Benzodiazepine-like substances and hepatic encephalopathy - Implications for treatment

Hepatic encephalopathy is a neuropsychiatric syndrome that can complicate acute and chronic liver disease. Recent research has focused on the role benzodiazepine-like substances play in the pathogenesis of this disorder. It has been proposed that potentiation of the action of the neuroinhibitory transmitter gamma-aminobutyric acid (GABA) through the binding of endogenous benzodiazepine agonists to the benzodiazepine receptor binding site accounts for the clinical and biochemical features of this condition. Increased levels of endogenous benzodiazepine-like substances have been noted in animal models of hepatic encephalopathy. In human studies, levels of these substances of up to 10 times those found in the body fluids of non-encephalopathic controls have been reported. The existence of such markedly elevated levels cannot be satisfactorily explained with reference to possible pharmaceutical or dietary origins. Further support for the role of benzodiazepines in the mediation of hepatic encephalopathy comes from the therapeutic effect reported after administration of the benzodiazepine receptor antagonist flumazenil. Improvements in the severity of hepatic encephalopathy have been documented in rats with fulminant hepatic failure given flumazenil, although results have been inconsistent according to the dose of flumazenil used and the procedure employed to induce the encephalopathy. Transient, but distinct, improvements in the grade of hepatic encephalopathy have also been documented in several human studies. In a placebo-controlled study involving patients with mild hepatic encephalopathy, a low dose of flumazenil (0.2 mg/kg) resulted in a significant improvement in reaction time. Research now needs to identify whether the beneficial effect of flumazenil is due to its antagonistic or inverse agonistic properties, and also to clarify the mechanisms by which the differential response to the drug in animal models of fulminant hepatic failure is mediated.