ORIGINAL ARTICLE

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

Hashimotos Thyroiditis, Risk of Coronary Heart

Disease, and L-Thyroxine Treatment: A Nationwide
Cohort Study

Wei-Hung Chen, Yen-Kung Chen, Cheng-Li Lin, Jiann-Horng Yeh,

and Chia-Hung Kao
Department of Neurology (W.-H.C., J.-H.Y.) and Department of Nuclear Medicine and PET Center
(Y.-K.C.), Shin Kong Wu Ho-Su Memorial Hospital, Taipei 111, Taiwan; School of Medicine (Y.-K.C., J.-
H.Y.), Fu-Jen Catholic University, New Taipei City 242, Taiwan; and Management Office for Health Data
(C.-L.L.); Graduate Institute of Clinical Medicine Science and School of Medicine (C.-H.K.), College of
Medicine (C.-L.L.); and Department of Nuclear Medicine and PET Center (C.-H.K.), China Medical
University Hospital, Taichung 404, Taiwan

Objective: Our objective was to investigate the risk of coronary heart disease (CHD) in patients with
Hashimotos thyroiditis (HT).

Methods: The Taiwan National Health Insurance Research Database was used to conduct a retro-
spective cohort analysis. The cohort study consisted of 1165 newly diagnosed HT patients and 4660
matched controls (non-HT patients) from 2000 to 2010. The median follow-up time was 5.46 years.
The risk of developing CHD for HT patients was measured using the Cox proportional hazards
model.

Results: The risk of developing CHD in HT patients was increased compared with the non-HT
controls, with an adjusted hazard ratio (HR) of 1.44 (95% confidence interval [CI] 1.051.99). The
risk was significant in women but not in men, and restricted to subjects younger than 49 years. HT
remained an independent risk factor after adjusting for comorbidities; however, combining with
hypertension or hyperlipidemia further increased the risk of CHD (adjusted HR 2.06, 95% CI
1.46 2.92; and adjusted HR 1.83, 95% CI 1.312.55, respectively). Furthermore, HT without T4
treatment and HT with treatment for less than 1 year were associated with higher risk of CHD
(adjusted HR 1.55, 95% CI 0.98 2.46; and adjusted HR 2.42, 95% CI 1.433.97, respectively).
The risk of CHD decreased after treatment with T4 for more than 1 year and did not differ from the
non-HT cohort (adjusted HR 0.84, 95% CI 0.0.471.52).

Conclusion: Patients with HT, are at higher risk of developing CHD compared with the general
population. Treatment with T4 reduces the risk of CHD. (J Clin Endocrinol Metab 100: 109 114,
2015)

ashimotos thyroiditis (HT), an autoimmune thyroid for coronary heart disease (CHD) in patients with sub-
H disease causing thyroid destruction, is a primary
cause of noniatrogenic hypothyroidism (1). Hypothyroid-
clinical hypothyroidism (5).
Most studies have focused on hypothyroidism, which
ism has been observed to increase the risk of cardiovas- has been presumed to cause CHD through hyperlipidemia,
cular disease and atherosclerosis (2 4). A recent meta- hypertension, diabetes, and obesity. Few studies have spe-
analysis reported an increased risk of approximately 20% cifically examined autoimmune thyroid disease, which

ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: CHD, coronary heart disease; CI, confidence interval; HR, hazard ratio; HT,
Printed in U.S.A. Hashimotos thyroiditis; LHID 2000, Longitudinal Health Insurance Database 2000; NHI,
Copyright 2015 by the Endocrine Society National Health Insurance.
Received July 21, 2014. Accepted September 26, 2014.
First Published Online October 1, 2014

doi: 10.1210/jc.2014-2990 J Clin Endocrinol Metab, January 2015, 100(1):109 114 jcem.endojournals.org 109

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 July 2016. at 23:56 For personal use only. No other uses without permission. . All rights reserved.
110 Chen et al Hashimotos Thyroiditis and Coronary Heart Disease J Clin Endocrinol Metab, January 2015, 100(1):109 114

can precipitate cardiovascular disease through chronic in- Statistical analysis

flammation in addition to hypothyroidism (6, 7).
The aim of this study was to investigate the risk of CHD
among HT patients in a large cohort and determine the
interaction between other cardiovascular risk factors and
the effect of T4 treatment.
Subjects and Methods
Data source
The National Health Insurance (NHI) program in Taiwan
was established on March 1, 1995. Under the NHI program,
99% of the islands population receives all forms of healthcare
service, including ambulatory care, outpatient and inpatient
treatment, dental services, and physician services (http://www.
nhi.gov.tw/english/index.aspx). We conducted a retrospective
cohort study by using the Longitudinal Health Insurance Data-
base 2000 (LHID 2000) released by the Taiwan National Health
Research Institutes. The LHID 2000 is composed of historical
claims data for 1 million people selected randomly from the
23.74 million people in the NHI registry of beneficiaries. In the
NHI program, diseases are diagnosed according to the Inter-
national Classification of Diseases, Ninth Revision, Clinical
Modification (ICD-9-CM). The NHI program has a rigorous
monitoring system to ensure that the claims for healthcare re-
imbursement are based on valid diagnoses. Personal information
is scrambled to protect privacy to ensure that all data are de-
identified and analyzed anonymously. This study was approved
by the China Medical University Institute Review Board
(CMU-REC-101-012).
The distributions of demographic characteristics were com-
pared between the HT cohort and the non-HT cohort, and the
differences were examined. The 2 test was used for categorical
variables, and the t test was used for continuous variables. The
follow-up person-years were used to estimate the incidence den-
sity for both cohorts. Univariable and multivariable Coxs pro-
portional hazards regressions were used to assess the risk of
developing CHD that was associated with HT. The multivariable
models were simultaneously adjusted for demographic charac-
teristics and the comorbidities of hypertension, diabetes hyper-
lipidemia, stroke, chronic kidney disease, and heart failure. The
hazard ratios (HRs) and 95% confidence intervals (CIs) were
estimated using the Cox model. Further analysis was performed
to assess whether L-T4 treatment played a role in the CHD
outcomes.
We assessed the cumulative incidence of CHD by using the
Kaplan-Meier method between the HT cohort and the non-HT
cohort and estimated their differences using the log-rank test. All
analyses were performed using the SAS statistical package (ver-
sion 9.2 for Windows; SAS Institute). A 2-tailed P value .05
was considered statistically significant.
Results
This cohort study consisted of 1165 newly diagnosed HT
patients and 4660 non-HT controls from 2000 to 2010,
with a median follow-up time of 5.46 (range 0.0712.0)
years. Table 1 shows the baseline demographic data and
comorbidities. Most patients were women (90.8%) and
49 years of age (77.0%). The mean ages of the non-HT

Sampled participants Table 1. Demographic Characteristics and

From the LHID 2000, the HT cohort consisted of patients Comorbidity in HT Patient and Non-HT Controlsa
aged 20 years and older newly diagnosed with HT (ICD-9-CM
Non-HT, HT, P
code 245.2) from 2000 to 2010. The index date for an HT patient Variable n 4650 n 1165 Value
was the date of the first clinic visit after the HT diagnosis. Patients
Gender 0.98
with a history of CHD (ICD-9-CM codes 410 414) before the Female 4222 (90.8) 1058 (90.8)
index date were excluded. The non-HT cohort was formed by Male 428 (9.20) 107 (9.18)
randomly selecting patients without a history of HT and CHD Age, y 0.99
from the claims data, frequency matched with the HT patients by 34 1744 (37.5) 436 (37.4)
sex; age (in 5-year bands); baseline comorbidities including hy- 35 49 1840 (39.6) 461 (39.6)
50 64 864 (18.6) 217 (18.6)
pertension, diabetes, hyperlipidemia, stroke, rheumatic heart
65 202 (4.34) 51 (4.38)
disease, chronic kidney disease, and heart failure; and index year, Age, mean (SD)b 40.9 (12.9) 41.1 (12.6) 0.65
at a ratio of 1:4. Comorbidity
Hypertension 624 (13.4) 156 (13.4) 0.98
Outcome and relevant variables Diabetes 388 (8.34) 98 (8.41) 0.94
Hyperlipidemia 672 (14.5) 169 (14.5) 0.96
Patients in both the HT and non-HT cohorts were followed Stroke 141 (3.03) 36 (3.09) 0.92
up until they were diagnosed with CHD or censored because of Rheumatic heart 28 (0.60) 9 (0.77) 0.51
loss of follow-up, withdrawal from insurance, death, or the end disease
of 2011. The baseline comorbidities considered were hyperten- Chronic kidney 30 (0.65) 8 (0.69) 0.88
sion (ICD-9-CM codes 401 405), diabetes (ICD-9-CM code disease
250), hyperlipidemia (ICD-9-CM code 272), stroke (ICD-9-CM Heart failure 29 (0.62) 8 (0.69) 0.81
codes 430 438), rheumatic heart disease (ICD-9-CM codes a
Data are presented as n (percentage) unless indicated otherwise. The
393398), chronic kidney disease (ICD-9-CM code 585), and 2 test was used for categorical variables.
b
heart failure (ICD-9-CM code 428). Two-sample t test.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 July 2016. at 23:56 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2014-2990 jcem.endojournals.org 111

of 7.56 vs 5.22 per 1000 person-years), with an adjusted

HR of 1.44 (95% CI 1.051.99) (Table 2). Although the
CHD incidence was higher in men than in women in both
cohorts, the sex-specific HT to non-HT cohort adjusted
HR of CHD was significant for women (adjusted HR
1.45, 95% CI 1.032.04). The age-specific incidence
rate of CHD showed that the incidence rate increased with
age in both cohorts; however, the HR was significant only
for those 49 years of age (adjusted HR 1.74, 95% CI
1.10 2.75).
The comorbidity-specific analysis showed that al-
though the incidence rate of CHD was consistently higher
in patients with comorbidities, the risk for developing
CHD was significant only in HT patients without comor-
bidities (adjusted HR 2.42, 95% CI 1.46 4.01).
Table 3 shows the results of univariate and multivariate
Cox proportional hazards analyses for the association be-
Figure 1. Cumulative incidence of CHD for patients with and without tween CHD and HT. After multivariable analysis for co-
HT.
morbidities, HT (HR 1.44, 95% CI 1.09 1.99), hy-
cohort and the HT cohort were 40.9 12.9 and 41.1 pertension (HR 2.06, 95% CI 1.46 2.92),
12.6 years, respectively. The HT cohort and non-HT co- hyperlipidemia (HR 1.83, 95% CI 1.312.55), and
hort were well-matched for comorbidities. heart failure (HR 2.21, 95% CI 1.09 4.49) remained
Figure 1 shows that the cumulative incidence of CHD independent risk factors for CHD.
was higher in the HT cohort than that in the non-HT Table 4 shows that the joint effects of hypertension or
cohort by 2.30% at the end of the follow-up period (log- hyperlipidemia and HT increased the overall risk for
rank test P .02). CHD. Compared with the non-HT cohort without hyper-
Table 2 shows the incidence rates of CHD for both tension, the HT cohort with hypertension had a signifi-
cohorts. Compared with the non-HT cohort, the crude cantly increased risk of CHD (adjusted HR 2.78, 95%
HR of CHD in the HT cohort was 1.44 times higher (a rate CI 1.58 4.90). Similarly, the HT cohort with hyper-

Table 2. Comparison of Incidence and HRs of CHD Stratified by Sex, Age, and Comorbidity Between HT Patients
and Non-HT Controls
Non-HT HT
Crude HRb Adjusted HRc
Variables Events PY Ratea Events PY Ratea (95% CI) (95% CI)
All 141 26 987 5.22 51 6747 7.56 1.44 (1.05, 1.99)e 1.44 (1.05, 1.99)e
Gender
Female 123 24 671 4.99 45 6181 7.28 1.46 (1.04, 2.05)e 1.45 (1.03, 2.04)e
Male 18 2315 7.77 6 566 10.6 1.35 (0.54, 3.39) 1.30 (0.51, 3.29)
Age, y
49 61 21 671 2.81 26 5454 4.77 1.69 (1.07, 2.67)e 1.74 (1.10, 2.75)e
50 64 52 4476 11.6 19 1094 17.4 1.49 (0.88, 2.52) 1.53 (0.90, 2.58)
65 28 839 33.4 9 199 30.1 0.90 (0.37, 2.17) 0.87 (0.36, 2.12)
Comorbidityd
No 40 20 160 1.98 24 5090 4.72 2.36 (1.43, 3.93)f 2.42 (1.46, 4.01)f
Yes 101 6827 14.8 27 1657 16.3 1.09 (0.71, 1.67) 1.09 (0.71, 1.66)
Abbreviation: PY, person-years.
a
Incidence rate per 1000 PY.
b
Relative HR.
c
Multivariable analysis including age and comorbidities of hypertension, diabetes, hyperlipidemia, stroke, chronic kidney disease, and heart failure.
d
Patients with any one of the comorbidities including hypertension, diabetes, hyperlipidemia, stroke, chronic kidney disease, and heart failure
were classified as the comorbidity group.
e
P .05.
f
P .001.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 July 2016. at 23:56 For personal use only. No other uses without permission. . All rights reserved.
112 Chen et al Hashimotos Thyroiditis and Coronary Heart Disease J Clin Endocrinol Metab, January 2015, 100(1):109 114

Table 3. Cox Model With HRs and 95% CIs of CHD Discussion
Associated With HT and Covariates
Our study consisted of a cohort of 1165 HT patients and
Crude HRa Adjusted HRb a control cohort of 4660 non-HT patients, matched by
Variable HR (95% CI) HR (95% CI) age, sex, comorbidities, and index year at a ratio of 1:4.
Age, y 1.07 (1.06, 1.09)d 1.05 (1.04, 1.06)d This study provides further evidence that HT is associated
Sex (female vs male) 1.52 (0.99, 2.33)
Baseline comorbidities with an increased risk of CHD irrespective of baseline
(yes vs no) comorbidities, including diabetes mellitus, hypertension,
HT 1.441.05, 1.99)c 1.44 (1.09, 1.99)c hyperlipidemia, stroke, chronic kidney disease, and heart
Hypertension 5.78 (4.35, 7.70)d 2.06 (1.46, 2.92)d disease. The adjusted HR for developing CHD in the cur-
Diabetes 3.20 (2.28, 4.48)d 1.25 (0.86, 1.81)
Hyperlipidemia 4.34 (3.25, 5.80)d 1.83 (1.31, 2.55)d rent HT cohort was 1.44, a figure higher than that re-
Stroke 2.84 (1.65, 4.90)d 0.91 (0.28, 2.90) ported in previous studies. Compared with previous stud-
Rheumatic heart 2.26 (0.72, 7.08) ies on subclinical hypothyroidism and CHD, our study
disease
Chronic kidney 3.14 (1.00, 9.83)c 0.91 (0.28, 2.90) was focused specifically on HT patients. The study group
disease is unique because of its female predominance (90.8%) and
Heart failure 9.43 (4.83, 18.4)d 2.21 (1.09, 4.49)c younger age at onset (mean age of 41.1 year), which is
a
Relative HR. consistent with demographic data from the HT popula-
b
Multivariable analysis including age and comorbidities of tion (1, 8).
hypertension, diabetes, hyperlipidemia, stroke, chronic kidney disease, When examining the sex-specific HR, only female HT
and heart failure.
patients showed a significantly higher risk for CHD, de-
c
P .05.
spite the CHD incidence being higher in men in both co-
d
P .001.
horts. The age-specific HR was significant only for those
lipidemia had a higher risk of CHD than did the non-HT 49 years of age with an adjusted HR of 1.74, higher than
cohort without hyperlipidemia (adjusted HR 2.85, those of 50 to 64 and 65 years of age (adjusted HR
95% CI 1.69 4.80). 1.53 and 0.87, respectively). Few studies have examined
The results of T4 treatment related to CHD risk are the sex- and age-related difference; however, data from a
shown in Table 5. Compared with the non-HT cohort, HT meta-analysis revealed that women have a higher risk for
without treatment and HT with treatment for less than 1 CHD than men do (adjusted HR 1.23 vs 1.06), and
year were associated with higher risk of CHD (adjusted those of younger age (18 49 years) have a higher risk than
HR 1.55, 95% CI 0.98 2.46, and adjusted HR those of older age do (50 64 years) (adjusted HR 1.55
2.42, 95% CI 1.433.97). By contrast, the risk of CHD vs 1.11) (9). Both age and sex are possibly related to CHD
decreased after treatment with T4 for more than 1 year and in patients with subclinical hypothyroidism, and the effect
did not differ from that of the non-HT cohort (adjusted is more significant in HT patients.
HR 0.84, 95% CI 0.471.52). HT patients are known to have a higher incidence of
diabetes and hyperlipidemia, which reflects the metabolic
Table 4. Cox Proportional Hazard Regression Analysis effects of hypothyroidism (10 12). Nevertheless, HT re-
for the Risk of CHD in HT Patients With Joint Effect of mains a significant risk factor for CHD after adjusting for
Hypertension and Hyperlipidemia comorbidities, as well as in patients without comorbidi-
Adjusted HRa ties, suggesting a mechanism independent of hypothyroid-
Variables n Events (95% CI) ism. Chronic inflammation in autoimmune diseases has
HT Hypertension been recognized as a contributing factor to atherosclerosis
No No 4026 74 1 (Reference) and cardiovascular disease (13, 14). A nationwide study
No Yes 624 67 2.75 (1.88, 4.02)d
Yes No 1009 34 1.85 (1.23, 2.77)c from Sweden investigated 31 immune-mediated diseases
Yes Yes 156 17 2.78 (1.58, 4.90)d and the risk of subsequent CHD, among which HT was
HT Hyperlipidemia listed as having the fourth highest risk, below chorea mi-
No No 3978 82 1 (Reference)
No Yes 672 59 2.34 (1.65, 3.32)d nor, systemic lupus erythematosus, and rheumatic fever,
Yes No 996 33 1.62 (1.08, 2.42)b with a standardized incidence ratio of 4.30 (95% CI
Yes Yes 169 18 2.85 (1.69, 4.80)d 3.87 4.75) (15). The results suggested that HT, an auto-
a
Adjusted for age and sex. immune disease, is a crucial risk factor for CHD. Several
b
P .05. studies have shown endothelial dysfunction in HT pa-
c
P .01. tients, which might further contribute to atherosclerosis
d
P .001. (16, 17).

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 July 2016. at 23:56 For personal use only. No other uses without permission. . All rights reserved.
doi: 10.1210/jc.2014-2990 jcem.endojournals.org 113

Table 5. Incidence, Crude and Adjusted HRs of CHD Compared Among HT Patients With and Without T4
Treatment and Non-HT Controls
Crude HRb Adjusted HRc
Variables n Events PY Ratea (95% CI) (95% CI)
Non-HT controls 4650 141 26 987 5.22 1 (Reference) 1 (Reference)
HT without T4 treatment 519 21 3004 6.99 1.33 (0.84, 2.11) 1.55 (0.98, 2.46)
HT with T4 treatment 1 y 281 18 1590 11.3 2.17 (1.33, 3.55)d 2.42 (1.47, 3.97)e
HT with T4 treatment 1 y 365 12 2153 5.57 1.06 (0.59, 1.91) 0.84 (0.47, 1.52)
Abbreviation: PY, person-years.
a
Incidence rate per 1000 PY.
b
Relative HR.
c
Multivariable analysis including age and comorbidities of hypertension, diabetes, hyperlipidemia, stroke, chronic kidney disease, and heart failure.
d
P .01.
e
P .001.

Although HT is a risk factor for future CHD, comor- strong relationship with risk of CHD. Second, the results
bidities with conventional cardiovascular risk factors, derived from a cohort study are generally of lower meth-
such as hypertension or hyperlipidemia, further increase odological quality than those derived from randomized
the risk (HT with hypertension HR 2.06 and HT with trials because a cohort study design is subject to bias re-
hyperlipidemia HR 1.83, respectively). Recognizing lated to adjustments for confounders. Despite our metic-
and treating the concomitant hypertension and hyperlip- ulous study design, including adequate control of con-
idemia in HT patients is therefore critical. founding factors, bias might have remained because of
The effect of T4 treatment in preventing CHD and re- possible unmeasured or unknown confounders. Third, the
ducing mortality is controversial. T4 therapy has been diagnoses recorded in NHI claims are used primarily for
shown to improve coronary flow (18), reverse cardiac dys- administrative billing; therefore, they are not subject to
function (19), and decrease hyperlipidemia in HT patients verification for scientific purposes. We were unable to con-
(20); all are beneficial for HT patients at risk for CHD. tact the patients directly to obtain additional information
However, Flynn et al (21) reported that nonfatal ischemic because of the anonymity ensured by the identification
heart disease and dysrhythmias increased in treated hy- numbers. However, the NHI program does have a rigorous
pothyroidism when adjusted for age, sex, diabetic status, monitoring system to ensure that the claims for healthcare
and previous vascular disease. A recent study that exam- reimbursement are based on valid diagnoses. Medical reim-
ined the risk for stroke in autoimmune thyroiditis dis- bursement specialists and peer review should scrutinize all
closed that the effect of autoimmune thyroiditis on stroke insurance claims. The diagnoses of HT and CHD were based
risk was highest in the first year after diagnosis, and the on the ICD-9 codes, which were judged and determined by
risk reduced after thyroid hormone replacement (22). This related specialists and physicians according to the standard
is because a prediagnosis of hypothyroidism can take time criteria. Therefore, the diagnoses and codes for HT and CHD
to reduce the risk after treatment. Alternatively, T4 treat- used in this cohort study should be correct and reliable. Of
ment might increase coagulation factor levels and inhibit course, misclassification of cases based on ICD-9 codes alone
fibrinolysis, which in turn leads to an increased ischemic without other more definitive criteria such as individual lab-
stroke risk (23). Our results are consistent with their find- oratory and imaging data is still one of the study limitations.
ings that HT patients with T4 treatment for less than 1 year Finally, we obtained no information regarding the serum
are at the highest risk, whereas continuing treatment for thyroid hormone level or the compliance of the patients to
more than 1 year significantly reduces the risk. Athero- document the adequacy of T4 treatment. However, a thera-
genesis in HT patients might be reversible after treatment, peutic supplement of T4 is well-tolerated with few adverse
although it takes time. However, an insufficient period of effects, and patients taking T4 for more than 1 year suggested
treatment adversely affects the outcome. positive compliance.
This study had a few limitations. First, the National In conclusion, this paper provides valuable information
Health Research Institutes does not provide detailed pa- regarding the association between HT and CHD. This was
tient information, such as smoking habits, alcohol con- a large-scale nationwide cohort study of an Asian popu-
sumption, body mass index, physical activity, socioeco- lation. Patients with HT, particularly women and younger
nomic status, and family history of CHD. These covariates patients, are at higher risk of developing CHD compared
might have affected the study results because of their with the general population.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 July 2016. at 23:56 For personal use only. No other uses without permission. . All rights reserved.
114 Chen et al Hashimotos Thyroiditis and Coronary Heart Disease J Clin Endocrinol Metab, January 2015, 100(1):109 114

For patients with HT, the comorbidities of hyperten-
sion or hyperlipidemia further increase the risk; treat-
ments for the concomitant hypertension and hyperlipid-
emia are crucial in preventing future CHD. Furthermore,
our results confirm that treatment with T4 reduces the risk
of CHD, and most importantly, the treatment should be
implemented early and continue for more than 1 year.
Acknowledgments
Address all correspondence and requests for reprints to:
Chia-Hung Kao, Professor, Graduate Institute of Clinical Med-
ical Science and School of Medicine, College of Medicine, China
Medical University, Taichung, Taiwan. No. 2, Yuh-Der Road,
Taichung 404, Taiwan. E-mail: d10040@mail.cmuh.org.tw.
This work was supported by grants from China Medical
University (CMU102-BC-2); Taiwan Ministry of Health and
Welfare Clinical Trial and Research Center of Excellence
(MOHW103-TDU-B-212-113002); Health and welfare sur-
charge of tobacco products, China Medical University Hospital
Cancer Research Center of Excellence (MOHW103-TD-B-111-
03, Taiwan). The funders had no role in study design, data col-
lection and analysis, decision to publish, or preparation of the
manuscript. No additional external funding was received for this
study.
All authors are in agreement with the content of the manu-
script, and all authors have contributed significantly, as follows:
conception/design, W.-H.C., Y.-K.C., and C.-H.K.; provision of
study materials, C.-H.K.; collection and/or assembly of data,
W.-H.C., Y.-K.C., and C.-H.K.; data analysis and interpreta-
tion, all authors; manuscript writing, all authors; final approval
of manuscript, all authors.
Disclosure Summary: The authors have no actual or potential
conflicts of interest.
References
1. Kumar V. The endocrine system. In: Kumar V, Abbas KA, Fausto N,
Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease. 8th
ed. Elsevier: Philadelphia, PA; 2010:11111205.
2. 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.
3. 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.
4. Rodondi N, Newman AB, Vittinghoff E, et al. Subclinical hypothy-
roidism and the risk of heart failure, other cardiovascular events, and
death. Arch Intern Med. 2005;165:2460 2466.
5. Ochs N, Auer R, Bauer DC, et al. Meta-analysis: subclinical thyroid
dysfunction and the risk for coronary heart disease and mortality.
Ann Intern Med. 2008;148:832 845.
6. Aho K, Gordin A, Palosuo T, et al. Thyroid autoimmunity and
cardiovascular diseases. Eur Heart J. 1984;5:43 46.
7. Vanderpump MP, Tunbridge WM, French JM, et al. The develop-
ment of ischemic heart disease in relation to autoimmune thyroid
disease in a 20-year follow-up study of an English community.
Thyroid. 1996;6:155160.
8. Caturegli P, De Remigis A, Rose NR. Hashimoto thyroiditis: clinical
and diagnostic criteria. Autoimmun Rev. 2014;13:391397.
9. 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.
10. Diekman T, Lansberg PJ, Kastelein JJ, Wiersinga WM. Prevalence
and correction of hypothyroidism in a large cohort of patients re-
ferred for dyslipidemia. Arch Intern Med. 1995;155:1490 1495.
11. Morris MS, Bostom AG, Jacques PF, Selhub J, Rosenberg IH. Hy-
perhomocysteinemia and hypercholesterolemia associated with hy-
pothyroidism in the third US National Health and Nutrition Exam-
ination Survey. Atherosclerosis. 2001;155:195200.
12. Shah JH, Motto GS, Papagiannes E, Williams GA. Insulin metab-
olism in hypothyroidism. Diabetes. 1975;24:922925.
13. Frostegrd J. Atherosclerosis in patients with autoimmune disor-
ders. Arterioscler Thromb Vasc Biol. 2005;25:1776 1785.
14. Roifman I, Beck PL, Anderson TJ, Eisenberg MJ, Genest J. Chronic
inflammatory diseases and cardiovascular risk: a systematic review.
Can J Cardiol. 2011;27:174 182.
15. Zller B, Li X, Sundquist J, Sundquist K. Risk of subsequent coro-
nary heart disease in patients hospitalized for immune-mediated
diseases: a nationwide follow-up study from Sweden. BMC Neurol.
2012;12:41.
16. Taddei S, Caraccio N, Virdis A, et al. Low-grade systemic inflam-
mation causes endothelial dysfunction in patients with Hashimotos
thyroiditis. J Clin Endocrinol Metab. 2006;91:5076 5082.
17. Xiang GD, He YS, Zhao LS, Hou J, Yue L, Xiang HJ. Impairment
of endothelium-dependent arterial dilation in Hashimotos thyroid-
itis patients with euthyroidism. Clin Endocrinol (Oxf). 2006;64:
698 702.
18. Oflaz H, Kurt R, Sen F, et al. Coronary flow reserve after L-thyroxine
therapy in Hashimotos thyroiditis patients with subclinical and
overt hypothyroidism. Endocrine. 2007;32:264 270.
19. Mariotti S, Zoncu S, Pigliaru F, et al. Cardiac effects of L-thyroxine
administration in borderline hypothyroidism. Int J Cardiol. 2008;
126:190 195.
20. Tagami T, Tamanaha T, Shimazu S, et al. Lipid profiles in the
untreated patients with Hashimoto thyroiditis and the effects of
thyroxine treatment on subclinical hypothyroidism with Hashimoto
thyroiditis. Endocr J. 2010;57:253258.
21. Flynn RW, Macdonald TM, Jung RT, Morris AD, Leese GP. Mor-
tality and vascular outcomes in patients treated for thyroid dysfunc-
tion. J Clin Endocrinol Metab. 2006;91:2159 2164.
22. Karch A, Thomas SL. Autoimmune thyroiditis as a risk factor for
stroke: a historical cohort study. Neurology. 2014;82:16431652.
23. Squizzato A, Gerdes VE. Comment: does L-thyroxine prevent or
cause stroke in hypothyroidism? Neurology. 2014;82:1650.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 05 July 2016. at 23:56 For personal use only. No other uses without permission. . All rights reserved.