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07-12-2024 | Hashimoto Thyroiditis | Original Article

Elevated thyroid-stimulating hormone levels, independent of Hashimoto’s thyroiditis, increase thyroid cancer risk: Insights from genetic and clinical evidence

Authors: Yingying Feng, Aoyi Xiao, Chengwei Xing, Qichen Dai, Xudong Liu, Jie Liu, Lin Feng

Published in: Endocrine

Abstract

Purpose

Hashimoto’s thyroiditis (HT) is a prevalent autoimmune disorder and thyroid cancer (TC) is the most prevalent endocrine malignancy. Recent debates have focused on whether HT increases the risk of developing TC. This study combined Mendelian randomization (MR) and observational methods to investigate the potential causal relationship between HT and TC risk.

Methods

First, we performed two-sample MR and multivariable MR (MVMR) analysis using the genome-wide association studies (GWAS) data from multiple databases, including European and East Asian populations, to estimate the effect of HT and thyroid-stimulating hormone (TSH) levels on TC risk. Second, we conducted an observational study using data from the National Health and Nutrition Examination Survey (NHANES) database and evaluated the association between HT, TSH, and TC prevalence through logistic regression model and restricted cubic spline model.

Results

Our MR findings revealed no significant association between HT and TC risk in both populations. However, elevated TSH levels significantly increased TC and papillary thyroid carcinoma (PTC) risk, while lower TSH levels were associated with reduced TC risk. Further MVMR analysis and an observational study confirmed this. Additionally, our observational study also indicated no significant relationship between HT and TC prevalence and abnormal TSH levels correlated with higher TC risk.

Conclusion

HT was not a TC risk factor, but high TSH levels increased TC risk. Controlling TSH within normal ranges through thyroid hormone replacement was recommended to reduce TC risk in HT patients with elevated TSH levels, even those without symptoms.

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S. Saevarsdottir, T.A. Olafsdottir, E.V. Ivarsdottir, G.H. Halldorsson, K. Gunnarsdottir, A. Sigurdsson et al. FLT3 stop mutation increases FLT3 ligand level and risk of autoimmune thyroid disease. Nature 584, 619–623 (2020). https://doi.org/10.1038/s41586-020-2436-0CrossRefPubMed

C.L. Burek, M.V. Talor, Environmental triggers of autoimmune thyroiditis. J. Autoimmun. 33, 183–189 (2009). https://doi.org/10.1016/j.jaut.2009.09.001CrossRefPubMedPubMedCentral

P. Caturegli, A. De Remigis, N.R. Rose, Hashimoto thyroiditis: clinical and diagnostic criteria. Autoimmun. Rev. 13, 391–397 (2014). https://doi.org/10.1016/j.autrev.2014.01.007CrossRefPubMed

M. Ralli, D. Angeletti, M. Fiore, V. D’Aguanno, A. Lambiase, M. Artico et al. Hashimoto’s thyroiditis: an update on pathogenic mechanisms, diagnostic protocols, therapeutic strategies, and potential malignant transformation. Autoimmun. Rev. 19, 102649 (2020). https://doi.org/10.1016/j.autrev.2020.102649CrossRefPubMed

S.M. Ferrari, F. Ragusa, G. Elia, S.R. Paparo, V. Mazzi, E. Baldini et al. Precision medicine in autoimmune thyroiditis and hypothyroidism. Front. Pharmacol. 12, 750380 (2021). https://doi.org/10.3389/fphar.2021.750380.

J. Klubo-Gwiezdzinska, L. Wartofsky, Hashimoto thyroiditis: an evidence-based guide to etiology, diagnosis and treatment. Pol. Arch. Intern. Med. 132, 16222 (2022). https://doi.org/10.20452/pamw.16222CrossRefPubMedPubMedCentral

E.M. Kyritsi, C. Kanaka-Gantenbein, Autoimmune thyroid disease in specific genetic syndromes in childhood and adolescence. Front. Endocrinol. 11, 543 (2020). https://doi.org/10.3389/fendo.2020.00543.

C.M. Kitahara, J.A. Sosa, The changing incidence of thyroid cancer. Nat. Rev. Endocrinol. 12, 646–653 (2016). https://doi.org/10.1038/nrendo.2016.110CrossRefPubMedPubMedCentral

M. Pizzato, M. Li, J. Vignat, M. Laversanne, D. Singh, C. La Vecchia et al. The epidemiological landscape of thyroid cancer worldwide: GLOBOCAN estimates for incidence and mortality rates in 2020. Diab. Endocrinol. 10, 264–272 (2022). https://doi.org/10.1016/S2213-8587(22)00035-3CrossRef

10.

T. Carling, R. Udelsman, Thyroid cancer. Annu. Rev. Med. 65, 125–137 (2014). https://doi.org/10.1146/annurev-med-061512-105739CrossRefPubMed

11.

K. Gul, A. Dirikoc, G. Kiyak, P.E. Ersoy, N.S. Ugras, R. Ersoy et al. The association between thyroid carcinoma and Hashimoto’s thyroiditis: the ultrasonographic and histopathologic characteristics of malignant nodules. Thyroid 20, 873–878 (2010). https://doi.org/10.1089/thy.2009.0118CrossRefPubMed

12.

B. Uhliarova, A. Hajtman, Hashimoto’s thyroiditis - an independent risk factor for papillary carcinoma. Braz. J. Otorhinolaryngol. 84, 729–735 (2018). https://doi.org/10.1016/j.bjorl.2017.08.012CrossRefPubMed

13.

C. Anil, S. Goksel, A. Gursoy, Hashimoto’s thyroiditis is not associated with increased risk of thyroid cancer in patients with thyroid nodules: a single-center prospective study. Thyroid 20, 601–606 (2010). https://doi.org/10.1089/thy.2009.0450CrossRefPubMed

14.

B. Jankovic, K.T. Le, J.M. Hershman, Clinical review: Hashimoto’s thyroiditis and papillary thyroid carcinoma: is there a correlation? J. Clin. Endocrinol. Metab. 98, 474–482 (2013). https://doi.org/10.1210/jc.2012-2978CrossRefPubMed

15.

D.S.A. McLeod, S.A. Bedno, D.S. Cooper, S.M. Hutfless, S. Ippolito, S.J. Jordan et al. Pre-existing thyroid autoimmunity and risk of papillary thyroid cancer: a nested case-control study of US active-duty personnel. J. Clin. Oncol. 40, 2578–2587 (2022). https://doi.org/10.1200/JCO.21.02618CrossRefPubMed

16.

Z. Fewell, G. Davey Smith, J.A.C. Sterne, The impact of residual and unmeasured confounding in epidemiologic studies: a simulation study. Am. J. Epidemiol. 166, 646–655 (2007). https://doi.org/10.1093/aje/kwm165CrossRefPubMed

17.

C. Casto, G. Pepe, A. Li Pomi, D. Corica, T. Aversa, M. Wasniewska, Hashimoto’s thyroiditis and graves’ disease in genetic syndromes in pediatric age. Genes 12, 222 (2021). https://doi.org/10.3390/genes12020222CrossRefPubMedPubMedCentral

18.

V.W. Skrivankova, R.C. Richmond, B.A.R. Woolf, J. Yarmolinsky, N.M. Davies, S.A. Swanson et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomization: the STROBE-MR statement. JAMA 326, 1614–1621 (2021). https://doi.org/10.1001/jama.2021.18236CrossRefPubMed

19.

V.W. Skrivankova, R.C. Richmond, B.A.R. Woolf, N.M. Davies, S.A. Swanson, T.J. VanderWeele et al. Strengthening the reporting of observational studies in epidemiology using Mendelian randomisation (STROBE-MR): explanation and elaboration. BMJ Clin. Res. Ed. 375, n2233 (2021). https://doi.org/10.1136/bmj.n2233CrossRef

20.

M.I. Kurki, J. Karjalainen, P. Palta, T.P. Sipilä, K. Kristiansson, K.M. Donner et al. Author correction: FinnGen provides genetic insights from a well-phenotyped isolated population. Nature 615, E19 (2023). https://doi.org/10.1038/s41586-023-05837-8CrossRefPubMedPubMedCentral

21.

K.J. Karczewski, R. Gupta, M. Kanai, W. Lu, K. Tsuo, Y. Wang et al. Pan-UK Biobank GWAS improves discovery, analysis of genetic architecture, and resolution into ancestry-enriched effects. 03.13.24303864 (2024). https://doi.org/10.1101/2024.03.13.24303864.

22.

A. Teumer, L. Chaker, S. Groeneweg, Y. Li, C. Di Munno, C. Barbieri et al. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation. Nat. Commun. 9, 4455 (2018). https://doi.org/10.1038/s41467-018-06356-1CrossRefPubMedPubMedCentral

23.

R.B.T.M. Sterenborg, I. Steinbrenner, Y. Li, M.N. Bujnis, T. Naito, E. Marouli et al. Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications. Nat. Commun. 15, 888 (2024). https://doi.org/10.1038/s41467-024-44701-9CrossRefPubMedPubMedCentral

24.

S. Sakaue, M. Kanai, Y. Tanigawa, J. Karjalainen, M. Kurki, S. Koshiba et al. A cross-population atlas of genetic associations for 220 human phenotypes. Nat. Genet. 53, 1415–1424 (2021). https://doi.org/10.1038/s41588-021-00931-xCrossRefPubMed

25.

K. Nam, J. Kim, S. Lee, Genome-wide study on 72,298 individuals in Korean biobank data for 76 traits. Cell Genom. 2, 100189 (2022). https://doi.org/10.1016/j.xgen.2022.100189CrossRefPubMedPubMedCentral

26.

S. Burgess, S.G. Thompson, CRP CHD Genetics Collaboration, Avoiding bias from weak instruments in Mendelian randomization studies. Int. J. Epidemiol. 40, 755–764 (2011). https://doi.org/10.1093/ije/dyr036CrossRefPubMed

27.

G. Hemani, J. Zheng, B. Elsworth, K.H. Wade, V. Haberland, D. Baird et al. The MR-Base platform supports systematic causal inference across the human phenome. eLife 7, e34408 (2018). https://doi.org/10.7554/eLife.34408CrossRefPubMedPubMedCentral

28.

J. Bowden, G. Davey Smith, P.C. Haycock, S. Burgess, Consistent estimation in mendelian randomization with some invalid instruments using a weighted median estimator. Genet. Epidemiol. 40, 304–314 (2016). https://doi.org/10.1002/gepi.21965CrossRefPubMedPubMedCentral

29.

C.L. Johnson, S.M. Dohrmann, V.L. Burt, L.K. Mohadjer, National Health and nutrition examination survey: sample design, 2011–2014. Vital Health Stat 2. 1–33 (2014).

30.

L. Li, Y.-X. Ying, J. Liang, H.-F. Geng, Q.-Y. Zhang, C.-R. Zhang et al. Urinary iodine and genetic predisposition to Hashimoto’s thyroiditis in a Chinese Han population: a case-control study. Thyroid 30, 1820–1830 (2020). https://doi.org/10.1089/thy.2020.0094CrossRefPubMed

31.

A.D. Shah, J.W. Bartlett, J. Carpenter, O. Nicholas, H. Hemingway, Comparison of random forest and parametric imputation models for imputing missing data using MICE: a CALIBER study. Am. J. Epidemiol. 179, 764–774 (2014). https://doi.org/10.1093/aje/kwt312CrossRefPubMedPubMedCentral

32.

T.J. VanderWeele, I. Shpitser, On the definition of a confounder. Ann. Stat. 41, 196–220 (2013). https://doi.org/10.1214/12-aos1058CrossRefPubMedPubMedCentral

33.

A. Konturek, M. Barczyński, W. Wierzchowski, M. Stopa, W. Nowak, Coexistence of papillary thyroid cancer with Hashimoto thyroiditis. Langenbecks Arch. Surg. 398, 389–394 (2013). https://doi.org/10.1007/s00423-012-1021-xCrossRefPubMed

34.

L. Mao, C. Zheng, S. Ou, Y. He, C. Liao, G. Deng, Influence of Hashimoto thyroiditis on diagnosis and treatment of thyroid nodules. Front. Endocrinol. 13, 1067390 (2022). https://doi.org/10.3389/fendo.2022.1067390CrossRef

35.

Z. Ye, D. Gu, H. Hu, Y. Zhou, X. Hu, X. Zhang, Hashimoto’s thyroiditis, microcalcification and raised thyrotropin levels within normal range are associated with thyroid cancer. World J. Surg. Oncol. 11, 56 (2013). https://doi.org/10.1186/1477-7819-11-56CrossRefPubMedPubMedCentral

36.

K.W. Kim, Y.J. Park, E.H. Kim, S.Y. Park, D.J. Park, S.-H. Ahn et al. Elevated risk of papillary thyroid cancer in Korean patients with Hashimoto’s thyroiditis. Head. Neck 33, 691–695 (2011). https://doi.org/10.1002/hed.21518CrossRefPubMed

37.

D. Repplinger, A. Bargren, Y.-W. Zhang, J.T. Adler, M. Haymart, H. Chen, Is Hashimoto’s thyroiditis a risk factor for papillary thyroid cancer? J. Surg. Res. 150, 49–52 (2008). https://doi.org/10.1016/j.jss.2007.09.020CrossRefPubMed

38.

C. Molnár, S. Molnár, J. Bedekovics, A. Mokánszki, F. Győry, E. Nagy et al. Thyroid carcinoma coexisting with Hashimoto’s Thyroiditis: clinicopathological and molecular characteristics clue up pathogenesis. Pathol. Oncol. Res. 25, 1191–1197 (2019). https://doi.org/10.1007/s12253-019-00580-wCrossRefPubMed

39.

J. Jonklaas, H. Nsouli-Maktabi, S.J. Soldin, Endogenous thyrotropin and triiodothyronine concentrations in individuals with thyroid cancer. Thyroid 18, 943–952 (2008). https://doi.org/10.1089/thy.2008.0061CrossRefPubMedPubMedCentral

40.

M.R. Haymart, D.J. Repplinger, G.E. Leverson, D.F. Elson, R.S. Sippel, J.C. Jaume et al. Higher serum thyroid stimulating hormone level in thyroid nodule patients is associated with greater risks of differentiated thyroid cancer and advanced tumor stage. J. Clin. Endocrinol. Metab. 93, 809–814 (2008). https://doi.org/10.1210/jc.2007-2215CrossRefPubMed

41.

E.S. Kim, D.J. Lim, K.H. Baek, J.M. Lee, M.K. Kim, H.S. Kwon et al. Thyroglobulin antibody is associated with increased cancer risk in thyroid nodules. Thyroid 20, 885–891 (2010). https://doi.org/10.1089/thy.2009.0384CrossRefPubMed

42.

F. Boi, L. Minerba, M.L. Lai, B. Marziani, B. Figus, F. Spanu et al. Both thyroid autoimmunity and increased serum TSH are independent risk factors for malignancy in patients with thyroid nodules. J. Endocrinol. Investig. 36, 313–320 (2013). https://doi.org/10.3275/8579CrossRef

43.

J. Jin, R. Machekano, C.R. McHenry, The utility of preoperative serum thyroid-stimulating hormone level for predicting malignant nodular thyroid disease. Am. J. Surg. 199, 294–297 (2010). https://doi.org/10.1016/j.amjsurg.2009.08.028.CrossRefPubMed

Title: Elevated thyroid-stimulating hormone levels, independent of Hashimoto’s thyroiditis, increase thyroid cancer risk: Insights from genetic and clinical evidence
Authors: Yingying Feng
Aoyi Xiao
Chengwei Xing
Qichen Dai
Xudong Liu
Jie Liu
Lin Feng
Publication date: 07-12-2024
Publisher: Springer US
Keywords: Hashimoto Thyroiditis
Thyroid Cancer
Thyroid Cancer
Thyroid Cancer
Published in: Endocrine
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI: https://doi.org/10.1007/s12020-024-04126-2

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