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University of Groningen
Clinical and epidemiological studies on thyroid function
Roos, Annemieke
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9
Summary
133
Chapter 9
The thyroid is an endocrine gland, found in the neck and producing thyroid hormones. The thyroid
hormones thyroxine (T4) and triiodothyronine (T3) strongly influence energy metabolism,
temperature regulation and body heat production. These hormones also play an important role
in skeletal muscle and cardiac contraction, memory and sleep. The synthesis of thyroid hormone
is dependent on factors like the nutritional availability of iodine, and predominantly regulated by
thyrotropin (thyroid stimulating hormone, TSH), a hormone secreted by the pituitary gland. The
synthesis and secretion of TSH are stimulated by hypothalamic TSH-releasing hormone (TRH)
and inhibited through negative feedback by thyroid hormone itself.
Thyroid diseases are frequently observed in clinical practice. They comprise both functional
abnormalities such as overproduction and underproduction of thyroid hormone as a consequence
of intrinsic thyroid diseases, as well as the development of structural abnormalities like goiter,
adenoma or carcinoma. Assessment of thyroid function is usually performed by measuring the
serum TSH concentration, followed by measuring the free T4 (FT4) concentration when TSH
levels are outside the normal reference range. Primary hypothyroidism, defined as an elevated
TSH concentration in combination with a decreased FT4 concentration, is a commonly
occurring disorder, most prevalent in women and most often caused by autoimmune thyroiditis.
It can present with classical symptoms like fatigue, weight gain and cold intolerance, however,
many patients only have few symptoms, or are even discovered by chance, when thyroid function
is measured routinely.
Primary hypothyroidism is associated with (increased risk of) atherosclerotic cardiovascular
disease, in part explained by thyroid hormonal effects on lipid metabolism and blood pressure.
The impact of less significant degrees of thyroid dysfunction (“subclinical hypothyroidism”)
on these factors, however, is not fully elucidated. The standard treatment of hypothyroidism
is suppletion with synthetic thyroxine (levothyroxine, L-T4). The average daily dose in adults
is approximately 1.6 microgram levothyroxine per kilogram body weight. The primary aim
of treatment is to abolish the complaints associated with dysfunction of the thyroid, which
often – but not always – is achieved when the dose of thyroxine is sufficient to normalize TSH
levels. The secondary aim of treatment is to normalize bodily functions and thereby to decrease
cardiovascular risk factors.
Chapter 1 provides an introduction in the characteristic features of the thyroid gland,
thyroid hormones, impaired thyroid function and the treatment of primary hypothyroidism.
Furthermore, the aims of the thesis are described: to gain more insight in the effects of thyroid
134
Summary
function on cardiovascular risk factors and related metabolic parameters as well as mortality,
to assess possible predictors for future hypothyroidism in a large, unselected population and to
optimize the treatment of hypothyroid patients.
Part A. Effects of the serum levels of thyroid stimulating hormone (TSH), free thyroxine
(FT4) and free triiodothyronine (FT3) within the euthyroid range on cardiovascular risk
factors and mortality
In chapter 2 we tested the hypothesis that thyroid function, in euthyroid subjects, is associated
with serum lipid concentrations, insulin resistance and components of the metabolic syndrome.
In a cross-sectional study, 2703 adult inhabitants of Groningen, the Netherlands, participated. A
total of 1122 subjects were excluded for they were not euthyroid, were taking thyroid medication
or medication for diabetes or medication data were not available. Insulin resistance was calculated
with the HOMA insulin resistance formula (homeostatic model assessment-estimated insulin
resistance, HOMA-IR; mU·mmol/L2): fasting insulin times fasting glucose (mmol/L) divided
by 22.5. The metabolic syndrome was defined according to National Cholesterol Education
Program Adult Treatment Panel (NCEP ATP) III criteria. After adjustment for age and sex, FT4
was significantly associated with total cholesterol (P=0.014), low-density lipoprotein cholesterol
(LDL-C; P=0.004), high-density lipoprotein cholesterol (HDL-C; P<0.001) and triglycerides
(P<0.001). Both FT4 and TSH were significantly associated with HOMA-IR (P<0.001 and
P=0.024 respectively). Median HOMA-IR increased from 1.42 in the highest tertile of FT4 to
1.66 in the lowest tertile of FT4. FT4 was significantly related to four out of five components
of the metabolic syndrome (abdominal obesity, triglycerides, HDL-C and blood pressure),
independent of insulin resistance. So we demonstrated an association between FT4 levels within
the normal reference range and lipids. Moreover, low normal FT4 levels were significantly
associated with increased insulin resistance. These results were in accordance with the earlier
observed association between (sub)clinical hypothyroidism and hyperlipidemia and also
consistent with an increased cardiovascular risk in subjects with low normal thyroid function.
In chapter 3, we aimed to investigate whether FT4, FT3, FT3/ FT4 ratio and TSH are markers
of healthy aging by investigating their association with mortality in euthyroid subjects. We
therefore designed a case-cohort study within a random subcohort of 2703 subjects, drawn from
the population-based PREVEND cohort, consisting of adults with an age at entry between 28
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Chapter 9
and 75 years. According to the case-cohort design, extra cases from the remaining PREVEND
cohort were added to the random subcohort. Subjects with abnormal TSH were excluded.
Vital status of the participants was checked through the municipal register. Cause of death was
obtained from the Central Bureau of Statistics. FT4 was positively and FT3/FT4 ratio inversely
associated with cardiovascular mortality (P=0.02 and P=0.006 respectively). FT3 and FT3/FT4
ratio both were inversely associated with non-cardiovascular mortality (P<0.0001 and P<0.0001
respectively) and all-cause mortality (P<0.0001 and P<0.0001 respectively). These associations
were independent of age, sex and potential confounders. No association of TSH with mortality
was found.In summary, these study results demonstrated that FT3, FT4 and FT3/FT4 ratio are
associated with mortality in euthyroid subjects.
Part B. Prediction of the development of hypothyroidism
Chapter 4 describes a prospective study regarding the relationship of baseline antithyroperoxidase antibodies (TPOAbs) and TSH with incident hypothyroidism in euthyroid
subjects in the general population This study was performed in the same random sample of
2703 adults as mentioned before. A total of 309 subjects was excluded from analyses, mainly for
the baseline TSH was outside the laboratory’s reference range (0.35–4.94 mIU/L; n=115) and
for the use of thyroid medication and/or medications that may affect thyroid function (n=92)
at baseline. Incident hypothyroidism was defined as initiation of L-thyroxine in the absence
of thyreostatic medication. Mean age at baseline was 47.7 yrs, 50.8% was female. Prevalence of
positive TPOAbs at baseline was 8.4%, increasing with higher TSH concentrations (P<0.001).
Median follow up was 9.1 yrs. A total of 15 (0.6%) subjects developed hypothyroidism (3.5% in
TPOAbs positive vs. 0.4% in TPOAbs negative subjects; P<0.001). In univariate Cox-regression
analyses, female sex (P=0.02), TSH (P<0.001) and log-transformed TPOAbs (P<0.001) were
significant predictors of incident hypothyroidism, and FT4 (P=0.08) reached borderline
significance. In multivariate analysis, TSH level and TPOAbs remained as independent
predictors (both P<0.001). We concluded that TPOAbs and TSH are independent predictors
for future hypothyroidism, even when TSH is still within the laboratory’s reference range.
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Summary
Part C. The treatment of overt hypothyroidism
In chapter 5 we evaluated signs of cardiac ischaemia in untreated hypothyroid patients without
angina pectoris. Hypothyroidism is regarded as a risk factor for coronary artery disease.
Possible factors involved in the association of hypothyroidism and coronary artery disease are
hyperlipidaemia and hypertension, both occurring with increased frequency in hypothyroid
patients. We studied 51 consecutive cardiac asymptomatic patients with a mean age of 47 years
(range 22–86 years) by cardiac evaluation with dobutamine stress echocardiography and bicycle
ergometry. To evaluate for possible risk factors for coronary artery disease, the blood pressure
(mean 129/81 mm Hg) and total cholesterol (mean 5.8 ± 1.6 mmol/L) were measured. Mean
values of body mass index and resting heart rate were 28.5 kg/m2 and 68 bpm respectively.
Median TSH was 51.9 mIU/L, mean FT4 7.3 ± 2.9 pmol/L (mean ± SD) and mean TT3 1.6
± 0.6 nmol/L. None of the patients had complaints of angina pectoris during dobutamine
stress echocardiography or bicycle ergometry and no evidence of myocardial ischaemia was
demonstrated. Exercise tolerance, assessed by dividing the maximum achieved workload by the
target performance (depending on body height, sex and age) for each patient, was diminished
in 38% of patients, significantly related to the degree of hypothyroidism. We concluded that no
angina pectoris or cardiac ischaemia at exercise or stress was found in cardiac asymptomatic
hypothyroid patients. The precise role of hypothyroidism as a risk factor for coronary artery
disease should further be elucidated.
In chapter 6 we describe the results of a prospective, randomized, double-blind trial that
compared a full starting L-T4 dose of 1.6 μg/kg with a low starting dose of 25 μg (increased
every four weeks) in patients with newly diagnosed cardiac asymptomatic hypothyroidism.
We postulated that the dogma of “starting low and going slow” was based on the association
of hypothyroidism with ischaemic heart disease, and that, however, a full starting dose would
also be safe. The safety and efficacy of different initial doses of L-T4 had never been studied
prospectively. We therefore conducted this prospective, randomized, double-blind trial. Seventyfive consecutive patients were enrolled, of whom 50 underwent randomization. Twenty-five
patients were excluded because of a history of cardiac disease (n=5), medication for longstanding
hypertension (n=9), unwillingness to participate in the study (n=6), hypothyroidism due to
postpartum thyroiditis (n=2), pregnancy (n=1), myxedema (pre)coma (n=1) or unwillingness
to follow the study protocol (n=1). Safety was studied by documenting cardiac symptoms and
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Chapter 9
events; efficacy was studied by monitoring TSH and FT4 levels and by assessing improvement
of signs and symptoms and quality of life. At baseline, the severity of hypothyroidism and age
were comparable in the full-dose (n=25) vs. the low-dose group (n=25): TSH, 61 vs. 48 mIU/L;
FT4, 7.2 vs. 8.2 pmol/L; and age, 47 vs. 47 years. Total follow-up during this study was 48 weeks.
No cardiac complaints or events were documented during treatment or at bicycle ergometry at
baseline, 12 weeks, or 24 weeks. Euthyroidism was reached in the full-dose vs. the low-dose group
in 13 vs. 1 (4 weeks), 19 vs. 3 (8 weeks), 19 vs. 9 (12 weeks), 20 vs. 14 (16 weeks), 20 vs. 18 (20 weeks),
and 21 vs. 20 (24 weeks) patients (P=.005). However, signs and symptoms of hypothyroidism
and quality of life improved at a comparable rate. We concluded that a full starting dose of
levothyroxine in cardiac asymptomatic patients with primary hypothyroidism is safe and may
be more convenient and costeffective than a low starting dose regimen.
Chapter 7 includes an editorial about subclinical thyroid disease and heart failure, commenting
Chen et al. who reported a prospective follow-up study on the relationship between TSH levels
and outcome in 5,599 patients with heart failure. Their results showed that both high TSH and
low TSH levels were associated with an increased mortality rate. These results are supported
by other recent studies. However no clear statement can be made about TSH cut-off levels with
respect to a clinically relevant increase in mortality. To define a clear answer on TSH cut-off
levels for treatment of subclinical thyroid disease, well-designed prospective studies should be
performed.
Chapter 8 is a general discussion on the effects of levels of TSH, FT4 and FT3 in the
euthyroid range with regard to the metabolic syndrome and mortality. We additionally discuss
predictive factors regarding the development of hypothyroidism and the treatment of overt
hypothyroidism. Finally, several perspectives of this thesis are discussed and recommendations
for future research are made.
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