Endocrinology and Diabetes (Lecture Notes) - Softcover

Sam, Amir H.; Meeran, Karim

Softcover

ISBN 10: 1405153458 ISBN 13: 9781405153454

Publisher: Wiley-Blackwell, 2009

Synopsis

This brand new title in the Lecture Notes series covers a core element of the medical school curriculum.

It presents the basic science needed to understand mechanisms of disease and describes the clinical presentations of the disorders associated with different glands, concluding with the relevant investigations and management.

Focusing on conditions commonly encountered on the wards and in exams, with key points to aid revision and recall, this new title is perfect as a course companion and is the ideal revision tool for medical students, specialist nurses, and doctors working on endocrinology rotations. Lecture Notes: Endocrinology and Diabetes is also essential for endocrinology trainees approaching the new Knowledge Based Assessment (KBA).

About this title

About the Author

Dr Amir Sam, BSc (Hons), MB BS (Hons), MRCP
Series editor of the Rapid Series, Editor of Rapid Differential Diagnosis and Co-author of Rapid Medicine.

Wellcome Trust Clinical Research Fellow and SpR in Endocrinology and Diabetes, Hammersmith Hospital, Imperial College, London, UK

Dr Karim Meeran, MD, FRCP, FRCPath

Professor of Endocrinology, Imperial College Healthcare NHS Trust, London, UK

Excerpt. © Reprinted by permission. All rights reserved.

Lecture Notes

Endocrinology and DiabetesBy Amir Sam Karim Meeran

John Wiley & Sons

Copyright © 2009 Blackwell Publishing
All right reserved.
ISBN: 978-1-4051-5345-4

Chapter One

Thyroid anatomy and physiology

Anatomy

The thyroid gland consists of left and right lobes connected by a midline isthmus (Fig. 1.1). The isthmus lies below the cricoid cartilage, and the lobes extend upward over the lower half of the thyroid cartilage. The thyroid is covered by the strap muscles of the neck and overlapped by the sternocleidomastoids. The pretracheal fascia encloses the thyroid gland and attaches it to the larynx and the trachea. This accounts for the upward movement of the thyroid gland on swallowing.

The thyroid gland develops from the floor of the pharynx in the position of the foramen caecum of the adult tongue as a downgrowth that descends into the neck. During this descent, the thyroid gland remains connected to the tongue by the thyroglossal duct, which later disappears. However, aberrant thyroid tissue or thyroglossal cysts (cystic remnants of the thyroglossal duct) may occur anywhere along the course of the duct (Fig. 1.2). Such thyroid remnants move upward when the tongue is protruded.

The thyroid gland is composed of epithelial spheres called follicles (Fig 1.3), whose lumens are filled with a proteinaceous colloid containing thyroglobulin. Two basic cell types are present in the follicles. The follicular cells secrete thyroxine ([T.sub.4]) and triiodothyronine ([T.sub.3]) and originate from a downward growth of the endoderm of the floor of the pharynx (see above). The parafollicular or C cells secrete calcitonin and arise from neural crest cells that migrate into the developing thyroid gland. The follicles are surrounded by an extensive capillary network.

Physiology

Thyroid hormones act on many tissues. They regulate:

organogenesis, growth and development (central nervous system, bone)

energy expenditure

protein, carbohydrate and fat metabolism

gut motility

one turnover

heart rate and contractility, and peripheral vascular resistance

beta-adrenergic receptor expression

muscle contraction and relaxation

the menstrual cycle

erythropoiesis.

Iodine is essential for normal thyroid function. It is obtained by the ingestion of foods such as seafood, seaweed, kelp, dairy products, some vegetables and iodized salt. The recommended iodine intake for adults is 150g per day (250g per day for pregnant and lactating women). Dietary iodine is absorbed as iodide. Iodide is excreted in the urine.

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 ([T.sub.4]) and triiodothyronine ([T.sub.3]) in a process known as coupling.

Thyroglobulin containing [T.sub.4] and [T.sub.3] is resorbed into the follicular cells by endocytosis and is cleaved by lysosomal enzymes (proteases and peptidases) to release [T.sub.4] and [T.sub.3]. [T.sub.4] and [T.sub.3] are then secreted into the circulation.

Uncoupled MIT and DIT are deiodinated, and the free tyrosine and iodide are recycled.

The thyroid gland stores [T.sub.4] and [T.sub.3] incorporated in thyroglobulin, and can therefore secrete [T.sub.4] and [T.sub.3] more quickly than if they had to be synthesized.

Extra-thyroidal [T.sub.3] production

[T.sub.4] is produced entirely by the thyroid gland. The production rate of [T.sub.4] is about 100[micro]g per day. However, only 20% of [T.sub.3] is produced directly by the thyroid gland (by coupling of MIT and DIT). Around 80% of [T.sub.3] is produced by the deiodination of [T.sub.4] in peripheral extra-thyroidal tissues (mainly liver and kidney). The total daily production rate of [T.sub.3] is about 35[micro]g.

[T.sub.4] is converted to [T.sub.3] (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 [T.sub.3] to reverse [T.sub.4] (the inactive metabolite) by 5-deiodination (inner ring deiodination), as shown in Fig. 1.5.

Changes in [T.sub.3] 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 [T.sub.4] production (by 5'-deiodination of [T.sub.3]) is reduced in acute illness and starvation.

Total and free [T.sub.4] and [T.sub.3]

Approximately 99.97% of circulating [T.sub.4] and 99.7% of circulating [T.sub.3] are bound to plasma proteins: thyroid-binding globulin (TBG), transthyretin (also known as thyroid-binding pre-albumin), albumin and lipoproteins.

Only the unbound thyroid hormone is available to the tissues. [T.sub.3] is less strongly bound and therefore has a more rapid onset and offset of action. The binding proteins have both storage and buffer functions. They help to maintain the serum free [T.sub.4] and [T.sub.3] levels within narrow limits, and also ensure continuous and rapid availability of the hormones to the tissues.

Free thyroid hormone concentrations are easier to interpret than total thyroid hormone levels. This is because the level of bound hormone alters with changes in the levels of thyroid-binding proteins, even though free [T.sub.4] (and [T.sub.3]) concentrations do not change and the patient remains euthyroid (Fig. 1.6). Box 1.1 summarizes factors that may alter TBG levels.

Other causes of increased serum total [T.sub.4] and [T.sub.3] levels include familial dysalbuminaemic hyperthyroxinaemia (due to the presence of an abnormal albumin with a higher affinity for [T.sub.4]) and the presence of anti-[T.sub.4] antibodies. Patients with these conditions are euthyroid, have normal serum thyroid-stimulating hormone (TSH) levels, and usually have normal serum free [T.sub.4] and [T.sub.3] levels when measured by appropriate methods.

Thyroid hormone metabolism

[T.sub.4] is degraded at a rate of 10% per day. Around 40% of the [T.sub.4] is deiodinated to [T.sub.3] and 40% to reverse [T.sub.3]. The remaining [T.sub.4] is conjugated with glucuronide and sulphate, deaminated and decarboxylated, or cleaved between the two rings.

[T.sub.3] is degraded (mostly by deiodination) at a rate of 75% per day. Reverse [T.sub.3] is degraded even more rapidly than [T.sub.3], mostly by deiodination.

Regulation of thyroid hormone production and release

[T.sub.3] and [T.sub.4] synthesis and secretion is stimulated by the thyroid-stimulating hormone (TSH) released from the anterior pituitary gland (Fig. 1.7). TSH production and release is increased by hypothalamic thyrotrophin-releasing hormone (TRH).

Thyrotrophin-releasing hormone

TRH is a tripeptide synthesized and released by the hypothalamus. TRH content is highest in the median eminence and paraventricular nuclei of the hypothalamus. TRH stimulates TSH secretion by activating a G-protein-coupled receptor and the phospholipase C-phosphoinositide pathway, resulting in mobilization of calcium from intracellular storage sites.

Chronic TRH stimulation also increases the synthesis and glycosylation of TSH, which increases its biological activity.

Thyroid-stimulating hormone

TSH is a glycoprotein secreted by the thyrotroph cells of the anterior pituitary. TSH is composed of alpha and beta subunits that are non-covalently bound. The alpha subunit is the same as that of luteinizing hormone, follicle-stimulating hormone and human chorionic gonadotrophin. However, the beta subunit is unique to TSH. TSH binds to specific plasma membrane receptors and activates adenylyl cyclase. TSH also stimulates phospholipase C activity.

TSH stimulates every step in thyroid hormone synthesis and secretion. It also stimulates the expression of many genes in thyroid tissue and causes thyroid hyperplasia and hypertrophy.

[T.sub.4] and [T.sub.3] inhibit TSH synthesis and release both directly (by inhibiting transcription of the TSH subunit genes) and indirectly (by inhibiting TRH release). [T.sub.4] and [T.sub.3] also decrease the glycosylation and hence bioactivity of TSH.

TSH secretion is regulated by very small changes in serum [T.sub.4] and [T.sub.3] concentrations. However, an important exception is that the reduced [T.sub.3] levels in patients with non-thyroidal illness have little effect on TSH secretion. This may be due to a greater contribution of serum [T.sub.4] to the nuclear [T.sub.3] content of the pituitary than other tissues.

Box 1.2 shows a list of the causes of increased and decreased TSH concentration.

Mechanism of action of thyroid hormones

Thyroid hormones enter cells via active membrane transporter proteins (e.g. MCT8). Inside the cells, [T.sub.3] formed from the deiodination of [T.sub.4] and [T.sub.3] that enters the cells from the serum is transferred to the nucleus. The thyroid hormone receptors (TRs) heterodimerize with the retinoid X receptor and act as nuclear transcription factors. TRs bind thyroid hormone response elements in the promoter region of thyroid hormone-responsive genes. In the absence of [T.sub.3], TRs bind co-repressor proteins that repress transcription. On [T.sub.3] binding, co-repressors are displaced and co-activator proteins bind the TRs, resulting in histone acetylation, generation of a permissive chromatin structure and induction of gene transcription.

There are two [T.sub.3] nuclear receptors-alpha and beta-encoded by separate genes located on chromosomes 17 and 3. Two forms of each TR are generated by alternative splicing. Only the beta-1, beta-2 and alpha-1 receptors bind [T.sub.3]. Liver predominantly expresses beta receptors, whereas heart and bone express alpha receptors. The hypothalamus and pituitary express beta-2 receptors which mediate the negative feedback regulation.

Box 1.1 Factors that may alter thyroid-binding globulin (TBG) levels

[up arrow] TBG Hereditary TBG excess (X-linked dominant) Pregnancy Drugs, e.g. oestrogen, tamoxifen, opiates, phenothiazines, 5-fluorouracil, clofibrate Hepatitis Acute intermittent porphyria

[down arrow] TBG Genetically determined Malnutrition Chronic liver disease Nephrotic syndrome Drugs, e.g. androgens, corticosteroids, phenytoin Cushing's syndrome Acromegaly

Box 1.2 Causes of increased and decreased thyroid-stimulating hormone (TSH) concentration

Increased TSH secretion Primary/subclinical hypothyroidism Secondary hyperthyroidism Recovery from non-thyroidal illness Thyroid hormone resistance Primary adrenal insufficiency Drugs: dopamine antagonists (metoclopramide, domperidone), amiodarone Patients with antibodies to the murine immunoglobulins used in the assay

Decreased TSH secretion Primary/subclinical hyperthyroidism Secondary hypothyroidism Non-thyroidal illness Drugs: dopamine agonists, octreotide, phenytoin, steroids Increased human chorionic gonadotrophin, e.g. early pregnancy, molar pregnancy, choriocarcinoma

Key points:

Thyroid hormone synthesis involves the transport of iodide into follicular cells, iodide oxidation into iodine, binding of iodine to thyroglobulin tyrosine residues (organification) to form MIT and DIT, and coupling of DIT and MIT to form [T.sub.4] and [T.sub.3]. The processes of iodide oxidation, organification and coupling are catalyzed by the thyroid peroxidase enzyme.

Thyroid hormone synthesis and secretion is stimulated by the TSH released from the anterior pituitary gland. TSH production and release is increased by hypothalamic TRH.

80% of [T.sub.3] is produced by the 5-deiodination of [T.sub.4] in peripheral extra-thyroidal tissues (mainly liver and kidney).

Free thyroid hormone concentrations are easier to interpret than total thyroid hormone levels as the level of bound hormone alters with changes in the levels of thyroid-binding proteins.

[T.sub.4] is largely a prohormone, and almost the entire nuclear-bound hormone is [T.sub.3].

(Continues...)

Excerpted from Lecture Notesby Amir Sam Karim Meeran Copyright © 2009 by Blackwell Publishing. Excerpted by permission.
All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
Excerpts are provided by Dial-A-Book Inc. solely for the personal use of visitors to this web site.

Edition details

• Publisher: Wiley-Blackwell
• Publication date: 2009
• Language: English
• ISBN 10: 1405153458
• ISBN 13: 9781405153454
• Binding: Paperback
• Edition number: 1
• Number of pages: 288