On the Centennial of Vitamin D-Vitamin D, Inflammation, and Autoimmune Thyroiditis: A Web of Links and Implications.

The 100th anniversary of the discovery of vitamin D3 (VitD3) coincides with significant recent advances in understanding its mechanism of action along with accumulating knowledge concerning its genomic and nongenomic activities. A close relationship between VitD3 and the immune system, including both types of immunity, innate and adaptive, has been newly identified, while low levels of VitD3 have been implicated in the development of autoimmune thyroiditis (AIT). Active 1,25(OH)2 D3 is generated in immune cells via 1-α-hydroxylase, subsequently interacting with the VitD3 receptor to promote transcriptional and epigenomic responses in the same or adjacent cells. Despite considerable progress in deciphering the role of VitD3 in autoimmunity, its exact pathogenetic involvement remains to be elucidated. Finally, in the era of coronavirus disease 2019 (COVID-19), brief mention is made of the possible links between VitD3 deficiency and risks for severe COVID-19 disease. This review aims to commemorate the centennial of the discovery of VitD3 by updating our understanding of this important nutrient and by drawing up a framework of guidance for VitD3 supplementation, while emphasizing the necessity for personalized treatment in patients with autoimmune thyroid disease. A tailored approach based on the specific mechanisms underlying VitD3 deficiency in different diseases is recommended.

The role of selenium in type-2 diabetes mellitus and its metabolic comorbidities.

This review addresses the role of the essential trace element, selenium, in type-2 diabetes mellitus (T2DM) and its metabolic co-morbidities, i.e., metabolic syndrome, obesity and non-alcoholic fatty liver disease. We refer to the dietary requirements of selenium and the key physiological roles of selenoproteins. We explore the dysregulated fuel metabolism in T2DM and its co-morbidities, emphasizing the relevance of inflammation and oxidative stress. We describe the epidemiology of observational and experimental studies of selenium in diabetes and related conditions, explaining that the interaction between selenium status and glucose control is not limited to hyperglycemia but extends to hypoglycemia. We propose that the association between high plasma/serum selenium and T2DM/fasting plasma glucose observed in many cross-sectional studies may rely on the upregulation of hepatic selenoprotein-P biosynthesis in conditions of hyperglycemia and insulin resistance. While animal studies have revealed potential molecular mechanisms underlying adverse effects of severe selenium/selenoprotein excess and deficiency in the pathogenesis of insulin resistance and ß-cell dysfunction, their translational significance is rather limited. Importantly, dietary selenium supplementation does not appear to be a major causal factor for the development of T2DM in humans though we cannot currently exclude a small contribution of selenium on top of other risk factors, in particular if it is ingested at high (supranutritional) doses. Elevated selenium biomarkers that are often measured in T2DM patients are more likely to be a consequence, rather than a cause, of diabetes.

Selenium and at-risk pregnancy: challenges and controversies.

Selenium (Se), an essential trace element, is inserted as selenocysteine into an array of functional proteins and forms the core of various enzymes that play a cardinal role in antioxidant defense mechanisms, in redox regulation, and in thyroid hormone metabolism. Variations in plasma Se are due to nutritional habits, geographic and ethnic differences, and probably to genetic polymorphisms, the latter still to be conclusively established. Se concentrations were reported to be low in women of reproductive age in the UK, decreasing further during pregnancy, this resulting in low plasma and placental antioxidant enzyme activities. Since low serum Se levels have been found in women with preeclampsia, it has been hypothesized that low maternal Se status during early gestation may be an indicator of preterm birth. Moreover, it is documented that Se administration during pregnancy tendentially reduced the markers of thyroid autoimmunity and the incidence of maternal hypothyroidism in the postpartum period. Importantly, low Se levels in pregnant women affect fetal growth and augment the risk of delivering a small-for-gestational age infant by reducing placental antioxidant defense, while low Se in the third trimester is thought to indicate increased demands by the placenta, an issue which requires further confirmation. There is evidently a need for double-blind, placebo-controlled studies to better determine the efficacy and safety of Se supplementation in pregnancy at high risk for complications, and for measurement of Se levels or of selenoprotein P, the most reliable parameter of Se status, particularly in selenopenic regions.

50 years of the ETA: "the selenium connection".

The recent celebration of the 50 years of the ETA closely coincided with that of the 200 years since the discovery and description of selenium, an essential trace element for normal thyroid gland function and thus an adjuvant in the treatment of thyroid diseases. The aim of this commentary is to briefly outline the half centennial of the ETA while also signaling important moments in the history of selenium, developments in its availability round the world, details of its connection with thyroid function and, finally, its current and projected modes of application.

Evidence for a manifold role of selenium in infertility.

This review aimed to assess the evidence from observational and interventional studies in humans and animals regarding the role of selenium (Se) in male and female infertility. As oxidative stress can seriously impair male, and possibly also female, reproductive functions, it can be speculated that the antioxidant properties of Se could constitute one of the pathways by which this element is involved in fertility. Specifically, there are strong indications that Se influences the growth, maturation, and replication of oocytes, though the precise mechanisms have not as yet been fully elucidated. Given that it is not clear at present which tissue sample (blood, serum, seminal plasma, sperm, or follicular fluid) renders the most accurate picture of Se concentration in terms of its role in reproduction, the data are still insufficient to recommend routine assessment of Se status in men and women seeking fertility. Nevertheless, the existing evidence, despite being of limited quantity and somewhat low quality, suggests that Se supplementation (< 200 µg/d) is possibly beneficial in men through its improvement of sperm motility. Well-designed, randomized control studies are needed to reveal the seemingly diverse protective/positive role of Se supplementation in men and women seeking fertility treatment.

Impaired Metabolism of Selenomethionine in Graves' Disease: A Biokinetics Study of Soft Gel Capsule Formulation.

Patients with Graves' disease are known to have low selenium (Se) status, Se supplementation resulting in clinical and biochemical improvement. Selenomethionine (SeMet) in a new soft gel capsule formulation was used in a pilot study in 6 patients with acute Graves' disease and low selenium levels (61.3±12.9 µg/l) before and in 4/6 patients 3 months after combined treatment with methimazole and SeMet 200 µg/day (113.3±46.3 µg/l), as well as in 6 euthyroid controls (82±11.8 µg/l). The biokinetics were studied following ingestion of 200 µg SeMet (single dose) soft gel capsule, Se serum concentrations being measured at various time points within 24 h. Se levels rose variably in all patients and controls. While levels peaked in all subjects following 8 h of intake, the increase was somewhat slower in acute hyperthyroidism as compared to 3 months later when these patients had been rendered euthyroid, this possibly due to derangement of Se storage capacity by SEPP or increased requirements in the acute phase of the disease, leading to depletion of the trace element. The compound was shown to be bioavailable and safe and patients treated for 3 months exhibited higher Se levels at the different time points. These findings are of major importance for sufferers of GD since they indicate that early Se supplementation, with its beneficial antioxidant impact on inflammatory activity, could slow, or possibly even forestall, the clinical progression of the disease.

Selenium: an element for life.

This review aims to illustrate the importance of selenium (Se) for maintenance of overall health, especially for the thyroid, immunity, and homeostasis. Furthermore, it outlines the role of Se in reproduction and in virology and discusses the effects of Se supplementation in critical illness. The multifaceted aspects of this essential nutrient have attracted worldwide clinical and research interest in the last few decades. Se exerts its activity in the form of the aminoacid selenocysteine incorporated in selenoproteins. The impact of Se administration should be considered in relation to its apparent U shaped effects, i.e., exhibiting major advantages in Se-deficient individuals but specific health risks in those with Se excess. Addition of selenium to the administration of levothyroxine may be useful in patients with low Se intake and with mild-form or early-stage Hashimoto's thyroiditis (HT). Serum Se concentration (possibly also at tissue level) decreases in inflammatory conditions and may vary with the severity and duration of the inflammatory process. In such cases, the effect of Se supplementation seems to be useful and rational. Meanwhile, Se's ability to improve the activity of T cells and the cytotoxicity of natural killer cells could render it effective in viral disease. However, the evidence, and this should be stressed, is at present conflicting as to whether Se supplementation is of benefit in patients with HT, though there are indications that it is advantageous in cases of mild/moderate Graves' Orbitopathy. The role of Se in type 2 diabetes mellitus (T2DM) is ambiguous, driven by both Se intake and serum levels. The evidence that insulin and glycaemia influence the transport and activity of Se, via regulatory activity on selenoproteins, and that high serum Se may have a diabetogenic effect suggests a 'Janus-effect' of Se in T2DM. Though the evidence is not as yet clear-cut, the organic form (selenomethionine), due to its pharmacokinetics, is likely to be more advantageous in long-term prevention, and supplementation efforts, while the inorganic form (sodium selenite) has proven effective in an acute, e.g., sepsis, clinical setting. Recent data indicate that functional selenoprotein single-nucleotide polymorphisms (SNPs) may interfere with Se utilization and effectiveness.

Toxic chemicals and thyroid function: hard facts and lateral thinking.

Increasing quantities of evidence-based data incriminate a large number of environmental pollutants for toxic effects on the thyroid. Among the many chemical contaminants, halogenated organochlorines and pesticides variably affect the hypothalamic-pituitary-thyroid axis and disrupt thyroid function. PCBs and their metabolites and PBDEs bind to thyroid transport proteins, such as transthyretin, displace thyroxine, and disrupt thyroid function. Meanwhile, at the molecular level, PCB congeners may activate phosphorylation of Akt, p-Akt, and forkhead box O3a (FoxO3a) protein resulting in inhibition of the natrium/iodide symporter. Given therefore the growing concern developing around these multiple toxic chemicals today invading numerous environments and their long-term deleterious effects not only on the thyroid but also on general health, we strongly advocate their strict regulation and, moreover, their gradual reduction. A good degree of "lateral thinking", we feel, will lead to a use of chemicals that will enhance life while concurrently carefully protecting the environment.

The evolving role of selenium in the treatment of graves' disease and ophthalmopathy.

Graves' disease (GD) and ophthalmopathy (GO) are organ-specific autoimmune-inflammatory disorders characterized by a complex pathogenesis. The inflammatory process is dominated by an imbalance of the antioxidant-oxidant mechanism, increased production of radical oxygen species (ROS), and cytokines which sustain the autoimmune process and perpetuate the disease. Recently, selenium, which is a powerful antioxidant, has been successfully applied in patients with mild GO, slowing the progression of disease, decreasing the clinical activity score, and appreciably improving the quality of life. The mechanisms of selenium action are variable. The aim of this review is to summarize the actions of selenium in GD and GO. Selenium as selenocysteine is incorporated in selenoproteins, such as glutathione peroxidase which catalyzes the degradation of hydrogen peroxide and lipid hydroperoxide that are increasingly produced in hyperthyroidism. Moreover, selenium decreases the formation of proinflammatory cytokines, while it contributes, in synergy with antithyroid drugs, to stabilization of the autoimmune process in GD and alleviation of GO. It is now to be clarified whether enforced nutritional supplementation has the same results and whether prolonging selenium administration may have an impact on the prevention of disease.

Sorafenib: rays of hope in thyroid cancer.

BACKGROUND: Sorafenib (BAY 43-9006) is an inhibitor of multiple-receptor tyrosine kinases involved in tumor growth and angiogenesis, which can be advantageously administered orally. Initially used as monotherapy in advanced renal cell carcinoma, sorafenib was proven to increase progression-free survival while enhancing disease control. Clinical trials on sorafenib are at present ongoing for the treatment of various malignancies, including thyroid cancer (TC). SUMMARY: Specifically, in two phase II studies recently conducted on papillary TC, although the respective results were not entirely compatible as regard partial response rate and progression-free survival, sorafenib demonstrated a relatively favorable benefit/risk profile. In another more recent phase II study, whose primary endpoint was the reinduction of radioactive iodine uptake at 26 weeks, although no reinduction of radioactive iodine uptake was observed, 59% had a beneficial response and 34% had stable disease. Sorafenib hence appears to be a valid alternative to conventional treatment of metastatic papillary TC refractory to radioiodine therapy. CONCLUSIONS: Further prospective investigations are required to define the characteristics of tumor response to the drug and the factors inducing resistance to treatment. A major issue demanding immediate attention involves optimization of sorafenib treatment: this concerns multidrug combination with different tyrosine kinase inhibitors or immunomodulating agents with the aim of reducing doses and thereby improving drug tolerability and antineoplastic capability.

Selenium and the thyroid: a close-knit connection.

CONTEXT: The recent recognition that the essential trace element selenium is incorporated as selenocysteine in all three deiodinases has decisively confirmed the clear-cut link between selenium and thyroid function. It has additionally been established that the thyroid contains more selenium than any other tissue and that selenium deficiency aggravates the manifestation of endemic myxedematous cretinism and autoimmune thyroid disease. EVIDENCE ACQUISITION: Clinical reports as well as a large number of biochemical articles linking selenium to thyroid have been considered. Interventional, prospective, randomized, controlled studies, including large observational studies, supplementing selenium in autoimmune thyroid disease, together with review articles published in Medline and Pubmed have undergone scrutiny. The methodological differences and variety of results emerging from these trials have been analyzed. EVIDENCE SYNTHESIS: Evidence in support of selenium supplementation in thyroid autoimmune disease is evaluated, the results herein presented demonstrating the potential effectiveness of selenium in reducing the antithyroid peroxidase titer and improving the echostructure in the ultrasound examination. However, considerable discord remains as to who should comprise target groups for selenium treatment, who will most benefit from such treatment, the precise impact of the basal antithyroid peroxidase level, and the effect of disease duration on the treatment outcome. Clearly, further in-depth studies and evaluation are required concerning the mechanism of action of selenium as well as the choice of supplements or dietary intake. CONCLUSIONS: Maintenance of "selenostasis" via optimal intake not only aids preservation of general health but also contributes substantially to the prevention of thyroid disease.

Environmental factors and autoimmune thyroiditis.

Autoimmune thyroiditis, of which Hashimoto thyroiditis represents the most frequent form, is an inflammatory state of the thyroid gland that results from the interaction between genetic variants that promote susceptibility and environmental factors. High iodine intake, selenium deficiency, pollutants such as tobacco smoke, infectious diseases such as chronic hepatitis C, and certain drugs are implicated in the development of autoimmune thyroiditis, primarily in genetically predisposed people. Long-term iodine exposure leads to increased iodination of thyroglobulin, which increases its antigenicity and initiates the autoimmune process in genetically susceptible individuals. Selenium deficiency decreases the activity of selenoproteins, including glutathione peroxidases, which can lead to raised concentrations of hydrogen peroxide and thus promote inflammation and disease. Such environmental pollutants as smoke, polychlorinated biphenyls, solvents and metals have been implicated in the autoimmune process and inflammation. Environmental factors have not yet, however, been sufficiently investigated to clarify their roles in pathogenesis, and there is a need to assess their effects on development of the autoimmune process and the mechanisms of their interactions with susceptibility genes.

The role of selenium in thyroid autoimmunity and cancer.

The essential micronutrient selenium (Se) occurs in the form of the amino acid selenocysteine in selenoproteins which exert various effects, while maintaining the cell reduction-oxidation balance. The discovery that all three deiodinases that convert thyroxine (T4) into triiodothyronine (T3) contain selenocysteine illustrates how the production of the active thyroid hormone is dependent on Se status. The selenoenzyme families of glutathione peroxidases (GPx) and thioredoxin reductases (TRx) possess powerful antioxidant properties and form a complex defense system that protects thyrocytes from oxidative damage. Se supplementation in patients with autoimmune thyroiditis seems to modify the immune response, probably by enhancing plasma GPx activity and decreasing excess levels of hydrogen peroxide. However, the enhancement of immunocompetence may also be the result of the synergistic action of various selenoproteins and not exclusively of GPx. There is evidence supporting considerable oxidative stress in Graves' disease where Se supplementation, because of its free radical scavenging properties, may increase the enzymatic antioxidant activity. TRx has been found significantly elevated in GD revealing its involvement in the pathogenesis of this condition and representing a potential future target for therapeutical intervention. Low Se serum levels have also been associated with increased risk of thyroid cancer and may play a role in carcinogenesis. It is noteworthy, that the Food and Drug Administration has recently determined that there is sufficient evidence to warrant a qualified health claim for Se and cancer. Furthermore, the recent discovery that defects in the SECIS-binding protein 2 (SBP2), which is an indispensable protein for the incorporation of Se into the selenoproteins, result in thyroid dysfunction, together with the recognition of the many roles of selenoprotein P in Se distribution and storage in the human body, reveal not only the indispensability of Se and the selenoproteins as essential factors in thyroid metabolism and pathogenesis, but open up new prospects for enhanced treatment.

Brain somatic cross-talk: ghrelin, leptin and ultimate challengers of obesity.

Energy balance is largely regulated by the central nervous system (CNS), which senses metabolic status from a wide range of humoral and neural signals, and controls energy intake. Accumulating evidence supports the model that stimulation of leptin- and ghrelin-responsive pathways, including the central melanocortin system, in the hypothalamus, contributes to the maintenance of body weight. Ghrelin is the brain-gut peptide with growth hormone-releasing and appetite-inducing activities. It is mainly secreted from the stomach and acts as an afferent signal to the hypothalamus and hindbrain. Leptin, the adipocyte hormone, is believed to tonically act as an afferent signal from adipose tissue to the brain, in particular hypothalamus, as a part of negative feedback loop regulating the size of energy stores and energy balance. Dysregulation of these pathways is a marker of changes in energy balance. Ghrelin is negatively correlated with weight and obese subjects have lower ghrelin levels than lean subjects, consistent with a compensatory rather than causal role for ghrelin in obesity. On the contrary, circulating leptin levels correlate in proportion to adiposity being high in obesity suggesting that human obesity is associated with insensitivity to leptin. The leptin resistance in diet-induced obesity emphasizes that environmental factors can modulate leptin sensitivity. It is speculated that through hypothalamic/pituitary axis ghrelin and leptin operate as a metabolic switch. Ghrelin actually transfers information from the stomach to the hypothalamus in cooperation with leptin and provides calories that growth hormone (GH) needs for growth and repair. Pharmacological manipulations of circulating hormone levels may work well in "cheating" the brain regarding information from the periphery. It might also be necessary to combine two or three agents to fight obesity. A combination of drugs that decrease preprandial appetite (ghrelin antagonist) and increase post-prandial satiety (gut hormone fragment peptide YY 3-36) might have a chance of achieving sustained weight loss. The administration of exogenous satiety hormone peptide YY 3-36 (PYY) may prevent the action of appetite-stimulating hypothalamic circuits on the anorexigenic melanocortin pathways.

Effects of a six month treatment with selenomethionine in patients with autoimmune thyroiditis.

OBJECTIVE: Selenium (Se) in the form of selenocysteine is an essential component of the family of the detoxifying enzymes glutathione peroxidase (Gpx) and of the iodothyronine selenodeiodinases that catalyse the extrathyroidal production of tri-iodothyronine (T(3)). Thus, Se deficiency may seriously influence the generation of free radicals, the conversion of thyroxine (T(4)) to T(3) and the autoimmune process. Therefore, we performed a randomised, placebo-controlled prospective study to investigate the effects of Se treatment on patients with autoimmune thyroiditis (AIT). DESIGN AND METHODS: Sixty five patients aged 22-61 years (median age 48 years) with AIT were recruited into two groups. Group I (Gr I) (n=34) was treated with selenomethionine (Seme) 200 microg, plus L-thyroxine (LT(4)) to maintain TSH levels between 0.3-2.0 mU/l, whereas group II (Gr II) (n=31) received LT(4) plus placebo over a period of 6 months. Moreover, the pharmacokinetics of Seme were studied in 10 patients and eight volunteers at baseline and 2 h, 4 h, 6 h and 24 h after oral administration of a 200 microg tablet of Seme. Finally, Se levels were measured at the end of the study in some patients of both groups and their results were correlated with thyroid hormone levels. RESULTS: In the pharmacokinetics study, basal serum concentration of Se (75+/-6 microg/l) was within the reference range (70-125 microg/l), it promptly increased at 2 h, peaked at 4 h (147+/-17 microg/l; P<0.0001) and it was abundant in serum at 24 h. In Gr I, antibodies against thyroid peroxidase (anti-TPO) levels showed an overall decrease of 46% at 3 months (from 1875+/-1039 U/l to 1013+/-382 U/l; P<0.0001) and of 55.5% at 6 months. In Gr II the overall decrease of anti-TPO amounted to 21% at 3 months and to 27% at 6 months (from 1758+/-917 U/l to 1284+/-410 U/l; P<0.005). There were no significant changes of antibodies against thyroglobulin levels between the groups. At the end of this study Se levels were found to be statistically significantly increased in Gr I (n = 9/34) compared with Gr II (n=11/31) (97+/-8.4 vs 79+/-8; P<0.01) but no correlation with thyroid hormone was found. CONCLUSIONS: Seme is proven to be rapidly absorbed by the gastrointestinal tract. It appears to be useful as adjunctive therapy with LT(4) in the treatment of AIT. The exact mechanism(s) is not very well determined, it might enhance the activity of detoxifying enzymes and enforce the defense against oxidative stress.