Brain indoles in human hepatic encephalopathy.

The neurotransmitter serotonin has a profound effect on the control of sleep; thus excess serotonin activity in the brain could be responsible for impaired consciousness in hepatic encephalopathy. Furthermore, an increased brain level of 5-hydroxy-indoleacetic acid has been a consistent finding in various animal models of the condition. In this study, using high-performance liquid chromatography with fluorometric detection, we examined levels of brain serotonin (5-hydroxytryptamine) and its precursors and metabolites in 16 patients dying with hepatic encephalopathy complicating acute and chronic liver disease and 9 control subjects matched for age, sex, postmortem delay in brain retrieval and length of frozen tissue storage. In patients with chronic liver disease, serotonin level was significantly increased in thalamus (p < 0.02); levels of its metabolite 5-hydroxyindoleacetic acid were increased in frontal cortex (p < 0.05), globus pallidus (p < 0.05) and putamen (p < 0.01). Levels of the precursor amino acid tryptophan were increased in thalamus (p < 0.01) and globus pallidus (p < 0.01); in both patient groups levels of 5-hydroxytryptophan and the tryptamine metabolite indoleacetic acid were increased in all brain areas studied. 5-Hydroxytryptamine levels were also increased in thalamus, frontal cortex and globus pallidus in the three patients with fulminant liver failure. Our findings are consistent with disordered neurotransmission, especially in the thalamus, an area of particular importance in the regulation of consciousness, alertness and attention in human beings.