Iodine deficiency disorders: Prof. Michael Zimmermann MD Swiss Federal Institute of Technology Zurich, Switzerland

Transcription

1 Iodine deficiency disorders: 2016 Prof. Michael Zimmermann MD Swiss Federal Institute of Technology Zurich, Switzerland

2 If you had $75 billion to spend on global development where should you start? 2

3 In 2008 and 2012, a panel of Nobel Laureate economists were asked that same question both times they gave the same answer. Did they say #1 Correcting Micronutrient Malnutrition EDUCATION ARMED CONFLICT CLIMATE CHANGE CHRONIC DISEASE INFECTIOUS DISEASE WATER & SANITATION POPULATION GROWTH 3

4 The smartest global investment 1 Best investment Copenhagen Consensus 2008: Micronutrients for children IMPROVED CHILD GROWTH AND HEALTH, BETTER SCHOOL LEARNING Correcting iodine deficiency $ 35 1 Best investment Copenhagen Consensus 2012: Micronutrient interventions with iodized salt LEADS TO EQUALS PAY-OFF HEALTHIER PREGNANCIES INCREASED WORK PRODUCTIVITY $1 Sight&Life,

5 The iodine deficiency disorders One of the most common human diseases One of the most common causes of mental retardation Iodine deficiency remains a major global problem Simple, inexpensive salt iodization can eliminate IDD Zimmermann et al. Lancet 2008

6 I am satisfied! I have seen the principal features of Swiss scenery Mount Blanc and the goiter and now for home! Mark Twain, US author, 1880 Myxedematous cretin, b.1908 Solothurn, Switzerland,

7 7 Outline 1. Effects of iodine deficiency 2. Prevalence of iodine deficiency and excess 3. DBS Tg: a new biomarker of iodine status 4. ID in industrialized countries

8 8 Severe iodine deficiency produces maternal hypothyroidism in the 2 nd and 3 rd trimester Iodine sufficient Swedish pregnant women Iodine deficient Sudanese pregnant women (Elnagar et al Eur J Clin Nutr 1998)

9 9 in utero iodine deficiency damages the developing brain Iodine repletion significantly reduces the prevalence of endemic cretinism Age RR (95%CI) of cretinism 4 y-olds 0.27 (0.12, 0.60) 10 y-olds 0.17 (0.05, 0.58) DQ/IQ points higher in children born to supplemented mothers Pharoah et al, 1971; Thilly et al,1994; Cao et al, 1994

10 Iodine repletion in newborns sharply decreases infant mortality Indonesian infants (n=617) received placebo or oral iodized oil (100 mg) at 6 wk 72% and 52% reduction in risk of death during the first 2 and 6 months (P < 0.05) Cobra et al, 1997

11 11 Iodine and Mental Development of Children 5 Years Old and Under: A Systematic Review and Meta-Analysis Average effect sizes were 0.68 (2 RCT studies), 0.46 (8 non-rct studies), 0.52 (9 cohort strat by mothers I status), and 0.54 (4 cohort strat by infants I status). This translates into 7-10 IQ points lower in ID children vs IS children Bougma et al. Nutrients 2013

12 12 Correction of mild iodine deficiency in children improves cognition and motor skills RCT of KI in mildly ID New Zealand children (n=184): improvement in the overall cognitive score of 0.2 SD vs. placebo RCT of iodized oil in moderately ID European schoolchildren (n=300), iodine improved 4 out of 7 tests: an IQ increase of 2-3 points Test Time (wk) Iodine (n=159) Placebo (n=151) Ravens Matrices ± ± 6.3 Adjusted treatment effect ± ± * Target marking ± ± ± ± * Symbol search ± ± ± ± * Rapid naming ± ± 16.6 Mean (95% CI) effect, overall score (p=0.011) ± ± * *p< Zimmermann et al, 2006; Gordon et al, 2009

13 13 Correction of mild iodine deficiency in schoolchildren improves cognition: meta-analysis Effect of iodine supplementation on global cognitive index in mild iodine deficiency : pooled adjusted standardized mean difference (SMD) of change from baseline = 0.27 Taylor Eur J Endocrinol 2014

14 14 WHO Systematic review on the effects of salt iodization in populations (2015) 9810 publications identified 89 studies included 2 RCT 6 non-rct 20 quasi-experimental 16 cohort observational 42 multiple cross sectional 3 mixed design Evidence grade: low to moderate Azerbaijan, Argentina, Bangladesh, China, Colombia, Cote d'ivoire, Denmark, Germany, Guatemala, India, Iran, Italy, Kazakhstan, Malaysia, Mongolia, Morocco, Pakistan, Poland, South Africa, Spain, Switzerland, Tajikistan, Thailand, Uganda, USA, Uzbekistan

15 73% reduction in risk for low IQ (< 70) (Aburto et al, WHO 2015) RR = 0.28 (0.21, 0.36)

16 16 Iodine deficiency in UK pregnancy and child development U.K. pregnant women in 1 st trimester (n=1000) Children (at 8 y) of women with an iodine-to-creat ratio <150 μg/g more likely to have scores in the lowest quartile for: verbal IQ (OR 1 58, 95% CI ; p=0 02) reading accuracy (1 69, ; p=0 007) reading comprehension (1 54, ; p=0 02) Adjusted for 21 potential confounding variables, but thyroid hormones not available and iodine status during childhood unknown Bath et al. Lancet 2013

17 17 Iodine deficiency causes multinodular goiter, which is disfiguring and often leads to hyperthyroidism Incidence rates of hyperthyroidism in Denmark: RR of MNTG=1.9 ( ) with increasing iodine deficiency muic=45 µg/l muic=61 µg/l 12 y-old and his 58 y-old grandmother, Morocco Zimmermann et al. Lancet Diab Endocrinol 2014

18 Iodine deficiency sharply increases risk of thyroid cancer from nuclear fallout >4,000 cases of thyroid cancer in children of the Chernobyl generation, most were iodine deficient Number likely >50% lower if children had been iodine sufficient Thyroid cancer, children<15y at diagnosis >400 nuclear reactors operating globally Daiichi nuclear plant Fukushima,

19 19 Cost-effectiveness of iodized salt: summary Estimated annual potential costs attributable to IDD in the developing world: $35.7 billion / yr prior to widespread salt iodization vs. $0.5 billion /yr cost for salt iodization a 70:1 benefit : cost ratio Horton S. The economic impact of micronutrient deficiencies. NNWSPP Vol.54. Geneva: Karger; 2004, and J. Nutr. 2006:136: Salt iodization remains the most cost-effective way to deliver iodine and improve cognition in children ICDSG, Lancet 2007

20 20 Key points Iodine deficiency >hypothyroidism > impaired brain myelinization, angiogenesis and architecture In severe ID, this results in cretinism and overall decreases in IQ in children of 6-10 points In mild-to-moderate ID at school-age, decreases in IQ of 3-4 points also a major cause of thyroid disorders in adults Because of this broad spectrum of adverse effects and the simplicity of iodizing salt, salt iodization has remarkably high cost-benefit

21 21 Outline 1. Effects of iodine deficiency 2. Prevalence of iodine deficiency and excess 3. DBS Tg: a new biomarker of iodine status 4. ID in industrialized countries

22 Urinary iodine concentration (UIC) Exposure biomarker Spot sample 3 ml A sensitive indicator of iodine intake (>90% excretion) Reflects recent iodine intake Population indicator - Intra- and inter-individual variation is high (35%) - n > 300 König et al., J Nutr, 2011 Andersen et al., Br J Nutr, 2008

23 23 Criteria for assessing iodine nutrition in a population based on median UI Median UI (µg/l) Iodine nutrition In school-aged children <20 Severe ID Moderate ID Mild ID Adequate More than adequate >300 Excess WHO, 2007

24 UIC data cover 97% of the global population Number of countries

25 25 Two decades of global progress against iodine deficiency : a public health triumph

26 countries iodine deficient

27 countries iodine deficient

28 countries iodine deficient

29 countries iodine deficient

30 2016 Iodine deficiency (median UIC <100 µg/l) Optimal iodine nutrition (median UIC µg/l) Excess iodine intake (median UIC 300 µg/l) Sub-national No data

31 3 decades of progress against IDD Goiter rate (%) countries iodine deficient in 1993 Country by region AFRO AMRO EMRO EURO SEARO WPRO muic (μg/l)

32 3 decades of progress against IDD Goiter rate (%) countries iodine deficient in 2015 Country by region AFRO AMRO EMRO EURO SEARO WPRO muic (μg/l)

33 33 Progress towards universal salt iodization Out of 128 countries with data: 37 countries coverage is 90% of households 39 countries coverage is <50% 70% households worldwide have access to well iodized salt UNICEF, SOWC 2012

34 Every day, 120,000 born iodine deficient at risk for mental and physical retardation Salt iodization needs to be strengthened and expanded

35 Excessive iodine intake in 8 countries Iodine deficiency (median UIC <100 µg/l) Optimal iodine nutrition (median UIC µg/l) Excess iodine intake (median UIC 300 µg/l) Armenia Benin Colombia Georgia Honduras Somalia Uganda Qatar Sub-national No data

36 36 Reasons for iodine excess in children vary by country Excessive intake in Japan: frequent consumption of foods with naturally high iodine content, including Laminaria, a type of kelp commonly labeled as kombu In regions of China, and perhaps in Somalia, high iodine in groundwater is a contributing factor in iodine excess But in most countries with iodine excess, high iodine intakes are due to excessively iodized salt combined with high household coverage, as for example in Georgia and Columbia In Chile in the 1990 s, iodine in iodized salt set too high, at 80 ppm, >excessive iodine intake (muic = 540 µg/l in SAC) National program changed iodized salt law to ppm, resulted in a normalization of iodine intakes in most regions of the country

37 Key points Global progress against iodine deficiency over the last two decades is a major public health triumph Achievements are fragile and need to be sustained Iodine excess becoming more common, usually due to over-iodized salt+ high coverage Need surveillance systems to detect both deficiency and excess

38 38 Outline 1. Effects of iodine deficiency 2. Prevalence of iodine deficiency and excess 3. DBS Tg: a new biomarker of iodine status 4. ID in industrialized countries

39 39 Limitations of conventional indicators UIC Sensitive indicator of recent changes in iodine nutrition, but not of thyroid function Goiter A poor indicator for mo/yr after beginning universal salt iodization Can we find a functional biomarker that responsive to recent changes in iodine intake?

40 40 Thyroglobulin (Tg) Tg, a thyroid-specific glycoprotein precursor to thyroid hormone Thyroglobulin Iodination Coupling I - Tg T4 T3 Iodine deficiency Tg 40

41 Thyroglobulin on dried blood spots (DBS-Tg) is a promising indicator of iodine status in children Simplifies collection and transport of samples Validated DBS Tg assay available (based on P-E Delfia serum Tg assay) Tg Certified Reference Material (CRM-457) available DBS-Tg was determined in an international sample of 5-14 y-old iodine sufficient children (n=700) International reference range for DBS-Tg 4-40 μg/l; median 14.5 μg/l (25 th -75 th %tiles: 9.4, 22.7) Zimmermann et al. JCEM, 2006 Recommended by WHO/ICCIDD (2007) for monitoring iodine 41 status in school aged children

42 μg/l DBS-Tg responds quickly to iodine repletion in children Intervention study in 6-15 yr-old Moroccan children Boxes contain data between the 25 and 75% percentiles with medians; whiskers are ranges Reference 97%tile = 40 µg/l Reference median = 14.5 µg/l Baseline 5 months 10 months 42 Zimmermann et al. JCEM, 2006

43 43 DBS-Tg in children Tg nadir at UIC range of µg/l Log DBS-Tg (µg/l) Log UIC (µg/l) Zimmermann et al. JCEM, 2013

44 Criteria for assessing iodine nutrition in a population based on median UIC Median UIC Iodine nutrition <20 µg/l Severe iodine deficiency µg/l Moderate iodine deficiency µg/l Mild iodine deficiency µg/l Adequate µg/l More than adequate 300 µg/l Excessive? 44 WHO 2007

45 Criteria for assessing iodine nutrition in a population based on median UIC Median UIC Iodine nutrition <20 µg/l Severe iodine deficiency µg/l Moderate iodine deficiency µg/l Mild iodine deficiency µg/l Adequate 300 µg/l Excessive The future? 45

46 46 Key points Tg a short-term indicator of thyroid function, normalizes in several months after iodine repletion in SAC, complements use of UIC (days) and goiter (months to years) May be appropriate to have a single UIC range of µg/l indicating adequate status in children

47 47 Outline 1. Effects of iodine deficiency 2. Prevalence of iodine deficiency and excess 3. DBS Tg: a new biomarker of iodine status 4. ID in industrialized countries

48 Of all WHO regions, Europe has one of the highest prevalences of iodine deficiency WHO region Europe Countries insufficient intake (no.) Insufficient iodine intake (UI < 100 µg/l) School-age children General population (%) Total no. (millions) (%) Total no. (millions) Australia mildly iodine deficient In SAC in NSW and Victoria, muic 89 μg/l and 74 μg/l Adolescent girls in United Kingdom are mildly iodine deficient, muic=80 µg/l 7% of school girls with increased Tvol Li et al.,

49 49 Pregnant women in the U.S. are iodine deficient NHANES women y, muic μg/l (in = 124 μg/l) NHANES muic (μg/l) women y Category n muic (95%CI) Total ( ) Pregnant ( ) Non-P ( ) 1 st T (50-219) 2 nd T (88-219) 3 rd T ( ) sufficient muic in pregnancy is μg/l Caldwell et al, Thyroid 2013

50 50 Iodine supplement use among U.S. women (NHANES ) Gahcche Group n % using any dietary % using dietary supplement supplement with iodine All women All pregnant All nonpregnant Gahche et al. J Nutr 2013 muic among U.S. women varies by quintiles of dairy intake

51 51 Decreasing iodine intakes from dairy products: a reason for reemergence of deficiency in UK, USA and Australia? Dairy a key dietary source of iodine in countries with Western diets Reduced amount of I supplements given to livestock and reduced use of milk iodophor disinfectants (and possibly, reduced milk intake) Lower UIC in UK girls predicted by: sampling in summer (p<0.0001) low intake of milk (p=0.03) Philips, 1997 Vanderpump et al, 2011

52 Average iodine content (µg/g or ml) Natural iodine in foods Geometric mean iodine content of selected food groups (Fordyce 2003) Iodine intake in industrialized countries: Relative contribution of various food groups (Fordyce 2003) 7% 8% 9% 5% 1% 20% % 0.09 Dairy Cereals Fish Meat Vegetables Sweets Fruits 8 µg iodine/100 ml milk

53 53 The perils of relying on iodine in milk as a major dietary source Adequate iodine is essential and either deficiency or excess can have adverse consequences Yet the major source of iodine in many Western diets is milk iodine. A source that is: Accidental Seasonal Unregulated and likely falling

54 In industrialized countries, iodizing table salt is not enough, processed foods need to contain iodized salt The Netherlands, bread salt iodization provides 50% of total iodine intake UIC (μg/l) School-aged children Iodine in bread Iodized table salt Other dietary sources Other Adults Iodizing only household salt will have little impact!

55 55 Key points Iodine deficiency is not only a problem in developing countries - unlike other MNDs, it occurs in high-income countries with high-quality diets Milk remains an important accidental source of iodine in Western diets In industrialized countries, iodizing table salt is not enough, processed foods must contain iodized salt

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