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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
Euthyroid sick syndrome is a thyroid hormone disorder where the levels of T3 (triiodothyronine) and/or T4 (thyroxine) are at unusual levels, in the setting of a nonthyroidal illness. Thyroid hormones play a major role in the metabolism, growth and maturation of the human body. Euthyroid sick syndrome is seen in conditions of starvation and critical illness such as sepsis, surgery, severe trauma, burns, metabolic disorders, bone marrow transplantation, and malignancy. During these stress conditions, there occurs hypermetabolism, increased energy expenditure, hyperglycemia, and muscle loss. It is speculated, that the body in order to contain this hypermetabolism induces some degree of hypothyroidism by inhibiting deiodination of T4 to T3 by the enzyme 5’-monodeiodinase. This is an adaptive process by which the body prevents further muscle and calorie loss. Euthyroid sick syndrome presents with low serum T3. Depending upon the severity and duration of the stress inducing condition, the thyroid-stimulating hormone(TSH), thyroxine (T4), and free T4 (FT4) are affected in variable proportions.[1][2][3]
Historical Perspective
Classification
Euthyroid sick syndrome may be classified according to the level of thyroid hormones and the severity of the underlying disease into mild, moderate, severe, and recovery phase.
Pathophysiology
Euthyroid sick syndrome is not a primary thyroid disorder but instead results from changes induced by the nonthyroidal illness. The pathophyisology of euthyroid sick syndrome is multifactorial. It is thought that euthyroid sick syndrome is the result of severe illness and inflammation. During these stress conditions, there occurs hypermetabolism, increased energy expenditure, hyperglycemia, and muscle loss. It is speculated, that the body in order to contain this hypermetabolism induces some degree of hypothyroidism by inhibiting deiodination of T4 to T3 by the enzyme 5’-monodeiodinase. This is an adaptive process by which the body prevents further muscle and calorie loss. Inflammation leads to increased production of cytokines that severely affect genes involved in the production and release of T4 and T3. There is also downregulation of TRH and TSH release from the hypothalamus and pituitary gland respectively. It may be signalled by a decrease in leptin caused by malnutrition. On gross pathology, euthyroid sick syndrome does not appear to be dysfunctional. On microscopic histopathological analysis, euthyroid sick syndrome presents with normal thyroid histology.
Causes
Euthyroid sick syndrome can be caused by any serious illness which leads to increased level of cytokines, decreased level of leptin, hyper-metabolism, decreased protein synthesis and decreased level of thyroid-binding globulin. The conditions include sepsis, malignancy, trauma, surgery, burns, bone marrow transplantation, metabolic disorders, and other inflammatory conditions.[4][5]
Differentiating Euthyroid sick syndrome from Other Diseases
Euthyroid sick syndrome must be differentiated from other causes of hypothyroidism on the basis of clinical features and laboratory findings. In euthyroid sick syndrome, serum T3 is decreased more than T4, the T3RU (T3 resin uptake) is high, and TSH is normal or mildly decreased. In primary hypothyroidism, serum T4 is decreased more than T3, the T3RU (T3 resin uptake) is low, and TSH is increased. Other causes of hypothyroidism include transient hypothyroidism, sub-clinical hypothyroidism, central hypothyroidism (pituitary or hypothaalmic) and peripheral resistance to TSH/TRH.[6][7][8]
Epidemiology and Demographics
Euthyroid sick syndrome is seen in 40-100% patients of nonthyroidal illness. The rate is higher for patients in intensive care unit (ICU). Euthyroid sick syndrome is more commonly seen in elderly population. There is no racial predilection for euthyroid sick syndrome and both men and women are affected equally.[9][10][11]
Risk Factors
Common risk factors in the development of euthyroid sick syndrome include iodine deficiency, female sex and pregnancy, radiation exposure, elderly, family history of thyroid disease, primary pulmonary hypertension, and infiltrative disease. Other less common risk factors are excessive intake of iodine, textile workers, and diabetes mellitus type I.[12][13][14][15]
Screening
There is insufficient evidence to recommend routine screening for euthyroid sick syndrome.
Natural History, Complications, and Prognosis
If left untreated, patients with euthyroid sick syndrome may progress to develop hypothyroidism or resolve spontaneously with correction of underlying condition. If underlying condition is not corrected, the thyroid hormone levels starts to drop after 2-3 weeks of initial illness. The symptoms of hypothyroidism may take some additional weeks before they start to appear. The complications of euthyroid sick syndrome depends upon other organ systems involved and underlying disease(s). The general complications of hypothyroidism as seen in euthyroid sick syndrome include hypothermia, bradycardia, heart failure, dyspnea, myopathy, confusion, apathy and psychosis. Laboratory finding will show increased levels of cholesterol and triglycerides. In addition, patients will have features of organs system involved. The prognosis varies and depends upon extent of the underlying disease at the time of diagnosis. Patients with low T3 (< 2.3 pg/ml) levels may have a longer hospital stay. Mortality rate is as high as 80% when serum T4 value is <3 mcg/dL.
Diagnosis
Diagnostic Criteria
The diagnosis of euthyroid sick syndrome is based on clinical presentation and thyroid function tests. An important part in diagnosing euthyroid sick syndrome is to be able to differentiate between other causes of hypothyroidism and euthyroid sick syndrome. Although the diagnosis of hypothyroidism is mainly a laboratory diagnosis, the coexisting conditions and wide variation in clinical presentation may make the diagnosis difficult. The best initial test is TSH, which in euthyroid sick syndrome can be low, normal, or elevated but not as high as it would be in hypothyroidism. Serum reverse T3 is elevated from inhibition of 5' monodeiodinase(type I). Patient having severe underlying illness, as in euthyroid sick syndrome have elevated levels of serum cortisol from underlying stress whereas patients of hypothyroidism have low serum cortisol from associated hypothalmic/pituitary abnormality.
History and Symptoms
Patients of euthyroid sick syndrome present with serious illness and are febrile with hypermetabolism. In euthyroid sick syndrome the symptoms of the underlying condition may overlap with features of hypothyroidism. Generally it takes atleast 2-3 weeks for thyroid hormone levels to decline and symptoms of hypothyroidism takes even longer period for expression. The common symptoms of hypothyroidism are fatigue, cold intolerance, decreased sweating, hypothermia, coarse skin, weight gain, depression, emotional lability, and attention deficit.
Physical Examination
Laboratory Findings
Laboratory findings consistent with the diagnosis of euthyroid sick syndrome include low T3, increased reverse T3 and variable proportions of T4 depending upon the severity of the disease. Patients having reduced concentration of T4 suggests progression of the underlying nonthyroidal illness. Complete thyroid function tests should be done which includes TSH, free T3, total T3, reverse T3, free T4, and total T4.[16][5][17][18]
Electrocardiogram
X-ray
There are no x-ray findings associated with euthyroid sick syndrome.
CT scan
There are no CT scan findings associated with euthyroid sick syndrome. However, a CT scan may be helpful in the diagnosis of complications associated with the underlying condition.
MRI
There are no MRI findings associated with euthyroid sick syndrome. However, a MRI may be helpful in the diagnosis of complications associated with the underlying condition.
Ultrasound
In euthyroid sick syndrome the thyroid gland appears normal. Therefore, there is no role of thyroid ultrasound in euthyroid sick syndrome.
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
In euthyroid sick syndrome emphasis is on rapid correction of the underlying disease. Many seriously ill patients have low levels of thyroid hormones but are not clinically hypothyroid and do not require thyroid hormone supplementation. Replacement of thyroid hormones in euthyroid sick syndrome is controversial except, in patients of congestive heart failure where liothyronine (LT3) or levothyroxine (LT4) may be recommended, to improve ventricular performance. Therefore, thyroid hormone therapy is generally not recommended for patients with euthyroid sick syndrome, except possibly those with chronic heart failure.
Surgery
Primary Prevention
Secondary Prevention
References
- ↑ Plank LD, Connolly AB, Hill GL (1998). "Sequential changes in the metabolic response in severely septic patients during the first 23 days after the onset of peritonitis". Ann. Surg. 228 (2): 146–58. PMC 1191454. PMID 9712558.
- ↑ Economidou F, Douka E, Tzanela M, Nanas S, Kotanidou A (2011). "Thyroid function during critical illness". Hormones (Athens). 10 (2): 117–24. PMID 21724536.
- ↑ Harris AR, Fang SL, Vagenakis AG, Braverman LE (1978). "Effect of starvation, nutriment replacement, and hypothyroidism on in vitro hepatic T4 to T3 conversion in the rat". Metab. Clin. Exp. 27 (11): 1680–90. PMID 30020.
- ↑ Silva MH, Araujo MC, Diniz EM, Ceccon ME, Carvalho WB (2015). "Nonthyroidal illnesses syndrome in full-term newborns with sepsis". Arch Endocrinol Metab. 59 (6): 528–34. doi:10.1590/2359-3997000000111. PMID 26677087.
- ↑ 5.0 5.1 Frączek MM, Gackowski A, Przybylik-Mazurek E, Nessler J (2016). "[The relation between the low T3 syndrome in the clinical course of myocardial infarction and heart failure]". Pol. Merkur. Lekarski (in Polish). 40 (240): 380–3. PMID 27403906.
- ↑ McDermott MT (2009). "In the clinic. Hypothyroidism". Ann. Intern. Med. 151 (11): ITC61. doi:10.7326/0003-4819-151-11-200912010-01006. PMID 19949140.
- ↑ Hollowell JG, Staehling NW, Flanders WD, Hannon WH, Gunter EW, Spencer CA, Braverman LE (2002). "Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III)". J. Clin. Endocrinol. Metab. 87 (2): 489–99. doi:10.1210/jcem.87.2.8182. PMID 11836274.
- ↑ Aoki Y, Belin RM, Clickner R, Jeffries R, Phillips L, Mahaffey KR (2007). "Serum TSH and total T4 in the United States population and their association with participant characteristics: National Health and Nutrition Examination Survey (NHANES 1999-2002)". Thyroid. 17 (12): 1211–23. doi:10.1089/thy.2006.0235. PMID 18177256.
- ↑ Di Napoli M, Reda G, Zannoni G, Russo S, Morace G, Vasselli C (1994). "[The euthyroid sick syndrome. Its incidence and clinical significance in an internal medicine department]". Minerva Med. (in Italian). 85 (4): 161–5. PMID 8028742.
- ↑ Vexiau P, Perez-Castiglioni P, Socié G, Devergie A, Toubert ME, Aractingi S, Gluckman E (1993). "The 'euthyroid sick syndrome': incidence, risk factors and prognostic value soon after allogeneic bone marrow transplantation". Br. J. Haematol. 85 (4): 778–82. PMID 7918043.
- ↑ Girvent M, Maestro S, Hernández R, Carajol I, Monné J, Sancho JJ, Gubern JM, Sitges-Serra A (1998). "Euthyroid sick syndrome, associated endocrine abnormalities, and outcome in elderly patients undergoing emergency operation". Surgery. 123 (5): 560–7. doi:10.1067/msy.1998.87238. PMID 9591009.
- ↑ Bruun T, Kristoffersen K (1978). "Thyroid function during pregnancy with special reference to hydatidiform mole and hyperemesis". Acta Endocrinol. 88 (2): 383–9. PMID 78652.
- ↑ Bober SA, McGill AC, Tunbridge WM (1986). "Thyroid function in hyperemesis gravidarum". Acta Endocrinol. 111 (3): 404–10. PMID 3083627.
- ↑ Vogelius IR, Bentzen SM, Maraldo MV, Petersen PM, Specht L (2011). "Risk factors for radiation-induced hypothyroidism: a literature-based meta-analysis". Cancer. 117 (23): 5250–60. doi:10.1002/cncr.26186. PMID 21567385.
- ↑ Curnock AL, Dweik RA, Higgins BH, Saadi HF, Arroliga AC (1999). "High prevalence of hypothyroidism in patients with primary pulmonary hypertension". Am. J. Med. Sci. 318 (5): 289–92. PMID 10555089.
- ↑ Golombek SG (2008). "Nonthyroidal illness syndrome and euthyroid sick syndrome in intensive care patients". Semin. Perinatol. 32 (6): 413–8. doi:10.1053/j.semperi.2008.09.010. PMID 19007679.
- ↑ Van den Berghe G (2014). "Non-thyroidal illness in the ICU: a syndrome with different faces". Thyroid. 24 (10): 1456–65. doi:10.1089/thy.2014.0201. PMC 4195234. PMID 24845024.
- ↑ Murakami M (2012). "[Nonthyroidal illness (NTI)]". Nippon Rinsho (in Japanese). 70 (11): 2005–10. PMID 23214076.