EUTHYROID SICK SYNDROME (ESS)
by Dr. Mukesh
Introduction:
The euthyroid sick syndrome, also known as non-thyroidal illness syndrome,
refers to changes seen in the patient thyroid function tests administered in
the medical intensive care unit during episodes of critical illness. It is not a true
syndrome, but it represents significant alterations in the hypothalamicpituitary-thyroid axis in about 75% of hospitalized patients. This condition is
often seen in patients with severe critical illness, deprivation of calories, and
following major surgeries. The most common hormone pattern in euthyroid
sick syndrome is a low total T3 and free T3 levels with low or normal T4 and
thyroid-stimulating hormone levels.
Etiology:
Causes of euthyroid sick syndrome vary to include several critical illnesses of different
etiology:
• Pneumonia, starvation, anorexia nervosa, sepsis, stress
• History of trauma like hip fracture, cardiopulmonary bypass, myocardial infarction,
malignancies, burns, organ transplantations, congestive cardiac failure, hypothermia,
inflammatory bowel disease, cirrhosis, major surgery, renal failure, and diabetic
ketoacidosis.
• The latest addition to this long list has been the reports about euthyroid sick
presentation after Covid-19 infection. The discovery of low T3 levels in Covid-19
patients was also a predictive marker for poor prognosis, even in the early stages of
the disease.
Epidemiology:
The most common abnormality, a total T3 level reduction, occurs in about 40%
to 100% of cases. In hospitalized patients, 10% are found to have low TSH
levels measured, an abnormality unrelated to thyroid pathology. 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 4
mcg/dL, the probability of death is approximately 50%, and when serum T4
levels are measured below 2 mcg/dL, the probability of death reaches over
80%.
Pathophysiology:
There are many proposed mechanisms regarding the pathogenesis of euthyroid sick syndrome. One
cause suggested is when the presence of thyroid-binding hormone inhibitors in the serum and different
body tissues inhibits the binding of the thyroid hormone to the thyroid-binding protein. The euthyroid
sick syndrome is also caused by cytokines such as interleukin 1, interleukin 6, tumour necrosis factoralpha, and interferon-beta affecting the hypothalamus and pituitary glands, thus inhibiting TSH,
thyroid-releasing hormone (TRH), thyroglobulin (TG), T3, and the thyroid-binding globulins (TBG)
production. Cytokines were also thought to reduce the activity of type1 deiodinase and decrease the
binding capacity of the T3 nuclear receptors.
The peripheral deiodinase activity type1 is down regulated, and the central type2 and type3 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 total T3 levels in
patients with a non-thyroidal illness, such as high serum cortisol and the use of exogenous
corticosteroid therapy as well as other medications like amiodarone and propranolol.
Serum albumin binds to fatty acids, which displaces thyroid hormones from the thyroid-binding
globulin. The fall in serum albumin level in euthyroid sick syndrome enhances the activity of different
competitors of T4 on thyroid-binding globulin. Aspirin and heparin drugs impair the protein binding of
the thyroid hormones, causing the reduction of total T3 and T4 levels and subsequently, temporary
elevation of free T3 and T4 levels.
Histopathology:
Histopathology of the euthyroid sick syndrome is associated with a 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 have been found to have a reduction in the volume of the
thyroid and also the development of fibrosis in the gland.