Association of Subclinical Hypothyroidism and Cardiovascular Disease With Mortality

Kosuke Inoue,Beate Ritz,Angela M Leung,Gregory A Brent,Ramin Ebrahimi,Connie M Rhee

doi:10.1001/jamanetworkopen.2019.20745

Abstract

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. 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. 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. 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). 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). 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.

Highlights

Subclinical hypothyroidism, or elevated thyrotropin (TSH) levels with normal levels of free thyroxine (FT4), is a common disorder affecting approximately 10% of the adult population.[1]
Throughout follow-up, serum thyroid function test results consistent with subclinical hypothyroidism and high-normal thyrotropin. SI conversion factor (TSH) concentrations were both associated with increased all-cause mortality compared with the middle-normal TSH group
Further studies are needed to examine the clinical benefit of thyroid hormone replacement therapy targeted to a middle-normal TSH concentration or active cardiovascular disease (CVD) screening for people with elevated TSH concentrations

Summary

Introduction

Subclinical hypothyroidism, or elevated thyrotropin (TSH) levels with normal levels of free thyroxine (FT4), is a common disorder affecting approximately 10% of the adult population.[1]. Inadequate serum thyroid hormone produces impairment of cardiac function and may result in bradycardia, endothelial dysfunction, increased intima-media thickness, diastolic dysfunction, increased vascular resistance, and pericardial effusion.[3] Other epidemiological studies[4,5,6,7] have found an association between subclinical hypothyroidism or high-normal TSH concentrations (ie, serum TSH concentrations at the upper end of the normal range) and dyslipidemia, increased insulin resistance, and hypertension—components of metabolic syndrome Despite these mechanisms and evidence about the potential burden of elevated TSH on cardiac metabolism, the potentially causal link between subclinical hypothyroidism, cardiovascular disease (CVD), and death remains unclear. Recent individual patient meta-analysis by the Thyroid Studies Collaboration[8,9,10,11] did not find higher risk of CVD and all-cause mortality among adults with subclinical hypothyroidism compared with those with euthyroidism, which is supported by current clinical guidelines proposing that thyroid hormone replacement therapy should not be routinely offered for adults with subclinical hypothyroidism.[12,13,14] some recent studies[5,15,16] have suggested that even high-normal TSH concentrations are associated with increased risk of CVD and mortality among the US general population or adults with chronic kidney disease, indicating the importance of considering variations in the normative range of TSH when assessing long-term adverse health outcomes

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