Selenium and the Thyroid Gland

More Good News for Clinicians

Anne Drutel; Françoise Archambeaud; Philippe Caron

Disclosures

Clin Endocrinol. 2013;78(2):155-164. 

In This Article

Selenium and Autoimmune Thyroid Diseases

Chronic Lymphocytic Thyroiditis

Chronic lymphocytic thyroiditis (CLT) is the most commonly observed autoimmune thyroid disease in cases where iodine supply is sufficient. Genetic predisposition or certain environmental factors including selenium deficits appear to be implicated in the pathogenesis of the disease.[44,45] Between 2002 and 2007, six prospective studies carried out in countries where selenium supply was lower than the normal limit assessed the effects of systematic selenium supplementation in patients with CLT.[46] In all studies, patients received levothyroxine substitution therapy so their TSH levels were within normal limits. Selenium was administered as selenomethionine or as sodium selenite at the dose of 200 μg/day for 3–12 months.

All the studies[48–50] except one[47] demonstrated a significant decrease in anti-TPO antibody levels at 3 months. Continued supplementation led to an additional decrease of anti-TPO antibody titres at 6 months,[49,50] 9 months[51] and 12 months[52] (Fig. 2). Recently, a study carried out in patients presenting with Hashimoto's thyroiditis with normal T4 levels and normal or slightly elevated TSH levels because of the absence of levothyroxine therapy demonstrated a significant decrease in anti-TPO antibody levels following 12 months supplementation with sodium selenite administered at physiological doses (80 μg/day).[53] It should be noted that the decrease in anti-TPO antibody levels was more important the higher their initial titre. In fact, Karanikas et al.[54] demonstrated a correlation between anti-TPO antibody levels and the production of inflammatory cytokines by thyroid lymphocytes, suggesting that the efficacy of selenium could be more marked during episodes of inflammation.

Figure 2.

Changes in anti-TPO antibody titres following selenium supplementation in patients presenting with chronic lymphocytic thyroiditis. The second part of the study, only included patients previously treated with selenium (according to Turker et al.).

Only one study demonstrated improvement in thyroid gland ultrasound structure in patients whose anti-TPO antibody levels had decreased to below 50 mUI/l,[48] with no hormonal changes (TSH, T4, T3) or changes in treatment with levothyroxine being observed. Finally, smoking has been identified as a resistance factor to selenium supplementation.[52]

On discontinuation of selenium supplementation, one study found that antibody levels increased to their initial levels after 3–6 months,[51] while another study found that the antibody levels remained stable.[52] In three studies, supplemented patients reported improved well-being, independently of the effect on anti-TPO antibodies. The positive effect appears to be related to a direct effect of selenium on cerebral and cognitive functions. Safety was found to be excellent in most patients except in a few rare cases where gastrointestinal disorders were reported.

Most authors consider that selenium affects the immune system through regulation of the production of the reactive oxygen species and their metabolites. Selenium supplementation appears to reinforce intrathyroidal GPX and TR activity, probably by increasing the concentration of selenium within the thyroid.[49] Recent data have also shown that a link exists between selenium and immune cells, namely T cells. Xue et al.[55] demonstrated a significant reduction in antithyroglobulin antibodies associated with decreased lymphocyte infiltration of the thyroid following selenium supplementation of mice with iodine-induced autoimmune thyroiditis. Finally, other data seem point to the participation of other selenoproteins, namely in macrophages. In mice with the tRNA (Ser) Sec gene specifically deleted in myeloid cells, aberrant migration of macrophages is observed, which perturbs the maintenance of tissue integrity in the body.[56]

Thus, the beneficial effects of selenium on thyroid autoimmune parameters appear to be interesting but currently, very few data are available on clinical applications. It is indispensible to carry out new studies assessing changes in levothyroxine dosages, thyroid ultrasound or cytologic and even histologic data to determine the efficacy of selenium supplementation in prevention and reversal of thyroid damage. Similarly, it would be interesting to be able to establish a relationship between the efficacy of selenium treatment, the initial titre of anti-TPO antibodies and/or early supplementation with respect to disease onset.

Autoimmunity and Pregnancy

Fifty per cent of women with anti-TPO antibodies are at a risk of developing postpartum thyroiditis in the 1st year after delivery and among them, 40% develop definitive hypothyroidism. In a prospective, randomized, placebo-controlled study, Négro et al.[57] studied variations in thyroid, ultrasound and autoimmune parameters in pregnant women with or without selenium supplementation.

The plasma selenium levels of all the women were in the lower range of normal at inclusion. Three groups were studied from the 10th week of amenorrhoea until the end of the 1st year postpartum: 77 TPO-positive women were given 200 μg/day of selenomethionine (group S1), 74 TPO-positive women did not receive supplementation (group S0) and a control group of TPO-negative women (group C) did not receive supplementation. During pregnancy, a significant decrease in anti-TPO antibodies was observed in both test groups, but the decrease was higher in the S1 group (62·4%) compared with the S0 group (43·9%) (P < 0·01). In the postpartum period, an increase in anti-TPO antibody titres was also observed in both groups, but the mean level and peak were lower in group S1 compared with group S0. During pregnancy, as many women in the S1 group (19·4%) as in the S0 group (21·6%) were treated with levothyroxine (mean dose of 52 μg/day, identical for both groups). Only 2·5% of the women in C group required levothyroxine. Ultrasound monitoring showed that the thyroid appearance remained stable in the S1 group throughout follow-up while marked degradation was observed in the S0 group. Postpartum thyroiditis was observed in 28·6% of patients from the S1 group of which 11·7% developed definitive hypothyroidism at the end of the study vs 48·6% in the S0 group, of which 20·3% developed definitive hypothyroidism. Thus, the percentage of patient presenting with postpartum thyroiditis and permanent hypothyroidism was significantly lower in the S1 group compared with the S0 group (P < 0·01 and P < 0·01, respectively). These study results are the first to demonstrate the clinical benefits of selenium supplementation in pregnant women presenting with thyroid autoimmunity.

Graves' Disease

Several studies have demonstrated an increase in oxidative stress during Graves' disease related to increased production of reactive oxygen species (excessive consumption of ATP and oxygen). Guerra et al.[58] found that urinary excretion of malondialdehyde content was increased in patients with hyperthyroidism compared with control subjects. Treatment with antithyroid drugs corrects these symptoms.[59]

In Graves' disease, the balance between intracellular and extracellular oxidants and antioxidants appears to be disturbed. Despite an increase in intracellular antioxidant enzymes such as GPX1 or TRs,[60] there is an overall decrease in the activity of GPXs[61] and other enzymes (superoxide dismutase, catalase)[59] or molecules (vitamin E, coenzyme Q10).[62] Based on these findings, several authors decided to study the benefits that could potentially be derived from selenium supplementation in patients with Graves' disease. Bacic-Vrca et al.[63] compared the efficacy of treatment with methimazole vs methimazole and a set combination of antioxidants (vitamin E, C, β carotene and selenium at the dose of 60 μg/day) in subjects presenting Graves' disease. The study was conducted in Croatia, a country where nutritional selenium levels are among the lowest in Europe. Plasma selenium concentrations increased in subjects receiving selenium and erythrocyte GPX activity increased in both groups, but significantly more markedly in the methimazole and antioxidant group (at day 30 and day 60). Finally, euthyroidal status was attained more rapidly in the methimazole and antioxidant group. A more recent study compared plasma selenium concentrations in Graves' disease patients in remission or with persistent or recurrent disease following discontinuation of treatment with antithyroid drugs. Although no significant differences were observed, it was in the group of patients in remission that selenium levels were the highest (>120 μg/l), and a negative correlation was demonstrated between TSH antireceptor antibody and plasma selenium levels in this group.[64] These data have boosted the interest for the 'selenium analogues' of synthetic antithyroid drugs. The first of these, methylselenoimidazole, was developed about 15 years ago,[65] but it was found to be less effective in terms of in vivo iodination inhibition than methimazole.[66] Other molecules offering new treatment perspectives are currently being developed.[67]

Graves' Orbitopathy

Orbitopathy is a common complication of Graves' disease. It may be severe, requiring treatment with glucocorticosteroids, radiotherapy or surgery, or more moderate and treated symptomatically (eye drops, sunglasses), but without really improving the patients' comfort.

A recent study of the EUGOGO (European Group of Graves' Orbitopathy) assessed the effects of selenium (sodium selenite, 200 μg/day) for the treatment of patients with mild inflammatory orbitopathy.[68] The randomized, double-blind, placebo-controlled study lasted 12 months (6 months of treatment and 6 months follow-up) and included 159 patients. The primary end-points at 6 and 12 months were assessed based on a full eye examination and on orbitopathy-specific quality of life questionnaire scores. Secondary end-points were assessed using Graves' orbitopathy clinical activity and severity score.

At 6 months, compared with placebo, selenium significantly improved the patients' quality of life (P < 0·001), decreased eye lesions (P = 0·01) and significantly slowed orbitopathy progression (P = 0·01). More than 70% of patients treated with selenium reported an improvement in quality of life vs 22% of patients receiving placebo. Orbital lesions were improved in 61% of patients receiving selenium vs 35% of patients treated with placebo. They worsened in 7% of patients treated with selenium vs 26% of patients receiving placebo (Fig. 3).

Figure 3.

Comparison of the effects of selenium (200 μg/day for 6 months) with placebo in the management of patients with mild to moderate Graves' orbitopathy (modified from Marcocci C et al.).

The clinical activity score decreased in all groups, but more significantly in the patients treated with selenium. The 12-month results were similar to the 6-month results. No side effects were observed in any of the 54 patients treated with selenium.

It should be noted, however, that in this study, plasma selenium concentrations were neither determined before supplementation nor during the study, which limits result interpretation. Most patients included were from selenium-deficient areas, which might explain the supplementation benefits observed. However, very little information was provided on the smoking habits of the patients.

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