When the aforementioned physiological requirements are not met in a given population, a series of functional and developmental abnormalities occur, including thyroid function abnormalities.
Iodine deficiency is now accepted as the most common cause of preventable brain damage in the world. According to the World Health Organization (WHO), iodine deficiency disorders (IDD) affect 740 million people throughout the world, and nearly 50 million people suffer from some degree of IDD-related brain damage. The spectrum of IDD includes endemic goiter and cretinism, endemic mental retardation, decreased fertility rate, increased perinatal death and infant mortality, and varying degrees of other growth and developmental abnormalities (table 2). Nearly 2.2 billion people throughout the world live in areas of iodine deficiency and risk its consequences. Major international efforts have produced dramatic improvements in the correction of iodine deficiency in the 1990 decade mainly through the use of iodized salt and iodized vegetable oil in iodine deficient countries .
The mechanism by which the thyroid gland adapts to an insufficient iodine supply is to increase the trapping of iodide as well as the subsequent steps of the intrathyroidal metabolism of iodine leading to preferential synthesis and secretion of T3. They are triggered and maintained by increased secretion of TSH, which is ultimately responsible for the development of goiter. The acceleration of the main steps of iodine kinetics and the degree of hyperstimulation by TSH are much more marked in the pediatric age groups, including neonates, and the
Table 2. The spectrum of IDD across the life-span (adapted from )
abortions deaf mutism stillbirths congenital anomalies increased perinatal mortality endemic cretinism deaf mutism neonatal goiter neonatal hypothyroidism endemic mental retardation increased susceptibility of the thyroid gland to nuclear radiation Child and adolescent goiter
(subclinical) hypothyroidism impaired mental function retarded physical development increased susceptibility of the thyroid gland to nuclear radiation
Adult goiter, with its complications hypothyroidism impaired mental function hyperthyroidism in the elderly (after iodized salt)
development of goiter appears as an unfavorable side effect in the process of adaptation to iodine deficiency during growth, because it leads to a vicious cycle of iodine loss and defective thyroid hormones synthesis  (table 3).
Endemic goiter is one of the earliest and most visible sign of iodine deficiency . According to iodine deficiency level this response may be adequate to preserve euthyroidism, but at the cost of an enlarged thyroid and the attendant risks of neck compression and eventual hyperfunctioning autonomous nodules with hyperthyroidism. An insufficient adaptation in adults produces hypothyroidism with its usual clinical stigmata. The damage is greater when iodine deficiency provokes hypothyroidism during fetal or early postnatal life, because thyroid hormone is necessary for proper development of the central nervous system, particularly its myelination. Individuals who were hypothyroid at this critical period frequently have permanent mental retardation, which cannot be corrected by later administration of thyroid hormone or iodine.
Most of the populations which live in areas of iodine deficiency are in developing countries, but many in the large industrialized countries of Europe
Table 3. Summary of mechanisms involved in the adaptation to iodine deficiency (adapted from )
Increased thyroid clearance of plasma inorganic iodine Hyperplasia of the thyroid and morphologic abnormalities Changes in iodine stores and thyroglobulin synthesis Modifications of the iodoamino acid content of the gland Enrichment of thyroid secretion in T3 Enhanced peripheral conversion of T4 to T3 in some tissues Increased thyroid-stimulating hormone production are also affected. Correcting this public health problem is the goal of a massive global campaign that is showing remarkable progress so far. But despite its importance to most other countries, iodine deficiency receives little attention in the United States because its elimination years ago has been widely assumed .
Health Consequences of Iodine Deficiency by Developmental Stage
Fetal iodine deficiency is caused by iodine deficiency in the mother. The result of iodine deficiency during pregnancy is impaired synthesis of thyroid hormones by the mother and the fetus. An insufficient supply of thyroid hormones to the developing brain may ensue in mental retardation [13-15].
An important issue on thyroid function and regulation in the fetus is the concept that during the first half of gestation the thyroid hormone available to the fetus is predominantly of maternal origin. T4 from the mother is the most important source of T3 for the fetal brain and protects it from a possible hormone deficiency until birth [16, 17]. Once the fetal thyroid secretion starts, fetal supplies are of mixed fetal and maternal origin. Although fetal thyroidal secretion is believed to constitute an increasing proportion of the hormone available to the developing fetus, maternal transfer of T4 may still contribute significantly to fetal needs (20-50% of normal values) up to term, mitigating the consequences of inadequate fetal thyroid function [17, 18]. The iodine content of the fetal thyroid increases progressively from less than 2 |xg at 17 weeks of gestation up to 300 |xg at term .
In conditions of mild iodine deficiency (iodine intake: 50-99 |xg/day) , the serum levels of free T4 steadily decrease during gestation while, in iodine sufficiency, there is only a slight (15%) decrease by the end of gestation. As a consequence, serum TSH levels increase progressively. This situation of chronic thyroid hyper stimulation results in an increase in serum TG and in an increase in thyroid volume by 20-30% during gestation, a figure twice higher than in conditions of normal iodine supply .
In moderate iodine deficiency (iodine intake: 20-49 |xg/day), the anomalies are of the same nature but more marked. The few studies conducted in populations with severe iodine deficiency  showed that the prevalence of goiter reaches peak values of up to 90% in females of child bearing age and that during pregnancy, serum T4 is extremely low and serum TSH is extremely high. Comparative studies carried out in New Guinea and the Democratic Republic of Congo showed that, in spite of the fact that the two areas are submitted to a similar degree of severe iodine deficiency (iodine intake <20 |xg iodine/day), serum T4 in pregnant women is much higher in the Congo (8.0 |xg/dl) than in New Guinea (3.0-5.0 |xg/dl). This discrepancy was understood only when it was demonstrated that in the Congo, iodine deficiency is aggravated by selenium deficiency and thiocyanate overload.
Accordingly, iodine deficiency results in relative hypothyroxinemia during pregnancy, thus leading to enhanced thyroidal stimulation (through the TSH feedback mechanisms) and goitrogenesis in both the mother and fetus. Goiter formation is the most directly 'visible' consequence of iodine deprivation, and pregnancy should therefore be viewed as an environmental factor to trigger the glandular machinery and induce functional and anatomical abnormalities of the thyroid in areas with a reduced iodine intake.
Infant mortality is increased in areas of iodine deficiency, and several studies have demonstrated an increase in childhood survival when iodine deficiency is corrected . Infancy is a period of rapid brain growth and development. Even in the absence of congenital hypothyroidism, iodine deficiency during infancy may result in abnormal brain development and, consequently, impaired intellectual development .
In mild iodine deficiency, the serum concentrations of TSH and TG are still higher in neonates than in their mothers. The frequency distribution of neonatal TSH on day 5, at the time of systematic screening for congenital hypothyroidism, is shifted towards elevated values. The frequency of values above 5 |xU/ml (blood) is 4.5%, while the normal value is below 3% .
In moderate iodine deficiency, the anomalies are of the same nature, but more drastic. The frequency of neonatal TSH above 20-25 |xU/ml (blood), that is above the cut-off point used for recalling the neonates because of suspicion of congenital hypothyroidism in programs of systematic screening for congenital hypothyroidism, is increased. This frequency is inversely related to the median urinary iodine of populations of neonates used as an index of their iodine intake. In addition, transient neonatal hypothyroidism can occur with a frequency approximately 6 times higher in Europe than in the United States, where the iodine intake is much elevated.
In severe iodine deficiency, the biochemical picture of neonatal hypothyroidism is exaggerated. In Congo, as many as 11% of the neonates have both a cord serum TSH above 100 |xU/ml and a cord T4 below 3.0 |xg/dl, i.e. a situation similar to the one found in thyroid agenesis.
The changes in neonatal TSH and thyroid function in the neonates in all conditions of iodine deficiency are much more frequent and severe than in their mothers. The hypersensitivity of neonates to iodine deficiency is explained by their very small intrathyroidal iodine pool, which requires increased TSH stimulation and a fast turnover rate in order to maintain a normal secretion of thyroid hormones.
The most important and frequent alterations of thyroid function due to iodine deficiency in Europe occur in neonates and young infants. The frequency of transient primary hypothyroidism is almost 8 times higher in Europe than in North America . This syndrome is characterized by postnatally acquired severe primary hypothyroidism lasting for a few weeks and requiring substitutive therapy . The risk of transient hypothyroidism in neonates increases with the degree of prematurity . The specific role played by iodine deficiency in the etiology of this type of hypothyroidism is demonstrated by the disappearance of neonatal transient thyroid failure in Belgian pre-terms following systematic supplementation with 30 |xg potassium iodide/day. In Toronto, where the iodine intake is elevated, the iodine content of the thyroid in full-term infants is 292 |xg. In Brussels, with a borderline iodine intake, the iodine content of the thyroid is 81 |xg and in Leipzig, which used to be severely iodine-deficient, the content is only 43 |xg. As the turnover rate of intrathyroidal iodine is markedly accelerated in iodine-deficient neonates, thyroid failure is more likely to occur. These neonatal data contrast with adult data which have shown that the iodine stores of the thyroid are not affected by iodine deficiency unless the degree of deficiency is severe .
Contrasting with the plentiful data on the consequences of iodine deficiency on thyroid function during pregnancy, in the neonate and in adults, there are few data on the impact of the deficiency on thyroid function in the young infant.
In conditions of mild iodine deficiency, as indicated earlier, the frequency distribution of neonatal TSH is shifted towards elevated values and the frequency of transient hyperthyrotropinemia and transient primary hypothyroidism is much higher than in iodine-replete areas . In particular, thyroid function of preterm infants is characterized by a biochemical picture including low total and free T4, elevated TSH and exaggerated TSH response to TRH. This picture of primary subclinical hypothyroidism is in contrast with the picture of tertiary hypothyroidism evidenced in preterm infants in iodine-replete areas, characterized by the fact that TSH remains normal in spite of low free T4.
In conditions of severe iodine deficiency, the data in infants are still scantier: in Congo, it was found that the frequency of biochemical signs of congenital hypothyroidism (9.0%) was as frequent in infants aged 5 days as in neonates . Follow-up studies showed that in some of these infants, the signs spontaneously corrected within a few weeks. The transient character of hypothyroidism in some of these infants may explain why the incidence of congenital hypothyroidism (close to 10%) is almost ten times higher than the prevalence of myxedematous endemic cretinism in the general population of the Ubangi area of northern Congo (1%). Another factor could be the high mortality rate of hypothyroid newborns and young infants . It was proposed that transient neonatal and infantile hypothyroidism in Congo resulted in endemic mental retardation while permanent hypothyroidism occurring during this critical period resulted in the long-term development of endemic cretinism .
Mechanisms of Brain Damage due to Iodine Deficiency during the
As mentioned, thyroid hormones are crucial for brain development both during fetal and early postnatal life . Type II 5'-iodothyronine deiodinase (DIO2) activity, which generates T3 from T4, is found during this period in the human fetal cerebral cortex . The effects of T3 on the central nervous system are mediated by the regulation of the expression of genes that synthesize proteins implicated in cerebral neurogenesis, neuronal migration and differentiation, axonal outgrowth, dendritic ontogeny and synaptogenesis. They are also necessary for cerebellar neurogenesis (predominantly during early postnatal life), gliogenesis (predominantly during late fetal life to 6 months postnatally) and myelogenesis (during the second trimester of gestation to 2 years of postnatal life). From clinical studies on the effect of iodine deficiency of both mother and fetus it becomes clear that T4 is required for brain development during gestation [18, 28, 29]. Low T4 levels during neonatal life, especially if persistent, could be a negative factor contributing to the neurodevelopmental problems of very preterm infants. Indeed, retrospective studies have shown a relationship between hypothyroxinemia and developmental delay and a increased risk of disabling cerebral palsy [30, 31]. In agreement, the most dramatic consequence of iodine deficiency on brain and physical development is endemic cretinism . This is a polymorphous clinical entity, which happen in remote, underdeveloped areas of the Third World and may affect up to 15% of populations living in conditions of severe iodine deficiency [33, 34] (fig. 1).
The disorder is found in India, Indonesia, China, Oceania (Papua New Guinea), Africa (Congo), and South America (Ecuador, Peru, Bolivia). In all these locations, with the exception of Congo, neurological features are predominant [33, 35]. Endemic cretinism may be defined essentially by severe and irreversible
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