Higher free thyroxine levels are associated with all-cause mortality in euthyroid older men: the Health In Men Study

in European Journal of Endocrinology

Objective

Thyroid dysfunction predicts poorer health outcomes, but the relationship between thyroid hormone levels within the reference range and mortality in older adults remains unclear. In this study, we examined the associations between the concentrations of free thyroxine (FT4) and TSH and all-cause mortality in older men without thyroid disease.

Subjects and methods

We performed a longitudinal study in community-dwelling men aged 70–89 years. Men with thyroid disease or taking thyroid-related medications were excluded. Baseline FT4 and TSH levels were assayed. Incident deaths were ascertained using data linkage.

Results

There were 3885 men without thyroid disease followed for (mean±s.d.) 6.4±1.5 years, during which time 837 had died (21.5%). Men who had died had higher baseline FT4 levels (16.2±2.3 vs 15.8±2.1 pmol/l, P<0.001), but comparable TSH levels (2.4±1.5 vs 2.3±1.5 mIU/l, P=0.250). After accounting for age, smoking, physical factors and medical comorbidities, higher circulating FT4 levels predicted all-cause mortality (quartile Q4 vs quartiles Q1–Q3: FT4 levels ≥17.32 vs <17.32 pmol/l: adjusted hazard ratio (HR)=1.19, 95% CI=1.02–1.39, P=0.025). TSH levels did not predict mortality. After excluding men with subclinical hyperthyroidism or hypothyroidism, there were 3442 men and 737 who had died (21.4%). In these men, higher FT4 levels remained independently associated with all-cause mortality (quartile Q4 vs quartiles Q1–Q3: adjusted HR=1.19, 95% CI=1.02–1.41, P=0.032).

Conclusions

Higher FT4 levels are associated with all-cause mortality in euthyroid older men, independently of conventional risk factors and medical comorbidities. Additional research is needed to determine whether or not this relationship is causal and to clarify the utility of thyroid function testing to stratify mortality risk in ageing men.

Abstract

Objective

Thyroid dysfunction predicts poorer health outcomes, but the relationship between thyroid hormone levels within the reference range and mortality in older adults remains unclear. In this study, we examined the associations between the concentrations of free thyroxine (FT4) and TSH and all-cause mortality in older men without thyroid disease.

Subjects and methods

We performed a longitudinal study in community-dwelling men aged 70–89 years. Men with thyroid disease or taking thyroid-related medications were excluded. Baseline FT4 and TSH levels were assayed. Incident deaths were ascertained using data linkage.

Results

There were 3885 men without thyroid disease followed for (mean±s.d.) 6.4±1.5 years, during which time 837 had died (21.5%). Men who had died had higher baseline FT4 levels (16.2±2.3 vs 15.8±2.1 pmol/l, P<0.001), but comparable TSH levels (2.4±1.5 vs 2.3±1.5 mIU/l, P=0.250). After accounting for age, smoking, physical factors and medical comorbidities, higher circulating FT4 levels predicted all-cause mortality (quartile Q4 vs quartiles Q1–Q3: FT4 levels ≥17.32 vs <17.32 pmol/l: adjusted hazard ratio (HR)=1.19, 95% CI=1.02–1.39, P=0.025). TSH levels did not predict mortality. After excluding men with subclinical hyperthyroidism or hypothyroidism, there were 3442 men and 737 who had died (21.4%). In these men, higher FT4 levels remained independently associated with all-cause mortality (quartile Q4 vs quartiles Q1–Q3: adjusted HR=1.19, 95% CI=1.02–1.41, P=0.032).

Conclusions

Higher FT4 levels are associated with all-cause mortality in euthyroid older men, independently of conventional risk factors and medical comorbidities. Additional research is needed to determine whether or not this relationship is causal and to clarify the utility of thyroid function testing to stratify mortality risk in ageing men.

Introduction

Clinically recognisable syndromes of hyperthyroidism or hypothyroidism are responsive to treatments that normalise thyroid hormone levels, leading to the relief of symptoms and improvement of clinical outcomes. Subclinical hyperthyroidism is defined as low or suppressed TSH concentrations and circulating thyroid hormone levels within the reference range (1). The associations of subclinical hyperthyroidism with an increased risk of atrial fibrillation and with all-cause and coronary heart disease mortality have been reported (2, 3). Subclinical hypothyroidism is defined as elevated TSH concentrations with circulating thyroid hormone levels within the reference range and is associated with an increased risk of coronary heart disease if TSH levels exceed 10 mIU/l (4, 5). Both higher and lower TSH levels have been reported to be associated with heart failure events (6). Consensus clinical guidelines based largely on observational studies recommend consideration of intervention in people with TSH levels <0.1 mIU/l in the case of subclinical hyperthyroidism or TSH levels >10 mIU/l in the case of subclinical hypothyroidism (1, 7). However, reversion to euthyroid hormone levels can occur in the absence of intervention (8), and data from randomised clinical trials are lacking to clarify the optimal management of people found to have subclinical thyroid disease.

It has been reported that an increase in TSH levels occurs during ageing, while free thyroxine (FT4) levels remain relatively stable (9, 10, 11). This may reflect reduced sensitivity of the pituitary to T4- or liothyronine (T3)-mediated suppression of TSH levels, altered TSH bioactivity or reduced thyroid sensitivity to TSH, requiring compensatory elevation of levels to maintain thyroid homeostasis (10). Small differences in thyroid function between euthyroid subjects have been reported to be associated with specific health-related outcomes including atrial fibrillation, reduced bone mineral density and incident dementia (12, 13, 14). However, the effect of differences in thyroid function in euthyroid older people on the key outcome of mortality remains unclear, with limited available data and inconsistent findings reported (11, 15, 16, 17). In this study, we tested the hypothesis that thyroid hormone levels within the normal range are an independent predictor of mortality in a large cohort of community-dwelling older men.

Subjects and methods

Study population

The recruitment of participants has been described in depth previously (18). Briefly, between 1996 and 1999, 19 352 men were randomly selected from the electoral roll (with enrolment to vote being compulsory for Australian citizens) and invited to join a screening trial of abdominal aortic aneurysm. Of these, 12 203 men (63.1%) visited a clinic and completed a questionnaire that assessed a range of demographic and clinical data (Wave 1). Men were almost entirely of Caucasian ethnic origin. Between 2001 and 2004, the surviving men (n=10 940) were encouraged to participate in a follow-up study: 4249 agreed to donate an early-morning blood sample (Wave 2) and represent our study cohort. The Human Research Ethics Committee of the University of Western Australia approved the study protocol, and all men provided written informed consent to participate in the study.

Physical measurements and medical comorbidities

Height (cm), weight (kg) and blood pressure were measured in clinic attendees during Waves 1 and 2. Questionnaire and clinical data obtained during Waves 1 and 2 were used to identify men with existing illnesses. Men were considered to have hypertension if they reported being diagnosed to have the condition by a doctor or were using anti-hypertensive medications (ATC codes C02, C03, C07, C08 and C09). Dyslipidaemia was defined as having HDL levels <0.9 mmol/l, LDL levels ≥3.4 mmol/l, triglyceride levels ≥1.8 mmol/l or total cholesterol levels ≥5.5 mmol/l or if they were undergoing lipid-lowering therapy (ATC code C10). Questionnaire data obtained during Waves 1 and 2 and biochemical assessment data obtained during Wave 2 were used to identify men with diabetes. Men who had been diagnosed with the condition reported the use of glucose-lowering medications (ATC code A10) or had fasting or non-fasting glucose levels ≥7 or ≥11.1 mmol/l respectively were considered to have diabetes. The presence of medical comorbidities was assessed using the Charlson index, which takes into account 17 common medical conditions that predict 1-year mortality: myocardial infarction, congestive heart failure, peripheral arterial disease, cerebrovascular disease, dementia, chronic pulmonary disease, connective tissue disease, ulcer disease, liver disease, diabetes (including diabetes with end organ damage), hemiplegia, renal disease, leukaemia, lymphoma, other tumours, metastatic tumours and AIDS (19). Medical diagnoses were weighted for severity and summed to provide a weighted index of medical comorbidity.

Identification of men with existing thyroid diseases

Questionnaire data obtained during Waves 1 and 2 were evaluated to identify men with existing thyroid diseases at baseline including those with a history of thyroidectomy, treatment with radioactive iodine or use of thyroid-related medications. In addition, we used the Western Australian Data Linkage System (WADLS) (20) to ascertain the presence of thyroid disorders. Briefly, the WADLS links together records from the Mental Health Information System, cancer register, death register and hospital morbidity data (which includes codes for multiple medical diagnoses for all admissions to private and public hospitals). Data were collected from 1990 to the time of blood sampling. The following thyroid disorders (ICD-10 codes) were used to identify men with thyroid disorders: iodine deficiency (E00, E01 and E02), established hypothyroidism or hyperthyroidism (E03 and E05), thyroiditis (E06), non-toxic goitre (E04) and other specified disorders of the thyroid (E07.8). The ICD-9 codes 240.x–246.x were also used for this purpose.

Ascertainment of incident deaths

The occurrence of death was ascertained using the WADLS (20), which contains both the original death certificate and an ICD-10-coded record generated from these data and other sources by the Australian Bureau of Statistics. The primary outcome was the occurrence of death from any cause. At the time of linkage, all deaths occurring in Western Australia up to the end of December 2010 were considered to have been recorded in the WADLS. The surviving men were censored 7 years after the collection of blood samples or on 31 December 2010, whichever occurred earlier.

Biochemical assays

Laboratory assays were performed on aliquots of serum and plasma prepared immediately after the collection of blood sampled during Wave 2 and stored at −80 °C until the time of assay, as described previously (21). Briefly, serum TSH and plasma FT4 concentrations were measured using an Elecsys 2010 immunoanalyser (Roche Diagnostics Australia). Between-run imprecision values (coefficient of variation) were 4.5 and 4.2% at 0.4 and 5.0 mIU/l TSH and 4.0 and 5.2% at 14 pmol/l and 37 pmol/l FT4. Reference intervals for these assays were 0.4–4.0 mIU/l for TSH and 10–23 pmol/l for FT4.

Statistical analyses

The statistical package Stata version 12.1 (StataCorp, College Station, TX, USA) was used to analyse the data. Baseline descriptive data are reported as mean and s.d. or percentages (%). Kaplan–Meier plots of cumulative mortality according to the quartiles of FT4 and TSH were constructed. For the primary longitudinal analysis, Cox proportional-hazards regression was performed to assess the associations of FT4 and TSH levels as continuous variables and also in quartiles with all-cause mortality. In regression analyses, adjustment was made for age and other factors that could plausibly affect an association with mortality. The models were age adjusted, with subsequent additional adjustment for smoking, BMI, waist:hip ratio; hypertension, dyslipidaemia and creatinine level; and then medical comorbidities using the Charlson index. Age, BMI, waist:hip ratio and creatinine level were modelled as continuous variables, while smoking, hypertension, dyslipidaemia and Charlson index scores were modelled as categorical variables. Schoenfeld residuals were examined to evaluate the proportional-hazards assumption. The analyses were repeated after exclusion of men with subclinical hyperthyroidism or hypothyroidism. A supplementary analysis was performed by stratifying men according to the quartiles of both FT4 and TSH. A sensitivity analysis was performed by excluding men who reported the use of frusemide. A P value <0.05 was considered significant.

Results

Study population

The disposition of the study participants is shown in Fig. 1. Of 4249 community-dwelling men aged 70–89 years assessed during Wave 2, 139 men who had a history of thyroid disease, thyroid surgery or treatment with radioactive iodine were excluded, as were 119 men taking thyroid-related medications, glucocorticoids or amiodarone and 82 men with missing data. We excluded five men with previously undiagnosed hyperthyroidism (TSH levels <0.4 mU/l and FT4 levels >23 pmol/l) and nine men with undiagnosed hypothyroidism (TSH levels >4 mU/l and FT4 levels <10 pmol/l). We also excluded ten outliers who had very low or very high FT4 levels with normal TSH values. Following these exclusions, there were 3885 men for inclusion into the analysis (Fig. 1). In this cohort, the log-linear inverse association of TSH levels with FT4 levels was preserved (21). Western Australia is regarded as an iodine-sufficient region (22).

Figure 1

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Figure 1

Study participant disposition scheme showing how the study cohort of 3885 men aged 70–89 years was derived.

Citation: European Journal of Endocrinology 169, 4; 10.1530/EJE-13-0306

Demographic, physical and medical characteristics

The characteristics of the study population stratified according to survival status are presented in Table 1. Men were followed for a mean (±s.d.) duration of 6.4±1.5 years, during which time 837 died (21.5%). Men who had died were older and more likely to be past or current smokers and had a lower BMI but a higher waist:hip ratio at baseline than men who were still alive (Table 1). Men who had died were more likely to have hypertension, had more medical comorbidities as reflected in the higher Charlson index scores, and had higher baseline creatinine levels than the surviving men. Men who had died had higher baseline FT4 levels than men who did not die (16.2±2.3 vs 15.8±2.1 pmol/l, P<0.001). TSH levels were similar in both the groups (2.4±1.5 vs 2.3±1.5 mIU/l, P=0.250).

Table 1

Demographic, physical and biochemical characteristics of the study population, stratified according to survival status. Data are means±s.d. or n (%).

Alive (n=3048)Died (n=837)P value
Age (years)76.6±3.478.5±4.0<0.001
Never smokers1093 (35.9)222 (26.5)<0.001
Past smokers1827 (59.9)542 (64.8)
Current smokers127 (4.2)71 (8.5)
BMI (kg/m2)26.6±3.526.2±3.90.003
Waist:hip ratio0.97±0.070.98±0.080.005
Hypertension2518 (82.6)729 (87.1)0.002
Dyslipidaemia1826 (59.9)488 (58.3)0.402
Charlson index
 01969 (64.6)384 (45.9)<0.001
 1–2791 (26.0)254 (30.4)
 3–4213 (7.0)125 (14.9)
 ≥574 (2.4)74 (8.8)
Creatinine (μmol/l)91.4±27.899.1±39.3<0.001
FT4 (pmol/l)15.8±2.116.2±2.3<0.001
TSH (mIU/l)2.30±1.452.35±1.510.250

OR, odds ratio.

Cumulative mortality in men according to FT4 and TSH levels

Kaplan–Meier plots of cumulative mortality according to the quartiles of FT4 and TSH are shown in Fig. 2. Men with FT4 levels in the highest quartile of values exhibited increased cumulative mortality compared with men with FT4 levels in the other three quartiles (Fig. 2A). There was no apparent separation of curves for cumulative mortality according to the quartiles of TSH (Fig. 2B).

Figure 2

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Figure 2

Cumulative hazard of all-cause mortality according to the quartiles of FT4 (A) and TSH (B) in 3885 community-dwelling older men. Y-axis shows the cumulative risk of death from any cause and X-axis shows the duration of follow-up in years.

Citation: European Journal of Endocrinology 169, 4; 10.1530/EJE-13-0306

No associations of subclinical thyroid disease with mortality

There were 27 men (0.7%) who were classified as having subclinical hyperthyroidism (TSH levels <0.4 mU/l and FT4 levels 10–23 pmol/l) and 416 (10.7%) as having subclinical hypothyroidism (TSH levels >4 mU/l and FT4 levels ≥10 pmol/l). Four men with subclinical hyperthyroidism had died (14.8%) and 95 with subclinical hypothyroidism (22.8%). Compared with euthyroid men, there was no significant difference in all-cause mortality for men with subclinical hyperthyroidism (hazard ratio (HR)=0.68, 95% CI=0.25–1.81, P=0.442) or subclinical hypothyroidism (HR=1.06, 95% CI=0.86–1.32, P=0.573).

Association of FT4 levels, but not TSH levels, with mortality in older men

The results of the Cox regression analyses of all-cause mortality according to FT4 and TSH levels in the whole cohort are given in Table 2. In keeping with the results of the Kaplan–Meier analysis, men with FT4 levels in the highest quartile had an increased HR for all-cause mortality, which was reduced following adjustment for covariates (Table 2). In the fully adjusted model, there was a statistically significant difference in all-cause mortality for men with FT4 levels in the highest quartile and all other men (quartile Q4 vs quartiles Q1–Q3: HR=1.19, 95% CI=1.02–1.39, P=0.025). TSH levels were not associated with all-cause mortality (Table 2).

Table 2

Associations of free thyroxine (FT4) and TSH levels in quartiles with all-cause mortality in 3885 community-dwelling men aged 70–89 years.

RangeDied (%)Univariate (HR (95% CI))Model 1 (HR (95% CI))Model 2 (HR (95% CI))Model 3 (HR (95% CI))Model 4 (HR (95% CI))
FT4 (pmol/l)
 Q19.64–14.4619.11.00 (reference)
 Q214.47–15.7818.50.97 (0.79–1.20)0.96 (0.78–1.18)0.97 (0.79–1.20)0.97 (0.78–1.19)0.97 (0.79–1.20)
 Q315.79–17.3121.31.13 (0.93–1.39)1.05 (0.86–1.29)0.99 (0.81–1.22)0.96 (0.79–1.18)0.94 (0.77–1.16)
 Q417.32–24.0527.41.51 (1.25–1.83)1.35 (1.11–1.63)1.24 (1.02–1.51)1.21 (0.99–1.48)1.16 (0.95–1.41)
 Q4 vs Q1–Q3≥17.321.46 (1.25–1.69)1.34 (1.15–1.56)1.26 (1.08–1.47)1.24 (1.06–1.45)1.19 (1.02–1.39)
TSH (mIU/l)
 Q10.01–1.4021.01.00 (reference)
 Q21.41–1.9821.01.00 (0.82–1.21)1.00 (0.82–1.21)0.99 (0.81–1.20)0.99 (0.81–1.20)0.97 (0.80–1.18)
 Q31.99–2.8021.71.04 (0.86–1.26)1.03 (0.85–1.25)1.06 (0.88–1.29)1.05 (0.86–1.28)1.06 (0.87–1.29)
 Q42.81–19.1222.41.07 (0.88–1.30)1.00 (0.83–1.22)1.02 (0.84–1.24)1.00 (0.82–1.21)0.98 (0.81–1.20)
 Q1 vs Q2–Q4≤1.400.96 (0.82–1.13)0.99 (0.84–1.16)0.97 (0.83–1.14)0.99 (0.84–1.16)1.00 (0.85–1.17)

Q, quartile; HR, hazard ratio; Model 1, adjusted for age; Model 2, adjusted for age and for smoking, BMI and waist:hip ratio; Model 3, adjusted for variables in Model 2 and for hypertension, dyslipidaemia and creatinine level; Model 4, adjusted for variables in Model 3 and for medical comorbidity (Charlson index).

Association of FT4 levels with mortality in euthyroid older men

After exclusion of all men with subclinical hyperthyroidism or hypothyroidism, there were 3442 euthyroid men and 737 men who had died (21.4%). The results of the Cox regression analyses for these men are presented in Table 3. On comparing the men in the highest quartile of FT4 with other euthyroid men, a significantly increased risk for all-cause mortality was observed (quartile Q4 vs quartiles Q1–Q3: adjusted HR=1.19, 95% CI=1.02–1.41, P=0.032). TSH levels were not associated with all-cause mortality in euthyroid men (Table 3).

Table 3

Associations of free thyroxine (FT4) and TSH levels in quartiles with all-cause mortality in 3442 euthyroid men aged 70–89 years.

RangeDied (%)Univariate (HR (95% CI))Model 1 (HR (95% CI))Model 2 (HR (95% CI))Model 3 (HR (95% CI))Model 4 (HR (95% CI))
FT4 (pmol/l)
 Q19.64–14.4618.71.00 (reference)
 Q214.47–15.7817.80.96 (0.76–1.20)0.94 (0.75–1.18)0.96 (0.76–1.21)0.96 (0.76–1.20)0.98 (0.78–1.23)
 Q315.79–17.3121.11.14 (0.92–1.42)1.03 (0.83–1.28)0.98 (0.79–1.23)0.96 (0.77–1.20)0.96 (0.77–1.20)
 Q417.32–24.0527.71.56 (1.27–1.92)1.35 (1.09–1.66)1.25 (1.01–1.54)1.22 (0.98–1.51)1.17 (0.94–1.44)
 Q4 vs Q1–Q3≥17.321.51 (1.29–1.77)1.36 (1.16–1.59)1.27 (1.08–1.50)1.25 (1.06–1.47)1.19 (1.02–1.41)
TSH (mIU/l)
 Q10.42–1.4021.21.00 (reference)
 Q21.41–1.9821.00.99 (0.81–1.20)0.98 (0.81–1.19)0.98 (0.80–1.19)0.98 (0.80–1.19)0.96 (0.79–1.17)
 Q31.99–2.8021.71.03 (0.85–1.25)1.01 (0.83–1.23)1.05 (0.87–1.28)1.04 (0.86–1.27)1.05 (0.86–1.28)
 Q42.81–4.0021.91.04 (0.83–1.30)1.02 (0.82–1.28)1.02 (0.82–1.28)1.00 (0.80–1.26)0.99 (0.79–1.25)
 Q1 vs Q2–Q4≤1.400.98 (0.84–1.16)1.00 (0.85–1.17)0.98 (0.83–1.16)0.99 (0.84–1.17)1.00 (0.85–1.18)

Q, quartile; HR, hazard ratio; Model 1, adjusted for age; Model 2, adjusted for age and for smoking, BMI and waist:hip ratio; Model 3, adjusted for variables in Model 2 and for hypertension, dyslipidaemia and creatinine level; Model 4, adjusted for variables in Model 3 and for medical comorbidity (Charlson index).

Supplementary analysis: stratification by both FT4 and TSH levels

Among the euthyroid men, there were 294 with FT4 levels in the highest quartile and TSH levels in the lowest quartile of values, of whom 79 had died (26.9%). There were 177 men with FT4 levels in quartile Q1 and TSH levels in quartile Q4, of whom 37 (20.9%) had died. In the multivariate regression analysis, there was no statistically significant difference in the risk of all-cause mortality for either group of men compared with the remaining men (adjusted HR=1.17, 95% CI=0.92–1.48, P=0.200, and 1.05, 0.75–1.47, P=0.775 respectively).

Sensitivity analysis

Exclusion of men who were receiving frusemide reduced the statistical power available for the analysis, as there were 2942 men who were alive and 732 who had died. In 3674 men, the fully adjusted HR for all-cause mortality for men with FT4 levels in the highest quartile compared with other men was 1.14 (95% CI=0.96–1.34). In 3258 euthyroid men, the fully adjusted HR was 1.14 (95% CI=0.96–1.36).

Discussion

In community-dwelling men aged ≥70 years free of overt thyroid disease at baseline, FT4 levels in the highest quartile of values predicted an increased all-cause mortality risk, independently of covariates and medical comorbidities. After excluding men with either subclinical hyperthyroidism or subclinical hypothyroidism, FT4 levels remained an independent predictor of all-cause mortality in euthyroid men. Therefore, in older men, high–normal circulating FT4 levels may be a causal factor or a biomarker for mortality risk.

Previously, Gussekloo et al. (15) had reported that FT4 levels as a continuous variable were associated with an increased all-cause mortality risk in 588 adults aged ≥85 years with normal TSH levels in their study cohort. In that study, low TSH levels predicted an increased mortality risk and the lowest mortality risk was observed in adults with high TSH levels and low FT4 levels. Waring et al. (11) reported an analysis of 843 long-term survivors from the Cardiovascular Health Study (‘All-Stars’) aged a mean of 85.3 years in whom higher FT4 levels, but not TSH levels, predicted mortality after adjustment for age, sex and race. However, it remained unclear whether a similar association was present in the more general population of older men rather than in the selected groups of the ‘oldest old’. Furthermore, the possibility that medical comorbidity might have modulated or confounded these apparent relationships needed to be explored. In a study of 403 men aged 73–94 years, van den Beld et al. (16) reported FT4 levels, but not TSH levels, to be associated with 4-year mortality risk after adjustment for age. By contrast, in 1587 men aged ≥65 years from the Osteoporotic Fractures in Men (MrOS) Study, Waring et al. (17) found that neither FT4 levels nor TSH levels predicted mortality in multivariate analyses. However, that study may have lacked the power to detect a moderate association as reflected in the wide CI observed. Our findings in a larger cohort of community-dwelling men aged ≥70 years differ, as after adjustment for age, smoking, BMI, waist:hip ratio and medical comorbidities, FT4 levels in the highest quartile of values (≥17.3 pmol/l) remained an independent and significant predictor of death from any cause. These associations were present in the cohort as a whole and in euthyroid men after exclusion of men with subclinical hyperthyroidism and hypothyroidism.

Collet et al. (3) pooled individual participant data from ten cohorts comprising 52 674 participants for a meta-analysis and found that adults with subclinical hyperthyroidism had an increased risk of all-cause mortality after adjustment for age and sex (HR=1.29). Individual studies within this meta-analysis have examined middle-aged and older men and women and either measured TSH levels only (23) or measured FT4 levels selectively in the setting of abnormal TSH levels (24, 25) or did not report FT4 levels as an independent variable in relation to the outcome of mortality (26, 27, 28, 29, 30, 31). A recent study not included in that meta-analysis did not find associations of subclinical thyroid disease with mortality (32). We did not detect any significant association of subclinical hyperthyroidism with mortality. However, the number of men in that category was small (n=27).

We did not find any association of TSH levels alone with all-cause mortality and nor did we find any significant excess of deaths in men with subclinical hypothyroidism. Several previous reports had not documented an association of subclinical hypothyroidism or higher TSH levels with mortality in men (23, 24, 25, 26, 29, 30, 33). By contrast, in other studies, subclinical hypothyroidism has been reported to be associated with an increased risk of coronary events and mortality (27, 28, 31). Explanations for these differences may be related to excess coronary events being more apparent in the relatively small number of men with TSH levels ≥10 mIU/l (4, 5, 6) or the possibility that the association between subclinical hypothyroidism and mortality risk may be more apparent in younger men than in older men (34).

The strengths of our study include the large sample size, the detailed characterisation of the men, the measurement of TSH and FT4 levels in the participants, the longitudinal nature of the study and the adjustment for multiple covariates. The focus on older men aged ≥70 years is timely, as demographic change is expanding the population of older men and these men have higher mortality rates. The large number of outcome events provides the power to determine associations with precision. The data linkage is robust with hospital morbidity data comparable to adjudication of medical records (35), and follow-up is complete as deaths across all of Western Australia are captured and few men of this age migrate outside the state (20). We included medical comorbidities as assessed by the Charlson index as a covariate in the analysis.

We acknowledge several limitations of this study. The cohort comprised 4249 men derived from the original sample of 12 203 men screened in 1996–1999 (18). Therefore, a ‘healthy survivor’ effect is possible. Consequently, our study cohort could be regarded as being more representative of healthier community-dwelling older men. Our study sample is almost entirely Caucasian; thus, the findings may not apply to younger men or men of other ethnic origins and we cannot comment on associations in women. Although finding an association of high FT4 levels with the risk of death from cardiovascular diseases could strengthen the argument for a causal association, data for specific causes of death are still being collated and verified, thus we could not analyse cause-specific mortality. While the longitudinal nature of the study is an advantage, these are observational data and causality cannot be confirmed. It is possible that FT4 levels are a biomarker rather than a causal factor for ill-health in ageing or that the higher FT4 levels resulted from an underlying predisposing cause. As frusemide has been reported to affect the assays of FT4 (36), we performed a sensitivity analysis excluding men taking frusemide. This reduced the HR from 1.19 to 1.14, although not to 1.0, suggesting that frusemide usage would not account entirely for the findings. Nevertheless, the magnitude of the association is moderate, and caution in extrapolating these findings to other groups is needed.

We measured FT4 and TSH levels in early-morning samples obtained at a single venesection and did not have the opportunity to collect serial specimens. However, intra-individual variability not captured by single sampling would be expected to attenuate rather than enhance any underlying associations. There is also the possibility that our results could have been confounded by the presence of non-thyroidal illness or ‘sick euthyroid’ syndrome. In this scenario, men with non-thyroidal illness might exhibit abnormal thyroid hormone levels, although FT4 levels are typically low (7). However, our men were community dwelling rather than institutionalised and all voluntarily visited a study clinic for venesection, suggesting that they were not acutely unwell. Another limitation of the study is that we did not assay triiodothyronine levels.

Our results illuminate the association of FT4 levels with mortality in a large cohort of men aged ≥70 years. The consideration of age may be relevant. It is possible that the effect of high–normal FT4 levels on mortality is subtle and cumulative, thus manifesting in older men and not in middle-aged men. Alternatively, age-associated exposures to environmental, lifestyle or health-related factors may result in increased vulnerability to putative deleterious effects of high–normal FT4 levels in older men. Higher FT4 levels are associated with metabolically more favourable indices of lower total cholesterol and LDL levels and reduced insulin resistance (37, 38), but there are plausible biological mechanisms that may account for the association of high–normal FT4 levels with mortality. Excessive exposure to thyroid hormones exerts deleterious effects on cardiac rate, rhythm and function (39). In a study of 5860 adults aged ≥65 years, Gammage et al. (12) reported that FT4 levels were independently associated with the presence of atrial fibrillation even in euthyroid subjects with normal TSH levels. Therefore, atrial fibrillation reflects one adverse cardiac consequence of excess thyroid hormone exposure on the cardiovascular system, which may be shared between people with subclinical hyperthyroidism and those with high–normal FT4 levels. Frailty is a syndrome characterised by the deterioration of multiple organ systems, leading to the loss of physiological reserve, diminished capacity to cope with stressors, and increased risk of disability and death (40). We have reported previously an association between higher FT4 levels and frailty in older men (21). Although we cannot discount the possibility that lower FT4 levels may be protective, the excess mortality risk was present for men with FT4 levels in the highest quartile of values. We postulate that exposure to FT4 levels in the higher end of the normal range may predispose to or be a biomarker for poorer health outcomes in ageing men.

In conclusion, higher FT4 levels are associated with all-cause mortality in older men, independently of conventional risk factors and medical comorbidities. Additional research is needed to determine whether or not this relationship is causal and to clarify the utility of thyroid function testing to stratify mortality risk in ageing men.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

B B Yeap is the recipient of a Clinical Investigator Award from the Sylvia and Charles Viertel Charitable Foundation, New South Wales, Australia. Hormone assays were funded by research grants from the Fremantle Hospital Medical Research Foundation, Fremantle Hospital, Western Australia, and the Ada Bartholomew Medical Research Trust, University of Western Australia. The Health In Men Study was funded by project grants 279408, 379600, 403963, 513823 and 634492 from the National Health and Medical Research Council of Australia. The funding sources had no involvement in the planning, analysis and writing of the manuscript.

Acknowledgements

The authors thank Roche Diagnostics Australia for the supply of assay reagents, the staff of PathWest Laboratory Medicine, Fremantle and Royal Perth Hospitals for their excellent technical assistance, and the staff and management of Shenton Park Hospital for their support. They especially thank all the men and staff who participated in the Western Australian Abdominal Aortic Aneurysm Program and the Health In Men Study.

References

  • 1

    FranklynJA. The thyroid – too much and too little across the ages. The consequences of subclinical thyroid dysfunction. Clinical Endocrinology20137818. (doi:10.1111/cen.12011).

  • 2

    BiondiBCooperDS. The clinical significance of subclinical thyroid dysfunction. Endocrine Reviews20082976131. (doi:10.1210/er.2006-0043).

  • 3

    ColletT-HGusseklooJBauerDCden ElzenWPJCappolaARBalmerPIervasiGAsvoldBOSgarbiJAVolzkeH. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Archives of Internal Medicine2012172799809. (doi:10.1001/archinternmed.2012.402).

  • 4

    OchsNAuerRBauerDCNanchenDGusseklooJCornuzJRodondiN. Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality. Annals of Internal Medicine2008148832845. (doi:10.7326/0003-4819-148-11-200806030-00225).

  • 5

    RodondiNden ElzenWPBauerDCCappolaARRazviSWalshJPAsvoldBOIervasiGImaizumiMColletTH. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. Journal of the American Medical Association201030413651374. (doi:10.1001/jama.2010.1361).

  • 6

    GencerBColletT-HVirginiVBauerDCGusseklooJCappolaARNanchenDden ElzenWPJBalmerPLubenRN. Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from six prospective cohorts. Circulation201212610401049. (doi:10.1161/CIRCULATIONAHA.112.096024).

  • 7

    CooperDSBiondiB. Subclinical thyroid disease. Lancet201237911421154. (doi:10.1016/S0140-6736(11)60276-6).

  • 8

    SomwaruLLRariyCMArnoldAMCappolaAR. The natural history of subclinical hypothyroidism in the elderly: the cardiovascular health study. Journal of Clinical Endocrinology and Metabolism20129719621969. (doi:10.1210/jc.2011-3047).

  • 9

    SurksMIBoucaiL. Age- and race-based serum thyrotrophin reference limits. Journal of Clinical Endocrinology and Metabolism201095496502. (doi:10.1210/jc.2009-1845).

  • 10

    BremnerAPFeddemaPLeedmanPJBrownSJBeilbyJPLimEMWilsonSGO'LearyPCWalshJP. Age-related changes in thyroid function: a longitudinal study of a community-based cohort. Journal of Clinical Endocrinology and Metabolism20129715541562. (doi:10.1210/jc.2011-3020).

  • 11

    WaringACArnoldAMNewmanABBuzkovaPHirschCCappolaAR. Longitudinal changes in thyroid function in the oldest old and survival: the Cardiovascular Health Study All-Stars Study. Journal of Clinical Endocrinology and Metabolism20129739443950. (doi:10.1210/jc.2012-2481).

  • 12

    GammageMDParleJVHolderRLRobertsLMHobbsFDWilsonSSheppardMCFranklynJA. Association between serum free thyroxine concentration and atrial fibrillation. Archives of Internal Medicine2007167928934. (doi:10.1001/archinte.167.9.928).

  • 13

    MurphyEGluerCCReidDMFelsenbergDRouxCEastellRWilliamsGR. Thyroid function within the upper normal range is associated with reduced bone mineral density and an increased risk of nonvertebral fractures in healthy euthyroid postmenopausal women. Journal of Clinical Endocrinology and Metabolism20119531733181. (doi:10.1210/jc.2009-2630).

  • 14

    YeapBBAlfonsoHChubbSAPPuriGHankeyGJFlickerLAlmeidaOP. Higher free thyroxine levels predict increased incidence of dementia in older men. The Health In Men Study. Journal of Clinical Endocrinology and Metabolism201297E2230E2237. (doi:10.1210/jc.2012-2108).

  • 15

    GusseklooJvan ExelEde CraenAJMeindersAEFrolichMWestendorpRG. Thyroid status, disability and cognitive function, and survival in old age. Journal of the American Medical Association200429225912599. (doi:10.1001/jama.292.21.2591).

  • 16

    van den BeldAWVisserTJFeeldersRAGrobbeeDELambertsSWJ. Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. Journal of Clinical Endocrinology and Metabolism20059064036409. (doi:10.1210/jc.2005-0872).

  • 17

    WaringACHarrisonSSamuelsMHEnsrudKELeBlancESHoffmanAROrwollEFinkHABarrett-ConnorEBauerDC. Thyroid function and mortality in older men: a prospective study. Journal of Clinical Endocrinology and Metabolism201297862870. (doi:10.1210/jc.2011-2684).

  • 18

    NormanPEFlickerLAlmeidaOPHankeyGJHydeZJamrozikK. Cohort profile: the Health In Men Study (HIMS). International Journal of Epidemiology2009384852. (doi:10.1093/ije/dyn041).

  • 19

    CharlsonMEPompeiPAlesKLMacKenzieCR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. Journal of Chronic Diseases198740373383. (doi:10.1016/0021-9681(87)90171-8).

  • 20

    HolmanCDBassAJRosmanDLSmithMBSemmensJBGlassonEJBrookELTrutweinBRouseILWatsonCR. A decade of data linkage in Western Australia: strategic design, applications and benefits of the WA data linkage system. Australian Health Review200832766777. (doi:10.1071/AH080766).

  • 21

    YeapBBAlfonsoHChubbSAWalshJPHankeyGJAlmeidaOPFlickerL. Higher free thyroxine levels are associated with frailty in older men. The Health In Men Study. Clinical Endocrinology201276741748. (doi:10.1111/j.1365-2265.2011.04290.x).

  • 22

    LiMEastmanCJWaiteKVMaGZacharinMRToplissDJHardingPEWalshJPWardLCMortimerRH. Are Australian children iodine deficient? Results of the Australian National Iodine Nutrition Study. Medical Journal of Australia2006184165169.

  • 23

    AsvoldBOBjoroTNilsonTIGunnellDVattenLJ. Thyrotrophin levels and risk of fatal coronary heart disease. Archives of Internal Medicine2008168855860. (doi:10.1001/archinte.168.8.855).

  • 24

    ParleJVMaisonneuvePSheppardMCBoylePFranklynJA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotrophin result: a 10-year cohort study. Lancet2001358861865. (doi:10.1016/S0140-6736(01)06067-6).

  • 25

    CappolaARFriedLPArnoldAMDaneseMDKullerLHBurkeGLTracyRPLadensonPW. Thyroid status, cardiovascular risk, and mortality in older adults. Journal of the American Medical Association200629510331041. (doi:10.1001/jama.295.9.1033).

  • 26

    RodondiNNewmanABVittinghoffEde RekeneireNSatterfieldSHarrisTBBauerDC. Subclinical hypothyroidism and risk of heart failure, other cardiovascular events, and death. Archives of Internal Medicine200516524602466. (doi:10.1001/archinte.165.21.2460).

  • 27

    WalshJPBremnerAPBulsaraMKO'LearyPLeedmanPJFeddemaPMichelangeliV. Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Archives of Internal Medicine200516524672472. (doi:10.1001/archinte.165.21.2467).

  • 28

    IervasiGMolinaroSLandiPTaddeiMCGalliEMarianiFL'AbbateAPingitoreA. Association between increased mortality and mild thyroid dysfunction in cardiac patients. Archives of Internal Medicine200716715261532. (doi:10.1001/archinte.167.14.1526).

  • 29

    BoekholdtSMTitanSMWiersingaWChatterjeeKBasartDCLubenRWarehamNJKhawK-T. Initial thyroid status and cardiovascular risk factors: the EPIC–Norfolk prospective population study. Clinical Endocrinology201072404410. (doi:10.1111/j.1365-2265.2009.03640.x).

  • 30

    IttermannTHaringRSauerSWallaschofskiHDorrMNauckMVolzkeH. Decreased serum TSH levels are not associated with mortality in the adult northeast German population. European Journal of Endocrinology2010162579585. (doi:10.1530/EJE-09-0566).

  • 31

    SgarbiJAMatsumuraLKKasamatsuTSFerreiraSRMacielRM. Subclinical thyroid dysfunctions are independent risk factors for mortality in a 7.5 year follow-up: the Japanese–Brazilian thyroid study. European Journal of Endocrinology2010162569577. (doi:10.1530/EJE-09-0845).

  • 32

    De JonghRTLipsPvan SchoorNMRijsKJDeegDJComijsHCKramerMHVandenbrouckeJPDekkersOM. Endogenous subclinical thyroid disorders, physical and cognitive function, depression and mortality in older individuals. European Journal of Endocrinology2011165545554. (doi:10.1530/EJE-11-0430).

  • 33

    HylandKAArnoldAMLeeJSCappolaAR. Persistent subclinical hypothyroidism and cardiovascular risk in the elderly: the cardiovascular health study. Journal of Clinical Endocrinology and Metabolism201398533540. (doi:10.1210/jc.2012-2180).

  • 34

    RazviSShakoorAVanderpumpMWeaverJUPearceSH. The influence of age on the relationship between subclinical hypothyroidism and ischemic heart disease: a metaanalysis. Journal of Clinical Endocrinology and Metabolism20089329983007. (doi:10.1210/jc.2008-0167).

  • 35

    BarrELTonkinAMWelbornTAShawJE. Validity of self-reported cardiovascular disease events in comparison to medical record adjudication and a statewide hospital morbidity database: the AusDiab Study. Internal Medicine Journal2009394953. (doi:10.1111/j.1445-5994.2008.01864.x).

  • 36

    HawkinsRC. Furosemide interference in newer free thyroxine assays. Clinical Chemistry19984425502551.

  • 37

    RoosABakkerSJLinksTPGansROWolffenbuttelBH. Thyroid function is associated with components of the metabolic function in euthyroid subjects. Journal of Clinical Endocrinology and Metabolism200792491496. (doi:10.1210/jc.2006-1718).

  • 38

    Garduno-Garcia JdeJAlvirde-GarciaULopez-CarrascoGMendozaMEPMehtaRArellano-CamposOChozaRSauqueLGaray-SevillaME. TSH and free thyroxine concentrations are associated with differing metabolic markers in euthyroid subjects. European Journal of Endocrinology2010163273278. (doi:10.1530/EJE-10-0312).

  • 39

    KleinIDanziS. Thyroid disease and the heart. Circulation200711617251735. (doi:10.1161/CIRCULATIONAHA.106.678326).

  • 40

    CooperCDereWEvansWKanisJARizzoliRSayerAASieberCCKaufmanJ-MVan KanGABoonenS. Frailty and sarcopenia: definitions and outcome parameters. Osteoporosis International20122318391848. (doi:10.1007/s00198-012-1913-1).

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    Study participant disposition scheme showing how the study cohort of 3885 men aged 70–89 years was derived.

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    Cumulative hazard of all-cause mortality according to the quartiles of FT4 (A) and TSH (B) in 3885 community-dwelling older men. Y-axis shows the cumulative risk of death from any cause and X-axis shows the duration of follow-up in years.

References

1

FranklynJA. The thyroid – too much and too little across the ages. The consequences of subclinical thyroid dysfunction. Clinical Endocrinology20137818. (doi:10.1111/cen.12011).

2

BiondiBCooperDS. The clinical significance of subclinical thyroid dysfunction. Endocrine Reviews20082976131. (doi:10.1210/er.2006-0043).

3

ColletT-HGusseklooJBauerDCden ElzenWPJCappolaARBalmerPIervasiGAsvoldBOSgarbiJAVolzkeH. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Archives of Internal Medicine2012172799809. (doi:10.1001/archinternmed.2012.402).

4

OchsNAuerRBauerDCNanchenDGusseklooJCornuzJRodondiN. Meta-analysis: subclinical thyroid dysfunction and the risk for coronary heart disease and mortality. Annals of Internal Medicine2008148832845. (doi:10.7326/0003-4819-148-11-200806030-00225).

5

RodondiNden ElzenWPBauerDCCappolaARRazviSWalshJPAsvoldBOIervasiGImaizumiMColletTH. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. Journal of the American Medical Association201030413651374. (doi:10.1001/jama.2010.1361).

6

GencerBColletT-HVirginiVBauerDCGusseklooJCappolaARNanchenDden ElzenWPJBalmerPLubenRN. Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from six prospective cohorts. Circulation201212610401049. (doi:10.1161/CIRCULATIONAHA.112.096024).

7

CooperDSBiondiB. Subclinical thyroid disease. Lancet201237911421154. (doi:10.1016/S0140-6736(11)60276-6).

8

SomwaruLLRariyCMArnoldAMCappolaAR. The natural history of subclinical hypothyroidism in the elderly: the cardiovascular health study. Journal of Clinical Endocrinology and Metabolism20129719621969. (doi:10.1210/jc.2011-3047).

9

SurksMIBoucaiL. Age- and race-based serum thyrotrophin reference limits. Journal of Clinical Endocrinology and Metabolism201095496502. (doi:10.1210/jc.2009-1845).

10

BremnerAPFeddemaPLeedmanPJBrownSJBeilbyJPLimEMWilsonSGO'LearyPCWalshJP. Age-related changes in thyroid function: a longitudinal study of a community-based cohort. Journal of Clinical Endocrinology and Metabolism20129715541562. (doi:10.1210/jc.2011-3020).

11

WaringACArnoldAMNewmanABBuzkovaPHirschCCappolaAR. Longitudinal changes in thyroid function in the oldest old and survival: the Cardiovascular Health Study All-Stars Study. Journal of Clinical Endocrinology and Metabolism20129739443950. (doi:10.1210/jc.2012-2481).

12

GammageMDParleJVHolderRLRobertsLMHobbsFDWilsonSSheppardMCFranklynJA. Association between serum free thyroxine concentration and atrial fibrillation. Archives of Internal Medicine2007167928934. (doi:10.1001/archinte.167.9.928).

13

MurphyEGluerCCReidDMFelsenbergDRouxCEastellRWilliamsGR. Thyroid function within the upper normal range is associated with reduced bone mineral density and an increased risk of nonvertebral fractures in healthy euthyroid postmenopausal women. Journal of Clinical Endocrinology and Metabolism20119531733181. (doi:10.1210/jc.2009-2630).

14

YeapBBAlfonsoHChubbSAPPuriGHankeyGJFlickerLAlmeidaOP. Higher free thyroxine levels predict increased incidence of dementia in older men. The Health In Men Study. Journal of Clinical Endocrinology and Metabolism201297E2230E2237. (doi:10.1210/jc.2012-2108).

15

GusseklooJvan ExelEde CraenAJMeindersAEFrolichMWestendorpRG. Thyroid status, disability and cognitive function, and survival in old age. Journal of the American Medical Association200429225912599. (doi:10.1001/jama.292.21.2591).

16

van den BeldAWVisserTJFeeldersRAGrobbeeDELambertsSWJ. Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. Journal of Clinical Endocrinology and Metabolism20059064036409. (doi:10.1210/jc.2005-0872).

17

WaringACHarrisonSSamuelsMHEnsrudKELeBlancESHoffmanAROrwollEFinkHABarrett-ConnorEBauerDC. Thyroid function and mortality in older men: a prospective study. Journal of Clinical Endocrinology and Metabolism201297862870. (doi:10.1210/jc.2011-2684).

18

NormanPEFlickerLAlmeidaOPHankeyGJHydeZJamrozikK. Cohort profile: the Health In Men Study (HIMS). International Journal of Epidemiology2009384852. (doi:10.1093/ije/dyn041).

19

CharlsonMEPompeiPAlesKLMacKenzieCR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. Journal of Chronic Diseases198740373383. (doi:10.1016/0021-9681(87)90171-8).

20

HolmanCDBassAJRosmanDLSmithMBSemmensJBGlassonEJBrookELTrutweinBRouseILWatsonCR. A decade of data linkage in Western Australia: strategic design, applications and benefits of the WA data linkage system. Australian Health Review200832766777. (doi:10.1071/AH080766).

21

YeapBBAlfonsoHChubbSAWalshJPHankeyGJAlmeidaOPFlickerL. Higher free thyroxine levels are associated with frailty in older men. The Health In Men Study. Clinical Endocrinology201276741748. (doi:10.1111/j.1365-2265.2011.04290.x).

22

LiMEastmanCJWaiteKVMaGZacharinMRToplissDJHardingPEWalshJPWardLCMortimerRH. Are Australian children iodine deficient? Results of the Australian National Iodine Nutrition Study. Medical Journal of Australia2006184165169.

23

AsvoldBOBjoroTNilsonTIGunnellDVattenLJ. Thyrotrophin levels and risk of fatal coronary heart disease. Archives of Internal Medicine2008168855860. (doi:10.1001/archinte.168.8.855).

24

ParleJVMaisonneuvePSheppardMCBoylePFranklynJA. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotrophin result: a 10-year cohort study. Lancet2001358861865. (doi:10.1016/S0140-6736(01)06067-6).

25

CappolaARFriedLPArnoldAMDaneseMDKullerLHBurkeGLTracyRPLadensonPW. Thyroid status, cardiovascular risk, and mortality in older adults. Journal of the American Medical Association200629510331041. (doi:10.1001/jama.295.9.1033).

26

RodondiNNewmanABVittinghoffEde RekeneireNSatterfieldSHarrisTBBauerDC. Subclinical hypothyroidism and risk of heart failure, other cardiovascular events, and death. Archives of Internal Medicine200516524602466. (doi:10.1001/archinte.165.21.2460).

27

WalshJPBremnerAPBulsaraMKO'LearyPLeedmanPJFeddemaPMichelangeliV. Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Archives of Internal Medicine200516524672472. (doi:10.1001/archinte.165.21.2467).

28

IervasiGMolinaroSLandiPTaddeiMCGalliEMarianiFL'AbbateAPingitoreA. Association between increased mortality and mild thyroid dysfunction in cardiac patients. Archives of Internal Medicine200716715261532. (doi:10.1001/archinte.167.14.1526).

29

BoekholdtSMTitanSMWiersingaWChatterjeeKBasartDCLubenRWarehamNJKhawK-T. Initial thyroid status and cardiovascular risk factors: the EPIC–Norfolk prospective population study. Clinical Endocrinology201072404410. (doi:10.1111/j.1365-2265.2009.03640.x).

30

IttermannTHaringRSauerSWallaschofskiHDorrMNauckMVolzkeH. Decreased serum TSH levels are not associated with mortality in the adult northeast German population. European Journal of Endocrinology2010162579585. (doi:10.1530/EJE-09-0566).

31

SgarbiJAMatsumuraLKKasamatsuTSFerreiraSRMacielRM. Subclinical thyroid dysfunctions are independent risk factors for mortality in a 7.5 year follow-up: the Japanese–Brazilian thyroid study. European Journal of Endocrinology2010162569577. (doi:10.1530/EJE-09-0845).

32

De JonghRTLipsPvan SchoorNMRijsKJDeegDJComijsHCKramerMHVandenbrouckeJPDekkersOM. Endogenous subclinical thyroid disorders, physical and cognitive function, depression and mortality in older individuals. European Journal of Endocrinology2011165545554. (doi:10.1530/EJE-11-0430).

33

HylandKAArnoldAMLeeJSCappolaAR. Persistent subclinical hypothyroidism and cardiovascular risk in the elderly: the cardiovascular health study. Journal of Clinical Endocrinology and Metabolism201398533540. (doi:10.1210/jc.2012-2180).

34

RazviSShakoorAVanderpumpMWeaverJUPearceSH. The influence of age on the relationship between subclinical hypothyroidism and ischemic heart disease: a metaanalysis. Journal of Clinical Endocrinology and Metabolism20089329983007. (doi:10.1210/jc.2008-0167).

35

BarrELTonkinAMWelbornTAShawJE. Validity of self-reported cardiovascular disease events in comparison to medical record adjudication and a statewide hospital morbidity database: the AusDiab Study. Internal Medicine Journal2009394953. (doi:10.1111/j.1445-5994.2008.01864.x).

36

HawkinsRC. Furosemide interference in newer free thyroxine assays. Clinical Chemistry19984425502551.

37

RoosABakkerSJLinksTPGansROWolffenbuttelBH. Thyroid function is associated with components of the metabolic function in euthyroid subjects. Journal of Clinical Endocrinology and Metabolism200792491496. (doi:10.1210/jc.2006-1718).

38

Garduno-Garcia JdeJAlvirde-GarciaULopez-CarrascoGMendozaMEPMehtaRArellano-CamposOChozaRSauqueLGaray-SevillaME. TSH and free thyroxine concentrations are associated with differing metabolic markers in euthyroid subjects. European Journal of Endocrinology2010163273278. (doi:10.1530/EJE-10-0312).

39

KleinIDanziS. Thyroid disease and the heart. Circulation200711617251735. (doi:10.1161/CIRCULATIONAHA.106.678326).

40

CooperCDereWEvansWKanisJARizzoliRSayerAASieberCCKaufmanJ-MVan KanGABoonenS. Frailty and sarcopenia: definitions and outcome parameters. Osteoporosis International20122318391848. (doi:10.1007/s00198-012-1913-1).

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