Update on Thyroid Hormone Levels and Thyroid Dysfunction in the Korean Population Based on Data from the Korea National Health and Nutrition Examination Survey VI (2013 to 2015)

Update on Thyroid Hormone Levels and Thyroid Dysfunction in the Korean Population Based on Data... Endocrinol Metab 2020;35:7-13 Review https://doi.org/10.3803/EnM.2020.35.1.7 pISSN 2093-596X · eISSN 2093-5978 Article Update on Thyroid Hormone Levels and Thyroid Dysfunction in the Korean Population Based on Data from the Korea National Health and Nutrition Examination Survey VI (2013 to 2015) Jae Hoon Chung Division of Endocrinology and Metabolism, Department of Medicine and Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea In 2017, the first Korean nationwide data on serum thyroid stimulating hormone (TSH) levels, serum free thyroxine (fT ) levels, and urinary iodine concentration (UIC) were published based on a population of 7,061 Koreans who participated in the Korea National Health and Nutrition Examination Survey VI. The mean TSH level was 2.16 mIU/L, with a reference interval of 0.59 to 7.03 mIU/L (men 2.09 mIU/L, women 2.24 mIU/L, P 0.001). A U-shaped association was found between serum TSH levels and age. The mean fT level was 1.25 ng/dL, and its reference interval was 0.92 to 1.60 ng/dL (men 1.29 ng/dL, women 1.20 ng/dL, P 0.0001). Serum 4 < fT levels decreased with age (P for trend 0.0001). Serum thyroid peroxidase antibody (TPOAb) was detected in 7.30% of partici- 4 < pants (men 4.33%, women 10.62%). TPOAb titers tended to increase with age, and were higher in women than in men. The median UIC was 294 μg/L, and UIC showed a U-shaped relationship with age. According to the World Health Organization recommenda - tions, only 23% of participants were in the adequate range of iodine intake, while 65% were in the above requirements or excessive, and 12% in insufficient. The prevalence of overt hyperthyroidism and hypothyroidism in Koreans was 0.34% to 0.54% and 0.73% to 1.43%, respectively. Keywords: Korea; Thyrotropin; Thyroxine; Iodine levels, and urinary iodine concentration (UIC) in the Korean INTRODUCTION population. Between 2013 and 2015, the Korea Centers for Dis- In this article, I would like to update a review article published ease Control and Prevention, in conjunction with the Korean in 2018 by presenting the findings of some additional studies Thyroid Association, conducted a project to gather and analyze that have been published subsequently [1]. nationwide data on serum TSH levels, serum fT levels, and Before 2013, there had been no nationwide studies on serum UIC in the healthy Korean population as part of the Korea Na- thyroid stimulating hormone (TSH) levels, free thyroxine (fT ) tional Health and Nutrition Examination Survey (KNHANES) Received: 28 January 2020, Revised: 31 January 2020, Copyright © 2020 Korean Endocrine Society Accepted: 5 February 2020 This is an Open Access article distributed under the terms of the Creative Com- Corresponding author: Jae Hoon Chung mons Attribution Non-Commercial License (https://creativecommons.org/ Division of Endocrinology and Metabolism, Department of Medicine and licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribu- Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of tion, and reproduction in any medium, provided the original work is properly Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea cited. Tel: +82-2-3410-3434, Fax: +82-2-3410-3849, E-mail: thyroid@skku.edu www.e-enm.org 7 Chung JH VI (2013 to 2015). The KNHANES VI was a Korean nation- dence limits. wide, cross-sectional study that used stratified, multistage, clus- The serum mean values and reference intervals of serum TSH tered probability sampling to select a representative sample of and fT were defined using 5,987 individuals based on the the civilian, non-institutionalized Korean population. Approxi- KNHANES VI [5,6]. The reference individuals were selected mately 2,400 individuals were selected each year between 2013 from TPOAb-negative ( 34.0 IU/mL), ambulatory, euthyroid and 2015 using stratified subsampling and underwent measure- subjects who had no personal or family history of thyroid dys- ments of serum TSH, fT , and thyroid peroxidase antibody function, no visible goiter, and were taking no medications. The (TPOAb). The final participants consisted of 7,061 individuals geometric mean value was defined as the nth root of the product over 10 years old. UIC was measured in a spot urine sample in of n numbers. The geometric mean serum TSH level was 2.16 6,564 individuals. All participants answered a number of de- mIU/L, and it was lower in the age group of 40 to 49 years and tailed questions. higher in the age groups of 10 to 19 years and 70 years or older [7]. Therefore, a U-shaped association was observed between serum TSH levels and age (Fig. 1). The mean TSH value was MEAN VALUES AND REFERENCE significantly higher in women than in men (2.24 mIU/L vs. 2.09 INTERVALS OF TSH AND fT IN THE mIU/L, P 0.001). The reference intervals were calculated from KOREAN POPULATION the 95% confidence limits of the log-transformed values. The Serum TSH levels might vary according to age, sex, smoking, serum TSH reference interval was 0.59 to 7.03 mIU/L (women, TPOAb positivity, genetic determinants, and the assay method 0.56 to 7.43 mIU/L vs. men, 0.62 to 6.57 mIU/L), which was [2,3]. Therefore, serum TSH reference intervals should be es- right-shifted, but not correlated with age [8]. The mean serum tablished using specimens from TPOAb-negative, ambulatory, fT level was 1.25 ng/dL, and its reference interval was 0.92 to euthyroid subjects who have no personal or family history of 1.60 ng/dL. The mean fT level in men was significantly higher thyroid dysfunction, no visible goiter, and are taking no medica- than that in women (1.29 ng/dL vs. 1.20 ng/dL, P 0.0001), and tions [4]. Serum TSH levels measured in a euthyroid reference serum fT levels significantly decreased with age after 20 years population show a left-skewed distribution with a long tail to- old (P for trend 0.0001) (Fig. 1). wards the higher levels. The values become more normally dis- A few clear differences exist between the results from Korea tributed when they are log-transformed. It is standard practice to (KNHANES VI) and those of previously published Western re- log-transform serum TSH levels to calculate the 95% confi- ports. First, the serum TSH levels in the Korean population All Men Women 2.6 1.4 2.6 2.6 1.4 1.4 2.4 2.4 2.4 1.3 1.3 1.3 2.2 2.2 2.2 1.2 1.2 1.2 2.0 2 2 1. 1.8 8 1.8 1.1 1.1 1.1 10−19 10-19 10-19 20−29 20-29 20-29 30−39 30-39 30-39 40−49 40-49 40-49 50−59 50-59 50-59 60−69 60-69 60-69≥ >70 70>70 10-19 10−19 10-19 20-29 20−29 20-29 30-39 30−39 30-39 40-49 40−49 40-49 50-59 50−59 50-59 60-69 60−69 60-69>70≥ >70 70 A B Y Ye ear arYear YearY Ye ear ar All All MenMen Wom W eom n en All All MenMen Wom W eom n en Fig. 1. Serum thyroid stimulating hormone (TSH) and free thyroxine (fT ) levels by age and sex. (A) Geometric mean TSH levels (mIU/L) by age. (B) Mean fT4 levels (ng/dL) by age. A U-shaped association was found between serum TSH levels and age. TSH levels were signifi- cantly higher in women than in men (P< 0.001). Serum fT4 levels significantly decreased with age (P for trend < 0.0001), and were signifi- cantly higher in men than in women (P< 0.0001). Adapted from Park et al. [6]. www.e-enm.org Copyright © 2020 Korean Endocrine Society TSH (mIU/L) TSH (mIU/L) TSH (mIU/L) FT4 (ng/dL) fT (ng/dL) FT4 (ng/dL) TSH (mIU/L) Korean TSH, Free T4, TPOAb, Urine Iodine Levels were markedly higher than those in Western reports. For exam- (Table 1). Previous studies have generally reported that TPOAb ple, the mean value and upper reference limit of serum TSH in a increased TSH level, while smoking decreased it. Park et al. report from the USA (National Health and Nutrition Examina- [12] recently evaluated the associations of smoking with TSH tion Survey [NHANES] III) were 1.40 and 4.12 mIU/L, respec- levels, TPOAb, and UIC using the KNHANES VI. They report- tively, whereas the corresponding Korean results were 2.16 and ed that a smoking-induced decrease in TSH levels was evident 7.03 mIU/L, respectively [2]. All Korean values were right- in individuals with iodine deficiency, and that the TPOAb posi- shifted, and these differences might be related to excessive io- tivity rate was high in non-smokers. Therefore, they concluded dine intake in the Korean population [9]. Genetic differences re- that smoking might be not associated with the presence of garding the set-point of thyroid hormone have been proposed, TPOAb or iodine intake, and that smoking may have a direct ef- and such differences might be another reason for the higher fect on thyroid function that is not mediated by autoimmune TSH levels found in Koreans [3,10]. Second, a U-shaped curve processes. between age and serum TSH levels, with lower levels in mid- dle-aged adults and higher levels in younger and older age Table 1. Prevalence of TPOAb in the Korean Population Ac- groups, was only found in the Korean results (Fig. 2). Most cording to Age and Sex studies reported that serum TSH levels gradually increased with Age, yr All, % Men, % Women, % age. However, a recent result from the Rotterdam Study report- ed that TSH levels remained stable with age [3]. A U-shaped 10–18 2.81 2.12 3.73 curve was also found between age and UIC. Therefore, changes 19–29 4.13 3.27 5.23 in serum TSH levels with age were influenced by changes in the 30–39 5.63 2.76 9.08 UIC (reflecting iodine intake) in the Korean population [9,11]. 40–49 7.94 4.22 12.54 50–59 11.71 5.97 17.78 60–69 10.01 7.71 11.80 PREVALENCE OF TPOAb IN THE KOREAN ≥70 3.13 3.13 3.14 POPULATION All ages 7.30 4.33 10.62 TPOAb positivity was defined as a level of 34.0 IU/mL. Se- Adapted from Kim et al. [5]. TPOAb positivity was defined as 34.0 rum TPOAb was detected in 7.30% of subjects (men 4.33%, IU/mL. Serum TPOAb titers tended to increase with age, but decreased after age 70. They were higher in women than in men. women 10.62%). TPOAb titers tended to increase with age, but TPOAb, thyroid peroxidase antibody. decreased after age 70. They were higher in women than in men UIC TSH 450 450 2.4 2.4 400 400 2.3 2.3 2.2 2.2 2.1 2.1 250 250 200 2 200 2.0 10-19 20-29 30-39 40-49 50-59 60-69 >70 10−19 20−29 30−39 40−49 50−59 60−69 ≥70 Years Year UIC TSH Fig. 2. Relationship of urinary iodine concentration (UIC) with serum thyroid stimulating hormone (TSH) levels. A U-shaped curve was found between age and serum TSH levels, with lower levels in middle-aged adults and higher levels in younger and older age groups. A U- shaped curve was also detected for the relationship between age and UIC. Therefore, changes in serum TSH levels with age may be influ- enced by changes in UIC in the Korean population. Adapted from Park et al. [6]. Copyright © 2020 Korean Endocrine Society www.e-enm.org UIC (μg/L) UIC (ug/L) TSH (mIU/L) Chung JH All Men Women 10−19 20−29 30−39 40−49 50−59 60−69 ≥70 Year Fig. 3. Urinary iodine concentration (UIC, μg/L) by age and sex. According to the World Health Organization recommendations, only 23% of subjects were in the adequate range (UIC, 100 to 199 μg/L), and 65% were classified as having an intake that was above requirements (UIC 200 to 299 μg/L) or excessive (UIC 300 μg/L). However, 12% had insufficient iodine intake (UIC 100 μg/L). The median UIC ≥ < was higher in school-aged children (6 to 12 years) and in the above 70 years age group than in other age groups. Adapted from Park et al. [6]. mass index, and smoking status, serum TSH levels were signifi- MEAN VALUES AND REFERENCE cantly correlated with UIC (r 0.154, P 0.0001). The changes = < INTERVALS OF UIC IN THE KOREAN in UIC with age showed a U-shape (Fig. 2). The median UIC POPULATION increased with household income level (P for trend 0.001). Most Koreans have been reported to have sufficient iodine in- Individuals living in seaside or urban areas had higher UIC val- take [9,13,14]. However, no nationwide survey had investigated ues than those in inland or rural areas. This trend is consistent iodine intake in a representative sample of the entire Korean with the findings of previous studies [20,21]. Choi et al. [22] population before 2013. In non-pregnant, non-lactating women, analyzed UIC in adolescents aged 10 to 18 years and their par- a UIC of 100 μg/L corresponds roughly to a daily iodine intake ents using the KNHANES VI. They reported that the prevalence of approximately 150 μg under steady-state conditions [15,16]. of iodine deficiency exceeded 10% in several regions of Korea, Kim et al. [17] published results on the UIC in Koreans based and that iodine intake status in Korean adolescents was primari- on the KNHANES VI, which was the first nationwide report on ly affected by their families’ eating habits and household in- this topic. They reported that the median UIC in the Korean come. population was 294 μg/L, corresponding to a level of iodine in- take that is above requirements according to the World Health PREVALENCE OF OVERT HYPERTHYROIDISM Organization (WHO) recommendations. The unique eating hab- AND HYPOTHYROIDISM its of Koreans, including the consumption of basic ingredients made from sea tangle or kelp and seaweed soup, are considered Kim et al. [5] investigated the prevalence of thyroid dysfunction to be a major cause of these trends [9,18,19]. According to the in the Korean population based on the KNHANES VI, and re- WHO recommendations, only 23% of participants were in the ported that the prevalence of overt and subclinical hyperthyroid- adequate range (UIC, 100 to 199 μg/L), and 65% were classi- ism was 0.54% (men, 0.30%; women, 0.81%) and 2.98% (men, fied as having an intake that was above requirements (UIC, 200 2.43%; women, 3.59%), respectively. They also reported that to 299 μg/L) or excessive (UIC 300 μg/L). However, 12% of the prevalence of overt and subclinical hypothyroidism (SCH) participants had insufficient iodine intake (UIC 100 μg/L). was 0.73% (men, 0.40%; women, 1.10%) and 3.10% (men, The median UIC was higher among school-aged children (6 to 2.26%; women, 4.04%), respectively, and its prevalence in- 12 years, 511 μg/L) and in those above 70 years of age than in creased with age until the age group of 50 to 59 years. Seo et al. other age groups (Fig. 3). After adjusting for age, sex, body [23,24] published results on the prevalence of overt hyperthy- www.e-enm.org Copyright © 2020 Korean Endocrine Society UIC (μg/L) Korean TSH, Free T4, TPOAb, Urine Iodine Levels Table 2. Prevalence of Hyperthyroidism and Hypothyroidism in Korea: Comparison of KNHANES VI Data with HIRA Data Kim et al. [5] Seo et al. [23,24] Publication Endocrinol Metab (Seoul) 2017;32:106-14 J Korean Thyroid Assoc 2013;6:56-63 Endocrinol Metab (Seoul) 2015;30:288-96 Data source KNHANES VI HIRA Inclusion Individuals who were not receiving treatment Subclinical patients receiving overtreatment Exclusion Well-controlled euthyroid patients with treatment Individuals who were not receiving treatment Prevalence Hyperthyroidism Overt 0.54% (men, 0.30%; women, 0.81%) 0.34% (men, 0.20%; women, 0.47%) Subclinical 2.98% (men, 2.43%; women, 3.59%) Hypothyroidism Overt 0.73% (men, 0.40%; women, 1.10%) 1.43% (men, 0.44%; women, 2.40%) Subclinical 3.10% (men, 2.26%; women, 4.04%) These two sets of results should not be compared without adjustment because of differences in the subjects. KNHANES, Korea National Health and Nutrition Examination Survey; HIRA, Health Insurance Review and Assessment Service. roidism and overt hypothyroidism using National Health Insur- CONCLUSIONS ance claims data provided by the Health Insurance Review and Assessment Service (HIRA) in 2013 and 2015, respectively. Based on the KNHANES VI, the mean TSH level in the Korean They reported that the prevalence of overt hyperthyroidism and population was 2.16 mIU/L, and its reference interval was 0.59 overt hypothyroidism was 0.34% (men, 0.20%; women, 0.47%) to 7.03 mIU/L. A U-shaped association was found between se- and 1.43% (men, 0.44%; women, 2.40%), respectively. The rum TSH levels and age. Serum TSH levels were significantly prevalence derived from the KNHANES VI data included indi- higher in women than men. The mean fT level was 1.25 ng/dL, viduals who were not receiving treatment, but excluded well- with a reference interval of 0.92 to 1.60 ng/dL. Serum fT levels controlled euthyroid patients with treatment, while the preva- significantly decreased with age, and were significantly higher lence derived from the HIRA data may have included subclini- in men than in women. Serum TPOAb was detected in 7.30% cal patients receiving overtreatment, while excluding individu- of subjects, a proportion that tended to increase with age. The als who were not receiving treatment. Therefore, these two sets median UIC was 294 μg/L, and a U-shaped relationship of UIC of results should not be compared without adjustment. Ha et al. with age was evident. Only 23% of subjects had an adequate io- [25] investigated the risk factors for SCH according to sex using dine intake according to the WHO criteria, and 65% were clas- KNHANES VI data. They reported that TPOAb positivity sig- sified as having an intake that was above requirements or exces- nificantly increased the risk of SCH in both men and women, sive. However, 12% had insufficient iodine intake. The preva- but smoking reduced it in men. The risk of SCH increased as lence of overt hyperthyroidism and overt hypothyroidism in the UIC increased, and this trend was more marked in men than in Korean population was 0.34% to 0.54% and 0.73% to 1.43%, women. The odds ratio for SCH for urban (vs. rural) residence respectively. was 1.78. When jointly evaluating these two nationwide sets of results, CONFLICTS OF INTEREST the prevalence of overt hyperthyroidism and overt hypothyroid- ism in the Korean population may be 0.34% to 0.54% (men, No potential conflict of interest relevant to this article was re- 0.20% to 0.30%; women, 0.47% to 0.81%) and 0.73% to 1.43% ported. (men, 0.40% to 0.44%; women, 1.10% to 2.40%), respectively (Table 2). ORCID Jae Hoon Chung https://orcid.org/0000-0002-9563-5046 Copyright © 2020 Korean Endocrine Society www.e-enm.org 11 Chung JH mination of the hypothalamic-pituitary-thyroid axis: where REFERENCES do we stand? Endocr Rev 2015;36:214-44. 1. Chung JH. Evaluation of thyroid hormone levels and uri- 11. Joung JY, Cho YY, Park SM, Kim TH, Kim NK, Sohn SY, nary iodine concentrations in Koreans based on the data et al. Effect of iodine restriction on thyroid function in sub- from Korea National Health and Nutrition Examination Sur- clinical hypothyroid patients in an iodine-replete area: a vey VI (2013 to 2015). Endocrinol Metab (Seoul) 2018;33: long period observation in a large-scale cohort. Thyroid 160-3. 2014;24:1361-8. 2. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, 12. Park S, Kim WG, Jeon MJ, Kim M, Oh HS, Han M, et al. Gunter EW, Spencer CA, et al. Serum TSH, T(4), and thy- Serum thyroid-stimulating hormone levels and smoking sta- roid antibodies in the United States population (1988 to tus: data from the Korean National Health and Nutrition Ex- 1994): National Health and Nutrition Examination Survey amination Survey VI. Clin Endocrinol (Oxf) 2018;88:969- (NHANES III). J Clin Endocrinol Metab 2002;87:489-99. 76. 3. Chaker L, Korevaar TI, Medici M, Uitterlinden AG, Hof- 13. Choi J, Kim HS, Hong DJ, Lim H, Kim JH. Urinary iodine man A, Dehghan A, et al. Thyroid function characteristics and sodium status of urban Korean subjects: a pilot study. and determinants: the Rotterdam study. Thyroid 2016;26: Clin Biochem 2012;45:596-8. 1195-204. 14. Lee J, Kim JH, Lee SY, Lee JH. Iodine status in Korean pre- 4. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt- school children as determined by urinary iodine excretion. Rasmussen U, Henry JF, et al. Laboratory medicine practice Eur J Nutr 2014;53:683-8. guidelines: laboratory support for the diagnosis and moni- 15. International Council for Control of Iodine Deficiency Dis- toring of thyroid disease. Thyroid 2003;13:3-126. orders; UNICEF; World Health Organization. Assessment 5. Kim WG, Kim WB, Woo G, Kim H, Cho Y, Kim TY, et al. of iodine deficiency disorders and monitoring their elimina- Thyroid stimulating hormone reference range and preva- tion: a guide for programme managers. 3rd ed. Geneva: lence of thyroid dysfunction in the Korean population: Ko- World Health Organization; 2007. rea National Health and Nutrition Examination Survey 2013 16. Chung JH. Low iodine diet for preparation for radioactive to 2015. Endocrinol Metab (Seoul) 2017;32:106-14. iodine therapy in differentiated thyroid carcinoma in Korea. 6. Park SY, Kim HI, Oh HK, Kim TH, Jang HW, Chung JH, et Endocrinol Metab (Seoul) 2013;28:157-63. al. Age- and gender-specific reference intervals of TSH and 17. Kim HI, Oh HK, Park SY, Jang HW, Shin MH, Kim SW, et free T4 in an iodine-replete area: data from Korean National al. Urinary iodine concentration and thyroid hormones: Ko- Health and Nutrition Examination Survey IV (2013-2015). rea National Health and Nutrition Examination Survey PLoS One 2018;13:e0190738. 2013-2015. Eur J Nutr 2019;58:233-40. 7. Kwon H, Kim WG, Jeon MJ, Han M, Kim M, Park S, et al. 18. Kim JY, Kim KR. Dietary iodine intake and urinary iodine Age-specific reference interval of serum TSH levels is high excretion in patients with thyroid diseases. Yonsei Med J in adolescence in an iodine excess area: Korea National 2000;41:22-8. Health and Nutrition Examination Survey Data. Endocrine 19. Rhee SS, Braverman LE, Pino S, He X, Pearce EN. High 2017;57:445-54. iodine content of Korean seaweed soup: a health risk for 8. Jeon MJ, Kim WG, Kwon H, Kim M, Park S, Oh HS, et al. lactating women and their infants? Thyroid 2011;21:927-8. Excessive iodine intake and thyrotropin reference interval: 20. Zou Y, Lou X, Ding G, Mo Z, Zhu W, Mao G. A cross-sec- data from the Korean National Health and Nutrition Exami- tional comparison study on the iodine nutritional status be- nation Survey. Thyroid 2017;27:967-72. tween rural and urban residents in Zhejiang Province, China. 9. Kang TS, Leem DG, Seo IW, Lee YJ, Yoon TH, Lee JH, et BMJ Open 2014;4:e005484. al. Monitoring of iodine in foods for estimation of dietary 21. Aghini-Lombardi F, Vitti P, Antonangeli L, Fiore E, Piaggi P, intake [Internet]. Cheongju: National Institute of Food and Pallara A, et al. The size of the community rather than its Drug Safety Evaluation; 2012 [cited 2020 Feb 3]. Available geographical location better defines the risk of iodine defi- from: file:///C:/Users/USER/Downloads/OA2014_Z4_0250. ciency: results of an extensive survey in Southern Italy. J pdf. Endocrinol Invest 2013;36:282-6. 10. Medici M, Visser WE, Visser TJ, Peeters RP. Genetic deter- 22. Choi YC, Cheong JI, Chueh HW, Yoo JH. Iodine status and www.e-enm.org Copyright © 2020 Korean Endocrine Society 12 Korean TSH, Free T4, TPOAb, Urine Iodine Levels characteristics of Korean adolescents and their parents based pothyroidism and causative diseases in Korea as determined on urinary iodine concentration: a nationwide cross-section- using claims data provided by the health insurance review al study. Ann Pediatr Endocrinol Metab 2019;24:108-15. and assessment service. Endocrinol Metab (Seoul) 2015;30: 23. Seo GH, Kim SW, Chung JH. Incidence & prevalence of 288-96. hyperthyroidism and preference for therapeutic modalities 25. Ha J, Lee J, Jo K, Lim DJ, Kang MI, Cha BY, et al. Sex dif- in Korea. J Korean Thyroid Assoc 2013;6:56-63. ferences in risk factors for subclinical hypothyroidism. En- 24. Seo GH, Chung JH. Incidence and prevalence of overt hy- docr Connect 2018;7:511-22. 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Update on Thyroid Hormone Levels and Thyroid Dysfunction in the Korean Population Based on Data from the Korea National Health and Nutrition Examination Survey VI (2013 to 2015)

Endocrinology and Metabolism, Volume 35 (1) – Mar 19, 2020

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Endocrinol Metab 2020;35:7-13 Review https://doi.org/10.3803/EnM.2020.35.1.7 pISSN 2093-596X · eISSN 2093-5978 Article Update on Thyroid Hormone Levels and Thyroid Dysfunction in the Korean Population Based on Data from the Korea National Health and Nutrition Examination Survey VI (2013 to 2015) Jae Hoon Chung Division of Endocrinology and Metabolism, Department of Medicine and Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea In 2017, the first Korean nationwide data on serum thyroid stimulating hormone (TSH) levels, serum free thyroxine (fT ) levels, and urinary iodine concentration (UIC) were published based on a population of 7,061 Koreans who participated in the Korea National Health and Nutrition Examination Survey VI. The mean TSH level was 2.16 mIU/L, with a reference interval of 0.59 to 7.03 mIU/L (men 2.09 mIU/L, women 2.24 mIU/L, P 0.001). A U-shaped association was found between serum TSH levels and age. The mean fT level was 1.25 ng/dL, and its reference interval was 0.92 to 1.60 ng/dL (men 1.29 ng/dL, women 1.20 ng/dL, P 0.0001). Serum 4 < fT levels decreased with age (P for trend 0.0001). Serum thyroid peroxidase antibody (TPOAb) was detected in 7.30% of partici- 4 < pants (men 4.33%, women 10.62%). TPOAb titers tended to increase with age, and were higher in women than in men. The median UIC was 294 μg/L, and UIC showed a U-shaped relationship with age. According to the World Health Organization recommenda - tions, only 23% of participants were in the adequate range of iodine intake, while 65% were in the above requirements or excessive, and 12% in insufficient. The prevalence of overt hyperthyroidism and hypothyroidism in Koreans was 0.34% to 0.54% and 0.73% to 1.43%, respectively. Keywords: Korea; Thyrotropin; Thyroxine; Iodine levels, and urinary iodine concentration (UIC) in the Korean INTRODUCTION population. Between 2013 and 2015, the Korea Centers for Dis- In this article, I would like to update a review article published ease Control and Prevention, in conjunction with the Korean in 2018 by presenting the findings of some additional studies Thyroid Association, conducted a project to gather and analyze that have been published subsequently [1]. nationwide data on serum TSH levels, serum fT levels, and Before 2013, there had been no nationwide studies on serum UIC in the healthy Korean population as part of the Korea Na- thyroid stimulating hormone (TSH) levels, free thyroxine (fT ) tional Health and Nutrition Examination Survey (KNHANES) Received: 28 January 2020, Revised: 31 January 2020, Copyright © 2020 Korean Endocrine Society Accepted: 5 February 2020 This is an Open Access article distributed under the terms of the Creative Com- Corresponding author: Jae Hoon Chung mons Attribution Non-Commercial License (https://creativecommons.org/ Division of Endocrinology and Metabolism, Department of Medicine and licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribu- Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of tion, and reproduction in any medium, provided the original work is properly Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea cited. Tel: +82-2-3410-3434, Fax: +82-2-3410-3849, E-mail: thyroid@skku.edu www.e-enm.org 7 Chung JH VI (2013 to 2015). The KNHANES VI was a Korean nation- dence limits. wide, cross-sectional study that used stratified, multistage, clus- The serum mean values and reference intervals of serum TSH tered probability sampling to select a representative sample of and fT were defined using 5,987 individuals based on the the civilian, non-institutionalized Korean population. Approxi- KNHANES VI [5,6]. The reference individuals were selected mately 2,400 individuals were selected each year between 2013 from TPOAb-negative ( 34.0 IU/mL), ambulatory, euthyroid and 2015 using stratified subsampling and underwent measure- subjects who had no personal or family history of thyroid dys- ments of serum TSH, fT , and thyroid peroxidase antibody function, no visible goiter, and were taking no medications. The (TPOAb). The final participants consisted of 7,061 individuals geometric mean value was defined as the nth root of the product over 10 years old. UIC was measured in a spot urine sample in of n numbers. The geometric mean serum TSH level was 2.16 6,564 individuals. All participants answered a number of de- mIU/L, and it was lower in the age group of 40 to 49 years and tailed questions. higher in the age groups of 10 to 19 years and 70 years or older [7]. Therefore, a U-shaped association was observed between serum TSH levels and age (Fig. 1). The mean TSH value was MEAN VALUES AND REFERENCE significantly higher in women than in men (2.24 mIU/L vs. 2.09 INTERVALS OF TSH AND fT IN THE mIU/L, P 0.001). The reference intervals were calculated from KOREAN POPULATION the 95% confidence limits of the log-transformed values. The Serum TSH levels might vary according to age, sex, smoking, serum TSH reference interval was 0.59 to 7.03 mIU/L (women, TPOAb positivity, genetic determinants, and the assay method 0.56 to 7.43 mIU/L vs. men, 0.62 to 6.57 mIU/L), which was [2,3]. Therefore, serum TSH reference intervals should be es- right-shifted, but not correlated with age [8]. The mean serum tablished using specimens from TPOAb-negative, ambulatory, fT level was 1.25 ng/dL, and its reference interval was 0.92 to euthyroid subjects who have no personal or family history of 1.60 ng/dL. The mean fT level in men was significantly higher thyroid dysfunction, no visible goiter, and are taking no medica- than that in women (1.29 ng/dL vs. 1.20 ng/dL, P 0.0001), and tions [4]. Serum TSH levels measured in a euthyroid reference serum fT levels significantly decreased with age after 20 years population show a left-skewed distribution with a long tail to- old (P for trend 0.0001) (Fig. 1). wards the higher levels. The values become more normally dis- A few clear differences exist between the results from Korea tributed when they are log-transformed. It is standard practice to (KNHANES VI) and those of previously published Western re- log-transform serum TSH levels to calculate the 95% confi- ports. First, the serum TSH levels in the Korean population All Men Women 2.6 1.4 2.6 2.6 1.4 1.4 2.4 2.4 2.4 1.3 1.3 1.3 2.2 2.2 2.2 1.2 1.2 1.2 2.0 2 2 1. 1.8 8 1.8 1.1 1.1 1.1 10−19 10-19 10-19 20−29 20-29 20-29 30−39 30-39 30-39 40−49 40-49 40-49 50−59 50-59 50-59 60−69 60-69 60-69≥ >70 70>70 10-19 10−19 10-19 20-29 20−29 20-29 30-39 30−39 30-39 40-49 40−49 40-49 50-59 50−59 50-59 60-69 60−69 60-69>70≥ >70 70 A B Y Ye ear arYear YearY Ye ear ar All All MenMen Wom W eom n en All All MenMen Wom W eom n en Fig. 1. Serum thyroid stimulating hormone (TSH) and free thyroxine (fT ) levels by age and sex. (A) Geometric mean TSH levels (mIU/L) by age. (B) Mean fT4 levels (ng/dL) by age. A U-shaped association was found between serum TSH levels and age. TSH levels were signifi- cantly higher in women than in men (P< 0.001). Serum fT4 levels significantly decreased with age (P for trend < 0.0001), and were signifi- cantly higher in men than in women (P< 0.0001). Adapted from Park et al. [6]. www.e-enm.org Copyright © 2020 Korean Endocrine Society TSH (mIU/L) TSH (mIU/L) TSH (mIU/L) FT4 (ng/dL) fT (ng/dL) FT4 (ng/dL) TSH (mIU/L) Korean TSH, Free T4, TPOAb, Urine Iodine Levels were markedly higher than those in Western reports. For exam- (Table 1). Previous studies have generally reported that TPOAb ple, the mean value and upper reference limit of serum TSH in a increased TSH level, while smoking decreased it. Park et al. report from the USA (National Health and Nutrition Examina- [12] recently evaluated the associations of smoking with TSH tion Survey [NHANES] III) were 1.40 and 4.12 mIU/L, respec- levels, TPOAb, and UIC using the KNHANES VI. They report- tively, whereas the corresponding Korean results were 2.16 and ed that a smoking-induced decrease in TSH levels was evident 7.03 mIU/L, respectively [2]. All Korean values were right- in individuals with iodine deficiency, and that the TPOAb posi- shifted, and these differences might be related to excessive io- tivity rate was high in non-smokers. Therefore, they concluded dine intake in the Korean population [9]. Genetic differences re- that smoking might be not associated with the presence of garding the set-point of thyroid hormone have been proposed, TPOAb or iodine intake, and that smoking may have a direct ef- and such differences might be another reason for the higher fect on thyroid function that is not mediated by autoimmune TSH levels found in Koreans [3,10]. Second, a U-shaped curve processes. between age and serum TSH levels, with lower levels in mid- dle-aged adults and higher levels in younger and older age Table 1. Prevalence of TPOAb in the Korean Population Ac- groups, was only found in the Korean results (Fig. 2). Most cording to Age and Sex studies reported that serum TSH levels gradually increased with Age, yr All, % Men, % Women, % age. However, a recent result from the Rotterdam Study report- ed that TSH levels remained stable with age [3]. A U-shaped 10–18 2.81 2.12 3.73 curve was also found between age and UIC. Therefore, changes 19–29 4.13 3.27 5.23 in serum TSH levels with age were influenced by changes in the 30–39 5.63 2.76 9.08 UIC (reflecting iodine intake) in the Korean population [9,11]. 40–49 7.94 4.22 12.54 50–59 11.71 5.97 17.78 60–69 10.01 7.71 11.80 PREVALENCE OF TPOAb IN THE KOREAN ≥70 3.13 3.13 3.14 POPULATION All ages 7.30 4.33 10.62 TPOAb positivity was defined as a level of 34.0 IU/mL. Se- Adapted from Kim et al. [5]. TPOAb positivity was defined as 34.0 rum TPOAb was detected in 7.30% of subjects (men 4.33%, IU/mL. Serum TPOAb titers tended to increase with age, but decreased after age 70. They were higher in women than in men. women 10.62%). TPOAb titers tended to increase with age, but TPOAb, thyroid peroxidase antibody. decreased after age 70. They were higher in women than in men UIC TSH 450 450 2.4 2.4 400 400 2.3 2.3 2.2 2.2 2.1 2.1 250 250 200 2 200 2.0 10-19 20-29 30-39 40-49 50-59 60-69 >70 10−19 20−29 30−39 40−49 50−59 60−69 ≥70 Years Year UIC TSH Fig. 2. Relationship of urinary iodine concentration (UIC) with serum thyroid stimulating hormone (TSH) levels. A U-shaped curve was found between age and serum TSH levels, with lower levels in middle-aged adults and higher levels in younger and older age groups. A U- shaped curve was also detected for the relationship between age and UIC. Therefore, changes in serum TSH levels with age may be influ- enced by changes in UIC in the Korean population. Adapted from Park et al. [6]. Copyright © 2020 Korean Endocrine Society www.e-enm.org UIC (μg/L) UIC (ug/L) TSH (mIU/L) Chung JH All Men Women 10−19 20−29 30−39 40−49 50−59 60−69 ≥70 Year Fig. 3. Urinary iodine concentration (UIC, μg/L) by age and sex. According to the World Health Organization recommendations, only 23% of subjects were in the adequate range (UIC, 100 to 199 μg/L), and 65% were classified as having an intake that was above requirements (UIC 200 to 299 μg/L) or excessive (UIC 300 μg/L). However, 12% had insufficient iodine intake (UIC 100 μg/L). The median UIC ≥ < was higher in school-aged children (6 to 12 years) and in the above 70 years age group than in other age groups. Adapted from Park et al. [6]. mass index, and smoking status, serum TSH levels were signifi- MEAN VALUES AND REFERENCE cantly correlated with UIC (r 0.154, P 0.0001). The changes = < INTERVALS OF UIC IN THE KOREAN in UIC with age showed a U-shape (Fig. 2). The median UIC POPULATION increased with household income level (P for trend 0.001). Most Koreans have been reported to have sufficient iodine in- Individuals living in seaside or urban areas had higher UIC val- take [9,13,14]. However, no nationwide survey had investigated ues than those in inland or rural areas. This trend is consistent iodine intake in a representative sample of the entire Korean with the findings of previous studies [20,21]. Choi et al. [22] population before 2013. In non-pregnant, non-lactating women, analyzed UIC in adolescents aged 10 to 18 years and their par- a UIC of 100 μg/L corresponds roughly to a daily iodine intake ents using the KNHANES VI. They reported that the prevalence of approximately 150 μg under steady-state conditions [15,16]. of iodine deficiency exceeded 10% in several regions of Korea, Kim et al. [17] published results on the UIC in Koreans based and that iodine intake status in Korean adolescents was primari- on the KNHANES VI, which was the first nationwide report on ly affected by their families’ eating habits and household in- this topic. They reported that the median UIC in the Korean come. population was 294 μg/L, corresponding to a level of iodine in- take that is above requirements according to the World Health PREVALENCE OF OVERT HYPERTHYROIDISM Organization (WHO) recommendations. The unique eating hab- AND HYPOTHYROIDISM its of Koreans, including the consumption of basic ingredients made from sea tangle or kelp and seaweed soup, are considered Kim et al. [5] investigated the prevalence of thyroid dysfunction to be a major cause of these trends [9,18,19]. According to the in the Korean population based on the KNHANES VI, and re- WHO recommendations, only 23% of participants were in the ported that the prevalence of overt and subclinical hyperthyroid- adequate range (UIC, 100 to 199 μg/L), and 65% were classi- ism was 0.54% (men, 0.30%; women, 0.81%) and 2.98% (men, fied as having an intake that was above requirements (UIC, 200 2.43%; women, 3.59%), respectively. They also reported that to 299 μg/L) or excessive (UIC 300 μg/L). However, 12% of the prevalence of overt and subclinical hypothyroidism (SCH) participants had insufficient iodine intake (UIC 100 μg/L). was 0.73% (men, 0.40%; women, 1.10%) and 3.10% (men, The median UIC was higher among school-aged children (6 to 2.26%; women, 4.04%), respectively, and its prevalence in- 12 years, 511 μg/L) and in those above 70 years of age than in creased with age until the age group of 50 to 59 years. Seo et al. other age groups (Fig. 3). After adjusting for age, sex, body [23,24] published results on the prevalence of overt hyperthy- www.e-enm.org Copyright © 2020 Korean Endocrine Society UIC (μg/L) Korean TSH, Free T4, TPOAb, Urine Iodine Levels Table 2. Prevalence of Hyperthyroidism and Hypothyroidism in Korea: Comparison of KNHANES VI Data with HIRA Data Kim et al. [5] Seo et al. [23,24] Publication Endocrinol Metab (Seoul) 2017;32:106-14 J Korean Thyroid Assoc 2013;6:56-63 Endocrinol Metab (Seoul) 2015;30:288-96 Data source KNHANES VI HIRA Inclusion Individuals who were not receiving treatment Subclinical patients receiving overtreatment Exclusion Well-controlled euthyroid patients with treatment Individuals who were not receiving treatment Prevalence Hyperthyroidism Overt 0.54% (men, 0.30%; women, 0.81%) 0.34% (men, 0.20%; women, 0.47%) Subclinical 2.98% (men, 2.43%; women, 3.59%) Hypothyroidism Overt 0.73% (men, 0.40%; women, 1.10%) 1.43% (men, 0.44%; women, 2.40%) Subclinical 3.10% (men, 2.26%; women, 4.04%) These two sets of results should not be compared without adjustment because of differences in the subjects. KNHANES, Korea National Health and Nutrition Examination Survey; HIRA, Health Insurance Review and Assessment Service. roidism and overt hypothyroidism using National Health Insur- CONCLUSIONS ance claims data provided by the Health Insurance Review and Assessment Service (HIRA) in 2013 and 2015, respectively. Based on the KNHANES VI, the mean TSH level in the Korean They reported that the prevalence of overt hyperthyroidism and population was 2.16 mIU/L, and its reference interval was 0.59 overt hypothyroidism was 0.34% (men, 0.20%; women, 0.47%) to 7.03 mIU/L. A U-shaped association was found between se- and 1.43% (men, 0.44%; women, 2.40%), respectively. The rum TSH levels and age. Serum TSH levels were significantly prevalence derived from the KNHANES VI data included indi- higher in women than men. The mean fT level was 1.25 ng/dL, viduals who were not receiving treatment, but excluded well- with a reference interval of 0.92 to 1.60 ng/dL. Serum fT levels controlled euthyroid patients with treatment, while the preva- significantly decreased with age, and were significantly higher lence derived from the HIRA data may have included subclini- in men than in women. Serum TPOAb was detected in 7.30% cal patients receiving overtreatment, while excluding individu- of subjects, a proportion that tended to increase with age. The als who were not receiving treatment. Therefore, these two sets median UIC was 294 μg/L, and a U-shaped relationship of UIC of results should not be compared without adjustment. Ha et al. with age was evident. Only 23% of subjects had an adequate io- [25] investigated the risk factors for SCH according to sex using dine intake according to the WHO criteria, and 65% were clas- KNHANES VI data. They reported that TPOAb positivity sig- sified as having an intake that was above requirements or exces- nificantly increased the risk of SCH in both men and women, sive. However, 12% had insufficient iodine intake. The preva- but smoking reduced it in men. The risk of SCH increased as lence of overt hyperthyroidism and overt hypothyroidism in the UIC increased, and this trend was more marked in men than in Korean population was 0.34% to 0.54% and 0.73% to 1.43%, women. The odds ratio for SCH for urban (vs. rural) residence respectively. was 1.78. When jointly evaluating these two nationwide sets of results, CONFLICTS OF INTEREST the prevalence of overt hyperthyroidism and overt hypothyroid- ism in the Korean population may be 0.34% to 0.54% (men, No potential conflict of interest relevant to this article was re- 0.20% to 0.30%; women, 0.47% to 0.81%) and 0.73% to 1.43% ported. (men, 0.40% to 0.44%; women, 1.10% to 2.40%), respectively (Table 2). ORCID Jae Hoon Chung https://orcid.org/0000-0002-9563-5046 Copyright © 2020 Korean Endocrine Society www.e-enm.org 11 Chung JH mination of the hypothalamic-pituitary-thyroid axis: where REFERENCES do we stand? Endocr Rev 2015;36:214-44. 1. Chung JH. Evaluation of thyroid hormone levels and uri- 11. Joung JY, Cho YY, Park SM, Kim TH, Kim NK, Sohn SY, nary iodine concentrations in Koreans based on the data et al. Effect of iodine restriction on thyroid function in sub- from Korea National Health and Nutrition Examination Sur- clinical hypothyroid patients in an iodine-replete area: a vey VI (2013 to 2015). Endocrinol Metab (Seoul) 2018;33: long period observation in a large-scale cohort. Thyroid 160-3. 2014;24:1361-8. 2. Hollowell JG, Staehling NW, Flanders WD, Hannon WH, 12. Park S, Kim WG, Jeon MJ, Kim M, Oh HS, Han M, et al. Gunter EW, Spencer CA, et al. Serum TSH, T(4), and thy- Serum thyroid-stimulating hormone levels and smoking sta- roid antibodies in the United States population (1988 to tus: data from the Korean National Health and Nutrition Ex- 1994): National Health and Nutrition Examination Survey amination Survey VI. Clin Endocrinol (Oxf) 2018;88:969- (NHANES III). J Clin Endocrinol Metab 2002;87:489-99. 76. 3. Chaker L, Korevaar TI, Medici M, Uitterlinden AG, Hof- 13. Choi J, Kim HS, Hong DJ, Lim H, Kim JH. Urinary iodine man A, Dehghan A, et al. Thyroid function characteristics and sodium status of urban Korean subjects: a pilot study. and determinants: the Rotterdam study. Thyroid 2016;26: Clin Biochem 2012;45:596-8. 1195-204. 14. Lee J, Kim JH, Lee SY, Lee JH. Iodine status in Korean pre- 4. Baloch Z, Carayon P, Conte-Devolx B, Demers LM, Feldt- school children as determined by urinary iodine excretion. Rasmussen U, Henry JF, et al. Laboratory medicine practice Eur J Nutr 2014;53:683-8. guidelines: laboratory support for the diagnosis and moni- 15. International Council for Control of Iodine Deficiency Dis- toring of thyroid disease. Thyroid 2003;13:3-126. orders; UNICEF; World Health Organization. Assessment 5. Kim WG, Kim WB, Woo G, Kim H, Cho Y, Kim TY, et al. of iodine deficiency disorders and monitoring their elimina- Thyroid stimulating hormone reference range and preva- tion: a guide for programme managers. 3rd ed. Geneva: lence of thyroid dysfunction in the Korean population: Ko- World Health Organization; 2007. rea National Health and Nutrition Examination Survey 2013 16. Chung JH. Low iodine diet for preparation for radioactive to 2015. Endocrinol Metab (Seoul) 2017;32:106-14. iodine therapy in differentiated thyroid carcinoma in Korea. 6. Park SY, Kim HI, Oh HK, Kim TH, Jang HW, Chung JH, et Endocrinol Metab (Seoul) 2013;28:157-63. al. Age- and gender-specific reference intervals of TSH and 17. Kim HI, Oh HK, Park SY, Jang HW, Shin MH, Kim SW, et free T4 in an iodine-replete area: data from Korean National al. Urinary iodine concentration and thyroid hormones: Ko- Health and Nutrition Examination Survey IV (2013-2015). rea National Health and Nutrition Examination Survey PLoS One 2018;13:e0190738. 2013-2015. Eur J Nutr 2019;58:233-40. 7. Kwon H, Kim WG, Jeon MJ, Han M, Kim M, Park S, et al. 18. Kim JY, Kim KR. Dietary iodine intake and urinary iodine Age-specific reference interval of serum TSH levels is high excretion in patients with thyroid diseases. Yonsei Med J in adolescence in an iodine excess area: Korea National 2000;41:22-8. Health and Nutrition Examination Survey Data. Endocrine 19. Rhee SS, Braverman LE, Pino S, He X, Pearce EN. High 2017;57:445-54. iodine content of Korean seaweed soup: a health risk for 8. Jeon MJ, Kim WG, Kwon H, Kim M, Park S, Oh HS, et al. lactating women and their infants? Thyroid 2011;21:927-8. Excessive iodine intake and thyrotropin reference interval: 20. Zou Y, Lou X, Ding G, Mo Z, Zhu W, Mao G. A cross-sec- data from the Korean National Health and Nutrition Exami- tional comparison study on the iodine nutritional status be- nation Survey. Thyroid 2017;27:967-72. tween rural and urban residents in Zhejiang Province, China. 9. Kang TS, Leem DG, Seo IW, Lee YJ, Yoon TH, Lee JH, et BMJ Open 2014;4:e005484. al. Monitoring of iodine in foods for estimation of dietary 21. Aghini-Lombardi F, Vitti P, Antonangeli L, Fiore E, Piaggi P, intake [Internet]. Cheongju: National Institute of Food and Pallara A, et al. The size of the community rather than its Drug Safety Evaluation; 2012 [cited 2020 Feb 3]. Available geographical location better defines the risk of iodine defi- from: file:///C:/Users/USER/Downloads/OA2014_Z4_0250. ciency: results of an extensive survey in Southern Italy. J pdf. Endocrinol Invest 2013;36:282-6. 10. Medici M, Visser WE, Visser TJ, Peeters RP. Genetic deter- 22. Choi YC, Cheong JI, Chueh HW, Yoo JH. Iodine status and www.e-enm.org Copyright © 2020 Korean Endocrine Society 12 Korean TSH, Free T4, TPOAb, Urine Iodine Levels characteristics of Korean adolescents and their parents based pothyroidism and causative diseases in Korea as determined on urinary iodine concentration: a nationwide cross-section- using claims data provided by the health insurance review al study. Ann Pediatr Endocrinol Metab 2019;24:108-15. and assessment service. Endocrinol Metab (Seoul) 2015;30: 23. Seo GH, Kim SW, Chung JH. Incidence & prevalence of 288-96. hyperthyroidism and preference for therapeutic modalities 25. Ha J, Lee J, Jo K, Lim DJ, Kang MI, Cha BY, et al. Sex dif- in Korea. J Korean Thyroid Assoc 2013;6:56-63. ferences in risk factors for subclinical hypothyroidism. En- 24. Seo GH, Chung JH. Incidence and prevalence of overt hy- docr Connect 2018;7:511-22. Copyright © 2020 Korean Endocrine Society www.e-enm.org

Journal

Endocrinology and MetabolismPubmed Central

Published: Mar 19, 2020

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