Pathogenesis of hepatic encephalopathy: update on molecular mechanisms

Abstract

Hepatic encephalopathy (HE) is a major neuropsychiatric complication of acute and chronic liver failure. Neuropathologically, HE in chronic liver failure is characterized by astrocytic (rather than neuronal) changes known as Alzheimer type II astrocytosis and in altered expression of key astrocytic proteins. Magnetic resonance imaging in cirrhotic patients reveals bilateral signal hyperintensities in globus pallidus on T1-weighted imaging, which appear to result from manganese deposition. Proton (1H) magnetic resonance spectroscopy shows an increase in glutamine resonance in brain, a finding that confirms previous biochemical studies and is consistent with increased uptake of ammonia by the brain (glutamine synthesis). Recent molecular biological studies show an increased expression of several genes coding for neurotransmitter-related proteins in chronic liver failure. Such genes include those for monoamine oxidase (MAO-A isoform), nitric oxide synthase (nNOS isoform) and the peripheral-type benzodiazepine receptor. Activation of these systems may lead to alterations of monoamine and amino acid neurotransmitter function and changes in cerebral blood flow in chronic liver failure.