Thyroid and Environment Szinnai G (ed): Paediatric Thyroidology. Endocr Dev. Basel, Karger, 2014, vol 26, pp 130–138 (DOI: 10.1159/000363160)
Iodine Deficiency in Children Elizabeth N. Pearce Section of Endocrinology, Diabetes and Nutrition, Boston University School of Medicine, Boston, Mass., USA
Abstract
Iodine is an essential trace mineral in humans, required for the production of thyroid hormone. Adequate thyroid hormone is needed for normal growth and neurodevelopment in infancy and childhood. Worldwide, iodine deficiency remains the leading preventable cause of intellectual deficits. Historically, endemic goiter was thought of as the primary result of iodine deficiency; however it is now recognized that iodine deficiency disorders encompass a spectrum of disease. Although international public health efforts over the past several decades have been highly effective, nearly one third of children globally remain at risk for iodine deficiency [1]. This review will discuss iodine physiology, iodine requirements, assessment of population iodine status, effects of iodine deficiency, and strategies for and effectiveness of iodine supplementation and food fortification.
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Iodine is an essential trace mineral, required for the production of thyroid hormone. Iodine deficiency may result in goiter, hypothyroidism, miscarriage, stillbirth, congenital anomalies, infant and neonatal mortality, and impaired growth. Adequate thyroid hormone is critically important for normal growth and neurodevelopment in fetal life, infancy and childhood. The population iodine status is most commonly assessed using median urinary iodine concentration values, but goiter prevalence (determined by palpation or by ultrasound), serum thyroglobulin levels, and neonatal thyroid-stimulating hormone values can also be used. Universal salt iodization programs have been the mainstay of public health efforts to eliminate iodine deficiency worldwide. However, in some regions targeted fortification of foods such as bread has been used to combat iodine deficiency. Iodine supplementation may be required in areas where dietary fortification is not feasible or where it is not sufficient for vulnerable groups such as pregnant women. Although international public health efforts over the past several decades have been highly effective, nearly one third of children worldwide remain at risk for iodine deficiency, and iodine deficiency is considered the leading preventable cause of © 2014 S. Karger AG, Basel preventable intellectual deficits.
Iodine Physiology
The only known use of iodine in the human body is in the production of thyroid hormone. After ingestion, iodide is rapidly absorbed through the stomach and duodenum [2]. Following absorption, iodide is transported through the circulation and is either taken up by the thyroid gland or renally excreted; approximately 90% of ingested iodine is ultimately excreted by the kidneys. The thyroid takes up iodine via the sodium/iodide symporter (NIS), which is expressed on the basolateral membrane of thyroid follicular cells. The activity of NIS is regulated by thyroid-stimulating hormone (TSH) and circulating iodide concentrations. Once inside thyroid cells, iodide is oxidized by thyroperoxidase and then incorporated into thyroid hormone.
Iodine Requirements
In order to maintain normal thyroid hormone production, most adolescents and adults need to ingest 150 µg iodine daily [3]. The recommended daily allowances for children are lower: 90 µg daily for children aged 1–3 years, 120 µg/day for children aged 4–8, and 150 µg daily for those aged 9–13. Due to limited data regarding their requirements, a recommended daily allowance has not been established for infants less than 1 year of age. Instead, adequate intake levels, conservative approximations, have been set at 110 µg/day for infants aged 0–6 months and 130 µg/day for infants aged 6–12 months [3]. These adequate intake levels are based on breast milk iodine concentrations measured in US women during a period when overall iodine intakes in the US population were excessive, and probably overestimate infants’ true requirements. Because of increased thyroid hormone production, increased renal iodine losses and fetal iodine requirements in pregnancy, dietary iodine requirements are increased for pregnant women. The recommended daily allowance for pregnant women is 220 µg daily [3]. Dietary requirements remain elevated following delivery, since lactating mothers secrete iodine into breast milk via the NIS, where it is the only source of iodine nutrition for exclusively breastfed infants. Breastfeeding mothers require ingestion of 290 µg iodine daily in order to meet their own needs and those of their infants [3].
Median spot urinary iodine concentrations (UICs) are most frequently used to determine population iodine status. Median thresholds for UIC have been identified for populations but cannot be used to determine individuals’ iodine status, given substantial day-to-day and diurnal variation in iodine intake [4]. Median UICs of 100–199 µg/l are consistent with optimal iodine nutrition in school-aged children, with median concentrations below 100, 50 and 20 µg/l considered consistent with mild, mod-
Iodine Deficiency Szinnai G (ed): Paediatric Thyroidology. Endocr Dev. Basel, Karger, 2014, vol 26, pp 130–138 (DOI: 10.1159/000363160)
131
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Assessing Iodine Status
erate and severe iodine deficiency, respectively. Although the median UIC in schoolaged children has been used as a proxy for overall population status, recent studies suggest that the UIC in school-aged children does not always predict the status of pregnant women from the same regions [1]. A median UIC >100 µg/l is consistent with iodine sufficiency in infants and children under 2 years of age [5]. A validated method has recently been developed for the collection of urine samples for iodine measurement in infants [6]. UICs of 150–249 µg/l are consistent with optimal iodine nutrition in pregnant women [5]. Finally, UICs >100 µg/l are consistent with adequate iodine intake in breastfeeding mothers; although their dietary requirements remain elevated, UICs decrease following pregnancy because some iodine is secreted into the breast milk rather than being lost in the urine. Goiter size, assessed by palpation or ultrasonography, may also be used to assess longterm iodine sufficiency. A simple grading system may be used to assess goiter by palpation [5]. Goiter rates should be 30% in severely iodine-deficient regions [5]. However, even among experienced examiners, palpation of goiter size may lead to high rates of misclassification. Ultrasound can provide more precise measurements of thyroid volume, and international reference ranges for ultrasonographic thyroid volume have been established for school-aged children [7]. Serum thyroglobulin levels tend to increase in states of both iodine deficiency and iodine excess. Thyroglobulin levels, which may be measured from dried blood spots, have recently been validated as a marker for population iodine status among schoolaged children. In iodine-sufficient populations, median thyroglobulin values are 40 μg/l [8]. Thyroglobulin is a good marker for relatively short-term iodine changes, since levels change over a period of weeks to months. Iodine-deficient children are at higher risk for the development of hypothyroidism than children from regions of iodine sufficiency. However, thyroid function testing is not a sensitive indicator of the population iodine status in children due to a large overlap in TSH, triiodothyronine and thyroxine values between iodine-sufficient and -deficient regions. Neonatal TSH values, obtained to screen for congenital thyroid dysfunction, tend to be higher in iodine-deficient regions and may be used as a marker for population iodine status. In iodine-sufficient populations, fewer than 3% of neonatal TSH values should be >5 mIU/l [5].
When dietary iodine intake is inadequate, serum thyroid hormone levels initially fall. The pituitary gland senses low thyroid hormone levels and increases TSH secretion. TSH, in turn, stimulates the growth of thyroid cells, thyroidal iodine uptake and thyroid hormone synthesis. Thyroid enlargement, or goiter, in response to iodine deficiency, may occur at any age. Goiter is typically initially diffuse but eventually be-
132
Pearce Szinnai G (ed): Paediatric Thyroidology. Endocr Dev. Basel, Karger, 2014, vol 26, pp 130–138 (DOI: 10.1159/000363160)
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/1/2015 6:27:41 PM
Effects of Iodine Deficiency
comes nodular. If iodine deficiency is severe enough, thyroid hormone production will fall, resulting in hypothyroidism. The consequences of iodine deficiency change across the life span. Both maternal and fetal hypothyroidism can result from severe iodine deficiency in pregnancy. Severe iodine deficiency in pregnant women has been associated with adverse obstetric and neonatal outcomes such as spontaneous abortion, stillbirth, congenital anomalies and infant mortality [2]. Very severe maternal iodine deficiency may result in children born with cretinism, a syndrome characterized by spasticity, deaf-mutism, dwarfism, mental deficiency and squint. Thyroid hormone plays a particularly vital role in fetal and infant neurodevelopment. Animal studies have demonstrated that low levels of thyroid hormone in early pregnancy impair the radial migration of neurons to the cortex and hippocampus and result in behavior changes [9, 10]. Meta-analyses have demonstrated that intelligence quotient (IQ) levels of children living in severely iodine-deficient areas are an average of 6–12 points lower than of those living in iodine-sufficient regions [11, 12]. The effects of mild-to-moderate iodine deficiency are less well characterized than those of severe iodine deficiency. However, recent studies have shown that even mild maternal iodine deficiency in pregnancy may result in intellectual deficits. An analysis of data from the Avon Longitudinal Study of Parents and Children in the UK concluded that children of mothers with an iodine-to-creatinine ratio of less than 150 μg/g were more likely to have verbal IQ, reading accuracy and reading comprehension scores in the lowest quartile than were those of mothers with UICs of ≥150 μg/g [13]. Among 9-year-old children from Tasmania, those whose mothers had UICs
Iodine Deficiency in Children Elizabeth N. Pearce Section of Endocrinology, Diabetes and Nutrition, Boston University School of Medicine, Boston, Mass., USA
Abstract
Iodine is an essential trace mineral in humans, required for the production of thyroid hormone. Adequate thyroid hormone is needed for normal growth and neurodevelopment in infancy and childhood. Worldwide, iodine deficiency remains the leading preventable cause of intellectual deficits. Historically, endemic goiter was thought of as the primary result of iodine deficiency; however it is now recognized that iodine deficiency disorders encompass a spectrum of disease. Although international public health efforts over the past several decades have been highly effective, nearly one third of children globally remain at risk for iodine deficiency [1]. This review will discuss iodine physiology, iodine requirements, assessment of population iodine status, effects of iodine deficiency, and strategies for and effectiveness of iodine supplementation and food fortification.
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/1/2015 6:27:41 PM
Iodine is an essential trace mineral, required for the production of thyroid hormone. Iodine deficiency may result in goiter, hypothyroidism, miscarriage, stillbirth, congenital anomalies, infant and neonatal mortality, and impaired growth. Adequate thyroid hormone is critically important for normal growth and neurodevelopment in fetal life, infancy and childhood. The population iodine status is most commonly assessed using median urinary iodine concentration values, but goiter prevalence (determined by palpation or by ultrasound), serum thyroglobulin levels, and neonatal thyroid-stimulating hormone values can also be used. Universal salt iodization programs have been the mainstay of public health efforts to eliminate iodine deficiency worldwide. However, in some regions targeted fortification of foods such as bread has been used to combat iodine deficiency. Iodine supplementation may be required in areas where dietary fortification is not feasible or where it is not sufficient for vulnerable groups such as pregnant women. Although international public health efforts over the past several decades have been highly effective, nearly one third of children worldwide remain at risk for iodine deficiency, and iodine deficiency is considered the leading preventable cause of © 2014 S. Karger AG, Basel preventable intellectual deficits.
Iodine Physiology
The only known use of iodine in the human body is in the production of thyroid hormone. After ingestion, iodide is rapidly absorbed through the stomach and duodenum [2]. Following absorption, iodide is transported through the circulation and is either taken up by the thyroid gland or renally excreted; approximately 90% of ingested iodine is ultimately excreted by the kidneys. The thyroid takes up iodine via the sodium/iodide symporter (NIS), which is expressed on the basolateral membrane of thyroid follicular cells. The activity of NIS is regulated by thyroid-stimulating hormone (TSH) and circulating iodide concentrations. Once inside thyroid cells, iodide is oxidized by thyroperoxidase and then incorporated into thyroid hormone.
Iodine Requirements
In order to maintain normal thyroid hormone production, most adolescents and adults need to ingest 150 µg iodine daily [3]. The recommended daily allowances for children are lower: 90 µg daily for children aged 1–3 years, 120 µg/day for children aged 4–8, and 150 µg daily for those aged 9–13. Due to limited data regarding their requirements, a recommended daily allowance has not been established for infants less than 1 year of age. Instead, adequate intake levels, conservative approximations, have been set at 110 µg/day for infants aged 0–6 months and 130 µg/day for infants aged 6–12 months [3]. These adequate intake levels are based on breast milk iodine concentrations measured in US women during a period when overall iodine intakes in the US population were excessive, and probably overestimate infants’ true requirements. Because of increased thyroid hormone production, increased renal iodine losses and fetal iodine requirements in pregnancy, dietary iodine requirements are increased for pregnant women. The recommended daily allowance for pregnant women is 220 µg daily [3]. Dietary requirements remain elevated following delivery, since lactating mothers secrete iodine into breast milk via the NIS, where it is the only source of iodine nutrition for exclusively breastfed infants. Breastfeeding mothers require ingestion of 290 µg iodine daily in order to meet their own needs and those of their infants [3].
Median spot urinary iodine concentrations (UICs) are most frequently used to determine population iodine status. Median thresholds for UIC have been identified for populations but cannot be used to determine individuals’ iodine status, given substantial day-to-day and diurnal variation in iodine intake [4]. Median UICs of 100–199 µg/l are consistent with optimal iodine nutrition in school-aged children, with median concentrations below 100, 50 and 20 µg/l considered consistent with mild, mod-
Iodine Deficiency Szinnai G (ed): Paediatric Thyroidology. Endocr Dev. Basel, Karger, 2014, vol 26, pp 130–138 (DOI: 10.1159/000363160)
131
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/1/2015 6:27:41 PM
Assessing Iodine Status
erate and severe iodine deficiency, respectively. Although the median UIC in schoolaged children has been used as a proxy for overall population status, recent studies suggest that the UIC in school-aged children does not always predict the status of pregnant women from the same regions [1]. A median UIC >100 µg/l is consistent with iodine sufficiency in infants and children under 2 years of age [5]. A validated method has recently been developed for the collection of urine samples for iodine measurement in infants [6]. UICs of 150–249 µg/l are consistent with optimal iodine nutrition in pregnant women [5]. Finally, UICs >100 µg/l are consistent with adequate iodine intake in breastfeeding mothers; although their dietary requirements remain elevated, UICs decrease following pregnancy because some iodine is secreted into the breast milk rather than being lost in the urine. Goiter size, assessed by palpation or ultrasonography, may also be used to assess longterm iodine sufficiency. A simple grading system may be used to assess goiter by palpation [5]. Goiter rates should be 30% in severely iodine-deficient regions [5]. However, even among experienced examiners, palpation of goiter size may lead to high rates of misclassification. Ultrasound can provide more precise measurements of thyroid volume, and international reference ranges for ultrasonographic thyroid volume have been established for school-aged children [7]. Serum thyroglobulin levels tend to increase in states of both iodine deficiency and iodine excess. Thyroglobulin levels, which may be measured from dried blood spots, have recently been validated as a marker for population iodine status among schoolaged children. In iodine-sufficient populations, median thyroglobulin values are 40 μg/l [8]. Thyroglobulin is a good marker for relatively short-term iodine changes, since levels change over a period of weeks to months. Iodine-deficient children are at higher risk for the development of hypothyroidism than children from regions of iodine sufficiency. However, thyroid function testing is not a sensitive indicator of the population iodine status in children due to a large overlap in TSH, triiodothyronine and thyroxine values between iodine-sufficient and -deficient regions. Neonatal TSH values, obtained to screen for congenital thyroid dysfunction, tend to be higher in iodine-deficient regions and may be used as a marker for population iodine status. In iodine-sufficient populations, fewer than 3% of neonatal TSH values should be >5 mIU/l [5].
When dietary iodine intake is inadequate, serum thyroid hormone levels initially fall. The pituitary gland senses low thyroid hormone levels and increases TSH secretion. TSH, in turn, stimulates the growth of thyroid cells, thyroidal iodine uptake and thyroid hormone synthesis. Thyroid enlargement, or goiter, in response to iodine deficiency, may occur at any age. Goiter is typically initially diffuse but eventually be-
132
Pearce Szinnai G (ed): Paediatric Thyroidology. Endocr Dev. Basel, Karger, 2014, vol 26, pp 130–138 (DOI: 10.1159/000363160)
Downloaded by: UCSF Library & CKM 169.230.243.252 - 3/1/2015 6:27:41 PM
Effects of Iodine Deficiency
comes nodular. If iodine deficiency is severe enough, thyroid hormone production will fall, resulting in hypothyroidism. The consequences of iodine deficiency change across the life span. Both maternal and fetal hypothyroidism can result from severe iodine deficiency in pregnancy. Severe iodine deficiency in pregnant women has been associated with adverse obstetric and neonatal outcomes such as spontaneous abortion, stillbirth, congenital anomalies and infant mortality [2]. Very severe maternal iodine deficiency may result in children born with cretinism, a syndrome characterized by spasticity, deaf-mutism, dwarfism, mental deficiency and squint. Thyroid hormone plays a particularly vital role in fetal and infant neurodevelopment. Animal studies have demonstrated that low levels of thyroid hormone in early pregnancy impair the radial migration of neurons to the cortex and hippocampus and result in behavior changes [9, 10]. Meta-analyses have demonstrated that intelligence quotient (IQ) levels of children living in severely iodine-deficient areas are an average of 6–12 points lower than of those living in iodine-sufficient regions [11, 12]. The effects of mild-to-moderate iodine deficiency are less well characterized than those of severe iodine deficiency. However, recent studies have shown that even mild maternal iodine deficiency in pregnancy may result in intellectual deficits. An analysis of data from the Avon Longitudinal Study of Parents and Children in the UK concluded that children of mothers with an iodine-to-creatinine ratio of less than 150 μg/g were more likely to have verbal IQ, reading accuracy and reading comprehension scores in the lowest quartile than were those of mothers with UICs of ≥150 μg/g [13]. Among 9-year-old children from Tasmania, those whose mothers had UICs
