CEREBRAL BENZODIAZEPINE RECEPTOR-BINDING IN-VIVO IN PATIENTS WITH RECURRENT HEPATIC-ENCEPHALOPATHY

Increased activation of the central benzodiazepine receptor (BZR) appe ars to play an important role in hepatic encephalopathy (HE), However, there is controversy regarding whether the density or affinity of BZR s is altered, A previous positron emission tomography (PET) study usin g the BZR antagonist [C-11]flumazenil (FMZ) found two-to threefold gre ater cerebral cortical tracer uptake in recurrent HE, but did not acco unt for impaired FMZ metabolism due to liver disease or assess the rel ative contributions of tracer delivery versus BZR binding, We hypothes ized that correcting for these factors would affect estimations of BZR binding in HE, Nine patients with recurrent HE and 13 age-comparable controls were studied with [C-11]FMZ PET. After intravenous administra tion of [C-11]FMZ, arterial blood samples were collected, and PET imag es were acquired over 60 minutes. FMZ transport and binding maps were calculated for each subject by using a physiological tracer kinetic mo del, In agreement with the previous report, we found that FMZ reached a much higher level and was retained longer in the HE cerebral cortex despite similar total blood radioactivity levels in the two groups, Ho wever, the patients showed impaired hepatic metabolism of FMZ. After p hysiological modeling incorporating these data, significant increases in BZR binding were found in the thalamus (13%), cerebellum (20%), and pens (23%). There were minor, statistically insignificant increases i n cerebral cortical (10%), putamen (12%), and whole brain (12%) BZR bi nding in patients with recurrent HE, These findings are in general agr eement with results of autopsy studies, confirming a lack of major inc reases in cortical or basal ganglial BZR binding in HE, They emphasize that physiological tracer modeling should be used and altered periphe ral radioligand metabolism considered in future PET studies of HE.