- Email: [email protected]
Women with alopecia exhibit a higher risk for thyroid cancer: A nationwide cohort study
Journal of Dermatological Science 74 (2014) 18–22
Contents lists available at ScienceDirect
Journal of Dermatological Science journal homepage: www.jdsjournal.com
Women with alopecia exhibit a higher risk for thyroid cancer: A nationwide cohort study Li-Min Sun a,1, Ming-Chia Lin b,1, Chih-Hsin Muo c, Ji-An Liang d,e, Fung-Chang Sung d, Chia-Hung Kao d,f,* a
Department of Radiation Oncology, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan Department of Nuclear Medicine, E-DA Hospital, Kaohsiung, Taiwan Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan d Graduate Institute of Clinical Medical Science, School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan e Department of Radiation Oncology, China Medical University Hospital, Taichung, Taiwan f Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 7 November 2013 Received in revised form 9 December 2013 Accepted 16 December 2013
Background: Several studies have investigated the relationship between alopecia and prostate cancer. However, little information is available regarding the relationship between alopecia and the risk of cancers in women. Objective: The purpose of this study was to evaluate the possible association between alopecia and thyroid cancer among Taiwanese women. Methods: We used data from the National Health Insurance system of Taiwan. The alopecia cohort comprised 4534 women, and each woman was randomly frequency matched by age, index month, and index year with 4 women from the general population without alopecia. A Cox proportional hazard regression analysis with Bonferroni correction was conducted to estimate the effects of alopecia on the risk of thyroid cancer. Results: In women with alopecia, the overall risk for developing cancer was 22% higher than for subjects without alopecia, but the difference was not significant [hazard ratio (HR) = 1.22, 97.5% confidence interval (97.5% CI) = 0.87–1.70]. However, the risk for developing thyroid cancer among women with alopecia was significantly higher (HR = 2.39, 97.5% CI = 1.05–5.42). Further analyses determined that the alopecia group had a higher incidence of Graves’ disease, but not Hashimoto thyroiditis. Conclusion: Although alopecia did not significantly increase cancer risks in women, we found that Taiwanese women with alopecia had a higher risk of developing thyroid cancer that is unlikely to be related to underlying thyroid diseases. ß 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
Keywords: Androgenic alopecia (AA) Thyroid cancer Population-based study National Health Insurance system
1. Introduction Androgenic alopecia (AA) is the most common cause of hair loss, followed by alopecia areata and telogen effluvium. AA affects nearly 50% of men [1,2]. In females, AA occurs much more frequently than is generally believed [3]. By contrast, approximately 2% of the general population develops alopecia areata [4]. AA is usually described as a genetically determined condition leading to the permanent loss of hair in men and women [5]. Japanese researchers have suggested that the Sox21 gene is a
* Corresponding author at: Graduate Institute of Clinical Medicine Science, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 40447, Taiwan. Tel.: +886 4 22052121x7412; fax: +886 4 22336174. E-mail addresses: [email protected], [email protected] (C.-H. Kao). 1 These authors contributed equally to this work.
master regulator of hair shaft cuticle differentiation, which provides evidence on the possible causes of human hair disorders [6]. It has been suggested that androgens play a central role in the pathophysiology of both prostate cancer and AA. A considerable amount of evidence supports the role of androgens in prostate cancer: Eunuchs rarely develop prostate cancer, castration has a palliative effect on prostate cancer, and testosterone alone can produce prostatic adenocarcinoma in rats [7,8]. Therefore, prostate cancer is typically considered a hormonally linked cancer. Likewise, eunuchs do not develop baldness if castrated before the age of 25 [9]. Several studies have investigated the relationship between AA and prostate cancer and have yielded inconsistent results [1,10–14]. Little information is available regarding the relationship between alopecia and the risk of hormone-related cancers in women. Thyroid cancer is thought to be a kind of hormone-related cancers [15]. Because hormones play an essential role in AA and alopecia was suggested to be related to certain
0923-1811/$36.00 ß 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jdermsci.2013.12.005
L.-M. Sun et al. / Journal of Dermatological Science 74 (2014) 18–22
19
Table 1 Demographics between study subjects with and without alopecia. p-Value
Alopecia No (N = 18,128)
Age, years <20 20–34 35–49 50–65 65 Mean (SD) Comorbidity Hypertension Diabetes
Yes (N = 4534)
n
%
n
%
3228 7548 5011 1857 484 32.9
17.8 41.6 27.6 10.2 2.67 (14.8)
807 1887 1253 465 122 32.8
17.8 41.6 27.6 10.3 2.69 (14.6)
>0.99
1435 590
7.92 3.25
380 176
8.38 3.88
0.94 0.30 0.04
Chi-square test and t-test.
thyroid diseases [16], we hypothesize that AA has an association with thyroid cancer in women. Based on a thorough review of relevant literature, there are no studies that outline the possible relationship between alopecia and the risk of cancer in women. This study investigates the risk of overall and thyroid cancers among women with alopecia in Taiwan. The results were generated from a retrospective cohort study of women with alopecia. The data was derived from the database of the National Health Insurance (NHI) system in Taiwan. 2. Methods This retrospective cohort study used the Longitudinal Health Insurance Database (LHID) and the Registry for Catastrophic Illness Patients. Those databases were formed by the Taiwan Bureau of National Health Insurance (TBNHI) and maintained by the National Health Research Institutes (NHRI). The TBNHI established a singlepayer NHI program on March 1, 1995 and this program covers over 99.5% of population in Taiwan [17]. The LHID comprised one million insurants randomly selected from the original beneficiaries in 2000 and included all medical records for insurants from 1996 to 2010. The NHRI scrambled the identification of the insurants in accordance with the Personal Information Protection Act before releasing the information to researchers. This study was provided the Institutional Review Board of the China Medical University and Hospital. Our research group has referenced the LHID in previous studies [18,19]. We collected information on women with diagnosed alopecia [The International Classification of Diseases, 9th Revision, clinical modification (ICD-9-CM) 704.0] from 2000 to 2010. We excluded those with any history of cancer (ICD-9-CM 140–208) and the duration of follow-up was <0.5 year. Controls were selected from women without a history of alopecia before the entry date. We randomly assigned the year and month to controls and the entry date was the middle of month. Four controls were randomly frequency matched with age (5 years stratified: for example 0–4, 5–9, 10–14 and so on.), entry month, and entry year. The excluded criteria were the same in the control and case groups. The demographic differences between the groups were analyzed using a chi-square test for the categorical variables of age group and comorbidity [including hypertension (ICD-9-CM 401405) and diabetes (ICD-9-CM 250)], and a t-test for the continuous variable of age. We counted the person-years from the entry date to the date of cancer occurrence, or until the end of 2010, and calculated the incidence per 10,000 person-years. The hazard ratio (HR) and 95% confidence intervals (CIs) for cancer were assessed using Cox proportional hazard regression and the multivariable model was adjusted for age and comorbidity. The risks for cancer
type assessed and the types were thyroid and others. According to Bonferroni correction, the significant level was set at 0.025 for multiple hypothesis testing. A Kaplan–Meier analysis was used to plot the cumulative incidence for cancer and a log-rank test was used to test the difference between the groups. In the further analysis, we estimated the risk levels for the subtypes of alopecia: unspecified, areata, and telogen effluvium. We also evaluated the effect of 2 thyroid autoimmune diseases (Graves’ disease and Hashimoto thyroiditis) on the relationship between alopecia and thyroid cancer. The NHRID encrypts the patients’ personal information for privacy protection and provides researchers with anonymous identification numbers associated with the relevant claim information, which includes the patient’s sex, date of birth, registry of medical services, and medication prescriptions. Patient consent is not required for accessing the NHIRD. This study was approved by the Institutional Review Board of China Medical University (CMUREC-101-012). Our IRB specifically waived the requirement for consent. 3. Results The case cohort comprised 4534 women with alopecia and the control cohort comprised 18,128 women. The majority of women were 20–34 years old (41.6%), and the mean age was 32.8 (standard deviation = 14.6). The case cohort was more likely to have a history of diabetes and hypertension than the control cohort, but only diabetes showed a significant difference (Table 1). After a nine-year follow-up, 59 and 192 events occurred in the case and control cohorts, respectively (Fig. 1A and Table 2). The incidences of overall cancer were 27.50 and 22.56 per 10,000 person-years for the alopecia and non-alopecia groups, respectively, and the HR was 1.22 (97.5% CI 0.87–1.70) compared with the control group. After analyzing the risk of subtypes of cancer, only thyroid cancer showed a significantly higher risk in the case cohort, with an HR of 2.39 (97.5% CI 1.05–5.42). Compared to controls, the women with unspecific alopecia had a significant 1.87-fold higher risk for thyroid cancer, but not for other cancers (Table 3). The cumulative incidence of thyroid cancer in the case cohort was significantly 0.3% higher than in the control cohort (log-rank P = .024, Fig. 1B). Women with alopecia had a significantly higher risk for Graves’ disease compared with women without alopecia (1.94% vs. 1.09%, P < .05), but the risk for Hashimoto thyroiditis was less and nonsignificant (0.26% vs. 0.33%). Because of the relatively small number of thyroid cancer cases in both groups of autoimmune diseases, the incidence rate does not reflect the statistical significance (Table 4). Table 5 illustrates that the positive
L.-M. Sun et al. / Journal of Dermatological Science 74 (2014) 18–22
20
Fig. 1. Cumulative incidence for alopecia and non-alopecia women in Kaplan–Meier model. (A) Overall cancer. (B) Thyroid cancer.
relationship between alopecia and thyroid cancer was limited to women younger than 50 years. 4. Discussion This nationwide cohort study discovered that patients with alopecia show a significantly higher risk of developing thyroid cancer. Further analyses showed that the significantly increased risk is limited to women younger than 50 years. The alopecia group showed a higher incidence of Graves’ disease but not Hashimoto
thyroiditis. Stratified analyses of these thyroid diseases did not reveal any significant difference in thyroid cancer between the alopecia and non-alopecia groups because of the relatively small number of cases in the subgroups. Alopecia is not uncommon in women. An earlier survey conducted on women in the United Kingdom found frontal and frontoparietal recessions in 13% of premenopausal and 37% of postmenopausal women [20]. A recent study revealed that the prevalence of alopecia in Taiwanese women 30 years and older was 11.8% (95% CI 11.5%–12.2%) and increased with advancing age [21]. Alopecia was suggested to be related to certain thyroid diseases [16]. Lo Sicco et al. performed a retrospective study to investigate thyroid structural abnormalities in alopecia patients and determined that 20.2% of alopecia patients had abnormal manual thyroid exams and 78.8% had an abnormal ultrasound finding [22]. The exact etiology of alopecia areata remains unclear, but evidence suggests that autoimmunity and endocrine dysfunction are involved [23,24]. A significant association between alopecia areata and thyroid autoimmunity has been reported in several studies [25,26]. Kurtev et al. diagnosed autoimmune thyroiditis in 22 of 46 children with alopecia areata [25]. Puavilai et al. determined that the prevalence of thyroid disease among patients with alopecia areata was 7.2% [27]. Our data revealed a significantly higher risk of thyroid cancer among women with alopecia. Fig. 1B illustrates that the difference in cumulative incidences of thyroid cancer between groups is consistent over time after a 2-year follow-up. We explored possible explanations for this result. Some autoimmune thyroid diseases have been suggested to be related to the development of thyroid cancer, although the precise mechanism of that relationship remains unclear [28–33]. Graves’ disease is the most prevalent autoimmune disorder in the United States [34] and is the underlying cause of 50%–80% of cases of hyperthyroidism [35]. Hyperthyroidism does not appear to protect patients from thyroid cancer [36], and a higher risk of thyroid cancer among patients with Graves’ disease has been reported in several studies [28–31]. A Taiwanese cohort study showed that patients with Graves’ disease had a significantly higher risk (adjusted HR = 10.4) of developing thyroid cancer [33]. By contrast, Hashimoto thyroiditis is also an autoimmune disease that causes the immune system to attack and destroy the thyroid gland [37]. An epidemiological association has been identified between Hashimoto thyroiditis and thyroid cancer [28,32,38–40], and the increased incidence of thyroid cancer in patients with Hashimoto thyroiditis suggests that it is a precancerous condition. Therefore, we hypothesized that the higher risk of thyroid cancer observed in our group of women with alopecia is partially attributable to the autoimmune thyroid diseases linked to both alopecia and thyroid cancer. However, our data did not support this assumption. The relatively small case numbers of Graves’ disease and Hashimoto thyroiditis in the study groups prevented us from detecting significant findings. The same concern applies for alopecia areata; because of the relatively small number of cases, statistically significant results were not expected.
Table 2 Adjusted hazard ratio and 97.5% confidence interval of cancer by alopecia in different cancers. Cancer type (ICD-9-CM)
Overall Thyroid cancer (193) Others IR, incidence rate, per 10,000 person-years. Adjusted for age and diabetes. * p < 0.025.
Non-alopecia
Alopecia
HR (97.5% CI)
Event no.
IR
Event no.
IR
192 20 172
22.56 2.35 20.21
59 12 47
27.50 5.59 21.91
1.22 (0.87–1.70) 2.39 (1.05–5.42)* 1.08 (0.75–1.57)
L.-M. Sun et al. / Journal of Dermatological Science 74 (2014) 18–22
21
Table 3 Adjusted hazard ratio and 97.5% confidence interval of cancers among women with different kinds of alopecia. Alopecia type All cancer Non-alopecia Alopecia, unspecified Alopecia areata Telogen effluvim Thyroid cancer Non-alopecia Alopecia, unspecified Alopecia areata Telogen effluvim
N
Event no.
IR
HR (97.5% CI)
18,128 2609 1909 16
192 33 26 0
22.56 27.38 27.78 0.00
1.00 1.22 (0.80–1.86) 1.22 (0.77–1.96) –
18,128 2609 1909 16
20 8 4 0
2.35 6.64 4.27 0.00
1.00 2.87 (1.12–7.33)* 1.80 (0.53–6.14) –
IR, incidence rate, per 10,000 person-years. Adjusted for age and diabetes. * p < 0.025.
Table 4 Autoimmune disease of thyroid in women study subjects. Autoimmune immune disease of thyroid
Graves’ disease+ No Yes Hashimoto’s thyroiditis No Yes
Non-alopecia (N = 18,128)
Alopecia (N = 4534)
n (%)
Thyroid cancer no.
19,730 (98.9) 198 (1.09)
20 0
18,069 (99.7) 59 (0.33)
18 2
IR
n (%)
Thyroid cancer no.
IR
2.37 0.00
4446 (98.1) 88 (1.94)
11 1
5.21 30.03
2.12 93.70
4522 (99.7) 12 (0.26)
12 0
5.60 0.00
IR, incidence rate for thyroid cancer, per 10,000 person-years. + Chi-square test p < 0.05.
Table 5 The risk of cancer compared to study subjects without alopecia stratified by age in Cox proportional hazard regression. Age, year
All cancer <50 50 Thyroid cancer <50 50
Non-alopecia
Alopecia
HR (97.5% CI)
Event no.
IR
Event no.
IR
120 72
1.61 6.89
39 20
2.07 7.63
1.27 (0.84–1.92) 1.09 (0.62–1.92)
17 3
2.28 2.87
11 1
5.84 3.82
2.54 (1.07–6.05)* 1.37 (0.10–18.2)
IR, incidence rate, per 10,000 person-years. Model adjusted for age and diabetes. * p < 0.025.
Our data showed that only women with alopecia who were younger than 50 years had a significantly higher risk for thyroid cancer. Again, the small number of cases of with alopecia who were 50 years and older hindered the possibly of significant association. Nevertheless, the prognosis of thyroid cancer is highly dependent on the age of the patient [41], and the significantly higher risk for younger women with alopecia should prompt public health authorities to perform extensive screenings of these patients to detect lesions as soon as possible. The strength of this study was its population-based design, which increased the generalizability of the results. However, some limitations must be addressed. First, potential misclassification of alopecia is a large concern with insurance-database-based research. Taiwan launched the NHI program in 1995, and it is operated by a single-payer, the government. All insurance claims should be scrutinized by medical reimbursement specialists and peer review. Therefore, the final diagnoses and coding of alopecia must be checked by at least 2 experienced dermatologists in the NHRID. In addition, several Taiwan studies had demonstrated the high accuracy and validity of diseases diagnoses in NHIRD [42,43]. The diagnoses of alopecia and cancer are based on highly reliable database and the concern of misclassification can be minimized.
Second, the diagnosis code in the NHIRD did not specify AA; thus, we cannot precisely evaluate its effect on the risk of cancer. Instead, we used unspecified alopecia to assess patients. The number of cases of unspecified alopecia was not sufficiently large to cover all the cases of AA. Third, the NHIRD does not provide information regarding cancer histology, and certain types of histological thyroid cancer are more commonly seen in thyroid autoimmune diseases [30,31,39,40]. However, we could not evaluate this because of the intrinsic limitations of the database. In conclusion, this population-based retrospective cohort study found a significantly increased risk of thyroid cancer in Taiwanese women with alopecia compared with the general population, especially in younger women. Although the underlying mechanisms remain unclear and our results must be verified in further investigations, the findings from this study should prompt the TBNHI to reconsider its policy regarding follow-up and cancer screenings in younger women with alopecia. Author contributions All authors have contributed significantly, and that all authors are in agreement with the content of the manuscript:
22
L.-M. Sun et al. / Journal of Dermatological Science 74 (2014) 18–22
Conception/Design: Li-Min Sun, Yu-Shu Yen, Chia-Hung Kao; Provision of study materials: Ji-An Liang, Fung-Chang Sung; Collection and/or assembly of data: Li-Min Sun, Ming-Chia Lin, Chia-Hung Kao; Data analysis and interpretation: Li-Min Sun, Ming-Chia Lin, Chih-Hsin Muo, Chia-Hung Kao; Manuscript writing: All authors; Final approval of manuscript: All authors. Acknowledgments This work was supported by the study projects (DMR-101-060 and DMR-102-023) in our hospital; Taiwan Department of Health Clinical Trial and Research Center and for Excellence (DOH102TD-B-111-004), Taiwan Department of Health Cancer Research Center for Excellence (DOH102-TD-C-111-005); and International Research-Intensive Centers of Excellence in Taiwan (I-RiCE) (NSC101-2911-I-002-303). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. References [1] Yassa M, Saliou M, De Rycke Y, Hemery C, Henni M, Bachaud JM, et al. Male pattern baldness and the risk of prostate cancer. Ann Oncol 2011;22: 1824–7. [2] Hawk E, Breslow RA, Graubard BI. Male pattern baldness and clinical prostate cancer in the epidemiologic follow-up of the first National Health and Nutrition Examination Survey. Cancer Epidemiol Biomarkers Prev 2000;9:523–7. [3] Ludwig E. Classification of the types of androgenetic alopecia (common baldness) occurring in the female sex. Br J Dermatol 1977;97:247–54. [4] Sehgal VN, Jain S. Alopecia areata: clinical perspective and an insight into pathogenesis. J Dermatol 2003;30:271–89. [5] Faydaci G, Bilal E, Necmettin P, Fatih T, Asuman O, Ugur K. Baldness, benign prostate hyperplasia, prostate cancer and androgen levels. Aging Male 2008;11:189–92. [6] Kiso M, Tanaka S, Saba R, Matsuda S, Shimizu A, Ohyama M, et al. The disruption of Sox21-mediated hair shaft cuticle differentiation causes cyclic alopecia in mice. Proc Natl Acad Sci U S A 2009;106:9292–7. [7] Demark-Wahnefried W, Schildkraut JM, Thompson D, Lesko SM, McIntyre L, Schwingl P, et al. Early onset baldness and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 2000;9:325–8. [8] Isaacs JT. Role of androgens in prostatic cancer. Vitam Horm 1994;49:433–504. [9] Randall VA. Androgens and human hair growth. Clin Endocrinol 1994;40:439–57. [10] Muller DC, Giles GG, Sinclair R, Hopper JL, English DR, Severi G. Age-dependent associations between androgenetic alopecia and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 2013;22:209–15. [11] Thomas JA, Antonelli JA, Banez LL, Hoyo C, Grant D, Demark-Wahnefried W, et al. Androgenetic alopecia at various ages and prostate cancer risk in an equal-access multiethnic case-control series of veterans. Cancer Causes Control 2013;24:1045–52. [12] Amoretti A, Laydner H, Bergfeld W. Androgenetic alopecia and risk of prostate cancer: a systematic review and meta-analysis. J Am Acad Dermatol 2013;68:937–43. [13] Cremers RG, Aben KK, Vermeulen SH, den Heijer M, van Oort IM, Kiemeney LA. Androgenic alopecia is not useful as an indicator of men at high risk of prostate cancer. Eur J Cancer 2010;46:3294–9. [14] Wright JL, Page ST, Lin DW, Stanford JL. Male pattern baldness and prostate cancer risk in a population-based case-control study. Cancer Epidemiol 2010;34:131–5. [15] Henderson BE, Feigelson HS. Hormonal carcinogenesis. Carcinogenesis 2000;21:427–33. [16] Artantas¸ S, Gu¨l U, Kilic¸ A, Gu¨ler S. Skin findings in thyroid diseases. Eur J Intern Med 2009;20:158–61.
[17] Cheng TM. Taiwan’s National Health Insurance system: high value for the dollar. In: Okma KGH, Crivelli L, editors. Six Countries, Six Reform Models: The Health Reform Experience of Israel, the Netherlands, New Zealand, Singapore, Switzerland and Taiwan. New Jersey: World Scientific; 2009. p. 71–204. [18] Kao GH, Sun LM, Chen PC, Lin MC, Liang JA, Muo CH, et al. A population-based cohort study in Taiwan – use of insulin sensitizers can decrease cancer risk in diabetic patients? Ann Oncol 2013;24:523–30. [19] Sun LM, Lin CL, Liang JA, Liu SH, Sung FC, Chang YJ, et al. Urinary tract infection increases subsequent urinary tract cancer risk: a population-based cohort study. Cancer Sci 2013;104:619–23. [20] Venning VA, Dawber RP. Patterned androgenic alopecia in women. J Am Acad Dermatol 1988;18:1073–7. [21] Su LH, Chen LS, Chen HH. Factors associated with female pattern hair loss and its prevalence in Taiwanese women: a community-based survey. J Am Acad Dermatol 2013;69:e69–77. [22] Lo Sicco K, McGuire S, English III JC. A retrospective study of thyroid structural abnormalities in alopecia patients. Dermatoendocrinology 2011;3:251–4. [23] Alkhalifah A. Alopecia areata update. Dermatol Clin 2013;31:93–108. [24] Hordinsky M, Ericson M. Autoimmunity: alopecia areata. J Investig Dermatol Symp Proc 2004;9:73–8. [25] Kurtev A, Iliev E. Thyroid autoimmunity in children and adolescents with alopecia areata. Int J Dermatol 2005;44:457–61. [26] Kasumagic´-Halilovic´ E. Thyroid autoimmunity in patients with alopecia areata. Acta Dermatovenerol Croat 2008;16:123–5. [27] Puavilai S, Puavilai G, Charuwichitratana S, Sakuntabhai A, Sriprachya-Anunt S. Prevalence of thyroid diseases in patients with alopecia areata. Int J Dermatol 1994;33:632–3. [28] Franks AL, Slansky JE. Multiple associations between a broad spectrum of autoimmune diseases, chronic inflammatory diseases and cancer. Anticancer Res 2012;32:1119–36. [29] Shu X, Ji J, Li X, Sundquist J, Sundquist K, Hemminki K. Cancer risk in patients hospitalised for Graves’ disease: a population-based cohort study in Sweden. Br J Cancer 2010;102:1397–9. [30] Majima T, Komatsu Y, Doi K, Shigemoto M, Takagi C, Fukao A, et al. Anaplastic thyroid carcinoma associated with Graves’ disease. Endocr J 2005;52:551–7. [31] Belfiore A, Garofalo MR, Giuffrida D, Runello F, Filetti S, Fiumara A, et al. Increased aggressiveness of thyroid cancer in patients with Graves’ disease. J Clin Endocrinol Metab 1990;70:830–5. [32] Ott RA, McCall AR, Jarosz H, Armin A, Lawrence AM, Paloyan E. The incidence of thyroid carcinoma in Hashimoto’s thyroiditis. Am Surg 1987;53:442–5. [33] Chen YK, Lin CL, Chang YJ, Cheng FT, Peng CL, Sung FC, et al. Cancer risk in patients with Graves’ disease: a nationwide cohort study. Thyroid 2013;237:879–84. [34] Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 1997;84:223–43. [35] Cooper DS. Hyperthyroidism. Lancet 2003;362:459–68. [36] Pazaitou-Panayiotou K, Perros P, Boudina M, Siardos G, Drimonitis A, Patakiouta F, et al. Mortality from thyroid cancer in patients with hyperthyroidism: the Theagenion Cancer Hospital experience. Eur J Endocrinol 2008;159: 799–803. [37] Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. N Engl J Med 1996;335:99–107. [38] Segal K, Ben-Bassat M, Avraham A, Har-El G, Sidi J. Hashimoto’s thyroiditis and carcinoma of the thyroid gland. Int Surg 1985;70:205–9. [39] Kim KW, Park YJ, Kim EH, Park SY, Park DJ, Ahn SH, et al. Elevated risk of papillary thyroid cancer in Korean patients with Hashimoto’s thyroiditis. Head Neck 2011;33:691–5. [40] Lun Y, Wu X, Xia Q, Han Y, Zhang X, Liu Z, et al. Hashimoto’s thyroiditis as a risk factor of papillary thyroid cancer may improve cancer prognosis. Otolaryngol Head Neck Surg 2013;148:396–402. [41] Crile Jr G, Hazard JB. Relationship of the age of the patient to the natural history and prognosis of carcinoma of the thyroid. Ann Surg 1953;138:33–8. [42] Cheng CL, Kao YH, Lin SJ, Lee CH, Lai ML. Validation of the National Health Insurance Research Database with ischemic stroke cases in Taiwan. Pharmacoepidemiol Drug Saf 2011;20:236–42. [43] Yu YB, Gau JP, Liu CY, Yang MH, Chiang SC, Hsu HC, et al. A nation-wide analysis of venous thromboembolism in 497,180 cancer patients with the development and validation of a risk-stratification scoring system. Thromb Haemost 2012;108:225–35.
Contents lists available at ScienceDirect
Journal of Dermatological Science journal homepage: www.jdsjournal.com
Women with alopecia exhibit a higher risk for thyroid cancer: A nationwide cohort study Li-Min Sun a,1, Ming-Chia Lin b,1, Chih-Hsin Muo c, Ji-An Liang d,e, Fung-Chang Sung d, Chia-Hung Kao d,f,* a
Department of Radiation Oncology, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan Department of Nuclear Medicine, E-DA Hospital, Kaohsiung, Taiwan Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan d Graduate Institute of Clinical Medical Science, School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan e Department of Radiation Oncology, China Medical University Hospital, Taichung, Taiwan f Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 7 November 2013 Received in revised form 9 December 2013 Accepted 16 December 2013
Background: Several studies have investigated the relationship between alopecia and prostate cancer. However, little information is available regarding the relationship between alopecia and the risk of cancers in women. Objective: The purpose of this study was to evaluate the possible association between alopecia and thyroid cancer among Taiwanese women. Methods: We used data from the National Health Insurance system of Taiwan. The alopecia cohort comprised 4534 women, and each woman was randomly frequency matched by age, index month, and index year with 4 women from the general population without alopecia. A Cox proportional hazard regression analysis with Bonferroni correction was conducted to estimate the effects of alopecia on the risk of thyroid cancer. Results: In women with alopecia, the overall risk for developing cancer was 22% higher than for subjects without alopecia, but the difference was not significant [hazard ratio (HR) = 1.22, 97.5% confidence interval (97.5% CI) = 0.87–1.70]. However, the risk for developing thyroid cancer among women with alopecia was significantly higher (HR = 2.39, 97.5% CI = 1.05–5.42). Further analyses determined that the alopecia group had a higher incidence of Graves’ disease, but not Hashimoto thyroiditis. Conclusion: Although alopecia did not significantly increase cancer risks in women, we found that Taiwanese women with alopecia had a higher risk of developing thyroid cancer that is unlikely to be related to underlying thyroid diseases. ß 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.
Keywords: Androgenic alopecia (AA) Thyroid cancer Population-based study National Health Insurance system
1. Introduction Androgenic alopecia (AA) is the most common cause of hair loss, followed by alopecia areata and telogen effluvium. AA affects nearly 50% of men [1,2]. In females, AA occurs much more frequently than is generally believed [3]. By contrast, approximately 2% of the general population develops alopecia areata [4]. AA is usually described as a genetically determined condition leading to the permanent loss of hair in men and women [5]. Japanese researchers have suggested that the Sox21 gene is a
* Corresponding author at: Graduate Institute of Clinical Medicine Science, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 40447, Taiwan. Tel.: +886 4 22052121x7412; fax: +886 4 22336174. E-mail addresses: [email protected], [email protected] (C.-H. Kao). 1 These authors contributed equally to this work.
master regulator of hair shaft cuticle differentiation, which provides evidence on the possible causes of human hair disorders [6]. It has been suggested that androgens play a central role in the pathophysiology of both prostate cancer and AA. A considerable amount of evidence supports the role of androgens in prostate cancer: Eunuchs rarely develop prostate cancer, castration has a palliative effect on prostate cancer, and testosterone alone can produce prostatic adenocarcinoma in rats [7,8]. Therefore, prostate cancer is typically considered a hormonally linked cancer. Likewise, eunuchs do not develop baldness if castrated before the age of 25 [9]. Several studies have investigated the relationship between AA and prostate cancer and have yielded inconsistent results [1,10–14]. Little information is available regarding the relationship between alopecia and the risk of hormone-related cancers in women. Thyroid cancer is thought to be a kind of hormone-related cancers [15]. Because hormones play an essential role in AA and alopecia was suggested to be related to certain
0923-1811/$36.00 ß 2013 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jdermsci.2013.12.005
L.-M. Sun et al. / Journal of Dermatological Science 74 (2014) 18–22
19
Table 1 Demographics between study subjects with and without alopecia. p-Value
Alopecia No (N = 18,128)
Age, years <20 20–34 35–49 50–65 65 Mean (SD) Comorbidity Hypertension Diabetes
Yes (N = 4534)
n
%
n
%
3228 7548 5011 1857 484 32.9
17.8 41.6 27.6 10.2 2.67 (14.8)
807 1887 1253 465 122 32.8
17.8 41.6 27.6 10.3 2.69 (14.6)
>0.99
1435 590
7.92 3.25
380 176
8.38 3.88
0.94 0.30 0.04
Chi-square test and t-test.
thyroid diseases [16], we hypothesize that AA has an association with thyroid cancer in women. Based on a thorough review of relevant literature, there are no studies that outline the possible relationship between alopecia and the risk of cancer in women. This study investigates the risk of overall and thyroid cancers among women with alopecia in Taiwan. The results were generated from a retrospective cohort study of women with alopecia. The data was derived from the database of the National Health Insurance (NHI) system in Taiwan. 2. Methods This retrospective cohort study used the Longitudinal Health Insurance Database (LHID) and the Registry for Catastrophic Illness Patients. Those databases were formed by the Taiwan Bureau of National Health Insurance (TBNHI) and maintained by the National Health Research Institutes (NHRI). The TBNHI established a singlepayer NHI program on March 1, 1995 and this program covers over 99.5% of population in Taiwan [17]. The LHID comprised one million insurants randomly selected from the original beneficiaries in 2000 and included all medical records for insurants from 1996 to 2010. The NHRI scrambled the identification of the insurants in accordance with the Personal Information Protection Act before releasing the information to researchers. This study was provided the Institutional Review Board of the China Medical University and Hospital. Our research group has referenced the LHID in previous studies [18,19]. We collected information on women with diagnosed alopecia [The International Classification of Diseases, 9th Revision, clinical modification (ICD-9-CM) 704.0] from 2000 to 2010. We excluded those with any history of cancer (ICD-9-CM 140–208) and the duration of follow-up was <0.5 year. Controls were selected from women without a history of alopecia before the entry date. We randomly assigned the year and month to controls and the entry date was the middle of month. Four controls were randomly frequency matched with age (5 years stratified: for example 0–4, 5–9, 10–14 and so on.), entry month, and entry year. The excluded criteria were the same in the control and case groups. The demographic differences between the groups were analyzed using a chi-square test for the categorical variables of age group and comorbidity [including hypertension (ICD-9-CM 401405) and diabetes (ICD-9-CM 250)], and a t-test for the continuous variable of age. We counted the person-years from the entry date to the date of cancer occurrence, or until the end of 2010, and calculated the incidence per 10,000 person-years. The hazard ratio (HR) and 95% confidence intervals (CIs) for cancer were assessed using Cox proportional hazard regression and the multivariable model was adjusted for age and comorbidity. The risks for cancer
type assessed and the types were thyroid and others. According to Bonferroni correction, the significant level was set at 0.025 for multiple hypothesis testing. A Kaplan–Meier analysis was used to plot the cumulative incidence for cancer and a log-rank test was used to test the difference between the groups. In the further analysis, we estimated the risk levels for the subtypes of alopecia: unspecified, areata, and telogen effluvium. We also evaluated the effect of 2 thyroid autoimmune diseases (Graves’ disease and Hashimoto thyroiditis) on the relationship between alopecia and thyroid cancer. The NHRID encrypts the patients’ personal information for privacy protection and provides researchers with anonymous identification numbers associated with the relevant claim information, which includes the patient’s sex, date of birth, registry of medical services, and medication prescriptions. Patient consent is not required for accessing the NHIRD. This study was approved by the Institutional Review Board of China Medical University (CMUREC-101-012). Our IRB specifically waived the requirement for consent. 3. Results The case cohort comprised 4534 women with alopecia and the control cohort comprised 18,128 women. The majority of women were 20–34 years old (41.6%), and the mean age was 32.8 (standard deviation = 14.6). The case cohort was more likely to have a history of diabetes and hypertension than the control cohort, but only diabetes showed a significant difference (Table 1). After a nine-year follow-up, 59 and 192 events occurred in the case and control cohorts, respectively (Fig. 1A and Table 2). The incidences of overall cancer were 27.50 and 22.56 per 10,000 person-years for the alopecia and non-alopecia groups, respectively, and the HR was 1.22 (97.5% CI 0.87–1.70) compared with the control group. After analyzing the risk of subtypes of cancer, only thyroid cancer showed a significantly higher risk in the case cohort, with an HR of 2.39 (97.5% CI 1.05–5.42). Compared to controls, the women with unspecific alopecia had a significant 1.87-fold higher risk for thyroid cancer, but not for other cancers (Table 3). The cumulative incidence of thyroid cancer in the case cohort was significantly 0.3% higher than in the control cohort (log-rank P = .024, Fig. 1B). Women with alopecia had a significantly higher risk for Graves’ disease compared with women without alopecia (1.94% vs. 1.09%, P < .05), but the risk for Hashimoto thyroiditis was less and nonsignificant (0.26% vs. 0.33%). Because of the relatively small number of thyroid cancer cases in both groups of autoimmune diseases, the incidence rate does not reflect the statistical significance (Table 4). Table 5 illustrates that the positive
L.-M. Sun et al. / Journal of Dermatological Science 74 (2014) 18–22
20
Fig. 1. Cumulative incidence for alopecia and non-alopecia women in Kaplan–Meier model. (A) Overall cancer. (B) Thyroid cancer.
relationship between alopecia and thyroid cancer was limited to women younger than 50 years. 4. Discussion This nationwide cohort study discovered that patients with alopecia show a significantly higher risk of developing thyroid cancer. Further analyses showed that the significantly increased risk is limited to women younger than 50 years. The alopecia group showed a higher incidence of Graves’ disease but not Hashimoto
thyroiditis. Stratified analyses of these thyroid diseases did not reveal any significant difference in thyroid cancer between the alopecia and non-alopecia groups because of the relatively small number of cases in the subgroups. Alopecia is not uncommon in women. An earlier survey conducted on women in the United Kingdom found frontal and frontoparietal recessions in 13% of premenopausal and 37% of postmenopausal women [20]. A recent study revealed that the prevalence of alopecia in Taiwanese women 30 years and older was 11.8% (95% CI 11.5%–12.2%) and increased with advancing age [21]. Alopecia was suggested to be related to certain thyroid diseases [16]. Lo Sicco et al. performed a retrospective study to investigate thyroid structural abnormalities in alopecia patients and determined that 20.2% of alopecia patients had abnormal manual thyroid exams and 78.8% had an abnormal ultrasound finding [22]. The exact etiology of alopecia areata remains unclear, but evidence suggests that autoimmunity and endocrine dysfunction are involved [23,24]. A significant association between alopecia areata and thyroid autoimmunity has been reported in several studies [25,26]. Kurtev et al. diagnosed autoimmune thyroiditis in 22 of 46 children with alopecia areata [25]. Puavilai et al. determined that the prevalence of thyroid disease among patients with alopecia areata was 7.2% [27]. Our data revealed a significantly higher risk of thyroid cancer among women with alopecia. Fig. 1B illustrates that the difference in cumulative incidences of thyroid cancer between groups is consistent over time after a 2-year follow-up. We explored possible explanations for this result. Some autoimmune thyroid diseases have been suggested to be related to the development of thyroid cancer, although the precise mechanism of that relationship remains unclear [28–33]. Graves’ disease is the most prevalent autoimmune disorder in the United States [34] and is the underlying cause of 50%–80% of cases of hyperthyroidism [35]. Hyperthyroidism does not appear to protect patients from thyroid cancer [36], and a higher risk of thyroid cancer among patients with Graves’ disease has been reported in several studies [28–31]. A Taiwanese cohort study showed that patients with Graves’ disease had a significantly higher risk (adjusted HR = 10.4) of developing thyroid cancer [33]. By contrast, Hashimoto thyroiditis is also an autoimmune disease that causes the immune system to attack and destroy the thyroid gland [37]. An epidemiological association has been identified between Hashimoto thyroiditis and thyroid cancer [28,32,38–40], and the increased incidence of thyroid cancer in patients with Hashimoto thyroiditis suggests that it is a precancerous condition. Therefore, we hypothesized that the higher risk of thyroid cancer observed in our group of women with alopecia is partially attributable to the autoimmune thyroid diseases linked to both alopecia and thyroid cancer. However, our data did not support this assumption. The relatively small case numbers of Graves’ disease and Hashimoto thyroiditis in the study groups prevented us from detecting significant findings. The same concern applies for alopecia areata; because of the relatively small number of cases, statistically significant results were not expected.
Table 2 Adjusted hazard ratio and 97.5% confidence interval of cancer by alopecia in different cancers. Cancer type (ICD-9-CM)
Overall Thyroid cancer (193) Others IR, incidence rate, per 10,000 person-years. Adjusted for age and diabetes. * p < 0.025.
Non-alopecia
Alopecia
HR (97.5% CI)
Event no.
IR
Event no.
IR
192 20 172
22.56 2.35 20.21
59 12 47
27.50 5.59 21.91
1.22 (0.87–1.70) 2.39 (1.05–5.42)* 1.08 (0.75–1.57)
L.-M. Sun et al. / Journal of Dermatological Science 74 (2014) 18–22
21
Table 3 Adjusted hazard ratio and 97.5% confidence interval of cancers among women with different kinds of alopecia. Alopecia type All cancer Non-alopecia Alopecia, unspecified Alopecia areata Telogen effluvim Thyroid cancer Non-alopecia Alopecia, unspecified Alopecia areata Telogen effluvim
N
Event no.
IR
HR (97.5% CI)
18,128 2609 1909 16
192 33 26 0
22.56 27.38 27.78 0.00
1.00 1.22 (0.80–1.86) 1.22 (0.77–1.96) –
18,128 2609 1909 16
20 8 4 0
2.35 6.64 4.27 0.00
1.00 2.87 (1.12–7.33)* 1.80 (0.53–6.14) –
IR, incidence rate, per 10,000 person-years. Adjusted for age and diabetes. * p < 0.025.
Table 4 Autoimmune disease of thyroid in women study subjects. Autoimmune immune disease of thyroid
Graves’ disease+ No Yes Hashimoto’s thyroiditis No Yes
Non-alopecia (N = 18,128)
Alopecia (N = 4534)
n (%)
Thyroid cancer no.
19,730 (98.9) 198 (1.09)
20 0
18,069 (99.7) 59 (0.33)
18 2
IR
n (%)
Thyroid cancer no.
IR
2.37 0.00
4446 (98.1) 88 (1.94)
11 1
5.21 30.03
2.12 93.70
4522 (99.7) 12 (0.26)
12 0
5.60 0.00
IR, incidence rate for thyroid cancer, per 10,000 person-years. + Chi-square test p < 0.05.
Table 5 The risk of cancer compared to study subjects without alopecia stratified by age in Cox proportional hazard regression. Age, year
All cancer <50 50 Thyroid cancer <50 50
Non-alopecia
Alopecia
HR (97.5% CI)
Event no.
IR
Event no.
IR
120 72
1.61 6.89
39 20
2.07 7.63
1.27 (0.84–1.92) 1.09 (0.62–1.92)
17 3
2.28 2.87
11 1
5.84 3.82
2.54 (1.07–6.05)* 1.37 (0.10–18.2)
IR, incidence rate, per 10,000 person-years. Model adjusted for age and diabetes. * p < 0.025.
Our data showed that only women with alopecia who were younger than 50 years had a significantly higher risk for thyroid cancer. Again, the small number of cases of with alopecia who were 50 years and older hindered the possibly of significant association. Nevertheless, the prognosis of thyroid cancer is highly dependent on the age of the patient [41], and the significantly higher risk for younger women with alopecia should prompt public health authorities to perform extensive screenings of these patients to detect lesions as soon as possible. The strength of this study was its population-based design, which increased the generalizability of the results. However, some limitations must be addressed. First, potential misclassification of alopecia is a large concern with insurance-database-based research. Taiwan launched the NHI program in 1995, and it is operated by a single-payer, the government. All insurance claims should be scrutinized by medical reimbursement specialists and peer review. Therefore, the final diagnoses and coding of alopecia must be checked by at least 2 experienced dermatologists in the NHRID. In addition, several Taiwan studies had demonstrated the high accuracy and validity of diseases diagnoses in NHIRD [42,43]. The diagnoses of alopecia and cancer are based on highly reliable database and the concern of misclassification can be minimized.
Second, the diagnosis code in the NHIRD did not specify AA; thus, we cannot precisely evaluate its effect on the risk of cancer. Instead, we used unspecified alopecia to assess patients. The number of cases of unspecified alopecia was not sufficiently large to cover all the cases of AA. Third, the NHIRD does not provide information regarding cancer histology, and certain types of histological thyroid cancer are more commonly seen in thyroid autoimmune diseases [30,31,39,40]. However, we could not evaluate this because of the intrinsic limitations of the database. In conclusion, this population-based retrospective cohort study found a significantly increased risk of thyroid cancer in Taiwanese women with alopecia compared with the general population, especially in younger women. Although the underlying mechanisms remain unclear and our results must be verified in further investigations, the findings from this study should prompt the TBNHI to reconsider its policy regarding follow-up and cancer screenings in younger women with alopecia. Author contributions All authors have contributed significantly, and that all authors are in agreement with the content of the manuscript:
22
L.-M. Sun et al. / Journal of Dermatological Science 74 (2014) 18–22
Conception/Design: Li-Min Sun, Yu-Shu Yen, Chia-Hung Kao; Provision of study materials: Ji-An Liang, Fung-Chang Sung; Collection and/or assembly of data: Li-Min Sun, Ming-Chia Lin, Chia-Hung Kao; Data analysis and interpretation: Li-Min Sun, Ming-Chia Lin, Chih-Hsin Muo, Chia-Hung Kao; Manuscript writing: All authors; Final approval of manuscript: All authors. Acknowledgments This work was supported by the study projects (DMR-101-060 and DMR-102-023) in our hospital; Taiwan Department of Health Clinical Trial and Research Center and for Excellence (DOH102TD-B-111-004), Taiwan Department of Health Cancer Research Center for Excellence (DOH102-TD-C-111-005); and International Research-Intensive Centers of Excellence in Taiwan (I-RiCE) (NSC101-2911-I-002-303). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. References [1] Yassa M, Saliou M, De Rycke Y, Hemery C, Henni M, Bachaud JM, et al. Male pattern baldness and the risk of prostate cancer. Ann Oncol 2011;22: 1824–7. [2] Hawk E, Breslow RA, Graubard BI. Male pattern baldness and clinical prostate cancer in the epidemiologic follow-up of the first National Health and Nutrition Examination Survey. Cancer Epidemiol Biomarkers Prev 2000;9:523–7. [3] Ludwig E. Classification of the types of androgenetic alopecia (common baldness) occurring in the female sex. Br J Dermatol 1977;97:247–54. [4] Sehgal VN, Jain S. Alopecia areata: clinical perspective and an insight into pathogenesis. J Dermatol 2003;30:271–89. [5] Faydaci G, Bilal E, Necmettin P, Fatih T, Asuman O, Ugur K. Baldness, benign prostate hyperplasia, prostate cancer and androgen levels. Aging Male 2008;11:189–92. [6] Kiso M, Tanaka S, Saba R, Matsuda S, Shimizu A, Ohyama M, et al. The disruption of Sox21-mediated hair shaft cuticle differentiation causes cyclic alopecia in mice. Proc Natl Acad Sci U S A 2009;106:9292–7. [7] Demark-Wahnefried W, Schildkraut JM, Thompson D, Lesko SM, McIntyre L, Schwingl P, et al. Early onset baldness and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 2000;9:325–8. [8] Isaacs JT. Role of androgens in prostatic cancer. Vitam Horm 1994;49:433–504. [9] Randall VA. Androgens and human hair growth. Clin Endocrinol 1994;40:439–57. [10] Muller DC, Giles GG, Sinclair R, Hopper JL, English DR, Severi G. Age-dependent associations between androgenetic alopecia and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 2013;22:209–15. [11] Thomas JA, Antonelli JA, Banez LL, Hoyo C, Grant D, Demark-Wahnefried W, et al. Androgenetic alopecia at various ages and prostate cancer risk in an equal-access multiethnic case-control series of veterans. Cancer Causes Control 2013;24:1045–52. [12] Amoretti A, Laydner H, Bergfeld W. Androgenetic alopecia and risk of prostate cancer: a systematic review and meta-analysis. J Am Acad Dermatol 2013;68:937–43. [13] Cremers RG, Aben KK, Vermeulen SH, den Heijer M, van Oort IM, Kiemeney LA. Androgenic alopecia is not useful as an indicator of men at high risk of prostate cancer. Eur J Cancer 2010;46:3294–9. [14] Wright JL, Page ST, Lin DW, Stanford JL. Male pattern baldness and prostate cancer risk in a population-based case-control study. Cancer Epidemiol 2010;34:131–5. [15] Henderson BE, Feigelson HS. Hormonal carcinogenesis. Carcinogenesis 2000;21:427–33. [16] Artantas¸ S, Gu¨l U, Kilic¸ A, Gu¨ler S. Skin findings in thyroid diseases. Eur J Intern Med 2009;20:158–61.
[17] Cheng TM. Taiwan’s National Health Insurance system: high value for the dollar. In: Okma KGH, Crivelli L, editors. Six Countries, Six Reform Models: The Health Reform Experience of Israel, the Netherlands, New Zealand, Singapore, Switzerland and Taiwan. New Jersey: World Scientific; 2009. p. 71–204. [18] Kao GH, Sun LM, Chen PC, Lin MC, Liang JA, Muo CH, et al. A population-based cohort study in Taiwan – use of insulin sensitizers can decrease cancer risk in diabetic patients? Ann Oncol 2013;24:523–30. [19] Sun LM, Lin CL, Liang JA, Liu SH, Sung FC, Chang YJ, et al. Urinary tract infection increases subsequent urinary tract cancer risk: a population-based cohort study. Cancer Sci 2013;104:619–23. [20] Venning VA, Dawber RP. Patterned androgenic alopecia in women. J Am Acad Dermatol 1988;18:1073–7. [21] Su LH, Chen LS, Chen HH. Factors associated with female pattern hair loss and its prevalence in Taiwanese women: a community-based survey. J Am Acad Dermatol 2013;69:e69–77. [22] Lo Sicco K, McGuire S, English III JC. A retrospective study of thyroid structural abnormalities in alopecia patients. Dermatoendocrinology 2011;3:251–4. [23] Alkhalifah A. Alopecia areata update. Dermatol Clin 2013;31:93–108. [24] Hordinsky M, Ericson M. Autoimmunity: alopecia areata. J Investig Dermatol Symp Proc 2004;9:73–8. [25] Kurtev A, Iliev E. Thyroid autoimmunity in children and adolescents with alopecia areata. Int J Dermatol 2005;44:457–61. [26] Kasumagic´-Halilovic´ E. Thyroid autoimmunity in patients with alopecia areata. Acta Dermatovenerol Croat 2008;16:123–5. [27] Puavilai S, Puavilai G, Charuwichitratana S, Sakuntabhai A, Sriprachya-Anunt S. Prevalence of thyroid diseases in patients with alopecia areata. Int J Dermatol 1994;33:632–3. [28] Franks AL, Slansky JE. Multiple associations between a broad spectrum of autoimmune diseases, chronic inflammatory diseases and cancer. Anticancer Res 2012;32:1119–36. [29] Shu X, Ji J, Li X, Sundquist J, Sundquist K, Hemminki K. Cancer risk in patients hospitalised for Graves’ disease: a population-based cohort study in Sweden. Br J Cancer 2010;102:1397–9. [30] Majima T, Komatsu Y, Doi K, Shigemoto M, Takagi C, Fukao A, et al. Anaplastic thyroid carcinoma associated with Graves’ disease. Endocr J 2005;52:551–7. [31] Belfiore A, Garofalo MR, Giuffrida D, Runello F, Filetti S, Fiumara A, et al. Increased aggressiveness of thyroid cancer in patients with Graves’ disease. J Clin Endocrinol Metab 1990;70:830–5. [32] Ott RA, McCall AR, Jarosz H, Armin A, Lawrence AM, Paloyan E. The incidence of thyroid carcinoma in Hashimoto’s thyroiditis. Am Surg 1987;53:442–5. [33] Chen YK, Lin CL, Chang YJ, Cheng FT, Peng CL, Sung FC, et al. Cancer risk in patients with Graves’ disease: a nationwide cohort study. Thyroid 2013;237:879–84. [34] Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 1997;84:223–43. [35] Cooper DS. Hyperthyroidism. Lancet 2003;362:459–68. [36] Pazaitou-Panayiotou K, Perros P, Boudina M, Siardos G, Drimonitis A, Patakiouta F, et al. Mortality from thyroid cancer in patients with hyperthyroidism: the Theagenion Cancer Hospital experience. Eur J Endocrinol 2008;159: 799–803. [37] Dayan CM, Daniels GH. Chronic autoimmune thyroiditis. N Engl J Med 1996;335:99–107. [38] Segal K, Ben-Bassat M, Avraham A, Har-El G, Sidi J. Hashimoto’s thyroiditis and carcinoma of the thyroid gland. Int Surg 1985;70:205–9. [39] Kim KW, Park YJ, Kim EH, Park SY, Park DJ, Ahn SH, et al. Elevated risk of papillary thyroid cancer in Korean patients with Hashimoto’s thyroiditis. Head Neck 2011;33:691–5. [40] Lun Y, Wu X, Xia Q, Han Y, Zhang X, Liu Z, et al. Hashimoto’s thyroiditis as a risk factor of papillary thyroid cancer may improve cancer prognosis. Otolaryngol Head Neck Surg 2013;148:396–402. [41] Crile Jr G, Hazard JB. Relationship of the age of the patient to the natural history and prognosis of carcinoma of the thyroid. Ann Surg 1953;138:33–8. [42] Cheng CL, Kao YH, Lin SJ, Lee CH, Lai ML. Validation of the National Health Insurance Research Database with ischemic stroke cases in Taiwan. Pharmacoepidemiol Drug Saf 2011;20:236–42. [43] Yu YB, Gau JP, Liu CY, Yang MH, Chiang SC, Hsu HC, et al. A nation-wide analysis of venous thromboembolism in 497,180 cancer patients with the development and validation of a risk-stratification scoring system. Thromb Haemost 2012;108:225–35.