Citation for published version (APA): Roos, A. (2014). Clinical and epidemiological studies on thyroid function [S.l.]: [S.n.]

Size: px

Start display at page:

Download "Citation for published version (APA): Roos, A. (2014). Clinical and epidemiological studies on thyroid function [S.l.]: [S.n.]"

Lindsay Wright
6 years ago
Views:

1 University of Groningen Clinical and epidemiological studies on thyroid function Roos, Annemieke IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2014 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Roos, A. (2014). Clinical and epidemiological studies on thyroid function [S.l.]: [S.n.] Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date:

2 7 Subclinical thyroid disease and heart failure Roos A, Links TP, Wolffenbuttel BHR European Journal of Heart Failure 2014;16:

3 Chapter 7 Editorial Subclinical hypothyroidism (SCH), defined as the finding of an elevated serum thyroidstimulating hormone (TSH) level with a normal free T4 level, is frequently observed in the general population. A recent publication, in data obtained from the LifeLines Cohort Study, showed a SCH prevalence of 10% in a relatively young group of individuals with mean age of 46 years. 1 Earlier studies have shown SCH prevalences of 4 20% in the adult population, mainly depending on age, sex, dietary iodine intake, and the cut-off concentrations of serum TSH used to define the condition. 2 In a large meta-analysis, Rodondi et al. 3 reported an association between SCH and the development of cardiovascular disease (CVD), but a significantly increased risk of both coronary heart disease (CHD) events and mortality was only seen in participants with TSH levels of 10 mu/l or higher. Subclinical hyperthyroidism, defined as the finding of a serum TSH level below the lower limit of the laboratory s reference range with a normal free T4 level, is less common. Reported prevalences range from 0.6% to 1.8% in the adult population, again depending on age, sex, and iodine intake. 2 Studies on the association of subclinical hyperthyroidism with mortality showed conflicting results: some studies demonstrated increased all-cause mortality, 4 while others did not. 5 However, recently an independent association has been shown between lower TSH levels and increased cardiovascular mortality during long-term follow-up in thyroid cancer patients on TSH-suppressive therapy. 6 It is known that an increased left ventricular mass, impaired diastolic dysfunction and increased risk on atrial fibrillation can be found during TSH-suppressive therapy. There are also several reports on the relationship between TSH and ageing, and both a progressive increase and decrease in TSH levels with advancing age have been reported. 7,8 Investigators from the Leiden 85-plus study 9 reported, in individuals aged 85 years and older, that SCH was associated with better survival than in subjects with normal TSH levels. However, such observational results should be interpreted with caution as other alterations in the oldest age group also are associated with better survival, such as high blood pressure and high cholesterol. In this issue, Chen et al. 10 report a very elegant prospective follow-up study on the relationship between TSH levels and outcome in patients with heart failure (HF). They followed a total of 5599 patients with a diagnosis of HF at a health maintenance organization and assessed both cardiac-related hospitalizations and mortality in this large cohort. The median follow-up period was slightly over 14 months. From their results it became apparent that both a high TSH level 106

4 Subclinical thyroid disease and heart failure and a low TSH level were associated with an increased mortality rate. Patients were divided in quartiles of TSH levels, and the mortality in the highest quartile was 36% higher than in the second quartile. This was observed in the entire cohort, which included subjects previously diagnosed with a thyroid disorder who were treated with levothyroxine and subjects without known thyroid disease. In addition, a low TSH level <0.45 mu/l was associated with reduced survival. When they looked at specific ranges of TSH (Table 3 in their paper), a value between 4.5 mu/l and 10 mu/l was associated with a 40% higher mortality, whereas subjects with TSH >10 mu/l had a more than twofold increase in mortality. These increased risks were even more pronounced in those without thyroid treatment. These results are supported by other recent studies. In the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial), 11 TSH levels were evaluated at baseline and during follow-up in patients with heart failure, randomized to treatment with placebo, amiodarone or implantable cardioverter defibrillator (ICD) therapy. It appeared that patients with baseline or new-onset abnormal thyroid function had 58% higher mortality rate than those with normal thyroid function, even after controlling for other known mortality predictors. Another study evaluated TSH levels in patients with cardiomyopathy who were, among others, treated with an ICD. The authors showed that both low and high TSH levels were associated with a higher mortality. 12 Even in cancer patients, investigators have been able to show that elevated TSH levels were independently associated with poor disease-specific survival. 13 Finally, in a recent meta-analysis of prospective cohort studies, it was shown that SCH was associated with an increased risk of CHD events, CHD mortality and HF events, especially in individuals with TSH levels 10.0 mu/l. 14 Which thyroid-stimulating hormone levels concur with increased mortality? Based on their observations, Chen et al. 10 conclude that TSH levels already above the normal value were independently associated with increased mortality and cardiac-related hospitalizations. However, as subjects with increased TSH levels were only further divided in two subgroups, TSH mu/l and TSH >10 mu/l, respectively, we are actually not informed about mortality in subjects with only a slightly increased TSH, for example <7 mu/l. Might it be that TSH is linearly related to mortality? It therefore remains unclear whether TSH levels just above the upper limit of the laboratory s reference range are clinically relevant with respect to mortality. The papers of both Mitchell et al. 11 and Azemi et al 12 provide no answers to this question because these authors did not subdivide subjects with increased TSH levels. 107

5 Chapter 7 The same holds true for the association of a low TSH (<0.45 mu/l) with mortality: because there was only a small number of subjects in this TSH category, Chen et al. 10 did not subdivide this group. Therefore, no statement can be made about below which TSH level a clinically relevant increase in mortality can be expected. This is especially true because of the conflicting results of other studies mentioned earlier. 4,5 Treatment necessary? There is still also uncertainty over whether treatment of SCH is warranted, because of the paucity of well-performed, large-size prospective clinical trials. Recently, Cooper and Biondi 2 recommended initiating hormone supplementation in subjects with mild subclinical hypothyroidism, but only in those younger than 75 years. They suggested that there is insufficient evidence to support an association with symptoms and that replacement does not improve cognition or quality of life. They also state that there is an association between subclinical hypothyroidism and better survival in the oldest patients. Unfortunately, to our knowledge, no prospective studies on the treatment of subclinical hypothyroidism with respect to HF have been performed in human subjects. However, in hamsters with cardiomyopathy treatment of subclinical hypothyroidism prevented progressive left ventricle dysfunction. 15 Similar findings in humans would promote treatment of SCH. In patients with heart failure there appears to be a small window of optimal TSH levels, and probably also free T4 levels, although Chen et al. 10 were unable to measure this in their study. We believe that only by carrying out well-designed prospective studies can we get a good answer to this question. Unfortunately, the number of currently ongoing trials is limited. Most studies look into or have been looking into intermediate outcome measures such as lipid profile, inflammation and oxidative stress, and apnoea hypopnoea index score ( clinicaltrials.gov, website accessed November 15, 2013). The effects of thyroid hormone supplementation is evaluated prospectively in 3000 subjects with subclinical hypothyroidism in a study called TRUST (Thyroid Hormone Replacement for Subclinical Hypo-Thyroidism Trial). In this study, subclinical hypothyroidism is defined as having a TSH levels between 4.5 mu/l and 20 mu/l, with free T4 levels still within the normal range. The primary outcome of the study (Clinical Trials identifier NCT ) is the development of fatal and non-fatal cardiovascular events, with a rather broad definition: fatal and non-fatal myocardial infarction and stroke, revascularization procedures including those for coronary and peripheral atherosclerotic vascular disease, amputations, and hospitalizations 108

6 Subclinical thyroid disease and heart failure for heart failure. The TRUST investigators will also evaluate thyroid-specific quality of life. It should be noted that the aim for thyroid hormone substitution in this study is to obtain a TSH level between 0.4 mu/l and 4.6 mu/l, and not necessarily a TSH of around 1.0 mu/l, which clinicians typically aim for in young patients with hypothyroidism. As part of TRUST, investigators in the Netherlands will specifically include participants aged 80 years and older (IEMO 80-plus Thyroid Trial: NTR3851 (Nederlands Trial Register, nl )), and study the effect of treatment on the same endpoints ranging from cardiovascular disease and mortality to cognitive and physical function and quality of life in these very old people. It should be noted that subjects with New York Heart Association IV congestive heart failure are excluded from this trial. Based on the results of Chen et al., 10 it would be wise to also include such patients, perhaps in a substudy of TRUST. Considering the effect size of elevated TSH associated with increased mortality, a 3-year prospective study in participants may be able to give an answer regarding the benefits and drawbacks of levothyroxine supplementation in these patients. Similar studies should be undertaken in those with suppressed TSH. 109

7 Chapter 7 References 1. Klaver EI, van Loon HC, Stienstra R, Links TP, Keers JC, Kema IP, Muller Kobold AC, Van der Klauw MM, Wolffenbuttel BHR. Thyroid Hormone Status and Health-Related Quality Of Life in the LifeLines Cohort Study. Thyroid 2013;23: Cooper DS, Biondi B. Subclinical thyroid disease. Lancet 2012;379: Rodondi N, den Elzen WPJ, Bauer DC, Cappola AR, Razvi S, Walsh JP, Asvold BO, Iervasi G, Imaizumi M, Collet TH, Bremner A, Maisonneuve P, Sgarbi JA, Khaw KT, Vanderpump MP, Newman AB, Cornuz J, Franklyn JA, Westendorp RG, Vittinghoff E, Gussekloo J; Thyroid Studies Collaboration. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA 2010;304: Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet 2001;358: van den Beld AW, Visser TJ, Feelders RA, Grobbee DE, Lamberts SW. Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. J Clin Endocrinol Metab 2005;90: Klein Hesselink EN, Klein Hesselink MS, de Bock GH, Gansevoort RT, Bakker SJ, Vredeveld EJ, van der Horst-Schrivers AN, van der Horst IC, Kamphuisen PW, Plukker JT, Links TP, Lefrandt JD. Long-term cardiovascular mortality in patients with differentiated thyroid carcinoma: an observational study. J Clin Oncol 2013;31: Atzmon G, Barzilai N, Hollowell JG, Surks MI, Gabriely I. Extreme longevity is associated with increased serum thyrotropin. J Clin Endocrinol Metab 2009;94: Atzmon G, Barzilai N, Surks MI, Gabriely I. Genetic predisposition to elevated serum thyrotropin is associated with exceptional longevity. J Clin Endocrinol Metab 2009;94: Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frölich M, Westendorp RG. Thyroid status, disability and cognitive function, and survival in old age. JAMA 2004;292: Chen S, Shauer A, Zwas DR, Lotan C, Keren A, Gotsman I. The effect of thyroid function on clinical outcome in patients with heart failure. Eur J Heart Fail 2014;16: Mitchell JE, Hellkamp AS, Mark DB, Anderson J, Johnson GW, Poole JE, Lee KL, Bardy GH. Thyroid Function in Heart Failure and Impact on Mortality. JACC Heart Fail 2013;1: Azemi T, Bhavnani S, Kazi F, Coleman CI, Guertin D, Kluger J, Clyne CA. Prognostic impact of thyroid stimulating hormone levels in patients with cardiomyopathy. Conn Med 2013;77: Seebacher V, Hofstetter G, Polterauer S, Reinthaller A, Grimm C, Schwameis R, Taucher S, Wagener A, Marth C, Concin N. Does thyroid-stimulating hormone influence the prognosis of patients with endometrial cancer? A multicentre trial. Br J Cancer 2013;109: Gencer B, Collet TH, Virgini V, Auer R, Rodondi N. Subclinical thyroid dysfunction and cardiovascular outcomes among prospective cohort studies. Endocr Metab Immune Disord Drug Targets 2013;13:

8 Subclinical thyroid disease and heart failure 15. Khalife WI, Tang YD, Kuzman JA, Thomas TA, Anderson BE, Said S, Tille P, Schlenker EH, Gerdes AM. Treatment of subclinical hypothyroidism reverses ischemia and prevents myocyte loss and progressive LV dysfunction in hamsters with dilated cardiomyopathy. Am J Physiol Heart Circ Physiol 2005;289:H

Supplementary Online Material

Supplementary Online Material Collet T-H, Gussekloo J, Bauer DC, et al; Thyroid Studies Collaboration. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med.