ANATOMY AND HISTOLOGY OF THE THYROID GLAND

The thyroid gland is composed of a right lobe and a left lobe that sit anterolateral to the trachea (Fig. 41-1). Normally, the lobes of the thyroid gland are connected by a midventral isthmus. The thyroid gland receives a rich blood supply. It is drained by three sets of veins on each side: the superior, middle, and inferior thyroid veins. The thyroid gland receives sympathetic innervation that is vasomotor but not secretomotor.

Figure 41-1 A and B, Anatomy of the thyroid gland. C, Image of pertechnetate uptake by a normal thyroid gland.

(Modified from Drake RL et al: Gray’s Anatomy for Students. Philadelphia, Churchill Livingstone, 2005.)

The functional unit of the thyroid gland is the thyroid follicle, a spherical structure about 200 to 300 μm in diameter that is surrounded by a single layer of thyroid epithelial cells (Fig. 41-2). The epithelium sits on a basal lamina, the outermost structure of the follicle, and is surrounded by a rich capillary supply. The apical side of the follicular epithelium faces the lumen of the follicle. The follicular lumen itself is filled with colloid, which is composed of thyroglobulin; thyroglobulin is secreted and iodinated by the thyroid epithelial cells. The size of the epithelial cells and the amount of colloid are dynamic features that change with activity of the gland. The thyroid gland contains another type of cell in addition to follicular cells. Scattered within the gland are parafollicular cells called C cells. These cells are the source of the polypeptide hormone calcitonin, which is discussed in Chapter 39.

Figure 41-2 Histology of the thyroid gland at low (upper panel) and high (lower panel) magnification. C, colloid; F, thyroid follicles; S, connective tissue septa.

(From Young B et al: Wheater’s Functional Histology, 5th ed. Philadelphia, Churchill Livingstone, 2006.)

PRODUCTION OF THYROID HORMONES

The secretory products of the thyroid gland are iodothyronines (Fig. 41-3), a class of hormones formed by the coupling of two iodinated tyrosine molecules. Approximately 90% of the thyroid’s output is 3,5,3′,5′ -tetraiodothyronine (thyroxine, or T₄). T₄ is primarily a prohormone. About 10% is 3,5,3′ -triiodothyronine (T₃), which is the active form of thyroid hormone. Less than 1% of thyroid output is 3,3′,5′ -triiodothyronine (reverse T₃, or rT₃), which is inactive. Normally, these three hormones are secreted in the same proportions as they are stored in the gland.

Figure 41-3 Structure of the iodothyronines T₄, T₃, and reverse T₃.

Because the primary product of the thyroid gland is T₄, yet the active form of thyroid hormone is T₃, the thyroid axis relies heavily on peripheral conversion through the action of thyronine-specific deiodinases (Fig. 41-3). Most conversion of T₄ to T₃ by type 1 deiodinase occurs in tissues with high blood flow and rapid exchanges with plasma, such as the liver, kidneys, and skeletal muscle. This process supplies circulating T₃ for uptake by other tissues in which local T₃ generation is too low to provide sufficient thyroid hormone. Type 1 deiodinase is also expressed in the thyroid (again, where T₄ is abundant) and has relatively low affinity (i.e., a K_m of 1 μM) for T₄. Levels of type 1 deiodinase are paradoxically increased in hyperthyroidism and contribute to the elevated circulating T₃ levels in this disease.

The brain maintains constant intracellular levels of T₃ by a high-affinity deiodinase called type 2 deiodinase that is expressed in glial cells in the central nervous system. Type 2 deiodinase has a K_m of 1 nM and maintains intracellular concentrations of T₃ even when free T₄ falls to low levels. Type 2 deiodinase is also present in the thyrotropes of the pituitary. In the pituitary, type 2 deiodinase acts as a “thyroid axis sensor” that mediates the ability of circulating T₄ to feed back on secretion of thyroid-stimulating hormone (TSH) (see later). Expression of type 2 deiodinase is increased during hypothyroidism, which helps maintain constant T₃ levels in the brain.

There is also an “inactivating” deiodinase called type 3 deiodinase. Type 3 deiodinase is a high-affinity, inner ring deiodinase that converts T₄ to the inactive rT₃. Type 3 deiodinase is increased during hyperthyroidism, which helps blunt the overproduction of T₄. All forms of iodothyronines are eventually further deiodinated to noniodinated thyronine.

Iodide Balance

Because of the unique role of iodide in thyroid physiology, a description of thyroid hormone synthesis requires some understanding of iodide turnover (Fig. 41-4). An average of 400 μg of iodide per person is ingested daily in the United States versus a minimum daily requirement of 150 μg for adults, 90 to 120 μg for children, and 200 μg for pregnant women. In the steady state, virtually the same amount, 400 μg, is excreted in urine. Iodide is actively concentrated in the thyroid gland, salivary glands, gastric glands, lacrimal glands, mammary glands, and choroid plexus. About 70 to 80 μg of iodide is taken up daily by the thyroid gland from a circulating pool that contains approximately 250 to 750 μg of iodide. The total iodide content of the thyroid gland averages 7500 μg, virtually all of which is in the form of iodothyronines. In the steady state, 70 to 80 μg of iodide, or about 1% of the total, is released from the gland daily. Of this amount, 75% is secreted as thyroid hormone and the remainder as free iodide. The large ratio (100 : 1) of iodide stored in the form of hormone to the amount turned over daily protects the individual from the effects of iodide deficiency for about 2 months. Iodide is also conserved by a marked reduction in the renal excretion of iodide as its concentration in serum falls.

Figure 41-4 Iodine distribution and turnover in humans. HI = hormone-associated iodine.

Overview of Thyroid Hormone Synthesis

To understand thyroid hormone synthesis and secretion, one must appreciate the directionality of each process as it relates to the polarized thyroid epithelial cell (Fig. 41-5). Synthesis of thyroid hormone requires two precursors: iodide and thyroglobulin. Iodide is transported across cells from the basal (vascular) side to the apical (follicular luminal) side of the thyroid epithelium. Amino acids are assembled by translation into thyroglobulin, which is then secreted from the apical membrane into the follicular lumen. Thus, synthesis involves a basal-to-apical movement of precursors into the follicular lumen (Fig. 41-5, blue arrows). Actual synthesis of iodothyronines occurs enzymatically in the follicular lumen close to the apical membrane of the epithelial cells (see later). Secretion involves receptor-mediated endocytosis of iodinated thyroglobulin and apical-to-basal movement of the endocytic vesicles and their fusion with lysosomes. Thyroglobulin is then enzymatically degraded, which results in the release of thyroid hormones from the thyroglobulin peptide backbone. Finally, thyroid hormones move across the basolateral membrane, probably through a specific transporter, and ultimately into blood. Thus, secretion involves apical-to-basal movement (Fig. 41-5, red arrows). There are also scavenger pathways within the epithelial cell that reuse iodine and amino acids after enzymatic digestion of thyroglobulin (Fig. 41-5, white arrows).

Figure 41-5 Synthesis (blue arrows) and secretion (red arrows) of thyroid hormones by the thyroid epithelial cell. White arrows denote pathways involved in the conservation of iodine and amino acids.

Synthesis of Iodothyronines within a Thyroglobulin Backbone

Iodide is actively transported into the gland against chemical and electrical gradients by a 2Na⁺-1I⁻ symporter) (NIS) located in the basolateral membrane of thyroid epithelial cells. Normally, a thyroid-plasma free iodide ratio of 30 is maintained. This so-called iodide trap requires the generation of energy by oxidative phosphorylation and displays saturation kinetics. NIS is highly expressed in the thyroid gland, but it is also expressed at lower levels in the placenta, salivary glands, and actively lactating breast. One iodide ion is transported uphill against an iodide gradient while two sodium ions move down the electrochemical gradient from extracellular fluid into the thyroid cell. The energy source for this secondary active transporter is provided by Na⁺,K⁺-ATPase in the plasma membrane. Expression of the NIS gene is inhibited by iodide and stimulated by TSH. Numerous inflammatory cytokines also suppress NIS gene expression. A reduction in dietary iodide intake depletes the circulating iodide pool and greatly enhances the activity of the iodide trap. When dietary iodide intake is low, the percentage of thyroid uptake of iodide can reach 80% to 90%.

The steps in thyroid hormone synthesis are shown in Figure 41-6. After entering the gland, iodide rapidly moves to the apical plasma membrane of epithelial cells. From there, iodide is transported into the lumen of the follicles by a sodium-independent iodide/chloride transporter named pendrin. Iodide is immediately oxidized to iodine and incorporated into tyrosine molecules (Fig. 41-5). The iodinated tyrosine molecules are not free in solution (Fig. 41-6) but are incorporated by peptide linkages within the protein thyroglobulin. Thyroglobulin is continually exocytosed into the follicular lumen and is iodinated to form both monoiodotyrosine (MIT) and diiodotyrosine (DIT) (see Fig. 41-6). After iodination, two DIT molecules are coupled to form T₄, or one MIT molecule and one DIT molecule are coupled to form T₃. Coupling also occurs between iodinated tyrosines that remain part of the primary structure of thyroglobulin. This entire sequence of reactions is catalyzed by thyroid peroxidase (TPO), an enzyme complex that spans the apical membrane. The immediate oxidant (electron acceptor) for the reaction is hydrogen peroxide (H₂O₂). The mechanism whereby H₂O₂ is generated in the thyroid gland involves NADPH oxidase, which is also localized to the apical membrane.

Figure 41-6 Reactions involved in the generation of iodide, MIT, DIT, T₃, and T₄.

When the availability of iodide is restricted, the formation of T₃ is favored. Because T₃ is three times as potent as T₄, this response provides more active hormone per molecule of organified iodide. The proportion of T₃ is also increased when the gland is hyperstimulated by TSH or other activators.

Secretion of Thyroid Hormones

Once thyroglobulin has been iodinated, it is stored in the lumen of the follicle as colloid (Fig. 41-2). Release of T₄ and T₃ into the bloodstream requires binding of thyroglobulin to the receptor megalin, followed by endocytosis and lysosomal degradation of thyroglobulin (Fig. 41-7; also see Fig. 41-5). Enzymatically released T₄ and T₃ then leave the basal side of the cell and enter the blood.

Figure 41-7 Before (A) and minutes after (B) rapid induction of thyroglobulin endocytosis by TSH.

(From Wollman SH et al: J Cell Biol 21:191, 1964.)

AT THE CELLULAR LEVEL

Several transporters mediate transport of thyroid hormones across cell membranes. Thyroid hormone transporters include sodium/taurocholate-cotransporting polypeptides (NCTPs), organic anion-transporting polypeptides (OATPs), L-type amino acid transporters (LATs), and the monocarboxylate transporters (MCTs). These transporters show specificity with respect to T₄ versus T₃ binding and cell-specific expression. Recently, mutations in MCT8 have been linked to human disease that may be due to an intracellular deficit of thyroid hormone, elevated T₃ levels, and severe psychomotor retardation.

The MIT and DIT molecules, which also are released during proteolysis of thyroglobulin, are rapidly deiodinated within the follicular cell by the enzyme intrathyroidal deiodinase (Fig. 41-5; white arrows). This deiodinase is specific for MIT and DIT and cannot utilize T₄ and T₃ as substrates. The iodide is then recycled into synthesis of T₄ and T₃. Amino acids from the digestion of thyroglobulin reenter the intrathyroidal amino acid pool and can be reused for protein synthesis (Fig. 41-5, white arrows). Only minor amounts of intact thyroglobulin leave the follicular cell under normal circumstances.

TRANSPORT AND METABOLISM OF THYROID HORMONES

Secreted T₄ and T₃ circulate in the bloodstream almost entirely bound to proteins. Normally, only about 0.03% of total plasma T₄ and 0.3% of total plasma T₃ exist in the free state (Table 41-1). Free T₃ is biologically active and mediates the effects of thyroid hormone on peripheral tissues, in addition to exerting negative feedback on the pituitary and hypothalamus (see later). The major binding protein is thyroxine-binding globulin (TBG). TBG is synthesized in the liver and binds one molecule of T₄ or T₃.

Table 41-1 Average Thyroid Hormone Turnover

IN THE CLINIC

Because of its ability to trap and incorporate iodine into thyroglobulin (called organification), the activity of the thyroid can be assessed by radioactive iodine uptake (RAIU). In this test a tracer dose of ¹²³I is administered and RAIU is measured by placing a gamma detector on the neck at 4 to 6 hours and at 24 hours. In the United States, where the diet is relatively rich in iodine, RAIU is about 15% after 6 hours and 25% after 24 hours (Fig. 41-8). Abnormally high RAIU (> 60%) after 24 hours indicates hyperthyroidism. Abnormally low RAIU (< 5%) after 24 hours indicates hypothyroidism. In individuals with extreme chronic stimulation of the thyroid (Graves’ disease-associated thyrotoxicosis), iodide is trapped, organified, and released as hormone very rapidly. In these cases of elevated turnover, 6-hour RAIU will be very high, but 24-hour RAIU will be lower (Fig. 41-8). A number of anions, such as thiocyanate (CNS⁻), perchlorate (HClO₄⁻), and pertechnetate (TcO₄⁻), are competitive or noncompetitive inhibitors of iodide transport via NIS. If iodide cannot be rapidly incorporated into tyrosine (organification defect) after its uptake by the cell, administration of one of these anions will, by blocking further iodide uptake, cause rapid release of iodide from the gland (Fig. 41-8). This release occurs as a result of the high thyroid-plasma concentration gradient.