Nonthyroidal illness in critically ill children.

PURPOSE OF REVIEW This review summarizes recent literature on nonthyroidal illness syndrome (NTI) and outcome of pediatric critical illness, to provide insight in pathophysiology and therapeutic implications. RECENT FINDINGS NTI is typically characterized by lowered triiodothyronine levels without compensatory TSH rise. Although NTI severity is associated with poor outcome of pediatric critical illness, it remains unclear whether this association reflects an adaptive protective response or contributes to poor outcome. Recently, two metabolic interventions that improved outcome also altered NTI in critically ill children. These studies shed new light on the topic, as the results suggested that the peripheral NTI component, with inactivation of thyroid hormone, may represent a beneficial adaptation, whereas the central component, with suppressed TSH-driven thyroid hormone secretion, may be maladaptive. There is currently insufficient evidence for treatment of NTI in children. However, the recent findings raised the hypothesis that reactivation of the central NTI component could offer benefit, which should be tested in RCTs. SUMMARY NTI in critically ill children can be modified by metabolic interventions. The peripheral, but not the central, component of NTI may be a beneficial adaptive response. These findings open perspectives for the development of novel strategies to improve outcome of critical illness in children.

[1]  G. Van den Berghe,et al.  Non-Thyroidal Illness Syndrome in Critically Ill Children: Prognostic Value and Impact of Nutritional Management. , 2019, Thyroid : official journal of the American Thyroid Association.

[2]  M. El-Mekkawy,et al.  [Prevalence and prognostic value of non-thyroidal illness syndrome among critically ill children]. , 2019, Anales de pediatria.

[3]  M. Antonelli,et al.  Effects of Thyroid Hormone Treatment on Diaphragmatic Efficiency in Subjects With Nonthyroidal Illness Syndrome and on Ventilation. , 2019, Respiratory care.

[4]  W. Cho,et al.  Thyroid dysfunction in children with leukemia over the first year after hematopoietic stem cell transplantation , 2018, Journal of pediatric endocrinology & metabolism : JPEM.

[5]  J. Kochanowski,et al.  Neuroendocrine aspects of anorexia nervosa and bulimia nervosa. , 2018, Neuro endocrinology letters.

[6]  Serhan Küpeli,et al.  Prevalence and Related Factors of Euthyroid Sick Syndrome in Children with Untreated Cancer According to Two Different Criteria , 2018, Journal of clinical research in pediatric endocrinology.

[7]  Oral Triiodothyronine for Infants and Children Undergoing Cardiopulmonary Bypass. , 2017, The Annals of thoracic surgery.

[8]  Patrick C Hanley,et al.  Thyroid Disorders in Children and Adolescents: A Review. , 2016, JAMA pediatrics.

[9]  R. Thakkar,et al.  Inflammation and innate immune function in critical illness , 2016, Current opinion in pediatrics.

[10]  T. Kirby Early versus late parenteral nutrition in critically ill children. , 2016, The Lancet. Respiratory medicine.

[11]  G. Van den Berghe,et al.  Early versus Late Parenteral Nutrition in Critically Ill Children. , 2016, The New England journal of medicine.

[12]  E. Fliers,et al.  Thyroid function in critically ill patients. , 2015, The lancet. Diabetes & endocrinology.

[13]  E. Fliers,et al.  The molecular basis of the non-thyroidal illness syndrome. , 2015, The Journal of endocrinology.

[14]  Long-Term Neurodevelopmental Outcome of Children Treated with Tri-Iodothyronine after Cardiac Surgery: Follow-Up of a Double-Blind, Randomized, Placebo-Controlled Study , 2015, Hormone Research in Paediatrics.

[15]  Guimei Li,et al.  Euthyroid sick syndrome in children with diabetic ketoacidosis , 2015, Saudi medical journal.

[16]  A. Groeneveld,et al.  Metabolic response to the stress of critical illness. , 2014, British journal of anaesthesia.

[17]  V. Thaker,et al.  Iodine-induced hypothyroidism in full-term infants with congenital heart disease: more common than currently appreciated? , 2014, The Journal of clinical endocrinology and metabolism.

[18]  G. Van den Berghe,et al.  Endocrine responses to critical illness: novel insights and therapeutic implications. , 2014, The Journal of clinical endocrinology and metabolism.

[19]  J. Zimmerman,et al.  Common endocrine issues in the pediatric intensive care unit. , 2013, Critical care clinics.

[20]  G. Van den Berghe,et al.  Impact of early nutrient restriction during critical illness on the nonthyroidal illness syndrome and its relation with outcome: a randomized, controlled clinical study. , 2013, The Journal of clinical endocrinology and metabolism.

[21]  G. Van den Berghe,et al.  Effect of tight glucose control with insulin on the thyroid axis of critically ill children and its relation with outcome. , 2012, The Journal of clinical endocrinology and metabolism.

[22]  G. Van den Berghe,et al.  Thyroid axis function and dysfunction in critical illness. , 2011, Best practice & research. Clinical endocrinology & metabolism.

[23]  G. Van den Berghe,et al.  Early versus Late Parenteral Nutrition in Critically Ill Adults , 2011, The New England journal of medicine.

[24]  M. Falagas,et al.  Association between thyroid function tests at baseline and the outcome of patients with sepsis or septic shock: a systematic review. , 2011, European journal of endocrinology.

[25]  T. Karl,et al.  Triiodothyronine Supplementation in Infants and Children Undergoing Cardiopulmonary Bypass (TRICC): A Multicenter Placebo-Controlled Randomized Trial: Age Analysis , 2010, Circulation.

[26]  A. Bianco,et al.  Paracrine signaling by glial cell-derived triiodothyronine activates neuronal gene expression in the rodent brain and human cells. , 2010, The Journal of clinical investigation.

[27]  B. Haugen Drugs that suppress TSH or cause central hypothyroidism. , 2009, Best practice & research. Clinical endocrinology & metabolism.

[28]  Seth D. Marks Nonthyroidal illness syndrome in children , 2009, Endocrine.

[29]  G. Van den Berghe,et al.  Changes in the central component of the hypothalamus-pituitary-thyroid axis in a rabbit model of prolonged critical illness , 2009, Critical care.

[30]  I. Rebeyka,et al.  Hypothalamic-pituitary-thyroid axis changes in children after cardiac surgery. , 2009, The Journal of clinical endocrinology and metabolism.

[31]  E. Fliers,et al.  Thyroid Hormone Receptor β Mediates Acute Illness‐Induced Alterations in Central Thyroid Hormone Metabolism , 2009, Journal of neuroendocrinology.

[32]  M. Stridsberg,et al.  Triiodothyronine Is an Indicator of Nutritional Status in Adolescent Girls with Eating Disorders , 2009, Hormone Research in Paediatrics.

[33]  Greet Van den Berghe,et al.  Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study , 2009, The Lancet.

[34]  J. Harney,et al.  Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxic-ischemic disease in rats. , 2008, The Journal of clinical investigation.

[35]  E. Fliers,et al.  Fasting-induced changes in the hypothalamus-pituitary-thyroid axis. , 2008, Thyroid : official journal of the American Thyroid Association.

[36]  T. Hirfanoğlu,et al.  Thyroid function and volume in epileptic children using carbamazepine, oxcarbazepine and valproate , 2007, Pediatrics international : official journal of the Japan Pediatric Society.

[37]  R. Lodha,et al.  Thyroid function in children with sepsis and septic shock , 2007, Acta paediatrica.

[38]  E. Fliers,et al.  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. , 2006, The Journal of endocrinology.

[39]  D. Kececioglu,et al.  Clinical review: Thyroid hormone replacement in children after cardiac surgery – is it worth a try? , 2006, Critical care.

[40]  W. Wiersinga,et al.  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. , 2006, The Journal of endocrinology.

[41]  P. Carney,et al.  Central hypothyroidism with oxcarbazepine therapy. , 2006, Pediatric neurology.

[42]  G. Van den Berghe,et al.  Increased thyroxine sulfate levels in critically ill patients as a result of a decreased hepatic type I deiodinase activity. , 2005, The Journal of clinical endocrinology and metabolism.

[43]  W. Hop,et al.  Euthyroid sick syndrome in meningococcal sepsis: the impact of peripheral thyroid hormone metabolism and binding proteins. , 2005, The Journal of clinical endocrinology and metabolism.

[44]  P. D. del Nido,et al.  A randomized, double-blind, placebo-controlled pilot trial of triiodothyronine in neonatal heart surgery. , 2005, The Journal of thoracic and cardiovascular surgery.

[45]  G. Van den Berghe,et al.  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. , 2005, The Journal of clinical endocrinology and metabolism.

[46]  W. Hop,et al.  Thyroid function and outcome in children who survived meningococcal septic shock , 2005, Intensive Care Medicine.

[47]  E. Fliers,et al.  Glucocorticoids decrease thyrotropin-releasing hormone messenger ribonucleic acid expression in the paraventricular nucleus of the human hypothalamus. , 2005, The Journal of clinical endocrinology and metabolism.

[48]  Y. Sertdemir,et al.  Thyroid Hormone Levels and their Relationship to Survival in Children with Bacterial Sepsis and Septic Shock , 2004 .

[49]  W. Wiersinga,et al.  Interleukin-18, a proinflammatory cytokine, contributes to the pathogenesis of non-thyroidal illness mainly via the central part of the hypothalamus-pituitary-thyroid axis. , 2004, European journal of endocrinology.

[50]  E. Fliers,et al.  Simultaneous changes in central and peripheral components of the hypothalamus-pituitary-thyroid axis in lipopolysaccharide-induced acute illness in mice. , 2004, The Journal of endocrinology.

[51]  C. Herrington,et al.  Thyroid dysfunction after pediatric cardiac surgery. , 2004, The Journal of thoracic and cardiovascular surgery.

[52]  W. Rand,et al.  Lipopolysaccharide induces type 2 iodothyronine deiodinase in the mediobasal hypothalamus: implications for the nonthyroidal illness syndrome. , 2004, Endocrinology.

[53]  W. Wiersinga,et al.  Contribution of interleukin-12 to the pathogenesis of non-thyroidal illness. , 2004, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[54]  F. Zegher,et al.  Dopamine suppresses pituitary function in infants and children , 1994, Pediatric Nephrology.

[55]  G. Van den Berghe,et al.  Endocrine and metabolic effects of growth hormone (GH) compared with GH-releasing peptide, thyrotropin-releasing hormone, and insulin infusion in a rabbit model of prolonged critical illness. , 2004, Endocrinology.

[56]  G. Van den Berghe,et al.  Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. , 2003, The Journal of clinical endocrinology and metabolism.

[57]  B. K. Das,et al.  Serum cortisol and thyroid hormone levels in neonates with sepsis , 2002, Indian journal of pediatrics.

[58]  L. Burmeister,et al.  Subclinical thyrotoxicosis and the heart. , 2002, Thyroid : official journal of the American Thyroid Association.

[59]  G. Van den Berghe,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 , 2002, Clinical endocrinology.

[60]  G. Umpierrez Euthyroid sick syndrome. , 2002, Southern medical journal.

[61]  B. Bistrian,et al.  Intensive insulin therapy in critically ill patients. , 2002, The New England journal of medicine.

[62]  I. Klein,et al.  A prospective randomized clinical study of thyroid hormone treatment after operations for complex congenital heart disease. , 2001, The Journal of thoracic and cardiovascular surgery.

[63]  M Schetz,et al.  Intensive insulin therapy in critically ill patients. , 2001, The New England journal of medicine.

[64]  V. Kyriazopoulou,et al.  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. , 2001, The Journal of clinical endocrinology and metabolism.

[65]  J. Hazelzet,et al.  Endocrine and metabolic responses in children with meningoccocal sepsis: striking differences between survivors and nonsurvivors. , 2000, The Journal of clinical endocrinology and metabolism.

[66]  G. Rosenthal,et al.  Triiodothyronine repletion in infants during cardiopulmonary bypass for congenital heart disease. , 2000, Journal of Thoracic and Cardiovascular Surgery.

[67]  M. Bettendorf,et al.  Tri-iodothyronine treatment in children after cardiac surgery: a double-blind, randomised, placebo-controlled study , 2000, The Lancet.

[68]  G. Berghe Euthyroid sick syndrome. , 2000 .

[69]  John P. Johnson,et al.  A trial of thyroxine in acute renal failure. , 2000, Kidney international.

[70]  S. Homma,et al.  A randomized double-blind study of the effect of triiodothyronine on cardiac function and morbidity after coronary bypass surgery. , 1999, The Journal of thoracic and cardiovascular surgery.

[71]  G. Van den Berghe,et al.  Neuroendocrinology of prolonged critical illness: effects of exogenous thyrotropin-releasing hormone and its combination with growth hormone secretagogues. , 1998, The Journal of clinical endocrinology and metabolism.

[72]  G. Van den Berghe,et al.  Thyrotrophin and prolactin release in prolonged critical illness: dynamics of spontaneous secretion and effects of growth hormone‐secretagogues , 1997, Clinical endocrinology.

[73]  M. Bettendorf,et al.  Transient Secondary Hypothyroidism in Children after Cardiac Surgery , 1997, Pediatric Research.

[74]  T. Visser,et al.  Different regulation of thyroid hormone transport in liver and pituitary: its possible role in the maintenance of low T3 production during nonthyroidal illness and fasting in man. , 1996, Thyroid : official journal of the American Thyroid Association.

[75]  H. van Toor,et al.  Effects of interleukin-1 beta on thyrotropin secretion and thyroid hormone uptake in cultured rat anterior pituitary cells. , 1996, Endocrinology.

[76]  Robert W. Anderson,et al.  Cardiovascular Effects of Intravenous Triiodothyronine in Patients Undergoing Coronary Artery Bypass Graft Surgery: A Randomized, Double-blind, Placebo-Controlled Trial , 1996 .

[77]  W. White,et al.  Cardiovascular effects of intravenous triiodothyronine in patients undergoing coronary artery bypass graft surgery. A randomized, double-blind, placebo- controlled trial. Duke T3 study group. , 1996, JAMA.

[78]  J. Kane,et al.  Prolonged effects of tumor necrosis factor-α on anterior pituitary hormone release , 1995, Peptides.

[79]  S. Thomas,et al.  Thyroid hormone treatment after coronary-artery bypass surgery. , 1995, The New England journal of medicine.

[80]  R. Utiger Altered thyroid function in nonthyroidal illness and surgery. To treat or not to treat? , 1995, The New England journal of medicine.

[81]  R. Lechan,et al.  Changes in adrenal status affect hypothalamic thyrotropin-releasing hormone gene expression in parallel with corticotropin-releasing hormone. , 1995, Endocrinology.

[82]  J. Kane,et al.  Prolonged effects of tumor necrosis factor-alpha on anterior pituitary hormone release. , 1995, Peptides.

[83]  A. Manios,et al.  Triiodothyronine administration in coronary artery bypass surgery: effect on hemodynamics. , 1994, The Journal of cardiovascular surgery.

[84]  B. D. Clark,et al.  Suppression of thyrotropin-releasing hormone gene expression by interleukin-1-beta in the rat: implications for nonthyroidal illness. , 1994, Neuroendocrinology.

[85]  T. Nogimori,et al.  Effects of immunoneutralization of endogenous opioid peptides on the hypothalamic-pituitary-thyroid axis in rats. , 1993, Hormone research.

[86]  N. Zuhdi,et al.  Triiodothyronine as an inotropic agent after open heart surgery. , 1989, The Journal of thoracic and cardiovascular surgery.

[87]  G. Brabant,et al.  The role of glucocorticoids in the regulation of thyrotropin. , 1989, Acta endocrinologica.

[88]  J. Zimmerman,et al.  Thyroid hormone metabolism and level of illness severity in pediatric cardiac surgery patients. , 1989, The Journal of pediatrics.

[89]  G. Brent,et al.  Thyroxine therapy in patients with severe nonthyroidal illnesses and low serum thyroxine concentration. , 1986, The Journal of clinical endocrinology and metabolism.

[90]  K. Mann,et al.  Anterior Pituitary Hormone Responses to a κ-Opioid Agonist in Man , 1986 .

[91]  K. Mann,et al.  Anterior pituitary hormone responses to a kappa-opioid agonist in man. , 1986, The Journal of clinical endocrinology and metabolism.

[92]  A. Grossman Brain opiates and neuroendocrine function. , 1983, Clinics in endocrinology and metabolism.

[93]  A. Mason,et al.  Hypermetabolic low triiodothyronine syndrome of burn injury , 1982, Critical care medicine.

[94]  R. Reid,et al.  Effects of Exogenous βh-Endorphin on Pituitary Hormone Secretionand Its Disappearance Rate in Normal Human Subjects* , 1981 .

[95]  S. Yen,et al.  Effects of exogenous beta h-endorphin on pituitary hormone secretion and its disappearance rate in normal human subjects. , 1981, The Journal of clinical endocrinology and metabolism.

[96]  J. Wilber,et al.  The effect of glucocorticoids on thyrotropin secretion. , 1969, The Journal of clinical investigation.