T4

**Synthesis (thyroid follicular cells):** 1. Iodide is taken up via the Na+/I− symporter (NIS), a secondary active transport process. 2. Pendrin moves iodide into the colloid. 3. Thyroid peroxidase (TPO) oxidizes iodide, iodinates tyrosine residues on thyroglobulin (organification) to form MIT and DIT, and couples them. MIT + DIT gives T3. DIT + DIT gives T4. 4. Thyroglobulin is endocytosed, and lysosomal proteases release T4 and T3 into the blood. - Propylthiouracil (PTU) and methimazole inhibit TPO (organification and coupling). PTU also inhibits peripheral 5'-deiodinase, so it blocks T4→T3 conversion. - The Wolff-Chaikoff effect is autoregulatory inhibition of thyroid hormone synthesis by a large iodine load. It is transient, and failure to escape it can cause hypothyroidism. Jod-Basedow is hyperthyroidism after iodine exposure in a patient with underlying nodular disease or iodine deficiency.

**Regulation:** - Hypothalamic TRH stimulates anterior pituitary TSH, which stimulates the thyroid to make T4 and T3. T4 and T3 provide negative feedback on the pituitary (and hypothalamus). - TSH is the best initial screening test for thyroid dysfunction (except central causes).

**Transport:** - >99% is protein-bound, mainly to thyroxine-binding globulin (TBG), plus transthyretin and albumin. Only free T4 is active and regulated. - Estrogen (pregnancy, OCPs) increases TBG, so total T4 rises but free T4 stays normal and the patient is euthyroid. - Androgens, glucocorticoids, and nephrotic syndrome (urinary loss) decrease TBG. Free T4 is again normal.

**Peripheral conversion:** - T4 is converted to T3 (about 4 times more potent, with higher receptor affinity) by 5'-deiodinase. T4 can also be converted to reverse T3 (inactive). - Reverse T3 production rises in severe illness (sick euthyroid, or low T3 syndrome). - Propranolol, glucocorticoids, and PTU inhibit this conversion. - T4 has a half-life of about 7 days, versus about 1 day for T3.

**Actions (via nuclear receptors, which alter gene transcription):** - Increase basal metabolic rate and Na+/K+-ATPase activity (increased O2 consumption and heat). - Increase β1-receptor expression in the heart (increased heart rate and contractility). - Support bone growth, CNS maturation (critical in fetal and neonatal life), and gluconeogenesis, glycogenolysis, and lipolysis. - Increase LDL receptor expression, so cholesterol falls in hyperthyroidism.

**Clinical correlations:** - Hypothyroidism has low T4 with high TSH in primary disease. The most common cause is Hashimoto thyroiditis (anti-TPO and antithyroglobulin antibodies) in iodine-sufficient areas. Features are fatigue, cold intolerance, weight gain, constipation, bradycardia, myxedema, and delayed reflex relaxation. Congenital hypothyroidism (cretinism) causes intellectual disability, macroglossia, and umbilical hernia. - Hyperthyroidism has high T4 with low TSH in primary disease. Causes include Graves disease (TSI antibodies, ophthalmopathy, pretibial myxedema), toxic multinodular goiter, and toxic adenoma. Features are heat intolerance, weight loss, tachycardia/AF, tremor, and diarrhea. - Central (secondary) hypothyroidism has low T4 with low or inappropriately normal TSH. - Subclinical hypothyroidism has high TSH with normal free T4. - Thyroid storm is treated with β-blocker (propranolol), PTU (preferred, since it blocks conversion), iodine (given after the thionamide), and steroids. - Levothyroxine (synthetic T4) is the treatment for hypothyroidism. Take it on an empty stomach, separate it from calcium, iron, and antacids, and monitor TSH. Needs increase in pregnancy. - Exogenous T4 (factitious thyrotoxicosis) causes high T4, low TSH, and low thyroglobulin. Struma ovarii has low radioactive iodine uptake in the neck. - Amiodarone is iodine-rich and inhibits 5'-deiodinase. It can cause either hypothyroidism or hyperthyroidism.

**Mnemonic:** T4 is the prohormone ("4 iodines"), and T3 is the active form ("3 is the one that does the work").