Hypothyroidism: A Possible Risk Factor for Liver Cancer in Patients With No Known Underlying Cause of Liver Disease

Reddy, Arvind; Dash, Chiranjeev; Leerapun, Apinya; Mettler, Teresa A.; Stadheim, Linda M.; Lazaridis, Konstantinos N.; Roberts, Rosebud O.; Roberts, Lewis R.

doi:10.1016/j.cgh.2006.07.011

Cited by 90 publications

(73 citation statements)

References 21 publications

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“…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.…”

Section: Replysupporting

confidence: 62%

Hypothyroidism and hepatocellular carcinoma: More questions than answers #

Hassan

Abbruzzese

2009

Hepatology

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Reply: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 signifi...

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Section: Replysupporting

confidence: 62%

Hypothyroidism and hepatocellular carcinoma: More questions than answers #

Hassan

Abbruzzese

2009

Hepatology

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“…In one of these studies, women with a history of hypothyroidism had a 2.8-fold higher risk of HCC (Hassan et al 2009); in the second 23:8 Human miR-34a T 3 treatment induces miR-34a expression Lu et al (2013) study, hypothyroidism was significantly more prevalent in patients with HCC of unknown aetiology than in HCC patients with alcoholic liver disease or HCV. Thus, these results suggest that hypothyroidism may be a permissive factor for the development of HCC (Reddy et al 2007). A hypothyroid status of HCC has been described in human HCC , Martinez-Iglesias et al 2016.…”

Section: Trs Hypo-and Hyperthyroidism and Hccmentioning

confidence: 70%

T3/TRs axis in hepatocellular carcinoma: new concepts for an old pair

Perra

Plateroti

Columbano

2016

Endocrine-Related Cancer

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Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide, and its burden is expected to further increase in the next years. Chronic inflammation, induced by multiple viruses or metabolic alterations, and epigenetic and genetic modifications, cooperate in cancer development via a combination of common and distinct aetiology-specific pathways. In spite of the advances of classical therapies, the prognosis of this neoplasm has not considerably improved over the past few years. The advent of targeted therapies and the approval of the systemic treatment of advanced HCC with the kinase inhibitor sorafenib have provided some hope for the future. However, the benefits obtained from this treatment are still disappointing, as it extends the median life expectancy of patients by only few months. It is thus mandatory to find alternative effective treatments. Although the role played by thyroid hormones (THs) and their nuclear receptors (TRs) in human cancer is still unclear, mounting evidence indicates that they behave as oncosuppressors in HCC. However, the molecular mechanisms by which they exert this effect and the consequence of their activation following ligand binding on HCC progression remain elusive. In this review, we re-evaluate the existing evidence of the role of TH/TRs in HCC development; we will also discuss how TR alterations could affect fundamental biological processes, such as hepatocyte proliferation and differentiation, and consequently HCC progression. Finally, we will discuss if and how TRs can be foreseen as therapeutic targets in HCC and whether selective TR modulation by TH analogues may hold promise for HCC treatment.

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“…This calculation was based on self-reported absence or presence of hypothyroidism because TH levels and data regarding substitution were not available. In this context, it is interesting that hypothyroidism was significantly more prevalent in patients with HCC of unknown etiology than in HCC patients with alcoholic liver disease or HCV in another case-control study (Reddy et al 2007), suggesting that hypothyroidism may be a permissive factor in the development of HCC.…”

Section: Epidemiology Suggests Tumor-promoting Effects Of Thmentioning

confidence: 99%

Thyroid hormone, thyroid hormone receptors, and cancer: a clinical perspective

Moeller¹,

Führer²

2013

Endocrine-Related Cancer

157

138

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Thyroid hormones (THs) may play a role in diseases other than hyper-and hypothyroidism. Several lines of evidence suggest tumor-promoting effects of TH and TH receptors. They are possibly mediated by phosphatidylinositol-3-kinase and MAPK and involve among others stimulation of angiogenesis via avb3. Thus, an increased risk for colon, lung, prostate, and breast cancer with lower TSH has been demonstrated in epidemiological studies, even suggesting a TH dose effect on cancer occurrence. Furthermore, higher TH levels were associated with an advanced clinical stage of breast and prostate cancer. In rodent models, TH stimulated growth and metastasis of tumor transplants, whereas hypothyroidism had opposite effects. In clinical studies of glioblastoma and head and neck cancer, hypothyroid patients showed longer survival than euthyroid patients. Also, patients with renal cell cancer that were treated with the tyrosine kinase inhibitor sunitinib and developed hypothyroidism in due course showed significantly longer survival than patients that remained euthyroid. Development of hypothyroidism was an independent predictor for survival in two studies. Yet, it is still possible that hypothyroidism is only a surrogate marker for treatment efficacy and does not positively influence treatment outcome by itself. Future cancer treatment studies, especially with substances that can induce hypothyroidism, should therefore be designed in a way that allows for an analysis of thyroid function status and its contribution on treatment outcome.

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Hypothyroidism: A Possible Risk Factor for Liver Cancer in Patients With No Known Underlying Cause of Liver Disease

Cited by 90 publications

References 21 publications

Hypothyroidism and hepatocellular carcinoma: More questions than answers #

Hypothyroidism and hepatocellular carcinoma: More questions than answers #

T3/TRs axis in hepatocellular carcinoma: new concepts for an old pair

Thyroid hormone, thyroid hormone receptors, and cancer: a clinical perspective

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