Hepatic encephalopathy: experimental approaches to human metabolic encephalopathy

Derangements in systemic metabolism are probably the most frequent cause of coma of unknown etiology. Within this group, coma due to liver failure is common. Systematic research into the mechanisms that underlie the development of hepatic coma is a topic that has interested investigators of as many backgrounds as there are theories that seek to explain the development of the disorder. This review seeks to summarize relevant basic science and clinical literature that focuses on potential etiological mechanisms. In the sections on actions of toxins including ammonia, mercaptans, and fatty acids, and descriptions of altered levels of plasma amino acid levels and abnormalities of neurotransmitter pharmacology, a complex pattern of interrelationships emerges. Discussions of ammonia inevitably require analysis of other seemingly unrelated topics, suggesting strongly that hepatic encephalopathy is indeed the multidimensional problem that might be suspected to follow disorders of this central organ of intermediary metabolism and digestion. The recent development of new technical and statistical methodology has started to make it possible to consider the impact of multiple isolated and seemingly unrelated abnormalities on patterns of functional interaction within the brain. These global aspects of brain function form the essential basis for the understanding of this fascinating disorder.