The mechanisms behind the changes in serum triiodothyronine (T 3 ), thyroxine (T 4 ) and TSH that occur in the nonthyroidal illness syndrome (NTIS) are becoming clearer. Induction of a central hypothyroidism occurs due to a diminution in hypothalamic thyrotropin-releasing hormone. This can be signalled by a decrease in leptin caused by malnutrition and possibly a localised increase in hypothalamic T 3 catalyzed by altered expression of hypothalamic iodothyronine deiodinases D2 and D3. Data from D1 and D2 knockout mice suggest that these enzymes may have little contribution to the low serum T 3 found in acute illness. The decline in serum T 3 and T 4 in models of acute illness precedes the fall in hepatic D1, suggesting that much of the initial fall in these hormones may be attributable to an acute phase response giving rise to a reduction in the thyroid hormone binding capacity of plasma. When measured by reliable methods, changes in serum free T 4 and free T 3 are modest in comparison to the fall seen in total thyroid hormone. Thyroid hormone transporter expression is up-regulated in many models of the NTIS, thus if diminished tissue uptake of hormone occurs in vivo, it is likely to be the result of impaired transporter function caused by diminished intracellular ATP or plasma inhibitors of transporter action. In man, chronic illness leads to an upregulation of thyroid hormone receptor (THR) expression at least in liver and renal failure. In contrast, human and animal models of sepsis and trauma indicate that expression of THRs and their coactivators are decreased in acute illness.

The trace element selenium (Se) is capable of exerting multiple actions on endocrine systems by modifying the expression of at least 30 selenoproteins, many of which have clearly defined functions. Well-characterized selenoenzymes are the families of glutathione peroxidases (GPXs), thioredoxin reductases (TRs) and iodothyronine deiodinases (Ds). These selenoenzymes are capable of modifying cell function by acting as antioxidants and modifying redox status and thyroid hormone metabolism. Se is also involved in cell growth, apoptosis and modifying the action of cell signalling systems and transcription factors. During thyroid hormone synthesis GPX1, GPX3 and TR1 are up-regulated, providing the thyrocytes with considerable protection from peroxidative damage. Thyroidal D1 in rats and both D1 and D2 in humans are also up-regulated to increase the production of bioactive 3,5,3 -tri-iodothyronine (T3). In the basal state, GPX3 is secreted into the follicular lumen where it may downregulate thyroid hormone synthesis by decreasing hydrogen peroxide concentrations. The deiodinases are present in most tissues and provide a mechanism whereby individual tissues may control their exposure to T3. Se is also able to modify the immune response in patients with autoimmune thyroiditis. Low sperm production and poor sperm quality are consistent features of Se-deficient animals. The pivotal link between Se, sperm quality and male fertility is GPX4 since the enzyme is essential to allow the production of the correct architecture of the midpiece of spermatozoa. Se also has insulin-mimetic properties, an effect that is probably brought about by stimulating the tyrosine kinases involved in the insulin signalling cascade. Furthermore, in the diabetic rat, Se not only restores glycaemic control but it also prevents or alleviates the adverse effects that diabetes has on cardiac, renal and platelet function.

Selenium as an essential component of selenocysteine-containing protein is involved in most aspects of cell biochemistry and function. As such, there is much potential for selenium to influence the immune system. For example, the antioxidant glutathione peroxidases are likely to protect neutrophils from oxygen-derived radicals that are produced to kill ingested foreign organisms. When the functions of all selenoproteins are described, only then will it be possible to fully understand their role in maintaining optimal immune function.

Regulation of synthesis of the selenoenzymes cytosolic glutathione peroxidase (GSH-Px), phospholipid hydroperoxide glutathione peroxidase (PHGSH-Px) and type-1 iodothyronine 5'-deiodinase (5'IDI) was investigated in liver, thyroid and heart of rats fed on diets containing 0.405, 0.104 (Se-adequate), 0.052, 0.024 or 0.003 mg of Se/kg. Severe Se deficiency (0.003 mg of Se/kg) caused almost total loss of GSH-Px activity and mRNA in liver and heart. 5'IDI activity decreased by 95% in liver and its mRNA by 50%; in the thyroid, activity increased by 15% and mRNA by 95%. PHGSH-Px activity was reduced by 75% in the liver and 60% in the heart but mRNA levels were unchanged; in the thyroid, PHGSH-Px activity was unaffected by Se depletion but its mRNA increased by 52%. Thus there is differential regulation of the three mRNAs and subsequent protein synthesis within and between organs, suggesting both that mechanisms exist to channel Se for synthesis of a particular enzyme and that there is tissue-specific regulation of selenoenzyme mRNAs. During Se depletion, the levels of selenoenzyme mRNA did not necessarily parallel the changes in enzyme activity, suggesting a distinct mechanism for regulating mRNA levels. Nuclear run-off assays with isolated liver nuclei showed severe Se deficiency to have no effect on transcription of the three genes, suggesting that there is post-transcriptional control of the three selenoenzymes, probably involving regulation of mRNA stability.

Selenium (Se), a micronutrient essential for human health, is incorporated into at least 25 selenoproteins including selenoprotein P (SePP), which transports Se within the body. This research identified two single nucleotide polymorphisms (SNPs) in the SePP gene, one in the coding region (position 24731, causing an Ala to Thr change) and one in the 3'untranslated region (position 25191). Their frequency was similar in Caucasian, Chinese, and South Asian populations. Prospectively genotyped volunteers were supplemented for 6 wk with 100 microg sodium selenite/day. Blood samples were analyzed for plasma Se and selenoprotein biomarkers at baseline, after supplementation, and during a washout period. Plasma Se, SePP, and glutathione peroxidase 3 (GPx3) levels increased with supplementation. Baseline plasma Se content depended on both SePP genotypes and body mass index. Presupplementation SePP concentration was associated with gender and genotype at SNP 24731 and postsupplementation concentration with SNP 25191. Both SNPs and gender were associated with differences in GPx3 activity, plasma, and erythrocyte thioredoxin reductase 1 concentrations and lymphocyte glutathione peroxidase 1 and 4 activities and concentrations. In conclusion, the data reveal two common functional SNPs within the human SePP gene that may predict behavior of biomarkers of Se status and response to supplementation and thus susceptibility to disease.