Hepatic encephalopathy: clinical and experimental studies

The pathogenesis of hepatic encephalopathy is still unsolved. Therapy, therefore, is often insufficient. For the development of effective, new therapies insight into the disease-inducing substrates and the mechanisms of its toxic actions in the central nervous system ·are required. For both studies on pathogenesis and therapy of hepatic encephalopathy, methods for the quantitation of its severity are needed. For the measurement of hepatic encephalopathy clinical grading, conventional electroencephalography and psychometric tests are mostly used. The former two methods are characterized by considerable intra- and interobserver error; the last one can only be used in mild encephalopathy. Quantitative EEG analysis has been shown to be useful! in longitudinal studies but its value for the classification of the whole spectrum of severities of encephalopathy had not been investigated. In studies on the pathogenesis of hepatic encephalopathy ammonia was considered as a major toxin from the beginning. However, its importance was rejected by many hepatologists because the correlation between plasma concentrations and encephalopathy is poor. New theories, especially the false neurotransmitter theory and the GABA-benzodiazepine receptor hypothesis, tried to explain cerebral dysfunction directly at the neuronal leveL The GABA-benzodiazepine receptor theory as originally proposed by Schafer and Jones resulted in the use of flumazenil, a benzodiazepine receptor antagonist, in hepatic encephalopathy. Uncontrolled clinical studies seemed to indicate remarkable therapeutic activity and therefore supported the presence of endogenous benzodiazepines. Besides specific toxins little attention has been given to the role of nonspecific metabolic factors, often present in liver failure, in the precipitation of encephalopathy in liver disease. With regard to these considerations the aims of this thesis were: 1. the development of an objective method, spectral analysis, for the measurement of hepatic encephalopathy; 2. to study the effect of flumazenil in hepatic encephalopathy; and 3. to study the role of aspecific factors in the induction of hepatic encephalopathy.