Pathogenesis of Hepatic Encephalopathy-with Special Reference to the Roles of Ammonia

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Abstract
Hepatic encephalopathy is a clinical syndrome consisting of an abnormal mental and neuromuscular state, liver disease, and characteristic but nonspecific laboratory and electroencephalographic findings. The disorder is classified as a metabolic one since it is often reversible and unaccompained by significant structural changes. It occurs in individuals with liver disease whose brain is apparently sensitive to a variety of toxins and physiologic abnormalities that may summate in their deleterious effect. Of the postulated toxins none has as much evidence in its favor as ammonia. The short-chain fatty acids need further evaluation, however, and it is likely that other, as yet unidentified, toxins may contribute to the induction of hepatic coma. The precise mechanism of the action of toxins on the brain is not known. As regards ammonia, the only likely toxin meaningfully investigated so far, the best guess is that it interferes with maintenance of normal energy stores in the brain, probably at the site of cerebral ammonia detoxication, i.e., at the α-ketoglutarate-glutamate-glutamine level. In acute coma, at least, the brainstem seems the most susceptible site. It should be emphasized that this is a simplified working hypothesis based on fragmentary human data obtained after the establishment of coma and on acute experimental animal models and this presents many dissimilarities from typical human encephalopathy. Perhaps the most vital stimulus to progress in this field would be the development of an animal model of chronic hepatic encephalopathy with more similarity to the clinical condition.