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15 Iodine and Brain Function John H. Lazarus CONTENTS 15.1 Introduction 15.2 Nature and Geology of Iodine 15.2.1 Nature 15.2.2 Geology 15.3 Iodine Deficiency 15.3.1 Thyroidal Adaptation to Iodine Deficiency 15.3.2 Iodine and the Developing Nervous System 15.3.2.1 Animal Data Relating Thyroid Hormone to Brain Development 15.3.2.2 Human Data Relating Thyroid Hormone to Brain Development 15.3.3 Epidemiology of Iodine Deficiency 15.3.4 Assessment of Iodine Deficiency 15.3.5 Impact of Iodine Deficiency on Development 15.3.5.1 Animal Studies 15.3.5.2 Human Studies 15.4 Iodine Excess 15.5 Iodine and Public Health References

15.1 INTRODUCTION The element iodine, a member of the seventh column of the periodic group of elements, was discovered in 1811 by Courtois. It was not recognized to be relevant to thyroid physiology until 1895, when its presence in the thyroid gland was first recognized. Marine in 1915 found that thyroid tissue from dogs who were fed iodine contained a large amount of the element, especially if the dog was goitrous. During the 20th century, following the introduction of radioisotopes and techniques of chemical analysis, the physiological role of iodine was extensively investigated. This chapter reviews the thyroidal and extrathyroidal physiology of iodine before discussing its critical role in nutrition and particularly in regard to the maturation of the developing brain.

15.2 NATURE AND GEOLOGY OF IODINE 15.2.1 NATURE Iodine is an essential element for normal growth and development in animals and humans. The healthy human contains 15–20 mg of iodine, of which 70–80% is in the thyroid gland. The normal daily requirement for dietary intake is 100–150 µg of iodine, but this requirement is increased in pregnancy to 200 µg/day. Following dietary ingestion, iodine is absorbed mainly in the jejunum and circulates in the plasma as inorganic iodine. The thyroid gland may be regarded as a factory

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utilizing iodine in synthesizing thyroid hormones (www.Thyroidmanager.org; Figure 15.1). Iodide is actively concentrated by the thyroid 20 to 40 times compared to the plasma concentration. The mechanism of the concentrating process (sometimes known as the iodide trap) is through an iodide symporter situated on the basolateral membrane of the follicular cell. The symporter gene was cloned in 1996, but more recently other iodide transporters have been described in the apical follicular membrane, which transport the anion into the follicular lumen, thus making it available for incorporation into tetraiodothyronine, that is, thyroxine (T4) (Spitzweg and Morris, 2002). This process occurs on thyroglobulin, a 660-kDa protein situated in the thyroid follicular lumen, whose structure may be adversely affected by alterations in iodine status. Once synthesized, T4 can enter the follicular cell, thereby reaching the peripheral circulation when required. T4 is essentially a prohormone that is peripherally converted to triiodothyronine (T3) by deiodinase enzymes. This deiodination is noted in many tissues, such as heart, kidney, liver and, importantly, the brain (Leonard and Koehrle, 2000). As discussed later, T4 is critically important for fetal central nervous system development and maturation and there is strong evidence for placental transfer of maternal T4 into the fetus.

GastroIntestinal Tract 1;I2

Somatic Cells Hormone Metabolism and Action T4 – T3

Renal Excretion

Plasma Iodide

Tsn 1XCIO4 TRAP

Peroxidase +H2O2 PTU

MIT + DIT

(Deiddination)

Liver Tch

MITDIT

TG

Kl

TBG,TBPA, ALB

T4 T3

Tch

Peroxidase PTU

TSH

Oxidized Iodine Intermediate "1"*

Deiddinase

T4-T3––1-

Plasma T4-T3

Thyroid Iodide

H2O2

MIT DIT MIT

DIT TG

Protease

Gut

Fecal Loss

FIGURE 15.1 Overview of the metabolism of iodine. Plasma iodide is derived from absorption from the gastrointestinal tract and concentrated by the thyroid gland (thyroid iodide). It is then incorporated into thyroid hormones, which circulate in the plasma. Note the role of deiodinase in maintaining thyroid iodide. Plasma thyroid hormones are metabolized by the liver and excreted in the feces whereas iodide is excreted in the urine. (From Rousset, BA, Dunn, JT In Thyroid Hormone Synthesis and Secretion. Thyroid Disease Manager. With permission.)

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15.2.2 GEOLOGY Most iodine is found in the oceans. It is believed that large amounts of the element have been leached from the surface soil by glaciation, snow, and rain resulting in carriage to the sea by rivers, floods, and wind. Older soils and those at high altitude are more likely to be iodine deplete. Iodine occurs in the soil and sea as iodide. Iodide ions are oxidized to the volatile elemental iodine, resulting in evaporation from the sea to the air. However, airborne iodine is subsequently returned to the soil, although in lesser quantities, thereby leading to iodine deficiency in the soil. This traditional view of the iodine cycle has been challenged by recent geochemical studies, which broadly indicate the presence of complex molecules in seawater that bind iodine. There are also inconsistencies in iodine concentrations between iodine-deficient populations and the soil (sampled by soil bores) on which they live. The 1993 World Health Organization (WHO) report on iodine deficiency disorders (IDDs) noted that “soil and inland bodies of water may become deficient of iodine due to the leaching effects of glaciation, snow, high rainfall and floods” (World Health Organization, Micronutrient Deficiency Information System, 1993). The accuracy of some of these assertions has been questioned by environmental scientists who have indicated that environmental levels have not been measured (Maberly et al., 1981; Fuge and Johnson, 1986). For example, IDDs have few or no borders in common with glaciation, as determined from a comprehensive global survey (Kelly and Snedden, 1958). The concentration and organification of iodine by algae occur in localized hot spots around the world’s oceans (Moore and Tokarczyk, 1992). These compounds (CH3I, C2H5I, CH2ICl, CH2IBr, CH2I2, C3H7I, and CH3CHICH3) are released into the atmosphere, possibly by volatilization but more likely under biological control. There is seasonal variation of atmospheric iodine, in association with the growth of marine algae. Iodine has been found in the atmosphere wherever it has been sought. This indicates that, although concentration decreases above the mean boundary layer (the line of separation above the surface-influenced atmosphere), iodine is transported easily around the globe. Once in the atmosphere, organic iodine in the gaseous phase interacts with ozone and other compounds in a complex of reactions. Iodine is more reactive than chlorine in ozone degradation. These reactions determine the transit time in the atmosphere of iodine, because different compounds have different weights and, accordingly, different depositional velocities due to gravity. Furthermore, it is likely that wet deposition (in rain and snow) and not dry deposition by gravity controls the amount of iodine delivered to the surface of the earth. There is a direct relationship between rainfall and depositional amounts of iodine (Truesdale and Jones, 1996). First rain contains more iodine than later rain in the same shower, indicating some form of cleansing from the atmosphere of iodine in gas and dust. Atmospheric input of iodine to the soil is more important than any input resulting from the degradation of the underlying rock, although it is not clear how the presumed initial high soil iodine came about or why it has changed. Iodine distribution in soils is governed both by the supply of iodine and the ability of the soil to retain it (Fuge and Johnson, 1986). Leaching of soil iodine is also unlikely as it is remarkably resistant to removal by hot or cold water. The relationship between soil and plant concentrations of iodine is not a straightforward one (Whitehead, 1979). Plants reject the large iodine ion by methylation and release into the local air, where it is moved and redeposited. Fuge (1996) suggests that this is the main mechanism for transporting iodine long distances inland despite evidence of iodine even in polar air. It is probable that if environmental iodine is related to the incidence of IDDs, then there would be a relationship between the distribution of IDDs and the atmospheric deposition and distribution across the earth’s surface of iodine.

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15.3 IODINE DEFICIENCY 15.3.1 THYROIDAL ADAPTATION

TO IODINE

DEFICIENCY

The thyroidal response to iodine deficiency involves adjustment of all the physiological processes of thyroid hormone production to maximize iodine use (Ingbar, 1985). The thyroid enlarges in response to iodine deficiency and large goiters may occur. The iodide-concentrating mechanism is stimulated, resulting in an increased thyroidal iodine uptake. Although thyroid stimulating hormone (TSH) is primarily responsible for thyroidal iodine uptake, its plasma concentration is often not elevated, suggesting a degree of thyroid autoregulation in this situation. There is a significantly increased thyroidal production of T3 as opposed to T4, as the former requires less iodine and is the biologically active circulating thyroid hormone in terms of action in peripheral tissues. In addition, very little iodine is stored in thyroglobulin and there is an increased iodine turnover.

15.3.2 IODINE

AND THE

DEVELOPING NERVOUS SYSTEM

During the early 20th century, studies of endemic cretinism had suggested that the fetal developing thyroid was dependent on factors that may impair the maternal thyroid reserve (Hetzel, 1994). Subsequently, a cause–effect relationship was shown between maternal iodine deficiency and the birth of neurological cretins. Furthermore, there was evidence that the degree of maternal hypothyroxinemia correlated with the CNS damage of the progeny. These data were difficult to explain at the time because it was not thought that transplacental thyroid hormone transport took place. The view was that the placenta was impermeable to iodothyronines and that small amounts possibly transferred would be of no physiological importance. It has now been shown convincingly that this does occur not only before the fetal thyroid starts to synthesize thyroid hormones (i.e., up to 12 weeks gestation) but right through pregnancy (Vulsma et al., 1989). 15.3.2.1 Animal Data Relating Thyroid Hormone to Brain Development Table 15.1 lists the availability of thyroid hormone to the fetal brain. Although fetal thyroid function does not commence until the equivalent of 12 weeks gestation in humans, the presence of functional fetal nuclear receptors for T3 are noted in early pregnancy, indicating that triiodothyronine exerts an action at this time (De Nayer and Dozin, 1989). Maternal thyroid hormone is necessary before the onset of fetal thyroid function, as shown by interference of cortical cell migration and the cortical expression of several genes in the fetuses of mothers rendered hypothyroid by goitrogens.

TABLE 15.1 Physiology of Thyroid Hormone Availability to Fetal Brain Before Onset of Fetal Thyroid Function: • T4 and T3 are present in embryonic and fetal fluids and tissues. • T4 and T3 are of maternal origin. • Nuclear receptors are present and occupied by T3. • D2 and D3 are expressed in the brain. Between Onset of Fetal Thyroid Function and Birth: • Maternal transfer continues. • Brain T3 is dependent on T4 and D2 and 3 not on systemic T3. • Normal maternal T4 protects fetal brain from T3 deficiency. • Normal T3 in low T4 mother does not prevent cerebral T3 deficiency.

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After fetal thyroid function is present, maternal thyroxine still contributes to the thyroid hormone available to the fetal tissues at term. Maternal T4 is sufficient to prevent fetal cerebral T3 deficiency until birth in a hypothyroid fetus. The T3 at this stage is locally produced in cerebral structures by deiodination of T4 by type 2 iodothyronine deiodinase — hence the requirement for T4. Both type 2 (D2) and type 3 (D3) deiodinases are critical in producing and modulating the supply of T4 to the fetus as well as producing locally derived T3. The type 3 enzyme is mainly placentally located and inactivates T4 and T3, thereby regulating the influx of T4 to the fetus. Corroborative data have been obtained by extensive studies of iodine deficiency in sheep (Hetzel and Mano, 1994). In these animals, induced iodine deficiency results in reduced brain weight, reduction in brain DNA, and retarded myelination. In keeping with earlier observations, morphological changes in the cerebellum were noted accompanied by delayed maturation (Hetzel et al., 1989). 15.3.2.2 Human Data Relating Thyroid Hormone to Brain Development The situation in humans is similar to that observed in animals, although placentation is different in some anatomical respects. Nuclear receptors have been demonstrated in brains of 10-week-old fetuses; low amounts of T4 have been found in coelomic fluid, and this provides enough for transport into the fetal nervous system. Table 15.1 gives an overview of thyroid hormone supply to the fetal brain.

15.3.3 EPIDEMIOLOGY

OF IODINE

DEFICIENCY

The epidemiological demonstration of the association of cretinism with goiter has been known for ca. 150 years and goiter was also found in ca. 30% of cases. In a seminal study in New Guinea (Pharoah and Connolly, 1994), it was discovered that cretinism could be prevented by iodine administration but only if given (as iodized oil in this case) before the onset of pregnancy. The reduction in cretinism in Europe in the early 20th century was due to the increase in iodine intake from a variety of foodstuffs as well as specific supplementation programs. Endemic goiter and cretinism have occurred widely in the world (Kelly and Snedden, 1958). Table 15.2 lists some of the most notable areas. These areas have been intensively studied and treatment regimes with iodine supplementation have been carried out by several different methods. An example of the complexity of the iodine deficiency situation is that which has pertained in Europe during the 20th century and even into the 21st century. In fact, iodine deficiency was under control in only five countries (Austria, Switzerland, Finland, Norway, and Sweden). This was due to the introduction of iodized salt in varying concentrations and also to milk consumption. The situation in other European countries is variable, being characterized by discrete areas of significant iodine deficiency in some countries (e.g., Spain and Italy) and other areas being iodine sufficient. In some countries, mild iodine deficiency persists and this is evidenced by studies of thyroid physiology in pregnancy (e.g., Belgium).

TABLE 15.2 Examples of Iodine-Deficient Countries Continent Latin America Africa Asia Europe

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Countries/Region Peru, Bolivia, Chile Zaire, Mali, Algeria, Nigeria India, Pakistan, Southeast Asia Switzerland, Spain, Poland

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TABLE 15.3 Recommended Daily Iodine Intake Group

µg) Intake (µ

Infants (first 12 months) Children (1–6 years) Schoolchildren (7–12 years) Adults (more than 12 years) Pregnant and lactating women

50 90 120 150 200

The WHO, United Nations Children’s Fund, and the International Council of the Control of Iodine Deficiency Disorders (ICCIDD) have published recommended iodine levels in salt and guidelines for monitoring their adequacy and effectiveness. Table 15.3 gives the recommended daily iodine intakes for different groups. The generally accepted method of supplying iodine to large populations is by consumption of appropriately iodized salt (Delange and Burgi, 1989). Iodine lost from salt is 20% from production site to household and another 20% during cooking before consumption. Assuming an average daily salt intake of 10 g, iodine concentration in salt at the point of production should be 20–40 mg of iodine (i.e., 34–66 mg potassium iodate) per kilogram of salt.

15.3.4 ASSESSMENT

OF IODINE

DEFICIENCY

Ideally, an accurate measure of iodine status should be obtained by estimating iodine in all foodstuffs ingested during a given time period. This has proved impractical for population studies, as has estimation by dietary questionnaire, although some useful data have been generated by the latter painstaking method. As it is very difficult or impossible to obtain data on iodine intake in most populations, iodine nutrition is classically evaluated by indirect indices. The urinary excretion of iodine can be readily measured on a random sample of urine obtained at any time of the day. It would be more accurate to determine the iodine concentration in a 24-h urine collection, but this is usually impractical, especially in developing countries. Casual urinary iodine estimations should be determined in at least 50 to 100 persons to allow for statistical variations due to dilution. There has been much debate as to whether the concentration of urinary iodine should be expressed as an iodine:creatinine ratio or just as micrograms of iodine per unit volume. The excretion of creatinine is usually very constant, although in areas of low protein nutrition it may vary considerably within a population and be significantly lower than that observed in a population with normal protein calorie nutrition. As endemic goiter generally occurs in developing countries and mainly in areas with a low socioeconomic level, a relative protein deficiency might be present without clinical signs of severe protein calorie malnutrition. If this is the case, then iodine:creatinine ratios may not be representative of the true iodine excretion (Knudsen et al., 2000). Advances in ultrasound technology have enabled thyroid volumetric ultrasound to be used as a reliable and valid index of endemic goiter and inferentially of iodine deficiency. The relevance of thyroid volume measurements by thyroid ultrasound for assessing iodine deficiency has been established by comparing thyroid volumes in schoolchildren from iodine-deficient and iodinesufficient areas (Vitti et al., 1994). Thyroid volume determination by ultrasound in children provides more reliable quantitative and reproducible data than palpation, particularly in mild goiter endemia (Vitti and Rago, 2002). Thus, thyroid volume measurement is a marker for iodine deficiency and may be used to assess the effect of iodination programs. Other thyroid parameters may also reflect iodine status in an indirect way. Thyroidal radioiodine uptake is significantly increased in iodine deficiency. The practicalities of this procedure now make

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TABLE 15.4 Health Indicators of Iodine Status Variable

Normal

Mild IDDs

Moderate IDDs

Severe IDDs

% Goiter in SAC % Thy vol in SAC >97th centile Median urinary I in SAC and adults (µg/l) % Neonatal TSH >5 mU/l