Mechanisms behind the non-thyroidal illness syndrome: an update

J Endocrinol. 2010 Apr;205(1):1-13. doi: 10.1677/JOE-09-0412. Epub 2009 Dec 16.


The mechanisms behind the changes in serum triiodothyronine (T(3)), thyroxine (T(4)) and TSH that occur in the non-thyroidal 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.

Publication types

  • Review

MeSH terms

  • Animals
  • Disease Models, Animal
  • Euthyroid Sick Syndromes / drug therapy
  • Euthyroid Sick Syndromes / metabolism*
  • Hormone Replacement Therapy
  • Humans
  • Iodide Peroxidase / genetics
  • Iodide Peroxidase / metabolism
  • Leptin / metabolism
  • Mice
  • Mice, Knockout
  • Receptors, Thyroid Hormone / metabolism
  • Thyroid Hormones / metabolism*
  • Thyrotropin-Releasing Hormone / metabolism


  • Leptin
  • Receptors, Thyroid Hormone
  • Thyroid Hormones
  • Thyrotropin-Releasing Hormone
  • Iodide Peroxidase