Hypothalamic-pituitary-thyroid axis

• Hypothalamus → thyrotropin releasing hormone (TRH)
• Pituitary → thyroid stimulating hormone (TSH)
• Thyroid → T3, T4

Thyroid hormone synthesis

1. Plasma iodide enters thyroid follicular cells via sodium iodine (NaI) cotransporter via secondary active transport.
2. Within the cell, thyroperoxidase (TPO) oxidizes iodide to either atomic iodine (I) or iodinium (I⁺).
3. Oxidized iodine species bind tyrosine residues of thyroglobulin, the major protein of thyroid colloid.
   • Tyrosine + a single iodine atom: monoiodotyrosine (MIT)
   • Tyrosine + two iodine atoms: diiodotyrosine (DIT)
4. MIT and DIT combine:
   • MIT + DIT: triiodothyronine (T3)
   • DIT + DIT: tetraiodothyronine (T4, also called thyroxine)
   • DIT + MIT: reverse T3 (rT3, which is biologically inactive)
5. Proteases digest release thyroglobulin, releasing the active hormones T3 and T4 into the bloodstream.
6. Peripherally, 5'-deiodinase converts T4 to the more active T3.

Pharmacology

Pathology

Hashimoto's thyroiditis

Most common cause of primary hypothyroidism in the US, F > M. Autoimmune, demonstrating lymphocytic infiltration microscopically. Associated with HLA-DR5. Clinical course may begin with hyperthyroidism resulting from thyroid destruction and release of thyroid hormone; ultimately results in hypothyroidism (fatigue, cold intolerance, weight gain, constipation, fragile hair, dry skin). Treated with hormone replacement (T4, levothyroxine).

Graves' disease

Most common cause of hyperthyroidism in US, F > M. Autoimmune, resulting from autoantibody stimulating the TSH receptor on thyroid follicular cells. Results in hyperthyroidism (heat intolerance, tachycardia, weight loss, diarrhea, hair/skin changes), frequently a diffuse goiter, and characteristic pretibial myxedema, retroorbital fibrosis, and exophthalmos. Treated with antithyroid drugs (propylthiouracil, methimazole, radioactive iodine). Exophthalmos is irreversible despite treatment.