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SHORT NOTE: Thyroid Hormone Synthesis, Release, and Antithyroid Drugs

(Guyton and Hall Textbook of Medical Physiology, 4th South Asia Edition - Chapter 77)

A. Thyroid Hormone Synthesis and Release

The thyroid gland consists of closed follicles (100-300 µm diameter) lined by cuboidal epithelial cells. The follicle lumen contains colloid, the major constituent of which is thyroglobulin - a large glycoprotein (MW ~335,000) carrying ~70 tyrosine residues that serve as the scaffold for hormone formation.

Steps of Synthesis (Enumerated)

Step 1 - Iodide Trapping (Active Transport) Iodide (I⁻) from the blood is actively pumped into the thyroid cell across the basolateral membrane by the Sodium-Iodide Symporter (NIS), co-transporting 1 I⁻ with 2 Na⁺. The energy comes from the Na⁺-K⁺ ATPase pump. This concentrates iodide to ~30× its plasma level (up to 250× when maximally stimulated by TSH). This is called iodide trapping.

Step 2 - Iodide Efflux into Follicle (Pendrin) Iodide is then transported out of the thyroid cell across the apical membrane into the follicular lumen by a Cl⁻/I⁻ counter-transporter called pendrin.

Step 3 - Thyroglobulin Synthesis and Secretion The thyroid cells synthesize thyroglobulin in the endoplasmic reticulum and Golgi apparatus, then secrete it into the follicular lumen as the colloid.

Step 4 - Oxidation of Iodide (I⁻ → I₂) At the apical membrane, the enzyme thyroid peroxidase (TPO) (using H₂O₂ as cofactor) oxidizes I⁻ to active iodine (nascent I⁰ or I₃⁻). This is essential - blocking peroxidase stops hormone formation entirely.

Step 5 - Organification (Iodination of Tyrosine) Active iodine binds to tyrosine residues within thyroglobulin, catalyzed by TPO. This produces:

MIT - Monoiodotyrosine (1 iodine atom)
DIT - Diiodotyrosine (2 iodine atoms)

Step 6 - Coupling Reaction TPO also catalyzes the coupling of iodinated tyrosines within the thyroglobulin molecule:

MIT + DIT → T₃ (triiodothyronine)
DIT + DIT → T₄ (thyroxine)

The iodinated thyroglobulin is then stored in the follicular colloid.

Step 7 - Release: Pinocytosis and Proteolysis When secretion is stimulated (by TSH):

The apical surface of follicular cells sends out pseudopod extensions that engulf colloid → pinocytic vesicles form.
Lysosomes fuse with these vesicles → proteases cleave thyroglobulin.
Free T₃ and T₄ diffuse through the base of the cell into surrounding capillaries.

Step 8 - Iodine Recycling MIT and DIT (which constitute ~75% of iodinated tyrosines) are not released into blood. Instead, a deiodinase enzyme cleaves iodine from them for recycling within the gland.

Secretion ratio: ~93% T₄, ~7% T₃ released; ~half of T₄ is peripherally deiodinated to T₃, which is the active form delivered to tissues.

Diagram (Fig. 77.2 - Guyton and Hall)

Figure 77.1 - Anatomy of the thyroid gland showing follicles, colloid, cuboidal epithelial cells, and C cells:

Anatomy and microscopic appearance of the thyroid gland showing follicles filled with colloid and lined by cuboidal epithelial cells

Figure 77.2 - Thyroid cellular mechanisms for iodine transport, T₃/T₄ formation and release (NIS, Pendrin, Peroxidase, Organification, Coupling, Pinocytosis, Proteolysis, Deiodination):

Thyroid cellular mechanisms showing NIS iodide transport, pendrin apical efflux, thyroglobulin synthesis in ER and Golgi, peroxidase-mediated iodination and coupling to form MIT, DIT, T3, T4, pinocytosis of colloid, and proteolytic release of T3 and T4 into capillaries

B. Antithyroid Drugs - Mechanism of Action

(Section: "Antithyroid Substances Suppress Thyroid Secretion" - Guyton & Hall, Ch. 77)

The three major classes of antithyroid drugs act at distinct steps:

1. Thiocyanate (and Perchlorate, Nitrate) - Block Iodide Trapping

The NIS pump that transports I⁻ also transports SCN⁻, ClO₄⁻, and NO₃⁻.
These ions competitively inhibit iodide transport - blocking the iodide-trapping mechanism.
Thyroglobulin synthesis continues but it cannot be iodinated → no thyroid hormones form.
Consequence: Low T₃/T₄ → increased TSH secretion (feedback) → goiter (thyroid enlargement without adequate hormone production).

2. Propylthiouracil (PTU), Methimazole, Carbimazole - Block Organification and Coupling

These thionamide drugs act by two mechanisms:
1. Inhibit thyroid peroxidase - blocking oxidation of iodide and therefore iodination of tyrosine.
2. Block the coupling reaction - prevent two iodinated tyrosines from joining to form T₃ or T₄.
Like thiocyanate, they do not prevent thyroglobulin synthesis.
Absence of T₃/T₄ leads to strong TSH feedback → goiter formation.
PTU additionally blocks peripheral conversion of T₄ → T₃ (by inhibiting deiodinase in peripheral tissues).

3. High-Concentration Iodides - Wolff-Chaikoff Effect

When plasma iodide is ~100× normal levels:
- Rate of iodide trapping decreases.
- Iodination of tyrosine is reduced.
- Most importantly, endocytosis of colloid is paralyzed → the first step of hormone release is blocked → rapid shutdown of thyroid secretion.
This is the Wolff-Chaikoff effect.
After days to weeks, the gland "escapes" by downregulating NIS expression → resumes normal function.
Unlike other antithyroid agents, high iodides decrease gland size and vascularity (opposite of goitrogenic drugs). This makes them useful for preoperative preparation (2-3 weeks before thyroidectomy) and treatment of thyroid storm.

Summary Table

Drug	Site of Action	Mechanism	Clinical Use
Thiocyanate/Perchlorate	NIS (basolateral)	Competitive inhibition of iodide trapping	Research; rarely clinical
PTU / Methimazole	Thyroid peroxidase	Blocks oxidation, organification, and coupling (PTU also blocks peripheral T₄→T₃)	Hyperthyroidism, Graves' disease
High-dose Iodides (Lugol's)	Colloid endocytosis + trapping	Wolff-Chaikoff effect; paralysis of colloid uptake	Pre-op thyroidectomy; thyroid storm

Reference: Guyton and Hall Textbook of Medical Physiology, 4th South Asia Edition, Chapter 77 - Thyroid Metabolic Hormones, pp. 930-933.

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