Cardiovascular Risk in Patients with Subclinical Hypothyroidism

European Endocrinology, 2014;10(2):157–60 DOI:


Subclinical hypothyroidism (SCH) has been associated with increased cardiovascular mortality due to adverse effects mainly on lipids and blood pressure (BP). There is evidence that SCH, especially in patients with thyroid-stimulating hormone (TSH) >10mU/l, may increase cardiovascular risk. Some uncertainty exists regarding the association of SCH with BP; however, that the coexistence of SCH with BP and hypercholesterolaemia has a negative cardiovascular impact is beyond doubt. Insulin resistance, by modulating various risk factors including coagulation, may potentially increase cardiovascular risk. Periodic health examinations including screening has been advised in patients >35 years of age, while treatment with thyroxine should be tailored to each patient.

Keywords: Subclinical hypothyroidism, cardiovascular risk, thyroid-stimulating hormone, lipids, blood pressure, the metabolic syndrome
Disclosure: Leonidas H Duntas and Luca Chiovato have no conflicts of interest to declare. No funding was received for the publication of this article.
Received: June 11, 2014 Accepted August 04, 2014
Correspondence: Leonidas H Duntas, Unit of Endocrinology, Metabolism and Diabetes, Evgenidion Hospital, University of Athens, 20 Papadiamantopoulou Street, 11520 Athens, Greece. E:

Hypothyroidism is usually a progressive disease that impacts the entirety of bodily functions. As the heart is the main target of thyroid hormone activity, hypothyroidism may precipitate or aggravate heart failure, influencing heart rate and blood pressure (BP) while increasing cardiovascular (CV) stiffness and also cardiomegaly.1,2 Overt hypothyroidism (OH) is therefore associated with heightened CV morbidity and mortality.3 Subclinical hypothyroidism (SCH) is defined as a condition characterised by elevated serum thyroid-stimulating hormone (TSH) concentrations (TSH: >4.5 mu/l), while circulating thyroxine (T4) and tri-iodothyronine (T3) levels remain within the population reference range.4 The incidence of SCH varies between 4 and 20 % depending upon the gender (females are more prone), age (older than 65) and population studied.5,6

The consequences of SCH are variable at several levels and may depend on the duration and the degree of elevation of serum TSH. Hence, a number of important questions arise relating to SCH, including whether it raises CV risk and therefore mortality, whether it negatively influences metabolic parameters and whether it should be treated with L-thyroxine.4,7

Besides the classic risk factors for CV disease (CVD), i.e. hypercholesterolaemia and diastolic hypertension, some newer risk factors such as a disrupted coagulability and insulin resistance have recently been evaluated.8 This review aims to update and discuss the available data regarding CV risk in patients with SCH.

Subclinical Hypothyroidism and Lipids
Clinical hypothyroidism has been associated with elevated levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (ApoB), all of which contribute substantially to heightened risk of coronary artery disease.9–11 Thyroid hormone controls the generation of cholesterol by regulating the activity of the 3-hydroxy- 3-methylglutaryl-coenzyme A (HMG-CoA) enzyme and its degradation rate by regulating the expression of the SREBP-2 gene, the transcription factor that positively regulates the activity of LDL receptor.12,13 Thus, thyroid hormone action on lipids mainly occurs through an increased expression of LDL receptors at the hepatic and peripheral levels and via an increased activity of the enzymes involved in the metabolism of lipoproteins and reverse cholesterol transport, such as hepatic lipase (HL), lipoprotein lipase (LPL), cholesterol ester transport protein (CETP) and lecithin–cholesterol acyltransferase LCAT.14,15 However, these effects are dependent on the efficiency of thyroid function and/ or the degree of thyroid dysfunction. Changes in HL activity seem to modify cholesterol metabolism in thyroid dysfunction, while the thyroid hormone influence on LPL would appear to be of importance mainly in the disruption of triglyceride (TG) metabolism.15

Several studies have reported increased lipid levels in SCH depending on the degree of hypothyroidism,16,17 though a TSH threshold has not as yet been established.18 In the 5th Tromsø study, a cross-sectional epidemiological, nested case-control study including 5,143 subjects, a significant and positive correlation between serum TSH levels and serum TC and LDL-C levels was registered in both genders.19 Accordingly, patients with newly diagnosed SCH exhibited a significant rise in TGs and LDL-C and low HDLcholesterol compared with the control group after adjustment for age and body mass index (BMI).20 Importantly, women with TSH levels higher than 10 mIU/l exhibited a significant increase in small dense LDL particles, which are associated with a higher atherogenic index,20 On the other hand, an association between free thyroxine (FT4) levels within the normal reference range and lipids, besides the association between SCH and hyperlipidaemia, has been demonstrated,21 while, in addition, low normal FT4 levels were significantly associated with increased insulin resistance, suggesting an increased CV risk in subjects with low normal thyroid function.

  1. Klein I, Ojamaa K. Thyroid hormone-targeting the heart, Endocrinology, 2001;142:11–2.
  2. Danzi S, Klein I, Thyroid disease and the cardiovascular system, Endocrinol Metab Clin North Am, 2014;43:517–28.
  3. McQuade C, Skugor M, Brennan DM, et al., Hypothyroidism and moderate subclinical hypothyroidism are associated with increased all-cause mortality independent of coronary heart disease risk factors: a PreCIS database study, Thyroid, 2011;21:837–43.
  4. Pearce SHS, Brabant G, Duntas LH, et al., 2013 ETA Guidelines: Management of Subclinical Hypothyroidism, Eur Thyroid J, 2013;2:215–28.
  5. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC, The Colorado thyroid disease prevalence study, Arch Intern Med, 2000;160:526–34.
  6. Vanderpump MP, Tunbridge WM, French JM, et al., The incidence of thyroid disorders in the community: a twentyyear follow-up of the Whickham Survey, Clin Endocrinol (Oxf), 1995;43:55–68.
  7. Biondi B, Cooper DS, The clinical significance of subclinical thyroid dysfunction, Endocr Rev, 2008;29:76–131.
  8. Cappola AR, Fried LP, Arnold AM, et al., Thyroid status, cardiovascular risk, and mortality in older adults, JAMA, 2006;295:1033–41.
  9. Althaus BU, Staub JJ, Ryff-De Lèche A, et al., LDL/HDL-changes in subclinical hypothyroidism: possible risk factors for coronary heart disease, Clin Endocrinol (Oxf), 1988;28:157–63.
  10. Walsh JP, Bremner AP, Bulsara MK, et al., Thyroid dysfunction and serum lipids: a community-based study, Clin Endocrinol (Oxf), 2005;63:670–5.
  11. Abrams JJ, Grundy SM, Cholesterol metabolism in hypothyroidism and hyperthyroidism in man, J Lipid Res, 1981;22:323–38.
  12. Chait A, Bierman EL, Albers J, Regulatory role of T3 in the degradation of LDL by cultured human skin fibroblast, J Clin Endocrinol Metab, 1979;48:887–9.
  13. Shin DJ, Osborne TF, Thyroid hormone regulation and cholesterol metabolism are connected through sterol regulatory element-binding protein-2 (SREBP-2), J Biol Chem, 2003;278:34114–8.
  14. Brenta G, Berg G, Zago V, et al., Proatherogenic mechanisms in subclinical hypothyroidism: hepatic lipase activity in relation to the VLDL remnant IDL, Thyroid, 2008;18:1233–6.
  15. Valdemarsson S, Hansson P, Hedner P, et al., Relations between thyroid function, hepatic and lipoprotein lipase activities, and plasma lipoprotein concentrations, Acta Endocrinol (Copenh), 1983;104:50–6.
  16. Bastenie PA, Bonnyns M, Vanhaelst I, Grades of subclinical hypothyroidism in asymptomatic autoimmune thyroiditis revealed by the thyrotropin-releasing hormone test, J Clin Endocrinol Metab, 1980;51:163–6.
  17. Staub JJ, Althaus BU, Engler H, et al., Spectrum of subclinical and overt hypothyroidism: effect on thyrotropin, prolactin, and thyroid reserve, and metabolic impact on peripheral target tissues, Am J Med, 1992;92:631–42.
  18. Duntas LH, Brenta G, The effect of thyroid disorders on lipid levels and metabolism, Med Clin North Am, 2012;96:269–81.
  19. Iqbal A, Jorde R, Figenschau Y, Serum lipid levels in relation to serum thyroid-stimulating hormone and the effect of thyroxine treatment on serum lipid levels in subjects with subclinical hypothyroidism: the Tromsø Study, J Intern Med, 2006;260:53–61.
  20. Hernández-Mijares A, Jover A, et al., Relation between lipoprotein subfractions and TSH levels in the cardiovascular risk among women with subclinical hypothyroidism, Clin Endocrinol (Oxf), 2013;78:777–82.
  21. Roos A, Bakker SJ, Links TP, et al., Thyroid function is associated with components of the metabolic syndrome in euthyroid subjects, J Clin Endocrinol Metab, 200;92:491–6.
  22. Fabbrini E, Magkos F, Patterson BW, et al., Subclinical hypothyroidism and hyperthyroidism have opposite effects on hepatic very-low-density lipoprotein-triglyceride kinetics, J Clin Endocrinol Metab, 2012;97:E414–8.
  23. Ito M, Kitanaka A, Arishima T, et al., Effect of L-thyroxine replacement on apolipoprotein B-48 in overt and subclinical hypothyroid patients, Endocr J, 2013;60:65–71.
  24. Meier C, Staub JJ, Roth CB, et al., TSH-controlled L-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: a double blind, placebocontrolled trial (Basel Thyroid Study), J Clin Endocrinol Metab, 2001;86:4860–6
  25. Psaty BM, Anderson M, Kronmal RA, et al., The association between lipid levels and the risks of incident myocardial infarction, stroke, and total mortality: the Cardiovascular Health Study, J Am Geriatr Soc, 52;1639–47
  26. Cooper DS, 2004 Thyroid disease in the oldest old: the exception to the rule, JAMA, 2004;292:2651–4
  27. Manuela C, Capalbo D, Wasniewska M, et al., Cardiovascular risk factors in children with long-standing untreated idiopathic subclinical hypothyroidism, J Clin Endocrinol Metab, 2014;99:2697–703.
  28. Duan Y, Peng W, Wang X, et al., Community-based study of the association of subclinical thyroid dysfunction with blood pressure, Endocrine, 2009;35:136–142.
  29. Walsh JP, Bremner AP, Bulsara MK, et al., Subclinical thyroid dysfunction and blood pressure: a community-based study, Clin Endocrinol (Oxf), 2006;65:486–91.
  30. Asvold BO, Bjøro T, Vatten LJ, Associations of TSH levels within the reference range with future blood pressure and lipid concentrations: 11-year follow-up of the HUNT study, Eur J Endocrinol, 2013;169:73–82.
  31. Cai YF, Shi JP, Meta analysis on the relationship between subclinical hypothyroidism and the levels of systolic blood pressure, Zhonghua Liu Xing Bing Xue Za Zhi, 2011;32:55–9.
  32. Owen PJ, Rajiv C, Vinereanu D, et al., Subclinical hypothyroidism, arterial stiffness, and myocardial reserve, J Clin Endocrinol Metab, 2006;91:2126–32.
  33. Biondi B, Klein I, Hypothyroidism as a risk factor for cardiovascular disease, Endocrine, 2004;24:1–13.
  34. Masaki M, Komamura K, Goda A, et al., Elevated arterial stiffness and diastolic dysfunction in subclinical hypothyroidism, Circ J, 2014;78:1494–500.
  35. Silva N, Santos OC, Morais FF, et al., Subclinical hypothyroidism represents an additional risk factor for coronary artery calcification, especially in subjects with intermediate and high cardiovascular risk score, Eur J Endocrinol, 2014;171:327–34.
  36. Pérez A, Cubero JM, Sucunza N, et al. Emerging cardiovascular risk factors in subclinical hypothyroidism: lack of change after restoration of euthyroidism, Metabolism, 2004;53:1512–5.
  37. Duntas LH, Biondi B, New insights into subclinical hypothyroidism and cardiovascular risk, Semin Thromb Hemost, 2011;37:27–34.
  38. Cantürk Z, Cetinarslan B, Tarkun I, et al., Hemostatic system as a risk factor for cardiovascular disease in women with subclinical hypothyroidism, Thyroid, 2003;13:971–7.
  39. Viswanathan G, Balasubramaniam K, Hardy R, et al., Blood thrombogenicity is independently associated with serum TSH levels in post non ST elevation acute coronary syndrome, J Clin Endocrinol Metab, 2014;99(6):E1050–4.
  40. Posadas-Romero C, Jorge-Galarza E, Posadas-Sánchez R, et al., Fatty liver largely explains associations of subclinical hypothyroidism with insulin resistance, metabolic syndrome, and subclinical coronary atherosclerosis, Eur J Endocrinol, 2014;171:319–25.
  41. Garin MC, Arnold AM, Lee JS, et al., Subclinical hypothyroidism, weight change, and body composition in the elderly: the Cardiovascular Health Study, J Clin Endocrinol Metab, 2014;99:1220–6.
  42. Iervasi G, Molinaro S, Landi P, et al., Association between increased mortality and mild thyroid dysfunction in cardiac patients, Arch Intern Med, 2007;167:1526–32.
  43. Ochs N, Auer R, Bauer DC, et al., Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality, Ann Intern Med, 2008;148:832–45.
  44. Walsh JP, Bremner AP, Bulsara MK, et al., Subclinical thyroid dysfunction as a risk factor for cardiovascular disease, Arch Intern Med, 2005;165:2467–72.
  45. Razvi S, Shakoor A, Vanderpump M, et al., The influence of age on the relationship between subclinical hypothyroidism and ischemic heart disease, J Clin Endocrinol Metab, 2008;93:2998–3007.
  46. Singh S, Duggal J, Molnar J, et al., Impact of subclinical thyroid disorders on coronary heart disease, cardiovascular and allcause mortality: a meta-analysis, Int J Cardiol, 2008;28:41–8.
  47. Cappola AR, Ladenson PW Hypothyroidism and Atherosclerosis, J Clin Endocrinol Metab, 2003;88:2438–44.
  48. Tseng FY, Lin WY, Lin CC, et al. Subclinical hypothyroidism is associated with increased risk for all-cause and cardiovascular mortality in adults, J Am Coll Cardiol, 2012;60:730–7.
  49. Zhang Y, Chang Y, Ryu S, et al., Thyroid hormones and mortality risk in euthyroid individuals: the Kangbuk Samsung Health Study, J Clin Endocrinol Metab, 2014;99:2467–76.
  50. Rodondi N, den Elzen WP, Bauer DC, et al., Thyroid Studies Collaboration. Subclinical hypothyroidism and the risk of coronary heart disease and mortality, JAMA, 2010;304:1365–74.
  51. Selmer C, Olesen JB, Hansen ML, et al., Subclinical and overt thyroid dysfunction and risk of all-cause mortality and cardiovascular events: A large population study, J Clin Endocrinol Metab, 2014;99:2372–82.
  52. Collet TH, Bauer DC, Cappola AR, et al., for the Thyroid Studies Collaboration. Thyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: An individual participant data analysis, J Clin Endocrinol Metab, 2014 [Epub ahead of print]
  53. Razvi S, Ingoe L, Keeka G, et al., The beneficial effect of L-thyroxine on cardiovascular risk factors, endothelial function, and quality of life in subclinical hypothyroidism: randomized, crossover trial, J Clin Endocrinol Metab, 2007;92:1715–23.
  54. Duntas LH, Wartofsky L, Cardiovascular risk and subclinical hypothyroidism: focus on lipids and new emerging risk factors. What is the evidence?, Thyroid, 2007;17:1075–84.
  55. Mariotti S, Cambuli VM, Cardiovascular risk in elderly hypothyroid patients, Thyroid, 2007;17:1067–73.
  56. Rotondi M, Leporati P, Rizza MI, et al., Raised serum TSH in morbid-obese and non-obese patients: effect on the circulating lipid profile, Endocrine, 2014:45:92–7.
  57. Palmieri EA, Fazio S, Lombardi G, Biondi B, Subclinical hypothyroidism and cardiovascular risk: a reason to treat? Treat Endocrinol, Eur J Endocrinol, 2004;3:233–4.
Keywords: Subclinical hypothyroidism, cardiovascular risk, thyroid-stimulating hormone, lipids, blood pressure, the metabolic syndrome