Tamoxifen is one of the most commonly used oncologic therapeutic agents. Ongoing studies are evaluating the potential of tamoxifen as a chemopreventive agent for breast cancer; a reduction in the risk for development of cardiovascular disease and osteoporosis are being used as secondary end points in these studies. Although its overall safety record has been good, tamoxifen has been associated with endometrial cancer, retinopathy, and thromboembolic events. We report a case of tamoxifen-induced steatohepatitis.

A 55-year-old woman had bilateral mastectomies for breast cancer. She began receiving tamoxifen after surgery. Results of liver function tests done before treatment were normal. Two years later, the patient was noted to have an alanine aminotransferase level of 164 U/L (normal, 0 to 30 U/L) and an aspartate aminotransferase level of 224 U/L (normal, 0 to 35 U/L). She was symptom-free and had no signs of recurrent breast cancer. She rarely drank alcohol, and tamoxifen was the only drug started after surgery. Results of serologic tests for hepatitis, iron studies, and serum protein electrophoresis were either negative or normal. An ultrasound of the liver was consistent with fatty infiltration. Liver biopsy was done after the aminotransferase levels had been elevated for 9 months; examination of the biopsy specimen showed diffuse macrovesicular fat, lobular inflammation, and a moderate amount of portal inflammation with fibrosis (Figure 1). Nonalcoholic steatohepatitis was diagnosed on the basis of these characteristic histologic findings and on the absence of alcohol use. Tamoxifen therapy was discontinued, and within 4 months, the aminotransferase levels were normal.

View larger version (139K): [in this window] [in a new window]   Figure 1. Percutaneous liver biopsy specimen showing macrovesicular fat infiltration, lobular inflammation, and portal inflammation with fibrosis. (Masson trichrome; original magnification, x 54.).

Liver damage secondary to tamoxifen use is rare. In the more than 20 years since the drug was introduced, no reports have associated it with nonalcoholic steatohepatitis. Predisposing factors for the disease include obesity, diabetes, hyperlipidemia, and female sex. The histologic findings are diagnostic and include steatosis, portal and lobular inflammation, Mallory bodies, and fibrosis [1-4]. These findings are indistinguishable from those of alcohol-induced liver disease but occur in patients without a history of alcohol use. Several drugs have been associated with nonalcoholic steatohepatitis, including estrogens, but the mechanism of this drug-induced liver injury is unknown. Tamoxifen does have weak estrogenic effects [5] and therefore may have a similar mechanism.

The diagnosis of nonalcoholic steatohepatitis is easily missed because of the absence of clinical manifestations [2]. This has serious clinical implications because it is now well established that the disease can progress to cirrhosis [2-4]. Therefore, patients receiving tamoxifen should have liver function tests before initiation of therapy and regularly during treatment.