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Library of Congress Cataloging-in-Publication Data
Names: Rees, Aled, author. | Levy, Miles, 1971- author. | Lansdown, Andrew,
1980- author.
Title: Clinical endocrinology and diabetes at a glance / Aled Rees, Miles Levy,
Andrew Lansdown.
Other titles: At a glance series (Oxford, England)
Description: Chichester, West Sussex, UK ; Hoboken, NJ : John Wiley & Sons Inc.,
2017. | Series: At a glance series | Includes index.
Identifiers: LCCN 2016039440| ISBN 9781119128717 (pbk.) | ISBN 9781119128724
(Adobe PDF) | ISBN 9781119128731 (epub)
Subjects: | MESH: Endocrine System Diseases—diagnosis | Diabetes
Mellitus—diagnosis | Handbooks
Classification: LCC RC648 | NLM WK 39 | DDC 616.4/8—dc23 LC record available at
https://lccn.loc.gov/2016039440
A catalogue record for this book is available from the British Library.
Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.
Cover image: © SHUBHANGI GANESHRAO KENE/Gettyimages
This concise and informative textbook is aimed primarily at medical undergraduates commencing their clinical rotations, and is the first of its kind to be aligned against a nationally endorsed curriculum (developed by the Society for Endocrinology, Diabetes UK and the Association of British Clinical Diabetologists). Feedback from our students has informed our approach to this book, which seeks to progress the reader from a fundamental understanding of the physiological mechanisms underpinning endocrine regulation through to disease processes which disturb this homeostatic balance. In addition to the core material on common endocrine and diabetes presentations, there is an emphasis on key practical skills and provision of clear guidance on peri-operative management, emergency presentations and acute illness. We therefore anticipate that Clinical Endocrinology and Diabetes at a Glance will form a helpful and accessible resource for junior doctors involved in the management of patients with diabetes and endocrine disorders. As with other books in the series there is a major emphasis on the use of clear illustrations and tables to complement the text and consolidate learning.
Parts 1 to 9 cover the regulation and assessment of the endocrine system, pituitary disorders, fluid and electrolyte balance, thyroid disease, metabolic bone disorders, adrenal disease, disorders of the reproductive system, neuroendocrine tumours and endocrine emergencies. Part 10 provides a comprehensive overview of all aspects of diabetes, lipid and weight disorders.
Finally, no textbook makes it to publication without the hard work of a number of contributors. We are particularly grateful to Karen Moore for her diligence in keeping our writing endeavours on track, and to Jan East and Kathy Syplywczak for their help in taking us through the production process.
We welcome any feedback, and hope you enjoy reading the book as much as we have enjoyed writing it.
Aled Rees
Miles Levy
Andrew Lansdown
February 2017
The endocrine system consists of glands, which secrete hormones that circulate and act at distant sites in the body. The key endocrine glands are the pituitary, thyroid, parathyroids, adrenals, pancreas and gonads. Endocrine disease can lead to hypo- or hypersecretion of hormones. Endocrine diseases include tumours, which are commonly benign, autoimmune diseases, enzyme defects and hormone receptor abnormalities.
The chemical structure of hormones includes steroids, polypeptides, glycoproteins and amines (Figure 1.1). Hormones are secreted by the hypothalamus at low concentration, acting locally on the anterior pituitary, which in turn secretes trophic hormones to the relevant target gland. Hormones are secreted directly into the circulation either in their final form or as a larger precursor molecule, such as proopiomelanocortin (POMC), which is cleaved to adrenocorticotrophic hormone (ACTH), melanocyte stimulating hormone (MSH) and other smaller peptides. Many hormones are transported in the circulation by binding proteins, but only the free hormone acts on the receptor. Examples of binding proteins are sex hormone binding globulin (SHBG), which binds testosterone, and cortisol binding globulin (CBG), which binds cortisol.
Peptide hormones act on cell-surface receptors and exert their effect by activating cyclic adenosine monophosphate (cAMP). Most peptide hormones act via G-protein coupled receptors, most commonly a 7-trans-membrane (7TM) receptor (Figure 1.1). Examples of peptide hormones are growth hormone (GH), thyroid stimulating hormone (TSH), prolactin and ACTH.
Lipid-soluble hormones such as steroids and thyroid hormones pass through the cell membrane and act on intranuclear receptors, causing altered gene transcription (Figure 1.1).
Hormones are usually controlled by a negative feedback mechanism (Figure 1.1). Using the thyroid axis as an example, the hypothalamus secretes its thyrotrophin releasing hormone (TRH), which travels down the portal tract to act on the anterior pituitary. The pituitary releases its trophic hormone (TSH) into the circulation, which acts on the target gland, stimulating the production of the relevant hormone (thyroxine). If the target gland hormone is too low, there is loss of negative feedback and a compensatory increase in the pituitary hormone (low T4, high TSH). If the target gland hormone is too high, there is increased negative feedback and suppression of the pituitary hormone (high T4, low TSH). All pituitary hormones are under predominantly stimulatory control by the hypothalamus apart from prolactin, which is under tonic inhibition by dopamine.
Some hormones are produced in a stable pattern with little circadian rhythmicity, for example thyroxine and prolactin. Other hormones have a significant diurnal variation. For example, cortisol is highest in the morning and lowest at midnight. Minor circadian rhythms can be seen with certain hormones such as testosterone, which is slightly higher in the morning than the afternoon. It is important to measure hormones at the appropriate time of day when assessing for deficiency or excess. Female hormones have a monthly cyclical variation and must be interpreted according to the time of the menstrual cycle.
Hormones are usually measured by immunoassay, which uses specific labelled antibodies that give a signal according to the concentration of hormone. Interfering antibodies can affect blood results, so some results are not reflective of the true concentration of hormone. Assay interference should be suspected in any blood result that does match the clinical picture. Mass spectrometry is a newer technique that provides a more specific measure, and is increasingly being adopted in endocrine laboratories.
When basal investigations are difficult to interpret because of diurnal variation or equivocal results, 24-hour urine collection or dynamic blood tests can be helpful. If hormone deficiency is suspected, a stimulation test is used. This involves administration of a hormone that stimulates the target gland to increase its hormone secretion. Examples are the Synacthen test (to stimulate cortisol in suspected primary adrenal failure) and the insulin tolerance test (to stimulate GH and ACTH in suspected hypopituitarism). If hormone excess is suspected, a suppression test is used. Examples are the dexamethasone suppression test (to suppress cortisol in suspected Cushing’s syndrome) and the oral glucose tolerance test (to suppress GH in suspected acromegaly).
The pituitary gland is the ‘conductor of the endocrine orchestra’, controlling all peripheral glands via trophic hormones. It is approximately the size of a pea and sits in the pituitary fossa at the base of the brain (Figure 2.1). The anterior pituitary is derived embryologically from Rathke’s pouch, derived from primitive gut tissue. The posterior pituitary is derived from a down-growth of primitive brain tissue. The optic chiasm lies superior to the pituitary gland. Lateral is the cavernous sinus, which contains cranial nerves III, IV and Va and the internal carotid artery (Figure 2.1).
Hypothalamic releasing and inhibiting factors are transported along the hypophyseal portal tract to the anterior pituitary. There are five pituitary axes: GH, ACTH, gonadotrophins (FSH and LH), TSH and prolactin (Table 2.1).
GH is secreted in a pulsatile manner with peak pulses during REM sleep. GH acts on the liver to produce IGF-1, which is used as a marker of GH activity. GH exerts its action both by direct effects of GH and via IGF-1. GH causes musculoskeletal growth in children and has an important role in adults. Growth hormone releasing hormone (GHRH) stimulates GH, while somatostatin inhibits it.
ACTH has a circadian rhythm, with peak pulses early in the morning and lowest activity at midnight. ACTH stimulates cortisol release, and is itself stimulated by corticotrophin releasing hormone (CRH). Cortisol is the only hormone that inhibits ACTH.
FSH leads to ovarian follicle development in women and spermatogenesis in men. In women, LH causes mid-cycle ovulation during the LH surge and formation of the corpus luteum. In men, LH drives testosterone secretion from testicular Leydig cells. Gonadotrophin releasing hormone (GnRH) stimulates LH and FSH release. Testosterone and oestrogen inhibit LH and FSH, while prolactin also has a direct inhibitory effect.
TSH drives thyroxine release via stimulation of TSH receptors in the thyroid gland. TRH stimulates TSH secretion and is a weak stimulator of prolactin secretion. Thyroxine directly inhibits TSH.
Prolactin causes lactation and inhibits LH and FSH. It is under predominantly negative control by dopamine and weak stimulatory control by TRH. Anything that inhibits dopamine leads to an elevation in prolactin level.
Pituitary tumours develop as a result of compression of local structures and/or the effects of endocrine hypo- or hypersecretion. Compression of the optic chiasm classically leads to a bi-temporal hemianopia. Assessment of visual fields with a red pin is a mandatory part of the clinical examination of patients with pituitary tumours. Automated visual field assessment has superseded Goldmann perimetry as the formal way of documenting visual field defects.
Prolactin and TSH do not have major circadian rhythms so can be checked at any time of day. Both free T4 (fT4) and TSH should be checked in pituitary disease because TSH is often normal in secondary hypothyroidism. In women, LH and FSH should be measured within the first 5 days of the menstrual cycle (follicular phase). In men, LH, FSH and basal testosterone should be checked at 09.00 in the fasting state. Basal cortisol should be checked at 09.00 to exclude deficiency, although a stimulatory (Synacthen) test is usually needed to confirm this. IGF-1 is a marker of GH activity: low or low–normal levels suggesting GH deficiency; high levels suggesting GH excess.
Dynamic endocrine tests are used to assess hormones that have a pulsatile secretion or circadian rhythm. If an endocrine deficiency is suspected, a stimulation test is used; if endocrine excess is suspected, a suppression test is used (Table 2.1). All endocrine tests should be interpreted in the clinical context.
This is predominantly used to assess primary adrenal failure, but also to assess pituitary ACTH reserve. After 2 weeks of ACTH deficiency, atrophy of the adrenal cortex leads to an inadequate response to synthetic ACTH (Synacthen). This test should not be used in the acute situation, such as pituitary apoplexy, or immediately post-pituitary surgery.
The insulin tolerance test (ITT) is the gold standard test of ACTH and GH reserve. Insulin-induced hypoglycaemia (glucose <2.5 mmol/L) causes physiological stress, leading to a rise in ACTH and GH. A normal cortisol response to hypoglycaemia is >550 nmol/L whereas a GH value >3 µg/dL after hypoglycaemia excludes severe GH deficiency in adults. The ITT is contraindicated in patients with ischaemic heart disease and epilepsy.
The ITT is the gold standard assessment of GH reserve, but is an invasive and unpleasant test to undergo. Glucagon can be used instead of the ITT, although it is a less robust test of GH reserve; nausea is a common side effect. The GHRH–arginine test has particular use in patients who have had pituitary radiotherapy. Common side effects of this are flushing, nausea and an unpleasant taste in the mouth.
Magnetic resonance imaging (MRI) is the imaging modality of choice for the pituitary gland (Figure 2.1). Dedicated pituitary views with injection of contrast highlight the difference between tumour and normal gland. Pituitary tumours >1 cm are termed macro-adenomas, while lesions <1 cm are called micro-adenomas. Computed tomography (CT) may be adequate in patients who are unable to undergo MRI. There is increasing interest in newer imaging modalities, including 11C-methionine positron emission tomography (PET).
Acromegaly, meaning ‘large extremities’ in Greek, is almost exclusively caused by a GH-secreting pituitary tumour. Patients have often had acromegaly for many years before the diagnosis is considered. The increased detection of incidental pituitary tumours can lead to early diagnosis if appropriate tests are performed. Untreated acromegaly can lead to disfiguring features and premature death, predominantly from cardiovascular disease.
Acromegaly is associated with a classic constellation of clinical features (Figure 3.1). Increased size of hands and feet occur commonly, and rings may need to be cut off as they become too tight. Facial features become coarser over time, with frontal bossing of the forehead, protrusion of the chin (prognathism) and widely spaced teeth (Figure 3.2). The diagnosis is often made after the first consultation with a new healthcare professional. Soft tissue swelling leads to enlargement of the tongue and soft palate, snoring and sleep apnoea, and puffiness of the hands with carpal tunnel syndrome. Other specific features of GH hypersecretion include sweating, headaches, hypertension and diabetes mellitus, which may resolve after treatment.
Comparison with old photographs can show when acromegalic features started to develop (Figure 3.3). Patients with large pituitary tumours may present with visual field disturbance resulting from optic chiasm compression and hypopituitarism. If acromegaly occurs before puberty, gigantism occurs. Organomegaly, cardiomyopathy and increased risk of colon cancer can occur in association with acromegaly.
It is relatively easy to confirm or refute a diagnosis of acromegaly once it is considered. An oral glucose tolerance test (OGTT) with 75 g glucose causes suppression of GH to <1 µg/L in patients who do not have acromegaly. Failure to suppress suggests autonomous GH secretion and a diagnosis of acromegaly. Typically, IGF-1 levels are elevated in acromegaly, reflecting increased GH activity. Some tumours co-secrete both GH and prolactin as they share the same cell origin, therefore prolactin may be simultaneously elevated.
Pituitary MRI will reveal either a macro-adenoma or a micro-adenoma. Typically, large tumours are associated with higher GH and IGF-1 levels. Patients with cavernous sinus invasion are likely to need additional treatment because this area is relatively inaccessible surgically.
Surgery is the most appropriate initial treatment for most patients as this is the only modality that offers the chance of permanent cure. With micro-adenomas, there is a high likelihood (>80%) of surgical remission, while remission is only achieved in approximately 60% of patients with macro-adenomas, hence additional treatment may be needed to achieve acceptable GH and IGF-1 levels.
Somatostatin analogues (e.g. octreotide, lanreotide and pasireotide) can improve symptoms and control GH and IGF-1 levels. These drugs are usually given as monthly injections. GH receptor blockers (pegvisomant) can control IGF-1 levels in patients with aggressive acromegaly although treatment is expensive and not widely available. Dopamine agonists can control GH in certain patients with acromegaly, although less effective in patients with very high levels of GH secretion.
In patients with significant residual tumour bulk and disease activity, additional treatment may be needed. External beam or stereotactic (‘gamma knife’ or radio-surgery) radiotherapy can be used. External beam radiotherapy is more established treatment with more published outcome data, but requires daily visits to hospital for administration over several weeks. Stereotactic radiotherapy provides a more targeted treatment at higher dosage and is increasingly used, but is only suitable for lesions well away from the optic chiasm. Radiotherapy can take many years to lower GH. Long-term side effects of radiotherapy include gradual-onset hypopituitarism because of damage to the normal pituitary, and possible cerebrovascular disease.
After initial surgery, repeat OGTT will indicate if there is persistent disease. Long-term follow-up is important to ensure adequate control of GH and IGF-1 levels, and exclude recurrence. Surveillance of disease status is by clinical assessment, IGF-1 measurement and a measure of GH activity (random GH, nadir GH to OGTT or mean GH from a GH day series). The target is GH <1 μg/L and normal IGF-1 although this is often difficult to achieve in practice. There may be a discrepancy between GH and IGF-1 levels in up to 30% of patients. Clinical assessment is important in such patients in deciding whether to treat or monitor. Because of the association of acromegaly with risk of neoplasia, periodic screening colonoscopy should also be considered.
