TSHCVD

Thyrotropin Levels and Risk of Fatal Coronary Heart
Disease
The HUNT Study

Bjørn O. Åsvold, MD; Trine Bjøro, MD, PhD; Tom Ivar L. Nilsen, PhD; David Gunnell, MD,
PhD; Lars J. Vatten, MD, PhD
Arch Intern Med. 2008;168(8):855-860.
http://archinte.ama-assn.org/cgi/content/full/168/8/855

ABSTRACT

Background Recent studies suggest that relatively low thyroid function within the
clinical reference range is positively associated with risk factors for coronary heart
disease (CHD), but the association with CHD mortality is not resolved.
Methods In a Norwegian population-based cohort study, we prospectively studied
the association between thyrotropin levels and fatal CHD in 17 311 women and 8002
men without known thyroid or cardiovascular disease or diabetes mellitus at baseline.

Results
During median follow-up of 8.3 years, 228 women and 182 men died of CHD. Of
these, 192 women and 164 men had thyrotropin levels within the clinical reference
range of 0.50 to 3.5 mIU/L. Overall, thyrotropin levels within the reference range
were positively associated with CHD mortality (P for trend = .01); the trend was
statistically significant in women (P for trend = .005) but not in men. Compared with
women in the lower part of the reference range (thyrotropin level, 0.50-1.4 mIU/L),
the hazard ratios for coronary death were 1.41 (95% confidence interval [CI],
1.02-1.96) and 1.69 (95% CI, 1.14-2.52) for women in the intermediate (thyrotropin
level, 1.5-2.4 mIU/L) and higher (thyrotropin level, 2.5-3.5 mIU/L) categories,
respectively.
Conclusions Thyrotropin levels within the reference range were positively and
linearly associated with CHD mortality in women. The results indicate that relatively
low but clinically normal thyroid function may increase the risk of fatal CHD.

INTRODUCTION

Emerging evidence indicates that levels of thyrotropin within the reference range are
positively and linearly associated with systolic and diastolic blood pressure (BP),1
body mass index,2 and serum lipid concentrations with adverse effects on
cardiovascular health.3 Furthermore, small studies of euthyroid patients with
atherosclerosis suggest that relatively low thyroid function is associated with more
severe coronary4-5 or carotid6 atherosclerosis.

Although studies indicate that there may be an increased risk of cardiovascular
disease in people with evidence of hypothyroidism7-8 or hyperthyroidism,9-10 there
is a lack of prospective studies that have assessed the relation of clinically normal
thyroid function with coronary heart disease (CHD). We prospectively examined the
association of thyrotropin levels within the reference range with CHD mortality in a
Norwegian population-based cohort study of more than 25 000 participants without
known thyroid disease, cardiovascular disease, or diabetes mellitus at baseline.

METHODS

STUDY POPULATION
Between 1995 and 1997, all inhabitants 20 years and older in Nord-Trøndelag County
in the middle part of Norway were invited to participate in the Nord-Trøndelag Health
Study (HUNT Study). Nord-Trøndelag County is characterized by a stable and
homogeneous population,11 and the Norwegian population is generally considered
to have sufficient iodine intake.12 A total of 92 936 individuals were eligible for the
HUNT Study, and 66 140 (71.2%) participated. The study has been described in detail
elsewhere.11 Briefly, the participants completed a self-administered questionnaire
that included questions on health and lifestyle and their medical history, including
thyroid disease,13 diabetes mellitus, angina, myocardial infarction, and stroke.
Information on the use of antihypertensive drugs was also collected.

Clinical measurements included BP, height, and weight. Blood pressure was
measured automatically 3 times at 1-minute intervals using a noninvasive BP monitor
based on oscillometry (Dinamap 845XT; Critikon, Tampa, Florida). The mean values of
the second and third measurements of systolic and diastolic BP were used in the
analyses. Body mass index was calculated as weight in kilograms divided by height in
meters squared.

A nonfasting venous blood sample was collected from each individual, and levels of
total serum cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and
creatinine were measured. Analysis of serum thyrotropin concentration was
performed in subsamples of the population, including all women older than 40 years
and a 50% random sample of men older than 40 years. In total, thyrotropin levels
were measured in 32 819 individuals (22 692 women and 10 127 men) from these
samples.

Of these 32 819 people, 25 313 (17 311 women and 8002 men) were included in the
present study. The exclusion criteria were a history of thyroid disease at baseline (n
= 2831); a history of angina, myocardial infarction, stroke, or diabetes mellitus at
baseline (n = 4007); and missing information on smoking status (n = 668). Each
participant contributed person-time from the date of attendance at the baseline
clinical examination (August 15, 1995, to June 18, 1997) until their date of death or
the end of follow-up (December 31, 2004), whichever came first.

LABORATORY MEASUREMENTS
The serum concentration of thyrotropin was analyzed at the Hormone Laboratory,
Aker University Hospital, Oslo, using a noncompetitive immunofluorometric assay
(DELFIA hTSH Ultra) (sensitivity, 0.03 mIU/L; total analytical variation, <5%) from
Wallac Oy, Turku, Finland. Reference ranges for thyrotropin levels from this population
have been published previously.13 Based on these results, the reference range for
thyrotropin in the present study was defined as 0.50 to 3.5 mIU/L.

Serum lipid and creatinine levels were analyzed at the Central Laboratory, Levanger
Hospital, Nord-Trøndelag, using an autoanalyzer (Hitachi 911 Autoanalyzer; Hitachi,
Mito, Japan), applying reagents from Boehringer Mannheim (Mannheim, Germany).
Total serum and HDL cholesterol levels were measured using an enzymatic
colorimetric cholesterol esterase method, and HDL cholesterol levels were measured
after precipitation with phosphotungstate and magnesium ions. Triglycerides were
also measured using an enzymatic colorimetric method, and serum creatinine
concentration was measured using the Jaffe method. The day-to-day coefficients of
variation were 1.3% to 1.9% for total serum cholesterol, 2.4% for HDL cholesterol,
0.7% to 1.3% for triglycerides, and 3.5% for creatinine.

MORTALITY END POINTS
The unique 11-digit identification number of every Norwegian citizen enabled linkage
of data from the HUNT Study with the national Cause of Death Registry at Statistics
Norway. The reporting of deaths by physicians and public health officers to the Cause
of Death Registry is mandatory. In this study, the end point was death from CHD
(International Classification of Diseases, Ninth Revision, codes 410-414 and
International Classification of Diseases, Tenth Revision, codes I.20-I.25).

STATISTICAL ANALYSES
Participants were grouped into 5 categories by thyrotropin level: 3 categories of
equal width within the reference range (0.50-1.4, 1.5-2.4, and 2.5-3.5 mIU/L), 1
category below the reference range (<0.50 mIU/L), and 1 category above the
reference range ( 3.6 mIU/L). In a Cox proportional hazards model, we calculated
hazard ratios (HRs) of dying of CHD in the 5 groups of thyrotropin, using the lower
part of the reference range (0.50-1.4 mIU/L) as the comparison group. We used
attained age as the time variable in the regression analyses and, thus, all the results
are age adjusted. We also adjusted for sex and smoking status (never, former, and
current smokers, where former smokers were subdivided by years since smoking
cessation). Statistical significance of trend within the reference range of thyrotropin
was assessed with P values using the categories of thyrotropin within the reference
range as an ordinal variable.

There seems to be a complex association between tobacco smoking and serum
thyrotropin levels.14 In a separate analysis, we restricted the study population to
nonsmokers (10 379 women and 4108 men) to avoid any effects of smoking on
thyrotropin levels. Nonsmokers were defined as never-smokers and former smokers
who had quit smoking 18 years or more ago. The 18-year cutoff point was based on
previous analyses of the relation of smoking to thyroid function in the same
population.14

Chronic diseases associated with fatal CHD could bias the present results because
nonthyroidal illness may affect thyroid function.15 We, therefore, excluded individuals
with known cardiovascular disease or diabetes mellitus at baseline. We also explored
whether preclinical CHD at baseline could have affected these results by starting
follow-up 2 years after baseline.

Furthermore, we explored whether the effect of thyrotropin could be mediated by
conventional cardiovascular risk factors. In women with thyrotropin levels within the
reference range, we, therefore, compared HRs derived from the age- and
smoking-adjusted analyses with HRs derived from additional adjustment for total
serum cholesterol level, HDL cholesterol level, triglycerides, systolic and diastolic BP,
use of antihypertensive medication, body mass index, and serum creatinine level. In
these analyses, we used thyrotropin as a continuous variable, yielding HRs per
1-mIU/L increase in thyrotropin. The data were analyzed using Stata version 9.0
(Stata Corp, College Station, Texas).

The HUNT Study is a collaborative effort of the Faculty of Medicine, Norwegian
University of Science and Technology; the Norwegian Institute of Public Health; and
the Nord-Trøndelag County Council. This study was approved by the regional
committee for medical research ethics and by the Norwegian Data Inspectorate.

RESULTS

Characteristics of the study population are given in Table 1. During median follow-up
of 8.3 years, 228 women (1.3%) and 182 men (2.3%) died of CHD. Of these, 192
women and 164 men had thyrotropin levels within the reference range. Thyrotropin
levels within the reference range were positively associated with risk of fatal CHD (P
for trend = .01 in the total population and P for trend = .007 in nonsmokers) (Table
2). There was some statistical evidence that associations of thyrotropin with fatal
CHD differed between women and men (P for interaction = .03 in the total population
and P for interaction = .16 in nonsmokers).

Thus, sex-specific analyses showed a positive association of thyrotropin level within
the reference range with risk of fatal CHD in women (P for trend = .005). Compared
with women in the lower part of the reference range (thyrotropin level, 0.50-1.4
mIU/L), the HRs were 1.41 (95% CI, 1.02-1.96) and 1.69 (95% CI, 1.14-2.52) for
women in the intermediate (thyrotropin level, 1.5-2.4 mIU/L) and higher (thyrotropin
level, 2.5-3.5 mIU/L) parts of the reference range, respectively. This association was
essentially unchanged when the analysis was restricted to nonsmokers (Table 2). In
men, thyrotropin levels within the reference range were not clearly related to fatal
CHD. In nonsmoking men, there was a positive association of thyrotropin levels
within the reference range with CHD mortality, but this association did not reach
conventional levels of statistical significance (P for trend = .27) (Table 2).

For the 1426 women and 422 men with thyrotropin levels higher than the reference
range, HRs for fatal CHD were 1.38 (95% CI, 0.88-2.17) and 1.15 (95% CI,
0.66-1.98), respectively, compared with individuals with thyrotropin levels in the
lower part of the reference range (thyrotropin level, 0.50-1.4 mIU/L). In nonsmokers
(1030 women and 293 men) with thyrotropin levels higher than the reference range,
the analogous HRs were 1.69 (95% CI, 1.01-2.82) and 1.57 (95% CI, 0.79-3.14),
respectively. Below the reference range of thyrotropin levels, there were too few
events (8 women and 0 men) to yield any meaningful estimates.

To exclude the possible effect of preclinical CHD on the thyrotropin level, we repeated
the analyses starting follow-up 2 years after baseline. The estimates, however,
remained essentially unchanged: thyrotropin levels within the reference range were
positively associated with fatal CHD in women (P for trend = .01). Compared with
women in the lower category, the HRs for fatal CHD were 1.43 (95% CI, 1.01-2.02)
and 1.61 (95% CI, 1.05-2.46) for women in the intermediate and higher categories of
the reference range, respectively.

Furthermore, we explored whether serum lipid concentrations, BP, body mass index,
and serum creatinine levels could mediate the association of thyrotropin with CHD
mortality in women. The analysis showed that the excess mortality was attenuated
by approximately one-fifth after adjustment for these factors and that serum lipid
levels and BP contributed to the attenuation (Table 3).

COMMENT

In this prospective mortality follow-up of more than 25 000 people from the general
population, thyrotropin levels within the reference range were positively and linearly
associated with fatal CHD in women. In men, there was no convincing evidence of an
association.

Previously, small cross-sectional studies have reported that low but clinically normal
thyroid function is associated with more severe coronary4-5 and carotid6
atherosclerosis and increased carotid artery intima media thickness.16 Also, recent
studies show that impaired endothelial function, suggesting early-stage
atherosclerosis,17 may be more prevalent in hypothyroid patients and in people with
thyrotropin levels in the upper part of the reference range.18 In old age, there is
some evidence that within the clinical reference range, higher levels of thyroid
function may be positively associated with total mortality.9 However, 1 prospective
study10 that specifically analyzed vascular disease mortality did not show any
association with thyrotropin levels in the reference range.

In previous studies, linear and positive associations between thyrotropin levels
within the reference range and BP1 and less favorable serum lipid profiles in people
with higher thyrotropin levels have been reported.3 In this study, we observed a
modest attenuation of the effect of thyrotropin level on CHD mortality after
adjustment for BP and serum lipids. This may indicate that the effect of thyrotropin
level at least partly may be mediated by these factors.

It has been suggested that thyrotropin levels within the reference range may be
positively associated with body mass index2 and negatively associated with insulin
sensitivity.19 Also, thyroid hormones may affect the cardiovascular system through
effects on vascular smooth muscle cells, cardiac myocytes,20 coronary
angiogenesis,21 renal function,22 hemostasis,23 oxidation of low-density
lipoproteins, and homocysteine levels.7 In addition, thyrotropin may have
cardiovascular effects that are not mediated by thyroid hormones. Thus,
administration of recombinant human thyrotropin was recently associated with acute
impairment of endothelial function.24 It has also been suggested, but not
convincingly shown, that inflammation associated with autoimmune thyroid disease
could contribute to atherosclerosis in people with low thyroid function.25-26

Subclinical hypothyroidism, characterized by elevated serum thyrotropin levels but
thyroid hormone levels within the reference range, has been associated with CHD in
some cross-sectional8, 25 and prospective27-29 studies, although results are
inconsistent.8, 30-31 We found evidence of an increased risk of fatal CHD in
nonsmoking women with thyrotropin levels higher than the reference range.
However, in the baseline survey forming the basis of this cohort, participants with
pathologic thyrotropin levels were recommended to consult their physician, and any
subsequent management may have altered their cardiovascular risk and could have
biased these risk estimates. Therefore, we focused our analysis on CHD mortality
associated with thyrotropin levels within the reference range.

Previous prospective studies9-10,27 indicate that high levels of thyroid function may
be associated with increased cardiovascular mortality. It has also been shown that
high thyroid function may be associated with a higher prevalence of hypertension,
impaired cardiac function,20 and atrial fibrillation.20, 32 Owing to few coronary
deaths in people with thyrotropin levels below the reference range, we could not
assess the association of hyperthyroid function with fatal CHD in this study.

To our knowledge, no clinical trial has tested whether thyroxine replacement could
protect against CHD. However, some clinical studies of patients with subclinical
hypothyroidism have shown that thyroxine treatment may improve serum lipid
levels,33-35 BP,36-37 and adiposity,35 as well as endothelial function35, 38 and
carotid artery intima media thickness.34 A beneficial effect of thyroxine treatment on
serum lipid levels has also been demonstrated in individuals with thyrotropin levels in
the upper part of the reference range.39

This study shows that CHD mortality increases in women with increasing levels of
thyrotropin within the reference range. These results indicate that relatively low but
clinically normal thyroid function may increase the risk of fatal CHD.

AUTHOR INFORMATION

Correspondence: Bjørn O. Åsvold, MD, Department of Public Health, Faculty of
Medicine, Norwegian University of Science and Technology, N-7489 Trondheim,
Norway (bjorn.o.asvold@ntnu.no ).
Accepted for Publication: November 1, 2007.

Author Contributions: Dr Åsvold had full access to all of the data in the study and
takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Åsvold, Bjøro, and Vatten. Acquisition of data: Bjøro and
Vatten. Analysis and interpretation of data: Åsvold, Nilsen, Gunnell, and Vatten.
Drafting of the manuscript: Åsvold and Vatten. Critical revision of the manuscript for
important intellectual content: Bjøro, Nilsen, Gunnell, and Vatten. Statistical analysis:
Åsvold and Nilsen. Obtained funding: Bjøro and Vatten. Administrative, technical, and
material support: Vatten. Study supervision: Bjøro, Nilsen, Gunnell, and Vatten.
Financial Disclosure: None reported.
Funding/Support: This study was supported by the Norwegian University of Science
and Technology and by the Central Norway Regional Health Authority.
Additional Contributions: The Hormone Laboratory, Aker University Hospital, analyzed
all thyroid function tests with financial support from Wallac Oy. The HUNT Research
Centre provided the data.
Author Affiliations: Department of Public Health, Faculty of Medicine (Drs Åsvold and
Vatten), and Human Movement Science Programme (Dr Nilsen), Norwegian University
of Science and Technology, Trondheim, Norway; St Olavs Hospital, Trondheim
University Hospital, Trondheim (Dr Åsvold); Department of Medical Biochemistry,
Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway (Dr Bjøro); and
Department of Social Medicine, University of Bristol, Bristol, England (Dr Gunnell).

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