Euthyroid sick Syndrome
I. What every physician needs to know.
Patients hospitalized with acute, severe illness are frequently found to have low triiodothyronine (T3) levels with normal or low normal thyroxine (T4) and thyroid stimulating hormone (TSH) levels. This constellation of findings is known by several names: euthyroid sick syndrome, low T3 syndrome, and non-thyroidal illness syndrome. Non-thyroidal illness syndrome (NTIS) is the preferred name at this time.
The most prevalent form of thyroid hormone is T4. This is converted in the peripheral tissues to the more potent and principally active thyroid hormone, T3, by deiodination. There are three iodothyroxine deiodinases: D1, D2, and D3. The conversion of T4 to T3 and reverse T3 (rT3), and the clearance of rT3 which is biologically inert, is mediated by hepatic D1. Starvation or cytokines like interleukin 1 (IL-1) suppress hepatic D1 causing decreased conversion of T4 to T3 and decreased clearance of reverse T3 (rT3). Deiodinase D2 is found in skeletal muscles, central nervous system, thyroid and the pituitary. Deiodinase D3, particularly induced by tissue hypoperfusion, is the major deactivating enzyme which causes conversion of T4 to rT3. Initially, the result is low T3 and normal T4 and TSH concentrations; most experts view this as an adaptive response to stress and illness. With prolonged critical illness, T4 and TSH may decline as well.
Thyroid levels should not be measured during critical illness unless there is a strong suspicion of underlying thyroid disorder.
II. Diagnostic Confirmation: Are you sure your patient has Euthyroid Sick Syndrome?
Low serum T3. Low pulsatile measurement of TSH. Low or normal serum concentrations of T4 and TSH, but TSH is usually not undetectable. Transient upsurge of TSH, generally less than 20 milliunits/liter (mU/L), may be seen with recovery.
A. History Part I: Pattern Recognition:
Typical case with NTIS is a hospitalized patient with severe acute illness. At first, the patient has low serum T3 levels with normal T4 and TSH levels. During prolonged illness, T4 and TSH levels may decrease. Most recent evidence suggests that central hypothyroidism and altered peripheral metabolism of T4 and T3 combine to produce a state marked by diminished serum and tissue supplies of thyroid hormones. Post-mortem brain samples of chronic critically ill patients show reduced hypothalamic messenger ribonucleic acid (mRNA) for thyrotropin releasing hormone (TRH) and lower TSH. These data indicate that production of thyroid hormone declines due to reduced hypothalamic stimulation of the thyrotropes, in turn leading to diminished stimulation of the thyroid gland. Rise in TSH levels preceding onset of recovery from severe illness supports this theory. Factors triggering hypothalamic suppression during prolonged critical illness are not completely known.
B. History Part 2: Prevalence:
In non-selected hospitalized patients the prevalence of NTIS is 11-18%. In the intensive care unit (ICU), it may be seen in upwards of 70-75% of patients. In congestive heart failure, the prevalence is 18- 23%. In a study looking at elderly patients in Italy, the prevalence was 31.9%. NTIS in the elderly was found to be predictive of mortality at 17.7%, compared to 3.9% in those who were euthyroid.
C. History Part 3: Competing diagnoses that can mimic Euthyroid Sick Syndrome.
Primary hypothyroidism: Primary hypothyroidism is characterized by an elevated TSH, low T4, and low or normal T3 and Free T3 (FT3).
Central hypothyroidism: Central hypothyroidism is characterized by low T4, low or normal T3, and low TSH or normal single measure of TSH. Central hypothyroidism, like NTIS, displays low pulsatile secretion of TSH versus elevated pulsatile secretion of TSH in primary hypothyroidism.
D. Physical Examination Findings.
The presence of NTIS does not correspond with any specific physical exam finding.
E. What diagnostic tests should be performed?
1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
Serum TSH, free T4 (FT4), FT3, and total T3.
– Elevated TSH could be diagnostic of very early or recovery phase of NTIS or may be diagnostic of hypothyroidism.
– Low or normal T4, low or normal TSH, low T3 in the critically ill patient is diagnostic of NTIS.
2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
There is no role for imaging tests in the diagnosis or management of NTIS.
F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
Thyroid levels should not be measured during critical illness unless there is a strong suspicion of underlying thyroid disorder.
III. Default Management.
Management is usually conservative and aimed at treating the underlying illness.
A. Immediate management.
Continue to manage primary illness.
B. Physical Examination Tips to Guide Management.
C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
D. Long-term management.
Thyroid function may take several months to recover after critical illness; outpatient monitoring is recommended.
E. Common Pitfalls and Side-Effects of Management.
IV. Management with Co-Morbidities.
A. Renal Insufficiency.
In animal models, treatment with thyroid hormone helped to reduce or reverse ischemic injury and toxic acute renal failure. These effects have not been verified in humans.
In one study, over 80% of acute kidney injury patients were noted to have abnormal thyroid function test, most commonly NTIS; spontaneous resolution was observed with improvement of renal function. In a small randomized trial of 59 patients with acute renal failure, treatment with T4 did not reverse renal injury, suppression of TSH was observed, and there was association with increased mortality. In another study of 54 patients undergoing renal transplant, treatment with T4 did not change the primary outcome of graft function in patients with delayed graft function.
In chronic kidney disease, inflammatory cytokines and oxidative stress may play a pivotal role in pathogenesis of NTIS. Treatment remains controversial. In a study of hemodialysis patients, low T3 was a frequent finding and did not predict outcome. However, FT3 was found inversely linked to mortality, possibly due to its association with suboptimal nutritional state and inflammation.
B. Liver Insufficiency.
In cirrhosis, the most common thyroid abnormalities are decreased free T3, T3, and elevated rT3. Some studies have suggested that low T4 and / or low T3 in cirrhosis may be indicative of disease severity and may correlate with decreased short- and long-term survival.
C. Systolic and Diastolic Heart Failure.
Low T3 has been implicated as an independent predictor of cardiac and all-cause mortality among critically ill patients.
Thyroid hormone increases inoptropy, chronotropy, blood volume, and decreases systemic vascular resistance. In dilated cardiomyopathy, T3 has been shown to increase left ventricular end systolic volume, increase stroke volume, and decrease heart rate.
D. Coronary Artery Disease or Peripheral Vascular Disease.
In coronary artery bypass, thyroid hormone increases cardiac output and decreases systolic vascular resistance.
In some small nonrandomized open heart surgery trials, T3 showed benefit when administered to those with poor myocardial function despite inotropic and intra-aortic balloon pump support.
Some experts advocate use of thyroid hormone therapy in patients with NTIS and myocardial depression, based on studies showing improvement in myocardial function in three conditions: transient regional myocardial ischemia and reperfusion, transient global myocardial ischemia in patients undergoing cardiac surgery or coronary artery bypass grafting, and transient inadequate myocardial perfusion in brain dead potential organ donors.
E. Diabetes or other Endocrine issues.
G. Immunosuppression (HIV, chronic steroids, etc).
Prior to the use of highly active antiretroviral therapy (HAART), nonthyroidal illness was a common feature of patients with terminal acquired immunodeficiency syndrome (AIDS). NTIS may affect up to 16% of those with human immunodeficiency virus (HIV). They characteristically have increased resting energy expenditure, poor oral intake, and increased prevalence of weight loss and wasting. Patients with nonthyroidal illness do not need therapy as it is a normal adaptive mechanism.
H. Primary Lung Disease (COPD, Asthma, ILD).
NTIS may be associated with prolonged weaning in intubated chronic obstructive pulmonary disease (COPD) patients.
I. Gastrointestinal or Nutrition Issues.
Thyroid function test was monitored in the EPaNIC trial, a large randomized controlled trial studying early versus late parenteral nutrition in critically ill adults. Findings suggested that tolerating macronutrient deficiency during the first week in ICU improved outcomes by reducing incidence of nosocomial infection, and was associated with faster recovery with fewer complications. Acute fasting induced NTIS phenotype, not seen in the group receiving parenteral nutrition. Possible benefits of acute NTIS include reduction in energy expenditure with low T3 levels, and also increased D3 activity locally in granulocytes enhancing bacterial killing.
J. Hematologic or Coagulation Issues.
K. Dementia or Psychiatric Illness/Treatment.
Up to one-third of psychiatric patients may show thyroid function abnormalities consistent with NTIS. These resolve spontaneously and treatment is not recommended.
V. Transitions of Care.
A. Sign-out considerations While Hospitalized.
No specific sign out considerations.
B. Anticipated Length of Stay.
C. When is the Patient Ready for Discharge.
Discharge planning is determined by the status of the underlying disease process, not resolution of NTIS.
D. Arranging for Clinic Follow-up.
Patient should have thyroid function tested as an outpatient and may benefit from Endocrinology follow up in cases where there is significant derangement in thyroid tests.
1. When should clinic follow up be arranged and with whom.
The patient should follow up with their primary care provider within 1 – 2 weeks of discharge. Depending on the degree of derangement in thyroid studies, referral to an Endocrinologist may be warranted. Due to the time required for recovery on normal thyroid function, 4 weeks would be a reasonable time frame.
2. What tests should be conducted prior to discharge to enable best clinic first visit.
3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.
TSH, FT4, T3, FT3
E. Placement Considerations.
Since NTIS is seen in seriously ill patients and its presence is predictive of increased mortality, it is likely that patients who have NTIS during their hospital admission will require discharge to a skilled nursing facility for subacute rehabilitation.
F. Prognosis and Patient Counseling.
The presence of NTIS in a population of elderly patients admitted to a hospital in Italy was associated with mortality of 17.7% versus 3.9 %, when compared to patients without NTIS.
The probability of death is 50% when free T4 is less than 4 microgram per deciliter and 80% when free T4 is less than 2 microgram per deciliter.
In a study of ICU patients, overall mortality was 12.7% compared to 17.6% p=0.396 for NTIS. However, NTIS with low T4 resulted in a mortality of 45.8%, p<0.001. The presence of NTIS was associated with the need for mechanical ventilation 50% versus 44.3% for euthyroidism. NTIS with low T4 was associated with 83.3% requiring mechanical ventilation.
VI. Patient Safety and Quality Measures.
A. Core Indicator Standards and Documentation.
B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.
VII. What's the Evidence?
Van den Berghe, G. “Non-Thyroidal Illness in the ICU: A Syndrome with Different Faces”. Thyroid. vol. 24. 2014. pp. 1456-1465.
DeGroot, LJ. “The Non-Thyroidal Illness Syndrome in www.endotext.org”. 2015.
Pereg, D, Tirosh, A, Elis, A. “Mortality and coronary heart disease in euthyroid patients”. Am J Med. vol. 125. 2012. pp. 826
Kowalczuk-Wieteska, A, Baranska-Kosakowska, A, Zakliczynski, M. “Do thyroid disorders affect the postoperative course of patients in the early post-heart transplant period”. Ann Transplant. vol. 16. 2011. pp. 77-81.
Ozen, KP, Asci, G, Gungor, O. “Nutritional state alters the association between free triiodothyronine levels and mortality in hemodialysis patients”. American Journal of Nephrology. vol. 33. 2011. pp. 305-312.
Pfister, R, Strack, N, Wielckens, K. “The relationship and prognostic impact of low-T3 syndrome and NT-pro-BNP in cardiovascular patients”. International Journal of Cardiology. vol. 144. 2010. pp. 187-190.
Eshraghian, A, Taghavi, SA. “Systematic review: endocrine abnormalities in patients with liver cirrhosis”. Arch Iran Med. vol. 17. 2014. pp. 713-721.
Novitzky, D, Cooper, DK. “Thyroid hormone and the stunned myocardium”. J Endocrinol. vol. 223. 2014. pp. R1-8.
Xu, G, Yan, W, Li, J. “An update for the controversies and hypotheses of regulating nonthyroidal illness syndrome in chronic kidney diseases”. Clin Exp Nephrol. vol. 18. 2014. pp. 837-843.
Chuang, CP, Jong, YS, Wu, CY, Lo, HM. “Impact of triiodothyronine and N-terminal pro-B-type natriuretic peptide on the long-term survival of critically ill patients with acute heart failure”. Am J Cardiol. vol. 113. 2014. pp. 845-850.
Parsa, AA, Bhangoo, A. “HIV and thyroid dysfunction”. Rev Endocr Metab Disord. vol. 14. 2013. pp. 127-131.
Iglesias, P, Olea, T, Vega-Cabrera, C. “Thyroid function tests in acute kidney injury”. JNephrol. vol. 26. 2013. pp. 164-172.
Dickerman, AL, Barnhill, JW. “Abnormal thyroid function tests in psychiatric patients: a red herring”. Am J Psychiatry. vol. 169. 2012. pp. 127-133.
Loh, KC, Eng, PC. “Prevalence and prognostic relevance of sick euthyroid syndrome in medical intensive care unit”. Ann Acad Med Singapore. vol. 24. 1995. pp. 802-806.
Togninbi, S, Marchini, F, Dardano, A. “Non-thyroidal illness syndrome and short-term survival in a hospitalized older population”. PubMed. vol. 39. 2010. pp. 46-50.
Acker, CG, Singh, AR, Flick, RP. “A trial of thyroxine in acute renal failure”. Kidney International. vol. 57. 2000. pp. 293-298.
Sutter, PM, Gunilla, T, Stromski, M. “Beneficial effect of thyroxin in the treatment of ischemic acute renal failure”. Pediatric Nephrology. vol. 2. 1988. pp. 1-7.
Casaer, MP, Dieter, M, Greet, H. “Early versus Late Parenteral Nutrition in Critically Ill Adults”. N Engl J Med. vol. 365. 2011. pp. 506-517.
Yasar, Z, kirakli, C, Cimen, P. “Is non-thyroidal illness syndrome a predictor for prolonged weaning in intubated chronic obstructive pulmonary disease patients”. Int J Clin Exp Med. vol. 8. 2015. pp. 10114-101121.
Fliers, E, Guldenaar, SE, Wiersinga, WM, Swaab, DF. “Decreased hypothalamic thyrotropin-releasing hormone gene expression in patients with nonthyroidal illness”. J Clin Endocrinol Metab. vol. 82. 1997. pp. 4032
Spencer, CA, LoPresti, JS, Patel, A. “Applications of a new chemiluminometric thyrotropin assay to subnormal measurement”. J Clin Endocrinol Metab. vol. 70. 1990. pp. 453
Attia, J, Margetts, P, Guyatt, G. “Diagnosis of thyroid disease in hospitalized patients: a systemic review”. Arch Intern Med. vol. 159. 1999. pp. 658
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- I. What every physician needs to know.
- II. Diagnostic Confirmation: Are you sure your patient has Euthyroid Sick Syndrome?
- A. History Part I: Pattern Recognition:
- B. History Part 2: Prevalence:
- C. History Part 3: Competing diagnoses that can mimic Euthyroid Sick Syndrome.
- D. Physical Examination Findings.
- E. What diagnostic tests should be performed?
- F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.
- III. Default Management.
- A. Immediate management.
- B. Physical Examination Tips to Guide Management.
- C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.
- D. Long-term management.
- E. Common Pitfalls and Side-Effects of Management.
- IV. Management with Co-Morbidities.
- A. Renal Insufficiency.
- B. Liver Insufficiency.
- C. Systolic and Diastolic Heart Failure.
- D. Coronary Artery Disease or Peripheral Vascular Disease.
- E. Diabetes or other Endocrine issues.
- F. Malignancy.
- G. Immunosuppression (HIV, chronic steroids, etc).
- H. Primary Lung Disease (COPD, Asthma, ILD).
- I. Gastrointestinal or Nutrition Issues.
- J. Hematologic or Coagulation Issues.
- K. Dementia or Psychiatric Illness/Treatment.
- V. Transitions of Care.
- A. Sign-out considerations While Hospitalized.
- B. Anticipated Length of Stay.
- C. When is the Patient Ready for Discharge.
- D. Arranging for Clinic Follow-up.
- 1. When should clinic follow up be arranged and with whom.
- 2. What tests should be conducted prior to discharge to enable best clinic first visit.
- 3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.
- E. Placement Considerations.
- F. Prognosis and Patient Counseling.
- VI. Patient Safety and Quality Measures.
- A. Core Indicator Standards and Documentation.
- B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.