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Iodide transport: implications for health and disease

Abstract

Disorders of the thyroid gland are among the most common conditions diagnosed and managed by pediatric endocrinologists. Thyroid hormone synthesis depends on normal iodide transport and knowledge of its regulation is fundamental to understand the etiology and management of congenital and acquired thyroid conditions such as hypothyroidism and hyperthyroidism. The ability of the thyroid to concentrate iodine is also widely used as a tool for the diagnosis of thyroid diseases and in the management and follow up of the most common type of endocrine cancers: papillary and follicular thyroid cancer. More recently, the regulation of iodide transport has also been the center of attention to improve the management of poorly differentiated thyroid cancer. Iodine deficiency disorders (goiter, impaired mental development) due to insufficient nutritional intake remain a universal public health problem. Thyroid function can also be influenced by medications that contain iodide or interfere with iodide metabolism such as iodinated contrast agents, povidone, lithium and amiodarone. In addition, some environmental pollutants such as perchlorate, thiocyanate and nitrates may affect iodide transport. Furthermore, nuclear accidents increase the risk of developing thyroid cancer and the therapy used to prevent exposure to these isotopes relies on the ability of the thyroid to concentrate iodine. The array of disorders involving iodide transport affect individuals during the whole life span and, if undiagnosed or improperly managed, they can have a profound impact on growth, metabolism, cognitive development and quality of life.

Introduction

Iodine, as its water-soluble iodide ion (I), is the rate-limiting substrate for thyroid hormone synthesis. The availability of iodide depends on oral intake and the recommended daily allowances are summarized in Table 1. Iodide is absorbed in the stomach and duodenum and cleared by the kidney and the thyroid. Seventy to eighty percent of the iodine body content is located in the thyroid gland and thyroid hormone synthesis requires a series of regulated steps. Altered regulation or defects in any of these steps can affect thyroid hormone synthesis and secretion. Furthermore, the understanding of iodide transport is used in the diagnosis, prevention and treatment of thyroid disorders and knowledge about the mechanisms underlying iodide transport is now applied to treat advanced forms of thyroid cancer and non-thyroidal malignancies.

Table 1 Recommendations for iodine intake by age and population group from the World Health Organization (WHO), UNICEF and ICCIDD[1]

Iodine intake and absorption

Iodine, as iodide (I), is available but not equally distributed in the environment. Most iodide is found in the oceans (sea water has 50 μg/L) and deficient soils are common in mountainous areas, regions that were glaciated and areas of frequent flooding; however, deficiency is also a problem in some coastal and island populations [25].

Plants grown in iodine deficient soils have as low as 10 μg/kg of dry weight, while plants grown in iodine rich soils have a concentration of 1 mg/kg. Overall, the natural iodine content of many foods and beverages is low (3–80 μg per serving), while foods from marine origin have a higher content. However, sea salt has negligible amounts, as iodide in seawater is sublimated into the atmosphere as volatile organic iodine [6]. The most important dietary sources of iodine in industrialized countries are breads containing iodized salt and milk [2]. Iodide absorption in the gastrointestinal tract is mediated by the sodium-iodide symporter (NIS), which also mediates the uptake of iodide into the thyroid follicular cell (see Figure 1) [7, 8]. Iodide is rapidly cleared from the circulation by the thyroid gland and kidneys. Thyroid clearance varies depending on iodine intake, from 10% of absorbed iodide in healthy individuals to more than 80% in chronic iodine deficiency [2].

Figure 1
figure 1

Mechanisms of Iodide transport in thyroid follicular cells. The first step in iodide uptake is mediated by the sodium-iodide symporter NIS, using the sodium gradient generated by the Na, K-ATPase. Active transport of potassium by the KCNE2/KCNQ1 potassium channel is also important, likely for maintaining the membrane potential of thyroid cells. At the apical membrane, pendrin and another yet unidentified transporter mediate iodide efflux. TPO, using H2O2 generated by the DUOX2/DUOXA system mediates the oxidation, organification and coupling reaction that result in the synthesis of the iodothyronines T4 and T3. Iodinated thyroglobulin is taken into the cell by micro- and macropinocytosis and digested in lysosomes. T4 and T3 are excreted via MCT8 and other transporters. The iodotyrosines MIT and DIT are dehalogenated by DEHAL1 and the released iodide is recycled. Purple boxes represent steps in basal iodide uptake. Orange boxes represent apical iodide uptake, oxidation, organification and coupling are mediated by TPO, represented in green boxes. The generation of H2O2 is represented in aqua. The recycling of iodide after digestion of iodinated thyroglobulin is represented in the red box. The secretion of thyroid hormones at the basolateral membrane is shown in the blue boxes.

Iodide transport in thyroid cells

As illustrated in Figure 1, the NIS ( SLC5A5), a member of the solute carrier family 5, located at the basolateral plasma membrane of the thyroid follicular cells actively transports iodide into the thyroid using the electrochemical gradient generated by the Na,K-ATPase [911]. This process also requires a constitutive active potassium channel consisting of the KCNQ1 and KCNE2 subunits promoting potassium efflux [1214]. Iodide efflux into the follicular lumen is mediated in part by pendrin, in conjunction with an as of yet unidentified channel. Pendrin (SLC26A4), a member of the multianion transporter solute carrier 26 family, is a coupled electroneutral iodide/chloride, iodide/bicarbonate, and chloride/bicarbonate exchanger [1517]. At the intraluminal side, iodide is oxidized, a reaction that requires hydrogen peroxide (H2O2). The oxidation of iodide is mediated by thyroid peroxidase (TPO). TPO is also responsible for the iodination of selected tyrosil residues of thyroglobulin (organification), forming monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues, and for the coupling of MIT and DIT resulting in the formation of T3 and T4[18]. The matrix for the synthesis and storage of T4 and T3 is thyroglobulin (Tg), a large glycoprotein secreted by the thyroid follicular cells [19, 20]. H2O2 is generated by the dual oxidase 2 (DUOX2), a calcium dependent flavoprotein NADPH oxidase, which requires a maturation factor known as DUOXA2 [21]. T3 and T4 are released into the bloodstream, following micro- or macropinocytosis and lysosomal digestion of thyroglobulin by endopeptidases and exopeptidases [2224]. Animal and cellular models suggest that the monocarboxylate channel (MCT8/SLC16A2) is involved in the efflux of thyroid hormones at the basolateral membrane [25, 26]. MIT and DIT are deiodinated by the iodotyrosine dehalogenase, DEHAL1. This allows the re-utilization of iodide within the thyroid cell [27]. The molar ratio of secreted T4 to T3 is 11 to 1 due to intrathyroidal deiodination of T4 to T3 by type 1 and 2 deiodinases (D1 and D2) [28]. However, most T3 production occurs in extrathyroidal tissues and both, T3 and T4 can be converted to inactive forms via deiodination of the inner ring, by either type 3 deiodinases (D3) or D1 [29, 30].

Regulation of iodide transport

Iodide transport is dependent on the nutritional availability of iodide and on the stimulation of the thyroid stimulating hormone receptor (TSHR). Although the TSHR is constitutively active, it is susceptible to enhanced activation by TSH [31, 32]. In addition, iodide uptake and organification are inhibited by high intracellular concentrations of iodide. Other factors have been shown to regulate iodide uptake, including thyroglobulin, cytokines, growth factors and estradiol.

  1. 1)

    TSH

    TSH stimulates thyroid hormone synthesis and secretion. TSH is a glycoprotein with two subunits. The α subunit is identical to the glycoprotein hormones LH, FSH and hCG, whereas the β subunit is specific for the four hormones. TSH is synthesized and secreted in response to TSH releasing hormone (TRH) from the hypothalamus. Thyroid hormones negatively regulate the synthesis and secretion of both TRH and TSH. TSH stimulation of the G-protein coupled TSHR increases cAMP, which in turn, stimulates NIS transcription, half-life and subcellular distribution. TSH also upregulates the expression of TPO, Tg and the endocytosis of iodinated Tg [11] and increases the translocation of pendrin to the apical membrane of the thyroid follicular cell, thereby enhancing iodide efflux [33].

  2. 2)

    Iodide

    Iodide is a major regulator of iodide accumulation and organification. Iodine intake has a negative effect on the expression of NIS and high doses of iodide block thyroid hormone synthesis via inhibition of organification (Wolff-Chaikoff effect) [3437]. The adaptation to the initial inhibitory effect (the escape from the Wolff-Chaikoff effect) occurs as a result of decreased iodide transport. The escape is secondary to complex regulatory phenomena that involve, among others, decreased NIS gene transcription, increased NIS protein degradation and decreased NIS activity [3840].

  3. 3)

    Thyroglobulin (Tg)

    A role for Tg as an intrinsic regulator of iodide transport and thyroid hormone synthesis has been proposed to explain the heterogeneity of thyroid follicles and its differential expression of thyroid genes. Tg has been shown to decrease the gene expression of NIS, TPO, and DUOX[4144].

  4. 4)

    Cytokines and growth factors

    Cytokines such as TNF and interleukins inhibit iodide uptake and NIS expression. Insulin like growth factor 1 (IGF-1) affects thyroid hormone synthesis by downregulating the expression of NIS [10, 4547]. Transforming Growth Factor-β (TGF-β) has been shown to downregulate iodide transport by several mechanisms in different species, including inhibition of mRNA expression of TSHR, TPO, NIS, the Na, K-ATPase and thyroglobulin [48].

  5. 5)

    Estradiol

    Estradiol downregulates the expression of NIS and iodide uptake in thyroid cells, possibly explaining the higher incidence of goiter in women. Estradiol also upregulates thyroglobulin [49, 50].

Thyroid conditions as they relate to iodide transport

The different mechanisms and disorders associated with abnormal iodide transport are summarized in Table 2. For detailed explanation, please refer to the text.

Table 2 Mechanisms and disorders associated with abnormal iodide transport

Disorders of iodine intake (DII)

Iodine deficiency causes hypothyroidism and goiter. Moreover, it is associated with an increased risk for abortion and stillbirths, congenital malformations, increased perinatal mortality, impaired growth and developmental retardation, impaired mental potential and decreased productivity. Iodine deficiency in critical periods of brain development and growth causes severe and permanent growth and cognitive impairment (cretinism) as thyroid hormones are required for myelination, neuronal differentiation and formation of neural processes in the cerebral cortex, the basal ganglia and the inner ear during the first trimester of gestation, and subsequently for brain growth and differentiation [11, 5158]. Importantly, pregnant women need higher amounts of iodide (Table 1). Even mild iodine deficiency during pregnancy may affect outcomes [54, 5961]. However, despite the efforts from the International Council for the Control of Iodine Deficiency Disorders (ICCIDD) to end a preventable form of hypothyroidism, goiter and mental retardation, thirty-two countries and about 246 million schoolchildren are estimated to have insufficient iodine intake [4, 5]. In the US, the median urinary iodine concentration decreased by over 50% between the early 1970s and the early 1990s and even though most of the US population remains iodine sufficient, the aggregate data from NHANES 2007–2010 indicates that a subset of young women and pregnant women may have mild iodine deficiency [3]. Popular foods among young women, marketed for weight loss, are deficient in iodine [62]. Furthermore, prenatal vitamins have inconsistent amounts of iodide content [63, 64]. Iodine supplementation is recommended not only for pregnancy, but also during lactation [65] as iodine supplementation given to a lactating mother provides adequate iodine to their infants [66]. Criteria for assessing iodine nutrition in populations based on school age children and in pregnant and lactating women are summarized in Table 3[2, 4, 58]. Thyroglobulin is also a sensitive method to assess iodine intake [67, 68]. Disorders of iodide transport (see below) are influenced by iodine intake. In addition, other questions remain, such as whether mild, transient congenital and/or subclinical hypothyroidism could be impacted by improving iodine intake.

Table 3 Epidemiological criteria for assessing iodine nutrition based on median iodine urine concentration in school age children and median iodine concentration in pregnant women[1]

Disorders of iodide transport

  1. 1)

    Disorders associated with abnormal basolateral uptake

    Mutations in the NIS gene

    Homozygous or compound heterozygous inactivating mutations of the NIS can cause congenital hypothyroidism. The thyroid may be normal at birth, but enlarges overtime due to TSH stimulation, unless thyroid hormone replacement is started. Affected individuals have an iodide-trapping defect with little or no uptake of radioactive iodide both in the thyroid and the salivary glands [69].

  2. 2)

    Disorders associated with abnormal apical iodide efflux

    2.2) Congenital hypothyroidism with hypoplastic thyroid gland due to PDS/SLC26A4 mutations

    Kühnen et al. [72] found biallelic mutations in the SLC26A4 gene in two individuals from two families with hypoplastic thyroid glands. They speculated that the hypoplasia may be caused by “secondary atrophy”. However, the described mutations have also been reported in patients with Pendred syndrome, while the patients described in this study had thyroid hypoplasia. One case had apparently a normal hearing test. Nevertheless, imaging studies of the inner ear were not obtained. A second patient had deafness and mental retardation. The authors did not comment of the hearing function of the other four patients with hypoplastic thyroid glands harboring mutations on the SLAC26A4 gene. Moreover, the thyroid volumes of the index patients early in life are unknown [72]. Hence, it is not clear if patients presenting with hypoplastic thyroid glands may be within the spectrum of Pendred syndrome or not, and the mechanism causing thyroid atrophy needs to be further elucidated; it could, e.g., involve destruction of thyroid cells by the retained misfolded proteins [17].

    2.1) Pendred syndrome

    Pendred syndrome is an autosomal recessive disorder caused by mutations in the PDS/SLC26A4 gene. It is characterized by sensorineural hearing loss associated with malformations of the inner ear (enlarged vestibular system), variable degrees of goiter and hypothyroidism and a partial iodine organification defect diagnosed by the perchlorate discharge test (see below) [17, 70, 71].

  3. 3)

    Disorders of organification and coupling

    3.3) Dual oxidases and its chaperones (DUOX2/DUOXA2)

    DUOX1 and DUOX 2 are NADPH flavoproteins that share 83% sequence similarity. Both DUOX genes are expressed in the thyroid but their expression is not restricted to the thyroid. The DUOX2 and DUOXA2 genes are contiguous (together with their homologues DUOX1 and DUOXA1) on the long arm of chromosome 15. Only mutations in DUOX2 and in DUOXA2 have been found to cause congenital hypothyroidism [21, 7678]. In some cases, transient hypothyroidism occurs. This was initially postulated to be secondary to heterozygous mutations, while biallelic DUOX2 mutations were thought to cause permanent hypothyroidism. However, transient hypothyroidism also occurs in individuals with biallelic mutations [77]. The role of DUOX1 in compensating for the loss of DUOX2 is unclear at this time and it is thought that iodide availability may also affect the phenotype.

    3.2) Thyroid peroxidase (TPO)

    Recessive TPO defects are among the most common causes of congenital hypothyroidism secondary to dyshormonogenesis. Patients may have a partial or total organification defect. A recent study in the Netherlands found that TPO gene defects are the most common cause of a total organification defect, as diagnosed by a positive perchlorate test with a discharge of < 90% [75].

    3.1) Thyroglobulin (Tg)

    Biallelic mutations in the Tg gene can cause congenital hypothyroidism. The clinical spectrum ranges from normal thyroid function to overt hypothyroidism. The majority of patients have congenital goiter or develop goiter shortly after birth. The serum Tg concentrations are very low. Affected individuals are homozygous or compound heterozygous for inactivating mutations. Defective Tg molecules are typically retained in the ER and routed for degradation. However, some truncated proteins can be secreted and are sufficient for partial thyroid hormone synthesis [19, 73, 74].

  4. 4)

    Disorder of intra-thyroidal iodide recycling

    4.1) Dehalogenase (DEHAL)

    Mutations in the DEHAL1 gene (IYD) can cause congenital hypothyroidism, goiter, increased MIT and DIT serum levels and urinary loss of MIT and DIT [27, 79, 80]. Variable mental deficits can occur, depending on age of diagnosis and on whether hypothyroidism occurs during development [11, 79].

Disorders of abnormal iodide transport regulation

  1. 1)

    Conditions affecting TSH signaling

    1.1) Hyperthyroidism

    Conditions causing overstimulation of the TSHR increase iodide uptake and thyroid hormone synthesis. In Graves’ disease, the production of TSHR-stimulating immunoglobulins causes increased thyroid cell proliferation, iodide uptake and thyroid hormone synthesis. These IgG antibodies can cross the placenta and are the most common cause of congenital hyperthyroidism [31, 32, 81]. Rarely, activating mutations of the TSHR are the cause of excessive iodide uptake and hyperthyroidism. They can present as somatic mutations in thyrotoxic adenomas, as autosomal dominant familial non-autoimmune hyperthyroidism, or as sporadic de novo germline mutations [31]. Activating mutations in the downstream G protein G can also cause non-autoimmune hyperthyroidism; this occurs through somatic mosaicism affecting thyroid cells in McCune Albright syndrome, or as isolated activating mutations in toxic adenomas [82, 83]. During pregnancy, hCG stimulates iodide transport and thyroid hormone synthesis through stimulation of the TSHR. hCG has structural similarity to TSH and leads to a transient increase in thyroid hormone synthesis, resulting in lower TSH levels. In some women, the high hCG levels can cause overt hyperthyroidism and be associated with hyperemesis gravidarum. hCG-secreting trophoblastic tumors (hydatidiform mole, choriocarcinoma) are rare causes of hyperthyroidism [84].

    1. 2)

      Iodine-induced conditions

    Medications or environmental agents can affect the concentration of intracellular iodide or its regulatory mechanisms. Amiodarone is an antiarrhytmic drug that contains two atoms of iodine in an inner benzene ring, similar to thyroid hormones. Each 200 mg tablet of amiodarone contains 75,000 μg of iodine [92]. It can cause amiodarone-induced thyrotoxicosis (AIT) via two different mechanisms. AIT type 1, which occurs more frequently in iodine deficient areas, is caused by excessive thyroid hormone synthesis by nodular thyroid tissue that has lost its autoregulatory capacity (Jod-Basedow phenomenon; Jod = iodine in German; Karl von Basedow = German physician who described thyrotoxicosis associated with exophthalmos and goiter) [9397]. The Jod-Basedow effect can be caused by any form of iodine excess such as contrast agents or iodine-containing solutions [98101]. Currently used, water soluble iodinated contrast agents provide exposure to about 13,500 μg of free iodine per computerized tomography (CT) imaging study [92]. AIT type 2 occurs secondary to amiodarone-induced thyroiditis. Amiodarone can also cause hypothyroidism (AIH), particularly in patients with underlying autoimmune thyroid disease. Lithium is another widely used drug known to affect thyroid function. Among other effects, it appears to promote iodide retention in the thyroid and it decreases the release of thyroid hormone from the gland [102104]. Other effects of amiodarone and lithium are reviewed elsewhere [9396, 102105].

    1.2) Hypothyroidism

    Conditions causing a decreased or absent response of the TSHR to TSH cause inadequate iodide uptake and thyroid hormone synthesis. Autoimmune hypothyroidism can be caused by the presence of blocking thyrotropin binding inhibitor immunoglobulins (TBII). These antibodies cross the placenta and may cause transient congenital hypothyroidism [85, 86]. Resistance to TSH can be caused by molecular defects affecting the transmission of the TSH stimulatory signal, most commonly due to biallelic loss of function mutations of the TSHR. The phenotypes vary from a hypoplastic thyroid gland with severe congenital hypothyroidism to mild hyperthyrotropinemia with an euthyroid state [87, 88]. Inactivating mutations in the G cause mild hypothyroidism, such as seen in pseudohypoparathyroidism [8991].

Consumptive hypothyroidism

Hemangiomas and gastrointestinal stromal tumors may express high levels of D3. This enzyme catalyzes the conversion of T4 to rT3 and of T3 to T2, i.e. inactive forms of thyroid hormone. This causes a unique form of hypothyroidism due to increased degradation of thyroid hormones at a rate that exceeds the synthetic capacity of the stimulated thyroid gland [106108]. These patients have significantly elevated rT3 levels and require unusually large doses of levothyroxine in order to compensate for the increased degradation of T4 and T3.

Drugs, diet and environmental agents affecting iodide transport and metabolism

  1. 1)

    Perchlorate, thiocyanate and other environmental agents

    In addition to its iodide transport activity, NIS also transports other anions [11, 109], including selenocyanate (SeCN), thiocyanate (SCN), chlorate (ClO3), and nitrate (NO3). Pertechnetate (TcO4), perrhenate (ReO4) and perchlorate (ClO4) are also NIS substrates [11]. Perchlorate is a competitive NIS inhibitor. Perchlorate salts are used as oxidizers in solid propellants for a wide range of uses; perchlorate is not biodegradable and it is found in drinking water, food and multivitamins [110, 111]. The Environmental Protection Agency (EPA) established a minimum reporting level (MRL) of 4 μg/L [112]. Perchlorate can be transported by NIS into the thyroid and the mammary gland, which would potentially decrease iodide supply in the breast milk and affect the newborn’s iodide uptake by the thyroid gland [113]. Kirk et al. found an inverse correlation between breast milk iodine and perchlorate concentration [114]. However, other studies do not show a similar correlation [115, 116]. In healthy adults, exposure to perchlorate for 6 months with doses as high as 3 mg/day did not affect thyroid function [117] and thus, the consequences of environmental perchlorate exposure still remain controversial [111]. Thiocyanate is a less potent inhibitor of NIS-mediated iodide transport than perchlorate. Exposure to thiocyanate comes mainly from cigarette smoke (containing cyanide, which is metabolized to thiocyanate) and from the diet (see below). Smoking seems to affect iodide secretion into the breast milk [118]. The available studies trying to address the effect of smoking on thyroid function are not conclusive. It appears that smoking is associated with goiter and hypothyroidism in iodine deficient regions, whereas smokers have lower TSH levels in iodine sufficient areas [119, 120]. Although the risks of perchlorate and thiocyanate exposure in healthy adults remain unresolved, a recent study indicates that a combination of perchlorate and thiocyanate exposure with low iodine intake lowers free thyroxine concentration by about 12% [121]. Nitrates are widely present in soils and water and come from natural decomposition of organic materials. Sodium nitrite is also used as a preservative. The average intake of nitrates in adults is 75–100 mg/day and 80% comes from vegetables. Vegetarians may ingest 2.5 times the average intake. High ingestion of nitrates usually comes from contaminated water. The EPA defined the maximum contaminant level at 10 mg/L or 10 ppm [112]. Exposure to high levels of nitrates due to polluted water has been shown to cause thyroid dysfunction and goiter [122, 123].

  2. 2)

    Medications used to treat hyperthyroidism

    The anti-thyroid drugs used in the US include propyl-thiouracil (6-propyl-2-thiouracil) and methimazole (1-methyl-2-mercaptoimidazole). Carbimazole, which is metabolized to methimazole, is widely used in other parts of the world. These thionamide drugs are actively concentrated in the thyroid and their primary effect consists in inhibiting the TPO-mediated organification [124].

  3. 3)

    Diet

    Cruciferous vegetables like cabbage, kale, broccoli, turnips and cauliflower contain glucosinolates. Cassava (linamarin), lima beans, sweet potatoes, sorghum and flaxseed contain cyanogenic glucosides. Both, glucosinolates and cyanogenic glucosides are metabolized to thiocyanate that competes for thyroid iodide uptake. These substances can aggravate iodine deficiency and contribute to goiter development. Hence, they are called goitrogens. Soy and millet contains flavonoids that may inhibit TPO activity. Use of soy-based formula without added iodide can produce hypothyroidism and goiter in healthy infants [125128].

Iodine as a tool for diagnosis and treatment of thyroid disorders

The ability of the thyroid to concentrate iodide is widely used in the diagnosis and treatment of thyroid disorders. Commonly used diagnostic tests such as the radioactive iodine uptake and (whole body) scan rely on the ability of thyroid tissue to concentrate radioactive labeled iodine. I−131, I−123 and I−124 (a positron emission tomography (PET) tracer) are the major radionuclide agents used for the diagnosis of thyroid diseases (Table 4). These tests can be used to differentiate a hyperactive thyroid, with increased uptake (e.g. Graves’ disease, toxic nodules), from an underactive thyroid with decreased iodine uptake, secondary to either thyroid damage or inactivation (e.g. thyroiditis, factitious thyrotoxicosis) or a blockade in thyroid uptake (e.g. mutation in NIS). Whole body scans with radioactive iodine are useful for the staging and planning of therapy of well-differentiated thyroid cancer [129]. Because of the ability of NIS to transport pertechnetate (TcO4), 99mTcO4, an isotope with no β emission and a short half-life, can be used to image thyroid tissue (see Table 3) [130132]. The perchlorate (ClO4) discharge test is a functional test that uses ClO4 to inhibit NIS and radioactive iodine to diagnose partial or total organification defects. This test relies on the fact that iodide transported into the thyroid is covalently bound to Tg (organification). Radioactive iodide is administered, followed by radioactive uptake measurement in the neck using a gamma camera. Two hours later, uptake is blocked using the competitive NIS inhibitor ClO4 and the radioisotope counts are measured again over the next hour. Organified iodine is retained, while free, unbound iodide is washed out. A test is considered positive if <10% of activity is discharged after ClO4 administration. Partial organification defects show a 10-90% discharge, while discharge <90% is consistent with total organification defect [19, 21, 133135].

Table 4 Radionuclides used for evaluation and management of thyroid disorders[132]

Iodine in the prevention of thyroid disorders and public health

Potassium iodide and potassium perchlorate can be used to protect the thyroid from exposure to I-131 after accidental release from nuclear plant reactors to prevent hypothyroidism and thyroid cancer [136].

New developments in iodide transport in the diagnosis and management of thyroid cancer

Poorly differentiated thyroid cancer cells show decreased or absent iodide uptake. This is associated with decreased expression or membrane insertion of NIS at the plasma membrane. For this, reason, there is a great interest in re-differentiating agents that increase NIS expression and membrane insertion [11]. For example, selumetinib, a MAPK (MEK1/MEK2) inhibitor can result in improved radioactive iodine uptake and retention in some patients with radioiodide resistant thyroid cancer [137].

Applications of iodide transport outside the thyroid

Outside the thyroid, non-regulated iodide accumulation, without organification, is known to occur in the lactating mammary gland, salivary and parotid glands, gastric mucosa, small intestine, choroid plexus and the ciliary body of the eye [11, 46]. In addition, NIS is expressed in other tissues [138], however, the physiological relevance of NIS in these tissues in unclear, except in the lung, where oxidation of iodide improves anti-viral defenses [11, 139]. Endogenous NIS expression occurs in breast cancer and cholangiocarcinoma. Currently, ongoing research is exploring the use of 131I to treat these types of cancers. The fact that NIS transports perrhenate defines 188ReO4 as a candidate to increase radiation dose delivery to these tumors [11]. Transduction of viral vectors containing the cDNA of NIS under the control of heterologous promoters (e.g. the PSA promoter) are used experimentally in order to treat other malignancies (such as prostate cancer) [140].

Conclusions

In conclusion, iodide transport is of essential physiological importance for thyroid hormone synthesis. The understanding of iodide transport and its regulation has been fundamental in characterizing the spectrum of thyroid disorders. The ability of thyroid follicular cells to concentrate iodide can be used for diagnostic and therapeutic purposes and the elucidation of the molecular events governing iodide uptake also has important implications because it allows to target NIS for re-differentiation therapies and to use it in non-thyroidal tissues.

Author’s information

LP is a Clinical Assistant Professor of Pediatric Endocrinology with interest in pediatric thyroid disorders and thyroid physiology. PK is an Associate Professor of Endocrinology and he is the director ad interim of the Center of Genetic Medicine at Northwestern University. His clinical focus is directed towards thyroid dysfunction and thyroid cancer. His research interests include genetic endocrine disorders, in particular of the thyroid and the pituitary gland.

Abbreviations

D1:

Type 1 deiodinase

D2:

Type 2 deiodinase

D3:

Type 3 deiodinase

DIT:

Diiodotyrosine

DUOX:

Dual oxidase

DEHAL1:

Dehalogenase

H2O2:

Hydrogen peroxide

ICCIDD:

International Council for the Control of Iodine Deficiency Disorders

MIT:

Monoiodotyrosine

PDS:

Pendrin

NIS:

Sodium iodide symporter

Tg:

Thyroglobulin

T3:

Triiodothyronine

T4:

Thyroxine

TPO:

Thyroid peroxidase

TRH:

TSH releasing hormone

TSH:

Thyroid Stimulating Hormone

TSHR:

TSH-receptor

WHO:

World Health Organization

US:

United States.

References

  1. Asessment of iodine deficiency disorders and monitoring their elimination. A guide for programme managers. [http://www.who.int/nutrition/publications/micronutrients/iodine_deficiency/9789241595827/en/index.html]

  2. Zimmermann MB: Iodine deficiency. Endocr Rev. 2009, 30 (4): 376-408.

    CAS  PubMed  Article  Google Scholar 

  3. Pearce EN, Andersson M, Zimmermann MB: Global iodine nutrition: Where do we stand in 2013?. Thyroid. 2013, 23 (5): 523-528.

    CAS  PubMed  Article  Google Scholar 

  4. Zimmermann MB, Andersson M: Update on iodine status worldwide. Curr Opin Endocrinol Diabetes Obes. 2012, 19 (5): 382-387.

    CAS  PubMed  Article  Google Scholar 

  5. International Council for the Control of Iodine Deficiency Disorders. [http://www.iccidd.org]

  6. Victor R, Preedy GNBaRW: Comprehensive Handbook of iodine. 2009, Oxford: Academic Press

    Google Scholar 

  7. Nicola JP, Reyna-Neyra A, Carrasco N, Masini-Repiso AM: Dietary iodide controls its own absorption through post-transcriptional regulation of the intestinal Na+/I- symporter. J Physiol. 2012, 590 (Pt 23): 6013-6026.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  8. Nicola JP, Basquin C, Portulano C, Reyna-Neyra A, Paroder M, Carrasco N: The Na+/I- symporter mediates active iodide uptake in the intestine. Am J Physiol Cell Physiol. 2009, 296 (4): C654-C662.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  9. Carrasco N: Iodide transport in the thyroid gland. Biochim Biophys Acta. 1993, 1154 (1): 65-82.

    CAS  PubMed  Article  Google Scholar 

  10. Dohan O, De la Vieja A, Paroder V, Riedel C, Artani M, Reed M, Ginter CS, Carrasco N: The sodium/iodide Symporter (NIS): characterization, regulation, and medical significance. Endocr Rev. 2003, 24 (1): 48-77.

    CAS  PubMed  Article  Google Scholar 

  11. Portulano C, Paroder-Belenitsky M, Carrasco N: The Na+/I- Symporter (NIS): Mechanism and Medical Impact. Endocr Rev. 2014, 35 (1): 106-149.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  12. Roepke TK, King EC, Reyna-Neyra A, Paroder M, Purtell K, Koba W, Fine E, Lerner DJ, Carrasco N, Abbott GW: Kcne2 deletion uncovers its crucial role in thyroid hormone biosynthesis. Nat Med. 2009, 15 (10): 1186-1194.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  13. Frohlich H, Boini KM, Seebohm G, Strutz-Seebohm N, Ureche ON, Foller M, Eichenmuller M, Shumilina E, Pathare G, Singh AK, Seidler U, Pfeifer KE, Lang F: Hypothyroidism of gene-targeted mice lacking Kcnq1. Pflugers Arch. 2011, 461 (1): 45-52.

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  14. Purtell K, Paroder-Belenitsky M, Reyna-Neyra A, Nicola JP, Koba W, Fine E, Carrasco N, Abbott GW: The KCNQ1-KCNE2 K(+) channel is required for adequate thyroid I(−) uptake. FASEB J. 2012, 26 (8): 3252-3259.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  15. Bizhanova A, Kopp P: Controversies concerning the role of pendrin as an apical iodide transporter in thyroid follicular cells. Cell Physiol Biochem. 2011, 28 (3): 485-490.

    CAS  PubMed  Article  Google Scholar 

  16. Wolff J: What is the role of pendrin?. Thyroid. 2005, 15 (4): 346-348.

    CAS  PubMed  Article  Google Scholar 

  17. Kopp P: Mutations in the Pendred Syndrome (PDS/SLC26A) Gene: An Increasingly Complex Phenotypic Spectrum From Goiter to Thyroid Hypoplasia. J Clin Endocrinol Metab. 2014, 99 (1): 67-69.

    CAS  PubMed  Article  Google Scholar 

  18. Ruf J, Carayon P: Structural and functional aspects of thyroid peroxidase. Arch Biochem Biophys. 2006, 445 (2): 269-277.

    CAS  PubMed  Article  Google Scholar 

  19. Targovnik HM, Esperante SA, Rivolta CM: Genetics and phenomics of hypothyroidism and goiter due to thyroglobulin mutations. Mol Cell Endocrinol. 2010, 322 (1–2): 44-55.

    CAS  PubMed  Article  Google Scholar 

  20. Citterio CE, Machiavelli GA, Miras MB, Gruneiro-Papendieck L, Lachlan K, Sobrero G, Chiesa A, Walker J, Munoz L, Testa G, Belforte FS, González-Sarmiento R, Rivolta CM, Targovnik HM: New insights into thyroglobulin gene: molecular analysis of seven novel mutations associated with goiter and hypothyroidism. Mol Cell Endocrinol. 2013, 365 (2): 277-291.

    CAS  PubMed  Article  Google Scholar 

  21. Grasberger H: Defects of thyroidal hydrogen peroxide generation in congenital hypothyroidism. Mol Cell Endocrinol. 2010, 322 (1–2): 99-106.

    CAS  PubMed  Article  Google Scholar 

  22. Dunn AD, Myers HE, Dunn JT: The combined action of two thyroidal proteases releases T4 from the dominant hormone-forming site of thyroglobulin. Endocrinol. 1996, 137 (8): 3279-3285.

    CAS  Google Scholar 

  23. Dunn AD, Crutchfield HE, Dunn JT: Proteolytic processing of thyroglobulin by extracts of thyroid lysosomes. Endocrinol. 1991, 128 (6): 3073-3080.

    CAS  Article  Google Scholar 

  24. Dunn AD, Crutchfield HE, Dunn JT: Thyroglobulin processing by thyroidal proteases. Major sites of cleavage by cathepsins B, D, and L. J Biol Chem. 1991, 266 (30): 20198-20204.

    CAS  PubMed  Google Scholar 

  25. Friesema EC, Jansen J, Jachtenberg JW, Visser WE, Kester MH, Visser TJ: Effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10. J Mol Endocrinol. 2008, 22 (6): 1357-1369.

    CAS  Article  Google Scholar 

  26. Di Cosmo C, Liao XH, Dumitrescu AM, Philp NJ, Weiss RE, Refetoff S: Mice deficient in MCT8 reveal a mechanism regulating thyroid hormone secretion. J Clin Invest. 2010, 120 (9): 3377-3388.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  27. Kopp PA: Reduce, recycle, reuse–iodotyrosine deiodinase in thyroid iodide metabolism. N Engl J Med. 2008, 358 (17): 1856-1859.

    CAS  PubMed  Article  Google Scholar 

  28. Laurberg P: Mechanisms governing the relative proportions of thyroxine and 3,5,3’-triiodothyronine in thyroid secretion. Metabolism. 1984, 33 (4): 379-392.

    CAS  PubMed  Article  Google Scholar 

  29. Gereben B, Zeold A, Dentice M, Salvatore D, Bianco AC: Activation and inactivation of thyroid hormone by deiodinases: local action with general consequences. Cell Mol Life Sci. 2008, 65 (4): 570-590.

    CAS  PubMed  Article  Google Scholar 

  30. Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR: Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev. 2002, 23 (1): 38-89.

    CAS  PubMed  Article  Google Scholar 

  31. Davies TF, Ando T, Lin RY, Tomer Y, Latif R: Thyrotropin receptor-associated diseases: from adenomata to Graves disease. J Clin Invest. 2005, 115 (8): 1972-1983.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  32. Michalek K, Morshed SA, Latif R, Davies TF: TSH receptor autoantibodies. Autoimmun Rev. 2009, 9 (2): 113-116.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  33. Pesce L, Bizhanova A, Caraballo JC, Westphal W, Butti ML, Comellas A, Kopp P: TSH regulates pendrin membrane abundance and enhances iodide efflux in thyroid cells. Endocrinol. 2012, 153 (1): 512-521.

    CAS  Article  Google Scholar 

  34. Wolff J, Chaikoff IL: The inhibitory action of excessive iodide upon the synthesis of diiodotyrosine and of thyroxine in the thyroid gland of the normal rat. Endocrinol. 1948, 43 (3): 174-179.

    CAS  Article  Google Scholar 

  35. Wolff J, Chaikoff IL: Plasma inorganic iodide as a homeostatic regulator of thyroid function. J Biol Chem. 1948, 174 (2): 555-564.

    CAS  PubMed  Google Scholar 

  36. Wolff J, Chaikoff IL, Goldberg RC, Meier JR: The temporary nature of the inhibitory action of excess iodine on organic iodine synthesis in the normal thyroid. Endocrinol. 1949, 45 (5): 504-513. illust

    CAS  Article  Google Scholar 

  37. Uyttersprot N, Pelgrims N, Carrasco N, Gervy C, Maenhaut C, Dumont JE, Miot F: Moderate doses of iodide in vivo inhibit cell proliferation and the expression of thyroperoxidase and Na+/I- symporter mRNAs in dog thyroid. Mol Cell Endocrinol. 1997, 131 (2): 195-203.

    CAS  PubMed  Article  Google Scholar 

  38. Eng PH, Cardona GR, Fang SL, Previti M, Alex S, Carrasco N, Chin WW, Braverman LE: Escape from the acute Wolff-Chaikoff effect is associated with a decrease in thyroid sodium/iodide symporter messenger ribonucleic acid and protein. Endocrinol. 1999, 140 (8): 3404-3410.

    CAS  Google Scholar 

  39. Braverman LE, Ingbar SH: Changes in Thyroidal Function during Adaptation to Large Doses of Iodide. J Clin Invest. 1963, 42: 1216-1231.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  40. Eng PH, Cardona GR, Previti MC, Chin WW, Braverman LE: Regulation of the sodium iodide symporter by iodide in FRTL-5 cells. Eur J Endocrinol. 2001, 144 (2): 139-144.

    CAS  PubMed  Article  Google Scholar 

  41. Sellitti DF, Suzuki K: Intrinsic Regulation of Thyroid Function by Thyroglobulin. Thyroid. 2014, 24 (4): 625-638.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  42. Yoshihara A, Hara T, Kawashima A, Akama T, Tanigawa K, Wu H, Sue M, Ishido Y, Hiroi N, Ishii N, Yoshino G, Suzuki K: Regulation of dual oxidase (DUOX) expression and H2O2 production by thyroglobulin. Thyroid. 2012, 22 (10): 1054-1062.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  43. Suzuki K, Kawashima A, Yoshihara A, Akama T, Sue M, Yoshida A, Kimura HJ: Role of thyroglobulin on negative feedback autoregulation of thyroid follicular function and growth. J Endocrinol. 2011, 209 (2): 169-174.

    CAS  PubMed  Article  Google Scholar 

  44. Ishido Y, Yamazaki K, Kammori M, Sugishita Y, Luo Y, Yamada E, Yamada T, Sellitti DF, Suzuki K: Thyroglobulin suppresses thyroid-specific gene expression in cultures of normal, but not neoplastic human thyroid follicular cells. J Clin Endocrinol Metab. 2014, 99 (4): E694-E702.

    CAS  PubMed  Article  Google Scholar 

  45. Dohan O, Carrasco N: Advances in Na(+)/I(−) symporter (NIS) research in the thyroid and beyond. Mol Cell Endocrinol. 2003, 213 (1): 59-70.

    CAS  PubMed  Article  Google Scholar 

  46. Riesco-Eizaguirre G, Santisteban P: A perspective view of sodium iodide symporter research and its clinical implications. Eur J Endocrinol. 2006, 155 (4): 495-512.

    CAS  PubMed  Article  Google Scholar 

  47. Garcia B, Santisteban P: PI3K is involved in the IGF-I inhibition of TSH-induced sodium/iodide symporter gene expression. Mol Endocrinol. 2002, 16 (2): 342-352.

    CAS  PubMed  Article  Google Scholar 

  48. Pisarev MA, Thomasz L, Juvenal GJ: Role of transforming growth factor beta in the regulation of thyroid function and growth. Thyroid. 2009, 19 (8): 881-892.

    CAS  PubMed  Article  Google Scholar 

  49. Furlanetto TW, Nunes RB, Sopelsa AM, Maciel RM: Estradiol decreases iodide uptake by rat thyroid follicular FRTL-5 cells. Braz J Med Biol Res. 2001, 34 (2): 259-263.

    CAS  PubMed  Article  Google Scholar 

  50. Santin AP, Furlanetto TW: Role of estrogen in thyroid function and growth regulation. J Thyroid Res. 2011, 2011: 875125-

    PubMed Central  PubMed  Article  CAS  Google Scholar 

  51. Delange F: The role of iodine in brain development. Proc Nutr Soc. 2000, 59 (1): 75-79.

    CAS  PubMed  Article  Google Scholar 

  52. de Escobar GM, Obregon MJ, del Rey FE: Iodine deficiency and brain development in the first half of pregnancy. Public Health Nutr. 2007, 10 (12A): 1554-1570.

    PubMed  Article  Google Scholar 

  53. de Escobar GM, Ares S, Berbel P, Obregon MJ, del Rey FE: The changing role of maternal thyroid hormone in fetal brain development. Semin Perinatol. 2008, 32 (6): 380-386.

    PubMed  Article  Google Scholar 

  54. Zimmermann MB: The adverse effects of mild-to-moderate iodine deficiency during pregnancy and childhood: a review. Thyroid. 2007, 17 (9): 829-835.

    CAS  PubMed  Article  Google Scholar 

  55. Melse-Boonstra A, Jaiswal N: Iodine deficiency in pregnancy, infancy and childhood and its consequences for brain development. Best Pract Res Clin Endocrinol Metab. 2010, 24 (1): 29-38.

    CAS  PubMed  Article  Google Scholar 

  56. Horn S, Heuer H: Thyroid hormone action during brain development: more questions than answers. Mol Cell Endocrinol. 2010, 315 (1–2): 19-26.

    CAS  PubMed  Article  Google Scholar 

  57. Zimmermann MB: The effects of iodine deficiency in pregnancy and infancy. Paediatr Perinat Epidemiol. 2012, 26 (Suppl 1): 108-117.

    PubMed  Article  Google Scholar 

  58. Zimmermann MB: The role of iodine in human growth and development. Semin Cell Dev Biol. 2011, 22 (6): 645-652.

    CAS  PubMed  Article  Google Scholar 

  59. Bath SC, Rayman MP: Iodine deficiency in the U.K.: an overlooked cause of impaired neurodevelopment?. Proc Nutr Soc. 2013, 72 (2): 226-235.

    CAS  PubMed  Article  Google Scholar 

  60. Hynes KL, Otahal P, Hay I, Burgess JR: Mild iodine deficiency during pregnancy is associated with reduced educational outcomes in the offspring: 9-year follow-up of the gestational iodine cohort. J Clin Endocrinol Metab. 2013, 98 (5): 1954-1962.

    CAS  PubMed  Article  Google Scholar 

  61. Bath SC, Steer CD, Golding J, Emmett P, Rayman MP: Effect of inadequate iodine status in UK pregnant women on cognitive outcomes in their children: results from the Avon Longitudinal Study of Parents and Children (ALSPAC). Lancet. 2013, 382 (9889): 331-337.

    CAS  PubMed  Article  Google Scholar 

  62. Kuriti M, Pearce EN, Braverman LE, He X, Leung AM: Iodine content of U.S. weight-loss food. Endocr Pract. 2014, 20 (3): 232-235.

    PubMed Central  PubMed  Article  Google Scholar 

  63. Zimmermann M, Delange F: Iodine supplementation of pregnant women in Europe: a review and recommendations. Eur J Clin Nutr. 2004, 58 (7): 979-984.

    CAS  PubMed  Article  Google Scholar 

  64. Leung AM, Pearce EN, Braverman LE: Iodine content of prenatal multivitamins in the United States. N Engl J Med. 2009, 360 (9): 939-940.

    CAS  PubMed  Article  Google Scholar 

  65. Becker DV, Braverman LE, Delange F, Dunn JT, Franklyn JA, Hollowell JG, Lamm SH, Mitchell ML, Pearce E, Robbins J, Rovet JF, Public Health Committee of the American Thyroid A: Iodine supplementation for pregnancy and lactation-United States and Canada: recommendations of the American Thyroid Association. Thyroid. 2006, 16 (10): 949-951.

    CAS  PubMed  Article  Google Scholar 

  66. Bouhouch RR, Bouhouch S, Cherkaoui M, Aboussad A, Stinca S, Haldimann M, Andersson M, Zimmermann MB: Direct iodine supplementation of infants versus supplementation of their breastfeeding mothers: a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014, 2 (3): 197-209.

    CAS  PubMed  Article  Google Scholar 

  67. Zimmermann MB, Andersson M: Assessment of iodine nutrition in populations: past, present, and future. Nutr Rev. 2012, 70 (10): 553-570.

    PubMed  Article  Google Scholar 

  68. Zimmermann MB, Aeberli I, Andersson M, Assey V, Yorg JA, Jooste P, Jukic T, Kartono D, Kusic Z, Pretell E, San Luis TO, Untoro J, Timmer A: Thyroglobulin is a sensitive measure of both deficient and excess iodine intakes in children and indicates no adverse effects on thyroid function in the UIC range of 100–299 mug/L: a UNICEF/ICCIDD study group report. J Clin Endocrinol Metab. 2013, 98 (3): 1271-1280.

    CAS  PubMed  Article  Google Scholar 

  69. Spitzweg C, Morris JC: Genetics and phenomics of hypothyroidism and goiter due to NIS mutations. Mol Cell Endocrinol. 2010, 322 (1–2): 56-63.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  70. Kopp P, Bizhanova A: Clinical and molecular characteristics of Pendred syndrome. Ann Endocrinol. 2011, 72 (2): 88-94.

    CAS  Article  Google Scholar 

  71. Bizhanova A, Kopp P: Genetics and phenomics of Pendred syndrome. Mol Cell Endocrinol. 2010, 322 (1–2): 83-90.

    CAS  PubMed  Article  Google Scholar 

  72. Kuhnen P, Turan S, Frohler S, Guran T, Abali S, Biebermann H, Bereket A, Gruters A, Chen W, Krude H: Identification of PENDRIN (SLC26A4) Mutations in Patients With Congenital Hypothyroidism and “Apparent” Thyroid Dysgenesis. J Clin Endocrinol Metab. 2014, 99 (1): E169-E176.

    PubMed  Article  Google Scholar 

  73. Medeiros-Neto G, Kim PS, Yoo SE, Vono J, Targovnik HM, Camargo R, Hossain SA, Arvan P: Congenital hypothyroid goiter with deficient thyroglobulin. Identification of an endoplasmic reticulum storage disease with induction of molecular chaperones. J Clin Invest. 1996, 98 (12): 2838-2844.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  74. Medeiros-Neto G, Targovnik HM, Vassart G: Defective thyroglobulin synthesis and secretion causing goiter and hypothyroidism. Endocr Rev. 1993, 14 (2): 165-183.

    CAS  PubMed  Google Scholar 

  75. Ris-Stalpers C, Bikker H: Genetics and phenomics of hypothyroidism and goiter due to TPO mutations. Mol Cell Endocrinol. 2010, 322 (1–2): 38-43.

    CAS  PubMed  Article  Google Scholar 

  76. Zamproni I, Grasberger H, Cortinovis F, Vigone MC, Chiumello G, Mora S, Onigata K, Fugazzola L, Refetoff S, Persani L, Weber G: Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism. J Clin Endocrinol Metab. 2008, 93 (2): 605-610.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  77. Hoste C, Rigutto S, Van Vliet G, Miot F, De Deken X: Compound heterozygosity for a novel hemizygous missense mutation and a partial deletion affecting the catalytic core of the H2O2-generating enzyme DUOX2 associated with transient congenital hypothyroidism. Hum Mutat. 2010, 31 (4): E1304-E1319.

    CAS  PubMed  Article  Google Scholar 

  78. Moreno JC, Bikker H, Kempers MJ, van Trotsenburg AS, Baas F, de Vijlder JJ, Vulsma T, Ris-Stalpers C: Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism. N Engl J Med. 2002, 347 (2): 95-102.

    CAS  PubMed  Article  Google Scholar 

  79. Moreno JC, Visser TJ: Genetics and phenomics of hypothyroidism and goiter due to iodotyrosine deiodinase (DEHAL1) gene mutations. Mol Cell Endocrinol. 2010, 322 (1–2): 91-98.

    CAS  PubMed  Article  Google Scholar 

  80. Moreno JC, Klootwijk W, van Toor H, Pinto G, D’Alessandro M, Leger A, Goudie D, Polak M, Gruters A, Visser TJ: Mutations in the iodotyrosine deiodinase gene and hypothyroidism. N Engl J Med. 2008, 358 (17): 1811-1818.

    CAS  PubMed  Article  Google Scholar 

  81. Levy-Shraga Y, Tamir L, Boyko V, Lerner-Geva L, Pinhas-Hamiel O: Follow up of newborns of mothers with Graves’ disease. Thyroid. 2014, Epub ahead of print. doi:10.1089/thy.2013.0489

    Google Scholar 

  82. Isotani H, Sanda K, Kameoka K, Takamatsu J: McCune-Albright syndrome associated with non-autoimmune type of hyperthyroidism with development of thyrotoxic crisis. Horm Res. 2000, 53 (5): 256-259.

    CAS  PubMed  Article  Google Scholar 

  83. Congedo V, Celi FS: Thyroid disease in patients with McCune-Albright syndrome. Pediatr Endocrinol Rev. 2007, 4 (Suppl 4): 429-433.

    PubMed  Google Scholar 

  84. Hershman JM: Physiological and pathological aspects of the effect of human chorionic gonadotropin on the thyroid. Best Pract Res Clin Endocrinol Metab. 2004, 18 (2): 249-265.

    CAS  PubMed  Article  Google Scholar 

  85. Ishihara T, Waseda N, Ikekubo K, Kuroda K, Akamizu T, Mori T: A predicted case with neonatal transient hypothyroidism due to blocking type thyrotropin binding inhibitor immunoglobulins (TBII). Endocrinol Jpn. 1985, 32 (1): 189-194.

    CAS  PubMed  Article  Google Scholar 

  86. Sato K, Okamura K, Yoshinari M, Ikenoue H, Kuroda T, Torisu M, Fujishima M: Goitrous hypothyroidism with blocking or stimulating thyrotropin binding inhibitor immunoglobulins. J Clin Endocrinol Metab. 1990, 71 (4): 855-860.

    CAS  PubMed  Article  Google Scholar 

  87. Persani L, Calebiro D, Cordella D, Weber G, Gelmini G, Libri D, de Filippis T, Bonomi M: Genetics and phenomics of hypothyroidism due to TSH resistance. Mol Cell Endocrinol. 2010, 322 (1–2): 72-82.

    CAS  PubMed  Article  Google Scholar 

  88. Persani L, Gelmini G, Marelli F, Beck-Peccoz P, Bonomi M: Syndromes of resistance to TSH. Ann Endocrinol. 2011, 72 (2): 60-63.

    CAS  Article  Google Scholar 

  89. Balavoine AS, Ladsous M, Velayoudom FL, Vlaeminck V, Cardot Bauters C, d’Herbomez M, Wemeau JL: Hypothyroidism in patients with pseudohypoparathyroidism type Ia: clinical evidence of resistance to TSH and TRH. Eur J Endocrinol. 2008, 159 (4): 431-437.

    CAS  PubMed  Article  Google Scholar 

  90. Pinsker JE, Rogers W, McLean S, Schaefer FV, Fenton C: Pseudohypoparathyroidism type 1a with congenital hypothyroidism. J Pediatr Endocrinol Metab. 2006, 19 (8): 1049-1052.

    PubMed  Article  Google Scholar 

  91. Joshi R, Kapdi M: Pseudohypoparathyroidism type 1b with hypothyroidism. Indian Pediatr. 2012, 49 (8): 667-668.

    PubMed  Article  Google Scholar 

  92. Leung AM, Braverman LE: Consequences of excess iodine. Nat Rev Endocrinol. 2014, 10 (3): 136-142.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  93. Danzi S, Klein I: Amiodarone-Induced Thyroid Dysfunction. J Intensive Care Med. 2013, 2013: 2013-

    Google Scholar 

  94. Cohen-Lehman J, Dahl P, Danzi S, Klein I: Effects of amiodarone therapy on thyroid function. Nat Rev Endocrinol. 2010, 6 (1): 34-41.

    CAS  PubMed  Article  Google Scholar 

  95. Bogazzi F, Tomisti L, Bartalena L, Aghini-Lombardi F, Martino E: Amiodarone and the thyroid: a 2012 update. J Endocrinol Investig. 2012, 35 (3): 340-348.

    CAS  Google Scholar 

  96. Bogazzi F, Bartalena L, Martino E: Approach to the patient with amiodarone-induced thyrotoxicosis. J Clin Endocrinol Metab. 2010, 95 (6): 2529-2535.

    CAS  PubMed  Article  Google Scholar 

  97. Bogazzi F, Bartalena L, Gasperi M, Braverman LE, Martino E: The various effects of amiodarone on thyroid function. Thyroid. 2001, 11 (5): 511-519.

    CAS  PubMed  Article  Google Scholar 

  98. Mushtaq U, Price T, Laddipeerla N, Townsend A, Broadbridge V: Contrast induced hyperthyroidism due to iodine excess. BMJ Case Reports. 2009, doi:10.1136/bcr.06.2009.1982

    Google Scholar 

  99. Burgi H: Iodine excess. Best Pract Res Clin Endocrinol Metab. 2010, 24 (1): 107-115.

    PubMed  Article  CAS  Google Scholar 

  100. Roti E, Uberti ED: Iodine excess and hyperthyroidism. Thyroid. 2001, 11 (5): 493-500.

    CAS  PubMed  Article  Google Scholar 

  101. Leung AM, Braverman LE: Iodine-induced thyroid dysfunction. Curr Opin Endocrinol Diabetes Obes. 2012, 19 (5): 414-419.

    CAS  PubMed  Article  Google Scholar 

  102. Barbesino G: Drugs affecting thyroid function. Thyroid. 2010, 20 (7): 763-770.

    PubMed  Article  Google Scholar 

  103. Lazarus JH: Lithium and thyroid. Best Pract Res Clin Endocrinol Metab. 2009, 23 (6): 723-733.

    CAS  PubMed  Article  Google Scholar 

  104. Kibirige D, Luzinda K, Ssekitoleko R: Spectrum of lithium induced thyroid abnormalities: a current perspective. Thyroid Res. 2013, 6 (1): 3-

    PubMed Central  PubMed  Article  Google Scholar 

  105. Roberto L: Lithium clearly and directly affects the activity of the thyroid gland in human. Hum Psychopharmacol. 2010, 25 (7–8): 586-author reply 587

    PubMed  Article  Google Scholar 

  106. Huang SA, Tu HM, Harney JW, Venihaki M, Butte AJ, Kozakewich HP, Fishman SJ, Larsen PR: Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N Engl J Med. 2000, 343 (3): 185-189.

    CAS  PubMed  Article  Google Scholar 

  107. Huang SA, Fish SA, Dorfman DM, Salvatore D, Kozakewich HP, Mandel SJ, Larsen PR: A 21-year-old woman with consumptive hypothyroidism due to a vascular tumor expressing type 3 iodothyronine deiodinase. J Clin Endocrinol Metab. 2002, 87 (10): 4457-4461.

    CAS  PubMed  Article  Google Scholar 

  108. Maynard MA, Marino-Enriquez A, Fletcher JA, Dorfman DM, Raut CP, Yassa L, Guo C, Wang Y, Dorfman C, Feldman HA, Frates MC, Song H, Jugo RH, Taguchi T, Hershman JM, Larsen PR, Huang SA: Thyroid hormone inactivation in gastrointestinal stromal tumors. N Engl J Med. 2014, 370 (14): 1327-1334.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  109. Eskandari S, Loo DD, Dai G, Levy O, Wright EM, Carrasco N: Thyroid Na+/I- symporter. Mechanism, stoichiometry, and specificity. J Biol Chem. 1997, 272 (43): 27230-27238.

    CAS  PubMed  Article  Google Scholar 

  110. Leung AM, Braverman LE, He X, Schuller KE, Roussilhes A, Jahreis KA, Pearce EN: Environmental perchlorate and thiocyanate exposures and infant serum thyroid function. Thyroid. 2012, 22 (9): 938-943.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  111. Leung AM, Pearce EN, Braverman LE: Perchlorate, iodine and the thyroid. Best Pract Res Clin Endocrinol Metab. 2010, 24 (1): 133-141.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  112. Environmental Protection Agency. [http://water.epa.gov/drink/contaminants/unregulated/perchlorate.cfm]

  113. Dohan O, Portulano C, Basquin C, Reyna-Neyra A, Amzel LM, Carrasco N: The Na+/I symporter (NIS) mediates electroneutral active transport of the environmental pollutant perchlorate. Proc Natl Acad Sci U S A. 2007, 104 (51): 20250-20255.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  114. Kirk AB, Martinelango PK, Tian K, Dutta A, Smith EE, Dasgupta PK: Perchlorate and iodide in dairy and breast milk. Environ Sci Technol. 2005, 39 (7): 2011-2017.

    CAS  PubMed  Article  Google Scholar 

  115. Pearce EN, Leung AM, Blount BC, Bazrafshan HR, He X, Pino S, Valentin-Blasini L, Braverman LE: Breast milk iodine and perchlorate concentrations in lactating Boston-area women. J Clin Endocrinol Metab. 2007, 92 (5): 1673-1677.

    CAS  PubMed  Article  Google Scholar 

  116. Leung AM, Pearce EN, Hamilton T, He X, Pino S, Merewood A, Braverman LE: Colostrum iodine and perchlorate concentrations in Boston-area women: a cross-sectional study. Clin Endocrinol. 2009, 70 (2): 326-330.

    CAS  Article  Google Scholar 

  117. Braverman LE, Pearce EN, He X, Pino S, Seeley M, Beck B, Magnani B, Blount BC, Firek A: Effects of six months of daily low-dose perchlorate exposure on thyroid function in healthy volunteers. J Clin Endocrinol Metab. 2006, 91 (7): 2721-2724.

    CAS  PubMed  Article  Google Scholar 

  118. Laurberg P, Nohr SB, Pedersen KM, Fuglsang E: Iodine nutrition in breast-fed infants is impaired by maternal smoking. J Clin Endocrinol Metab. 2004, 89 (1): 181-187.

    CAS  PubMed  Article  Google Scholar 

  119. Wiersinga WM: Smoking and thyroid. Clin Endocrinol. 2013, 79 (2): 145-151.

    CAS  Article  Google Scholar 

  120. Andersen SL, Olsen J, Wu CS, Laurberg P: Smoking reduces the risk of hypothyroidism and increases the risk of hyperthyroidism: evidence from 450 842 mothers giving birth in Denmark. Clin Endocrinol. 2014, 80 (2): 307-314.

    Article  Google Scholar 

  121. Steinmaus C, Miller MD, Cushing L, Blount BC, Smith AH: Combined effects of perchlorate, thiocyanate, and iodine on thyroid function in the National Health and Nutrition Examination Survey 2007–08. Environ Res. 2013, 123: 17-24.

    CAS  PubMed  Article  Google Scholar 

  122. Gatseva PD, Argirova MD: High-nitrate levels in drinking water may be a risk factor for thyroid dysfunction in children and pregnant women living in rural Bulgarian areas. Int J Hyg Environ Health. 2008, 211 (5–6): 555-559.

    PubMed  Article  Google Scholar 

  123. Tajtakova M, Semanova Z, Tomkova Z, Szokeova E, Majoros J, Radikova Z, Sebokova E, Klimes I, Langer P: Increased thyroid volume and frequency of thyroid disorders signs in schoolchildren from nitrate polluted area. Chemosphere. 2006, 62 (4): 559-564.

    CAS  PubMed  Article  Google Scholar 

  124. Cooper DS: Antithyroid drugs. N Engl J Med. 2005, 352 (9): 905-917.

    CAS  PubMed  Article  Google Scholar 

  125. Doerge DR, Chang HC: Inactivation of thyroid peroxidase by soy isoflavones, in vitro and in vivo. J Chromatogr B Analyt Technol Biomed Life Sci. 2002, 777 (1–2): 269-279.

    CAS  PubMed  Article  Google Scholar 

  126. Fitzpatrick M: Soy formulas and the effects of isoflavones on the thyroid. N Z Med J. 2000, 113 (1103): 24-26.

    CAS  PubMed  Google Scholar 

  127. Messina M, Redmond G: Effects of soy protein and soybean isoflavones on thyroid function in healthy adults and hypothyroid patients: a review of the relevant literature. Thyroid. 2006, 16 (3): 249-258.

    CAS  PubMed  Article  Google Scholar 

  128. Merritt RJ, Jenks BH: Safety of soy-based infant formulas containing isoflavones: the clinical evidence. J Nutr. 2004, 134 (5): 1220S-1224S.

    PubMed  Google Scholar 

  129. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Schlumberger M, Sherman SI, Steward DL, Tuttle RM, American Thyroid Association Guidelines Taskforce on Thyroid N, Differentiated Thyroid C: Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009, 19 (11): 1167-1214.

    PubMed  Article  Google Scholar 

  130. Lee JH, Anzai Y: Imaging of thyroid and parathyroid glands. Semin Roentgenol. 2013, 48 (1): 87-104.

    CAS  PubMed  Article  Google Scholar 

  131. Joyce JM, Swihart A: Thyroid: nuclear medicine update. Radiol Clin North Am. 2011, 49 (3): 425-434.

    PubMed  Article  Google Scholar 

  132. Wahl RL: Thyroid Radionuclide uptake and imaging studies. Werner & Ingbar’s The Thyroid. Edited by: Braverman LE. 2013, Philadelphia: Lippincott Williams and Wilkins, 10

    Google Scholar 

  133. Takeuchi K, Suzuki H, Horiuchi Y, Mashimo K: Significance of iodide-perchlorate discharge test for detection of iodine organification defect of the thyroid. J Clin Endocrinol Metab. 1970, 31 (2): 144-146.

    CAS  PubMed  Article  Google Scholar 

  134. Khan SU, Khan AU, Khan A, Khan K, Ullah H: Thyroid dyshormonogenesis detected through a modified perchlorate discharge test using a gamma-camera. Nucl Med Commun. 2009, 30 (7): 574-576.

    PubMed  Article  Google Scholar 

  135. Leslie WD: Thyroid scintigraphy and perchlorate discharge test in the diagnosis of congenital hypothyroidism. Eur J Nucl Med. 1996, 23 (2): 230-

    CAS  PubMed  Article  Google Scholar 

  136. Reiners C, Schneider R: Potassium iodide (KI) to block the thyroid from exposure to I-131: current questions and answers to be discussed. Radiat Environ Biophys. 2013, 52 (2): 189-193.

    CAS  PubMed  Article  Google Scholar 

  137. Ho AL, Grewal RK, Leboeuf R, Sherman EJ, Pfister DG, Deandreis D, Pentlow KS, Zanzonico PB, Haque S, Gavane S, Ghossein RA, Ricarte-Filho JC, Domínguez JM, Shen R, Tuttle RM, Larson SM, Fagin JA: Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med. 2013, 368 (7): 623-632.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  138. Wapnir IL, van de Rijn M, Nowels K, Amenta PS, Walton K, Montgomery K, Greco RS, Dohan O, Carrasco N: Immunohistochemical profile of the sodium/iodide symporter in thyroid, breast, and other carcinomas using high density tissue microarrays and conventional sections. J Clin Endocrinol Metab. 2003, 88 (4): 1880-1888.

    CAS  PubMed  Article  Google Scholar 

  139. Fischer AJ, Lennemann NJ, Krishnamurthy S, Pocza P, Durairaj L, Launspach JL, Rhein BA, Wohlford-Lenane C, Lorentzen D, Banfi B, McCray PB J: Enhancement of respiratory mucosal antiviral defenses by the oxidation of iodide. Am J Respir Cell Mol Biol. 2011, 45 (4): 874-881.

    PubMed Central  CAS  PubMed  Article  Google Scholar 

  140. Spitzweg C, Dietz AB, O’Connor MK, Bergert ER, Tindall DJ, Young CY, Morris JC: In vivo sodium iodide symporter gene therapy of prostate cancer. Gene Ther. 2001, 8 (20): 1524-1531.

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

LP is grateful to Alejandro Comellas for his critical appraisal, which contributed to the final version.

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Correspondence to Liuska Pesce.

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LP made significant contributions to the conception, planning, review of literature, writing, reviewing and editing the manuscript. PK made significant contributions to reviewing content, editing and approving the final version of the manuscript. Both authors read and approved the final manuscript.

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Pesce, L., Kopp, P. Iodide transport: implications for health and disease. Int J Pediatr Endocrinol 2014, 8 (2014). https://doi.org/10.1186/1687-9856-2014-8

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Keywords

  • Iodide transport
  • Iodine
  • Thyroid
  • Thyroid hormones
  • Hypothyroidism
  • Hyperthyroidism
  • Thyroid cancer
  • Iodine deficiency
  • Radioactive iodine