Thyroid Hormone Production, Metabolism, and Storage
Thyroid hormones are primarily produced in the thyroid gland, converted in the liver and other peripheral tissues, stored in the thyroid follicular lumen, and broken down through multiple pathways including deiodination, sulfation, and glucuronidation.
Production of Thyroid Hormones
The thyroid gland is a butterfly-shaped organ located in the front of the neck just above the trachea, weighing approximately 15-20g in adults 1.
Thyroid hormone production is primarily regulated by thyroid stimulating hormone (TSH) from the pituitary gland, which controls multiple aspects of thyroid hormone synthesis including iodide uptake, activation of thyroid peroxidase enzyme, and regulation of oxidation and organification of iodide 2.
The synthesis of thyroid hormones crucially involves thyroglobulin, an iodoglycoprotein that serves as the precursor for T3 and T4 formation 3.
Within the thyroid follicular lumen, tyrosine residues in thyroglobulin become iodinated to form mono-iodotyrosine (MIT) and di-iodotyrosine (DIT), which then couple to form T3 and T4 3:
- T4 formation involves coupling between two DIT side chains
- T3 formation involves coupling between an MIT donor and a DIT acceptor
Adequate iodine intake (150 μg/day in adults) is essential for proper thyroid hormone synthesis 2.
Storage of Thyroid Hormones
Thyroid hormones are stored as thyroglobulin in the thyroid follicular lumen through a process of extracellular phase separation 4.
Thyroglobulin undergoes ionic strength-dependent phase separation, forming liquid-like condensates that age over time into gel-like high-density storage depots 4.
This storage mechanism follows a "last-come-first-served" process, providing organizational specificity without requiring membrane-mediated confinement 4.
Spherical globules of thyroglobulin protein dense phase are present in the follicular lumen of mouse and human thyroid follicles, consistent with phase separation 4.
Conversion of Thyroid Hormones
The liver is the primary site where T4 (thyroxine) is converted to T3 (triiodothyronine), the more active form of thyroid hormone 5.
This conversion is catalyzed primarily by type 1 5'-deiodinase (DIO1), a selenoenzyme that requires selenium as a cofactor 5.
The conversion process involves monodeiodination, is ATP-dependent, and is essential for normal thyroid hormone action since T3 is the major active form 5.
Nutritional factors affect the conversion process:
Breakdown of Thyroid Hormones
Thyroid hormones are metabolized through several pathways 6:
Deiodination: The primary pathway of thyroid hormone metabolism, which can lead to either activation (T4 to T3 conversion) or inactivation 6.
Sulfation: This pathway primarily leads to deactivation of thyroid hormones and facilitates deiodination 6.
Glucuronidation: This process increases water solubility of thyroid hormones, facilitating their excretion through bile and urine 6.
Ether-link cleavage: An alternative pathway for thyroid hormone metabolism 6.
Clinical Significance
The peripheral conversion of T4 to T3 is essential for normal thyroid hormone action, as T3 is the major active form 5.
Thyroid hormones influence basal metabolic processes, enhance oxygen consumption in nearly all body tissues, and affect linear growth, brain function, neural development, dentition, and bone development 1.
Thyroid dysfunction can manifest as hypothyroidism (insufficient thyroid hormone production) or hyperthyroidism (excess thyroid hormone production), both of which significantly impact metabolism 2.
TSH levels alone are not a sensitive indicator of iodine status, as concentrations are usually maintained within normal range despite frank iodine deficiency 2.