Selenium supplementation in people with Hashimoto's thyroiditis might reduce antibody levels and result in a decreased dosage of levothyroxine (LT4) and may provide other beneficial effects (e.g. on mood and health-related quality of life). The aim of our systematic review was to assess the effects of selenium supplementation on Hashimoto's thyroiditis. We searched The Cochrane Library, MEDLINE, EMBASE and Web of Science for randomized controlled trials. Study selection, data extraction, assessment of risk of bias and analyses were carried out by two independent review authors. We assessed the quality of the evidence of included studies using GRADE. Four studies rated at unclear to high risk of bias comprising 463 participants were included. One study at high risk of bias showed statistically significant improvement in subjective well-being with sodium selenite 200 μg plus titrated LT4 compared with placebo plus titrated LT4 (RR 4.67, 95% CI 1.61-13.50). Selenomethionine 200 μg as a single treatment or combined with LT4 reduced the serum levels of anti-thyroid peroxidase antibodies compared with placebo (or placebo plus LT4) in three studies (p < 0.001). Although the changes from baseline were statistically significant in these three studies, their clinical relevance is unclear. In conclusion, the results of these four studies, assessed at unclear to high risk of bias, show that evidence to support or refute the efficacy of selenium supplementation in people with Hashimoto's thyroiditis is incomplete and not reliable to help inform clinical decision making.
Hashimoto's thyroiditis or chronic lymphocytic thyroiditis is a common autoimmune disorder which tends to run in families and affects both genders at any age, although it is most often seen in middle-aged women [1,2]. Its prevalence is influenced by ethnicity, environmental factors, such as iodine and selenium status, age and gender [1,2]. Clinical manifestations of the disease are caused primarily by low levels of thyroid hormones, for which the treatment is hormone replacement therapy, which usually consists of levothyroxine (LT4) .
Selenium is an essential trace element that is required for the correct functioning of the immune system with a recommended daily intake for adults of 55 μg . Natural selenium-rich sources include Brazil nuts, organ meat, muscle meat, cereals, shellfish and fish . Selenomethionine and sodium selenite are the two most common oral forms of selenium supplementation that are available in variable dosages (100 and 200 μg/day) [6,7]. It has recently been established that selenium plays a key role in thyroid cell physiology . It is incorporated in the molecular structure of several enzymes in the thyroid gland [8,9]. One of these enzymes, glutathione peroxidase (GPx), is critically involved in protecting the gland against oxidative damage. Thyroid peroxidase uses hydrogen peroxide (H2O2), a free radical capable of inflicting oxidative damage, as a substrate in catalyzing the iodination and coupling of tyrosyl residues in thyroglobulin to produce thyroid hormone. The active form of thyroid hormone, tri-iodothyronine (T3), is produced by de-iodination of the prohormone T4 by type I and type II iodothyronine de-iodinasesin, a two-substrate ‘ping-pong' mechanism of reaction, along with degradation of H2O2 to water by GPx. Iodothyronine de-iodinases are also selenoproteins, as is GPx.
If there is selenium deficiency, these two enzymes cannot function properly, which results in both ineffective production of T3 and inefficient protection against free radicals, the latter facilitating cell damage and autoimmune destruction of the gland [6,8,9]. In view of the pivotal role of selenium in thyroid physiology, it is conceivable that selenium supplementation may be of benefit to patients with Hashimoto's thyroiditis, particularly in clinical situations of selenium deficiency . Several studies have suggested that selenium treatment reduces antibodies levels , allows lower dosage of LT4 supplementation and may provide other beneficial effects (e.g. on mood and health-related quality of life; HRQoL) in patients with Hashimoto's thyroiditis . We performed a systematic review to assess the effects of selenium supplementation for Hashimoto's thyroiditis, and this report is a summary of the Cochrane systematic review .
Material and Methods
We conducted a systematic review of randomized controlled trials (RCTs) assessing the effects of selenium supplementation in adults with Hashimoto's thyroiditis. Selenium 100 μg or 200 μg (sodium selenite or selenomethionine) only or combined with titrated LT4 (to maintain basal TSH within normal range) was compared with: no selenium or no selenium plus titrated LT4, respectively; placebo tablets or placebo tablets plus titrated LT4, respectively (table 1).
We searched for RCTs in The Cochrane Library, MEDLINE, EMBASE and Web of Science and in reference lists of articles (from inception until 2 October 2012). We also examined several online trial registries for on-going trials and attempted to contact trial investigators to provide missing data or to clarify study details. Two review authors (E.J.v.Z. and A.Y.A.) independently assessed the titles and abstracts for eligible RCTs.
Our three primary outcomes were: (1) change from baseline in HRQoL assessed using any validated quality-of-life instrument; (2) change from baseline in symptoms, such as mood, fatigue and muscle weakness, assessed using any validated instrument, and (3) proportion of participants reporting an adverse event throughout the study period. Secondary outcomes were: (a) change from baseline in serum levels of anti-thyroid peroxidase antibodies; (b) change from baseline in LT4 replacement dosage, and (c) economic costs.
Data Extraction and Synthesis
Three review authors (E.J.v.Z., A.Y.A. and Z.F.) extracted study details and data using a structured data extraction form and any disagreements were resolved by discussion. The risk of bias in each study was assessed independently by the same 3 authors using the Cochrane Collaboration's domain-based evaluation tool as described in Chapter 8, Section 8.5, in the Cochrane Handbook for Systematic Reviews of Interventions . We presented continuous outcomes data on the original scale as reported in each individual study. Dichotomous outcomes data were presented as risk ratios (RRs) and if significant were converted to the number needed to treat (NNT) for an additional beneficial outcome. All outcomes data were reported with their associated 95% CIs and were analyzed using a random-effects model and the Mantel-Haenzel test for dichotomous outcomes data and invariance analysis for continuous outcomes data, unless stated otherwise. The degree of heterogeneity between the studies was assessed using the I2 statistic. We reported heterogeneity as important if it was at least moderate to substantial (I2 between 50 and 90%). If heterogeneity could be explained by clinical reasoning and a coherent argument could be made for combining the studies, we planned to enter these into a meta-analysis.
From the searches, we identified 110 studies for abstract review (fig. 1). Six studies were excluded after careful evaluation of the full text of the publication [10,14,15,16,17,18]. These appeared to be controlled (i.e. nonrandomized) clinical trials, of which four [10,16,17,18] were confirmed to be quasi-randomized after communication with the trialists (i.e. allocation was done on the basis of a pseudo-random sequence, e.g. odd/even hospital number or date of birth, alternation). Eventually, only four studies comprising 463 participants met our inclusion criteria and were included [7,19,20,21].
Risk of Bias of the Included Studies
We assessed the studies for risk of bias and have reported the judgements for the individual domains in the ‘risk of bias' table (fig. 2). The overall ‘risk of bias' of the four studies was assessed as ‘unclear risk of bias' to ‘high risk of bias' (plausible bias that raises some to serious doubts about the results). In two studies [7,19], one of the key domains, ‘sequence generation', was assessed as high risk of bias and, in all of the studies, 4-6 domains were assessed as ‘unclear risk of bias'.
Effects of Interventions
See table 2 for a summary of the key results.
The primary outcome of HRQoL was not addressed in any study. Two of our secondary outcomes (‘change from baseline in LT4 replacement dosage at the end of the study' and ‘economic costs') were not assessed either. One study at high risk of bias showed a statistically significant improvement in subjective well-being with sodium selenite 200 μg plus titrated LT4 compared with placebo plus titrated LT4. In three studies [7,20,21], selenomethionine 200 μg supplementation was associated with a decrease in serum levels of anti-thyroid peroxidase antibodies, and although the changes from baseline were statistically significant, their clinical significance is unclear. Pooling of the studies by Krysiak and Okopien  and Negro et al. [20 ]was not feasible due to extreme heterogeneity (I2 = 99%).
This reduction in serum anti-thyroid peroxidase antibodies was not confirmed in the study which assessed sodium selenite 200 μg plus titrated LT4. The two studies that reported on adverse events demonstrated that selenium supplementation did not lead to a statistically significant increase in the number of adverse events when compared with placebo. The effectiveness and safety of selenium (+ LT4) versus placebo (+ LT4) are presented in a GRADE summary of findings table (table 3) .
Based on the four studies assessed at unclear to high risk of bias that provided limited data, no clinically relevant conclusions can be drawn. As Hashimoto's thyroiditis is associated with many debilitating symptoms, outcomes, such as change in HRQoL, and improvement in symptoms, such as mood, fatigue and muscle weakness, are important and clinically meaningful markers. The results of these studies provide incomplete evidence to support or refute the efficacy of selenium in people with Hashimoto's thyroiditis. We identified three on-going studies that may eventually help to fill in some of the gaps in evidence for the efficacy of selenium as a supplement in people with Hashimoto's thyroiditis.
Another systematic review, which attempted ‘to summarize available data and provide an evidence-based recommendation regarding selenium supplementation in the treatment of Hashimoto's thyroiditis' included a meta-analysis of data extracted exclusively from studies that were ‘blinded, randomized, placebo-controlled in design' . Although the review could be regarded as fairly transparent, as it relied on a consensus process negotiated between the reviewers, we dispute the robustness of its methodological approach. Incomplete reporting of some of the critical steps taken in study assessment and dealing with missing trial details and data illustrated a lack of clarity in the process and limitation in its reproducibility. There was no indication if contact had been made with the principal investigators of the included studies for clarification of the methods used to generate the sequence, allocation concealment or blinding or to retrieve missing data. Risk of bias assessment was not undertaken and two of the studies included in the meta-analysis by Toulis et al.  were excluded in our review as after E-mail contact with the trial investigators these were confirmed to have been quasi-randomized [10,16]. Furthermore, it was unclear from the review how the quality of evidence was rated, or how the strength of the subsequent recommendations was graded.
The recently updated summary in DynaMed, a clinical reference derived from systematic literature surveillance, was largely in concordance with our assessments of the overall quality of the evidence and conclusions on the efficacy of selenium supplementation for Hashimoto's thyroiditis .
The results of our systematic review demonstrate that at present, there is insufficient objective evidence to support clinical decision making regarding the use of selenium supplementation for the treatment of patients with Hashimoto's thyroiditis. Well-designed randomized placebo-controlled trials to evaluate the effects of selenium in people with Hashimoto's thyroiditis are still needed and can ultimately provide reliable evidence to support clinical decision making.
The authors would like to thank Dr. Brian Alper, who provided free access to the DynaMed summary on this topic.
The authors have no conflict of interest to declare.
This paper is based on a Cochrane review published in Issue 6, June 2013 of The Cochrane Library 2013 (see http://www.CochraneLibrary.net for further information). Cochrane reviews are regularly updated as new evidence emerges and in response to comments and criticisms. The Cochrane Library should be consulted for the most recent version of this review.