Prevalence of Subclinical Hypothyroidism among Patients with Acute Coronary Syndrome

Objectives: to detect prevalence of subclinical hypothyroidism (SCH) among acute coronary syndrome patients and to assess its association with both inhospital morbidity and mortality. Methods: The study included 300 patients admitted with the diagnosis of acute coronary syndrome (either STEMI or NSTEMI or UA) with close follow up during the inhospital stay to detect any morbidity or mortality. All subjects underwent complete lipid profile (TC-TG-LDL-C-HDL-C-VLDL-C) and thyroid profile (free T3-free T4-TSH). Results: SCH was associated with hypercholesterolemia (in 83.1% of patients), hypertriglyceridemia (in 80% of patients), increased LDL-C (in 83.3% of patients), decreased HDL-C (in 85.7% of patients) and increased VLDL-C (in 86.6% of patients). The prevalence of SCH among ACS patients was 5%. Morbidity was 34.6% in ACS patients with normal thyroid profile (euthyroid) vs. 20% in those with SCH (p value 0.7). Mortality was 2.5% in ACS patients with normal thyroid profile (euthyroid) vs. 0% in those with SCH (p value more than 0.05). Conclusion: Prevalence of SCH is 5% in ACS patients and it has no association with inhospital morbidity and mortality.


Introduction
Subclinical hypothyroidism, also referred to as mild thyroid failure, is diagnosed when serum free thyroid hormone levels are within the normal range, but thyroid stimulating hormone (TSH) is mildly elevated [1]. It is a common problem, occurring in 3% to 8% in the population without known thyroid disorders and carries a risk of development to overt hypothyroidism of 2-5% per year [2,3]. There is growing evidence that subclinical hypothyroidism is associated with increased risk of cardiovascular morbidities mainly due to dyslipidemia, particularly in older women [4,5]. It is known that overt hypothyroidism is associated with increased prevalence of coronary heart disease which is at least partly due to the lipid metabolism abnormalities leading to premature atherosclerosis [6,7]. The link between hypothyroidism and atherosclerosis can be explained by possible mechanisms other than dyslipidemia which include disturbances in coagulation system, homocysteine metabolism and parasympathetic function [4,8]. Coronary artery disease (CAD), its acute form, and acute coronary syndrome (ACS) are the major cause of death all over the world [9]. ACS is the umbrella term of clinical signs and symptoms of myocardial ischemia including unstable angina (UA), ST-segment elevation myocardial infarction (STEMI) and non-ST segment elevation myocardial infarction (NSTEMI) [10]. Several prospective, population-based cohort studies found that subclinical hypothyroidism was associated with increased risks of atherosclerotic coronary heart diseases and cardiovascular mortality, whereas other studies showed no correlation. Because of these conflicting reports and the large numbers of populations afflicted by this condition, there is an urgent need for settling the controversy.
Aim: The aim of the study is to detect the prevalence of subclinical hypothyroidism among patients with acute coronary syndrome and its association with both in-hospital morbidity and mortality.

Study design
This is a prospective, randomized study that involved 300 patients from the attendants of the cardiology department at Matarya Teaching hospital, admitted with the diagnosis of acute coronary syndrome, including ST-segment elevation Myocardial infarction (STEMI)/Non ST-segment elevation Myocardial infarction (NSTEMI)/Unstable Angina (UA) irrespective of age, gender, race and clinical severity, during the period from March 2015 to March 2016 and followed up during the inhospital stay.
Exclusion criteria: Patients were excluded from the study if they were using amiodarone, corticosteroids or received any iodinated contrast agent within the previous two weeks or those with diseases that are known to affect thyroid function tests, such as neoplasia, chronic renal failure, liver cirrhosis, active infection, chronic obstructive pulmonary disease requiring antibiotic therapy and diabetic ketoacidosis. Approval from institutional medical research committee was obtained and an informed consent from all patients was obtained.

Methods
The following data were collected: Complete and detailed medical history: With attention to the risk factors for developing CAD (smoking status, hypertension, diabetes mellitus, and family history of premature CAD in first degree relatives).
Full clinical examination: Including heart rate & rhythm, systolic & diastolic blood pressure and heart & chest auscultation. Electrocardiography: Resting standard 12 leads electrocardiogram was done for each patient to detect any findings consistent with CAD either ST elevation or ST depression or T wave inversion or pathological Q waves or new onset LBBB.
Echocardiography: Two-dimensional echocardiography and Doppler examination were performed for all patients in the left decubitus position during normal respiration using a GE Vivid 5 Ultrasound Machine (Echo Pac; GE Vingmed, Horten, Norway) to detect any wall motion abnormalities or ischemic complications.
Laboratory tests: Venous blood samples were obtained from all patients on arrival for serum cardiac markers (including cardiac troponin (cTn) and creatine kinase MB isoenzyme (CK-MB), liver and kidney functions , lipid profile (including Total cholesterol (TC),high density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein Cholesterol (LDL-C), very low density lipoprotein-Cholesterol (VLDL-C) and triglycerides (TG) and thyroid profile (including free T3,free T4 and TSH). We defined high serum levels as TC ≥ 200 mg/dl, LDL-C ≥130 mg/dl, VLDL-C ≥ 40 mg/dl and TG ≥ 150 mg/dl; a low serum level of HDL-C was defined as ≤ 40 mg/dl. FreeT3, FreeT4, TSH were measured using electrochemiluminescent method (cobas-e411-Roche). Measured hormones and their respective reference values were: free T3 (1.3-5 pg/ml), free T4 (0.8-2 ng/dl) and TSH (0.4-4 mIU/l). All the patients were followed up during the inhospital stay for any morbidity and mortality.

Statistical analysis
Data management and analysis were performed using SPSS program; version 17. The numerical data were statistically presented in terms of mean and standard deviation. Categorical data were summarized as percentages. Comparisons between numerical variables were done by unpaired Student's t-test. Comparing categorical variables were done by Chi-square test or Fisher exact test for small sample size. A probability value p<0.05 was considered statistically significant, a P value <0.001 was considered highly significant and P value >0.05 was considered non-significant.

Thyroid status and lipid profile abnormalities
This study showed that euthyroid status was the most prevalent among the whole study population (81%) while subclinical hypothyroidism represents only 5% (

Morbidity and mortality among patients in the study population
This study showed that the total morbidity among patients in the study population was 36% distributed as shown in (Table 4) taking in consideration that one patient may have more than one morbidity while the total mortality among patients in the study population was 4 % due to different causes as shown in (Table 5).

Subclinical hypothyroidism and its association with inhospital morbidity and mortality
This study showed that the prevalence of SCH among the whole study population was 5% (15 patients). According to age, prevalence of SCH was 5.6% in patients who are sixty or older vs. 4.7% in patients who are below age of sixty , and according to gender, prevalence of SCH was 4.5% in males vs.5.9% in females while according to the type of ACS, prevalence of SCH was 8.3% in patients presented by UA vs.
3.1% in those presented by MI and it was 2.8% in patients presented by ST elevation ACS vs. 6.2% in those presented by Non-ST elevation ACS (Table 6).
There is also no statistically significant difference between both morbidity and mortality in both patients who had normal thyroid profile (euthyroid) vs. who had subclinical hypothyroidism (P value for both morbidity and mortality was not significant). Morbidity was 34.6% in ACS patients with normal thyroid profile (euthyroid) vs. 20% in those SCH (P value 0.7). Mortality was 2.5% in ACS patients with normal thyroid profile (euthyroid) vs. 0% in those with SCH with nonsignificant P value (Table 7).

Discussion
Subclinical hypothyroidism is a common clinical problem, diagnosed mainly by laboratory methods. Screening is needed to detect SCH in most cases since most patients with this disorder are asymptomatic. It is recognized by abnormally high serum TSH value with normal FT4 and FT3 concentrations. Although it was recently reported that SCH is associated with elevated risks of cardiovascular events, cardiac dysfunction, lipid metabolism abnormalities and neuropsychiatric disorders, it is still debated whether long-term subclinical hypothyroidism is associated with systemic complications.
Regarding association between lipid profile and thyroid status, our study showed that in euthyroid status, the prevalence of hypercholesterolemia was 61.7%, hypertriglyceridemia was 83.1%, LDL-C level was increased in 40.7%, HDL-C level was decreased in 74.8% and VLDL-C was increased in 72% while in the subclinical hypothyroid status, Hypercholesterolemia occurred in 66.6%, hypertriglyceridemia occurred in 80%, LDL-C level was increased in 60%, HDL-C level was decreased in 73.3% and VLDL-C level was increased in 72%. Our results were consistent with Duntas and Wartofsky study in which SCH was associated with lipid profile abnormalities, especially increases in the concentrations of serum total and LDL cholesterol, but its effects on serum HDL-C and triglycerides concentrations were unclear [11,12]. It is also consistent with the results of Colorado study in which patients with SCH had higher serum total cholesterol concentrations than euthyroid individuals [13]. However, our results were disconcordant with NHANES III cohort study which showed higher total cholesterol and triglycerides concentrations in subclinical hypothyroid patients than in euthyroid subjects, but these changes were no longer observed after adjustment of different variables such as age, sex, race, and management with lipid lowering drugs [2]. The inconsistency between these studies may be due to the differences of the populations studied, including selection criteria based on sex, age, race, smoking history, and insulin resistance as well as variations in serum TSH concentrations used to define SCH.
Regarding prevalence of SCH, this study showed that the prevalence of SCH was 5% among the whole ACS patients (UA, STEMI, and NSTEMI). These results are supported by Cooper and Biondi study which showed that the prevalence of SCH in adults has been reported to range from 4% to 20%. This wide range can be explained explained by differences in age, gender, race, body mass index, and dietary iodine intake in the studied populations as well as differences in serum TSH evaluation methods [14]. Our results are also concordant with the results of the Colorado study in which the prevalence of SCH ranged from 4 to 21% in women and 3 to 16% in men [13]. However, our results are disconcordant with the results of Whickham Survey [15] and NHANES III [2] which showed higher prevalence of SCH in older population and obese individuals. In fact, in people who are in their 70 s-90 s, the 95 percentile for TSH may go as high as 6-9 mU/l [16]. Thus, an 80 year old woman with a serum TSH of 6.3 mU/l and a normal free T4 level may be a normal healthy individual, rather than a person with subclinical hypothyroidism. Higher serum TSH concentrations are also reported in overweight and obese subjects, which may result in a false diagnosis of subclinical hypothyroidism [17]. Mild increases in serum TSH concentration in obese individuals are usually associated with serum T3 values at the upper limit of the normal range. Therefore, the frequently cited high prevalence of SCH in the general population, especially in the elderly and obese needs to be re-examined in light of these new data.
Regarding prevalence of subclinical hypothyroidism according to age, gender and type of ACS at presentation, this study showed no statistically significant difference in the prevalence of SCH between both males and females. It was 4.5% in males' vs.5.9% in females. Also this study showed no statistically significant difference in the prevalence of subclinical hypothyroidism between persons (who are sixty or older) when compared to persons (who are below age of sixty).
higher in the female population [2] and Colorado study which showed that the percentage of women with elevated serum TSH concentration was higher than that of men in each decade of life, ranging from 4 to 21% in women and 3 to 16% in men [13] while in Ertugrul et al. study, prevalence of SCH was higher among men with AMI with more prominence of severe SCH among women with AMI [18]. This disconcordance can be explained by the high prevalence of elevated serum TSH in the elderly, with about 10% of individuals above the age of sixty having serum TSH levels above the reference range [19] and also by antithyroid peroxidase antibodies which were more prevalent in women than in men and in whites than in blacks leading to more prevalence of SCH in these groups [2]. This study showed no statistically significant difference in prevalence of SCH between patients presented by UA (8.3%) vs. those presented by myocardial infarction (MI) (3.1%) (P value 0.3). Up to our knowledge no previous study assessed the difference in the Prevalence of subclinical hypothyroidism between patients presented by UA vs. those presented by myocardial infarction (MI). This study also showed no statistically significant difference in prevalence of SCH between patients presented by ST elevation ACS (2.8%) vs. those presented by Non-ST elevation ACS (6.2%) (P value 0.6). Up to our knowledge no previous study assessed the difference in the prevalence of subclinical hypothyroidism between patients presented by ST elevation ACS vs. those presented by Non-ST elevation ACS.
Regarding association between SCH and in-Hospital morbidity and mortality in ACS patients, we have compared both morbidity and mortality in both patients who had normal thyroid profile (euthyroid) vs. who have subclinical hypothyroidism and we did not find a statistically significant difference between both (p value for both morbidity and mortality was not significant). Morbidity was 34.6% in ACS patients with normal thyroid profile (euthyroid) vs. 20% in those with SCH (p value 0.7). Mortality was 2.5% in ACS patients with normal thyroid profile (euthyroid) vs. 0% in those with SCH (p value not significant).
Our results were consistent with the results of the study conducted by Rodondi et al. in which SCH was not related to increase overall CHD events and cardiovascular mortality risk in elderly individuals [20]. It was also consistent with the results of Gussekloo study which showed that despite higher serum total cholesterol levels in individuals with subclinical hypothyroidism, they had lower cardiovascular events and mortality than euthyroid controls and it also showed decreased mortality in subclinical hypothyroid individuals older than 85 years which might be attributed to the associated lower metabolic rate [21]. However, our results were inconsistent with Razvi study which showed higher ischemic heart disease events and cardiovascular mortality rate only in subclinical hypothyroid patients younger than 65 years [22] and it was also inconsistent with the results of the study conducted by Ochs et al. which showed mild increased risk for CHD and mortality in subclinical hypothyroidism and hyperthyroidism [23]. This discrepancy can be explained by the elevated diastolic blood pressures and elevated serum total cholesterol levels in subclinical hypothyroid patients than in euthyroid controls [24] and that SCH is considered a potent risk factor for atherosclerosis and myocardial infarction in postmenopausal women [25].

Conclusion
Prevalence of SCH is 5% among patients with ACS. There is no association between SCH and inhospital morbidity and mortality in ACS patients. Longitudinal prospective study of larger groups of subclinical hypothyroid patients, after exclusion of other baseline confounding factors is needed.