The thyroid gland produces two related hormones, thyroxine (T4) and triiodothyronine (T3) (Fig. 341-1). Acting through thyroid hormone receptors α and β, these hormones play a critical role in cell differentiation during development and help maintain thermogenic and metabolic homeostasis in the adult. Autoimmune disorders of the thyroid gland can stimulate overproduction of thyroid hormones (thyrotoxicosis) or cause glandular destruction and hormone deficiency (hypothyroidism). In addition, benign nodules and various forms of thyroid cancer are relatively common and amenable to detection by physical examination.
Structures of thyroid hormones. Thyroxine (T4) contains four iodine atoms. Deiodination leads to production of the potent hormone triiodothyronine (T3), or the inactive hormone reverse T3.
The thyroid (Greek thyreos, shield, plus eidos, form) consists of two lobes connected by an isthmus. It is located anterior to the trachea between the cricoid cartilage and the suprasternal notch. The normal thyroid is 12–20 g in size, highly vascular, and soft in consistency. Four parathyroid glands, which produce parathyroid hormone (Chap. 353), are located posterior to each pole of the thyroid. The recurrent laryngeal nerves traverse the lateral borders of the thyroid gland and must be identified during thyroid surgery to avoid injury and vocal cord paralysis.
The thyroid gland develops from the floor of the primitive pharynx during the third week of gestation. The developing gland migrates along the thyroglossal duct to reach its final location in the neck. This feature accounts for the rare ectopic location of thyroid tissue at the base of the tongue (lingual thyroid) as well as the occurrence of thyroglossal duct cysts along this developmental tract. Thyroid hormone synthesis normally begins at about 11 weeks' gestation.
Neural crest derivatives from the ultimobranchial body give rise to thyroid medullary C cells that produce calcitonin, a calcium-lowering hormone. The C cells are interspersed throughout the thyroid gland, although their density is greatest in the juncture of the upper one-third and lower two-thirds of the gland. Calcitonin plays a minimal role in calcium homeostasis in humans but the C-cells are important because of their involvement in medullary thyroid cancer.
Thyroid gland development is orchestrated by the coordinated expression of several developmental transcription factors. Thyroid transcription factor (TTF)-1, TTF-2, and paired homeobox-8 (PAX-8) are expressed selectively, but not exclusively, in the thyroid gland. In combination, they dictate thyroid cell development and the induction of thyroid-specific genes such as thyroglobulin (Tg), thyroid peroxidase (TPO), the sodium iodide symporter (Na+/I, NIS), and the thyroid-stimulating hormone receptor (TSH-R). Mutations in these developmental transcription factors or their downstream target genes are rare causes of thyroid agenesis or dyshormonogenesis, though the causes of most forms of congenital hypothyroidism remain unknown (Table 341-1). Because congenital hypothyroidism occurs in approximately 1 in 4000 newborns, neonatal screening is now performed in most industrialized countries (see below). Transplacental passage of maternal thyroid hormone occurs before the fetal thyroid gland begins to function and provides partial hormone support to a fetus with congenital hypothyroidism. Early thyroid hormone replacement in newborns with congenital hypothyroidism prevents potentially severe developmental abnormalities.
Table 341-1 Genetic Causes of Congenital Hypothyroidism
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Table 341-1 Genetic Causes of Congenital Hypothyroidism
|Defective Gene Protein||Inheritance||Consequences|
|PROP-1||Autosomal recessive||Combined pituitary hormone deficiencies with preservation of adrenocorticotropic hormone|
|PIT-1||Autosomal recessive Autosomal dominant||Combined deficiencies of growth hormone, prolactin, thyroid-stimulating hormone (TSH)|
|TSHβ||Autosomal recessive||TSH deficiency|
|TTF-1 (TITF-1)||Autosomal dominant||Variable thyroid hypoplasia, choreoathetosis, pulmonary problems|
|TTF-2 (FOXE-1)||Autosomal recessive||Thyroid agenesis, choanal atresia, spiky hair|
|PAX-8||Autosomal dominant||Thyroid dysgenesis|
|TSH-receptor||Autosomal recessive||Resistance to TSH|
|Gsα (Albright hereditary osteodystrophy)||Autosomal dominant||Resistance to TSH|
|Na+/I− symporter||Autosomal recessive||Inability to transport iodide|
|THOX2||Autosomal dominant||Organification defect|
|Thyroid peroxidase||Autosomal recessive||Defective organification of iodide|
|Thyroglobulin||Autosomal recessive||Defective synthesis of thyroid hormone|
|Pendrin||Autosomal recessive||Pendred syndrome: sensorineural deafness and partial organification defect in thyroid|
|Dehalogenase 1||Autosomal recessive||Loss of iodide reutilization|
The thyroid gland consists of numerous spherical follicles composed of thyroid follicular cells that surround secreted colloid, a proteinaceous fluid containing large amounts of thyroglobulin, the protein precursor of thyroid hormones (Fig. 341-2). The thyroid follicular cells are polarized—the basolateral surface is apposed to the bloodstream and an apical surface faces the follicular lumen. Increased demand for thyroid hormone is regulated by thyroid-stimulating hormone (TSH), which binds to its receptor on the basolateral surface of the follicular cells, leading to Tg reabsorption from the follicular lumen, proteolysis within the cytoplasm, yielding thyroid hormones for secretion into the bloodstream.
Regulation of thyroid hormone synthesis. Left. Thyroid hormones T4 and T3 feed back to inhibit hypothalamic production of thyrotropin-releasing hormone (TRH) and pituitary production of thyroid-stimulating hormone (TSH). TSH stimulates thyroid gland production of T4 and T3. Right. Thyroid follicles are formed by thyroid epithelial cells surrounding proteinaceous colloid, which contains thyroglobulin. Follicular cells, which are polarized, synthesize thyroglobulin and carry out thyroid hormone biosynthesis (see text for details). TSH-R, thyroid-stimulating hormone receptor; Tg, thyroglobulin; NIS, sodium iodide symporter; TPO, thyroid peroxidase; DIT, diiodotyrosine; MIT, monoiodotyrosine.
TSH, secreted by the thyrotrope cells of the anterior pituitary, plays a pivotal role in control of the thyroid axis and serves as the most useful physiologic marker of thyroid hormone action. TSH is a 31-kDa hormone composed of α and β subunits; the α subunit is common to the other glycoprotein hormones [luteinizing hormone, ...