Essential Revision Notes for MRCP Fourth Edition

edited by Philip A Kalra MA MB BChir FRCP MD Consultant and Honorary Professor of Nephrology, Salford Royal NHS Foundation Trust and The University of Manchester Contents

Contributors to Fourth Edition vii Contributors toThird Edition x Permissions xii Preface to the Fourth Edition xiii

CHAPTER 1. Cardiology 1 J E R Davies, S Nijjer 2. ClinicalPharmacology,ToxicologyandPoisoning 65 S Waring 3. Dermatology 87 H Robertshaw 4. Endocrinology 107 T Kearney, S Giritharan, M Kumar 5. Epidemiology 143 J Ritchie 6. Gastroenterology 157 S Lal, D H Vasant 7. Genetics 205 E Burkitt Wright 8. Genito-urinary Medicine and AIDS 223 B Goorney 9. Haematology 237 K Patterson 10. Immunology 279 J Galloway 11. Infectious Diseases andTropical Medicine 295 C L van Halsema 12. Maternal Medicine 329 L Byrd

v Contents

13. Metabolic Diseases 359 S Sinha 14. Molecular Medicine 395 K Siddals 15. Nephrology 435 P Kalra 16. Neurology 493 M Jones, C Kobylecki, D Rog 17. Ophthalmology 561 K Smyth 18. Psychiatry 583 E Sampson 19. Respiratory Medicine 611 H Green 20. Rheumatology 657 M McMahon 21. Statistics 685 E Koutoumanou Index 703

vi Chapter 4 Endocrinology

CONTENTS

4.1 Hormone action 4.4 Hyponatraemia and SIADH 4.1.1 Types of hormone 4.1.2 Hormones that act at the cell 4.5 The thyroid gland surface 4.5.1 Hyperthyroidism and 4.1.3 Hormones that act hypothyroidism intracellularly 4.5.2 Causes of thyrotoxicosis 4.1.4 Hormone resistance syndromes 4.5.3 Thyroid cancer and nodules 4.5.4 Drugs and the thyroid 4.2 Speci¢c hormone physiology 4.5.5 Autoimmunity and eye signs in 4.2.1 Hormones in illness thyroid disease 4.2.2 Hormone changes in obesity 4.5.6 Thyroid function tests 4.2.3 Hormones in pregnancy 4.2.4 Investigations in endocrinology 4.6 Adrenal disease and hirsutism 4.2.5 Growth hormone 4.6.1 Cushing syndrome 4.2.6 Prolactin 4.6.2 Primary hyperaldosteronism 4.2.7 Adrenal steroids 4.6.3 Congenital adrenal hyperplasia 4.2.8 Thyroid hormone metabolism 4.6.4 Hypoadrenalism 4.2.9 Renin–angiotensin–aldosterone 4.6.5 Polycystic ovary syndrome and 4.2.10 Calcium, PTH and vitamin D hirsutism 4.2.11 Atrial natriuretic peptide 4.7 Phaeochromocytoma and 4.3 The pituitary gland multiple endocrine neoplasia 4.3.1 Anatomy syndromes 4.3.2 Pituitary tumours 4.3.3 Diabetes insipidus 4.8 Puberty/growth/intersex 4.3.4 Acromegaly 4.8.1 Normal puberty 4.3.5 Prolactinomas 4.8.2 Precocious puberty 4.3.6 Hypopituitarism and growth 4.8.3 Delayed puberty/short stature hormone deficiency in adults 4.8.4 Intersex

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4.9 Diabetes mellitus 4.9.1 Risk factors and clinical features of types 1 and 2 diabetes mellitus 4.9.2 Diagnostic criteria for diabetes 4.9.3 Treatment of type 1 diabetes 4.9.4 Treatment of type 2 diabetes 4.9.5 Glycated HbA1c 4.9.6 Microvascular and macrovascular complications of diabetes 4.9.7 Autonomic neuropathy

4.10 Hypoglycaemia 4.10.1 Hypoglycaemia in diabetes mellitus 4.10.2 Hypoglycaemia unrelated to diabetes

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Endocrinology

4.1 HORMONE ACTION bind to an intracellular receptor and affect gene transcription. Glucagon is not a steroid or an amine There are three main types of hormone: so it must be a polypeptide hormone, which has a • amine short circulation half-life, acts via a cell surface • steroid receptor and probably utilises a second messenger • peptide. (adenosine cyclic monophosphate, or cAMP, in fact). Knowing which category a particular hormone fits into makes it possible to guess much of its physiol- ogy. Thyroxine is an exception to this, as shown 4.1.2 Hormones that act at the cell below. surface Peptide and amine hormones act at the cell surface 4.1.1 Types of hormone via specific membrane receptors. The signal is trans- • Amine: catecholamines, serotonin, thyroxine mitted intracellularly by one of three mechanisms: • Steroid: cortisol, aldosterone, androgens, • Via cAMP oestrogens , progestogens and vitamin D • Via a rise in intracellular calcium • Peptide: everything else! (made up of a series of • Via receptor tyrosine kinases. amino acids). Thyroxine is chemically an amine but it acts like a If in doubt, assume the action of a peptide or amine steroid. Vitamin D has the structure of a steroid hormone (excluding thyroxine) is via cAMP, unless hormone and it acts like one. it is insulin or has the word ‘growth’ in its name, in which case it is likely to act via a receptor tyrosine kinase (Table 4.1). Amines/peptides

• Short half-life (minutes) Cyclic AMP and G-proteins • Secretion may be pulsatile • Act on a cell surface receptor Hormone receptors linked to cAMP (eg thyroid- • Often act via a second messenger stimulating hormone [TSH] receptor) typically have seven transmembrane domains. The receptor does not directly generate cAMP but acts via separate ‘G- Steroids proteins’ on the cell surface which, in turn, interact with the cAMP-generating enzyme, adenylyl • Longer biological half-life (hours) cyclase, on the cell surface. (See Figure 14.4 in • Act on an intracellular receptor Chapter 14, Molecular Medicine.) • Act on DNA to alter gene expression Hormones that raise the level of cAMP intracellu- larly (all hormones in this category except somato- This information can be used to predict hormone statin) act via a stimulatory G-protein, ‘Gs’. action, eg aldosterone is a steroid hormone so it Hormones that lower the level of cAMP (somato- must have a biological half-life of several hours, statin) act via an inhibitory G-protein, ‘G i’.

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Table 4.1 Mechanisms of hormone action

Via cAMP Via Ca 2+ Via receptor tyrosine kinases

Adrenaline (â receptors) GnRH Insulin All pituitary hormones except GH, PRL TRH GH, PRL Glucagon Adrenaline (Æ receptors) ‘Growth factors’: IGF-1, EGF Somatostatin cAMP, adenosine cyclic monophosphate; EGF, epidermal growth factor; GH, growth hormone; GnRH, gonado- trophin-releasing hormone; IGF-1, insulin-like growth factor 1; PRL, prolactin; TRH, thyrotrophin-releasing hormone.

G-proteins are important in endocrinology because pseudohypoparathyroidism). The dysmorphic mutations in Gs have been found to be associated bone features are sometimes referred to as with certain diseases: ‘Albright’s hereditary osteodystrophy’ and can be present in either the maternally or the paternally • Acromegaly: 40% of patients with acromegaly inherited form. have an activating somatic mutation of Gs in their pituitary tumour. As a result, the cells are always ‘switched on’ and continuously make 2+ growth hormone (GH), resulting in acromegaly Intracellular Ca • McCune–Albright syndrome: an activating Some hormones release intracellular Ca 2+ as a sec- mutation of Gs early in embryonic development ond messenger (see Table 4.1 for examples). The causes hyperfunction of one or more endocrine receptors for these hormones activate different G- glands with the following sequelae: precocious proteins (eg Gq), which in turn activate the cyto- puberty (gonad hyperfunction), acromegaly (GH plasmic enzyme phospholipase C (PLC). PLC re- hypersecretion), Cushing syndrome (adrenal leases the small molecule inositol-1,4,5- gland hyperfunction), thyrotoxicosis or triphosphate (IP3) from membrane phospholipids. hyperparathyroidism. The syndrome is IP3 in turn binds to the IP3-sensitive receptor on the associated with cafe´-au-lait spots and endoplasmic reticulum within the cell, causing Ca 2+ polyostotic fibrous dysplasia. As the mutation to be released from stores in the endoplasmic retic- occurs after the zygote stage, affected ulum into the cytoplasm. The Ca 2+ subsequently individuals are a mosaic and different patterns affects cell metabolism by binding to the protein of tissue involvement may be seen between calmodulin. individuals • Pseudohypoparathyroidism: inactivating germline mutations in Gs result in Receptor tyrosine kinases pseudohypoparathyroidism type 1A if maternally inherited, with dysmorphic features (including The insulin, GH, prolactin and growth factor recep- short fourth or fifth metacarpal) and resistance to tors do not use second messengers. The receptors a variety of hormones that act via cAMP themselves can act as enzymes that phosphorylate (including parathyroid hormone, TSH and (‘kinase activity’) other proteins when hormone is gonadotrophins). Spontaneously occurring or bound at the cell surface. This is followed by a paternally inherited mutations cause the cascade of proteins phosphorylating other proteins dysmorphic features alone (pseudo- until gene transcription in the nucleus is modulated.

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4.1.3 Hormones that act hormone (TRH), TSH and L-thyroxine/L-triiodothyro- intracellularly nine (T4/T3). It is orchestrated by the hypothalamus, not by the end-organs. Hormones involved in the Steroids, vitamin D and thyroxine are sufficiently stress response may rise. lipid-soluble that they do not need cell surface receptors but can diffuse directly through the cell Hormones that fall membrane. They then bind to receptors in the cytoplasm, which results in shedding of heat shock • TSH, T4/T3a proteins that protect the empty receptor. The hor- • mone–receptor complex migrates into the nucleus LH, FSH • Testosterone, oestrogen where it alters the transcription of a large number of • genes (see Figure 14.6 in Chapter 14, Molecular Insulin (starvation) Medicine). May rise (stress hormones)

4.1.4 Hormone resistance syndromes • GH (though IGF-1 falls) • ACTH, glucocorticoids The following are conditions of hormone resistance • Adrenaline with the site of the defect shown. • Glucagon (starvation) • Prolactin • Receptor defect (hormone involved) a • Laron’s dwarfism (GH) In this case conversion of T4 to T3 is inhibited so T3 • Leprechaunism (Donahue’s syndrome, falls more than T4 ACTH, adrenocorticotrophic hormone; FSH, follicle- Rabson–Mendenhall syndrome [insulin]) stimulating hormone; GH, growth hormone; IGF-1, • Nephrogenic diabetes insipidus insulin-like growth factor 1; LH, luteinising hormone; (antidiuretic hormone [ADH]) T3, L-triiodothyronine; T4, L-thyroxine; TSH, thyroid- • Androgen resistance (testicular stimulating hormone. feminisation syndrome (testosterone)) • Vitamin-D-dependent rickets type 2 – In starvation alone, without illness, all hormones fall hereditary vitamin D resistance rickets except glucagon. In anorexia nervosa there is also (vitamin D) a stress: all hormones fall except glucagon, GH and • Second messenger defect glucocorticoids. • Pseudohypoparathyroidism • Defect unknown • Type 2 diabetes 4.2.2 Hormone changes in obesity aVitamin D-dependent rickets type 1 is due to a failure In the absence of other diseases (eg type 2 dia- of 1-hydroxylation of vitamin D. betes), which might develop in obese patients, the following changes are seen in obesity: • Hyperinsulinaemia • 4.2 SPECIFIC HORMONE Increased cortisol turnover but not PHYSIOLOGY hypercortisolism • Increased androgen levels in women • 4.2.1 Hormones in illness Reduced GH • Conversion of androgens to oestrogens During illness/stress, the body closes all unneces- • A proatherogenic lipid profile develops (low sary systems down ‘from the top’, eg the thyroid high-density lipoprotein [HDL], high low- axis closes down by a fall in thyrotrophin-releasing density lipoprotein [LDL] and triglyceride).

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Leptin, adipokines and other hormones Derived from tissue-specific cleavage of involved with appetite and weight proglucagon • Oxyntomodulin: also released from L cells and Leptin was identified as a product of the ‘ ob’ gene derived from proglucagon; appears to act on the in 1994. Ob/ob mice make no leptin, owing to a same receptor as GLP-1, but with less incretin, homozygous ob gene mutation, and are grossly and has more of an appetite-suppressing effect obese. • Neuropeptide Y (NPY), from the hypothalamus • Leptin is a polypeptide hormone, released from itself, and Agouti-related protein (AgRP) increase fat cells, that acts on specific receptors in the appetite, whereas Æ-melanocyte-stimulating hypothalamus to reduce appetite hormone (Æ-MSH, a melanocortin) reduces • Circulating leptin levels are directly proportional appetite. to fat mass, and so they tell the brain how fat an individual is In addition to leptin, a number of other hormones • Leptin appears to have stimulatory effects on have recently been identified as being released from metabolic rate and levels fall in starvation fat cells. These ‘adipokines’ include adiponectin, (appropriate change for weight homeostasis) which reduces insulin resistance, and resistin and • Adequate leptin levels are required for the onset acylation-stimulating protein (ASP), which both in- of puberty crease insulin resistance. Visfatin (also known as • Persistently obese individuals appear relatively nicotinamide phosphoribosyltransferase [NAMPT] resistant to leptin and pre-B-cell colony-enhancing factor) is released • Congenital leptin deficiency presents in predominantly from visceral fat and has insulin-like childhood with gross obesity and hyperphagia. actions. The role of these adipokines in the associa- This changes dramatically with treatment of tion between obesity and insulin resistance remains exogenous leptin. uncertain.

Several other hormones have recently been shown 4.2.3 Hormones in pregnancy to affect appetite and weight: As a general rule, most hormone levels rise in preg- • Ghrelin: this was first identified as a GH- nancy. Insulin resistance develops, causing a rise in releasing hormone. It is released from the circulating insulin levels. Insulin requirements are stomach when subjects are fasting or in highest in the last trimester but fall slightly in the conditions of negative energy balance and last 4 weeks of pregnancy. triggers hunger. It stimulates gastric contraction Other key features of hormone metabolism in preg- and hence gastric emptying. Ghrelin levels fall nancy are as follows: after gastric bypass surgery, which may help weight loss by reducing appetite • Prolactin levels rise steadily throughout • Peptide YY (a member of the neuropeptide Y pregnancy and, in combination with oestrogen, family): released from L cells in the small and prepare the breast for lactation. Post-partum large bowel. Levels rise after meals and reduce surges of prolactin and oxytocin are generated appetite. This may be the main regulator of day- by the nipple stimulation of breastfeeding. to-day appetite However, after several weeks, prolactin levels • Glucagon-like peptide-1 (GLP-1): also released fall almost to normal, even if breastfeeding from L cells of the intestine after meals and continues powerfully promotes insulin secretion in • LH/FSH from the pituitary are no longer response to raised glucose (‘incretin effect’), as necessary after conception for continued well as possibly reducing appetite. Inactivated pregnancy (although the pituitary may double in by the enzyme dipeptidylpeptidase-4 (DPP-4). size) and the placenta takes over

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• Thyroid axis : thyroid-binding globulin (TBG) of which is constant and which mediates almost all levels rise in the first trimester, causing a rise in the actions of GH, ie GH does not act directly. The total T4 and total T3. However, human effective levels of IGF-1 are influenced by changes chorionic gonadotrophin (hCG) from the in the level of its six binding proteins (IGF-BP 1–6). placenta shares its Æ subunit with TSH, and very high levels in the first trimester can cause true 4.2.6 Prolactin mild thyrotoxicosis (not just a binding protein rise), especially associated with hyperemesis Prolactin causes galactorrhoea but not gynaecomas- gravidarum. Note that T4 and T3 do not cross tia (oestrogen does this). Raised prolactin levels are the placenta very efficiently, but sufficient T4 essentially the only cause of galactorrhoea, does cross to prevent a fetus with congenital although occasionally prolactin levels in the normal hypothyroidism becoming hypothyroid until range can cause milk production in a sensitised after birth. breast. Raised prolactin levels also ‘shut down’ the gonadal axis ‘from the top’ (hypothalamic level), 4.2.4 Investigations in endocrinology resulting in low GnRH, LH and oestrogen/testoster- one levels. Surprisingly, prolactin is a stress hor- The plasma level of almost all hormones varies mone and can rise in various levels of stress, from through the day (because of pulsatile secretion, anxiety about venepuncture to an epileptic fit. environmental stress or circadian rhythms) and is influenced by the prevailing values of the substrates Prolactin release from the pituitary is under negative that they control. This makes it hard to define a control by dopamine from the hypothalamus. Oes- ‘normal range’, eg insulin values depend on the trogens (the pill, pregnancy) and nipple stimulation glucose level, and GH levels depend on whether a raise prolactin. pulse of GH has just been released or the blood sample is taken in the trough between pulses. Prolactin is raised by

Dynamic testing is therefore frequently used, ie • Phenothiazines, haloperidol (not tricyclics) suppression or stimulation tests. The principle is, ‘If • Antiemetics (eg metoclopramide) you think a hormone level may be high, suppress it; • Damage to hypothalamus (eg radiation) if you think it may be low, stimulate it’. • Pregnancy • • Nipple stimulation Suppression tests are used to test for hormone • EXCESS, eg dexamethasone suppression for Damage to pituitary stalk (eg pressure from Cushing syndrome, glucose tolerance for GH in a pituitary tumour) • Oestrogens acromegaly • • Stimulation tests are used to test for hormone Polycystic ovary syndrome DEFICIENCY, eg Synacthen tests for hypoadrenalism, insulin-induced hypoglycaemia Prolactin is suppressed by for GH deficiency and/or hypoadrenalism. • Dopamine agonist drugs (eg bromocriptine, cabergoline) 4.2.5 Growth hormone This is secreted in pulses lasting 30–45 minutes Gynaecomastia separated by periods when secretion is undetect- able. The majority of GH pulses occur at night This is due to a decreased androgen:oestrogen ratio (‘children grow at night’). In response to GH pulses, in men. Gynaecomastia is unrelated to galactor- the liver makes insulin-like growth factor 1 (IGF-1, rhoea (which is always due to prolactin). Breast previously called somatomedin C), the plasma level enlargement is not necessary to make milk.

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Causes of gynaecomastia: 4.2.8 Thyroid hormone metabolism • Pubertal (normal) More than 95% of thyroid hormones are bound to • Obesity – not true gynaecomastia plasma proteins in the circulation, predominantly • Hypogonadism (eg Klinefelter’s syndrome, TBG and thyroid-binding prealbumin (TBPA). T4 testicular failure) (four iodine atoms per molecule) has a half-life of 7 • Cirrhosis, alcohol days (so, if a patient is in a confused state, it is • Hyperthyroidism possible to administer his or her total weekly dose • Drugs: including spironolactone, digoxin, of thyroxine once a week). It is converted partly in oestrogens, cimetidine, anabolic steroids, the thyroid and partly in the circulation to T3 (three marijuana iodine atoms per molecule), which is the active • Tumours, including adrenal or testicular, making form and has a half-life of 1 day. oestrogen; lung, pancreatic, gastric, making There are three deiodinase enzymes that act on hCG; hepatomas converting androgens to thyroid hormones (D1–D3). D1 and D2 promote oestrogens. the generation of active hormone (T3) by converting T4 to T3 (Figure 4.1). D3 opposes this by promoting 4.2.7 Adrenal steroids conversion of T4 to reverse T3 (rT3) and destroying T3 by conversion to T2 (inactive). The D1 and D2 These act intracellularly to alter the transcription of enzymes are inhibited by illness, propranolol, pro- DNA to mRNA (see Section 4.1, Hormone action). pylthiouracil, amiodarone and ipodate (formerly Surprisingly, the mineralocorticoid (aldosterone) and glucocorticoid receptors have an equal affinity for cortisol. However, the cellular enzyme 11- â- Figure 4.1 Metabolism of thyroid hormones, hydroxysteroid dehydrogenase ‘protects’ the miner- D1–D3, different deiodinase enzymes that act alocorticoid receptor by chemically modifying any on thyroid hormone. cortisol that comes near the receptor to an inactive T3 (active form) form, while having no effect on aldosterone itself. Inactivating mutations of this enzyme, or inhibition D1 , D 2 of it by liquorice, causes ‘apparent mineralocorti- coid excess’, because cortisol (which circulates at T4 much higher concentrations than aldosterone) is able to stimulate the mineralocorticoid receptor. D3 The effects of adrenal steroids and their duration of rT3 (reverse T 3 ) action are given in Table 4.2.

Table 4.2 Adrenal steroids

Relative Relative Duration of action glucocorticoid effect mineralocorticoid effect

Cortisol ¼ hydrocortisone 1 þ Short Prednisolone 4 Æ Medium Dexamethasone 30 À Long Fludrocortisone 10 þþþ

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used as X-ray contrast medium for study of gall- Renin is released from the JGA (juxtaglomerular bladder disease). This reduces the level of active apparatus) of the kidney in response to low Na + hormone, T3, with little change or a rise in T4. delivery or reduced renal perfusion. Renin is an Reverse T3 levels rise (T4 spontaneously converts to enzyme that converts angiotensinogen to angioten- rT3 if the monodeiodinase is not available), but rT3 sin I (10 amino acids). ACE (angiotensin-converting is not detected in laboratory tests of T3 levels. enzyme) in the lung converts angiotensin I to angio- tensin II, which is the active form. ACE also breaks It is said that you should ‘never measure thyroid down bradykinin: ACE inhibitors (eg captopril) are function tests on the intensive care unit because believed to cause cough as a result of a build-up of you will not be able to interpret them’. In illness, bradykinin in the lung. The renin–angiotensin sys- TSH and free T3 levels fall (‘sick euthyroidism’). The tem is designed to restore circulating volume. It is only interpretable finding in sick patients is a raised therefore activated by hypovolaemia (Figure 4.2) free T3 – this would almost definitely indicate and its end product, angiotensin II, has three actions thyrotoxicosis. that restore volume: • Releasing aldosterone from the adrenal (retains 4.2.9 Renin^angiotensin^aldosterone Na +, excretes K + in the distal tubule) Aldosterone secretion is controlled almost comple- • Vasoconstriction (powerful) tely by the renin–angiotensin system, not by ACTH. • Induction of thirst (powerful). The initial letters of the zones of the adrenal cortex from outside inwards spell ‘GFR’, similar to glomer- ular filtration rate: glomerularis, fasciculata, reticu- 4.2.10 Calcium, PTH and vitamin D laris. Aldosterone is the ‘outsider hormone’ and is made on the ‘outside’ (zona glomerulosa). (See also Chapter 13, Metabolic Diseases.)

Figure 4.2 The renin–angiotensin system.

ϩ Low Na delivery Angiotensinogen

Renal perfusion RENIN reduced Release Angiotensin I

Angiotensin-converting â-adrenoreceptor enzyme (ACE) in the lung stimulates Also inactivates bradykinin α-adrenoreceptor inihibits Angiotensin II Aldosterone Thirst secretion

ϩ Retain Na Vasoconstriction ϩ ϩ Excrete K /H (distal tubule)

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Plasma calcium is tightly regulated by parathyroid • Natriuretic: it causes a natriuresis (urinary hormone (PTH) and vitamin D, acting on the kidney excretion of sodium). It thereby reduces (PTH), bone (PTH) and gut (vitamin D). circulating volume (opposite of renin– angiotensin). As you would predict, therefore, it PTH controls Ca 2+ levels minute to minute by is secreted in conditions of hypervolaemia – via mobilising Ca 2+ from bone and inhibiting Ca 2+ stretch of the right atrial and ventricular walls. It excretion from the kidney. Vitamin D has a more also antagonises the other actions of angiotensin long-term role, predominantly by promoting Ca 2+ II by causing vasodilatation and reduced thirst/ absorption from the gut. Its actions on the kidney salt craving and bone are of lesser importance. Ca 2+ levels are • Peptide : it is a peptide hormone (which acts via sensed by a specific calcium-sensing receptor on cAMP). the parathyroid glands. Mutations that reduce the activity of this receptor result in a resetting of There are two other natriuretic peptides, B-type and calcium and PTH to higher levels (familial hypocal- C-type natriuretic peptides (BNP and CNP). BNP is ciuric hypercalcaemia, FHH). Activating mutations similar to ANP, and is produced from the heart, can also occur, which result in a picture almost especially in heart failure. Serum levels are more indistinguishable from hypoparathyroidism, with a stable than those of ANP, and BNP is proving to be low Ca 2+ (autosomal dominant hypocalcaemia with a useful test of heart failure. CNP is produced by hypercalciuria). It is important to identify these con- the vascular endothelium rather than cardiac myo- ditions because they run a benign course and only cytes. attempted treatment causes problems (eg raising the serum Ca 2+ in autosomal dominant hypocalcaemia will predispose to renal stone formation). 4.3 THE PITUITARY GLAND Precursor vitamin D, obtained from the diet or synthesised by the action of sunlight on the skin, 4.3.1 Anatomy requires activation by two steps: The anatomical relations of the pituitary (Figure 4.3) • 25-hydroxylation in the liver • are important because enlarging pituitary tumours 1-hydroxylation in the kidney. may press on surrounding structures. PTH can promote 1-hydroxylation of vitamin D in • Above: optic chiasma (classically causing the kidney, ie it can activate vitamin D, thereby bitemporal hemianopia if compressed, but any 2+ indirectly stimulating Ca absorption from the gut. visual field defect may occur), pituitary stalk, hypothalamus, temporal lobes Calcitonin (from the C cells of the thyroid) behaves • almost exactly as a counter-hormone to PTH Below: sphenoid sinus (in front and below to 2+ 2+ allow trans-sphenoidal surgery), nasopharynx (secreted by high Ca , acts to lower serum Ca by • inhibiting Ca 2+ release from bone), but its physio- Lateral: cavernous sinus, internal carotid logical importance is in doubt (thyroidectomy does arteries, III, IV, V , and V and VI cranial nerves. 2+ not affect Ca levels if the parathyroid glands are Expanding pituitary tumours may also compromise undisturbed). remaining anterior pituitary function, but rarely af- fect posterior pituitary hormones. 4.2.11 Atrial natriuretic peptide Atrial natriuretic peptide (ANP) physiology can be 4.3.2 Pituitary tumours predicted from its name: A microadenoma is a pituitary tumour ,10 mm in • Atrial: it is synthesised by the myocytes of the size. The size and frequency of pituitary tumours right atrium and ventricle are related.

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Figure 4.3 Schematic sagittal section through the pituitary to show its relation to surrounding structures. Supraoptic recess Hypothalamus

Optic chiasm

Suprasellar cistern Pituitary stalk Cavernous sinus Temporal lobe III IV V1 V Internal carotid 2 artery

Sphenoid sinus Pituitary gland

Sphenoid bone

Pituitary tumours excessive ACTH production from the pituitary gland • (usually by a microadenoma). They are in them- Large – non-secreting (typically selves rare. chromophobe): 50% of all tumours • Large – prolactinomas in men: 25% of all For further discussion about Cushing syndrome tumours diagnosis and management, please see Section • Medium – acromegaly (typically 4.6.1. ‘acidophil’, 70% are about 1 cm): 12% of Excessive secretion of GH from the pituitary gland all tumours • in adults is termed ‘acromegaly’. There is a prepon- Small – Cushing’s disease (often derance to macroadenomas with blunting of the undetectable on CT/MRI, typically normal pulsatile GH secretion. basophil): 5–10% of all tumours • Small – TSH secreting: 1% (very rare) Pituitary apoplexy is sudden enlargement of the pituitary by haemorrhage into a tumour, typically causing the combination of headache, neck stiffness The most common tumours are small, non- and sudden blindness associated with cardio- functioning microadenomas, which have been re- vascular collapse due to hypopituitarism. Treatment ported to occur in up to 20% of people post is with steroid replacement and urgent surgery for mortem. visual loss (to decompress optic chiasma). In pitui- tary failure the only two hormones that must be Prolactinomas are the most common functioning replaced for survival are T4 and hydrocortisone. It is pituitary tumours. Microprolactinomas are more fre- important to ensure that the patient is adequately quent than macroprolactinomas. replaced with glucocorticoids before starting True Cushing’s disease is used to describe pituitary- replacement of T4, because levothyroxine increases dependent Cushing syndrome. This is caused by glucocorticoid clearance.

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Craniopharyngiomas are benign tumours that arise Causes of nephrogenic DI from remnants of Rathke’s pouch. Two-thirds arise in the hypothalamus itself (suprasellar) and a third Reduced action of ADH on the kidney can in the sella. They are usually cystic, frequently have several causes: calcify, often recur after aspiration and, although • Primary they represent an embryonic remnant, they not • Childhood onset: X-linked/dominant infrequently present in adulthood. abnormality in tubular ADH receptor • Secondary (common) 4.3.3 Diabetes insipidus • Hypercalcaemia • Hypokalaemia ADH (also called vasopressin or arginine–vasopres- • Renal disease (particularly if it involves sin, AVP) is synthesised in the hypothalamus and the medullary interstitium) transported to the posterior pituitary, along with • Lithium oxytocin, for storage and release. Diabetes insipidus • Demeclocycline (DI) is caused either by a failure to secrete vasopres- sin from the posterior pituitary (central or cranial DI) or resistance to the action of vasopressin in the Water deprivation test kidney (nephrogenic DI). To cause cranial DI, the A water deprivation test (Table 4.3) is used to hypothalamic nuclei (supraoptic and paraventricular) identify the cause of polydipsia and/or polyuria. It is need to be damaged – it is not sufficient simply to worth confirming polyuria (urine output .3000 mL/ compress the posterior pituitary, because vasopressin 24 h) before proceeding to a water deprivation test. can be secreted directly from the hypothalamus Major metabolic causes should first be excluded (eg itself. Pituitary tumours therefore rarely cause Dl. hyperglycaemia, hypercalcaemia, hypokalaemia, chronic renal failure). The patient is then deprived Major causes of cranial diabetes of water (from the night before if polyuria is not insipidus excessive) and hourly urine and plasma osmolality are measured until 3% of the body weight is lost. • Idiopathic The patient is then given an injection of DDAVP (a • Craniopharyngiomas synthetic analogue of ADH). • Infiltrative processes of the hypothalamus (eg sarcoid, histiocytosis X) Interpretation of the water deprivation test • Trauma • • Pituitary surgery Primary polydipsia (compulsive water drinking): • Lymphocytic hypophysitis in this condition the patient is not dehydrated • Dysgerminomas but water overloaded in the resting state (Na+ ,140 mmol/l). Chronic polydipsia in this

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Table 4.3 Interpretation of the water deprivation test

Initial plasma Final urine osmolality Urine osmolality Final plasma ADH osmolality (mosmol/kg) post-DDAVP (mosmol/kg)

Normal Normal .600 .600 High Cranial Dl High ,300 .600 Low Nephrogenic Dl High ,300 ,300 High Primary polydipsia Low 300–400 (approx.) 400 (approx.) Moderate Partial cranial Dl High 300–400 400–600 Relatively low

ADH, antidiuretic hormone; DI, diabetes insipidus.

condition can result in washout of the renal 4.3.4 Acromegaly medullary-concentrating gradient so that, even if The common features of acromegaly are well the patient does become dehydrated, with a rise known (hand and foot enlargement, coarse facial in ADH, urine cannot be concentrated features, overbite of the lower jaw, splaying of the • Cranial DI : in this condition there is failure to teeth) but the following also occur (see box). concentrate urine due to lack of ADH. This is observed with a high plasma osmolality and a relatively low urine osmolality throughout the Features of acromegaly test. Administration of DDAVP allows the • Diabetes kidneys to concentrate urine, thus raising the • osmolality. If the thirst mechanism is intact, Arthropathy – often pseudogout • Sleep apnoea patients attempt to compensate by increasing • their fluid intake orally. If, however, this Carpal tunnel syndrome • Multinodular goitre mechanism is disrupted (patient is unconscious • or has intracerebral lesion rendering the patient Increase in malignancies, especially colonic adipsic), there is a significant risk of becoming polyps • Hypertension dehydrated very quickly • • Partial cranial DI : in this condition there is Twofold increase in death from weak ADH production. There is a similar effect cardiovascular disease • Cardiomyopathy on the renal medullary-concentrating gradient to • that seen in primary polydipsia, and so the two Left ventricular hypertrophy • Enlarged testes conditions cannot be differentiated unless a • post-hydration serum ADH level is obtained Renal stones (hypercalciuria) • • Raised phosphate Nephrogenic diabetes inspidus: despite • adequate circulating ADH, there is renal Raised prolactin, galactorrhoea, menstrual change resistance to the action of ADH, resulting in an • inability to concentrate urine. Therefore urine Raised triglycerides osmolality does not improve on administration of DDVAP during the water deprivation test. Acromegaly is almost always due to a GH-secreting Treatment is by correcting the underlying cause pituitary tumour. Rarely, the condition is due to and ensuring adequate hydration. Sometimes ectopic GH-releasing hormone (GHRH) secretion high doses of DDAVP can be used. from a tumour (typically carcinoid) which stimulates

119 Essential Revision Notes for MRCP

the normal pituitary (no discrete tumour seen on cases, with shrinkage of the tumour in about 85%. MRI). Biochemical tests usually reveal a raised Surgery is usually reserved for patients who are serum IGF-1 level (above the age- and gender- intolerant or resistant to dopamine agonists. specific normal range). The diagnosis is confirmed by failure to suppress GH to a nadir of 0.4 ng/mL on an oral glucose tolerance test. 4.3.6 Hypopituitarism and growth hormone de¢ciency in adults First-line treatment is trans-sphenoidal surgery to resect the pituitary tumour (or transcranial surgery if Panhypopituitarism can be caused by enlarging there is a large suprasellar extension of the tumour). pituitary tumours, cranial irradiation (including The cure rate is very variable (40–80%), and is specific pituitary radiotherapy), pituitary apoplexy, dependent on the extent of lateral and superior Sheehan’s syndrome (infarction after post-partum extension and the skill of the surgeon. Alternative haemorrhage), and then by any of the conditions therapies are dopamine agonists (bromocriptine, that can cause cranial diabetes insipidus (see box cabergoline, quinagolide, pergolide, which reduce on p. 118). GH secretion in approximately 20% of cases), so- Patients present with a soft, smooth ‘baby’ skin, matostatin analogues (octreotide, which inhibit GH ‘crows’ feet’ lines around the eyes and features secretion), GH antagonists (pegvisamant, which related to their specific hormonal deficiencies – blocks GH) and pituitary radiotherapy (may take hypotension in relation to ACTH deficiency, weight years to take effect and may result in hypopituitar- gain in relation to TSH deficiency, etc. ism). After successful treatment of acromegaly most physical features do not regress, although some soft- Typically, hormone loss follows a common pattern, tissue effects do. Features of active disease are in- with GH deficiency being most common, followed creased sweating and oedema, together with evi- in order by LH, FSH, ACTH and TSH deficiency. dence of metabolic effects such as poor glycaemic Secondary hypothyroidism is suggested by a low and hypertensive control. free T4 (fT4) in the context of a low or inappropri- ately normal TSH. ACTH deficiency is diagnosed by 4.3.5 Prolactinomas an insulin stress test or glucagon test or, if long- standing, may be suggested by a failed short Prolactinomas are the most common functioning Synacthen test with low or inappropriately normal pituitary tumours. They present with galactorrhoea, ACTH levels, although this test depends on the gonadal dysfunction (amenorrhea, oligomenor- presence of adrenal atrophy subsequent to ACTH rhoea, poor libido, erectile dysfunction, subfertility) deficiency. The following points should be noted: and symptoms of mass effect (headache and dete- • Only replacement therapy with corticosteroids rioration in visual fields). Diagnosis is based on and T4 is essential for life raised serum prolactin concentrations and demon- • In suspected hypopituitarism, the steroids should stration of a pituitary lesion on MRI. Microadeno- be given first and certainly before thyroid mas can be hard to detect on imaging and may replacement therapy. This is because correction appear as gland asymmetry, but generally speaking of hypothyroidism will accelerate cortisol the size of the lesion is proportional to the prolactin metabolism and would precipitate a level. hypoadrenal crisis (if T4 is given before Treatment is aimed at normalising the prolactin exogenous steroids) level, restoring gonadal function and reducing the • If the pituitary is damaged, GH production is size of the lesion. The first-line treatment of prolacti- lost early, so that most patients are GH-deficient nomas is medical management. Dopamine agonists (see below) such as cabergoline and bromocriptine suppress • Despite conventional hormone replacement prolactin levels to normal in approximately 95% of therapy (T4, glucocorticoid and sex steroids),

120 Endocrinology

mortality rates are increased in hypopituitarism ADH will be secreted even if the osmolality is low. due to cardiovascular events or malignancy. The This explains the hyponatraemia seen in renal, potential for GH therapy to reverse this trend is cardiac and liver failure, as well as after excessive currently undergoing research. sodium loss (eg diarrhoea). Other stimuli can also commonly override control of ADH secretion by GH de¢ciency osmolarity (see Syndrome of inappropriate ADH secretion [SIADH] below). The main role for GH in children is growth; how- ever, in adults GH is required for musculoskeletal, Syndrome of inappropriate ADH secretion metabolic and possibly psychological wellbeing. Many common stimuli override the control of os- Adult GHD is associated with the following: molality and cause inappropriate amounts of ADH • Reduced muscle tone and power, increased fat to be secreted, causing hyponatraemia. Sodium mass, easy fatigability, poor exercise tolerance concentration should be high in the urine (exclud- • Low mood, poor concentration and memory ing hypovolaemia), renal, adrenal and thyroid func- • Osteoporosis tion should be normal, and diuretic therapy needs • Increased cardiovascular risk (impaired to be excluded before SIADH is diagnosed. Treat- endothelial function, proatherogenic lipid ment is by fluid restriction or, if necessary, oral profile, impaired left ventricular function). demeclocycline. Based on guidance of the National Institute for Causes of inappropriate secretion of Health and Care Excellence (NICE), GH replace- ADH include ment in adults is indicated for impaired quality of life in patients with severe GH deficiency (defined • as a peak GH response ,9 mU/L [3 ng/mL] during Nausea • Pain a stimulation test). These symptoms are reassessed • after a 9-month period of treatment. Fits • Pneumonia Treatment is with recombinant GH given nightly by • Other central nervous system/lung insults subcutaneous injection. Longer-acting preparations • Smoking are currently under review • Chlorpropamide • Carbamazepine • Head injury • 4.4 HYPONATRAEMIA AND SIADH Cerebrovascular accidents (CVAs) • Tumours making ectopic ADH (eg ADH (or vasopressin) is synthesised in magnocellu- bronchus) lar neurons in the supraoptic and paraventricular nuclei of the hypothalamus and stored in the poster- If a tumour is the cause, it is usually obvious: a ior pituitary. ADH is released in response to rising search for malignancy beyond a chest radiograph is plasma osmolality and acts on the distal tubule and not required in SIADH. Smoking makes you pass renal collecting ducts to increase water permeabil- less urine (releases ADH); drinking (alcohol) makes ity. Water is reabsorbed and the urine becomes you pass more (inhibits ADH secretion). more concentrated. When the ADH system is work- ing normally, ‘the urine should reflect the blood’, ie Causes of hyponatraemia concentrated urine should occur when the plasma osmolality is high, and vice versa. Hyponatraemia can be divided into three cate- gories: However, hypovolaemia is also a strong signal for ADH release, and in the presence of hypovolaemia, • ‘Real’ (low serum osmolality)

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• Pseudohyponatraemia: high triglycerides, high features. ‘Recognised’ features of the two major protein (eg myeloma) (normal serum osmolality) thyroid syndromes are summarised in Table 4.5. • Dilutional: high glucose, ethanol, mannitol (serum osmolality may be raised).

If hyponatraemia is confirmed to be ‘real’ (low Features of hyper- and hypothyroidism plasma osmolality, glucose not raised, and no sug- gestion of ethanol or mannitol in blood), then the Amenorrhoea may be associated with hyperthyroid- following clinical and laboratory pointers must be ism because of associated weight loss. In hypothyr- considered: oidism, everything slows down except the periods! • The menorrhagia can cause a microcytic anaemia Careful history for drug use (especially diuretics) in contrast to the more usual macrocytosis. In both and of fluid loss (eg diarrhoea) • conditions there may be subfertility. In the gastro- Examination for circulatory volume status intestinal tract, the symptoms of hyperthyroidism are (oedema, postural hypotension and skin turgor) • almost indistinguishable from those of anxiety. The Measurement of urinary sodium concentration diarrhoea is actually more like the increased bowel (Table 4.4). frequency before an examination. Hypoadrenalism is the most important diagnosis not • Both hyperthyroidism (if Graves’ disease) and to be missed, because untreated, it can result in hypothyroidism can cause periorbital oedema death. (see note in Section 4.5.5 on eye signs in thyrotoxicosis) • The leukopenia of thyrotoxicosis can be 4.5 THE THYROID GLAND misdiagnosed: thionamide drugs (eg carbimazole) used as treatment also commonly 4.5.1 Hyperthyroidism and cause a lymphopenia. Both of these are separate hypothyroidism from the agranulocytosis that rarely occurs with thionamide drugs The common features of hyperthyroidism (eg weight • In hyperthyroidism the urticaria due to the loss, tremor, palpitations) and hypothyroidism (eg disease itself can cause confusion with the weight gain, lethargy, dry skin) are well known but maculopapular rash, which develops in 10% of questions are often asked on the more unusual patients treated with thionamide drugs.

Table 4.4 Causes of hyponatraemia

Urine sodium (mmol/L) Hypovolaemia present Euvolaemia/Hypervolaemia 6 oedema

.20 Diuretics SIADH Hypoadrenalism Hypothyroidism Salt-losing nephropathy Renal failure

,10 Vomiting, diarrhoea Congestive cardiac failure, cirrhosis, nephrotic syndrome Loss of other fluid

SIADH, syndrome of inappropriate antidiuretic hormone secretion.

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Table 4.5 Features of hyper- and hypothyroidism

Features Hyperthyroidism Hypothyroidism

General Weight gain (rarely) Weight gain Gynaecomastia Serous effusions (pleural, pericardial, ascites, Occult in elderly people joint) Hair loss Hair loss

Gynaecological Raised sex hormone-binding globulin Amenorrhoea, menorrhagia (SHBG) Infertility

Gastrointestinal Raised alkaline phosphatase (derived Diarrhoea from liver and bone) Constipation Vomiting

Muscle Proximal myopathy Raised creatine kinase Periodic paralysis (especially Chinese) Chest pain (muscular) Muscle cramps

Cardiovascular Atrial fibrillation with high stroke rate Dyspnoea system High-output cardiac Hypercholesterolaemia Ischaemic heart disease failure

Bone Osteoporosis Hypercalcaemia

Neurological ‘Apathetic thyrotoxicosis’ Deafness Ataxia, confusion, coma

Eyes Eye signs (see Section 4.5.5) Periorbital oedema

Blood Leukopenia Macrocytic anaemia Microcytic anaemia Microcytic, if menorrhagia

Skin Urticaria Dry, orange (carotenaemia)

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Side-e¡ects of anti-thyroid drugs be presumed to be benign. In order of increasing (carbimazole, propylthiouracil) malignancy and decreasing frequency, the thyroid epithelial cancers are: • Common • papillary • Rash • follicular • Leukopenia • anaplastic. • Rare • Agranulocytosis Lymphomas occur in Hashimoto’s disease. Medul- • Aplastic anaemia lary thyroid cancer is from the C cells (calcitonin), • Hepatitis not from the thyroid epithelium. Serum calcitonin is • Fever a tumour marker for this cancer, which often occurs • Arthralgia in families, sometimes as part of the multiple endo- • Vasculitis (propylthiouracil) crine neoplasia type 2 syndrome (see Section 4.7).

(See also Chapter 2, Clinical Pharmacology, Toxi- 4.5.4 Drugs and the thyroid cology and Poisoning) • Lithium 4.5.2 Causes of thyrotoxicosis • Inhibits T4 release from the gland, causing hypothyroidism The three common causes of thyrotoxicosis are: • Oestrogens • • Raised TBG and hence ‘total’ T4 /T3 Graves’ disease • • toxic multinodular goitre Amiodarone • • toxic (hot) nodule. Inhibits T4 to T3 conversion, increasing reverse T3 In all these conditions all or part of the gland is • High iodine content can cause hyper- or overactive and the gland takes up a normal or hypothyroidism a increased amount of radioiodine. • Iron – if taken at the same time as In the following conditions, there is thyrotoxicosis thyroxine, can reduce its absorption • Interferon without increased production of new hormone by • the thyroid gland itself, ie radioiodine uptake is Induces anti-thyroid autoantibodies and suppressed: hypothyroidism (usually transient) aNote on amiodarone-induced hyperthyroidism. This • Excess thyroxine ingestion may be due to drug-induced damage (thyroiditis) or to • Thyroiditis: post-viral (de Quervain’s), post- the excess iodine in amiodarone, and can be very partum or silent thyroiditis resistant to treatment. • Ectopic thyroid tissue, eg lingual thyroid or ovary (struma ovarii) • Iodine administration: gland is actually still active, but cold iodine competes with 4.5.5 Autoimmunity and eye signs in radioiodine during scanning. thyroid disease In areas such as the UK, where there is relatively 4.5.3 Thyroid cancer and nodules little iodine deficiency, more than 90% of sponta- neous hypothyroidism is due to autoimmunity. Anti- Only 5–10% of thyroid nodules are malignant (the thyroglobulin autoantibodies are present in 60% of rest are adenomas). Thyroid cancer virtually never cases and anti-microsomal antibodies (now identi- causes hyperthyroidism, so ‘hot nodules’ can usually fied as anti-thyroid peroxidase antibodies) are

124 Endocrinology

present in up to 90%. Antibodies that block the Conditions that alter thyroid-binding TSH receptor may also be present. Similar anti- globulin (TBG) bodies are present in Graves’ disease, but the anti- TSH receptor antibodies are stimulatory, causing the Raised TBG Low TBG thyrotoxicosis. Pregnancy Nephrotic syndrome Oestrogen Congenital TBG The eye signs in thyroid disease are shown in the Hepatitis abnormality box (see also Chapter 17, Ophthalmology). Retro- Congenital TBG orbital inflammation and swelling of the extraocular abnormality muscles are only seen in Graves’ disease. Note that each of the features listed can occur separately in thyroid eye disease (eg diplopia with- Interpretation of thyroid function tests out exophthalmos) and, surprisingly, disease of the This is generally straightforward in ambulant out- two eyes is usually asymmetrical. The target of the patients if the causes of different patterns of thyroid antibody or T-cell reaction causing this inflamma- function tests (TFTs) are known (Table 4.6). Special tion is not known for certain, and eye disease care in interpretation should be taken in the follow- activity can occur in the absence of thyrotoxicosis ing circumstances: and even with hypothyroidism. • Known or suspected pituitary disease (TSH is Thyrotoxicosis from any cause misleading and should NOT be used as a test) • Acutely ill patients (eg in intensive care) – TSH • often low with low free T3 (fT3) Lid retraction • • Lid lag Patients taking T3 supplements alone.

Graves’ disease only 4.6 ADRENAL DISEASE AND • Soft-tissue signs: periorbital oedema, HIRSUTISM conjunctival injection, chemosis • Proptosis/exophthalmos 4.6.1 Cushing syndrome • Diplopia/ophthalmoplegia Cushing syndrome refers to the sustained over-pro- • Optic nerve compression causing visual duction of cortisol (hypercortisolism), which causes failure the following: • centripetal obesity with moon face • 4.5.6 Thyroid function tests ‘buffalo hump’ • hirsutism TSH is the most sensitive measure of thyroid status • recurrent infections in patients with an intact pituitary. T4 and T3 are • osteoporosis over 95% protein-bound, predominantly to TBG. • oligomenorrhoea The conditions in the box alter TBG levels and • hypokalaemia hence total, but not free, hormone levels. • striae

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Table 4.6 Thyroid function tests

TSH

Low Normal Raised

Raised fT4/fT3 Thyrotoxicosis Rare: (applies to both normal and raised) • TSH-secreting pituitary tumour (TSHoma) • Thyroid hormone resistance (receptor defect) • Hypoadrenalism • Acute psychiatric illness • Intermittent T4 therapy (poor compliance) • T4 acute overdose (TSH normal) • Interfering anti-T4/T3 antibody (TSH normal) • Familial dysalbuminaemic hyperthyroxinaemia (TSH normal)

Normal fT4/fT3 Subclinical thyrotoxicosis: Normal Subclinical • Excess thyroxine hypothyroidism: • Steroid therapy • Poor compliance with • Non-thyroidal illness T4 therapy • Dopamine infusion • Interfering (heterophile) antibody • Recovery from non- thyroidal illness • Hypoadrenalism

Low fT4/fT3 Non-thyroidal illness: (applies to both low and normal) Hypothyroidism • Pituitary failure • Recent (excessive) treatment for hyperthyroidism

• acne genic Cushing syndrome secondary to steroid use, • proximal muscle weakness Cushing syndrome is rare. Other endocrine causes • hyperglycaemia of obesity should be excluded: • psychiatric disturbances • hypothyroidism • hypertension. • leptin deficiency If untreated, the mortality rate is high (59% within 5 • hypothalamic tumours (hyperphagia) years), and death is usually due to cardiovascular • Prader–Willi syndrome disease or infection. Fortunately, apart from iatro- • GH deficiency.

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Possible causes of Cushing syndrome are: of the pituitary causing Cushing’s disease are often too small to see and, second, incidental • Adrenal tumour tumours of both the pituitary and adrenal are • Pituitary tumour (Cushing’s disease) common and may not be functional. Tests used • Ectopic production of ACTH – either from to identify the causes of Cushing syndrome are cancer (eg small-cell cancer of lung) or from a shown in Table 4.7 bronchial adenoma (often very small) • Inferior petrosal sinus sampling (IPSS) is an • Ectopic production of corticotrophin-releasing invasive radiological technique in which blood hormone (CRH) (very rare). samples are drawn from the sinuses, draining The diagnosis of Cushing’s is made in three phases. the left and right sides of the adrenal gland, and also from the periphery. By looking at the ACTH Screening tests gradients between samples, localisation may be determined. However, due to cross-drainage • Loss of diurnal variation (midnight cortisol and difficulties in cannulating the sinuses, similar to morning cortisol) results may be difficult to interpret. • Overnight dexamethasone suppression test (1 mg at midnight then 9am cortisol). Cortisol should suppress to ,50 nmol/L Treatment of Cushing syndrome • Raised urinary free cortisol (24-hour collection). The aim of treatment is to normalise cortisol levels. Primary treatment is therefore surgical resection of Diagnostic tests the tumour with either pituitary or adrenal surgery. • Low-dose dexamethasone suppression test (0.5 mg four times daily for 48 hours). Cortisol Surgery should suppress to ,50nmol/l Pituitary • ACTH will be inappropriately normal/raised in Cushing’s disease is primarily treated with trans- pituitary (Cushing’s disease) or ectopic ACTH sphenoidal surgery (successful in approximately secretion, both of which are referred to as 60% of cases). ‘Biochemical cure’ is achieved if ‘ACTH-dependent Cushing syndrome’ post-operative cortisol levels are undetectable, as • ACTH will be suppressed in adrenal disease non-tumorous pituitary tissue will have been dor- (Cushing syndrome or ‘non-ACTH-dependent mant in the presence of the ACTH-producing Cushing syndrome’). tumour and may remain dormant for up to 2 years If one or more of these are positive then one can post-operatively. During this time, the patient will proceed to localisation. Note that depression or require cortisol replacement therapy. Sometimes re- alcoholism can cause cortisol overproduction covery never occurs and the patient remains perma- (‘pseudo-Cushing syndrome’). If these conditions nently ACTH-deficient. are present, further investigation is very difficult. If surgical cure has not been achieved, due to incomplete resection of the tumour, then pituitary Localisation studies radiotherapy or medical treatment may be offered. • High-dose/low-dose dexamethasone suppression test (2 mg four times daily for 48 Adrenal hours). ACTH levels suppress by 50% in 50% of Adrenal cortisol-secreting tumours are usually treated people with pituitary disease, but not with with laparoscopic resection, although occasionally ectopic production. Many have now abandoned this is not possible due to the large size. The whole this test due to lack of sensitivity adrenal is resected and cortisol levels should be • MRI of the adrenal or pituitary alone cannot be undetectable post-operatively, as the contralateral relied on to localise the cause. First, the tumours adrenal gland will be dormant due to lack of ACTH

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Table 4.7 Tests used to identify causes of Cushing syndrome

Adrenal Pituitary Ectopic

ACTH Suppressed Mid-range High High-dose No change in cortisol Suppression of cortisol a No change dexamethasone suppression

CRH stimulation test No change Rise in ACTH and No change cortisola

Metyrapone Rise in 11-deoxycortisol Rise in 11-deoxycortisol Rise in 11-deoxycortisol ,220-fold .220-folda ,220-fold

Petrosal sinus sampling Equals peripheral level Higher than peripheral Equals peripheral level ACTH b level a’Under pressure’ (ie at high doses), pituitary adenomas behave like a normal pituitary in dynamic endocrine testing, whereas adrenal or ectopic sources do not. A positive response to high-dose suppression (2 mg four times daily for 48 h) is .10% suppression of plasma cortisol or 24-hour urinary free cortisol. bIn a petrosal sinus sampling, a catheter is placed in the draining sinus of the pituitary gland, via a femoral or jugular venous approach. The ACTH level is compared with that in the peripheral blood before and after CRH injection.

stimulation. Recovery of this adrenal gland may take Medical therapy up to 2 years, although, as with the pituitary gland, Where surgery is not possible, normalisation of this may never occur and the patient will remain cortisol levels can be sought with metyrapone cortisol-dependent. Failure to cure because of incom- (although long-term complications include hirsuit- plete resection may be treated medically. ism and hypertension) and more recently SOM230, which also inhibits cortisol production. Ketocona- Occasionally, bilateral adrenalectomy is performed zole, previously used with a similar intent, has when it is not possible to normalise ACTH secretion recently been withdrawn because of concerns of (source unknown, or pituitary surgery/radiotherapy hepatotoxicity. Mitotane can be used in patients has been ineffective). This causes cortisol deficiency with adrenal cortical carcinoma as adjunct chemo- but may result in Nelson’s syndrome: loss of sup- therapy. However, medical therapies rarely normal- pression (provided by the previously high cortisol ise cortisol levels long term. levels) may allow a pre-existing pituitary adenoma to grow very rapidly, years later, causing local damage and generalised pigmentation. 4.6.2 Primary hyperaldosteronism Radiotherapy Primary hyperaldosteronism comprises hyper- Pituitary irradiation may reduce ACTH production tension, hypokalaemia (80% of cases), hypomagne- and reduce tumour growth. It is insidious in onset saemia and metabolic alkalosis. Patients can, but can be effective for up to 15 years. however, have a serum potassium within the normal

128 Endocrinology

range. Primary hyperaldosteronism is now thought (See Chapter 1, Cardiology, Section 1.9.3 Systemic to account for 1–3% of all cases of hypertension. hypertension. See also Chapter 15, Nephrology, Section 15.3.4 for differential diagnoses of hypoka- • Symptoms (if present) relate to hypokalaemia : laemia.) weakness, muscle cramps, paraesthesiae, polyuria and polydipsia. Patients rarely develop peripheral oedema (‘sodium escape’ 4.6.3 Congenital adrenal hyperplasia mechanism) Two enzyme defects account for 95% of all CAH: • Causes: aldosterone-secreting adenoma (Conn’s syndrome is almost never caused by a • 21-hydroxylase (90%) malignancy), idiopathic bilateral adrenal • 11-hydroxylase (5%). hyperplasia, unilateral hyperplasia (rare) • Investigations (not standardised): the The block caused by these enzyme defects leads to aldosterone:renin ratio (ARR) should be reduced production of cortisol, but increased pro- assessed to confirm high aldosterone levels in duction of other intermediates in steroid metabolism, the presence of low renin. Ideally, the ratio including androgenic steroids. 17-hydroxylase, should be assessed after the patient has ceased 3- â-hydroxysteroid dehydrogenase and cholesterol antihypertensive drugs ( â blockers reduce renin side-chain cleavage enzyme defects are very rare levels and therefore increase the ARR, giving a causes of congenital adrenal hyperplasia (CAH) and false-positive result. Spironolactone, calcium have different effects (see the box). channel blockers, ACE inhibitors and angiotensin antagonists increase renin levels Features of congenital adrenal causing a lowering of ARR and therefore a false- hyperplasia negative result. Alpha blockers (eg doxazosin) • Autosomal recessive have the least effect. Ideally, where possible, • these agents should be stopped to allow a Both gene deletions and point mutations can occur washout period of between 4 and 6 weeks. If • hyperaldosteronism is confirmed, a CT or MR Plasma ACTH is high (renin is high if salt- losing) scan of the abdomen may identify a unilateral • adrenal adenoma. However, the tumours are Can cause male precocious puberty (not usually ,2 cm in diameter and so, if imaging is 17-hydroxylase or side-chain enzyme); can negative, adrenal vein sampling may be cause ambiguous genitalia in females (not 17-hydroxylase or side-chain enzyme) required in order to distinguish unilateral • hypoplasia or a tiny adenoma from idiopathic Treat with glucocorticoids mineralocorticoids at night bilateral hyperplasia • • Treatment : spironolactone and amiloride are Can have a minor, late-onset form resembling polycystic ovary syndrome often successful treatments when the cause is • bilateral hyperplasia. Eplerenone is a selective Surgery may be required to correct ambiguous genitalia/cliteromegaly aldosterone antagonist that can be used in • patients who develop gynaecomastia or breast Antenatal steroid therapy to the mother has soreness with spironolactone. An adenoma or been used unilateral adrenal hyperplasia may be surgically removed; hypertension may persist if this was It is possible to distinguish between the different previously long-standing. enzyme defects in CAH (Table 4.8).

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Table 4.8 Differentiating features in congenital adrenal hyperplasia

21-hydroxylase 11-hydroxylase 17-hydroxylase/ side-chain enzyme

Frequency 90% cases 5% cases Very rare

Presentation in females Virilising, intersex 70% salt-losing a Virilising, Non-virilising hypertension, low K + (intersex in boys)

Biochemistry Raised 17-hydroxylase, progesterone Raised 11- dehydroxycortisol aSalt-losing individuals can have Addisonian crises soon after birth.

4.6.4 Hypoadrenalism corticoids continue to be secreted via the renin– angiotensin–aldosterone system. In the UK, spontaneous hypoadrenalism is most commonly due to autoimmune destruction of the The gold standard in diagnosing hypoadrenalism is adrenal glands (Addison’s disease – adrenal by failure of plasma cortisol to rise above 550 nmol/ autoantibodies present in 70% of cases). Vitiligo is L at 30 or 60 min after intramuscular or intravenous present in 10–20% of cases and can be associated injection of 250 g synthetic ACTH (short Synacthen with other autoimmune diseases. Other causes of 1 test). primary adrenal insufficiency include tuberculosis Treatment is with steroid replacement, and this is (TB), HIV or haemorrhage into the adrenal glands. most commonly done with oral hydrocortisone. Secondary hypoadrenalism is due to ACTH defi- Patients are told to double their steroid doses in ciency, most commonly caused by a pituitary times of stress or intercurrent illness. It is imperative lesion. Hypoadrenalism after withdrawal of long- that steroid replacement is not stopped, and there- standing steroid therapy is similar to secondary fore if patients are unable to take their tablets for hypoadrenalism. any reason (ie vomiting), they are told to seek medical attention. The following are ‘recognised’ features of hypo- adrenalism: • Biochemical: raised urea, hypoglycaemia, Acute adrenal failure (Addisonian crisis) hyponatraemia, hyperkalaemia, raised TSH, hypercalcaemia Acute adrenal failure is one of the few endocrine • Haematological: eosinophilia, lymphocytosis, emergencies. Addisonian crisis presents with hypo- normocytic anaemia volaemia, hyponatraemia, hyperkalaemia (if primary • Clinical features : weight loss, abdominal pain, adrenal failure), hypoglycaemia and cardiovascular psychosis, loss of pubic hair in women, collapse, which can be fatal. A mildly raised TSH hypotension, auricular cartilage calcification, may also be seen even in the absence of thyroid increased pigmentation. disease. Urgent treatment is necessary, and this includes intravenous fluid and electrolyte replace- ment as well as, most importantly, steroid replace- Hyperkalaemia and increased pigmentation are ment. All patients with hypoadrenalism are advised absent in secondary hypoadrenalism, because there to wear/carry a MedicAlert bracelet with them at all are low levels of circulating ACTH and mineralo- times.

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4.6.5 Polycystic ovary syndrome and oligo-/amenorrhoea and subfertility. The following hirsutism are recognised associations of PCOS: Hirsutism (Table 4.9) is the increased growth of • Clinical features: obesity, acanthosis nigricans, terminal (dark) hairs in androgen-dependent areas. oligomenorrhoea, polycystic ovaries, subfertility, Virilisation is temporal hair recession (male pattern), hypertension, premature balding in male breast atrophy, voice change, male physique and relatives, hirsutism (most important) cliteromegaly. Hirsutism and acne • Biochemical: insulin resistance and are invariably also present. hyperinsulinaemia, raised testosterone, raised LH/FSH ratio, raised prolactin, low HDL. A serum testosterone 4.5 nmol/L (normal ,1.8 nmol/L), recent onset of hirsutism and signs of Treatment : metformin will lower insulin resistance virilisation in women should prompt a search for and it has been shown to promote ovulation, im- other causes (eg a tumour). Dehydroepiandrostene- prove conception rates and reduce hirsutism. dione (DHEA) is a weak androgen produced in the Weight loss may also be beneficial. Separate speci- adrenal only. fic treatments are available for hirsutism (eg fluta- • Measure the 17-hydroxyprogesterone level after mide, cyproterone, finasteride, topical creams) and stimulation with ACTH to check for late-onset infertility (ovulation induction). 21-hydroxylase deficiency (partial enzyme deficiency) • Other than androgens, the drugs listed strictly 4.7 PHAEOCHROMOCYTOMA AND cause hypertrichosis, an increase in vellus hair, MULTIPLE ENDOCRINE rather than an increase in androgen-sensitive NEOPLASIA SYNDROMES terminal hairs (see Chapter 3, Dermatology). Phaeochromocytomas are rare tumours of the adre- nal medulla or ganglia of the sympathetic nervous Polycystic ovary syndrome system. They are the ‘tumour of 10%’: There is no widely recognised definition, and up to • 10% are outside the adrenal glands – 20% of women have a degree of hirsutism. In prac- paragangliomas (including organ of tice, the three main presenting complaints in poly- Zuckerkandl) cystic ovarian syndrome (PCOS) are hirsutism/acne, • 10% are multiple (eg bilateral)

Table 4.9 Causes of hirsutism

Ovarian Adrenal Drugs

PCOS (.90% of cases) CAH (may be late onset) Minoxidil Virilising tumour Cushing syndrome/adrenal carcinoma Phenytoin Diazoxide Ciclosporin Androgens

CAH, congenital adrenal hyperplasia; PCOS, polycystic ovarian syndrome.

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• 10% are malignant • Important features of 10% are familial. phaeochromocytomas • The most sensitive and specific test for the diagnosis 70% have persistent rather than episodic hypertension of phaeochromocytoma is the measurement of • plasma or urinary fractionated metanephrines. This The triad of headache, sweating and palpitations is said to be .90% predictive is not available in all centres and measurement • of urinary catecholamines is an alternative Extra-adrenal tumours do not make (measurement of urinary catecholamine metabolites adrenaline (they secrete noradrenaline/ dopamine) – 3-methoxy-4-hydroxymandelic acid or vanillyl- • mandelic acid [VMA] – has now been superseded). Hypotension or postural hypotension may occur, particularly if adrenaline is produced As is the case with most endocrine tumours, the • histology is not a reliable guide to the malignant They give characteristically a ‘bright’ (white) signal on T2-weighted MRI potential in phaeochromocytomas. The diagnosis of • malignancy is made by the presence of metastases. MIBG (m-iodobenzylguanidine) scanning may help localisation • Phaeochromocytomas may produce chromogranin A • Preoperative preparation is with Familial phaeochromocytomas occur in Æ-adrenergic blockade (eg phenoxybenzamine) before â blockade • Multiple endocrine neoplasia type 2 (see below) • Spontaneously in some families (not associated with a syndrome) • Causes of episodic sweating and/or £ushing Von Hippel–Lindau syndrome (retinal and • cerebral haemangioblastomas and renal Oestrogen/testosterone deficiency (eg menopause, castration) cystic carcinomas) • • Von Recklinghausen’s disease Carcinoid syndrome (flushing, diarrhoea, wheeze) (neurofibromatosis) – 1–2% • • Carney’s triad: gastric leiomyosarcoma, Phaeochromocytoma (sweat but do not flush) • Hypoglycaemia (in diabetes) pulmonary chondroma, Leydig’s testicular • tumour Thyrotoxicosis (not usually episodic) • • Systemic mastocytosis (histamine release) Paraganglioma syndromes (PGL types 1–4): • associated with head and neck Allergy. paragangliomas and phaeochromocytomas. Mutations in one of the four succinate Multiple endocrine neoplasia (MEN) syndromes are dehydrogenase subunits (SDH), especially syndromes with multiple benign or malignant endo- SDHD (PGL1) and SDHB (PGL 4) crine neoplasms (Table 4.10). They should not be confused with polyglandular autoimmune

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Table 4.10 Classification of multiple endocrine neoplasia (MEN)

MEN-1 MEN-2A MEN-2B

Genetics The menin gene The ret gene The ret gene Chromosome 11 Chromosome 10 Chromosome 10 Tumours Parathyroid Parathyroid Parathyroid Pituitary Phaeochromocytoma Phaeochromocytoma Pancreas (carcinoid) Medullary thyroid cancer Medullary thyroid cancer (Adrenal adenomas) Marfanoid Mucosal neuromas

syndromes which relate to autoimmune endocrine 4.8 PUBERTY/GROWTH/INTERSEX diseases. 4.8.1 Normal puberty • MEN-1 was formerly known as Werner’s syndrome. MEN-2A was known as Sipple’s In 95% of children, puberty begins between the syndrome. All MEN syndromes are autosomal ages of 8 and 13 years in females and 9 and 14 dominant. Genetic (DNA-based) screening is years in males. The mean age of menarche is 12.8 available for both MEN-1 and MEN-2. The years. The events of puberty occur in a particular MEN-2 mutation in ret activates the protein. order, although the later stages overlap with the Inactivating mutations of ret are seen in earlier ones. Hirschsprung’s disease • All MEN syndromes can be associated with Order of events in normal puberty hypercalcaemia. This is usually due to (earliest events listed ¢rst) hyperplasia of all four parathyroids, not a single parathyroid adenoma as with sporadic • Male hyperparathyroidism. Hypercalcaemia is often • Scrotal thickening (age 9–14) the first manifestation in MEN-1 • . • Testicular enlargement ( 2 mL) Gastrinomas and insulinomas are the most • Pubic hair common pancreatic tumours in MEN-1. Of the • Phallus growth pituitary tumours, prolactinomas are the most • Growth spurt (age 10–16) + increasing common, followed by acromegaly and bone age Cushing’s disease. • Female • Breast development (age 8–13) • Growth spurt • Pubic hair Medullary thyroid cancer (MTC) is always malig- • Menstruation (age 10–16) + increasing nant, secretes calcitonin and is preceded by C-cell bone age hyperplasia. Prophylactic thyroidectomy in patients with genetically confirmed MEN-2 should be per- formed to prevent this most serious manifestation. 4.8.2 Precocious puberty The exact site of the ret gene determines the age at which thyroidectomy should be performed, in many True precocious puberty is rare. It is diagnosed if cases under the age of 2 years. multiple signs of puberty develop before age 8 in

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females and age 9 in males, accompanied by in- Causes of delayed puberty/short stature creased growth rate, accelerated bone age and raised sex steroid levels. Isolated premature breast • General causes development (thelarche) or the appearance of pubic • Overt systemic disease hair alone (from adrenal androgens – adrenarche) • Social deprivation are both benign conditions if no other stages of • Anorexia, excess exercise puberty are entered. • Chemotherapy/gonadal irradiation • Cranial irradiation Causes of precocious puberty • Syndromes causing delayed puberty/short stature • True ‘central’ gonadotrophin-dependent • Turner’s syndrome (XO) precocious puberty • Noonan’s syndrome (‘male Turner’s • Idiopathic syndrome’) • Other CNS disease (eg hydrocephalus, • Prader–Willi syndrome encephalitis, trauma) • Occult systemic disease • CNS hamartoma (eg pineal) • Renal failure/renal tubular acidosis • Other causes (gonadotrophin-independent) • Crohn’s/coeliac disease • Adrenal, ovarian tumour • Hypothyroidism • CAH (males) • Asthma • Testotoxicosis (males) • Anterior pituitary disease • Exogenous oestrogen (females) • Hyperprolactinaemia • McCune–Albright syndrome • Isolated GH deficiency • Follicular cysts (females) • Syndromes causing delayed puberty but • Profound hypothyroidism normal stature • Androgen insensitivity (testicular McCune–Albright syndrome is more common in feminisation – XY female) girls (see Section 4.1.2 on activating G-protein mu- • Polycystic ovary syndrome (delayed tations). menarche only) • Kallman’s syndrome (XY), anosmia • Klinefelter’s syndrome (XXY) – males 4.8.3 Delayed puberty/short stature Short stature in children is often due to delayed In Turner’s syndrome, Noonan’s syndrome, andro- puberty and hence the two problems are usually gen insensitivity and Klinefelter’s syndrome, raised grouped together. Three per cent of children are LH and FSH are present. Kallman’s syndrome is due ‘statistically delayed’, ie for girls no breast develop- to failure of GnRH-secreting neurons migrating to ment by age 13 or menses by age 15, and for boys the hypothalamus. LH and FSH levels, as well as no testicular enlargement by age 14. The majority sex steroids, are low and patients typically have will have ‘constitutional delay’ and will later enter associated anosmia. Mutations in at least five genes puberty spontaneously. However, there is no endo- can cause the syndrome, the best recognised being crine test that can reliably distinguish constitutional the classic X-linked locus (KAL-1 also known as delay from other organic causes of delayed puberty. anosmin-1 – the syndrome associated with anosmia) and the autosomal loci fibroblast growth factor In investigation, systemic diseases or syndromes that receptor 1 (FGFR1, a syndrome associated with can cause delayed puberty should be excluded orofacial clefting and hypodontia). before considering pituitary testing. A karyotype (for Turner’s syndrome) should always be requested in However, gene mutations account for only around girls (see following text). 40% of cases of idiopathic hypogonadotrophic

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hypogonadism. There is no biochemical test that Causes of intersex can currently distinguish Kallman’s syndrome from constitutional delay of puberty, and therefore a • Virilised female (XX) clinical diagnosis is made when delayed puberty is • CAH (21-OH or 11-OH) associated with anosmia. • Maternal androgen ingestion • Turner’s syndrome (XO) (see Chapter 7, Genetics) Non-masculinised male (XY) • occurs in 1 in 2500 live births. The typical features Unusual CAH (17-OH/side-chain/3- â- (abnormal nails, neonatal lymphoedema, web neck, OH) • widely spaced nipples, wide carrying angle) may be Androgen resistance: • absent. A karyotype should always be requested in Receptor defect (‘testicular girls with short stature/delayed puberty because the feminisation’) • final height can be increased by early treatment 5Æ-reductase deficiency with high doses of growth hormone. Other impor- tant complications which may occur in Turner’s syndrome include aortic root dilatation (often the cause of death) or coarctation, renal abnormalities, Mothers who have a virilised daughter with CAH abnormal liver function tests and deafness. Women can be treated antenatally with steroids in subse- with Turner’s syndrome are generally infertile, but in quent pregnancies in order to suppress androgen some cases will have relatively minor X deletions production by the fetus. Steroids are continued until and/or chimaerism with cells of a normal karyotype, the sex of the baby can be established by chorionic so both menstruation and pregnancy can occur. villous sampling. Klinefelter’s syndrome (XXY) (see Chapter 7, Genet- ics) occurs in 1 in 1000 live births (by meiotic non- disjunction), but is usually undiagnosed until adult- hood. Testosterone production is around 50% of 4.9 DIABETES MELLITUS normal, but is sufficient to allow secondary sexual characteristics and normal height to develop. Diabetes may be defined as chronic hyperglycaemia Patients usually come to attention because of small at levels sufficient to cause microvascular complica- testes, gynaecomastia or infertility. tions: • 10% of cases are due to type 1 diabetes where 4.8.4 Intersex there is autoimmune destruction of the pancreatic islets of Langerhans (See also Chapter 7, Genetics.) Ambiguous genitalia • Around 85% are due to type 2 diabetes at birth require urgent diagnosis with steroid profile characterised by insulin resistance and relative and karyotype to assign the appropriate sex of rear- deficiency of insulin secretion ing and identify the risk of a salt-losing crisis (CAH). • The remaining 5% of cases are due to a Causes can be grouped as shown in the box. collection of secondary causes

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4.9.1 Risk factors and clinical and is actually more strongly inherited than type 1 features of types 1 and 2 diabetes, despite being ‘adult-onset’. diabetes mellitus Maturity onset diabetes of the young (MODY) is a Table 4.11 summarises the differences between type term used to describe a group of disorders describ- 1 and type 2 diabetes mellitus. Note that type 2 ing autosomal dominantly inherited monogenic dia- diabetes is more common in non-Caucasian races betes. It causes 1–2% of diabetes and there is

Table 4.11 Comparison between type 1 and type 2 diabetes mellitus

Type 1 Type 2

Genetics Both parents affected: up to 30% risk Both parents affected: 75% risk for child for child Identical twins: up to 90% concordance Identical twins: 64% concordance by 60 years Asian, Black, Hispanic, Native Americans Over 20 genes have been identified that Caucasians increase susceptibility

Increased risk conferred by over 15 gene loci identified so far, the more of these present, the greater the risk

Autoantibodies In new type 1 diabetics: No antibody association 60–75% have insulin antibodies 70–80% have GAD (glutamic acid decarboxylase) antibodies 65–75% have IA-2 (islet antigen-2) antibodies 70–80% have ZnT8 (zinc transporter-8) antibodies

Incidence Approximately 1/10 000 per year and Approximately 1/200 per year rising

Prevalence Approximately 1/1000 Approximately 5/100

Clinical features Age ,40 Age usually .20 but increasing numbers of paediatric patients Insidious onset Weight loss Overweight Ketosis prone Usually ketone negative Insulin deficient Insulin resistant Autoimmune aetiology (other Acanthosis nigricans autoimmune disorders may be present) Associated with metabolic syndrome (with obesity, hypertension, dyslipidaemia)

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usually a family history. Age of onset of diabetes is • HbA1c >48 mmol/mol or 6.5% usually less than 25 years and the condition is • Without symptoms: fasting glucose .7.0 caused by beta cell dysfunction. Treatment depends mmol/L or random glucose 11.1 mmol/L on on the underlying gene defect (Table 4.12). 2 occasions • Impaired glucose tolerance is defined by a 4.9.2 Diagnostic criteria for diabetes 2 hour OGTT value of 7.8–11.1 mmol/L • Impaired fasting glucose is a value .5.6 but This remains an area of ongoing debate. There have ,7.0 mmol/L. been recent changes to the diagnostic criteria for *Values are based on venous rather than capillary blood diabetes with the official addition of the use of values. HbA1c for diagnosis rather than to solely look at glycaemic control. The current practical use of the OGTT (oral glucose tolerance test) is for those patients with a fasting glucose level between 6.0 Impaired fasting glucose (IFG) and impaired glucose and 7.0 mmol/L, or in the diagnosis of gestational tolerance (IGT) are two conditions of ‘pre-diabetes’. diabetes. IGT confers increased cardiovascular risk. Twenty percent of patients with IGT will progress to type 2 Diagnoses of diabetes and pre-diabetes* diabetes within 5 years. A number of interventions have been identified that can reduce the risk of this • With symptoms: fasting glucose occurring or slow the progression. A programme of .7.0 mmol/L or random glucose over 11.1 diet and exercise, weight loss (any cause including mmol/L or glucose over 11.1 mmol/L 2 bariatric surgery), and drugs including metformin, hours into an OGTT acarbose, thiazolindenediones and orlistat have all been shown to be effective.

Table 4.12 Classification of MODY (maturity-onset diabetes of young people) disorders

Gene Percentage of Classification MODY cases

Glucokinase 20 MODY 2 – mild, complications are rare HNF-1Æ 60 MODY 3 – progressive beta cell failure but very sensitive to sulphonylureas HNF-4Æ 1 MODY 1 – neonatal hyperinsulinism HNF 1â 1 MODY 5 – associated renal anomalies or cysts IPF-1 1 MODY 4 – very rare ,1 MODY 6–11 Unknown 15 MODY X SUR1, Kir6.2 ,1 Hyperinsulinism in infancy and â cell failure in adulthood

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Classi¢cation of diabetes glycaemic control reduces the risk of complications. Subcutaneous insulin administration can vary from • Type 1 diabetes two to five injections per day. Multiple dose regimes • Type 2 diabetes with a combination of basal insulin (intermediate or • Genetic disorders usually long acting) and varying doses of rapid- • MODY acting insulin meals according to capillary glucose • Mitochondrial disorders eg MELAS, levels, carbohydrate intake and exercise, allow MIDD greater flexibility and improve control. In the UK, • Exocrine pancreas disease eg NICE has licensed continuous subcutaneous insulin • Pancreatitis infusions (CSII, insulin pumps) for type 1 diabetics • Pancreatectomy in whom multiple dose regimes of insulin have not • Haemochromatosis improved control sufficiently (HbA1c over 8.5%, • Cystic fibrosis 69mmol/mol) or led to disabling hypoglycaemic • Neoplasm episodes. Additional treatments include islet cell • Drugs eg corticosteroids, antipsychotics transplantation and whole pancreas transplantation, • Endocrine disorders eg which may be indicated in patients with recurrent • Cushings severe hypoglycaemia despite best medical treat- • Acromegaly ment. In addition, cardiovascular risk factor man- • Thyrotoxicosis agement is also indicated in all patients. Types of • Phaeochromocytoma insulin are shown in Table 4.13. • Other genetic syndromes eg • Down’s syndrome • Klinefelter’s syndrome 4.9.4 Treatment of type 2 diabetes • Turner’s syndrome There are a number of drug categories available to • Wolfram syndrome (also known as treat patients with type 2 diabetes (Table 4.14), and DIDMOAD – diabetes insipidus, drug choice needs to be based on a number of diabetes Mellitus, optic atrophy and factors including glycaemic control, patient prefer- deafness) ence, side effects and associated comorbidities. A • Gestational diabetes mellitus gradual decline in insulin reserves leads to an in- creasing requirement for medication and around 4.9.3 Treatment of type 1 diabetes 30% of type 2 diabetics ultimately need insulin therapy to achieve glycaemic targets. Weight loss Insulin replacement is essential in type 1 diabetes. (whether by diet and exercise, medication or baria- There is ample evidence to show that improved tric surgery) is an important adjunct to medication

Table 4.13 Types of insulin

Examples Peak (hours) Duration (hours)

Rapid Aspart, Lispro 1 3–4 Short Regular 2–4 6–8 Intermediate NPH 4–8 12–16 Long Detemir – 18–24 Glargine – 20–24 Mixed Insuman Comb 25 Varies depending on type – combined intermediate and Humulin M3 rapid acting insulin

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Table 4.14 Drugs used in the glucose control of type 2 diabetes

Drug Action/comments

Sulphonylureas Increase insulin secretion; risk of hypoglycaemia, weight gain

Biguanides (eg metformin) Reduced insulin resistance (lower hepatic glucose production). GI side effects. Rare risk of lactic acidosis (usually in the context of concurrent illness and reduced GFR)

Æ-Glucosidase inhibitors Slows carbohydrate absorption. Unacceptable flatus production for most (eg acarbose) patients

Thiazolindenediones (eg Activate intracellular PPAR- ª thereby reducing insulin resistance. Can cause pioglitazone) fluid retention, osteoporosis and link with bladder cancer

Insulin Used frequently in combination with other drugs; causes weight gain

Glucagon-like peptide Increase secretion of endogenous insulin, suppress glucagon, reduce appetite agonists (eg exenatide) and promote weight loss. Injected

Dipeptidyl peptidase IV Increase secretion of endogenous insulin. No weight gain inhibitors (eg sitagliptin)

SGLT-2 inhibitors (eg Allow glycosuria by blocking glucose reabsorption in the kidneys. Some weight dapagliflozin) loss. Increased risk of urinary tract infections to improve glycaemic control, and in some cases can cause the remission of diabetes. In addition, Abnormally low HbA1c cardiovascular risk reduction with control of hyper- tension, lipids and the use of aspirin are important • Haemolysis for management. • Increased red cell turnover • Blood loss • HbS or HbC

4.9.5 Glycated HbA1c Abnormally high HbA1c Red cell haemoglobin is non-enzymatically gly- • cated at a low rate according to the prevailing level Persistent HbF • Thalassaemia of glucose. The percentage of glycated haemoglobin • provides an accurate estimate of mean glucose Uraemia (carbamylated haemoglobin) levels over the preceding 2–3 months and correlates with the risk of microvascular complications. Mod- One thing this does highlight is the potential pitfall ern assays for HbA1c are rarely misleading but a of using HbA1c in the diagnosis of diabetes – care few considerations should be made if home glucose must be taken if there is a high red cell turnover or monitoring results don’t correlate well: if symptoms are of a rapid onset.

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4.9.6 Microvascular and amputation (0.5–1%). Some patients with macrovascular complications of neuropathy develop Charcot’s osteoarthropathy diabetes with collapse of the bony architecture of the foot and development of deformity. Long-term diabetic complications are due to vascu- lar damage. Damage to the microvasculature and its consequences correlate well with levels of glycae- mic control and can be delayed or prevented by Micro- and macrovascular complications maintaining near-normal glucose levels. Microvas- of diabetes cular complications usually take a minimum of 5 years to develop, even with poor glycaemic control. • Microvascular In paediatric cases, the changes in hormones during • Retinopathy (90%)* puberty lead to acceleration of risk as compared to • Neuropathy (70–90%)* pre-puberty. Complications may be apparent at • Nephropathy (30–40%)* diagnosis in type 2 diabetes due to delayed diag- • HbA1c dependent nosis. Neuropathy (70–90%) and retinopathy (90%) • Macrovascular occur in virtually all patients with suboptimal con- • Ischaemic heart disease (accounts for up trol and longer duration of diabetes. Thirty to forty to 70% of deaths in diabetes) per cent of patients will develop diabetic nephro- • Peripheral Vascular disease pathy, usually within 20 years of onset of diabetes. • Cerebrovascular disease • Less HbAC1c-dependent The incidence of microvascular complications was reduced in type 1 diabetics by around 50% in the *Approximate percentages of diabetics who will have Diabetes Control and Complications Trial (DCCT) this complication to some degree during their lifetime by tight glycaemic control. (data from retrospective studies). In contrast, macrovascular disease, which is respon- sible for most of the increased mortality in diabetes, does not appear to be as closely related to the level of glycaemic control. The increased risk of macro- 4.9.7 Autonomic neuropathy vascular disease is partly explained by a combina- tion of hypertension, lower HDL and higher Autonomic complications of diabetes may occur in triglyceride levels. Treatment of hypertension re- long-standing diabetes, especially in the context of duces not only cardiovascular risk but also the risk poor control. Complications can be very difficult to of neuropathy and retinopathy (especially the use of treat and there is high morbidity, reduced quality of ACE inhibitors). life and increased mortality. • Note that chest pain due to ischaemic heart disease is often absent or atypical in diabetes Manifestations of diabetic autonomic and easily missed neuropathy • Proteinuria is a strong risk factor for ischaemic heart disease in diabetes, presumably as a • Postural hypotension marker of endothelial dysfunction. Individuals • Gastroparesis with microalbuminuria or proteinuria should • Gustatory sweating have more aggressive blood pressure control. • • Generalised sweating Peripheral neuropathy predisposes to foot • Cardiac arrhythmia (‘dead in bed’) ulceration (occurs in 10% of patients) and, • Diarrhoea, constipation particularly in combination with peripheral • Reduced appreciation of cardiac pain vascular disease, increases the risk of

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4.10 HYPOGLYCAEMIA 4.10.2 Hypoglycaemia unrelated to diabetes 4.10.1 Hypoglycaemia in diabetes mellitus True hypoglycaemia unrelated to diabetes is rel- atively rare. Whipple’s triad consists of symptoms Autonomic symptoms of hypoglycaemia (sweating, consistent with hypoglycaemia, measured hypogly- tremor) appear when the blood glucose is ,3.5 caemia and resolution of symptoms with correction mmol/L, but can also occur at higher levels when of the low glucose. A supervised 72-hour fast can be diabetics have poorer glycaemic control, or when used to precipitate and document an episode, parti- there is a rapid drop in glucose levels. Neurogyco- cularly to diagnose an insulinoma (where there will paenic symptoms (impaired cerebral function, be inappropriately elevated insulin and C-peptide coma, seizures) occur when glucose levels drop levels in conjunction with a low glucose level). ,2.5 mmol/L. In patients on insulin, failure of the normal counter-regulatory responses (sympathetic Causes of hypoglycaemia nervous system activation, adrenaline and glucagon release) may develop in long-standing diabetes, • Fasting particularly in the context of frequent hypoglycae- • Insulinoma mic episodes. This results in hypoglycaemic • Tumour (IGF-2 mediated) unawareness. With no warning of impending neuro- • Hypoadrenalism logical impairment, the patient cannot take appro- • Alcohol priate action. More frequent hypoglycaemic • Severe liver failure episodes result, exacerbating the problem – ‘hypos • Factitious (insulin or sulphonylurea) beget hypos’. Hypoglycaemic awareness can be • Drugs restored by relaxing control to allow a prolonged • Anti-insulin antibodies (delayed post- hypoglycaemia-free period. prandial release of insulin) • Post prandial • Post-gastrectomy/bariatric surgery • Reactive • Idiopathic (rare)

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