RELATIONSHIP BETWEEN PLASMA BENZODIAZEPINE RECEPTOR-LIGAND CONCENTRATIONS AND SEVERITY OF HEPATIC-ENCEPHALOPATHY

Levels of benzodiazepine receptor ligands were measured in plasma samp les from 25 patients in various stages of hepatic encephalopathy due t o fulminant liver failure who were not exposed to pharmaceutical benzo diazepines immediately before or during hospitalization. Chromatograph ic analysis of extracted plasma samples revealed one to nine fractions containing material that competitively inhibited [H-3]flumazenil bind ing to benzodiazepine receptors with the pharmacological properties of benzodiazepine receptor agonists. Two of these peaks were positively identified as the 1,4-benzodiazepines diazepam and N-desmethyldiazepam on the basis of chromatographic, ultraviolet and mass spectral eviden ce. The plasma levels of diazepam and N-desmethytdiazepam were signifi cantly increased above control values in stage 4 hepatic encephalopath y, whereas total benzodiazepine receptor ligand concentrations were in creased above control in stages 1 through 4. A significant but weak li near correlation was found between the relative increase in the levels of diazepam, N-desmethyldiazepam and total benzodiazepine receptor li gands and the severity of hepatic encephalopathy. Thus increased conce ntrations of benzodiazepine receptor ligands appear to contribute to t he enhancement of GABAergic neurotransmission in hepatic encephalopath y, particularly in stage 4. These results constitute further support f or a role for benzodiazepine receptor ligands in the pathogenesis of h epatic encephalopathy associated with acute liver failure.