Is Subclinical Hypothyroidism a Risk Factor for Coronary Artery Disease?
Subgroup: Volume 3, Issue 2, Spring
Date: June 2005
Start Page: 63
End Page: 66
ubclinical hypothyroidism is defined as serum TSH levels above the upper limit of normal (4.0 or 5.0 mIU/L depending on the laboratory) despite normal serum free thyroxine.1,2 For diagnosis of subclinical hypothyroidism, other causes of elevated TSH, such as recovery from non-thyroidal illness, assay variability, heterophile antibodies, and certain cases of central hypothyroidism with biologically inactive TSH, should be excluded.2Subclinical hypothyroidism, or mild thyroid failure, is a very common problem, with a prevalence of 4–8.5% in the United States adult population, in patients without known thyroid disease.1-4 The prevalence increases with increasing age and is higher in the female population.1 Some studies, including our own, show that the prevalence in men approaches that of women, with a combined prevalence over 10%, after the sixth decade of life.5 In mild thyroid failure, 75% have TSH values less than 10 mIU/L.1Adverse effects of subclinical hypothyroidism are the subject of heated debate.6,7 Therapy of mild elevation of TSH and the
upper limit of normal for serum TSH are also controversial.6,9 Some scientific societies have suggested lowering the upper limit of normal serum TSH to 3 mIU/L.8 Some suggest therapy for all cases of mildly elevated TSH7 and some argue for selective therapy and individualization.10,11 The most important argument in favor of therapy is possibility of adverse cardiac effects and likelihood of increased cardiovascular end points associated with mild thyroid failure.12,13 If it is proven that elevated serum TSH has adverse cardiac effects, then therapy of all cases of subclinical hypothyroidism will make sense. Evidence for both association and for lack of association with cardiac events and cardiovascular mortality has been published.12,14 However, the published data are insufficient and the subject remain controversial.10Adverse effects of subclinical hypothyroidism on cardiovascular function have been extensively studied by Italian investigators.15 There is evidence for slowed left ventricular(LV) relaxation time, increased vascular tone at rest and LV systolic dysfunction with exercise. Some studies have shown improvement of cardiac contractibility and systolic time interval with thyroxine therapy.16 Although studies were not categorized for various levels of TSH, there is more evidence for
adverse effects for serum TSH levels above 10 mIU/L.10Does subclinical hypothyroidism increase the risk factors for cardiovascular disease? Overt hypothyroidism is a risk factor for coronary heart disease because of associated metabolic abnormalities. The atherogenic aspects of subclinical hypothyroidism are less clear. Possible atherogenic factors other than hyperlipidemia,16,17 such as increased homo-cysteine and lipoprotein (a) [Lp(a)] levels, have been suggested in mild thyroid failure.18-24 It is now clear that although homo-cysteine levels are elevated in overt hypothyroidism, they are not elevated in subclinical hypothyroid patients.25 Evidence for increased Lp(a) is also insufficient.20 Recent reports indicate elevated CRP (C-reactive protein) in mild thyroid failure, raising the possibility of association of an inflammatory process contributing to atherosclerosis.18,19,21
In the population-based Whickham cohort study, in a 20-year follow up, the mortality from cardiovascular causes was not higher in the group who had subclinical hypothyroidism at baseline, as compared with normal counterparts.14 In a study from United Kingdom, an association of abnormally low TSH with cardiovascular mortality in a 10-year follow up was noted, but there was no association with elevated serum TSH.26 However, in a recent case-control study from Rotterdam, Holland,12 subclinical hypothyroidism in women, with a mean age of 69 years, was associated with a greater age-adjusted prevalence of aortic atherosclerosis (odds ratio 1.7) and myocardial infarction (odds ratio 2.3). The difference persisted after adjustment for body mass index, systolic and diastolic blood pressure, tobacco abuse, and total cholesterol and high-density lipoprotein levels. Surprisingly, a more recent study in individuals aged over 80 showed increased survival benefit for mildly elevated TSH.27 This report raises the possibility that, at least in older individuals, normalization of TSH may not have survival benefits, and the opposite may be the case. Because of these conflicting reports and the large numbers of populations afflicted by this condition, there is an urgent need for settling the controversy. Carefully designed randomized trials are required since the results will impact management of millions of patients who have subclinical hypothyroidism.
In this issue of the International Journal of Endocrinology, Shams and colleagues supply new information on the subject28 The message of the Shams and colleague study is that elevated serum TSH level does not predict presence of CAD in patients undergoing coronary angiography. They measured serum TSH levels in 390 persons (239 men and 151 women) who were referred for coronary angiography. They found no correlation between TSH levels or subclinical hypothyroidism and presence or severity of angiographically demonstrated coronary artery disease. There were only 25 patients who had abnormally elevated serum TSH levels. Nine of 119 persons with normal coronaries and 16 of 271 patients with CAD had subclinical hypothyroidism. Although this is useful information, the authors correctly cite several limitations of their study. The number of patients with subclinical hypothyroidism was small. The study was confounded because of selection bias and the study subjects were all patients with possible coronary symptoms and did not represent a cross section of general population. Thus, the conclusion that subclinical hypothyroidism is not associated with coronary artery disease cannot be generalized from this small selected group of patients with subclinical hypothyroidism. Although the authors indicate that non-thyroidal illness did not play a role, it is likely that patients with CAD were sicker, and TSH levels might have been lower in that group. Furthermore, if the assumption of Parle and colleagues is correct that low levels of TSH below 0.5 mIU/L are associated with cardiovascular mortality,26 the data might have been confounded by lower levels of TSH in the CAD group. In other words, if both elevated and lower serum TSH levels are associated with CAD, then correlation of TSH level with coronary atherosclerosis may not be detected. The authors do not give data for abnormally low TSH in their study group. Studies of larger groups of subclinical hypothyroid patients after exclusion of other baseline confounding factors in a longitudinal, prospective study are needed.
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- Fatourechi V. Mild thyroid failure [subclinical hypothyroidism]: to treat or not to treat? Compr Ther. 2002 Summer;28(2):134-9.
- Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch Intern Med. 2000;160(4): 526-34.
- Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Me-tab. 2002;87(2):489-99.
- Fatourechi V, Lankarani M, Schryver PG, Vanness DJ, Long KH, Klee GG. Factors influencing clinical decisions to initiate thyroxine therapy for patients with mildly increased serum thyrotropin (5.1-10.0 mIU/L). Mayo Clin Proc. 2003;78(5):554-60.
- Chu JW, Crapo LM. The treatment of subclinical hypothyroidism is seldom necessary. J Clin Endocrinol Metab. 2001;86(10):4591-9.
- McDermott MT, Ridgway EC. Subclinical hypothyroidism is mild thyroid failure and should be treated. J Clin Endocrinol Metab. 2001;86(10):4585-90.
- American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocr Pract.8:(6):457-69, 2002.
- Fatourechi V, Klee GG, Grebe SK, Bahn RS, Brennan MD, Hay ID, et al. Effects of reducing the upper limit of normal TSH values. JAMA. 2003;290(24):3195-6.
- Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, et al. Subclinical thyroid disease: scientific review and guidelines for
- Fatourechi V. Subclinical hypothyroidism: how should it be managed? Treat Endocrinol. 2002;1(4):211-6.
- Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, Witteman JC. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intern Med. 2000;132(4):270-8.
- Kahaly GJ. Cardiovascular and atherogenic aspects of subclinical hypothyroidism. Thyroid. 2000;10(8):665-79.
- Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark F, et al. The development of ischemic heart disease in relation to autoimmune thyroid disease in a 20year follow-up study of an English community. Thyroid. 1996;6(3):155-60.
- Biondi B, Palmieri EA, Lombardi G, Fazio S. Effects of subclinical thyroid dysfunction on the heart. Ann Intern Med. 2002;137(11):90414.
- Danese MD, Ladenson PW, Meinert CL, Powe NR. Clinical review 115: effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: a quantitative review of the literature. J Clin Endocrinol Me-tab. 2000;85(9):2993-3001.
- Meier C, Staub JJ, Roth CB, Guglielmetti M, Kunz M, Miserez AR, et al. TSH-controlled L-thyroxine therapy reduces cholesterol levels and clinical symptoms in subclinical hypothyroidism: a double blind, placebo-controlled trial (Basel Thyroid Study). J Clin Endocrinol Metab. 2001;86(10):4860-6.
- Luboshitzky R, Herer P. Cardiovascular risk factors in middle-aged women with subclinical hypothyroidism. Neuro Endocrinol Lett. 2004;25(4):262-6.
- Jublanc C, Bruckert E. Hypothyroidism and cardiovascular disease: role of new risk factorsand coagulation parameters. Semin Vasc Med. 2004;4(2):145-51.
- Perez A, Cubero JM, Sucunza N, Ortega E, Arcelus R, Rodriguez-Espinosa J, et al. Emerging cardiovascular risk factors in subclinical hypothyroidism: lack of change after restoration of euthyroidism. Metabolism. 2004;53(11):1512-5.
- Tuzcu A, Bahceci M, Gokalp D, Tuzun Y, Gunes K. Subclinical hypothyroidism may be associated with elevated high-sensitive c-reactive protein (low grade inflammation) and fasting hyperinsulinemia. Endocr J. 2005; 52(1):89-94.
- Yildirimkaya M, Ozata M, Yilmaz K, Kilinc C, Gundogan MA, Kutluay T. Lipoprotein(a) concentration in subclinical hypothyroidism before and after levo-thyroxine therapy. Endocr J. 1996;43(6):731-6.
- Catargi B, Parrot-Roulaud F, Cochet C, Ducassou D, Roger P, Tabarin A. Homocysteine, hypothyroidism, and effect of thyroid hormone replacement. Thyroid. 1999;9(12):11636.
- Canturk Z, Cetinarslan B, Tarkun I, Canturk NZ, Ozden M, Duman C. Hemostatic system as a risk factor for cardiovascular disease in women with subclinical hypothyroidism. Thyroid. 2003;13(10):971-7.
- Deicher R, Vierhapper H. Homocysteine: a risk factor for cardiovascular disease in subclinical hypothyroidism? Thyroid. 2002;12(8): 733-6.
- Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10year cohort study. Lancet. 2001;358(9285): 861-5.
- Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frolich M, Westendorp RG. Thyroid status, disability and cognitive function, and survival in old age. JAMA. 2004;292(21): 2591-9.
- Shams M, Sharif-Kazemi MB, Lankarani KB, Sadegholvad AS and Omrani GR. Are Serum Thyrotropin Level and Subclinical Hypothyroidism Predisposing Factors for Coronary Artery Disease? IJEM. IJEnd Met. 2005;3(2):66 72.