Abstract
Non-thyroidal illness is the term used to describe the changes in thyroid hormone and thyroid-stimulating hormone (TSH) with acute illness not caused by an intrinsic abnormality of thyroid function. In children, non-thyroidal illness is most commonly seen in acutely ill patients admitted to pediatric or neonatal intensive care units (ICUs). The characteristic decrease in thyroid hormone levels also can be seen with starvation, trauma, or surgical procedures. Non-thyroidal illness probably occurs with any severe illness, and the pattern of changes in thyroid hormones correlates with the severity of illness. Typically, the first changes are a decrease in serum triiodothyronine (T3) and a rise in reverse T3 (rT3) levels. This disorder has been referred to as the low-T3 syndrome or the euthyroid sick syndrome. However, as there is disagreement about whether patients truly are “euthyroid,” non-thyroidal illness syndrome (NTIS) is the term preferred at present.
The changes in thyroid hormone and TSH concentrations with NTIS are believed to be an adaptive mechanism, in that they protect the body from high metabolic demands in the face of starvation or acute illness. However, there are certain clinical situations where this concept has been challenged, with the belief that the changes are maladaptive and clinical improvement may be seen with treatment with triiodothyronine (l-T3) or levothyroxine (l-T4). In particular, there is some evidence that preterm babies <27 weeks’ gestation may show improvement in IQ scores with l-T4 treatment and that infants and children undergoing cardiac surgery may show improved post-op cardiac function with l-T3 treatment. Further research is needed to resolve these issues.
Keywords
Non-thyroidal illness syndrome—thyroid hormone changes Thyroxine (T4) Free T4 (FT4) Triiodothyronine (T3) Free T3 (FT3) Reverse T3 (rT3) Thyroid-stimulating hormone (TSH) Thyrotropin-releasing hormone (TRH) Thyroxine-binding globulin (TBG) Transthyretin Albumin Hypothalamic–pituitary–thyroid (HPT) axis Central hypothyroidism Leptin Paraventricular nucleus Tanycyte Cytokines Cortisol Deiodinase type 1 (D1) Deiodinase type 2 (D2) Deiodinase type 3 (D3) Thyroid hormone receptor (THR) Thyroid hormone transporters Monocarboxylate transporter 8 (MCT8) Heparin Dopamine Glucocorticoids Furosemide Salicylates Preterm infants Neurodevelopmental outcome Cardiac–renal insufficiency Cystic fibrosis Psychiatric disorders Depression Bipolar disorder Attention-deficit hyperactivity disorder (ADHD)References
- 1.Warner MH, Beckett GJ. Mechanisms behind the non-thyroidal illness syndrome: an update. J Endocrinol. 2010;205:1–13.CrossRefGoogle Scholar
- 2.Wiersinga WM, Van Den Berghe G. Nonthyroidal illness. In: Braverman LE, Copper DS, editors. Werner & Ingbar’s the thyroid. 10th ed. Philadelphia: Lippincott, Williams & Williams; 2013. p. 203–17.Google Scholar
- 3.De Groot LJ. Non-thyroidal illness syndrome is a manifestation of hypothalamic–pituitary dysfunction, and in view of current evidence, should be treated with appropriate replacement therapy. Crit Care Clin. 2006;22:57–86.CrossRefGoogle Scholar
- 4.Kaptein E, Grieb D, Spencer CA, Wheeler WS, Nicoloff JT. Thyroxine metabolism in the low thyroxine state of critical nonthyroidal illnesses. J Clin Endocrinol Metab. 1981;53:764–71.CrossRefGoogle Scholar
- 5.Beckett GJ, Wilkinson E, Rae PW, et al. The clinical utility of a non-isotropic two-step assay (DELPHIA) and an analogue radioimmunoassay (SimulTRAC) for free thyroxine compared. Ann Clin Biochem. 1991;28:335–44.CrossRefGoogle Scholar
- 6.Chopra IJ. Simultaneous measurements of free thyroxine and free 3,5,3′-triiodothyronine in undiluted serum by direct equilibrium dialysis/radioimmunoassay: evidence that free triiodothyronine and free thyroxine are normal in many patients with the low triiodothyronine syndrome. Thyroid. 1998;8:249–57.CrossRefGoogle Scholar
- 7.Faber J, Siersback-Nielsen K. Serum free 3,5,3′-triiodothyronine (T3) in non-thyroidal somatic illness, as measured by ultrafiltration and immunoextraction. Clin Chim Acta. 1996;256:115–23.CrossRefGoogle Scholar
- 8.Wehman RE, Gregerman RI, Burns WH, et al. Suppression of thyrotropin in the low-thyroxine state of severe nonthyroidal illness. N Engl J Med. 1985;312:546–52.CrossRefGoogle Scholar
- 9.Balogh A, Carayon P, Conte-Devolx B, et al. Guidelines Committee, National Academy of Clinical Biochemistry. Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid. 2003;13:1–126.Google Scholar
- 10.Adriaanse R, Romijn JA, Brabant G, et al. Pulsatile thyrotropin secretion in nonthyroidal illness. J Clin Endocrinol Metab. 1993;77:1313–7.PubMedGoogle Scholar
- 11.Fliers E, Guldenaar SEF, Wiersinga WM, et al. Decreased hypothalamic thyrotropin-releasing hormone gene expression in patients with nonthyroidal illness. J Clin Endocrinol Metab. 1997;82:4032–6.PubMedGoogle Scholar
- 12.Legradi G, Emerson CH, Ahima RS, et al. Leptin prevents fasting-induced suppression of prothyrotropin-releasing hormone messenger ribonucleic acid in neurons of the hypothalamic paraventricular nucleus. Endocrinology. 1997;138:2569–76.CrossRefGoogle Scholar
- 13.Van der Poll T, van Zee KJ, Endert E, 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;80:1341–6.PubMedGoogle Scholar
- 14.Lechan RM, Fekete C. Role of thyroid hormone deiodination in the hypothalamus. Thyroid. 2005;15:883–97.CrossRefGoogle Scholar
- 15.Bianco AC, Kim BW. Intracellular pathways of iodothyronine metabolism/implications of deiodination for thyroid hormone action. In: Braverman LE, Cooper DS, editors. Werner & Ingbar’s the thyroid. 10th ed. Philadelphia: Lippincott, Williams & Williams; 2013. p. 93–103.Google Scholar
- 16.Peeters RP, Wouters PJ, Kaptein E, et al. Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. J Clin Endocrinol Metab. 2003;88:3202–11.CrossRefGoogle Scholar
- 17.St Germain DL, Galton VA, Hernandez A. Minireview: defining the roles of the iodothyronine deiodinases: current concepts and challenges. Endocrinology. 2009;150:1097–107.CrossRefGoogle Scholar
- 18.Jaume JC, Mendel CM, Frost PH, Greenspan FS, Laughton CW. Extremely low doses of heparin release lipase activity into the plasma and can thereby cause artifactual elevations in the serum-free thyroxine concentrations as measured by equilibrium dialysis. Thyroid. 1996;6:79–83.CrossRefGoogle Scholar
- 19.Mebis L, Paletta D, Debaveye Y, et al. Expression of thyroid hormone transporters during critical illness. Eur J Endocrinol. 2009;161:243–50.CrossRefGoogle Scholar
- 20.Fisher DA. Thyroid function and dysfunction in premature infants. Pediatr Endocrinol Rev. 2007;4:317–28.PubMedGoogle Scholar
- 21.Williams FL, Ogston SA, van Toor H, et al. Serum thyroid hormones in preterm infants: associations with postnatal illnesses and drug usage. J Clin Endocrinol Metab. 2005;90:5954–63.CrossRefGoogle Scholar
- 22.Hadeed AJ, Assay LK, Klein AH, Fisher DA. Significance of transient postnatal hypothyroxinemia in premature infants with and without respiratory distress syndrome. Pediatrics. 1981;68:494–8.PubMedGoogle Scholar
- 23.Reuss ML, Paneth N, Pinto-Martin JA, et al. The relation of transient hypothyroxinemia in preterm infants to neurologic development at two years of age. N Engl J Med. 1996;334:821–7.CrossRefGoogle Scholar
- 24.Delahunty C, Falconer S, Hume R, Jackson L, Midgley P, Mirfield M, et al. Levels of neonatal thyroid hormone in preterm infants and neurodevelopmental outcomes at 5 ½ years: millennium cohort study. J Clin Endocrinol Metab. 2010;95:4898–908.CrossRefGoogle Scholar
- 25.Williams FL, Simpson J, Delahunty C, et al. Developmental trends in cord and postpartum serum thyroid hormones in preterm infants. J Clin Endocrinol Metab. 2004;89:5314–20.CrossRefGoogle Scholar
- 26.Van Wassenaer AG, Kok JH, de Vijlder JJM, et al. Effects of thyroxine supplementation on neurologic development in infants born at less than 30 weeks’ gestation. N Engl J Med. 1997;336:21–6.CrossRefGoogle Scholar
- 27.Van Wassenaer AG, Briet JM, van Baar A, Smit BJ, Tamminga P, de Vijlder JJ, Kok JH. Free thyroxine levels during the first weeks of life and neurodevelopmental outcome until the age of 5 years in very preterm infants. Pediatrics. 2002;110:534–9.CrossRefGoogle Scholar
- 28.Osborn DA, Hunt RW. Postnatal thyroid hormones for preterm infants with transient hypothyroxinemia. Cochrane Database Syst Rev. 2007;(1):CDC005945.Google Scholar
- 29.Hebbar K, Rigby MR, Felner EI, Easley KA, Fortenberry JD. Neuroendocrine dysfunction in pediatric critical illness. Pediatr Crit Care Med. 2009;10:35–40.CrossRefGoogle Scholar
- 30.Hu YY, Li GM, Want W. Euthyroid sick syndrome in children with diabetic ketoacidosis. Saudi Med J. 2015;36:243–7.CrossRefGoogle Scholar
- 31.Brent GA, Hershman JM. Thyroxine therapy in patients with severe nonthyroidal illness and low serum thyroxine concentration. J Clin Endocrinol Metab. 1986;63:1–8.CrossRefGoogle Scholar
- 32.Becker RA, Vaughan GM, Ziegler MG, Seraile LG, Goldfarb IW, Mnnsour EH, McManus WF, Pruitt BA, Mason AD Jr. Hypermetabolic low triiodothyronine syndrome of burn injury. Crit Care Med. 1982;10:870–5.CrossRefGoogle Scholar
- 33.Dimmick SJ, Badawi N, Randell T. Thyroid hormone supplementation for the prevention of morbidity and mortality in infants undergoing cardiac surgery (Review). Cochrane Collab. 2009:1–23.Google Scholar
- 34.Mainwaring RD, Nelson JC. Supplementation of thyroid hormone in children undergoing cardiac surgery. Cardiol Young. 2001;12:211–7.CrossRefGoogle Scholar
- 35.Babazadeh K, Tabib A, Eshragi P, Bakhshandeh H, Zamani H. Non-thyroidal illness syndrome and cardiopulmonary bypass in children with congenital heart disease. Caspian J Intern Med. 2014;5:235–42.PubMedPubMedCentralGoogle Scholar
- 36.Haas NA, Camphausen CK, Kececioglu D. Clinical review: thyroid hormone replacement in children after cardiac surgery—is it worth a try? Crit Care. 2006;10:213–20.CrossRefGoogle Scholar
- 37.Kaptein EM, Sanchez A, Beale E, Chan LS. Thyroid hormone therapy for postoperative nonthyroidal illnesses: a systemic review and synthesis. J Clin Endocrinol Metab. 2010;95:4526–34.CrossRefGoogle Scholar
- 38.Bettendorf M, Schmidt KG, Grulich-Henn J, Ulmer HE, Heinrich UE. Tri-iodothyronine treatment in children after cardiac surgery: a double-blind, randomised, placebo-controlled study. Lancet. 2000;356:529–34.CrossRefGoogle Scholar
- 39.Portman MA, Fearneyhough C, Ning X-H, Duncan BW, Rosenthal G, Lupinetti FM. Triiodothyronine repletion in infants during cardiopulmonary bypass for congenital heart disease. J Thorac Cardiovasc Surg. 2000;120:604–8.CrossRefGoogle Scholar
- 40.Chowdhury D, Ojamaa K, Parnell VA, McCahon C, Sison CP, Klein I. A prospective randomized clinical study of thyroid hormone treatment after operations for complex congenital heart disease. J Thorac Cardiovasc Surg. 2001;122:1023–5.CrossRefGoogle Scholar
- 41.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;130:810–6.CrossRefGoogle Scholar
- 42.Kaptein EM. Thyroid hormone metabolism and thyroid diseases in chronic renal failure. Endocr Rev. 1996;17:45–63.CrossRefGoogle Scholar
- 43.Ramirez G, Jubiz W, Futch CF, Bloomer HA, Siegler R, Kolff WJ. Thyroid abnormalities in renal failure. Ann Intern Med. 1973;79:500–4.CrossRefGoogle Scholar
- 44.Pasqualini T, Zantleifer D, Balzateti M, Branillo E, Fainstein-Day P, Ramirez J, Ruiz S, Gutman R, Ferraris J. Evidence of hypothalamic–pituitary–thyroid abnormalities in children with end-stage renal disease. J Pediatr. 1991;118:873–8.CrossRefGoogle Scholar
- 45.Cm H, Domenech JM, Montoya E. Thyrotropin-releasing hormone responsiveness and degradation in children with chronic renal failure: effect of time of evolution. Acta Endocrinol. 1982;99:508–16.Google Scholar
- 46.Acker CG, Singh AR, Flick RP, Bernardini J, Greenberg A, Johnson JP. A trial of thyroxine in acute renal failure. Kidney Int. 2000;57:293–8.CrossRefGoogle Scholar
- 47.Acker CG, Flick R, Shapiro R, Scantlebury VP, Jordan ML, Vivas C, Greenberg A, Johnson JP. Thyroid hormone in the treatment of post-transplant acute tubular necrosis (ATN). Am J Transplant. 2002;2:57–61.CrossRefGoogle Scholar
- 48.Lee SY, Chesdachai S, Moon JL, He XM, Tangpricha V, Braverman LE. Thyroid function in patients with cystic fibrosis: no longer a concern? Thyroid. 2016;26:875–9.CrossRefGoogle Scholar
- 49.Holtmann M, Duketis E, Goth K, Poustka L, Boelte S. Severe affective and behavioral dysregulation in youth is associated with increased serum TSH. J Affect Disord. 2010;121:184–8.CrossRefGoogle Scholar
- 50.Gracious BL, Findling RL, Seman C, Youngstrom EA, Demeter CA, Clabrese JR. Elevated thyrotropin in bipolar youths prescribed both lithium and divalproex sodium. J Am Acad Child Adolesc Psychiatry. 2004;43:215–20.CrossRefGoogle Scholar
- 51.Hillegers MH, Reighart CG, Wais M, Verhulst FC, Ormel J, Nolen WA, Drexhage HA. Signs of higher prevalence of autoimmune thyroiditis in female offspring of bipolar parents. Eur Neuropsychopharmacol. 2007;17:394–9.CrossRefGoogle Scholar
- 52.Kirkegaard C, Faber J. The role of thyroid hormones in depression. Eur J Endocrinol. 1998;138:1–9.CrossRefGoogle Scholar
- 53.Altshuler LL, Bauer M, Frye MA, et al. Does triiodothyronine augmentation accelerate tricyclic antidepressant response? A review and meta-analysis of the literature. Am J Psychiatry. 2001;158:1617–22.CrossRefGoogle Scholar
- 54.Hauser P, Xametkin AJ, Martinez P, Vitiello B, Matochik JA, Misxon AJ, Weintruab BD. ADHD and the thyroid controversy. J Am Acad Child Adolesc Psychiatry. 1994;33:756–8.CrossRefGoogle Scholar
- 55.Elia J, Gulotta C, Rose SR, Marin G, Rapoport JL. Thyroid function and attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 1994;33:169–72.CrossRefGoogle Scholar
- 56.Verrotti A, Laus M, Scardapane A, Franzoni E, Chiarelli F. Thyroid hormones in children with epilepsy during long-term administration of carbamazepine and valproate. Eur J Endocrinol. 2009;160:80–6.CrossRefGoogle Scholar