Hepatic encephalopathy: An update of pathophysiologic mechanisms

Hepatic encephalopathy (HE) is a neuropsychiatric disorder that occurs in b oth acute and chronic liver failure. Although the precise pathophysiologic mechanisms responsible for HE are not completely understood, a deficit in n eurotransmission rather than a primary deficit in cerebral energy metabolis m appears to be involved. The neural cell most vulnerable to liver failure is the astrocyte, In acute liver failure, the astrocyte undergoes swelling resulting in increased intracranial pressure; in chronic liver failure, the astrocyte undergoes characteristic changes known as Alzheimer type II astr ocytosis. In portal-systemic encephalopathy resulting from chronic liver fa ilure, astrocytes manifest altered expression of several key proteins and e nzymes including monoamine oxidase B, glutamine synthetase, and the so-call ed peripheral-type benzodiazepine receptors, In addition, expression of som e neuroneal proteins such as monoamine oxidase A and neuronal nitric oxide synthase are modified. In acute liver failure, expression of the astrocytic glutamate transporter GLT-1 is reduced, leading to increased extracellular concentrations of glutamate, Many of these changes have been attributed to a toxic effect of ammonia and/or manganese, two substances that are normal ly removed by the hepatobiliary route and that in liver failure accumulate in the brain. Manganese deposition in the globus pallidus in chronic liver failure results in signal hyperintensity on T1-weighted Magnetic Resonance Imaging and may be responsible for the extrapyramidal symptoms characterist ic of portal-systemic encephalopathy, Other neurotransmitter systems implic ated in the pathogenesis of hepatic encephalopathy include the serotonin sy stem, where a synaptic deficit has been suggested, as well as the catechola minergic and opioid systems. Further elucidation of the precise nature of t hese alterations could result in the design of novel pharmacotherapies for the prevention and treatment of hepatic encephalopathy.