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EDITORIAL |
Endocrinology, Department of Medical Sciences, Presidio di Monserrato, University of Cagliari, Strada Statale 554-bivio Sestu, I-09042, Monserrato, Cagliari, Italy
Address all correspondence and requests for reprints to: Professor Stefano Mariotti, M.D., Endocrinology, Department of Medical Sciences, Presidio di Monserrato, University of Cagliari, Strada Statale 554-bivio Sestu, I-09042 Monserrato, Cagliari, Italy. E-mail: mariotti{at}medicina.unica.it.
It has been recognized for many years that thyroid function and aging are related (1). Aging is associated with an increased prevalence of serum antithyroid antibodies and overt and mild1 hypothyroidism and hyperthyroidism. Moreover, circulating thyroid hormone and TSH abnormalities characteristic of the "non-thyroidal illness" syndrome due to age-associated diseases may be frequently observed. Finally, an age-dependent decline of thyroid function, at least partially independent from associated "non-thyroidal illness," has been documented in the oldest-old (>85 yr) population (1, 2). Although the detrimental effects of overt thyroid dysfunction in elderly patients are universally recognized, the clinical relevance of mild forms of hypothyroidism and hyperthyroidism remains a matter of debate. This is an important issue, given the high prevalence of mild thyroid dysfunctions (particularly hypothyroidism) in the general population older than 65 yr, and the possibility that mild alterations of thyroid economy might directly or indirectly influence the aging process and/or the pathogenesis of age-associated diseases. However, despite a very large number of studies performed over many decades, no consensus has been reached about the actual health impact of mild thyroid dysfunction and the wisdom of screening for or treating these conditions (3, 4, 5). This uncertainty is the consequence of the small number of epidemiological studies with appropriate statistical power, and of the lack of well-designed randomized controlled trials designed to assess the effects of correcting mild thyroid dysfunction.
A further area of uncertainly is represented by the health consequences of subtle thyroid dysfunction on the oldest-old fraction of the elderly population (i.e. those >85 yr), in whom, as noted previously, a decline in serum T3 and TSH and an increase of rT3 are often present (1, 2). In particular, the question of whether and to what extent this phenomenon represents a physiological adaptive mechanism to different metabolic needs, or subtle dysfunction contributing to the aging process, remained a matter of speculation until the recent publication of two important Dutch studies. In the first, Gussekloo et al. (6) found lower all-cause and cardiovascular mortality in hypothyroid subjects aged 85 yr followed for 4 yr, when compared with euthyroid individuals. In the second, van den Beld et al. (7) showed that low-serum free T4 and T3 (with normal rT3) concentrations were associated with a better 4-yr survival and physical performance, whereas subjects with low-serum T3 and high rT3 concentrations (i.e. fulfilling the criteria for the "low T3 syndrome") did not show any survival advantage and had lower baseline physical activity. Together, these two studies support the concept that some degree of physiologically decreased thyroid activity at the tissue level might have favorable effects in the oldest-old subjects but also show that caution should be exercised when interpreting the predictive value of thyroid dysfunction in old subjects, which may give a double-faced "Janus response," if not considered in the appropriate context (8).
One of the most debated issues regarding the health consequences of mild hypothyroidism is represented by the potential increase of ischemic heart disease (IHD), possibly mediated by dyslipidemia and still undefined immunological mechanisms associated with thyroid autoimmunity. As reported in detail in recent reviews and metaanalyses (9, 10, 11, 12, 13, 14), epidemiological evidence supporting a role of mild thyroid failure as a risk factor of IHD is contradictory, providing odds ratios (ORs) ranging from more than 3.0 to less than 1.0, when the largest population-based cross-sectional and longitudinal studies are considered. On the basis of the results of the recent Dutch studies showing no detrimental (actually favorable) effects of hypothyroidism in the oldest-old group, it has been hypothesized that different age-dependent susceptibilities to slightly reduced thyroid function may explain the contradictory results (8, 15). Support for this concept actually came from two recent reviews. The first, a concise review focused on the cardiovascular risk in elderly hypothyroid patients (11), reported an inverse correlation between the mean age of the subjects examined in several cross-sectional and longitudinal studies, and the OR for IHD associated with mild hypothyroidism. The second, an extensive review on the clinical significance of the entire spectrum of mild thyroid dysfunction, confirmed this observation for IHD, and found a similar age-related pattern for hypothyroid symptoms and mood/cognitive abnormalities (13). However, the value of the aforementioned observations was limited by the lack of stringent methodological criteria in selecting and analyzing the published data.
In the present issue of the journal, Razvi et al. (16) have performed a detailed metaanalysis on the relationship between mild hypothyroidism and IHD, in which for the first time, the age of the subjects examined was considered. There were 15 studies fulfilling strict quality criteria selected from over 2000 publications, providing a sufficiently large number of mild hypothyroid and euthyroid subjects to be analyzed. The results obtained showed that both the incidence and prevalence of IHD were higher in mild hypothyroidism only in studies including subjects younger than 65 yr [OR (95% confidence interval): 1.57 (1.19–2.06) vs. 1.01 (0.87–1.18) and 1.68 (1.27–2.23) vs. 1.02 (0.85–1.22), respectively]. Cardiovascular as well as all-cause mortality was also increased in studies involving subjects younger than 65 yr, but not in studies of older people [OR: 1.37 (1.04–1.79) vs. 0.85 (0.56–1.29)]. As the authors state in their discussion, this finding "led to robust confirmation of the hypothesis that the age of the cohort studies has an important bearing on the relative influence of subclinical hypothyroidism on the IHD prevalence, incidence and outcome." The high quality of this analysis appears to overcome some inherent limitations of this metaanalysis, especially the heterogeneous nature of the selected study populations.
The possible mechanisms involved in the age-dependent susceptibility to mild hypothyroidism can be presently only hypothesized (Fig. 1
). At a younger age, hypothyroidism may synergize (through dyslipidemia, endothelial dysfunction, or direct effect on the heart) with other genetic or environmental factors to increase the risk for IHD. In contrast, older subjects (and particularly the oldest-old population aged >85 yr) represent a selected population with longer survival and lower cardiovascular risk, who might rather benefit from the energy sparing effects of mild thyroid failure. Moreover, given the increased cardiovascular risk of middle-aged subjects with mild thyroid failure, it is conceivable that the majority of subjects with mild thyroid failure die at a younger age. A similar selection effect has been hypothesized to explain the low prevalence of antithyroid antibodies in healthy subjects older than 85–90 yr, including centenarians (17). Alternative explanations may also be considered, as pointed out by Razvi et al. (16): a larger contribution in the older subjects of non-thyroid-related conventional vascular risk factors, masking the contribution of mild thyroid failure, and different degree of "medicalization" of subjects with thyroid dysfunction, leading them to report more IDH symptoms or be subject to more medical investigation. Finally, age-dependent differences in peripheral tissue response to thyroid hormones (1) may exist together with the aforementioned mechanisms to explain the age-dependant variation of IHD risk in mild hypothyroidism. It should be noted that mild hypothyroidism is not the only hormonal model showing different effects on cardiovascular risk at different ages. Beside the example quoted by Ravzi et al. (16) related to obesity (18), a unifying hypothesis reconciling previous contradictory data supporting either protective or deleterious effects of estrogens on the cardiovascular system has been proposed. According to this hypothesis, estrogens reduce the risk of developing atherosclerosis in premenopausal women, whereas in postmenopausal women who may have established atherosclerotic disease, estrogens increase the cardiovascular risk through effects on plaque stability and clot formation (19, 20).
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Footnotes
1 In this Editorial the term "subclinical" hypothyroidism will be avoided and substituted with "mild." This is because the term "subclinical" is somewhat ambiguous, especially for aged patients, in whom symptoms may be absent even in the presence of marked serum thyroid hormone alterations. 
Abbreviations: IHD, Ischemic heart disease; OR, odds ratio.
Received June 6, 2008.
Accepted June 13, 2008.
References
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