Euthyroid sick syndrome

Euthyroid sick syndrome also known as nonthyroidal illness syndrome, refers to abnormal findings on thyroid function tests seen in patient in the medical intensive care unit during episodes of critical illness, without preexisting hypothalamic-pituitary and thyroid gland dysfunction ¹. Euthyroid sick syndrome is not a true syndrome and there are significant alterations in the hypothalamic-pituitary-thyroid axis in about 75% of the hospitalized patients ¹. Euthyroid sick syndrome often is seen in patients with severe critical illness, deprivation of calories, and following major surgeries. Multiple alterations in serum thyroid function test findings have been recognized in patients with a wide variety of euthyroid sick syndrome without evidence of preexisting thyroid or hypothalamic-pituitary disease. The most common hormone pattern in sick euthyroid syndrome is a low total T3 (triiodothyronine) and free T3 levels with normal T4 (thyroxine) and thyroid-stimulating hormone (TSH) levels ².

The most common abnormality, a T3 reduction, occurs in about 40% to 100% of cases, with about 10% of having low TSH (thyroid-stimulating hormone). 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% ³.

These changes in thyroid function test results are observed in most of the acute and chronic illnesses. Examples of illness include the following:

• Gastrointestinal diseases
• Pulmonary diseases
• Cardiovascular diseases
• Renal diseases
• Infiltrative and metabolic disorders
• Inflammatory conditions
• Myocardial infarction (heart attack)
• Starvation
• Sepsis
• Burns
• Trauma
• Surgery
• Malignancy (cancer)
• Bone marrow transplantation.

Alterations in thyroid function test findings may reflect changes in production of thyroid hormone by effects on the thyroid itself, on the hypothalamic-pituitary-thyroid axis, on peripheral tissue metabolism of the hormones, or by a combination of these effects.

What causes euthyroid sick syndrome?

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.

A study by Petrone et al ⁵ 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 obstructive sleep apnea but occurred in none of the controls. Mean nocturnal oxygen saturation was worse in persons with euthyroid sick syndrome than in other obstructive sleep apnea patients. Treatment of obstructive sleep apnea resulted in a rise in free T3 to normal range.

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.

Euthyroid sick syndrome symptoms

History and physical examination findings are specific to the causative 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.

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

Euthyroid sick syndrome diagnosis

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 ⁶.

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.

Euthyroid sick syndrome treatment

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 ⁷.

Thyroid hormones have been used in the setting of euthyroid sick syndrome in various settings with T4 and T3 replacement and still remain controversial ⁸. De Groot ⁹ has supported the notion that nonthyroidal illness syndrome is a manifestation of hypothalamic-pituitary dysfunction, and in view of current evidence, he proposed that treatment should be considered with appropriate replacement therapies such as pituitary hormones, hypothalamic factors in addition to thyroid hormones.

A randomized, doubled-blind, placebo-controlled trial by Zhang et al ¹⁰ reported that in children who underwent congenital heart disease repair with cardiopulmonary bypass, the severity of postoperative euthyroid sick syndrome was reduced when oral, small-dose thyroid hormone treatment was administered preoperatively.

A retrospective study by Li et al ¹¹ indicated that in patients with nonthyroidal illness syndrome associated with enterocutaneous fistula, enteral nutrition therapy can contribute to the syndrome’s resolution.

Euthyroid sick syndrome 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 3 microg/dL have been associated with mortality rates in excess of 85%.

References

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9. 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.
10. 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
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