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Nonthyroidal illness (NTI) was initially characterized as a selective deficiency of serum and tissue T3 (triiodothyronine) in patients dying with severe prolonged illness.This syndrome of low total and free serum T3, normal, low or high total serum T4 (thyroxine), increased T4 sulfate, normal to high free T4, and normal serum thyroid-stimulating hormone (TSH) concentrations has now been reported in a variety of situations. These include the premature neonate (see Chapter 527) patients with protein-calorie malnutrition or anorexia nervosa, fasting subjects, postoperative patients, and patients with a variety of severe acute and chronic illnesses. The latter have included patients with diabetic ketoacidosis, severe trauma, burns, febrile states, cirrhosis, and renal failure. In addition, a number of drugs have been observed to produce a similar syndrome; these drugs include dexamethasone, selected radiographic contrast agents, propylthiouracil, propranolol, and amiodarone. There is no convincing evidence that treatment with thyroid hormones, either T4 or T3, is effective in most patients with nonthyroidal illness. Treatment should be directed to the primary systemic illness. There is some evidence to suggest that treatment may be beneficial in selected clinical conditions such as postoperative cardiac surgery.

Three patterns of change in thyroid hormone levels have been described: low T4, normal T4, and high T4 nonthyroidal syndromes.The low serum and tissue T3 levels in this syndrome occur as a result of inhibition of monodeiodinase type 1 (MDI-1) activity and a decreased rate of T3 production from T4 in nonthyroidal tissues. In mice, interleukin-1 (IL-1) cytokine inhibition of transcription of iodothyronine MDI-1 results in decreased hepatic T4-to-T3 conversion, and this reduction can be reversed by steroid receptor coactivator 1 (SRC-1) induction of MDI-1.rT3 degradation is decreased because the degradation of rT3 is mediated by the same type I deiodinase enzyme that mediated the conversion of T4 to T3. Thus, serum T3 levels fall, and rT3 levels tend to remain normal or increase. In some patients, serum T4 levels also fall (the low T4 syndrome), and low T4 levels in patients with severe nonthyroidal illness have been associated with increased mortality. Thyroid-binding globulin (TBG) levels may be reduced in such patients, and an inhibitor of T4 binding to TBG has been described in the serum and derived from the tissues of such patients.

Elevated thyroid-stimulating hormone (TSH) levels with normal thyroid hormone levels are observed in patients with asymptomatic euthyroid hyperthyrotropinemia. This disorder is relatively common and may be transient or permanent. The prevalence of transient hyperthyrotropinemia in Europe approximates 1 in 8000 births, with 50% due to perinatal iodine exposure. Other causes include defects in TSH or the TSH receptor, a mild intrathyroidal synthetic defect, a hemithyroid gland, or a resetting of the TSH feedback control system. Germline inactivating mutations of the TSH ...

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