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PATHOPHYSIOLOGY

The most brilliant example of the situation when the affection of liver demands urgent measures is a hepatic insufficiency.

It is defined as the syndrome developed as a result of lesions of hepatic cells that lead to the disorder of all functions of the liver and, after all, to hepatic coma. The causes of hepatic insufficiency are very varied and this defines a variety of pathogenesis and clinical picture. They may be, tentatively, divided into those causing an overloading of the liver with bilirubin (blood transfusion, hematoma, hemolysis), injuring hepatic cells (virus hepatitis, cirrhosis, exacerbation of chronic hepatitis, hypoxia, shock, medicamentous lesions, poisoning with hepatotropic poisons), producing intrahepatic cholestasis (infection, drug) and extrahepatic one (lesion of biliary ducts, pancreatitis, cholelithiasis).

A direct cause of hepatic insufficiency is, most often, cirrhosis, as far as just with this pathology ends the majority of diseases of the liver. It may be said that every grave, progressing affection of the liver — it is the beginning of cirrhosis. That is not only the point that destroyed hepatic cells are replaced by connective tissue and these areas are already not able to perform their function. After all, 30% of cells are sufficient that the functional ability of the liver would meet the organism's demands. But in cirrhosis a normal structure of circulation of blood, lymph and bile is disturbed as well. And this is manifested in signs of hepatic insufficiency long before its final stage — hepatic coma.

A narrowing of hepatic bed at the expense of vegetations of connective tissue leads to the elevation of portal pressure up to 20-30 cm water column and more. This causes development of portacaval shunts that decrease the pressure, as long as they can receive to 90% of normal hepatic blood flow. Veins of the lower third of esophagus become varicosed, they lie directly under a mucous membrane and as a result of this are easily injured. Hemorrhoidal veins are dilated. Telangiectases and dilated subcutaneous veins appear on the anterior abdominal wall. A portal hypertension, in the patients with pronounced bypass blood flow, is often accompanied by hypercirculatory syndrome with elevation of VCB and CVP.

Transition of portal blood directly to systemic circulation, without its entry into the liver, may cause a hepatic coma as a result of intoxication with products of metabolism and decrease of the brain oxygenation. Along with the others, veins of spleen are also changed that leads to its enlargement and induration. It has a negative effect on erythropoiesis and thrombopoiesis — anemia arises and a threat of hemorrhage increases.

Portal hypertension and hypoalbuminemia observed in cirrhosis because of decrease of the number of hepatocytes synthetizing protein, lead to the rise of ascitis.

Intensification of plasma filtration through fenestrae of the epithelial covering of sinusoids of Disse's space occurs. A decrease of protein concentration in plasma lowers its oncotic pressure and increases a volume of lymph. If the level of albumin in plasma drops down to 3 g%, instead of usual 3 1 of lymph we recieve 7-11 1/day. It is relatively rich in protein, therefore it penetrates easily into Disse's space from sinusoids. The increase of volume of lymph production exceeds transport potentialities of the lymphatic paths in the liver and this leads to lymph exudation on the liver surface that is to production of ascitis. In so doing, a volume of vascular fluid decreases, u nal blood flow lowers, renin-angiotensin system is activated that leads to a release of aldosterone from adrenals. This secondary aldosteronism stimulates reabsorption of sodium and water in renal tubules. Though the excretion of sodium decreases gradually down to insignificant quantities, but its concen­tration in serum does not diminish, as far as the kidneys reabsorb both water and sodium equally actively.

So, a massive elevation of total sodium content in the organism is combined with almost its normal level in serum that supports aldosterone activity and intensifies a secondary aldosteronism. Aldosterone also causes a loss of potassium through the kidneys. Hypokalemia means a real decrease of the quantity of potassium in the organism in cirrhosis of the liver requiring its replenishment.

Clinical picture. Hepatic insufficiency is manifested in the symptoms of gravity of general condition with undue fatiguability, muscular weakness, anorexia, meteorism, muscular tremor and elevation of body temperature. Characteristic is a smell of the raw liver from the mouth. As a rule, jaundice arises. Edema, ascitis, changes on the skin (spider's naevi, erythema of palms) and endocrine symptoms appear in case of chronic development of hepatic insufficiency. Later, neurologic disorders start to predominate with a picture of precoma and hepatic coma. Laboratory and clinical signs of blood coagulation disorders are growing on.

In significant loss of function (acute hepatitis) of the bulk of hepatic cells (cirrhosis) the protein synthesis decreases, and it is manifested in hypoproteinemia. The rate of decrease of the concentration of different proteins in plasma depends on the time of their half-life: the shorter is their half-life, the sooner is it. According to this, blood coagulation disorders arise earlier than hypoalbuminemia that develops a little later.

A decrease of protein synthesis influences the production of numerous enzymes that, by their chemical nature, are proteins. A decrease of hepatic enzymes' production may slow down or stop the work of the liver in relation to its support of metabolism. A dyshormonal state is manifested, for example, in secondary aldosteronism and sex disorders. Fat-soluble drugs and exogenic toxins delay in the organism for a long time continuing to act. Sometimes, helps the fact that enzymatic system even of the injured liver may be induced as, for example, in the treatment with phenobarbital.

An increase of bilirubin concentration in blood serum higher than 34.0 mmol/1 (1.7-20.5 mmol/1 in the norm) leads to jaundice. It depends on the share of conjugated bilirubin in the total bilirubin, as long as this water-soluble form penetrates sooner into the tissues staining them. Bilirubin has selectivity to elastic fibers with which the skin and sclerae are, particularly, rich. Usually, at first, a yellowing of sclerae is noted. The skin becomes, at first, canary-yellow, in 1-2 weeks — red-yellow, and later — green-yellow.

Hyperbilirubinemia is observed in the intense degradation of hemoglobin ("prehepatic" cause — hemolytic jaundice) when hepatocytes transform bilirubin into bile rather inactively ("intrahepatic" cause — parenchymatous jaundice) or if the outflow of bile to the intestine ("posthepatic" cause — mechanical jaundice) is affected.

In hemolytic jaundice, on the background of anemia, unconjugated, indirect bilirubin is, primarily, elevated. In parenchymatous and mechanical jaundice — primarily conjugated, direct bilirubin.

In all the cases, without exception, constituent parts of bile come into blood. Bile salts are excreted with sweat onto the skin surface causing, typical for jaundice, itch. If the bile is not supplied to the duodenum, the absorption of fat-soluble substances, including vitamin K, needed for synthesis of a number of blood coagulation factors, in the intestine reduces or stops at all.

The final point of progressing hepatic insufficiency is hepatic coma. In its basis lies a nonspecific disorder of cerebral function under the effect of toxins that are formed, even in healthy people in the intestine under the action of bacteria, from proteins, including ammonia, phenol, amines, mercaptan, fatty acids, etc. These substances are accumulated in great amounts because of the insufficiency of detoxication function of the liver or by-passing the liver get into the brain through portacaval shunts.

Hepatic coma is characterized by symptoms of mental disorders (labile, bad mood, mental confusion, disorientation in space and time, disorders of the rhythm of sleep and staying awake, changes of personality with disinhibition, "faded" speech) and motor disorders (hyperreflexia, areflexia, tremor of hands).

In the course of hepatic coma three stages are distinguished:

I degree — mild changes of psychics, consciousness and motility;

II degree — coarse mental and motor disorders with disorientation in space
and time;

III degree — deep coma with unconsciousness that may be detailed by the
stage by stage principle in anesthesia (III,, III₂, III₃).

Hepatic coma is the state reversible, in principle. To the extent of recovery, for example, in hepatitis, the depth of coma undergoes a reverse development. Often hepatic insufficiency is accompanied by acute renal and respiratory failure.

The intensive care of hepatic insufficiency stipulates cessation of hepatonecrosis, improvement of function of the affected liver, support and replacement of hepatic function with active methods of detoxication, as well as correction of other vitally important functions and disorders of homeostasis.

It is known that if to stop hepatonecrosis, hepatic cells regenerate in the course of 10-15 days. However, it is necessary for this period, as fully as possible, to replace the function of hepatocyte in order to maintain the lift: of the organism.

The intensive care should be started with measures directed to elimination of the action of etiologic factor. A lesion of hepatocyte occurs at the expense of injury of the cell membranes and edema of the cells themselves. A use of glucocorticoids, namely, prednisolone up to 300 mg, hydrocortisone to 1500 ing, dexamethason to 64 mg a day contributes to stabilization of membranes and so the protection of hepatocytes from further destruction. A decrease of the edema of hepatocytes may be achieved by increasing oncotic and osmotic pressure of blood plasma. For this, they prescribe 10% albumin solution i/v by 200-300 ml a day, conserved blood plasma of the same group up to 400 ml a day, especially since in these patients a hypoproteinemia is always observed, and proteins have to be excluded from food ration. Mannitol is also prescribed by 1-1.5 g/kg body mass i/v drop by drop in the form of 15% solution, a daily dose mustn't exceed 140-180 g.

Improvement of hepatic blood flow contributes to the restoration of functional potentialities of hepatocytes. It is achieved by elimination of hypovolemia, enteroparesis, drainage of thoracic lymphatic duct, improvement of the cardiac contractility, medicamentous therapy (euphilline by 10 ml 2.4% solution, complamin by 2 ml 15% solution i/m 2 times per day, droperidol — after stabilization of hemodynamics, reopoliglucin and reogluman for improvement of rheologic properties of blood, etc.).

To decrease a hypoxia of the liver an oxygen therapy is applied (oxygen inhalation, HBO, etc,) in combination with antihypoxants (A-oxybutyric acid, barbiturates, vitamin E). Its effectiveness can be increased by means of agents that improve oxygen utilization by hepatic cells (pangamic acid, cytochrome C, cocarboxylase, /3-lipoic acid, Co-enzyme A, gutilin and diphosphopyridin-dinucleotide).

In order to prevent a degradation of its own tissue proteins, it is necessary to ensure the energy processes in the liver. It is achieved by intravenous administration of glucose no less than 5 g/kg body mass a day in the form of 10% solution with addition of insulin (1 U per 4-6 g of glucose dry mass).

To bind ammonia circulating in blood, preparations of glutamic or malic acid by 7-15 mg, glutathione — 500-1000 mg, arginine 25-75 mg a day are prescribed.

With the aim of improvement of lipotransport mechanisms, stabilization of the energy exchange in hepatocytes and their protection from fatty degeneration, methionine 1 g 6 times a day, lipocaine, choline chloride drop by drop i/v 1-2 g a day are prescribed. In hemolytic and parenchymatous jaundice with the elevation of unconjugated bilirubin level to induce the enzymes for bilirubin conjugation luminal by 0.05 g 2-3 times a day is prescribed.

For normalization of metabolism a complex of vitamines B, C, A retinol, inhibitors of proteolysis (gordox, trasylol or contrycal by 20 thnd U a day) are indicated.

The majority of the enumerated above vitamins is a part of complex preparations — essentiale, eparmepholin. They contain also phospholipids — main elements in the structure of cell membrane and mitochondria of hepatocytes. These preparations regulating lipid and carbohydrate metabolism, improve a functional state of operating hepatocytes including their detoxication function, contribute to maintenance and restoration of hepatocytes' structure, restrain a formation of cirrhosis of the liver.

They start to apply essentiale combining parenteral and peroral administrations. It is introduced i/v by 10-20 mg 2-3 times per day drop by drop at the rate of no more than 40-50 drops per min, dissolving this preparation in 5% glucose or dextrose solution, and per os by 2 capsules 2-3 times per day. In proportion to the improvement of patient's condition they change over to the treatment only with capsules.

Water-electrolyte disorders revealed are carefully corrected, having remembered the need to avoid sodium administration under the conditions of secondary aldosteronism accompanying hepatic insufficiency, removal of the excessive amounts of water by means of diuretics and careful replenishment of potassium ions. AAB is also corrected.

In order to slow down the process of ammonia formation in the intestine in the patients with hepatic insufficiency one should restrict or completely exclude proteins from their rations, to make purgation with the help of high clysters, laxatives and tube gastric lavage. Antibiotics are prescribed per os, gentamicin in particular, to prevent intestinal hemorrhage blood coagulability is increased by administration of aminocaproic acid, vicasol, calcium gluconate and vitamin C.

The above-given medicamentous agents are recommended to infuse into the umbilical vein that is especially dilated by an operative method, and then a catheter is introduced into it through which all the infused medicaments get directly into hepatic circulation.

In connection with not so high effectiveness of medicamentous therapy in hepatic insufficiency more active methods are applied to maintain and replace hepatic functions, first of all, a detoxication one. At present, drainage of thoracic duct, plasmapheresis, hemofiltration, hemo- and lymphosorption and liver transplantation are applied and considered as more effective. The latter is, for the present, available only to a quite limited number of clinics.

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