Nina Simeonova

Pathologic Physiology

Part V

Kyiv–2008

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 CHAPTER 27

PATHOLOGY OF THE DIGESTIVE SYSTEM

The function of the digestive system provides the intake of food which are transformed
into simple chemical compounds to be absorbed and necessary for life maintenance and
supply of energy and plastic material.
Different sections of the digestive system are interconnected due to continuity of the
alimentary canal, common nervous and humoral mechanisms of regulation. This
interconnection is especially evident in pathology as the dysfunction of the section of the
digestive system brings about the impairment of others. The union of different organs of the
digestive system is manifested in substitutional (compensatory) possibilities of this system.
The pathology in digestive system include disoders of
 digestive channel, in turn it is subdiveded in to disorder of
 oral cavity,  stomach,  small intestine,  bowels,  digestive glands –
pancreas and liver.
DIGESTION IMPAIRMENT
IN THE ORAL CAVITY
Digestion impairment in the oral cavity may be connected with dysfunction of
 mastication, which occurs in case of injury or absence of teeth due to dental caries or
paradontosis,
 masticatory muscles due to paralysis (disease of the nervous system),
 tempora-mandibularis joints,
 salivary glands.
Besides alimentary function, the saliva plays a significant role of the media wetting the
teeth and the mucous membrane of the oral cavity and giving protective and trophic effect.
In the normal conditions 0.5-2 1 of the saliva is excreted per day. In pathology its amount
arise up to 6-7 1.
Hypersalivation is observed in stomatitis, gingivitis, pregnancy, pulpitis, parodontitis as
well as preparation of the teeth with a drilling machine.
As a result of saliva hypersecretion the following processes occur:
 Reduction of K + concentration in the saliva and increase of total
concentration of nonorganic components of the saliva.
 Neutralization of the gastric juice by basic pH of saliva and impairment of stomach
digestion.
 Dehydration and cachexia due to loss of a large amount of the saliva.

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 Hyposalivation (the reduction of the saliva secretion) is connected with infections
and feverish processes. The disturbances of salivation and microflora changes
promote dental calculus formation(calculus sialoadenitis).
There is severe systemic lesion of the salivary and lacrimal glands (Shegren's
syndrome), which is characterised by dryness of the mucous membrane of the oral
cavity, eyes and upper respiratory tracts.
Severe disorders of carbohydrate metabolism may appear due to hyposalivation. A
dysfunction of the glands of the stomach occurs. Glucose and fat do not stimulate
gastric acid secretion.

GENERAL CHARACTERISTICS OF STOMACH PATHOLOGY

Regulation of Gastric Functions

The neurogenic regulation is connected with trophicity of the gastroduodenal area.

In the anterior portion of the hypothalamus there are trophotropic centres which
influence metabolism. The main nerve of this system is the vagus whose branches go to the
stomach. In the vagus excitation neurotransmitter of the parasympathetic nervous system
(acetylcholine) is discharged. It influences the stomach as follows:
 Vagus is the main secretory nerve of the stomach. It stimulates the production of
hydrochloric acid and pepsin.
 Vagus effects on the circulation in the submucous layer of the stomach, i. e. acetylcholine
dilates the vessels of the submucous layer.
In the posterior portion of the hyphothalamus there are centres of the symphathetic
nervous system. It arranges its influence on the stomach through the sympathetic nervous
system. Excitation of this system leads to ejection of noradrenalin, which influences all cells
of the organism, the stomach in particular
It promotes contraction of the vessels and smooth muscles of the submucosa of the
stomach.
Noradrenalin effects the cell through the membrane adrenoreceptor.
Humoral Regulation. The intermediate portion of the hypothalamus realises the stress. Its
main parts are the hypothalamus-pituitary-adrenal glands. The hormones of the adrenal
glands cortex are glucocorticoids (hydrocortisone, cortizol, corticosteron).
They influence the gastric mucosa and cause inhibition of the discharge of the gastric
mucous by mucocytes (additional cells), intensify production of hydrochloric acid and
pepsin.
Glucocorticoids have a special effect on noradrenalin, the so-called permissible effect.
Digestion in the stomach is achieved with the aid of the digestive enzyme pepsin. Its
predecessor pepsinogen is activated by hydrochloric acid.
The secretory process is divided it into three phases — cephalic, gastric and
intestinal.

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 The сephalic phase is initiated by taste, smell, chewing and swallowing of food.
This phase is mediated by direct vagal stimulation of parietal cells but may also
involve vagal stimulation of gastrin release.
The gastric phase involves stimulation of mechanical and chemi cal receptors in the
gastric wall. The chemical stimuli, the most important of which are digested proteins
and aminoacids, induce the release of gastrin, the most potent mediator of acid
secretion. Fat and glucose in the stomach do not stimulate gastric acid secretion.
The intestinal phase is initiated when food containing digested proteins enter the
proximal small intestine.
Acethylcholine, gastrin and histamine stimulate the K +, H+, ATPase located on the
lamina surface of the parietal cells. They stimulate gastric secretion.
Histamin, acetylcholin and gastrin are the messengers of gastric secretion Via the
central nervous system they transmit the stimulating impulse to the nuclei of the vagus.
Then, the receptors of the cells, having received mechanical and chemical stimuli,
stimulate additional messengers — cyclic nucleotides stimulating parietal cells (HC1) and
main cells (pepsin) of the stomach.
The various secretory products, some of which are also present in the intramural
autonomic nerve terminals, act as chemical messengers and modulate normal digestive
functions by a combination of endocrine, paracrine and neurocrine mechanisms. Some of
them act as the С-cells of the thyroid, the chromaffin cells of the adrenal medulla, the
corticotrophs and melanotrophs of the pituitary gland and certain cells in the carotid
body, the bronchi, the hypothalamus, and the sympathetic ganglia.
A study of the gastric juice acidity is used for the characteristic of the functional state
of stomachic digestion. Stimulation of stomach with the aid of the histamine is achieved
for this. The dynamics of a change in the acidity of gastric juice is measured after
stimulation. Dynamics is expressed in form of curves.
There are four types of pathological gastric secretion - excited, asthenic, inert,
inhibited according to its dynemics. They have the following differences -
 The excitable type is characterized by gastric juice secretion increasing in the
mechanical and chemical stimuli.
 The astenic type is characterized by increasing gastric secretion in the mechanical
stimuli and reducing in the chemical one.
 The inertion type is characterized by reducing in the mechanical stimuli and
elevation under the chemical ones.
 The inhibition type is characterized by depression of both me chanical and
chemical stimuli.
At maximal secretory rates the intraluminal concentration of hydrogen ion in the
stomach is 3 million times greater than that of the blood and tissues.

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 All substances and mechanisms, which function in stomach, are divided into
stimulating (many of them are aggressive) and protective. Their ratio plays important
role in pathology of stomach.
Stimulative (and aggressive) factors are the following
 active pepsin
 hydrochloric acid
 nervous activity and stimulation,
 vagotonus,
 catecholamines (adrenaline, noradrenaline),
 glucocorticoids,
 gastrin.
Increased action of them can be aggressive and the factors of stomach damage.
Pathological influences may be exogenous and endogenous. Pathology may be primary
(initially develops in the stomach) and secondary (as a result of pathology, which
develops in another organs that may influence the stomach functins). In pathology it
happens in
 disorder of nervous regulation, overloading of nervous system, emotional stress,
 increased tone of vagus,
 hypersecretion of catecholamines,
 hypersecretion of glucocorticoids,
 factors causing angiospasm in stomach, ischemia and the necrosis of the mucous
membrane of stomach

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 hypersecretion of gastrin (tumor),
 bile (bilious acids), which fall into the stomach (it is called reflux).
All pathologic processes, which were studied earlier, can be developed in the stomach -
 inflammation (gastritis),
 allergy - the formation of autoantibodies against the mucous membrane of the stomach
 tumor (carcinoma).
 hemorrhare,
 necrosis (stomach ulcer),
 genetic mechanisms (predisposition to certain pathology).
All general laws governing inflammation, tumor, necrosis realize in the stomach
pathology. At the same time, the peculiarity of localization of these processes have a
significance.
In addition to endogenous, many exsogenous factore may damage the stomach and
mucosal barrier up to gastric mucosal erosions or ulcers. They are -
 the character of nutrition (regimen, rhythm, quality), irregular nourishment,
 abuse of alcohol and cigarettes,
 infection, b. Gelikobakter pylory plays exlusive role,
 medicines - particularly aspirin and hormones (corticosteroids).
Together with the aggressive factors, which damage the mucous membrane of
stomach, protective ones are also exist, which oppose the corrosive affects of acid-
peptic gastric secretion.
The factors of the protection of the mucous membrane of stomach are the
following -
 stomachic mucus (gastric mucosal barrier),
 blood supply of the mucosa,
 intestinal hormones (enterogastrin);
 pancreatic hormone glucagon,
 somatostatin,
 PG
 bicarbonates of the pancreas, stomach and duodenum.
 high regenerative ability of the epithelial cells.
Mucous membrane of stomach possesses high regenerative properties. In a healthy
person the mucosa of the gastrointestinal tract is renewed every 1-5 days. Glucocorticoids
impede this property. At that moment the cells giving frequent mitoses are exposed to
different negative effects.
The ratio of factors of aggression and protection plays a significant role in pathology of
stomach.

GASTRITIS

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 Gastritis is an inflammation of the mucouse membrane of stomach.
All the general laws, governing the inflammation, appear with the inflammation of
stomach (the stages of process, alteration, disorder of microcirculation, production of BAS,
regeneration). In fact, the special features are obtained. They are connected with
appearance of specific aggressive factors, the correlation of stomach with other parts of
digestive tract.
The humoral mediators of inflammation (histamine, bradykinin, kallikrein-kinin
system) are the critical damaging factors due to stimulation of hudrochloride acid and
pepsin secretion. Bradykinin effects the cell membrane where it activates the enzyme
phospholipase A. This enzyme destroys the phospholipid layer of the membranes.
Dystrophic process develops.
Depending on the extend of alteration, inflammation is divided into several types:
 acute gastritis,
 acute hemorrhagic gastritis,
 acute erosive gastritis,
 chronic gastritis.
According the level of gastric acidity, all these inflammatory processes in the
stomach may be hyper-, hypo- and anacidity types.
Together with aggressivity and effect on secretion activity of pepsin, the level of
gastric acidity influence the gastric motility.
Hyperaciditas is connected with delayed emptying of gastric contents, including reflux,
into the duodenum and increased gastrin secretion. It is may be a cause of gastric ulcer
formation. Hypoaciditas is an accelerated emptying of gastric contents, resulting in
damage of normal digestive function.
The hypersecretory and hyposecretory (anaciditas) type of inflammation may lead to
ulcer or cancer development.
The disorder of digestion in the stomach involves the underlying divisions of the
digestive tract into the disturbance of digestion.

ACID PEPTIC DISEASE

Peptic ulcer is a recurrent disease characterized by areas of destruction of the mucous

membrane under the influence of hydrochloric acid and pepsin. Peptic ulcers are the most
common in the antral section of the stomach and proximal section of the duodenum, some-
times in the inferior part of the esophagus.

ETIOLOGY

The etiological factors of ulcer are divided into the exogenous and endogenous, and
exogenous are subdivided into the physical, chemical and biological.
Physical factors are the chronic injury of mucous membrane of stomach in the form
the disturbance of the mode of nutrition.

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 Chemical factors are the damage of the mucous membrane of stomach by the chemical
substances, among which the abuse of medicines has great significance. Glucocorticoids
contribute to the damage. Alcohol and smoking, as well as vitamin and microelement
deficiency must be added.
Biological factors are
 infection (b. Helikobacter pylory),
 constant neuroemotional overloading, emotional stress and negative emotions play the
main role,
 immune factors (injection of the heterogeneous serum, which contains anti-gastric
antibodies).
Endogenous factors sometimes play a role of etiology, sometime the role of conditions,
sometimes are the mechanisms of pathogenesis. They are
 disorder of the regulation of the gastric secretion, which lead to an increase in the
acidity of gastric juice and the hypersecretion of pepsin. Corrosive effect of acid and
pepsin, secreted by the stomach, play a key role in gastric ulcer, duodenal ulcer and acute
erosive gastritis.
 autoimmune agression,
 genetic predisposition.
A specific infectious agent — the Helicobacteria pylori, has been implicated in
predisposition to a number of forms of acid-peptic disease.
The Helicobacteria pylori is an extremely common pathogen, found in 50% of the world
population, expecially in the poorest countries, where sanitation facilities and standards of
personal hygiene are unadequate. The most likely route of spread from person to person
is fecal-oral.
There was discovered an etiological role of Helicobacteria pylori in the development of
recurrent ulcers of the stomach and duodenum. It is a gram-negative microorganism,
which is isolated in 90% of patients with duodenal ulcer and in 60-70% with gastric
ulcer.
The most likely mechanism is diminished mucosal defences through inflammation.
Helicobacleria pylori affects the gastric epithelium. The causative agent opsonized secretory
IgA and serum immunoglobulins, acts as "barrier destroyer" and thus promotes reverse
diffusion of the acid and development of ulcerative defect of the gastric wall.
Despite this high rate of association of inflammation with Helicobacteria pylory
infection, the important role of other factors is indicated by the fact that only about 15% of
infected persons have ever develop a clinically significant ulcer.
Genetic Predisposition. Correlation between pepsinogens is genetically dominated.
There are 2 types of pepsinogens: the 1st type includes five fractions of pepsinogens, the
2nd type — two fractions. There was established a correlation between the 1st type and
ulcer. This factor is determined as "non-secreted".
There are antigens A and B in the erythrocytes. Their content resembles the gastric
mucosa, which plays the role of the protective mechanism. The human organism has genes,
which contribute to entrance of antigens A and В of the erythrocytes into the saliva. The

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saliva is swallowed and these antigens enter the stomach interacting with the gastric mucosa.
Antigens A and В are absent in people having blood group I that is why they are
predisposed to ulcer development.
The risk factors are usage of nonsteroidal antiinflammatory drug injection,
smoking, psychological stress.

PATHOGENESIS

The main link in the pathogenesis is a disturbance the balance between the factors of
damage and defense in the mucous membrane of stomach.
Development of ulcer is observed in prevalence of factors of aggression.
It causes chronic gastritis, which also plays a role in ulcer.
Hence, if there are disturbances in coordination of this processes, there are conditions for
ulcer development.
The leading factors of ulcer development are bacterial and neurogenic.
The neurogenic factor is connected with the vagus excitation and neurotransmitter of
the parasympathetic nervous system (acetylcholine). Vagus stimulates the production of
aggressive digestive factors - hydrochloric acid and pepsin. Vagus (acetylcholine) dilates
the vessels of the submucous layer. The arterial blood, without exchange in the submucous
layer, flows into the veins. It results in development of hypoxia.
Trophicity of gastroduodenal area is disturbed. Dystrophic process arises which is
joined by peptic factor (pepsin + hydrochloric acid).
Dystrophy results from neuro-psychological overloading, accompanied by severe
emotional stress.
Stress influence is spread to the sympathetic, parasympathetic nervous system and the
system of hypothalamus-pituitary-adrenal glands.
Excitation of symphathetic nervous systems leads to excretion of noradrenalin, which
constricts the vessels of the microcirculatory flow. It results in spasm and then hypoxia.
It promotes contraction of the smooth muscles of the submucosa of the stomach. Spasm
may be very severe and long so that stasis (circulation arrest) occurs. It leads to
haemorrhage in the gastric mucosa and erosion. It exerts injurious influence on the cell
membranes of the gastric mucosa, avoiding blood vessels.
During stress the amount of noradrenalin in the blood and stomach is at its maximum. It
activates the Haghemann's factor (XII factor of blood coagulation), which is the activator of
the callicrein-kinin system.
During stress glucocorticoids influence the gastric mucosa and cause inhibition of the
discharge of the gastric mucous by mucocytes, intensify production of hydrochloric acid
and pepsin.
The humoral factors of inflammation — bradykinin effects the cell membrane where it
activates the enzyme phospholipase A. This enzyme destroys the phospholipid layer of the
membranes. The neurodystrophic process develops. Bradykinin along with histamine is a
humoral agent of pain.

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 Increased activity of kallicrein-kinin system, which is 2-10 times increased in comparison
with the norm may be noted.
Regenerative abilities of the gastric mucosa are decreased. Healing of the mucosa is
diminished and injurious effect of the peptic factor (HC1 + pepsin) is intensified.
As many as 90% of infected individuals show signs of inflammation (gastritis or
duodenitis) on endoscopy, despite this high rate of association of inflammation with
Helicobacteria pylory infection, the important role of other factors is indicated by the fact
that only about 15% of infected persons develop a clinically significant ulcer. These other
factors (both genetic and environmental) must account for the individual variations and are
pathophysiologically important.
Motility defects have been proposed to contribute to development of gastric ulcer in at
least three ways:
 by a tendency of duodenal contents to reflux backthrough 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;
 by delayed emptying of gastric contents, including reflux of materials into the
duodenum,
 by delayed gastric emptying and hence food retention, resulting in increased gastrin
secretion and gastric acid production and therefore gastric ulcer formation.
Mucosal ischemia may play a role in the gastric ulcer development. Prostaglandins are
known to increase mucosal blood flow as well as bicarbonate and mucus secretion and to
stimulate mucosal cell repair and renewal.

Manifestations

Pain, though typically many of these individuals are clinically asymptomatic.

Pathophysiologic Groundation of Therapy

Therapy should be directed at

 intensification of the protective factors (cytoprotectors);
 neutralization of the aggressive factors (prostoglandins);
 antiacid preparations inhibiting acidopepsine secretion - Al, Mg (almagel);
 cholinoblockers (atropin) and histamine blockers.

PATHOLOGY OF PANCREAS

Pancreas is a source of the digestive enzymes, among which amylase and strong
proteolytic enzymes - trypsin and hemotripsin have a value.
The proteolytic enzymes are formed in the pancreas in the inactive state – tripsinogen
and hemotripsinogen. Only in the intestine they are activated by bile (bilious acids). If

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they are activated in the tissue of pancreas, it leads to the necrosis of gland. Then these
active enzymes fall into the blood, and it leads to death of patient. Reason of death is a
decrease of the arterial blood pressure and shock.
This situation is possible with the inflammation of pancreas.

PANCREATITIS

Pancreatitis is an inflammation of pancreas.

Not infrequently inflammation of the pancreas has an acute course and may be
accompanied by development of pancreatic shock dangerous for life.

ETIOLOGY

Etiological factors of pancreatitis occur exogenous and endogenous.

Among the exogenous factors trauma and infection plays the leading part.
Trauma of a sphincter of the hepatic-pancreatic ampule may occurs in surgical
interventions.
Infection factors are viral (in parotitis and hepatitis), cocci, bacterial infection.
Conditions and risk factors play a critical role in etiology of pancreatitis. They aggravate
the action of etiological factors. The risk factors are - overeating and abuse of fatty food
(cause increased secretion of the 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 the endogenous factors the following reasons play a role
 disorder of blood circulation,
 sclerosis of vessels,
 occlusion of the ducts by inflammatory exudate, concrements (bile stones), polyps of
the pancreatic duct,
 entry of bile into duct and into the gland (reflux).
The named factors activate trypsinogen and hemotripsinogen intra-organ.
Autoimmune aggression play a role in chronic forms of pancreatitis.
PATHOGENESIS

Like any other form of inflammation, pancreatitis proceeds in three stages – alteration,
exudation and proliferation. Like any other form of inflammation, pancreatitis have local
(in the pancreas) and systemic (in the entire organism) manifestations.
The special feature of the inflammation of the pancreas lies in the fact that alteration
(secondary) predominates above all other stages of inflammation. The significance of the
systemic changes in the organism predominate the local (in pancreas).

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 Any etiological factor starts inflammation. In response, as usually in inflammation, the
microcirculation is disordered. Hyperemia and edema lead to the increased pressure in the
pancreas duct. The bile and duodenal chyme (containing enterokinase) by reflux enters
pancreas. Avacuation of pancreatic secret becomes difficult. Due to this fact as well as the
general lows of inflammatory process, BAS are formed. They activate trypsinogen and
hemotrepsinogen intra-organ. The premature activation (autocalalysis) of enzymes (tripsin,
callicrein, elastase, phospholipase A) directly in ducts and cells of the pancreatic gland, which
occurs under the effect of bile, enterokinase and other BAS, is the main point in pancreatitis
pathogenesis. As a cascade, all systems of BAS-formation are activated. As a result, the
active proteolytic enzymes (trypsin and hemotripsin) damage pancreas. This damage of
pancreas (secondary alteration) is very severe. It results in autolysis of the gland tissue,
necrosis of its separate areas and production of toxic (lysolecithin) and biologic active
substances including kinins (activation of blood kallikrein-kinin system) having powerful
vascular and hypotensive effect. All of them are vasoactive. Necrosis of pancreocytes
develops vascular permeability increase. Active proteolytic enzymes fall into the blood.
Coming of peptidases and other pancreatic enzymes into blood results in severe disorder of
hemodynamies, respiration and other vitally important functions.
As a result, the arterial blood pressure falls. It is a picture of a shock, which is called
pancreatic shock. 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 pancreatitis.
A definite significance in pathogenesis of pancreatitis, especially of a chronic form,
belongs to arterial hypertension as well as immunologic factor (autoallergy). It is proved
by detection of antipancreatic antibodies in the blood of some patients with
cholecystopancreatitis.

DISORDER OF INTESTINAL DIGESTION

The process of protein digestion continues in the duodenum. The duodenum is the most
important section of the intestine containing secretion of the duodenal glands, bile and
pancreatic juice.
The duodenum produced secretin, cholecyslokinin, and motilin, which regulate the
alimentary system functioning, metabolic processes and possesing neurotropic, in
particular, hypothalamotropic effect.
The liver forms the bile, which contains bilious acids, which are secreted into the small
intestine. The bile, which is excreted from the liver, plays a large role in the intestinal
digestion. Bilious acids activate enzymes – trypsinogen, hemotripsinogen, lipase.
The outlet of the acidic mass from stomach into the duodenum stimulates the production
of secretin that stimulates the pancreas and production of bicarbonates.

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 Bicarbonates neutralize the acidic mass and as a result PH increases from 1.5-2.5 to
7.0 that activates proteolytic ferments (trypsin, chymotripsin, carboxypeptidases).
Under their influence proteins transform into a mixture of free aminoacids and
oligopeptides, which are observed in the small intestine.
Over-boiling of nutrients up to the end products, which are sucked into the blood,
occurs in the small intestine. Small intestine has the digestive glands, which secrete entire
spectrum of the digestive enzymes. Proteins are splited to the amino acids, fats – to the
fatty acids, di- and polysaccharides - to the monosaccharides.
The intestines fulfil secretory, motor, absorptive incretory and excretory function.
The intestines accomplish cavity and membranous (parietal) digestion. Lately there has
been distinguished an intermediate stage between cavity and membranous digestion:
hydrolysis of the nutrients in the mucous layers. Cavity digestion takes place in the lumen of
the intestines and consists in destruction of the over-molecular systems and large molecules.
Membranous digestion takes place on the membrane of the columnar cells of the intestinal
villi. The final stages of nutrient hydrolysis and absorption occur here.
Enzymes are produced by the columnar cells of the intestinal villi. Being produced on
the cell surface enzymes participate in membranous digestion. The main way of
penetration of enzymes into the intestinal juice is rejection and destruction of the columnal
cells (under normal conditions the cycle of their renewal is 3 days).
Over-boiling and suction of final products in the small intestine are combined. Both
these processes occur in sterile conditions. The membranous digestion is created in the
evolution in such a way that the end products (amino acids, glucose, and fatty acids) are
not accessible for the microorganisms, which are located in the bowels.
Disturbance of cavity digestion depends, first of all, on disorder of production of bile
and pancreatic juice.
Disturbance of enzyme production by the columnar cells plays the main role in pathology
of membranous digestion.
The disturbance of digestion in the small intestine has a value in the development of
allergy. If the barrier properties of the mucous membrane of bowels are disrupted, the
products of incomplete over-boiling of protein can be sucked into the blood and be the
source of the sensitization of organism (food allergy).

INDIGESTION CONNECTED WITH DISORDER OF BILE SECRETION

If bile does not enter the bowels ( with the obstruction of the duct of gall bladder by
stones), then digestion significantly is disrupted (details in the chapter ” Pathology of the
liver”).
Absence of bile (acholia) or its insufficient coming (hypocholia) into the duodenum
arises due to disturbance of cholepoiesis and bile secretion. They are accompanied by
indigestion and malabsorption of fats, decreased peristalsis of the bowels and increased
processes of decay and fermentation in them.

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 INDIGESTION CONNECTED WITH DISORDER OF PANCREATIC
JUICE SECRETION

Serious indigestions is caused by changes of the pancreatic secretion, as the pancreas

produces the main digestive enzyjmes. The main mass of proteins of the pancreatic juice
(over 70%) is proteolytic ferments: tripsin, chirnotripsin, elastase, carboxypeptidase (A and
B) and callicrein. All these ferments as well as phospholipase A are produced in inactive
condition (as symogens). The other ferments — lipase, amylase, RNAase and DNAase are
secreted in the active form.
In lack of the pancreatic juice, a considerable part of fat is not digested and excreted
with feces (steatorrhea). Indigestion of proteins arises in insufficient production of
peptidase by the pancreas as well as in their activation disorder. So, tripsinogen is acti-
vated by enterokinase of the intestinal juice and autocatalytical ly, the rest of proteolytic
ferments and phospholipase A are activated by tripsin. In decreased pancreatic secretion
there are hydrolysis disturbance of the food nucleic acids.
Disturbance of secretion of the pancreatic juice is observed in occlusion or compression
of the pancreas, cystic fibrosis, acute and chronic pancreatitis or duodenitis, in disturbance
of neuro-humoral mechanisms of the pancreatic secretion regulation. The secretory nerve
of the pancreas is the vagus. Humoral regulation is accomplished by secretin, which
activates excretion of water and hydrocarbonates, cholecystokinin (pancreosimin)
stimulating enzyme production, and pancreatic polypeptide inhibiting it.

Disorder of Membranous Digestion

Membranous (parietal) digestion is accomplished by enzymes fixed on the surface of

the striated edge, which is formed by microvilli of the columnar cells of the intestinal
villi. It is characterised 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 mm) where microorganisms can't penetrate. Enzymes
of membranous digestion are synthetized inside the columnar cells and transported to the
surface of their cellular membranes.
The pathology of membranous digestion is caused by the following factors:
 damage of the villi and ultrastructure of the surface of the columnar cells,
 change of the fermentative layer of the intestinal surface and absorptive properties of
the membranes,
 peristalsis disorder when the transportation of substrate from the intestinal cavity to
membranes surface is impaired.
Reduction of the digestive surface at the expense of atrophy and decrease of the
number of the villi or microvilli is found in cholera, ileojejunitis, after intensive usage of

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some antibiotics (neomicin), gastrojejunostomy and stomach resection. The example of
impairment of the fermentative layer of the intestinal surface is milk intolerance in lactase
(galactosidases) deficiency or saccharose intolerance in saccharose (a-glucosidases)
deficiency.

Disorder of Absorptive Functions of the Intestines

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 cell membrane are closely conjugated.
Therefore, all factors causing disturbance of membranous digestion lead to malabsorption.
The syndrome of malabsorption may be primary (hereditary) or secondary (acquired).
The hereditary syndrome of malabsorplion is more often characterized by selective
deficiency of enzymes or transport carriers. As a result absorption of one or several nutri-
ents is disturbed. This group of malabsorption includes
 monosaccharidase intolerance (intolerance to lactose, saccharose, isomaltose),
 insufficiency of peptidases,
 aminoacids (cystinuria, triptofanmalabsorption, methyonin malabsorption),
 malabsorption of vitamins (cyancobalamin, folic acid).
The acquired syndrome of malabsorption is observed
 after gastrectomy,
 in intestinal diseases (enterocolitis, Crohn's disease, etc.),
 diseases of the pancreas (pancreatitis, cystic fibrosis),
 diseases of liver,
 in radiant diseases,
 as side-effect of medicamentous therapy.
Absorption of the nutrients in the small intestine may be disturbed in weakening of the
cavity digestion in the stomach and intestines as well as in disorders of blood and lymph
circulation. Disorders of blood circulation disturb release of the absorbing substances, their
concentration ingredients and energy supply of the active transport. Weakening of the
active transport also arises under the influence of poisons blocking enzyme activity and in
water-electrolyte disbalance. Ions of sodium and ATP-energy are of special importance in
the active transport of glucose, aminoacids and other compounds.
Increased permeability of the intestinal wall vessels in inflammation and hyperemia may
be accompanied by absorption of substances of antigenic nature and the organism
sensitization.

Disorder of Excretory Functions of the Intestine

15
 Excretory function of the intestines is closely connected with the absorptive one. The
intestines excrete the terminal products of hemoglobin and cholesterol metabolism, metal
salts, lactic acid, purins, some hormones, phenols, salicylates, sulfanilamides, dye-stuff, etc.
In renal insufficiency there is compensatory increased excretion of nitrous "wastes" (urea,
uric acid, etc.).

The Study about APUD-System

It is established that disturbance of the structure and function of the stomach leads to
disturbance of hormone production of the alimentary tract.
Over 20 substances are known that are produced by neuroendocrine cells of APUD
system (amine precursor uptake and decarboxilation). These hormones influence not only
on digestion and absorption but also on the blood circulation, metabolism, the nervous and
endocrine systems. The hormones of the alimentary system are connected with hypothalamic
pituitary system and other glands. For example, gastrin, cholecystokmine and glucagon
stimulate the production of calcitonin and, therefore, play a definite role in disturbance of
calcium exchange. Gastroinhibiting peptide (GIP) and secretin stimulate the production of
insulin and glucagon that stimulate their role in pathogenesis of obesity and cachexia.
It is established that disturbance of hormone production of the alimentary tract results in
deep disturbances of digestion, metabolism and activity of organs and systems. Hormone-
producing cells of the alimentary organs may be liable to malignization and lead to
development of cancerous tumours.

Disorder of the Motor Function of the Intestine

Disturbance of the motor function of the intestines may be manifested by increase or

decrease of peristalsis.
Increased motor functions of the intestines arise
 in inflammatory processes (enteritis, colitis),
 under the influence of mechanical or chemical stimuli by undercooked food,
 due to the effect of bacterial toxins,
 in disturbance of the neural and humoral regulation.
The contraction of the intestinal muscular membrane increases. It is inhibited in the
vagus stimulation. Serotonin, gastrin, motilin activate the intestinal peristalsis and
vasoactive intestinal peptide and glucagon inhibit it.
The example of the disturbed neural and humoral regulation of the intestine mobility is
"syndrome of the irritated intestines". The negative emotions change the motor and
absorptive functions of the intestines and become the cause of pain and diarrhea frequently
followed by constipation.

16
 Increase of peristalsis usually leads to accelerated movement of nutritious masses in
the bowels, disorder of their digestion and absorption, diarrhea. Promoting excretion of
the toxic substances from the organism (in food intoxication) or excess of the indigested
food, diarrhea may play a protective role. However a prolonged diarrhea, especially in
children leads to dehydration of the organism and loss of electrolytes (Na+, K+).
Hypovolemia develops and in severe cases cardiovascular collapse occurs.

THE DISORDER OF DIGESTION IN BOWELS

Digestion practically does not take place in bowels. The formation of feces and water
suction occurs here.
Abundant microflora is found in the bowels. It has physiological value. Important
significance has a composition of this microflora.

Diarrhea

Mechanism of diarrhea is connected with osmotic disturbances — generalized

malabsorption of some salts, glucose, galactose or fructose; secretory damage due to
enterotoxins, tumor products, serotonin.
There are the following forms and causes of diarrhea:
 Acute form lasts 2-3 weeks. The causes are viral and bacterial infection (E. Coli),
parasitic infections (Salmonella, amebiasis), fungal infection, heavy metal intoxication,
food poisining, pelvic inflammation.
 Chronic diarrhea in chronic inflammatory process (rectal syphilis, rectal gonorrhea,
herpes simplex).
 Chronic and recurrent diarrhea. Irritable bowel syndrome, malabsorption syndrome.
 Acquired immune deficiency syndrome (AIDS).
 colon cancer.
 Disbacteriosis.
 Enzymopathy.
The human intestines, especially in the large and lower section cf the ileum have
abundant microflora consisting mainly of obligatory anaerobic sporeless bacilli Bacteroides
and Bifidobacterium. Optionally anaerobic colon bacillus, lactic acid bacteria, streptococci
and others constitute about 10% of microflora. Normal microflora of the intestines plays a
protective role inhibiting development of pathogenic microorganisms and promoting natural
immunity. Microflora of the bowels synthetizes vitamins.
I. Mechnikov was the first to suggest using microbial antagonism for fight with intestinal
autointoxication.

Acute Intestinal Obstruction (Ileus)

17
 Acute intestinal obstruction (ileus) may be
 mechanical (compressive),
 occlusive, or obstructive (by feces),
 dynamic (due to spasm or paralysis of the muscular membrane of the bowels).
Obstruction arises due to congenital abnormality, helminthiasis, postoperative
complication, in undernourishment and taking food of poor quality.
So, paralytic obstruction (postoperative and in peritonitis) is frequently conditioned by
powerful discharge of the sympathoadrenal system and activation of - and -adrenergic
receptors, which inhibit contraction of the muscular membrane of the bowels. Spastic
obstruction in carcinoid (serotonin-producing tumour from argiroffinocytes of the small
intestine) may be connected with increased activity of the muscular membrane of the
bowels under the influence of serotonin excess.
Disturbances of water-electrolyte metabolism are of primary significance conditioned
by secretion disorder (usually it is increased) and reverse absorption of the alimentary
juices. There are vomiting, dehydratation (up to 5-7 1 of the alimentary secretion are lost
per day), loss of ions of Na, K, H, hydrocarbonates and chlorides. There are hypovolemia,
hypotension and hemoconcentration that result in disturbance of blood circulation and the
state resembling shock. К ions loss promotes intestinal atony development.
In ileus there is also acid-base disbalance. Excreticn of hydrocarbonates (the pancreatic
and intestinal juice) exceeds leakage of the H ions (the gastric juice) resulting in
development of nongas acidosis. Acidosis is also promoted by aggravation of blood
supply of the kidneys. When excretion of the acidic gastric content prevails, there is nongas
alkalosis. The following processes play an important role in pathogenesis of ileus, they are
indigestion, formation of toxic substances and their absorption in blood (autointoxication).
Formation of increased quantity of biologically active substances, especially kinines, are
also of great importance, they arise due to premature activation of the pancreatic enzymes.
The disturbances of the neurohumoral regulation are very important in development of
all above-mentioned changes, they occur under the influence of reflex stimuli (distention of
the bowels, pain, etc.). They are especially significant in strangulation ileus accompanied
by compression of the mesentery and disturbance of blood supply of the affected area of
the intestine.

CHAPTER 28

PATHOPHYSIOLOGY OF THE LIVER

18
 The liver is an organ with the numerous functions. The liver is one of the most
important glandular organs providing homeostasis in the organism. Metaphorically it is
called as "a big chemical laboratory".
The morphology of the liver consists of three functional parts - hepatic cells
(hepatocytes), apparatus of bile secretion (bilious ducts and gall bladder) and system of
blood circulation (portal), which assembles the blood from the organs of digestion.
The functions of the liver are the following :
 Excretory function consists of (a) bile formation (cholepoiesis) and (b) bile secretion
(cholediaresis). Bile is formed by hepatic cells and is excreted by bile tracts. Gall
bladder is the place of accumulation and retention of bile. The composition of bile are
bilious acids, cholesterol, conjugated bilirubin, water, salt and other.
 Digestive – participation in over-boiling of foodstuffs in the bowels. Bile activates the
proenzymes of the pancreas (trypsinogen and chemotripsinogen) and the lipase of
bowels.
 Metabolic - participation in metabolism of
 Proteins - synthesis of proteins (blood plasma proteins and procoagulants among them),
their deposition, as well as transamination and desamination of aminoacids, the
formation of urea, the synthesis of creatinin;
 Carbohydrates - synthesis of glycogen from monosaccharides;
 Lipids - oxidation of fatty acids, metabolism of cholesterol, the formation of acetone
and ketone bodies;
 pigments - formation and circulation of bilirubin (unconjugated, indirect) and
conjugated (direct), as well as stercobilin and urobilin;
 vitamins - deposition and metabolism of vitamins А, В, К, D;
 deposition of iron, copper, zinc ions ;
 regulation of acidic-base balance.
 Antitoxic - neutralization of the toxic substances, which enter from the bowels;
 Defensive or protective - phagocytosis, detoxication, the development of collaterals,
regeneration, the bactericidal function of bile;
 Hemostatic - regulation of the balance between coagulant and anticoagulant blood
systems, the formalion of heparin,
 Hemodynamic - maintenance of vascular tone and influence on the total volume of the
blood, deposition of plasma of blood, regulation of a total amount of blood;
 Hemopoietic - hemopoiesis in embryo,
 Endocrine – participation in the metabolism of hormones.

HEPATIC INSUFFICIENCY

Taking into account multiplicity and the variety of the functions of the liver, it is
possible to give the following determination of hepatic insufficiency.
Hepatic insufficiency is the totality of the syndromes, connected with the
disturbance of the ability of the liver to fulfill its functions.

19
TYPES
(classifications)

Etiological classification divides hepatic insufficiency into acquired and hereditary.

Pathophysiological classification divides hepatic insufficiency into the total and
partial. The latter in turn is subdivided into the
 cholestatic (excretory) as a result of the disturbance of chole formation and chole
excretion (cholestasis is a disturbance of the chole outflow followed by the
accumulation of its components in the liver and blood).
 hepatocellular (parenchymatous) as a result of the dystrophic and necrotic
disturbances of the hepatocytes;
 hepatovascular as a result of disturbance of blood circulation in the liver.
Clinical classification divides hepatic insufficiency into the acute and chronic.
There can be distinguished primary and secondary affection of the liver. All functions
of the liver can be disturbed as primary (independent liver diseases, e. g. viral hepatitis) and
secondary as hepatic syndrome, which is associated with another systemic diseases.

ETIOLOGY

The etiological factors, which cause hepatic insufficiency, are divided into the
exogenous and endogenous , inherited and acquired.
Exogenous factors arise direct lesion of the hepatic tissue by agents of physical,
chemical and biological origin.
 Physical are the ionizing radiation (X-ray hepatitis) and the mechanical trauma of the
liver.
 Chemical are noninfectious organic and inorganic toxic substances and poisons
(phosgene, carbon tetrachloride, arsenic, insecticides; medicines — sulphanilamides,
chlortetracycline, tetracycline, cytostatics; vegetable poisons — aphlatoxin, muscarin),
large dose of alcohol.
 Biological are
 infectious are viruses and bacteria among which the viral hepatitis occupies special
position; causes of tuberculosis and lues, parasites in the gall bladder and malaria
plasmodiums must be added;
 immune factors associated with vaccination, injection of immune serums, food and
medicine allergens.
 alimentary factors are lack of food (starvation), vitamin deficiency, abuse of fat food
and alcohol.
Endogenous factors are also physical, chemical and biological, but of internal origin.
They are:

20
 physical factor is the trauma of bile tracts with the presence of stones in the bilious
tract and the gall bladder.
 Chemical factors are endogenous poisons (metabolits) and the products of the tissue
decomposition in burn, crush-syndrome, toxicosis of pregnancy, hypothyroidism,
adiposal syndrome, uremic and diabetic coma.
 Biological are
 autoimmune e.i. hepatotrophic autoantibodies, sensitized lymphocytes, T- killers and
BAS during allergic reactions;
 genetic (hereditary enzymopathy),
 inborn structural defects of the liver,
 disorder of blood circulation in the liver as a result of thrombosis, embolism,
cardioascular insufficiency;
 tumors both as primary (hepatocarcinoma) and metastatic (in cancer of the stomach,
lungs, mammary gland, leukemic infiltrates).
 dyskinesia of the bile tracts, as a result of nervous regulation disorder.

PATHOGENESIS

All previously studied typical pathologic processes can occur in the liver. They are:
 inflammation (hepatitis) of infectious and non-infectious origin;
 allergy as a result of the autoantigen formation against pathologically changed
hepatocytes and the development of autoallergic reactions of humoral and
cellular types. The liver is damaged by microcircular disorders, BAS and
immune cytolysis with T-killers;
 tumors (primary and metastatic);
 local disorders of blood circulation - thrombosis, embolism,
 typical metabolic disorders,
 dystrophy (hepatosis) which is a result of primary changes in metabolism of
hepatocytes;
 sclerosis (cirrhosis) e.i. the diffuse growth of the connective tissue on the background
of dystrophy or parenchyme. As a rule, the chronic inflammatory and metabolic
affections of the liver result in the development of cirrhosis,
 hypoxia.
Damage of the liver can be primary (by direct effect of the etiological factor) and
secondary (indirect, as involvement of the liver into another pathology -allergy, the
disturbance of systemic blood circulation in heart insufficiency, hypoxia).
As a result of anatomical and functional connections between liver and other
organs of the digestive system as well as spleen and kidneys, a high frequency of
combined disturbances of the liver and these organs (hepatolienal syndrome,
hepatorenal syndrome) is typical for the liver pathology.

21
 Compansatory Reactions

As any other pathology, the liver pathology consists not only of pathologic structure
and functional disturbances, but also compensatory reactions which are intended to
stop pathological process in the organ.
These are the following reactions:
 increase excretion of toxic substances;
 intensification of the metabolic detoxication,
 intensification of the energy production in the liver,
 redistribution of the blood;
 development of collaterals (anastamosis),
 phagocytosis,
 regenerative hypertrophy (the liver capability of regeneration can be evident
both during resection and in diffuse affection of the liver tissue).
Finally, at the end of discussion about general etiology and pathogenesis of hepatic
insufficiency, it is necessary to mention, that its each form has peculiarities of etiology
and pathogenesis.

CHOLESTATIC HEPATIC INSUFFICIENCY

Cholestatic hepatic insufficiency is the totality of the syndromes, connected with

the disturbance of bile formation and bile secretion.
For the cholestatic hepatic insufficiency the term cholestasis is uses as the disturbance
of the secretion of bile. Cholestasis can be primary as a result of the inhibition of the
excretory function of hepatocytes and secondary due to obstacle to chole outflow in chole
ducts.

Etiology

The basic reason for the disturbance of bile secretion is the obstruction of bile tracts.
Usually it is the obstruction of bilious ducts by stones. The spasm of bile tracts
(inflammation) also can be a reason.
The degree of bile tracts obstruction (complete or partial) is a decisive condition of
cholestatic hepatic insufficiency development.

Pathogenesis

The sudden complete obstruction of bilious ducts is accompanied by the severe pain,
which bears the name of hepatic colic. Urgent aid is necessary to patient. Spasmolytics
sometimes help. Urgent surgical intervention is sometimes necessary.
If the obstruction of bile tracts is partial and the chronic difficulty of the entering of
bile into the bowels occurs, then the pathogenesis of the disorders is another.

22
 Bile participation in the intestinal digestion stops. The components of bile enter the
blood.
Three pathophysiological syndromes develop – acholic syndrome, cholemic syndrome
and mechanical jaundice.

Acholic Syndrome (Acholia)

Acholic syndrome is the totality of the symptoms, connected with the nonentry of
bile into the bowels and the disturbance of digestion.

Etiology

The cause of its development is a steady disturbance of bile transport from the bile
capillaries, gallbladder or its duct into a duodenum. It is caused by narrowing or total
obstruction of bile duct (by stones, inflammatory process, presence of parasites in the
gallbladder, dyskinesia of the bilious tracts, tumors).

Pathogenesis

The following processes, which are associated with the presence of bile in the intestine,
get disordered:
 Emulgation of fats in the bowels, which is necessary for further over-boiling and
sucking of lipids,
 activation of the pancreatic ferments (tripsinogen and hemotripsinogen) and lipases of
bowels,
 vitamins suction in the bowels, which relate to the group of fat-soluble (K, A, D, E),
 Pigments rotation (direct bilirubin does not enter with the bile into the bowels and does
not participates in the pigments rotation).
 Motoricy of intestine and bowel.
 Bacrericidity in the bowel.

Pathophysiological and Clinical Manifastations

Acholic syndrome has the following manifestations:

 disturbances of proteolysis and lypolysis of nutritiants in digestive tract and, as a result,
the disorder of intestinal digestion (malabsorption),
 dysbacteriosis,
 aggravation of putrefaction processes in the bowels, cused by dysbacteriosis,
disfermentation in the intestines,
 meteorism,
 decrease of the tone and depression of intestinal peristalsis,
 constipation, alternated with diarrhea,

23
 abdominal pain,
 the presence of fat in the feces, which acquires the specific look (steatorrhea);
 discoloration of feces because of absence of stercobilin in it;
 hemorrhage syndrome (due to vitamin K lack), which is aggrevated by disturbance of
procoagulants synthesis and increased permeability of the microvascular walls.
Hypocoagulation of the blood is one of the most dangerous complications,
 A-, D-, E-hypovitaminosis with corresponding clinical sings – worsening in the quality
of the skin, dryness, disorder of the sexual hormones synthesis.

Cholemic Syndrome (Cholemia)

Cholemic syndrome is the totality of the symptoms, connected with the entering of
the components of the bile into the blood.
It is necessary to take into consideration, that the bile acids as well as glycocholic and
taurocholic acids are the most toxic component of bile.

Etiology

Cholemic syndrome accompanies acholic syndrome and is caused by the same reasons.

Pathogenesis

Pathogenesis consists of the entering of the toxic components of the bile into the blood.
The most eminent effect is the cerebrotoxical one. The nervous system is the most
sensitive to the toxic action of bilious acids and other substances. It leads to the
disturbance of its functional condition. Cholemia is characterized by decrease of activity of
inhibitory neurons of the cerebral cortex that is accompanied by irritability and
excitability. Later the centers of the brain and spinal cord are inhibited.
Bilious acids increase the tone of the nervus vagus center. It has an effect on the
regulation of arterial blood pressure, heart activity and digestion.
Falling into the skin, bilious acids irritate nervous receptors, causing unpleasant skin
sensations (itching).
Bilious acids can destroy erythrocytes, acting on their membrane (detergent action of
bile). Hemolysis of erythrocytes is a result.
The level of cholesterol is increased in blood (hypercholeserinemia), that leads to
appearance of xanthomas (frequently in the epidermis of the skin of eyelids).

Pathophysiological and Clinical Manifastations

Cholemic syndrome has the following manifestations:

 Nervous disorders are the main and disturb the self-sensation of patient most of all.
They are - asthenia, disturbance of daily rhythm of sleep and awaking (sleepiness in

24
 the daytime and insomnia at night), headache, irritability, excitation, depression, slight
fatigability, decrease of tendon reflex;
 skin pruritis is provoked by irritation of nervous endings by bile acids,
 arterial hypotension,
 bradycardia,
 hemolysis of erythrocytes and consequent anemia.

Mechanical Jaundice

Jaundice is the yellow coloration of the skin and the mucous membranes as a result of
the accumulation in the tissues of the pigment bilirubinum.
There are several types of jaundice (see below). One of them is represented here.
Mechanical jaundice is a yellow coloration of the skin as a result of the
accumulation of conjugated (direct) bilirubinum, which falls into the blood from the
liver with the obstruction of the bile-secreting ways.
Mechanical jaundice is isolated in the separate syndrome because just it obviously is
combined with other two syndromes of the cholestatic hepatic insufficiency – acholic and
cholemic, which are expressed to the extreme degree. Not jaundice is a main link in the
pathogenesis of disorders. Jaundice is the visible clinical manifestation, but its combination
with acholic and cholemic syndrome gives grounds to easily diagnostics the main reason
for disorders – obstruction of the bile-secreting ways.

Etiology

Mechanical jaundice accompanies other syndromes of cholemic hepatic insufficiency

(acholic and cholemic) and is caused by the same reasons.

Pathogenesis

The disturbance of bile outflow is accompanied by increased pressure in bile capillaries.

The rupture of the bile capillaries is possible in the cases of acute total obturation of the
bilious tracts. Bile, coming into contact with the hepatic tissue, provokes its damage and
development of inflammatory process, that is called biliary hepatitis. The reverse diffusion
of bile components into the blood capillaries occurs.
Yellow coloring of the skin is provoked by increase of the level of conjugated (direct)
bilirubin in the blood.
Indirect bilirubinum possesses a certain toxic action in the high concentrations, but its
toxic action is not compared with the toxic action of bilious acids.
Conjugated (direct) bilirubinum in combination with bile acids (cholaluria) which fell
into the blood, are filtered into the urine and gives to it dark coloration.

25
 The development of two syndromes is typical for obstructive jaundice: cholemia and
acholia.

Manifestation

Manifestation consist of the combination of the symptoms of acholia, cholemia (see

above) and yellow coloration of the skin. Blood examination shows increased content of
direct bilirubin in the blood.

CELLULAR (PARENCHYMATOUS) HEPATIC INSUFFICIENCY

Cellular (parenchymatous) hepatic insufficiency is the totality of the symptoms,

which are developed as a result the defeat of hepatic cells (hepatocytes).

Etiology

Cellular (parenchymatous) hepatic insufficiency may be primary as injury of hepatic

cells (hepatocytes) by etiological factors and secondary.
Direct lesion of the hepatic tissue occurs by exogenous and endogenous etiological
factors of physical, chemical and biological nature.
They are:
 ionazing radiation,
 poisoning by salts of heavy metals, phosphorus salts, organic and inorganic poisons (for
example, tetrachloride hydrocarbon), high doses of alcohol,
 viral infection,
 poisoning by fungus poison,
 hepatotrophic antibodies and sensitized lymphocytes,
 endogenous products of metabolism (in uremia and nephropathy of pregnant),
 disturbance of portal blood circulation,
 extirpation of the liver in experiment.

Pathogenesis

Disorders of hepatic functions depend on the degree of damage and mass of impaired
hepatocytes. Damage, beginning from the change of the structure of the cellular
membranes and (or) suppression of activities of ferments, may be completed by disorder of
bile-synthetic and bile-secretory functions of the hepatocytes in the zone of lesion.
The disturbance of structure and function of the hepatocytes occurs – namely, the
disturbance of the membranes, mitochondria, cell nucleus, lysosome.
Pathogenesis of hepatic insufficiency can be presented as the following chain of events:
 disorder of molecular architectonics of hepatocyte membranes,

26
 increase of permeability,
 Intensification of free radical peroxic oxydation of lipids,
 release of hydrolases from lysosomes and following intensification of damage of the
cell membranes,
 release of necrosogenic factors and interleukins from damaged macrophages and
promoting development of inflammatory and immune reactions in the liver,
 formation of autoantibodies and autosensibilized T-killers, that promote functional
autoallergic damage of hepatocytes.
The pathophysiological manifestations of parenchymatous hepatic insufficiency are
connected with the disturbance of the basic functions of the hepatocytes.
It is a disorder of
 metabolism,
 antitoxic function, and the development of hepatic coma as the heaviest disturbance,
 production and secretion of bile (parenchymatous jaundice),
 acholic and cholemic syndromes.

Metabolic Disorders

Carbohydrate metabolism is disordered due to disturbances of liver participation in it and

is manifested by:
 disorder the glycogen synthesis (e.i. an abiliy of hepatocytes to convert glucose into
glycogen and split glycogen to glucose). It causes a characteristic sign of hepatic
insufficiency - decreased blood sugar level (hypoglycemia on an empty stomach, but
after meal hyperglycemia develops).
 disturbance of the glucuronic acid formation from glycogen. A reduction of glycogen in
the pathologicaliy alterated liver results in weakening of its disintoxication function,
where glycogen takes part converting into glycuronic acid.
Lipid metabolism gets disordered and manifested by
 disorder of the fats disintegration,
 activation of peroxide oxidation of lipids.
 accumulation of the incompletely oxidized lipid products (ketosis),
 disturbance of the complex lipids synthesis (lipoproteins, phospholipids with
antiaterogenic effect),
 disturbance of the steroid hormones synthesis,
 disturbance of the cholesterol metabolism, conversion of more aterogenic form of
cholesterol (free cholesterol) into less aterogenic cholesterol-ester. It leads to increase
of the free cholesterol level and decrease of antiaterogenic phospholipids of blood. Both
these changes thus promote cholesterol deposition in the vessels walls and
predisposition to the atherosclerosis development,
 disturbance of formation and secretion of bile by the liver and development of jaundice,
 predisposition to the adipose dystrophy of the liver development.

27
 Protein metabolism gets disordered and manifested by:
 reduction of the synthesis of important proteins by hepatocytes (albumins and
globulins of the blood, the proteins of the coagulative system - prothrombin, fibrinogen
and other),
 decrease in oncotic pressure of the blood (hypoonkia ) due to hypoproteinemia,
 tendency toward the development of edemas due to hypoalbuminemia and
hypoonkia and at the stage of development of portal hypertension promotes
development of ascites;
 the disturbance of the disintegration of proteins (amino acids) to the end products,
reduction of intensity of desamination of aminoacids,
 reduction in the synthesis of urea from aminogroups and ammonia, reduction in the
quantity of urea in the blood, accumulation of ammonia in the blood,
 tendency toward hypocoagulation due to decreased biosynthesis of protocoagulants
(prothrombin, proconvertin), that causes development of coagulopathies with an
inclination to bleeding. A decrease of intestinal absorption of fat-dissolved vitamin К
promotes that too,
 hepatic failure is combined with a disturbance of bile-forming and bile-excreting
functions of the liver;
 disturbance of biosynthesis of ferments by hepatocytes consists in reduction of
hepatocytes ferments secretion, which are produced there (cholinesterase, ANDP, NAD,
etc.).
 damage of hepatocytes is accompanied by the increase of their out of intracellular
ferments into the blood: alkaline-transaminase and glutamate-transaminase.
Vitamins disbalance consists in the development of hypovitaminosis due to:
 reduction of absorption of fat-dissolved vitamins A, D, E, K;
 decrease of ability of hepatocytes to convert provitamins into active form (e. g. carotene
into vitamin A);
 disturbance of the process of formation of cofactors for vitamins (e. g. acetyl-
cofactor A, piruvate of cocarboxilase for vitamin B).
All enumerated changes lead to development of endogenous (hepatic) hypovitaminosis.
Acid-base disbalane is manifested by the accumulation of the incompletely oxidized
products and the development of metabolic acidosis.

Disturbance of the Antitoxic Function of the Liver

The barrier function of the liver consists in neutralization of exogenous and

endogenous toxins (from the bowels, ammonia, medicines), the formation of urea from
ammonia.
A disturbance of antitoxic function of the liver is characterized by decrease of
disintoxication by the liver of
 internal poisons (phenol, indol, skatol);
 metabolites,

28
 low-molecular fat acids (valeric, capronic),
 sulphur-containing acids (cystine, methionin),
 exogenic poisons (fungic, microbal, parasitic, chemical, etc.),
 colloid particles and microorganisms with cupfer cells.
Progressive hepatic insufficiency eventuates in hepatic coma.

Hepatic (Hepatocellular) Coma

Hepatic coma is the heaviest manifestation of parenchymatous hepatic insufficiency.

Hepatic coma is the damage of the function of the central nervous system as a result
of the disturbance of the antitoxic function of the liver.

Hepatic coma is a syndrome, caused by a toxical lesion of the central nervous system with
profound disorders of its functions (loss of consciousness, absence of reflexes, cramps, a
disturbance of blood circulation and respiration).

Pathogenesis

Hepatocellular coma appears in massive necrosis of the hepatic parenchyma, when its
homeostatic and barrier functions are decreased essentially.
The disturbances of nervous system have the following interconnected pathogenic
mechanisms, which are the base of coma development.
 Hypoglycaemia is one of them. It was demonstrated in the experiment, when an
extirpation of the liver in animals leads to death in 5-8 hours because of acute
hypoglycemia. The term of life is prolonged till 20-40 hours by artificial supporting
of the normal level of glucose.
 Increased the aminoacids level in the blood. The disturbance of aminoacidic and
albuminous metabolisms is important in a mechanism of coma development. The
impaired liver isn't able to support the proper quantity and correlation of separate
aminoacids and fractions of protein in blood. Excess of one and deficiency of another
aminoacid make the normal metabolism of proteins impossible in the tissues of the
organism. Increase of aminoacids in blood and their appearance in urine is a
manifestation. The quantity of highly toxic products of decay of aromatic aminoacids
(indole, skatole, phenol) and also of albuminous putrefaction (putrescine, cadaverin) in
blood is increased.
 The level of ammonia is increased in blood. It is conditioned by disturbance of its
transformation into urea in hepatocytes. Besides, the part of urea, which is excreted by
mucous membrane of the intestine, is split in it by ureasis with the formation of
ammonia, which is sucked in blood. Excess of ammonia damages the cells of the organs
and tissues, suppresses the fermentative reactions in them.

29
 Acidosis is another essential mechanism of coma development. It was demonstrated that
the acid-base correction allows prolonging the life of animals till 2-3 days after
extirpation of liver in experiment.
 Appearance of cerebrotoxical substances (aromatic amino acids). The intoxication of
the organism is an important pathogenic link of coma. It is conditioned by appearance
and increase of the level of substances in blood, which exert the general toxic and,
especially, cerebrotoxic influence.
 Accumulation of unconjugated bilirubinum in the blood. Bile pigments take part in
intoxication of the organism too. The level of free (unconjugated) bilirubin is increased in
blood. It influences toxically on the cellular membranes.
 Systemic hemodynamics is disturbed due to intoxication.
 Decrease of the circulating blood volume.
 Arterial hypotension develops, decrease in the arterial blood pressure and the
disturbance of cerebral blood circulation.
 Cardiac output is decreased.
 Disturbances in the system of blood coagulation (deficiency of prothrombin, fibrinogen
and others) are the cause of development of bleedings, hemorrhages in the microvessels
of the organs and tissues.
 Damaged hepatocytes are exposed to the destruction. The substances, containing in them,
get into the blood and exert the pathogenic influence on the cells of the organs and
tissues, including the cells of the nervous system.
 The progressing general hypoxia appears.

Manifestations

Manifestations are - loss of consciousness, the absence of reflexes, and the disturbance
of systemic blood circulation and respiration.

Parenchymatous Jaundice

The yellow coloration of the skin occurs with the parenchymatous insufficiency.
Parenchymatous jaundice is the yellow coloration of the skin as a result of the
accumulation of direct and indirect bilirubinum in the blood as a result of the
disturbance of the metabolic balance of bilirubinum in the hepatocytes.
Hepatocellular (parenchymatous) and enzymopathic varieties of jaundices are related to
hepatogenous jaundice.

Etiology

30
 Parenchymatous jaundice appears as a result of a direct lesion of the hepatic tissue by
agents of infectious (viruses, bacteria and their toxins, malaria plasmodiums and others)
and noninfectious origin (organic and inorganic poisons, for example, tetrachloride
hydrocarbon, high doses of alcohol; hepatotrophic antibodies and sensitized lymphocytes;
tumors and others).

Pathogenesis

An increase of bilirubin in the blood – direct and indirect, including the toxic form of
bilirubinum - occurs.
Cholemic and acholic syndromes are also present, although not to this degree as with
the cholestatic hepatic insufficiency.
Enzymopathic jaundice is conditioned by disturbances of intrahepatocytic metabolism
of bilirubin. In these cases we speak about a partial form of hepatic insufficiency, which is
connected with decrease of synthesis of ferments which take part in pigmental metabolism.
By origin, this jaundice is mainly hereditary.
Gilbert's Syndrome. This form of jaundice is based on development of the disturbance of
active catching and transport of unconjugated bilirubin from blood into the hepatic cells.
The cause of it is a genetic defect of synthesis of proper ferments. The increase of the level
of total bilirubin is stipulated by increase of contents of free (unconjugated) bilirubin in it.
Crigler-Nagar Syndrome. This variant of enzymopathic jaundice develops as a result of
deficiency of glucoronyltransferase — the key ferment of transformation of free bilirubin
into conjugated one.
Dubin-Johnson Syndrome. This variant of jaundice appears as a result of defect of
ferments, which participate in excretion of bilirubinglucuronide through the membrane of
the hepatic cells in bile capillaries. As a result of this direct bilirubin comes not only into
bile capillaries, but also in blood.

VASCULAR HEPATIC INSUFFICIENCY

Vascular hepatic insufficiency is a result of the disturbance of the hemodynamic

function of the liver, deposition of the blood in the portal system of blood circulation,
an increase in the tone in the vein porta.

Etiology

Those causes, which lead to cirrhosis of the liver (chronic toxic damage), are the main
reasons.

Pathogenesis

31
 Chronic toxic damage of the liver and chronic inflammation lead to the development of
sclerous process in parenchyma and stroma of the liver. As result, the passage of the blood
from the portal system of blood circulation through the liver hinders. The phenomenon of
congestion is developed in the portal system (portal arterial hypertension).
The compensatory reactions, directed toward unloading of portal blood circulation occur.
Portacaval and cavacaval vascular shunts are developed. However, this unloading is
achieved passing the liver. The neutralization of the toxic products of the digestive tract is
suppressed.
As a compensatory reaction, the output of liquid part of the blood into the abdominal
cavity occurs. Specific edema, which is called ascites develops.

Manifestations

Vascular hepatic insufficiency has all signs of parenchymatous and cholestatic hepatic
insufficiency (acholic and cholemic syndromes, the disturbance of metabolism, jaundice,
hepatic coma).
The dilated vessels are visible on the skin of front abdominal wall with the inspection
of patient (caput to medusea ).
Shunt Hepatic Coma

This variety of coma arises as a consequence of severe affection of the liver of a

sclerotic (cirrhotic) character.
Cirrhosis of the liver can be an outcome of acute and chronic hepatitis, chronic venous-
stagnative hypoxia of the liver, and may be accompanied by the development of portal
hypertension. Long-term steady portal hypertension leads to the development of porto-caval
anastamosis (through hemorrhoidal, esophageal, umbilical viens), by which some part of
blood, sometimes a considerable one, is thrown out into general blood stream passing the
liver. II causes intoxication of the organism with products of metabolism, which normally
are inactivated in the liver. This variant of hepatic coma has its own peculiarities: firstly,
coma can arise in relatively small disorders of gall-forming (biligenesis) and gall-excretion
(bilification) functions of the liver (jaundice is absent at all or is poorly manifested).
Secondly, its arising is closely connected with functional condition of intestinal digestion
and with a character of consumed food. Food, which is rich in proteins, increases the
ability of coma development being the cause of absorption of toxical products of protein
disintegration, coming into a systemic blood stream, for example, ammonia, cadaverin,
methionin.
Ascites is also the most demonstrative pathophysiological and clinical manifestation.

JAUNDICE

32
 Jaundice is the yellow coloration of the skin and the mucous membranes, sclerae as a
result of increased bilirubin content in the blood and deposition of the bile pigments in
them.
This symptom attracts attention first of all with the inspection of patient.
Jaundice is always connected with the increase of bilirubinum pigment in the blood,
but it is not always connected with the pathology of the liver.
The unconjugated (free) bilirubin is the basic bile pigment, which is present in
blood in the norm. Level of unconjugated biirubin depends on intensity of hemolysis of
erythrocytes. Unconjugated bilirubin is not filtered in the glomeruli of the kidneys and
is absent in urine, even if its level exceeds the norm.
Hepatocytes catch actively the unconjugated bilirubin and turn it into the conjugated
(direct) one. Conjugated bilirubin is turned into urobilinogen in the bile ducts and in
superior part of the small intestine excreting in a composition of bile, and turned into
stercobilinogen.
Urobilinogen is absorbed in the small intestine together with fatty acids and get into the
blood of portal vein system, caught by hepatic cells and destroyed in them. The part of
stercobilinogen is absorbed together with water in the lower section of the intestine into the
inferior cava vein system through porto-caval anastomoses. It is slightly filtered in the
kidneys and excreted with urine giving it a yellow color, because stercobilinogen is
dissolved in water and not bound with protein.
The process of conjugation of unconjugated bilirubin with glucuronic acid is disturbed in
connection with decrease of activity of glucoronyl transferase. Quantity of forming
bilirubin diglucuronide (conjugated bilirubin) is decreased as the result of this. The
damaged hepatocytes start to secrete the bile synthesis not only in bile capillaries, but also
in blood capillaries parallel to this. It stipulates the appearance of free bile acids in blood,
increase of the level of total bilirubin in it owing to conjugated, and also its appearance in
urine. Besides, crashing of bile capillaries by damaged edematic hepatocytes hamper the
evacuation of bile from them and make the conditions for increasing of its resorption in
blood capillaries of the liver. The coming of bile into the intestines is disturbed due to
manifestation of cholemia.
The total lack of ability of hepatocytes to catch and transform unconjugated bilirubin in
conjugated one occurs in the case of serious lesion of the liver (stage of precoma). The
level of unconjugated bilirubin begins to increase in the blood, in connection with this the
contents of conjugated bilirubin in the blood begin to decrease and, as a rule, urobilinogen
disappears. Disturbance of the barrier and other functions of the liver, appear ance of toxic
forms of bilirubin and other metabolites in blood, lead to the essential disturbance of
homeostasis of the organism and threat of hepatic coma development.

Types

33
 There are three forms of jaundice. The jaundices are divided into three kinds depending
on their origin: hemolytic (suprahepatic), mechanical (subhepatic), hepatogenous
proper.
Two of them are connected with the disturbance of the function of the liver –
mechanical (underhepatic) and parenchymatous (hepatic). These 2 forms of jaundice are
described above and are accompanied by acholic and cholemic syndromes.
The third form of jaundice is not connected with the disturbance of the function of the
liver, but it is also connected with the accumulation of the bilirubinum pigment. It is
hemolytic jaundice (suprahepatic).

Hemolytic Jaundice

Etiology

The main reason for hemolytic jaundice is the destruction (hemolysis) of erythrocytes.
Reasons can be acquired and inherited (described in the chapter “The pathology of the
red blood”).
The cause of hemolytic jaundice is an excessive destruction of erythrocytes, the increase
of unconjugated bilirubin in the blood is observed at the background of anemia and
hemoglobinemia. It is a result of excessive formation of unconjugated bilirubin from
hemoglobin, and inability of normal hepatic cells to catch and transform the unconjugated
bilirubin.

Pathogenesis

Increased disintegration of erythrocytes leads to excessive formation from hemoglobin

of non-conjugated (indirect) bilirubinum, which colorate the skin. It does not possess the
expressed toxic properties in contrast to direct bilirubin.
If the function of the liver is not disrupted, the indirect bilirubinum is converted in the
liver into direct one, which enters bile and the bowels. A quantity of pigments in the feces
and in urine is increased.
A quantity of non-conjugated bilirubinum (indirect) in the blood is increased, and
direct bilirubinum is absent in the blood.
Hypoxia promotes this process. Hypoxia develops due to hemolysis of erythrocytes and
limits the activity of ferments of hepatocytes, including participation in deglucuronizaton of
unconjugated bilirubin.
Excess of unconjugated bilirubin in blood conditions the coloring of the skin and mucous
membranes, the increased excretion of stercobilin and urobilin with the foces and urine.

34
However, the cholemic syndrome (bile acids don't come into the blood) and digestive
disturbance in the intestines (acholic syndrome is absent in other jaundices) are absent.
Hepatocellular jaundice can be combined with hemolytic one, if hepatocytes are damaged
simultaneously with hemolysis; as well as with mechanical jaundice as a result of occlusion
of the bile canals by bile thrombi and stones from bilirubin, cholesterin and calcium.

Manifestations

Besides jaundice, clinical manifestations are connected with the anemia. Cholemia
and acholia are absent. The formation of stercobilinum is increased and gives strong
coloration to feces.

CHAPTER 29

PATHOPHYSIOLOGY OF KIDNEYS

Kidney is a complex parenchymatous organ with numerous functions. Kidneys consist

of parenchyma (nephron) and stroma (interstinum). Each of these parts has its own
functions.
The functions of kidneys are the following:
Excretory (secretory) function is a urine formation and elimination. Under the
pathologic conditions the kidney excrets foreign and toxic substances.
Metabolic function cocnsists in supporting homeostasis (constancy of the internal
medium of the organism). In comparison with the liver, which refers to the carbohydrates,
lipids and proteins balance, the kidneys refers to the balance of water (constancy of fluid
volume is called isovolemia), electrolytes (isoionia), osrmotic concentration (isotonia), and
regulation of acid-base balance (concentration of hydrogen ions - isohydria). The kidneys
are also important for excretion of the products of nitrous metabolism.
Incretory (endocrine) function of kidneys is the function the interstice of kidneys.
Substances, which are produced there, are increted directly into the blood, but not into the
urine. They are renin (renin-angiotensin system), prostaglandins, erythropoietins, and
erythropoietin inhibitor.
Hemodynamic function is a participation in the regulation of arterial blood pressure
and volume of the circulating blood.
Hemopoietic (erythropoietic) function is the function interstice. The formation of
stimulators (erythropoietins) and inhibitors of erythropoiesis occurs here.

35
 Hemostatic function is the influence of kidneys on the function of coagulation,
anticoagulation and fibrinolysis.
In parenchyma of kidneys three physiological processes, namely, the filtration,
reabsorption and secretion are accomplished.
The kidneys are characterized by intensive blood supply, high level of energy
metabolism which defines their increased sensitivity to blood circulation disorder.
The special feature of blood circulation in the kidneys lies in the fact that just there the
dual network of capillaries exists, namely, in the region of the glomeruli, where filtration is
accomplished, and also in the region of the tubules, where reabsoption and secretion are
achieved.
Nephritic filter is located in the glomeruli and consists in endothelium of capillaries and
basal membrane.
Primary urine is a nonprotein filtrate of the blood plasma. In the primary urine there is
no cellular elements of the blood. Quantity of primary urine is approximately 180 liters
daily.
The reverse reabsorption into the blood of the primary urine components (water,
glucose, amino acids, bicarbonate, and ions) takes place in the tubules. Enzymes,
hormones (insulin, aldosterone, vasopressin) and energy are necessary for transmembrane
transport and reabsorption.
Secretion of some products (acidogenesis, ammoniogenesis) occurs in the tubules. Toxic
products and medicines are removed into urine in this part of nephron.
The stroma of kidneys is the place of many substances formation, which fulfill the
function of regulation - renin, erythropoietin, prostaglandins.
The hormonal control on the kidneys function is achieved by insulin (it ensures the
reverse glucose reabsorption), aldosteronone of the adrenal cortex (it ensures the reverse
sodium reabsorption and Na secretion), vasopressin (antidiuretic hormone) which provides
a reverse water reabsorption.

RENAL INSUFFICIENCY

On the basis the enumerated functions of kidneys, the following definition of the renal
insufficiency is possible to propose -
Renal insufficiency is the totality of syndromes and disorder of homeostasis as a
result of the impossibility of kidneys to fulfill their functions.

TYPES
Classification

Etiological classification divides the renal insufficiency into acquired and inherited,
infectious and noninfectious.
Topographic classification divides the renal insufficiency into the prerenal, renal and
postrenal. This classification is built on the basis, where the reason for the kidney

36
insufficiency and the leading link of its pathogenesis is localized. Division into the
interstitial and parenchymatous (pathology of nephron) is based on the morphological
principle. The latter in turn is subdivided into the glomerular and tubular.
Pathogenetic classification divides the renal insufficiency into the total and partial. The
latter in turn is divided into filtrative (glomerular), reabsorbtive, secretory.
Clinical classification divides the kidney insufficiency into the acute and chronic.

ETIOLOGY

Etiological factors are divided into the exogenous and the endogenous, acquired and
inherited.
Exogenous factors are physical, chemical and biological.
Physical factors are cold, radiation, and mechanical trauma.
Chemical factors are nephrotropic poisons. Among them salts of heavy metals,
medicine (nonsteroid preparations – indometicin, ibobrufen, and also antibiotics,
sulfamides, corticosteroids).
Biological factors are fungus and snake poisons, hemolytic streptococcus. To this
category of etiological factors immune one relates. Examples are the artificial modelling of
immune mechanisms in the experiment (introduction of heterogeneous nephrotoxical
antibodies), the mismatched hemotransfusion (it is accompanied by massive hemolysis
and damage of nephritic filter), serum disease.
Exogenic factors may be the sources of antigens: bacterial, viral, parasitic, medicamentous,
food, compounds of heavy metals, etc. DNA, denaturated nucleoproteins, proteins of tumor
origin and thyroglobulin may serve as exogenic antigens. Antibodies produced in response
to these antigens are mostly of IgM class.
Endogenous factors are physical (injury by stones), chemical - the products of
metabolism (diabetic nephropathy, nephropathy of pregnant females), biological
(autoimmune aggression, the disturbance of the hormonal control of nephritic functions,
ischemia and thrombosis of nephritic artery), genetic (enzymopathy).
The important conditions, which aggrevate the action of etiological factors are the
following –
 The accessibility of kidneys as the organs of excretion to the damaging factors.
Actually, precisely, kidneys derive toxins, medicines, and immune complexes.
 The special features of blood circulation in the kidneys. High arterial blood pressure
in renal artery and duble netwet of nephron capillaries is in mind.
 The peculiarity of the antigenic composition of the kidneys, which contribute to
autoimmune aggression.
 Reduction of the reactivity of the organism (diabetes mellitus, atherosclerosis, obesity,
chronic intoxication, etc.)

37
  The pathology arises due to penetration of the causative agent of infection into the
kidneys by hematogenic way or by spreading it upward by the urinary tract. The causative
agents are mostly colon bacillus, cocci.
Prerenal factors are:
 Blood loss, burns, incontrollable vomiting, profuse diarrhea, and the use of diuretics
resulting in decrease of the volume of the intravascular and extracellular fluids.
 Vascular forms of shock (septic, anaphylactic), accompanied by reduction of the
arterial blood pressure, collapse.
 Acute (myocardial infarction, embolism of the pulmonary artery) and chronic cardiac
insufficiency,
 massive crush of tissues,
 mismatched hemotransfusion.
Postrenal factors are:
 Obstruction of the ureter (calculi, tumors).
 Retention of the urine at the level of the bladder outlet (adenoma of the prostate).
The etiological factors of chronic renal insufficiency are all causes of kidney
inflammation, vascular and metabolic disorder.

PATHOGENESIS

All typical pathologic processes - inflammation, tumor, allergy, typical disorders of

peripheral blood circulation (thrombosis, embolism), hypoxia, typical disorders of the
metabolism (diabetes mellitus), disorders of hemostasis (DIS-syndrome) occur in the
kidneys.

Role of Allergy (Infectious and of Autoimmunization)

Allergic process is a very frequent pathologic process, which develops in the kidneys.
Exogenic factors may be the sources of antigens: bacterial, viral, parasitic, medicamentous,
food, etc. DNA, denaturated nucleoproteins, proteins of tumor origin and thyroglobulin
may serve as exogenic antigens. Antibodies produced in response to these antigens are
mostly of IgM class.
The following mechanisms underly the predisposition of kidneys to allergic diseases.
 Antigenic similarity between the alpha-hemolytic streptococcus and the basal
membrane of nephritic filter. That's why in this infection the antibodies, which are formed
against microbe, simultaneously damage nephritic filter.
 Immune complex antigen+antibody, which are formed in the blood, are adsorbed on
the nephritic filter and damage it, causing an immune inflammation. Basal membrane is
damaged. Antibodies against the basal membrane of the nephron of kidneys are revealed in

38
the blood. The function of nephritic filter in this case is disrupted. Pathogenetic therapy is
effective only in the form desensitization.
 High immunogenicity of glycoproteins and collagen, which compose the structure of
nephritic filter. In the chapter “Allergy” it was mentioned, that precisely these components
of connective tissue are most autoimmunogenic.

The protein composition of the renal tissue is characterized by antigenic similarity to

proteins of the connective tissue. That's why some diseases of the kidneys (acute and
chronic diffuse glomerulonephritis) depend on diffuse impairments of the connective tissue
and diseases of streptococcus origin.

Role of the Medicines

It is widely known that the medicines can be the factor of the damage of kidneys. There
are several reasons -
 precisely kidneys excrete entire of the medicines and can be damaged by them.
 The damaged tissue of nephritic filter can become autoantigenic.
 Medicines can be haptene and be converted into the complex antigen together with the
proteins of nephritic filter.
When medicines serve as exogenic antigens, antibodies are produced in response and are
mostly of IgM class.

The Role of Genetic Factors

A large quantity of the ferments and other proteins participates in the functions of
kidneys. It means that the genetic problems develop frequently.
Enzymopathy is a frequent pathology of kidneys and is genetically determined.
The genetic pathology of nephritic receptors (to the hormones) is also possible.

GLOMERULAR (FILTRATIVE ) RENAL INSUFFICIENCY

For glomeruli characteristics, the so-called clearance index is used. It shows the amount
of plasma or blood serum (in milliliters) which is completely cleared from the exogenic and
endogenic 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). To determine the amount
of glomerulus filtration the exogenic (polysaccharide inulin) as well as endogenic
(creatinine) substances, which are filtrated in the glomeruli and are not reabsorbed and
secreted in the tubules are used. Normal creatinine clearance is 180-90 ml/min (it means

39
that 180-90 ml of plasma is cleared from creatinine by the healthy kidneys per minute
and the same amount of primary urine is formed). The phenol red clearance is 400 ml/min.

Increased Filtration

Increased filtration is caused preferably by the following extrarenal mechanisms:

 increase of the systemic blood presure,
 increase of the hydrostatic pressure on the wall of the glomerular capillaries which is
observed in the increased volume of the intravascular fluid,
 decrease of the oncotic blood pressure (hypoalbuminemia).

Decreased Filtration

Decreased filtration may have renal and extrarenal mechanisms. The decrease of
filtration may be in the following cases:
 decrease of the hydrostatic pressure on the capillary walls. It is connected with blood
circulation insufficiency,
 decrease of the arterial blood pressure up to 80 mm H.g due to shock and collapse of
different genesis,
 decrease of the volume of the circulating blood (blood loss),
 elevation of the blood oncotic pressure above 25-30 mm Hg due to
hemoconcentration because of dehydratation of the organism.
 Increased pressure in the capsule of the giomeruli above 25 mm Hg which is observed
in the delayed reabsorption of fluid in the proximal part of the tubules of the nephrons, in
occlusion of the tubules lumen by cylinders, necrotic masses and in obstruction of the
ureter (necrosis, clots, calculi and tumors).
 Reduction of a number of the functioning glomeruli, total filtration surface, the
number, square and diameter of the pores, thickening of the glomerular membrane and
its physical and chemical properties. Such changes are observed in
 inflammatory process affecting the glomerular membrane (glomeruionephritis, etc.),
 dystrophy of the glomerular membrane due to disturbances of blood supply of the
kidneys,
 hypoxia,
 different toxic influences.

Pathogenesis

Most of nephrotic conditions are caused by allergic mechanisms, mostly of the delayed
type. Exogenic factors may be the sources of antigens (bacterial, viral, parasitic, etc.). DNA,
denaturated nucleoproteins, proteins of tumor origin and thyroglobulin may serve as
exogenic antigens. Antibodies, which are produced in response to these antigens, belong
mostly to IgM class.

40
 The damage of the glomeruli of the renal is connected with deposition of amyloid, glyco-
and lipoproteins, fibrinogen 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 and physical and chemical properties
are changed, its permeability is increased.
The number of the functioning glomeruli, total filtration surface, the number, square
and diameter of the pores are reduced. Thickening of the glomerular membrane and its
physical and chemical properties occurs. Such changes are ob served in inflammatory
process affecting the glomerular membrane. Damage of the renal filter and decrease of the
glomerular filtration and diuresis may be observed in dystrophy of the glomerular
membrane due to disturbances of blood supply of the kidney hypoxia or different toxic
influences.
The function of nephritic filter is disrupted into form of increased or reduced
permeability of nephritic filter. It means that the nephritic filter begins to pass through
itself that substancies that it must not pass, namely, proteins, and cellular elements of the
blood. Specifically, these substances and cells are determined in the composition of the
urine when it is investigated.
At the same time, filter ceases to filter those substances, which must be filtered, namely,
nitrous substances, urea, uric acid, amino acid, and electrolytes. Specifically, these
substances are determined in the blood in patients with the kidney insufficiency.
The clinical singhs mentioned above, desplay the disorder of glomerular fitration, which
is the manifestation of an increase in the permeability glomerular membrane of nephritic
filter.

Proteinuria

Proteinuria is an appearance of a protein in the urine. It is a leading sign of the increased

permeability of the glomerular membrane. It is an excretion in urine of plasma proteins with
urine above the amount of the physiological conditions (30-100 mg/day) as well as
presence of proteins with large molecular mass.
The mechanism of proteinuria caused by increased permeability of the glomeruli is
due physical and chemical changes in the basal membrane. Organic proteinuria (in acute
and chronic glomeruionephritis, nephritic syndrome and other organic impairments of the
kidneys) is characteristic of presence of plasma proteins with high relative molecular mass of
70,000-820,000 in urine.

Hematuria

Hematuria (renal glomeruiar hematuria) is an appearance of erythrocytes in the urine.

The injury of the glomerular membrane may be accompanied by coming out of
erythrocytes into the glomerular lumen and their appearance in urine as "shadows".

Azotemia

41
 Azotemia is an increase in the content of nitrous substances in the blood. Specifically,
they are very toxic and cause poisoning being the reason for uremia.
Dysfunction of the glomeruli is manifested by delay of excretion of nitrous metabolism
products and their increased concentration (residual nitrogen) in blood — azotemia. It is
caused by accumulation of urea, uric acid, creatine, creatinine, and ammonia in blood as
well as aminoacids, toxic products resulted from decay in the intestines — indican, fenol,
indole.and skatole.
The level of azotemia 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.

Renal Glomerular (Azotemic) Acidosis

As a result of excretory dysfunction of the glomeruli there is delay of excretion of

organic acids (aminoacides) and their increased concentration in blood — hyperacidemia.
Acids push out hydrocarbonates, decrease the alkaline reserve of the blood to 18-13.5
mmol/1 (25-31 mmol/1 in the norm) that results in acidosis.

Electrolyte Disorders

There is accumulation of ions of magnesium and potassium in the extracellular space and
blood (hyperkaliemia, hypermagniemia) with decreased concentration of sodium
(hyponatriemia) and chlorine (hypochloremia) in blood plasma.
As a result of excretory dysfunction of the glomeruli there is delay of excretion of
phosphates, sulfates and their increased concentration in blood — hyperphosphatemia,
hypersulfatemia. Anions of these substances push out hydrocarbonates in the extracellular
fluid, decrease the alkaline reserve of blood that aggrevates acidosis.

TUBULAR RENAL INSUFFICIENCY

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 substences appear in final urine or accumulated in the blood.
Reabsorption is desordered (suppessed or activated) with the hormonal insufficiency.
Glucosuria develops in the insulin deficiency (diabetes mellitus). Sodium (bicarbonates)
and potassium are lost with the urine in aldosterone deficiency. Increased secretion of
aldosterone results in systemic edemas, tubular acidosis and arterial hypertension. Deficit

42
of the antidiuretic hormone of hypophysis (vasopressin) results in loss of water with the
urine when more than 10 l of water is derived with the urine).
Tubular insufficiency is manifested also in the form proteinuria and cylindruria (they are
the proteins, coagulated in the tubules and also the exfoliated epithelium of tubules).
For the reversed reabsorption of aminoacides, the specific enzymes are needed for every
of them. Genetically determined deficit (enzymopathy) of them is the frequent reason of
tubular renal insufficiency. In such a cases, corresponding aminoacid is detected in final
urine.

Disorder of Tubular Secretion

By secretion in tubules, the kidneys reveal hydrogen (acidogenesis) and ammonium

(ammoniogenesis). The disorder of these processes results in the acid-base disbalance
(described in chapter “Disorder of acid-base balance”) as excretory non-respiratory
acidosis.
Excretion of medicines from the organism also occurs by tubular secretion. The
pharmacodynamics is disrupted in tubular renal insufficiency.

INTERSTITIAL RENAL INSUFFICIENCY

Interstitial renal insufficiency underlies disorder of incretory function of kidneys.

Hypersecretion of renin results in arterial hypertension development and (by stimulation
of aldosteron secretion) systemic edema. On the background of sclerotic process in renal
interstitium, the incretion of renin is supressed, but it is not affects arterial blood pressure
significantly because this deficit is compensated by other vasopressive mechanisms, which
are too numerouse in organism. The critical significance belongs to reduction in the renal
prostaglandin secretion. Arterial blood pressure rises together with the development the
renal form of arterial hypertension.
Erythropoietins deficit results in anemia.

MANIFESTATIONS OF THE RENAL INSUFICIENCY

URINARY SYNDROME

The analysis of urine plays a central role for the characteristics of the renal function
disorders.
Diuresis is a daily amount of urine. The amount of urine produced by the kidneys is equal
to difference between the amounts of fluid having been filtered in the glomeruli and

43
reabsorbed in the tubules. So, a change in the total quantity of urine may result of
dysfunction of the glomeruli or 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 its decrease less than 100 ml/day.
A change in the urine gravity is characterized by such terms -
Hyposthenuria is a decrease of urine gravity lower than 1010 (to 1002). This urine
gravity conferms the fact that the kidney is capable of accomplishing 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 of urine gravity higher than 1010 (to 1040). This urine
gravity conferms the fact that the kidney is capable to concentrate the primary urine. The
development of uremia will not be typical for the patient. However, the ability to dilute the
primary urine is reduced. Consequently, the development of systemic edema is possible.
Isostenuria is monotonic urine gravity with constant indice 1010. This urine gravity
conferms the fact that the kidneys are not capable neither concentrate nor dilute the
primary urine. Consequently, the development of edema and uremia is possible.
Pathologic admixtures in the urine is an appearance of substances or cells, which are not
typical for the standard.
Glucosuria is an appearance of glucose in the urine. Glucosuria is the central symptom
of diabetes mellitus.
Proteinuria is an appearance of a protein in the urine. The types of renal proteinuria
(glomerular and tubular) caused by increased permeability of the glomeruli is due
physical and chemical changes in the basal membrane observed above.
Extrarenal proteinuria (false proteinuria) is not connected with renal impairment and
may occur in
 hard work,
 overcooling,
 fluid loss in babies,
 after having meal with large amount of proteins, especially in children (alimentary
proteinuria),
 circulatory insufficiency,
 infectious diseases,
 some toxic conditions,
 thyrotoxicosis,
 mechanical and parenchymatous jaundice,
 enterocolitis,
 ileus,
 burns,
 inflammatory process in the ureter (usually protein is no more than l g/1).

44
 Urine acidity togather with increased content of ammonium salts are the signs of the
systemic acidosis.
Hematuria is an appearance of erythrocytes in the final urine and is determined as the
cellular pathologic admixtures while microscopy examination of urinary sediment. Renal
hematuria caused by damage and increased permeability of the glomeruli was observed
above.
Renal hematuria should be differentiated from extrarenal one, caused by trauma or
inflammation of the ureter. There is a large amount of fresh erythrocytes in the urine.
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.

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 it is breef rimind
without detailed explanation.
Nephritic edema is described in the chapter “Pathology of the water balance”. The
excessive secretion of renin, other mechanisms of the regulation of water balance
(aldosterone and vasopressin), and also hypoproteinemia underly the pathogenesis.
Systemic changes in the organism (hypoproteinemia, dysproteinemia, hypoalbuminemia,
hyper-a2-globulinemia) can lead to edematous syndrome. Simultaneously, secondary
aldosteronism develops due to hypovolemia (the cause of which is "leakage" of fluid into
the tissues, decrease of the renal blood flow and increased production of renin).
Arterial hypertension is described in the chapter “Pathophyology of systemic blood
circulation”. The excessive secretion of renin and the insufficient secretion of renal
prostaglandins play the leading role in the pathogenesis.
Anemic syndrome is described in the chapter “Pathophysiology of blood”. The deficit
of erythropoietins, the intoxication of bone marrow by toxic metabolic substances, which
appear in renal insufficiency, play the leading role.
Non-respiratory secretory acidosis is described in the chapter “Pathology of acid-base
balance”. In turn, it is divided into the glomerular (delay of amino acids in the blood) and
the tubular (disorder of acido- and ammoniogenesis, and also lack of reabsoption of
bicarbonates).
Disorder of hemocoagulation is diplaied as DIS-syndrone in acute or chronic renal
insufficiency.
Nephrolithiasis is a formation of concrements from the components of the urine
(urolithic disease).
Syndrome of nephrogenous cardic insufficiency is connected with the disbalance of
electrolytes - sodium, potassium, and calcium.

45
 Syndrome of nephrogenous osteodistrophy is connected with the disbalance of
calcium and its salts.

ACUTE RENAL INSUFICIENCY

Acute renal insufficiency is a state characterized by acute disorder of homeostasis

due to considerable and quick decrease of the rate of the glomerular filtration.
It is frequently a reason of patient death.

ETIOLOGY
Acute renal insufficiency is connected with tree groups of factors: prerenal, renal and
postrenal.
Prerenal factors are:
 blood loss, burns, incontrollable vomiting, profuse diarrhea, use of diuretics
resulting in acute decrease of the intravascular and extracellular fluids volume.
 vascular forms of shock (septic, anaphylactic), collapse, accompanied by acute
hypotension (decrease of the arterial blood pressure less then 80 mm Hg),
 acute (myocardial infarction, embolism of the pulmonary artery) and chronic cardiac
insufficiency,
 mismatched hemotransfusion,
 massive trauma of tissues (crush-syndrome).
Renal factors are:
 injury by nephrotropic poisons,
 ischemia of kidney,
 thrombosis of renal artery,
 disseminated intravascular blood coagulation (DIS-syndrom).
Postrenal factors are:
 obstruction of the ureter (calculi, tumors),
 retention of the urine at the level of the bladder outlet (adenoma of the prostate).

PATHOGENESIS

Pathogenesis consists in the acute disorder of nephritic filtration.

The main mechanism of acute renal insufficiency development is a temporary ischemia of
the kidneys conditioned by hypovolemia, spasm of the afferent arterioles, disseminated
intravascular blood coagulation with microthrombosis or direct damage of the renal vessels.
In consequence there is marked decrease of the filtration pressure and glomerular
filtration, switching off of a definite number of the nephrons.

46
 Under the influence of the nephrotoxic factors (toxic, infectious) together with disorder of
the cortical blood flow, direct damage of the glomerular and tubular structures becomes
important. The rate of the glomerular filtration may be decreased secondarily due to
obstruction of the tubular lumen by necrotic masses or due to leakage of the filtrate
through the wall of the damaged tubules into the interstitium.
Increased pressure in the Shumlyansky-Bowmen capsule results in decrease of effective
filtration pressure.
In damage of the cells of the proximal tubule reabsorption of Na + is disturbed. Its
increased concentration in the distal tubules is taken by mascula dense that result in
activation of renin-angiotensin system.
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 homeostasis and acid-base balance.

STAGES

There are four stages are distinguished in 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.

MANIFASTATIONS

The main clinical manifestations are nausea, vomiting, the brain edema, interstitial
lung edema, the clinical picture of water intoxication of the organism, severe disorders of
blood circulation, decrease of contractile function of the heart, arrhythmia as extrasystole,
bradycardia, blockade, arterial hypotension with transformation into arterial hypertension,
dyspnoe by Kussmaul's type (a sign of acidosis), severe dysfunctions of the nervous
system (headache, vomiting, loss of consciousness, convulsions, coma), anemia.
All these events are symptomes of azotemia.
Most of patients suffering from acute renal insufficiency die. Treatment is based on
the usage of artificial dialysis.

CHRONIC RENAL INSUFFICIENCY

Chronic renal insufficiency is a clinical picture of the leading nephritic

functions disorder as a result of the chronic disease of kidneys.

ETIOLOGY

47
 The etiological factors of chronic renal insufficiency most frequently are intrarenal.
They are the causes of chronic progress in kidneys of nflammatory (chronic
glomerulonephritis, chronic pyelonephritis, etc.), vascular (arterial hy pertension,
stenosis of the renal artery) and metabolic (diabetic g lomerulosclerosis, amyloidosis,
gout) origin.

PATHOGENESIS

Pathogenesis consists in the decrease of amount of the nephrons.

Chronic renal insufficiency develops as a result of simultaneous or subsequent decrease

of the mass of the acting nephrons and reduction of the renal functions.
The initial signs appear in reduction of the mass of acting nephrons to 50-70% of
the original amount of the nephrons. Clinically marked picture develops in
reduction of mass to 30-10%. Further reduction of mass and glomerular filtration
(below 10% of the norm) leads to terminal stage of renal insufficiency — uremia.

STAGES

There are three clinical stages are distinguished -

 initial stage develops when the remainder of the nephrons composes 50-30%. This
stage is characterized by polyuria. Diuresis increases as a result of the acute decrease of the
reabsorption of water. The urine gravity approaches 1010,
 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.

UREMIA

The main manifestations are conditioned by azotemia. Uremia is an accumulation

in the blood of those substances, which must be excreted with the urine. They are urea,
creatine, creatinine, phenols, indoles, aminoacids, hormones. Furthermore, many new toxic
substances are formed. Over 200 toxic substances are revealed. Just they determine
the organism intoxication and associated symptoms.
They are anorexia (loss of appetite), dyspeptic signs (vomiting, diarrhea), reduction of
the body mass, weakness, headache, apathy, disorders of taste, hearing, itching, dyspnoe,
progressive anemia, uremic pericarditis, myocarditis, pleuritis, arthritis, convulsions and
coma.

48
GLOMERURONEPHRITIS

Glomerulonephritis is a bilateral infectious-allergic disease of the kidneys of

the inflammatory origin with the preferred demage of the nephrons.
There are acute and chronic (diffuse) glomerulonephritis.

Experimental Models

The experimental models of glomerulonephritis in animals are interesting because

they conferm, that the inflammation of kidneys cannot be reproduced in the experiment by
any usual inflammatory agent, but only by way of the reproduction of immunological
reactions.
In 1901 V. K. Linderman (in Kiev University) observed the main manifestations of
nephritis in the rabbit in the intravenous introduction of nephrotoxic serum of the guineapig
immunized with suspension of the rabbit kidney.
In 1933 by using the same scheme of experiment, a Japanese scientist Masugi
reproduced the clinical picture of nephritis in rabbit by introducing serum of the duck blood
immunized with the tissue of the rabbit's kidneys.
There are two phases of pathogenesis of the experimental glomerulonephritis:
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 for nephrotoxic globulin.

ETIOLOGY

Acute glomerulonephritis arises in (or after) some infection, mostly of

streptococcus nature. It is considered, that hemolytic streptococcus A group is a specific
"nephritogenic" biological factor. Other infections play a definite role, including viruses,
parasites. Glomerulonephritis may arise in cooling, diffuse lesions of the connective tissue
(systemic lupus erythematosis, rheumatoid arthritis, and nodular periarteritis) as well as in
serum disease and others, which are related to the immune complexes.
There are the following forms of the acute glomerulonephritis:
 infectious (poststreptococcal, in malaria, syphilis, tuberculosis);
 non-infectious (serum, vaccine, medicamentous, in intoxication by different
poisons, traumatic, in thrombosis of the renal veins);
 in diffuse diseases of the connective tissue (rheumatoid ar thritis, lupus
erythromatosus, hemorrhagic vasculites, etc.);
 special (radiation, hereditary, etc.)

PATHOGENESIS

49
 The antibodies, which are formed to the antigen of microbe simultaneously, damage the
basal membrane of nephritic filter. Further, the damaged nephritic tissue becomes the
object of autoimmune aggression. Autoantibodies against own tissue of kidneys are
determined in patient.
There are two main mechanisms of glomeruli damage:
1. Affection of the basal membrane of the glomeruli of the nephrons by antibodies, so-
called nephrotoxic glomerulonephritis (it has a quick progressive course).
Glycoprotein is a carrier of antigenic proteins of the basal membrane.
2. Development of the inflammatory process in the glomeruli due to fixation of
the immune complexes on the basal membrane — immunocomplex
glomerulonephritis.
The mechanism is characterized by either exogenic (of infectious or noninfectious
origin) or endogenic (tissue protein, DNA) antigen. The formed antibodies (IgG,
IgM) begin to interact with the mentioned antigens in blood serum and then as
immune complexes (antigen-antibody-complement) enter the glomeruli
accumulating on their basal membrane. The impairment of the immune complexes and
nephrotoxic antibodies is realized by induction of the immune inflammation.

Manifestations

Clinical and pathophysiological manifestations of acute glomerulonephritis

reflect changes in kidneys, mainly glomerular and extrarenal functions.
Violent onset, oliguria, azotemia, arterial hypertension characterize the classical
course of the disease. Proteinuria, hematuria, and leukocyturia characterize urinary
syndrome. Arterial blood pressure is increased. Edema develops due to retention of
sodium, hypoproteinemia, hypervolemia, and increased permeability of capillaries.
Disorders of the nervous system must be added. The prolonged course of this disease
leads to the development of chronic kidney insufficiency and uremia.

Treatment

Understanding the pathogenesis of this disease is important for constructing the proper
pathogenetic therapy. Not one antipyretic or anti-inflammatory drug can be effective. The
desensitizing therapy is necessary. Imunodepressants (glucocorticoids) are used most
frequently.

Chronic (Diffuse) Glomerulonephritis

50
 Etiology
Chronic glomerulonephritis may result from acute one, but more often it develops
primary.

Pathogenesis

Hypersensitivity of the delayed type plays a certain role. The following forms are
distinguished clinically -
1.The latent form (65% of all cases with chronic glomerulonephritis) is manifested by
isolated urine syndrome — moderate proteinuria, hematuria. Some patients (20-25%) are
observed to have edema and transitory hypertension.
2. The hypertensive form (32% of patients) is characterized by stable increase of the arterial
blood pressure. 1/3 of patients have edema, 2/3 — hematuria, all patients have proteinuria
and half of them have cylmduria and leukocyturia.
3. The nephrotic form (2-4% of patients) which is distinguished by edematous syndrome
(2/3 of patients) marked proteinuria and cylinduria (in all patients) and characteristic changes
in blood (hyperproteinemia and hyperlipidemia).
4.The mixed or nephrotic hypertensive form (2.4% of patients) is characterized by
edemas and hypertension (in all patients).

Nephrotic Syndrome

Nephrotic syndrome includes various affections of the kidneys and other organs which
are characterized by marked proteinuria, hypovolemia, dysproteinemia, hyperlipidemia and
edematous syndrome. 

Consequences of Albuminuria in Nephrotic Syndrome

Table

Proteinuria Consequences of
diminished amount of
Albumin Hypooncia, edema
Antithrombin III Predispose to thrombosis
and thromboembolism
Factors of Hemorrhagic syndrome
blood
Components of Decreased resistance to infection
[gG Decreased resistance to infection
HDL Predispose to atherosclerosis
Proteins and Deficiency of Fe, Zn, Cu
Proteins Endocrine disturbances
transporting

51
 Etiology

By origin, nephrotic syndrome is divided into primary and secondary.

Primary nephrotic syndrome is not connected with the kidneys disease. Frequently its
development is based on genetically conditioned defects of metabolism (lipoid nephrosis) or
transplacental transfer of specific antirenal antibodies from the mother to the fetus
(congenital family nephrosis).
Secondary nephrotic syndrome may be caused by some diseases of the kidneys
(glomerulonephritis) or other organs (nephropathy of the pregnant women, diabetes mellitus,
amyloidosis, lupus erythematosus, serum disease, staphylococcal sepsis, etc.). It may be
observed in intoxication with salts of heavy metals, burns, radiactive affection, rejection of
the renal transplant, use of some medicines (sulfa drugs, penicillin, corticosteroids) and in
disturbance of blood supply of the kidneys.
For those forms of nephrotic syndrome where immunological mechanisms are not
proved, the most suitable are metabolic and physico-chemical mechanisms. So, nephrotic
proteinuria is explained by decrease of the electric charge of the wall of the capillary net,
and disappearance of sialoprotein from it. At the places of maximal loss of ions and
sialoproteins, polymorpho-nuclear leukocytes are accumulated whose lysosomal ferments
damage the basal membrane of the capillary vessels. Systemic changes in the organism
(hypoproteinemia, dysproteinemia, hypoalbuminemia, hyper-a2-globulinemia) can lead to
edematous syndrome. Simultaneously, secondary aldosteronism develops due 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 by nephrotic syndrome, is brought about, mainly,
by thriglycerides, cholesterol and pathogenetically it is connected with protein metabolism
and suppression of the lipolytic activity of blood plasma.

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 intestinal tissue.

Etiology and Pathogenesis

The disease arises due to penetration of the causative infectious agent into the kidneys by
hematogenic way or by spreading it upward from the urinary tract. The causative agents are
mostly colon bacillus, cocci.

52
 Development of the disease and transition of acute pyelonephritis into chronic one is
promoted by different conditions causing urine congestion (constriction, occlusion of the
ureter, adenoma of the prostate), dystrophy of the urinary tracts, systemic diseases, which
reduce the reactivity of the organism (diabetes mellitus, atherosclerosis, obesity, chronic
intoxication, etc.)

CHAPTER 30

PATHOPHYSIOLOGY OF ENDOCRINE SYSTEM

Endocrine system plays important role in the 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 effect.

Regulation of Endocrine Function

The function of endocrine system is regulated by nervous and endocrine mechanisms.

In spite of relative independence, endocrine glands are subordinated to the regulator
influences of nervous system. The disorder of the endocrine glands functions with the
emotional stress confirms the participation of brain in the regulation of endocrine function.
The nuclei of limbic system, reticulated formation and diencephalon influence the
secretion  of hormones.
The participation of vegetative nervous system in the regulation of physiological and
pathologic processes in endocrine system also takes place. The vagus excitation
strengthens the secretion of insulin; sympathetic nerves stimulate the adrenaline secretion
from the adrenal glands.
The central regulation of endocrine functions is achieved in two ways - nervous and
neurohumoral.
The main centers of the endocrine system regulation are located in hypothalamus. In
turn, hypothalamus function is connected with other divisions of brain. Neurosecretory
cells of the hypothalamus produce peptide neuropituitary hormones (vasopressin and
oxytocin), accumulating in the posterior lobe of the pituitary and coming into the blood
from there. They are addressed to the peripheral target cells. Hypothalamus regulates the
function of pituitary gland with the aid of the releasing-factors (stimulating oligopeptides
liberins and the inhibiting ones are statins).
The tropic hormones of pituitary gland are the important mechanism of the regulation
of peripheral endocrine glands.
Interrelations between the central (hypothalamus, pituitary gland) and peripheral
endocrine glands are characterized by important peculiarity – it is the regulated
mechanism of direct and reversed relations. Increased concentration of the hormone
inhibits stimulating effect on this hormone synthesis. Decreased concentration causes an
adverse effect.

53
 Interglandular hormonal connections are the important mechanism of regulation.
Interrelations between the hormones are characterized as antagonism, synergism and
permissive function. The latter consists in the providing optimal conditions for the
physiological activity of one hormone by another.
The regulated influences of hormones are achieved with the aid of the receptors, which
are located on the cellular membrane of endocrine cells. Intracellular messengers provide
the transmission of the regulated influences from the receptors to the cellular nucleus.
The synthesis of any hormone requires specific substrates and enzymes and determines
by genetic mechanisms.
The predecessors of hormone are transformed into the final hormone.
The secretion of hormone from the glandular cells is an energy depending process.

Mechanisms of the Hormones Peripheral Effect

Released hormone is transported to the target 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
fermentative process.
The hormonal effect on a target 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.
The brief enumeration of the physiological aspects of the endocrine glands functions
helps to understand a numerous reasons, which lead to the endocrine pathology.

Participation of Hormones in the Development of Typical Pathologic Processes and

Leading Pathophysiological Syndromes

The participation of endocrine system in the development of different pathological

processes 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 the development of inflammation was
mentioned. Glucocorticoids were mentioned as the leading therapeutic means for allergy
treatment.
Hormones play important role in the development of all typical metabolic disorders –
the role of insulin in the development of diabetes mellitus, thyroxine - in the disturbance of
basal metabolism, aldosterone and vasopressin in the development of edema.
In the development of arterial hypertension catecholamines (adrenaline), aldosterone and
vasopressin play important role. The role of aldosterone and electrolyte disbalance in the
development of the myocardial necroses (infarct) was mentioned also.
It was mentioned, that in hepatic insufficiency the destruction of hormones is depressed,
and the picture of endocrine hyperfunction with the relative surplus of hormones is

54
observed. The kidney insufficiency, as it was mentioned, is accompanied with arterial
hypertension of nephritic origin and edema, in the development of which an important role
belongs to renin (hormone-like substance), aldosterone and vasopressin (antidiuretic
hormone).

ENDOCRINE INSUFFICIENCY

Endocrine insufficiency is an acquired and the 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 hypofunction,
hyperfunction and disfunction.

TYPES
Classification

Several classifications of endocrine insufficiency are suggested depending on the

different principle, which are the basis of classification.
As to the participation of genetic mechanisms it is divided into acquired and
hereditary.
Monoglandular endocrine insufficiency is the pathology of one signal endocrine gland.
The polyglandular endocrine insufficiency is the 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 is disrupted.
The division of endocrine insufficiency into the relative and absolute reflects the fact
that the production of hormone can be normal, however, metabolic dismetabolism is
similar to those that occur with the absolute deficit or surplus of hormone. The reasons of
relative endocrine insufficiency are located out of the endocrine gland. Relative endocrine
insufficiency can be complicated by absolute.
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
illness.
As to the clinical current, endocrine insufficiency is divided into acute and chronic.
The age of patient has great significance in the 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 also significant.
Each form of endocrine pathology is manifested in turn in the form of three syndromes –
hyperfunction, hypofunction or dysfunction. Dysfunction means the differently directed

55
changes of the production of different hormones in one gland or the formation of atypical
hormonal compounds.

METHODS OF EXPERIMENTAL STUDY

It is most easy to illustrate the role of experiment in the pathophysiology and its forms
by experimental study of the endocrine pathology.
The method of removal is the extirpation (ectomy) of endocrine gland.
The method of overload consists in the introduction of hormones or endocrine gland
extract into the animal.
Method of damage is the injury of endocrine gland by radioisotopes or immune
antibodies.

ETIOLOGY

Etiological factors, which lead to the endocrine insufficiency, are physical, chemical and
biological.
Among the physical factors the mechanical trauma and especially ionizing radiation
have the greatest value.
Among the chemical factors both deficit and surplus of microcells (iodine, cobalt),
poisons, radioactive nuclide and medicines have a value.
Biological factors include infectious, 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 the hypophysis - somatotropic STH or of thyrotropic TTH, prolactin,
antidiuretic hormone of hypophysis - vasopressin, and insulin) is possible. The production
of autoantibodies against the cells of endocrine gland, and also against the receptors on the
membrane of endocrine cells or target cells is possible also. There is a type of delayed type
autoimmune reactions, so-called, stimulating, when antibodies perform the stimulating role
for the receptors 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 protein
receptor, the defects of the endocrine glands genesis. Chromosomal and moleculo-genetic
diseases include the pathology of endocrine system. The patients with the syndromes of
Turner -Shereshevsky, Klinefelter are sterile.
Psychogenic overload and stress can be the factor of damage (cause thyrotoxicosis,
diabetes mellitus, disturbances of ovarian-menstrual cycle).

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

56
glands function. These pathologic processes are the following - inflammation (including
allergic and infectious), tumor, thrombosis, the disturbance of hemostasis, atrophy,
dystrophy, genetic disorder, dismetabolism.

Preglandular Disregulatory Endocrine Insufficiency.

Disorder of the Central Mechanisms of the Endocrine System Regulation

In such cases the pathology develops in the organs, which regulate endocrine functions.
The following reasons and mechanisms are possible:
 Disorder of high nervous activity, for example, mental trauma frequently lead to the
endocrine diseases (diabetes mellitus, thyrotoxicosis, amenorrhea). It is the so-called
psychogenic endocrinopathy. Destruction or stimulation of limbic system, reticulate
formation, diencephalon together with irritation or blockade of the central and
peripheral mechanisms of vegetative innervation damage formation and secretion of
hormones.
 Disorder of the neuroendocrine regulation of endocrine system is caused by pathology
of hypothalamus or other part of the brain connected with it. Hypothalamus pathology
usually involves entire endocrine system. These diseases are called neuroendocrine
(hypothalamic syndrome). The damage of central regulatory mechanisms are
accompanied by pluriglandular endocrine insufficiency.
 Pathology of the hypophysis, which secretes the tropic regulated 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. Reduction in hypothalamus sensitivity to the
effect of peripheral hormones leads to the more intensive production of releasing-
factors and tropic hormones of hypophysis. As a result, the peripheral gland activates
its function and results in exhaustion and insufficiency. Most frequently peripheral
gland answers not by activation of function, but the growth and the formation of
tumor (adenoma of prostate gland, the fibromyoma of utery). If patient uses some
hormone for the purpose of treatment (for example, prednisolone with the rheumatism),
the peripheral gland becomes less sensitive to the corresponding tropic hormone of
adenohypophysis. It creates a problem of cancellation of hormonal therapy.
 All endocrine glands act as united system due to the interendocrine relations. It leads
to the situation, when the pathology of one gland causes another. For example, the
removal of the thyroid gland leads to the disturbance of the sexual glands and adrenal
cortex.
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

57
 Glandular form of hormonal insufficiency appears as a result the 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 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).
Hypofunction, hyperfunction and dysfunction manifest this form of hormonal
insufficiency.
The following mechanisms are possible:
 Disorder of receptor system on the surface of endocrine cell, namely, the sensitivity of
these receptors and endocrine gland to regulatory signals. As a result, the synthesis of
hormone in response to the regulatory nervous and hormonal influences stops.
 Disorder of intracellular messengers (adenylate cyclase system) which transfer signals
from the receptors to the genetic apparatus of cells. Damage of the Ca-ion entering into
the cell.
 Deficit of the substrates, microelements and ferments, which are necessary for the
hormone synthesis.
 Infectious damage of endocrine gland.
 Immune damage of gland (formation of antibodies against the gland).
 Destructive changes of gland (tumor, cirrhotic and inflammatory processes, a sclerotic
changes in the vessels).
 Cytotoxic damage of glandular cells by chemical (including medicinal) substances.
 Disorder of the prohormone transformation into the final hormone.
 Disorder of the hormone secretion.
 Genetic problems of the glandular cells functioning.
 Overproduction of hormones as a result of neoplasia (adenoma).

Postglandular Disorders.
Disorder of the Peripheral Hormone Effect

The postglandular disturbances of endocrine function lead to the relative hormonal

insufficiency. It is characterized by normal hormone production, however, the
dismetabolism 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).

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 Pathology of receptors to the hormone on the target cells, which determine the
sensitivity of cells 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 hormone
resistance. While aging, a quantity and sensitivity of receptors usually decreases. The
manifestations of hormonal insufficiency in elderly people are connected with it.
 Genetic pathology of the proteins, which participate in the endocrine function –
antagonists, transport proteins, receptor proteins, ferments that determine the hormone
synthesis, ferments that determine binding and release of hormones from the transport
blood proteins.

Compensatory-Adaptive Reactions

Endocrine system is a regulatory system of endocrine glands, transportation and

destruction of hormones. 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 change. They are the following:
 Presence of paired endocrine organs (the adrenal glands, ovaries).
 Hypertrophy of the pare organ during pathological process or removing one of them.
 Reverse connections between peripheral and central organs of endocrine system.
 Synergestic and permissive action of the hormones.
 Liability of the binding of hormone with the transport protein.
 Change in the quantity of receptors to the hormone on the target cells in dependence
with the content of hormone in the blood.
Concluding the account of the common concept of etiology and pathogenesis of
endocrine insufficiency, one should emphasize, that the common that is united all
endocrine glands was dismantled.
The points of hormone effect are the target cells. For each hormone they are specific.
The pathophysiological and clinical manifestations of endocrine insufficiency depend on
the endocrine gland and type of target cells, which function is disrupted.

PATHOLOGY OF PITUITARY GLANDS

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 pituitary. They are vasopressin (antidiuretic hormone, which
influences revealing of water from the organism), oxytocin.

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 Pituitary insufficiency may be total (panhypopituitarism) and partial in form of separate
pathology of adeno- or neuropituitary, hyper- and hypofunction.

Panhypopituitarism

Total insufficiency of the pituitary function may be congenital or acquired. The most
often causes of this disease are tumor, postnatal necrosis of the pituitary, inflammation,
thrombosis and viral infection. The affection of the glands in embryo leads to a dwarfism
(hypophysal nanism), hypogenitalism, and decrease of the function of the thyroid gland,
endocrine-methabolic disorders and decreases of the reactivity.
When more than 95% of the gland mass is destroyed, the adult people develop
hypophysial cachexia or 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.

Pathology of Neurohypophysis

The increased secretion of vasopressin (antidiuretic hormone) promotes the

accumulation of the liquids in the organism. It plays an important role in the pathogenesis
of reflex anuria (for example in pain shock) and edema, especially in cirrhosis of the liver,
when inactivation of the hormones is inhibited.

Deficiency of vasopressin disturbs 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 relative density per day. Sometimes diuresis consists of 10-12 liters and
more.

Hyperfunction of Adenopituitary

The hyperfunction of adenohypophysis is more frequently partial. It is the development

of benign tumor (adenoma) from some cells.
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 the ability of the hormone to increase the permeability of the cell membrane
to amine acids. Also it has an ability to accelerate their inclusion in synthesized proteins, to
stop disintegration proteolysis.

60
 Increased lypolysis and inhibition of the lipid formation from the carbohydrates increases
the mobilization of fat from depot, contents of non-estherised fatty acids in blood, their
oxidation in the liver and formation of ketone bodies. 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 mellitus).
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 the pathology begins. Hypophysial gigantism
develops in excessive secretion of somatotropin in the young age, before the epiphysial car-
tilages get closed. Later after closing the epiphysial sutures and completion of the
growth hormonal shifts cause acromegaly.
In this disease separate parts of the body are disproportionately enlarged, the features of
the face are enlarged. Simultaneously splanchnomegaly (enlargement of the liver, the spleen
and the 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 basophilic cells which produce adrenocoritcotropin,
Itsenko-Cushing disease develops. The consequence of corticotropin hyperproduction is a
excessive secretion of cortizol and other glycocorticaids by the adrenal cortex glands.

Hypofunction of Adenohypophysis

Total hypofunction is more frequentl when all regions of adenohypophysis are

disrupted. Reason are inflammation of entire gland or its necrosis. It is manifasted by
severe fatal disease - Simonds, cachexia.
Partial hypofunction is a decreased production of any hormone of the pituitary.
Early falling out or depression of the somatotropic function of the pituitary leads to the
development of dwarfism or pituitary nanism. The diminution of the speed of synthesis of
proteins 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.
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.

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 PATHOLOGY OF THYROID GLAND

The basic hormone of the thyroid gland thyroxine influences metabolism.

There are five types of thyroid dysfunctions:
 hyperthyroidism (thyrotoxicosis), caused by an excess of thyroid hormone,
 hypothyroidism (myxedema), caused by a deficiency of thyroid hormone,
 goiter (Basedow's disease), a diffuse enlargement of the thyroid gland, caused by
promoted elevation of TSH,
 thyroid nodule, a focal enlargement of a portion of a gland, caused by a benign or
malignant neoplasm,
 abnormal thyroid functions tests in a clinically euthyroid patient.
The pathogenesis of the most common thyroid diseases involves an autoimmune
process with sensitization of the host's own lymphocytes by various thyroidal antigens.
Three major thyroidal antigens have been documented:
 thyroglobulin (Tg),
 thyroidal peroxidase (TPO),
 TSH receptor (TSH-R).
Both environmental factors (e.g. viral or bacterial infection or a high iodine intake) and
genetic factors (T- suppressor- lymphocytic immunodeficiency) may be responsible for
initiating of autoimmune thyroid disease.

HYPERFUNCTION ( HYPERTHYROIDISM )

These are many pathologic phenomena which are conditioned by the toxic action of the
exceeding quantity of thyroxin and thrijodtyronine.
The main mechanisms of increased effect of thyroid hormones which lead to
thyrotoxicosis development are:

 Increased thyroid hormones production ,

 weakening of thyroxin with thyroxin connected globulin,

 disorders of the metabolism of the thyroid gland hormones,

 increased sensitivity of the tissues targets to its influence.

Basedow Disease

Basedow disease is the most often manifestation is the diffuse toxic goiter.

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 Etiology. The most important etiological factor of thyrotoxicosis for the person is the
mental trauma. Infection and overcooling are considered to be predisposing factors.

Pathogenesis

In abundance of thyroxin and thrijodtyronine, the number of mitochondria in the cells

increases, they swell, increase the activity of oxidizing ferments (succinatdehydrogenase,
cytochromeoxidase, glycerophosphate-dehydrogenase), Na+, ATP-ase, etc.
Due to the high disintegration 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
in fats, accelerates disintegration of cholesterol and its utilization of the tissues, intensifies
oxidation of the fats in the liver and also increases the sensitivity of fatty tissues to
lipolytic action of adrenaline. Due to these changes mobilization of fats from depot arises,
explaining why the patients with thyrotoxicosis lose their weight and why
hyperchoiesterinemia and ketonemia occure.
Negative nitrogen balance gives evidence of the predominance of catabolism of
proteins.

Manifastations

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, excitation, vibration, increase in the basal
metabolism, emaciation.
The thyroid hormones disturb the metabolism of the cardiac muscle. Dystrophic
changes in the myocardium, disorder of atrio-ventricular conductivity, overloading of the
left ventricle are revealed. The energetic and plastic maintenance of the cardiac activity is
disturbed. 'Thyrotoxic" heart reacts inadequately to cholinergic and adrenergic
influences.

HYPOFUNCTION (HYPOTHYROIDISM)

Etiology

Etiological factors of hypothyroidism in the people are:

 congenital defects of biosynthesis of the thyroid hormones, which are connected with
congenital hypoplasia or aplasia of the thyroid gland,
 autoimmune aggression against glandular epithelium,

63
 infectious processes,
 surgical intervention,
 damage of the gland by thyrostatic preparations,
 radioactive iodine due to overdosage,
 deficiency of iodine and cobalt coming into the organism.
Hypothyreoidism is manifested by reduction of basal metabolism, decrease of the
blood sugar level, tendency toward atherosclerosis, edema.
Autoimmune aggression has great significance in the development of hypothyroidism.
In severe degree of the thyroid gland insufficiency, congenital or arisen in the early
childhood cretinism develops, in the adult people — myxedema.

Myxedema

Myxedema is a hypothyrosis with mucous edema.

Myxedema is characterized by decrease of metabolism and body temperature, obesity, and

immobility. 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 puffy with
poor mimics, the nose and the lips become thicker. Brittleness of the nails, hear falling out
and other trophic disorders are marked. The sexual function gradually subsides, the
intelligence decreases, memory is reduced, apathy and sleepiness appear, and in the late
period of the disease dementia appears.

Goiter

Goiter is an enlargment of the thyroid gland.

There are 3 types of goiter:
 thyrotoxic, with the increased function of thyroid gland (Basedow disease),
 hypothyroid, with reduced function of the thyroid gland,
 endemic with the normal function of the thyroid gland.
The first two types are observed above.
Endemic goiter is an enlargement of the thyroid gland due to iodine deficit in the
environment (in the water, in the food). In this case the production of the hormone of
thyroxine can be normal only because of an increase in the mass of gland.
This disease is widespread in Alp and other mountain regions of the world, where the
salt 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

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 Calcitonin interacts with receptors in kidneys and bones. This interaction stimulates
adenyl-cyclase activity and the generation of cAMP. Receptors for calcitonin are
localized in the cortical ascending limb of Henle's loop, while in bones, calcitonin receptors
are found on osteoclasts.
The main function of calcitonin is to lower serum calcium. This hormone is rapidly
released in response to hypercalcemia. Calcitonin inhibits osteoclastic 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 the inhibition of
resorption, ultimately decreases the level of serum calcium and phosphate.
Calcitonin accomplishes its antiresorptive effect acting directly on the osteoclast.
Calcitonin blocks bone resorption induced by a variety of hormones, including PTH and
vitamin D. The potency of calcitonin depends on the underlying rate of bone resorption.
Calcitonin also has a modest affect on the kidney to produce mild phosphaturia. With
prolonged administration of calcitonin, "escape" from its effects occurs.

PATHOPHYSIOLOGY OF PARATHYROID GLANDS

Primary hyperparathyroidism occurs due to excessive production and release of PTH by

the parathyroid gland. The main cause are:
 adenoma (80-85%),
 carcinoma (2-5%),
 diffuse hyperplasia (10% ) .
Secondary hyperparathyroidism occurs due to a defect outside the parathyroid gland. In
patients with chronic renal failure, there are many causative factors that contribute to the
enlargement of the parathyroid glands. They include
 decreased 1,25-(OH)2D production,
 reduced intestinal Ca absorption,
 skeletal resistance to PTH,
 renal phosphate retention.
In most cases of secondary hyperparathyroidism, parathyroid hyperplasia regresses
substantially with correcting underlying abnormality.

65
 In animal with experimental chronic parathyrosis we observe osteoporosis,
accumulation of the calcium salts in the kidneys, lungs, heart and other intestinal organs.
The walls of the vessels become thick, and the blood pressure increases. The animals die
from anemia as a rule.

Hyperparathyrosis

The origin of hyperparathyrosis in the people is connected with adenoma or

hyperplasia of the parathyroid gland. General fibrosis, osteodystrophy develop and is char-
acterized by pain in the muscles, bones, osteomalacia, deformation of the skeleton. Mineral
components go out from the bones and accumulate in the muscles and the internal organs.
Nephrocalcinoses, constriction of the lumen of the tubules of the nephrons or their
occlusion by calculi (nephrolithiasis) develop that result in renal insufficiency. Due to
calcareous deposition in the wall of the magistral vessels, hemodynamics and blood supply
of the tissues are disturbed.

The formation and the activity of the osteoclasts intensifies, their differentiation into
the osteoblasts inhibits. They participate in the formation of the bone tissue. The
absorsorption of calcium in the intestine increases, the reverse reabsorption of the
phosphate ions in the tubules of the nephrons gets decreased, the formation of the soluble
salts of calcium in the bone tissue and insoluble phosphate calcium in different organs
especially in the kidneys also increased.

Hypoparathyroidism

In the experiment hypoparathyroidism is reproduced by removal of the glands in dogs and

cats. In 1-2 days after the operation the animals become flaccid, refuse to take food, have
thirst, low body temperature, dyspnoe. There is a change of correlation of one-valent (Na,
K) and two-valent (Ca, Mg) ions due to reduction of calcium concentration in blood from
2.25-2.99 to 1.0-1.25 mmol/1.
Feeding of parathyroectomized dogs by meat intensifies tetany due to insufficient
disintoxication of products of nitrous metabolism, in particular, weakened ability of the
liver to convert ammonium into urea.
Etiology
Causes of hypoparathyroidism in people are:
 complication of thyroid or parathyroid surgery,
 autoimmune aggression,
 post- I,31 therapy for Graves' disease or thyroid cancer,

66
 secondary to iron overload, Wilson's disease,
 DiGeorge syndrome: autosomal recessive disorder with congenital absence of the
parathyroid glands and thymic dysgenesis or agenesis,
 hereditary forms of hypoparathyroidism: autosomal dominant or recessive and X-
linked recessive.
 secondary to magnesium depletion,
 tumor invasion (very rare),
 hereditary nephrosis.
Relative hypofunction of the glands is marked in accelerated growth, pregnancy,
lactation and other conditions when the organism requires more calcium and salts of
calcium.

Pathogenesis

The main evidence of hypoparathyroidism is hypocalcemia, which eventuates in

different disorders.
Simultaneously with hypocalcemia blood has increased contents of non-organic
phosphorus. The mineral disbalance is conditioned by inhibition of resorption of the bone
tissue, absorption of the calcium in the intestines and increased reabsorption of
phosphates in the tubules of the nephrons.
A definite importance is attributed to the disorder of desintoxicating function of the liver
in the pathogenesis of parathyroprival tetany.
Pathogenesis and clinical picture of hypoparathyroidism in the human are close to those
observed in the experiment.
Increase of neuro-muscular excitability. There are multiple fibrillar convulsions of
the body muscles, which are then followed by episodes of clonic convulsions. Clonic
convulsions change into tonic ones, opisthotonus comes. Spasm contractions may spread to
the inner organs (pylorospasm, laryngospasm). The animals die during one of such
episodes.
Dysfunction of the parathyroid glands results in development of parathyroprival tetany.
Children of 1st and 2nd year of life in have spasmophilia — periodic spasms of the
muscles, arising in the increase of the environmental temperature and other unfavorable
influences.
Laryngospasm is very dangerous as it may cause asphyxia and death.

PATHOLOGY OF ADRENAL GLANDS

There are 2 important parts of the adrenal glands – cortex and cerebral.
There are 3 groups of hormones produced in adrenal cortex – glucocorticoids
(hydrocortisone), mineralocorticoids (aldosterone) and sexual.

67
 Hypofunction of the Cortical Substance of the Adrenal Glands

Acute Insufficiency
After adrenalectomy the depot of glycogen in the liver and muscles is exhausted. It is due
to a reduction of glucose-6-phosphatase activity. The speed of glycogenolysis in the cells of
the liver is reduced. The formation of glucose from amine acids is delayed simultaneously.
All this leads to hypoglicemia, reduced sensitivity to insulin, increased tolerance to
glucose.
On the later stage of adrenal insufficiency blood pressure is decreased. Hypotension is
conditioned by reduction of the volume of the circulating blood, bradicardia and the
weakening of the vasoconstrictor action of catecholamins, for which corticosteroids are
permisive factor.
In the genesis of the acute adrenal gland insuffisiency the disorders of the water-
electrolyte metabolism play the main role. In physiological conditions aldosteron supports
sodium "pump", ensures the reabsorption of sodium ions in the distal parts of the tubules of
the nephron, but glucocorticoids increase the glomerular filtration.
After removal of the adrenal glands the sodium ions go out of the body with the urine
and that's why the content of sodium in plasma of blood is reduced. At the beginning, there
is marked polyuria and than oliguria and anuria, "water poisoning" (high cells hydration).
It is explained by the fact that due to disorders of sodium pump the intracellular concentra-
tion of soduim ions and the osmotic pressure are increased. The acute increase of
potasium ions concentration in plasma is the cause of bioelectric processes disorders. Force
and rhythm of cardiac contractions (up to ciliary arrhythmia), weakening of the contractive
ability of the striated muscle tissue take place.
In a terminal stage of acute adrenal gland insufficiency, the urination completely stops.
The pulse and the breathening are slowered down. The animal goes in coma and dies. The
life term of dogs and cats with ectomized adrenal gland ranges from 2-3 days up to 9-11
days.
Acute adrenocortical insufficiency in a human can happen due to hemorrhage in the
adrenal glands.

Chronic Insufficiency

Chronic insufficiency of cortical substance of the adrenal gland in a human 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 or
prolonged treatment by corticosteroid preparations.
Chronic hypoadrenocorticism is characterized by emaciation, psychical tiredness, bad
appetite, dysfunction of the alimentary canal, arterial hypotension, progressive
hyperpegmentation of the skin. The mechanism of hyperpegmentation is connected with
intensification of melanostimulating activity of the pituitary gland, which is concomitant to the
increase of corticotropin secretion during hypoadrenocorticism. In the patient with Addison's

68
disease, different pathogenic effects such as trauma, infection, hemorrhages and even tooth
extraction can cause acute insufficiency of the cortical substance of the adrenal glands.

Hyperfunction and Dysfunction of the Adrenal Cortex

The excessive secretion of cortisole, aldosteron (hyperaldosteronism), androgens
(adrenogenital syndrome) or estrogens (corticoestroma) are the leading pathogenic points,
determining the clinical picture of hyperfunction and dysfunction of the cortical substance.
Itsenko-Cushing Syndrome

The reason for this disease is adenoma of the cells, which produce hydrocortisone.
Etiology of Itsenko-Cushing syndrome and Itsenko-Cushing disease is various, but the
clinical symptoms and the pathogenesis are very similar. The disease arises as a result of
the excessive secretion of corticotropin in adenopituitary tumors or diencephalic
regulation disorder. The syndrome is the result of the primary affection of the cortical
substance of the adrenal glands by tumor.

Medicamentous Synrome of Hypercorticism

Glucocorticoids (prednisolone) are used as immunodepressant while treatment of

different inflamatory and allergic diseases (bronchial asthma, rheumatism). The side
effects of this therapy resemble the picture of the hyperfunction of the adrenal cortex
(Itsenko- Cushing disease).
Clinical picture has the following manifestations:
 decreased synthesis of protein, the weakness of skeletal muscles,
 hyperglycemia can assume the form of diabetes mellitus (metasteroid),
 deposition of fat on face,
 increase of the arterial blood pressure,
 increase in the acidity of gastric juice and an increase in the risk of the stomach ulcer
formation.
The prolonged application of a hormonal therapy forms hormone-dependence. It means
that the production of own hormone is reduced. The exidental cancellation of this
hormonal therapy is accompanied by the development of the syndrome of cancellation.
Clinical picture is manifested as the acute hypofunction of the adrenal cortex.
The clinical manifestations of the syndrome of cancellation are the following:
 hypoglycaemia,
 hypotension,
 reduction in the resistance of organism,
 muscular weakness,
 depression,
 disorder of growth and maturation of children.

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 Hyperaldosteronism

Under the influence of excessive aldosterone, sodium and water ions are retained in the
organism. The high concentration of sodium ions in the cells, especially in vessels walls,
increases their sensitivity to sympathetic mediators. In consequence, arterial hypertension
develops. Loss of considerable amount of potassium and chlorine ions causes myasthenia and
paresis, attack of the skeleton muscular cramps, disorders of myocardial contractive function,
non-gas alkaloids. The tubules of the nephrones are subject to dystrophic change and lose
ability to react to vasopressin. So, poliuria arises, which explains absence of edemas in
primary hyperaldosteronism.
In many pathologic conditions (cardiac insufficiency, cirrhosis of the liver, kidney
diseases with disorders of kidneys circulation, etc.), excessive production of aldosterone is
observed (secondary hyperaldosteronism). Decrease of blood pressure, hypovolemia, and
insufficiency of kidney depressor system and increased secretion of rennin by
juxtaglomerular cells with the following formation of angiotensin play the main role in
development of such sings. It is known that cells in the clustered zone of the adrenal glands
intensify production of aldosterone under the influence of angiotensin, ACTH (permissive
effect), abundance of K+ and Na+ deficit in blood plasma. Atrium natriuretical hormone
(antagonist of angiotensin), dopamine and high outcellular Na+ concentration inhibit secretion
of aldosterone.
Secondary hyperaldosteronism promotes retention of sodium and water in the organism,
loss of potassium and chlorine, development of edema, increase of blood pressure.

Adrenogenital Syndrome

Adrenogenital syndrome in a child is a clinical manifestation of congenital hyperplasia of

the cortical substance of the adrenal glands.
Arising of the syndrome is connected with hereditary blockade of cortisol synthesis.
Secretion of corticotropin becomes disinhibited which stimulates secretion of androgens of
the adrenal glands. The latter has a virilizing effect — appearance and more evident signs of
the masculine sex in the intrauterine period. Consequences of hormonal disorders may be
different — from mild masculinisation 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. One of the androgenital syndrome variants in
children is characterized by deep disorder of ferments, which participate in biosynthesis of
steroid hormones and accompanied by severe disorders of water-electrolyte metabolism.
Without substitutional therapy with corticosteroids children die at early age.

70
 If the hormone synthesis is blocked at the last stage, which is catalizated by 1.1-
hydroxilase, the excess of desoxicosterone is formed. In consequence, severe arterial
hypertension develops.
Adults and children can have hyperestrogenisation and hyper-androgenisation of the
organism in tumor of net (internal) zone of the adrenal glands cortical substance.
Depending on hormone secretion character, women can have development of virilisation,
men can have feminization (heterosexual syndrome) or person have premature sexual
development (isosexual syndrome).

Dysfunction of the Cerebral Part of the Adrenal Glands

Hypersecretion of catecholamines is observed in pheochromocytome. It is a tumor

originated from the cerebral substance of the adrenal glands with paroxysmal or stable
arterial hypertension or attack of tachycardia, acute pain in epigastrium, profuse
sweating. The attack is a result of massive throw out of adrenaline and noradrenaline into the
blood under the influence of psychical and physical loading and other provocatory effects.

CONCEPT OF STRESS

Stress was mentioned in many chapters as a reason of a disease (arterial hypertension,

myocardial infarction, stomach ulcer, diabetes mellitus, thyrotoxicosis and others).
The study about the 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 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 adrenal cortex.
Physiological role of glucocorticoids was revealed. It consists in
 activation of glyconeogenesis,
 increase of glucose blood level (hyperglycemia),
 increase of energy formation,
 reorganization of metabolism,

71
 protection of the membranes from damage,
 antipyretic effect,
 antiallergic effect,
 support of catecholamin effect.
Selye interpreted these changes as non-specific protective-adaptive reactions
developed at maximum. This group of symptoms he named as general (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 adaptive hormones.
Earlier W. Cannon and L. Orbelly studied the role of the sympathetic part of the
vegetative nervous system in the adaptive and trophic reactions. Selye added the concept
about the 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 neuro-humoral reaction with participation of the nervous
system and endocrine glands.
At the same time Selye revealed in experiments, that prolong tenseness of non-specific
adaptive reactions causes a typical complex of non-specific sighs of damage. They are:
 involution of the thymico-lymphatic apparatus,
 hemorrhage ulcers in the mucous membrane of the gastrointestinal tract.
Selye connected it with the prolong effect of adrenal cortex hormones. Really, in
experiment on rats, the prolong introduction of corticosteroids (combined with sodium
chloride) results in development of necrotic changes of the myocardium. Ulcers are observed
in pituitary ectomized animals.
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 damage under the action of any strong influence (stressor).
So, we see the dual significance of stress. From one side, it is a tenseness of
adaptation, promoting life due to releasing of adaptive hormones, from another side
(with the prolonged duration) it is a damage.

Stages of Stress

Stress is manifested in three stages. They are :

 anxiety reaction (alarm reaction),
 the stage of resistance,
 the stage of exhaustion.
Alarm reaction means immediate mobilization. In turn, it is subdivided into shock and
antishock stages.

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 In the 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 blood pressure,
muscular tonus and blood glucose level. Increase of corticotropin and corticosteroid
secretion occurs with release of hormone reserves.
In the stage of resistance the cortical substance of the adrenal glands is hypertrophied
and secretes an additional amount of glucocorticoids. Anabolic processes prevale.
Glyconeogenesis is intensified.
At this stage not only the resistance toward the factor, causing stress, is increased, but
also to other different factors, even lethal agents. It is manifested in diminishing of
inflammation, prevention of the heart, kidneys and other organs impairment arising under
the additional influence of pathogenic factors. It is called as increase of nonspecific
organism resistance.
In prolonged effect of the injurious agent adaptation gets broken. The transition of
resistance stage into the stage of exhaustion is characterized by exhaustion of the functional
reserves. 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 the arterial blood pressure, activation of proteolysis, development of
hemorrhagic ulcers in the stomach and duodenum characterize the third stage of stress.
In general, the stress outcome depends on the ratio of the force and duration of the
stressor effect and potential abilities of protective reactivity of the organism.

Diseases of Adaptation

Complex of adaptive reactions can be disturbed. According to Selye, endocrine

insufficiency (first of all hypo- and hyderfunction of pituitary and adrenal cortex) causes
adaptation insufficiency.
Introduction of glucocorticoids to the animals inhibits inflammation and immune re-
actions, cause impairment of the stomach and duodenum. Introduction of large doses of
desoxicorticosterone predisposes to the development of arterial hypertension,
nephrosclerosis, hyalinosis of the organs. Insufficiency of glucocorticoid secretion promotes
hyperergic course of inflammation and other pathogenic effects.
Selye considered rheumatism, bronchial asthma, some diseases of the kidneys, heart and
vessels, some skin diseases and others to be the diseases of adaptation. Any additional
influence of moderate force (overcooling, overheating, physical overstrain, excessive
intake of salt) is of a great significance in their arising.

Significance of Stress Concept

Stress concept has great influence on medicine development.

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 The study about the stress started the clinical use of hormones of the adrenal cortex in
medical practice. Selye gave theoretical groundation to corticosteroid therapy. It is used in
the gravest conditions in the departments of reanimation for increasing the resistance of
organism.
Use of the glucocorticoids, as immunodepressants, in allergy takes place. However, the
prolonged use of these hormones has sideline effect, which were named above.
Nonspecific therapy (autohemotherapy and acupuncture) was explained on its basis as
well as mechanisms of training with systematic influences of weak and moderate stimuli
(cold, physical exercises; muscular tension protects the animal from myocardial necrosis
caused by intravenous injection of proteolytic enzymes) on the organism, which support
the readiness of the endocrine system to adaptive reactions.

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