Iodination of thyroglobulin. One or two iodine atoms are then added to the specific tyrosine residues of thyroglobulin. This process occurs in the colloid at the microvillar surface of the follicular cells and is also catalyzed by thyroid peroxidase (TPO). Addition of one iodine atom to a single tyrosine residue forms monoiodotyrosine (MIT). Addition of a second iodine atom to the MIT residue forms a diiodotyrosine (DIT) residue.
4.
Formation of T3 and T4 by oxidative coupling reactions. The thyroid hormones are formed by oxidative coupling reactions of two iodinated tyrosine residues in close proximity. For example, when neighboring DIT and MIT residues undergo a coupling reaction, T3 is formed; when two DIT residues react with each other, T4 is formed. After iodination, T4 and T3 as well as the DIT and MIT residues that are still linked to a thyroglobulin molecule are stored as the colloid within the lumen of the follicle.
5. Resorption of colloid. In response to TSH, follicular cells take up thyroglobulin from the colloid by a process of  receptor-mediated endocytosis. After endocytosis, thyroglobulin follows at least two different intracellular pathways. In the lysosomal pathway, thyreoglobulin is internalized and transported within endocytotic vesicles to early endosomes. They eventually mature into lysosomes or fuse with existing lysosomes. Resorption of thyroglobulin at this stage can be confirmed by the presence of large endocytic vesicles called colloidal resorption droplets in the apical region of the follicular cells. Thyroglobulin is then degraded by lysosomal proteases into constituent amino acids and carbohydrates, leaving free T4, T3, DIT, and MIT molecules (see 5L labeled pathway in Fig 21.16). Under physiological condition, this is a major pathway of colloid resorption.
 In the transepithelial pathway, thyroglobulin is transported intact from the apical to the basolateral surface of follicular cells. To enter this pathway thyroglobulin binds to its receptor megalin, a 330-kilodalton member of the LDL endocytic receptor family. Megalin is a transmembrane protein expressed at the apical surface of follicular epithelial cells directly facing colloid. Thyreoglobulin internalized by megalin avoids the lysosomal pathway and endocytic vesicles are delivered to the basolateral membrane of follicular cells (see 5TE labeled pathway in Fig 21.16). In pathologic conditions of high TSH or TSH-like stimulation, megalin expression is increased and large amounts of thyroglobulin follow the transepithelial pathway. This pathway may reduce the extent of T4 and T3 release by diverting thyroglobulin away from the lysosomal pathway.
Patients with Graves’ and other thyroid diseases have detectable amounts of circulating thyroglobulin that contains portion of megalin receptor.
If the levels of TSH remain high, the amount of colloid in the follicle is reduced because it is synthesized, secreted, iodinated, and resorbed too rapidly to accumulate.