Uptake of Iodide ++ Iodine ingested in the diet reaches the circulation in the form of iodide ion (I−). Normally, the I− concentration in the blood is very low (0.2–0.4 μg/dL; ~15–30 nM). The thyroid actively transports the ion via a specific membrane-bound protein, termed sodium iodide symporter (NIS) (Kogai and Brent, 2012; Portulano et al., 2014). As a result, the ratio of [I−]thyroid to [I−]plasma is usually between 20 and 50 and can exceed 100 when the gland is stimulated. Iodide transport is inhibited by a number of ions, such as thiocyanate and perchlorate. TSH stimulates NIS gene expression and promotes insertion of NIS protein into the membrane in a functional configuration. Thus, decreased stores of thyroid iodine enhance iodide uptake by increasing TSH, and the administration of iodide can reverse this situation by decreasing NIS protein expression. Iodine is accumulated by other tissues, including the salivary glands, gut, and lactating breast, and it is all mediated by a single NIS gene. Individuals with congenital NIS gene mutations have absent or defective iodine concentration in all tissues known to concentrate iodine. +++ Oxidation and Iodination ++ Transport of iodine from the thyroid follicular cell to the colloid is facilitated by the apical transporter pendrin. The oxidation of iodide to its active form is accomplished by thyroid peroxidase. The reaction results in the formation of monoiodotyrosine (MIT) and diiodotyrosine (DIT) residues in thyroglobulin, a process referred to as organification of iodine, just prior to its extracellular storage in the lumen of the thyroid follicle. +++ Formation of Thyroxine and Triiodothyronine From Iodotyrosines ++ The remaining synthetic step is the coupling of two DIT residues to form T4 or of an MIT and a DIT residue to form T3. These oxidative reactions also are catalyzed by thyroid peroxidase. Intrathyroidal and secreted T3 are also generated by the 5′-deiodination of T4. +++ Synthesis and Secretion of Thyroid Hormones ++ Because T4 and T3 are synthesized and stored within thyroglobulin, proteolysis is an important part of the secretory process. This process is initiated by endocytosis of colloid from the follicular lumen at the apical surface of the cell, with the participation of a thyroglobulin receptor, megalin. This “ingested” thyroglobulin appears as intracellular colloid droplets, which apparently fuse with lysosomes containing the requisite proteolytic enzymes. TSH enhances the degradation of thyroglobulin by increasing the activity of lysosomal thiol endopeptidases, which selectively cleave thyroglobulin, yielding hormone-containing intermediates that subsequently are processed by exopeptidases. The liberated hormones then exit the cell primarily as T4 along with some T3. The T3 secreted by the thyroid derives partly from T3 within mature thyroglobulin and partly from deiodination of T4 (Figure 47–3), which also occurs peripherally (Figure 47–4).

The thyroid gland produces two fundamentally different types of hormones. The thyroid follicle produces the iodothyronine hormones T4 and T3. The thyroid’s parafollicular cells produce calcitonin, a peptide with 32 amino acids, which is not an important endogenous hormone but can be useful as a therapeutic agent in hypercalcemia and osteoporosis (see Chapter 52). Figures 47–1 and 47–2 show the structures of the thyroid hormones and their pathways of synthesis, storage, and release.

second