University of Groningen Clinical and epidemiological …...The synthesis of thyroid hormone is dependent on factors like the nutritional availability of iodine, and is predominantly

University of Groningen

Clinical and epidemiological studies on thyroid functionRoos, Annemieke

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9

1 Introduction and aims of the thesis

10

Chapter 1

TRH

TSH

T4

T3

T4

T3

T3

T4

+

–

–

+

Hypothalamus

Pituitary

Thyroid

Liver

Figure 1. Simplified overview of the hypothalamus-pituitary-thyroid axis.1 TRH stimulates TSH secretion by the pituitary gland. TSH regulates the production and secretion of T4 by the thyroid. Most T3 is derived from conversion out of T4 in extra-thyroidal tissues.

11

Introduction and aims of the thesis

Introduction

Thyroid and thyroid hormones

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. They 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 is 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 (Figure 1).1 Thyroxine (T4) and 3,5,3'-triiodothyronine (T3) are the two biologically active thyroid hormones. They are composed of a phenyl ring attached via an ether linkage to a tyrosine molecule. Both have two iodine atoms on their tyrosine (inner) ring. They differ, however, in the total number of iodine atoms, with T4 having two iodine atoms on its phenyl (outer) ring, while T3 has only one (Figure 2). Another difference is that T4 is solely produced by the thyroid gland, while only 20% of T3 is produced by the thyroid gland. About 80% of T3 is produced in extrathyroidal tissues, through deiodination of T4 by specific intracellular enzymes (Figure 1).1 While T4 and T3 in serum are almost entirely bound to plasma proteins, mainly to thyroxine-binding globulin (TBG), free serum concentrations of T4 (FT4) and T3 (FT3) determine the hormone’s biological activity.2–4

Impaired thyroid function

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. In community surveys, prevalence rates of elevated TSH levels – indicating impaired thyroid hormone secretion – range from 4–10%5,6 while prevalence rates of decreased TSH levels – indicating thyroid hormone overproduction – range from 0.7–1.5 %.6,7 Assessment of thyroid function is usually performed by measuring the serum TSH concentration, followed by measuring the FT4 concentration when TSH levels are outside the normal reference range of 0.5–4.0 mIU/L. Primary hypothyroidism, defined as an elevated TSH concentration in combination with a decreased FT4 concentration, is a commonly occurring

12

Chapter 1

disorder, most prevalent in women and most often caused by autoimmune thyroiditis, in which the immune system produces antibodies against normal thyroid tissue substances and/or antibodies which block the TSH receptor, thereby interfering with normal regulation of thyroid hormone synthesis.5,6 Overt hypothyroidism can present with classical symptoms of fatigue, weight gain, cold intolerance, constipation, lethargy, dry skin, loss of hair, and bradycardia. However, many patients only have few symptoms, and almost half of patients with primary hypothyroidism are discovered by chance, when thyroid function is measured routinely. The term ‘subclinical hypothyroidism’ has been reserved for the situation in which TSH levels are only moderately elevated, between 4.0 and 10.0 mIU/L, while FT4 levels are still within the normal range. Subclinical hypothyroidism may occur in the presence or absence of (mild) symptoms of hypothyroidism.

Primary hypothyroidism is associated with (increased risk of) atherosclerotic cardiovascular disease.8–11 This association is undisputed for overt hypothyroidism, but there is still controversy

T4 T3

NH2CHCOOH

CH2

O

I

OH

I

NH2CHCOOH

CH2

O

I II

OH

II

Figure 2. Structure of thyroxine (T4) and 3,5,3'-triiodothyronine (T3).

13

Introduction and aims of the thesis

as to whether this association is also present for subclinical hypothyroidism.9–12 The association of thyroid disease with atherosclerotic cardiovascular disease may in part be explained by thyroid hormonal effects on lipid metabolism and blood pressure. It is known that overt hypothyroidism leads to an increase of the levels of plasma total and LDL-cholesterol and blood pressure.13,14 Endothelial dysfunction has also been mentioned as a potential mechanism15,16 of the higher risk of cardiovascular disease. The impact of less significant degrees of thyroid dysfunction on these factors, however, is not fully elucidated. However, most studies on subclinical hypothyroidism show a comparable, but less pronounced increase of cholesterol and blood pressure than in overt hypothyroidism.6,16 It is not known whether these associations extend into the euthyroid range. In other words, might already subtle to moderate reductions in thyroid function, still within the euthyroid range, influence lipid metabolism and blood pressure, and thereby increase the risk of cardiovascular morbidity and mortality?

The euthyroid range is obviously determined by the definition of what is considered to be a normal TSH concentration. In recent years there has been considerable discussion regarding the normal reference values for TSH and FT4 concentrations.17,18 Some authors have defended the viewpoint that normal serum TSH values lie between 0.5 and 2.0 mIU/L, and that signs of autoimmune thyroiditis – as reflected by the presence of autoantibodies against thyroid substance such as thyroid peroxidase (TPO) – should be absent.19 There is also strong evidence that each individual has its own setpoint for FT4, thus a specific normal value.20 Population-based ‘normal’ FT4 values vary – generally anywhere between 10 and 22 pmol/L – depending on the assay used to measure this hormone. As a consequence of this rather broad range the normal value in individual cases is difficult to assess. For example, a decline of 33% from 18 to 12 pmol/L still reflects a value within the normal range. This decline may lead to a significant increase in TSH levels in certain individuals. Therefore, one can debate whether subclinical hypothyroidism is really ‘subclinical’. It would be interesting to know which of currently euthyroid subjects, with serum TSH levels in the high normal range, are at increased risk for development of thyroid dysfunction in the near future. This knowledge will possibly implicate earlier diagnosis, and therefore earlier treatment, of hypothyroidism.

It is well known that higher prevalence rates of hypothyroidism are found with advancing age, when relatives have been diagnosed with a thyroid disorder, and when thyroid autoantibodies are present,5,6,21,22 the last particularly in women. Several antibodies against thyroid antigens have been described, including antibodies against thyroglobulin (Tg) and thyroid peroxidase (TPO). Tg is synthesized by follicular cells of the thyroid gland and it is secreted into the

14

Chapter 1

lumen of the thyroid follicle, where it is stored in colloid. TPO catalyzes the iodination of tyrosine residues of Tg to form monoiodotyrosine and diiodotyrosine.2 The presence of TPO antibodies (TPOAbs) has been suggested to serve as a marker of future thyroid failure.23 This was confirmed in a prospective study in a selected population of female relatives of patients with autoimmune thyroid disease.24 Whether presence of TPOAbs is associated with future development of hypothyroidism in subjects with TSH levels in the euthyroid range is not established. Only two prospective studies investigated the value of TPOAb titers and TSH values in subjects with normal levels of TSH.25,26 Geul et al. found that 19 out of 406 middle-aged women developed elevated serum TSH levels over 10 years follow up. The incidence in thyroid microsomal antibodies (TMA) positive women was nine times the incidence in TMA negative women.25 Li et al. found that 59 out of 2,665 subjects developed elevated serum TSH levels over 5 years follow up. The incidence in TPOAbs positive subjects was five times the incidence in TPOAbs negative subjects.26 In these studies, presence of elevated TSH levels during follow-up was assessed by screening. Screening for hypothyroidism is, however, not part of current clinical practice. Currently, the value of presence of thyroid peroxidase antibodies as a risk factor for future development of clinical thyroid failure in currently euthyroid subjects of the general population remains therefore to be established.

Treatment of hypothyroidism

Suppletion with synthetic thyroxine (T4; levothyroxine) is the standard treatment to correct the hormonal imbalance in primary hypothyroidism. The average daily dose in adults is approximately 1.6 microgram levothyroxine per kilogram body weight, but it varies from patient to patient depending on the severity of thyroid failure2 and on the gastrointestinal absorption.27 Some authors have suggested that lean body mass is a better determinant of levothyroxine suppletion dosage than total body weight.28 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 levothyroxine is sufficient to normalize TSH levels. The secondary aim of treatment is to normalize bodily functions and thereby to decrease cardiovascular risk factors.

Thyroid hormone has generally been adviced to take once daily in the fasting state, in order to maximize gastrointestinal absorption. Levothyroxine normally has a half-life of one week, which is extended to 9–10 days in case of hypothyroidism and in elderly people. Because of this, after initiation of therapy or change of levothyroxine dose, it takes about 5–6 weeks to achieve a new steady state. Therefore, it is generally considered not useful to measure TSH levels or adjust

15

Introduction and aims of the thesis

the levothyroxine dose earlier.3 Because of the association of primary hypothyroidism with atherosclerotic cardiovascular disease, it is generally advised to start levothyroxine suppletion with a low dose, and only slowly and gradually increase the dose in 4–6 weeks intervals. This adagium of “starting low and going slow” has been common clinical practice for a long time, irrespective of the age or clinical situation of a patient. It was based on old reports on subjects with primary hypothyroidism with unknown coronary atherosclerotic disease who developed precordial chest pains as a consequence of an increased cardial oxygen consumption.29–31 However, publications were often based on studies performed on hypothyroid patients using desiccated thyroid extracts which in these days contained differing and therefore unpredictable amounts of both T4 and T3, with relatively high amounts of T3 compared to T4, often leading to higher than normal plasma T3 levels. It has long been noted that T3 has positive inotropic effects, and can increase heart rate. Both these phenomena are associated with increased myocardial oxygen demand.32 Nowadays, most patients are treated with levothyroxine, which only consists of T4. Recommendations for the starting dose of this T4 vary considerably: from 50 µg to a full replacement dose of 1.6 or 1.7 µg/kg body weight in healthy adult patients younger than 65 years old and from 25 to 50 µg daily in older patients and patients with known ischaemic heart disease.22, 33–35

Considerations and aims for this thesis

The aim of this thesis is to gain more insight in the effects of thyroid function on cardiovascular risk factors and related metabolic parameters as well as mortality. We therefore initiated both a cross-sectional evaluation and a case-cohort study in a large population-based study. In addition, we aimed to assess possible predictors for future hypothyroidism in a large, unselected population. Finally, we studied the improvement of complaints in hypothyroid patients treated with a high starting dose of levothyroxine compared to patients treated with a low starting dose. We evaluated the safety by registration of cardiac symptoms and events in both groups.

16

Chapter 1

The specific aims of this thesis are:

Part A: Effects of levels of thyroid stimulating hormone (TSH), free thyroxine (FT4) and

free triiodothyronine (FT3) within the euthyroid range on cardiovascular risk factors

and mortality

1. To investigate the relationship between thyroid function, serum lipids, insulin resistance, and the metabolic syndrome in euthyroid subjects in the PREVEND study, a large population-based study in the general (Western-European) population (chapter 2).

2. To investigate whether thyroid function predicts mortality in euthyroid subjects in a general Western-European population (chapter 3).

Part B: Prediction of the development of hypothyroidism

3. To investigate, in an unselected sample of euthyroid subjects within the general population, the relationship of the presence of thyroid peroxidase antibodies (TPOAbs) with levels of TSH within the normal reference range, and to assess whether the presence of the TPOAbs and levels of TSH predict the development of clinical hypothyroidism (chapter 4).

Part C: The treatment of overt hypothyroidism

4. To determine the prevalence of silent cardiac ischaemia in untreated hypothyroid patients (chapter 5).

5. To study whether levothyroxine suppletion aiming to restore plasma TSH and FT4 levels within the normal reference range results in earlier reduction of complaints and whether normalization of metabolic parameters can be performed with a straightforward high dose regimen without an increased risk of major adverse cardiac events (chapter 6).

17

Introduction and aims of the thesis

References

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2. Ross DS. Thyroid hormone synthesis and physiology. Cooper JS, Mulder JE, editors. www.uptodate.com 2012.

3. Kopp P. Thyroid hormone synthesis. In: Braverman LE, Utiger RD, editors. Werner & Ingbar’s The Thyroid, a fundamental and clinical text, 9th edition Philadelphia, USA: Lippincott Williams & Wilkins, 2005:52–76.

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10. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med 2001;344:501–509.11. Cappola AR, Fried LP, Arnold AM, Danese MD, Kuller LH, Burke GL, Tracy RP, Ladenson PW.

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of coronary heart disease: a meta-analysis. Am J Med 2006;119:541–551.13. Duntas LH. Thyroid disease and lipids. Thyroid 2002;12:287–293. 14. Fommei E, Iervasi G. The role of thyroid hormone in blood pressure homeostasis: evidence from

short-term hypothyroidism in humans. J Clin Endocrinol Metab 2002;87:1996–2000.15. Lekakis J, Papamichael C, Alevizaki M, Piperingos G, Marafelia P, Mantzos J, Stamatelopoulos S,

Koutras DA. Flow-mediated, endothelium-dependent vasodilation is impaired in subjects with hypothyroidism, borderline hypothyroidism, and high-normal serum thyrotropin (TSH) values. Thyroid 1997;7:411–414.

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Chapter 1

18. Hamilton TE, Davis S, Onstad L, Kopecky KJ. Thyrotropin levels in a population with no clinical, autoantibody, or ultrasonographic evidence of thyroid disease: implications for the diagnosis of subclinical hypothyroidism. J Clin Endocrinol Metab 2008;93:1224–1230.

19. Kratzsch J, Fiedler GM, Leichtle A, Brügel M, Buchbinder S, Otto L, Sabri O, Matthes G, Thiery J. New reference intervals for thyrotropin and thyroid hormones based on National Academy of Clinical Biochemistry criteria and regular ultrasonography of the thyroid. Clin Chem 2005;51:1480–1486.

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21. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, Braverman LE. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87:489–99.

22. Roberts CG, Ladenson PW. Hypothyroidism Lancet 2004;363:793–803.23. Strieder TG, Prummel MF, Tijssen JG, Endert E, Wiersinga WM. Risk factors for and prevalence

of thyroid disorders in a cross-sectional study among healthy female relatives of patients with autoimmune thyroid disease. Clin Endocrinol 2003;59:396–401.

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32. Masullo P, Venditti P, Agnisola C, Di Meo S. Role of nitric oxide in the reperfusion induced injury in hyperthyroid rat hearts. Free Radic Res. 2000;32:411–421.

33. Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, Pessah-Pollack R, Singer PA, Woeber KA; American Association Of Clinical Endocrinologists And American Thyroid Association Taskforce On Hypothyroidism In Adults. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid 2012;22:1200–1235.

34. Ross DS. Treatment of hypothyroidism. Cooper DS, Mulder JE, editors. www.uptodate.com 2013.35. Dekkers OM, Berghout A, Muller AF, Smit JWA, Wiersinga WM, Peeters RP, van der Ploeg MJ, de

Jong NW, Hermus ARMM. Thyroid function disorders – Guidelines of the Netherlands Association of Internal Medicine 2012:123–134

A Effects of levels of thyroid stimulating hormone (TSH), free thyroxine (FT4) and free triiodothyronine (FT3) in the euthyroid range on cardiovascular risk factors and mortality