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Pathophysiology of digestion

June 8, 2024

PATHOPHYSIOLOGY OF DIGESTION. PATHOPHYSIOLOGY OF LIVER

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

· vomitting

· 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

· dispeptic

· 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.

Helicobacter pylori

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.

Liver cirrhosis

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 ).

Hepatocerebral coma

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.