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 Thyroid Diseases

Myxoedematous Cretinism

The first clinical data establishing a link between selenium levels and thyroid metabolism were collected in Central Africa. The prevalence of myxoedematous cretinism is very high in this region where the population suffers from severe iodine and selenium deficiencies. Myxoedematous cretinism is characterized by the persistence of hypothyroidism despite supplementation with iodine alone.[23] Physical examination of subjects shows the thyroid gland to be firm and atrophic, suggestive of cell damage and secondary fibrosis. Conversely, selenium supplementation without prior iodine repletion may aggravate hypothyroidism and may even result in myxoedematous coma,[1] which suggests that selenium deficiency may play a protective role in subjects with combined iodine and selenium deficiency.

Several hypotheses can explain the pathogenesis of myxoedematous cretinism. Iodine deficiency leads to increased production of H2O2 through an increase in TSH, and selenium deficiency results in a decrease in GPX activity, namely GPX3. The excess of H2O2 cannot be neutralized by GPXs resulting in cell destruction and fibrosis due to macrophage infiltration. The macrophages synthesize TGF-β, which blocks the proliferation of epithelial cells and stimulates that of fibroblasts. These pathogenic mechanisms seem to commence shortly after birth and lead to the total destruction of the thyroid gland over a few years. In parallel, the activity of type 1 and type 3 deiodinases decreases, which reduces the turnover of the thyroid hormones, and limits loss of iodine through the urine. Conversely, hypothyroidism increases the activity of type 2 deiodinase, namely in the brain, thereby maintaining local production of sufficient T3 (at least during the prenatal and early postnatal periods), which is indispensible for neurological development. Thus, selenium repletion without prior iodine repletion aggravates the consequences of iodine deficiency.[24]

Similar iodine and selenium deficiencies may be observed in other regions of the world, namely in Tibet and China, but they are not associated with a high prevalence of myxoedematous cretinism. Additional environmental factors appear to promote thyroid disorders such as thiocyanate intake related to the consumption of manioc.[25] This worsens the iodine deficit because of competition between iodine and the iodine symporter or TPO.

Selenium and Thyroid Metabolism

Several studies have assessed the impact of selenium repletion on thyroid function in different population groups from industrialized countries ( Table 2 ).[26] Selenium supplements between 10 and 300 μg/day were administered on a daily basis to populations in good apparent health over 3 months,[27] 5 months,[28,29] 6 months[30] or 12 months.[31] In some of the studies, the subjects had selenium deficiencies;[32–34] while in others, they did not.[34–36]

Four studies demonstrated a significant increase in plasma selenium levels in subjects benefiting from selenium repletion compared with the control group. However, only two studies demonstrated changes in thyroid hormone concentrations and/or in TSH levels.

The first study[27] that included a small number of elderly subjects in good health showed a significant decrease in T4 levels in the group given 100 μg of selenium per day for 3 months compared with the control group. In another study, the same author demonstrated that the elderly euthyroidal subjects presented with disrupted thyroid parameters with a decreased T3/T4 ratio, higher TSH values that were associated with a decrease in plasma selenium levels and erythrocyte GPX activity.[32] In reality, the abnormalities appear to be related to a decrease in peripheral deiodinase activity and therefore to decreased T3 production. Similar results were observed in phenylketonuric subjects,[33] in patients with cystic fibrosis[34] or in subjects nourished exclusively by the parenteral route[35] and who are at a risk of selenium deficiency due to restricted or inadequate protein intake.

In the second study that included patients aged between 60 and 90 years presenting with low plasma levels of selenium, subjects were supplemented with 10–40 μg of selenium per day for 5 months.[28] Plasma concentrations of selenium increased in all supplemented groups. Levels of T4 decreased in all the groups, but the decrease was only significant in the group receiving 10 μg of selenium per day or when the results of all the groups were combined and compared with the control group.

Other studies found no significant changes in thyroid parameters in elderly subjects in good health following selenium supplementation,[36] particularly the study by Rayman et al.[30] The authors assessed the effects of selenium repletion with different doses of selenium (100, 200 and 300 μg/day) in a population of 501 elderly euthyroidal subjects over a 6-month period. No changes in thyroid function (TSH concentration, total T4, free T4, total T3, free T3, total T3/T4 ratio, free T3/T4 ratio) were observed in the subjects receiving supplementation compared with the control group despite an increase in the plasma levels of selenium. It should be noted, however, that no significant selenium deficiencies were observed following assay of plasma levels of the patients prior to inclusion in the study (91 μg/l). Similarly, other authors found no change in thyroid parameters following selenium supplementation in deficient[29] or nondeficient populations.[31]

Thus, clinical data concerning the effects of selenium intake on thyroid function have not demonstrated a clear link between deiodinase expression and activity and selenium status. Finally, only very severe selenium deficiencies appear to affect thyroid function, and namely T3 synthesis. These clinical observations are consistent with fundamental data showing that small selenium concentrations are sufficient for satisfactory deiodinase expression.

Selenium, Goitres and Nodules

In addition to the role it plays in the metabolism of thyroid hormones, selenium appears to have an impact on thyroid volume. In children with a goitre living in areas where there are iodine and selenium deficiencies, iodine repletion alone does not reduce the volume of the goitre and does not improve thyroid function. In reality, the more severe the selenium deficiency, the less iodine supplementation helps to reduce thyroid volume.[37] In the French SUVIMAX study, the correlation between thyroid volume and selenium status was only established in women. So far, the molecular mechanism making women more sensitive to low selenium intake has not been elucidated.

Recently, Rasmussen et al.[38] published the results of a study on the correlations between selenium status, thyroid volume and nodule formation. Similarly to the French SUVIMAX study, the population presented with moderate iodine deficiency. A negative correlation was found between thyroid volume and plasma selenium levels, but the result was only statistically significant for the general population or for subjects supplemented with iodine. Therefore, the effect of selenium status on thyroid volume does not appear to be related to iodine deficiency. Finally, in the study, low plasma selenium concentrations were correlated with a risk of formation of multiple nodules over 10 mm in size, but did not impact the risk of development of solitary nodules. Similarly, Samir et al.[39] found low plasma selenium concentrations in 22 subjects presenting with multinodular goitre compared with a control group of 15 subjects. Conversely, Derumeaux et al.[40] did not find that the global risk of developing nodules was increased in selenium-deficient patients.

There are numerous hypotheses relating to the molecular mechanisms responsible for the increase in the risk of development of a goitre and nodules in selenium-deficient patients and they mainly concern GPX abnormalities.

Selenium and Thyroid Cancer

It is difficult to formally establish a link between selenium and thyroid cancer based on current data. The 'Janus Serum Bank' Norwegian study demonstrated a reverse correlation between the incidence of thyroid carcinomas and plasma selenium concentrations.[41] Moreover, tissue concentrations were lowest in patients presenting with cancer.[42] Thus, the decrease in plasma or thyroid selenium concentrations appears to lead to defence mechanism and cell protection changes, particularly in the presence of activating mutations of the RAS oncogene, mutations which appear to be the cause of the increased production of reactive oxygen species.[43]

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