Thyroid anatomy and physiology

Figure 1.2 Possible sites of remnants of the thyroglossal duct.

Thyroid hormone synthesis

Figure 1.4 illustrates different steps in thyroid hormone synthesis:

Thyroglobulin is synthesized in the rough endoplasmic reticulum and is transported into the follicular lumen by exocytosis.
Iodide is transported into the thyroid follicular cells via a sodium–iodide symporter on the basolateral membrane of the follicular cells. Iodide transport requires oxidative metabolism.
Inside the follicular cells, iodide diffuses to the apical surface and is transported by pendrin (a membrane iodide–chloride transporter) into the follicular lumen.
Thyroid peroxidase (TPO) enzyme catalyzes the process of oxidation of the iodide to iodine and its binding (organification) to the tyrosine residues of thyroglobulin to form monoiodotyrosine (MIT) and diiodotyrosine (DIT).
DIT and MIT molecules are linked by TPO to form thyroxine (T₄) and triiodothyronine (T₃) in a process known as coupling.
Thyroglobulin containing T₄ and T₃ is resorbed into the follicular cells by endocytosis and is cleaved by lysosomal enzymes (proteases and peptidases) to release T₄ and T₃. T₄ and T₃ are then secreted into the circulation.
Uncoupled MIT and DIT are deiodinated, and the free tyrosine and iodide are recycled.

Figure 1.3 (a) A low-power histological image of thyroid tissue showing numerous follicles filled with colloid and lined by cuboidal epithelium. (b) A high-power view of follicles lined by cuboidal epithelium. (c) Thyroid follicles (lined by follicular cells), surrounding capillaries and parafollicular cells.

The thyroid gland stores T₄ and T₃ incorporated in thyroglobulin, and can therefore secrete T₄ and T₃ more quickly than if they had to be synthesized.

Extra-thyroidal T₃ production

T₄ is produced entirely by the thyroid gland. The production rate of T₄ is about 100 μg per day. However, only 20% of T₃ is produced directly by the thyroid gland (by coupling of MIT and DIT). Around 80% of T₃ is produced by the deiodination of T₄ in peripheral extra-thyroidal tissues (mainly liver and kidney). The total daily production rate of T₃ is about 35μg.

T₄ is converted to T₃ (the biologically active metabolite) by 5′-deiodination (outer-ring deiodination). 5′-Deiodination is mediated by deiodinases type 1 (D1) and type 2 (D2). D1 is the predominant deiodinating enzyme in the liver, kidney and thyroid. D2 is the predominant deiodinating enzyme in muscle, brain, pituitary, skin and placenta. Type 3 deiodinase (D3) catalyzes the conversion of T₃ to reverse T₃ (the inactive metabolite) by 5-deiodination (inner ring deiodination), as shown in Fig. 1.5.

Changes in T₃ concentration may indicate a change in the rate of peripheral conversion and may not be an accurate measure of the change in thyroid hormone production. For example, the rate of T₃ production (by 5′-deiodination of T₄) is reduced in acute illness and starvation.

Total and free T₄ and T₃

Approximately 99.97% of circulating T₄ and 99.7% of circulating T₃ are bound to plasma proteins: thyroid-binding globulin (TBG), transthyretin (also known as thyroid-binding pre-albumin), albumin and lipoproteins.

Figure 1.4 Steps in thyroid hormone synthesis. (1) Thyroglobulin (TG) is synthesized in the endoplasmic reticulum (ER) in the thyroid follicular cells and is transported into the follicular lumen. The small blue squares represent the amino acid residues comprising TG. (2) Iodide is transported into the follicular cell by the sodium–iodide (Na⁺/I⁻) symporter (NIS). (3) Iodide diffuses to the apical surface and is transported into the follicular lumen by pendrin (P). (4) Iodide is oxidized and linked to tyrosine residues in TG to form diiodotyrosine (DIT) and monoiodotyrosine (MIT) molecules. (5) Within the TG, T₄ is formed from two DIT molecules, and T₃ is formed from one DIT and one MIT molecule. (6) TG containing T₄ and T₃ is resorbed into the follicular cell by endocytosis. (7) TG is degraded by lysosomal enzymes to release T₄ and T₃ molecules, which move across the basolateral membrane of the follicular cell into the adjacent capillaries. TPO, thyroid peroxidase.