{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:52:49Z","timestamp":1753890769340,"version":"3.41.2"},"reference-count":66,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T00:00:00Z","timestamp":1713139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Hepatobiliary cancer (HBC), including hepatocellular carcinoma (HCC) and biliary tract cancer (BTC), is currently one of the malignant tumors that mainly cause human death. Many HBCs are diagnosed in the late stage, which increases the disease burden, indicating that effective prevention strategies and identification of risk factors are urgent. Many studies have reported the role of thyroid hormones on HBC. Our research aims to assess the causal effects and investigate the mediation effects between thyroid function and HBC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Utilizing the Mendelian randomization (MR) approach, the study employs single nucleotide polymorphisms (SNPs) as instrumental variables (IVs) to explore causal links between thyroid function [free thyroxine (FT4), thyroid stimulating hormone (TSH), hyperthyroidism and hypothyroidism] and HBC. Data were sourced from the ThyroidOmic consortium and FinnGen consortium. The analysis included univariable and multivariable MR analysis, followed by mediation analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The study found a significant causal association between high FT4 levels and the reduced risk of BTC, but not HCC. However, TSH, hyperthyroidism and hypothyroidism had no causal associations with the risk of HBC. Notably, we also demonstrated that only higher FT4 levels with the reference range (FT4-RR) could reduce the risk of BTC because this protective effect no longer existed under the conditions of hyperthyroidism or hypothyroidism. Finally, we found that the protective effect of FT4-RR on BTC was mediated partially by decreasing the risk of metabolic syndrome (MetS) and reducing the waist circumference (WC).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The findings suggest that higher FT4-RR may have a protective effect against BTC, which is partially mediated by decreased risk of MetS and a reduction in WC. This study highlights the potential role of FT4 in the pathogenesis of BTC and underscores that MetS and WC may play mediation effects as two mediators in this process.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fendo.2024.1379607","type":"journal-article","created":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T04:14:16Z","timestamp":1713154456000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Protective effect of higher free thyroxine levels within the reference range on biliary tract cancer risk: a multivariable mendelian randomization and mediation analysis"],"prefix":"10.3389","volume":"15","author":[{"given":"Yuxian","family":"Chen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Dong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Baozhen","family":"Qu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuezhen","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"LinLin","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,4,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"17","DOI":"10.3322\/caac.21763","article-title":"Cancer statistics, 2023","volume":"73","author":"Siegel","year":"2023","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1157","DOI":"10.1186\/s12885-021-08904-3","article-title":"Survival improvement and prognosis for hepatocellular carcinoma: analysis of the SEER database","volume":"21","author":"Ding","year":"2021","journal-title":"BMC Cancer"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)00153-7","article-title":"Biliary tract cancer","volume":"397","author":"Valle","year":"2021","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-0155","article-title":"Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States","volume":"74","author":"Rahib","year":"2014","journal-title":"Cancer Res"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.34308","article-title":"Personal comorbidities and their subsequent risks for liver, gallbladder and bile duct cancers","volume":"152","author":"Hemminki","year":"2023","journal-title":"Int J Cancer"},{"key":"B6","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1111\/liv.14095","article-title":"Cholangiocarcinoma: Epidemiology and risk factors","author":"Khan","year":"2019","journal-title":"Liver Int"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13260","article-title":"Thyroid hormones in diabetes, cancer, and aging","volume":"19","author":"Gauthier","year":"2020","journal-title":"Aging Cell"},{"key":"B8","doi-asserted-by":"publisher","first-page":"292","DOI":"10.1038\/nrc1836","article-title":"Pathogenetic mechanisms in thyroid follicular-cell neoplasia","volume":"6","author":"Kondo","year":"2006","journal-title":"Nat Rev Cancer"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2019.00059","article-title":"Thyroid hormones and cancer: A comprehensive review of preclinical and clinical studies","volume":"10","author":"Krashin","year":"2019","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1210\/er.2009-0007","article-title":"Molecular aspects of thyroid hormone actions","volume":"31","author":"Cheng","year":"2010","journal-title":"Endocr Rev"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1101\/gad.189365.112","article-title":"Links between metabolism and cancer","volume":"26","author":"Dang","year":"2012","journal-title":"Genes Dev"},{"key":"B12","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1111\/apha.12648","article-title":"Emerging role of thyroid hormone metabolites","volume":"217","author":"Gnocchi","year":"2016","journal-title":"Acta Physiol (Oxf)"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/0303-7207(92)90138-V","article-title":"Effect of 3,3'-diiodothyronine and 3,5-diiodothyronine on rat liver oxidative capacity","volume":"86","author":"Lanni","year":"1992","journal-title":"Mol Cell Endocrinol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1996.sp021536","article-title":"Calorigenic effect of diiodothyronines in the rat","volume":"494","author":"Lanni","year":"1996","journal-title":"J Physiol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0116498","article-title":"3,5-Diiodo-L-thyronine activates brown adipose tissue thermogenesis in hypothyroid rats","volume":"10","author":"Lombardi","year":"2015","journal-title":"PLoS One"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s10863-011-9366-3","article-title":"3,5-diiodo-L-thyronine increases F0F1-ATP synthase activity and cardiolipin level in liver mitochondria of hypothyroid rats","volume":"43","author":"Cavallo","year":"2011","journal-title":"J Bioenerg Biomembr"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0052328","article-title":"3,5-Diiodo-L-thyronine administration to hypothyroid rats rapidly enhances fatty acid oxidation rate and bioenergetic parameters in liver cells","volume":"8","author":"Cavallo","year":"2013","journal-title":"PLoS One"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2019.00532","article-title":"The role of thyroid hormones in hepatocyte proliferation and liver cancer","volume":"10","author":"Gionfra","year":"2019","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B19","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1677\/jme.1.01911","article-title":"Mediation of the inhibitory effect of thyroid hormone on proliferation of hepatoma cells by transforming growth factor-beta","volume":"36","author":"Yen","year":"2006","journal-title":"J Mol Endocrinol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2009.265","article-title":"Thyroid hormone receptor mutants implicated in human hepatocellular carcinoma display an altered target gene repertoire","volume":"28","author":"Chan","year":"2009","journal-title":"Oncogene"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2010.464","article-title":"Thyroid hormone receptor \u03b21 domains responsible for the antagonism with the ras oncogene: role of corepressors","volume":"30","author":"Garc\u00eda-Silva","year":"2011","journal-title":"Oncogene"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-2198","article-title":"Thyroid hormone receptor \u03b21 acts as a potent suppressor of tumor invasiveness and metastasis","volume":"69","author":"Mart\u00ednez-Iglesias","year":"2009","journal-title":"Cancer Res"},{"key":"B23","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1530\/EJE-17-0197","article-title":"Lower TSH and higher free thyroxine predict incidence of prostate but not breast, colorectal or lung cancer","volume":"177","author":"Chan","year":"2017","journal-title":"Eur J Endocrinol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2016-2104","article-title":"Thyroid function and cancer risk: The rotterdam study","volume":"101","author":"Khan","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.32283","article-title":"Serum concentration of thyroid hormones in abnormal and euthyroid ranges and breast cancer risk: A cohort study","volume":"145","author":"Kim","year":"2019","journal-title":"Int J Cancer"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.4158\/EP15733.OR","article-title":"Serum thyrotropin concentrations are not predictive of aggressive breast cancer biology in euthyroid individuals","volume":"21","author":"Villa","year":"2015","journal-title":"Endocr Pract"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/hep.22793","article-title":"Association between hypothyroidism and hepatocellular carcinoma: a case-control study in the United States","volume":"49","author":"Hassan","year":"2009","journal-title":"Hepatology"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/onco.13755","article-title":"An underdiagnosed hypothyroidism and its clinical significance in patients with advanced hepatocellular carcinoma","volume":"26","author":"Shao","year":"2021","journal-title":"Oncologist"},{"key":"B29","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1186\/s12876-016-0527-z","article-title":"Increasing mortality in the United States from cholangiocarcinoma: an analysis of the National Center for Health Statistics Database","volume":"16","author":"Yao","year":"2016","journal-title":"BMC Gastroenterol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2008.09.008","article-title":"Cholangiocarcinoma","volume":"69","author":"Mosconi","year":"2009","journal-title":"Crit Rev Oncol Hematol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2022.987401","article-title":"Hypothyroidism has a protective causal association with hepatocellular carcinoma: A two-sample Mendelian randomization study","volume":"13","author":"Lu","year":"2022","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B32","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1002\/gepi.21998","article-title":"Bias due to participant overlap in two-sample Mendelian randomization","volume":"40","author":"Burgess","year":"2016","journal-title":"Genet Epidemiol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1093\/ije\/dyg070","article-title":"'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease","volume":"32","author":"Smith","year":"2003","journal-title":"Int J Epidemiol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/s40471-017-0128-6","article-title":"Recent developments in mendelian randomization studies","volume":"4","author":"Zheng","year":"2017","journal-title":"Curr Epidemiol Rep"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddu328","article-title":"Mendelian randomization: genetic anchors for causal inference in epidemiological studies","volume":"23","author":"Davey Smith","year":"2014","journal-title":"Hum Mol Genet"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1002\/sim.3034","article-title":"Mendelian randomization: using genes as instruments for making causal inferences in epidemiology","volume":"27","author":"Lawlor","year":"2008","journal-title":"Stat Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1093\/ije\/dyw127","article-title":"Commentary: Two-sample Mendelian randomization: opportunities and challenges","volume":"45","author":"Lawlor","year":"2016","journal-title":"Int J Epidemiol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2021.18236","article-title":"Strengthening the reporting of observational studies in epidemiology using mendelian randomization: The STROBE-MR statement","volume":"326","author":"Skrivankova","year":"2021","journal-title":"JAMA"},{"key":"B39","doi-asserted-by":"publisher","first-page":"4455","DOI":"10.1038\/s41467-018-06356-1","article-title":"Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation","volume":"9","author":"Teumer","year":"2018","journal-title":"Nat Commun"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05473-8","article-title":"FinnGen provides genetic insights from a well-phenotyped isolated population","volume":"613","author":"Kurki","year":"2023","journal-title":"Nature"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.22295","article-title":"A comparison of robust Mendelian randomization methods using summary data","volume":"44","author":"Slob","year":"2020","journal-title":"Genet Epidemiol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1002\/sim.7221","article-title":"A framework for the investigation of pleiotropy in two-sample summary data Mendelian randomization","volume":"36","author":"Bowden","year":"2017","journal-title":"Stat Med"},{"key":"B43","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1097\/EDE.0000000000000559","article-title":"Sensitivity analyses for robust causal inference from mendelian randomization analyses with multiple genetic variants","volume":"28","author":"Burgess","year":"2017","journal-title":"Epidemiology"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1002\/sim.6522","article-title":"Detecting pleiotropy in Mendelian randomization studies with summary data and a continuous outcome","volume":"34","author":"Greco M","year":"2015","journal-title":"Stat Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1007081","article-title":"Orienting the causal relationship between imprecisely measured traits using GWAS summary data","volume":"13","author":"Hemani","year":"2017","journal-title":"PLoS Genet"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-0631-4","article-title":"Mendelian randomization accounting for correlated and uncorrelated pleiotropic effects using genome-wide summary statistics","volume":"52","author":"Morrison","year":"2020","journal-title":"Nat Genet"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0066711","article-title":"Morbidity before and after the diagnosis of hyperthyroidism: a nationwide register-based study","volume":"8","author":"Brandt","year":"2013","journal-title":"PLoS One"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-12-0219","article-title":"Thyroid hormone, thyroid hormone receptors, and cancer: a clinical perspective","volume":"20","author":"Moeller","year":"2013","journal-title":"Endocr Relat Cancer"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2006.07.011","article-title":"Hypothyroidism: a possible risk factor for liver cancer in patients with no known underlying cause of liver disease","volume":"5","author":"Reddy","year":"2007","journal-title":"Clin Gastroenterol Hepatol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0181878","article-title":"The impact of thyroid hormones on patients with hepatocellular carcinoma","volume":"12","author":"Pinter","year":"2017","journal-title":"PLoS One"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgab183","article-title":"Causal association between serum thyrotropin and obesity: A bidirectional, mendelian randomization study","volume":"106","author":"Wang","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"key":"B52","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1089\/thy.2016.0171","article-title":"Association between changes in thyroid hormones and incident type 2 diabetes: A seven-year longitudinal study","volume":"27","author":"Jun","year":"2017","journal-title":"Thyroid"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2022.08.001","article-title":"NAFLD and thyroid function: pathophysiological and therapeutic considerations","volume":"33","author":"Hatziagelaki","year":"2022","journal-title":"Trends Endocrinol Metab"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-20-1123","article-title":"Opposing effects of thyroid hormones on cancer risk: a population-based study","volume":"184","author":"Krashin","year":"2021","journal-title":"Eur J Endocrinol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2010.48","article-title":"Thyroid hormones induce activation of rat hepatic stellate cells through increased expression of p75 neurotrophin receptor and direct activation of Rho","volume":"90","author":"Zvibel","year":"2010","journal-title":"Lab Invest"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00071.2014","article-title":"L-Thyroxine promotes a proliferative airway smooth muscle phenotype in the presence of TGF-\u03b21","volume":"308","author":"Dekkers","year":"2015","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B57","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1242\/dev.101907","article-title":"Integrin \u03b1v\u03b23 and thyroid hormones promote expansion of progenitors in embryonic neocortex","volume":"141","author":"Stenzel","year":"2014","journal-title":"Development"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-07-587337","article-title":"Integrin \u03b1v\u03b23 acting as membrane receptor for thyroid hormones mediates angiogenesis in Malignant T cells","volume":"125","author":"Cayrol","year":"2015","journal-title":"Blood"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1002\/cbf.3013","article-title":"Thyroid hormones differentially regulate phosphorylation of ERK and Akt via integrin \u03b1v\u03b23 receptor in undifferentiated and differentiated PC-12 cells","volume":"32","author":"Barbakadze","year":"2014","journal-title":"Cell Biochem Funct"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-15-0245","article-title":"Thyroid hormones and tetrac: new regulators of tumor stroma formation via integrin \u03b1v\u03b23","volume":"22","author":"Schmohl","year":"2015","journal-title":"Endocr Relat Cancer"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24397","article-title":"Metabolic syndrome increases the risk of primary liver cancer in the United States: a study in the SEER-Medicare database","volume":"54","author":"Welzel","year":"2011","journal-title":"Hepatology"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.2147\/CMAR.S175628","article-title":"Metabolic syndrome and the risk of cholangiocarcinoma: a hospital-based case-control study in China","volume":"10","author":"Xiong","year":"2018","journal-title":"Cancer Manag Res"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2021-324915","article-title":"Epidemiological trends and trajectories of MAFLD-associated hepatocellular carcinoma 2002-2033: the ITA.LI.CA database","volume":"72","author":"Vitale","year":"2023","journal-title":"Gut"},{"key":"B64","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.jhep.2019.09.007","article-title":"Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: A systematic review and meta-analysis","volume":"72","author":"Clements","year":"2020","journal-title":"J Hepatol"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.3389\/fnut.2023.1124468","article-title":"Trends in elevated waist-to-height ratio and waist circumference in U.S. adults and their associations with cardiometabolic diseases and cancer, 1999-2018","volume":"10","author":"Yang","year":"2023","journal-title":"Front Nutr"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1186\/s12916-020-01877-3","article-title":"Body mass index and waist circumference in relation to the risk of 26 types of cancer: a prospective cohort study of 3.5 million adults in Spain","volume":"19","author":"Recalde","year":"2016","journal-title":"BMC Med"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2024.1379607\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T04:14:21Z","timestamp":1713154461000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2024.1379607\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,15]]},"references-count":66,"alternative-id":["10.3389\/fendo.2024.1379607"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2024.1379607","relation":{},"ISSN":["1664-2392"],"issn-type":[{"type":"electronic","value":"1664-2392"}],"subject":[],"published":{"date-parts":[[2024,4,15]]},"article-number":"1379607"}}