Histologic changes in liver allograft biopsies associated with elevated whole blood and tissue cyclosporine concentrations.

Cyclosporine is used in the postoperative management of rejection in liver allograft recipients. Despite its efficacy in the treatment of allograft rejection, the drug exhibits toxicity at elevated whole blood concentrations including nephrotoxicity with associated histologic changes, and evidence of hepatotoxicity as determined by liver function studies. To date, there have been few published reports describing histologic changes in liver biopsies from patients with elevated blood cyclosporine levels. In the present study, we retrospectively examined biopsies from 16 liver allograft recipients, seven patients with elevated whole blood cyclosporine levels (> 1000 ng/ml) and nine control patients who had whole blood cyclosporine levels in the therapeutic range (558 to 993 ng/ml). In each case, frozen liver biopsy tissue was available to measure tissue levels of cyclosporine and metabolites. The blood and tissue drug levels were then correlated with the histologic changes present in the biopsy specimens. Patients with increased cyclosporine levels displayed histologic changes consisting of hypertrophy of the bile ductal epithelium with cytoplasmic vacuoles and the presence of "foamy" material within the hepatic sinusoids that were either absent or occurred less frequently in the control group. The histologic changes correlated best with cyclosporine metabolite levels rather than tissue levels of native drug. When liver function studies were correlated with cyclosporine levels, only gamma glutamyl transpeptidase (GGT) demonstrated a significant positive correlation with the histologic changes.(ABSTRACT TRUNCATED AT 250 WORDS)