INTRODUCTION

Hepatic encephalopathy (HE) or portosystemic encephalopathy (PSE) is a reversible syndrome of impaired brain function occurring in patients with advanced liver failure. (See "Hepatic encephalopathy in adults: Clinical manifestations and diagnosis".) However, HE is not a single clinical entity. It may reflect either a reversible metabolic encephalopathy, brain atrophy, brain edema, or any combination of these conditions. The mechanisms causing brain dysfunction in liver failure are still unknown. In advanced coma, the effects of brain swelling, impaired cerebral perfusion, and reversible impairment of neurotransmitter systems cannot be distinguished. Furthermore, these events overlap, at least in models of acute liver failure.

Data on cerebral function in HE are usually derived from animal studies since brains of patients with HE cannot be studied with neurochemical or neurophysiologic methods. It is beyond the scope of this review to discuss each of the animal models in detail, but it must be appreciated that they may not accurately reflect human disease.

The metabolic factors that contribute to the development of HE will be reviewed here [1]. Ammonia is clearly implicated; in addition, there may be a role for inhibitory neurotransmission through gamma-aminobutyric acid (GABA) receptors in the central nervous system (CNS) and changes in central neurotransmitters and circulating amino acids. These hypotheses are not mutually exclusive, and multiple factors may be present at the same time. Currently available therapies for hepatic encephalopathy are based upon these hypotheses. (See "Hepatic encephalopathy in adults: Treatment".)

These factors are directly related to liver failure (eg, decreased metabolism of ammonia). In addition, concurrent disorders can contribute to the development of HE. These include (table 1):

• Decreased oxygen delivery, which can result from a variety of factors including gastrointestinal bleeding, sepsis, the effects of cytokines or compounds released from necrotic liver tissue [2]. In particular, proinflammatory cytokines may have a pivotal role in impairing several brain functions [3,4]. The effects of hypotension on cerebral perfusion may be magnified in liver failure because of an associated impairment in the autoregulation of cerebral blood flow [5,6].
• Functional and structural changes in cerebral function independent of the liver failure as in alcoholics, intravenous drug users, and patients with Wilson's disease.
• Creation of a portosystemic shunt to treat portal hypertension, as with a transjugular intrahepatic portosystemic shunt, precipitates HE in approximately 30 percent of patients. (See "Transjugular intrahepatic portosystemic shunts: Complications".)
• Other events which can precipitate HE such as the administration of sedatives, hypokalemia, and hyponatremia. (See "Hyponatremia in patients with cirrhosis".) The effect of hypokalemia is thought to be mediated by potassium movement out of the cells to replenish extracellular stores [7]. Electroneutrality is maintained in part by the movement of extracellular hydrogen into the cells; the ensuing intracellular acidosis in renal tubular cells increases the production of ammonia [8]. The often concurrent metabolic alkalosis may contribute by promoting the conversion of ammonium (NH4+), a charged particle which cannot cross the blood-brain barrier, into ammonia (NH3) which can enter the brain [8].