Abstract
Toulis et al. recently reviewed selenium (Se) supplementation to treat Hashimoto's thyroiditis (HT) (1). Unfortunately, they were limited to just four clinical trials for their thorough meta-analysis. In addition, the geographical distribution was limited as the studies came from Europe or near Europe, where Se status is low. This likely contributes to or even explains the positive effects of Se in the studies they analyzed. Studies from North America, South America, and parts of Asia, where dietary Se status is sufficient, might not replicate this therapeutic success.
Regrettably, baseline Se status was not chosen (1) as a criterion for subanalysis of the data. Instead, the relative efficiencies of two different selenocompounds (selenomethionine vs. selenite) were compared. Although these compounds have different metabolic pathways, they both enhance selenoprotein biosynthesis and blood Se concentrations in Se deficiency (2). Thus, it is not likely that differences in metabolism explain differences in their effects. In fact, positive effects of Se supplementation have been reported for both selenomethionine and selenite.
These reservations aside, the analysis by Toulis et al. is the first one in this area. It is timely as there are few satisfactory treatment options for HT that deal with the disease itself. It also provides encouragement to those who use Se supplementation as an adjuvant treatment for HT in Se-deficient areas. Despite some success in Europe, the potential health risks of Se supplementation, particularly outside Se-deficient regions, need to be discussed.
The studies covered in the metanalysis (1) were published between 2002 and 2007. At that time Se supplementation and type 2 diabetes mellitus (T2DM) appeared unrelated. This notion changed in 2007, when the follow-up of a large Se-based cancer prevention study (NPC trial) indicated a higher prevalence of T2DM in the Se arm than in controls (3). At the same time, a cross-sectional analysis of U.S. adults showed a higher prevalence of T2DM in the highest quintile than in the lowest quintile stratified by serum Se (4). Both studies support the concept that there is an upper limit for dietary Se from all sources, which should not be surpassed if side-effects are not to override benefits as well as there being a level of baseline Se above which there are toxic, and perhaps no beneficial effects of Se supplementation. For example, in the NPC trial, cancer preventive effects of Se were observed in the lower two tertiles of baseline serum Se concentrations, but not in the upper one (>123 μg Se/l) (5). Similarly, increased T2DM prevalence is observed only when comparing highest to lowest quintile of serum Se, but there is no linear relationship across the lower four quintiles covering the range until 138 μg Se/l (4). These observations with respect to T2DM and cancer prevention might be relevant to Se supplementation as a treatment for HT. In the studies analyzed by Toulis et al. (1), high Se levels were not present before or even after daily Se supplementation. Such is not likely to be the case if Se supplementation was given in regions without Se deficiency. In regions without Se deficiency, Se supplementation could produce toxic effects.
It should be noted that the data from the studies relating to risk of T2DM (3,4) indicate that the increased risk is confined to men. The reason for the increased sensitivity of men to toxic effects of Se supplementation is not clear; since the majority of patients with HT are women, a study of Se supplementation in Se-sufficient regions might not uncover toxic effects unless it contains a sufficient number of men in the control and treatment groups. In fact, the increased risk of T2DM incurred by Se supplementation is largely confined to those men with a body mass index of >25, reaching significance only with a body mass index >30 (4).
In summary, future studies of Se supplementation in HT must carefully consider the baseline Se status, gender, and weight of patients who should be studied. These considerations are relevant to what benefits might be incurred and the risks to the Se-supplemented patients. The positive evidence presented in the metaanalysis (1) comes mainly from adult female patients with low Se status under L-T4 treatment. In these patients, Se supplementation corrected an Se deficit and yielded a positive effect, and potential benefits appear to outweigh the risks. A possible approach for studies in Se-sufficient patients is to first study only women. If no beneficial effect of Se supplementation in the treatment of HT is noted in Se-sufficient women, it is unlikely that men who are otherwise similar with respect to disease characteristics would benefit from Se supplementation. Rather the overall outcome in men could be even poorer than in women.