Kosuke Inoue1, Beate Ritz1,2, Gregory A Brent3,4, Ramin Ebrahimi5, Connie M Rhee6, Angela M Leung3,4. 1. Fielding School of Public Health, Department of Epidemiology, University of California, Los Angeles. 2. David Geffen School of Medicine, Department of Neurology, University of California, Los Angeles. 3. David Geffen School of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of California, Los Angeles. 4. VA Greater Los Angeles Healthcare System, Los Angeles, California. 5. David Geffen School of Medicine, Division of Cardiology, Department of Medicine, University of California, Los Angeles. 6. Harold Simmons Center for Chronic Disease Research and Epidemiology, University of California Irvine School of Medicine, Orange.
Abstract
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.
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.
Authors: Xiaodong Liu; Carlos K H Wong; Wendy W L Chan; Eric H M Tang; Yu Cho Woo; Shirley Y W Liu; Cindy L K Lam; Brian H H Lang Journal: BJS Open Date: 2022-07-07
Authors: Johannes Wolfgang Dietrich; Rudolf Hoermann; John E M Midgley; Friederike Bergen; Patrick Müller Journal: Front Endocrinol (Lausanne) Date: 2020-10-26 Impact factor: 5.555