Page 1 of 29 Thyroid Subclinical Thyroid Dysfunction and Functional Capacity among Elderly (dot: 10. 1089/ thy. 2013. 0071) This article has been peer-reviewed and accepted for publication, but has yet to undergo copyediting and proof correction. The final published version may differ from this proof. Subclinical Thyroid Dysfunction and Functional Capacity among Elderly 1 Vanessa S. Virgini, MD *, Liselotte W. WiJsman, MD *, Nicolas Rodondi, MD, MAS , Douglas C. 4 5 6 Bauer, MD, PhD , Patricia M. Kearney, MD, PhD ,JacobiJn Gussekloo, MD, PhD , Wendy p.
J. den 6 7 2 Elzen, MD, PhD Wouter Jukema, MD, PhD , Rudi G. J. Westendorp, MD, PhD , Ian Ford, MD,8 9 PhD , David J. Stott, MD, PhD and Sit-non P. M00ijaart, MD, PhD , on behalf of the PROSPER study group. Department of General Internal Medicine, Inselspital, University Hospital of Bern, Bern, Switzerland 2 (Vanessa. [email protected] ch, Nicolas. [email protected] ch); Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands (L. W. [email protected] nl, 3 R. G. J. [email protected] nl, S. P. [email protected] l); Netherlands Consortium for Healthy Aging, 4 Leiden, the Netherlands; Department of Internal Medicine, San Francisco University Center, San 5 Francisco, the United States of America ([email protected] ucsf. edu); Department of Epidemiology and 6 Public Health, University College Cork, Cork, Ireland (patricia. [email protected] ie); Department of Public Health and Primary Care, Leiden 0. [email protected] nl, W. P. J. [email protected] nl); Department of Cardiology, Leiden University 8 Medical Center, Leiden, the Netherlands 0. W. [email protected] l); Institute of Health and Wellbeing, 9 Robertson Centre, University of Glasgow, Glasgow, Scotland (Ian. [email protected] ac. uk); Institute of Cardiovascular (David. J. [email protected] ac. uk); Sciences, f Glasgow, Scotland 10 Institute for Evidence-Based Medicine in Old Age, Leiden, the Running head: Subclinical thyroid function and functional capacity Key words: Subclinical, thyroid, function, capacity, elderly, PROSPER page 2 of 29 Abstract Background Subclinical thyroid dysfunction is common among older people and has been associated with decreased functional capacity, but with conflicting data.
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The aim of this study was to assess the association between subclinical thyroid dysfunction and functional capacity in an elderly population. Methods We included 5182 participants with a mean age of 75. years from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Self-reported functional capacity was assessed using the Barthel Index (81) and the Instrumental Activities of Daily Living (IADL) scores at baseline and during follow-up. Participants with subclinical hyperthyroidism (n=65) and subclinical hypothyroidism (n=173) were compared to euthyroid participants (n=4944).
The association between persistent subclinical thyroid dysfunction and functional capacity and decline was also investigated. Results At baseline, compared to euthyroid participants [Bl 19. 63?±SE 0. 9, IADL 13. 62?± 0. 02], there was no difference in functional capacity for participants with subclinical hyperthyroidism [Bl 19. 63?±0. 09, IADL 13. 60?±0. 12] or subclinical hypothyroidism [Bl 19. 85?± 0. 05, ‘ADL 13. 63?± 0. 07, all p-values > 0. 05]. Over a mean 3. -year follow-up period, there was no association between thyroid function and annual decline of either Bl or IADL (all p-values > 0. 05). No association was found between persistent subclinical thyroid dysfunction and functional capacity at baseline or during follow up (all p-values > 0. 05). Results were similar after excluding articipants with a maximum Barthel and/or IADL score at baseline. Conclusion Among well-functioning community-dwelling elderly, we found no evidence that subclinical thyroid dysfunction contributes to decreased functional capacity.
Page 4 of 29 4 Introduction Subclinical thyroid dysfunction is a common condition, particularly among older people (1-3). It is defined as a biochemical perturbation of TSH values with normal free T4 levels (1 ;3;4), irrespective of the presence or absence of symptoms (3;5;6). The prevalence of subclinical thyroid dysfunction increases with age, reaching up to 4% or subclinical hyperthyroidism (1-3) and up to 20% for subclinical hypothyroidism in subjects over the age of 65 years (1 ;3;7).
Subclinical thyroid dysfunction has been associated with several adverse outcomes, such as cardiovascular disease (8-10), osteoporosis (1 ;11-13) and cognitive dysfunction (6;14;15). Furthermore, subclinical thyroid dysfunction has also been associated with decreased functional capacity (16) and neuromuscular abnormalities (17), but data are conflicting (17-20) and reliable evidence on the association between subclinical thyroid dysfunction and functional capacity in an older population is acking.
Both subclinical hyperthyroidism and subclinical hypothyroidism may progress to overt disease or revert to euthyroidism, in the course of months (21). Studies with repeated TSH measurements, which can identify persistent thyroid dysfunction, may be more strongly associated with specific end points than studies with a single persistent subclinical thyroid dysfunction and functional capacity. Therefore, we assessed the association between subclinical thyroid dysfunction and functional capacity in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) (22).
In over five thousand participants, we investigated the association between thyroid status at baseline and persistent thyroid status after six months and differ from this proof. Page 5 of 29 repeated assessments of functional capacity during a mean 3. 2-year follow-up period. Page 6 of 29 Methods Subjects All subjects were participants of the PROSPER trial, designed to assess if pravastatin would reduce the risk of cardiovascular events in an elderly population with cardiovascular disease or at high risk of developing cardiovascular disease.
Details on the study design have been previously described (23). A total of 5804 men and women aged 70 to 82 years with pre-existing cardiovascular disease (including coronary, cerebrovascular or peripheral artery disease) or at risk to develop such a condition (current cigarette smoking, hypertension, known diabetes mellitus or fasting blood glucose over 7 mmol/L) were randomized to receive either pravastatin 40 mg daily or placebo over a mean 3. 2-year period in Scotland, Ireland and the Netherlands.
Participants with congestive heart failure (New York Heart Association Ill or ‘V), physical or mental inability to attend the clinic for the screening visit or poor the PROSPER trial. From the initial trial population, we excluded participants with missing TSH and/or free T4 levels and with missing Barthel Index (81) or Instrumental Activities of Daily Living (IADL) scores. Participants using antithyroid medication and/or thyroxine supplementation were also excluded. The trial protocol was approved by the Medical Ethic Committees of all involved centers, and all participants provided written informed consent. age 7 of 29 Thyroid function TSH was measured at baseline in all participants. Measurements were performed in three respective laboratory centers (Glasgow in Scotland, Cork in Ireland, Leiden in he Netherlands). Indications for additional measurements of free T4 were different between countries. In Scotland and Ireland, free T4 levels were measured when TSH was abnormal based upon specific cut-off levels of TSH (when TSH was 10 mlU/L in Scotland, and 5 mlU/L in Ireland), while they were measured in all participants in the Netherlands, independently of the TSH result.
TSH and free T4 levels were measured using state-of-the-art immunoassays (third generation assays with a functional sensitivity of 0. 05 mlU/L or less). For both measurements, estimated inter- and intra- easured again at 6 months of follow-up in available frozen plasma samples of all participants, which were stored at the University of Glasgow. The same electrochemiluminescence immunodetection method on a Roche Elecsys 2010 (Burgess Hill, I-JK) was used. The limits of detection were below 0. 005 mlU/L and 0. 3 for TSH and free T4 (reference range: 12-22 pmol/L) respectively.
A reference range between 0. 45 and 4. 50 mllJ/L derived from relevant literature was used for TSH (4;9). The narrowest free T4 reference range (12-18 pmol/L) was chosen to take inter- laboratory differences into account (24). On the basis of previous publications 4;25-28), we classified participants into three thyroid states groups. At baseline, subclinical hypothyroidism was defined as TSH levels 4. 5 mlU/L with normal free T4 levels. Subclinical hyperthyroidism was defined as TSH levels 0. 45 mlU/L with normal free T4 levels.
Participants with normal TSH Page 8 of 29 8 levels (0. 45-4. 5 mlU/L) were considered euthyroid. At 6 months, we used the same classification to define subclinical thyroid status. Participants with the same condition at baseline and after 6 months were defined as having persistent subclinical hypothyroidism, persistent subclinical hyperthyroidism or persistent euthyroidism. Based on previous studies (4;8;9;24;26;28) and expert reviews (4;27), we further stratified our analyses for other TSH ranges (TSH < 0. 1, TSH 0. 1-0. 45, TSH 4. 5-10 and TSH > 10 mlU/L).
Functional capacity Functional capacity was measured using two questionnaires: the Barthel Index (81) and the Instrumental Activities of Daily Living (IADL). Both questionnaires have previously been proven to be sensitive to detect changes in an elderly population (29;30). The measurements were performed at baseline, after 9, 18, 30 months and at the end of the study, which varied between 36 and 42 months. The Bl is a common questionnaire used to assess self-care activities of daily living and level of dependence of an individual (31).
The Bl consists often items, in which fecal and urinary continence, grooming, toilet use, feeding, transfers (e. g. from chair to bed), walking, dressing, climbing stairs and bathing are scored. The maximum score of the Bl is 20 points; a higher score represents higher independence and mobility, i. e. higher functional capacity. interaction with the physical and social environment (32), and is therefore questioning Page 9 of 29 about more complex tasks compared to the Bl.
The questionnaire includes 7 items, including housework, taking medication as prescribed, managing money, shopping for groceries or clothing, use of telephone or other form of communication, using technology and transportation within the community. The maximum score of the IADL is 14 points; a higher score also means higher independence and mobility in both indoor and outdoor environment, i. e. higher functional capacity. Statistical analyses Baseline characteristics are reported in three thyroid subgroups, according to thyroid status.
T-tests and chi-square tests were used to compare participants with ubclinical thyroid dysfunction to euthyroid participants. We performed linear regression analyses to assess the cross-sectional association between subclinical thyroid status and functional capacity. Adjustments were made for age, sex, country, history of vascular disease, history of diabetes, history of hypertension and current smoking. Since treatment with pravastatin did not affect functional capacity (22), we combined data from both groups to investigate the association between subclinical thyroid dysfunction and functional decline.
For this longitudinal association, we used linear ixed models, which included baseline thyroid status or persistent thyroid status, time (in years) and the interaction term between time and baseline thyroid status or persistent thyroid status. The dependent variable was the score on Bl and IADL questionnaires. The change in functional capacity per year for each group was represented by the estimated value for annual change over time. Models were adjusted for age, sex, country, statin treatment, history of vascular disease, history of diabetes, history of hypertension and current smoking.
Additionally, we further performed analyses in which we 1) investigated participants ith suppressed or elevated TSH levels (TSH 10 mlJ/L); 2) included TSH levels as a continuous variable in our analyses; 3) stratified the analyses by cardiovascular disease and risk factors to investigate their potential confounding effect; 4) excluded participants with a maximum Barthel and/or IADL score at baseline; 5) stratified the longitudinal analyses by treatment group and 6) used a wider FT4 range, with 10. pmol/L to 25. 7 pmol/L considered normal according to relevant literature (4;33). Finally, since we previously reported that subclinical hypothyroidism with TSH levels 10 mlJ/L was associated with a higher rate of heart failure in PROSPER (24); a decreased level of functional capacity among those participants is expected. Therefore, we further investigated whether excluding these participants from the analyses changed our results. P-values below 0. 05 were considered statistically significant.
All analyses were conducted using SPSS (version 20. 0, PASW Statistics Inc, Chicago, Ill). Page 1 1 of 29 11 Results Baseline characteristics From the initial study population of 5804 participants, 8 individuals with missing TSH value, 303 with abnormal TSH and unknown free T4 values, 136 with overt thyroid isease and 1 with missing Bl and IADL scores were excluded (Figure 1). Six participants taking antithyroid medication and 160 participants using thyroxine supplementation were excluded.
The final sample of our study was 5182 subjects. The mean age of the study population was 75. 3 years (standard deviation (SD) 3. 3 years) (Table 1). A total of 65 participants had subclinical hyperthyroidism. In line with our expectation, this condition was more common in women (73. 8%) than in men. Subclinical hypothyroidism was found in 173 participants, and 64. 2% were women. Groups were similar on most variables, except for body mass index (BMI) and