Could Thyroid Function Tests Decrease Mortality Rates in the Elderly?

Keywords::

• aging
• mortality
• thyroid
• thyroid function test

Thyroid function is affected by the overall modifications of hormonal status that occur with the aging processes and thyroid dysfunctions are frequently observed in the elderly. The prevalence of serum thyroid antibodies may be increased in elderly subjects [1] and the prevalence of overt and subclinical hypothyroidism in older populations has been reported to be as high as 20% [2]. Subclinical hyperthyroidism also increases with aging, with a prevalence of 1–2% in iodine-sufficient areas and 7–8% in iodine-deficient areas [3]. The occurrence of nonthyroidal illness, often in the context of age-associated diseases, has also been reported to be more frequent in elderly subjects [1].

Whether and to what extent all these thyroid abnormalities may affect the health status of aging subjects has been the object of several studies. The issue is particularly important for subclinical thyroid diseases, which are the most frequent thyroid abnormalities encountered in the aging population. In spite of the large number of studies, difficulties exist in reaching a consensus on the real health impact of subclinical thyroid diseases in the elderly and on the recommendations of screening and treating elderly patients affected by these thyroid dysfunctions. One of the most important points which would support the need for detection of subclinical thyroid abnormalities in the elderly is that subclinical thyroid disease may itself influence the aging processes and worsen the clinical outcome of aging-associated diseases. With regard to subclinical hypothyroidism, divergent results have been reported by observational studies that compared the outcome of subclinically hypothyroid elderly subjects with euthyroid subjects. Uncertainty exists on whether subclinical hypothyroidism may influence the quality of life. In some experiences, a slight, although significant, increase in the score of symptoms of hypothyroidism was demonstrated in subclinically hypothyroid subjects [4]. However, difficulties exist in the diagnosis of subclinical hypothyroidism in the elderly due to the fact that the typical findings of hypothyroidism are less common in the elderly and, when present, are often attributed to age, drugs, depression or chronic illnesses. Subclinical hypothyroidism may influence the motor system and studies reported that it may increase the risk of hip fracture in elderly men [5]. However, other experiences demonstrated that mobility itself is not affected by this thyroid dysfunction and even a slight improvement in physical function may be observed in individuals with mild elevation in thyrotropin (TSH) [6]. Specific attention has been devoted to the relationship between cardiovascular function and subclinical hypothyroidism. In 2005, Rodondi and coworkers reported data from a study of 2730 subjects, aged 70–79 years, in whom baseline TSH measurements and 4-year follow-up were performed [7]. The diagnosis of subclinical hypothyroidism was made according to the presence of circulating concentrations of TSH of 4.5 mIU/l or greater. Congestive heart failure, coronary heart disease (CHD), stroke, as well as cardiovascular and total mortality were evaluated. As compared with euthyroid subjects, congestive heart failure events were more frequently observed among participants with TSH levels of 7.0 mIU/l or greater in comparison to those with TSH levels between 4.5 and 6.9 mIU/l. Multivariate analyses demonstrated that the risk of congestive heart failure was higher among participants with TSH levels of 7.0–9.9 mIU/l (hazard ratio [HR]: 2.58; 95% CI: 1.19–5.60) and higher than 10.0 mIU/l (HR: 3.26; 95% CI: 1.37–7.77). However, subclinical hypothyroidism was not associated with increased risk for CHD, stroke or cardiovascular-associated mortality or total mortality [7]. In agreement with these findings, other reports have demonstrated that subclinical hypothyroidism is associated with increased ischemic heart disease and cardiovascular mortality only in subjects from the younger populations and not in elderly subjects [8].

Whether subclinical hypothyroidism may increase mortality in elderly subjects is a matter of debate. In a recent reanalysis of the Whickham Survey cohort, subclinical hypothyroidism was associated with increased mortality in adult subjects followed for 20 years [9]. Further literature reports have demonstrated that subjects with increased TSH levels, especially with concentrations of 10 mIU/l or greater, have an increased risk of CHD events and CHD mortality [10]. On the contrary, recent reports did not show any relationship between subclinical hypothyroidism and mortality in an elderly population [11], further underlining the concept, suggested by several reports, of a general protective effect of mild hypothyroidism especially in the oldest old.

With regard to subclinical hyperthyroidism, a high number of studies have reported negative effects of this thyroid dysfunction on several clinical outcomes. In elderly individuals, subclinical hyperthyroidism has been shown to determine an impairment of bone metabolism leading to an increased risk of hip fractures [5]. Elderly subjects affected by subclinical hyperthyroidism may have an impairment of cognitive and physical function [3,12]. A particular aspect of the adverse clinical outcomes associated with subclinical hyperthyroidism in elderly subjects is represented by the negative effects of this thyroid dysfunction on the cardiovascular system and the possibility of an associated increase in mortality. However, only a few studies have addressed the relationship between subclinical hyperthyroidism and mortality in elderly subjects. In 2001, Parle and coworkers assessed mortality in a population-based study of 1191 individuals aged 60 years or older who were followed for 10 years [13]. In years 2–5, subjects with low serum TSH were characterized by an increase in mortality from all causes (HRs for years 2, 3, 4 and 5 of 2.1, 2.2, 1.8 and 1.8, respectively) and from cardiovascular causes (HRs at years 2, 3, 4 and 5 of 3.3, 3.0, 2.3 and 2.2, respectively) [13,14]. Using data from the Cardiovascular Health Study, a large, prospective cohort study, in 2006, Cappola et al. examined the relationship between thyroid status, cardiovascular risk and mortality in older adults [15]. The occurrence of incidental atrial fibrillation, CHD, cerebrovascular disease, cardiovascular and all-cause death was assessed. An increase in the incidence of atrial fibrillation was demonstrated in subjects with subclinical hyperthyroidism when compared with those with normal thyroid function (67 vs 31 events per 1000 person-years; p < 0.001, and an adjusted HR of 1.98; 95% CI: 1.29–3.03). However, no differences were demonstrated between subclinical hyperthyroid subjects and euthyroid subjects in CHD, cerebrovascular disease, cardiovascular death or all-cause death [15].

The contrasting results on the relationship between subclinical hyperthyroidism and mortality, especially of cardiovascular type, still represent an unsolved problem [16] and have been recently underlined by two studies that simultaneously appeared in the literature. In one of these studies a lack of association between subclinical hyperthyroidism and all-cause or cardiovascular mortality was demonstrated in a north-east German population [17]; on the contrary, the association was positive in another study on a Japanese–Brazilian population [18]. In both studies, data were adjusted for age, sex and other potential confounders.

Altogether, therefore, data on thyroid dysfunction, especially of subclinical type, and mortality in older individuals are still undefined. Several factors may be involved in this phenomenon, such as differences in the TSH cutoff for considering each single subclinical thyroid abnormality, difference in iodine intake, as well as in selection criteria, including age, sex, ethnicity, sample size of patients, differences in the duration of follow-up and presence of comorbidities. Nevertheless, the concept that mortality may represent an adverse clinical outcome of subclinical thyroid dysfunction, especially of subclinical hyperthyroidism, in elderly subjects remains an interesting issue. Thyroid dysfunction, especially of subclinical type, may undergo misdiagnosis in elderly subjects because of the presence of several concomitant confounding factors typical of the aging processes. Therefore, the possibility to detect the presence of a thyroid abnormality, by means of a thyroid function test to be performed in elderly individuals, would represent an interesting perspective. However, some open questions remain. For example, studies aimed at the demonstration of a reduced mortality following treatment of subclinical hyperthyroidism are still lacking although the treatment of this thyroid disorder has been contemplated in the guidelines on the management of thyrotoxicosis which have been recently issued [19]. Furthermore, a single thyroid function test could be insufficient, at least theoretically, resulting in the unpredictability of any further modification of thyroid function especially in areas which are endemic for the development of thyroid nodules, which can become hyperfunctioning with time. Again, in order to consider the beginning of a screening program by thyroid function test in the elderly, the aging cutoff would represent an open issue. Therefore, at present our knowledge may be considered insufficient to recommend a screening program by thyroid function test in all elderly individuals. However, the thyroid function test represents a useful completion of the general evaluation in elderly patients in cases of history (including familial history) of thyroid disorders or clinical suspicion, suggesting the presence of an underlying thyroid abnormality, including cardiac dysfunction, cognitive impairment or mood disorders. Both observational and intervention trials on the effect of treatment of subclinical hyperthyroidism, especially in middle-aged and elderly subjects, on clinical outcomes will give more defined information in order to better address the question of whether if and when a screening program by thyroid function test could prevent mortality in elderly individuals.

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The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.