Impact of Subclinical Hypothyroidism on Cardiometabolic Biomarkers in Women

Paulo H. N. Harada; Julie E. Buring; Nancy R. Cook; Michael E. Cobble; Krishnaji R. Kulkarni; Samia Mora


J Endo Soc. 2017;1(2):113-123. 

In This Article

Abstract and Introduction


Context: Whether subclinical hypothyroidism (SCH) is associated with cardiometabolic abnormalities is uncertain.

Objective: To examine diverse cardiometabolic biomarkers across euthyroid, SCH, and overt hypothyroidism (HT) in women free of cardiovascular disease.

Design: Cross-sectional adjusted associations for lipids, lipoprotein subclasses, lipoprotein insulin resistance score, inflammatory, coagulation, and glycemic biomarkers by analysis of covariance for thyroid categories or thyroid stimulating hormone (TSH) quintiles on a Women's Health Study subcohort.

Setting: Outpatient.

Patients or Other Participants: Randomly sampled 3914 middle-aged and older women for thyroid function analysis (TSH, free T4), of whom 3321 were not on lipid-lowering therapy.

Intervention: None.

Main Outcome Measure: Associations of SCH and HT with cardiometabolic markers.

Results: Going from euthyroid to HT, the lipoprotein subclass profiles were indicative of insulin resistance (respective values and P for trend): larger very-low-density lipoprotein size (nm) (51.5 [95% confidence interval (CI), 51.2, 51.8] to 52.9 [51.8, 54.1], P = 0.001); higher low-density lipoprotein (LDL) particle concentration (nmol/L) [1283 (95% CI, 1267, 1299) to 1358 (1298, 1418), P = 0.004], and smaller LDL size. There was worsening lipoprotein insulin resistance score from euthyroid (49.2; 95% CI, 48.3, 50.2) to SCH (52.1; 95% CI, 50.1, 54.0) and HT (52.1; 95% CI, 48.6, 55.6); P for trend of 0.008. Of the other biomarkers, SCH and HT were associated with higher high-sensitivity C-reactive protein and hemoglobin A1c. For increasing TSH quintiles, results were overall similar.

Conclusions: In apparently healthy women, SCH cardiometabolic profiles indicated worsening insulin resistance and higher cardiovascular disease risk markers compared with euthyroid individuals, despite similar LDL and total cholesterol. These findings suggest that cardiometabolic risk may increase early in the progression toward SCH and overt HT.


Subclinical hypothyroidism (SCH) and overt hypothyroidism (HT) are common diseases, affecting, respectively, 9.0% and 0.4% of the United States population,[1] predominantly women. As thyroid function has multisystemic effects, its derangement could affect a broad range of cardiometabolic pathways potentially related to clinical manifestations. However, the definition of normal thyroid function has been intensely debated, with some experts advocating for lowering the upper limit of normal for thyroid stimulating hormone (TSH)[2] and others for maintaining the current standard.[3] In this regard, thyroid-related risk for incident type 2 diabetes (T2D) and cardiovascular disease (CVD) may impact the definition of TSH normality. In the one hand, HT has been associated with incident T2D;[4] on the other hand, findings are mixed for CVD, especially in the gray zone of SCH.[5–8]

The potential relationship of thyroid hypofunction with T2D and CVD may be mediated by abnormalities in lipids, lipoprotein subclasses, endothelial function, coagulation, inflammatory pathways, and insulin resistance.[9,10] To date, there have been inconsistent data regarding thyroid function across the spectrum of euthyroid to HT and its potential cardiometabolic mediators, both in direction and magnitude.[11–13] Detailed assessment of thyroid function effects on these mediators/markers may have high population health implications, especially along the milder hypofunction spectrum within euthyroidism and SCH. Understanding the role of thyroid function in cardiometabolic pathways may guide the clinically relevant definition of thyroid function and unveil potential targets for controlling related morbidity.

Therefore, in this study of apparently healthy middle-aged and older women, we examined thyroid function across the spectrum of euthyroid to HT in relationship to cardiometabolic pathways represented by lipids, lipoproteins, inflammation, coagulation, glycemic, and insulin resistance biomarkers.