Tamoxifen-induced nonalcoholic steatohepatitis

Tamoxifen is a potent antagonist of estrogen and evidently improves the prognosis of patients with estrogen receptor-positive breast cancer. However, although tamoxifen has been shown to induce hepatic steatosis in one-third of nonobese breast cancer patients, the pathogenic mechanisms have not yet been defined. Impaired fatty acid beta oxidation has been proposed as a possible pathogenic mechanism involved in tamoxifen-induced hepatic steatosis, because fatty acid beta oxidation activity is impaired in aromatase-deficient mice lacking intrinsic estrogen, and because either estradiol supplementation or administration of bezafibrate improved impaired beta oxidation activity to prevent the progression of hepatic steatosis. Previously, we investigated why tamoxifen is such a potent estrogen antagonist and found that the serum estradiol level was extremely low (<10pg/ml) in most premenopausal breast cancer patients treated with tamoxifen. Therefore, tamoxifen is not merely an antagonist of estrogen but it also efficiently suppresses estrogen production in one-third of breast cancer patients treated with tamoxifen. Impaired activity of CYP17 alpha, which is the essential enzyme for estrogen synthesis, may contribute to the suppression of estrogen synthesis. From these observations, we deduced that an increased body mass index and a reduction in the ratio of pregnanetriol to pregnanediol concentrations in urine are two independent risk factors for the development of hepatic steatosis in tamoxifen-treated breast cancer patients.