History

History is specific to each NTI.

Physical

On physical examination, there are no typical findings for patients with NTI. The examination findings in each patient reflect the characteristics of her or his nonthyroidal disease. Findings on examination of the thyroid gland are unremarkable.

NTI can have an effect on patients who have preexisting thyroid diseases. Coexisting NTI can mask physical findings of hypothyroidism and hyperthyroidism.

Causes

Multiple explanations have been proposed for the causes of NTI, including the following:

Accuracy of test assays in NTI
Cytokines
Deiodination
Inhibition of TRH and TSH secretion
Inhibition of plasma membrane transport of iodothyronines
Thyroid-binding globulin decrease/desialation
Reduction in TR expression as well as DNA binding
Drugs that influence thyroid function

A study by Petrone et al indicated that euthyroid sick syndrome can result from obstructive sleep apnea (OSA) with severe nocturnal hypoxemia. The syndrome was found in 13 out of 125 patients in the study (10.4%) with moderate to severe OSA but occurred in none of the controls. Mean nocturnal oxygen saturation was worse in persons with euthyroid sick syndrome than in other OSA patients. Treatment of OSA resulted in a rise in free T3 to normal range.^[19]

The aforementioned study by Wang et al reported that independent risk factors for CABG-associated euthyroid sick syndrome include advanced age, a higher EuroSCORE II value, and moderate and poor left ventricular ejection fraction.^[18]

Differential Diagnoses

Lee S, Farwell AP. Euthyroid Sick Syndrome. Compr Physiol. 2016 Mar 15. 6 (2):1071-80. [QxMD MEDLINE Link].
Ganesan K, Wadud K. Euthyroid Sick Syndrome. StatPearls. 2020 Jan. [QxMD MEDLINE Link]. [Full Text].
Bartalena L, Bogazzi F, Brogioni S, Grasso L, Martino E. Role of cytokines in the pathogenesis of the euthyroid sick syndrome. Eur J Endocrinol. 1998 Jun. 138 (6):603-14. [QxMD MEDLINE Link].
de Vries EM, Fliers E, Boelen A. The molecular basis of the non-thyroidal illness syndrome. J Endocrinol. 2015 Jun. 225 (3):R67-81. [QxMD MEDLINE Link].
Sagar GD, Gereben B, Callebaut I, Mornon JP, Zeöld A, da Silva WS, et al. Ubiquitination-induced conformational change within the deiodinase dimer is a switch regulating enzyme activity. Mol Cell Biol. 2007 Jul. 27 (13):4774-83. [QxMD MEDLINE Link].
Fekete C, Sarkar S, Christoffolete MA, Emerson CH, Bianco AC, Lechan RM. Bacterial lipopolysaccharide (LPS)-induced type 2 iodothyronine deiodinase (D2) activation in the mediobasal hypothalamus (MBH) is independent of the LPS-induced fall in serum thyroid hormone levels. Brain Res. 2005 Sep 14. 1056 (1):97-9. [QxMD MEDLINE Link].
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 Apr. 145 (4):1649-55. [QxMD MEDLINE Link].
Zeöld A, Doleschall M, Haffner MC, Capelo LP, Menyhért J, Liposits Z, et al. Characterization of the nuclear factor-kappa B responsiveness of the human dio2 gene. Endocrinology. 2006 Sep. 147 (9):4419-29. [QxMD MEDLINE Link].
Gereben B, Zeöld A, Dentice M, Salvatore D, Bianco AC. Activation and inactivation of thyroid hormone by deiodinases: local action with general consequences. Cell Mol Life Sci. 2008 Feb. 65 (4):570-90. [QxMD MEDLINE Link].
Yu J, Koenig RJ. Induction of type 1 iodothyronine deiodinase to prevent the nonthyroidal illness syndrome in mice. Endocrinology. 2006 Jul. 147(7):3580-5. [QxMD MEDLINE Link].
Beigneux AP, Moser AH, Shigenaga JK, et al. Sick euthyroid syndrome is associated with decreased TR expression and DNA binding in mouse liver. Am J Physiol Endocrinol Metab. 2003 Jan. 284(1):E228-36. [QxMD MEDLINE Link].
Docter R, Krenning EP, de Jong M, Hennemann G. The sick euthyroid syndrome: changes in thyroid hormone serum parameters and hormone metabolism. Clin Endocrinol (Oxf). 1993 Nov. 39(5):499-518. [QxMD MEDLINE Link].
Melmed S, Geola FL, Reed AW, et al. A comparison of methods for assessing thyroid function in nonthyroidal illness. J Clin Endocrinol Metab. 1982 Feb. 54(2):300-6. [QxMD MEDLINE Link].
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 Dec. 82 (12):4032-6. [QxMD MEDLINE Link].
Tognini S, Marchini F, Dardano A, et al. Non-thyroidal illness syndrome and short-term survival in a hospitalised older population. Age Ageing. 2010 Jan. 39(1):46-50. [QxMD MEDLINE Link].
Bello G, Pennisi MA, Montini L, et al. Nonthyroidal illness syndrome and prolonged mechanical ventilation in patients admitted to the ICU. Chest. 2009 Jun. 135(6):1448-54. [QxMD MEDLINE Link].
Swistek M, Broncel M, Gorzelak-Pabis P, Morawski P, Fabis M, Wozniak E. Euthyroid Sick Syndrome as a Prognostic Indicator of COVID-19 Pulmonary Involvement, Associated With Poorer Disease Prognosis and Increased Mortality. Endocr Pract. 2022 May. 28 (5):494-501. [QxMD MEDLINE Link]. [Full Text].
Wang J, Yuan W, Dong R, Liu N, Liu D, Zhou Y. Predictors for euthyroid sick syndrome and its impact on in-hospital clinical outcomes in high-risk patients undergoing coronary artery bypass grafting. Perfusion. 2019 Nov. 34 (8):679-88. [QxMD MEDLINE Link].
Petrone A, Mormile F, Bruni G, Quartieri M, Bonsignore MR, Marrone O. Abnormal thyroid hormones and non-thyroidal illness syndrome in obstructive sleep apnea, and effects of CPAP treatment. Sleep Med. 2016 Jul. 23:21-5. [QxMD MEDLINE Link].
Gangemi EN, Garino F, Berchialla P, et al. Low triiodothyronine serum levels as a predictor of poor prognosis in burn patients. Burns. 2008 Sep. 34(6):817-24. [QxMD MEDLINE Link].
Velissaris T, Tang AT, Wood PJ, et al. Thyroid function during coronary surgery with and without cardiopulmonary bypass. Eur J Cardiothorac Surg. 2009 Jul. 36(1):148-54. [QxMD MEDLINE Link].
Michalaki M, Vagenakis AG, Makri M. 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 Sep. 86(9):4198-205. [QxMD MEDLINE Link].
Pimentel CR, Miano FA, Perone D, et al. Reverse T(3) as a parameter of myocardial function impairment in heart failure. Int J Cardiol. 2009 May 8. [QxMD MEDLINE Link].
Iglesias P, Díez JJ. Thyroid dysfunction and kidney disease. Eur J Endocrinol. 2009 Apr. 160(4):503-15. [QxMD MEDLINE Link].
Hekmat R, Javadi Z, Layghian Javan M, et al. Thyroid hormone changes in early kidney transplantation and its correlation with delayed graft function. Urol J. 2010 Winter. 7(1):30-4. [QxMD MEDLINE Link].
Unachukwu CN, Uchenna DI, Young EE. Endocrine and metabolic disorders associated with human immune deficiency virus infection. West Afr J Med. 2009 Jan. 28(1):3-9. [QxMD MEDLINE Link].
Kami M, Tanaka Y, Chiba S, et al. Thyroid function after bone marrow transplantation: possible association between immune-mediated thyrotoxicosis and hypothyroidism. Transplantation. 2001 Feb 15. 71(3):406-11. [QxMD MEDLINE Link].
Casulari LA, Mangieri P, Naves LA, et al. Nonthyroidal illness syndrome in patients with subarachnoid hemorrhage due to intracranial aneurysm. Arq Neuropsiquiatr. 2004 Mar. 62(1):26-32. [QxMD MEDLINE Link].
Premachandra BN, Kabir MA, Williams IK. Low T3 syndrome in psychiatric depression. J Endocrinol Invest. 2006 Jun. 29(6):568-72. [QxMD MEDLINE Link].
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 therapies. Crit Care Clin. 2006 Jan. 22(1):57-86, vi. [QxMD MEDLINE Link].
Zhang JQ, Yang QY, Xue FS, et al. Preoperative oral thyroid hormones to prevent euthyroid sick syndrome and attenuate myocardial ischemia-reperfusion injury after cardiac surgery with cardiopulmonary bypass in children: a randomized, double-blind, placebo-controlled trial. Medicine (Baltimore). 2018 Sep. 97 (36):e12100. [QxMD MEDLINE Link]. [Full Text].
Li R, Ren J, Wu Q, et al. Role of enteral nutrition in nonthyroidal illness syndrome: a retrospective observational study. BMC Endocr Disord. 2015 Nov 4. 15:69. [QxMD MEDLINE Link].
Rothberger GD, Gadhvi S, Michelakis N, Kumar A, Calixte R, Shapiro LE. Usefulness of Serum Triiodothyronine (T3) to Predict Outcomes in Patients Hospitalized With Acute Heart Failure. Am J Cardiol. 2017 Feb 15. 119 (4):599-603. [QxMD MEDLINE Link].
Iglesias P, Munoz A, Prado F, 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. [QxMD MEDLINE Link].

Media Gallery

Euthyroid sick syndrome. Relationship between serum thyroid hormone concentrations and severity of nonthyroidal illness (NTI). Abbreviations: reverse triiodothyronine (rT3), thyroid-stimulating hormone (TSH), free thyroxine (FT4), thyroxine (T4), triiodothyronine (T3).
Euthyroid sick syndrome. Relationship between severity and duration of nonthyroidal illness (NTI) and thyroid hormone levels. Abbreviations: reverse triiodothyronine (rT3), free thyroxine (free T4), thyroxine (T4), triiodothyronine (T3).

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Author

Serhat Aytug, MD, FACE Endocrinologist, Division of Endocrinology, Diabetes and Metabolism, St Jude Heritage Medical Group; Associate Professor of Medicine – Endocrinology, Diabetes and Metabolism, Council of Higher Education of Turkey

Serhat Aytug, MD, FACE is a member of the following medical societies: American Association of Clinical Endocrinologists, Endocrine Society

Disclosure: Nothing to disclose.

Coauthor(s)

Lawrence E Shapiro, MD Chief, Division of Endocrinology and Metabolism, Professor of Medicine, Department of Medicine, Winthrop University Hospital

Lawrence E Shapiro, MD is a member of the following medical societies: American Diabetes Association, American Thyroid Association, Endocrine Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Don S Schalch, MD Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, University of Wisconsin Hospitals and Clinics

Don S Schalch, MD is a member of the following medical societies: American Diabetes Association, American Federation for Medical Research, Central Society for Clinical and Translational Research, Endocrine Society

Disclosure: Nothing to disclose.

Chief Editor

Romesh Khardori, MD, PhD, FACP (Retired) Professor, Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Eastern Virginia Medical School

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, Endocrine Society

Disclosure: Nothing to disclose.

Additional Contributors

Steven R Gambert, MD Professor of Medicine, Johns Hopkins University School of Medicine; Director of Geriatric Medicine, University of Maryland Medical Center and R Adams Cowley Shock Trauma Center

Steven R Gambert, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for Physician Leadership, American College of Physicians, American Geriatrics Society, Endocrine Society, Gerontological Society of America, Association of Professors of Medicine

Disclosure: Nothing to disclose.

Sections Euthyroid Sick Syndrome
Overview
Presentation
- History
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- Causes
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Euthyroid Sick Syndrome Clinical Presentation

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