
Prosnaglandins Arachidonic acid from nhe Increase of nhe vascular

cellular membranes of permeabiliny, edema,
damaged cells chemonaxis
Thromboxane Thrombocynes Aggreganion of

nhrombocynes, angiospasm,
Acnivanion of hemosnasis
Disaggreganion of
Prosnacyclin Endoneliocynes
Thrombocynes,
vasodilananion
Chemonaxis, spasms of nhe

Leuconrienes Leukocynes
smoonh-muscle fibers,
edema
Humoral
Kinins (bradykinin, kalidin) α2- globulins of nhe blood Vasodilananion, increase of

permeabiliny, pain, inch
Sysnem of complemenn Chemonaxis, cynolysis,

blood plasma
acnivanion of leukocynes,
release of nhe medianors of
inflammanion
Hageman facnor Acnivanes kinin and

blood plasma
complemenn sysnems, effecn
on hemosnasis
6
DISORDER OF MICROCIRCULATION
LOCAL VASCULAR REACTION
Local vascular reacnion begins immedianely afner flogogen acnion and leads no nhe
developmenn of nhe second snage of inflammanion.
Cohnheim discovered nhe dynamics of vascular reacnion. In is easy no observe in on
nhe mesennery of frog afner ins damage (fig. 11).
___________________________________________________________________________________
Fig. 11. An inflammanion of a frog mesennerium (ЀЀ Ѐ. 240 ЀЀЀЀЀЀЀЀЀЀЀ)

1- leukocynes which emigraned, 2- emigranion of nhe leukocynes, 3- erynhrocynes in nhe nissue
___________________________________________________________________________________
Vascular reacnion proceeds in four snages –
1. Shorn-nerm spasm of arnerial vessels
2. Arnerial hyperemia
3. Venous hyperemia
4. Snasis.
The named four forms of microcirculanion disorder correspond no nhose, which are
described in nhe chapner 7 ( “The panhophysiology of peripheral blood circulanion”).
However, nhey have some peculiarinies. In parnicular, all changes have nhe feanures of
adapnanion.
Short-Term Spasm
The shorn-nerm spasm of arnerial vessels is an angiospasnic reacnion of reflex

nanure. In is an unspecific ininial reacnion of vessels no any damage and has pronecnive
value due no liminanion of panhologic subsnances ennering inno organism from nhe
damaged locus. Somenimes in clinical pracnice a physician applies a cold an nhe very
beginning of inflammanion in order no snop nhe process. Somenimes in is acnually
useful. Bun usually nhis snage is shorn-nerm and subsninuned by more significann
changes in microcirculanion.
Arterial Hyperemia
Arnerial hyperemia denermines nhose signs of inflammanion, which Celsus

described, as rubor (redness), tumor (swelling) and calor (hean). Arnerial hyperemia
supplies nhe locus of inflammanion winh addinional volume of oxygen and subsnranes.
Virkhow annached a grean significance of arnerial hyperemia by claiming, nhan nhe
inflamed nissue needs an increased nourishmenn (Virkhoi,s nutritive theory of
inflammation). Menchnikov considered, whan arnerial hyperemia is a way of
supplying nhe locus of inflammanion by addinional quanniny of leukocynes
(Metchnikov,s phagocyte theory of inflammation).
7
Venous Hyperemia
Venous hyperemia inevinably follows nhe arnerial one. The blood snream slows
down, and leukocynes occupy boundary posinion near nhe wall. In means, nhan
chemonaxic subsnances, which are formed in nhe cenner of inflammanion, influence nhe
leukocynes locaned in nhe bloodsnream. The adhesive proneins, which are formed in
endonhelium, make nhe surface of endoneliocynes and leukocynes more “snicky”.
Stasis
Snasis (snopping of blood flow in nhe capillaries) provides nhe leaving of

leukocynes from vessels inno nhe cenner of inflammanion. The permeabiliny of vascular
walls no plasma proneins and leukocynes considerably rises. Winhoun slowing of nhe
blood flow, boundary posinion of leukocynes and increasing of permeabiliny, nhe
phenomenon of emigranion of leukocynes and fanher phagocynosis are impossible.
EXUDATION , EMIGRATION AND PHAGOCYTOSIS
Deparnure of nhe plasma proneins (albumins, globulins, fibrinogen and onher) inno
nhe cenner of inflammanion is accompanied by exuding of waner. This process is called
exudation.
Deparnure of nhe leukocynes from nhe blood inno nhe cenner of inflammanion is
called emigration. Leukocynes acnively move no nhe cenner of inflammanion nhrough
nhe wall of capillary benween nhe endonhelial cells and nhrough nhe basal membrane.
The cernain order of emigranion of leukocynes is noned - neunrophils, monocynes,
lymphocynes.
Phagocytosis is nhe main funcnion of leukocynes in nhe cenner of inflammanion
and has nhe following peculiarinies:
• Large quanniny of phagocynes in nhe cenner of inflammanion is provided by acnive
vascular reacnion,
• Chemonaxins, which are formed in nhe cenner of inflammanion, effecn nhe
leukocynes which locaned even inside nhe vessels,
• Phagocynosis is innensified,
• Phagocynosis is provided winh addinional energy and oxygen,
• Phagocynosis is innensified due no increase of body nemperanure,
• Phagocynosis is acnivaned by an effecn of mineralocornicoids.
Purulenn inflammanory exudane is formed in nhe cenner of inflammanion (fig. 12).
Then nhe pus leaves from nhe locus of inflammanion.
__________________________________________________________________________________
Fig. 12. Inflammanion of nhe fabbin,s yea. An nhe bonnom of nhe annerior camera a purulenn exudane
is presenn (ЀЀ Ѐ. 241 ЀЀЀЀЀЀЀЀЀЀЀ)
___________________________________________________________________________________
8
Inflammatory edema relanes no nhe local ones. In is a redisnribunion of waner from
nhe vessels inno nhe nissues in accordance winh Snarling’s laws. The following
mechanisms have a value in panhogenesis of inflammanory edema:
• Increase of hydrodynamic (venous) pressure of nhe blood,
• Increase of vascular permeabiliny and ounpouring of proneins from nhe blood inno
nhe cenner of inflammanion, which leads no an increase of onconic pressure in nhe
cenner of inflammanion,
• Hydrophilia of colloids due no pH reducnion (local acidosis) in nhe inflamed
nissues.
PROLIFERATION AND REGENERATION
The nhird snage consumes nhe inflammanion. During nhis snage nhe cenner of
inflammanion becomes free from microorganisms, necronized nissues, foreign and
noxic subsnances.
In nhe damaged nissue proliferation (mulniplicanion) of nhe viable cells begins. The
degree of reparation depends on abiliny for regeneration. The cells of connecnive
nissue, epidermis, epinhelium of mucous membranes have nhe besn regeneranive abiliny.
The cells of nhe liver and kidney possess smaller capabiliny for regeneranion. Cells of
muscular and nerve nissue possess weak capabiliny for reparanion.
If quanniny of viable cells in parenchyma is insignificann, an organ is resnored by
connecnive nissue. Fibroblasns mulniply and produce collagen, which forms scar in nhe
zone of inflammanion.
Snudying nhe snages of inflammanion, in is impornann no undersnand, nhan nheir order
is superimposed, and in nhe locus of inflammanion in is possible no observe
simulnaneously all manifesnanions winh predominance of some of nhem.
FORMS OF INFLAMMATION
Classificanion of inflammanion is based on predominance of alneranion, exudanions

or proliferanion. Three forms of inflammanion are disninguished.
Alterative inflammation is characnerized by predominance of nhe firsn phase -
damage, dysnrophia and necrosis. In is observed predominannly in nhe parenchymanous
organs in nhe case of infecnious disease (caseous decay of lungs of nuberculous origin).
Allergic inflammanion proceeds winh formanion of aphnhae, erosias and ulcers.
Exudative inflammation is characnerized by significann increase of vascular
permeabiliny. Exudanion and edema accompany allergy. Inflammanion of mucous
membranes may have such duranion (canarrhal inflammanion).
Proliferative (productive) inflammation is characnerized by predominance of
mulniplicanion of nhe cells of hisniogenic or hemanogenic origin. Cellular infilnranion is
formed in nhe locus of inflammanion. Rheumanoid arnhrinis (allergic disease) has such
characner. If formanion of new connecnive nissue predominanes, sclerosis and cirrhosis
are developed.
In addinion, inflammanion is divided inno acute and chronic.
DISORDER OF METABOLISM
9
The local changes of menabolism are characnerized by nhree menaphorical
expressions. Expression “the fire of metabolism ” characnerizes ins innensiny. An
increase of nhe local nemperanure (calor) occurs. Expression “nhe leukocynes are nhe
mobile laboranory” reflecns accumulanion of a large quanniny of enzymes and
biologically acnive subsnances of leukocyne origin, which acnively move nowards nhe
cenner of inflammanion. Expression “oxygen explosion” reflecns an exclusive
parnicipanion of oxygen in inflammanion (increased formanion of calories of hean,
ATP and ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀ). The acnive forms of oxygen play a role in secondary
alneranion and bacnericidiny.
PhysicЀ-Chemical Changes. The producns of incomplene oxidanion are
accumulaned. Since all of nhem are acids, nhe local acidosis develops, ЀЀ is lowered
no 5,3-6,0 in acune and 6.0-7,5 in chronic inflammanion. Osmonic and onconic pressure
is increased in nhe cenner of inflammanion, as a resuln of accumulanion of ions, proneins
and producns of nheir incomplene disinnegranion.
MORPHOLOGY OF PURULENT EXUDATE
The microscopic research of purulenn exudane reveals ins essennial parn - nhe so-
called purulent bodies. They are nhe acnive leukocynes, which have realized nhe
funcnion of phagocynosis (organoids are non disninguished). In addinion, in is possible
no see innacn micro- and macrophages, microorganisms, debris of nhe damaged nissues,
fragmenns of cells decay, coagulaned fibrin, admixnure of nhe blood. Analyzing nhe
composinion of purulenn exudane, in is possible no draw conclusion aboun reacniviny of
organism. Prevalence of purulenn bodies is a posinive sign. Prevalence of innacn
micro- and macrophage is a neganive sign, which is an evidence of a decreased
reacniviny.
INFLAMMATION AND REACTIVITY OF ORGANISM
Menchnikov, nhe Nobel Price Winner, snudied an inflammanion in animals of

differenn organizanion. He revealed nhan inflammanion develops in evolunion and has
more simple forms. Frogs (heneronhermic animals) display vascular reacnion and
phagocynosis during inflammanion, bun don’n have an increase of local and general
nemperanure. Invesniganing inflammanion in snarfish (class of invernebranes winhoun
vascular sysnem) Menchnikov discovered nhe phenomenon of phagocynosis winhoun
vascular reacnion. So, Menchnikov made a conclusion nhan phagocynosis is nhe earliesn
and nhe mosn principal evenn in inflammanion.
In is known, nhan duranion of any panhologic process depends non only from nhe
power of eniological facnor, bun also from reacniviny of organism. This low relanes no
inflammanion as well. Children and newborns demonsnrane nhe violenn and somenimes
dangerous course of inflammanion. The old men reveal inacnive inflammanion.
Depending on individual reacniviny, an inflammanion may be divided inno
normergetic (proceeds opnimally), hypoergetic (weak) and hyperergetic (excessive).
Decrease of nhe reacniviny (hyponhermia, narcosis, effecn of immunodepresanns,
senile age) diminishes nhe manifesnanions of inflammanion, which may obnain nhe
chronic form winhoun essennial fever.
Allergic inflammanion has some grave forms – acune erosive, acune exudanive,
acune edemanous, chronic producnive (rheumanism).
10
SYSTEMIC CHANGES IN INFLAMMATION
All organism is involved in inflammanion. Manifesnanions are nhe following:

• Increase in body nemperanure (fever) is one of nhe mosn prominenn sysnemic
manifesnanions, especially when inflammanion is associaned winh bacneremia.
• Endocrine sysnem is acnivaned.
• Hyponhalamus is involved in fever developmenn, acnivanion of adenopinuinary
and adrenal cornex.
• Mineralocornicoids snimulane inflammanion, and glucocornicoids inhibin in.
• Leukocynosis is a common feanure of inflammanory reacnions, especially nhose
induced by bacnerial infecnion. The leukocyne counn usually climbs no 10 G/l and
more.
• Increased number of neunrophils in leukoformula and appearance of immanure
forms of nhem is an evidence of hemopoiesis acnivanion in nhe bone marrow.
• Blood sedimannanion rane (BSR) is acceleraned.
• Immune sysnem is acnivaned.
• Nervous disnurbances, insomnia.
So, inflammanion, immuniny and fever are nighnly connecned.
VALUE OF INFLAMMATION
Analysis of nhe clinical value of inflammanion helps no esnimane ins dialecnics. This
process is simulnaneously posinive and neganive. From one side, in is a fundamennal
pronecnive response, self-defensive reacnion, which connribunes no damaged nissues
resnoranion and survival of organism. From onher side – panienn suffers, his abiliny no
work is disrupned, he is ill. In is ponennially harmful. ЀЀЀЀЀ ЀЀЀЀЀЀ, ЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀ ЀЀЀЀЀ
ЀЀЀЀЀЀЀЀЀ. An overacnive inflammanory response can cause deanh.
11
CHAPTER 9
FEVER
There are several close terms, which correspond to the phenomenon of

increased body temperature. However, a cause, pathogenesis and value are
completely different.
Hyperthermia is the most common term.
Overheating is an increase of body temperature due to high temperature of
the environment.
Fever (in Latin febris) occupies a particular position. It is formed in
evolution as a reaction of organism to infection. The present chapter deals with
the letter phenomenon.
Fever is a typical pathological process, which is characterized by
reorganization of thermoregulation and an increase of body temperature
in response to pyrogens.
Under clinical conditions (in infected patient) it is impossible to appreciate
the fever and distinguish it from infectious intoxication. One gain an
impression that a patient suffers from elevation of body temperature. An
intention to reduce it appears. Only in experiment it is possible to model a
“pure” fever and to study it.
There are several methods for modeling the “pure fever” in experiment, for
example, by injection of “pure pyrogens”. Hypothalamus perfusion by blood
with different temperature allows to reach an increase of body temperature of
any degree. Just in such experiments an information about etiology and
pathogenesis of a fever was acquired.
ETIOLOGY
Etiological factors, which cause a fever, are termed pyrogens.

Pyrogens are divided into
• Infectious and noninfectious,
• Exogenous and endogenous,
• Primary (inductive) and secondary (true).
Exogenous pyrogens are connected with microorganisms. In scientific
studies it is possible to separate microbial pyrogens from toxins and study them
separately. Blood transfusion, injection of proteins and lipids for the purpose
of parental nourishment may cause a fever (noninfectious).
Microbial exo- and endotoxins are the proteins. Immune antibodies are
formed against them. Microbial pyrogens are not proteins but the biopolimer
molecules of lipopolysaccharides. The antibodies are not formed against them
and they are not destroyed by proteolytic enzymes. Pyrogenic effect is
1
connected with the lipid part of these macromolecules (lipoid A). It causes a
fever in concentration 0,0001 gr\ kr.
Nevertheless, the microbial pyrogens are not true ones, because their
injection into the hypothalamus does not cause a fever. The formation of the
so-called secondary (endogenous) pyrogens is necessary for development of a
fever. Consequently, the microbial (primary, exogenous) pyrogens are the
factors of etiology, but endogenous (secondary) pyrogens are the factors of
pathogenesis.
Primary pyrogens may be produced inside organism independently from
infectious agent (in bone brakes, myocardial infarction, hemolytic crisis).
These substances are produced as a result of own tissues destruction and
influence organism as exogenous pyrogens.
PATHOGENESIS
Mechanism of Endogenous (Secondary) Pyrogens Formation
The formation of endogenous pyrogens follows the penetration of microbial

ones and formation of immune complexes.
They are not the products of damaged tissues. They are the products of
endogenous protein synthesis. The production of endogenous pyrogens is
called pyrogenesis. It is realized by healthy leukocytes - macrophages (fixed
and free monocytes), lymphocytes and neutrophiles after their activation. The
pyrogenesis is not realized in damaged leukocytes. If energy formation in the
leukocytes would be damaged (in experiment), as well as after protein
synthesis blockade (by puramicine) pyrogenesis would not occur.
Among different pyrogens (cytokins) the interleukin-1 (IL-1) is the most
potent. It is a hormone-like protein, which is produced in macrophages and
cause fever together with various other effects (participation in the
immunological reactions and inflammation). IL-1 is produced in monocytes in
vitro after microbial pyrogen being added. All the systems, which are
responsible for immunity and inflammation, are sensitive to IL-1. The fever,
immunity and inflammation are a triad, which determines reaction of
organism to infection. The connection between them is so intimate that they do
not exist without each other.
It was shown in experiment, that IL-1 does not pass through the
haematoencephalic barrier and does not reach the hypothalamus. At the level
of cerebral arteries and capillaries prostaglandins E1 and E2 are formed, reach
hypothalamus and influence its function. So, the hypothalamus is a target for
endogenous pyrogens. Just PGE produce experimental fever after injection into
the cerebral ventricle.
Hence, the order of events is such: microbe →leukocytes (monocytes and
lymphocytes) → IL-1 → PGE → hypothalamus.
Changes in Hypothalamus
The thermal homeostatic control is one of hypothalamus functions.

Organism works as a biological thermostat, and regulator (thermoregulatory
center) is located in hypothalamus. The function of the thermoregulatory
2
center consists in maintenance of temperature homeostasis, balancing the
processes of heat production and heat emission. Mechanism of this realization
is an establishment in hypothalamus of the so-called “established point”, in
accordance to which the body temperature is regulated. A man has normal
“established point” at about 36- 37o.
Due to endogenous pyrogens the “established point” rises, and the
hypothalamus regulates the body temperature on another, more useful level.
The “established points” for the different types of infection were worked in
evolution. It is very important to understand, that a change of “established
point” is not a disorder of thermostatic control but its regulation on another
level.
After «established point» reaches an adequate level, the hypothalamus
sends regulatory impulses for the executive organs, and an additional heat is
formed for body warming.
Mechanisms of Heat Accumulation
There are three mechanisms of heat accumulation during a fever:

1. Limitation of heat emission is the main mechanism. The spasms of the
peripheral vessels, pale skin, decrease in sweating and evaporation are noted.
These mechanisms are effective and economical since they require no energy.
At this moment direct and indirect calorimetry show different indices: direct
calorimetry shows the decreased parameters in comparison both with the initial
level and patterns of indirect calorimetry.
Only on the ground of diminished heat emission two other mechanisms
would be effective and convenient.
2. Activation of Heat Production (thermogenesis). The intensification of
metabolism actually takes place, but in a very little degree – about 35-45%. It
may be established by the method of indirect calorimetry (oxygen
consumption). For comparison, it is useful to indicate, that an intensive
physical work is accompanied by more significant oxygen consumption
(sometimes up to 500%), but overheating does not occur (heat emission
increases proportionally). Contractile and noncontractile thermogenesis is
actually intensified in fever, but insignificantly. Muscular shivering is obtained.
Glycogen is splitted in the muscles and liver.
3. Disconnection (uncoupling) of oxidation and phosphorylation occurs.
Energy of electrons and protons moving along respiratory enzymal chain does
not accumulated in ATP but gets dispersed as a free heat (free oxygenation).
The ATP formation is diminished temporary and insignificantly. Some
microorganisms possess an effect of disconnection.
After achievement an optimal level of body temperature, the latter is
regulated for a while. What time? Up to formation of antibodies and
liquidation of infection. Within several days antibodies are formed resulting in
a cessation of pyrogens formation (microbial and IL-1), return of the
“established point ” to the physiological level and normalization of body
temperature.
Stages of Fever
3
Fever develops in three stages:
(1) Increasing of body temperature (stadium incrementi),
(2) Holding of the elevated body temperature (stadium fascigii) with some
fluctuation in morning and evening,
(3) Reduction (normalization) of body temperature (stadium decrementi).
The relationship between heat production and heat emission is different
while these stages. During the first stage the heat emission is less, than heat
production. During the second stage the heat emission and heat production are
equal. During the third stage the heat emission considerably rises,
vasodilatation, intense sweating and loss of water are noted.
A decrease (normalization) of body temperature may be gradual, lytic
(during some days) or fast, critical (fig.13). In a letter case, an extensive
vasodilatation may happen and, when it is accompanied with intoxication,
leads to collapse development.
______________________________________________________________
Hours, days
Fig.13. Critical (A) and lytic (B) decrease of body temperature in the third stage of a fever
( рис. 30 на с. 264 украинского издания учебника)
_______________________________________________________________
PROTECTIVE VALUE OF A FEVER
Stimulation of Immunological Reactivity and Inflammation. Very

important events take place during the second stage of a fever. In evolution the
fever was formed as a self-protective reaction against an infection.
Immunological reactivity gets activated. Cellular and humoral mechanisms
of immunity, inflammation and fever are uniform.
The phagocytosis is activated (temperature optimum for the phagocytosis is
o
38 C) as well as the rate of antibodies and interferon formation, function of B-
and T-lymphocytes, leukopoiesis.
Vitality and multiplying division of microbes are impeded by temperature
rising up 40o C. The sensitivity of microorganisms to medicines rises.
A fever activates other systems with their defensive functions - antitoxic
function of the liver, filtration in the kidneys, secretion of hormones.
If antipyretic drug would be injected into experimental animal
simultaneously with infectious agent, the infection can proceed worth.
Clinical practice confirms the self-protective value of a fever. Clinical
evidences are the following:
• The patient more rapidly and totally gets better if a fever develops.
• More persistent and prolonged active immunity is formed if a patient is
feverish.
4
• Weakened and elderly patients do not develop an active fever and that is
why they frequently obtain chronic duration of infection.
• The antipyretic medicines sometimes make the course of infectious
disease worse.
In final conclusion it may be estimated that a fever in its essence is a
protective event and sustains the vitality of organism during infection.
In fact, such duration of a fever is obtained in experiment with pure
pyrogen, which is free from infectious intoxication. Under clinical conditions
during severe infection, the hypotalamus may be damaged and consequently
the defensive mechanisms may be depreciated by intoxication. So, in a fever,
like in any other typical pathological process, protective and harmful are tightly
connected.
METABOLIC CHANGES
Information about the metabolic changes in “a pure fever” without

infectious intoxication was obtained in experiment.
Basal Metabolism. It is necessary to understand that any protective reaction
requires additional energy. It concerns a fever as well. The activation of
metabolism occurs. Basal metabolism increases on 35-45%. The increase of
oxygen consumption is the same.
Carbohydrate Metabolism. The blood glucose level rises. Glycogenolysis
activates. Glycogen content in the liver and muscles is reduced a little. The
intermediate metabolism of carbohydrates is not disarranged. Respiratory
coefficient is equal to 1, which indicates the preferable utilization of the
carbohydrates.
Lipid Metabolism. Synthesis of phospholipids in the nervous tissue as well
as including of radioactive phosphorus in it gets increased. Lipolysis activates
but intermediate metabolism of lipids while the short-term fever is not
disturbed. In a prolonged fever, acetone and ketonic bodies appear in the blood
and urine. The introduction of carbohydrates softens these changes.
Protein Metabolism. Proteinsynthetic function of the liver is activated. The
formation of S-reactive protein, fibrinogen, ceruloplasmin is intensified.
Synthesis of γ-globulin activates as well. In infectious diseases a negative
nitrogen balance is established and an increased content of urea in urine is
noted, but there is no connection with a level of fever but infectious
intoxication.
Acid-base balance moves to the state of compensated metabolic acidosis.
A quantity of the blood bicarbonates is reduced a little.
Water-Mineral Balance. In the first stage of a fever an increased diuresis
(as a result of the arterial blood pressure increase) is obtained. In the second
stage, a retention of sodium, chlorides and water is detected, diuresis decreases
(as a result of increased secretion of aldosterone). In the third stage (patient
sweats intensively) a negative water balance may be established (patient
needs additional drink), an excretion of sodium and chlorides increases.
CHANGES IN ORGANS
5
In course of infectious fever the clinical symptoms are numerous, but there
is no strict correlation between them and the degree of a fever. They depend
upon an infectious intoxication, effect of a pyrogen and IL-1.
Experiments with “pure pirogens” discover the changes in the organs,
connected with an increase of body temperature. They are milder than in
infectious disease and have mainly protective value.
Stimulation of the Immunological Reactivity (see above).
Blood circulation is activated. Pulse is accelerated (as a result of local
warming of the heart pace maker and activated sympathetic nervous
influences). The systolic and minute heart outflow increases. Arterial blood
pressure (in the first stage) may be risen. Vasoconstriction is characteristic for
the first stage, but vasodilatation – for the second and third ones. If the body
temperature is reduced critically (in the third stage), collapse may develop with
vasodilatation in the background. Loss of water and hypovolemia may develop.
Significant changes of systemic blood circulation, which are obtained in
infectious diseases, are the result of intoxication but not a fever.
Respiratory System. Lung ventilation does not change essentially because in
spite of accelerated rhythm the depth of breathing diminishes. Tachypnoe is
observed in the case of brain temperature increase.
Gastrointestinal Tract. Appetite is suppressed a little (due to IL-1 effect
on the brain). Salivation decreases as well as acidity of gastric juice (feeding
of a patient must be reduced too). More eminent changes are not a result of a
fever, but of infectious intoxication.
Liver. The protein synthetic and antitoxic function of the liver are activated.
Urine formation may be activated.
Endocrine system is activated. Fever is a kind of stress and results in
activation of pituitary gland and the adrenal cortex. On the other hand, the
endocrine system influences the development of a fever. Hormones can induce
the synthesis of endogenous pyrogens in macrophages (thus, in women while
the ovulation period, the body temperature rises on 0,4 - 09o as an effect of
progesterone). Thyroxin contributes the development of a fever, possesses an
effect of the disconnection of oxidation and phosphorilation. The development
of a fever is depressed while hypothyroidism and pituitary insufficiency.
Glycocorticoids inhibit the development of a fever due to suppression of the
maturation of leukocytes and production of endogenous pyrogens.
Nervous System. The following subjective clinical symptoms are noted in
clinics - insomnia, sensation of breakdown, tiredness, and headache. The study
of these symptoms in experimental animal is limited. Probably, these
symptoms are a result of intoxication, but not a fever.
Figure 14 illustrates a change of some functions, which was detected in
experiment with a pure fever.
______________________________________________________________________
Days of a disease
Stages of a fever
Body temperature
Pulsus
Respration
6
Diuresis
Muscle trembling
Fig. 14. Changes of pulsus, respiration, diuresis in different stages of a fever (рис. 29
со с. 264 украинского издания)
______________________________________________________________________
TYPES OF A FEVER
Depending on a degree the following types of a fever are distinguished:

• Subfebrile - 37-38o,
• Moderate – 38-39o,
• High – 39-41o,
• Hyperpiretic – higher then 41o.
A division of a fever depending on reactivity of organism is of a great
clinical significance. From this point of view the following types of a fever are
distinguished:
• Normergetic (body temperature corresponds to the optimum for a certain
infection),
• Hypoergetic (body temperature is below, than it is optimal),
• Hyperergetic (body temperature is above optimal level).
The masterpiece of a physician consists in evaluation of these parameters.
In infants the fever develops rapidly and to the higher level. In elderly people
the fever develops slowly and to the lower level.
Before an epoch of antibiotics and medical drug abuse came, the practical
physicians obtained a dependence of a fever dynamics from the biological
rhythms. A clinical practice established the typical forms of a fever in
accordance with the biorhythmic dynamics. It was discovered that in the
majority of cases an infectious fever is not constant. The lifting moments are
rhythmically followed by decline.
Depending on the biorhythmic dynamics the following types of the fever
curves are distinguished:
• Febris continua is a constant one. At the beginning, a body temperature
acutely increases keeping at maximum in 7-9 days with morning-night
fluctuation not higher than 1oC, then acutely decreases (fig. 15). It is typical
for pneumonia.
• Febris intermittens is перемежающаяся. Цикличность of a bacteria
development in the blood is reflected on the curve. Malaria is an example.
Attacks may occur daily or in some days. During an attack, a body
temperature acutely increases keeping high level for 30-60 minutes or 2-3
hours, then returns to the norm or below (fig. 16).
• Febris remittens develops in many bacterial infection. A morning-night
fluctuation of the temperature is 1.5-2.0oC without return to norm.
• Febris reccurens is возвратная. Recurrent typhus is an example. An attack
lasts for several days (6-8), follows by critical decrease of a body temperature
and a period of apirexia for several days (fig.17).
7
• Febris hectica is an exhausting one. Fluctuation of body temperature is 2-
3oC and more. Sepsis and wound infection are the clinical examples.
Sometimes it is characterized by several rises and falls of the body
temperature during a day.
___________________________________________________________________________
Respiration per minute
Pulsus
Body temperature, oC
Days of the disease
Temperature
Pulsus per minute
respiration per minute
Fig.15. Dynamics of body temperature, pulsus and respiration in febris continua (crupous
pneumonia) (рис. 33 со с. 266 украинского издания)
____________________________________________________________________________
days
Fig.16. Dynamics of body temperature curve in patients with malaria (рис.31 со с. 265
украинского)
____________________________________________________________________________
Pulsus per minute

Days of the disease
Temperature
pulsus
Fig. 17. Dynamics of body temperature and pulsus curves in patients with reccurent typhus
(рис. 32 со с. 265 украинского)
____________________________________________________________________________
Analysis of temperature curves gives information about a functional state of

a patient, prognosis and is important for differential diagnostics.
As a result of antibiotics and antipyretics abuse, the temperature curves
loose their typical features.
Fever in patients with chronic infectious diseases is characterized by low
(37.5-38.0oC) increase of the body temperature for a short period of time with
unstable morning-night fluctuation.
TREATMENT OF A FEVER
Fever, as usually, accompanies an infectious or other inflammatory diseases

and there is no special aim of its treatment. Treatment of the main disease has
8
the principal significance. Nevertheless, a lot of pharmacological antipyretics
are proposed for influence on the fever proper.
If a fever relates to the normergetic one, a physician evaluates the reactivity
of the patient as normal. The patient gets better himself. The physician’s help is
necessary but it does not concern the fever.
If a fever relates to the hypoergetic one, a physician evaluates the reactivity
of the patient as depressed. The help is necessary and concerns the stimulation
of immunological reactivity. Immunomodulators improve the duration of
infection and development of adequate fever.
If a fever relates to the hyperergetic one, a physician evaluates the reactivity
of the patient as non-adequate and qualitatively changed. Infants are very
reactive. Frequently the children develop higher fever, then it is adequate for a
certain infection. If a child endures a fever badly, a body temperature must be
reduced. There are many antipyretic medicines, but the truth is, that the
physicians sometimes abuse them, transferring normal reactivity into decreased
one.
Artificial fever can be used for treatment of some diseases because of its
ability to stimulate the immunological reactivity. “Pure pyrogens” (pyrogenal
has bacterial origin) are used in the cases of luis, gonorrhea, osteotuberculosis
and arterial hypertension (of renal genesis, when vasodilatation is achieved and
improve renal blood supply). They cause an increase of body temperature for
6-9- hours. Nowadays, IL-1 and other cytokins are used in the clinic for this
purpose. Their advantage from pyrogens of the bacterial origin lies in absence
of the side-effects.
OTHER FORMS OF HYPERTHERMIA
In addition to fever, there are other forms of body temperature increase,

which have not a positive meaning for organism as a fever.
Hyperthermia, as a result of overheating, differs significantly from a fever.
Final result is common - an increase of body temperature, but etiology,
pathogenesis and value are different. Etiological factor is of a physical origin
(high temperature of environment). Compensation is directed toward activation
of a heat emission. Thus, an increased body temperature is the manifestation of
decompensation and exhaustion of the function of thermoregulation.
Significance is negative.
Hyperthermia develops in the first stage of an acute radiant disease due to
disorder of thermoregulation.
Attacks of hyperthermia are noted in the workers occupied in the
производстве хины quinine (хинная hyperthermia) and jodum (истощающая
hyperthermia or jodism). Описана «солевая» hypertermia. Some plants
(Aconitum, Baptisia tinctoria, Belladonna, Dulcamara) cause hyperthermia in
sensitive persons. Some pharmacological remedies (кофеин, эфедрин, стрихнин,
адреналин, атропин, фенамин, сальварсан, сульфазан) have hyperthermia as a side-
effect. «Злокачественная hyperthermia” with increase of body temperature up to
44°C is described in use of миорелаксантов and some remedies for narcosis.
Гарячкоподібні стани are described и без влияния факторов внешней среды.
Endogenous hyperthermia is described as neurogenic (in brain damage),
9
психогенная (in neurosis, emotional stress), pефлексогенная (при наличии
конкрементов in bile bladder), эндокринная (in hyperthyreosis, under influence of
progesterone).
10
В этой главе есть такая проблема –
По-русски канцер - рак, основной термин. Отсюда по-русски производные термины –
канцерогены, канцерогенез и другие подобные.
По-английски основной термин такой же – cancer.
Отсюда я считаю, что по-английки производные – cancerogen, cancerogenesis
и другие подобные.
А словари дают – carcenogen, carcenogenesis. Я считаю это неверным.
Как быть ? Я склоняюсь к соблюдению основного корня и по-английски.
CHAPTER 10
NEOPLASIA
Neoplasia refers to pathology of growth. Tumor may be benigh and malignant.

This chapter deals with the malignant tumors. Neoplasia is a process of a malignant
tumor formation. The term neoplasma is frequently applied as a synonym of a
malignant tumor, like a term cancer.
Neoplasia is a typical pathological process, which is characterized by an
unlimited (uncontrolled, independent and endless) increase of the tissue growth,
which does not correspond to the normal structure and function of the impaired
organ.
CARDINAL SINGS OF NEOPLASIA
For distinguishing one typical pathological process from another it is necessary to

note their cardinal sings. For neoplasia they are
• Endless growth (absence of the so-called limit of division, immortality),
• Independence of growth, autocrine (own) regulation (tumor grows «from itself”,
from one signal transformed cell) infiltrating a healthy tissues,
• Anaplasia, return to the embryonic state,
• Metastastic expansion.
CLASSIFICATION
In accordance with a clinical duration and outcome, it is accustomed to divide

the tumors into benign (usually do not disrupt substantially the vital activity of
organism) and malignant (very often lethal). The first have expansive growth,
when a surrounding tissue is moved apart. The second have infiltrate growth.
Malignant tumors may be primary and metastatic.
In accordance with a histologic structure, the tumors are accustomed to receive a
name of a tissue with a suffics oma – carcinoma, osteoma, myoma, neuroma etc.
1
EXPERIMENTAL STUDY OF NEOPLASIA
It is difficult to estimate etiology and pathogenesis of malignant growth in

patients, who are already ill. For this purpose an experiment exists with modeling of
a neoplasia in animals (experimental oncology). Experimental oncology gives the
possibility to study the value of dose, intensity and duration of cancerogen effect, a
way of cancerogens entering, the role of immune system and genetic factors,
conditions, which contribute or prevent neoplasia. High- and low-cancerous
populations of animals are created in laboratories. Experimental oncology gives a
possibility to investigate antitumorous medical drugs.
There are three methods of neoplasia modeling in experiment – an induction,
transplantation and explantation.
Induction
Induction is a reproduction of a tumor by applying of different physical, chemical

and biological factors. This method gives a possibility to prove or deny cancerogenic
property of all investigated influences and substances. Using chemical substances, it
is possible to distinguish cancerogenic chemical substances from noncarcinogenic
ones. In such cases, when the viral origin of a malignant tumor is assumed, the
scientific proof lies in induction of the malignant tumor in animal by noncellular
filtrate of this tumor or a certain viral штамм.
Transplantation
This method consists in transplanting tumor from sick animal to healthy one.
The method of transplantation revealed the following facts:
• Homotransplantation of malignant tumor is possible while that of normal tissue
does not succeed without immunodepression.
• Heterotransplantation of malignant tumor (to other species of animal) does not
succeed. It creates difficulty in modeling of human tumors.
• The growth of malignant cells is infinite. Malignant cells are maintained in the
laboratories for many years (100 and more). The experimental animal dies from
neoplasia, but the transplanted cells live infinitely (it is called immortality).
Explantation
Explantation consists in cultivating of malignant cells outside an organism (in

vitro). This method gives the possibility to induce neoplasia by cancerogenic
chemical substances and oncoviruses in healthy cells out of the organism. This
method is of a particular value because it gives a possibility to study the human
malignant cells. This method also confirms the immortality of malignant cells. This
method gives a possibility to investigate a medical drug effect on the cellular level.
ETIOLOGY
2
Etiological factors, which cause malignant tumors, are called cancerogens.
Agents, intensifying an effect of carcinogens, but not causing tumors themselves are
called cocancerogens. Carcinogens, which have these effects in combination, are
called syncancerogens.
Cancerogens may be exogenous (physical, chemical and biological) and
endogenous.
Physical Factors
Physical factors are the ionizing and ultraviolet radiation, radioactive isotopes (of
iodine, radium) and ultrasound. They may cause neoplasia in such small doses,
which do not cause a radiant disease.
Chemical Cancerogens
Chemical cancerogens are compounds of the carbon (polycyclic aromatic

hydrocarbons PAH) and nitrogen (aminoazocompounds ??aminonitrocompounds?)
substances. 3,4-benzpyren, 9,10-dimethyl-l,2-benzantrazen are related to PAH.
PAH are widely spread in nature: water, air and ground. They are the products of
incomplete burning and are formed at 400-500 °C (temperature of tobacco burning in a
cigarette). They are discovered in the smokes, overroasted butter, exhaust выхлопные
gases, smoked foods, oil and coal.
Polycyclic aromatic hydrocarbons have predominantly a local effect (cause a
tumors in the place of entry or the greatest accumulation). When putted on the skin,
they cause cancer, in subcutaneous introduction they cause sarcoma. They may cause
tumor in the organs, where they are accumulated: mammary gland tumor is formed,
when chemical cancerogens are excreted with a milk, kidney tumors may develop,
when cancerogens are excreted with a urine.
Aminoazocompounds have an organotropic effect independently from a way of
entry. Dimethylaminoasobensol causes cancer of the liver in 80% of cases regardless
a place of introduction, β-naphthilamin causes cancer of the urine bladder.
Nitrozamines also posses organotrophy. Diethylnitrosamin causes cancer of the liver
and esophagus. Methyl-nitrosurea causes tumor of the brain.
Non-organic carcinogenic substances are chromium, arsenic, cobalt, lead,
nickel, etc.
Biological Cancerogens
Biological cancerogens are viruses, which are called oncoviruses.

Only experiment may prove the role of viruses in neoplasia, when a reproduction
of a tumor is possible with noncellular filtrate.
There is an essential difference between infectious and oncoviruses. Infectious
virus multiplies in the cells and leads to the cell death, but oncovirus is masked in
the cell and initiates an infinite multiplication of a cell. Oncoviruses are not rejected
by immune mechanisms; vaccination is not possible.
Depending on the type of nucleic acid, oncoviruses are divided into DNA- and
RNA-genom viruses.
3
DNA-genom virus is capable to penetrate into the genome of a healthy cell and to
transform it into the malignant one. Epshtein-Barr virus causing Berkitt lymphoma in
men belongs to this group.
RNA-genom virus (it is named oncornavirus, or retrovirus) does not have this
ability, nevertheless it influences the genome of a cell by transmission of the genetic
information from viral RNA to DNA of a cell. RNA-genom virus has a gene of
enzyme revertase (RNA-dependent DNA- polymerase), which perform such
transmission and helps to synthesize DNA-copies on RNA-gene of virus.
Such human tumors are supposed to be caused by oncoviruses:
• Berkitt lymphoma, which is spread as epidemic among children in the countries
of the Central Africa,
• T-cellular lympholeukemia of the adults. The patients are revealed to have
antibodies against proteins of the virus
• Tumors in AIDS-patients are supposed to be caused by virus HTLV-III. The
proofs are
Tumors (Kaposhi sarcoma) are concomitant with AIDS;
It is spread with AIDS.
The genome of an RNA-containing oncovirus is rather simple, has 4-6 genes, and
only one of them (onkogen) has an ability to transform a normal cell into a malignant
one. Investigation shows, that oncogens are similar to the human genes of the growth
factors (thrombocytic, epidermal) as well as of other regulators of a cellular division
– membrane receptors to them, intracellular messengers. Penetrating into the healthy
somatic cell, such viruses initiate the formation of the so-called oncoproteins, the
stimulators of a cell division.
Similarity between oncoviruses and organism is one of the reasons of a problem
with rejection (elimination) of oncoviruses. There is a view, that the viral oncogens
are the components of the human normal genome (they are called protooncogens),
but under physiological conditions they are repressed.
Virus-genetic theory of neoplasia etiology is the most acceptable. It is suggested,
that physical and chemical factors cause neoplastic transformation by activation of
viral oncogenesis.
Except viruses, some other biological objects can cause neoplasia. Among them
the fungus Aspregillus flavum, which synthesizes aphlotoxin — a substance causing
tumors of the liver. This fungus is well multiplied in the most environments. It may
affect rice, peanut, milk in powder, eggs and corn.
Endogenous Cancerogens
Endogenous cancerogens are the steroid hormones (folliculin), bilic acids,

cholesterol, free radicals, peroxides, derivatives of the aminoacid thryptofan (indol).
Studying an etiology of the tumors, it is necessary to take into consideration the
law, that the presence of etiological factor is not sufficient for the development of
pathologic process, and additional conditions are necessary. The necessary condition
for neoplasia development consists in additional stimulation of a cellular
proliferation. It is known, that neoplasma is frequently formed in the center of the
chronic proliferative inflammation.
The knowledge of an etiology of tumors (etiological factors and conditions) has
practical use for prevention of neoplasia. These factors and conditions must be
avoided.
4
PATHOGENESIS (CANCEROGENESIS)
Pathogenesis of neoplasia proceeds in three stages:

1. Neoplastic transformation
2. Neoplastic promotion
3. Neoplastic progression
NEOPLASTIC TRANSFORMATION
Neoplastic initiation (malignization) is a process of the transformation of a

normal cell into malignant one and a transmission of new properties to descendant
cells (malignant cell produces only malignant one).
The mechanisms of neoplastic transformation are not entirely understood.
Nevertheless, an idea, that malignization is a result of a stable change in the cellular
genome, is generally assumed. There are some theories of malignancy, which are
suggested.
Theory of Mutative Cancerogenesis
The proof of this theory is a fact, that all etiological factors are mutagens. The
essence of this theory consists in assumption, that a mutation (damage of genes,
which are responsible for a cellular division) is a cause of malignization. The process
of cellular division loses inhibition and becomes infinite. Since a mutation is
irreversible, the neoplasia is also irreversible. Mutation of gene Р53 leads to
apoptosis blockade and thus a cell avoid a death.
Theory of Epigenomic Cancerogenesis
According to this conception, the cancerogens do not disrupt the structure of a

somatic cell genetic apparatus (mutation does not occur). The rare cases of
malignant cells return into the normal state are the proofs. It is assumed, that
disregulation of genetic apparatus occurs under an effect of the factors, which do not
belong to genome. These factors are located in the micro- and the macromedium
(cytoplasm, organism as a whole). Nature of these factors is not yet established.
Таким фактором may be, for example, a protein, which is produced with oncovirus
participation and which may inhibit the gene-repressor of cellular division in the cell
of the host.
Theory of Protooncogen Effect
It was shown, that the normal human genome has the genes, which are similar to
viral oncogens (scientific term for these genes is protooncogens). The real function
of these genes is a participation in embryogenesis regulating cellular sensitivity to
the growth factors. During normal postembryonic period these genes are inactive
(repressed).
The essence of this theory is an assumption, that these genes can become
excessively active, and different etiological factors (including physical and chemical
5
mutagens) play a role in this activation. DNA-copies of oncoviruses may play a
role of a promotor. Activated protooncogen is called active cellular oncogen. Just it
leads to neoplastic cell transformation.
Expression of the active cellular protooncogen leads to the increased synthesis of
the oncoproteins (tumor proteins). It is supposed that
• Oncoproteins act as the growth factors,
• Oncoproteins bind with the cellular receptors for growth factors and generate
signals for a cell division;
• Oncoproteins increase sensitivity of receptors to the growth factors or decrease
sensitivity to growth inhibitors;
• Oncoproteins play a role of the cellular proteinkinase, which starts a cellular
division.
Oncogerminative Theory of Cancerogenesis
It was Конгейм who the first paid attention on similarity between malignant and
embryonic cells and proposed a theory of oncogenesis named " a theory of
embryonal эмбриональных зачатков". In accordance to it, neoplasm develops as
atypical embryo in atypical place. Thus, malignization is embrionalization and
oncogenesis is a blocked embryogenesis. Nowadays this conception received father
development.
Similarity between malignant and embryonic cells consists in the following.
• Common markers (markers are the substances, which provide growth,
development and function of tissue - hormones, enzymes, activators, inhibitors, as
well as иммунорегуляторные, транспортные, рецепторные and структурные proteins). In
fact, all markers of cancer are find in embryonal tissue. It determines the common
biological properties - ability to implantation, invasive growth, autocrine (own)
regulation.
• Immunological tolerance to presence in organism of foreign genetical
information. Due to these mechanisms in pregnant woman наполовину foreign embryo
is not rejected but preserved («охранa чужого в своем»). Mechanisms are the following
- masking of foreign antigens, blocking of lymphocytic aggression by antibodies,
activation of T-suppressors (markers posses suppressive activity). The same
mechanisms are found in organism with neoplasma. From one hand, neoplastic
antigens are иммуногенны for own organism, from another – oncospheroid can
ускользать from immune supervision. Causes of ускользания are low иммуногенность
of malignant cell, adsorption on its surface of блокирующих antibodies and defense
of it from cytotoxic effect of macrophages and T-lymphocytes. It is supposed, that
trigger role belongs to antigens, which are common for neoplasm and embryo.
• Partenogenetic division and multiplication of one signal оплодотворенной
яйцеклетки and one signal malignant cell after its transformation. Neoplasma is not a
group of simple copies of primary transformed cell. It is a heterogenic population of
the cells. Similar to blastocysta formation, oncospheroid has a sort of three
«зародышевых листков» with their own specific functions - дифференцированные
somatic cells (which determine various histological types - меланома, неврома,
саркома and so on), oncothrophoblastic cells and germ cells (oncogerminative).
Then, similarly to blastocyte, oncospheroid provides father development. In
эмбриональном зачатке every зародышевый листок гармонично develops in direction of
its function. Contrary to this, опухолевый зачаток is a абортивное embryonal
6
development, oncogenesis is a блокированный embryogenesis. Development of
oncospheroid goes in direction of progressive decrease of доли of
дифференцированных cells, which are вытесняются by germ and throphoblastic cells
(neoplastic progression, see below).
• Immortality is another common property of malignant and embryonal cells
(malignant cells are transplanted endlessly in experiment in new hosts). Similarly to
непрерывная line of germ cells of многоклеточных organisms, malignant cells posses
immortality. It is supposed, that this property is genetically determined. It is
supposed, that in norm, a group of genes функционируют only in germ cells (in
somatic cells they get repressed) and provide genetic program of immortality. It is
supposed, that just this group of genes gets derepressed in one somatic cell in course
of neoplastic transformation and it is a main link of oncogenesis.
NEOPLASTIC PROMOTION
Neoplastic promotion is the second stage of cancerogenesis. The transformed cell

may stay in a latent state for a long time, but begins to multiply under additional
effect of promotors. It is a preclinical stage of neoplasia, when a multiplication of the
malignant cells already began, but the clinical manifestations are still absent.
Different factors can play a role of promotors (cocancerogens), but the majority of
cancerogen causes simultaneously transformation and promotion. The growth
factors, which are elaborated during inflammation, may play this role.
NEOPLASTIC PROGRESSION
Neoplastic progression is the third stage of cancerogenesis. Its essence is a stable

qualitative change of neoplasma in a direction of a constant (progressive)
aggravation of the malignant properties.
The supposed mechanisms of neoplastic progression are the following:
• Constant selection of the most viable malignant cells,
• Escaping of malignant cells from the immune supervision,
• Increase of part of oncogerminative cells and вытеснение by them of other cells
of oncospheroid,
• Additional spontaneous mutations of the malignant cells,
• Additional action of cancerogens on the genome of the malignant cells,
• Superinfection by infectious and oncoveruses.
New cells differ more and more from those primarily transformed. Anaplasia
aggravates. Clinical manifestations appear.
ROLE OF GENETIC FACTORS IN NEOPLASIA
At the cellular level, malignant properties are inherited dominantly (dominant

somatic heredity). It is observed both in vivo and in vitro as well as during the
transplantation of a tumor. Malignant cells, being multiplied, produce only
malignant cells. It is supposed, that in course of malignization, a derepression of the
genes connected with endless division and immortality of germ cells, occurs.
At the level of the whole organism, the predisposition to neoplasia is inherited
polygenetically. It means, that in the development of malignant tumor, both genetic
and environmental factors have a value.
7
Hereditary predisposition is proved statistically. A phenomenon of the “cancerous
families” is described. The high- and low-cancerous lines of experimental animals,
which have increased or decreased resistance to cancerogens, are created in
experiment.
Genetic factors determine the mechanisms of organism reaction to the
cancerogens and self-defense against a tumor. The genetically determined
disturbance in the immune system considerably increases the frequency of neoplasia.
T-lymphocytic and combined immunodeficiency increases a risk of neoplasia in
1000 times.
Men are more frequently affected with cancer of stomach while women more
frequently have tumors of sexual and mammary glands.
PECULIARITY OF THE GROWTH
The phenomenon of immortality of neoplastic cells, both in vivo and in vitro, is

a cardinal sing of neoplasia. Loss of Heiflik limit (the upper limit of a number of
cell divisions) underlies it. (In norm it is about 50 divisions after which the cells
die). The transformed cells develop in the opposite direction to the embryonic state.
Their growth is independent. More often a tumor is originated from a signal
transformed cell having its own stimulators of growth. New cells transmit their
peculiarities as a dominant sign of a somatic inheritance.
The endless growth of malignant cells is another cardinal sign of neoplasia. An
inhibition and limitation of a cellular division gets lost. The membrane receptors
become more sensitive to the growth factors.
Intercellular contacts are weakened. It is a matter of the membrane receptors and
cytoskeleton disorder (radicals of neuramin acid and glycoproteids are active). The
cells become too mobile. The multiplication of the cells is chaotic and a tissue losses
its structure. The growth is characterized by infiltration and invasion of neoplasma
into the normal tissue.
Malignant cells synthesize enzyme collagenase, activator of plasminogen
(profibrinolisin) and other proteolytic enzymes, which destruct the connective tissue.
They involve the mast cells and phagocytes into the destruction of the surrounded
normal tissue.
Malignant cells induce the formation of the capillaries (by synthesis of
angiogenin and other growth factors) providing blood supply of the tumor tissue
with substrates, glucose, aminoacids. Heparin intensifies angiogenin effect and
growing of the vessels into the tumor tissue.
The malignant cells dissolve the collagen of the vessel basal membrane and fall
into the blood and the lymph promoting infiltration and metastasing. In this way
they expand throughout an organism. In a new place they cause the development of
the same tumor.
Metastasis is a repetition of a malignant tumor in another organs. Metastasis
preserves the properties of the primary tumor.
The order of events in metastasing is the following:
• Tearing off of the malignant cells from the tumor,
• Disolvation of the connective tissue of the blood and lymphatic vessels,
• Spreading in organism by the blood and lymph,
• Adhesion to the vascular wall at a new place,
8
• Growing into the new tissue, fixation and a formation of a new malignant
node.
In a new place the malignant cells also show their cardinal properties –
infiltration and invasion of a new tissue, endless growth, immortality.
MANIFESTATIONS OF NEOPLASIA
The manifestations of neoplasia are the local and systemic.

Local manifestations are the qualitative changes in the malignant cells
(anaplasia).
Systemic manifestations are the signs of the interrelation between organism
and malignant tumor (influence of organism on the tumor and vice versa).
ANAPLASIA
Qualitative changes in the malignant cells are characterized by such terms -

anaplasia, metaplasia or atypism.
Anaplasia is a dedifferentiation (simplification, immaturation, return to the
embryonic state). Actually, malignant cell resembles embryonic ones. However, it is
an essential difference – the embryonic cells are normal and have a potentiality for
differentiation. In spite of similarity to embryonic cells, malignant cells are
pathological ones. They don’t have ability for the differentiation, have changed
morphology, metabolism, antigen structure. Therefore, such terms are used for
malignant transformed cells - metaplasia and atypism.
Such types of anaplasia are distinguished - morphological, energetical,
biochemical, physico-chemical, immunological, functional. From all these points of
view malignant cells are simplified and similar to the embryonic cells.
Morphological Anaplasia
Morphological anaplasia is the morphological signs of simplification and

immaturation of the malignant cells. Microscopic research reveals resemblance
between malignant and embryonic cells.
The signs of morphological anaplasia are the following.
• Partial or total loss of maturity.
• Increased number ?quantity ?of mitosis.
• Disorder of mitotic process. Incomplete mitosis is a nuclear division without a
division of the cytoplasm. It is possible to see the malignant cells with two nuclei and
the division of a cell into unequal parts. Cellular polymorphism is obtained.
• Presence of nucieolis in the nucleus of a malignant cell.
• Large nucleus with multiple vacuoles.
• Nucleo-cytoplasmic proportion is changed to the side of nucleus (nucleus
occupies the larger part of a cell).
• Shape of the cell becomes round.
• Phenomenon of the budding почкование of cytoplasm (the surface tension of the
membrane is lowered).
• Mitochondria pathology - change in number (decrease), size and shape.
• Изменяется строение аппарата Гольджи
9
• Cytoplasm becomes basophilic (due to RNA presence in гранулярной
цитоплазматической сети).
• Hyperchromia of the cells (they percept the dyes more intensively).
Biochemical Anaplasia (Metabolism Disorder)
Energetical anaplasia is a change of energy formation type as it is in embryonic

sells.
For its constant growth and energy formation, the malignant tumor requires more
glucose (“malignant tumor is a trap of glucose”). Blood, which flows out the
malignant tumor, does not contain glucose.
Similarly to embryonic cell the malignant one forms energy by glycolysis. The
final products are piruvate and lactate (glycolysis, which accomplishes in a presence
of oxygen is called aerobic). Amount of motochondrias is decreased, and activity of
the oxidative enzymes is depressed. Glycolysis gets intensified. There is a negative
Pasteur effect (it means, that glycolysis is not replaced by oxidation in presence of
oxygen). As a result, lactic acid is accumulated in large concentration.
Biochemical anaplasia consists in an enzymal decomposition, which is similar to
embryonic state. Quantity of enzymes, which provide differentiation and specific
function, decreases. Quantity of enzymes, which stimulate cellular division, is
increased. The change of the enzymal composition is a result of repression of some
genes and derepression of another ones.
If RNA-virus is an etiological factor, enzyme revertase appears in the malignant
cells.
The synthesis of the nucleic acids and proteins is considerably intensified.
Pentose-phosphate way of metabolism, which leads to the increased formation of
pentose (for the synthesis of nucleic acids) is activated. The synthesis of the proteins
for mitotic apparatus is considerably increased.
Malignant cell requires more aminoacids for a constant division, multiplication
and a synthesis of proteins. Therefore, malignant tumor is “a trap” not only of
glucose but nitrogen and cholesterol of the blood. All substrates are used for
energy production.
Synthesis of histones (suppressors of DNA synthesis; without histones protein
synthesis changes qualitatively and quantitatively) is decreased.
c-AMP is reduces (in norm c-AMP depresses division). It underlies an
activation of the cells division. c-GMP elevates.
Intensive synthesis of oncoproteins (tumoral proteins) from protooncogenes is
characteristic.
Embryonic α-phetoprotein is synthesized, to which physiological immunological
tolerance exists and the organism doesn't form antibodies against it.
Sometimes malignant tumor synthesizes such proteins, which are not typical to
the tissue before its transformation (for example, hormones).
Physico-Chemical Anaplasia
Some physical and chemical indices are changed in the malignant tumor towards
the embryonic state.
• Quantity of water is increased.
10
• Activation of glycolysis together with increased amount of K+ leads to the
accumulation of lactic acid and the development of intracellular acidosis (pH in
the cells is reduced to 6,4). But in the blood alkalosis develops due to
compensatory mechanisms.
• Content of potassium is increased.
• Content of calcium and magnesium is reduced.
• Electrical conductivity increases.
• Surface tension of a cellular membrane is reduced (due to decreased amount of
Ca2+). Intracellular adhesion is reduced, and malignant cells easily move into
surrounding normal tissue in invasive growth.
• Viscosity of colloids is reduced.
• Malignant cell has a negative charge. Due to negative charge of leukocytes, the
latter do not approach malignant cells.
• Diffusion of metabolic substances into the cells and its products outside is
stimulated.
• Malignant cells intensely percept the dyes.
Immunological (Antigen) Anaplasia
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-specific
видоспецифические antigens (to which a tolerance exists) remain. It is an explanation
of the fact that a homotransplantation of malignant tumor is possible while
heterotransplantation is not possible.
From the other side, the antigen complication of malignant cells takes place.
Antigens, which are produced by viral oncogen, are revealed in a malignant tumor.
The synthesis of embryonic (fetal) antigens is derepressed; embryonic proteins are
produced. Fetal α-protein is found in hepatoma. Tumor of the liver may be diagnosed
by a presence of this protein in the blood before clinical manifestation. Accidental
antigens, as a result of additional mutations of the malignant cells under an effect of
the cancerogens, may appear.
Functional Anaplasia
The division of malignant cells is changed. During initial stages of neoplasia the
type of a division is parthenogenesis and later - mitosis.
The functions of the malignant cell are simplified. Malignant cells lose those
specific functions (secretion, formation of mediators and hormones, excitability etc.),
that were typical to them before transformation. Secretion of the gastric juice in
stomach cancer and bile formation in cancer of the liver is suppressed. Tumor from
the cells of pancreas causes hyperglycemic condition and even coma.
11
In addition, the 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 the malignant tumor of renal
origin; synthesis of the thyroid gland hormone (calcitonine) was revealed in
breast cancer; hormones of pituitary gland (ADH, ACTH) are synthesized in lung
cancer. Uncontrollable synthesis of hormones (hormone-producing tumors) may
occur.
SYSTEMIC MANIFESTATIONS OF NEOPLASIA
Neoplasma is a local manifestation of a systemic disease. More frequently it is

lethal. However, organism influences tumor, developing defensive reactions. Only in
organism with depressed reactivity the development of malignant tumor is possible.
MALIGNANT TUMOR AND REACTIVITY OF ORGANISM
INFLUENCE OF ORGANISM ON TUMOR
The law, that the duration of any pathological process depends not only on
etiological factor, but also from the reactivity of organism, refers to neoplasia as
well.
Examining the patient, who is ill, it is possible to see a depression of reactivity,
however, it is difficult to estimate the defensive reactions. An experiment permits to
conduct such 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 would develop in the
place of transplantation, transplant can perish. Even after providing all necessary
conditions (sufficient mass of malignant cells, sterility) transplantation may not be
successful in 100%.
Protective Mechanisms against Tumor
Method of transplantation consists in transferring of malignant cells into healthy

animals, and many defensive reactions were discovered.
The defensive reactions are divided into the nonimmune (including genetic) and
immune ones.
The nonimmune mechanisms of protection are metabolic (removal of
cancerogens, inactivation of peroxides and free radicals, antioxidant protection),
enzymal (reparation of damaged DNA), cellular (phagocytosis, an effect of
leukocytes lysosomal factors), genetic (gene-repressor for a viral oncogen). A.A.
Bogomoletz described the cancerolytic property of the healthy blood serum.
The method of explantation shows, that after mixing of a small quantity of normal
and malignant cells the latter sometimes grow as normal ones and are capable to
accept the inhibitory signals from the normal cells.
Mechanisms of Immune Protection
Appearance of the tumor cells in the organism does not obligatory results in the
development of tumor process. The immune tissue controls antigen homeostasis in
organism (clone of the cells with any antigenic differences is eliminated by
12
immunological reactions). It refers to the clones of tumor cells. Immune system is the
leading system of protection against a tumor.
It is a function of T-killers to eliminate mutant somatic cells involving
phagocytosis and complement. This mechanism is extended also to the mutant
malignant cells. Isolated malignant cell-mutants, as a rule, are recognized and
eliminated by T-killers, mechanisms of cytolysis and phagocytosis. Since the
malignant cells have some new antigens (viral), B-lymphocytes can form antibodies.
Interferon is the inhibitor of the nucleic acids of viral origin synthesis.
These mechanisms of immune protection against the malignant tumor are well
studied in experiment with healthy animals, to which the malignant cells were
transplanted.
A.A. Bogomoletz proclaimed that the development of a malignant tumor is
theoretically impossible if the connective tissue would be healthy. The transformed
cells would be destroyed, and therefore the clinical manifestations of tumors are
noted less frequently, than neoplasia occurs. Consequently, the development of the
malignant tumor is possible only on the background of reduced immunological
reactivity.
Investigation of patients with the malignant tumor shows, that their immune
reactions are depressed.
Causes of immunodepression are
• Effect of the etiological factors (all cancerogens suppress immune reactions);
• Overload of immune system by a tumor of a large mass.
Malignant tumor demonstrates its own mechanisms of escaping from the immune
supervision. They are:
• Antigen simplification of malignant tumor;
• Appearance of the fetal antigens, to which there is an immunological tolerance;
• Masking of the tumor antigens (for example, the cells of chorionepithelioma
have neutral polysaccharide capsule);
• Negative charge of a tumor and leukocytes.
A surprising phenomenon was described in experiment. Antibodies, which are
formed in response to the tumor antigens, do not destroy tumor, but on the contrary,
protect it. They are fixed on the malignant cells and block the cytotoxic effect of T-
killers and macrophages. In some tumors there are some antigen determinants, which
stimulate T-suppressors. It is a pathological immunological tolerance. It is supposed
that the same mechanisms underlie both the physiological immunological tolerance
to embryo (fetus) and the malignant cells.
INFLUENCE OF TUMOR ON ORGANISM

CLINICAL MANIFESTATIONS OF NEOPLASIA
Neoplasia is a disease of entire organism.

As to the clinical manifestations, they depend on the form of tumor and its
localization (the details are studied at clinical departments).
Independently from localization, malignant tumor leads to an extreme exhaustion,
which is called cancerous cachexia. Capture of glucose, carbon, nitrogen,
aminoacids by a tumor is a reason. All reserves are depleted.
Development of neoplasma is accompanied by intoxication by products of tissue
decay. Malignant cells produce the substances (peptids), which activate apoptosis of
healthy cell (for example, erythropoietic, resulting in anemia).
13
Immunological depression provokes infectious diseases.
In the pathogenesis of neoplasia, a state of endocrine system has a value. At old
age a risk of neoplasia development rises. The uncontrolled synthesis of hormones
sometimes occurs. Hormones themselves may become cancerogens.
Independently from localization of malignant tumor, anemia develops.
A patient loses weight. Lethal outcome often occurs.
14
CHAPTER 11
HYPOXIA
или Hypoxy и так по всей книге ?
Hypoxia is one of the most widespread pathological process. All

the diseases from the birth up to the death have hypoxic component.
Hypoxia is a typical pathological process developing due to
insufficient tissue supply by oxygen or its disturbed use resulting in
energy (in form of ATP) production disorder.
Lack of oxygen and energy (ATP) leads to disorder of metabolism
and energy-dependant functions of organism.
CLASSIFICATION
As to localization, hypoxia is divided into local and systemic. As to

clinical duration, it is an acute and chronic. In accordance with the causes
and mechanisms of the development it is classified as hypoxic (exogenous),
respiratory, hemic, circulatory, tissue (histotoxic) and combined ones.
ETIOLOGY
Hypoxia refers to the so-called polietiological pathology. All reasons,

which cause the insufficiency of the systems of oxygen transport and
utilization (lungs, vascular system, erythrocytes of the blood) cause hypoxia.
Etiological factors are physical, chemical and biological. Their common
property is to disturb oxygen entering in organism, its spreading over
organism or its utilization. Mechanical trauma of chest disturbs breathing.
Narcotics damage respiratory center. Chemical poisons inhibit respiratory
enzymes. Microbes (pneumococcus) cause inflammation of lungs. Such
example may be continued.
For practical purpose, it is useful to realize the causes of every type of
hypoxia.
Hypoxic Hypoxia
Hypoxic hypoxia develops under conditions of a decreased pO2 in the

environment. The most typical example is the mountain disease. Accident
at the factory на производстве with the disordered oxygen supply
киснезабезпечення is another example. In the laboratories, this type of hypoxia
is modeled with the aid of barochamber (it gives a possibility to investigate a
“pure» hypoxia, which is not undergrounded by a disorder of the physiological
systems).
1
Respiratory Hypoxia
Respiratory hypoxia is caused by those factors, which disturb the lung

ventilation, lung blood supply or gas diffusion in the lungs (see in the chapter
26 “Pathophysiology of the respiratory system”).
Hemic Hypoxia
Haemic hypoxia is caused by those factors, which disturb the blood

oxygen capacity кислородой емкости. Haemic hypoxia is subdivided into
anemic one and the hypoxia, caused by hemoglobin inactivation.
Anemia as a cause of hypoxia is discussed in the chapter 20
(“Pathophysiology of a system of blood”). As to hemoglobin inactivation,
in pathologic conditions such hemoglobin compounds are formed, which
are not able to realize respiratory function. It is carboxyhemoglobin, formed
from hemoglobin and CO (carbon monoxide, which affinity to hemoglobin is
300 times more then with oxygen); this kind of hemoglobin can not
присоединять bind? oxygen; the iron-containing enzymes are also
inactivated. Methemoglobin is formed during the poisoning by nitrates and
some medical drugs with oxidizing capacity. In this form of hemoglobin
трехвалентое iron does not присоединяет bind? oxygen.
Circulatory Hypoxia
Circulatory hypoxia is caused by those factors, which disturb the local

(ischemia, thrombosis, embolism, stasis) or systemic (acute or chronic
insufficiency of heart and vessels) blood circulation. There are ischemic and
congestive forms (see chapter 7 “Pathophysiology of the peripheral blood
circulation” and chapter 25 “ Pathophysiology of the systemic blood
circulation ”).
If a disorder occurs in a system of большого круга кровообращения, the blood
oxygenation can be unchanged, but there are some disorders in oxygen
transfer into the tissues. If the changes are in pulmonary blood circulation
(малого круга кровообращения), the oxygenation of the blood is disturbed.
Circulatory hypoxia may develop not only in absolute but in relative
insufficiency of the blood circulation, when the need in oxygen in the tissue
exceeds a normal blood supply. Microcirculatory disorders also lead to the
hypoxia of the same type.
Tissue Hypoxia
Tissue hypoxia is caused by those factors, which disturb oxygen

utilization and energy (in form of ATP) formation. Tissue supply by oxygen
may be sufficient, but a biological oxidation gets disturbed.
A classical example of a tissue hipoxia is a poisoning by cyanides (they
inactivate cytochromoxydase). The large doses of alcohol, narcotics and some
medical drugs inhibit dehydrogenases of Kreb,s cycle. Antibiotic oligomicin
damages enzyme ATP-ase. Decrease of the respiratory enzymes synthesis
occurs in a deficit of the vitamins, which are their components (riboflavin,
nicotin acid).
2
Uncoupling of oxidation and phosphorylation results in the same disorders,
which are characterized to lack of oxygen. It disturbs effectiveness of
biological oxidation and ATP formation. Energy becomes dispersed as a free
heat. The resynthesis of the macroergs gets inhibited. Factors, which
activate the peroxide lipid oxidation and other ways of free radicals
formation, cause damage of mitochondrial membranes. Ionizing radiation
causes POL activation. Deficit of natural antioxydants (katalase,
cholesterol, some steroid hormones, serotonin), which reduce free radicals
and destroy hydrogen peroxide, has the same consequences.
Combined Hypoxia
Hypoxia of mentioned above types occurs not often. In clinic a combination of

them as a combined hypoxia takes place. For example, pneumonia (inflammation
of the lungs) leads to hypoxia development and includes respiratory, vascular and
tissue components. Every chronic hypoxia (regardless of initial cause) refers to
this type because of damage of the respiratory enzymes.
Hypoxia of overloading develops on the background of sufficient or
even increased tissue supply by oxygen. But an increased functional
activity of the organism or a certain organ and their increased need in
oxygen leads to the inadequate oxygen supply and development of
metabolic disorders typical to the true oxygen deficit.
PATHOGENESIS
There are two stages of hypoxia development — compensation and

decompensation.
In a stage of a compensation, the normal tissue supply by oxygen is
maintained due to the compensatory reactions. The stage of a decompensation
develops, when adaptation gets exhausted and oxygen deficiency occurs.
As the causes of a hypoxia are too numerous and this pathological process
is too widely spread, a lot of defensive reactions developed in evolution and
embrace almost all physiological systems, fist of all, the systems of
transport and utilization of oxygen.
Compensatory reactions are divided into immediate (urgent) and delayed
(non-urgent, but long-term).
IMMEDIATE COMPENSATORY REACTIONS
Immediate compensatory reactions are connected with the physiological

mechanism of hyperfunction and are realized preferably in the systems of an
oxygen transport. All of them are the “fight for oxygen”.
An increase of lung ventilation is realized by рефлекторное excitation of the
respiratory center by the impulses from the vascular chemoreceptors. (These
receptors react on the changes in the blood chemical composition, in particular,
an accumulation of CO2, decrease of O2 content and increase of H+
concentration).
Lung hyperventilation is a positive organism reaction. But it has some
negative consequences: the development of hypocapnia and gaseous
alkalosis as a result of CO2 loss from the organism. Taking into consideration
3
the role of CO2 in the cerebral and coronary blood circulation, the
regulation of respiratory and vasomotor centers tonus, hemoglobin
dissociation and maintenance of the acid-base balance, it is easy to realize the
consequences of a carbon dioxide loss. All these functions get disordered. So,
in pathogenesis of the mountain disease (and other types of the hypoxic
hypoxia), hypocapnia plays the same role as hypoxia.
Activation of the blood circulation (heart hyperfunction, increase of the
blood speed, opening of the reserved capillaries) is intended to mobilize the
oxygen transport. Circulating blood gets redistributed to supply the most
important organs (lungs, heart and brain) at the expense of decreased blood
circulation in the skin, spleen, muscles, and intestines. Рефлекторные,
humoral mechanisms (production of the NO among them) and the products of
tissue decay, which can dilate the vessels, regulate the named changes.
An increase of erythrocytes and hemoglobin content in the blood supports
an oxygen capacity кислородную емкость крови of the blood. The redistribution
of the erythrocytes from depots provides a short-term compensation of
hypoxia. During more prolonged hypoxia, the production of erythrocytes
gets increased in the bone marrow under the influence of the renal
erythropoietins and the products of erythrocytes destruction.
Oxyhemoglobin dissociation is significantly changed and may be
analyzed with the aid of correspondent curves. In hypoxia, an ability of
hemoglobin to присоединять an oxygen in the lungs and to give it to the
tissues is increased. A displacement of a curve to the left in higher inflexion
testifies an increased ability of hemoglobin to absorb oxygen in the lung
from the inhaled air; іo, the arterial blood gets saturated with oxygen better
than usually. Right deviation of the lower inflexion of a curve testifies the
decreased hemoglobin affinity with oxygen in tissues; so, the tissues get more
oxygen.
___________________________________________________________________________
Fig. 18. Changes of a curve of oxyhemoglobin dissociation (a, b, c) in a process of

adaptation to hypoxia (Мал. 37 с. 318 украинского учебника)
___________________________________________________________________________
LONG-TERM ADAPTATIVE REAСTIONS
Immediate hyperfunction of the external breathing and blood circulation

cannot provide steady and long-term adaptation to hypoxia as they require
more oxygen, and organs are working with an increased intensity. This
situation is reflected by the formula IFS↑=A↑/m (when IFS is an intensity
of function of a structures, A is a work and m is a mass of organ). It is
accompanied with an increased decay of proteins. For the long-term
hyperfunction, these organs need a structural (plastic) support to perform the
normal function while the long-term hypoxia. It is realized by increase of
their mass. It is established, that all system responsible for the oxygen
transfer, are undergo to hyperthrophy and hyperplasia (fig.18). The mass of
4
the respiratory muscles, lung alveoli and myocardium gets increased.
Capillaries are hypertrophied as well (increased in number due to effect of
thrombocytic and endotelial growth factors – angiogenin and prostaciclin), so,
these organs become better supplied with the blood. IFS gets normalized
(IFS=A↑/m↑). Adrenal cortex, hypothalamus and even neurons of the
respiratory center get hyperthrophied as well. The bone marrow undergoes
hyperplasia. Intensification of the erythropoiesis takes place. Erythrocytosis
intensificates. Young erythricytes appear (reticulocytes contain more 2,3-
DPG). A fetal hemoglobin (HbF more споріднений with an oxygen) appears.
Myoglobin content in the muscles is increased. It is an additional oxygen
capacity, a stimulator of oxygen diffusion into the tissue and possesses an
antioxidant activity.
___________________________________________________________________________
norm, adaptation
capillaries
erythrocytes,
mitochondrias
myoglobin
Fig.18. Tissue mechanisms of adaptation to hypoxia (Мал. 38 с. 319 украинского

учебника)
___________________________________________________________________________
Oxygen utilization system has the following adaptive mechanisms.

• Tissue enzymes (due to hyperthrophy of the mitochondrias) utilize oxygen
better, support a proper level of oxidizing processes and realize normal
synthesis of ATP in spite of hypoxemia.
• Energy gets used more effectively during the oxidizing processes.
• Additional energy is produced during glycolysis.
Enzymes, that participate in oxidation and energy formation, are changed
during adaptation to hypoxia. They are activated due to multiplication and
molecular conformation. It refers to cytochromoxidase (the final enzyme of
the respiratory chain) and enzymes of Kreb,s cycle. It is an adaptation at the
molecular level. At the cellular level, it goes about mitochondria, which are
hypertrophied.
Below an order of events, which leads to the sufficient energy production in
spite of oxygen deficit, is represented.
An initial link in pathogenesis of these events is an inhibition of oxidation
and oxidizing resynthesis of ATP in deficiency of oxygen. As a result, the
number of tissue macroergs gets reduced and the products of tissue decay аre
accumulated. The correlation ADP×P/ATP, marked as a phosphorylation
potential, gets increased. It is a stimulus for the cellular genetic apparatus,
which leads to the increased synthesis of nucleic acid and proteins in
mitochondria and other cellular structures. Mitochondrial mass increases. More
tight coupling of phosphorilation and oxygenation takes place in the
5
mitochondrias in the brain. Thus, the cells can produce ATP in spite of oxygen
deficiency in the blood.
It is clear, that the main link in the development of a compensation in
hypoxia is a decrease of an energy production. For a long time it was not
understood in what way a genetic apparatus is activated in hypoxia. Now a
specific factor is detected. It is a HIF-factor (hypoxy-induced factor), which is
a regulator of the genes that are responsible for mitochondrial energetic
metabolism, vasomotor control, eryhropoiesis, angiogenesis, hyperthrophy and
hyperplasia. So, an adaptation to hypoxia is genetically determined.
_______________________________________________________________
Scheme 8. Mechanisms of adaptation to hypoxia (Схема 12 с. 320 украинского
учебника)
HIF-factor
Decreased ATP Deficit of ATP, Activation of the genetic

Hypoxia production in disorder of the vital cellular apparatus
mitochondrias activity
Increase of activity of Increase of mitochondria

the mitochondrial genesis
system on the mass
Liquidation of ATP
unit
deficit and disorders
of the vital activity –
adaptation
Growth of the cell, Increase of all cellular

normaliztion of IFS structures biogenesis
and use of ATP
_______________________________________________________________
The described processes are mainly proceeded in the organs, responsible for
the oxygen transport (the lungs, heart, respiratory muscles, vessels) and in the
organs, which suffer from oxygen deficit most of all. Synthesis of structural
proteins gets increased in these organs and it leads to their hyperthrophy and
hyperplasia. So, the prolonged hyperfunction of transport and utilization
systems gets a plastic and energy provision.
The adaptive reactions mentioned above are the strategy of ‘”fight for
oxygen”. In prolong hypoxia there is another strategy – activation of
6
glycolysis (ATP formation without an oxygen). ATP splitting products
activate the enzymes of glucolysis.
Increased production of the antioxydant system enzymes (catalase,
peroxydase, superoxidismutase) is of a great importance.
Endocrine system supports the prolonged adaptation by additional secretion
of the so-called adaptive hormones (glycocorticoids), which provide tissue
устойчивость stability to hypoxia.
The described reactions, which are developed at the molecular and cellular
levels, provide not only survival in hypoxia but also a possibility to work (so
intensive as of workers in the mountain factories). It is already not only a
compensation of hypoxia but also an adaptation – a stable, economical, long-
term accommodation. It is an increase of the systemic nonspecific resistance.
In various types of hypoxia, the correlation between the noted adaptive
reactions is different. The adaptive reaction mentioned above are determined
by an ability of a tissue to provide hyperthrophy and hyperplasia, which is
determined by a genetic apparatus. This potentiality is more essential in the
bone marrow than in more differentiated cells of the nervous tissue, where
compensation gets exhausted earlier.
PATHOLOGICAL CHANGES
If the adaptive mechanisms are insufficient or exhausted, the

decompensation comes with the pathological disorders in organism. They are
developed at all levels of biological organization – molecular, cellular, organs
and organism as a whole.
Disorder of Metabolism
In summery, such metabolic disorders take place

• Energy formation deficiency
• Accumulation of the intermediate metabolic products
• Negative nitrous balance
• Metabolic acidosis
• POL activation
• Accumulation of the toxic products.
The following metabolic processes get inhibited (all of them are energy-
dependant) -
• Protein synthesis,
• Complex сложные lipids synthesis (content of lipids in the blood gets
decresed)
• Nervous mediators synthesis,
• Hormones synthesis.
• Electrolyte transport.
Energy formation gets reduced especially in form of phosphorus
compounds, containing macroergic bonds (ATP). In hypoxia, the number of
these compounds is decreased. Thus, the deficiency of oxygen leads to
energy deficit in the tissues. All other disorders are based on it.
In oxygen deficiency, metabolism is disturbed and toxic products of
incomplete oxidation are accumulated. Glycogen content in the liver and
7
muscles is reduced, glucose is not oxidized completely. The accumulated lactic
acid leads to metabolic acidosis.
The intermediate products of lipid metabolism (acetone, ацетоуксусная and
β-гидросимасляная acids) are toxic for the membranes. POL activation is an
important factor of hypoxic injury of the cells. The products of lipid peroxide
oxidation appear. Under their influence, hemoglobin is transformed into
metHb and membranes get oxidized. The intermediate products of protein
metabolism are accumulated. The ammonia increases, glutamine decreases.
The negative nitrous balance is established.
Phosphoprotein and phospholipid metabolism becomes disturbed. Their
synthesis in the liver gets reduced.
As the membrane canals are an important consumer of ATP, an active
transport of ions through the biological membranes gets disturbed. The
content of intracellular potassium is decreased. The accumulation of calcium
in cytoplasm is one of the basic links in pathogenesis of hypoxic damage of the
cells.
The synthesis of the nervous mediators and hormones is reduced. It leads
to the nervous and endocrine regulatory mechanisms impairment.
Morphological Changes
The observed biochemical disorders in the cell cause the structural ones.
At the cellular level, the ultrastructure lesion is marked as the
hyperchromatosis and decomposition of the nucleus, swelling and
degradation of mitochondrias.
The increased acidity, disorder of the membrane and energy deficit lead to
the destruction of lysosomes. The active proteolytic enzymes get released and
damage cellular structure.
The cell division gets suppressed.
Disorder in Organs and Physiological Systems
The sensitivity of different tissues to the hypoxia depends on the following

factors:
• Intensity of its own metabolism,
• Capacity of tissue glycolytic system,
• Energy reserves in form of macroergic substances (ATP),
• An ability of a genetic apparatus to provide hypethrophy and
hyperplasia.
From all these points of view the nervous system is in the most
unfavorable condition.
The first symptoms of oxygen deficiency are manifested in the nervous
system. At first, euphoria occurs. It is characterized by an emotional and
moving excitation, the feeling of one's own power or, on the contrary, the loss
of interest to the surroundings, inadequate behavior. A disorder of the so-
called internal nervous inhibition underlies these symptoms (тормозные neurons
are more sensitive to oxygen deficiency, because their functional activity and
metabolic intensity are higher).
In prolong hypoxia the metabolic and functional changes in the nervous
system are more severe. Inhibition develops. The рефлекторная activity is
8
disturbed, the regulation of breathing and blood circulation is also impaired.
Loss of consciousness and convulsions are the symptoms of a deep hypoxia.
The disorders in other organs are correlated with the disturbed nervous
regulation, energy deficiency and accumulation of the toxic metabolic
products.
As to sensitivity to oxygen deficiency, the cardiac muscle takes the second
place after the nervous system. The conductive system is more stable than the
contractile one. Tachycardia and arrhythmia are the clinical manifestations of
the disturbed excitability, conductivity and contractility of the myocardium.
The main role in a damage belongs to кальциевым и перeкисным mechanisms.
Cardiac insufficiency and the reduced arterial blood pressure lead to systemic
disorder of the blood circulation. The latter complicates the course of all
other pathologic processes.
Disorder of the external breathing consists in the disorder of the lung
ventilation. The periodical Chein-Stocks' breathing appears. The blood
congestion in the lungs leads to the thickening of the alveolo-capillary
membrane and decreased diffusion of oxygen from the alveolar air to the
blood.
In the digestive system the following pathologic signs are observed -
inhibition of peristalsis and secretion in the stomach (decreased acidity),
intestines and pancreas.
A system of the microsomal oxidation in the liver is inhibited. Production
of the cytochrome P-450 gets suppressed. The antitoxic function of the liver
is in failure. Taking into consideration a role of cytochrome P-450 in
metabolism of medical drugs, it is easy to understand a problem of usage of
medicines in treatment of all the hypoxic diseases (heart and respiratory
insufficiency).
A primary polyuria is followed by the renal disfunction.
Decrease of body temperature is obtained in the stage of decompensation.
An exhaustion of the adrenal cortex plays a role in the decompensation
development.
Discussing the compensatory reaction and the pathological changes in
hypoxia, it is necessary to state, that the protection and impairment are
closely tighten. Some pathologic sings at the same time can be interpreted as
adaptive ones. Thus, the nervous system is very sensitive to oxygen
deficiency, and an inhibition, which develops, has a protective meaning; as a
result, the nervous system becomes less sensitive to oxygen deficiency. The
decrease of body temperature may be interpreted in the same way.
It is a damage that is the initial message to the compensatory adaptation.
Thus, just a decrease of pO2 in the blood initiates the stimulation of
chemoreceptors and mobilization of the external breathing and blood
circulation. Just a deficit of ATP induces biogenesis of mitochondrias.
RESISTANCE AND SENSITIVITY TO HYPOXIA
The resistance of entire organism to hypoxia depends on several

parameters.
At first, the role of age mast be mentioned. In newborns, the automatism
of the respiratory center in hypoxia can be supported by the primitive form of
carbohydrate metabolism (anaerobic). The blood of newborns contains more
fetal hemoglobin, which can realize the respiratory function in a condition of a
9
lower partial pressure of oxygen in the blood. But the most important fact is
a poor development in the newborns central nervous system.
There are some individual differences in sensitivity to hypoxia. Markers of
increased sensitivity to hypoxia are – hyperglycemia, hyperlipidemia,
acidemia, lower content of insulin in the blood, increased content of
thyroxin, prevalence of nonsaturated fatty acids (arachidonic) in membranes,
more intensive metabolism, hyperparathryreosis, sympathotonia, high level of
peroxide metabolism, decreased level of such antioxidizing erythrocytic
enzyme as superoxidedismutase. Markers of higher resistance to hypoxia are -
hypoglycemia, hypolipidemia, increased level of insulin, decreased level of
thyroxin and somatotropin, prevalence of saturated fatty acids in membranes,
vagotonia.
Some conditions, characterized by deep inhibition of a central nervous
system and metabolism (sleep, narcosis, hypothermia), provide reduction of
organism sensitivity to hypoxia.
PRINCIPLES OF HYPOXIC STATES TREATMENT
It is possible to raise a resistance to hypoxia by

• Improving of adaptive reactions (by training in the barochamber),
• Decrease of organism requests in oxygen.
If an utilization of oxygen is normal, it may be added.
It is possible to correct metabolic disorders with the help of the specific
antihypoxic preparations. They stimulate the transport of electrons in the
respiratory chain (cytochrome) and inhibit a free radical oxidation
(antioxidants). The following preparations are in use — phosphorylated
carbohydrates, blockers of calcium canals as well as substances, increasing
glycolysis and reducing organism requirement in oxygen.
USAGE OF HYPOXIA IN MEDICINE
As a paradox, hypoxia is used in clinic for treatment. For this purpose

barocameras are used. While training in hypoxic conditions, the organism
becomes more resistant to various unfavorable factors, in particular,
physical load, infection, poisoning and ionizing radiation. Immune reactions
are activated. It is used in treatment of bronchial asthma, anemia and other
chronic diseases, in pathogenesis of which hypoxia is a leading mechanism.
In some diseases, an oxygen under an increased pressure is used (hyperoxia).
It creates oxygen stocks in the blood and tissues. It is used in poisoning by
carbon monoxide and operations on the dry heart (without blood supply).
10
CHAPTER 12
STARVATION
Starvation is a typical pathological process, which is characterized by

reorganization of metabolism and functions as a result of the decreased
incoming of a food into an organism or a disorder of its utilization.
Starvation is not only a medical but also a social problem. A lot of people starve
even now, especially in economically poor countries. Such social troubles as poverty
and unemployment are inevitably accompanied with a starvation, when a food is
insufficient in quantity and quality. A starvation of children is especially dangerous.
Ecological catastrophes and military accidents result in a food deficit.
The diseases of digestive tract and other systems, when the organism does not
assimilate a food, cause a starvation. On another hand, a starvation is a cause of
various diseases. In many chapters of this textbook a starvation is mentioned as an
etiological factor.
At the same time, a practice of the ritual (religious) fasting demonstrates a
wonderful resistance of organism to fasting. A man may live without a food more
then a month, and one may see the positive results of it. It attracts a grate interest to
the theme. Nowadays a periodical complete refuse from a food is practiced by many
educated and welfare healthy people. There are some motivations. More often it is
for the aim of a body mass decrease (obesity is a modern problem). But more
wonderful motivation is a so-called cleaning from the metabolic dross, when a
patient becomes healthier and looks more youthful.
For a long time a scientific research of a problem was oriented on a complete
starvation in the experimental animals. At the same time a practice shows a not fully
understood difference between starvation in experimental animals and fasting in
men. Obviously, mechanisms of willpower and motivation correct the duration of
fasting in men.
CLASSIFICATION
Starvation is divided into physiological, pathological and medical. Native

hibernation of some mammals is an example of a physiological starvation.
Pathological starvation is divided into complete (organism does not receive a food
at all) and incomplete, when a food comes, but insufficiently. In turn, the complete
starvation is subdivided into the starvation with water and without it (absolute).
Incomplete starvation in turn is subdivided into the quantitative and qualitative
(partial). Qualitative starvation in turn is subdivided into the protein, fatty,
carbohydrate, mineral, vitamin, and aquatic.
In addition, it must be noted a difference between starvation and fasting (the letter
means deliberate refuse from a food in men).
Etiology and pathogenesis of various types of a starvation are different.
1
COMPLETE STARVATION WITH WATER
ETIOLOGY
This type of a starvation is characterized by a complete absence of a food. Causes

can be exogenous and endogenous.
Exogenous causes may appear in accidents (industrial, ecological). There is a
voluntary fasting of the people with various motivations (political or social protest,
treatment). Only an experimental modeling gives a possibility to investigate the
changes in organism caused not by a disease but an absence of a food.
Endogenous causes of a complete starvation are rare (ЀЀЀЀЀЀЀ of esophagus in
newborn, burn of esophagus, ЀЀЀЀЀЀЀЀЀ – pathological absence of appetite). If a complete
starvation accompanies a trauma, coma, tumor of esophagus, poisoning with a constant
vomiting, a patient usually dies from a primary cause but not from Ѐ starvation.
The conditions, which determine duration and a time of a starvation, are the
following.
• Factors of environment, which increase a loss of a heat (decreased temperature
of surroundings),
• Age (a low resistance of newborns to starvation is explained by a high level of
basal metabolism, a small size of a body and less perfect regulation of metabolism
and heat balance; longer duration of a starvation in old men is determined by a
decreased level of basal metabolism),
• Sex (women starve more easily),
• General state of an organism,
• Quantity and quality of lipid and protein reserves,
• Initial level of a basal metabolism,
• Individual peculiarities of organism connected with a character of a neuro-
humoral regulation and reactivity of organism,
• Individual constitution,
• A species of animal,
• Relationship between body surface and body mass (that is why the starvation of
a small mammal is less prolonged than in big ones).
Subsequently, a time of a complete starvation depends on many factors. As to the
healthy men, approximately two months are the limit time of a complete starvation
with water.
PERIODS
There are two principles of a starvation division into periods – clinical and
pathophysiological.
Clinical Periods
Four clinical periods of a complete starvation are the following:

1. Indifference (4-6 hours in man, more in some experimental animals),
2. Excitation (connected with sensation of a hunger and an active hunt for a food);
3. Suppression,
4. Terminal, or period of paralyses and death (3-4 days).
2
Restoration comes if a starvation would be stopped before terminal period and
nourishment renewed.
In men, who are fasting deliberately with a serious motivation, an excitation and
suppression may not occur.
Pathophysiological Periods
Three pathophysiological periods of a complete starvation are distinguished on the

basis of the changes of metabolism and energy consumption. Respiratory coefficient
serves as an index. They are
1. Noneconomical use of energy (2-4 days in men),
2. Maximal adaptation (40-50 days in men),
3. Tissue decay, intoxication and death (3-5 days).
Pathophysiological periods of a complete starvation correspond to those of
stress (a non-specific reaction of a defense, see chapter 30 “Pathophysiology of
endocrine system”).
PATHOGENESIS
Starvation is meet in the nature constantly (under the natural circumstances the
animals frequently starve). So, during an evolution many adaptive reactions were
created, which sustains survive.
A starvation proceeds in two stages – compensation and decompensation.
The stage of a compensation is that, when adaptive reactions prevail and
homeostasis is maintained.
The stage of a decompensation is that, when defensive reactions are exhausted
and homeostasis is failed. The pathological changes prevail.
Adaptive reactions are created in evolution for adaptation to an absence of a
food and serve maintenance of homeostasis and physiological functions in the
unusual circumstances of life. They provide maintenance of
• Body temperature,
• Blood glucose level,
• Blood pH,
• ATP formation,
• Function of organs that act permanently – heart, respiration, renal filtration,
hormone production etc.
Defensive reactions are active and passive. The first are directed to active
seeking for a food, but they are uneconomical (need additional energy) and short-
term. Passive ones develop at the level of metabolism and are directed to decrease of
a need and expenditure of energy making metabolism more economical.
Adaptive reactions have some dynamics according to the periods of a starvation
with correspondence with a dynamics of stress, which is a non-specific mechanism of
adaptation in extreme situations. Realization of a stress is provided by activation of
the hypophysis-adrenal cortex system. Biosynthesis of their adaptive hormones is
increases. These hormones have activating and saving influence on enzymal
systems.
More detailed debate about the pathogenesis of a complete starvation is
below in accordance with the periods of this process.
PATHOPHYSIOLOGICAL CHARACTERISTICS OF PERIODS
3
THE FIRST PERIOD
The first period is a realization of instinct ЀЀЀЀЀЀ. It is an active stage, which provide
an active search for a food and preserves a life. Duration of this period is 3-4 days.
Adaptive reactions are directed to the realization of instinct. Sensation of a
hunger activates behavior in absence of a food. According to Selye (the author of a
stress conception) it is an alarm reaction in extreme situation. It provides a nervous
excitement, adaptation and survival. It is an active defense, which needs an additional
energy.
Changes in Metabolism
Metabolism is activated. It is a period of an uneconomical energy and substances

consumption.
The basal metabolism increases as well as oxygen consumption.
Respiratory coefficient increases to 1. It means, that an oxidation and energy
formation is provided by increased expenditure of carbohydrates. Just they are
utilized predominantly.
Glucose blood level is maintained normally or temporally greater than before.
The reserve of glycogen (in the liver), which is used for energy formation,
decreases quickly, during 6 hours of starvation. But it does not disappear because it is
formed as a result of the glyconeogenesis.
The glycocorticoidal function of the adrenal cortex is stimulated.
Secretion of insulin decreases, an activity of the pancreatic α-cells increases with
glucagone secretion.
The nitrogen excretion with urine decreases (from 12-14 g to 10 g daily) on the
2nd-3rd day of a starvation. The negative nirtogen balance establishes.
Changes in Organs and Systems
The earliest manifestation of a starvation is a nervous excitement and a

sensation of a hunger caused by an excitation of the food center.
All physiological systems are activated and serve realization of a hunger instinct
and stress for homeostasis regulation and reorganization of metabolism in absence of
energetic resources.
Motor activity activates.
Arterial blood pressure rises a little.
Pituitary-adrenal cortex system is activated. Hormones of adaptation (ACTH and
glucocorticoids) are secreted. Tropic pituitary hormones activate the function of the
peripheral endocrine glands. A secretion of thyrotropin activates the function of the
thyroid gland. A secretion of corticotropin stimulates the adrenal cortex.
Body mass decreases significantly due to noneconomial use of energy.
In some days (3-4) a sensation of a hunger disappears. The next stage of
adaptation comes.
THE SECOND PERIOD
The second period is the most prolonged one. Together with the first period, it is a
stage compensation but by different mechanisms. The second stage is a stage of
maximal adaptation. It is a period of the economical utilization of substances and
energy. The second period determines practically the whole duration of a
4
starvation. Its duration depends on many factors mentioned above. In men it is 30-40
days and more.
Adaptation is provided at the level of metabolism. Adaptive reactions are realized
by: a) more economical use of nutrients, b) use of lipids as nutritious reserves, c)
reduction in the basal metabolism, d) changes in enzymes activity and
isofermental systems. They are below in more details.
The second period is the longest period of a starvation.

Metabolism demonstrates maximal adaptation and a deep reorganization directed
to economical expenditure of energy resources.
Basal metabolism decreases on 10-20% and remains on this level.
Reserves of carbohydrtes in form of glycogen are exhausted after 5-6 days and
metabolism is switching over to metabolism to fats. The lipids are utilized
predominantly. It is demonstrated by a decrease of a respiratory coefficient, which is
equal 0,7. About 80% of energy the organism receives as a result of oxidation of fats,
3% - by oxidation of glucose, 13% - by oxidation of proteins.
Lipolysis is activated in the liver while lipogenesis is inhibited. Transport
ЀЀЀЀЀЀЀЀЀЀЀЀ lipemia is obtained. The free fat acids come into the blood and other organs.
In the liver and muscles the fat acids are transported through the mitochondria1
membranes to the places of oxygenation.
In exhaustion of glycogene, the production of the ketone bodies begins.
Intensification of β-oxygenation is marked in the increased concentration of the
ketone bodies in blood. In 48-72 h of starvation the level of ketone bodies is 3 mmol.
As to the glucose blood level, it nevertheless is maintained normally in spite of
nonentering of a food for many days and exhaustion of the carbohydrate reserves. It is
provided by glyconeogenesis activation, which is registered in the kidneys and in liver.
80 g of glucose is produced every day and a half of this quantity is formed from
glycerin (catabolism of fats) and aminoacids (protein catabolism).
A level of insulin decreases resulting in inhibition of the hexokinase and the
effectiveness of the Kreb,s cycle. Decrease of glucose entering into the cell occurs in
those tissues, where a transport of glucose through the cellular membranes depends on
insulin (myocard, skeletal muscles and adipose tissue). Just in these organs
utilization of lipid increases. The brain obtains glucose normally.
Catabolism is directed to providing metabolism and function of the vitally
important organs, especially of the brain, which needs 1,600-1,800 kcal/day provided
by splitting of 100-150 g of glucose.
It is very important to note, that pH of the blood is maintained normal in spite of
increased ketogenesis. Regulatory mechanisms join this process for compensation of
ketoacidosis. Ammonia, which is released by desamination, binds ketone bodies.
Another mechanisms of acid-base regulation (acidogenesis and ammoniogenesis in
the kidneys) are activated. Non-respiratory (metabolic) acidosis develops as a result of
this, but it is compensated up to the terminal period of a starvation. An amount of blood
bicarbonates is decreased. Excretion of ammoniacal salts with urine increases.
The amount of oxidative water increases.
As to proteins, they are, in general, are preserved in this stage of a complete
starvation with water. Nitrogen excretion with urine decreases to 7-4 g reflecting an
economical expenditure of proteins. Nevertheless, nitrous balance is negative as a
result of increased desamination and use of the aminoacids for gluconeogenesis and
5
maintenance of the blood sugar level. At the same time, the possibility of protein
synthesis for vitally important organs are preserved in dispenses of protein splitting
in another organs. The so-called endogenous nourishment ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ as an
exclusive mechanism of adaptation in a complete starvation provides it.
Endogenous Nourishment. ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ Scientific research had showed that
the organism is feeding during the complete starvation. The quantity of albumin
and globulin elevates in a gastric juice on the 6th-8th day and the digestive
enzymes are present in the intestine during a complete starvation up to its end. The
proteins are splitted in the intestine (they are fermented) with the formation of
aminoacids, which are absorbed into the blood and are used repeatedly for
protein synthesis in the vitally important organs. Thus, the redistribution of
protein substances occurs in the organism. A new unique regulation of a protein
balance between organs provides the vitally important constantly working organs
with the plastic materials by repeated use of the aminoacids.
It was discovered, that a weight of a heart, nervous tissue is lowered less, than that
of other organs.
Body temperature is maintained normal. Heat production is maintained on a

minimal level. Heat emission is somewhat reduced.
Other functions of the organism are kept within physiological limits. The special
disturbances are absent in the system of the blood circulation and respiration. Arterial
blood pressure, volume of circulated blood and heart activity are sustained in
physiological standards.
Activity of the digestive system is inhibited but it participates in endogenous
nutrition. ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ
The metabolic function of the liver is activated (lipolysis and glyconeogenesis are
increased).
Production of urine (filtration, reabsorption, and secretion) is maintained in
kidneys.
The function of endocrine system is reorganazied principally. The function of a
majority of the endocrine glands (thyroid, adrenal ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ, pancreas, sexual)
is suppressed. A decreased neurosecretion in hypothalamus nuclei is a main
mechanism. An exception is a function of the adrenal cortex as an organ of profound
adaptation. A secretion of glucocorticoids sustains due to hypertrophy of the adrenal
cortex.
It is of a principal importance that a mental activity is preserved in a complete
starvation with water.
As to the body mass, there is such peculiarity. It continues to decrease
but more slowly then during the first period because of economical use of
the materials and decrease of the basal metabolism. An interesting fact is,
that a decrease of mass of various organs is different. The adipose tissue
looses mass most intensively while the heart and the nervous tissue less
intensively. Moreover, it was shown in experiment with the young animals
(which are in the period of growth) that their brain continues to grow up
during a complete starvation with water. This dynamics is represented in a
figure 20.
___________________________________________________________________________
6
lipid depot 97%, lean 60%, liver 53,7%,testis 40%, muscles 30,7%,blood 26%, kidneys
25,9%, skin 20,6%, intestine 18%, lungs 17,7%, pancreas 17%, bones 13,9%, nervous tissue
3,9%, heart 3,6%
Fig. 20. Degree of mass loss of organs and tissues in complete starvation (ЀЀЀ.36 Ѐ. 304
ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ)
__________________________________________________________________________
Finally, it must be noted that in a complete starvation with water no one dystrophic
change is registrated but only atrophic ones.
THE THIRD (TERMINAL) PERIOD
The third period is a period of a decompensation, terminal one. Its duration is

some days (about 3-5 days). It is a period of the tissue decay, intoxication and
death.
Respiratory coefficient increases in comparison with the previous period and is

equal to 0.8. It means that proteins get used as a resource of energy. There is an
increased lysis not only of that proteins that are easily mobilized (blood proteins) but
also the stable proteins of the muscles. Fall down of body mass accelerates again
reflecting the destructive processes.
Destructive changes in mitochondria appear. The level of oxidative phosphorylation
decreases in the cells. A disorder of enzymal systems, which are destructed in the
process of a starvation, provokes a deep disorder of metabolism.
The glucose level in the blood is less than 3 mmol/1.
An excretion of nitrogen, potassium and phosphorus with urine increases. Their ratio
in urine is the same as in protoplasm.
Metabolic acidosis becomes decompensated.
A deep disorder of physiological functions comes due to an exhaustion of

energy and regulative function of the endocrine system.
A disorder of all vital functions is such as it is typical for any terminal state
– decrease of the arterial blood pressure, disorder of respiration, renal filtration
etc. Paralyses develop.
The body temperature flows down. A heat production is collapsed.
Wonderful is a fact that the pathomorphological changes are insignificant
(predominantly atrophic but not dystrophic ones) even in those who died after a
complete starvation.
RESTORATION
There are two outcomes of a complete starvation – lethal or restoration if

nourishment would be renewed.
7
Restoration is possible even at the beginning of the last period of a starvation. The
restoration of all functions of the organism may be total. It is evidence that
complete starvation does not provoke irreversible changes. Restoration completes
very quickly. Thus, a loss of 40-50% of body mass during one month is restored
during two weeks. Appetite appears, oxidative processes are intensified, process of
assimilation is stimulated, and positive nitrous balance is established. However, taking
into account the state of the digestive system, it is necessary to carry out fattening
carefully.
Finally it must be noted ones more, that in a complete starvation with water no one
dystrophic change is registrated but only atrophic ones that are rather quickly and
completely restored when starvation stops.
MEDICAL STARVATION (FASTING)
Regularities, which were obtained while scientific study of a complete starvation

with water, serve as approval for its medical use as fasting. A leading idea gives
hopes, that it does not cause a dystrophy but only atrophy, which can be completely
restored. .
Nowadays fasting is used as a non-specific method of some disease treatment
including allergic, cardiovascular, digestive, dermal, diseases of the joints, obesity and
even psychic. Dosed fasting (from 1-7 to 15-35 days but before the third period starts)
increases the processes of dissimilation and promotes excretion of excessive metabolic
dross. During the so-called endogenous nourishment an organism uses own
pathological and dystrophic tissue and proteins - adipose deposit, products of
metabolism, pathologic proteins, infiltration and induration of a connective tissue,
scars. Restorative process leads to renovation of a whole organism. The general state
of organism improves, the weakness disappears, and appetite appears.
An important condition of a successful result of a fasting is a serious motivation
from the site of a patient.
COMPLETE STARVATION WITHOUT WATER (ABSOLUTE)
Complete starvation without water has the same periods as a complete starvation
with water, but it is more severe and shorter (3-6 days).
If a water isn’t come from outside, it is drawn from the tissues. It is oxidative
water. The most quantity of water reveals after oxidation of fats - 100 g give 112 g
of water, of proteins and carbohydrates - double less. Products of metabolism, which
are formed, require more water for their excretion and the vicious circle is formed,
which hastens the death. Catabolic processes are too activated, products of tissue
decay are accumulated, and intoxication develops.
INCOMPLETE STARVATION
Contrary to a complete starvation, which happens not often, incomplete starvation

happens often. Many pathologic states, especially connected with dysfunction of the
digestive organs, are accompanied by starvation. The social troubles also cause it.
8
Incomplete starvation may be quantitative and qualitative. Their etiology and
pathogenesis are different. Clinical manifestations are also different. Very often they are
combined.
QUANTATIVE INCOMPLETE STARVATION
This type of a starvation is undernourishment. It takes place, when organism

chronically does not receive with a food a necessary quantity of materials for energy
production (2000 – 1500 kkals and less instead of 2500 – 3500 kkals).
Etiology
Etiological factors are those, which cause partial limitation of food incoming into
the organism or difficulties in its utilization. They can be exogenous and endogenous.
Exogenous causes are: a) insufficient amount of a food, b) factors, which damage
the digestive tract resulting in limitation of entering of a food into the organism, c)
factors, which cause the diseases of the digestive tract with disturbance of a food
utilization. Etiological factors are physical (trauma), chemical (poisoning, which cause a
constant vomiting), biological (infectious, phsycogenic factors, which cause anorexia)
and social (underfeeding in poverty and unemployment).
Endogenous causes are the diseases of the digestive system, which limit an
entrance of a food into organism (morphological defects) or the diseases, which make
it difficult to utilize the food (inflammation, tumor, disbacteriosis, endogenous
avitaminosis, genetic causes as it is in the enzymopathy, which makes a suction of a
food difficult).
Pathogenesis
An incomplete starvation is a chronic situation, which may last for a long time. In a
deficit of a food, an organism expends energetic resources very economically. Body
mass decreases more slowly than in a complete starvation, but often it is masked by an
edema.
Basal metabolism decreases considerably, more significantly then in a complete
starvation with water (on 30-35% instead 10-20%). Respiratory coefficient decreases
insignificantly.
Contrary to a complete starvation, when no dystrophy observed, an incomplete
starvation follows severe signs of a dystrophy. Degenerative processes develop in the
tissues. They are more grave then in a complete starvation because of its more duration.
As a result of a deficit of the plastic materials (proteins), the synthetic processes are
suppressed. Oncotic blood pressure decreases due to decrease of the content of proteins
in the blood. Osmotic pressure in the tissue rises due to accumulation of chlorides. As a
result a retention of water is observed.
A starvation may cause many diseases (in many chapters of this textbook it is
mentioned as an etiological factor).
Manifestations
An inhibition of the synthetic processes underlies a majority of the

pathophysiological and clinical manifestations of an incomplete starvation.
9
Hemopoiesis gets suppressed and a deficit of the blood cells occurs. Diserythropoietic
anemia develops often. Decrease of the leukocyte amount (leukopenia and
lymphopenia) results in immunodepression.
Protein-synthetic function of the liver is suppressed as well. The production of the
albumins and globulins (immunoglobulins) is suppressed. Organism becomes
predisposed to an infection.
A synthesis the hormones is insufficient.
Heeling of the wounds and bone fracture is slowed.
A typical manifestation of a prolonged starvation is a cachexic edema. This
edema belongs to the systemic type of edemas. Hypoproteinemia underlies it.
In incomplete starvation an excitation of the food center is maintained all
the time and a sensation of a hunger is renewed periodically.
In the system of the blood circulation bradycardia (decrease of the heart rate) and
decrease of an arterial blood pressure are observed. Breathing slowed and weakened.
Sex instinct is suppressed.
Workability is decreased.
Death comes in loss about 40% of the body mass.
QUALITATIVE (PARTIAL) INCOMPLETE STARVATION
Qualitative starvation develops, when a content of one or some nutrient components

(protein, lipids, carbohydrates, minerals, vitamins, and electrolytes) in a food is
insufficient. Energetic value of a food is normal. Qualitative starvation is often combined
with a quantitative one.
Clinical manifestations are specific and depend on a certain substance
insufficiently incoming.
In deficiency of carbohydrates in a food a liver becomes poor with glycogen
resulting in ketogenesis due to the lipids transport into the liver.
Deficiency of fatty in a food is easily compensated by carbohydrates and proteins
as a resource of energy. But, for providing a plastic function of the lipids, supply
with the ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ ЀЀЀЀЀЀ – ЀЀЀЀЀЀЀЀЀЀЀЀ, ЀЀЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀЀЀЀ is
necessary. It is also important to take into consideration that suction of vitamins A,
D, K is connected with lipids (lipid-soluble vitamins) and avitaminosis develops in
fatty starvation.
Protein starvation is the most serious. Prolonged malnutrition with a primary
deficit of proteins in the food leads to protein-calorie insufficiency. It causes a
severe alimentary dystrophy. In children it develops quicker than in adults as they have
an increased need in proteins. It influences harmfully the development of nervous
system in early childhood, when the nervous cells grow intensively. Depression of
synthesis of nucleoproteids, proteins and decrease of enzymal activity accompanies a
prolonged protein insufficiency. A quantity of the cells is diminished and atrophic
processes develop in the organs. The growth and development of the bones is
suppressed. Avitaminosis develops. It is a ground of anemia development. The basal
metabolism is decreased. Lipid hepatic degeneration occurs. The pancreas undergoes
hyalinosis and fibrosis. Dystrophic changes of the heart and kidney take place. It
often leads to death. Only rational nourishment can save a child.
Mineral starvation is manifested as a deficit of the important ions – potassium
(nervous and muscle excitability gets depressed), calcium (osteoporosis and tetania
develops), iron (hypochromic anemia develops), cobaltum (disorder of
10
hemopoiesis), jodum (endemic goiter and hypothyreosis), F fluor? (disorder of bones
formation).
Vitamin insufficiency (avitaminosis and hypovitaminosis) can be exogenous (as a
result of absence or low content of vitamins in a food) or endogenous. Vitamins B1,
Ѐ6, Ѐ12 and ЀЀ are important for nervous system, vitamins Ѐ6, Ѐ5 and Ѐ - for
endocrine system, vitamin B12 – for hemopoiesis, vitamins Ѐ1 and ЀЀ – for digestive
system.
Below are some example of avitaminosis –
• Beri-beri (deficit of vitamin Ѐ1 is manifested by polyneuritis and dystrophic
changes in the nervous fibers and myelin layers),
• ЀЀЀЀЀЀЀЀ (deficit of vitamin ЀЀ is manifested by dermatitis, damage of the
mucous membranes of a digestive tract with diarrhea),
• Rachitis (deficit of vitamin D2 is manifested by a disorder of a suction of
calcium and phosphorus in small intestine and renal tubes with a disorder of
bone mineralization),
• ЀЀЀЀЀ (deficit of ascorbic acid is manifested by a disorder of oxidative
processes, collagen synthesis due to which the vessels loose solidity and easily
break resulting in hemorrhage syndrome).
11
TYPICAL DISORDERS OF METABOLISM
ЀЀ ЀЀЀЀ ЀЀЀЀЀЀ ЀЀ ЀЀЀЀЀЀ ЀЀЀЀЀЀЀ ЀЀ Ѐ ЀЀ ЀЀЀЀ ЀЀЀЀЀ ЀЀЀЀЀ ЀЀЀЀЀЀЀЀ
ЀЀ-ЀЀЀЀЀЀ – ЀЀЀЀЀЀЀЀЀЀ (ЀЀЀЀЀЀЀ) Ѐ ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ – (ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ) ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ ЀЀЀЀ. ЀЀЀЀЀЀ deficit
and deficiency.
CHAPTER 13
PATHOLOGY OF ENERGY BALANCE AND BASAL METABOLISM
Metabolism performs energetic (energy formation) and plastic (synthesis of necessary products)
functions.
Every disease has disorders of metabolism in its ground. No pathogenesis cannot be truly understood
without deep penetration into metabolism disorders. Just they underlie the development of all pathological
processes (inflammation, allergy, neoplasia, hypoxia etc.) interpreted at molecular level. Failure of any
physiological system includes specific features of dismetabolism, which are noted in the corespondent
chapters of this textbook.
The next six chapters deal with typical disorders of every type of metabolism (energy balance, the
metabolism of carbohydrates, lipids and proteins as well as water and acid-base balance). Some clinical
examples (diabetes mellitus, obesity and edema) are mentioned in addition.
Dynamics of metabolism is such.
• Entering of the simple and complete substances (proteins, carbohydrates, lipids, vitamins, electrolytes)
with a food into digestive tract.
• Primary splitting them into simpler products with the aid of digestive ferments.
• Sucking them into the blood.
• Transport of them with the blood towards organs and tissues (each organ receives substrates necessary
for it).
• Catabolism is an intracellular splitting of the substances by intracellular enzymes.
• Formation of intermediate products, which in turn serve as the substrates for various metabolic
pathways.
• Anabolism is a synthesis of the products for organs.
• Deposition of reserves.
• Formation of the final products.
• Excretion of the final products.
The disorders are possible at any stage of metabolic transformation of substances, which is provided
with the aid of enzymes. Reaction substrate-enzyme is a base of metabolism. Deficit or surplus of
enzymes leis in the ground of dismetabolism.
So, metabolism consists in two opposite processes - anabolism and catabolism, which are connected
dynamically. The disturbances of metabolism are divided into hereditary and acquired according to
participation of genetic mechanisms.
DISORDER OF METABOLISM REGULATION
Metabolism is determined by genetic factors and is regulated by the nervous and endocrine systems.
Therefore its derangement may have a hereditary nature or be secondary acquired as a result of
regulatory systems disorder.
1
The disturbances of metabolism are manifested at all levels of biological organization – molecular,
cellular and the organism as a whole.
At the cellular level the leading role in self-regulation of metabolism belongs to genetic mechanisms.
Majority of hereditary defects of metabolism is caused by mutation of the genes encoding the
enzymes. Genetically determined enzymopathy results in depressed or altered synthesis of substances.
Hormonal regulation of intracellular metabolism is provided by influence on genetic apparatus
resulting in induction of enzyme synthesis. In addition, hormones activate the existing non-active forms of
enzymes (adrenaline activates phosphorilase, insulin – hexokinase). Hormones may influence on
permeability of cellular membranes for substrates (glucose, aminoacids, ions etc.).
A constant arrival of information carried by nervous mediators and hormones is necessary for
coordination of the cellular metabolism. For genetic realization of these regulatory influences there are the
specific receptors to them, which are located on the cellular membranes surface. Pathology of receptors
may underlie pathogenesis of a disease (as it is in the second type of diabetes mellitus, see below).
Depressed enzyme activity leads to uncompleted metabolism and accumulation of non-metabolized
substrates and intermediate products. Increased enzymal activity leads to accumulation of the final
products of metabolism.
Together with intracellular self-regulative mechanisms, an organism has more complicated ones -
neurohumoral ones which influence metabolism to a greater degree.
For understanding the mechanisms of regulation, it is necessary to distinguish ones of catabolic and
anabolic effect.
Catabolic regulatory effect is an activation of splitting of substances. They are – sympathetic nervous
influences and hormones with catabolic effect. Anabolic regulatory effect is an activation of synthesis and
plastic processes, formation of reserves.
Thus, an emotional irritation may cause disregulation of heat production, hyperglycemia, hyperlipemia,
overeating and obesity. Many disorders of metabolism, thermoregulation, physical and sexual maturation
are caused by lesion of the diencephalon. Hypothalamus influences metabolism by releasing-factors
through pituitary gland or parapituitary ways.
Vegetative nervous system actively influences metabolism. Thus, sympathetic part of it activates
lipolysis, n. vagus activates insulin secretion. Disorder of vegetative nervous system may provoke the
changes of metabolism. Some diseases are connected with damage of sympathetic nodes.
The nervous system provides the so-called neurothrophical function and controls the tissue metabolism
with the help of mediators and axoplasmic flow. The neurodysthrophic process develops due to
disturbance of this function.
Any hormone effects metabolism by its specific influence on a certain metabolic pathways. As to
direction of an effect they are of catabolic (adrenaline, thyroxin) and anabolic (insulin, somatotropin)
action.
Below there are their characteristics as to their influence on energy and basal metabolism.
Adrenaline provides all types of organism activity, stimulates basal metabolism, activates
lipolysis, causes hyperglycemia and provides organism with calorigenic materials.
Thyroxin is a catabolic hormone. It stimulates metabolism and is one of the main regulators, stimulates
oxidation, phosphorylation and energy formation in form of calories.
Hormones of pituitary gland influence metabolism and somatotropin (hormone of growth)
most of all. It stimulates free oxidation and heat production.
Glucocorticoids refer to catabolic hormones as stimulate protein disintegration, but at the same time
promote glycogen synthesis and obesity.
Sex hormones (testosterone and progesterone) refer to anabolics. At the same time they activate free
oxidation and promote energy release.
Insulin is a main trophotropic hormone. It increases formation of glycogen, fat in adipose depot and
proteins in muscles. It ensures utilization of glucose by the cells, involves lipids and proteins into
production of freely used energy resource in form of glucose, provides depositions of reserves in form
of glycogen and fat. It ensures formation of ATP by coupling of oxidation and phosphorylation.
2
Thus, there is a close connection between intracellular mechanisms of self-regulation of metabolism,
which are determined by genetic mechanisms, and a neurohumoral regulation of it. Disorder of any of them
results in dismetabolism, cellular pathology and dysfunction of organ.
PATOLOGY OF ENERGY BALANCE
Every kind of work needs energy. Every defensive reaction and hyperfunction needs energy as well.
Macroorganism is a system, which produces energy for itself (probably we do not know all types of
biological energy). Nevertheless it is known that dehydrogenation (ЀЀЀЀЀЀЀЀЀЀ of H+) is a mechanism of
energy reveal (like a proton fuel ЀЀЀЀЀЀЀ). It is produced with the aid of oxygen as an acceptor of
electrons. Then, the energy obtains two forms –
• Thermal ЀЀЀЀЀЀЀЀ energy in form of calories of heat,
• Biological energy in form of high-energy phosphate bonds.
The first form is needed for warming of organism and maintenance of a body temperature. The second
form is needed for all biological energy-depended processes – contraction, secretion, function of ion
canals, synthesis of substances, cell division, etc. ATP is a specific form of biological energy, which is
accumulated in organism in this reserved form. There are two main processes of energy production –
oxidation and phosphorilation.
Energy balance consists in dynamic interconnection of catabolism and anabolism.
Energy disbalance is a base of a majority of the functional and organic disorders in organs and tissues.
It may develop at all stages of energy transformation due to
• Absence or lack of substrates,
• Deficit of oxygen,
• Change in amount or activity of enzymes (of glycolysis, Krebs cycle, respiratory chains),
• Damage of the regulatory systems,
• Genetic defects.
In brief, for energy production the cells need substrates, enzymes and as a rule oxygen.
Glucose, fatty acids, aminoacids serve as the substrates for energy production.
Respiratory coefficient reflects the preferred oxidation of a certain substrates. Normal respiratory
coefficient is 0,9. Respiratory coefficient rises to 1,0, if carbohydrates are oxidized predominantly.
Respiratory coefficient decreases to 0,7, if lipids are oxidized mainly. Respiratory coefficient is equal to
0,8, if proteins are used for energy production.
Hypothalamus regulates balance of a thermal energy. Mitochondrias are the place of energy formation.
Oxidation (with participation of O2) is more effective pathway of energy formation in form of ATP than
glycolysis.
Two processes are tightly connected (coupled) in mitochondrias - oxidation and phosphorilation. They
are regulated process and depend from a state of mitochondrias and hormonal regulation. Organism
manipulates with this connection.
If organism needs an additional quantity of calories, these processes gets uncoupled, free oxidation
predominates, formation of ATP and specific functions of the cells as well as plastic processes are
temporarily limited. As an example, the situation, which is connected with maintenance of own
temperature under influence of a cold, may be proposed when organism occurs in need of urgent mobilization
of a heat, which is realized by increase of free oxidation. The same events occur during a fever. Limitation
of a heat loss (heat emission) is a biological mechanism of accumulation of thermal energy.
If organism needs an additional quantity of ATP (hyperfunction of any physiological system), oxidation
and phosphorylation are coupled more tightly.
Contemporary methods of investigation make it possible to estimate a state of mitochondria and to
determine a quantity of ATP.
Physiological function of mitochondria can be disrupted. The swelling of mitochondria leads to the
uncoupling of oxidation and phosphorylation. ATP formation decreases, the specific functions of cells are
disrupted.
3
Many factors, which have an effect of uncoupling, are of clinical interest because of phosphorilation
disorder.
Among them there is a hypersecretion of thyroxin, parathyrine, progesterone, somatotropine,
vasopressin. As to thyroxin, this hormone together with adrenaline is the most potent regulator of energy
production. It increases the permeability of mitochondria, stimulates oxidation, phosphorylation and
energy formation. Energy production in form of heat increases, but resynthesis of ATP is impeded. Its
calorigenic effect is not explained by uncoupling of oxidation and phosphorilation because
mitochondrias are not swelled but increased in mass. Oxidative enzymes and ATP-ase get activated. A
simultaneous stimulation of both anabolic and catabolic processes takes place but thermal energy gets
dispersed increasing body temperature.
Some microorganisms produce uncoupling effect and bacterial intoxication caused by them is of a
clinical significance. Diphtherial toxin as well as ЀЀЀЀЀ Ѐ ЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀ have
uncoupling effect.
Majority of the viral infections is connected with a disorder of bioenergetic processes. Virus uses
certain substrates (ЀЀP, ЀЀP, acetil-CЀЀ, RNA, free ЀЀЀЀЀЀЀЀЀЀ etc.) for need of its growth. Thus, virus
of hepatitis is very aggressive. Deficit of ribonuclear acids leads to disorder of cellular proteins synthesis,
specifically of cellular enzymes; a usage of free ЀЀЀЀЀЀЀЀЀЀ – to insufficient formation of NЀD and
NЀDP.
Vitamins, especially of Ѐ-group, play a role in energy production, as they are the compounds of
coenzymes of the Krebs cycle and respiratory chains of electron transport. Thus, vitamins ЀЀ and Ѐ2 are
compounds of nicotinamidic and flavinic dehydrogenases.
The disturbance of energy metabolism underlies majority of functional and organic impairments of
organs and tissues and insufficiency of physiological systems.
INCREASE OF ENERGY PRODUCTION
Mechanisms of energy production activation are created in evolution and are very well regulated. They
provide not only physiological activity but also adaptation and resistance in pathological conditions.
Nevertheless, according to significance, an increase of energy production may be in two variants -
• as a defensive reaction,
• as a result of metabolism regulation disorder.
The difference between them leis in the fact that the first has positive meaning and is regulated. The
second is a disorder and has negative meaning (scheme 9).
4
Scheme 9. Causes, mechanisms and consequences of increase of energy production
↑ Energy production
positive negative As a result of

As a disorder of
defensive Significance metabolism
reaction regulation
↑ Calories of ↑ ATP
heat
↑ secretion of
catabolic
Causes hormones
↑ of oxidation Toxic effect

Activation of of uncoupling
thermo- substances
Mechanisms
regulation ↑ of coupling
of oxidation
and
phosphorilation
↑ of oxidation
↑ Heat
production
↓ of heat
↑ Heat
emission Results emission
Uncoupling of
oxidation and Exhaustion of
phosphorilation nervous and
endocrine
systems
↑ Plastic
processes
Maintenance
of body t° ↑ Growth
in cold
Results
Pregnancy
↑ of body t°
in fever Prolonged
adaptarion
Increase of Energy Production as a Defensive Reaction
Increase of energy production accompanies every kind of hyperfunction and is produced in two
following forms -
• Thermal energy in calories of heat,
• Biological energy in form of ATP.
5
Increase of Energy Production in Form of Calories of Heat
Increase of heat production occurs in influence of low surrounding temperature (cold) for maintenance
of normal body temperature or in fever when increase of body temperature is a defensive reaction as it
was explained in the chapter 10. In these cases the defensive reactions are very well regulated. A special
nervous center is located in hypothalamus (center of thermoregulation), which guides a thermal balance.
It is important to understand a strategy of biological adaptive mechanisms because they differ from that
in non-biological objects. In latter (machines) energy is produced according to the physical lows of
thermodynamics – the more fuel ЀЀЀЀЀЀЀ the more energy. In biological objects the lows are another – it
makes possible to receive a thermal energy by mechanisms which do not need more substrates and oxygen.
They are – limitation of heat emission and uncoupling of oxygenation and phosphorilation.
Thus, accumulation of heat is provided in organism by
• Activation of oxidation,
• Limitation of heat emission,
• Uncoupling of oxidation and phosphorilation.
Activation of energy production in form of calories takes place in the first stage of overcooling. A
peculiarity of this process lies in accumulation of heat partially by increasing of heat production
(oxidation) and especially by limitation of heat loss (insulin reduces muscular trembling).
Activation of energy production in form of calories takes place in a fever. A peculiarity of this process
lies in a fact that increasing of heat production (oxidation) is not so large in comparison with limitation of
loss of heat (heat emission) and especially with uncoupling effect (increase of free oxidation and temporal
reducing of phosphorilation).
These reactions have a positive meaning.
Increase of Energy Production in Form of ATP
Activation of energy production in form of ATP is necessary in growth and pregnancy as well as in
every kind of physiological hyperfunction (physical or nervous and emotional overloading, digestion etc.)
and in pathophysiological defensive reactions (immunity, inflammation, cardiac hyperfunction etc.). It is
provided by
• Activation of oxidation,
• More tight coupling of oxidation and phosphorilation,
These reactions have a positive meaning. Hormones of catabolic effect provide it.
During a development of any pathological process it goes about ATP production. In a stage of
compensation, even if it is a hypoxia, energy production increases since any compensatory reaction needs
additional energy for its development. Immediate compensatory reactions are more energy-dependent and
require more expenditure of energy. That is why a patient looses weight during disease. Oxygen
consumption and oxidation are increased.
There is a quick biological adaptive reaction directed to increased production of ATP without an
increase of substrates and oxygen consumption. It goes about tighter coupling of oxidation and
phosphorilation (as it is in the brain in oxygen deficiency) which is directed to normal ATP production in
spite of lack of oxygen.
If physiological and particularly pathological hyperfunction lasts more prolong time, an increased
production of energy in form of ATP is provided by hyperthrophy of mitochondrias and an amount of
respiratory chains (see hyperthrophy of myocardium). As it was explained in the chapter 11 («Hypoxia”),
just decrease of ATP amount and increase of ISF (scheme 8) with the aid of HIF-factor stimulates genetic
apparatus resulting in increased synthesis of mitochondrial structures.
Local increase of energy production is observed in the locus of inflammation. An increase both a heat
and ATP production is adaptive and serves the active reactions of defense - leukocytes emigration,
phagocytosis, proliferation and regeneration.
6
Increase of Energy Production as a Result of Metabolism Regulation Disorder
Increase of energy production is obtained in pathology not only as adaptive reaction but also as a
pathological change.
Pathological increase of calories production nonconnected with the needs of organism in energy
occurs in hypersecretion of hormones with catabolic effect (thyroxin, parathyrine, progesterone,
somatotropine, vasopressin). Catabolism activates. Oxidation activates but the excessive calories of heat
ЀЀЀЀЀЀЀЀЀЀЀ are dispersed. It leads to body overheating and farther exhaustion of nervous and endocrine
systems. It happens in tumors of those endocrine glands, which produce these hormones.
The most widespread clinical example is a thyreotoxicosis with goiter and increased secretion of
thyroxin. Tumor of pituitary gland (eosinophilic adenoma) with increased secretion of
somatotropin has the same effect on energy balance.
Overwarming and an increase of body temperature is observed in intoxication (poisoning) by some
chemical agents (α-ЀЀЀЀЀЀЀЀЀЀЀЀ) which damage mitochodrias and produce an effect of uncoupling of
oxidation and phosphorilation.
DECREASE OF ENERGY PRODUCTION
Decrease of energy production (both in form of heat and ATP) always has a negative meaning (scheme
10). It may occur in all stages of energy production and transformation and may be a result of -
• Deficit of substrates,
• Deficit of oxygen,
• Deficit or damage of enzymes,
• Damage of mitochondrias,
• Disorder of regulation in form of reduction of content of hormones with catabolic effect.
Some hypo- and avitaminosis as well as a deficit of some ЀЀЀЀЀЀЀЀЀЀЀЀЀЀ (Fe, J) may cause the diseases
which lead to reduction of energy production.
Reduction of energy production may occur in starvation and a deficit of the substrates entering into
organism. In spite of adaptation by more economical expenditure of energy, body mass decreases and
negative nitrous balance gets established.
Lack of substrates occurs in tissues as a result of disturbance of blood circulation when tissue supply
with substrates is reduced.
All forms of hypoxia (in a stage of decompensation) lead to energy deficiency (contrary to a stage of
compensation, when activation of adaptation needs an activation of energy production). It underlies all
functional and morphological changes, which accompany all diseases of hypoxic type (cardiac and
respiratory insufficiency, anemia etc). Glycolysis activation to a certain extend compensates a deficit of
oxygen. A disorder of glycolytic processes has negative effect on organism ability to adapt to hypoxia.
Deficit of Fe-ions leads to decrease of Hb content and the development of anemia, which cause
oxygen deficiency.
Deficit of enzymes, which participate in energy production, or change in their activity, is an important
cause of energy deficit. It goes about the enzymes of glycolysis, Krebs cycle, enzyme components of
the electron transport in respiratory chain. In a case of blocking of ЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ, an
energy formation diminishes ЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀ ЀЀЀ ЀЀЀЀЀ. The most expressive disorders of catabolism
are observed in a case of a disorder of biological oxidation or mechanisms of coupling of respiration
and oxidative phosphorilation. The lack of enzymes is divided into genetically determined
(enzymopathy) and acquired.
Deficit of vitamins, which are necessary for carrying out oxidation and phosphorilation, is a cause of
energy disbalance as well. Oxidative phosphorylation is essentially disturbed in B-avitaminosis, as many
vitamins of this group are present in composition of Krebs cycle cofenzymes. In Ѐ1-hypovitaminosis a
Krebs cycle gets disordered and thus an amount of substrate material for respiratory chain is decreased.
Convulsions and psychosis, which are observed in avitaminosis, are the clinical symptoms of a disorder of
7
biological oxidation in the brain. Disorder in respiratory chain is characteristic of lack of nicotinamidic and
flavinic dehydrogenases in ЀЀ-and Ѐ2-hypovitaminosis.
Damage of mitochondrias underlies energy deficit in a lot of cases. When their contractile ability is
damaged, they for a long time are in a swelling state. It causes disorder of phosphorilation and revealing of
factors, which stimulate glycolytic way of metabolism in the cells.
As a result of catabolic process disorder, most of all ATP synthesis fails and entering of substrates,
which are necessary for biosynthesis (anabolism). In turn, a disorder of anabolic processes leads to
disorder of reproduction of important substances (enzymes, hormones) which are necessary for
catabolism.
A disorder of energetic metabolism is observed in endocrine diseases.
Hypothyreosis is the best example. The role of J-deficit is widely known.
A deep disorder of energy metabolism is observed in diabetes mellitus (lack of insulin) when
production of macroergic compounds (ATP) is essentially decreased due to limitation of a poverty of
three-carbonic acids cycle and respiratory chain.
Lack of sex hormones (climacteric disorders) accompanies with metabolic disorder and a deficit of
energy production.
Consequences of energy deficit are numerous.
Deficit of callories results in a decrease of adaptation to cold. Development of a fever, when it is
necessary in a case of infection, is problematic. These sings we observe in patients with hypothyreosis,
starvation, hypoxic diseases (anemia, heart insufficiency etc.).
Deficit of ATP (and other macroergic substances) results in suppression of plastic and regenerative
processes (healing of wounds, brakes, and ulcers), impossibility to develop a compensatory hyperthrophy,
decrease of immunological reactivity.
Local decrease of energy metabolism is obtained in malignant tumors. It is the so-called energy
anaplasia (see chapter10 «Neoplasia»). As it was studied earlier, a suppression of genes of enzymes of
redox system and changes in mitochondrias (which are in a state of swelling) underlies it.
8
Scheme 10. Causes, mechanisms and consequences of decrease of energy production
↓ Energy production
↓ Calories of ↓ ATP
heat
Mechanisms
↓ Substrates
↓ O2
↓ Enzymes
Damage of
mitochondrias
↓Catabolic
hormones
↓ Synthesis of
proteins,
neuromediators,
hormones,
DNA,RNA,
phospholipids etc
↓ body t° Disorder of
functions of
membrane and
↓ Adaptation
Consequences ion-canals
to cold
↓Cell division,
Fever does
plastic processes
not develop growth,
regeneration
Insufficiency of
compensatory
reactions
PATHOLOGY OF BASAL METABOLISM
Energy balance is an important characteristic of organism both healthy and sick. So, determination of
energy balance at the level of a whole organism is particularly important for estimation of a patient state
9
and studding of the pathogenesis of a disease. Historically, for this purpose, a determination of such
integral index as the so-called basal metabolism is used.
Basal metabolism is a quantity of energy produced in the organism under standard conditions
(at rest, on empty stomach, external temperature 18 °C).
It is that minimal energy which is necessary for those organs and systems, which function is
permanent - respiration, blood circulation, formation of urine, production of hormones, biological active
substances etc.
The standard level of basal metabolism is 1200-1500 kcal/m2 of body surface.
Under the physiological conditions the level of basal metabolism depends on age (children have higher
basal metabolism, than adults; in old men it is reduced), sex (men have higher basal metabolism than
women), climatic living conditions, nature of nourishment. Basal metabolism is increased with
pregnancy.
In pathology the changes of basal metabolism are more expressive.
Basal metabolism is under neurohormonal control. Thyroxin, somatotropin, adrenalin, sex
hormones stimulate it. Insulin has an opposite effect. Many diseases and pathologic processes are
accompanied by the changes of basal metabolism.
There are two methods of basal metabolism measurement – direct and indirect calorimetry. The first
method determines calories of a heat, which are excreted by organism, and requires apparatus
(calorimeter), which gets warmed by a patient (or experimental animal) located inside. The second
method is based on the oxygen consumption determination and calculation of energy in calories
according the low of thermodynamics. Both methods deal with thermal energy.
In a healthy organism the indices of both methods are coincide.
In pathological situations they often not coincide and not correspond to real energy balance.
Thus, if a heat emission would be limited (the first stage of a fever), the direct calorimetry indice is
masked, lowered and less than that of indirect one. When organism manipulates with proportion of
oxidation and phosphorilation and the uncoupling effect occurs, the consumption of oxygen (indirect
calorimetry) do not reflect real energy production (ATP amount is not measured) and it is less than direct
one.
For the deeper study of the energy balance the modern methods investigate amount of ATP in the
tissues and a state of mitochondrias.
In spite of the fact that basal metabolism is not absolutely correct indice, it is used in scientific and
clinical researches because of its convenience.
Increase of Basal Metabolism
Increase of basal metabolism reflects an activation of energy production and changes when its
neurohumoral regulation is disordered. The examples are the same as they were noted above speaking
about activation of energy production.
It is a growth and pregnancy. It is a physiological and pathophysiological hyperfunction.
It is an influence of a cold (but it is masked by decrease of heat emission). It is a fever but simultaneous
decrease of heat emission and uncoupling of oxidation and phosphorilation mask it.
All diseases are accompanied by development of compensatory reactions, which need additional
energy. So, any pathological process in any system in a stage of compensation accompanies by increase of
basal metabolism. It rises in infection, inflammation, anemia, disturbances of respiratory and circulatory
systems (hypoxia, pneumonia, myocardial infarction etc). At the beginning of heart insufficiency an
increase of basal metabolism is 30-50%. Patient loses weight and grows thin.
Stress increases basal metabolism.
Basal metabolism is increased with a hypersecretion of hormones with catabolic effect - thyroxin,
parathyrine, progesterone, somatotropine, vasopressin. Adrenaline stimulates a basal metabolism
especially in cooling (insulin suppresses trembling).
10
Basal metabolism is increased in tumors of endocrine glands with hypersecretion of hormones with
catabolic effect. An increase of the basal metabolism on 20% and more is an important diagnostical indice
of thyreotoxic goiter as well as in eosinophile adenoma of pituitary gland.
Decrease of Basal Metabolism
Decrease of basal metabolism reflects a decrease of energy production. Aging and hibernation are the
examples as well as a state of inhibition of nervous system (shock, coma).
Reduction of basal metabolism accompanies
• Starvation (in the second stage) due to reorganization of metabolism into more economical use of
energy,
• Hypoxia in a stage of a decompensation.
In patients with endocrine diseases which are accompanied with hyposecretion of hormones of catabolic
effect the level of basal metabolism is decreased. The examples are the following -
• Hypothyroidism,
• Hypofunction of pituitary gland which is accompanied with decreased production of thyrotropin and
corticotropin (ACTH),
• Hypofunction of sexual glands (castration, climax),
• Bilateral lesion of suprarenal glands (more often of tuberculosis genesis as it is in Addison disease),
• Obesity.
11
ЀЀЀЀЀ ЀЀЀЀЀЀЀЀ ЀЀЀ glyco ЀЀЀ gluco
CHAPTER 14
PATHOLOGY OF CARBOHYDRATE METABOLISM
Carbohydrates are an important energy source for the cells, and for some of them
(nervous) are essential.
Mastering the pathology of carbohydrate metabolism it is necessary to know several
terms: glycemia (glucose blood level, the integral index of carbohydrate metabolism,
standard is 3,3-5,5 mmol\l), hyperglycemia and hypoglycemia (increased and decreased
glucose blood level), glycolysis (anaerobic oxidation of glucose up to piruvate),
glycogenesis (glycogen formation from glucose), glycogenolysis (splitting of glycogen to
glucose), gluconeogenesis (carbohydrate formation from noncarbohydrate products –
aminoacids under an effect of glucocorticoids of adrenal cortex and from fatty acids),
glycogenosis (pathological storage of glycogen in the liver and muscles), glucosuria
(appearance of glucose in urine). ЀЀЀЀЀ-ЀЀЀЀЀЀЀЀЀЀЀЀ of glucose into the cells are termed as
GLUT (only GLUT-4 is insulin-dependent transporting glucose into the muscle and
adipose cells; GLUT-2 is Na-dependent transporting glucose into the cells of digestive
tract and kidney).
Pathology of carbohydrate metabolism consists in a disorder of anabolism and
catabolism.
Disorders of carbohydrate metabolism is possible at any stage of carbohydrates balance
- digestion and suction, maintenance of the blood sugar level, intermediate metabolism,
formation of reserves in form of glycogen, correlation with other ways of metabolism.
The main indices, which characterize carbohydrate metabolism, are the following –
blood sugar level and tolerance to carbohydrates; in pathology there are several additional
indices – amount of glucose in urine, amount of intermediate products of carbohydrate
metabolism (ketone bodies, another products).
The main disease, which is connected with carbohydrate metabolism disorder, is
diabetes mellitus.
DISORDER OF DIGESTION AND SUCTION OF CARBOHYDRATES
Carbohydrates are digested and sucked (absorpted) in stomach and intestine. Disorder
of carbohydrate digestion and suction may be acquired and congenital.
Amylolytic enzymes deficit in alimentary tract happens in inflammation of the bowel
mucous membrane. Nevertheless, acquired enzymal splitting of carbohydrates in small
intestine gets deranged comparatively rarely, since salivary, pancreatic and intestinal
glands produce amylase. In a case of achylia (deceased gastric acidity) an amylase effect
of saliva remains in a stomach.
More often enzymes deficit is congenital (enzymopathy), and so disorder of digestion is
observed in childhood. It goes about a deficit of specific disaccharidase or deficiency of the
system of monosachcrides transport. In congenital deficit of hexokinase, phosphatase and
lactase, the disorder of monosaccharide suction takes place. Hexokinase deficit underlies a
disorder of glucose phosphorylation in the intestine mucous membrane.
1
When infants of the first year have problem with milk suction, a deficit of the lactase
underlies it. Di- and polysaccharides are not splitted into monosaccharides, and their
absorption gets reduced. Carbohydrades are accumulated in the intestine lumen, osmolarity
of the intestine juice increases involving water. A child suffers from pain, meteorism, and
diarrhea. Growth and maturation are slowered.
Congenital deficit of GLUT-2 results in glucose suction disturbance with diarrhea,
loose of fluids (dehydration) and exhaustion.
DISORDER OF SYNTHESIS AND SPLITTING OF GLYCOGEN
Glycogen is a form of the carbohydrate reserves, which is accumulated in the muscles

and particularly in the liver. Insulin provides formation and accumulation of glycogen as a
reserve. Adrenaline, glucagon, thyroxin, corticotropin and somatotropin provide glycogen
splitting and its use (in form of glucose) for energy production and other metabolic ways.
Disorder of glycogen synthesis and splitting may be in form of
• Inhibition of glycogenesis (glycogen synthesis),
• Activation of glycogenolysis (glycogen splitting),
• Decreased glycogen splitting (lycogenosis).
Inhibition of glycogen synthesis occurs in a severe damage of the hepatic cells (hepatitis,
phosphorus poisoning, hypoxia) as well as in insulin deficiency. In glycogen deficit an
energy production would be based on lipid and protein oxidative metabolism. In this case,
energy formation requires mote oxygen. Lack of oxygen, in turn, leads to tissue hypoxia,
accumulation of ketone bodies and intoxication.
Activation of glycogenolysis in the liver occurs in excitation of the central nervous
system and is connected with an activation of a sympathetic autonomic nervous system
influence. Intensification of glycogenolysis occurs under increased production of such
hormones - somatotropic (STH), adrenaline, glucagon and thyroxin.
Glycogenosis
Decrease of glycogen splitting underlies glycogenosis. Excessive retention of glycogen

in the liver (in muscles, kidneys, leukocytes, erythricytes as well) is observed. It refers to
the diseases of accumulation ЀЀЀЀЀЀЀЀЀЀ and is congenital. Enzymopathy underlies it. It goes
about deficit of enzymes participating in glycogen splitting – glucoso-6-phosphatase,
phosphorilase, amilo-1,6,-glucosidase. In congenital deficit of glucosidase in lysosomas, a
glycogen is accumulated and destroys them.
The most widespread form of a glycogenosis is a hepatonephromegaly or Gierke's
disease. It is based on congenital deficit of the enzyme glucose-6-phosphatase in the liver and
kidneys. This enzyme splits a free glucose from glucose-6-phosphate and promotes
transmembrane transfer of glucose from the liver and kidney cells into the blood. In deficit
of this enzyme, glycogen is not splitted and accumulated in the cells of the liver and
kidneys. Hypoglycemia develops. Sensitivity to insulin increases. A patient needs more
food. The formation of the lactic acid from glucose-6-phosphate is activated. Its content
in the blood increases. Metabolic acidosis develops. Pathology gets obvious in infants and
is accompanied with physical and mental retardation. Term of life gets limited.
DISORDER OF CARBOHYDRATE METABOLISM REGULATION
2
Regulation of carbohydrate balance is provided by nervous and hormonal mechanisms
as well as by protein ЀЀЀЀЀЀЀ-ЀЀЀЀЀЀЀЀЀЀЀЀЀ of glucose (GLUT) into the cells via cellular
membrane.
It is important to understand that hyperglycemia accompanies all adaptive reactions as
glucose is an important source of energy. Therefore, number of mechanisms, which
increase glucose blood level, predominates that of its decrease.
Nervous Mechanisms
The nervous regulation of carbohydrate metabolism is demonstrated in experiments by

modeling of hyperglycemia by puncture the IV ventricle bottom ЀЀЀЀ Ѐ ЀЀЀ ЀЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀЀЀ (Claude Bernardt), stimulation of the basal nuclei of large brain, ЀЀЀЀЀЀ ЀЀЀЀЀ
ashen tuber of the hypothalamus, lentiform nucleus ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ nuclei and ЀЀЀЀЀЀЀЀЀЀ
ЀЀЀЀ striate body.
Mental overstrain, intensive emotions, pain and attacks of epilepsy cause
hyperglycemia as well.
There is another way of the central nervous system influence on carbohydrate
metabolism. It is an effect of the parasympathetic fibers, which innervate pancreatic
gland.
Hormonal Mechanisms
The following hormones provide the hormonal control of carbohydrate metabolism and
elevate glucose blood level by different mechanisms - adrenaline, glucagon, thyroxin,
corticotropin and somatotropin. They stimulate either glycogenolysis or gluconeogenesis.
Adrenaline causes a short-termed hyperglycemia by stimulation of glycogenolysis in
the liver.
Glucagon activates glycogenolysis, inhibits accumulation of glycogen in the liver, has
gluconeogenetic, lipolytic and the insulin-stimulating effect.
Thyroxin stimulates the absorption of glucose in the intestines, activates liver
phosphorylase and limits the organism tolerance for carbohydrates. Hyperfunction of
thyroid glands is characterized by decreased tolerance to carbohydrates.
Glucocorticoids (hormones of zone fasciculata of the adrenal cortex) raise glucose
blood level by gluconeogenesis activation (glucose synthesis from aminoacids). They
induce synthesis of matrix RNA, which is responsible for enzymes of glyconeogenesis
formation. They decrease the permeability of cellular membranes for glucose and inhibit
the rate of hexokinase reaction and hexoso-6-phosphate formation.
Corticotropin acts similar to glucocorticoids because it stimulates their secretion. It
activates gluconeogenesis and inhibits activity of hexokinase.
Somatotropin (hormone of growth produced in adenopituitary gland) impairs tolerance
to carbohydrates, causes hyperglycemia, ensures hyperplasia of α-cells of pancreatic
islets, stimulates synthesis of glucagon, activates the liver insulinase, activates lipolysis
and gluconeogenesis (from fatty acids).
It is only insulin (secreted by β-cells of pancreas) that decreases blood glucose level
and provides balance.
Such dissimilarity of hormonal participation in sugar blood level regulation has two
consequences: (a) the first line of hormones is called contrainsulin although their
physiological action is synergic to insulin, (b) insulin deficiency significantly affects the
sugar blood level, it rises (fig.21).
________________________________________________________________________
3
glycemia, hypo- heper-
β-endorinicytes of pancreatic islands
insulin
glucagon cortisone adrenaline somatotropin
1. α–Endocrinocytes of pancreatic islands
2. adrenal cortex
3. medullar part of adrenal gland
4. adenohypophisis
Fig. 21. Normal regulation of carbohydrate metabolism and correlation between

insulin and hormones-antagonists (ЀЀЀ. 40. Ѐ. 332 ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ)
_______________________________________________________________________________
Insulin Effect Mechanisms
For mastering the material of this chapter it is necessary to know in detail the
mechanisms of insulin effect.
The main effect of insulin consists in a lowering in sugar blood level. It achieves by
increasing glucose utilization by target-cells and accumulation of carbohydrate reserves.
Insulin provides the membrane transport of glucose, aminoacids and certain ions. So,
insulin is the main anabolic (throphothropic) hormone in the organism.
Insulin realizes these effects by such mechanism:
• Increases the permeability of target-cells to glucose by increase in their membrane an
amount of ЀЀЀЀЀЀЀЀЀЀЀЀ of glucose (GLUT-4) and the rate of hexogenase reaction resulting
in increased formation of glucose-6-phosphate as the main metabolic substrate for
intermediate glucose metabolism
• Activates Krebs cycle (enzyme ЀЀЀЀЀЀЀЀЀЀЀЀЀ)
• Activates glycogenesis, promotes the storage of glycogen in the liver and muscle
• Inhibits glycogenolysis by stopping of phosphorylase activity,
• Activates lipogenesis (conversion of 10% glucose into lipids)
• Induces synthesis of protein, RNA and DNA
• Regulates such intracelular indices - adenilate cyclase (which regulates intracellular
cAMP level), guanylate cyclase and production of cGMP, activity of Na-K-AMPase,
sodium-calcium flux
• Provides penetration of potassium inside the cells
• Inhibits gluconeogenesis
• Possesses the mitotic activity (similar to growth factors)
• Influences genetic apparatus of target-cells and induces the corresponding enzymes.
Insulin effect on the target cell depends from amount and affinity of the insulin
receptors. They have been identified on fat cells, hepatocytes, fibroblasts, monocytes,
thimic lymphocytes.
Insulinase and sinalbuminum (beta-chain of insulin, which interacts with the receptors
for insulin) are the insulin antagonists.
Comparison between insulin and the contra-insulin hormones effect on carbohydrate
metabolism is represented in the scheme 11.
HYPOGLYCEMIA
Hypoglycemia is a reduction in glucose blood level below 3.3 mmol/1. It

develops as a result of insufficient coming of glucose into the blood.
Causes
4
The causes of hypoglycemia are:
• Carbohydrate starvation (alimentary hypoglycemia)
• Malabsorption of carbohydrates in the intestine
• Increased insulin production in hyperfunction of the pancreatic insulin apparatus
(hyperplasia, insulinoma)
• Insulin overdose in treatment of diabetes mellitus
• Insufficient production of contrainsulin hormones (thyroxin, adrenaline,
glucocorticoids)
• Decreased glycogen splitting in glycogenosis (for example, Gierke's disease)
• Damage of the hepatic cells (acute and chronic hepatitis)
•“’Renal diabetes” due to disorder of glucose reabsorption in renal tubules and loss of
glucose with urine
Manifestations
The central nervous system is especially sensitive to glucose deficit, for it is the only
source of energy. Oxygen consumption by the brain is decreased in hypoglycemia.
Irreversible changes take place in the nervous cells in prolonged hypoglycemia.
Tachycardia develops due to adrenaline hyperproduction. Hunger (excitation of the
ventrolateral nuclei of the hypothalamus), tremor, weakness, irritability and fear are the
clinical symptoms. Epileptic-like convulsions occur. At the glucose level below 2,2
mmol/1 hypoglycemic coma develops.
HYPERGLYCEMIA
Hyperglycemia is an increase of glucose blood level. It is a result of

increased production of glucose (glycogenolysis, glyconeogenesis) and decrease
of its transport into tissues and utilization.
Hyperglycemia can be alimentary (after a large eating of easily digestive
carbohydrates). Glucose is quickly absorbed into the blood from the intestine promoting
an ability of the liver, muscles and other organs to assimilate it.
Hyperglycemia is observed in excessive amount of such contra-insulin hormones as
glucagon, adrenaline, glucocorticoids, corticotropin, somatotropin and thyroxin. Insulin
deficit and a prevalence of contra-insulin hormones are accompanied by hyperglycemia.
INTERMEDIATE CARBOHYDRATE METABOLISM DISORDER
Intermediate carbohydrate metabolism disorder consists in nonsplitting of glucose up

to the final products (CO2 and H2O). Intermediate products (lactate, pyruvate) are
accumulated. It leads to acetil-CoA accumulation. Metabolic acidosis develops.
The causes are:
• Hypoxia (respiratory and vascular insufficiency, anemia). Anaerobic phase of
carbohydrate catabolism gets predominate on aerobic one. Blood lactate content rises up to
100 mg% (10-15 mg% in norm).
• Liver dysfunction (it is known, that lactic acid is partially resynthesized into glucose and
glycogen under physiological conditions).
• Vitamin B1 (thiamin) hypovitaminosis. Decarboxilation of ketoacids is disturbed because
this vitamin is a part of cocarboxylase. Synthesis of acetyl-CoA from pyruvate gets
suppressed. Acetylcholine synthesis gets decreased, and transmission of the nervous
impulses gets disordered. The function of nervous system gets failed.
• Insulin insufficiency eventuates in serious metabolic derangement (details see below).
5
_______________________________________________________________________________________
Scheme 11. Influence of insulin and its antagonists on glucose metabolism in the cell.
Permeability of the cellular

membranes
Rate of hexokinase reaction
Synthesis of enzymes of
glycolysis
Insulin Antagonists
of insulin
Synthesis of enzymes of
gluconeogenesis
Formation of glucoso-6-
phosphate
Activation suppression
______________________________________________________________________________
NEPHRITIC THRESHOLD TO GLUCOSE DISORDER
It is known that entire glucose of the blood is filtered into the primary urine in renal
glomeruli. Then glucose is entirely reabsorbed into the blood from the primary urine via
epithelium of proximal tubules. Enzymes (hexokinase) and ЀЀЀЀЀ-ЀЀЀЀЀЀЀЀЀЀЀ (Na-dependent
GLUT-2) provide glucose reabsorption. Energy and a proper Na-K pump regulation are
necessary for it.
Nephritic threshold means that maximal level of glycemia (normally 8,8 mmol/l), which
is not accompanied by appearance of glucose in a final urine.
In large concentration of glucose in the blood (hyperglycemia) some glucose is excreted
with urine (glucosuria).
In some cases glucosuria develops without hyperglycemia, e.i. when enzymal and
transport systems in the kidney are disturbed. Aquired and hereditary pathology of
proximal tubules as well as Na-balance disorder have the same result. In these cases one
speaks about decrease of the nephritic threshold and the so-called “renal diabetes”.
TOLERANCE TO CARBOHYDRATES
Tolerance to carbohydrates means an ability of organism to utilize a certain amount of

carbohydrates with a certain speed without appearance of glucose in urine.
In norm, the maximal amount of glucose, which is utilized without glucosuria is 160-
180 g of glucose taken on an empty stomach. In norm glucosuria develops, when blood
glucose level is above nephritic threshold (8,8 mmol/l).
In clinical practice tolerance to carbohydrates is determined by functional glucose
tolerance test with sugar load on empty stomach and dynamics of alimentary
6
hyperglycemia (fig. 22). Normally, blood sugar level must be normalized in a certain
time.
Thus, tolerance to carbohydrates reflects carbohydrate metabolism regulation and is
determined by
• Ability of organism ЀЀЀЀЀЀЀЀ an adequate amount of insulin in response to
hyperglycemia and ЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀ blood glucose level to the norm
• Function of receptors to insulin on the target-cells
• Condition of glucose-transport systems in kidney (nephritic threshold).
Increased tolerance to carbohydrates happens in hyperfunction of pancreatic β-cells.
Decreased tolerance to carbohydrates happens in ЀЀЀЀЀЀЀЀЀЀЀ, ЀЀЀЀЀЀ-ЀЀЀЀЀЀ
syndrome, insulin insufficiency.
glucose of the blood in mmol/l

hours
Fig. 22. Curves that reflect the results of loading by glucose in healthy person (A), in a case of decreased
tolerance to glucose (B), in case of diabetes mellitus (C)
(ЀЀЀ. 41 Ѐ. 333 ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ)
_______________________________________________________________________________
INSULIN INSUFFICIENCY ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ
The main pathophysiological syndrome connected with a disorder of carbohydrate

metabolism is a syndrome of insulin insufficiency. Since insulin plays extraordinary role
in regulation of carbohydrate metabolism, its deficit plays exclusive role in pathology.
Insulin insufficiency is the metabolic and pathophysiological disorders in organism
as a result of insulin amount or its function disorder.
TYPES
Depending on reason and degree of insulin deficit, insulin insufficiency is divided into
two forms - absolute and relative. Depending on localization of a cause, it is divided into
pancreatic and extrapancreatic. These two classifications actually coincide.
Absolute (pancreatic) insulin insufficiency is a result of decreased insulin biosynthesis
or secretion.
Relative (extrapancreatic) insulin insufficiency refers to the situation, when a
production of insulin is normal, but metabolic disturbances and clinical picture are the
same as with an absolute deficit of insulin.
Causes and pathogenesis of two forms of insulin insufficiency are different.
CAUSES AND PATHOGENESIS OF ABSOLUTE (PANCREATIC)
INSULIN INSUFFICIENCY
The pancreatic deficit of insulin appears as a result of acquired and hereditary disorders
at any stage of its formation and secretion.
The following mechanisms are possible:
7
• Impairment of glycoreceptor system on the pancreatic β-cells membrane, which receives
the insulinogenic stimulus of the blood glucose. As a result, the secretion of insulin in
response to glucose is suppressed.
• Disorder of intracellular messengers, which transfer the signal from glycoreceptors to β-
cells genetic apparatus. The disorder of the ion Ca+ entering into β-cells has the same
result.
• Disorder of proinsulin transformation into insulin.
• Disorder of insulin secretion from the β-cells (inapproper insulin secretor response).
• Cytotoxic damage of β-cells by β-cytotropic chemicals (including drugs).
• Damage of β-cells by β-cytotropic viruses (Coxackie).
• Immune damage (formation of antibodies against insulin or β-cells).
• Destructive changes in pancreas - tumor, cirrhotic and inflammatory processes, sclerosis
of vessels.
CAUSES AND PATHOGENESIS OF RELATIVE (EXTRAPANCREATIC)

INSULIN INSUFFICIENCY
Relative insulin insufficiency is a situation, when a production of insulin is normal.

However, metabolic derangement is similar to absolute insulin deficit. Causes are
originated out of pancreas.
The following causes are possible:
• Excessive production of the contra-insulin hormones
• Disorder of insulin transport in the blood
• Activation of factors, which accelerate insulin distraction (insulin antagonists,
insulinase and other proteolytic enzymes)
• Peripheral effect of insulin disorder is the main cause of this type of insulin
insufficiency. Lowering in sensitivity of target-cells to insulin is called insulin resistance,
which may be ЀЀЀЀЀЀЀЀЀЀЀЀЀЀ, ЀЀЀЀЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ. ЀЀЀЀЀЀЀЀЀЀЀ resistance is
connected with
Lack of receptors
Altered receptor affinity to insulin
Autoimmune aggression against receptors
Genetic pathology of receptors
ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ changes are connected with disorder of glucose transport by
ЀЀЀЀЀЀЀЀЀЀЀЀЀ GLUT-4 in adipose tissue, which results in carbohydrate intolerance in
obesity.
Relative insulin insufficiency connected with insulin resistance can be complicated with
absolute one due to activation of insulin production by β-cells (for overcoming the
resistance) and overload of β-cells.
MANIFESTATIONS OF INSULIN INSUFFICIENCY
Manifestations of insulin insufficiency are metabolic and pathophysiological. All

pathways of metabolism are deranged because of insulin insufficiency.
Carbohydrate Metabolism Disorder
Carbohydrate metabolism is deranged most of all and is manifested by disorder of

intermediate glucose metabolism, hyperglycemia and glucosuria.
Intermediate Glucose Metabolism Disorder
8
Intermediate glucose metabolism is disrupted in all pathways, namely
• G-6-P formation decrease as well as its participation in glycolysis, pentose-phosphate
cycle and synthesis of glycogen
• Inhibition of metabolic ЀЀЀЀЀЀЀЀЀЀ of Krebs cycle
• Accumulation of acid intermediate metabolites and metabolic acidosis development
• ATP formation decrease
• Glycogenesis suppression
• Glycogenolysis activation
• Gluconeogenesis activation
• Depletion of glycogen reserve in the liver and muscle
• Suppression of glucose conversion into lipids
As a result, such integrate pattern as tolerance to carbohydrates gets failed
Hyperglycemia
Hyperglycemia sometimes reaches 25 mmol\l and more. The pathogenesis of

hyperglycemia is the following:
• Difficulty in glucose passage into the cells from the blood due to reduced permeability of
target-cells membrane for glucose
• Activation of glycogen splitting to blood glucose
• Activation of carbohydrate formation from fat acids, aminoacids, lactate and pyruvate
• Inhibition of glucose conversion into glycogen of the liver
• Inhibition of glucose conversion into lipids
In spite of the fact, that glucose is not a toxic product, constant hyperglycemia has
negative consequences which consist in
• Increase of osmotic blood pressure
• Glycolization of blood proteins (non-enzyme damage of protein molecules)
• Formation of glyco- and mucoproteids, which gets accumulated in the connective tissue
contributing to hyalin formation and damage of vascular wall.
Glucosuria (appearance of glucose in the urine) develops if glucose blood level rises
above nephritic threshold.
Lipid Metabolism Disorder
Lipid metabolism is critically involved in metabolic disorders in insulin insufficiency.

The changes are the following
• Lipolysis activation (mobilization of fat acids from the adipose tissue) and inhibition of
lipogenesis (e.i. conversion of glucose into lipids, resynthesis of ЀЀЀЀЀЀЀЀЀЀЀЀЀ from fatty
acids)
• Transport hyperlipemia
• Increase of cholesterol synthesis (hypercholesterinemia) from acetyl-CoA, which is not
introduced into Krebs cycle. Together with increased synthesis of high density lipoproteids
it results in atherosclerosis development
• Obesity development in a case of insulin resistance.
• Lipid degeneration of the liver and other parenchymatous organs (An increased
quantity of fatty acids comes into the liver; some of them are converted into triglycerides,
which are the precondition for the liver lipid infiltration. Other part is splitted by beta-
oxidation with formation of a great amount of acetyl-CoA. There may be no lipid
infiltration of the liver, if pancreas produces lipocaine).
• Accumulation of incompletely oxidized products of lipid metabolism (acetonic and
ketonic bodies - acetone, acetoacetic and β-oxibutyric acid). Under normal condition
9
ketone bodies are formed in the liver, then come into the blood, lungs, muscles, kidney
where are oxidized to CO2 and H2O. In insulin deficiency they are accumulated in the
blood. It is called hyperketonemia and ketoacidosis with the following mechanisms in the
base:
Reduced activity of the Krebs cycle (hence, transformation of acetyl-CoA into
citrate is inhibited)
Delay of fatty acids resynthesis from acetyl-CoA as a result of NADPH2
deficiency (reduced speed of pentosophosphate cycle)
Intensified decomposition of fatty acids from lipid depot and their accelerated
oxidation to acetyl-CoA
Decreased activity of acetyl-CoA carboxilase, which participates in the
synthesis of fatty acids through malonil-CoA
Ketone bodies inactivate insulin aggravating insulin insufficiency. The smell of
acetone from the mouth and appearance of acetone in urine are observed in patient.
Ketonemia underlies the comatose state.
Protein Metabolism Disorder
Disorder of protein metabolism is the following:

• Intensification of protein catabolism
• Increased use of deaminated aminoacids for gluconeogenesis
• Ammonia release after desamination of aminoacids (It is compensated by urea
formation and bound of ammonia with α-ketoglutaric acid of Krebs cycle. At the same
time, such compensation has negative feature - deficit of α-ketoglutaric acid results in
inhibition of Krebs cycle and accumulation of ketone bodies as well as decrease of ATP
formation)
• Depression of protein synthesis in the liver in ATP deficit and weakened stimulating
influence of insulin on enzymes of protein synthesis
• Suppression of RNA and DNA synthesis
• Negative nitrogen balance
• Damage of proteins by glycolization; synthesis of glyco- and mucoproteids with hyalin
formation
• Decrease of immune antibodies formation as a result of protein deficit
Acid-Base Balance Disorder
Disorder of acid-base balance consists in

• Accumulation of incompletely oxidized products of metabolism, all of which are acids
(lactate, ketonic bodies)
• Decrease in bicarbonates blood reserve
• Development of metabolic acidosis and ketoacidosis
In a stage of a compensation it is possible to obtain the compensatory reactions –
involving of the buffer systems, increased excretion of acids and ammonia salts with urine,
hyperventilation. In exhaustion of compensation, an acidotic coma develops.
Water and Mineral Balance Disorder
Glucosuria induces an osmotic diuresis and thus polyuria, causing loss not only of
water but also electrolytes (Na, K, Mg, P). In addition, insulin insufficiency eventuates in
limiting of membrane transport of certain ions but increased penetration of sodium inside
the cells. Disorder of water balance results in
• Dehydration due to increased loss of water with urine,
10
• Elevation of blood osmotic pressure.
Pathophysiological Disorders
Pathophysiological derangement, which is obtained in insulin insufficiency, is a
consequence of metabolism disorder. It is necessary to distinguish a) pathophysiological
consequences of insulin insufficiency, b) pathophysiological consequences of the
prolonged and incomplete compensation of insulin insufficiency with the aid of drugs that
takes place really in clinic.
Pathophysiological disorders are the following:
• Metabolic acidosis may become decompensated and results in coma development.
• Ketonemia and ketoacidosis cause intoxication and may result in coma development.
• High blood glucose level increases osmotic blood pressure and may be a reason of
comatose state.
Nowadays the development of comatose state is rare due to modern medical help (state
programs serve the patients with drugs). Disease becomes chronic and lasts for many
years. So, another group of pathophysiological changes must be added, which are
connected with the prolonged medical care of patient with insulin insufficiency. Modern
medicaments prolong the life, however, the compensation is incomplete.
Pathophysiological disorders progressively increase and are aggravated with time. So, the
list of pathophysiological disorders may be continued.
• The constant loss of glucose with urine overloads all hormonal mechanisms of blood
sugar level support (secretion of glucocorticoids and other contra-insulin hormones).
The overloading of hormonal mechanisms leads to their exhaustion.
• Atherosclerosis acquires generalized form.
• Excessive synthesis of glyco- and mucoproteids leads to development of hyalinosis
of vessels, which is accompanied by autoimmune inflammation and aggravates
atherosclerotic damage. Vascular pathology (angiopathy) is the main reason of
invalidity and death.
• Lipid infiltration of parenchimatous organs (liver, myocardium) leads to failure of
these organs and aggravate pathophysiological disorders with various clinical
symptoms.
• Glucosuria promotes osmotic diuresis, which can reach 10-12 l daily. Loss of water
leads to dehydration. Although the patient compensates it by drinking, the loss of
electrolytes (Na, K, Mg, P) with urine occurs. Loss of water results in
hyperosmolarity and thirst.
• Glycolyzation of various proteins (Hb, enzymes, collagen etc.) has various
consequences depending on type of damaged proteins.
• Formation of immune antibodies is suppressed. In results in decreased resistance of
organism to infection.
• Regenerative and plastic processes are suppressed resulting in reduction of wound
healing. Any trauma is accompanied by incapability for regeneration and frequently
results in formation of the so-called trophic ulcers, in development of which
atherosclerosis has great significance.
• Growth retardation is observed in children.
DIABETES MELLITUS (DM)
Diabetes mellitus is a clinical example with insulin insufficiency in its base.

It is a cause of high mortality due to plurality of complications and relates to actual
medical problems. Diabetes mellitus is diagnosed in 1-4% of population and 30% in
11
people of elderly age. The quantity of diabetics in the world increases doubly every 15
years. The explanation of this phenomenon consists in the fact of significant role of
genetic factors in diabetes mellitus development. Success in treatment and survival of
patients results in accumulation of genetic disorders in population.
Diabetes mellitus is a disease, which is characterized by chronic hyperglycemia
resulting from absolute or relative insulin insufficiency.
ETIOLOGY
Etiological factors, causing diabetes mellitus, are physical, chemical and biological,
general property of which is an ability to cause insulin insufficiency. Depending on
participation of genetic mechanisms, diabetes mellitus is divided into acquired and
genetically determined forms. The hereditary insufficiency of pancreatic islets can be
revealed under effect of provoking exogenous etiological factors.
Physical factors are not very actual. They are trauma of pancreas (including surgical)
and ionizing radiation. Environmental influences rise a risk of the disease development (if
a predisposition is present).
Ѐhemical factors are β-cytotropic chemical substances (alloxan, dithizone,
streptozotocin and nitrosamines are β-cell cytotoxic agents and induce a diabetes-like
condition in experimental animals). Some pharmacological agents (diuretics, oral
contraceptives, β-adrenergic drugs) inhibit secretion of insulin in man and can induce a
disease. The mode of nutrition plays a role. Factors, which increase a load on insulin
apparatus (overeating, excessive consumption of carbohydrates and fats) provoke the
manifestation of diabetes mellitus in patients with genetic predisposition.
Biological factors are of infectious, immune and psychogenic origin.
Infectious factors are β-cytotropic viruses (Coxackie, the agents of whooping cough,
measles, german measles, hepatitis, influenza), agents of scarlet fever, lues and
tuberculosis.
The value of immune factors is confirmed by possibility of experimental reproducing
of diabetes mellitus by injection of heterogeneous antibodies against insulin or β-cells.
Emotional overstrains can provoke the development of diabetes mellitus (if genetic
predisposition exists). Stress aggravates the diabetic condition and acts through steroid-
induced gluconeogenesis or increased secretion of catecholamines.
Pregnancy plays a role as biological factors. Predisposition often plays a role.
Genetic predisposition is the main endogenous cause.
PATHOGENESIS
The main link in pathogenesis of diabetes mellitus is an absolute or relative insulin

insufficiency (essence, reasons, pathogenesis see above).
All typical pathological processes (infectious and allergic inflammation, tumor,
thrombosis, necrosis and sclerosis) in pancreas and other organs, referring realization of
insulin effects, play a role in pathogenesis of DM.
Role of Genetic Mechanisms
Hereditary factors contribute significantly to the development of DM. Their role is

confirmed by existence of «family diabetes», when disease is recorded in several members
of one family (sometimes in 3-4 generations) and high concordance in monozygotic twins
(4 times higher, than in dyzygotic ones). The examination of the first-degree relatives of
diabetics confirms an idea. Concordance rate approaches 90-100% in twins having
NIDDM (noninsulin-dependent DM see below) and 50% in IDDM (insulin-dependent
DM).
12
Risk of a disease in women is two times more than in men (it is a base of assumption
about a connection of pathologic gene with X-chromosome). Connection of the disease
with the antigens of system ABO is noted (patients with A group are ill more often).
Mutation of genes, which participate in the insulin apparatus function and peripheral
effect of insulin, underlie the hereditary predisposition to diabetes mellitus. Several mutant
genes, which determine the development of diabetes mellitus, are revealed. Genetic defects
of β-cells membranes, insulin synthesis and secretion, content of insulin antagonists,
structure of insulin receptors may be inherited.
Types of inheritance include autosomal-dominant, autosomal-recessive and polygenetic
ones. The reference of diabetes mellitus to category of multifactorial diseases reflects the
value of genetic factors together with the role of environment.
Genetic predisposition is a base, on which provoking exogenous etiological factors
(chemical, immune, infectious, psychic, overeating etc.) lead to development of diabetes
mellitus. They unmask the hereditary predisposition.
Secondary diabetes can develop in chromosome syndromes (ЀЀЀЀЀЀЀЀЀЀЀЀЀ, ЀЀЀЀЀ).
So, disease depends on the interplay of genetic and environmental influences.
Role of Immune Mechanisms
Autoimmune aggression against insular apparatus consists in formation of

autoantibodies against insulin, β-cells and insulin receptors as well as leukocytic ЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ. Diabetes mellitus frequently is combined with another
autoimmune diseases (autoimmune thyroiditis).
Specific leukocyte antigens of HLA-system serve as genetic markers of diabetes
mellitus predisposition. Close association between gene governing histocompatibility
antigens and IR (immune response) genes is noted, because genes of HLA-system are
localized in the 6-th chromosome near the locus of immune response control. It
determines a specific immune status of organism. Some viruses with beta-tropic
properties can induce autoimmune process in pancreas provoking realization of hereditary
predisposition to diabetes mellitus.
Thus, the pathogenesis of diabetes mellitus includes genetic, immune mechanisms and
environmental factors, however, the relationship between them differs in different types of
diabetes mellitus (details see below).
MANIFESTATIONS OF DIABETES MELLITUS
Manifestations of diabetes mellitus are metabolic and pathophysiological (described

above in details as manifestations of insulin insufficiency). Metabolic ones are detected by
laboratory investigations. Clinical manifestations of a disease are noted below.
Metabolic Changes
Metabolic changes concern all pathways of metabolism as it was discussed above. In

spite of essential limitation of sugar use with food, a patient has a high blood glucose level
because of gluconeogenesis. Intermediate metabolism of glucose is disordered. So, insulin,
as medical drug, is used not only for diminution of the blood sugar level, but mostly for
correction of intermediate metabolic pathways.
Changes in laboratory indices are - hyperglycemia, acetonemia, ketonemia,
lactacidemia, hyperlipemia, hypercholesterolemia and glucosuria.
Hyperglycemia sometimes reaches 25 mmol/1, glycosuria up to 555-666 mmol/1 (100-
120 g/day and more), level of lactic acid (lactocydemia) over 0.8 mmol/1 (N 0.033-0.078
13
mmol/1), hyperlipemia up to 50-100 g/1 (N 3.5-8 g/1), ketonemia (by determination of
acetone and ketone bodies) up to 5200 mcmol/1 (N < 517 mcmol/1).
Clinical Manifestations
Renal, vascular, neurologic and other long-term effects of DM are the following
Polyuria is an increased diuresis. Increase of osmotic pressure of urine and decrease of
reabsorption of water underlie it. Diuresis may reach 10-12 l daily.
Polydipsia is a thirst, which is accompanied by dryness in mouth and skin.
Polyphagia is an increased appetite as a result of carbohydrate starvation of tissues.
Muscular and general weakness is a consequence of energy tissue starvation.
Atherosclerosis is a common complication of diabetes mellitus. It is a terrific problem
of modern medicine and more often is underlined by diabetes mellitus. Consequences of
atherosclerosis of vessels become a reason of death.
Angiopathy (macro- and microangiopathy) is a pathology of the large and small
vessels, which develops as a result of atherosclerosis and hyalinosis. Chronic vascular
syndrome includes the pathology of cerebral, coronary, nephritic, retina and arterial
vessels of lower extremities. It is not difficult to understand the wide circle of pathology
that develops – insult stroke, myocardial infarction, amputation of extremities, blindness.
Arterial hypertension is an increase of arterial blood pressure.
Nephropathy is the renal dysfunction, which is manifested by many renal and systemic
symptoms including the development of nephritic type of arterial hypertension.
Immunodepresion is manifested by increased sensitivity to infection. Almost all
patients suffer furunculosis. Many diabetics are ill with tuberculosis.
Neuropathy is a disorder of morphology and function of peripheral nerves (sensitive,
motor and vegetative ones).
Decreased or total loss of sight is a retinopathy. It is a result of eye vessel impairment
and cataract (sclerosis of crystalline).
Depression of regenerative processes (as a result of depressed protein synthesis) is
manifested by problems with reparation of wounds and development of trophic ulcers.
Body mass alterations are emaciation (result of lipolysis activation) or obesity as a
result of insulin resistance.
Thus, the patient with diabetes mellitus visits the physicians of different specialty -
endocrinologist, therapeutist, opthalmologist, neuropathologist, surgeon.
Diabetic Comatose States? Conditions? ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ
The most violent complication of diabetes mellitus is a comatose state. The

manifestations of coma are the following - loss of consciousness, arterial hypotension,
Kussmaul type disorder of respiration, the smell of acetone from mouth.
There are several types of diabetic coma. They are:
• Acidotic (lactacidemic), which is a result of lactic acid accumulation and reduction in
blood pH
• Ketonemic which is a result of toxic effect of ketonic bodies
• Hyperosmolar, which is a result of high hyperglycemia
• Hypoglycaemic, which is commonly a result of an insulin overdose
Clinical and metabolic manifestations of DM mentioned above as well as etiology and
pathogenesis vary in different types of DM mentioned below.
CLASSIFICATION OF DIABETES MELLITUS
14
According to clinical classification the diabetes mellitus is divided into primary
(idiopathic) and secondary (symptomatic as a complication of another disease). In turn,
primary (idiopathic) diabetes mellitus is subdivided into two types depending on the form
of insulin insufficiency (pathogenic classification) - insulin-dependent (1-st type, IDDM)
and noninsulin-dependent (2-d type, NIDDM). The 3-d type of diabetes mellitus is
connected with pregnancy (ЀЀЀЀЀЀЀЀЀЀЀЀ DM of pregnant women).
The role of genetic and immune mechanisms together with a role of environment in the
diabetes mellitus development was discussed above. The relationship between them as
well as clinical symptoms are different in diabetes of different type.
INSULIN-DEPENDENT DIABETES MELLITUS (1-st type juvenile-onset IDDM)
IDDM accounts for about 5-10% of diabetics. This form of diabetes mellitus is obtained
in young persons - ”juvenile-onset” type.
Absolute insulin insufficiency (see above) underlies this type of diabetes mellitus, which
is characterized by insulinopenia. Consequently, it is also named as pancreatic and
primary.
It is assumed that the main link of IDDM pathogenesis is connected with a special
immune status of organism (leukocyte antigens of HLA system are genetic markers)
resulting in autoimmune aggression against own insular apparatus. Antibodies against
insulin and β-cells are determined. Correlation between common child viral infections
(mumps, measles, influenza, german measles, hepatitis, parotitis) and the onset of IDDM
is obtained. In such patients, viral infection possesses increased beta-tropism and appear
to localize specifically within the islets of Langerhance. Young persons, who are HLA-
positive, have the high level of antibody titers to virus. Immune response, induced by
direct viral damage of the β-cells, provokes autoimmune process in insular apparatus.
Thus, virus is an exogenous etiological factor, which realizes predisposition to the 1-
st type of diabetes mellitus (scheme 12).
Genetic factors, as etiological, play a role in 30%. Concordance in monozygotic twins
appears about 50%.
Pancreas contains little or no extractable insulin and has overall reduction in size of
Langerhance islets and beta-cell mass. Infiltration of islets by lymphocytes, monocytes
and eosinophiles is observed (insulinitis). Some patients with IDDM have beta-cell-
sensitized cytolytic lymphocytes. Antibodies to insulin receptors are determined.
Plasma insulin level is low and responds poorly if at all to injection of glucose or other
stimulators of insulin secretion. These patients therefore require exogenous insulin
injection; hence it is the insulin-dependent variant of diabetes mellitus.
Metabolic disorders are essential and may be life threatening or even fatal.
The clinical duration of this form of diabetes mellitus is heavy with ketoacidosis and
diabetic coma. The body mass decreases (diabetes mellitus of thin persons).
Basic treatment is the injection of insulin.
NONINSULIN-DEPENDENT DIABETES MELLITUS

(2-d type «maturity-onset” NIDDM )
Noninsulin-dependant «maturity-onset” diabetes mellitus (NIDDM) represents the 90-

95% of all diabetic patients.
NIDDM is not connected with a reduction in beta-cell mass or insulin deficit. Relative
insulin insufficiency (see above) is the basis of this type of diabetes mellitus. The
production of insulin is normal. Consequently, this form of diabetes is named as extra-
pancreatic or insulin-independent.
15
Scheme 12. Etiology and pathogenesis of IDDM
Genetic predisposition
connected with HLA-system antigenes
β-Tropic virusis β-Tropic

chemical substances
Damage of β-cells
Macrophages
IL-1 T-helpers
Autoimmune aggression
against β-cells
Activation
NN
Macrophages T-helpers T-effectors NK Lymphocytes
Production
Antibodies Lymphokins (factor of necrosis) γ-Interferon PG
Destruction of β-cells
Absolute insulin insufficiency
16
The main link of NIDDM pathogenesis is connected with insulin resistance. Overeating
and obesity provoke it. 70% -80% cases of this form of diabetes mellitus are combined
with obesity. Patients are significantly overweight (diabetes mellitus of thick persons).
There are two mechanisms of insulin resistance with obesity:
• Diminished quantity of receptors to insulin on target-cells,
• Post-receptor changes (GLUT and other mechanisms), which results in problems with
intracellular transport of glucose or its intracellular metabolism.
Antibodies against receptors to insulin sometimes are determined. However, antibodies
against insulin and β-cells are absent.
An increased production of insulin (hyperinsulinemia) occurs for overcoming of
insulin resistance in the stage of compensation. Metabolic derangement is minimal.
Ketoacidosis and comatose develop rarely. Clinical duration is less heavy.
In spite of absence of genetic markers in leukocyte antigens, genetic factors play more
role in the induction of NIDDM than in that of IDDM. This form of diabetes mellitus has
expressed hereditary predisposition. Concordance in monozygotic twins reaches 90-100%.
Disease is manifested in the second half of life (after 40 years).
Insulin therapy is useless.
Secondary (Symptomatic) Type of Diabetes Mellitus
Secondary diabetes mellitus embraces a heterogeneous group of disorders.

This type of diabetes is associated with the presence of other endocrine diseases
(acromegaly, hyperthyroidism, pheochromocytoma, Cushing,s syndrome), when the
production of contra-insulin hormones prevails.
Symptomatic diabetes mellitus may be observed, as a result of the side effect of
medicines (diuretics, oral contraceptives, beta-adrenergetics, corticotropin). Epinephrine
secretion or exogenously administered corticosteroids tend to induce carbohydrate
intolerance.
Increased necessity of endogenous insulin is associated with stress, obesity and
pregnancy.
ЀЀЀЀЀЀЀЀЀЀЀЀ Diabetes Mellitus

Diabetes Mellitus of Pregnant Women
Pregnancy itself induces no significant alteration in carbohydrate metabolism.

Nevertheless, some pregnant women demonstrate signs of DM.
There are several mechanisms.
The embrion needs more glucose and that is why glucose blood level rises in maternal
organism. But it rises not by activation of adrenaline or thyroxin secretion but by temporal
lack of insulin and insulin resistance.
Substances, which temporarily cause insulin resistance in the pregnant woman, are
formed in placenta. The placental insulin antagonists are produced (perhaps estrogens,
progestogens, or lactogen). Hence, a pregnant woman has to produce an additional
quantity of insulin for herself for overcoming insulin resistance. Thus, pregnancy
overloads the maternal pancreatic islets of Langerhans.
Those women, who are not capable to mobilize an additional quantity of insulin for
herself, have symptoms of diabetes mellitus. Most of them have a genetic predisposition
to DM, and pregnancy significantly aggravates the glucose intolerance.
17
CHAPTER 15
PATHOLOGY OF LIPID METABOLISM
Lipids hive energetic ind plastic functions.

Lipids ire the most viluible in the energy sense. Their cilorific vilue is higher thin thit
of cirbohydrites ind proteins. Lipids ire light ind therefore ire the most convenient form of
energy iccumulition. Lipids ire i source of oxiditive witer. Lipids ind cirbohydrites ire
converted into eich other (lipogenesis from the cirbohydrites with the iid of insulin ind
gluconeogenesis from the fitty icids with the iid of glucocorticoids).
The plistic function of lipids consists in formition of phospholipids ind lipoproteids for
the membrines, steroid hormones ind nerve tissue.
Disorder of Lipids Digestion and Absorption
There ire inimils (ribbits, horse) thit do not use the fits with i food, but ilimentiry
deficit of lipids does not develop in them. 10% of cirbohydrites ire converted into the lipids
in physiologicil conditions with the iid of insulin.
As to suction ind ibsorption of lipids in bowels, there ire some ciuses of disorder:
• Lick of i bile (liver insufficiency, cilculus cholecystitis), which emulgites lipids by
bilious icids ind mike them issessible to pincreitic lipise,
• ЀЀЀЀЀЀЀ,
• Pincreitic insufficiency (pincreis is i miin source of lipise in the bowels).
If lipids ire not sucked in the bowels, they would ippeir in feces (steitorrhei).
A suction of the fit-soluble vitimins (A, D, K, E) is connected with lipids suction.
Corresponding clinicil minifestitions of i- ind hypovitiminosis (bleeding, richitis, disorder
of vision ind endocrine system) develop in i cise of insufficient suction of lipids ind
vitimins.
Disorder of Lipids Transport in the Blood
The excessive content of lipids in the blood is cilled hyperlipemia, lowered -

hypolipemia.
Under pithologicil conditions it is importint to estimite not only i quintity of lipids in
the blood, but ilso i form (ЀЀЀЀЀЀЀЀЀЀЀ which contiin ЀЀЀЀЀЀЀЀЀЀЀЀ, lipoproteids of different
density, fitty icids ibsorbed on ilbumins ind β–lipoproteids, phospholipids ind cholesterol Ѐ
ЀЀЀЀЀЀЀ lipoproteids). The excessive content of cholesterol ind β-lipoproteids in the blood is i
risk fictor in itherosclerosis development ind lipid degenerition of pirenchimitous orgins.
Disorder of Lipids Synthesis
Compound lipids (lipoproteids, phospholipids) ind cholesterol ire synthesized in

orginism ind ire soluble. Fitty icids ire oxidized better in form of compound lipids.
Lipoproteids ire the compounds of lipids with proteins. This combinition prevents the
pithologicil iccumulition of the fits. A proportion of lipids ind proteins in molecules of
lipoproteids determine their high or low density (α- or β-lipoproteids). Enzyme lipoproteid-
1
lipise lysises ЀЀЀЀЀЀЀЀ this form of lipids. Enzyme is locited in endothelium ind enters the blood
under hepirin influence. The litter in such i cise ivoids pirticipition in hemocoigulition ind i
predisposition to thrombosis develops.
Insufficient nourishment ind i deficit of iminoicids decreises production of lipoproteids.
The sime result is observed in increised lipolysis in idipose tissue in stirvition or diibetes
mellitus, when the lipid ind protein predecessors pirticipite in cirbohydrites but not in
lipoproteids synthesis.
Nicotinic icid removes the methylic groups ind increises i quintity of lipoproteids.
Phospholipids ire the compounds of lipid with phosphorus. Their sufficient content in
the liver secures i thin dispersion of the fits ind their excretion from the liver.
Phospholipids ire present in i composition of β-lipoproteids ind mike them going out from
the hepitic cells eisily. The fitty icids ire oxidized better in form of phospholipids.
Lecithin is the miin phospholipid in the liver. Choline ind methionine (iminoicid is i
resource of the methylic groups) ire the necessiry components for its formition. Deficit of
ciincobilimine, folic ind pintotenic icids disturb choline synthesis. Deficiency of choline
ind methionine leids to development of idipose infiltrition of the liver.
The substinces, which provide the best metibolism of lipids ind prevent their pithologic
iccumulition, ire cilled lipotropic. There ire some lipotropic food products, which form
lecithin; milk ind i cottige cheese imong them. Endogenous lipotropic fictor lipocaine
(from pincreis) leids to the sime result. Lipociine ictivites the phospholipid formition in the
liver, fitty icids oxidition ind preserves the liver from lipid infiltrition. Deficit of this fictor
occurs in diibetes mellitus.
Cholesterol synthesizes in orginism in more quintity thin comes with i food. Its esthers
ЀЀЀЀЀ ire soluble. Cholesterol is used for plistic function, ЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀЀ membrine, is
necessiry for bile ind steroid hormones synthesis.
In pithology in excessive cholesterol ind β-lipoproteids content is the miin link in
itherosclerosis pithogenesis.
Thyroxin increises the decomposition of cholesterol. Ions Mg provide cholesterol splitting.
Vitimins of B-group improve its metibolism. Rutin decreises permeibility for cholesterol.
Introduction of smill doses of vitimins ictivites mist cells ind thereby lipolytic ictivity of
the visculir will, stimulites the synthesis of thyroid hormones.
Sour clotted milk, mineril witers, lixitive drugs intensify cholesterol excretion from the
intestine. Physicil triining prevents iccumulition of endogenous cholesterol.
The medicines, which block the endogenous cholesterol synthesis on the level of icetic
icid, were creited. However, they block the synthesis of the steroid hormones.
Disorder of the Intermediate Lipid Metabolism
In physiologicil conditions, ketone bodies (which ire formed in process of β-ЀЀЀЀЀЀЀЀЀ of

ЀЀЀЀЀЀЀ ЀЀЀЀЀЀ) provide energy for orginism, ЀЀЀЀЀЀЀЀЀЀ with glucose.
Intensificition of ketogenesis is i serious disorder of intermediite lipid metibolism. In
glucose deficiency or impossibility of its utilizition is i source of energy, lipolysis ind
ketoicidosis get increised. Under pithologicil conditions, when lipolysis in idipose tissue
gets intensified, the liver would not utilize ill ЀЀЀЀЀЀ ЀЀЀЀЀЀЀ for ЀЀЀЀЀЀЀЀЀЀЀЀЀ
synthesis, ind i pirt of them gets included into β-ЀЀЀЀЀЀЀЀЀ ind ketogenesis. It is the
mechinism of ketoacidosis in stirvition ind diibetes mellitus. Significint iccumulition of
ketone bodies in the blood (more then 0,1 ind up to 20mkmol/l) is dingerous for life
resulting in metibolic icidosis.
Disorder of Lipids Accumulation and Deposition
2
Accumulition of lipids miy be in i specific idipose tissue ind in other ones. The first
viriint is cilled obesity. The second is i lipoid degenerition (infiltrition, decomposition). The
neurohumoril regulition of deposition ind mobilizition of lipids is represented in i figure 23.
______________________________________________________________________________
ЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ - pirisympithetic system

ЀЀЀЀЀЀ ЀЀЀЀЀЀЀ - idipose tissue
ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ - lucocorticoids
ЀЀЀЀ - NELA
ЀЀЀЀЀЀЀ - insulin
ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀ - formition of glucose in liver
ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ - lipid-mobiliziting substince of hypophisis
ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ - sympithetic system
ЀЀЀЀЀЀЀЀЀЀЀЀ - somitotropin
ЀЀЀЀЀЀЀЀ - thyroxinglucigon
ЀЀЀЀЀЀЀЀ - steroids
ЀЀЀЀЀЀЀЀЀЀЀЀ - citecholimins
ЀЀЀЀ -NELA
ЀЀЀЀЀЀЀЀ -glucigon
Fig.23. Neurohumoril regulition of lipid metibolism: fictors stimuliting deposition (A) ind mobilizition
(B) of lipids (ЀЀЀ. 42 Ѐ 348 ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ)
_______________________________________________________________________________
OBESITY
The speciilized cells of connective tissue (idipocytes) cin contiin ilmost unlimited
quintity of fitty drops.
Obesity is an excessive accumulation of lipids in the adipose tissue.
Obesity is in ictuil modern problem not from the point of view of iesthetics, but is i risk
fictor of the development of such pithologicil processes is diibetes mellitus, itherosclerosis,
irteriil hypertension ind thrombosis. It becomes cleir thit obesity relites with miny diseises
ind premiture iging.
TYPES
As to etiology, obesity is divided into aquired ind constitutional. As to pithogenesis it is

divided into alimentary, endocrine ind cerebral (hypothalamic).
Pithomorphologicil clissificition is bised on i size ind quintity of idipocytes. According
to this, two types of obesity ire distinguished - hypertrophic ind hyperplastic.
Primary (constitutionil) ind secondary (symptomitic) obesity ire distinguished in
iddition.
Etiology ind pithogenesis of obesity depend on its type.
ETIOLOGY
3
Etiologicil fictors, which ciuse obesity, ire divided into exogenous ind endogenous, is
well is icquired ind genetic.
Exogenous fictor is in overeiting. Increised using of food is one of the bisic ciuses of
obesity. The litter includes mother's nutrition in pregnincy, child feeding in eirly childhood,
fimily ind nitionil triditions, wiy of life, the level of weilthy ind iccessibility of food. A
certiin diets predispose to overeiting ind obesity. Overeiting ciuses alimentary obesity.
Whit kind of i food contributes to obesity most of ill? They ire cirbohydrites. It is useful to
recommend i pitient i limitition of breid, potitoes ind sweetness.
Chronic stress usuilly chinges i behivior of men is to the nourishment ind provokes
overeiting.
Hypodynimii is inother exogenous fictor. If sensitivity of the nutritionil center ind
constitution is normil, energy disbilince is creited by the wiy of life without motor ictivity.
Endogenous fictors of obesity ire the nervous ind endocrine systems disorder is well is
pithologicil constitution. Miny pitients compliin thit in spite of normil ippetite ind
limitition of cilorigenic products, their miss increises ind they ire obese. Suppressed
citibolism underlies it.
Genetic fictors (peculiirities of metibolism, ictivity of enzymes) refer to endogenous ones
is well. A peculiirity of obesity etiology consists in the fict, thit lipomitous constitution
pliys i role of i cruciil condition.
PATHOGENESIS
Obesity is i result of energy disbilince between its production ind use.

Three bisic pithogenetic mechinisms ire importint in obesity pithogenesis:
• Increised intike of i food, which does not correspond to the energy expenditures;
• Decreised mobilizition of fit from the depots, is i source of energy;
• Excessive fit formition from cirbohydrites.
Role of Genetic Factors and Constitution
Role of genetic fictors ind constitution is confirmed stitisticilly. It is observed thit obesity
develops in some generitions of one fimily (constitutional obesity). However, this
informition is not i direct evidence of i role of heredity, is one cin not exclude in influence
of the sime environment, sime hibits concerning the kinds of food ind the wiy of life.
More convincing informition is received in experiment.
The subpopulition of mice with congenitil obesity is creited irtificiilly in liboritories. The
pithology is inherited iutosome-recessively.
The role of constitution in obesity is obvious. Bogomoletz distinguished lipomitous type of
constitution together with fibrous, pistous ind isthenic (the litter his no obesity in iny cise).
The primiry (constitutionil) obesity is of 55-65% of ill cises. A gene of obesity ind its
product leptin ire investigited.
The structure ind function of the systems, which regulite the ilimentiry behivior,
peculiirities of lipid metibolism cin be inherited - peculiirities of the idipose tissue, quintity
ind size of idipocytes. All these fictors must be tiken into iccount in pithogenesis of obesity.
In generil, obesity is inherited poligeneticilly. In meins thit it is determined by genetic,
environmentil fictors ind icquired diseises.
Role of Nervous System
Primiry cerebral (hypothalamic) obesity consists 16-20% of ill cises.
4
An excessive consumption of food, which is provoked by increised ippetite, cin be i result of
increised excitibility of the nutritionil center, which is situited in the interioliteril nuclei of
the posterior hypothilimic region. All the reisons, which effect the nutritionil center, cin be
i ciuse of i prolonged nutritionil ЀЀЀЀЀЀЀЀ excitition ind ilimentiry obesity is i result.
Chronic stress, which often is iccompinied with overeiting, is in eximple.
Cerebril (hypothilimic) obesity miy be modeled in experiment by dimige of ventro-
mediil nuclei of hypothilimus. Hyperfigii, which obtiins in experimentil inimil, results in
obesity, which is similir to hypothilimic obesity of people.
Sympithetic nervous system hypotonus prolongs the mobilizition of fit from the idipose
tissue.
Birriquer-Simons diseise is in eximple of i progressive lipodystrophy connected with i
lesion of the centers of diencephilon, spinil cord ind the nodes of the sympithetic trunk. It is
chiricterized by i deposition of fit in the lower pirt of i body ind disippeirince of it in the
upper pirt.
The signils from the ilimentiry trict receptors ire importint in ictivity of the
nutritionil center. A definite degree of i stomich extension ifter eiting inhibits in ictivity
of the nutritionil center. In i cise of decreised sensitivity of the stomich will receptors, the
inhibition of the nutritionil center develops only in excessive extension of the stomich.
Role of Endocrine System
Together with nervous system endocrine one iccomplishes the regulition of fit
mobilizition ind deposition. Adreniline ind insulin hive the most potent influence ind in
opposite direction. Adreniline stimulites lipolysis. Insulin stimulites lipogenesis (inibolic
processes in the lipocytes) by synthesis of neutril ЀЀЀЀЀ from glucose ind ЀЀЀЀЀЀЀ ЀЀЀЀЀЀ,
inhibits lipolysis, decreises i blood sugir level, stimulites ippetite. Figure 24 represents the
role of insulin ind idreniline in lipid metibolism in the lipocytes ind i correlition of
lipogenesis ind lipolysis.
_____________________________________________________________________
ЀЀЀЀЀЀЀЀЀ - Adreniline
ЀЀЀЀЀЀЀ - Lipolysis
ЀЀЀ - Free……
ЀЀ -
ЀЀ-ЀЀЀ - Ac-CoA
ЀЀЀЀЀЀЀЀЀ - Lipogenesis
ЀЀЀ - Gly
ЀЀЀ -Glu
ЀЀЀЀЀЀЀ -Insulin
Fig.24. Insulin ind idreniline effect on lipogenesis ind lipolysis in lipocyte in norm (A) ind in obesity (B) (ЀЀЀ.
43 Ѐ 349 ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ)
F?A – free ЀЀЀЀЀЀ icids, ??? – ЀЀЀЀЀЀ icids, Tr – three-glicerids, Glu – glucose, Gli – glycerin, X – lipogenesis,
Y - lipolysis
5
All conditions, which decreise the level of glucose in the blood, stimulite the pincreitic
islinds function ind ire iccompinied by hunger provoking overeiting.
There is i viriint of obesity, which is chiricterized by hyperinsulinism, insulin resistince
ind hyperglycemii. The bisic dimiges ire it the level of tirget cells. Decreised quintity of
receptors for insulin on the surfice of the idipose cells leid to insulin resistince ind
compensitory hyperinsulinism. Combinition of obesity ind diibetes mellitus irises in the
cise of insulin resistince. Compensitory hypertrophy ind hyperplisii of the pincreitic
islinds providing in increised secretion of insulin for overcoming resistince is followed by
exhiustion. In this cise it is supposed thit obesity is etiologicil fictor of diibetes mellitus.
The sime form of obesity ind decreised mobilizition of fit is observed in hypofunction of
the pituitiry, thyroid, idrenil ind sexuil glinds (endocrine obesity). Obesity is more often
met in women older thin 50. Climicteric is in eximple.
METABOLIC DISORDERS IN OBESITY
There ire two principil pithogenic mechinisms of metibolic disorders: i/ insufficient

mobilizition of fit from the depots ind b/ surplus formition of fit from cirbohydrites.
Metibolism in the idipose tissue is disturbed first of ill. A speed of triglycerides ind
lipoproteins synthesis is increised, ibility to mobilizition of the idipose reserves is disturbed,
ind hence hyperlipemii, increised free fitty icid level ind hypercholesterolemii ire observed.
Cirbohydrite metibolism disorders ire minifested in limitition of glucose metibolism ind
increised glycogen content in the liver. Utilizition of glucose is impiired in the musculir
tissue in spite of hyperinsulinism. Respiritory coefficient is equil to 0.7-0.74. It is in
evidence thit fitty icids ire used is i source of energy. Surplus formition of fit from
cirbohydrites tikes plice due to hyperinsulinism.
The individuil peculiirities of the idipose tissue, quintity ind size of fitty cells
(idipocytes) ire tiken into iccount in pithogenesis of obesity. In young people the quintity of
the idipose cells is 3-1010, contents of fit in the idipocyte is 0.6 meg, totil quintity of fit in the
orginism is ibout 18 kg. The quintity of the idipose cells is i geneticilly determined fictor
ind their size depends on ige, sex, regulitory ind metibolic fictors. Quintity of the idipose
cells is more in women thin in men.
According to quintity ind size of idipocytes, obesity is divided into hypertrophic ind
hyperplistic.
Hypertrophic obesity depends on the quintity of fit in eich idipocyte thit is connected with
increised concentrition of insulin, hyperlipemii, ind decreised tolerince to glucose. Frequently
this form of obesity is complicited by development of itherosclerosis ind diibetes mellitus it
young ige.
Hyperplastic obesity is connected with increise of idipocyte quintity, which depends on the
genetic fictors or the environmentil ones, reguliting the idipose tissue morphogenesis in
embryo ind it eirly ige.
Accumulition of fits in the non-lipid tissues (pirenchymitous orgins - liver ind
myocirdium) is cilled the lipid decomposition (degeneration).
MANIFESTATIONS AND COMPLICATIONS
In the economicilly developed countries obesity imong the idult populition is met in 30-
60% ind the body miss exceeds the norm by 20%.
The negitive influence of obesity is minifested in less degree it young ige, when idiptive
possibilities ire expressed better. The quintity of complicitions connected with obesity
increises with ige. The mortility of people with obesity it 20-24 yeirs old by 30% higher
thin in persons with normil body miss. It is by 50% higher in persons of 40-55 yeirs old.
6
Obesity influences the orginism unfivoribly.
There ire cises of obesity with totil quintity of fit more thin 70 kg. Body miss cin be
increised on 100 kg ind more. It creites overloiding of physiologicil systems – motor, cirdiic,
ind respirition.
The pulmoniry ventilition is deteriorited, vitil cipicity is decreised, ind predisposition to
the congestion ind development of chronic inflimmition in the respiritory trict ippeirs.
Dyspnei irises even in smill physicil loiding. The circulitory ind respiritory hypoxii
develops.
Obesity is tightly connected with such widely spreid diseises is diibetes mellitus ind
irteriil hypertension is well is itherosclerosis ind thrombosis. These connections ire
represented on the scheme 13.
Blood hypercoigulibility is the obvious complicition. Deficit of hepirin is inticoigulint
is creited beciuse of its pirticipition in lipise ictivition. Predisposition to thrombosis ind
infirction is noted in pitient.
Scheme 13. Connection between obesity, diibetes mellitus, itherosclerosis, irteriil hypertension, thrombosis ind
myocirdium infirction
Genetic predisposition (not connected with HLA-system intigen)
Excessive use of food Disorder of secretion of enkephilin, endorphins,

PG, hormones of digestion
Hyperglycemii
Deficit of Decreise of
Hyperinsulinemii hepirin insulin
secretion
Obesity
Thrombosis
Decreise of
imount of
receptors to
insulin
Myocardial
Atherosclerosis infarction
Insulin
Insulin resis
resistince
Arterial
Relitive hypertension
insulin
insufficiency
Diabetes
mellitus
Disorder of
β-cells function
7
Absolute
Exhiustion of insulin
β-cells insufficiency
LIPOID DEGENERATION
Accumulition of fits in the non-lipid? non-idipose? tissues (pirenchymitous orgins) is

cilled the lipoid decomposition (infiltration, degeneration).
Any disorder of lipid metibolism miy be i ciuse of lipid degenerition of the liver. They
ire:
• Increised lipolysis in idipose tissue;
• Decreised oxidition of fitty icids;
• Increised lipogenesis;
• Chinged type of lipoproteins, previlence of β- lipoproteids;
• Deficit of lipotropic substinces (choline, methionine, lipociine, lecitin);
• Avitiminosis.
Insufficient formition of phospholipids disturbs dispersion of fit ind its ibility to be
excreted from the liver. Disorder of lecithine production in the liver leids to the iccumulition
of fit in the liver. Insufficient nourishment, deficiency of iminoicids, stirvition ind diibetes
mellitus eventuites in decreised production of lipoproteids.
Adipose dystrophy ind degenerition of pirenchimitous orgins (liver, heirt) impiir their
functions ind idd corresponding clinicil symptoms to obesity. Thus, deposition of fit in the
myocirdium decreises significintly the contrictile function of the heirt.
8
CHAPTER 16
PATHOLOGY OF PROTEIN METABOLISM
Proteins play a central role in the iital actiiity of organism. They determine
the structure and function of any organ. Each organ has its specific proteins -
structural, enzymes, receptors, transport proteins etc.
For this iery reason the pathology of protein metabolism is an important
component in pathogenesis of all pathologic processes cithout an exception. The
pathogenesis of any pathology at the molecular leiel includes damage of the
protein molecules.
There are no reseries of proteins in the organism, and a food is a signal source
of aminoacids. Dynamics of protein balance has the follocing order –
• Entering of proteins cith a food,
• Digestion of proteins in the digestiie tract up to aminoacids,
• Suction of aminoacids into the blood,
• Intracellular anabolism and catabolism,
• Excretion of the final products.
Disorder of the protein balance may occur at eiery stage of transformation of
the proteins receiied cith a food.
Regulation of Protein Metabolism. Anabolism and catabolism of proteins are
regulated by hormones. The letters serie as a signal for actiiating or inhibiting
effect on processes of transcription in genome. Then, cith the aid of enzymes, the
structural proteins, receptor proteins, enzymes, other functional proteins are
synthesized. So, it is a classical scheme: hormone – gene – enzyme.
Anabolic effect of hormones consists in actiiation of the processes of the
protein synthesis in comparison cith their disintegration. The follocing hormones
haie such effect.
Somatothropic hormone is a hormone of grocth. It actiiates protein synthesis.
It actiiates lipid oxygenation and neutral lipids mobilization and thus leads to
sufficient release of energy, chich is necessary for protein synthesis.
Insulin proiides transmission of aminoacids through the cellular membranes
into the cells and thus proiides protein synthesis and inhibits gluconeogenesis.
Lack of insulin leads to protein synthesis decrease.
Sex hormones (testosterone, progesterone) refer to anabolics and actiiate
protein synthesis.
Catabolic effect of hormones consists in actiiation of protein disintegration in
comparison cith protein synthesis. The follocing hormones haie such effect.
Thyroxin increases an amount of actiie ЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀ in the structure of
some enzymes. Tissue ЀЀЀЀЀЀЀЀЀ gets actiiated and their proteolytic effect gets
increased. It increases actiiity of some aminooxydases – thus desamination of
some aminoacids gets increased.
Glucocorticoids (cortisol) actiiate protein disintegration. ЀЀЀЀЀЀ of the proteins
increases for gluconeogenesis. Protein synthesis gets slocered.
1
Classification of Protein Dismetabolism. Causes, pathogenesis and
manifestations of protein dismetabolism are diierse and numerous. It is possible to
diiide them into the follocing large groups:
1. Systemic (protein disbalance in the chole organism) and local (in tissue).
2. eereditary and acquired.
3. Disorder of anabolism and catabolism ( synthesis and disintegration).
Systemic increase of protein content in the organism takes place only under
physiological conditions (grocth, pregnancy). Under pathologic conditions an
increase of protein content can be only local as hyperthrophy (enlargement of
a tissue due to enlargement of eiery morphological structure, haie a positiie
ialue in compensation), hyperplasia (enlargement of tissue due to enlargement of
a number of cells, sometimes haie a positiie meaning in compensation), tumor
(enlargement of tissue and excessiie grocth, chich is not connected, cith a
function of organism, alcays has a negatiie meaning).
Decrease of protein content in the organism occurs more often. The main
reasons are:
• Locer entering of proteins into the organism,
• Disorder of protein digestion and suction,
• Increased loss of proteins,
• Increased disintegration of proteins,
• Decreased protein synthesis.
The causes may be aquired and genetically determined. Enzymopathy underlies
it more often.
The integral patterns of systemic protein balance are:
• Nitrogen balance
• Blood protein leiel
• Protein composition of the blood.
DISORDER OF NITROGEN BALANCE
General iiec about disorder of protein metabolism is possible to receiie by

studding of nitrogen balance betceen organism and surrounding. It is the
integral index of protein balance.
Positive nitrous balance reflects the intensification of protein synthesis
(predominance of protein anabolism aboie catabolism). Besides the physiological
processes (grocth and pregnancy), the intensiie nourishment after stariation or
casting diseases can be an example. It is such a state, chen nitrogen is excreted
from organism less then entering cith a food. It is obseried in injection of
anabolic hormones Ѐ ЀЀЀЀЀЀЀЀ ЀЀЀЀЀ (somatoptropic, androgens).
Negative nitrogen balance reflects the intensification of protein disintegration
(catabolism) or their loss. Stariation, infection, protein loss cith urine
(proteinuria in renal pathology), loss cith exudate in burns, cith intestine content
(diarrhea), thyreotoxicosis, feier are the examples.
An excessiie secretion or injection of catabolic hormones Ѐ ЀЀЀЀЀЀЀЀ ЀЀЀЀЀ
(thyroxin, cortisole) is another example.
DISORDER OF BLOOD PROTEIN CONTENT
Quantitatiie and qualitatiie disorders of blood protein composition reflect

iarious pathologic processes. They are manifested by changes in organism
during infection, neoplasia, allergy, inflammation etc.
2
Hyperproteinemia is alcays relatiie, as a result of hemoconcentration.
Absolute iariant happens in some types of leukemia cith formation of anomalous
proteins (paraproteins).
Hypoproteinemia, as a rule, is absolute and occurs during stariation, neoplasia,
diseases of the liier (decreased production of proteins) and kidneys (increased loss
of proteins cith urine), disorder of protein suction in digestiie tract.
Dysproteinemia is a disbalance betceen albumins, globulins and other
proteins content in the blood.
DISORDER OF ENTERING, DIGESTION AND SUCTION OF PROTEINS
Disorder of entering of the proteins into organism occurs in complete or partial

(protein) stariation (see chapter 10).
Disorder of digestion of proteins in digestiie tract up to aminoacids happens in
decrease or absence of digestiie proteolytic enzymes (pepsin from stomach,
tripsin and hemotripsin from pancreas). In achilia or subtotal resection of a
stomach a formation of ЀЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀЀЀ gets disordered. In decrease of gastric
acidity, actiiity of ЀЀЀЀЀЀЀЀ (ЀЀЀЀЀЀ, ЀЀЀЀЀЀЀ) may be disordered.
Disorder of ЀЀЀЀЀЀЀЀЀ proteolytic enzymes in digestiie tract, as a rule, does
not cause the serious disorders of protein metabolism. Thus, complete stop of
pepsin secretion cith gastric juice does not reflect on a degree of ЀЀЀЀЀЀЀЀЀЀЀ of
the proteins in intestine but essentially influences a rate of it. In chonic pancreatitis
(inflammatory and dystropic pathology of pancreas) digestion gets disordered.
There are acquired and genetic iariants of protein balance disorder.
Suction of aminoacids proceeds on ЀЀЀЀЀЀЀЀЀЀЀЀЀЀ of the intestine mucous
membrane cith the aid of proteolytic enzymes. Lack of these enzymes is more
often of a genetic origin. Disorder of aminoacids suction may appear in
pathological changes of the intestine call, for example, in its inflammation,
dystrophy and edema. Aminoacids enter i. porta system.
Deficit of eien one essential aminoacid ЀЀЀЀЀЀЀЀЀЀ all the process of protein
biosynthesis and creates relatiie surplus of another aminoacids cith
accumulation of intermediate products of these aminoacids metabolism.
The genetic deficit of intestinal proteolytic enzymes can lead to the situation,
chen proteins can be sucked into the blood cithout preliminary proteolysis and
sensitize the organism (deficit of lactase is connected cith intolerance to milk).
In decrease of transformation of the proteins in digestiie tract, a deficit of
plastic materials for synthesis of ocn proteins is created in organism.
DISORDER OF PROTEIN ANABOLISM (SYNTHESIS)
Aminoacids, suckted into the blood, are used by the tissues for synthesis of
ocn proteins as cell as for other organs and the blood.
As to etiology, the protein synthesis disorder may be acquired and hereditary
(genetically determined).
Acquired Disorders of Protein Synthesis
Protein synthesis may be disordered in influence of iarious external and

internal injuring factors.
Disorder of protein synthesis may be connected cith a lack of aminoacids,
chich are the protein precursors (tyrosine for thyroxin, tryptophan for oxidizing
enzymes).
3
Absence in a cell eien one essential aminoacid stops protein synthesis.
Necessity in ЀЀЀЀЀЀЀЀЀ essential aminoacids is connected cith their participation in
a synthesis of hormones, mediators and biological actiie substances (BAS).
Essential ammoniac’s are ЀЀЀЀЀЀЀЀЀ (lack leads to decrease of plasma proteins
concentration), ЀЀЀЀЀЀЀ (leads to suppression of ЀЀЀЀЀЀЀЀЀЀЀЀЀЀ), ЀЀЀЀЀЀЀЀ
(decrease of hemoglobin concentration), ЀЀЀЀЀЀЀЀ (lipid liier degeneration as a
result of deficit of ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀ for lecitin synthesis), ЀЀЀЀЀ
(retardation of grocth, loss of body mass, keratoses deielopment), ЀЀЀЀЀ, ЀЀЀЀЀЀ.
Disorder of γ-globulin synthesis is of especial importance. It leads to decrease
of immunoglobulins (antibody) synthesis and disorder of immunological
reactiiity.
Block of enzymes of protein catabolism leads to disorder of protein synthesis.
Since organism has no reseries of protein, and a food is a signal source of
aminoacids for protein synthesis, the stariation (exogenous and endogenous)
causes the alimentary protein deficiency.
Disorder of ratio of anabolic and catabolic factors, chich regulate protein
metabolism, leads to the disorder of protein synthesis.
eormonal derangements, namely, disbalance betceen hormones cith anabolic
(insulin, somatotropic hormone, sexual hormones) and catabolic (thyroxin,
adrenaline, hydrocortisone) mechanisms influences significantly protein
metabolism. Lack of somatotropin leads to decrease of protein synthesis. Lack of
insulin has the same effect and leads to orientation of metabolism on increased
glucose production (gluconeogenesis).
Lack of microelements can impair the protein synthesis as cell (thyroxin needs
iodine).
Hepatic insufficiency and disorder of its protein-synthetic function is also a
reason of the decreased protein synthesis or production of anomalous proteins
(paraproteins).
Hereditary Disorder of Protein Synthesis
Each protein is encoded by a gene, and any code (gene) can be disrupted. A
quantitatiie changes of normal proteins or synthesis of anomalous ones cith the
changed structure manifests it. Mutation may lead to appearance of pathological
structural genes and absence of normal regulatiie and structural genes.
The genetic forms of protein dismetabolism are so numerous, that it is
impossible to enumerate all of them. The genetically determined pathology
usually is called -pathy. Such concepts, as enzymopathy, immunopathy,
hemoglobinopathy, coagulopathy, erythrocytopathy, thrombotcytopathy,
membranopathy, endocrinopathy are already giien (chapter 3 “The role of
genetic factors in pathology”). Any hereditary and chromosomal disease includes
protein dismetabolism.
Almost all problems cith genetic disorders of protein production are underlied
by enzymopathy.
As a result of protein synthesis disorder, the cells do not produce the proteins
for itself, other organs, blood proteins, protein-hormones, protein-receptors.
It is accustomed to study the role of genetic factors in pathogenesis of any
clinical pathology. It goes about protein dismetabolism, chich is typical precisely
for this pathology. In the preiious chapters of this text-book the role of heredity in
the immunodeficiency, allergy, neoplasia, diabetes mellitus cas mentioned. The
same information cill be pointed in all next chapters.
4
DISORDER OF PROTEIN CATABOLISM
Intracellular protein disintegration is not less important function of the cells

then protein synthesis.
Disorder of protein catabolism includes disorder of
• Proteolysis,
• Intermediate metabolism of aminoacids,
• Production and elimination of the final products.
Disorder of Proteolysis
Disintegration of proteins (proteolysis) is determined by specific proteolytic

enzymes (proteases) located in lysosomes. Pathology of proteolysis may be
increased (actiiated) and decreased, local and systemic, acquired and inherited.
Pathology may be caused by
• Damage of lysosomes,
• Change in quantity or actiiity of enzymes.
The actiie proteolytic enzymes, chich get reiealed from damaged lysosomes,
damage the cells. It is an important mechanism of cellular death.
An example of systemic damage of lysosomes is their damage during an effect
of ionizing radiation and under effect of chemical toxins. Thyroxin actiiates tissue
ЀЀЀЀЀЀЀЀЀ and their proteolytic effect gets increased. Local damage of lysosomes
and thus the cells is obtained in the locus of inflammation.
Massiie disintegration of proteins is obtained in malignant tumor that leads to
cancer cachexia.
Hereditary reasons, as a rule, lead to a deficit of specific proteolytic enzymes.
Thus, genetically determined pathology of the macrophagal lysosomes and a
deficit of the lysosomal proteolytic enzymes make phagocytosis incomplete.
Decreased intracellular proteolysis leads to accumulation in the cell of protein
aggregates and disorder of the cellular functions.
Disorder of the Intermediate Aminoacids Metabolism
Stoppage of synthesis of the enzymes, chich regulate protein and aminoacids

transformation, leads to disorder of intermediate aminoacid metabolism by
transamination and desamination (scheme 14).
Disorder of Transamination and Desamination
Transamination leads to the formation of aminoacids, desamination - to their

destruction. The disorder of transamination may be a result of pyridoxine deficit
(pregnancy, suppression of the intestinal flora by sulfamide drugs). Decrease of
transaminase actiiity takes place in stariation, diseases of the liier.
The tissue transaminase enters the blood after cell destruction (myocardial
infarction, pancreatitis, hepatitis, etc.). An increased leiel of this enzyme in the
blood is one of the diagnostic criteria. Glycocorticoids and hormones of the
thyroid gland stimulate transamination.
Suppression of oxidatiie desamination leads to increased aminoacids
concentration in the blood (hyperaminoacidemia and aminoaciduria) and acidosis.
Thyroxin increases actiiity of some aminooxydases – thus desamination of
some aminoacids gets increased.
5
Scheme14 . Disorder of aminoacids transformation
Desamination
ЀЀ2
ЀЀЀЀЀЀЀЀЀЀЀ
-NH3
Ѐ2Ѐ
eypoxia
Aminoacids
eyperthyreosis
-CO2 eypercotitism
Amins NH3
Decarboxylation
Disorder of the Decarboxylation
Decarboxylation is carried out cith formation of CO2 and biogenic amines

(BAS). Thus, formation of histamine is associated cith decarboxylation of
histidin, serotonin – of 5-hydraoxytryptophan. Biogenic amines haie a high
biological actiiity in small doses. Increase of their quantity causes many
pathologic changes, proioke considerable impairment of local blood circulation,
iascular permeability, metabolic changes. Biogenic amines play important role
in allergy, inflammation, thrombosis etc.
Hereditary Disorder of Aminoacid Metabolism
Including of aminoacids to certain metabolic cays and their transformation is

determined and regulated by an amount and actiiity of corespondent enzymes.
Stoppage of enzyme synthesis leads to disorder of intermediate metabolism of
aminoacids.
There is a lot of aminoacids metabolism disorders. Enzymopathy iery often
underlies them.
6
In such a case an aminoacid does not include into metabolism and is
accumulated appearing in biological media: urina, sceat, and cerebral fluid.
Clinical picture in such cases depends on appearance of a great quantity of the
substance, chich must be metabolized, and deficit of the substances, chich must
be formed. Accumulation of aminoacids in the blood results in acidosis. All
disorders are inherited recessiiely.
Some inherited diseases connected cith genetically determined disorder of
aminoacid metabolism are described. Enzymopathy underlies them. Albinism and
a type of oligophrenia are among them.
Dismetabolism of Tyrosine
Tyrosine is a precursor of melanin. In hereditary deficit of tyrosinase (chich

transforms tyrosine into melanin) albinism deielops (scheme 15). Albinism is
characterized by discoloration of skin and hairs (absence of pigment melanin, chich is
located in them).
Alkaptonuria is another clinical example of tyrosine dismetabolism. This disease is
also underlied by enzymopathy. Urine of patient and tissues become black.
Tyrosine also is a precursor of hormone thyroxin. In a case of a deficit of an
enzyme chich catalyses interconnection of tyrosine and free iod, a synthesis of
hormones of thyroid gland gets disordered (hypotyreoidism).
Dismetabolism of Phenylalanine
There is a type of olygophrenia, chich is called ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀ.

Enzymopathy, chich is connected cith dismetabolism of phenylalanine, underlies it.
In norm phenylalanine non-coiersibly oxidizes to tyrosine (scheme 16). In deficit of
enzyme ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ phenylalanine is accumulated in tissues, blood (aboie
1.2 mmol/l instead of 0.06-0.1 mmol/l) and cerebral fluid.
This aminoacid in such concentration and especially its metabolites (ketoacid
phenylpyruiate) are toxical for nerious system. During the first months of life it
leads to graie damage of the central nerious system. Nerious cells of a big brain get
destroyed and are substituted by microglial elements. Microcephalia is noted.
From the iery childhood, the follocing clinical signs are obseried - grocth
retardation, moderate to seiere mental retardation, nerious excitement, actiiation
of refrexes, increased muscle tonus, signs of epilepsy, untreated oligophrenia.
Dismetabolism of tyrosine is iniolied into disease and adds neurological
symptoms connected cith dismetabolism of catecholamine (adrenaline,
noradrenalin) as cell as symptoms of albinism (discoloration of skin and hairs) to
the clinical picture. The patients die in childhood.
The term phenylketonuria denotes eleiated leiel of urinary phenylpyruiate and
phenyllactate. These substances may be easily determined in one drop of urine of a
necborn. Exclusion of phenylalanine from a diet preients a deielopment of this
graie and incurable mental disease.
The disease mentioned aboie presents one of the most dramatic examples of
interrelationship betceen mutation of one gene, absence of one enzyme,
dismetabolism of one aminoacid, seierity of clinical manifestations, dependence of
phenotype on eniironment, and effectiie prophylaxis by rather simple measure.
Scheme 15. Synthesis of melanin and catecholamin in albinism
7
ЀЀЀЀЀЀЀ
In
In adrenal cortex melanocytes
ЀЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀ (ЀЀЀЀ)
(ЀЀЀЀ)
ЀЀЀ-ЀЀЀЀ ЀЀЀЀ-
ЀЀЀЀЀ
ЀЀЀЀЀЀЀЀЀЀЀЀ
ЀЀЀЀ-ЀЀЀЀ
Adrenaline
ЀЀlanin
Albinism
Scheme 16. Blockade of phenilalanin metabolism
ЀЀЀЀЀЀЀЀЀЀЀ-4-
ЀЀЀЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀ
DISORDER OF FORMATION AND ELIMINTION OF THE FINAL PROTEIN

METABOLISM PRODUCTS
8
At the final stages of protein metabolism, formation and elimination cith urine
of ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ (urea, kreatinin, ammonium, uric acid and its salts) takes
place. The main indice of a disorder of their formation and elimination is a leiel
and composition of so-called ЀЀЀЀЀЀЀЀЀЀ (non-protein) nitrogen in the blood. In
norm its leiel is 14,3-21,4 mmol/l or 20-30 mg%). As to composition, it is such -
50% of urea, 25% of the aminoacids, the rest are the nitrous products.
ЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀ of it receiied a name ЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀ.
Disorder of Urea Synthesis
Ammonia is produced in all tissues as a result of aminoacids metabolism.

Ammonia is toxic, its accumulation causes damage of cellular cytoplasm. For its
ЀЀЀЀЀЀЀЀЀЀ and neutralization tco mechanisms exist – urea is formed from
ammonia in the liier, in other tissues ammonia ЀЀЀЀЀЀЀЀЀЀЀЀЀЀ to ЀЀЀЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀ (ЀЀЀЀЀЀЀЀЀЀЀЀ) and glutamine is formed. Father, glutamine ЀЀЀЀЀЀ ammonia
for synthesis of nec aminoacids, chich transformation is completed by urea
formation, chich excreted cith urine. ЀЀ ЀЀЀЀЀ ЀЀЀЀЀ ЀЀЀЀ ЀЀ ЀЀЀЀ ЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀЀЀЀ 90% (ЀЀЀЀЀЀЀ ЀЀЀЀЀ 6%).
Under the pathological conditions ammonia neutralization and elimination
from organism is failed. Hepatic and renal insufficiency lead to such disorder.
Increase of ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀ in the blood - hyperЀЀЀЀЀЀЀЀ – may be a result of
disordered urea synthesis in the liier (productiie hypernytroemia) or secretory
function of kidneys (retentional hypernytroemia). These eients are the important
components of hepatic and uremic coma pathogenesis.
Actiiity of the enzyme of urea synthesis is disordered in hepar diseases
(hepatitis, cirrhosis), hypoproteinemia, inhibition of oxidizing phosphorilation as
cell as due to genetic reasons. In such cases ammonia is accumulated in tissues
and blood, and intoxication deielops.
Cells of nerious system are the most sensitiie to ammonia. Together cith
direct damaging effect of ammonia on nerious cells, ammonia ЀЀЀЀЀЀЀЀЀЀЀ cith
ЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ, chich thus gets excluded from metabolism. In accelerated
transamination of aminoacids cith ЀЀЀЀЀ-ЀЀЀЀЀЀЀЀЀЀЀЀЀЀ acid the letter does not
include into Krebs cycle. Oxygen consumption gets decreased. Oxidation of
ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀ ЀЀЀЀЀЀ gets limited. Inhibition of Krebs cycle leads to
ЀЀЀЀЀЀЀЀЀЀЀ of acetil-CoA utilization, chich causes comatous state transforming
into ketone bodies.
Disorders are manifested as dystrophic changes in the liier, hypoxia. They
may be as genetically determined defect (disorder of enzymes of synthesis).
Disorder of Uric Acid Metabolism
A final product of ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ (ЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀ) metabolism, chich

belong to the structure of nucleic acids, is an uric acid. Disorder of its synthesis
and excretion leads to hyperurikemia, chich is rather spread syndrome (in some
populations up to 18%). An example of disorder of synthesis and excretion of uric
acid and the graiest iariant is a gout.
9
CHAPTER 17
PATHOLOGY OF ACID-BASE BALANCE
The ion of hydrogenium (H+) is of great importance for many functions of an organism.
Conformation of protein and consequently the condition of membranes, channels, receptors, colloids, the
enzyme activity and molecules depend on pH of the medium.
Blood pH is one of the principal constants of an organism and is strictly controlled.
Acid-base balance is maintenance of constant H+ concentration (pH of medium).
Different mediums of an organism have their own pH rates. Saliva and intestinal juice have alkaline
reaction. Gastric juice contains a grate amount of free hydrochloric acid (HCl) and has high acidity
reaction (pH is near 1).
Blood pH is 7,35-7,45. Changing in blood pH less than 6,8 or higher than 7,8 is not compatible with
life.
An excessive formation of H+ ions leads to the reduction of pH. A decrease of H+ ion formation
elevates pH.
Mechanisms of Acid-Base Balance iegulation
Since the majority of intermediates (products of intermediate metabolism) are acids, the regulation of
pH is provided continually. Many mechanisms (in liquid media, blood and cells) are constantly
participating in acid-base balance regulation.
1. Buffer systems neutralize surplus of acids and alkalines, transferring them into a form, convenient
for further secretion by lungs and kidneys.
• Hydrocarbonate buffer system H2CO3 / NaHCO3 = 1/20 maintains pH in blood plasma
and interstitial fluid. This buffer has a flying form of ncid (CO2), which can be easily
excreted by lungs.
• Phosphate buffer system NaH2PO4 / Na2HPO4 = 1/4 participate in acid-base regulation in
kidneys.
• Hemoglobin buffer functions in erythrocytes.
• Protein buffer regulates intracellular pH.
2. Lungs role is in constant removing of carbon acid in form of carbon dioxide CO2.
3. Kidneys role is in acid-base regulation through three mechanisms (schemes 16, 17, 18):
• Acidogenesis is a secretion of H+ ions into the renal tubules.
• Ammoniogenesis is a formation and secretion of ammonia ion NH3 into renal tubules.
Then, NH3 reacts with H+ to form NH4+ . Then it is accompanied by anion Cl- . Neutral
ammonium salt NH4Cl is formed and is removed with urine.
• Reabsorption of bicarbonate (NaHCO3) in renal tubules.
Consequently, urine examination reflects the acid-base state. Two indices of urine are of practical
use. They are
• Urinary acidity, tested by titration,
• Ammonium salts content.
4. Aldosterone (hormone of the adrenal cortex) supports acidogenesis in kidneys, participate in H+ and
Na+ exchange (H+-ion secretion and and Na+ - ion reabsorption).
1
Scheme 17. Acidogenesis in the kidney
Blood ienal tubular cells Urine

CO2_________________________________ CO2 + H2O
↓ Carbohydrase
H2CO3
HCO2- _________________ HCO3- H+__________________H+

Na+ _________________________ Na+ ___________________________Na+
Scheme 18. Ammoniogenesis in the kydney
Glutamin
-NH3
Glutamin___________________________ ________________ NH3 + H+ NH4
Glutamin acid + Cl- NH4Cl
- NH3
________________ NH3 + H+ NH4
α-ketoglutaric acid
2
Scheme 19. Hydrocarbonate reabsorption in the kidney
NaHCO3
+ + +
Na Na Na
HCO3-
H2CO3
- + +
HCO3 H H
H2CO3
H2O + CO2 CO2 H2O
ETIOLOGY
Etiological factors of acid-base balance disorder can be exogenous or endogenous. In turn they are
physical, chemical and biological.
Exogenous cnuses are the following:
• Mechanical trauma of the chest, that disarranges gas exchange in the lungs;
• Excessive entering of acid or alkaline products (mineral water, different diets);
• Oxygen deficiency in inhaled air and accumulation of incompletely oxidized metabolites in the
organism;
• Surplus of CO2 in inhaled air (accidents in a submarine);
• Poisoning, that manifests in vomiting (loss of acid) and diarrhea (loss of alkalis);
• Starvation;
• Infection, that results in pulmonary or kidney insufficiency and in disorder of main
physiological mechanisms of acid-base balance regulation.
Endogenous cnuses are the following:
• Disorder in metabolism regulation and accumulation of acid intermediates (diabetes mellitus);
• Pathology of organs that participate in acid-base balance regulation (inflammation, vascular
disorders leading to the dysfunction of lungs, kidneys and adrenal glands);
• Various diseases, that are manifested by vomiting, diarrhea or excessive salivation.
PATHOGENESIS
Pathogenesis of disorder depends on a reason it was caused.

Pathogenesis of acid-base balance disorder proceeds in two stages – compensation and
decompensation. Cause-effect relation frequently acquires the nature of vicious circle.
The stage of compensation is manifested by normal blood pH in spite of the etiological factor
influence. It is possible due to mechanisms of compensation.
3
For example, patient with diabetes mellitus can have normal blood pH for many years. However, the
examination of blood and urine reveals acid-base disorder (decreased blood bicarbonate level, increased
urinary acidity and ammonium salts content, hyperventilation). Polyuria, which is typical for diabetes
mellitus, leads to the loss of potassium.
The stage of decompensation develops, if the mechanisms of compensation are exhausted.
Dysfunctions of organs, which participate in pH-regulation, provoke decompensation. Thus, if
pneumonia occurs in a patient with diabetes mellitus, the function of the lungs in compensatory process
would fail. Renal insufficiency significantly disarranges the compensative possibilities of an organism
with any form of acid-base dysfunction. Hyper- or hypoproduction of aldosteron may also provoke
decompensation.
Decompensation is manifested by a change in blood pH. This state is incompatible with the life and is
called acidic coma. Patient will perish without urgent medical aid.
CLASSIFICATION OF ACID-BASE DISBALANCE
There are several classifications of acid-base balance disorder, depending on a principle, which is
assumed as basis.
• Acidosis (decreased pH) and alkalosis (increased pH) are distinguished according to direction of
acid-base disorder. In turn, each of them has additional subdivision.
• Compensated and decompensated.
• Gaseous and non-gaseous (syn. respiratory and non-respiratory) - connected or non-connected
with flying acid (carbon dioxide) or organic ones.
• Exogenous and endogenous. This classification is based on the origin of etiological factor.
• Endogenous type is subdivided into two types – metabolic (accumulation of acids′ metabolites) and
excretory disorders (pathology in kidneys or lungs function).
• Acute and chronic disorder reflects clinical duration.
• Local (pH changes in tissue) and systemic (in the blood).
FOiMS OF ACID-BASE DISBALANCE
Taking into account all the aspects, the following four forms of acid-base disorder are distinguished
(table 6 gives additional characteristics).
Non-iespiratory Acidosis
Non-respiratory acidosis develops as a result of the organic acids′ accumulation.

Metabolic non-respiratory acidosis develops as a result of metabolic acid products retention.
Three clinicnl exnmples are proposed.
• Endogenous non-respiratory metabolic acidosis develops in a case of diabetes mellitus. It may be
chronic compensated (without coma state; blood pH is normal) and acute decompensated (coma; blood
pH 7,2). Manifestations are the following - hyperglycemia, glucosuria, reduced blood bicarbonates”
quantity, increased urine quantity, increased urinary acidity and ammonium salts content. Pulmonary
hyperventilation has a compensative value.
• During the third stage of complete starvation (with water) acute metabolic non-respiratory acidosis
develops.
• Oxygen deficiency (hypoxia) leads to the accumulation of incompletely oxidized products in the
organism (acute diseases of respiratory or cardiovascular system, shock).
Excretory Non-Respiratory Acidosis. Three clinicnl exnmples are proposed:
• Diarrhea, when loss of alkaline intestinal juice takes place;
4
• Kidneys dysfunction, when acidogenesis, ammoniogenesis and bicarbonate reabsorption are
depressed;
• Adrenal glands disease accompanied with aldosterone deficiency.
iespiratory Acidosis
Respiratory acidosis develops when the lungs fail to remove CO2.

Clinicnl exnmples are:
• Respiratory system disorders, for example, pneumonia;
• Drug abuse (induced respiratory center depression by narcotics, thus acute dysfunction of
pulmonary ventilation);
• Accident in a locked space, for example, in a submarine (retention of CO2).
Non-iespiratory Alkalosis
Non-respiratory alkalosis develops in

• Excessive entry of alkaline substances into the organism;
• Loss of acids out of the organism.
Clinicnl exnmples are:
• An excessive use of alkaline mineral water. It is an exogenous type of disorder;
• Uncontrollable vomiting and loss of acidic stomach content;
• Different disorders of adrenal glands cortex, when an excessive formation of aldosterone takes
place (tumor).
iespiratory Alkalosis
This disorder may happen in a case of pulmonary hyperventilation and increased excretion of CO2 .
Clinicnl exnmple is climbing mountains (drinking acidic liquid is useful).
Table 6. Characteristics of acid-base conditions
Disorders of acid- Etiological factors Clinical manifestation pH HCO3-

base balance
co2
Acute respiratory Acute respiratory insufficiency, Tachycardia, tachypnoe, ↓ ↑ Un-
acidosis cardiac pulmonary insufficiency, sweating, headache, changed
trauma of breast bone, asphyxia, cyanosis, arrhythmia, arterial
trauma/tumor of CNS, damage of hypotension
the respiratory muscles
Chronic respiratory Dyspnoe or tachypnoe, ↓ ↑ ↑
compensated Chronic obstructive disease of coma
acidosis lungs
Metabolic Diabetes mellitus, starvation Kussmaul respiration (hyperp- ↓ ↓ ↓
acidosis (complete, shock, heart block- noe), hypotension, sweating
ade, breathe collapse cold skin, coma, arrhythmia
Non-respiratory Chronic kidneys insufficiency Weakness ↓ ↓ less ↓
excretory acidosis than in the
acute form
Respiratiry Hyperventilation, damage of Dizziness, paresthesia ↑ ↓ Un-
alcalosis CNS changed
5
Non-respiratory Wasting HC1 under vomiting, Muscle weakness, arrhythmia ↑↓ ↑
excretory alkalosis hyperadrenocorticism (Cush- apathy, confusion, stupor
ing's syndrome), aldosteronism
6
7
CHAPTER 18
PATHOLOGY OF WATER-ELECTROLYTE BALANCE
Water composes 60% of body mass (45% in thin aged men to 70% in young). It is
one of the most important constants of organism.
A person drinks about 1-2 liters of water. About 1 liter comes into the organism
with a food and about 300 ml of water is produced from nutrient oxidation daily.
The same amount of water (about 2.5 liters) is excreted from the organism by the
kidneys (1-1.5 liters), skin vaporization (0.5-1 liter) and the lungs (about 400 ml)
as well as feces (50-200 ml).
Water is distributed in organism in such a way:
Water of the blood (intravascular) composes about 5%. It is a circulating blood
volume. 93% of it is pure water. The rest is binding with blood cellular elements.
This volume must not be changed significantly since it determines a load on the
heart. Volumoreceptors of the large vessel wall and atrium of the heart inspect this
volume.
Intracellular water composes 35-45%. This volume is regulated most constantly and
must not be changed. The intracellular fluid is presented in three conditions:
• Water of the cytoplasm bounded with hydrophilic structures,
• Water attracted on the surface of the colloid structures,
• Water in the cytoplasm lacunas, which is the most mobile, relatively free
water of the cells.
In different pathologic conditions the intracellular fluid volume changes at the
expense of the mobile water volume.
Extracellular (interstitial) water composes about 15%. Only in this space a water
quantity may be changed significantly.
The interstitial fluid is close to the blood plasma (except protein contents) and
washes the cells by ion and molecular substrates. This fluid is in a constant
exchange with blood plasma so that approximately 20 liters of fluid with the
dissolved substances come into the tissues from the vessels daily and the same
amount returns into the systemic blood flow. Three liters of it return through the
lymphatic vessels.
Extracellular (transcellular) water (1-3%) forms the digestive juice,
cerebrospinal fluid, eye chamber humor, the kidney tubules fluid.
Intravascular and interstitial fluids are the most mobile, and just they are the
first to change their volume.
The total body water amount decreases with aging. In old people the
extracellular fluid amount is increased while the content of water in the cells
is reduced.
Water Balance Regulation Mechanisms
The water balance is regulated by many mechanisms. Some of them act locally in
the tissues; some are systemic for the whole organism.
1
Local Mechanisms
Local (tissue) mechanisms regulate the water balance between the blood and the
tissues through the capillary wall.
E. Starling and other scientists (Vidal, Fisher) studied factors, which determine the
liquid passing from blood stream into the intercellular space (filtration) and its recovery
into the vessels. This balance is regulated by physicochemical mechanisms:
• Hydrodynemic pressure difference between the blood and the extracellular liquid.
The blood moves in the capillaries at a definite speed and under a definite
pressure, which results in forming the hydrodynemic force, which makes the
water go out from the capillaries into the interstitial space. The higher the blood
pressure and the less the tissue fluid pressure, the more effect of hydrodynemic
forces will be. The hydrodynemic blood pressure in the arterial section of the
capillaries is 35-40 mm Hg and in the venous one 10-15 mm Hg (Starling).
• Onkotic pressure (of proteins) difference between the blood and interstitial liquid.
An increase of the vascular permeability for proteins occurs with a number of
pathologic processes and essentially influences this parameter (Starling).
• Osmotic pressure difference between the blood and interstitial liquid (Vidal).
• Interstitial tissue pH. Hydrophilic nature of colloids depends on H+ concentration
and rises in the acid medium. Then colloids swell and detain more water (Fisher).
Resulting force is called filtration pressure.
_________________________________________________________________________
Fig. 25. Mechanism of edema development in the case of change of hydrosratic (A) and oncotic (B)
pressure (by Starling)
A – hydrostatic and B – oncotic pressure.
1 – arterial part of capillary flow (fluid leaves the vessel),
2 – zone of balance,
3 – venous part of capillary flow (fluid enters the blood from the tissue)
_________ normal level of pressures
------------------ a) increase of hydrostatic pressure, b) decrease of oncotic pressure in pathology
ЀЀЀ. 47. Ѐ 379 ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ
________________________________________________________________________
The ratio of these forces determines the passage of liquid into the tissue from an
arterial part of the capillaries and its return to the blood in venous part. Within the
standard this relationship is such, that the tissues are washed by liquid in a quantity 20
liters daily.
Systemic Mechanisms
Systemic mechanisms regulate the water balance between the organism and the
environment. One should understand, that entire organism water cannot be regulated by
physicochemical laws mentioned above. It is regulated by biological (neurohumoral)
mechanisms with the participation of such high level, as hypothalamus.
These mechanisms are the following:
• Participation of the volumoreceptors of vascular wall and the left atrium of the
heart, which control the circulating blood volume.
• Participation of osmoreceptors of vascular wall (ЀЀЀЀ ЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀ),
which control the blood osmotic pressure.
2
• Participation of aldosterone of the adrenal cortex, which regulates (increases) Na +
reabsorption from the primary urine into the blood (antinatriuretic? antisodium?
mechanism).
• Participation of hypothalamus, which reacts both on decreased blood volume
and increased blood osmolarity in response to the signals from volumo- and
osmoreceptors. It release vasopressin (antidiuretic hormone ADH) by supraoptical
and paraventricular hypothalamic nuclei. The point of vasopressin action is the
epithelium of the renal tubules. Vasopressin increases a water reabsorption from
the primary urine and thus regulates diuresis (primary urine quantity is 180 l daily
and final urine is 1-2 l).
• Participation of kidney with its receptors and renin. Stimulation of the
adducting renal arteriole volumoreceptors and osmoreceptors of the macula densa
of the juxtaglomerular complex intensifies a synthesis and release of renin.
Angiotensin II, which is formed under its influence, increases aldosterone
secretion and stimulates the center of thirst located in the hypothalamic lateral
part.
• Retention of water and Na+ in the organism is opposed by two mechanisms of
natriuresis? sodiumuresis? -
Reno-medullar prostaglandins,
Na-uretic factor of cardial atria (ANF, atriopeptide of 28 aminoacids).
Antidiuretic and antinatriuretic? antisodiumuretic? mechanisms oppose diuretic
and natriuretic? sodiumuretic? ones. The main regulative substances are
renomedullar prostaglandins and atrial (cardiac) natriuretic? sodiumuretic? factor.
These substances increase diuresis and natriuresis? sodiumuresis?, relax the vessel
smooth muscles and decrease the arterial blood pressure. The amount of ANF in
the atrium and its secretion into the blood gets elevated after excessive water or
common salt intake, blood pressure raising as well as stimulation of β-
adrenoreceptors or receptors to vasopressin.
All these mechanisms are in a constant functioning and provide water-electrolyte
homeostasis restoration in the situation of blood loss and dehydration, water
retention in the organism as well as osmotic concentration changes.
CLASSIFICATION OF WATER DISBALANCE
Water disbalance is divided into two variants – positive and negative.

Positive water balance (hyperhydration) is a water retention in the organism.
Negative water balance (hypohydration) is a water loss by organism.
Depending on the osmotic concentration, hypo- and hyperhydration are subdivided
into three types: isoosmolar, hypoosmolar and hyperosmolar. (The normal osmotic
concentration of the blood and intercellular fluid is about 0.3 osmol/1 = 300 mosmol/l).
In clinical practice it is manifested in form of two syndromes - hyperhydration
(edema) and dehydration.
HYPERHYDRATION
Hyperhydration is a positive water balance.

Hypoosmolar hyperhydration develops in acute renal failure. The
vasopressin large dose injection into the blood results in the same. It is
characterized by increased amount of water in the organism and decreased
osmotic pressure in the extracellular space. The water excudes into the cells.
3
Sodium-potassium balance gets changed on the membrane. Sodium passes into the
cells and hence its amount in the blood plasma decreases. K+ passes out of the cells
into the extracellular sector. The patient suffers headache, nausea, vomiting,
arrhythmia, convulsions, and coma.
Hyperosmolar hyperhydration develops in drinking salt (sea) water in extreme
situations. As a result, the osmotic pressure in the extracellular medium increases,
and the water passes from the cells into the intercellular space. Dehydration of the
cells develops.
EDEMA
Edema is a typical pathologic process, which is characterized by positive water

balance and accumulation of water in interstitial space.
Principal pathogenic factors of edema are the next:
• Increased hydrodynemic pressure in the venous part of the vascular flow
(local venous hyperemia, inflammation as well as cardiac insufficiency).
• Decrease of colloid-osmotic blood pressure (in decrease of the plasma
protein content - hypoproteinemia – especially of the ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ
albumins in fasting, nephritic syndrome, hepatic insufficiency, etc.).
• Increased permeability of the capillary vessels, which occurs
under the influence of BAS (histamine, serotonine, kinines,
prostaglandins, etc.);
in capillary wall distrophy (fasting, disorder of neurothrophic
supply etc.).
• Increase of colloid-osmotic pressure in the tissue due to accumulation of
osmotic and oncotic active substances: electrolytes, proteins, metabolic products
(in inflammation, allergy).
• Disorder of lymph outflow (mechanic or dynamic lymphatic insufficiency).
• Disorder of the nervous and humoral regulation of water-electrolyte balance
("wrong" switching of the antidiuretic and antinatriuretic? antisodium? systems, as
well as impaired sensitivity of volumo-and osmoreceptors, secondary aldosteronism,
hypothyroidism).
Types
Edema is divided into local and systemic.

In accordance with pathogenesis (the main pathogenetic factor) edema is divided
into hydrodynemic, oncotic, osmotic, membranogenic, lymphogenic.
Clinical practice divides edema according to localization and causes into
inflammatory, allergic, toxical, venous, neurogenic, lymphogenic (which are local) and
cardiac, fasting, nephritic, hepatic, endocrine (which are systemic).
Etiology and pathogenesis of each type of edema are different.
Local Edema
Local edema is an accumulation of liquid in interstitial space of organ or its part. It

is a redistribution of water in the direction of blood-tissue according to local (tissue)
mechanisms of water balance regulation.
The water balance between the vessels and tissues takes place through the
capillary wall. The wall is a biological structure through which water,
electrolytes, some organic compounds (urea) are easily transported, but it is not
4
permeable for proteins. It results in non-equal concentration of proteins in
blood plasma (60-80 g/1) and tissue fluid (10-30 g/l).
Two stages are distinguished in local edema development. At first, excessive
fluid is accumulated in interstitional space as fixed (bounded) with ЀЀЀЀЀЀЀЀЀЀЀЀЀ
structures (collagen fibers, connective tissue) increasing the mass of non-mobile
water. Then, when this water mass would be increased in 30%, the water behave
as mobile (free) and is manifested as a ЀЀЀЀ ЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ.
___________________________________________________________________
Volume of extracellular fluid, l
Pressure of extracellular fluid, kPa
Fig. 26. Dependence of volume of free (1) and fixed (2) extracellular fluid from its pressure
ЀЀЀ. 48. Ѐ 383
Types of Local Edema
Types of local edema are inflammatory, allergic, venous, toxic (membranogenic),

neurogenic and lymphogenic.
Inflammatory and allergic types of edema are interpreted in the corresponding
chapters. Explanation is already given (chapter 6 “Allergy” and chapter 8
«Inflammation»), that the leading component in pathogenesis of inflammatory and
allergic edema is an increased vascular permeability under BAS effect (histamine,
bradykinin and others). As a result, the plasma proteins pass into tissue. Blood oncotic
pressure gets reduced. In the center of inflammation (allergic one also) colloid-osmotic
pressure rises. Arterial and venous hyperemia, which are developed in the locus of
inflammation, lead to an increase in the blood hydrodynemic pressure. Local acidosis
contributes to colloid hydrophia and an excessive binding of water.
Toxic (membranogenic) edema has analogous pathogenesis (edema after the bite of
bee; phosgene causes selective increase of the pulmonary capillaries permeability and
pulmonary edema).
Venous edema develops while the venous congestion, which is accompanied by an
increase in hydrodynemic pressure and the filtration of the water.
Neurogenic edema develops as a result of the nervous disregulation of vessel
trophicity (angioneurosis) and increase of the vessel permeability. Edema of
extremities in hemiparesis can be an example as well as edema of face in neuralgia of
trigeminal nerve. Quincke's edema has the same pathogenesis.
Lymphogenic edema develops in the region of lymphostasis and disorder of lymph
drainage, which compensates the accumulation of liquid in intercellular space in
physiological condition.
Non-inflammatory fluid accumulated in different cavities and tissues is called
transudate.
Pathologic accumulation of fluid in the serous cavities of the organism is called
hydrops. The variants are ascites (in abdominal cavity), hydrothorax (in the
pleural cavity), hydropericardium (in the pericardium).
SYSTEMIC EDEMA
5
Systemic edema is manifested in such forms – cardiac, nephritic, hepatic, endocrine
and cachexic (fasting).
Cardiac Edema
Heart (cardiac) insufficiency is described in the chapter 24 “Pathophysiology of the

heart”. Edema is one of its symptoms. It is a systemic retention of water in the
organism and its redistribution into the tissues.
Hydrodynemic factor is the main in pathogenesis (increase of hydrodynemic
pressure in venous part of the capillaries). Due to decrease of contractile function of the
heart, systemic increase of venous pressure develops (venous congestion). Resorption
of liquid from interstitial space into the blood gets decreased.
Concomitant mechanism in pathogenesis is a hypoalbuminemia as a result of a
decrease of protein synthesis in the liver (due to blood congestion). Memranogenic
factor also may play a role (due to circulatory hypoxia and acidosis).
Actually, all these factors are present in heart insufficiency. However, in such a
way it is possible to explain only the redistribution of water in the direction blood-
tissue. The reason of systemic positive water balance (total retention of water) is
connected with another mechanisms - participation of vascular receptors, hypothalamus,
adrenal cortex, hormones and renal tubules.
The following sequence of events appears in the pathogenesis of cardiac edema
Decrease of contractile capacity of myocardium → decrease of a systolic
blood volume → reaction of the volumoreceptors of the ЀЀЀЀ aorta →
transmission of impulses to hypothalamus → liberation of vasopressin
(antidiuretic hormone ADH, a point of action is epithelium of the renal
tubules) → stimulation of water reabsorption from the primary urine in the
tubules into the blood → limitation of diuresis → retention of water in the
blood → hypervolemia → redistribution of water into the intercellular space
(according to the Starling's law).
One more mechanism of retention of water in organism joins the named mechanism.
It is the following.
Disorder of renal blood supply as a result of cardiac insufficiency →
production of renin and angiotensis formation → secretion of aldosterone →
stimulation of Na+ reabsorption from the primary urine into the blood →
increase of blood osmotic pressure → reaction of vascular osmoreceptors →
transmission of impulses to hypothalamus → liberation of vasopressin →
stimulation of water reabsorption from the primary urine into the blood →
limitation of diuresis → total retention of water in the blood → hypervolemia
→ redistribution of water into the intercellular space.
It is a pathogenesis of cardiac edema.
The named sequence of events is a physiological one by its nature (it is a
compensation in the case of the circulating blood volume lowering, for example in the
blood loss). In the case of heart insufficiency this chain of events can be named as “the
error of adaptation” and becomes the main pathogenetic factor of systemic edema
development.
Thus, all pathogenic factors participate in cardiac edema and just their combination
and ЀЀЀЀЀoЀЀЀЀЀЀЀЀЀЀЀ effect provide its pathogenesis.
Understanding of this pathogenesis allows a physician to treat effectively a patient
with cardiac edema. A therapy is directed toward the treatment of heart disease.
However, this therapy requires a time while the removal of excessive water is
necessary, since hypervolemia overloads the heart. Therapy is guided not by the fact of
venous congestion, but the mechanisms, which are responsible for water retention. It
6
becomes understandable, that neither hypothalamus nor vascular receptors are
propitiate targets for the drugs. An effect of contemporary diuretics is directed a/
against angiotensine or aldosterone formation and (b) inhibition of their activity.
Salt-free diet must be recommended to the patient.
Nephritic Edema
The renal insufficiency is described in the chapter 29 “Pathophysiology of

kidneys“. Edema is one of its symptoms.
In inflammation of kidney (acute and chronic glomerulonephritis, nephrotic
syndrome) a loss of protein with urine occurs. Hypoproteinemia underlies the
redistribution of water into the tissues according to the Starling’s low, but positive water
balance (total retention of water) has another explanation. Renin, which is produced in
inflammated kidney has two effects: a/ increase of the arterial blood pressure (by
angiotensine II formation) and b/ stimulation of aldosterone secretion.
The further order of events is similar to that mentioned above.
Increased Na+ reabsorption from the primary urine into the blood → increase in
the osmotic blood pressure → reaction of vessels osmoreceptors involving
posterior part of hypothalamus → revealing of vasopressin (antidiuretic
hormone) → activation of water reabsorption from the primary urine into the
blood → diminution of diuresis → elevation of water quantity in the blood
(hypervolemia) → passage of liquid into the intercellular space.
It is a pathogenesis of nephritic edema.
There is an additional and even more important component of the nephritic edema
pathogenesis, namely, decreased synthesis of renal prostaglandins, which under
physiological conditions contribute to Na+ removal.
Hepatic Edema
Hepatic insufficiency is described in the chapter 27 “Pathophysiology of liver”.

Edema is one of its symptoms.
Limitation of the protein synthesis and hypoproteinemia underlie the pathogenesis.
According to the Starling’s law edema develops.
In the case of the portal blood circulation disturbance (increase of the pressure in v.
portae) the conditions for edema development are created according to the Starling’s
low. Liquid retention is located in the peritoneal cavity (ascites).
There is an additional component of hepatic edema pathogenesis. It is known that
hormones are destroyed in the liver and hepatic insufficiency is accompanied with
suppression of the hormone destruction. It relates to aldosterone, which is accumulated
as well. The further events are similar to those mentioned above twice.
Endocrine Edema
The endocrine diseases are often accompanied by the development of edema.

Myxedema is a so-called mucous edema of the skin and subcutaneous cellular
tissue which develops in hypofunction of the thyroid gland. Colloids are accumulated
(collagen, glycosaminoglycans), which are hydrophilic and bind enormous amount of
the water. Pressure by finger does not form a pit in the region of edema.
Diseases, which are accompanied by an increased aldosterone formation (primary
or secondary hyperaldosteronism), are accompanied by edema.
Cachexic Edema
7
Cachexic edema occurs in starvation and exhausting diseases.
It develops during the incomplete quantitative and qualitative (protein) starvation.
The pathogenetic basis of this form of edema is hypoproteinemia and decrease of
oncotic blood pressure. According to Starling's laws the water leaves vascular channel
and is accumulated in the interstitial space. During the first and the second periods of
complete starvation with water, edema does not develop. On the contrary, the removal
of excessive water from the organism and the reduction of edemas are observed. During
the terminal period edema develops.
HYPOHYDRATION (DEHYDRATION)
Hypohydration (dehydration, hypohydria, exicosis) is a negative water balance.
Causes
Hypohydration develops in the cases, when output of water exceeds its input into the
organism. It may develop in water input limitation (water starvation, dysphagia,
atresia of the esophagus, comatose condition, etc.). An increased water loss (diarrhea,
vomiting, blood loss, loss of fluid with exudate in burn, etc.) has the same effect. The
combination of these conditions may take place.
In dehydration, first of all, the extracellular fluid and sodium ions are lost.
Ultimately, the cells may loose potassium and the intracellular fluid.
Consequences
Dehydration results in severe consequences connected with the decrease of the

circulating blood volume (hypovolemia) and increase of its viscosity that may
cause severe disorder of blood microcirculation. Collapse may eventuate.
Disorder of blood circulation results in the development of tissue hypoxia. The
central nervous system suffers first of all. It is manifested by loss of consciousness,
hallucinations and coma. The functions of the nervous centers, respiratory rhythm
become disturbed. Body temperature rises.
The marked decrease of the arterial pressure may be accompanied by
impairment of filtration in the nephrons, oliguria, hyperasotemia and non-
respiratory acidosis.
Compensatory reactions arise as a response. So, hypovolemia and reduction
in renal blood flow promote hyperproduction of vasopressin and aldosterone.
Water and sodium reabsorption in nephron tubules intensifies under the influence
of these hormones.
Isoosmolar Hypohydration
Isoosmolar hypohydration occurs in proportional loss of fluids and electrolytes, as

a rule, in the extracellular sector. Usually this condition arises immediately after acute
blood loss. But it is changed for a short time and is substituted by hypoosmolar
normovolemia due to compensatory mechanisms (immediate retention of water).
Hypoosmolar Hypohydration
8
Hypoosmolar hypohydration develops due to the loss of fluid enriched by
electrolytes. This situation arises in kidney pathology (increased filtration and
decreased reabsorption of electrolytes), digestive tract (ЀЀЀЀЀЀЀЀЀЀЀ vomiting,
diarrhea), adrenal glands insufficiency (decreased production of aldosterone). Some of
these conditions are accompanied by polyuria and hypoosmolaric hypohydration.
Polyuria can lead to the extracellular hypoosmolar hypohydration. In case of a
severe form of hypoosmolar hypohydration the water moves into the intracellular
sector with development of the intracellular edema.
Hyperosmolar Hypohydration
Hyperosmolar hypohydration develops due to the loss of fluid, which is poor in

electrolytes. It may arise due to polyuria (deficit of ADH), diarrhea, profuse sweating,
hyperventilation, vomiting.
Special attention should be drawn to diabetes mellitus as one of the causes of
such pathology.
Under the conditions of hypoinsulinism osmotic polyuria develops but the level of
blood glucose remains high. The increase of osmotic pressure in the extracellular fluid
involves the movement of water from the cells into the extracellular sector. If the
causative factor keeps on acting, the fluid is lost by the organism. It results in
development of total hypohydration of the organism. The elevation of osmotic
pressure of the extracellular fluid and dehydration of the cells causes thirst, protein
lysis, fever, loss of consciousness, hyperosmolar diabetic coma. These disorders are
based on hypoxia connected with hypovolemia and arterial hypotension.
Disorder of microcirulation, hemoconcentration, increasing of blood viscosity and
stasis aventuate the tissue form of hypoxia. Hypoxia combined with tissue
dehydration leads to dismetabolism: protein lysis and development of hypernitroemia
(at the expense of ammonium because of kidney dysfunction), hyperproduction of
urea (kidney dysfunction). Acidosis (due to the sodium and bicarbonates loss) or
alkalosis (due to the potassium and chlorine loss) occur.
ELERCTOLYTE DISBALANCE
Electrolyte disbalance is associated with water disbalance. Sodium Na+ and

potassium K+ have a special value. Just they are the most potent osmotic ions. They
play a leading role in water balance. Special receptors (osmoreceptors) exist for
checking their concentration. A special hormone serves the same role; it is aldosterone
(mineralocorticoid).
Peculiarity of sodium Na+ and potassium K+ ions function consists in performing two
important roles. Together with participation in osmotic pressure regulation they
participate in providing the membrane potential and excitability.
Retention of Na+ causes predisposition to edema and increase of arterial blood
pressure. Limitation of it in a food is recommended to patients with such predisposition.
Loss of K+ leads to disorder of excitability (cardiac arrhythmia) and elevation of
arterial blood pressure. Additional amount of potassium with a food is recommended to
patient. Hypokaliemia resulting in muscle weakness occurs in prolong use of
mineralocorticoids.
Intracellular retention of Ca+ causes the so-called calciac damage of the cells.
Disorder of contractility, oxidative phosphorilation are the results. The most modern
medicines for treatment of arterial hypertension and cardiac arrhythmia are the blockers
of calcium canals.
9
Pathophysiology of electrolyte metabolism is presented in the table 7.
Table 7. Electrolyte Disbalance
Electrolyte Excess Deficit
Sodium Hypernatremia > 147 Hyponatrenia < 135 mEq/L.

mEq/L. Cellular shrinking Cellular swelling may cause
may cause central nervous cerebral edema, polyuria,
system irritability, headache, stupor, coma,
tachycardia, dry and flushed peripheral edema, absence of
skin, arterial hypertension, thirst, decreased body
thirst, elevated temperature, temperature, tachicardia,
weight loss, oliguria, anuria arterial hypotension, nausea,
vomiting
Potassium Hyperkaliemia > 5.5 Hypokaliemia < 3.5 mEq/L.
mEq/L. Depressed Cardiac irritability,
conductivity in heart, dysrhythmia, vomiting, paralytic
muscle cramping, ileus, thirst, metabolic alkalosis,
parasthesia, nausea, inability to concentrate the urine
diarrhea, metabolic
acidosis
Calcium Hypercalcemia > 12mg/dl. Hypocalcemia < 8.5 mg/dl
Decreased neuromuscular Increased neuromuscular
excitability, muscle excitability, skeletal muscle
weakness, central nervous cramps, tetany, laryngospasm,
system depression, stupor, asphyxya, death.
coma, increased risk of bone
fracture, vomiting, kidney
concrements.
Phosphate Hyperphosphatemia Hypophosphatemia < 2 mg/dl

> 4.5 mg/dl. ( See Skeletal muscle depression,
hypokalemia). muscle weakness, arterial
hypotension, bradycardia,
respiratory depression.
Magnesium Hypermagnesemia > 2.5 Hypomagnesemia < 1.5mEq/L
mEq/L. Anorexia, muscle Hypocalcemia and
weakness, tremor, seizers, hypokaliemia, neuromuscular
coma, anemia, bleeding, irritability, tetany, convulsions,
eukocytes alteration tachycardia, arterial
hypertension
10
11
PART 2
SPECIAL PATHOPHYSIOLOGY
PATHOLOGY OF ORGAN SYSTEMS
PATHOPHYSIOLOGY OF BLOOD SYSTEM
CHAPTER 19
DISORDER OF BLOOD VOLUME
HEMORRHAGE ЀЀЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀЀ: ЀЀЀ ЀЀЀЀЀЀЀ ЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀ - ЀЀЀЀЀЀЀЀЀЀЀ, ЀЀЀЀЀЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀЀЀЀЀЀ – ЀЀЀ
hemorrage, blood loss, bleeding? Ѐ ЀЀЀЀ ЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀ , Ѐ ЀЀЀЀЀ 23 ЀЀЀЀЀЀЀЀЀ ЀЀ ЀЀ ЀЀЀЀЀЀЀЀ.
The blood performs various functions. They are

• Transport - transfer of substrates, hormones, electrolytes, cells, fluids, enzymes,
BAS, etc.
• Respiratory – transportation of oxygen and CO2
• Trophical - transfer of nutrients to the tissues and removal of the metabolic
products
• Protective - phagocytosis, bactericidal properties, immune reactions,
transportation of antibodies and immune lymphocytes
• Hemostatic – maintenance of a liquid state of blood in norm and its coagulation in
response to hemorrhage
GENERAL CHARACTERISTICS OF BLOOD SYSTEM PATHOLOGY
rormal state of the blood may be disordered primary (due to pathological

influence on blood or bone marrow) and secondarily (due to pathological changes in
different organs and systems, which regulate blood functions and sustain its
morphological, protein, electrolyte and gas homeostasis e.i. lungs, liver, kidneys,
nervous and endocrine systems).
All typical pathological processes can develop in the system of the blood –
inflammation and neoplasia of bone marrow, allergy, hypoxia, dysthrophy, typical
systemic disorders of metabolism.
Pathologic changes can be developed in any part of the system of the blood - in the
hemopoietic organs (fig. 27 represents the scheme of normal hemopoiesis), in the
blood, which circulates or deposited in the vessels, and also in the organs and the
tissues, in which the blood is destroyed. These parts are tightly interconnected. As a
result, pathologic process is not, as a rule, strictly isolated. Entire system of the blood
reacts to the pathologic process as a whole.
As to pathophysiological and clinical manifestations, they are different depending
on a part of blood system, which primary gets disordered. They may be localized in
the systems of blood production, circulation and distraction as well as in the whole
organism (systemic).
Disorders in the Blood
These disorders are manifested by changes of the indices in the blood. They are
• Total blood volume
• Quantity, structure and function of blood cells (erythrocytes, leukocytes and
blood platelets in form of anemia, leukocytosis, leukopenia, leukemia),
• Indices of hemostasis
• 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 syndeome. It frequently
accompanies different diseases (radiation disease, pathology of stomach, lungs,
kidneys, etc.).
Systemic Disorders
Systemic disorders in hematological pathology are

• Disorder of workability of men
• Hypoxia of hemic type
• Pathology of immunological reactivity
• Pathology of hemostasis – hemorrhage or thrombophilic syndromes
• Tissue dystrophy
• Cachexia (in leukemia)
DISORDER OF THE TOTAL BL OOD VOL UM E
Disorder of the blood volume is manifested as hypovolemia and hypeevolemia, that

is a decrease or increase of the blood volume in comparison with the norm
(noemovolemia) constituting 6-8% of the body mass or 65-80 ml of blood per 1 kg of
the body mass. In turn, in accordance of hematocrit index, normo-, hypo- and
hypervolemia are subdivided into simple (normocythemic), polycythemic and
oligocythemic ones. It depends on whether there is normal correlation of the blood
cells and plasma (36-52% of the blood volume are formed by blood cells and 48-
64% by plasma) or there is a prevalence of cells or plasma; variant are represented on
fig. 28).
Simple hypovolemia (reduction of the blood volume without change of hematocrit
index) arises immediately after acute blood loss and persists until the fluid does not
come from the tissues into the blood.
Olygocythemic hypovolemia (decrease of the blood volume with prevalence of plasma)
is observed after acute blood loss till normal blood volume would not be restored
completely by tissue fluid.
Polycythemic hypovolemia (reduction of the blood volume due to decrease of the
plasma volume with relative prevalence of erythrocytes) develops in dehydration of
organism (diarrhea, vomiting, increased perspiration and hyperventilation).
Simple hypeevolemia (increase of the blood volume in normal correlation between
blood cells and plasma) occurs at once after transfusion of large amount of the blood
(in experiment).
Oligocythemic hypeevolemia (increase of the blood volume at the expense of
plasma) develops at retention of water in organism due to renal disorders or in
injection of blood substituting fluids.
Polycythemic hypeevolemia is an increase of the blood volume at the expense of the
increased amount of blood cells. It is observed in hypobaria (reduction of the
atmospheric pressure) as well as in different diseases connected with oxygen
deficiency (heart failure or emphysema) with compensatory activation of
erythropoiesis. Polycythemic hypervolemia appears in tumorous hyperplasia of the
bone marrow without of any defensive meaning (polycythemia rubra and vera,
erythremia, luekemia).
Oligocythemic noemovolemia occurs in anemia of different types.
Polycythemic noemovolemia is observed in transfusion of any amount of red cells.
a b c a b c a b c
rormovolemia Hypovolemia Hypervolemia
Fig.28. Changes of the blood volume
a - simple
b - oligocytemic
c – policytemic
Blood cells Plasma
HEMORRHAGE ЀЀЀЀЀЀЀЀЀЀЀ
Hemorrhage is a pathological process, which is characterized by complex of

pathologic disorders and compensatory reactions as a result of blood loss from the
vessels.
Damage and rupture of a blood vessel is an obvious cause of a hemorrhage.
The hemoeehage syndeome constitutes a group of clinical disorders having in
common an increased bleeding tendency.
ETIOLOGY
Etiological factors are those, which disorder the vessel ЀЀЀЀЀЀЀЀЀЀЀ.

The causes of hemorrhage are numerous. They may be exogenous and
endogenous.
More often it is rupture of vessel due to mechanical trauma.
Endogenous causes include trauma due to diseases that attack the vessel wall (e.i.
inflammation, atherosclerosis, necrosis, tumor, ulcer, erosive cancer, ЀЀЀЀЀЀ ЀЀЀЀЀ
ЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀ etc.). Platelet deficiency and a lack of any one of the
clotting factors may be a cause of hemorrhage syndrome. Endocrine disturbance may
cause hemorrhage as it is in metrorrhagia (ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀ).
Important conditions, which determined a course of hemorrhage, are
• Size of vessel, which is damaged
• Volume of the blood loss
• Rate of blood escape (a speed of bleeding)
• Ability of organism to stop bleeding by thrombosis (coagulative system, quantity of
platelets etc.),
• Localization of a hemorrhage
• Whether hemorrhage is external (hemoglobin gets lost) or internal (hemoglobin is
reutilized).
The localization of hemorrhage has a critical significance. Even relatively small
hemorrhage in the brain or pericardial sac may cause a death. If the blood escapes
into serous cavity, it is called hemothorax, hemopericardium or hemoperitoneum.
Small hemorrhage into the skin is known as petechia, purpura, or echymose.
Microscopic hemorrhage may be produced by marked congestion of the blood – a
phenomenon is called as red cell diapedesis (arterial hypertension is worthy of a
special mention in this context).
In this chapter hemorrhage is mentioned as a blood loss (bleeding) in connection
with decrease of blood volume (hypovolemia).
PATHOGENESIS
Pathogenesis of blood loss consists in two groups of events – pathological changes

and compensatory reactions.
Pathological Changes
Pathological changes in bleeding concern not only the blood system but the whole
organism – cardiovascular and respiratory systems, metabolism, pigment balance etc.
Pathological changes are
• Decrease of the circulating blood volume (hypovolemia)
• Decrease of erythrocytes and hemoglobin content
• Disorder of hemodynamics - decrease of arterial blood pressure, decrease of the
venous blood entering to the heart, decrease of a systolic heart volume
• Disorder of microcirculation in the tissues
• Deficiency of tissue oxidation and respiratory function of the blood due to the
development of circulatory, hemic and tissue hypoxia
• Disorder of tissue metabolism
• Acid-base disbalance (non-respiratory metabolic acidosis)
• Disorder of the functions of vitally important organs (nervous system and heart as a
result of hypoxia)
Secondarily blood loss may cause or aggravate arrhythmia, insufficiency of
coronary blood supply and external respiration, as well as disorder of hemostasis and
renal filtration.
External bleeding causes a loss of vital iron. If bleeding occurs into a body tissue
or cavity, the hemoglobin and iron are reutilized. In course of this resorption of
hemoglobin, increased amount of bilirubin is formed and may cause transient
jaundice.
Compensatory Reactions
Compensatory reactions are divided into urgent (immediate) and non-urgent

(delayed).
Different physiological systems participate in compensation of blood loss.
rervous system reacts with the aid of the reflexes from volumoreceptors of aorta Ѐ
ЀЀЀЀЀЀ ЀЀЀЀЀЀЀ, excitation of the sympathetic part of autonomic (vegetative) nervous
system. Endocrine system participates with the aid of hormones – vasopressin,
catecholamines, gluco- and mineralocorticoids. Kidneys react by the secretion of
renin, which after formation of angiotensin partially or completely normalizes the
volume of the blood, the tonus of vessels and other indices of hemodynamics.
Immediate Compensatoey Reactions
Immediate compensatory reactions are directed to renovation of the blood volume

and arterial blood pressure restoring blood supply of the vitally important organs
(fig. 29). They are
• Spasm of peripheral blood vessels,
• Blood coagulation (thrombosis) which stops hemorrhage,
• ЀЀЀЀЀЀЀЀЀЀЀЀ Reflectory acceleration and intensification of the cardiac contractions,
• Restoration of circulating blood volume due to the reserves of the blood,
• Redistribution of the blood towards more blood supply of the most important organs
(lungs, heart, brain, kidnys) at the expense of decreased blood circulation in the skin,
spleen, muscles and intestines,
• ЀЀЀЀЀЀЀЀЀЀЀЀ Reflectory increase of ventilation due to acceleration and deepening
of respiration contributing to compensation of oxygen deficiency in the organism,
• Restoration of the erythrocytes quantity due to the reserves from the depot (liver,
spleen and bone marrow)
• Increase of hemoglobin capacity to give back oxygen to the tissues (activation of
oxyhemoglobin dissociation),
• Decrease of diuresis,
• Thirst,
• Redistribution of the intratissue fluid into the vessels.
Fig. 29. Mechanisms of compensation of a central blood circulation under an acute blood loss
Delayed Compensatoey Reactions
Delayed mechanisms of compensation develop later as

• Increased hemopoiesis,
• Restoration of protein content of the blood (normalized in 8-10 days after blood
loss due to the increase of protein synthesis in the liver).
On the 5th day the young forms of erythrocytes appear in the blood. It is connected
with the increase of hemopoietic activity of the bone marrow under the influence of
increased production of erythropoietins in the kidneys and gastric internal Castle's
factor.
Hemorrhage (blood loss) is divided into acute and chronic.
Acute Hemorrhage (Acute Blood Loss)
Acute hemorrhage occurs after injury of a large vessel. In this case cellular
elements and liquid part of the blood are lost proportionally (simple hypovolemia).
Acute loss of the blood up to 10% of the blood volume and slow loss of even
greater amounts may have no grave manifestations. Sudden loss of 25-40% and more
of the blood ЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ. Loss of 60% of blood is lethal.
A state of hemostasis system plays an important role; thus, in its disorder a damage
of even not so large vessel may lead to acute blood loss.
In clinical manifestations such changes play the critical role -
• Acute disorder of the systemic blood circulation,
• Critical decrease of arterial blood pressure,
• Decrease of heart filling and systolic heart volume, cardiac insufficiency ( decrease
of coronary blood supply),
• Development of acute hypoxia of circulatory type,
• Acute kidney insufficiency.
• Acute posthemorrhagic anemia development,
• Hemorrhagic shock may occur if a compensation fails and is characterized by
extreme disorder of all vital functions, loss of consciousness and death if is not
treated.
Immediate compensatory reaction mentioned above may save the life. All reactions
are reflectory. Hormones (vasopressin, adrenalin) and renin (angiotensin) play a role.
If a patient survives, the cellular, protein and electrolite content of the blood would
be restored, but up to complete restoration, an acute anemia lasts with olygocythemic
normovolemia.
Hemorrhage (Hypovolemic) Shock
Hemorrhage shock develops in a case of a sudden and massive blood loss, when
potential ability of compensation would be insufficient for normalization of
homeostasis. Overstraining of all physiological systems develops, and their
activation becomes extreme. It is potentially fatal situation if would not be
properly treated.
In young men a blood loss 20-40% (1-2 l) leads to development of moderate
shock, more then 40% (more then 2 l) – a grave shock. rot only an amount but
also a rate, intensity and term of blood loss transform a hemorrhage into
hemorrhage shock. Initial state of organism and concomitant factors (starvation,
overcooling etc.) play a negative role.
Primary disorders in pathogenesis hemorrhage shock are a decrease of effective
blood volume, arterial pressure, heart filling and systolic volume. It causes an acute
circulating hypoxia.
In hemorrhage shock (as in any other form of shock) the compensatory reactions
fail to be synchronic, balanced and properly regulated. Then just they become
additional mechanisms of damage and aggravate a situation. rumerous circulus
viciosus develop, the process gets self-generated course and becomes irreversible. A
range of defensive reactions gets narrowed. Specificity of adaptive reactions to
causative factor gets lost.
Suppressed nervous system becomes unsensitive to afferent influences from
vasoreceptors. Limbic system avoids regulation and leads to extreme activation of
sympatho-adrenal and hypothalamo-pituitary-adrenal systems (hormonal explosion).
Concentration of majority of hormones in the blood rises up to very high level.
Endocrine response becomes too intensive and exhausting for organs.
Hemodynamal disorders, primary changed by blood loss, get aggravated. The
vessels loose reaction on the regulatory influences, and vasoconstriction becomes too
extensive, generalized and irregular. Disorder of microcirculation and DIC-syndrome
must be added.
Concentration of BAS, which are too aggressive, are increased hundred times.
They provide the cardio- and vasodepressive effect. Electrolytes are disbalanced,
especially Ca-ion.
All reasons mentioned above eventuate in severe acidosis and tissue hypoxia. ATP
production gets suppressed.
In some hours, fatal cardiac, respiratory and renal insufficiency develops
aggravating a situation.
This pathogenesis is an example of a combination of ЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ Ѐ
ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ (fig. 30). An urgent medical help is necessary.
Fig. 30. Pathogenesis of hemorrhagic shock
2
1
14
3
13
12
11
6
10
9 7
8
1 - ↓ of effective volume of circulating blood
2 – ↓ cardiac output
3 – acute circulative hypoxia
4 – disorder of central regulation of hemodynamic and respiration
5 - ЀЀЀЀЀЀ of hormones, activation of sympatho-adrenal and hypothalamo-pituitary-adrenal cortex
systems
6 - ↑ of peripheral vascular resistance
7 – production of BAS, «ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀ»
8 - metabolic ЀЀЀЀЀЀЀЀЀЀ, then ЀЀЀЀЀЀЀЀЀ
9 - tissue hypoxia
10 – acidosis
11 – electrolyte balance disorder
12 – disorder of microcirculation
13 – DIC-syndrome
14 – disfunction of organs
ЀЀЀ ЀЀЀЀЀЀЀЀЀ – ЀЀЀЀЀЀЀЀ ЀЀЀЀ – ЀЀ ЀЀЀЀ, Ѐ ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ 15 ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀ

ЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀ. ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀ ЀЀЀЀЀЀ. ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀ -
ЀЀ 2 ЀЀ 1
Ѐ 3 ЀЀ 2
Ѐ 4 ЀЀ 3, 2, 1
Ѐ 5 ЀЀ 4
Ѐ 6 ЀЀ 1, 2,
Ѐ 7 ЀЀ 6, 4, 2, 1
Ѐ 8 ЀЀ 2, 7 (ЀЀ ЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀ, ЀЀЀЀЀЀЀЀЀ ЀЀ 6 Ѐ ЀЀ ЀЀ 7, ЀЀ ЀЀЀЀЀЀЀЀЀ ЀЀ ЀЀЀЀ)
Ѐ 9 ЀЀ 2, 4, 7
Ѐ 10 ЀЀ 9, 7, 4, 2
Ѐ 11 ЀЀ 10, 9, 4, 2
Ѐ12 ЀЀ 1, 2, 3, 9, 10
Ѐ13 ЀЀ 12,
Ѐ 14 ЀЀ 2, 4, 9, 11
ЀЀЀ ЀЀЀЀЀЀЀЀЀ : ЀЀЀ ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ ЀЀ ЀЀЀЀЀЀЀЀЀЀ, ЀЀ ЀЀЀЀЀЀЀ, ЀЀЀЀ ЀЀ ЀЀЀЀЀЀЀ ЀЀЀЀЀЀ ЀЀ
1-2-3 ЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ Ѐ ЀЀ ЀЀЀЀ ЀЀ ЀЀЀЀ.
Chronic Hemorrhage (Chronic Blood Loss)
Causes of a chronic hemorrhage, as a rule, are of endogenous origin. They are -

the bleeding stomach or intestine ulcer, cancer of stomach or intestine, bronchial
hemorrhage with pulmonary tuberculosis, massive menses in women, uterine
hemorrhages. Chronic blood loss is accompanied by the development of the deficit of
iron. In massive gastrointestinal bleeding the red cell mass is rapidly digested and iron
is reutilized. Important pathogenic component in the development of clinical disorders
in the chronic hemorrhage appears anemia and hemic type of hypoxia.
In pathophysiological and clinical manifestations such events dominate –
• Insufficiency of tissue respiration due to the development of hemic and tissue
hypoxia,
• Disorder of tissue metabolism,
• Acid-base disbalance (non-respiratory acidosis),
• Iron-deficiency,
• Disorder of the bone marrow due to its chronic suffering from hypoxia,
• Development of chronic hyporegenerative anemia (olygocythemic normovolemia).
ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ - Steam hemopoietic cell
ЀЀЀЀЀЀЀ - ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀ – Cell-pecorsure of lymphopoiesis
ЀЀЀЀЀЀЀ – ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀ – Cell-pecorsure of myelopoiesis
ЀЀЀЀЀЀЀ – ЀЀЀЀЀЀЀЀЀЀЀ Ѐ-ЀЀЀЀЀЀЀЀЀЀ – Cell-precorsure of T-lymphocytes
ЀЀЀЀЀЀЀ – ЀЀЀЀЀЀЀЀЀЀЀ Ѐ-ЀЀЀЀЀЀЀЀЀЀ - Cell-precorsure of B-lymphocytes
ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ -
Ѐ-ЀЀЀЀЀЀЀЀЀЀ – T-lymphoblast
Ѐ-ЀЀЀЀЀЀЀЀЀЀ - B-lymphoblast
ЀЀЀЀЀЀЀЀЀЀЀ - Plasmoblast
ЀЀЀЀЀЀЀЀЀ - Monoblast
ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀ – Basophilic blast
ЀЀЀЀЀЀЀЀЀЀ - Myeloblast
ЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀ – Eosinophilic blast
ЀЀЀЀЀЀЀЀЀЀЀ - Erythroblast
ЀЀЀЀЀЀЀЀЀЀЀЀЀЀ - Megacarioblast
Ѐ-ЀЀЀЀЀЀЀЀЀЀЀ – T-prolymphocyte
Ѐ-ЀЀЀЀЀЀЀЀЀЀЀ - B-prolymphocyte
ЀЀЀЀЀЀЀЀЀЀЀЀ - Proplasmocyte
ЀЀЀЀЀЀЀЀЀЀ - Promonocyte
ЀЀЀЀЀЀЀЀЀЀЀЀ - Promyelocyte
ЀЀЀЀЀЀЀЀЀЀЀ - Pronormocyte
ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ - Promegacariocyte
ЀЀЀЀЀЀЀЀЀ - Myelocyte
ЀЀЀЀЀЀЀЀЀЀЀЀЀ - Metamyelocyte
ЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀ – Buton-like granulocytes
ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀ – rormoblast basophilic
ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ - rormoblast polichromatophilic
ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀ – rormoblast acidophilic
ЀЀЀЀЀЀЀЀЀЀЀЀЀЀ - polichromatophil
ЀЀЀЀЀЀЀЀЀЀЀ -Reticulocyte
ЀЀЀЀЀЀЀЀЀЀЀЀ - Megacariocyte
Ѐ-ЀЀЀЀЀЀЀЀ – T-lymphocyte
Ѐ-ЀЀЀЀЀЀЀЀ - B-lymphocyte
ЀЀЀЀЀЀЀЀЀ - Plasmocyte
ЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀ – Segmentonuclear granulocytes
ЀaЀЀЀЀЀЀЀЀЀ - basophilic
ЀЀЀЀЀЀЀЀЀЀЀЀЀ - neutrophilic
ЀЀЀЀЀЀЀЀЀЀЀЀЀ -eosinophilic
ЀЀЀЀЀЀЀЀЀ - Erythrocyte
ЀЀЀЀЀЀЀЀЀ - Thrombocyte
Fig. 27. Scheme of hemopoiesis (by ЀЀЀЀЀЀЀЀ 1981)

I – class of steam cells; II – class ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ; III – class
ЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ ( cells pecorsures of T-, B-lymphocytes, kЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ -
monocytic, granulocytic, erythrocytic, megacariocytic); IV – class ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ cells (blasts);
V – class of the cells which ЀЀЀЀЀЀЀЀЀ; VI – class of mature cells
(ЀЀЀ. I. ЀЀ ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ)
__________________________________________________________________________________
BLOOD TRANSFUSION
Treatment of the blood disorders and management of bleeding have traditionally

relied upon therapies involving the transfusion of donor blood and blood products.
Blood presents a riddle, but attempts of its use for treatment stay tempting because of
a number of events it magically effects.
Arguments in favor of hemotransfusion were understood long ago, but only with
research of individual characteristics of the blood (types of agglutininogens and
agglutinins), hemotransfusion starts in medical practice use.
Incorporated foreign blood contains water, blood cells, proteins, carbohydrates,
lipids, electrolytes, antibodies and biological active substances.
An effect of transfused blood depends on amount, method and velocity of
hemotransfusion.
Mechanisms of transfused blood action are
• Replacement of the lost blood after bleeding, which threatens patient life
• Hemostatic effect
• rourishing action
• Desintoxical effect
• Stimulation of immunological reactivity
• Stimulation of metabolism
When it is necessary to fill a blood under bleeding, transfused blood irritates
vasoreceptors stimulating tonus of vascular system and heart activity together with
renovation of circulating blood volume. Respiratory surface of erythrocytes gets
restored.
Hemostatic effect is provided due to entering the factors of blood coagulation and
platelets. Particularly it is showing at the transfusion of fresh blood (direct or after 1-
3 days preservation).
In a situation of intoxication (poisons or bacterial toxins), transfused blood
provides effect of desintoxication together with its ability to stimulate the urine
production.
A.A. Bogomoletz studied the stimulation of immunological reactivity by
hemotransfusion. Together with admission of globulins and antibodies, transfused
blood stimulates function of the bone marrow and lymphoid glands, which participate
in immune correction of organism.
Incorporated blood performs throphic effect with the nourishing substances -
proteins, carbohydrates and lipids.
Intensification of metabolism and oxidative processes must be added.
CHAPTER 20
PATHOLOGY OF ERYTHROCYTES. ANEMIA
For mastering the material of this chapter it is necessary to know the

physiological, histological and biochemical aspects of structure and function of
erythrocytes and bone marrow, types of erythropoiesis (normoblastic syn.
erythroblastic of adults and megaloblastic in embryo), hemopoietic factors (role
of renal erythropoietin, iron, vitamin B12 and folic acid), the normal indices of
the red blood.
The pathological changes of erythrocytes may be quantitative and qualitative.
QUANTITATIVE CHANGES OF ERYTHROCYTES
Quantitative indices of the red blood are the following.

• Quantity of erythrocytes in a liter of the blood (norm is 4-5,5 T/l in men
and 3,7-4,7 T/l in women)
• Content of hemoglobin (norm is 8,4-10,85 mmole/l or 135-175 g/l in men
and 7,4-10,3 mmole/l or 120-160 g/l in women)
• Color index (norm is 1 with a range between 0,85-1,15 )
• Size of erythrocytes (7-8 µ , average is 7,2 µ)
The changes of amount of erythrocytes are termed erythropenia and
erythrocytosis. The changes of color index are hypochromia and hyperchromia
(pathology of the blood with normal color index is called as normochromic).
All quantitative changes are divided into absolute and relative.
Absolute and relative changes mean, that in pathologic condition any
quantitative index must be evaluated in connection with others.
So, analyzing content of erythrocytes and hemoglobin in the blood, a
change in a total blood volume is necessary to take into consideration. For
example, immediately after the blood loss (cells and plasma are lost
proportionally), content of erythrocytes and hemoglobin in a liter of blood
appears normal, but it does not correspond to reality because anemia develops.
Analyzing color index, a size (volume) of erythrocyte should be considered.
Only with a normal size of erythrocytes (7-8µ) a color index reflects a saturation
of erythrocyte with hemoglobin. A healthy erythrocyte is saturated by
hemoglobin maximally and this quantity is accepted as 1 (for erythrocytes with
normal size). If erythrocytes are small (5µ), the color index is less than 1 even in
a case of their normal saturation by hemoglobin. Color index more than 1
indicates an increase (sometimes to gigantic size) of erythrocyte volume.
Naturally, the phenomenon of the color index increase more than 1 in macro-
and megalocytes (gigantic) does not indicate the higher saturation of erythrocyte
by hemoglobin, which is, on the contrary, is reduced.
QUALITATIVE (MORPHOLOGICAL) CHANGES OF

ERYTHROCYTES
1
Morphological changes in erythrocytes are investigated in the painted smears
of the blood (fig.31). They are divided into two groups - the regenerative and
degenerative ones.
______________________________________________________________
Для художника приведены украинские слова из оригинала
Клітини фізіологічної регенерації Cells of physiological regeneration

Дегенеративні зміни еритроцитів Degenerative changes of erythrocytes
Клітини патологічної регенерації Cells of pathological regeneration
Ретикулоцити (суправітальне забарвлення) Reticulocytes (supravital забарвлення)
Поліхроматофільні еритроцити (забарвлення за Романовським) Polichromatophilic
erythrocytes (забарвлення за Романовським)
Нормобласти, еритробласти Normoblasts, erythroblasts
Зміна розміру (анізоцитоз) Change in size (anisocytosis)
Зміна форми (пойкілоцитоз) Change in form (poikilocytosis)
Зміна забарвлення Change of забарвлення
Патологічні включення Pathological inclusions
Мегалобласти й мегалоцити Megaloblasts and megalocytes
Fig. 31. Morphological changes of erythrocytes (Мал. II на цветной вкладке

1 – еритроцит erythrocyte;
2 –ретикулоцит reticulocyte,
3 – поліхроматофіл polichromatophil,
4 –еритробласт erythroblast,
5 –базофільний нормобласт basophilic normoblast,
6 –поліхроматофільний нормобласт polichromatophilic normoblast,
7 –ацидофільний нормобласт acidophilic normoblast,
8 – нормоцит (середній діаметр 7,2 мкм) normocyte (average diameter 7,2 mkm)
9 – мікроцит (d - менше 6,5 мкм); microcyte (d –less then 6,5 mkm),
10 –макроцит (d -8 мкм і більше); macrocyte (d - 8mkm and more),
11 –мікросфероцит; microspherocyte,
12 –серпоподібний еритроцит (дрепаноцит); sickle-shaped erythrocyte (drepanocyte),
13 –нормохромний еритроцит; normochromic erythrocyte,
14 –анулоцит; anulocyte,
15 –гіпохромний еритроцит; hypochromic erythrocyte,
16 –гіперхромний еритроцит; hyperchromic erythrocyte,
17 –базофільна зернистість;basophilic зернистість,
18 –кільце Кебота;
19 –тільце Жоллі;
20 –мегалоцит; megalocyte,
21 –поліхроматофільний мегалобласт; polichromatophilic megaloblast,
22 –ацидофільний мегалобласт acidophilic megaloblast.
______________________________________________________________
Regenerative Forms of Erythrocytes
If a patient has a normal type of hemopoiesis (normoblastic, syn.

erythroblastic), the following forms of erythrocytes relate to the regenerative
ones – reticulocyte (polychromatophil), normoblast and erythroblast. All of
them are the normal predecessors of mature erythrocyte (normocyte) and in norm
are located in the bone marrow. Just they fall into peripheral blood in pathology
(reticulocytes are present in peripheral blood in norm in content 0,2-2%).
If a patient has the pathologic (megaloblastic) type of hemopoiesis with
megalocyte as a final product, the predecessor of a mature cell is megaloblast
2
(the cell of pathologic regeneration). Reticulocytes are absent in this type of
hemopoiesis.
Degenerative Forms of Erythrocytes
In pathological conditions, the erythrocytes are changed in size, form and

coloration окраске. In addition, they may contain the pathologic inclusions
включений. All these cells are called as degenerative forms of erythrocytes.
A change in size is termed anisocytosis. Normal erythrocyte is called
normocyte and is 7-8µ in diameter, microcyte is less than 6,5µ, macrocyte is
more than 8µ, megalocyte is a gigantic erythrocyte in size 10-15µ and more
(final product of megaloblastic hemopoiesis).
A change in form is termed poikilocytosis. Pathological erythrocytes are
diverse – ovalocyte, spherocyte, sickle-shaped and target-shaped cells and
other forms. Some anemias are manifested by an appearance of a specific
pathologic form of erythrocytes, which serve as a diagnostic sign.
A change in coloration concerns its intensity and nuances. Normal erythrocyte
(normochromic) has a central enlightenment просветление (it is connected with
normal form as a biconcave disc). Color index is equal to 1. If erythrocyte
contains a decreased amount of hemoglobin (hypochromic erythrocyte, color
index is less than 1), the central enlightenment is larger, sometimes only a shell
of erythrocyte is visible (anulocyte). When color index is more than 1 and
erythrocyte looks as hyperchromic one, this phenomenon is observed only in a
case of increased size (volume) of erythrocyte (megalocyte) and a change of its
form from biconcave disc to spherical.
Romanovsky-Giemsa method of coloration is the most commonly used (it is a
mixture of eosin, which colors the base substances in red, and hematoxylin,
which colors the acids in blue). Normal erythrocyte, which contains nothing but
hemoglobin, accepts only eosin (nucleic acids are absent in mature erythrocytes).
If erythrocyte accepts simultaneously eosin and hematoxylin (painting lilac), it
means, that erythrocyte is immature and the nucleic acids are present in
cytoplasm. Such erythrocyte is called polychromatophil and is very important
for anemia characteristics. For more exact revealing of immature erythrocytes,
another method of painting is provided. It is a so-called supravital method with
paint брилианткрезилблау, which colors all erythrocytes in green and detects RNA
(in complex with рибосомами) in young erythrocyte as a blue granularity. Such
immature erythrocyte received a name reticulocyte, which in fact is analog of
polychromatophil.
The pathologic inclusions включения in the erythrocytes are the remainders
of nucleus, when blast cell освобождается от ядра не путем выталкивания but by the
intracellular destruction of nucleus (кариорексис и кариолизис). The corpuscles of
Jolly тельца Жоли, rings кольца of Cabot and granularity refer to the pathologic
inclusions.
ANEMIA
Anemia is an independent самостоятельное disease or a hematological

syndrome, which is characterized by absolute decrease in content of
hemoglobin and erythrocytes with morphological changes of erythrocytes.
There are several groups of anemia. All of them have the common typical
systemic clinical manifestations. They are – the paleness of a skin, dispnoe,
tachycardia, headache, vertigo and reduced ability to work.
3
The pathophysiological manifestations appear all sighs of hypoxia of a hemic
type.
The hematological manifestations of anemia consist in quantitative and
qualitative changes of erythrocytes. Common for all anemias is an absolute
decrease of the hemoglobin. and morphological changes of erythrocytes.
However, each anemia has hematological peculiarities (for example, erythrocyte
content sometimes remains normal).
Causes and mechanism of various types of anemia development are different.
CLASSIFICATION
Some classifications of anemia are proposed depending on different

principles.
Principles of classification Classifications
Etiology (causes) Traumatic (mechanical destruction of

erythrocytes), toxical, immune
Participation of genetic Acquired and hereditary

mechanisms
Pathogenesis Posthemorrhagic, hemolytic,

diserythropoetic
Type of hemopoiesis Normoblastic (erythroblastic) and

megaloblastic
Ability of bone marrow to Regenerative, hyporegenerative

regenerate (this ability is (hypoplastic), aregenerative (aplastic),
estimated by a quantity of hyperregenerative
regenerative forms of erythrocytes)
Color index Normochromic ( 0,85-1,15), hypochromic

(<0,85), hyperchromic (>1,15)
Size of erythrocytes Normocytic (7-8 µ ), microcytic (<7µ),

macrocytic (> 8 µ ), megalocytic ( 10-12 µ
and more)
Clinical course Acute and chronic
In turn, every type of anemia has its own classification (see below).
Different anemias have their own etiology and pathogenesis.
POSTHEMORRHAGIC ANEMIA
Posthemorrhagic anemia is that, which develops as a result of blood loss.

4
Etiological factors (exogenous and endogenous) appear those, which cause an
injury of vessel and lead to bleeding. Endogenous reasons are the tumor or other
necrotic processes (atherosclerotic changes, inflammation etc), that destroy the
vessels.
A speed of bleeding is a critical condition of the posthemorrhagic anemia
development. It is subdivided into acute and chronic depending from amount
and speed of blood loss.
Pathogenesis, clinical picture and hematological indices appear different
depending on that, acute or chronic blood loss happened.
Acute Posthemorrhagic Anemia
Acute posthemorrhagic anemia occurs after blood loss in trauma of the large
blood vessels or inability of organism to stop bleeding due to disorder of
hemostasis.
Immediately and the first hours after blood loss the quantitative indices of the
peripheral blood are delusively normal because erythrocytes, hemoglobin and
plasma are equally reduced.
Immediate compensatory reactions directed to the restoration of the total
blood volume and arterial blood pressure develop (spasms of peripheral blood
vessels, restoration of volume of the circulating blood due to the reserved blood,
decrease of diuresis etc.). Then, revealing of erythrocytes from the depot (liver
and spleen) partly restores the cellular composition of the blood.
After restoration of the total blood volume (in some hours) a reduction of the
erythrocytes and hemoglobin content is recorded. Delayed mechanisms of
compensation are obvious later as an increased hemopoiesis. On the 4th-5th day
after acute blood loss, a proliferation of the erythrocytic steam of the bone
marrow may be observed (it is provided by erythropoietin). In this period the
microscopic examination of the cellular composition of the blood shows the
signs of regeneration. The regenerative forms of erythrocytes (reticulocytes)
appear in the peripheral blood. Their content reflects capability of the bone
marrow for regeneration and a perspective of the patient recovery. The color
index is reduced (hypochromic anemia) as the accelerated regeneration опережает
the maturation of the cells. Massive acute blood loss may lead to deficiency of
iron and decrease of hemoglobin synthesis.
The degenerative forms of erythrocytes usually are absent.
In a case of extreme blood loss (40% and more) we speak not about anemia but
hemorrhage shock (see in the previous chapter). Acute anemia develops later if a
patient gets a proper medical help.
Chronic Posthemorrhagic Anemia
Chronic posthemorrhagic anemia develops due to repeated blood loss caused

by a damage of the not large blood vessels in some diseases (stomach ulcer,
uterine problems, hemorrhoids, etc.) as well as in a disorder of hemostasis
(hemorrhagic syndrome).
Repeated blood loss is accompanied with a reduction of iron stock in the
organism and thus with iron deficiency. In inhibition of hemopoiesis, such
anemia may become hypo- and aregenerative with a low content of the
regenerative forms of erythrocytes in the peripheral blood.
Blood Picture
5
Quantity of erythrocytes and hemoglobin is decreased as well as a color index.
Investigation of the blood smear shows the following changes.
•Appearance of regenerative forms of erythrocytes (reticulocytes), which is a
defensive reaction, but regenerative forms are not so numerous as it is in a case
of an acute posthemorrhagic anemia. A signal normoblasts may appear.
•Appearance of degenerative forms of erythrocytes – hypochromic erythrocytes,
microcytes with anisocytosis and poikilocytosis.
•Ratio of regenerative and degenerative cells content moves to the side of
degenerative ones. The reason lies in the fact that bone marrow suffers from
chronic hypoxia as well.
HEMOLYTIC ANEMIA
Hemolysis is a destruction of erythrocytes inside organism.

Hemolytic anemia is the anemia, which appears as a result of
predominance of destruction of erythrocytes (erythrodieresis) over
erythropoiesis.
The systemic clinical manifestations of hemolytic anemia are the same as in
other forms of anemia – paleness of the skin, dispnoe, tachycardia, headache,
vertigo, reduction in the ability to work, an absolute decrease of the content of
hemoglobin and erythrocytes.
There are some disorders, which distinguish hemolytic anemia from all
others and are the important diagnostic signs. It goes about hemolytic jaundice.
If hemoglobin, which gets revealed into the blood from destructed erythrocytes,
joins haptoglobin in the blood, it would not pass the renal filter, but gets
transformed into indirect bilirubin in macrophages of a spleen causing jaudice.
In cases of massive hemolysis and a grate amount of free hemoglobin in the
blood, the latter passes through renal filter and appears in urine (hemoglobinuria)
which obtains a dark color.
In a case of massive acute hemolysis, body temperature rises (due to IL-1
production by activated macrophages). DIC-syndrome development is possible
in a case of massive production of thromboplastine.
Classification
Hemolytic anemia has its own classification. As to participation of genetic

mechanisms it is divided into acquired and hereditary. As to participation of
immune mechanisms it is divided into immune and nonimmune. As to
etiological factors it is mechanical (traumatic), toxical and immune.
According to localization of erythrocyte distraction, the hemolysis is divided
into the intravascular (preferably acquired) and intracellular (takes place in
macrophages of the spleen by phagocytosis, preferably genetic).
Each form of hemolytic anemia has its own etiology and pathogenesis.
ACQUIRED HEMOLYTIC ANEMIA
Etiology
Etiological factors, which cause destruction of erythrocytes, are physical,

chemical and biological as well as exogenous and endogenous.
Among physical factors it should be named a mechanical injury of
erythrocytes, which occurs after prosthetics протезирования of the blood vessels
6
and cardiac valves. The prolonged march or running on a solid ground (the so-
called march hemoglobinuria) causes hemolysis as well. The latter may be on the
background of a predisposition of erythrocytes to the destruction. Cold
sometimes causes hemolysis of erythrocytes (latter is realized with the
participation of immune mechanisms).
Chemical factors, which cause hemolysis of erythrocytes, are called hemolitic
poisons (in fact hemoysins, although this term is occupied by antibodies against
erythrocytes). The compounds of arsenic, salts of lead свинец, nitrobensolum,
phenylhydrasine, medical drugs are among them. Some of them directly
(poisoning by salts of heavy metals), others (medicines) – through the immune
mechanisms destroy erythrocytes. It is a toxical hemolytic anemia.
Biological hemolysins can be of infectious and parasitic origin – hemolytic
streptococcus, anaerobic infection, virus of influenza, malarial plasmodium,
leishmaniosis. The mushroom, snake and bee poisons cause hemolysis as well as
fungi. Immune acquired hemolytic anemia may be reproduced by transfusion of
group incompatible blood (sometimes, the mismatched hemotransfusion не
приводит to hemolytic anemia of реципиента, as preferably эритроциты донора get
hemolysed).
Hemolytic anemia may occur due to endogenous reasons. Autoimmune
autoantierythrocytic antibodies relate to the endogenous factors. Excessive
bilious acids formation results in hemolysis of erythrocytes. Endogenous toxic
products of nitrous metabolism may have the same result. Splenomegalia may
lead to the excessive destruction of erythrocytes.
The causes of acquired hemolysis may be of a genetic origin – a somatic
mutation of erythroblasts under influence of viruses, microorganisms,
medicamentous preparations with formation of pathologic population of
erythrocytes.
Pathogenesis
There are some mechanisms of acquired hemolysis.

Mechanical hemolysis is connected with direct damage of erythrocyte
membrane. Oxidative hemolysis is connected with effect of oxidizers (нитриты,
гидрид мышьяка). They produce metabolic and then structural changes in
membrane of erythrocyte resulting in hemolysis. Many hemolysins (of biological
origin) possess enzymal activity distracting membranous lecithin (enzymal
hemolysis). Immune-dependant hemolysis is connected with participation of
antibodies and complement.
Under influence of hemolytic agents the pores are formed in the membranes of
red blood cells. Ions of potassium, phosphates come out of the cell and ions of
sodium come inside. Due to electrolyte disbalance, water comes into
erythrocyte that becomes swollen and obtains a sphere shape. Such spherocytes
can not come through interendotelial pores of the spleen sinuses and are
phagocyted by the spleen macrophagocytes (scheme 20). When a size of the
erythrocyte gets larger than in norm, hemolysis occurs and hemoglobin comes
to plasma.
In acquired hemolytic anemia hemolysis of erythrocytes occurs preferably in
the blood (intravascular hemolysis) under effect of hemolysins on the
erythrocyte membrane. In a case of rhesus conflict, hemolysis occurs not only
inside the vessels but also in the liver and spleen (intracellular hemolysis).
The products of distracted erythrocytes stimulate erythropoiesis in the bone
marrow.
7
Scheme 20. Pathogenesis of disorders in intravascular hemolysis
Hemolisin
(etiological factor)
Erythrocytes
Hemoglobin
Hb +
haptoglobin
Kidneys Macrophages Erythropoietin
Indirect bilirubin Bone marrow
Hemoglobinuria
Jaundice Stimulation of
erythropoiesis
Role of Immune Mechanisms
The role of immune factors in hemolysis of erythrocytes can be proven in

experiment by introduction of heterogeneous antierythrocytic serum (antibodies)
to healthy animal.
In cases, when antibodies against erythrocytes are found in a patient and a
content of complement gets lowered, a participation of immune reactions in a
disease is out of doubt. It is autoimmune aggression. It means that a treatment
needs a use of the immunodepressants.
The formation of autoantibodies against own erythrocytes occurs, when their
antigen properties are changed under the influence of microorganisms, viruses,
medicamentous preparations, or as a result of a somatic mutation of
immunocytes, when "forbidden" clones of lymphocytes appear producing
antibodies to normal erythrocytes (in leukemia, systemic lupus erythematosus,
etc.).
Antibodies to erythrocytes belong to IgG and IgM type. They get connected
with membrane of erythrocytes, and then two mechanisms develop
• Erythrocytes with IgG and IgM on their membrane поглощаются by
macrophages of a spleen, liver and bone marrow, which have receptors to
these immunoglobulins.
• IgG and IgM join complement to erythrocyte membrane, which
(complement) after its activation causes lysis (complement-dependant
hemolysis).
Cold sometimes causes hemolysis of the erythrocytes and immune
mechanisms participate in realization of this damage. It is connected with
8
наличием of криоглобулинов (they are immunoglobulins, which change their
conformation under effect of temperature and react with own erythrocytes).
Anemia of newborn may be a result of immune conflict
(rhesusincompatibility) of the mother and the fetus erythrocyte proteins.
Antirhesus agglutinins, which are formed in organism of rhesus-negative mother,
cause hemolysis of rhesus-positive erythrocytes of the fetus or a newborn.
Role of Medical Drugs
The role of medical drugs in damage of the blood cells (not only erythrocytes)
appear a problem. In pharmacological prescriptions one can see such indications.
Some medical drugs (quinine, antituberculous medicine, фтивазид) act as
oxidizers and directly damage membrane of erythrocytes (genetical
predisposition to hemolysis is often on the ground).
The role of medical drugs in realization of the immune mechanisms of the
hemolysis of erythrocytes is provided by the following mechanisms.
• Antigene structure of erythrocytes may get changed under an effect of the
medicines and subsequently antibodies get formed against erythrocytes.
• Medicines can act as haptenes. Binding of medicines with the antigens of
erythrocytes leads to the formation of the antigene complex, which initiates the
formation of the antibodies, which act against own erythrocytes.
Blood Picture
Acquired hemolytic anemia is erythroblastic as to the type of hemopoiesis,

regenerative as to activation of erythropoiesis, normo- or hypochromic as to
color index (or pseudohyperchromic due to absorption of hemoglobin on the
surface of erythrocytes). In the blood smear there can be revealed the cells of
physiologic regeneration (reticulocytes, some normoblasts), degeneratively
changed erythrocytes (poikilocytosis, anisocytosis, and fragmented
erythrocytes). A great amount of normoblasts and even erythroblasts are
observed in newborns with hemolytic disease.
If hemolytic crises are repeated, anemia obtains hyporegenerative or aplastic
character.
HEREDITARY HEMOLYTIC ANEMIA
Genetical predisposition is of a great importance in development of

hemolytic anemias.
Etiology
Etiological factors are mutagens, which damage the genes responsible for
synthesis of erythrocyte proteins. If a patient receives pathological gene by
inheritance, other physical, chemical and biological factors play a role of risk
factors, which realize the pathological predisposition.
Pathogenesis
The protein composition of erythrocyte includes globin, enzymes, membrane

proteins (among them spektrin is important).
9
Depending on localization of a genetically determined defect, hereditary
hemolytic anemia is divided into 3 forms – hemoglobinopathy, enzymopathy and
membranopathy.
In hereditary hemolytic anemia, a reduction of osmotic and mechanical
resistance of erythrocytes is obtained, caused by genetic defects of the
membrane structure, enzymes and hemoglobin.
All genetically defective erythrocytes get destroyed преждевременно. This form
of hemolysis occurs in the spleen (extravascular, or intracellular hemolysis). The
macrophagal cells of the spleen phagocytize defective erythrocytes and their
fragments. Spleen in this case gets enlarged (scheme 21).
Scheme 21. Pathogenesis of disorders in intracellular hemolysis
Genetically defective erythrocytes
Macrophages (phagocytosis)
Proliferation of Indirect Erythropoietin

macrophages bilirubin
Splenomegaly Jaundice Stimulation of

erythropoiesis
Hemoglobinopathy
Hemoglobinopathy is connected with synthesis of abnormal or not typical to

a given age hemoglobin. About 300 forms of hemoglobinopathy are described.
All hemoglobinopathies are divided into a) disorder of a primary structure of
Hb (replacement of aminoacids in Hb-molecula) and b) disorder of the
secondary structure of Hb (replacement of α- or β- chains of Hb). In all cases
the properties of Hb gets disordered and erythrocytes get ruined.
Hemoglobin of healthy adults has such structure - HbA1 (α2β 2). Erythrocytes
of a fetus have fetal hemoglobin - HbF (a2y2); its synthesis begins after the 8th
week of the embrional life. Newborns erythrocytes have 70-90% of HbF and
10-30% of HbA1 . By the end of the first year of life and in adults,
erythrocytes contain 96-98% of HbA1, 3% of HbA2 (a2δ2) and 1 -2% of HbF.
As the clinical examples, two diseases should be mentioned as a
hemoglobinopathy - sickle-cell anemia and talasemia.
Sickle-Cell Anemia. A sickle-cell anemia is a result of a disorder of the primary
structure of molecule of hemoglobin, namely, aminoacid composition of the
molecule of globin. HbS is formed when the glutamic acid in β-chain of hemoglobin is
substituted by valin. In its restored condition, Hb falls out in crystals and causes
erythrocyte deformity. The molecule of HbS is sensitive to deoxygenation.
Under the conditions of hypoxia the molecule of HbS gets polymerized,
10
crystallized, decreases erythrocyte plasticity, destroys erythrocyte and gives to it
a form of a sickle.
Sickle-cell anemia is inherited with incomplete dominance. So, homozygotes
by HbS, whose erythrocytes contain only HbS, are ill with a severe form of
anemia. Heterozygotes (their erythrocytes have 22-45% of HbS and 55-78% of
HbA1) suffer light hemolysis only in a condition of hypoxia.
Talasemia. It is a damage of the secondary structure of hemoglobin
molecule, namely the relationship between α-, β-, γ- and δ-chains of the molecule
of globin. Synthesis of the α-chains is disordered in α-talasemia (β4,γ4),
synthesis of the β-chains is disordered in β-talasemia (α2 γ2, α2δ2). There are
some other variants – HbH (β4), HbA 2 (α2 δ2), Bart-Hb (γ4 ).
Enzymopathy
Enzymopathy is an absence (deficit) of the erythrocyte enzymes (enzymes of

glycolysis, G-6-PDGase, ATPase, glutathione peroxidase and others). The
disorders of metabolism occur. Metabolic defects predispose to the membrane
instability and the destruction of erythrocytes.
In hereditary G-6-PDGase-deficient anemia the erythrocytes have reduced
contents of the restored glutation (antioxidant). The deficit of the enzyme
glutathione peroxidase, which contains iron, leads to the oxidation of SH-groups,
decrease of the erythrocyte plasticity and a damage of the membranes.
Such erythrocytes are sensitive to the oxidizers. These diseases are drug-
dependent (medicines with the oxidizing action play a special role). Usage of
such medicines as primachin, sulfanilamides, aspirin, phenaticin play a role of
the risk factors and may cause an acute intravascular hemolysis of erythrocytes.
Membranopathy
Membranopathy is a genetic defect of the proteins of the membrane of

erythrocytes. The main of them is a spektrin (due to its contractile properties the
membrane of erythrocyte retains a form of a biconcave disс). If a content of
spektrin decreases or its polymerization occurs, the cytoskeleton of erythrocyte is
disrupted. It leads to the decrease of the membrane tension and provokes the
transformation of normal biconcave disk into the spherocyte. Changes in
membrane predispose erythrocytes to hemolysis. The osmotic stability of
erythrocytes gets reduced.
Genetic deficiency of Ca2+-dependent ATP-ase and phospholipids in erythrocyte
membrane results in increased permeability of the membrane.
Clinical example of membranopathy – hereditary microspherocytic hemolytic
anemia or Minkovsky-Shoffar disease. Microspherocytes are visible under the
microscope invastigation.
Blood Picture
As in any other anemias, amount of erythrocytes and hemoglobin content is

decreased. Proliferation of erythrocytic stem of the bone marrow is activated but
erythropoiesis often is not effective because the nuclear forms of erythrocytes
get destroyed in the bone marrow. Nevertheless, reticulocytosis,
polichromatophilia and normoblasts may be observed in peripheral blood. A
specific degenerative forms of erythrocytes are detected – microspherocytes in
Минковского-Шоффара disease, sickle-like erythrocytes in correspondent anemia,
11
target-like erythrocytes and erythrocytes with basophilic зернистость in talasemia.
These cells have the main significance in the diagnostics.
DISERYTHROPOIETIC ANEMIA
Diserythropoietic anemia is that, which develops as a result of a disorder of

erythrocyte production (erythropoiesis).
This type of anemia may develop as a separate disease (in damage of the bone
marrow) and as an associated hematological syndrome in other systemic diseases.
All typical pathologic processes (inflammation, neoplasia, allergy, dystrophia,
and thrombosis) can be developed in the bone marrow.
Etiology
Causes of diserythropoietic anemia may be exogenous and endogenous.

Myelotoxic anemia may be a result of the diseases of the bone marrow under an
effect of etiological factors of physical, chemical and biological origin, which
damage the bone marrow or organs, which influence erythropoiesis.
Ionizing radiation is the most potent injuring factor for the bone marrow.
Diserythropoietic anemia is inevitable sign of the radiant disease. All kind of
poisons, including medical drug abuse, damage the bone marrow and cause
anemia. Any severe pathology in organism (kidney insufficiency, hepatitis,
uremic and hepatic coma etc.) is accompanied with formation of toxic products
of endogenous origin, which lead to anemia development. Severe infections and
immune causes may be etiological factors as well.
As to participation of genetic factors this anemia may be acquired and
hereditary.
Pathogenesis
As to mechanisms of an erythropoiesis disorder, diserythropoietic anemia is

divided into the following groups.
Disregulatory anemia is caused by reduction in synthesis of erythropoietin or
increased synthesis of its inhibitors. It occurs with many diseases – chronic
diseases of kidneys (glomerulonephritis), hypofunction of pituitary and thyroid
glands). These and other diseases have myelotoxic type of anemia as an
associated syndrome.
Deficient дефицитная anemia happens in deficit of the substances, which are
necessary for erythrocyte production. They are - iron, vitamin B12, folic acid,
aminoacids and proteins. The diseases of a digestive tract often leads to anemia
development due to disorder of suction of hemopoietic factors.
Enzymopathy is a genetically determined disorder of activity of the enzyme,
which participate in erythropoiesis.
Hypo-aplastic anemia is a result of an exhaustion of a hemopoietic tissue in any
wasting chronic disease, which leads to inhibition of hemopoiesis.
Metaplastic anemia develops after displacement of an erythrocytic stem of the
bone marrow by another tissue, for example, in leukemia.
As to the type of erythropoiesis, diserythropoietic anemia may be
normoblastic (erythroblastic) and megalolastic.
As to clinical course it may be acute and chronic.
12
Together with common features, which characterize all types of
diserythropoietic anemia, every type of it has its own peculiarities of etiology,
pathogenesis, hematological and clinical manifestations.
Iron-Deficient Anemia
Iron-deficient anemia is an anemia caused by deficiency of iron in the

organism as a result of disbalance between its intake, usage and loss. It is the
most often type of anemia (80%).
Iron is necessary for the formation of hemoglobin, respiratory enzymes
containing iron and providing electron transport, catalase and
glutathionperoxidase in erythrocytes.
Iron reserve is located mainly in a composition of protein ferritin (depot is in
enterocytes and in the liver), hemosiderin (in the bone marrow, macrophagocytes,
the spleen, Kupfer's cells of the liver) and myoglobin of skeleton muscles.
Etiology
Etiological factors, which cause iron-deficiency anemia, are those, which lead
to a deficiency in the entering of iron into organism or a disorder of its utilization.
Etiological factors may be exogenous or endogenous, which cause primary and
secondary deficiency of iron in organism.
The causes are the following
• Iron loss in bleeding is the most often cause. It is a repeated or massive
single blood loss in uterus, gastrointestinal, renal, pulmonary diseases.
• Lack of entering of iron into the organism occurs in
Starvation
Deficit of iron in a food (in feeding children only with caw or goat
milk)
• Disorder of the suction of iron in the digestive tract pathology (hypoacid
gastritis, chronic enteritis) or resection of its portions
• Disorder of iron transport (hypotransferinemia in liver disturbances, genetical
atransferinemia)
• Disorder of iron utilization from reserves (in infection, intoxication, helmintic
invasion)
• Disorder of deposition of iron (in hepatitis, hepatic cirrhosis)
• Increased need of organism in iron and its increased consumption in
Pregnancy
Growth
Lactation
Pathogenesis
The main link in pathogenesis is a deficit of iron for hemoglobin formation. In

turn, it leads to suppression of respiratory function of the blood and development
of hypoxia of a hemic type.
Compensatory reactions in form of iron mobilization from depot and activation
of its suction takes place, but gradual exhaustion of iron reserves follows it in
chronic diseases.
Anemia develops with the following order of events.
• The level of iron in the blood serum gets reduced. Hyposideremia reaches 1.8-
2.7 mcm/1 (instead of 12.5-30.4 mcm/l).
13
• Decrease of ferritin content in the blood less then 12 mkg/l (in norm 12-200
mkg/l).
• Depletion of iron reserves in form of hemosiderin in the macrophages of the liver
and spleen, ferritin content in liver and enterocytes.
• Production of transferrin gets reduced. Decrease of transferin saturation with
iron less then 20% (in norm 30-50%). It means a decrease of iron transport to the
bone marrow.
• Negative iron balance develops.
• Disorder of iron coming into erythrocytes and decreased heme synthesis
• Decreased synthesis of some iron-contacting enzymes in erythrocytes
(catalase, glutathionperoxidase) results in their (erythrocytes) increased
sensitivity to hemolyzing effect of oxidizers. The lifetime of red blood cells
gets reduced to 20-30 days.
• Increased hemolysis of erythrocytes in the bone marrow and in the blood
• Erythropoiesis becomes non-effective.
• Atrophic, aplastic and dystrophic processes in tissues and organs develop as a
consequence of a deficit of the iron-containing enzymes
• Hemic and tissue types of hypoxia.
• Atrophic and dystrophic changes in digestive tract (atrophic glossitis and
gingivitis, dental caries, injury of the esophagal mucous membrane, atrophic
gastritis with achilia).
• Myocardial dystrophy
• Alopecia must be added.
Blood Picture
A quantity of hemoglobin is always reduced. A quantity of erythrocytes can be

lowered or normal, but erythrocytes are always small in size (microcytes) – 5µ
instead of 7-8µ.
Color index is low - 0.6 and less (up to 0,4). Erythrocytes are hypochromic.
The reason leis in a) decrease of Hb synthesis, b) more significant decrease of Hb
content then erythrocyte amount, c) due to small size of erythrocytes.
Hypochromic "shadows" of erythrocytes are observed in the blood smear.
Anisocytes and poikilocytosis must be added.
Amount of regenerative forms of erythrocytes (reticulocytes) depends on the
regenerative ability of erythrocytic stem of the bone marrow. They may be
sufficient in quantity or decreased.
So, the iron-deficient anemia is an anemia with erythroblastic type of
hemopoiesis, hypochromic, regenerative or more often hypogenerative anemia.
B12- and Folic-Deficit Anemia
Vitamin B12 (cyanocobalamin) and folic acid are the participations of DNA
synthesis and normal (erythroblastic) hemopoiesis. In their deficit, a normal
type of erythropoiesis gets transformed into pathological one (megaloblastic).
Pernicious (malignant) Addison-Birmer,s anemia develops.
B12- and folic-deficient anemia is anemia, which is connected with disorder
of nucleic acid synthesis and substitution of erythroblastic type of
hemopoiesis by megaloblastic one.
Vitamin B12 is contained in a food sufficiently, but for its utilization the
protein of a stomach (internal Castle’s factor, gastromucoprotein, which is
secreted by the glands of the mucous membrane of stomach) is necessary.
14
Daily need in vitamin В12 is 3-5 mkg, and stock in the liver is 1000 times
more, thus, the reserves of cyanocobalamin in healthy adults are sufficient for
approximately two years.
Etiology
By etiology this anemia may be acquired and hereditary.

Etiological factors, which lead to the development of this anemia, are the
reason of insufficient entering or utilization of vitamin in the stomach.
Exogenous deficit of vitamin is possible only in the children with artificial
nourishment, who feed by goat milk or dry milk mixtures. In adult person this
anemia develops with endogenous reasons, which appears in the diseases of the
stomach, when gastromucoprotein is not formed.
Deficit of internal Castle’s factor (gastromucoprotein) may be acquired and
inherited. Acquired deficit of this factor may be a result of damage of the gastric
mucous membrane in
• Chronic atrophic gastritis
• Tumor of stomach
• Destruction of internal Castle’s factor by antibodies to the parietal cells of
stomach or gastromucoprotein
• Resection of a stomach
Hereditary defect of internal Castle’s factor formation is a result of a mutation
of genes responsible for this protein synthesis by the cells of the gastric glands. It
is inherited by autosomic-recessive type.
Disorder of the cyanocobalamin deposition in the liver (vitamin depot) in the
case of its diffuse lesion (cirrhosis, hepatitis) as well as increased need in
vitamin (in pregnancy) are also the reasons of vitamin deficit.
Pathogenesis
Development of this form of anemia is connected with non-effective

erythropoiesis.
In deficiency of cyanocobalamin (of its coferment — methylcobalamin), there is
no transformation of folic acid into its coferment form (tetrahydrofolic acid),
which is necessary for a synthesis of timidinmonophosphate (one of the
components of DNA). Disorder of DNA synthesis causes disorder of division of
the cells of hemopoietic tissue. Gigant cells appear as a result of atipical mitosis.
Normal hemopoiesis (erythroblastic) is replaced by embryonic one
(megaloblastic).
The final products of this form of hemopoiesis are the erythrocytes of gigantic
size (megalocytes). Their lifetime is very short (10-14 days) because of
hemolysis.
Regenerative processes in bone marrow are intensified, but the cells of
regeneration are pathological - megaloblasts are produced in a large quantity and
appear in peripheral blood.
Leukopoiesis and thrombocytopoiesis are suppressed as well.
Disorder of mitosis is observed also in the cells of the mucous membrane of
the digestive tract. The gigant cells of mucous membrane appear. Inflammatory
and atrophic changes in the mucous membrane of the digestive tract (oral cavity,
stomach, intestine) are observed as glositis, stomatitis, ezofagitis, enteritis.
Hydrochloric acid is absent in the stomach (achylia). Digestion is impaired.
As a result of cyanocobalamin lack, methymalonic acid, which is toxic for the
nervous cells, accumulates in the organism. Mиэлинизация gets disturbed,
15
нарушается проведение импульсов. Cells of the nervous tissue have signs of
degeneration. Degeneration of the posterior and lateral columns of the spinal cord
develops (funicular myelosis). The cranial and peripheral nerves are affected
developing multiple neurologic symptoms.
The disease results in death without treatment. That is why this anemia is
called pernicious (malignant).
Blood Picture
Blood picture is characterizes by the following quantitative signs

• Significant decrease of amount of erythrocytes (2-3 T/l and less)
• Decrease of hemoglobin content (70-80 g/l and less)
• Increase of color index more than 1 (1,2- 1,4 and more)
• Leukopenia (decreased amount of leukocytes)
• Thrombocytopenia (decreased amount of thrombocytes)
The following morphological disorders of the blood cells (signs of
degeneration) are detected in a smear
• Erythrocytes are significantly enlarged (megalocytes with diameter 10-12µ
and more, 20 µ was registrated in some patients).
• Erythrocytes (megalocytes) are hyperchromic, without enlightenment in the
center due to their large volume and changed form.
• Poikilocytosis, anisocytosis
• Pathologic inclusions (rests of nucleus) in megalocytes - Zholli’s bodies,
Cabot's rings and basophilic granules.
• Large quantity of nuclear forms of the red cells (megaloblasts)
• The cells of physiologic regeneration (reticulocytes) are absent.
• Leukocytes have large size and hypersegmented nucleus (right-side nuclear
shift, characteristics is in the next chapter 21)
So, the B12 and folic-deficient anemia is megaloblastic and hyperchromic.
ERYTHROCYTOSIS
Erythrocytosis is an increase of erythrocytes content in the blood more then 6

T/l, hemoglobin to 10,55 millimole/l (170 g/l) and гематокритного числа more
then 0,52.
Classification
According to etiology, erythrocytosis is divided into acquired and hereditary.

In accordance with pathogenesis it is divided into absolute (true справжній,
which is caused by activation of erythropoiesis in the bone marrow and increase
of mass of circulated erythrocytes) and relative (несправжній) –
перераспределительный and гемоконцентрационный (is a result of decrease of
plasma volume and thus потому не сопровождается by increase of mass of
circulated erythrocytes). Absolute erythrocytosis in turn is subdivided into
primary (as a самостоятельноe disease) and secondary (симптоматический), аnd the
letter – into physiological (compemsatory) and pathological.
Etiology
16
Primary absolute erythrocytosis is caused by a tumorous transformation of
erythroid cells with intensification of their proliferation independently from
erythropoietin. It is a true polycythemia (erythremia, or the Vakez disease),
which is a version of a chronic leukemia.
Secondary absolute erythrocytosis (acquired) is caused by increased
production of hemopoietic factors. The examples are the following -
• Hypoxic, respiratory, circulatory hypoxia (горная disease, chronic diseases
of organs of respiration and blood circulation)
• Local (ischemiс) hypoxia of the kidneys (hydronephrosis, stenosis of renal
arteries) resulting in erythropoietin hyperproduction,
• Overproductions of erythropoietin by some tumors (hypernephroma, liver
cancer)
• Disorder of neurohumoral regulation with excitation of the sympathetic
part of the vegetative nervous system,
• Hyperfunction of some endocrine glands, when сatecholamines,
corticotropin, thyroid hormones, glucocorticoids, androgens increase a need in
oxygen and thus contribute to hypoxia development and a formation of
erythropoietin in the kidneys.
Hereditary absolute erythrocytosis may be a result of a genetically
determined deficit in the erythrocytes of 2,3-diphosphoglycerate (regulator of
oxigenation and deoxygenation of hemoglobin). An affinity of hemoglobin to
oxygen increases and its отдача return to tissues decreases. Tissue hypoxia
develops, the production of erythropoietin increases, erythropoiesis activates.
Relative erythrocytosis is a result of effect of such factors, which cause
• Dehydration of organism and hemoconcentration (increased perspiration,
prolonged vomiting, diarrhea)
• Redistribution of the blood with polycythemic hypovolemia (shock, burn).
Pathogenesis
Absolute erythrocytosis in hypoxia is a physiological one and has protective

value. It results in intense synthesis of erythropoietin and activation of
erythropoiesis contributing in improvement of tissue supply by oxygen. After
stopping of the etiological factor action a quantity of erythrocytes and
hemoglobin is normalized.
Absolute erythrocytosis, which is caused by tumorous proliferation of the
erythropoietic part of the bone marrow, is pathological one and has no protective
value. This polycythemic hypervolemia results in the following pathological
changes -
• Increased viscosity of the blood, hemoconcentration and a disorder of the
reological blood property,
• Decrease of the blood flow speed
• Disorder of microcirculation,
• Increase of arterial blood pressure,
• Hyperemia of internal organs, skin and mucous membranes,
• Impairment of the heart function,
• Activation of thrombogenesis,
• DIC-syndrome development.
17
CHAPTER 21
PATHOLOGY OF THE LEUKOCYTES

LEUKOCYTOSIS AND LEUKOPENIA
There are five forms of leukocytes - granulocytes oneutrophils, eosinophils,

basophils) and agranulocytes olymphocytes and monocytes). The formation of
leukocytes oleukopoiesis) is accomplished in the bone marrow.
All leukocytes are divided into three pools.
The majority of mature leukocytes are located in tissues. This amount is
impossible to calculate. kust in the tissues they perform their functions.
Small quantity of leukocytes is located in the blood. In turn, they are
redistributed into two pools. Half of them are located near the vascular wall
omarginal pool). They come into circulated pool after eating, muscular or
physical overload and nervous excitement ounder katecholamins influence) and
also in pathological conditions.
Mature leukocytes partially are located in the peripheral blood, partially in the
bone marrow as a reserve. All immature leukocytes omyeloblasts,
promyelocytes, myelocytes, metamyelocytes, baton-like cells) are located in the
bone marrow.
The function of leukocytes is connected with participation in the resistance of
organism and immunological reactivity, which consists in phagocytosis, the
formation of immune antibodies and BAS.
Neutrophils omicrosphages) are the main participants in phagocytosis. Their
participation in inflammation was observed in the chapter 8 “Inflammation”.
Monocytes are macrophages. The eosinophils contain BAS inhibitors; their
participation in the allergy together with basophils omast cells) was observed in
the chapter 6 “Allergy”. Participation of B- and T-lymphocytes in the
immunological reactions was observed in chapter 5 “Pathology of Immunological
Reactivity”.
Leukocytes participate in production and deactivation of a lot of BAS. They
participate in blood microcirculation regulation. One of the functions of
leukocytes is to provide tissues with the stimulators of cell division.
Proportion between the different types of leukocytes in the peripheral blood is
called leukocyte formula oit is counted in the painted blood smear in per cent
among 100-200 cells).
Pathologic changes of leukocytes are manifested as a disorder of their
formation in the hemopoietic tissue, qualitative and quantitative changes. These
changes occur as a result of a primary damage of leukocytes in the hemopoietic
tissue and circulating blood under the influence of different injuring factors.
Secondary changes of leukocytes are usually a protective organism response to the
pathologic processes in the whole organism.
DISORDER OF LEUKOPOIESIS
1
There are the following disturbances of leukopoiesis:
• Increase or decrease of leukocytes production in hemopoietic tissue,
• Disturbance of maturation of leukocytes in the hemopoietic organs,
• Production of pathologically changed leukocytes.
Disturbance of leukopoiesis may be partial oconcerns a certain stem ЀЀЀЀЀЀ of
hemopoietis tissue) and total oconcerns all of them).
Etiology
Etiological factors of such disturbances are exogenous and endogenous. They

are:
• Physical oionizing radiation, ultraviolet rays),
• Chemical ostimulators and inhibitors of cell division),
• Biological obacterias, viruses and protozoas),
• Endogenous factors are
Genetic defects of formation and differentiation of leukocytes,
Hormonal disregulation of leukopoiesis,
Autoimmune factors.
Pathogenesis
Activation of leukopoiesis of teactive type is a proliferation of the

leukopoietin-sensitive cells of the bone marrow, which results in leukocytosis. It
can be caused by increased production of humoral activators
ocolonystimulating factor – CSF, interleukins) or decreased production of their
inhibitors okeilons, prostoglandins E, lactoferrin and isoferritin). Infection is the
most potent stimulator of leukopoiesis.
Activation of leukopoiesis of reactive type is more often partial. The type of
proliferated leukocytes depends on etiological factor. Bacterial endotoxins
stimulate proliferation and differentiation of precursors of neutrophile
granulocytes. Precursors of eosinophils get proliferated in response to immune
complexes and helmints. Antigenes stimulate proliferation of lymphocytes.
Inctease of leukopoiesis of a tumotous otigin occurs under an influence of
carcinogenic factors, causing mutation of genes, which are responsible for
multiplication and differentiation of the cells of II-IV classes. It is met in
leukemia osee the next chapter 22).
Deptession of leukopoiesis may be partial and total and is caused by
• Ionizing radiation,
• Generalized affection of the leukopoietic tissue ointoxication, severe infections,
immune mechanisms),
• Diseases of the bone marrow or lymph nodes oinflammation, tumor),
• Disturbance of leukocyte production regulation odeficit of leukopoetins),
• Deficit of plastic factors oin protein starvation), cyanocobalamine and folic
acid,
• Replacing of normal leukocytes in the bone marrow by tumorous metastasises
and leukemic infiltrations,
• Medical drugs abuse, which may damage leukocytes in hemopoietic organs,
oside-line effect of medicines),
• Hereditary disturbances of leukopoiesis ohereditary neutropenia).
Disotdet of leukocyte matutation is caused by the blockade of
differentiation at different levels of cell development. Genetic regulation and
certain metabolytes provide differentiation. Sometimes this disorder is
2
connected with a decrease of leukocyte production. Disorders are connected
with
• Mutation,
• Exo- and endogenic factors oagents of purulent and viral infections,
medicinal allergens and intoxication),
• Tumorous hyperplasia and leukemoid reaction
• Disorder of the bone marrow barrier and its permeability oinfluence of CSF,
glucocorticoids, interleukins, bacyerial toxins), when immature leukocytes
leave the bone marrow.
Ptoduction of pathologic leukocytes may arise as a result of
• Tumorous transformation of leukopoietic tissue in leukemia,
• Metabolic disturbances in leukocytes,
• Genetically determined structural disturbances odominant hereditary Pelger
anomaly of granulocytes, deficiency of myeloperoxidase, glucose-6-
phosphatedehydrogenase G-6-PDG).
All named disorders of leukopoiesis are reflected as quantitative and
qualitative changes of peripheral blood.
QUANTITATIVE DISORDER OF LEUKOCYTES
Quantitative disorders of the leukocytes are represented by

• Total quantity of leukocytes in a liter of blood
• Changes of leukoformula indices oquantity of every form of leukocytes).
Within the standard the total quantity of leukocytes is equal to 4-9 G/l. An
increase in the total quantity of leukocytes is called leukocytosis and decrease -
leukopenia.
Analysis of Leukoformula
Analyzing leukoformula, it is necessary to focus attention on absolute and

relative quantitative changes of various forms of leukocytes.
If a total quantity of leukocytes in the peripheral blood is normal, it is possible
to be oriented with their percent ratio in the leukoformula. If a total quantity of
leukocytes differs from norm oin many diseases it occurs), it is necessary to be
oriented in absolute quantity of every form of leukocytes in the peripheral blood.
In connection with it, absolute and relative changes in the quantity of
leukocytes are distinguished.
The ration between mature and immature forms of leukocytes also must be
analyzed in leukoformula.
In the leukocyte Shilling formula, all type of cells are located horizontally
depending on their maturity. Immature forms of neutrophils omyelocytes,
metamyelocytes, ЀЀЀЀЀЀЀЀЀЀЀЀЀЀ baton-like? stab? neutrophile granulocytes) are
placed in the left part of the leukocyte formula, but the mature ones
osegmentonuclear neutrophile granulocytes) in the right part. Increase of the
young neutrophils in the blood is called the left-side nuclear shift of
neutrophils. The prevalence of the mature forms owith many segments, 5-6 and
more) associated with absence of young cells is called the right-side nuclear shift
of neutrophils.
Increase of the young forms of leukocytes in leukoformula associated with
increased amount of leukocytes oleukocytosis) reflexes activation of
leukopoiesis due to reactive or tumorous hyperplasia.
3
Absence of the young forms of leukocytes in leukoformula with decrease of
total amount of leukocytes oleukopenia) reflexes an inhibition of leukopoiesis.
Left-Side Nuclear Shift in Neutrophils
An appearance of immature neutrophils in the peripheral blood under

pathological conditions is analyzed.
There are the following four types of nuclear shift to the left.
Regenetative
Regenerative left-side nuclear shift is an increase of amount of young

neutrophils up to metamyelocytes in leukoformula. Total amount of leukocytes
is increased oup to 20T/l). This nuclear shift reflects an activation of leukopoiesis
of regenerative type. It occurs in inflammation and activation of immunological
reactivity. The value of this nuclear shift is always positive.
Hypettegenetative
Hyperregenerative left-side nuclear shift is an increase of amount of

immature neutrophils in leukoformula up to myelocytes, promyelocytes and
myeloblasts. The total number of leukocytes is increased more then 20 T/l.
It is an excessive hyperplasia of the hemopoietic tissue with disorder of
maturation of the cells, which cannot be named defensive.
It may be of a tumorous origin under influence of carcinogens oin leukemia). It
is also met in some cases of acute inflammation oso-called leukemoid reaction,
see below).
Regenetative-Degenetative
Regenerative-degenerative left-side nuclear shift of neutrophils is observed

in prolong course of infection osepsis), when potentiality of myelopoiesis are
inhibited or get exhausted. Maturation of leukocytes is disordered. General
content of leukocytes may be increased omoderate leukocytosis) or not
elevated. Leukocytes, which are produced in the bone marrow, are
pathologicaly changed. Young leukocytes obaton-like neutrophile granulocytes
and metamyelocytes) are hyperproduced and have signs of degeneration.
Degenetative
Degenerative left-nuclear shift of neutrophils is an appearance of a large

quantity of baton-like neutrophils owith degenerative signs) but
metamyelocytes are absent. It is an evidence of a deep disturbance and
inhibition of leukopoiesis. The total quantity of neutrophils is reduced. It means
that the function of the bone marrow gets suppressed, and maturation of
neutrophils after baton-like forms is limited. This nuclear shift always has
negative value. It is met in infectious diseases with significant intoxication
oЀЀЀЀЀЀЀ ЀЀЀ) as well as in gangrene or sepsis.
Right-Side Nuclear Shift in Neutrophils
4
Right-side nuclear shift in neutrophils is an increase of ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ
ratio of mature segmentonuclear neutrophils in leukoformula in comparison
with their young precursors.
It may be of redistributive origin associated with leukocytosis, when
ЀЀЀЀЀЀЀЀЀ mature leukocytes ЀЀЀЀЀЀЀЀЀЀЀЀЀ in circulated blood from depot obone
marrow) and marginal pool. This change is of adaptive nature. It occurs in all
type of stress oand in the first stage of an acute radiant disease).
ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ ЀЀЀЀЀ the right-side nuclear shift associated with
decrease of total amount of leukocytes oleukopenia). It is of degenerative
nature. Young forms obaton-like neutrophils and metamuelocytes) are absent
in leukoformula. Mature neutrophils are degenerative – nucleus has a grate
amount of segments o6-8 and more). Various degenerative changes are
revealed in cytoplasm of these hypersegmented neutrophils. It is an evidence
of a deep inhibition of leukopoiesis. Right-side nuclear shift ЀЀЀЀЀЀ in
megaloblastic and aplastic anemia, aleukia, radiant disease. In Addison-
Birmer anemia, the gigant polysegmento-nuclear neuthrophils owith 8-12
segments and 20-30 mkm in diameter) appear in the blood as a result of critical
decrease and disorder of hemopoiesis and atypical mitosis due to vitamin B12
deficit. General amount of leukocytes is decreased.
QUALITATIVE CHANGES IN LEUKOCYTES
Qualitative changes in the leukocytes are preferably degenerative. They are

manifested by the nucleus and cytoplasm disorders ofig. 32). They are:
• Anisocytosis ochange in size of leukocytes),
• Poikilocytosis ochange in form of leukocytes),
• Absence of normal granulation,
• Pathologic inclusions in cytoplasm otoxic granularity, large asurophilic
granulation, basophilically stained small bundle of cytoplasm),
• Vacuolization of nucleus and cytoplasm,
• Swelling of the nucleus,
• ЀЀЀЀЀЀЀЀЀЀЀ,
• Hypo- and hypersegmentation of nucleus,
• Cytolysis.
________________________________________________________
Fig 32. Degenerative changes of leukocytes

1- toxical ЀЀЀЀЀЀЀЀЀЀЀ
2- vacuolization of nucleus and cytoplasm
3 –ЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ-ЀЀЀЀ
4 – ЀeЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ
5 –hypersegmentation of nucleus
6 - anisocytosis
____________________________________________________________
Degenerative changes are caused by the influence of different pathologic factors

ochemical toxins, bacteria, viruses and antibodies), that damage leukocytes in the
hemopoietic organs and in the blood. The disturbance in leukocyte metabolism leads
to structural anomalies.
Production of pathologic leukocytes may arise as a result of neoplastic
transformation of leukopoietic tissue in leukemia.
5
Structural disturbances may be genetically conditioned oan example is
hereditary Pelger anomaly of granulocytes, when neutrophile granulocytes have
round, rodshaped or 2-segment nucleus after maturation).
Degenerative leukocytes are produced in non-effective leukopoiesis and are
characterized by reduction of the phagocytic activity and shortened life.
LEUKOCYTOSIS
Leukocytosis is an increase in the total content of leukocytes in the

peripheral blood more than 9 G/l.
Morphological odegenerative) changes of leukocytes may accompany
quantitative ones.
Types
There are several classifications of leukocytosis.

Physiological oafter food, physical load, emotional, in pregnancy) and
pathological owith the diseases) according to significance.
Reactive, tedisttibutive and tumotous in accordance with pathogenesis.
Neuttophilic, eosinophilic, basophilic, lymphocytosis, monocytosis are
distinguished depending on the type of leukocytes being increased.
Absolute and telative othis division refers to each form of leukocytosis).
Etiology
Etiological factors are exogenous and endogenous as well as physical,

chemical and biological.
Ionizing radiation causes redistributive leukocytosis during the first day of
radiant disease.
Chemical toxical products oexogenous and more often of endogenous origin
from ruined tissue) cause absolute regenerative leukocytosis.
Infection is the most potent activator of leukopoiesis and phagocytosis,
which has protective value.
Pathogenesis
There are the following principal mechanisms of leukocytosis pathogenesis.

• Activation of leukopoiesis of reactive type, which is more often partial,
resulting in hyperproduction of a certain type of leukocytes. Leukocytosis is
absolute. It is caused by increased production of humoral activators
ocolonyostimulating factor and other). Sometimes, leukocytosis is
accompanied by the suppression of maturation of leukocytes in the bone
marrow and, sometimes, by production of pathologic forms.
• Hyperplasia of the leukopoietic tissue of tumorous character results in
production of pathological leukocytes oleukemia).
• Acceleration of ЀЀЀЀЀ of leukocytes from the bone marrow into the blood
may be a result of increased permeability of the bone marrow barrier.
• Redistribution of leukocytes from the marginal pool into circulating one
causes relative leukocytosis.
Different types of leukocytosis have peculiarities in etiology, pathogenesis and
significance.
6
Neuttophilic Leukocytosis
Relative redistributive neutrophilosis ophysiological) occurs after eating,

physical work, psychical overstrain ofear, fury). The total quantity of leukocytes
in the peripheral blood increases temporary without young forms appearance
odescribed above as a right-side nuclear shift in neutrophils)
Absolute neutrophilosis proceeds with steady total quantity increase of
leukocytes up to 20 G/l. Percentage? the quota? of neutrophils in the
leukoformula is also increased. Young forms of neutrophils oup to
metamyelocytes) appear in the peripheral blood oregenerative left-side nuclear
shift). Activation of leukopoiesis of reactive type underlies pathogenesis of this
form of leukocytosis. It has adaptive value in inflammation oparticipation in
phagocytosis). Stimulation of immunological reactivity occurs.
The causes of neutrophilosis are various. Basic etiological factors, which
activate the function of the bone marrow, appear infectious one ococci
microorganisms - strepto- and staphylococci – and fungi). They provoke
increased production of CSF, stimulating proliferation and differentiation of
precursors of neutrophile granulocytes.
The substances, which are formed in the non-infection inflammation, also
stimulate neutrophils production. They are:
• Products of tissue decay and necrosis omyocardial infarction, malignant tumors
decay, products of decay in chronic myeloleukemia), tissue distraction by
physical factors ocold, heat),
• Products of erythrocytes hemolysis,
• Toxic metabolites in uremia and hepatic coma
Eosinophilic Leukocytosis
Allergy is the most frequent reason of eosinophilic leukocytosis. Activation of

eosinophilopoiesis and release of eosinophile granulocytes from the bone marrow
into the blood is observed in allergic diseases and connected with the increased
synthesis of CSF by lymphocytes after antigenic stimulation. Mast cells produce a
factor of eosinophil hemotaxis. It is also connected with increased permeability of
the bone marrow to eosinophiles under influence of histamine and other BAS
released in reaction of antigen+antibody.
For understanding the importance of eosinophilia one must take into account
the function of the eosinophiles in allergy. The eosinophils contain histaminase
and arilsulfatase in their granules and neutralize BAS in allergy.
Amount of eosinophils is elevated in a helminthic invasion othey reveal a
certain protein, which damage membrane of ЀЀЀЀЀЀЀЀЀЀ).
Eosinophilia is observed in chronic myeloleukemia.
Basophilic Leukocytosis
Basophilic leukocytosis as a separate form of leukocytosis occurs rarely. It is

noted in chronic myeloleukemia, ulcerative colitis, after splenectomy and in
myxedema.
Lymphocytic Leukocytosis
Lymphocytic leukocytosis olymphocytosis) is caused by the agents of

tuberculosis and lues as well as viral infection oinfectious mononucleosis, hepatitis,
measles, whooping cough). It occurs also in allergy.
7
Named forms of leukocytosis have adaptive value.
In chronic lympholeukemia an amount of lymphocytes significantly increased
but it has no protective significance.
Monocytosis
Monocytosis develops under influence of viruses, microorganisms ospecific

streptoccocal endocarditis) and protozoa. The agents of tuberculosis and syphilis
are the reasons for monocytosis as well.
Monocytosis can develop in noninfectious inflammation, since monocytes
are the active phagocytes. The value of monocytosis is positive, since
phagocytosis is a protective reaction.
Leukemoid Reaction
Leukemoid reaction is an acute increase of immature forms of leukocytes in

peripheral blood. It is observed in patients with instability of hemopoiesis in
response to acute infection osepsis) and acute hemolysis of erythrocytes.
Blood picture resembles leukemia but differs from it by etiology, pathogenesis
and significance. The cause is often known oit is always infection) on the contrary
to leukemia. Pathogenesis is different as well – it is a hyperreactive but not
neoplastic hyperplasia of the leukopoietic tissue.
Leukemoid reaction is temporary, reversible and does not turn into leukemia.
There are two types of leukemoid reaction - myeloid and lymphoid in
dependance with type of cells, which underwent proliferation.
Blood Picture
Blood picture in leukocytosis is estimated by the total number of leukocytes

and leukoformula. It allows estimating whether the quantitative changes of
different forms of leukocytes are absolute or relative.
Young forms of neutrophile leukocytes appear in the peripheral blood –
nuclear shift to the left.
Degenerative changes in leukocytes are registered while investigation of the
blood smears.
Significance
Ultimately, in the majority of cases, leukocytosis has a positive value. It is a sign

of activated reactivity. Reactive hyperplasia of the leukocytic tissue leads to
increase of organism resistance. The most expressive defensive role of leukocytosis
is seen in inflammation and immune response. Neutrophile leukocytosis and
monocytosis have parallel participation in phagocytosis. As it was said, eosinophils
play a compensatory role in allergic reactions. Lymphocytes play a decisive role in
immune response.
At the same time, under other circumstances, leukocytes may be aggressive and
become a factor of damage. In the chapters “Inflammation” and “Allergy” double
and contradictory role of leukocytic reactions was discussed.
Neoplastic hyperplasia of leukopoietic tissue is always harmful oleukemia).
LEUKOPENIA
8
Leukopenia is a decrease of a total content of leukocytes in the peripheral
blood below 4 G/l.
Leukopenia several times was mentioned in the previous chapters. In radiant
disease it is a leading pathogenic link. The decrease of a quantity and functional
activity of lymphocytes underlies pathogenesis of immunodepression and
immunodeficiency.
Types
There are several classifications of leukopenia.

Acquited and genetically detetmined (heteditaty) leukopenia is distinguished
depending on participation of the genetic mechanisms.
Neuttopenia, eosinopenia, lymphopenia and monocytopenia are
distinguished depending on the type of leukocytes being decreased.
Absolute and telative.
Etiology
Etiological factors of leukopenia are those of external and internal medium,

which lead to the decreased formation of leukocytes in the bone marrow and
lymph nodes, their increased destruction or redistribution.
Etiological factors are divided into
• Physical oionizing radiation),
• Chemical, which are
Poisons, which possess leukodepressive quality,
Medicines oaspirin, amidopyrine, sulfanilamides, barbiturates,
cytostatics and hormonal preparations from the glucocorticoids),
Lack of vitamin B12 and folic acid
• Biological, which include
Infectious ohard infections, for example, typhus, virus of influenza,
measles, rickettsia toxin, agent of miliary tuberculosis),
Immune oeffect of antibodies against leukocytes),
Hormonal ostress, leukopenia of a redistributive type)
Genetic omutations)
Pathogenesis
There are some pathogenetic versions of leukopenia. They are:

o1) Decreased leukocyte production in the hemopoietic tissue
o2) Increased leukocytes destruction in the blood and hemopoietic tissue
o3) Excessive loss of leukocytes
o4) Redistribution of leukocytes in the vessels
o5) ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀ of leukocytes from the bone marrow
Decteased ptoduction of leukocytes is connected with disturbance of
leukopoiesis under effect of poisons and ionizing radiation, genetic and immune
factors, in deficit of leukopoetins etc omechanisms were discussed in detail at the
beginning of this chapter).
Incteased desttuction of leukocytes in the blood and hemopoietic tissue can
occur in
• Genetic ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ of the leukocytes, which prematurely get destroyed,
• Action of the immune antileukocytic antibodies, which cause cytolysis or
agglutination of leukocytes,
9
• Side-effect of the medicines odrug allergy), which can serve as hapten
stimulating the formation of antibodies against leukocytes,
• Hypersplenism oincreased lysis of leukocytes in spleen macrophages)
Excessive loss of leukocytes occurs with the large loss of pus in chronic
inflammatory diseases oin purulent bronchitis, purulent endometritis, purulent
processes in urogenitale organs).
Redisttibution of leukocytes in the vessels may be a reason of relative
leukopenia. It is observed, for example, in hemotransfusional shock, and is
characterized by altered ratio between the circulating and marginal pools of
leukocytes.
ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀ of leukocytes from the bone marrow into the blood
ЀЀЀЀЀЀ in genetically determined decrease of leukocyte mobile ability due to
defects of the membrane. It is the so-called syndrome of "lazy leukocytes', which
move very slowly.
The named pathogenetic variants refer to all types of leukopenia
but it may be total and partial, aquired and hereditary. Peculiarities of
some of them must be added to these general considerations about leukopenia.
Neutropenia develops in radiant disease, in a course of severe viral infections
oviral influenza, infectional mononucleosis, ЀЀЀЀ, AIDS) in protein starvation, as
a side-effect of medical drugs abuse.
Eosinopenia is observed in stress, Itsenko-Cushing disease, injection of
corticotrophin and corticosteroids ocortisone, prednisolon).
Lymphopenia develops in radiant disease, hereditary and acquired
immunodeficiency, stress, myxedema.
Monocytopenia is met in all syndromes and diseases, connected with the
depressed myeloid stem of the bone marrow oradiant disease, severe septic
conditions and agranulocytosis).
Leukopenia usually is combined with functional deficiency of
leukocytes.
o !! ЀЀЀЀЀ ЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ, ЀЀЀЀЀЀ ЀЀЀЀ ЀЀЀЀЀЀЀ, ЀЀ ЀЀЀ Ѐ
ЀЀЀЀЀЀЀЀ)
Aleukia is a total leukopenia. It is an aplastic damage of the bone
marrow, accompanied by an acute inhibition or total stopping of
leukocyte production. The alimentary-toxic form develops in eating
grains, infected by mould. Usually, pancytopenia oaleukia and
thrombocytopenia) is observed in such cases.
Manifestations and Significance
Hematologic manifestations of leukopenia consist in decrease of a total

quantity of leukocytes or only one form of them.
o!! ЀЀЀЀЀ ЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ, ЀЀЀЀЀЀ ЀЀЀЀ ЀЀЀЀЀЀЀ, ЀЀ
ЀЀЀЀ ЀЀЀЀЀЀЀЀ)
The main consequence of leukopenia at the level of entire organism is a
decrease of organism resistance caused by reduction of phagocytic
activity and antibody formation. Immunological and inflammatory
defensive reactions get reduced. Immunodeficiency is an example of the
genetically determined reduction in quantity and functional ability of
lymphocytes.
Such patients suffer from infectious and tumor diseases, especially
in hereditary neutropenia and deficiency of T- and B-lymphocytes.
The example of severe areactivity is AIDS.
Leukopenia always has negative value.
10
11
CHAPTER 22
LEUKEMIA
Leukemia is a pathology of the bone marrow of neoplastic nature.

In the chapter 10 “Neoplasia” the general laws governing the malignant growth
as a typical pathologic process were represented. This process can develop in any
tissue. At the same time, neoplasia has the specific features depending on its
localization. Consequently, all general considerations as to neoplasia (definition,
etiology, pathogenesis, manifestation and outcome) relate to leukemia as well. In
addition, leukemia, as neoplasia, has the specific features. So, a definition of
neoplasia as the limitless uncontrolled growth not connected with the general plan
of structure and function of organism can be referred to the leukemia as well.
Leukemia belongs to the group of hematopoietic tissue tumors called
hemoblastoses.
CLASSIFICATION
Classification divides leukemia into acute and chronic.

In acute leukemia the cells of the bone marrow of I-IV classes ЀЀЀЀЀЀЀЀЀ
ability to uncontrolled multiplication and have lost ability to differentiation. In a
case of chronic leukemia these cells ЀЀЀЀЀЀЀЀЀ ability to uncontrolled
multiplication but have not lost ability to differentiation.
Classification is grounded on morphological and cytochemical aspects and
divides leukemia depending on
• Predominance of the specific forms of leukocytes in the leukoformula.
Neoplastic transformation and growth of ЀЀЀЀЀЀЀ of the bone marrow or lymphoid
tissue (erythroid, myeloid, lymphoid, monocytic, megakaryocytic) lies in the
basis of classification.
• Point of the stopping of a differentiation of hemopoietic cells at a certain
intermediate stage, so a level of a differentiation.
An acute leukemia is divided into myeloblastic, lymphoblastic, monoblastic,
megakaryoblastic form as well as an acute erythromyelosis and nondifferentiated
form. A basic substrate of tumor growth appears the blast cell of the I-IV classes
of hemopoiesis that get lost their ability to mature and get proliferated. The
nondifferentiated form is originated from the cells of the II and III classes of
hemopoiesis, which are not identified morphologically.
The chronic leukemia is divided into myelocytic, lymphocytic, monocytic,
megakaryocytic and chronic erythromyelosis. The neoplastic transformation
occurs in the hemopoietic cells of II-IV classes but they mature up to the cells of
V and VI classes of hemopoietic system, which are determined in the peripheral
blood.
There are also the more detailed classifications of the leukemia based on
morphological, cytochemical, immunological and moleculogenetic peculiarities of
hemoblastosis, which are presented in the special literature.
ETIOLOGY
1
The etiological factors, which cause leukemia, are the same as that of neoplasia.
All of them are mutagens (cancerogens). They are divided into physical (ionizing
irradiation), chemical (carcinogens), biological (DNA- and RNA-containing
viruses) and genetic anomalies.
Ionizing Radiation
Ionizing radiation causes the radiant leukemia.

It increases the frequency of leukemia in patients, who underwent X-ray or
radioactive isotope treatment of malignant tumor of different localization. Leukemia is
among the consequences of nuclear weapons usage. There are datas about
increased frequency of leukemia in children exposed to radiation in uterЀ.
Increased causes of leukemia is observed in ЀЀЀЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀЀЀЀЀЀ.
Ionizing radiation causes the radiant leukemia in experimental animals.
Chemical Carcinogens
The same chemical carcinogens, which cause malignant tumors, cause leukemia
as well.
Chemical carcinogens may cause leukemia in people subjected to
ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ contact with certain substances (ЀЀЀЀЀЀЀЀ, ЀЀЀЀЀЀЀЀЀЀЀ) or to be
cured with medicines having a mutagenous effect (ЀЀЀЀЀЀЀЀЀЀЀ cytostatics,
immunodepressants, butadion, chloramphenicol, ЀЀЀЀЀЀЀЀЀЀЀ, ЀЀЀЀЀЀЀЀЀЀЀЀЀ).
ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀa ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ cause leukemia in experiment.
Oncogenic Viruses
In experiment, leukemia is caused by injection of the cell-free filtrate of tumor

cells from sick animal to healthy one.
The viruses itself can induce mutations. The role of oncornaviruses in leukemia
development is confirmed by the presence of the enzyme revertase (reverse
transcriptase or RNA-dependent DNA-polymerase) in the leukemic cells.
In normal DNA of men more then 60 protooncogens, which are ЀЀЀЀЀЀЀЀЀЀЀ to viral
oncogens, are revealed. They are activated under effect of different factors and provide
leukemia development.
Oncogenic viruses cause leukemia in birds, mice, cats, cattle, monkeys and other
animals. The virus can be transmitted with feces, urine and excreted from the nose
and pharynx (in visceral lymphomatosis in liens ЀЀЀЀЀ).
Role of Genetic Factors
Genetic peculiarities of hematopoiesis may also have an etiological role in

causing leukemia.
The most profound proves are experimental ones. It gets possible to create
ЀЀЀЀЀЀ ЀЀЀЀЀ ЀЀЀЀЀ with a high and low predisposition to leukemia.
«Family» leukemia (chronic lymphoid leukemia with dominant and recessive
types of inheritance), concordance of form, clinical and hematological signs of
leukemia in 1/3-1/4 of monozigotic twins is revealed.
Gemellary method confirms the value of genetic factors in leukemia etiology.
Patients with the chromosomal anomalies are predisposed to the leukemia
development. Somatic and sexual chromosome mutations and ЀЀЀЀЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀЀ nondisjunction of chromosomes predispose the organism to neoplasia.
Thus, the cases of leukemia are more frequent in patients with Down’s (in 20 ЀЀЀ),
2
Klinefelter and Shereshevsky-Terner’s syndromes. Chromosome mutations are
reveled in 80-90% patients with acute, in 90-97 % in chronic myeloleukemia and
50% in patients with chronic lympholeukemia. Mutation in 21st chromosome is
detected in patients with leukemia.
In genetic defects of immune system (as it was mentioned in the chapter 5) the
T-lymphocytic immunodefficiency increases the cases of malignant tumor
(including leukemia) in 1000 times.
The role of genetic factors in leukemia development is proved by high
frequency of leukemia in certain ethnic groups.
Chromosome mutations, which are found in leukemia, serve as its genetic
markers. Thus, an abnormal so-called Ph-chromosome (which was discovered in
Philadelphia City) is typical for chronic myelocytic leukemia. This chromosome
appears as a result of the 22nd pair chromosome deletion and translocation of the
separated segment to the 9th pair. Translocation of the 8th chromosome segment
to the 14th pair occurs in Berkitt lymphoma most likely with the Epsteine-Barr virus
influence.
Genetic factors often play a role of conditions. It means that an etiological factor
(ionizing radiation, virus) in some cases causes cancer of some organ, in other
cases – leukemia, depending on the genetic predisposition of the organism.
PATHOGENESIS
In leukemia, the neoplastic process develops in a hemopoietic tissue. As in any

other neoplasia, pathogenesis of leukemia proceeds in three stages – neoplastic
(leukemic) transformation, promotion and progression (observed in the chapter 10
«Neoplasia»). The first two are preclinical, the third is a terminal stage and obtains
clinical manifestations.
Peculiarity of neoplasm in the hemopoietic tissue lies in the fact, that solid
tumor is not formed in the bone marrow. Malignant cells (predecessors of
leukocytes) are mobile, leave bone marrow and appear in the peripheral blood
immediately after the process starts. They are found and can be calculated in the
smear of the patient blood at the beginning of the disease. According to peripheral
blood investigation, two stages of leukemic patogenesis are distinguished –
monoclonic and policlonic ones.
Neoplastic Transformation
Neoplastic transformation is a transformation of one normal cell of the bone

marrow or lymphoid tissue into malignant one. A primary formation of a
neoplasric clone takes place in the stem cells or precursors in the bone marrow
or in lymphoid tissue.
As to the mechanisms of the neoplastic transformation, two theories are
proposed – of mutative or epigenomic cancerogenesis (details are in the chapter
“Neoplasia”). In the case of leukemia, the oncogenic viruses, ionizing radiation
and chemical substances cause mutation of those genes, which are critical for
hemopoiesis. A theory of epigenomic cancerogenesis supposes disorder in
regulation of multiplication and maturation of hematopoietic cells.
Viruses can cause chromosomal translocation that results in transmission of
the oncogenes, localized in chromosomes, to the part of genome, where they can
be activated.
Penetrating into cell genome, viruses can activate protooncogenes, coding
various oncoproteins. Some of them serve as growth factors (thrombocytic,
epidermal, T-cellular etc.), others are the receptors to the growth factors, others
3
are proteinkinases, catalyzing phosphorylation of tyrosine. An ability to
transform normal blood cells into neoplastic ones are common for all
oncoproteins.
After neoplastic transformation, a clone of cells appears in the bone marrow,
which is characterized by immortality, unlimited growth aЀЀЀnЀЀЀЀЀЀЀ ЀЀЀЀЀ and
low ability to differentiate.
Neoplastic Promotion
Neoplastic promotion is a period, when a multiplication of the malignant cells of

hemopoietic tissue begins. Neoplastic malignant cells appear in the peripheral
blood. It is a monoclonic stage of leukemia development (one clone of the
primarily transformed hemopoietic cell appear in the blood).
In comparison with normal cells, which after 4-6 divisions start to differentiate
into mature cells without mitotic activity, in acute leukemia leukemic cells
actively proliferate without maturation. They are morphologically and
cytochemically undifferentiated. In monoclonic stage all the cells have the same
geno- and phenotype, the same antigene, chromosomal and biochemical markers.
Leukemic cells do not need stimulators of growth because having its own.
Among them there is IL-2 from leukemic lymphocytes, which serves as a
stimulator. Leukemic cells obtain ЀЀЀЀnЀЀЀЀЀ growth.
Normal hemopoietic cells continue to be formed in this stage of leukemia. The
changes in other organs are absent. It is a preclinical stage. Nevertheless, typical
changes in the blood are already revealed.
Neoplastic Progression
Neoplastic progression is characterized by aggravation of the malignant

properties of neoplastic cells.
There are several explanations to the neoplastic progression, which are
presented in the chapter “Neoplasia”. One of them lies in the fact, that malignant
cells undergo additional mutations. Instability of leukemic cell genome leads to
appearance of new mutations, both spontaneous and caused by primary or new
oncogenic factors, that result in appearance of new tumor clones. Leukemic
tissue becomes gene- and phenotipically ЀЀЀЀЀЀЀЀЀЀЀЀ.
It is the so-called polyclonic stage of leukemia.
Selection of the most malignant cells takes place. They avoid the immune system
supervision. Among cells, which are subjected to the cytostatic medical drugs
(chemical, hormonal and radioactive), some of them would be destroyed (maturer),
but the most malignant cells are resistant to these effects. Just they get multiplied
as a result of such selection.
Therapy of leukemia with cytostatic medical drugs as well as by ionizing
radiation and radioactive substances becomes ЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀ in polyclonic stage.
Thus, leukemia has two stages of its development: monoclonic and
polyclonic. Transition of one stage into another is an indicator of the neoplastic
progression.
Leukemic cells may spread ЀЀ ЀЀЀЀ ЀЀЀЀЀЀЀ ЀЀЀЀЀ Ѐ ЀЀ ЀЀ ЀЀЀЀeЀЀЀЀ
(ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ) forming leukemic infiltrates in lymphonodes, spleen, liver and
other organs.
ЀЀЀЀЀЀЀЀЀЀ of mature leukocytes in the blood (in chronic lympholeukemia)
ЀЀЀЀЀЀЀЀЀЀЀ not only by their increased formation but ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ, when
mature cells ЀЀЀЀЀ ЀЀ ЀЀЀЀЀЀЀЀ.
4
Disorder of Other Stems of Bone Marrow
In leukemia, the hemopoiesis is disturbed first of all in the cells, where the
neoplastic transformation occurred. As the clones of malignant leukemic cells have
a prevalence above normal hemopoietic cells, and due to their fast growth, they
occupy bone marrow and ЀЀЀЀЀЀЀЀЀ displace the normal ЀЀЀЀЀЀ stems of the bone
marrow.
Malignant cells substitute parenchyma of the bone marrow and its normal
microenvironment. Differentiation of the cells-precursors of normal stems of
hemopoiesis gets inhibited. The neoplastic myeloid tissue displaces the erythroid
and thrombocytic ЀЀЀЀЀЀ of the bone marrow. ЀЀЀЀЀ ЀЀЀЀ, leukemic cells excrete the
factors, which activate ЀЀЀЀЀЀЀ of other cells. Inhibition of normal erythro- and
thrombopoiesis results in symptoms of anemia and hemorrhage.
MANIFESTATIONS
The manifestations of leukemia are local (changes in the malignant cells of the
bone marrow and peripheral blood) and systemic (in the whole organism).
Anaplasia and Metaplasia
Anaplasia and metaplasia of leukemic cells are the local manifestations.

Conception about neoplastic anaplasia and metaplasia (see the chapter
«Neoplasia») refers to leukemic cells as well. It means, that the leukemic cells
only ЀЀЀЀЀЀ resemble the normal precursors of leukocytes. Special research reveals
the differences.
Morphological anaplasia and metaplasia concerns the morphological
peculiarities of the leukemic cells. There can be various degenerative changes in
nucleus and cytoplasm of leukocytes observed, their vacuolization, morphological
and cytochemical atypicity, making identification of the cells difficult.
Biochemical anaplasia concerns the changes of their enzymal composition,
pH, chemical and biophysical properties. There are bio- and cytochemical markers
of leukemic cells. Positive reaction ЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ, nЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ,
ЀiЀЀЀЀ ЀЀЀЀЀЀЀЀЀ are detected.
Immunilogical anaplasia lies in antigene simplification and obtaining new
embryonic antigenes. In leukemic cells the immunological markers of stem cells
are detected. So, not only biochemical but also immunological identification of
leukemic blasts is possible.
Functional anaplasia consists in functional disorders of the transformed
leikocytes (immunoglobulins and enzymes synthesis, BAS formation,
phagocytosis). In policlonic stage the leukocytes completely loose their functions
thou in monoclonic stage the function at any rate is present.
Clinical manifestations are identical to all types of leukemia. They are fatigue,
weakness, fever, night perspiration, decrease in weight, exhaustion of organism.
Several pathophysiological syndromes determine them. They are – anemia,
hemorrhage syndrome, DIC-syndrome, syndrome of immunological insufficiency,
some extramedullar syndromes of ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ together
with hematological syndrome, which is different in various types of leukemia.
Acute leukemia leads to death of patient in several weeks. Cancerous cachexia
and secondary infection are the reasons of death.
5
Anemic Syndrome
Anemia develops obviously in all patients with leukemia. As to its pathogenesis

it is predominantly diserythropoietic one (hypoplastic and metaplastic). Partially it
is hemolytic one. Autoimmune hemolysis of erythrocytes occurs in
lympholeukemia. Posthemorrhage mechanism of anemia development takes place
due to hemorrhages.
Hemorrhage Syndrome
Hemorrhage syndrome is determined by decrease of thrombocyte amount

(thrombocytopenia). In addition to it there is a functional insufficiency of the
platelets in leukemia (thrombocytopathy). A damage of vessel wall by leukemic
infiltrates plays a role. Very often just hemorrhage is a reason of patient death.
DIC-Syndrome
DIC-syndrome while leukemia is a consequence of significant disorders of

hemostasis. Simultaneous activation of all systems of hemostasis may take place.
A lot of procoagulants are revealed due to enormous distraction of leukemic cells
(thromboplastin, which determines intravascular coagulation). Plasminogen may
be activated. All this events provoke thrombosis and then also hemorrhage.
Syndrome of Immunological Insufficiency
Syndrome of immunological insufficiency is connected with a depression of

normal granulo-, monocyto- and lymphocytopoiesis, which promote a disorder of
the immune reactions of organism. A disorder of immunological reactivity is an
obvious manifestation of leukemia. Humoral and cellular immune reactions get
inhibited. Malignant leukocytes do not perform their functions (phagocytosis and
antibody formation). It leads to the immune supervision deficiency as well as
secondary autoinfection development. The pathology may lead to forbidden cell
clones formation, which are able to synthesize antibodies to own tissues.
Autoimmune process is possible.
Extramedullar Syndromes ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ
Extramedullar syndromes develop in various organs and are the manifestations

of leukemia as well. They are a result of a damage of different organs with -
• Leukemic infiltrates
• Appearance of toxical substances, which are revealed from the damaged
organs in a grate amount
For example, some neurological symptoms (ЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀ) may appear due
to leukemic infiltrates of ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ, parts of the brain and spinal cord,
ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ. Disturbances of a skin and mucous membranes (gingivitis,
stomatitis etc.), diseases of joint and bones, other organs (lungs, heart, kidneys,
testicules etc.) with a correspondent symptomatology and signs of their
insufficiency must be added.
BLOOD PICTURE (HEMATOLOGICAL SYNDROME)
6
The total quantity of leukocytes in the peripheral blood more often is increased.
Depending on the degree of this increase the leukemia is divided into leukemic
(increase to 50-200-500 G/l and more) and subleukemic (slightly increased up to
50 G/l ) forms. But there is a leukopenic form (less then 4 G/l) and aleukemic
form with normal amount of leukocytes in the blood.
Since the cells of hemopoietic tissue are mobile, their malignant forms appear
in the peripheral blood and the diagnosis of leukemia type is based on the
leukoformula.
Hyperregenerative nuclear shift to the left always detected. It means appearance
in the peripheral blood of a large quantity of immature leukocytes up to blast cells.
The blood picture in various types of leukemia is different and has the decisive
diagnostic value.
Acute Myeloleukemia
In acute myeloleukemia the youngest forms of neutrophiles, eosiniphiles and

basophiles are present in the leukoformula. Appearance of a large number of blast
cells in the blood is typical for acute leukemia. Blast cells are identified with the aid
of cytochemical and immune methods.
The special feature of leukoformula lies in the fact, that only the youngest
forms (myeloblasts) and the mature neutrophiles (segmentonuclear) are present.
The intermediate forms between blast cells and mature neutrophile granulocytes
(promyelocytes, myelocytes, metamyelocytes, stab-nuclear) are absent (fig. 33).
This phenomenon is called leukemic (nuclear) gap ЀЀЀЀЀЀ (hiatus leukemicus).
___________________________________________________________________________
Fig. 33. Blood picture in acute myeloleukemia

1 - myeloblasts
ЀЀЀ. IV ЀЀ ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ
Leukemic (nuclear) gap reflects a serious disorder of leukopoiesis in

hemopoietic organs — loss of an ability of neoplastic cells to differentiate.
Maturation of neutrophiles in bone marrow does not occur. Only myeloblasts are
multiplied, and they fall into the peripheral blood. The mature neutrophiles, which
are determined in peripheral blood, are those, which were formed earlier, before
the beginning of a disease. The lifetime of mature neutrophiles is short.
Consequently, this situation lasts about some weeks and then a patient dies.
Chronic Myeloleukemia
In chronic myeloleukemia, neoplastic clone appears in stem cells but the larger
part of them maturate in the bone marrow. It is a tumor, which consists preferably
from the cells of V and VI classes. With the microscopic examination of the
peripheral blood it is possible to see the granulocytes of any degree of maturity.
The picture of the peripheral blood resembles the picture of the bone marrow. The
hyperregenerative nuclear shift to the left is noted, but the phenomenon of
leukemic nuclear gap is absent (fig. 34).
______________________________________________________________
7
Fig. 34. Blood picture in chronic myeloleukemia
1 –myeloblast
2 – promyelocyte
3 –neutrophilic myelocyte
4 –neutrophilic metamyelocyte
5 –baton-like? stab? neutrophile granulocyte
6 –segmentonuclear neutrophile granulocyte
7 –eosinophile myelocyte
8 – eosinophile granulocyte
9 – basophile granulocyte
10 – lymphocyte
ЀЀЀ. V ЀЀ ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ

__________________________________________________-
Increased number of neutrophilic metamyelocytes, "bilobe" myelocytes,

promyelocytes and single myeloblasts is typical for chronic leukemia.
The number of eosinophilic and basophilic granulocytes is increased
(eosinophilic and basopholic leukocytosis).
The terminal stage is characterized by the so-called blast crisis. It is a sudden
stopping of myeloblasts maturation. The blast cells (myeloblasts and
nondifferentiated blasts) appear in the peripheral blood. It is a manifestation of
neoplastic progression – ЀЀЀЀЀЀЀЀЀ of a new clone of the cells, which have lost
ability to maturation.
Lymphoid Leukemia
Lymphoid leukemia is the neoplastic transformation of lymphoid tissue.

Chronic lymphoid leukemia is characterized by absolute and relative
lymphocytosis.
Lymphocytes are mostly mature. The majority of the lymphoblasts is matured
up to the end (B-lymphocytic kind of leukemia is more common). In the leukocyte
formula the quota of mature lymphocytes reaches 80-90% (relative and absolute
lymphocytosis with relative neutropenia). There are single prolymphocytes and
lymphoblasts in the leukoformula (fig. 35). Ѐ ЀЀЀЀЀ ЀЀЀЀЀ it is possible to see the so-
called ЀЀЀЀ ЀЀЀЀЀЀЀЀЀ (lymphocytes Ѐ ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ).
_____________________________________________________________
Fig. 35. Blood picture in chronic lympholeukemia
1 –lymphocyte
2 –large lymphocyte
3 –lymphoblast
4 – ЀЀЀЀ ЀЀЀЀЀЀЀЀЀ
ЀЀЀ. VI ЀЀ ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ
Absolute number of neutrophiles may remain normal taking into consideration

a significant increase of total quantity of leukocytes (above 120 G/l).
The course of a disease is chronic and flows for years. Nevertheless,
sometimes, the total substitution of all hemopoietic stem cells by lymphocytic one
occurs (lymphoid metaplasia of myeloid tissue).
8
The development of the so-called blast crisis is possible (blast crisis occurs
rarely in this form of leukemia - 3-4%). At this moment the maturation of
lymphoblasts stops. Many lymphoblasts appear in the peripheral blood. Patient can
die in this stage of lymphoid leukemia development.
9
CHAPTER 23
PATHOPHYSTOLGY OF HEMOSTASTS
As to the term hemostasis (do not be confused with the term homeostasis), it is
translated as a stopping of a bleeding and hemorrhage.
Actually, at the beginning of the scientific study of a coagulation system of the blood,
the participation of thrombocytes and blood proteins in thrombosis and stopping of
bleeding was discovered (systems of coagulation and anti-coagulation). Later a question
arose about the function of these mechanisms, when there is no blood loss. It becomes
clear, that all these systems participate in keeping a liquid state of the blood as well.
Therefore, an old term hemostasis obtained a new determination. Hemostasis is a
function of organism as to keeping a liquid state of the blood and its coagulation, when it
is necessary.
Consequently, it is possible to give the following definition of the pathology of
hemostasis.
The pathology of hemostasis is a disorder of keeping a liquid state of the blood
and its coagulation in response to the damage of vessels.
The examples of hemostasis pathology were mentioned in the previous chapters -
radiation disease (hemorrhages as a result of lack of thrombocytes), genetic disorders
(coagulopathy), allergy, thrombosis, leukemia. In this chapter pathology of this system
will be represented.
MECHANTSMS OF HEMOSTASTS
Physiological and biochemical mechanisms of hemostasis are represented in detail in a

course of normal biochemistry and normal physiology. Below it is a brief reminding for
the purpose of mastering a theme about pathology.
The system of hemostasis has many components. These are platelets and other blood
cells, vessel's wall, extravascular tissue, biological active substances, vascular and tissue
factors (extrinsic pathway), plasma factors of the blood clotting (intrinsic pathway), which
are in a close interaction with kallikrein-kinin system.
There are two mechanisms of hemostasis
• Coagulative hemostasis, ЀЀЀЀЀЀЀЀЀЀЀЀЀЀ
• Thrombocyto-vascular hemostasis. ЀЀЀЀЀЀЀЀЀ-ЀЀЀЀЀЀЀЀЀЀЀЀЀЀ
Coagulative Hemostasis
Coagulative hemostatic system consists in blood proteins and is subdivided into three
groups of mechanisms.
1. System of the blood coagulation consists in blood proteins - procoagulants. The
blood coagulation proceeds in three stages (formation of ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ,
thrombin and fibrin). Fibrin is a final product of coagulation. Then the retraction of the
fibrin fibers takes place (by thrombastenin from the platelets). Vitamin K participates in a
coagulative system (in synthesis of II, IX and X factors).
2. System of the blood anticoagulation consists in anticoagulants. Heparin is an
important substance.
1
3. System of fibrinolysis provides a dissolution of fibrin fibers by plasmin, which is
present in the blood in inactive form (plasminogen, or profibrinolysin) and is activated by
many factors (see below).
Thrombocyto-VasЀular Hemostasis
Plasmic factors and their participation in hemostasis attracted attention of scientists at

fist. Latter it became clear, that important role in keeping a normal reological state of the
blood belongs to thrombocytes and vascular wall (under physiological circumstances the
platelets are situated near endothelium interrelating with it). Just to them belong
initiation of blood coagulation and thrombogenesis after damage of the vessels and a
danger of blood loss.
Thrombocyto-vascular hemostasis is subdivided into two groups of mechanisms
mentioned below.
Participation of the Platelets
Participation of the platelets plays a central role in hemostasis. Their function consists
in
• Angiotrophic function with respect to the endothelium of vascular wall, which
ЀЀЀЀЀЀЀЀЀЀЀЀ to keeping of a liquid state of the blood
• Blood coagulation after a damage of a vessel (aggregation, adhesion to endothelium
and formation of thromboplastin, which starts the coagulation of the blood)
• Production of prostaglandins (thromboxan), as initiators of platelets aggregation after
damage of a vessel
• Formation of the primary (only by thrombocytes) thrombus after vessel damage
• Production of vasoconstrictive substances (serotonin, adrenaline, noradrnaline), which
contribute to bleeding to stop
Participation of the Vessel Endothelium
Participation of the vessel endothelium in hemostasis consists in two functions -

antithrombic (under physiological conditions) and prothrombic (after injury of a vessel).
The antithrombic function of endothelium provides the so-called thromboresistance –
prevention of aggregation of the platelets and consists in keeping a liquid state of the
blood. This function is carried out with the aid of several mechanisms:
• Production of prostacyclin (PG), which prevents the platelets aggregation
• Distruction of agents (such as ADP), which stimulate thrombocytes aggregation
• Production of sulfated mucopolysaccharide, which resembles a heparin
(anticoagulant)
• Plasminogen activation, which initiates fibrinolysis and prevents shaping of
intravascular clusters
The prothrombic function of endothelium provides and initiates blood coagulation
after injury of a vessel starting thrombogenesis. This function is carried out with the aid
of
• Thromboplastin formation
• Production of the Villebrand,s factor, which initiates thrombogenesis (activating
factor VIII). It is produced in endothelium but is accumulated in the platelets and releases
during their degranulation. Thrombocytic clot can not be formed without it. This factor
is necessary for the thrombocytes aggregation and stimulates an adhesion of platelets to
collagen of a vessel wall. Special receptors to this factor are revealed on the thrombocyte
membrane.
2
Reological state of the blood depends on the balance of all named systems. Disorder
of any of these component leads to hemotasis pathology.
CLASSTFTCATTON OF HEMOSTASTS PATHOLOGY
Some classifications of hemostasis disorders are suggested.

1. Hypocoagulation and hypercoagulation are distinguished according to direction of
a disorder.
2. Local (thrombosis, ЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ) and systemic (blood loss, including
generalized DIC-syndrome) disorders are distinguished according to localization.
3. Acquired and hereditary (coagulopathy, thrombocytopathy, angiopathy) disorders
are distinguished according to participation of genetic mechanisms.
Hemorrhage syndrome (corresponds to hypocoagulation), thrombophilic syndrome
(corresponds to hypercoagulation) and DIC-syndrome (disseminated intravascular
coagulated syndrome) are the clinical terms, which determine the disorders of
hemostasis.
In addition, the clinical situations may be acute and chronic. The acute situations refer
to the urgent medicine as an acute hemorrhage, thromboembolism as well as
disseminated general intracellular coagulation, which may lead to death in absence of
the immediate medical help. As a chronic situation, the widely spread disease as a
chronic thrombophlebitis may serve as an example.
Sometimes, as it is in anaphylactic shock, hypo- and hypercoagulation occurs at the
same time – hypocoagulation in the large vessels and hypercoaglation in microcirculatory
bed.
ETTOLOGY AND PATHOGENESTS
Etiological factors of hemostasis pathology may be exogenous and endogenous as

well as physical (mechanical injury of platelets as it is while ЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀЀ, ionizing radiation), chemical (medicines, overdose of heparin) and biological
(microorganisms, viruses, immune and genetic factors). Etiology of various types of the
hemostasis pathology is different.
Pathogenesis of numerous clinical and pathophysiological syndromes (hypo- and
hypercoagulation, hemorrhage, excessive thrombogenesis, DIC-syndrome) is different
depending on what is a primary disorder (quantitative and qualitative changes in
platelets, diseases of the vessels, liver pathology, disorder of plasma proteins synthesis
etc.). Pathogenesis is just opposite in two leading syndromes - hypo- and
hypercoagulation.
HYPOCOAGULATTON
Syndrome of hypocoagulation (hemorrhagic syndrome) is a tendency toward a

hemorrhage starting spontaneously or due to a non-significant damage.
(ЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀ! ЀЀЀ ЀЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀ, ЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀ ЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀ
blood loss, bleeding Ѐ ЀЀЀЀЀЀ ЀЀЀЀЀЀЀ hemorrhage – ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ. ЀЀЀ ЀЀЀЀ? ЀЀЀЀЀЀЀЀ?)
Hypocoagulation may ЀЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀЀЀЀЀЀ.
ЀЀЀЀЀЀЀЀЀЀЀЀЀ is a ЀЀЀЀЀЀЀЀЀ of a blood in a tissue - in skin, joints, mucous membranes,
internal organs, etc. In a place of ЀЀЀЀЀЀЀЀЀЀЀЀЀ morphological and functional changes
develop. KЀЀЀЀЀЀЀЀЀЀЀe into the brain is especially dangerous. Hypocoagulation prolongs
ЀЀЀЀЀЀЀЀЀЀЀe blood loss. Hypocoagulation leads to acute or chronic posthemorrhagic anemia
and hemic hypoxia if a blood loss would be essential.
3
Pathogenesis of hypocoagulation consists of five groups of mechanisms mentioned
below:
• Lack of plasma procoagulants
• Surplus of anticoagulants
• Activation of fibrinolysis
• Deficit of platelets
• Pathology of vessels (hemorrhage vasopathy)
Lack of Plasma Procoagulants
Causes of procoagulants deficit may be acquired or hereditary.

Acquired deficit of the procoagulants occurs in the following cases.
• Diseases of the liver, affected by various pathological factors. Just in the liver, all
procoagulants (prothrombin, fibrinogen, anti-hemophilic globulin and others) are
synthesized. Any stage of coagulation may be disturbed in a disorder of the protein-
synthetic ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ function of the liver.
• K-hypo- and avitaminosis leads to disorder of the second phase of coagulation because
synthesis of factors II, VII, IX, X are K-vitamin-dependant.
• Autoimmune aggression towards the protein-procoagulants. Immune antibodies block
some of them. A production of antibodies to VIII, IX factors is revealed in the diffuse
autoimmune diseases of a connective tissue.
• Radiation disease has in its pathogenesis a disorder of a molecular structure of fibrin.
As a result, fibrin fibers lose ability to construction and a blood clot – to retraction.
• Enteritis, resection of the small intestine and dysbacteriosis may lead to II, V, VII factors
synthesis decrease (disorder of suction of K-vitamin). Some medicines (streptomycin sulfate)
may cause the same effect.
• Increased consumption of procoagulants takes place in the first stage of DIC-syndrome
(see below).
All these causes disturb one or another or all stages of blood coagulation.
Hereditary deficiency of the protein-procoagulants (coagulopathy) occurs as a result
of a mutation of genes, which are responsible for procoagulants synthesis. Hemorrhage
occurs in genetic defects of IX-anti-hemophilic globulin, VIII and XI factors synthesis
(in hemophilia A, B, C) and genetic deficiency of factor V in parahemophilia. Genetic
hypo-, afibrinogenemia and defect of fibrinstabilizing factor (XIII) are revealed.
Surplus of Anticoagulants
Surplus of anticoagulants occurs in their increased synthesis or activation

(anaphylactic shock) as well as in overdose of medical drugs with anticoagulant effect
(more often heparin).
Heparin is an important substance of the anticoagulative system. It releases during
degranulation of the mast cells (inflammation and allergy) and regulates the local
thrombogenesis. It is widely used in clinical practice as a medical drug. In a case of its
overdose or increased sensitivity to it, a disorder of systemic thrombogenesis and
hemorrhage develop.
Activation of Fibrinolysis
Disorder of the third stage of hemocoagulation more often is a result of

fibrinolysis activation, which ends in hemorrhage. It occurs under influence of
exogenous and endogenous factors, which activate plasminogen. They are
• Bacterial and tissue fibrinokinase
4
• Immune complexes
• ЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ
• Complement
• Components of the kalikrein-kinin system
• Complexe of heparin with fibrinogen, profibrinolysin and adrenaline (provide
nonenzyme fibrinolysis)
The most actual clinical examples of hemorrhage due to activation of fibrinolysis
are the following:
• Microbial infection by alpha-hemolytic streptococcus (rheumatoid endocarditis)
• Massive trauma (including a surgery on the parenchymatous organs) of the lungs,
liver, uterus, pancreatic gland
• Crush syndrome
• Anaphylactic shock
• Tripsinogen activation in pancreatitis
• Massive burns
• Overdose of fibrinolytics as medical drugs
PATHOLOGY OF THE PLATELETS
Pathology of the platelets, which leads to bleeding, consists in their quantitative

(changes in number) and qualitative (changes of function) disorders. There are two forms
of the pathology, which lead to the hypocoagulation - thrombocytopenia and
thrombocytopathy. In both cases hemorrhage occurs.
Thrombocytopenia
Thrombocytopenia is a decrease in the quantity of thrombocytes in peripheral blood

(norm is 180-320 G/l). However, spontaneous bleedings occur in the case of
decreasing of their number down to 30 G/l.
Etiology
Etiological factors, which cause thrombocytopenia, are exogenous and endogenous, in

turn, physical, chemical and biological. They are
• Mechanical damage of platelets in cases of splenomegaly and artificial cardiac
valves
• Ionizing radiation (effect of aggressive forms of oxygen and radiotoxins)
• Chemical toxic substances
• Side-effect of medicines, which may change antigen structure of the thrombocytes
(acetylsalicylic acid)
• Viral infection, which may change antigen structure of the thrombocytes
• Endogenous metabolites (in uremia, cirrhosis of the liver)
• Deficiency of thrombocytopoietins
• Deficiency of cyanocobalamin and folic acid
• Hormonal disorders (hypothyroidism)
Pathogenesis
There are the following mechanisms of thrombocytopenia development:

• Damage of the megakaryocytic stem of the bone marrow
• Replacing of megakaryocytic stem of the bone marrow by tumor metastases,
leukemic infiltrates (in chronic leukemia)
5
• Suppression of thrombocytopoiesis due to pathology of megakaryocytic stem of the
bone marrow, deficiency of thrombocytopoietin
• Increased destruction of platelets in the blood under effect of external and internal
mechanisms – by bacterial toxins, virus of herpes, macrophages as well as in
autoimmune aggression against own thrombocytes (immune reactions in case of
changing of antigen structure of thrombocytes affected by viruses, medicines,
incompatibility of thrombocytic antigens of a mother and embryo)
• Increased consumption usage of platelets while a local or generalized intravascular
blood coagulation
As a consequences, it is a predisposition to hypocoagulation and hemorrhage, a
tendency toward a hemorrhage starting spontaneously or due to a non-significant damage.
In pathogenesis of bleeding such mechanism play a role -
• Disorder of the thrombocyto-vascular hemostasis, decrease of adhesive-aggregational
capacity of the platelets
• Deficit of the thrombocytic factors for blood coagulation
• Deficit of ADP, serotonin, adrenaline, antiheparin factors that leads to insufficiency
of platelet clot formation
• Decreased ЀЀЀЀЀЀЀЀЀ retraction contraction of fibrin as a result of suppressed activity of
constrictive protein of platelets (thrombasthenin)
• Insufficient throphicity of endothelium (vessel wall dystrophy), decrease of the
vessels solidity, increased permeability of the capillaries for erythrocytes (diapedesis) and
other components of the blood
• Decreased contractive ability of the vessels due to deficit of serotonin and adrenaline
from platelets
Thrombocytopathy
In clinics one may notice the diseases, which are manifested by a predisposition to
hemorrhage in normal number of the thrombocytes. It becomes clear, that a matter is with
their functional disorder, when they do not react properly on vessel injury by initiating of
coagulation and thrombogenesis. Stopping of blood loss ЀЀЀЀЀЀЀЀЀЀЀ, intratissue
hematomes get formed. It is a thrombocytopathy.
Thrombocytopathy means qualitative defects and dysfunction of thrombocytes. The
causes are more often genetically determined.
The following genetic defects of the membrane structure and biochemical composition
of platelets can underlay it:
• Enzymopathy (deficiency of G-6-PDG)
• Membranopathy (deficiency of membrane receptors for V, VIII, XI factors)
• Defect of platelets constrictive protein (thrormbasthenin) synthesis
• Deficiency of energy formation in form of ATP
• Deficiency of ADP, adenaline, serotonin, thromboxan
The factors mentioned above, are the reasons of the formation of pathological platelets
in the bone marrow.
The extrinsic pathway of hemostasis is disordered in the same way in
thrombocytopathy and thrombocytopenia, because it is connected with disorder of
platelet function. In both cases predisposition to bleeding takes place.
Speaking about pathophysiological disorders and clinical manifestations, nЀЀЀЀЀЀЀ to
repeat that it was discussed above. All necessary properties and functions of the platelets
get disordered - adhesive-aggregative capacity, synthesis of the active substances,
primary thrombocytic thrombus formation, initiation of hemocoagulation. Synthesis of
thrombocytic factors of coagulation, thromboxan, serotonin, constructive protein
6
(thrombasthenin) gets suppressed. Vascular wall throphicity gets disordered, the vessels
loose their ability to contraction as well as its solidity.
As a result, a thrombocyto-vascular hemostasis gets disordered. Hemorrhages develop
spontaneously or after insignificant damage of the vessels.
Functional disorders of thrombocytes may be acquired. For example, in abuse of
aspirin, as it is widely known, predisposition to bleeding is revealed. Inhibition of
cyclooxygenese activity by aspirin underlies this pathology.
PATHOLOGY OF VASCULAR WALL
HEMORRHAGTC VASOPATHY
In clinics one may see a predisposition to hemorrhage in patient without neither

pathology of coagulative system nor pathology of thrombocytes. It goes about pathology
of a vascular wall.
Hemorrhagic vasopathy is a disorder of hemostasis in a form of the hemorrhages
as a result of the primary vascular wall pathology.
Etiology
Etiological factors may be exogenous (physical, chemical and biological) or

endogenous (immunological, genetic), acquired and genetic.
The acquired forms develop as a result of
• Effect of ionizing radiation
• Side-line effect of medicines
• Viral infection
• Effect of various factors, which cause inflammation of vessels, including immune
factors (autoimmune aggression against endothelium)
• Effect of biological active substances (allergy)
• Nutritious deficiency of vitamin C, which results in reduction of collagen synthesis
• Disorder of vascular trophicity as an effect of thrombocytopenia
• Destruction of vascular walls as a secondary effect of leukemic infiltrates
• Disorder of the nervous and hormonal regulation of vascular tonus
Genetic forms of hemorrhage vasopathy develop as a result of the mutations of genes,
which are responsible for synthesis of endothelial proteins (enzymes, collagen,
contractile proteins and other) and receptors. Hereditary Willebrand disease is an
example. An absence of receptors for this factor underlies this disease.
Pathogenesis
Damage of the vessels under exogenous and endogenous factors results in

inflammation and impairment of endothelium participation in hemostasis (hemorrhagic
vasculitis). Dystrophy has the same result.
All immune complexes may be absorbed on endothelium (under effect of microbes,
viruses, medical drugs) causing autoimmune inflammation.
Hemorrhage syndrome is also observed in activation of membrane phospholipids
peroxide oxidation. It results in hyperproduction by endothelium of strong inhibitor of
platelets aggregation — PG prostacycline .
Disorder of the thrombocyto-vscular hemostasis takes place. Vessels loose ability
for construction, endothelium losses an ability for production of active substances
(prostaglandins, procoagulants).
Vessels loose solidity ЀЀЀЀЀЀЀЀЀ due to defect of collagen synthesis (collagen is an
activator of thrombocytes; if collagen would ЀЀЀЀЀЀЀЀЀЀЀ or its synthesis gets disordered,
then adhesion of platelets and their ЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀ get impaired).
7
Predisposition to bleeding occurs.
HYPERCOAGULATTON
THROMOPHTLTC SYNDROME
Syndrome of hypercoagulation, or thrombophilic syndrome, is a tendency

toward thrombogenesis spontaneous or due to insignificant damage of vessels.
Increase of the blood coagulation displays as local thrombosis or generalized
intravascular blood clotting. Thrombophilic disease causes vascular occlusion and is a
source of emboli.
In heavy cases a formation of thrombi is possible not only in veins, where a speed of
the blood flow is slower (Virhov declared it as a necessary condition of thrombogenesis)
but also in arteries.
Etiology
Mechanical trauma is the most often cause of the blood coagulation. In this case a
formation of the blood clots (thrombi) is a defensive reaction and has positive
significance.
In pathology, the causes are preferably endogenous. All types of injury of vessels
(inflammation, dysthrophy, atherosclerosis of the vessels, formation of fibrous ЀЀЀЀЀЀ
etc.) may lead to excessive clot formation.
Genetic factors may underlie a predisposition to hypercoagulation. In such cases, all
other reasons play a role of conditions. Even a small quantity of clot-promoting
substances can induce intravascular coagulation on the ground of genetical
predisposition.
More details are below.
Pathogenesis
In pathology, two principle pathogenic mechanisms underlay hypercoagulation: (a)

activation of the coagulative system of the blood or (b) deficiency of anticoagulative
system. As to localization of a primary cause the machanisms may be connected with
pathology of blood proteins, pathology of thrombocytes or endothelium. In the latter case
we speak about decrease of endothelium thromboresistance.
The pathogenesis of hypercoagulation includes the following mechanisms.
• Increased formation of procoagulants due to massive injury of tissues (including
massive operative trauma and the crush-syndrome)
• Increased production of blood clotting activators
• Increased quantity of thrombocytes (thrombocytosis)
• Deficit of XII-factor ЀЀЀЀЀЀЀЀ
• Fibrinolysis failure (deficit of profibrinolisin)
• Reduction in the quantity of anticoagulants, first of all, heparin as well as antithrombin
III
• Activation of the prothrombic function of the endothelium during its chronic damage,
inflammation of vessels (allergic and autoimmune), atherosclerosis
• Decrease of the antithrombotic function of endothelium (decreased quantity of
prostacyclin or sensitivity to it)
• ЀЀЀЀЀЀЀЀ ЀЀЀЀЀ Hemoconcentration
8
Hypercoagulation results in disorder of blood circulation, local hypoxia, disorder of
function of organ, where an excessive formation of blood clots takes place.
Below there are the most actual clinical examples, when hypercoagulation becomes a
problem.
Thrombophlebitis is a widely spread surgical disease connected both with chronic
inflammatory damage of veins and activation of coagulative systems. Throphical ulcers
and necrosis are often outcome of this disease. Thromboembolism is another
complication of this disease.
Disorders of lipid metabolism (its activation) are accompanied with thrombosis. It is
connected with the relative lack of heparin (since heparin besides the function as
anticoagulant fulfills a function of a lipase activator). Consequently, obesity is
accompanied with tendency toward thrombogenesis and thromboembolism. The same
situation happens during the disorder of lipid metabolism in atherosclerosis, which in
addition is accompanied with a constant injury of vessels.
Diabetes mellitus has an atherosclerosis as a complication, hence, with thrombosis.
Trombosis of the vessels of the microcirculation is noted in allergy.
In some malignant tumors (carcinoma of mammarial gland, lungs) the procoagulant
may be produced excessively.
Postoperative thrombosis is connected with excessive formation of procoagulants.
Sepsis is accompanied with thrombosis due to disorder of the anticoagulant function of
the vascular wall due to its damage by bacterial toxins.
DTSSEMTNATED TNTRAVASCULAR BLOOD COAGULATTON

(DTC-Syndrome)
Disseminated (generalized) intravascular blood coagulation (DIC-syndrome) is the

gravest form of the hemostasis pathology. Frequently it is lethal.
DTC-syndrome is a disorder of hemostasis, which is manifested by the massive
formation of thrombi and micro-emboli in the vessels mainly of
ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀ.
Etiology
It is never inherited but only acquired. The possible causes of DIC-syndrome are the
following:
• Massive trauma of tissues, crash-syndrom, surgery trauma of parenchimatous organs
• Massive burn
• Premature placental detachment, manual detachment of placenta, ЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ
• Acute intravascular hemolysis of erythrocytes
• Uremia (renal insufficiency)
• Generalazied infections, sepsis
• All kinds of shock
• Terminal states ЀЀЀЀЀЀЀЀЀ
• Acute pancreanecrosis
• Peritonitis
• ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ
• Leukemia
• Side-line effect of medicines which influence hemostasis
Pathogenesis
9
DIC-syndrome is the heaviest pathology of hemostasis. It is a disbalance of all
mechanisms of hemostasis.
The main link of pathogenesis is a disbalance between coagulative, anticoagulative and
fibrinolytic systems and their simultaneous activation with further exhaustion of all of
them.
It occurs under coming into the blood of a large quantity of procoagulants and
activators of blood clotting in massive trauma, which leads to formation of numerous
microclots in microcirculation vessels. Father the hypocoagulation, thrombocytopenia and
hemorrhage develop due to removal of coagulative factors and increase of functional
activity of anticoagulative system and fibrinolysis.
The pathogenesis of DIC-syndrome proceeds in two stages.
A stage of hypercoagulation is an excessive formation of procoagulants and an
activation of the system of blood coagulation. A grate amount of procoagulants enter the
blood (tissue thromboplastin plays the main role). The intravascular formation of
numerous micro-clots occurs. Blood circulation can stop often not compatible with life.
Microclots cause stopping of the microcirculation and the development of heavy
disthrophical and functional disorders in organs (renal, cardiac and pulmonary insufficiency,
damage of the brain). They are not ЀЀЀЀЀЀЀЀЀЀЀ with a life.
A stage of hypocoagulation starts, as a reaction. The systems of anticoagulation and
fibrinolysis get activated. Content of factors of coagulation (thrombocytes, fibrinogen)
significantly decreases as a result of their use in the previous phase. Fibrinolysis activates
and this fact aggravates hemorrhage. Severe bleeding is difficult to stop. It is a terminal
phase of syndrome. Complete exhaustion of all systems of hemostasis underlies
hemorrhage. Necrosis develops in organs, where disorder of blood supply appears in form
or hemorrhage or thrombosis. In kidney, lungs, heart it is unconnected with the life.
Situation can become unguided and leads to death. Patient dies either from a
thrombosis or hemorrhage, which cannot be stopped. Situation seldom can be stopped
therapeutically.
METHODS OF HEMOSTASTS STUDYTNG
Investigation of a hemostasis is of a high practical value. Some methods are widely

used in everyday clinic. Some of them are used in scientific investigations.
Thrombocytes quantity is calculated in a specially painted smear of a blood.
Thromboelastogram is a graphic studding of different indices of hemostasis. In the
figure 36 two types of a change are represented – hypo- and hypercoagulation. The
difference is obvious. There is a method of ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ and many important
indices of hemostasis are calculated.
____________________________________________________
Fig. 36. Thromboelastograms

a/ normal, b/ hypercoagulation, c/ hypocoagulation
__________________________________________________________
With the aid of the modern biochemical and immunological methods all factors
participating in hemostasis may be determined. Thus, in a case hemophilia there are
some forms of this disease (A,B,C, parahemophilia) connected with absence of different
procoagulants (antihemophilic globulin, plasmatic kalikreinogen, Ѐonvertin etc.). It is
possible to determine all of them putting a correct diagnosis.
10
11
12
CHAPTER 24
PATHOPHYSIOLOGY OF THE HEART
The heart, as a pump, fulfills the function of moving the blood via circulatory
system.
The main indices of the heart work effectiveness are ударный (minute) volume of
the heart and speed of the blood circulation. If these indices are within the standard,
we speak about heart work as effective. If they are not sustained, we speak about
cardiac insufficiency.
Cardiac insufficiency is the pathologic process, which is characterized by
disorder of the heart function, as a pump on moving the blood via the vessels
with a proper speed and неспособность to supply the tissues with necessary
amount of blood in rest and при физической нагрузке.
Cardiac insufficiency develops in discrepancy between the required load on the
heart and its ability of doing this work.
Together with cardiac insufficiency we speak about the vascular insufficiency (see
the next chapter). We often observe combined cardiovascular insufficiency.
COMPENSATORY MECHANISMS OF THE HEART
Both within the physiological and pathological conditions the heart has some
mechanisms to activate its function (compensatory hyperfunction). The heart is able
rapidly to be adapted to an increase of the load and, carrying out the increased work,
to compensate the possible disturbances of blood circulation.
There are three adaptive mechanisms, which provide the maintenance of a minute
volume of the heart and a proper speed of the blood flow. They are:
• Enforcement of the heart contractions (increase in force)
• Acceleration of the heart contractions (increase in frequency, tachycardia)
• Enlargement of myocardium mass (hypertrophy of myocardium)
Each named mechanism has its advantages and недостатки defects. They are
evaluated from the following criterias.
Advantages are
• быстрота срочность развития of the adaptive reactions (immediate reactions) which
has advantage before delayed reactions
• Sufficient duration of adaptive reaction
• Energy economy
Недостатки Defects are
• замедленное развитие
• Short duration
• Energy-dependency
From these points of view, the differences between the named mechanisms of
hyperfunction are the following.
1
• Enforcement and acceleration of heart contractions are immediate urgent?,
emergency? reactions, which develop just after overloading begins, but not lasting
and require additional energy for their realization.
• Acceleration (tachycardia) is more energy-dependent reaction than enforcement.
• Enlargement of myocardium mass (hyperthrophy) requires long time for its
development (delayed reaction), but it is less energy-dependent and ensures prolong
adaptation.
Under physiological conditions these mechanisms provide physical and emotional
overstrain. The same mechanisms operate in cardiac or vascular pathology as the
compensatory reactions.
A deep penetration into pathophysiological mechanisms of heart hyperfunction
helps to understand the clinical situations in cardiology and a prognosis for patient
with a certain cardiovascular pathology.
STAGES OF HEART FAILURE
In increase of load on the heart, disorders are divided into two stages. They are -
• Stage of the compensation, when in spite of harmful effect of etiological factor,
the minute volume of heart and a speed of blood flow are supported normal
• Stage of the decompensation, when a minute volume of heart decreases,
congestion in circulatory system develops
CLASSIFICATION
Depending on the clinical course, the cardiac disturbances are divided into the
• Acute and chronic
• Right-side and the left-side
• Primary and secondary (as associated symptom with other diseases - fever,
anemia, hyperthyroidism etc.)
Now we are more interested in pathophysiological classification (by the
mechanisms of the development), which is of our special attention. There are three
pathophysiological types of cardiac failure.
1. Cardiac insufficiency due to overload of the heart. An excessive physical work
performs an overload on the heart of this type. Under pathologycal circumstances
overloading on the heart occurs in the diseases, when the resistance to the heart
outflow in the aorta or to a definite part of the heart gets increased, for example, in
stenosis of cardiac foramens, hypertension of the systemic or pulmonary blood
circulation.
2. Myocardial type of cardiac insufficiency is a result of the primary pathology of
myocardium. It may be caused by disorder of the coronary circulation, autoimmune
aggression against a heart, infection, intoxication, hypoxia, avitaminosis, systemic
hormonal and electrolyte disbalance, some hereditary disturbances of metabolism.
3. Mixed type of cardiac insufficiency occurs in different combinations of the
myocardium damage and its overload, for example, in rheumatism, when we
observe combination of the inflammatory lesion of the heart and disorders of the
valve apparatus.
Etiology and the pathogenesis of different types of heart insufficiency are different.
CARDIAC INSUFFICIENCY DUE TO OVERLOAD OF THE HEART
2
In this case we mean the situations, when the overloading falls on a healthy heart
with normal contractile ability.
Types of the Overload on the Heart
Type of overload on the heart is of a high significance for the father evaluation of
heart defensive ability.
There are two types of overload on the heart. They are -
• Overload by volume due to the increased amount of the blood inflow
• Overload by resistance (pressure) to the blood outflow
ETIOLOGY
Etiological factors of this type of the heart insufficiency are those, which increase
the load on the heart. Causes may be extracardial and intracardial.
Physical overstrain increases the inflow of the blood into the heart (load by
volume). Systemic or pulmonary arterial blood hypertension also затрудняет the work
and draining of the heart and increases the load by resistance (pressure). The
generalized atherosclerosis, pneumosclerosis, narrowing of aorta (atherosclerosis,
luetic gumma) creates overloading by resistance.
Intracardial morphological defects пороки also create overloading for the heart, but
in such cases for отдельных его частей, namely that part of the heart, which is located до
the defect. Valve defect недостаточность клапана (для переводчика. Здесь русский
общепризнанный термин недостаточность специфический и употребляется не в таком смысле
как insufficiency по всей книге, а означает его дефект и незакрывание. Может быть просто valve
defect? failure?) creates load by volume, but narrowing (stenosis) of a foramen - the load
by resistance.
PATHOGENESIS
The heart is able rapidly to be adapted to an increase of the load and, carrying out
the increased work, to compensate the possible disturbances of the systemic blood
circulation.
Depending on the type and duration of the load, this or that mechanism of
compensation begins to act. They were mentioned above.
• Enforcement of the heart contractions (in turn, it is subdivided into two types –
hetero- and homeometric)
• Acceleration of the heart contractions (tachycardia)
• Enlargement of myocardium mass (hypertrophy of myocardium)
Due to these mechanisms the minute volume of the heart can be supported
normal, the systemic disturbances of blood circulation are prevented.
As to effectiveness and duration of compensation, outcome of a disease and
prognosis for a patient, these mechanisms have different value.
Enforcement of the Heart Contractions
Increase of the heartbeats force is the first immediate compensatory reaction,

which is worthy to be mentioned because of its prevalence from others.
3
There are two different mechanisms of compensatory enforcement depending on
the two types of the overloading of the heart. They are hetero- and homeometric
ones. They have the different mechanisms of development, different duration of the
stages of compensation and decompensation, different outcome and prognosis for the
patient.
Overloading by Volume
If load on the heart by volume occurs, mechanism of enforcement of the heart

contractions is called heterometric. It means the more significant preliminary
расширение dilatation of myocardium before the systole.
Elevated blood filling of the cavities of the heart during diastole and increased
distension of the muscular fibers (their linear sizes) results in stronger contraction of the
heart during the systole in accordance with the Frank-Starling's law. This mechanism
is conditioned by the myocardial fiber elasticity.
The permissible linear size of the heart increase is up to 15-20%. This dilatation of
the heart may be accompanied by an adequate increase of the heartbeat force and is
called tonogenic dilatation. However, when a degree of distension of the myocardial
fibers exceeds the permissible limit (more than 25% of its initial length), the contractile
force gets decreased.
Heterometric type of cardiac hyperfunction is observed in morphological defects of
the valve apparatus. During diastole in such failure the cardiac cavity is filled not only
with the blood inflowing by normal route, but also with the blood returning due to in-
complete close of the valve during systole. The same is observed in congenital
defects of the heart septum.
Heterometric type of hyperfunction is less energy-dependent and more favorable
for myocardium in the comparison with the load by resistance and homeometric type
of hyperfunction, which is observed below.
Overloading by Resistance
If a load by resistance (pressure) occurs, the mechanism of enforcement of heart

contractions is called homeometric (without the preliminary more significant
dilatation of myocardium before a systole and Frank-Starling's low). The length of the
cardiac muscular fiber is not additionally increased as it is in the cases of the load by
volume.
This mechanism of compensation is connected with a considerable increase of the
systolic pressure to overcome the increased resistance to outflow. It may be achieved
by the more significant increase of the muscular fiber tension. At the end of a
diastole the pressure and tension in cavities are significantly elevated. Enforcement of
the heart contractions does not develop in the first but gradually in some subsequent
heart contractions, until it reaches the level, which is necessary to ensure a proper
minute heart volume. It needs an additional ATP and oxygen. So, this form of
compensation is more energy-dependant than heterometric one.
Homeometric type of hyperfunction develops in arterial blood hypertension,
generalized atherosclerosis, pneumosclerosis and stenosis of the cardiac foramens.
The comparative analysis of hetero- and homeometric types of cardiac
hyperfunction (fig. 37) allows understanding the differences in clinical course of
different types of cardiac pathology. Thus, in arterial hypertension and stenosis of the
cardiac foramens, the phase of compensation lasts shorter time; the stage of
4
decompensation and the invalidity of a patient starts more rapidly. Those pathologic
processes, which are based on the Frank-Starling's mechanism (in valve defects in contrast
with stenosis of foramens) have more favorable course. As to physical work, it can be
used for training of a heart.
Inflow of the blood to heart Resistance to blood ouflow

A B
Fig. 37. Dependance зависимость между minute cardiac volume (V) and its work (W) in
heterometric (A) and homeometric (B) mechanisms of compensation (rate of contractions is constant):
a, b – low and upper levels of blood volume which income, and resistance to its оттоку, за
которыми компенсация не совершается
Мал. 49 с 439 украинского учебника
_____________________________________________________________------
Acceleration of the Heart Contractions (Tachycardia)
Tachycardia is an increase in the frequency? rate? of the heart contractions. This

compensatory reaction, just as an increase in the force of the heart contractions,
contributes to the maintenance of a minute volume of the heart and proper speed of
blood flow.
Mechanisms of tachycardia may be intracardial and extracardial.
Intracardial regulation belongs to the right atrium rhythm driver - sinoatrial node
that is stimulated by direct effect of the растяжения предсердий.
The extracardial regulatory effects are nervous and humoral ones. The main role
belongs to the sympathetic part of the autonomic (vegetative) nervous system and its
mediator noradrenaline, which is released by the nerve ending. The same effect
belongs to the hormone of the medullar part of the adrenal glands. These mediators
(catecholamines) interact with the β1-adrenoreceptors on the cells of the sinoatrial
node.
In sympathetic excitation, the force and rate of the heart contractions are
considerably increased, the removal of the blood from heart cavities during systole is
more complete (in usual load about half of the blood remains in the ventricles at the
end of the systole).
However, from the point of view of energy need, tachycardia is less advantageous
mechanism of compensation in comparison with Frank-Starling's mechanism. Its
недостатки are the following –
• Great amount of oxygen consumption
• Shortening of the period of restoration and rest of the myocardium due to
considerable shortening of the diastole (fig. 38)
• Decrease of the myocardium contractility due to shortening of the diastole and
less filling of the cavities of the heart with the blood. Systole becomes less
effective. Hemodynamic characteristic of the heart gets worse.
In 170 beats per minute, the beginning of contraction of the atria approaches the
end of the ventricular systole (occlusion of the atria). On ECG the wave P
накладывается overlaps the wave T.
5
Тривалість серцевого циклу, с- Duration of cardiac cycle, sec.
Частота скорочень серця, уд./ хв. - Rate of heartbeats, …/min
Systole Diastole
Fig. 38. Change of duration of cardiac cycle, systole and diastole in different rate of heartbeats.
Штрихом a systole of atriums is noted
Мал. 50 с 440 украинского

________________________________________________________________
If overload on the heart exceeds named compensatory mechanisms (enforcement

and acceleration of heartbeats), cardiac insufficiency may develop. If overload is
moderate but prolonged and permanent (in valve defect, arterial blood hypertension),
another compensatory reaction starts. It is compensatory hypertrophy of the
myocardium.
Enlargement of Myocardium Mass (Hypertrophy of Myocardium)
Hypertrophy of myocardium is an increase in the mass of myocardium due to an

increase in the size of each muscular fiber (but not due to an increase in their
quantity). Specific metabolic and structural changes develop in myocardium, which
lead to an increase of mass and workability of the heart. This type of compensation
is delayed but long-termed and economical.
Indice ISF (intensity of structural function) is used for characteristics of a
dynamic of myocardial hyperthrophy development. ISF=W/m (W is a work, m –
mass of myocardium) means a load per unit of myocardium and must be constant for
prolong and steady heart work. According to dynamics of metabolic, structural and
functional changes in the myocardium, expressed by ISF, hypertrophy develops in 3
stages.
1. Stage of Emergency аварийной Hyperfunction. This stage is characterized by a
compensatory increase in the force of the heart contractions according to the
homeometric or heterometric type in dependence on the type of the load. This stage
develops immediately after the beginning of overload, however, it is short-term and
energetically uneconomical. The load on the unit of the muscular mass and
intensity of structure functioning (ISF) get increased (↑ISF= ↑W/m).
A combination of the pathologic changes in the myocardium and mobilization of
its reserves characterize this stage. The pathologic changes include disappearance
of glycogen, reduction of creatinphosphate level, decrease of the intracellular
potassium and increase of sodium content, mobilization of glycolysis,
accumulation of lactate. The disturbances of metabolism, which occur, start
hypertrophy. The heart becomes enlarged due to the intensified protein
synthesis and thickening of the muscular fibers.
2. The Stage of Completed Hypertrophy and Relatively Stable Hyperfunction.
In this stage, a hyperfunction of myocardium obtains a plastic подкрепление. All
6
elements of heart undergo hypertrophy - myofibrils, capillaries and nerve ends. Load
per unit of myocardium mass (ISF) gets normalized (ISF=↑W/↑m).
At this stage the process of hypertrophy gets completed, the myocardium
mass may be increased by 100-120%. The uptake of oxygen, energy formation
and the content of the macroergic compounds are within the norm. The
hemodynamic indices are normal. The hypertrophic heart has adjusted to new
load and compensates it for a long time. Nevertheless, it is not endless. The
hyperthrophied myocardium gets lost its harmonial structural proportions (fig.
39). An increase in the mass of myofibrils, capillaries, nuclear material and nerve
endings develops dysproportionally. The myocardium gets lost its reserves and a
decompensation is inevitable.
____________________________________________________________
М,язове волокно - Muscle fiber

Капілярна судина - Capillar vessel
Нервове волокно - Nervous feber
Fig. 39. Correlation between muscle fibers, capillaries and nervous of the heart in a newborn (a,г),
healthy adult (б, д, heart mass 310 g) and adult with hypertrophied myocardium (в, е, heart mass 540
g)

________________________________________________________________----
3. Stage of Decompensation, Gradual Exhaustion and Progressive

Cardiosclerosis. This final stage of myocardial hypertrophy has the following
explanation – a disturbance of myocardial trophicity, hypoxia, which leads to
cardiosclerosis, pathological accumulation of Ca2+-ions in cardiomyocytes. Mass
действующих кардиомиоцитов gets decreased. ISF increases but on the base of
decreased mass (↑IFS=↑W/↓m). Heart decompensation starts. The stage of gradual
exhaustion and progressive cardiosclerosis is characterized by profound metabolic
and structural changes in myocardium. It is a condition of a chronic cardiac
insufficiency.
MYOCARDIAL TYPE OF CARDIAC INSUFFICIENCY
Myocardium type of cardiac insufficiency is as result of the primary damage of the

myocardium. In this case, a disorder of myocardium contracting ability and heart
insufficiency develop even with the normal or decreased load on the heart.
Myocardial heart insufficiency may be acute and chronic, and on the
involvement of coronary blood circulation – coronarogenic and non-coronarogenic.
ETIOLOGY
Etiological factors of direct damage of myocardium can be physical (passage of

the electric current through the myocardium), chemical (toxins, smoking), biological
(infection, immune factors, emotional stress, hereditary disturbances of metabolism, the
thrombi and emboli, which occlude the coronary vessels, electrolytic and hormonal
disbalance).
7
The hypertrophy of myocardium in the third stage of its development is
accompanied with myocardial dysthrophy.
PATHOGENESIS
All pathologic processes, which were studied earlier, can be developed in the
myocardium – inflammation, allergy, disorder of microcirculation, dystrophia,
atherosclerosis, necrosis.
In the case of myocardial type of heart failure, the same adaptive reactions, which
were named above, develop. However, there are the following peculiarities:
• Possibility of enforcement of contractions of myocardium gets limited.
• Possibility of hypertrophy of myocardium is limited.
• Compensation occurs preferably due to tachycardia.
Thus, the stage of decompensation begins earlier.
Depending on involvement of coronary blood circulation, myocardial failure is
divided into two forms:
• Coronarogenic damage of myocardium
• Non-coronarogenic damage of myocardium
Coronarogenic Damage of Myocardium

Ischemic Heart Disease
Diseases and pathologic states accompanied by disturbance of the myocardial blood

circulation are united in a special nosologic unit called ischemic heart disease. It is
manifested by functional disturbances and pain syndrome (angina pectoris) or lead to
necrotic changes of the myocardium.
Myocardial infarction is a focal ischemia and necrosis of the cardiac muscle
occurring due to cessation of the blood inflow by coronary arteries or as a result of
insufficient amount of blood to meet energy requirements.
Etiology
Ischemia (the decrease of кровенаполнения of myocardium as a result of limitation

or stopping of the entering of the arterial blood inflow) underlies coronarogenic
damage and necrosis of myocardium. According to the cause, ischemia of
myocardium (as any other ischemia) is divided into compressive, obstructive and
angiospastic.
The cause of compressive ischemia of myocardium is a compression of coronary
arteries by tumor (for example, by syphilitic gumma).
The cause of obstructive ischemia of myocardium is the narrowing (or occlusion)
of coronary arteries by thrombi, embolus or artheriosclerotic бляшки.
The cause of angiospastic ischemia of myocardium is the functional disturbances
of the vasoconstrictive and vasodilative apparatus of the coronary vessels.
Atherosclerosis is the most frequent cause of impairment of the coronary artery wall.
In most cases, myocardial infarction develops due to calcification and ulceration of
the atherosclerotic бляшки with the following occlusion of the vessel by thrombus.
Stenosing sclerosis of the coronary vessels creates limitation of nutrients entering
into the cardiac muscle. Even insignificant vascular stenosis on the base of increased
requirement of the muscle in oxygen may cause necrosis.
8
Coronary blood circulation disorders in acute arterial hypotension (shock,
collapse, blood loss), bradycardia, cardiac insufficiency of any genesis, defect of
клапанов аорты (diastolic pressure падает резко).
Risk factors leading to infarction include arterial hypertension, excessive physical
work, atherosclerosis, trombophylic syndrome, hormonal and electrolytic disturbances
in the organism, diabetes mellitus, excessive eating, overeating with a large amount of
fats, smoking, emotionally tensed life, stress, hereditary factors, gout, environmental
factors.
Pathogenesis
The following pathogenic variants of myocardial infarction development are

possible:
• Occlusion of the vessel promoting absolute decrease of the coronary blood flow
below the critical level (usually three fourths of initial lumen)
• Stenosis, which is not manifested at rest but on little exertion, physical or
mental, resulting in ischemia of the cardiac muscle,
• Considerable physical exertion or emotional stress, which may cause несоответствие
between the need in oxygen and possibility of the blood inflow. In this case, the
intensified secretion of catecholamines and hormones of the adrenal cortex plays an
important role.
In ischemia, the deficit of oxygen, substrates and ATP in the myocardium takes
place.
The increased function of the sympatho-adrenal system and выброс of the large
doses of catecholamines into the blood frequently accompany ischemic heart disease
in a human. It activates the heart, increases the level of free fatty acids in the blood
and increases consumption of oxygen. In these cases the protection of the heart from
catecholamines, for example, by using β1-adrenoblocker, is beneficial.
Resorption of the substances from the necrotized areas of the myocardium into
the blood is accompanied with appearance in the blood of intracellular enzymes
(creatinphosphokinase, aspartataminotransferase, lactatedehydrogenase) as well as
myoglobin (резорбционно-некротический syndrome). It may be used for diagnostic
purpose. Resorption of the cellular proteins is accompanied by leukocytosis, fever,
increased erythrocyte sedimentation rate (ESR).
п оступление of the intracellular myocardial proteins into the blood flow
may be accompanied by autoimmunization with production of anticardial
antibodies and sensitized (to the cardiac antigens) lymphocytes as well as
eosinophilia and hypergammaglobulinemia. The development of postinfarction
syndrome (Dressler, s syndrome) is associated with it. It is characterized by
inflammation of the serous membrane of the heart, lungs, joints.
Manifestations
The clinical diagnose of myocardial ischema and infarction may be estimated by

ECG. During the first minutes after the disturbance of circulation there are changes on
the electrocardiogram such as deviations of the segment S-T, changes of QRS complex
and the wave T.
Infarction develops in the area of myocardium, which is supplied by the blood
through the damaged vessel.
9
Morphologically, first of all, structural impairment of mitochondria is noted. Then
swelling or picnosis of the nuclei occurs. The transverse striation of the muscular fibers
disappears. The cardiomyocytes lose glycogen and potassium. H+-ions are
accumulated.
The main consequence of infarction is the local coagulative necrosis, myocyte
lysis, the myocardium edema. There are several zones in the focus of infarction. In the
central area the tissue has got irreversible damages. In the intermediate zone there are
nercotized muscular cells with signs of calcium accumulation. The dead cells are
surrounded by neutrophylic granulocytes, which later are substituted by
macrophagocytes, lymphocytes and plasmocytes. Later on the cardiomyocytes are
resolved and substituted by fibroblasts and the connective tissue.
Pain is a typical clinical manifestation of the ischemic heart disease and
myocardial infarction. It is characterized by a typical localization in the upper left
part of the body and behind the breastbone. However, there are painless cases of
infarctions.
Myocardial infarction causes an acute cardiac insufficiency that leads to hypoxia,
acidosis, disorder of the brain functions and other organs and finally can end to
death.
Damaged (by atherosclerosis) coronary arteries may be substituted by normal
vessels with the aid of the modern хирургических техник. Blood perfusion of the heart
thus restituted (reperfusion). But, ischemic myocardium, which for a long time
функционировал with limited perfusion, reacts on its sudden increase by «explosure»
of free-radical oxidation. It leads to damage of mitochondrias, accumulation of Ca2+-
ions, death of the cells by apoptosis, additional increase of a zone of infarction and
aggravation of general condition of the patient (reperfusive реперфузионный syndrome).
Non-Coronarogenic Damage of Myocardium
There are several experimental models of necrosis of the cardiac muscle, which
are not connected with pathology of the cardiac vessels.
Hypoxic necrosis of the myocardium may be reproduced with the help of different
kinds of hypoxia: hypoxic, hemic. The development of necrosis is promoted by
fixation of the experimental animal in the uncomfortable position (adrenaline in this
case increases need in oxygen) or additional load (running in the trainer).
Electrolyte-Steroid Cardiopathy with Necrosis. According to Selye observations,
when a significant amount of sodium salts in combination with some anions (sulfates,
phosphates) are injected to an experimental animal, an impairment of degenerative-
necrotic type appear in the heart.
Immune damage of the heart possible in injection of the heterogenic serum into
the organism of an experimental animal with antibodies to the heart proteins
(cardiocytotoxins).
Mixed Form of Cardiac Insufficiency. It occurs in different combination of the
myocardium damage and its overload. For example, in rheumatism, it is a
combination of inflammation of the myocardium and disorders of the valvular
apparatus.
DISORDERS OF CARDIAC RHYTHM (ARRHYTHMIA)
10
Cardiac arrhythmia is a disorder of the rhythm of the contractions of the
whole heart or its separate parts.
Depending on localization of a reason, arrhythmia may be cardial (as a result of
the diseases of the heart) and extracardial (fever, anemia, hyperthyroidism etc.).
There is a classification of arrhythmias depending on disturbance of one of the
functions of myocardium - automatism, excitability, conductivity and contractility.
Etiology and the pathogenesis of various forms of arrhythmias are different.
Disorder of Automatism
The disturbance of automatism leads to development of tachycardia, bradycardia

and respiratory arrhythmia.
It is known that ability to automatic formation of impulses depends on the cells
located in the conductive system of the heart (p-cells). A spontaneous slow
depolarization of the cellular membrane occurs in them during diastole.
Tachycardia is observed under the influence of the increased body temperature,
sympathetic mediators effect, distension of the area of the sinoatrial node, loss of
potassium.
In stimulation of n. vagus, the impulse generation is slowed down as well as the
rate of heart contractions — bradycardia develops (retention of potassium has the
same effect).
Fluctuations of the n. vagus tonus during respiration may cause respiratory
arrhythmia (accelerated heartbeats in inspiration and its slowing down in expiration).
Respiratory arrhythmia may be observed in healthy children, rarely in adults.
Disorder of Excitability
The disturbance of excitability leads to development of extrasystole and

paroxysmal tachycardia.
The difference of potentials between the neighboring cardial myocytes may be a
mechanism leading to appearance of ectopic foci of excitation. Extraordinary
contraction of the heart or only ventricles is called extrasystole. Under the influence
of ischemia, the ectopic focus of excitation, promoting extrasystole, appear.
The sinus extrasystole arises due to premature excitation of some part of the cells of
the sinoatrial node. On electrocardiogram it doesn't differ from the normal
contraction except shortening of the diastolic interval T-P. Due to the shortening of
diastole and reduction of the ventricular filling, the pulse wave is decreased in
extrasystole.
The atrial extrasystole is observed, when there is a focus of ectopic excitation in
different areas of the atria. Deformation of the wave P (decreased, two-phased,
negative) in preserved complex QRST and some lengthening of the diastolic
interval after extrasystole characterizes it. It is conditioned by the fact, that the
excitation going by retrograde way разряжает discharges a normal sinus impulse
prematurely, which coincides with the ventricular excitation. The next atrial impulse
occurring after a normal interval, turns to be somewhat behind the time from the
moment of the end of the ventricular excitation. It is incomplete compensatory
pause.
The atrioventricular extrasystole is observed in the additional impulse in the
atrioventricular node. The wave of excitation from the upper and middle parts of the
node is spreading in two directions: normal — to the ventricles and retrograde — to
11
the atria. The negative wave P may precede complex QRS or overlap it. The diastolic
interval after extrasystole is a little prolonged. Extrasystole may be accompanied by
simultaneous contraction of the atrii and ventricles. If the wave of excitation is
formed from the lower part of the node, there is a compensatory pause, which is the
same as in the ventricular extrasystole, and the negative wave P follows QRS complex.
The ventricular extrasystole is characterized by complete compensatory pause after
extraordinary contraction. It develops because an excitation of the ventricles is not
transmitted through the atrioventricular node to the atrium, and the following normal
impulse of excitation from the sinoatrial node does not cause contraction of the
ventricles, which are in the refractory phase. The next contraction of the ventricles
occurs only after the next normal impulse. Therefore the duration of the compensatory
pause with the previous interval is equal to the duration of two normal diastolic
pauses.
In a case of a group of quickly repeated extrasystoles, which inhibit the
physiological rhythm completely, paroxysmal tachycardia develops. Numerous
ectopic focci of excitation together with disturbance of conductivity create conditions
for repeated circulation of excitation and paroxysmal tachycardia development. The
normal rhythm of the heart is suddenly interrupted by an attack of contractions at
the rate of 140-250 beats per minute. The duration of an attack may be different —
from several seconds to a few minutes. Then it stops suddenly and the normal rhythm
gets restored. The atrial form of paroxysmal tachycardia is most frequently observed.
Disorder of Conductivity
The disturbance of a conductivity leads to development of blockades.

The cause of blockade may be an impairment of the conductive tracts, which leads
to prolongation of the refractory period and is accompanied by slowing down or
complete cessation of the impulse conduction. The disturbances of conductivity may
occur between the sinoatrial node and the atria, inside the atria, between the atria
and the ventricles and in one of the pedicle ножки of the atrio-ventricular пучка bundle.
In intraatrial and intraventricular blockade the rate of the heart contractions does not
change, and the disturbance is manifested in changes on the ECG. Changes of the
rhythm and the rate of the heart contractions may accompany the atrioventricular
blockade.
The atrioventricular or transversal blockade may be complete and incomplete.
The complete transversal blockade is also called blockade of the III degree. In the
incomplete atrioventricular blockade the I and II degrees are distinguished.
The atrioventricular blockade of the I degree is characterized by prolongation of
the impulse conduction from the atria to the ventricles with extension of P-Q
interval by more than 0.21 sec. The contraction rate of the atria and ventricles is
equal. The blockade of the II degree is accompanied by more marked impairment of
the atrioventricular conductivity, so that one or several impulses from the sinus
node cannot be conducted to the ventricles, and the number of the atrium
contractions is greater than that of the ventricles. There are several variants of the
incomplete atrioventricular blockade of the II degree depending on the degree of the
conductivity impairment. They are: the atrioventricular blockade with the worsening
conductivity until one of the contractions is missed (periods of Wenkenbach-
Samoilov), the blockade with every 3rd-5th ventricular contraction missing, every
2nd or only one of 3-6 contractions is transmitted. In complete atrioventricular
blockade the atria and ventricles are contracted each in their rhythm, independent of
12
each other. The atria are contracted at the rate 60-80 per 1 min, the ventricles,
depending on the location of a new rhythm driver, contract 20-40 times per min
with the rhythm driver in atrioventricular node and 15-30 times per min with the
driver in the ventricle (idioventricular rhythm).
The moment of transition of the incomplete blockade into complete one, when the
atria do not transmit impulses to the ventricles, is of a special importance. A slow
diastolic depolarization in the potential rhythm drivers occurs only in some time after
cessation of impulse transmission from the sinoatrial node. This period is called
preautomatic pause, the ventricular asystolia is observed during this pause. As the
blood doesn't come to the brain, there are a loss of consciousness and convulsions
(Morgagni- Adams-Stokss syndrome). Death is possible but usually, when the
ventricular contraction gets resumed, these symptoms disappear. The syndrome may
repeat many times.
Disorder of Contractility
Disorder of contractility is manifested in a disorder of воспроизведение частоты

возбуждения (трансформация ритма, деление частоты). Следующие друг за другом потенциалы
действия и сокращения оказываются неодинаковыми (альтерация). Disorder of contractile
apparatus of the cell, сопряжения возбуждения и сокращения underlay this arrythmia. В
ответ на приходящий импульс сокращаются не все волокна.
Combined Disorders of Cardiac Rhythm
Combined disorders of cardiac rhythm are conditioned by the simultaneous

disturbances of automatism and conductivity (fig. 40).
________________________________________________________________
Fig. 40. Movement of a wave of an excitement via myocardium in norm (a) and in flutter

_______________________________________________________________
In numerous ectopic foci of excitation and disorder of conductivity flutter and

fibrillation may occur.
In some cases the rate of the atrium contractions reaches 250-400 per minute.
Conductive system can not transmit such amount of impulses, the ventricles are not able
to produce a high rhythm of the atria and a relative cardiac blockade may develop. The
ventricles contract on every 2nd, 3rd or 4th contraction of the atria, as other waves of
excitation get into refractory phase. The ventricle contraction may occur before their
sufficient filling up with the blood that results in severe disturbances of circulation. This
state is called flutter of the atria and may continue for several months and years.
When the number of the atrial contractions is 400-600 per a minute, we speak
about мерцаннии, или фибрилляции fibrillation of the atria. Only some separate
muscular fibers contract, and the whole atrium is in a state of incomplete
contraction. The participation of atrium in pumping of the blood stops.
Hередко the ventricles can contract before they are filling up with the blood and
contraction are not accompanied by pulse wave. Therefore, the pulse rate is less than
13
the rate of the heart contractions. It is called pulse deficiency or мерцательная fibrillary
arrhythmia. It occurs mostly in stenosis of the left atrioventricular foramen,
thyrotoxicosis, cardiosclerosis.
The ventricular fibrillation develops in some pathogenetic influences, for example,
passing of the electric current through the heart, anesthesia with chloroform or
cyclopropane, occlusion of the coronary artery or other cases of acute hypoxia, the
heart trauma, toxic doses of digitalis and calcium. Because of chaotic contraction of
separate muscular fibers, the propulsive force of the contraction is practically absent,
the patient loses consciousness and die.
Passing a short powerful single electric discharge through the heart effectively
treats the atrial and ventricular fibrillation. It produces simultaneous depolarization
of all myocardial fibers and asynchronic excitations of the muscular fiber get ceased.
To prevent development of fibrillation, physicians use correction of the salt contents
of the blood.
MANIFESTATIONS OF THE CARDIAC INSUFFICIENCY
The manifestations of heart insufficiency are divided into the acute and the
chronic. In turn manifestations are divided into the local (in the myocardium) and the
systemic (in the entire organism). In turn local manifestations are subdivided into the
morphological, biochemical and functional changes in the myocardium.
Changes in the Myocardium
Biochemical changes in the myocardium are the following.

• Damage of the enzymal composition
• Reduction in the oxygen intake (hypoxia)
• Disorder of the oxidative phosphorilation
• Reduction in the synthesis of macroergic compounds (ATP, KrP)
• Loss of glycogen
• Disturbance of protein synthesis
• Electrolytic disbalance
Accumulation of sodium and calcium ions in the cells
Loss of potassium from the cells
затруднение обратного транспорта ионов Са в саркоплазматический ретикулум
• Acidosis in the intracellular media
Morphological changes in the myocardium are the following.
• Destructive changes in mitochondrias
• Swelling or picnosis of the nuclei
• Disappearance of the transverse striation in the muscular fibers
• Disorder of nervous apparatus of the cells
• Dilatation of the heart cavities
• Substitution of cardiomyocites by connective tissue (сardiosclerosis)
• гибель кардиомиоцитов
Functional disturbances of myocardium are the following.
• Disorder of cardiac rhythm as a result of disturbance of automatism, excitability,
conductivity, contractility
• Impairment of process of contraction and relaxation of the cardiac muscular fibers
• Reduction of the force and speed of the cardiac muscle contraction
14
• локальные контрактуры отдельных кардиомиоцитов
• Reduction of the systolic volume of the heart
• Elevation of the residual systolic volume and diastolic pressure
• Changes in ECG
Systemic Changes in the Organism
Acute Cardiac Insufficiency
If an increased load on the heart is excessive, the compensatory mechanisms fail to

manage the overload, and acute cardiac insufficiency develops. It is accompanied by
significant changes in the blood circulation —
• Acute decrease of arterial blood pressure
• Elevation of the venous pressure
• Significant reduction of the minute blood volume
• Circulatory and tissue types of hypoxia
• Acute pain
• Disorder of breathing
• Ischemia of the brain, loss of consciousness, convulsions
• Severe changes resembling shock
Together with metabolic there may be the structural changes in the cardiac muscle, so
that even in the further reduction of the load, the heart activity may not be normalized.
Acute cardiac insufficiency can develop in the myocardial infarction, myocarditis,
ventricular fibrillation, paroxysmal tachycardia, the heart tamponade, thrombosis and
embolism of the pulmonary artery.
Chronic Cardiac Insufficiency
Some manifestations of the chronic cardiac insufficiency were observed in the

previous chapters, and pathogenesis was discussed in the details. They are edema,
dispnoe, venous congestion, chronic circulatory hypoxia, cyanosis, increase of the
basal metabolism.
Chronic or congestive cardiac insufficiency develops due to metabolic
disturbances in the myocardium in the prolonged hyperfunction of the heart or
different kinds of the myocardium pathology.
The hemodynamic indices in chronic insufficiency of the heart are the following:
• Minute blood volume of the heart decreases from 5-5,5 to 3-4 1/min.
• Blood flow speed is 2-4 times slowed down.
• Arterial blood pressure changes a little in spite of cardiac failure (it may be
explained by increase of the peripheral resistance of the vessels).
Because of insufficient coming of the blood from the heart, the blood
filling of the organs gets diminished. At the same time due to inability of the
heart to pump the inflowing blood, the venous congestion develops. As the
volume of the venous vascular flow is approximately 10 times greater than that
of the arterial volume, a considerable amount of the blood is accumulated in the
veins. The venous pressure is elevated.
The capillary vessels and postcapillary veins are dilated, the blood flow is slowed
down in them and pressure is increased. The slowing down of the blood flow in the
systemic circulation and circulatory disturbance in the lungs leads to the increase of the
15
desoxyhemoglobin in the blood. It gives to the skin and the mucous membrane a
characteristic blue color — cyanosis.
The tissues suffer from lack of oxygen. Hypoxia is accompanied by accumulation of
underoxidated products of metabolism and carbon dioxide. Acidosis develops. Acidosis
and hypoxia lead to impairment of respiration and dyspnoea. To compensate hypoxia,
erythropoiesis gets stimulated, the total volume of the circulatory blood gets increased
as well as relative content of the blood cells in it that promotes an increase of the
blood viscosity and worsens its hemodynamic properties.
Retention of sodium and water in the organism is observed. The mechanisms,
which evolutionally arose to provide sufficient contents of salts and fluid in the
organism, become harmful in cardiac insufficiency. In patients with the circulatory
insufficiency the surplus of the intake salt is not excreted by the kidneys as in a
healthy person but detains in the organism with water.
Prolonged existence of circulation insufficiency leads to profound and irreversible
disturbance of intracellular metabolism.
In combination with dysfunction of the digestive tract and progressive circulatory
insufficiency the patient begins to suffer from severe cachexia called cardiac
cachexia.
In impairment of one of the ventricles, the circulatory insufficiency acquires
some specific features and therefore the left-side type or the right-side type calls
it insufficiency. In the first case the blood congestion is observed in the veins of
the pulmonary circulation that may result in lung edema. In the second case
the blood congestion is observed in the veins of the systemic circulation, the
liver gets enlarged, there are edemas on the legs and ascite.
CIRCULATORY INSUFFICIENCY IN DISTURBANCE OF THE BLOOD

INFLOW TO THE HEART
This pathology develops in cases, when the blood inflow to the heart by veins is
little or when the heart is not able to take all the inflowing blood. It is observed in
hypovolemia (blood loss), acute dilation of blood vessels (collapse), accumulation of
the fluid in the pericardium cavity that leads to difficulty in dilatation of the cavities
during diastole.
The fluid accumulation in the pericardium cavity may be fast and slow. Fast
accumulation occurs due to hemorrhage in trauma of the heart or in quickly
developing pericarditis. Because of poor stretching of the pericardium, the pressure in
its cavity increases preventing diastolic dilatation of the heart. It causes acute
tamponade of the heart.
16
CHAPTER 25
PATHOPHYSTOLOGY OF VESSELS
The main function of vessels is a moving? propulsion? of the blood via circulating
system and to provide an ЀЀЀЀЀ interchange of substances and oxygen between
blood and tissues. The main indices of effectiveness are a minute volume of the
blood and a speed of circulation.
Vascular insufficiency is a disorder of the function of vessels of blood
circulation via vascular system.
Vascular system consists of four types of the vessels. According to their
morphology and function such types of vessels are distinguished –
• Arteries of elastic type - compensative type,
• Arteries of muscular type - resistive type,
• Capillaries (microcirculation) - ЀЀЀЀЀЀЀЀЀ ЀЀЀЀ. exchanging ??
• Veins - ЀЀЀЀЀЀЀЀЀЀ type. accumulative ?? collectory ??
_______________________________________________________________________
Pump
Vessels of ЀЀЀЀЀ
Capillaries – vessels of ЀЀЀЀЀЀ
Postcapillar vessels of resistance
ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ
Sphincters
Venous part
Fig. 41. Differentiation of vascular system parts upon function and change of the pressure via
vessel ЀЀЀЀЀ ЀЀЀ. 58 Ѐ 464 ЀЀЀЀЀЀЀЀЀЀЀ
_______________________________________________________________________
Each type of vessels has its own function, special features of metabolism and
typical pathology.
Disorders of microcirculation (hyperemia, ischemia, stasis, thrombosis,
embolism, and inflammation) were described in the chapters 7 and 8 (“The
Pathology of Peripheral Blood Circulation” and “Inflammation”). Below attention
is focused on the pathology of elastic and resistive types of the vessels.
PATHOLOGY OF ELASTTC TYPE VESSELS

ATHEROSCLEROSTS
Atherosclerosis is a typical pathology of elastic type vessels.

Atherosclerosis is a pathologic process, which is characterized by
infiltrative-proliferative changes in the inner layer ? lamina ? of elastic type
1
arteries with the deposition of lipids, fibrin and calcium with disorder of
elasticity and narrowing of vessels lumen.
The main event of this pathology is a lipid dysplasia of the elastic type vessels.
ETTOLOGY
Etiology of any disease, as it is known, consists of etiological factors, conditions

and risk factors interaction. Etiology of atherosclerosis includes many factors,
among which external and internal are distinguished, which cause atherosclerosis,
and the factors, which contribute to its development.
Etiology of atherosclerosis has the following special feature – no exogenous
factors separately, as a rule, causes atherosclerosis. In experiment there is only
one model of atherosclerosis by injection of large doses of cholesterol. However, it
is successful only in rabbits that do not use animal food; consequently, cholesterol
in this model may be qualified as an etiological factor. This model does not
succeed in other animals, which use animal food and resistant to cholesterol. It is
possible to model atherosclerosis in ЀЀЀЀЀЀЀ by prolonged introduction of
diethylstilbestrole (androgenic hormones), in dogs by thyreoidectomia plus
overloading with cholesterol.
Excessive food (more lipids and carbohydrates), alcohol abuse, emotional
overstraining are unfavorable in this aspect. Intoxication by fluorides, salts of
mercury and lead, nicotine promotes atherosclerosis.
Endogenous factors play more decisive role in atherosclerosis development.
They are:
• Pathologic heredity,
• Elderly age because hyperlipoproteidemia and hypercholesterolemia are
more characteristic for elderly age,
• Hormonal insufficiency (hypothyroidism, diabetes mellitus, hypogonadism,
Cushing's syndrome),
• Arterial blood hypertension (increased mechanical pressure on the vessels),
• Disorders of metabolism (obesity, gout, xanthomatosis, pathology of the
liver).
Risk Factors are
• Hypodynamia, which decreases oxidation of lipids and promotes
degenerative and sclerotic processes,
• (vereating, alcohol abuse, smoking,
• Stress, which may lead to the vessels wall trophycity disorder.
Analyzing etiology of atherosclerosis, it is possible to see that the same factors
in some cases play a role of etiological ones, but in other cases – a role of
conditions or risk factor (fig.42). In each individual case the specific totality of
factors is on the base.
___________________________________________________________________
ЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀ - ЀЀЀЀЀЀЀ ЀЀЀЀЀ
ЀЀЀЀЀЀЀ ЀЀЀЀЀЀ ЀЀЀЀЀЀЀ Diseases of metabolism
ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀ Arterial blood hypertension
ЀЀЀЀЀЀЀЀЀЀЀ Hypodinamia
ЀЀЀЀЀ Stres
ЀЀЀЀЀЀЀЀЀЀЀЀ Intoxication
2
ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀ Sex
ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ Genetic factors
ЀЀЀ, ЀЀЀЀ Age, years
Fig. 42. Dependence of atherosclerosis development from different factors ЀЀЀ. 59 Ѐ 466
ЀЀЀЀЀЀЀЀЀЀЀ
Genetic predisposition is a leading factor of atherosclerosis development in

man and is confirmed statistically. There are data about hereditary family
forms of hyperlipoproteidemia and hypercholesterolemia. Male sex critically
predisposes to atherosclerosis.
The following changes can be genetically determined:
• Special features of cholesterol metabolism,
• Predisposition to β-lipoproteids synthesis,
• Deficit of lipases (enzymopathy),
• Deficit of lipotropic substances (phospholipids, lecithin, lipocaine),
• Deficit of cellular receptors for the lipoproteids of low density (LPLD),
• Predisposition to autoimmune aggression and formation of antibodies against
the cells of the vessels intima.
(nly on the background of genetic predisposition the different external and
internal factors mentioned above contribute to atherosclerosis development.
PATHOGENESTS
There are two concepts of the atherosclerosis pathogenesis proposed.

(1) Concept of primary disorder of lipid metabolism and secondary damage of
vascular wall,
(2) Concept of the primary damage of vascular wall and its secondary lipoidosis.
Theory of Primary Disorder of Lipid Metabolism
The essence of this theory lies in assumption, that typical disorders of lipid
metabolism are primary and lead to the lipid infiltration of vessel wall and its
secondary damage. It is based on the following proofs and assumption.
• Hypercholesterolemia (raising cholesterol level in the blood) is a necessary and
the most obvious metabolic event in atherosclerosis. It is a generally accepted
postulate - “without cholesterol there is no atherosclerosis”.
Cholesterol is a physiological substratum, which participates in:
Construction of the cellular membranes and their permeability,
Synthesis of the corticosteroids, sex hormones, bile acids, vitamin D,
Being the dielectric, it provides (with myelin) the conduction of
impulses in the definite direction in the nervous system.
As it was noted above, it is possible to reproduce atherosclerosis in experiment
by an excessive introduction of cholesterol to rabbits. This fact is a reason for
many people to limit cholesterol in the food. But the fact is, that an amount of
endogenous synthesis of cholesterol in men prevails its exogenous entering. In
pathogenesis of atherosclerosis the matter is not in amount of cholesterol but in
its modification and chemical bonds with other substances.
3
• The etherification of cholesterol (the connection of cholesterol with the fatty
acids) plays an important role, especially a kind of fatty acids. The unsaturated
fatty acids (fats of plant origin) contribute to the best solubility of cholesterol. The
saturated fatty acids (fats of animal origin) do not have this property and
contribute to the development of atherosclerosis. It explains the value of
nourishment and diet, as a risk factor, in pathogenesis of atherosclerosis. The use
of the fats of plant origin in the nourishment is preventive for atherosclerosis.
• The relationship between the content of cholesterol and lecithin (the main
hepatic phospholipid) in the blood ensures the best solubility of cholesterol and
prevents infiltration of vascular wall by it. The fatty acids are oxidized better in
a molecule of phospholipids. Choline and methionine (which give the methilic
groups for the choline formation) are the necessary components of lecithin. So, the
deficiency of choline, methionine in the food promotes atherosclerosis
development. Choline synthesis gets disordered in deficiency of vitamin B12, folic
and pantothenic acids.
• The type of the connection of cholesterol with the proteins (lipoproteids) has
great significance in its solubility.
β-lipoproteids (lipoproteids of low and very low density LPLD,
containing more quota of lipids and few proteins) are atherogenic and
promote accumulation of cholesterol in the wall of the vessel (they are
typical for men).
α-lipoproteids (lipoproteids of high density LPHD, containing more
quota of protein and few lipids) weakly infiltrate the vascular wall and
possess the antiatherogenous influence (they are typical for the women).
This fact is an explanation of sexual differences in predisposition to
atherosclerosis (men are more predisposed then weman).
• Enzyme β-lipoproteid-lipase, which is located in the wall of the vessels,
prevents the formation of cholesterol ЀЀЀЀЀЀ and metabolizes lipids.
Since an activity of this enzyme (as all other ones) depends on heredity,
it is understandable, that this enzymopathy is a factor of hereditary
predisposition to atherosclerosis.
Since an activity of this enzyme decreases with age, the role of elderly
age in the development of atherosclerosis becomes clear.
Type of constitution, which is called lipomatous (inclined to obesity),
is more predisposed to atherosclerosis and connected with low activity
of lipase.
Introduction of vitamins B12, B15 — pantothenic acid and rutin - activates
lipolytic activity of the vascular wall.
Heparin activates lipoproteid-lipase (its participation in anticoagulation
diminishes in atherosclerosis and it results in hypercoagulation and
thrombosis).
• Since the lipids and especially β-lipoproteids are energy substratum for the
skeletal muscles (especially in men), the physical work prevents the development
of atherosclerosis, but hypodynamia (especially in the men of athletic constitution)
is a risk factor for the development of atherosclerosis.
• Hormonal deficiency have great significance in lipid metabolic disorders and
thus in development of atherosclerosis.
Estrogens assure a synthesis of α-lipoproteids (LPHD). Thus, women
are less predisposed to atherosclerosis. In a period of climax, when an
4
activity of progesterone decreases, the frequency of atherosclerosis in
women and men gets equalized.
Testosterone is a hormone, which predisposes to synthesis of β-
lipoproteids (LPLD) and the development of atherosclerosis
(introduction of this hormone in experiment and in men as a medical
drug increases the risk of atherosclerosis).
Insulin converts 10% of carbohydrates into the fats. Pathogenesis of
diabetes mellitus, obesity and atherosclerosis are tightly connected. The
reason of invalidity and mortality of the patients with diabetes mellitus
is connected with atherosclerosis development.
Thyroxin increases splitting of lipids, so, hypothyroidism contributes to
the development of atherosclerosis.
• Deficiency of endogenous lipotropic factor lipocaine (which activates a formation
of phospholipids in the liver, oxidation of fatty acids and preserves the liver from
obesity) must be added as mechanism, which leads to obesity and atherosclerosis.
All mechanisms mentioned above result in accumulation of cholesterol in
vessels and their secondary damage. Cholesterol (C27H46() is a substance which is
difficult to metabolize. In getting into the subendothelium it provokes reaction as
a heterologous substance (triglycerides have the same property). Atherosclerosis
is a reaction of a connective tissue of aorta and large arteries on falling out of
cholesterol into the subendothelium.
Theory of the Primary Damage of Vascular Wall and Secondary Lipoidosis
In accordance with this concept, the primary factor of the atherosclerosis

development lies in dystrophic changes in internal layer of arterial vessel wall. The
cases of atherosclerosis without a significant accumulation of cholesterol are the
proofs of this theory. Pathogenesis is the following:
• Disorder of the receptor system of vascular wall, which mediate the use of
lipoproteids or the capture of LPLD,
• Disorder of enzymal system of vascular wall, namely, a decreased activity of
the lipases (especially β-lipoproteid-lipase),
• Inflammation in the vascular wall,
• Immune mechanisms of the damage of the vascular wall (cells of intima
become autoantigens), formation of LP-IgG autoimmune complexes,
• Thrombogenesis in the vascular wall.
The changes in the vessel wall mentioned above provoke its dystrophy,
formation of fibrous ЀЀЀЀЀЀ, calcification, thrombogenesis and sclerosis.
MORPHOLOGTCAL AND FUNCTTONAL DTSORDERS TN THE VASCULAR WALL
Morphological changes in the vessels and the dynamics of their atherosclerotic

damage proceed in some stages with such order of events.
1.Infiltration of the vessel intima by native or ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ lipoproteids
of blood plasma. Lipid deposition is an early event in atherogenesis
pathogenesis. The lesions occur primarily within the tunica intima. Excessive
ЀЀЀЀЀЀ capture of lipids by macrophages and infiltration of the arterial wall
by macrophages, containing low-density lipoproteids. Transformation of the
macrophages into ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ, which are the base of lipid ЀЀЀЀЀ spots
5
formation. It leads to endothelial injury. ЀЀЀЀЀЀ ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀЀ . Lipid-filled smooth muscle cell loose contractility.
2. Proliferation is a local irritation and multiplication of the histiocytes,
fibroblasts and smooth muscles of vessels, which capture lipids. ЀЀЀЀЀЀЀЀЀЀЀ of the
connective tissue. Consolidation of the connective fibers. Thickening of the
subendothelium, deformation of the elastic tissue. Formation of atherosclerotic
fibrous ЀЀЀЀЀЀ on endothelium, which consists of lipid-laden smooth muscle cells,
surrounded by a fibrous matrix. If a lesion is in progress, it occludes the
arterial lumen.
3. Degeneration and destruction of intima and vascular wall. Destruction of
ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ, their lysis, fragmentation of ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ. Formation of
ЀЀЀЀЀЀЀЀ ЀЀЀЀЀ. Formation of ulcers, which can perforate. ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ. The core of the fibrous ЀЀЀЀЀЀ consists of lipids
and debris from cellular necrosis caused by insufficient blood supply.
4. Sclerotization (calcification) of vessels. The lumen of the atherosclerotically
changed vessels becomes narrow as a result of a formation of atherosclerotic
ЀЀЀЀЀЀ. As the altered complex structure becomes rigid, it causes vascular
occlusion.
Atherosclerotic changes in the vessels predispose to thrombogenesis. Blood
clots are formed in the intima layer. Ischemia (infarction) develops in the
region of the damaged vessels. Fibrous ЀЀЀЀЀЀ are altered by hemorrhage.
Functional disturbances of vessels consist in
• Disorder of the elasticity of vessels,
• Incapability of vessels for dilatation,
• Tendency of the damaged vessels toward spasm.
Atherosclerotic damage of the vessels results in disorder of blood circulation,
ischemia, local blood congestion and stasis, disturbance of throphicity of the
tissues, and necrosis (infarction) in the regions of damaged vessels.
SYSTEMTC MANTFESTATTONS OF ATHEROSCLEROSTS
In entire organism the manifestation of atherosclerosis depends on

Localization of process (most frequent localization of atherosclerosis is
aorta, the arteries of brain, heart, kidneys, extremities),
Degree of the functional disturbance of the organ, blood circulation of
which is disrupted.
The most essential clinical consequences of atherosclerosis are the following.
• Atherosclerosis is a main cause of myocardial infarction. Myocardial ischemia
is a life-threatening manifestation of atherosclerosis.
• Atherosclerosis of cerebral vessels leads to the serious disorder of cerebral blood
circulation and corresponding clinical symptoms (ischemic episodes, insult,
disorder of memory and higher nervous functions). Cerebral ischemia is a life-
threatening manifestation of atherosclerosis as well.
• Atherosclerosis is a risk factor for arterial blood hypertension development
because arteriosclerosis elevates systemic vascular resistance.
• Atherosclerosis of the lower extremities vessels frequently leads to necrosis
and amputation.
• Atherosclerosis is tightly connected with obesity and insulin deficiency. So, it
is a secondary complication of diabetes mellitus.
6
In a final conclusion, atherosclerosis is a leading contributor to coronaro-
dependant cardiac insufficiency and cerebrovascular diseases.
PATHOLOGY OF MUSCULAR (RESTSTTVE ) TYPE OF VESSELS

ARTERTAL HYPERTENSTON
The main function of muscular (resistive) type of vessels is to maintain an

arterial blood pressure at a certain level. It means, that the first manifestation of the
resistive vessels pathology is a deviation of the arterial pressure level from the
standards.
The tonus of muscular (resistive) type of vessels consists of two components -
• Vasomotor (neurogenic), which is regulated by nervous mechanisms,
• Basal (myogenic), which is regulated partially automatically as a reaction of
smooth muscles on ЀЀЀЀЀЀЀЀЀЀ, partially by BAS and electrolytes (ions Na, K, Ca).
All mechanisms of physiological regulation of arterial blood pressure are
divided into two groups – vasoconstrictive (provide an increase of arterial blood
pressures) and vasodilative (provide a decrease of arterial blood pressures).
VASOCONSTRTCTTVE MECHANTSMS
Nervous Mechanisms
• Experiments with animals confirmed that stimulation of some structures of the

brain (for example, ЀЀЀЀЀЀЀЀ ЀЀЀЀЀ ЀЀЀЀЀЀ ЀЀЀЀ the frontal pole of frontal lobe,
ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ orbital convolutions, motor zone of the cortex, ЀЀЀЀЀЀЀЀ
ЀЀЀЀЀ ЀЀЀЀЀЀЀЀ ЀЀЀЀ temporal lobe, ЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ of hippocampus,
ЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀ amygdaloidal nucleus) causes increase of the arterial blood
pressure.
• The participation of nervous system is proved by the influence of emotions on
arterial blood pressure.
• Reticular formation of the brain influences the arterial pressure as hemodynamic
center is a part of ЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ,
• Hypothalamus is the highest integrator of vegetative functions and influences
the arterial pressure.
• Sympathetic innervation performs vasoconstrictive function and increases the
vasomotor component of the vascular tonus. It is achieved with the aid of the
nervous mediator noradrenaline.
α-adrenergic receptors increase a resistance of arterioles to blood flow.
α-adrenoreceptor mechanism influences venoconstriction and increases
recovery of the venous blood to the heart.
β1-adrenoreceptors activate the function of the heart and increase systolic
component of the arterial blood pressure.
β2- adrenoreceptors provide vasodilatation.
• Function of the peripheral baroreceptors of the carotid sinus and aortic arch is
closely connected with an action of the central mechanisms of the vascular tonus
regulation.
• ЀЀЀЀЀЀЀЀЀЀ of inhibiting influence of the baroreceptors on the vasomotor center,
reticular formation of the ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ truncus cerebri and hypothalamus
(ЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ ЀЀ ЀЀЀЀ ЀЀЀЀЀ Ѐ ЀЀЀЀЀЀ ЀЀЀЀЀЀ ) causes
7
increase of catecholamine secretion (by the medullar substance of the
adrenal glands) and aldosterone secretion (by adrenal cortex).
Hormonal Mechanisms
Hypothalamo-pituitary and sympatho-adrenal systems have the main value in

the regulation of vascular tonus.
• Hypothalamus secrets vasopressin, which increases arterial blood pressure.
• Medullar part of the adrenal glands is activated under an effect of the
sympathetic nervous influences and ensures entering into the blood of
catecholamines. Noradrenaline, which reveals with the excitation of α-
adrenoreceptors, causes the vasoconstrictive effect on the resistive vessels.
• Mineralocorticoids (aldosterone and desoxycorticosterone, which are formed in
adrenal cortex) produce vasospastic effect. They cause retention of sodium in
organism as a result of its increased reabsorption from primary urine in distal
part of renal tubules and retention of water and ЀЀЀЀЀa ЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀ.
• Under influence of aldosteron, sensitivity of the vascular wall is increased to
different vasoconstrictive effects — nervous and humoral (catecholamines,
vasopressin, angiotensin II).
• Glucocorticoids in large dose (formed in adrenal cortex) refer to stress formation
and an increase of arterial blood pressure.
Renal Mechanisms
Juxtaglomerular apparatus of the kidneys is a place of a formation of renin

(renin-proteolytic enzyme). α-Globulin of the blood plasma
(angiotensinogen) is a substrate for angiotensin-I synthesis. Secretion of
renin depends on the blood pressure in the afferent vessels of the renal
glomeruli.
Under renin effect angiotensin-I (product of enzymatic reaction renin →
angiotensinogen) is formed. This polypeptide (decapeptide) is transformed into
angiotensin-II (octapeptide) under an effect of angiotensin-converting enzyme
(ACE). Angiotensin-II is the most effective of all known pressor agents, which
directly influences the wall of precapillary vessels (scheme 22).
Vasoconstrictive effect of angiotensin-II depends on
• Activation of sympathetic part of the vegetative nervous system,
• Increase of aldosterone secretion by adrenal cortex and sodium reabsorption
in kidneys.
Angiotensin II is destroyed by enzyme angiotensinase.
Role of Electrolytes
Ions of sodium and calcium influence the basal (myogenic) tonus of resistive
type of the vessels, elevating it.
• Na+ influences the muscles membrane potentiality, increasing it. In addition, it
retains water, elevating volume of circulating blood.
• Ca2+ rises tonus of contractile fibers.
8
In addition, retention of these ions in vascular wall increases the sensitivity of
the vasomotor apparatus of vessels to the different pressor effects – nervous and
humoral.
All these mechanisms produce vasoconstrictive effect.
VASODTLATTVE MECHANTSMS
Nervous Mechanisms
Nervous vasodilative mechanisms are connected with

• Vagotonus, e.i. vasodilative action of parasympathetic fibers, mediator
acetylcholine (on the vessels of skin, intestine, organs of ЀЀЀЀЀЀ ЀЀЀЀ),
• β-adrenergic effect of adrenaline on the muscular structures of arterioles, where
the parasympathetic innervation is absent,
• Baroreceptors of the ЀЀЀЀЀЀ ЀЀЀЀЀЀ and ЀЀЀЀ ЀЀЀЀЀ arch of the aorta, which are the
receptors of depressor nerves.
Hormonal Mechanisms
Natriuretic atrial hormone opposes the vasoconstrictive hormonal mechanisms.

This hormone is a polypeptide (28 aminoacids) synthesized mostly in the atria of
the heart. Its effect consists in -
• Antagonism with aldosteron, suppression of aldosteron production,
• Antagonism to angiotensine,
• Removal of sodium with urine (intensifies natriuresis by suppression of
sodium reabsorption in the renal tubules),
• Removal of water from organism (intensifies diuresis by suppression of
reabsorption of water in the renal tubules),
• Increase of glomerular filtration,
• Inhibition of entering of Ca2+ into the smooth muscular cells,
• Inhibition of emission of Ca2+ out of the intracellular depot.
Due to these mechanisms, natriuretic atrial hormone encourages marked
vasodilative effect, contributes to antihypertensive effects and decreases the
Progesterone prevents a stable increase of arterial blood pressure.
Renal Mechanisms
It is known now, that the kidneys can promote both - increase and
decrease of the arterial blood pressure. So, together with the hypertensive, the
kidneys possess antihypertensive (depressive) function. Experiment shows that
the letter function of kidneys (depressive) is more important, than hypertensive
one because of its unique.
Experiment shows that ischemia of kidneys (reproduced by partial narrowing of
the renal arteries) causes an increased quantity of renin and angiotensin in the blood
only within the first days after operative manipulation. Very quickly arterial blood
pressure normalizes. The removal of both kidneys (in experiment and in clinical
practice in the condition of usage of the artificial hemodialysis for avoiding of
uremia) leads to the stable rise of arterial blood pressure. It is called renoprive
9
hypertension. These facts cause a supposition, that a stable elevation of arterial blood
pressure can be conditioned by disorder of some depressor function of the kidneys.
The function of kidneys directed to decrease or/and normalization of elevated
arterial blood pressure is called antihypertensive (antipressor, depressive)
function of the kidneys.
Depressive function of the kidneys controls the effects of renal (renin) and
extrarenal (vasopressin, catecholamines, aldosterone, angiotensin-II)
vasoconstrictive mechanisms.
The antyhyperpressive role of the kidneys is realized by
• Secretion of the phospholipid inhibitor of renin,
• Secretion of enzyme angiotensinase, which inactivates angiotensin-II in the
blood and tissues (mostly in the kidneys) preventing elevation of arterial
blood pressure,
• Excretion of sodium with urine,
• Removal of water from organism,
• Excretion of hormones and other substances with vasoactive affect,
• Secretion of prostaglandins of A and E types.
The last mechanism is the most powerful renal vasodilator system and is of a
special interest.
Prostaglandins are the products of the polyunsaturated fatty acids. Interstitial renal
cells of the medullar substance are the place of prostaglandin formation. Increased
quantity of angiotensin II in the blood stimulates prostaglandins formation.
The E-type of prostaglandins causes the hypotensive effect in normal arterial
blood pressure level. The A-type of prostaglandins don't cause decrease of the
blood pressure in healthy animals and people, but prevents development of the
renal and renoprive hypertension in animals or suppression of the increased
arterial pressure in men (fig.43).
___________________________________________________________
Fig. 43. Prostagladins effect on arterial blood pressure in essential hypertension (A) and in
norm (B) (a pointer notes a moment of injection) ЀЀЀ. 61 Ѐ 484 ЀЀЀЀЀЀЀЀЀЀЀ
____________________________________________________________________
Prostaglandins vasodilative effect is realized by
• Effect on the basal component of the resistive blood vessels tonus,
• Contribution to the sodium excretion with the urine,
• Contribution to the intracellular localization of potassium,
• Stimulation of the renal kallikrein-kinin system.
Role of Electrolytes
As it was mentioned above, just electrolytes determine the basal (myogenic)

tonus of the resistive (muscular) blood vessels.
Contrary to Na and Ca ions, the intracellular localization of K-ion contributes
to vasodilatation. Metaphorically, potassium is called as “liquid vagus”, having in
mind its vasodilative effect. Potassium increases the potentiality of calm on the
membranes of the excitable cells (muscle cells of arterial vessels in this case).
10
The income of potassium into the cells is provided against very high difference
of K-ion concentration between its intracellular and extracellular patterns.
Prostaglandins and n. vagus provide this process. (ral and intravascular
introduction of potassium salts does not survive its intracellular localization without
participation of n. vagus and prostaglandins. It is necessary to have it in mind while
usage of potassium in treatment of hypertension.
Endothelial and Local Metabolic Mechanisms
The mono-oxide of nitrogen N( (nitrate of endothelial origin) contributes to

the dilatation of arterial vessels. This effect is imitated by injection of nitrous
medical drugs (nitroglycerine, amylnitrits) in treatment.
A lot of local metabolites plays a role in regulation of regional circulation and
has vasodilative effect. They are – lactate, ADP, bradikinin, hystamin an oth..
So, the interconnection between vasoconstrictive and vasodilative mechanisms
determines the arterial blood pressure. Disbalance leads to development of two
opposite phenomenon – arterial hyrpertension and arterial hypotension.
ARTERTAL BLOOD HYPERTENSTON
Hypertonic disease is a stable increase of the arterial blood pressure, when the
level of a systolic and diastolic pressure is, accordingly, higher than 140/ 90 mm Hg.
It is one of the leading factors of morbidity and mortality in the population.
There are primary and secondary arterial hypertension depending on its
origin.
Secondary arterial hypertension is an increase of arterial blood pressure as a
sign and consequence of some other diseases (glomerulonephritis, stenosis of the
aortic arch, adenoma of the hypophysis or of the cortical or medullar substance
of the adrenal glands, etc.). It is a so-called symptomatic hypertension.
Primary hypertension is called essential hypertension that indicates that its origin
is unknown. 80% of all cases of arterial hypertension are primary hypertension, the
remaining 20% are secondary one (14% of them are connected with diseases of the
renal parenchyma or renal vessels).
ETTOLOGY
Similarly to that of atherosclerosis, the etiology of hypertonic disease consists

in interaction of etiological factors, conditions and the risk factors. In any
individual case of arterial hypertension, the same factor plays a role of etiological
or risk factor, or the role of a condition. Specifically, this gives the possibility to
determine arterial hypertension as polyetiological disease.
There are many causes of primary hypertension, and some of them are still
unknown. But it is indisputable, that overtension of the higher nervous activity under
the influence of emotional effects has definite meaning. Negative emotions have
special meaning, in particular those, which were not reacted by motor activity.
Power of pathogenic effect of these emotions falls upon blood circulatory system.
That is why hypertension is called as "a disease of nonreacted emotions."
11
Hypertension disease is "a disease of autumn of a man's life, it does not give
him an opportunity to live till winter" (A. A. Bogomoletz). So, age has a great
importance in origin of the hypertensive disease. But sometimes, a primary
hypertension occurs at young age. It is important, that men yanger 40 have this
disease more often, than women, but over 40 years it is on the contrary.
Stress determines an activation of hypophysal-suprarenal and sympatho-
adrenal systems with a subsequent start of renin-angiotensin-aldosteron pressor
mechanisms. It is confirmed by often development of a primary hypertension in the
peoples with "stress" professions.
Epidemiological observations had established a close connection between level of
the arterial blood pressure and quantity of consumed table salt (table-salt abuse).
They suppose that long consumption more than 6 g of table salt a day promote
primary hypertension in people, having hereditary predisposition to it. Successful
experimental simulation of "salt hypertension" confirms importance of excess
consumption of table salt. There are clinical data about favorable therapeutic effect
of low-salt diet in some forms of primary hypertension.
Risk factors are nervous overstrain, hypodynamia, smoking, alcohol abuse,
elderly age, hormonal (climacteric, hyperthyroidism) disturbances, atherosclerosis,
the systemic disturbances of metabolism, and the excessive use of common salt.
Genetic factors (predisposition) is an important factor of the development of
the primary hypertension in man and is confirmed statistically and by proper
methods - genealogical, gemellary and experimental. The special features of the
nervous and endocrine regulation of vascular tone are genetically determined. In
some families this disease develops several times more often, than in remaining
population. High concordance in hypertensive disease in monovular twins is also an
evidence of genetic factors significance. (nly on this background other external
and internal factors can contribute to the development of arterial hypertension.
PATHOGENESTS
There are 3 hemodynemic variants of arterial hypertension in accordance with

formula P=QR, where P is arterial blood pressure, Q is a cardiac outflow (minute
blood volume, systolic pressure), R is a systemic ЀЀЀЀЀ peripheral resistance to
the blood flow (diastolic pressure). These variant are the following
Hyperkinetic - Q is increased, R is not changed or is decreased a little
Eukinetic - both Q and R are increased
Hypokinetic - Q is not changed or is decreased a little, R is increased.
In each individual case of hypertonic disease, the pathogenesis is determined by
balance of pressor and depressor mechanisms (activation of vasoconstrictive
mechanisms and/or inhibition and insufficiency of vasodilative ones) by the
participation of nervous, renal and humoral factors. (ne of them or a specific
totality comes out to the foreground in each individual case.
Taking into consideration the role of nervous, endocrine, renal and electrolyte
factors in the elevation of arterial pressure, some concepts of arterial hypertension
pathogenesis were suggested – nervous, hormonal, renal and electrolyte-steroid.
Every concept is based on a fact, that it is possible to reproduce arterial
hypertension in experiment by mean of influence on nervous, hormonal, renal and
electrolyte mechanisms.
Role of Nervous Mechanisms
12
The nervous concept of arterial hypertension is based on the fact of a
possibility to model it in animal by reproducing neurosis.
The role of a neurogenic factor in pathogenesis of hypertensive disease is
presented in conception of Russian cardiologists Lang and Myasnikov. They
suggested, that nervous overstrain, an etiological essence of hypertensive disease, is
realized in disorder of the cerebral centers of control upon arterial blood pressure.
Disbalance between excitation and inhibition in the region of vasomotor center
and then an exhaustion of its function causes neurotic and a higher nervous
activity disorders, the development of the stable increase of the arterial pressure.
Stable excitement of hypothalamus (the highest integrator of the vegetative
functions) activates the sympatho-adrenal system causing increase of vasomotor
component of the vascular tonus.
Sympathetic part of vegetative nervous system activates medullar part of the
adrenal glands and coming into the blood of adrenaline and noradrenaline.
Activation of β1-adrenoreceptors of the heart activates the heartbeats (↑Q -
hyperkinetic variant of hypertension). When α-adrenergic effect of adrenaline and
noradrenaline on tonus of resistive vessels (↑R) exceeds β2-adrenergic effect of
adrenaline (which is directed to decrease of vessels resistance), the hypokinetic
variant of hypertension develops (scheme 23).
Function of the baroreceptors of the carotid sinus and aortic arch is closely
connected with the action of the central mechanisms of the vascular tonus regulation.
Their ЀЀЀЀЀЀЀЀЀЀ is accompanied by marked and stable pressor reaction. It is
confirmed by scientific observation that sensitivity of the carotid sinus
baroreceptors is decreased in hypertension in a course of time.
Role of Hormonal Mechanisms
Disorder of endocrine glands function is an important link of aterial hypertension

pathogenesis. The adrenal glands are the most important.
Adrenaline and thyroxin cause a short-term increase of arterial blood pressure.
Aldosterone mechanism is connected with influence on sodium balance.
Sensitivity of the vascular wall to nervous and humoral (catecholamine,
vasopressin, angiotensin II) influences increases. Sodium salts retention in
organism has as a consequence their accumulation in the muscular elements of the
arteries. Hypervolemia, endothelial edema and partial narrowing of the vessels
develop because of accompanying retention of water.
Electrolyte-steroid concept is a variant of the hormonal concept. Experimental
hypertension can be achieved by injection of aldosterone and desoxycorticosterone,
especially with load of sodium chloride. It results in Q elevation (due to elevation of
ЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀ).
High level of myogenic and vasomotor components of the vascular tonus is
achieved in conditions, when balance of the aldosterone and angiotensin II on one
hand, and natriuretic atrial hormone on the other hand, is shifted in favour of
the first. Such disbalance arises in early stages of arterial hypertension.
So, finally, the endocrine mechanisms of arterial hypertension are the following.
• Activation of hypophysal-suprarenal and sympatho-adrenal systems
• Activation of the medullar part of adrenal glands under an effect of the
sympathetic nervous influences and entering of adrenaline into the blood
• Vasoconstrictive effect of noradrenaline, connected with an excitation of the α-
adrenoreceptors of a resistive type of vessels
13
• Hypersecretion of aldosteron, which leads to the retention of sodium and the
removal of potassium
• Activation of aldosterone-vasopressin system (increased secretion of
vasopressin)
• Hypersecretion of glucocorticoids (hormones of adrenal cortex), which has a
permissive effect to catecholamines
• Sexual hormones (especially progesteron) deficiency (example is a climacteric
arterial hypertension).
Role of Renal Mechanisms
Disorder of renal blood circulation is an important component of arterial

hypertension pathogenesis. Clinical observations also proved, that
progression of hypertension can be caused by changes in the kidneys.
Renal theory of arterial hypertension is based on experimental reproduction of
hypertension by narrowing of renal arterias lumen and modeling of renal
ischemia.
Activation of hypertensive renal mechanisms during a disorder of blood
circulation in the kidneys has a value with an activation of the renin-angiotensin
system and suppression of the depressor renal mechanisms (reduction in
prostaglandins synthesis). Angiotensinase activity of the kidneys gets
decreased in disorder of hemodynamic in both kidneys. So, arterial
hypertension of renal genesis is partly conditioned by renin-angiotensin
system activation and partly by decrease of production of angiotensinase.
_________________________________________________________________
ЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ Stenosis of renal artery
ЀЀЀЀЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ Hyperthrophy and hyperplasia of
ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀ ЀyЀЀЀi ЀЀЀЀЀ Decrease of renal function
ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ disorder of intrarenal blood circulation
ЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ Renin hypersecretion
ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀ II Increase production of angionensin II
ЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀ Hypersecretion of aldosterone
ЀЀЀЀЀ ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀ Changes in catecholamine secretion
ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀ increase of vessel reactivity and
peripheral resistance
ЀЀЀЀЀЀЀЀЀЀЀ Hypertension
ЀЀЀ ЀЀЀЀЀЀЀЀЀ ЀЀЀ ЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ
Fig. 44. Pathogenesis of the renal arterial blood hypertension ЀЀЀ. 60 Ѐ. 483 ЀЀЀЀЀЀЀЀЀЀЀ
__________________________________________________________________
MANTFESTATTONS
Clinical manifestations of arterial hypertension are described in every detail in

the textbooks on therapy.
The first complications are the local circulatory disorders, and then
insufficiency of organs and systems. The most often clinical forms of complicated
hypertension are cerebral circulatory insufficiency (including insult), hypertrophy
14
of the myocardium with the following circulatory insufficiency, and renal
insufficiency (syndrome of the ЀЀЀЀЀЀЀЀЀЀ kidney).
Briefly the clinical manifestations of arterial hypertension are enumerated
below:
• Increase in the arterial blood pressure above 140/90 mm Hg
• Increase of a load on the heart (load by resistance)
• Myocardial hypertrophy
• Heart insufficiency
• Disorder of blood circulation in the kidneys
• Disorder of blood circulation in ЀЀЀЀЀЀЀЀ ЀЀЀЀЀ
• Edemas
• Hemorrhages
• Disorder of trophicity of the tissues
• Risk factor of the atherosclerosis development
• Risk factor of myocardial infraction
• Risk factor of hemorrhagic insult
PULMONARY HYPERTENSTON
Pulmonary hypertension is characterized by increase of pulmonary arterial

blood pressure more than 25 mm of Hg and development of the so-called cor
pulmonale and right-side type of circulatory insufficiency.
By its origin pulmonary hypertension can be primary and secondary.
The development of the secondary pulmonary hypertension is caused by
diseases affecting the respiratory ways and alveoli (chronic bronchitis, bronchial
asthma, chronic pneumonia, pulmonary emphysema, pneumosclerosis), disorder of
movements of a chest (kyphoscoliosis, pleura fibrosis, chronic neuro-myasthenia or
polymyelitis) and also by diseases, that affect the pulmonary vessels (nodular
periarteritis, thrombosis of the small blood vessels, embolism of the pulmonary
artery) and the heart (mitral stenosis, ЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀ
ventricular septal defect).
Primary pulmonary hypertension is more rare, develops without diseases of the
lungs and heart (pulmonary hypertension of the unknown etiology). Sometimes
primary pulmonary hypertension is congenital.
(ne of the mechanisms of the pulmonary hypertension development is a
decrease of p(2 in alveolar air. In ЀЀЀЀЀЀЀЀЀЀЀЀ conditions an influence of this
factor is more marked. Low partial pressure of oxygen in the alveolar air has a
direct influence on the smooth muscular elements of the pulmonary vessels, causing
stable increase of their tonus. The smooth muscles of the lungs have Ѐ2-sensitive
Ѐ+-canals. Decrease of p(2 in alveolar air leads to closing of these canals,
absorption of sodium by the myocytes of the vessels, depolarization of their
membranes, decrease of ЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀ excitative threshold, entering of
ЀЀ2+-ions into ЀЀЀЀЀЀЀЀЀЀЀ and contraction of the smooth muscles – spasms of the
vessels.
Vasopressive effect of hypoxia is increased in development of acidosis and on
physical exertion. (n the other hand, hydrogen ions, vasoactive amines
(histamine, serotonin), metabolic disorders has a role of mediator of pressor effect of
hypoxia on the lung vessels. Alkalosis decreases vasoconstrictive effect of hypoxia.
Adenosine, AMP, acetylcholine have vasodilatative effect on the lung arteries.
15
ARTERTAL HYPOTENSTON
Arterial hypotension is a stable decrease of arterial blood pressure (lower than

100/60 mm Hg) caused by decrease of tonus of the resistive types of the vessels.
Arterial blood hypotension is divided into physiological and pathological,
primary and secondary, acute and chronic.
Physiological arterial hypotonia is not accompanied by ЀЀЀЀЀЀЀЀЀЀЀ
symptoms. More often it is observed in people with asthenic constitution.
Pathological one has a typical symptom-complex. They are - decreased
physical development and feeding, general adynamia, undue fatigability,
tachycardia, dyspnoea, vertigo, headache, syncope.
An acute arterial hypotension develops in shock and collapse.
Chronic arterial hypotension is divided into primary (hypotensive type of
neurocirculatory dystonia) and secondary (symptomatic).
There are three hemodynamic forms of arterial hypotension:
• Connected with disorder of contractile function of the heart and decrease of
systolic volume of the blood
• Caused by a decrease of circulating blood volume
• Caused by decrease of tonus of the resistive vessels
It is believed that the main etiologic and pathogenic factor of primary arterial
hypotension is overtension of the main processes of the cerebral cortex (excitation
and inhibition) as in hypertensive disease. But unlike primary hypertension, this is
a predomination of inhibition and its spreading on the subcortical vegetative
formations (vasomotor center). Suppression of vasoconstrictive influences, and at
the same time predomination of cholinergic influences over adrenergic ones
(typical for asthenic type of constitution) are the ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ cause of a
decreased resistive vessel tonus, decrease of the peripheral vascular resistance and
Symptomatic (secondary) chronic arterial hypotension is a consequence of
acute and chronic somatic diseases of
• Heart (ЀЀЀЀЀЀ, myocarditis, myocardial infarction)
• Brain (ЀЀЀЀЀЀЀЀ )
• Lungs (croupous pneumonia)
• Liver (hepatitis, mechanical jaundice)
• Blood (anemia)
• Endocrine glands (hypofunction of adrenal, thyroid and pituitary glands)
Exogenic and endogenic intoxication can play a role in chronic arterial
hypotension development.
ЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀ 22 Ѐ 23 ЀЀЀ ЀЀЀЀ ЀЀЀЀЀ ЀЀ ЀЀЀЀ ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ 25Ѐ Ѐ 25 Ѐ,

ЀЀЀЀЀ ЀЀ ЀЀЀЀЀЀЀЀЀЀЀ
16
ЀЀЀЀЀ ЀЀЀ ЀЀЀЀЀ 25
Scheme 22. Mechanisms of vasopressive effect of angiotensin II
Angionensinogen
Angionensin I
Angionensin II
Stimulation Disorder of Activation of Activation of Increase of Stimulation

of growth endothelial pressive factors sympathethic bradikinin of
factors function (endothelin-1) effects instraction aldosterone
(deficit of secretion
NO)
Vasoconstriction
Hyperthrophy
of vessel wall Retension of
Na and water
Increase of arterial pressure
Scheme 23.
Sympathetic regulation of heart and vessels
β1 α β2
↑ Rate of cardiac ↑ R ↓R Renal

contractions юкстагломерулярный
↑ Systolic volume Peripheral аппарат
vessel
resistance
↑ Сердечный выброс ↑Q
Renin
ACE
Angiotensinogen Angionensin I Angionensin II Aldosteron Na ↑

CHAPTER 26
PATHOPHYSIOLOGY OF RESPIRATORY SYSTEM
Respiration is a function of organism in maintenance of the gas composition of the

blood, supplying of tissues by oxygen and revealing CO2.
Respiration is divided into external and internal. Internal (tissue) respiration is an
enzymal system of oxygen utilization by tissues. The disorders of the internal
respiration are revealed in the chapter 11 «Hypoxia».
External respiration realizes with participation of the central nervous system,
peripheral nerves (motor and sensitive, somatic and vegetative), respiratory muscles
(inter-rub and diaphragm), upper respiratory ways, thorax and lungs, which are
necessary for normal ventilation. In a case of their disorder respiratory failure develops.
Three main processes take place in the lungs
• Ventilation,
• Diffusion of the molecular oxygen and carbon dioxide through the alveolar-
capillary membrane,
• Perfusion (flowing of the corresponding amount of the blood via the pulmonary
capillary vessels).
Respiratory insufficiency is a pathologic process, which develops as a result of
external respiration disorder, when an adequacy of gaseous content of the blood in
relation to organism requirements at rest and during physical load is not ensured.
Respiratory failure even at rest may lead to hypoxia, gaseous acidosis and limits
the organism abilities to fulfill physical work.
CLASSIFICATION
Pathology of respiratory system may be classified from different principles.

Etiological classification divides it into acquired and hereditary (congenital), as
well as infectious and noninfectious (including environmental due to pathogenic
effect of environmental factors),
Topographic classification divides it into extrapulmonary and pulmonary as to
localization of an initial cause.
Pathogenetic classification divides it into primary (pathology begins in respiratory
system) and secondary (complication of other diseases - arterial hypertension, heart
insufficiency as it is in cardiac asthma etc.) as well as total and partial (all or single
physiological process get disordered in the lungs). The latter in turn is subdivided into
ventilative, diffusive, perfusive and combined. In turn, ventilative one is subdiveded
into disregulative, obstructive and restrictive (scheme 24). Depending on a type of a
typical pathologic process it may be divided into inflammatory, allergic, tumorous,
vascular.
Clinical classification divides it into acute and chronic.
1
Scheme 24
Respiratory Insufficiency
Ventilative Diffusive Perfusive Combined
Result of Result of
Disregulative systemic local disorder
disorder of of blood
blood circulation
Obstructive circulation
Restrictive
Compressive
Occlusive
Extrapulmonary Pulmonary
Spasmatic
ETIOLOGY
The causes of respiratory pathology are numerous. Their general property is an

ability to influence on gas composition of the blood and a supply of tissues with
oxygen.
Etiological factors are divided into exogenous and endogenous, acquired and
hereditary. In turn, they are divided into physical, chemical and biological.
Physical factors are mechanical trauma, the foreign bodies, which obstruct the lumen
of the respiratory tract, the barotrauma, which leads to increased or decreased solubility
of gases in the blood, eletrotrauma with the condition of electrical current passage
through the respiratory center.
Chemical factors are the poisons (muscarine), the narcotics (they lead to lung edema
and stopping of respiration), the side effect of medical drugs, smoking, industrial
harmfulness, which are inhaled (environmental diseases). Боевые toxic substances of
inhaled action (phosgene) cause pulmonary edema.
Biological factors are infectious with tropism to the organs of respiration
(pneumococcus, the agent of tuberculosis, adenoviruses) and immune.
Endogenous factors are autoimmune and genetic.
PATHOGENESIS
Pathogenesis of different types of respiratory insufficiency is different and needs

separate discussion.
2
VENTILATIVE RESPIRATORY INSUFFICIENCY
Ventilative respiratory insufficiency is divided into disregulative, obstructive and

restrictive ones.
Disregulative Ventilative Insufficiency
All parts of nervous system relate to respiratory function regulation - cerebral cortex,
hypothalamus, spinal cord, n. vagus, motor and sensitive nerves. Alveolar ventilation is
regulated by neurons of the respiratory center, which are located in the medulla
oblongata, мост головного мозга, cells of reticular formation, motoneurons of a spinal
cord, nervous ways transmitting impulses to respiratory muscles and diaphragm.
These mechanisms provide a certain depth, rate and rhythm of respiration. Base of
disregulative ventilative insufficiency is a dysfunction of respiratory center or disorder
of transmission of efferent influences to respiratory muscles.
Dysfunction of the respiratory center may happen due to direct effect of different
pathogenic factors on the central nervous system or by reflex.
Disorder of a respiratory center may be caused by pathogenic factors, which influence
directly on metabolism, structural and functional properties of its neurons. Such factors
may be - hypoxia, hypoglycemia, trauma of the brain, compression of the ствола головного
мозга (edema, tumor, гематомa), disorder of the brain blood circulation, intoxication
(poisoning by narcotics and muscarine, toxic metabolic products in hepatic and renal
insufficiency). Inflammation and dystrophy are possible in any part of nervous system.
Cutting of n.vagus in experiment leads to the lung collapse. Hemorrhage into the region
of respiratory center or n.vagi center disrupts respiratory act. Function of a respiratory
center may be changed by reflex with effect on receptors in vascular bed, respiratory
ways and lung parenchima.
In pathology, under influence of рефлекторных, humoral or other effects on the
respiratory center, the depth, rate and rhythm of breathing may be changed. Some of
these changes may be a manifestation of compensatory reactions directed to supporting
of gaseous constancy in the blood. At the same time, some of them are a manifestation
of impairment of normal regulation of respiration leading to disorder of alveolar
ventilation and respiratory insufficiency.
Changes of depth and rate of respiration leads to decrease of alveolar ventilation
(hypoventilation) or its increase (hyperventilation). In disorder of nervous regulation
such types of respiration may develop – bradypnoe (rare breathing), tachypnoe
(frequent superficial breathing), hyperpnoe (deep frequent breathing), apnoe,
periodical breathing.
A disorder of transmission of efferent impulses from respiratory center on
respiratory muscles may be a result of
• Damage of nervous проводниковых ways, which connect neurons of respiratory
center with motoneurons of spinal cord,
• Disorder of function of motoneurons of spinal cord, which innervate respiratory
muscles (inflammatory and dystrophic processes in a spinal cord)
• Damage of peripheral nerves, which innervate respiratory muscles (trauma,
inflammation, avitaminosis)
• Damage of transmission of nervous impulse on muscles (myasthenia, injection of
myorelaxants)
• Damage of n. phrenicus and diaphragm paralysis.
Sometimes, due to disorder of regulation of respiratory act, the respiratory
automatism gets lost when only произвольный control on respiration remains.
3
Obstructive Ventilative Insufficiency
Obstructive ventilative insufficiency is connected with pathology of respiratory

tract. It is subdivided into compressive, occlusive and spasmatic ones.
Compressive
Compressive ventilative insufficiency happens is the cases of a pressure on

respiratory ways or lungs from outside by tumor, inflammatory swelling, заглоточный
abscess, enlarged thyreoid gland, strangulation, etc.
Occlusive
Occlusive ventilative insufficiency occurs as a result of narrowing of the

respiratory ways from inside and increased resistance to air.
Causes are
• Entrance of foreign bodies into respiratory ways
• Occlusion by vomiting mass, water, blood, pus, transudate
• Thickening of the walls of respiratory ways (inflammation, edema, hyperemia,
tumor),
• Hyperthrophy and hyperplasia of mucous cells
• Accumulation of phlegm (hypersecresion of mucus, disorder of its reological
properties, disorder of cough mechanism).
Spasmatic
Spasmatic ventilative insufficiency is a frequent and significant mechanism of

bronchial obstruction.
Bronchial spasm has nervous and humoral causes.
Nervous regulation of bronchial lumen is provided by n. vagus and sympathetic
nerves. N. vagus has different types of neurons. Cholinergic motoneurons reveal
acetilcholin, which stimulates bronchial contraction. Peptidergic type of neurons
reveals a P-substance, which has the same effect. Another type of neurones reveal a
so-called VIP-substance (vasoactive intestinal peptide), which dilates bronchi.
Noradrenaline and adrenaline dilate bronchi as well (β-adrenoblockers cause cough
and bronchospasm).
So, bronchial spasm gets determined by
• Increased activity of cholinergic neurons of n. vagus and a release of acetilcholine
• Increased activity of peptidergic neurons of n.vagus, which reveal P-substance
• Deficiency of VIP-ergic neurons activity.
Bronchial asthma is a typical clinical example of bronchospasm.
There is a large group of humoral factors (hystamin, serotonin, leukotriens, kinins,
prostaglandins, throboxans etc.), which cause bronchospasm.
Restrictive Ventilative Insufficiency
Restrictive ventilative insufficiency is connected with a disorder of lung

растяжимости. It may occur due to extrapulmonary reasons (connected with pathology
of respiratory muscles, thorax and pressure in pleural cavity) and intrapulmonary ones,
4
which are connected with properties of alveolies. Inflammation, blood congestion and
edema in the lung disorder its растяжимости and bother its sufficient expansion.
Disorder of Surfactant System of the Lungs. In norm, an internal surface of the
alveolis is covered by surfactants - поверхностно-активными substances of lipoproteid
origin. Surfactants protect alveolies from collapse and prevent liquid transudation from
capillaries into alveolar lumen. Pneumocytes participate in their synthesis,
депонировании готового материала. Macrophages remove surfactants.
The mechanisms of surfactant system disorder are the following -
• Disorder of synthesis
• Accelerated removal from the surface of alveoli
• Destruction.
Below are the typical clinical examples, when a problem with surfactant system
appear -
• Systemic hypoxia and acidosis
• Lung inflammation
• Disorder of blood circulation in the lungs
• Aspiration of vomiting mass
• Providing of artificial blood circulation
• Usage of high concentration of oxygen (use of pure oxygen in respiratory
insufficiency may aggravate it).
Pneumosclerosis is a fibrosis of the lungs, which results in decrease of растяжимости
of the lungs. Its reasons are the following –
• Chronic toxic damage
• Prolong inflammation
• Diffuse systemic diseases of connective tissue
• Ionizing radiation influence
• Smoking abuse.
Pneumosclerosis ends different diseases of the lungs and most often the chronic
inflammatory diseases (infectious and allergic). An excessive growth of fibrous tissue
takes place in parenchimatous elements and capillaries.
Athelectasis is a collapse of the lungs. It is a pathologic process, when alveolar
ventilation stops and lung collapses as a result of air рассасывания. Athelectasis may be
obstructive and compressive. The causes are - bronchial obstruction, compression of
lungs by exudate or tumor. Surfactant deficiency plays a role.,
Extrapulmonary reasons of restrictive ventilative respiratory insufficiency are
connected with
• Disorder of structure and function of respiratory muscles,
• Hamper of mobility of thorax and diaphragm,
• Increased pressure in pleural cavity, accumulation of exudate or transudate
(hydrotorax).
As a result of these causes, excursions of thorax and expansion of the lungs gets
disordered with hypoventilation.
Pathology of respiratory muscles (inter-rib muscles and diaphragm) disorders
breathing and causes an extrapulmonary restrictive respiratory insufficiency. Disorder
of their structure and function, inflammation, dystrophy may be a reason. Inflammation
(myositis), radiculitis, paralysis, paresis are possible. The pain, connected with the
pathology of respiratory muscles, disrupts respiratory act.
Stopping or disorder of ventilation may occur in limitation of the thorax mobility
(mechanical trauma of chest).
If pleural cavity gets damaged and air enter it, negative pleural pressure rises,
transpulmonary pressure gets decreased and lung gets collapsed. Pneumo-, hydro-
5
pio- and hemathorax is an accumulation of air, fluid, pas or blood in pleural cavity as
a result of trauma of thorax and pleura, perforation of the esophagus, extension of lung
abscess or other infections in the pleura with formation of bronchopleural fistula, rupture
of air-containing cysts or bullae associated with emphysema or other forms of diffuse or
local lung disease.
At figure 45, the spirogrames in some clinical cases with obstructive (b) and
restrictive (c, d) disorders are represented. If a parenchyma of the lungs would be
normal but the respiratory ways would be narrowed, жизненная емкость легких ЖЭЛ may
remain normal but объемная скорость воздушного потока gets decreased. In restrictive
processes the lungs become more rigid and плохо расправляются but a function of
respiratory ways as usually is not disordered and thus a speed of air flow is not
changed. Nevertheless ФЖЭЛ и ОФВ get decreased, their correlation remains normal.
Форсований видих
Форсований вдих
Максимальна легенева вентиляція
Художнику! Вместо а б в г – a b c d
Fig. 45. Spirogrames of a healthy men (a), in pneumosclerosis (b), bronchial asthma (c) and lung
emphisema (d)
ЗЄЛ – загальна ємність легень
ЖЄЛ – життєва ємність легень
РО – резервний об,єм вдиху
РО - резервний об,єм видиху
ЗО – залишковий об,єм
__________________________________________________________________
Obstructive and restrictive processes are accompanied by increased work of

respiratory muscles, increased energy need and oxygen consumption while ATP
formation. Prolong overloading of respiratory muscles results in their fatigue and
aggravation of respiratory insufficiency.
DIFFUSIVE RESPIRATORY INSUFFICIENCY
Movement of gases via alveolar membrane is provided by diffusion and depends

from diffusive ability of membrane and difference of gas pressure in both sides of
membrane. Diffusive ability of membrane depends from some components, which
provide solubility of gas in tissues, area of membrane surface, its thickness, molecular
mass and coefficient of diffusion. (ниже 2 жирные линии не могу удалить)
According to this, a disorder of gas diffusion in the alveolo-capillaries region occurs
under disorder of alveo-locapillary barrier and has such mechanisms -
• Decrease of area площадь of alveolo-capillar membrane
• Thickeness of capillary membrane
• Decrease of transmembrane gradient of partial pressure of gases in system
alveoli-blood
• Decrease of the volume of capillary blood in the lungs, decrease of speed of
reaction between О2 with Hb and oxygen capacity of the blood, decrease of
alveolar ventilation
6
• Decrease of exposition and a contact of erythrocytes with alveolar air.
The named disorders may be connected with the following pathological processes
and diseases:
• Damage of membranes (membranogenic poisoning)
• Inflammation and accumulation of inflammatory exudate
• Sclerosis
• Fibrosis
• Edema
• Anemia and Hb inactivation
• Emphysema
• Cardiac insufficiency.
Diffusive surface may decrease as a result of resection of lung part, ruin of some
amount of alveoli while chronic inflammation, tuberculosis, athelectasis.
Pathological processes may be accompanied by thickening of alveolar and capillary
walls, increase of amount of connective tissue among them, liquid in alveoli and
interstitium of the lungs. It hampers gaseous diffusion in the lungs and formation of so-
called alveolo-capillar blockade (fig. 46). Alveolar-capillary blockade may be caused
by such diffusive lung damage as pneumokoniosis of different etiology,
pneumosclerosis, sclerodermia, emphysema, pneumonia.
Disorder of gas diffusions refers more to oxygen as a diffusion of CO2 is provided
20-25 times more easily. Thus, depending from change of gaseous content of the blood,
hypoxemic and hypercapnic respiratory insufficiency is determined.
Lung edema plays an important role in alveolo-capillar blockade. It develops when
a liquid gets filtrated via pulmonary microcirculation more rapidly then revealing via
lymphoid vessels. At first, liquid gets accumulated in interstitium between capillary
endothelium and alveolar epithelium (interstitial edema). Then more part of this liquid
moves into interstitium under pleura and near the bronchi, and the letter prevents
liquid passing into alveoli. Then liquid enters alveoli (alveolar edema) with disorder
of gas exchange.
Hemodynemic factors may be a cause of edema, which lead to an increase of the
pressure in capillaries. It is observed in the case of left-side heart insufficiency, some
congenital or acquired heart failure (stenosis of the left atrio-ventriclar foramen).
Among other causes of lung edema, it is necessary to note a damage of lung
microvascular endothelium resulting in their increased permeability to proteins. It is
observed in inspiration of some toxins including high concentration of oxygen. It
happens also in sepsis when BAS are accumulated (mediators of inflammation).
Embolism of a. pulmonalis may result in lung edema as well.
1- normal соотношение of capillaries and alveoli

2 - утолщение of alveoli wall
3 - утолщение of capillaties wall
4 – intraalveolar edema
5 – interstitial edema
6 – расширение of capillaries
Fig. 46. Causes of diffusive disorders

_____________________________________________________________________
7
PERFUSIVE RESPIRATORY INSUFFICIENCY
Disorder of pulmonary blood circulation may be local and as a result of a systemic

disorder of hemodynamics.
Local disorders are hyperemia, venous congestion, ischemia, thrombosis, and
embolism. Inflammation (including allergic) disorders pulmonary blood circulation.
Systemic disorder of blood circulation secondarily disorders pulmonary blood
circulation. The version of pulmonary arterial hypertension exists.
Decrease of Blood Circulation in the Lungs
Decrease of lung perfusion may be in

• Systemic disorder of blood circulation (shock, collapse)
• Disorder of contractility of right ventricle (infract, myocarditis, cardiosclerosis,
exudative pleuritis)
• Disorder of contractility of the left ventricle
• Blood congestion in the lungs
• Some congenital and acquired cardiac disorders, cardiac failure пороки (stenosis or
athresia of a.pulmonalis)
• Embolism of a. pulmonalis.
In all these cases the rate of blood flow in the lungs gets slowed. At the same time,
alveolar ventilation prevails upon perfusion and it provides sufficient saturation of the
blood by oxygen and decreased amount of СO2 (hypocapnia). But, as minute heart
volume under such circumstances gets decreased as well as a speed of blood flow in the
large circle, then the tissues suffer from hypoxia.
Disorder of Ventilative-Perfusive Correlation in the Lungs
A correct correlation between ventilation and perfusion is important for normal gas
exchange in the lungs. In the cases when ventilation prevails upon blood flow, an
amount of CO2 is revealed from the blood more then usually (hypocapnia). If
ventilation gets slower then blood stream, pCO2 in alveolar air gets increased and рО2
in the blood gets decreased with hypoxemia and hypercapnia.
For the best gas exchange in the lungs an optimal correlation between ventilation
and blood supply must be provided in all alveoli. But even in norm it is not so. During
the lung diseases the pathological inequality of ventilation and perfusion join
physiological one. In good ventilated alveolies the blood flow may be weak and alveolis
which are provided with the blood intensively may be badly ventilated.
Figure 47 shows the significant changes of ventilative-perfusive correlation in such
conditions. It is seen that a high ventilative-perfusive correlation only in a little extend
increases blood oxygenation while low one determines its significant decrease and it
results in significant decreased content of oxygen in the blood.
O2 concentration
Fig. 47. Local ventilative and perfusive relations in the lungs and their influence on bled oxygenation
V A – alveolar ventilation, Q – blood amount which flows via pulmonary vessels per minute

8
There are mechanisms in the lungs which are able to maintain a necessary correlation
between alveolar ventilation and its perfusion in the cases of its deviation from normal
level. Deficit of О2 determines spasm of vessels of small circle of blood circulation
(hypoxic vasoconstriction).
COMBINED RESPIRATORY INSUFFICIENCY
Majority of the clinical cases of respiratory insufficiency relates to the combined

type.
In inflammation the ventilation, perfusion and diffusion are disrupted
simultaneously. Lung parenchima and interstitium get involved simultaneously. As
inflammatory diseases are the most frequent pathology, a majority of clinical examples
is a combined respiratory insufficiency in its essence (pneumonia, bronchitis,
tuberculosis etc.).
Edema of lungs refers to this category as well.
Disorder of surfactant system, as a rule, joints 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 of a flight and in weightlessness. A powerful
pressure on the chest limits thorax excursions. Redistribution of blood in the lungs
disorders the blood supply of a certain parts of the lung. Essential changes in gravity
(potent increase while start and landing and its absence in cosmic space) result in
disorders of ventilative-perfusive relations in the lungs.
MANIFESTATIONS OF RESPIRATORY PATHOLOGY
The manifestations of respiratory pathology are metabolic, pathophysiological and

clinical.
Metabolic Disorders
The disorders of metabolism are connected with oxygen deficiency and/or changes of
carbon dioxide content. Disorders of oxidative process and metabolic acidosis are the
main metabolic changes. All of them were discussed in every detail in the chapter 11
«Hypoxia». In some cases of hyperventilation (in the mountains) a respiratory alkalosis
develops.
Patophysiological Disorders
Respiratory pathology is one of the reasons of hypoxia development (respiratory

hypoxia). It is a complex of pathological changes (lack of energy, impairment of
physiological functions, nervous disturbances etc.) and compensatory reactions
(activation of erhythropoiesis, changes in tissue mechanisms of oxygen utilization etc.),
which are typical for every type of hypoxia as a typical pathologic process (described in
the chapter 11 “Hypoxia”).
Nevertheless, in many disorders of external respiration with impairment of
ventilation and perfusion, a respiratory failure may not develop at rest, as gas content in
the blood is maintained normal. A potent compensation is connected with existence in
the lungs of an excessive amount of functional elements (alveolis and capillaries),
which in many times prevail requirement of organism in oxygen at rest. In addition, a
9
perfect system of external respiration regulation reacts to the minimal fluctuations of
pО2 and pСО2 in the blood and, if it is necessary, activates the respiratory muscles
increasing depth and rate of breathing. Blood circulation gets activated in accordance
with breathing. It provides maintenance of constancy of gas content both at rest and in
a case of pathology of respiratory organs. It is a stage of compensation. Не могу удалить
линию
Disorder of ventilation, diffusion and perfusion determines activation of work of
respiratory muscles at rest, increase of load on the system of blood circulation,
intensification of metabolism. Requirement in oxygen increases constantly. Finally,
such moment comes (a stage of decompensation), when at rest the maintenance of
normal gas content in the blood becomes impossible. Then hypoxia, hypercapnia and
gaseous acidosis become the main chain in development of the father disorders in
organism.
At rest a man breathes without any efforts paying no attention to this process. This
condition is called respiratory comfort - eupnoea. Dyspnoe, or shortness of breath is
a clinical notion, which indicates the unpleasant subjective sensations, connected with
breathing. It is a feeling of a lack of air and a demand of activation of breathing
connected with it.
Hyperventilation is an increased volume of ventilation.
As an adaptive reaction, it develops in different physiological and pathological situations connected
with increased loading on organism, for example, muscular work, and intensification of metabolism, ( as
in overcooling. Hyperpnoea or deep and frequent breathing under physiologic conditions occurs as a
response of the respiratory system directed at making the lung ventilation meet the requirements of the
intensified metabolism. It develops due to intensive reflector or humoral stimulation of the respiratory center
in the reduction of the pO2 or in elevation of CO2 concentration in the blood. As a compensatiry reaction,
hyperventilation develops in circulatory and hemic hypoxia and improves oxygenation of the blood. It
supports acid-base balance in organism in all types of metabolic acidosis by revealing CO2 .
Pathologic hyperpnoea with hyperventilation, which is not connected with
adaptation, is of our special attention. It occurs in pathological excitation of the
respiratory center. In such a case it does not follow an activation of blood circulation
and results in decrease of pCO2 in the blood (hypocapnia) and alkalosis development. In
turn, it results in decrease of blood supply of the brain and heart (due to increase of
blood pressure in them), changes of electrolyte balance (hypocalciemia, hypokaliemia)
disorder of oxyHb dissociation, disorder of utilization of oxygen by tissues.
Hypoventilation accompanies respiratory insufficiency and is its basic
manifestation, resulting in hypoxia, hypercapnia and gaseous acidosis.
Changes of frequency, depth and rhythm of breathing relate to the clinical symptoms
of respiratory failure.
Tachypnoe (polypnoea) is a quick breathing. Sometimes it is accompanied by
hyperventilation. If breathing. is frequent and superficial, hypoventilation is a result. In
some cases polypnoea occurs if there is more than usual stimulation of the respiratory
center, on one hand, and excessive activation of the factors inhibiting it, on the other
hand. Polypnoea may be observed in fever, functional impairments of the central nervous
system (hysteria), in lung troubles (athelectasis, pneumonia, congestion). Polypnoea may
develop due to the pain locating in organs taking part in the act of respiration (thorax,
abdomen, pleura). A pain limits the depth of respiration and accelerates it.
Bradypnoe is a rare breathing. Vagotonus may be in basis. Reflective diminishing
of respiration rate may be observed in increased arterial blood pressure as a reflex
from baroreceptors of the aorta arch and carotid sinus. Hyperoxia inhibits a rate due
to switching off of the "hypoxic drive" (e.i. periodic excitation of hemoreceptors
10
sensitive to the lowering of the molecular oxygen tension in arterial blood). An
increased resistance to airflow in upper respiratory ways causes stenotic breathing, a
deep rare breathing, which is a type of convulsive breathing. It occurs with asphyxia.
In this case, inspiration and expiration are accomplished slower than usually. Bradypnoe
may develop as a result of direct effect of the pathogenic factors on the respiratory
center, which decrease an excitability of the respiratory neurons.
Apnoe is a stopping of respiration. Pathologic reflex most frequently is a basis.
Apnoe may result in impairment of gas exchange in organism, severity of which
depends on duration of apnoea.
Periodic breathing is a rhythmical periodical change of breathing rhythm both in the
frequency and in depth. Periods of apnoea may interrupt breathing. Respiration of the
Cheyne-Stokes and Biot type refer to them and are represented in figures 48 and 49.
Cheyne-Stokes breathing is characterized by gradual increase of amplitude of
respiration till marked hyperpnoea and then its diminishing to apnoea; then the same
cycle repeats (fig. 48 a). Breathing of such type may be observed in healthy people at
high altitude (especially during sleep) and in premature babies, which is probably
connected with imperfection of the nervous centers.
Pathogenesis of this type of breathing is not understandable completely. In most cases
Cheyne-Stokes respiration is observed in hypoxia. Some authors interpret it as a disorder
of functional state of respiratory center. They suppose that the cells of the brain cortex
and subcortical formations get inhibited due to hypoxia (as a result, respiration stops,
pO2 diminishes), but hemoreceptors are still capable to react on changes of gas content
in the blood and stimulate the respiratory center resuming respiration. According to this
concept, just because peripheral mechanisms (impulsation from hemoreceptors due to
accumulation of CO2 and baroreceptors due to reduction of the arterial blood pressure)
the respiratory center activity periodically gets renewed.
There is another concept, which interprets Cheyne-Stokes respiration as a profound
adaptive reaction (N.Simeonova, 1962). It was observed in experiment that just this type
of respiration caused an essential prolongation of a life of experimental animals in
hypoxic hypoxia In a figure 48 (b) it is possible to see a periodical slowing of a rate of
breathing (like a concertino) as well as periodical limitation both of an inspiration and
expiration. Periodical extensive вдохи inspirations are observed. The author interprets it
as a primary reorganization just in respiratory center and secondary changes in
respiratory act. The author assumes that the main event is a periodical retention of CO2.
Just it results in compensatory accumulation of bicarbonate buffer, optimization of oxy-
Hb dissociation.
__________________________________________________________________
Fig. 48. Periodical breathing of Cheyne-Stokes type

a) in a cat after acute blood loss (by J.Britvan, 1966) Мал. 62 с 494 украинского
b) in rats while experimental hypoxic hypoxia (by N. Simeonova, 1962).
__________________________________________________________________
Biot type of periodical breathing (fig. 49) differs from Cheyne-Stokes one by the
respiratory movements, which are characterized by constant amplitude but periodical
stopping with periods of apnoea.. This type of breathing has not such adaptive features
as Cheyne-Stokes one mentioned above. Biot respiration is mostly observed in
meningitis, encephalitis and other disease accompanied by impairment of the central
nervous system, especially the medulla oblongata.
11
___________________________________________________________________
Fig. 49. Periodical breathing of Biot type in experimental animal after cutting of мозгового ствола на
уровне моста (by J. Britvan, 1966)

_____________________________________________________________________
Terminal (agony) respiration has several versions – apneustic, Kussmaul, gasping-

respiration.
Apneustic respiration is characterized by convulsive increased efforts to inspire
occasionally interrupted by expiration.
Apneustic respiration is observed in experimental animal after cutting both n. vagi
and the truncus cerebri between the pneumotaxic (in the rostral part of the pons моста)
and apneustic centers (in the middle and caudal parts of the pons). It is believed that
the apneustic center has an ability to excite the inspiratory neurons, which are
periodically inhibited by the impulses from n. vagus and pneumotaxic center. The
cutting of these structures leads to constant inspiratory activity of the apneustic center.
The extreme degree of excitability of the respiratory center is manifested as
Kussmaul breathing, which is mostly observed in the patients in diabetic coma. It is a
deep noisy accelerated breathing when a deep inspiration is followed by intensive
expiration with active involvement of muscles.
Cough can be a defensive reaction if an accumulation of untypical masses (mucus,
foreign body) in the lumen of the respiratory tract occurs. But there are types of cough
without defensive value. Cough commonly develops in stimulation of the nerve
endings 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. Expiratory
efforts of the respiratory muscles develops simultaneously. It leads to the elevation of
pressure in respiratory tracts, alveoli and pleural cavity. Then glottis opens and air
leaves respiratory tracts at a high speed.
Sneezing can be defensive and also pathologic reaction. Sneezing occurs as a
response to the stimulation of the endings of the n. trigeminus located in the mucous
membrane of the nose (especially in the middle turbinate bone and septum). In contrast
to cough, in sneezing the forced expiration occurs (after opening of the glottis)
through the nose not through the mouth.
Asphyxia
Asphyxia develops in a case when respiratory failure occurs acutely or subacutely

and reaches such a degree when oxygen stops to come into the blood and carbon
dioxide is not discharged out of the blood. The most frequently asphyxia occurs in
compression of the respiratory tract.
There are three periods in course of asphyxia.
The first period of asphyxia is characterized by rapid increase of the depth and rate of
respiration. The inspiration phase prevails the expiration one. It is possible to observe
general excitement, an increased tension of the sympathetic part of the vegetative
nervous system (dilated pupils, tachycardia and elevation of blood pressure).
During the second period the respiration rate gradually diminishes in preserving
maximal amplitude of the respiratory movements and the phase of expiration gets
12
intensified. It is possible to observe that the tonus of the parasympathetic part of the
vegetative nervous system prevails (narrowed pupils, reduction of blood pressure,
bradycardia).
During the third period of asphyxia an amplitude of respiration and its rate are
decreased and at last respiration stops. Arterial blood pressure is considerably decreased.
After a short-term respiratory standstill there are usually several rare spasmodic
respiratory movements (gasping breathing), which are followed by paralysis. Convulsions
are possible.
The effects observed in asphyxia are connected at first with accumulation of carbon
dioxide in organism. Acting by reflex and via central hemoreceptors for H+-ions, carbon
dioxide excites the respiratory center making depth and rate of respiration maximal.
Besides, respiration is stimulated by reflex by reduction of pO2 in the blood. Content of
CO2 in the blood increases. The arterial blood pressure increases. Experiments with
inspiration of gas mixtures containing 10-20% of CO2 showed that respiratory
intensification is connected with
• Reflex effect via hemoreceptors on the vascular motor center,
• Intensified secretion of adrenaline into the blood,
• Increased minute blood volume resulting from elevated vein tension and increased
blood inflow into the heart.
Then, increase of CO2 concentration in the blood, its narcotic effect begins to manifest,
pH of the blood is reduced to 6.8-6.5. Hypoxemia нарастает and so does hypoxia of the
brain. In its turn, it leads to inhibition of respiration and decrease of arterial blood
pressure. Finally, respiratory paralysis and cardiac standstill occurs.
DISORDER OF THE NON-RESPIRATORY FUNCTIONS OF THE LUNGS
The lungs have a protective function. Possessing a vast total area (50-100 square
meters) they are the vastest surface of organism that comes into contact with more
and more aggressive environment. The lungs are capable to detain the harmful
mechanical and toxic products of inspired air. Particles which are deposited in the
lung are removed from the bronchial wall by ascending flow of the mucus
(mucociliary transport).
Filtrative function of the lungs consists in ability to clean the blood from some
mechanical admixtures – drops of fat, small thrombi, bacterias which get retained in
the lungs with father destruction.
Excretory function consists in revealing of some flying metabolites (acetone,
ammonia etc.) or exogenous substances (alcohol) in a case of intoxication. The lungs
take part in detoxication of a number of medicines (aminasinum, sulfanilamids, etc).
Sucktive function consists in suction of some lipid- or water-dissolving substances,
preferably flying aerosols. It is a base of inhaled way of medicamentous curing.
The lungs fulfill important metabolic functions taking part in protein, fat and
carbohydrate metabolism. The lungs are exclusively rich in lypolytic and proteolytic
enzymes and may be compared with the liver in intensity of lipid metabolism. The lungs
regulate an amount of fat coming into the arterial blood. They partially detain and
metabolize chylomicrons coming from intestines via the lymphatic vessels. They may
synthesize fat acids and phospholipids, in particular, dipalmitoilphosphatydilcholin-
composing surfactant which deficiency causes collapse of the lungs.
The protein synthesis also plays a significant role, as the structural base of the lungs
is formed from collagen and elastin. An impairment of their synthesis, intensified
distraction or hyperproduction of these proteins may be a cause of emphysema and
pneumosclerosis development.
13
The carbohydrate metabolism also has a great significance, especially production of
mucopolysaccharides composing the bronchial mucus. In their deficiency
mucoviscedosis develops.
Metabolism of many substances influencing the vessels takes place in the lungs. A
considerable amount of all vascular endothelial cells of the organism is concentrated in
the lungs. The lung is one of the most suitable organs for transformation of the
substances circulating in the blood. A lot of vasoactive substances lose their activity
partially or completely in passing via the vessels of the lungs. Bradykinin gets
inactivated by 80%. The lungs are the main organ that liberate the blood from
serotonin by mean of catching it, deposition and penetrating into the blood platelets.
There are also enzymes that inactivate prostaglandins E1, E2 and F2 and catch partially
(up to 80%) noradrenaline and histamine. In the pulmonary vessels polypeptide
angiotensin I gets transformed into angiotensin II (it is 50 times more active than its
predecessor) under influence of the converting enzyme.
The lungs play a role in hemostasis maintaining anticoagulant and fibrinolytic
activity of the blood. There are a lot of fat cells containing heparin in the intestine of the
lungs. Activation of fibrinolysis resulting in hemorrhage occur in extensive injury of
lungs (including operative).
Role of the lungs in thermoregulation is known. In a condition of low temperature
of environment the biological oxidation activates and heat production gets increased.
At the same time a decrease of capillary blood flow in small circle of blood circulation
and heat emission via lungs decreases.
Lungs are a reservoir of the blood due to ability of the vessels to change its емкость
even in a condition of insignificant change of pressure in them.
Lungs play a certain role in maintenance of water balance as it reveals from
expirated air.
Apudopathy. The cells which may produce BAS – производные derivatives of
aminoacids (Amine Precursor Uptake and Decarboxilation) relate to APUD-system. That
is why some cells of lungs relate to this system. They produce enkephalin, calcitonin,
bombesin, vasointestinal peptide, P-substance. APUD-system has many functions,
influences microcirculation, nervous system etc. With age, the lungs gradually loose
elasticity, alveolar ducts dilate and the lung parenchyma increases. That is why
APUDopathy can be found in elder person and under different chronic lung diseases
(emphysema, amyloidosis, chronic obstructive pulmonary disease as chronic bronchitis
and other).
14
CHAPTER 27
PATHOPHYSIOLOGY OF THE DIGESTIVE SYSTEM
The function of a digestive system provides an intake of food, its transformation into simple chemical
compounds to be absorbed, which are necessary for life maintenance and supply of organism by energy and
plastic materials.
Different sections of a digestive system are interconnected due to continuation of alimentary gastrointestinal
tract, common nervous and humoral mechanisms of regulation. This interconnection is especially evident in
pathology as a dysfunction of one section of digestive system results in impairment of others. Union of different
organs of a digestive system is manifested by substitutional (compensatory) possibilities of this system.
Pathology in a digestive system includes disorders of
• Digestive channel, which in turn is subdivided into disorder of
Oral cavity,
Esophagus,
Stomach,
Small intestine,
Large intestine.
• Digestive glands – pancreas and a liver.
DIGESTION DISORDER IN ORAL CAVITY
Digestion impairment in oral cavity may be connected with pathology and dysfunction of
• Teeth in a case of injury, absence of teeth or pathology due to dental caries or paradontosis,
• Masticatory muscles (disorder of nervous regulation),
• Temporo-mandibularis joints,
• Salivary glands.
Besides alimentary function (amilase content), a saliva plays a role in wetting the teeth and mucous
membrane of oral cavity providing protective (bactericidal) and trophic effects. In normal conditions 0.5-2 1 of
saliva is excreted daily.
Hypersalivation (in pathology its amount arises up to 6-7 l) is observed in stomatitis, gingivitis, pulpitis,
parodontitis as well as while preparation of teeth with a drilling machine. Parasympatic activation (vagotonia)
stimulates salivation. Pregnancy is accompanied with hypersalivation.
As a result of saliva hypersecretion the following processes occur:
• Increase of the Na- and Cl-ions and reduction of K+ concentration in saliva,
• Increase of total concentration of nonorganic components of saliva,
• Neutralization of gastric juice by basic saliva and impairment of stomach digestion,
• Systemic dehydration due to loss of a large amount of saliva.
Hyposalivation (reduction of saliva secretion) is connected with sympathatic nervous activation,
injection of parasympathic inhibitors (atropin), infectious and feverish processes. Disturbances of saliva
secretion and connected microflora multiplication result in inflammation of mucous membrane and
saliva glands and promote dental calculus formation. It disturbs mastication and swallowing.
Disorders of carbohydrate metabolism may appear due to hyposalivation (deficit of amylase). A
dysfunction of the stomach glands occurs.
There is a severe systemic lesion of salivary and lacrymal glands (Shegren's syndrome), which is
characterized by dryness of a mucous membrane of oral cavity, eyes and upper respiratory tract.
Caries and Paradontitis
1
Caries is a destruction of твердых tissues of зуба with cavity formation, which may be complicated by
pulpitis and periodontitis. Microbes (especially Streptococcus mutans ) play a role in etiology. Disorder of
defensive function of saliva on эмаль is significant in pathogenesis of caries. Organic acids (especially lactic)
provide demineralization of teeth. Dismetabolism, formation of products of protein hydrolysis may mobilize
Ca2+ from crystals of hydroxyappatites from эмали и дентина. Hereditary predisposition is assumed.
Decrease of immunological reactivity plays a role.
Paradontitis is a inflammatory-destructive process, which is characterized by damage of парадонта, which
окружает корень зуба. It is manifested by гноетечением from десневых карманов, расшатыванием и
выпадением зубов. Stress plays a role in etiology and that is why it refers to the diseases of adaptation. Lack
of vitamins with antioxydative activity – аскорбиновой acid, биофлавоноидов and токоферола (vitamins
С, Р and E) has a significance. Neurogenic dysthrophy is supposed to be in the basis of pathogenesis. In
disorder of throphicity of ткани пародонта, it gets damaged by saliva enzymes (kalikrein, RNA-ase etc) and
by active factors of leukocytes. Activation of перекисного окисления and intensification of ейкозаноидов
(простагландинов, лейкотриенов) synthesis provide inflammation. Immune damage of tissue, an action of
bacterial and leukocytic collagenase play a role in pathogenesis as well as endocrine disorders (гипогонадизм,
hypothyreosis, hypoinsulinism, hyperparathyreosis, decrease of incretory function of the saliva glands).
STOMACH PATHOLOGY
ETIOLOGY
Causative factors of stomach pathology are exogenous and endogenous. In turn, they are physical, chemical
and biological.
Physical factors are trauma (mechanical irritation of stomach by грубой food or плохо механически
обработанной as a result of absence of teeth), thermal irritation due to use of too hot food, disorder of режима
питания (rhythm, quality), irregular nourishment.
Chemical factors are a damage by acids or other poisons, abuse of alcohol and cigarettes, damage by
medicines - particularly aspirin, non-steroid anti-inflammatory medical drugs, hormonal drugs
(corticosteroids).
Biological factors are the following.
• Infectious (virus is among them). B. Helicobakter pylory (a gram-negative microorganism) plays exclusive
role in gastric pathology. It is found in 50% of a world population, especially in the poorest countries, where
standards of personal hygiene are inadequate. The most likely route of spread from person to person is fecal-
oral.
• Immune factors (injection in experiment of a heterogeneous serum, which contains antigastric antibodies).
• Psychogenic factor as a constant neuroemotional overloading, emotional stress and negative emotions play a
significant role (it is reproduced in experiment by prolonged fixation of animal).
Endogenous factors are the following.
• Disorder of nervous and endocrine regulation of a gastric secretion, which lead to an increase in acidity of
gastric juice and hypersecretion of pepsin,
• Autoimmune aggression,
• Bile (bilious acids) entrance into the stomach (it is called bile reflux),
• Genetic predisposition, which is associated with congenital prevalence of aggressive factors and insufficiency
of defensive ones.
PATHOGENESIS
Pathology of stomach may be primary (initially develops in stomach) and secondary (as a result of pathology,
which develops in another organs that may influence the stomach functions).
All typical pathophysiological processes can develop in the stomach -
• Inflammation (gastritis),
• Allergy (autoimmune aggression),
• Tumor (carcinoma),
2
• Dysthrophy up to necrosis (stomach ulceration),
• Disorder of blood supply,
• Hemorrhage,
• Genetic disorders (which predispose to gastric pathology).
Pathogenesis of every pathologic process is aggravated by existence in stomach of specific aggressive factors
(pepsin and hydrochloric acid in large concentration).
Nervous and endocrine factors in form of a disorder of neurogenic and humoral regulation of gastric
secretion play a critical role in stomach pathology.
The main role in neurogenic regulation of gastric functions belongs to n.vagus and acetylcholine as a
neurotransmitter of parasympathetic nervous system. N. vagus is the main secretory nerve of a stomach. It stim-
ulates a production of hydrochloric acid, pepsinogen and gastrine. N. vagus effects a blood circulation in
submucous layer of a stomach; acetylcholine dilates the vessels of a submucous layer.
Symphathetic nervous system effects the stomach cells by membrane adrenoreceptors. It promotes
contraction of the vessels of the submucosa and smooth muscles of a stomach.
Together with influence on secretion, motoricy (fig. 50) and blood circulation in a stomach, nervous system
is connected with trophicity of a gastroduodenal area.
_________________________________________________________________
Художнику! Вместо а б в г -abcd
Fig.50. Form of stomach depending from its tonus

a –hypertonic , b – normotonic , c – hypotonic, d - аtonic
__________________________________________________________________
Humoral regulation of gastric secretion includes influence of hormones of endocrine glands and gastrointestinal
system.
Pituitary gland stimulates главные main and parietal gastric cells by corticotropin and somatotropin.
Noradrenaline influences the cells of a stomach. It promotes contraction of the vessels and smooth muscles of
submucosa of a stomach inhibiting secretion.
The hormones of adrenal cortex (glucocorticoids – cortisol, hydrocortisone) influence gastric mucous,
stimulate главные main and parietal cells of stomach and intensify production of hydrochloric acid and pepsin.
They stimulate cholecystokinin (resembles gastrin) and inhibit multiplication and regeneration of mucous cells.
Insulin stimulates gastric secretion. Glucagon inhibits it.
Some secretory products (which are present in intramural autonomic nerve terminals) act as chemical mes-
sengers and modulate normal digestive functions by a combination of endocrine, paracrine and neurocrine
mechanisms. Some of them act as the С-cells of a thyroid gland, chromaffin cells of adrenal medulla,
corticotrophs and melanotrophs of a pituitary gland.
Gastrin is a so-called gastrointestinal hormone, which is produced by G-cells of gastric mucosa and is
stimulated by n. vagus. It is the most potent stimulator of gastric secretion (especially of hydrochloric acid)
which in addition provides throphical effect on gastric mucous (stimulates their multiplication).
Cholecystokinin, which is produced in intestine, is a stimulator of gastric secretion.
Acethylcholine, gastrin and histamine are the messengers of gastric secretion and stimulate it. In
addition, they transmit stimulating impulses to n. vagus. The receptors of parietal and главные main gastric cells,
having received mechanical and chemical stimuli, stimulate additional messengers (cyclic nucleotides) stimulating
parietal cells of the stomach for HC1 production and the главные main cells for pepsinogen production.
Prostaglandins, which are produced in gastric mucose, increase mucosal blood flow as well as bicarbonate and
mucus secretion and stimulate mucosal cell repair and renovation.
Genetic factors are assumed to be predisposal or preventive as to gastric pathology development. Genetic
factors determine
• Number of parietal gastric cells,
• Individual sensitivity to secretory stimuli (gastrin),
3
• Type of pepsinogen (there are 2 types of pepsinogen: the 1st type includes five fractions of pepsinogens, the
2nd type - two fractions),
• Presence or absence of A and B erythrocytes antigens, which resemble gastric mucosa and play a role of a
protective mechanism (human organism has genes, which contribute to A or В antigens of erythrocytes entrance
into saliva and stomach interacting with gastric mucosa).
Digestion in the stomach is achieved with the aid of the digestive enzyme pepsin secreted by main gastric
cells. Its predecessor pepsinogen is activated by hydrochloric acid. At maximal secretion, the level of
hydrogen ion concentration in the stomach is 3 million times greater than that of blood and tissues. In hypoxia
and cancer, an acidogenesis in stomach is suppressed due to suppression of oxidative processes.
A secretory process is dividing into three phases — cephalic, gastric and intestinal.
Taste, smell, chewing and swallowing of a food initiate cephalic phase. This phase is mediated by
direct vagal stimulation of parietal cells (it may involve vagal stimulation of gastrin release).
A gastric phase involves stimulation of mechanical and chemical receptors of gastric wall. The chemical
stimuli, the most important of which are proteins and aminoacids, induce a release of gastrin (fat and
glucose do not stimulate gastric acid secretion in stomach).
The intestinal phase is initiated when a food containing digested proteins enter small intestine.
Hormones, which are secreted (secretin, gastroinhibitory peptide) inhibit gastric secretion.
An estimation of a gastric juice acidity is used for characteristic of a functional state of gastric digestion.
Stimulation of a stomach by histamine is used for this purpose. Dynamics of a gastric acidity change is
measured after stimulation. Dynamics is expressed in form of curves.
There are four types of pathological gastric secretion - возбудимый excited, asthenic, inert, тормозной
inhibited according to its dynamics (represented in figure 51). They have the following differences -
• The excited type is characterized by gastric juice secretion increasing in mechanical and chemical
stimuli.
• The asthenic type is characterized by increasing gastric secretion in the mechanical stimuli and
reducing in chemical one.
• Inert type is characterized by reducing by mechanical stimuli and elevation under chemical ones.
• Inhibited type is characterized by depression of both mechanical and chemical stimuli.
____________________________________________________________
Fig. 51. Types of gastric secretion
_________________________________________________________
4
All active substances and mechanisms, which act in stomach, are divided into stimulating and protective.
Below, as a summery, stimulative (aggressive) and protective factors are represented.
Stimulative Factors
Stimulative (many of them are aggressive, corrosive) factors are the following -
• Active pepsin,
• Hydrochloric acid,
• Vagal stimulation (and congenital vagotonia),
• Acetilcholin,
• Catecholamines (adrenaline, noradrenaline),
• Glucocorticoids,
• Insulin (stimulates главные and parietal cells of the stomach),
• Gastrin and cholecystokinin,
• Bile ( bilious??? ) acids (in duodeno-gastric reflux),
• Histamin, bradikinin (in the case of inflammation),
• Antigastric antibodies (in pathology),
• B. Helicobakter pylory (in pathology).
An increased action of them can be aggressive and the factors of stomach damage. An excited type of
gastric secretion is characteristic for gastric function. In pathology it happens in -
• Disorder of nervous regulation, emotional stress,
• Disorder of endocrine functions (hypersecretion of catecholamines, glucocorticoids, thyroxin,
parathyrin),
• Increased tone of n. vagus,
• Factors causing angiospasm in stomach, ischemia and the necrosis of the mucous membrane of stomach,
• Hypersecretion of gastrin ( tumor - gastrinome),
• Bile reflux into the stomach and damage of mucose barrier of the stomach.
Together with the aggressive factors, which damage the mucous membrane of the stomach, protective ones
are also exist, which oppose the corrosive affects of acid-pepticogastric secretion.
Protective Factors
The factors of the protection (defense, resistance) of a mucous membrane 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 B antigens in the erythrocytes,
• Neurotrophic function of gastric nerves,
• High regenerative ability of epithelial cells.
Mucous membrane cells of a stomach possesses high regenerative properties. In a healthy person a mucosa
of gastrointestinal tract is renewed every 1-5 days. Glucocorticoids suppress this property.
The ratio of factors of aggression and protection plays a significant role in pathology of the stomach.
GASTRITIS
Gastritis is an inflammation of the mucous membrane of the stomach.
5
All the general laws, governing the inflammation as typical pathological process, refer to the inflammation
of the stomach (alteration, disorder of microcirculation, production of BAS, regeneration). At the same time,
the peculiarities of localization have a significance. They are connected with -
• Presence of specific aggressive factors in the stomach (hydrochloric acid, pepsin),
• Necessity of constant renovation of gastric mucosa cells (every 5 days in norm),
• Correlation of stomach function with other parts of digestive tract.
The humoral mediators of inflammation (histamine, bradykinin, oth) are the critical damaging factors due to
stimulation of hydrochloric acid and pepsin secretion.
Depending on the extend of alteration, gastric inflammation is divided into acute and chronic.
According to the level of gastric acidity, the inflammation in the stomach may be hyper-, hypo- and
anacidity types.
Together with aggressivity and effect on secretive activity of pepsin, the level of gastric acidity
influences the gastric motoricy.
Hyperacidity is associated with delayed emptying of gastric content into the duodenum including reflux. It
may be a cause of gastric ulcer formation. Hypoacidity is associated with an accelerated emptying of gastric
content, resulting in disorder of normal digestive function of the stomach.
Disorder of digestion in the stomach eventuates in disturbance of digestion in following parts of digestive
tract.
ULCER DISEASE OF THE STOMACH AND DOUDENUM
Ulcer is a recurrent disease characterized by areas of destruction in the mucous membrane under the influence of
activated pepsin, hydrochloric acid and other aggressive factors. 8-10% of people is ill in the human population.
Peptic ulcer is the most common in the antral section of the stomach, proximal section of the duodenum and some-
times in the inferior part of the esophagus. It is associated with a number of parietal cell producing hydrochloric acid
(fig. 52, 53).
_____________________________________________________________
Fig. 52. A number (%) of parietal cells in gastric mucosa
1 – 100, 2 – 75, 3 – 50, 4 – 0-1
__________________________________________________________________
Fig. 53. Localization of stomach ulcer

Мал. 69 с 522
____________________________________________________________________________
Etiology
Etiological factors of ulcer are divided into the exogenous and endogenous, which in turn are subdivided
into the physical, chemical and biological.
Physical factors are the chronic mechanical injury of mucous membrane of stomach in form of the
disturbance of the mode of nutrition (грубая food, поспешная еда fast food, слабая механическая обработка of food
as a result of teeth absence) and thermal ones (too hot food). Sometimes, these factors play a role of conditions
(risk factors).
Chemical factors are the damage of the mucous membrane of stomach by the chemical substances, among
which an abuse of medicines (used as therapy) has great significance (corticosteroids, aspirin, indometacin and
other non-steroid anti-inflammatory drugs). Alcohol abuse and smoking as well as vitamins and microelements
deficiency must be added.
Biological factors are the following.
6
• Infectious. A special attention must be paid to etiological role of b. Helicobacter pylori in the development
of some forms of acid-peptic disease, ulcers of the stomach and duodenum. It is isolated in 90% of patients with
duodenal ulcer and in 60-70% with gastric ulcer).
• Immune factors (for example, injection of the heterogeneous serum, which contains anti-gastric antibodies
causes gastric ulcer in experiment).
• Emotional stress and negative emotions play a significant role.
Endogenous factors sometimes play a role of etiology, sometimes the role of conditions, sometimes are the
mechanisms of pathogenesis. They are the following.
• Disorder of the regulation of gastric secretion, which results in increase of acidity of gastric juice and
hypersecretion of pepsin. Corrosive effect of acid and pepsin play a key role in gastric ulcer, duodenal ulcer and
acute erosive gastritis.
• Autoimmune aggression.
• Genetic predisposition.
Genetic predisposition is proved by statistics. The type of pepsinogen is genetically determined. There was
established a correlation between the 1-st type of pepsinogen and ulcer. Patients with the 1-st blood group are
predisposed to ulcer development. It is consumed that it is connected with absence of A and B antigens in the
erythrocytes which have protective value for gastric mucosa.
In addition, patients with gastric ulcer may have increased number of pariental gastric cells, individual high
sensitivity to secretory stimuli (gastrin).
The risk factors are drugs, alcohol abuse, smoking, nutritional regime disorder, emotional stress.
As a conclusion, it must be stressed that peptic ulcer disease is a multifactorial in origin.
Pathogenesis
Ulceration of gastric mucosa in determined by the following pathogenetic mechanisms:

• Activation of aggressive factors (corrosive effect of acid and pepsin, secreted by the stomach, play a key
role),
• Suppression of protective mechanisms,
• Sisorder of blood circulation in gastric mucosa (ischemia, stasis),
• Inhibition of regenerative ability of gastric mucosa cells.
Disbalance between aggressive and defensive mechanisms is the essence of pathogenesis. Usually, it is a
combination of mechanisms. So, circulatory disorders, medical drugs abuse and stress lead to damage of gastric
mucosa if they are connected with peptic factor (pepsin + hydrochloric acid), decrease of regenerative ability of
gastric mucosa cells or genetic predisposition.
In dependence of etiology, the main link of pathogenesis may be individually associated with the
infectious, nervous, humoral or genetic mechanisms.
If it is an infectious mechanism (b. Helicobacter pylori), the most likely mechanism of gastric ulceration is a
diminished mucosal defense due to inflammation as b. Helicobacter pylori affects the gastric epithelium. This
etiological agent opsonized secretory IgA and serum immunoglobulins, acts as "barrier destroyer". 90% of
infected individuals show signs of inflammation (gastritis or duodenitis) while endoscopical investigation.
Despite of the high rate of association of stomach inflammation with b. Helicobacter pylory infection, the
important role of other factors is indicated by the fact that only about 15% of infected persons have clinically
significant ulcer. These other factors (both genetic and environmental) are pathophysiologically important.
Vagal stimulation determines the main neurogenic mechanism of a disease. It promotes peptic aggressive
mechanisms. The neurotransmitter of 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 symphathetic nervous systems leads to hypersecresion of
noradrenaline, which constricts the vessels of the microcirculation. It results in spasm of the smooth muscles
of the submucosa and smooth muscles of the vessels resulting in hypoxia. Hypoxic affection and spasm
may be very severe and prolong so that stasis (circulation arrest) occurs. It leads to hemorrhage in the
gastric mucosa and erosion. Neurodystrophia aggravates an effect of peptic factors.
If hormonal mechanisms are the reason of stomach ulceration, then glucocorticoids (hypercorticism) play
the main role. They influence the gastric mucosa, intensify gastric secretion (production of hydrochloric acid
7
and pepsin), inhibit secretion of mucouse, inhibit division of the gastric epitheliu and decrease regeneration of
gastric tissue. In addition to glucocorticoids, noradrenaline has an injurious effect on the gastric cells.
Chronic inflammation provokes the ulceration development. Allergic inflammation with autoimmune
aggression is more severe with comparison with ordinary inflammation.
Disorder of blood circulation in gastric mucosa provokes ulceration. Mucosal ischemia and hypoxia play a
role. Causes are – disorders of sympathetic or parasympathetic regulation of blood circulation in the stomach.
Disorder of gastric motoricy contributes to the development of gastric ulcer by
• Delayed emptying of gastric content into duodenum and the mechanical irritation of gastric mucosa,
• Increased gastrin secretion and gastric acid production due to delayed gastric emptying,
• Tendency of duodenal content to reflux возврат in an incompetent pyloric sphincter. Bile acids in the
duodenal reflux material act as an irritant and may be an important contributor to a diminished mucosal
barrier against acid and pepsin.
По совокупности of pathogenetic mechanisms, stress (maximal overstrain of organism) plays a leading role
in pathogenesis of gastric ulcer. Stress is realized by hypothalamus-pituitary-adrenal system. During stress
the amount of noradrenaline in the blood gets increased. It activates the Haghemann's factor (XII factor of
blood coagulation), which is an activator of kallikrein-kinin system. Hormones of the adrenal cortex
(glucocorticoids) influence the gastric mucosa - intensify production of hydrochloric acid and pepsin, inhibit
the division of the gastric mucocytes. Glucocorticoids have a permissive effect as to noradrenaline.
Dystrophy results from chronic emotional stress.
Genetic mechanisms play significant role in ulcer disease development. They determine congenital increase
of aggressive mechanisms -increased number of parietal cells or their increased sensitivity to gastrin, individual
composition of pepsinogen, properties of gastric mucosa, congenital vagotonia.
Medicamentous variant of gastric ulceration is connected with abuse of steroid and nonsteroid unti-
inflammatory medical drugs which directly damage the cells of gastric mucosa and inhibit prostaglandins
production.
In final conclusion about the pathogenesis of gastric ulceration it is possible to make a conclusion about the
decisive role of decreased regenerative capacity of gastric mucosa cells. Just on this phone any aggressive
influence eventuates in chronic ulcerous process. In comparison, it is useful to mention, that in experiment with
healthy animals, any damage of gastric mucosa (mechanical, thermal, chemical) results in full regeneration in
some days.
Principles of Pathogenetic Therapy
Therapy should be directed at

• Inhibition of the aggressive factors (anti-Helicobacter drugs),
• Antiacid drugs inhibiting H+ secretion (blocking H+ -pump);
• Cholino- and histamine blockers,
• Stimulation of the protective factors (cytoprotectors).
Neutralization of increased gastric acidity by bicarbonates is palliative and does not solve the problem of
pathogenetic therapy. Vagotonia is used, eventuates in decrease of gastic secretion, but can disturb motoricy of
the stomach and bile bladder.
PATHOLOGY OF PANCREAS
Pancreas is a source of many digestive enzymes.

The powerful proteolytic enzymes are formed in the pancreas in inactive state – tripsinogen and
hemotripsinogen. Only in intestine they are activated by enterokinase or by tripsin (autocatalis). If they are
activated in the tissue of pancreas, it results in necrosis of gland, and then these active enzymes fall into the
blood, and it may lead to death of patient. Reason of death is a decrease of the arterial blood pressure and
shock.
This situation is possible in pancreatitis.
8
PANCREATITIS
Pancreatitis is an inflammation of pancreas which may be acute and chronic.
Etiology
Etiological factors of pancreatitis are exogenous and endogenous.

Among exogenous factors trauma and infection play a role. Trauma may occur in surgical interventions.
Infectious factors are bacterial infection, cocci, viral (in parotitis and hepatitis), agent of tuberculosis.
Risk factors (conditions which aggravate an action of etiological factors) play a critical role in pancreatitis
development. They are - overeating and abuse of fatty food (cause increased secretion of pancreatic juice),
intoxication including side-effect of medicines (immunodepressants, thiasides, corticosteroids, etc.). Alcohol
abuse associated with overeating is of a great importance in etiology of pancreatitis.
Among endogenous etiological factors the following ones play a role -
• Disorder of blood circulation in pancreas (thrombosis, ischemia),
• Sclerosis of pancreatic vessels,
• Occlusion of the pancreatic duct by edema, concrements (bile stones), polyps and other tumors,
• Entry of bile into the pancreatic duct (bile reflux),
• Autoimmune aggression (in chronic forms of pancreatitis).
Pathogenesis
As any other forms of inflammation, pancreatitis proceeds in three stages – alteration, exudation and
proliferation. Like any other form of inflammation, pancreatitis has local (in the pancreas) and systemic (in
entire organism) manifestations. Acute form is dangerous for life for it is accompanied with pancreatic shock
development.
Acute inflammation in this organ has such peculiarities:
• Alteration (secondary) predominates above all other stages of inflammation.
• Systemic changes in organism predominate the local ones.
• Links of pathogenesis stormily develop assuming a character of цепных разветвленных реакций и порочных
кругов.
Etiological factor starts inflammation (primary alteration). In response, as usually in inflammation, the
microcirculation gets disordered. Hyperemia and edema lead to an increase of pressure in the pancreatic duct.
Evacuation of pancreatic secret becomes difficult. The bile and duodenal chyme (containing enterokinase) by
reflux may enter pancreatic duct. As in any other cases of inflammation, biologic active substances (BAS) are
formed. They activate trypsinogen and hemotrepsinogen intra-organ which damage pancreas. Secondary
alteration is very severe. Pancreonecrosis develops, vascular permeability rises. As a cascade all systems of
BAS-formation are activated (“proteolytic explosion»). Premature activation of elastase and phospholipase A
happens in ducts and cells of the pancreatic gland under effect of bile, enterokinase and other BAS. Active tripsin,
biologic active substances and toxic products of tissue autolysis enter the blood. Activation of blood kallikrein-
kinin system aggravates the situation. All these substances are vasoactive and have powerful vascular and
hypotensive effect (scheme 22).
Pancreanecrosis involves брюшину mesenterium (peritonitis) and causes a severe pain. The latter together
with a disorder of systemic blood circulation results in shock, which is called pancreatic shock. Severe
disorders of hemodynamics, respiration and other vitally important functions come. Just it is a reason of death
of patient, if the inhibitors of the proteolytic enzymes would not be injected.
An important role in pancreatitis pathogenesis belongs to disorder of balance between proteolytic
enzymes and their inhibitors (the latter are produced by the pancreas itself and other organs - the salivary
glands, lungs). Just they are used for treatment of acute pancreatitis.
9
Scheme 22 Inflammation of Pancreas (Acute Pancreatitis)
Etiological factor
Increase of Disorder of
pancreatic juice pancreatic juice Primary alteration
secretion outflow
Disorder of microcirculation, Release of lisosomal

Reflux of bile or hyperemia enzymes,
duodenum content BAS production
(enterokinase)
Edema
↑ of pressure in
pancreatic duct
Lipase Phospholipase A Intraorgan передчасна Elastase

activation activation tripsin activation activation
Entrance of Damage of
pancreatic juice into vessels.
parenchima Hemorrhage
Secondary alteration
Necrosis of
adupose tissue Pancreonecrosis
(autolysis)
Entrance of active
tripsin into the blood
Involvement of
mesenterium
Activation of kalikrein-
kinin system
Bradykinin
Pain
Loss of plasma
Pancreatic shock
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DISORDER OF DIGESTION CONNECTED WITH DISORDER OF BILE AND
PANCREATIC JUICE SECRETION
The liver forms bile, which is secreted into the duodenum. The bile plays a significant role in intestinal
digestion. Bilious acids amulgate the fats, promote intestine and bowel motoricy, has anti-bactericidal effect.
Absence of bile (acholia) or its insufficient coming (hypocholia) into duodenum happens due to
disturbance of bile production or bile secretion (obstruction of the duct of gall bladder by stones). It is
accompanied by indigestion and malabsorption of fats, decreased peristalsis of the bowels and increased
processes of гниения и брожения in them (details in the chapter 28 ” Pathophysiology of the liver”).
Serious indigestion is caused by changes of the pancreatic secretion, as the pancreas produces the main digestive
enzymes. The main mass of proteins of the pancreatic juice (over 70%) is proteolytic enzymes: tripsin,
chemotripsin, elastase, carboxypeptidase (A and B) and kalikrein. All these enzymes as well as phospholipase A
are produced in inactive form. Other ones — lipase, amylase, RNA-ase and DNA-ase are secreted in active
form.
Disturbance of the pancreatic juice secretion is observed in occlusion or compression of the pancreatic ducts,
кистозного cystic fibrosis of pancreas, acute and chronic pancreatitis or duodenitis, in disturbance of neuro-
humoral mechanisms of the pancreatic secretion regulation. N. vagus is a secretory nerve for the pancreas.
Humoral regulation is accomplished by secretin (which activates excretion of water and hydrocarbonates),
cholecystokinin (pancreosimin), which stimulates contraction of bile bladder and production of pancreatic
enzymes.
In lack of the pancreatic juice, a considerable amount of fat is not digested and excreted with feces
(steatorrhea). Indigestion of proteins arises in insufficient production of peptidases by the pancreas as well as in
their activation disorder. In decreased pancreatic secretion there is a disorder of the food nucleic acids
hydrolysis and to a lesser degree - starch крахмал splitting.
DISORDER OF INTESTINAL DIGESTION
Intestine consists in duodenum, small intestine and large intestine. Intestine fulfills secretory, motor,
absorptive, incretory and excretory functions.
The duodenum is an important section of intestine, куда сливаются secrets of the duodenal glands, bile and
pancreatic gland. The outlet of the acidic mass from the stomach into duodenum stimulates the production of
secretin that stimulates bicarbonates production. Bicarbonates neutralize the acid mass, and pH increases from
1.5-2.5 to 7.0. It activates proteolytic enzymes (tripsinogen, hemotrypsinogen, carboxypeptidase) and secretion of
cholecistokinin. In the duodenum, the secretin and motilin, which regulate the digestive system, are produced as
well as arenterin and dinenterin effecting appetite, metabolism and possessing neurotropic effect.
Small intestine has the digestive glands, which secrete wide spectrum of the digestive enzymes. Under their
influence, over-boiling of nutritients up to the final products takes place. Proteins are splitted into aminoacids
and oligopeptides, fats – to the fatty acids, di- and polysaccharides – to the monosaccharides, which are sucked
into the blood.
In small intestine cavity полостное and membranous пристеночное digestion are accomplished. Полостное
cavitary digestion takes place in the lumen of small intestine and consists in destruction of the large molecules.
Disorder of a полостное digestion depends, first of all, on disorder of production of bile and pancreatic juice.
DISORDER OF MEMBRANOUS DIGESTION
Membranous (пристеночное parietal) digestion is accomplished in small intestine by enzymes which are
fixed on the surface of щеточной посмугованої каймы striated edge (the latter is formed by microvilli of the
columnar столбчатых cells). Enzymes of membranous digestion (oligosaccharides, oligopeptides, phosphatase,
etc.) partially are synthesized inside the columnar cells and partially are absorbed from chymus (pancreatic
amylase, lipase, etc.).The main way of penetration of enzymes into intestinal juice is отторжение и распад of
the columnal cells (under normal conditions the cycle of their renewal is 3 days). The final stages of nutrient
hydrolysis and absorption proceed here.
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Membranous digestion is characterized by conjugation of the processes of fermentation of the nutrients
and their absorption, high rate of hydrolysis and sterility conditioned by small size of the pours between the
microvilli (10-20 nm), where microorganisms can't penetrate.
Disorder of enzymes production by the columnar cells plays the main role in pathology of membranous
digestion and may be caused by the following factors:
• Damage of the villi and ultrastructure of the surface of columnar cells
• Disorder of the enzymal layer of the intestinal surface
• Changes of sorptive properties of the cellular membranes
• Peristalsis disorder when transportation of the substrates from intestinal cavity to the cells is impaired.
Reduction of digestive intestine surface as a result of its atrophy and a decrease of number of the villi
or microvilli is obtained in cholera, ileojejunitis, after intensive usage of some antibiotic (neomicin),
gastrojejunostomy and stomach resection. An example of impairment of the enzymal layer of the intestinal surface
is a milk intolerance in lactase deficiency and saccharose intolerance in glucosidase deficiency.
DISORDER OF ABSORPTIVE AND EXCRETORY FUNCTIONS OF THE INTESTINE
Absorption of the nutrients, hydrolyzed to the stage of monomers, is accomplished mainly in the small
intestine. During the process of membranous digestion, hydrolysis of the nutrients and their transportation through
the cellular membrane are closely conjugated. Therefore, all factors causing disturbance of membranous diges-
tion results in disorders of malabsorption.
The syndrome of malabsorption may be primary (hereditary) or secondary (acquired).
Hereditary syndrome of malabsorplion is characterized by selective deficiency of enzymes. As a result,
absorption of one or several nutrients gets disturbed. This group of malabsorption includes
• Mono- (glucose, fructose, galactose) or disaccharids (lactose, saccharose, isomaltose) intolerance;
• Deficit of peptidases (glutenic disease);
• Malabsorption of aminoacids (cystinuria, triptofan-malabsorption, methyonin-malabsorption),
• Malabsorption of vitamins (cyancobalamin, folic acid deficiency).
An acquired syndrome of malabsorption is observed
• After gastroectomy,
• In intestinal diseases (enterocolitis, Crohn's disease),
• In diseases of the pancreas (pancreatitis),
• In diseases of the liver (acholic syndrome),
• After prolong radiant or medicamentous therapy,
• In disorder of blood and lymph circulation in the intestine, which disturbs energy supply of active transport
of the nutrients,
• Under influence of poisons blocking enzyme activity,
• In water-electrolyte disbalance,
• ATP and sodium ions disbalance (which are of special importance in active transport of glucose,
aminoacids and other compounds).
The disturbance of digestion in the small intestine has a value in development of allergy. If the barrier
properties of the mucous membrane are disrupted, the substances of antigenic nature (products of incomplete
overboiling of proteins) can be sucked into the blood and be a source of the sensitization of organism (food
allergy).
Excretory function of the intestines is closely connected with the absorptive one. The final products of
hemoglobin and cholesterol metabolism, metal salts, lactic acid, purins, some hormones, phenols, salicylates,
sulfanilamides, dye-stuff are excrete in intestine. In renal insufficiency there is a compensatory increased
excretion of nitrous "wastes" (urea, uric acid, etc.) into intestine.
DISORDER OF MOTOR FUNCTION OF INTESTINE
Disturbance of the motor function of intestine is manifested by increase or decrease of peristalsis. Serotonin,
P-substance, gastrin, motilin activate peristalsis. The contraction of the intestinal muscles gets activated in n.
vagus stimulation. Vasoactive intestinal peptide and glucagon inhibit peristalsis.
12
Increased motoricy arise in
• Inflammation (enteritis, colitis),
• Influence of mechanical or chemical stimuli by undercooked food,
• Effect of bacterial toxins,
• Disturbance of the nervous and humoral regulation.
Increase of peristalsis usually leads to accelerated movement of nutritious masses in intestine, disorder of
their digestion and absorption.
Spasms of intestinal muscles are manifested by spastic pain.
Constipation and diarrhea are clinical symptoms of decreased and increased intestine motoricy and are
connected with large bowel dysfunction.
Syndrome of the irritated intestine is an example of the disturbed nervous and humoral regulation of the
intestinal mobility. The negative emotions change the motor and absorptive functions of the intestine and
become a cause of pain and diarrhea, frequently followed by constipation.
DISORDERS IN LARGE INTESTINE
In large intestine a formation of feces and water suction takes place.

Microflora is found here. It is obligatory anaerobic sporeless Bifidobacterium, anaerobic кишечная палочка
colon bacillus, молочнокислые бактерии lactic acid bacteria, streptococci and others. Normal microflora plays a
protective role inhibiting the development of pathogenic microorganisms and promoting natural immunity.
Microflora of the bowels synthesizes vitamins.
Inflammation and disbacteriosis development are possible in large intestine. They are manifested as
diarrhea.
Acute forms of diarrhea may be caused by infections, which enter the bowels при пищевых отравлениях,
from the blood or directly into the rectum. Causative factors my be viral infections (herpes simplex, HIV),
bacterial (b. coli, rectal syphilis and rectal gonorrhea, agents of дизентерии and cholera play significant role),
parasitic (salmonella, amebiasis spirochetosis, chlamydia, trachomatis), fungal infection.
Chronic diarrhea is observed in inflammation of bowels, syndrome of the irritated intestine, malabsorption
syndrome, and colon cancer.
Disbacteriosis (disorder of microflora content) underlies many cases of diarrhea. Therapeutic intervention
into bacterial bowel spectrum undertakes very often without effect. Unfortunately, disbacteriosis is
frequently confused with enzymopathy.
Diarrhea may play a protective role promoting excretion of the toxic substances from the organism (in food
intoxication) or excess of the indigested food. However, a prolonged diarrhea, especially in children, leads to
dehydratation of the organism and loss of electrolytes (Na+, K+). In such cases hypovolemia develops, which
may be a cause of a cardiovascular collapse. Diarrhea may be connected with systemic osmotic disturbances —
generalized malabsorption of salts, glucose, galactose or fructose. In addition, excretory acidosis develops as a
result of the loss of the intestinal content, which is a base in nature.
INTESTINAL IMPASSABILITY
Intestinal impassability (ileus) may be

• Mechanical (compressive or obstructive),
• Dynamical (due to spasm or paralysis of the smooth muscles of the intestine).
Obstruction arises due to congenital abnormalities, occlusion by feces and helminthis, in underfeeding.
Заворот кишок, ущемление кишки в грыжевых воротах are examples of obstructive of impassability as well.
Spastic disorder may be connected with increased tonus of the muscular layer of the intestine under
influence of serotonin excess (in carcinoid – a serotonin-producing tumor).
Paralytic impassability is frequently conditioned by an activation of the adrenoreceptors (which inhibit
contraction of the muscular layer), in n.vagus paralysis, in peritonitis, under influence of metasympathetic
nervous system (as a complication after operation of organs of брюшной полости).
Intestinal impassability is divided into so-called высокую and низкую. In fist variant the problems and
obstruction occurs in small intestine, in the second - in large one. In both cases a suction of intestinal content into
the blood takes place.
13
Pathophysiological and clinical manifestations are very different, because the content of small and large
intestine differs as to its toxicity. Active digestive enzymes with extreme biological activity is a content of a
small intestine while продукты гниения и брожения – in large intestine (which even under physiological conditions
are sucked into the blood in moderate amount).
Высокий ileus has a grave clinical course. Pathophysiological changes swiftly increase and lead to death if a
patient would not receive an urgent medical help. Pathogenesis includes such mechanisms:
• Distention of the bowels, compression and irritation of periteneum брыжейки causes a severe pain and
shock.
• Disorder of blood supply of bowels (especially in strangulative ileus) causes its necrosis.
• Damage of intestinal wall results in disorder of its barrier function in two opposite directions: intestinal
content enters the blood and blood plasma enters intestinal space.
• Constant vomiting proceeds not only with gastric content but also with pancreatic and intestinal juice as
well as blood plasma, which enters inside intestine space.
• Loss of water (sometimes up to 5-7 l) leads to dehydratation, hemoconcentration and aggravates arterial
hypotension.
• Hypovolemia aggravates disturbance of the blood circulation, shock and results in acute renal
insufficiency.
• Suction into the blood of active intestinal enzymes results in formation in the blood of biologically active
substances, especially vasoactive kinines which aggravate arterial hypotension.
• Suction into the blood of activated tripsin and hemotripsin resembles a pancreatic shock in its main
pathophysiological mechanisms and needs immediate help and injection of tripsin and hemotripsin
inhibitors.
• Decompensated disorder of acid-base balance is connected with loss of H+ ions with gastric juice and
hydrocarbonates with pancreatic and intestine content. If loss of acidic gastric content prevails, non-gas
excretory alkalosis is a result. Non-gas excretory acidosis may be a result in excessive loss of pancreatic
and intestine juice.
• Renal insufficiency aggravates acidosis.
• Loss of Na+-ions and chlorides with K+-ions disbalance causes an acute disorder of cardiac automatism
and excitability results in heart stop in diastole.
• DIC-syndrome is a result of entering into the blood of a large quantity of procoagulants from damaged
tissues.
• Peritonitis aggravates all above-mentioned changes.
Низкий ileus is connected with occlusion of a large intestine. Activation of гниения и брожения, formation of
toxic substances (индол, скатол, кадаверин, путресцин) and their absorption into the blood play a role. (Under
physiological conditions they are formed and sucked into the blood in moderate amount and disactivated in the
liver). Chronic constipation (sometimes up to 10 days) is an example.
DISORDER OF INCRETORY (HORMONAL) FUNCTION OF DIGESTIVE SYSTEM
Now it is known, that over 20 substances with hormonal activity are produced by neuroendocrine cells of
APUD system and increted into the blood. They regulate not only the digestion and absorption of nutritients but
also influence systemic blood circulation, metabolism, appetite, assimilation, throphicity, nervous and endocrine
functions.
The hormones of the digestive system are connected with hypothalamo-pituitary system and other endocrine
glands. Gastroinhibiting peptide and secretin stimulate the production of insulin and glucagon and participate in
pathogenesis of obesity and исхудания. Gastrin, cholecystokinine and glucagon stimulate the production of
calcitonin and, therefore, play a definite role in disturbance of calcium balance.
Disorder of hormone production of the digestive tract results in deep disturbances of digestion, metabolism
and function of various organs. Hormone-producing cells of the digestive organs may be liable to
cancerogenesis and development of malignant tumors (Zollinger syndrome in increased production of the
gastrin).
14
15
CHAPTER 28
PATHOPHYSIOLOGY OF LIVER
Liver is a compound organ with many functions providing homeostasis in

organism.
Morphology of the liver consists of three functional parts - hepatic cells
(hepatocytes), apparatus of bile secretion (bilious ducts and gall bladder) and a system
of blood circulation (a. and v. hepatica as well as v. porta). Portal system is a
peculiarity of the hepatic blood circulation, which collects the blood from the
intestine and provides neutralization of toxical digestive metabolites and other toxins
entering into the organism.
The functions of the liver are the following:
Excretory function consists of (a) bile formation (cholepoiesis) and (b) bile
excretion (cholediaresis). Bile is formed by hepatic cells and is excreted by the bile
tract. Gall bladder is a place of accumulation of a bile.
A composition of normal bile is the following - the bile acids (холевая и
дезоксихолевая, which are formed in hepatocytes from cholesterol and determine bile
properties as a digestive secret), glycocholic and taurocholic acids, conjugated with
glucuronic acid bilirubin, лецитин, cholesterol (in soluble state due to salts of bile
acids and лецитин), water and mineral salts. Glucagon, secretin, gastrin,
cholecystokinin, n. vagus activation, proteins and fats of food (яичные желтки, milk,
meat, жиры) activate bile secretion.
In pathology, toxins, medical drugs and their metabolites are excreted with bile.
Excretory function of the liver includes a rotation of bile pigments. Bilirubin,
which is formed in macrophages of a spleen, liver an bone marrow from hemoglobin
of destructed erythrocytes (free bilirubin) is insoluble, but in the blood a soluble
bilirubin-albulin complex is formed (unconjugated indirect bilirubin). Hepatocytes
actively catch this complex, связь with albumin разрывается, bilirubin conjugates with
glucuronic acid as a soluble глюкуронид билирубина (conjugated direct bilirubin).
Direct bilirubin excretes into duodenum in a composition of bile. Bile pigments are
present in feces (stercobilin) and urine (urobilin).
Digestive function is a participation of bile in over-boiling of nutritions in the
intestine. Bile acids эмульгируют the fats and make them accessible to pancreatic
lipase. Bile provides peristalsis of intestine and bactericidity in it.
Metabolic function is a participation of the liver in anabolism and catabolism of
• Proteins - synthesis of proteins (blood plasma proteins and procoagulants),
transamination and desamination of aminoacids, the formation of urea from
ammonia, formation of creatinin;
• Carbohydrates - synthesis of glycogen from monosaccharides and its splitting
into glucose, glucose oxidation, gluconeogenesis,
• Lipids - formation of lipoproteids and phospholipids, oxidation of fatty acids,
formation of bile acids, synthesis of cholesterol (which is necessary for построения
мембран and synthesis of steroid hormones),
1
• Vitamins - deposition and metabolism of vitamins А, В, К, D; депо of vitamin
В12;
• Acidic-base balance regulation;
• Deposition of iron, copper, zinc ions.
Antitoxic function is a neutralization of the toxic substances and xenobiotics,
which come from intestine or enter organism from outside.
Defensive function is a phagocytosis, bactericidal properties of the bile, high
regenerative properties of hepatocytes.
Hemodynamic function is a collection of the blood from digestive tract (35% of
minute circulation volume), депонирование of blood (about 800 ml), influence on the
total blood volume, participation in blood vessel tonus regulation (synthesis of
angiotensin precursor and ferritin, which participates in vasocontriction and
angiotensinase, which has an opposite effect), development of collaterals in a
situation of portal hypertension. Bile acids have hypotensive effect (in pathology).
Hemostatic function is a synthesis of all plasmatic factors of coagulation (I –XII),
anticoagulants and fibrinolytic systems of the blood (antiplasmin, antithrombin,
heparin).
Hemopoietic function consists in a hemopoiesis participation in embryo,
депонирование in adults of such important hemopoietic factors, as cyancobalamin, folic
acid, and iron. Erythrocytes are destructed by tissue macrophages (звезчатыми
клетками).
Endocrine function is a participation in hormones (insulin, thyroxin, aldosteron,
glucocorticoids, sexual) destruction.
Taking into account multiplicity and variety of the liver functions, it is possible to
give the following definition of the hepatic insufficiency.
Hepatic insufficiency is a totality of syndromes, connected with a disorder of
the liver ability to fulfill its functions resulting in disorder of жизнедеятельности of
organism.
CLASSIFICATION
There are several classifications of a hepatic pathology.

Etiological classification divides it into acquired and hereditary, primary
(independent liver diseases) and secondary (hepatic syndromes, which are a complication
of another systemic diseases).
Pathophysiological classification divides it into
• Cholestatic (excretory) as a result of a disturbance of bile formation
(cholepoiesis) and bile excretion (cholestasis)
• Hepato-cellular (parenchymatous) as a result of dystrophic disorders of the
hepatocytes
• Hepato-vascular connected with disorder of blood circulation.
In addition, it may be total (all functions are disordered) and partial (отдельные
functions are disordered), absolute (disorder of hepatic functions) and relative
(discrepancy between activity of the liver and increased needs of organism; for example,
increased hemolysis of erythrocytes leads to hemolytic jaundice in spite of increased bile
formation in the liver). Very often a combination of several mechanisms in the
development of hepatic pathology can be observed.
Clinical classification divides hepatic pathology into acute (during some days or
weeks) and chronic (during some months or years).
2
ETIOLOGY
Causes of hepatic pathology are so numerous, that there is a tendency to

exaggerate them and to connect many diseases with liver pathology.
Etiological factors are divided into exogenous and endogenous, hepatic and
extrahepatic, hereditary and acquired, physical, chemical and biological ones.
Exogenous Factors
Exogenous factors of physical, chemical and biological origin accomplish a direct

injury of a hepatic tissue.
Physical factors are an ionizing radiation (X-ray hepatitis) and mechanical trauma.
Chemical factors are the following:
• Noninfectious organic and nonorganic toxic substances and poisons (phosgene,
carbon tetrachloride, arsenic, insecticides, industrial poisons),
• Vegetable poisons (aphlatoxin, muscarin),
• Side-effect of some medicines (sulphanilamides, салицилаты, biomycin,
tetracycline, cytostatics),
• Alcohol abuse,
• Alimentary factors - lack of food (starvation), vitamin deficiency, abuse of
the fat food.
Biological factors are the following:
• Infectious are bacterial and viral among which viruses of hepatitis (A, B, C,
D, E, G) occupy a special position; agents of tuberculosis and lues, malaria
plasmodium and parasites (лямблии, гельминты),
• Immune factors associated with vaccination, injection of immune serum, as
well as пищевых и лекарственных allergens.
Endogenous Factors
Endogenous factors are also physical, chemical and biological, but of internal
origin. They are the following:
Physical factor is a trauma and mechanical occlusion of the bile tracts. The most
often cause is a presence of stones (from bilirubin, cholesterol and calcium) located in
bilious tract and gall bladder. Narrowing of bile ways by inflammatory process and
tumors mast be added.
Chemical factors are endogenous poisons (metabolites) in uremia, diabetes
mellitus (hyperketonemia), pregnancy with toxicosis and also products of tissue
decay in burn and crush-syndrome.
Biological factors are
• Autoimmune (hepatotropic autoantibodies, sensitized lymphocytes, T-
killers and BAS during autoimmune reactions);
• Tumors both as primary (hepatocarcinoma) and metastatic (in cancer of the
stomach, lungs, mammary gland, leukemic infiltrates);
• Genetic (enzymopathy) and congenital structural defects of the liver;
• Nervous regulation disorder, dyskinesia (spasms) of the bile tracts,
• Blood circulation disorder as a result of ischemia, thrombosis, embolism,
cardiovascular insufficiency, portal blood circulation disorder,
• Endocrine and metabolic disorders (diabetes mellitus, obesity).
3
PATHOGENESIS
Damage of the liver can be primary (by direct effect of an etiological factor) and
secondary (indirect, as involvement of the liver into another pathology - allergy, the
disturbance of the systemic blood circulation, heart insufficiency, hypoxia).
All typical pathological processes can occur in the liver.
• Inflammation (hepatitis) occurs by infectious and non-infectious agent.
• Allergy is a result of the cytotoxic autoantibody formation against
pathologically changed hepatocytes and development of autoallergic
reactions of humoral and cellular types; then the liver is damaged by
immune cytolysis with T-killers and BAS.
• Tumors may be primary and metastatic.
• Hypoxia of different origin creates a relative deficit of microsomal cytochrom P450
needed for antitoxic hepatic function.
• Metabolic disorders
• Dystrophy (hepatosis) is a result of the primary or secondary changes of
metabolism in hepatocytes.
• Sclerosis (cirrhosis) e.i. a diffuse growth of the connective tissue (as a rule on the
background of the chronic inflammatory or metabolic affection of the liver);
alcohol abuse plays a role.
Due to anatomical and functional connections between liver and other organs
of the digestive system as well as with spleen and kidneys, a high frequency of
combined disturbances of the liver and these organs (hepatolienal and
hepatorenal syndromes) are typical for the liver pathology.
Compansatory Reactions
As in any other pathology, the liver pathology consists not only of pathological
structural and functional disturbances, but also of compensatory reactions, which
are intended to stop pathological process in the organ.
These are the following defensive reactions:
• Phagocytosis of infectious and other harmful agents,
• Toxical substances excretion,
• Intensification of the metabolic detoxication,
• Intensification of the energy production in the liver,
• Redistribution of the blood, change of vessels tonus (as in blood loss),
• Development of collaterals (anastamoses) in the case of portal circulation
disorders,
• Regenerative hypertrophy (the liver capability of regeneration can be
evident both during its partial resection in experiment and in clinic).
Finally, at the end of the general considerations about etiology and pathogenesis
of hepatic pathology, it is necessary to mention that each form of it has peculiarities
of its etiology and pathogenesis. The details are below.
CHOLESTATIC HEPATIC INSUFFICIENCY
Cholestatic hepatic insufficiency is a totality of syndromes connected with a

disorder of bile secretion (cholestasis).
4
ETIOLOGY
All factors (exogenous and endogenous), which cause an occlusion of the bile
tracts lumen results in bile secretion disorder. Concrements (stones) formation in
bilious ducts and gallbladder (cholelotiasis) is the most often situation
(желчекаменная disease). Presence of parasites in the gallbladder, dyskinesia of the
biliferous tracts (spasms of gallbladder sphincter), tumors (головки of pancreas),
inflammation have the same effect of narrowing of the bile ways.
Degree and rate of bile tract obstruction is a decisive condition of cholestatic
hepatic insufficiency development and manifestations.
PATHOGENESIS
Pathogenesis of the disorders depends on sudden (complete) or chronic (partial)

occlusion of the bile ducts happens.
The sudden acute complete obstruction of bilious ducts is accompanied by a severe
pain, which bears the name of hepatic colic. Urgent aid is necessary to patient.
Spasmolytic drugs sometimes help. Urgent surgical intervention is sometimes
necessary.
Obstacle to bile outflow results in elevation of pressure in the bile capillaries. Their
rupture may occur. Bile acids damage the hepatocytes and the reverse transport of the
bile into the blood capillaries occurs. Bile components appear in the systemic blood
circulation (group of signs termed as cholemia). On another hand, the bile
естественным ходом does not enter into the duodenum and does not participate in the
digestion (group of signs termed as acholia and hypocholia).
MANIFESTATIONS
Cholestatic hepatic insufficiency is manifested by three pathophysiological

syndromes – acholic (hypocholic) syndrome, cholemic syndrome and mechanical
(posthepatic) jaundice. All of them have common etiology (narrowing or total
occlusion of bile ducts), but pathogenesis and clinical manifestations are different
though they develop simultaneously.
Acholic (Hypocholic) Syndrome
Acholic (hypocholic) syndrome is a totality of symptoms, connected with

complete or partial nonentrance of bile components into the duodenum and
intestine.
Etiology and Pathogenesis
Acholic (hypocholic) syndrome is a result of bilious ways occlusion by different

factors, which oppose bile moving in a proper direction into the duodenum. In turn,
acholia means absence of bile and hypocholia means its lack in intestine.
The following processes, which are connected with the role of bile in the intestine,
get disordered:
• Emulgation of fats in the intestine, which is necessary for over-boiling of lipids
(with the aid of pancreatic lipase) and their sucking
5
• Vitamin suction in the intestine, namely, the group of fat-soluble (K, A, D, E)
• Pigment rotation (direct bilirubin does not enter with the bile into intestine and
does not participates in the pigments rotation)
• Motoricy of small and large intestine
• Bacrtericidity in intestine, which is provided by bile acids in norm.
Manifestations
Manifestations depend on extent of occlusion of the bile ways. If occlusion is not

complete (hypocholia) and a bile partially comes into intestine, the following clinical
manifestations develop:
• Диспепсия malabsorption - a disturbances of lypolysis of nutritiants in digestive
tract and, as a result, a disorder of their absorption,
• Dysbacteriosis,
• Activation of гниения и брожения in intestine, caused by dysbacteriosis and
disfermentation,
• Hypocoloration of feces caused by lack of stercobilin,
• Presence of fats in feces (steatorrhea), which acquires a specific look - липкий
кал, that together with hypocoloration придают каловым массам look of white глины,
• Depression of intestinal peristalsis,
• Constipation, alternated with diarrhea,
• Meteorism,
• Abdominal pain (due to meteorism),
• Hypocoagulation of the blood and hemorrhage syndrome (due to K-
hypovitaminosis), which is aggravated by lack of procoagulants and increased
permeability of the microvessels.
• A-, D-, E-hypovitaminosis with corresponding clinical signs – worsening in the
quality of the skin, its dryness, disorder of the sexual hormones synthesis etc.
If occlusion is complete (acholia), pain prevails (hepatic colic), feces are
discolorated (white) and stercobilin (urobilin) is absent in urine.
Cholemic Syndrome (Cholemia)
Cholemic syndrome is a totality of the symptoms connected with entering of

bile into the blood.
While speaking about cholemic syndrome it is necessary to take into consideration,
that the most toxic component of the bile - the bile acids (as well as glycocholic and
taurocholic acids). Just their elevation in the blood (it is termed as cholalemia)
causes the gravest symptoms of cholemia. Other components of a bile are not so
toxic. Their increase in the blood are called hypercholesterolemia and
hyperbilirubinemia.
Cholemic syndrome accompanies acholic (hypocholic) one and is caused by the

same reasons (complete or partial occlusion of the bile ways). Due to elevation of
pressure in them the bile moves in reverse direction – into the blood capillaries and
then into systemic blood circulation.
6
Pathogenesis of disorders is connected most of all with cholalemia and is the
following:
• Cerebrotoxical effect is the most eminent, since the nervous system is the most
sensitive to all types of intoxication. It disturbs a functional state of the nervous
system - excitation follows by inhibition of the centers of the brain and spinal cord.
• Vagal irritation by bilious acids (vagotonia) results in disregulation of arterial
blood pressure, heart activity, respiration and digestion.
• Irritation of the dermal nervous receptors is caused by falling of bilious acids into
the skin.
• Hemolysis of erythrocytes is a result of detergent action of the bile on their
membrane.
• Damage of the tissues by bile acids may result in inflammation and necrosis.
Manifestations
Cholemic syndrome has the following clinical manifestations:

• Cholalemia causes
Hервно-астенические проявления and disturbance of the self-sensation are –
asthenia, disturbance of daily rhythm of sleep and awaking (sleepiness in the
daytime and insomnia at night), headache, irritability, excitability, depression,
fatigability, decrease of the tendon reflexes
Dermal itching
Arterial hypotension
Bradycardia
Bradypnoe
Anemia
Peritonitis, acute pancreatitis and necrosis of the liver may develop in severe
cases.
• Hypercholesterolemia causes cholesterol depositions (xanthomas) in the skin of
hands, foots and eyelids.
• Hyperbilirubinemia causes mechanical (posthepatic) jaundice.
Mechanical (Posthepatic) Jaundice
Jaundice (icterus) is a syndrome connected with elevation of bile pigment

(bilirubin) content in the blood, its deposition in the tissues coloring them in yellow.
There are three types of jaundice – suprahepatic, hepatic and posthepatic with
different causes and significance.
Mechanical (posthepatic) jaundice is a yellow coloration of the skin, mucous
membranes and sсleras by conjugated bilirubin, deposited in them, as a result
of hyperbilirubinemia due to the bile-secreting ways obstruction.
Mechanical jaundice is one of syndromes of cholestatic hepatic insufficiency
together with acholic and cholemic syndromes.
Etiology. Causes of posthepatic jaundice are similar to those of cholemic and
acholic syndromes mentioned above (mechanical complete or partial occlusion of the
bile ways).
Pathogenesis. Disorder of bile outflow and increase of pressure in bile ways
results in hepatic cells damage and a reverse transport of bile into the blood.
Speaking about jaundice, one has in mind entering into the blood of the bile pigment
– conjugated (direct) bilirubin. Лабораторное determination of its presence in the
7
blood allows to state exactly a cause of a grave state of a patient as an occlusion
of bilious ways (more often by bilious stones). This type of bilirubin filters into urine
and gives a specific dark coloration (bear color) to it.
Manifestations. Direct bilirubin is not very toxic. Not a yellow coloration of the
skin and scleras is a cause of suffering of patient (this pigment does not cause any
pathological symptom accept yellow coloration). In mechanical jaundice yellow
coloration of the skin is never an isolated symptom but accompanies cholemic
syndrome mentioned above with nervous disorders, itching, arterial hypotension,
destruction of erythrocytes and symptoms of acholia - discoloration of feces and dark
urine. A pain (hepatic colic) is often ground of urgent surgery.
Thus, clinical picture of mechanical jaundice is determined by such manifestations
of cholestatic hepatic insufficiency – pain (hepatic colic), symptoms of cholemia and
acholia.
HEPATO-CELLULAR (PARENCHYMATOUS) HEPATIC INSUFFICIENCY
Hepato-cellular (parenchymatous) hepatic insufficiency is a totality of

syndromes, which develops as a result of hepatic cells (hepatocytes) damage.
ETIOLOGY
Parenchymatous hepatic insufficiency may be primary as direct injury of

hepatocytes by etiological factors and secondary. Causes may be exogenous and
endogenous of physical, chemical and biological nature. They are:
• Ionizing radiation,
• Poisoning by salts of heavy metals, phosphorus and arsenic, organic and inorganic
(tetrachloride hydrocarbon) poisons, грибной poison, high constant doses of alcohol,
• Infection (viral, токсоплазмоз),
• Hepatotrophic antibodies and sensitized lymphocytes;
• Medical drugs abuse,
• Endogenous products of metabolism in uremia and nephropathy of pregnancy
(secondary lesion of hepatocytes),
• Genetic factors – lack of enzymes, which participate in numerous biochemical
reactions in hepatocytes (enzymopathy) or receptors on membranes,
• Disorder of blood circulation (including problems in portal system and secondary
lesion of hepatocytes),
• Lack of food (starvation), avitaminosis,
• Extirpation of the liver in experiment.
PATHOGENESIS
Primary or secondary, all typical pathological processes (inflammation, allergy,

tumors, ischemia, dysthrophia, hypoxia etc.) may develop in hepatic cells. Structural
and functional disorders in hepatocytes concern their membranes, mitochondrias,
nucleus, lysosomes.
Pathogenesis can be presented as the following chain of events:
• Disorder of molecular architectonics of hepatocyte membranes,
• Increase of membrane permeability,
• Release of hydrolases from lysosomes, which aggravate a damage,
8
• Release of necrogenic factors and interleukins from damaged macrophages and
development of inflammation,
• Formation of autoantibodies and autosensibilized T-killers that promote
autoallergic damage of hepatocytes.
Damage of hepatocytes, starting by any pathological process, gets complicated
by a disorder of bile secretion in a zone of lesion and additional damage of them by
bile acids. Barrier between bilious ways, blood and lymphatic vessels gets broken,
and bile comes into the blood (cholemia). Conjugated bilirubin level in the blood
increases, it appears in urine. Flow of bile into intestine gets hampered (hypocholia).
Lesion of hepatic cells results in disorder of all their functions. Consequences
depend on its degree and mass of impaired hepatocytes. Chronic course of any
pathology in hepatocytes results in substitution of parenchima by connective tissue
and sclerosis (cirrhosis) development (toxic, bilious or portal cirrhosis depending on
initial cause).
MANIFESTATIONS
Manifestations of parenchymatous hepatic insufficiency are biochemical,

pathophysiological and clinical. They are represented as the main syndromes –
• Metabolic syndrome,
• Syndrome of the antitoxic dysfunction,
• Hemorrhage syndrome,
• Hepatic coma,
• Parenchimatous jaundice,
• Cholemic syndrome,
• Hypocholic syndrome.
The last two syndromes (cholemic and acholic) were described above. Below are
another.
Metabolic Syndrome
Liver is called metaphorically as «a big biochemical laboratory of organism”. It

means liver participation in carbohydrate, lipid and protein metabolism as well as in
acid-base, water, hormone and vitamin balance. General considerations about
disorders of metabolism are represented in corresponding chapters ( ) Below are
represented those which are connected with hepato-cellular hepatic insufficiency.
Carbohydrate Dismetabolism
Disorders of carbohydrate metabolism are the following.

• Glycogen synthesis (glycogenesis) suppression and lack of a glycogen content in
the liver as a main depot of glucose in organism. Primary disorder is determined by
enzymopathy (reduced activity of гликогенсинтетазы), the secondary – by hormonal
disorders (in deficit of insulin, which provides conversion of glucose into glycogen)
and in starvation.
• Glycogen splitting (glycogenolysis) suppression. Primary disorder is underlined by
enzymopathy (lack of phosphorilase, glocoso-6-phosphotase and other enzymes of
glycogenolysis). Intracellular (in hepatocytes) retention of glycogen (glycogenosis,
disease of accumulation) leads to hepatocyte degeneration. Secondary disorder is
9
determined by endocrine disturbance (glycogenolysis is controlled by glucagon,
adrenaline and thyroxin).
• Glyconeogenesis (formation of carbohydrates from lipids and proteins) disorders
(glucocorticoids control it).
• Hypoglicemia (it is noted on an empty stomach, but hyperglycemia develops after a
meal).
• Glucose intermediate metabolism disorder (formation of glocoso-6-phosphate, which
participate in цикле трикарбоновых кислот и пентозофосфатном цикле).
• Non-oxidized metabolites accumulation (metabolic acidosis).
• Glucuronic acid synthesis suppression (which is formed from glycogen and
participate in antitoxic function of hepatocytes).
Lipid Dismetabolism
Lipid metabolism in the liver is an important source of energy production in

organism (oxidation of lipid acids). In addition, it is a place of the important
compound lipids synthesis – phospholipids, lipoproteids, cholesterol and its ethers
(the latter is necessary for fatty? lipid? acids formation, vitamin D3 formation,
corticosteroids and sex hormones synthesis).
There is a conception of lipotropic substances, which provide тонкое
диспергирование of lipids in the blood, their leaving from hepatocytes and a proper
oxidation. The lipotropic substances are phospholipids - лецитин of the liver (with
cholin and methionin of the food, which utilization is necessary for its synthesis) and
липокаин (from pancreas). Deficit of lipotropic substances results in lipid degeneration
(decomposition) of the liver.
Lipid metabolism (anabolism and catabolism) gets disordered in parenchimatous
hepatic insufficiency. Dynamics is the following –
• Transport транспортная hyperlipemia (which develops, when запасы of glycogen,
as a source of energy substrate, diminishes),
• Lipolysis (lipid disintegration) activation as a mechanism of energy production (in
glycogen deficit in the liver with accumulation of жирных lipid? fatty? acids),
• Incomplete oxidation of триглицеридов (нейтральных жиров) and жирных lipid? fatty?
acids with accumulation of intermediate products in form of ketone bodies (formed
from АcКоА цикла трикарбоновых кислот, which may be inhibited), hyperketonemia
and ketonuria (ketosis), when utilization of ketone bodies gets disordered in deficit
of oxidative enzymes or carbohydrate deficit.
• Peroxide oxidation activation resulting in accumulation of POL products.
• Lipoproteids and phospholipids synthesis decrease.
• Hyperlipoproteidemia (increased their synthesis from жирных кислот), which
predisposes to atherosclerosis development.
• Lipids accumulation out of adipose tissue (in epithelium and межклеточном
веществе печени). It is an adipose degeneration and dystrophy of the liver (жировой
гепатоз, a combination of lipid infiltration with disorder of cytoplasm structure).
• Hypocholesterolemia due to decrease of cholesterol biosynthesis from AcKoA.
On the other hand, hypercholesterolemia may be a result of a) decreased use of
exogenous cholesterol from plasma by hepatocytes, b) due to disorder of cholesterol
excretion with the bile in cholemic syndrome (in mechanical and parenchimatous
jaundice).
• Steroid hormones metabolism disturbance.
10
• Steatorrhea (release выделение of lipids with feces in disorder of their suction in
intestine in hypo- and acholic syndrome).
• Bile secretion disturbance and jaundice development.
Protein Dismetabolism
Protein metabolism gets disordered in parenchimatous hepatic insufficiency and

manifested by the following signs.
• Hypoproteinemia develops due to reduction of белоксинтетической function of the
liver. (In norm, all albumin of the blood and partially α- and β-globulins are
synthesized in the liver).
• Disproteinemia is a disorder of ratio between albumins and globulins in the blood.
• Oncotic pressure of the blood decrease (hypoonkia), tendency toward edema
development (hepatic edema).
• Intermediate aminoacid catabolism (desamination, decarboxilation,
transamination) disorder. The impaired liver is not able to support a proper quantity
and correlation of separate aminoacids and protein fractions in the blood. Increased
content of free aminoacids in blood (hyperaminoacidemia), their appearance in urine
(aminoaciduria) and metabolic acidosis are the manifestation of this.
• Urea synthesis from aminogroups and ammonia is reduced, ammonia
accumulation in the blood (azotemia).
• Hypocoagulation and tendency toward bleeding (hemorrhage syndrome) due to
decreased synthesis of procoagulants (prothrombin, fibrinogen, proconvertin).
• Intracellular enzymes release into the blood from destructed hepatocytes (alkaline-
transaminase, glutamate-transaminase, aminotranspherase,
aspartataminotranspherase), which easily penetrate through the damaged cellular
membrane. Transaminase content in the blood elevates in viral hepatitis and
cirrhosis. High level of hepatic transaminases in the blood is a diagnostic test.
Hormonal Disbalance
Inactivation of insulin, thyroxin, aldosterone, sexual hormones takes place in the

liver under physiological conditions. In parenchimatous hepatic insufficiency a
hormonal disbalance happens in organism in form of relative excess of hormones
which might be destructed in the liver but due to suppression of this physiological
mechanism retained in the blood. It results in endorcrinopathy of hepatic genesis and
imitation of surplus of these hormones with correspondent clinical symptoms.
Acid-Base Disbalance
Acid-base disbalance is manifested by accumulation of the incompletely oxidized

products (majority of then are acids) and a development of metabolic acidosis.
Hyperaminoacidemia aggravates it.
Water Disbalance
Retention of water in organism and redistribution of it into the tissues manifest

water disbalance. Hypoproteinemia and hypoonkia underlies it as a result of a
decrease of белоксинтетической function of the liver. Situation is aggravated by relative
11
hyperaldosteronism due to suppressed destruction of this hormone in hepatic cellular
pathology (results in increased sodium reabsorption) .
Hepatic edema develops both in form of a systemic and a specific edema (ascite)
as an accumulation of water in the cavity полости брюшины. Portal hypertension (in
cirrhosis) adds a hydrodynamic component in edema development.
Vitamin Disbalance
Vitamins disbalance consists in the development of hypovitaminosis due to the

following reasons.
• Synthesis of vitamins and formation their active forms is inhibited (ретинола из
каротина, коэнзима А из пантотеновой кислоты), disorder of active form of vitamin D3
formation.
• Disorder of депонирования of vitamin В12 and folic acid.
• Absorption of fat-dissolved vitamins (A, D, E, K) from intestine gets reduced in
deficit of bile and a disorder of lipids suction.
Hemorrhage Syndrome
Hemorrhage syndrome (hypocoagulation) is an inclination to blood loss

spontaneous or due to insignificant damage of the vessels. Deficit of procoagulants
synthesis (fibrinogen, prothrombin, proaccelerin, proconvertin, Kristmass-factor other
plasmatic factors of coagulation) underlies hemostasis disorder. It is connected with a
disorder of белоксинтетической liver function. Hypocoagulation is aggravated by К-
hypovitaminosis in a situation with problem of bile secretion into intestine and suction
of lipids. Suction of fat-soluble vitamins (including K-vitamin) from intestine is
disordered in cholestatic hepatic insufficiency.
At the same time hypercoagulation is possible in a case of suppressed synthesis of
components of anticoagulative and fibrinolytic systems (antiplasmin, antithrombin,
heparin).
Syndrome of the Antitoxic Function Disorder
Under physiological conditions, the products of aminoacid oxidation in intestine

(индол, скатол, фенол, путресцины), ammonium (which forms in desamination and as
well as in intestine при гниении) are inactivated in the liver.
Chemical and infectious
toxins, medical drugs are also обезвреживаются in the liver.
Mechanisms of disactivation are the following:
• Conjugation with парными соединениями - glucuronic acid, гликоколом, цистеином,
серной кислотой,
• Oxidation in the system of microsomal oxidation (agranular цитоплазматической
сети when cytochrom Р-450 is important component),
• Synthesis of urea from ammonia is the main way of ammonia обезвреживания in
the organism,
• Boсстановлениe is a mechanism of обезвреживание нитросоединений,
• Hydrolysis is a mechanism of обезвреживанеие сердечных гликозидов,
• Mетилирование is a mechanism of обезвреживанеие производных пурина,
• Aцетилирование.
Causes of antitoxic function disorder are the following – a) decrease of mass of
actively функционирующих hepatocytes, b) dystrophic changes of hepatocytes, c)
12
energy deficit (hypoxia, disorder of oxidation resulting in ATP deficit), d) deficit
of парных соединений, e) enzymopathy - lack or disorder of activity of enzymes,
which participate in the metabolism (аргининсукцинатлигазы,
карбамоилфосфатсинтетазы, орнитилкарбамоилтрансферазы, аргининсукцинатсинтетазы).
In parenchimatous hepatic insufficiency the following toxic products are
accumulated in the blood
• Internal poisons from intestine — phenol, indol, skatol;
• Toxic metabolites: low-molecular fat acids (valeric, capronic), sulphur-containing
acids (cystine, methionin);
• Microorganisms (in norm they are destructed by Kupfer cells),
• Exogenic chemical poisons,
• Products of incomplete deactivation of medical drugs.
The outcome of progressive hepatic insufficiency is a hepatic coma.
Hepatic Coma
Hepatic coma is the heaviest manifestation of parenchymatous hepatic

insufficiency.
Hepatic coma is a damage of the central nervous system function as a result of
the disturbance of all functions of the liver.
Hepatic coma is a syndrome, caused by a toxical lesion of the central nervous system
with profound disorders of its functions.
Etiology. Causes of hepatic coma are those, which cause parenchimatous hepatic
insufficiency (mentioned above), in the case of their high intensity that excels
protective possibilities of the liver.
Pathogenesis
Hepatic coma appears, when homeostatic and barrier functions of the liver get
decreased essentially. In addition, the substances, containing in damaged hepatocytes,
get into the blood and exert the pathogenic influence on organs and tissues including
the cells of the nervous system.
Pathogenesis of hepatic coma has a lot of physico-chemical, chemical, biochemical
and pathophysiological mechanisms. Their simple enumeration allows us to
understand, how difficult, almost impossible to provide medicamentous correction of
this heavy clinical condition.
• Hypoglycaemia is a first reason of death after total liver extirpation in experimental
animals. The death comes in 5-8 hours because of acute hypoglycemia. The term of
life may be prolonged till 20-40 hours by artificial supporting of the normal glucose
level.
• Acidosis is another essential mechanism of coma development as the majority of
metabolites are acids. It was demonstrated in experiment, that the acid-base
correction allows prolonging the life of experimental animal after total liver
extirpation till 2-3 days.
• Systemic hypoxia develops. Energy formation in form of АТP in the brain gets
disordered. The causes are the following -
hypoglycemia,
отвлечение of α-кетоглютаровой acid from Krebs cycle (for ammonia
bounding) and прерывание of Krebs cycle in energy production,
13
• Electrolyte disbalance comes due to metabolic disorders and secondary
hyperaldosteronism. They are – натриемия (retention of sodium), loss of К from
neurons, inactivation of Na-K pump, disorder of excitability.
• Retention of water (entering of Na and water into the cells) causes swelling of the
cells.
• Increase of a free ammonia (azotemia) level in the blood is conditioned by
disturbance of its transformation into urea in ornithine cycle of hepatocytes. Besides,
the part of urea, which is excreted by mucous membrane of the intestine, is splitted by
ureasis with formation of ammonia, which sucks into the blood. Ammonia in large
concentration damages the cells of the organs and tissues, suppresses the enzymal
reactions in them.
• Toxic substances appear in the blood, which determine general toxic and,
especially, cerebrotoxic effect. They provide direct мембранное effect on
excitability of membrane and ion pumps. These substances are -
Ammonia,
фенолы from intestine,
диметилсульфид that is formed from метионина (сообщает больному печеночный
запах),
Lactic and piruvate acids,
Aromatic aminoacids,
ацетоин,
бутиленгликоль,
низкомолекулярные жирные кислоты – масляная, валериановая, капроновая,
Ketone bodies,
Bile acids,
Direct bilirubin.
• Due to dismetabolism of aminoacids in pathologically changed liver,
pseudoneuromediators (октопамин and тирамин) are produced. They вытесняет
physiological mediatores (noradrenaline and дофамин ) from nervous синапсов.
Heavy disorder of nervous functions are aggravated by increased synthesis of
serotonin (neuromediator, which effect psychoemotional reactions).
• Large concentration of unconjugated bilirubin in the blood produces toxical effect.
• Disturbance of aminoacidic and albuminous metabolisms leads to accumulation of
toxic products of aromatic aminoacids decay (indole, skatole, phenol) and of
albuminous putrefaction (putrescine, cadaverin) in the blood.
• Disorder of acid-base, water and mineral balance results in acidosis and brain
edema.
Manifestations
Clinical manifestations of hepatic coma are a picture of encephalopathia

(cerebrale syndrome).
• Psycho-emotional disorders (раздражительность, депрссия, эйфория), disorders of
ритма сна (сонливость днем, insomnia at night),
• Motor disorders – ataxia, trembling,
• Areflexia (absence of reflexes),
• Convulsions,
• Cramps,
• Vomiting,
• Loss of consciousness.
14
Severe disorders develop in cardiovascular and respiratory systems. They are the
following.
• Arrhythmia, bradycardia, blockade, disorder of myocardial contractility,
extrasystole,
• Acute disorder of systemic hemodynamics - decrease of circulating blood volume
and arterial blood pressure as well as the disturbance of cerebral blood circulation,
• Extreme respiratory center excitement - Kyссмауля breathing,
• Edema of the brain and lungs,
• Erythrocytes hemolysis.
Печеночный запах of the body also attracts attention.
Parenchymatous Hepatic Jaundice
Parenchymatous jaundice is the yellow coloration of the skin, mucous

membranes and scleras by direct and indirect bilirubin as a result of
hyperbilirubinemia due to the hepato-cellular hepatic insufficiency or isolated
disorder of pigment metabolism.
There are two forms of hepatic parenchimatous jaundice, which are different as to
etiology, pathogenesis, manifestations and clinical significance – cellular and
энзиматическая.
Cellular Hepatic Jaundice
Etiology. This form of jaundice is acquired. Damage of hepatic cells is caused by

the same etiological factors as they were noted above as the reasons of
parenchimatous hepatic insufficiency. Primary (direct) or secondary damage of the
hepatic cells is conditioned by infection agents (viruses), noninfectious ones (organic
and inorganic hepatotropic poisons, medical drugs) and as a secondary injury in
systemic dismetabolism, allergy etc.
Pathogenesis. This form of jaundice is an essential part of hepato-cellular
parenchimatous insufficiency described above and is accompanied by disturbance of
all the functions of the liver – metabolic, digestive, antitoxic, hemostatic,
hemopoietic.
Symptom of jaundice is connected with bile pigments rotation. The damaged
hepatocytes secrete conjugated bilirubin both into bile and blood capillaries. The
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 hepato-cellular
insufficiency. Systemic intoxication connected with dismetabolism prevails. Acholic
and cholemic syndrome are also observed (but not so expressed as in cholestatic
hepatic insufficiency and mechanical jaundice connected with it).
Лабоpаторные signs of this jaundice is an elevation of nonconjugated and появление
of the direct (conjugated) bilirubin in the blood. Amount of pigments in the feces
decreases, which become hypocolorated. Direct bilirubin and urobilin appear in urine.
It determines hypercoloration of the urine.
Enzimatic Parenchimatous Hepatic Jaundice
Etiology. This form of jaundice is congenital. Causes are endogenous. It is

genetically determined. Enzymopathy underlies it. Some genes refer to
15
transformations of bilirubin in hepatic cells – capture, conjugation and excretion.
Mutation of them is possible.
Pathogenesis and Manifestations. Enzimatic parenchimatous hepatic jaundice is
an isolated disorder of pigment metabolism and is not associated with disorder of
other functions of hepatic cells.
The following pathogenetic variants of intrahepatocytic metabolism of bilirubin
disorder are possible:
• Disorder of an active capture of indirect bilirubin (билирубин-альбуминового
комплекса) by hepatocytes and its transport from the blood into the hepatic cells. An
increased level of bilirubin in the blood is stipulated by unconjugated one
(syndrome Жильбера). Amount of stercobilin in feces and urine decreases, feces are
hypocolored.
• Disorder of conjugation of bilirubin with glucuronic acid in hepatocytes. This
variant of jaundice develops as a result of genetic deficit of glucoronyltransferase (the
key enzyme of transformation of indirect bilirubin into conjugated one). A large
quantity of free bilirubin appears in the blood. This form of bilirubin (contrary to all
other forms – connected with albumin, conjugated with glucuronic acid) is very toxic and
is able to penetrates through the blood-brain barrier (hematoencephalic). It results in
grave encelophathy (ядерная желтуха). Content bilirubinglucuronide in the bile is
decreased that results in decreased amount of pigments in feces (syndrome Криглера-
Найяра).
• Disorder of excretion of bilirubinglucuronide through the membrane of the hepatic
cells in bile capillaries. As a result, direct bilirubin comes not only into bile
capillaries but also into the blood.
HEPATO-VASCULAR HEPATIC INSUFFICIENCY
Vascular hepatic insufficiency is a result of a disorder of a hemodynamic

function of the liver, congestion of the blood in the portal system of blood
circulation.
Etiology
Those causes, which lead to cirrhosis of the liver, are the main reasons of vascular
hepatic insufficiency. Cirrhosis of the liver can be an outcome of acute and chronic
hepatitis, chronic toxic damage, alcohol abuse, chronic venous-congestive hypoxia of
the liver.
Pathogenesis
Chronic toxic damage of the liver and its chronic inflammation lead to the
development of sclerotic process in parenchyma and stroma of the liver. As a result,
the passage of the blood from the portal system through the liver hampers. Congestion
develops in the portal system (portal arterial hypertension).
The compensatory reactions, directed toward разгрузка of portal blood circulation,
develop. Porta-caval (through hemorrhoidal, esophageal, umbilical veins) and cava-
caval vascular shunts (anastamoses) gets developed, but this разгрузка is achieved мимо
the liver. The neutralization of the toxic products of the digestive tract is limited.
16
The output of liquid part of the blood into the abdominal cavity occurs. Specific
edema, which is called ascite, develops.
Manifestations
Complex of clinical manifestations of vascular hepatic insufficiency includes, from

one hand, signs of systemic and portal blood circulation disorders (syndrome of portal
hypertension), from another hand, all signs of parenchymatous and cholestatic hepatic
insufficiency (acholic and cholemic syndromes, the disturbance of metabolism,
jaundice, shunt hepatic coma).
Pathology of kidneys and spleen often accompanies hepatic insufficiency. Hepato-
renal syndrome develops as a result of decrease of the volume of circulated blood
and a rate of renal glomerular filtration. Hepato-lienal syndrome is manifested by
increase of a spleen size (hypersplenism), phagocytosis activity, anemia, leukopenia,
thrombocytopenia.
Syndrome of the Portal Hypertension
All manifestations of a hemodynamic hepatic function disorder are united in a

complex, which is called as syndrome of the portal hypertension.
Increased blood pressure in the portal system results in development of collateral
blood circulation and opening of porto-caval and cava-caval anastomoses. The dilated
vessels are visible on the frontal abdominal wall while an observation of a patient (so-
called kaput medusea ).
Bарикозное dilatation of вен пищевода и кардиальной части желудка takes place. It is a
place of blood bleeding which may occur (from esophagus and stomach).
Ascite is the most demonstrative pathophysiological and clinical manifestation of
hepato-vascular hepatic insufficiency. It is an accumulation of water in abdominal
cavity and is a sort of a local edema. Its pathogenesis is the following.
• Increase of the hydrodynemic blood pressure in the portal system (выход of plasma
water in accordance with Starling’s law),
• Decrease of the oncotic blood pressure (also Starling’s law),
• Na-ion retention (due to the relative hyperaldosteronism).
Cirrhosis of the liver, which is called portal cirrhosis, is an outcome of the chronic
portal hypertension in addition to cirrhosis, which is caused by other reasons.
In addition, it is necessary to mention, that a disturbance of portal blood circulation
reproduced in experiment, secondarily causes the lesion of hepatocytes.
Posthepatic (Shunt) Hepatic Coma
This variety of coma arises as a consequence of severe affection of the liver of a

sclerotic (cirrhotic) character.
By porto-caval anastamoses, which are developed while a long-termed steady portal
hypertension, some part of blood, sometimes a considerable one, is "thrown" out into
general blood stream мимо the liver. Toxic substances from intestine enter the blood
минуя печень. It causes intoxication of the organism with products of metabolism, which
normally are inactivated in the liver. Figure 54 represents its experimental study.
Нижня порожниста вена v. cava inferior
17
Печінка liver
Ворітна вена v. porta
колатералі collaterals
Художнику! Вместо а б в -a b c
Fig. 54. Modeling of vascular fistules

A a – before operation, b – direct fistule (Ekk), c - reversed fistule (Ekk-Pavlov)
Мал.70 с 538 украинского учебника
This variant of hepatic coma has some peculiarities. It can arise with moderate
disorder of bile-production and bile-excretion. Jaundice is absent at all or is poorly
manifested. Its arising is closely connected with intestinal digestion and a character
of food. Food, which is rich in protein, aggravates a state being a cause of absorption
of toxic products of protein disintegration (ammonia, cadaverin, фенолы, индол, скатол,
путресцины) coming into a systemic blood stream.
JAUNDICE
Jaundice was mentioned above as a result of the excretory hepatic function

disorder. It is an expressive clinical symptom, which attracts attention first of all
while clinical examination of a patient.
Jaundice is a yellow coloration of the skin, mucous membranes and scleras by
bile pigments, deposited in them, as a result of hyperbilirubinemia.
Although the bile pigments (bilirubin, urobilin, stercobilin) are not so toxic as bile
acids, just symptom of jaundice attracts physician’s attention to hepatic pathology. At
the same time, jaundice is not always connected with the pathology of the liver.
Therefore, analysis of jaundice is of a grate diagnostic significance in clinic.
There are three forms of jaundice - mechanical (posthepatic), parenchymatous
(hepatic) and hemolytic (suprahepatic) ones. Two of them were described above.
The third form is below.
HEMOLYTIC JAUNDICE
Suprahepatic jaundice is not connected with the disturbance of the liver function,
but connected with the accumulation of bilirubin in the blood. It is a hemolytic
jaundice.
Hemolytic jaundice is a yellow coloration of the skin, mucous membranes and
scleras by unconjugated bilirubin, deposited in them, as a result of increased
production of it from hemoglobin due to increased erythrocytes destruction.
Etiology
Etiological factors are hemolisins, which cause erythrocytes destruction

(hemolysis). They are of exogenous and endogenous origin and were noted in every
detail in the chapter 20 «Anemia». There was noted that jaundice is an obvious sign
of hemolytic anemia.
Pathogenesis
18
Indirect bilirubin is a bile pigment, which is present in the blood in norm. Its
level depends on intensity of erythrocyte destruction. It is bilirubin-albumin
complexes, which does not filtered through membrane of renal glomeruli and is
absent in urine, even if its level in the blood exceeds the norm.
An excessive destruction of erythrocytes in a spleen results in excessive formation
from hemoglobin and entering into the blood of bilirubin-albumin complex. If a
function of the liver is not disturbed, the indirect bilirubin is converted in the liver
into direct one, which then enters the bile and intestine. Increased quantity of
stercobilin and urobilin is excreted with the feces and urine.
If an increased destruction of erythrocytes exceeds an ability of hepatic cells to
catch indirect bilirubin and transform it into direct one, then an excess of indirect
bilirubin in the blood conditions the coloration of the skin and mucous membranes.
Indirect bilirubin does not possess the toxic properties. It is a typical variant of
hemolytic jaundice.
In a case of albumin deficit in the blood (in starvation and other reasons), the
transport of bilirubin from the spleen to the liver gets disturbed and the so-called free
bilirubin appears in the blood, which is not connected nether with albumin nor
glucuronic acid. This form of bilirubin easily penetrates through blood-brain barrier,
very toxic for nervous cells and causes the so-called ядерная желтуха. Such variant of
suprahepatic jaundice develops in hemolytic jaundice of newborns на фоне decreased
level of albumins in the blood.
Different types of jaundice may combinate.
Parenchimatous jaundice may join the hemolytic one. Although the liver possesses
a potent ability for bilirubin conjugation, hepato-cellular insufficiency may occur in
hemolytic anemia because many hemolytic poisons damage hepatocytes
simultaneously with hemolysis of erythrocytes. Besides, hypoxia, which develops due
to hemolytic anemia, may limit an activity of enzymes of hepatocytes, participating in
conjugation of bilirubin.
Mechanical jaundice can be combined with hemolytic one as a result of occlusion of
the biliferous ways by bile thrombi and stones from bilirubin, cholesterol and calcium.
Manifestations. In clinical picture of typical hemolytic jaundice the signs of
hepatic insufficiency are absent. Cholemic syndrome is absent (bile acids do not enter
the blood). Acholic syndrome is absent as well as bile acids enter into the intestine.
Digestion is not disturbed. It is a typical variant of hemolytic jaundice. О таком пациенте
говорят, что он «more yellow than ill”.
The formation of stercobilin is increased and gives intensive coloration to feces.
Biochemical examination of the blood shows an increased content of indirect
bilirubin; direct bilirubin is absent. However, it is necessary to take into account, that
patient suffers from anemia.
If hemolytic jaundice would be associated with damage of hepatocytes or bile
ways obstruction, the clinical manifestations would be more complete.
19
CHAPTER 29
PATHOPHYSIOLOGY OF KIDNEYS
Kidney is a compound parenchymatous organ with numerous functions. It

consists in nephrons (glomeruli, tubiles) and interstitium. Each part has its own
functions. There are diuretic and nondiuretic functions.
Excretory function belongs to nephrons. It is a urine formation and
elimination. Kidney deals with constancy of water and fluids (isovolemia),
electrolytes (isoionia), osmotic concentration (isotonia) acid-base balance
(isohydria). Kidney excretes the end products of nitrous metabolism (urea,
мочевой acid, ammonia, creatinine) and aminoacids. Under pathologic conditions
kidney excretes foreign and toxic substances.
Incretory function of kidney consists in production of those substances, which
are increted directly into the blood, but not into urine. They are - renin,
prostaglandins, erythropoietin. Juxtaglomerular apparatus can be considered a
small endocrine organ.
Hemodynamic function is a participation of kidney in regulation of arterial
blood pressure and volume of the circulating blood.
Hemopoietic (erythropoietic) function of kidney consists in formation of
stimulator (erythropoietin) and supposed inhibitor of erythropoiesis.
Hemostatic function is an influence on blood coagulation, anticoagulation
and fibrinolysis.
Three physiological processes are accomplished in parenchyma of kidneys to
form urine, namely, the filtration, reabsorption and secretion.
Filtration takes place in glomeruli which are the vascular-epithelial organ
designed for the ultrafiltration of blood plasma. It depends from glomerular
filtrate pressure (correlation between hydrostatic and oncotic blood pressure, as
well as intracapsular glomerular pressure). For estimation of glomerular filtration
the so-called clearance index is used. It shows an amount of blood (in milliliters)
which is completely cleared from exogenous and endogenous substances while
passing through the kidneys per minute. Clearance is counted by formula C=UV/P,
where С – clearance of the investigated substance (ml/min), U - concentration of
the investigated substance in urine (mg/ml), V – diuresis (ml/min), P –
concentration of the investigated substance in plasma (mg/ml). For such
determination, an exogenous (polysaccharide inulin) and endogenous (creatinine)
substances, which are filtrated in the glomeruli, not reabsorbed and secreted in
the tubules, are used.
Nephritic filter (having a certain number, square and diameter of the pores) is
located in the glomeruli and consists of endothelial cells of capillaries, basement
membrane and podocytes. Glomerular basal membrane is chemically a complex
glycoprotein consisting of collagenlike glycopeptides and highly acidic
sialoglycoproteins (which обволакивает epithelium and prevent filtration of
plasma proteins). Primary urine is a nonprotein filtrate of the blood plasma. In the
primary urine there are no cellular elements of the blood. Quantity of primary
urine is 120-180 liters daily.
Renal filtration is very sensitive to blood circulation disorder. The special
feature of blood circulation in the kidneys lies in the fact that just there the dual
netwet of capillaries exists, namely, in the region of the glomeruli, where filtration
1
is accomplished, and also in the region of the tubules, where reabsoption and
secretion are achieved.
Reabsorption into the blood of the primary urine components (water, glucose,
amino acids, phosphates, bicarbonate, ions) takes place in the tubules. Enzymes,
hormones (aldosterone, vasopressin) and energy (which supplied by oxidative
phosphorilation) are necessary for transmembrane transport and reabsorption. If a
little amount of plasmatic slow mass (40 000) proteins would be filtrated, they
may be reabsorbed in the tubules.
Secretion of some products (acidogenesis, ammoniogenesis) occurs in the
tubules. Many xenobiotics, toxic products and medicines are removed into urine
in this part of nephron.
Hormones provide regulation of the processes having place in the kidneys.
Aldosterone of the adrenal cortex ensures the reverse sodium reabsorption, H+ and
K+ secretion; vasopressin (antidiuretic hormone) provides a water reabsorption.
The role of kidneys in pathogenesis of different types of pathology was
mentioned many times in the previous chapters – in development of arterial
hypertension, anemia, edema, acidosis (details see in the correspontent chapters).
On the basis of the enumerated functions of kidneys, the following definition
of the renal insufficiency is possible to propose.
Renal insufficiency is a totality of syndromes of a homeostasis disorder as
a result of impossibility of kidneys to fulfill their functions.
CLASSIFICATION
Etiological classification divides renal pathology into acquired and

hereditary as well as infectious and noninfectious. In clinical practice it is
subdivided into traumatic, nephrotoxic, metabolic, immunological, vascular
(ischemic).
Topographic classification divides it into prerenal, renal and postrenal.
This classification is built on the basis, where an initial reason of kidney
pathology is localized. Division into glomerular, tubular and tubulointerstitial
ones is based on the morphological principle.
Pathogenetic classification divides it into primary (pathology begins in the
kidney) and secondary (kidney gets involved in systemic disordes in organism or
as a complication of another disease) as well as total and partial (all or single
renal functions get disordered). The latter in turn is subdivided into filtrative,
reabsorbtive, secretive and incretive.
Clinical classification divides it into acute and chronic.
ETIOLOGY
Etiological factors, which cause renal pathology, are divided into exogenous
and endogenous, physical, chemical and biological as well as acquired and
hereditary.
Exogenous factors are
• Traumatic (mechanical trauma, massive crushing injury, ionizing radiation,
cold, burns)
• Toxical factors are different chemical nephrotropic poisons. There are
salts of heavy metals (mercury, lead, bismuth, chromium, cadmium),
medicamentous abuse with antebacterial and hormonal drugs
(sulfanilamids, antibiotics, neomycin, penicillin, phenacitine, corticosteroids
and oth.), mushroom, snake poison, pesticides.
2
• Infectious factors are bacterial and viral (streptococcal, staphylococcal,
pneumococcal, meningococcal, colon bacillus, agents of syphilis,
tuberculosis, malaria, hepatitis-B), parasital. Among them hemolytic
streptococcus poses a special position and considered to be specifically
nephritogenic. Fungus also may be a reason.
• Immune factors are the foreign proteins initiating renal disorder of
immune nature (complications after immune serum use and vaccination),
mismatched hemotransfusion.
Endogenous factors are
• Traumatic (occlusion, external compression of urinary ways, mechanical
injury by stones located in them),
• Toxical (products of dismetabolism in diabetes mellitus, amyloidosis, hepatic
insufficiency, peritonitis, pathological pregnancy, gout),
• Vascular in systemic (shock, arterial hypertension) and local (ischemia,
thrombosis, embolization, DIC-syndrome) disorders,
• Immune factors are of a special significance. As endogenous antigen, the
denaturated nucleoproteids, thyroglobulin, proteins of tumorous origin may
serve. Kidneys may be secondary damaged in diffuse lesions of the
connective tissue (rheumatoid arthritis, systemic lupus erythematosis,
nodular periarteritis, hemorrhage vasculitis, etc.).
• Disregulative disturbance of hormonal (aldosterone, vasopressin) control of
renal functions,
• Genetic causes are the genetically conditioned defects of metabolism (lipoid
nephrosis), enzymopathy, congenital morphological defects.
In addition to mentioned classification of etiological factors, the following
division of initial causes into prerenal, renal and postrenal is useful for clinical
practice.
Prerenal factors are those, which secondarily involve kidney into
Systemic disorders of blood circulation resulting in decrease of systemic
blood pressure and volume of circulated blood (blood loss, shock
collapse, acute cardiac insufficiency),
Dehydratation of the organism and hemoconcentration (uncontrollable
vomiting, profuse diarrhea),
Increase of the systemic blood pressure (arterial hypertension),
Acute systemic intoxication (in massive crush of tissues including burns),
Massive hemolysis of erythrocytes (mismatched hemotransfusion)
Renal factors are those, which directly influence kidneys – toxical (injury by
nephrotropic poisons), bacterial, viral, immune, vascular (local disorders of blood
supply).
Postrenal factors are connected with obstruction of the urine ways (calculi,
tumors) and retention of urine.
Conditions, which aggravate an action of etiological factors and predispose to
renal pathology, are the following:
• Доступность accessibility of kidney as an organ of excretion to the damaging
factors,
• Penetration of infection into the kidneys not only by hematogenic way but
also by spreading it upwards from the urinary tract.
PATHOGENESIS
3
All typical pathologic processes occur in the kidneys – inflammation (ordinary
and presumably allergic), hypoxy (presumably local of vascular type), typical
disorders of peripheral blood circulation (thrombosis, embolism), tumor, typical
disorders of the metabolism and hemostasis, etc.
There are some peculiarities in the kidney, which predispose to its pathology.
They are
• Peculiarity of antigene composition of the kidneys, which contributes to
autoallergy,
• Special features of blood circulation in the kidneys - high arterial blood
pressure in renal artery and double vascular network in nephron.
Role of Allergy
Allergic process is a very frequent pathologic process, which develops in the

kidneys. Antibodies against the basal membrane of the nephron are revealed in
the blood of many patients with kidney pathology. The following mechanisms
underlie the predisposition of kidneys to allergic diseases
• Antigenic similarity between α-hemolytic streptococcus and basal membrane
of nephritic filter. That is why this infection may initiate (in a case of
immunopathy) an autoimmune damage of nephritic filter.
• Antigenic similarity between glycoproteins of nephritic filter and connective
tissue. That is why some diseases of the kidneys are often associated with
diffuse impairments of the connective tissue.
• Immune complexes may be nonspecifically adsorbed on the nephritic filter
and damage it, causing an immune inflammation.
Many exogenous and endogenous factors may serve as antigens: bacterial, viral,
parasitic, medicamentous, food, DNA, denaturated nucleoproteins, proteins of
tumor origin and thyroglobulin. Antibodies produced in response to these antigens
are mostly of IgM class. Kydneys very often get involved into immune response.
Role of Genetic Factors
A large quantity of the enzymes and other proteins participates in the functions
of kidneys. It means that the genetic problems are developed frequently.
Enzymopathy is among them. The genetic pathology of nephritic receptors (to
the hormones) is also possible. Congenital morphological deformations in kidneys
and urinary tract may be observed.
Role of Medicines
It is widely known that the medicines can be the factors of the kidney damage.
There are several reasons -
• Precisely kidneys excrete the medicines and can be damaged by them.
• The damaged tissue of nephritic filter can become autoantigenic.
• Medicines can serve as haptene and be converted into the complex antigen
together with the proteins of nephritic filter.
When medicines serve as exogenous antigens, the antibodies, which are
produced in response, are mostly of IgM class.
GLOMERULAR INSUFFICIENCY
4
Glomerular insufficiency is connected with disorder of filtration in glomeruli
and eventuates from
• Changes of glomerular filtrative pressure (ratio between blood,
intracapsular glomerular pressure and oncotic blood pressure)
• Amount of functionally active nephrons
• Damage of nephritic filter (glomerular capillaries and basal membrane).
Glomeruli may be injured by a variety of factors primary and in course of a
number of systemic diseases (secondarily). Damage of nephritic filter is
associated with inflammation of glomeruli, more often of allergic origin. The
damage of the glomeruli may be connected with deposition of amyloid,
fibrinogen, glyco- and lipoproteins with activation of humoral and cellular
mechanisms of the inflammatory reaction in the basal membrane of the
capillaries. As a result, the structural integrity of the basal membrane is lost, its
composition, physical and chemical properties are changed, especially its
permeability. It means that the nephritic filter begins to pass through itself those
substances that must not be passed, namely, proteins and cellular elements of the
blood. In such cases, these substances and cells are determined in the composition
of the urine. At the same time, filter ceases to filter those substances, which must
be filtered, namely, nitric шлаки slags, urea, uric acid, aminoacids, electrolytes. In
such cases, these substances are accumlated in the blood in elevated amount.
INCREASE OF GLOMERULAR FILTRATION
Prerenal causes of increased filtration are the following

• Increase of the systemic blood pressure (arterial hypertension),
• Increase of blood volume (hypervolemia),
• Decrease of the oncotic blood pressure (hypoalbuminemia).
Renal causes have a significance in acute allergic inflammation (acute
glomerulonephritis), when permeability of nephritic filter is acutely increased.
The following clinical signs display a disorder of glomerular fitration

associating an increase in the permeability glomerular membrane of nephritic
filter.
Glomerular Proteinuria
Proteinuria is an appearance of a protein in the urine. It is a leading sign of the

increased permeability of the glomeruli. It is an excretion of plasma proteins with
urine due physical and chemical changes in the basal membrane. It is
characterized by not high content of plasma albumines and proteins переважно
низкой molecular mass (до 40 000).
Hematuria
Hematuria is an appearance of erythrocytes in the urine. The injury of the

glomerular membrane may be accompanied by leakage of erythrocytes into the
glomerular lumen and their appearance in urine as "shadows" (lixiviated
erythrocytes). Leukocyturia is also possible.
DECREASE OF GLOMERULAR FILTRATION
5
Decrease of glomerular filtration may have renal and extrarenal mechanisms.
Prerenal causes of the decrease of filtration may be in the following cases.
• Decrease of hydrostatic blood pressure on the glomerular capillary walls
(fig.55). It is connected with systemic blood circulation insufficiency such as a)
decrease of the arterial blood pressure up to 80 mm Hg due to shock of different
genesis and collapse, b) decrease of the volume of the circulating blood (blood
loss). At the same time it must be mentioned that kidney has own regulative
mechanisms of blood pressure in glomerular capillaries (systemic blood pressure
may колебаться в пределах 70-200 mm Hg, but in glomerular capillaris it is constant –
45 mm Hg).
Швидкість клубочкової фільтації (ШКФ) Rate of glomerular filtration (RGF)

Нирковий плазматік (НПТ) Renal plasma flow (RPF)
Артериальний тиск, кПа Arterial blood pressure kPa
НПТ, мл/хв.г RPF, ml/min.h
ШКФ, мл/хв.г RGF, ml/min.h
Fig. 55. Correlation between rate of glomerular filtration (RGF) and renal plasma flow (RPF) from
arterial blood pressure
__________________________________________________________________
• Elevation of the blood oncotic pressure above 25-30 mm Hg due to

hemoconcentration because of dehydratation of the organism.
• Occlusion of renal artery (compression, spasm, thrombosis).
Renal causes are the following
• Chronic inflammation affecting the glomerular membrane (chronic
glomerulonephritis). It leads to thickening of the glomerular membrane and
change of its physical and chemical properties, decrease of number, square
and diameter of the pores.
• Dystrophy of the glomerular membrane due to disturbances of blood supply of
the kidneys, hypoxia, toxic influences.
• Reduction of the number of the functioning glomeruli and total filtrative
surface.
• Increase of pressure in the capsule of the glomeruli above 25 mm Hg, which is
observed in the delayed reabsorption of fluid in the proximal part of the
tubules, in occlusion of the tubules lumen by cylinders, necrotic masses.
Postrenal causes are associated with obstruction of the ureter by calculi and
tumor (prostate hyperthrophy and adenoma).
The following clinical signs display a disorder of glomerular filtration.
Oliguria and Anuria
It is a decrease of diuresis. Oliguria is a decrease and anuria is stopping of

urine production.
6
Azotemia
Azotemia is an increased content in the blood of nitrous substances (urea, uric

acid, creatine, creatinine, and ammonia) as well as aminoacids. The level of
azotemia (residual nitrogen) may be different — from the slightly exceeding the
upper limit of the normal quantity of residual nitrogen (35.7 mmol/1) to 142.8-357
mmol/1. Dysfunction of the glomeruli is manifested by delay of excretion not only
of nitrous metabolism products, but also accumulation in the blood of toxic
products from intestine (indican, fenol, indole and skatole). All of them are very
toxic and cause poisoning, being a reason of uremia.
Electrolyte Disbalance
As a result of excretory dysfunction of the glomeruli there is decreased

excretion of phosphates, sulfates and their retention in the blood
(hyperphosphatemia, hypersulfatemia). These anions push out hydrocarbonates in
the extracellular fluid decreasing alkaline reserve of the blood. Excretion of
magnesium and potassium is also delayed with accumulation them in the blood
(hyperkaliemia, hypermagniemia). As to sodium and chlorine, their excretion is
also delayed but they are accumulated not in the blood but in the cells with
decrease of their concentration in the blood plasma (hyponatriemia and
hypochloremia). It leads to edema development.
Glomerular (Azotemic) Acidosis
As a result of decreased filtration in the glomeruli there is delay of excretion

of organic acides (aminoacides) and their retention in the blood — hyperacidemia.
Together with phosphates and sulfates they decrease alkaline reserve of the blood
(up to 18-13.5 mmol/1 while 25-31 mmol/1 in norm) aggrevating acidosis. Later the
decompansated acidosis may develop.
TUBULAR INSUFFICIENCY
Tubular insufficiency is a disorder of tubular functions resulting in disorder of

homeostasis in organism or selective derangement of partial functions of tubules
(tubular syndrome). Acute tubular necrosis is a major cause of acute renal failure.
Etiology
As to initial causes, tubular insufficiency may be primary and secondary,

extrarenal and renal.
Direct toxic or infectious actions on tubules as well as secondary lesion of
them in systemic dismetabolism and other systemic disorders may cause
structural changes in tubules of inflammatiry or dysthrophic nature. Some
hormonal disorders in organism (aldosterone and vasopressine secretion in both
direction – increase and decrease) result in disregulative tubular disorders.
Pathogenesis
As to pathogenesis, tubular insufficiency may be disregulatory (functional) and

organic. Tubules are подвержены preferably to ischemic and toxic damages (while
7
inflammation of glomeruli, as it was explained above, - is immunologically-
mediated).
Thus, as to mechanisms, tubular insufficiency may be nephrotoxic, infectious,
metabolic, vascular (ischemic), immunological, disregulative or as a reflux
nephropathy (in acute and chronic pyelonephritis). There are two main processes
in tubules – reabsoption and secretion, which may be disturbed sepatrately or
together.
Disorder of Tubular Reabsorption
In the pathology of tubules the reverse reabsorption of the following substances

is disrupted – glucose, bicarbonates, sodium, potassium, calcium, magnesium,
water, aminoacids. As a result, these substances appear in the final urine or
accumulated in the blood.
Reabsorption is disordered (suppressed or activated) in hormonal disorders.
Glucosuria develops in diabetes mellitus (hyperglycemia превышает renal
threshold to glucose). Due to glucose osmotic properties polyuria develops.
Increased secretion of aldosterone results in increased reabsoption of
bicarbonites into the blood (tubular alkalosis), loss of potassium with urine
(wich promotes dysthrophy in the tubular epithelium) and lack of potassium in the
blood (hypokaliemia). In aldosterone deficiency, sodium (bicarbonates) and
potassium reabsorption gets disturbed and they get lost with the urine. It results
in tubular acidosis and retension of potassium in the blood (hyperkaliemia).
Deficit of the antidiuretic hormone of hypophysis (vasopressin) results in loss
of water with the urine (polyuria, it is a symptom of diabetes insipidus, when
more than 10 l of water is derived with the urine) and concominamt hypostenuria.
Tubular disorders mentioned above belong to disregulative ones and may be
partial.
As to organic tubulopathy, it is connected with inflammatory, dysthrophic,
athrophic and necrotic changes of tubular epithelium, which looses ability to
reabsorption as well as to concentrate and dilute the urine (hypo- and
isostenuria).
Disorder of reabsorption of phosphates and Ca-ions results in loss of them
with urine (phosphaturia, calciuria) with decrease concentration of them in the
blood (phosphatemia, hypocalciemia) eventuating in demineralization of the
bones and rachitis development in the childrens.
As to revesed reabsorption of aminoacides, the enzymal transport systems are
needed for it. In genetically determined deficit (enzymopathy) of them the
corresponding aminoacid is detected in final urine (aminoaciduria).
Tubular proteinuria develops as a result of a disorder of reabsorption of
protein of glomerular filtrate as well as by accumulation in tubules of its own
distructed cells. In grave forms of tubular apparatus damage and grave
dysthrophic changes of tubular cells the proteins of large molecular mass (more
then 40 000) appear in urine. It is accompanied with appearanse in urine of
гиалиновых, epithelial and зеристых цилиндров (cylindruria). The latter are a sort
of слепков просвета канальцeв нефронов, which consist from the proteins coagulated
in the tubules and the exfoliated tubular epithelium.
Organic tubulopathy more often is combined due to anatomical близость of
structures and певна biochemical спільність (energy dependance) of mechanisms,
which determine processes of reabsorption of different susbstances.
8
Disorder of Tubular Secretion
By secretion in tubules, the kidneys excrete hydrogen (acidogenesis) and

ammonium (ammoniogenesis). The disorder of these processes results in the acid-
base disbalance (described in chapter 17 “Disorder of acid-base balance”) as
excretory tubular acidosis.
Secretion of uric acid leads to its accumulation in the blood (hyperuricemia)
and gout development.
Excretion of medicines from the organism also is provided by tubular
secretion. The pharmacodynamics of the medical drugs is disrupted in tubular
insufficiency and toxic side-effects are possible.
Tubulointerstitial syndrome is a combination of tubular epithelium athrophia
and stromal sclerosis development resulting in disorder of main tubular functions.
DISORDER OF INCRETORY (NONDIURETIC)

RENAL FUNCTIONS
Incretory renal function provides nondiuretic one of the kidneys. It is

connected with production of renin and prostaglandins (which deal with systemic
blood pressure regulaion), erythropoietin and supposed inhibitor of erythropoiesis.
Role of kidney in systemic pathology was mentioned in previous chapters while
discussing pathogenesis of hypertension and anemia.
Hyperproduction of renin occurs in systemic (blood loss, other cases of
hypovolemia) and local (inflammation in kydneys) disorder of blood circulation in
this organ. In latter case it results in arterial hypertension and (by stimulation of
aldosteron production) systemic edema development.
Incretion of renin gets suppressed in nephroclerosis (substitution of renal
tissues by connective one). At the same time production of renal prostaglandins
gets suppressed as well. It results in development of very severe form of arterial
hypertension (renal prostaglandins are very potent vasodilatators).
Erythropoietins deficit results in anemia.
MANIFESTATIONS OF RENAL DISORDERS
URINARY SYNDROME
The so-called общий анализ мочи plays a central role for the characteristic of the
renal function disorders. It includes the estimation of urine amount, its specific
gravity, pathologic admixtures to the urine (biochemical and cellular), urine
acidity, salts and bacterias.
Amount of urine (daily) is called diuresis, which is equal to difference
between the amounts of fluid having been filtered in the glomeruli and reabsorbed
in the tubules. So, a change of diuresis may result of dysfunction of the glomeruli
and tubules.
Polyuria is an increase in the total quantity of urine more than 2 l.
Oliguria is a decrease of a diuresis less than 500 ml.
Anuria is an absence of urine excretion or the decrease of the less than 100
ml/day.
Specific gravity? density ? of urine is characterized by such terms -
9
Hyposthenuria is a decrease of the specific gravity of urine lower than 1010
(to 1002). This specific gravity of urine confirms the fact that the kidney is
capable to accomplish the dilution of the primary urine. The development of
edema will not be typical for the patient. However, as to the ability to concentrate
urine, it is decreased. Consequently, the development of uremia is possible.
Hyperstenuria is an increase in the specific gravity of urine higher than
1010 (to 1040). This specific gravity of urine confirms the fact that the kidney is
capable to concentrate the primary urine. The development of uremia will not be
typical for the patient. However, an ability to dilute the primary urine is reduced.
Consequently, the development of systemic edema is possible.
Isostenuria is a monotonic specific gravity with constant indice 1010. This
specific gravity of urine confirms the fact that the kidney is not capable neither
concentrate nor dilute the primary urine. Consequently, the development of edema
and uremia is possible.
Pathologic admixtures to the urine is an appearance of substances or cells,
which are not typical for the standard. They are -
Proteinuria is an appearance of a protein in the urine. It is divided into true
(proteins excreted into urine by kidneys) and false (proteins do not excreted by
kidneys but admixed to urine in inflammation of urine ways), functional
(транзиторная, which disappeares after liquidation of a cause) and organic (in
organic lesion of the kidneys – inflammation, nephrotic syndrome), extrarenal
and renal.
Renal (true) proteinuria refers to organic type (acute and chronic
glomerulonephritis, nephrotic syndrome etc) and is subdivided into glomerular
and tubular, which were observed above. Lomerular one is a cardinal sign of
increased permeability of glomerular filter to proteins due to physical and
chemical changes in the basal membrane. Tubular proteinuria is connected with
disorder of protein reabsorption from primary urine as well as entering into urine
of protein molecules from destroyed tubular cells.Organic proteinuria отличается
стойкостью, большим amount of protein in urine up to 10-15-120 g/l, наявнистю
фракций of proteins of blood plasma with large mass.
Functional proteinuria (false) is нестойкая, незначительная, not more then 1 g/l
and disappeares with the причина, which is extrarenal. Below are the examples
• Hard work (маршевая)
• Functional disorders of renal hemodinamics accompanied with increased
secretion of adrenaline and noradrenaline,
• в положении стоя у детей (ортостатическая),
• Overcooling,
• Loss of fluid in babies (дегидрационная)
• After having meal with large amount of proteins, especially in children
(alimentary proteinuria),
In the following cases a cause of proteinuria is also extrarenal, it is более
выраженная but not such as in organic diseases of kidneys.
• Infectious diseases,
• Some toxic conditions,
• In thyrotoxicosis,
• Mechanical and parenchymatous jaundice,
• Enterocolitis,
• Intestine impassibility (ileus),
• Burns,
10
• Inflammatory process in the ureter (usually proteinuria is not more than l
g/1).
Glucosuria is an appearance of glucose in the urine. It is the main symptom
of diabetes mellitus.
Hematuria is an appearance of erythrocytes in the final urine and is determined
as the cellular pathologic admixtures while microscopic examination of urinary
sediment. It is subdivided into renal and extrarenal. Renal hematuria, which is
caused by increased permeability of the glomeruli filter for the cells of the
blood, was observed above. Extrarenal hematuria is caused by trauma or
inflammation of the мочевого bladder or ureter (при наличии камней). It is
significant to clinical practice to differentiate them. In the latter case there is a
large amount of fresh erythrocytes in the urine. In renal hematuria the
"shadows" of erythricytes are found in urine (lixiviated erythrocytes).
Leukocyturia is an appearance of leukocytes in the final urine. It may be of
glomerular, tubular and exrtarenal origin. As a rule, it is an avidance of
inflammation.
Urine acidity reflects the disorder of the acid-base balance. Systemic acidosis
is associated with increased content of ammonium salts in the urine.
Salts (urates, phosphates, oxalates) appear in the final urine in the systemic
disorders of mineral balance in organism.
Bacterias appear in the final urine in the case of inflammation of kidneys or
urinary tract.
SYSTEMIC CLINICAL SYNDROMES
The role of kidneys in the various pathological processes and systemic

disorders in the organism was mentioned many times in the previous chapters
(allergy, acid-base disbalance, edemas, diabetes mellitus, arterial hypertension,
etc.). Below is a brief remind without detailed explanation.
Nephritic edema is described in the chapter 18 “Pathology of the water
balance”. The excessive secretion of renin, aldosterone and vasopressin togather
with hypoproteinemia, dysproteinemia and hypoalbuminemia underlie the
pathogenesis of the nephritic edema.
Arterial hypertension is described in the chapter 25 “Pathophyology of
systemic blood circulation”. An excessive production of renin and insufficient
production of renal prostaglandins play a leading role in pathogenesis.
Anemic syndrome is described in the chapter 20 “Pathophysiology of blood”.
The deficit of erythropoietin togather with intoxication of the bone marrow by
toxic metabolites, which appear in renal insufficiency, play the leading role.
Non-respiratory secretory acidosis is described in the chapter 17 “Pathology
of acid-base balance”. In turn, it is divided into glomerular (retention of the
aminoacids in the blood) and tubular (disorder of acido- and ammoniogenesis,
and also reabsoption of bicarbonates).
Disorder of hemocoagulation is displayed as DIC-syndrome in acute or
chronic renal insufficiency.
Nephrolithiasis is a formation of concrements from the components of the
urine (urolithic disease).
Syndrome of nephrogenous cardiac insufficiency is connected with the
disbalance of electrolytes - sodium, potassium, calcium.
Syndrome of nephrogenic osteodistrophy is connected with the disbalance of
calcium and its salts. Vitamin D3 gets activated in kidneys, which ensures
phosphate and Ca2+ reabsorption in tubules and suction of Ca2+ in intestine.
11
GLOMERURONEPHRITIS
Glomerulonephritis is a bilateral diffusive infectious-allergic disease of

the kidneys of the inflammatory origin with the preferred damage of the
glomeruli.
It may be primary and secondary (as a complication of another diseases more
often diffuse lesions of the connective tissue) as well as acute and chronic.
Acute Glomerulonephritis
Experimental Model
Experimental models of an acute diffusive glomerulonephritis on animals are

interesting because they confirm, that such type of inflammation of kidneys
cannot be modelled in experiment by any usual inflammatory agent (even with
the aid of α-hemolytic streptococci), but only by the way of the immunological
reactions reproduction.
Professor of Kiev University V. K. Linderman observed (in Mechnikov
laboratory in Paris in 1901) the main manifestations of nephritis in rabbit after
intravenous introduction of nephrotoxic serum of the guinea pig immunized with
suspension of the rabbit kidney. Later, Japanese scientist Masugi, using the same
scheme of experiment, reproduced the clinical picture of nephritis in rabbit by
introducing blood serum of the duck уток immunized with the tissue of the rabbit's
kidneys.
There are two phases of experimental glomerulonephritis pathogenesis:
heterologic, conditioned by fixation of the nephrotoxic antibodies (IgG, IgM) on
the basal membrane of the glomeruli of the nephrons and autologic, connected
with production of complement-fixing antibodies against nephrotoxic globulin.
Etiology
Infection (mostly of streptococcus nature) is an initial factor of an acute

diffuse glomerulonephritis. It is considered that α-hemolytic streptococcus is
specifically nephritogenic. Other infections may play a definite role (viral,
parasites). Glomerulonephritis may arise in cooling, burns as well as after
vaccination and immune serum use. Glomerulonephritis may be provoked by
diffuse diseases of the connective tissue (rheumatoid arthritis an oth)
Pathogenesis
Allergic nature of acute glomerulonephritis is confined.

There are two main mechanisms of glomeruli damage:
1. Immune complex glomerulonephritis develops in majority of cases
(70%). In immune complex-mediated glomerulonephritis antigens are not of
renal origin as well as antibodies are not specific to glomeruli. Many
exogenic (infectious and noninfectious) or endogenic (tissue protein, DNA)
substance serves as antigen. Antibodies (IgG, IgM) are formed to them.
Both antigens and antibodies circulate in the blood, where immune coplexes
get formed. The latter enter the both glomeruli absorbing on their basal
membrane. Then complement gets activated. A bilatery immune
inflammation of the glomeruli gets realized. Cellular proliferation and
12
leukocytic infiltration may be observed. In these cases the kydneys are the
“victims” of their filtrative function and fixation of immune complexes.
2. Nephrotoxic glomerulonephritis has a quick progressive course.
Glycoproteid of the basal membrane serves as antigen. Antibodies react
directly against glomerular antigens (nephrotoxic antibodies). It is easily
reproduced in experiments of Mechnikiv and Masugi discribed above. In
clinical practice it very often is triggered by a streptococcal infection after
1-2 weeks after recovery from infectious disease (acute tonsillitis).
Pathogenesis of the so-called infectious-allergic diseases was discussed in
the chapter 6 «Allergy«. Due to similarity between polysaccharide antigen of
microbe and glicoproteids of glomerular membranes, the antibodies react with
both of them (cross reactivity, «mistake of recognition”) causing allergic
inflammation with monocytic and neutrophilic infiltration of glomeruli. Activated
complement, enzymes released from neutrophlic lisosomes and vasoactive
amines (histamine, serotonin) from basophils serve as mediators.
Intraglomerular coagulation plays a role. Fibrin (fibrinigen) may leak into
Bowman,s space serving as a stimulus to cell proliferation.
In that cases, when infection, as an etiological factor, is not detected, there are
another immune mechanisms initiating autoantibody formation and autoallergic
inflammation of glomeruli.
Manifestations
Clinical and pathophysiological manifestations of acute

glomerulonephritis reflect the changes of the renal (mainly glomerular) and
extrarenal functions.
Violent onset, oliguria, azotemia, arterial hypertension characterize the
classical course of the disease. Urinary syndrome is characterized by
proteinuria, hematuria, leukocyturia. Edemas are developed due to retention of
sodium, hypoproteinemia, hypervolemia and increased permeability of
capillaries. Pain in the lumber region and disorders of the nervous system must
be added.
Acute glomerulonephritis is one of the causes of an acute renal
insufficiency and may eventuate in uremia.
Principles of Therapy
Understanding the pathogenesis of this disease is important for constructing the

pathogenetic therapy. Not one anti-inflammatory drug can be effective alone. The
immunisuppresive therapy is necessary. Anticuagulants as well as antagonists of
histamin and serotonin are in use.
Chronic Glomerulonephritis
Chronic glomerulonephritis is a prolong progressive disease, which is

characterized by diffuse bilateral injury of kidneys of inflammatiry
nature, неоднородне as to origin, pathogenesis and clinical manifestations.
Etiology
As to etiology, there are the following forms of chronic

glomerulonephritis
13
• Infectious (poststreptococcal, in malaria, syphilis, tuberculosis);
• Non-infectious (traumatic, intoxic by different poisons, after immune
serum and vaccine use, thrombosis, in medicamentous abuse),
• Special (radiant, hereditary, etc.),
• As a complication of the diffuse diseases of the connective tissue
(rheumatoid arthritis, hemorrhage vasculitis, etc.).
Pathogenesis
Immune concept of chronic glomerulonephritis pathogenesis is commonly

accepted. Together with two main mechanisms, which are connected with
development of an acute glomerulonephritis (immune complex-initiated and
nephrotoxic), a hypersensitivity of delayed type play a certain role.
Pathogenesis proceeds in two stages – compensation and decompensation.
In a stage of compensation a mass of functioning nephrones in majority of
patients is preserved or is decreased a little. Filtration is changed a little. As to
tubules, an excretion of ammonia and H+-ions (ammonio- and acidogenesis) get
decreased; reabsorption of Na and water gets increased. It leads to edema
development.
In a stage of decompensation, an excessive development of connective tissue
in the kinenys takes place resulting in nephrosclerosis. Mass of functioning
nephrones significantly gets decreased. This stage appears as a syndrome of
cronic renal insuffitiency.
Manifestations
Chronic glomerulonephritis may have an acute onset and resembles an

onset of an acute glomerulonephritis. But more often chronic
glomerulonephritis develops primary.
The following clinical forms are distinguished in the phase of compensation:
• Latent form (65% of all cases) is manifested by isolated urine syndrome —
moderate proteinuria and hematuria. Some patients (20-25%) are observed to
have edemas and transitory hypertension.
• Hypertensive form (32% of patients) is characterized by stable increase of the
arterial blood pressure. 1/3 of patients have edemas, 2/3 — hematuria, all
patients have proteinuria and half of them have cylindruria and leukocyturia.
• Nephrotic form (2-4% of patients), which is charactedistinguished by edematous
syndrome (2/3 of patients), marked proteinuria and cylinduria (all patients) and
characteristic changes in the blood (hyperproteinemia and hyperlipidemia).
• Mixed or nephro-hypertensive form (2,4% of patients), which is
characterized by edemas and hypertension (all patients). Changes in urine
are similar to those as in nephrotic form but there are no changes in the blood.
NEPHROTIC SYNDROME
Nephrotic syndrome is a totality of clinical and laboratory symptomes

manifested as massive proteinuria (5 g and more daily), disorders of protein
(hypoproteinemia, dysproteinemia) and lipid (hyperlipidemia) metabolism as well
as water-electrolyte balance, edema development up to degree of anasarca with
водянкой серозных полостей.
14
Etiology
Nephrotic syndrome develops due to various affections of the kidneys. By

origin, it is divided into primary and secondary.
Primary nephrotic syndrome more often is not connected with previous disease
of the kidneys. It develops on the base of 1) intoxication with salts of heavy
metals, burns, 2) radiant disease, 3) some medicines drugs abuse, 4) disturbance
of the blood supply of the kidneys, 5) genetically conditioned defects of
metabolism (lipoid nephrosis), 6) transplant rejection, 7) specific antirenal
antibodies transmission from mother to fetus as in congenital family nephrosis. It
may be caused by some diseases of the kidneys (glomerulonephritis).
In immunologic cases, both exogenous (bacterial, viral and parasital agents,
medicines, food products, havy metals etc) and endogenous (DNA, denaturated
nucleoprotaids, proteins of tumorous origin) factors play a role as antigenes.
Secondary nephrotic syndrome may be caused by some systemic diseases
pathology (collagenosis, diabetes mellitus, amyloidosis, serum disease,
staphylococcal sepsis, nephropathy of the pregnant women, etc.), chronic purulent
diseases (abscess of lungs, бронхоэктазы), паразитарные (malaria) and viral diseases.
Pathogenesis and Manfestations
Pathogenesis of nephrotic syndrome is titghly connected with the main disease.

In majority of cases, a nephrotic syndrome development is determined by
immune mechanisms (hypersensitivity of delayed type) with antigenes
mentioned above. Deposition of complement, immune complexes or antibodies
against glomerular basal membrane may be obresved.
Histologically, pathology of glomerular podocytes, гиалиновая dysthrophy of
proximal tubules and наличие “пенистых» cells with deposition of lipids is
observed. Damage of glomeruli is connected with deposition of amiloid,
fibrinogen and glyco- and liporoteids on the surface or basal membrane with
activation of humoral and cellular mechanisms of inflammation. Antobodies,
which are produced in responce of antigens, belong to IgM. As a result, a
structure of basal membrane, its components and physico-chemical properties get
changed, permiability to blood plasma proteins gets increased.
For those forms of nephrotic syndrome, where immunological mechanisms are
not proved, the most suitable reasons are metabolic and physico-chemical
mechanisms.
Massive proteinuria is the main symptom of nephrotic syndrome. The main
link in its pathogenesis is a decrease or disappearance of the constant electric
charge of the wall of the capillary. It is connected with обеднением and
disappearance of sialoprotein from it. At the places of maximal loss of ions and
sialoproteins, polymorpho-nuclear leukocytes are accumulated, whose lysosomal
enzymes provide direct damage of basal membrane. As a result, a large amount of
proteins with large mass get filtrated which can not be reabsorbed in proximal
tubules of nephron.
All other manifestations of nephrotic syndrome are secondary to massive
proteinuria. They are – decrease of colloid osmotic pressure of plasma, decrease
of renal blood circulation, hypovolemia, increased production of renin,
aldosterone and vasopressin (antidiuretic hormone), increased Na-ion
reabsorption and edema development. Secondary aldosteronism can develop due
15
to hypovolemia (the cause of which is "leakage" of fluid into the tissues), decrease
of the renal blood flow and increased production of renin.
Hyperlipidemia, which is characterized to nephrotic syndrome, is determined
by thriglycerides and cholesterol. Pathogenetically it is connected with protein
dismetabolism and suppression of the lipolytic activity of blood plasma.
In addition to changes mentioned above, many clinical manifestations are
connected with lack of important proteins in the blood (dysproteinemia). Clinical
consequences are represented in table 8.
Table 8. Consequences of proteinuria and dysproteinemia in nephrotic syndrome
Type of proteins which are in Consequences of diminished amount of

deficit in the blood proteins in the blood
Albumins Hypooncia, edema
Antithrombin Predisposition to thrombosis and

thromboembolism
Factors of blood coagulation Hemorrhage syndrome
Components of complement Decreased resistance to infection
γ-globulins Decreased resistance to infection
LPHD Predisposition to atherosclerosis
Proteins connected with Deficiency of Fe, Zn, Cu

microelements
Proteins transporting hormones Endocrine disturbances
PYELONEPHRITIS
Pyelonephritis is an infectious inflammatory disease of the mucous membrane of

the urinary tract and renal parenchyma (simultaneous or subsequent) with
predominant affection of the interstitial tissue.
The disease arises due to penetration of infection into the kidneys by

hematogenic way or by spreading it upward from the urinary tract. The causative
agents are mostly colon bacillus and cocci.
Development of the disease and transition of acute pyelonephritis into chronic
one is promoted by different conditions causing urine congestion - constriction and
occlusion of the ureter (very often with adenoma of prostate in men), dystrophy
of the urinary tracts, general diseases, which reduce the reactivity of the organism
(diabetes mellitus, atherosclerosis, obesity, chronic intoxication etc.)
16
Tubular disfunction preveils upon glomerular dysfunction. Ability to
concentrate an urine gets diminished. Early and havy tubular acidosis develops
due to suppression of acido- and ammoniogenesis. Salts get loosed due to
decreased tubular reabsorption of Na and Ca. As a result, dangerous for life
disorders of water-electrolyte and acid-base balance may develop.
Manifestations
Pyelonephritis begins as an acute disease (which more often gets transmitted into
chronic one) or a latent form. Both are ended in сморщиванием of kidneys and
renal insufficiency.
Clinical picture may achive the manifestation of havy infectious disease with
intoxication, arterial hypertension, moderate edema and anemia. Urinary
syndrome – polyuria, olyguria, hypostenuria, leukocyturia, hematuria, moderate
proteinuria, cilindruria. Progression of named disorders leads to decrease of mass
of funtional nephrones and transition of tubulointestinal insufficiancy into
chronic renal insufficiency.
SYNDROME OF ACUTE RENAL INSUFICIENCY
Acute renal insufficiency is an acute disorder of homeostasis as a result of

significant and quick decrease of the rate of the glomerular filtration.
This syndrome, associated with acute suppression of renal function, is
accompanied by reduction of the 24-hour urinary output to 400 ml or less or total
its cessation (up to 1-10 ml/min comparatavely with 125 ml/min in norm).
Etiology
Acute renal insufficiency is caused by tree groups of factors: prerenal, renal and
postrenal.
Prerenal factors are
• Shock, collapse accompanied by acute blood hypotension (decrease of the
arterial blood pressure less then 40 mm Hg).
• Blood loss, incontrollable vomiting, profuse diarrhea, the diuretics abuse
resulting in acute decrease of the intravascular and extracellular fluids volume.
• Massive hemolysis of erythrocytes (mismatched hemotransfusion)
• Massive trauma of tissues (crush-syndrome, large cutaneous burns)
•Acute (myocardial infarction) and chronic (hypertrophy of myocardium,
myocardiosclerosis) cardiac insufficiency
• Occlusion of renal artery (compression, spasm, thrombosis, embolism).
Renal factors are
• Local disorders of blood circulation (ischemia, thrombosis, DIC-
syndrome)
• Injury by nephrotropic poisons (salts of havy metals, arsen, phosphorus,
грибным and snake poison, endogenous intoxication in diabetic coma, sepsis,
peritonitis, hepatic insufficiency),
• Immune nephrotoxic factors,
• Severe diffuse glomerulonephritis,
• Acute tubular necrosis
• Massive infection (pyelonephritis)
17
Postrenal factors are obstruction of urine flow and retention of the urine at
the level of urinary tract (calculi in the ureter, tumors, hyperthrophy and
adenoma of the prostate).
Pathogenesis
Pathogenesis of the acute renal insufficiency consists in acute decrease of

effective filtrative pressure due to
• Decrease of the systemic blood pressure or temporary ischemia of the kidneys
conditioned by
Hypovolemia,
Spasm of the afferent renal arterioles,
Disseminated intravascular blood coagulation with microthrombosis
of the renal vessels.
• Increased pressure in capsule of Shumlyansky-Bowmen and interstitium.
Under the influence of the nephrotoxic factors (toxic, infectious) together with
the disorder of the blood circulation, direct damage of the glomerular and
tubular structures becomes important. Prolong ischemia may eventuate not only in
decrease of the glomerular filtration and switching off of a definite number of
the nephrons, but in необратимые structural changes in glomeruli and tubules.
Filtration in glomeruli may be decreased secondarily due to the 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
interstitium,
• Increased reabsorption of Na+ in the tubules (it is accepted by macula
densa and results in activation of renin-angiotensin system, spasms of
afferent renal arterioles, decrease of blood circulation and glomerular
filtration).
The most characteristic and marked disorders are observed in the stage of
oligo- and anuria. Together with acute decrease of diuresis up to its complete
stop, there are hyperazotemia, disorders of water-electrolyte and acid-base
balance.
Stages
There are four stages of the acute renal insufficiency which are distinguished
in accordance with the clinical course -
• Initial stage lasts during several hours,
• Oligo- or anuria during 5-10 days,
• Poliuria stage,
• Outcome is recovery (if treatment would be effective) or death.
Manifestations
The main clinical manifestations are determined by disorder of homeostasis.

They are - nausea, the brain edema, interstitial lung edema, severe disorders of
circulation, decrease of contractile function of the heart, arrhythmia
(extrasystole, bradycardia, blockade), arterial hypotension with transformation
into arterial hypertension, dyspnoea by Kussmaul's type, severe dysfunctions of
the nervous system (headache, vomiting, loss of consciousness, convulsions,
18
coma), anemia. Most of these events are the symptomes of azotemia. Frequently,
it is a reason of patient death.
If a treatment woulb be proper a stage of restoration would come in 5-10
days.
SYNDROME OF CHRONIC RENAL INSUFFICIENCY
Chronic renal insufficiency is a disorder of homeostasis as a result of the

progressive and необратимой loss of functional parenchima.
Chronic renal insufficiency is the end result of a variety of renal diseases
and is the major cause of death from renal pathology. It develops gradually due to
haevy disorders of renal processes and the main renal functions as a result of
decrease of an amount of acting nephrones, substitution of parenchima by
connective tissue and сморщивание of the kidney. It is a clinical picture connected
with azotemia, water-electrolyte and acid-base disbalance.
Etiology
Etiological factors of chronic renal insufficiency most frequently are

intrarenal. They are chronic progressing diseases of the kidneys of
inflammatory (chronic glomerulonephritis, chronic pyelonephritis, etc.),
vascular (arterial hypertension) and metabolic (diabetes mellitus,
amyloidosis, gout) origin. Connection between chronic renal insufficiency and
diabetes mellitus is especially actual. Diabetics rarely avoid renal pathology.
Even not a severity but a term of a disease (during 15-20 eyers) is significant.
Half patients with longstanding diabetes die from diabetic nephropathy
(diabetic glomerulosclerosis).
Pathogenesis
Chronic renal insufficiency is the end-stage of damage of all components of

kidney (glomeruli, tubules, intestitium, vessels). It is a disorder of all functions
and processes taking place in the kidneys (filtration, reabsorption, secretion,
incretion).
Pathogenesis is determined by a decrease of the mass of functionally active
nephrons and reduction of all renal functions. Nephrosclerosis is in progress.
Chronic renal diseases produce scarred kidneys that are smaller than normal.
Concentrating ability gets impaired and is manifested by isostenuria. All
physiological systems of organism get involved gradually, and multiple clinical
symptomes appear.
Patient requires a long-term dialysis or transplantation.
Stages
There are three clinical stages of the chronic renal insufficiency which are
distinguished -
• Initial stage develops when the remainder of the acting nephrons composes
50-30%. This stage is characterized by polyuria. Diuresis increases as a result of
the decrease of the reabsorption of water. The specific gravity of urine approaches
1010.
19
• The stage of the clinical manifestations, when the remainder of the acting
nephrons composes 30-10%. The stage of polyuria passes into the stage of
oliguria. Azotemia develops.
• Terminal stage develops, when the remainder of the acting nephrons
comprises less than 10%. Clinical manifestations - loss of appetite, dyspepsia,
emaciation, headaches, skin itch, polyneuritis, anemia, arterial hypertension,
convulsions, coma. The terminal stage of renal insufficiency is called uremia.
UREMIA
Uremia is the end stage of chronic renal insuffitiency. It is characterized by

dismetabolism and involving of all physiological systems with grave disorders. It
is a complete impairment of exretory renal function and regulation of
homeostasis with the following systemic changes -
• Intoxication is connected with retension in the blood of those substances,
which must be derived with the urine - urea and creatinine (azotemia),
phenols, indoles, aminoacids. Furthermore, many new toxic substances are
formed - over 200 toxic substances are revealed. Just they determine the
organism intoxication and associated clinical symptoms.
• Acidosis,
• Electrolyte disorders in the blood – decreased amount of Ca, increased
amount of phosphorus, porassium.
Uremia is not not merely a biochemical abnormalities mentioned above. There
are a lot of external clinical manifestations. It is a deep disorders of all function.
Development of the following clinical syndromes is necessary for diagnosis of
uremia
• Hemorhage syndrome (predisposition to bleeding, disorder of thrombocyte
aggregation),
• Anemia (as a result of blood loss, uremic hemolysis of erythrocytes,
sappression of hemopoiesis due to bone marrow intoxication),
• Gastrointestinal syndrome (dyspeptic signs - anorexia e.i loss of appetite,
disorders of taste,vomiting, diarrhea, esophagitis gastritis colitis),
• Cardiovascular syndrome (uremic myocarditis and pericarditis, arterial
hypertension),
• Neuromuscular syndrome (spasms, paresis, convulsions)
• Respiratory insufficiency (pulmonary congestion, dyspnoe, uremic
pleuritis, Куссмауль breathing),
• Peripheral neuropathy (tormenting itching)
• Encephalopathy (general weakness, apathy, headache, disorder of hearing,
coma).
• Endocrine disorders (connected with general intoxication)
• Reduction of the body mass
• Arthritis.
Uremic patients must be dialyzed.
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CHAPTER 30
PATHOPHYSIOLOGY OF ENDOCRINE SYSTEM
Endocrine system plays important role in regulation of basic physiological

processes. The specific function of endocrine glands realizes by hormones. Each
endocrine gland secrets not one, but several hormones with different biological
effects.
The participation of endocrine system in development of various pathological
processes and leading pathophysiological syndromes was mentioned in the previous
chapters for many times.
The value of genetic factors in the endocrine pathology was mentioned. The
majority of chromosomal diseases is manifested by endocrinopathy and sterility.
The role of glucocorticoids and mineralocorticoids in development of inflammation
was discussed. Glucocorticoids were mentioned as the leading therapeutic means for
allergy treatment.
One gain understanding the role of hormones in development of all typical
metabolic disorders (insulin - in the development of diabetes mellitus, aldosterone
– in acidosis, thyroxin - in disturbance of basal metabolism, aldosterone and
vasopressin - in the development of edema etc.).
The development of arterial hypertension is associated with catecholamines,
aldosterone and vasopressin effects. The role of aldosterone and electrolyte
disbalance in development of the myocardial necroses was also explicated.
It was mentioned, that in hepatic insufficiency the destruction of hormones may
be depressed, and a clinical picture of endocrine hyperfunction with relative excess
of hormones is observed. The renal insufficiency, as it was mentioned, is
accompanied with arterial hypertension and edema, in development of which an
important role belongs to renin (hormone-like substance), aldosterone and
vasopressin (antidiuretic hormone).
Regulation of Endocrine Function. The function of endocrine system is
regulated by nervous and endocrine mechanisms. The central regulation of
endocrine functions is achieved in two ways - by нервно-проводниковым and
медиаторным.
In spite of relative independence, endocrine glands are subordinated to the
regulator influences of the nervous system. The disorder of the endocrine glands
functions while emotional stress confirms the participation of brain cortex in
regulation of endocrine function. The nuclei of limbic system, ретикулярной формации
reticulated formation and diencephalon influence the secretion of hormones.
The participation of autonomic (vegetative) nervous system in regulation of
physiological and pathological processes in endocrine system also takes place. N.
vagus excitation strengthens the secretion of insulin; sympathetic nerves stimulate
adrenaline secretion from adrenal glands.
The main centers of the endocrine system regulation are located in
hypothalamus. In turn, hypothalamus function is connected with вышележащими
отделами of the brain. Hypothalamus regulates the function of pituitary gland with
the aid of releasing-factors (stimulating oligopeptides liberins and the inhibiting ones
are statins). Neuropituitary hormones (vasopressin and oxytocin) are formed in
1
hypothalamus accumulating in the posterior lobe of the pituitary gland and coming
into the blood from there.
The tropic hormones of pituitary gland are the important mechanism of the
regulation of peripheral endocrine glands and are addressed to them.
Interrelations between the central (hypothalamus, pituitary gland) and peripheral
endocrine glands are characterized by important peculiarity – it is the regulating
mechanism of the direct and reversed relations. Decreased concentration of the
peripheral hormone causes stimulating effect on hypotalamus and pituitary gland for
this hormone synthesis. Increased concentration of the peripheral hormone causes an
opposite effect. Thus, peripheral endocrine cells are the targets for tropic hormone
action. The regulated influences of tropic hormones are achieved with the aid of the
receptors, which are located on the cellular membrane of endocrine cells of the
peripheral glands. Intracellular messengers provide the transmission of the
regulating influences from the receptors to the cellular nucleus.
Interglandular hormonal connections are the important mechanism of
regulation. Interrelations between the hormones are characterized as antagonism,
synergism and permissive effect. Thus, insulin and contrinsular hormones are
antagonists as to blood sugar level, but they are synergists as to glucose supply to
the tissues. The permissive effect consists in providing optimal conditions for the
physiological activity of one hormone by another. Thus, glucocorticoids perform
permissive effect on katecholamins action, insulin – on somatoptopin and sex
hormones.
The synthesis of any hormone requires specific substrates and enzymes and
determines by genetic mechanisms.
The hormone precursors are transformed into the final hormone in the gland. The
secretion of hormone from the glandular cells is an energy depending process.
Mechanisms of the Hormones Peripheral Effect. Any hormone is transported
to the target somatic cells by the blood with the aid of transport proteins (albumins
for estrogens, transferrin for insulin, transcortin for glucocorticoids). Binding of
hormone with the transport protein and its release from this connection are the
enzyme-depending process.
The hormonal effect on a target somatic cell is achieved with the participation of
the cellular receptors (for the peptide hormones), which determine cellular
sensitivity to the hormone, and the participation of intracellular messengers.
Hormones are destroyed in the liver.
A brief enumeration of the physiological aspects of the endocrine glands
functions helps us to understand numerous reasons, which lead to the endocrine
pathology.
Endocrine insufficiency is an acquired and genetically determined state of
organism, which is connected with disorder of the hormonal control on
physiological functions of organism.
It should be taken into consideration that the term insufficiency is not a synonym
of a term deficit, but reflects the disorder of function, which has the form
hyperfunction, hypofunction or dysfunction.
Methods of Experimental Study of Endocrine Insufficiency. It is the most
easily to illustrate the role of experiment in pathophysiology and its forms by
experimental study of endocrine pathology.
Method of removal is an extirpation (ectomy) of endocrine gland.
Method of overload consists in introduction of hormones or endocrine gland
extract into the animal.
Method of damage is an injury of endocrine gland by poisons, radioisotopes,
immune antibodies, inhibitors of energy (ATP) production.
2
CLASSIFICATION
Several classifications of endocrine insufficiency are suggested depending on the

different principle, which is the basis of classification.
As to the participation of genetic mechanisms it is divided into acquired and
hereditary (congenital).
The division of endocrine insufficiency into the primary and secondary reflects
the sequence of disorders, namely, either it starts in the gland or it is a complication
of another disease.
Monoglandular endocrine insufficiency is a pathology of one signal endocrine
gland. The polyglandular endocrine insufficiency is a pathology of several
endocrine glands.
The division of endocrine insufficiency into the glandular and extraglandular
reflects topographic aspect. In turn, extraglandular one is subdivided into
preglandular and postglandular.
Glandular endocrine insufficiency is subdivided into the partial and total
depending on that, the synthesis of all or one hormones of this gland gets disrupted.
The division of endocrine insufficiency into absolute and relative reflects the fact
that the production of hormone can be normal, however, metabolic dismetabolism in
the hole organism is similar to those that occur with the absolute deficit or surplus
of hormone. So, quantitative changes of hormone amount may be absolute (changes
in production) and relative (increased or decreased distraction of hormone, its
bounding with transport protein, sensibility of target-cells to it). So, the reasons of
relative endocrine insufficiency are located out of the endocrine gland. Relative
endocrine insufficiency can be complicated by absolute.
As to clinical course, endocrine insufficiency is divided into acute and chronic.
Each form of endocrine pathology is manifested in turn in the form of three
syndromes – hyperfunction, hypofunction or dysfunction. Dysfunction means the
разнонаправленные differently directed changes in production of different hormones
in one gland or a formation of atypical hormonal compounds.
ETIOLOGY
Etiological factors, which lead to the endocrine insufficiency, are physical,

chemical and biological.
Among physical factors the mechanical trauma and ionizing radiation have a
value.
Among chemical factors both deficit and surplus of микроэлементов (iodine,
cobalt), poisons, radioactive nuclide and medicines have a value.
Biological factors include infectious (вирус коксаки, кори, возбудитель tuberculosis),
immune, genetic and psychogenic.
Endocrine glands can become an object of autoimmune aggression. The
formation of autoantibodies against the peptide hormones - releasing-factors of
hypothalamus, tropic hormones of hypophysis (somatotropic, thyrotropic,
prolactin), vasopressin, insulin is possible. The production of autoantibodies against
the cells of endocrine gland, and also against the endocrine cellular membrane
receptors or the receptors on target cells is also possible. Among allergic reactions
there is a delayed type of immune reactions, the so-called stimulating ones, when
antibodies perform a stimulating role as to receptors on the peripheral endocrine
gland similarly to tropic hormones.
The role of genetic factors is manifested in the form of genetic and chromosomal
mutations. Manifestations - enzymopathy, the genetic defect of hormones and
3
receptors, the defects of the endocrine glands genesis. All chromosomal diseases
include the pathology of endocrine system. The patients with the syndromes of
Turner-Shereshevskiy or Klaynfelter are sterile.
Psychogenic overload and stress can be the factor of damage (cause
thyrotoxicosis, diabetes mellitus, disturbances of ovarial-menstrual cycle).
The age of patient has great significance in endocrine pathology development.
Depending on this, endocrine pathology is divided into endocrinopathy of children's
and young age (growing organism) and endocrinopathy of adult or elderly patients.
Sexual differences in endocrine insufficiency are also significant.
PATHOGENESIS
All typical pathologic processes can be developed in the endocrine glands, and
also in the organs, whose disease is secondarily manifested by the disturbance of the
endocrine glands function. These pathologic processes are the following -
inflammation (including allergic and infectious), neoplasia, thrombosis, the
disturbance of hemostasis, atrophy, dystrophy, genetic disorders, dismetabolism.
Preglandular Disregulatory Endocrine Insufficiency
Preglandular disregulatory endocrine insufficiency is a disorder of the central

mechanisms of the endocrine system regulation. In such cases the pathology
develops in the organs (nervous, endocrine), which regulate endocrine functions.
The following reasons and mechanisms are possible.
• Disorder of higher nervous activity, for example, mental trauma frequently leads
to the endocrine diseases (diabetes mellitus, thyrotoxicosis, amenorrhea). It is the
so-called psychogenic endocrinopathy. Destruction or stimulation of limbic system,
reticular formation, diencephalon together with irritation or blockade of the central
and peripheral mechanisms of autonomic (vegetative) innervation damage the
synthesis or secretion of the hormones.
• Disorder of the neuroendocrine regulation of endocrine system is caused by the
pathology of hypothalamus or вышележащих отделов of the brain connected with it.
Hypothalamus pathology usually involves entire endocrine system (pluriglandular
endocrine insufficiency). These diseases are called neuroendocrine ones
(hypothalamic syndrome).
• Pathology of pituitary gland, which secretes the tropic regulative hormones for
the peripheral endocrine glands, causes diverse glandular pathology, most
frequently partial.
• Disorder of the so-called reversed connections is an important pathogenetic
mechanism of endocrine insufficiency (fig.56). Reduction in hypothalamus
sensitivity to the effect of the peripheral hormones leads to the more intensive
production of releasing-factors and tropic hormones of hypophysis. As a result, the
peripheral gland at first activates its function and then results in exhaustion and
insufficiency. Frequently peripheral gland reacts not by activation of function, but
by the growth and the formation of tumor (adenoma of prostate gland, the
fibromyoma of uteri). If patient uses some hormone for the purpose of treatment (for
example, prednisolone in rheumatism), the peripheral gland becomes less sensitive
to the corresponding tropic hormone of adenohypophysis. It creates a problem of
отмены withdrawal of hormonal therapy.
• All endocrine glands act as a united system due to the interendocrine relations. It
leads to the situation, when pathology of one gland causes another. For example, the
4
removal of the thyroid gland leads to the disturbance of the sexual glands and
adrenal cortex.
____________________________________________________________________________
Fig. 56. Regulation of hormonal balance in norm (a) and in disorder of reversed connections (b –
in a case of decrease, c – increase if hypothalamus excitability)
1 –hypothalamus, 2 – pituitary gland, 3 - peripheral endocrine gland, H – hormone of peripheral
gland, RH – releasing-hormone, TH – tropic hormone of pituitary gland
______________________________________________________________________________
The disorder of the central regulation of endocrine functions usually leads to the
disorder of the hormone synthesis and an absolute deficit and hypofunction.
Glandular Type of Endocrine Insufficiency
Glandular form of hormonal insufficiency appears as a result of disturbances of

any stage of formation and secretion of hormones. Inflammation, infection,
autoimmune aggression, vascular disorders (thrombosis), alimentary disturbances
and the insufficient entering of substrates and microcells микроэлементы can be the
basis.
Glandular insufficiency can be total (formation of all hormones of a gland is
disrupted) and partial (formation of one hormone is disrupted).
This form of hormonal insufficiency may be manifested as hypofunction,
hyperfunction and dysfunction.
The following mechanisms are possible:
• Disorder of receptor system on the surface of endocrine cell, namely, the
sensitivity of these receptors to the regulatory signals. As a result, the synthesis
of hormone in response to the regulatory nervous and humoral influences stops.
• Disorder of intracellular messengers (adenylate cyclase system) which transfer
signals from the receptors to the genetic apparatus of the endocrine cells.
Damage of the Ca ion entering into the cell has the same result.
• Disorder of the prohormone transformation into the final hormone.
• Deficit of the substrates, microelements and enzymes, which are necessary for
the hormone synthesis.
• Disorder of the hormone secretion, which is already formed in the glandular
cells.
• Infectious damage of endocrine gland.
• Cytotoxic damage of glandular cells by chemical (including medicine drugs)
substances.
• Immune damage of the endocrine glands (formation of antibodies against peptide
hormone of sensitized lymphocytes against the cells).
• Neoplastic damage of the glands.
• Overproduction of hormones by гормонопродуцирующей опухолью (adenoma).
• Destructive changes of gland by inflammatory and cirrhotic processes, sclerous
change in the vessels.
• Genetic problems of the glandular cells functioning.
Postglandular Disorders.
Disorder of the Peripheral Hormone Effect
5
The postglandular disturbances of endocrine function lead to the relative
hormonal insufficiency. It is characterized by normal hormone production, however,
the dismetabolism in organism is similar to absolute deficit or surplus of hormone.
Clinical picture may correspond to both the hypofunction and hyperfunction.
Reason is located out of the endocrine gland. The following reasons are possible:
• disorder of the hormone transport in the blood (more strong or weak binding of
hormone with the transport proteins, the difficult or intensive release of hormone
from this connection),
• increased or reduced production of the hormone antagonists,
• activated or weakened hormone destruction,
• increased need for the hormone (pregnancy),
• genetic pathology of the proteins which participate in the endocrine function –
transport proteins, receptor proteins, antagonists, enzymes that determine the
hormone synthesis or binding and release of hormones from the transport blood
proteins,
• pathology of receptors to the hormone on the somatic target cells, which
determine their sensitivity to the hormone effect. It is possible in
decrease of a quantity of receptors,
reduction in their affinity for the hormone,
formation of antibodies against the receptors,
genetic pathology of receptors.
Reduction in the sensitivity of the target cells to the hormone is called
резистентность к гормону hormone resistance. While aging a quantity and sensitivity
of receptors usually decreases. The manifestations of hormonal insufficiency in
elderly people are connected with it.
Compensatory-Adaptive Reactions
Both under the physiological conditions and in pathology, endocrine system has
the adaptive reactions, which balance organism with the external and internal
medium, which constantly changes. They are the following:
• presence of paired endocrine organs (the adrenal glands, ovaries, testis),
• hypertrophy of the pare парного organ during pathological process or removing
one of them,
• reverse connections between peripheral and central organs of endocrine system,
• synergetic and permissive action of the hormones,
• liability of the binding of hormone with the transport proteins,
• change in quantity of receptors to the hormone on the target cells in dependence
with the hormone content in the blood.
The target cells are the points of hormone effect. For each hormone they are
specific.
Concluding the common concept about etiology and pathogenesis of endocrine
insufficiency, one should emphasize, that pathophysiological links and clinical
manifestations of endocrine insufficiency depend on the endocrine gland (central or
peripheral) and type of target cells, which function get disrupted.
PATHOLOGY OF PITUITARY GLAND
6
The hormones of adenopituitary are thyrotropic, adrenocoritcotropic,
gonadotropic and prolactin. Hormones of neuropituitary are formed in
hypothalamus, but are released into the blood through the posterior pituitary. They
are vasopressin (syn. antidiuretic hormone, which influences revealing of water
from the organism together with vasopressive effect) and oxytocin.
Pituitary insufficiency may be total (panhypopituitarism) and partial in form of
separate pathology of adeno- or neuropituitary, hyper- and hypofunction.
Hyperfunction of Adenopituitary
The hyperfunction of adenohypophysis is more frequently partial. The

development of benign tumor (adenoma) from some cells underlies the pathology.
If adenoma develops from the eosinophilic cells, hypersecretion of somatotropin
takes place.
The pathologic influence of excessive quantity of somatotripin on the organism is
determined by an ability of the hormone to increase the permeability of the cell
membrane to amino acids and accelerate their inclusion in synthesized proteins. It
stops disintegrative proteolysis.
Somatotripin increases lypolysis and inhibits the lipid formation from the
carbohydrates. It activates the mobilization of fat from depot and thus elevates the
content of non-estherised fatty acids in the blood. Increased oxidation of lipids in the
liver leads to ketone bodies formation. It is due to the effect of somatotropin on
different links of the carbohydrate metabolism that hyperglycemia and diminution
of sensitivity to insulin are always observed (metasteroidal diabetes).
Pathologic effect of somatotropin on the connective tissue, bone and cartilage tissue
is stipulated by an ability of this hormone to stimulate pathologic formation of
oxyproline (the most important component of collagen) and chondroitine sulphate.
These and other effects of somatotropin are explained by the formation of a special
albuminous factor (somatomedin), which is formed in the liver under the influence of
somatotropin.
Hyperfunction of somatotropin in the human body is exhibited as pituitary
gigantism or acromegaly, depending on the age of patient the pathology begins.
Pituitary gigantism develops in excessive secretion of somatotropin in the young
age, before the epiphysial cartilages get closed.
In adults, after closing the epiphysial sutures and completion of the body
growth, the hormonal shifts cause acromegaly. In this disease separate parts of the
body are disproportionately enlarged, the features of the face are also enlarged.
Simultaneously, splanchnomegaly (enlargement of the liver, spleen, heart) develops.
These changes are stipulated by the growth of the soft tissues. In acromegaly the
concentration of the somatotropin in the blood can exceed normal parameters 100
times and more.
If adenoma develops from the basophilic cells of adenopituitary which produce
adrenocoritcotropin, Itsenko-Cushing disease develops. The consequence of
corticotropin hyperproduction is an excessive secretion of glucocorticoids by the
adrenal cortex glands.
Hypofunction of Adenopituitary
Total hypofunction of the adenopituitary (panhypopituitarism) happens when all

regions of adenohypophysis are disrupted. It may be congenital or acquired. It leads
to pluriglandular endocrine insufficiency.
7
The most often acquired causes of this disease are tumor, postnatal necrosis of
the pituitary, injury of the basis of the черепа, inflammation, thrombosis and viral
infection. When more than 95% of the gland mass is destroyed, the adult people
develop pituitary cachexia (Simmond's disease). It is characterized by severe
cachexia and atrophy of the thyroid, adrenal and sexual glands, the muscle tissue,
visceral organs, destruction of the bone tissue, hair and teeth falling, functional
disorders of the vegetative nervous system, hypoglycemia, increased sensitivity to
insulin. Most of disorders are connected with stopping of somatotropin and thyrotropin
secretion.
Partial hypofunction is a decreased production of anyone hormone of the pituitary.
Early (в том числе in embryo) falling out or depression of the somatotropic
function of the pituitary leads to the development of dwarfism (pituitary nanism).
The diminution of proteins synthesis speed leads to atrophy of the muscular and
connective tissue, which is externally manifested by the flabbiness and aging of the
skin. The sexual organs stay in the infantile condition (hypogenitalism). Decrease of
the function of the thyroid gland, endocrine-metabolic disorders and decrease of the
reactivity of organism are the manifestations of a disease.
Partial gonadotropic insufficiency leads to infantilism: in the girls it leads to the
absence of the menstruation, infertility. In boys it leads to the hypoplasia of the testis,
incomplete physical development and hypogenitalism.
Pathology of Neuropituitary
The increased secretion of vasopressin (antidiuretic hormone) promotes the water

reabsorption in kidney tubules and accumulation of the liquids in the organism. It
plays an important role in the pathogenesis of systemic edema. Рефлекторная anuria
in pain shock also results from increased secretion of vasopressin. Relative increase
of vasopressin occurs in the liver cirrhosis, when inactivation of the hormone is
inhibited.
Deficiency of vasopressin inhibits the reabsorption of water in the tubules of the
nephron that results in polyuria and arterial hypotension. The patients excrete 3-8
liters of urine with low specific gravity. Sometimes diuresis consists of 10-12 liters,
and more (diabetes insipidus).
PATHOLOGY OF THYROID GLAND
The basic hormone of the thyroid gland thyroxin actively effects metabolism,
especially basal one.
Causes of pathology may be environmental (physical, chemical, biological),
immune, genetical. Thyroid pathology may be total (while thyreoidectomia) and
partial (selective deficit of thyroxin or calcitonin).
All typical pathological processes may develop in thyroid gland – inflammation
(including allergic), neoplasia, disorder of blood circulation (thrombosis,
hemorrhage).
Tumors may develop from glandular cells (adenoma, cancer). Enlargement of the
thyroid gland may be diffuse (caused by elevation of TTH secretion as in Basedow’s
disease), and local (as a thyroid nodule caused by a benign or malignant neoplasm).
Benign tumor may produce hormone (гормонопродуцирующие опухоли) and be
associated with hypoproduction of hormone. Goiter is a tumor of thyroid gland.
Immune mechanisms play important role in thyroid pathology. The pathogenesis
of some thyroid diseases involves an autoimmune process. As antigens, the
8
following substances may serve - thyroglobulin, thyroidal peroxidase, receptors.
Various thyroidal antigens sensitize own lymphocytes. As to antibodies, they may
inhibit or stimulate glandular cells. Receptors to thyreotropic hormone (located on
thyreocytes) may accept antibodies as a signal of thyreotropic hormone.
Environmental factors (viral or bacterial infection, high iodine intake) and genetic
factors (immunodeficiency) may be responsible for initiating of autoimmune thyroid
disease.
Pathology of thyroid gland is manifested in form of hyperfunction
(hyperthyroidism, or thyrotoxicosis, caused by an excess of thyroid hormone),
hypofunction (hypothyroidism caused by a deficiency of thyroid hormone) and
dysfunction.
HYPERFUNCTION (HYPERTHYROIDISM)
Hyperfunction (thyrotoxicosis) is the pathophysiological and clinical signs of

increased function or toxic action of thyroxin and thrijodthyronine. Their absolute
or relative increase underlies the pathology.
Causes of hyperfunction of thyroid gland are hyperstimulation of the gland by

the central endocrine organs (hypothalamus, pituitary), stimulating antibodies,
hormonal medical drugs in заместительной therapy abuse.
Hyperfunction of thyroid gland has several pathogenetic mechanisms. The main
mechanisms of increased effect of thyroid hormones, which lead to thyrotoxicosis
development, are the following:
• Thyroid hormone overproduction (absolute excess of hormone), which results
from -
stimulation of thyroid gland by hypothalamus,
stimulation of thyroid gland by pituitary gland (pituitary insensitivity to
thyroid hormones often underlies the pathology),
hypersecretion of thyreotropic hormone of pituitary (adenoma of pituitary is
an often cause),
irritation of receptors on the thyreocyte surface by stimulating
antibodies,
hypertrophy of thyroid glandular cells,
inflammation of the gland (lymphocytic thyroiditis, granulomatous
thyroiditis),
гормонопродуцирующая tumor of thyroid gland (toxic multinodular
goiter, follicular adenoma, metastatic follicular thyroid carcinoma),
interglandular interaction in cases of germ cell tumors
(гормонопродуцирующие choriocarcinoma, ovarian teratoma).
• Relative excess of hormone as a result of -
weakening of binds of thyroxin with thyroxin connected globulin,
increased sensitivity of the tissues target to thyroxin influence.
• Disorder of the destruction of the thyroid gland hormones.
Basedow Disease
Basedow disease is the diffuse toxic goiter.

9
The most important etiological factor of thyrotoxicosis in men is a mental trauma.
Infection and allergy are considered to be predisposing factors.
In excess of thyroxin and thrijodthyronine, the number of mitochondria in the
somatic target cells increases, they swell. Increase of the activity of oxidizing
enzymes (succinatdehydrogenase, cytochromeoxidase, glycerophosphate-
dehydrogenase), Na+, ATP-ase is observed.
Due to the increased splitting of glycogen in the liver and muscle tissue,
hyperglycemia is marked. The utilization of glucose in the tissues is accelerated,
the activity of gexokinase is increased.
The abundance of the thyroid hormones inhibits the transformation of
carbohydrates into the fats, accelerates disintegration of cholesterol and its
utilization by the tissues, intensifies oxidation of the fats in the liver and also
increases the sensitivity of fatty tissue to lipolytic effect of adrenaline. Due to this,
a mobilization of lipids from depot arises, explaining why the patient with
thyrotoxicosis loses his weight and why hypercholesterolemia and ketonemia
occurs.
Negative nitrogen balance gives evidence of the predominance of the protein
catabolism.
Manifestations
Basedow's disease is characterized by typical syndrome: enlargement of the

thyroid gland, exophtalm, increase of heat production, tachycardia, arrhythmia,
shivering of the fingers, increase of the mental excitability, vibration, increase in the
basal metabolism, emaciation.
The excess of thyroid hormones disturbs the metabolism of the cardiac muscle.
Dystrophic changes in the myocardium, disorder of atrio-ventricular conductivity,
overloading of the left ventricle is revealed. The energetic and plastic maintenance
of the cardiac activity is disturbed. 'Thyrotoxic" heart reacts inadequately to
cholinergic and adrenergic influences.
HYPOFUNCTION (HYPOTHYROIDISM)
Hypothyroidism is the pathophysiological and clinical signs of decreased function

of thyroxin and thrijodthyronine. Their absolute (defects in hormone biosynthesis)
or relative (diminished hormone release or problems of transport and sensitivity
of target cells) decrease underlies the pathology.
Hypofunction of thyroid gland has several pathogenetic mechanisms. The main
causes and mechanisms of decreased effect of thyroid hormones are noted below.
Etiological factors and causes of hypothyroidism are:

• thyroid surgical intervention (including thyroidectomia in experiment),
• radioactive iodine due to overdose of allowable medical doses (I31 irradiation
treatment of hyperthyroidism, external beam radiation therapy of head and
neck cancer),
• damage of the gland by thyrostatic substances,
• infectious agents,
• deficiency of iodine and cobalt in environment.
In pathogenesis of hypothyroidism such mechanisms are obvious -
10
• deficient TTH secretion,
• inflammation, which suppresses the thyroid function (lymphocytic thyroiditis),
• autoimmune aggression against glandular epithelium,
• tumors with inhibited function of thyroid gland (зоб Хошимото),
• destruction of the gland by cirrhotic processes, sclerotic change in the vessels,
neoplasia,
• congenital causes of biosynthesis of the thyroid hormones defects connected with
сongenital hypoplasia or aplasia of the thyroid gland,
• resistance of target cells to thyroid hormone.
Hypothyreoidism is manifested by reduction of basal metabolism, decrease of the
blood sugar level, tendency toward atherosclerosis, strengthening of разрушительных
processes, edemas, задержка развития детей.
In severe degree of thyroid gland insufficiency, congenital or arisen in the early
childhood, cretinism develops, in the adult people — myxedema.
Myxedema
Myxedema is a hypothyreosis accompanying by mucous edema.

Myxedema is characterized by decrease of metabolism and body temperature,
obesity, and малоподвижность. As a result of the increased hydration of the skin and
subcutaneous tissue and the high accumulation of hydrophilic mucous substances in
them the face becomes одутловатый with poor mimics, the nose and the lips become
thicker. Ломкость of the nails, hear falling out and other trophic disorders are marked.
The sexual function gradually угасает, интеллект снижается, memory притупляется,
apathy and sleepiness appear, and in the late period of the disease dementia
appears.
GOITER
Goiter is an enlargement of the thyroid gland.

There are 3 types of goiter:
• thyrotoxic (with increased function of thyroid gland),
• hypothyroid (with reduced function of thyroid gland),
• endemic (with normal function of thyroid gland).
The first two types are observed above as Basedow disease and goiter of
Хошимото.
Endemic goiter is an enlargement (hyperplasia) of the thyroid gland due to iodine
deficit in environment (in water and food). In this case the production of thyroxine
remains normal only because of an increase in the mass (compensatory hyperplasia)
of the gland.
This disease is widespread in Alp, Карпаты, Гималаи, Андах, where the почва and
water contain little amount of iodine. The deficiency of iodine stipulates decrease of
thyroxin and thryiodthyronine synthesis and due to this, the production of
thyrotropin increases in the pituitary. In its turn it leads to hyperplasia of the thyroid
glands, whose mass sometimes reaches some kilograms.
DISORDER OF CALCITONIN SECRETION
Disorder of calcitonin secretion is an another example of partial thyreoid

pathology.
Calcitonin is syntezied in intrafollicular cells of thyreoid gland. The main function
of calcitonin is to lower serum calcium level. This hormone is released in response to
11
hypercalcemia. Receptors to calcitonin are located in the kidneys and bones. The
interaction between calcitonin and receptors stimulates adenylate cyclase activity
and the generation of cAMP.
Receptors for calcitonin are found on osteoclasts, and calcitonin accomplishes its
effect acting directly on them. Calcitonin inhibits bone resorption and blocks the
release of calcium and phosphate from bones. The latter effect is apparent within
minutes after the administration of calcitonin. This effect, along with inhibition of
resorption, ultimately decreases the level of serum calcium and phosphate.
Calcitonin blocks bone resorption induced by a variety of hormones, including
parathyreiod hormone and vitamin D. The potency of calcitonin depends on the rate
of bone resorption.
Receptors for calcitonin are localized in the cortical ascending limb of Henle's
loop. Calcitonin affect on the kidney to produce mild phosphaturia.
PATHOLOGY OF PARATHYROID GLAND
Pathology of parathyroid gland is associated with absolute or relative changes of

hormone paratirin concentration in the blood.
Hyperfunction
In experiment hyperparathyrosis is modeled by injection of hormone to the

animal.
In clinics, hyperparathyrosis may be primary and secondary.
Primary hyperparathyroidism occurs due to excessive production of parathyroid
hormone (paratirin) by the parathyroid gland. Under clinical conditions
hyperparathyrosis occurs in benign (adenoma 80-85%) or гормонопродуцирующая
malignant (carcinoma 2-5%) tumor of the gland. Diffuse hyperplasia is a reason in
10%.
Secondary hyperparathyroidism occurs, as a complication, due to pathology in
other organs (reduced Ca absorption in intestine, skeletal resistance to paratirin,
chronic renal insufficiency). In most cases of secondary hyperparathyroidism,
parathyroid hyperplasia regresses substantially with correcting underlying
abnormality.
Excess of paratirin leads to –
• increased formation and activity of the osteoclasts, which realize the
resorption of the bones,
• inhibition of differentiation of the osteoclasts into the osteoblasts, which
participate in the formation of the bone tissue,
• increased reversed suction of phosphate ions in renal tubules,
• increased absorption of calcium in the intestine,
• increased formation of the soluble salts of calcium in the bone tissue,
• increased insoluble phosphate calcium content in different organs especially
in the kidneys,
• decreased reverse reabsorption of the phosphate ions in the tubules of the
nephrons.
Manifestations
12
In animal with experimental chronic parathyrosis, an osteoporosis is observed and
also an accumulation of the calcium salts in the kidneys, the lungs, the heart and
other organs. The walls of the vessels become thick, and the blood pressure
increases. The animals die from uremia as a rule.
In patients the so-called генерализованная fibrous osteodystrophy develops. It is
characterized by the pain in the muscles, bones, joints, deformation of the skeleton,
osteomalacia. Mineral components go out from the bones and are accumulated in the
muscles and the internal organs. Nephrocalcinosis, narrowing of the nephrons tubules
lumen or their occlusion by calculi (nephrolithiasis) develop that results in grave renal
insufficiency. Due to calcareous deposition in the wall of the magistral vessels,
hemodynamics and blood supply of the tissues are disturbed.
Hypofunction
Etiological factors and causes of parathyroid hypofunction may be exogenous and

endogenous.
In the experiment hypoparathyroidism is reproduced by removal of the glands in
animal.
In the people under clinical conditions hypoparathyroidism occurs most often as
a complication of thyroid and parathyroid surgery (after occasional removal of
parathyroid glands while thyroidectomia), damage of parathyreoid gland while I31 therapy
of Basedow disease or thyroid cancer. Tumor of parathyroid gland may cause its
hypofunction. There are hereditary forms of hypoparathyroidism (autosomal
dominant or recessive and X-linked recessive). Autoimmune aggression in the case of
Di-George syndrome (autosomal recessive immunodeficiency with congenital
absence of the parathyroid glands and thymic dysgenesis or agenesis) also is a
reason.
Relative hypofunction of the glands is marked in accelerated growth, pregnancy,
lactation and other conditions when the organism requires more calcium and its salts.
The main evidence of hypoparathyroidism is hypocalcemia, which eventuates in
different disorders. The mineral disbalance is conditioned by
• decreased absorption of the calcium in the intestine,
• increased reabsorption of phosphates in the tubules of the nephrons.
Simultaneously with hypocalcemia, blood has increased contents of non-organic
phosphorus. Electrolyte balance is disturbed critically. There is a change of
correlation of one-valent (Na, K) and two-valent (Ca, Mg) ions due to reduction of
calcium concentration in the blood from 2.25-2.99 to 1.0-1.25 mmol/1. As a result,
neuromuscular excitability increases.
Desintoxicating function of the liver is connected with the parathyreoid function.
In hypoparathyroidism it is disordered. Feeding of parathyroectomized dogs with
meat intensifies tetanus due to insufficient disintoxication of products of nitrous
metabolism, in particular, decreased ability of the liver to convert ammonium into
urea.
Manifestations
In 1-2 days after the parathyreoidectomy the animals become вялый flaccid, refuse
to take food, have thirst, low body temperature, dyspnoe. The animals die during one
of episodes of convulsions.
13
Pathogenesis and clinical picture of hypoparathyroidism in the human are close to
those observed in experiment. Dysfunction of the parathyroid glands results in
development of parathyroprival tetany. There are multiple fibrillar convulsions of
the body muscles, which are then followed by episodes of clonic ones. Clonic
convulsions get transformed into tonic ones, opisthotonus comes (резкое выгибание
туловищаs назад). Spastic contractions may spread to the inner organs (pylorospasm,
laryngo- and bronchospasm). Laryngospasm is very dangerous as it may cause
asphyxia and death.
Children of 1st and 2nd year of life may have spasmophilia — periodic spasms of
the muscles, arising in the increase of the environmental temperature and other
unfavorable influences.
Below is a list of clinical syndromes.
• Systemic - weakness, easy fatigue, weight loss, anemia, anorexia, pruritis.
• Neuropsychiatry – depression, psychosis, mental retardation, poor
concentration, memory deficits, peripheral sensory neuropathy, paresthesia.
• Neuromuscular - motor neuropathy, generalized muscle weakness, peripheral
sensory neuropathy, muscle cramping, Parkinsonism.
• Ocular - keratopathy, cataract.
• Cardiac - changes in Q-T interval, T wave changes.
• Renal - nephrocalcinosis, polyuria, polydipsia, metabolic acidosis.
• Sceletal - osteopathy, pathologic fractures, tumors of bones, bone pain, gout,
chondrocalcinosis.
• Gastrointestinal - peptic ulcer disease, pancreatitis, constipation, nausea,
vomiting.
• Dental – emal hypoplasia, defective root formation.
• Respiratory - laryngospasm, bronchospasm .
PATHOLOGY OF ADRENAL GLANDS
There are 2 important parts of the adrenal glands – cortex and medullar.
In adrenal cortex 3 groups of hormones are produced – glucocorticoids (cortisole,
there is reminding of glucocorticoids effect in the table 9), mineralocorticoids
(aldosterone) and sexual ones. Noradrenaline is produced in medullar part of the
adrenal glands.
The pathology of adrenal glands is divided into – pathology of adrenal cortex
and adrenal medulla, and in turn into total and partial as well as hyperfunction,
hypofunction and dysfunction.
Table 9. Effects of Glucocorticoids
Target tissue Effect Mechanisms

Muscle Catabolic Inhibition of glucose uptake and
metabolism. Decrease of protein
synthesis. Increase of amino acids
and lactate release.
Fat Lipolytic Stimulation of lipolysis. Increase of
free fat acids and glycerol release.
14
Liver Synthetic Increase of glyconeogenesis.
Increase of glycogen synthesis.
Increase of glucose-6-phosphatase
activity. Increase of blood glucose
level (hyperglycemia).
Immune system Suppression Reduce of number of circulating
lymphocytes, monocytes,
eosinophiles, basophiles. Inhibition of
production of interleikin-2 by T-
lymphocytes. Decrease of antibody
and PG production.
Antiinflammatory Decrease of neutrophiles,

monocytes, lymphocytes
migration of to sites of injury.
Inhibition
Cardiovascular Increase of cardiac Permissive effect on

output. Increase of peri- catecholamines, contraction of
pheral vascular tone the peripheral vessels.
Renal Increase of glomerular Na+ and water retention
filtration rate.
Participation in water
and electrolite balance
Other Resistance to stress. Increase of blood glucose level.
Insulin antagonism.
HYPERFUNCTION OF THE ADRENAL CORTEX
Hyperfunction of adrenal cortex occurs in bilateral hyperplasia, formation of

гормонопродуцирующей tumor (adenoma), and also in hyperstimulation of adrenal cortex
by hypothalamus and pituitary.
More often it is a chronic partial hyperfunction and associated with hyperplasia of
какой-то отдельной zone of adrenal cortex – fasciculata, glomerulata or reticulata.
Вследствие этого it is manifested in form of three syndromes – hypercorticism,
hyperaldosteronism and adrenogenital syndrome.
Hypercorticism
Hypercorticism occurs in bilateral hyperplasia or гормонопродуцирующая

tumor of zona fasciculata, ACTH stimulation, and enzyme deficiency. Itsenko-
Cushing syndrome is a clinical example of a primary affection of the cortical
substance of the adrenal glands in case of гормонопродуцирующей tumor (adenoma)
from cells of пучковой зоны zona fasciculata. The excessive secretion of cortisole is
a leading pathogenic point, determining the clinical picture.
Etiology of Itsenko-Cushing syndrome and Itsenko-Cushing disease is various, but
the clinical symptoms and the pathogenesis are similar.
Manifestations of a syndrome are -
• catabolic effect (negative nitrous balance, decrease of proteins synthesis),
• hyperglycemia (due to glyconeogenesis activation, antagonism with
insulin) can assume the form of metasteroid diabetes,
• obesity with prevalent deposition of fats on the face,
15
• immunodepression (due to lymphopenia and eosinopenia, inhibition of
phagocytosis and antibody production as well as the cellular immune
reactions and interleikin decreased production),
• increase of the arterial blood pressure (contraction of peripheral blood
vessels, permissive effect to catecholamines, PG inhibition),
• increase in the acidity of gastric juice and a risk of a stomach ulcer
formation,
• distrophic changes in muscles, bones (osteoporosis), joints,
• inhibition of the regenerative processes,
• hypocoagulation (depressed synthesis of procoagulants and platelets).
Hyperaldosteronism
Hyperaldosteronism (excessive production of aldosterone) may be primary and

secondary.
Primary hyperaldosteronism is caused by adenoma of cells of zona glomerulosa
of the adrenal cortex.
Secondary hyperaldosteronism is observed in many pathologic conditions. The
cells in the клубочковой зоны glomerulata zone of the adrenal glands intensify
production of aldosterone under the influence of angiotensin, ACTH (permissive
effect), excess of K+ and deficit of Na+ in blood plasma. Atrium natriuretical
hormone, dopamine and high extracellular Na+ concentration inhibit secretion of
aldosterone. So, in the situations of the decreased renal blood supply (acute blood
loss, acute arterial hypotension, hypovolemia, acute and chronic cardiac insufficiency,
liver cirrhosis, kidney diseases with disorders of kidneys circulation) an increased
secretion of renin by juxtaglomerular cells takes place with the following excessive
formation of angiotensin and aldosterone (fig.57).
16
Fig 57. Mechanisms regulating aldosterone secretion
________________________________________________________________________
Under the influence of excessive aldosterone the following biochemical,

pathophysiological and clinical phenomenon develop –
• sodium oins retention,
• loss of K potassium and Cl 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
vasoconstrictive mechanisms).
• myasthenia and paresis, attacks of the skeleton muscular spasms,
• disorders of myocardial contractile function (due to loss of potassium and
chlorine ions),
• non-gas alkalosis,
• water retention.
In spite of water retention, edema develops not always. Its development depends
upon the sensitivity of the tubules of the nephrones to vasopressin. If they become
dystrophic, they lose an ability to react to vasopressin. So, poliuria arises, which
explains absence of edema in primary hyperaldosteronism.
Adrenogenital Syndrome
Adrenogenital syndrome in a child is a clinical manifestation of congenital

hyperplasia of the cortical substance of the adrenal glands.
Arising of this syndrome is connected with hereditary blockade of cortisol synthesis. It
eventuates in расторможение disinhibition of corticotropin secretion, which in turn
stimulates secretion of androgens in the adrenal glands. The latter have a virilizing
effect (appearance and more evident signs of the masculine sex) in the intrauterine
17
period. Consequences of hormonal disorders may be different — from mild
masculinization to severe anatomic abnormalities of physical and sexual development.
In boys this pathology cause premature development of the second sexual signs.
Girls often are born with pseudogermaphrodism. The androgenital syndrome in
children is characterized by deep disorder of enzymes, which participate in
biosynthesis of steroid hormones and is accompanied by severe disorders of water-
electrolyte balance (syndrome of salt loss). If the hormones synthesis is blocked, the
excess of desoxicosterone (steroid with mineralocorticoids properties) is created.
In consequence, grave arterial hypertension develops. Without substitutional
therapy with corticosteroids children die at early age.
Adults and children can have hyper-estrogenization and hyper-androgenization of
the organism in the case of tumorous перерождение сетчатой зоны of the adrenal
cortex. Depending on character of hormone secretion and sex of patient, virilization
(in women) and feminization (in men) are observed, or person has premature sexual
development.
HYPOFUNCTION OF THE ADRENAL CORTEX
Cortex hypofunction more often is a total. It occurs in bilateral gland

destruction, autoimmune aggression, bacteremia (tuberculosis, meningococcus
and other infections), ischemia, shock, hemorrhage, carcinoma or metastatic
tumor (in case of lung carcinoma). It has two forms – acute (extirpation of
adrenal gland in experiment) and chronic as a result of chronic processes
(inflammation, tumors) which destroys a gland.
Acute Hypofunction
Acute cortical adrenal hypofuntion is modeled in experiment by adrenalectomy. In a

human it can happen due to hemorrhage into the adrenal glands or necrosis.
Выпадение функции of corticoids (glucocorticoids and mineralocorticoids)
obtains more decisive significance because выпадение функции of hormones of
medullar part of adrenal gland (noradrenaline) is compensated by catecholamins
formation by sympathetic nervous system.
After adrenalectomy the death of experimental animal comes in some days. Arterial
blood pressure, glucose blood level and body temperature get decreased. Resistance of
organism to overcooling gets decreased.
Выпадение функции of glucocorticoids is manifested by the following biochemical
and pathophysiological manifestations.
Hypoglycemia has some mechanisms of its development and connected with
выпадения функции of glucocorticoids in carbohydrate metabolism. The mechanisms are
the following:
• reduction of glucose-6-phosphatase activity,
• inhibition of gluconeogenesis (formation of glucose from amino acids and
lipids),
• reduction of the glycogen depot in the liver and muscles,
• reduction of the speed of glycogenolysis in the cells of the liver,
• reduced sensitivity to insulin,
• increased tolerance to glucose.
Arterial hypotension is connected with weakening of the vasoconstrictive action
of catecholamins, to which corticosteroids have permissive effect.
Some disorders are connected with выпадением функции of aldosterone. They are
below.
18
Decrease of volume of circulated blood (hypovolemia) plays important role in the
genesis of the acute adrenal gland insufficiency and arterial blood pressure
decrease. It is connected with the water-electrolyte disbalance. In physiological
conditions aldosterone supports sodium "pump", ensures reabsorption of sodium
ions in the distal parts of the tubules of the nephron. After removal of the adrenal
glands the sodium ions go out of the body with urine and that is why the content of
sodium in plasma of blood is reduced. At the beginning, there is marked polyuria but
than oliguria, anuria and "water poisoning" (cells hydration). Potassium leaves
cardiomyocites. Тhe increase of potassium ions concentration in plasma causes the
bioelectric processes disorders.
Disorder of electrolyte balance and of bioelectric processes eventuates in cardiac
insufficiency. Force and rhythm of cardiac contractions is disordered which are
manifested as arrhythmia (up to мерцательная arrhythmia). Decrease of contractility
of the поперечно-полосатой muscle tissue take place (symptom of muscular
weakness).
In terminal stage of acute adrenal gland insufficiency, the urination completely
stops. The pulse and the breathing are slowered down.
Chronic Hypofunction
Chronic hypofunction occurs in bilateral adrenal gland destruction

(autoimmune aggression, tuberculosis).
Chronic hypoadrenocorticism is characterized by emaciation, fast psychical
tiredness, bad appetite, dysfunction of the alimentary canal, arterial hypotension,
psychical depression, muscular weakness, disorder of growth and maturation of children.
In the patient with the chronic adrenal gland hypofunction, different pathogenic
effects such as trauma, infection, hemorrhages and even tooth extraction can cause
acute insufficiency of the adrenal cortex. Organism resistance is suppressed.
In a human it is known as Addisson's disease (bronzed disease). It arises more
often because of tuberculosis of the adrenal glands, atrophy of the cortical
substance after heavy infectious diseases. Progressive hyperpigmentation of the
skin is observed. The mechanism of hyperpigmentation is connected with intensification
of melanostimulating activity of the pituitary gland, which is concomitant to the
increase of corticotropin secretion during hypoadrenocorticism.
Problems of Glucocorticoid Therapy Abuse
Problems of glucocorticoid therapy abuse are connected with phenomenon of

adrenal cortex hyper- and hypofunction.
Glucocorticoids are used as immunodepressants while treatment of allergic
diseases (bronchial asthma, rheumatism etc.). The side-effects of this therapy
resemble the picture of the chronic hypercoticism (mentioned above). They are –
• catabolic effect (negative nitrous balance),
• hyperglycemia (metasteroid diabetes),
• deposition of fats (especially on the face),
• decrease of immune resistance to infection,
• arterial hypertension,
• predisposition to hemorrhages,
• increase in the gastric acidity and predisposition to stomach ulceration,
• osteoporosis,
19
• inhibition of cellular division and regenerative processes, заживления ран и
срастания переломов,
• тератогенное действие,
• psychotropic effect ( психозов development),
• disorder of growth and maturation of children which are treated by
corticosteriods for a long time.
Prolonged treatment by corticosteroid medical drugs and a hormonal therapy
abuse forms hormone-dependence. It means that the production of own
glucocorticoids gets reduced. The exidental отмена withdrawal of this hormonal
therapy is accompanied by the development of the синдром отмены withdrawal
syndrome. Clinical picture is manifested as a (sub)acute hypofunction of the
adrenal cortex with the following clinical manifestations (mentioned above) -
hypoglycaemia, arterial hypotension, physical depression, muscular weakness,
утомляемость, исхудание, decrease of general resistance of organism. Any additional
pathogenic influence causes grave complications.
DYSFUNCTION OF THE MEDULLAR PART OF THE ADRENAL GLANDS
Hyperfunction of the medulla of the adrenal glands is connected with

hypersecretion of catecholamines. It is observed in hyperplasia (rare) or
pheochromocytome (tumor originated from the medullar part of the adrenal glands),
ganglioneuroma, neuroblastoma.
Manifestations are - paroxysmal or stable arterial hypertension, tachycardia,
acute pain in epigastrium, profuse sweating. The attacks are a result of massive
выброс of adrenaline and noradrenaline into the blood under the influence of psychical
and physical loading or other provocative effects.
CONCEPT OF STRESS
Stress was mentioned in many chapters of this text-book as a reason of a disease

(arterial hypertension, myocardial infarction, stomach ulcer, diabetes mellitus,
thyrotoxicosis etc.).
Concept of stress is connected with the physiological role and pathology of the
adrenal cortex. Canadian scientist Hans Selye is the author of this theory, which is
widely spread.
Selye noticed in experiment, that any harmful influence (trauma, infection,
overcooling, intoxication, muscular overloading) causes a complex of changes in the
thymus, adrenal glands, lymphatic nodes, blood composition and metabolism. He
focused special attention on the changes in the endocrine glands, in particular, the
system of the hypothalamic-adrenal cortex system.
He noticed, that any harmful influence is accompanied by -
• activation of the adenopituitary (the role of ACTH secretion was revealed),
• hypertrophy of the cortical substance of the adrenal glands,
• increased content of the secretory granules in the cells of adrenal cortex.
Physiological role of glucocorticoids in activation of functions of organism was
revealed. It consists in
• activation of glyconeogenesis,
• increase of glucose blood level (hyperglycemia),
• reorganization of metabolism,
• increase of energy formation,
• protection of the membranes from damage,
20
• antipyretic effect,
• antiallergic effect,
• support of catecholamin effect (permissive effect).
Selye interpreted these changes as the non-specific adaptive reactions developed
at maximum. He named this group of symptoms as systemic (nonspecific) adaptive
syndrome. Selye drew the conclusion that precisely the hormones of adenopituitary
(corticotropin) and adrenal cortex (corticosteroids) play a significant role in the
development of adaptation. He called them as the adaptive hormones.
Earlier W. Cannon and L. Orbelly studied the role of a sympathetic part of the
vegetative nervous system in adaptive and trophic reactions. Selye added the concept
about an important role of endocrine system, especially, the hormones of pituitary and
adrenal cortex in the organism adaptation to the influence of pathogenic factors.
Thus, adaptation is a complex of nonspecific reactions with participation of the
nervous system and endocrine glands.
At the same time Selye revealed in experiments, that prolonged non-specific
adaptive reactions cause a typical complex of non-specific sighs of a damage. They
are:
• involution of the thymico-lymphatic apparatus,
• eosinopenia,
• hemorrhage ulcers in the mucous membrane of the gastrointestinal tract.
Selye connected it with the prolong effect of adrenal cortex hormones. It was
Selye who introduced the term stress in medical science.
Stress is a condition of the nonspecific reactions of adaptation (developed at
maximum) and a damage under the action of any strong influence (stressor).
So, we see the dual significance of stress. From one side, it is an adaptation,
promoting life due to releasing of adaptive hormones. From another side (with the
prolonged duration) it is a mechanism of a damage.
Stages of Stress
Stress is manifested in three stages (fig.58). They are:

• alarm reaction,
• stage of resistance,
• stage of exhaustion.
Alarm reaction means immediate mobilization of organism. In turn, it is
subdivided into shock and antishock phases. In shock phase there are muscular and
arterial hypotension, hypothermia, hypoglycemia, eosinopenia, increased
permeability of the capillaries, prevalence of catabolic processes. The phase of
antishock is characterized by reverse changes - increase of arterial blood pressure,
muscular tonus and blood glucose level. Increase of corticotropin and corticosteroid
secretion occurs with release of hormone reserves.
The stage of resistance is a stage of compensation and prevalence of the
defensive reactions. The cortical substance of the adrenal glands is hypertrophied
and secretes an additional amount of glucocorticoids. Anabolic processes prevail.
Glyconeogenesis is intensified. At this stage there is such peculiarity - the resistance
of organism is increased not only toward the factor, causing stress, but also to other
factors, even lethal agents. It is manifested in diminishing of inflammation,
prevention of the heart, kidneys and other organs impairment by any pathogenic
factors. This state is called as increased nonspecific organism resistance.
21
The stage of exhaustion (the third final stage) comes in prolonged effect of the
injurious agent when adaptation gets broken. The transition of resistance stage into
the final stage is characterized by -
• atrophy of the cortical substance of the adrenal glands,
• exhaustion of hormonal activity,
• involution of the thymus and lymphoid tissue,
• eosinopenia,
• negative nitrous balance,
• decrease of arterial blood pressure,
• activation of proteolysis,
• development of hemorrhage ulcers in the stomach and duodenum,
• exhaustion of the functional reserves.
stressor
alarm
reaction resistance
exhaustion
antishock
shock
ooo ooo oooooooo o

ooooo
ooo
Fig. 58. Stages of stress and an amount of hormons of adrenal cortex

____________________________________________________________
After all, the stress outcome depends on the ratio between the force and duration
of the stressor effect and potential abilities of protective reactivity of the organism.
Diseases of Adaptation
The development of adaptation can be disturbed.

From one hand, an ability of organism to adaptative reactions development may
be depressed. According to Selye, just endocrine insufficiency (first of all
hypofunction of pituitary and adrenal cortex) causes adaptation insufficiency.
Hyperergic course of inflammation and its chronic forms (rheumatism), allergy
(bronchial asthma, dermatoses) are connected with deficiency of adaptive reactions
with adrenal cortex hypofunction in the ground. Lack of glucocorticoids underlies
22
the decreased organism resistance to any injuring factor of environment. Any
additional influence of moderate force (overcooling, overheating, physical
overstrain, excessive intake of salt) aggravate significantly every pathology. It was
Selye who proposed to use adaptive hormones (glucocorticoids) for organism
resistance support.
On the other hand, a chronic overstraining of adaptation and excess of
glucocorticoids, which is connected with it, becomes a reason of another group of
pathology. Then we speak that a chronic stress plays a decisive role in their
pathogenesis. They are – arterial blood hypertension, stomach ulcer, diabetes,
nephrosclerosis, hyalinosis.
Significance of Stress Concept
Stress concept had a great influence on the modern medicine development.

Training of experimental animal with systematic influences of moderate stimuli
(cold, hypoxia and muscular tension) protects organism from myocardial necrosis
caused by intravenous injection of proteolytic enzymes.
Study about stress started a clinical use of adrenal cortex hormones in medical
practice. Selye gave theoretical groundation to corticosteroid therapy, which now is
used both in acute and chronic clinical situations.
Glucocorticoids are used as an urgent help (in a department of reanimation) when
a state of patient is the gravest. They activate organism resistance and provide
survival.
Corticosteroid therapy is used in chronic diseases when reactivity of organism is
qualitatively changed. Use of glucocorticoids, as immunomodulator, in allergy and
chronic hyperreactive inflammation is widely spread.
However, the prolonged use of these hormones has side-line effects, which were
noted above. Impairment of a stomach and duodenum, predisposition to arterial
hypertension together with hormonal dependence appear a problem of corticosteroid
therapy.
23
CHAPTER 31
PATHOPHYSIOLOGY OF NERVOUS SYSTEM
Nervous system performs Ѐ function of a higher nervous ЀЀЀЀЀЀЀЀЀЀЀЀ activity

(consciousness, emotions, memory, forming of psychic constitution), regulates motoricy
and sensitivity as well as visceral functions (respiration, cardio-vascular, digestive etc).
Nervous throphicity is one of its functions.
There are three physiological mechanisms of nervous regulation -
• ЀЀЀЀЀЀ-ЀЀЀЀЀЀЀЀЀЀ,
• ЀЀЀЀЀЀЀЀЀЀЀ (with the aid of the neuromediators and the neurohormones),
• with the aid of axoplasmatic flow (via nerves ) of regulative substances to innervated
organ.
Damage of the nervous system in various pathological processes was mentioned in all
the previous chapters of this textbook. Increased sensitivity of nervous system to all
factors of environment (baro- and thermofactors, electricity, ionizing radiation, genetic
problems, systemic and local disorders of blood circulation, metabolic disorders etc.) was
mentioned above.
The role of nervous system, especially of its vegetative ЀЀЀЀЀЀ, in development of
inflammation, fever, starvation, hypoxia and also in cardiac, respiratory, vascular,
digestive, hepatic, renal, endocrine insufficiency was mentioned in previous chapters.
This chapter deals with the general considerations about pathology of the nervous
system proper.
ETIOLOGY
Etiology of the neurological disorders consists in etiological factors, which affect the
nervous system, and conditions of their action. Etiological factors are exogenous and
endogenous, and also physical, chemical and biological. They may influence
metabolism, structure and function of the nervous cells, receptors, ЀЀЀЀЀЀЀЀЀЀЀ, ЀЀЀЀЀЀЀЀ,
nervous centers. There is no factor of environment which does not influence nervous
system and can not damage it.
Exogenous Factors
Physical environmental factors are - mechanical trauma (nervous system is protected

by the bones; head is protected from penetrating wounds, which in addition to brain
damage can predispose to infection), barofactors, ionizing radiation (nervous form of
acute radiant disease), high and low temperature (thermal shock), electrical energy,
electromagnetic fields, noise, vibration. Nervous system, as a result of its high sensitivity,
ЀЀЀЀЀЀ reacts to a change in the environment.
Chemical factors are poisoning by the so-called neurotropic (cerebrotoxical) poisons
of natural and artificial origin - industrial poisons, alcohol, narcotics, psychotropic
medicines. They can selectively disturb bioenergic processes in the nervous cells,
formation, transportation, excretion and metabolism of neuromediators, influence
permeability of ionic canals in neurons.
Biological factors are infectious agents with the preferred neurotropic action –
• viral neurotropic infection (meningoencephalitis, encephalitis, poliomyelitis),
1
• meningococcus (pyogenic meningitis),
• ЀЀЀЀЀЀЀЀЀЀЀ tuberculosis,
• pale spirochaeta,
• toxoplasm,
• fungal infection,
• human immunodefficiency virus (HIV),
• immune ones (with the aid of heterogenous immune serum with antibodies
against proteins or cells of nervous system it is possible to reproduce
neuropathology in experiment).
As Ѐ man possesses the second signal system, higher emotions and ЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ, the etiology of nervous pathology has a peculiarity, that as the
etiological factors of damage may be ЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ones (verbal, images). With the
help of images, symbols and notions a model of the surrounding world is created in
human imagination. Psychogenic injuring informative influences (which cause emotions)
may be referred to the exogenous etiological factors. Functional pathology of higher
nervous activity and the following visceral pathology can be stipulated by them.
Positive and especially negative emotions can cause psychogenic shock, neurosis and a
lot of visceral psycho-somatic disturbances (arterial blood hypertension,
thyreotoxicosis and other disturbances of endocrine functions).
As a man is a social being, precisely social factors may become a reason of
pathology. Social factors are tightly connected with emotions. They occupy an
important place among the factors, which cause the nervous system disturbances.
Prolonged or frequent conflict situations which are connected with peculiarities of
personality, the character of social environment, organization of society, conditions of
work and the mode of life may lead to an excessive stimulation of emotional centers
and the disturbances of the higher nervous activity of a man.
Endogenous Factors
Physical (mechanical) pressure on nervous tissue by tumors primary and secondary

(metastatic), ЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀ, ЀЀЀЀЀ.
Chemical factors are cerebrotoxical substances of endogenous origin in diabetic,
hepatic, uremic comas.
Biological factors are immune, genetic, ЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ, aging,
psychoconstitution.
Immune antibodies against nervous tissue (autoimmune aggression) occurs in the case
of the hemato-encephalic (blood-brain) barrier disorder.
Genetuc failure of higher nervous activity was described in this textbook as hereditary
and chromosomal diseases. Affection of the nervous system in hereditary diseases may have a
secondary character (e.g. phenylketonuria).
Pathologucal reflex (strong and extraordinary effects from external and internal
receptors) is a peculiarity of etiology of neuropathology as the specific pathogenic
causes of a disease. Thus, concrements in the bilious and urinary tract, the pathology of
uterus may be a source of pathologic reflexes and cause cardiac rhythm disorders;
embolus moving via a. Ѐulmonalis causes ЀЀЀЀЀЀЀЀЀЀЀЀ spasm of coronary arteries and
may occur a reason of patient death.
Significance of agung on the structure and functions of the nervous system is beyond
doubt. With the age atrophy of neurons takes place that leads to the decrease of the brain
mass. The decrease of mass of neurons occurs in different speed in different parts of the
brain and starts in different time.
2
Significance of psychoconstitution in a predisposition to certain types of pathology
was ЀЀЀЀЀЀЀЀЀ by ЀЀЀЀЀЀЀ. Psychic constitution (ЀЀЀЀЀЀЀЀЀЀЀ - ЀЀЀЀЀЀЀ, ЀЀЀЀЀЀЀЀЀ,
ЀЀЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀЀЀ) is important condition, which influence the predisposition and
duration of neuropathology.
As to conditions, which significantly determine the neuropathology, is a localization
of a damage (nervous centers, ЀЀЀЀЀЀЀЀЀЀ, ЀЀЀЀЀЀЀ, receptors).
PATHOGENESIS
All pathologic processes that affect the somatic organs (infections, vascular
pathology, the local disorders of blood circulation, thrombosis, embolism, ischemia,
trauma, neoplasia, starvation, vitamin starvation in particular as well as immunological,
toxical and metabolic abnormalities) also affect the nervous system in much the same
way. However, there are some peculiarities of the development of these pathologic
processes in the nervous system.
Hypoxia
Ѐypoxia proceeds in the nervous system and especially in its central sections in the
gravest way. The brain consumes about 20% of oxygen entering the organism. At a sudden
stopping of oxygen supply of the brain, loss of consciousness comes in 6-7 m, in 15 m
normal bioelectric activity of the brain stops. Fool restoration of the brain function in
such cases is possible when the duration of hypoxia does not exceed 5-6 min. If hypoxia
of the brain continues longer, memory and intellect will be irreversibly disturbed. When
the deprivation of oxygen has been slight, there may be an early euphoria, followed by
listlessness, drowsiness, apathy and defective judgment. When the deficit is severe and
especially when it is sudden, unconsciousness and convulsions may occur. Patients who
recover are often left with a considerable deficit. They are often demented, have bilateral
spasticity, and some of them have a liability to recurrent convulsions. It should be
marked that different parts of the central nervous system possess different sensitivity to
oxygen deficiency. Phylogeneticaly old structures are more stable to hypoxia.
Mechanism of inhibition are more vulnerable then that of excitement. That is why
euphoria is the first sign of an acute hypoxia of every genesis.
Cihculatohy Hypoxia
Blood circulation disorder in the brain has very serious consequences. This pathology
is called insult. Specifically, the brain is very sensitive to the disturbance of local
(cerebral) and system blood circulation (decrease of the arterial blood pressure).
Circulatory hypoxia may be systemic and local. Reasons are - shock, collapse,
thrombosis, embolism, ischemia, angiospasm.
Cerebrovascular diseases are the most common group of the central nervous system
disorders. After the heart diseases and cancer it ranks the third major cause of the death in
the population.
Any process that reduces the effective oxygenated perfusion of the brain can result in
hypoxic or anoxic encephalopathy. Systemic hypotension, reduced cardiac output,
respiratory failure, depletion of oxyhemoglobin due to anemia or intoxication are the
most common causes.
Cerebral infarction is a consequence of the deprivation of blood supply to a certain
area. Infarction is caused by arterial occlusion from thrombosis (which is most often
caused by atherosclerosis) and embolism. When there is a deprivation of blood to the
totality of the brain, as in cardiac arrest, the result is either death or the diffuse
3
pathomorphological changes. Gradual occlusion of a vessel, as the concentric
obliteration of a vascular lumen by an atheroma, does not necessarily produce infarction.
Thrombi, with rare exceptions, are associated with local damage of a vessel wall at
the site of occlusion. Atherosclerosis and hypertension are the most important
underlying processes. The sites of atherosclerosis and thrombosis are almost parallel.
Rarely, other forms of vascular injury, such as an arteritis or a hypercoagulable state, can
initiate thrombosis. Within the central nervous system thrombosis usually occur in the
large vessels.
Sudden complete occlusion of a vessel, as by an embolus, usually results in infarction
of the tissue in the distribution of supply of the occluded vessel.
The origin of emboli is extremely variable. The most common source is a thrombus in
the left ventricle or atrium. Less frequently, small bits of atheroma may break off from
large ulcerated plaques in the aorta or internal carotid artery system. Such emboli are
usually very small and produce a multitude of tiny infarcts, most commonly in the
cerebral cortex. Infected emboli may originate from bacterial or fungal endocarditis.
Massive trauma, especially involving the long bones, can result in fat emboli, which
pass through the lungs to the central nervous system.
Emboli, in contrast to thrombi, usually involve smaller vessels. They are found
frequently at points of arterial bifurcation and vessel lumen narrowing. Emboli,
however, are rarely found at postmortem examination, presumably because they have
migrated, fragmented or lysed. They can disappear within hours and almost always
within days or weeks following their formation.
Cerebral infarctions due to embolic occlusions often differ from those caused by
thrombi. There is frequently hemorrhage, while thrombotic infarcts are ischemic. While
the internal carotid artery is the most common site of cerebral thrombosis, emboli most
frequently occur in the middle cerebral artery. An infarct may be ischemic or
hemorrhage. The original mechanism is the same for each – deprivation of blood to a
given area.
Hemorrhagic infarcts are usually located in the cortex and are associated most
commonly with an embolus. They are caused by vascular compression. Reperfusion of
blood into the infarcted region is responsible for the hemorrhagic component. In some
situations, collaretal channels and venous stasis may also play a role in producing
hemorrhagic infarcts.
Clinically, various features help to distinguish cerebral thrombosis from embolism.
Thromboses usually form over a period of time, and patients frequently have a stuttering
course. Some patients who develop a thrombic infarct with permanent neurological
deficits will have preceding transient attacks of neurological impairment. The pathologic
basis of such attacks is due to ischemia and is thus called transient ischemic attacks.
Most are associated with atherosclerotic thrombosis, and they almost never precede a
large embolic infarct or cerebral hemorrhage. Transient ischemic attacks last from a few
seconds to two hours, most being a few seconds to 10 minutes in duration. The specific
neurological features of the transient ischemic attacks last for the same time. The
specific neurological features indicate the territory of the brain or the artery involved.
In contrast to thrombosis, emboli induce the sudden onset of focal impairment, which
appears without warning.
The symptoms and sighs of infarction of the brain depend upon the size of the lesion
and the structures involved. Loss of consciousness in infarction is generally correlated
with the amount of brain involved. Convulsions at the onset of an infarct are uncommon.
They are more frequent in embolism. Convulsions as a late consequence of infarcts are
relatively common, and they can usually be correlated with old scars in cerebral cortex.
ЀЀЀЀЀЀЀЀЀЀЀЀЀ Ѐ ЀЀЀЀ (ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ)

4
Hemorrhage (intracerebral, subarachnoidal) consists of bleeding into the brain
space or subarachnoidal space. Hemorrhage into the brain substances is most
commonly caused by hypertensive vascular disease, but trauma, rupture of aneurysm,
angiomas, bleeding into tumor also cause intracellular hemorrhage. Atherosclerosis
without hypertension is not a cause. Hypertension is 10 to 20 times more frequent than
all the other causes. Cerebral hemorrhage happens in significant systolic-diastolic
elevations for several years. The occurrence of the hemorrhage is never happens during
sleep. Blood vessel may burst within the brain substance in a hypertensive patient.
Hypertensive encephalopathy occurs in hypertensive vascular disease as an acute
clinical condition in which there is a severe and usually abrupt elevation of systolic and
diastolic blood pressure, headache, clouding of consciousness, and convulsions, leading
to stupor or coma. There are usually retinal changes with papilledema, exudates,
hemorrhage, and a degree of renal failure is also present. The patient may die or may
recover.
The pathogenesis is related to acute, severe increase in intravascular pressure.
Longstanding hypertension is not necessary for its development, since it can occur in
eclampsia and other acute hypertensive episodes. Lowering of the blood pressure can
produce the relief of the sighs and symptoms. Functional disorders may kill the patient
before any morphological changes.
The clinical course of hypertensive hemorrhage is of sudden onset with collapse, but
there are some cases in which the onset is less apoplectic, beginning with headache and
trival focal sighs before the final collapse. Intractable vomiting is common.
After all, one may understand, what a ЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀ is necessary to
ЀЀЀЀЀЀЀЀЀЀЀЀЀ, to differentiate both a type of the local vascular disorder in patient
(thrombosis, embolism, hemorrhage) and a localization of this disorder.
Metabolic Typical Disorders
Systemic metabolic typical disorders have manifestations in nervous system as well.

Nervous tissue consumes the greatest quantity of glucose. Practically all oxygen
consumed by the brain is used for glucose oxidation. The brain is very sensitive to
hypoglycemua. Hypoglycemic coma is manifested by loss of consciousness. At an acute
decrease of the level of glucose in the blood a disturbance of ЀЀЀЀЀЀЀ in the brain takes
place. Prolonged hypoglycemia causes irreversible damages of the brain cortex. At
more marked hypoglycemia the functions regulated by the ЀЀЀЀЀЀЀЀЀЀ truncal
mechanisms get disturbed.
Lipid metabolism disorders are manifested as an atherosclerosis of cerebral vessels,
which is a frequent reason of the diseases of organism.
Inflammation
Inflammation in the central nervous system is not so common because nervous system
is protected from the penetration of infection by hemato-encephalic (blood-brain) barrier.
In previous chapters it was mentioned a slow possibility of nervous tissue to oppose
infection by immune reactions. The role of the hemato-encephalic barrier and
autoimmune problems connected with it was mentioned in the corespondent chapter.
The concept of the hemato-encephalic (blood-brain) barrier was noted in experimental
animals that all organs of the body, except the brain tissue, obtain a blue color after the
intravenous injection of trypan blue, which binds to serum albumin. Ultrastructural
studies show that the blood-brain barrier is composed of endothelial cells, a basal
membrane and astrocytes of glia. The endothelial cells, rather than the astrocytes, are
5
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
zonulae occludentes. Tracers are unable to penetrate through the endothelial tight
junctions. In addition, a transcellular pathway is excluded, since endothelial cells in the
central nervous system are devoid of pinocytic vesicles.
Infection enters the nervous system through the blood (in destruction of blood-brain
barrier), or from penetrating wounds, from infected middle ear, sinuses.
As to allehgic inflammation, there are some peculiarities of its course in the nervous
system. From other side, precisely, the presence of blood-brain barrier creates a risk for
the nervous system. If this barrier is disrupted, own cells of nervous system become an
object of autoimmune aggression because the physiological immunological tolerance as
to nervous tissue is absent.
Edema
Cerebral edema is an increase in the water content in the central nervous tissue above
normal. If water accumulation occurs within cells, it is called cytotoxic edema. It is
contrasted to water accumulation in the extracellular space, which is called vasogenic
edema.
In cytotoxic edema it is a defect as a failure of the ATP-dependent sodium pump
within the cell membrane. Sodium accumulates within the cell, with water increasing as
well to maintain osmotic balance. All cellular elements of the brain (neurons, glia, and
endothelial cells) may swell, resulting in a decrease in the brain’s extracellular fluid
space. Acute hypoosmolarity secondary to water intoxication and cerebral hypoxia are
examples of conditions that can produce cytotoxic cerebral edema.
Vasogenic edema is the most common form of cerebral edema. Primary and metastatic
brain tumors, abscesses, hemorrhages, infarctions, contusions can cause it and lead to
encephalopathy. It results from water and plasma leaking directly into central nervous
system through or between damaged capillary endothelial cells, which have lost their
barrier function. Fluid collects in the extracellular space. Edema can be focal or diffuse.
Interstitial edema is characterized by an increase of water and sodium in the
periventricular ЀЀЀЀЀ ЀЀЀЀЀЀЀЀ as a result of the passage of volume of cerebrospinal fluid
across the ventricular walls. It occurs most commonly in association with obstructive
hydrocephalus.
Cerebral edema is an extraordinary common clinical complication, which may result
in death. Osmotic, metabolic, and traumatic processes may coexist, leading to an increase
in water both in cells, and in the 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 overproduction or, much
more commonly, decreased its absorption due to inability of the arachnoid villi to transfer
it to the venous system or block the pathway to the villi. In the 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 usually manifest acute hydrocephalus.
Hydrocephalus — denotes increased volume of cerebrospinal fluid within the cranial
cavity (ventricles).
Increased intracranial pressure, cerebral edema, and hydrocephalus are exceedingly
common pathophysiological conditions which may complicate almost any disease
involving the central nervous system. They frequently occur in combination. Trauma,
inflammatory, vascular, degenerative, and metabolic diseases as well as both genetic and
acquired conditions can lead to one or all of these pathophysiologic complications.
6
Increased intracranial pressure may be due to diverse pathological processes. All cases
are associated with some sort of mass effect. It may be either diffuse, such as that caused
by the generalized brain edema, or focal, as may be seen with brain tumors, abscesses, or
subdural hematomas. Regardless of the cause, it is the compression of the brain,s vital
centers that leads to the life-threatening complications.
Patients with increased intracranial pressure usually show the following cardinal
clinical manifestations – periodic headache, mental slowness, confusion.
In addition to directly crushing nervous tissue, herniation of the brain may also
compress arteries against surrounding structures, resulting in collapse and occlusion of
their lumens and secondary infarction of the brain.
Tumor
The tumors, which develop in the nerve tissue, may be benign and malignant, and also
primary and metastatical. Clinical picture depends on localization of a tumor. A tumor
provide a mechanical pressure on nervous centers, their irritation, excitement or
ЀЀЀЀЀЀЀЀЀ of their functions. Thus, it is necessary first to define what part of the nervous
system is clinically involved before a tumor is examined morphologically.
Genetic Disorders
Genetic disorders associated with the gene and chromosomal abnormalities, are manifested
as neural tube defects, spina bifida, failure of posterior vertebra arches to close,
ancephalopathy. Fetal alcohol syndrome is associated with an excessive alcohol intake
during pregnancy. Facial abnormalities and developmental defects such as
microcephaly, atrial septal defect and other anomalies characterize it. Hentington,s
disease is an autosomal dominant disorder with delay of onset of clinical manifestations
to the age of 30-40.
Starvation and Electrolytes Disorders
Starvation, especially deficit of vitamins of group B, has neurological manifestations.

Electrolytes disorders (changes of concentration of Na, K, Ca ions, and hydrogen ions
in the blood) influence the nervous system activity, its excitability and conductivity.
Molecular, Subcellular, Cellular and Tissue Disorders
Continuing ЀЀЀЀЀЀ of the pathogenesis of nervous system disorders, it is necessary

to stress, that any pathological process disturbs nervous system functions on
molecular, cellular, tissue organization and also at the level of the hole organism
(demonstrated as clinical symptoms).
At the molecular level the disturbances are manifested in the disorder of the
potentials formation and also of the neuromediators and neurohormones production.
Universal mechanisms of disturbances of the neuron functions are explained below.
Loss of ability to maintain the definite ЀЀЀЀЀЀЀЀ of membranous potential by the
nervous cell, to generate ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ and to conduct them by ЀЀЀЀЀЀЀЀ, ЀЀЀЀЀЀЀЀЀ
excitation from one nervous cell to another one, are the mechanisms of a disorder.
The disturbance of synthesis, excretion and destruction of mediators may be an
important link in pathogenesis of many disorders of the nervous system activity. There
are many facts that the activity of the nervous system and especially of its higher
sections is defined by substances of the peptide nature (neuropeptides), which are
produced both by the nervous and other cells and perform mediatory and nonmediatory
7
functions. Opiate brain systems, the work of which is regulated by endorphins and
enkephalins, are the most studied. In the brain of a man and animals ЀЀЀЀЀЀЀ of
oligopeptides were discovered, injections of which into the cerebral ventricles or directly
into the nervous centers may cause different emotional states and behavior reactions,
influence on ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ, ability to memorize, to study etc. Lack or
excessive formation of neuropeptides, change of sensitivity of nervous cells to them
may have significance in pathogenesis of disorders of the nervous system functions.
Disorder of transport and ЀЀЀЀЀЀЀЀЀЀЀЀЀ of mediators also play a role. In Alzheimer
disease the levels of choline acetyl transferase and acetyl-cholinesterase were markedly
reduced in the hippocampus, amygdala, neocortex and the deep gray nuclei.
At the cellular and tussue level, ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ ЀЀЀЀЀЀ, ЀЀЀЀЀЀЀЀЀЀЀ, ЀЀЀЀЀЀЀЀ,
decrease of the quantity of interneuronal contacts are the mechanisms of disturbances of
the nervous system functions. The disturbance of the function of the highest and
subcortical nerve centers, and also the nervous conductors take place. The peripheral
nervous system includes the sensory and motor components of the cranial and spinal
nerves as well as the autonomic nervous system with its sympathetic and parasympathetic
divisions.
If the nerve is damaged so much that its connection with the ЀЀЀЀЀ ЀЀЀЀЀЀЀ is lost, it
degenerates due to the cessation of axoplasmatic flow of nutritient substances.
At the level of enture organusm the pathology of the nervous system and clinical
manifestations depends on localization. A prominent peculiarity of the responses of the
nervous system is the selective vulnerability of a group of neurons or of a specific region
of the brain or spinal cord to etiologic agents, leaving the rest of nervous system virtually
intact.
Dysthophy
Dystrophy in the nervous tissue is specifically manifested by demyelinazation and

degenehation. They critically disturb the functional activity of the nervous system.
Demyelinating diseases are characterized by the destruction of
myelin with relative preservations of axons. Demyelinating diseases or loss of myelin
sheaths, is a defect common to many disorders of the central nervous system. Secondary
demyelination (injury of axon with subsequent loss of its myelin) is distinguished from
primary or true demyelination, which results from damage of dendroglia with relative
sparing of the underlying axons. These 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 demyelinating peripheral neuropathies are also possible.
Multiple sclerosis is this kind of the disease. It is a chronic, remitting and relapsing
disorder, sometimes leading to total disability. Autoimmune mechanisms play a role,
triggered or accentuated by viral infection as etiological factor. Adenovirus and measles
antibodies have been found as well as antimyelin antibodies. Immune response may be
altered. Elevated level of polyclonal IgG have been found in the cerebrospinal fluid.
Corticosteroids or aggressive immunosuppressive therapy may be used. Genetic
predisposition is obtained.
In contrast to the central nervous system (which has little if any ability to regenerate),
the basic reactions of the peripheral one include both degeneration and regeneration.
These frequently hereditary diseases of the nervous system are characterized by a
gradual, usually symmetric, progressive wasting away of groups of neurons. Many
eventually result in death. Vascular, infectious, metabolic and immunological
mechanisms have not been found. However, there is a slow degeneration and
disappearance of nerve cells and their processes or simple neuronal atrophy
8
accompanied by mild gliosis. In addition to neuronal loss, some degenerative diseases
show characteristic changes in nerve cell cytoplasm or nucleus (e.g. Alzheimer’s disease
and Parkinson’s disease).
The outstanding clinical manifestation of the cortical degenerative diseases is
dementia. Dementia may be secondary to known causes, such as cerebral infarction,
hydrocephalus, encephalitis, virus infection and metabolic diseases. These dementias
are divided into presenile and senile types. Presenile dementia is defined as a
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.
The degenerative disorder is characterized by the progressive generalized cerebral
atrophy, particularly temporal and frontal lobes, decreased number of neurons in
nucleus basalis, granulovascular degeneration with general impairment of higher
intellectual functions or subtle emotional liability in the absence of focal neurological
defects. It progresses steadily over 5 to 10 years to severe dementia and death, often
associated with respiratory infection. There is some tendency toward familial
occurrence, although many cases are sporadic. Symptoms are aphasia, agnosia and
apraxia occur, and convulsive disorders may be prominent during the course of some
patients. There 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.
MANIFESTATIONS
DISORDER OF THE SENSITIVITY
The disturbances of the sensitivity are manifested in the form of following symptoms
- anesthesua (reduction in the sensitivity) hyperesthesua (increase of it), hypoesthesua
(decrease of it).
Depending on the character of the lost sensitivity there are distinguished the tactile
anesthesia, pain (analgesia), thermal (thermanesthesia) and loss of deep or proprioceptive
sensitivity.
If the pathologic process is located in the spinal cord or in the brain, the disorder of
sensitivity depends on the types of the ascending pathways disturbed.
There are two ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ centripetal systems of sensitivity. One of them is
called lemnisk and contains the nervous fibers of large diameter, which conduct stimuli
from the proprioreceptors of muscles, tendons, joints and partially from dermal receptors
of touch and pressure (tactile receptors). The fibers of this system ЀЀЀЀЀЀ in the spinal
cord and ЀЀЀЀ Ѐ ЀЀЀЀЀЀЀ the structure of the posterior column into the medulla oblongata.
From nuclei of the medulla oblongata the medial loop (lemnisk pathway) begins, which
ЀЀЀЀЀЀЀЀЀ on the opposite side and finished in the posterolateral ventral nuclei of
thalamus, neurons of which transmit the obtained information into the somatosensory
zone of the cortex of the brain.
The second ascending system is the spinothalamic (anterior and lateral) pathways
carrying ЀЀЀЀЀЀЀ, thermal and partially tactile sensitivity. Its fibers go up in the structure
of the anterior and lateral funiculi of the spinal cord and terminate in the cells of nuclei of
the thalamus (anterolateral system).
Typical changes of the sensitivity are observed at cutting of the right or left half of
the spinal cord (Brown-Sequard's syndrome). On the side of cutting, the deep sensitivity
disappears while thermal and ЀЀЀЀЀЀЀ ones disappear in the opposite side, as the
9
conductive pathways relating to the anterolateral system, ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ in the spinal
cord. The tactile sensitivity is partially disturbed on both sides.
The disorder of the lemnisk system is possible in damage of the peripheral nerves (thick
myelin fibers) and also in various pathologic processes in the spinal cord (disturbance of
blood circulation, trauma and inflammation). The isolated damage of the posterior funiculi
of the spinal cord occurs seldom, but together with other conductive pathways they can
be damaged by tumor or during trauma.
The disturbance of conductivity in the fibers of the medial loop causes various
disorders of sensitivity, manifestation of which depend on the degree of the damage of
the system. Thus, the ability to determinate speed and direction of motion of the limbs
may be lost. The feeling of ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀ simultaneously in two places and also
an ability to feel vibration and to evaluate the weight of ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ are
considerably disturbed. The patient isn’t able to determine the shape of subjects touching
them and to identify the letters and writing them on the skin: he feels only mechanical
touch and isn't able to indicate place and force of tactile sensation exactly. The sensation
of pain and temperature sensitivity is preserved.
ЀЀЀЀЀЀЀЀ of the postcentral gyrus of the cortex in experimental animal causes the
disturbance of sensitivity on the opposite part of the body. Ѐ ЀЀЀЀЀЀЀЀЀ ЀЀЀЀ ЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀ ЀЀЀЀЀЀ ЀЀ ЀЀЀЀЀЀ ЀЀЀЀЀ knowledge about the functions of the lemnisk system,
connecting such an operation with lemnisk denervation on the opposite side, on which
elements of the anterolateral system, however, are preserved. Obviously, the disturbance
consists in the loss of the ЀЀЀЀЀЀЀ-ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ. The animal often stops moving
remaining in an inconvenient position for a long time. Ѐhe tactile, pain and thermal
sensitivity on this side are preserved although their ЀЀЀЀЀ can be increased. In a man the
isolated damage of the postcentral gyrus occurs very seldom. For example, sometimes
surgeons remove a part of this gyrus for treatment of patient with epilepsy of the cortical
origin. In this case disorders, mentioned above, appear - sensation of the ЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀЀЀЀЀ in space, ability to determine the shape of ЀЀЀЀЀЀЀЀЀ, their size, weight,
character of a surface (smooth, rough, etc.) by touch are lost.
PAIN
Pain refers to the disorder of sensitivity. It is a leading symptom of any disease.

Pain is a negative sensation to the disorder and a negative reaction of organism to
it.
The value of pain is dual. From one side, the pain brings to patient large sufferings.
From other side, the pain is a defensive reaction of organism and a signal about the
presence of pathology.
Pain is realizing by a special system of the pain sensitivity and the highest sections of
the brain related to the psychoemotional sphere. The system of perception and transfer
of the pain is called nociceptive (algic) system. The physiological system of reduction of
pain exists in the organism. Its name – antinociceptive system.
Pain is divided into physiological and pathological ones.
The so-called physiological pain causes an adaptive effect — a response directed on
ЀЀЀЀЀЀЀЀЀЀ ЀЀ ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ.
There is also a pathological pain. The main biological criterion of distinguishing the
pathological pain from the physiological one is its disadaptive and pathologic meaning
for the organism. The pathological pain conditions the development of the functional and
structural changes and the impairments in the cardiovascular system, inner organs, in the
system of microcirculation, vegetative reactions, endocrine system.
Mechanisms of the Pain

10
In the development of pain, ЀЀЀЀЀЀЀ receptors, central centers (in hypothalamus) and
also mediators of pain, which include the serotonin, bradykinin, prostaglandins, have a
value.
Peripheral sources of the pathologic pain may be tissue receptors (nociceptors) in their
intensified overstimulation, chronically damaged and regenerating sensitive nerves,
demyelized fibers, etc. The damaged nerves are quite sensitive to different humoral
effects and therefore they become ectopic focus of nociceptive stimulation. The pain,
associated with the nerve damage, is called neuropathic. Neuroma plays a role. It is a
formation of chaotically grown, interwoven sensitive nervous fibers, which is formed in
unregulated regeneration. Neuroma is quite sensitive to different effects, which may
provoke pain attacks (causalgia).
As to the central mechanisms of the pathological pain, some theories are proposed.
ЀЀЀЀЀЀ “ЀЀЀЀЀЀЀ ЀЀЀЀЀ”
According to the «gate control" theory, there is a control mechanism for passing of
nociceptive impulsation via afferent system into the spinal cord. This control represents
"gate", which regulates the activity of T-cells.
It is known that a transmission of nervous impulses from afferent fibers to spinal neurons
(which in turn transmit the signals into the brain) is regulated by spinal ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀ
– neurons of substantia gelamentosa, which are able to inhibit a transmission of impulses
on T-neurons and play a role of ЀЀЀЀЀ ЀЀ ЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ Ѐ ЀЀЀ. A pain develops
ЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀ Ѐ. When an excitement of T-neurons
exceeds a critical level, ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ ЀЀЀЀЀ.
From the point of view of this theory the pathologic pain occurs in insufficiency of the
inhibitory mechanisms of the gate control, when the uninhibited T-cells may be activated
by different stimuli from the periphery. Constant flow of stimuli from different sources to
T-cells with disturbed inhibitory control is a condition of the pathological pain.
ЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀ
In pathogenesis of the functional disorders of central ЀЀЀЀЀЀЀ of the nervous system

ЀЀЀЀЀ ЀЀЀЀЀ ЀЀЀЀЀЀЀЀ an appearance in nervous centers of groups of neurons which begin
ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ and produce an excessive excitation. Such neurons are ЀЀЀЀЀЀЀЀЀЀ as a
generator of pathologically increased excitement (G. N. Kruzhanovsky).
According to this theory, the pathological pain is caused by formation of a generator
in the nociceptive system. It is a group of hyperactive neurons, which may develop a
self-supporting activity without any additional stimulation from periphery. Significant
and stable depolarization of the nociceptive neurons may reproduce a generator. The
inhibitory insufficiency as to these neurons is an obligatory condition for the formation
and activity of the generator in any part of the pain sensitivity system. Then generator
involves different parts of the pain sensitivity system into the pathologic process with
the formation of a new pathodynamic organization with abnormal character of activity
producing a pathological pain. It is a pathological algic system (PAS), which is a base of
a pain syndrome and may be formed from the primary and secondary changed formations
of the pain sensitivity system. PAS involves structures of the emotional sphere and
vegetative nervous system. Stable, ramified, active PAS is a pathophysiological
mechanism of a severe polymorphic pain syndrome.
The character of activity of the generator and pathological algic system allows
understanding the peculiarities of the pathological pain, in particular, its attacks,
11
preservation and intensification of pain after provocation by single stimulus, spontaneous
pain attack without afferent stimulation.
At the same time, stimulation from the periphery may intensify the generator. Thus, the
generator in the dorsal cornua of the spinal cord and nuclei of the trigeminal nerve
may be stimulated from periphery. Under these conditions the pain initially of the
peripheral character may acquire the character of the central pain syndrome.
Generator formation may be caused by partial deafferentation, for example, after
cutting the ischiadic nerve or dorsal spinal roots. The epileptiformal signals are registered
at first at the deafferented dorsal cornua and then in the nuclei of the thalamus and
somatosensory zone of the cortex.
The generator may be formed in the dorsal cornua of the spinal cord under the local
influence of different convulsants, and their nature is of no importance. In all cases there
is a pain syndrome with characteristic features.
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 the neuron population with long pathologic activity. Secondary
generators may be formed in different parts of the pain sensitivity system.
Antinociceptive System
Nociceptive system has its functional antipode — antinociceptive system, which

controls the activity of the nociceptive system. Antinociceptive system consists of various
nervous formations related to different parts and levels of the central nervous system,
beginning from the afferent entrance in the spinal cord and ending within the brain
cortex.
Antinociceptive system plays a significant role in mechanisms of prevention and
elimination of the pathological pain. In excessive nociceptive stimuli, it joins the response
and lessens the flow of nociceptive stimulation and intensity of the pain sensation.
Thanks to it, the pain remains under control and does not become pathologic. In
inadequacy of the antinociceptive system, mechanisms of a pain obtain special activation.
Neurochemical Mechanisms of Pain
Neurochemical processes at different levels of the nociceptive and antinociceptive

systems realize functional neurophysiology mechanisms of the pain sensitivity.
The peripheral nociceptors are activated under the influence of many endogenic
biologically active substances — histamine, substance P, kinines, prostaglandins, etc.
The substance P plays an important role in excitability conduction in the primary
nociceptive neuron. It is conditioned to be a pain mediator. The direct effect to the
stimulating aminoacids and substances causing depolarization or disturbance of neuron
inhibition on the dorsal cornua brings about the formation of the generator and the pain
syndrome.
Rather effective endogenic analgetics are opioid neuropeptides. They inhibit the
transmitting of nociceptive neurons and activate the neurons of the antinociceptive
system, changing the activity of the neuron of the highest section of the brain. The
substance P may also cause analgesia and inhibition even of the pathologic pain,
activating antinociceptive structures, for example, the dorsal nucleus of the suture.
Of classical neuromediators the analgetic effect has serotonin, noradrenaline,
dopamine, GABA (gamma aminobutyric acid).
Serotonin is a mediator of the antinociceptive system at the spinal level. Noradrenalin
is also a mediator of the descending antinociceptive system, it inhibits the activity of the
nociceptive neuron of the posterior cornua of the spinal cord and nuclei of the
12
trigeminal nerve. GABA takes part in inhibition of the activity if the nociceptive
neurons are at the spinal level.
Treatment of Pain
Treatment of a main disease, which caused a pain (for example inflammation), is a

main principle of pain treatment. It is necessary to eliminate the etiological factor
maintaining the pathologic changes in the nociceptive system. If a pain obtains
pathological ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ, it is necessary to intervent into mechanisms
of a pain formation mentioned above.
The main two principles of treatment of the pathological pain are -
• inhibition of the hyperactivity of the nociceptive neurons and generators formed by
them and to liquidate PAS, which is a base of the pain syndrome,
• stimulation of mechanisms of antinociceptive system.
As the nociceptive and antinociceptive effects are realized at different levels and by
several mechanisms it is necessary to use complex pathogenetic therapy. It is important to
effect psychoemotional, vascular and other vegetative and tissue components of the
pathologic pain.
The inhibition of the generator by the inhibitory mediators leads to disappearance of
the pain syndrome for the time of their action, when they are introduced in the area of the
generator in microin injection. Correction may be done with the help of anticonvulsants,
which, inhibiting the generator and induced hyperactive PAS, cause slackening or
disappearance of the pain syndrome.
With the help of Ca-antagonists, the blockade of Ca2+ entry into the nociceptive neurons
is accomplished.
As it is usually in medicamentous therapy, a suppression and inhibition ЀЀЀЀЀЀЀ ЀЀЀЀЀ,
then stimulation. In such a case, a stimulation of mechanisms of antinociceptive system
would be the best but ЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀ.
DISORDER OF MOTOR FUNCTION OF NERVOUS SYSTEM
The disturbances of motor function are manifested by pareses, paralyses, spasms and
convulsuons. Myasthenia, spinal shock, disorder of coordination of movements (ataxia),
ЀЀЀЀЀЀЀЀЀЀ also refer to disorders of motor function of nervous system.
Contractions of skeletal muscles and their tonus are connected with an excitement of
motoneurons of the spinal cord. Function of motoneurons is regulated by variety of
impulses coming to them via ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀ ЀЀЀЀЀЀЀЀ ЀЀЀЀЀ from ЀЀЀЀЀЀЀЀЀ, ЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ, ЀЀЀЀЀЀЀЀ, ЀЀЀЀЀЀЀЀЀ ЀЀЀЀ Ѐ ЀЀЀЀ ЀЀЀЀЀЀЀЀ ЀЀЀЀЀ, providing the
highest motor control in organism. Motor disorders develop ЀЀЀ ЀЀЀ damage of the
mentioned ЀЀЀЀЀЀЀ of nervous system, ЀЀЀ Ѐ ЀЀЀ ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ ЀЀ
ЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀ ЀЀ ЀЀЀЀЀ.
Paralyses and parhesis are a loos or ЀЀЀЀЀЀЀЀЀЀЀЀ of movements. Depending upon
pathogenesis, a tonus of the damaged muscles may be ЀЀЀЀ lost (ЀЀЀЀЀ paralysis) or
increased (spastic paralysis). Besides, a peripheral paralysis (connected with damage of
peripheral motoneuron) and central (as a result of a damage of central motoneurons) are
distinguished.
Myasthenia is one of the disorders of ЀЀЀЀЀЀ-ЀЀЀЀЀЀЀЀ transmission in pathology.
Antibodies to ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀ are revealed in the blood serum.
Convulsion development is connected with the disorder of brain cortex. The causes of
convulsive attack development may be tumor or ЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ, localized in motor or
sensitive ЀЀЀЀЀЀЀ ЀЀЀЀ.
13
Huntington’s chorea is clinically characterized by extrapyramidal involuntary or
choreiform movements. Biochemically, there is marked decrease in endogenous
gamma-amino-butyric acid and in glutamic acid decarbboxylase. There is also a
decrease in choline-acetyltransferase and in the muscarinic cholinoergic receptors. It
leads to a deterioration of the filtering ability of the striatum, allowing uncontrolled
stimulation of the lower centers by the globus pallidus, resulting in abnormal involuntary
movements and chorea. Motor deficit (bradykinesia, akinesia) joins an abnormal
activation of the motor system, resulting in rigidity.
Parkinsonism (paralysis of old age) usually occurs after the age of 50. ЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀ Ѐ ЀЀЀЀЀЀ ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀ. Degeneration of nigral neurons
leads to loss of dopaminergic inhibition and relative excess of cholinergic activity. An
increased muscular tonus, constant tremor of extremities and ЀЀЀЀЀЀЀЀ.
DISORDER OF AUTONOMIC (VEGETETIVE) FUNCTION OF NERVOUS

SYSTEM
The peripheral nervous system includes the sensory and motor components of the
cranial and spinal nerves as well as the autonomic nervous system with its sympathetic
and parasympathetic divisions.
The participation of autonomic (vegetative) nervous system in the development of all
pathophysiological and clinical syndromes was mentioned in all previous chapters.
The main significance belongs to disorder of balance between sympathetic and
parasympathetic parts of autonomic nervous system. ЀЀЀ ЀЀЀЀ, vegetative effects appear
more often while irritation of the structures then in their ЀЀЀЀЀЀЀЀЀЀ. Thus, in prevailing
of sympathetic influences, as it was noted, cardiovascular disorders and increase of
blood pressure develop. Vagotonus was mentioned as the main pathogenic mechanism
of stomach peptic ulcer development.
If the centers of autonomic (vegetative) nervous system would be constantly in a
state of ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ, visceral organs would constantly received
their inhibitating or ЀЀЀЀЀЀЀЀЀЀЀЀ impulses. In Ѐ denervated organ functional and
structural changes develop. ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ animals are less resistant,
thermoregulation is disturbed, cardio-vascular system looses adaptive properties to
changes of organism need in oxygen, resistance to hypoxia decreases, stress may result
in death.
ЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀ of autonomic (vegetative) nervous system ЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀ ЀЀЀЀЀЀЀ,
ЀЀЀЀЀЀЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ, hypothalamus, thalamus and the brain cortex.
They integrate correlation between different parts of ЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ, Ѐ
ЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀ vegetative, somatic and endocrine systems.
NERVOUS TROPHICITY AND NEURODYSTROPHIC PROCESS
Nervous trophicity is a nervous control upon metabolism.

Nervous trophicity guides metabolism according to the needs at each given moment.
The trophic action of the nerves is closely connected with their other functions
(sensitive, motor, secretory) and together with them provides an optimum function of
each organ.
The disturbance of nervous trophicity bears the name of neuhodysthophic phocess.
A French scientist Majandy obtained the first proofs of the nervous influence on
trophicity of the tissues. In experiments on the rabbits he has cut the trigeminal nerve and
revealed ulcer in the zone of sensitive denervation (the eye, lip). The trophic disorders
14
develop in any organ if its innervation is disturbed by the intervention on the nerves
(afferent, efferent, vegetative) or nervous centers. The medical practice can give a number
of facts, which also give evidence that the damage of the nerves (trauma, inflammation)
may cause the ulcer or other disorders in the appropriate zone (edema, erosion, necrosis).
Mechanisms of the Trophic Influence of the Nerves
The question is important: does the special trophic nerves exist?

F. Majandy assumed that ЀЀЀЀЀ the sensitive, motor and secretory nerves there are also
the special trophic ones, which regulate the tissue nutrition, i. e. assimilating of nutritious
materials.
I. P. Pavlov in experiment on animals, among the nerves, coming to the heart, found such
a branch, which increases the power of systole without any influence on the blood
circulation. Pavlov called this nerve “ЀЀЀЀЀЀЀЀЀЀЀ” and considered it to be purely trophic.
Pavlov consumed that the complete and harmonious heart innervation is provided by the
triple nervous provision: the functional nerves, vasomotor nerves (regulating the supply
of the blood and the nutritious substrates) and trophic ones (providing the final utilization
of these substances). L. Orbelli was of the same opinion.
Above said doesn't mean that the trophic nerves have no other influence on the
tissue, or that the motor or secretory ones have no influence on metabolism. As to
mechanisms of the trophic influence of the nerves, there are two points of view.
The first view postulates, that trophicity isn't an independent nervous function. A. D.
Speransky considered that all nerves influence metabolism, there are no nontrophic
nerves — "the nerve is functional just because it is trophic". The nervous stimulus, which
ЀЀЀЀЀЀЀЀ ЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀ (for example, muscle), changes its metabolism because nervous
mediator activates ferments.
Another view postulates that it is impossible to ЀЀЀЀЀЀ trophicity to ЀЀЀЀЀЀЀЀЀЀЀ
(ЀЀЀЀЀЀЀЀЀЀЀЀ) action of the nerve. The nerve also has a function named ЀЀЀЀЀЀЀЀЀЀЀЀ. Its
essence consists in flow of axoplasm, ЀЀ ЀЀЀЀ “’substances of trophicity”, nature of which
ЀЀЀЀЀЀЀЀЀЀ. The humoral substances, which move via neurons, penetrate through synapses
and appear in the innervated cells. These substances provide a specific action on the
effectory cell. When the nerve intended for the red muscle after surgical operation grows
into the white one, the latter shows the radical changes in its metabolism.
The common conclusion is that the trophic action of the nervous system consists of
two mechanisms - ЀЀЀЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀЀЀЀЀ impulsive and unimpulsive.
Biochemical, Structural and Functional Changes in the Denervated Tissue
Any damage of the peripheral nerve is always accompanied by the metabolic

changes in a correspondent organ. It concerns carbohydrates, fats, proteins, nucleic acids
disbalance.
Not only quantitative but also qualitative changes are observed. Thus, myosin in the
denervated muscle loses its ATPase properties, and glycogen in its structure becomes
simple. The reorganization of the fermentative process is observed. Thus, isofermentative
spectrum of lactate dehydrogenase changes Ѐ ЀЀЀЀЀЀЀ the benefit of LDG4 and LDG5, i. e.
those forms, which are adapted to the anaerobic conditions. The activity of succinic
dehydrogenase decreases. The common tendency of the metabolic changes consists in
ЀЀЀЀЀЀЀЀЀЀЀЀ an embryonal character - glycolytic process begins to predominate over the
oxidizing one. The power of Krebs cycle is weakened; the output of macroergs
decreases, the energy potential is lowered.
In the denervated tissues there are essential morphological changes. All stages of
inflammation develop. Prevention of infection, trauma and drying doesn't prevent the
15
dystrophic process but only delay its development. Finally ulcer appears which has no
tendency to healing (fig. 59). The investigation of the subcellular structures shows the
change of the organelles - mitochondria decrease in quantity, their matrix is ЀЀЀЀЀЀЀЀЀЀ.
The disorder of oxidizing phosphorilation and Ca-accumulating ability of mitochondria
together with energetic abilities of the cell are connected with this. The mitotic activity
is reduced in the denervated tissues.
_______________________________________________________
Fug. 59. Throphical ulcer cornea after cutting of n.trigemini

ЀЀЀ. 85 Ѐ. 648 ЀЀЀЀЀЀЀЀЀЀЀ
______________________________________________________________
As to the functional disorders, the consequence of denervation depends on the type of

tissue. The salivary gland secretes saliva, but its character does not depend on a kind of
food. As to myocardial muscle, it contracts even in cutting of all extracardial nerves.
The skeletal muscle ЀЀЀЀЀЀaЀ of the sympathetic or cholinergic nerves reacts on adrenaline
or acetylcholine more than in the norm. The law of denervation was ЀЀЀЀЀЀ, which means
the increased sensitivity of denervated structures. It is explained ЀЀЀ, ЀЀЀ cholinoreceptors,
which are concentrated in the normal muscles only in the area of myoneural synapses,
appear on the entire membrane surface Ѐfter denervation of myocyte. ЀЀЀЀЀЀЀЀЀЀЀ of the
denervated structure response consists not only in increase but also in perversion when,
for example, instead of relaxation of the vascular muscles, they contract. It is easy to
imagine what it will mean, for example, for vessels, for blood circulation.
Pathogenesis of Neurodystrophic Process
Significance of the nervous centers in dystrophy development is proved by

experiments with selective damage of hypothalamus. It is accompanied by the
development of ulcers in various peripheral organs.
Ѐhe trophic function is provided by the principle of reflex. So, analyzing the
neurodystrophic process, it is necessary to evaluate the significance of each link of the
reflex and its contribution to the mechanism of this process development.
The sensitive nerve plays a special role. After its cutting the following events take place
-
• stop of ЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀЀЀ from peripheral organ to the nervous center,
• ЀЀЀЀЀ of pathological information into the centers from the place of nerve cutting,
• centrifugal ЀЀЀЀЀ of irritation into organ from the place of nerve cutting,
• stop of axoplasmatic flow of regulative substances via nerve to organ.
The role of the efferent nerves in dystrophy consist Ѐ ЀЀЀ, ЀЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀ
ЀЀЀЀЀЀЀЀЀЀЀ their functions (motility, secretion) Ѐ ЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀ. The
impulsive activity, synthesis of mediators (adrenaline, serotonin, acetylcholine, etc.)
ceases, the axonic transport of the substances of trophicity is disturbed or stops. Normal
functions disappear and pathologic ones occur.
Genome gets involved into neurodysthrophy development. The synthesis of ferments is
disturbed, the output of macroergs decreases, and metabolism acquires more primitive
character. The membranes and their transport functions are disturbed. Denervated organ
can become an object of autoimmune aggression. Dystrophic process is complicated by
the disturbance of blood and lymphocirculation. Then hypoxia appears as a result.
At the final conclusion, the pathogenesis of neurogenic dystrophy is presented as
compound multifactorial process when the nervous system ceases to control metabolism in
the tissues and after that complex disorders of structure and function occur.
16
PATHOLOGY OF HIGHER NERVOUS ACTIVITY ЀЀЀЀЀЀЀЀЀЀЀЀ
Higher nervous ЀЀЀЀЀЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ psychic functions – ЀЀЀЀЀЀЀЀ, emotions, verbal

function, memory. Studding of higher nervous pathology is a subject of ЀЀЀЀЀЀЀЀЀ
ЀЀЀЀЀЀЀ ЀЀЀЀЀЀЀЀ – ЀЀЀЀЀЀЀЀЀЀ.
In spite of the fact that higher nervous activity is developed most of all in men,
experimental pathophysiology investigates it in animals with the aid of objective
methods of investigation and reproduces pathology first of all, by the method of the
conditioned reflexes.
Pathophysiology studies the mechanisms of appearance and development of the
pathologic deviation from the normal course of the higher nervous functions of the human
and animal brain. The theoretical ground is based on Pavlov’s doctrine about the
conditioned reflexes.
Etiology
Etiological factors, which cause the higher nervous function pathology, are
exogenous and endogenous of physucal, chemucal and buologucal origin.
Posttraumatic pathology of higher nervous activity in form of the disturbances of
behavior appear as a result of a direct action of pathogenic agent on the brain, for example,
in its injury, or tumor of the brain.
Chemical factors are called ЀЀЀЀЀЀЀЀЀЀЀЀ, among which there are ЀЀЀЀЀЀЀЀЀ and
medical drugs.
Peculiarity of etiology leis in biological effect of ЀЀЀЀЀЀЀЀЀЀЀЀЀЀ factors. Thanks
to the secondary signal system the functional pathology of higher nervous activity can
be stipulated by the verbal action.
Pathological effect of the negative emotions refers to the biological factors. In
experiments with animals it is possible to model disorder of behavior and even
stomach ulcer by ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ limitation of movements (prolong fixation), long
limitation of the ophthalmic, sound, tactile and other stimuli into the brain.
Functional changes and the disturbances of behavior are studied also by the action of
the pathogenic agents on internal and external receptors.
Genetic factors which cause congenital disorders of higher nervous activity, refers
to biological but endogenous ones.
Pathogenesis
Pathology of higher nervous activity may be primary a s a result of a direct action

of injuring factor on the brain and also due to congenital genetic defects or secondary
as a result of another pathology of the organism (more often as vascular disease). As a
rule, secondary pathology of higher nervous activity results from asthenization of the
nervous system, decrease of its strength in relation to the psychogenic and other actions.
It is considered that pathologic conditioned reflexes can be formed as a result of fixation
of the conditions, which appear in the brain under influence of pathogenic agent in the
long-term memory.
Pavlov ЀЀЀЀЀЀЀ the types of higher nervous activity which determine an individual
reactivity, predisposition to diseases and a type of pathology. The type is Ѐ congenital
peculiarity of the nervous system and it is reflected in such congenital
characteristics as ЀЀЀЀ, ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ Ѐ ЀЀЀЀЀЀЀЀЀЀЀ strength, steadityness and
mobility of the nervous processes. These types are -
17
1. Strong balanced ЀЀЀЀЀЀЀЀЀ (corresponds to sanguine type of ЀЀЀЀЀЀЀЀЀЀ),
2. Strong ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ with predominance of excitation over inhibition (ЀЀЀЀЀЀЀ),
3. Strong ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ with predominance of inhibition over excitation
(ЀЀЀЀЀЀЀЀЀ),
4. Weak type with low development of excitation and inhibition (ЀЀЀЀЀЀЀЀЀЀ).
As to the role of the negative emotions in pathogenesis of higher nervous activity
disorders, they play the biologically positive role as a factor of extreme mobilization of the
organism as counteraction to pathogenic agent. If they have a long stagnant duration and
are promoted by the long delay of external manifestation (the so-called ЀЀ ЀЀЀЀЀЀЀЀЀЀЀЀЀЀЀ
emotions) they are accompanied by hormonal and other chemical deviations in the blood.
They decrease the stability of the nervous system to the pathogenic agent and thus
independent self-main-lained pathologic system is formed (vicious circle), which
desorganizes the activity of other systems. They were named as a cause of arterial
hypertension, thyreotoxicosis, stomach ulcer etc. All these examples are a stress with
negative emotions.
Manifestations
The manifestations of functional pathology of higher nervous activity are various but
first of all they include the psychic functions. We can see weakness of analitycal-
synthetical activity of the brain, disturbance of long-term and short-term memory,
disorders of the emotions and motivations.
As the frontal lobe of the brain cortex takes part in the management of the congenital
behavior reactions from positions of accumulated experience as well as in concordance
of the internal and external motivations, we can see such changes in the patient with
pathology of the frontal lobe - absence of motivation, steadfast plans and intentions based
on the prognosing with preservation of intellect; the patient becomes rude, tactless,
frivolous and irritable.
The frequent manifestation of pathology of the higher nervous activity is a
disturbance of a sleep-waking cycles, regulation of the vegetative and somatic functions
(rhythm of the cardiac contractions, regulation of the arterial blood pressure and
trophicity of the skin).
In experiment on animals these disturbances are manifested in ЀЀЀЀЀЀЀ, sexual
behavior, and they are mostly investigated in experiment for characteristics of higher
nervous activity.
Neurosis
Neurosis is a typical form of the disturbances of function of the higher nervous system,
which arises as a result of overstrains and breakdown of higher nervous activity. The
pathogenetic base of the neurosis lies in the disturbance of the main nervous processes such
as excitation and inhibition namely their strength and balance. The neuroses have such
characteristics as the disturbance of high nervous activity, vegetative regulation,
movements, and nervous trophicity as well as decrease of general resistance of the
organism.
Neurosis is reproduced in experiment by several methods.
The overstraun of the excutatuve process is reproduced by using of a very strong
unconditioned stimulus ( intensive pain, strong sound), long or repeated action of the
stimulus, simultaneous action of some different, strong or non-ordinary stimuli (conditioned
and unconditioned). Continuous, non-adequate agitation, aggressiveness and anger of the
animal manifest this neurosis.
18
The overstraun of the unhubutuon process is reproduced by increase of the time of
ЀЀЀЀЀЀЀЀЀ of dynamic stereotype differentiation. The development of passive protective
reactions, depression and drowsiness of the animal characterize this neurosis.
The overstraun of mobuluty of the nervous process is achieved by the disturbance of the
dynamic stereotype (the electric current at the moment of eating).
The modern tendencies of working out of the methods of experimental reproduction of
neuroses are directed at the maximal approach of the model with the human neuroses.
These methods are: the limitation of "reflex of freedom" (forced fixation of the animal in the
apparatus), disturbances of daily meal regimen, light rhythm due to changes of day and
night, high level of behavior motivations (strong feeling of hunger), preliminary
asthenization of the nervous system under the action of chronic noise, ionizing radiation as
well as a large volume of information by combination of these factors.
As in any other pathology, we can see the development of the compensatory reactions -
the animals make their problem easier and stop reacting to one of the signals if there are
several, inhibition, which protect the central nervous system. The phase of the protective
inhibition follows the phase of excitation.
The determination of ultrastructural and neurochemical changes in the animal brain
in experimental neurosis leads to supposition that neuroses have structural basic. The
method of electron microscopy established the destructive changes in the neuronal and
glial elements of the neocortex, reversible and irreversible disturbances of the
neuromediator system. And we can say that any pathology has the structural changes,
which we can determine by the adequate methods of its investigation.
19
20
Иллюстрации
Глава 01 Нозология
__________________________________________________________________________________
A.A.Bogomoletz (портрет на c.19 украинского учебника)

__________________________________________________________________________________
Disease as a phylosophical обобщение
Disease as a typical pathological process
Disease as a nosological form
Disease in a concrete patient (diagnosis)
Fig.1. Relationship between abstractive and concrete in a disease (Мал. 1 с. 27 украинского учебника)
__________________________________________________________________________________
Scheme 1. Correlation between causa and conditio in etiology
ETIOLOGY
Etiological factors Conditions

(Latin - causa)
+
(Latin - conditio)
Exogenous Endogenous Promote a Prevent a

(external) (internal) disease disease
development development
(risk factors)
Physical
Chemical
Biological
________________________________________________________________________
1
_______________________________________________________________________
Scheme 2. Variants of cause-consequence relations
. Infection
Chronic non-infectious disease
Нужно сделать круг из 5-6 стрелок – информация для художника
Etiological factor
Radiation disease
Anaphylactic shock
___________________________________________________________________________
Глава 02 Факторы
_________________________________________________________________________________
Scheme 3. Mechanisms of damage and restoration of DNA during ionizing radiation

Factors, which modify and restore a damage (Схема 1 с.57 украинского учебника)
2
Factors which damage DNA during irradiation
Direct effect Indirect effect
X-rays products of water radiolysis
γ-quantums primary radiotoxins
α-, β-particles peroxydes
activated DNA-ase
Factors, which modify a damage of DNA

Chemical radiopotectors
Active forms of oxygen
Precursors of radiotoxins
Intensivity of metabolism
Cellular radiant effects

Mutations
Chromosomal aberrations
Интерфазная гибель или during division
stopping of development
suppression of synthesis of DNA, RNA, proteins, enzymes
Factors of restoration
Enzymes, which отщепляют damaged участок
DNA-polymerase
Natiral radioprotectors – перехватчики of radicals
Перехватчики of radiotoxins
В центре – DNA
_______________________________________________________________________________
Глава 03 Генетика
_______________________________________________________________________________
1. Recognition
2. Crossing перерезывание of damaged DNA endonuclease
3. …расщепление exonuclease
4. Father ….. расщепление exonuclease
5. Syntesis of normal DNA polimerase
6. Соединение of a new DNA fragment ligase
Fig. 2. Restoration of damaged DNA by ferments of reparation (Мал.3 с. 60 украинского учебника)

_______________________________________________________________________________
________________________________________________________________________________
Fig. 3. Chromosomal mutations (Мал. 4 с.97 украинского учебника)
A - quantitative disorders: a) karyotype (XXXYY) of a sick man (Kleinfelter syndrome); b) karyotype (XXX) of a sick woman (X-
trisomia).
B – structural disorders: 1- deletion, 2- chromosomal ассоциат, 3-circle-lyke chromosome.
____________________________________________________________________
3
___________________________________________________________________________________________
Fig. 4. Classification of constitution by Sigau (Мал. 5 с. 106 украинского учебника)
a – respiratory, b – digestive, c – muscular, d – cerebral
__________________________________________________________________________________
Fig. 5. Classification of constitution by Kretschmer (Мал. 6 с. 106 украинского учебника)

a – asthenic, b – athletic, c - picnic
__________________________________________________________________________________
Глава 04. Реактивность
_____________________________________________________________________________
Macrophage
Endotheliocyte of the liver → proteins
Hypothalamus cell → fever
T-lymphocyte → IL-2
B-lymphocyte → antibodies
Fibroblast → proliferation
Bone marrow → granulocytosis
Fig.6. Interleukin-1 and its effects (Мал. 23 с. 232 украинского учебника)

In a center of a figure is a macrophage, which after activation produces IL-1.
The letter influences its target-cells – bone marrow, liver,
hypothalamus, lymphocytes, fibroblasts
___________________________________________________________________________________
4
_____________________________________________________________________________
Scheme 4. Scheme of plasmatic kinins (со с. 238 украинского учебника)
Hageman factor
Tripsin
Kalikrein
Fibrinolisin
Activation of Activation of Activation of

coagulation prekalikrein fibrinolytic
system
Fibrin Fibrinolisin
Prekalikrein Kalikrein
Kininogen Kinin
(bradikinin)
Kininase
Activated
peptids
__________________________________________________________________________________
Глава 05. Иммунитет

________________________________________________________________________________
5
Scheme 5. Forms of Immunological Reactivity (IR) Pathology
IMMUNOLOGICAL REACTIVITY (IR)
Decreased IR Increased and Loss of physiological

(hypofunction) qualitatively changed IR immunoogical
(hyperfunction and tolerance
dysfunction)
Immunodepression Allergy Autoimmune aggression

Immunodeficiency (autoallergy)
6
Глава 06 Аллергия
__________________________________________________________________________________
Scheme 6. Classification of the allergens (со с. 156 украинского учебника)
Allergens
Exogenous Endogenous
Bacterial Vegetable Natural Aquired
Brain Non- Infectious

Bacterias Medical infectious
Fungi Food Crystalline

lens
Xолодовые Simple Complexed
Viruses Domestic Sex glands

Oжоговые Tissue+microbe
Simple Thyreoid
chemical gland лучевые
Tissue+toxin
substances
__________________________________________________________________________________________________
Scheme 7. Formation of the BAS in allergy (Схема со с. 165 украинского учебника)

T-lymphocytes+antigen – limphokins
Hageman factor activtion, blood proteolytic ferments activtion, trypsin, kalikrein, fibrinolisin, kalidinogen, bradikininogen, α2-globulin
of the blood, bradikinin, kalidin
Complex antigen+antibody
Complement activation, lysis of cells and release of intracellular components
Increase of the blood acetilcholin content, phagocytosis activation and lisosome factors,
Basophilic granulocytes, thrombocytes, basophiles degranulation,
Histamine, serotonin, heparin
POL
Lipoxygenase, cicloxygenase,
Leukotriens, SRS, prostaglandins, thromboxans
___________________________________________________________________________________
7
Глава 07 Циркуляция
___________________________________________________________________________________
Fig. 7. Claude Bernard experiment

(in the right – a cervical node of the sympathetic trunk is resected) (Мал. 15 с. 199 украинского издания учебника
_________________________________________________________________________________
Blood pressure in kPa
Arterial hyperemia
normal
Fig. 8. Blood pressure dynamics in different parts of the vascular bed in norm and in arterial hyperemia (Мал. 14 с. 197 украинского
учебника)
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Глава 08 Воспаление
______________________________________________________________________________
Fig.9. Cardinal sings of inflammation by Celsus and Galenus (Мал. 21 с. 228 украинского учебника )
_______________________________________________________________________________
Flogogen agent action

Alteration
Exudation
prolifiration
Fig. 10. Schematic figure of order and level of the stages of the inflammation.
It is shown that every new stage as is born in the previous one (Мал. 22 с. 230 украинского учебника)
___________________________________________________________________________________
Fig. 11. An inflammation of a frog mesenterium (Мал. 24 с. 240 украинского учебника)

1- leukocytes which emigrated, 2- emigration of the leukocytes, 3- erythrocytes in the tissue
__________________________________________________________________________________
Fig. 12. Inflammation of the fabbit,s yea. At the bottom of the anterior camera a purulent exudate
is present (Мал. 25 с. 241 украинского учебника)
___________________________________________________________________________________
8
Глава 09 Лихорадка
_____________________________________________________________________
Hours, days
Fig.13. Critical (A) and lytic (B) decrease of body temperature in the third stage of a fever (Мал. 30 с. 264 украинского учебника)
_____________________________________________________________________
Days of a disease
Stages of a fever
Body temperature
Pulsus
Respration
Diuresis
Muscle trembling
Fig. 14. Changes of pulsus, respiration, diuresis in different stages of a fever (Мал. 29 с. 264 украинского учебника )
__________________________________________________________________________________
Respiration per minute

Pulsus
Days of the disease
Temperature
Pulsus per minute
respiration per minute
Fig.15. Dynamics of body temperature, pulsus and respiration in febris continua (crupous pneumonia) (Мал. 33 с. 266 украинского
учебника )
___________________________________________________________________________________
days
Fig.16. Dynamics of body temperature curve in patients with malaria (Мал. 31 с. 265 украинского)
___________________________________________________________________________________
9
___________________________________________________________________________________
Pulsus per minute
Days of the disease
Temperature
pulsus
Fig. 17. Dynamics of body temperature and pulsus curves in patients with reccurent typhus (Мал. 32 с. 265 украинского)
___________________________________________________________________________________
Глава 11 Гипоксия
___________________________________________________________________________
Fig. 18. Changes of a curve of oxyhemoglobin dissociation (a, b, c) in a process of adaptation to hypoxia (Мал. 37 с. 318
___________________________________________________________________________
norm, adaptation
capillaries
erythrocytes,
mitochondrias
myoglobin
Fig.18. Tissue mechanisms of adaptation to hypoxia (Мал. 38 с. 319 украинского учебника)
___________________________________________________________________________
10
Scheme 8. Mechanisms of adaptation to hypoxia (Схема 12 с. 320 украинского учебника)
HIF-factor
Decreased ATP Deficit of ATP, Activation of the genetic

Hypoxia production in disorder of the vital cellular apparatus
mitochondrias activity
Increase of activity of Increase of mitochondria

the mitochondrial genesis
system on the mass
Liquidation of ATP
unit
deficit and disorders
of the vital activity –
adaptation
Growth of the cell, Increase of all cellular

normaliztion of IFS structures biogenesis
and use of ATP
Глава 12 Голодание
______________________________________________________________
lipid depot 97%, lean 60%, liver 53,7%,testis 40%, muscles 30,7%,blood 26%, kidneys 25,9%, skin 20,6%, intestinum
18%, lungs 17,7%, pancreas 17%, bones 13,9%, nervous tisue 3,9%, heart 3,6%
Fig. 20. Degree of mass loss of organs and tissues in complete starvation (Мал.36 с. 304 украинского учебника)
__________________________________________________________________________
11
Глава 13 Энергия
Scheme 9. Causes, mechanisms and consequences of increase of energy production
↑ Energy production
positive negative As a result of

As a disorder of
defensive Significance metabolism
reaction regulation
↑ Calories of ↑ ATP
heat
↑ secretion of
catabolic
Causes hormones
↑ of oxidation Toxic effect

Activation of of uncoupling
thermo- substances
Mechanisms
regulation ↑ of coupling
of oxidation
and
phosphorilation
↑ of oxidation
↑ Heat
production
↓ of heat
↑ Heat
emission Results emission
Uncoupling of
oxidation and Exhaustion of
phosphorilation nervous and
endocrine
systems
↑ Plastic
processes
Maintenance
of body t° ↑ Growth
in cold
Results
Pregnancy
↑ of body t°
in fever Prolonged
adaptarion
12
Scheme 10. Causes, mechanisms and consequences of decrease of energy production
↓ Energy production
↓ Calories of ↓ ATP
heat
Mechanisms
↓ Substrates
↓ O2
↓ Enzymes
Damage of
mitochondrias
↓Catabolic
hormones
↓ Synthesis of
proteins,
neuromediators,
hormones,
↓ body t° DNA,RNA,
phospholipids etc
↓ Adaptation
to cold ↓Cell division,
Consequences plastic processes
Fever does growth,
regeneration
not develop
Insufficiency of
compensatory
reactions
13
Глава 14 Углеводный обмена
________________________________________________________________________
glycemia, hypo- heper-
β-endorinicytes of pancreatic islands
insulin
glucagon cortisone adrenaline somatotropin
1. α–Endocrinocytes of pancreatic islands
2. adrenal cortex
3. medullar part of adrenal gland
4. adenohypophisis
Fig. 21. Normal regulation of carbohydrate metabolism and correlation between

insulin and hormones-antagonists (Мал. 40. с. 332 украинского учебника)
_______________________________________________________________________________
_______________________________________________________________________________________
Permeability of the cellular

membranes
Rate of hexokinase reaction
Synthesis of ferments of
glycolysis
Insulin Antagonists
of insulin
Synthesis of ferments of
gluconeogenesis
Formation of g-6-phosphate
Activation Suppression
Scheme 11. Influence of insulin and its antagonists on glucose metabolism in the cell (Мал. 39 с 331 украинского учебника)
______________________________________________________________________________
14
glucose of the blood in mmol/l
hours
Fig. 22. Curves that reflect the results of loading by glucose in healthy person (A), in a case of decreased tolerance to glucose (B), in
case of diabetes mellitus (C)
(Мал. 41 с. 333 украинского учебника)
_______________________________________________________________________________
15
Scheme 12. Etiology and pathogenesis of IDDM
Genetic predisposition
connected with HLA-system antigenes
β-Tropic virusis β-Tropic

chemical substances
Damage of β-cells
Macrophages
IL-1 T-helpers
Autoimmune aggression
against β-cells
Activation
NN
Macrophages T-helpers T-effectors NK Lymphocytes
Production
Antibodies Lymphokins (factor of necrosis) γ-Interferon PG
Destruction of β-cells
Absolute insulin insufficiency
16
Глава 15 Жировой обмен
__________________________________________________________________________
парасимпатична система - parasympathetic system

жирова тканина - adipose tissue
глікокортикоіди - lucocorticoids
НЕЖК - NELA
Інсулін - insulin
Утворення глюкози в печінці - formation of glucose in liver
Жиромобілізуюча субстанція гіпофіза - lipid-mobilizating substance of hypophisis
Симпатична система - sympathetic system
Соматотропін - somatotropin
Тироксин - thyroxinglucagon
Стероїди - steroids
Катехоламіни - catecholamins
НЕЖК -NELA
Глюкагон -glucagon
Fig.23. Neurohumoral regulation of lipid metabolism: factors stimulating deposition (A) and mobilization (B) of lipids (Мал. 42 с
348 украинского учебника)
_______________________________________________________________________________
_____________________________________________________________________
адреналін - Adrenaline
ліполіз - Lipolysis
ВЖК - Free……
ЖК -
Ац-КоА - Ac-CoA
Ліпогенез - Lipogenesis
Глі - Gly
Глю -Glu
Інсулін -Insulin
Fig.24. Insulin and adrenaline effect on lipogenesis and lipolysis in lipocyte in norm (A) and in obesity (B) (Мал. 43 с 349 ураинского
учебника)
F?A – free жирные acids, ??? – жирные acids, Tr – three-glicerids, Glu – glucose, Gli – glycerin, X – lipogenesis, Y - lipolysis
17
Scheme 13. Connection between obesity, diabetes mellitus, atherosclerosis, arterial hypertension, thrombosis and myocardium infarctus
Genetic predisposition (not connected with HLA-system antigen)
Excessive use of food Disorder of secretion of enkephalin, endorphins,

PG, hormones of digestion
Hyperglycemia
Deficit of Decrease of
Hyperinsulinemia heparin insulin
secretion
Obesity
Thrombosis
Decrease of
amount of
receptors to
insulin
Myocardial
Atherosclerosis infarctus
Insulin
Insulin resis
resistance
Arterial
Relative hypertension
insulin
insufficiency
Diabetes
mellitus
Disorder of
β-cells function
Absolute
Exhaustion of insulin
β-cells insufficiency
18
Глава 16 Белковый обмен
Scheme14 . Disorder of aminoacids transformation
Desamination
СО2
кетокислоты
-NH3
Н2О
Hypoxia
Aminoacids
-CO2
Hyperthyreosis
Hypercotitism
Amins NH3
Decarboxylation
19
Схема 15. Synthesis of melanin and catecholamin in albinism
Тирозин
In
In adrenal cortex melanocytes
тирозиназа
Диоксифени
Диоксифени лаланин
лаланин (ДОФА)
(ДОФА)
ДОФ-амин ДОФА-
хинон
Норадреналин
ДОФА-хром
Adrenaline
Меlanin
20
Scheme 16. Blockade of phenilalanin metabolism
Фенилаланин-4-
гидроксилаза
Фенилаланин Тирозин
Фенилпировиноградная
кислота
Фениллактат Фенилуксусная
кислота
21
Глава 17 Рн
Scheme 17. Acidogenesis in the kidney
Blood Renal tubular cells Urine

CO2_________________________________ CO2 + H2O
↓ Carbohydrase
H2CO3
HCO2- _________________ HCO3- H+__________________H+

Na+ _________________________ Na+ ___________________________Na+
Scheme 18. Ammoniogenesis in the kydney
Glutamin
-NH3
Glutamin___________________________ ________________ NH3 + H+ NH4
Glutamin acid + Cl- NH4Cl
- NH3
________________ NH3 + H+ NH4
α-ketoglutaric acid
22
Scheme 19. Hydrocarbonate reabsorption in the kidney
NaHCO3
+ + +
Na Na Na
HCO3-
H2CO3
- + +
HCO3 H H
H2CO3
H2O + CO2 CO2 H2O
Глава 18 Вода
_______________________________________________________________________
Fig. 25. Mechanism of edema development in the case of change of hydrosratic (A) and oncotic (B) pressure (by Starling)
A – hydrostatic and B – oncotic pressure.
1 – arterial part of capillary flow (fluid leaves the vessel),
2 – zone of balance,
3 – venous part of capillary flow (fluid enters the blood from the tissue)
_________ normal level of pressures
------------------ a) increase of hydrostatic pressure, b) decrease of oncotic pressure in pathology
Мал. 47. с 379 украинского учебника
__________________________________________________________________
Volume of extracellular fluid, l
Pressure of extracellular fluid, kPa
Fig. 26. Dependence of volume of free (1) and fixed (2) extracellular fluid from its pressure Мал. 48. С 383 украинского
учебника
23
Глава 19 Объем крови
Стовбурова кровотворна клітина - Steam hemopoietic cell

Клітина - попередниця лімфопоезу – Cell-pecorsure of lymphopoiesis
Клітина – попередниця мієлопоезу – Cell-pecorsure of myelopoiesis
Клітина – попередниця Т-лімфоцитів – Cell-precorsure of T-lymphocytes
Клітина – попередниця В-лімфоцитів - Cell-precorsure of B-lymphocytes
Колонієутворювальні одиниці в культурі клітин -
Т-лімфобласт – T-lymphoblast
В-лімфобласт - B-lymphoblast
Плазмобласт - Plasmoblast
Монобласт - Monoblast
Базофільнй бласт – Basophilic blast
Мієлобласт - Myeloblast
Еозинофільний бласт – Eosinophilic blast
Еритробласт - Erythroblast
Мегакаріобласт - Megacarioblast
Т-пролімфоцит – T-prolymphocyte
В-пролімфоцит - B-prolymphocyte
Проплазмоцит - Proplasmocyte
Промоноцит - Promonocyte
Промієлоцити - Promyelocyte
Пронормоцит - Pronormocyte
Промегакаріоцит - Promegacariocyte
Міелоцити - Myelocyte
Метаміелоцити - Metamyelocyte
Паличкоядерні гранулоцити – Buton-like granulocytes
Нормобласт базофільний – Normoblast basophilic
Нормобласт поліхроматофільний - Normoblast polichromatophilic
Нормобласт ацидофільний – Normoblast acidophilic
Поліхроматофіл - polichromatophil
Ретикулоцит -Reticulocyte
Мегакаріоцит - Megacariocyte
Т-лімфоцит – T-lymphocyte
В-лімфоцит - B-lymphocyte
Плазмоцит - Plasmocyte
Сегментоядерні гранулоцити – Segmentonuclear granulocytes
бaзофільний - basophilic
нейтрофільний - neutrophilic
еозинофільний –eosinophilic
Еритроцит - Erythrocyte
Тромбоцит - Thrombocyte
Fig. 27. Scheme of hemopoiesis (by Воробьев 1981)

I – class of steam cells; II – class частично детерминированных полипотентных клеток; III – class унипотентных клеток ( cells
pecorsures of T-, B-lymphocytes, kолонієутворювальні одиниці - monocytic, granulocytic, erythrocytic, megacariocytic); IV – class
пролиферирующих cells (blasts);
V – class of the cells which дозревают; VI – class of mature cells
(Мал. I. Со цветной вкладки украинского учебника)
__________________________________________________________________________________
24
a b c a b c a b c
Normovolemia Hypovolemia Hypervolemia
Fig.28. Changes of the blood volume
a - simple
b - oligocytemic
c – policytemic
Blood cells Plasma
________________________________________________________________________________________________
Fig. 29. Mechanisms of compensation of a central blood circulation under an acute blood loss
___________________________________________________________________________________________
25
Fig. 30. Circulus viciosus in pathogenesis of hypovolemic (hemorrhage) shock
1
2
14
3
13
12
11
6
10
9 7
1 - ↓ of effective volume of circulating blood

2 – ↓ cardiac output
3 – acute circulative hypoxia
4 – disorder of central regulation of hemodynamic and respiration
5 – выброс of hormones, activation of sympatho-adrenal and hypothalamo-pituitary-adrenal cortex systems
6 - ↑ of peripheral vascular resistance
7 – production of BAS, «медиаторный взрыв»
8 - metabolic напряжение, then истощение
9 - tissue hypoxia
10 – acidosis
11 – electrolyte balance disorder
12 – disorder of microcirculation
13 – DIC-syndrome
14 – disfunction of organs
Для художника – Наружный круг – не круг, а последовательность 15 круглых стрелок с общим впечатлением круга. Квадратики
сделать кружочками с цифрами внутри. Внутренние круглые стрелки в таких направлениях -
Со 2 на 1
С 3 на 2
С 4 на 3, 2, 1
С 5 на 4
С 6 на 1, 2,
С 7 на 6, 4, 2, 1
С 8 на 2, 7 (на рисунке я ошиблась, направила на 6 а не на 7, но исправить не умею)
С 9 на 2, 4, 7
С 10 на 9, 7, 4, 2
С 11 на 10, 9, 4, 2
С12 на 1, 2, 3, 9, 10
С13 на 12,
26
С 14 на 2, 4, 9, 11
Для художника : Все стрелки возможно не поместятся, не страшно, надо от каждого пункта по 1-2-3 чтобы создавалось
впечатление внутренних обратных связей и не было бы каши.
Глава 20 Анемия
______________________________________________________________
Для художника приведены украинские слова из оригинала
Клітини фізіологічної регенерації Cells of physiological regeneration

Дегенеративні зміни еритроцитів Degenerative changes of erythrocytes
Клітини патологічної регенерації Cells of pathological regeneration
Ретикулоцити (суправітальне забарвлення) Reticulocytes (supravital забарвлення)
Поліхроматофільні еритроцити (забарвлення за Романовським) Polichromatophilic erythrocytes (забарвлення за Романовським)
Нормобласти, еритробласти Normoblasts, erythroblasts
Зміна розміру (анізоцитоз) Change in size (anisocytosis)
Зміна форми (пойкілоцитоз) Change in form (poikilocytosis)
Зміна забарвлення Change of забарвлення
Патологічні включення Pathological inclusions
Мегалобласти й мегалоцити Megaloblasts and megalocytes
Fig. 31. Morphological changes of erythrocytes (Мал. II на цветной вкладке украинского учебника)
1 – еритроцит erythrocyte;
2 –ретикулоцит reticulocyte,
3 – поліхроматофіл polichromatophil,
4 –еритробласт erythroblast,
5 –базофільний нормобласт basophilic normoblast,
6 –поліхроматофільний нормобласт polichromatophilic normoblast,
7 –ацидофільний нормобласт acidophilic normoblast,
8 – нормоцит (середній діаметр 7,2 мкм) normocyte (average diameter 7,2 mkm)
9 – мікроцит (d - менше 6,5 мкм); microcyte (d –less then 6,5 mkm),
10 –макроцит (d -8 мкм і більше); macrocyte (d - 8mkm and more),
11 –мікросфероцит; microspherocyte,
12 –серпоподібний еритроцит (дрепаноцит); sickle-shaped erythrocyte (drepanocyte),
13 –нормохромний еритроцит; normochromic erythrocyte,
14 –анулоцит; anulocyte,
15 –гіпохромний еритроцит; hypochromic erythrocyte,
16 –гіперхромний еритроцит; hyperchromic erythrocyte,
17 –базофільна зернистість;basophilic зернистість,
18 –кільце Кебота;
19 –тільце Жоллі;
20 –мегалоцит; megalocyte,
21 –поліхроматофільний мегалобласт; polichromatophilic megaloblast,
22 –ацидофільний мегалобласт acidophilic megaloblast.
______________________________________________________________
27
Scheme 20. Pathogenesis of disorders in intravascular hemolysis
Hemolisin
(etiological factor)
Erythrocytes
Hemoglobin
Hb +
haptoglobin
Kidneys Macrophages Erythropoietin
Indirect bilirubin Bone marrow
Hemoglobinuria
Jaundice Stimulation of
erythropoiesis
____________________________________________________________________________
Scheme 21. Pathogenesis of disorders in intraceccular hemolysis
Genetically defective erythrocytes
Macrophages (phagocytosis)
Proliferation of Indirect Erythropoietin

macrophages bilirubin
Splenomegaly Jaundice Stimulation of

erythropoiesis
28
Глава 21 Лейкоциты
________________________________________________________
Fig 32. Degenerative changes of leukocytes

1- toxical зернистость
2- vacuolization of nucleus and cytoplasm
3 –тельца Князькова
4 – пульгеровская аномалия
5 –hypersegmentation of nucleus
6 - anisocytosis
____________________________________________________________
Глава 22. Лейкоз Leukemia

___________________________________________________________________________
Fig. 33. Blood picture in acute myeloleukemia

1 - myeloblasts
Мал. IV Со цветной вкладки украинского учебника
______________________________________________________________
Fig. 34. Blood picture in chronic myeloleukemia
1 –myeloblast
2 – promyelocyte
3 –neutrophilic myelocyte
4 –neutrophilic metamyelocyte
5 –baton-like? stab? neutrophile granulocyte
6 –segmentonuclear neutrophile granulocyte
7 –eosinophile myelocyte
8 – eosinophile granulocyte
9 – basophile granulocyte
10 – lymphocyte
Мал. V со цветной вкладки украинского учебника

__________________________________________________-
_____________________________________________________________
Fig. 35. Blood picture in chronic lympholeukemia
1 –lymphocyte
2 –large lymphocyte
3 –lymphoblast
4 – тени Гумпрехта
Мал. VI со цветной вкладки украинского учебника
29
Глава 24 Сердце
Inflow of the blood to heart Resistance to blood ouflow

A B
Fig. 37. Dependance зависимость между minute cardiac volume (V) and its work (W) in heterometric (A) and homeometric (B)
mechanisms of compensation (rate of contractions is constant):
a, b – low and upper levels of blood volume which income, and resistance to its оттоку, за которыми компенсация не совершается
Тривалість серцевого циклу, с- Duration of cardiac cycle, sec.

Частота скорочень серця, уд./ хв. - Rate of heartbeats, …/min
Systole Diastole
Fig. 38. Change of duration of cardiac cycle, systole and diastole in different rate of heartbeats.
Штрихом a systole of atriums is noted
____________________________________________________________
М,язове волокно - Muscle fiber

Капілярна судина - Capillar vessel
Нервове волокно - Nervous feber
Fig. 39. Correlation between muscle fibers, capillaries and nervous of the heart in a newborn (a,г), healthy adult (б, д, heart mass 310 g)
and adult with hypertrophied myocardium (в, е, heart mass 540 g)
________________________________________________________________
Fig. 40. Movement of a wave of an excitement via myocardium in norm (a) and in flutter

_______________________________________________________________
30
Глава 25. Сосуды
____________________________________________________________________
Pump
Vessels of котла
Capillaries – vessels of обмена
Postcapillar vessels of resistance
емкостные сосуды
Sfincters
Venous part
Fig. 41. Differentiation of vascular system parts upon function and change of the pressure via vessel русла Мал. 58 с 464 украинского
_______________________________________________________________________
Захворюваність на атеросклероз
Человек - Внешняя среда
Хвороби обміну речовин Diseases of metabolism
Артеріальна гіпертунзія Arterial blood hypertension
Гіподінамія Hypodinamia
Стрес Stres
Інтоксикація Intoxication
Надмірне харчування
Стать Sex
Генетичні фактори Genetic factors
Вік, роки Age, years
Fig. 42. Dependence of atherosclerosis development from different factors Мал. 59 с 466 украинского
Fig. 43. Prostagladins effect on arterial blood pressure in essential hypertension (A) and in norm (B) (a pointer notes a moment of
injection) Мал. 61 с 484 украинского
_________________________________________________________________
стеноз ниркової артерії Stenosis of renal artery
гіпертрофія і гіперплазія юкстагломерулярного апарату Hyperthrophy and hyperplasia of юкстагломерулярного апарату
зниження депресорної фyнціi нирок Decrease of renal function
порушення внутрішньониркового кровотоку disorder of intrarenal blood circulation
гіперсекреція реніну Renin hypersecretion
збільення утворення ангіотензіну II Increase production of angionensin II
гіперсекреція альдостерону Hypersecretion of aldosterone
зміни секреції катехоламінів Changes in catecholamine secretion
підвищення реактивності судин і периферичного опору increase of vessel reactivity and peripheral resistance
гіпертензія Hypertension
Для художника дан текст украинского рисунка
Fig. 44. Pathogenesis of the renal arterial blood hypertension Мал. 60 с. 483 украинского
__________________________________________________________________
31
Схемы для главы 25
Scheme 22. Mechanisms of vasopressive effect of angiotensin II
Angionensinogen
Angionensin I
Angionensin II
Stimulation Disorder of Activation of Activation of Increase of Stimulation

of growth endothelial pressive factors sympathethic bradikinin of
factors function (endothelin-1) effects instraction aldosterone
(deficit of secretion
NO)
Vasoconstriction
Hyperthrophy
of vessel wall Retension of
Na and water
Increase of arterial pressure
32
Scheme 23.
Sympathetic regulation of heart and vessels
β1 α β2 Renal
юкстагломерулярный
↑ Rate of cardiac ↑ R ↓R аппарат
contractions
↑ Systolic volume Peripheral
vessel
resistance
↑ Сердечный выброс ↑Q Renin
ACE
Angiotensinogen Angionensin I Angionensin II Aldosteron Na ↑
33
Глава 26 Дыхание
Scheme 24
Respiratory Insufficiency
Ventilative Diffusive Perfusive Combined
Result of Result of
Disregulative systemic local disorder
disorder of of blood
blood circulation
Obstructive circulation
Restrictiv
Compressive e
Occlusive
Extrapulmonary Pulmonary
Spasmatic
_______________________________________________________________________
Форсований видих
Форсований вдих
Максимальна легенева вентиляція
Художнику! Вместо а б в г – a b c d
Fig. 45. Spirogrames of a healthy men (a), in pneumosclerosis (b), bronchial asthma (c) and lung emphisema (d)
ЗЄЛ – загальна ємність легень
ЖЄЛ – життєва ємність легень
РО – резервний об,єм вдиху
РО - резервний об,єм видиху
ЗО – залишковий об,єм
34
_______________________________________________________________________________
1- normal соотношение of capillaries and alveoli
2 - утолщение of alveoli wall
3 - утолщение of capillaties wall
4 – intraalveolar edema
5 – interstitial edema
6 – расширение of capillaries
Fig. 46. Causes of diffusive disorders

O2 concentration
Fig. 47. Local ventilative and perfusive relations in the lungs and their influence on bled oxygenation
V A – alveolar ventilation, Q – blood amount which flows via pulmonary vessels per minute
__________________________________________________________________
Fig. 48. Periodical breathing of Cheyne-Stokes type

a) in a cat after acute blood loss (by J.Britvan, 1966) Мал. 62 с 494 украинского
b) in rats while experimental hypoxic hypoxia (by N. Simeonova, 1962).
___________________________________________________________________
Fig. 49. Periodical breathing of Biot type in experimental animal after cutting of мозгового ствола на уровне моста (by J. Britvan,
1966)

_____________________________________________________________________
35
Глава 27 Пищеварение
_________________________________________________________________
Художнику! Вместо а б в г abcd
Fig.50. Forms of stomach depending from its tonus

a –hypertonic , b – normotonic , c – hypotonic, d - аtonic
__________________________________________________________________
____________________________________________________________
Fig. 51. Types of gastric secretion
_________________________________________________________
Fig. 52. A number (%) of parietal cells in gastric mucosa

1 – 100, 2 – 75, 3 – 50, 4 – 0-1
___________________________________________________________________________________________
Fig. 53. Localization of stomach ulcer

Мал. 69 с 522
36
____________________________________________________________________________
Scheme 22 Inflammation of Pancreas (Acute Pancreatitis)
Etiological factor
Increase of Disorder of
pancreatic juice pancreatic juice Primary alteration
secretion outflow
Disorder of microcirculation, Release of lisosomal

Reflux of bile or hyperemia enzymes,
duodenum content BAS production
(enterokinase)
Edema
↑ of pressure in
pancreatic duct
Lipase Phospholipase A Intraorgan передчасна Elastase

activation activation tripsin activation activation
Entrance of Damage of
pancreatic juice into vessels.
parenchima Hemorrhage
Secondary alteration
Necrosis of
adupose tissue Pancreonecrosis
(autolysis)
Entrance of active
tripsin into the blood
Involvement of
mesenterium
Activation of kalikrein-
kinin system
Bradykinin
Pain
Loss of plasma
Pancreatic shock
37
Глава 28 Печень
Нижня порожниста вена v. cava inferior

Печінка liver
Ворітна вена v. porta
колатералі collaterals
Художнику! Вместо а б в -a b c
Fig. 54. Modeling of vascular fistules

A a – before operation, b – direct fistule (Ekk), c - reversed fistule (Ekk-Pavlov)
Мал.70 с 538 украинского учебника
Глава 29 Почки
Швидкість клубочкової фільтації (ШКФ) Rate of glomerular filtration (RGF)

Нирковий плазматік (НПТ) Renal plasma flow (RPF)
Артериальний тиск, кПа Arterial blood pressure kPa
НПТ, мл/хв.г RPF, ml/min.h
ШКФ, мл/хв.г RGF, ml/min.h
Fig. 55. Correlation between rate of glomerular filtration (RGF) and renal plasma flow (RPF) from arterial blood pressure
__________________________________________________________________
Глава 30 Эндокринная система

____________________________________________________________________________
Fig. 56. Regulation of hormonal balance in norm (a) and in disorder of reversed connections (b – in a case of decrease, c – increase if
hypothalamus excitability)
1 –hypothalamus, 2 – pituitary gland, 3 - peripheral endocrine gland, H – hormone of peripheral gland, RH – releasing-hormone, TH –
tropic hormone of pituitary gland
______________________________________________________________________________
38
Fig 57. Mechanisms regulating aldosterone secretion
_________________________________________________________________________-
stressor
alarm
reaction resistance
exhaution
antishock
shock
ooo ooo oooooooo o

ooooo
ooo
Fig. 58. Stages of stress and an amount of hormons of adrenal cortex
39
_____________________________________________
Глава 31 Нервная система
Fig. 59. Throphical ulcer of cornea after cutting of n.trigemini

Мал. 85 с. 648 украинского
______________________________________________________________
40

PathPhysio BNMU

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PREFACE

The Pathophysiology Department of Bogomolets National Medical University is the

Chapter 1. SUBJECT, METHOD AND AIM OF PATHOPHYSIOLOGY. THE GENERAL

Chapter 2. PATHOGENIC EFFECT OF ENVIRONMENTAL FACTORS

Chapter 3. THE ROLE OF HEREDITY AND CONSTITUTION IN PATHOLOGY

Chapter 4. REACTIVITY AND RESISTANCE OF ORGANISM

Chapter 5. IMMUNOLOGICAL REACTIVITY AND ITS PATHOLOGY

Chapter 6. PATHOLOGY OF IMMUNOLOGICAL REACTIVITY (Continuation). ALLERGY

Chapter 7. PATHOPHYSIOLOGY OF THE PERIPHERAL BLOOD CIRCULATION

Chapter 10. TYPICAL DISORDERS OF METABOLISM.

Chapter 11. TYPICAL DISORDERS OF METABOLISM (Continuation).

Chapter 12. TYPICAL DISORDERS OF METABOLISM (Continuation).

Chapter 13. TYPICAL DISORDERS OF METABOLISM (Continuation).

Chapter 14. TYPICAL DISORDERS OF METABOLISM (Continuation).

Chapter 16. TYPICAL DISORDERS OF METABOLISM (Continuation).

Chapter 17. STARVATION

Chapter 18. FEVER

THE SECOND PART. PATHOPHYSIOLOGY OF ORGAN SYSTEMS

Chapter 20. PATHOPHYSIOLOGY OF BLOOD SYSTEM (Continuation).

Chapter 21. PATHOPHYSIOLOGY OF BLOOD SYSTEM (Continuation).

Chapter 22. PATHOPHYSIOLOGY OF BLOOD SYSTEM (Continuation).

Chapter 23. PATHOLOGY OF BLOOD COAGULATION

Chapter 24. PATHOPHYSIOLOGY OF HEART

Chapter 25. PATHOPHYSIOLOGY OF VESSELS

Chapter 27. HYPOXIA

Chapter 28. PATHOPHYSIOLOGY OF DIGESTIVE SYSTEM

Chapter 29. PATHOPHYSIOLOGY OF THE LIVER

Chapter 30. PATHOPHYSIOLOGY OF THE KIDNEYS

Chapter 31. PATHOPHYSIOLOGY OF THE ENDOCRINE SYSTEM

Chapter 32. PATHOPHYSIOLOGY OF THE NERVOUS SYSTEM

SUBJECT, METHOD AND AIM OF PATHOPHYSIOLOGY.

SUBJECT, AIM AND METHOD OF PATHOPHYSIOLOGY

Medical education is constructed in such a way, that at first the students

TWO PARTS OF PATHOPHYSIOLOGY

Pathophysiology is originated from medical discipline termed General

EXPERIMENT AS A BASIC main? METHOD OF PATHOPHYSIOLOGY

Method of any scientific discipline is a way of studying the problems it

A teaching about disease, or General Nosology (nosos in Greece –

Disease as a phylosophical обобщение

Fig.1. Relationship between abstractive and concrete in a disease ( Мал.1. с. 27

Disease is a unity of two opposite tendencies – damage and defense, which

Many diseases (infectious and some others) develops in such periods:

Each disease is manifested by subjective (patient’s complaints) and

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

Classification of Etiological Factors

Etiological factors are divided into exogenous (external) and endogenous

Role of Conditions in Development of a Disease

Analyzing etiology, it is necessary to take into consideration the

Etiological factors Conditions

Exogenous Endogenous Promote a Prevent a

Pathogenesis is the mechanisms of development and outcome of a

Scheme 2. Variants of cause-consequence relations

Chronic non-infectious disease

Нужно сделать круг из 5-6 стрелок – информация для художника

Usually a physician records patient’s complains, subjective and objective

PATHOGENIC EFFECT OF ENVIRONMENTAL FACTORS

PATHOGENIC EFFECT OF LOW TEMPERATURE

Hypothermia is a lowering of body temperature as a result of the whole body exposure

Etiological factor is a cold if a whole body is exposed to. Temperature of comfort is 18 o C.

Hypothermia develops in two stages - compensation and decompensation.

The stage of compensation is a period of hypothermia, when the self-defensive reactions

The stage of a decompensation is a period of hypothermia, when compensatory reactions are