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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 5 2145-2149
Copyright © 2004 by The Endocrine Society

Thyroid Function and Carotid Wall Thickness

Henry Völzke, Daniel M. Robinson, Ulf Schminke, Jan Lüdemann, Rainer Rettig, Stephan B. Felix, Christof Kessler, Ulrich John and Wieland Meng

Institute of Epidemiology and Social Medicine (H.V., U.J.), Department of Medicine (D.M.R., W.M., S.B.F.), Department of Neurology (U.S., C.K.), Institute of Clinical Chemistry (J.L.), and Institute of Physiology (R.R.), Ernst Moritz Arndt University, D-17487 Greifswald, Germany

Address all correspondence and requests for reprints to: Henry Völzke, M.D., Institute of Epidemiology and Social Medicine, Ernst Moritz Arndt University, Walther Rathenau Strasse 48, D-17487 Greifswald, Germany. E-mail: voelzke{at}uni-greifswald.de.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Decreased serum TSH levels predict vascular mortality in older people. There is a need to investigate mechanisms that could explain this association. This study was designed to investigate the relationship between thyroid function and the carotid intima-media thickness (IMT).

The Study of Health in Pomerania is a population-based survey in Germany. Data from 2086 individuals at least 45 yr old with carotid ultrasound and without known thyroid disorders were analyzed. Twenty-nine participants (1.4%) had elevated serum TSH levels, 300 (14.4%) had decreased serum TSH levels, and 12 (0.6%) participants were hyperthyroid. A linear relationship between thyroid function and IMT was found. The highest IMT values were observed in participants with hyperthyroidism, the lowest in subjects with elevated serum TSH levels (P < 0.01). A multivariable regression analysis identified thyroid function as an independent risk factor for increased IMT. Other risk factors for increased IMT included male gender, advanced age, diabetes mellitus, current smoking, and the use of antihypertensive medication; increased pulse pressure, serum low-density cholesterol, and total cholesterol/high-density lipoprotein ratio; as well as a decreased heart rate and a positive history of myocardial infarction.

We conclude that there is an independent association between thyroid function and the IMT of the carotid artery.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
LOW SERUM TSH levels have been reported to predict all-cause and circulatory mortality in individuals aged 60 yr or older (1). This is of special interest in regions with iodine deficiency where decreased serum TSH levels are a common finding. Hyperthyroidism causes atrial fibrillation, a risk factor for stroke (2). In individuals with suppressed serum TSH levels of less than or equal to 0.1 mU/liter an increased incidence of atrial fibrillation has been found (2). However, the number of individuals with suppressed serum TSH levels is rather low, approximately 3% being affected (2). Thus, the increased rate of atrial fibrillation seen in these individuals cannot solely account for the increased risk of cerebrovascular mortality, nor does it account for the increased cardiovascular mortality in individuals with decreased serum TSH levels.

The intima-media thickness (IMT) of the carotid artery can be measured noninvasively and accurately by ultrasound techniques. An increased IMT has been shown to be associated with a high prevalence of atherosclerotic end points such as myocardial infarction and stroke (3, 4, 5). A risk prediction model revealed a positive correlation between IMT and the 11.5-yr risk of death from circulatory diseases (6). To our knowledge, there are no studies that have focused on the relationship between thyroid function and IMT.

The aim of the present study was to investigate possible associations between thyroid function and carotid IMT.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The Study of Health in Pomerania (SHIP) is a cross-sectional epidemiological survey in West Pomerania, the northeast area of Germany (7). The study region is a formerly iodine-deficient area with a high prevalence of iodine deficiency-related disorders such as goiter, thyroid nodules, and decreased serum TSH levels (8). In 1983, iodine supplementation was improved by mandatory iodine prophylaxis. However, after the reunification of Germany in 1989 and the adaptation of the voluntary principle, the iodine intake decreased again. In 1993, legislation was approved to facilitate the iodization of table salt in Germany. This has resulted in a stable and adequate iodine supply in the study area during the past decade.

A random sample from the population aged 20–79 yr was drawn. Selection of the sample was done using population registries and performed in two steps. First, the three cities of the region (with 17,076–65,977 inhabitants) and the 12 towns (with 1516–3044 inhabitants) were selected, and then 17 of 97 smaller towns (with less than 1500 inhabitants) were drawn at random. Second, from each of the selected communities, subjects were drawn at random, proportional to the population size of each community, and stratified by age and gender. Only individuals with German citizenship and main residency in the study area were included. Finally, 7008 subjects were sampled, with 292 persons of each gender in each of the twelve 5-yr age strata. To minimize dropouts by migration or death, subjects were selected in two waves. The net sample (without migrated or deceased persons) comprised 6267 eligible subjects. Selected persons received a maximum of three written invitations. In case of nonresponse, letters were followed by a phone call or by home visits if contact by phone was not possible. The SHIP population finally comprised 4310 participants (corresponding to a final response rate of 68.8%).

There were 989 men and 968 women who refused participation in SHIP (31.2% of eligible subjects). Reasons for the nonresponse were no interest in the study (39.7%), health problems (23.0%), no time (16.7%), satisfaction with general medical care (11.6%), and fear of bad results (3.0%). No information concerning the causes of refusal was available in 6.0% of the nonrespondent persons (7).

There were 349 (62 men and 287 women) of the 4310 subjects with known thyroid disease. The disease was diagnosed within the past year in 50 of these participants (14.4%). Two hundred and eighty persons (80.5%) reported taking thyroid medication according to the anatomic, therapeutic, and chemical code H03 (iodine, thyroid hormone replacement, suppression therapy, or thyrostatics). The 349 individuals with known thyroid disease were excluded from analysis together with an additional 20 participants with uncertainty regarding a possible thyroid disorder and 166 persons with no blood drawn. Of the remaining 3775 participants 1689 were younger than 45 yr. Ultrasound investigation of the carotid arteries was performed only in participants who were 45 yr or older. This resulted in a study population of 2086 participants (1134 men and 952 women) who were available for the present analysis. All participants gave informed written consent. The study protocol is consistent with the principles of the Declaration of Helsinki and was approved by the Ethics Committee of the University of Greifswald.

Sociodemographic characteristics and medical histories on thyroid disorders, hypertension, the use of antihypertensive drugs, diabetes, and current smoking were assessed by computer-aided face-to-face interviews. Height and weight were measured for the calculation of the body mass index [BMI = weight (kg)/ height2 (m2)]. After a 5-min rest period, heart rate as well as systolic and diastolic blood pressure were measured three times in the right arm of seated subjects with each reading being followed by an additional rest period of 3 min. Pulse pressure was defined as the difference between mean systolic and diastolic measurements. Hypertension was defined as a systolic blood pressure of 140 mm Hg or more, a diastolic blood pressure of 90 mm Hg or more, or self-reported use of antihypertensive medication. Diabetes was defined as self-reported physician diagnosis of diabetes or serum hemoglobin A1c more than 7%. Blood samples were taken, and laboratory parameters were analyzed in a central laboratory. Serum low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol were precipitated and measured photometrically (Boehringer GmbH, Mannheim, Germany). Serum TSH, free T4 (FT4), and FT3 levels were analyzed by immunochemiluminescent procedures (FT3 by LUMItest, Brahms, Berlin, Germany; TSH and FT4 by LIA-mat, Byk Sangtec Diagnostica GmbH, Frankfurt, Germany). All measurements of thyroid function were performed in one central laboratory. The functional sensitivity of the TSH assay was 0.03 mIU/liter. The reference range was 0.3- 3 mIU/liter. Reference ranges for FT4 and FT3 were 8–20 ng/liter and 2.2–4.6 ng/liter, respectively. The coefficients of variations were 5.42 for TSH, 7.02 for FT4, and 6.49 for FT3.

Certified medical assistants examined the extracranial carotid arteries bilaterally with B-mode ultrasound using a 5-MHz linear array transducer and a high-resolution instrument (Diasonics VST Gateway, Santa Clara, CA). Scans from the distal straight portion (1 cm in length) of both common carotid arteries were recorded. Certified readers calculated the mean far-wall IMT by averaging the 10 consecutive measurement points (in 1-mm steps) from the bulb of both sides. All measurements of intrareader, intraobserver, interreader, and interobserver agreements revealed Spearman correlation coefficients of greater than 0.9 and mean differences ± 2 SD of less than 1% ± less than 10% (9).

Statistics

A thyroid function index was formed by dividing participants into three groups according to the serum TSH levels: 1) elevated serum TSH (serum TSH > 3.0 mIU/liter); 2) euthyroid (serum TSH in the normal range); and 3) decreased serum TSH (serum TSH levels < 0.3 mIU/liter). A fourth group was formed by additional means of the serum FT3 and FT4 levels: 4) hyperthyroid (serum TSH concentrations < 0.1 mIU/liter with elevated serum FT3 and/or FT4 levels). Individuals who had serum TSH concentrations less than 0.1 mIU/liter but no elevated serum FT3 and/or FT4 levels were assigned to group 3.

Comparisons between groups were made using one-way ANOVA (continuous data) and {chi}2 test (nominal data). Post hoc significances in the ANOVA were assessed by least-significant difference (10). Multivariable linear regression analysis was used to evaluate independent risk factors for increased IMT. Known risk factors (11) for increased IMT such as demographic variables (age and gender), data on risk behavior (smoking status), and clinical characteristics (hypertension, use of antihypertensive agents, systolic and diastolic blood pressure, pulse pressure, heart rate, diabetes, body mass index, serum cholesterol, and HDL- and LDL-cholesterol levels) were included in the analysis. Furthermore, the thyroid function index (four categories) was obtained for analysis. Polynomial regression analysis was performed to test for linearity in the relationship between the thyroid function index and carotid IMT. Collinearity was assessed by using the tolerance and variation-inflation factor (VIF). Collinearity was found if the tolerance was less than 0.2 and the VIF more than 5, respectively. The model fit was measured by the adjusted R2. The IMT increments for independent variables were calculated from the ß-coefficients for a one-unit change, and standard increments were computed for the independent variables with continuous scale, corrected for SD. Multivariable comparisons between groups were performed by ANOVA. Additional analyses were performed using TSH, FT3, and FT4 instead of the thyroid function index as exposure variables. A value of P < 0.05 was considered statistically significant. All statistical analyses were performed with SPSS software, version 10.0.7 (SPSS GmbH Software, Munich, Germany).

Role of the funding source

The funding source was not involved in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Twenty-nine participants (1.4%) had elevated serum TSH levels, and 300 (14.4%) had decreased serum TSH levels. Twelve participants (0.6%) were hyperthyroid. The four groups of the thyroid function index were compared with respect to demographic and clinical characteristics (Table 1Go). Participants with elevated serum TSH levels had higher serum HDL-cholesterol concentrations, less often diabetes, and a higher pulse pressure than euthyroid participants. Individuals with decreased serum TSH levels were older than euthyroid participants. Participants with decreased serum TSH levels and hyperthyroid individuals had lower serum total cholesterol and LDL-cholesterol levels than euthyroid subjects (Table 1Go). There was a linear relationship between the thyroid function index and IMT (P < 0.01); a second- or higher-order model could be excluded by polynomial regression analyses. The highest IMT values were observed in participants with hyperthyroidism, the lowest in subjects who had elevated serum TSH levels (Fig. 1Go). Statistical significance was found for the differences in IMT between individuals with elevated serum TSH and individuals with decreased serum TSH as well as hyperthyroid participants. The difference in IMT between euthyroid individuals and participants with decreased serum TSH were also statistically significant (Fig. 1Go).


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  		TABLE 1. Demographic and clinical characteristics with respect to thyroid function

 


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  		FIG. 1. The IMT of the carotid artery with respect to thyroid function. *, P < 0.05 (ANOVA, unadjusted).

 
Multivariable statistical analysis was performed to identify independent risk factors for increased IMT. Collinearity was found between hypertension, the use of antihypertensive agents, systolic and diastolic blood pressure, and pulse pressure as well as between serum cholesterol and HDL- and LDL-cholesterol concentrations. Therefore, data on systolic and diastolic blood pressure and a history of hypertension were excluded from analysis, and the total cholesterol/HDL ratio was calculated. For all variables in the final model the tolerance was greater than 0.5 and the VIF was less than 2, respectively. The thyroid function index was identified as an independent risk factor for IMT (Table 2Go). The adjusted IMT values were 0.831 ± 0.030, 0.841 ± 0.011, 0.860 ± 0.014, and 0.892 ± 0.044 mm for the four groups with elevated TSH, euthyroid, decreased serum TSH, and hyperthyroid, respectively. Adjusted pairwise comparisons attained statistical significance for the difference between the euthyroid and the decreased serum TSH group. Furthermore, the regression analysis identified male gender, advanced age, diabetes mellitus, current smoking, and the use of antihypertensive medication; increased pulse pressure, serum low-density cholesterol, and total cholesterol/HDL ratio; as well as a decreased heart rate and a positive history of myocardial infarction as independent risk factors for increased carotid IMT (Table 2Go). There were no first-order interactions of the thyroid function index with other factors with respect to IMT. The whole regression model explained 28.8% of the variability in IMT.


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  		TABLE 2. Results of multivariable regression analysis (dependent variable: IMT of the carotid artery)

 
Additional analyses were performed using serum TSH levels instead of the thyroid function index as the exposure variable. Linear regression did not reveal a linear trend for TSH with respect to IMT (P = 0.22). The IMT increment for TSH was –0.58 µm for 1 mIU/liter change; the standard increment was –5.34 µm. For intergroup comparisons, the study population was divided into four categories according to the quartiles of the TSH distribution. The lowest quartile was further divided using the functional sensitivity of the TSH assay (0.03 mIU/liter) as a cutoff point. Persons (n = 28) with a serum TSH level less than or equal to 0.03 mIU/liter had significantly higher IMT values compared with those individuals belonging to the second (n = 536, TSH 0.39–0.60 mIU/liter) and third (n = 527, TSH > 0.60–0.87 mIU/liter) TSH quartile. Persons belonging to the first quartile but who had serum TSH levels greater than 0.03 mIU/liter showed a tendency toward higher IMT values compared with those persons belonging to the second and third quartile.

Additional analyses with the use of FT3 or FT4 as exposure variables represented the linear trend between thyroid function and IMT values. Trends and intergroup comparisons, however, did not attain statistical significance.

Multivariable analyses were again repeated after adding the primarily excluded persons with known thyroid disorders. The linear trend between the thyroid function index and IMT was confirmed with borderline statistical significance (P = 0.09). The difference between euthyroidism and subclinical hyperthyroidism also bordered statistical significance (P = 0.10).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present analysis revealed a linear relationship between the thyroid function index and carotid IMT. Participants with decreased serum TSH levels and hyperthyroid individuals had higher IMT than individuals with elevated serum TSH levels. This relationship remained statistically significant after appropriate adjustment for known IMT risk factors had been made. Furthermore, participants with low serum TSH levels had higher IMT values compared with subjects with serum TSH levels within the second and the third quartile of the TSH distribution.

Parle et al. (1) demonstrated that the group with high serum TSH had the lowest all-cause and vascular mortality. These results and our findings are at variance with some studies (12, 13) that found an association between hypothyroidism and an elevated risk for atherosclerosis. The relationship between hypothyroidism and atherosclerosis is biologically plausible because there is a known link between thyroid failure and disturbances of lipid metabolism (14). IMT is regarded to be a marker for generalized atherosclerosis (3, 4, 5). Therefore, one could expect the opposite of our findings, i.e. increased IMT in persons with hypothyroidism.

The association between hyperthyroidism and increased IMT might be explained by mechanisms for which there exists experimental and clinical evidence. Hyperthyroidism provokes peripheral vasodilation with the consequence of a decrease in renal perfusion pressure and an activation of the renin-angiotensin system (15). Besides increased sodium reabsorption and blood volume, angiotensin II stimulates vascular smooth muscle cell growth (16) and matrix synthesis (17). It has also been shown that treatment with T3 causes hypertrophy of coronary arteries (18). Vascular hypertrophy is associated with increased vascular stiffness. Such increased vascular stiffness of the carotid arteries has recently been reported in patients with hyperthyroid Graves’ disease (19, 20).

It is not clear whether additional mechanisms may contribute to the thickness of arterial vessel walls in hyperthyroidism. An increased IMT may merely reflect an adaptive response of the vessel wall to changes in shear stress and tensile stress (21). Such circumstances may also be caused by hyperthyroidism via an increased heart rate and an increased pulse pressure (20).

The predictive value of IMT for atherosclerosis also depends on the specific localization of the measure (22, 23). IMT measures both the intimal and medial layers, and medial hypertrophy could be a response to the described functional changes in hyperthyroidism. This might be particularly the case in the common carotid artery, where blood flow is laminar. Thus, increased IMT in the common carotid artery, as measured in our study, may be more strongly related to medial hypertrophy than to true intimal atherosclerosis. However, the pattern of independent risk factors for increased carotid IMT demonstrated by the present study is similar to the pattern usually found for other atherosclerotic end points. This argues in favor of IMT measured from the common carotid artery as a valid marker for atherosclerosis.

The strength of association between thyroid function and IMT was also assessed by the regression model. In comparison with other risk factors, the influence of the thyroid function index on IMT appears to be rather weak. Although weak, this influence can be explained by thyroid function alone, independently of other known risk factors for increased IMT such as age, blood pressure, and diabetes (11). Furthermore, according to the present regression model, the contribution of the thyroid function on IMT was similar to the influence of diabetes or current smoking on IMT. Increased pulse pressure may give rise to a potential common causal pathway between thyroid function and IMT, so that models that included pulse pressure may have been over-adjusted and therefore underestimated the influence of thyroid function on the end point.

In comparison with serum TSH levels, serum FT3 and FT4 levels are known to be less sensitive and specific in the diagnosis of thyroid disorders (24). Especially, severe illness and a variety of drugs may influence the levels of the free thyroid hormones. Furthermore, single measurements of serum FT3 and FT4 are unable to diagnose subclinical thyroid disorders. This might explain why the thyroid function index and TSH groups but not FT3 and FT4 were independently associated with IMT.

The exclusion of patients with known thyroid disorders resulted in small numbers of individuals with hypothyroidism or overt hyperthyroidism, limiting the power of the statistical analysis. We therefore repeated the analyses including these persons. The results confirmed the trend toward a linear relationship between the thyroid function index and IMT; however, the relationship between these two parameters was no longer statistically significant. In patients with known thyroid disease, the thyroid function status may change dramatically over time mainly due to the effects of treatment. In the present study, this may have masked the relationship between the thyroid function index and IMT when known patients were included in the analysis. Additional confounding variables in patients with known thyroid disease may include medical treatment, better health education, and more frequent and intense contact with medical personnel.

Limitations of the study

This is the first study that shows a direct and independent relationship between thyroid function and carotid IMT. The present data are derived from a cross-sectional study. Therefore, additional studies are needed to confirm this association. Follow-up investigations are required to investigate the prognostic value of the relationship between thyroid function and IMT, to further understand the mechanisms that cause an increased vascular mortality in individuals with decreased serum TSH levels, and to address the question of whether treatment could improve the prognosis of such individuals. The first 5-yr follow-up of SHIP was started in October 2002.

We conclude that there is an independent and direct association between thyroid function and the IMT of the carotid artery.


   Footnotes
 
This work is part of the Community Medicine Research net (CMR) of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grant ZZ9603), the Ministry of Cultural Affairs, as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. The CMR encompasses several research projects that are sharing data of the population-based Study of Health in Pomerania (http://www.medizin.uni-greifswald.de/cm).

Abbreviations: BMI, Body mass index; FT4, free T4; HDL, high-density lipoprotein; IMT, intima-media thickness; LDL, low-density lipoprotein; VIF, variation-inflation factor.

Received June 13, 2003.

Accepted February 4, 2004.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals