{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T18:56:32Z","timestamp":1792176992710,"version":"4.4.0"},"reference-count":86,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,1,19]],"date-time":"2020-01-19T00:00:00Z","timestamp":1579392000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Objective: levothyroxine prescriptions have increased remarkably during the last decade, and it is most likely to be prescribed in subclinical hypothyroidism. The aim of this review was to present data on when levothyroxine treatment should be initiated, and the effects of treatment in subclinical hypothyroidism on symptoms such as weight, quality of life, vitality, cognition, and cardiovascular disease. We also discuss evidence for different thyroid-hormone medications. In addition, the option to withhold medication when there is uncertain diagnosis or lack of clinical improvement is discussed. Methods: a literature search in PubMed on the term \u201ctreatment of subclinical hypothyroidism\u201d in combination with \u201cquality of life\u201d, \u201cweight\u201d, \u201ccognition\u201d, and \u201ccerebrovascular disease\u201d. Results: current research supports that levothyroxine should be initiated in patients with a thyroid stimulating hormone (TSH) &gt;10 mIU\/L. Treatment for hypothyroidism is becoming more frequent. Symptoms related to vitality, weight, and quality of life in subclinical disease often persist with levothyroxine treatment, and other causes should be explored. Patients with cardiovascular-risk factors may benefit from treatment, especially younger patients. Caution is necessary when treating elderly subjects with levothyroxine. Conclusion: lifelong treatment with levothyroxine should normally only be considered in manifest hypothyroidism. However, in subclinical hypothyroidism with a TSH &gt;10 mIU\/L, therapy is indicated. In milder subclinical forms, a wait-and-see strategy is advocated to see if normalization occurs. Subgroups with cardiovascular risk and subclinical hypothyroidism may benefit from levothyroxine therapy.<\/jats:p>","DOI":"10.3390\/medicina56010040","type":"journal-article","created":{"date-parts":[[2020,1,20]],"date-time":"2020-01-20T04:27:09Z","timestamp":1579494429000},"page":"40","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["To Treat or Not to Treat Subclinical Hypothyroidism, What Is the Evidence?"],"prefix":"10.3390","volume":"56","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2088-5814","authenticated-orcid":false,"given":"Jan","family":"Calissendorff","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden"},{"name":"Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, SE-171 76 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5622-6987","authenticated-orcid":false,"given":"Henrik","family":"Falhammar","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden"},{"name":"Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, SE-171 76 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,1,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1670","DOI":"10.1089\/thy.2014.0028","article-title":"Guidelines for the treatment of hypothyroidism: Prepared by the american thyroid association task force on thyroid hormone replacement","volume":"24","author":"Jonklaas","year":"2014","journal-title":"Thyroid"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"988","DOI":"10.4158\/EP12280.GL","article-title":"Clinical practice guidelines for hypothyroidism in adults: Cosponsored by the american association of clinical endocrinologists and the american thyroid association","volume":"18","author":"Garber","year":"2012","journal-title":"Endocr. Pract."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1159\/000356507","article-title":"2013 eta guideline: Management of subclinical hypothyroidism","volume":"2","author":"Pearce","year":"2013","journal-title":"Eur. Thyroid J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.mcna.2012.01.005","article-title":"Hypothyroidism: Etiology, diagnosis, and management","volume":"96","author":"Almandoz","year":"2012","journal-title":"Med. Clin. N. Am."},{"key":"ref_5","first-page":"w14058","article-title":"Subclinical hypothyroidism: Summary of evidence in 2014","volume":"144","author":"Baumgartner","year":"2014","journal-title":"Swiss Med. Wkly."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1111\/j.1365-2265.1995.tb01894.x","article-title":"The incidence of thyroid disorders in the community: A twenty-year follow-up of the whickham survey","volume":"43","author":"Vanderpump","year":"1995","journal-title":"Clin. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1001\/jama.291.2.228","article-title":"Subclinical thyroid disease: Scientific review and guidelines for diagnosis and management","volume":"291","author":"Surks","year":"2004","journal-title":"JAMA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1089\/thy.2005.15.24","article-title":"Consensus statement #1: Subclinical thyroid dysfunction: A joint statement on management from the american association of clinical endocrinologists, the american thyroid association, and the endocrine society","volume":"15","author":"Gharib","year":"2005","journal-title":"Thyroid"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/S2213-8587(18)30371-1","article-title":"Reference intervals in the diagnosis of thyroid dysfunction: Treating patients not numbers","volume":"7","author":"Jonklaas","year":"2019","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1089\/thy.2018.0251","article-title":"Trends, determinants, and associations of treated hypothyroidism in the united kingdom, 2005\u20132014","volume":"29","author":"Razvi","year":"2019","journal-title":"Thyroid"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1210\/jcem.87.2.8182","article-title":"Serum tsh, t(4), and thyroid antibodies in the united states population (1988 to 1994): National health and nutrition examination survey (nhanes iii)","volume":"87","author":"Hollowell","year":"2002","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1001\/jama.2019.9052","article-title":"Subclinical hypothyroidism: A review","volume":"322","author":"Biondi","year":"2019","journal-title":"JAMA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"l2006","DOI":"10.1136\/bmj.l2006","article-title":"Thyroid hormones treatment for subclinical hypothyroidism: A clinical practice guideline","volume":"365","author":"Bekkering","year":"2019","journal-title":"BMJ"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/S2213-8587(16)30276-5","article-title":"Levothyroxine overuse: Time for an about face?","volume":"5","author":"Maraka","year":"2017","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_15","first-page":"CD003419","article-title":"Thyroid hormone replacement for subclinical hypothyroidism","volume":"3","author":"Villar","year":"2007","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1001\/jamainternmed.2013.11312","article-title":"Falling threshold for treatment of borderline elevated thyrotropin levels-balancing benefits and risks: Evidence from a large community-based study","volume":"174","author":"Taylor","year":"2014","journal-title":"JAMA Intern. Med."},{"key":"ref_17","first-page":"555","article-title":"Orders for thyroid function tests\u2014Changes over 10 years","volume":"41","author":"Bayram","year":"2012","journal-title":"Aust. Fam. Physician"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1111\/cen.12824","article-title":"Management of primary hypothyroidism: Statement by the british thyroid association executive committee","volume":"84","author":"Okosieme","year":"2016","journal-title":"Clin. Endocrinol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1590\/S0004-27302013000300003","article-title":"The brazilian consensus for the clinical approach and treatment of subclinical hypothyroidism in adults: Recommendations of the thyroid department of the brazilian society of endocrinology and metabolism","volume":"57","author":"Sgarbi","year":"2013","journal-title":"Arq. Bras. Endocrinol. Metabol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.4158\/EP161308.OR","article-title":"Italian association of clinical endocrinologists statement-replacement therapy for primary hypothyroidism: A brief guide for clinical practice","volume":"22","author":"Guglielmi","year":"2016","journal-title":"Endocr. Pract."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2534","DOI":"10.1056\/NEJMoa1603825","article-title":"Thyroid hormone therapy for older adults with subclinical hypothyroidism","volume":"376","author":"Stott","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1016\/j.beem.2013.10.003","article-title":"Pitfalls in the measurement and interpretation of thyroid function tests","volume":"27","author":"Koulouri","year":"2013","journal-title":"Best Pract. Res. Clin. Endocrinol. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1001\/archinte.167.14.1533","article-title":"Serum thyrotropin measurements in the community: Five-year follow-up in a large network of primary care physicians","volume":"167","author":"Meyerovitch","year":"2007","journal-title":"Arch. Intern. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1001\/archinte.1981.00340070053012","article-title":"Elevations of thyroid-stimulating hormone during acute nonthyroidal illness","volume":"141","author":"Wong","year":"1981","journal-title":"Arch. Intern. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1159\/000213189","article-title":"Longitudinal study of thyroid function in acutely ill elderly patients using a sensitive tsh assay-defer testing until recovery","volume":"36","author":"Bhakri","year":"1990","journal-title":"Gerontology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1159\/000486957","article-title":"2018 european thyroid association (eta) guidelines for the management of amiodarone-associated thyroid dysfunction","volume":"7","author":"Bartalena","year":"2018","journal-title":"Eur. Thyroid J."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1530\/EJE-15-0883","article-title":"Variability in the detection of macro tsh in different immunoassay systems","volume":"174","author":"Hattori","year":"2016","journal-title":"Eur. J. Endocrinol.\/Eur. Fed. Endocr. Soc."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1111\/cen.12643","article-title":"Macro tsh in patients with subclinical hypothyroidism","volume":"83","author":"Hattori","year":"2015","journal-title":"Clin. Endocrinol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1016\/S0025-6196(12)65044-7","article-title":"Heterophilic serum antibodies: A cause for falsely elevated serum thyrotropin levels","volume":"62","author":"Brennan","year":"1987","journal-title":"Mayo Clin. Proc."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1093\/ajcp\/108.4.417","article-title":"Heterophilic antibodies remain a problem for the immunoassay laboratory","volume":"108","author":"Ward","year":"1997","journal-title":"Am. J. Clin. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1089\/thy.2016.0457","article-title":"2017 guidelines of the american thyroid association for the diagnosis and management of thyroid disease during pregnancy and the postpartum","volume":"27","author":"Alexander","year":"2017","journal-title":"Thyroid"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1089\/thy.2018.0369","article-title":"Prescribing therapy for hypothyroidism: Influence of physician characteristics","volume":"29","author":"Jonklaas","year":"2019","journal-title":"Thyroid"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1089\/thy.2006.0252","article-title":"Health status, psychological symptoms, mood, and cognition in l-thyroxine-treated hypothyroid subjects","volume":"17","author":"Samuels","year":"2007","journal-title":"Thyroid"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1210\/jc.2009-1625","article-title":"Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy","volume":"95","author":"Flynn","year":"2010","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4046","DOI":"10.1200\/JCO.2013.49.1043","article-title":"Long-term cardiovascular mortality in patients with differentiated thyroid carcinoma: An observational study","volume":"31","author":"Gansevoort","year":"2013","journal-title":"J. Clin. Oncol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1111\/j.1365-2265.2010.03855.x","article-title":"Diseases associated with thyroid autoimmunity: Explanations for the expanding spectrum","volume":"74","author":"Weetman","year":"2011","journal-title":"Clin. Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1111\/j.1365-2265.1989.tb02230.x","article-title":"Acute changes in serum thyrotrophin in treated addison\u2019s disease","volume":"30","author":"Ismail","year":"1989","journal-title":"Clin. Endocrinol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1136\/bmj.308.6931.763","article-title":"Population based study of fatigue and psychological distress","volume":"308","author":"Pawlikowska","year":"1994","journal-title":"BMJ"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1080\/14034940410028406","article-title":"Fatigue in the general population: A translation and test of the psychometric properties of the norwegian version of the fatigue severity scale","volume":"33","author":"Lerdal","year":"2005","journal-title":"Scand. J. Public Health"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1097\/HTR.0b013e3181f20146","article-title":"Chronic stress and fatigue-related quality of life after mild to moderate traumatic brain injury","volume":"26","author":"Bay","year":"2011","journal-title":"J. Head Trauma Rehabil."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1001\/archinte.1990.00040031685016","article-title":"The prevalence of symptoms in medical outpatients and the adequacy of therapy","volume":"150","author":"Kroenke","year":"1990","journal-title":"Arch. Intern. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1001\/archinte.160.4.526","article-title":"The colorado thyroid disease prevalence study","volume":"160","author":"Canaris","year":"2000","journal-title":"Arch. Intern. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1210\/jc.2005-1775","article-title":"Neuropsychological function and symptoms in subjects with subclinical hypothyroidism and the effect of thyroxine treatment","volume":"91","author":"Jorde","year":"2006","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1001\/jama.2018.13770","article-title":"Association of thyroid hormone therapy with quality of life and thyroid-related symptoms in patients with subclinical hypothyroidism: A systematic review and meta-analysis","volume":"320","author":"Feller","year":"2018","journal-title":"JAMA"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1089\/thy.2018.0014","article-title":"Levothyroxine replacement therapy and overuse: A timely diagnostic approach","volume":"28","author":"Livadas","year":"2018","journal-title":"Thyroid"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2624","DOI":"10.1210\/jc.2006-0099","article-title":"Small changes in thyroxine dosage do not produce measurable changes in hypothyroid symptoms, well-being, or quality of life: Results of a double-blind, randomized clinical trial","volume":"91","author":"Walsh","year":"2006","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1046\/j.1365-2265.2002.01654.x","article-title":"Psychological well-being in patients on \u2018adequate\u2019 doses of l-thyroxine: Results of a large, controlled community-based questionnaire study","volume":"57","author":"Saravanan","year":"2002","journal-title":"Clin. Endocrinol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1530\/eje.1.02025","article-title":"Cognitive functioning and well-being in euthyroid patients on thyroxine replacement therapy for primary hypothyroidism","volume":"153","author":"Wekking","year":"2005","journal-title":"Eur. J. Endocrinol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1210\/jc.2008-1696","article-title":"High frequency of and factors associated with thyroid hormone over-replacement and under-replacement in men and women aged 65 and over","volume":"94","author":"Somwaru","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_50","first-page":"418","article-title":"Kinetic analysis of drug release from compounded slow-release capsules of liothyronine sodium (t3)","volume":"21","author":"Bakhteyar","year":"2017","journal-title":"Int. J. Pharm. Compd."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1038\/nrendo.2013.258","article-title":"Paradigm shifts in thyroid hormone replacement therapies for hypothyroidism","volume":"10","author":"Wiersinga","year":"2014","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_52","first-page":"235","article-title":"Effectiveness of various hormonal preparations in adults with hypothyroidism (author\u2019s transl)","volume":"10","author":"Baillet","year":"1981","journal-title":"Nouv. Presse Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1016\/0002-9343(78)90057-8","article-title":"Why does anyone still use desiccated thyroid usp?","volume":"64","author":"Jackson","year":"1978","journal-title":"Am. J. Med."},{"key":"ref_54","first-page":"1","article-title":"Replacement therapy with l-thyroxine: Serum thyroid hormone and thyrotropin levels in hypothyroid patients changing from desiccated thyroid to pure thyroxine substitution therapy","volume":"24","author":"Krenning","year":"1981","journal-title":"Neth. J. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1001\/archpedi.1980.02130130008003","article-title":"Elevated serum concentrations of triiodothyronine in hypothyroid patients. Values for patients receiving usp thyroid","volume":"134","author":"Penny","year":"1980","journal-title":"Am. J. Dis. Child."},{"key":"ref_56","first-page":"59","article-title":"The serum concentrations of t3, t4 and tsh in evaluating replacement therapy in primary hypothyroidism","volume":"32","author":"Bindels","year":"1988","journal-title":"Neth. J. Med."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1210\/jc.2012-4107","article-title":"Desiccated thyroid extract compared with levothyroxine in the treatment of hypothyroidism: A randomized, double-blind, crossover study","volume":"98","author":"Hoang","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1089\/thy.2017.0681","article-title":"An online survey of hypothyroid patients demonstrates prominent dissatisfaction","volume":"28","author":"Peterson","year":"2018","journal-title":"Thyroid"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Gullo, D., Latina, A., Frasca, F., Le Moli, R., Pellegriti, G., and Vigneri, R. (2011). Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0022552"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2592","DOI":"10.1210\/jc.2006-0448","article-title":"Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: Meta-analysis of randomized controlled trials","volume":"91","author":"Fraser","year":"2006","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"895","DOI":"10.1530\/EJE-09-0542","article-title":"Effect of combination therapy with thyroxine (t4) and 3,5,3\u2032-triiodothyronine versus t4 monotherapy in patients with hypothyroidism, a double-blind, randomised cross-over study","volume":"161","author":"Nygaard","year":"2009","journal-title":"Eur. J. Endocrinol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"3104","DOI":"10.1172\/JCI107137","article-title":"A new radioimmunoassay for plasma l-triiodothyronine: Measurements in thyroid disease and in patients maintained on hormonal replacement","volume":"51","author":"Surks","year":"1972","journal-title":"J. Clin. Investig."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1159\/000339444","article-title":"2012 eta guidelines: The use of l-t4 + l-t3 in the treatment of hypothyroidism","volume":"1","author":"Wiersinga","year":"2012","journal-title":"Eur. Thyroid J."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1997","DOI":"10.1210\/jc.2017-02668","article-title":"Effects of altering levothyroxine (l-t4) doses on quality of life, mood, and cognition in l-t4 treated subjects","volume":"103","author":"Samuels","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1530\/eje.1.02333","article-title":"The association between tsh within the reference range and serum lipid concentrations in a population-based study. The hunt study","volume":"156","author":"Asvold","year":"2007","journal-title":"Eur. J. Endocrinol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Ning, Y., Cheng, Y.J., Liu, L.J., Sara, J.D., Cao, Z.Y., Zheng, W.P., Zhang, T.S., Han, H.J., Yang, Z.Y., and Zhang, Y. (2017). What is the association of hypothyroidism with risks of cardiovascular events and mortality? A meta-analysis of 55 cohort studies involving 1,898,314 participants. BMC Med., 15.","DOI":"10.1186\/s12916-017-0777-9"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2181","DOI":"10.1210\/jc.2015-1438","article-title":"Subclinical hypothyroidism and the risk of stroke events and fatal stroke: An individual participant data analysis","volume":"100","author":"Chaker","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1001\/jama.2010.1361","article-title":"Subclinical hypothyroidism and the risk of coronary heart disease and mortality","volume":"304","author":"Rodondi","year":"2010","journal-title":"JAMA"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1001\/archinternmed.2012.1159","article-title":"Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality","volume":"172","author":"Razvi","year":"2012","journal-title":"Arch. Intern. Med."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.arcmed.2005.05.008","article-title":"Depression, anxiety, health-related quality of life, and disability in patients with overt and subclinical thyroid dysfunction","volume":"37","author":"Gulseren","year":"2006","journal-title":"Arch. Med. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1210\/jc.2017-01247","article-title":"Subclinical hypothyroidism and incident depression in young and middle-age adults","volume":"103","author":"Kim","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1623","DOI":"10.1210\/jc.2008-1301","article-title":"Common variation in the dio2 gene predicts baseline psychological well-being and response to combination thyroxine plus triiodothyronine therapy in hypothyroid patients","volume":"94","author":"Panicker","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"6296","DOI":"10.1210\/jc.2005-0451","article-title":"Polymorphisms in type 2 deiodinase are not associated with well-being, neurocognitive functioning, and preference for combined thyroxine\/3,5,3\u2032-triiodothyronine therapy","volume":"90","author":"Appelhof","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"E75","DOI":"10.1152\/ajpendo.00571.2004","article-title":"A new polymorphism in the type ii deiodinase gene is associated with circulating thyroid hormone parameters","volume":"289","author":"Peeters","year":"2005","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1111\/j.1365-2265.2008.03474.x","article-title":"Thr92ala polymorphism in the type 2 deiodinase is not associated with t4 dose in athyroid patients or patients with hashimoto thyroiditis","volume":"71","author":"Heemstra","year":"2009","journal-title":"Clin. Endocrinol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1159\/000469709","article-title":"Hypothyroid patients encoding combined mct10 and dio2 gene polymorphisms may prefer l-t3 + l-t4 combination treatment\u2014Data using a blind, randomized, clinical study","volume":"6","author":"Carle","year":"2017","journal-title":"Eur. Thyroid J."},{"key":"ref_77","doi-asserted-by":"crossref","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":"ref_78","doi-asserted-by":"crossref","first-page":"3584","DOI":"10.1210\/jc.2013-2760","article-title":"The normal tsh reference range: What has changed in the last decade?","volume":"98","author":"Biondi","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1210\/jc.2012-2180","article-title":"Persistent subclinical hypothyroidism and cardiovascular risk in the elderly: The cardiovascular health study","volume":"98","author":"Hyland","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2591","DOI":"10.1001\/jama.292.21.2591","article-title":"Thyroid status, disability and cognitive function, and survival in old age","volume":"292","author":"Gussekloo","year":"2004","journal-title":"JAMA"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1161\/CIRCULATIONAHA.112.096024","article-title":"Subclinical thyroid dysfunction and the risk of heart failure events: An individual participant data analysis from 6 prospective cohorts","volume":"126","author":"Gencer","year":"2012","journal-title":"Circulation"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1507\/endocrj.K09E-206","article-title":"Favorable influence of subclinical hypothyroidism on the functional outcomes in stroke patients","volume":"57","author":"Baek","year":"2010","journal-title":"Endocr. J."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2926","DOI":"10.1016\/j.jstrokecerebrovasdis.2017.07.015","article-title":"Ischemic stroke and impact of thyroid profile at presentation: A systematic review and meta-analysis of observational studies","volume":"26","author":"Dhital","year":"2017","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1089\/thy.2017.0414","article-title":"Subclinical hypothyroidism and the risk of cardiovascular disease and all-cause mortality: A meta-analysis of prospective cohort studies","volume":"28","author":"Moon","year":"2018","journal-title":"Thyroid"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"177","DOI":"10.3389\/fendo.2019.00177","article-title":"Overt and subclinical hypothyroidism in the elderly: When to treat?","volume":"10","author":"Calsolaro","year":"2019","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1002\/jbmr.3426","article-title":"Thyroid stimulating hormone and bone mineral density: Evidence from a two-sample mendelian randomization study and a candidate gene association study","volume":"33","author":"Noordam","year":"2018","journal-title":"J. Bone Miner. 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