Studies of "endogenous" benzodiazepine in human hepatic encephalopathy

As will be discussed by Dr E.A. Jones based on observations in animal models of hepatic encephalopathy (HE) in 1984 we commenced our studies on the possible role of "endogenous" benzodiazepines (BZs) in human HE in 1986. Unlike animals our initial studies in humans with HE were complicated by the frequent intake of prescription BZs by these patients. Re-education of our staff on the appropriate use of BZs in patients with liver disease and a carefully devised system to exclude patients who have received prescription BZs in the 3 months preceding hospital admission was instigated before our studies could commence. Initially, we examined CSF of patients with HE for the presence of BZ-like activity using a radiometric assay. Our findings of significantly increased activity have since been confirmed by other investigators. Subsequently we discovered fairly large quantities of BZs in blood and urine of these patients, the level of which correlated with the degree of severity of HE. The ultimate finding that this BZ-like activity was due to diazepam, desmethyldiazepam and some other 1-4 benzodiazepine compounds again raised the possibility that our findings were due to occult ingestion of commercially synthesized BZs even though similar findings were made in animal models of HE. Concurrently with this work it became apparent that the food cycle contains trace amounts of the same BZs. However, the levels of "natural BZs" in food cannot yet explain the high levels of BZs seen in patients with HE. The source for this high level of BZs is currently our main area of research.