Abstract
Neuroendocrine changes in the hypothalamic–pituitary–thyroid axis during critical illness result in nonthyroidal illness syndrome (NTIS) characterized by abnormal thyrotropin (TSH) and thyroid hormone levels. Studies looking at the natural history of neuroendocrine changes during critical illness have revealed the presence of NTIS. NTIS has been described in a variety of patient settings. Many studies have tried to uncover the pathophysiology behind NTIS and several theories are proposed. Whether NTIS requires treatment or intervention is still controversial and the results of the treatment studies are arguably mixed. Whether implicitly stated or not, the underlying purpose of all the natural history, pathophysiology, or treatment studies is to determine whether NTIS is adaptive or maladaptive. Some studies have illustrated a correlation between illness severity and the degree of NTIS but a cause and effect relationship is still elusive. The human studies can be divided between those with either adult or pediatric subjects, with much less data available in the latter. This review examines the available literature on NTIS with an emphasis on the pediatric literature.
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G. Van den Berghe, F. de Zegher, R. Bouillon, J. Clin. Endocrinol. Metab. 83, 1827–1834 (1998)
G. Van den Berghe, Eur. J. Endocrinol. 143, 1–13 (2000)
I.J. Chopra, J. Clin. Endocrinol. Metab. 82, 329–334 (1997)
L.J. De Groot, J. Clin. Endocrinol. Metab. 84, 151–164 (1999)
L.F. Span, A.R. Hermus, A.K. Bartelink, A.J. Hoitsma, J.S. Gimbrere, A.G. Smals, P.W. Kloppenborg, Intensive Care Med. 18, 93–96 (1992)
I. Vermes, A. Beishuizen, R.M. Hampsink, C. Haanen, J. Clin. Endocrinol. Metab. 80, 1238–1242 (1995)
R.E. Shangraw, F. Jahoor, H. Miyoshi, W.A. Neff, C.A. Stuart, D.N. Herndon, R.R. Wolfe, Metab. Clin. Exp. 38, 983–989 (1989)
R.R. Wolfe, Baillieres Clin. Endocrinol. Metab. 11, 645–657 (1997)
H.J. Voerman, R.J. Strack van Schijndel, H. de Boer, E.A. van der Veen, L.G. Thijs, Neth. J. Med. 41, 229–244 (1992)
R. Ross, J. Miell, E. Freeman, J. Jones, D. Matthews, M. Preece, C. Buchanan, Clin. Endocrinol. 35, 47–54 (1991)
G.L. Noel, H.K. Suh, J.G. Stone, A.G. Frantz, J. Clin. Endocrinol. Metab. 35, 840–851 (1972)
Q. Dong, F. Hawker, D. McWilliam, M. Bangah, H. Burger, D.J. Handelsman, Clin. Endocrinol. 36, 399–404 (1992)
G. Van den Berghe, F. de Zegher, P. Lauwers, J.D. Veldhuis, Clin. Endocrinol. 41, 563–569 (1994)
C. Wang, V. Chan, T.F. Tse, R.T. Yeung, Clin. Endocrinol. 9, 249–253 (1978)
P.D. Woolf, R.W. Hamill, J.V. McDonald, L.A. Lee, M. Kelly, J. Clin. Endocrinol. Metab. 60, 444–450 (1985)
G. Van den Berghe, Best Pract. Res. Clin. Endocrinol. Metab. 15, 405–419 (2001)
N. Stathatos, C. Levetan, K.D. Burman, L. Wartofsky, Best Pract. Res. Clin. Endocrinol. Metab. 15, 465–478 (2001)
E. Fliers, A. Alkemade, W.M. Wiersinga, Best Pract. Res. Clin. Endocrinol. Metab. 15, 453–464 (2001)
R. Adriaanse, J.A. Romijn, G. Brabant, E. Endert, W.M. Wiersinga, J. Clin. Endocrinol. Metab. 77, 1313–1317 (1993)
J.A. Romijn, W.M. Wiersinga, J. Clin. Endocrinol. Metab. 70, 35–42 (1990)
S.J. Maturlo, R.L. Rosenbaum, C. Pan, M.I. Surks, J. Clin. Invest. 66, 451–456 (1980)
P.M. Rothwell, P.G. Lawler, Crit. Care Med. 23, 78–83 (1995)
C. Spencer, A. Eigen, D. Shen, M. Duda, S. Qualls, S. Weiss, J. Nicoloff, Clin. Chem. 33, 1391–1396 (1987)
V.S. Lim, V.S. Fang, A.I. Katz, S. Refetoff, J. Clin. Invest. 60, 522–534 (1977)
G.A. Brent, J.M. Hershman, J. Clin. Endocrinol. Metab. 63, 1–8 (1986)
R.A. Becker, G.M. Vaughan, M.G. Ziegler, L.G. Seraile, I.W. Goldfarb, E.H. Mansour, W.F. McManus, B.A. Pruitt Jr., A.D. Mason Jr., Crit. Care Med. 10, 870–875 (1982)
W.F. Bremner, K.M. Taylor, S. Baird, J.E. Thomson, J.A. Thomson, J.G. Ratcliffe, T.D. Lawrie, W.H. Bain, J. Thorac. Cardiovasc. Surg. 75, 392–399 (1978)
G. Robuschi, D. Medici, F. Fesani, G. Barboso, M. Montermini, L. d’Amato, E. Gardini, E. Borciani, E. Dall’Aglio, M. Salvi et al., Horm. Res. 23, 151–158 (1986)
D.K. Cooper, D. Novitzky, J. Thorac. Cardiovasc. Surg. 104, 526–527 (1992)
D. Novitzky, D.K. Cooper, C.I. Barton, A. Greer, J. Chaffin, J. Grim, N. Zuhdi, J. Thorac. Cardiovasc. Surg. 98, 972–977 (1989); discussion 977–8
M.F. Slag, J.E. Morley, M.K. Elson, T.W. Crowson, F.Q. Nuttall, R.B. Shafer, JAMA 245, 43–45 (1981)
A. Lalani, S. Dhuper, in The Endocrine Society 2004 Annual Meeting Poster Session (P2-462) (New Orleans, LA, 2004)
A.R. Zucker, B. Chernow, A.I. Fields, W. Hung, K.D. Burman, J. Pediatr. 107, 552–554 (1985)
N. Uzel, O. Neyzi, Pediatr. Infect. Dis. 5, 516–519 (1986)
K.F. Joosten, E.D. de Kleijn, M. Westerterp, M. de Hoog, F.C. Eijck, W.C.J. Hop, E.V. Voort, J.A. Hazelzet, A.C. Hokken-Koelega, J. Clin. Endocrinol. Metab. 85, 3746–3753 (2000)
H. Hashimoto, N. Igarashi, A. Yachie, T. Miyawaki, T. Sato, J. Clin. Endocrinol. Metab. 78, 288–291 (1994)
J. Simpson, F.L. Williams, C. Delahunty, H. van Toor, S.Y. Wu, S.A. Ogston, T.J. Visser, R. Hume, J. Clin. Endocrinol. Metab. 90, 1271–1279 (2005)
N. Mungan, D. Yildizdas, K. Topaloglu, B. Yuksel, G. Ozer, in The Endocrine Society 2004 Annual Meeting Poster Session (P2-489) (New Orleans, LA, 2004)
M. den Brinker, B. Dumas, T.J. Visser, W.C. Hop, J.A. Hazelzet, D.A. Festen, A.C. Hokken-Koelega, K.F. Joosten, Intensive Care Med. 31, 970–976 (2005)
M. den Brinker, K.F. Joosten, T.J. Visser, W.C. Hop, Y.B. de Rijke, J.A. Hazelzet, V.H. Boonstra, A.C. Hokken-Koelega, J. Clin. Endocrinol. Metab. 90, 5613–5620 (2005)
D.A. Osborn, Cochrane Database Syst. Rev. CD001070 (2001)
D.A. Osborn, R.W. Hunt, Cochrane Database Syst. Rev. CD005945 (2007)
D.A. Osborn, R.W. Hunt, Cochrane Database Syst. Rev. CD005946 (2007)
D.A. Osborn, R.W. Hunt, Cochrane Database Syst. Rev. CD005948 (2007)
M. Bettendorf, K.G. Schmidt, U. Tiefenbacher, J. Grulich-Henn, U.E. Heinrich, D.K. Schonberg, Pediatr. Res. 41, 375–379 (1997)
S.D. Marks, C. Haines, I.M. Rebeyka, R.M. Couch, J. Clin. Endocrinol. Metab. 94, 2781–2786 (2009)
B. Murzi, G. Iervasi, S. Masini, R. Moschetti, V. Vanini, G. Zucchelli, A. Biagini, Ann. Thorac. Surg. 59, 481–485 (1995)
B.A. Lynch, D.M. Brown, C. Herrington, E. Braunlin, J. Thorac. Cardiovasc. Surg. 127, 1509–1511 (2004)
O.C. Ross, A. Petros, Intensive Care Med. 27, 1124–1132 (2001)
D.B. Allen, K.A. Dietrich, J.J. Zimmerman, J. Pediatr. 114, 59–62 (1989)
D.G. Ririe, J.F. Butterworth, M. Hines, J.W. Hammon Jr, G.P. Zaloga, Anesth. Analg. 87, 543–548 (1998)
R.D. Mainwaring, R.M. Healy, F.A. Meier, J.C. Nelson, W.I. Norwood, Cardiol. Young 11, 295–300 (2001)
R.D. Mainwaring, J.J. Lamberti, G.F. Billman, J.C. Nelson, Ann. Thorac. Surg. 58, 1078–1082 (1994)
R.D. Mainwaring, J.J. Lamberti, T.L. Carter Jr., J.C. Nelson, J. Card. Surg. 9, 322–331 (1994)
A. Belgorosky, G. Weller, E. Chaler, S. Iorcansky, M.A. Rivarola, J. Endocrinol. Invest. 16, 499–503 (1993)
K. Saatvedt, H. Lindberg, O.R. Geiran, A. Fiane, E. Seem, S. Michelsen, T. Pedersen, T.A. Hagve, Acta Anaesthesiol. Scand. 42, 1100–1103 (1998)
I.M. Mitchell, J.C. Pollock, M.P. Jamieson, S.F. Donaghey, R.D. Paton, R.W. Logan, J. Thorac. Cardiovasc. Surg. 103, 800–805 (1992)
I.M. Mitchell, Ann. Thorac. Surg. 60, 745–747 (1995)
D.J. Cullen, J.M. Civetta, B.A. Briggs, L.C. Ferrara, Crit. Care Med. 2, 57–60 (1974)
I.J. Chopra, D.H. Solomon, G.N. Teco, J.B. Eisenberg, Science 215, 407–409 (1982)
R.B. Wilcox, J.C. Nelson, R.T. Tomei, Eur. J. Endocrinol. 131, 9–13 (1994)
P.R. Pannall, W.R. Fuller, A.R. Peisach, J. Marshall, S. Stuart, C.P. Reilly, M.L. Wellby, Clin. Chem. 26, 1925–1926 (1980)
R.P. Peeters, S. van der Geyten, P.J. Wouters, V.M. Darras, H. van Toor, E. Kaptein, T.J. Visser, G. Van den Berghe, J. Clin. Endocrinol. Metab. 90, 6498–6507 (2005)
M.M. Kaplan, R.D. Utiger, J. Clin. Invest. 61, 459–471 (1978)
R.P. Peeters, P.J. Wouters, E. Kaptein, H. van Toor, T.J. Visser, G. Van den Berghe, J. Clin. Endocrinol. Metab. 88, 3202–3211 (2003)
Y. Debaveye, B. Ellger, L. Mebis, E. Van Herck, W. Coopmans, V. Darras, G. Van den Berghe, Endocrinology 146, 5604–5611 (2005)
A.L. Maia, B.W. Kim, S.A. Huang, J.W. Harney, P.R. Larsen, J. Clin. Invest. 115, 2524–2533 (2005)
L. Mebis, L. Langouche, T.J. Visser, G. Van den Berghe, J. Clin. Endocrinol. Metab. 92, 3330–3333 (2007)
F.E. De Jongh, A.C. Jobsis, J.W. Elte, Eur. J. Endocrinol. 144, 221–226 (2001)
L. Bartalena, E. Martino, L.S. Brandi, M. Falcone, A. Pacchiarotti, C. Ricci, F. Bogazzi, L. Grasso, C. Mammoli, A. Pinchera, J. Clin. Endocrinol. Metab. 70, 293–296 (1990)
E. Fliers, S.E. Guldenaar, W.M. Wiersinga, D.F. Swaab, J. Clin. Endocrinol. Metab. 82, 4032–4036 (1997)
G. Van den Berghe, R.C. Baxter, F. Weekers, P. Wouters, C.Y. Bowers, A. Iranmanesh, J.D. Veldhuis, R. Bouillon, Clin. Endocrinol. 56, 655–669 (2002)
G. Van den Berghe, F. de Zegher, R.C. Baxter, J.D. Veldhuis, P. Wouters, M. Schetz, C. Verwaest, E. Van der Vorst, P. Lauwers, R. Bouillon, C.Y. Bowers, J. Clin. Endocrinol. Metab. 83, 309–319 (1998)
G. Van den Berghe, P. Wouters, F. Weekers, S. Mohan, R.C. Baxter, J.D. Veldhuis, C.Y. Bowers, R. Bouillon, J. Clin. Endocrinol. Metab. 84, 1311–1323 (1999)
A. Boelen, M.C. Platvoet-Ter Schiphorst, W.M. Wiersinga, J. Clin. Endocrinol. Metab. 80, 971–976 (1995)
A. Boelen, M.C. Platvoet-Ter Schiphorst, W.M. Wiersinga, J. Clin. Endocrinol. Metab. 77, 1695–1699 (1993)
P.H. Davies, E.G. Black, M.C. Sheppard, J.A. Franklyn, Clin. Endocrinol. 44, 199–205 (1996)
T. Kimura, T. Kanda, N. Kotajima, A. Kuwabara, Y. Fukumura, I. Kobayashi, Eur. J. Endocrinol. 143, 179–184 (2000)
C.K. McMahon, I. Klein, K. Ojamaa, Thyroid 13, 301–304 (2003)
A. Boelen, M.C. Platvoet-ter Schiphorst, O. Bakker, W.M. Wiersinga, J. Endocrinol. 146, 475–483 (1995)
J.M. Stouthard, T. van der Poll, E. Endert, P.J. Bakker, C.H. Veenhof, H.P. Sauerwein, J.A. Romijn, J. Clin. Endocrinol. Metab. 79, 1342–1346 (1994)
T. van der Poll, J.A. Romijn, W.M. Wiersinga, H.P. Sauerwein, J. Clin. Endocrinol. Metab. 71, 1567–1572 (1990)
A. Boelen, M.C. Platvoet-ter Schiphorst, W.M. Wiersinga, J. Endocrinol. 153, 115–122 (1997)
J. Yu, R.J. Koenig, J. Biol. Chem. 275, 38296–38301 (2000)
R.S. Ahima, D. Prabakaran, C. Mantzoros, D. Qu, B. Lowell, E. Maratos-Flier, J.S. Flier, Nature 382, 250–252 (1996)
G. Legradi, C.H. Emerson, R.S. Ahima, J.S. Flier, R.M. Lechan, Endocrinology 138, 2569–2576 (1997)
D. Modan-Moses, S. Ehrlich, H. Kanety, O. Dagan, C. Pariente, N. Esrahi, D. Lotan, T. Vishne, Z. Barzilay, G. Paret, Crit. Care Med. 29, 2377–2382 (2001)
Y.M. Cho, M.S. Kim, C.S. Shin, D.J. Park, K.S. Park, H.K. Yang, K.U. Lee, B.Y. Cho, H.K. Lee, S.Y. Kim, Horm. Res. 59, 100–104 (2003)
C.F. Lim, R. Docter, T.J. Visser, E.P. Krenning, B. Bernard, H. van Toor, M. de Jong, G. Hennemann, J. Clin. Endocrinol. Metab. 76, 1165–1172 (1993)
L.S. Gotzsche, J. Weeke, J. Thorac. Cardiovasc. Surg. 104, 273–277 (1992)
V. Coiro, A. Harris, H.M. Goodman, A. Vagenakis, L. Braverman, Endocrinology 106, 68–75 (1980)
B.L. Shulkin, R.D. Utiger, J. Clin. Endocrinol. Metab. 58, 1184–1187 (1984)
H. Shigematsu, R.A. Smith, C.H. Shatney, Crit. Care Med. 15, 933–938 (1987)
K. Plumpton, N.A. Haas, Intensive Care Med. 31, 581–587 (2005)
E.M. Kaptein, C.A. Spencer, M.B. Kamiel, J.T. Nicoloff, J. Clin. Endocrinol. Metab. 51, 387–393 (1980)
G. Van den Berghe, F. de Zegher, P. Lauwers, Clin. Endocrinol. 41, 731–737 (1994)
G. Brabant, A. Brabant, U. Ranft, K. Ocran, J. Kohrle, R.D. Hesch, A. von zur Muhlen, J. Clin. Endocrinol. Metab. 65, 83–88 (1987)
N.A. Haas, C.K. Camphausen, D. Kececioglu, Crit. Care 10, 213 (2006)
T.V. Brogan, S.L. Bratton, A.M. Lynn, Crit. Care Med. 25, 1583–1587 (1997)
N. Linder, B. Sela, B. German, N. Davidovitch, J. Kuint, J. Hegesh, D. Lubin, J. Sack, Arch. Dis. Child. Fetal Neonatal Ed. 77, F239–F240 (1997)
J.M. Hulst, J.B. van Goudoever, T.J. Visser, D. Tibboel, K.F. Joosten, Clin. Nutr. 25, 154–162 (2006)
R. Holzer, B. Bockenkamp, P. Booker, P. Newland, G. Ciotti, M. Pozzi, Pediatr. Cardiol. 25, 522–528 (2004)
P.R. Larsen, M.J. Berry, Annu. Rev. Nutr. 15, 323–352 (1995)
A. Avenell, D.W. Noble, J. Barr, T. Engelhardt, Cochrane Database Syst. Rev. CD003703 (2004)
B.J. Voerman, R.J. Strack van Schijndel, A.B. Groeneveld, H. de Boer, J.P. Nauta, L.G. Thijs, Crit. Care Med. 23, 665–673 (1995)
H.J. Voerman, R.J. van Schijndel, A.B. Groeneveld, H. de Boer, J.P. Nauta, E.A. van der Veen, L.G. Thijs, Ann. Surg. 216, 648–655 (1992)
D.N. Herndon, R.E. Barrow, K.R. Kunkel, L. Broemeling, R.L. Rutan, Ann. Surg. 212, 424–429 (1990); discussion 430–1
J. Takala, E. Ruokonen, N.R. Webster, M.S. Nielsen, D.F. Zandstra, G. Vundelinckx, C.J. Hinds, N. Engl. J. Med. 341, 785–792 (1999)
D. Novitzky, P.A. Human, D.K. Cooper, Ann. Thorac. Surg. 45, 50–55 (1988)
D. Novitzky, P.A. Human, D.K. Cooper, J. Thorac. Cardiovasc. Surg. 96, 600–607 (1988)
J.D. Klemperer, J. Zelano, R.E. Helm, K. Berman, K. Ojamaa, I. Klein, O.W. Isom, K. Krieger, J. Thorac. Cardiovasc. Surg. 109, 457–465 (1995)
J.D. Walker, F.A. Crawford Jr., F.G. Spinale, Ann. Thorac. Surg. 60, 292–299 (1995)
D. Novitzky, D.K. Cooper, A. Swanepoel, Eur. J. Cardiothorac. Surg. 3, 140–145 (1989)
S.L. Mullis-Jansson, M. Argenziano, S. Corwin, S. Homma, A.D. Weinberg, M. Williams, E.A. Rose, C.R. Smith, J. Thorac. Cardiovasc. Surg. 117, 1128–1134 (1999)
J.D. Klemperer, I. Klein, M. Gomez, R.E. Helm, K. Ojamaa, S.J. Thomas, O.W. Isom, K. Krieger, N. Engl. J. Med. 333, 1522–1527 (1995)
R.D. Mainwaring, J.C. Nelson, Cardiol. Young 12, 211–217 (2001)
D. Chowdhury, K. Ojamaa, V.A. Parnell, C. McMahon, C.P. Sison, I. Klein, J. Thorac. Cardiovasc. Surg. 122, 1023–1025 (2001)
S. Dimmick, N. Badawi, T. Randell, Cochrane Database Syst. Rev. CD004220 (2004)
M.A. Portman, C. Fearneyhough, X.H. Ning, B.W. Duncan, G.L. Rosenthal, F.M. Lupinetti, J. Thorac. Cardiovasc. Surg. 120, 604–608 (2000)
U.S. National Institutes of Health: ClinicalTrials.gov: Study of triostat in infants during heart surgery. Retrieved May 12, 2009, from http://clinicaltrials.gov/ct2/show/NCT00027417?term=portman+thyroid&rank=1 (2005)
M.A. Portman, C. Fearneyhough, T.R. Karl, E. Tong, K. Seidel, A. Mott, G. Cohen, T. Tacy, M. Lewin, L. Permut, M. Schlater, A. Azakie, Am. Heart J. 148, 393–398 (2004)
A.S. Mackie, K.L. Booth, J.W. Newburger, K. Gauvreau, S.A. Huang, P.C. Laussen, J.A. DiNardo, P.J. del Nido, J.E. Mayer Jr., R.A. Jonas, E. McGrath, J. Elder, S.J. Roth, J. Thorac. Cardiovasc. Surg. 130, 810–816 (2005)
N.A. Haas, C.K. Camphausen, J. Thorac. Cardiovasc. Surg. 131, 505–506 (2006). author reply 506
M. Bettendorf, K.G. Schmidt, J. Grulich-Henn, H.E. Ulmer, U.E. Heinrich, Lancet 356, 529–534 (2000)
R.D. Mainwaring, J.J. Lamberti, J.C. Nelson, G.F. Billman, T.L. Carter, K.H. Schell, Cardiol. Young 7, 194–200 (1997)
J. Bialkowski, Cardiol. Young 8, 139–140 (1998)
D. Rosen, M. Serafini, L. Phillips, M. Steiner, C. Ashton, R. Gustafson, Crit. Care Med. 24, A154 (1996)
D. Chowdhury, V.A. Parnell, K. Ojamaa, R. Boxer, R. Cooper, I. Klein, Am. J. Cardiol. 84, 1107–1109 (1999)
T. Carrel, F. Eckstein, L. Englberger, R. Mury, P. Mohacsi, Eur. J. Heart Fail. 4, 577–582 (2002)
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Marks, S.D. Nonthyroidal illness syndrome in children. Endocr 36, 355–367 (2009). https://doi.org/10.1007/s12020-009-9239-2
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DOI: https://doi.org/10.1007/s12020-009-9239-2