ORIGINAL ARTICLE

E n d o c r i n e C a r e

Thyroid Function Tests and Mortality in Aged

Hospitalized Patients: A 7-Year Prospective
Observational Study

Pedro Iglesias, Elena Ridruejo, Anglica Muoz, Florentino Prado,

Mara Cruz Macas, Mara Teresa Guerrero, Pilar Tajada, Carmen Garca-Arvalo,
and Juan Jos Dez
Department of Endocrinology (P.I., J.J.D.), Hospital Ramn y Cajal, 28034 Madrid, Spain; and
Departments of Geriatrics (E.R., A.M., F.P., M.C.M., M.T.G.) and Biochemistry (P.T., C.G.-A.), Hospital
General, 28007 Segovia, Spain

Context: Several alterations in thyroid function test (TFT) results have been associated with mor-
tality in elderly patients.

Objective: Our aim was to investigate the relationship between TFT results and all-cause and
cardiovascular (CV) mortality in aged hospitalized patients.

Design: A 7-year prospective observational study was conducted. TFTs were performed at hospital
admission, and mortality was registered in the follow-up period.

Patients: Participants were 404 patients aged 65 years admitted to the Department of Geriatrics,
Hospital General, Segovia, Spain, for any reason during 2005.

Main Outcome Measures: The study evaluated the association between TFT results and mortality
from all causes and CV diseases.

Methods: TSH, free T4, and free T3 (FT3) were measured on the first day of admission. In-hospital
and total survival times, number of deaths, and all-cause and CV mortality were registered until the
census date on January 1, 2012.

Results: During the study, 323 patients (80%) died. Kaplan-Meier analysis showed that median
survival time for all-cause mortality was significantly lower in patients in the first tertile of
serum FT3, in the first tertile of TSH, and in the first tertile of serum free T4 concentrations.
Multivariate adjusted Cox regression analysis showed that the history of cancer (hazard ratio,
1.60; 95% confidence interval, 1.122.28; P .009), age (1.03; 1.011.06; P .003), and FT3 levels
(0.72; 0.63 0.84; P .001) were significant factors related to all-cause mortality. The cause of
death was known in 202 patients. Of this group, 61 patients (30.2%) died of CV disease. Patients
in the first tertile of TSH and FT3 exhibited a significant higher mortality due to CV disease. In
the adjusted Cox regression analysis, FT3 was a significant predictor of CV mortality (0.76;
0.63 0.91; P .004).

Conclusions: Alterations in TFT results during hospitalization are associated with long-term mor-
tality in elderly patients. In particular, low FT3 levels are significantly related to all-cause and CV
mortality. (J Clin Endocrinol Metab 98: 4683 4690, 2013)

ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: CHF, congestive heart failure; CHD, coronary heart disease; CV, cardiovas-
Printed in U.S.A. cular; FT3, free T3; FT4, free T4; NTIS, nonthyroidal illness syndrome; TFT, thyroid function
Copyright 2013 by The Endocrine Society test.
Received November 7, 2012. Accepted September 25, 2013.
First Published Online October 30, 2013

doi: 10.1210/jc.2012-3849 J Clin Endocrinol Metab, December 2013, 98(12):4683 4690 jcem.endojournals.org 4683

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 06 July 2016. at 00:04 For personal use only. No other uses without permission. . All rights reserved.
4684 Iglesias et al Thyroid and Mortality in the Elderly J Clin Endocrinol Metab, December 2013, 98(12):4683 4690

hyroid dysfunction is a common disorder in the gen- for mortality during hospitalization in elderly patients
T eral population, mainly in women of advanced age
(15). The prevalence of overt hypothyroidism and hyper-
(20, 21).
In summary, some epidemiological studies suggest that
thyroidism ranges between 1% and 7% and between 0.5% different derangements in TFT results are related to mor-
and 3.0%, respectively (2, 3, 6 8), increasing to 14% to tality in elderly individuals in diverse clinical situations.
18% and higher than 5% when subclinical hypothyroidism Our aim has been to analyze whether a single TFT (TSH,
and subclinical hyperthyroidism are considered (3, 8). FT4, and free T3 [FT3]) measurement could be a predictive
Untreated thyroid disorders in elderly individuals are factor of a better or worse vital prognosis not only during
associated with significant morbidity (9 11). Several hospitalization but also in the long-term, as well as its
studies (1216), but not all (10, 17), suggest a relationship relationship with all-cause and cardiovascular (CV) mor-
between altered thyroid function test (TFT) results and tality in elderly patients admitted because of an acute
mortality in elderly individuals. Low levels of TSH or el- process.
evated levels of free T4 (FT4) have been related to an in-
creased mortality rate in this population (1215, 18). On
the contrary, a high TSH level or low serum FT4 level was Patients and Methods
associated with lower mortality (13, 15, 16). A recent sur-
vey showed that a single measurement of thyroid function Study design
A 7-year (between January 1, 2005, and January 1, 2012)
(TSH and T4) was not able to predict total or cause-specific
prospective observational study including patients older than 65
mortality in a cohort of community-dwelling older men years hospitalized because of an acute process during 2005 was
over an 8-year period of follow-up (17). carried out. Patients were recruited from a previous cross-sec-
Alterations in TFT results have also been associated tional study (21). All patients admitted to our geriatric unit were
with morbidity and mortality in older hospitalized pa- included in the study regardless of the cause of hospitalization.
All patients taking medications known to modify thyroid func-
tients. A recent retrospective study has shown that low T4
tion (antithyroid drugs, thyroxine, glucocorticoids, octreotide,
and high TSH levels were associated with a worse prog- dopamine, lithium, or amiodarone) were excluded.
nosis in these patients (19). It was also reported that a low Demographic, clinical, and laboratory data were recorded
serum T3 concentration behaves as a powerful predictor (Table 1). In-hospital and total survival times, number of deaths,

Table 1. Clinical and Analytical Data and Prevalent Comorbidities of the Study Patients
Women Men Total
No. of patients, % 247 (61.1) 157 (38.9) 404
Age, y 86.7 6.3 84.8 6.3 85.9 6.4
Hypertension, % 153 (61.9)a 67 (42.7) 220 (54.4)
Diabetes, % 67 (27.1) 34 (21.7) 101 (25.0)
Dyslipidemia, % 37 (15.0) 23 (14.6) 60 (14.8)
Cardiovascular disease, % 84 (34.0) 46 (29.3) 130 (32.2)
CHD 18 (7.3) 20 (12.7) 38 (9.4)
Stroke 46 (18.6) 19 (12.1) 65 (16.1)
Peripheral arterial disease 8 (3.2) 18 (11.5) 26 (6.4)
CHF 45 (18.2) 16 (10.2) 61 (15.1)
Arrhythmia 94 (38.0) 52 (33.1) 146 (36.1)
Cancer, % 26 (10.5) 28 (17.8) 54 (13.4)
Alterations in TFT results, % 180 (72.9) 115 (73.2) 295 (73.0)
NTIS 151 (61.1) 100 (63.7) 251 (62.1)
Subclinical hypothyroidism 16 (6.5) 7 (4.4) 23 (5.7)
Overt hypothyroidism 2 (0.8) 2 (1.3) 4 (1.0)
Subclinical hyperthyroidism 5 (2.0) 3 (1.9) 8 (2.0)
Overt hyperthyroidism 6 (2.4) 3 (1.9) 9 (2.2)
Body mass index, kg/m2 27.4 6.2 27.2 3.5 27.3 5.1
Systolic blood pressure, mm Hg 130 (110 150) 130 (110 140) 130 (110 150)
Diastolic blood pressure, mm Hg 70 (60 80) 70 (60 80) 70 (60 80)
Thyrotropin, mU/L 1.5 (0.8 2.6) 1.5 (0.8 2.5) 1.5 (0.8 2.5)
FT4, pmol/L 17.2 (15.219.7)a 16.3 (14.318.4) 16.9 (14.8 19.1)
FT3, pmol/L 3.7 0.9 3.5 0.9 3.6 0.9
Data represent the number of patients (percentage) and/or the mean SD for normally distributed data and median (interquartile range) for
nonnormally distributed data.
a
Level of significance for multiple comparisons was adjusted using the Bonferroni correction to : P .004

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 06 July 2016. at 00:04 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2012-3849 jcem.endojournals.org 4685

and all-cause and CV mortality were registered until the census
date on January 1, 2012. The vital status of every patient was
evaluated through telephone, hospital medical reports, civil reg-
istration, and contact with the primary care physicians of the
patients. The cause of death was obtained through the clinical
information of the hospital medical reports and death certificates
of the patients. CV death was defined as death from stroke,
coronary heart disease (CHD), congestive heart failure (CHF),
arrhythmia, myocardial infarction, or sudden death. This study
was approved by our local ethics committee, and informed con-
sent was given by subjects or their relatives before participation
in the study.
the effects of several quantitative (age, TSH, FT4, and FT3) and
qualitative (sex, hypertension, diabetes mellitus, dyslipidemia,
CV disease, and cancer) variables on the risk of death. Hazard
ratios (HRs) and their 95% confidence intervals (CIs) for all-
cause and CV mortality were estimated. Patients were classified
according to tertiles of TSH, FT4, and FT3 levels obtained from
3 approximately equal groups based on the data analyzed. This
analysis implies a possible bias or lack of generalization of these
tertiles in other patient groups. Differences were considered sig-
nificant when P .05.

Thyroid functional status

Results
Thyroid function was assessed by measuring serum concen- TFT results and morbidity
trations of TSH, FT4, and FT3. Patients were classified according
to the type and severity of thyroid dysfunction in overt hyper- TFT results were abnormal in most of the patients
thyroidism (low TSH and high FT4 and/or high FT3), subclinical (73%); NTIS was the most common alteration (251 pa-
hyperthyroidism (low TSH and normal FT4 and FT3), overt hy- tients [62.1%]), followed by subclinical hypothyroidism
pothyroidism (high TSH and low FT4), and subclinical hypo- (23 patients [5.7%]), overt hyperthyroidism (9 patients
thyroidism (high TSH levels with normal FT4). Nonthyroidal [2.2%]), subclinical hyperthyroidism (8 patients [2.0%]),
illness syndrome (NTIS) or low T3 syndrome was also assessed.
and overt hypothyroidism (4 patients [1.0%]) (Table 1).
Patients Prevalent comorbidities are shown in Table 1. The pres-
From an initial group of 447 patients, we excluded 43 patients ence of diabetes, dyslipidemia, CV disease, and cancer did
who were taking thyroid-altering medications. We finally se- not result in significantly different serum concentrations
lected a group of 404 patients (Table 1). Clinical analytical data of TSH, FT4, and T3. Only hypertensive patients showed
for the study patients are summarized in Table 1. significantly higher serum FT4 levels than nonhyperten-
sive subjects.
Hormone assays The main causes for hospital admission were CHF (77
TSH, FT4, and FT3 serum concentrations were measured in
all patients. Fasting samples of venous blood were obtained from
patients [19.1%]), stroke (64 patients [15.8%]), respira-
an antecubital vein between 8:30 and 9:00 AM for hormonal tory tract infection (54 patients [13.4%]), acute digestive
quantifications on the first day of admission. Serum TSH, FT4, hemorrhage (25 patients [6.2%]), CHD (23 patients
and FT3 were measured by an electrochemiluminescence immu- [5.7%]), exacerbation of chronic obstructive pulmonary
noassay by using an E170 analyzer (Roche Diagnostics, Mann- disease (23 patients [5.7%]), cancer (14 patients [3.5%]),
heim, Germany). Maximal intra- and interassay coefficients of
sepsis (11 patients [2.7%]), urinary tract infection (11 pa-
variation as indicated in the package inserts of the commercial
kits were 1.35% and 1.16% for TSH, 2.04% and 3.89% for FT4, tients [2.7%]), anemia (7 patients [1.7%]), syncope (7 pa-
and 2.87% and 10.17% for FT3. The sensitivities of the TSH, tients [1.7%]), acute gastroenteritis (7 patients [1.7%]),
FT4, and FT3 assays were 0.005 mU/L, 0.3 pmol/L, and 0.4 confusion syndrome (6 patients [1.5%]), bradycardia (6
pmol/L, respectively. Reference values were as follows: TSH, 0.4 patients [1.5%]), cellulitis (5 patients [1.2%]), pancreati-
to 5.0 mU/L; FT4, 11 to 23 pmol/L; and FT3, 3.9 to 6.8 pmol/L.
tis (3 patients [0.7%]), and other conditions (61 patients
[15.1%]). No significant differences in TSH and FT4 were
Statistical analysis
For quantitative variables, results are expressed as mean SD found among these groups. Patients with sepsis had the
for normally distributed data and as median (interquartile range) lowest FT3 levels (2.7 0.8 pmol/L), which were signif-
for nonnormally distributed data. The normality of the data dis- icantly different from those found in patients with stroke
tribution was tested using the Kolmogorov-Smirnov test. Cate- (3.9 1.0 pmol/L, P .002) and CHD (3.8 0.9 pmol/L,
gorical variables are described as percentages. For comparisons P .001).
of means between 2 groups of subjects, the Student t test was used
for normally distributed data, and the Mann-Whitney test was
used for nonnormally distributed data. For the comparison of TFT results and mortality
2 independent groups, one-way ANOVA and Kruskal-Wallis During the study, 323 patients (80%) died (median sur-
tests were used for normally and nonnormally distributed data, vival time, 9 months; interquartile range, 131 months; 61
respectively. For categorical comparisons, the 2 test or the patients [15.1%] died during hospitalization). Distribu-
Fisher exact test was used. Bonferroni correction to the level
tion of the patients according to the reference values of
was applied when tests with multiple comparisons were per-
formed. Survival time was estimated by the Kaplan-Meier meth- thyroid parameters in relation to vital status and time of
od; the log rank test was used to compare arms. Unadjusted and death is shown in Table 2. The percentage of patients with
stepwise multivariate Cox regression models were used to assess low T3 levels was significantly higher in the group of pa-

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 06 July 2016. at 00:04 For personal use only. No other uses without permission. . All rights reserved.
4686 Iglesias et al Thyroid and Mortality in the Elderly J Clin Endocrinol Metab, December 2013, 98(12):4683 4690

Table 2. Distribution of Patients According to Reference Values of Thyroid Parameters in Relation to Their Vital
Status
Dead in the Hospital (n 61) Dead After Discharge (n 262) Survivors (n 81)
P
Low Normal High Low Normal High Low Normal High Value
TSH 7 (11.5) 52 (85.2) 2 (3.3) 24 (9.2) 221 (84.4) 17 (6.5) 1 (1.2) 72 (88.9) 8 (9.9) .007
FT4 3 (4.9) 57 (93.4) 1 (1.6) 7 (2.7) 238 (90.8) 17 (6.5) 3 (3.7) 74 (91.4) 4 (4.9) NS
FT3 52 (85.2) 9 (14.8) 0 170 (64.9) 91 (34.7) 1 (0.4) 37 (45.7) 44 (54.3) 0 .001
Abbreviation: NS, not significant. Data represent number of patients (%). Normal range: TSH, 0.4 to 5.0 mU/L; FT4, 11 to 23 pmol/L, and FT3, 3.9
to 6.8 pmol/L.

tients who died in the hospital compared with those who who died of CV disease during hospitalization and those
did after discharge. Only 9 of 144 patients (6.2%) with who died after discharge.
normal FT3 levels died during hospitalization, making Kaplan-Meier analysis showed a median survival time
that finding highly predictive of survival. for all-cause mortality of 3.0 (95% CI, 1.1 4.9), 13.0
Patients who died were older and showed lower values (6.119.8), and 19.0 (12.113.3) months for patients be-
of FT3 than patients who survived (Table 3). The presence longing to the first (FT3 3.18 pmol/L), second (3.18
of abnormal TFT results was positively associated with FT3 3.96 pmol/L), and third (FT3 3.96 pmol/L) tertiles
mortality (P .001). Among patients who died, both TSH of FT3, respectively (P .001) (Figure 1). In regard to
(1.2 [0.72.2] vs 1.6 [0.9 2.6] mU/L, P .047] and FT3 TSH, median survival times for all-cause mortality were
(3.2 0.8 vs 3.7 0.9 pmol/L, P .001) were lower in 3.0 (95% CI, 0.6 5.4), 17.0 (9.9 24.1), and 12.0 (5.7
those who died during hospitalization than among those 18.3) months for patients belonging to the first (TSH
who survived to hospital discharge. No significant differ- 1.06 mU/L), second (1.06 TSH 2.09 mU/L), and
ences in FT4 were found. third (TSH 2.09 mU/L) tertiles of TSH, respectively (P
Of the 323 patients who died, we only could find the .006) (Figure 1). In the same way, median survival times
cause of death in 202 patients (62.5%). CV disease was the for all-cause mortality were 6.0 (3.6 8.4), 19.0 (12.8
main cause of death in 61 of these patients (30.2%). We 25.1), and 11.0 (6.6 15.4) months for patients belonging
did not find any significant difference in clinical and an- to the first (FT4 15.4 pmol/L), second (15.4 FT4
alytical data and TFT results among patients who died of 18.2 pmol/L), and third (FT4 18.2 pmol/L) tertiles of
CV disease and those who died of other causes. No dif- FT4, respectively (P .004) (Figure 1). Similar findings for
ferences were found in TSH, FT3, and FT4 among patients TSH (log rank test 6.4, P .041) and FT3 (log rank test

Table 3. Clinical and Analytical Data of the Study Patients at Entry According to Their Vital Status at the End of the
Study
P
Alive Dead Value
Patients, n (%) 81 (20) 323 (80)
Age, y 84.0 6.8 86.4 6.2 .002
Hypertension, % 48 (59.3) 172 (53.2) NS
Diabetes, % 15 (18.5) 86 (26.6) NS
Dyslipidemia, % 11 (13.6) 49 (15.1) NS
CV disease, % 27 (33.3) 103 (31.9) NS
CHD 5 (6.2) 33 (10.2)
Stroke 16 (19.7) 49 (15.2)
Peripheral arterial disease 2 (2.5) 24 (7.4)
CHF 10 (12.3) 51 (15.8)
Cancer, % 8 (9.9) 46 (14.2) NS
Body mass index, kg/m2 27.3 6.0 27.4 5.0 NS
Systolic blood pressure, mm Hg 135 (120 150) 130 (110 150) NS
Diastolic blood pressure, mm Hg 75 (70 80) 70 (60 80) NS
Thyrotropin, mU/L 1.8 (0.9 2.8) 1.5 (0.8 2.4) NS
FT4, pmol/L 17.2 (14.9 19.3) 16.8 (14.8 19.0) NS
FT3, pmol/L 4.0 0.9 3.5 0.9 .001
Abbreviation: NS, not significant. Data represent the number of patients (%) or the mean SD for normally distributed data and median
(interquartile range) for nonnormally distributed data.
a
Level of significance for multiple comparisons was adjusted using the Bonferroni correction to : P .004

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 06 July 2016. at 00:04 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2012-3849 jcem.endojournals.org 4687

Figure 1. Kaplan-Meier survival analysis for all-cause (left panels; n 404) and CV mortality (right panels; n 283) in elderly patients admitted
for acute illness stratified according to tertiles of TSH, FT4, and FT3.

25.6, P .001), were found when mortality due to CV In an unadjusted Cox regression model, only age
disease was analyzed. Survival analysis in relation to ter- (years) (HR, 1.03; 95% CI, 1.011.0; P .001) and FT3
tiles of FT4 did not show significant differences in this (picomoles per liter) (0.71; 0.62 0.82; P .001) were
group of patients (Figure 1). significantly related to all-cause mortality; whereas in the

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 06 July 2016. at 00:04 For personal use only. No other uses without permission. . All rights reserved.
4688 Iglesias et al Thyroid and Mortality in the Elderly J Clin Endocrinol Metab, December 2013, 98(12):4683 4690

multivariate (adjusted) analysis, a history of cancer (1.60;
1.122.28; P .009), age (1.03; 1.011.06; P .003),
and FT3 levels (0.72; 0.63 0.84; P .001) were signifi-
cant factors related to all-cause mortality. In regard to CV
mortality, only age (1.05; 1.021.07; P .001) and FT3
levels (0.71; 0.60 0.83; P .001) were significant factors
in the unadjusted analysis. In the multivariate (adjusted)
analysis FT3 (0.76; 0.63 0.91; P .004) behaved as a
significant factor associated with CV mortality along with
cancer (1.64; 1.06 2.55; P .027) and age (years) (1.05;
1.021.08; P .003) (Table 4).
Discussion
Our results clearly show a significant relationship between
TFT results and mortality in aged hospitalized patients not
only during hospitalization but also long term after hos-
pital discharge. Low serum levels of TSH, FT4, and, in
particular, FT3 were associated with increased all-cause
mortality. Low FT3 was a significant predictor of all-cause
mortality both before and after hospital discharge. In ad-
dition, low TSH and low FT3 levels were associated with
higher CV mortality. However, multivariate analysis
showed that only FT3 and age were independent predic-
tors for CV mortality in this population. Lastly, we could
not find any significant relationship between thyroid sta-
tus and comorbidity with the exception of increased FT4
levels in hypertensive patients and decreased FT3 levels in
patients who were admitted for sepsis.
Several studies have investigated the prevalence of thy-
roid dysfunction, as well as its relationship with morbidity
and mortality in elderly populations (12, 13, 1518, 20
25). Some of them were performed in an apparently
healthy elderly population (12, 13, 1518), whereas oth-
ers were performed in hospitalized (20 24) or institution-
alized (26) elderly patients. Our findings confirm that the
prevalence of alterations in TFT results in elderly hospi-
talized patients is notably high, about three quarters of
patients, mainly with NTIS, as reported previously (20,
21, 23).
The association between alterations in TFT results and
comorbidity has been well established (27). In elderly in-
dividuals, some studies found a relationship between sub-
clinical thyroid hyperfunction and atrial fibrillation but
not with other CV disorders (10, 28). Others relate sub-
clinical hyperthyroidism (TSH 0.1 mU/L) and subclin-
ical hypothyroidism (TSH 10 mUl) with an increase in
the risk of incident CHF in elderly patients with known CV
risk factors or previous CV disease (27, 29). Our study
shows no significant relationship between TFT results and
prevalent CV disease or known risk factors for CV disease,
including diabetes mellitus and dyslipidemia. Only hyper-
tensive patients showed higher FT4 levels, although within
the normal range, with FT3 and TSH levels similar to those
of nonhypertensive patients. This observation is in accor-
dance with a recent report showing a positive correlation
between FT4 and left ventricular mass in hypertensive eu-
thyroid patients (30).
Low T3 syndrome affects 60% to 66% of elderly
patients hospitalized for acute illness (19, 21, 23). This
alteration is usually transient, serum T3 levels normalizing
in about 30% a month after hospital discharge (31). Our
survey did not find any association between the presence
of low T3 syndrome and the prevalent comorbidity, sug-
gesting that this alteration would be more closely related
to the acute illness than to the type of chronic conditions

Table 4. Nonadjusted and Adjusted HRs (with 95% CIs) for the Development of All-Cause and CV Mortality in
Patients Classified According to Several Clinical and Analytical (TFTs) Variables
All-Cause Mortality CV Mortality

Multivariate (Adjusted) Multivariate (Adjusted)

Unadjusted Analysis Analysis Unadjusted Analysis Analysis
P P P P
Variable HR (95% CI) Value HR (95% CI) Value HR (95% CI) Value HR (95% CI) Value
Male sex 1.05 (0.84 1.31) NS NS 1.24 (0.94 1.65) NS NS
Age, y 1.03 (1.011.05) .001 1.03 (1.011.06) .003 1.05 (1.021.07) .001 1.05 (1.021.08) .003
Hypertension 1.19 (0.96 1.50) NS NS 1.06 (0.811.40) NS NS
Diabetes mellitus 1.01 (0.78 1.29) NS NS 0.98 (0.711.36) NS NS
Dyslipidemia 1.14 (0.84 1.55) NS NS 1.06 (0.711.59) NS NS
CV disease 0.97 (0.76 1.24) NS NS 0.90 (0.66 1.23) NS NS
Cancer 0.75 (0.54 1.03) NS 1.60 (1.122.28) .009 0.80 (0.54 1.17) NS 1.64 (1.06 2.55) .027
TSH, mU/L 1.00 (0.971.04) NS NS 1.01 (0.951.07) NS NS
FT4, pmol/L 0.98 (0.951.01) NS NS 0.96 (0.921.00) NS NS
FT3, pmol/L 0.71 (0.62 0.82) .001 0.72 (0.63 0.84) .001 0.71 (0.60 0.83) .001 0.76 (0.63 0.91) .004
Abbreviation: NS, not significant.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 06 July 2016. at 00:04 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2012-3849 jcem.endojournals.org 4689

of the patients; however, the latter only could have been the selection bias because we could not find the cause of
demonstrated by comparing FT3 values before admission death in a nonnegligible number of patients.
with those at admission. In conclusion, our results show that alterations in TFT
FT3 was significantly decreased in patients admitted results are related to mortality in aged patients hospital-
with sepsis compared with that in those admitted for other ized for acute illness not only during hospitalization but
causes. This finding confirms the results of previous stud- also long term after discharge. Low FT3, low FT4, and low
ies that showed a correlation of low T3 concentrations TSH serum concentrations are associated with decrease
with the severity of illness in elderly hospitalized patients survival time, although only low FT3 behaves as a signif-
(23). All the factors that inhibit 5-monodeiodinase, an icant predictor of all-cause and CV mortality.
enzyme involved in the peripheral 5 deiodination of T4 to
T3, such as malnutrition, low caloric intake, drugs, and
increased inflammatory cytokines seem to be the main Acknowledgments
factors responsible for the development of low T3 syn-
Address all correspondence and requests for reprints to: Dr
drome during the hospitalization for acute illness (3234). Pedro Iglesias, Department of Endocrinology, Hospital Ramn
Some, but not all, reports have suggested that decreased y Cajal, Ctra. de colmenar, Km 9,100, 28034 Madrid, Spain.
TSH and increased FT4 levels are associated with an in- E-mail: piglo65@gmail.com.
crease in mortality in elderly individuals (1215, 18), Disclosure Summary: The authors have nothing to disclose.
whereas mild subclinical hypothyroidism appears to be
related to an increase in survival in this population (13, 15,
16). A recent retrospective study performed in hospital- References
ized patients older than 60 years showed that low total T4 1. Chuang CC, Wang ST, Wang PW, Yu ML. Prevalence study of
and high TSH levels were associated with a worse prog- thyroid dysfunction in the elderly of Taiwan. Gerontology. 1998;
44:162167.
nosis for morbidity and mortality during hospitalization 2. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado
and for 18 months after discharge (19). To the best of our thyroid disease prevalence study. Arch Intern Med. 2000;160:526
knowledge, our survey is the first study that has prospec- 534.
3. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter
tively evaluated the relationship between the TFT results EW, Spencer CA, Braverman LE. Serum TSH, T4, and thyroid an-
at hospital admission for acute illness and mortality in tibodies in the united states population (1988 to 1994): National
elderly patients in the long term. We found that alterations Health and Nutrition Examination Survey (NHANES III). J Clin
Endocrinol Metab. 2002;87:489 499.
in TFT results were associated with mortality, but, unlike 4. Valeix P, Dos Santos C, Castetbon K, Bertrais S, Cousty C, Hercberg
Mingote et al (19), we found that patients who died had S. Thyroid hormone levels and thyroid dysfunction of French adults
serum levels of TSH and FT3 significantly lower than those participating in the SU.VI.MAX study. Ann Endocrinol (Paris).
2004;65:477 486.
of patients who survived, with no differences in FT4 levels. 5. Empson M, Flood V, Ma G, Eastman CJ, Mitchell P. Prevalence of
Moreover, survival analysis showed a significantly lower thyroid disease in an older Australian population. Intern Med J.
median survival time for the lowest tertiles of FT3, FT4, 2007;37:448 455.
6. Brochmann H, Bjro T, Gaarder PI, Hanson F, Frey HM. Prevalence
and TSH. Such differences may be related to the type of of thyroid dysfunction in elderly subjects. A randomized study in a
hormones measured (FT4 and FT3 in our study), patient Norwegian rural community (Naeroy). Acta Endocrinol (Copenh).
selection criteria, and interference with drugs affecting 1988;117:712.
7. Vanderpump MP, Tunbridge WM, French JM, et al. The incidence
thyroid function. of thyroid disorders in the community: A twenty-year follow-up of
There is a well-known association between serum T3 the Whickham survey. Clin Endocrinol (Oxf). 1995;43:55 68.
concentrations and mortality in critically ill patients (21, 8. Aghini-Lombardi F, Antonangeli L, Martino E, et al. The spectrum
of thyroid disorders in an iodine-deficient community: The Pesco-
3537). In fact, a low T3 level has also been considered to pagano survey. J Clin Endocrinol Metab. 1999;84:561566.
be a significant predictive marker for mortality in several 9. Rehman SU, Cope DW, Senseney AD, Brzezinski W. Thyroid dis-
pathological states, including heart disease (35), acute orders in elderly patients. South Med J. 2005;98:543549.
10. Cappola AR, Fried LP, Arnold AM, et al. Thyroid status, cardio-
stroke (38), and the need for hemodialysis (39). Our study vascular risk, and mortality in older adults. JAMA. 2006;295:1033
confirms this association between low FT3 levels and all- 1041.
cause and CV mortality, being the most important pre- 11. Faggiano A, Del Prete M, Marciello F, Marotta V, Ramundo V,
Colao A. Thyroid diseases in elderly. Minerva Endocrinol. 2011;
dictor of 7-year CV mortality in octogenarian patients, 36:211231.
even more than age. 12. Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA.
The relatively large number of patients and the long Prediction of all-cause and cardiovascular mortality in elderly peo-
ple from one low serum thyrotropin result: a 10-year cohort study.
time of follow-up are the main strengths of this study. Our Lancet. 2001;358:861 865.
results related to CV mortality evaluation are limited by 13. Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frlich M,

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 06 July 2016. at 00:04 For personal use only. No other uses without permission. . All rights reserved.
4690 Iglesias et al Thyroid and Mortality in the Elderly
Westendorp RG. Thyroid status, disability and cognitive function,
and survival in old age. JAMA. 2004;292:25912599.
14. Singer RB. Mortality in a complete 4-year follow up of 85-year-old
residents of Leiden, classified by serum level of thyrotropin and
thyroxine. J Insur Med. 2006;38:14 19.
15. Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frlich M,
Westendorp RG. Thyroid function, activities of daily living and
survival in extreme old age: the Leiden 85-plus Study. Ned Tijdschr
Geneeskd. 2006;150:90 96.
16. van den Beld AW, Visser TJ, Feelders RA, Grobbee DE, Lamberts
SW. Thyroid hormone concentrations, disease, physical function,
and mortality in elderly men. J Clin Endocrinol Metab. 2005;90:
6403 6409.
17. Waring AC, Harrison S, Samuels MH, et al. Thyroid function and
mortality in older men: A prospective study. J Clin Endocrinol
Metab 2012;97:862 870.
18. Waring AC, Arnold AM, Newman AB, Bzkov P, Hirsch C, Cap-
pola AR. Longitudinal changes in thyroid function in the oldest old
and survival: the cardiovascular health study all-stars study. J Clin
Endocrinol Metab. 2012;97:3944 3950.
19. Mingote E, Merono T, Rujelman R, et al. High TSH and low T4 as
prognostic markers in older patients. Hormones (Athens). 2012;11:
350 355.
20. Bossoni S, Cossi S, Marengoni A, et al. Low T3 syndrome and out-
come in elderly hospitalized geriatric patients. J Endocrinol Invest
2002;25(10 suppl):7374.
21. Iglesias P, Muoz A, Prado F, et al. Alterations in thyroid function
tests in aged hospitalized patients: prevalence, aetiology and clinical
outcome. Clin Endocrinol (Oxf). 2009;70:961967.
22. Atkinson RL, Dahms WT, Fisher DA, Nichols AL. Occult thyroid
disease in an elderly hospitalized population. J Gerontol. 1978;33:
372376.
23. Simons RJ, Simon JM, Demers LM, Santen RJ. Thyroid dysfunction
in elderly hospitalized patients. Effect of age and severity of illness.
Arch Intern Med. 1990;150:1249 1253.
24. Bossoni S, Cossi S, Marengoni A, et al. The negative role of sub-
clinical thyrotoxicosis on the outcome of hospitalized geriatric pa-
tients. J Endocrinol Invest 2002;25(10 suppl):64 65.
25. Dez JJ, Molina I, Ibars MT. Prevalence of thyroid dysfunction in
adults over age 60 years from an urban community. Exp Clin En-
docrinol Diabetes. 2003;111:480 485.
26. Cobler JL, Williams ME, Greenland P. Thyrotoxicosis in institu-
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 06 July 2016. at 00:04 For personal use only. No other uses without permission. . All rights reserved.
J Clin Endocrinol Metab, December 2013, 98(12):4683 4690
tionalized elderly patients with atrial fibrillation. Arch Intern Med.
1984;144:1758 1760.
27. Gencer B, Collet TH, Virgini V, et al. Subclinical thyroid dysfunc-
tion and the risk of heart failure events: an individual participant
data analysis from 6 prospective cohorts. Circulation 2012;126:
1040 1049.
28. Sawin CT, Geller A, Wolf PA, et al. Low serum thyrotropin con-
centrations as a risk factor for atrial fibrillation in older persons.
N Engl J Med. 1994;331:1249 1252.
29. Nanchen D, Gussekloo J, Westendorp RG, et al. Subclinical thyroid
dysfunction and the risk of heart failure in older persons at high
cardiovascular risk. J Clin Endocrinol Metab 2012;97:852 861.
30. Iida M, Yamamoto M, Ishiguro Y, Yamazaki M, Honjo H, Kamiya
K. Thyroid hormone within the normal range is associated with left
ventricular mass in patients with hypertension. J Am Soc Hypertens.
2012;6:261269.
31. Iglesias P, Muoz A, Prado F, et al. Serum thyrotropin concentration
is an early marker of normalization of low triiodothyronine syn-
drome in aged hospitalized patients after discharge. J Endocrinol
Invest. 2010;33:607 611.
32. van der Poll T, Romijn JA, Wiersinga WM, Sauerwein HP. Tumor
necrosis factor: a putative mediator of the sick euthyroid syndrome
in man. J Clin Endocrinol Metab. 1990;71:15671572.
33. Stouthard JM, van der Poll T, Endert E, et al. Effects of acute and
chronic interleukin-6 administration on thyroid hormone metabo-
lism in humans. J Clin Endocrinol Metab. 1994;79:13421346.
34. Adler SM, Wartofsky L. The nonthyroidal illness syndrome. Endo-
crinol Metab Clin North Am 2007;36:657 672, vi
35. Iervasi G, Pingitore A, Landi P, et al. Low-T3 syndrome: a strong
prognostic predictor of death in patients with heart disease. Circu-
lation. 2003;107:708 713.
36. Peeters RP, Wouters PJ, van Toor H, Kaptein E, Visser TJ, Van den
Berghe G. Serum 3,3,5-triiodothyronine (rT3) and 3,5,3-triiodo-
thyronine/rT3 are prognostic markers in critically ill patients and are
associated with postmortem tissue deiodinase activities. J Clin En-
docrinol Metab. 2005;90:4559 4565.
37. Plikat K, Langgartner J, Buettner R, et al. Frequency and outcome
of patients with nonthyroidal illness syndrome in a medical intensive
care unit. Metabolism. 2007;56:239 244.
38. Alevizaki M, Synetou M, Xynos K, Pappa T, Vemmos KN. Low
triiodothyronine: a strong predictor of outcome in acute stroke pa-
tients. Eur J Clin Invest. 2007;37:651 657.
39. Zoccali C, Mallamaci F. Thyroid function and clinical outcomes in
kidney failure. Clin J Am Soc Nephrol. 2012;7:1214.