Cardiovascular Risk in Patients with Subclinical Hypothyroidism

European Endocrinology, 2014;10(2):157–60 DOI: http://doi.org/10.17925/EE.2014.10.02.157

Abstract:

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: ledunt@otenet.gr

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.

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Keywords: Subclinical hypothyroidism, cardiovascular risk, thyroid-stimulating hormone, lipids, blood pressure, the metabolic syndrome