Cover Page

Cite item


Nonthyroidal illness syndrome is characterized by alterations of thyroid status in patients with severe nonthyroidal illness who are clinically euthyroid. Mechanisms of nonthyroidal illness syndrome are poorly understood and controversial. Our investigations on nonthyroidal illness syndrome in acute endotoxicosis revealed two principal mechanisms of its development. The peripheral mechanism is the first to develop and referred to disturbance of thyrocytes secretory cycle due to increase of thyroglobulin synthesis, endocytosis and decrease of its proteolytic cleavage. It manifests with drop of serum thyroxine, not triiodthyronine, and increase of serum thyroid stimulating hormone. The central mechanism is associated with hypothalamic-pituitary hypofunction developed simultaneously with systemic inflammatory response. Rate of supplementation of the peripheral mechanism with the central one accounts for different types of nonthyroidal illness syndrome with high, normal and low serum levels of thyroid stimulating hormone. Our research showed that thyroid hormone replacement in nonthyroidal illness syndrome could only suppress thyroid function. Unlike thyroid hormones administration of thyroid stimulating hormone restores thyroid hormone secretion in nonthyroidal illness syndrome, decreases endotoxinemia and secretion of proinflammatory cytokines and improves liver function.

About the authors

N. V. Yaglova

Institute of Human Morphology of Russian Academy of Medical Sciences, Moscow, Russian Federation

Author for correspondence.

доктор медицинских наук, заведующая лабораторией развития эндокринной системы ФГБУ «НИИ морфологии человека» РАМН
Адрес: 117418, Москва, ул. Цюрупы, д. 3; тел.: (499) 120-80-65

Russian Federation


  1. De Groot L. Non-thyroidal illness syndrome is functional central hypothyreoidism, and if severe, hormone replacement is appropriate in light of present knowledge. J. Endocrinol. Invest. 2003; 26: 1163–1170.
  2. De Groot L. Non-thyroidal illness syndrome is a manifestation of hypothalamic-pituitary disfunction, and in view of current evidence, should be treated with appropriate replasement therapies. Crit. Care Clin. 2006; 22 (1): 57–86.
  3. Eber B., Schumacher M., Langsteger W., Zweiker R., Fruhwald F., Pokan R., Gasser R., Eber O., Klein W. Changes in thyroid hormone parameters after acute myocardial infarction. Cardiology. 1995; 66 (2): 152–156.
  4. Joosten K., de Kleijn E., Westerterp M., de Hoog M., Eijck F.C., Hop W.C.J., Voort E.V., Hazelzet J.A., Hokken-Koelega A.C. Endocrine and metabolic responses in children with meningococcal sepsis: striking differences between survivors and nonsurvivors.
  5. J. Clin. Endocrinol. Metab. 2000; 85 (10): 3746–3753.
  6. Phillips R., Valente W., Caplan E., Connor T., Wiswell J. Circulating thyroid hormone changes in acute trauma: prognostic implications for clinical outcome. J. Trauma. 1984; 24: 116–119.
  7. Vexiau P., Perez-Castiglioni P., Socie G., Devergie A., Toubert M., Aractingi S., Gluckman E. The euthyroid sick syndrome: incidence, risk factor and prognostic value soon after allogenic bone marrow transplantation. Brit. J. Hematol. 1993; 85 (4): 778–782.
  8. Warner M., Beckett G. Mechanism behind the non-thyroidal illness syndrome: an update. J. Endocrinol. 2010; 205: 1–13.
  9. Kaptein E. Clinical relevance of thyroid hormone alterations in nonthyroidal illness. Thyroid Int. 1997; 4: 22–25.
  10. Maldonado S., Murata G., Hershman J., Braunstein G. Do thyroid function tests independently predict survival in the critically ill? Thyroid. 1992; 2 (2): 119–123.
  11. Peeters R., Wouters P., van Toor H. van Toor H., Kaptein E., Visser T., van der Berge G. Serum 3,3’,5’-triiodothyronone (rT3) and 3,5,3’-triiodothronine/rT3 are prognostic markers in critically
  12. ll patients and are associated with postmortem tissue deiodinase activities. J. Clin. Endorinol. Metab. 2005; 90 (8): 4559–4565.
  13. Fliers E., Guldenaar S., Wiersinga W., Swaab D. Decreased hypothalamic thyritropine-releasing hormone gene expression in patients with nonthyroidal illness. J. Clin. Endocrinol. Metab. 1997; 82: 4032–4036.
  14. den Brinker M., Joosten C., Visser T., Hop W., de Rijke Y., Hazelzet J., Boonstra V., Hokken-Koelega A. Euthyroid sick syndrome in meningococcal sepsis: the impact of peripheral thyroid hormone metabolism and binding proteins. J. Clin. Endorinol. Metab. 2005; 90 (10): 5613–5620.
  15. Boelen A., Kwakkel J., Thijssen-Timmer D., Alkemade A., Fliers E., Wiersinga W. Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide induced acute illness in mice. J. Endocrinol. 2004; 182 (2): 315–323.
  16. Docter R., Krenning E., de Jong M., Hennemann G. The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism. Clin. Endocrinol. (Oxf). 1993; 39: 499–518.
  17. Adler S., Wartofsky L. The nonthyroidal illness syndrome. Endocrinol. Metab. Clin. N. Am. 2007; 36: 657–672.
  18. Galton V., Schneider M., Clark A., St. Germain D. Life without T4 to T3 conversion: studies in mice devoid of the 5’-deiodinases. Endocrinology. 2009; 150 (6): 2957–2963.
  19. Dumont J., Maenhaut C., Pirson I., Maenhaut C. Growth factors controlling the thyroid gland. Baillieres Clin. Endocrinol. Metab. 1991; 5 (4): 727–754.
  20. Thompson S., Franklyn J., Watkinson J., Verhaeg J., Sheppard M., Eggo M. Fibroblast growth factor 1 and 2 and fibroblast growh factor receptor 1 are elevated in thyroid hyperpasia. J. Clin. Endorinol. Metab. 1998; 83: 1336–1341.
  21. Derwahl M., Broecker M., Kraiem Z. Thyrotropin may not be the dominant growth factor in benign and malignant thyroid tumors. J. Clin. Endorinol. Metab. 1999; 84: 829–834.
  22. Vella V., Pandini G., Sciacca L., Mineo R., Vigneri R., Pezzino V. A novel autocrine loop involving IGF-II and the insulin receptor isoform-A stimulates growth of thyroid cancer. J. Clin. Endorinol. Metab. 2002; 87 (2): 245–254.
  23. Yamazaki K., Suzuki K., Yamada E., Yamada T., Takeshita F., Mat-sumoto M., Mitsuhashi T., Obara T., Takao K., Sato K. Suppression of iodide uptake and thyroid hormone synthesis with stimulation of the type I interferon system by double-stranded ribonucleic acid in cultured human thyroid follicles. Endocrinology. 2007; 148 (7): 3226–3235.
  24. Nicola J., Velez M., Lucero A., Fozzati L., Pellizas C., Masini-Repiso A. Functional toll-like receptor 4 conferring lipopolysaccharide responsiveness is expressed in thyroid cells. Endocrinology. 2009; 150 (1): 500–508.
  25. Yaglova N.V., Berezov T.T. Regulyatornaya rol' lipopolisakharida v funktsional'noi deyatel'nosti shchitovidnoi zhelezy i gipofiza. Biomed. khimiya. 2010; 56 (2): 179–186.
  26. Yaglova N.V. Morfofunktsional'nyi analiz razvitiya sindroma netireoidnykh zabolevanii pri eksperimental'nom endotoksikoze. Byull. eksp. biol. i meditsiny. 2009;148 (11): 584–588.
  27. Yaglova N.V. Morfofunktsional'nye izmeneniya shchitovidnoi zhelezy krys pri ostrom eksperimental'nom endotoksikoze. Arkh. patol. 2010; 3: 24–27.
  28. Yaglova N.V. Ul'trastrukturnye izmeneniya v follikulyarnykh kletkakh shchitovidnoi zhelezy pri vozdeistvii lipopolisakharida. Klin. i eksp. morfol. 2012; 1: 47–53.
  29. Yaglova N.V. Rol' endotoksina gramotritsatel'nykh bakterii v mekhanizmakh regulyatsii tireoidnogo statusa organizma. Vopr. pitaniya. 2010; 3: 18–24.
  30. De Jongh F., Jobsis A., Elte J. Thyroid morphology in lethal non-thyroidal illness: a post-mortem study. Eur. J. Endocrinol. 2001; 144: 221–226.
  31. Khmel'nitskii O.K. Shchitovidnaya zheleza zhitelei Sankt-Peterburga v norme i pri patologii. S.-Pb.: SPbMAPO. 2003. 228 s.
  32. Cherenkov I.A., Glumova V.A., Chuchkova N.N. Morfologicheskie osobennosti shchitovidnoi zhelezy cheloveka v razlichnykh ekologicheskikh usloviyakh. Sovr. naukoemk. tekhnol. 2005; 2: 48.
  33. Khmel'nitskii O.K. Tsitologicheskaya i gistologicheskaya diagnostika zabolevanii shchitovidnoi zhelezy. Rukovodstvo. S.-Pb.: SOTIS. 2002. 288 s.
  34. Boelen A., Kwakkel J., Platvoet-Ter Schiphorst M., Baur A., Kohrle J., Wiersinga W. Contribution of interleukin-12 to the pathogenesis of nonthyroidal illness. Horm. Metabol. Res. 2004; 36 (2): 101–106.
  35. Boelen A., Kwakkel J., Platvoet-Ter Schiphorst M., Mentrup B., Baur A., Kohrle J., Wiersinga W. Interleukin-18, a proinflammatory cytokine, contributes to the pathogenesis of nonthyroidal illness mainly via the central part of the hypothalamus-pituitary-thyroid axis. Eur. J. Endocrinol. 2004; 151 (4): 497–502.
  36. Boelen A., Platvoet-Ter Schiphorst M., Bakker O., Wiersinga W. The role of cytokines in the lipopolisaccharide-induced sick euthyroid syndrome in mice. J. Endocrinol. 1995; 146 (3): 475–483.
  37. Boelen A., Platvoet-Ter Schiphorst M., Wiersinga W. Association between serum interleukin-6 and serum 3,5,3’-triiodothyronine in nonthyroidal illness. J. Clin. Endocrinol. Metab. 1993; 80 (6): 1695–1699.
  38. Boelen A., Platvoet ter-Schiphorst M., Wiersinga W. Immunoneutralization of interleukin-1, tumor necrosis factor, interleukin-6 or interferon does not prevent the LPS-induced sick euthyroid syndrome in mice. J. Endocrinol. 1997; 153 (1): 115–122.
  39. van der Poll T., Van Zee K., Endert E., Coyle S., Stiles D., Pribble J., Catalano M., Moldawer L., Lowry S. et al. Interleukin-1 receptor blockade does not affect endotoxin-induced changes in plasma thyroid hormone and thyrotropine concentration in man.
  40. J. Clin. Endocrinol. Metab. 1995; 80 (4): 1341–1346.
  41. Makarova O.V., Yablonskaya A.M., Mikhailova L.P., Yaglova N.V. Individual'nye razlichiya reaktsii organov-mishenei i immunnoi sistemy pri eksperimental'nom endotoksikoze. Arkh. patol. 2009; 4: 37–43.
  42. Yaglova N.V. Vzaimosvyaz' funktsional'noi aktivnosti shchitovidnoi zhelezy i urovnya provospalitel'nykh i immunoregulyatornykh tsitokinov pri ostrom eksperimental'nom endotoksikoze. Byull. eksp. biol. i meditsiny. 2009; 49 (6): 635–638.
  43. Yaglova N.V., Berezov T.T. Rol' polyarizatsii immunnogo otveta v razvitii sindroma netireoidnykh zabolevanii. Vopr. biol., med. i farmatsevticheskoi khimii. 2009; 4: 17–20.
  44. Siegel N., Gaudio K., Katz L., Reilly H., Ardito T., Hendler F., Kashqarian M. Beneficial effect of thyroxin on recovery from toxic acute renal failure. Kidney Int. 1984; 6: 906–911.
  45. Brent G., Herschman J. Thyroxine therapy in patients with severe non-thyroidal illnesses and lower serum thyroxine concentration.
  46. J. Clin. Endorinol. Metab. 1986; 63 (1): 1–8.
  47. Chapital A., Hendrick S., Lloyd L., Pieper D. The effects of triiodothyronine augmentation on antithrombin III levels in sepsis. Am. Surg. 2001; 67: 253–255.
  48. Sumita S., Ujike Y., Namiki A., Watanabe H., Kawamata M., Watanabe A. Suppression of thyrotropine response to thyrotropine-releasing hormone and its association with severity of critical illness. Crit. Care Med. 1994; 22: 1603–1609.
  49. Yaglova N.V. Narusheniya sekretornogo tsikla follikulyarnykh tirotsitov i ikh korrektsiya tireotropnym gormonom pri eksperimental'nom sindrome netireoidnykh zabolevanii. Byull. eksp. biol. i meditsiny. 2011; 152 (8): 215–219.
  50. Yaglova N.V., Berezov T.T. Rol' tireotropnogo gormona v izmenenii gormonal'nogo i tsitokinovogo profilya pri eksperimental'nom sindrome netireoidnykh zabolevanii. Immunologiya. 2010; 3 (3): 146–151.
  51. Klein J., Wang H. Characterization a novel set of resident intrathyroidal bone marrow-derived hematopoietic cells: potential for immune-endocrine interactions in thyroid homeostasis. J. Exp. Biol. 2004: 207: 55–65.
  52. Kruger T. Immunomodulation of peripheral lymphocytes by hormones of the hypothalamo-pitutary- thyroid axis. Adv. Neuroimmunol. 1996; 6: 387–395.
  53. Scofield V., Montufar-Solis D., Cheng E., Estes M., Klein J. Intestinal TSH production is localized in villus «hotblocks» and is coupled to IL-7 production. Immunol. Lett. 2005; 99: 36–44.
  54. Klein J. The immune system as a regulator of thyroid hormone activity. Exp. Biol. Med. 2006; 231: 229–236.
  55. Provinciali M., Di Stefano G., Fabris N. Improvement in the proliferanive capacity of natural killer cell activity of murine spleen lymphocytes by thyrotropin. Int. J. Immunopharmacol. 1992; 14: 865–870.
  56. Bagriacik E., Klein J. The thyrotropin receptor is expressed on murine dendritic cells and on a subset of CD43Rbhigh lymph node T cells: functional role of thyroid stimulating hormone during immune activation. J. Immunol. 2000; 164: 6158–6156.
  57. Yaglova N.V., V.V. Yaglov. Sekretsiya tuchnykh kletok shchitovidnoi zhelezy pri vozdeistvii tireotropnogo gormona. Klin. i eksp. morfol. 2012; 2: 36–40.
  58. Yaglova N.V., Berezov T.T. Regulyatornoe vliyanie tireotropnogo i tireoidnykh gormonov na funktsional'nye pokazateli sostoyaniya pecheni pri ostrom eksperimental'nom gramotritsatel'nom endotoksikoze. Vopr. biol., med. i farmatsevticheskoi khimii. 2011; 10: 42–47.

Comments on this article

View all comments

Copyright (c) 1970 "Paediatrician" Publishers LLC

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies