Thyroid Hormone Synthesis: Sequential Steps
Overview of the Biosynthetic Process
Thyroid hormone synthesis occurs through a highly coordinated sequence of steps within thyroid follicles, beginning with iodide uptake and culminating in the release of T4 and T3 into circulation. 1, 2
Step 1: Iodide Uptake (Basolateral Transport)
- Iodide is actively transported from the bloodstream into thyroid follicular cells (thyrocytes) via the sodium/iodide symporter (NIS) located on the basolateral plasma membrane 2, 3
- This process is TSH-regulated and represents the first critical step in concentrating iodine within the thyroid gland 4, 2
- The transport is ATP-dependent and moves iodide against its concentration gradient 3
Step 2: Iodide Efflux (Apical Transport)
- Iodide is then transported across the apical membrane into the follicular lumen, likely via pendrin (a chloride/iodide transporting protein) 3
- This apical efflux completes the transepithelial iodide transport and positions iodide at the site where thyroid hormone synthesis occurs 3
- Under physiological conditions, this transport occurs without intracellular iodination due to rapid degradation of hydrogen peroxide by cytosolic glutathione peroxidase 3
Step 3: Iodide Oxidation
- Iodide is oxidized to an active iodine species by thyroid peroxidase (TPO) at the apical plasma membrane 5, 2
- This oxidation requires hydrogen peroxide (H₂O₂) as an electron acceptor, which is generated at the apical cell surface 5, 3
- TPO enzyme activity is stimulated by TSH 4, 5
Step 4: Organification (Iodination of Thyroglobulin)
- Oxidized iodine is incorporated into tyrosyl residues of thyroglobulin (TG) to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) 5, 1, 2
- Thyroglobulin is a high molecular weight protein secreted by thyrocytes into the follicular lumen 2
- This iodination process occurs at the apical plasma membrane interface between the thyrocyte and follicular lumen 2, 3
- The reaction requires the interaction of iodide, thyroglobulin, hydrogen peroxide, and TPO 2
Step 5: Coupling Reaction
- MIT and DIT residues undergo oxidative coupling reactions on the thyroglobulin molecule to form thyroid hormones 5, 1
- T4 (thyroxine) is formed by coupling two DIT molecules 1
- T3 (triiodothyronine) is formed by coupling one MIT donor with one DIT acceptor 1
- These coupling reactions occur at selective tyrosine residues on thyroglobulin that lead to preferential hormone formation at distinct sites 1
- TSH regulates post-translational changes in thyroglobulin that selectively enhance T3 formation, particularly important during iodine deficiency 1
Step 6: Storage
- Iodinated thyroglobulin containing T4 and T3 is stored in the follicular lumen 1, 3
- This storage form contains not only thyroid hormones but also iodine incorporated in iodotyrosine residues (MIT and DIT) 3
Step 7: Endocytosis and Proteolysis
- Upon TSH stimulation, iodinated thyroglobulin is taken up from the follicular lumen into thyrocytes via pinocytosis 5
- The internalized thyroglobulin undergoes lysosomal degradation 5
- This process releases T4, T3, MIT, and DIT from the thyroglobulin backbone 5
Step 8: Deiodination and Iodide Recycling
- MIT and DIT are deiodinated intracellularly, and the released iodide is recycled back to participate in new thyroid hormone synthesis 3
- This iodide recycling mechanism is crucial for maintaining normal thyroid function, especially during periods of iodine deficiency 2, 3
Step 9: Hormone Secretion
- Free T4 and T3 are released from thyrocytes into the bloodstream through the basolateral membrane 5, 2
- T4 is the predominant hormone secreted by the thyroid gland 6
- This secretion process is stimulated by TSH 4, 5
Regulatory Control
- The entire synthesis process is under tonic control of thyroid-stimulating hormone (TSH) from the pituitary gland 4, 5, 2
- TSH regulates multiple steps including iodide uptake, TPO activation, oxidation and organification of iodide, and hormone secretion 4
- Production is also regulated by a negative feedback loop between serum T4/T3 levels and TSH 5
- Elevated intracellular iodine concentration can inhibit TPO and hydrogen peroxide formation, providing internal regulation 5
Essential Cofactors
- Adequate iodine intake is essential, with daily requirements of 150 μg/day in adults 4
- Selenium is required as a cofactor for deiodinase enzymes involved in iodide recycling and peripheral T4 to T3 conversion 4, 7
- Iron deficiency can impair thyroid metabolism 4, 7
Clinical Pitfalls
- In iodine deficiency, chronic TSH stimulation causes compensatory thyroid enlargement (goiter) as the gland attempts to maximize iodine uptake and recycling 4
- TSH levels may remain within normal range despite frank iodine deficiency, making TSH an insensitive indicator of iodine status 4
- Disruption of any step in this synthesis pathway can lead to thyroid hormone deficiency and clinical hypothyroidism 5
- 167 different mutations in the TG gene encoding thyroglobulin can lead to defective thyroid hormone synthesis, resulting in congenital hypothyroidism 1