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Hepatic encephalopathy

A syndrome of altered consciousness, altered neuromuscular activity in a patient with hepatocellular failure or portosystemic shunting.

Mechanism

The mechanism and cause of hepatic encephalopathy is not known. However, several factors are believed to be important in the pathogenesis of this disease. The most important two factors are liver cell failure and portal hypertension. This results in intrahepatic and extrahepatic shunting of portal venous blood into the systemic circulation so that the liver is largely bypassed. As a result of these processes, various toxic substances absorbed from the intestine are not detoxified by the liver and lead to metabolic abnormalities in the central nervous system (CNS).

Ammonia

Blood levels of ammonia is commonly raised in many patients with hepatic encephalopathy. Furthermore, ammonia levels decrease on recovery from encephalopathy. Hence, ammonia has long been regarded as the main contributing factor.

Other toxins

Other compounds and metabolites that may contribute to the development of encephalopathy include mercaptans (derived from intestinal metabolism of methionine), short-chain fatty acids, and phenol. False neurochemical transmitters (e.g., octopamine), resulting in part from alterations in plasma levels of aromatic and branched-chain amino acids, may also play a role.

An increase in the permeability of the blood-brain barrier to some of these substances may be an additional factor.

GABA

Several observations suggest that excessive concentrations of g-aminobutyric acid (GABA), an inhibitory neurotransmitter, in the CNS are important in the reduced levels of consciousness seen in hepatic encephalopathy. Increased CNS GABA may reflect failure of the liver to extract precursor amino acids efficiently or to remove GABA produced in the intestine. In support of this, there is also evidence to suggest that endogenous benzodiazepines, which act through the GABA receptor, may contribute to the development of hepatic encephalopathy.

Manganese deposits in the basal ganglia

Finally, the observation of hyperintensity in the basal ganglia by magnetic resonance imaging in cirrhotic patients suggests that excessive manganese deposition may also contribute to the pathogenesis of hepatic encephalopathy.

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Symptoms of encephalopathy

Encephalopathy may be acute and reversible or chronic and progressive. In severe cases, irreversible coma and death may occur. Acute episodes may recur with variable frequency.

The complex neuropsychiatric syndrome is characterized by disturbances in consciousness and behavior, personality changes, fluctuating neurologic signs, asterixis or "flapping tremor," and distinctive electroencephalographic changes.

In the patient with otherwise stable cirrhosis, hepatic encephalopathy often follows a clearly identifiable precipitating event.

  • Gastrointestinal bleeding: which leads to an increase in the production of ammonia and other nitrogenous substances, which are then absorbed.
  • increased dietary protein may precipitate encephalopathy as a result of increased production of nitrogenous substances by colonic bacteria.
  • Electrolyte disturbances, particularly hypokalemic alkalosis secondary to overzealous use of diuretics, vigorous paracentesis, or vomiting, may precipitate hepatic encephalopathy. Systemic alkalosis causes an increase in the amount of nonionic ammonia (NH3) relative to ammonium ions NH4+). Only nonionic (uncharged) ammonia readily crosses the blood-brain barrier and accumulates in the CNS. Hypokalemia also directly stimulates renal ammonia production.
  • Injudicious use of CNS-depressing drugs (e.g., barbiturates, benzodiazepines) and acute infection may trigger or aggravate hepatic encephalopathy, although the mechanisms involved are not clear.
  • Other potential precipitating factors include superimposed acute viral hepatitis, alcoholic hepatitis, extrahepatic bile duct obstruction, constipation, surgery, and other coincidental medical complications.

Diagnosis

The diagnosis of hepatic encephalopathy should be considered when four major factors are present:

  1. Acute or chronic hepatocellular disease and/or extensive portal-systemic collateral shunts
  2. Disturbances of awareness and mentation, which may progress from forgetfulness and confusion to stupor and finally coma;
  3. Shifting combinations of neurologic signs, including asterixis (flapping tremors), rigidity, hyperreflexia, extensor plantar signs, and rarely, seizures. Fetor hepaticus, a unique musty odor of the breath and urine believed to be due to mercaptans, may be noted in patients with varying stages of hepatic encephalopathy.
  4. A characteristic (but nonspecific) symmetric, high-voltage, triphasic slow-wave (2 to 5 per second) pattern on the electroencephalogram.

The diagnosis of hepatic encephalopathy is usually one of exclusion.

Treatment

Early recognition and prompt treatment of hepatic encephalopathy are essential. Patients with acute, severe hepatic encephalopathy (stage IV) require the usual supportive measures for the comatose patient. Specific treatment of hepatic encephalopathy is aimed at (1) elimination or treatment of precipitating factors and (2) lowering of blood ammonia (and other toxin) levels by decreasing the absorption of protein and nitrogenous products from the intestine.

In the setting of acute gastrointestinal bleeding, blood in the bowel should be promptly evacuated with laxatives (and enemas if necessary) in order to reduce the nitrogen load. Protein should be excluded from the diet, and constipation should be avoided. 

Intestinal ammonia production by bacteria can also be decreased by oral administration of a "nonabsorbable" antibiotic such as neomycin. Equal benefits may be achieved with broad-spectrum antibiotics such as metronidazole.

The use of agents such as levodopa, bromocriptine, keto analogues of essential amino acids, and intravenous amino acid formulations rich in branched-chain amino acids in the treatment of acute hepatic encephalopathy remains of unproven benefit.

Flumazenil, a short-acting benzodiazepine antagonist, may have a role in management of hepatic encephalopathy precipitated by use of benzodiazepines, if there is a need for urgent therapy.

Hemoperfusion to remove toxic substances and therapy directed primarily toward coincident cerebral edema in acute encephalopathy are also of unproven value. The efficacy of extracorporeal liver assist devices employing hepatocytes of porcine or human origin to bridge patients to recovery or transplantation is as yet unproven but is currently being studied.

Chronic encephalopathy may be effectively controlled by administration of lactulose. Management of patients with chronic encephalopathy should include dietary protein restriction (usually to 60 g/d) in combination with low doses of lactulose or neomycin. Nephrotoxicity or ototoxicity may be limiting in prolonged usage of neomycin. There are suggestions that vegetable protein may be preferable to animal protein.

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