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(BQ) Part 2 book “Essential endocrinology and diabetes” has contents: The thyroid gland, calcium and metabolic bone disorders, pancreatic and gastrointestinal endocrinology and endocrine neoplasia, overview of diabetes, complications of diabetes,…. And other contents.
165 CHAPTER The thyroid gland Key topics ■ Embryology 166 ■ Anatomy and vasculature 168 ■ Thyroid hormone biosynthesis 168 ■ Circulating thyroid hormones 172 ■ Metabolism of thyroid hormones 172 ■ Function of thyroid hormones 173 ■ Clinical disorders 175 ■ Key points 187 ■ Answers to case histories 187 Learning objectives ■ To appreciate the development of the thyroid gland and its clinical consequences ■ To understand the regulation, biosynthesis, function and metabolism of thyroid hormones ■ To recognize the clinical consequences of thyroid underactivity and overactivity ■ To understand the clinical management of thyroid nodules and cancer This chapter integrates the basic biology of the thyroid gland with the clinical conditions that affect it Essential Endocrinology and Diabetes, Sixth Edition Richard IG Holt, Neil A Hanley © 2012 Richard IG Holt and Neil A Hanley Publlished 2012 by Blackwell Publishing Ltd 166 / Chapter 8: The thyroid gland To recap ■ Regulation of the thyroid gland occurs as part of a negative feedback loop, the principle of which is introduced in Chapter ■ Thyroid hormones are synthesized from tyrosine; review the biosynthesis of hormones derived from amino acids (Chapter 2) ■ Like steroid hormones, thyroid hormones act in the nucleus; review the principles of nuclear hormone action covered in Chapter Cross-reference ■ The thyroid is regulated by the hypothalamus and anterior pituitary thyrotroph, which are covered in Chapter ■ Medullary carcinoma of the thyroid is part of multiple endocrine neoplasia type 2, covered in Chapter 10 ■ Other autoimmune endocrinopathies can co-exist with autoimmune thyroid disease, especially Addison disease (see Chapter 6) and type diabetes (see Chapter 12) The thyroid gland is responsible for making thyroid hormones by concentrating iodine and utilizing the amino acid tyrosine (review Chapter 2) The hormones play major metabolic roles, affecting many different cell types in the body Clinical conditions affecting the thyroid gland are common Therefore, a thorough understanding is important Tongue Tooth Foramen caecum Thyroid gland Embryology Understanding development of the thyroid and its anatomical associations underpins the gland’s examination and surgical removal to treat overactivity or enlargement In the fourth week of human embryogenesis, the thyroid begins as a midline thickening at the back of the tongue that subsequently invaginates and stretches downward (Figure 8.1) This creates a mass of progenitor cells that migrates in front of the larynx and comes into close proximity with the developing parathyroid glands (see Chapter 9) In adulthood, the pea-sized parathyroids located on the back of the thyroid as pairs of upper and lower glands regulate calcium by secreting parathyroid hormone (PTH) The lower parathyroids originate higher in the neck than the upper glands and only achieve their final position by migrating downwards The migrating thyroid also comes into Larynx Thyroid gland Upper parathyroid gland Lower parathyroid gland Figure 8.1 The thyroid gland and its downward migration The point of origin in the tongue persists as the foramen caecum Common sites of thyroglossal cysts ( ) are shown The final position of the paired parathyroid glands ( ) is also indicated Modified from Moore KL The Developing Human W.B Saunders, Philadelphia Chapter 8: The thyroid gland / 167 contact with cells from the lower part of the pharynx These latter cells eventually comprise ∼10% of the gland as future C-cells, which will secrete calcitonin (see Chapter 9) Towards the end of the second month, the thyroid comprises two lobes joined at an isthmus in front of the trachea It lies just below the larynx, which forms a convenient landmark for locating the bowtie-shaped gland during clinical examination (see Box 8.12) The thyroglossal duct atrophies and loses contact with the thyroid in all but ∼15% of the population, in whom a finger-like pyramidal lobe of thyroid projects upward By ∼11 weeks, primitive follicles are visible as simple epithelium surrounding a central lumen (Figure 8.2) This signals the gland’s first ability to trap iodide and synthesize thyroid hormone, although it only responds to thyroid-stimulating hormone (TSH) from the anterior pituitary towards the end of the second trimester Abnormal embryology can be clinically important (Box 8.1) Thyroid agenesis or hypoplasia caused by loss-of-function mutation in genes, such as PAX8, requires immediate detection and treatment with thyroid hormone in order to minimize severe and largely irreversible neurological damage Box 8.1 Embryological abnormalities with clinical consequences • Failure of the gland to develop causes congenital hypothyroidism • Under- or over-migration of the thyroid can cause a lingual or retrosternal thyroid respectively • Failure of thyroglossal duct to atrophy can lead to a thyroglossal cyst (a) Lymphatic vessel Follicular epithelial cell Colloid C-cell C-cell Basement membrane Sympathetic nerve ending (b) Capillary (c) Figure 8.2 Histology of the human thyroid gland (a) Euthyroid follicles are shown lined with cuboidal epithelium and lumens filled with gelatinous colloid that contains stored thyroid hormone Surrounding each follicle is a basement membrane enclosing parafollicular C-cells within stroma containing fenestrated capillaries, lymphatic vessels and sympathetic nerve endings (b) Underactive follicles with flattened epithelial cells and increased colloid (c) Overactive follicles with tall, columnar epithelial cells and reduced colloid 168 / Chapter 8: The thyroid gland in the infant Less critically, thyroglossal cysts can occur in the midline and move upwards on tongue protrusion (a clinical test) Anatomy and vasculature The adult thyroid weighs 10–20 g, is bigger in women than men and is also larger in areas of the world with iodine deficiency It enlarges during puberty, pregnancy and lactation The right lobe is usually slightly larger than the left Its outer capsule is not well-defined, but attaches the thyroid posteriorly to the trachea The parathyroid glands are situated between this and the inner capsule, from which trabeculae of collagen pervade the gland carrying nerves and a rich vascular supply (Figure 8.2) The thyroid receives ∼1% of cardiac output from superior and inferior thyroid arteries, which are branches of the external carotid and subclavian arteries respectively Per gram of tissue, this blood supply is almost twice that of the kidney and is increased during autoimmune overactivity when it may cause a bruit on auscultation (Box 8.2; and see Box 8.12) Blood flow through fenestrated capillaries is controlled by post-ganglionic sympathetic nerves from the middle and superior cervical ganglia The functional unit of the thyroid is the follicle, comprised of cuboidal epithelial (‘follicular’) cells around a central lumen of colloid Colloid is composed almost entirely of the iodinated glycoprotein, thyroglobulin (pink on periodic acid-Schiff (PAS) staining) There are many thousands of follicles 20–900 µm in diameter, interspersed with blood vessels, an extensive network of lymphatic vessels, connective tissue and the parafollicular calcitoninsecreting C-cells When the gland is quiescent (e.g in hypothyroidism from iodine deficiency), follicles Box 8.2 The thyroid gland • Thyroid enlargement is called goitre • The gland is encapsulated: ° Breaching the capsule is a measure of invasion in thyroid cancer • The thyroid receives a large arterial blood supply: ° May cause a bruit in Graves disease are distended with colloid and the epithelial cells are flattened with little cytoplasm Conversely, in an overactive gland, follicular cells are columnar and there is less stored colloid (Figure 8.2) Thyroid hormone biosynthesis There are two active thyroid hormones: thyroxine (3,3′,5,5′-tetra-iodothyronine; abbreviated to T4) and 3,5,3′-tri-iodothyronine (T3); the subscripts and represent the number of iodine atoms incorporated on each thyronine residue (Figure 8.3) These hormones are generated from the sequential iodination and coupling of the amino acid tyrosine and inactivated by de-iodination and modification to 3,3′,5′-tri-iodothyronine [reverse T3 (rT3)] and diiodothyronine (T2) The equilibrium between these different molecules determines overall thyroid hor mone activity Synthesis of thyroid hormone can be broken down into several key steps (Figure 8.4) Uptake of iodide from the blood Synthesis of thyroid hormone relies on a constant supply of dietary iodine as the monovalent anion iodide (I−) When the element is scarce the thyroid enlarges to form a goitre (Figure 8.5 and Box 8.3) Circulating iodide enters the follicular cell by active transport through the basal cell membrane The sodium (Na+)/I− pump is linked to an adenosine triphosphate (ATP)-driven Na+/potassium (K+) pump This process concentrates I− within the thyroid gland to 20–100-fold that of the remainder of the body This selectivity allows use of radioiodine both diagnostically and therapeutically (see later) Several structurally related anions can competitively inhibit the I− pump For instance, large doses of perchlorate (ClO4−) can block I− uptake in the short term (e.g to treat accidental ingestion of radioiodine) The pertechnetate ion incorporating a γ-emitting radioisotope of technetium is also taken up by the I− pump, allowing the thyroid to be imaged diagnostically The synthesis of thyroglobulin Thyroglobulin (Tg) is the tyrosine-rich protein that is iodinated within the colloid to yield stored Chapter 8: The thyroid gland / 169 I COOH CH2 HO CH CH2 HO NH2 I I I HO I CH2 CH I CH2 CH I NH2 3, 5, 3' - Tri-iodothyronine (T3) I CH2 CH I I COOH O COOH O 5' Thyroxine (T4) HO I 3' HO NH2 I I NH2 Di-iodotyrosine COOH O CH I Mono-iodotyrosine HO COOH CH2 CH O NH2 I 3, 3', 5' - Tri-iodothyronine (reverse-T3) Capillary Na + I– TSH NH2 3, 3' - Di-iodothyronine (T2) Basal membrane Active process Receptor Apical membrane (microvilli on the surface) Na + Thyroglobulin and TPO biosynthesis and packaging I– TPO cAMP Thyroglobulin degradation Figure 8.4 Thyroid hormone biosynthesis within the follicular cell Active iodide (I−) import is linked to the Na+/K+-ATPase pump Thyroglobulin is synthesized on the rough endoplasmic reticulum, packaged in the Golgi complex and released from small, Golgi-derived vesicles into the follicular lumen Its iodination is also known as ‘organification’ Cytoplasmic microfilaments Colloid Thyroglobulin + I– TPO Intracellular effects (see Box 8.5) I– T4, T3 Figure 8.3 The structures of active and inactive thyroid hormones and their precursors Monoiodotyrosine and di-iodotyrosine are precursors Thyroxine (T4) and tri-iodothyronine (T3) are the two thyroid hormones, of which T3 is the biologically more active Reverse T3 and T2 are inactive metabolites formed by de-iodination of T4 and T3 respectively The numbering of critical positions for iodination is shown on the structure of T3 COOH Pendrin Active TPO ‘Organification’ Thyroglobulincontaining thyroid hormone I– and microtubules organize the return of iodinated thyroglobulin into the cell as endocytotic vesicles of colloid, which is broken down to release thyroid hormone TSH, thyroid-stimulating hormone; TPO, thyroid peroxidase; T4, thyroxine; T3, tri-iodothyronine Modified from Williams’ Textbook of Endocrinology, 10th edn Saunders, 2003, p 332 170 / Chapter 8: The thyroid gland Box 8.3 Iodine deficiency Figure 8.5 A large goitre caused by iodine deficiency in rural Africa Note the engorged veins overlying the gland, implying venous obstruction Image kindly provided by Professor David Phillips, University of Southampton thyroid hormone It is synthesized exclusively by the follicular cell, such that the small amount in the circulation can serve as a tumour marker for thyroid cancer Tg contains ∼10% carbohydrate, including sialic acid responsible for the pink PAS staining of colloid Tg is transcribed, translated, modified in the Golgi apparatus and then packaged into vesicles that undergo exocytosis at the apical membrane to release Tg into the follicular lumen (Figure 8.4; and review Figures 2.3 and 2.4) Iodination of thyroglobulin Thyroid peroxidase (TPO) catalyzes the iodination of Tg (mature Tg is ∼1% iodine by weight) The enzyme is synthesized and packaged alongside Tg into vesicles at the Golgi apparatus (Figure 8.4) TPO becomes activated at the apical membrane where it binds I− and Tg (at different sites), oxidizes I−, and transfers it to an exposed Tg tyrosine residue The enzyme is particularly efficient at iodinating fresh Tg; as the reaction proceeds, the efficiency of adding further I− decreases Drugs inhibiting TPO and iodination are used to treat hyperthyroidism (Box 8.4) Some naturally-occurring chemicals [e.g milk from cows fed on certain green fodder or from Some areas of the developing world remain iodine-deficient, which can cause particularly large goitres (Figure 8.5) and hypothyroidism Thyroglobulin in the normal thyroid stores enough thyroid hormone to supply the body for ∼2 months When dietary I− is limited (