S P E C I A L F E A T U R E

R e v i e w

Is Subclinical Hypothyroidism a Cardiovascular Risk

Factor in the Elderly?

Giuseppe Pasqualetti, Sara Tognini, Antonio Polini, Nadia Caraccio,

and Fabio Monzani
Geriatrics Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy

Context: The negative impact of subclinical hypothyroidism (sHT) on cardiovascular risk, widely
recognized in young adults (aged 55 60 y), is still debated in the elderly (65 y), especially in the
oldest olds (80 y).

Evidence Acquisition: We searched Medline for reports published with the following search terms:
hypothyroidism, subclinical hypothyroidism, ageing, elderly, L-thyroxin, thyroid,
guidelines, treatment, quality of life, cardiovascular risk, heart failure, coronary heart
disease (CHD), atherosclerosis, and endothelial dysfunction. We limited our search to reports
in English published after 1980, although we incorporated some reports published before 1980. We
supplemented the search with records from personal files, textbooks, and relevant articles. Ana-
lyzed parameters included the epidemiology of thyroid failure, the effect of thyroid hormone on
the aging process, cardiovascular function, and CHD risk factors. We also included the potential
benefits of L-T4 therapy on the quality of life, cardiovascular events, and survival.

Evidence Synthesis: TSH levels increase with age, even in older people without thyroid disease.
Most longitudinal studies show an increased risk for CHD events and mortality in sHT participants.
This increase is less evident in the elderly, mainly in cases of serum TSH values above 10 mIU/L. Lower
mortality rate in a cohort of the oldest olds (85 y) has been reported.

Conclusions: sHT in older people should be not regarded as a unique condition, and moderately
old patients (aged 70 75 y) could be considered clinically similar to the adult population, albeit
with a higher optimal TSH target value. Conversely, the oldest old subjects should be carefully
followed with a wait-and-see strategy, generally avoiding hormonal treatment. The decision to
treat elderly people is still an unresolved clinical challengefirst, due to a lack of appropriately
powered randomized controlled trials of L-T4 in sHT patients, examining cardiovascular hard end-
points in various classes of age; and second, because of the negative effects of possible
overtreatment. (J Clin Endocrinol Metab 98: 2256 2266, 2013)

ubclinical hypothyroidism (sHT), defined as serum changes, arterial hypertension, reduced glomerular filtra-
S TSH concentration above the upper limit of the refer-
ence range in the face of normal free T4 (FT4) and free T3
tion rate, and neuropsychiatric alterations (511). The
negative impact of sHT in terms of coronary heart disease
(FT3) levels, is common in the elderly (13). This biochemical (CHD) and global cardiovascular (CV) risk is mostly ac-
condition encompasses several pathological entities, mainly knowledged in young adults, whereas it remains to be
represented by chronic autoimmune thyroiditis even if increas- established in the elderly, especially in the oldest old
ing TSH may represent a physiological aging process (4). (aged 80 y) (4). Moreover, the clinical significance of
Depending on the degree of TSH elevation, sHT has laboratory data consistent with sHT should be interpreted
been related to hyperlipidemia, intermediary metabolism in relation to the physiological changes of thyroid function

ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: CHD, coronary heart disease; CV, cardiovascular; FT3, free T3; FT4, free T4;
Printed in U.S.A. HF, heart failure; HPTP, hypothalamus-pituitary-thyroid-peripheral; sHT, subclinical
Copyright 2013 by The Endocrine Society hypothyroidism.
Received November 5, 2012. Accepted April 1, 2013.
First Published Online April 4, 2013

2256 jcem.endojournals.org J Clin Endocrinol Metab, June 2013, 98(6):2256 2266 doi: 10.1210/jc.2012-3818

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doi: 10.1210/jc.2012-3818 jcem.endojournals.org 2257

with aging (8, 12, 13). Consequently, the fundamental lighted the importance of genetics on determining long-
clinical questions regarding older persons with slightly el- lived phenotypes. Accordingly, a concomitant cross-sec-
evated serum TSH values is how they should be dealt with tional study carried out in home-dwelling subjects born in
and, in the case of confirmed thyroid dysfunction, whether southern Europe confirmed lower serum FT3 and TSH
they need hormone replacement therapy (14, 15). There- levels in centenarians children and nieces/nephews with
fore, a correct diagnosis of sHT is challenging in the elderly respect to age-matched controls (28). The assertion that
but crucial in avoiding significant misclassification of pa- aging is associated with a decreasing concentration of TSH
tients with abnormal TSH, who may or may not have a in healthy elderly humans appears, nonetheless, at odds
thyroid dysfunction and may receive unnecessary or even with data from large naturalistic studies. These studies
harmful therapy (13, 15). demonstrated that serum TSH distribution clearly shifts
toward higher concentrations with age and that extreme
longevity is associated with a further increase in TSH lev-
Thyroid Hormones and the Aging Process els, at least in Ashkenazi Jews (19 21, 29, 30). These find-
ings, obtained in disease-free subjects with negative thy-
The relationship between thyroid function and aging was roid antibody titer, suggest that a TSH increase may arise
hypothesized many years ago, but only during the last from age-related alterations in the TSH set point or re-
decades has its clinical impact been extensively evaluated duced TSH bioactivity rather than occult thyroid disease.
(16, 17). It is widely recognized that features of aging are, As an individual ages, there can be changes in TSH bio-
in part, similar to those of hypothyroidism and that, in activity, thyroidal TSH responsiveness, factors regulating
both conditions, the basal metabolic rate decreases (18). thyroid hormone uptake and metabolism, thyroid hor-
Modifications of the hypothalamus-pituitary-thyroid-pe- mone receptors, and/or cofactors that modulate the T3-
ripheral (HPTP) axis are well documented in older people. responsiveness of a given gene in a given tissue, which in
Several clinical studies have shown an age-dependent de- turn may affect the expression and transduction of some
crease of thyroid function, including iodine uptake and genes that contribute to the TSH set point. Accordingly,
hormone production (19 23). However, there exist con- older people have lower TSH responses to thyrotropin-
flicting results concerning age-related serum TSH varia- releasing hormone stimulation than do young people. In
tions between earlier studies (mainly case-control or cross- the oldest olds, the nocturnal surge of TSH is partially or
sectional) and recent large naturalistic studies (3, 16, 17, completely lost, whereas the inhibitory effect of cortico-
19 23). Former studies showed either unchanged or re- steroids is attenuated (23, 31).
duced serum TSH values along with declining FT3 con- Overall, these data suggest that aging well is charac-
centrations in healthy elderly humans (especially the old- terized by a certain degree of down-regulation of the HPTP
est old), with low serum T3 associated with better physical axis, and this might lead to the idea that a mild decline of
performance and higher lean body mass (16, 17, 23, 24). thyroid activity at the tissue level has favorable effects.
This condition has been interpreted as an adaptive mech- However, sharing this interpretation with older people at
anism to prevent excessive catabolism and should be dis- all should be done with caution because a mild elevation
tinguished from the so-called nonthyroidal illness syn- of serum TSH may occur by either the aging process itself
drome (frequently observed in older people), in which or an actual thyroid disease.
serum FT3 decreases while FT4 (within the normal range
of healthy adults) and rT3 (above the normal range of
healthy adults) increase (25). The low serum T3 of non- Epidemiology and Clinical Presentation
thyroidal illness syndrome reflects a catabolic state and is
associated with a lower physical function and poorer Several observational studies found that the prevalence of
prognosis (24, 26). These findings raise the question sHT ranges from 5 to 15% of the general population, with
whether the decrease of thyroid function represents the a significant increase in the older age classes, especially in
consequence of the age-related reduction of metabolic ho- women with thyroid autoimmunity and rich diet iodine
meostasis or a protective condition in healthy aging. In this intake (3, 20, 21, 3234). The wide range of prevalence
setting, a recent naturalistic study reported that the mid- rates could be related to the heterogeneity of the popula-
dle-aged offspring of northern European nonagenarian tion of published trials, which differs according to pa-
siblings had lower serum FT3 levels along with a beneficial tients age, lifestyle, comorbidity, treatment, ethnicity, as
cardiometabolic profile than their middle-aged partners, well as the limits of normal TSH range utilized in each
thus hinting at a role of the HPTP axis in the regulation of study (35, 36). Thus, by the first-generation TSH RIA
human health and longevity (27). The study also high- assays, the upper normal limit was considered about 10

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2258 Pasqualetti et al Subclinical Hypothyroidism in the Elderly
mIU/L, whereas recently the normal reference range of
serum TSH is usually between 0.4 and 4.0 mIU/L (36). It
should be noted that some third-generation TSH assays
seem to have steeper TSH doseresponse slopes than oth-
ers, making it more difficult to compare TSH values be-
tween studies that have used different assays (20). Thus, a
TSH reported as being slightly elevated on 1 assay could
be reported to be normal on another assay. Moreover,
using age-specific reference ranges for TSH reduces the
fraction of patients who would be given a diagnosis of
sHT, although only by 2% for patients older than 75 years
and by 5% for those over age 90 (19, 20, 37). As a result,
the widely accepted high prevalence of sHT in older people
could be an overestimate, being affected by various con-
founding factors (35). These findings should be taken into
account in interpreting the conflicting results on the effect
of sHT in older people.
Hypothyroidism should be considered as a graded phe-
nomenon that encompasses a wide variety of clinical con-
ditions from full-blown myxedema to sHT (38). There is
scientific consensus that sHT has the same etiology as overt
hypothyroidismthe most common being Hashimotos thy-
roiditisand that symptoms experienced by sHT pa-
tients, if present, are the same although less evident than
those observed in overt hypothyroidism (4, 38, 39). How-
ever, most hypothyroid symptoms are unspecific, espe-
cially in the elderly, and are shared with several other
conditions, making it difficult to clinically distinguish eu-
thyroid subjects from sHT patients (4, 8, 39). Another
aspect to take into account in older patients with sHT is the
rate of progression to clinically overt hypothyroidism
(40). As observed in younger people, the presence of au-
toimmunity and a TSH level higher than 10 mIU/L are the
most important markers of thyroid failure progression
(40 42). However, a significant number of sHT subjects
do not show progression, and some subjects experience
serum TSH normalization (43 45). In this setting, the
Cardiovascular Health Study, enrolling almost 4000 sub-
jects aged over 65 years, recently confirmed that sHT per-
sists in almost half of patients at 2- and 4-year follow-up,
with high rates of reversion to euthyroidism in those with
lower TSH concentrations (7 mIU/L) and negative se-
rum thyroid peroxidase antibody titer (40).
Thyroid Hormone and the CV System
Hypothyroidism produces changes in myocardial oxygen
consumption, cardiac contractility and output, as well as
systemic vascular resistances (46, 47). The effects of thy-
roid hormone deficiency on the CV system have been eval-
uated from many points of view, such as myocardial
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J Clin Endocrinol Metab, June 2013, 98(6):2256 2266
contractility, endothelial function, systemic vascular re-
sistance, and blood pressure, as well as exercise perfor-
mance (6, 48 53). In most patients, CV changes are re-
versible when the underlying thyroid function failure is
recognized and treated (47, 54 56). To understand better
the impact of hypothyroidism on the CV system, it is nec-
essary to take into account the molecular effects of thyroid
hormones and the modifications that they exert at the
tissue level (5759). The complex interaction of T3 with
myocardium clearly explains the early cardiac diastolic
impairment and prolonged isovolumic relaxation phase of
hypothyroid patients (51, 54). Interestingly, these func-
tional alterations resemble the progressive age-related car-
diac changes, which result in increased myocardial stiff-
ness and diastolic failure (60, 61). Also, T3 induces arterial
relaxation (47, 59), and a large cross-sectional study on
almost 30 000 healthy individuals showed a linear rela-
tionship between systemic blood pressure and serum TSH
values (6).
sHT and CV Disease Risk
The modifications of the CV system observed in sHT pa-
tients qualitatively resemble those produced by overt hy-
pothyroidism, even if less evident (4, 46). Early alterations
of cardiac performance, endothelial function, systemic
blood pressure, and lipid profile have been described in
sHT patients, supporting a biologically plausible role for
mild hypothyroidism in the development of early athero-
sclerosis (6, 10, 11, 52, 54, 62 66). Moreover, data from
a large prospective cohort of community-dwelling older
people (aged 70 79 y at beginning), recently showed that
sHT (serum TSH 10 mIU/L) is associated with increased
odds of prevalent, although not incident, metabolic syn-
drome (67). Nonetheless, a physiological age-depen-
dent impairment of endothelial and cardiac function as
well as lipid profile is well documented (60, 68 70), and
the effective burden of mild thyroid failure on the CV
system of older people, mainly the oldest old, is still to be
established and is widely debated (4, 71).
sHT and heart failure (HF)
HF, defined as an impaired ability of the ventricle to fill
with blood or eject blood, represents a common clinical
condition, with increasing prevalence in the last decades of
life (72, 73). The aging modification of heart structure
such as interstitial fibrosis and myocyte loss as well as
cardiac hypertrophy and remodeling may contribute per
se to the development of heart dysfunction (especially di-
astolic) (60). Some prospective studies were carried out to
evaluate the possible relationship between mild thyroid
doi: 10.1210/jc.2012-3818 jcem.endojournals.org 2259

failure and the risk of HF progression and events in various represent an independent risk factor for HF development
clinical settings (74 78). Most studies showed an in- and progression. Accordingly, a meta-analysis of 6 large,
creased risk of HF progression and events in sHT patients, prospective studies on community-dwelling subjects con-
yet with different strength of association and, generally, firmed that sHT patients (TSH 10 mIU/L) had an age-
for serum TSH values higher than 10.0 mIU/L (Table 1) independent increased rate of HF events (80). However, a
(74 77). sHT may worsen the age-related cardiac altera- very recent prospective study failed to demonstrate any
tions, resulting in increased risk of HF progression and association between sHT and a 10-year risk of HF events,
events, as shown by The Prospective Study of Pravastatin although a trend for increased incident HF after 8 years of
in the Elderly at Risk (76). In this large cohort of older follow-up was observed in the case of patients with TSH
people (5316 subjects, aged 70 82 y) with previous CV 10 mIU/L (78). Moreover, even if small clinical studies,
risk, the persistence of elevated serum TSH value (10 some of which were randomized and placebo-controlled,
mIU/L) was associated with an age- and sex-adjusted in- have shown that restoration of euthyroidism by L-T4 ther-
creased risk of HF events over 3.2 years of follow-up. In apy is able to improve indexes of cardiac function (54, 66,
addition, sHT was independently associated with a 81), no large controlled trials have been performed so far
greater likelihood of disease progression and a risk factor to evaluate the effect of hormone replacement therapy in
for increased mortality in hospitalized patients with inci- preventing HF progression and events.
dent HF (75, 79). However, increased prevalence of HF
events over a period of 12 years was described also in older sHT and CHD
sHT patients (aged 65 y, with serum TSH 10 mIU/L) Several cohort studies investigated the association be-
without previous CV risk (74). Thus, sHT may not only tween sHT and CHD events and mortality with conflicting
act as a worsening condition in HF patients but could also results (8290) (Tables 1 and 2). The Whickham Survey

Table 1. CV Risk of sHT Patients in Most Representative Population-Based, Longitudinal Studies

First Study Participants Age TSH Follow-up
Author (Ref.) Population (sHT) (y) (mIU/L) (y) Endpoints Outcome
Hyland (78) Community 4863 (679) 73.4 5.7 6.7 2.6 10 CHD HR, 1.37 (CI 1.0 1.87)
dwelling HF HR, 0.89 (CI 0.631.25)
CVM HR, 0.97 (CI 0.64 1.48)
Waring (41) Community 832 (85) 85.3 3.7 4.50 19.99 13 Survival HR, 0.97 (CI 0.66 1.43)
dwelling
Waring (95) Community 1503 (116) 74 4.79 10.00 8.3 Survival HR, 1.01 (CI 0.711.44)
dwelling
Tseng et al (87) Community 115 746 (1841) 47.1 14.0 7.07 2.44 10 Survival HR, 0.38 (CI 1.08 1.78)
dwelling CVD HR, 1.80 (CI 1.073.01)
Razvi (105) Community 1642 (823) 70 6.77 1.38 7 CHD HR, 0.99 (CI 0.59 1.33)
dwelling
Nanchen (76) Community 5245 (199) 75.3 3.2 7.84 3.75 3.2 HF TSH 10.0
dwelling HR, 0.36 (CI 0.09 1.44)
TSH 10.0
HR, 3.01 (CI 1.12 8.11)
Asvold (100) Hospital 35 664 (1746) 54 (46 67) 4.00 12.3 CHD HR, 1.38 (CI 1.031.84)
series HF HR, 1.00 (CI 0.70 1.42)
Razvi (94) Community 2376 (97) 49.9 17.9 6.00 15.00 20 CHD HR, 1.76 (CI 1.152.71)
dwelling
Iervasi (79) Hospitalized 2113 (208) 60.9 (59.1 62.7 6.70 (6.017.44) 2.7 Survival HR, 2.0 (CI 1.333.04)2
CVM HR, 2.4 (CI 1.6 4.21)
Bauer (98) Community 438 (37) 71.5 5.0 5.50 11.9 Survival HR, 1.23 (CI 0.552.74)
dwelling
Cappola (83) Community 3135 (496) 72.7 5.6 6.67 2.54 13 Survival HR, 1.10 (CI 0.951.27)
dwelling CHD HR, 1.04 (CI 0.871.23)
van den Beld (24) Community 359 (6) 77.8 (7394) 4.30 4 Survival NS
dwelling
Rodondi (74) Community 3000 (474) 73 5.5 4.50 9.90 12 HF HR, 0.92 (CI 0.731.17)
dwelling 10.00 HR, 1.88 (CI 1.053.34)
Imaizumi (86) Community 2650 (257) 62.7 11.1 7.16 4.82 12.2 Total HR, 1.9 (CI 1.13.2) (men only)
dwelling mortality
(6 y)
Gussekloo (99) Community 502 (30) 85 4.80 4 MR MR, 0.76 (CI 62 0.92)
dwelling
Parle (90) Community 1120 (94) 60 5.00 10 CVM MR, 0.9 (CI 0.6 1.3)
dwelling

Abbreviations: HR, hazard ratio; MR, mortality risk; CI, 95% confidence interval; survival, overall survival; CVM, CV mortality; CVD, CV disease; NS,
not significant. Age and TSH are reported as mean SD or median (confidence interval or range).

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2260 Pasqualetti et al Subclinical Hypothyroidism in the Elderly J Clin Endocrinol Metab, June 2013, 98(6):2256 2266

Table 2. CV Risk of sHT Patients in Most[b] Representative Large Cross-Sectional Studies

First Author Study Participants
(Ref.) Population (sHT) Age (y) TSH (mIU/L) Endpoint Outcome
Hak (84) Postmenopausal 1149 (124) 69.0 7.9 4.0 CHD OR, 2.3 (CI 1.3 4.2)
women
Lindeman (88) Community 755 (112) 74.1 8.2 Not shown CHD TSH4.7
dwelling P NS
TSH 10.0
P .007
Walsh (85) Community 2025 (119) 58.1 14.9 6.26 (4.0 50.1) CHD TSH 4.0
dwelling
OR, 1.8 (CI 1.0 3.8)
TSH 10.0
OR, 2.8 (CI 1.17.3)
Kvetny (96) Community 1212 (249) 42 13 3.70 (2.91 8.61) CVD Men 50 y old
dwelling
OR, 3.3 (CI 1.6 6.8)
Takashima (89) Community 3607 (377) 64.7 11.3 8.32 11.42 CVD P NS
dwelling
Abbreviations: OR, odds ratio; CI, 95% confidence interval; NS, not significant; CVD, CV disease. Age and TSH are reported as mean SD or
median (confidence interval).

(82), an early population-based study of 2779 communi- prospective study on 1587 community-dwelling older
ty-dwelling individuals stratified by thyroid function and men (aged 65 y) did not support any association be-
thyroid autoantibody status, found no association be- tween sHT and CV events or total mortality despite the
tween sHT and CHD over 20 years of follow-up. In ad- rate of TSH elevation, although only 8 men had a serum
dition, data from 3233 community-dwelling subjects TSH value above 10 mIU/L (95). Moreover, another re-
older than 65 years did not show significant difference in cent prospective study enrolling 4863 participants aged
the prevalence of CHD, stroke, or peripheral artery dis- 65 years at baseline showed no association between sHT
ease between sHT patients and euthyroid individuals (83). and incident CHD, HF, or CV mortality in multivariate
However, 3 meta-analyses of the most relevant prospec- models with 10 years of follow-up (78). Additional anal-
tive studies showed a positive association between sHT yses stratified by degree of TSH elevation (4.5 to 6.9, 7.0
and CHD events and mortality, although less evident in to 9.9, and 10.0 to 19.9 mIU/L) confirmed no increase in
older people (9193). Moreover, a reanalysis of data from CV risk. However, a trend for increased incidence of CV
the Whickham Survey found a relationship between sHT deaths in the entire sHT group as compared with the eu-
and CHD events and mortality by including L-T4 replace- thyroid group after 6 years of follow-up emerged in the
ment as covariate, at least in young adults (mean age, latter study. In addition, almost one-third of patients ini-
49.9 y) (94). The relationship between sHT and CHD tially classified as having sHT were treated with thyroid
persisted after adjustment for traditional risk factors, sug- hormone and could have been placed into the euthyroid
gesting an alternative mechanism by which sHT increases group. This could have altered CV outcomes and calls into
CV risk, at least in younger individuals of an Australian question the applicability of these data for treatment of
cohort (85). Interestingly, a meta-analysis of 10 pooled older patients with sHT.
studies enrolling 14 449 participants found a pattern of In summary, the negative effect of sHT on CV events
moderately increased risk for CHD and mortality in sHT and mortality appears well established in young adults
patients together with evidence for statistical heterogene- (aged 55 60 y) but less evident in moderately older peo-
ity. Specifically, they found a relationship between sHT ple (70 75 y) and could vanish in the oldest old
and CHD according to either the mean age of enrolled (80 85 y). Potential explanations for these age differ-
individuals (above or below 65 y) or the degree of serum ences might be competing mortality (for example, due to
TSH elevation (above or below 10 mIU/L) (92). Nonethe- cancer) or more challenging (inherited or constitutional)
less, a large meta-analysis, in which all individual data on risk factors for CHD among very old people, which could
more than 50 000 participants from 11 prospective co- overshadow the negative effect of sHT on the CV system.
horts were collected, showed that the overall risk of CHD
events and mortality was significantly increased in sHT Degree of TSH elevation and CV outcome
patients with serum TSH values above 10 mIU/L, regard- The results of the studies reported above suggest that a
less of age and gender (Table 3) (91). At odds, a subsequent difference in the incidence of CV events exists in relation

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doi: 10.1210/jc.2012-3818 jcem.endojournals.org 2261

Table 3. CV Risk of sHT Patients in Most Representative Meta-Analyses

First No. of Study
Author Analyzed Population Subanalysis
(Ref.) Studies (no. of sHT) Age (y)a Endpoints Outcomes (Patients > 65 y old)
Razvi (93) 15 29 022 (2531) 42 85 CVM HR, 1.09 (CI 0.84 1.41) HR, 0.85 (CI 0.56 1.29)
CHD events HR, 1.27 (CI 0.951.22) HR, 1.02 (CI 0.851.22)
Rodondi (91) 11 55 287 (3450) 46 85 CHD events HR, 1.18 (CI 0.99 1.42) 80 y, HR, 1.20 (CI 0.951.51)
80 y, HR, 1.30 (CI 0.931.82
CVM HR, 1.09 (CI 0.96 1.24) 80 y, HR, 1.32 (CI 1.08 1.62)
80 y, HR, 1.01 (CI 0.621.63)
Ochs (92) 10 14 449 (1491) 46 85 CHD events HR, 1.20 (CI 0.971.49) 80 y, HR, 1.06 (CI 0.911.24)
80 y, HR, 0.47 (CI 0.111.90)
CVM HR, 1.18 (CI 0.98 1.42) 80 y, HR, 1.12 (CI 0.99 1.28)
80 y, HR, 0.55 (CI 0.24 1.25)
Haentiens (109) 9 13 329 (290) 50 85 Total mortality HR, 1.22 (CI 0.96 1.57) In cohorts with comorbidity
HR, 1.76 (CI 1.36 2.30)
Singh (110) 6 11 495 (935) 58 75 CHD events RR, 1.18 (CI 1.021.37) ND
(3 studies)
Total mortality RR, 1.11 (CI 0.99 1.25) ND
(3 studies)
Gencer (80) 6 25 390 (2068) 58 85 HF events TSH 10 mIU/L TSH 4.5 mIU/L
HR, 1.65 (CI 0.84 3.23) 80 y, HR, 1.31 (CI 0.921.87)
TSH 10 mIU/L 80 y, HR, 1.01 (CI 0.69 1.46)
HR, 1.86 (CI 1.272.72)
Abbreviations: HR, hazard ratio; RR, relative risk; CI, 95% confidence interval; ND, not done; CVM, CV mortality.
a
Age is reported as range of means of the analyzed studies.

to the degree of TSH elevation, mainly in the elderly. In- and rate of TSH elevation, found an age- and sex-adjusted
deed, a meta-analysis of 6 large, prospective studies on increased risk of CHD events over 20 years of follow-up.
25 390 community-dwelling older individuals (mean age, Peculiarly, Tseng et al (87), in a large cohort of mainly
70 y) showed that only those with serum TSH values above young adults (mean age, 47.1 y), reported an increased
10 mIU/L had an age-independent increased rate of HF risk of all-cause and CV mortality in sHT patients with
events (80). Moreover, a very large meta-analysis (ana- serum TSH below 10 mIU/L, but not in those with higher
lyzing 11 prospective cohort studies with 55 287 individ- values (possibly because of the small number of such pa-
uals) clearly demonstrated that, in age- and sex-adjusted tients). On the other hand, a cross-sectional study of 1101
analyses, the risk of CHD mortality and events, but not of individuals aged 65 years showed a significantly higher
total mortality, increases with rising serum TSH level, prevalence of CHD only in sHT patients with the highest
reaching statistical significance only in patients with TSH serum TSH levels (10 mIU/L) (88). In addition, in a large
values above 10 mIU/L (91). The results did not change cohort of older people (5316 subjects, aged 70 82 y) with
after further adjustment for traditional CV risk factors. previous CV risk, increased HF events over 3.2 years of
However, a previous meta-analysis of 15 studies showed follow-up was reported only in sHT patients with serum
that sHT is associated with increased CHD prevalence and TSH above 10 mIU/L (76).
events only in subjects from younger populations (aged 65 y), Although the scientific literature is not univocal in the
in whom increased incidence (not prevalence) of CHD was ob- definition of the effect of sHT with mild TSH elevation
served also for serum TSH below10 mIU/L (93). (10 mU/L) in terms of CV events and mortality, available
These findings suggest that the relationship between data suggest an impact of this clinical condition only in
CV events and degree of TSH elevation should be inter- younger patients (65 y), especially men.
preted by also taking into account the age and gender of
the enrolled populations. Accordingly, in a Danish cross- Gender differences
sectional study involving 1212 individuals younger than There is some evidence suggesting a different impact of
50 years, men with sHT and TSH values below 10 mIU/L sHT between men and women in relation to CV surrogate
had a higher risk of CV disease (96). Increased CHD events endpoints, as well as major risk factors such as lipid profile
and all-cause mortality were found over a 10-year fol- and blood pressure (4, 26, 97). On the other hand, several
low-up in a cohort of male subjects with mean age of 58.8 cohort studies aimed at determining CV outcomes were
years and similar serum TSH elevation (86). Moreover, exclusively related to women or men (84, 95, 98), whereas
Walsh et al (85), in a cohort of subjects with similar age others reported sex-adjusted results but did not analyze

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2262 Pasqualetti et al Subclinical Hypothyroidism in the Elderly J Clin Endocrinol Metab, June 2013, 98(6):2256 2266

separately hard endpoints in each gender (78, 85, 99). TSH do not experience adverse effects and may have a
Only a few studies assessed the CV effects of sHT by gen- prolonged life span. The study, however, focused on a
der (86, 88, 96, 100). Specifically, in a Japanese cohort, specific class of individuals, and the results should be in-
sHT emerged as an independent risk factor for CHD, with terpreted considering the potential weakness of a single
increased all-cause mortality over a 6-year follow-up in observational study. Although the impact of sHT on CHD
men only, although statistical significance was lost with risk and mortality clearly presents an age-dependent fea-
further follow-up (87). Similarly, in a Danish cross-sec- ture, which seems to vanish in the last decades of life, a
tional study involving 1212 patients, sHT was a signifi- large meta-analysis (including also data from the latter
cant predictor of CV disease in young men only (aged study) showed no significant favorable effect of sHT on
50 y) (96). Nonetheless, the New Mexico Elder Health total mortality in very old people (91). Thus, these results
Survey, a cohort of 1101 older individuals (aged 65 y), should be interpreted with caution and should be con-
showed a significantly higher prevalence of CHD in sHT firmed by stratified analyses in future prospective cohort
patients without gender differences (88). Accordingly, in studies with a wide age range and long follow-up. None-
2 meta-analyses, gender does not seem to really influence theless, these data, along with those linking longevity with
the clinical outcome of older sHT patients in terms of CV a certain degree of down-regulation of the HPTP axis (27),
events and survival (91, 93). Thus, gender seems to affect suggest that older people could be seen as a heterogeneous
the relationship between sHT and CV disease mainly in group: nonagenarians representing a genetically selected
young adults, also because premenopausal women present cluster of subjects with a favorable inherited background,
reduced risk of CHD events (101). Instead, in older classes which might act as a shield against unsuccessful aging and
of age, sHT-associated CV risk tends to be balanced, with- CHD events, thus heralding an intriguing link between
out gender differentiation. gene, thyroid status, and longevity (Figure 1).

The hypothetical paradox of the oldest old Interventional studies

population There are few randomized clinical studies evaluating
Surprisingly, a Dutch study carried out on 599 partic- the effect of hormone replacement in sHT patients and, to
ipants, who were followed from ages 85 to 89 years, our knowledge, none aimed at determining the impact of
showed a relationship between hypothyroidism and a therapy on CV events and mortality in older people. The
lower mortality rate, which remained after adjustments available clinical trials (some randomized) carried out in
for degree of TSH elevation, baseline disability, and health small cohorts of sHT patients suggest that L-T4 therapy
status (99). No association was found between serum TSH may improve cardiac performance as well as surrogate
level and disability in daily life, depressive symptoms, and endpoints of CV disease such as lipid profile, endothelial
cognitive impairment either at baseline or during follow- function, and carotid artery intima-media thickness (10,
up. These data support the hypothesis that in the oldest old 53, 54, 65, 102104). Some authors, on the basis of the
population, individuals with abnormally high levels of reduction of serum low-density lipoprotein cholesterol

A B
Heart Failure risk
Cardiovascular risk

sHT early
sHT early onset
onset

Euthyroid
subjects Euthyroid
subject

sHT late
onset sHT late
onset

40 50 60 70 80 90 Years 40 50 60 70 80 90 Years

Figure 1. A, Graphical representation of CV risk over time in euthyroid subjects (bold line) and in patients with early onset (aged 60 y) or late
onset (aged 80 y) sHT (fine line) as derived from the best scientific evidence. B, Graphical representation of HF events over time in euthyroid
subjects (bold line) and in patients with early onset (aged 60 y) or late onset (aged 80 y) sHT (fine line) as derived from the best scientific
evidence. Dotted lines refer to uncertain area or unexplored classes of patients.

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doi: 10.1210/jc.2012-3818 jcem.endojournals.org 2263

level induced by L-T4 therapy, estimated that the risk of CV Disclosure Summary: The authors report no conflicts of in-
mortality could be reduced about 10 20% (10, 65). In this terest in this work.
regard, a randomized, double-blind, crossover study en-
rolling 100 sHT patients (aged 18 80 y; TSH 4.0
mIU/L) showed a significant improvement of either serum References
lipid profile or endothelial function after short-term (12 1. Ceresini G, Morganti S, Maggio M, et al. Subclinical thyroid dis-
wk) L-T4 replacement (105). Moreover, a recent reanalysis ease in elderly subjects. Acta Biomed. 2010;81:3136.
of the results of the Whickham survey showed that L-T4 2. Ross DS. Subclinical hypothyroidism. In: Braverman LE, Cooper
D, eds. Werner & Ingbars the thyroid, a fundamental and clinical
treatment attenuated the risk of CHD events and mortality
text. 9th ed. Philadelphia: Lippincott Williams and Wilkins; 2004:
in sHT patients over 20 years of follow-up (94). However, 1070 1078.
a very recent prospective analysis of data from the United 3. Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado
thyroid disease prevalence study. Arch Intern Med. 2000;160:526
Kingdom General Practitioner Research Database dem-
534.
onstrated that L-T4 replacement therapy was associated 4. Cooper DS, Biondi B. Subclinical thyroid disease. Lancet. 2012;
with fewer CHD events in younger sHT patients (aged 379:11421154.
5. Ashizawa K, Imaizumi M, Usa T, et al. Metabolic cardiovascular
40 70 y), but not in the oldest old population (mean age
disease risk factors and their clustering in subclinical hypothyroid-
around 80 y) (106). Interestingly, in a very recent study, ism. Clin Endocrinol (Oxf). 2010;72:689 695.
enrolling moderately old sHT patients (mean age, 63.2 y) 6. Asvold BO, Bjoro T, Nilsen TI, Vatten LJ. Association between
blood pressure and serum thyroid-stimulating hormone concen-
with chronic kidney diseases, L-T4 treatment was able to
tration within the reference range: a population-based study. J Clin
reduce significantly the rate of glomerular filtration de- Endocrinol Metab. 2007;92:841 845.
cline over 2 years of follow-up (107). 7. Asvold BO, Bjro T, Vatten LJ. Association of thyroid function
with estimated glomerular filtration rate in a population-based
study: the HUNT study. Eur J Endocrinol. 2011;164:101105.
8. Mitrou P, Raptis SA, Dimitriadis G. Thyroid disease in older peo-
Conclusions ple. Maturitas. 2011;70:59.
9. Tan ZS, Beiser A, Vasan RS, et al. Thyroid function and the risk of
In summary, the scientific literature herein reviewed sug- Alzheimer disease: the Framingham Study. Arch Intern Med. 2008;
168:1514 1520.
gests that sHT in older people should not be regarded as 10. Caraccio N, Ferrannini E, Monzani F. Lipoprotein profile in sub-
a unique condition. Moderately old patients (70 75 y) clinical hypothyroidism: response to levothyroxine replacement, a
could be considered clinically similar to the adult popu- randomized placebo-controlled study. J Clin Endocrinol Metab.
2002;87:15331538.
lation, albeit with a higher optimal TSH target value 11. Cappola AR, Ladenson PW. Hypothyroidism and atherosclerosis.
(around 23 mIU/L), whereas the oldest old subjects J Clin Endocrinol Metab. 2003;88:2438 2444.
(80 85 y) should be carefully followed with a wait-and- 12. Carle A, Laurberg P, Pedersen IB, et al. Age modifies the pituitary
TSH response to thyroid failure. Thyroid. 2007;17:139 144.
see strategy, generally avoiding hormonal treatment. The 13. Laurberg P, Andersen S, Carle A, Karmisholt J, Knudsen N, Ped-
decision to treat (moderately) old sHT patients should ersen IB. The TSH upper reference limit: where are we at? Nat Rev
derive from a specific evaluation of the possible thyroid Endocrinol. 2011;7:232239.
14. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease:
dysfunction causes, pre-existent CV risk, the presence of
scientific review and guidelines for diagnosis and management.
HF, comorbidity, or frailty as well as the actual level of JAMA. 2004;291:228 238.
serum TSH. Treatment must be individualized, gradual, 15. Villar HC, Saconato H, Valente O, Atallah AN. Thyroid hormone
replacement for subclinical hypothyroidism. Cochrane Database
and closely monitored once any underlying coexisting
Syst Rev. 2007;3:CD003419.
morbidity or pharmacological interference has been ex- 16. Mariotti S, Barbesino G, Caturegli P, et al. Complex alteration of
cluded. Yet, appropriately powered randomized con- thyroid function in healthy centenarians. J Clin Endocrinol Metab.
1993;77:1130 1134.
trolled trials of L-T4 in sHT patients, examining CV hard
17. Mariotti S, Franceschi C, Cossarizza A, Pinchera A. The aging
endpoints in various classes of age, are warranted (108). thyroid. Endocr Rev. 1995;1:686 715.
18. Piers LS, Soares MJ, McCormack LM, ODea K. Is there evidence
for an age-related reduction in metabolic rate? J Appl Physiol.
1998;85:2196 2204.
Acknowledgments 19. Surks MI, Hollowell JG. Age-specific distribution of serum thyro-
tropin and antithyroid antibodies in the US population: implica-
Address all correspondence and requests for reprints to: Fabio tions for the prevalence of subclinical hypothyroidism. J Clin En-
Monzani, MD, Geriatrics Unit, Department of Clinical and Ex- docrinol Metab. 2007;92:4575 4582.
perimental Medicine, University of Pisa, Via Roma 67, 56126 20. Bremner AP, Feddema P, Leedman PJ, et al. Age-related changes in
thyroid function: a longitudinal study of a community-based co-
Pisa, Italy. E-mail: fabio.monzani@med.unipi.it.
hort. J Clin Endocrinol Metab. 2012;97:1554 1562.
The study was partly supported by grants from the Ministero 21. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH, T(4),
Istruzione Universit Ricerca (PRIN 2009). and thyroid antibodies in the United States population (1988 to

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 July 2016. at 23:45 For personal use only. No other uses without permission. . All rights reserved.
2264 Pasqualetti et al Subclinical Hypothyroidism in the Elderly
1994): National Health and Nutrition Examination Survey
(NHANES III). J Clin Endocrinol Metab. 2002;87:489 499.
22. Sawin CT, Chopra D, Azizi F, Mannix JE, Bacharach P. The aging
thyroid. Increased prevalence of elevated serum thyrotropin levels
in the elderly. JAMA. 1979;242:247250.
23. Monzani F, Del Guerra P, Caraccio N, et al. Age-related modifi-
cations in the regulation of the hypothalamic-pituitary-thyroid
axis. Horm Res. 1996;46:107112.
24. 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.
25. Wiersinga WM, van den Berghe G. Nonthyroidal illness syndrome.
In: Braverman LE, Cooper D, eds. Werner & Ingbars the thyroid,
a fundamental and clinical text. 9th ed. Philadelphia: Lippincott
Williams and Wilkins; 2004:246 263.
26. Tognini S, Polini A, Pasqualetti G, et al. Age and gender substan-
tially influence the relationship between thyroid status and the
lipoprotein profile: results from a large cross-sectional study. Thy-
roid. 2012;22:1096 1103.
27. Rozing MP, Houwing-Duistermaat JJ, Slagboom PE, et al. Familial
longevity is associated with decreased thyroid function. J Clin En-
docrinol Metab. 2010;95:4979 4984.
28. Corsonello A, Montesanto A, Berardelli M, et al. A cross-section
analysis of FT3 age-related changes in a group of old and oldest-old
subjects, including centenarians relatives, shows that a down-reg-
ulated thyroid function has a familial component and is related to
longevity. Age Ageing. 2010;39:723727.
29. Boucai L, Hollowell JG, Surks MI. An approach for development
of age-, gender-, and ethnicity-specific thyrotropin reference limits.
Thyroid. 2011;21:511.
30. Atzmon G, Barzilai N, Hollowell JG, Surks MI, Gabriely I. Ex-
treme longevity is associated with increased serum thyrotropin.
J Clin Endocrinol Metab. 2009;94:12511254.
31. Iovino M, Steardo L, Monteleone P. Impaired sensitivity of the
hypothalamo-pituitary-thyroid axis to the suppressant effect of
dexamethasone in elderly subjects. Psychopharmacology (Berl).
1991;105:481 484.
32. Rivolta G, Cerutti R, Colombo R, Miano G, Dionisio P, Grossi E.
Prevalence of subclinical hypothyroidism in a population living in
the Milan metropolitan area. J Endocrinol Invest. 1999;22:693
697.
33. Wang C, Crapo LM. The epidemiology of thyroid disease and
implications for screening. Endocrinol Metab Clin North Am.
1997;26:189 218.
34. Szabolcs I, Podoba J, Feldkamp J, et al. Comparative screening for
thyroid disorders in old age in areas of iodine deficiency, long-term
iodine prophylaxis and abundant iodine intake. Clin Endocrinol
(Oxf). 1997;47:8792.
35. Klubo-Gwiezdzinska J, Wartofsky L. Thyrotropin blood levels,
subclinical hypothyroidism, and the elderly patient. Arch Intern
Med. 2009;169:1949 1951.
36. Wartofsky L, Dickey RA. The evidence for a narrower thyrotropin
reference range is compelling. J Clin Endocrinol Metab. 2005;90:
54835488.
37. Kahapola-Arachchige KM, Hadlow N, Wardrop R, Lim EM,
Walsh JP. Age-specific TSH reference ranges have minimal impact
on the diagnosis of thyroid dysfunction. Clin Endocrinol (Oxf).
2012;77:773779.
38. Cooper DS. Clinical practice. Subclinical hypothyroidism. N Engl
J Med. 2001;345:260 265.
39. Canaris GJ, Steiner JF, Ridgway EC. Do traditional symptoms of
hypothyroidism correlate with biochemical disease? J Gen Intern
Med. 1997;12:544 550.
40. Somwaru LL, Rariy CM, Arnold AM, Cappola AR. The natural
history of subclinical hypothyroidism in the elderly: the Cardio-
vascular Health Study. J Clin Endocrinol Metab. 2012;97:1962
1969.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 July 2016. at 23:45 For personal use only. No other uses without permission. . All rights reserved.
J Clin Endocrinol Metab, June 2013, 98(6):2256 2266
41. 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.
42. Diez JJ, Iglesias P. Spontaneous subclinical hypothyroidism in pa-
tients older than 55 years: an analysis of natural course and risk
factors for the development of overt thyroid failure. J Clin Endo-
crinol Metab. 2004;89:4890 4897.
43. Fatourechi V. Subclinical hypothyroidism: an update for primary
care physicians. Mayo Clin Proc. 2009;84:6571.
44. Huber G, Staub JJ, Meier C, et al. Prospective study of the spon-
taneous course of subclinical hypothyroidism: prognostic value of
thyrotropin, thyroid reserve, and thyroid antibodies. J Clin Endo-
crinol Metab. 2002;87:32213226.
45. Diez JJ, Iglesias P, Burman KD. Spontaneous normalization of
thyrotropin concentrations in patients with subclinical hypothy-
roidism. J Clin Endocrinol Metab. 2005;90:4124 4127.
46. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular sys-
tem. N Engl J Med. 2001;344:501509.
47. Danzi S, Klein I. Thyroid hormone and the cardiovascular system.
Med Clin North Am. 2012;96:257268.
48. Klein I, Ojamaa K. Thyroid hormone: targeting the vascular
smooth muscle cell. Circ Res. 2001;88:260 261.
49. Monzani F, Caraccio N, Siciliano G, Manca L, Murri L, Ferrannini
E. Clinical and biochemical features of muscle dysfunction in sub-
clinical hypothyroidism. J Clin Endocrinol Metab. 1997;82:3315
3318.
50. Caraccio N, Natali A, Sironi A, et al. Muscle metabolism and ex-
ercise tolerance in subclinical hypothyroidism: a controlled trial of
levothyroxine. J Clin Endocrinol Metab. 2005;90:4057 4062.
51. Klein I, Danzi S. Thyroid disease and the heart. Circulation. 2007;
116:17251735.
52. Lekakis J, Papamichael C, Alevizaki M, et al. Flow-mediated, en-
dothelium-dependent vasodilation is impaired in subjects with hy-
pothyroidism, borderline hypothyroidism, and high-normal serum
thyrotropin (TSH) values. Thyroid. 1997;7:411 414.
53. Taddei S, Caraccio N, Virdis A, et al. Impaired endothelium-de-
pendent vasodilatation in subclinical hypothyroidism: beneficial
effect of levothyroxine therapy. J Clin Endocrinol Metab. 2003;
88:37313737.
54. Monzani F, Di Bello V, Caraccio N, et al. Effect of levothyroxine
on cardiac function and structure in subclinical hypothyroidism: a
double blind, placebo-controlled study. J Clin Endocrinol Metab.
2001;86:1110 1115.
55. Brenta G, Mutti LA, Schnitman M, Fretes O, Perrone A, Matute
ML. Assessment of left ventricular diastolic function by radionu-
clide ventriculography at rest and exercise in subclinical hypothy-
roidism, and its response to L-thyroxine therapy. Am J Cardiol.
2003;91:13271330.
56. Alibaz Oner F, Yurdakul S, Oner E, Kubat Uzum A, Erguney M.
Evaluation of the effect of L-thyroxin therapy on endothelial func-
tions in patients with subclinical hypothyroidism. Endocrine.
2011;40:280 284.
57. Kahaly GJ, Dillmann WH. Thyroid hormone action in the heart.
Endocr Rev. 2005;26:704 728.
58. Ketzer LA, Arruda AP, Carvalho DP, de Meis L. Cardiac sarco-
plasmic reticulum Ca2-ATPase: heat production and phospho-
lamban alterations promoted by cold exposure and thyroid hor-
mone. Am J Physiol Heart Circ Physiol. 2009;297:H556 H563.
59. Ojamaa K, Klemperer JD, Klein I. Acute effects of thyroid hormone
on vascular smooth muscle. Thyroid. 1996;6:505512.
60. Strait JB, Lakatta EG. Aging-associated cardiovascular changes
and their relationship to heart failure. Heart Fail Clin. 2012;8:
143164.
61. Biondi B, Klein I. Hypothyroidism as a risk factor for cardiovas-
cular disease. Endocrine. 2004;24:113.
62. Taddei S, Caraccio N, Virdis A, et al. Low-grade systemic inflam-
doi: 10.1210/jc.2012-3818
mation causes endothelial dysfunction in patients with Hashimo-
tos thyroiditis. J Clin Endocrinol Metab. 2006;91:5076 5082.
63. Napoli R, Guardasole V, Zarra E, et al. Impaired endothelial- and
nonendothelial-mediated vasodilation in patients with acute or
chronic hypothyroidism. Clin Endocrinol (Oxf). 2010;72:107
111.
64. Bindels AJ, Westendorp RG, Frlich M, Seidell JC, Blokstra A,
Smelt AH. The prevalence of subclinical hypothyroidism at differ-
ent total plasma cholesterol levels in middle aged men and women:
a need for case-finding? Clin Endocrinol (Oxf). 1999;50:217220.
65. Meier C, Staub JJ, Roth CB, et al. TSH-controlled L-thyroxine
therapy reduces cholesterol levels and clinical symptoms in sub-
clinical hypothyroidism: a double blind, placebo-controlled trial
(Basel Thyroid Study). J Clin Endocrinol Metab. 2001;86:4860
4866.
66. Biondi B, Fazio S, Palmieri EA, et al. Left ventricular diastolic
dysfunction in patients with subclinical hypothyroidism. J Clin
Endocrinol Metab. 1999;84:2064 2072.
67. Waring AC, Rodondi N, Harrison S, et al; Health, Ageing, and
Body Composition (Health ABC) Study. Thyroid function and
prevalent and incident metabolic syndrome in older adults: the
Health, Ageing and Body Composition Study. Clin Endocri-
nol(Oxf). 2012;76:911918.
68. Higashi Y, Kihara Y, Noma K. Endothelial dysfunction and hy-
pertension in aging. Hypertens Res. 2012;35:1039 1041.
69. El Assar M, Angulo J, Vallejo S, Peir C, Snchez-Ferrer CF, Ro-
drguez-Maas L. Mechanisms involved in the aging-induced vas-
cular dysfunction. Front Physiol. 2012;3:132.
70. Tet S, Tripodi D, Rosati M, et al. Endothelial cells, cholesterol,
cytokines, and aging. Int J Immunopathol Pharmacol. 2012;25:
355363.
71. Mariotti S. Thyroid function and aging: do serum 3,5,3-triiodo-
thyronine and thyroid-stimulating hormone concentrations give
the Janus response? J Clin Endocrinol Metab. 2005;90:6735
6737.
72. Jessup M, Abraham WT, Casey DE, et al. 2009 Focused update:
ACCF/AHA guidelines for the diagnosis and management of heart
failure in adults: a report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice
Guidelines: developed in collaboration with the International So-
ciety for Heart and Lung Transplantation. Circulation. 2009;119:
19772016.
73. Hunt SA, Abraham WT, Chin MH, et al; American College of
Cardiology Foundation; American Heart Association. 2009 Fo-
cused update incorporated into the ACC/AHA 2005 Guidelines for
the Diagnosis and Management of Heart Failure in Adults: a report
of the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines Developed in
Collaboration with the International Society for Heart and Lung
Transplantation. J Am Coll Cardiol. 2009;53:e1 e90.
74. Rodondi N, Bauer DC, Cappola AR, et al. Subclinical thyroid
dysfunction, cardiac function, and the risk of heart failure. The
Cardiovascular Health Study. J Am Coll Cardiol. 2008;52:1152
1159.
75. Iacoviello M, Guida P, Guastamacchia E, et al. Prognostic role of
sub-clinical hypothyroidism in chronic heart failure outpatients.
Curr Pharm Des. 2008;14:2686 2692.
76. Nanchen D, Gussekloo J, Westendorp RG, et al. Subclinical thy-
roid dysfunction and the risk of heart failure in older persons at
high cardiovascular risk. J Clin Endocrinol Metab. 2012;97:852
861.
77. Rodondi N, Newman AB, Vittinghoff E, et al. Subclinical hypo-
thyroidism and the risk of heart failure, other cardiovascular
events, and death. Arch Intern Med. 2005;28:2460 2466.
78. Hyland KA, Arnold AM, Lee JS, Cappola AR. Persistent subclinical
hypothyroidism and cardiovascular risk in the elderly: the Cardio-
vascular Health Study. J Clin Endocrinol Metab. 2013;98:533
540.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 July 2016. at 23:45 For personal use only. No other uses without permission. . All rights reserved.
jcem.endojournals.org 2265
79. Iervasi G, Molinaro S, Landi P, et al. Association between increased
mortality and mild thyroid dysfunction in cardiac patients. Arch
Intern Med. 2007;167:1526 1532.
80. Gencer B, Collet TH, Virgini V, et al; Thyroid Studies Collabora-
tion. Subclinical thyroid dysfunction and the risk of heart failure
events: an individual participant data analysis from 6 prospective
cohorts. Circulation. 2012;126:1040 1049.
81. Ripoli A, Pingitore A, Favilli B, et al. Does subclinical hypothy-
roidism affect cardiac pump performance? Evidence from a mag-
netic resonance imaging study. J Am Coll Cardiol. 2005;45:439
445.
82. Vanderpump MP, Tunbridge WM, French JM, et al. The incidence
of thyroid disorders in the community: a twenty-year follow-up of
the Whickham Survey. Clin Endocrinol (Oxf). 1995;43:55 68.
83. Cappola AR, Fried LP, Arnold AM, et al. Thyroid status, cardio-
vascular risk, and mortality in older adults. JAMA. 2006;295:
10331041.
84. Hak AE, Pols HA, Visser TJ, Drexhage HA, Hofman A, Witteman
JC. Subclinical hypothyroidism is an independent risk factor for
atherosclerosis and myocardial infarction in elderly women: the
Rotterdam Study. Ann Intern Med. 2000;132:270 278.
85. Walsh JP, Bremner AP, Bulsara MK, et al. Subclinical thyroid dys-
function as a risk factor for cardiovascular disease. Arch Intern
Med. 2005;165:24672472.
86. Imaizumi M, Akahoshi M, Ichimaru S, et al. Risk for ischemic heart
disease and all-cause mortality in subclinical hypothyroidism.
J Clin Endocrinol Metab. 2004;89:33653370.
87. Tseng FY, Lin WY, Lin CC, et al. Subclinical hypothyroidism is
associated with increased risk for all-cause and cardiovascular
mortality in adults. J Am Coll Cardiol. 2012;60:730 737.
88. Lindeman RD, Romero LJ, Schade DS, Wayne S, Baumgartner RN,
Garry PJ. Impact of subclinical hypothyroidism on serum total
homocysteine concentrations, the prevalence of coronary heart dis-
ease (CHD), and CHD risk factors in the New Mexico Elder Health
Survey. Thyroid. 2003;13:595 600.
89. Takashima N, Niwa Y, Mannami T, Tomoike H, Iwai N. Char-
acterization of subclinical thyroid dysfunction from cardiovascular
and metabolic viewpoints: the Suita study. Circ J. 2007;71:191
195.
90. Parle JV, Maisonneuve P, Sheppard MC, Boyle P, Franklyn JA.
Prediction of all-cause and cardiovascular mortality in elderly peo-
ple from one low serum thyrotropin result: a 10-year cohort study.
Lancet. 2001;358:861 865.
91. Rodondi N, den Elzen WP, Bauer DC, et al. Subclinical hypothy-
roidism and the risk of coronary heart disease and mortality.
JAMA. 2010;304:13651374.
92. Ochs N, Auer R, Bauer DC, et al. Meta-analysis: subclinical thy-
roid dysfunction and the risk for coronary heart disease and mor-
tality. Ann Intern Med. 2008;148:832 845.
93. Razvi S, Shakoor A, Vanderpump M, Weaver JU, Pearce SH. The
influence of age on the relationship between subclinical hypothy-
roidism and ischemic heart disease: a metaanalysis. J Clin Endo-
crinol Metab. 2008;93:2998 3007.
94. Razvi S, Weaver JU, Vanderpump MP, Pearce SH. The incidence
of ischemic heart disease and mortality in people with subclinical
hypothyroidism: reanalysis of the Whickham Survey cohort. J Clin
Endocrinol Metab. 2010;95:1734 1740.
95. Waring AC, Harrison S, Samuels MH, et al; Osteoporotic Fractures
in Men (MrOS) Study. Thyroid function and mortality in older
men: a prospective study. J Clin Endocrinol Metab. 2012;97:862
870.
96. Kvetny J, Heldgaard PE, Bladbjerg EM, Gram J. Subclinical hy-
pothyroidism is associated with a low-grade inflammation, in-
creased triglyceride levels and predicts cardiovascular disease in
males below 50 years. Clin Endocrinol (Oxf). 2004;61:232238.
97. Monzani F, Dardano A, Caraccio N. Does treating subclinical hy-
pothyroidism improve markers of cardiovascular risk? Treat En-
docrinol. 2006;5:65 81.
2266 Pasqualetti et al Subclinical Hypothyroidism in the Elderly
98. Bauer DC, Rodondi N, Stone KL, Hillier TA; Study of Osteopo-
rotic Fractures Research Group: Universities of California (San
Francisco), Pittsburgh, Minnesota (Minneapolis); Kaiser Perma-
nente Center for Health Research, Portland. Thyroid hormone use,
hyperthyroidism and mortality in older women. Am J Med. 2007;
120:343349.
99. Gussekloo J, van Exel E, de Craen AJ, Meinders AE, Frlich M,
Westendorp RG. Thyroid status, disability and cognitive function,
and survival in old age. JAMA. 2004;292:25912599.
100. Asvold BO, Bjro T, Platou C, Vatten LJ. Thyroid function and the
risk of coronary heart disease: 12-year follow-up of the HUNT
Study in Norway. Clin Endocrinol (Oxf). 2012;77:911917.
101. Kim HC, Greenland P, Rossouw JE, et al. Multimarker prediction
of coronary heart disease risk: the Womens Health Initiative. J Am
Coll Cardiol. 2010;55:2080 2091.
102. Monzani F, Caraccio N, Kozkow M, et al. Effect of levothyrox-
ine replacement on lipid profile and intima-media thickness in sub-
clinical hypothyroidism: a double-blind, placebo- controlled
study. J Clin Endocrinol Metab. 2004;89:2099 2106.
103. Cooper DS, Halpern R, Wood LC, Levin AA, Ridgway EC. L-
Thyroxine therapy in subclinical hypothyroidism. A double-blind,
placebo-controlled trial. Ann Intern Med. 1984;101:18 24.
104. Kong WM, Sheikh MH, Lumb PJ, et al. A 6-month randomized
trial of thyroxine treatment in women with mild subclinical hypo-
thyroidism. Am J Med. 2002;112:348 354.
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J Clin Endocrinol Metab, June 2013, 98(6):2256 2266
105. Razvi S, Ingoe L, Keeka G, Oates C, McMillan C, Weaver JU. The
beneficial effect of L-thyroxine on cardiovascular risk factors, en-
dothelial function, and quality of life in subclinical hypothyroid-
ism: randomized, crossover trial. J Clin Endocrinol Metab. 2007;
92:17151723.
106. Razvi S, Weaver JU, Butler TJ, Pearce SH. Levothyroxine treat-
ment of subclinical hypothyroidism, fatal and nonfatal cardiovas-
cular events, and mortality. Arch Intern Med. 2012;172:811 817.
107. Shin DH, Lee MJ, Kim SJ, et al. Preservation of renal function by
thyroid hormone replacement therapy in chronic kidney disease
patients with subclinical hypothyroidism. J Clin Endocrinol
Metab. 2012;97:27322740.
108. Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines
for hypothyroidism in adults: cosponsored by the American As-
sociation of Clinical Endocrinologists and the American Thyroid
Association. Thyroid. 2012;22:1200 1235.
109. Haentjens P, Van Meerhaeghe A, Poppe K, Velkeniers B. Subclin-
ical thyroid dysfunction and mortality: an estimate of relative and
absolute excess all-cause mortality based on time-to-event data
from cohort studies. Eur J Endocrinol. 2008;159:329 341.
110. Singh S, Molnar J, Maldonado F, Barsano CP, Arora R. Impact of
subclinical thyroid disorders on coronary heart disease, cardiovas-
cular and all-cause mortality: a meta-analysis. Int J Cardiol. 2008;
125:41 48.