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International Journal of Pediatric Endocrinology

Erschienen in:

Open Access 01.12.2014 | PES Review

Iodide transport: implications for health and disease

verfasst von: Liuska Pesce, Peter Kopp

Erschienen in: International Journal of Pediatric Endocrinology | Ausgabe 1/2014

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.

Authors’ original file for figure 1

Electronic supplementary material

The online version of this article (doi:10.1186/1687-9856-2014-8) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

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.

Type 1 deiodinase

Type 2 deiodinase

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

Thyroglobulin

Triiodothyronine

Thyroxine

TPO

Thyroid peroxidase

TRH

TSH releasing hormone

TSH

Thyroid Stimulating Hormone

TSHR

TSH-receptor

WHO

World Health Organization

United States.

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]

Age or population group	Recommended daily allowance (μg)
Pre-school children (0–59 months)	90
School children (6–12 years)	120
Adolescents and adults (above 12 years)	150
Pregnant and lactating women	250

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 [2‐5].

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].

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 [9‐11]. This process also requires a constitutive active potassium channel consisting of the KCNQ1 and KCNE2 subunits promoting potassium efflux [12‐14]. 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 [15‐17]. 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 [22‐24]. 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.

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].

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) [34‐37]. 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 [38‐40].

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[41‐44].

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, 45‐47]. 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].

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

Etiology	Conditions, drugs or environmental agents affecting this step in iodide transport	Manifestations
Deficient nutritional iodine intake	Iodine deficiency disorders	All ages:
		• Goiter
		Mother/fetus:
		• Abortion
		• Stillbirth
		• Congenital anomalies
		• Perinatal mortality
		Newborn:
		• Infant mortality
		• Cretinism with neurological deficits and mental retardation
		Child and adolescent:
		• Growth retardation and delayed puberty
		Child, adolescent and adult:
		• Impaired mental function
		• Hypothyroidism
		• Increased risk to develop iodide induced-hyperthyroidism and toxic nodular goiter after exposure to iodine
Abnormal basal iodide uptake	NIS mutations (autosomal recessive)	Congenital hypothyroidism, typically with goiter. Iodide-trapping defect with little or no uptake of radioactive iodide both at the thyroid and salivary gland level
	Perchlorate, thiocyanate and nitrates	Increased risk of goiter development and hypothyroidism, specially in iodine deficient populations
	Goitrogens (soy and other flavonoids, glucosinolates and cyanogenic glucosides)	Increased risk of goiter development and hypothyroidism in iodine deficient populations
Apical iodide efflux	Pendred syndrome. Mutations in the SLC26A4 gene (autosomal recessive)	Sensorineural hearing loss, variable phenotype of goiter and hypothyroidism and partial organification defect
Apical iodide efflux	Congenital hypothyroidism with atrophic thyroid gland associated with SLC26A4 mutations (autosomal recessive)	Congenital hypothyroidism
Organification and coupling	Tg gene mutations (autosomal recessive)	Congenital hypothyroidism and/or variable degrees of goiter and hypothyroidism with low Tg levels
	TPO gene mutations (autosomal recessive)	Congenital hypothyroidism and/or variable degrees of goiter and hypothyroidism with partial or total organification defects
	Mutations in DUOX2 or DUOXA2 (autosomal recessive or dominant)	Transient or permanent congenital hypothyroidism
	Anti-thyroid medications (i.e. PTU, methimazole, carbimazole)	Medication-induced hypothyroidism
Recycling of iodide	Mutations in DEHAL1 (autosomal recessive)	Congenital hypothyroidism, goiter, increased MIT and DIT serum levels and severe urinary loss of MIT and DIT
Thyroid hormone degradation exceeds thyroid synthetic capacity	Overexpression of D3 in hemangiomas and gastrointestinal stromal tumors	Consumptive hypothyroidism with elevated rT3 and resistance to treatment with physiological doses of levothyroxine
Increased stimulation or constitutive activity of the TSHR or downstream pathways	TSHR stimulating immunoglobulins	Graves’ disease
	Transient congenital hyperthyroidism
	TSHR activating mutations	Sporadic congenital or autosomal dominant familial non-autoimmune hyperthyroidism (germline mutations)
	Toxic adenomas (somatic mutations)
	Pregnancy	hCG-induced gestational hyperthyroidism
	Somatic, activating mutations of G_sα	Toxic nodular hyperthyroidism and hyperthyroidism in McCune Albright syndrome
Decreased stimulation or inactivation of the TSHR or downstream pathways	Presence of TSHR blocking immunoglobulins	Hypothyroidism
	Inactivating mutations of the TSHR (autosomal recessive)	Resistance to TSH with overt or compensated hypothyroidism
	Inactivating G_sα mutations	Hypothyroidism in the context of pseudohypoparathyroidism type Ia
Iodide mediated alterations in thyroid function	Iodine containing solutions	Transient hypothyroidism (Wolff-Chaikoff effect)
		In iodine deficiency: Hyperthyroidism (Jod-Basedow)
	Iodine containing contrast agents (iodine containing IV contrasts)	Transient hypothyroidism (Wolff-Chaikoff effect)
		In iodine deficiency: Hyperthyroidism (Jod-Basedow)
	Amiodarone	Amiodarone induced thyrotoxicosis (AIT): type 1: iodine inducedthyrotoxicosis, Jod-Basedow type 2: thyroiditis
		Amiodarone induced hypothyroidism (AMH); often associated with underlying autoimmune thyroid disease
Other defects in thyroid hormone release	Lithium	Hypothyroidism due to decrease release of T4

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, 51‐58]. Importantly, pregnant women need higher amounts of iodide (Table 1). Even mild iodine deficiency during pregnancy may affect outcomes [54, 59‐61]. 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]

Population	Median urinary iodine (μg/L)	Iodine intake
School age children (older than 6 years old)	<20	Insufficient (severe)
	20-49	Insufficient (moderate)
	50-99	Insufficient (mild)
	100-199	Adequate
	200-299	Above requirement
	<300	Excessive
Pregnant and lactating women	<150	Insufficient
	150-249	Adequate
	250-499	Above requirements
	<500	Excessive

Disorders of iodide transport

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].

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].

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, 76‐78]. 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].

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

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_sα 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].

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) [93‐97]. The Jod-Basedow effect can be caused by any form of iodine excess such as contrast agents or iodine-containing solutions [98‐101]. 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 [102‐104]. Other effects of amiodarone and lithium are reviewed elsewhere [93‐96, 102‐105].

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_sα cause mild hypothyroidism, such as seen in pseudohypoparathyroidism [89‐91].

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 [106‐108]. 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

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].

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].

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 [125‐128].

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) [130‐132]. 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, 133‐135].

Table 4

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

Radionuclide	Radioactive emissions (keV*)	Half-life	Clinical use
¹²³ I	γ 159 keV	13.2 hours	Thyroid and whole body scanning
¹³¹ I	γ 364 keV	8.09 days	Thyroid and whole body scanning
¹³¹ I	β 637 keV	8.09 days	Treatment of Graves’ disease, toxic adenomas, thyroid cancer
¹²⁴ I	β⁺ (positron emitter) γ 603 keV	4.2 days	Whole body scanning Dosimetry
^99m T _c O ₄	γ 140 keV	6 hours	Thyroid scanning

*keV = kiloelectron volt (1.60217657 × 10⁻¹⁶ joules)

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.

Acknowledgements

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

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

Authors’ original submitted files for images

Below are the links to the authors’ original submitted files for images.

Authors’ original file for figure 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]

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

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

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

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

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

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.PubMedCentralPubMedCrossRef

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.PubMedCentralPubMedCrossRef

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

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.PubMedCrossRef

11.

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

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.PubMedCentralPubMedCrossRef

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.PubMedCentralPubMedCrossRef

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.PubMedCentralPubMedCrossRef

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.PubMedCrossRef

16.

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

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.PubMedCrossRef

18.

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

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.PubMedCrossRef

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.PubMedCrossRef

21.

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

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.

23.

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

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.PubMed

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.CrossRef

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.PubMedCentralPubMedCrossRef

27.

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

28.

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

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCentralPubMedCrossRef

32.

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

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.CrossRef

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.CrossRef

35.

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

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. illustCrossRef

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.PubMedCrossRef

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.

39.

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

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.PubMedCrossRef

41.

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

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.PubMedCentralPubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

50.

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

51.

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

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.PubMedCrossRef

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.PubMedCrossRef

54.

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

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.PubMedCrossRef

56.

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

57.

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

58.

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

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCentralPubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

67.

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

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.PubMedCrossRef

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.PubMedCentralPubMedCrossRef

70.

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

71.

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

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.PubMedCrossRef

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.PubMedCentralPubMedCrossRef

74.

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

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.PubMedCrossRef

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.PubMedCentralPubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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

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.PubMedCrossRef

83.

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

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

88.

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

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.PubMedCrossRef

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.PubMedCrossRef

91.

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

92.

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

93.

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

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.PubMedCrossRef

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.

96.

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

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.PubMedCrossRef

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

99.

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

100.

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

101.

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

102.

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

103.

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

104.

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

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 587PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCentralPubMedCrossRef

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.PubMedCrossRef

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.PubMedCentralPubMedCrossRef

111.

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

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.PubMedCentralPubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.CrossRef

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.PubMedCrossRef

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.PubMedCrossRef

119.

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

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.CrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

124.

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

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.PubMedCrossRef

126.

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

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.PubMedCrossRef

128.

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

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.PubMedCrossRef

130.

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

131.

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

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

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.PubMedCrossRef

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.PubMedCrossRef

135.

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

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.PubMedCrossRef

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.PubMedCentralPubMedCrossRef

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.PubMedCrossRef

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.PubMedCentralPubMedCrossRef

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.PubMedCrossRef

Titel: Iodide transport: implications for health and disease
verfasst von: Liuska Pesce
Peter Kopp
Publikationsdatum: 01.12.2014
Verlag: BioMed Central
Erschienen in: International Journal of Pediatric Endocrinology / Ausgabe 1/2014
Elektronische ISSN: 1687-9856
DOI: https://doi.org/10.1186/1687-9856-2014-8

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Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Iodide transport: implications for health and disease

Abstract

Electronic supplementary material

Competing interests

Authors’ contributions

Introduction

Iodine intake and absorption

Iodide transport in thyroid cells

Regulation of iodide transport

Thyroid conditions as they relate to iodide transport

Disorders of iodine intake (DII)

Disorders of iodide transport

Disorders of abnormal iodide transport regulation

Consumptive hypothyroidism

Drugs, diet and environmental agents affecting iodide transport and metabolism

Iodine as a tool for diagnosis and treatment of thyroid disorders

Iodine in the prevention of thyroid disorders and public health

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

Applications of iodide transport outside the thyroid

Conclusions

Author’s information

Acknowledgements

Competing interests

Authors’ contributions

Authors’ original submitted files for images

Neu im Fachgebiet Pädiatrie

Mit dem Seitenschneider gegen das Reißverschluss-Malheur

Ähnliche Überlebensraten nach Reanimation während des Transports bzw. vor Ort

Alter der Mutter beeinflusst Risiko für kongenitale Anomalie

Begünstigt Bettruhe der Mutter doch das fetale Wachstum?

Update Pädiatrie

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

Abstract

Electronic supplementary material

Competing interests

Authors’ contributions

Introduction

Iodine intake and absorption

Iodide transport in thyroid cells

Regulation of iodide transport

Thyroid conditions as they relate to iodide transport

Disorders of iodine intake (DII)

Disorders of iodide transport

Disorders of abnormal iodide transport regulation

Consumptive hypothyroidism

Drugs, diet and environmental agents affecting iodide transport and metabolism

Iodine as a tool for diagnosis and treatment of thyroid disorders

Iodine in the prevention of thyroid disorders and public health

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

Applications of iodide transport outside the thyroid

Conclusions

Author’s information

Acknowledgements

Competing interests

Authors’ contributions

Authors’ original submitted files for images

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