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Background/aim: Despite some controversy, it has been suggested that endogenous benzodiazepine plays a role in the pathogenesis of hepatic encephalopathy. The aim of the present study was to evaluate the concentrations of endogenous benzodiazepines and the peptide, diazepam binding inhibitor, in the blood of patients with liver cirrhosis with and without overt encephalopathy, and to compare these levels with those of consumers of commercial benzodiazepines., Subjects: Normal subjects (90), benzodiazepine consumers (14), and cirrhotic patients (113) were studied., Methods: Endogenous benzodiazepines were measured by the radioligand binding technique after high performance liquid chromatography (HPLC) purification. The presence of diazepam and N-desmethyldiazepam was assayed by HPLC-electrospray tandem mass spectrometry. Diazepam binding inhibitor was studied in serum by radioimmunoassay., Results: Endogenous benzodiazepines were below the limit of detection in 7% of patients with encephalopathy. When detectable, their levels were at least comparable with those of benzodiazepine consumers and correlated with the liver dysfunction but not the stage of encephalopathy. Serum levels of diazepam binding inhibitor tended to decrease when endogenous benzodiazepines levels increased., Conclusions: Endogenous benzodiazepines may accumulate in patients with liver cirrhosis during the course of the disease, and the phenomenon appears to be independent of the presence or absence of encephalopathy.

Background: Portal systemic encephalopathy (PSE) is a complex neuropsychiatric syndrome associated with hepatic failure. Small scale studies have shown the benzodiazepine receptor antagonist flumazenil to be effective in ameliorating PSE., Aims: To determine the efficacy of flumazenil in patients with non-comatous mild to moderate PSE (stages I to III) due to severe chronic liver disease., Patients: 49 male and female adults without symptoms of severe bleeding and sepsis and who screened negative for benzodiazepine in both blood and urine, were included in the study., Methods: Patients were randomised to receive either three sequential bolus injections of flumazenil (0.4, 0.8, and 1 mg) or placebo at one minute intervals, followed by intravenous infusions of either flumazenil (1 mg/h) or placebo for three hours. Clinical PSE grading and vital signs were assessed hourly during baseline and post-treatment periods and half hourly during treatment. The main outcome measures were improvement in group average PSE score and reduction of two points in individual PSE score (clinically relevant improvement)., Results: The mean average improvement in the PSE score in the subjects treated with flumazenil was not statistically significantly different from placebo. However, for patients showing clinically relevant improvement, the difference between flumazenil and placebo was statistically significant (seven of 28 v none of 21; p = 0.015). Flumazenil was well tolerated., Conclusions: A subgroup of patients with PSE resulting from chronic liver disease may benefit from the administration of flumazenil.

Visual evoked potential recordings were examined in 45 liver cirrhosis patients with (n = 29) and without (n = 16) encephalopathy, in 15 normal volunteers, and in one patient with an opioid induced stupor state. Visual evoked potential parameters were classified on the basis of EEG recordings. Plasma concentrations of amino acids, octopamine, and ammonia were assayed in order to document the metabolic change of hepatic encephalopathy. Latencies and wave patterns recorded after flash stimulation differentiated the four degrees of the coma one from another according to EEG classification in the 29 patients with encephalopathy. In the group of 16 patients without clinical and EEG evidence of encephalopathy the visual potential recordings discriminated a group of patients (n = 10) in a preclinical stage of encephalopathy. Biochemical parameters and subsequent clinical observation of patients confirmed our judgement of a preclinical stage of encephalopathy. These results suggest that visual evoked potentials are a simple, suitable and objective method for differentiating the degrees of encephalopathy and for identifying the preclinical stage of encephalopathy.