Alopecia areata and overt thyroid diseases_ A nationwide

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ORIGINAL ARTICLE
Alopecia areata and overt thyroid diseases: A nationwide
population-based study
Tae Young HAN,1 June Hyunkyung LEE,1 Tai Kyung NOH,1 Min Wha CHOI,1
Jae-Seung YUN,2 Kyung Ho LEE,3 Jung Min BAE4
1Department of Dermatology, Eulji General Hospital, Eulji University, Seoul, 2Division of Endocrinology and Metabolism, Department
of Internal Medicine, St Vincent’s Hospital, 3Department of Dermatology, Bucheon St Mary’s Hospital, 4Department of Dermatology, St
Vincent’s Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
ABSTRACT
An association between alopecia areata (AA) and other autoimmune diseases has been reported. We investigated
the associations between AA and overt autoimmune thyroid diseases. A nationwide, population-based, cross-sec-
tional study was performed using the Korea National Health Insurance claims database. We defined patients with
AA as those whose records showed at least four physician contacts in which AA, alopecia totalis (AT) or alopecia
universalis (AU) was the principal diagnosis. We also established an age- and sex-matched control group without
AA. In a subgroup analysis, patients with AT or AU were classified into the severe AA group, and the remainder
were classified into the mild to moderate AA group. Patients with AA were at an increased risk of Graves’ disease
(odds ratio [OR], 1.415; 95% confidence interval [CI], 1.317–1.520) and Hashimoto thyroiditis (OR, 1.157; 95% CI,
1.081–1.237), and the associations were stronger in the severe AA group (Graves’ disease: OR, 1.714; 95% CI,
1.387–2.118; Hashimoto thyroiditis: OR, 1.398; 95% CI, 1.137–1.719). In conclusion, AA was significantly associated
with overt autoimmune thyroid diseases. Furthermore, the risk was much higher in the severe AA group.
Key words: alopecia areata, autoimmune disease, autoimmune thyroid disease, Graves’ disease, Hashimoto
thyroiditis.
INTRODUCTION
Alopecia areata (AA) is a common, inflammatory and non-scar-
ring form of hair loss that occurs on the scalp and other hair-
bearing skin. AA affects both sexes equally and patients of all
ages, and has a 2% lifetime incidence.1,2 The characteristic
patch of AA is usually round or oval, bald and smooth. Occa-
sionally, AA may progress to involve all scalp hairs (alopecia
totalis [AT]) or other body hairs beyond the scalp (alopecia uni-
versalis [AU]).3,4 AT and AU have long been viewed as highly
challenging conditions, with no treatment modalities guarantee-
ing a satisfactory response.
Although the etiopathogenesis of AA has not been com-
pletely established yet, an autoimmune nature of the disease
has been suspected with genetic predisposition.5 The hair folli-
cle is an inherently immune-privileged site with low expression
levels of major histocompatibility complex.6 It is assumed that
AA results from a breakdown in immune privilege and subse-
quent assault on the follicle by CD8+ T lymphocytes.7 A recent
study conclusively revealed a key role of a specific cytotoxic
T-cell subset, NKG2D+CD+ cytotoxic T cells, in the infiltration
and destruction of the upper part of the hair bulb, without
harming regenerative stem cells.7,8
The autoimmune etiology of AA has been also supported by
epidemiological studies of the association between AA and
several autoimmune diseases, including autoimmune thyroid
diseases, vitiligo, psoriasis, lupus erythematosus and perni-
cious anemia.9 Among them, the abnormal thyroid hormone
level and antithyroid autoantibodies have been frequently
reported in AA patients, and screening tests for thyroid dys-
function are sometimes recommended for patients with AA.10–13
However, the results of thyroid function tests often do not reflect
the actual thyroid disease status.
South Korea has one of the largest national health insurance
(NHI) systems in the world, and enrollment in the system is
mandated by law. The Korean NHI covers up to 98% of the
50 million people living in Korea, and the NHI claims database
has been used to provide reliable estimates of the prevalence
of certain diseases throughout the country.14,15 In this study,
we investigated the risk of overt thyroid disease in patients
with AA using the Korean NHI claims database to identify
associations applicable to the real world.
Correspondence: Kyung Ho Lee, M.D., Ph.D., Department of Dermatology, Bucheon St Mary’s Hospital, 327, Sosa-ro, Wonmi-gu, Bucheon
14647, Korea. Email: beauty4u@catholic.ac.kr and Jung Min Bae, M.D., Ph.D., Department of Dermatology, St Vincent’s Hospital, 93 Jungbu-
daero, Paldal-gu, Suwon 16247, Korea. Email: jminbae@gmail.com
Received 29 May 2018; accepted 12 August 2018.
1© 2018 Japanese Dermatological Association
doi: 10.1111/1346-8138.14648 Journal of Dermatology 2018; ��: 1–7
http://orcid.org/0000-0003-0317-9635
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METHODS
Study design and database
This nationwide, population-based, cross-sectional study
used the Korea NHI claims database, which records diag-
noses based on the International Classification of Disease,
Tenth Revision (ICD-10) and contains all claims information
from the NHI and Korean Medical Aid programs from 2009
until 2013.
Study population
To minimize misclassification, we defined patients with AA as
those who had at least four documented visits to physician
offices between 2009 and 2013, during which time AA (ICD-10
code L63), AT (L630) or AU (L631) was the principal diagnosis
(AA group). The control group initially consisted of all individu-
als who had undergone hemorrhoidectomy or appendectomy
and had not visited a physician with a diagnosis of AA during
the same period. Next, we randomly selected controls (two per
AA patient) after frequency matching for age and sex between
the AA and control groups.
Definition of overt and active thyroid disease
In this study, the outcomes of interest were concurrent
Graves’ disease, Hashimoto’s thyroiditis and thyroid cancer.
Patients with Graves’ disease were defined as those with
hyperthyroidism (E05, E050, E058 or E059) as the principal
diagnosis and who took antithyroid medications (methimazole,
propylthiouracil or carbimazole) for at least 60 days between
2009 and 2013. Patients with Hashimoto’s disease were
defined as those with thyroiditis (E063 or E069) as the princi-
pal diagnosis and who took thyroid hormone replacements
(levothyroxine sodium or liothyronine sodium) for at least
60 days between 2009 and 2013. Patients with thyroid cancer
were defined as those with at least four documented visits to
a physician’s office attributed to thyroid cancer (C73) during
the same period.
Subgroup analyses
Subgroup analyses were carried out by disease severity, sex
and age group (<20, 20–39, 40–59 and ≥60 years). The severe
AA group included patients with AT or AU, and the mild to
moderate AA group included patients with AA and excluded
patients with AT or AU.
Statistical analysis
Categorical variables are expressed as percentages and were
compared using the v2-test. Multivariable logistic regression
analyses were used to examine the associations between AA
and each thyroid disease after adjusting for age, sex and insur-
ance type. All data were analyzed using SAS version 9.4 soft-
ware (SAS Institute, Cary, NC, USA).
RESULTS
Characteristics of the patients with AA and control
subjects
A total of 248 370 patients with AA (127 557 females and
120 813 males) and 496 740 controls without AA were identi-
fied. Among the AA patients, 234 068 (94.2%) were included in
the mild to moderate AA group and 14 302 (5.8%) were in the
severe AA group (AT or AU). In both groups, the prevalence
was higher among the males. The peak age of incidence was
30–39 years (25.9%) in the mild to moderate AA group and
40–49 years in the severe AA group (23.6%)(Table 1).
Graves’ disease
The prevalence of overt Graves’ disease was 0.52% in
patients with AA and 0.37% in the control group (Table 2).
Table 1. Demographics of the study population
Healthy control AA patients
Mild to moderate
AA patients Severe AA patients
Total 496 740 (100%) 248 370 (100%) 234 068 (100%) 14 302 (100%)
Age group, years P = 1.000 P < 0.001
<10 10 800 (2.2%) 5400 (2.2%) 5145 (2.2%) 255 (1.8%)
10–19 39 950 (8.0%) 19 975 (8.0%) 18 802 (8.0%) 1173 (8.2%)
20–29 88 636 (17.8%) 44 318 (17.8%) 41 924 (17.9%) 2394 (16.7%)
30–39 127 758 (25.7%) 63 879 (25.7%) 60 521 (25.9%) 3358 (23.5%)
40–49 121 040 (24.4%) 60 520 (24.4%) 57 144 (24.4%) 3376 (23.6%)
50–59 75 358 (15.2%) 37 679 (15.2%) 35 239 (15.1%) 2440 (17.1%)
60–69 24 960 (5.0%) 12 480 (5.0%) 11 520 (4.9%) 960 (6.7%)
70–79 7138 (1.4%) 3569 (1.4%) 3267 (1.4%) 302 (2.1%)
≥80 1100 (0.2%) 550 (0.2%) 506 (0.2%) 44 (0.3%)
Sex P = 1.000 P < 0.001
Male 255 114 (51.4%) 127 557 (51.4%) 119 900 (51.2%) 7657 (53.5%)
Female 241 626 (48.6%) 120 813 (48.6%) 114 168 (48.8%) 6645 (46.5%)
Insurance type P < 0.001 P < 0.001
Health insurance 491 870 (99.0%) 241 803 (97.4%) 227 947 (97.4%) 13 856 (96.9%)
Medical aid 4870 (1.0%) 6567 (2.6%) 6121 (2.6%) 446 (3.1%)
AA, alopecia areata.
2 © 2018 Japanese Dermatological Association
T.Y. Han et al.
After adjusting for age, sex and insurance type, patients with
AA were at a significantly increased risk for Graves’ disease
(odds ratio [OR], 1.415; 95% confidence interval [CI], 1.317–
1.520).
In subgroup analysis by disease severity, the prevalence
was 0.51% in the mild to moderate AA group and 0.64% in the
severe AA group (Table 3, Fig. 1a). The risk of Graves’ disease
was higher in the severe AA group (OR, 1.714; 95% CI, 1.387–
2.118). In the subgroup analysis by sex and age, the associa-
tion between AA and Graves’ disease was stronger in females
(OR, 1.487; 95% CI, 1.364–1.622) than males (OR, 1.274; 95%
CI, 1.122–1.448). Graves’ disease had the strongest associa-
tion with AA among children and adolescents (aged <20 years:
OR, 1.779; 95% CI, 1.235–2.561).
Hashimoto’s thyroiditis
The prevalence of Hashimoto’s thyroiditis was 0.54% in
patients with AA and 0.47% in the control group (Table 2).
After adjusting for age and sex, the risk of Hashimoto’s thy-
roiditis was significantly increased in patients with AA (OR,
1.157; 95% CI, 1.081–1.237), and was higher in the severe AA
group (OR, 1.398; 95% CI, 1.137–1.719) (Table 4, Fig. 1b). The
association was also stronger in males (OR, 1.330; 95% CI,
1.074–1.647) than females (OR, 1.142; 95% CI, 1.063–1.226),
and was strongest in children and adolescents (aged
<20 years: OR, 3.436; 95% CI, 2.140–5.518).
Thyroid cancer
The prevalence of thyroid cancer in patients with AA was
0.81% versus 0.92% in the control group. No association
between AA and thyroid cancer was observed (Table 2).
DISCUSSION
There have been a series of studies on the associations
between AA and autoimmune thyroid diseases (Table 5); how-
ever, most of these were based on the presence of serum thy-
roid autoantibodies or on the results of thyroid function
tests,10–13,16–22 where the laboratory findings do not actually
index the disease state. Furthermore, results vary among stud-
ies. Positive thyroglobulin antibodies were found in 22–46% of
patients with AA and positive thyroid peroxidase antibodies
were found in 9–48% of patients with AA.11,12,17,19,22 Abnormal
thyroid function tests were found in 8.9–27% of patients with
Table 2. Associations between alopecia areata and each type of overt thyroid disease
Incidence rate
Univariable analysis Multivariable analysis
Crude OR (95% CI) P Adjusted OR (95% CI)† P
Graves’ disease
Healthy controls 0.37% (1815/496 740) Reference Reference
AA patients 0.52% (1291/248 370) 1.425 (1.326–1.530) <0.0001 1.415 (1.317–1.520) <0.0001
Hashimoto’s thyroiditis
Healthy controls 0.47% (2329/496 740) Reference Reference
AA patients 0.54% (1347/248 370) 1.158 (1.082–1.238) <0.0001 1.157 (1.081–1.237) <0.0001
Thyroid cancer
Healthy controls 0.82% (4059/496 740) Reference Reference
AA patients 0.81% (2010/248 370) 0.990 (0.939–1.045) 0.7223 0.998 (0.946–1.053) 0.8237
†Adjusted by age, sex and insurance type. AA, alopecia areata; CI, confidence interval; OR, odds ratio.
Table 3. Subgroup analysis of the association between alopecia areata and Graves’ disease
Incidence rate
Univariable analysis Multivariable analysis
Crude OR (95% CI) P Adjusted OR (95% CI)† P
Severity
Mild to moderate AA 0.51% (1200/234 068) 1.405 (1.306–1.512) <0.0001 1.395 (1.297–1.502) <0.0001
Severe AA 0.64% (91/14 302) 1.746 (1.414–2.157) <0.0001 1.714 (1.387–2.118) <0.0001
Sex
Male 0.30% (388/127 557) 1.281 (1.128–1.456) <0.0001 1.274 (1.122–1.448) <0.0001
Female 0.75% (903/120 813) 1.498 (1.373–1.633) <0.0001 1.487 (1.364–1.622) <0.0001
Age, years
<20 0.22% (55/25 375) 1.805 (1.253–2.600) 0.0013 1.779 (1.235–2.561) 0.0018
20–39 0.53% (576/108 197) 1.168 (1.045–1.305) 0.0063 1.157 (1.035–1.293) 0.0101
40–59 0.59% (579/98 199) 1.259 (1.134–1.397) <0.0001 1.240 (1.117–1.376) <0.0001
≥60 0.49% (81/16 599) 1.267 (0.959–1.674) 0.0956 1.288 (0.974–1.702) 0.1232
†Adjusted by age, sex and insurance type. AA, alopecia areata; CI, confidence interval; OR, odds ratio.
3© 2018 Japanese Dermatological Association
Alopecia areata and thyroid diseases
AA.11,12,18,20,22 The variability in these results is believed to
stem from the small sample sizes of the studies and from
methodological differences. Most of the studies used observa-
tional or case–control designs, included only dozens to hun-
dreds of patients with AA and were conducted in a single
institution.
In the present study, we demonstrated that patients with AA
(n = 248 370) were significantly more likely to have overt
Graves’ disease (OR, 1.415; 95% CI, 1.317–1.520) or Hashimo-
to’s thyroiditis (OR, 1.157; 95% CI, 1.081–1.237) than controls
without AA (n = 496,740). The prevalence rates of Graves’ dis-
ease and Hashimoto’s thyroiditis were 0.52% and 0.54% in
patients with AA, respectively, compared with 0.37% and
0.47% in age- and sex-matched controls without AA, respec-
tively. These rates were slightly lower than those of previous
reports; this is likely because we only identified patients
who were taking relevant thyroid medications. Unlike
autoimmune thyroid diseases, the prevalence rates of thy-
roid cancer were similar between the AA and control group,
and no significant association was observed between AA
and thyroid cancer.
Chu et al.9 performed a nationwide study on the comorbidity
profiles of patients with AA (n = 4334) in Taiwan. They showed
an increased risk of thyroid diseases in patients with AA;
Grave's disease
Male
Female
<20 year
20-39 year
40-59 year
≥60 year
Mild-to-moderate AA
Severe AA
Total
OR (95% CI)
1.274 (1.122–1.448)
1.487 (1.364–1.622)
1.779 (1.235–2.561)
1.620 (1.451–1.809)
1.240 (1.117–1.376)
1.288 (0.974–1.702)
1.395 (1.297–1.502)
1.714 (1.387–2.118)
1.415 (1.317–1.520)
Controls
606/255 114
1209/241 626
61/50 750
705/216 394
921/196 398
128/33 198
1815/496 740
1815/496 740
1815/496 740
Alopecia areata
388/127 557
903/120 813
55/25 375
576/108 197
579/98 199
81/16 599
1200/234 068
91/14 302
1291/248 370
0.050 0.500 5.0000.5 1 5
Hashimoto's thyroidi�s
Male
Female
<20 year
20-39 year
40-59 year
≥60 year
Mild-to-moderate AA
Severe AA
Total
OR (95% CI)
1.330 (1.074–1.647)
1.142 (1.063–1.226)
1.157 (1.035–1.293)
1.112 (1.014–1.220)
1.034 (0.814–1.313)
1.141 (1.064–1.222)
1.398 (1.137–1.719)
1.157 (1.081–1.237)
Controls
212/255 114
2117/241 626
27/50 750
845/216 394
1262/196 398
195/33 198
2329/496 740
2329/496 740
2329/496 740
Alopecia areata
140/127 557
1207/120 813
47/25 375
493/108 197
703/98 199
104/16 599
1252/234 068
95/14 302
1347/248 370
0.050
0.5 1 5
(a)
(b)
3.436 (2.140–5.518)
Figure 1. Forest plots of the associations between alopecia areata (AA) and overt thyroid diseases. (a)Graves’ disease. (b) Hashi-
moto’s thyroiditis. CI, confidence interval; OR, odds ratio.
Table 4. Subgroup analysis of the association between alopecia areata and Hashimoto’s thyroiditis
Incidence rate
Univariable analysis Multivariable analysis
Crude OR (95% CI) P Adjusted OR (95% CI)† P
Severity
Mild to moderate AA 0.53% (1252/234 068) 1.142 (1.066–1.223) 0.0002 1.141 (1.064–1.222) 0.0002
Severe AA 0.66% (95/14 302) 1.421 (1.157–1.746) 0.0008 1.398 (1.137–1.719) 0.0015
Sex
Male 0.11% (140/127 557) 1.321 (1.067–1.636) 0.0103 1.330 (1.074–1.647) 0.0095
Female 1.00% (1207/120 813) 1.142 (1.063–1.226) 0.0003 1.142 (1.063–1.226) 0.0003
Age, years
<20 0.19% (47/25 375) 3.486 (2.171–5.598) <0.0001 3.436 (2.140–5.518) <0.0001
20–39 0.46% (493/108 197) 1.637 (1.466–1.828) <0.0001 1.620 (1.451–1.809) <0.0001
40–59 0.72% (703/98 199) 1.115 (1.016–1.223) 0.0212 1.112 (1.014–1.220) 0.0268
≥60 0.63% (104/16 599) 1.067 (0.840–1.355) 0.5939 1.034 (0.814–1.313) 0.6717
†Adjusted by age, sex and insurance type. AA, alopecia areata; CI, confidence interval; OR, odds ratio.
4 © 2018 Japanese Dermatological Association
T.Y. Han et al.
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t.
5© 2018 Japanese Dermatological Association
Alopecia areata and thyroid diseases
however, they did not specify thyroid diseases. Moreover, they
defined the diagnosis only based on the ICD-10 disease codes
without considering drug use, and therefore the results do not
reflect the actual presence of thyroid disease.
Until now, no clear explanation has been offered for the sig-
nificant associations between AA and autoimmune thyroid dis-
eases. However, a genome-wide association study in patients
with AA revealed several risk loci in common with other
autoimmune diseases, in particular cytotoxic T-lymphocyte-
associated protein 1, interleukin (IL)-2/IL-21, IL-2RA and genes
critical to regulatory T-cell maintenance.23,24 Another Japanese
study suggested that specific human leukocyte antigen (HLA)
haplotypes contribute to autoimmunity against the thyroid gland
in AA.17,25 In addition to genetic aspects, the development of
AA could also have systemic effects on the thyroid gland.4
Although not currently substantiated in AA, the circulating
inflammatory cytokines may have the potential to cause damage
to other organs, as seen in other autoimmune diseases like pso-
riasis, systemic lupus erythematosus and rheumatoid arthri-
tis.4,26–28 Further research is needed to identify the underlying
shared pathogenesis between these two diseases.
In our study, the association between AA and autoimmune
thyroid diseases was stronger in the severe AA group. Bin
et al.10 reported that patients with a severe subtype of AA had
higher thyroid autoantibodies and serum thyroid-stimulating
hormone levels than did mild AA patients. We demonstrated
that patients with severe AA had a higher risk of autoimmune
thyroid diseases in the real world. We assumed that the pro-
nounced autoimmune inflammation present in patients with
severe AA may influence the thyroid gland. However, we did
not identify a causal relationship between AA and autoimmune
thyroid disease, and also do not know if the treatments for AA
and thyroid diseases interacted with each other.
In subgroup analysis, the children and adolescents group
(aged <20 years) showed the strongest association with
Graves’ disease (OR, 1.779; 95% CI, 1.235–2.561) and Hashi-
moto’s thyroiditis (OR, 3.463; 95% CI, 2.140–5.518), while
autoimmune thyroid diseases were more prevalent in the older-
aged group.29,30 We assumed that the genetic background of
patients with early onset AA could also contribute to autoim-
munity against the thyroid gland. Early onset of AA, for exam-
ple, marked by extensive hair loss and refractory disease, is
also considered to be a poor prognostic factor and seems to
indicate the underlying genetic background of AA.31 Subgroup
analysis by sex revealed that the associations between AA and
Graves’ disease were stronger in females. On the contrary, the
associations between AA and Hashimoto’s thyroiditis were
stronger in males, even though Hashimoto’s thyroiditis is not
common in male patients.
Our study had several limitations. First, information about
disease duration, disease onset, personal and family history,
and treatment modalities were not available from the NHI
claims database. However, using the detailed ICD-10 diagnos-
tic codes, we could specify autoimmune thyroid diseases and
perform association analysis according to the severity of AA.
Second, some diagnoses in the database may be incorrect. To
minimize this problem, we defined patients with AA as those
with at least four documented visits to a physician’s office in
relation to a principal diagnosis of AA, or as those who were
taking a thyroid medication for a certain type of thyroid dis-
ease. Third, the population included in this study was entirely
Korean and this homogeneity may limit the generalizability of
the results.
In conclusion, we demonstrated that the risk of overt
autoimmune thyroid diseases was significantly higherin AA
patients. Furthermore, the risk was much higher in the severe
AA group and in younger patients. Based on our results, we
recommend that AA patients with a severe disease subtype
and young age should be evaluated for thyroid function.
ACKNOWLEDGMENTS: This work was supported by the
National Research Foundation of Korea (NRF) grant funded by the
Korea government (MSIP; Ministry of Science, ICT &Future Planning)
(No. NRF-2017R1C1B5017825).
CONFLICT OF INTEREST: None declared.
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7© 2018 Japanese Dermatological Association
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