Role of cytokines in the pathogenesis of the euthyroid sick syndrome.

Nonthyroidal illness (NTI) is associated with complex changes in thyroid function tests and thyroid regulation known as the euthyroid sick syndrome (ESS) (1). The most common abnormality is a reduction in serum total triiodothyronine (TT3) and, to a lesser extent, free T3 (FT3) concentrations (2). Kinetic studies showed that the daily production rate (PR) of T3 is decreased, while its clearance is unchanged in NTI (3). The reduction in serum TT3 concentration is usually accompanied by an increase in serum reverse T3 (rT3) concentration (1), although the latter is normal in patients with chronic renal failure (4), AIDS (5), or traumatic brain injury (6). PR of rT3 is unchanged, but its clearance is reduced (3). These changes in serum TT3 and rT3 concentrations are related to inhibition of the activity of type I 5-deiodinase (5-DI), the enzyme catalyzing deiodination of thyroxine (T4) to T3 and of rT3 to 3,3 -diiodothyronine (7). Serum thyrotropin (TSH) concentration is usually normal, although suppressed values may be found in a minority of patients (1). In addition, a decrease in the nocturnal surge of TSH has been consistently reported in patients with NTI (8–12). Abnormalities of TSH glycosylation causing its decreased biological activity were also described (13). The decrease in serum TSH secretion is in some instances related to the use of dopamine and glucocorticoids in critically ill patients (14). The pathogenesis of changes in serum thyroid hormone and TSH concentrations leading to ESS is not completely understood. Reduced T3 generation in peripheral tissue may be related not only to a decreased 5-DI activity, but also to decreased T4 transport into tissues (15). Substances, such as 3-carboxy-4-methyl-5propyl-2-furanpropanoic acid (CMPF) and indoxylsulfate, which are increased in chronic renal failure, and bilirubin and free fatty acids (FFA), which are increased in other NTI, were reported to decrease T4 uptake in rat liver tissue (16, 17). Interestingly, CMPF and indoxyl-sulfate did not affect TSH secretion in cultured rat anterior pituitary cells (18). Recently, particular attention was focused on the role of cytokines in the pathogenesis of ESS. Cytokines are multifunctional molecules with different biological effects and target cells, which can exert autocrine (on the same cells that secrete them) and paracrine (on adjacent cells), but also endocrine (on distant cells) actions (19). They are usually produced in response to inflammation, infections and cellular injury, and their physiological role remains to be clarified (19). In general, cytokines act through binding to specific cellsurface receptors that were demonstrated also in thyrocytes (20, 21). In addition, thyrocytes synthesize and release cytokines, which might be involved in autocrine or paracrine regulation of thyroid function (22–32). The importance of cytokines in thyroid pathophysiology was recently underscored (Fig. 1). They participate in the pathogenesis of thyroid autoimmune disease by contributing to the growth and differentiation of B and T cells, by inducing expression of HLA class II antigens and adhesion molecules, by recruiting and activating immune cells and by modulating the course of the disease (33). Interleukin-6 (IL-6) and possibly other cytokines are useful markers of thyroid-destructive processes (34). Cytokines have a role in the pathogenesis of Graves’ ophthalmopathy, since they induce orbital fibroblast proliferation and glycosaminoglycan production, and expression of HLA class II antigens, adhesion molecules and heat shock proteins in orbital fibroblasts (35). Numerous studies in vitro and in vivo (both in animals and humans) were carried out in recent years on the effects of cytokines on thyroid function. Since the number of published papers on this issue is very large, in this review we analyzed the most crucial studies to discuss the role of cytokines in the pathogenesis of ESS.