The Benefit and Concern for Universal Salt Iodination Zhongyan SHAN Department of Endocrinology, The First Affiliated Hospital of China Medical University 1

Content The reason for USI The benefit about USI The concern about USI

Distribution of Iodine Deficiency Worldwide IDD Disorders in Developing Countries Iodine deficiency WHO86819 Source: ACC/SCN, 1987

Distribution of endemic goiter in China before 1979 Iodine Status in China Iodine deficiency Distribution of endemic goiter in China before 1979 Ma Tai et al. People's Health Publishing House 1980

Spectrum of IDD across the Life-span Neonate Neonatal goiter Neonatal hypothyroidism Endemic mental retardation Increased susceptibility of the thyroid gland to nuclear radiation Child and adolescent Goiter hypothyroidism hyperthyroidism Impaired mental function Retarded physical development Increased susceptibility of thyroid gland to nuclear radiation Adult Goiter, with its complications Hypothyroidism Impaired mental function Spontaneous hyperthyroidism in the elderly Iodine-induced hyperthyroidism Abortions Stillbirths Congenital anomalies perinatal mortality Endemic cretinism Deaf mutism Fetus Iodine status worldwide WHO Global Database on Iodine Deficiency

Characteristic Features of IDD M. B Zimmermann et al. Lancet 2008; 372: 1251–62. ACC/SCN State-of -the-art series nutrition policy discussion paper No 3.1988

Strategy for Iodine Supplementation USI Safe, feasible and highly cost-effective strategy Others Iodine supplementation of foods and water for human consumption Iodine medications (notably oral administration of iodized oil) to directly supplement the inhabitants at risk of IDD in endemic areas. Active prophylaxis of domestic animals; use of iodine materials for plants or iodine deficient soils.

Content The reason for USI The benefit about USI The concern about USI

Benefit in Infant and Childhood After IS in moderate-to-severe iodine deficient area Prevalence of iodine deficiency decreased Prevalence of Cretinism reduced Mean developmental quotient increased Infant mortality reduced Cognition of childhood increased Somatic growth of childhood improved in mild-to-moderate iodine deficient area Potential benefit during pregnancy remain unclear

Prevalence of ID Decreased after IS In 2003 In 2007 In 2012 There were 32 countries with ID in total 150 WHO countries. Iodine status worldwide, WHO Global Database on Iodine Deficiency, 2004 M. B Zimmermann et al. Lancet 2008; 372: 1251–62 . Zimmermann M B, and Andersson M Curr Opin Endocrinol Diabetes Obes 2012, 19:382–387

Prevalence of Cretinism Reduced after IS In an severe iodine deficient area in Papua New Guinea Alternate families received saline (control) or iodized oil injection. The primary outcome was the prevalence of cretinism at 4- and 10-yr follow-up Design at 10 yrs 1.0 1.1 1.2 0.05 0.1 Reduction of endemic cretinism at 4 yrs 0.17(0.05-0.58) RR(95%CI) 0.2 0.3 0.4 0.5 0.6 0.27(0.12-0.60) Results Pharoah POD et al. Lancet. 1971, 13;1(7694):308-10. Pharoah PO, Connolly KJ. Int J Epidemiol 1987, 16:68–73

Developmental Quotient Increased after IS Iodine Supplementation Reduced Cretinism in Severe Iodine Deficient Areas Developmental Quotient Increased after IS Design In a severe iodine deficient area in western China Intervention was oral iodized oil at each trimester of pregnancy Children were divided into Untreated children: 1–3 yr of age Treated children born to treated women were followed for 2 yr. The main outcomes: neurological examination head circumference Development quotient Cao XY, et al. N Engl J Med 1994,331:1739–1744

Cognition at School Age Improved After IS A placebo-controlled, double-blind, 6-month intervention trial Moderately iodine-deficient area in Albania 10- to 12-yr-old children (n= 310) were randomized Receive either 400 mg of iodine as oral iodized oil or placebo. Children were given a serial of seven cognitive and motor tests Median UI in the treated group was 172μ g/liter at 24 wks Mean T4 increased approximately 40% compared with placebo Zimmermann MB, et al.Am J Clin Nutr2006 83:108–114 13

Cognition at School Age Improved After IS 1.0 1.5 2.0 2.5 3.0 0.5 Cognitive Improvement Ravens matrices 4.7(3.8-5.8) 2.8(1.6-4.0) 3.5 RR(95%CI) 4.0 4.5 5.0 5.5 6.0 Rapid target marking Symbol search 2.8(1.9-3.6) Rapid naming 4.5(2.3-6.6) cognitive impairment Zimmermann MB, et al.Am J Clin Nutr2006 83:108–114 14

Infant Mortality Reduced after IS the infant mortality rate In three areas of severe iodine deficiency in Xinjiang, China Potassium iodate for women of childbearing age over a 2- to 4-wk period Observe neonatal and infant mortality in the following 2–3 yr. the infant mortality rate (/1000 births) The odds of neonatal death were reduced by 65% in iodine treated groups DeLong GR, et al. Lancet, 1997, 350:771–773.

Zimmermann MB, et al. J Clin Endocrinol Metab 2007, 92:437–442 Somatic Growth of Childhood Improved After IS Aim: to determine whether iodine repletion improves growth in school-age children Design: Three prospective, double-blind intervention studies in severely, moderately , and mildly iodine-deficient areas. Intervention: receiving either 400mg of oral iodized oil or placebo for 6 months Zimmermann MB, et al. J Clin Endocrinol Metab 2007, 92:437–442

Zimmermann MB, et al. J Clin Endocrinol Metab 2007, 92:437–442 Somatic Growth of Childhood Improved After IS Height-for-age z-score Weight-for-age z-score Zimmermann MB, et al. J Clin Endocrinol Metab 2007, 92:437–442

Controlled Studies in Mild-to-Moderate ID Author UI Time Number Amount Main Results Romano (1991) Italy 31–37 μg/L T1 SI N=17 Con N=18 120-180μg iodized salt In controls, a 16% increase in TV. Treatment had no effect on maternal TSH Pedersen (1993) Denmark 55 G17 to term SI N=28 Con N=26 200μg KI Maternal TV increased 16% in the treated group vs. 30% in controls. Maternal Tg and TSH were lower in the treated group. Glinoer (1995) Belgium 36 G14 to-term SI N=36 Con N=36 100μg KI The treated women had smaller TV, and lower TSH and Tg , compared with controls. TV: thyroid volume

Controlled Studies in Mild-to-Moderate ID Author UI Time Number Amount Main Results Liesenkotteer (1996) Germany 53 g/g Cr G11 to term SI N=38 Con N=70 300μg KI Treatment had no significant effect on maternal TSH, T3, T4, TV, or Tg. Antonangeli (2002) Italy 74g/g Cr G18–26 to G29–33 wk. SI-1 N=32 SI-2 N=35 200μg KI 50μg KI no differences in maternal FT4, FT3, TSH, Tg, or TV between groups. TV: thyroid volume

Controlled Studies in Mild-to-Moderate ID A Summary mild-to-moderate iodine deficiency：37-70μg/L After iodine supplementation of 150~300μg/d UI concentration increased Maternal thyroid volume decreased Neonatal thyroid volume decreased No effect on maternal FT4, FT3, TSH, and Tg No long-term follow-up data potential benefit of iodine supplementation in mild-to-moderate iodine deficiency during pregnancy remain unclear Zimmermann M: Thyroid, 2007, 17: 829-835

Benefit about USI in Adulthood In adults, iodine supplementation can change the subtype of thyroid cancer decrease the risk of diffuse goiter

Prevalence of Thyroid Goiter in China Before and After USI (1995–2005) Time SIC (mg/kg) UIC (μg/L) TGR(%) palpation B ultrasound Rate of qualified iodized salt 1995 16.2 164 20.4 - 39.9 1997 37.0 330 10.9 9.6 81.1 1999 42.3 306 8.8 8.0 88.9 2002 31.4 241 5.8 5.1 2005 30.8 246 5.0 4.0 90.2

Changes of Type of Thyroid Cancer after USI Iodine deficiency sufficiency Undifferentiated thyroid cancer follicular thyroid cancer papillary thyroid cancer

Content The reason for USI The benefit about USI The concern about USI

Recommended Dietary Allowance and Upper Limit of Iodine Intake (μg/d) Recommendation by the U.S. National Academy of Sciences Jean Vanderpas. Annu. Rev. Nutr. 2006. 26:293–322

between Iodine Intake and Thyroid Diseases U-Shaped Curve between Iodine Intake and Thyroid Diseases Iodine Intake Level Thyroid Disease Laurberg P et al: Thyroid 2001,11(5):457

Criteria for Assessing Iodine Nutrition Based on Median of urinary iodine concentrations In school-aged children WHO, UNICEF,ICCIDD, 2007. Geneva: WHO

Optimal Iodine Nutrition and Corresponding Iodine Intake WHO, UNICEF, ICCIDD 2001 A guide for programme managers. WHO publ., Geneva.

Spectrum of Disorders Depends on UIC MUI P LaurbergBest. Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 13–27

Prevalence of Hypothyroidism Increased after USI * *:compared with another area,P<0.05 Prevalence(%)] * MUI Denmark n=523 the elderly *:compatred with other two areas,P<0.05 #:Compared with area with the lowest UI,P<0.05 * Prevalence(%)] # * # Hungary n=346 the elderly Laurberg：J Clin Endocrinol Meatb, 1998,83:765. Szabolcs，Clin Endocrinol,97,47:87.

Incidence of Hypothyroidism Increase after USI Aalborg P Laurberg, Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 13–27

Incidence of Hyperthyroidism Increased after USI % ppm ppm /100,000 Zimbabwe ，1995 Austria ，1998 Lancet 1995, 346:1563 Eur J Nucl Med 1998, 25:367

Types of hyperthyroidism in populations with different iodine intake levels Iodine intake level 50-60 μg/day Iodine intake level 250-350 μg/day P Laurberg, Best Practice & Research Clinical Endocrinology & Metabolism 24 (2010) 13–27

Prevalence of AIT and Thyroid Cancer after USI Prevalence of AIT in Poland Prevalence of Thyroid Cancer in Australia Thyroid, 1997, 7: 733-741. Euro J Endocrinol,2002,146:19-26.

Iodine Nutrition of Population in China From 1995 to 2005 330 Excessive 306 MUI(mcg/L) 241 246 More than Adequate 165 Adequate Deficient USI Salt iodine was adjusted

Epidemiologic Studies about Iodine and Thyroid Diseases in China Date Subject Contents population 1999 IITD-1 3 rural communities with MUI 84μg/L, 243 μg/L and 651 μg/L. 3,761 2004 IITD-2 IITD-1 follow-up ( 5 years) 3,018 2007 IITD-3 2 rural communities with MUI 145 μg/L and 261μg/L 3,813 2010 IITD-4 6 cities with more than adequate iodine intake and 4 cities with adequate iodine intake 15,181 2002 PPT Screening pregnant women and followed-up for 12 months 610 IITD: iodine-induced thyroid diseases; PPT: postpartum thyroiditis; 36

IITD-1, IITD-2 Teng WP, Shan ZY, et al: New Engl J Med 354: 2783-2793

IITD-1, IITD-2 Study Design Zhangwu Panshan Huanghua Study Design Three communities with iodine- : Mild deficiency (84μg/L) More than adequacy (243μg/L) Excess (614μg/L) Baseline study in 1999 and follow-up in 2004 To obtain prevalence and incidence of thyroid diseases and an association with iodine intake Teng WP, Shan ZY, et al: New Engl J Med 354: 2783-2793 38

Overt hyperthyroidism Subclinical hyperthyroidism IITD-1, IITD-2 HYPERTHYROIDISM, Prevalence Panshan 103μg/L Zhangwu 375μg/L Huanghua 615μg/L 4.8 3.9 3.7 4 3.2 Prevalence rate[%] 2.4 2 1.6 1.2 1.6 1.1 0.8 * Overt hyperthyroidism Subclinical hyperthyroidism *:Compared with Panshan and Zhangwu，P<0.05

Subclinical hyperthyroidism IITD-1, IITD-2 HYPERTHYROIDISM, Incidence Panshan 103μg/L Zhangwu 375μg/L Huanghua 615μg/L 1.36 0.94 1.97 0.81 1.04 0.5 1 1.5 2 Cumulative incidence[%] Subclinical hyperthyroidism Overt hyperthyroidism

IITD-1, IITD-2 * * HYPOTHYROIDISM, Prevalence 6.1 2.9 2.0 0.9 0.9 0.3 # 2.9 2.0 * 0.9 # 0.9 0.3 * *: Compared with Panshan, P<0.05 #: Compared with Panshan and Zhangwu, P<0.05 Teng WP, Shan ZY, et al: New Engl J Med 354: 2783-2793

IITD-1, IITD-2 * HYPOTHYROIDISM, Incidence 2.9 2.6 0.5 0.3 0.2 *: Compared with Panshan，P<0.05 * 2.9 2.6 0.2 0.3 0.5 Teng WP, Shan ZY, et al: New Engl J Med 354: 2783-2793

IITD-1, IITD-2 THYROID GOITER, Prevalence Prevalence rat (%) * * 19.5 20 20 15 * 13.6 15 Prevalence rat (%) 10 10 * 5.1 # 5 5 3.7 3.5 2.5 Panshan Zhangwu Huanghua Panshan Zhangwu Huanghua Diffuse goiter Nodular goiter *:Compared with Huanghua,P<0.05 #: Compared with Huanghua and Panshan,P<0.05

IITD-1, IITD-2 THYROID GOITER, Incidence Incidence rate(‰/year) 10 10 7.5 7.08 7.5 6.9 5.01 Incidence rate(‰/year) * 4.4 * 5 5 * 2.41 # 2.5 2.5 0.85 * Panshan Zhangwu Huanghua Panshan Zhangwu Huanghua Diffuse goiter Nodular goiter *:Compared with Huanghua,P<0.05 #: Compared with Huanghua and Zhangwu,P<0.05 *:Compared with Zhangwu,P<0.05

Teng XC, Shan ZY, Teng WP: Euro J Endocrinol, 2011,164: 943-950 IITD-3 Teng XC, Shan ZY, Teng WP: Euro J Endocrinol, 2011,164: 943-950 45

Teng XC, Shan ZY, Teng WP: Euro J Endocrinol, 2011,164: 943-950 IITD-3 Compare difference of thyroid diseases between adequate iodine intake and more than adequate iodine intake Rongxing Chengshan Study Design Two communities with iodine- : Adequate (145μg/L) More than adequate (261μg/L) A cross-sectional study in 2007 Teng XC, Shan ZY, Teng WP: Euro J Endocrinol, 2011,164: 943-950 46

Teng XC, Shan ZY, Teng WP: Euro J Endocrinol, 2011,164: 943-950 IITD-3 Characteristics of Two Communities Teng XC, Shan ZY, Teng WP: Euro J Endocrinol, 2011,164: 943-950 47

Teng XC, Shan ZY, Teng WP: Euro J Endocrinol, 2011,164: 943-950 IITD-3 HYPOTHYROIDISM prevalence * # #: Compared with Chengshan, P<0.01 *: Compared with Chengshan, P<0.05 Teng XC, Shan ZY, Teng WP: Euro J Endocrinol, 2011,164: 943-950

Teng XC, Shan ZY, Teng WP: Euro J Endocrinol, 2011,164: 943-950 IITD-3 ANTI-THYROID ANTIBODIES prevalence * *: Compared with Chengshan, P<0.05 Teng XC, Shan ZY, Teng WP: Euro J Endocrinol, 2011,164: 943-950

A survey of iodine status and thyroid diseases in ten cities in China IITD-4 A survey of iodine status and thyroid diseases in ten cities in China National Cooperation Group of IITD-4 Study Weiping Teng Lulu Chen Chao Liu Binyin Shi Lixin Shi Zhongyan Shan Nanwei Tong Shu Wang Jianping Weng Xiaoping Xing Jiajun Zhao 50 50

IITD-4 Distribution of Samples – 10 Cities Shenyang Beijing Jinan Guangzhou Shanghai Jinan Nanjing Beijing Guiyang Xi’an Shenyang Wuhan Chengdu 51 51

IITD-4 Demographic Characteristics of 10 Cities City n Gender (M：F) Average of Age Range of Age Beijing 1539 1：1.9 47.3±13.4 20-88 Chengdu 1500 1：1.2 45.8±15.2 15-82 Guangzhou 1505 1：1.4 45.0±15.2 18-83 Guiyang 1512 45.2±14.8 20-78 Jinan 1：1.5 45.3±14.9 20-82 Nanjing 1572 44.7±15.4 17-92 Shanghai 45.1±14.9 17-82 Shenyang 1549 45.1±15.1 20-84 Wuhan 17-85 Xi’an 46.1±14.8 20-83 Total 15181 45.5±14.9 15-92 52 52

IITD-4 Iodine Nutrition Status in 10 Cities 6 cities with adequate iodine intake 4 cities with more than adequate iodine intake Excessive 282 241 More than Adequate 228 207 196 184 185 174 169 169 156 Adequate Deficient Xi’an Wuhan Shenyang Shanghai Nanjing Jinan Guiyang Guangzhou Chengdu Total Beijing Beijing Beijing Beijing Beijing Beijing Beijing Beijing Beijing Beijing Beijing Chengdu Chengdu Chengdu Chengdu Chengdu Chengdu Chengdu Chengdu Chengdu Guiyang Guiyang Guiyang Guiyang Guiyang Guiyang Guiyang Jinan Jinan Jinan Jinan Jinan Jinan Nanjing Nanjing Nanjing Nanjing Nanjing Shanghai Shanghai Shanghai Shanghai Shenyang Shenyang Shenyang Wuhan Wuhan Xi’an Total Total Total Total Total Total Total Total Total Total Guangzhou Guangzhou Guangzhou Guangzhou Guangzhou Guangzhou Guangzhou Guangzhou 53 53

IITD-4 HYPERTHYROIDISM - Prevalence * N=15,177 Prevalence (%) 3.2% Prevalence (%) P=0.000 1.6% 1.2% 1.0% Clinical Hyperthyroidism Subclinical Hyperthyroidism 54

IITD-4 HYPOTHYROIDISM - Prevalence * * N=15,181 Prevalence (%) 8.2% P=0.000 Prevalence (%) * 3.8% P=0.043 2.1% 0.8% Overt Hypothyroidism Subclinical Hypothyroidism 55 55

IITD-4 ANTITHYROID ANTIBODIES - Prevalence * * N=15,181 P=0.008 13.4% 12.4% 12.0% 11.0% 56 56

IITD-4 GOITER - Prevalence N=15,181 * P=0.000 1.4% 4.5% 57 57

IITD-4 THYROID NODULE - Prevalence * N=15,181 12.4% P=0.000 9.3% 8.4% 3.4% 58 58

Postpartum Thyroiditis 59

Iodine and Postpartum Thyroiditis Effect of Iodine Intake on Post-partum Thyroiditis Study Design 610 pregnant women enrolled from an iodine-sufficient area The patients with thyroid dysfunction were followed for 12 months after delivery TSH, thyroid hormones and urinary iodine were tested every 3 months Guan HX, Li CY, Teng WP J Endocrinol Invest. 2005, 2 : 876

Iodine and Postpartum Thyroiditis PPT prevalence * Guan HX, Li CY, Teng WP J Endocrinol Invest. 2005, 2 : 876

Iodine and Thyroid Dysfunction during Pregnancy Thyroid dysfunction during late gestation is associated with excessive iodine intake in pregnant women Sang Zhongna et al. J Clin Endocrinol Metab 2012，97：E1363-1369

Excessive Iodine Intake Increase Thyroid Dysfunction during late Gestation Sang Zhongna et al. J Clin Endocrinol Metab 2012，97：E1363-1369

Summary USI is a feasible and highly cost-effective strategy Iodine supplementation (IS) can prevent and treat iodine-deficiency disorders Iodine levels that are more than adequate or excessive could increased risk of subclinical hypothyroidism and autoimmune thyroiditis Iodine intake should be maintained at a safe level, MUI between 100 and 200µg/L is a optimal range 64

China Medical University The First Hospital of CMU 65