Essential Revision Notes for MRCP Fourth Edition - Pastest · PDF fileEssential Revision Notes for MRCP Fourth Edition ... Clinical Pharmacology,ToxicologyandPoisoning 65 ... Essential

Essential

Revision Notes

for MRCP

Fourth Edition

edited by

Philip A Kalra MA MB BChir FRCP MDConsultant 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 1J E R Davies, S Nijjer

2. Clinical Pharmacology,Toxicology and Poisoning 65S Waring

3. Dermatology 87H Robertshaw

4. Endocrinology 107T Kearney, S Giritharan, M Kumar

5. Epidemiology 143J Ritchie

6. Gastroenterology 157S Lal, D H Vasant

7. Genetics 205E Burkitt Wright

8. Genito-urinaryMedicine andAIDS 223B Goorney

9. Haematology 237K Patterson

10. Immunology 279J Galloway

11. InfectiousDiseases andTropical Medicine 295C L van Halsema

12. Maternal Medicine 329L Byrd

v

13. Metabolic Diseases 359S Sinha

14. MolecularMedicine 395K Siddals

15. Nephrology 435P Kalra

16. Neurology 493M Jones, C Kobylecki, D Rog

17. Ophthalmology 561K Smyth

18. Psychiatry 583E Sampson

19. RespiratoryMedicine 611H Green

20. Rheumatology 657M McMahon

21. Statistics 685E Koutoumanou

Index 703

Contents

vi

Chapter 4Endocrinology

CONTENTS

4.1 Hormone action4.1.1 Types of hormone4.1.2 Hormones that act at the cell

surface4.1.3 Hormones that act

intracellularly4.1.4 Hormone resistance syndromes

4.2 Speci¢c hormonephysiology4.2.1 Hormones in illness4.2.2 Hormone changes in obesity4.2.3 Hormones in pregnancy4.2.4 Investigations in endocrinology4.2.5 Growth hormone4.2.6 Prolactin4.2.7 Adrenal steroids4.2.8 Thyroid hormone metabolism4.2.9 Renin–angiotensin–aldosterone4.2.10 Calcium, PTH and vitamin D4.2.11 Atrial natriuretic peptide

4.3 The pituitary gland4.3.1 Anatomy4.3.2 Pituitary tumours4.3.3 Diabetes insipidus4.3.4 Acromegaly4.3.5 Prolactinomas4.3.6 Hypopituitarism and growth

hormone deficiency in adults

4.4 Hyponatraemia and SIADH

4.5 The thyroid gland4.5.1 Hyperthyroidism and

hypothyroidism4.5.2 Causes of thyrotoxicosis4.5.3 Thyroid cancer and nodules4.5.4 Drugs and the thyroid4.5.5 Autoimmunity and eye signs in

thyroid disease4.5.6 Thyroid function tests

4.6 Adrenal disease and hirsutism4.6.1 Cushing syndrome4.6.2 Primary hyperaldosteronism4.6.3 Congenital adrenal hyperplasia4.6.4 Hypoadrenalism4.6.5 Polycystic ovary syndrome and

hirsutism

4.7 Phaeochromocytoma andmultiple endocrine neoplasiasyndromes

4.8 Puberty/growth/intersex4.8.1 Normal puberty4.8.2 Precocious puberty4.8.3 Delayed puberty/short stature4.8.4 Intersex

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4.9 Diabetesmellitus4.9.1 Risk factors and clinical

features of types 1 and 2diabetes mellitus

4.9.2 Diagnostic criteria for diabetes4.9.3 Treatment of type 1 diabetes4.9.4 Treatment of type 2 diabetes4.9.5 Glycated HbA1c4.9.6 Microvascular and

macrovascular complications ofdiabetes

4.9.7 Autonomic neuropathy

4.10 Hypoglycaemia4.10.1 Hypoglycaemia in diabetes

mellitus4.10.2 Hypoglycaemia unrelated to

diabetes

Essential Revision Notes for MRCP

108

Endocrinology

4.1 HORMONE ACTION

There are three main types of hormone:

• amine• steroid• peptide.

Knowing which category a particular hormone fitsinto makes it possible to guess much of its physiol-ogy. Thyroxine is an exception to this, as shownbelow.

4.1.1 Types of hormone

• Amine: catecholamines, serotonin, thyroxine• Steroid: cortisol, aldosterone, androgens,

oestrogens , progestogens and vitamin D• Peptide: everything else! (made up of a series of

amino acids).

Thyroxine is chemically an amine but it acts like asteroid. Vitamin D has the structure of a steroidhormone and it acts like one.

Amines/peptides

• Short half-life (minutes)• Secretion may be pulsatile• Act on a cell surface receptor• Often act via a second messenger

Steroids

• Longer biological half-life (hours)• Act on an intracellular receptor• Act on DNA to alter gene expression

This information can be used to predict hormoneaction, eg aldosterone is a steroid hormone so itmust have a biological half-life of several hours,

bind to an intracellular receptor and affect genetranscription. Glucagon is not a steroid or an amineso it must be a polypeptide hormone, which has ashort circulation half-life, acts via a cell surfacereceptor and probably utilises a second messenger(adenosine cyclic monophosphate, or cAMP, infact).

4.1.2 Hormones that act at the cellsurface

Peptide and amine hormones act at the cell surfacevia specific membrane receptors. The signal is trans-mitted intracellularly by one of three mechanisms:

• Via cAMP• Via a rise in intracellular calcium• Via receptor tyrosine kinases.

If in doubt, assume the action of a peptide or aminehormone (excluding thyroxine) is via cAMP, unlessit is insulin or has the word ‘growth’ in its name, inwhich case it is likely to act via a receptor tyrosinekinase (Table 4.1).

Cyclic AMPand G-proteins

Hormone receptors linked to cAMP (eg thyroid-stimulating hormone [TSH] receptor) typically haveseven transmembrane domains. The receptor doesnot directly generate cAMP but acts via separate ‘G-proteins’ on the cell surface which, in turn, interactwith the cAMP-generating enzyme, adenylylcyclase, on the cell surface. (See Figure 14.4 inChapter 14, Molecular Medicine.)

Hormones that raise the level of cAMP intracellu-larly (all hormones in this category except somato-statin) act via a stimulatory G-protein, ‘Gs’.Hormones that lower the level of cAMP (somato-statin) act via an inhibitory G-protein, ‘Gi’.

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109

G-proteins are important in endocrinology becausemutations in Gs have been found to be associatedwith certain diseases:

• Acromegaly: 40% of patients with acromegalyhave an activating somatic mutation of Gs intheir pituitary tumour. As a result, the cells arealways ‘switched on’ and continuously makegrowth hormone (GH), resulting in acromegaly

• McCune–Albright syndrome: an activatingmutation of Gs early in embryonic developmentcauses hyperfunction of one or more endocrineglands with the following sequelae: precociouspuberty (gonad hyperfunction), acromegaly (GHhypersecretion), Cushing syndrome (adrenalgland hyperfunction), thyrotoxicosis orhyperparathyroidism. The syndrome isassociated with cafe-au-lait spots andpolyostotic fibrous dysplasia. As the mutationoccurs after the zygote stage, affectedindividuals are a mosaic and different patternsof tissue involvement may be seen betweenindividuals

• Pseudohypoparathyroidism: inactivatinggermline mutations in Gs result inpseudohypoparathyroidism type 1A if maternallyinherited, with dysmorphic features (includingshort fourth or fifth metacarpal) and resistance toa variety of hormones that act via cAMP(including parathyroid hormone, TSH andgonadotrophins). Spontaneously occurring orpaternally inherited mutations cause thedysmorphic features alone (pseudo-

pseudohypoparathyroidism). The dysmorphicbone features are sometimes referred to as‘Albright’s hereditary osteodystrophy’ and can bepresent in either the maternally or the paternallyinherited form.

Intracellular Ca2+

Some hormones release intracellular Ca2+ as a sec-ond messenger (see Table 4.1 for examples). Thereceptors for these hormones activate different G-proteins (eg Gq), which in turn activate the cyto-plasmic enzyme phospholipase C (PLC). PLC re-leases the small molecule inositol-1,4,5-triphosphate (IP3) from membrane phospholipids.IP3 in turn binds to the IP3-sensitive receptor on theendoplasmic reticulum within the cell, causing Ca2+

to be released from stores in the endoplasmic retic-ulum into the cytoplasm. The Ca2+ subsequentlyaffects cell metabolism by binding to the proteincalmodulin.

Receptor tyrosine kinases

The insulin, GH, prolactin and growth factor recep-tors do not use second messengers. The receptorsthemselves can act as enzymes that phosphorylate(‘kinase activity’) other proteins when hormone isbound at the cell surface. This is followed by acascade of proteins phosphorylating other proteinsuntil gene transcription in the nucleus is modulated.

Table 4.1 Mechanisms of hormone action

Via cAMP Via Ca2+ Via receptor tyrosine kinases

Adrenaline (â receptors) GnRH InsulinAll pituitary hormones except GH, PRLGlucagon

TRHAdrenaline (Æ receptors)

GH, PRL‘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-releasinghormone.


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4.1.3 Hormones that actintracellularly

Steroids, vitamin D and thyroxine are sufficientlylipid-soluble that they do not need cell surfacereceptors but can diffuse directly through the cellmembrane. They then bind to receptors in thecytoplasm, which results in shedding of heat shockproteins that protect the empty receptor. The hor-mone–receptor complex migrates into the nucleuswhere it alters the transcription of a large number ofgenes (see Figure 14.6 in Chapter 14, MolecularMedicine).

4.1.4 Hormone resistance syndromes

The following are conditions of hormone resistancewith the site of the defect shown.

• Receptor defect (hormone involved)• Laron’s dwarfism (GH)• Leprechaunism (Donahue’s syndrome,

Rabson–Mendenhall syndrome [insulin])• Nephrogenic diabetes insipidus

(antidiuretic hormone [ADH])• Androgen resistance (testicular

feminisation syndrome (testosterone))• Vitamin-D-dependent rickets type 2 –

hereditary vitamin D resistance rickets(vitamin D)a

• Second messenger defect• Pseudohypoparathyroidism

• Defect unknown• Type 2 diabetes

aVitamin D-dependent rickets type 1 is due to a failure

of 1-hydroxylation of vitamin D.

4.2 SPECIFIC HORMONEPHYSIOLOGY

4.2.1 Hormones in illness

During illness/stress, the body closes all unneces-sary systems down ‘from the top’, eg the thyroidaxis closes down by a fall in thyrotrophin-releasing

hormone (TRH), TSH and L-thyroxine/L-triiodothyro-nine (T4/T3). It is orchestrated by the hypothalamus,not by the end-organs. Hormones involved in thestress response may rise.

Hormones that fall

• TSH, T4/T3a

• LH, FSH• Testosterone, oestrogen• Insulin (starvation)

May rise (stress hormones)

• GH (though IGF-1 falls)• ACTH, glucocorticoids• Adrenaline• Glucagon (starvation)• Prolactin

aIn this case conversion of T4 to T3 is inhibited so T3

falls more than T4

ACTH, adrenocorticotrophic hormone; FSH, follicle-

stimulating hormone; GH, growth hormone; IGF-1,

insulin-like growth factor 1; LH, luteinising hormone;

T3, L-triiodothyronine; T4, L-thyroxine; TSH, thyroid-

stimulating hormone.

In starvation alone, without illness, all hormones fallexcept glucagon. In anorexia nervosa there is alsostress: all hormones fall except glucagon, GH andglucocorticoids.

4.2.2 Hormone changes in obesity

In the absence of other diseases (eg type 2 dia-betes), which might develop in obese patients, thefollowing changes are seen in obesity:

• Hyperinsulinaemia• Increased cortisol turnover but not

hypercortisolism• Increased androgen levels in women• Reduced GH• Conversion of androgens to oestrogens• A proatherogenic lipid profile develops (low

high-density lipoprotein [HDL], high low-density lipoprotein [LDL] and triglyceride).

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Leptin, adipokines and other hormones

involved with appetite and weight

Leptin was identified as a product of the ‘ob’ genein 1994. Ob/ob mice make no leptin, owing to ahomozygous ob gene mutation, and are grosslyobese.

• Leptin is a polypeptide hormone, released fromfat cells, that acts on specific receptors in thehypothalamus to reduce appetite

• Circulating leptin levels are directly proportionalto fat mass, and so they tell the brain how fat anindividual is

• Leptin appears to have stimulatory effects onmetabolic rate and levels fall in starvation(appropriate change for weight homeostasis)

• Adequate leptin levels are required for the onsetof puberty

• Persistently obese individuals appear relativelyresistant to leptin

• Congenital leptin deficiency presents inchildhood with gross obesity and hyperphagia.This changes dramatically with treatment ofexogenous leptin.

Several other hormones have recently been shownto affect appetite and weight:

• Ghrelin: this was first identified as a GH-releasing hormone. It is released from thestomach when subjects are fasting or inconditions of negative energy balance andtriggers hunger. It stimulates gastric contractionand hence gastric emptying. Ghrelin levels fallafter gastric bypass surgery, which may helpweight loss by reducing appetite

• Peptide YY (a member of the neuropeptide Yfamily): released from L cells in the small andlarge bowel. Levels rise after meals and reduceappetite. This may be the main regulator of day-to-day appetite

• Glucagon-like peptide-1 (GLP-1): also releasedfrom L cells of the intestine after meals andpowerfully promotes insulin secretion inresponse to raised glucose (‘incretin effect’), aswell as possibly reducing appetite. Inactivatedby the enzyme dipeptidylpeptidase-4 (DPP-4).

Derived from tissue-specific cleavage ofproglucagon

• Oxyntomodulin: also released from L cells andderived from proglucagon; appears to act on thesame receptor as GLP-1, but with less incretin,and has more of an appetite-suppressing effect

• Neuropeptide Y (NPY), from the hypothalamusitself, and Agouti-related protein (AgRP) increaseappetite, whereas Æ-melanocyte-stimulatinghormone (Æ-MSH, a melanocortin) reducesappetite.

In addition to leptin, a number of other hormoneshave recently been identified as being released fromfat cells. These ‘adipokines’ include adiponectin,which reduces insulin resistance, and resistin andacylation-stimulating protein (ASP), which both in-crease insulin resistance. Visfatin (also known asnicotinamide phosphoribosyltransferase [NAMPT]and pre-B-cell colony-enhancing factor) is releasedpredominantly from visceral fat and has insulin-likeactions. The role of these adipokines in the associa-tion between obesity and insulin resistance remainsuncertain.

4.2.3 Hormones in pregnancy

As a general rule, most hormone levels rise in preg-nancy. Insulin resistance develops, causing a rise incirculating insulin levels. Insulin requirements arehighest in the last trimester but fall slightly in thelast 4 weeks of pregnancy.

Other key features of hormone metabolism in preg-nancy are as follows:

• Prolactin levels rise steadily throughoutpregnancy and, in combination with oestrogen,prepare the breast for lactation. Post-partumsurges of prolactin and oxytocin are generatedby the nipple stimulation of breastfeeding.However, after several weeks, prolactin levelsfall almost to normal, even if breastfeedingcontinues

• LH/FSH from the pituitary are no longernecessary after conception for continuedpregnancy (although the pituitary may double insize) and the placenta takes over


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• Thyroid axis: thyroid-binding globulin (TBG)levels rise in the first trimester, causing a rise intotal T4 and total T3. However, humanchorionic gonadotrophin (hCG) from theplacenta shares its Æ subunit with TSH, and veryhigh levels in the first trimester can cause truemild thyrotoxicosis (not just a binding proteinrise), especially associated with hyperemesisgravidarum. Note that T4 and T3 do not crossthe placenta very efficiently, but sufficient T4does cross to prevent a fetus with congenitalhypothyroidism becoming hypothyroid untilafter birth.

4.2.4 Investigations in endocrinology

The plasma level of almost all hormones variesthrough the day (because of pulsatile secretion,environmental stress or circadian rhythms) and isinfluenced by the prevailing values of the substratesthat they control. This makes it hard to define a‘normal range’, eg insulin values depend on theglucose level, and GH levels depend on whether apulse of GH has just been released or the bloodsample is taken in the trough between pulses.

Dynamic testing is therefore frequently used, iesuppression or stimulation tests. The principle is, ‘Ifyou think a hormone level may be high, suppress it;if you think it may be low, stimulate it’.

• Suppression tests are used to test for hormoneEXCESS, eg dexamethasone suppression forCushing syndrome, glucose tolerance for GH inacromegaly

• Stimulation tests are used to test for hormoneDEFICIENCY, eg Synacthen tests forhypoadrenalism, insulin-induced hypoglycaemiafor GH deficiency and/or hypoadrenalism.

4.2.5 Growth hormone

This is secreted in pulses lasting 30–45 minutesseparated by periods when secretion is undetect-able. The majority of GH pulses occur at night(‘children grow at night’). In response to GH pulses,the liver makes insulin-like growth factor 1 (IGF-1,previously called somatomedin C), the plasma level

of which is constant and which mediates almost allthe actions of GH, ie GH does not act directly. Theeffective levels of IGF-1 are influenced by changesin the level of its six binding proteins (IGF-BP 1–6).

4.2.6 Prolactin

Prolactin causes galactorrhoea but not gynaecomas-tia (oestrogen does this). Raised prolactin levels areessentially the only cause of galactorrhoea,although occasionally prolactin levels in the normalrange can cause milk production in a sensitisedbreast. Raised prolactin levels also ‘shut down’ thegonadal axis ‘from the top’ (hypothalamic level),resulting in low GnRH, LH and oestrogen/testoster-one levels. Surprisingly, prolactin is a stress hor-mone and can rise in various levels of stress, fromanxiety about venepuncture to an epileptic fit.

Prolactin release from the pituitary is under negativecontrol by dopamine from the hypothalamus. Oes-trogens (the pill, pregnancy) and nipple stimulationraise prolactin.

Prolactin is raised by

• Phenothiazines, haloperidol (not tricyclics)• Antiemetics (eg metoclopramide)• Damage to hypothalamus (eg radiation)• Pregnancy• Nipple stimulation• Damage to pituitary stalk (eg pressure from

a pituitary tumour)• Oestrogens• Polycystic ovary syndrome

Prolactin is suppressed by

• Dopamine agonist drugs (eg bromocriptine,cabergoline)

Gynaecomastia

This is due to a decreased androgen:oestrogen ratioin men. Gynaecomastia is unrelated to galactor-rhoea (which is always due to prolactin). Breastenlargement is not necessary to make milk.

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Causes of gynaecomastia:

• Pubertal (normal)• Obesity – not true gynaecomastia• Hypogonadism (eg Klinefelter’s syndrome,

testicular failure)• Cirrhosis, alcohol• Hyperthyroidism• Drugs: including spironolactone, digoxin,

oestrogens, cimetidine, anabolic steroids,marijuana

• Tumours, including adrenal or testicular, makingoestrogen; lung, pancreatic, gastric, makinghCG; hepatomas converting androgens tooestrogens.

4.2.7 Adrenal steroids

These act intracellularly to alter the transcription ofDNA to mRNA (see Section 4.1, Hormone action).Surprisingly, the mineralocorticoid (aldosterone)and glucocorticoid receptors have an equal affinityfor cortisol. However, the cellular enzyme 11-â-hydroxysteroid dehydrogenase ‘protects’ the miner-alocorticoid receptor by chemically modifying anycortisol that comes near the receptor to an inactiveform, while having no effect on aldosterone itself.Inactivating mutations of this enzyme, or inhibitionof it by liquorice, causes ‘apparent mineralocorti-coid excess’, because cortisol (which circulates atmuch higher concentrations than aldosterone) isable to stimulate the mineralocorticoid receptor.The effects of adrenal steroids and their duration ofaction are given in Table 4.2.

4.2.8 Thyroid hormone metabolism

More than 95% of thyroid hormones are bound toplasma proteins in the circulation, predominantlyTBG and thyroid-binding prealbumin (TBPA). T4(four iodine atoms per molecule) has a half-life of 7days (so, if a patient is in a confused state, it ispossible to administer his or her total weekly doseof thyroxine once a week). It is converted partly inthe thyroid and partly in the circulation to T3 (threeiodine atoms per molecule), which is the activeform and has a half-life of 1 day.

There are three deiodinase enzymes that act onthyroid hormones (D1–D3). D1 and D2 promotethe generation of active hormone (T3) by convertingT4 to T3 (Figure 4.1). D3 opposes this by promotingconversion of T4 to reverse T3 (rT3) and destroyingT3 by conversion to T2 (inactive). The D1 and D2enzymes are inhibited by illness, propranolol, pro-pylthiouracil, amiodarone and ipodate (formerly

Table 4.2 Adrenal steroids

Relativeglucocorticoid effect

Relativemineralocorticoid effect

Duration of action

Cortisol ¼ hydrocortisone 1 þ ShortPrednisolone 4 � MediumDexamethasone 30 ÿ LongFludrocortisone 10 þþþ

T (active form)3

rT (reverse T )3 3

D , D1 2

D3

T4

Figure 4.1 Metabolism of thyroid hormones,D1–D3, different deiodinase enzymes that acton thyroid hormone.


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used as X-ray contrast medium for study of gall-bladder disease). This reduces the level of activehormone, T3, with little change or a rise in T4.Reverse T3 levels rise (T4 spontaneously converts torT3 if the monodeiodinase is not available), but rT3is not detected in laboratory tests of T3 levels.

It is said that you should ‘never measure thyroidfunction tests on the intensive care unit becauseyou will not be able to interpret them’. In illness,TSH and free T3 levels fall (‘sick euthyroidism’). Theonly interpretable finding in sick patients is a raisedfree T3 – this would almost definitely indicatethyrotoxicosis.

4.2.9 Renin^angiotensin^aldosterone

Aldosterone secretion is controlled almost comple-tely by the renin–angiotensin system, not by ACTH.The initial letters of the zones of the adrenal cortexfrom outside inwards spell ‘GFR’, similar to glomer-ular filtration rate: glomerularis, fasciculata, reticu-laris. Aldosterone is the ‘outsider hormone’ and ismade on the ‘outside’ (zona glomerulosa).

Renin is released from the JGA (juxtaglomerularapparatus) of the kidney in response to low Na+

delivery or reduced renal perfusion. Renin is anenzyme that converts angiotensinogen to angioten-sin I (10 amino acids). ACE (angiotensin-convertingenzyme) in the lung converts angiotensin I to angio-tensin II, which is the active form. ACE also breaksdown bradykinin: ACE inhibitors (eg captopril) arebelieved to cause cough as a result of a build-up ofbradykinin in the lung. The renin–angiotensin sys-tem is designed to restore circulating volume. It istherefore activated by hypovolaemia (Figure 4.2)and its end product, angiotensin II, has three actionsthat restore volume:

• Releasing aldosterone from the adrenal (retainsNa+, excretes K+ in the distal tubule)

• Vasoconstriction (powerful)• Induction of thirst (powerful).

4.2.10 Calcium, PTH and vitamin D

(See also Chapter 13, Metabolic Diseases.)

Low Na delivery1

Angiotensinogen

Angiotensin I

Angiotensin II

Aldosteronesecretion

Retain NaExcrete K /H(distal tubule)

1

1 1

Vasoconstriction

Thirst

Angiotensin-convertingenzyme (ACE) in the lungAlso inactivates bradykinin

Renal perfusionreduced

RENINRelease

â-adrenoreceptorstimulates

α-adrenoreceptorinihibits

Figure 4.2 The renin–angiotensin system.

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Plasma calcium is tightly regulated by parathyroidhormone (PTH) and vitamin D, acting on the kidney(PTH), bone (PTH) and gut (vitamin D).

PTH controls Ca2+ levels minute to minute bymobilising Ca2+ from bone and inhibiting Ca2+

excretion from the kidney. Vitamin D has a morelong-term role, predominantly by promoting Ca2+

absorption from the gut. Its actions on the kidneyand bone are of lesser importance. Ca2+ levels aresensed by a specific calcium-sensing receptor onthe parathyroid glands. Mutations that reduce theactivity of this receptor result in a resetting ofcalcium and PTH to higher levels (familial hypocal-ciuric hypercalcaemia, FHH). Activating mutationscan also occur, which result in a picture almostindistinguishable from hypoparathyroidism, with alow Ca2+ (autosomal dominant hypocalcaemia withhypercalciuria). It is important to identify these con-ditions because they run a benign course and onlyattempted treatment causes problems (eg raising theserum Ca2+ in autosomal dominant hypocalcaemiawill predispose to renal stone formation).

Precursor vitamin D, obtained from the diet orsynthesised by the action of sunlight on the skin,requires activation by two steps:

• 25-hydroxylation in the liver• 1-hydroxylation in the kidney.

PTH can promote 1-hydroxylation of vitamin D inthe kidney, ie it can activate vitamin D, therebyindirectly stimulating Ca2+ absorption from the gut.

Calcitonin (from the C cells of the thyroid) behavesalmost exactly as a counter-hormone to PTH(secreted by high Ca2+, acts to lower serum Ca2+ byinhibiting Ca2+ release from bone), but its physio-logical importance is in doubt (thyroidectomy doesnot affect Ca2+ levels if the parathyroid glands areundisturbed).

4.2.11 Atrial natriuretic peptide

Atrial natriuretic peptide (ANP) physiology can bepredicted from its name:

• Atrial: it is synthesised by the myocytes of theright atrium and ventricle

• Natriuretic: it causes a natriuresis (urinaryexcretion of sodium). It thereby reducescirculating volume (opposite of renin–angiotensin). As you would predict, therefore, itis secreted in conditions of hypervolaemia – viastretch of the right atrial and ventricular walls. Italso antagonises the other actions of angiotensinII by causing vasodilatation and reduced thirst/salt craving

• Peptide: it is a peptide hormone (which acts viacAMP).

There are two other natriuretic peptides, B-type andC-type natriuretic peptides (BNP and CNP). BNP issimilar to ANP, and is produced from the heart,especially in heart failure. Serum levels are morestable than those of ANP, and BNP is proving to bea useful test of heart failure. CNP is produced bythe vascular endothelium rather than cardiac myo-cytes.

4.3 THE PITUITARY GLAND

4.3.1 Anatomy

The anatomical relations of the pituitary (Figure 4.3)are important because enlarging pituitary tumoursmay press on surrounding structures.

• Above: optic chiasma (classically causingbitemporal hemianopia if compressed, but anyvisual field defect may occur), pituitary stalk,hypothalamus, temporal lobes

• Below: sphenoid sinus (in front and below toallow trans-sphenoidal surgery), nasopharynx

• Lateral: cavernous sinus, internal carotidarteries, III, IV, V , and V and VI cranial nerves.

Expanding pituitary tumours may also compromiseremaining anterior pituitary function, but rarely af-fect posterior pituitary hormones.

4.3.2 Pituitary tumours

A microadenoma is a pituitary tumour ,10 mm insize. The size and frequency of pituitary tumoursare related.


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Pituitary tumours

• Large – non-secreting (typicallychromophobe): 50% of all tumours

• Large – prolactinomas in men: 25% of alltumours

• Medium – acromegaly (typically‘acidophil’, 70% are about 1 cm): 12% ofall tumours

• Small – Cushing’s disease (oftenundetectable on CT/MRI, typicallybasophil): 5–10% of all tumours

• Small – TSH secreting: 1% (very rare)

The most common tumours are small, non-functioning microadenomas, which have been re-ported to occur in up to 20% of people postmortem.

Prolactinomas are the most common functioningpituitary tumours. Microprolactinomas are more fre-quent than macroprolactinomas.

True Cushing’s disease is used to describe pituitary-dependent Cushing syndrome. This is caused by

excessive ACTH production from the pituitary gland(usually by a microadenoma). They are in them-selves rare.

For further discussion about Cushing syndromediagnosis and management, please see Section4.6.1.

Excessive secretion of GH from the pituitary glandin adults is termed ‘acromegaly’. There is a prepon-derance to macroadenomas with blunting of thenormal pulsatile GH secretion.

Pituitary apoplexy is sudden enlargement of thepituitary by haemorrhage into a tumour, typicallycausing the combination of headache, neck stiffnessand sudden blindness associated with cardio-vascular collapse due to hypopituitarism. Treatmentis with steroid replacement and urgent surgery forvisual loss (to decompress optic chiasma). In pitui-tary failure the only two hormones that must bereplaced for survival are T4 and hydrocortisone. It isimportant to ensure that the patient is adequatelyreplaced with glucocorticoids before startingreplacement of T4, because levothyroxine increasesglucocorticoid clearance.

Supraoptic recess

Hypothalamus

Optic chiasm

Suprasellarcistern

Cavernoussinus

IIIIV

V1

V2

Pituitary stalk

Temporal lobe

Internal carotidartery

Pituitary gland

Sphenoid bone

Sphenoid sinus

Figure 4.3 Schematic sagittal section through the pituitary to show its relation to surroundingstructures.

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Craniopharyngiomas are benign tumours that arisefrom remnants of Rathke’s pouch. Two-thirds arisein the hypothalamus itself (suprasellar) and a thirdin the sella. They are usually cystic, frequentlycalcify, often recur after aspiration and, althoughthey represent an embryonic remnant, they notinfrequently present in adulthood.

4.3.3 Diabetes insipidus

ADH (also called vasopressin or arginine–vasopres-sin, AVP) is synthesised in the hypothalamus andtransported to the posterior pituitary, along withoxytocin, for storage and release. Diabetes insipidus(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 thekidney (nephrogenic DI). To cause cranial DI, thehypothalamic nuclei (supraoptic and paraventricular)need to be damaged – it is not sufficient simply tocompress the posterior pituitary, because vasopressincan be secreted directly from the hypothalamusitself. Pituitary tumours therefore rarely cause Dl.

Major causes of cranial diabetes

insipidus

• Idiopathic• Craniopharyngiomas• Infiltrative processes of the hypothalamus

(eg sarcoid, histiocytosis X)• Trauma• Pituitary surgery• Lymphocytic hypophysitis• Dysgerminomas

Causes of nephrogenic DI

Reduced action of ADH on the kidney canhave several causes:

• Primary• Childhood onset: X-linked/dominant

abnormality in tubular ADH receptor• Secondary (common)

• Hypercalcaemia• Hypokalaemia• Renal disease (particularly if it involves

the medullary interstitium)• Lithium• Demeclocycline

Water deprivation test

A water deprivation test (Table 4.3) is used toidentify the cause of polydipsia and/or polyuria. It isworth confirming polyuria (urine output .3000 mL/24 h) before proceeding to a water deprivation test.Major metabolic causes should first be excluded (eghyperglycaemia, hypercalcaemia, hypokalaemia,chronic renal failure). The patient is then deprivedof water (from the night before if polyuria is notexcessive) and hourly urine and plasma osmolalityare measured until 3% of the body weight is lost.The patient is then given an injection of DDAVP (asynthetic analogue of ADH).

Interpretation of thewater deprivation test

• Primary polydipsia (compulsive water drinking):in this condition the patient is not dehydratedbut water overloaded in the resting state (Na+,140 mmol/l). Chronic polydipsia in this


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condition can result in washout of the renalmedullary-concentrating gradient so that, even ifthe patient does become dehydrated, with a risein ADH, urine cannot be concentrated

• Cranial DI: in this condition there is failure toconcentrate urine due to lack of ADH. This isobserved with a high plasma osmolality and arelatively low urine osmolality throughout thetest. Administration of DDAVP allows thekidneys to concentrate urine, thus raising theosmolality. If the thirst mechanism is intact,patients attempt to compensate by increasingtheir fluid intake orally. If, however, thismechanism is disrupted (patient is unconsciousor has intracerebral lesion rendering the patientadipsic), there is a significant risk of becomingdehydrated very quickly

• Partial cranial DI: in this condition there isweak ADH production. There is a similar effecton the renal medullary-concentrating gradient tothat seen in primary polydipsia, and so the twoconditions cannot be differentiated unless apost-hydration serum ADH level is obtained

• Nephrogenic diabetes inspidus: despiteadequate circulating ADH, there is renalresistance to the action of ADH, resulting in aninability to concentrate urine. Therefore urineosmolality does not improve on administrationof DDVAP during the water deprivation test.Treatment is by correcting the underlying causeand ensuring adequate hydration. Sometimeshigh doses of DDAVP can be used.

4.3.4 Acromegaly

The common features of acromegaly are wellknown (hand and foot enlargement, coarse facialfeatures, overbite of the lower jaw, splaying of theteeth) but the following also occur (see box).

Features of acromegaly

• Diabetes• Arthropathy – often pseudogout• Sleep apnoea• Carpal tunnel syndrome• Multinodular goitre• Increase in malignancies, especially colonic

polyps• Hypertension• Twofold increase in death from

cardiovascular disease• Cardiomyopathy• Left ventricular hypertrophy• Enlarged testes• Renal stones (hypercalciuria)• Raised phosphate• Raised prolactin, galactorrhoea, menstrual

change• Raised triglycerides

Acromegaly is almost always due to a GH-secretingpituitary tumour. Rarely, the condition is due toectopic GH-releasing hormone (GHRH) secretionfrom a tumour (typically carcinoid) which stimulates

Table 4.3 Interpretation of the water deprivation test

Initial plasmaosmolality

Final urine osmolality(mosmol/kg)

Urine osmolalitypost-DDAVP(mosmol/kg)

Final plasma ADH

Normal Normal .600 .600 HighCranial Dl High ,300 .600 LowNephrogenic Dl High ,300 ,300 HighPrimary polydipsia Low 300–400 (approx.) 400 (approx.) ModeratePartial cranial Dl High 300–400 400–600 Relatively low

ADH, antidiuretic hormone; DI, diabetes insipidus.

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the normal pituitary (no discrete tumour seen onMRI). Biochemical tests usually reveal a raisedserum IGF-1 level (above the age- and gender-specific normal range). The diagnosis is confirmedby failure to suppress GH to a nadir of 0.4 ng/mLon an oral glucose tolerance test.

First-line treatment is trans-sphenoidal surgery toresect the pituitary tumour (or transcranial surgery ifthere is a large suprasellar extension of the tumour).The cure rate is very variable (40–80%), and isdependent on the extent of lateral and superiorextension and the skill of the surgeon. Alternativetherapies are dopamine agonists (bromocriptine,cabergoline, quinagolide, pergolide, which reduceGH secretion in approximately 20% of cases), so-matostatin analogues (octreotide, which inhibit GHsecretion), GH antagonists (pegvisamant, whichblocks GH) and pituitary radiotherapy (may takeyears to take effect and may result in hypopituitar-ism). After successful treatment of acromegaly mostphysical features do not regress, although some soft-tissue effects do. Features of active disease are in-creased sweating and oedema, together with evi-dence of metabolic effects such as poor glycaemicand hypertensive control.

4.3.5 Prolactinomas

Prolactinomas are the most common functioningpituitary tumours. They present with galactorrhoea,gonadal dysfunction (amenorrhea, oligomenor-rhoea, poor libido, erectile dysfunction, subfertility)and symptoms of mass effect (headache and dete-rioration in visual fields). Diagnosis is based onraised serum prolactin concentrations and demon-stration of a pituitary lesion on MRI. Microadeno-mas can be hard to detect on imaging and mayappear as gland asymmetry, but generally speakingthe size of the lesion is proportional to the prolactinlevel.

Treatment is aimed at normalising the prolactinlevel, restoring gonadal function and reducing thesize of the lesion. The first-line treatment of prolacti-nomas is medical management. Dopamine agonistssuch as cabergoline and bromocriptine suppressprolactin levels to normal in approximately 95% of

cases, with shrinkage of the tumour in about 85%.Surgery is usually reserved for patients who areintolerant or resistant to dopamine agonists.

4.3.6 Hypopituitarism and growthhormone de¢ciency in adults

Panhypopituitarism can be caused by enlargingpituitary tumours, cranial irradiation (includingspecific pituitary radiotherapy), pituitary apoplexy,Sheehan’s syndrome (infarction after post-partumhaemorrhage), and then by any of the conditionsthat can cause cranial diabetes insipidus (see boxon p. 118).

Patients present with a soft, smooth ‘baby’ skin,‘crows’ feet’ lines around the eyes and featuresrelated to their specific hormonal deficiencies –hypotension in relation to ACTH deficiency, weightgain in relation to TSH deficiency, etc.

Typically, hormone loss follows a common pattern,with GH deficiency being most common, followedin order by LH, FSH, ACTH and TSH deficiency.Secondary hypothyroidism is suggested by a lowfree T4 (fT4) in the context of a low or inappropri-ately normal TSH. ACTH deficiency is diagnosed byan insulin stress test or glucagon test or, if long-standing, may be suggested by a failed shortSynacthen test with low or inappropriately normalACTH levels, although this test depends on thepresence of adrenal atrophy subsequent to ACTHdeficiency. The following points should be noted:

• Only replacement therapy with corticosteroidsand T4 is essential for life

• In suspected hypopituitarism, the steroids shouldbe given first and certainly before thyroidreplacement therapy. This is because correctionof hypothyroidism will accelerate cortisolmetabolism and would precipitate ahypoadrenal crisis (if T4 is given beforeexogenous steroids)

• If the pituitary is damaged, GH production islost early, so that most patients are GH-deficient(see below)

• Despite conventional hormone replacementtherapy (T4, glucocorticoid and sex steroids),


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mortality rates are increased in hypopituitarismdue to cardiovascular events or malignancy. Thepotential for GH therapy to reverse this trend iscurrently undergoing research.

GH de¢ciency

The main role for GH in children is growth; how-ever, in adults GH is required for musculoskeletal,metabolic and possibly psychological wellbeing.

Adult GHD is associated with the following:

• Reduced muscle tone and power, increased fatmass, easy fatigability, poor exercise tolerance

• Low mood, poor concentration and memory• Osteoporosis• Increased cardiovascular risk (impaired

endothelial function, proatherogenic lipidprofile, impaired left ventricular function).

Based on guidance of the National Institute forHealth and Care Excellence (NICE), GH replace-ment in adults is indicated for impaired quality oflife in patients with severe GH deficiency (definedas a peak GH response ,9 mU/L [3 ng/mL] duringa stimulation test). These symptoms are reassessedafter a 9-month period of treatment.

Treatment is with recombinant GH given nightly bysubcutaneous injection. Longer-acting preparationsare currently under review

4.4 HYPONATRAEMIA AND SIADH

ADH (or vasopressin) is synthesised in magnocellu-lar neurons in the supraoptic and paraventricularnuclei of the hypothalamus and stored in the poster-ior pituitary. ADH is released in response to risingplasma osmolality and acts on the distal tubule andrenal collecting ducts to increase water permeabil-ity. Water is reabsorbed and the urine becomesmore concentrated. When the ADH system is work-ing normally, ‘the urine should reflect the blood’, ieconcentrated urine should occur when the plasmaosmolality is high, and vice versa.

However, hypovolaemia is also a strong signal forADH release, and in the presence of hypovolaemia,

ADH will be secreted even if the osmolality is low.This explains the hyponatraemia seen in renal,cardiac and liver failure, as well as after excessivesodium loss (eg diarrhoea). Other stimuli can alsocommonly override control of ADH secretion byosmolarity (see Syndrome of inappropriate ADHsecretion [SIADH] below).

Syndromeof inappropriate ADH secretion

Many common stimuli override the control of os-molality and cause inappropriate amounts of ADHto be secreted, causing hyponatraemia. Sodiumconcentration should be high in the urine (exclud-ing hypovolaemia), renal, adrenal and thyroid func-tion should be normal, and diuretic therapy needsto be excluded before SIADH is diagnosed. Treat-ment is by fluid restriction or, if necessary, oraldemeclocycline.

Causes of inappropriate secretion of

ADH include

• Nausea• Pain• Fits• Pneumonia• Other central nervous system/lung insults• Smoking• Chlorpropamide• Carbamazepine• Head injury• Cerebrovascular accidents (CVAs)• Tumours making ectopic ADH (eg

bronchus)

If a tumour is the cause, it is usually obvious: asearch for malignancy beyond a chest radiograph isnot required in SIADH. Smoking makes you passless urine (releases ADH); drinking (alcohol) makesyou pass more (inhibits ADH secretion).

Causes of hyponatraemia

Hyponatraemia can be divided into three cate-gories:

• ‘Real’ (low serum osmolality)

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• Pseudohyponatraemia: high triglycerides, highprotein (eg myeloma) (normal serum osmolality)

• Dilutional: high glucose, ethanol, mannitol(serum osmolality may be raised).

If hyponatraemia is confirmed to be ‘real’ (lowplasma osmolality, glucose not raised, and no sug-gestion of ethanol or mannitol in blood), then thefollowing clinical and laboratory pointers must beconsidered:

• Careful history for drug use (especially diuretics)and of fluid loss (eg diarrhoea)

• Examination for circulatory volume status(oedema, postural hypotension and skin turgor)

• Measurement of urinary sodium concentration(Table 4.4).

Hypoadrenalism is the most important diagnosis notto be missed, because untreated, it can result indeath.

4.5 THE THYROID GLAND

4.5.1 Hyperthyroidism andhypothyroidism

The common features of hyperthyroidism (eg weightloss, tremor, palpitations) and hypothyroidism (egweight gain, lethargy, dry skin) are well known butquestions are often asked on the more unusual

features. ‘Recognised’ features of the two majorthyroid syndromes are summarised in Table 4.5.

Features of hyper- and hypothyroidism

Amenorrhoea may be associated with hyperthyroid-ism because of associated weight loss. In hypothyr-oidism, everything slows down except the periods!The menorrhagia can cause a microcytic anaemiain contrast to the more usual macrocytosis. In bothconditions there may be subfertility. In the gastro-intestinal tract, the symptoms of hyperthyroidism arealmost indistinguishable from those of anxiety. Thediarrhoea is actually more like the increased bowelfrequency before an examination.

• Both hyperthyroidism (if Graves’ disease) andhypothyroidism can cause periorbital oedema(see note in Section 4.5.5 on eye signs inthyrotoxicosis)

• The leukopenia of thyrotoxicosis can bemisdiagnosed: thionamide drugs (egcarbimazole) used as treatment also commonlycause a lymphopenia. Both of these are separatefrom the agranulocytosis that rarely occurs withthionamide drugs

• In hyperthyroidism the urticaria due to thedisease itself can cause confusion with themaculopapular rash, which develops in 10% ofpatients treated with thionamide drugs.

Table 4.4 Causes of hyponatraemia

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

.20 Diuretics SIADHHypoadrenalismSalt-losing nephropathy

HypothyroidismRenal failure

,10 Vomiting, diarrhoea Congestive cardiac failure, cirrhosis, nephroticsyndrome

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)GynaecomastiaOccult in elderly peopleHair loss

Weight gainSerous effusions (pleural, pericardial, ascites,joint)Hair loss

Gynaecological Raised sex hormone-binding globulin(SHBG)

Amenorrhoea, menorrhagiaInfertility

Gastrointestinal Raised alkaline phosphatase (derivedfrom liver and bone)Vomiting

DiarrhoeaConstipation

Muscle Proximal myopathyPeriodic paralysis (especially Chinese)

Raised creatine kinaseChest pain (muscular)Muscle cramps

Cardiovascularsystem

Atrial fibrillation with high stroke rateHigh-output cardiac

DyspnoeaHypercholesterolaemiaIschaemic heart diseasefailure

Bone OsteoporosisHypercalcaemia

Neurological ‘Apathetic thyrotoxicosis’ DeafnessAtaxia, confusion, coma

Eyes Eye signs (see Section 4.5.5) Periorbital oedema

Blood LeukopeniaMicrocytic anaemia

Macrocytic anaemiaMicrocytic, if menorrhagia

Skin Urticaria Dry, orange (carotenaemia)

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Side-e¡ects of anti-thyroid drugs

(carbimazole, propylthiouracil)

• Common• Rash• Leukopenia

• Rare• Agranulocytosis• Aplastic anaemia• Hepatitis• Fever• Arthralgia• Vasculitis (propylthiouracil)

(See also Chapter 2, Clinical Pharmacology, Toxi-cology and Poisoning)

4.5.2 Causes of thyrotoxicosis

The three common causes of thyrotoxicosis are:

• Graves’ disease• toxic multinodular goitre• toxic (hot) nodule.

In all these conditions all or part of the gland isoveractive and the gland takes up a normal orincreased amount of radioiodine.

In the following conditions, there is thyrotoxicosiswithout increased production of new hormone bythe thyroid gland itself, ie radioiodine uptake issuppressed:

• Excess thyroxine ingestion• Thyroiditis: post-viral (de Quervain’s), post-

partum or silent thyroiditis• Ectopic thyroid tissue, eg lingual thyroid or

ovary (struma ovarii)• Iodine administration: gland is actually still

active, but cold iodine competes withradioiodine during scanning.

4.5.3 Thyroid cancer and nodules

Only 5–10% of thyroid nodules are malignant (therest are adenomas). Thyroid cancer virtually nevercauses hyperthyroidism, so ‘hot nodules’ can usually

be presumed to be benign. In order of increasingmalignancy and decreasing frequency, the thyroidepithelial cancers are:

• papillary• follicular• anaplastic.

Lymphomas occur in Hashimoto’s disease. Medul-lary thyroid cancer is from the C cells (calcitonin),not from the thyroid epithelium. Serum calcitonin isa tumour marker for this cancer, which often occursin families, sometimes as part of the multiple endo-crine neoplasia type 2 syndrome (see Section 4.7).

4.5.4 Drugs and the thyroid

• Lithium• Inhibits T4 release from the gland,

causing hypothyroidism• Oestrogens

• Raised TBG and hence ‘total’ T4 /T3• Amiodarone

• Inhibits T4 to T3 conversion, increasingreverse T3

• High iodine content can cause hyper- orhypothyroidisma

• Iron – if taken at the same time asthyroxine, can reduce its absorption

• Interferon• Induces anti-thyroid autoantibodies and

hypothyroidism (usually transient)

aNote on amiodarone-induced hyperthyroidism. This

may be due to drug-induced damage (thyroiditis) or to

the excess iodine in amiodarone, and can be very

resistant to treatment.

4.5.5 Autoimmunity and eye signs inthyroid disease

In areas such as the UK, where there is relativelylittle iodine deficiency, more than 90% of sponta-neous hypothyroidism is due to autoimmunity. Anti-thyroglobulin autoantibodies are present in 60% ofcases and anti-microsomal antibodies (now identi-fied as anti-thyroid peroxidase antibodies) are


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present in up to 90%. Antibodies that block theTSH receptor may also be present. Similar anti-bodies are present in Graves’ disease, but the anti-TSH receptor antibodies are stimulatory, causing thethyrotoxicosis.

The eye signs in thyroid disease are shown in thebox (see also Chapter 17, Ophthalmology). Retro-orbital inflammation and swelling of the extraocularmuscles are only seen in Graves’ disease.

Note that each of the features listed can occurseparately in thyroid eye disease (eg diplopia with-out exophthalmos) and, surprisingly, disease of thetwo eyes is usually asymmetrical. The target of theantibody or T-cell reaction causing this inflamma-tion is not known for certain, and eye diseaseactivity can occur in the absence of thyrotoxicosisand even with hypothyroidism.

Thyrotoxicosis from any cause

• Lid retraction• Lid lag

Graves’ disease only

• Soft-tissue signs: periorbital oedema,conjunctival injection, chemosis

• Proptosis/exophthalmos• Diplopia/ophthalmoplegia• Optic nerve compression causing visual

failure

4.5.6 Thyroid function tests

TSH is the most sensitive measure of thyroid statusin patients with an intact pituitary. T4 and T3 areover 95% protein-bound, predominantly to TBG.The conditions in the box alter TBG levels andhence total, but not free, hormone levels.

Conditions that alter thyroid-binding

globulin (TBG)

Raised TBG Low TBGPregnancy Nephrotic syndromeOestrogen Congenital TBGHepatitis abnormalityCongenital TBGabnormality

Interpretation of thyroid function tests

This is generally straightforward in ambulant out-patients if the causes of different patterns of thyroidfunction tests (TFTs) are known (Table 4.6). Specialcare in interpretation should be taken in the follow-ing circumstances:

• Known or suspected pituitary disease (TSH ismisleading and should NOT be used as a test)

• Acutely ill patients (eg in intensive care) – TSHoften low with low free T3 (fT3)

• Patients taking T3 supplements alone.

4.6 ADRENAL DISEASE ANDHIRSUTISM

4.6.1 Cushing syndrome

Cushing syndrome refers to the sustained over-pro-duction of cortisol (hypercortisolism), which causesthe following:

• centripetal obesity with moon face• ‘buffalo hump’• hirsutism• recurrent infections• osteoporosis• oligomenorrhoea• hypokalaemia• striae

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• acne• proximal muscle weakness• hyperglycaemia• psychiatric disturbances• hypertension.

If untreated, the mortality rate is high (59% within 5years), and death is usually due to cardiovasculardisease or infection. Fortunately, apart from iatro-

genic Cushing syndrome secondary to steroid use,Cushing syndrome is rare. Other endocrine causesof obesity should be excluded:

• hypothyroidism• leptin deficiency• hypothalamic tumours (hyperphagia)• Prader–Willi syndrome• GH deficiency.

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:• Excess thyroxine• Steroid therapy• Non-thyroidal illness• Dopamine infusion

Normal Subclinicalhypothyroidism:• Poor compliance with

T4 therapy• 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 forhyperthyroidism


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Possible causes of Cushing syndrome are:

• Adrenal tumour• Pituitary tumour (Cushing’s disease)• Ectopic production of ACTH – either from

cancer (eg small-cell cancer of lung) or from abronchial adenoma (often very small)

• Ectopic production of corticotrophin-releasinghormone (CRH) (very rare).

The diagnosis of Cushing’s is made in three phases.

Screening tests

• Loss of diurnal variation (midnight cortisolsimilar to morning cortisol)

• Overnight dexamethasone suppression test(1 mg at midnight then 9am cortisol). Cortisolshould suppress to ,50 nmol/L

• Raised urinary free cortisol (24-hour collection).

Diagnostic tests

• Low-dose dexamethasone suppression test(0.5 mg four times daily for 48 hours). Cortisolshould suppress to ,50nmol/l

• ACTH will be inappropriately normal/raised inpituitary (Cushing’s disease) or ectopic ACTHsecretion, both of which are referred to as‘ACTH-dependent Cushing syndrome’

• ACTH will be suppressed in adrenal disease(Cushing syndrome or ‘non-ACTH-dependentCushing syndrome’).

If one or more of these are positive then one canproceed to localisation. Note that depression oralcoholism can cause cortisol overproduction(‘pseudo-Cushing syndrome’). If these conditionsare present, further investigation is very difficult.

Localisation studies

• High-dose/low-dose dexamethasonesuppression test (2 mg four times daily for 48hours). ACTH levels suppress by 50% in 50% ofpeople with pituitary disease, but not withectopic production. Many have now abandonedthis test due to lack of sensitivity

• MRI of the adrenal or pituitary alone cannot berelied on to localise the cause. First, the tumours

of the pituitary causing Cushing’s disease areoften too small to see and, second, incidentaltumours of both the pituitary and adrenal arecommon and may not be functional. Tests usedto identify the causes of Cushing syndrome areshown in Table 4.7

• Inferior petrosal sinus sampling (IPSS) is aninvasive radiological technique in which bloodsamples are drawn from the sinuses, drainingthe left and right sides of the adrenal gland, andalso from the periphery. By looking at the ACTHgradients between samples, localisation may bedetermined. However, due to cross-drainageand difficulties in cannulating the sinuses,results may be difficult to interpret.

Treatment of Cushing syndrome

The aim of treatment is to normalise cortisol levels.Primary treatment is therefore surgical resection ofthe tumour with either pituitary or adrenal surgery.

Surgery

PituitaryCushing’s disease is primarily treated with trans-sphenoidal surgery (successful in approximately60% of cases). ‘Biochemical cure’ is achieved ifpost-operative cortisol levels are undetectable, asnon-tumorous pituitary tissue will have been dor-mant in the presence of the ACTH-producingtumour and may remain dormant for up to 2 yearspost-operatively. During this time, the patient willrequire cortisol replacement therapy. Sometimes re-covery never occurs and the patient remains perma-nently ACTH-deficient.

If surgical cure has not been achieved, due toincomplete resection of the tumour, then pituitaryradiotherapy or medical treatment may be offered.

AdrenalAdrenal cortisol-secreting tumours are usually treatedwith laparoscopic resection, although occasionallythis is not possible due to the large size. The wholeadrenal is resected and cortisol levels should beundetectable post-operatively, as the contralateraladrenal gland will be dormant due to lack of ACTH

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stimulation. Recovery of this adrenal gland may takeup to 2 years, although, as with the pituitary gland,this may never occur and the patient will remaincortisol-dependent. Failure to cure because of incom-plete resection may be treated medically.

Occasionally, bilateral adrenalectomy is performedwhen it is not possible to normalise ACTH secretion(source unknown, or pituitary surgery/radiotherapyhas been ineffective). This causes cortisol deficiencybut may result in Nelson’s syndrome: loss of sup-pression (provided by the previously high cortisollevels) may allow a pre-existing pituitary adenomato grow very rapidly, years later, causing localdamage and generalised pigmentation.

RadiotherapyPituitary irradiation may reduce ACTH productionand reduce tumour growth. It is insidious in onsetbut can be effective for up to 15 years.

Medical therapyWhere surgery is not possible, normalisation ofcortisol levels can be sought with metyrapone(although long-term complications include hirsuit-ism and hypertension) and more recently SOM230,which also inhibits cortisol production. Ketocona-zole, previously used with a similar intent, hasrecently been withdrawn because of concerns ofhepatotoxicity. Mitotane can be used in patientswith adrenal cortical carcinoma as adjunct chemo-therapy. However, medical therapies rarely normal-ise cortisol levels long term.

4.6.2 Primary hyperaldosteronism

Primary hyperaldosteronism comprises hyper-tension, hypokalaemia (80% of cases), hypomagne-saemia and metabolic alkalosis. Patients can,however, have a serum potassium within the normal

Table 4.7 Tests used to identify causes of Cushing syndrome

Adrenal Pituitary Ectopic

ACTH Suppressed Mid-range HighHigh-dosedexamethasonesuppression

No change in cortisol Suppression of cortisola No change

CRH stimulation test No change Rise in ACTH andcortisola

No change

Metyrapone Rise in 11-deoxycortisol,220-fold

Rise in 11-deoxycortisol.220-folda

Rise in 11-deoxycortisol,220-fold

Petrosal sinus samplingACTHb

Equals peripheral level Higher than peripherallevel

Equals peripheral level

a’Under pressure’ (ie at high doses), pituitary adenomas behave like a normal pituitary in dynamic endocrinetesting, whereas adrenal or ectopic sources do not. A positive response to high-dose suppression (2 mg four timesdaily 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 orjugular venous approach. The ACTH level is compared with that in the peripheral blood before and after CRHinjection.


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range. Primary hyperaldosteronism is now thoughtto account for 1–3% of all cases of hypertension.

• Symptoms (if present) relate to hypokalaemia:weakness, muscle cramps, paraesthesiae,polyuria and polydipsia. Patients rarely developperipheral oedema (‘sodium escape’mechanism)

• Causes: aldosterone-secreting adenoma (Conn’ssyndrome is almost never caused by amalignancy), idiopathic bilateral adrenalhyperplasia, unilateral hyperplasia (rare)

• Investigations (not standardised): thealdosterone:renin ratio (ARR) should beassessed to confirm high aldosterone levels inthe presence of low renin. Ideally, the ratioshould be assessed after the patient has ceasedantihypertensive drugs (â blockers reduce reninlevels and therefore increase the ARR, giving afalse-positive result. Spironolactone, calciumchannel blockers, ACE inhibitors andangiotensin antagonists increase renin levelscausing a lowering of ARR and therefore a false-negative result. Alpha blockers (eg doxazosin)have the least effect. Ideally, where possible,these agents should be stopped to allow awashout period of between 4 and 6 weeks. Ifhyperaldosteronism is confirmed, a CT or MRscan of the abdomen may identify a unilateraladrenal adenoma. However, the tumours areusually ,2 cm in diameter and so, if imaging isnegative, adrenal vein sampling may berequired in order to distinguish unilateralhypoplasia or a tiny adenoma from idiopathicbilateral hyperplasia

• Treatment: spironolactone and amiloride areoften successful treatments when the cause isbilateral hyperplasia. Eplerenone is a selectivealdosterone antagonist that can be used inpatients who develop gynaecomastia or breastsoreness with spironolactone. An adenoma orunilateral adrenal hyperplasia may be surgicallyremoved; hypertension may persist if this waspreviously long-standing.

(See Chapter 1, Cardiology, Section 1.9.3 Systemichypertension. See also Chapter 15, Nephrology,Section 15.3.4 for differential diagnoses of hypoka-laemia.)

4.6.3 Congenital adrenal hyperplasia

Two enzyme defects account for 95% of all CAH:

• 21-hydroxylase (90%)• 11-hydroxylase (5%).

The block caused by these enzyme defects leads toreduced production of cortisol, but increased pro-duction of other intermediates in steroid metabolism,including androgenic steroids. 17-hydroxylase,3-â-hydroxysteroid dehydrogenase and cholesterolside-chain cleavage enzyme defects are very rarecauses of congenital adrenal hyperplasia (CAH) andhave different effects (see the box).

Features of congenital adrenal

hyperplasia

• Autosomal recessive• Both gene deletions and point mutations

can occur• Plasma ACTH is high (renin is high if salt-

losing)• Can cause male precocious puberty (not

17-hydroxylase or side-chain enzyme); cancause ambiguous genitalia in females (not17-hydroxylase or side-chain enzyme)

• Treat with glucocorticoidsmineralocorticoids at night

• Can have a minor, late-onset formresembling polycystic ovary syndrome

• Surgery may be required to correctambiguous genitalia/cliteromegaly

• Antenatal steroid therapy to the mother hasbeen used

It is possible to distinguish between the differentenzyme defects in CAH (Table 4.8).

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4.6.4 Hypoadrenalism

In the UK, spontaneous hypoadrenalism is mostcommonly due to autoimmune destruction of theadrenal glands (Addison’s disease – adrenalautoantibodies present in 70% of cases). Vitiligo ispresent in 10–20% of cases and can be associatedwith other autoimmune diseases. Other causes ofprimary adrenal insufficiency include tuberculosis(TB), HIV or haemorrhage into the adrenal glands.

Secondary hypoadrenalism is due to ACTH defi-ciency, most commonly caused by a pituitarylesion. Hypoadrenalism after withdrawal of long-standing steroid therapy is similar to secondaryhypoadrenalism.

The following are ‘recognised’ features of hypo-adrenalism:

• Biochemical: raised urea, hypoglycaemia,hyponatraemia, hyperkalaemia, raised TSH,hypercalcaemia

• Haematological: eosinophilia, lymphocytosis,normocytic anaemia

• Clinical features: weight loss, abdominal pain,psychosis, loss of pubic hair in women,hypotension, auricular cartilage calcification,increased pigmentation.

Hyperkalaemia and increased pigmentation areabsent in secondary hypoadrenalism, because thereare low levels of circulating ACTH and mineralo-

corticoids continue to be secreted via the renin–angiotensin–aldosterone system.

The gold standard in diagnosing hypoadrenalism isby failure of plasma cortisol to rise above 550 nmol/L at 30 or 60 min after intramuscular or intravenousinjection of 250 g synthetic ACTH (short Synacthen1 test).

Treatment is with steroid replacement, and this ismost commonly done with oral hydrocortisone.Patients are told to double their steroid doses intimes of stress or intercurrent illness. It is imperativethat steroid replacement is not stopped, and there-fore if patients are unable to take their tablets forany reason (ie vomiting), they are told to seekmedical attention.

Acute adrenal failure (Addisonian crisis)

Acute adrenal failure is one of the few endocrineemergencies. Addisonian crisis presents with hypo-volaemia, hyponatraemia, hyperkalaemia (if primaryadrenal failure), hypoglycaemia and cardiovascularcollapse, which can be fatal. A mildly raised TSHmay also be seen even in the absence of thyroiddisease. Urgent treatment is necessary, and thisincludes intravenous fluid and electrolyte replace-ment as well as, most importantly, steroid replace-ment. All patients with hypoadrenalism are advisedto wear/carry a MedicAlert bracelet with them at alltimes.

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-losinga Virilising,hypertension, low K+

Non-virilising(intersex in boys)

Biochemistry Raised 17-hydroxylase, progesterone Raised 11-dehydroxycortisol

aSalt-losing individuals can have Addisonian crises soon after birth.


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4.6.5 Polycystic ovary syndrome andhirsutism

Hirsutism (Table 4.9) is the increased growth ofterminal (dark) hairs in androgen-dependent areas.Virilisation is temporal hair recession (male pattern),breast atrophy, voice change, male physique and(most important) cliteromegaly. Hirsutism and acneare invariably also present.

A serum testosterone 4.5 nmol/L (normal,1.8 nmol/L), recent onset of hirsutism and signs ofvirilisation in women should prompt a search forother causes (eg a tumour). Dehydroepiandrostene-dione (DHEA) is a weak androgen produced in theadrenal only.

• Measure the 17-hydroxyprogesterone level afterstimulation with ACTH to check for late-onset21-hydroxylase deficiency (partial enzymedeficiency)

• Other than androgens, the drugs listed strictlycause hypertrichosis, an increase in vellus hair,rather than an increase in androgen-sensitiveterminal hairs (see Chapter 3, Dermatology).

Polycystic ovary syndrome

There is no widely recognised definition, and up to20% of women have a degree of hirsutism. In prac-tice, the three main presenting complaints in poly-cystic ovarian syndrome (PCOS) are hirsutism/acne,

oligo-/amenorrhoea and subfertility. The followingare recognised associations of PCOS:

• Clinical features: obesity, acanthosis nigricans,oligomenorrhoea, polycystic ovaries, subfertility,hypertension, premature balding in malerelatives, hirsutism

• Biochemical: insulin resistance andhyperinsulinaemia, raised testosterone, raisedLH/FSH ratio, raised prolactin, low HDL.

Treatment: metformin will lower insulin resistanceand it has been shown to promote ovulation, im-prove conception rates and reduce hirsutism.Weight loss may also be beneficial. Separate speci-fic treatments are available for hirsutism (eg fluta-mide, cyproterone, finasteride, topical creams) andinfertility (ovulation induction).

4.7 PHAEOCHROMOCYTOMA ANDMULTIPLE ENDOCRINENEOPLASIA SYNDROMES

Phaeochromocytomas are rare tumours of the adre-nal medulla or ganglia of the sympathetic nervoussystem. They are the ‘tumour of 10%’:

• 10% are outside the adrenal glands –paragangliomas (including organ ofZuckerkandl)

• 10% are multiple (eg bilateral)

Table 4.9 Causes of hirsutism

Ovarian Adrenal Drugs

PCOS (.90% of cases) CAH (may be late onset) MinoxidilVirilising tumour Cushing syndrome/adrenal carcinoma Phenytoin

DiazoxideCiclosporinAndrogens

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

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• 10% are malignant• 10% are familial.

The most sensitive and specific test for the diagnosisof phaeochromocytoma is the measurement ofplasma or urinary fractionated metanephrines. Thisis not available in all centres and measurementof urinary catecholamines is an alternative(measurement of urinary catecholamine metabolites– 3-methoxy-4-hydroxymandelic acid or vanillyl-mandelic acid [VMA] – has now been superseded).As is the case with most endocrine tumours, thehistology is not a reliable guide to the malignantpotential in phaeochromocytomas. The diagnosis ofmalignancy is made by the presence of metastases.

Familial phaeochromocytomas occur in

• Multiple endocrine neoplasia type 2 (seebelow)

• Spontaneously in some families (notassociated with a syndrome)

• Von Hippel–Lindau syndrome (retinal andcerebral haemangioblastomas and renalcystic carcinomas)

• Von Recklinghausen’s disease(neurofibromatosis) – 1–2%

• Carney’s triad: gastric leiomyosarcoma,pulmonary chondroma, Leydig’s testiculartumour

• Paraganglioma syndromes (PGL types 1–4):associated with head and neckparagangliomas and phaeochromocytomas.Mutations in one of the four succinatedehydrogenase subunits (SDH), especiallySDHD (PGL1) and SDHB (PGL 4)

Important features of

phaeochromocytomas

• 70% have persistent rather than episodichypertension

• The triad of headache, sweating andpalpitations is said to be .90% predictive

• Extra-adrenal tumours do not makeadrenaline (they secrete noradrenaline/dopamine)

• Hypotension or postural hypotension mayoccur, particularly if adrenaline is produced

• They give characteristically a ‘bright’ (white)signal on T2-weighted MRI

• MIBG (m-iodobenzylguanidine) scanningmay help localisation

• Phaeochromocytomas may producechromogranin A

• Preoperative preparation is withÆ-adrenergic blockade(eg phenoxybenzamine) before â blockade

Causes of episodic sweating and/or £ushing

• Oestrogen/testosterone deficiency (egmenopause, castration)

• Carcinoid syndrome (flushing, diarrhoea,wheeze)

• Phaeochromocytoma (sweat but do not flush)• Hypoglycaemia (in diabetes)• Thyrotoxicosis (not usually episodic)• Systemic mastocytosis (histamine release)• Allergy.

Multiple endocrine neoplasia (MEN) syndromes aresyndromes with multiple benign or malignant endo-crine neoplasms (Table 4.10). They should notbe confused with polyglandular autoimmune


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syndromes which relate to autoimmune endocrinediseases.

• MEN-1 was formerly known as Werner’ssyndrome. MEN-2A was known as Sipple’ssyndrome. All MEN syndromes are autosomaldominant. Genetic (DNA-based) screening isavailable for both MEN-1 and MEN-2. TheMEN-2 mutation in ret activates the protein.Inactivating mutations of ret are seen inHirschsprung’s disease

• All MEN syndromes can be associated withhypercalcaemia. This is usually due tohyperplasia of all four parathyroids, not a singleparathyroid adenoma as with sporadichyperparathyroidism. Hypercalcaemia is oftenthe first manifestation in MEN-1

• Gastrinomas and insulinomas are the mostcommon pancreatic tumours in MEN-1. Of thepituitary tumours, prolactinomas are the mostcommon, followed by acromegaly andCushing’s disease.

Medullary thyroid cancer (MTC) is always malig-nant, secretes calcitonin and is preceded by C-cellhyperplasia. Prophylactic thyroidectomy in patientswith genetically confirmed MEN-2 should be per-formed to prevent this most serious manifestation.The exact site of the ret gene determines the age atwhich thyroidectomy should be performed, in manycases under the age of 2 years.

4.8 PUBERTY/GROWTH/INTERSEX

4.8.1 Normal puberty

In 95% of children, puberty begins between theages of 8 and 13 years in females and 9 and 14years in males. The mean age of menarche is 12.8years. The events of puberty occur in a particularorder, although the later stages overlap with theearlier ones.

Order of events in normal puberty

(earliest events listed ¢rst)

• Male• Scrotal thickening (age 9–14)• Testicular enlargement (.2 mL)• Pubic hair• Phallus growth• Growth spurt (age 10–16) + increasing

bone age• Female

• Breast development (age 8–13)• Growth spurt• Pubic hair• Menstruation (age 10–16) + increasing

bone age

4.8.2 Precocious puberty

True precocious puberty is rare. It is diagnosed ifmultiple signs of puberty develop before age 8 in

Table 4.10 Classification of multiple endocrine neoplasia (MEN)

MEN-1 MEN-2A MEN-2B

Genetics The menin geneChromosome 11

The ret geneChromosome 10

The ret geneChromosome 10

Tumours ParathyroidPituitaryPancreas (carcinoid)(Adrenal adenomas)

ParathyroidPhaeochromocytomaMedullary thyroid cancer

ParathyroidPhaeochromocytomaMedullary thyroid cancerMarfanoidMucosal neuromas

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females and age 9 in males, accompanied by in-creased growth rate, accelerated bone age andraised sex steroid levels. Isolated premature breastdevelopment (thelarche) or the appearance of pubichair alone (from adrenal androgens – adrenarche)are both benign conditions if no other stages ofpuberty are entered.

Causes of precocious puberty

• True ‘central’ gonadotrophin-dependentprecocious puberty• Idiopathic• Other CNS disease (eg hydrocephalus,

encephalitis, trauma)• CNS hamartoma (eg pineal)

• Other causes (gonadotrophin-independent)• Adrenal, ovarian tumour• CAH (males)• Testotoxicosis (males)• Exogenous oestrogen (females)• McCune–Albright syndrome• Follicular cysts (females)• Profound hypothyroidism

McCune–Albright syndrome is more common ingirls (see Section 4.1.2 on activating G-protein mu-tations).

4.8.3 Delayed puberty/short stature

Short stature in children is often due to delayedpuberty and hence the two problems are usuallygrouped together. Three per cent of children are‘statistically delayed’, ie for girls no breast develop-ment by age 13 or menses by age 15, and for boysno testicular enlargement by age 14. The majoritywill have ‘constitutional delay’ and will later enterpuberty spontaneously. However, there is no endo-crine test that can reliably distinguish constitutionaldelay from other organic causes of delayed puberty.

In investigation, systemic diseases or syndromes thatcan cause delayed puberty should be excludedbefore considering pituitary testing. A karyotype (forTurner’s syndrome) should always be requested ingirls (see following text).

Causes of delayed puberty/short stature

• General causes• Overt systemic disease• Social deprivation• Anorexia, excess exercise• Chemotherapy/gonadal irradiation• Cranial irradiation

• Syndromes causing delayed puberty/shortstature• Turner’s syndrome (XO)• Noonan’s syndrome (‘male Turner’s

syndrome’)• Prader–Willi syndrome

• Occult systemic disease• Renal failure/renal tubular acidosis• Crohn’s/coeliac disease• Hypothyroidism• Asthma• Anterior pituitary disease• Hyperprolactinaemia• Isolated GH deficiency

• Syndromes causing delayed puberty butnormal stature• Androgen insensitivity (testicular

feminisation – XY female)• Polycystic ovary syndrome (delayed

menarche only)• Kallman’s syndrome (XY), anosmia• Klinefelter’s syndrome (XXY) – males

In Turner’s syndrome, Noonan’s syndrome, andro-gen insensitivity and Klinefelter’s syndrome, raisedLH and FSH are present. Kallman’s syndrome is dueto failure of GnRH-secreting neurons migrating tothe hypothalamus. LH and FSH levels, as well assex steroids, are low and patients typically haveassociated anosmia. Mutations in at least five genescan cause the syndrome, the best recognised beingthe classic X-linked locus (KAL-1 also known asanosmin-1 – the syndrome associated with anosmia)and the autosomal loci fibroblast growth factorreceptor 1 (FGFR1, a syndrome associated withorofacial clefting and hypodontia).

However, gene mutations account for only around40% of cases of idiopathic hypogonadotrophic


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hypogonadism. There is no biochemical test thatcan currently distinguish Kallman’s syndrome fromconstitutional delay of puberty, and therefore aclinical diagnosis is made when delayed puberty isassociated with anosmia.

Turner’s syndrome (XO) (see Chapter 7, Genetics)occurs in 1 in 2500 live births. The typical features(abnormal nails, neonatal lymphoedema, web neck,widely spaced nipples, wide carrying angle) may beabsent. A karyotype should always be requested ingirls with short stature/delayed puberty because thefinal height can be increased by early treatmentwith high doses of growth hormone. Other impor-tant complications which may occur in Turner’ssyndrome include aortic root dilatation (often thecause of death) or coarctation, renal abnormalities,abnormal liver function tests and deafness. Womenwith Turner’s syndrome are generally infertile, but insome cases will have relatively minor X deletionsand/or chimaerism with cells of a normal karyotype,so both menstruation and pregnancy can occur.

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% ofnormal, but is sufficient to allow secondary sexualcharacteristics and normal height to develop.Patients usually come to attention because of smalltestes, gynaecomastia or infertility.

4.8.4 Intersex

(See also Chapter 7, Genetics.) Ambiguous genitaliaat birth require urgent diagnosis with steroid profileand karyotype to assign the appropriate sex of rear-ing and identify the risk of a salt-losing crisis (CAH).Causes can be grouped as shown in the box.

Causes of intersex

• Virilised female (XX)• CAH (21-OH or 11-OH)• Maternal androgen ingestion

• Non-masculinised male (XY)• Unusual CAH (17-OH/side-chain/3-â-

OH)• Androgen resistance:

• Receptor defect (‘testicularfeminisation’)

• 5Æ-reductase deficiency

Mothers who have a virilised daughter with CAHcan be treated antenatally with steroids in subse-quent pregnancies in order to suppress androgenproduction by the fetus. Steroids are continued untilthe sex of the baby can be established by chorionicvillous sampling.

4.9 DIABETES MELLITUS

Diabetes may be defined as chronic hyperglycaemiaat levels sufficient to cause microvascular complica-tions:

• 10% of cases are due to type 1 diabetes wherethere is autoimmune destruction of thepancreatic islets of Langerhans

• Around 85% are due to type 2 diabetescharacterised by insulin resistance and relativedeficiency of insulin secretion

• The remaining 5% of cases are due to acollection of secondary causes

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4.9.1 Risk factors and clinicalfeatures of types 1 and 2diabetes mellitus

Table 4.11 summarises the differences between type1 and type 2 diabetes mellitus. Note that type 2diabetes is more common in non-Caucasian races

and is actually more strongly inherited than type 1diabetes, despite being ‘adult-onset’.

Maturity onset diabetes of the young (MODY) is aterm used to describe a group of disorders describ-ing autosomal dominantly inherited monogenic dia-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% riskfor childIdentical twins: 64% concordance by60 years

Caucasians

Increased risk conferred by over 15 geneloci identified so far, the more of thesepresent, the greater the risk

Both parents affected: 75% risk for childIdentical twins: up to 90% concordance

Asian, Black, Hispanic, Native AmericansOver 20 genes have been identified thatincrease susceptibility

Autoantibodies In new type 1 diabetics:60–75% have insulin antibodies70–80% have GAD (glutamic aciddecarboxylase) antibodies65–75% have IA-2 (islet antigen-2)antibodies70–80% have ZnT8 (zinc transporter-8)antibodies

No antibody association

Incidence Approximately 1/10 000 per year andrising

Approximately 1/200 per year

Prevalence Approximately 1/1000 Approximately 5/100

Clinical features Age ,40

Weight lossKetosis proneInsulin deficientAutoimmune aetiology (otherautoimmune disorders may be present)

Age usually .20 but increasing numbers ofpaediatric patientsInsidious onsetOverweightUsually ketone negativeInsulin resistantAcanthosis nigricansAssociated with metabolic syndrome (withobesity, hypertension, dyslipidaemia)


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usually a family history. Age of onset of diabetes isusually less than 25 years and the condition iscaused by beta cell dysfunction. Treatment dependson the underlying gene defect (Table 4.12).

4.9.2 Diagnostic criteria for diabetes

This remains an area of ongoing debate. There havebeen recent changes to the diagnostic criteria fordiabetes with the official addition of the use ofHbA1c for diagnosis rather than to solely look atglycaemic control. The current practical use of theOGTT (oral glucose tolerance test) is for thosepatients with a fasting glucose level between 6.0and 7.0 mmol/L, or in the diagnosis of gestationaldiabetes.

Diagnoses of diabetes and pre-diabetes*

• With symptoms: fasting glucose.7.0 mmol/L or random glucose over 11.1mmol/L or glucose over 11.1 mmol/L 2hours into an OGTT

• HbA1c >48 mmol/mol or 6.5%• Without symptoms: fasting glucose .7.0

mmol/L or random glucose 11.1 mmol/L on2 occasions

• Impaired glucose tolerance is defined by a2 hour OGTT value of 7.8–11.1 mmol/L

• Impaired fasting glucose is a value .5.6 but,7.0 mmol/L.

*Values are based on venous rather than capillary blood

values.

Impaired fasting glucose (IFG) and impaired glucosetolerance (IGT) are two conditions of ‘pre-diabetes’.IGT confers increased cardiovascular risk. Twentypercent of patients with IGT will progress to type 2diabetes within 5 years. A number of interventionshave been identified that can reduce the risk of thisoccurring or slow the progression. A programme ofdiet and exercise, weight loss (any cause includingbariatric surgery), and drugs including metformin,acarbose, thiazolindenediones and orlistat have allbeen shown to be effective.

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

Gene Percentage ofMODY cases

Classification

Glucokinase 20 MODY 2 – mild, complications are rareHNF-1Æ 60 MODY 3 – progressive beta cell failure but very sensitive to

sulphonylureasHNF-4Æ 1 MODY 1 – neonatal hyperinsulinismHNF 1â 1 MODY 5 – associated renal anomalies or cystsIPF-1 1 MODY 4 – very rare

,1 MODY 6–11Unknown 15 MODY XSUR1, Kir6.2 ,1 Hyperinsulinism in infancy and â cell failure in adulthood

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Classi¢cation of diabetes

• Type 1 diabetes• Type 2 diabetes• Genetic disorders

• MODY• Mitochondrial disorders eg MELAS,

MIDD• Exocrine pancreas disease eg

• Pancreatitis• Pancreatectomy• Haemochromatosis• Cystic fibrosis• Neoplasm

• Drugs eg corticosteroids, antipsychotics• Endocrine disorders eg

• Cushings• Acromegaly• Thyrotoxicosis• Phaeochromocytoma

• Other genetic syndromes eg• Down’s syndrome• Klinefelter’s syndrome• Turner’s syndrome• Wolfram syndrome (also known as

DIDMOAD – diabetes insipidus,diabetes Mellitus, optic atrophy anddeafness)

• Gestational diabetes mellitus

4.9.3 Treatment of type 1 diabetes

Insulin replacement is essential in type 1 diabetes.There is ample evidence to show that improved

glycaemic control reduces the risk of complications.Subcutaneous insulin administration can vary fromtwo to five injections per day. Multiple dose regimeswith a combination of basal insulin (intermediate orusually long acting) and varying doses of rapid-acting insulin meals according to capillary glucoselevels, carbohydrate intake and exercise, allowgreater flexibility and improve control. In the UK,NICE has licensed continuous subcutaneous insulininfusions (CSII, insulin pumps) for type 1 diabeticsin whom multiple dose regimes of insulin have notimproved control sufficiently (HbA1c over 8.5%,69mmol/mol) or led to disabling hypoglycaemicepisodes. Additional treatments include islet celltransplantation and whole pancreas transplantation,which may be indicated in patients with recurrentsevere hypoglycaemia despite best medical treat-ment. In addition, cardiovascular risk factor man-agement is also indicated in all patients. Types ofinsulin are shown in Table 4.13.

4.9.4 Treatment of type 2 diabetes

There are a number of drug categories available totreat patients with type 2 diabetes (Table 4.14), anddrug choice needs to be based on a number offactors including glycaemic control, patient prefer-ence, side effects and associated comorbidities. Agradual decline in insulin reserves leads to an in-creasing requirement for medication and around30% of type 2 diabetics ultimately need insulintherapy to achieve glycaemic targets. Weight loss(whether by diet and exercise, medication or baria-tric surgery) is an important adjunct to medication

Table 4.13 Types of insulin

Examples Peak (hours) Duration (hours)

Rapid Aspart, Lispro 1 3–4Short Regular 2–4 6–8Intermediate NPH 4–8 12–16Long Detemir

Glargine––

18–2420–24

Mixed Insuman Comb 25Humulin M3

Varies depending on type – combined intermediate andrapid acting insulin


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to improve glycaemic control, and in some casescan cause the remission of diabetes. In addition,cardiovascular risk reduction with control of hyper-tension, lipids and the use of aspirin are importantfor management.

4.9.5 Glycated HbA1c

Red cell haemoglobin is non-enzymatically gly-cated at a low rate according to the prevailing levelof glucose. The percentage of glycated haemoglobinprovides an accurate estimate of mean glucoselevels over the preceding 2–3 months and correlateswith the risk of microvascular complications. Mod-ern assays for HbA1c are rarely misleading but afew considerations should be made if home glucosemonitoring results don’t correlate well:

Abnormally low HbA1c

• Haemolysis• Increased red cell turnover• Blood loss• HbS or HbC

Abnormally high HbA1c

• Persistent HbF• Thalassaemia• Uraemia (carbamylated haemoglobin)

One thing this does highlight is the potential pitfallof using HbA1c in the diagnosis of diabetes – caremust be taken if there is a high red cell turnover orif symptoms are of a rapid onset.

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 andreduced GFR)

Æ-Glucosidase inhibitors(eg acarbose)

Slows carbohydrate absorption. Unacceptable flatus production for mostpatients

Thiazolindenediones (egpioglitazone)

Activate intracellular PPAR-ª thereby reducing insulin resistance. Can causefluid retention, osteoporosis and link with bladder cancer

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

Glucagon-like peptideagonists (eg exenatide)

Increase secretion of endogenous insulin, suppress glucagon, reduce appetiteand promote weight loss. Injected

Dipeptidyl peptidase IVinhibitors (eg sitagliptin)

Increase secretion of endogenous insulin. No weight gain

SGLT-2 inhibitors (egdapagliflozin)

Allow glycosuria by blocking glucose reabsorption in the kidneys. Some weightloss. Increased risk of urinary tract infections

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4.9.6 Microvascular andmacrovascular complications ofdiabetes

Long-term diabetic complications are due to vascu-lar damage. Damage to the microvasculature and itsconsequences correlate well with levels of glycae-mic control and can be delayed or prevented bymaintaining near-normal glucose levels. Microvas-cular complications usually take a minimum of 5years to develop, even with poor glycaemic control.In paediatric cases, the changes in hormones duringpuberty lead to acceleration of risk as compared topre-puberty. Complications may be apparent atdiagnosis in type 2 diabetes due to delayed diag-nosis. Neuropathy (70–90%) and retinopathy (90%)occur in virtually all patients with suboptimal con-trol and longer duration of diabetes. Thirty to fortyper cent of patients will develop diabetic nephro-pathy, usually within 20 years of onset of diabetes.

The incidence of microvascular complications wasreduced in type 1 diabetics by around 50% in theDiabetes Control and Complications Trial (DCCT)by tight glycaemic control.

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 levelof glycaemic control. The increased risk of macro-vascular disease is partly explained by a combina-tion of hypertension, lower HDL and highertriglyceride levels. Treatment of hypertension re-duces not only cardiovascular risk but also the riskof neuropathy and retinopathy (especially the use ofACE inhibitors).

• Note that chest pain due to ischaemic heartdisease is often absent or atypical in diabetesand easily missed

• Proteinuria is a strong risk factor for ischaemicheart disease in diabetes, presumably as amarker of endothelial dysfunction. Individualswith microalbuminuria or proteinuria shouldhave more aggressive blood pressure control.

• Peripheral neuropathy predisposes to footulceration (occurs in 10% of patients) and,particularly in combination with peripheralvascular disease, increases the risk of

amputation (0.5–1%). Some patients withneuropathy develop Charcot’s osteoarthropathywith collapse of the bony architecture of thefoot and development of deformity.

Micro- and macrovascular complications

of diabetes

• Microvascular• Retinopathy (90%)*• Neuropathy (70–90%)*• Nephropathy (30–40%)*• HbA1c dependent

• Macrovascular• Ischaemic heart disease (accounts for up

to 70% of deaths in diabetes)• Peripheral Vascular disease• Cerebrovascular disease• Less HbAC1c-dependent

*Approximate percentages of diabetics who will have

this complication to some degree during their lifetime

(data from retrospective studies).

4.9.7 Autonomic neuropathy

Autonomic complications of diabetes may occur inlong-standing diabetes, especially in the context ofpoor control. Complications can be very difficult totreat and there is high morbidity, reduced quality oflife and increased mortality.

Manifestations of diabetic autonomic

neuropathy

• Postural hypotension• Gastroparesis• Gustatory sweating• Generalised sweating• Cardiac arrhythmia (‘dead in bed’)• Diarrhoea, constipation• Reduced appreciation of cardiac pain


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4.10 HYPOGLYCAEMIA

4.10.1 Hypoglycaemia in diabetesmellitus

Autonomic symptoms of hypoglycaemia (sweating,tremor) appear when the blood glucose is ,3.5mmol/L, but can also occur at higher levels whendiabetics have poorer glycaemic control, or whenthere is a rapid drop in glucose levels. Neurogyco-paenic symptoms (impaired cerebral function,coma, seizures) occur when glucose levels drop,2.5 mmol/L. In patients on insulin, failure of thenormal counter-regulatory responses (sympatheticnervous system activation, adrenaline and glucagonrelease) may develop in long-standing diabetes,particularly in the context of frequent hypoglycae-mic episodes. This results in hypoglycaemicunawareness. With no warning of impending neuro-logical impairment, the patient cannot take appro-priate action. More frequent hypoglycaemicepisodes result, exacerbating the problem – ‘hyposbeget hypos’. Hypoglycaemic awareness can berestored by relaxing control to allow a prolongedhypoglycaemia-free period.

4.10.2 Hypoglycaemia unrelated todiabetes

True hypoglycaemia unrelated to diabetes is rel-atively rare. Whipple’s triad consists of symptomsconsistent with hypoglycaemia, measured hypogly-caemia and resolution of symptoms with correctionof the low glucose. A supervised 72-hour fast can beused to precipitate and document an episode, parti-cularly to diagnose an insulinoma (where there willbe inappropriately elevated insulin and C-peptidelevels in conjunction with a low glucose level).

Causes of hypoglycaemia

• Fasting• Insulinoma• Tumour (IGF-2 mediated)• Hypoadrenalism• Alcohol• Severe liver failure• Factitious (insulin or sulphonylurea)• Drugs• Anti-insulin antibodies (delayed post-

prandial release of insulin)• Post prandial

• Post-gastrectomy/bariatric surgery• Reactive• Idiopathic (rare)

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