Plasma thyrotropin levels below 0.3 mIU/L were considered to be abnormally
low; levels above 4.8 mIU/L were considered to be abnormally high. Plasma
free thyroxine levels below 1.01 ng/dL (13 pmol/L) were considered to be abnormally
low; levels between 1.01 and 1.79 ng/dL (13 and 23 pmol/L) were considered
to be normal.
Gussekloo J, van Exel E, de Craen AJM, Meinders AE, Frölich M, Westendorp RGJ. Thyroid Status, Disability and Cognitive Function, and Survival in Old Age. JAMA. 2004;292(21):2591-2599. doi:10.1001/jama.292.21.2591
Author Affiliations: Section of Gerontology
and Geriatrics (Drs Gussekloo, van Exel, de Craen, and Westendorp), Departments
of General Internal Medicine (Drs Gussekloo, van Exel, de Craen, Meinders,
and Westendorp) and Clinical Chemistry (Dr Frölich), Leiden University
Medical Center, Leiden, the Netherlands.
Context Despite the equivocal outcomes of randomized controlled trials, general
clinical opinion favors screening and treatment of elderly individuals with
subclinical thyroid disorders.
Objectives To determine whether subclinical thyroid dysfunction should be treated
in old age and the long-term impact of thyroid dysfunction on performance
and survival in old age.
Design, Setting, and Participants A prospective, observational, population-based follow-up study within
the Leiden 85-Plus Study of 87% of a 2-year birth cohort (1912-1914) in the
municipality of Leiden, the Netherlands. A total of 599 participants were
followed up from age 85 years through age 89 years (mean [SD] follow-up, 3.7
Main Outcome Measures Complete thyroid status at baseline; disability in daily life, depressive
symptoms, cognitive function, and mortality from age 85 years through 89 years.
Results Plasma levels of thyrotropin and free thyroxine were not associated
with disability in daily life, depressive symptoms, and cognitive impairment
at baseline or during follow-up. Increasing levels of thyrotropin were associated
with a lower mortality rate that remained after adjustments were made for
baseline disability and health status. The hazard ratio (HR) for mortality
per SD increase of 2.71 mIU/L of thyrotropin was 0.77 (95% confidence interval
[CI], 0.63-0.94; P = .009). The HR for
mortality per SD increase of 0.21 ng/dL (2.67 pmol/L) of free thyroxine increased
1.16-fold (95% CI, 1.04-1.30; P = .009).
Conclusions In the general population of the oldest old, elderly individuals with
abnormally high levels of thyrotropin do not experience adverse effects and
may have a prolonged life span. However, evidence for not treating elderly
individuals can only come from a well-designed, randomized placebo-controlled
Thyroid dysfunction in elderly individuals often occurs unnoticed. Hence,
screening for both hypothyroidism and hyperthyroidism has been recommended,
especially in old age.1,2 Apart
from finding individuals with previously unrecognized overt hypothyroidism
and hyperthyroidism, screening will also reveal persons with subclinical thyroid
dysfunction. These individuals have abnormal plasma levels of thyrotropin
combined with normal plasma levels of free thyroxine.
Subclinical thyroid dysfunction has been associated with various negative
clinical outcomes and an increased risk of overt thyroid dysfunction. Two
recent literature reviews of subclinical thyroid dysfunction rated the evidence
as inconclusive for an association between subclinical thyroid disease and
clinical symptoms.3,4 Furthermore,
the outcomes of randomized placebo-controlled clinical trials evaluating the
treatment effect of subclinical thyroid disease on symptoms and lipid levels
are inconsistent.5- 11 Despite
these ambiguities, policy makers have recommended screening and treatment
of subclinical thyroid dysfunction to prevent progression to overt thyroid
dysfunction and to improve clinical outcomes, especially in elderly individuals.12- 15
To determine whether subclinical thyroid dysfunction should be treated
in old age, clinical correlates of thyroid status were studied in an unselected
population-based cohort of 599 elderly individuals aged 85 years. Moreover,
these elderly individuals were prospectively followed up to determine the
long-term impact of thyroid dysfunction on performance and survival in old
The Leiden 85-Plus Study is a prospective, population-based study of
all individuals aged 85 years (birth cohort, 1912-1914) and living in Leiden,
the Netherlands between September 1997 and September 1999. There were no exclusion
criteria. Of the 705 eligible individuals, 14 died before they could be enrolled
and 92 refused to participate, resulting in a cohort of 599 participants enrolled
at baseline (response rate of 87%).16 Baseline
plasma samples were obtained from 558 participants. Starting within 1 month
after their 85th birthday, participants received annual home visits during
which extensive data on health, functioning, and well-being were collected.
The ethical committee of the Leiden University Medical Center approved the
study and all participants provided oral informed consent for study participation.
Further information on the design of the study and characteristics of the
cohort have been published elsewhere.17
Samples were stored at –80°C. Plasma levels of thyrotropin
and free thyroxine were measured in 1 batch with an Elecsys 2010 system (Hitachi,
Tokyo, Japan) in a completely automated laboratory robot. An electrochemiluminescence
technique was applied (Boehringer, Mannheim, Germany). The plasma level of
free triiodothyronine was measured by a microparticle enzyme immunoassay (Abbott
Diagnostics, Abbott Park, Ill). For thyrotropin, the variation coefficients
were between 5% and 11%; free thyroxine, between 5% and 8%; and free triiodothyronine,
between 3% and 8%. In our laboratory, the reference values for thyrotropin
were 0.3 mIU/L to 4.8 mIU/L; free thyroxine, 1.01 to 1.79 ng/dL (13-23 pmol/L);
and free triiodothyronine, 305 to 532 pg/dL (4.7-8.2 pmol/L). The ratio of
free triiodothyronine to free thyroxine was considered to be a marker of the
Information on the use of thyroid medication (antithyroid medication
and/or L-thyroxine) was obtained annually from computerized
registries of pharmacy records, which were virtually complete for all participants
from age 85 years through 87 years. All participants with newly detected overt
thyroid dysfunction during the baseline assessment were advised to consult
with their primary care physician for further evaluation and to consider treatment.
To study the clinical course of subclinical thyroid disorders, assessments
of thyrotropin and free thyroxine were repeated at age 88 years.
Performance was annually assessed using the Groningen Activity Restriction
Scale, which assesses disability in 9 activities of daily living (ADLs) and
9 instrumental ADLs.18 Disability scores in
ADLs and in instrumental ADLs ranges from 9 points (fully independent in all
activities) to 36 points (fully dependent in all activities).
Depressive symptoms were annually assessed with the 15-item Geriatric
Depression Scale (GDS-15), a screening instrument used in elderly individuals.
The GDS-15 could only be administered to those with a Mini-Mental State Examination
(MMSE) score of higher than 18 points. Scores on the GDS-15 range from zero
points (no depressive symptoms) to 15 points. Participants with a GDS-15 score
of 4 points or more were considered depressed.19
Global cognitive function was assessed annually with the MMSE. The MMSE
scores range from zero points (very severe cognitive impairment) to 30 points
(optimal cognitive function). In participants with MMSE scores above 18 points,
various domains of cognitive function were further investigated by the Stroop
test, the Letter Digit Coding test, and the Word Learning Test.20,21 The
Stroop test assesses attention; the outcome parameter used was the total number
of seconds to complete the third Stroop card containing 40 words. The Letter
Digit Coding test assesses cognitive speed; the outcome parameter used was
the total number of correct digits filled in within 60 seconds. The 12-word
learning test assesses immediate and delayed memory. The outcome parameter
of immediate recall was the sum of recalled pictures in 3 procedures (range,
0-36 pictures). After 20 minutes, delayed recall was tested; the outcome parameter
used was the number of pictures recalled (range, 0-12 pictures).
All participants were followed up prospectively for mortality until
age 89 years (censoring date). The date of death was obtained from the civic
registry of Leiden. Survival time was defined as number of days between the
85th birthday and the censoring date, or the date of death. Shortly after
the civic registry reported the death of a participant, the treating physician
(primary care physician or nursing home physician) was interviewed to obtain
the cause of death using a standardized questionnaire. Two senior internal
medicine specialists, who were unaware of the present analyses, determined
the causes of death by consensus according to the 10th version of the International Classification of Diseases (ICD-10). Causes
of death were divided into 2 groups: cardiovascular mortality (ICD-10 codes I00-I99, I20-I25, and I60-I69) and noncardiovascular mortality
(all other ICD-10 codes).
Self-reported educational level was dichotomized around 6 years of schooling
and entered as a dichotomous variable in the analyses. Indication of baseline
health status was obtained by using plasma levels of albumin and C-reactive
protein, number of chronic diseases, MMSE score at baseline, and subjective
health on a 5-point scale. Based on medical history, blood analysis, or electrocardiogram
at baseline, the included chronic diseases were history of type 2 diabetes,
myocardial infarction, stroke, chronic obstructive pulmonary disease, arthritis,
and Parkinson disease.
Thyroid function was investigated using 2 different strategies. First,
based on plasma levels of thyrotropin and free thyroxine, thyroid status was
stratified according to general clinical consensus.3 Plasma
levels of thyrotropin between 0.3 mIU/L to 4.8 mIU/L were defined as normal,
plasma thyrotropin levels above 4.8 mIU/L were defined as abnormally high,
and plasma thyrotropin levels below 0.3 mIU/L were defined as abnormally low. Overt hypothyroidism was defined as having an abnormally
high thyrotropin level combined with a free thyroxine level below 1.01 ng/dL
(13 pmol/L). Subclinical hypothyroidism was defined
as an abnormally high thyrotropin level combined with a normal level of free
thyroxine (1.01-1.79 ng/dL [13-23 pmol/L]). Overt hyperthyroidism was defined as an abnormally low thyrotropin level combined with a
free thyroxine level above 1.79 ng/dL (23 pmol/L). Subclinical
hyperthyroidism was defined as an abnormally low level of thyrotropin
combined with a normal free thyroxine level (1.01-1.79 ng/dL [13-23 pmol/L]).
In the second strategy, levels of thyroid hormones were entered in the analytic
models as continuous variables. The results of these analyses are presented
per SD increase for each of the hormones.
To investigate the feedback between free thyroxine and thyrotropin,
the association between the logarithms was assessed using linear regression.
The association between levels of thyroid hormones at baseline and performance
during follow up was analyzed with linear mixed models.22,23 These
models included the terms level of thyroid hormone, time, and interaction of level of thyroid
hormone and time. The estimate for thyroid hormone level reflects the
cross-sectional association between thyroid hormone and performance, and is
presented as the baseline difference. The estimate for time reflects the annual
change in performance, and is presented as change over time. The estimate
for interaction of level of thyroid hormone and time reflects the additional
annual change in performance per SD increase of thyroid hormones at baseline
and is presented as additional annual change. All estimates were adjusted
for sex and educational level. We standardized the estimates per SD increase
of thyroid hormone levels by using the formula: (individual plasma level –
mean plasma level in the population)/SD in the population.
A Kaplan-Meier curve illustrates the association between the clinical
strata of thyroid function and all-cause mortality. Differences in survival
between these groups were compared with Cox regression. Crude hazard ratios
(HRs) are expressed per SD increase of thyroid hormones at baseline and after
adjustment for sex. Assumption for proportionality of the mortality hazards
was assessed by visual inspection of cumulative hazard logarithm plots. To
exclude confounding by baseline differences, we further adjusted the crude
HRs for differences in baseline disability and health status (including plasma
levels of albumin and C-reactive protein, number of chronic diseases, MMSE
score at baseline, and subjective health as indicated above). None of these
variables were entered as time-dependent covariates. Finally, we repeated
the analyses and included only participants with normal thyroid function.
The comparisons between the subgroups of clinical thyroid status and
the analyses with the thyroid function as continuous variables were all preplanned.
We also performed several post hoc analyses (eg, the analyses in participants
with normal thyroid function). We used SPSS software (version 12.0.1, SPSS
Inc, Chicago, Ill) for all statistical analyses.
At baseline, we obtained complete thyroid status for 558 participants.
Baseline characteristics of these participants, all aged 85 years, are presented
in Table 1. Figure 1 presents the number of elderly individuals participating
at each year of follow up. In total, 70 participants refused further participation
(≤5% per year). Twelve died within 1 month after refusal and another 35
died at or by age 89 years. During follow-up, 209 (37%) of 558 participants
died. The mortality rate increased from 27% in those without chronic diseases
at baseline to 36% in those with 1 chronic disease and to 51% in participants
who had 2 or more chronic diseases.
Of the 558 participants, 472 (85%) had normal thyroid function, 67 (12%)
had abnormally high levels of thyrotropin, and 19 (3%) had abnormally low
levels of thyrotropin (Table 1). At
baseline, 21 participants (4%) were taking thyroid medication (L-thyroxine
and/or antithyroid medication). Thirty-nine participants with newly detected
overt thyroid dysfunction were referred to their primary care physician or
nursing home physician for further clinical evaluation. Pharmacy records were
checked for these 39 participants at age 86 years and at age 87 years—none
were taking L-thyroxine and/or antithyroid medication. Apparently,
among this age group the primary care physicians do not start treatment for
disorders that are identified by screening only.
There was a significant, inverse correlation at baseline between plasma
levels of thyrotropin and free thyroxine (r = –0.38, P<.001). Table 2 presents
several baseline characteristics for clinical strata of thyroid function.
Higher levels of thyrotropin were associated with a higher body mass index
(P = .02), higher cholesterol levels (P = .04), and higher levels of triglycerides
(P = .004). Levels of C-reactive protein
were not associated with thyroid function.
To study the course of thyroid status over time, assessments of thyrotropin
and free thyroxine were repeated at age 88 years in 376 participants. A total
of 296 (95%) of 310 participants had normal thyroid function at ages 85 and
88 years. Twenty-one of the 30 participants with subclinical hypothyroidism
at baseline were reassessed at age 88 years. None had developed overt hypothyroidism,
8 continued to have subclinical hypothyroidism, 11 had normal thyroid function,
and 2 participants had overt hyperthyroidism at age 88 years. Thyroid status
of 12 of the 17 participants with subclinical hyperthyroidism at baseline
was reassessed at age 88 years. One participant had developed overt hyperthyroidism,
5 participants had subclinical hyperthyroidism, 5 participants now had normal
thyroid function, and 1 participant developed subclinical hypothyroidism.
At baseline, there was no association between levels of thyrotropin
and disability in ADLs, disability in instrumental ADLs, depressive symptoms,
and cognitive function (Table 3, baseline
differences per SD, all P>.30). All measures of performance
significantly deteriorated over time (Table 3, change over time, all P<.001). Increasing
baseline levels of thyrotropin were not associated with an accelerated increase
in disability in ADLs, depressive symptoms, or cognitive decline during follow-up
(Table 3, additional annual change per
SD, all P>.20). However, increasing thyrotropin levels
at baseline were associated with a significant decelerated increase in disability
in instrumental ADLs (–0.12 per year per SD thyrotropin at baseline, P = .03), the interpretation being that higher
plasma levels of thyrotropin at baseline protected against dependency in instrumental
ADLs during follow-up.
At baseline, there was also no association between levels of free thyroxine
and disability in ADLs, disability in instrumental ADLs, depressive symptoms,
and cognitive function (Table 3, baseline
differences per SD, all P>.10). All measures of performance
significantly deteriorated over time (Table 3, change over time, all P<.001). Increasing
levels of free thyroxine at baseline were not associated with an accelerated
increase in disability in ADLs, disability in instrumental ADLs, and depressive
symptoms over time, neither with an accelerated cognitive decline (Table 3, additional annual change per SD, all P>.08).
During follow-up until age 89 years, 209 (37%) of 558 participants died. Figure 2 presents the cumulative all-cause mortality
based on the clinical stratification of thyroid function. Thyroid function
was significantly associated with mortality; participants with abnormally
low levels of thyrotropin at baseline had highest mortality rate, and participants
with abnormally high thyrotropin levels and abnormally low levels of free
thyroxine had the lowest mortality rate (Cox regression, P for trend = .03).
The sex-adjusted HRs for all-cause mortality per SD increase in baseline
level of thyrotropin and free thyroxine appear in Table 4. Increasing levels of thyrotropin were associated with decreased
mortality. Mortality per SD increase of thyrotropin at baseline of 2.71 mIU/L
was 0.76-fold lower (95% confidence interval [CI], 0.62-0.92; P = .005). This decreased mortality risk remained unchanged
after adjustment for baseline disability and health status (including plasma
levels of albumin and C-reactive protein, number of chronic diseases, MMSE
score at baseline, and subjective health). Moreover, increasing levels of
free thyroxine were associated with increased all-cause mortality. Mortality
risk per SD increase of baseline free thyroxine of 0.21 ng/dL (2.67 pmol/L)
was 1.22-fold higher (95% CI, 1.08-1.37, P = .001).
After adjustment for baseline disability and health status, the increased
mortality risk remained. The increased mortality risk also remained in a restricted
analysis that included participants with normal levels of thyrotropin only
Increasing levels of thyrotropin were associated with decreased all-cause
mortality in both men (HR, 0.57; 95% CI, 0.38-0.85) and women (HR, 0.84; 95%
CI, 0.68-1.03). Increasing levels of free thyroxine were associated with increased
mortality in both men (HR, 1.32; 95% CI, 1.02-1.72) and women (HR, 1.18; 95%
During follow-up, 87 (42%) of the 209 participants died from cardiovascular
causes, 119 (58%) died from noncardiovascular causes, and the primary cause
of death was unknown for 3 participants. Increasing levels of thyrotropin
were associated with a decreased risk of both cardiovascular (sex-adjusted
HR, 0.66; 95% CI, 0.48-0.98) and noncardiovascular (sex-adjusted HR, 0.84;
95% CI, 0.66-1.07) mortality. Increasing levels of free thyroxine were associated
with an increased risk of both cardiovascular (sex-adjusted HR, 1.26; 95%
CI, 1.05-1.52) and noncardiovascular (sex-adjusted HR, 1.10; 95% CI, 0.93-1.32)
Participants who survived until age 89 years had higher ratios of free
triiodothyronine to free thyroxine at baseline compared with the participants
who died during follow-up (mean [SD], 0.25 [0.05] vs 0.23 [0.05]; independent t test, P<.001). This indicates
an increased peripheral 5′deiodination activity in those participants
who survived at least 4 years.
Decreasing levels of free triiodothyronine were associated with poor
outcome on virtually all domains of functional performance at baseline (Table 3). Low levels of free triiodothyronine
also were associated with an accelerated increase of disability in ADLs, disability
in instrumental ADLs, and depressive symptoms during follow-up, and with an
accelerated decline of global cognitive function (Table 3). Decreasing levels of free triiodothyronine were associated
with increased mortality; the sex-adjusted HR per SD decrease of free triiodothyronine
of 35.7 pg/dL (0.55 pmol/L) was 1.31 (95% CI, 1.15-1.52; P<.001). However, this association disappeared after adjustment
for baseline disability and health status (HR, 1.05; 95% CI, 0.91-1.20; P = .50).
To study whether levels of free thyroxine and free triiodothyronine
were independent predictors of mortality, the risks of mortality of free triiodothyronine
and free thyroxine were estimated simultaneously, with adjustments for baseline
disability and health status. In this model, the increased mortality associated
with increasing baseline level of free thyroxine was independent of the level
of free triiodothyronine. The HR per SD increase of free thyroxine was 1.18
(95% CI, 1.05-1.33; P = .005). The HR per
SD decrease of free triiodothyronine, however, decreased to 1.10 (95% CI,
0.95-1.27; P = .20).
All analyses described above were repeated after exclusion of the 21
participants who took medication for thyroid disease at baseline. In these
restricted analyses, there were marginal significant findings on the performance
of instrumental ADLs and the immediate word learning test. Increasing levels
of thyrotropin were associated with a lower increase of disability during
follow-up (additional annual change, β, –0.14 [SE, 0.06]; P = .02) and with better memory during follow-up
(additional annual change, β, 0.13 [SE, 0.06]; P = .03).
The mortality risk per SD increase of thyrotropin at baseline was 0.78-fold
lower (95% CI, 0.65-0.93; P = .006) whereas
the mortality risk per SD increase of free thyroxine was 1.21-fold higher
(95% CI, 1.07-1.37; P = .002).
In this prospective observational study of a population-based cohort
of individuals aged 85 years, no consistent associations were found between
thyroid status and ADLs, depressive symptoms, and cognitive performance, neither
in the cross-sectional nor in the prospective analyses. In addition, we found
that increasing levels of thyrotropin and decreasing levels of free thyroxine,
both representing lower thyroid function, were associated with a survival
Both subclinical and overt thyroid dysfunction are supposed to have
a negative effect on performance.3,4 The
absence of associations between thyroid status and various parameters of performance
in this population of community-dwelling elderly is therefore unexpected.
Although various cross-sectional studies have found associations between thyroid
function, depressive symptoms, and cognitive decline,24- 28 thyroid
function was not a risk factor for cognitive impairment or depressive symptoms,
neither in the cross-sectional analysis, nor in the prospective analysis.
It is unlikely that the study was underpowered to show differences in performance.
For instance, the overall annual increase in ADL disability was estimated
at 1.2 points per year. The additional annual change due to thyroid dysfunction
was estimated at –0.01 points per SD increase of thyrotropin at baseline
(95% CI, –0.11 to 0.09 points). The corresponding 95% CI indicates that
larger effects on ADL disability than the reported range can be excluded.
Effect sizes due to abnormal thyrotropin levels higher than 10% of the overall
annual deterioration of ADL are thus unlikely. In a similar reasoning, given
the small variance of the risk estimates and the considerable deterioration
in performance after age 85 years, additional worsening due to thyroid dysfunction
higher than 10% (disability and global cognitive function) and 20% (depressive
symptoms) can be excluded.
On the other hand, one may argue that we have not separated participants
with biochemical thyroid dysfunction with accompanying symptoms from those
who had biochemical signs of thyroid dysfunction only. However, when studying
the relationship between thyroid function and clinical symptoms, it is essential
to uncouple biochemical features from clinical features. For the present analyses
we have defined subclinical thyroid dysfunction as those with abnormal levels
of thyrotropin but normal levels of free thyroxine, whereas participants with
overt thyroid dysfunction have abnormal levels of both. These definitions
are in line with the recent consensus statement.3
Thyroid dysfunction, disability, depressive symptoms, and cognitive
impairment are prevalent in old age. Therefore, primary care physicians will
face a considerable number of elderly individuals who have a combination of
these disorders. This explains that a relatively high proportion of elderly
individuals with disability, depressive symptoms, or cognitive impairment
who are screened will have biochemical evidence of thyroid dysfunction. The
classic reasoning is that this thyroid dysfunction causes these disorders.
However, our data indicate that for most of these patients it is unlikely
that the thyroid dysfunction is causal. The alternative explanation is that
the abnormal thyroid dysfunction is just co-occurring with all of these disorders.
In 1928, Robertson28 reported that mice
fed with desiccated thyroid throughout their life had a shorter life span
than control mice. In addition, rats fed with thyroxine did not live as long
as controls29; and Wistar rats with experimental
hypothyroidism had significantly longer life spans than normal rats.30 Moreover, Ames and Snell dwarf mice with undetectable
levels of pituitary hormones (prolactin, growth hormone, and thyrotropin)
due to genetic mutations have a 50% to 64% prolonged life span compared with
their age-matched wild-type littermates.31- 33 From
a biological point of view, our finding that decreased levels of free thyroxine
are associated with longer life span is expected. Our findings are also in
line with an earlier study in elderly individuals that found a single measurement
of low serum thyrotropin to be associated with increased rates of mortality
from all causes.34 These data contrast with
a recent study in middle-aged participants in which males with subclinical
hypothyroidism have a higher rate of mortality from all causes, the risk being
absent in women.35 The latter finding indicates
that consequences of thyroid dysfunction during middle age cannot be extrapolated
to old age, and vice versa.
It is tempting to speculate on how or why abnormal high thyrotropin
levels are associated with lower all-cause mortality. Lower metabolic rate
is related with increased survival in several species36 and
it may be suggested that a lower metabolic rate underlies the lower mortality
in humans with decreased free thyroxine. Moreover, caloric restriction is
known to prolong life in rodent models, an effect that may be the result of
lower thyroid function and a lower metabolic rate.37- 39 It
is not known whether mild hypothyroidism in elderly individuals, commonly
caused by autoimmune thyroiditis, has a similar effect on metabolism. Outcomes
from clinical experiments comparing substitution therapy are needed to judge
whether this interpretation is correct.
For many years, thyroid dysfunction and mortality have been coupled
in the low triiodothyronine syndrome, which is found in patients with serious
nonthyroidal illnesses.40- 43 These
low levels of triiodothyronine are thought to be the consequence of a decreased
conversion of thyroxine into triiodothyronine by a lower capacity or a lower
amount of 5′selenodeiodinase in peripheral tissues due to disease-related
factors.44,45 In our study, we
found significant associations between low levels of free triiodothyronine,
poor performance, and increased mortality. The association between free triiodothyronine
and mortality disappeared when we adjusted for baseline disability and health
status. Moreover, this association also disappeared when we simultaneously
estimated the effects of both free thyroxine and free triiodothyronine on
mortality in 1 model. The finding that the increased mortality risk for higher
free thyroxine was independent of the level of free triiodothyronine indicates
that the association between free thyroxine and mortality was not explained
by an underlying low triiodothyronine syndrome.
The strength of the present study is that it seems to reflect the natural
history of elderly individuals with different thyroid function given the population-based
character and 87% enrollment of the 85-year olds, the few number of individuals
who were lost to follow-up, the fact that specific therapeutic interventions
were seldom, and the annual repeated measurements of performance. The weakness
is that it relies on a single baseline assessment of thyroid function with
a repeated measurement available only at age 88 years. Moreover, because of
the observational nature of the data we cannot exclude that residual confounding
is at play and therefore we are not able to draw final conclusions on causality.
Abnormal levels of thyrotropin are often found in elderly individuals,
as are disturbances in mood, cognitive function, and cardiovascular risk factors.
A commonly used explanation is that the latter are adverse effects of (subclinical)
thyroid dysfunction. The data presented herein argue against a causal interpretation.
Therefore, we believe that thyroid substitution therapy in older individuals
with abnormally high thyrotropin levels is unlikely to be beneficial and may
even be harmful. Our observations in the relatively small subgroup with abnormally
low levels of thyrotropin suggest that treatment of high thyroid function
might lead to better survival without threatening performance in daily living.
In the general population of the oldest old, we found no association
between levels of thyrotropin and performance. Moreover, elderly individuals
with abnormally high levels of thyrotropin were found to have a prolonged
life span. Hence, current clinical practice of treating these elderly persons
may have limited clinical benefit. Final proof for not treating elderly individuals
with abnormally high thyrotropin levels can only come from a well-designed
randomized placebo-controlled clinical trial.
Corresponding Author: J. Gussekloo, MD,
PhD, Section of Gerontology and Geriatrics, C-2-R Room 133, Leiden University
Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands (firstname.lastname@example.org).
Author Contributions: Dr Gussekloo had full
access to all the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Gussekloo, van Exel,
de Craen, Meinders, Westendorp.
Acquisition of data: Gussekloo, van Exel, Frölich,
Analysis and interpretation of data: Gussekloo,
van Exel, de Craen, Frölich, Westendorp.
Drafting of the manuscript: Gussekloo, Westendorp.
Critical revision of the manuscript for important
intellectual content: Gussekloo, van Exel, de Craen, Meinders, Frölich,
Statistical analysis: Gussekloo, van Exel,
de Craen, Westendorp.
Obtained funding: Gussekloo, Westendorp.
Administrative, technical, or material support:
Gussekloo, van Exel, Meinders, Frölich, Westendorp.
Study supervision: Gussekloo, de Craen, Westendorp.
Funding/Support: The Leiden 85-Plus Study was
partly funded by an unrestricted grant from the Dutch Ministry of Health,
Welfare and Sports.
Role of the Sponsor: The Dutch Ministry of
Health, Welfare and Sports had no role in the design and conduct of this study;
no role in the collection, analysis, and interpretation of the data; and no
role in the preparation, review, or approval of the manuscript.