Benzodiazepines are a class of heterocyclic compounds typically represented by the antianxiety drug diazepam. About 15 years ago, a high-affinity binding site for benzodiazepines was discovered in brain tissue, and it appeared that this receptor was in some way part of the receptor complex for the inhibitory neurotransmitter GABA (1). Subsequently, with the cloning of the GABA, receptor, it was found that the GABA-benzodiazepine receptor complex comprises multiple subunits, with distinct binding sites for both GABA and benzodiazepines (2, 3). Furthermore, it appeared that the benzodiazepine receptor acted as an allosteric modulatory site for the GABAA receptor. That is, certain benzodiazepines, as well as other compounds, could bind to this receptor and could act to enhance the inhibitory actions of GABA. Heightened GABAergic inhibition has been postulated to be involved in hepatic encephalopathy, and several reviews on this topic have been written in recent years (4-7).
For decades, theories on the cause of hepatic encephalopathy have come and gone. Most agree that it is a multifactorial disorder and that several substances likely contribute to the altered mental status. A new hypothesis (8) suggesting that endogenous benzodiazepine-like substances could contribute to the disorder was generated in the 1980s when specific benzodiazepine receptor antagonists were shown to ameliorate the disease in animal models and in anecdotal reports and uncontrolled clinical trials in human subjects (9-13).
Those observations were very exciting because the specific benzodiazepine antagonist used, flumazenil, has little other intrinsic activity at the doses used, suggesting that the drug must be blocking other, possibly endogenous, benzodiazepine receptor ligands. Subsequently, several groups showed that serum or cerebrospinal fluid contained increased amounts of benzodiazepine-like substances in animal models and in human beings with hepatic encephalopathy (14-20). The papers by Pornier-Layrargues et al. ( 21) and Basile et al. (22) in this issue extend those earlier observations and strengthen the hypothesis that benzodiazepine-like receptor ligands contribute to the pathogenesis of hepatic encephalopathy .