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Risk for Ischemic Heart Disease and All-Cause Mortality in Subclinical Hypothyroidism

Departments of Clinical Studies (M.I., M.A., S.I., A.H., M.S., R.M.) and Statistics (E.N.), Radiation Effects Research Foundation, Nagasaki 850-0013, Japan; First Department of Internal Medicine, Graduate School of Biomedical Sciences (M.I., T.U., K.E.) and Department of Molecular Medicine, Atomic Bomb Disease Institute (K.A.), Nagasaki University, Nagasaki 852-8523, Japan; Nagasaki Saiseikai Hospital (N.Y.), Nagasaki 850-0003, Japan; and Japan Radioisotope Association (S.N.), Tokyo 113-8941, Japan

Address all correspondence and requests for reprints to: Misa Imaizumi, Radiation Effects Research Foundation, 1-8-6 Nakagawa, Nagasaki 850-0013, Japan. E-mail: misaima{at}rerf.or.jp.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
We investigated possible associations between subclinical hypothyroidism and atherosclerotic diseases (ischemic heart disease and cerebrovascular disease) and mortality. Of 2856 participants (mean age 58.5 yr) in a thyroid disease screening between 1984 and 1987, 257 subjects with subclinical hypothyroidism (TSH > 5.0 mU/liter) and 2293 control subjects (TSH range 0.6–5.0 mU/liter) were analyzed. In the baseline cross-sectional analysis, subclinical hypothyroidism was associated with ischemic heart disease independent of age, systolic blood pressure, body mass index, cholesterol, smoking, erythrocyte sedimentation rate, or presence of diabetes mellitus [odds ratio (OR), 2.5; 95% confidence interval (95% CI), 1.1–5.4 in total subjects and OR, 4.0; 95% CI, 1.4–11.5 in men] but not in women. However, there was no association with cerebrovascular disease (OR, 0.9; 95% CI, 0.4–2.4). We were unable to detect an influence of thyroid antibody presence on the association between subclinical hypothyroidism and ischemic heart disease. In a 10-yr follow-up study until 1998, increased mortalities from all causes in yr 3–6 after baseline measurement were apparent in men with subclinical hypothyroidism (hazard ratio, 1.9–2.1) but not in women, although specific causes of death were not determined. Our results indicate that subclinical hypothyroidism is associated with ischemic heart disease and might affect all-cause mortality in men.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
SUBCLINICAL HYPOTHYROIDISM IS defined by the presence of elevated TSH levels but normal free T₄ level, and is reasonably common. Its prevalence in the general population is 1–10% but approaches about 15% in women who are over 60 yr of age (1, 2, 3). Clinical manifestations of subclinical hypothyroidism include abnormal lipid metabolism (4, 5, 6), cardiac dysfunction (7, 8), and neurological and mental dysfunction (9), and several cross-sectional studies have suggested that it confers an elevated risk of atherosclerosis and coronary heart disease (10, 11, 12). However, neither of these associations has been confirmed by others (3, 13). This discrepancy may reflect the small size of the studies or participation in studies limited to one sex. Also, few longitudinal studies have been conducted. The relationship between subclinical hypothyroidism and cardiovascular disease is therefore controversial, and possible outcomes of the condition remain unclear. Importantly, several previous studies suggesting that thyroid autoimmunity is a risk factor for coronary heart disease (10, 14, 15) remain surrounded by controversy (13, 16).

The Nagasaki Laboratory of the Radiation Effects Research Foundation (RERF, formerly the Atomic Bomb Casualty Commission) has been conducting biennial health examinations of atomic bomb survivors in Nagasaki since 1958. Using this cohort, we examined the possible associations between subclinical hypothyroidism and atherosclerotic disease (either ischemic heart disease or cerebrovascular disease) in 2856 subjects of both sexes who agreed to participate in thyroid disease screening between 1984 and 1987 (17). We followed up the subjects until 1998 to screen for a possi-ble association between subclinical hypothyroidism and mortality.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects and definitions

A total of 7564 subjects (3374 men and 4190 women) have undergone biennial health examinations in Nagasaki since 1958 in the follow-up of atomic bomb survivors by RERF. A detailed description of this program has been published elsewhere (18) and in the Atomic Bomb Casualty Commission and Radiation Effects Research Foundation (Research Plan for RERF Research Protocol 2-75, 1975).

At the baseline period, between October 1984 and April 1987, 2856 people (1119 men, 1737 women, mean age 58.5 yr) agreed to participate in thyroid disease screening among 4693 people who were available for the health examinations at RERF (1863 men, 2830 women, mean age, 60.2 yr). Among the 2856 participants, those with a history of treatment with thyroid hormone or antithyroid medication (n = 73) were excluded from our study subjects. Subjects with TSH levels greater than 5.0 mU/liter and normal free T₄ levels [0.8–2.5 ng/dl (10.3–32.3 pmol/liter)] were defined as having subclinical hypothyroidism (n = 257). Subjects with TSH levels of 0.6–5.0 mU/liter and normal free T₄ levels were treated as controls (n = 2293). Our study therefore involved 2550 subjects. Among 257 subjects with subclinical hypothyroidism, 240 had TSH levels between 5 and 10 mU/liter and 17 had levels greater than 10 mU/liter.

Among the subjects with subclinical hypothyroidism, people who were treated with thyroid hormone after baseline measurement (n = 7) were excluded from the analysis of the 10-year follow-up study. The Dosimetry System 1986 (19) was used in estimating the radiation doses of individual subjects. Both the thyroid disease screening study and a mortality study were reviewed and approved by Research Protocol Committee and Human Investigation Committee in RERF.

Clinical examination and laboratory methods at the baseline study

Participants visited the RERF Nagasaki Laboratory for clinical examination between 1984 and 1987. A trained nurse recorded information on current and past health including thyroid disease, medication, and lifestyle. Current and past smokers were both categorized as smoker.

Body mass index (BMI) (in kilograms per square meter) was body weight divided by the square of standing height. Sitting blood pressure (in millimeters of mercury) was measured on the left arm after an adequate sedentary period. A standard 12-lead electrocardiogram was obtained by the regular procedure.

A fasting blood sample was drawn for a hematological test, biochemical test, thyroid function test including free T₄ and TSH levels, and thyroid autoantibody test. Commercial kits for RIA were used to measure TSH levels (Eiken RIA, Eiken Chemical Co. Ltd., Tokyo, Japan) (20) and free T₄ levels (Gammacoat RIA, Travenol Lab Inc., Tokyo, Japan). Serum thyroid antibodies (antithyroglobulin and antimicrosome antibodies) were measured by passive hemagglutination methods (FUJIREBIO, Inc., Tokyo, Japan). Subjects were described as positive for thyroid autoantibodies if tests proved positive for either antithyroglobulin antibody or antimicrosome antibody at a dilution in excess of 1:100. Thyroid function and thyroid antibodies were not measured after the baseline measurement during a follow-up period, although subjects had undergone biennial health examinations. Diabetes mellitus was reevaluated according to 1998 World Health Organization criteria (21).

Confirmation of ischemic heart disease and cerebrovascular disease at baseline

Diagnosis of ischemic heart disease (myocardial infarction and angina pectoris) and cerebrovascular disease (intracranial hemorrhage and cerebral infarction) at baseline period was based on self-report, electrocardiographic findings, and information provided by general practitioners. An experienced cardiologist reviewed the electrocardiographic findings of all participants. The presence of myocardial infarction was confirmed by the presence of one or more of the following conditions: typical electrocardiographic evidence of myocardial infarction, compared with previous electrocardiographic findings; chest pain with typical acute electrocardiographic changes; and elevation of myocardial enzymes. The presence of angina pectoris was confirmed by evidence from a positive result in an exercise electrocardiogram or diagnosis by a physician and medical treatment. Cerebrovascular disease was defined as rapid onset of a new neurological deficit in the absence of underlying potentially important nonvascular causes and lasting at least 24 h. Brain imaging and other diagnostic tests were used to determine the type of cerebrovascular disease in most patients. An expert panel of internists reviewed the diagnoses of ischemic heart disease and cerebrovascular disease while unaware of the subjects’ thyroid status.

Confirmation of end points for mortality study

RERF followed the vital status of all participants using Japan’s family registration system. We collected all death certificates of subjects who died between the start of the thyroid disease screening study and December 31, 1998. The primary cause of death was classified according to the International Classification of Diseases, ninth version (ICD9).

Statistical analysis

The Statistical Analysis System package for personal computers (SAS Institute, Cary, NC) was used for statistical analysis. Differences in baseline characteristics between controls and subjects with subclinical hypothyroidism were assessed by the ² and Wilcoxon rank sum tests. General linear-model procedures were used to compare the age-adjusted baseline characteristics. Multivariate logistic regression analysis was used to evaluate the association between subclinical hypothyroidism and ischemic heart disease or cerebrovascular disease, adjusting for sex, age, systolic blood pressure, BMI, total cholesterol, smoking status, erythrocyte sedimentation rate (ESR), and the presence of diabetes mellitus. Kaplan-Meier analysis was performed to assess survival rates. Cox proportional hazards regression was used to compare the mortality of subjects diagnosed as having subclinical hypothyroidism with controls, after adjustment for age, sex, and smoking status. Hazard ratios (HRs) with 95% confidence interval (CI) were used to estimate the adjusted relative risk of subjects with subclinical hypothyroidism. The relative risk for death from all causes and cause-specific death associated with subclinical hypothyroidism was calculated at 3, 4, 5, 6, and 10 yr after baseline measurement. Analyses conducted at 3, 4, 5, 6, and 10 yr after the baseline measurement included all events observed before the respective years. All significance tests were two sided and P < 0.05 was considered significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The prevalence of subclinical hypothyroidism among all participants in the thyroid disease screening study was 292 of 2856 or 10.2% overall, with 110 of 1119 (9.8%) in men and 182 of 1737 (10.5%) in women before subjects taking thyroid medication with increased or decreased free T₄ levels or decreased TSH levels had been excluded.

The baseline characteristics of controls and subjects with subclinical hypothyroidism are shown in Table 1. The sex ratios of controls and subjects with subclinical hypothyroidism did not differ (P = 0.53). Men and women with subclinical hypothyroidism were older than controls (P < 0.01). In thyroid function tests, as anticipated, TSH levels were significantly elevated in men and women with subclinical hypothyroidism. Free T₄ levels were significantly lower in women with subclinical hypothyroidism, although they were within normal range. The positive rates for thyroid autoantibodies were significantly higher in both men and women with subclinical hypothyroidism, although the positive rates were low (less than 20%) because the antibodies were detected by a hemagglutination method but not by a highly sensitive method such as RIA. After adjusting the clinical and laboratory data for age, individuals with subclinical hypothyroidism appeared to have higher ESR results (if male) or higher BMI results (if female). However, there were no consistent differences in systolic blood pressure, heart rate, total cholesterol level, white blood cell count, hemoglobin level, or presence of diabetes mellitus. Furthermore, no difference was observed in thyroid radiation dose between subjects with subclinical hypothyroidism and controls (Table 1), and radiation dose had no significant effect on the presence of subclinical hypothyroidism by logistic analysis (data not shown).

To investigate possible outcomes of subclinical hypothyroidism, we collected death information during an average follow-up of 12.2 yr after the baseline period. We compared the survival rates of subjects with subclinical hypothyroidism and those of controls using the Kaplan-Meier method (Fig. 1). Survival was lower in men with subclinical hypothyroidism, but no comparable difference was apparent in women. Mortality from all causes was significantly higher in men with subclinical hypothyroidism than in controls according to the analyses at 3, 4, 5, and 6 yr after baseline measurement (Table 3, HR 1.9–2.1). There were also significantly more deaths from nonneoplastic disease in men with subclinical hypothyroidism in the assessment 6 yr after baseline [Table 3, HR 2.2 (95% CI, 1.1–4.2)]. Table 4 shows the specific causes of death from nonneoplastic disease in men with subclinical hypothyroidism as recorded 6 yr after baseline and indicates that no significant cause of death was observed, although each HR increased and the HR of ischemic heart disease was suggestive [HR 4.8 (95% CI, 0.8–29.3)]. In the subset analysis of mild subclinical hypothyroidism (baseline TSH levels 10 mU/liter), HRs for all-cause mortality in men slightly decreased at all stages, but a significant increased risk was observed at 6 yr after baseline measurement (Table 3). The significant increases in mortality in men with subclinical hypothyroidism were no longer apparent when the assessment was made 10 yr after baseline measurement (Table 3). There was no evidence of increased mortality in women with subclinical hypothyroidism at any stage in the follow-up period (Table 3).

View larger version (16K): [in this window] [in a new window]   FIG. 1. Kaplan-Meier survival curves show that the survival rate was lower in men with subclinical hypothyroidism than in the controls, but no comparable difference was apparent in women. A, Men. B, Women.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Overt hypothyroidism, defined as low thyroid hormone levels accompanied by elevated TSH levels, is associated with cardiovascular disease, presumably because of hypercholesterolemia and hypertension (22, 23). However, direct evidence of an effect of overt hypothyroidism on cardiovascular disease is lacking (24). Subclinical hypothyroidism has been shown to be associated with cardiovascular disease in several case-control studies (10, 13), but the results are inconsistent (3, 10, 11, 12, 13). Interestingly, a Rotterdam cross-sectional study of elderly women indicated that subclinical hypothyroidism does appear to be associated with myocardial infarction, even after controlling for coronary risk factors (11). The results of our study are in broad agreement with the Rotterdam result, in that we are reporting an association between subclinical hypothyroidism and the prevalence of ischemic heart disease that is independent of coronary risk factors such as blood pressure, BMI, total cholesterol level, smoking status, ESR, and presence of diabetes mellitus. Furthermore, in a follow-up study, an increase in all-cause and nonneoplastic disease deaths was also apparent in men when assessed during the first 6 yr after baseline, although specific causes of death were not determined. We also found that mild subclinical hypothyroidism (baseline TSH levels 10 mU/liter) was associated with ischemic heart disease in a cross-sectional study and is accompanied by an increase in all-cause mortality in a longitudinal follow-up study at 6 yr after baseline measurement. This result indicated that untreated subclinical hypothyroidism, even mild subclinical hypothyroidism, might directly or indirectly affect fatal diseases. However, increased mortality that became apparent during the first 6 yr after baseline had disappeared by the 10-year mark (Table 3). This finding is not unexpected because the death rates from malignant diseases as well as atherosclerotic diseases caused by various risk factors increase with aging, irrespective of baseline TSH values. We thus cannot expect initial high TSH levels and elevated mortality to be so closely associated for such a long time period. Interestingly, the association between subclinical hypothyroidism and ischemic heart disease and the predictive value of subclinical hypothyroidism for mortality were both only apparent in men. This may be a reflection of the relative youth of our female study population and their not having reached the key end points in the lifetime of the study. The mean age of women at baseline in our study (58 yr) was much younger than in the Rotterdam study (69 yr) (11). On the other hand, cerebrovascular disease is also a major atherosclerotic disease, but there was no evidence of an association between cerebrovascular disease and subclinical hypothyroidism in the present study. Further study will be required for understanding the relationship between subclinical hypothyroidism and other atherosclerotic diseases.

There are several possible mechanisms that might explain the elevated risk of ischemic heart disease in subclinical hypothyroidism subjects. One involves the thyroid autoimmunity found in subclinical hypothyroidism together with the possibility that coronary vascular stenosis is induced by local inflammation from the pathological immune reactivity in autoimmune thyroid disease (10, 14, 15). However, this suggestion was not confirmed by our study or other studies (13, 16). We think our results weaken the hypothesis that organ-specific autoimmunity such as autoimmune thyroiditis is associated with coronary artery disease (10).

Our study and most cross-sectional studies have detected no significant differences in total serum cholesterol levels between subjects with subclinical hypothyroidism and euthyroid subjects (5, 6, 25, 26, 27). Lipoprotein (a), a putative contributing factor in the development of atherosclerosis, was suggested to be related to subclinical hypothyroidism (28, 29). Other studies, however, failed to provide confirmation (30, 31), and thus the relationship between abnormal lipid metabolism and ischemic heart disease in subclinical hypothyroidism remains controversial. A recent report also suggests that flow-mediated vasodilatation (a marker of endothelial function), which is considered an early sign of atherosclerosis, may be impaired in patients with subclinical hypothyroidism (8). Several studies have also demonstrated the presence of TSH receptor mRNA in coronary arteries, atria, and ventricles (32, 33). Elevated TSH may directly affect coronary arteries.

A limitation of our study is that the numbers of end point events were small, probably for two reasons. First, the power of the study may not be sufficient because this study was performed on people who were examined at RERF during the period of 1984 through 1987 and agreed to undergo thyroid examinations. Second, the age of subjects was relatively young to reach the key end points (mean age ± SD, 58.5 ± 10.2 yr). However, the significant association between subclinical hypothyroidism and ischemic heart disease in men was observed even after adjustment for all coronary risk factors, and we consider the association to be well grounded. Further studies using a larger number of subjects or more elderly subjects will be required to assess particular relationships between subclinical hypothyroidism and ischemic heart disease in women, cerebrovascular disease, and cause-specific mortality.

We have clearly demonstrated that subclinical hypothyroidism is associated with ischemic heart disease, especially evident in men in a cross-sectional study, and is accompanied by an increase in all-cause mortality in a longitudinal follow-up study. Our study indicates the importance of thyroid-status screening, especially in people who are close to reaching the age at which the incidence of ischemic heart disease is high. Optimal patient outcome for people with subclinical hypothyroidism, including mild subclinical hypothyroidism, in the future is highly likely to be dependent on careful follow-up. Further prospective studies are necessary to confirm the association between subclinical hypothyroidism and ischemic heart disease, other atherosclerotic diseases, and cause-specific mortality. Also, the validity of thyroid hormone replacement therapy in subclinical hypothyroidism is left for future studies.

	Acknowledgments

 
We thank Drs. Donald G. MacPhee and Richard Haber for reviewing the manuscript. We also thank Mrs. Kaoru Yoshida for general assistance.

	Footnotes

 
This work was supported by RERF Research Protocol 01-83. The RERF, Hiroshima and Nagasaki, Japan, is a private, nonprofit foundation funded by the Japanese Ministry of Health, Labor, and Welfare and the U.S. Department of Energy, with the latter funding provided through the National Academy of Sciences.

Abbreviations: BMI, Body mass index; CI, confidence interval; ESR, erythrocyte sedimentation rate; HR, hazard ratio; ICD9, International Classification of Diseases, ninth version; OR, odds ratio.

Received June 25, 2003.

Accepted March 29, 2004.

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