triiodothyronine

**Synthesis (thyroid follicular cells):** - Na+/I- symporter (NIS) takes up iodide (secondary active transport) → pendrin moves it into the colloid → thyroid peroxidase (TPO) oxidizes iodide, iodinates tyrosine residues on thyroglobulin (organification), and couples them. - MIT + DIT = T3; DIT + DIT = T4. - TSH stimulates every step (Gs → cAMP). Thyroglobulin is endocytosed and cleaved by lysosomal proteases, which releases T3 and T4. - The thyroid secretes mostly T4 (~90-93%) and little T3.

**Peripheral activation:** - Type 1 (liver, kidney, thyroid) and type 2 (brain, pituitary, brown fat, skeletal muscle) 5'-deiodinases convert T4 → T3 (active). Type 3 deiodinase converts T4 → reverse T3 (inactive). - Reverse T3 rises in severe illness, starvation, and with glucocorticoids, propranolol, and PTU (non-thyroidal illness / "sick euthyroid": low T3, high rT3, normal TSH). - Selenium is a cofactor for deiodinases.

**Transport:** - >99% is protein bound, mainly to thyroxine-binding globulin (TBG), plus transthyretin and albumin. Only free hormone is active. - Estrogen (pregnancy, OCPs) increases TBG, so total T3/T4 rise but free levels are normal. Androgens, glucocorticoids, and nephrotic syndrome decrease TBG. - T3 has lower protein binding and a shorter half-life (~1 day) than T4 (~7 days). T3 is more potent and acts faster.

**Mechanism of action:** - It enters cells and binds nuclear thyroid hormone receptors (a steroid/thyroid receptor superfamily member, with a heterodimer partner, RXR) at thyroid response elements → altered gene transcription. - Effects take hours to days.

**Physiologic effects ("everything goes up" — the 4 B's):** - **Brain maturation:** essential for normal CNS development. Deficiency in infancy causes cretinism. - **Bone growth:** works synergistically with GH and IGF-1. - **Beta-adrenergic effects:** upregulates β1 receptors → ↑HR, ↑contractility, ↑cardiac output. - **BMR:** ↑Na+/K+-ATPase activity, ↑O2 consumption, ↑heat production. - Metabolic effects: ↑glycogenolysis, ↑gluconeogenesis, ↑lipolysis, ↑LDL receptor expression (↓cholesterol).

**Regulation:** - The hypothalamus releases TRH → the anterior pituitary releases TSH → the thyroid releases T4/T3. T3 (made locally from T4 in the pituitary) provides negative feedback on TRH and TSH. - Dopamine, somatostatin, and glucocorticoids suppress TSH.

**Clinical correlations:** - **Graves disease:** TSH receptor-stimulating IgG antibodies (type II hypersensitivity). Findings: hyperthyroidism, diffuse goiter, ophthalmopathy, pretibial myxedema. Labs: ↑T3/T4, ↓TSH, diffusely ↑ radioactive iodine uptake. Treat with methimazole or PTU, β-blockers, RAI, or surgery. - **T3 toxicosis:** isolated ↑T3 with normal T4, seen in early Graves disease or toxic nodules. - **Hypothyroidism:** Hashimoto thyroiditis (anti-TPO, antithyroglobulin antibodies) causes fatigue, cold intolerance, weight gain, constipation, bradycardia, and myxedema. Labs: ↑TSH, ↓T4. Treat with levothyroxine (T4). - **Thyroid storm:** treat with β-blocker (propranolol also reduces T4 → T3 conversion), PTU (also blocks peripheral conversion), then iodide (Wolff-Chaikoff effect), and glucocorticoids. - **Drugs:** - PTU blocks TPO and peripheral 5'-deiodinase. Methimazole blocks TPO only. - Amiodarone, glucocorticoids, and propranolol inhibit peripheral T4 → T3 conversion. - Liothyronine is synthetic T3, used in myxedema coma or short-term in thyroid cancer preparation, because it has a rapid onset. - **Lab interpretation:** TSH is the best initial screen. Free T4 confirms. Resin T3 uptake is an indirect test of binding protein availability.

**High-yield pearls:** - T4 is the main secreted form (a prohormone). T3 is the active form. - T3 and T4 are iodinated amino acids derived from tyrosine, but unlike other amine hormones they act via nuclear receptors (like steroids). - Thyroid hormones require TBG for transport, and TBG levels change total hormone but not free hormone.