Biomarkers of Nutrition for Development Iodine Review 1 4

Transcription

1 The Journal of Nutrition Supplement: Biomarkers of Nutrition for Development (BOND) Expert Panel Reviews, Part 1 Biomarkers of Nutrition for Development Ioine Review 1 4 Fabian Rohner, 5,6,15 Michael Zimmermann, 7,8,15 Pieter Jooste, 9,10,15 Chanrakant Panav, 11,12,15 Kathleen Calwell, 13,15 Ramkripa Raghavan, 14 an Daniel J. Raiten 14 * 5 Grounwork LLC, Crans-près-Céligny, Switzerlan; 6 Global Alliance for Improve Nutrition (GAIN), Geneva, Switzerlan; 7 Institute of Foo, Nutrition an Health, Swiss Feeral Institute of Technology (ETH), Zurich, Switzerlan; 8 The International Council for the Control of Ioine Deficiency Disorers (ICCIDD) Global Network, Zurich, Switzerlan; 9 Centre of Excellence for Nutrition, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa; 10 Southern Africa Office, The ICCIDD Global Network, Capetown, South Africa; 11 Centre for Community Meicine, All Inia Institute of Meical Sciences, New Delhi, Inia; 12 South Asia Office, The ICCIDD Global Network, New Delhi, Inia; 13 National Center for Environmental Health, CDC, Atlanta, GA; an 14 Eunice Kenney Shriver National Institute of Chil Health an Human Development, NIH, Bethesa, MD Abstract The objective of the Biomarkers of Nutrition for Development (BOND) project is to provie state-of-the-art information an service with regar to selection, use, an interpretation of biomarkers of nutrient exposure, status, function, an effect. Specifically, the BOND project seeks to evelop consensus on accurate assessment methoologies that are applicable to researchers (laboratory/clinical/surveillance), clinicians, programmers, an policy makers (ata consumers). The BOND project is also intene to evelop targete research agenas to support the iscovery an evelopment of biomarkers through improve unerstaning of nutrient biology within relevant biologic systems. In phase I of the BOND project, 6 nutrients (ioine, vitamin A, iron, zinc, folate, an vitamin B-12) were selecte for their high public health importance because they typify the challenges face by users in the selection, use, an interpretation of biomarkers. For each nutrient, an expert panel was constitute an charge with the evelopment of a comprehensive review covering the respective nutrientõs biology, existing biomarkers, an specific issues of use with particular reference to the nees of the iniviual user groups. In aition to the publication of these reviews, materials from each will be extracte to support the BOND interactive Web site ( This review represents the first in the series of reviews an covers all relevant aspects of ioine biology an biomarkers. The article is organize to provie the reaer with a full appreciation of ioineõs backgroun history as a public health issue, its biology, an an overview of available biomarkers an specific consierations for the use an interpretation of ioine biomarkers across a range of clinical an population-base uses. The review also inclues a etaile research agena to aress priority gaps in our unerstaning of ioine biology an assessment. J. Nutr. 144: 1322S 1342S, Backgroun: Overview of Ioine Nutrition Introuction Ioine is an essential nutrient ue to its role as a component of thyroi hormones an because it must be obtaine via exogenous/ietary sources. Unlike most other essential ietary nutrients, ioine status is not linke to socioeconomic evelopment but rather to geography. The ioine content of local foos 1 Publishe in a supplement to The Journal of Nutrition. The Biomarkers of Nutrition for Development (BOND) project was evelope by the nutrition program staff of the Eunice Kenney Shriver National Institute of Chil Health an Human Development (NICHD) of the NIH within the U.S. Department of Health an Human Services (DHHS). The initial 6 nutrients, ioine, vitamin A, iron, zinc, folate, an vitamin B-12, selecte were chosen for their high public health importance. Expert panels on each nutrient were constitute an charge with eveloping comprehensive reviews for publication in the BOND series. The BOND program receive its core funing from the Bill an Melina Gates Founation, PepsiCo, the NIH Division of Nutrition Research Coorination, an the Office of Dietary Supplements, NIH. The Supplement Coorinators for this supplement were Daniel J. Raiten an Ramkripa Raghavan (NICHD). Supplement is epenent on soil ioine content an therefore low ioine concentrations in soil an water will result in ioine-eficient plants an animals. Although ioine (as ioie) is present in soils, the content may fluctuate wiely within an across regions as a result of a number of factors (e.g., ifferences that occurre uring geological formation, impact of glaciation, flooing, an soil erosion). In the ocean, ioie is converte into elemental ioine, Coorinator isclosures: no conflicts of interest. This supplement is the responsibility of the Guest Eitor to whom the Eitor of The Journal of Nutrition has elegate supervision of both technical conformity to the publishe regulations of The Journal of Nutrition an general oversight of the scientific merit of each article. The Guest Eitor for this supplement was Kevin L. Schalinske. Guest Eitor isclosure: no conflicts of interest. Publication costs for this supplement were efraye in part by the payment of page charges. This publication must therefore be hereby marke "avertisement" in accorance with 18 USC section 1734 solely to inicate this fact. The opinions expresse in this publication are those of the authors an are not attributable to the sponsors or the publisher, Eitor, or Eitorial Boar of The Journal of Nutrition. ã 2014 American Society for Nutrition. 1322S Manuscript receive July 2, Initial review complete September 4, Revision accepte May 21, First publishe online June 25, 2014; oi: /jn

2 a volatile form that is carrie into the atmosphere as part of an ecological cycle, returning it to the lan through rain an snow. However, this cycle is slow an inconsistent in its impact/ reistribution an is incapable of aequately replenishing soils an freshwater otherwise poor in ioine (1). Consequently, humans epenent on foo sources grown in ioine-eplete or -eficient areas become ioine eficient in the absence of any other source of the nutrient. In such areas, ioine can only enter the foo supply through eliberate efforts such as the ioization of salt (2). A summary of available sources of ioine is foun in Table 1. Role in health an isease Ioine eficiency an relate isorers. Among the roles of thyroi hormones in human health are the regulation of numerous physiologic processes, incluing growth, key aspects of neurologic evelopment, an reprouctive function. During the first trimester of pregnancy, maternal thyroi hormone crosses the placenta to serve as the primary source of this essential hormone to the fetus prior to the evelopment of its own functional thyroi an may account for up to 20 40% of cor bloo thyroi hormone at birth (32). Known an potential roles of thyroi hormones an ioine are liste in Table 2. The numerous effects of ioine eficiency on growth an evelopment are known collectively known as ioine eficiency isorers (IDDs) 16 (Table 3). Resulting funamentally from a eficiency of thyroi hormone, the constellation of averse effects associate with IDD represents some of the most important an common human iseases (35). Many regions most affecte by ioine-eplete soils are also among the most heavily populate (Table 4), resulting in a large at-risk population for eficiency. Before the introuction of salt ioization programs or other measures to correct ioine eficiency, cretinism was frequent an goiter affecte up to 80% of chilren in severely eficient areas (38) an likely affecte other population groups. The classical manifestation of ioine eficiency is an enlargement of the thyroi referre to as goiter. The sequence of events an clinical manifestations associate with goiter inclue increase secretion of thyroi-stimulating hormone (TSH), representing an effort to maximize thyroi uptake of iminishing sources of ioine; 2 The BOND project was fune in part by the Bill an Melina Gates Founation; PepsiCo; the Office of Dietary Supplements, NIH; the Division of Nutrition Research Coorination, NIH; an the Eunice Kenney Shriver National Institute of Chil Health an Human Development (NICHD), NIH. The Ioine Review was written in response to an invitation from the NICHD, NIH, within the U.S. Department of Health an Human Services (DHHS). The content represents the views of the Ioine Expert Panel an other invite contributors an oes not necessarily reflect the opinions of the NICHD, the NIH, or the DHHS. In aition, iniviual members of the expert panel may not enorse all statements in this report. The BOND project thanks the European Recommenations Aligne (EURRECA) program, the Micronutrient Genomics Project, the WHO, an the CDC for their partnership. 3 Author isclosures: F. Rohner, M. Zimmermann, P. Jooste, C. Panav, K. Calwell, R. Raghavan, an D. J. Raiten, no conflicts of interest. 4 Supplemental Figure 1 an Supplemental Tables 1 4 are available from the Online Supporting Material link in the online posting of the article an from the same link in the online table of contents at 15 Member of the BOND Ioine Expert Panel. 16 Abbreviations use: AI, Aequate Intake; DBS, rie bloo spot; BOND, Biomarker of Nutrition for Development; EAR, Estimate Average Requirement; IDD, ioine eficiency isorer; I-EP, Ioine Expert Panel; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor bining protein; IOM, Institute of Meicine; IQ, intelligence quotient; MGP, Micronutrient Genomics Project; T3, triioothyronine; T4, thyroxine; TSH, thyroi-stimulating hormone; UIC, urinary ioine concentration; UL, Tolerable Upper Intake Level. *To whom corresponence shoul be aresse. raiten@mail.nih.gov. TABLE 1 Dietary sources of ioine Ioine is naturally low in most foos an beverages. Generally, common foo sources provie 3 80 mg/serving (3,4), but the content largely epens on the fooõs origin an is usually insufficient to meet aily requirements. Ioine content is relatively high in most saltwater fish an seafoo because of their ability to concentrate ioine from seawater. However, they o not contribute substantially to ietary ioine intake unless consume regularly (5 7). Ioine content in some seawee is relatively high (8), an the population consuming seawee may obtain high ioine concentrations through their iet (9 11). Sometimes, ioine can also be obtaine through rinking water rawn from certain aquifers or water isinfecte with ioine (9,12,13). Ioine from househol salt an milk consumption: Ioize salt use for cooking an at the table in househols continues to be the major source of ioine in many countries aroun the worl (5,8,9,14). Accoring to label eclarations, the ioine content in commercially available salt ranges from mg ioine/kg salt (5,9,14 16). In aition to ioize salt, milk an other airy proucts are goo sources of ioine (9), especially in chilren, in countries such as the Unite States, Canaa, an Switzerlan (3,5,7,17,18). Although naturally low, the ioine content in fortifie winter cattle foer an perhaps the ioine resiues in milk from the isinfecting agents (ioophors) use in airying contribute to airy ioine (3,19 22). Some countries such as the Unite Kingom an Norway o not have regulation of ioize salt, an in those countries aventitious ioine in the milk is the main source (7,9,23). Ioine in processe foos: The salt use in processe foos contributes to ;60 80% of total salt intake in inustrialize countries (9,24 26). In a typical Western iet, processe foos such as brea, airy proucts, an processe meats provie the main salt source, which may or may not be ioize (9,27 29). Although processing woul entail boiling, baking, an canning of foos manufacture with ioate salt, it results in minimal loss (generally #10%) in ioine content (8,30). Ioine from ietary supplements: Base on ata from the NHANES , 18.5% of nonpregnant an 22% of pregnant women in the Unite States use supplements that contain ioine; for aults, the meian ioine intake from supplements was ;144 mg/ (8,31). thyroi hypertrophy an hyperplasia (34,39); evelopment of iffuse, homogeneous thyroi enlargement in early stages an fusion of thyroi follicles, which become encapsulate, leaing to a conition terme noular goiter uring later stages (35); an physical problems create by large goiters, incluing obstruction of the trachea an esophagus an amage to the recurrent laryngeal nerves, which can lea to hoarseness; surgery to reuce goiter has substantial risks, incluing bleeing, nerve amage, an hypothyroiism consequent to removal of thyroi tissue (32). In aults with mil-moerate ioine eficiency, an increase risk exists for iffuse goiter, noular goiter, an accompanying hyperthyroiism, as well as the potential for seconary neurologic impairment (e.g., ecrease work capacity, physical enurance, an cognitive ability) (40). In ioine-eficient iniviuals, particularly chilren, thyroial raioactive ioine uptake TABLE 2 Thyroi hormone functions Integral for brain evelopment an influences cell growth an migration (33) Important for growth an maturation Elevates energy metabolism an increases the basal metabolic rate Other suggeste functions for ioine inclue the following: Potential link to fibrocystic breast isease May be important for the immune response May alter gastric cancer risk (31,34) Biomarkers of nutrition for evelopment ioine review 1323S

3 TABLE 3 Age group All ages Fetuses Neonates Chilren an aolescents Aults Ioine eficiency isorers by age group Health consequences of ioine eficiency Goiter Increase susceptibility of the thyroi glan to nuclear raiation Abortion Stillbirth Congenital anomalies Perinatal mortality Infant mortality Enemic cretinism Impaire mental function Delaye physical evelopment Impaire mental function Reuce work prouctivity Toxic noular goiter; ioine-inuce hyperthyroiism Increase occurrence of hypothyroiism in moerate-to-severe ioine eficiency; increase occurrence of hypothyroiism in mil-to-moerate ioine eficiency after exposures from nuclear accients is high, resulting in an increase risk of thyroi cancer, compare with ioine-sufficient iniviuals. Ioine an chil growth an evelopment. Although goiter remains the carinal sign of ioine eficiency, IDD in chilren has many other manifestations incluing subclinical hypothyroiism associate with a more atherogenic lipi profile that may be associate with increase cariovascular isease risk (41,42). But the most serious consequences of ioine eficiency are associate with its impact on infant/chil growth an evelopment. Ioine status may influence growth through its effects on the thyroi axis. Putative mechanisms for the impact of ioine eficiency on growth have been suggeste an may be associate with a ecrease in insulin-like growth factor (IGF) 1 an IGF bining protein (IGFBP) 3 concentrations (43). The role of ioine in growth an the prophylactic effect of ioine interventions have been well ocumente (44). Ioine eficiency uring pregnancy has substantial consequences, with the most severe outcome being cretinism an short stature. The characteristics of the 2 types of cretinism are liste in Table 5. Aitional averse outcomes of severe ioine eficiency uring pregnancy inclue increase risk of stillbirths, abortions, an congenital abnormalities (35). Globally, perhaps the most profoun impact of ioine eficiency is its impact on neurologic evelopment an relate outcomes. Ioine eficiency is one of the most common causes of preventable mental retaration worlwie. Even in areas of mil-to-moerate ioine eficiency, cognitive impairment in school-age chilren is at least partially reversible by aministration of ioine (49,50). A meta-analysis of 18 stuies conclue that moerate-to-severe ioine eficiency is associate with reuctions in mean intelligence quotient (IQ) scores of 13.5 points (51). A more recent systematic review focusing on young chilren estimate that ioine eficiency in utero or uring early chilhoo may reuce IQ scores by ;8 IQ points (N. Aburto, personal communication, 2014). Among the functions of thyroi hormones for the eveloping nervous system are normal neuronal migration an myelination of the brain. Low concentrations of thyroi hormone uring the fetal stage an early infancy are associate with irreversible brain amage, incluing mental retaration an neurologic abnormalities (33). The key factors influencing the extent an magnitue of the neurologic complications are the timing an severity of the ioine eficiency an consequent thyroi hormone eficits. Subtle impairment of cognitive function is likely to occur even among offspring of pregnant women with mil or asymptomatic hypothyroiism (52,53). Consequences of ioine excess. Ioine malnutrition inclues not only insufficiency/eficiency but also excess. The putative mechanisms an causes by which ioine excess can affect thyroi function an effects have been escribe (54 58) an are highlighte in Table 6. Global efforts to aress ioine malnutrition. In 1952, a WHO technical group recommene ioization of all foo salt in ioine-eficient areas (60). In the first global estimate of the prevalence of goiter, WHO estimate that 20 60% of the worlõs population was at risk of IDD, with the highest risk in low- to mile-income countries (61). Despite the recognition that many countries were affecte by goiter, the serious health implications of this problem were not wiely accepte. Consequently, little attention an limite resources were evote to aressing ioine eficiency in public health programs or policies. During the perio of , as a result of emerging evience from controlle trials in areas with enemic ioine insufficiency, this tren began to change. Asie from the preicte outcomes of these intervention stuies, several other important functional consequences were highlighte. One of the important emerging areas was the recognition that ioine interventions improve cognitive function an thus ha a clear TABLE 4 Regions with low soil ioine 1 Asia, incluing parts of China, Inia, Banglaesh, the Himalayan hillsies, an Inonesia Africa, incluing the mountains of Morocco an Algeria (e.g., Atlas Mountains); much of west an central Africa (e.g., Nigeria, Cameroon, the Central African Republic, Democratic Republic of Congo), an some areas of East Africa (e.g., Ugana, Ethiopia) Europe, incluing the European Alps an the Pyrenees, inlan areas of Englan an Wales, Greece, an The Netherlans South America, incluing the Anes an inlan Brazil Miwestern Unite States Southern Australia Highlans of New Guinea TABLE 5 Types an characteristics of cretinism 1 Neurologic cretinism is characterize by the following: Growth retaration Severe mental retaration with squint Deaf-mutism Motor spasticity Myxeematous cretinism is characterize by the following: Growth retaration Less severe mental retaration when compare with neurologic cretinism Other clinical manifestations of hypothyroiism an elaye sexual maturation 1 Data from references 1, 36, an Data from references S Supplement

4 TABLE 6 Mechanisms an causes of ioine excess 1 TABLE 7 Seminal events in the history of ioine Wolff an Chaikoff effect (59): high ioie exposure in rats has been shown to result in a transient inhibition of thyroi hormone synthesis lasting ;24 h s Mechanism: possibly via the generation of intrathyroial ioolactones or ioolipis, which inhibit TPO activity s Continue aministration of ioie results in normal thyroi hormone synthesis referre to as ``escape from the acute Wolff-Chaikoff effect an may be cause by an inhibition of NIS synthesis, a reuction in intrathyroial ioine, an a ecrease in the ioine-inuce inhibitors of hormone synthesis (57) The J o-baseow phenomenon or ioine-inuce hyperthyroiism represents a failure of the acute Wolff-Chaikoff effect, may occur in iniviuals with a history of noular goiters cause by ioine eficiency Failure to ``escape from the acute Wolff-Chaikoff effect may also result in ioineinuce hypothyroiism Risk factors for ioine-inuce hypothyroiism inclue unerlying thyroi autoimmunity such as Hashimoto thyroiitis or a history of partial thyroiectomy Causes of ioine excess an relate consequences might inclue the following: s Exposure to amioarone, an antiarrhythmic meication that is 37% ioine by weight, or after exposure to ioinate raiographic contrast agents (34) s Ingestion of foos or supplements with very high ioine content, such as kelp, or where there is high ioine content in rinking water s Transient increases in rates of hyperthyroiism have been reporte in historically ioine-eficient regions with the initiation of salt ioization benefit from an economic/evelopment perspective (40). Ioine fortification also ha ancillary benefits to humans because ioine fortification of salt for animal consumption improve the viability an quality of livestock. Ioine eficiency was thus shown to have social an economic consequences beyon the immeiate benefits to human health. Table 7 provies an overview of some of the seminal events in recognition of ioine as an important meical an public health issue. This changing view allowe ioine eficiency to be repositione from a purely meical concern to one with a broaer evelopment perspective. The actualization of a global strategy was further aie by the coining of the more expansive term ioine eficiency isorer, rather than the traitional an limite reference to goiter. It was also note that ue to their relatively high biologic nees, pregnant women an young chilren are particularly susceptible. Consequently, the term ioine eficiency isorer more comprehensively covers those ioine-relate conitions that affect almost 2 billion people worlwie (40,64). The potential of low-cost interventions to affect the health an evelopment of billions of iniviuals mae programs to aress IDD politically an morally attractive. The fact that a program that costs between $0.02 an $0.05 per capita can result in such huge benefits both in humanitarian an economic terms continues to be a compelling impetus for the global health community (65). By 1990, a hanful of countries (Unite States, Australia, Canaa, several Scaninavian countries, The Netherlans, an Switzerlan) were consiere to be ioine sufficient. Generally, salt is consiere aequately ioize if ioine amounts are mg/kg, which is base on the assumption that aily per capita intake of salt is in the range of 10 g. The key policy evelopments in a global effort to eliminate IDD are highlighte in Table 8. The number of countries with effective salt ioization as a safe, cost-effective, an sustainable strategy to ensure sufficient intake of ioine has increase (35) to the point that ;70% of the worl has access to aequately ioize salt (71,72). `` `` 1 NIS, soium/ioie symporter; TPO, thyroperoxiase. Greeks (Galen) use sponge an seawee as cures for swollen neck Italian physicians of the School of Salerno were the first to report the specific use of the sponge an rie seawee to treat goiter 13th century: e Villanova cautione that the effect of the sponge on goiter was limite; it coul cure goiter of recent origin in young people but ha only a moest effect on large, chronic goiters 1811: Courtois iscovere ioine when he ae sulfuric aci to burnt seawee ash an prouce an intense violet vapor that crystallize on col surfaces Gay-Lussac subsequently ientifie this substance as a new element, an name it ioine from the Greek for ``violet 1813: Coinet, a physician in Geneva, Switzerlan, hypothesize that the effectiveness of seawee or sponges in treating goiter was ue to their ioine content (62). He began giving oral ioine tinctures to goitrous patients an claime his treatment was effective an safe Boussingault, working in the Anes, was the first to avocate prophylaxis with naturally ioine-rich salt to prevent goiter 1851: Chatin became the first to publish the hypothesis that ioine eficiency was the cause of goiter an subsequently propose istributing ioize salt in the goitrous zones of France : Marine an Kimball introuce ioine supplements in the Miwest region of the Unite States to treat enemic goiter 1918: the Swiss physician Bayar conucte the first ose-response trial of ioine to treat goiter (63). Bayar establishe that as little as 30 mg of ioine aily ha a clear beneficial effect on goiter 1922: the surgeon Eggenberger introuce ioize salt to prevent goiter an cretinism in northeastern Switzerlan `` Despite the local, regional, an global efforts to eraicate IDD, the prevalence remains high in many settings (Supplemental Fig. 1, Table 9), which provies an unerpinning for why this continue monitoring is important an will set the stage for iscussions on biomarkers. The following is an overview of the relevant features of ioine absorption, metabolism, an utilization. Ioine Biology: Factors Affecting Ioine Digestion, Absorption, Metabolism, an Utilization Absorption an metabolism The absorption an metabolism of ioine has been well characterize an consists of the following key elements: To maintain the normal concentration of boy ioine (10 20 mg of ioine, of which 70 80% is in the thyroi), humans require an exogenous source that may be provie in any of several chemical forms, each with unique absorptive or metabolic features: TABLE 8 IDD Policy Development an Milestones : the Unite Nations Worl Summit for Chilren an the Worl Health Assembly coifie efforts to eliminate IDD 1991: the Conference on Ening Hien Hunger aopte the ambitious goal of virtually eliminating IDD as a public health problem by the turn of the century (66 69) 1993: the WHO reaffirme the utility of salt ioization an proclaime this as the key strategy to achieving this goal (9,69) 2007: the International Chil Development Steering Group ientifie ioine eficiency as 1 of the 4 key global risk factors for impaire chil evelopment where the nee for intervention remains urgent (70) 1 IDD, ioine eficiency isorer. Biomarkers of nutrition for evelopment ioine review 1325S

5 TABLE 9 Countries in 2013 that were milly or moerately ioine eficient or ha excessive ioine intakes base on meian UICs in school-age chilren 1 Moerately ioine eficient (meian UIC: mg/l) Milly ioine eficient (meian UIC: mg/l) Excessive ioine intake (meian UIC:.300 mg/l) Afghanistan Albania Armenia Algeria Buruni Benin Angola Democratic PeopleÔs Republic of Korea Brazil Central African Republic Estonia Colombia Ethiopia Finlan Georgia Gambia Guatemala Honuras Ghana Haiti Paraguay Papua New Guinea Hungary Somalia Vanuatu Irelan Ugana Italy Uruguay Lebanon Lithuania Mali Morocco Mozambique New Zealan Russian Feeration Suan Ukraine Unite Kingom 1 Countries are liste alphabetically in each category (34). School-age chilren are efine as chilren age 6 12 y. UIC, urinary ioine concentration. s Ioie: characterize by its rapi an nearly complete (>90%) absorption in the stomach an upper small intestine (73,74) s Ioate: the primary source of ioine for salt ioization, ioate is reuce to ioie an absorbe in the gut s Organically boun ioine: most of organically boun ioine is igeste to release the ioie for absorption; however, some forms, e.g., thyroxine (T4), can be absorbe intact (;70% of an oral T4 ose) (74) Absorbe ioine is cleare from the circulation primarily by the thyroi an kiney: s Renal ioine clearance is fairly constant s Thyroi clearance in contrast varies with ioine intake: in conitions of aequate ioine supply, #10% of absorbe ioine is taken up by the thyroi; in chronic ioine eficiency, where the content of the thyroi may ecrease to <20 mg, the fraction of ioine absorbe can excee 80% (75 77) Circulating ioine is rapily turne over s Uner normal circumstances, plasma ioine has a half-life of ;10 h s Uner conitions of ioine eficiency or hyperthyroiism, resulting in an overactive thyroi, this turnover is shortene (75 77) s During lactation, the mammary glan concentrates ioine an secretes it into breast milk to provie ioine for the newborn (78) Ioine metabolism an homeostatic control Unerstaning of ioine absorption, metabolism, homeostasis, an thyroi function was previously reviewe (62). For the purposes of this review, some essential components are highlighte in Table 10 an in Figures 1 3. Even though we have learne much about the mechanisms an impact of ioine eficiency it shoul be note that the presentation an severity of IDD (e.g., goiter, thyroi ysfunction) are extremely variable between an within populations even in enemic areas. Our ability to unerstan why this might be the case is limite by an incomplete appreciation of the ietary, environmental, an/or genetic factors that might contribute to this variability. The following sections escribe some factors that might contribute to this variability. Dietary consierations Dietary inhibitors of ioine metabolism: goitrogens. A number of ietary factors have been ientifie that negatively affect thyroi metabolism. These substances are collectively referre to as goitrogens an seem to exert their eleterious effects primarily via an exacerbation of ioine eficiency through several mechanisms (81 83) (Table 11). More than 100 aitional naturally occurring an synthetic substances were reporte to affect thyroi function or thyroi hormone metabolism, but most of these have not yet been well characterize in human stuies (84). Population groups that may be particularly vulnerable to exposure to goitrogens are infants an young chilren. Examples of substances of concern inclue perchlorate, which was shown to interfere with ioine transport into the thyroi (85,86). Another group of suspecte substances are flavonois commonly foun in soy an millet. Although the consumption of soy-base foos oes not appear to present a problem for aults, without the aition of ioine it can pose a risk to infants consuming soybase formulas (87). Nutrient-nutrient interactions. Although ioine clearly plays a unique role in human health, like most nutrients it is also the case that interactions can occur that affect absorption, metabolism, an function. In the case of ioine, examples of these interactions are outline in Table 11. The following provies some aitional etail with regar to specific nutrients: 1326S Supplement

6 TABLE 10 Thyroi hormone prouction an metabolism uring ioine insufficiency an sufficiency 1 Mechanisms of normal thyroi hormone prouction an metabolism Uner conitions of ioine aequacy, aults accumulate ;60 mg ioine/ in the thyroi glan to account for losses an thyroi hormone prouction A transmembrane protein in the basolateral membrane of the thyrocyte, referre to as the NIS, is responsible for transferring ioie into the thyroi glan (79) (see Fig. 1) Prouction of thyroi hormone is a multistep process that inclues: s Oxiation of ioie via the action of the enzymes TPO an hyrogen peroxie at the apical surface of the thyrocyte s The prouct is attache to tyrosyl resiues on thyroglobulin to prouce MIT an DIT s TPO then catalyzes the linkage of the phenyl groups of the iootyrosines to form T4 (via linkage of 2 DIT molecules) an T3 (via linkage of an MIT an a DIT); T3 an T4 are therefore structurally ientical except for an extra ioine Relevant features of T3/T4: s 65% an 59% of the weights of T4 an T3 is ioine (see Fig. 2) (62) s Thyroglobulin contains % of its weight as ioine an is store extracellularly in the luminal colloi of the thyroi follicle Thyroglobulin that is igeste unergoes enocytosis an subsequent igestion by enosomal an lysosomal proteases to release T4 an T3 into the circulation T4 an T3 are broken own in the periphery (the half-life of circulating T4 is 5 8 ; that of T3 is ) The fate of the liberate ioine is to enter the plasma ioine pool for uptake by the thyroi or be excrete by the kiney More than 90% of ingeste ioine is ultimately excrete in the urine (35), with only a small amount appearing in the feces Mechanisms of response to ietary ioine insufficiency In non-pregnant, non-lactating aults, maintenance of intake above a threshol of ;60 mg/, even in the face of a ecrease in circulating plasma inorganic ioine, allows the ioine content of the thyroi to remain within normal limits (;10 20 mg) Below this threshol, espite high fractional clearance of plasma inorganic ioine, the ioine content of the thyroi is eplete, an the potential for evelopment of goiter ensues Responses to low intake inclue: s Marke moification of thyroi activity, triggere by increase secretion of TSH by the pituitary (see Fig. 3) s Increase plasma ioine clearance by the thyroi; in otherwise healthy iniviuals, ioine intake below ;100 mg/ results in increase TSH secretion resulting in increasing plasma inorganic ioie clearance by the thyroi through stimulation of NIS expression (8) s The increase ioine clearance by the thyroi leas to a progressive reuction in renal ioie excretion s TSH also stimulates breakown of thyroglobulin an preferential synthesis an release of T3 into the bloo The profile of thyroi hormones in ioine eficiency is: s In areas of moerate-to-severe ioine eficiency, chilren will have a variably elevate TSH, a low serum T4, an a normal or high-normal T3 s A similar pattern is seen in aults, but less preictably, an it may not be present s In conitions of low ioine intake, serum thyroglobulin concentration is typically elevate s Thyroi failure an cretinism usually evelop only in regions of chronic, severe ioine eficiency accompanie by low circulating T4 an T3 an ramatically elevate TSH (80) FIGURE 1 Ioine pathway in the thyroi cell. Ioie (I 2 ) is transporte into the thyrocyte by NIS at the basal membrane an migrates to the apical membrane. I 2 is oxiize by the enzymes TPO an H 2 O 2 an attache to tyrosyl resiues in thyroglobulin to prouce the hormone precursors MIT an DIT. The resiues then couple to form T4 an T3 within the thyroglobulin molecule in the follicular lumen. Thyroglobulin enters the cell by enocytosis an is igeste. T4 an T3 are release into the circulation, an nonhormonal ioine on MIT an DIT is recycle within the thyrocyte. Aapte from reference 79 with permission. DIT, iiootyrosine; H 2 O 2, hyrogen peroxiase; MIT, monoiootyrosine; NIS, soium/ioie symporter; TPO, thyroperoxiase; T3, triioothyronine; T4, thyroxine. s in goitrous chilren, iron eficiency anemia negatively affects the efficacy of interventions to prevent ioine eficiency. s Iron supplementation improves the efficacy of ioize oil an ioize salt (89). s Iron eficiency anemia uring pregnancy can result in both higher TSH an lower T4 concentrations (90). Requirements an Tolerable Upper Intake Levels Ioine requirements by age an life stage are shown in Table 12. The efinitions of key categories an their use, accoring to the 1 DIT, iiootyrosine; MIT, monoiootyrosine; NIS, soium/ioie symporter; T3, triioothyronine; T4, thyroxine; TPO, thyroperoxiase; TSH, thyroi-stimulating hormone. Selenium: the selenium-epenent enzymes glutathione peroxiase an the eioinases are impaire in selenium eficiency. The accumulate peroxiases may amage the thyroi, whereas eioinase eficiency impairs thyroi hormone synthesis. These effects have been implicate in the etiology of myxeematous cretinism (88). Iron eficiency s reuces heme-epenent thyroperoxiase activity in the thyroi, resulting in impaire prouction of thyroi hormone; FIGURE 2 Ioine is an essential component of the thyroi hormones triioothyronine an thyroxine. Reprouce from reference 62 with permission. Biomarkers of nutrition for evelopment ioine review 1327S

7 FIGURE 3 The physiologic stages of ioine status. The graph shows a simplifie moel of human ioine an thyroi status at ifferent stages (left to right) of ioine intake: sufficient ioine intake, low ioine intake without thyroi ysfunction, an finally, low ioine intake with hypothyroiism. The 3 stages are separate by vertical ashe bars. The scientific evience is limite with regar to the absolute levels of habitual aily ioine intake at which thyroi stores ecrease an thyroi ysfunction occurs; this likely varies strongly among iniviuals. Reprouce from reference 9 with permission. TSH, thyroi-stimulating hormone. U.S. Institute of Meicine (IOM) in the erivation of the current ietary recommenations, are iscusse below. These efinitions, an in particular their use, will set the stage for the following sections on specific biomarkers an their relative utility for clinical an population assessments. Estimate Average Requirement (EAR): The aily nutrient intake that meets the requirement of half of the healthy iniviuals in a particular life-stage (age/gener) group. Use: This category is not use for iniviual assessment but can be use for population/group analyses. RDA: The average aily intake sufficient to meet the nutrient requirement of 97 98% of healthy iniviuals in a life-stage (age/gener) group. Use: It can be use as a reference point or goal for the aily nutrient intake of iniviuals. Aequate Intake (AI): A recommene average aily intake amount base on observe or experimentally etermine estimates of nutrient intake by a (gener/age) group (or groups) of apparently healthy people presume to have aequate intakes. Use: The AI is erive when there are insufficient ata to generate an RDA. Because the AI is intene to efine the amount of a nutrient neee in essentially all iniviuals in a target group, it can be use as a goal for iniviual intake. For ioine, there is an AI for infants base on observe mean intakes by healthy full-term breast-fe infants in ioine-sufficient areas. Tolerable Upper Intake Level (UL): The highest average aily nutrient intake that poses no risk of averse health effects to almost all iniviuals in an otherwise healthy population (88). The UL for ioine is liste in Table 13. Use: The UL is use as a reference for safety. For ioine, metabolic aaptations to chronic eficiency may result in averse responses to intakes lower than the UL. In aition to the IOM terminology, the joint FAO/WHO committee publishe several efinitions erive in a consultation conucte in 2001 (92). Several of the terms use are similar to those use by the IOM (e.g., UL), but some, although essentially representing the same concepts, are ifferent in name [e.g., Recommene Nutrient Intake (RNI)]. FAO/WHO efines the RNI as the intake estimate to cover the nees of Ônearly allõ healthy iniviuals in a specific age/gener group. The RNI for ioine is inclue in Table 12. Currently Available Biomarkers Overview Table 14 summarizes the currently available biomarkers of ioine an provies an overview of the utility for the ifferent purposes an user groups (i.e., research, clinical, program, policy) an inclues a rating system for the usefulness of each inicator for a specific use. Biomarker-specific issues This section is an overview of the conclusions of the Ioine Expert Panel (I-EP) with regar to those ioine biomarkers that are reay for wie application across ifferent user groups TABLE 11 Goitrogens an micronutrient eficiencies that affect ioine metabolism an thyroi function 1 Mechanism Cassava, lima beans, linsee, sorghum, sweet potato Cruciferous vegetables: cabbage, kale, cauliflower, broccoli, turnips, rapesee Soy, millet Inustrial pollutants (that enter foo an water) Perchlorate, nitrate Others (e.g., isulfies from coal processes) Smoking Nutrients Selenium eficiency Iron eficiency Vitamin A eficiency Contain cyanogenic glucosies that are metabolize to thiocyanates an act by competing with ioine for uptake by thyroi glan Contain glucosinolates; these metabolites act by competing with ioine for thyroial uptake (36) Flavonois impair thyroi peroxiase activity Competitive inhibitors of the soium/ioie symporter; they act by ecreasing transportation of ioine to the thyroi Reuce thyroial ioine uptake One of the important goitrogens; uring breastfeeing, smoking is known to be linke to reuce ioine content in the breast milk; the mechanism behin this is that in smoking women, the higher serum concentrations of thiocyanate compete with ioine for active transport into the secretory epithelium of the lactating breast (35) Accumulate peroxies ue to selenium eficiency may amage the thyroi, an eioinase eficiency may impair the synthesis of thyroi hormone The activity of heme-epenent TPO is reuce an the efficacy of ioine prophylaxis may be compromise Due to the eficiency there is a ecrease in vitamin A meiate suppression of the pituitary TSHb gene an an associate increase in TSH stimulation an goiter 1 TPO, thyroperoxiase; TSH, thyroi-stimulating hormone. 1328S Supplement

8 TABLE 12 Recommenations for ioine intake by age or population group 1 Institute of Meicine WHO Life-stage group EAR AI or RDA Life-stage group RNI mg/ mg/ mg/ Infants 0 12 mo Chilren 0 5 y 90 Chilren 1 8 y Chilren 6 12 y 120 Chilren 9 13 y Aults.12 y 150 Aults $14 y Pregnancy Pregnancy 250 Lactation Lactation Data from references 31 an 64. AI, Aequate Intake; EAR, Estimate Average Requirement; RNI, Recommene Nutrient Intake. targete by the Biomarkers of Nutrition for Development (BOND) program. For each of the priority biomarkers selecte, the I-EP provie responses to a specific set of issues erive from an outline evelope by the BOND Secretariat. This approach was use by each of the nutrient-specific BOND expert panels. The outline can be foun in Supplemental Table 1 an on Tier 1 of the BOND Web site (93). The aim of this approach was to provie a common format for the work of all BOND nutrient expert panels, an aress core issues that might be important to the range of user groups to be serve by the BOND. On the basis of the evaluation system presente in Table 14, the I-EP selecte the following priority biomarkers for in-epth evaluation in this review: urinary ioine concentration (UIC); TSH; thyroglobulin; T4 an triioothyronine (T3); an goiter. The characteristics an technical consierations for each of these biomarkers are liste in Supplemental Table 2. The following sections provie some general information about these biomarkers as well as some aitional consierations with regar to specific exposure-relate aspects of ioine assessment. In aition to the consieration of the priority biomarkers, the I-EP conclue that a summary of issues pertaining to ioine exposure methoologies was an essential precursor to the iscussion of ioine nutrition. Consequently, the following TABLE 13 Tolerable Upper Intake Level for ioine 1 Life-stage group European Commission/Scientific Committee on Foo Institute of Meicine mg/ mg/ 1 3 y y y y y 500 Ault Pregnant an lactating women Data from references 31 an 91. TABLE 14 Overview of currently available biomarkers for the assessment of ioine nutrition 1 Usefulness assessment 2 Exposure Status Function Effect Research Clinical Program Research Clinical Program Research Clinical Program Research Clinical Program Biomarker Salt ioine content (table or cooking) Dietary assessment Urinary ioine TSH Thyroglobulin T3/T Goiter T3, triioothyronine; T4, thyroxine; TSH, thyroi-stimulating hormone. 2 The usefulness assessment uses the following graing system: 0, not useful for the specific purpose; +, useful to some extent an in certain population groups but either not commonly use or has important isavantages (e.g., no reference values); ++, useful in certain population groups, often use with some limitations (e.g., lack of specificity or sensitivity); +++, useful, often use in relevant population groups; no or only minor limitations. Biomarkers of nutrition for evelopment ioine review 1329S

9 sections provie overviews of several issues pertaining to ioine exposure incluing househol coverage of (aequately) ioize salt an ietary assessment of ioine intake. As oppose to the presentation of the priority biomarkers foun in Supplemental Table 2, the iscussion of exposure is presente in text because neither househol surveillance nor ietary assessment are biomarkers per se but rather proxies an thus answer a slightly ifferent set of questions. Househol coverage of (aequately) ioize salt Ioine in salt use in househols. The importance of salt ioization was coifie in 1994 by the Joint UNICEF/WHO Committee on Health Policy (94), which outline policy for salt ioization intene for all types of salt estine for human an animal consumption, incluing salt use in the foo inustry. Momentum for universal salt ioization programs grew substantially throughout the 1990s, an by 2007 salt ioization strategies ha been enacte in at least 120 countries (95). Rapi an inexpensive fiel kits that visibly etect ioine in salt have been wiely use to measure the presence of ioize salt in househols throughout the worl. This has helpe to ocument the progress of universal salt ioization strategies. Measuring the ioine concentration in househol salt. Househol ioize salt coverage is the most feasible process inicator for assessing the reach of salt ioization strategies across countries an is commonly use as the key inicator of progress of salt ioization strategies over time. Figure 4 shows the global map with percentages of househol consuming ioize salt. The success of elivering ioize salt to househols is assesse either by the proportion of househols using salt with any ioine concentration or, preferably, those using aequately ioize salt, i.e., salt containing at least 15 mg/kg of ioine. Accoring to the WHO, the salt ioine content shoul be in the range of 15 to 40 mg/kg; however, in large national surveys the upper en of this range is rarely applie for practical reasons. The accepte stanar threshol efining a successful ioization program is coverage of $90% of househols using aequately ioize salt (64). To generate ata on the aequacy of ioine in salt, it is necessary to use quantitative tools. An aitional benefit erive from quantitative ata on the ioine content in househol salt is the ability to generate a istribution curve of the ioine content in househol salt to compare the relative value of ifferent ioine cutoff points (66). Moreover, because neither the coverage nor the meian ioine value gives an inication of the existence or extent of excessively ioize salt in the househols, the istribution curve provies important aitional information in this regar. Quantitative vs. qualitative measurements at the househol level. Ieally, national ioine strategy planning, surveillance, an ecision making rely on quantitative ata on salt ioine contents. Quantitative ata also facilitate accurate tracking of the progress of the salt ioine content as well as coverage of aequately ioize househol salt over time. Currently, rapi test kits are the most prominent tool use in national surveys to estimate the proportion of househols using ioize salt. By implication, this estimate also provies the proportion of househols not using ioize salt, which can provie useful information for planning corrective action. There are, however, certain limitations to the use of rapi test kits (F. van er Haar, R. Houston, A. Timmer, K. Coling, J. Gorstein, unpublishe results, 2009) (66). Paramount among these is an inability to accurately ientify salt ioize at <15 mg/kg of ioine, an in particular salt containing <10 mg/kg of ioine. In aition, the rapi test kits cannot ientify overioize salt at concentrations that may excee mg/kg (see Househol coverage of ioize salt section). In light of these limitations, the use of the rapi test kits shoul be viewe as more of a qualitative test rather than a semiquantitative or even quantitative test. FIGURE 4 Percentage of househols consuming ioize salt. With exception of New Zealan, this inicator is not formally measure in inustrialize nations. However, examples of effective ioize salt regulation in the Western worl inclue Austria, Czech Republic, Belgium, Canaa, Denmark, The Netherlans, an Switzerlan. Aapte from reference 72 with permission. 1330S Supplement

10 Sampling salt at the househol level. The analytical metho use for measuring salt ioine content etermines the amount of salt sample require. For quantitative analysis by means of the titration or equivalent metho, at least 10 g (2 teaspoons) are require. Using <10 g of salt for the titration analysis may lea to ubious results, particularly in the case of coarse salt an salt containing impurities. For repeat or uplicate analyses, at least 20 g of salt is require. In many emographic an health surveys, multiple inicator cluster surveys, or similar population surveys, househol salt ioine content is analyze by using rapi test kits. However, in some recent large-scale surveys [e.g., the 2010 Tanzania Demographic an Health Survey (96)], househol salt was sample an brought to a central laboratory for quantitative measurements of ioine content. In terms of statistical sampling methos, the probability proportional to population size, a cluster sampling metho, has been reliably applie to househol salt sampling as part of national or subnational surveys in communities or in schools. Other sampling methos, such as a representative sample weighte for population ensity in ifferent geographical areas, will also work (97). Analytical capacity. As outline in the Quantitative vs. qualitative measurements at the househol level section, accurate an reliable quantitative analysis of salt ioine content (i.e., by means of the titration metho) requires suitably equippe public or private laboratories. Many countries have central as well as regional analytical laboratories for this purpose. As is further elaborate in the Househol coverage of ioize salt section, it is critical that the laboratory or the network of laboratories provies reliable ata from continuous quality assessments of the results obtaine with their salt ioine measurements. Relation between coverage of ioize salt an ioine eficiency an IDD. The coverage of househols with (aequately) ioize salt is a population inicator reflecting the ioine intake above the customary ioine consumption from common foos an water. In countries where the salt ioization regulation also manates the ioization of salt use in the foo inustry, any foos manufacture with ioize salt also a to the ietary ioine supply. This situation is especially relevant for assessments in wealthier househols an in urban areas in eveloping countries. UIC is the prime inicator of ioine status in a population an is use in conjunction with analyses reflecting salt ioization to assess the nature, timeliness, an extent of the relation of househol coverage with the populationõs ioine status. It has been well ocumente that when ioize salt is introuce in the markets, the istribution of UIC levels in initially eficient populations rapily shifts to the right (98). Irrespective of whether the coverage of househols is expresse as any ioize salt or as aequately ioize salt, the nature of the response in a populationõs UIC istribution to increases in househol coverage is consistent over time an with the salt ioine intake. Several factors influence the pace by which salt ioization programs influence househol/population ioine status (Table 15). Dietary assessment of ioine intake Variability of ioine intake. Although assessment of salt ioization ( ) can serve as a useful proxy for ioine exposure uner efine circumstances an espite its relative ease of implementation [see Househol coverage of (aequately) ioize salt section], the quantification of ioine content in table salt may not be sufficient in assessing ioine exposure in certain contexts. In part, this challenge is ue to settings where there is a shift to consumption of fewer homeprepare foos. Such shifts will necessitate a greater nee to assess overall ietary ioine intake. As summarize in Table 1, the natural ioine content of foo sources iffers consierably, which contributes to the fluctuations in aily ioine intake of iniviuals (107,108). The ioine exposure scenarios vary greatly ue to not only ifferences in inherent content of foo (3,19,23,109,110) but also to factors such as seasonality of foo intake patterns (20,110), sources, an ioine content of milk (23,110). Foo processing is another critical factor affecting ioine exposure (e.g., choice of processe foo mae with ioize salt, iscretionary use of ioize salt in cooking or at the table). Methos use to assess ietary ioine intake. The goal of ietary ioine assessment is to quantify the relative contribution of habitual intake from ioine-containing foos in terms of amounts an frequency (111,112). The primary tools to accomplish this inclue FFQs (105,113,114), foo iaries or 24-h recalls (115), or weighte foo recors (5). The relative strengths an weaknesses of the ietary assessment methos an other biomarkers ientifie by the I-EP are liste in Table 16.As is true across the fiel of ietary assessment, the assessment tools use to measure ioine exposure are imprecise ( ). Foo composition tables. All ietary assessment methos require accurate information on the ioine content of foos. A number of constraints exist that impinge on the accurate analysis an ocumentation of ioine content of foos, incluing the following: Methoologies: The most reliable metho for measuring the ioine content of foo is inuctively couple plasma MS (3). The major limitation to this metho is that it is only available to a relatively limite number of laboratories worlwie. The quality of foo ioine content ata foun in foo composition tables is contingent on s the metho use to assess the ioine content (i.e., is it up-to-ate an vali an reliable?); s whether the natural variability in ioine content was taken into account; s whether the source an nature of salt use in processe foos inclue in composition tables were accounte for in the analyses (i.e., tables generally contain information on the salt content of foos but rarely specify if the salt is ioize or not; commercial proucers often fail to eclare this information); an s the generalizability of certain atabases (processe foo even from the same manufacturer or the same bran often contains ifferent amounts/types of salt in ifferent settings/countries, limiting the generalizability of certain atabases). TABLE 15 programs 1 Factors affecting implementation of salt ioization Househol wealth level (66,99) Resiential area an motherõs eucation (100) Quality assurance efforts uring the commercial ioization of eible salt, as reflecte by the salt ioine content in househols 1 It has been shown that quality assurance efforts have a strong relation to urinary ioine concentrations, particularly in countries in which the salt use in househols is the major or sole aitional source of ioine consumption ( ). Biomarkers of nutrition for evelopment ioine review 1331S