Mechanisms behind the non-thyroidal illness syndrome: an update

Abstract

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.

Thyroid Function and Dysfunction in Term and Premature Equine Neonates

“…A variety of mechanisms have been described to explain the hormonal changes in NTIS. As recently reviewed,34, 35 NTIS likely results from a combination of central hypothyroidism, altered local TH metabolism, and an acute phase response that leads to decreased TH‐binding proteins. TRH neurons in the hypothalamus appear to play a key role in altering the set point of the hypothalamic‐pituitary‐thyroid axis.…”

Type 1 iodothyronine deiodinase in human physiology and disease

“…Indeed, the decrease in the concentration of circulating T 3 relative to that of T 4 and an increase in rT 3 concentrations in fasting humans was one of the earliest indications that the peripheral metabolism of thyroid hormones could be modulated by physiological or physiopathological events (Portnay et al 1974). Nevertheless, the complex physiopathological mechanisms responsible for these systemic changes remain poorly understood (Warner & Beckett 2010). Changes in deiodinases expression have been postulated to play important roles in the altered circulating levels of thyroid hormones in fasting and nonthyroidal illness syndrome (NTIS) (Debaveye et al 2008, Kwakkel et al 2009).…”

Association between thyroid function tests at baseline and the outcome of patients with sepsis or septic shock: a systematic review

“…Low triiodothyronine (T 3 ) is commonly observed in the latter group of patients, which can be attributed to increased deiodination of thyroxine (T 4 ) to reverse T 3 (rT 3 ), rather than T 3 , and increased catabolism of T 3 to 3,3-diiodothyronine (T 2 ) (4-6). With increasing severity of illness, low total and free T 4 , and sometimes low TSH, can be observed (6). Decrease in plasma T 4 -binding globulin (TBG) or transthyretin as well as accumulation of substances that lower the plasma thyroid hormone-binding capacity appear also to be important for the above-mentioned alterations in thyroid hormone levels during critical illness (4).…”