International Journal of Pediatric Endocrinology volume 2014, Article number: 8 (2014) Cite this article Show
AbstractDisorders 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. IntroductionIodine, 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] Full size table Iodine intake and absorptionIodine, 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]. 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. Full size image Iodide transport in thyroid cellsAs 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 transportIodide 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.
Thyroid conditions as they relate to iodide transportThe 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 Full size table 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] Full size table Disorders of iodide transport
Disorders of abnormal iodide transport regulation
Consumptive hypothyroidismHemangiomas 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
Iodine as a tool for diagnosis and treatment of thyroid disordersThe 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] Full size table Iodine in the prevention of thyroid disorders and public healthPotassium 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 cancerPoorly 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 thyroidOutside 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]. ConclusionsIn 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 informationLP 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. AbbreviationsD1: Type 1 deiodinase D2: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 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
Download references AcknowledgementsLP is grateful to Alejandro Comellas for his critical appraisal, which contributed to the final version. Author informationAuthors and Affiliations
Authors
Corresponding authorCorrespondence to Liuska Pesce. Additional informationCompeting interestsThe authors declare that they have no competing interests. Authors’ contributionsLP 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. Authors’ original submitted files for imagesRights and permissionsThis 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. Reprints and Permissions About this articleCite this articlePesce, 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 Download citation
Keywords
How is iodide taken up by the thyroid follicular cell from the bloodstream?It is absorbed via an active transport protein on the apical surfaces of enterocytes called the sodium–iodide symporter (NIS). NIS expression is downregulated when the concentration of iodide from food increases. Once in the circulation, the thyroid gland and the kidney quickly take up the iodide.
How is iodide transported into the thyroid gland?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].
How is iodine converted to iodide in the body?Iodine from the diet is absorbed throughout the gastrointestinal tract. Dietary iodine is converted into the iodide ion before it is absorbed. The iodide ion is bio-available and absorbed totally from food and water. This is not true for iodine within thyroid hormones ingested for therapeutic purposes.
|