FK506 hepatotoxicity in liver allograft recipients

FK506 (FK) and cyclosporine (CsA) share similar immunosuppressive and toxicity profiles. Both produce nephrotoxicity, neurotoxicity, and diabetes; in addition, we have recently reported severe gastrointestinal toxicity associated with FK therapy. We have been able to reverse severe side effects of FK by conversion to CsA-based immunosuppression. In patients who eventually required conversion from FK to CsA for severe toxic side effects, we noted a pattern of liver enzyme abnormalities that suggests a hepatotoxic effect attributable to FK therapy. We sought to confirm such a hepatotoxic effect and distinguish it from liver function derangements associated with rejection or hepatitis. We reviewed the records of 50 liver transplant recipients who received FK as primary immunosuppression between March 1991 and October 1992. In patients who had abnormal liver enzyme activities in the absence of rejection and hepatitis, we identified drug-related hepatotoxicity using criteria established by a consensus development panel of the Council for International Organization of Medical Sciences. According to the panel, liver injury exists if there is an increase in alanine aminotransferase (ALT) or conjugated bilirubin to more than twice the upper limit of normal. Evidence that such liver injury has been caused by a specific drug is "very suggestive" if, within 1 week after cessation of the drug, ALT decreases by 50% of the excess over the upper limit of normal; the evidence is "suggestive" if such a decrease in ALT occurs within 1 month of discontinuation.