Iodine deficiency disorders are still prevailing in many regions of the world including developed countries with affluent health systems [1▪▪,2–4]. Although WHO and the Iodine Global Network have been very successful in increasing public and political awareness of the deleterious impact of inadequate iodine intake for fetal and postnatal brain development and intelligence quotient, iodine deficiency disorders have not been eradicated yet. Evidence suggests that even with adequate iodine intake, thyroid development and function might be impaired by concomitant deficiencies of several other essential trace elements required for synthesis, secretion, metabolism and action of thyroid hormone. Apart from iodine, selenium, iron, zinc, copper and calcium are involved in control of this hormone network, and especially selenium and iron are limiting nutritional factors as shown by epidemiology and intervention studies in benign thyroid diseases [5–13,14▪,15,16]. Thyroid diseases have high prevalence and represent a significant cost factor and burden for health and economic systems as they require regular diagnostic tests, therapy or medical monitoring and intervention [18–21]. As L-thyroxine still ranks among the top 10 drugs prescribed by physicians in many countries mainly for patients with autoimmune thyroiditis and after thyroidectomy [17,20,21], a higher awareness of crucial interactions between nutritional, environmental and genetic components affecting and regulating thyroid hormone function is mandatory and systematic screening of thyroid function in pregnant women is discussed [22▪]. Both excess and deficiencies of these trace elements impair thyroid function and significant additive or antagonistic interactions have been described, indicating the need in obtaining an adequate balance achieved by either nutritional intake or additional supplementation. Adequate or elevated supply of one trace element (e.g. iodine) might unmask underlying deficiencies in the nutritional supply of others (e.g. selenium or iron), thus leading to impaired thyroid function or even tissue damage [7–13,14▪,15,16]. On the contrary, altered macronutrient intake and changing eating habits accompanying economic development in many rural societies might require additional trace element supplementation to ensure increased thyroid hormone production associated with higher food and calorie intake. Studies in developing countries have shown that iron, essential for efficient iodine utilization and thyroid hormone synthesis, might be nutritionally deficient in many parts of the world and thus impair thyroid hormone synthesis, storage and secretion even if iodine supply is adequate [12,13,14▪]. Similar interactions are known between selenium and iodine, as excess selenium intake is known to aggravate consequences of iodine deficiency in endemic regions, whereas adequate selenium supply attenuates adverse effects of iodine excess on the thyroid gland, preventing inflammation, fibrosis and destruction in animal models [5–10,23–25]. Such observations in sophisticated experimental animal models as well as interventional studies in regions of endemic imbalance of trace element supply or genetically susceptible risk groups or populations provide strong evidence for the need to carefully consider, monitor and – if necessary – intervene in these relevant interactions between nutritive, environmental and hormonal factors in maintenance and regulation of thyroid function and thyroid hormone action on development, growth, metabolism and homeostasis.
Pharmacological or nutritional exposure to iodine excess has been connected with manifestation of some thyroid diseases or altered disease patterns such as transiently increased incidence of autoimmune thyroid disease [26▪▪,27], autonomous thyroid nodules and papillary thyroid carcinoma , whereas the incidence of the more problematic variant of follicular thyroid cancer is decreasing similar to goiter incidence and volume and impaired brain development. The molecular basis of decreased ratio of follicular/papillary thyroid cancer with unaltered total incidence is not clear. Enhanced iodine supply, possibly in context with inadequate intake of the other protecting trace elements selenium and iron, may unmask autonomy of thyroid nodules and various pre-existing thyroid diseases, which then manifest as structural changes, somatic mutations and dysfunction of thyroidal tissue stressed under the preceding pressure of long-standing iodine deficiency, elevated thyroid-stimulating hormone (TSH) and enhanced H2O2 formation. Generally, the benefits of adequate iodine intake by far outweigh side-effects of iodine excess, which may cause problems if administered at those high gram doses contained in various medical products and drugs (iodinated X-ray contrast agents, amiodarone etc.) . Monitoring of iodine deficiency is still required and includes determination of increased thyroid volume by ultrasound, decreased urinary iodine excretion normalized to creatinine clearance, or analysis of serum thyroglobulin concentration, which is increased in iodine deficiency .
SELENIUM AND SELENOPROTEINS AS RELEVANT CONSTITUENTS OF FUNCTIONAL THYROID TISSUE
The thyroid gland in humans and several species is unique as the tissue with the highest selenium content per tissue unit  retaining selenium and expressing selenoproteins even under conditions of severe deficiency similar to testis, brain and several other endocrine organs [7,31,32▪,33▪▪,34]. Although some other tissues also accumulate significant selenium concentrations with increasing age because of deposition of insoluble cadmium, mercury and lead selenides (e.g. kidney and pituitary) [7,35], the majority of thyroid selenium is contained in functional selenoproteins of thyrocytes [31,36–38]. These observations revealed another level of complexity in the tissue-specific supply of selenium compounds under conditions of inadequate intake, the so-called tissue hierarchy of selenium supply.
The cellular uptake of various selenium compounds is not fully understood. Although selenite and selenate are transported via sulfate/sulfite sodium-dependent transport systems, the uptake of mixed selenosulfides, such as selenium-glutathione conjugates, is unclear [38,39]. One major cellular uptake mechanism for selenium involves selenoprotein P, a selenoprotein secreted by the liver and circulating in blood, wherein it constitutes up to 70% of selenium content. Selenoprotein P contains up to 10 selenocysteine residues in humans and acts as selenium delivery and storage protein [40–42]. Apolipoprotein E2 (ApoE2) receptor and/or megalin receptor-mediated selenoprotein P uptake has been described for several tissues such as testis and kidney but not for thyrocytes [33▪▪,41–45]. Surprisingly, knockout of selenoprotein P, which impairs selenium status of several tissues such as kidney, testis and others , does not affect selenium content and selenoprotein function in the thyroid gland. Thyroidal selenium uptake appears to be independent of selenoprotein P-mediated selenium supply, and thus resembles to some extent the brain, which is independent of hepatic selenoprotein P supply, and influenced more by a local independent and/or backup selenoprotein P synthesis and transport system [46,47]. Maternal–fetal selenium transfer across placenta also involves the selenoprotein P–ApoE2 receptor pathway .
Expression of most known selenoproteins has been demonstrated in the thyroid gland of several species at the transcript, the protein or functional levels [31,36–38]. Surprisingly then, genetic inactivation of selenoprotein biosynthesis by inactivation of tRNA[(Ser)]Sec selectively in thyrocytes revealed only a very minor phenotype with respect to thyroid cell biology and function . This genetic inactivation led to the lack of expression of all selenoproteins, such as glutathione peroxidases (GPxs), thioredoxin reductases and deiodinases in thyrocytes. However, absence of these selenoproteins did not impair the organization of the thyroid gland, its essential angiofollicular unit, or colloid deposition. Although expression of selenoproteins could not be demonstrated in thyrocytes, no major morphological changes associated with documented enhanced reactive oxygen species (ROS), oxidative stress, structural damage, nor significant invasion of immune cells were observed. Even a strong goitrogenic challenge in these animals on low iodine intake by administration of perchlorate and antithyroid drugs did not lead to the expected worsening of the phenotype; only minor structural changes, slightly elevated TSH and normal serum thyroid hormone levels were observed in older animals .
This outcome of gene inactivation in transgenic mice was unexpected and is inconsistent with several studies that had demonstrated protective and preventive effects of adequate selenium supply on thyroid function in animal models and humans, in which adequate selenium intake has been demonstrated to improve structural and functional integrity of the angiofollicular functional unit and the structure of the thyroid gland [5–7,25,38]. Therefore, several questions remain to be addressed in future studies. Do (mouse) thyrocytes express a further backup system independent from the first-line antioxidative defense system provided by GPx and thioredoxin reductase selenoproteins to cope with iodine deficiency, TSH or TRAK stimulation or oxidative stress? Are beneficial effects of selenium compounds observed in goiter prevention, improvement in autoimmune thyroid disease or prevention of thyroid cancer in humans and experimental animal models mediated by endothelial cells or cells of the immune system? Are there species differences in expression, function and regulation of selenoproteins in thyrocytes?
SELENIUM BIOLOGY AND SELENOPROTEIN BIOSYNTHESIS
The biological impact of a rare genetic defect in selenoprotein biosynthesis presents as altered thyroid hormone status and developmental impairments related to deficient thyroid hormone synthesis and action [38,49▪,50–53] accompanied by further clinical signs of tissue-specific impairment of selected selenoproteins [50–53]. Thus, it was a surprising discovery that compromised function of selenocysteine insertion sequence-binding protein 2 (SBP2), essential for cotranslational incorporation of selenocysteine into selenoproteins, was initially identified by elevated T4 and TSH but low T3 levels [49▪,50–53]. In these rare cases, increased selenium intake only partially rescued the impaired synthesis of selenoproteins, as documented in a Saudi Arabian family . Depending on the severity of impaired SBP2 function, the phenotype appears to be variable, and transgenic mouse models supported the interpretation of SBP2 as a limiting factor in the biosynthesis of several selenoproteins and impaired thyroid hormone activation and function [38,55,56].
Apart from their thyroid hormone-related phenotype, these patients may present with sensorineural hearing loss, impaired bone development and maturation, aspects of myopathy also found in patients with mutations in the selenoprotein N gene (SEPN) , various signs of impaired brain development and motor function, ultraviolet-sensitive skin, altered immune function and a remarkable redistribution of white body adipose tissue from the visceral compartment to subcutaneous fat, resulting in high insulin sensitivity [49▪,50–53]. Several of these clinical aspects are probably not directly related to altered thyroid function but to impaired tissue-specific expression of other selenoproteins. In one case, growth retardation was responsive to growth hormone (GH) treatment, which also decreased serum TSH but did not normalize serum free T4 and free T3 concentrations , suggesting persistently impaired hepatic deiodinase 1 activity, which typically responds to GH in adolescent and adult GH-deficient patients with normal selenium homeostasis [58–60].
Cell culture experiments and experimental transgenic animal models in which selenium status can be manipulated to an extent incompatible with long-term survival of the mice or humans have revealed important insight into tissue-specific expression and function of selenoproteins, including the three deiodinase enzymes [7,31,45,56]. Remarkably, a pronounced tissue-specific, development-associated and disease-dependent deiodinase expression pattern has been described. These experiments have indicated that among several selenoproteins expressed in tissues and cells, deiodinases rank rather high in availability of limiting amounts of selenium required for their biosynthesis and function [7,38]. In several tissues, more abundant selenoproteins such as GPx1 and other selenoproteins might even provide sufficient selenium locally liberated during their proteosomal or lysosomal turnover, thus enabling cellular deiodinases and other highly essential selenoproteins such as thioredoxin reductases and GPx4 to be synthesized and remain functional, whereas other selenoproteins’ expression is decreased or severely impaired [7,38,33▪▪,61].
THYROID HORMONE DEIODINASES ARE SELENOPROTEINS
All three deiodinases, the key enzymes catalyzing thyroid hormone activation to the thyromimetically active T3 as well as inactivation of T3 and its prohormone T4, were identified as selenocysteine-containing proteins [7,62–64]. Also GPxs, highly expressed in the thyroid gland, are selenoproteins involved in degradation of H2O2 and lipid peroxides together with the thioredoxin reductase selenoprotein family [7,38].
Deiodinases and the other selenoproteins encoded by 25 genes in humans contain essential selenocysteine residues in their active site. Thus, initial cell culture and animal experimental studies indicated that adequate nutritional selenium supply appears to limit expression of functional deiodinases during development and in the adult organism [7,47,65–67]. However, the deiodinative turnover of thyroid hormones requires only minimal amounts of active enzymes, in contrast to enzymatic pathways acting on abundant metabolic intermediates (e.g. carbohydrate, fatty acid, amino acid or proteins). This might be one of the reasons why inadequate intake of the essential trace element selenium does not initially manifest as impaired deiodinase activity, but rather affects those metabolic pathways, which are catalyzed by more abundant selenoenzymes acting at higher substrate concentrations. These include GPxs and thioredoxin reductases involved in cellular redox control, several endoplasmatic reticulum-associated selenoproteins as well as selenoprotein N, all of which contribute to protein biosynthesis or represent structural components of cells and tissues [68▪,69,70,71▪].
SELENIUM AND MYXEDEMATOUS CRETINISM
The role of an adequate selenium supply in achieving normal thyroid function had been discovered during the 1980s by investigators in Brussels, who identified selenium deficiency as a key factor in the development of myxedematous cretinism in Central Africa [7,23]. Combined selenium and iodine deficiency, further deteriorated by food containing goitrogens, provoke myxedematous cretinism. Animal experimental data supported this hypothesis based on human pathophysiology, demonstrating more pronounced thyroid and developmental damage in animals deficient in iodine and selenium [23,72]. Transforming growth factor β-dependent processes contribute to thyroid tissue damage initiated by high TSH levels with subsequently enhanced production of H2O2, ROS and reactive oxygen intermediates . Adequate selenium status prevented these damaging effects even if high iodine doses were administered in rodent models of thyroid involution after long-standing iodine deficiency [7–9,23,24,72]. In contrast, results from iodination programs in Zaire have suggested that selenium supplementation under conditions of inadequate iodine intake might initially worsen thyroid dysfunction, and thus it has been recommended that adequate iodine status has to be established prior to increasing selenium intake . A possible mechanism of such adverse selenium effects has been proposed. Selenium-induced activation of peripheral thyroid hormone metabolism by deiodinase selenoproteins may lead to higher thyroid hormone turnover, deiodination and renal loss of iodide . Enhanced thyroid hormone turnover and iodide loss have only been reported in individuals with very severe deficiencies of both trace elements but not among those with mild selenium and iodine deficiency or intake at the lower recommended reference levels.
DOES ADEQUATE SELENIUM INTAKE AND EXPRESSION OF SELENOPROTEINS IN THYROCYTES PROTECT FROM TYHROID DISEASE?
Adequate selenium intake increases the efficiency of thyroid hormone synthesis in animal studies . The hemoprotein thyroperoxidase (TPO), which requires sufficient intake of the trace element iron, catalyzes iodide oxidation, organification and coupling of iodinated tyrosyl residues to generate iodothyronines that are still part of the thyroid hormone synthesis and storage protein thyroglobulin. One hypothesis might be that excess H2O2, known to inactivate TPO, might be degraded by the selenoprotein GPx3, which is secreted into the colloid lumen by thyrocytes . Furthermore, TSH-stimulated excess H2O2 and ROS such as OH-radicals, O2-radicals and others, not fully consumed during thyroid hormone synthesis in iodine deficiency, might be degraded by the antioxidative enzymatic defense line mounted by cellular GPxs, thioredoxin reductases, superoxide dismutases and catalase, all of which are expressed in thyrocytes [31,37]. Adequate selenium intake and supply in the thyrocytes might improve function of selenium-dependent quality control proteins (selenoprotein p15 and selenoprotein S) located at the endoplasmic reticulum [38,74,75]. They might improve synthesis, post-translational modification and apical secretion of the large dimeric glycoprotein thyroglobulin into the colloid lumen. Adequate GPx and thioredoxin reductase functions might also prevent cellular damage exerted by radical or redox cycling reactions, depending on Fe2+–Fe3+ ions liberated from hemoprotein TPO [12,13], especially under conditions in which TPO is inactivated by excess H2O2.
Recently, several selenium-based analogs of antithyroid drugs have been developed and tested with respect to their inhibitory potencies on TPO and deiodinases or as synthetic mimics of these selenoproteins [76,77▪,78,79]. Structure–activity relationships were identified, providing relevant information on the mechanism of action of TPO and deiodinases, as well as allowing development and testing of selenium-based antithyroid drugs that selectively interfere with TPO or deiodinases [76,77▪,79]. As the currently used antithyroid drugs, which are based on thiourea pharmacophores (e.g. methimazole or thiouracil derivatives), exhibit significant and frequent side-effects , the design, development and validation of novel antithyroid compounds blocking either thyroid hormone biosynthesis and/or thyroid hormone activation is of high medical interest. Hyperthyroid diseases due to autonomous thyroid function, Graves’ disease and/or drug-induced and iodine-induced hyperthyroidism may be potential targets .
SELENIUM STATUS, THYROID FUNCTION AND THYROID DISEASE
The first large interventional study using a combination of trace elements and vitamins, Supplémentation en Vitamines et Minéraux Antioxydants (SUVIMAX), revealed that inadequate selenium intake is associated with increased thyroid volume in women, but not men . This observation of a negative correlation between selenium status and thyroid volume was confirmed in a Danish population , in which a trend toward increased numbers of thyroid nodules was observed with inadequate selenium status. Serum selenium status is altered in several benign and malignant diseases, including thyroiditis and Graves’ disease . Lower selenium levels were observed in newly diagnosed Graves’ disease and autoimmune hypothyroidism , but correlations of selenium status with serum titers of TSH receptor (TRAK), TPO or thyroglobulin autoantibodies are less consistent [85▪▪]. The major problems with this large series of retrospective, case–control or double-blind, placebo-controlled prospective studies are the typically small number of cases, mix of women, men and various patient subgroups, short duration of intervention and follow-up monitoring, and use of several different chemical forms of selenium compounds that prevent major and broadly applicable conclusions and interpretation.
Selenium status affects major benign thyroid diseases and thyroid cancer in the following ways [7,38]:
- Autoimmune thyroiditis (Hashimoto's thyroiditis)
- T-cell-associated thyroid destruction (Th1 induced) resulting in hypothyroidism
- Graves’ disease (or Basedow's disease);
Iodine deficiency and goiter development/goitrogen-induced thyroid growth;
- Hyperstimulation of the thyrocytes by TSH receptor autoantibodies (TRAK) (Th2 induced) resulting in hyperthyroidism;
- Postpartum thyroiditis
- Silent thyroiditis
- Subacute thyroiditis
- Primary (idiopathic) myxoedema; and
Thyroid diseases, both benign and malignant forms, preferentially affect women already before puberty, in their reproductive phase and also after menopause [86–89,90▪,91]. The molecular basis for this imbalance is still unclear and sex steroids may contribute but other X-chromosomal adverse (or Y-chromosomal protective) factors, X-chromosome inactivation or sex differences of the immune system per se might be involved. Therefore, it is of interest that thyroid-related beneficial selenium effects have been observed mainly in women in contrast to several beneficial selenium actions on other target tissues in men [38,92–95].
Limited data support the hypothesis that low selenium status  is associated with a worldwide increased incidence of thyroid cancer [97–99], particularly papillary thyroid cancer. In experimental animal models, epidemiological studies and some, but not all, interventional studies, marked protective effects of adequate (or even pharmacologically high) selenium concentrations against tumor initiation, progression and metastasis have been reported for several cancers, but not for thyroid cancer [39,100,101]. The proposed link between low selenium status and thyroid cancer [96,102] has recently been addressed in further epidemiological studies and a meta-analysis, but was not confirmed [103▪–105▪,106]. Again, retrospective analyses, a low number of thyroid cancer cases (<250), a single determination of selenium status and probably too short observation times may prevent clear interpretation or conclusions with impact on prevention or treatment by selenium compounds.
It also remains unclear whether decreased serum selenium levels rather are consequence and not cause of the disease state or merely associated with disease-related proinflammatory conditions, which impair expression and secretion of hepatic selenoprotein P, the major contributor to serum selenium content [40,107–109]. Alternatively, impaired selenium status and tissue supply might cause dysfunction of thyroid hormone synthesis and metabolism. Both rodent  and human data [83,84,111,112] indicate an interaction between iodine status and thyroid selenium content or selenoprotein expression, as partially reflected by selenium status in the blood. High iodine intake or exposure decreases thyroid selenium content and selenoprotein expression, whereas low iodine intake might be associated with elevations of thyroid selenium, selenoprotein and selenium markers in blood [5,10,15,16,38,113▪,114]
SELENIUM AND AUTOIMMUNE THYROID DISEASE
Selenium status affects T-cell differentiation. There is evidence that higher selenium favors mounting of a Th1 and regulatory T cells response , whereas selenium deficiency is associated with elevated Th2 cells and markers . Selenium supplementation in a rat model of experimental thyroglobulin-induced autoimmune thyroiditis dose dependently attenuated Th1 response and interleukin-2 increase and reduced inflammation and thyroid tissue damage . Selenium supplementation in healthy men altered leukocyte gene expression and decreased numbers of killer cell activity T cells in the blood . These observations suggest beneficial effects of selenium compounds in autoimmune diseases of the thyroid [38,119,120] and other endocrine glands, and may help further understanding of the role of selenium status in inflammation, allergic reactions and asthma. In women at risk for postpartum thyroiditis, adequate selenium status prevents its development. In a prospective placebo-controlled double-blind preventional study , not yet confirmed [113▪], there were fewer cases of postpartum thyroiditis and hypothyroidism.
From several interventional studies in various countries that have examined several selenocompounds, doses and time of administration, there has been no evidence to support any direct effect of increased selenium intake on thyroid hormone and TSH serum concentrations [7,25,94,122], although most of these studies were not done in individuals with severe selenium deficiency. This indicates that deiodinase selenoproteins in peripheral tissues and anterior pituitary thyrotropes are adequately supplied with selenium even under conditions of marginal selenium deficiency. In contrast, stimulating effects of selenium on deiodinase expression are clearly demonstrated in severe selenium deficiency using animal experimental and cell culture models.
Several prospective, placebo-controlled and double-blind studies have been performed to improve quality of life, well-being, thyroid hormone status and disease symptoms of autoimmune thyroiditis or pregnancy [113▪,123]. Recent metaanalyses have summarized the diverse findings of four of these studies performed in areas of different iodine intake, unclear basal selenium status and in different patients groups, such as newly diagnosed disease, patients already treated with thyroid hormone and individuals with very different antibody titers [85▪▪,119]. Although initial studies clearly demonstrated decreased thyroid antibody titers and increased quality of life after at least 3 months of treatment with high doses of selenite or selenomethionine, subsequent reports were more ambiguous. In general, most of these studies were underpowered, too short or with too broad inclusion criteria to draw clear conclusions. For Graves’ disease, only one major multicentric prospective, placebo and serum-controlled study demonstrated improved quality of life and disease activity scores . At present, several confirming studies are ongoing for both autoimmune thyroiditis and Graves’ disease [125,126] (see also https://clinicaltrials.gov/ct2/show/NCT02112643?term=selenium+and+thyroid).
SELENIUM STATUS AND RELEVANT BIOMARKERS
Adequate selenium intake, with respect to proper thyroid function or other beneficial health effects, can be monitored by analysis of serum or plasma selenoproteins [e.g. selenoprotein P or plasma glutathione peroxidase 3 (pGPx3)] [127–131]. pGPx3 is secreted by the kidney, whereas circulatory selenoprotein P is mainly of hepatic origin. Careful analysis of selenium status and levels of selenoproteins in serum or plasma revealed that plateau levels of pGPx3 (pGPx3 >125 μU/l) are reached at 1 μM selenium concentration in the blood (125 μg selenium intake/day). Higher selenium intake is needed for maximal levels of selenoprotein P, which are reached beyond >125 μg/l of selenium. Maximal levels of both GPx3 and selenoprotein P may provide best systemic protection and function of selenium-dependent processes. Selenoprotein P is the major selenoprotein in plasma, accounting for up to 70% of plasma selenium, and is crucial for the specific distribution and transport of selenium to several target tissues, which need adequate selenoprotein P concentrations to supply selenium to tissues dependent on receptor-mediated selenoprotein P delivery [34,130–134,135▪▪]. Impaired selenoprotein P status has been observed in several pathologic conditions, including negative acute-phase reactions, inflammation and various cancers, and experimental animal models [40,107–109]. Determination of GPx1 activity in erythrocytes might provide a long-term indicator of selenium based on the lifetime of erythrocytes. Determination of selenium by fluorescence methods, inductively coupled plasma mass spectrometry or atom absorption spectrometry in serum, plasma, whole blood or body fluids provides an integral measure of selenium supply, but lacks specific information of biomarkers, such as hepatic selenoprotein P or renal pGPx3. Analysis of selenium status from hair or nails is not recommended because of artifacts resulting from cosmetic or external application of selenium-containing compounds.
Thyroid selenium content and selenoprotein expression are typically not reflected by serum selenium status [5–7,21,31,36,38]. This suggests that analyses of serum, plasma or erythrocyte selenium content do not necessarily reflect tissue or cell-specific selenium content or selenoprotein expression, which may be altered by transmembrane transport of selenium compounds or by ApoE2 receptor-mediated targeting of selenium-rich selenoprotein P [33▪▪]. Tissue and cell-dependent expression profiles of selenoproteins might differ from each other and from selenium biomarker levels in blood. These profiles might be concordant or discordant with selenium status represented by serum selenium levels. These observations suggest the need to develop and validate tissue-specific biomarkers and endpoints of selenium bioavailability and cellular action. There is no selenium-related parameter that has been established for the thyroid gland or systemic and cellular thyroid hormone action. Selenoprotein gene polymorphisms in many human populations living on different nutritional selenium intake provided evidence of genetic adaptation to inadequate nutritional supply [136▪].
Plasma selenium markers are different in individuals of low-income classes on inadequate nutrition as recently demonstrated between black and white Americans or among individuals with different genetic variants in selenoprotein P gene [137–139]. Furthermore, apart from nutritional intake of selenium, iodine and the other trace elements essential for thyroid hormone synthesis and thyroid function and also involuntarily exposure to nutritional and environmental endocrine active compounds (‘endocrine disrupters’) might interfere with and disturb thyroid hormone homeostasis [140–142]. Ongoing functional and genetic analysis of genes and their encoded protein variant, for which no biological or enzyme function has yet been identified [143▪], will add to a better understanding of the distinguished role of the essential trace element selenium to thyroid hormone synthesis and action, hormonal homeostasis as well as prevention and treatment of thyroid-related diseases.
Selenium compounds and selenoproteins protect the thyroid gland from H2O2 and ROS damage. Thyroid hormone synthesis and metabolism represent a remarkable example of coevolution of biology and function of three essential trace elements: iodine, selenium and iron. Many studies, primarily of women, have shown that adequate selenium status benefits thyroid-related diseases. Low selenium status is observed in patients with newly diagnosed Graves’ disease and autoimmune thyroiditis. The possible mechanisms of action of selenoproteins in benign and malignant thyroid disease, and the action of selenocompounds in thyrocytes, endothelial cells, angiofollicular units and/or immune cells remain to be established. Nutritional, environmental, genetic, life-phase and disease-related factors modulate the fine-tuned interaction between the three trace elements, selenium, iodine and iron, thyroid function and thyroid hormone homeostasis and thus play an important role in maintenance of human health, prevention and treatment of diseases.
The expert secretarial assistance of Elke Abdel-Karim is highly appreciated.
Financial support and sponsorship
The research project is funded by Deutsche Forschungsgemeinschaft (DFG) DFG-Schwerpunktprogramm SPP 1629 ThyroidTransAct and Charité-University Medicine Berlin.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
1▪▪. Zimmermann MB, Boelaert K. Iodine deficiency and thyroid disorders. Lancet Diabetes Endocrinol 2015; 3:286–295.
Review discussing benefit of adequate iodine intake for human development and health including transient alterations of thyroid axis to increased iodine intake.
2. Li M, Eastman CJ. The changing epidemiology of iodine deficiency. Nat Rev Endocrinol 2012; 8:434–440.
3. Meisinger C, Ittermann T, Wallaschofski H, et al. Geographic variations in the frequency of thyroid disorders and thyroid peroxidase antibodies in persons without former thyroid disease within Germany. Eur J Endocrinol 2012; 167:363–371.
4. Ittermann T, Khattak RM, Nauck M, et al. Shift of the TSH reference range with improved iodine supply in Northeast Germany. Eur J Endocrinol 2015; 172:261–267.
5. Köhrle J. Pathophysiological relevance of selenium. J Endocrinol Invest 2013; 36 (Suppl 10):1–7.
6. Schomburg L, Köhrle J. On the importance of selenium and iodine metabolism for thyroid hormone biosynthesis and human health. Mol Nutr Food Res 2008; 52:1235–1246.
7. Köhrle J, Jakob F, Contempré B, Dumont JE. Selenium, the thyroid, and the endocrine system. Endocr Rev 2005; 26:944–984.
8. Contempre B, Le Moine O, Dumont JE, et al. Selenium deficiency and thyroid fibrosis. A key role for macrophages and transforming growth factor beta (TGF-beta). Mol Cell Endocrinol 1996; 124:7–15.
9. Contempre B, Dumont JE, Denef JF, Many MC. Effects of selenium deficiency on thyroid necrosis, fibrosis and proliferation: a possible role in myxoedematous cretinism. Eur J Endocrinol 1995; 133:99–109.
10. Liu Y, Huang H, Zeng J, Sun C. Thyroid volume, goiter
prevalence, and selenium levels in an iodine-sufficient area: a cross-sectional study. BMC Public Health 2013; 13:1153.
11. Knudsen N, Brix TH. Genetic and noniodine-related factors in the aetiology of nodular goitre. Best Pract Res Clin Endocrinol Metab 2014; 28:495–506.
12. Hess SY. The impact of common micronutrient deficiencies on iodine and thyroid metabolism: the evidence from human studies. Best Pract Res Clin Endocrinol Metab 2010; 24:117–132.
13. Zimmermann MB. The influence of iron status on iodine utilization and thyroid function. Annu Rev Nutr 2006; 26:367–389.
14▪. Yu X, Shan Z, Li C, et al. Iron deficiency, an independent risk factor for isolated hypothyroxinemia in pregnant and nonpregnant women of childbearing age in China. J Clin Endocrinol Metab 2015; 100:1594–1601.
Large study revealed that iron deficiency is associated with hypothyroxinemia in women with adequate iodine intake without TPO antibodies.
15. Jain RB, Choi YS. Interacting effects of selected trace and toxic metals on thyroid function. Int J Environ Health Res 2015; [Epub ahead of print].
16. Jain RB. Thyroid function and serum copper, selenium, and zinc in general U.S. population. Biol Trace Elem Res 2014; 159:87–98.
17. Cooper R, Pinkney J, Ayling RM. Appropriateness of prescribing thyroxine in primary care. Ann Clin Biochem 2015; 52 (Pt 4):497–501.
18. Biron VL, Bang H, Farwell DG, Bewley AF. National trends and factors associated with hospital costs following thyroid surgery. Thyroid 2015; 25:823–829.
19. Nexo MA, Watt T, Pedersen J, et al. Increased risk of long-term sickness absence, lower rate of return to work, and higher risk of unemployment and disability pensioning for thyroid patients: a Danish register-based cohort study. J Clin Endocrinol Metab 2014; 99:3184–3192.
22▪. Stagnaro-Green A. Screening pregnant women for overt thyroid disease. J Am Med Assoc 2015; 313:565–566.
Summary of arguments to screen pregnant women for inadequate thyroid function in order to prevent impaired fetal development.
23. Contempré B, Duale NL, Dumont JE, et al. Effect of selenium supplementation on thyroid hormone metabolism in an iodine and selenium deficient population. Clin Endocrinol (Oxf) 1992; 36:579–583.
24. Xu J, Liu XL, Yang XF, et al. Supplemental selenium alleviates the toxic effects of excessive iodine on thyroid. Biol Trace Elem Res 2011; 141:110–118.
25. Köhrle J, Gärtner R. Selenium and thyroid. Best Pract Res Clin Endocrinol Metab 2009; 23:815–827.
26▪▪. Wiersinga WM. Thyroid autoimmunity. Endocr Dev 2014; 26:139–157.
Recent overview on current concepts and mechanisms involved in manifestation of autoimmune thyroid disease.
27. Luo Y, Kawashima A, Ishido Y, et al. Iodine excess as an environmental risk factor for autoimmune thyroid disease. Int J Mol Sci 2014; 15:12895–12912.
28. Prete A, Paragliola RM, Corsello SM. Iodine supplementation: usage ‘with a grain of salt’. Int J Endocrinol 2015; 2015:312305.
29. Leung AM, Braverman LE. Consequences of excess iodine. Nat Rev Endocrinol 2014; 10:136–142.
30. Ma ZF, Skeaff SA. Thyroglobulin as a biomarker of iodine deficiency: a review. Thyroid 2014; 24:1195–1209.
31. Chiu-Ugalde J, Wirth EK, Klein MO, et al. Thyroid function is maintained despite increased oxidative stress in mice lacking selenoprotein
biosynthesis in thyroid epithelial cells. Antioxid Redox Signal 2012; 17:902–913.
32▪. Duntas LH, Benvenga S. Selenium: an element for life. Endocrine 2015; 48:756–775.
Recent overview of the various functions of selenium in human health and disease.
33▪▪. Burk RF, Hill KE Regulation of selenium metabolism and transport. Annu Rev Nutr 17; 35:109–134.
Comprehensive update and review of molecules and mechanisms contributing to tissue-specific metabolism of selenium compounds, expression and function of selenoproteins including the role of apolipoprotein E receptor 2 in uptake of selenoprotein P.
34. Ashton K, Hooper L, Harvey LJ, et al. Methods of assessment of selenium status in humans: a systematic review. Am J Clin Nutr 2009; 89:2025S–2039S.
35. Ralston NV, Raymond LJ. Dietary selenium's protective effects against methylmercury toxicity. Toxicology 2010; 278:112–123.
36. Schmutzler C, Mentrup B, Schomburg L, et al. Selenoproteins of the thyroid gland: expression, localization and possible function of glutathione peroxidase 3. Biol Chem 2007; 388:1053–1059.
37. Schweizer U, Chiu J, Köhrle J. Peroxides and peroxide-degrading enzymes in the thyroid. Antioxid Redox Signal 2008; 10:1577–1592.
38. Schomburg L. Selenium, selenoproteins and the thyroid gland: interactions in health and disease. Nat Rev Endocrinol 2011; 8:160–171.
39. Fairweather-Tait SJ, Bao Y, Broadley MR, et al. Selenium in human health and disease. Antioxid Redox Signal 2011; 14:1337–1383.
40. Renko K, Hofmann PJ, Stoedter M, et al. Down-regulation of the hepatic selenoprotein
biosynthesis machinery impairs selenium metabolism during the acute phase response in mice. FASEB J 2009; 23:1758–1765.
41. Schomburg L, Schweizer U, Holtmann B, et al. Gene disruption discloses role of selenoprotein
P in selenium delivery to target tissues. Biochem J 2003; 370 (Pt 2):397–402.
42. Burk RF, Hill KE, Motley AK, et al. Deletion of selenoprotein
P upregulates urinary selenium excretion and depresses whole-body selenium content. Biochim Biophys Acta 2006; 1760:1789–1793.
43. Olson GE, Winfrey VP, Nagdas SK, et al. Apolipoprotein E receptor-2 (ApoER2) mediates selenium uptake from selenoprotein
P by the mouse testis. J Biol Chem 2007; 282:12290–12297.
44. Schweizer U, Dehina N, Schomburg L. Disorders of selenium metabolism and selenoprotein
function. Curr Opin Pediatr 2011; 23:429–435.
45. Burk RF, Hill KE, Motley AK, et al. Selenoprotein
P and apolipoprotein E receptor-2 interact at the blood-brain barrier and also within the brain to maintain an essential selenium pool that protects against neurodegeneration. FASEB J 2014; 28:3579–3588.
46. Schweizer U, Weitzel JM, Schomburg L. Think globally: act locally. New insights into the local regulation of thyroid hormone availability challenge long accepted dogmas. Mol Cell Endocrinol 2008; 289:1–9.
47. Schomburg L, Riese C, Michaelis M, et al. Synthesis and metabolism of thyroid hormones is preferentially maintained in selenium-deficient transgenic mice. Endocrinology 2006; 147:1306–1313.
48. Burk RF, Olson GE, Hill KE, et al. Maternal-fetal transfer of selenium in the mouse. FASEB J 2013; 27:3249–3256.
49▪. Fu J, Dumitrescu AM. Inherited defects in thyroid hormone cell-membrane transport and metabolism. Best Pract Res Clin Endocrinol Metab 2014; 28:189–201.
Review on molecular basis, phenotype and clinical consequences of the first genetic defects in selenoprotein biosynthesis that manifest in altered thyroid hormone status and function.
50. Dumitrescu AM, Liao XH, Abdullah MS, et al. Mutations in SECISBP2 result in abnormal thyroid hormone metabolism. Nat Genet 2005; 37:1247–1252.
51. Azevedo MF, Barra GB, Naves LA, et al. Selenoprotein
-related disease in a young girl caused by nonsense mutations in the SBP2 gene. J Clin Endocrinol Metab 2010; 95:4066–4071.
52. Schoenmakers E, Agostini M, Mitchell C, et al. Mutations in the selenocysteine insertion sequence-binding protein 2 gene lead to a multisystem selenoprotein
deficiency disorder in humans. J Clin Invest 2010; 120:4220–4235.
53. Hamajima T, Mushimoto Y, Kobayashi H, et al. Novel compound heterozygous mutations in the SBP2 gene: characteristic clinical manifestations and the implications of GH and triiodothyronine in longitudinal bone growth and maturation. Eur J Endocrinol 2012; 166:757–764.
54. Schomburg L, Dumitrescu AM, Liao XH, et al. Selenium supplementation fails to correct the selenoprotein
synthesis defect in subjects with SBP2 gene mutations. Thyroid 2009; 19:277–281.
55. Seeher S, Atassi T, Mahdi Y, et al. Secisbp2 is essential for embryonic development and enhances selenoprotein
expression. Antioxid Redox Signal 2014; 21:835–849.
56. Conrad M, Schweizer U. Unveiling the molecular mechanisms behind selenium-related diseases through knockout mouse studies. Antioxid Redox Signal 2010; 12:851–865.
57. Castets P, Lescure A, Guicheney P, Allamand V. Selenoprotein
N in skeletal muscle: from diseases to function. J Mol Med (Berl) 2012; 90:1095–1107.
58. Jørgensen JO, Møller J, Laursen T, et al. Growth hormone administration stimulates energy expenditure and extrathyroidal conversion of thyroxine to triiodothyronine in a dose-dependent manner and suppresses circadian thyrotrophin levels: studies in GH-deficient adults. Clin Endocrinol (Oxf) 1994; 41:609–614.
59. Portes ES, Oliveira JH, MacCagnan P, Abucham J. Changes in serum thyroid hormones levels and their mechanisms during long-term growth hormone (GH) replacement therapy in GH deficient children. Clin Endocrinol (Oxf) 2000; 53:183–189.
60. Kalina-Faska B, Kalina M, Koehler B. Effects of recombinant growth hormone therapy on thyroid hormone concentrations. Int J Clin Pharmacol Ther 2004; 42:30–34.
61. Gross M, Oertel M, Köhrle J. Differential selenium-dependent expression of type I 5’-deiodinase and glutathione peroxidase in the porcine epithelial kidney cell line LLC-PK1. Biochem J 1995; 306 (Pt 3):851–856.
62. Behne D, Kyriakopoulos A, Meinhold H, Köhrle J. Identification of type I iodothyronine 5’-deiodinase as a selenoenzyme. Biochem Biophys Res Commun 1990; 173:1143–1149.
63. Arthur JR, Nicol F, Beckett GJ. Hepatic iodothyronine 5’-deiodinase. The role of selenium. Biochem J 1990; 272:537–540.
64. Berry MJ, Banu L, Chen YY, et al. Recognition of UGA as a selenocysteine codon in type I deiodinase requires sequences in the 3’ untranslated region. Nature 1991; 353:273–276.
65. Humann-Ziehank E, Renko K, Mueller AS, et al. Comparing functional metabolic effects of marginal and sufficient selenium supply in sheep. J Trace Elem Med Biol 2013; 27:380–390.
66. Guyot H, de Oliveira LA, Ramery E, et al. Effect of a combined iodine and selenium supplementation on I and Se status of cows and their calves. J Trace Elem Med Biol 2011; 25:118–124.
67. Gereben B, Zavacki AM, Ribich S, et al. Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr Rev 2008; 29:898–938.
68▪. Labunskyy VM, Hatfield DL, Gladyshev VN. Selenoproteins: molecular pathways and physiological roles. Physiol Rev 2014; 94:739–777.
Review on mechanisms involved in cotranslational incorporation of selenocysteine into selenoproteins, description of their function in development and metabolism and their impact on human health.
69. Pillai R, Uyehara-Lock JH, Bellinger FP. Selenium and selenoprotein
function in brain disorders. IUBMB Life 2014; 66:229–239.
70. Hatfield DL, Tsuji PA, Carlson BA, Gladyshev VN. Selenium and selenocysteine: roles in cancer, health, and development. Trends Biochem Sci 2014; 39:112–120.
71▪. Roman M, Jitaru P, Barbante C. Selenium biochemistry and its role for human health. Metallomics 2014; 6:25–54.
Overview on the biological role of the trace element selenium and for human health.
72. Contempré B, de Escobar GM, Denef JF, et al. Thiocyanate induces cell necrosis and fibrosis in selenium- and iodine-deficient rat thyroids: a potential experimental model for myxedematous endemic cretinism in central Africa. Endocrinology 2004; 145:994–1002.
73. Golstein J, Corvilain B, Lamy F, et al. Effects of a selenium deficient diet on thyroid function of normal and perchlorate treated rats. Acta Endocrinol (Copenh) 1988; 118:495–502.
74. Shchedrina VA, Zhang Y, Labunskyy VM, et al. Structure-function relations, physiological roles, and evolution of mammalian ER-resident selenoproteins. Antioxid Redox Signal 2010; 12:839–849.
75. Turanov AA, Shchedrina VA, Everley RA, et al. Selenoprotein
S is involved in maintenance and transport of multiprotein complexes. Biochem J 2014; 462:555–565.
76. Bhowmick D, Srivastava S, D'Silva P, Mugesh G. Highly efficient glutathione peroxidase and peroxiredoxin mimetics protect mammalian cells against oxidative damage. Angew Chem Int Ed Engl 2015; 54:8449–8453.
77▪. Raja K, Mugesh G. Remarkable effect of chalcogen substitution on an enzyme mimetic for deiodination of thyroid hormones. Angew Chem Int Ed Engl 2015; 54:7674–7678.
A synthetic compound can mimic deiodinase function in thyroid hormone metabolism.
78. Manna D, Roy G, Mugesh G. Antithyroid drugs and their analogues: synthesis, structure, and mechanism of action. Acc Chem Res 2013; 46:2706–2715.
79. Rijntjes E, Scholz PM, Mugesh G, Köhrle J. Se- and S-based thiouracil and methimazole analogues exert different inhibitory mechanisms on type 1 and type 2 deiodinases. Eur Thyroid J 2013; 2:252–258.
80. Weissel M. Propylthiouracil: clinical overview of its efficacy and its side effects more than 50 years after the introduction of its use in thyrostatic treatment. Exp Clin Endocrinol Diabetes 2010; 118:101–104.
81. Gershengorn MC, Neumann S. Update in TSH receptor agonists and antagonists. J Clin Endocrinol Metab 2012; 97:4287–4292.
82. Derumeaux H, Valeix P, Castetbon K, et al. Association of selenium with thyroid volume and echostructure in 35- to 60-year-old French adults. Eur J Endocrinol 2003; 148:309–315.
83. Rasmussen LB, Schomburg L, Köhrle J, et al. Selenium status, thyroid volume, and multiple nodule formation in an area with mild iodine deficiency. Eur J Endocrinol 2011; 164:585–590.
84. Bülow Pedersen I, Knudsen N, Carlé A, et al. Serum selenium is low in newly diagnosed Graves’ disease. A population based study. Clin Endocrinol (Oxf) 2013; 79:584–590.
85▪▪. van Zuuren EJ, Albusta AY, Fedorowicz Z, et al. Selenium supplementation for Hashimoto's thyroiditis
. Cochrane Database Syst Rev 2013; 6:CD010223.
Most recent and critical review and comprehensive metaanalysis on selenium supplementation in autoimmune thyroiditis.
86. Vanderpump MP. The epidemiology of thyroid disease. Br Med Bull 2011; 99:39–51.
87. Bauer M, Glenn T, Pilhatsch M, et al. Gender differences in thyroid system function: relevance to bipolar disorder and its treatment. Bipolar Disord 2014; 16:58–71.
88. Vannucchi G, De Leo S, Perrino M, et al. Impact of estrogen and progesterone receptor expression on the clinical and molecular features of papillary thyroid cancer
. Eur J Endocrinol 2015; 173:29–36.
89. Simmonds MJ, Kavvoura FK, Brand OJ, et al. Skewed X chromosome inactivation and female preponderance in autoimmune thyroid disease: an association study and meta-analysis. J Clin Endocrinol Metab 2014; 99:E127–E131.
90▪. Li H, Li J. Thyroid disorders in women. Minerva Med 2015; 106:109–114.
Review of prevalence of benign and malignant thyroid disease in women and discussion of underlying molecular mechanisms.
91. Effraimidis G, Wiersinga WM. Mechanisms in endocrinology: autoimmune thyroid disease: old and new players. Eur J Endocrinol 2014; 170:R241–R252.
92. Riese C, Michaelis M, Mentrup B, et al. Selenium-dependent pre and posttranscriptional mechanisms are responsible for sexual dimorphic expression of selenoproteins in murine tissues. Endocrinology 2006; 147:5883–5892.
93. Stoedter M, Renko K, Hög A, Schomburg L. Selenium controls the sex-specific immune response and selenoprotein
expression during the acute-phase response in mice. Biochem J 2010; 429:43–51.
94. Combs GF Jr, Midthune DN, Patterson KY, et al. Effects of selenomethionine supplementation on selenium status and thyroid hormone concentrations in healthy adults. Am J Clin Nutr 2009; 89:1808–1814.
95. Schomburg L, Schweizer U. Hierarchical regulation of selenoprotein
expression and sex-specific effects of selenium. Biochim Biophys Acta 2009; 1790:1453–1462.
96. Glattre E, Nygård JF, Aaseth J. Selenium and cancer prevention: observations and complexity. J Trace Elem Med Biol 2012; 26:168–169.
97. Colonna M, Uhry Z, Guizard A, et al. Recent trends in incidence, geographical distribution, and survival of papillary thyroid cancer
in France. Cancer Epidemiol 2015; 2015 May 20. pii: S1877-7821(15)00097-1. [Epub ahead of print].
98. Davies L, Welch HG. Current thyroid cancer
trends in the United States. JAMA Otolaryngol Head Neck Surg 2014; 140:317–322.
99. Pellegriti G, Frasca F, Regalbuto C, et al. Worldwide increasing incidence of thyroid cancer
: update on epidemiology and risk factors. J Cancer Epidemiol 2013; 2013:965212.
100. Davis CD, Tsuji PA, Milner JA. Selenoproteins and cancer prevention. Annu Rev Nutr 2012; 32:73–95.
101. Rayman MP. Selenium and human health. Lancet 2012; 379:1256–1268.
102. Moncayo R, Kroiss A, Oberwinkler M, et al. The role of selenium, vitamin C, and zinc in benign thyroid diseases and of selenium in malignant thyroid diseases: low selenium levels are found in subacute and silent thyroiditis
and in papillary and follicular carcinoma. BMC Endocr Disord 2008; 8:2.
103▪. Shen F, Cai WS, Li JL, et al. The association between serum levels of selenium, copper, and magnesium with thyroid cancer
: a meta-analysis. Biol Trace Elem Res 2015; [Epub ahead of print].
Review on role and interaction between trace elements in thyroid cancer and discussion of regional differences possibly related to ethnic or environmental factors.
104▪. Ren Y, Kitahara CM, Berrington de Gonzalez A, et al. Lack of association between fingernail selenium and thyroid cancer
risk: a case-control study in French Polynesia. Asian Pac J Cancer Prev 2014; 15:5187–5194.
This comprehensive study did not observe direct associations between selenium status and thyroid cancer risk.
105▪. O’Grady TJ, Kitahara CM, DiRienzo AG, Gates MA. The association between selenium and other micronutrients and thyroid cancer
incidence in the NIH-AARP Diet and Health Study. PLoS One 2014; 9:e110886.
No strong association was observed between selenium and trace element status with thyroid cancer incidence.
106. Przybylik-Mazurek E, Zagrodzki P, Kuźniarz-Rymarz S, Hubalewska-Dydejczyk A. Thyroid disorders-assessments of trace elements, clinical, and laboratory parameters. Biol Trace Elem Res 2011; 141:65–75.
107. Hesse-Bähr K, Dreher I, Köhrle J. The influence of the cytokines Il-1beta and INFgamma on the expression of selenoproteins in the human hepatocarcinoma cell line HepG2. Biofactors 2000; 11:83–85.
108. Dreher I, Jakobs TC, Köhrle J. Cloning and characterization of the human selenoprotein
P promoter. Response of selenoprotein
P expression to cytokines in liver cells. J Biol Chem 1997; 272:29364–29371.
109. Becker NP, Martitz J, Renko K, et al. Hypoxia reduces and redirects selenoprotein
biosynthesis. Metallomics 2014; 6:1079–1086.
110. Hotz CS, Fitzpatrick DW, Trick KD, L’Abbé MR. Dietary Iodine and selenium interact to affect thyroid hormone metabolism of rats. J Nutr 1997; 127:1214–1218.
111. Rasmussen LB, Hollenbach, Laurberg P, et al. Serum selenium and selenoprotein
P status in adult Danes – 8-year followup. J Trace Elem Med Biol 2009; 23:265–271.
112. Brauer VF, Schweizer U, Köhrle J, Paschke R. Selenium and goiter
prevalence in borderline iodine sufficiency. Eur J Endocrinol 2006; 155:807–812.
113▪. Mao J, Pop VJ, Bath SC, et al. Effect of low-dose selenium on thyroid autoimmunity and thyroid function in UK pregnant women with mild-to-moderate iodine deficiency. Eur J Nutr 2014; [Epub ahead of print].
No effect of selenium supplementation on TPO antibody titers but on thyroid function was observed; dose might have been too low and follow-up of postpartum thyroid function has not been studied in detail.
114. Koukkou E, Ilias I, Alexiou M, et al. Urine selenium changes during pregnancy do not correlate with thyroid autoantibodies in a mildly iodine deficient population. Biol Trace Elem Res 2014; 157:9–13.
115. Xue H, Wang W, Li Y, et al. Selenium upregulates CD4(+)CD25(+) regulatory T cells in iodine-induced autoimmune thyroiditis
model of NOD.H-2(h4) mice. Endocr J 2010; 57:595–601.
116. Huang Z, Rose AH, Hoffmann PR. The role of selenium in inflammation and immunity: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal 2012; 16:705–743.
117. Tan L, Sang ZN, Shen J, et al. Selenium supplementation alleviates autoimmune thyroiditis
by regulating expression of TH1/TH2 cytokines. Biomed Environ Sci 2013; 26:920–925.
118. Hawkes WC, Richter D, Alkan Z. Dietary selenium supplementation and whole blood gene expression in healthy North American men. Biol Trace Elem Res 2013; 155:201–208.
119. Toulis KA, Anastasilakis AD, Tzellos TG, et al. Selenium supplementation in the treatment of Hashimoto's thyroiditis
: a systematic review and a meta-analysis. Thyroid 2010; 20:1163–1173.
120. Drutel A, Archambeaud F, Caron P. Selenium and the thyroid gland. More Good News for Clinicians. Clin Endocrinol 2013; 78:155–164.
121. Negro R, Greco G, Mangieri T, et al. The influence of selenium supplementation on postpartum thyroid status in pregnant women with thyroid peroxidase autoantibodies. J Clin Endocrinol Metab 2007; 92:1263–1268.
122. Rayman MP, Thompson AJ, Bekaert B, et al. Randomized controlled trial of the effect of selenium supplementation on thyroid function in the elderly in the United Kingdom. Am J Clin Nutr 2008; 87:370–378.
123. Eskes SA, Endert E, Fliers E, et al. Selenite supplementation in euthyroid subjects with thyroid peroxidase antibodies. Clin Endocrinol (Oxf) 2014; 80:444–451.
124. Marcocci C, Kahaly GJ, Krassas GE, et al. European Group on Graves’ Orbitopathy. Selenium and the course of mild Graves’ orbitopathy. N Engl J Med 2011; 364:1920–1931.
125. Watt T, Cramon P, Bjorner JB, et al. Selenium supplementation for patients with Graves’ hyperthyroidism (the GRASS trial): study protocol for a randomized controlled trial. Trials 2013; 14:119.
126. Winther KH, Watt T, Bjørner JB, et al. The chronic autoimmune thyroiditis
quality of life selenium trial (CATALYST): study protocol for a randomized controlled trial. Trials 2014; 15:115.
127. Burk RF, Hill KE, Selenoprotein
P. an extracellular protein with unique physical characteristics and a role in selenium homeostasis. Annu Rev Nutr 2005; 25:215–235.
128. Burk RF, Norsworthy BK, Hill KE, et al. Effects of chemical form of selenium on plasma biomarkers in a high-dose human supplementation trial. Cancer Epidemiol Biomarkers Prev 2006; 15:804–810.
129. Hollenbach B, Morgenthaler NG, Struck J, et al. New assay for the measurement of selenoprotein
P as a sepsis biomarker from serum. J Trace Elem Med Biol 2008; 22:24–32.
130. Hoeflich J, Hollenbach B, Behrends T, et al. The choice of biomarkers determines the selenium status in young German vegans and vegetarians. Br J Nutr 2010; 104:1601–1604.
131. Combs GF Jr, Watts JC, Jackson MI, et al. Determinants of selenium status in healthy adults. Nutr J 2011; 10:75.
132. Xia Y, Hill KE, Li P, et al. Optimization of selenoprotein
P and other plasma selenium biomarkers for the assessment of the selenium nutritional requirement: a placebo-controlled, double-blind study of selenomethionine supplementation in selenium-deficient Chinese subjects. Am J Clin Nutr 2010; 92:525–531.
133. Hurst R, Collings R, Harvey LJ, et al. EURRECA-Estimating selenium requirements for deriving dietary reference values. Crit Rev Food Sci Nutr 2013; 53:1077–1096.
134. Hurst R, Armah CN, Dainty JR, et al. Establishing optimal selenium status: results of a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr 2010; 91:923–931.
135▪▪. Combs GF Jr. Biomarkers of selenium status. Nutrients 2015; 7:2209–2236.
Critical overview on currently available tissue and blood selenium biomarkers, their limits and applications, aspects and risks of inadequate or excess selenium intake.
136▪. White L, Romagné F, Müller E, et al. Genetic adaptation to levels of dietary selenium in recent human history. Mol Biol Evol 2015; 32:1507–1518.
Analysis of selenoprotein gene in many human populations provides evidence for genetic adaptation to environments with different and inadequate nutritional selenium supply.
137. Hargreaves MK, Liu J, Buchowski MS, et al. Plasma selenium biomarkers in low income black and white Americans from the southeastern United States. PLoS One 2014; 9:e84972.
138. Epplein M, Burk RF, Cai Q, et al. A prospective study of plasma selenoprotein
P and lung cancer risk among low-income adults. Cancer Epidemiol Biomarkers Prev 2014; 23:1238–1244.
139. Hellwege JN, Palmer ND, Ziegler JT, et al. Genetic variants in selenoprotein
P plasma 1 gene (SEPP1) are associated with fasting insulin and first phase insulin response in Hispanics. Gene 2014; 534:33–39.
140. Köhrle J. Environment and endocrinology: the case of thyroidology. Ann Endocrinol (Paris) 2008; 69:116–122.
141. Leung AM, Pearce EN, Braverman LE. Environmental perchlorate exposure: potential adverse thyroid effects. Curr Opin Endocrinol Diabetes Obes 2014; 21:372–376.
142. Rogan WJ, Paulson JA, Baum C, et al. Council on Environmental Health. Iodine deficiency, pollutant chemicals, and the thyroid: new information on an old problem. Pediatrics 2014; 133:1163–1166.
143▪. Romagné F, Santesmasses D, White L, et al. SelenoDB 2.0: annotation of selenoprotein
genes in animals and their genetic diversity in humans. Nucleic Acids Res 2014; 42 (Database issue):D437–D443.