Iodine requirements and the risks and benefits of correcting iodine deficiency in populations

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1 ARTICLE IN PRESS Journal of Trace Elements in Medicine and Biology 22 (2008) INVITED REVIEW Iodine requirements and the risks and benefits of correcting iodine deficiency in populations Michael B. Zimmermann a,b, a The Human Nutrition Laboratory, ETH Zürich, Switzerland b Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands Received 4 February 2008; accepted 5 March 2008 Abstract Iodine deficiency has multiple adverse effects on growth and development due to inadequate thyroid hormone production that are termed the iodine deficiency disorders (IDD). IDD remains the most common cause of preventable mental impairment worldwide. IDD assessment methods include urinary iodine concentration, goiter, thyroglobulin and newborn thyrotropin. In nearly all iodine-deficient countries, the best strategy to control IDD is salt iodization, one of the most cost-effective ways to contribute to economic and social development. When salt iodization is not possible, iodine supplements can be targeted to vulnerable groups. Introduction of iodized salt to regions of chronic IDD may transiently increase the incidence of thyroid disorders, and programs should include monitoring for both iodine deficiency and excess. Although more data on the epidemiology of thyroid disorders caused by differences in iodine intake are needed, overall, the relatively small risks of iodine excess are far outweighed by the substantial risks of iodine deficiency. r 2008 Elsevier GmbH. All rights reserved. Keywords: Iodine; Goiter; Thyroid; Cognition; Requirement Contents Deficiency Diffuse goiter and mutinodular toxic goiter Neurocognitive impairment Epidemiology Assessment and diagnosis Thyroid size Urinary iodine concentration Thyroid stimulating hormone Thyroglobulin Treatment and prevention Salt fortification with iodine Laboratory for Human Nutrition, Swiss Federal Institute of Technology Zu rich, Schmelzbergstrasse 7, LFV E19, CH-8092 Zu rich, Switzerland. Tel.: ; fax: address: michael.zimmermann@ilw.agrl.ethz.ch X/$ - see front matter r 2008 Elsevier GmbH. All rights reserved. doi: /j.jtemb

2 82 ARTICLE IN PRESS M.B. Zimmermann / Journal of Trace Elements in Medicine and Biology 22 (2008) Iodine supplementation Excess and toxicity Conclusions References Deficiency Iodine deficiency (ID) has multiple adverse effects on growth and development in animals and humans. These are collectively termed the iodine deficiency disorders (IDD) (Table 1), and are one of the most important and common human diseases [1,2]. They result from inadequate thyroid hormone production due to lack of sufficient iodine. Diffuse goiter and mutinodular toxic goiter Thyroid enlargement (goiter) is the classic sign of ID. It is a physiologic adaptation to chronic ID. As iodine intake falls, secretion of thyroid stimulating hormone (TSH) increases in an effort to maximize uptake of available iodine, and TSH stimulates thyroid hypertrophy and hyperplasia. Initially, goiters are characterized by diffuse, homogeneous enlargement, but over time, nodular goiter often develops. Many thyroid nodules Table 1. The iodine deficiency disorders, by age group (Refs. [1,2,65]) Age groups All ages Fetus Neonate Child and adolescent Adults Health consequences of iodine deficiency Goiter, including toxic nodular goiter Increased occurrence of hypothyroidism in moderate-to-severe iodine deficiency; decreased occurrence of hypothyroidism in mild-to-moderate iodine deficiency Increased susceptibility of the thyroid gland to damage and thyroid cancer from iodine radioisotopes (e.g. from radioactive fall-out) Abortion Stillbirth Congenital anomalies Perinatal mortality Infant mortality Endemic cretinism Impaired mental function Delayed physical development Impaired mental function Iodine-induced hyperthyroidism Overall, moderate-to-severe iodine deficiency causes subtle but widespread adverse effects in a population secondary to hypothyroidism, including decreased educability, apathy, and reduced work productivity, resulting in impaired social and economic development derive from a somatic mutation and are of monoclonal origin [3]; the mutations appear to be more likely to result in nodules under the influence of a growth promoter, such as ID. ID is associated with a high occurrence of multinodular toxic goiter, mainly seen in women older than 50 yr [4]. Large goiters may be cosmetically unattractive, can obstruct the trachea and esophagus, and may damage the recurrent laryngeal nerves and cause hoarseness. Surgery to reduce goiter has significant risks, including bleeding and nerve damage, and hypothyroidism may develop after removal of thyroid tissue. Neurocognitive impairment Although goiter is the most visible effect of ID, the most serious adverse effect is damage to the fetus. Maternal thyroxine (T4) crosses the placenta before onset of fetal thyroid function at weeks and represents up to 20 40% of T4 measured in cord blood at birth [5]. Normal levels of thyroid hormones are required for neuronal migration and myelination of the fetal brain, and lack of iodine irreversibly impairs brain development [6]. Severe ID during pregnancy increases risk for stillbirths, abortions, and congenital abnormalities [7 9]. Iodine treatment of pregnant women in areas of severe deficiency reduces fetal and perinatal mortality and improves motor and cognitive performance of the offspring [10,11]. Severe ID in utero causes a condition characterized by gross mental retardation along with varying degrees of short stature, deaf mutism, and spasticity that is termed cretinism [1,2]. Two distinct types neurological and myxedematous have been described; it may also present as a mixed form. The more common, neurologic cretinism, has specific neurologic deficits that include spastic quadriplegia with sparing of the distal extremities. The myxedematous form is seen most frequently in central Africa, and has the predominant finding of profound hypothyroidism, with thyroid atrophy and fibrosis. In areas of severe ID, cretinism can affect 5 15% of the population. Iodine prophylaxis has completely eliminated the appearance of new cases of cretinism in previously iodine-deficient Switzerland and other countries, but it continues to occur in isolated areas of Western China [12]. The potential adverse effects of mild-to-moderate ID during pregnancy are unclear. Maternal subclinical hypothyroidism (an increased TSH in the second

3 ARTICLE IN PRESS M.B. Zimmermann / Journal of Trace Elements in Medicine and Biology 22 (2008) trimester) and maternal hypothyroxinemia (a free T4 concentration o10 percentile at 12-weeks gestation) are associated with impaired mental and psychomotor development of the offspring [13,14]. However, in these studies, the maternal thyroid abnormalities were unlikely due to ID. In Europe, several randomized controlled trials of iodine supplementation in mild-tomoderately iodine-deficient pregnant women have been done [15]. Iodine reduced maternal and newborn thyroid size, and, in some, decreased maternal TSH. However, none of the trials showed an effect on maternal and newborn total or free thyroid hormone concentrations, probably the best surrogate marker for healthy fetal development [16], and none measured long-term clinical outcomes, such as maternal goiter, thyroid autoimmunity, or child development. Although ID in utero impairs fetal growth and brain development, its postnatal effects on growth and cognition are less clear. Cross-sectional studies of moderate-to-severely iodine-deficient children have generally reported impaired intellectual function and fine motor skills; two meta-analyses estimated that populations with chronic ID experience a reduction in IQ of points [17,18]. However, observational studies are often confounded by other factors that affect child development, and these studies could not distinguish between the persistent effects of in utero ID and the effects of current iodine status. Several randomized trials have examined the impact of iodine supplementation on the cognitive performance of children, but their results are equivocal, and methodological problems limit their interpretation [19]. In a recent controlled trial in yr-old moderately iodine-deficient Albanian children who received 400 mg of iodine as oral iodized oil or placebo, iodine treatment significantly improved information processing, fine motor skills, and visual problem solving compared to placebo. Thus, in children born and raised in areas of ID, cognitive impairment is at least partially reversible by iodine repletion [19]. Data from cross-sectional studies on iodine intake and child growth are mixed, with most studies finding modest positive correlations [20]. In five Asian countries, household access to iodized salt was correlated with increased weight-for-age and mid-upper-arm circumference in infancy [21]. However, controlled intervention studies of iodized oil alone and iodine given with other micronutrients have generally not found effects on child growth [20]. In iodine-deficient children, impaired thyroid function and goiter are inversely correlated with insulin-like growth factor (IGF)-1 and insulin-like growth factor binding protein (IGFBP)-3 concentrations [22]. Recent controlled trials found iodine repletion increased IGF-1 and IGFBP-3 and improved somatic growth in children [20]. Overall, ID produces subtle but widespread adverse effects in a population, including decreased educability, apathy, and reduced work productivity, resulting in impaired social and economic development. Because mild-to-moderate ID affects up to 30% of the global population (see next section) and can impair cognition in children, ID is considered the most common cause of preventable mental retardation worldwide. The International Child Development Steering Group identified ID as one of four key global risk factors for impaired child development where the need for intervention is urgent [23]. Epidemiology Only a few countries Switzerland, some of the Scandinavian countries, Australia, the US and Canada were completely iodine sufficient before Since then, globally, the number of households using iodized salt has risen from o20% to 470%, dramatically reducing ID [24]. This effort has been spurred by a coalition of international organizations, including ICCIDD, WHO, MI, and UNICEF, working closely with national IDD control committees and the salt industry; this informal partnership was established after the World Summit for Children in It has been funded by Kiwanis International, the Gates Foundation, and country aid programs. In 2007, WHO estimated nearly two billion individuals have an insufficient iodine intake, including 1/3 of all school-age children [25] (Table 2). The lowest prevalence of ID is in the Americas (10.6%), where the proportion of households consuming iodized salt is the highest in the world (E90%). The highest prevalence of ID is in Europe (52.0%), where the household coverage with iodized salt is the lowest (E25%), and many countries have weak or non-existent IDD control programs. The number of countries where ID remains a public health problem is 47. However, there has been progress since 2003: 12 countries have progressed to optimal iodine status and the percentage of school-aged children at risk of iodine deficiency has decreased by 5% (Fig. 1). However, iodine intake is more than adequate, or even excessive, in 34 countries, an increase from 27 in 2003 [25]. In Australia and the US, two countries previously iodine sufficient, iodine intakes are falling. Australia is now mildly iodine deficient [26], and in the US, the median UI is 145 mg/l, still adequate but half the median value of 321 mg/l found in the 1970s [27]. These changes emphasize the importance of regular monitoring of iodine status in countries, to detect both low and excessive intakes of iodine. There are several limitations to these WHO prevalence data. First, extrapolation from a population

4 84 ARTICLE IN PRESS M.B. Zimmermann / Journal of Trace Elements in Medicine and Biology 22 (2008) Table 2. Prevalence of iodine deficiency, as total number (millions) and percentages, in general population (all age groups) and in school-age children (6 12 yr) in 2007 (Ref. [25]) and the % of households with access to iodized salt (Ref. [67]) WHO regions a Population with urinary iodine o100 mg/l b % of households with access to iodized salt c General population School-age children Africa (41.5%) 57.7 (40.8%) 66.6 Americas 98.6 (11.0%) 11.6 (10.6%) 86.8 Eastern Mediterranean (47.2%) 43.3 (48.8%) 47.3 Europe (52.0%) 38.7 (52.4%) 49.2 Southeast Asia (30.0%) 73.1 (30.3%) 61.0 Western Pacific (21.2%) 41.6 (22.7%) 89.5 Total (30.6%) (31.5%) 70.0 a 193 WHO Member States. b Based on population estimates for 2006 (United Nations, Population Division, World Population Prospects: the 2004 revision). c These figures do not include data for non-unicef countries (e.g., the US and Western Europe) Percentage Africa America Eastern Mediterranean Europe WHO Region South-East Asia Western Pacific Global Fig. 1. Change in the prevalence of iodine deficiency in school-age children (defined as a urinary iodine concentration o100 mg/l) by WHO region and globally, between 2003 and 2007 (data from Ref. [25]). indicator (median UI) to define the number of individuals affected is problematic, e.g. a country in which children have a median UI of 100 mg/l would be classified as being iodine sufficient, yet at the same time 50% of children would be classified as having inadequate iodine intakes. Second, nationally representative surveys represent only 60% of the global population included in the WHO data, and sub-national data may under or overestimate the extent of ID [25]. Finally, there are insufficient data from nearly all countries to estimate the prevalence of ID in pregnant women. Assessment and diagnosis Recommendations for iodine intake for different age groups are shown in Table 3. Four methods are generally recommended for assessment of iodine nutrition in populations: urinary iodine concentration (UI), the goiter rate, TSH, and thyroglobulin (Tg). These indicators are complementary, in that UI is a sensitive indicator of recent iodine intake (days) and Tg shows an intermediate response (weeks to months), whereas changes in the goiter rate reflect long-term iodine nutrition (months to years).

5 ARTICLE IN PRESS M.B. Zimmermann / Journal of Trace Elements in Medicine and Biology 22 (2008) Table 3. Recommendations for iodine intake (mg/day) by age or population group Age or population group a US Institute of Medicine (Ref. [34]) Age or population group b World Health Organization (Refs. [1,51]) Infants 0 12 months c Children 0 5 yr 90 Children 1 8 yr 90 Children 6 12 yr 120 Children 9 13 yr 120 Adults X14 yr 150 Adults 412 yr 150 Pregnancy 220 Pregnancy 250 Lactation 290 Lactation 250 a Recommended daily allowance. b Recommended nutrient intake. c Adequate intake. Thyroid size Two methods are available for measuring goiter: neck inspection and palpation, and thyroid ultrasonography. Goiter surveys are usually done in school-age children. By palpation, a thyroid is considered goitrous when each lateral lobe has a volume greater than the terminal phalanx of the thumbs of the subject being examined. In the classification system of WHO (1), grade 0 is defined as a thyroid that is not palpable or visible, grade 1 is a goiter that is palpable but not visible when the neck is in the normal position (i.e., the thyroid is not visibly enlarged), and grade 2 goiter is a thyroid that is clearly visible when the neck is in a normal position. Palpation of goiter in areas of mild ID has poor sensitivity and specificity; in such areas, measurement of thyroid volume by ultrasound is preferable for classifying goiter [28]. Portable ultrasound equipment can be used in the field, and goiter classified according to international reference criteria for iodinesufficient children by age, gender, and body surface area [29]. The total goiter rate is used to define severity using the following criteria: o5%, iodine sufficiency; %, mild deficiency; %, moderate deficiency; and 430%, severe deficiency [1]. In areas of endemic goiter, although thyroid size predictably decreases in response to increases in iodine intake, thyroid size may not return to normal for months or years after correction of ID [30]. During this transition period, the goiter rate is difficult to interpret, because it reflects both a population s history of iodine nutrition and its present status. A sustained salt iodization program will decrease the goiter rate by ultrasound to o5% in school-age children [31] and this indicates disappearance of ID as a significant public health problem [1]. Urinary iodine concentration Because 490% of ingested iodine is excreted in the urine, UI is an excellent indicator of recent iodine intake. Most methods of measuring UI are based on the Sandell Kolthoff reaction, in which iodide catalyzes the reduction of yellow ceric ammonium sulfate to the colorless cerous form, in the presence of arsenious acid. UI can be expressed as a concentration (mg/l), in relationship to creatinine excretion (mg iodine/g creatinine), or as 24-h excretion (mg/day). For populations, because it is impractical to collect 24-h samples in field studies, UI can be measured in spot urine specimens from a representative sample of the target group, and expressed as the median, in mg/l [1]. Variations in hydration among individuals generally even out in a large number of samples, so that the median UI in spot samples correlates well with that from 24-h samples. For national, school-based surveys of iodine nutrition, the median UI from a representative sample of spot urine collections from E1200 children (30 sampling clusters 40 children per cluster) can be used to classify a population s iodine status [1] (Table 4). However, the median UI is often misinterpreted. Individual iodine intakes, and, therefore, spot UI concentrations are highly variable from day-to-day [32], and a common mistake is to assume that all subjects with a spot UIo100 mg/l are iodine deficient. To estimate iodine intakes in individuals, 24-h collections are preferable, but difficult to obtain. An alternative is to use the age- and sex-adjusted iodine: creatinine ratio in adults, but this also has limitations [33]. Creatinine may be unreliable for estimating daily iodine excretion from spot samples, especially in malnourished subjects where creatinine concentration is low. Daily iodine intake for population estimates can be extrapolated from UI, using estimates of mean 24-h urine volume and assuming an average iodine bioavailability of 92% using the formula: Urinary iodine (mg/l) body weight (kg) ¼ daily iodine intake [34]. Using this formula, a median UI of 100 mg/l corresponds roughly to an average daily intake of 150 mg.

6 86 ARTICLE IN PRESS M.B. Zimmermann / Journal of Trace Elements in Medicine and Biology 22 (2008) Table 4. Epidemiological criteria for assessing iodine nutrition in a population based on median and/or range of urinary iodine concentrations (Refs. [1,51]) Median urinary iodine (mg/l) Iodine intake Iodine nutrition School-aged children o20 Insufficient Severe iodine deficiency Insufficient Moderate iodine deficiency Insufficient Mild iodine deficiency Adequate Optimal More than adequate Risk of iodine-induced hyperthyroidism in susceptible groups 4300 Excessive Risk of adverse health consequences (iodine-induced hyperthyroidism, autoimmune thyroid disease) Pregnant women o150 Insufficient Adequate More than adequate X500 Excessive a Lactating women b o100 Insufficient X100 Adequate Children less than 2 yr old o100 Insufficient X100 Adequate a The term excessive means in excess of the amount required to prevent and control iodine deficiency. b In lactating women, the figures for median urinary iodine are lower than the iodine requirements because of the iodine excreted in breast milk. Thyroid stimulating hormone Because serum TSH is determined mainly by the level of circulating thyroid hormone, which in turn reflects iodine intake, TSH can be used as an indicator of iodine nutrition. However, in older children and adults, although serum TSH may be slightly increased by ID, values often remain within the normal range. TSH is therefore a relatively insensitive indicator of iodine nutrition in adults [1]. In contrast, TSH is a sensitive indicator of iodine status in the newborn period [35]. Compared to the adult, the newborn thyroid contains less iodine but has higher rates of iodine turnover. Particularly when iodine supply is low, maintaining high iodine turnover requires increased TSH stimulation. Serum TSH concentrations are therefore increased in iodine-deficient infants for the first few weeks of life, a condition termed transient newborn hypothyroidism. In areas of ID, an increase in transient newborn hypothyroidism, indicated by 43% of newborn TSH values above the threshold of 5 mu/l whole blood collected 3 4 days after birth, suggests ID in the population [30,36]. TSH is used in many countries for routine newborn screening to detect congenital hypothyroidism. If already in place, such screening offers a sensitive indicator of iodine nutrition [1]. Newborn TSH is an important measure because it reflects iodine status during a period when the developing brain is particularly sensitive to ID. Thyroglobulin Tg is synthesized only in the thyroid, and is the most abundant intrathyroidal protein [37]. In iodine sufficiency, small amounts of Tg are secreted into the circulation, and serum Tg is normally o10 mg/l. In areas of endemic goiter, serum Tg increases due to greater thyroid cell mass and TSH stimulation. Serum Tg is well correlated with the severity of ID as measured by UI [38]. Tg can also be assayed on dried blood spots taken by a finger prick [39,40], simplifying collection and transport. In prospective studies, dried blood spot Tg has been shown to be a sensitive measure of iodine status and reflects improved thyroid function within several months after iodine repletion [39,40]. An international reference range and a reference standard is now available; the reference interval in iodinesufficient children is 4 40 mg/l [40]. In contrast, thyroid hormone concentrations are poor indicators of iodine status. In iodine-deficient populations, serum T3 increases or remains unchanged, and serum T4 usually decreases. However, these changes are often within the normal range, and the overlap with

7 ARTICLE IN PRESS M.B. Zimmermann / Journal of Trace Elements in Medicine and Biology 22 (2008) DALYs Lost (thousands) E. Asia/Pacific Europe/Central Asia Latin America M. East/North Africa South Asia Sub-Saharan Africa Fig. 2. Disability-adjusted life years (DALYs) (thousands) lost due to iodine deficiency among children under age 5, by region. A DALY is calculated as the present value of the future years of disability-free life that are lost as a result of the premature deaths or cases of disability occurring in a particular year (data from Ref. [44]). iodine-sufficient populations is large enough to make thyroid hormone levels an insensitive measure of iodine nutrition [1]. Treatment and prevention Salt fortification with iodine In nearly all regions affected by ID, the most effective way to control ID is through salt iodization [1]. Universal salt iodization (USI) is a term used to describe the iodization of all salts for human (food industry and household) and livestock consumption. Although the ideal, even in countries with successful salt iodization programs, USI is rarely achieved, as food industries are often reluctant to use iodized salt, and many countries do not iodize salt for livestock. WHO/UNICEF/ICCIDD recommends that iodine is added at a level of mg iodine/kg salt, depending on local salt intake [1]. Iodine can be added to salt in the form of potassium iodide (KI) or potassium iodate (KIO3). Because KIO3 has higher stability than KI in the presence of salt impurities, humidity, and porous packaging [41,42], it is the recommended form in tropical countries and those with low-grade salt. Iodine is usually added after the salt has been dried. Two techniques are used: (1) the wet method, where a solution of KIO3 is dripped or sprayed at a regular rate on to salt passing by on a conveyor belt; (2) the dry method, where KI or KIO3 powder is sprinkled over the dry salt. Optimally, packaging should be in low-density polyethylene bags. In a multi-country study, high humidity combined with porous packing resulted in up to 90% losses of iodine in 1 yr of storage in high-density polyethylene bags, compared to 10 15% from lowdensity polyethylene bags [42]. Salt iodization remains the most cost-effective way of delivering iodine and of improving cognition in iodinedeficient populations [43]. Worldwide, the annual costs of salt iodization are estimated at US$ per child covered, and the costs per child death averted are US$1000 and per disability-adjusted life year (DALY) gained are US$34 36 US (Fig. 2) [44]. Looked at in another way, prior to widespread salt iodization, the annual potential losses attributable to ID in the developing world have been estimated to be US$35.7 billion as compared with an estimated US$0.5 billion annual cost for salt iodization, i.e., a 70:1 benefit:cost ratio [45]. The World Bank [46] strongly recommends that governments invest in micronutrient programs, including salt iodization, to promote development, concluding: Probably no other technology offers as large an opportunity to improve lives at such low cost and in such a short time. Iodine supplementation In some regions, iodization of salt may not be practical for control of ID, at least in the short term. This may occur in remote areas where communications are poor or where there are numerous small-scale salt producers. In these areas, iodized oil supplements can be used [1]. Iodized oil is prepared by esterification of the unsaturated fatty acids in seed or vegetable oils, and addition of iodine to the double bonds. It can be given orally or by intramuscular injection [47]. The intramuscular route has a longer duration of action, but oral administration is more common because it is simpler. Usual doses are mg iodine/yr and it is often targeted to women of child-bearing age, pregnant women, and children [10,11] (Table 5). Iodized oil given in the first and second trimesters of pregnancy decreased the prevalence of neurological abnormalities and

8 88 ARTICLE IN PRESS M.B. Zimmermann / Journal of Trace Elements in Medicine and Biology 22 (2008) Table 5. Recommendations for iodine supplementation in pregnancy and infancy in areas where o90% of households are using iodized salt and the median UI is o100 mg/l in schoolchildren (Ref. [51]) Women of childbearing age Women who are pregnant or lactating Children aged 0 6 months Children aged 7 24 months old a Recommended nutrient intake. A single annual oral dose of 400 mg of iodine as iodized oil Or A daily oral dose of iodine as potassium iodide should be given so that the total iodine intake meets the RNI a of 150 mg/day of iodine A single annual oral dose of 400 mg of iodine as iodized oil Or A daily oral dose of iodine as potassium iodide should be given so that the total iodine intake meets the new RNI of 250 mg/day iodine Iodine supplements should not be given to a woman who has already been given iodized oil during her current pregnancy or up to 3 months before her current pregnancy started A single oral dose of 100 mg of iodine as iodized oil Or A daily oral dose of iodine as potassium iodide should be given so that the total iodine intake meets the RNI of 90 mg/day of iodine Should be given iodine supplements only if the mother was not supplemented during pregnancy or if the child is not being breast-fed A single annual oral dose of 200 mg of iodine as iodized oil as soon as possible after reaching 7 months of age Or A daily oral dose of iodine as potassium iodide should be given so that the total iodine intake meets the RNI of 90 mg/day of iodine improved developmental test scores through 7 yr, compared with supplementation later in pregnancy or treatment after birth [48]. Its disadvantages are an uneven level of iodine in the body over time and the need for direct contact with individuals with the accompanying increased costs. Iodine can also be given as KI or KIO3 as drops or tablets. Single oral doses of potassium iodide monthly (30 mg) or biweekly (8 mg) can provide adequate iodine for school-age children [49]. Lugol s iodine, containing E6 mg iodine per drop, and similar preparations are often available as antiseptics in rural dispensaries in developing countries and offer another simple way to deliver iodine locally. Whether providing preterm infants with supplemental iodine prevents morbidity and mortality is uncertain [50]. In countries or regions where a salt iodization program covers X90% of households and has been sustained for X2 yr, and the median UI indicates iodine sufficiency (Table 4), pregnant and lactating women do not need iodine supplementation [51]. In iodine-deficient countries or regions that have weak iodized salt distribution, supplements should be given to pregnant women, lactating women and infants, according to the strategy shown in Table 5 [51]. Excess and toxicity Acute iodine poisoning caused by ingestion of many grams causes gastrointestinal irritation, abdominal pain, nausea, vomiting, and diarrhea, as well as cardiovascular symptoms, coma, and cyanosis [52]. Excess iodine intake may very rarely precipitate iodermia, a skin disorder consisting of acneiform eruptions, pruritic rash, and urticaria [53]. In areas of iodine sufficiency, healthy individuals are remarkably tolerant to iodine intakes up to 1 mg per day, as the thyroid is able to adjust to a wide range of intakes to regulate the synthesis and release of thyroid hormones [54]. However, doses of iodine in the mg range may cause hypothyroidism in those with damaged thyroid glands because normal down-regulation of iodine transport into the gland does not occur. Individuals with nodular goiter may also respond adversely to intakes lower than 1 mg/day. In children, chronic intakes of X500 mg/day are associated with increased thyroid volume, an early sign of thyroid dysfunction [55]. European [56] and USA [34] expert committees have recommended tolerable upper intake levels for iodine (Table 6), but caution that individuals with chronic ID may respond adversely to intakes lower than these. In monitoring populations consuming iodized salt, the WHO/UNICEF/ICCIDD recommendations for the median UI that indicates more than adequate and excess iodine intake are shown in Table 4. An increase in iodine intake of populations with chronic ID may precipitate iodine-induced hyperthyroidism (IIH) [57]. It has been reported in the introductory phase of several USI programs, including an outbreak in Zimbabwe and the DR of the Congo due to excessively iodized salt. IIH primarily affects older adults with longstanding nodular goiter whose iodine intake is rapidly increased. Thyrocytes in nodules often become insensitive to TSH control, and if iodine supply is suddenly increased, these autonomous nodules may overproduce thyroid hormone [58]. Symptoms of IIH include weight loss, tachycardia, muscle weakness, and

9 ARTICLE IN PRESS M.B. Zimmermann / Journal of Trace Elements in Medicine and Biology 22 (2008) Table 6. Age group Tolerable upper intake level for iodine (mg/day) European Commission/Scientific Committee on Food (Ref. [56]) 1 3 yr yr yr yr yr Adult Pregnant women US Institute of Medicine (Ref. [34]) skin warmth, without the ophthalmopathy of Graves disease. It is nearly always transient and its incidence reverts to baseline after 1 10 yr of intervention. However, it is dangerous when superimposed on underlying heart disease, and may be lethal [57]. IIH prevention includes careful monitoring of salt iodine levels and training of regional health staff in IIH identification and treatment. To investigate the effects of iodine intake on thyroid disorders in China [59,60], a 5-yr, prospective community-based survey was done in three rural Chinese communities with mild-deficient, more than adequate (previously mild ID corrected by iodized salt), and excessive iodine intake from environmental sources; the median UI was 88, 214, and 634 mg/l, respectively. For the three communities, the cumulative incidence of hyperthyroidism was 1.4%, 0.9%, and 0.8%; of overt hypothyroidism, 0.2%, 0.5%, and 0.3%; of subclinical hypothyroidism, 0.2%, 2.6%, and 2.9%; and of autoimmune thyroiditis, 0.2%, 1.0%, and 1.3%, respectively. In most individuals, these later two disorders were not sustained. Among subjects with euthyroidism and antithyroid antibodies at baseline, the 5-yr incidence of elevated serum thyrotropin levels was greater among those with more than adequate or excessive iodine intake than among those with mildly deficient iodine intake. In all three communities, independent of iodine intake, either positive TPOAb (OR ¼ 4.2 (95% CI ) or goiter (OR ¼ 3.1 (95% CI ) in original healthy participants was associated with the occurrence of hyperthyroidism. Denmark has documented the pattern of thyroid disease after careful introduction of iodized salt [61,62]. New cases of overt hypothyroidism were identified in two areas of Denmark with previous moderate and mild ID, respectively (Aalborg, median UI ¼ 45 mg/l; and Copenhagen, median UI ¼ 61 mg/l) before and for the first 7 yr after introduction of a national program of salt iodization. The overall incidence rate of hypothyroidism modestly increased during the study period: baseline, 38.3/100,000 yr; after salt iodization, 47.2/100,000 (vs. baseline, RR ¼ 1.23; 95% CI ¼ ). There was a geographic difference because hypothyroidism increased only in the area with previous moderate ID. The increase occurred in young and middle-aged adults. Similarly, new cases of overt hyperthyroidism in these two areas of Denmark before and for the first 6 yr after iodine fortification were identified [62]. The overall incidence rate of hyperthyroidism increased [baseline, 102.8/100,000/yr; after salt iodization 138.7/100,000 (P for trend o0.001)]. Hyperthyroidism increased in both sexes and in all age groups, but in contrast to IIH where most cases occur in older individuals, many of the new cases were observed in young subjects the increase was highest in adults aged yr and were presumably of autoimmune origin. The authors suggested that further monitoring is expected to show a decrease in the number of elderly subjects suffering from nodular hyperthyroidism. The overall incidence of differentiated thyroid carcinoma in populations does not appear to be influenced by iodine intake. A study in Denmark suggested modest differences in iodine intake between regions did not affect thyroid cancer incidence or the distribution of its subtypes [63]. However, other studies have suggested the distribution of the subtypes of thyroid carcinoma is related to iodine intake; in areas of higher iodine intake, there appear to be fewer of the more aggressive follicular and anaplastic carcinomas, but more papillary carcinomas [64]. When iodine prophylaxis is introduced in populations, there may be an increase in the ratio of papillary to follicular carcinoma, and this shift toward less malignant types of thyroid cancer, as well as a lower radiation dose to the thyroid in case of nuclear fallout, are benefits of the correction of mild-tomoderate ID [65]. Conclusions Concerns about potential increases in iodine-induced thyroid disease continue to delay or limit the implementation of iodine prophylaxis in iodine-deficient populations. Are these concerns justified? Looking at the benefits vs. the risks of iodine prophylaxis, it is clear that severe ID in pregnancy can cause hypothyroidism, poor pregnancy outcome, cretinism, and irreversible mental retardation. Mild-to-moderate ID in utero and in childhood results in less-severe learning disability, poor growth, and diffuse goiter. In adults, mild-to-moderate ID appears to be associated with higher rates of more aggressive subtypes of thyroid cancer, and increases risk for nontoxic and toxic nodular goiter and associated hyperthyroidism. However, increasing iodine intakes in deficient populations is not without risk. Mild ID may be associated with a decreased risk of overt and subclinical

10 90 ARTICLE IN PRESS M.B. Zimmermann / Journal of Trace Elements in Medicine and Biology 22 (2008) hypothyroidism, as well as autoimmune thyroiditis. In China, chronic excess iodine intakes are associated with a small increase in subclinical hypothyroidism and autoimmune thyroiditis, but not overt hypo- or hyperthyroidism. In contrast, in Denmark, correcting mild-to-moderate deficiency modestly increased rates of hypo- and hyperthyroidism. The differing effects of varying iodine intakes in these studies may be related to differences in underlying thyroid autonomy, genetic susceptibility or other environmental variables. It is possible that nutritional determinants of thyroid function (e.g. selenium, vitamin A, iron) differ in the populations studied. More prospective data on the epidemiology of thyroid disorders caused by changes in iodine intake in other countries would be valuable. Clearly, programs of iodine prophylaxis need to carefully monitor for both ID and excess. Overall, the relatively small risks of iodine excess are far outweighed by the substantial risks of iodine deficiency pregnancy loss, goiter, and mental retardation [66], which continue to affect up to a 1/3rd of the global population [25,67]. References [1] World Health Organization/International Council for the Control of the Iodine Deficiency Disorders/United Nations Childrens Fund (WHO/ICCIDD/UNICEF). Assessment of the iodine deficiency disorders and monitoring their elimination. 2nd edition. Geneva: WHO; [2] Delange F, Hetzel B. The iodine deficiency disorders. In: DeGroot LE, Hannemann G, editors. The thyroid and its diseases. Available at: / Accessed January 18, [3] Kopp P, Kimura ET, Aeschimann S, Oestreicher M, Tobler A, Fey MF, et al. Polyclonal and monoclonal thyroid nodules coexist within human multinodular goiters. J Clin Endocrinol Metab 1994;79(1): [4] Laurberg P, Pedersen KM, Vestergaard H, Sigurdsson G. 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