Introduction
Chronic autoimmune (AIT) or Hashimoto’s thyroiditis affects 1–2 % of the population with increasing prevalence with age and a female preponderance. In communities replete in iodine intake, it is the predominant cause of hypothyroidism [
1,
2]. The etiology is multifactorial and based on genetic susceptibility in a complex interaction with numerous environmental triggers [
3,
4], possibly including selenium deficiency [
5]. No cure exists, and the standard treatment is life-long levothyroxine substitution (LT4) to normalize circulating thyrotropin [thyroid stimulating hormone (TSH)] levels. Recent insights suggest that LT4 cannot ensure a euthyroid state in all tissues simultaneously [
6], and a place for selenium supplementation in the treatment of AIT has been much debated [
7]. Selenium is an essential micronutrient with a wide range of effects in, e.g. redox homeostasis, immunity, and thyroid hormone metabolism [
8]. Since 2002, a number of trials have investigated the effects of selenium supplementation in AIT. In a meta-analysis from 2010, based on four trials, [
9], the authors reported decrease in thyroid peroxidase autoantibody (TPO-Ab) levels and improvement in well-being and/or mood, after 3 months of selenium supplementation, as compared to placebo. Similar conclusions were reached in another meta-analysis from 2014, including nine trials [
10]. Finally, a Cochrane Collaboration systematic review from 2013, also including four studies, [
11] reached no conclusion regarding effects on HRQL, and did not perform a meta-analysis of change in TPO-Ab because of considerable heterogeneity among the included studies. While TPO-Ab levels are central to the diagnosis of AIT [
12], their clinical importance is less clear once treatment is initiated. The GRADE guidelines provide a framework for determining outcomes of interest [
13], and rate morbidity or disease remission as crucial when evaluating treatment effects [
13]. However, none of these outcomes were reported in the previous systematic reviews [
9‐
11]. Further, the safety of upper tolerable selenium intake limits has been questioned [
14], underlining that supplementation should only be administered to correct deficits or on solid clinical indication.
Due to insufficient trial evaluation of clinically relevant outcomes, and in view of recent safety concerns, we hypothesized that selenium supplementation does not currently have a place in the treatment of AIT, and tested this hypothesis in a systematic review and meta-analysis.
Discussion
A key aspect in our evaluation of the nine included trials was the division into populations of LT4-treated and -untreated patients. This was done, according to GRADE recommendations [
13], because the outcomes deemed important a priori were different in the respective populations. Three of the included trials enrolled patients receiving LT4 [
16,
17,
36], four trials dealt exclusively with untreated patients [
20,
38,
39,
42], and two trials included both untreated and treated patients [
41,
43].
In the three trials where selenium was administered adjuvant to LT4, thyroid function could not readily be assessed as an outcome due to the impact of LT4 per se. Mortality, morbidity and disease remission are rated as crucial according to the GRADE recommendations, and of obvious concern, since hypothyroidism is associated with increased somatic [
44] and psychiatric morbidity [
45], as well as excess mortality [
46]. However, these endpoints are relatively infrequent, occur over longer periods of time [
13], and were not assessed in any of the identified trials. LT4 dose and/or HRQL constitute more readily assessable relevant outcomes. No previous trials reported LT4 dose as an outcome, but data on HRQL [
33,
35,
36] have previously been synthesized into meta-analyses [
9,
10]. One reported that patients assigned to selenium supplementation experienced improved well-being or mood, as compared with controls [
9], and the other study showed no change [
10]. However, neither of the previous reviews assessed the quality of evidence, which we consider to be low due to unclear blinding in relation to this subjective outcome. Furthermore, none used a validated HRQL instrument for hypothyroid patients, such as the ThyPRO [
47,
48]. By assessment with this instrument we have demonstrated widely impaired HRQL, that is not normalized following six months of LT4 treatment [
49]. Finally, independent effects on thyroid morphology, on top of the well-known effects of LT4 on thyroid size [
50], are difficult to assess in this group because the trials [
36,
43] did not account for disease duration.
In the LT4-untreated population, we prioritized disease progression as the most important outcome. It can be evaluated categorically by the proportion of patients developing subclinical or overt hypothyroidism during the time of intervention or follow-up. Two studies reported direct data for this aspect [
20,
42], showing no effect. In addition, our meta-analysis for effects on TSH levels, reached the same conclusion. Two trials assessed HRQL effects [
20,
42], and we found no significant effects in a meta-analysis on any SF-36 domains. While HRQL is always an outcome of some importance, it might be of limited relevance in untreated euthyroid patients, who are more likely to be unaffected than are hypothyroid treated patients. Two trials also investigated thyroid volume and echogenicity quantitatively [
20,
38]. The studies yielded contradictory results for echogenicity, but when synthesized in a meta-analysis, the studies showed no effect.
Selenium supplementation did not significantly impact the incidence of adverse effects, which were reported only in two double-blinded trials [
39,
42]. Evaluation of long-term morbidity following trial participation, would address recently voiced safety concerns [
14], e.g. regarding the implications of selenium supplementation for glucose metabolism. This issue was evaluated in only one trial and found blood glucose levels unaltered [
20].
Interestingly, direct clinical outcomes have been assessed in another thyroid patient group. In a randomized placebo-controlled trial, 169 euthyroid TPO-Ab positive pregnant women were allocated to 200 μg/d selenomethionine or matching placebo from 12 weeks gestation to 12 months after delivery [
28]. Post partum thyroid dysfunction and permanent hypothyroidism were significantly less prevalent in patients receiving selenium, as compared to placebo. Based on this, the authors concluded that selenium supplementation reduced thyroid inflammatory activity and the incidence of hypothyroidism in the post partum phase [
28].
Seven of the included nine trials reported selenium status in their patients. Six European trial populations [
15,
33,
35,
36,
38,
39] were within a narrow range (70–85 μg/L) of baseline serum/plasma selenium concentrations, while it was lower (37 μg/L) in the Brazilian trial [
40]. The current selenium reference range is 100–120 μg/L [
51], implying marginal selenium deficiency in the European and more marked deficiency in the Brazilian participants. The nine identified trials intervened with 80–200 μg/day, using different formulations with varying bioavailablity; the absorption of selenite is approximately 2/3 of the absorption of selenomethionine [
52]. In a recent narrative review it was suggested that selenomethionine might be more effective than selenite in lowering thyroid autoantibody levels [
53]. However, no such trends were observed for any of the clinical outcomes assessed in our study. The duration of intervention exceeded six months only in two trials [
20,
38]. Just in one trial [
20] did selenium levels at the end of intervention exceed the reference range, and in the Brazilian trial [
43], the plasma selenium concentration in the intervention group increased only to 63.4 μg/L. Thus, trial findings should mainly be interpreted in relation to correcting marginal deficits, rather than administering supranutrional doses.
There are limitations to our study, and while the GRADE approach rates the quality of evidence systematically, it does not eliminate judgment [
54], which is a limitation per se
. A statistical source of error is that one study presented data in median with IQR [
20] and another in median with range [
42], both of which may be unreliable for calculating a mean and a SD for the meta-analysis [
20]. However, excluding these studies [
20,
42] had no influence on the results. Finally, the meta-analysis were performed on the basis on very few studies, limiting the quality of the evidence.
Future trials of selenium supplementation in AIT should pay close attention to the selenium status of the study populations, and identify outcomes of clinical importance relating to the eligibility criteria set for trial participants. In euthyroid individuals, whose tolerance to TPO or thyroglobulin is broken, but where clinical disease is absent, we recommend disease progression as an important outcome. However, we found no effects on TSH level, which may be considered as a surrogate marker, or on HRQL or thyroid echogenicity. In hypothyroid patients, a rigorous trial investigating LT4-dose titration as an outcome could unmask implications for disease remission. Finally, although the quality of evidence is low, previous trial results give some promise of beneficial effects on HRQL. This outcome can now be evaluated using validated disease-specific instruments [
47,
48,
55], one of which (ThyPRO) is the primary outcome in an ongoing trial [
56].
There have been conflicting reports as to whether selenium supplementation is of benefit in patients with AIT [
53]. Our conclusion is that current evidence does not justify the emerging use of selenium supplementation in the treatment of AIT [
57]. While the correction of a selenium deficit may offer other health benefits [
8], routine selenium supplementationin AIT patients should, at present, be discouraged [
58].