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Euthyroid Sick Syndrome

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Last Update: December 16, 2018.

Introduction

The euthyroid sick syndrome, also known as nonthyroidal illness syndrome, refers to changes seen in patient thyroid function tests administered in the medical intensive care unit during episodes of critical illness. It is not a true syndrome, and there are significant alterations in the hypothalamic-pituitary-thyroid axis in about 75% of the hospitalized patients. This condition often is seen in patients with severe critical illness, deprivation of calories, and following major surgeries. The most common hormone pattern in sick euthyroid syndrome is a low total T3 and free T3 levels with normal T4 and thyroid-stimulating hormone levels.[1][2][3]

Etiology

Causes of euthyroid sick syndrome vary to include critical illness, pneumonia, starvation, anorexia nervosa, sepsis, stress, history of trauma, cardiopulmonary bypass, myocardial infarction, malignancies, congestive cardiac failure, hypothermia, inflammatory bowel disease, cirrhosis, major surgery, renal failure, and diabetic ketoacidosis.[4]

Epidemiology

The most common abnormality, a T3 reduction, occurs in about 40% to 100% of cases, with about 10% of having low TSH. The highest incidence occurs in the most severely ill group. The probability of death correlates with the level of serum total T4. When total T4 levels drop below four microg/dL, the probability of death is approximately 50%, and when serum T4 levels are below two microg/dL, the probability of death reaches 80%.[5][6]

Pathophysiology

There are many proposed mechanisms regarding the pathogenesis of euthyroid sick syndrome. One cause is when the presence of thyroid binding hormone inhibitor in serum and body tissues inhibits the binding of thyroid hormone to thyroid-binding protein. Euthyroid sick syndrome also is caused by cytokines such as interleukin 1, interleukin 6, tumor necrosis factor alpha, and interferon-beta affecting the hypothalamus and pituitary thus inhibiting TSH, thyroid-releasing hormone, thyroglobulin, T3, and thyroid-binding globulins production. Cytokines also were thought to reduce the activity of type 1 deiodinase thus decreasing the binding capacity of T3 nuclear receptors.

Peripheral deiodinase activity type 1 is downregulated and central type 2 and type 3 deiodinase activities are up-regulated in critically ill patients. Several other mechanisms can contribute to the inhibition of 5'-monodeiodination, causing a decrease in the concentration of serum T3 in patients with a nonthyroidal illness such as high serum cortisol and exogenous corticosteroid therapy, amiodarone, and propranolol.

Serum albumin binds to fatty acids, which displaces thyroid hormones from thyroid binding globulin. The fall in serum albumin in euthyroid sick syndrome enhances the activity of competitors of T4 on thyroid binding globulin. Aspirin and heparin impair the protein binding of thyroid hormones, causing the reduction of total T3 and T4 and temporary elevation of free T3 and T4.

Histopathology

Histopathology of euthyroid sick syndrome is associated with reduced follicular size and weight of the thyroid gland in chronically ill patients. Acute liver disease and chronic kidney disease are associated with an increase in the volume of the thyroid gland. Patients with a history of chronic alcoholism are associated with the reduction in volume and fibrosis of the thyroid gland.

History and Physical

History and physical examination findings are specific to the etiologic factors, with no typical findings specific to euthyroid sick syndrome. The condition may affect patients who have preexisting thyroid issues and coexisting euthyroid sick syndrome can mask the typical physical examination findings of hypothyroidism and hyperthyroidism.

Evaluation

Euthyroid sick syndrome has been classified as (1) low T4 syndrome, (2) low T3 -low T4 syndrome, (3) high T4 syndrome, and (4) other abnormalities. Low serum total T3 is the most common abnormality in euthyroid sick syndrome, and it is seen in about 70% of hospitalized patients. The serum level of reverse T3 (rT3) is increased in euthyroid sick syndrome, except in renal failure. Elevated rT3 is predominantly due to decreased activity of the type I iodothyronine 5'-monodeiodinase (deiodination of T4 to T3 as well as rT3 to 3,3'-diiodothyronine). Both low T3 and the T4 syndrome are observed in critically ill patients admitted to intensive care units. Low serum total T4 correlates with a bad prognosis; thyroid binding globulin is normal, and the free T4 index is low in those patients. This combination of findings in euthyroid sick syndrome has been explained by the presence in the circulation of a thyroid binding hormone inhibitor.[7][8]

The free T4 level is reduced in euthyroid sick syndrome patients who had treatment with dopamine and steroids by decreasing TSH levels. Serum thyroid binding globulin is increased in patients with acute intermittent porphyria and chronic hepatitis, causing normal free T4 and high serum total T4. Total, as well as free T4 concentrations, are increased in patients who were treated with amiodarone and radiocontrast agents such as iopanoic acid. These cause the decrease in hepatic uptake of T4 and 5' monodeiodination of T4 to T3 and precipitate hyperthyroidism in patients who have an autonomous thyroid nodule by accelerating Jod Basedow phenomenon. HIV patients have unusual variations of thyroid function causing an increase in T4 and TBG, decreases in reverse T3 and rT3/T4 ratio, and normal T3 and T3/T4 ratio.

Treatment / Management

Thyroid hormone replacement is not needed in patients with euthyroid sick syndrome. Treatment and management of underlying medical illness is the focus; however, periodic monitoring of thyroid function should be done while the patient is in the hospital. After discharge from the hospital, thyroid function abnormalities may persist for several weeks. In a clinically euthyroid patient, thyroid function tests should be repeated six weeks after hospitalization to confirm overt thyroid dysfunction with persistent TSH abnormality or confirm euthyroid sick syndrome with normalization of TSH.[9]

Differential Diagnosis

Differential diagnoses of euthyroid sick syndrome include Hashimoto thyroiditis, hyperthyroidism, thyrotoxicosis, panhypopituitarism, and thyroid dysfunction induced by amiodarone therapy.

Prognosis

Low serum T3 is correlated with an increased length of hospital stay, intensive care unit admission, and the need for mechanical ventilation in patients with acute heart failure. The serum T4 value also correlates with outcome in critically ill patients; values under three microg/dL have been associated with mortality rates in excess of 85%.

Pearls and Other Issues

Two general guidelines are important in evaluating a critically ill patient. 

  1. First, measure TSH only if there is a high clinical suspicion of thyroid dysfunction. If TSH is abnormal, then further workup is done. If the TSH is greater than 20 microUnits/mL or is undetectable, euthyroid sick syndrome is less likely to be the cause, and overt thyroid dysfunction should be strongly considered. 
  2. When serum TSH is not elevated, euthyroid sick syndrome should be considered in patients with known thyroid disease and low serum-free T4.

Enhancing Healthcare Team Outcomes

Healthcare workers including nurse practitioners should be aware that the euthyroid sick syndrome is often seen in ill patients, especially after major surgery. The key is to manage the primary illness and not the abnormalities seen in thyroid hormone levels. The outlook for patients with euthyroid sick syndrome depends on the primary condition; as long as the primary disorder is being treated, patients will continue to show an aberration in the thyroid function tests.

Questions

To access free multiple choice questions on this topic, click here.

References

1.
Lee YJ, Lee HY, Ahn MB, Kim SK, Cho WK, Lee JW, Chung NG, Cho B, Suh BK. Thyroid dysfunction in children with leukemia over the first year after hematopoietic stem cell transplantation. J. Pediatr. Endocrinol. Metab. 2018 Nov 27;31(11):1241-1247. [PubMed: 30325734]
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Akbaş T, Sahin İE, Ozturk A. Alterations in thyroid hormones in brain-dead patients are related to non-thyroidal illness syndrome. Endokrynol Pol. 2018;69(5):545-549. [PubMed: 30132587]
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Gutch M, Kumar S, Gupta KK. Prognostic Value of Thyroid Profile in Critical Care Condition. Indian J Endocrinol Metab. 2018 May-Jun;22(3):387-391. [PMC free article: PMC6063192] [PubMed: 30090732]
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El-Ella SSA, El-Mekkawy MS, El-Dihemey MA. [Prevalence and prognostic value of non-thyroidal illness syndrome among critically ill children]. An Pediatr (Barc). 2018 Apr 05; [PubMed: 29628400]
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Duyu A, Çıtak EC, Ak E, Küpeli S, Yağcı Küpeli B, Bayram İ, Sezgin G, Eskendari G, Sezer K. Prevalence and Related Factors of Euthyroid Sick Syndrome in Children with Untreated Cancer According to Two Different Criteria. J Clin Res Pediatr Endocrinol. 2018 Jul 31;10(3):198-205. [PMC free article: PMC6083463] [PubMed: 29553046]
6.
Wang B, Liu S, Li L, Yao Q, Song R, Shao X, Li Q, Shi X, Zhang JA. Non-thyroidal illness syndrome in patients with cardiovascular diseases: A systematic review and meta-analysis. Int. J. Cardiol. 2017 Jan 01;226:1-10. [PubMed: 27776249]
7.
Cho EB, Min JH, Cho HJ, Seok JM, Lee HL, Shin HY, Lee KH, Kim BJ. Low T3 syndrome in neuromyelitis optica spectrum disorder: Associations with disease activity and disability. J. Neurol. Sci. 2016 Nov 15;370:214-218. [PubMed: 27772762]
8.
Krysicki M, Jaworska M, Popowicz B, Jankiewicz-Wika J, Klencki M, Słowińska-Klencka D. [The incidence of hypothyroidism symptoms and risk factors for cardiovascular events in subclinical hypothyroidism]. Pol. Merkur. Lekarski. 2014 Jul;37(217):10-6. [PubMed: 25154193]
9.
Smallridge RC. Metabolic and anatomic thyroid emergencies: a review. Crit. Care Med. 1992 Feb;20(2):276-91. [PubMed: 1737461]
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Bookshelf ID: NBK482219PMID: 29489255

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