Cardiovascular morbidity and mortality in thyroid dysfunction

This review summarizes present knowledge from clinical and epidemiological studies with respect to cardiovascular complications in thyroid disorders, focusing on cardiovascular morbidity and mortality. Consistently, good evidence exists for an increased cardiovascular morbidity in overt hyperthyroidism, and an association with predictors of cardiovascular mortality like ventricular hypertrophy, ventricular dysfunction, and atrial fibrillation. As for subclinical hyperthyroidism evidence is conclusive only with respect to an up to 5.2-fold elevated risk for atrial fibrillation. The cardiovascular risk profile of overt hypothyroidism is characterized mainly by risk factors of atherosclerosis such as hypercholesterolemia and hypertension, but also by possible development of heart failure. In contrast, data on such parameters are inconsistent for subclinical hypothyroidism. Although many of these cardiovascular alterations may hypothetically worsen prognosis, results from cohort and retrospective studies do not consistently point towards increased mortality. Only for overt hyperthyroidism an up to 1.7 fold elevated risk for cardiovascular diseases and up to 1.7 fold increased cardiovascular mortality rates have been demonstrated. However, the evidence for similarly increased cardiovascular morbidity and mortality rates in subclinical hyperthyroidism and hypothyroidism is inconclusive, and the evidence is non-existent for overt hypothyroidism. Further randomized clinical studies and population-based cohort-studies are required and should consider major cardiovascular risk factors and adverse cardiovascular events and mortality.     

Does Treating Subclinical Hypothyroidism Improve Markers of Cardiovascular Risk?

Subclinical hypothyroidism is defined as an elevated serum thyroid-stimulating hormone (TSH) level in the face of normal free thyroid hormone values. The overall prevalence of subclinical hypothyroidism is 4-10% in the general population and up to 20% in women aged >60 years. The potential benefits and risks of therapy for subclinical hypothyroidism have been debated for 2 decades, and a consensus is still lacking. Besides avoiding the progression to overt hypothyroidism, the decision to treat patients with subclinical hypothyroidism relies mainly on the risk of metabolic and cardiovascular alterations. Subclinical hypothyroidism causes changes in cardiovascular function similar to, but less marked than, those occurring in patients with overt hypothyroidism. Diastolic dysfunction both at rest and upon effort is the most consistent cardiac abnormality in patients with subclinical hypothyroidism, and also in those with slightly elevated TSH levels (>6 mIU/L). Moreover, mild thyroid failure may increase diastolic blood pressure as a result of increased systemic vascular resistance. Restoration of euthyroidism by levothyroxine replacement is generally able to improve all these abnormalities. Early clinical and autopsy studies had suggested an association between subclinical hypothyroidism and coronary heart disease, which has been subsequently confirmed by some, but not all, large cross-sectional and prospective studies. Altered coagulation parameters, elevated lipoprotein (a) levels, and low-grade chronic inflammation are regarded to coalesce with the hypercholesterolemia of untreated patients with subclinical hypothyroidism to enhance the ischemic cardiovascular risk. Although a consensus is still lacking, the strongest evidence for a beneficial effect of levothyroxine replacement on markers of cardiovascular risk is the substantial demonstration that restoration of euthyroidism can lower both total and low-density lipoprotein-cholesterol levels in most patients with subclinical hypothyroidism. However, the actual effectiveness of thyroid hormone substitution in reducing the risk of cardiovascular events remains to be elucidated. In conclusion, the multiplicity and the possible reversibility of subclinical hypothyroidism-associated cardiovascular abnormalities suggest that the decision to treat a patient should depend on the presence of risk factors, rather than on a TSH threshold. On the other hand, levothyroxine replacement therapy can always be discontinued if there is no apparent benefit. Levothyroxine replacement therapy is usually safe providing that excessive administration is avoided by monitoring serum TSH levels. However, the possibility that restoring euthyroidism may be harmful in the oldest of the elderly population of hypothyroid patients has been recently raised, and should be taken into account in making the decision to treat patients with subclinical hypothyroidism who are aged >85 years.     

Relationship of low-density lipoprotein (LDL) particle size to thyroid function status in Koreans

Objective  Dyslipidaemia is a well-known manifestation of thyroid dysfunction. Recently, small low-density lipoprotein (LDL) particle size has been linked with development of cardiovascular disease. To better understand the effects of thyroid dysfunction on the development of cardiovascular disease, we examined LDL particle size and lipid profiles in subjects with different thyroid function.
Methods  Included were 46 patients with overt hypothyroidism, 57 patients with subclinical hypothyroidism, 46 patients with overt hyperthyroidism, 51 patients with subclinical hyperthyroidism, and 110 age- and sex-matched healthy control subjects. We measured LDL particle size and lipid profiles in these subjects.
Results  No significant differences were found in LDL particle size between the groups with different thyroid function. Serum total cholesterol and LDL-cholesterol levels were significantly higher in the cases of hypothyroidism than in the cases of hyperthyroidism and the healthy control subjects. Serum triglyceride levels were higher in subjects with overt hypothyroidism than in those with overt hyperthyroidism or healthy control subjects.
Conclusions  LDL particle size, the emerging risk factor for atherosclerosis, did not appear to be significantly affected by the degree of thyroid dysfunction. Increased risk of atherosclerosis in hypothyroidism does not appear to be associated with LDL particle size, the non-traditional cardiovascular risk factor.     

A review of the evidence for and against increased mortality in hypothyroidism

The lifetime risk of overt hypothyroidism is around 5%, and this disease is usually preceded by subclinical hypothyroidism, which has an even higher prevalence (estimated to be up to 9%). Hypothyroidism has been linked with cardiac dysfunction, atherosclerosis, hypertension and coagulopathy. Intuitively, this increased morbidity is expected to shorten patients' lifespan, but definitive data are lacking on whether either of these hypothyroid states (particularly overt hypothyroidism) increase mortality. Study findings are inconsistent and, overall, the pooled data do not demonstrate increased mortality in patients with either subclinical or overt hypothyroidism. However, none of the available studies was adequately designed to answer this question. This Review discusses major shortcomings in those studies, such as population dissimilarities, hypothyroid state classification and misclassification, the inclusion of nonthyroidal illness, drug interference from concurrent therapies, serious comorbidities (for example, cardiovascular disease), differences in duration of follow-up and the number of levothyroxine-treated individuals. Taken together, the data exhibit little evidence of systematic bias and no strong scientific proof of increased mortality related to either subclinical or overt hypothyroidism. Future studies, however, should take the above-mentioned shortcomings and potential genetic confounding into consideration.     

亚临床甲状腺机能减退与2型糖尿病大血管病变的相关性研究

目的观察探讨亚临床甲状腺机能减退与2型糖尿病大血管病变的相关性研究。方法选取该院2015年12月—2016年11月收治的530例糖尿病患者进行回顾性资料分析,汇总高危因素对105例伴有亚临床甲状腺机能减退的糖尿病患者大血管病变特点进行总结分析。结果伴有亚临床甲状腺机能减退的糖尿病患者在心血管病变、动脉粥样硬化、周围神经病变、脑梗塞等方面与单纯组相比明显更多(P<0.05),在是否有高血压方面差异无统计学意义(P>0.05);伴有亚临床甲状腺机能减退的糖尿病患者在T4、TSH、HDL-C、LDL-C、TSH、总胆固醇、甘油三酯等方面与单纯组相比差异有统计学意义(P<0.05);危险因素回归分析后结果可知,亚临床甲状腺机能减退是影响糖尿病患者发生大血管病变的主要危险因素差异有统计学意义(P<0.05)。结论亚临床甲状腺机能减退是糖尿病患者发生大血管病变的独立危险因素。     

Cardiovascular effects of mild hypothyroidism.

The cardiovascular risk is increased in patients with overt hypothyroidism, and several potential cardiovascular risk factors were similarly reported in patients with subclinical hypothyroidism. Only recently have more data become available about the effects of mild hypothyroidism on the cardiovascular system. An impaired left ventricular diastolic function, which is characterized by slowed myocardial relaxation and impaired ventricular filling, is the most consistent cardiac abnormality in patients with mild thyroid hormone deficiency. Impaired left ventricular diastolic function on effort was also documented by radionuclide ventriculography. Studies performed by ultrasonic myocardial textural analysis suggest an altered myocardial composition in patients with mild hypothyroidism. Moreover, pulsed tissue Doppler analysis revealed that patients with mild hypothyroidism had changes in myocardial time intervals in several left ventricular segments. Finally, alterations in cardiac hemodynamic were documented by cardiac magnetic resonance imaging in presence of mild disease. Vascular function is impaired in patients with mild and subclinical hypothyroidism, as documented by the increase in systemic vascular resistance and arterial stiffness and by the impaired endothelial function. The negative effect induced by mild hypothyroidism on cardiovascular system can be reverted restoring euthyroidism with levothyroxine (L-T4) therapy. Based on the data available, it appears that L-T4 replacement should be considered in patients with mild hypothyroidism in presence of associated cardiovascular risk factors in the attempt to reverse these negative prognostic factors and improve the cardiovascular risk.     

Hypoglycemia-induced myocardial infarction: an unusual adverse effect of sulfonylureas

The diagnosis of subclinical hypothyroidism and detection of its effects on cardiovascular system is important. Also, the patients with subclinical hypothyroidism even at the very early stage are at increased risk for developing atherosclerosis. We evaluated coronary microvascular circulation and endothelial dysfunction of epicardial coronary arteries by the measurement of coronary flow velocity reserve via a non invasive technique, transthoracic Doppler echocardiography in subclinical hypothyroidism. Coronary flow reserve in patients with subclinical hypothyroidism such as in overt hypothyroidism was lower than that of euthyroid subject. As a conclusion, endothelial and microvascular dysfunction, which are early harbingers of atherosclerosis, are shown in overt and subclinical hypothyroidism.     

Postprandial lipemia as a risk factor for cardiovascular disease in patients with hypothyroidism

Postprandial lipoprotein metabolism is suggested to play a role in the pathogenesis of atherosclerosis. In this study, we investigated postprandial lipemia and its relationship to cardiovascular risk factors in patients with overt and subclinical hypothyroidism. Twentynine female patients with TSH levels greater than 5 μIU/mL and 12 euthyroid control female subjects were included in the study. Fifteen patients had subclinical hypothyroidism and 14 had overt hypothyroidism. All subjects underwent an oral lipid tolerance test. If triglyceride levels increased by 80% or more, subjects were considered postprandial lipemia positive. Control, overt hypothyroid, and subclinical hypothyroid groups were not statistically different with respect to anthropometric measurements, fasting blood C-reactive protein, uric acid, homocysteine, glucose, insulin, lipoprotein (a), apolipoprotein B levels, and homeostasis model assessment index. Fasting triglyceride levels correlated positively with TSH levels. Postprandial lipemia frequency was higher in overt hypothyroid subjects than in the control group. The subclinical hypothyroid group did not differ from the hypothyroid group with respect to postprandial lipemia frequency. In subjects with TSH levels higher than 5 μIU/mL, PPL risk was increased sevenfold. The results of this study show that postprandial triglyceride metabolism is affected in hypothyroidism.     

Homocysteine: a risk factor for cardiovascular disease in subclinical hypothyroidism?

The role of homocysteine as a causal risk factor for cardiovascular disease remains controversial. Moderately elevated total plasma homocysteine levels have been reported in patients with overt hypothyroidism, a condition that is associated with an increased risk for cardiovascular disease. Recently, subclinical hypothyroidism has been identified as an independent risk factor for atherosclerosis and myocardial infarction in elderly women. Therefore, we measured prospectively total fasting plasma homocysteine levels in 37 consecutive subjects (6 males, 31 females, mean age 50 +/- 18 standard deviation [SD] years) with newly diagnosed subclinical hypothyroidism at baseline and after 3-4 months of levothyroxine supplementation. During levothyroxine treatment concentrations of thyrotropin (TSH) decreased from 10.1 +/- 5.8 (SD) to 1.5 +/- 1.8 mU/L. Fasting total plasma homocysteine levels were not elevated at baseline (9.9 +/- 2.9 micromol/L) and remained unchanged (9.6 +/- 3.5 micromol/L) after levothyroxine treatment. Serum folate or vitamin B(12) levels also remained unchanged. We conclude that subclinical hypothyroidism is not associated with hyperhomocysteinemia. Levothyroxine supplementation has no influence on total plasma homocysteine levels in subclinical hypothyroidism. Hence, total plasma homocysteine does not appear to contribute to the increased risk for atherosclerotic disease and myocardial infarction in patients with subclinical hypothyroidism.     

Subclinical hypothyroidism is associated with a low-grade inflammation, increased triglyceride levels and predicts cardiovascular disease in males below 50 years

OBJECTIVE: Mild thyroid failure is associated with an increased risk for development of atherosclerosis, but whether subclinical hypothyroidism is related to risk for cardiovascular disease is controversial. The purpose of the present study was to examine a possible association between subclinical hypothyroidism and cardiovascular disease. DESIGN: Cross-sectional study of a general population. PATIENTS: Twelve hundred and twelve subjects, men and women, between 20 and 69 years old without thyroid disease not treated with drugs interfering with thyroid function or analysis of TSH were included. MEASUREMENTS: Clinical signs of cardiovascular disease based on a questionnaire and medical records and laboratory analysis of lipids, atherothrombotic risk markers, C-reactive protein and TSH. RESULTS: The main findings were a high incidence of subclinical hypothyroidism (19.7%) in a general population. Subclinical hypothyroidism was associated with higher concentrations of triglycerides and C-reactive protein. Below 50 years of age cardiovascular disease was more frequent in males with subclinical hypothyroidism compared to euthyroid males. Subclinical hypothyroidism was a predictor of cardiovascular disease in males below 50 years with an odds ratio of 3.4 (95% confidence interval 1.6-6.8) for developing cardiovascular disease compared to euthyroid age-matched males. CONCLUSION: Our study demonstrates that patients with subclinical hypothyroidism have increased levels of triglycerides and signs of low-grade inflammation (raised C-reactive protein levels) and that subclinical hypothyroidism might be a risk factor for development of cardiovascular disease in younger males.     

Is subclinical hypothyroidism a cardiovascular risk factor?

OBJECTIVES: Subclinical hypothyroidism defined by the presence of elevated TSH levels but normal free T4 level is a common situation. Its consequences on health are yet on debate and the interest of a precocious treatment remains surrounded by controversy. KEY POINTS: The relationship between subclinical hypothyroidism and cardiovascular disease has been evaluated by several cross-sectional and longitudinal studies. Subclinical hypothyroidism has direct but subtle effects on the heart function, on the peripheral vascular resistance, and is associated with a mild elevation of LDL-cholesterol levels; all abnormalities may be partly reversed by a thyroxine supplementation. Data of the literature give insufficient evidence as to whether subclinical hypothyroidism is an independent cardiovascular risk factor. However treatment of subjects with TSH levels up or near to 10 mU/l would probably be beneficial in the prevention of cardiovascular disease. FUTURE PROSPECTS: Based on observational and interventional studies there are some arguments on the benefit of euthyroidism restoration only in patients with TSH levels superior to 10 mU/l.     

Hypothyroidism as a risk factor for cardiovascular disease

The cardiovascular risk in patients with hypothyroidism is related to an increased risk of functional cardiovascular abnormalities and to an increased risk of atherosclerosis. The pattern of cardiovascular abnormalities is similar in subclinical and overt hypothyroidism, suggesting that a lesser degree of thyroid hormone deficiency may also affect the cardiovascular system. Hypothyroid patients, even those with subclinical hypothyroidism, have impaired endothelial function, normal/depressed systolic function, left ventricular diastolic dysfunction at rest, and systolic and diastolic dysfunction on effort, which may result in poor physical exercise capacity. There is also a tendency to increase diastolic blood pressure as a result of increased systemic vascular resistance. All these abnormalities regress with L-T₄ replacement therapy. An increased risk for atherosclerosis is supported by autopsy and epidemiological studies in patients with thyroid hormone deficiency. The “traditional” risk factors are hypertension in conjunction with an atherogenic lipid profile; the latter is more often observed in patients with TSH>10 mU/L. More recently, C-reactive protein, homocysteine, increased arterial stiffness, endothelial dysfunction, and altered coagulation parameters have been recognized as risk factors for atherosclerosis in patients with thyroid hormone deficiency. This constellation of reversible cardiovascular abnormalities in patient with TSH levels<10 mU/L indicate that the benefits of treatment of mild thyroid failure with appropriate doses of l-thyroxine outweigh the risk.     

An Association Between Varying Degrees of Hypothyroidism and Hypercholesterolemia in Women: The Thyroid-Cholesterol Connection

Evidence of an association between subclinical hypothyroidism and cardiovascular disease is mounting. The impact of thyroid hormone on lipid levels is primarily mediated through triiodothyronine (T₃)-bound thyroid protein binding and activation of the promoter regions of the low-density lipoprotein receptor and 3-hydroxy-3-methylglutaryl coenzyme A-reductase genes, leading to a reduction in serum cholesterol levels. Thus, the decreased T₃ seen in hypothyroidism may result in increased serum cholesterol. Although a clear correlation exists between overt hypothyroidism and clinically significant hypercholesterolemia, there is a logarithmic relationship between thyroid-stimulating hormone and cholesterol, and the effects of subclinical hypothyroidism on cardiovascular disease are under debate. However, current data suggest that normalizing even modest thyroid-stimulating hormone elevations may result in improvement in the lipid profile.     

Subclinical hypothyroidism and cardiovascular risk: recommendations for treatment

The definition of subclinical hypothyroidism (SCH) is solely biochemical: a serum free T4 level within the reference range in the presence of an elevated serum thyroid-stimulating hormone (TSH) level. While overt hypothyroidism is associated with an increased cardiovascular disease risk, SCH, the mildest form of hypothyroidism, may also be associated with an increased cardiovascular disease risk, but to a lesser degree. Recent evidence points to a significant trend toward an increase in cardiovascular risk at higher TSH levels, with TSH levels ≥10 mIU/L associated with increased cardiovascular morbidity and mortality. It is generally recommended to treat with thyroid hormone those individuals with SCH and TSH values ≥10 mIU/L. Treatment of patients with SCH and TSH values <10 is controversial but may be considered in selected patients.     

Thyroid and the Heart

Thyroid hormones modulate every component of the cardiovascular system necessary for normal cardiovascular development and function. When cardiovascular disease is present, thyroid function tests are characteristically indicated to determine if overt thyroid disorders or even subclinical dysfunction exists. As hypothyroidism, hypertension, and cardiovascular disease all increase with advancing age, monitoring of thyroid-stimulating hormone, the most sensitive test for hypothyroidism, is important in this expanding segment of our population. A better understanding of the impact of thyroid hormonal status on cardiovascular physiology will enable health care providers to make decisions about thyroid hormone evaluation and therapy in concert with evaluating and treating hypertension and cardiovascular disease. The goal of this review is to access contemporary understanding of the effects of thyroid hormones on normal cardiovascular function and the potential role of overt and subclinical hypothyroidism and hyperthyroidism in a variety of cardiovascular diseases.     

亚临床甲状腺功能异常与心血管疾病的关系

临床研究显示,亚临床甲状腺功能异常与心血管疾病之间存在密切的关系.亚临床甲状腺功能减退通常伴有血脂异常、高凝状态、纤维蛋白溶解活性减低等心血管疾病危险因素,其与动脉粥样硬化、冠心病和心血管死亡的风险显著相关.另一方面,亚临床甲状腺功能亢进与心房颤动发生风险显著相关,但与心血管死亡风险的相关性尚不清楚.对于亚临床甲状腺功能异常进行治疗是否能够带来心血管获益,目前尚无确切结论.     

亚临床甲状腺功能异常与心血管疾病的关系

临床研究显示,亚临床甲状腺功能异常与心血管疾病之间存在密切的关系.亚临床甲状腺功能减退通常伴有血脂异常、高凝状态、纤维蛋白溶解活性减低等心血管疾病危险因素,其与动脉粥样硬化、冠心病和心血管死亡的风险显著相关.另一方面,亚临床甲状腺功能亢进与心房颤动发生风险显著相关,但与心血管死亡风险的相关性尚不清楚.对于亚临床甲状腺功能异常进行治疗是否能够带来心血管获益,目前尚无确切结论.     

开展亚临床甲状腺功能减退症的临床研究

亚临床甲状腺功能减退症 (甲减 )是一种常见的内分泌专业亚临床疾病 ,主要诊断依据是血清TSH水平增高 ,而血清FT4正常。亚临床甲减的主要不良后果是发展为临床甲减和促进缺血性心脏病的发生。影响亚临床甲减发展为临床甲减的主要因素有两个 :血清TSH水平和甲状腺自身抗体 ,两个因素有叠加作用。甲状腺激素替代治疗对于阻止亚临床甲减发展为临床甲减的效果尚不确切 ;亚临床甲减与高胆固醇血症、高血压、吸烟和糖尿病一样 ,构成动脉粥样硬化和心肌梗塞的独立危险因素 ,其对此两病的危险度分别为 1.9和 3 .1。甲状腺素纠正亚临床甲减对降低血清胆固醇有一定效果 ;妊娠妇女的亚临床甲减对后代的智力影响已经引起高度关注。我国一组根据对流行病学调查的结果 ,提出了血清TSH、甲状腺自身抗体 (TPOAb、TgAb)的正常值范围 ,以及与疾病相关的甲状腺自身抗体的切割点值 ,可供参考。     

亚临床甲状腺功能异常与心血管疾病的关系

临床研究显示,亚临床甲状腺功能异常与心血管疾病之间存在密切的关系.亚临床甲状腺功能减退通常伴有血脂异常、高凝状态、纤维蛋白溶解活性减低等心血管疾病危险因素,其与动脉粥样硬化、冠心病和心血管死亡的风险显著相关.另一方面,亚临床甲状腺功能亢进与心房颤动发生风险显著相关,但与心血管死亡风险的相关性尚不清楚.对于亚临床甲状腺功能异常进行治疗是否能够带来心血管获益,目前尚无确切结论.     

Subclinical hypothyroidism is a risk factor for nephropathy and cardiovascular diseases in Type 2 diabetic patients.

AIMS: The purpose of this study was to determine the relationship between subclinical hypothyroidism and prevalence of retinopathy and nephropathy, incident cardiovascular disease, and mortality in Type 2 diabetic patients without taking thyroid medication. METHODS: Serum thyrotropin and free thyroxine concentrations were measured in 588 Type 2 diabetic subjects in Taipei Veterans General Hospital, Taiwan. In a cross-sectional study, we examined the prevalence of retinopathy and nephropathy. In a longitudinal study, we examined the risk of cardiovascular disease events, cardiovascular mortality and total mortality in the 4-year follow-up. RESULTS: In the cross-sectional analysis, subclinical hypothyroidism was associated with a greater prevalence of diabetic nephropathy (odds ratio, 3.15 [95% CI, 1.48-6.69]) and did not show a high prevalence of diabetic retinopathy (odds ratio, 1.15 [95% CI, 0.59-2.26]) compare to euthyroid diabetics. During the 44.0 +/- 7.4 months of follow-up, 51 participants had cardiovascular events. The risk of cardiovascular events was significantly increased in Type 2 diabetics with subclinical hypothyroidism after adjustment for age, sex, A1C, other standard cardiovascular risk factors and medication (hazard ratio, 2.93; 95% CI, 1.15-7.48; P = 0.024), but it became nonsignificant after additional adjustment for urinary albumin-to-creatinine ratio (hazard ratio, 2.06; 95% CI, 0.67-6.36; P = 0.211). The rates of cardiovascular-related and total mortality did not significantly differ by thyroid status. CONCLUSIONS: Type 2 diabetic patients with subclinical hypothyroidism are associated with an increased risk of nephropathy and cardiovascular events, but not with retinopathy. Our data suggest that the higher cardiovascular events in subclinical hypothyroidism with Type 2 diabetes may be mediated with nephropathy.