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Endocrinology Unit Department of Medical Sciences "M. Aresu" University of Cagliari I-09042 Monserrato Cagliari, Italy
Address all correspondence and requests for reprints to: Prof. 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}pacs.unica.it.
Janus:
Roman god of doorways and archways, after whom the month of January is named.
Often depicted as a double-faced head, he was a deity of beginnings and ends.
Britannica Concise Encyclopedia
Several thyroid function abnormalities are observed in the elderly (1, 2). An increased prevalence of serum thyroid antibodies and clinical and subclinical hypothyroidism have been consistently reported, reaching a value as high as 20% in women older than 60–65 yr (3). The prevalence of subclinical hyperthyroidism is also increased in aged subjects of both sexes, affecting 1–1.5% of the general population in iodine-sufficient areas (3) and up to 7–8% in iodine-deficient areas (4). Moreover, the coexistence of several age-associated diseases may account for serum thyroid hormone and TSH abnormalities characteristic of the nonthyroidal illness (NTI) syndrome (1). Finally, an age-dependent decline of thyroid function, at least partially independent from associated NTI, has been documented, particularly in the oldest-old (>85 yr) population (1, 5).
Despite a very large number of studies, no consensus has been reached so far about the actual health impact of subclinical thyroid dysfunction, and different recommendations have been made recently about screening and treating these conditions (3, 6, 7, 8, 9, 10). One of the strongest arguments employed in favor of active detection and treatment of subclinical thyroid dysfunction is the possibility that subclinical thyroid disease may directly or indirectly influence the aging process and/or the pathogenesis of age-associated diseases.
Several investigators found a significant association between thyroid autoimmunity and/or subclinical hypothyroidism and atherosclerotic cardiovascular disease, possibly mediated by dislipidemia and poorly defined autoimmune mechanisms, but this finding has not been confirmed by others (see Ref.1 for review). Divergent results were also obtained in recent large epidemiolgical studies, two supporting a role of subclinical hypothyroidism in atherosclerosis and myocardial infarction in middle-aged Dutch women (11) and in Dutch males aged less than 50 yr (21), and two failing to find any relationship between thyroid autoimmunity, mild thyroid failure, and ischemic heart disease in an English community (12) and in a cohort of subjects older than 65 yr from New Mexico (22). Recently, a significant increase of all-cause mortality was observed in a cohort of middle-aged Japanese men with subclinical hypothyroidism followed for 12 yr (13). However, no agreement has been reached in favor or against active screening and/or treatment of mild thyroid failure (3, 6, 7, 8, 9, 10); L-T4 therapy has been discouraged in aged subjects, because the increased oxygen consumption consequent to thyroid hormone administration could be dangerous in the presence of coexisting coronary heart disease.
Subclinical hyperthyroidism may also represent an important health problem in the elderly. A large longitudinal study of subjects aged 60 yr or older, forming part of the Framingham population, provided evidence for three times increased risk of atrial fibrillation in people with suppressed (
0.1 mU/liter) serum TSH concentrations (14). The concept that mild thyroid hormone excess might result in an increase in cardiovascular morbidity is also supported by a subsequent large longitudinal study carried out in the UK in subjects aged 60 yr and older (15) followed for 10 yr. A significant increase in all-cause mortality (mostly accounted by mortality for cardiovascular diseases) was found from the second to the fifth year of follow-up in subjects with low, but not necessarily undetectable, serum TSH concentration (0.5 mU/liter) at the beginning of the study. Several questions remain unsolved, particularly the potential interference of associated NTI and the lack of thyroid function data during the follow-up. Subclinical hyperthyroidism might also be implicated in other health problems of the elderly. For example, both exogenous and endogenous subclinical hyperthyroidism are associated with reduced bone mineral content, which could lead to an increased risk of fractures (16). Moreover, in a short-term (2 yr) longitudinal study on 1843 Dutch subjects aged 55 yr or older, low serum TSH and higher serum T4 concentration were associated with a more than 3-fold increased risk of dementia and Alzheimer disease (17). In contrast to subclinical hypothyroidism, the recommendations of recent guidelines tend to support active treatment of most patients with subclinical hyperthyroidism, despite an almost complete lack of evidence-based data on the effectiveness of antithyroid therapy (3, 7, 9). This attitude is probably the consequence of a prudent clinical approach, given the universally recognized dangerous effects of excess thyroid hormone on the heart and skeleton.
Until recently, no studies were available on the health consequences of subtle thyroid dysfunction on the oldest-old fraction of the elderly population. Although a decline of serum T3 and TSH and an increase of rT3 (partially independent from associated NTI) has been consistently reported after the ninth decade of life (1, 5), whether and to what extent this phenomenon represents a physiological adaptive mechanism to different metabolic needs, or a subtle dysfunction contributing to the aging process, remains unclear. In 2004, Gussekloo et al. (18) enrolled a large cohort of subjects aged 85 yr who were followed annually for 4 yr. In this particular population, subjects with subclinical hypothyroidism actually had lower all-cause and cardiovascular mortality than euthyroid individuals, and there were no negative effects on performance status or mood. Surprisingly, no effects on mortality or performance were found even in subjects with untreated overt hypothyroidism. In contrast, an increased risk of cardiovascular mortality was associated with low serum TSH and increasing serum free T4 concentrations. These results support the concept that some degree of decreased thyroid activity at the tissue level might have favorable effects in the oldest-old subjects, whereas subtle thyroid hyperfunction may be detrimental. An important practical implication of this concept would be not treating oldest-old subjects with subclinical hypothyroidism and using lower replacement doses of L-T4 in overt hypothyroidism.
In the present issue of the journal, van den Beld et al. (19), again from The Netherlands, report the results of a new cross-sectional and longitudinal study on the health implications of subtle thyroid dysfunction in advanced age. In this study serum TSH, free and total T4, T3, rT3, and thyroxine binding globulin were measured together with a complete evaluation of physical function (activities of day living, physical performance, muscle strength, bone mineral density, and body composition) in 403 free living men aged 73–94 yr (thus, mostly oldest-old); mortality was reported over the next 4 yr. Although this study has important limitations (it was carried out only in men, no follow-up thyroid function data were available, and thyroid autoimmunity was not evaluated), it is particularly relevant for the assessment of the relationships between subtle changes of thyroid function/thyroid hormone metabolism and health status and survival in advanced age, in the absence of the disturbing interference of major NTI. The results showed that low serum free T4 (FT4) and T3 (with normal rT3) concentrations were associated with a better 4-yr survival and physical performance. On the other hand, subjects with low serum T3 and high rT3 concentrations (i.e. fulfilling the criteria for the "low T3 syndrome") had lower baseline physical activity. Reduced physical performance was also observed in subjects with isolated higher serum rT3 (and FT4) concentrations. It would appear that elderly subjects with low serum T3 concentrations may be subdivided into two groups: those with low serum FT4 and normal rT3, represented by subjects in good health in whom a longer survival is expected, and those with worse health, with high serum rT3 and FT4, probably reflecting the effect of subtle NTI, and/or an increased catabolic state. Although these results support the concept that lower thyroid status may indeed reflect an adaptive age-associated mechanism, the predictive value for health conditions of low serum T3 in old subjects may give a double-faced "Janus response" if it is not considered in the appropriate clinical and hormonal context. A somewhat surprising result found by van den Beld et al. (19) was the absence of any correlation between serum TSH concentration and either mortality or physical function. Indeed, serum TSH concentration is considered the best single marker of thyroid function, and abnormal TSH levels have been found to significantly correlate with all-cause and cardiovascular mortality in previous epidemiological studies (11, 13, 15, 18). Several possible explanations for this apparent paradox can be suggested. First, the prevalence of subclinical hypo- and hyperthyroidism in the entire cohort of the elderly subjects studied was surprisingly low, a likely explanation being it was composed entirely of males. Consequently, there was a narrower range of serum TSH concentrations, which could mask the effects of potential covariables. Secondly, the effects of subtle thyroid dysfunction are probably different in elderly populations with different age ranges. The main studies supporting a role for subclinical hypo- and hyperthyroidism as risk factors for atherosclerosis, cardiovascular disease, and all-cause mortality have been carried out in "young elderly" populations aged 55–60 yr or older. Interestingly, the risk for all-cause and cardiovascular mortality associated with low serum TSH in subjects aged 60 yr became insignificant after 10 yr follow-up (15) and the increase of mortality observed in Japanese with subclinical hypothyroidism disappeared after 6 yr (13). As underscored by van den Beld et al. in their discussion, the low number of patients with subclinical hypo- and hyperthyroidism may be due to the selection of relatively healthy oldest-old subjects. It is indeed conceivable that the majority of subjects with subclinical thyroid disorder were dead at a younger age, given the increased mortality reported for populations aged 55–70 yr (13, 15). A similar selection effect has been hypothesized to explain the low prevalence of antithyroid antibodies in healthy centenarians (20). Third, it is very probable that, in free-living oldest-old male subjects, a low TSH may be more often the consequence of physiological aging (1, 5), rather then the expression of subtle hyperthyroidism or severe NTI. Again, a reduced serum TSH in elderly subjects may give the "Janus response" in terms of prediction of mortality risk, depending on the absolute age and the presence or absence of underlying thyroid and nonthyroidal disease.
In conclusion, older and more recent studies provide evidence that mild thyroid dysfunction may represent a significant health problem for the elderly. Subclinical hyperthyroidism appears to be a significant risk factor for all-cause and cardiovascular mortality in subjects aged from 55–60 yr to the oldest-old. Subclinical hypothyroidism might be also associated with increased mortality in middle aged and "young elderly" subjects (possibly through its atherogenic potential), but mild thyroid failure appears to be devoid of detrimental effects and even possibly protective in oldest-old subjects. Although further data are needed to confirm this scenario, relevant information will only be obtained from studies that distinguish elderly subjects with primary thyroid diseases from those with normal thyroid health, in whom adaptive changes in hypothalamic-pituitary-thyroid function (consequent to NTI and/or to physiological aging) may have occurred. Without this perspective, considering serum thyroid hormone and TSH concentrations as risk factors in the elderly will always give the "Janus response."
Footnotes
Abbreviations: FT4, Free T4; NTI, nonthyroidal illness.
Received October 6, 2005.
Accepted October 14, 2005.
References
This article has been cited by other articles:
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  S. Mariotti Mild Hypothyroidism and Ischemic Heart Disease: Is Age the Answer? J. Clin. Endocrinol. Metab., August 1, 2008; 93(8): 2969 - 2971. [Full Text] [PDF]
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S. Razvi, A. Shakoor, M. Vanderpump, J. U. Weaver, and S. H. S. Pearce The Influence of Age on the Relationship between Subclinical Hypothyroidism and Ischemic Heart Disease: A Metaanalysis J. Clin. Endocrinol. Metab., August 1, 2008; 93(8): 2998 - 3007. [Abstract] [Full Text] [PDF]
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