Changes in cerebral receptors for gamma aminobutyric acid in patients with hepatic encephalopathy

ABSTRACT— If the gamma‐aminobutyric acid (GABA) inhibitory neurotransmitter system plays an important role in the mediation of hepatic encephalopathy (HE) in man, changes in the status of receptors for GABA in the brain may occur in patients with HE. To test this possibility, brains were obtained at autopsy from 11 patients who had died of causes unrelated to liver disease and from 11 patients who had died with chronic liver disease. Eight of the liver disease group had overt HE at the time of death. The specific binding of GABA to synaptic membranes isolated from frontal cortex was determined. Mean specific binding of GABA for patients with cirrhosis without overt HE was similar to that for control patients. In contrast, corresponding means for patients who had mild HE (stages I–III) and for patients who had severe HE (stage IV) were 45% higher (p<0.05) and 43% lower, respectively, than that for control patients. The mean specific binding of GABA was significantly greater for patients with mild HE than in patients with severe HE (p<0.025). Scatchard plots of the GABA binding data were curvilinear and consistent with a model of GABA receptors with two independent binding sites. Computer‐assisted analysis of the binding data indicated that the altered GABA binding observed in patients with HE is attributable to changes in the affinity rather than the density of both GABA receptors (increased affinities in mild HE, and decreased affinities in hepatic coma). These findings are compatible with the hypothesis that alterations in GABAergic neurotransmission are associated with and contribute to the syndrome of HE in man.