T3

**Synthesis and secretion:** Thyroid follicular cells take up iodide via the Na+/I- symporter (NIS). Thyroid peroxidase (TPO) oxidizes iodide, iodinates tyrosine residues on thyroglobulin (organification) to form MIT and DIT, and couples them: DIT + DIT = T4, MIT + DIT = T3. The thyroid secretes mainly T4 (~90%) and a smaller amount of T3. Most circulating T3 (~80%) comes from peripheral conversion of T4 by 5'-deiodinase (type 1 in liver, kidney and thyroid; type 2 in brain, pituitary, brown fat and muscle). Reverse T3 (rT3) is the inactive product of 5-deiodinase (type 3). Regulation runs through the HPT axis: hypothalamic TRH stimulates pituitary TSH, which stimulates the thyroid. T3 and T4 give negative feedback on the pituitary and hypothalamus.

**Transport:** >99% is protein-bound, mainly to thyroxine-binding globulin (TBG), plus transthyretin and albumin. Only free hormone is active. T3 is less tightly bound than T4, so it has a shorter half-life (~1 day vs ~7 days for T4). Estrogen (pregnancy, OCPs) raises TBG, which raises total T3/T4 but leaves free hormone and clinical status normal. Androgens, glucocorticoids and nephrotic syndrome lower TBG.

**Mechanism:** T3 enters cells, binds nuclear thyroid hormone receptors (thyroid hormone response elements, with RXR heterodimers), and changes gene transcription. T3 has ~10x higher receptor affinity than T4, so T4 acts largely as a prohormone.

**Effects (high-yield):** - Increases BMR, O2 consumption and heat production (Na+/K+-ATPase up). - Upregulates β1-adrenergic receptors in the heart, which raises HR, contractility and CO (this is why thyrotoxicosis causes tachycardia, AF, and responds to propranolol). - Increases glycogenolysis, gluconeogenesis, lipolysis and cholesterol clearance (LDL receptors up, so hypothyroidism raises LDL). - Bone growth and CNS maturation. Deficiency in utero or in infancy causes congenital hypothyroidism (cretinism). - Increases GI motility.

**Clinical correlations:** - *Graves disease:* TSH-receptor-stimulating IgG antibodies (type II hypersensitivity) cause diffuse goiter, exophthalmos and pretibial myxedema. Labs show low TSH and high free T4/T3. Radioiodine uptake is diffusely increased. - *T3 toxicosis:* Hyperthyroidism with high T3 but normal T4, seen in early Graves or toxic nodules. - *Hashimoto thyroiditis:* Anti-TPO and anti-thyroglobulin antibodies. Initial hashitoxicosis is followed by hypothyroidism (high TSH, low T4/T3). - *Subacute (de Quervain) thyroiditis:* Painful thyroid with high ESR, and low radioiodine uptake. - *Thyroid storm:* Treat with β-blocker, PTU (blocks peripheral T4→T3 conversion plus TPO) or methimazole, iodide (Wolff-Chaikoff effect), and glucocorticoids (also block conversion). - *Sick euthyroid (nonthyroidal illness):* Low T3, high rT3, normal TSH, from decreased 5'-deiodinase in acute illness. Do not treat. - *Amiodarone:* Inhibits 5'-deiodinase and contains iodine, so it can cause either hypothyroidism or hyperthyroidism. - *Treatment:* Liothyronine is synthetic T3, with rapid onset and short half-life, used in myxedema coma (often with levothyroxine). Levothyroxine (T4) is first-line for hypothyroidism. - *Resin T3 uptake test:* Indirectly assesses TBG binding sites. It is high in hyperthyroidism and low in hypothyroidism.

**Mnemonic:** T3 is 3 times more potent than T4 (roughly), while T4 is the "Storage/Transport" form with the longer half-life (4 → 7 days).