【Abstract】The trace element selenium has important biological significance to human beings and is an essential trace element in the human body, and the thyroid gland contains the highest amount of selenium among human organs. The main form of selenium in the body to function in the selenocysteine as the active center of the protein, called selenoproteins. Twenty-five selenoproteins have been identified from the human body, and there are six main groups: glutathione peroxidase family (GSH-Px), iodothyronine deiodinase family (DI), selenoprotein P, selenoprotein W, thioredoxin reductase (TR) and selenosubstituted phosphate synthase (SPS). Selenium plays a variety of biological roles in the body, such as antioxidant, immune function enhancing, and antitumor. Selenium is involved in the synthesis, activation and metabolic processes of thyroid hormones, and plays an important subterfuge in the thyroid disturbance oxidation system and immune system. Selenium deficiency is closely related to goiter, autoimmune thyroid disease, low T3 syndrome, thyroid cancer and other diseases. Administration of selenium-containing preparations to patients with certain thyroid disorders can improve thyroid function, which provides an alternative approach to the treatment of thyroid disorders.
1.Overview of selenium
Since the discovery of selenium by the Swedish scholar Berzelius in 1817, the understanding of its biological significance has been deepened. 1957 Schwarz study found that low concentration of selenium helps to prevent liver necrosis, so it is classified as an essential trace element for life. Selenium deficiency is associated with more than 40 diseases such as thyroid disease, Creutzfeldt-Jakob disease, cancer, cardiovascular disease, diabetes, infertility, Alzheimer’s disease and Parkinson’s disease [1,2].
Selenocysteine (Sec) is the main bioactive form of selenium in the body and selenoprotein is the main functional form of selenium in the organism. Twenty-five selenoproteins have been identified from the human body and there are six main classes: the glutathione peroxidase family (GSH-Px), the iodothyronine deiodinase family (DI), selenoprotein P, selenoprotein W, thioredoxin reductase (TR) and selenosubstituted phosphate synthase (SPS), the latter two being newly discovered selenium-containing enzymes. Among them, glutathione peroxidase family, deiodinase family and thioredoxin reductase family have been studied in depth. The glutathione peroxidase family was found to have four members, including intracellular glutathione peroxidase, extracellular glutathione peroxidase, phospholipid peroxidase (or membrane-type glutathione peroxidase) and gastrointestinal glutathione peroxidase, whose main function is to assist in scavenging free radicals. The deiodinase family includes three members. At least 3 members of thioredoxin reductase have been identified. Selenoprotein P is a plasma selenoprotein that is presumed to be a selenium transporter protein and may be involved in heme metabolism. Selenoprotein W is an intracellular selenoprotein that is required for the maintenance of normal muscle tissue function [2,3]. Selenium exists in the organism in various forms other than selenoprotein, such as selenosubstituted amino acids, alkylates of selenium, and selenoglutathione, many of which have redox activity [3,4].
Recent studies have revealed that selenium plays an important role in the antioxidant system of the thyroid gland, the immune system, and in the synthesis, activation, and metabolism of thyroid hormones [3]. In this paper, we will focus on the close relationship between selenium and thyroid gland.
2. Biological functions of selenium and selenoprotein
2.1 Scavenging free radicals
It was found that selenase has significant anti-free radical damage, especially GPx can reduce hydrogen peroxide, lipid and phospholipid hydrogen peroxide, which can reduce the concentration of free radicals and reactive oxygen species. In the cyclooxygenase and lipoxygenase pathways, GPx reduces the intermediate products of hydroperoxides, thereby inhibiting the production of inflammation-causing prostacyclins and leukotrienes. Glutathione peroxidase is widely distributed in the body and is an important component of the antioxidant system, promoting the reduction of toxic peroxides, such as hydrogen peroxide and superoxide anion, to hydroxylates, which decompose peroxides, scavenge free radicals, prevent oxidative stress reactions in biological macromolecules, repair molecularly damaged proteins, and maintain cell membrane structure and function. Thioredoxin reductase is very important for maintaining the intracellular reduced state. Studies have proved that in the presence of NADPH, thioredoxin reductase can scavenge hydrogen peroxide and lipid peroxides, and its scavenging efficiency is even higher than that of glutathione peroxidase. In addition, GPx can regulate respiratory burst by removing hydrogen peroxide and reducing superoxide production [5,6].
2.2 Enhancement of immunity
Selenium has an important role in the function of immune cells. Selenium has significant immune stimulatory effects such as enhanced Tc cell killing activity, increased NK cell killing, T cell proliferation, increased responsiveness to antigenic stimuli, enhancement of nonspecific immunity of the body, and regulation of cytokine secretion, which have also been demonstrated in therapeutic studies in tumor patients [7]. Studies have shown that antioxidant and metabolic modulation through selenase may be an important way in which selenium enhances immune function. Thioredoxin, the catalytic substrate of thioredoxin reductase, stimulates interleukin 2 receptor alpha expression. Therefore, thioredoxin is classified as a T-cell growth factor [8,9]. The reading frames of the mRNAs of various T cell-related genes (e.g. IL-15, CD4, CD8, HLA-DR, etc.) contain up to 10 in-frame UGA codons with a stem-loop structure upstream similar to the selenocysteine insertion sequence, which may allow these mRNAs to compile T cell selenoproteins [9].
2.3 Metabolic regulation
The metabolism of eicosanoid arachidonic acid must be catalyzed by glutathione peroxidase to synthesize functional molecules such as thromboxane and prostaglandins. It has been shown that low selenium status can lead to decreased prostaglandin levels increased thromboxane levels, causing vasoconstriction and platelet aggregation and a hypercoagulable state, which is considered as one of the possible mechanisms for the anti-cardiovascular disease effect of selenium supplementation [9]. Deiodinase catalyzes the deiodination of the T45′ position during the synthesis and regulation of thyroxine to produce T3. It was found that thioredoxin constitutes a key cysteine residue on some translation factors, adrenocorticotropic hormone receptors and NF-κB molecules, which can undergo conformational changes as a catalytic substrate for thioredoxin reductase. This regulates cell differentiation and proliferation. Thioredoxin reductase also has an important regulatory role on nucleoside diphosphate reductase activity. Selenite has a persistent activating effect on adipocyte mitogen-activated protein kinase and S6 ribosomal protein kinase, which are important components in the phosphorylation cascade of insulin signaling, suggesting that selenium is involved in insulin-mediated metabolic regulation [10,11].
2.4 Antagonizing toxic substances
Selenium, as a negatively charged nonmetallic ion, has a strong affinity for positively charged metals and can combine with mercury, methylmercury, cadmium and lead, which are harmful heavy metals in the body, to form metal-selenium-protein complexes and excrete them from the body, thus acting as a detoxification and detoxification agent. Studies have shown that high doses of arsenic can cause high levels of arsenic in the blood, liver and kidney of mice, and after selenium antagonism, the blood and kidney arsenic levels of mice decreased significantly compared with the experimental group of arsenic alone, indicating the role of selenium on arsenic toxicity [12]. As another example, the levels of mercury in the hair of mice were comparable to or slightly higher than those of the mother, and the levels of selenium were basically higher than those of the mother, suggesting that mice can take in more selenium from the mother to counteract mercury toxicity during their fetal developmental stage, and likewise confirming that selenium has an antagonistic effect on mercury toxicity [13].
2.5 Promoting reproduction
Idiopathic miscarriage has repeatedly been shown to be associated with selenium deficiency. Studies have found that women who miscarried or re-miscarried in the first trimester also had significant low serum selenium and that early pregnancy failure may be associated with reduced biofilm and DNA antioxidant protection due to low selenium-dependent GPx concentrations. Studies have also found that selenium levels were lower in nulliparous women who experienced recurrent miscarriages than in control women [2,14].
Both selenium levels and sperm formation are closely related, and selenium is essential for male fertility; selenium is required for testosterone biosynthesis, sperm formation and normal development, and the effect of selenium deficiency on testosterone biosynthesis is significant. Therefore, selenium is essential for the maintenance of male fertility. The spermatozoa of animals fed with selenium-deficient diet showed structural abnormalities in the body, poor sperm motility and a tendency to break the tail, thus reducing the chances of fertilization [2,15].
3, Selenium is involved in thyroid physiological functions
The thyroid gland is known to contain the highest amount of selenium among human organs, especially the follicular epithelial cells express numerous functional selenocysteine-containing enzymes, four types have been identified: Gpx, type I 5′-deiodinase, thioredoxin reductase and selenoprotein P. Selenium has the following major important effects on thyroid function [13].
3.1 Selenium and the thyroid antioxidant system
The synthesis of thyroid hormones in vivo requires the oxidation of iodine to active iodine by thyroid peroxidase (TPO) in the presence of H2O2, followed by iodination of tyrosine residues. During this process, thyroid follicular epithelial cells continuously produce H2O2 in concentrations greater than those required for the iodination of thyroglobulin. Therefore, effective protection against H2O2 and reactive oxygen intermediates is important for the maintenance of normal thyroid function. Glutathione peroxidase is an antioxidant enzyme that removes H2O2 lipids and phospholipid peroxides, thus maintaining the integrity of the cell membrane.
Gpx is divided into intracellular Gpx (eGpx), serum Gpx (pGpx), gastrointestinal Gpx, and phospholipid peroxidase Gpx (PHGpx), the first three of which all break down H2O2 and are composed of four identical subunits, each containing one atom of selenium; while PHGpx prefers to break down phospholipid peroxides and is a membrane-bound enzyme containing one atom of selenium. The thyroid follicular capsule contains selenium and the thyroid gland can be highly expressed COX; moreover, eGpx, pGpx, and PHGpx are all expressed in the thyroid gland [9,15]. In addition, selenoprotein P and thioredoxin reductase have been identified on the thyroid gland. These selenoproteins are associated with various cellular functions, such as redox of transcription factors and cytodetoxification. The presence of the above mentioned selenoproteins forming an antioxidant system is necessary for the thyroid to maintain its normal function.
3.2 Selenium and deiodinase
Thyroid hormones are a class of iodine-containing tyrosine derivatives that are synthesized and secreted by the thyroid follicular epithelium. Thyroid can be divided into 3 types: thyroxine (T4), triiodothyronine (T3) and anti-T3 (rT3). The iodinated methionine deiodinase family (ID enzyme family) is a homodimer consisting of 27 KD subunits and includes three types of iodinated enzymes: IDI, IDII, and IDIII. IDI is found in the liver, kidney, and pituitary gland, and its function is to convert T4 to T3. IDII is found in tissues that cannot utilize T3 in the blood circulation, and its function is to convert T4 to T3 in tissues that cannot utilize T3 in the peripheral circulation. ID III is distributed in the brain, skin and placenta and converts T4 to rT3 and converts T3 to diiodothyronine. Therefore, selenium is involved in the regulatory process of thyroid hormone metabolism. the activity of the ID enzyme system is affected by selenium, with IDI having the greatest influence. Selenium is present in the active center of IDI and is involved in the composition of IDI protein peptide chain in the form of selenocysteine, which has an important role in the functioning of IDI. Therefore, IDI is a prerequisite for the maintenance of normal thyroid function. When the body is deficient in selenium, the activity or expression of IDI is affected and must lead to abnormalities in thyroid hormone metabolism, i.e., elevated plasma thyroid stimulating hormone (TSH) and T4 and decreased T3. And when both selenium and iodine are deficient at the same time, the elevated plasma TSH and T4 concentrations are more pronounced [2,3,16].
4, Selenium and thyroid disease
The role of selenium in the physiological processes of the thyroid gland is pivotal. Abnormal levels of selenium in the body can lead to a variety of diseases such as goiter, autoimmune thyroid disease (AITD), low T3 syndrome and thyroid cancer.
4.1 Goiter
Several studies have shown that plasma selenium and Gpx activity are significantly reduced in children with goiter in low iodine areas, thus inferring that goiter is not only related to iodine, but low selenium also plays an important role. The mechanism may be: (1) low selenium can also cause metabolic disorders in tissues, especially myocardial tissues; mitochondrial oxidative phosphorylation is dysfunctional, and the body needs a relatively stable level of T3 to ensure the metabolic energy required for normal oxidative phosphorylation; deiodinase activity is reduced, and the production of T3 is insufficient to meet the metabolic needs of the body, and TSH elevation feedback regulates the thyroid to secrete more T3; (2) low selenium makes IDI activity in liver and kidney tissues decreases, the production of T3 in peripheral tissues decreases, while the concentration of T4 in blood increases and the concentration of T3 decreases; at the same time, IDII activity in the pituitary gland decreases, which decreases the production of T3 in the pituitary gland and decreases the negative feedback effect of T4, which increases the release of TSH from the pituitary gland; (3) low selenium also affects Gpx activity in the thyroid gland, which makes the clearance of H2O2 produced by cellular metabolism impaired, and then Low selenium causes enhanced thyroid synthesis and secretion due to the above-mentioned reasons, insufficient T3, T4 and iodine reserves in thyroid tissue, increased iodine uptake by the thyroid gland, increased protein-bound iodine, and increased TSH levels resulting in compensatory enlargement of the thyroid gland [17-19].
4.2 Autoimmune thyroiditis (AIT)
Autoimmune thyroiditis (AIT) includes Hashimoto’s thyroiditis, subacute lymphoblastic thyroiditis, and postpartum thyroiditis. It is a T-cell mediated autoimmune attack resulting in the destruction of thyroid cells. The first prospective placebo-controlled clinical trial of selenium for autoimmune thyroiditis was in a selenium-deficient city in eastern Germany [20], where Gartner et al. treated 70 female AIT patients treated with L-T4 replacement, 36 with sodium selenite (Na2SeO3) 200 µg/day (2.53 mmol/day) and 34 were given placebo control. After 3 months, the blood TPOAb titers of patients in the treatment group decreased significantly, with a mean decrease of 36%, and in patients with TPOAb levels greater than 1200 IU/ml TPOAb decreased up to 60%, and 9 patients had completely normal blood TPOAb levels. There was no significant decrease in antibody levels in the control group of patients. In Greece, Mazokopakis et al. treated 80 patients with HT with selenomethionine (SeMet) 200 µg/day (2.53 mmol/day) for 6 months and the mean rate of decrease in patients’ blood TPOAb titers was 9.9%. Subsequently, 40 patients were randomly assigned to group A, which continued selenium supplementation at the original dose for 6 months, and another 40 to group B, which discontinued selenium supplementation, and it was found that TPOAb titers in group A decreased further, with a total decrease of 21% after 12 months , whereas patients in group B had a 4.8% increase in blood TPOAb titers in the latter 6 months compared to the previous period [21]. In Turkey, Turker et al. treated AIT patients with selenomethionine 100 µg/day and found an increase in TPOAb levels (38.1%) after 3 months and a significant decrease in TPOAb levels when the dose was adjusted to 200 µg/day, suggesting that a therapeutic dose of selenium greater than 100 µg/day is necessary to effectively reduce TPOAb and increase Gpx activity in patients [22]. However, Nacamulli et al. studied a physiological dose of selenium (sodium selenite 80 µg/day) to treat milder AIT patients and prevent disease progression and found a 30% and 19% decrease in TPOAb and TgAb, respectively, after 12 months. This is the first trial to show that long-term fixed physiological doses of inorganic selenium can treat AIT [23].
Recently, in a trial in Austria, 18 patients with AIT were treated with sodium selenite 200 µg/day for 3 months without significant changes in blood TPOAb levels [24]. Therefore, there are still many questions about selenium treatment for AIT, such as: why some AIT patients have no effect on selenium supplementation? Is it related to individual differences, duration and modality of treatment, iodine levels in different regions, and what TPOAb values are greater than that when selenium supplementation therapy is needed? etc. More experiments are needed to further prove this.
4.3 Graves’ disease
Wertenbruch [25] et al. found in a study of 83 patients with GD that the TRAb in the non-remitting hair group of GD was significantly higher than that in the remitting group, and although the difference in blood selenium levels between the two groups was not statistically significant, all GD patients with blood selenium concentrations greater than 120 g/L were in remission. Bacic-Vrca et al. found that in 56 patients with GD treated with MMI combined with selenium preparations, thyroid function returned to normal faster in the former group compared with another group of GD patients treated with MMI alone [26].
4.4 Thyroid cancer
Several epidemiological evidences have shown that selenium intake is negatively associated with cancer mortality.Kucharewski et al. found that selenium levels in thyroid tissue were significantly lower in thyroid cancer than in other thyroid diseases and healthy populations, suggesting that low selenium levels in the thyroid gland may increase the risk of thyroid cancer. The possible mechanisms are: selenium-containing compounds can affect the proliferative cycle and regulation of tumor cells; selenium also has many effects on cell biochemistry and function; in addition, selenium can affect the immune function of the body [18, 27-29].
4.5 Low T3 syndrome
Studies have shown that those who were given selenium salts to critically ill patients suffering from severe diseases (especially those in ICU wards) recovered their T4 and T3 levels earlier than controls, and despite normal thyroid function in ICU patients, they also often showed a significant decrease in serum T3 with normal T4, and such patients were often accompanied by low blood selenium values. It is suggested that low T3 may be related to reduced IDI activity, and selenium supplementation may reduce the degree of serum T3 decrease. In addition, reduced blood selenium may be associated with negative emotional (e.g., pain, anxiety, etc.) effects in critically ill patients [30, 31].
5, Conclusion
In conclusion, selenium plays an important role in the maintenance of normal body functions as well as the function of the thyroid axis, and selenium deficiency is associated with many thyroid disorders. Due to the lack of specificity, serum selenium levels cannot be used as diagnostic criteria for thyroid disorders. Given that most studies have found that serum selenium levels are significantly lower in patients with thyroid disease than in healthy populations, appropriate selenium supplementation should be considered, which provides new ideas for clinical practice, but the timing and dose of selenium supplementation should be mastered. In addition, except for the pathogenesis of selenium on goiter which is well studied, the role of selenium on other thyroid diseases is not perfect and needs to be explored more deeply.