![]() The changes in thyroid hormone levels are associated with duration and severity of the disease. Whether these changes are due to adaptive physiological mechanisms to reduce the metabolic rate during stressful circumstances or a consequence of the underlying process is still a matter of debate. About 50% NTIS patients will also present decreased TSH levels, indicating concomitant changes in the hypothalamic/pituitary regulation ( Fliers et al., 1997 Plikat et al., 2007). At early stages, serum T4 tends toward normal levels but its fall is observed in severe or end-stage cases ( Docter et al., 1993). The changes in serum thyroxine (T4) levels are more complex. As the disease progresses, additional decreases in T3 and further reductions in the T3/rT3 ratio are observed, whereas thyrotropin (TSH) levels typically remain within the normal range or slightly increased ( Kaptein et al., 1982 Mebis and Van den Berghe, 2011). The acute phase of critical illness, observed in a variety of clinical situations, is marked by low triiodothyronine (T3) and free T3 and high reverse T3 (rT3) levels. The non-thyroidal illness syndrome (NTIS), also known as low T3 syndrome or euthyroid sick syndrome, reflects alterations in thyroid hormone levels that occur in almost every form of acute or chronic illness ( Larsen et al., 2008). Here we aim to present an updated picture of the advances in understanding the mechanisms that result in the fall of thyroid hormone levels in the acute phase of NTIS. Changes in the intracellular redox state may disrupt deiodinase function by independent mechanisms, which might include depletion of the as yet unidentified endogenous thiol cofactor. On the other hand, oxidative stress due to augmented reactive oxygen species (ROS) generation is characteristic of many diseases that are associated with NTIS. ![]() ![]() Increased inflammatory cytokines, which occurs in response to virtually any illness, has long been speculated to play a role in derangements of deiodinase expression. Over the last decades, several studies have attempted to elucidate the mechanisms underlying the changes on circulating thyroid hormones in NTIS. In contrast, type 3 deiodinase (D3) catalyzes the inactivation of both T4 and T3. The conversion of T4 to T3 is catalyzed by type 1 (D1) and type 2 (D2) deiodinases via outer-ring deiodination. The early phase seems to reflect changes occurring primarily in the peripheral thyroid hormone metabolism, best seen in humans since 80–90% of the circulating T3 are derived from the pro-hormone T4. The pathophysiological mechanisms are poorly understood but the acute and chronic changes in pituitary–thyroid function are probably the consequence of the action of multiple factors. Affected individuals have low T3, elevated rT3, and inappropriately normal TSH levels. The non-thyroidal illness syndrome (NTIS) refers to changes in serum thyroid hormone levels observed in critically ill patients in the absence of hypothalamic–pituitary–thyroid primary dysfunction. Thyroid Section, Endocrine Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brasil.There continues to be no indication for thyroid hormone therapy in the vast majority of patients with the nonthyroidal illness syndrome, although interesting data suggest a possible role for treating a small subset of patients. The mediators of these alterations are still largely unclear. ![]() Some of these changes are physiologic and some are pharmacologic. These data show that acute and chronic illness affect all aspects of thyroid hormone metabolism and action. Multiple factors lead to the development of the nonthyroidal illness syndrome, including alterations in type 1 and 3 deiodinase activity, thyrotropin-releasing hormone and thyroid-stimulating hormone secretion, hormone binding to plasma proteins, thyroid hormone transporter expression and activity, and the thyroid hormone nuclear receptor complex. Therapy of the nonthyroidal illness syndrome remains a controversial topic. New studies suggest that alterations in thyroid hormone transport into tissues and alterations of the nuclear thyroid hormone receptors may also play a role. Previous studies attributed the development of the nonthyroidal illness syndrome to alterations in three main areas of thyroid hormone metabolism: deiodinase activity, thyroid-stimulating hormone secretion, and hormone binding to serum proteins. The current state of the pathophysiology, diagnosis, and therapeutic implications of the nonthyroidal illness syndrome is reviewed.
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