• 1
    Cheng SY, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev 2010;31:13970.
  • 2
    Scanlan TS. Minireview: 3-Iodothyronamine (T1AM): a new player on the thyroid endocrine team? Endocrinology 2009;150:110811.
  • 3
    Maldonado LS, Murata GH, Hershman JM, Braunstein GD. Do thyroid function tests independently predict survival in the critically ill? Thyroid 1992;2:11923.
  • 4
    Iervasi G, Pingitore A, Landi P, Raciti M, Ripoli A, Scarlattini M et al. Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation 2003;107:70813.
  • 5
    Scoscia E, Baglioni S, Eslami A, Iervasi G, Monti S, Todisco T. Low triiodothyronine (T3) state: a predictor of outcome in respiratory failure? Results of a clinical pilot study. Eur J Endocrinol 2004;151:55760.
  • 6
    Slag MF, Morley JE, Elson MK, Crowson TW, Nutall FQ, Shafer RB. Hypothyroxinemia in critically ill patients as a predictor of high mortality. JAMA 1981;245:435.
  • 7
    Fliers E, Guldenaar SE, Wiersinga WM, Swaab DF. Decreased hypothalamic thyrotropin-releasing hormone gene expression in patients with nonthyroidal illness. J Clin Endocrinol Metab 1997;82:40326.
  • 8
    Iglesias P, Muñoz A, Prado F, Guerrero MT, Macías MC, Ridruejo E et al. Serum thyrotropin concentration is an early marker of normalization of low T3 syndrome in aged hospitalized patients after discharge. J Endocrinol Invest 2010 Feb 24. doi: 10.3275/6870.
  • 9
    Tognini S, Marchini F, Dardano A, Polini A, Ferdeghini M, Castiglioni M et al. Non-thyroidal illness syndrome and short-term survival in a hospitalised older population. Age Ageing 2010;39:4650.
  • 10
    Peeters PR, Wouters PJ, van Toor H, Kaptein E, Visser TJ, van den Berghe G. Serum 3,3′,5′-Triiodothyronine (rT3) and 3,5,3′-Triiodothyronine-rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities. J Clin Endocrinol Metab 2005;90:455965.
  • 11
    Friberg L, Drvota V, Bjelak AH, Eggertsen G, Ahnve S. Association between increased levels of reverse triiodothyronine and mortality after acute myocardial infarction. Am J Med 2001;111:699703.
  • 12
    Iglesias P, Muñoz A, Prado F, Guerrero MT, Macias MC, Ridruejo E et al. Alterations in thyroid function tests in aged hospitalized patients: prevalence, aetiology and clinical outcome. Clin Endocrinol (Oxf) 2009;70:9617.
  • 13
    Alevizaki M, Synetou M, Xynos K, Pappa T, Vemmos KN. Low triiodothyronine: a strong predictor of outcome in acute stroke patients. Eur J Clin Invest 2007;37:6517.
  • 14
    Forestier E, Vinzio S, Sapin R, Schlienger JL, Goichot B. Increased reverse triiodothyronine is associated with shorter survival in independently-living elderly: the Alsanut study. Eur J Endocrinol 2009;160:20714.
  • 15
    Warner MH, Beckett GJ. Mechanisms behind the non-thyroidal illness syndrome: an update. J Endocrinol 2010;205:113.
  • 16
    Portnay GI, O’Brian JT, Bush J, Vagenakis AG, Azizi F, Arky RA et al. The effect of starvation on the concentration and binding of thyroxine and triiodothyronine in serum and on the response to TRH. J Clin Endocrinol Metab 1974;39:1914.
  • 17
    Burger A, Nicod P, Suter P, Vallotton MB, Vagenakis P, Braveman L. Reduced active thyroid hormone levels in acute illness. Lancet 1976;1:6535.
  • 18
    Forceville X, Vitoux D, Gauzit R, Combes A, Lahilaire P, Chappuis P. Selenium, systemic immune response syndrome, sepsis and outcome in critically ill patients. Crit Care Med 1998;26:153644.
  • 19
    Schneider MJ, Fiering SN, Thai B, Wu SY, St Germain E, Parlow AF et al. Targeted disruption of the type 1 selenodeiodinase gene (Dio1) results in marked changes in thyroid hormone economy in mice. Endocrinology 2006;147:5809.
  • 20
    Debaveye Y, Ellger B, Mebis L, Darras VM, Van den Berghe G. Regulation of tissue iodothyronine deiodinase activity in a model of prolonged critical illness. Thyroid 2008;18:55160.
  • 21
    Maia AL, Kim BW, Huang SA, Harney JW, Larsen PR. Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans. J Clin Invest 2005;115:252433.
  • 22
    Peeters RP, Wouters PJ, Kaptein E, van Toor H, Visser TJ, Van den Berghe G. Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. J Clin Endocrinol Metab 2003;88:320211.
  • 23
    Mebis L, Langouche L, Visser TJ, Van den Berghe G. The type II iodothyronine deiodinase is up-regulated in skeletal muscle during prolonged critical illness. J Clin Endocrinol Metab 2007;92:33303.
  • 24
    Rodriguez-Perez A, Palos-Paz F, Kaptein E, Visser TJ, Dominguez-Gerpe L, Alvarez-Escudero J et al. Identification of molecular mechanisms related to nonthyroidal illness syndrome in skeletal muscle and adipose tissue from patients with septic shock. Clin Endocrinol (Oxf) 2008;68:8217.
  • 25
    Heemstra KA, Soeters MR, Fliers E, Serlie MJ, Burggraaf J, van Doorn MB et al. Type 2 iodothyronine deiodinase in skeletal muscle: effects of hypothyroidism and fasting. J Clin Endocrinol Metab 2009;94:214450.
  • 26
    Kwakkel J, van Beeren HC, Ackermans MT, Platvoet-Ter Schiphorst MC, Fliers E, Wiersinga WM et al. Skeletal muscle deiodinase type 2 regulation during illness in mice. J Endocrinol 2009;203:26370.
  • 27
    Simonides WS, Mulcahey MA, Redout EM, Muller A, Zuidwijk MJ, Visser TJ et al. Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxic- ischemic disease in rats. J Clin Invest 2008;118:97583.
  • 28
    Boelen A, Kwakkel J, Alkemade A, Renckens R, Kaptein E, Kuiper G et al. Induction of type 3 deiodinase activity in inflammatory cells of mice with chronic local inflammation. Endocrinology 2005;146:512834.
  • 29
    Beigneux AP, Moser AH, Shigenaga JK, Grunfeld C, Feingold KR. Sick euthyroid syndrome is associated with decreased TR expression and DNA binding in mouse liver. Am J Physiol Endocrinol Metab 2003;284:E22836.
  • 30
    Kwakkel J, Chassande O, van Beeren HC, Fliers E, Wiersinga WM, Boelen A. Thyroid hormone receptor {alpha} modulates lipopolysaccharide-induced changes in peripheral thyroid hormone metabolism. Endocrinology 2010;151:195969.
  • 31
    Kwakkel J, Chassande O, van Beeren HC, Wiersinga WM, Boelen A. Lacking thyroid hormone receptor beta gene does not influence alterations in peripheral thyroid hormone metabolism during acute illness. J Endocrinol 2008;197:1518.
  • 32
    Boelen A, Platvoet-Ter Schiphorst MC, Wiersinga WM. Association between serum interleukin-6 and serum 3,5,3′-triiodothyronine in nonthyroidal illness. J Clin Endocrinol Metab 1993;77:16959.
  • 33
    Michalaki M, Vagenakis AG, Makri M, Kalfarentzos F, Kyriazopoulou V. Dissociation of the early decline in serum T(3) concentration and serum IL-6 rise and TNFalpha in nonthyroidal illness syndrome induced by abdominal surgery. J Clin Endocrinol Metab 2001;86:4198205.
  • 34
    Kimura T, Kanda T, Kotajima N, Kuwabara A, Fukumura Y, Kobayashi I. Involvement of circulating interleukin-6 and its receptor in the development of nonthyroidal illness syndrome in patients with acute myocardial infarction. Eur J Endocrinol 2000;143:17984.
  • 35
    Boelen A, Maas MA, Lowik CW, Platvoet MC, Wiersinga WM. Induced illness in interleukin-6 (IL-6) knock-out mice: a causal role of IL-6 in the development of the low 3,5,3′-triiodothyronine syndrome. Endocrinology 1996;137:52504.
  • 36
    Van der Poll T, Romijn JA, Wiersinga WM, Sauerwein HP. Tumor necrosis factor: a putative mediator of the sick euthyroid syndrome in man. J Clin Endocrinol Metab 1990;71:156772.
  • 37
    Nagaya T, Fujieda M, Otsuka G, Yang JP, Okamoto T, Seo H. A potential role of activated NF-kappa B in the pathogenesis of euthyroid sick syndrome. J Clin Invest 2000;106:393402.
  • 38
    Kwakkel J, Wiersinga WM, Boelen A. Differential involvement of nuclear factor-kappaB and activator protein-1 pathways in the interleukin-1beta-mediated decrease of deiodinase type 1 and thyroid hormone receptor beta1 mRNA. J Endocrinol 2006;189:3744.
  • 39
    Kwakkel J, Wiersinga WM, Boelen A. Interleukin-1beta modulates endogenous thyroid hormone receptor alpha gene transcription in liver cells. J Endocrinol 2007;194:25765.
  • 40
    Corssmit EP, Heyligenberg R, Endert E, Sauerwein HP, Romijn JA. Acute effects of interferon-alpha administration on thyroid hormone metabolism in healthy men. J Clin Endocrinol Metab 1995;80:31404.
  • 41
    Boelen A, Platvoet-ter Schiphorst MC, Bakker O, Wiersinga WM. The role of cytokines in the lipopolysaccharide-induced sick euthyroid syndrome in mice. J Endocrinol 1995;146:47583.
  • 42
    Boelen A, Schiphorst MC, Wiersinga WM. Relationship between serum 3,5,3′-triiodothyronine and serum interleukin-8, interleukin-10 or interferon gamma in patients with nonthyroidal illness. J Endocrinol Invest 1996;19:4803.
  • 43
    van der Poll T, van Zee KJ, Endert E, Coyle SM, Stiles DM, Pribble JP et al. Interleukin-1 receptor blockade does not affect endotoxin-induced changes in plasma thyroid hormone and thyrotropin concentrations in man. J Clin Endocrinol Metab 1995;80:13416.
  • 44
    Kaptein EM, Robinson WJ, Grieb DA, Nicoloff JT. Peripheral serum thyroxine, triiodothyronine and reverse triiodothyronine in the low thyroxine state of acute nonthyroidal illnesses. A noncompartmental analysis. J Clin Invest 1982;69:52635.
  • 45
    Mebis L, Paletta D, Debaveye Y, Ellger B, Langouche L, D’Hoore A et al. Expression of thyroid hormone transporters during critical illness. Eur J Endocrinol 2009;161:24350.
  • 46
    Adriaanse R, Romijn JA, Brabant G, Endert E, Wiersinga WM. Pulsatile thyrotropin secretion in nonthyroidal illness. J Clin Endocrinol Metab 1993;77:13137.
  • 47
    Mebis L, Debaveye Y, Ellger B, Derde S, Ververs EJ, Langouche L et al. Changes in the central component of the hypothalamus-pituitary-thyroid axis in a rabbit model of prolonged critical illness. Crit Care 2009;13:R147.
  • 48
    Boelen A, Kwakkel J, Wiersinga WM, Fliers E. Chronic local inflammation in mice results in decreased TRH and type 3 deiodinase mRNA expression in the hypothalamic paraventricular nucleus independently of diminished food intake. J Endocrinol 2006;191:70714.
  • 49
    Boelen A, Kwakkel J, Thijssen-Timmer DC, Alkemade A, Fliers E, Wiersinga WM. Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide-induced acute illness in mice. J Endocrinol 2004;182:31523.
  • 50
    Fekete C, Gereben B, Doleschall M, Harney JW, Dora JM, Bianco AC et al. Lipopolysaccharide induces type 2 iodothyronine deiodinase in the mediobasal hypothalamus: implications for the nonthyroidal illness syndrome. Endocrinology 2004;145:164955.
  • 51
    Lechan RM, Fekete C. Infundibular tanycytes as modulators of neuroendocrine function: hypothetical role in the regulation of the thyroid and gonadal axis. Acta Biomed 2007;78(Suppl 1):8498.
  • 52
    Freitas BC, Gereben B, Castillo M, Kalló I, Zeöld A, Egri P et al. Paracrine signaling by glial cell-derived triiodothyronine activates neuronal gene expression in the rodent brain and human cells. J Clin Invest 2010;120:220617.
  • 53
    Brent GA, Hershman JM. Thyroxine therapy in patients with severe nonthyroidal illnesses and low serum thyroxine concentration. J Clin Endocrinol Metab 1986;63:18.
  • 54
    Novitzky D, Fontanet H, Snyder M, Coblio N, Smith D, Parsonnet V. Impact of triiodothyronine on the survival of high-risk patients undergoing open heart surgery. Cardiology 1996;87:50915.
  • 55
    Mullis-Jansson SL, Argenziano M, Corwin S, Homma S, Weinberg AD, Williams M et al. A randomized double-blind study of the effect of triiodothyronine on cardiac function and morbidity after coronary bypass surgery. J Thorac Cardiovasc Surg 1999;117:112834.
  • 56
    Bennett-Guerrero E, Jimenez Jl, White WD, D’Amico EB, Baldwin BI, Schwinn DA. Cardiovascular effects of intravenous triiodothyronine in patients undergoing coronary artery bypass graft surgery. A randomized, double-blind, placebo-controlled trial. Duke T3 study group. JAMA 1996;275:68792.
  • 57
    Hamilton MA, Stevenson LW, Fonarow GC, Steimle A, Goldhaber JI, Child JS et al. Safety and hemodynamic effects of intravenous triiodothyronine in advanced congestive heart failure. Am J Cardiol 1998;8:4437.
  • 58
    Spratt DI, Frohnauer M, Cyr-Alves H, Kramer RS, Lucas FL, Morton JR et al. Physiological effects of nonthyroidal illness syndrome in patients after cardiac surgery. Am J Physiol Endocrinol Metab 2007;293:E3105.
  • 59
    Pingitore A, Galli E, Barison A, Iervasi A, Scarlattini M, Nucci D et al. Acute effects of triiodothyronine (T3) replacement therapy in patients with chronic heart failure and low T3-syndrome: a randomized, placebo-controlled study. J Clin Endocrinol Metab 2008;93:13518.
  • 60
    Klemperer JD, Klein I, Gomez M, Helm RE, Ojamma K, Thomas SJ et al. Thyroid hormone treatment after coronary-artery bypass surgery. N Engl J Med 1995;333:15227.
  • 61
    Moruzzi P, Doria E, Agostoni PG. Medium-term effectiveness of L-thyroxine treatment in idiopathic dilated cardiomyopathy. Am J Med 1996;10:4617.
  • 62
    Bettendorf M, Schmidt KG, Grulich-Henn J, Ulmer HE, Heinrich UE. Triiodothyronine treatment in children after cardiac surgery: a double-blind, randomised, placebo-controlled study. Lancet 2000;356:52934.
  • 63
    Mackie AS, Booth KL, Newburger JW, Gauvreau K, Huang SA, Laussen PC et al. A randomized, double-blind, placebo-controlled pilot trial of triiodothyronine in neonatal heart surgery. J Thorac Cardiovasc Surg 2005;130:8106.
  • 64
    Goarin JP, Cohen S, Riou B, Jacquens Y, Guesde R, Le Bret F et al. The effects of triiodothyronine on hemodynamic status and cardiac function in potential heart donors. Anesth Analg 1996;83:417.
  • 65
    Pérez-Blanco A, Caturla-Such J, Cánovas-Robles J, Sanchez-Payá J. Efficiency of triiodothyronine treatment on organ donor hemodynamic management and adenine nucleotide concentration. Intensive Care Med 2005;31:9438.
  • 66
    Van den Berghe G, Baxter RC, Weekers F, Wouters P, Bowers CY, Iranmanesh A et al. The combined administration of GH-releasing peptide-2 (GHRP-2), TRH and GnRH to men with prolonged critical illness evokes superior endocrine and metabolic effects compared to treatment with GHRP-2 alone. Clin Endocrinol (Oxf) 2002;56:65569.
  • 67
    Villicev CM, Freitas FR, Aoki MS, Taffarel C, Scanlan TS, Moriscot AS et al. Thyroid hormone receptor beta-specific agonist GC-1 increases energy expenditure and prevents fat-mass accumulation in rats. J Endocrinol 2007;193:219.
  • 68
    Williams GR, Franklyn JA, Neuberger JM, Sheppard MC. Thyroid hormone receptor expression in the “sick euthyroid” syndrome. Lancet 1989;2:147781.
  • 69
    Chopra IJ. Euthyroid sick syndrome: is it a misnomer? J Clin Endocrinol Metab 1997;82:32934.
  • 70
    Kaptein EM, Beale E, Chan LS. Thyroid hormone therapy for obesity and nonthyroidal illnesses: a systematic review. J Clin Endocrinol Metab 2009;94:366375.