Euthyroid sick syndrome (ESS) is a state of adaptation or dysregulation of thyrotropic feedback control[1] wherein the levels of T3 and/or T4 are abnormal, but the thyroid gland does not appear to be dysfunctional.

This condition may result from allostatic responses of hypothalamus-pituitary-thyroid feedback control, dyshomeostatic disorders, drug interferences, and impaired assay characteristics in critical illness.

[2] An alternative phenotype with a largely inverse hormonal pattern is seen in several physiological and pathological conditions, including pregnancy, obesity, endurance training, and psychiatric diseases.

It is typically associated with high-T3 syndrome, increased plasma protein binding of thyroid hormones, and an elevated set point of the homeostatic system.

[2] Causes of classical euthyroid sick syndrome include a number of acute and chronic conditions, including pneumonia, fasting, starvation, anorexia nervosa, sepsis, trauma,[4] cardiopulmonary bypass, malignancy, stress, heart failure, hypothermia, myocardial infarction, kidney failure, cirrhosis, diabetic ketoacidosis,[1] surgery, infection, brain injury, shock, cancer,[5] and HIV.

This may play an important role in the pathogenesis of the central component of thyroid allostasis in critical illness, tumors, uremia and starvation (TACITUS).

[citation needed] Euthyroid sick syndrome probably represents an overlap of an allostatic response with pathologic reactions and drug interferences.

Thyroid storm, though, represents allostatic failure, where the organism is unable to develop NTIS in the situation of thyrotoxicosis.

[3][5] Thyrotropin releasing hormone (TRH) neurons in the hypothalamus integrate global signals about the body's energy state.

[2] In critical illness, inflammation increases tanycyte D2 in the paraventricular nucleus (PVN) of the hypothalamus, leading to local tissue hyperthyroidism.

[5] During NTIS, alterations arise in the concentrations of thyroid hormone transporters such as MCT8 and MCT10, although whether the levels are increased or decreased depends on the study.

The altered concentrations are thought to be a result of NTIS, rather than a cause; a study in rabbits showed that administering thyroid hormones normalized transporter expression.

Originally, selenium deficiency as a result of malnutrition was thought to reduce D1 catalytic activity, but this theory has not been supported as a cause of NTIS.

[5][10] Ιn fasting animals, administering leptin reverses NTIS symptoms and restores thyroid hormone concentrations.

Low leptin increases NPY and AGRP (associated with appetite), which inhibit TRH gene expression; this effect is enhanced by ghrelin (the hunger hormone).

This can occur during pregnancy, obesity, cold adaptation, stay in high altitudes, endurance exercise, acute psychosis, and post-traumatic stress disorder.

[2][12] According to newer theories,[2] elevated concentrations of TSH and thyroid hormones in type 2 allostasis result from an up-regulated set point of the feedback loop, which ensues from increased TRH expression in the basolateral amygdala and the paraventricular nucleus of the hypothalamus in response to stress.

During endurance exercise, before exhaustion, elevated thyroid hormone levels may happen due to increased expected energy demand (type 2 allostatic load).

[12][19] Affected patients may have normal, low, or slightly elevated TSH depending on the spectrum and phase of illness.

NTIS is a component of a complex endocrine adaptation process, so affected patients might also have hyperprolactinemia and elevated levels of corticosteroids (especially cortisol) and growth hormone.

[2] Several trials have investigated a possible therapy for NTIS, but they yielded inconsistent and partly contradictory results.