CLINICAL MANAGEMENT OF THE
GERIATRIC PATIENT
Diagnosis and Management of Subclinical Hypothyroidism in
Elderly Adults: A Review of the Literature
James V. Hennessey, MD,* and Ramon Espaillat, MD
The estimated prevalence of subclinical hypothyroidism
(SCH) in the general population is 3% to 8%. As the average
age of the population in the United States and other countries
continues to increase, the overall prevalence of SCH may
also be expected to increase. Although age-related changes in
thyroid function are well described, normal thyroid-stimu-
lating hormone (TSH) reference limits, derived for age-spe-
cific populations, are not routinely used to identify thyroid
dysfunction in elderly adults. Therefore, currently accepted
values for the upper limit of normal of TSH may be inappro-
priate for diagnosing SCH in individuals aged 65 and older,
resulting in potential overestimation of the prevalence of
SCH in this population. This review discusses the current
evidence of the effects of SCH on cardiovascular health and
neuropsychiatric function in older adults. Although the
results of some studies are conflicting, the overall evidence
suggests that the consequences of SCH may be different for
elderly adults than for younger populations. Treatment of
SCH in older individuals requires special consideration with
regard to thyroid hormone replacement therapy and
expected clinical outcomes. Although careful identification
of individuals with persistent SCH who could benefit from
levothyroxine treatment is necessary, current evidence sug-
gests that individuals with TSH levels greater than 10 mIU/L
who test positive for antithyroid antibodies or are symptom-
atic may benefit from levothyroxine treatment to reduce the
risk of progression to overt hypothyroidism, decrease the
risk of adverse cardiovascular events, and improve their
quality of life. After treatment is initiated, careful monitoring
is essential. J Am Geriatr Soc 63:16631673, 2015.
Key words: subclinical hypothyroidism; elderly; diagno-
sis; symptoms; morbidity; cognitive function; cardiovas-
cular morbidity; levothyroxine therapy
From the *Division of Endocrinology, Harvard Medical School, Beth
Israel Deaconess Medical Center, Boston, Massachusetts; and AbbVie
Inc., North Chicago, Illinois.
Address correspondence to James V. Hennessey, Associate Professor of
Medicine, Division of Endocrinology, Diabetes and Metabolism, Harvard
Medical School, Beth Israel Deaconess Medical Center, 330 Brookline
Ave, GZ6, Boston, MA 02215. E-mail: jhenness@bidmc.harvard.edu
DOI: 10.1111/jgs.13532
JAGS 63:16631673, 2015
2015 The Authors.
The Journal of the American Geriatrics Society published by Wiley Periodicals, Inc. on behalf of The American Geriatrics Society.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and
distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
EPIDEMIOLOGY/AGE-RELATED RISK FACTORS
AND PREDISPOSITIONS
T hyroid-stimulating hormone (TSH) concentration
increases with age;1 whether this change is a normal
adaptive response associated with senescence or an actual
increase in abnormal function is unclear. It has also been
proposed that the greater prevalence of thyroid abnormali-
ties and dysfunction associated with aging results from
damage to thyroid cells from oxidative stress, due to con-
tinual exposure to reactive oxygen species (hydrogen per-
oxide) needed for the production of thyroid hormones.2
Subclinical hypothyroidism (SCH), a laboratory diagnosis
characterized by a high TSH level (>4.5 mIU/L) but a nor-
mal free thyroxine (FT4) level, is commonly encountered
in clinical practice.3 Epidemiological studies have esti-
mated the prevalence of SCH to be 3.1% to 8.5% in the
general population; variability in reported overall preva-
lence rates can be attributed to the environmental charac-
teristics of the area sampled and differing definitions for
the upper limit of normal for TSH.4,5 SCH is associated
with aging, is more prevalent in women, and is more fre-
quent in whites and Mexican Americans than blacks.1,5
Because the average age of the population in the United
States and other countries continues to increase, the over-
all prevalence of SCH (based on a TSH level above the
expected laboratory range) is also expected to increase.
SCH is thought to represent mild thyroid failure, with
some but not all individuals eventually developing overt
hypothyroidism. Therefore, it is important for clinicians to
be aware of SCH and its clinical effect in elderly adults,
understand how it is diagnosed, and recognize situations
in which treatment may be appropriate. Clinicians must
also be mindful of the potential risks, such as the greater
incidence of fractures and arrhythmias,6,7 that could result
from overtreatment of individuals with mildly high TSH
levels.
Evidence that a modified range for the normal limits
of TSH concentration would be more appropriate for diag-
nosing the elderly population complicates the diagnosis
0002-8614/15/$15.00
1664 HENNESSEY AND ESPAILLAT AUGUST 2015VOL. 63, NO. 8 JAGS

and treatment of thyroid dysfunction in elderly adults. An
analysis of the National Health and Nutrition Examina-
tion Survey III (NHANES III) found that the mean, med-
ian, and 97.5th percentile of TSH concentrations increased
with age. The 97.5th percentiles were 5.9 mIU/L for indi-
viduals aged 70 to 79 and 7.5 mIU/L for those aged 80
and older.8 The authors of that study suggest that the use
of the currently accepted upper limit of normal value for
TSH, which was determined based on the all-age US popu-
lation, may lead to overdiagnosis of SCH in older people.
Table 1 summarizes TSH levels according to age reported
in published studies.
In contrast to most analyses, another study in a popu-
lation without thyroid disease (N = 148,938) concluded
that age-specific TSH reference limits are unnecessary.9 No
significant changes (P = .22) in the 2.5th percentile were
seen across age groups, although statistically significant
increases in the mean (P = .02) and 97.5th percentile
(P < .01) TSH values were seen with increasing age. Even
so, the authors concluded that applying age-adjusted upper
reference limits, instead of using a universal cutoff of
4.0 mIU/L, would have little effect on thyroid function
classification for adults aged 55 to 85; only 0.1% to 2.0%
in each 5-year age group would be incorrectly classified. In
contrast, 4.7% would be misclassified in individuals aged
90 and older.9
The Cardiovascular Health Study (CHS), a longitudi-
nal study investigating cardiovascular risk factors (includ-
ing thyroid function) in individuals aged 65 and older, has
been ongoing since 1989.10 The All-Stars cohort is a longi-
tudinal extension study of surviving members of the origi-
nal cohort.11 Thyroid function was analyzed in 533
reference subjects from the All-Stars cohort with a mean
age of 85 at the final assessment who did not have thyroid
disease at the final assessment.11 Between the baseline and
13-year follow-up measurements, TSH levels increased
12%, FT4 levels increased slightly, and triiodothyronine
(T3) levels declined 13%.11 A cross-sectional analysis
according to age found that the 97.5th percentile of TSH
increased from 6.16 mIU/L in participants aged 80 to 84
to 6.41 mIU/L in those 85 to 89 and to 7.96 mIU/L in
those aged 90 and older. The authors concluded that the
increase in TSH, accompanied by a slight rise in FT4, was
not indicative of an increasing prevalence of thyroid dis-
ease with aging and advised against reflexively offering
thyroid hormone therapy based on mildly high TSH
levels.11
Taken together, studies have shown that it is likely
that age affects TSH levels, and some studies suggest that
modified reference limits for elderly adults should be con-
sidered in the diagnosis of mild thyroid failure. In the next
section, the evidence base for the potential effect of SCH
on cardiovascular and neuropsychiatric clinical outcomes
in elderly adults will be reviewed.
CLINICAL MANIFESTATIONS
Coronary Heart Disease
Individual Studies
Results of epidemiological studies of cardiovascular risk in
individuals with SCH have been inconsistent (Table 2). An
association between SCH and adverse cardiovascular out-
comes was reported for women aged 55 and older with
mild thyroid failure in the Rotterdam cohort; the odds of

Table 1. Comparison of Reported TSH Concentrations Stratified According to Age in Disease-Free Reference Popu-
lations
Surks and Hallowell Kahapola-Arachchige Bremner et al.
(2007)8 Boucai et al. (2011)53 et al. (2012)9 Waring et al. (2012)11 (2012)54

TSH, mIU/L TSH, mIU/L TSH, mIU/L TSH, mIU/L TSH, mIU/L

97.5th 97.5th 97.5th 97.5th Upper

Age n Median Centile n Median Centile n Median Centile n Median Centile n Mean Limita

6064 1,430b 1.67b 4.33b NR 1.66b 4.70b 13,610 1.72 4.24 334c 1.34c 4.70c
6569 10,285 1.79 4.40
7074 1,001d 1.76d 5.90d NR 1.74d 5.60d 8,155 1.80 4.37 224e 1.66e 5.28e
7579 6,192 1.84 4.72 15f 1.56f 2.67f
8084 668g 1.90g 7.49g NR 1.90g 6.30g 4,715 1.82 4.81 264h 2.20h 6.16h
8589 2,478 1.84 5.00 175i 2.59i 6.41i
90 1,224 1.91 5.64 79j 2.53j 7.96j
a
Mean + 2 standard deviations of log-transformed serum TSH concentrations.
b
Data reported for ages 6069.
c
Data reported for ages 6070.
d
Data reported for ages 7079.
e
Data reported for ages >70.
f
Data reported for ages 7579.
g
Data reported for ages 80.
h
Data reported for ages 8084.
i
Data reported for ages 8589.
j
Data reported for ages 90.
NR = not reported; TSH = thyroid-stimulating hormone.
 JAGS

Table 2. Studies of Relationship Between SCH and Cardiovascular Health

Participants

Author, Year Study Description n Age TFTs and Criteria for SCH Outcomes Comments

Individual Studies of CHD

Hak et al. Population-based study 1,055 Mean 68.9 TSH >4.0 mIU/L (n = 124) Risk of MI (OR = 2.3, 95% CI = 1.34.0) and aortic
(2000)12 of postmenopausal Normal FT4 (0.91.9 ng/dL) atherosclerosis (OR = 1.7, 95% CI = 1.12.6) greater
women in the with SCH than euthyroida
Netherlands Risk of MI (OR = 3.1, 95% CI = 1.56.3) and aortic
atherosclerosis (OR = 1.9, 95% CI = 1.13.6) greater with
SCH and antithyroid peroxidase antibody than euthyroida
AUGUST 2015VOL. 63, NO. 8

Imaizumi et al. Longitudinal study of
(2004)13 Japanese atomic bomb
survivors
Tseng et al. Observational study of 115,746
(2012)14 Taiwanese participants
aged 20
Asvold et al. Observational study of 25,313
(2008)15 Norwegian participants
aged 20
Selmer et al. Population-based study 563,700
(2014)16 of individuals in primary
care in Denmark aged
18
Parle et al. Individuals in primary
(2001)17 care aged 60 from a
single UK practice
Razvi et al. Retrospective review of
(2012)18 LT4 use in individuals
with SCH (aged 40)
from a large UK primary
2,856b Mean 58.5 TSH >510 mIU/L (n = 240) SCH significantly associated with risk of IHD (OR = 2.6,
TSH >10 mIU/L (n = 17) 95% CI = 1.25.6; P = .02)c
Normal FT4 (0.82.5 ng/dL) Significantly greater risk of IHD in men (OR = 4.5, 95%
CI = 1.612.8; P < .01) but not women (OR = 1.7, 95%
CI = 0.56.1; P = .70) with mild SCH (TSH 10 mIU/L)
during follow-up (mean 12.2 years)c
Mean 47.1 (SCH) TSH 5.019.96 mIU/L Risk of death greater with SCH over 10-year follow-up SCH treatments
and 42.9 (euthyroid) (n = 1,841) period; highest risks for aged 65 initiated in follow-
>65 y, n = 9798 Normal FT4 (57.9 All-cause deaths up period not
154.4 nmol/dL) Overall: RR = 1.30, 95% CI = 1.021.66 identified or
Aged 65: RR = 1.53, 95% CI = 1.112.11 evaluated
Deaths from CVD
Overall: RR = 1.68, 95% CI = 1.022.76
Aged 65: RR = 2.02, 95% CI = 1.103.70
Means 5663d TSH reference range TSH 2.53.5 mIU/L: risk of CHD death significantly greater Stratification
0.53.6 mIU/L (HR = 1.43, 95% CI = 1.061.92) than with TSH 0.50 within each TSH
TSH 3.6 mIU/L (n = 1,426) 1.4 mIU/L (low normal) reference range:
TSH 3.6 mIU/L: no greater risk of CHD death (women: 0.501.4,
HR = 1.38, 95% CI = 0.882.17; men: HR = 1.15, 95% 1.52.4,
CI = 0.661.98) than with low normal TSH 2.53.5 mIU/L
Mean 48.6 TSH >5.0 mIU/L (n = 11,560) Risk of MI (IRR = 1.13, 95% CI = 1.011.27) greater with
FT4 922 pmol/L SCH than euthyroid
Total thyroxine 60140 mmol/L Risk of all-cause death (IRR = 0.92, 95% CI = 0.870.97)
lower with SCH
1,191 Median 69 TSH reference range No association between TSH >5 mIU/L and death (all-cause Effects of LT4
0.55.0 mIU/L or from circulatory disease) vs euthyroid (TSH 0.5 use in SCH group
TSH >5 mIU/L (n = 94) 5.0 mIU/L) in follow-up (mean 8.2 years) after baseline
(40%) not
evaluated
4,735 Mean for aged TSH >5.0110.0 mIU/L Aged 70: no statistically significant difference in incidence Participants
4069, 56 Normal FT4 (0.71.9 ng/dL) of IHD events, cerebrovascular accidents, or death stratified
(n = 3,093) (circulatory, IHD, or any cause) between LT4-treated and according to age
Mean for aged untreated groups (4069, 70)
SUBCLINICAL HYPOTHYROIDISM IN ELDERLY ADULTS

care database 70, 80 Aged <70: LT4 treatment associated with lower risk of IHD
(n = 1,642) event and death (circulatory, IHD, or any cause)

(Continued)
1665
Table 2 (Contd.)
1666

Participants

Author, Year Study Description n Age TFTs and Criteria for SCH Outcomes Comments

CHD Analyses of CHS Cohort

Cappola et al. Longitudinal population- 3,233 Mean 72.7 TSH 4.520 mIU/L (n = 496) No difference between SCH and euthyroid groups in AF, Postbaseline
(2006)10 based study of adults Normal FT4 (0.71.7 ng/dL) CHD, and cerebrovascular disease events or all-cause death thyroid
aged 65 (CHS cohort) in follow-up (mean 12.5 years) medication use
factored into data
analysis
Waring et al. CHS participants re- 1,677 Mean 85.3e TSH 4.520 mIU/L (n = 85)f No effect of SCH, TSH, or triiodothyroid levels on mortality
HENNESSEY AND ESPAILLAT

(2012)11 recruited 1317 years Normal FT4 (0.71.7 ng/dL) Higher FT4 level associated with greater risk of death (HR
later (CHS All-Stars per 1 ng/dL = 2.57, 95% CI = 1.325.02)
cohort) Median follow-up, 5.1 years
Hyland et al. CHS cohort 4,863 Mean 74.1 TSH 4.520 mIU/L No difference in 10-year incidence of CHD, HF, or CV death 2 TFTs (2 years
(2013)19 2,633g (SCH) and Normal FT4 for SCH (persistent or transient) vs euthyroid apart) used
73.4 (euthyroid)h Persistent SCH (n = 206) Persistent
(n = 85) SCH = SCH in
Transient SCH (n = 129) 2 TFTs
Transient
SCH = SCH in
1 TFT
Cappola et al. CHS cohort 2,843 Mean 74.5 TSH reference range, Nonsignificant trend for improved outcomes (AF, CHD, HF, Assessment of
(2014)20 0.454.5 mIU/L and death) with higher vs lower TSH within normal range TSH and FT4
FT4 reference range, Higher FT4 within normal range associated with increased within euthyroid
0.71.7 ng/dL risk of AF and HF group only
Meta-Analyses of CHD
Razvi et al. Meta-analysis of 1,085,841 Means 4285i TSH 2.810 mIU/Lj Overall: SCH vs euthyroid: greater risk of prevalent IHD
(2008)21 15 population-based or (n = 126,590) (OR = 1.23, 95% CI = 1.021.48; P = .03); no greater risk
longitudinal cohort of incident IHD or CV death
studies Aged 65: no difference in prevalent or incident IHD risk or
CV death
Aged <65: statistically significantly greater risk of prevalent
and incident IHD and CV death (P .02)
Rodondi et al. Meta-analysis of 55,287 Medians 4685k TSH 4.520 mIU/L TSH >10 mIU/L: statistically significantly greater risk of CHD Stratification
(2010)22 individual data from (n = 3,450) event (HR = 1.89, 95% CI = 1.282.80) and CHD death according to age
11 prospective studies Normal FT4l (HR = 1.58, 95% CI = 1.102.27) vs euthyroid and TSH level
Aged 6579: greater risk of CHD death (HR = 1.33,
95% CI = 1.071.65) and total death (HR = 1.22, 95%
CI = 1.031.45) with SCH
Aged 80: no greater risk of CHD event or death (CHD or
total) with SCH
Studies of HF
Rodondi et al. CHS cohort 3,044 Mean 72.6 TSH 4.520 mIU/L Greater risk of incident HF event with TSH 10 mIU/L
(2008)23 (n = 474) (HR = 1.88, 95% CI = 1.053.34)
AUGUST 2015VOL. 63, NO. 8

Normal FT4 (0.71.7 ng/dL) No greater HF risk with TSH 4.510 mIU/L than euthyroid

(Continued)
JAGS
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Table 2 (Contd.)

Participants

Author, Year Study Description n Age TFTs and Criteria for SCH Outcomes Comments

Nanchen et al. Post hoc analysis of a 5,245 (199 SCH, Mean 75 TSH >4.5 (n = 199) No greater HF risk with SCH than euthyroid
AUGUST 2015VOL. 63, NO. 8

(2012)24 pravastatin randomized, 5,046 euthyroid) Normal FT4 (1222 pmol/dL) Increased risk of HF hospitalization with TSH >10 mIU/L
controlled trial (HR = 3.01, 95% CI = 1.128.11)
(Prospective Study of Greater risk of HF hospitalization with TSH >10 mIU/L
Pravastatin in the Elderly after 6 months (HR = 3.84, 95% CI = 1.2012.29)
at Risk)
Gencer et al. Meta-analysis of 25,390 Median 70 TSH 4.519.9 mIU/L Risk of HF event in SCH vs euthyroid
(2012)25 individual data from (n = 2,068) Overall: HR = 1.26, 95% CI = 0.911.74
6 prospective studies Normal FT4l Aged 6579: HR = 1.3, 95% CI = 0.921.87
Aged 80: HR = 1.01, 95% CI, 0.691.46
Stratification according to TSH level within SCH group
showed a significantly greater HF risk with higher TSH
(P < .01)
TSH 4.56.9 mIU/L: HR = 1.01, 95% CI = 0.811.26
TSH 7.09.9 mIU/L: HR = 1.65, 95% CI = 0.843.23
TSH 10.019.9 mIU/L: HR = 1.86, 95% CI = 1.272.72
a
Adjusted for age.
b
Individuals with a history of thyroid medication use excluded from analysis (n = 73).
c
Adjusted for blood pressure, body mass index, cholesterol, smoking, diabetes mellitus, and erythrocyte sedimentation rate.
d
Mean age for groups varied according to thyroid-stimulating hormone (TSH) stratification and sex.
e
Participants with thyroid test data from the Cardiovascular Health Study (CHS; n = 1,049).
f
Participants not currently taking thyroid medication who had original thyroid function tests (TFTs) from CHS.
g
Participants with two TFTs obtained 2 years apart.
h
n = 4,863.
i
Mean ages varied according to study and thyroid status.
j
Upper limit of normal for TSH for SCH diagnosis varied in the individual studies.
k
Median ages varied according to study.
l
Reference limits varied according to study.
AF = atrial fibrillation; CHD = coronary heart disease; CI = confidence interval; CVD = cardiovascular disease; FT3 = free triiodothyronine; FT4 = free thyroxine; HF = heart failure; HR = hazard ratio;
IHD = ischemic heart disease; IRR = incidence rate ratio; LT4 = levothyroxine; MI = myocardial infarction; OR = odds ratio; RR = risk ratio; SCH, subclinical hypothyroidism; TFT, thyroid function test.
SUBCLINICAL HYPOTHYROIDISM IN ELDERLY ADULTS
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historical myocardial infarction (MI; according to electro- tive study of cardiovascular outcomes in individuals with
cardiogram) and aortic calcification were 2.3 and 1.7 times treated and untreated SCH, diagnosed according to a sin-
as high.12 The simultaneous presence of antithyroid anti- gle TSH measurement of 5.1 to 10 mIU/L with normal
bodies and SCH, which may reflect eventual progression FT4 levels, found no statistically significant difference in
to more-severe hypothyroidism, increased the odds of ath- the incidence of IHD events, death due to any cause, death
erosclerosis to 1.9 times as high and MI to 3.1 times as attributed to circulatory or IHD reasons, or cerebrovascu-
high as in euthyroid controls.12 An association between lar accidents in individuals aged 70 and older assessed over
SCH and cardiovascular mortality was subsequently found an 8-year period (median 5.2 years).18
in a group of 2,856 Japanese atomic bomb survivors, who
had a mean age of 58.5 at enrollment and were followed CHS Cohort Analyses
for an average of 12.2 years.13 SCH was found in 10.2%
Multiple analyses of data from the CHS have failed to find
of the population, with 93.4% having mild SCH (TSH
a relationship between thyroid dysfunction and cardiovas-
10 mIU/L). Men with mild SCH had an overall odds
cular outcomes (Table 2).10 Subjects were recruited in two
ratio (OR) of 4.5 (95% confidence interval (CI) = 1.6
phases in the late 1980s and early 1990s. In the first
12.8; P < .01) for ischemic heart disease (IHD) when con-
report, 3,233 subjects (mean age 72.7) were screened, and
trolled for blood pressure, body mass index, cholesterol,
496 were classified as having SCH based on a single base-
smoking, diabetes mellitus, and erythrocyte sedimentation
line TSH value between 4.5 and 20.0 mIU/L. During a
rate (as a measure of chronic inflammation). Women with
mean follow-up of 12.5 years, 28.6% of the initial sub-
mild SCH also had a somewhat higher, but nonsignificant,
population with SCH (n = 142) began thyroid hormone
IHD risk (OR = 1.7, 95% CI = 0.56.1; P = .70).13 The
replacement therapy; no data were provided on reversion
association between SCH (TSH 5.019.96 mIU/L, normal
to euthyroidism or persistence of SCH. In this population,
FT4) and all-cause and cardiovascular disease (CVD) mor-
SCH was not associated with negative effects on cardio-
tality was evaluated in Taiwanese participants aged 20 and
vascular, cerebrovascular, or overall mortality outcomes.10
older (N = 115,746), of whom 1.6% (n = 1,841) were cat-
The effects of thyroid status in the CHS All-Stars
egorized as having SCH.14 After 10 years of follow-up,
cohort (n = 1,677; Table 2) were reported.11 A subcohort
analysis of the adjusted risk ratios found that SCH
of 843 individuals naive to thyroid medication (mean age
increased the risk of death from any cause by 30% (and
85.3) were retested to establish a new baseline for thyroid
from CVD by 68%). The investigators noted that they had
function. Ten percent of the subcohort (n = 85) had TSH
no information on whether study participants were subse-
values greater than 4.5 mIU/L. After a median follow-up
quently treated for SCH or on the potential effect of such
of 5.1 years, no relationship was found between SCH,
a regimen on the risk of death. A subgroup analysis of
TSH, or T3 and mortality, although a positive relationship
individuals aged 65 and older at enrollment found that the
between FT4 and mortality was noted. The authors analy-
highest risk of all-cause or cardiovascular mortality was in
sis of the thyroid diseasefree subset of the cohort
this subgroup.14 In the cross-sectional, population-based
(n = 533) suggested that a TSH level of 6.41 mIU/L was
Nord-Trndelag Health Study (N = 25,313), the risk of
the expected 97.5th percentile for euthyroid individuals
coronary heart disease (CHD) mortality was significantly
aged 85 to 89.11
greater at the upper end of normal TSH (2.53.5 mIU/L),
In a third analysis of the CHS data, published in 2013,
but not for TSH of 3.6 mIU/L or greater, than at the
persistent SCH was diagnosed as a TSH level between 4.50
lower end of normal TSH (0.501.4 mIU/L) in individuals
and 20.0 mIU/L in both of two tests taken approximately
with an average age of approximately 60.15 A recent large
2 years apart (Table 2).19 The 10-year incidence of CHD
study found that individuals with SCH (n = 11,560; based
was similar in the persistent SCH group, the transient SCH
on 1 assessment (TSH >5.0 mIU/L, normal FT4, normal
group, and the euthyroid reference group. Likewise, the risk
total thyroxine)) had a significantly greater risk of MI than
of heart failure (HF) and cardiovascular death was similar
a euthyroid population (n = 540,710), although SCH was
across cohorts, leading the authors to conclude that the
associated with a significantly lower risk of all-cause mor-
SCH did not increase the risk of any of these cardiovascular
tality.16 As with most studies, the certainty of the analyses
events.19 An analysis of the euthyroid members of the CHS
is low because TSH assessments were not repeated.
cohort indicated that there were trends toward more mor-
Other similarly sized studies failed to demonstrate an
bidity (incidence of atrial fibrillation, CHD, and HF) and
association between SCH and significant morbidity and
mortality with lower TSH levels within the normal ranges,
mortality (Table 2). In 1,191 individuals in primary care
suggesting that moderately high TSH levels may be not
aged 60 and older at enrollment who were not receiving
harmful in elderly adults.20 High FT4 levels, even within the
thyroid-related treatments, 8% (n = 94) were categorized
normal reference range, were associated with significantly
as having SCH based on a single TSH greater than
greater rates of atrial fibrillation and HF and a trend toward
5.0 mIU/L.17 When vital status was analyzed up to
greater mortality in this study.20
10 years later (mean follow-up, 8.2 years), no association
between SCH and mortality (all-cause or due to circula-
Meta-Analyses
tory diseases) was observed. Forty percent of the study
subjects progressed to overt hypothyroidism and were Several meta-analyses have evaluated the relationship
treated with levothyroxine during the follow-up observa- between SCH and CVD and found no greater risk in
tion period, but rates of reversion to euthyroidism were elderly adults (Table 2). One meta-analysis of 15 studies
not reported.17 These factors may have obscured the investigated the effects of mild thyroid dysfunction on
potential negative effect of SCH on outcomes. A retrospec- IHD risk or cardiovascular morbidity and mortality.21 In
JAGS AUGUST 2015VOL. 63, NO. 8
the individual studies analyzed, the lower TSH cutoff for
SCH diagnosis ranged from 2.8 to 6.0 mIU/L, and the
upper cutoff was always at least 10 mIU/L; mean TSH lev-
els ranged from 3.7 to 8.9 mIU/L. The prevalence of IHD
risk was greater in individuals with SCH than in the euthy-
roid group (P = .03), although this difference was not
observed when the analysis was limited to studies that
included only individuals aged 65 and older. The incidence
of IHD risk (median follow-up 8.6 years) and the risk of
cardiovascular mortality (median follow-up 10 years) were
not greater in individuals with SCH than in those who
were euthyroid overall, although individuals with SCH
who were younger than 65 had a greater risk of incident
IHD and cardiovascular mortality, whereas those with
SCH who were aged 65 and older did not.21
A meta-analysis of 11 studies, using individual data
for SCH and cardiovascular outcomes, determined that
higher TSH levels correlated with a trend toward greater
risk of CHD events and CHD mortality; a statistically sig-
nificantly greater risk of CHD morbidity and mortality
was seen when TSH levels were 10 mIU/L or greater
(Table 2).22 The risks were significantly higher for CHD
mortality and total mortality in multivariate stratified
analyses for individuals aged 65 to 79, but not for those
aged 80 and older, than for euthyroid controls.22
Congestive Heart Failure
Subanalyses of the CHS (N = 3,044; mean age 72.6)23 and
the Prospective Study of Pravastatin in the Elderly at Risk
(PROSPER; N = 5,316 (199 with SCH, 5,046 euthyroid,
71 with subclinical hyperthyroidism; mean age 75)24 found
that the risk of HF was significantly greater in participants
with TSH levels of 10 mIU/L or greater and greater than
10 mIU/L, respectively, than in euthyroid controls
(Table 2). Neither study showed any greater risk for TSH
levels between 4.5 and 10.0 mIU/L.23,24 As previously
mentioned, the absence of data on reversion to euthyroid
status in the CHS limits its interpretability.23 In PROS-
PER, greater risk of hospitalization for HF was associated
with a TSH level greater than 10 mIU/L that persisted for
6 months than for persistent euthyroidism.24
An analysis of individual data from six prospective cohort
studies of thyroid function and HF, representing 25,390 par-
ticipants with an average age of 70 (range 21100), deter-
mined that there was an association between TSH level and
risk of an HF event (Table 2).25 The overall age- and sex-
adjusted hazard ratio (HR) of HF events was 1.26 (95%
CI = 0.911.74) for participants with SCH (TSH 4.5
19.9 mIU/L) versus euthyroid participants (TSH 0.45
4.49 mIU/L). Furthermore, there was a statistically significant
trend (P < .01) toward greater HF event risk as TSH levels
increased, although when the population was stratified
according to age, no significant differences in the risks were
noted between participants with SCH and those who were
euthyroid. Participants with SCH aged 65 to 79 had no
greater risk of HF events than their euthyroid counterparts.25
The effects of SCH on other cardiovascular risk fac-
tors such as dyslipidemia are less clear and have been
reviewed in detail elsewhere,26,27 but the effect of increas-
ing age on such risks in individuals with SCH has not been
thoroughly analyzed.
SUBCLINICAL HYPOTHYROIDISM IN ELDERLY ADULTS 1669
Neuropsychiatric Function
Overt hypothyroidism has been linked to depression and
impaired cognitive function.28 Many studies have evalu-
ated the relationship between SCH and cognitive ability,
with mixed results.29,30 Small sample sizes, limitations of
study design or execution such as the advanced age of the
subjects, and inadequate assessments of cognitive function
have often complicated attempts to establish a relationship
between thyroid status and cognition in older adults.30
Elderly adults are also more prone to mood alterations
and cognitive decline, regardless of thyroid function.
A report on thyroid status and cognitive function in
elderly adults was published in 2004 as part of the Leiden
85-Plus study.31 Initially, 30 of 558 subjects (5.3%)
85 years old were diagnosed with SCH based on a single
test with a TSH level greater than 4.8 mIU/L and a normal
FT4 level. Cognitive function was similar in subjects with
SCH and those who were euthyroid at study entry.
Although this study concluded that cognitive function in
euthyroid elderly adults was indistinguishable from that in
those with SCH, many individuals in the SCH group may
have been initially misdiagnosed. Of the 21 subjects with
SCH who were reassessed at age 88, none had progressed
to overt hypothyroidism, eight (38%) had persistent SCH,
11 (52%) had normal TSH values, and two (10%) were
hyperthyroid.31
The Longitudinal Aging Study Amsterdam (LASA) in
individuals aged 65 and older (N = 1,219; mean age 75.5)
reported that SCH, diagnosed according to a normal FT4
level and a single TSH measurement greater than 4.5 mIU/L
(mean 6.9 mIU/L; 5.3% of participants), was not associ-
ated with poor cognitive function or depressive symptoms
during a median of 10.7 years of follow-up.32 The authors
commented that the absence of longitudinal TSH measure-
ments may have resulted in an initial misclassification.32
An earlier study of 5,868 individuals aged 65 and older
(mean age 73.6) with subclinical thyroid function also
found no relationship between TSH level and cognition,
depression, or anxiety, although because the criterion for
SCH diagnosis was a TSH level greater than 5.5 mIU/L,
unadjusted for age, and TSH measurements were not
repeated, some participants diagnosed as having SCH may
have been misclassified.33 A randomized, blinded, cross-
over study found impairment of working memory in indi-
viduals with induced SCH (TSH levels 1020 mIU/L).34
Another larger study (N = 5,182) of the relationship
between thyroid status, cognitive decline, and functional
capacity in elderly adults (mean age 75.6, range 7082)
included 173 individuals with TSH levels of 4.5 mIU/L
and greater.35,36 A repeat measurement of TSH at
6 months identified 93 participants (54% of participants
with SCH, 2% of the study population) with persistent
SCH. Cognitive and functional capabilities were similar at
baseline and during the mean 3.2-year follow-up period in
the group with persistent SCH and the euthyroid group.
Statistical significance was not reached when a secondary
analysis adjusted for the small (13%) subgroup of SCH
subjects with TSH levels greater than 10 mIU/L.35,36 The
distribution of TSH levels in participants with SCH was
not reported, so it is unclear whether a sufficient number
of participants would have been included, if age-adjusted
1670 HENNESSEY AND ESPAILLAT
Table 3. Follow-Up Thyroid Status of Individuals Initially Diagnosed with SCH
Baseline
Thyroid-Stimulating
Hormone
Participants, Age at Concentration,
Study n Baseline
Gussekloo et al. (2004)31 21a 85
Diez et al. (2004)42 71 61.2b
Somwaru et al. (2012)43
Total 369 65
Thyroid-stimulating hormone strata 256
72
41
a
Two participants developed overt hyperthyroidism during follow-up.
b
Mean.
Includes c25 (7%), d10 (4%), e6 (8%), and f9 (22%) individuals who started thyroid hormone replacement therapy during follow-up.
SCH, subclinical hypothyroidism.
TSH level ranges were used for inclusion and persistence,
to have affected the results of the study.
In summary, inconsistency among studies continues to
confound the true clinical effect of SCH in elderly adults.
The assessment of thyroid function based on a single
non-age-adjusted TSH measurement is a critical limitation
of many of these studies. Euthyroid individuals may be
erroneously included in the SCH groups, masking any clin-
ical effects attributable to SCH.
DIAGNOSTIC APPROACH
Proper diagnosis of SCH, although challenging, is critical
in the identification of individuals who may benefit from
thyroid hormone replacement therapy. Detection of SCH
depends on laboratory findings, given that the manifesta-
tions of the condition often are not clinically obvious. Dif-
ferential diagnosis of SCH in elderly adults requires
consideration of many factors that can influence TSH con-
centrations. In addition to the natural rise in TSH levels
with aging, other underlying causes of thyroid dysfunction
that can affect thyroid hormone levels and may be more
prevalent in older adults include Hashimotos thyroiditis,
ineffectual thyroxine replacement therapy (due to inade-
quate dosage or poor adherence), prior treatment of
hyperthyroidism with radioiodine, and Graves disease.37
Clinicians should also be mindful that medications for con-
ditions as diverse as mood disorders (lithium), cardiac dys-
function (amiodarone), and malignancies (the tyrosine
kinase inhibitor sunitinib) are associated with high TSH
and thyroid dysfunction.37,38 Individuals recovering from
various nonthyroidal illnesses or who have recently
received iodine-containing contrast agents may also experi-
ence a transitory rise in TSH levels that is generally unre-
lated to underlying thyroid disease.37,39
Symptoms of hypothyroidism include fatigue, cold
intolerance, constipation, muscle pain, hair loss, and dry
skin.3,40 Clinicians may overlook these often-subtle symp-
toms in elderly populations, attribute them to other ill-
nesses, or see them as a consequence of aging. Although
some studies5 have found a greater prevalence of these
symptoms in people diagnosed with SCH than in euthyroid
AUGUST 2015VOL. 63, NO. 8 JAGS
Follow-Up, Overt
mIU/L Years Euthyroid SCH Hypothyroidism
>4.8 3 11 (52) 8 (38) 0
5.09.9 3.2b 37 (52) 30 (42) 4 (6)
4.519.9 2 128 (35) 208 (56) 33 (9)c
4.56.9 118 (46) 125 (49) 13 (5)d
7.09.9 7 (10) 58 (81) 7 (9)e
>10 3 (7) 25 (61) 13 (32)f
controls, a study in older adults determined that thyroid sta-
tus cannot be reliably predicted based on symptoms alone.41
Because the symptoms of hypothyroidism are neither sensi-
tive nor specific, it is perhaps not surprising that document-
ing clear differences between individuals with SCH and
euthyroid individuals has been challenging. The value of
TSH screening in the general population remains a topic of
debate; multiple groups recommend screening of older
adults, especially women.3 An indication for the treatment
of individuals presenting with high TSH levels (10 mIU/L)
and normal FT4 is almost universally recognized,3,40 but
strategies for the management of mild SCH characterized by
TSH levels between 4.5 and 10 mIU/L are controversial.
Although the relief of symptoms thought to be secondary to
underlying hypothyroidism may be a potential reason to ini-
tiate treatment of SCH, a better justification for treatment is
the prevention of progression to overt hypothyroidism.
It is recommended that individuals with a TSH level
above the upper limit of normal be reassessed 6 to
12 months later to confirm persistent SCH and exclude a
transient increase in TSH level, which may represent a dis-
turbance of the pituitarythyroidal axis that is too brief to
warrant concerns about subsequent morbidity.29 Several
studies have reported normalization of TSH values with fol-
low-up (Table 3). In one study of 71 individuals aged 55
and older followed for 6 to 72 months (mean 31.7 months)
after diagnosis of SCH, 52.1% (n = 37) who had initial
TSH levels between 5.0 and 9.9 mIU/L had reverted to nor-
mal levels at the end of the follow-up period, and 5.6%
(n = 4) had progressed to overt hypothyroidism.42 In a
cohort of individuals aged 65 and older, 35% of those ini-
tially classified with SCH were euthyroid when reassessed
after 2 years.43 Baseline TSH levels were inversely corre-
lated (P < .001) with the likelihood of reversion at 2 years
(4.56.9 mIU/L, 46%; 7.09.9 mIU/L, 10%; 10 mIU/L,
7%).43 Another study found high rates of TSH level normal-
ization in participants aged 85 and older at entry (11/21,
52%) when they were reevaluated 3 years later.31
Measurement of antithyroid antibodies should also be
considered. High levels of antithyroid antibodies are
associated with greater risk of progression to overt
hypothyroidism.44,45 In individuals with a TSH level of
JAGS AUGUST 2015VOL. 63, NO. 8
4.5 mIU/L or greater, an age-related increase in the preva-
lence of antithyroid antibodies up to the age of 70 was
found.7 The 20-year follow-up of one of these studies
found that women who had high antithyroid antibodies
and serum TSH levels had a 4.3% annual risk of develop-
ing overt hypothyroidism.44
Based on the discussion above, an individual present-
ing with TSH levels above the laboratory reference range
should be considered subclinically hypothyroid if the TSH
level exceeds the expected level for age. As previously dis-
cussed, the persistence and progression potential of SCH
may depend on the initial degree of TSH elevation, with
individuals with higher TSH levels less likely to normalize
over time.31,42,43 Individuals with confirmed TSH levels
greater than 10 mIU/L should be considered candidates for
intervention to ameliorate the risk of morbidity. Once a
diagnosis of SCH is made, the benefits and risks of treat-
ment or a strategy of watchful waiting will need to be
weighed for the individual.
THERAPEUTIC INTERVENTIONS
Especially in elderly adults, preexisting CVD, other mor-
bidities, and the risk of progression to overt hypothyroid-
ism should all be considered in the clinicians decision to
initiate treatment. Levothyroxine sodium, the drug used to
treat SCH, has a narrow therapeutic index. Therefore, it is
critical to determine the optimal dose, especially in older
adults. Current guidelines advise starting individuals aged
50 to 60 and older at a 50-lg dose of levothyroxine
replacement therapy, unless they have a history of CVD,
in which case an initial dose of 12.5 to 25 lg should be
given.3 It has been suggested that targeted TSH levels with
intervention be 3 to 4 mIU/L for individuals aged 60 to 75
and 4 to 6 mIU/L for those older than 75.29
Effects of Treatment
Recent studies have suggested that normalization of TSH
levels using levothyroxine therapy can ameliorate the
effects of comorbidities in older adults. This can include
effects through indirect mechanisms; for example, one
study of older adults (mean age 81.5) showed that levothy-
roxine significantly improved hemoglobin levels (P = .02)
and normalized TSH (P = .008) in individuals with mild
anemia and hypothyroidism (n = 9).46 Another study
found that levothyroxine treatment lowered the risk
(HR = 0.41, 95% CI = 0.170.97) of fatal and nonfatal
IHD events in individuals aged 61 to 70 at study entry,
suggesting that treatment of SCH with levothyroxine may
produce some modest benefits in individuals younger than
70.18 In individuals aged 70 and older, often diagnosed
with SCH according to a single, non-age-adjusted TSH
determination, treatment neither improved these cardiovas-
cular outcomes (HR = 0.99, 95% CI = 0.591.33) nor
increased the risk of atrial fibrillation.18
Levothyroxine therapy significantly attenuated the
decline in estimated glomerular filtration rates in 113 par-
ticipants (mean age 63.2) with Stage 2 to 4 chronic kidney
disease (CKD) and a mean TSH level of 8.86 mIU/L.47
Based on data from this study, it was estimated using lin-
ear regression that levothyroxine may reduce the incidence
SUBCLINICAL HYPOTHYROIDISM IN ELDERLY ADULTS 1671
of progression to Stage 5 CKD over 10 years by four-fifths
(from 46.9% to 8.8%).47
Cognitive function and mood were similar with
levothyroxine and placebo in a randomized, double-blind
trial of levothyroxine replacement therapy in 94 partici-
pants aged 65 and older (mean age 74) diagnosed with
SCH based on a single TSH measurement greater than
5.5 mIU/L.48 Although 82% of participants in the levothy-
roxine group were euthyroid at 6 months and 84% at
12 months, reversion to a euthyroid state occurred in 35%
and 50% of the placebo group (who received no levothy-
roxine) at the same respective time points. These observa-
tions suggest that a substantial part of the randomized
cohort had transiently high TSH levels at the time of inclu-
sion and were probably not truly hypothyroid.48
In a study to ascertain the value of population-wide
screening for thyroid disease to improve quality of life
(QOL), 4,365 adults (women aged 5079, men aged 65
79) were screened for hypothyroidism.49 Sixty-four indi-
viduals with baseline TSH levels ranging from 4.1 to
13.0 mIU/L who met other study inclusion requirements
consented to participate in a randomized, double-blind,
placebo-controlled crossover trial of levothyroxine treat-
ment that evaluated hypothyroid symptoms, QOL, and
neurocognitive function (forgetfulness and poor concentra-
tion). Of the 64 individuals, 56 completed 4 months of
treatment in each arm. The only outcome that improved
with treatment was the overall sense of well-being, but
only in participants with two TSH samples that were
greater than 4.0 mIU/L (12/15; P = .04), suggesting that
individuals with persistent hypothyroidism may be the
only ones who benefit from levothyroxine intervention.
Risk of Overtreatment
Despite the evidence that accurately diagnosed individuals
can realize clinical benefit from treatment, it has been esti-
mated that 20% of individuals receiving levothyroxine are
overtreated, leading to low TSH levels and possible adverse
effects associated with hyperthyroidism.29 Considering that
elderly adults may be overdiagnosed with SCH because age-
adjusted normal limits of TSH are not routinely used in clin-
ical practice, they may be in even greater jeopardy of delete-
rious side effects as a result of overtreatment. Although the
decision to treat older adults with mildly high TSH may be
deemed appropriate for symptom relief or mitigation of car-
diovascular risk, any potential benefits must be evaluated
against the possibility of exacerbating other risks to which
they are more susceptible. If the initiation of levothyroxine
replacement therapy is deemed appropriate, careful moni-
toring of TSH levels is recommended. A population-based
study of 17,684 individuals with a mean age of older than
60 receiving long-term (>6 months) levothyroxine treatment
found that TSH concentrations greater than 4 mIU/L or less
than 0.03 mIU/L were associated with a greater risk of car-
diovascular events, arrhythmias, and fractures.50 Consider-
ing that older individuals have a greater likelihood of these
conditions regardless of thyroid function, this study high-
lights the need for careful titration of levothyroxine to
achieve appropriate TSH levels. Because drugdrug interac-
tions can affect the pharmacokinetics of levothyroxine,3
awareness of concomitant medication use is also essential.
1672 HENNESSEY AND ESPAILLAT
Additionally, because of differences in the bioavailability of
different formulations of synthetic levothyroxine, it is rec-
ommended that individuals remain on the same brand of
levothyroxine treatment; if a change to another levothyrox-
ine product is required, TSH levels should be closely moni-
tored and dosing adjusted accordingly to avoid adverse
effects.51
Future Directions
Well-designed, randomized, placebo-controlled trials with
clinically relevant outcomes are needed to assess the optimal
strategy for the treatment of SCH in elderly populations.
Currently, at least two clinical trials of SCH treatment in
elderly adults are ongoing: the Institute for Evidence-based
Medicine in Old Age 80-plus thyroid trial (NTR3851,
www.trialregister.nl/trialreg/admin/rctview.asp?TC=3851)
and the Thyroid Hormone Replacement for Untreated older
adults with Subclinical hypothyroidism Trial (TRUST,
NCT01660126, http://clinicaltrials.gov/show/NCT01660
126). Both studies are multicenter, randomized, placebo-
controlled trials of thyroxine replacement therapy, with car-
diovascular and QOL outcomes measured. Initial results
from these studies are expected in 2016 or 2017.
PREVENTIVE MEASURES
Because no way to prevent hypothyroidism or the increase
in TSH levels associated with aging in iodine-sufficient
areas has been identified, clinician judgment will continue
to be crucial in the management of SCH in older adults.52
Elderly individuals with mildly high TSH may be improp-
erly classified as having SCH because age-adjusted ranges
of normal TSH concentrations are not routinely used in
clinical practice. Repeat TSH measurements in 6 to
12 months, to exclude laboratory error or a transient TSH
elevation,29 should be considered before thyroid hormone
replacement therapy is initiated.
Until the results of clinical studies provide conclusive
evidence of the value of treating SCH in elderly adults and
define an optimal TSH threshold for the initiation of levo-
thyroxine replacement therapy in this population, the
potential benefits of treatment must be weighed against the
risks. Thyroid hormone replacement therapy to improve
QOL, reduce the potential for progression to overt hypo-
thyroidism, or ameliorate cardiovascular risks may be
appropriate for individuals who experience symptoms of
hypothyroidism, are positive for antithyroid antibodies, or
have TSH levels greater than 10 mIU/L. Because studies of
the relationship between mild SCH and clinical outcomes
such as cardiovascular risk, dyslipidemia, and renal func-
tion in older adults are conflicting and often included indi-
viduals based on a single TSH measurement, the decision
to treat should be made on a case-by-case basis. Careful
patient selection and close monitoring is the best approach
when treating SCH in elderly adults.
ACKNOWLEDGMENTS
Conflict of Interest: The authors have received no financial
support in conceiving of, planning, researching, editing, or
AUGUST 2015VOL. 63, NO. 8 JAGS
directing the completion of this manuscript. Financial sup-
port for medical writing and editorial assistance was pro-
vided by AbbVie Inc. James V. Hennessey has received
consulting fees from AbbVie for the education of personnel
in bioequivalence issues and FDA labeling of levothyroxine
in 2013. R.E. is an employee of AbbVie and may hold
AbbVie stock or stock options.
Author Contributions: This article reflects the opinions
of the authors as to the scope of the endeavor, the focus
of review, the methods for identifying the most recent lit-
erature, and the addition of relevant citations of great clin-
ical importance. Each author reviewed the manuscript,
providing extensive comment on the main clinical points
to be emphasized, limitations of the literature cited, and
relevance of these limitations to apply the information to
clinical care, at all stages of development. The authors
determined final content, and both authors read and
approved the manuscript.
Sponsors Role: AbbVie provided suggestions for topic
ideas and authors for this article. Ramon Espaillat, an
employee of AbbVie, is an author of this article and was
involved in the development and review of the manuscript
with the author and the medical writer. AbbVie had the
opportunity to review and comment on the manuscript.
Lisa M. Havran, PhD, of Complete Publication Solutions,
Horsham, PA, provided medical writing and editorial sup-
port to the authors in the development of this article. Abb-
Vie provided financial support to Complete Publication
Solutions for medical writing and editorial assistance.
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