Subclinical Hypothyroidism and Cardiovascular Risk: How to End the Controversy

Abstract

T he indications for screening and TSH threshold levels for treatment of subclinical hypothyroidism have remained a clinical controversy for over 20 years. Subclinical thyroid dysfunction is a common finding in the growing population of older adults, occurring in 10 -15% among those age 65 and older, and may contribute to multiple common problems of older age, including cardiovascular disease, muscular impairment, mood problems, and cognitive dysfunction (1). In 2004, both the U.S. Preventive Services Task Force (2) and a clinical consensus group of experts (3) concluded that the existing evidence about the association between subclinical hypothyroidism and cardiovascular risks, primarily cross-sectional or case-control studies (4), was insufficient. For example, a frequently cited analysis from the Rotterdam study found a cross-sectional association between subclinical hypothyroidism and atherosclerosis, as measured by abdominal aortic calcification (odds ratio, 1.7; 95% confidence interval [CI], 1.1-2.6) and prevalent myocardial infarction (MI) (odds ratio, 2.3; 95% CI, 1.3-4.0) (5). Conversely, the prospective part of this study included only 16 incident MIs; the hazard ratio (HR) for subclinical hypothyroidism was 2.50, with broad 95% CIs (0.70 -9.10). Potential mechanisms for the associations with cardiovascular diseases among adults with subclinical hypothyroidism include elevated cholesterol levels, inflammatory markers, raised homocysteine, increased oxidative stress, insulin resistance, increased systemic vascular resistance, arterial stiffness, altered endothelial function, and activation of thrombosis and hypercoagulability that have all been reported to be associated with subclinical hypothyroidism (1, 6).Since 2004, several large prospective cohorts investigated this issue, leading to conflicting data on the associations between subclinical hypothyroidism and cardiovascular risk (7-9). Study-level meta-analyses tried to clarify these conflicting data (9, 10), and found modestly increased risks for coronary heart disease (CHD) and CHD mortality, but with heterogeneity among individual studies that used different TSH cutoffs, different confounding factors for adjustment, and varying CHD definitions (9). To help clarify this issue, we formed the Thyroid Studies Collaboration, which successfully collected individual participant data from 55 287 participants with 542 494 person-years of follow-up from 11 international prospective cohorts. In a series of individual participant data analyses, generally considered the highest level of nonrandomized evidence (11), we found that subclinical hypothyroidism was associated with an increased risk of CHD events and CHD mortality in adults with higher TSH levels (12) and with an increased risk of heart failure events (13), particularly when TSH exceeds 10 mU/L.A particular shortcoming of the available evidence to date is the lack of randomized clinical trials on relevant clinical outcomes (2, 3). Small, short-term trials among individuals with subclinical hypothyroi...

Effects of thyroid hormones on the heart

“…Conversely, minimal TSH elevations are not associated with an increased risk of CHD events and CHD mortality. 55,56 Moreover, SHyper in age and sex-adjusted analyses was associated with increased total mortality, CHD mortality, CHD events and AF. Risks did not differ significantly by age, sex, or preexisting cardiovascular disease, and were similar after further adjustment for cardiovascular risk factors, with an attributable risk of 14.5% for total mortality and 41.5% for AF.…”

Role of Thyroid Hormones in Different Aspects of Cardiovascular System

“…The risk of both CHD mortality and CHD events, but not of total mortality, increases with higher concentrations of TSH, and is significantly elevated in adults with TSH levels of 10 μIU/mL or greater [55,56].…”

Lipids and Ischemia Modified Albumin in Mild Subclinical Hypothyroidism: Response to Levothyroxine Replacement

“…SCH is a well-established clinical entity with biochemical evidence of cardiovascular risk similar to that of overt hypothyroidism in relation to atherogenic lipids and oxidative stress (OXs) markers when thyroid-stimulating hormone (TSH) levels are >10 µIU/ml [4][5][6].…”