Reassessing Selenium for the Management of Hashimoto's Thyroiditis: The Selini Shines Bright for Autoimmune Thyroiditis Patients

Selenium (Se) derived its name from the Greek word σɛλήνη (meaning “moon” or the ancient Greek goddess of the moon ^* ). It is an essential trace element that participates in a crucial way in the production of thyroid hormones, immune system regulation, and maintenance of bodily homeostasis. Se, in the form of the 21st proteinogenic amino acid selenocysteine, is incorporated in at least 25 unique selenoproteins, which play a vital role in the life of animals and humans. ¹

Autoimmune thyroiditis (AIT), of which Hashimoto's thyroiditis (HT) is the most common form, occurs when the immune system mistakenly attacks the thyroid gland, causing inflammation and impaired hormone production. ² Genetic susceptibility is triggered by environmental factors, with stress, nutrition (e.g., high iodine intake, Se and Vit D3 deficiencies), and viruses being among the most important. ³ Indeed, recent data from China suggest that Se deficiency elevates the risk of developing AIT and precipitates its progression, ⁴ impairing antioxidant defense mechanisms and thus facilitating the generation of thyroid autoantibodies and inflammation.

Several studies have investigated the effects of Se supplementation on AIT, although with somewhat conflicting results. ⁵ The reasons might be the different Se species, low levels of environmental Se, the inhomogeneity of the study group concerning severity of disease and gender, the duration of the studies, and technical issues. Both forms of Se supplementation, organic (selenomethionine) and inorganic (selenite), have been shown to significantly reduce thyroid peroxidase antibodies (TPOAB) titers. However, organic Se, in the form of selenomethionine (SeMet) or yeast enriched with SeMet, is likely to be more efficient. SeMet is bound to proteins, its therapeutic action developing slowly but constantly with gradual accumulation in blood over the time of administration accompanied by increased activity of glutathione peroxidase (GPX1), one of the most antioxidant mediators in humans. ^6,7 Moreover, the increase of selenoprotein thioredoxin reductase activity, an antioxidant factor that protects cells from the toxic effects of free radicals and participates in the oxidation of hydrogen peroxide

[H₂O₂] and lipid hydroperoxides contribute substantially to the antioxidant effects of Se supplementation. ⁸

In this issue of the journal, Huwiler et al. from the University Hospital of Bern, Switzerland, report on the results of a systematic review and meta-analysis of randomized controlled trials (RCTs). ⁹ Specifically, this meta-analysis reviewed and analyzed the effect of Se supplementation on thyrotropin (TSH), free and total thyroxine, and free and total triiodothyronine, as well as on TPOAb, thyroglobulin antibodies, thyrotropin receptor antibodies, ultrasound (US) examinations, and immune biomarkers [interleukin (IL) 2 and 10 (IL10)], while also evaluating patient outcomes and adverse effects of the trace element. Furthermore, a meta-analysis of 35 studies including 2036 patients showed that Se supplementation decreased TSH in patients without levothyroxine treatment [LT4T] (standardized mean difference [SMD] −0.21 [95% CI −0.43, −0.02]), while TPOAb (SMD −0.96 [95% CI −1.36, −0.56]) and malondialdehyde (SMD −1.16 [95% CI −2.29, −0.02]), an indicator of oxidative stress and inflammation, was statistically significantly reduced in patients with and without LT4T. No significant changes were observed in the other thyroid hormone levels, in immune parameters, or in thyroid volume in US examinations. However, the certainty of evidence was moderate by applying the Grading Recommendations Assessment, Development, and Evaluation method.

The authors, who have conducted a meticulous analysis of the existing RCTs by using various complex statistical methods, have delivered important data. The most relevant result of this meta-analysis is the decrease of TSH in those HT patients without LT4T. A similar finding was reported only in one RCT. ⁷ The decrease of TSH remained consistent, or even strengthened, in euthyroid patients, in patients with subclinical hypothyroidism, in adults, and in those receiving Se for up to 6 months. The reduction of TSH via Se supplementation in non-LT4T patients is, admittedly, difficult to explain. Most of the selenoproteins are expressed in the thyroid; therefore, enhanced activity of local selenoproteins, such as iodothyronine deiodinases (DIOs), selenoprotein P (SELENOP), GPXs, and thioredoxin reductases, among others, may lead to upregulation of antioxidant defense mechanisms, modulation of TPO activity, and heightened H2O2 production, thereby resulting in regulation of oxidative stress. However, a central component in this mechanism is not excluded as the increased Se content in the brain provided by SELENOP may increase intracellular GPX and reverse the inhibition of DIO2 and DIO3 by H2O2, as shown in translational studies. ¹⁰

Another important aspect of the meta-analysis is the confirmation of the safety of Se in the reported doses of up to 200 μg/day. As shown in many other studies, patient safety was ensured, and no serious adverse effects were reported with the applied doses.

Very recently, the results of the chronic autoimmune thyroiditis quality of life selenium trial (CATALYST), a multicenter study from Denmark investigating the effects of Se supplementation on disease-specific QoL in patients with hypothyroidism due to HT, were published. ¹¹ No impact on QoL was reported, in agreement with four out of six studies evaluated in the current meta-analysis which also did not show any effect on well-being. The CATALYST also reported a decrease in TPOAb titers following 200 μg Se supplementation in the form of Se-enriched yeast over 12 months, as compared to the matched placebo group.

Se has long been recognized as a polyvalent nutrient with a narrow therapeutic-to-toxic range. The results of this analysis pave the way to future studies with a longer period of treatment of euthyroid AIT patients with positive TPOAb to determine whether they can be seroconverted and if there is any relation to Se levels, duration of disease, and gender. Though the clinical benefit of Se supplementation in patients under LT4T is not at present clear, it is hypothesized that Se administration may attenuate the intensity of the inflammatory process. Further trials are warranted to corroborate the current findings.

However, these studies are difficult to replicate in seleniferous countries such as the United States and Canada, which have a higher Se soil content than many other countries. It is also of note that Se may interact with several drugs such as contraceptives and statins, among others. ^12,13

The encouraging findings of the above studies tend to promote the use of Se for the treatment of HT. It thus seems likely that Se's previous image as all too often a toxic compound is behind us and that this once “mysterious” element named after the “enigmatic” “selini”/moon, is, in various ways, gradually showing us ever brighter sides.

Author's Contributions

L.H.D. is responsible for the conceptualization, writing, reviewing, and editing of this article.