Hormone Synthesis

A. Thyroid Hormone Synthesis

Thyroid hormone synthesis is a complex, multi-step process occurring within the thyroid follicular cells and the follicular lumen (colloid). It integrates iodine trapping, oxidation, and protein synthesis under the primary control of TSH.

1. Iodide Trapping:

Circulating iodide (I⁻) is actively transported from the plasma into the thyroid follicular cell against an electrochemical gradient.

• Transporter: This is mediated by the Sodium-Iodide Symporter (NIS) (gene: SLC5A5) located on the basolateral membrane.
• Stimulation: NIS activity is upregulated by TSH.

2. Transport and Oxidation (Iodination):

Iodide diffuses to the apical membrane, where it is transported into the follicular lumen (colloid) by the Pendrin transporter (SLC26A4).

• Enzyme: At the apical-colloid interface, Thyroperoxidase (TPO), a heme-containing enzyme, catalyzes the oxidation of iodide (I⁻) to reactive iodine (I⁰ or I⁺).
• Cofactor: This oxidation requires Hydrogen Peroxide (H₂O₂), which is generated by the apical membrane-bound DUOX2 (Dual Oxidase 2) and its maturation factor DUOXA2.

3. Organification (Iodination of Tyrosyl Residues):

Simultaneously, the follicular cell synthesizes Thyroglobulin (Tg), a large glycoprotein, which is exocytosed into the colloid.

• Process: The reactive iodine (I⁰) rapidly iodinates specific tyrosyl residues on the massive Tg molecule.
• Products: This TPO-catalyzed reaction forms Monoiodotyrosine (MIT) and Diiodotyrosine (DIT), still attached to the Tg backbone.

4. Coupling (Iodotyrosine Coupling):

TPO further catalyzes the coupling of these iodotyrosines within the Tg molecule.

• T₄ Synthesis: DIT + DIT ⟶ Thyroxine (T₄)
• T₃ Synthesis: MIT + DIT ⟶ Triiodothyronine (T₃)
• Note: More T₄ is synthesized than T₃ (ratio approx. 10-20:1).

5. Storage and Release:

The iodinated Tg (colloid) is stored in the follicular lumen.

• Endocytosis: Upon TSH stimulation, colloid droplets are endocytosed back into the follicular cell.
• Proteolysis: These endosomes fuse with lysosomes. Lysosomal proteases (e.g., Cathepsins) cleave T₄, T₃, MIT, and DIT from the Tg backbone.
• Release: The "free" hormones, T₄ and T₃, are lipophilic and exit the cell at the basolateral membrane (e.g., via MCT8 transporter) into the bloodstream, where they bind to transport proteins (TBG, transthyretin, albumin).

6. Deiodination (Iodide Recycling):

The metabolically inactive byproducts, MIT and DIT, are salvaged within the follicular cell.

• Enzyme: Iodotyrosine Deiodinase (DEHAL1 or IYD) removes iodine from MIT and DIT.
• Recycling: This "salvaged" iodide re-enters the intracellular iodide pool for reuse, conserving the body's iodine stores.

B. Derangements of Thyroid Hormone Synthesis

Derangements in synthesis are known as Dyshormonogenesis. These are a group of autosomal recessive inborn errors of metabolism, each affecting a specific step in the synthesis pathway. They account for 10-15% of permanent congenital hypothyroidism (CH) and typically present with goitrous hypothyroidism.

Types of Dyshormonogenesis (Classified by Defective Step):

1. Iodide Trapping Defect:

• Defect: Mutation in the SLC5A5 (NIS) gene.
• Features: CH with goiter. Diagnosis is confirmed by demonstrating absent or very low 123-Iodine uptake (RAIU) in the thyroid gland.

2. Organification and Coupling Defects (Most Common):

These defects result in the inability to incorporate iodine into thyroglobulin.

• TPO Defects: Mutations in the TPO gene are the most common cause of dyshormonogenesis. This causes a Total Organification Defect (TOD).
• H₂O₂ Generation Defect: Mutations in DUOX2 or DUOXA2 genes lead to insufficient H₂O₂ for TPO-mediated oxidation.
• Pendred Syndrome: Mutations in SLC26A4 (Pendrin) cause a partial organification defect associated with sensorineural deafness (often with Mondini dysplasia of the cochlea).
• Diagnostic Test: These defects are characterized by a Positive Perchlorate Discharge Test.
• Principle: Radioactive iodine (¹²³I) is given. After 1-2 hours (allowing trapping), perchlorate (a competitive inhibitor of NIS) is administered.
• Positive Result: In an organification defect, the trapped ¹²³I cannot be organified (bound to Tg) and is "washed out" of the gland by perchlorate. A discharge of >10-15% of the trapped iodine is diagnostic.

3. Thyroglobulin (Tg) Synthesis Defect:

• Defect: Mutations in the TG gene.
• Features: Impaired synthesis or transport of Tg. Leads to CH with goiter.
• Diagnostic Clue: Serum Tg levels are very low or undetectable (in contrast to other dyshormonogenesis types where Tg is often high).

4. Deiodinase (Dehalogenase) Defect:

• Defect: Mutations in the DEHAL1 (or IYD) gene (Iodotyrosine deiodinase).\
• Mechanism: Inability to recycle iodide from MIT and DIT. These iodotyrosines leak from the cell and are lost in the urine, causing significant iodide wasting.
• Features: Goitrous CH. Requires high iodine intake for compensation.