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Selenium and Iodine in Autoimmune Thyroiditis Edoardo Guastamacchia*, Vito Angelo Giagulli, Brunella Licchelli and Vincenzo Triggiani Endocrinology and Metabolic Diseases, Interdisciplinary Department of Medicine, University of Bari “A. Moro”, Bari, Italy Abstract: Selenium and iodine are essential for thyroid hormone synthesis and function. Selenium, in form of selenocysteine, is found either in the catalytic center of enzymes involved in the protection of the thyroid gland from free radicals originating during thyroid hormone synthesis, and in three different iodothyronine deiodinases catalyzing the activation and the inactivation of thyroid hormones. Iodine is an essential constituent of thyroid hormones and its deficiency causes different disorders that include goiter, hypothyroidism, reduced fertility and alteration in growth, physical and E. Guastamacchia neurological development. These two micronutrients could be involved in the pathogenesis of autoimmune thyroid diseases, a spectrum of pathological conditions including Hashimoto’s thryoiditis, post-partum thyroiditis, the so-called painless thyroiditis, Graves’ disease and Graves’ ophtalmopathy. Aim of this paper is to review the role played by selenium and iodine in autoimmune thyroiditis.
Keywords: Autoimmune thyroid disorders, autoimmune thyroiditis, iodine intake, selenium intake, selenoproteins. INTRODUCTION The thyroid gland is highly vulnerable to autoimmune disorders. The incidence of chronic autoimmune thyroiditis and Graves’ disease has dramatically increased over the last few decades, afflicting up to 5% of the general population. In particular, chronic autoimmune thyroiditis represents the most common cause of acquired hypothyroidism in children living in non-endemic goiter areas [1]. Selenium and iodine can be involved in the pathogenesis of autoimmune thyroid diseases (AITDs), a spectrum of pathological entities including not only Hashimoto’s thyroiditis and Graves’ disease, but also post-partum thyroiditis, painless thyroiditis, and Graves’ ophtalmopathy. Aim of this paper is to briefly review the role played by these two micronutrients in these diseases. AUTOIMMUNE THYROIDITIS Hashimoto’s thyroiditis, the most common form of AITDs, is characterized by lymphocytic infiltration of the thyroid, progressive destruction of the gland and production of thyroid-specific auto-antibodies [2]. Autoimmune thyroid disorders result from a complex interplay of genetic, endogenous, and environmental factors. In particular, a combination of these factors is required to initiate thyroid autoimmunity [3, 4]. Genetic factors can account for approximately 80% of the likelihood of developing AITDs [5, 6]. At least six AITD susceptibility genes are involved: the immunomodulatory gene products HLA-DR, CD40, cytotoxic T lymphocyte-associated factor (CTLA-4), and protein tyrosine phosphatase 22 (PTPN22), and the thyroid-specific gene products thyroglobulin (Tg) *Address correspondence to this author at the Endocrinology and Metabolic Diseases, Interdisciplinary Department of Medicine, University of Bari “A. Moro”, Bari, Italy; Tel/Fax: 0039805478819; E-mail
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and thyroid-stimulating hormone receptor (TSHR). Among the endogenous factors, the main involved are female sex, puberty, rapid growth, pregnancy, menopause, aging, emotional vulnerability. Environmental factors such as pollution, stress, drugs and infections can play a role in determining the development of AITDs, and the same is true for two micronutrients involved in thyroid hormones syntesis, function and metabolism: selenium and iodine. The possible mechanism leading to the development of Hashimoto’s thyroiditis can be summarized as follows [7, 8]. Genetically predisposed subjects could be negatively influenced by enviromental factors (bacterial and viral infections [9, 10], pregnancy [11], cytokine therapy [12], excess of iodine [13], etc) that can act as triggers inducing a breakdown of immune tolerance leading to an autoimmune response against thyroid-specific antigens. A large number of autoreactive T helper and cytotoxic T lymphocites and autoantibodies-producing B lymphocites infiltrate the gland. The prevailing autoimmune response is TH1-mediated and the cytotoxic effect as well as the induction of apoptosis of thyreocytes lead to an impairment of thyroid function and consequent hypothyroidism [7]. SELENIUM Selenium in form of selenocysteine is found either in the catalytic center of enzymes involved in the protection of the thyroid cells from free radicals (hydrogen peroxide) originating during thyroid hormone synthesis, the glutathione peroxidase and the phospholipid hydroperoxide glutathione peroxidase, and in three different iodothyronine deiodinases (DIOs type I, II and III) catalyzing the activation and the inactivation of thyroid hormones [14] (Table 1). Selenium content varies in different foods. The richest food sources are represented by organ meats and seafood, whereas selenium vegetal content depends on its presence in the soil [15]. Selenium supplements are available either as seleniomethionine and in inorganic forms as sodium selenate © 2015 Bentham Science Publishers
Selenium and Iodine in Autoimmune Thyroiditis
Table 1.
Endocrine, Metabolic & Immune Disorders - Drug Targets, 2015, Vol. 15, No. 4
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Selenoproteins and their functions in protecting thyrocytes from oxidative stress and in thyroid hormones metabolism and function. Selenoproteins
Function
Cytosolic Glutathione Peroxidase
Protection from oxidative stress (reduction of hydrogen peroxide)
Extracellular Glutathione Peroxidase
Antinflammatory role
Phospholipid Glutathione Peroxidase
Reduces Phosholipid hydroperoxides
Cytosolic Thioredoxin Reductase
Regulates redox level, development and proliferation of cells
Mitochondrial Thioredoxin Reductase
Regulates cell proliferation
Type I Iodothyronine Deiodinase
Catalyzes the conversion of T4 to T3 (systemic)
Type II Iodothyronine Deiodinase
Catalyzes the conversion of T4 to T3 (intracellular)
Type III Iodothyronine Deiodinase
Catalyzes the conversion of T4 to rT3
Selenoprotein P
Antioxidant; involved in Se transport
Selenoprotein N
Catalyzes the reduction of hydrogen peroxide
or selenite [16]. There is a high diversity in selenium status of different human populations worldwide. The mean daily intake is about 40 mcg in Europe and 93 mcg and 134 mcg respectively for women and men in the US. The daily dose recommendations vary in different countries: 55 mcg/day in the US and in Italy, 75 in men and respectively 60 mcg/day in women in the UK. Selenium administration does not cause changes in free or total T4 and T3 levels. Plasma selenium concentrations are in general comprised in the range 60-120 mcg/l. Human thyroid contains the highest selenium concentrations per unit weight among all tissues [17, 18]. Nonetheless, endogenous pathways ensure that the thyroid gland and thyroid selenoproteins are exceptionally well supplied with selenium and largely resistant to selenium deficiency [19].
different dietary habits in different areas and also in the same regions [14]. Processed foods may contain higher levels of iodine as a consequence of the addition of iodized salt or iodine-containing additives, while iodization of salt is the main way to accomplish iodine prophylaxis and prevent iodine deficiency disorders [14]. Urinary iodine excretion gives a measure of daily iodine intake: from less than 10 mcg in areas of extreme iodine deficiency to several hundred milligrams in patients treated with iodine-containing drugs such as amiodarone. The recommended intake for iodine is 150 mcg/day for adults, 70-120 mcg for children and at least 200-250 mcg for pregnant or lactating women [14, 23]. Iodine excess in the diet can cause both hyperthyroidism (Jod-Basedow) and hypothyroidism (iodide mixedema). In particular, hypothyroidism occurs because of a failure to escape from the Wolff-Chaikoff block following an iodine overload that can take place in individuals with a preexisting thyroid autoimmunity, often unrecognized or subclinical. Of course, iodine could play a direct role also in inducing de novo thyroid autoimmunity [8].
People whose serum or plasma selenium concentration is already 122 mcg/L or higher should not be supplemented with selenium, while people with selenium concentration less than 122 mcg/L may have benefits from rising their selenium status [15].
SELENIUM, IODINE AND AITDs
Recently, Selenium has been extensively reviewed by Duntas and Benvenga [20].
High iodine and low selenium intake may influence thyroid autoimmunity [1].
IODINE Iodine is an essential constituent of thyroid hormones and its deficiency causes a wide spectrum of disorders that include goiter, hypothyroidism, reduced fertility and alteration in growth, physical and neurological development, involving more than one billion people in the world [14]. Iodine is quite rare in nature. In particular, the soil of the oldest mountainous regions and the flood river valleys is very poor in iodine content [21]. In these iodine deficient regions, vegetables and animal tissues are low in iodine content and humans are exposed to iodine deficiency if the diet is based only upon food coming from these areas [22]. The intake of iodine varies widely also as a consequence of
The so-called “accelerator hypothesis [24] may be applied to AITDs pathogenesis. In a context of genetic predisposition, different factors such as obesity, rapid growth, pollutants, infections as well as high iodine intake and low selenium in the diet could act as accelerators, determining a condition of metabolic stress in thyroid cells. This thyrotoxicity may promote autoimmunity. The role of dietary iodine has been established in animal models of AITDs and some evidence also exists for humans [25-27]. In experimental conditions, excessive iodine intake can precipitate spontaneous thyroiditis in genetically predisposed strains of beagles, rats or chickens [28].
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Potential mechanisms involved thyroiditis in animal models include:
in
iodine-induced
1) triggering of thyroid autoimmune reactivity by increasing the immunogenicity of thyroglobulin; and/or 2) damage to the thyroid and cell injury by free radicals. Iodine may stimulate thyroid follicular cells to produce chemokines such as CCL2, CXCL8, and CXCL14 [29]. Iodine at high concentrations, therefore, could induce AITDs by means of chemokine upregulation, attracting lymphocytes into the thyroid gland. Furthermore, a high iodine intake increases the iodine content of the thyroglobulin molecule, possibly increasing its immunogenicity [30]. Iodine, however, rather than inducing de novo thyroid autoimmunity can impair thyroid function in individuals with a pre-existing thyroid autoimmunity. Autoimmune thyroiditis, in fact, is much frequent in iodine deficient areas after the introduction of iodine prophylaxis [31]. Iodine intake per se, therefore, could be a factor enhancing ongoing autoimmune responses more than a trigger of thyroid autoimmunity. Aggravation or induction of autoimmune thyroiditis can therefore be due to iodine supplementation. An increased frequency of Hashimoto’s thyroiditis following the introduction/implementation of salt iodization has been showed [32-34]. Acute massive iodine overload (50 mg daily) in healthy adults resulted in a sharp increase in thyroid peroxidase antibody titers and elevated prevalence of goiter and serum TSH values. The prevalence of all abnormalities decreased after removal of iodine excess [35]. Exposure to excess iodine ingestion, therefore, can induce thyroid autoimmunity in healthy people with otherwise normal thyroid glands. The frequency of thyroid autoantibodies and hypothyroidism is higher in iodine sufficient populations than in iodine deficient ones. It is also recognized that the frequency of thyroid antibodies and autoimmune thyroiditis is higher in the US than in Europe, where the iodine intake is lower [36]. In case of a very high iodine intake, such as in patients treating with amiodarone, there could be the onset of hyperthyroidism either due to a pre-existent autonomously functioning areas or due to a direct toxic effect by the iodine, determining a destructive process [37, 38]. Amiodaroneinduced hypothyroidism due to the above mentioned mechanisms is even more frequent as reported by many studies, including some published by our group [39, 40]. Two hypothesis could explain how selenium deficiency can impair thyroid function: 1) in selenium deficiency, sensitive target cells could become insufficiently supplied to allow adequate DIOs expression for local thyroid hormone activation and inactivation; 2) selenium deficiency is likely to constitute a risk factor for a derangement of the immune system-thyroid interaction. Selenium deficiency, in fact, is accompanied by loss of immunocompetence with impairment of humoral and cell-mediated immunity. Selenium supplementation has
Guastamacchia et al.
immunostimulating effects: the expression of IL-2 receptor is upregulated. There is an increase of natural killer cell activity and a proliferation of activated T cells. Immune cells have an important functional need for selenium: activated T cells show upregulated selenophosphatase activity and increased synthesis of selenocysteine. Furthermore, mRNAs of several T cell-associated genes encode functional selenoproteins. Se deficiency can also interact with virus infection. Viral infections, in fact, have been considered to be possible etiological factors in autoimmune diseases, and also in AITDs, by different mechanisms: cell destruction with antigens delivery, altered antigens formation, molecular mimicry, non-specific secretion of IL-2, DR expression or CD8+ T cell responses to viral antigens expressed onto the cell surface. Human T lymphotrophic virus-1, for example, has been associated with autoimmune disorders, including Hashimoto’s thyroiditis [41]. Furthermore, Se deficiency leading to oxidative stress in the host can alter a viral genome such that a normally benign or mildly pathogenic virus becomes highly virulent in a Se-deficient, oxidatively stressed host [42]. This was demonstrated for Se-deficient mice infected with a mild strain of influenza virus: they developed much more severe lung pathology compared with Se-adequate mice. Immune function, in fact, was altered in the Se-deficient mice, and the viral genome changed to a more virulent genotype. However, no clear evidence of virus-induced autoimmune thyroiditis has been demonstrated in humans. Se deficiency decreasing the activity of selenoproteins, including glutathione peroxidases, can lead to increased concentrations of hydrogen peroxide promoting inflammation and disease. Serum selenium has been showed to be low in newly diagnosed Graves’ Disease compared with random controls and this observation supports a link between inadequate selenium supply and overt AITDs, especially Graves’ Disease [43]. It is not clear whether these low selenium serum levels are due to an increased need related to an increased request of thyroid selenium enzymes in response to an increased production of hydrogen peroxide for thyroid hormone synthesis or selenium deficiency can play a direct role in thyroid growth and function as for TSH receptors antibodies or growth factors [44]. In Graves’ disease, selenium supplementation (6 months) is associated with reduced eye involvement, slower progression of orbitophathy, and related improvement in quality of life [45]. In a study by Wimmer et al., slightly lower selenium levels were found in patients with autoimmune thyroiditis than in normal persons, but this trend was statistically insignificant [46]. There are some trials which demonstrated the effectiveness of selenium supplementation in reducing TPOAb titers in subjects with AITDs [47-53]. Three out of these studies [47, 53] showed also an improvement of echo pattern in selenium supplemented patients. Other studies, however, failed to demonstrate an effect of selenium in reducing TPOAb in AITDs patients [54-58]. Moreover, the results of the Cochrane review about “Selenium
Selenium and Iodine in Autoimmune Thyroiditis
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supplementation for Hashimoto’s thyroiditis” demonstrate that at the moment the objective evidence is insufficient to support clinical decision making regarding the use of selenium supplementation for the treatment of patients with Hashimoto’s thyroiditis [59].
[5]
The CATALYST trial, an investigator-initiated randomized, blinded, multicentre clinical trial of selenium supplementation versus placebo in patients with chronic autoimmune thyroiditis will probably give the answer to the question whether Se administration can be of benefit in these patients [60].
[7]
[6]
[8] [9] [10]
CONCLUSION An augmented iodine intake could impair thyroid function in patients with latent thyroid autoimmunity and could be possibly involved in the onset of de novo thyroid autoimmunity. However, the increased number of cases of autoimmune thyroiditis as well as of hyperthyroidism registered in the general population after the introduction of iodine prophylaxis is outweighed by the benefits in terms of reduction of iodine-deficiency disorders in those iodine insufficient areas [61, 62]. Even though selenium is likely to exert multiple effects on human health, data from clinical studies are still controversial. In fact, some studies showed that selenium supplementation (80 µg or 200 µg per day) decreases the TPOAb titers in chronic autoimmune thyroiditis, whereas other studies found no improvement. Selenium supplementation, therefore, can be taken into consideration particularly in case of AITDs with high TPOAb titers and subclinical hypothyroidism, in case of severe thyroid autoimmune inflammation, in pregnant patients with positive TPOAb, and either in Graves’ disease without ophtalmopaty and in mild Graves’ orbitopathy, even if the evidence are in many cases not conclusive. Further researches are needed to clarify all the possible benefits of its supplementation and the trials should take into account not only the selenium status but also an accurate genotyping of participants as polymorphisms in selenoproteins could affect selenium status itself.
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CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest.
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ACKNOWLEDGEMENTS
[24]
Declared none. [25]
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Received: 13 March, 2015
Accepted: 17 June, 2015
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