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Is Subclinical Thyroid Dysfunction in the Elderly Associated with Depression or Cognitive Dysfunction?
7 auth. L. Roberts, H. Pattison, A. Roalfe, J. Franklyn, Sue Wilson, F. Hobbs, ...
Context The relationship between subclinical thyroid dysfunction and disorders of cognition and mood is unclear. Contribution The authors studied 5868 general practice patients 65 years of age or older with a detailed medical history, thyroid tests,…
Context The relationship between subclinical thyroid dysfunction and disorders of cognition and mood is unclear. Contribution The authors studied 5868 general practice patients 65 years of age or older with a detailed medical history, thyroid tests, and standardized tests of cognition and mood. They found no association between subclinical thyroid dysfunction and anxiety, depression, or cognitive impairment in prediction models that adjusted for age, sex, social deprivation, medications, and comorbid diseases. Implications This study provides good evidence that subclinical thyroid dysfunction is not related to disorders of cognition and mood in older persons. The Editors The advent of automated sensitive assays for thyroid hormones and thyroid-stimulating hormone (TSH) and the increasingly widespread use of such tests have led to a substantial increase in the identification of mild thyroid dysfunction, especially in elderly patients. This, in turn, has led many physicians to treat subclinical (also known as mild) dysfunction. However, the clinical significance of mild thyroid dysfunction remains uncertain, and evidence on the efficacy or safety of treatment is limited (13). Subclinical thyroid dysfunction is characterized by an abnormal serum level of TSH in association with normal serum levels of thyroid hormone. Subclinical hypothyroidism is defined biochemically as an increased serum TSH level with a normal serum free thyroxine (T4) level, and subclinical hyperthyroidism as a decreased serum TSH level with normal levels of free T4 and free triiodothyronine. One postulated consequence of minor abnormalities of thyroid function, especially subclinical hypothyroidism, is an effect on cognitive functioning and mood. The association between overt hypothyroidism and cognitive dysfunction is well established (4, 5), although more recent evidence suggests that this association is confounded by mood (6). Whether a similar association exists with mild or subclinical hypothyroidism is uncertain. Some studies report no association between subclinical hypothyroidism and measures of cognition (5, 79), whereas others have identified between-group differences in cognitive functioning when patients with subclinical hypothyroidism were compared with euthyroid controls (10). A recent study (11) with a case-matched design demonstrated no differences in cognitive functioning between subclinically hypothyroid and euthyroid patients, although the criteria for defining subclinical hypothyroidism were atypical (an upper TSH limit of 3.5 mIU/L) and external validity was reduced by the exclusion of patients with serious illness or a history of cardiovascular disease. Associations between subclinical hypothyroidism and depression have also been described (6, 10, 12, 13), but many of these studies were based on small samples and were subject to selection and recruitment bias. An association between subclinical dysfunction and anxiety has also been demonstrated (14). Nevertheless, the largest reported study to date (30589 patients) (15) showed no association between subclinical hypothyroidism and depression or anxiety, findings that have been reported elsewhere (9, 11). A recent systematic review that aimed to determine any association between thyroid dysfunction and cognitive function and mood concluded that evidence is insufficient to confirm or refute an association with subclinical hypothyroidism or subclinical hyperthyroidism (1). We used standard diagnostic criteria to examine these possible associations in a large community-based cohort of persons 65 years of age or older (the Birmingham Elderly Thyroid Study). We recorded measures of thyroid function, cognitive functioning, depression, and anxiety and report on associations after controlling for the confounding effects of comorbid illness and medication use. Methods Recruitment and Participants Participants were recruited from 20 primary care practices in central England. The sample was selected to encompass patients from a range of socioeconomic backgrounds. To maximize generalizability to the primary care population, all patients who did not have an active diagnosis of thyroid disease were included. Patients were excluded if they had received antithyroid treatment within the previous 12 months or were currently receiving treatment for a thyroid disorder, or if their family physician deemed that contact was inappropriate (for example, because of recent bereavement or inability to give informed consent). All other patients 65 years of age or older were eligible and were invited to participate by letter. Because the uptake rate was only 14.6% among the first 699 patients older than 85 years of age who were contacted, recruitment was subsequently limited to patients 65 to 84 years of age (inclusive) for the remainder of the study, although previously contacted patients who were older than 84 years of age remained eligible. Patients who accepted the invitation received an appointment with a research or trained primary care nurse at their usual primary care practice or their home. Ethical approval was obtained from the Multi-Centre Research Ethics Committee (Scotland), and local approval was confirmed before commencement of the study. Written informed consent was obtained from all participants. Measurements and Sample Size Patients were placed under no restrictions on eating or medication use before serum samples were obtained for testing. Serum samples were obtained during normal office hours and were treated and collected according to the practice's usual procedure for blood collection. Serum TSH and free T4 were measured by using a chemiluminescent immunoassay (Adiva Centaur [Bayer Diagnostics, Newbury, United Kingdom]) in the Regional Endocrine Laboratory of the University Hospital Birmingham National Health Service Trust. Interassay coefficients of variation were 4.4% to 10.9% over 0.41 to 24.5 mIU/L for the TSH assay and 8.2% to 9.8% over 8.2 to 54.9 pmol/L for the free T4 assay. The laboratory reference range was 0.4 to 5.5 mIU/L for TSH and 9.0 to 20.0 pmol/L for free T4. Serum free triiodothyronine was measured by chemiluminescent assay (Avida Centaur) in all cases in which the TSH level was less than 0.4 mIU/L or a within-range TSH level was accompanied by an elevated free T4 level. The reference range for the triiodothyronine assay was 3.5 to 6.5 pmol/L, and the interassay coefficient of variation was 4.2% to 6.9% over 4.0 to 16.0 pmol/L. The Index of Multiple Deprivation 2004 (16) was calculated for each participant on the basis of his or her postal code. This proxy measure of socioeconomic deprivation encompasses 7 domains: income; employment; health and disability; education, skills, and training; barriers to housing and services; living environment; and crime. All major current or previous medical diagnoses and current drug therapies were recorded on the basis of patient reporting and validation from primary care records. Diagnoses were categorized in line with recognized disease groupings. Medications that are known to interact with thyroid function, anxiety, depression, or cognition were coded under generic headings. Cognition was assessed by using the Folstein Mini-Mental State Examination (MMSE) (17), which is widely used to determine cognitive status in clinical and research settings, and the Middlesex Elderly Assessment of Mental State (MEAMS) (18), which was developed as a screening test to detect gross impairment of specific cognitive skills in elderly persons and systematically surveys the major areas of cognitive performance. Aspects covered by MEAMS include orientation, learning, memory, numeracy, perception, attention, and language skills. Both tests comprise a range of tasks that all elderly persons without cognitive impairment should be able to complete, regardless of intelligence. Possible scores on the MMSE range from 0 to 30. Subtests in MEAMS can be used alone, or a combined score can be produced (range, 0 to 12). In both tests, higher scores indicate less dysfunction. Nurses were trained in the administration of all tests to the required standard. Symptoms of depression and anxiety were self-reported by using the Hospital Anxiety and Depression Scale (HADS) (19), which consists of 7 items for depression and 7 for anxiety. Each item is scored from 0 to 3, and the maximum total score on each scale is 21. Scores of 8 to 10 indicate mild disorder, scores of 11 to 14 indicate moderate disorder, and scores of 15 or greater indicate severe anxiety or depression. Assuming a prevalence of 9% for subclinical hypothyroidism and 6% for subclinical hyperthyroidism, a planned sample size of 6200 patients was sufficient to detect a difference between the subclinical and euthyroid groups of 0.4 unit (SD, 2.2) in MMSE score (20) and 0.7 unit (SD, 3.6) in HADS score (21), with 90% power and 5% significance. Data Management and Coding Participants were classified according to serum free thyroid hormone and TSH levels into 1 of 5 categories: overt hypothyroidism, subclinical hypothyroidism, euthyroidism, subclinical hyperthyroidism, and overt hyperthyroidism. Euthyroidism was further subdivided into quartiles before analysis. Participants who could not be categorized on the basis of thyroid function results were excluded from analyses. Table 1 shows details of criteria for classification. Table 1. Values Used to Categorize Thyroid Status In cases where only 1 item per scale was missing on the HADS data, the missing value was imputed by using mean scores. Missing values on MEAMS and MMSE were not imputed because of the heterogeneity of individual tests (which measured distinct aspects of cognitive processing) and the fact that some processes are assessed by only 1 or 2 items. Participants for whom data were incomplete were excluded from corresponding analyses. Statistical Analysis Analyses were done by using SAS software, version 9.1 (SAS Institute, Inc., Cary, North C
Published in
Annals of Internal Medicine
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11
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7 | 2006 |
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