How are thyroid hormones made — the big picture?
Thyroid hormones are iodinated derivatives of tyrosine, but the tyrosines are never free — they are residues within thyroglobulin (Tg), a 660 kDa glycoprotein secreted into the follicular lumen and stored as colloid. Synthesis depends on three things: iodide supply, TSH stimulation and tyrosine residues on thyroglobulin. The reactions happen at the apical (colloid) surface of the follicular cell (thyrocyte).
- Trapping — iodide enters across the basolateral membrane through the sodium-iodide symporter (NIS).
- Transport to colloid — pendrin, an apical Cl−/I− exchanger, moves iodide into the follicular lumen.
- Oxidation — thyroid peroxidase (TPO) uses H2O2 (made by the apical NADPH oxidase DUOX2) to oxidise iodide.
- Organification — TPO attaches iodine to tyrosine residues of thyroglobulin → MIT and DIT.
- Coupling — TPO joins MIT + DIT → T3 and DIT + DIT → T4, still within thyroglobulin.
- Storage — iodinated thyroglobulin is stored in the colloid.
- Release — thyroglobulin is endocytosed, digested in lysosomes, and T4 and T3 leave the cell (via the MCT8 transporter); free MIT and DIT are deiodinated so the iodide can be reused.
How does the thyroid trap iodide?
The NIS on the basolateral membrane is a secondary active transporter: it couples the inward movement of Na+ down its electrochemical gradient (maintained by the Na+/K+-ATPase) to the inward movement of iodide against its gradient. The normal thyroid keeps free iodide 20 to 50 times higher than plasma; in Graves disease the ratio can exceed 100:1.
- Other tissues with NIS — salivary glands, gastric mucosa, lactating breast and choroid plexus also concentrate iodide. Breast NIS transfers iodide into milk.
- Competitive inhibitors — thiocyanate and perchlorate block iodide transport in the thyroid, salivary glands and stomach.
- TSH increases iodide uptake; NIS expression is increased in Graves disease and hyperfunctioning nodules and decreased in adenomas and carcinomas, which appear as cold nodules on scintigraphy.
- Pendrin (apical) — mutations cause Pendred syndrome: sensorineural deafness with goitre.
What does thyroid peroxidase do?
Thyroid peroxidase (TPO) sits on the apical membrane with its catalytic heme site facing the colloid. It needs hydrogen peroxide, supplied by DUOX2 (a thyroid NADPH oxidase), and catalyses three linked reactions.
| Step | Reaction | Product |
|---|---|---|
| Oxidation | Iodide (I−) is oxidised using H2O2 | Reactive iodine |
| Organification (iodination) | Iodine added to tyrosine residues on thyroglobulin | MIT (1 iodine) and DIT (2 iodines) |
| Coupling | Two iodotyrosines joined by an ether bond within thyroglobulin | MIT + DIT → T3; DIT + DIT → T4 |
- Iodine supply changes the mix — more iodine increases DIT/MIT and T4/T3 ratios; iodine deficiency lowers them (relatively more T3).
- TPO mutations — congenital hypothyroidism with an iodide organification defect.
- DUOX2 mutations — no H2O2 → congenital hypothyroidism.
- Anti-TPO antibodies (the old 'anti-microsomal' antibodies) are present in Hashimoto thyroiditis.
How are T3 and T4 stored and released?
Hormone is stored pre-formed within thyroglobulin in the colloid, where thyroglobulin reaches very high concentrations (200–300 g/L). On TSH stimulation, thyrocytes take up colloid by endocytosis; lysosomes fuse with the endosome and proteases cleave thyroglobulin into MIT, DIT, T3 and T4.
- T4 and T3 are released into the fenestrated capillaries through the MCT8 transporter. StatPearls gives the secreted output as roughly 80% T4 and 20% T3.
- MIT and DIT are not secreted; iodotyrosine deiodinase (DEHAL1) strips their iodine for reuse. DEHAL1 defects cause iodide loss and hypothyroidism.
- MCT8 deficiency is X-linked and presents in boys with high serum T3 and low reverse T3.
- In blood, over 99% of thyroid hormone is protein-bound — to thyroxine-binding globulin (TBG), transthyretin and albumin. TBG carries about two-thirds of T4.
What are the deiodinases (D1, D2, D3)?
| Enzyme | Main sites | Reaction | Net effect |
|---|---|---|---|
| Type 1 (DIO1) | Liver, kidney, muscle, thyroid | T4 → T3 | Activation |
| Type 2 (DIO2) | Liver, kidney, muscle, thyroid | T4 → T3 | Activation; major source of peripheral T3 |
| Type 3 (DIO3) | CNS and placenta | T4 → reverse T3 (rT3) | Inactivation |
Reverse T3 is inactive. Peripheral conversion of T4 to T3 is reduced by several agents used in thyroid storm: PTU, glucocorticoids, propranolol and iodinated contrast agents.
What are the Wolff-Chaikoff and Jod-Basedow effects?
| Effect | What happens | Mechanism | Typical setting |
|---|---|---|---|
| Wolff-Chaikoff effect | Excess iodide acutely inhibits hormone synthesis | Excess iodide inhibits H2O2 generation, blocking thyroglobulin iodination (organification) | Seen with iodide therapy; described in patients with autoimmune thyroiditis, where it can cause hypothyroidism |
| Escape from Wolff-Chaikoff | Normal glands resume synthesis despite continued iodide | NIS expression falls, reducing iodide entry so intracellular iodide drops | Explains why iodide's effect is temporary |
| Jod-Basedow effect | Iodine load induces hyperthyroidism | Glands already prone to overactivity make excess hormone once iodine is supplied | Graves disease, toxic multinodular goitre or toxic adenoma exposed to dietary iodine, contrast media or amiodarone |
Which drugs act at each step of synthesis?
| Step blocked | Drug | Key exam point |
|---|---|---|
| Iodide trapping (NIS) | Perchlorate, thiocyanate | Competitive inhibitors; also act on salivary and gastric NIS |
| Oxidation, organification, coupling (TPO) | Methimazole, carbimazole, propylthiouracil (thionamides) | Carbimazole is a prodrug of methimazole |
| Peripheral T4 → T3 | PTU, glucocorticoids, propranolol, iodinated contrast | PTU is favoured in thyroid storm for this small additional effect |
| Release of stored hormone | Iodide (SSKI — supersaturated potassium iodide) | Give at least an hour after a thionamide so the iodide load is not used to make more hormone |
| Gland destruction | Radioactive iodine (I-131) | Definitive therapy; hypothyroidism is common long term (about 60% at 20 years after I-131 for hyperfunctioning nodules) |
| Feature | Propylthiouracil (PTU) | Methimazole / carbimazole |
|---|---|---|
| Inhibits TPO | Yes | Yes |
| Inhibits peripheral T4 → T3 | Yes (small additional effect) | Not listed among conversion blockers |
| Pregnancy | Preferred in the first trimester | Preferred in the second and third trimesters (fetal anomalies in the first) |
| Signature toxicity | Hepatotoxicity; ANCA-associated vasculitis | Teratogenicity in early pregnancy |
| Shared serious risk | Agranulocytosis — sore throat or fever needs an urgent count | Agranulocytosis, usually in the first 3 months |
What happens when a step of synthesis fails?
Each step has a matching inherited defect, grouped as thyroid dyshormonogenesis — a cause of goitrous congenital hypothyroidism. The gland enlarges because low hormone output raises TSH, which keeps stimulating growth. The same logic explains iodine-deficiency goitre: inadequate iodine → inadequate hormone → increased TSH secretion → goitre as the gland tries to compensate.
| Step | Defective protein | Clue |
|---|---|---|
| Trapping | NIS (commonest mutation T354P) | Iodide transport defect — the gland cannot concentrate iodide |
| Transport to colloid | Pendrin | Pendred syndrome — sensorineural deafness with goitre; thyroid effect often mild |
| H2O2 supply | DUOX2 / DUOX maturation factor | Congenital hypothyroidism, permanent or transient; positive perchlorate discharge |
| Organification | TPO (more than 60 mutations described) | Total organification defect → severe permanent hypothyroidism |
| Iodide recycling | Iodotyrosine deiodinase (DEHAL1) | Iodide from MIT and DIT is not reclaimed for reuse → hypothyroidism |
| Hormone exit / cell entry | MCT8 | X-linked; high T3 with low reverse T3 |
What are the common exam traps?
- The central enzyme of synthesis is TPO — it does oxidation, organification and coupling.
- NIS is basolateral; pendrin and TPO are apical. Iodide entry into the cell is active; exit into the colloid is passive.
- T3 = MIT + DIT, T4 = DIT + DIT — never 'MIT + MIT'.
- Most T3 is made in the periphery, not secreted.
- Iodide blocks release (and acutely synthesis via Wolff-Chaikoff); thionamides block synthesis, not release of hormone already stored in the colloid.
- PTU in the first trimester, methimazole afterwards.
- Hormone in blood is over 99% protein-bound; only the small unbound (free) fraction is active. TBG carries about two-thirds of T4; transthyretin and albumin carry the rest.
- Salivary glands and stomach also trap iodide (they share NIS), which is why perchlorate and thiocyanate act there too — the thyroid, salivary glands and gastric mucosa share a common embryological origin from the primitive alimentary tract.