Role of Iodine, Selenium and Other Micronutrients in ...

Endocrine, Metabolic & Immune Disorders - Drug Targets, 2009, 9, 277-294

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Role of Iodine, Selenium and Other Micronutrients in Thyroid Function and Disorders Vincenzo Triggiani1,*, Emilio Tafaro1, Vito Angelo Giagulli2, Carlo Sabbà3, Francesco Resta4, Brunella Licchelli1 and Edoardo Guastamacchia1 Endocrinology and Metabolic Diseases, University of Bari, Bari, Italy; 2Department of Internal Medicine, Metabolic Diseases and Diabetes, Conversano-Monopoli, Italy; 3Internal Medicine, Department of Internal Medicine and Public Medicine (DI.MI.M.P.) University of Bari. Bari, Italy; 4Geriatrics and Gerontology, Department of Internal Medicine, Immunology and Infectious Disease (M.I.D.I.M.) University of Bari, Bari, Italy

Copia fornita a scopo di studio per uso personale. I trasgressori sono punibili a norma di legge (L. 22 Aprile 1941 n. 633, e successive modificazioni).

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Abstract: Micronutrients, mostly iodine and selenium, are required for thyroid hormone synthesis and function. Iodine is an essential component of thyroid hormones and its deficiency is considered as the most common cause of preventable brain damage in the world. Nowadays about 800 million people are affected by iodine deficiency disorders that include goiter, hypothyroidism, mental retardation, and a wide spectrum of other growth and developmental abnormalities. Iodine supplementation, under form of iodized salt and iodized vegetable oil, produced dramatic improvements in many areas, even though iodine deficiency is still a problem not only for developing countries. In fact, certain subpopulations like vegetarians may not reach an adequate iodine intake even in countries considered iodine-sufficient. A reduction in dietary iodine content could also be related to increased adherence to dietary recommendations to reduce salt intake for preventing hypertension. Furthermore, iodine intakes are declining in many countries where, after endemic goiter eradication, the lack of monitoring of iodine nutrition can lead to a reappearance of goiter and other iodine deficiency disorders. Three different selenium-dependent iodothyronine deiodinases (types I, II, and III) can both activate and inactivate thyroid hormones, making selenium an essential micronutrient for normal development, growth, and metabolism. Furthermore, selenium is found as selenocysteine in the catalytic center of enzymes protecting the thyroid from free radicals damage. In this way, selenium deficiency can exacerbate the effects of iodine deficiency and the same is true for vitamin A or iron deficiency. Substances introduced with food, such as thiocyanate and isoflavones or certain herbal preparations, can interfere with micronutrients and influence thyroid function. Aim of this paper is to review the role of micronutrients in thyroid function and diseases.

INTRODUCTION It is remarkable that the production as well as the metabolism of thyroid hormone are dependent on two trace elements: iodine and selenium. The thyroid gland requires iodine for the synthesis of thyroid hormones: thyroxine (3,5, 3’,5’-tetraiodothyronine or T4) and triiodothyronine (3,5,3’triiodothyronine or T3). T3, the physiologically active thyroid hormone, is produced either directly by the thyroid and by means of conversion catalyzed by selenium-containing deiodinases from the circulating T4 in peripheral tissues. It can bind to specific receptors in the nuclei of cells and regulate gene expression particularly in the liver, pituitary, muscle, and brain. In this way, thyroid hormones regulate a number of physiologic processes, including growth, development, metabolism, and reproductive function [1, 2]. The regulation of thyroid function involves factors produced and delivered by the hypothalamus and the pituitary and iodine itself. In response to thyrotropin-releasing hormone (TRH) secretion by the hypothalamus, the pituitary gland secretes thyroid-stimulating hormone (TSH), which stimulates each step of thyroid hormone synthesis: iodine *Address correspondence to this author at the via Repubblica Napoletana n.7, 70123 Bari, Italy; Tel: 0039 805478814; E-mail: [email protected] 1871-5303/09 $55.00+.00

trapping and oxydation, thyroglobulin synthesis, iodothyrosynes coupling and thyroid hormone release by the gland [3]. Iodine trapping is enhanced by iodine deficiency and reduced by iodine excess; so iodine itself regulates its own uptake by the thyroid. The presence of adequate circulating amount of T4 decreases the sensitivity of the pituitary gland to TRH, limiting the secretion of TSH. When circulating T4 levels decrease, the pituitary increases its secretion of TSH, resulting in increased iodine trapping, as well as increased production and release of T3 and T4. Iodine deficiency results in inadequate production of T4. In response to decreased blood levels of T4, the pituitary gland increases its output of TSH and persistently elevated TSH levels may lead to hypertrophy of the thyroid gland (goiter), in order to enhance trapping and utilization of iodine to synthesize thyroid hormones [3]. This adaptation response may be enough to provide the body with sufficient thyroid hormone. However, more severe cases of iodine deficiency result in hypothyroidism. IODINE Iodine is a non-metallic trace element essential for animals and humans, discovered by Bernard Courtois in 1811 and classified as chemical element by Gay-Lussac in 1813. The only known role of iodine in the metabolism is its incor© 2009 Bentham Science Publishers Ltd.

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poration into the thyroid hormones, T4 and T3, corresponding respectively to 65% and 59% of their molecular weights. The term iodide refers to the biologic form of the free element (inorganic), while iodine includes both inorganic iodide (I-) and iodine covalently bound to thyrosine [3]. Metabolism and Functions Iodine is ingested either in the inorganic or in organically bound forms but its intestinal absorption probably takes place in the form of inorganic iodide. The thyroid contains the largest pool of body iodine, mostly in the form of iodinated amino acids. In the body, iodide is nearly all in the extra cellular fluid where its concentration is 10-15 mcg/L. The peripheral pool is only about 250 mcg, a very small percentage of total body iodine, being this fraction turned over several times daily [3]. Iodide is removed from extra cellular fluid by the kidneys and the thyroid. Small quantities are lost through the skin, in expired air, in the stool, and in the milk in lactating women [3]. The renal clearance of iodide is 30-50 ml plasma/min [46] and depends principally on glomerular filtration, without evidence of tubular secretion or active transport [7]. Reabsorption is partial and passive. Renal clearance of iodide is decreased in hypothyroidism and increased in hyperthyroidism [4, 8]. Thyroid clearance for iodine is 10 to 20 ml/min, ranging from 3 ml/min after chronic iodine ingestion of 500-600 mg/day to 100 ml/min in severe iodine deficiency. About 20% of the iodide perfusing the thyroid is removed at each passage through the gland [9]. The thyroid is able to trap iodide by means of natrium-iodide symporter (NIS), expressed at the basolateral plasma membrane of thyrocytes, that actively transport iodide against concentration and electrochemical gradients, maintaining a concentration of free iodide 20 to 50 times higher than that of plasma [10], with highest concentration gradient (100:1) in hyperthyroidism due to Graves’ disease. The transport requires energy and oxygen (ATPase activity) [11]. NIS expression is stimulated by TSH [12]. The transport of iodide from cytoplasm to follicular lumen is passive and mediated by Apical Iodide Transporter (AIT) [13], while the role of pendrin [14, 15] remains uncertain. Once transported into the thyroid iodide is either oxidized and organified or diffuses back into the extracellular fluid. TSH enhances the transport of iodide and its organification in iodothyrosines molecules. There is also an internal autoregulatory system through which the iodide transport mechanism and its responsiveness to TSH vary inversely with the glandular content of organic iodine. In this way, thyroid/plasma ratios rise when the thyroid is depleted of organic iodine or is stimulated by TSH. When iodide increases in concentration in the extracellular fluid, the iodide transported into the thyroid decreases progressively [3]. In other words, the quantity of iodine that undergoes organification displays a biphasic response to increasing doses of iodine: at first increasing and then decreasing as a result of a relative blockade of organic binding. This decreasing yield of organic iodine from increasing doses of iodide is named Wolff-Chaikoff effect and depends on the establishment within the thyroid of a sufficient concentration of inorganic

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iodide [16]. Thyroid iodide transport depends on NIS expression that is increased in Graves’ disease and autonomously functioning nodules [17] and decreased after iodide overload [18], as well as in adenomas and carcinomas appearing as cold nodules at scintigraphy [19]. Other monovalent anions, such as pertechnectate, perchlorate and thiocyanate can act as competitive inhibitors of iodide transport [3]. Iodide is also generated in the thyroid by the deiodination of iodothyrosines liberated during the hydrolysis of thyroglobulin. Part of this iodide is reorganified, and the remainder is lost from the gland (iodide leak). Iodine derived from degradation of thyroid hormones in peripheral tissues is also partially reutilized for producing thyroid hormones and then is finally excreted in the urine. The capacity of the thyroid to concentrate iodide is shared by salivary and mammary glands, gastric mucosa and choroid plexus; all these tissues express NIS on cell membrane [2022]. Milk iodine content depends on iodine intake, ranging from about 1 Ag/dl in iodine deficient areas to 18 Ag/dl in iodine supplemented areas [23]. The thyrocyte endoplasmic reticulum synthesizes two key proteins, thyroglobulin (tg) and thyroid peroxidase (TPO), under TSH control. The former is a 660 Kda glycoprotein secreted into the follicular lumen, whose thyrosyls residues serve as substrate for iodination and hormone synthesis; the latter is an heme-containing enzyme expressed at the apical plasma membrane, where it reduces the H2O2 generated by a NADPH oxydase, elevating the oxidation state of iodide to an iodinating species and catalizes the iodination of thyrosyls in the tg molecule [3]. The tg is stored and concentrated in the colloid deposited into the follicles. When turnover increases (Graves’ disease), less tg is stored in the colloid [4]. Within the thyroid, iodide is therefore oxidated and incorporated in the molecule of thyrosines to form mono(MIT) and diiodothyrosynes (DIT), amino acids that are part of thyroglobulin molecule. The fusion of two DIT residues leads to T4 formation; the fusion of one MIT and one DIT generates the molecule of T3. These molecules (iodothyronines) are still part of the thyroglobulin molecule. In this form thyroid hormones are stored in the colloid deposited into the follicular lumen. When thyroid hormone is needed, the first step in thyroid hormone release is the endocytosis of colloid droplets from the follicular lumen; the endocytotic vescicles fuse with lysosomes where tg is digested by proteases (endoand exopeptidases); the proteolysis releases thyroid hormones into the thyroid follicular cells and then into the plasma, where specific proteins carry them to target tissues [3]. The release of thyroid hormones is under TSH control [3]. Iodine deficiency decreases the ratios DIT/MIT and T4/T3, while iodine supply increases them. H2O2 is essential for many steps in thyroid hormone synthesis catalyzed by TPO enzyme under TSH control: iodide oxidation, tyrosine iodination, and coupling of iodinated tyrosine residues to iodothyronine [24, 25]. H2O2 is reduced to H2O during the process of synthesis. However, H2O2 is produced in excess [26, 27]. In this way, thyroid is exposed

Role of Iodine, Selenium and Other Micronutrients

Endocrine, Metabolic & Immune Disorders - Drug Targets, 2009, Vol. 9, No. 3 279

to oxidative stress due to free radicals [26-29]. The exposure of intracellular compartments and membranes to H2O2 and other reactive oxygen species (ROS) is avoided because the production of H2O2 takes place into the follicular lumen at the surface of the apical membrane toward which is oriented the active site of the integral membrane enzyme TPO. Furthermore, protection against H2O2 and resulting free radicals is warranted by vitamins C and E and enzymes such as catalase, superoxide dismutase, and Se- containing enzymes, such as glutathione peroxidase (GPx) and phospholipid hydroperoxide glutathione peroxidase (PHGPx) [30-36]. The average normal secretion is 94-110 Eg T4 and 10-22 Eg T3 daily [37]. As reported above, TSH influences virtually every step in thyroid hormone synthesis and secretion: it stimulates the expression of NIS, TPO, tg, the generation of H2O2; it increases the formation of T3 relative to T4 and promotes the internalization of tg by thyrocytes [3]. Sources Iodine is quite rare and occurs in nature as iodide and iodate. Its mineral forms occur in igneous rocks and soils. It is liberated by weathering and erosion, and, because of its water-solubility, it leaches by rainwater into surface water, the sea and the oceans. In this way, the soil becomes progressively poorer in iodide [38]. The oldest mountainous regions, such as the Himalayas, the Andes, and the Alps, the lesser ranges of Africa and flooded river valleys (e.g. Ganges Valley in India, Irawaddy Valley in Burma, Songkala Valley in China) are among the most severely iodine deficient areas in the world [1]. Liberated elemental iodine sublimates into the atmosphere because of its volatility and is precipitated by rainfall onto the land surface where small amounts of iodide are taken up by plants, which do not have a requirement for this element. Where the soil is poor in iodine, plants and animal tissues are low in iodine content and humans are exposed to iodine deficiency if the diet is based only upon food produced in these areas [39]. Vegetables do not provide an adequate dietary iodine intake and vegetarians and vegans are exposed to iodine deficiency also in iodine-sufficient areas [40, 41]. On the contrary, foods of animal origin (meat, milk, eggs and fish) represent an important dietary source of iodine in human nutrition. T4 contains about 65 % of the body iodine [42], while the concentration in tissues other than thyroid is rather low, the mean iodine concentration in animal tissues being about 0.1 mg kg-1 [43]. In general, the iodine content of animal tissues depends on the type of food and iodine supplementation of animal feed. Seaweeds, seafood and sea fish are rich in iodine because marine plants and animals can concentrate the iodine from seawater. Fresh water contains less iodine than salt water and the same is true for fish living in rivers or lakes [44, 45]. Iodine deficiency affects thyroid function in animals in the same way and with the same geographic pattern as in humans, decreasing the production of thyroid hormones and subsequently the metabolism and the capacity of reproduction as well as growth and development of the progeny [46, 47]. Iodine supplements are used in order to improve the health and productivity of domestic animals. The daily dietary intake in humans varies widely throughout the world, depending not only on environmental factors,

such as the iodine content of the soil and water, but also on dietary habits in different areas. Furthermore, even in a single area, iodine intake varies among different individuals and in the same individual from day to day. There are also different pattern of iodine intake in different age groups in the same area [48-51]. For example, in Germany milk and dairy products provide on average 37 %, meat and meat products 21 %, bread and cereal-based foods 19 %, whereas fish only 9 % of dietary iodine intake [48]. Milk provides more than 44 % iodine in the Danish population [49], while in Dutch schoolchildren seafood is a minor source of iodine, being consumed only once a month [50]. Milk provides 40-50% iodine intake for children in Swizerland, more than two-fold than in adults [51]. Processed foods may contain slightly higher levels of iodine due to the addition of iodized salt or iodine-containing food additives, such as calcium iodate and potassium iodate. Iodophors used as sterilizing agents in the milk industry in U.S. add iodine to the food chain. Iodine may enter the body also via medications (amiodarone), topical antiseptics (povidone iodine), diagnostic agents (radiocontrast medium) and multivitamin preparations. For example, 200 mg of amiodarone contains 75 mg of iodine, while contrast materials contain grams of iodine. Iodization of salt for human food consumption is the strategy internationally recommended in order to reach the goal of sustainable elimination of iodine deficiency. Recommended Intake The daily iodine intake varies from less than 10 Eg in areas of extreme iodine deficiency to several hundred milligrams for some persons receiving iodine-containing drugs. An intake of 150 g of iodine is recommended for adults, at least 200-250 g for pregnant or lactating women, and lower amounts for children (70-120 g) and neonates (40 g). Aging has not been associated with significant changes in the requirement for iodine. These recommendations come from consensus statements by the International Council for Control of Iodine Deficiency Disorders (ICCIDD), the World Health Organization (WHO), the UNICEF, and the Food and Nutrition Board of the U.S. National Academy of Sciences. They are calculated on the basis of daily thyroid hormone turnover in euthyroid subjects, the amount of thyroid hormone replacement therapy necessary to restore euthyroidism in patients with thyroid agenesis or submitted to thyroidectomy and considering the iodine intake associated with the lowest values for serum TSH and thyroglobulin, the smallest thyroid volumes and the lowest incidence of transient hypothyroidism in neonatal screening [2, 52]. Because about 85-90% of iodine is excreted in the urine, urinary iodine excretion gives a measure of iodine intake [3]. The median urinary iodine concentration in casual samples (g/L], is currently the most practical biochemical laboratory marker of community iodine nutrition, more useful and much simpler than other measure like 24-hours samples or urinary iodine/creatinine ratios. The minimal urinary iodine concentration for reaching iodine sufficiency is 100 g/L, corresponding roughly to a daily intake of 150 g of iodine. The


tolerable upper intake level (UL) of iodine is uncertain and varies widely among individuals and populations. Iodine Deficiency Nowadays, according to the WHO, iodine deficiency disorders (IDD), including goiter, hypothyroidism, mental retardation, reproductive impairment, decreased child survival and varying degrees of growth and developmental abnormalities affect about 800 million people in the world (Table 1) [1, 53-55]. The use of iodized salt and iodized vegetable oil led to a dramatic improvements in the correction of iodine deficiency in many iodine deficient countries throughout the world [52]. Almost one third of the world’s population, however, still lives in areas of iodine deficiency and risks its consequences, especially in developing countries [56]. Goiter, one of the earliest and most visible signs of iodine deficiency, is due to persistent stimulation by TSH and perhaps other growth factors. In mild iodine deficiency, this adaptation response may be sufficient to preserve euthyroidism. The goiter, however, can cause signs and symptoms of neck compression and hyperthyroidism due to the formation of hyperfunctioning autonomous nodules. The term “endemic” goiter refers to populations where more than 5% of the school-age children (6-12 years) have enlarged thyroid glands [57] as assessed by clinical examination, being each lobe greater than the distal phalanx of the subject’ s thumb. A variety of agents have been identified as goitrogenic in man [58, 59]: sulphurated organics (thocyanate, isothiocyanate, etc.), flavonoids (polyphenols), pyridines, phtalate esters, polychlorinated and polybrominated biphenyls, organochlorines like DDT, polycyclic aromatic hydrocarbons, excess iodine, lithium [59]. These agents act at various levels. Thiocyanate and isothiocyanate inhibit iodide transport; phenolic compounds and phtalate derivatives interfere with oxidation and organification of iodine; iodide and lithium inhibit proteolysis and hormone release; polybro-minated biphenyls increase the rate of thyroid hormone metabolism [58].

Table 1.

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Large colloid goiters represent a maladaptation instead of adaptation to iodine deficiency because the thyroglobulin is poorly iodinated and its hydrolysis leads to enhanced urinary loss of iodide, further aggravating iodine deficiency [60, 61]. If iodine deficiency is more severe it may result in hypothyroidism. An adequate iodine intake in the diet will generally reduce the size of goiters, while the reversibility of the effects of hypothyroidism depends on the stage of development. In fact, iodine deficiency is most damaging to the developing brain in the fetus and neonate, because thyroid hormone is important for the myelination of the central nervous system, which takes place before and shortly after birth [2, 52]. The effects of hypothyroidism are more subtle in the brains of adults than children, resulting in slower response times and impaired mental function [1]. To date, endemic goiter has almost disappeared in many European countries, while subclinical iodine deficiency is still a potential widespread problem in Western and Central Europe [62, 63]. Iodine requirement is increased in pregnant and breastfeeding women [52]. Iodine deficiency during pregnancy has been associated with increased incidence of miscarriage, stillbirth, and birth defects and may result in congenital hypothyroidism in the offspring [64], while iodine deficient women who are breastfeeding may not be able to provide sufficient iodine to their infants [1]. Congenital hypothyroidism, a condition that is named cretinism and is characterized by irreversible mental retardation, occurs in two forms. The neurologic form is characterized by mental and sometimes physical retardation and various neurological deficits including deaf-mutism. Patients do not exhibit signs of hypothyroidism and have goiters as well as the rest of the population. It has been suggested that neuro-pathological basis of this form includes underdevelopment of the cochlea for deafness, maldevelop-ment of the

Iodine Deficiency Disorders Fetus

Neonate

Abortion

Child and Adolescent

Goiter

Stillbirth

Hypothyroidism

Congenital anomalies

Impaired mental function

Increased perinatal mortality

Retarded physical development

Endemic cretinism

Increased susceptibility to nuclear radiation

Goiter

Adult

Goiter

Hypothyroidism

Hypothyroidism

Mental retardation

Impaired mental function

Increased susceptibility to nuclear radiation

Spontaneous hyperthyroidism (elderly) Iodine-induced hyperthyroidism Increased susceptibility to nuclear radiation



cerebral neocortex for mental retardation and maldevelopment of the corpus striatum for the motor disorders [65]. The myxedematous or hypothyroid form is characterized by dwarfism, marked delayed bone and sexual maturation, mental retardation and signs of severe hypothyroidism. Unlike the normal population of the same area, the patients present no goiter. On the contrary, the thyroid is atrophic [66]. Neurological cretinism is due to thyroid hormone deficiency in early foetal development, being the result of maternal iodine deficiency that affects the fetus before its own thyroid is functional [67-69], while myxedematous cretinism is associated with thyroid insufficiency during late pregnancy and early infancy [70-72]. Pure forms of myxede-matous cretinism predominate in Central Africa, but there are also neurological cretins and myxedematous cretins with neurological defects. In other endemic regions like New Guinea or in South America, only neurological cretinism is detected. Both forms, along with intermediates, coexist in India [70, 73]. The distinct geographical distribution of the two types of cretinism, as well as their different phenotypes suggest that factors other than iodine are involved: hereditary factors, circulating TSH inhibitory antibodies [74, 75], nutritional habits like cassava (thiocyanate) consumption [76], factors reducing cell defences against free radicals, such as deficiencies involving trace element like selenium, zinc, copper, manganese, iron, thus impairing the activity of certain enzymes [77-79], deficiency in components of the antioxidant network like vitamin A and E, and enzyme deficiencies (superoxide dismutase or glucose-6-phosphate-dehydro-genase), leading to decreased efficacy in glutathione reduction [80].

abnormal brain development and impaired intellectual development [96]. In fact, children in iodine deficient areas show lower IQs, poorer school performance, and a higher incidence of learning disabilities than matched controls from iodine-sufficient areas [97, 98]. Goiter is frequent, especially in adolescent girls.

Thiocyanate overload and selenium deficiency, in particular, can play an important role for the myxedematous form, interacting with thyroid hormone metabolism and leading to thyroid destruction, a slow process that begins in utero, and continues during the first years of life when brain development depends on the presence of thyroid hormone [72, 81-87]. TSH stimulation due to iodine deficiency in the presence of selenium deficiency and thiocyanate exposure leads to thyroid necrosis and fibrosis [88]. Thyroid destruction explains the lack of goiter and the development of severe hypothyroidism. Furthermore, thyroid damage within the rest of the population decreases the efficacy of iodine supplementation programs [89] by decreasing iodide trapping and impairing the adaptive mechanisms [83].

Although iodine intake in the U.S. and in many other countries remains sufficient, careful monitoring of iodine intake is still recommended [103, 104]. In fact, in countries like Colombia, Guatemala, Mexico and Thailand, where adequate programs of iodine prophylaxis led to endemic goiter eradication, the lack of appropriate monitoring of iodine nutrition indicators (i. e. urinary iodine, serum TSH, thyroglobulin, thyroidal radioiodine uptake, incidence of transient hypothyroidism in neonatal screening programs) caused the reappearance of goiter [105].

Thiocyanate contained in the cassava roots [90, 91] competes with iodide for trapping by NIS and for oxidation by the TPO [92], inducing both a release of iodide from the thyroid cell and a decrease of thyroid hormone synthesis. Selenium-containing enzymes (GPx, PHGPx) participate in the protection of thyroid cells against H2O2 and free radicals. The H2O2 exposure is greatest when TSH levels are higher, as is the case of iodine deficiency. Thus, iodine deficiency increases H2O2 generation, whereas Se deficiency, impairing the enzyme activity, decreases its disposal. The role of autoimmunity in the etiology of endemic cretinism is still debated [75, 93-94]. Infant mortality is increased in areas of iodine deficiency, and it decreases, sometimes by 50% or more, when iodine deficiency is corrected [95]. Because thyroid hormone is essential for normal brain development, iodine deficiency during infancy may result in

Iodine deficient individuals of all ages are more susceptible to radiation-induced thyroid cancer [1]. Radioactive iodine, especially 131I, may be released into the environment as a result of nuclear reactor accidents. Thyroid accumulation of radioactive iodine increases the risk of developing thyroid cancer, especially in children. Potassium iodide administered in pharmacologic doses (50-100 mg for adults) within 48 hours before or 8 hours after radiation exposure from a nuclear reactor accident could significantly reduce thyroid uptake of 131I and decrease the risk of radiationinduced thyroid cancer [99, 100]. While the risk of iodine deficiency for populations living in iodine-deficient areas without adequate iodine fortification programs is well recognized, concerns have been raised that certain subpopulations may not consume adequate iodine in countries considered iodine-sufficient. Vegetarian and nonvegetarian diets that exclude iodized salt, fish, and seaweed have been found to contain very little iodine [1, 52, 101, 102]. Furthermore, urinary iodine excretion studies suggest that iodine intakes are declining in Switzerland, New Zealand, and the U.S., possibly due to increased adherence to dietary recommendations to restrict salt intake for reducing the incidence of hypertension.

Iodine Excess It is rare for diets of natural foods to supply iodine in excess. People living in the northern coastal regions of Japan have been found to have iodine intakes ranging from 50,000 to 80,000 mcg (50-80 mg) of iodine/day due a large amounts of seaweed in the diet [1]. Most people can be exposed to large amounts of iodine without apparent problems [106]. Iodine supplementation programs in iodine-deficient populations leading to iodine intakes of 150-200 mcg/day have been associated with an increased incidence of iodine-induced hyperthyroidism, mainly in older people with multinodular goiter. Iodine deficiency, in fact, increases the risk of developing autonomous thyroid nodules that are unresponsive to the normal thyroid regulation system, resulting in hyperthyroidism after iodine supplementation [107, 108]. This is a complication of iodine profilaxis usually of short duration in a given population, but it can be a very serious health problem for a given patient, because of the high risk of atrial fibrillation [109].


The large benefit of iodization programs, however, outweighs the small risk of iodine-induced hyperthyroidism in iodine-deficient populations [1, 110-112]. An increased incidence of autoimmune thyroid disease frequently parallels an increased dietary iodine intake [113]. In iodine-sufficient populations (e.g., the U.S.), in fact, excess iodine intake is most commonly associated with elevated blood levels of thyroid stimulating hormone (TSH), hypothyroidism and goiter. Thyroid autoimmunity is depressed in iodine deficiency but it is “reset to normal” after its correction. Prolonged intakes of more than 18 mg/day have been found to increase the incidence of goiter (coastal endemic goiter in Japan-China) due to increased TSH stimulation [114-116]. In countries that were previously iodine deficient such as Argentina and Austria, salt iodization programs have resulted in relative increases in thyroid papillary cancers and relative decreases in thyroid follicular cancers [113]. Epidemiological studies show a good correlation between dietary iodine intake and the presence of occult papillary cancer, ranging from 9% on autopsy studies in iodine-deficient Poland to 36% in iodine-enriched Finland. The reasons are not well understood. In general, however, thyroid papillary cancers are less aggressive and have a better prognosis than thyroid follicular cancers [117]. Acute iodine poisoning due to doses of many grams is rare and characterized by burning of the mouth, throat, and stomach, fever, nausea, vomiting, diarrhea and coma [52]. The tolerable upper intake level (UL) of iodine is about 2 to 4 times higher than the recommended level. In particular, the UL is 200 mcg/day for children of 1-3 years, 250 mcg/day between 4 and 6 years, 300 mcg/day between 7 and 10 years, 450 mcg/day between 11 and 14, 500 mcg/day between 15 and 17 and 600 mcg/day for adults, even if pregnant or lactating. Acute and massive excess of iodide can inhibit the process of synthesis of hormones by the thyroid gland through an inhibition of the process of iodide organification, the socalled Wolff-Chaikoff effect. This occurs as soon as the ratio of intrathyroidal iodide to organic iodine reaches a critical level. Thus, the risk increases when iodine stores of the thyroid gland are low, such as in neonates following maternal iodide overload and young infants in iodine-deficient areas. SELENIUM Se is an essential trace element discovered by Berzelius in 1817 that play an essential role in regulating thyroid function [118-120]. Metabolism and Functions Se is ingested and absorbed as selenite, selenate and selenomethyonine. The human thyroid contains the highest Se concentrations per unit weight among all tissues and most of Se is incorporated into proteins of thyrocytes [121-126]. Se participates in the antioxidant network. The enzyme selenophosphate synthetase catalyzes the synthesis of mono-

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selenium phosphate, a precursor of selenocysteine [127, 128], an amino acid found in the catalytic center of many enzymes involved in cell defence against free radicals and in thyroid hormones metabolism and functions [129-137]. Three type of Se-containing glutathione peroxidases (GPx) have been found in thyroid tissue: cellular GPX, plasma GPx and phospholipid hydroperoxide GPx. GPx have been identified in many tissues and act as antioxidant enzymes that reduce potentially damaging ROS, such as hydrogen peroxide and lipid hydroperoxides by coupling their reduction with the oxidation of glutathione [129]. In this way, Se supports the activity of vitamin E in limiting the oxidation of lipids and prevents some of the damage resulting from vitamin E deficiency [118]. In thyroid tissue, GPx cooperate with peroxisomal catalase in H2O2 degradation protecting cells from free radicals attack [36]. Another Se-containing enzyme is the thioredoxin reductase that mantains thioredoxin in a reduced form, participating in the regeneration of several antioxidant systems, such as vitamin C [128, 130]. The three iodothyronine deiodinases are selenoenzymes. They catalyze the reductive cleavage of aromatic C-I bonds in ortho position to either a phenolic or a diphenylether oxygen atom in iodothyronines. The three types differ in their substrate affinity, reaction mechanism, inhibitor sensitivity, tissue specificity, development-specific expression, and regulation by substrates, products or other factors and response to pharmacological agents [138-140]. Type I iodothyronine deiodinase (D1), the most abundant and best characterized of the three deiodinases, catalyzes the 5’-deiodination of T4, rT3, and other iodothyronines or their sulfoconjugates [141]. It is expressed mostly in the liver, kidney, thyroid, and pituitary [140, 142]. Liver and thyroid D1 produce most of the circulating T3 under normal conditions. D1 also participates in the local production of T3 from T4 in some organs. It is an integral membrane enzyme localized in the endoplasmic reticulum of the epatocytes, while in the kidney and thyroid it is found in the basolateral plasma membrane, being its active site directed toward the cytosol [143-145]. The substrate and/or products of the enzyme (T4 , T3) induce its expression. D1 activity, in fact, is stimulated in hyperthyroidism and decreased in hypothyroidism in most [138, 139, 146-152]. Fasting decreases and carbohydrate feeding stimulates hepatic D1 activity. In the thyroid, TSH and TSH receptor autoantibodies increase D1 activity in several species [153-155]. Severe Se deficiency reduces D1 protein and activity, and repletion increases it [156, 157]. D1 is potently inhibited by Propyltiouracil (PTU). Type II iodothyronine deiodinase (D2) generates T3 from T4 with high specificity for T4 and a higher affinity for T4 than D1. Furthermore, D2 is rapidly inactivated by T4 and rT3 [158]. Its transcription is inhibited by T3; thus, its regulation is inverse to that of D1 and D3 [159]. D2 is assumed to generate T3 from local T4 sources for intracellular demands independent from circulating T3, while the contribution of D2 to circulating T3 is considered to be limited. D2 is thought to be unaffected by PTU [160-162]. It does not catalyze the iodination of sulphated iodothyrosines and its activ-



ity is increased in hypothyroidism and decreased in hyperthyroidism [163-166]. It is highly expressed in the central nervous system, with the highest levels in astroglial cells and tanycytes, while neurons, in which most of the T3 receptors are expressed, show rather low D2-enzyme activity. Thus, T3 is produced by D2 action in glial cells and then transported to surrounding neurons containing T3 receptors. There is a close relationship between local thyroid hormone production in the hypothalamus and neuroendocrine TRH-producing cells in the paraventricular nucleus [167]. cAMP stimulation of D2 activity and expression has been demonstrated in glial cells, human thyroid, and brown adipose tissue of rodents [168-171]. In brown adipose cells, D2 is highly expressed and generates T3 essential for stimulation of expression of uncoupling proteins (UCPs) and thermogenesis in synergism with catecholamines. The major regulator of D2 expression in the brain is the thyroid hormone status itself. Because the brain strongly depends on T4 supply from the thyroid and circulating serum T3 probably reaches the brain only in limited quantities or under pathological conditions, proper thyroid function and adequate Se supply are crucial both during development and in the adult organism. Stress, circadian rhythm, and several neuroactive drugs affect brain deiodinase enzymes and local thyroid hormone levels [172-175]. Se deficiency impairs cold tolerance in animals, by means of a lower expression of D2 in brown adipose tissue associated with decreased T3 production and subsequent reduction of UCPs expression and catecholamine-stimulated thermogenesis [176]. D2 serves to maintain tissue T3 levels in the face of varying plasma T4 and T3 concentrations, even though, the identification of D2 expression in skeletal muscle can lead to the hypothesis that part of plasma T3 may be generated by D2 activity. The Type III iodothyronine deiodinase (D3) mediates the inactivation of thyroid hormones. In fact, the products of deiodination of iodothyronines at the tyrosyl ring in 5-(or 3-) position are devoid of thyromimetic activity and do not bind to nuclear T3 receptors. The main metabolite of D3, rT3 , competes for T4 deiodination by D1 and thus might have a regulatory function in thyroid hormone metabolism. Because circulating rT3 levels are in the range of T3 and high rT3 formation is found in the central nervous system [177], a biological role for this metabolite during brain development, such as modulation of the polymerization state of the actin cytoskeleton, neuronal migration, and neurite outgrowth, has been suggested [178]. D3 activity is expressed in many tissues; particularly in developing brain, in pregnant rat uterus, and in foetal human liver. In adulthood, high D3 levels are maintained in the brain and skin, several other tissues, and the placenta [179-184]. No D3 expression is found in the normal adult liver and kidney. The brain is the predominant D3 expressing tissue in adult animals and may thus be the main site for plasma T3 clearance and plasma rT3 production. D3 is thought to prevent inappropriate exposure of cells or tissues to the active hormone T3 and placental and uterine expression of D3 might play a major role in protection of the fetus from excessive thyroid hormone exposure [185, 186]. D3 activity is increased in hyperthiroidism and decreased in hypothyroidism in brain and skin but not in placenta [187]. No evidence for regulation of brain D3 expression by the Se status and very minor evidence for placenta has been pre-

sented [180, 188]. Various growth factors such as basic fibroblast growth factor (bFGF), the MAPK kinase- ERK cascade, cAMP, phorbol esters, thyroid hormone, and retinoic acid may induce D3 expression via defined response elements in its promoter [189-192]. High expression of D3 in vascular tumors may result in subclinical and even overt hypothyroidism in patients with such tumors (consumptive hypothyroidism) [193, 194]. The same has been demonstrated in liver and skeletal muscle of patients who died after severe illness and the low T3 syndrome of non-thyroidal illnesses could be dependent, in part, on an increased expression of D3 [195]. Sources The richest food sources of Se are organ meats and seafood, followed by muscle meats, while vegetable content depends on soil Se content [196]. Se supplements are available either in inorganic (sodium selenate and sodium selenite) and organic forms (selenomethionine) [131]. Both inorganic and organic forms can be metabolized to selenocysteine and incorporated into selenoenzymes [197]. The recommended intake ranges from 20-40 mcg/day in infancy to 55 in adulthood; 60 mcg and 70 mcg are recommended respectively for pregnant and lactating women respectively. Se Deficiency No evident clinical manifestations result from Se deficiency. Se deficient individuals, however, appear to be more susceptible to additional physiological stresses [118]. Se deficiency could enhance the virulence and the progression of certain viral infections. This is the case of Keshan disease, a cardiomyopathy caused by a Coxsackievirus in a Se deficient region of China [118, 198-200]. Low Se levels in HIV patients have also been associated with progression and severity of AIDS [201]. Se-depleted cells devoid of sufficient antioxidative defence capacity because of decreased activity of GPx might experience aberrant intracellular iodination of proteins, leading to deleterious events such as apoptosis, exposure of unusual epitopes, recognition by the immune system, or aberrant targeting and processing of iodinated proteins. Se also has a protective role against cytotoxic H2O2 effects in thyrocytes [202]. These observations might provide an experimental biochemical basis for the pathogenesis of myxedematous endemic cretinism and a rationale for beneficial effects of Se supplementation reported in prospective controlled studies in patients with Hashimoto’s thyroiditis [203, 204]. The low relative incidence of neurological cretinism in Africa might result from Se deficiency; low T4 deiodination in the mother and in the embryo would allow higher net T4 supply to the foetal brain, mitigating at this level the decrease in maternal T4 due to iodine deficiency [205-208], while the presence of goitrogens in the diet interferes with thyroid hormone production [64]. Se deficiency increases the sensitivity of the thyroid gland to necrosis caused by iodide overload in iodine-deficient thyroid glands [209-214]. Se deficiency increases the inflammatory reaction initiated by iodide overload that then evolves to fibrosis, whereas the non-Se-deficient thyroid exhibits no fibrosis [215]. Fibrosis was associated with increased fibro-


blast proliferation and decreased thyroid follicular cell proliferation [215]. Trasforming Growth Factor beta (TGF) was prominent in thyroid macrophages in Se deficiency and was proposed to be responsible for both effects [216, 217]. Indeed, TGF stimulates the proliferation of fibroblasts and promotes fibrosis, and, on the other hand, it impairs TSHinduced proliferation [218]. Thiocyanate overload instead of iodine might elicit the necrosis. It would aggravate the effects of iodine deficiency by competing with iodide for transport and generate toxic derivatives as well. Correcting the Se deficiency first would be a daring strategy, because it induces T4 deiodination and consequently increases iodine loss, which worsens the hypothyroidism [219]. Low serum Se levels were highly correlated to the incidence of thyroid cancer, but no direct relationship between actual tissue or serum Se content and thyroid cancer manifestation at the time of diagnosis could be found [220-222]. A European cross-sectional study [223] found an inverse association between Se and thyroid volume and a protective effect of Se against goiter. Several studies reported on the benefit of Se treatment both in Hashimoto’s thyroiditis and Graves’ disease. In two of these blind, placebo-controlled prospective studies, serum levels of thyroid anti-TPO autoantibody decreased, and patients’ self-assessment of the disease process improved, compared with a placebo group, after 3 to 6 months of treatment with 200 mcg/day sodium selenite or selenomethionine. All patients were substituted with levotiroxine to maintain TSH within the normal range. Se substitution may improve the inflammatory status in patients with autoimmune thyroiditis, especially in those with high activity. These studies were performed in areas of Europe with limited nutritional Se supply. Se supplementation led to increased plasma Se and GPx activity [203, 204, 224]. Se supplementation during pregnancy and in the postpartum period reduced thyroid inflammatory activity and the incidence of hypothyroidism [225]. Karanikas et al. [226], however, found no significant immunological changes in term of TPOAb level and CD4+ or CD8+ cytokine pattern in patients affected by autoimmune thyroiditis after Se administration. Initially, the discovery of D1 as a selenoenzyme with high expression in the liver [131, 132] led to the assumption that the observed disturbance of Se metabolism in severe illness, sepsis, burns, or other nonthyroidal illnesses associated with the euthyroid sick syndrome (ESS) or low-T3 syndrome, might lead to impaired hepatic T3 production and to the decreased serum and tissue T3 levels observed under these conditions [138, 227-234]. No direct link between Se supply and the pathogenesis of the ESS or low-T3 syndrome has been shown. Impaired hepatic T3 production by D1 in ESS or low-T3 syndromes might represent adaptive changes and not causal events for the impaired clinical situation. Alterations of serum thyroid hormone levels compatible with decreased hepatic D1 activity have been reported in children [235] and elderly with insufficient Se supply [236]. A selenomethionine supplementation study in euthyroid T4-substituted children with congenital hypothyroidism who had de-

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creased Se, Tg, and T3 concentrations and increased TSH, rT3, and T4 levels found no effect on serum thyroid hormone concentrations. However, elevated Tg and TSH levels returned to those of controls after a 3-month Se treatment [237]. The authors interpreted these observations as evidence against a direct effect of Se supplementation on peripheral deiodinases, whereas pituitary feedback control of TSH by local 5’-deiodination might be normalized. Disturbed serum Se status and altered thyroid hormone serum levels are also found in patients on protein-poor diets (e.g., phenylketonuria), on long-term total parenteral nutrition (TPN), or suffering from cystic fibrosis or Crohn's disease or people who have had a large portion of the small intestine surgically removed, and in animal models, e.g., during lactation or intoxication by heavy metals (mercury, cadmium) [235, 238-242]. TPN solutions and specialized diets are now supplemented with selenium to prevent such problems [118]. Metabolic disturbances in chronic hemodialysis involve several minerals and trace elements and, most importantly, decreases in serum Se and serum GPx levels. Decreased levels of its activity combined with decreased total serum Se seem plausible, because pGPx originates from kidney tubular cells and contributes up to 30% of plasma Se content [243]. However, biological data also indicate a condition similar to the ESS or the low-T3 syndrome. Because the kidney contributes only slightly to circulating T3 levels, this suggests interference of this metabolic condition with liver and or thyroid function. The association of low serum Se and low T3 values with normal to elevated T4 and normal, decreased, or increased TSH initially suggested causal relationships between low Se and decreased hepatic D1 activity [244-247]. Attempts of Se supplementation normalized serum Se levels partially, but had variable or no effect on serum thyroid hormone parameters [245, 248]. Factors other than dialysis might interfere with pituitary and thyroid function, such as interference by uremia at several levels of hormonal regulation [249, 250]. Nevertheless, Se supplementation might be beneficial to counter oxidative stress with its long-term role in the cardiovascular defects, cancer incidence, and elevated mortality in dialysis patients [251]. Selenium deficiency has been associated with impaired function of the immune system. Moreover, selenium supplementation in individuals who are not overtly selenium deficient appears to stimulate the immune response [132, 133, 201, 252]. Cancer mortality rates are higher in areas with low soil Se and relatively low selenium dietary intake and Se supplementation at high doses significantly reduced tumor incidence [119]. Several mechanisms have been proposed. At nutritional or physiologic doses (~ 40-100 mcg/day in adults) Se could improve the activity of antioxidant selenoenzymes, the immune system function, and the metabolism of carcinogens. At supranutritional or pharmacologic levels of Selenium (~ 200-300 mcg/day in adults) the formation of selenium metabolites, especially methylated forms, may also exert anticarcinogenic effects inhibiting tumor cell growth [120].



Although Se supplementation shows promise for the prevention of prostate cancer, its effects on the risk for other types of cancer is unclear. Optimizing selenoenzyme activity could decrease the risk of cardiovascular disease by reducing lipid peroxidation and influencing the metabolism of prostaglandins. However, prospective studies in humans have not demonstrated cardioprotective effects of selenium. Excessive Se Selenium in high doses can be toxic. Acute and fatal toxicities have occurred with accidental or suicidal ingestion of gram quantities of Se while smaller doses over long periods of time can lead to hair and nail brittleness and loss, gastrointestinal disturbances, skin rashes, fatigue, irritability, and nervous system abnormalities (selenosis). The Food and Nutrition Board set the tolerable upper level (UL) for selenium at 400 mcg/day in adults [131]. OTHER MICRONUTRIENTS Minerals such as magnesium, manganese and potassium may interfere with thyroid function. Copper, zinc (as superoxide dismutase), and iron (as catalase) are critical components of antioxidant enzymes. Iron deficiency also leads to decreased cGPx activity in several rat tissues [153], and T4 and T3 disposal rates were also decreased [154]. Impaired efficiency of thyroid hormone synthesis in iron-deficient goitrous children and adults has been recently reported [255, 256], indicating that sufficient iron supply is required for effective thyroid hormone synthesis after iodide supplementation. Calcium could be goitrogenic when in excess in the diet. Administration of 2 g calcium per day, in fact, was associated with decreased iodide clearance by the thyroid [257]. Furthermore, calcium reduces the absorption of thyroxine [258, 259]. Nitrate in the diet could interfere with 131I uptake in the thyroid [260]. Bromine is concentrated by the thyroid and interferes with the thyroidal 131I uptake in animals [261, 262] and humans, possibly by competitive inhibition of iodide transport into the gland. It can also induce alterations in cellular architecture, blood supply and it can lead to a reduction in T4 and T3 levels [263]. Fluorine is not concentrated by the thyroid but has a mild antithyroid effect, possibly by inhibiting the iodide transport process [264]. In large amounts, it is goitrogenic. Dietary fluorine may exacerbate an iodine deficiency [265]. Cobalt inhibits iodide binding by the thyroid [266] with an unknown mechanism. Cobalt deficiency is associated with a reduction in D1 activity and a fall in T3 [267] while cobalt excess may produce goiter and decreased thyroid hormone production [268]. It has been used in the treatment of thyrotoxicosis [269]. Zinc, rubidium, cadmium and mercury might interact with or impair the function of Se in thyroid physiology. Rubidium is goitrogenic in rats [270], the mechanism being unknown. Administration of cadmium to rats or mice dec-

reases serum levels of T4 and T3 [271, 272]. It also decreases the activity of hepatic D1 [271, 273]. Lithium ion used in the treatment of maniac-depressive psychosis can induces goiter and myxedema [274]. Experimentally, it increases thyroid weight and impairs thyroid iodine release [275]. Lithium carbonate determines a reduction in the release of thyroidal iodine [276] and decreases the rate of degradation of T4 in both hyperthyroid and euthyroid subjects [277]. Inhibition of thyroid hormone release may be the dominant effect of the ion [278]. Therefore, the decrease in serum T3 concentration is greater in hyperthyroid patients, and changes in the rT3 level are minimal [279-281]. Lithium administration causes an enhancement of iodide-induced block of binding and hormone release [282, 283], perhaps because it is concentrated by the thyroid [284] and increases the intrathyroidal iodide concentration [276, 279]. Lithium inhibits the adenylate cyclase activity in the thyroid gland as well as in other tissues [285]; furthermore, it blocks the cAMP-mediated translocation of thyroid hormone, inhibiting the hormone release, probably through the stabilization of thyroid microtubules [286]. In rat brain, lithium administration decreased both the levels of the D2 and D3 [287] and may also lead to an alteration in the distribution of thyroid hormone receptors with the alpha 1 isoform being increased in the cortex and decreased in the hypothalamus while the beta isoform was also decreased in the hypothalamus [288]. Although much less frequent, lithium therapy has been associated with the development of thyrotoxicosis [278] and exophthalmos, a protrusion of the globe without the other changes of infiltrative ophthalmopathy of Graves' disease, during chronic therapy [289, 290]. L-tyrosine, carnitine, vitamins A, B1, B2 and B3 can also influence thyroid function. No published data support the claim that ingestion of tyrosine increases the production of thyroid hormone. Vitamin A deficiency increases TSH, thyroglobulin and goiter size in severely iodine deficient people, reducing the risk of hypothyroidism; on the other hand, the association of vitamin A supplementation to iodized salt improves iodine efficacy. This effect could be related to vitamin A-mediated suppression of TSH- gene [291]. ANTINUTRIENTS Cyanogenic plant foods (cauliflower, broccoli, cabbage, Brussel sprouts, mustard seed, turnip, radish, bamboo shoot and cassava) exert antithyroid activity via inhibition of thyroid peroxidase [292, 293]. The hydrolysis of some glucosinolates found in cruciferous vegetables (e.g., progoitrin) may yield a compound known as goitrin, which has been found to interfere with thyroid hormone synthesis. The hydrolysis of another class of glucosinolates, known as indole glucosinolates, results in the release of thiocyanate ions, which can compete with iodine for uptake by the thyroid gland. Increased exposure to thiocyanate ions from cruciferous vegetable consumption, however, does not appear to increase the risk of hypothyroidism unless accompanied by iodine deficiency. The consumption of 150 g/day of cooked Brussels sprouts for four weeks had no adverse effects on thyroid function [294].


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Thiocyanate deriving from tobacco smoking may be associated with an increased risk of goiter in iodine deficient areas [295].

an adequate synthesis and supply of thyroid hormone, principally through modifications in iodide accumulation and binding in the thyroid gland.

Soybean, an important source of protein in many third world countries, has goitrogenic properties when iodine intake is limited. The soybean isoflavones, genistein and daidzein, in fact, have been found to inhibit the activity of thyroid peroxidase, lowering thyroid hormone synthesis [296-298]. Furthermore, soybean interrupts the entero-hepatic cycle of thyroid hormone [299]. However, high intakes of soy isoflavones do not appear to increase the risk of hypothyroidism when iodine consumption is adequate. Since the addition of iodine to soy-based formulas in the 1960s, there have been no further reports of hypothyroidism developing in soy formula-fed infants [300]. The amount of levothyroxine required for adequate thyroid hormone replacement has been found to increase in infants with congenital hypothyroidism fed soy formula [300, 301]. Several clinical trials in premenopausal and postmenopausal women with sufficient iodine intakes have not found high intakes of soy isoflavones to result in clinically significant changes in circulating thyroid hormone levels [302-305]. Soy protein administration increased the levothyroxine dose required for adequate thyroid hormone replacement in an adult with hypothyroidism [306].

Iodine deficiency is still a problem not only for developing countries but also for many western nations where iodine supplementation has gained growing acceptance and diffusion, leading to an improvement or even a disappearance of iodine related diseases, but poor monitoring of iodine nutrition and particular dietary habits (vegetarianism, low salt intake) can cause a reappearance of goiter and other disorders.

Soybeans are by far the most concentrated source of isoflavones in the human diet [307, 308]. Small amounts are found in a number of legumes, grains and vegetables. Average dietary isoflavone intakes in Asian countries, in particular in Japan and China, range from 11-47 mg/day due to the traditional Asian foods made from soybeans including tofu, tempeh, miso and matte [309, 310], while dietary isoflavone intakes are considerably lower in western countries (2 mg/ day) [311, 312]. Soy products (meat substitutes, soy milk, soy cheese, and soy yogurt), however, are gaining popularity in western countries.

Iodization of salt for human food consumption remains the recommended strategy in order to reach the goal of sustainable elimination of iodine deficiency, while the related risks (iodine-induced hyperthyroidism, in particular) are outweighted by the large benefits. An important role is played also by the so-called “silent prophylaxis” resulting from socioeconomic development and the availability of food coming from different areas of the world. Se is an important constituent of enzymes involved in thyroid hormone regulation and in protecting thyroid from free radicals attack as in autoimmune thyroid diseases. For this reason, diet must warrant an adequate intake of this micronutrient as well as iron, vitamin A and other antioxidants. Physicians and patients must be aware that certain foods and herbal preparations contain substances that can modify thyroid function and cause thyroid disorders. ABBREVIATIONS T4

=

Thyroxine

T3

=

Triiodothyronine

TRH

=

Thyrotropin releasing hormone

TSH

=

Thyroid stimulating hormone

NIS

=

Natrium iodide symporter

AIT

=

Apical iodide transporter

Tg

=

Thyroglobulin

TPO

=

Thyroid peroxidase

MIT

=

Monoiodiothyrosynes

DIT

=

Diiodothyrosynes

ROS

=

Reactive oxygen species

CONCLUSIONS

Se

=

Selenium

Since thyroid hormone plays a central role in the regulation of total body metabolism, it is not surprising that nutritional factors may profoundly alter the regulation, supply, and disposal of this thermogenic hormone. The most and important effects of dietary changes that can affect thyroid economy are total caloric intake and supply of iodine. The changes induced by caloric deprivation appear homeostatic in nature producing alterations in thyroid hormones which would preserve energy through a reduction in catabolic expenditure. The modifications observed in case of deficiency or excess of iodine supply generally serve to maintain

GPx

=

Glutathione peroxidase

PHGPx

=

Phospholipid peroxidase

UL

=

Tolerable upper intake level (upper Limit)

IDD

=

Iodine deficiency disorders

D1

=

Type I iodothyronine deiodinase

rT3

=

reverseT3

PTU

=

Propyltiouracil

HERBAL PREPARATIONS Several herbal preparations may affect thyroid function. Ashwagandha herbal extract can induce thyrotoxicosis [313]. Olive leaf extract can either stimulates the thyroid or increases peripheral conversion from T4 to T3 [314]. Other botanicals that may alter thyroid function are garlic, pineapple, oats, capsaicin, forskolin, echinacea, meadowsweet, Fucus vesiculosis, Ginkgo biloba, licorice, Hypericum perforatum, Asian ginseng, saw palmetto, valerian and ginger.

hydroperoxide

glutathione


D2

=

Type II iodothyronine deiodinase

UCPs

=

Uncoupling proteins

D3

=

Type III iodothyronine deiodinase

bFGF

=

Fibroblast growth factor

TGF

=

Transforming growth factor beta

ESS

=

Euthyroid sick syndrome

TPN

=


[2] [3]

[4] [5]

[6] [7]

[8]

[9] [10] [11]

[12]

[13]

[14]

[15]

[16] [17]

[18]

[20]

Total parenteral nutrition

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Received: 20 June, 2008

Accepted: 21 June, 2008

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