Study Title:

Selenium and Thyroid Autoantibodies

Study Abstract

In areas with severe selenium deficiency there is a higher incidence of thyroiditis due to a decreased activity of selenium-dependent glutathione peroxidase activity within thyroid cells. Selenium-dependent enzymes also have several modifying effects on the immune system. Therefore, even mild selenium deficiency may contribute to the development and maintenance of autoimmune thyroid diseases. We performed a blinded, placebo-controlled, prospective study in female patients (n = 70; mean age, 47.5 +/- 0.7 yr) with autoimmune thyroiditis and thyroid peroxidase antibodies (TPOAb) and/or Tg antibodies (TgAb) above 350 IU/ml. The primary end point of the study was the change in TPOAb concentrations. Secondary end points were changes in TgAb, TSH, and free thyroid hormone levels as well as ultrasound pattern of the thyroid and quality of life estimation. Patients were randomized into 2 age- and antibody (TPOAb)-matched groups; 36 patients received 200 microg (2.53 micromol) sodium selenite/d, orally, for 3 months, and 34 patients received placebo. All patients were substituted with L-T(4) to maintain TSH within the normal range. TPOAb, TgAb, TSH, and free thyroid hormones were determined by commercial assays. The echogenicity of the thyroid was monitored with high resolution ultrasound. The mean TPOAb concentration decreased significantly to 63.6% (P = 0.013) in the selenium group vs. 88% (P = 0.95) in the placebo group. A subgroup analysis of those patients with TPOAb greater than 1200 IU/ml revealed a mean 40% reduction in the selenium-treated patients compared with a 10% increase in TPOAb in the placebo group. TgAb concentrations were lower in the placebo group at the beginning of the study and significantly further decreased (P = 0.018), but were unchanged in the selenium group. Nine patients in the selenium-treated group had completely normalized antibody concentrations, in contrast to two patients in the placebo group (by chi(2) test, P = 0.01). Ultrasound of the thyroid showed normalized echogenicity in these patients. The mean TSH, free T(4), and free T(3) levels were unchanged in both groups. We conclude that selenium substitution may improve the inflammatory activity in patients with autoimmune thyroiditis, especially in those with high activity. Whether this effect is specific for autoimmune thyroiditis or may also be effective in other endocrine autoimmune diseases has yet to be investigated.

CHRONIC AUTOIMMUNE thyroiditis with euthyroidism or hypothyroidism is a common disease, affecting more than 10% of females and 2% of males. There are several explanations for the development of this disease. There is a genetic background, as patients with human leukocyte antigens DR3 and DR5 and polymorphism of the cytotoxic T lymphocyte A4 promoter are more susceptible to the development of autoimmune thyroiditis compared with the normal population. There also are environmental factors, such as iodide intake, immunotherapeutic agents, or viral infections, that may initiate the disease (1).

In areas with combined endemic selenium and iodine deficiency, the supplementation of iodide alone leads to myxedematous cretinism (2, 3), which is defined by not only fetal hypothyroidism, but persistent hypothyroidism from early life. The thyroid of these patients is small and firm, suggesting fibrotic degeneration initiated by thyroid cell damage (4). The cause of this cell damage has been further investigated in animal studies. In severe selenium deficiency, the activity of the selenoenzyme glutathione peroxidase (GPx) is decreased, and therefore peroxide cleavage within the thyroid cells is diminished. Severe nutritional selenium deficiency therefore leads to an increased rate of thyroid cell necrosis and invasion of macrophages (5, 6). Whether this also may induce a higher incidence of autoimmune thyroiditis is unknown. It may be assumed, however, that thyroid cell damage may initiate or maintain autoimmune thyroiditis, especially in patients susceptible to the development of autoimmune diseases (7).

Furthermore, selenium has an important impact on immune function (8, 9). Selenium deficiency is accompanied by loss of immune competence. Both cell-mediated immunity and B cell function can be impaired. This might be related to the fact that the selenium-dependent enzymes, GPx and thioredoxin reductase (TxR), have antioxidative effects; they decrease free radical formation and reduce hydrogen peroxide and lipid and phospholipid hydroperoxides (9). In selenium-sufficient environment, the hydroperoxide intermediates of the cyclooxygenase and lipoxygenase pathways are therefore reduced and lead to diminished production of proinflammatory PGs and leukotrienes (10). In addition, both GPx and TxR modulate the respiratory burst and reduce superoxide production (11, 12, 13).

The possible therapeutic effect of selenium has already been shown in a double blind, randomized trial in patients with rheumatoid arthritis, in whom the supplementation of 200 µg selenium for 3 months significantly reduced pain and joint involvement (14). Selenium supplementation of 500-1000 µg has also been shown to improve survival in patients with hemorrhagic pancreatitis (15) and severe sepsis (16), which may be due to the antiinflammatory effect of a higher selenium supply.

The three known deiodinases also are selenium-dependent enzymes (11, 17, 18, 19). Their activity, however, in contrast to GPx activity, is only decreased in extremely severe selenium deficiency. T4 plasma concentrations are then elevated, and selenium supplementation lowers T4 and increases T3 concentrations (20).

In Germany, there is mild iodine deficiency (21) as well as mild selenium deficiency, as in most European countries (22). As selenium deficiency may influence both the immune response as well as peroxidation of thyroid cell components, it seems reasonable to investigate whether a selenium substitution may influence the natural course of chronic autoimmune thyroiditis (23). There is one small pilot study showing a significant decrease in both thyroid peroxidase antibodies (TPOAb) as well as TSH receptor antibody concentrations in patients with lymphocytic autoimmune thyroiditis (24). We therefore conducted a blinded, placebo-controlled study in patients with chronic autoimmune thyroiditis to show whether supplementation with 200 µg (2.53 µmol) sodium selenite has any effect on plasma TPOAb concentrations, free thyroid hormones, and the ultrasound pattern of the affected thyroid in patients with overt autoimmune thyroiditis.

Study Information

Gärtner R, Gasnier BC, Dietrich JW, Krebs B, Angstwurm MW.
Selenium supplementation in patients with autoimmune thyroiditis decreases thyroid peroxidase antibodies concentrations.
J Clin Endocrinol Metab.
2002 April
Department of Endocrinology, Medizinische Klinik Innenstadt, University of Munich, D-80336 Munich, Germany.

Full Study

http://jcem.endojournals.org/cgi/content/full/87/4/1687