Thyroid hormone: liver and breast cancer

Liver Cancer and Thyroid Hormone

Liver cancer is a bit unusual in that it seems that thyroid hormone is protective, there could be various reasons including associations between hypothyroidism and obesity, insulin resistance and hyperlipidemia. Liver cancer accounts for about 3% of UK cancer deaths. If you are interested in more detail here is a study Abnormal and Euthyroid Ranges of Thyroid Hormones in Serum and Liver Cancer Mortality: A Cohort Study Won Sohn, Yoosoo Chang, Yong Kyun Cho, Yejin Kim, Hocheol Shin and Seungho Ryu Cancer Epidemiol Biomarkers Prev October 1 2020 29 DOI: 10.1158/1055-9965.EPI-20-0283

Breast Cancer and Thyroid Hormone

This section presents evidence that higher levels of thyroid hormone (both T3 and T4) stimulate breast cancer, perhaps because thyroid hormone has oestrogenic effects. It is not intended to review breast cancer and thyroid hormone in detail, just show that breast cancer is a special case which confounds our discussion of the integrin αvβ3 receptor and thyroxine. It may be that the effects of T3 on breast cancer are greater than the benefit it gives in lowering T4 levels. Thus, when studying the effects of T4 on the Integrin αvβ3 receptor we should treat breast cancer as an exception. Breast cancer accounts for about 7% of all UK cancer deaths. The studies are presented in chronological order.

Tosovic, A., Bondeson, AG., Bondeson, L. et al. Prospectively measured triiodothyronine levels are positively associated with breast cancer risk in postmenopausal women. Breast Cancer Res 12, R33 (2010).

This study measured TSH and T3 (not T4) and followed up breast cancer cases that occurred at least three years later thus avoiding the effects of cancer on TFTs. The study found a strong dose-response relation between T3 and breast cancer in post-menopausal women (see Table 3). No association with TSH was found and T4 was not measured. Only people who had an abnormal TSH, a history of thyroid disease or an enlarged thyroid were included in the study.

Tosovic, A., Becker, C., Bondeson, A.-G., Bondeson, L., Ericsson, U.-B., Malm, J. and Manjer, J. (2012), Prospectively measured thyroid hormones and thyroid peroxidase antibodies in relation to breast cancer risk. Int. J. Cancer, 131: 2126-2133.

This study used stored blood samples to compare TSH, fT3, fT4 in breast cancer patients and controls. So, unlike the previous study it wasn’t limited to those with abnormal thyroids. There was no association between fT3 and breast cancer whereas breast cancer was strongly associated with fT4.

Tosovic A, Bondeson AG, Bondeson L, Ericsson UB, Manjer J. Triiodothyronine levels in relation to mortality from breast cancer and all causes: a population-based prospective cohort study. Eur J Endocrinol. 2013;168:483–90.

This is a follow-up to the first study with a similar cohort. This study looks at breast cancer mortality as opposed to cases. It finds that pre-diagnostic T3 levels are positively associated with the risk of breast cancer-specific death in post menopausal women (see Table 3). The hazard ratios were higher than in the previous study suggesting that T3 not only increases the risk of breast cancer but also makes it more deadly. There was no link between T3 and other forms of cancer.

Leese GP, Soto-Pedre E, Donnelly LA. Liothyronine use in a 17 year observational population-based study – the tears study. Clin Endocrinol. (2016) 85:918–25. doi: 10.1111/cen.13052

This is an observational study not a prospective one. (The full paper can be obtained via Sci-Hub). Table 3 shows a breast cancer hazard ratio (HR) of 1.754 for people who have ever taken liothyronine compared to levothyroxine only. Fig 1 shows similar or higher HRs according to the percentage of liothyronine prescriptions (vs levothyroxine) received. We don’t know whether the people receiving liothyronine were on higher overall thyroid hormone doses. There wasn’t a clear cut relationship between percent liothyronine prescriptions and HR which might suggest it is the hormone dose and not the form (L-T3 or L-T4) that is associated with breast cancer. This study is not good evidence for breast cancer and T3 but it is a large scale well known study, hence its inclusion.

Kim EY, Chang Y, Lee KH, et al. Serum concentration of thyroid hormones in abnormal and euthyroid ranges and breast cancer risk: A cohort study. Int J Cancer. 2019; 145(12): 3257- 3266.

This is a large study over a relatively short period of just under five years on average. They measured free T3 and T4 whereas other studies tended to measure total T3 and T4. As can be seen in Tables 2 and 4 a high fT4 was associated with an increased risk of breast cancer and a high TSH with a lower risk. fT3 within the reference interval showed no association with breast cancer link but there was increased breast cancer risk for post-menopausal women with a high fT3.

Summary: Liver and Breast Cancer

From the integrin αvβ3 receptor perspective liver and breast cancers should be viewed as exceptions. Thyroid hormone appears to be protective against liver cancer and to promote breast cancer. These cancers account for about 10% of cancer deaths. We will look at how thyroxine acting on the integrin αvβ3 receptor increases overall cancer risk and mortality.