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Review Subclinical Hypothyroidism Subclinical Hypothyroidism – What is Responsible for its Association with Cardiovascular Disease? Alexander Sorisky Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada S ubclinical hypothyroidism (SH) is a common condition, with prevalence estimates ranging from 4–20%, depending on the population demographics. Although epidemiological analysis associates it with an increased risk of cardiovascular disease, clinical practice guidelines express uncertainty about whether to monitor or to treat. As we await large-scale, well-designed randomised clinical trials regarding treatment of SH, a review of pathophysiological considerations may be informative to better understand this disorder. Keywords Subclinical hypothyroidism, cardiovascular disease, thyroid-stimulating hormone, inflammation, cholesterol, adipocytes, endothelial cells, vascular smooth muscle cells Disclosure: Alexander Sorisky has nothing to declare in relation to this article. No funding was received for the publication of this article. Acknowledgements: This work was funded by an operating grant from the Canadian Institutes of Health Research MOP-102585. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 19 April 2016 Accepted: 25 May 2016 Citation: European Endocrinology, 2016;12(2):96–8 Corresponding Author: Alexander Sorisky, Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. E: Subclinical hypothyroidism (SH), sometimes referred to as mild hypothyroidism, is a cumbersome term used to describe the compensatory increase in thyroid-stimulating hormone (TSH) levels to preserve normal thyroid hormone levels before they fall below normal, thus averting thyroid gland failure. An unresolved issue is whether SH merits treatment when diagnosed, or whether observation is acceptable to monitor for progression to overt hypothyroidism, as there is a lack of evidence from well-designed randomised clinical trials measuring clinical outcomes. 1 The objective of this review is to provide an overview of studies that have investigated the association of SH with an elevated cardiovascular disease (CVD) risk. Is there a link between subclinical hypothyroidism and cardiovascular disease risk? A series of longitudinal population studies have found that SH is associated with a higher risk of CVD, and this was confirmed in a large meta-analysis published in 2010. 2 The extent of the CVD risk was proportional to the degree of the TSH elevation. The effect was not related to traditional risk factors such as obesity, hypertension or dyslipidemia, and it was not related to the underlying autoimmune dysfunction that underlies the most common cause of SH, Hashimoto’s thyroiditis. 3 No effect of age was noted in this meta-analysis, 2 although an earlier population study suggested that the elderly may have reduced CVD risk with SH. 4 A higher risk of stroke, another major vascular disease, with SH was observed in subjects younger than 65 and those with higher TSH concentrations. 5 What mediates the higher cardiovascular disease risk of subclinical hypothyroidism? SH is a pro-inflammatory and pro-coagulant state. Elevations in interleukin (IL)-6 and C-reactive protein (CRP) have been detected in SH patients. 6,7 Metabolic effects include higher levels of free fatty acids (FFA), which can also lead to inflammatory cellular actions. 8 SH patients also display platelet hyper-reactivity. 9 Endothelium-dependent relaxation is also impaired in these patients, 6,7 and an altered pattern of endothelial-derived microparticles is associated with SH in patients with heart failure. 10 A recent meta-analysis addressed the controversy about whether lipid profiles are altered in SH, and found evidence of higher serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides. 11 In a small intervention study, thyroxine treatment of subjects with SH reduced the elevated levels of serum total cholesterol and LDL-C. 12 Are these alterations mediated by extra-thyroidal thyroid-stimulating hormone action? To explore whether TSH is capable of inducing such responses, investigators have studied thyroid cancer survivors who have been treated with thyroidectomy and radioiodine ablation of any remnant tissue, and who are on treatment with levothyroxine. Some of these patients undergo exogenous TSH administration to screen for early evidence of thyroid cancer recurrence by determining if stimulated thyroglobulin blood levels are high or not. For these few days, TSH levels 96 TOU C H ME D ICA L ME D IA