Development of the thyroid gland

The thyroid gland (Greek thyreos, shield; eidos, form) develops as a median endodermal downgrowth at the base of the tongue. A transient structure, the thyroglossal duct, connects the developing gland to its point of origin, the foramen cecum, at the back of the tongue.

The thyroglossal duct disappears completely, leaving the thyroid to develop as a ductless gland. Persistent thyroglossal duct tissue remnants may give rise to cysts.

The thyroid gland responds to thyroid-stimulating hormone (TSH) at about week 22 in the fetus. The congenital absence of the thyroid gland causes irreversible neurologic damage in the infant (cretinism).

The thyroid gland consists of two lobes connected by a narrow band of thyroid tissue called the isthmus.

The thyroid gland is located below the larynx and the lobes rest on the sides of the trachea. The larynx provides a convenient landmark for locating the thyroid gland. The thyroid gland is surrounded by a double connective tissue capsule. Two pairs of parathyroid glands are located on the posterior surface of the thyroid gland, between or outside the two capsules.

Histologic organization of the thyroid gland

Each lobe of the thyroid gland consists of numerous follicles. The thyroid follicle, or acinus, is the structural and functional unit of the gland. It consists of a single layer of cuboidal epithelial cells, the follicular epithelium (Figures 19-1 and 19-2), enclosing a central lumen containing a colloid substance rich in thyroglobulin, an iodinated glycoprotein, yielding a periodic acid–Schiff (PAS)–positive reaction.

Figure 19-1 Histology of the thyroid gland

Figure 19-2 Structure of the thyroid follicular cells

The follicular epithelium also contains about 10% of scattered parafollicular cells, also called C cells. C cells, derived from the neural crest, contain small cytoplasmic granules representing the stored hormone calcitonin (hence the designation C cells).

When the thyroid gland is hypoactive, as in dietary iodide deficiency, the follicle is enlarged with colloid. Because no triiodothyronine (T₃) or thyroxine (T₄) is made to exert a negative feedback, TSH synthesis and secretion increase. TSH stimulates growth and vascularization of the thyroid gland. Consequently, the gland enlarges.

When the thyroid gland is active, the follicular epithelium is columnar, and colloid droplets may be seen within the cells as well as large apical pseudopodia and microvilli (see Figure 19-2).

The thyroid epithelium is surrounded by a basal lamina and reticular fibers. A network of vasomotor and sympathetic nerve fibers and blood vessels, including fenestrated capillaries, can be observed in the connective tissue among thyroid follicles.

Function of the thyroid gland

In contrast to other endocrine organs, which have a limited storage capacity, the production of thyroid hormones depends on the follicular storage of the prohormone thyroglobulin in the colloid.

A characteristic feature of the thyroid follicular epithelium is its ability to concentrate iodide from the blood and synthesize the hormones thyroxine and triiodothyronine.

The synthesis and secretion of thyroid hormones involve two phases (Figure 19-3): (1) an exocrine phase and (2) an endocrine phase.

Figure 19-3 Synthesis and secretion of thyroid hormones T₃ and T₄

Both phases are regulated by TSH by a mechanism that includes receptor binding and cyclic adenosine monophosphate (cAMP) production, as discussed in Chapter 3, Cell Signaling.

The exocrine phase (see Figure 19-3) consists of (1) the uptake of inorganic iodide from the blood, (2) the synthesis of thyroglobulin, and (3) the incorporation of iodine into tyrosyl residues of thyroglobulin by thyroid peroxidase.

The uptake of iodide requires an adenosine triphosphate (ATP)–driven iodide pump present in the basal plasma membrane of the follicular cells. This active transport system is referred to as the iodide trap. Intracellular iodide rapidly diffuses against both its concentration and electrical gradients to end up extracellularly in the colloid. Anions, such as perchlorate (ClO₄⁻), are used clinically as a competitive inhibitor of the iodide pump to block iodide uptake by the thyroid follicular cell.

The rough endoplasmic reticulum and Golgi apparatus are sites involved in the synthesis and glycosylation of thyroglobulin, a 660-kd glycoprotein composed of two identical subunits. Thyroglobulin is packed in secretory vesicles and released by exocytosis into the colloidal lumen. Thyroglobulin contains about 140 tyrosine residues available for iodination.

Thyroid peroxidase, the enzyme responsible for the iodination of thyroglobulin, is a heme-containing glycoprotein anchored in the membrane of the same secretory vesicle that contains thyroglobulin. After exocytosis, thyroid peroxidase is exposed at the luminal surface of the thyroid cell.

Thyroid peroxidase is activated during exocytosis. Activated thyroid peroxidase oxidizes iodide to iodine within the colloid; the iodine is then transferred to acceptor tyrosyl residues of thyroglobulin. Thyroid peroxidase activity and the iodination process can be inhibited by propylthiouracil and methyl mercaptoimidazole (MMI). These antithyroid drugs are used to inhibit the production of thyroid hormones by hyperactive glands.

The endocrine phase starts with the TSH-stimulated endocytosis of iodinated thyroglobulin into the follicular cell (see Figure 19-3):

T₃ has a shorter half-life (18 hours), is more potent, and less abundant than T₄. The half-life of T₄ is 5 to 7 days and represents about 90% of the secreted thyroid hormones.

Thyroid hormones increase the basal metabolic rate. The primary site of action of T₃, and to a lesser extent T₄, is the cell nucleus. T₃ binds to thyroid hormone receptor bound to a specific DNA region, called thyroid hormone–responsive element (TRE), to induce specific gene transcription. In cardiocytes (heart), thyroid hormone regulates the expression of genes encoding phospholamban in the sarcoplasmic reticulum, β-adrenergic receptors, Ca²⁺-ATPase, and others. In the absence of T₃, unoccupied nuclear receptors bound to the TRE repress genes that are positively regulated by thyroid hormone.

Clinical significance: Hyperthyroidism (Graves’ disease) and hypothyroidism

Graves’ disease is an autoimmune disease in which the thyroid gland is hyperfunctional (Figure 19-4). Autoantibodies (called thyroid-stimulating immunoglobulins or TSIs), produced by plasma cells derived from sensitized T cells against TSH receptors present at the basal surface of thyroid follicular cells, bind to the receptor and mimic the effect of TSH, stimulating cAMP production.

Figure 19-4 Graves’ disease: Unregulated synthesis and secretion of thyroid hormones T₃ and T₄

As a result, thyroid follicular cells become columnar and secrete large amounts of thyroid hormones in the blood circulation in an unregulated fashion. Enlargement of the thyroid gland (goiter), bulging of the eyes (exophthalmos; see Figure 19-4), tachycardia, warm skin, and fine finger tremors are typical clinical features.

In the adult, hypothyroidism is generally caused by a thyroid disease, and a decrease in the basal metabolic rate, hypothermia, and cold intolerance are observed. Decreased sweating and cutaneous vasoconstriction make the skin dry and cool. Afflicted individuals tend to feel cold in a warm room. In the adult, hypothyroidism is manifested by coarse skin with a puffy appearance due to the accumulation of proteoglycans and retention of fluid in the dermis of the skin (myxedema) and muscle. Cardiac output is reduced, and the pulse rate slows down. Except for developmental disturbances, most symptoms are reversed when the thyroid disorder is corrected.

In the fetus, a lack of thyroid hormone causes cretinism. This condition is observed in iodide-deficient geographic areas. The symptoms of hypothyroidism in newborns can include respiratory distress syndrome, poor feeding, umbilical hernia, and retarded bone growth. Untreated hypothyroidism in children results in mental retardation.

Hashimoto’s disease is an autoimmune disease associated with hypothyroidism.

It is caused by autoantibodies targeted to thyroid peroxidase and thyroglobulin. Antibodies to thyroid peroxidase are known as antimicrosomal antibodies. A progressive destruction of the thyroid follicles leads to a decrease in the function of the thyroid gland.

Calcium regulation

Ca²⁺ is found inside and outside cells, is a major component of the skeleton, is required for muscle contraction, blood clotting, nerve impulse transmission, and enzymatic activities. Ca²⁺ is an essential mediator in cell signaling (for example, through calcium-binding calmodulin).

The maintenance of Ca²⁺ homeostasis is regulated by (1) parathyroid hormone, (2) calcitonin, and (3) vitamin D (calcitriol, or 1,25-dihydroxycholecalciferol).

Parathyroid hormone acts on bone and the kidneys to raise Ca²⁺ levels in serum. Calcitonin, secreted by C cells in the thyroid follicle, lowers Ca²⁺ levels. Vitamin D is produced in the kidneys and increases the intestinal absorption of Ca²⁺ by stimulating synthesis of Ca²⁺-binding protein by intestinal epithelial cells (enterocytes). These two aspects will be discussed later in this chapter.

Development of the parathyroid glands

The four parathyroid glands derive from the third and fourth branchial pouches. The third branchial pouch differentiates into the inferior parathyroid glands and the thymus. The fourth branchial pouch develops into the superior parathyroid glands and the ultimobranchial body.

Parathyroid glands are found on the posterior surface of the thyroid gland, between its capsule and the surrounding cervical connective tissue. In addition to the four parathyroid glands, accessory glands may be found in the mediastinum or in the neck.

The accidental removal of the normal parathyroid glands during thyroid surgery (thyroidectomy) causes tetany, characterized by spasms of the thoracic and laryngeal muscles, leading to asphyxia and death.

Histologic organization of the parathyroid glands

The parenchyma of the parathyroid glands consists of two cell populations supplied by sinusoidal capillaries (Figure 19-5): (1) the more numerous chief or principal cell, and (2) the oxyphil or acidophilic cell. Cells are arranged in cordlike or follicular-like clusters.

Figure 19-5 Structure and function of the parathyroid gland

Chief or principal cells contain cytoplasmic granules with parathyroid hormone, an 84-amino-acid peptide derived from a large precursor of 115 amino acids (preproparathyroid hormone). This precursor gives rise to proparathyroid hormone (90 amino acids), which is processed by a proteolytic enzyme in the Golgi apparatus into parathyroid hormone. Parathyroid hormone is stored in secretory granules. Glycogen inclusions are also observed in chief cells.

The Ca²⁺-sensing receptor (CaSR) is associated to G protein in the plasma membrane of chief cells. Serum Ca²⁺ binding to the extracellular region of the CaSR triggers the release of intracellular signals suppressing the secretion of parathyroid hormone, with the consequent decrease in the serum Ca²⁺ concentration. When the serum Ca²⁺ concentration decreases, the secretion of parathyroid hormone is stimulated, resulting in an increase in serum Ca²⁺. In most cells, Ca²⁺ enters a cell through a membrane-associated channel. Chief parathyroid cells are rather unusual because Ca²⁺ is a ligand for the CaSR resulting in the activation of G protein.

Oxyphil or acidophilic cells contain abundant mitochondria, which give this cell its typical stain. This cell type may represent transitional chief cells.

Function of the parathyroid hormone

Parathyroid hormone regulates the Ca²⁺ and PO₄^3- balance in blood by acting on two main sites:

An increase in serum Ca²⁺ levels (hypercalcemia) suppresses the release of parathyroid hormone from chief cells. A decrease in Ca²⁺ levels (hypocalcemia) stimulates parathyroid hormone release by chief cells.

When Ca²⁺ levels are low, parathyroid hormone reestablishes homeostasis by acting on osteoblasts, which induce osteoclasts to reabsorb bone.

Parathyroid hormone binds to a cell surface receptor of the osteoblast to regulate the synthesis of three proteins essential for the differentiation and function of osteoclasts (Figure 19-6; see also the discussion of osteoclasts in Chapter 4, Connective Tissue):

Figure 19-6 Parathyroid hormone regulates osteoclastogenesis

You should be aware that RANKL not only regulates osteoclastogenesis but also is expressed by dendritic cells, T and B cells, components of the immune system. This is an important consideration in anti-RANKL treatment of some forms of osteoporosis, as discussed under Bone in Chapter 4, Connective Tissue.

Clinical significance: Hyperparathyroidism, hypoparathyroidism, and CaSR mutations

Hyperparathyroidism is caused by a functional benign tumor of the gland (adenoma). An abnormal increase in the secretion of parathyroid hormone causes:

Inactivating mutations of one allele of the CaSR prevent parathyroid chief cells to sense increases in serum Ca²⁺, which results in an increase of parathyroid hormone secretion. This condition, called familial benign hypercalcemia, can be severe when two inactivated CaSR alleles exist. This condition, detected in newborns, requires immediate parathyroidectomy.

Idiopathic hypoparathyroidism results in a failure of tissues to respond to parathyroid hormone. An activating mutation of the CaSR leads the parathyroid gland into assuming that the Ca²⁺ serum level is elevated when it is not. This condition determines a reduction in serum Ca²⁺ and parathyroid hormone levels.

CaSR can also be a target of autoimmunity and either activate (causing hypoparathyroidism) or inactivate the CaSR (causing a syndrome similar to familial benign hypercalcemia). Calcimimetic drugs, which activate CaSR, reduce pathologic elevations of parathyroid hormone. CaSR-blocking drugs, called calcilytics, may be useful for the treatment of osteoporosis.

Clinical significance: Multiple endocrine neoplasia syndrome

Tumors of C cells (medullary carcinoma of the thyroid gland) result in excessive production of calcitonin. However, calcium levels in serum are normal, with no apparent bone damage.

The presence of a calcitonin-producing tumor of the thyroid gland may be associated with pheochromocytoma, a tumor of the adrenal medulla (multiple endocrine neoplasia [MEN] syndrome).