Pre-diagnosis thyroid hormone dysfunction is associated with cancer mortality

in Endocrine-Related Cancer
Authors:
Eilon Krashin Translational Oncology Laboratory, Meir Medical Center, Kfar-Saba, Israel
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Search for other papers by Eilon Krashin in
Current site
Google Scholar
PubMed Close
,
Barbara Silverman Israel National Cancer Registry, Ministry of Health, Gertner Institute, Sheba Medical Center, Tel Hashomer, Israel
School of Public Health, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Search for other papers by Barbara Silverman in
Current site
Google Scholar
PubMed Close
,
David M Steinberg Department of Statistics and Operations Research, Tel Aviv University, Tel Aviv, Israel

Search for other papers by David M Steinberg in
Current site
Google Scholar
PubMed Close
,
Daniel Yekutieli Department of Statistics and Operations Research, Tel Aviv University, Tel Aviv, Israel

Search for other papers by Daniel Yekutieli in
Current site
Google Scholar
PubMed Close
,
Shmuel Giveon Clalit Health Services, Tel Aviv, Israel

Search for other papers by Shmuel Giveon in
Current site
Google Scholar
PubMed Close
,
Offer Fabian Translational Oncology Laboratory, Meir Medical Center, Kfar-Saba, Israel

Search for other papers by Offer Fabian in
Current site
Google Scholar
PubMed Close
,
Aleck Hercbergs Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio, USA

Search for other papers by Aleck Hercbergs in
Current site
Google Scholar
PubMed Close
,
Paul J Davis Department of Medicine, Albany Medical College, Albany, New York, USA

Search for other papers by Paul J Davis in
Current site
Google Scholar
PubMed Close
,
Martin Ellis Translational Oncology Laboratory, Meir Medical Center, Kfar-Saba, Israel
Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel
Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Search for other papers by Martin Ellis in
Current site
Google Scholar
PubMed Close
, and
Osnat Ashur-Fabian Translational Oncology Laboratory, Meir Medical Center, Kfar-Saba, Israel
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

Search for other papers by Osnat Ashur-Fabian in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0001-8624-3182

Correspondence should be addressed to O Ashur-Fabian: osnataf@gmail.com
DOI:
https://doi.org/10.1530/ERC-21-0187
Volume/Issue:
Volume 28: Issue 11
Article Type:
Research Article
Page Range:
705–713
Online Publication Date:
20 Sep 2021
Copyright:
© Society for Endocrinology 2021
Restricted access
Rent on DeepDyve

Sign up for journal news

Research on the association between thyroid hormone levels and cancer mortality remains limited and inconclusive. We determined the relation of thyroid stimulating hormone (TSH), free T4 (FT4), and free T3 (FT3) levels with mortality in overall cancer and specific tumor types. Thyroid hormone levels 1–5 years prior to cancer diagnosis, as well as multiple clinical and demographic parameters, were retrospectively collected for 10,325 Israeli cancer patients, diagnosed between 2000 and 2016. Patients treated with thyroid altering medications were excluded. Cancer diagnosis was determined via the Israel National Cancer Registry. Multivariate-adjusted Cox proportional hazards model was used to assess the hazard ratios (HRs) based on thyroid hormone function for cancer mortality. A total of 5265 patients died during the follow-up period (median of 4.4 years). TSH, FT4, and FT3 levels in the hypothyroid range were associated with increase in overall mortality (adjusted HR 1.20, 1.74, 1.87, respectively). We further analyzed the association between TSH and mortality in 14 cancer subgroups. Specifically, TSH in both the hyperthyroid and hypothyroid range was associated with melanoma mortality (adjusted HR 2.20, 4.47, respectively). In conclusion, pre-diagnosis of thyroid dysfunction is associated with increased cancer mortality, a relation likely driven by specific cancer types. These findings suggest that thyroid hormones may potentially serve as prognostic markers in cancer.

Supplementary Materials

    • Supplementary Figure 1: Flow chart of study participants
    • Supplementary Table 1: List of ICD‐O3 codes for cancer site
    • Supplementary table 2: Hazard ratio for overall cancer mortality by thyroid hormone status one year prior to diagnosis
    • Supplementary Table 3: List of ICD‐9 codes for comorbidity definition
    • Supplementary Table 4: Baseline characteristics of study participants by TSH strata
    • Supplementary Table 5: Unadjusted and FDR adjusted p-values of omnibus test of model coefficients for inclusion of TSH function categories in cancer risk model

Endocrine-Related Cancer is committed to supporting researchers in demonstrating the impact of their articles published in the journal.

The two types of article metrics we measure are (i) more traditional full-text views and pdf downloads, and (ii) Altmetric data, which shows the wider impact of articles in a range of non-traditional sources, such as social media.

More information is on the Reasons to publish page.

Sept 2018 onwards Past Year Past 30 Days
Full Text Views 563 63 1
PDF Downloads 395 22 1

 

  • Collapse
  • Expand
Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
© Society for Endocrinology 2021
Page(s):
9
Received Date:
04 Aug 2021
Accepted Date:
25 Aug 2021
Print Publication Date:
01 Nov 2021
Online Publication Date:
20 Sep 2021
Keywords:
cancer; thyroid hormone; hypothyroidism; hyperthyroidism survival

  • Ang E & Newton LV 2018 Thirty-day mortality after systemic anticancer treatment as a real-world, quality-of-care indicator: the Northland experience. Internal Medicine Journal 48 403–408. (https://doi.org/10.1111/imj.13618)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ashur-Fabian O, Zloto O, Fabian I, Tsarfaty G, Ellis M, Steinberg DM, Hercbergs A, Davis PJ & Fabian ID 2018 Tetrac delayed the onset of ocular melanoma in an orthotopic mouse model. Frontiers in Endocrinology 9 775. (https://doi.org/10.3389/fendo.2018.00775)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Benjamini Y & Hochberg Y 1995 Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society: Series B 57 289–300. (https://doi.org/10.1111/j.2517-6161.1995.tb02031.x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Berghoff AS, Wippel C, Starzer AM, Ballarini N, Wolpert F, Bergen E, Wolf P, Steindl A, Widhalm G & Gatterbauer B et al.2020 Hypothyroidism correlates with favourable survival prognosis in patients with brain metastatic cancer. European Journal of Cancer 135 150–158. (https://doi.org/10.1016/j.ejca.2020.05.011)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Brandt F, Thvilum M, Almind D, Christensen K, Green A, Hegedüs L & Brix TH 2013 Graves’ disease and toxic nodular goiter are both associated with increased mortality but differ with respect to the cause of death: a Danish population-based register study. Thyroid 23 408–413. (https://doi.org/10.1089/thy.2012.0500)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Brandt J, Borgquist S, Almquist M & Manjer J 2016 Thyroid function and survival following breast cancer. British Journal of Surgery 103 1649–1657. (https://doi.org/10.1002/bjs.10284)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cengiz SE, Cetinkaya E, Altin S, Gunluoglu Z, Demir A, Gunluoglu G & Epozturk K 2008 Nutritional and prognostic significance of sick euthyroid syndrome in non-small cell lung cancer patients. Internal Medicine 47 211–216. (https://doi.org/10.2169/internalmedicine.47.0423)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chan YX, Knuiman MW, Divitini ML, Brown SJ, Walsh J & Yeap BB 2017a Lower TSH and higher free thyroxine predict incidence of prostate but not breast, colorectal or lung cancer. European Journal of Endocrinology 177 297–308. (https://doi.org/10.1530/EJE-17-0197)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chan YX, Alfonso H, Chubb SA, Fegan PG, Hankey GJ, Golledge J, Flicker L & Yeap BB 2017b Higher thyrotropin concentration is associated with increased incidence of colorectal cancer in older men. Clinical Endocrinology 86 278–285. (https://doi.org/10.1111/cen.13271)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dişel U, Beşen A, Karadeniz C, Mertsoylu H, Sezer A, Köse F, TanerSümbül A, Gürkut O, Muallaoğlu S & Abali H et al.2012 Prevalence of thyroid dysfunction in untreated cancer patients: a cross-sectional study. Medical Oncology 29 3608–3613. (https://doi.org/10.1007/s12032-012-0254-4)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ellerhorst JA, Sendi-Naderi A, Johnson MK, Cooke CP, Dang SM & Diwan AH 2006 Human melanoma cells express functional receptors for thyroid-stimulating hormone. Endocrine-Related Cancer 13 1269–1277. (https://doi.org/10.1677/erc.1.01239)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fabian ID, Rosner M, Fabian I, Vishnevskia-Dai V, Zloto O, Shinderman Maman E, Cohen K, Ellis M, Lin HY & Hercbergs A et al.2015 Low thyroid hormone levels improve survival in murine model for ocular melanoma. Oncotarget 6 11038–11046. (https://doi.org/10.18632/oncotarget.3566)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Falstie-Jensen AM, Kjærsgaard A, Lorenzen EL, Jensen JD, Reinertsen KV, Dekkers OM, Ewertz M & Cronin-Fenton DP 2019 Hypothyroidism and the risk of breast cancer recurrence and all-cause mortality: a Danish population-based study. Breast Cancer Research 21 44. (https://doi.org/10.1186/s13058-019-1122-3)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fritz AG, Percy C, Jack A, Shanmugaratnam K, Sobin L, Parkin DM & Whelan S 2013 International Classification of Diseases for Oncology (ICD-O), 3rd ed. Geneva, Switzerland: World Health Organization.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Garmendia Madariaga A, Santos Palacios S, Guillén-Grima F & Galofré JC 2014 The incidence and prevalence of thyroid dysfunction in Europe: a meta-analysis. Journal of Clinical Endocrinology and Metabolism 99 923–931. (https://doi.org/10.1210/jc.2013-2409)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Goldman MB, Monson RR & Maloof F 1990 Cancer mortality in women with thyroid disease. Cancer Research 50 2283–2289.

  • Hassan MM, Kaseb A, Li D, Patt YZ, Vauthey JN, Thomas MB, Curley SA, Spitz MR, Sherman SI & Abdalla EK et al.2009 Association between hypothyroidism and hepatocellular carcinoma: a case-control study in the United States. Hepatology 49 1563–1570. (https://doi.org/10.1002/hep.22793)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hellevik AI, Asvold BO, Bjøro T, Romundstad PR, Nilsen TI & Vatten LJ 2009 Thyroid function and cancer risk: a prospective population study. Cancer Epidemiology, Biomarkers and Prevention 18 570–574. (https://doi.org/10.1158/1055-9965.EPI-08-0911)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Journy NMY, Bernier MO, Doody MM, Alexander BH, Linet MS & Kitahara CM 2017 Hyperthyroidism, hypothyroidism, and cause-specific mortality in a large cohort of women. Thyroid 27 1001–1010. (https://doi.org/10.1089/thy.2017.0063)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Khan SR, Chaker L, Ruiter R, Aerts JG, Hofman A, Dehghan A, Franco OH, Stricker BH & Peeters RP 2016 Thyroid function and cancer risk: the Rotterdam study. Journal of Clinical Endocrinology and Metabolism 101 5030–5036. (https://doi.org/10.1210/jc.2016-2104)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Krashin E, Silverman B, Steinberg DM, Yekutieli D, Giveon S, Fabian O, Hercbergs A, Davis PJ, Ellis M & Ashur-Fabian O 2021 Opposing effects of thyroid hormones on cancer risk: a population-based study. European Journal of Endocrinology 184 477–486. (https://doi.org/10.1530/EJE-20-1123)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • L’Heureux A, Wieland DR, Weng CH, Chen YH, Lin CH, Lin TH & Weng CH 2019 Association between thyroid disorders and colorectal cancer risk in adult patients in Taiwan. JAMA Network Open 2 e193755. (https://doi.org/10.1001/jamanetworkopen.2019.3755)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mellemgaard A, From G, Jørgensen T, Johansen C, Olsen JH & Perrild H 1998 Cancer risk in individuals with benign thyroid disorders. Thyroid 8 751–754. (https://doi.org/10.1089/thy.1998.8.751)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mendes D, Alves C, Silverio N & Batel Marques F 2019 Prevalence of undiagnosed hypothyroidism in Europe: a systematic review and meta-analysis. European Thyroid Journal 8 130–143. (https://doi.org/10.1159/000499751)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Moeller LC & Fuhrer D 2013 Thyroid hormone, thyroid hormone receptors, and cancer: a clinical perspective. Endocrine-Related Cancer 20 R19–R29. (https://doi.org/10.1530/ERC-12-0219)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Moon S, Kim MJ, Yu JM, Yoo HJ & Park YJ 2018 Subclinical hypothyroidism and the risk of cardiovascular disease and all-cause mortality: a meta-analysis of prospective cohort studies. Thyroid 28 1101–1110. (https://doi.org/10.1089/thy.2017.0414)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mu G, Mu X, Xing H, Xu R, Sun G, Dong C, Pan Q & Xu C 2015 Subclinical hypothyroidism as an independent risk factor for colorectal neoplasm. Clinics and Research in Hepatology and Gastroenterology 39 261–266. (https://doi.org/10.1016/j.clinre.2014.08.002)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • O’Brien ME, Borthwick A, Rigg A, Leary A, Assersohn L, Last K, Tan S, Milan S, Tait D & Smith IE 2006 Mortality within 30 days of chemotherapy: a clinical governance benchmarking issue for oncology patients. British Journal of Cancer 95 1632–1636. (https://doi.org/10.1038/sj.bjc.6603498)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ratcliffe JG, Stack BH, Burt RW, Radcliffe WA, Spilg WG, Cuthbert J & Kennedy RS 1978 Thyroid function in lung cancer. British Medical Journal 1 210–212. (https://doi.org/10.1136/bmj.1.6107.210)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Razvi S, Weaver JU, Butler TJ & Pearce SH 2012 Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality. Archives of Internal Medicine 172 811–817. (https://doi.org/10.1001/archinternmed.2012.1159)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP, Asvold BO, Iervasi G, Imaizumi M & Collet TH et al.2010 Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA 304 1365–1374. (https://doi.org/10.1001/jama.2010.1361)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Rowe CW, Paul JW, Gedye C, Tolosa JM, Bendinelli C, McGrath S & Smith R 2017 Targeting the TSH receptor in thyroid cancer. Endocrine-Related Cancer 24 R191–R202. (https://doi.org/10.1530/ERC-17-0010)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Søgaard M, Farkas DK, Ehrenstein V, Jørgensen JO, Dekkers OM & Sørensen HT 2016 Hypothyroidism and hyperthyroidism and breast cancer risk: a nationwide cohort study. European Journal of Endocrinology 174 409–414. (https://doi.org/10.1530/EJE-15-0989)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sohn W, Chang Y, Cho YK, Kim Y, Shin H & Ryu S 2020 Abnormal and euthyroid ranges of thyroid hormones in serum and liver cancer mortality: a cohort study. Cancer Epidemiology, Biomarkers and Prevention 29 2002–2009. (https://doi.org/10.1158/1055-9965.EPI-20-0283)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Tseng FY, Lin WY, Li CI, Li TC, Lin CC & Huang KC 2015 Subclinical hypothyroidism is associated with increased risk for cancer mortality in adult Taiwanese-a 10 years population-based cohort. PLoS ONE 10 e0122955. (https://doi.org/10.1371/journal.pone.0122955)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wallington M, Saxon EB, Bomb M, Smittenaar R, Wickenden M, McPhail S, Rashbass J, Chao D, Dewar J & Talbot D et al.2016 30-day mortality after systemic anticancer treatment for breast and lung cancer in England: a population-based, observational study. Lancet: Oncology 17 1203–1216. (https://doi.org/10.1016/S1470-2045(16)30383-7)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yasar ZA, Kirakli C, Yilmaz U, Ucar ZZ & Talay F 2014 Can non-thyroid illness syndrome predict mortality in lung cancer patients? A prospective cohort study. Hormones and Cancer 5 240–246. (https://doi.org/10.1007/s12672-014-0183-0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Young JL, Roffers SD, Ries LAG, Fritz AG & Hurlbut AA 2001 SEER Summary Staging Manual – 2000: Codes and Coding Instructions (NIH Pub. No. 01-4969). Bethesda, MD, USA: National Cancer Institute.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zhang Y, Chang Y, Ryu S, Cho J, Lee WY, Rhee EJ, Kwon MJ, Pastor-Barriuso R, Rampal S & Han WK et al.2014 Thyroid hormones and mortality risk in euthyroid individuals: the Kangbuk Samsung health study. Journal of Clinical Endocrinology and Metabolism 99 2467–2476. (https://doi.org/10.1210/jc.2013-3832)

    • PubMed
    • Search Google Scholar
    • Export Citation