Flutamide and cyproterone acetate (CPA) are both oral anti-androgens commonly used to treat advanced prostatic cancer. We report a case of drug-induced hepatotoxicity after consecutive treatment with flutamide and CPA. A 78-year-old male with advanced prostatic adenocarcinoma had been treated with flutamide 750 mg/day p.o. and leuproleride acetate 22.5 mg/3 months i.m. Three months later, the patient complained of choluria and jaundice. Laboratory examination revealed severe hepatocellular insufficiency. Flutamide-induced hepatotoxicity was suspected and therefore flutamide was withdrawn. His liver function abnormalities resolved after drug discontinuation. He was subsequently started on CPA 150 mg/day and again developed hepatotoxicity with severe hepatocellular impairment, which completely recovered after drug discontinuation. Other causes of acute liver failure were appropriately ruled out in both episodes and there was no evidence of active prostate cancer or liver metastases in both episodes. The occurrence of hepatotoxicity associated with flutamide and CPA on separated occasions suggests the possibility of a common mechanism of injury. It may become necessary to reassess the common practice of switching to another anti-androgen when hepatotoxicity appears. A closer monitoring of liver enzymes might be necessary in such cases, as an increased risk of a new severe hepatotoxicity event cannot be ruled out.

Hepatotoxicity is a serious adverse reaction potentially induced by all antiandrogens. We have reviewed here the published cases of hepatotoxicity induced by steroidal and nonsteroidal antiandrogens, and compared the type and characteristics of liver damage.

Using two different databases: MEDLINE and IDIS (Iowa Drug Information Service), we searched for published cases of liver injury induced by antiandrogens. Analysis was made of the type of hepatotoxicity, therapeutic indication, other pharmacological treatments and evolution. Mean values of latency and recovery periods of the adverse reactions and liver function tests were also evaluated.

Hepatitis was the most common type of hepatotoxicity reported, and was associated with all antiandrogens. This adverse reaction does not seem to be dependent on the patients age, therapeutic indication or the dose prescribed. Hepatitis showed a longer latency period for cyproterone acetate than for flutamide. Some transaminase levels were significantly higher for flutamide than for cyproterone acetate, although the evolution was no worse in the cases reported for flutamide. We also found occasional reports of hepatocellular carcinoma and hepatic cirrhosis suspected of being induced by cyproterone acetate.

Although there are differences in the clinical features of hepatotoxicity induced by steroidal and nonsteroidal antiandrogens, these do not predict which patients will develop hepatotoxicity during treatment or evolution. Serial liver function tests are required for early detection of liver damage.

Although the year 2001 did not see any prescription drugs withdrawn because of drug-induced liver disease, the US Food and Drug Administration requested that dietary supplements containing comfrey be taken off the market because of the danger of hepatic injury. The Food and Drug Administration remains very involved in the process by which drug-induced liver disease can be detected early in drug development and in the determination of how best to prevent hepatotoxicity after drug approval. A workshop on drug-induced liver disease cosponsored by the Food and Drug Administration, the Pharmaceutical Research and Manufacturers Association, and the American Association for the Study of Liver Diseases was held in Washington, DC, in February 2001, and the resulting white paper outlined several areas for research. A number of agents were newly described as causing various forms of liver injury, and several others had drug-induced liver disease confirmed by additional reports. Several investigators dealt with the difficulties inherent in establishing causality of drug-induced liver disease and the potential negative consequences of wrongly attributing hepatotoxicity to a particular agent. In one recent series, more than half the instances of alleged drug-induced liver disease were found to have other causes, often leading to a delay in the actual diagnosis and appropriate management. Case reports in particular were often misleading. Although several drug assessment scales have been developed, none appears to be foolproof.