PATHOPHYSIOLOGY OF DIGESTION. PATHOPHYSIOLOGY OF LIVER

PATHOPHYSIOLOGY OF KIDNEYS. DISORDERS OF ACID-BASE BALANCE. DISORDER OF WATER-ELECTROLYTIC BALANCE

PATHOPHYSIOLOGY OF  DIGESTION. ULCER DISEASE

Basic Functional Anatomy of the Digestive System

The digestive system is composed of the digestive or alimentary tube and accessory digestive organs. The basic terminology used to describe parts of the digestive system is shown below and more detailed description of each is presented in later sections.

Most of the digestive organs (like the stomach and intestines) are tube-like and contain the food as it makes its way through the body. The digestive system is essentially a long, twisting tube that runs from the mouth to the anus, plus a few other organs (like the liver and pancreas) that produce or store digestive chemicals.

The Digestive Process:

The start of the process – the mouth: The digestive process begins in the mouth. Food is partly broken down by the process of chewing and by the chemical action of salivary enzymes (these enzymes are produced by the salivary glands and break down starches into smaller molecules).

On the way to the stomach: the esophagus – After being chewed and swallowed, the food enters the esophagus. The esophagus is a long tube that runs from the mouth to the stomach. It uses rhythmic, wave-like muscle movements (called peristalsis) to force food from the throat into the stomach. This muscle movement gives us the ability to eat or drink even when we’re upside-down.

In the stomach – The stomach is a large, sack-like organ that churns the food and bathes it in a very strong acid (gastric acid). Food in the stomach that is partly digested and mixed with stomach acids is called chyme.

In the small intestine – After being in the stomach, food enters the duodenum, the first part of the small intestine. It then enters the jejunum and then the ileum (the final part of the small intestine). In the small intestine, bile (produced in the liver and stored in the gall bladder), pancreatic enzymes, and other digestive enzymes produced by the inner wall of the small intestine help in the breakdown of food.

In the large intestine – After passing through the small intestine, food passes into the large intestine. In the large intestine, some of the water and electrolytes (chemicals like sodium) are removed from the food. Many microbes (bacteria like Bacteroides, Lactobacillus acidophilus, Escherichia coli, and Klebsiella) in the large intestine help in the digestion process. The first part of the large intestine is called the cecum (the appendix is connected to the cecum). Food then travels upward in the ascending colon. The food travels across the abdomen in the transverse colon, goes back down the other side of the body in the descending colon, and then through the sigmoid colon.

The end of the process – Solid waste is then stored in the rectum until it is excreted via the anus.

In many ways, the digestive system can be thought of as a well-run factory in which a large number of complex tasks are performed. The three fundamental processes that take place are:

·        Secretion: Delivery of enzymes, mucus, ions and the like into the lumen, and hormones into blood.

·        Absorption: Transport of water, ions and nutrients from the lumen, across the epithelium and into blood.

·        Motility: Contractions of smooth muscle in the wall of the tube that crush, mix and propel its contents.

Each part of the digestive tube performs at least some of these tasks, and different regions of the tube have unique and important specializations.

The diet of human contains hundreds if not thousands of different molecules, but the bulk of the ingested nutrients are in the form of huge macromolecules that cannot be absorbed into blood without first being reduced to much simpler and smaller forms – even table sugar (sucrose) cannot be absorbed without first being enzymatically ripped apart into glucose and fructose. The most important enzymatic reaction in digestion of foodstuffs is hydrolysis – the breaking of a chemical bond by the addition of a water molecule.

Proteins

Proteins are polymers of amino acids linked together by peptide bonds. Chain length varies tremendously and many dietary proteins have been modified after translation by addition of carbohydrate (glycoproteins) or lipid (lipoprotein) moieties. These modifications will be almost totally ignored in this text. Very short proteins, typically 3 to 10 amino acids in length, are called peptides. Although very small peptides can be absorbed to a limited degree, for all intents and purposes, proteins must be reduced to single amino acids before they can be absorbed. Enzymes that hydrolyze peptide bonds and reduce proteins or peptides to amino acids are called proteases or peptidases. Protein digestion begins in the stomach with the action of pepsin. Pepsinogen, the enzyme precursor of pepsin, is secreted by the chief cells in response to a meal and acid pH. Acid in the stomach is required for the conversion of pepsinogen to pepsin. Pepsin is inactivated when it enters the intestine by the alkaline pH. Proteins are broken down further by pancreatic enzymes, such as trypsin, chymotrypsin, carboxypeptidase, and elastase. As with pepsin, the pancreatic enzymes are secreted as precursor molecules. Trypsinogen, which lacks enzymatic activity, is activated by an enzyme located on the brush border cells of the duodenal enterocytes. Activated trypsin activates additional trypsinogen molecules and other pancreatic precursor proteolytic enzymes. The amino acids are liberated intramurally or on the surface of the villi by brush border enzymes that degrade proteins into peptides that are one, two, or three amino acids long. Similar to glucose, many amino acids are transported across the mucosal membrane in a sodium-linked process that uses ATP as an energy source. Some amino acids are absorbed by facilitated diffusion processes that do not require sodium.

Lipids

Fatty acids are present in only small amounts in animal and plant tissues, but are the building blocks of many important complex lipids. True fatty acids possess a long hydrocarbon chain terminating in a carboxyl group. Nearly all fatty acids have an eveumber of carbons and have chains between 14 and 22 carbons in length. The principle differences among the many fatty acids are the length of the chain (usually 16 or 18 carbons) and the positions of unsaturated or double bonds. For example, stearic acid (pictured below) has 18 carbons and is saturated.

The so-called “short-chain” or volatile fatty acids are 2 to 4-carbon molecules of great importance in intermediary metabolism and as the mainstay of ruminant nutrition. They are represented by acetic, butyric and proprionic acids. The most abundant storage form of fat in animals and plants, and hence the most important dietary lipid, is neutral fat or triglyceride. A molecule of triglyceride is composed of a molecule of glycerol in which each of the three carbons is linked through an ester bond to a fatty acid. Triglycerides cannot be efficiently absorbed, and are enzymatically digested by pancreatic lipase into a 2-monoglyceride and two free fatty acids, all of which can be absorbed. Other lipases hydrolyse a triglyceride into glycerol and three fatty acids. A triglyceride (triacylglycerol): tristearin.

The average adult eats approximately 60 to 100 g of fat daily, principally as triglycerides containing long-chain fatty acids. These triglycerides are broken down by gastric and pancreatic lipase. Bile salts act as a carrier system for the fatty acids and fat-soluble vitamins A, D, E, and K by forming micelles, which transport these substances to the surface of intestinal villi, where they are absorbed. The major site of fat absorption is the upper jejunum. Mediumchain triglycerides, with 6 to 10 carbon atoms in their structures, are absorbed better than longer-chain fatty acids because they are more completely broken down by pancreatic lipase and they form micelles more easily. Because they are easily absorbed, medium-chain triglycerides often are used in the treatment of persons with malabsorption syndrome. The absorption of vitamins A, D, E, and K,  which are fat-soluble vitamins, requires bile salts. Fat that is not absorbed in the intestine is excreted in the stool. Steatorrhea is the term used to describe fatty stools. It usually indicates that there is 20 g or more of fat in a 24-hour stool sample. Normally, a chemical test is done on a 72-hour stool collection, during which time the diet is restricted to 80 to 100 g of fat per day.

Carbohydrates

The diversity of dietary carbohydrates necessitates discussion of several classes of these molecules, ranging from simple sugars to huge, branched polymers.

Monosaccharides or simple sugars are either hexoses (6-carbon) like glucose, galactose and fructose, or pentoses (5-carbon) like ribose. These are the breakdown products of more complex carbohydrates and can be efficiently absorbed across the wall of the digestive tube and transported into blood.

Disaccharides are simply two monosaccharides linked together by a glycosidic bond. The disaccharides most important iutrition and digestion are:

·         lactose or “milk sugar”: glucose + galactose ; sucrose or “table sugar”: glucose + fructose ; maltose: glucose + glucose

Oligosaccharides, which include disaccharides, are relatively short chains of monosaccharides which typically are intermediates in the breakdown of polysaccharides to monosaccharides.

Polysaccharides are the most abundant dietary carbohydrate for all except very young animals. You should be familiar with three important polysaccharides, each of which is a large polymer of glucose:

·         Starch is a major plant storage form of glucose. It occurs in two forms: alpha-amylose, in which the glucoses are linked together in straight chains, and amylopectin, in which the glucose chains are highly branched. Except for the branch points of amylopectin, the glucose monomers in starch are linked via alpha(1-4) glycosidic bonds, which, in the digestive tract of mammals, are hydrolyzed by amylases.

·         Cellulose is the other major plant carbohydrate. It is the major constituent of plant cell walls, and more than half of the organic carbon on earth is found in cellulose. Cellulose is composed on unbranched, linear chains of D-glucose molecules, linked to one another by beta(1-4) glycosidic bonds, which no vertebrate has the capacity to enzymatically digest. Herbivores subsist largely on cellulose, not because they can digest it themselves, but because their digestive tracts teem with microbes that produce cellulases that hydrolyze cellulose.

·         Glycogen is the third large polymer of glucose and is the major animal storage carbohydrate. Like starch, the glucose molecules in glycogen are linked together by alpha(1-4) glycosidic bonds.

Carbohydrates must be broken down into monosaccharides, or single sugars, before they can be absorbed from the small intestine. The average daily intake of carbohydrate in the American diet is approximately 350 to 400 g. Starch makes up approximately 50% of this total, sucrose (i.e., table sugar) approximately 30%, lactose (i.e., milk sugar) approximately 6%, and maltose approximately 1.5%. Digestion of starch begins in the mouth with the action of amylase. Pancreatic secretions also contain an amylase. Amylase breaks down starch into several disaccharides, including maltose, isomaltose, and α-dextrins. The brush border enzymes convert the disaccharides into monosaccharides that can be absorbed (Table 38-3). Sucrose yields glucose and fructose, lactose is converted to glucose and galactose, and maltose is converted to two glucose molecules. When the disaccharides are not broken down to monosaccharides, they cannot be absorbed but remain as osmotically active particles in the contents of the digestive system, causing diarrhea. Persons who are deficient in lactase, the enzyme that breaks down lactose, experience diarrhea when they drink milk or eat dairy products. Fructose is transported across the intestinal mucosa by facilitated diffusion, which does not require energy expenditure. In this case, fructose moves along a concentration gradient. Glucose and galactose are transported by way of a sodium-dependent carrier system that uses adenosine triphosphate (ATP) as an energy source. Water absorption from the intestine is linked to absorption of osmotically active particles, such as glucose and sodium. It follows that an important consideration in facilitating the transport of water across the intestine (and decreasing diarrhea) after temporary disruption in bowel function is to include sodium and glucose in the fluids that are taken.

The basic role of digestive system consists of digestion of food components  that get into  alimentary chanel (proteins, fats, carbohydrates), absorption of formed nutrients and removing from an organism of some end-products of metabolism. Numerous functions of digestive system are regulated by  central and vegetative nervous system, humoral and endocrine influences. Disorders of regulation cause disturbance of normal course of the processes in  alimentary channel, leads to insufficiency of digestion and promote development of many diseases.

Insufficiency of digestion

Insufficiency of digestion is a pathological condition at which the digestive system does not provide assimilation of the nutrients that get inside the organism. As a result starvation can develop.

Depending on ethiology there are hereditary caused (some kinds malabsorption) and the acquired insufficiencies of digestion.

The reasons that cause the development of insufficiency of digestion may be:

         1. Alimentary (food) factors:

a) reception of bad and rough food; b) live on dry rations; c) irregular reception of food;

d) disbalanced meal (for example, reduction of the maintenance of vitamins, proteins in a diet); e) overindulge in alcohol.

         2. Physical factors. Among factors of this group the greatest role belongs to radiation which effects epithelial cells of the alimentary channel which have high mitotic activity.

         3. Chemical agents are the reason of digestion  disorders after poisonings with inorganic and organic substances during manufacture and in life.

         4. Biological factors:

a) bacteria (for example, v.cholera, causative agents of dysentery, typhoid fever, paratyphus);

b) bacterial toxins (for example, at salmonellosis,  staphylococcal infection);

c) viruses (for example, adenoviruses);

d) helminths.

         5. Organic effects:

a) congenital anomalies of digestive system;

b) postoperative conditions;

c) tumours of digestive system.

         6. Disorders of nervous and humoral regulation. Disorders of digestion can develop during:

a) psychoemotional disorders (neurotic and neurosis-like conditions);

b) mental diseases (schizophrenia, a manic – depressive syndrome);

c) organic diseases of the central nervous system (encephalites);

d) lesions of peripheral structures of vegetative nervous system;

e) reflex disorders (various viscero-visceral reflexes). Disorders of humoral regulation of digestion may be connected to disorders of synthesis and secretion of gastrointestinal hormones (gastrine, secretin, cholecystokinin-pancreazymin etc.).

Insufficiency of digestion may be shown by the following syndromes:

1) starvation;  2) dispeptic syndrome; 3) dehydratation; 4) disturbance of the acid-basic balance; 5) intestinal autointoxication; 6) the painful syndrome.

Dispeptic syndrome includes different combinations of the following symptoms:

·                    Anorexia; heartburn; eructation; nausea; vomiting; meteorism; constipations; diarrhea.

Anorexia is a full absence of appetite combined with an objective need of food. Anorexia represents a loss of appetite. Several factors influence appetite. One is hunger, which is stimulated by contractions of the empty stomach. Appetite or the desire for food intake is regulated by the hypothalamus and other associated centers in the brain. Smell plays an important role, as evidenced by the fact that appetite can be stimulated or suppressed by the smell of food. Loss of appetite is associated with emotional factors, such as fear, depression,  frustration, and anxiety. Many drugs and disease states cause anorexia. In uremia, for example, the accumulation of nitrogenous wastes in the blood contributes to the development of anorexia. Anorexia often is a forerunner of nausea, and most conditions that cause nausea and vomiting also produce anorexia.

There are following kinds of anorexia:

а) intoxical – develops during acute and chronic poisonings (for example, salts of mercury, medical products, bacterial toxins);

b) dispeptic –arises at diseases of digestive system, has more often behavior-reflex nature;

c) neurodynamic –  develops as a result of reciprocal  inhibition of appetite the centre after overexcitation of separate structures  of limbic systems (for example, a painful syndrome during  heart attacks, colics, peritonitis);

d) neurotic –  it is connected with excessive excitation of cortex  brain and strong emotions (especialy  negative);

e) psychogenic – is connected with conscious restriction of food (for example, with an aim of getting thin or as result of mental disorders); 

f) neuroendocrinopathy –  is caused by organic lesions of the central nervous system (hypothalamus) and endocrine diseases (hypophysial cachexia, Addison’s disease).

In the basis of development of anorexia two mechanisms may take place:

1) reduction of excitability of the food centre: Intoxical; dyspeptic; neuroendocrinopathy 

2) inhibition of food centre neurons: Neurodynamic; neurotic; psychogenic

Anorexia affects whole body

The heartburn is a feeling of heat or burnings along the esophagus. Its development is connected with irritation of receptors of the esophagus during pelting contents of  stomach into an esophagus gullet (reflux). Gastrointestinal reflux refers to the backward movement of gastric contents into the esophagus, a condition that causes heartburn. Although most persons experience occasional esophageal reflux and heartburn, persistent reflux can cause esophagitis. Complications can result from persistent reflux, which produces a cycle of mucosal damage that causes hyperemia, edema, and erosion of the luminal surface. Persistent reflux can result in Barrett’s esophagus, a condition associated with increased risk for development of esophageal cancer. Gastroesophageal reflux is a common problem in infants and children. Reflux commonly corrects itself with age, and symptoms abate in most children by 2 years of age. Although many infants have minor degrees of reflux, some infants and small children have significant reflux that interferes with feeding, causes esophagitis, and results in respiratory symptoms and other complications. It may be caused by:

а) a large quantity of formed gastric juice;

 b) functional insufficiency of cardial sphincter.

The eructation is a sudden involuntary allocation into oral cavity of gas from a stomach esophagus, sometimes with small portions of  stomach contents.

The nausea is a burdensome sensation in epigastric area,  chest and in oral cavity, quite often previous to vomiting and frequently is accompaned general weakness, sweatness, increasing of salivation, coldness of arms and legs, pallor of  skin, decrease of arterial pressure that is connected to activation parasympathetic nervous system. In the basis of  nausea stays excitation of the emetic centre, which is insufficient for occurrence of vomiting.

Vomiting is the complex-reflex act which results to eruption of  stomach contents  outside through the mouth. It is a result of the emetic centre excitation  which is situated in medulla oblongata.

Pathogenesis of nausea and vomiting

Meteorism is  surplus accumulation of gases in the digestive channel due to their increased formation or insufficient removing from intestines.

Constipations are slowing down, difficulty or regularly insufficient emptying of intestines.

There are two mechanisms of development of constipations – spastic and atonic. The first is caused by long constant contraction of smooth muscles of intestines, the second – because of their atonia.

 Spastic constipations are:

а) inflammatory – arise owing to local spastic reflexes with changed  mucous membrane;

b) proctogenic – develop in case of anorectal area  pathology;

c) mechanical –arise in case of  impassability of guts;

d) toxic – is a result of poisonings  by lead, mercury, thallium.

Atonic constipations are:

а) alimentary – develop with consuming of light food containing(little quantity of cellulose;

b) neurogenic – is  result of disorders of nervous regulation of intestinal motility ;

c) hypodynamic – arise in bed-patients,  old men, people with very low motor activity;

d) constipations in case of  anomalies of  thick gut (Girshprungs disease);

e) constipations as a consequensce of water-electrolyte metabolism disorders .

Diarrhea is a freguent emptying of intestines with discharging of diluted and plentiful excrements.

The pain frequently accompanies  development of the alimentary channel diseases. Depending to the reasons and pathogenesis pain may have different characters.

There are following mechanisms of pain occurrence at lesions of digestive organs:

а) the spastic mechanism. The pain is caused by a spasm of smooth muscles of different parts of the alimentary channel. It is considered, that in this case the reason of  pain is constriction of the vessels which are laying in the wall of hollow organs owing to what the ischemia develops. It causes appearance of metabolic  products  from the working organs, and their influence on pain receptors. At sharply arising strong spasm  colic pain develops;

b) the hypotonic mechanism. At reduction of smooth muscles  tone  (hypotonia) the pain appears from  stretching of the wall of hollow organs (stomach, guts, gall bladder) by their contents. Thus the mechanical stretching of tissues causes irritation of the nervous endings; c) influence of biological active substances (histamine, serotonin, kinines, prostaglandins) on the nervous endings.

In the basis of indigestion the following disturbances of functions of digestive system may take place:

1. Disturbance of secretion in digestive system:

       A. hypersecretion conditions:

·        Hypersalivation; gastric hypersecretion; pancreatic hypersecretion; hypercholia

       B. Hyposecretion conditions:

·        Hyposalivation; gastric hyposecretion; pancreatic hyposecretion; acholia

          2. Disturbance of motor function of the alimentary channel:

disturbance of chewing; disturbances of swallowing – dysphagia; gastric dyskinesias; intestinal dyskinesias; dyskinesia of gall bladder and biliary ducts; disturbances of defecation

       3. Disturbance of absorbtive functions –  syndrome of malabsorption

Disturbance of stomach functions.

Disturbance of  hydrochloric acid, pepsin, mucus secretion. Hydrochloric acid is excreted by parietal cells of  mucous membrane of  stomach which number in a healthy person is about 1 billion. Secretion of it is regulated by complicated mechanisms which include three interconnected phases of secretion: neurogenic (vagal), gastric (gastrine) and intestinal which is regulated by irritation of receptors and intestinal hormones.

In regulation of functional activity of parietal cells nervous system (through mediator acethylcholine), and also various hormones (serotonin, insulin) take place. The basic mechanisms of parietal cells  regulation of stomach   can be presented  as follows. The parietal cell contains receptors to histamine which is released from enterochromaphilic cells (ECL), gastrin and cholecystokinin (CCK-receptors), and also receptors for acethylcholine (M₃-receptors), Stimulation of H₂-histamine receptors promotes formation of cAMP and stimulation of CCK-receptors and M₃-receptors results to increasing of endocellular calcium (Са⁺⁺) level. Besides the stimulation of M₃-receptors increases, in comming  of Са⁺⁺ into a cell and due to increasing of inositolthreephosphate (IP₃) level  strengthens an output of endocellular Са⁺⁺. Gastrin, cholecystokinin and histamine also raise output of Са⁺⁺ due to action on IP₃ . Parietal cell has a receptor for prostaglandin E₂ (PGE₂) stimulation which reduces  level of cAMP and results to inhibition of hydrochloric acid secretion .

Secretion of  hydrochloric acid by parietal cell is carried out by a principle of the proton pump in which K⁺ exchanges on H⁺, and Cl‾ on HCO₃‾. An important role in this process is played by H⁺, K⁺ -ATPase which, using energy of ATP, provides transport of H⁺ from parietal cells and K⁺ into the cell. The difficult mechanism of regulation of hydrochloric acid production  explains increasing or decreasing of its secretion under the influenee of numerous factors.

Hypersecretion of  hydrochloric acid which plays an important role in development of several gastroenterologic disease may be observed in hereditary caused increasing  of parietal cells weight the increased tone of a vagal nerve  stretching of antral part of  stomach during disorder of emptying, increasing of gastrin secretion, increasing of ECL-cells quantity  in the mucous membrane of  stomach (in patients with carcinoid syndrome).

Besides  hydrochloric acid main cells of  mucous membrane of  stomach produce pepsin from pepsinogen.

Now there are seven types of pepsinogen distinguished. Disturbance of pepsin formation function of a stomach matters in appearance of number of gastroenterologic diseases (for example,  stomach ulcer).

Gastric mucus is secreted by mucous cells of stomach  mucous membrane. The content of gastric musous is formed by glycosaminoglycans and glycoproteins. From sialic acids N-acethylneuraminic acid provides ability of gastric mucus to form  water-insoluble viscose coverings of stomach mucous membrane. Secretion of gastric mucus takes place continuously. Irritation adreno- and cholinoreceptors, prostaglandins render stimulating influence on formation of mucus. In process of mucus formation the certain role is played by stability of lysosomes. Hydrolases of lysosomes cause dehydratation of glycoproteins.

Gastric mucus (together with bicarbonates) takes part in formation of a mucus barrier which supports  рН gradient  between  hollow of  stomach and its mucous membrane and late H+.

Gastric mucus: secretion and function

Disturbance of this barrier as a result of reduction  of prostaglandins synthesis  in the stomach wall  is one of mechanisms of   mucous membrane damage under the action of some medical products (aspirin, not steroid anti-inflammatory drugs). On the contrary, synthetic prostaglandins have cell protective properties, raise mucus formation and prevent damage of  stomach.

According to quantity of gastric juice and its quality there are gastric hyper- and hyposecretion.

Gastric hypersecretion is characteristed by:

·        increase of the quantity of gastric juice as after reception of food, and also on the empty stomach;

·        hyperaciditas and hyperchlorhydria –  increase of the common acidity and  maintenance of the free hydrochloric acid in gastric juice;

·        increase of digestive ability of gastric juice.

The disturbances of digestion connected with gastric hypersecretion, are caused by a long delay of food in the stomach (pylorus is closed, because of neutralization of very sour contents that go into duodenum, demands a lot  time). This circumstance has such consequences:

1)  small guantity of contents go into intestine,  that results in reduction   of guts peristaltics and to development of constipations;

2) in the stomach processes of fermentation and formation gases increase. It causes appearance of an eructation and a heartburn;

3) motor activity of  stomach is increased, what leads to  hypertonus and hyperkinesis of smooth muscles.

Formation   of active gastric juice plenty is the important factor promoting formation of ulcers in  stomach and  duodenum.

Gastric hyposecretion is  characterised by:

·        reduction of quantity of gastric juice on an empty stomach and after reception of food;

·        decreased or zero acidity of gastric juice (hypo-or unacidity), reduction of the contents in it or absence of  free hydrochloric acid (hypo- or achlorhydria);

·        reduction of digesting ability of gastric juice due to achylia (the full stop formation of hydrochloric acid and enzymes).

Reduction of gastric secretion results to disturbances of digestion along alimentary channel. It is caused by insufficient formation of gastric juice that keeps pylorus opened also contents of  stomach quickly pass into  duodenum  where environment becomes constantly alkaline. Thus there is inhibition  of secretine  formation that results  decreased of pancreatic juice secretion  and processes of hollow digestion in guts are broken. Insufficiently digested components of food irritate receptors of  mucous membrane of guts that result in  strengthening of peristaltics and diarrheas. Besides due to the absence of  hydrochloric acid growth of microflora in the stomach increases. Activation of processes of rotting and fermentation in the stomach and appearance of such disturbance of digestion, as  eructation, the impose tongue etc are also cconnected with.

Disturbance of stomach motor function

Disturbance of stomach  motor function is called gastric diskinesia. There are two kinds of gastric diskinesia: hypertonic and hypotonic.

Hypertonic kind is characterised by strengthening of peristaltics(hyperkinesia) and increasing of stomach muscles tone  (hypertonia). The hypotonic kind, on the contrary, is characterized by  hypotonia and hypokinesia.

The reasons of motor gastric disturbance of hypertonic type may be:

·        some food factors (rough food, alcohol); increase of gastric secretion; increase of a tone of vagal nerve; some gastrointestinal hormones (motilin).

Hypertension and hyperkinesia of stomach leads:

·        to a long delay of food in stomach that promotes increase of gastric secretion and development of ulcers on  mucous membrane;

·        to development of antiperistaltics of stomach that results in development of dispeptic disturbances (eructation,  nausea, vomitting).

One of the forms of stomach  diskinesia of hypertonic type is pylorospasm. It is observed mainly in babies, especially in the first weeks and months of life. Pylorospasm in children is caused by functional disturbances of the nervous- muscular system of stomach pyloric part. It is observed mainly at the excitable children who have suffered  intra-uterine hypoxia, born in asphyxia with attributes of  birth trauma of the central nervous system.

 Pylorospasm is marked by weak development of muscles in cardial part of  stomach and its more expressed development in the area of pylorus. It promotes development of vomitting and eructation.

Reduction of motor activity of  stomach may be caused by:

·        alimentary factors (fat food); reduction of gastric secretion (hypoacid gastritis); reduction of  vagal nerve  tone; action inhibiting  motility of  stomach through gastrointerstitial hormones (gastroinhibiting peptide, secretine etc.); removal of pyloric part of  stomach; the common weakening of organism, an exhaustion, gastroptosis.

At hypotonic diskinesias time of  food staying in the stomach is shortened that conducts to disturbance of its digestion. Action of the undigested components of food on receptors of  guts  mucous membrane causes the increase of peristaltics and diarrhea.

The reasons and pathophysiologic mechanisms of  stomach ulcer

The stomach ulcer is  chronic relapsing disease which is characterized by formation of ulcer in  stomach and duodenum.

        

Stomach ulcer

Ethiology of  ulcer disease is still not fully established. It is considered, that in development of stomach and duodenal ulcers the following factors take place .

·        Psychoemotional negative overstrains (negative emotions, disputed situations, feeling of constant alarm, strain etc.).

·        Stress.

·        Hereditary predisposition. Value of this factor proves to be true concerning high (40-50 %) frequency of disease in parents and relatives of the patients, especially of the young age. It is established, that patients with the burdened heredity mucous membrane of stomach have 1.5-2 times bigger  of parietal cells than in  healthy person. Characters of genetic predisposition are also 0(1) group of blood,  deficiency of α₁-antitripsin and fucoglycoproteins.

·        Errors iutrition: eating of rough or spicy (hot) food, bad chewing , fast meal, absence of the teeth, the insufficient maintenance(contents) in food of proteins and vitamins.

·        Chronic gastritis and duodenitis with increased secretion of glands of mucus membrane.

·        Microbic factor – Helicobacter pylori.

·        Harmful habits – smoking, overindulge of alcohol.

According to modern representations, pathogenesis of stomach ulcer in general is reduced to disturbance of balance between factors of acid-peptic aggressions of gastric contents and elements of protection of  stomach  mucous membrane and duodenum. Sufficient formation of bicarbonates, good regeneration of epithelial cells, constant blood supply of  mucous membrane, normal formation and  maintenance of prostaglandins in  wall of  stomach, sufficient gastric formation of mucus are factors that protect mucous membrane.

During last years an important role in weakening of protective properties of stomach mucus membrane and  duodenum is given to microorganisms Helicobacter pylori. These bacterias produce a lot enzymes (urease, protease, phospholipase), damaging  protective barrier of  mucous membrane, and also various cytotoxins. The most pathogenic are Vac A-strain, that produce vacuolizating cytotoxin which results in formation of cytoplasmatic vacuoles and destructions of epithelial cells, and the Cag A-strain which expresses gene associated with cytotoxin. This gene codes protein which has direct damaging effect on  mucous membrane. Helicobacter pylori promotes liberation in  mucous membrane of  stomach interleukines, lysosomal enzymes, TNF_α, that causes development of inflammatory processes in the mucous membrane of stomach.

Pathophysiologic  mechanisms of duodenum ulcer  development  in 95 % of cases is associated with Helicobacter.

Contaminating the mucous membrane of the stomach by Helicobacter is accompanied by development of superficial anthral gastritis and duodenitis and leads to increase of gastrin  level with the subsequent increase of  hydrochloric acid secretion. The plenty quantity of  hydrochloric acid getting into a lumen of duodenum in conditions of deficiency of pancreatic bicarbonates promotes development of duodenitis and besides causes appearance of gastric sites  metaplasia in duodenum (reorganization of epithelium of duodenal mucous membrane on gastric type) which are quickly contaminated by Helicobacter. Further in case of unfavourable course especially when there are additional ethiology factors (hereditary predisposition, 0 (1) group of blood, smoking, psychological  overstrain etc.). In sites of metaplased mucous membrane ulcer defect is formed. However connection of stomach ulcer occurrence  with infection of stomach  mucus membrane by Helicobacter is  not always revealed. Approximately in 5 % of patients with ulcers of  duodenum  and in 15-20 % of patients with stomach ulcers, disease develops without participation of these microorganisms.

To gastroduodenal ulcers which have beeot associated with Helicobacter belong, to erosion-ulcer defects and are caused by using of aspirin and other non steroid anti-inflammatory drugs, stress ulcers etc.

Disturbance of intestinal functions

Functions of intestines may be broken owing to many organic diseases. In some cases these disturbances arise owing to disorders of nervous regulation of  small and large intestine motilit.

Disturbance of digestion and absorbtion in intestines. The complex of disturbances which appear in an organism as a result of disturbance of digestion processes and absorbtion, has received the name of  syndrome of maldigestion and malabsorbtion.

        The syndrome of maldigestion is disturbances of primary digestion, caused by insufficient receiption of digestive enzymes into guts  in particular in case of pancreatic hyposecretion.

        This syndrome is presented by:

·        disturbance of digestion of fats (absence of lipase and phospholipase). About 60-80 % of fat that gets into intestines is deduced with feaces – steatorrhea (fat in feaces);

·        disturbance of absorbtion of fat-soluble vitamins – causes the development  of hypovitaminosis A, E and K;

·        disturbance of   proteins digestion (absence of digestive proteases). About 30-40 % of food protein are not acquired. In feaces there is a plenty of muscular fibres;

·        disturbance of digestion of carbohydrates (absence of amylases);

·        disturbance of decomposition of nucleinic acids (absence of nucleases).

         The syndrome of malabsorption  is a complex of symptoms which appears result  of absorbtion disturbance of substances in guts. Persons with intestinal malabsorption usually have symptoms directly referable to the gastrointestinal tract that include diarrhea, steatorrhea, flatulence, bloating, abdominal pain, and cramps. Weakness, muscle wasting, weight loss, and abdominal distention often are present. Weight loss often occurs despite normal or excessive caloric intake. Steatorrheic stools contain excess fat. The fat content causes bulky, yellow-gray, malodorous stools that float in the toilet and are difficult to dispose of by flushing. In a person consuming a diet containing 80 to 100 g of fat each day, excretion of 7 to 9 g of fat indicates steatorrhea. Along with loss of fat in the stools, there is failure to absorb the fat-soluble vitamins. This can lead to easy bruising and bleeding (i.e., vitamin K deficiency), bone pain, a predisposition to the development of fractures and tetany (i.e., vitamin D and calcium deficiency), macrocytic anemia, and glossitis (i.e., folic acid deficiency). Neuropathy, atrophy of the skin, and peripheral edema may be present.

   

Disturbance of absorbtion in guts may be caused by  disturbances that appear on three levels:

·         preenterocytic disturbance. Develop as a result of disturbances of digestion  processes before absorbtion;

·         enterocytic  from disturbance of intestinal mucous membrane  epithelial cells  activity;

·         postenterocytic disturbance.

       There are  consequence  of the processes disturbance that provide receiption of absorbed substances into internal environment of an organism (blood, lymph).

        Preenterocytic disturbances:

·        Disturbances of motor function of the alimentary channel.

·        Disturbances of primary digestion (a syndrome of maldigestion). By origin they may be gastrogenic, pancreatogenic, hepatogenic, enterogenic, disregulated, iatrogenic (connected with long usage of antibiotics and other medical products).

·        Disturbance of memrane digestion.

       More often they are caused by disturbances of formation and embedding of enzymes into plasmatic membrane of enterocytic microvillis.

        Interstitial pathology of enzymes are hereditary caused disturbances of digestive enzymes synthesis  by microvillis which provide processes of membrane digestion. Among the interstitial pathologies of enzymes  intolerance to disaccharides (lactoses, saccharoses, tregaloses) and insufficiency of peptidase (gluten enteropathy, celiac disease) occur the most often .

The reasons of malabsorbtion may be such enterocytic disturbances:

·         reduction of absorbtion area (a condition after  resection of a gut, an atrophy of villi and microvillis)

·         hereditary caused and acquired disturbances of formation of proteins – carriers monosaccharides (intolerance to glucose, galactose, fructose), amino acids (tryptophanmalabsoption), ions of calcium (hypovitaminosis D)         

·         disturbances of functioning ion pumps of enterocytes (transport of monosaccharides and amino acids is connected with the work of Na-K-pump)

·         deficiency of energy (absorption of the majority of substances – energydependent process )

·         disturbance of assembly of convey complexes (chilomicrones, lipoproteids) in enterocytes

       The reasons of malabsorption may be such postenterocytic disturbances:          

·         disturbances of blood circulation in  wall of intestines, may be caused by disturbances of general haemodynamics in system of v. porta and local disturbances (ischemia, venous hyperaemia, thrombosis, embolia, reactions of vessels on inflammation) 

·         disturbances of lymph flow

·          Besides general dosorders of lymph circulation they may be connected to disturbances of villis contraction of intestinal wall. Such contraction is usually carried out due to local reflexes with a part of submucous nervous plexus and due to participation of  hormone villikinin.

Disturbances of intestine motor function

        Disturbances of motor function of guts refer to intestinal dyskinesia. There are two types of intestinal dyskinesia: hyperkinetic and hypokinetic. The first type is characterized by strengthening of the peristaltics, segmentary and pendulum-like movements, and is manifastatied as diarrheas. The second, on the contrary, is characterized by weakening of motor activity of guts which result to development of constipations.

        The reasons of intestinal dyskinesias of hyperkinetic type may be:

·         increase excitability of guts  receptors to adequate irritators that accompanies development of  inflammation of  intestines  mucous membrane (enteritis, colics)

·         action  unusual, pathological irritators  undigested food (for example, for achylia), products of rotting and fermentation, toxic substances etc. on  receptors of guts

·         increase  of the centres of  vagal nerve excitability

·         increase  of some gastrointerstitial  hormones formation that strengthen peristaltics of guts (motilin)

       Consequences of intestinal dyskinesias of hyperkinetic type are:

·         disturbances of digestion (digestion, absorption)

·         dehydratation

·         secretory non gas acidosis (loss of hydrocarbonates)

        Intestinal dyskinesias of hypokinetic type are manifestated by reduction intestinal peristaltics. That results in appearance of constipations. According to mechanisms of development there are two kinds of constipations: spastic and atonic.

        Spastic constipations result from long tonic contraction of smooth muscles of guts (spasm) and may be caused by viscero-visceral reflexes, or action of toxic factors (for example,  poisoning with lead).

        The reason of atonic constipations  development connected with reduction of contractive  function of  guts smooth muscles  may be:

·         malnutrition low contents of cellulose in consumed food

·         excessive digestion of food in the stomach (for example, in gastric hypersecretion)

·         age changes of receptor system of guts in old men, and also structural changes of an intestinal wall during obesity

·         decrease of  vagal nerve tone

·   disturbances of intraintestinal innervation, for example, during Girshprungs disease – absence of ganglion cells of Auerbachs plexus in sigmoideum and rectum

          Intestinal dyskinesis of hypokinetic type lead to:

·        development of intestinal autointoxication

·        occurrence of meteorism

·        formation of feces stones

·        in extreme cases intestinal obstruction may develop

LIVER INSUFFICIENCY. PROTEIN, CARBOHYDRATE AND FATTY METABOLISM DISORDERS. AT CASE OF CIRRHOSIS AND HEPATITIS

The main liver functions are as follows: metabolic, disintoxicative, bile-forming and bile excretory. Besides that, liver participates in digestion, blood coagulation, thermoregulation, hemodynamics, phagocytosis and other processes.

 

In the prevailing majority of cases, liver pathology is presented by two processes:

1)   hepatitis – liver inflammation;

2)   cirrhosis – the intensified diffuse growth of the new connective liver tissue (stroma) on the background of dystrophic and necrotic hepatocytes (parenchyma) damage.

Liver diseases are caused by the great number of factors:

·        infectious agents – hepatitis virus, Koch’s bacillus, pale Spirochaeta, Actynomyces, Echinococcuses, Ascarises;

·        hepatotropic poisons, including medicines – tetracycline, PASA (paraaminosalycil acid), sulphanilamides, industrial poisons (CCl₄, arsenic, chloroform); plants poisons ( aphlatoxine, muscarine);

·        physical influences – ionizing radiation;

·        biological substancies – vaccines, serums;

·        blood flow violations – thrombosis, embolism, venous hyperemia;

·        endocrine pathology – diabetes mellitus, hyperthyroidism;

·        tumors;

·        hereditary enzymes pathology.

 Liver diseases pathogenesis is characterized by two main mechanisms:

– the direct hepatocytes affection – dystrophy, necrosis;

– autoimmune injury  of hepacytes by autoantibodies, which are formed in response to hepacytes antigens structure changed.

Liver affection by any of the above described etiologic factors may lead to such state, when the liver becomes not capable to execute its functions and to provide the homeostasis. That state is called the liver insufficiency. It may be total, when all functions are suppressed; or partial, when only some functions suffer, e.g., the bile-forming one.

Metabolic function failure

Liver is the central organ of the chemical homeostasis. It is placed between the collar vein from one side, and the systemic circulation from the other. Its placement should be recognized as the optimal one for the execution of the metabolic function. All substances coming with food, excluding only those, which are transported via mesentery lymphatic vessels into the breast blood stream, must go through the liver. Only in such way, with liver participation, food is either decomposed, or expelled, or deposited.

The metabolic liver function means liver participation in the chemical elements metabolism of almost all classes – carbons, fats, proteins, enzymes, vitamins. Hepatocytes affectioegatively influence each of those metabolisms.

Carbohydrate  metabolism disorder

Glycogen synthesis and its splitting are the main regulatory processes, with the help of which liver keeps glucose homeostasis, particularly its level in blood.

                  

Glycogen synthesis

The slowing-down of glycogen synthesis may happen at any hepatocytes affection. That leads to the simultaneous limitation of glucuronic acid formation, which is indispensable in disintoxication of many exogenic poisons (industrial toxins) and final metabolites (cadaverine, putrescine) and unconjugated bilirubin.

The slowing-down of glycogen splitting in liver is conditioned by corresponding enzymes defect or their total absence. The diseases belonging to that group, are called glycogenosises, all being of inheritable origin. They are manifested by glycogen accumulation in liver, by hepatomegalia and hypoglycemia. Several forms are distinguished among them, depending which enzymes is not synthesized.

Glycogenosis of type I is caused by the defect of glucose-6-phosphatase (Hirke disease). This enzymes provides the formation of 90 % of glucose, which is released in liver from glycogen, thus it plays the central role in glucose homeostasis. Glucose, which is formed at glycosis or gluconeogenesis, undergoes phosphorilation to glucose-6-phosphate (G-6-Ph). Before entering the blood stream, it should get rid of the phosphate group. If that does not take place (G-6-Ph deficit), then glucose does not come into blood and hypoglycemia appears. Then the majority of G-6-Ph is used for glycolysis with the formation of lactate with hyperlactatemia development (metabolic acidosis). A part of G-6-Ph participates in the pentosophosphatic cycle and is turned into 5-ribosilpirophosphate – the predecessor of the lithic acid. The urates production increases, the urates being badly removed through kidneys at hyperlactatemia. The combined hyperuricemia takes place – productive + retentive.

Glycogenosis of type III (Korri disease, Forbs disease, so called debrancher enzyme defect) is the deficit of amilo-1,6-glucosidase, the enzymes, which breaks the connections in the places of glycogen molecule branching. That is why the branched molecule does not turn into a direct chain of glucose monomers. In response to the decrease of glucosa level in blood, glycogen is rended only to the branching areas. In the result of that, a lot of unsplitted glycogen accumulates in hepatocytes. Hepatomegalia, hypoglycemia and cramps take place. However, some part of glucose does come into blood.

Glycogenosis of type VI (Gers’s disease) is conditioned by the deficit of liver phosphorilasis complex – proteinkinasa, phosphorilasa kinasa and phosphorilasa. Glycogen mobilization in response to glucagone action becomes not possible, as the result liver is enlarged. However, hypoglycemia is not characteristic for that state.

The galactose-I-phosphaturidiltranspherasa deficit causes galactozemia and hepatomegalia.

Fat metabolism disorder. Liver fatty infiltration

One of the most striking liver functions is the critical evaluation of the correlation among food substances, which come to it from the stomach via the collar vein.

If there is no balance in food ingredients, the liver reacts very peculiarly – it takes for a temporal depositing the surplus substances and stores them until the necessary product appears to construct macromolecules and to expel them into blood.  At pathologic conditions, liver stores mainly fats. That phenomenon is called the fatty liver infiltration.

Fatty liver infiltration

Exogenic triglycerides are hydrolyzed in the intestines, and in enterocytes they are resynthesized and come into the liver as a part of hylomicrones. They come into hepatocytes and are decomposed to fatty acids and glycerin. Fatty acids are partly oxidized and partly participate in the formation of triglycerides, phospholipids and cholesterin ethers. The formed triglycerides are expelled by the liver into blood in the form of lipoproteides of very low and of low density.

The production of lipoproteides by the liver demands the close linkage of the processes of lipidic and albumin synthesizes. The availability of the starting products is also indispensable, but in the balance amount. The reason of fats infiltration can be any agent, which violates this balance in such way, that lipids amount become higher in the correlation to albumins amount. In the result of that it is impossible to involve the liver lipids into the synthesis of lipoproteides and to excret them into blood. A part of lipids deposits in liver.

Liver fats infiltration becomes possible in such cases:

a) The increased lipolysis in the fat tissue, most often – at the decompensated diabetes mellitus. The lipidic predecessors of lipoproteides (fatty acids) are so high at diabetes patients, that they have no time to start to participate in triglycerides synthesis and the last – in lipoproteides synthesis.

b) Hypoglycemia (at starvation or glycogenosis) can provoke the liver fats infiltration. In the conditions of glucose deficit, the insulin production secondarily decreases and lipolysis is activated. The excess of free fat acids, which come into the liver, can exceed the abilities to join triglycerides into lipoproteides. The incompatibility between the delivery and synthesis processes provokes the fats infiltration.

c) Lipoproteides production and fats expelling from the liver decrease in the conditions, when sources of aminoacids  are restricted (e.g., at albumin starvation), thus apoproteines synthesis is decreased. Lipides, as raw material for lipoproteides synthesis, remain unused because the deficit of protein component.

d) The fatty infiltration can be caused by the  lipotropic aminoacids deficit (choline and metionine) in food.

e) The same picture can be caused by B₁₂ – hypovitaminosis and folic acid deficit, because it is caused by endogenic choline deficit.

f) The fatty infiltration can be also conditioned by toxins influences, for example amanitotoxine, which blockes ß-oxidixation of fatty acids in mitochondrias.

g) Hypoxia is believed to be one of the important pathogenic link of fatty infiltration. All factors, which cause the lasting hypoxia or suppress mitochondrias,  the limit of hepatocytes energy synthezise, lead to the fatty distrophy of the liver.

Protein metabolism infringement

The main consequences of albumin metabolism infringement at the liver affection are as follows:

·        Hypoproteinemia is the result  of blood level  decrease of albumins, α- and β-globulins, which are synthesized by hepatocytes. It leads to hypooncia and as the result edema develops.

·        Hyper-gamma-globulinemiais the result  of   gamma-globulines synthesize increase by Kuffer’s cells and plasmocytes.

·        Dysproteinemia is the result of  macroglobulins and crioglobulins accumulation.

·        Hemorrhagic syndrome in the result of the decreased synthesis of blood coagulation factors (besides  УШ factor).

·        The increase of blood RN (retarded nitrogen) in the result of the decreased urea synthesis and ammonia accumulation. That happens at 80% parenchyma affection.

·        increase of enxymes level in blood (aminotranspherases).

 

Microelements metabolism disorder

The well-known example is Wilsons disease, when copper deposits in hepatocytes. Normally, the copper, which comes into a hepatocyte, is distributed among the cytoplasm and the subcellular organals. There is a special albumin in the liver – metall-thionein, which binds copper. It functions as a temporal copper depositor. In some time, the deposited copper enters the metal-containing enzymes, or is withdrawn with bile. Some persons have got metall-thionein with very high relation to copper, which is determined hereditary. That shifts of copper liver pool balance in such a way, that leads to the drop of its secretion with bile and to the decrease of its joining the ceruloplasmin, an albumin, that transports copper in blood. At the long-term copper accumulation by abnormal  metall-thionein, the binding centres satiate, and copper excess is absorbed by liver lysosomes. The metal is accumulated in hepatocytes and leads to hepatomegalia.

Cirrhosis

In the final result, the metabolism violation in the liver may lead to cirrhosis. This is a complicated process, which results in abnormal connective tissue growth. The clue of understanding of this matter lies in anatomic connection of the liver lobe with the microcirculation unit – a blood capillary, a billary duct and a lymphatic vessel. The more stable to demage and capable to regenerate are the hepatocyte of 1-st zone, and the less stable to demage and capable to regenerate are the hepatocyte of 3-d zonemore sensible, wich are localised afar to  the microcirculation unit.

The cirrhosis development depends on the nature, the level and the duration of the unfavourable influence onto the liver parenchyma. The liver has got a wonderful ability to regenerate. If a rat is ablated of  50-70 % of  the liver, this organ regenerates its initial mass within quite a short period of time. In that case, however, the damage has only the quantitative and local character, and not the difuse one, when damage captures more sensible cells in the whole organ simultaneously.

                   

E.g., at Wilson’s disease hepatocytes are liable to chronic influence of the unphisiologically high copper concentrations. That damage is not local any more, it spreads over the whole liver. Hepatocytes of zone 3, which are the least capable to withstand a damage, die and are replaced with the more resistant hepatocytes of  zones 2-nd and 1-st. That leads to the unorganized parenchyma regeneration, that is characteristic for cirrhosis. Parallel, fibroblasts are activated, and the additional connective tissue starts to be synthesized. Its growth is a determinant process in the cirrhosis formation.

Fibroblasts activation leads to the excess synthesis by them of glucosaminoglycanes, glycoproteides and collagen. Normally, collagen is adjusted to cellular surface, and its synthesis is restricted by the cellular surface. However, in the process of fibrosis, collagen is formed behind its connection with a cell, and is located chaotically. Anatomic correlations in a liver lobe alter. The lobe structure is distorted by the regenerating parenchyma nodules and the nodules of the fibrous connective tissue. The blood stream through the lobes is violated, and that leads to further death of hepatocytes, fibrosis spreading and the loss of hepatocytes ability to regenerate. The cell mass decreases. The decreased parenchyma does not correspond to the metabolism demands.

The liver insufficiency takes place.

Ascites at case of liver cirrhosis

Antitoxic function disorder

The antitoxic liver function aggravation is connected to the violation of certain reactions directed to rendering harmless the toxic substances, which are formed in an organism or come from outside:

a) Urea synthesis disorder resulting in ammonia accumulations.

b) Conjugation disorder, i.e. the formation of pair compounds with glucuronic acid, glycin, cystine, taurine. In such way unconjugated bilirubin, scatol, indol, phenol, kadaverin, thyramin, etc. become harmless.

c) Acetylization disorder leading to sulphamides accumulation at their long-term usage.

d) Oxidization disorder leading to the accumulation of aromatic carbons.

Deep disorders of the antitoxic liver function bring forward liver encephalopathy and liver coma.

Hepatocerebral coma

The hepatocerebral coma is a syndrome developing in the result of the liver insufficiency. It is characterized by the deep affection of the central nervous system (consciousness loss, reflexes loss, cramps, blood flowand breathing disorders ).

The most frequent liver coma reasons are as follows: viral hepatitis, toxic liver dystrophy, cirrhosis, portal hypertensia. The main mechanism of the central nervous system damage is the accumulation of toxic neurotropic substances:

a) Ammonia. In liver mytochondria urea is synthesized from ammonia. At liver affection, ammonia does not join the urea cycle (ornitative cycle). Ammonia binds with α-ketoglutaric acid and forms glutaminic acid. Exclusion of α-ketoglutaric acid from Krebs cycle slows down ATP and decreases energy outcome ieurons, decreases their repolarization and function.

b) Rotting products, which are absorbed from the large intestine – phenol, indol, skatol, kadaverine, thyramine.

c) Low-molecular fatty acids – oleic, capronic, valeric. They interact with lipids of neurons membranes and slow down the excitement transfer.

d) Pyroracemic acid derivatives – acetoine, butylenglicol.

Other pathogenic links:

a) Aminoacid disbalance in blood – the decrease of valine, leucine, isoleucine: the increase of phenylalanine, thyrosine, thryptophane, metionine. In the result of that, false mediators are synthesized – oktopamine, β-phenilethyramine, which displace noradrenaline and dophamine from synaptosomes and block synaptic transfer to the central nervous system.

b) Hypoglycemia resulting from gluconeogenesis or glycogenolysis weakening in hepatocytes, that additionally restricts ATP synthesis in the brain.

c) Hypoxia of hemic type in connection with the blockage of the breathing surface of erythrocytes by toxic substances.

d) Hypopotassiumia as the result of the secondary aldosteronism.

e) Disorder of the acid-basic balance ieurones and in intercellular liquid.

INSUFFICIENCY OF EXCRETORY LIVER FUNCTION. JAUNDICE

Liver cells secret bile. It consists of water, bile acids, bile pigments, cholesterine, phospholipids, fat acids, mucin and other ingredients. The main indicator of bile formation and bile secretion is the secretion of bile pigments, i.e. bilirubin and its derivatives.

 Bilirubin is formed in SMP cells (liver, spleen, red bone marrow) from the gem by chipping-off iron by means of hemoxygenase (biliverdin) and further renovation by biliverdin-reductase (unconjugated bilirubin). Its paradoxical, but the transformation of biliverdin into bilirubin decreases the substance solutability, and its secretion becomes problematic. Unmconjugated bilirubin is not soluble in water. In blood, 75 % of it binds with albumin and circulates in such form. Unconjugated bilirubin approaches the hepatocyte and binds with lipandin, the albumin placed on its surface, or with γ-albumin, which might be identical to glutation-5-transpherasa. Ligandin transports unconjugated bilirubin to microsomes, where it binds with glucuronic acid (conjugation). The reaction is catalized by microsomic UDP-glucuroniltranspherasa (uridine-dyphosphate- glucuroniltranspherasa). Monoglucuronide and bilirubin dyglucuronide are formed. The conjugated bilirubin is secreted into the duodenum and is removed from the organism as stercobilin with feces and urine. A part of the conjugated bilirubin is restored up to urobilinogen in liver ducts, gallbladder and small intestines under the influence of microflora enzymes. Urobilinogen does not enter the general blood flow and normally is not excreted. It is absorbed into the liver vein and is splitted by the liver to pirolites.

The violation of bile formation and bile excretion is manifested by characteristic syndromes: jaundice, cholemia and steatorrhea.

Jaundice (icterus)

This means yellowishing of skin, mucous membranes and sclera in the result of bile pigments depositing in them.

There are three types of jaundice:

A.        Hemolytic jaundice, conditioned by the surplus formation of unconjugated bilirubin or by the violation of its transportation.

B.        Parenchimatous jaundice, conditioned by hepatocytes pathology.

C.        Obstructive jaundice, which takes place on the basis of the insufficient bile outflow

Hemolytic jaundice appears, as a rule, in the result of the excess erythrocytes hemolysis.

Hemolytic jaundice

              Its reasons are the same as for the haemolytic anemia. The special features of bile pigments exchange at this jaundice are as follows: in the blood – high level of unconjugated bilirubin; in the feces – stercobilin concentration is increased; in the urine – stercobilin concentration is increased too, and no cholemia.

Parenchymatous jaundice is conditioned by endogenic (inheritable) and outside influences. The basis of inheritable hepatic jaundice is the violations of the unconjugated bilirubin capture by hepatocytes, its insufficient conjugation or its insufficient isolation of the conjugated bilirubin from the hepatocyte.

The insufficient capture of the unconjugated bilirubin brings forward Jilbert’s syndrome. The genetic defect means the blockage of ligandin (γ-albumin) synthesis, which transports unconjugated bilirubin through the membrane to the inside of the hepatocyte.

The low intensity of conjugation depends on the defecit of UDP-glucuroniltranspherasa of hepatocytes. Krigler-Nayar syndrome takes place. At the total absence of the enzymes (type I), the classic bilirubinous encephalopathy develops; at autopsy the nucleus jaundice is found out. The majority of sick children die, and those, who don’t, suffer with choreoathetosis. Child’s brain is especially disposed to the development of bilirubinous encephalopathy within the first weeks or months of life. At type II the conjugative ability of hepatocytes increases after phenobarbital introduction. The introduction this substance within 2-3 weeks normalizes bilirubin level in blood.

The laboured discard of the conjugated bilirubin from the hepatocyte into the bile is clinically displayed by two syndromes: Dubin-Johnson and Rotor.

The acquired liver jaundice is connected with the hepatocytes affection by virous, toxic and other agents. Its pathogenetic mechanism is the decrease of conjugation processes.

Parenchimatous jaundice is characterized by the following violations of bile pigments metabolism: in the blood – the unconjugated bilirubin concentration is increased and the conjugated bilirub appears; in the feces – stercobilin drops; in the urine – stercobilin drops, the appearance of urobilin and conjugated bilirubin.

Obstructive jaundice is connected with the obstruction for bile outflow (tumour, cholelithiasis).

Cholelithiasis

Peculiarities of bile pigments metabolism at this type of jaundice are as follows: in the blood – the increase of the unconjugated bilirubin and the appearance of the conjugated bilirubin;  in the feces – the absence or the drop of stercobilin; in the urine –  the absence or the drop of stercobilin, the appearance of the conjugated bilirubin.

Cholemic syndrome appears at obstructive and parenchimatous jaundices, when bile comes into blood. It is caused by bile acids and the main symptoms are the next: bradycardia, hypotension, excitability, skin itch.

Steatorea  is a syndrome, which is based on the violation of digestion and fats absorption. Fats are excreted with feces. The fat-like vitamins are being lost together with fats.

The so-called hepatobiliary system consists of the gallbladder; the left and right hepatic ducts, which come together to form the common hepatic duct; the cystic duct, which extends to the gallbladder; and the common bile duct, which is formed by the union of the common hepatic duct and the cystic duct. The common bile duct descends posterior to the first part of the duodenum, where it comes in contact with the main pancreatic duct. These ducts unite to form the hepatopancreatic ampulla. The circular muscle around the distal end of the bile duct is thickened to form the sphincter of the bile duct. The gallbladder is  a distensible, pear-shaped, muscular sac located on the ventral surface of the liver. It has an outer serous peritoneal layer, a middle smooth muscle layer, and an inner mucosal layer that is continuous with the linings of the bile duct. The function of the gallbladder is to store and concentrate bile. Entrance of food into the intestine causes the gallbladder to contract and the sphincter of the bile duct to relax, such that bile stored in the gallbladder moves into the duodenum. The stimulus for gallbladder contraction is primarily hormonal. Products of food digestion, particularly lipids, stimulate the release of a gastrointestinal hormone called cholecystokinin from the mucosa of the duodenum. Cholecystokinin provides a strong stimulus for gallbladder contraction. The role of other gastrointestinal hormones in bile release is less clearly understood. Passage of bile into the intestine is regulated largely by the pressure in the common duct. Normally, the gallbladder regulates this pressure. It collects and stores bile as it relaxes and the pressure in the common bile duct decreases, and it empties bile into the intestine as the gallbladder contracts, producing an increase in common duct pressure. After gallbladder surgery, the pressure in the common duct changes, causing the common duct to dilate. The flow of bile then is regulated by the sphincters in the common duct. Two common disorders of the biliary system are cholelithiasis (i.e., gallstones) and inflammation of the gallbladder (cholecystitis) or common bile duct (cholangitis). At least 10% of adults have gallstones. Approximately twice as many women as men have gallstones, and there is an increased prevalence with age—after 60 years of age, 10% to 15% among men and 20% to 40% among women.

 

Cholesterol gallstones

Acute and chronic cholecystitis

The term cholecystitis refers to inflammation of the gallbladder. Both the acute and chronic forms of cholecystitis are associated with cholelithiasis. Acute cholecystitis may be superimposed on chronic cholecystitis. Acute cholecystitis almost always is associated with complete or partial obstruction. It is believed that the inflammation is caused by chemical irritation from the concentrated bile, along with mucosal swelling and ischemia resulting from venous congestion and lymphatic stasis. The gallbladder usually is markedly distended. Bacterial infections may arise secondary to the ischemia and chemical irritation. The bacteria reach the injured gallbladder through the blood, lymphatics, or bile ducts or from adjacent organs. Among the common pathogens are staphylococci and enterococci. The wall of the gallbladder is most vulnerable to the effects of ischemia, as a result of which mucosal necrosis and sloughing occur. The process may lead to gangrenous changes and perforation of the gallbladder. Chronic cholecystitis results from repeated episodes of acute cholecystitis or chronic irritation of the gallbladder by stones. It is characterized by varying degrees of chronic inflammation. Gallstones almost always are present. Cholelithiasis with chronic cholecystitis may be associated with acute exacerbations of gallbladder inflammation, common duct stones, pancreatitis, and, rarely, carcinoma of the gallbladder.

Manifestations. The signs and symptoms of acute cholecystitis vary with the severity of obstruction and inflammation. Pain, initially similar to that of biliary colic, is characteristic of acute cholecystitis. It often is precipitated by a fatty meal and may initiate with complaints of indigestion. It does not, however, subside spontaneously and responds poorly or only temporarily to potent analgesics. When the inflammation progresses to involve the peritoneum, the pain becomes more pronounced in the right upper quadrant. The right subcostal region is tender, and the muscles that surround the area spasm. Approximately 75% of patients have vomiting, and approximately 25% have jaundice.51 Fever and an abnormally high white blood cell count attest to inflammation. Total serum bilirubin, aminotransferase, and alkaline phosphatase levels usually  are elevated.The manifestations of chronic cholecystitis are more vague than those of acute cholecystitis. There may be intolerance to fatty foods, belching, and other indications of discomfort. Often, there are episodes of colicky pain with obstruction of biliary flow caused by gallstones. The gallbladder, which in chronic cholecystitis usually contains stones, may be enlarged, shrunken, or of normal size.

 

PATHOPHYSIOLOGY OF KIDNEYS. DISORDERS OF ACID-BASE BALANCE. DISORDER OF WATER-ELECTROLYTIC BALANCE

PATHOPHYSIOLOGY OF KIDNEYS

Kidney is major organ, which determine outcell liquid of an organism persistance and regulates structure surroundy cells environmental. The kidneys are remarkable organs. Each is smaller than a person’s fist, but in a single day the two organs process approximately 1700 L of blood and combine its waste products into approximately 1.5 L of urine. As part of their function, the kidneys filter physiologically essential substances, such as sodium and potassium ions, from the blood and selectively reabsorb those substances that are needed to maintain the normal composition of internal body fluids. Substances that are not needed for this purpose or are in excess pass into the urine. In regulating the volume and composition of body fluids, the kidneys perform excretory and endocrine functions. The renin-angiotensin mechanism participates in the regulation of blood pressure and the maintenance of circulating blood volume, and erythropoietin stimulates red blood cell production.

                                                                         

 the kidney prevent internal changes and provide maintenance  such main  homeostasis parameters as: isovolemia –  blood volume constancy, isotonia – osmotic pressure constancy, isoionia – ionic structure constancy, isohydria – concentration  hydrogen ions constancy. Homeostasis maintenance includes three processes: plasma filtering   by glomerulus, selective canalicules reabsorbtion, ions of hydrogen secretion, ammonium and other substances secretion. (film). The kidneys are paired, bean-shaped organs that lie outside the peritoneal cavity in the back of the upper abdomen, one on each side of the vertebral column at the level of the 12th thoracic to 3rd lumbar vertebrae. The right kidney normally is situated lower than the left, presumably because of the position of the liver. In the adult, each kidney is approximately 10 to 12 cm long, 5 to 6 cm wide, and 2.5 cm deep and weighs approximately 113 to 170 g. The medial border of the kidney is indented by a deep fissure called the hilus. It is here that blood vessels and nerves enter and leave the kidney. The ureters, which connect the kidneys with the bladder, also enter the kidney at the hilus. The kidney is a multilobular structure, composed of up to 18 lobes. Each lobule is composed of nephrons, which are the functional units of the kidney. Each nephron has a glomerulus that filters the blood and a system of tubular structures that selectively reabsorb material from the filtrate back into the blood and secrete materials from the blood into the filtrate as urine is being formed. On longitudinal section, a kidney can be divided into an outer cortex and an inner medulla. The cortex, which is reddish-brown, contains the glomeruli and convoluted tubules of the nephron and blood vessels. The medulla consists of light-colored, cone-shaped masses—the renal pyramids— that are divided by the columns of the cortex  that extend into the medulla. Each pyramid, topped by a region of cortex, forms a lobe of the kidney. The apices of the pyramids form the papillae, which are perforated by the openings of the collecting ducts. The renal pelvis is a wide, funnel-shaped structure at the upper end of the ureter. It is made up of the calices or cuplike structures that drain the upper and lower halves of the kidney. The kidney is ensheathed in a fibrous external capsule and surrounded by a mass of fatty connective tissue, especially at its ends and borders. The adipose tissue protects the kidney from mechanical blows and assists, together with the attached blood vessels and fascia, in holding the kidney in place. Although the kidneys are relatively well protected, they may be bruised by blows to the loin or by compression between the lower ribs and the ilium. Because the kidneys are outside the peritoneal cavity, injury and rupture do not produce the same threat of peritoneal involvement as rupture of organs such as the liver or spleen. Each kidney is supplied by a single renal artery that arises on either side of the aorta. As the renal artery approaches the kidney, it divides into five segmental arteries that enter the hilus of the kidney. In the kidney, each segmental artery subdivides and branches several times. The smallest branches, the intralobular arteries, give rise to the afferent arterioles that supply the glomeruli Each kidney is composed of more than 1 million tiny, closely packed functional units called nephrons. Each nephron consists of a glomerulus, where blood is filtered, and a tubular component. Here, water, electrolytes, and other substances needed to maintain the constancy of the internal environment are reabsorbed into the bloodstream while other unneeded materials are secreted into the tubular filtrate for elimination.

The Glomerulus. The glomerulus consists of a compact tuft of capillaries encased in a thin, double-walled capsule, called Bowman’s capsule. Blood flows into the glomerular capillaries from the afferent arteriole and flows out of the glomerular capillaries into the efferent arteriole, which leads into the peritubular capillaries. Fluid and particles from the blood are filtered through the capillary membrane into a fluid-filled space in Bowman’s capsule, called Bowman’s space. The portion of the blood that is filtered into the capsule space is called the filtrate. The mass of capillaries and its surrounding epithelial capsule are collectively referred to as the renal corpuscle. The glomerular capillary membrane is composed of three layers: the capillary endothelial layer, the basement membrane, and the single-celled capsular epithelial layer. The endothelial layer lines the glomerulus and interfaces with blood as it moves through the capillary. This layer contains many small perforations, called fenestrations. The epithelial layer that covers the glomerulus is continuous with the epithelium that lines Bowman’s capsule. The cells of the epithelial layer have unusual octopus-like structures that possess a large number of extensions, or foot processes, which are embedded in the basement membrane. These foot processes form slit pores through which the glomerular filtrate passes. The basement membrane consists of a homogeneous acellular meshwork of collagen fibers, glycoproteins, and mucopolysaccharides. Because the endothelial and the epithelial layers of the glomerular capillary have porous structures, the basement membrane determines the permeability of the glomerular capillary membrane. The spaces between the fibers that make up the basement membrane represent the pores of a filter and determine the size-dependent permeability barrier of the glomerulus. The size of the pores in the basement membrane normally prevents red blood cells and plasma proteins from passing through the glomerular membrane into the filtrate. There is evidence that the epithelium plays a major role in producing the basement membrane components, and it is probable that the epithelial cells are active in forming new basement membrane material throughout life. Alterations in the structure and function of the glomerular basement membrane are responsible for the leakage of proteins and blood cells into the filtrate that occurs in many forms of glomerular disease. Another important component of the glomerulus is the mesangium. In some areas, the capillary endothelium and the basement membrane do not completely surround each capillary. Instead, the mesangial cells, which lie between the capillary tufts, provide support for the glomerulus in these areas. The mesangial cells produce an intercellular substance similar to that of the basement membrane. This substance covers the endothelial cells where they are not covered by basement membrane. The mesangial cells possess (or can develop) phagocytic properties and remove macromolecular materials that enter the intercapillary spaces. Mesangial cells also exhibit contractile properties in response to neurohumoral substances and are thought to contribute to the regulation of blood flow through the glomerulus. Iormal glomeruli, the mesangial area is narrow and contains only a small number of cells. Mesangial hyperplasia and increased mesangial matrix occur in a number of glomerular diseases.

Tubular Components of the Nephron. The nephron tubule is divided into four segments: a highly coiled segment called the proximal convoluted tubule, which drains Bowman’s capsule; a thin, looped structure called the loop of Henle; a distal coiled portion called the distal convoluted tubule; and the final segment called the collecting tubule, which joins with several tubules to collect the filtrate. The filtrate passes through each of these segments before reaching the pelvis of the kidney. Nephrons can be roughly grouped into two categories. Approximately 85% of the nephrons originate in the superficial part of the cortex and are called cortical nephrons. They have short, thick loops of Henle that penetrate only a short distance into the medulla. The remaining 15% are called juxtamedullary nephrons. They originate deeper in the cortex and have longer and thinner loops of Henle that penetrate the entire length of the medulla. The juxtamedullary nephrons are largely concerned with urine concentration. The proximal tubule is a highly coiled structure that dips toward the renal pelvis to become the descending limb of the loop of Henle. The ascending loop of Henle returns to the region of the renal corpuscle, where it becomes the distal tubule. The distal convoluted tubule, which begins at the juxtaglomerular complex, is divided into two segments: the diluting segment and the late distal tubule. The late distal tubule fuses with the collecting tubule. Like the distal tubule, the collecting duct is divided into two segments: the cortical collecting tubule and the inner medullary collecting tubule. Throughout its course, the tubule is composed of a single layer of epithelial cells resting on a basement membrane. The structure of the epithelial cells varies with tubular function.

Filtration disorder

Glomerules filtration process  is possible to consider as water and molecules pushing through sieve under infuence of  arterial pressure in a remote capillary. This passive process depends  on hydrostatic exacter,  on filtration pressure, which displace a liquid part from capillary blood  into a canaliculus lumen of  and does not require energy.

Urine formation begins with the filtration of essentially protein-free plasma through the glomerular capillaries into Bowman’s space. The movement of fluid through the glomerular capillaries is determined by the same factors (i.e., capillary filtration pressure, colloidal osmotic pressure, and capillary permeability) that affect fluid movement through other capillaries in the body. The glomerular filtrate has a chemical composition similar to plasma, but it contains almost no proteins because large molecules do not readily cross the glomerular wall. Approximately 125 mL of filtrate is formed each minute. This is called the glomerular filtration rate (GFR). This rate can vary from a few milliliters per minute to as high as 200 mL/minute. The location of the glomerulus between two arterioles allows for maintenance of a high-pressure filtration system. The capillary filtration pressure (approximately 60 mm Hg) in the glomerulus is approximately two to three times higher than that of other capillary beds in the body. The filtration pressure and the GFR are regulated by the constriction and relaxation of the afferent and efferent arterioles. Constriction of the efferent arteriole increases resistance to outflow from the glomeruli and increases the glomerular pressure and the GFR. Constriction of the afferent arteriole causes a reduction in the renal blood flow, glomerular filtration pressure, and GFR. The afferent and the efferent arterioles are innervated by the sympathetic nervous system and also are sensitive to vasoactive hormones, such as angiotensin II. During periods of strong sympathetic stimulation, such as occurs during shock, constriction of the afferent arteriole causes a marked decrease in renal blood flow and thus glomerular filtration pressure. Consequently, urine output can fall almost to zero.

The glomerules filtation  can be decreased or increased. There are some reason of filtation decrease:

1. Hydrostatic pressure decrease in glomerules capillaries: in general decreasing  of arterial pressure decrease (heart insufficiency, shock, collapse, hypovolemia), narrowing glomerules afferent arterioles  (arterial hypertension, pain):  aorta and kidneys arteries organic defeats  (aorta coarctation, stenosic aorta atherosclerosis due to hypertonic  illness), kidneys arteries thrombosis or embolism.

2. Plasma oncotic pressure increase – protein blood substitutes transfusion in large volumes .

3. Intrakidney pressure increase –  canalicules block with cylinders or urinary tract with stones.

4.  Glomerulus filter disorder – quantity functioning glomerulus decrease,  glomerulus a membrane thickening, an pores amount and diameter decrease, basal membrane glycoproteid  components autoallergic defeat  .

The most characteristic manifestations  of filtration limitation in glomerules are:

nitrogenemia (accumulation in blood of nitrogen metabolic and blood residual nitrogen increase) and renal nitrogenemic acidosis owing to delay in an organism phosphates, sulfates and organic acids.

increase of filtering performs resulting blood  pressure increase  excessive consumption  water, decomplication  edema or  oncotic plasma  pressure decrease   (hepatitis, cirrhosis).

 Major  increased glomerulus filter permeability  manifestations concern:

proteinuria –evacuation with urine of plasma proteins over physiological norm (30-80 mg/day) and in urine protein fractions appearance with molecular weight  more than 70 kD

hematuria – erythrocytes   kidneys outlet in canalicules lumen of and their appearance. 

Reabsorption disorder

The daily ultrafiltrate amount, which gets into canalicules makes equal  99 % of this volume is exposed to a converse absorption mainly in proximal canalicules.  Reabsorption proteins, glucose, aminoacids, electrolytes, bicarbonates, phosphates and water almost completely are exposed. the reabsorbtion selectivity provides kidneys epithelium  ability to reabsorp  one substance and simultaneously  prevents the other. This function is executed by specific molecules – which are the carriers. The dependence of reabsorbtion processes on  molecules membrane – carriers means the limited  canaliculus epithelium ability to transport  reabsorbed substance. If the concentration of substance in glomerulus filtrat exceeds possibilities transport system,  then given substance threshold  exceeding. Takes place maximal  reabsorption substrate speed is named  as a maximal tubular one.

Disorder of the canalicules function is called as tubular  insufficiency. It can be hereditary or acquired. The selective disorders reabsorption of separate ultrafiltrate  components are convenient to separate considering .

Disorder sodium and water reabsorbtion. The increase of reabsorption is observed in fallowing case: hyperaldosteronism, oliguri stage of acute kidney insufficiency, reabsorption decrease – hypoaldosteronism, diabetes insipidus. Sodium and water reabsorption is decreased as a result of  canalicules epithelium metabolism inhibition by some poisons, including  medicines, in particular, mercury diuretics. Reabsorbtion is limited because of glomerulus filtrate osmotic active substances (glucose, urin), increase owing to that so-called osmotic diuresis arises (example, diabetes mellitus). The heavy disorders of sodium and water resorbtion arise in case dystrophic and inflammatory canaliculus epithelim changes, so canalicules lose the ability to liquid concentration and cultivation. Loss of concentration ability is called hypostenuria, relative density aqual in  state changes within the limit of 1,006-1,012 (norma – 1,002-1,035). If density  urine is kept at  1,010 level and is not changed with influence water load, it is called  isostenuria (monotone diuresis).

The disorder of proteins reabsorption appears as tubular proteinuria. It is observed for want of poisoning cadmium, of hypoxia, burns, septicemia. Moderate tubular  insufficiency is characterized by the rather low contents in urine of albumins and other proteins with weight up to 40 kD (selective proteinuria). For want of rough dystrophic defeats canaliculus of the device in urine appearence proteins with molecular weight more than 40 kD (unselective proteinuria).

The disorder of reabsorbtion proteins appears as a tubular proteinuria. It is observed in case cadmium poisoning, hypoxia, burns, septicemia. Moderate tubular in sufficiency is characterized by rather albumins and other proteins with weight up to 40 kD is characterized in urine (selective proteinuria). In case of rougn dystrophic canaliculuc defeats, there are proteins in urine with molecular weight more 40 kD (unselective proteinuria).

The glucose reabsorbtion disorders cause glucosuria (dayly norm of glucose loss with urine- up to 1g), which happens kidneys and extra kidneys of  origin. Renal glucosuria in blood as a dominative hereditary anomalia   membrane carriers deficiency as well: enzymes hexokihase and glucose-6-phoaphatase, which provide glucose canalicules reabsorption. Besides, it arises owing to acquired decrease of these enzymes activity in case of chronic poisonings with lead, mercury, uranium compounds. Experimentally it is possible to resynthesise it with the help of floridsine,which oppresses phosphorilation in canalicules cells. Extrorenal  glucosuria arises on a background of hyperglycemia which excuds renal threshold (9.0 – 10 mmol/l). More often  it is observed due to diabetes mellitus.

The inorganic phosphate and calcium disorder reabsorbtion have got a hereditary character. Renal phosphate diabetes appears with phosphaturia, calciuria, rachitis, resistance to vitamin D, canalicules sensitiviby to parathormone increase.(pseudohyperparathyroidism). Hereditary osteodystrofias are characterized with hypocalciemia, hypophosphatemia, parathormone canalicules resistantion because of appropriate receptors absence ( pseudohyperparathyroidism).

 The aminoacids  reabsorbtion disorder  causes aminoaciduria. It can be renal and extrarenal origin. Renal aminoaciduria  develops on  background of the normal aminoacids contents in blood and is explained by hereditary transport or membrane molecules-carriers deficiency. Extrarenal origin aminoaciduria is observed in case of amplified catabolism proteins (disintegration tumour, inflammation), phenylketonuria, cystinosis, hyperglycinemia.

Combined tubulopathia. Ultrafiltrate two and more components reabsorbtion combined disorder are observed in this state. The most known example of such disorders type is the Fankony syndrome. In  basis of this  symptomocomplex  lays kidneys canalicules function generalized disorder. It includes glucosuria, aminoaciduria, phosphaturia, hypercalciuria, hypernatriuria, proteinuria, proximal renal canalicules acidosis with bicarbonaturia, rachitis with resistantion to vitamin D.

Disoder of secretion

The main manifestation – canaliculus acidosis; ammonium- and acidogenesis inhibition and secretion  H⁺-ions lays it is basis . Hyperuricemia, which develops owing to urinary  acid  secretion disorder and lead to gout (renal form).

Kidneys functions disorders of can be completed with their insufficiency, which are acute and chronic.

ACUTE RENAL INSUFFICIENCY (ARI)

It is a clinical syndrome of various ethiology (ARI), which is characterized by significant and acute decrease of  glomerular filtration speed (GFS). Normal GFS significance  – 100-140 ml/mines. Acute renal insufficiency develops, when GFS is reduced to 1-10  ml/mines. Osmotic active substances amount is derivated which is easily excrete in volume  water of 1,5-2 l (daily diuresis) for one day with, the normal diet and normal metabolism out of organism. The minimum quantity  liquid, from which they can still be excreted makes 500 ml. Acute renal insufficiency  is characterized by such disorder renal functions when diuresis is reduced to 500 ml. This state is called as oliguria. If daily urine does not exceed 100 ml, takes place anuria.

Acute renal failure is caused by conditions that produce an acute shutdown in renal function.

It can result from decreased blood flow to the kidney (prerenal failure), disorders that disrupt the structures in the kidney (intrinsic or intrarenal failure), or disorders that interfere with the elimination of urine from the kidney (postrenal failure).

Acute renal failure, although it causes an accumulation of products normally cleared by the kidney, is a reversible

process if the factors causing the condition can be corrected.

The acute renal insufficiency reasons are divided into three groups – prerenal,  renal and postrenal.

Prerenal factors include: circulatting liquid decrease (traumatic shock, blood loss, burns, vomitis, diarrhea), dilatation of  vessels  and vessels  capacity increase (sepsis, anaphylaxia), heart insufficiency (infarction of myocardium).

Renal factors include: ischemia kidneys, action nephrotoxical (antibiotics, heavy metals, organic solvents, X-ray contrast substances), intravessels   erythrocytes hemolysis, glomerulonephritis, states assosiated to pregnancy (septic abortion, eclampsia in pregnant,  bleeding).

Postrenal factors include: ureters obstruction ureters (calculus, blood clots, tumour) and urinal channel obstruction (prostat hypertrophy, carcinoma).

All circumstances, which result in acute prerenal  insufficiency, have  characteristic generality –  renal perfusion decrease. Postrenal reason of diuresis decrease are reduced to urine outflow obstacle at any urinary path level. Pathophysiological mechanisms, which act in  acute renal insufficiency are caused more complicated and caot be put into common universal mechanism.

         The clinical course of acute renal insufficiency can be presented in four phases. Initial phase – is a period, which courses from lesion of   kidneys untill, oliguria development. It takes several hours (ischemia) up to about one week (after action nephrotoxine).

         Oliguric phase is characterized by acute decrease of GFS. It duration course last several days up to several weeks (two weeks in average ). The patients perish just in this phase.

          Diuretic phase is characterized by gradual increase of urine volume. Phase of recovery – period, during which renal function completely are restored, though easy  or moderate GFS decrease can be saved  in some patients.

Acute renal insufficiency is accompanied by high death, data ischemic and traumatic form  about 50-70 % other form – about 10-35 %.

CHRONICAL RENAL INSUFFICIENCY (CRI)

As chronic kidneys defeat  any constant GFS decrease in called. Insufficiency is spoke  when every the significant containance plasma disorder is observed. Symptoms  chronical renal insufficiency develops in case GFS 25 %  over out of norm. The main reasons: primary  glomerulus diseases (chronic glomerulonephritis), the primary canaliculus diseases (chronic pielonephritis tuberculosis), vescular diseases (hypertonic illness, thrombosis, embolism), diffuse connective tissue  diseases (sclerodermia, nodular periarteriitis),  illness metabolism (gout, diabetes mellitus), obstructive nephropathia (urolithiasis, hydronephrosis), hereditary anomalies ( kidneys polycystic).

Chronic renal failure represents the end result of conditions that greatly reduce renal function by destroying renal nephrons and producing a marked decrease in the glomerular filtration rate (GFR).

Because of the remarkable ability of the kidneys to adapt, signs of renal failure do not appear until 50% or more of the renal functional tissue has been destroyed. After this, signs of renal failure begin to appear as renal function moves from renal insufficiency (GFR 50% to 20% normal), to renal failure with a GFR of less than 50% of normal or a need for renal replacement therapy (dialysis or kidney transplantation).

The manifestations of chronic renal failure represent the inability of the kidney to perform its normal functions in terms of regulating fluid and electrolyte balance, controlling blood pressure through fluid volume and the reninangiotensin system, eliminating nitrogenous and other waste products, governing the red blood cell count through erythropoietin synthesis, and directing parathyroid and skeletal function through phosphate elimination and activation of vitamin D.

Renal functions  decrease occurs due to decrease of function nephrons amount  acting nephrons. The initial  chronical renal in sufficincy signs occur for want to mass of acting nephrons   decrease down to  50-30  % . The expressed clinic develops due  to acting nephrons decrease down to 30-10 %.  Further acting nephrons weight decrease (is lower than 10 %) results in  terminal kidneys insufficiency stage – uremia.

Anemia – is obviously the most characteristic sign of stic chronical renal insufficiency. The main factor, which cause it is development is considered lowering of  erythropoitin. It’s also important that  degree hemolys is increased, which shortens erythrocytes life duration. Uremia, besides oppress bone marrow ability to erythropoietin reaction , and because  even due to it enough amount bone marrow  response is not adequate. At last, the  chronical renal insufficiency in patient an alimentary channel bleeding is anusual state.  Continuous loss  blood result in deficiency  iron, which promotes anemia development.

In the patients have a qualitative thrombocytes chronical renal insufficiency.  Chronical renal insufficiency in the patients have a qualitative thrombocytes  operation defect (thrombocylopathy). It appears as bleeding duration increase. Thrombocytes function   gets oppressed with guanidinic  and oxyphenilacetic acids.

Heart is damaged owing to hypertension. The combination of hypertension, anemia, liquid overloading and acidosis promotes heart insufficiency  development. In half of patients chronical renal terminal insufficiency stage pericarditis develops .

The   lung damage is performed with so-called uremic pneumonitis, which is   the stagnant phenomena in vessels of peritracheal .

Arterial hypertension is observed in 50 % of terminal chronical renal insufficiency stage. It arises is connected to hyperproduction renine vasodilatative prostaglandins, oppression limitation sodium excretion  of extracellular  liquid volume  increase.

Gastrointestinal disorder – anorexia, nausea, vomitis. The bleeding from alimentary channel is often phenomenon.Their source are the small surface ulcers, which  bleeding slowly.

To extent  of kidneys weight decrease excretion phosphates decreases, that result in their level in blood  increase. Result  hydroxiapatite is derivation and ionized  calcium level is decrease, thus it stimulates parathyroid glands. If GFS falls below    25 % of norm,  secondary hyperparathyreosis  become obvious. Resorbtion of bones is increased and their density  is decreased. Besides in fact acting for want of weight  nephrones  is less  than 25 %, the  25-ОН-  vitamin D transformation to the activer form – 1,25 (OH)2-vitamin D transformation is decelerated. It is the reason of calcium delay absorbtion  in alimentary channel. Osteodistrophy, which arises  according to mentioned above changes, includes such disorders: а) fibrosis-cystoses osteitis as result of secondary hyperparathyreosis; it appears subperiosteol bone resorbtion; b) osteomalation – bones defeat which organic matrix mineralisation    process mineralisation infringed; c) osteosclerosis –bone density increase; d) osteoporosis – bone weight decrease   and microstructural, which increase bone  fragility.

Uremic encephalopathy appears with sleepiness, inability to concentration, absent-mindness, and then – amnesia, hallutinations, delirium, cramps.

These bones  change are capable to render destructive action on  organism. Delay growth in children in adult bones delay pain fractures, compression vertex os femoris head, necrosis and skeleton deformation. Arterial medial layer calcification can be observed  with ischemic necrosis soft tissue skin calcification with intolerable itch, periarteriitis owing to calcium oxyapatitis precipitation, calcification.

Uremia  

Uremia is a term, which is used for chronical renal insufficiency terminal phase description. The majority of symptoms become well expressed in GFS ratio below than 10 ml/min.

Uremic syndrome pathogenesis has become  subject of intensive learning for a long time. the numerous attempts were made to identify substances, which are accumulated in renal insufficiency  terminal phase  and reach dangerous to the vital function data. Some substances group, which can be considered as uremic toxins is outlined. All of them represent nitrogen metabolism products. They are: urea, guanidine derivatives (methylguanidine, guanidinsuccinic  and guanidinacetative acids, kreatine and kreatine), aromatic compounds (phenole, indole, aromatic amines), conjugated aminoacids, lowmolecular peptides. In uremia development  significance is  peptides hormones accumulation –  parathhormone, insuline, glucagone, gastrine, vasopressine, adrenocorticotropic and somatotropic hormones.  In the kidneys is catabolysed 25 % of peptide hormones. The plasma  blood level increase in chronical renal insufficiency occurs partially because of the catabolism decrease.

Some effect is done by compounds deficiency, which are not synthesized due to uremia. Examples – erythropoietine and 1,25-dioxyеnolecalciferole deficiency.

Manifestations of chronic renal failure

 

DISORDERS OF ACID-BASE BALANCE

Acid-base balance is one of main homeostasis constants. It consists in maintenance of permanent concentration of hydrogen ions (Н⁺) in organism liquids – blood, lymph, tissue and spinal liquid. In practical medicine one has a business with the indexes of blood acid-base balance.

The main index of this balance is рН, that is actual blood acidity. This is the concentration logarithm of hydrogen ions, which’s taken with contrary sign. Healthy man’s рН is 7,35-7,45 (average value – 7,40). So, blood reaction of healthy man is lightly alkaline. In such conditions there is  possibility of optimum enzymic systems  action.

Organism is daily satiated by acid substances, and alkaline reaction. They are in food and derirate in metabolism processes in cells. Vegetable food is rich by alkaline salts, meat in acid matters.

In process of metabolism mainly acid substances derivate. Main classes of acid substances are :

а) organic acids – lactic, acetous, hydrocarbonic; pending of days in organism derivate 13000 mmol of СО₂;

b) ketone bodies – acetoacetous acid, b-hydroxybutyrate acid, acetone;

 c) inorganic acids – sulfuric, phosphoric. Although рН holds out in lightly alkaline range.

There is a special regulatory mechanism. It consists of buffer systems and organs.

Buffer systems are the mixtures of substances with acid and alkaline reaction.  Buffer system counteracts to pH changes. If acid arrives into system, it gets neutralized by alkaline buffer component. If alkaline arrives into system, it  gets neutralized by acid buffer component. As a result, рН remains within the norm. The buffer systems of organism include:

1. Bicarbonate buffer. It consists of carbonic acid (acid buffer components) and anion of carbonic acid (alkaline buffer component). Alkaline component is in 20 times stronger, than acid one. Bicarbonate buffer can be represented by following image: H₂CO₃/HCO₃^– = 1/20.

  2. Phosphate buffer. It consist of once-replaced salt of phosphoric acid (acid component) and twice-replaced salt of phosphoric acid (alkaline component). Alkaline component is in 4 times stronger, than acid one. Phosphate buffer can be represented thus: NaH₂PO₄/ Na₂HPO₄ = 1/4.

         3. Protein buffer. Proteins are ampholites. They react in both ways: as acid, and as alkali.

         4. Hemoglobin buffer. Oxidized hemoglobin (desoxyhemoglobin) has alkali properties. Oxyhemoglobin is in 70 times stronger as acid, than desoxyhemoglobin. Hemoglobin buffer can be presented this way: HbO₂ (acid)/ Hb (basis) = 70/1.

    Besides buffer systems, some organs play an important role in regulation of acid-base balance :

1. Lungs – eliminate carbonic acid (850 g in day).

2. Stomach – in stomach cavity hydrochloryc acid is secreted.

3. Bowels – in bowels cavity bicarbonates are secreted.

4.  Kidney participation in regulation of acid-base balance veries. Firstly – kidney support bicarbonates level in blood by augmentation dint of diminution of their reabsorbtion in canaliculi. secondly – the kidney secrete the various acid non-volatile substances, which are hydrogen ions.

The hydrogen ions excretion is performed in three ways:

1. Acidogenesis – free organic acids excretion. organic acids anions in form of sodium salts get filtered in glomeruli and arrive into the primary urine. Besides in space of canaliculi hydrogen ions are secreted. So, in space of canaliculi pure organic acids derivate to go into secondary urine: NaAn + Н⁺ → Na⁺ + НАn. Sodium return into blood.

2. Ammoniogenesis – inorganic acids excretion in form of ammonium salts. Ammoniogenesis takes place in distal canaliculi and in collective tubules. Inorganic acids are more stronger, than organic. Therefore it is impossible to excrete them in free form. In effect of urine (рН beneath 4,5) canaliculious epithelium can be destroyed. There is also other mechanism of inorganic acids excretion. It consists of  following. Sodium salts of inorganic acids get filtered in glomeruli into primary urine. In cells of distal canaliculi and in collective tubules ammonia (NН₃⁺) is synthesized from glutamine acid. In space of canaliculi ammonia salts of inorganic acids are derivated. They go to secondary urine, and sodium returns into blood. We will show this mechanism on example of sulfuric acid: NaHSO₄ + NH₃⁺ → (NH₄)₂SO₄ + Na⁺.

3. Transformation of alkaline phosphates into acid: Na₂HPO₄ + H⁺ → NaH₂PO₄ + Na⁺. Last are excreted from organism. The sodium ions return into blood.

Except рН, there are other indexes, which describe acid-base balance. Main of them are following: а) pСО₂ – pressure of carbonic acid in blood (physiological range – 34-45 mm Hg average norm – 40 mm Hg); b) SB – standard blood bicarbonate (norm – 21-25 mmol/l); c) BB – sum of buffer blood bases (norm – 45-52 mmol/l);          d) BЕ – surplus or deficit of buffer bases (norm is (-2,3)-(+2,3) (mmol/l).

Types of acid-base balance disorder

Acid-base balance can displace in both in acid, and alkaline side. Hereupon arise states, which are called acidosis and alkalosis. Acidosis is such an acid-base disorder, which arises when a surplus amount of acids in organism accumulates and concentration of hydrogen ions increases. Alkalosis appears, when amount of bases in organism increases and concentration of hydrogen ions decreases.

Accoding to рН changes acidoses and alkaloses are divided into groups:

 а) сompensated – if рН holds in range of physiological norm (7,34-7,45); 

b) decompensated – if рН is out of norm range.

life is possible in case of the extreme values of рН, egual to 6,8-7,8.

According to origin acidoses and alkaloses are also divided into groups –  metabolic and gas.

Metabolic acidosis

This is very freguent and very serious form of acid-base balance disorder. There are two types of metabolic acidosis: а) metabolic acidosis with raised anion difference (delta-acidosis); b) metabolic acidosis with normal anion difference (nondelta-acidosis).

Anion difference, or anion interval is the difference between of sodium and potassium (Na⁺, K⁺) ions concentrations the sum in blood plasma, due to chlorine and bicarbonate (Cl^­ˉ, НСО^ˉ₃) ions concentrations sum. A difference between kations and anions is designated by letter and is named simply “delta”. However, there is a little quantity of potassium ions in plasma, their concentration is changes unsignificantly. Therefore potassium ions can be neglected. Then value “delta” can be represented in equalization appearance: ∆ = (Na⁺) – ([Cl^ˉ] + [HCO^ˉ₃]). Iorm the average anion difference is 12±4 mmol/l. It is conditioned by the presence of many negatively charged anions in plasma – sulipoproteinshates, phosphates, anions of organic acids, negatively charged proteins. In usual practice the mentioned anions are determined. The determination of their summary amount (anion difference) has a diagnostic importance.

Metabolic acidosis with raised anion difference (delta-acidosis). Such acidosis arises when, strong organic acids act up on organism. Classic example of delta-acidosis is diabetic ketoacidosis. It is typical for insulin-dependent diabetes mellitus. attached to diabetes ketones react with bicarbonates (NaНСО₃) and carbonic acid is derivated (Н₂СО₃). It disintegrates to carbonic gas (СО₂) and water (Н₂О). Carbonic gas is excreted by lungs. As a result, bicarbonate concentration diminishes, while sodium and chlorine ions concentration does not change. Therefore the anion difference increases.

Delta-acidosis also includes lactic-acidosis. It is conditioned by accumulation of acid. More freguent lactic-acidosis is observed attached to shock, collapse, heart stop, large vessels compression. 

Acidosis with high anion difference arises to much hereditary metabolic disturbances in children, for example attached to glycogenesis of type І (Girke’s disease), glutaraciduria, unsufficiency of piruvate–dehydrogenase, etc. All of these metabolic disorders are attended with strong organic acids derivation and accumulation in organism.

Another typical example of delta-acidosis is diarrhea in infants. Pathogenicity of this acidosis is complicated. firstly, children with metabolic disorders badly consume food. They are frequently in  state of starvation. Consequently, ketone bodies are derivated. Secondly, undigested food stays too long in digestive tract of such children. Under the oral bacterium influence, digestive tract strong acids are derivated. They are absorbed to blood. Thirdly, these children have frequently got a dehydratation development, therefore glomerular filtration diminishes in kidneys. Accordingly to that acids excretion diminishes.

Delta-acidosis development is also attached to nephritic insufficiency (uremic acidosis). This acidosis is conditioned mainly by diminution of ammonium ions excretion. Inorganic acids (sulfuric, phosphoric) are excreted with urine nominally as ammonium salts. Attached to nephritic unsufficiency they accumulate in blood and titer bicarbonate. Its amount gets diminished. The hydrogen ions run from blood into cells, mainly into osseous tissue. Calcium salts leave bones for blood in exchange on hydrogen ions. Bones lose mineral components. The osteodistrophy  develops.

Some poisons can also cause acidosis with high anion difference. Ethyl alcohol changes an intermediate metabolism and cause final derivation of lactic acid and ketones amount. Poisoning by methyl alcohol leads to acidosis, because methanole turns into methyle acid. Attached to poisoning by ethylenglycole, oxalic and glyoxalic acids are derivated. Thus, all of enumerated poisons cause derivation of organic acids. These acids titer bicarbonate and multiply anion difference.

Metabolic acidosis with normal anion difference (non-delta-acidosis). This kind of metabolic acidosis is characterised by: а) diminution of bicarbonate concentration in blood; b) augmentation of chlorine ions concentration in blood, which is hyperchorinemia; c) contrary bicarbonate and chlorine mutually equilibrate, therefore anion difference does not change.

Prime example is acidosis due to bicarbonate loss over bowels (diarrea in adult, fistula of pancreas). Attached to these states there is loss of liquid. Volume of circulatory blood diminishes. Synthesis of aldosterone in adrenal cortex increases. It reinforces sodium chloride reabsorbtion in kidney. Hyperchlorinemia occurs. Thus, bicarbonate loss over bowels is compensated by chlorine delay in kidney. Anion difference does not change.

Non-delta-acidosis occur also in infants with hereditary metabolic disturbances. Such children are treated by artificial mixtures, which contain synthetic amino acids. Attached to their katabolism big amount of hydrogen ions is derivated. This leads to acidosis.

Another type of hyperchlorinemic metabolic acidosis is nephritic canalicular acidosis. There are two type of such nephritic canalicular acidosis and proximal nephritic canalicular acidosis.

A cause of distal acidosis arises in fact, that distal department of nephrone caot secrete sufficient amount of hydrogen ionin space of canaliculus. Urine pН is not lower than 6,0. Alkaline urine substances do not titer. Endogenic acids stay too long in organism. There are hereditary and acquired distal canalicular acidoses. It is observed attached to such illness: kidney kystosis, chronic pyelonephritis, systematic rheumatic disease, sickle-cell anemia, hyperparathyreosis, fructosuria.

Proximal canalicular acidosis is related to disorder of bicarbonate reabsorption in proximal canaliculi. Because of this many bicarbonates are getting lost with urine. Bicarbonate concentration in blood lowers. Simultaneously volume of extracellular liquid diminishes. There are many causes of proximal acidosis. Usually, this is hereditary or acquired disorders of metabolism. Proximal acidosis can be caused by medicines, for example sulfanilamides. They oppress carboanhydrase of canalicular epithelium, and this enzyme is necessary for reabsorbtion of bicarbonates. Proximal canalicular acidosis is frequently combined with Fankoni’s syndrome. Attached to this disease reabsorption of many substances – amino acids, glucose,  including bicarbonate, is violated.

Other causes of proximal canalicular acidosis are galactosemia, some types of glycogenoses, Wilson’s disease, poisoning by salts of heavy metals.

Compensatory mechanisms of metabolic acidosis are:

1. Bicarbonate buffer. Attached to augmentation of acids in blood, bicarbonate neutralizes them. Neutralization mechanism is following. Alkaline anion НСО^ˉ₃ (mainly sodium salt) bind hydrogen ion. Carbonic acid is formed. It rapidly dissociates to Н₂О and СО₂. During acids neutralization amount of bicarbonate diminishes. Diminution of bicarbonate is very typical index of metabolic acidosis.

2. Reinforcement of pulmonary ventilation. Accumulation of carbonic acid stimulates respiratory centre. breathing becomes deep and frequent. СО₂ is the strongest physiological stimulator of respiratory centre. Heightening of carbonic acid (рСО₂) pressure in blood up to 10 mm Hg multiplies pulmonary ventilation in 4 times. Hyperventilation of lungs is the major compensatory mechanism of metabolic acidosis. It reaches  maximum already in a few hours from acidosis beginning.

3. Nephritic mechanisms – heightening of acidosis and ammoniagenesis, heightened excretion of acid phosphates.

4. Interchange of ions between blood and cells also has some compensatory importance. The hydrogen ions come into erythrocytes, osteocytes. Alkaline metals – potassium calcium ions exit from cells in blood. Thus, there is another typical sign of metabolic acidosis – hyperpotassemia.  

Negative consequences of metabolic acidosis include: 

1. Secondary hypocapnia. Because of continuous hyperventilation of lungs, pressure of СО₂ in blood and other liquids decreases. Accordingly to this decreases excitability of respiratory centre.  A breathing pauses – coma treads. 

 2. Hypotonia – weakening of smooth muscles. Collapse treads after diminution of cardiac volume. Blood pressure decreases. Nephritic filtration diminishes. Anuria treads.

 3. Electrolytes loss in cells. Erythrocytes, osteocytes and other cells lose the potassium and calcium ions. Amount of them in cells diminishes, but in extracellular liquid – increases. Osmotic pressure of extracellular liquid increases. Water delays in tissues oedema develops. Simultaneously liquid leaves cells. Intracellular dehydratation develops.

Main pathogenic medical arrangement, which is attached to metabolic acidosis of any origin, is intravenous infusion of bicarbonate solution.

Gas acidosis

This form of acidosis occurs seldom and it’s cours is less serious. Acidosis is caused by carbonic acid delaing in organism. СО₂ pressure increases  in blood.

Reason of gas acidosis are: respiratory system diseases and disorder of gases interchange between blood and air – lung oedema pneumonia, atelectasis, emphysema, asphyxia, pneumothorax; oppression of respiratory centre by botulotoxine, morphia, barbiturates; artificial respiration by aerial mixture with high content of CO₂; damage of diaphragmal nerves and intercostal muscles.

Hemoglobin buffer is the main compensatory mechanism of gas acidosis. This is intracellular, erythrocyte buffer. It includes 75 % of all blood buffer capacities.

During the blood flowing over tissue capillaries it receives from cells some number of acid products. They are the intermediate and final products of metabolism, which produce hydrogen ions in plasma and attampt to рН decrease. This displacement is prevented by hemoglobin. In capillaries oxygemoglobin gives up oxygen and turns into reduced form. Herewith it loses its acid properties. Desoxyhemoglobin behaves a like weak base. It binds up hydrogen ions and gives up the free potassium ions, which bind whis erythrocytes.

Attached to gas acidosis organism is literally saturated by carbonic gas. СО₂ also arrives into erythrocytes, carbonic acid is derivated there. Then acid binds up potassium ions and turns into bicarbonate (КНСО₃). By such method pH holds out within the norm range for a long time.

In lungs hemoglobin buffer acts other gates. a venous blood contacts with alveolar air in pulmonary capillaries. Oxygen goes into blood, while carbonic acid goes from blood into alveolar air. first of all the carbon gas pressure lowers in plasma, and in erythrocytes later. Рh begins to increase. However in-parallel hemoglobin with oxygen reduces. Acid oxyhemoglobin is formed up (to 98 %). It prevents рН increasing.

Kidneys are very important in gas acidosis compensation. There is straight dependence between carbonic acid pressure in blood and bicarbonate reabsorbtion speed.  Tension СО₂  rises – bicarbonate gets reabsorped faster, СО₂ pressure desrease – reabsorption of bicarbonate slows down. Maximum effect of nephritic gas acidosis compensation treads over a few days from the beginning of acidosis.

The main consequence of gas acidosis is hypercapnia. It causes smooth muscles of vessels spasm. Arterial hypertension treads. Heart work becames difficult.

Medical arrangements: а) cause of CO₂ delay removal in organism;  b) introduction of  antispasmic medicines; c) artificial respiration by air with high oxygen contents.

Metabolic alkalosis

Metabolic alkalosis is a result of bases accumulation in organism or non-volatile acids losses. Herewith a bicarbonate concentration in blood rises, рН iscreases. Causes: 1. Consuming of big amount of alkali. Usually, this happens to patients with ulcerous stomach disease. Sometimes they consume a lot of soda. 2. Cure of acidemia. For example, cure of ketoacidic coma in patients with diabetus mellitus sometimes leads to alkalosis. 3. Loss of big amount of gastric hydrochloric acid in pregnant with indomitable vomiting, pylorostenosis, pyloric cancer. In all of cases hydrochloric acid is lost and a strong base НСО₃^‾ remains. Thus, this is hydrochloremic alkalosis. 4. Hyperproduction of mineralocorticoids (primary aldosteronism). Mechanism of alkalosis is following. Attached to aldosteronism potassium reabsorption in kidney decreases, it is lost with urine. potassium leave cells for blood as compensation. In exchange on potassium cells enter hydrogen ions. Hypopotassemia alkalosis occurs.

Major compensation mechanisms of metabolic alkalosis – lung hypoventilation, nephritic mechanisms.

Serious consequences of metabolic acidosis are increasing of nervously-muscular excitability (tetany). Plural muscles contractions, cramps occur. Tetany is caused by diminution of ionized calcium in blood.

Gas alkalosis

This is very rare and very light form of acid-base balance disorder. Primary mechanism is lowering of carbonic acid pressure in blood because of lung hyperventilation. carbonic acid and hydrogen ions concentration decreases in blood. Causes: breathing by rarefied air on height, lack of breath attached to organic defeat of cerebrum (encephalitis, hypothalamus tumor, bleeding), functional central nervous system changes (epilepsy, hysteria), lack of breath attached to hyperthermia, strong weeping in children, very intensive artificial breathing.

nephritic mechanisms stand in first place among compensation mechanisms. Some role plays protein buffer.

Evaluation of acid-basic balance of the patients

Diagnostics of a type of disorder of acid-basic balance of the patient consists of the following stages.

1.  Determination of the actual acidity of blood (рН) with the help of the Astrup’s device

The Astrup’s device  (or it’s analogue) is used for exact determination of blood рН during constant temperature (+ 38 °C). Blood is taken from a finger or ear lobe without access of air into three special capillaries. In the first portion рН is determined without access of air, that is in the same conditions, in which it stayed in a vascular channel. Other portion is saturated with mixture of oxygen with the low contents of СО₂ (about 3 %) from a cylinder and after that рН is determined. A third portion is saturated with mixture of oxygen with a high content of СО₂ (about 8 %) and also рН is determined. In such a way three values of рН are received:

pН₁ (first test) – with the  true value of рСО₂ in researched blood;

pН₂ (second test) – with the low (about 3 %) content of СО₂ in equilibrial gas mixture under condition of complete saturation of hemoglobin with oxygen (HbO₂ = 100 %) and temperature + 38 °C (РСО₂ = 28 mm Hg).

pН₃ (third test) – with the  high (about 8 %) content of СО₂ in equilibrial gas mixture under condition of complete saturation of hemoglobin with oxygen (HbO₂ = 100 %) and temperature + 38 °C (РСО₂ = 58 mm Hg).

2. Determination of main parameters of acid-basic balance with the help of an alignment chart of Sihard-Anderson (fig. 1) The alignment chart represents the special logarithmic schedule. On an axis of abscissas the meanings of рН are postponed within the limits of 6,8-7,8, and on an axis of ordinates – pСО₂ is postponed within the limits of 10-150 mm Hg. On an alignment chart there are three lines: а) isobara – horizontal line, conducted on a level of normal meaning of рСО₂ in arterial blood (40 mm Hg); b) a line “ of the buffer basics ”; c) a line “ of shift of the buffer basics ”. On an alignment chart the main parameters of acid-basic balance – SB, ВВ, ВЕ, pСО₂ are determined.

Example: In the Astrup’s device the following meanings of рН of equilibrial blood are obtained: pН₁ – 7,24, pН₂ – 7,39, pН₃ – 7,18. Determine on an alignment chart the following: SB, ВВ, ВЕ, pСО₂.

Sequence of operations:

1. Determination of SB. On an alignment chart we put a meaning of  рН₃ (7,18) and appropriate meaning of рСО₂ (58 mm Hg). We find a point of their intersection А. Similarly we put meanings of рН₂ (7,39) and pСО2 (28 mm Hg). Find a point of their intersection В. Through points A and B make a line (“a buffer line”), which intersects isobara, line “of the buffer basics” and line “of shift of the buffer basics”. A crosspoint “of a buffer line” with isobara (pСО₂ = 40 mm Hg) gives the SB value (in this case – 17,5 mmole/l).

2. Determination of ВВ. A crosspoint “of a buffer line” with a line “of the buffer basics” (38 mmole/l) corresponds to this value.

3. Determination of ВЕ. A crosspoint “of a buffer line” with a line “of shift of the buffer basics” (-7 mmole/l) corresponds to this value.

4. Determination of рСО2 of researched blood. For this purpose on an alignment chart postpone the meaning of рН₁ (7,24). The crosspoint of a line рН₁ with “a buffer    line” (point С) corresponds to a unknown maning of рСО2 (47 mm Hg).

An alignment chart of Sihard-Anderson

3. Determination of the type of disorder of acid-basic balance

The parameters of acid-basic balance, obtained from the patient, are compared to parameters of norm and there changes are compared to data of tab. 1.           

Changes of parameters of acid-basic balance  in various types of acidosis and alkalosis

The notes:          1. A badge “minus” designates decreasing, and badge “plus” – increasing of a parameter, comparetively norm.

                           2. ТA – titre acidity of urine; it is the amount of mililiters of a 0,1-molar solution of NaОН, which is used for titrating of urine up to рН = 7,40.

                          3. The asterisks designate changes of parameters of acid-basic balance in diseases of kidneys.

                   4. In the title of the table the boundaries of norm of    appropriate parametersare indicated.

In our example the changes of parameters рН, SВ, ВВ and ВЕ correspond to metabolic acidosis, however the meaning of рСО2 is higher (instead of lower) thaorm. It specifies thr presence of disorders of breathing and allows to assume the mixed character of acidosis.

4. Clarification of character of acidosis and alkalosis with the help of the formulas

4.1. Formula of Winters and co-authors for metabolic acidosis:

pСО₂ = 1,5 [НСО3-] + 8.

The actual meaning of рСО2 of the patient (found on an alignment chart of Sihard-Anderson) can appear above or below the one designed on the formula of Winters and co-authors. If the difference is more than 2, it will testify not only about presence of metabolic acidosis, but also about violation of breath. In our case the obtained data of рСО2 = 1,5 × 17,5 + 8 = 34,25 mm Hg. This value differs from actual data рСО2 (47 mm Hg) b 47 – 34,25 = 12,75 mm Hg. Such large difference confirms our assumption of the mixed character acidosis of the patient.

     4.2. Formula of Van Ipersel de Strian and France for metabolic alkalosis:

pСО₂ = 0,9 [НСО₃^ˉ ] + 15,6.

If the pСО₂ value of the patient found on an alignment chart, differs a lot from designed on the formula, it is possible to think not only of presence of metabolic alkalosis, but also about existence of additional respiratory violation.

5. Identification of the mixed disorder of acid-basic balance with the help of an acid-alkaline chart

The method is offered by Goldberg and co-authors in 1978. The acid-alkaline chart represents the schedule, on an axis of abscissas of which the data of рСО₂ are marked, and on an axis of ordinates – data of рН are postponed. Six sectors are selected on a card: “metabolic acidosis”, “acute respiratory acidosis”, “chronic respiratory acidosis”, “metabolic alkalosis”, “acute respiratory alkalosis”, “chronic respiratory alkalosis”. To determine a type of disorder violation of acid-basic balance, two direct lines should be drawn on a chart: first – through a point of an axis of ordinates, which corresponds to actual meaning of рН (7,24); second – through a point of an axis of abscissas, which corresponds to actual meaning of рСО₂ (47 mm Hg). The crosspoint of these lines is between sectors “metabolic acidosis” and “acute gas acidosis”. It testifies to the mixed character of acidosis.

Development of Alkalosis

The pH of blood depends on the ratio of HCO3 – to CO2 concentration: pH = pK + log HCO3 CO2 pK contains the dissociation constant of H2CO3 and the reaction constant of CO2 to H2CO3. Alkalosis (pH > 7.44) thus occurs either when the CO2 concentration in blood is too low (hypocapnia, respiratory alkalosis), or that of HCO3 – is too high (metabolic alkalosis). Respiratory alkalosis occurs in hyperventilation. Causes include emotional excitement, salicylate poisoning, or damage to the respiratory neurons (e.g., by inflammation, injury, or liver failure). Occasionally a lack of O2 supply in the inspiratory air (e.g., at high altitude) causes increased ventilation resulting in an increased amount of CO2 being expired. Numerous disorders can lead to metabolic alkalosis:  In hypokalemia the chemical gradient for K+ across all cell membranes is increased. In some cells this leads to hyperpolarization, which drives more negatively charged HCO3 – from the cell. Hyperpolarization, for example, raises HCO3 – efflux from the proximal (renal) tubule cell via Na+(HCO3–)3 cotransport. The resulting intracellular acidosis stimulates the luminal Na+/H+ exchange and thus promotes H+ secretion as well as HCO3 – production in the proximal tubule cell. Ultimately both processes lead to (extracellular) alkalosis.  In vomiting of stomach contents the body loses H+. What is left behind is the HCO3 – produced when HCl is secreted in the parietal cells. Normally the HCO3 – formed in the stomach is reused in the duodenum to neutralize the acidic stomach contents and only transiently leads to (weak) alkalosis.  Vomiting also reduces the blood volume. Edemas as well as extrarenal and renal loss of fluid can similarly result in volume depletion. Reduced blood volume stimulates Na+/H+ exchange in the proximal tubules and forces increased HCO3 – reabsorption by the kidneys even in alkalosis. In addition, aldosterone is released in hypovolemia, stimulating H+ secretion in the distal nephron. Thus, the kidneys ability to eliminate HCO3 – is compromised and the result is volume depletion alkalosis. Hyperaldosteronism can lead to alkalosis without volume depletion.  Parathyroid hormone (PTH) normally inhibits HCO3 – absorption in the proximal tubules. Hypoparathyroidism can thus lead to alkalosis.  The liver forms either glutamine or urea from the NH4 + generated by amino acid catabolism. The formation of urea requires, in addition to two NH4 +, the input of two HCO3 – that are lost when urea is excreted. (However, NH4 + is split off from glutamine in the kidney and then excreted as such). In liver failure hepatic production of urea is decreased, the liver uses up less HCO3 –, and alkalosis develops. However, in liver failure respiratory alkalosis often predominates as a result of damage to the respiratory neurons (see above).  An increased supply of alkaline salts or mobilization of alkaline salts from bone, for example, during immobilization, can cause alkalosis.  Metabolic activity may cause the accumulation of organic acids, such as lactic acid and fatty acids. These acids are practically completely dissociated at blood pH, i.e., one H+ is produced per acid. If these acids are metabolized, H+ disappears again. Consumption of the acids can thus cause alkalosis.  The breakdown of cysteine and methionine usually produces SO4 2– + 2 H+, the breakdown of arginine and lysine produces H+. Reduced protein breakdown (e.g., as a result of a protein- deficient diet; reduces the metabolic formation of H+ and thus favors the development of an alkalosis. The extent to which the blood’s pH is changed depends, among other factors, on the buffering capacity of blood, which is reduced when the plasma protein concentration is lowered. 

            

Development of Acidosis

The pH of blood is a function of the concentrations of HCO3 – and CO2. An acidosis (pH < 7.36) is caused by too high a concentration of CO₂ (hypercapnia, respiratory acidosis) or too low a concentration of HCO3 – (metabolic acidosis) in blood. Many primary or secondary diseases of the respiratory system as well as abnormal regulation of breathing can lead to respiratory acidosis. This can also be caused by inhibition of erythrocytic carbonic anhydrase, because it slows the formation of CO2 from HCO3 – in the lung and thus impairs the expiratory elimination of CO2 from the lungs. There are several causes of metabolic acidosis:  In hyperkalemia the chemical gradient across the cell membrane is reduced. The resulting depolarization diminishes the electrical driving force for the electrogenic HCO3 – transport out of the cell. It slows down the efflux of HCO3 – in the proximal tubules via Na+(HCO3 –)3 cotransport. The resulting intracellular alkalosis inhibits the luminal Na+/H+ exchange and thus impairs H+ secretion as well as HCO3 – production in the proximal tubule cells. Ultimately these processes lead to (extracellular) acidosis.  Other causes of reduced renal excretion of H+ and HCO3 – production are renal failure, transport defects in the renal tubules, and hypoaldosteronism. (Normally aldosterone stimulates H+ secretion in the distal tubules;).  PTH inhibits HCO3 – absorption in the proximal tubules; thus in hyperparathyroidism renal excretion of HCO3 – is raised. As PTH simultaneously promotes the mobilization of alkaline minerals from bone, an acidosis only rarely results. Massive renal loss of HCO3 – occurs if carbonic anhydrase is inhibited, because its activity is a precondition for HCO3 – absorption in the proximal tubules.  Loss of bicarbonate from the gut occurs in vomiting of intestinal contents, diarrhea, or fistulas (open connections from the gut or from excretory ducts of glands). Large amounts of alkaline pancreatic juice, for example, can be lost from a pancreatic duct fistula.  As the liver needs two HCO3 – ions when incorporating two molecules of NH4 +; in the formation of urea, increased urea production can lead to acidosis. In this way the supply of NH4Cl can cause acidosis. In certain circumstances the infusion of large amounts of NaCl solution can lead to an acidosis, because extracellular HCO3 – is “diluted” in this way. In addition, expansion of the extracellular space inhibits Na+/H+ exchange in the proximal tubules as a result of which not only Na+ absorption in the proximal tubules but also H+ secretion and HCO3 – absorption is impaired.  Infusion of CaCl2 results in the deposition of Ca2+ in bone in the form of alkaline salts (calcium phosphate, calcium carbonate). H+ ions, formed when bicarbonate and phosphate dissociate, can cause acidosis.  Mineralization of bone, even without CaCl2, favors the development of acidosis.  Acidosis can also develop when there is increased formation or decreased breakdown of organic acids. These acids are practically fully dissociated at the blood pH, i.e., one H+ is formed permolecule of acid. Lactic acid is produced whenever the energy supply is provided from anaerobic glycolysis, for example, in O2 deficiency, circulatory failure, severe physical exercise, fever, or tumors. The elimination of lactic acid by gluconeogenesis or degradation is impaired in liver failure and some enzyme defects. Fatty acids, “-hydroxybutyric acid and acetoacetic acid accumulate in certain enzyme defects but especially in increased fat mobilization, for example, in starvation, diabetes mellitus, and hyperthyroidism.  A protein-rich diet promotes the development of metabolic acidosis, because when amino acids containing sulfur are broken down (methionine, cystine, cysteine), SO4 2– + 2 H+ are generated; when lysine and arginine are broken down H+ is produced. The extent of acidosis depends, among other factors, on the blood’s buffering capacity. 

 

Disorder of wAter-electrolyte   metabolism. Dehydration

Distribution of water in the organism

Water is the major component of  internal environment in the organism and it is approximately 60 % of body weight varying from 45 % (in the fat elderly people) up to 70 % (in young men). Women have more fat, less  muscles, and total quantity of water is 50 %. The normal deviations are observed approximately within the limits of 15 %. In children the content of water is higher, than in the adult. With age the content of water gradually decreases. The large part of water (35-45 % of body weight) is inside the cells  (intracellular fluid). Extracellular fluid is 15-25 % of body weight and is divided on to intravascular (5 %), interstitid (12-15 %) and transcellular (1-3 %).

During 24 hours in organism of the person there arrives about 1,2 l of water with drinking, with food – about 1 l, about 300 ml of water is formed in oxidation of food substances. In normal water balance as much the same quantity of water (about 2,5 l) is excreted from the organism: by kidneys (1-1,5 l), by perspiration (0,5-1 l) and lungs (about 400 ml), and also with feces (50-200 ml).

The fluids are in constant movement: the liquid, which washes the cells, brings nutritives substances and oxygen and removes the products of metabolism and carbondioxyde. Cell membranes are freely permeable for water, but are not permeable for many dissolved substances, that’s why movement of  liquid between intracellular and extracellular takes place by osmotic gradient, which is created by osmotically active substances. By the law of isoosmolarity the water moves through the biologic membranes to the side of higher concentration of dissolved substances. Dissolved substances, which are freely permeable for  membrane, do not influence the movement of water. For example, urea freely moves through biological membranes and consequently  does not influence on the movement of water normally. The exchange of water between vessels and tissues is carried out by Starling’s mechanism: water, electrolytes, some organic substances easily move through the capillary walls, but more difficult proteins are transported. In healthy person for one day from blood to tissue 20 l of a fluid is filtered, 17 l is absorbed back to capillaries and about 3 l flows from tissue by lymphatic capillaries and through the lymphatic system comes back to the vessels.

Sodium  is main cation of extracellular fluid. Chloride and bicarbonate represent anionic electrolyte group of extracellular space. In cell space the main cation is potassium and anionic group is represented by phosphates, sulfates, proteins residual anions and bicarbonate. Electrolytes provide 94-96 % of plasma osmolarity and sodium as a main ion of extracellular fluid – 50 % of osmotic pressure. As the capillary membrane is not permeable for proteins, colloid-osmotic pressure is the main force which moves free water and electrolytes through the capillary membrane by osmatic laws. Generally the organism is irresistable to osmotic gradients. The sudden change of fluid osmolarity in intracellular space leads to moving of fluid through cell membrane, therefore osmotic gradients are balanced.

Water-electrolyte exchange is characterized by persistance, which is supported by nervous, endocrine mechanisms, and also by osmotic and electric forces. Its main parameter is water balance. The most important condition of persistance of water cell environments is their isotonic state. The value of cationic charges should be equal to the value of anionic charges both inside the cell and outside it. However, in biologic objects the intracellular potential prevails. In this condition the difference of potentials as between the cell and environment equal to 80 mV, as between separate elements of the cell (nucleus, protoplasm and shell or membrane) also is kept. Just the preservation of  difference of potentials is one of main qualities of a cell ensuring possibility of realization of metabolic processes and its specific function.

Changes of extracellular and  intracellular fluid volume

The persistance of volume and osmolarity of intracellular fluid is supported by regulatory mechanisms, main effectory organ of which are kidneys. The increase of blood plasma osmolarity by loss of pure water is specific irritant of osmoreceptors situated in anterior hypothalamus. In result there is feeling of thirst. The thirst is one of main and the most sensitive signs of water deficiency. The presence of thirst shows that water volume in extracellular space is reduced concerning the content of salts in it. The irritation of osmoreceptors of hypothalamic area (in increase of blood osmolarity), and also volume receptors in left atrium (in decrease of blood volume) stimulates the secretion of vasopressin (ADH) by supraoptical and paraventricular nuclea of hypothalamus. Vasopressin strengthens water reabsorption in distal canaliculi of nephron through activation of V₂ receptors of epithelium and derivation of cAMP, which increases their permeability for water. The stimulating effect of ADH is determined by permissive action of ACTH from adenohypophysis. It leads to decrease of diuresis, increase of volume of circulatting blood. Besides ADH contracts the arteriolas and increases the arterial pressure.

The irritation of receptors in afferent artery of kidneys (decrease of renal circulation, blood loss) and sodium receptors of dense spot in juxtaglomerular apparatus (sodium deficiency) strengthens synthesis and clearing release of renine. Under influence of renine the angiotensinogen of blood plasma will transforn to angiotensin I. This substance doesn’t have biological activity yet. In passing through lung capillaries angiotensin І under action of converting enzyme of endothelial cells will transform to angiotensin II. Further under influence of angiotensinases there is formation of angiotensin III. Angiotensin II has two effects: 1) causes contraction of smooth muscles in arteriolas, therefore there is their narrowing and arterial pressure is increased; 2) acting on glomerular zone of adrenal cortex, it activates the secretion of aldosteron. Angiotensin III has only one action – it increases the secretion of aldosteron.

The main functional effects of aldosteron are connected with its influence on kidneys. Acting on distal curre canaliculi of nephrons, aldosteron causes: 1) increases reabsorption of Na⁺; 2) increases secretion of K⁺; 3) increases secretion of Н⁺ (strengthens acidogenesis).

Antidiuretic and antisodiumuretic mechanisms are opposite to diuretic and sodium-uretic. Their primary factors are renomodular prostaglandins and atrial sodium-uretic. It is synthesized in the cells of atrium left atrium. It increases diuresis and Na-uresis, weakens smooth muscle fibres of vessels and decreases arterial pressure. The content of atrial sodium-uretic factor in left atrium and its secretion to blood is increased after redundant consumption of water and salts, owing to atrial dilation, increase of arterial pressure, and also stimulation of a-adrenoreceptors and receptors of vasopressin. These mechanisms function constantly and provide restoring of water-electrolyte  balance after blood loss, dehydration, in case of water excess in the organism, and also change of osmotic concentration of extracellular fluid.

In pathological states the integration of regulatory mechanisms of water balance can be disturbed. For example, in cardiac insufficiency, liver cirrhosis, nephrotic syndrome the tendency to delay of water and sodium, is kept despite of increased volume of extracellular fluid and general content of sodium and water. In other situations the mechanisms of preservation of water and sodium are disturbed, their loss therefore is observed.

dehydrations

  The disturbances of water-salt metabolism are divided on dehydration and hyperhydration. Depending on change of osmotic concentration (the ratio of water and electrolytes) dehydration and hyperhydration are subdivided on isoosmolaric, hypoosmolaric and hyperosmolaric.

Isoosmolaric dehydration develops in equivalent loss of water and electrolytes. It is observed in polyuria, intestinal toxicosis, acute bleeding, vomiting, diarrhea. The decrease of amount of tissue fluid goes mainly for the account of extracellular.

Hypoosmolaric dehydration is characterized by decrease of osmotic pressure of extracellular fluid and is observed in case of salt’s loss mainly. It develops in loss of stomach and intestinal secreation (diarrhea, vomiting), increased sweating, if the water loss is compensed by drinking without salt. In such case the decrease of osmotic pressure in extracellular environment results in transition of water in cells, owing to this the condensation of blood and disturbance of blood circulation, hypovolemia occur; the filtrating ability of kidneys is decreased, dehydration of cells develops (in particularly nervous) and violation of their function.

Dehydration and loss of electrolytes results in violation of acid-base balance. So, dehydration with loss of chlorides and H⁺ ions of gastric juice results in alcalosis. Decrease of pancreatic and intestinal juices, which contain more sodium and hydrocarbonates, leads to acidosis.

Hyperosmolaric dehydration develops at loss of water, therefore osmotic pressure of intracellular liquid is increased. It is observed when the loss of water exceeds loss of electrolytes (first of all, sodium), for example, for want of hyperventilation, proffuse sweating, loss of saliva, and also at diarrhea, vomiting, polyuria, when reimbursement of water loss is not enough. In this case the decrease of volume of extracellular fluid and increase of its osmoticity occurs.

The increase of osmotic pressure of extracellular fluid leads to moving of water from cells. Dehydration of cells causes painful feeling of thirst, strengthening of fiber disintegration, increase of temperature, and sometimes – darkening of consciousness, coma. The increase of osmotic pressure of intercellular fluid leads to intracellular dehydration and increase of intracellular concentration of electrolytes, that leads violation of hydrate coverings of protein molecules. The solubility of fibers decreases, they are sedimented, that is presented by violation of their functions.

Account of an amount and structure of a liquid for introduction to the patient for want of dehydratation

Example. Data of an inspection of a patient: weight of body – 70 kg, hematocrit – 0,50 l/l, contents sodium in serumof blood – 132 mmol/l (average norm – 142, oscillation – 135-145), contents calium – 3,8 mmol/l (norm – 5, oscillation – 3,9-5,8).

Conclusions: 1. Inthe patient hypoosmolar dehydratation with deficiency of  potassium.

                    2. It is necessary to the patient to fill water, sodium and potassium.

Stages of account

1.  Determination  deficiency of water

1.1. Determination  a degree of dehydratation (percent of loss extracelular of a liquid):

1.2. Determination of quantity extracelular liquid in the patient:

1.3. Determination of quantity extracelular liquid before disease:

1.4. It is necessary to enter quantity lost liquid, to the patient:

15,7 – 14,0 = 1,7 l

2. Determination  deficiency of sodium

2.1. Determination deficiency of sodium in 1 l extracelular liquid:

142 – 132 = 10 mmol/l

2.2. Determination deficiency of sodium in all extracelular liquid:

10 х 14 = 140 mmol

2.3. Determination percentage concentration of solution NaCl for transfusion. We prepare such solution, that 1 ml it contained 1 mmol NaCl, and 1 l – accordingly 1 mol NaCl (that is 58,5 g of dry substance). It – approximately 5,8 %  solution.

 

3. Determination deficiency of potassium

3.1. Determination deficiency of potassium in the 1 l extracelular  liquid:

5,0 – 3,8 = 1,2 mmol/l

3.2. Determination deficiency of potassium in the all extracelular  liquid:

1,2 х 14 = 16,8 mmol

3.3. Determination percentage concentration of a solution КСl for transfusion. We prepare a solution from account, that in 1 ml it was 1 mmol КСl. Then 1 l will contain 1 mol КСl, that is 75,5 g (approximately 7,5 % a solution).

The answer: it is necessary to the patient to drip transfuse 1,7 l isotonic solution of glucose (5,25 %) where to add 140 ml 5,8 % of a solution NaCl and 16,8 ml 7,5 % of a solution КСl.

 

The deficiency of a liquid and electrolites can be also  calculated under the formulas Mc Criston and Miller:

1. 

2.  D_е = 0,2 х M х (E_n – E_e)

The denotations in the formulas:

D_H2O  – deficiency of  extracelular water (l)

DE – deficiency of electrolytes in extracelular  water (mmol)

        Нсn – average value hematocrit iorm (0,45 l/l)

        Нс – significance hematocrit in the patient

        E_n – average concentration electrolyte in serum blood iorm (mmol/l)

        EE – Concentration of electrolyte in whey of blood of the patient (mmol/l)

        М – Weight of a body of the patient

        0,2 – Volume of extracelular liquid (20 %)

The decrease of water in cells results in decrease of their volume and in decrease of an active surface of cell membranes. As a result of it the functions connected with plasmatic membrane – intercellular interactions, perception of regulatory signals, migration etc. are infringed.

Among general violations on the level of organism intracellular dehydration appears by disorders of the function in central nervous system neurons. It appears by development of intolerable thirst, darkening of consciousness, hallucinations, violations of rhythm breath. Dehydration of endothelial cells leads to increase of intervals between them, increase of permeability of vessel wall. It can cause an exit from capillaries in tissue of fibers of blood plasma and its form elements – hemorrhages develop.

The increased leadingout of water from an organism is observed for want of diabetes insipidus. The major factor of pathogenesis of diabetes insipidus is the decrease of production of vasopressin. The reason of diabetes insipidus can be tumours, inflammatory process, sarcoidosis or trauma injuring neurohypophysis. The second form of illness – primary polydypsia of psychogenic origin, which is accompanied with secondary polyuria. The third form of illness is nephrogenic diabetes insipidus, in which basis the reduction of sensitivity of kidneys to vasopressin lays. In this case the decrease of production in epithelium of canaliculi of cAMP and decrease of permeability of distal part of nephron canaliculus for water is marked.

The decrease of water contents in liquid part of blood leads to anhydremia, hypovolemia and decrease of volume of circulatting blood. Extreme manifestation of extracellular dehydration is the development of anhydremic shock. Major importance in it development belongs to: 1) hypovolemia (decrease of volume of circulating blood). It is the reason of violation of general hemodynamic. Minute volume of blood and arterial pressure decrease, that leads to development of circulatory hypoxia and metabolic acidosis. In result of hemodynamic violations develops acute renal insufficiency: filtrating pressure decreases, oligo- and anuria, hyperazotemia and uremia develop; 2) hemoconcentration (condensation of blood, increase of its viscosity). It causes first of all violations of microcirculation, circulation in capillaries is decelerated, the sludg-syndrome, true capillary stasis develops. A consequence of such disorders is the development of hypoxia and acidosis. Hypoxia, acidosis and intoxication are major factors infringing the functions of CNS and other life-impotant organs and causing of death. The signs of severe anhydremia and death occur at the adult after loss 1/3, in children – 1/5 of volume of extracellular fluid.

hyperhydrations

Extracellular hyperhydration is an increase of volume of fluid in extracellular sector of an organism. It is a result of positive water balance.

The reasons of extracellular hyperhydration can be: 1. Redundant receipt of water in an organism: а) drinkingo of salty water, not compensating thirst; b) intravenosus introduction of big quantity of liquid to the patient. 2. Delay of water in an organism owing to violation of its excretion by kidneys: а) renal insufficiency; b) violation of regulation of kidneys (primary and secondary hyperaldosteronism, hyperproduction of antidiuretic hormone).

At isoosmolaric hyperhydration osmotic pressure of extracellular fluid is not changed. This kind of violations can be observed for a while after introduction of redundant amount of isotonic solution.

Hypoosmolaric hyperhydration (the water poisoning) is characterized by decrease of osmotic pressure of extracellular fluid. This kind of hyperhydration in experiment on animals is simulated by repeated introductions of water into stomach on a background of introduction of vasopressin, aldosterone or removal of adrenal glands. In clinic the water poisoning is possible in reflectory anuria, and also in the second stage of acute renal insufficiency.

Hyperosmolaric hyperhydration is characterized by increase of osmotic pressure of extracellular fluid and can develop in use for drinking of salty marine water.

In extracellular hyperhydration the following defending-compensatory responses develop:

1. Extracellular hyperhydration is accompanied by increase of volume of circulating blood. It leads to mechanical expansion of atrial cells, which in the response release in blood atrial sodium-uretic hormone. The last increases Na-uresis and diuresis, owing to what volume of circulating blood decreases.

2. The increase of volume of circulating blood is the reason of decreased impulsation from volumoreceptors, therefore the secretion of antidiuretic hormone decreases and diuresis increases.

The redundant amount of fluid is not usually detained in blood, and passes in tissue, first of all in extracellular environment, that results in development of latent and obvious edemas.

EDEMAS

Edemas is a redundant accumulation of fluid in tissues of an organism and serous cavities.

There are general and local edemas. General edemas are manifestation of extracellular hyperhydration, local are connected with the dislocation of fluid balance in the limited site of a tissue or organ.

Depending on mechanisms of development edemas can be: 1) hydrostatic;            2) oncotic; 3) membranogenic; 4) lymphogenic; 5) as a result of violation of neuro-endocrine regulation.

Hydrostatic edemas can be stipulated by the following mechanisms: 1) increase of blood volume (hypervolemic edemas); 2) increase of venosus pressure (congestive edemas); 3) primary violation of microcirculation – dilation of arteriolas and spasm of venules (microcirculatory edemas). Hypervolemic edemas in extracellular hyperhydration and edemas, connected with delay in an organism of sodium ions, for example, in cardiac insufficiency, secondary aldosteronism. Congestive edemas occurs in violation of blood outflow by venous vessels, increase of venous pressure and filtrating pressure in capillaries. The most often reason of increase of venous pressure in conditions of pathology are the defects of cardiac valves leading to cardiac insufficiency and congestion of blood in veins. Venous pressure is increased also in compression or obstipation (thrombosis) of veins, violation of their valve apparatus, in continued standing. In some cases filtrating pressure in capillaries can be increased without essential changes of venous pressure. It is observed in violation of microcirculation: the dilation of arteriolas and contraction of venules. Such violations quite often arise under influence of humoral factors, which regulate arteriolar lumen and tone of precapillary sphincters (biogenic amines, products of metabolism etc.). The dilation of arterioles with consequent increase of volume of interstitial fluid can be observed also iormal conditions, for example, in a working muscle. The increase of filtrating pressure can be stipulated also sharply by negative pressure in intercellular space. So, in burn the negative pressure of intercellular fluid can be increased owing to evaporation of water from surface and changes of colloids, that causes derivation of moving forces. This mechanism is considered to be the main in pathogenesis of edema in burn of skin.

Oncotic edemas naturally develop in decrease of the contents in blood plasma of proteins (albumins) and decrease of gradient of osmotic pressure between blood and intercellular fluid. It arises first of all in hypoproteinemia (proteinuria, starvation, liver cirrhosis) owing to decrease of oncotic pressure of blood, and also in accumulation of osmotically active substances (Na⁺, proteins, products of metabolism) in intercellular space. Edema is increased in increase of oncotic pressure in interstitial fluid, which in turn strengthens filtering. Oncotic pressure of an interstitial fluid is increased also in blockade of lymph circulation. Hydrofilness of tissue colloids depends also on concentration of Н⁺. In shift of рН in the acidic side edema of parenchymatous elements and dehydration of connective tissue occurs. In shift of рН in the alkaline side connective tissue is hydrated.

Membranogenic edemas arises owing to increase of permeability of vessel wall. In an organism hydrostatic, oncotic and osmotic pressure can show the action only in certain state of vessel permeability. The increase of permeability is accompanied by an exit of proteins from blood into interstitial environment, decrease of oncotic pressure of blood plasma and its increase in interstitial space. Therefore increase of permeability of capillaries is the premise of edema development. This mechanism is leading in development of allergic, inflammatory, toxic edemas.

Queek’s edema

Lymphogenic edemas arises owing to violations of lymph formation and lymph circulation. In this case the leadingout of proteins with lymph, iorm filtered in tissue is infringed, and tissue oncotic pressure is increased. Among the reasons of development of lymphogenic edemas it is necessary to define the compression of lymphatic vessels by scar tissue; increase of central venous pressure (insufficiency of heart), prohibitive to inflow of lymph in the system of blood circulation. It is found out, that venous congestion, which is accompained by increase of pressure in upper vena cava (as well as local venous congestion, for example, in thrombophlebitis), causes reflectory spasm of lymphatic vessels. Besides collected in edemas interstitial fluid compresses lymphatic vessels.

The delay of water connected with disorder of regulation of water-electrolyte metabolism, is observed in hypofunction of thyroid gland (myxedema), increase of production of vasopressin, insulin, raising hydrofilness of tissue colloids, in primary, and also secondary hyperaldosteronism (for example, in cardiac insufficiency, nephritic syndrome, liver cyrrhosis etc.). Hormonal factors in regulation of disorder of water-electrolyte metabolism act in close connection with neurogenic. This interrelation distinctly is visible in pituitary-adrenal mechanism playing the important role in development of cardiac and other kinds of edemas.

In pathogenesis of edemas there are two stages. The first stage – is accumulation of the connected water. Edematic liquid contacts with tissue colloids and is stored mainly in gel-like structures (collagenic fibres, main substance of connective tissue). In such case the clinical signs of edema insignificant – turgor of tissue is increased a little.

The second stage is accumulation of free water. When weight of the connected water is increased approximately on 30%, and the hydrostatic pressure in tissue achieves atmospheric, free untied water is increased. Then there are expressed signs of edema: free water moves according to force of gravitation, there is a symptom of “fossa” in pressing on tissue.

The main reason of intracellular hyperhydria is decrease of osmotic pressure of extracellular fluid, that is connected to development of hyponatriemia. In these conditions water under the laws of osmos goes from interstitial space in cells – there are signs of generalized cell edema.

Among mechanisms of cell edema major importance belongs to:

1) Disintegration of intracellular structures, proteins, owing to what connected with them cations (are in main ions K⁺) and intracellular osmotic and oncotic pressure is increased;

2) Disturbances of permeability of cell membrane, therefore the ions of sodium and chlorine arrive into a cell and increase osmotic pressure of cytoplasm;

3) Disorders of functioning of sodium-potassium pumps causing accumulation of sodium ions in a cell.

Edema of a cell aggravates processes of its damage. It is connected with that:    а) the permeability of cell membranes as a result of their osmotic expansion is increased; b) the phenomenon of electrical “damage” of plasmatic membrane of excitable cells is possible; c) there is a mechanical break of membranes in their expansion.

Depending on the reasons and mechanisms of occurrence there are cardiac, renal, liver, cachectic, inflammatory, toxic, allergic, lymphogenic, neurogenic, endocrine etc.

Cardiac, or congestive edema arises mainly in case of venous congestion and increase of venous pressure, that is accompanied by increase of filtering of blood plasma in capillary vessels. Developing in blood congestion hypoxia results in disturbance of permeability of a vessel wall. The large significance in occurrence of cardiac edemas in insufficiency of circulation belongs also to reflectory-renin-adrenal mechanism of water delay.

Renal edema. In pathogenesis of edema at glomerulonephritis primary significance is decrease of glomerular filtering, that leads to delay of water in an organism. In such case sodium reabsorption iephron canaliculi is also increased, in what the known role belongs to secondary aldosteronism, and also increase of permeability of vessels. In presence of nephrotic syndrome on the foreground the factor of hypoproteinemia (owing to proteinuria) acts which is combined with hypovolemia and stimulation of production of aldosteron.

In development of liver edema in liver injury the important role hypoproteinemia plays, owing to violation of synthesis of proteins in liver. Some value in this case has increase of production or violation of inactivation of aldosterone. In development of ascites in cirrhosis the main role belongs to difficulty of liver blood circulation and increase of hydrostatic pressure in the system of portal vein.

Cachectic edema develops in alimentary dystrophia (starvation), hypotrophia at children, malignant tumours and other exhaustive diseases. The major factor in its pathogenesis is hypoproteinemia, stipulated by violation of protein synthesis, increase of permeability of wall of capillaries and accumulation of products of disintegration in tissues.

In pathogenesis of inflamantory and toxic edemas (in action of chemical substances, bites of bees and other poisonous insects) the primary role is played by disorders of microcirculation in the center of injury and increase of permeability of capillary vessels wall. In development of these violations the important role belongs to released vasoactive mediators: biogenic amines (histamine, serotonin), prostaglandins, leukotriens, kinins.

Allergic edemas arises in connection with development of allergic respons (urticaria, injury of joints etc.). The mechanism of development of allergic edemas in many things is similar to pathogenesis of inflammatory and neurogenic edema. The disorder of microcirculation and permeability of capillary vessels wall is caused by biologically active substances and immune complexes.

Neurogenic edema develops as a result of damage of nervous regulation of water metabolism, tissue and vessels trophics. Here edema of limbs in hemiplegia and syringomyelia, edema of face ieuralgia of trigeminal nerve and Quincke’s edema are concerned. In origin of neurogenic edema the important role belongs to increase of permeability of vessel wall and disorder of metabolism in damaged tissues.

Myxedematous edemas is special variant of edemas, in which basis the increase of hydrophilic tissue colloids lays. In this case in tissues the amount of  connected water increases. Myxedematous (“mucous”) edemas are characteristic for hypofunction of thyroid gland.

The consequences of edema depend on its degree. The significant accumulation of fluid causes compression of tissues, violation of their functions. The congestion of fluid in body cavities infringes the function of neighboring organs. So, ascites in pleural cavity aggravates the breath, and the accumulation of transsudate in pericardium infringes activity of heart.