Treatment with levothyroxin in subclinical hypothyroidism is associated with increased mortality in the elderly

  • Alon Grossman
    Department of Internal Medicine E, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel

    Sackler Faculty of Medicine, Tel Aviv University, Israel
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  • Ilan Feldhamer
    Clalit Health Services Research and Information Department, Chief Physician Office, Israel
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  • Joseph Meyerovitch
    Corresponding author at: Sackler Faculty of Medicine, Tel Aviv University, Israel.
    Sackler Faculty of Medicine, Tel Aviv University, Israel

    The Jesse Z and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel and Medicine Wings, Community Division, Clalit Health Services, Tel Aviv, Israel
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Published:November 22, 2017DOI:


      • Treatment of scH is associated with mortality in individuals >65 years old.
      • Use of iron salts in patients with scH treated with LT4 increases the association between treatment and mortality.
      • Excess mortality in patients treated with LT4 is not caused by atrial fibrillation or femoral fractures.



      It is uncertain whether subclinical hypothyroidism should be treated with levothyroxine, particularly in the elderly. This study evaluated the association between levothyroxine treatment and mortality in individuals 65 years or older with subclinical hypothyroidism and TSH values <10 mIU/L.


      A case-control study in which patients 65 years or older with TSH levels of 4.2–10 mIU/L who died in the years 2012–2016 (‘cases’) were compared with matched individuals who did not die during this period (‘controls’). Matching was based on gender, age, Charlson comorbidity index, date of TSH testing, duration of follow-up and TSH quartile. All cases of known thyroid disease or cases in which anti-thyroid medications or glucocorticoids were dispensed in the year preceding the TSH evaluation were excluded. Use of levothyroxine was compared between groups.


      During the follow-up period, 419 individuals died and these were matched with 1558 individuals who did not. Factors found to be associated with mortality were age, senile dementia, congestive heart failure, chronic renal failure and a history of cerebrovascular disease. On multivariate analysis, treatment with levothyroxine was associated with significantly increased mortality (HR = 1.19 CI 1.03–1.38). Femoral fractures and atrial fibrillation following initiation of levothyroxine therapy were not more prevalent in individuals who died during the follow-up period.


      Treatment with levothyroxine is associated with significantly increased mortality in individuals 65 years or older with subclinical hypothyroidism and TSH < 10.


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        • Gussekloo J.
        • van Exel E.
        • de Craen A.J.
        • Meinders A.E.
        • Frölich M.
        • Westendorp R.G.
        Thyroid status, disability and cognitive function, and survival in old age.
        JAMA. 2004; 292: 2591-2599
        • Rodondi N.
        • den Elzen W.P.
        • Bauer D.C.
        • Cappola A.R.
        • Razvi S.
        • Walsh J.P.
        • et al.
        Subclinical hypothyroidism and the risk of coronary heart disease and mortality.
        JAMA. 2010; 304: 1365-1374
        • Hyland K.A.
        • Arnold A.M.
        • Lee J.S.
        • Cappola A.R.
        Persistent subclinical hypothyroidism and cardiovascular risk in the elderly: the cardiovascular health study.
        J Clin Endocrinol Metab. 2013; 98: 533-540
        • Waring A.C.
        • Harrison S.
        • Samuels M.H.
        • Ensrud K.E.
        • LeBLanc E.S.
        • Hoffman A.R.
        • et al.
        Thyroid function and mortality in older men: a prospective study.
        J Clin Endocrinol Metab. 2012; 97: 862-870
        • Grossman A.
        • Weiss A.
        • Koren-Morag N.
        • Shimon I.
        • Beloosesky Y.
        • Meyerovitch J.
        Subclinical thyroid disease and mortality in the elderly–a retrospective cohort study.
        Am J Med. 2015; 129: 423-430
        • Nanchen D.
        • Gussekloo J.
        • Westendorp R.G.
        • Stott D.J.
        • Jukema J.W.
        • Trompet S.
        • et al.
        Subclinical thyroid dysfunction and the risk of heart failure in older persons at high cardiovascular risk.
        J Clin Endocrinol Metab. 2012; 97: 852-861
        • Lindeman R.D.
        • Romero L.J.
        • Schade D.S.
        • Wayne S.
        • Baumgartner R.N.
        • Garry P.J.
        Impact of subclinical hypothyroidism on serum total homocysteine concentrations, the prevalence of coronary heart disease (CHD), and CHD risk factors in the New Mexico Elder Health Survey.
        Thyroid. 2003; 13: 595-600
        • Jaeschke R.
        • Guyatt G.
        • Gerstein H.
        • Patterson C.
        • Molloy W.
        • Cook D.
        • et al.
        Does treatment with l-thyroxine influence health status in middle-aged and older adults with subclinical hypothyroidism?.
        J Gen Intern Med. 1996; 11: 744-749
        • McDermott M.T.
        • Ridgway E.C.
        Subclinical hypothyroidism is mild thyroid failure and should be treated.
        J Clin Endocrinol Metab. 2001; 86: 4585-4590
        • Meier C.
        • Staub J.J.
        • Roth C.B.
        • Guglielmetti M.
        • Kunz M.
        • Miserez A.R.
        • et al.
        TSH-controlled l-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: a double blind, placebo-controlled trial (Basel Thyroid Study).
        J Clin Endocrinol Metab. 2001; 86: 4860-4866
        • Razvi S.
        • Weaver J.U.
        • Butler T.J.
        • Pearce S.H.
        Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality.
        Arch Intern Med. 2012; 172: 811-817
        • Stott D.J.
        • Rodondi N.
        • Kearney P.M.
        • Ford I.
        • Westendorp R.G.
        • Mooijaart S.P.
        • et al.
        Thyroid hormone therapy for older adults with subclinical hypothyroidism.
        N Engl J Med. 2017; ([Epub ahead of print])
        • Charlson M.E.
        • Pompei P.
        • Ales K.L.
        • et al.
        A new method of classifying prognostic comorbidity in longitudinal studies: development and validation.
        J Chronic Dis. 1987; 40: 373-383
        • Benvenga S.
        When thyroid hormone replacement is ineffective?.
        Curr Opin Endocrinol Diabetes Obes. 2013; 20: 467-477
        • Klee G.G.
        • Hay I.D.
        Biochemical testing of thyroid function.
        Endocrinol Metab Clin North Am. 1997; 26: 763-775
        • Van Wijk M.A.
        • van der Lei J.
        • Mosseveld M.
        • Bohnen A.M.
        • van Behmel J.H.
        Compliance of general practitioners with guideline-based decision support system for ordering blood tests.
        Clin Chem. 2002; 48: 9-10
        • Chen I.W.
        • Sperling M.I.
        in: Kaplan L.A. Pesce A.J. Clinical chemistry: theory, analysis and correlation. 2nd ed. CV Mosby, St. Luis1989: 956-959
        • Cappola A.R.
        • Fried L.P.
        • Arnold A.M.
        • Danese M.D.
        • Kuller L.H.
        • Burke G.L.
        • et al.
        Thyroid status, cardiovascular risk, and mortality in older adults.
        JAMA. 2006; 295: 1033-1041
        • Selmer C.
        • Olesen J.B.
        • Hansen M.L.
        • von Kappelgaard L.M.
        • Madsen J.C.
        • Hansen P.R.
        • et al.
        Subclinical and overt thyroid dysfunction and risk of all-cause mortality and cardiovascular events: a large population study.
        J Clin Endocrinol Metab. 2014; 99: 2372-2382
        • Rhee C.M.
        • Curhan G.C.
        • Alexander E.K.
        • Bhan I.
        • Brunelli S.M.
        Subclinical hypothyroidism and survival: the effects of heart failure and race.
        J Clin Endocrinol Metab. 2013; 98: 2326-2336
        • Akirov A.
        • Gimbel H.
        • Grossman A.
        • Shochat T.
        • Shimon I.
        Elevated TSH in adults treated for hypothyroidism is associated with increased mortality.
        Eur J Endocrinol. 2017; 176 ([Epub 2016 Oct 19]): 57-66
        • Kong W.M.
        • Sheikh M.H.
        • Lumb P.J.
        • et al.
        A 6-month randomized trial of thyroxine treatment in women with mild subclinical hypothyroidism.
        Am J Med. 2002; 112: 348-354
        • Surks M.I.
        • Ortiz E.
        • Daniels G.H.
        • Sawin C.T.
        • Col N.F.
        • Cobin R.H.
        • et al.
        Subclinical thyroid disease: scientific review and guidelines for diagnosis and management.
        JAMA. 2004; 291: 228-238
        • Sawin C.T.
        • Geller A.
        • Kaplan M.M.
        • Bacharach P.
        • Wilson P.W.
        • Hershman J.M.
        Low serum thyrotropin (thyroid-stimulating hormone) in older persons without hyperthyroidism.
        Arch Intern Med. 1991; 151: 165-168