A 2018 meta-analysis of randomized controlled trials shows that adjuvant selenium supplementation may enhance the restoration of normal thyroid function in patients with Graves’ Disease [Zheng].
Graves’ Disease is the most common cause of hyperthyroidism in adults. It is characterized by below-normal serum TSH levels and increased serum levels of free thyroxine (FT4) and/or triiodothyronine (T3). The basal metabolic status of Graves’ Disease patients is accelerated; the result is an increase in the production of harmful free radicals and reactive oxygen species [Zheng].
Intra-cellular antioxidant enzymes such as superoxide dismutase (SOD), glutathione reductase, and glutathione peroxidase (GPx) protect against the cellular damage caused by oxidative stress.
Selenium Essential for Healthy Thyroid Hormone Metabolism
In the body, very little of the selenium from selenium supplements exists in the elemental form. Some of the selenium is incorporated in the amino acid selenocysteine. The selenocysteine in turn becomes a component of 25 known selenoproteins, one of which is glutathione peroxidase.
Glutathione peroxidase is the name for a family of eight different glutathione peroxidase seleno-enzymes. Glutathione peroxidase enzymes catalyze the degradation of hydrogen peroxide and lipid hydroperoxide, both of which are increased in cases of Graves’ Disease.
Selenium and Autoimmune Thyroiditis
Selenoproteins are known to have an irreplaceable role in thyroid autoimmune processes [Zheng]:
- Selenium deficiency is an important factor in the initiation and progression of autoimmune thyroid disease.
- Serum selenium levels of patients with newly diagnosed Graves’ Disease are generally lower than those of random controls.
- Serum selenium levels greater than 120 micrograms per liter have been observed in the remission group of one study of outcomes of Graves’ Disease.
- Selenium supplementation may increase the efficacy of drug therapy and ameliorate thyroid function in cases of recurrent hyperthyroidism caused by Graves’ Disease.
- Low selenium status is associated with Graves’ ophthalmopathy.
- A 2016 meta-analysis showed that selenium supplementation significantly reduces thyroid auto-antibody levels in patients with chronic autoimmune thyroiditis [Wichman].
- A 2014 meta-analysis showed that selenium supplementation is associated with a significant decrease in thyroid peroxidase auto-antibodies at 6 and 12 months; after the selenium supplementation, patients had a higher chance to improve their mood without significant adverse events [Fan].
Selenium Supplementation and Graves’ Disease: Meta-Analysis
The researchers analyzed the results of nine randomized, double-blind, placebo-controlled trials enrolling 736 participants [Zheng].
- The aggregated data showed that, compared with the control group, the combination of selenium supplementation with the conventional hyperactive thyroid medication was associated with a significant decrease in the FT3 at 3 months (two studies) and at 6 months (four studies) but not at 9 months (three studies) [Zheng]
- The pooled data on FT4 levels in the nine trials (736 participants) showed a significant decrease in the FT4 levels among participants in the adjuvant selenium treatment group compared to the control participants at 3 months (two studies) and at 6 months (four studies) but not at 9 months (three studies) [Zheng].
- In seven of the trials, involving 651 participants, adjuvant selenium treatment was associated with a significant increase in the TSH levels at 6 months (three studies) compared to the control group but not at 3 months (one study) or at 9 months (three studies) [Zheng].
- In six studies with 736 participants, the adjuvant selenium treatment group had a significant decrease in TRAb levels at 6 months (three studies) but not at 9 months (three studies) compared with the control group [Zheng].
Why the Selenium Effect at 6 Months but not 9 Months?
The meta-analysis showed clinically important and statistically significant effects of combined selenium and conventional thyroid medication on the FT4, FT3, TSH, and TRAb levels in patients with Graves’ Disease at 3 months and 6 months of adjuvant supplementation.
Why, then, was 9 months of the adjuvant selenium supplementation seemingly no more effective in controlling Graves’ Disease than conventional thyroid medication alone?
U-Shaped Curve of Selenium Effect
The researchers suggest that the positive effect of the adjuvant selenium supplementation at 6 months and the neutral effect at 9 months may be related to what is called the U-Shaped Theory of Selenium Status.
Professor Margaret P. Rayman in Figure 2 in her 2019 review article entitled “Selenium intake, status, and health: a complex relationship” indicates that the optimal serum selenium status for good health is around 125 micrograms per liter [Rayman].
At serum levels much less than this, in particular at 85 micrograms per liter or lower, there is increased risk of thyroid autoimmune disease, poorer immune response, increased mortality, etc [Rayman].
Similarly, at serum levels considerably above 125 micrograms per liter – Professor does not specify an upper threshold – there are presumably also increased health risks [Rayman].
In the case of adjuvant selenium supplementation of Graves’ Disease patients, it could be that the selenium supplementation during the first six months builds up the patients’ serum status to the extent that gives a beneficial effect.
Then, in the next three months up to nine months of selenium supplementation, it could be that the serum selenium status has increased to the point that the effect begins to flatten out. At that point, there is no longer a significant difference between the effect of conventional thyroid medication alone and the effect of selenium supplementation together with conventional thyroid medication.
Selenium Supplementation for Patients with Graves’ Hyperthyroidism (the GRASS Trial)
Meanwhile, we wait for the GRASS trial of selenium supplementation for patients with Graves’ hyperthyroidism to be completed and the results to be published. The GRASS trial is a multi-center randomized, double-blind, placebo-controlled study in which the researchers intend to enroll 492 participants, randomized (1:1) to two tablets of 100 micrograms of selenium once daily for the 24 to 30 months intervention period versus two identical placebo tablets once daily [Watt].
The primary outcome of the GRASS trial is the proportion of participants with anti-thyroid drug treatment failure at the end of the intervention period (24 to 30 months) [Watt].
Secondary outcomes are [Watt]:
- thyroid-specific quality of life during the first year after randomization
- level of thyroid stimulating hormone-receptor antibodies at 18 months after randomization and at the end of the intervention period (24 to 30 months)
- hyperthyroid symptoms during the first year after randomization
- eye symptoms during the first year after randomization and at the end of the intervention period (24 to 30 months)
- adverse reactions during the intervention period
- serious adverse events during the intervention period
Sources
Fan Y, Xu F, Zhang H, Cao W, Wang K, Chen G, Di H, Cao M & Liu C. (2014). Selenium supplementation for autoimmune thyroiditis: a systematic review and meta-analysis. International Journal of Endocrinology Volume 2014, Article ID 904573. http://dx.doi.org/10.1155/2014/904573
Rayman, MP. (2019). Selenium intake, status, and health: a complex relationship. Hormones, doi: 10.1007/s42000-019-00125-5. [Epub ahead of print].
Watt, T, Cramon P, […], & Krogh Rasmussen Å. (2013) Selenium supplementation for patients with Graves’ hyperthyroidism (the GRASS trial): study protocol for a randomized controlled trial. Trials; 14: 119.
Wichman J, Winther KH, Bonnema SJ & Hegedüs L (2016). Selenium supplementation significantly reduces thyroid autoantibody levels in patients with chronic autoimmune thyroiditis: a systematic review and meta-analysis,” Thyroid, 26(12):1681–1692.
Zheng H, Wei J, Wang L, Wang Q, Zhao J, Chen S & Wei F. (2018). Effects of selenium supplementation on Graves’ Disease: a systematic review and meta-analysis. Evidence-Based Complementary and Alternative Medicine; Volume 2018, Article ID 3763565. https://doi.org/10.1155/2018/3763565
The information presented in this review article is not intended as medical advice and should not be used as such.
3 February 2020