Cerebral energy metabolism in hepatic encephalopathy and hyperammonemia

Hepatic encephalopathy (HE) is an important cause of morbidity and mortalit y in patients with severe liver disease. Although the molecular basis for t he neurological disorder in HE remains elusive, elevated ammonia and its ch ief metabolite glutamine are believed to be important factors responsible f or altered cerebral functions, including multiple neurotransmitter system(s ) failure, altered bioenergetics, and more recently oxidative stress. Accum ulated evidence suggests that direct interference of ammonia at several poi nts in cerebral energy metabolism, including glycolysis, TCA cycle, and the electron transport chain, could lead to energy depletion. Additionally, re cent studies from our laboratory have invoked the possibility that ammonia and glutamine may induce the mitochondrial permeability transition in astro cytes, a process capable of causing mitochondrial dysfunction. Altered mito chondrial metabolism appears to be an important mechanism responsible for t he cerebral abnormalities associated with HE and other hyperammonemic state s.