Hepatic encephalopathy: pathogenesis

The pathogenesis of hepatic encephalopathy is not fully understood. The research shows the dysfunction of several neurotransmitter systems. With hepatic encephalopathy, a complex set of disorders is observed, none of which provides an exhaustive explanation. As a result of violations of liver clearance or peripheral metabolism in patients with cirrhosis, the level of ammonia, neurotransmitters and their precursors, which affect the brain, increases.

Hepatic encephalopathy can occur with a number of syndromes. Thus, with fulminant hepatic insufficiency (FPN), encephalopathy is combined with signs of actual hepatectomy. Encephalopathy in liver cirrhosis is partly due to portosystemic shunting, an important role is played by hepatic-cell (parenchymal) insufficiency and various provoking factors. Chronic neuropsychiatric disorders are observed in patients with the presence of portosystemic shunting, and irreversible changes in the brain can develop. In such cases, hepatic-cell insufficiency is relatively small.

The various symptoms of hepatic encephalopathy probably reflect the number and type of "toxic" metabolites and transmitters that form. Coma in acute liver failure is often accompanied by psychomotor agitation and edema of the brain; The inhibition and drowsiness characteristic of chronic encephalopathy can be accompanied by damage to astrocytes.

In the development of hepatic encephalopathy and hepatic coma, parenchymal (hepatocellular) insufficiency (endogenous hepatic encephalopathy and hepatic coma) plays a key role in patients with acute diseases and liver lesions. In patients with cirrhosis of the liver, the portocaval shunting factor may play a decisive role; shunts can be spontaneous, i.e. Developing during the course of the disease or created as a result of surgical treatment ( portosystemic encephalopathy and coma). In a number of cases, the combination of necrosis of the liver parenchyma and portocaval anastomoses (mixed hepatic encephalopathy and coma) is important.

The main pathogenetic factors of hepatic encephalopathy and coma:

• Loss of detoxification of the liver and effects on the brain of toxic substances

Violation of the detoxifying function of the liver is of paramount importance in the development of hepatic encephalopathy and hepatic coma. The main toxins are ammonia and mercaptans.

Normally, about 4 g of ammonia are formed in the intestine within a day, it is absorbed and supplied with blood to the liver. In the liver, about 80% of ammonia is rendered harmless and converted to urea, the main part of which is excreted in the urine, and a small amount is excreted into the intestine. The remaining ammonia, not converted to urea, is transformed into the liver into glutamic acid, then into glutamine. The latter is carried by blood to the liver and kidneys, where it is hydrolyzed into ammonia, which turns into urea or is excreted in the urine.

With hepatic-cell failure (acute and subacute massive necrosis of the liver), ammonia metabolism is disturbed, its quantity in the blood sharply increases, its cerebro-toxic effect is manifested. With cirrhosis of the liver, ammonia enters the total blood flow through the portocaval anastomoses and, thus, is turned off from the liver metabolism and is not rendered harmless, portosystemic hepatic encephalopathy develops.

The mechanism of the cerebro-toxic action of ammonia is as follows:

• reduces the formation and use of brain cells by ATP;
• decreases the content of y-aminobutyric acid - the main neurotransmitter of the brain;
• increases the concentration in the brain of y-aminobutyrate, which possesses the properties of a neuroinhibitor;
• shows a direct toxic effect of ammonia on the brain cells.

The greatest value of intoxication with ammonia is with portocaval hepatic encephalopathy and coma.

In the development of hepatic encephalopathy and hepatic coma, the accumulation of other cerebro-toxic substances in the blood: sulfur-containing amino acids (tauric acid, methionine, cysteine) is of great importance; products of methionine oxidation (methionine sulfone and methionine sulfoxide); metabolic products of tryptophan (indole, indolyl), formed in the large intestine; short chain fatty acids (oily, valeric, kapron), derivatives of pyruvic acid.

There is an opinion that cerebro-toxic substances can also be formed during autolysis of hepatocytes (with endogenous hepatic coma). The nature of autolytic hepatic cerebrotoxins has not yet been established.

• The appearance in the blood of false neurotransmitters

When liver failure is observed, increased protein catabolism and increased use as an energy source of amino acids with branched chain - valine, leucine, isoleucine. These processes are accompanied by the entry into the blood of significant amounts of aromatic amino acids - phenylalanine, tyrosine, tryptophan, the metabolism of which normally occurs in the liver.

The ratio of valine + leucine + isoleucine / phenylalanine + tyrosine + tryptophan is normally 3-3.5, and in hepatic encephalopathy it decreases in blood and cerebrospinal fluid to 1.5 or less.

Aromatic amino acids are the precursors of false neurotransmitters (neurotransmitters) - octoplasmine, beta-phenylethylamine, tyramine. False neurotransmitters compete with normal brain mediators - norepinephrine, dopamine, adrenaline and lead to the depression of the nervous system and the development of encephalopathy. Similar effect has also a product of tryptophan metabolism - serotonin.

• Violations of acid-base balance

When endogenous hepatic coma develops metabolic acidosis, due to the accumulation of pyruvic and lactic acids in the blood. In conditions of acidosis, the penetration of toxic substances into the cells of the brain increases. Metabolic acidosis leads to hyperventilation, and respiratory alkalosis can develop in the future, which contributes to the penetration of ammonia into the brain.

• Electrolyte disturbances

Electrolyte disorders in hepatic encephalopathy and hepatic coma are most often manifested by hypokalemia. Deficiency of extracellular potassium leads to the release of potassium from the cell and the development of extracellular alkalosis, sodium and hydrogen ions enter the cell - intracellular acidosis develops. In conditions of metabolic extracellular alkalosis, ammonia easily penetrates into the brain cells and has a toxic effect. Accumulation of ammonia leads to hyperventilation due to its exciting effect on the respiratory center.

• Hypoxemia and hypoxia of organs and tissues

Violation of all kinds of metabolism and energy formation leads to the development of hypoxemia and hypoxia of organs and tissues, primarily of the central nervous system and promotes the development of hepatic encephalopathy and coma.

• Hypoglycaemia

With massive liver necrosis, the formation of glucose in it is disturbed, a large amount of insulin is circulating in the blood (its degradation in the liver is disturbed). In this regard, hypoglycemia develops, which contributes to the development and then aggravation of hepatic encephalopathy and coma. With cirrhosis of the liver accompanied by hepatic insufficiency, hyperglycemia is most often observed due to hyperproduction of glucagon and peripheral insulin resistance. There is also an accumulation in the blood and CSF of pyruvic, lactic, citric, a-ketoglutaric acids, which have a pronounced toxic effect.

• The syndrome of disseminated intravascular coagulation

Starting factors of the development of DIC syndrome in liver diseases are: the release of thromboplastin from the damaged liver, intestinal endotoxemia, the deficit of antithrombin III due to a decrease in its formation in the liver; hyperergic vascular damage and microcirculatory disturbances.

DIC-syndrome promotes further disruption of the functional capacity of the liver and central nervous system.

• Impaired renal function

In the progression of hepatic encephalopathy and the development of hepatic coma, a certain role is played by impaired renal function due to intoxication, DIC-syndrome, a decrease in perfusion in the cortical substance of the kidneys.

[1], [2], [3], [4], [5], [6], [7], [8]