HEPATOLOGY Concise Review
are compatible with the behavioral effects of ammonia observed in both animals and patients with hyperammonemia. Specifically, infusing animals with ammonium salts induces Ammonia and GABA-ergic a preconvulsive state, followed by overt seizures. 11 Similarly, convulsions commonly occur in the congenital hyperammo-Neurotransmission: nemias. 6,12 However, these neuroexcitatory actions of ammonia superficially appear to be at variance with a central role Interrelated Factors in the for ammonia in the pathogenesis of HE, which is characterized by a global increase in neuronal inhibition, not excita-Pathogenesis of Hepatic tion. 2 HE is only rarely associated with seizures in patients with chronic liver disease, and the reported changes in the Encephalopathy electroencephalogram and visual evoked responses induced by ammonia are not characteristic of those observed in HE. 11,13,14 Although total brain ammonia concentrations may ANTHONY S. BASILE 1 AND E. ANTHONY JONES 2 rise above 1.5 mmol/L in stage IV HE (coma), 15,16 the suppression of IPSPs and EPSPs may not significantly contribute to Although hepatic encephalopathy (HE) has long been recthe manifestations of HE in its earlier stages (0-III), in which ognized as a clinically important manifestation of hepatoceltotal brain ammonia levels are typically below 1.5 mmol/L. lular failure, the precise pathogenesis of this common syn-It is clear that brain ammonia levels increase in liver faildrome remains elusive. Currently, the two factors considered ure and that ammonia modulates neuronal activity. Howto be most important in the pathogenesis of this syndrome ever, the relationship between the concentrations of ammoare elevated central nervous system (CNS) levels of ammonia in the various compartments of the CNS, the particular nia 1 and increased g-aminobutyric acid (GABA)-mediated mechanisms by which ammonia alters neuronal function, and neurotransmission. [2][3][4] The hypotheses implicating these two the manifestations of HE in its different stages are not factors in the pathogenesis of HE have appeared to be unreknown. Indeed, the mechanisms by which ammonia contrilated. Indeed, much research has been directed toward probutes to the global depression of the CNS in HE remains viding evidence that provides support for or detracts from one unclear. Accordingly, an important question is whether amof these hypotheses, rather than toward determining whether monia, in concentrations commonly observed in liver failure, the two hypotheses are interrelated and mutually compatican increase neuronal inhibition. ble. To facilitate understanding of the possible interrelationship between ammonia and the enhancement of GABA-ergic