Thyroid Hormone Biosynthesis

The iodinated compounds in thyroid follicular cells (thyrocytes) are derived by enzymatic condensation of the iodinated tyrosyl residues in thyroglobulin (Fig. 42-1). Among these are the two major thyroid hormones, L-isomers of T₄ and T₃. All of the T₄ that is made is derived from the thyroid. In contrast, only a small fraction of the most biologically active form, T₃, is produced and released from the thyroid. Most T₃ is produced by peripheral tissues by removing an iodide from the outer ring of T₄ through the action of 5’-deiodinase.

FIGURE 42–1 Structures of tyrosine and its iodinated derivatives.

The synthesis and release of T₃ and T₄ are shown in Figure 42-2. Thyrocytes concentrate iodide from the circulation via a symporter present on their basolateral surface that admits Na⁺ down its electrochemical gradient. This sodium/iodide symporter, which is also present in salivary glands, breast, and stomach, can transport other anions, such as pertechnetate and perchlorate, which can competitively inhibit iodide transport. Once iodide enters the thyrocyte, it is transported to the follicular lumen by an anion transporter in the apical membrane termed pendrin. As iodide reaches the follicular lumen, it is oxidized by a mechanism involving thyroperoxidase, H₂O₂, and two reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. Activated iodide forms covalent links with specific tyrosyl residues on thyroglobulin (Tg), which is present in the follicular lumen, producing the thyroid hormone precursors monoiodotyrosine (MIT) and diiodotyrosine (DIT). This process is referred to as organification of iodide. MIT or DIT can donate their iodinated phenolic rings to acceptor iodotyrosyl residues on DIT in the Tg backbone and form an ether linkage with the acceptor phenolic ring to form T₄ and T₃ covalently bound to Tg. This process is called coupling. Iodinated Tg is transported to and stored associated with the apical membrane. When thyroid hormone is required, iodinated Tg is transported into follicular cells by endocytosis, where it undergoes proteolysis, releasing T₄ and T₃ into the circulation. MIT and DIT are deiodinated and reused.

FIGURE 42–2 Intrathyroidal synthesis and processing of thyroid hormones. (1) Iodide is taken up at the basolateral cell membrane and transported to the apical membrane. (2) Polypeptide chains of Tg are synthesized in the rough endoplasmic reticulum, and posttranslational modifications take place in the Golgi. (3) Newly formed Tg is transported to the cell surface in small apical vesicles (AV). (4) Within the follicular lumen, iodide is activated and iodinates tyrosyl residues on Tg, producing fully iodinated Tg containing MIT, DIT, T₄, and a small amount of T₃ (organification and coupling), which is stored as colloid in the follicular lumen. (5) Upon TSH stimulation, villi at the apical membrane engulf the colloid and endocytose the iodinated Tg as either colloid droplets (CD) or small vesicles (MPV). (6) Lysosomal proteolysis of the droplets or vesicles hydrolyzes Tg to release its iodinated amino acids and carbohydrates. (7) T₄ and T₃ are released into the circulation. (8) DIT and MIT are deiodinated, and the iodide and tyrosine are recycled.

If the circulating level of iodide is elevated persistently, it may cause the thyroid to overproduce thyroid hormone. Thyrocytes use several mechanisms to maintain iodide homeostasis to prevent hormone overproduction from occurring. Initially, high levels of iodide cause thyrocytes to shut down organification and coupling, an inhibitory response referred to as the Wolff-Chaikoff effect. With continued iodide elevations, this inhibitory effect diminishes. However, the activity of the sodium/iodide symporter decreases in response to elevated iodide levels, preventing overproduction of thyroid hormone. In some patients with thyroiditis or in the fetus, the thyroid does not escape from the Wolff-Chaikoff effect, and persistently high iodine levels can cause hypothyroidism, leading to goiter formation.

Hormone synthesis in thyrocytes is regulated by TSH released from the pituitary. If the circulating level of thyroid hormone is abnormally elevated, pituitary sensitivity to thyrotropin-releasing hormone (TRH) is reduced, causing decreased production of TSH. Pituitary portal blood also carries counter-regulatory compounds that inhibit TSH release (i.e., dopamine and somatostatin) (see Chapter 38).

If levels of circulating thyroid hormone are abnormally decreased, pituitary sensitivity to TRH is increased, which stimulates TSH secretion and ultimately increases the release thyroid hormone.

Thyroid Hormone Receptors

Thyroid hormones exert their major effects by binding to thyroid hormone receptors (TRs), members of the nuclear receptor superfamily (see Chapter 1). Two genes encode TRs, and each can be transcribed into alternatively spliced products. The relative proportions of each isoform expressed are developmentally dependent and tissue specific. TRs can homodimerize but are generally present as heterodimers, most commonly with the receptor for 9-cis-retinoic acid but also with other nuclear hormone receptors. TRs associate with DNA as part of a complex of transcription factors, even in the absence of thyroid hormone. When T₃ binds to its receptor, the interactions of the receptor with transcription corepressors and coactivators change, and local chromatin structure is modified by changes in histone acetylation. Binding of T₃ increases transcription of some genes and decreases the transcription of others. Thyroid hormones also regulate the processing of ribonucleic acid transcripts and the stability of specific messenger ribonucleic acids, and have other non-nuclear actions. Another potential regulatory process is the expression of the TR splice variant (TRα2), which interacts with thyroid hormone response elements but is not activated by T₃. Consequently, expression of TRα2 can reduce sensitivity to thyroid hormone.