Hepatic encephalopathy (HE) is a complex, potentially reversible neuropsychiatric condition that occurs as a consequence of acute or chronic liver disease. It is characterized by changes of personality, consciousness, behavior and neuromuscular function (Table 20). Early features include reversal of sleep pattern, apathy, hypersomnia, irritability and personal neglect. In later stages, delirium and coma may occur. Neurologic signs may include hyperreflexia, rigidity, myoclonus and asterixis. Asterixis is not specific to hepatic encephalopathy and may be present in other causes of metabolic encephalopathy. Seizures and lateralizing signs are uncommon and are more commonly seen in acute than chronic liver failure. Clinically, a number of encephalopathic patterns can be observed: acute, acute recurrent, chronic recurrent and chronic permanent encephalopathy (the last often forms part of the spectrum of acquired hepatocerebral degeneration).

There is no specific biochemical test for hepatic encephalopathy. Blood tests should help to rule out other causes of encephalopathy and detect precipitating factors such as hypoglycemia or electrolyte imbalance. An elevated serum ammonia level is characteristic but not essential, and correlates poorly with the level of encephalopathy. The cerebrospinal fluid is usually normal or may show increased protein with increased GABA levels. Lumbar puncture and CT scan may be necessary to rule out other concomitant CNS pathology. The EEG shows slow, triphasic wave activity found mainly over frontal areas, but this pattern is not specific.

Factors of importance in the pathogenesis of encephalopathy are the shunting of blood around the hepatocytes into the systemic circulation and the presence of hepatocellular dysfunction. Encephalopathy probably results from one or more toxic products of gut origin that are usually metabolized by the liver entering this systemic circulation and reaching the brain. Abnormalities of ammonia metabolism are most frequently implicated in the pathophysiology. The normal gut flora produce a urease that enzymatically cleaves NH₃ from protein in the lumen. Nonionized ammonia is then absorbed into the portal circulation. It reaches the systemic circulation because of shunts and the inability of the liver to metabolize the ammonia. Other hypotheses relate to the findings of increased levels of short-chain fatty acids and increased levels of aromatic amino acids associated with the decreased levels of branched-chain amino acids. As well, the principal neuro-inhibitory neurotransmitter g-aminobutyric acid (GABA) is increased in encephalopathy. Other concepts include other false neurotransmitters, including an endogenous modulator of GABA receptors, suggesting involvement of the GABA-diazepam receptor complex in the pathogenesis of HE. It is likely that hepatic encephalopathy results from the complicated interplay of many factors, not just one.

Hepatic encephalopathy may arise spontaneously but more commonly will develop as a result of some precipitating factor in the course of acute or chronic liver disease (Table 21).

The most important aspect of management is prompt recognition and treatment of these precipitating factors. Exogenous factors include increased dietary protein, administration of certain drugs (such as sedatives), gastrointestinal bleeding, azotemia, electrolyte imbalance from diuretic therapy, hypoxia and infection. Also important is the necessity to provide meticulous care of the confused and often comatose patient. Otherwise, the goal of therapy is to lower the level of toxic substances by reducing or excluding protein from the diet and by cleaning nitrogenous materials from the gut. To this end, constipation is avoided by the use of laxatives and, in more urgent cases, cleansing of the gut with enemas or colonic lavage. A commonly used laxative is lactulose, a synthetic disaccharide that is degraded by intestinal bacteria to produce acidification and an osmotic diarrhea. The acidification of colonic contents reduces ammonia absorption in part by trapping nitrogenous compounds in the lumen. The dosage of lactulose should be titrated to the patient to achieve two to four loose stools per day. The average daily dosages are 45-90 g. Too much diarrhea can result in fluid and electrolyte depletion and can worsen HE and cause renal failure. Its chronic use can reduce the frequency of episodes of encephalopathy. Alternatively, antibiotics such as metronidazole may be used; these inhibit urea splitting and deaminating bacteria, reducing the production of ammonia and other potential toxins. The previously commonly used antibiotic neomycin is no longer recommended as it has the potential for ototoxic and nephrotoxic side effects.

Other experimental therapeutic approaches exist, particularly when the encephalopathy becomes refractory. On the basis of increased aromatic amino acids and decreased branched-chain amino acids found in encephalopathy (and the resulting effect on neurotransmitter synthesis), branched-chain amino acids given orally or intravenously have a potentially therapeutic role in improving encephalopathy. Some of the new benzodiazepine-receptor antagonists may be of value. These drugs, which block the benzodiazepine/ GABA-receptor complex, may lead to a decrease in inhibitory GABA-mediated transmission in the brain and lessen the encephalopathy. Based on the possible relationship of a defect in dopaminergic neurotransmission and encephalopathy, both L-dopa and bromocriptine have been tried, with controversial results. Orthotopic liver transplantation should entirely reverse the hepatic encephalopathy. Thus, this should be considered in all patients with hepatic encephalopathy whose liver disease makes them suitable for liver transplantation.