Hypothyroidism and hepatocellular carcinoma: More questions than answers #
Authors: Manal M. Hassan, James L Abbruzzese
Journal: Hepatology (2009)

We appreciate the thoughtful comments of Drs. Purnak and Ozaslan, who made three points in reference to our recently published article.1 First, they requested information about the histological features of hepatocellular carcinoma (HCC) in patients with hypothyroidism. In our article, we reported that 49 patients with HCC (33 women and 16 men) recalled having a prior history of hypothyroidism. Pathological and/or radiological evidence of cirrhosis was found in 30 patients (61%), whereas pathological evidence of steatosis and/or fibrosis was found in an additional 10 patients (20%). Among female patients, evidence of cirrhosis, fibrosis, or steatosis was found in 25 (76%). With respect to HCC risk factors, 15 women had no hepatitis virus infection, no history of heavy alcohol consumption, and no diabetes; among the 15, pathological evidence of cirrhosis, fibrosis, and steatosis was found in 10 (67%). Second, Drs. Purnak and Ozaslan believed that our assumption of hypothyroidism-induced obesity and hyperinsulinemia is an invalid mechanism to explain the association between hypothyroidism and HCC. The reason for their belief is that patients with hypothyroidism were appropriately treated and should have experienced euthyroid conditions at the time of HCC diagnosis. We would like to clarify that our suggestion was based on the following: (1) A previous study reported that the prevalence of hypothyroidism was higher in patients with nonalcoholic steatohepatitis and in HCC than in controls,2 (2) our data indicated that a prior history of being obese or overweight was positively correlated with a prior history of hypothyroidism, particularly among patients with early-onset hypothyroidism or a long duration of hypothyroidism (data not presented), and (3) there is a high prevalence of cryptogenic cirrhosis among patients with hypothyroidism. Nevertheless, we would like to emphasize that our study had a case-control design, in which a history of hypothyroidism was reported by cases and controls, but without information about disease severity, treatment monitoring, and response. We believe that cohort studies of patients with hypothyroidism would more appropriately answer Dr. Purnak and Ozaslan's concern. A cohort design would allow patients with hypothyroidism to be followed for HCC development and frequently assessed for hormonal levels, complications, treatment response, and histological changes in the liver. Finally, Drs. Purnak and Ozaslan pointed out that the observed relationship between hypothyroidism and HCC in women is simply attributed to the frequency of hypothyroidism among women. We agree with Drs. Purnak and Ozaslan's point, and we presented the effect measure modification of sex in our Results section. Even though the effect of hypothyroidism on HCC development cannot be simply attributed to the high frequency of hypothyroidism among cases, a point of estimate for such association should be measured; in this study, the estimated odds ratio for the association between hypothyroidism and HCC was significant among women, and the prevalence of hypothyroidism among control subjects was comparable to that among the general population. Meanwhile, although our observation was supported by a previous study,3 we cannot conclude that hypothyroidism causes HCC. We have suggested that the observed association between hypothyroidism and HCC needs to be confirmed by other studies and in different populations. Moreover, experimental studies are warranted to explain the biological mechanism of HCC development in patients with hypothyroidism. Manal M. Hassan M.D., Ph.D.*, James L Abbruzzese M.D., F.A.C.P.*, * Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas M. D. Anderson Cancer Center, Houston, TX.