Q J Med 2003; 96: 317
© 2003 Association of Physicians
Correspondence |
Danazol-induced hepatocellular carcinoma
Department of Internal Medicine Department of Haematology Department of Surgery, Hospices Civils de Lyon, Lyon, France e-mail: christiane.broussolle{at}chu-lyon.fr
Sir,
Danazol, an inhibitor of pituitary gonadotropin with weak androgenic effects, is currently used in the treatment of endometriosis, hereditary angio-oedema, systemic lupus erythematosus, and idiopathic thrombocytopenic purpura (ITP). Its hepatological side-effects have been well documented. These include reversible elevations of serum aminotransferase values,1 cholestatic hepatitis,2 hepatic peliosis3 and hepatocellular adenomas.4 Only a few cases of danazol-associated hepatocellular carcinoma (HCC) have been described.5–7 We report a new case.
A 37-year-old female with ITP refractory to corticotherapy, intravenous immunoglobulins, vincristine and splenectomy, was treated with 600 mg danazol daily in March 1995. Danazol induced a dramatic clinical and biological response, settling thrombocytes counts at 40x109/l, without any bleeding. Biannual assessments of serum aminotransferases and alkaline phosphatases showed normal results. In August 2000, the patient complained of right hypochondrium pain. The physical examination revealed hepatomegaly. Ultrasonography, computed tomographic scan, and magnetic resonance imaging showed numerous hypervascular hepatic tumours, the largest measuring 10 cm in diameter in the left lobe (Figure 1
). Serum aminotransferases and alkaline phosphatases were normal; alpha-feto protein (AFP) was at 4 µg/l (normal value <10); serological markers of hepatitis A, B, and C, and auto-antibodies were negative; serum ferritin concentrations were normal. Liver biopsy directed by ultrasound in a segment IV lesion led to the diagnosis of well-differentiated HCC. The danazol therapy was stopped. A left hepatectomy with multiple biopsies of the right lobe tumours was performed. Histological examination confirmed the diagnosis of multinodular well-differentiated trabeculovesicular HCC developed on a non-cirrhotic liver. Liver capsule and lymph nodes were not invaded. No metastases were detected. In June 2001, after chemoembolization, the patient benefited from an orthotopic liver transplantation. Immunosuppressive therapy included prednisone and tacrolimus. She has remained in excellent condition during the year after surgery.
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Our case represents an example of danazol-induced HCC in a 37-year-old woman with ITP in the absence of other aetiology: no alcohol consumption, no hepatitis virus marker, no haemochromatosis. To our knowledge, this is the fourth report of danazol-induced HCC.5–7 Consistent with the use of danazol in endometriosis, hereditary angio-oedema, systemic lupus erythematosus, and ITP, these HCC occur in young women. Except for the first case described by Buamah et al.,5 HCC develops after long-term treatments of 4–13 years, and at high daily dosages of 400 to 600 mg.6,7 Tumours are large well-differentiated HCC, developed on non-cirrhotic livers. Only Buamah et al. have reported a severe underlying steatosis. Although the pathogenesis is not clear, the onset on a healthy liver suggests a mechanism different from the classical hepatic carcinogenesis hypothesis;8 danazol and weak androgens may have a direct mutagen effect on healthy liver. Like androgen-associated tumours, danazol-induced HCC do not metastasize; unlike androgen-associated tumours,9 they do not regress following discontinuation of danazol. Except for the case of Buamah et al. who reported extremely high serum AFP levels, biochemical tests, including serum aminotransferases, alkaline phosphatases, and AFP, are normal in danazol-induced HCC, highlighting the importance of liver ultrasonography in tumour detection. Therefore, close follow-up with liver ultrasonography is mandatory during danazol treatment, with examination at least once a year. Furthermore, the benefits of long-term treatment with danazol have to be regularly assessed, and repeated attempts made to reduce the daily dosages.
References
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