Chain of Causation: Iodine Deficiency → Goitre

Step 1 — Iodine is deficient in the diet. Iodine is the essential substrate for attaching iodine atoms to thyroglobulin during thyroid hormone synthesis. Without iodine, the enzymatic iodination step (catalysed by thyroid peroxidase) cannot proceed.

Step 2 — T3 and T4 synthesis is impaired. The follicular cells of the thyroid cannot complete T3/T4 synthesis. Blood levels of T3/T4 begin to fall below normal.

Step 3 — Negative feedback is reduced. T3/T4 normally suppress TRH from the hypothalamus and TSH from the anterior pituitary. When T3/T4 fall, this negative feedback signal weakens.

Step 4 — TRH rises. The hypothalamus, sensing reduced negative feedback, secretes more TRH.

Step 5 — TSH rises (compensatory). Elevated TRH stimulates anterior pituitary thyrotrophs to secrete more TSH. TSH levels rise significantly.

Step 6 — TSH acts on the thyroid. TSH binds TSH receptors on thyroid follicular cells, stimulating:

• Uptake of more iodide (iodine trapping)
• Increased thyroglobulin synthesis
• Increased thyroid peroxidase activity
• Hypertrophy AND hyperplasia of follicular cells

Step 7 — Thyroid gland enlarges (goitre). Despite TSH's best efforts, iodine remains scarce. The gland cannot make adequate T3/T4, but the structural growth continues. The thyroid enlarges progressively = visible neck swelling (goitre).

Step 8 — Paradox: large gland, low hormone. The enlarged gland represents a failed attempt at compensation. This is why simple goitre = hypothyroid state with enlarged thyroid. The condition improves when iodine is supplemented.

Contrast with Graves' disease: In Graves', TSI (autoimmune antibodies) mimic TSH → autonomous T3/T4 overproduction → TSH suppressed → goitre (TSI-driven) + hyperthyroidism. Large gland + HIGH T4 = toxic goitre.