Hepatic encephalopathy - Pathogenesis

The pathogenesis of hepatic encephalopathy is not fully understood. Studies have shown dysfunction of several neurotransmitter systems. Hepatic encephalopathy involves a complex set of disorders, none of which provides a complete explanation. As a result of impaired liver clearance or peripheral metabolism, patients with liver cirrhosis have elevated levels of ammonia, neurotransmitters, and their precursors, which affect the brain.

Hepatic encephalopathy can be observed in a number of syndromes. Thus, in fulminant liver failure (FLF), encephalopathy is combined with signs of actual hepatectomy. Encephalopathy in liver cirrhosis is partly due to portosystemic shunting, an important role is played by hepatocellular (parenchymatous) insufficiency and various provoking factors. Chronic neuropsychiatric disorders are observed in patients with portosystemic shunting, and irreversible changes in the brain may develop. In such cases, hepatocellular insufficiency is expressed relatively little.

The various symptoms of hepatic encephalopathy probably reflect the amount and type of "toxic" metabolites and transmitters produced. Coma in acute liver failure is often accompanied by psychomotor agitation and cerebral edema; the lethargy and drowsiness characteristic of chronic encephalopathy may be accompanied by damage to astrocytes.

In the development of hepatic encephalopathy and hepatic coma in patients with acute liver diseases and lesions, the main role is played by parenchymatous (hepatocellular) insufficiency (endogenous hepatic encephalopathy and hepatic coma). In patients with liver cirrhosis, the decisive role can be played by the factor of portocaval shunting; 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 some cases, a combination of necrosis of the liver parenchyma and portocaval anastomoses is important (mixed hepatic encephalopathy and coma).

The main pathogenetic factors of hepatic encephalopathy and coma:

• Loss of liver detoxification function and exposure of the brain to toxic substances

Impairment of the liver's detoxifying function is of the utmost importance in the development of hepatic encephalopathy and hepatic coma. The main toxins are ammonia and mercaptans.

Normally, about 4 g of ammonia is formed in the intestine per day, 3.5 g is absorbed and enters the liver with the blood. In the liver, about 80% of the ammonia is neutralized and converted into 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 into urea, is transformed in the liver into glutamic acid, then into glutamine. The latter is carried by the blood to the liver and kidneys, where it is hydrolyzed into ammonia, which is converted into urea or excreted in the urine.

In hepatocellular insufficiency (acute and subacute massive liver necrosis), ammonia metabolism is disrupted, its amount in the blood increases sharply, and its cerebrotoxic effect is manifested. In liver cirrhosis, ammonia enters the general bloodstream through portocaval anastomoses and, thus, is excluded from liver metabolism and is not neutralized, and portosystemic hepatic encephalopathy develops.

The mechanism of cerebrotoxic action of ammonia is as follows:

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

Ammonia intoxication is most significant in portocaval hepatic encephalopathy and coma.

In the development of hepatic encephalopathy and hepatic coma, the accumulation of other cerebrotoxic substances in the blood is also of great importance: sulfur-containing amino acids (tauric acid, methionine, cysteine); methionine oxidation products (methionine sulfone and methionine sulfoxide); tryptophan metabolism products (indole, indolyl), formed in the large intestine; short-chain fatty acids (butyric, valerianic, caproic), derivatives of pyruvic acid.

There is an opinion that cerebrotoxic substances can also be formed in the process of hepatocyte autolysis (in endogenous hepatic coma). The nature of autolytic liver cerebrotoxins has not yet been established.

• The appearance of false neurotransmitters in the blood

In liver failure, there is increased protein catabolism and increased use of branched-chain amino acids - valine, leucine, isoleucine - as an energy source. 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 the blood and cerebrospinal fluid to 1.5 or less.

Aromatic amino acids are precursors of false neurotransmitters - octoplasmin, beta-phenylethylamine, tyramine. False neurotransmitters compete with normal brain mediators - norepinephrine, dopamine, adrenaline and lead to depression of the nervous system and development of encephalopathy. A similar effect is also produced by the product of tryptophan metabolism - serotonin.

• Acid-base imbalance

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

• Electrolyte disturbances

Electrolyte disturbances in hepatic encephalopathy and hepatic coma are most often manifested by hypokalemia. Extracellular potassium deficiency leads to potassium leaving the cell and the development of extracellular alkalosis, sodium and hydrogen ions enter the cell - intracellular acidosis develops. Under conditions of metabolic extracellular alkalosis, ammonia easily penetrates into brain cells and has a toxic effect. The accumulation of ammonia leads to hyperventilation due to its stimulating effect on the respiratory center.

• Hypoxemia and hypoxia of organs and tissues

Disruption of all types of metabolism and energy production leads to the development of hypoxemia and hypoxia of organs and tissues, primarily the central nervous system, and contributes to the development of hepatic encephalopathy and coma.

• Hypoglycemia

In massive liver necrosis, glucose formation in the liver is disrupted, and a large amount of insulin circulates in the blood (its degradation in the liver is disrupted). In this connection, hypoglycemia develops, which contributes to the development and then aggravation of hepatic encephalopathy and coma. In liver cirrhosis accompanied by liver failure, hyperglycemia is more often observed due to hyperproduction of glucagon and peripheral insulin resistance. Accumulation of pyruvic, lactic, citric, and a-ketoglutaric acids in the blood and cerebrospinal fluid is also noted, which have a pronounced toxic effect.

• Disseminated intravascular coagulation syndrome

The triggering factors for the development of DIC syndrome in liver diseases are: the release of thromboplastin from the damaged liver, intestinal endotoxemia, deficiency of antithrombin III due to a decrease in its formation in the liver; hyperergic damage to blood vessels and microcirculation disorders.

DIC syndrome contributes to further impairment 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 caused by intoxication, DIC syndrome, and decreased perfusion in the renal cortex.

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