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    1 Comment for this article
    Looking at wrong markers
    Randolph Whipps, M.D. FACC | LifeMed Institute
    We all grew up thinking the TSH was the end all and be all. Need to be looking at the free T3 which is the active form of thyroxine. T4 is more a pro hormone. Pituitary is looking at both T4 and T3. There are many patients out there with normal TSH but all the symptoms of hypothyroid. When you look their free T3 it is in the lower range (remember the reference range is NOT a normal range but a statistical determination). Raise their free T3 and they feel much better. These are not rare patients. Treat the patient, not the numbers.
    Original Investigation
    Diabetes and Endocrinology
    February 7, 2020

    Association of Subclinical Hypothyroidism and Cardiovascular Disease With Mortality

    Author Affiliations
    • 1Fielding School of Public Health, Department of Epidemiology, University of California, Los Angeles
    • 2David Geffen School of Medicine, Department of Neurology, University of California, Los Angeles
    • 3David Geffen School of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of California, Los Angeles
    • 4VA Greater Los Angeles Healthcare System, Los Angeles, California
    • 5David Geffen School of Medicine, Division of Cardiology, Department of Medicine, University of California, Los Angeles
    • 6Harold Simmons Center for Chronic Disease Research and Epidemiology, University of California Irvine School of Medicine, Orange
    JAMA Netw Open. 2020;3(2):e1920745. doi:10.1001/jamanetworkopen.2019.20745
    Key Points español 中文 (chinese)

    Question  To what extent are subclinical hypothyroidism or high-normal serum thyrotropin (TSH) concentrations associated with mortality through cardiovascular disease among US adults?

    Findings  In this cohort study of 9020 US adults, higher TSH levels were associated with increased risk of all-cause mortality. Cardiovascular disease mediated 14.3% and 5.9% of the association of subclinical hypothyroidism and high-normal TSH concentrations with all-cause mortality, respectively.

    Meaning  This study found that cardiovascular disease mediated the association between subclinical hypothyroidism and all-cause mortality, indicating that investigations are needed to examine the clinical benefit of medical intervention for people with elevated TSH concentrations.


    Importance  Subclinical hypothyroidism is a common clinical entity among US adults associated in some studies with an increase in the risk of cardiovascular disease (CVD) and mortality. However, the extent to which CVD mediates the association between elevated serum thyrotropin (TSH) and mortality has not yet been well established or sufficiently quantified.

    Objective  To elucidate the extent to which subclinical hypothyroidism, elevated serum TSH and normal serum free thyroxine, or high-normal TSH concentrations (ie, upper normative–range TSH concentrations) are associated with mortality through CVD among US adults.

    Design, Setting, and Participants  This cohort study relied on representative samples of US adults enrolled in the National Health and Nutrition Examination Survey in 2001 to 2002, 2007 to 2008, 2009 to 2010, and 2011 to 2012 and their mortality data through 2015. Data were analyzed from January to August 2019.

    Main Outcomes and Measures  Cox proportional hazards regression models were used to investigate associations between the TSH concentration category (subclinical hypothyroidism or tertiles of serum TSH concentrations within the reference range; low-normal TSH, 0.34-1.19 mIU/L; middle-normal TSH, 1.20-1.95 mIU/L; and high-normal TSH, 1.96-5.60 mIU/L) and all-cause mortality. Mediation analysis was used within the counterfactual framework to estimate natural direct associations (not through CVD) and indirect associations (through CVD).

    Results  Of 9020 participants, 4658 (51.6%) were men; the mean (SD) age was 49.4 (17.8) years. Throughout follow-up (median [interquartile range], 7.3 [5.4-8.3] years), serum thyroid function test results consistent with subclinical hypothyroidism and high-normal TSH concentrations were both associated with increased all-cause mortality (subclinical hypothyroidism: hazard ratio, 1.90; 95% CI, 1.14-3.19; high-normal TSH: hazard ratio, 1.36; 95% CI, 1.07-1.73) compared with the middle-normal TSH group. Cardiovascular disease mediated 14.3% and 5.9% of the associations of subclinical hypothyroidism and high-normal TSH with all-cause mortality, respectively, with the CVD mediation being most pronounced in women (7.5%-13.7% of the association) and participants aged 60 years and older (6.0%-14.8% of the association).

    Conclusions and Relevance  In this study, CVD mediated the associations of subclinical hypothyroidism and high-normal TSH concentrations with all-cause mortality in the US general population. Further studies are needed to examine the clinical benefit of thyroid hormone replacement therapy targeted to a middle-normal TSH concentration or active CVD screening for people with elevated TSH concentrations.