Type 1 diabetes mellitus (DM) Essence Diabetes results from a lack (or diminished effectiveness) of endo-genous insulin.

The hyperglycaemia for which diabetes is so famous is just one aspect of a far-reaching metabolic derangement which typically leads to serious vascular events (stroke, MI, retinopathy, and limb ischaemia). Type 1 and type 2 DM (p294) are different entities, with different causes, and natural histories. Type 1 DM (formerly called insulin-dependent diabetes mellitus, IDDM) is usually of juvenile onset but may occur at any age, and is characterized by insulin deficiency. Patients always need insulin, and are prone to ketoacidosis and weight loss. It is associated with other autoimmune diseases (HLA DR3 & DR4; +ve islet cell antibodies at diagnosis). Concordance is >30% in identical twins. 4 genes are importantone (6q) determines islet sensitivity to damage (eg from viruses or cross-reactivity from cows' milk-induced antibodies). Presentation Acute: Ketoacidosis (p818)unwell, hyperventilation, ketones on breath, weight loss, polyuria and polydipsia, fatigue. Subacute: History as above but longer and in addition lethargy, infection (pruritus vulvae, boils). Diagnosis Mainly clinical with venous fasting plasma glucose 7mmol/L. Plasma HCO3- and arterial pH may be low, ketones may be present in urine. Treatment Insulin (see BOX). Education on adjusting insulin dose in the light of exercise & calorie intake to achieve normoglycaemia is vital. Give anti-smoking, foot-care (p298), & pre-conception advice (OHCS p94). If pregnant, share care with an interested obstetrician (OHCS p156). Monitor: BP; HbA1c; creatinine; fundi, p296. There is a need for renal protection eg with ACE-i if microalbuminuria is present (p288). Dose adjustment for normal eating (DAFNE): One way to optimize control is to use the principles of adult education (eg explicit learning objectives; group learning) in multi-disciplinary teams (specialist diabetic nurses; podiatrists) to fully engage people in self-management. The aim is to promote autonomy and independence (not passive dependency). The randomized DAFNE study found that training in flexible, intensive insulin dosing improved glycaemic control as well as well-being/quality of life.[diskette]2 It is resource-intensive. Insulin dosing during intercurrent illnesses (eg influenza) Illness often increases insulin requirements despite reduced food intake. Maintain calorie intake using milk or soft drinks containing sugar.

Check blood glucose 4 times a day: insulin doses if glucose rising. Patients may need to seek advice from a specialist diabetes nurse or GP. Admit if the patient is thirsty, polyuric, dehydrated, or ketotic. Admit early if a child or pregnant.

If vomiting, admitand treat with IV fluids and insulin. Same regimen may be needed during any serious illness. Sliding scales of insulin: see p470. Managing type 1 diabetes

The aim is to optimize glycaemic control, without risking dangerous hypoglycaemia. 5 other areas need addressing. Maintain renal function (see p288 for the kidney in DM); this will usually mean giving an ACE-i or AT-2 blocker (p288). Control of blood pressure.

Prevent eye complications by regular screening (eg retinal photography). Prepare for pregnancy (check contraception if pregnancy not wanted). See OHCS p156 for diabetes in pregnancy. Emotional and psychological factors which may be perpetuating unhealthy lifestyles.

Insulin Strength: 100U/mL. There are many types, falling into 6 groups. Ultra-fast acting, eg Humalog and Novorapid; inject at start of meal (or immediately after). Soluble insulin eg Humulin S or Actrapid: inject 1530min before meals.

Intermediate Humulin I or Insulatard. Long-acting (lente), eg Ultratard. Long-acting analogue, eg Lantus/insulin glargine, see below. Pre-mixed insulins, eg with ultra-fast component (eg Humalog Mix 25); or with soluble insulin (eg Humulin M3 or Mixtard 30).

Some commonly used insulin regimens Design the insulin regimen to suit your patient's lifestyle (not vice versa). Twice daily premixed insulins by pen injectoruseful in type 2 DM or type 1 with regular lifestyle. Before meals ultra-fast or soluble insulin with bedtime intermediate- or long-acting analogue: useful in type 1 DM for achieving a flexible life style (eg skipping meals).

Once daily before bed intermediate- or long-acting analoguegood initial insulin regimen when switching from tablets in type 2 DM. Begin with at least a total daily dose of 1 unit of insulin for every unit of body mass index in adults. NB: Insulin glargine is a long-acting recombinant human insulin analogue used once daily at bedtime in type 1 or 2 DM; however, not recommended for routine use in type 2 DM (see BNF; NICE guidance).[diskette]3 Molecular modification has made an insulin that is soluble at acid pH, but precipitates in subcutaneous tissue and is slowly released from a depot. Given once daily, insulin glargine has comparable efficacy to that of insulins used twice daily. Its rate of hypoglycaemia is to that of standard insulins, and there is evidence of less nocturnal hypoglycemia. It may be combined with ultrashort acting insulins given at the times of meals. In type 2 DM, if oral agents are failing, it can be added only if a bd dosing is problematic (NICE guidance).[diskette]4

Strict plasma glucose control does reduce renal, CNS, & retinal damage.[diskette]5 [diskette]6

Type 2 diabetes mellitus (DM Type 2 DM appears to be prevalent at epidemic levels in many places (part of the increase is due to better diagnosis and improved longevity).[diskette]7 In areas of Australia, 7% of people over 25yrs old have DM (mostly type 2).[diskette]8 Higher prevalence occurs in Asians, men, and the old (18% in men over 80 in Liverpool).[diskette]9 Avoid the terms noninsulin-dependent dm (niddm) and maturity-onset dm: most are over 40yrs, but teenagers are increasingly getting type 2 DM. Cause Insulin secretion and insulin resistance associated with obesity (diabesity), exercise lack, and calorie excess. [greater than or equivalent to]80% concordance in identical twins.1 Typical natural history A preliminary phase of impaired glucose tolerance (IGT) or IFG, see below. (This a unique window of opportunity for lifestyle intervention.) A symptomatic phase: Thirst, polyuria, weight loss. A phase of complications: Infections, neuropathy (eg foot ulcers), retinopathy, or arterial disease (eg MI or claudication). Diagnosis/tests/monitoring Blood: Fasting venous glucose (>7mmol/L, unless already on insulin); HbA1c ([greater than or equivalent to] 6.5%; monitor eg 24 times/yr). Random blood glucose tests are unreliable, but if >11.1mmol/L and symptomatic, this is diagnostic. Urine: Microalbuminuria (eg annually; defines renal risks, p288); urine analysis. MSU if ill. Fundoscopy (p296). BP: Keep systolic <140mmHg. Lipids: p706. Foot exam: Take off shoes and socks at each visit, to assess circulation, sensation, and skin quality; warn not to go barefoot.[diskette]10 Diagnostic criteria If no diabetic symptoms, do not base a diagnosis on 1 glucose value alone. If there is any doubt, use the 2h value in an oral glucose tolerance test (OGTT): look for a level >11.1mmol/L. How to do a 2h OGTT: Fast overnight and give 75g of glucose in 300mL water to drink. Measure venous plasma glucose before and 2h after the drink. NB: Severe hyperglycaemia in acute infection, trauma, or circulatory or other stress may be transitory: delay formal diagnosis (but not management). Plasma HbA1c values: If >7%, DM is likely (specificity 99.6%; sensitivity 99%), and risk of microvascular complications occurs. Screening for glycosuria: This is easy but ~1% of the population have low renal threshold for glucose; the sensitivity is only 32% (specificity: 99%). Impaired glucose regulation not amounting to diabetes

This state lies between normal glucose homeostasis and diabetes. Impaired glucose tolerance (IGT): Fasting plasma glucose < 7mmol/L and OGTT 2h glucose 7.8mmol/L but <11.1mmol/L. Impaired fasting glucouse (IFG): Fasting glucose levels > nor-mal range, but below the diagnostic level for DM, ie fasting plasma glucose 6.1mmol/L but <7mmol/L. Diabetes UK (British Diabetic Association) recommends all those with IFG should have an OGTT to exclude DM. IFG and IGT denote different abnormalities of glucose regulation (fasting and post-prandial). There may be lower risk of progression to DM in IFG than IGT. Both are managed with lifestyle advice (eg exercise & diet, p91), and regular review. NB: Giving those with heart failure and IFG ACE-i drugs can prevent progression to DM (3% vs 48% over 3yrs).[diskette]11 Gestational diabetes: This term now includes both gestational impaired glucose tolerance (GIGT) and gestational diabetes mellitus (GDM). Use the same diagnostic values as IGT and diabetes above. As glucose tolerance changes during pregnancy, the gestation at which the diagnosis was made needs to be stated. 6wks post-partum, do a further 75g OGTT whether she still has diabetes or IGT/IFG. Regardless of the 6wk post-pregnancy result, these women are at risk of later diabetes. See OHCS p156. Managing type 2 diabetes Patient motivation and education are central. Aim to avoid complicationshypoglycaemia as well as the long-term effects of hyperglycaemia. Tight BP control (eg systolic [less than or equivalent to]140mmHg) is most important for preventing macrovascular disease and mortality. [diskette]12 So do a global assessment of risk: glucose, BP, left ventricular hypertrophy, cholesterol,1 and smoking. Don't treat DM in isolation. In the UK, a National Service Framework (NSF) governs the delivery of care, setting aims, and prioritizing quality initiatives. [diskette]13 Educate and negotiate on drugs, diet, and the benefits of these issues: Specialist nurse/dieticians, chiropodists, diabetic associations/patient's groups. Regular follow-up and regular exercise ( insulin resistance & risk of MI).

Legal obligations to inform their driving licence authority (p162). Diet: p208saturated fats, sugar, starch-carbohydrate, moderate protein; don't prohibit coffee (may insulin sensitivity).[diskette]14 If creatinine or microalbuminuria (p288), restrict protein, and give ACE-i (p139) or AT-2 blocker (p283). If diet and exercise do not control glycaemia, use drugs.

Oral hypoglycaemics Start with metformin (a biguanide). This helps maintain weight loss (if achieved!) and insulin sensitivity. SE: anorexia; D&V; B12 absorption; not hypoglycaemia. Avoid if creatinine [greater than or equivalent to]150mol/L. Dose: 0.51g/8h PO pc. Stop if tissue hypoxia (eg MI; sepsis) and 48h before GA and for 3d after contrast medium containing iodine (do U&E).[diskette]15 Next add in a sulfonylurea to insulin secretion (some authorities, but not NICE,[diskette]16 say a glitazone2 is more appropriate as the 2nd add-in drug).[diskette]17 Tolbutamide: Shortacting (hypoglycaemia is rare); 0.51.5g in 23 doses. Gliclazide: Medium-acting; 40160mg PO as a single dose, max 160mg/12h). Glibenclamide: Long-acting; 2.515mg/24h PO at breakfast (rarely used).

Glitazones Rosiglitazone 4mg/24h. CI: LFT. SE: headache, diarrhoea, dyspepsia, fluid retention (caution in CCF); do LFT every 2 months for 1yr; stop if ALT up >3-fold; alternative: pioglitazone 1530mg/24h. Glitazones insulin resistance. Use if metformin + sulfonylurea combination is problematic: the glitazone replaces whichever is contraindicated or not tolerated. [diskette]18 Other agents Acarbose (an -glucosidase inhibitor) decreases breakdown of starch to sugar. Use as an add-on drug,[diskette]19 eg 50mg chewed at start of each meal, start with a once daily dose; max 200mg/8h. SE: wind (can be terrible; less if slow dose build-up), abdominal distension/pain, diarrhoea. Nateglinide: -cell insulin release by binding to sulfonylurea receptors. 120mg 30min a.c. Alternative: Repaglinide. They may be no better than metformin/glibenclamide at lowering HbA1c. They target post-prandial hyperglycaemia (t is short[diskette]20 metformin works mostly on fasting glucose); they may have a role in those with irregular mealtimes if glycaemic control is poor.[diskette]21 Other considerations ACE-i (p139; many good effects, not just BP); aspirin + statins (p706; ?for all with DM) to overall risk. Exercise also helps. Footnotes 1 As DM has so many vascular events, give a statin (p706) if LDL >3mmol/L or BP >140. Even consider a statin whatever the pre-treatment cholesterol; discuss with your patient. L Lindholm 2003 Lancet 361 2000 2 Glitazones may preserve -cells and control glycaemia for longer than secretagogues or biguanides. Causes of insulin resistance Syndrome X (central obesity, arteriopathy, glucose, and hyperinsulinaemia + BP) Obesity; acromegaly Werner's syn, OHCS p758 Renal failure (all types) Polycystic ovary, p316 Asians1, pregnancy TB drugs; cystic fibrosis Mechanisms: Obesity may cause insulin resistance by rate of release of non-esterified fatty acids causing post-receptor defects in insulin's action. Mutation of genes encoding insulin receptors.

Circulating autoantibodies to the extracellular domain of the insulin receptor. [prescription take] for syndrome X: Exercise more; weight; statins; hypotensives, hypoglycaemics (eg glitazones).[diskette]22

Diabetes may be secondary to eg drugs (steroids and thiazides); pancreatic disease (pancreatitis, surgery in which >90% pancreas is removed, haemochromatosis, cystic fibrosis, pancreatic cancer); endocrine disease (Cushing's disease, acromegaly, phaeochromocytoma, thyrotoxicosis); others (acanthosis nigricans, congenital lipodystrophy with insulin receptor antibodies, and glycogen storage diseases). Helping people with established diabetes

Focus on education and lifestyle advice. Promote exercise (to insulin sensitivity), healthy eating (p208) and weight reductionp208; NICE comments that drugs such as orlistat have a role here if weight loss of >2.5kg has been achieved by lifestyle advice and BMI >28kg/m2. Find out what problems are being experienced (glycaemic control and morale). Pre-empt complications. Assess those modifiable risk factors important in DM BP: Aim for systolic <140mmHg; smoking; cholesterol (p706). Glycaemic control: (1) Glycated (glyco-sylated) haemoglobin (= HbA1c)levels relate to mean glucose level over previous 8 wks (ie RBC half-life). The target HbA1c must be set individually. Tight control is especially vital in pregnancy (OHCS p156) and if there are microvascular complications. In other patients it may occasionally be sensible to opt for less tight control. NB: The 2003 UK prospective diabetes study (UKPDS; N=2489) shows that in type 2 DM, HbA1c levels remain stubbornly high, despite intensive therapy[diskette]23 (making recent UK HbA1c targets of [less than or equivalent to]7.4% seem impossible). Complications increase with increasing HbA1c. NB: fructosamine (glycated plasma protein) levels reflect control over 23 wks: useful in pregnancy to assess shorter term control, and in haemoglobinopathies which interfere with HbA1c tests. (2) History of hypoglycaemic attacks (and whether symptomatic). (3) Home fingerstick glucose records may be useful. Look for complications Check injection sites for infection/fat necrosis, then: Vascular disease: Commonest cause of death. Look for evidence of cerebrovascular, cardiovascular, and peripheral vascular disease. MI is 35 times more common in DM and is more likely to be silent (ie without classic symptoms). Stroke is at least twice as common. Women are at high riskDM removes the cardiovascular advantage conferred by female gender. Reduce other risk factors (see p91). NB: ACE-i also slows progression of renal disease (p283). Treat lipid disorders (p706)statins, eg simvastatin 40mg nocte, are 1st-line. Good glycaemic control also helps. Fibrates may be useful for triglycerides and HDL. An aspirin a day may risk of MI in diabetics as in non-diabetics (no significant risk to the eye). Kidneys (p283): Microalbuminuria (p288) reflects early renal disease, and indicates risk for macrovascular disease. Control BP with ACE-i: see p139.

Diabetic retinopathy: (Dilate pupils with 0.5% tropicamide.) Blindness is not common and is usually preventable. Arrange regular fundoscopy for all patients, including retinal photography, if possible. Refer if maculopathy or pre-proliferative changes or any uncertainty at or around the macula (the most sacred retinal site and the only place capable of 6/6 vision). Pre-symptomatic screening enables laser photocoagulation to be used. For images of DM retinopathy, see OHCS p508 and its associated colour plates. Background: Microaneurysms (dots), microhaemorrhages (blots), and hard exudates. Refer to specialist if near the macula. See PLATE 13. Pre-proliferative retinopathy: Cotton-wool spots (infarcts); microhaemorrhages. Proliferative retinopathy: New vessels form. Needs urgent referral. Maculopathy: More common in type 2 DM. Suspect if visual acuity.

Pathogenesis: Capillary endothelial change vascular leak microaneurysms capillary occlusion hypoxia+ischaemia new vessel formation. High retinal blood flow caused by hyperglycaemia (& BP & pregnancy) triggers this, causing capillary pericyte damage. Microvascular occlusion causes cotton-wool spots ( blot haemorrhages at interfaces with perfused retina). New vessels form on disc or ischaemic areas, proliferate, bleed, fibrose, and can detach the retina. Aspirin (2mg/kg/d) may prevent it; there is no evidence of bleeding.1 Cataracts: May be juvenile snowflake form, or senilewhich occur earlier in diabetic subjects. Osmotic changes in the lens induced in acute hyperglycaemia reverse after normoglycaemia (so wait before buying glasses). Rubeosis iridis: New vessels on iris: occurs late and may lead to glaucoma. Metabolic complications: p818. Diabetic feet: p298. Neuropathy: p298. Starting insulin in those with type 2 DM This is frequently required when control with oral agents is suboptimal (eg HbA1c >7.58.0% on maximum oral therapy). The patient must be blood glucose self-testing. Transfer is supervised by a diabetes nurse spe-cialist and dietician. Insulin (p293) may be given initially once or twice a day. Continue metformin to limit weight gain. NICE has commented that long-acting insulin glargine (p293) is not normally needed in this context, unless there is recurrent symptomatic hypoglycaemia or it is necessary to avoid twice daily insulin doses (eg if assistance is needed to inject). Controlling BP in those with diabetes3 typical scenarios BP <145/80 and no microalbuminuria and 10yr coronary event risk (CER10, p22) 15%, simply check BP every 6 months, or more often. BP 140/80 and <160/100 and CER10 >15%, but no microalbuminuria, start an antihypertensive (NICE recommends ACE-i, A2A, -blocker, or a thiazide). Target BP <140/80. For doses and discussion, see p142.

BP 140/80 and microalbuminuria is present (urine albumin:creatine ratio 2.5mg/mmol in men or 3.5 in women): ensure ACE-i or A2A are part of the approach (unless CI, p139); target BP: <135/75. (NICE guidelines)

Aspirin prophylaxis (75mg/d PO) is indicated eg if CER10 >15%.1 Footnote 1 Aspirin is known to leucocyte adhesion in diabetic retinal capillaries. It expression of integrins on the surface of leucocytes and it nitric oxide synthetase (eNOS) levels and production of the vasoactive cytokine, tumour necrosis factor, known to be raised in diabetic retinopathy. BMJ 2003 327 1060 Diabetic neuropathy and diabetic foot care Amputation is preventable: good care saves legs. Examine feet regularly. Distinguish between ischaemia (eg critical toes absent dorsalis pedis pulses) and peripheral neuropathy (injury/infection over pressure points, eg the metatarsal heads). In practice, many have ischaemia and neuropathy. Symptoms Numbness, tingling, and burning, often worse at night. Signs

Sensation (especially vibration) in stocking distribution; absent ankle jerks; deformity (pes cavus, claw toes, loss of transverse arch, rocker-bottom sole). Neuropathy is patchy, so examine all areas. If the foot pulses cannot be felt, consider Doppler pressure measurement. Any evidence of neuropathy or vascular disease puts the patient at high risk of foot ulceration. Educate (daily foot inspection, comfortable shoesie very soft leather, increased depth, cushioning insoles, weight-distributing cradles, extra cushioningno barefoot walking, no corn-plasters). Regular chiropody. Treat fungal infections (p612). Foot ulceration: Usually painless, punched-out ulcer in an area of thick callous superadded infection, pus, oedema, erythema, crepitus, odour. Assess degree of: Neuropathy (clinical). Ischaemia (clinical and Dopplers; consider angiographyeven elderly patients may benefit from angioplasty).

Bony deformity, eg Charcot joint (clinical, x-ray). Infection (do swabs, blood culture, x-ray; probe ulcer to assess depth).

Management: Regular chiropody (remove dead tissue). Relieve high-pressure areas with bedrest therapeutic shoes (Pressure Relief Walkers and similar shoes may be as good as total contact casts[diskette]24); metatarsal head surgery may be needed. In ischaemia, shoes must be widefitting with deep toe boxes to protect vulnerable forefoot margins and toes.[diskette]25 If there is cellulitis, admission is mandatory for IV antibiotics: start with benzylpenicillin 600mg/6h IV and flucloxacillin 500mg/6h IV metronidazole 500mg/8h IV, refined when microbiology results are known. Get surgical help. Ensure normoglycaemia. Absolute indications for surgery Abscess or deep infection Spreading anaerobic infection

Severe ischaemiagangrene/rest pain Suppurative arthritis

The degree of peripheral vascular disease, patient's general health, and patient request will determine whether local excision and drainage, vascular reconstruction, and/or amputation (and how much) is appropriate. Types of neuropathy in diabetes Motor & sensory neuropathy: Symmetric sensory polyneuropathydistal numbness (glove and stocking anaesthesia), tingling, and visceral pain, eg worse at night. Batting order of drugs to try: aspirin/paracetamol tricyclic (amitriptyline 1025mg nocte; gradually ; max 150mg) gabapentin. Alternatives: carbamazepine (p380);[diskette]26 lamotrigine;[diskette]27 0.075% capsaicin cream (a counter-irritant). Decompression may help.[diskette]28 Mononeuritis multiplex

especially III & VI cranial nerves. Treatment is difficult. If sudden and severe, immunosuppression with corticosteroids, IV immuno-globulins, and ciclosporin (=cyclosporin) has been tried.[diskette]29 Amyotrophy painful wasting of quadriceps and other pelvifemoral muscles. Use electrophysiology to show eg lumbosacral radiculopathy, plexopathy, or proximal crural neuropathy.[diskette]30 Natural course: variable with gradual but often incomplete improvement. IV immunoglobulins have been used.[diskette]31 Autonomic neuropathy: (biology: p390) Excessive postural BP drop; cerebrovascular autoregulation; urine retention; erectile dysfunction (ED); diarrhoea at night. The latter may respond to long-term codeine phosphate (the lowest dose to control symptoms, eg 15mg/8h PO). Gastroparesis (early satiety, post-prandial bloating, nausea/vomiting) is diagnosed by gastric scintigraphy with a 99 technetium-labelled low-fat meal.[diskette]32 It may respond to antiemetics. Postural hypotension may respond to fludrocortisone 100300g/24h PO (SE: oedema). Preventing loss of limbs: primary or secondary prevention? Traditionally prevention has involved foot care advice in diabetic clinics (eg don't go barefoot ), and maintaining good glycaemic and BP control.1 But despite this, the sight of a diabetic patient minus 1 limb is not rare: whenever we see such patients we should redouble our commitment to primary preventionie stopping those at risk from ever getting diabetes. In one randomized prospective study of those with impaired glucose tolerance (IGT) and other risk factors, after 3 yrs, the incidence of diabetes per 100 person-years was 5 in those receiving simple exercise and diet advice, 8 in a group given metformin, and 11 in the placebo group. Advice and metformin decreased incidence of diabetes by 58% (NNT 7) and 31% (NNT 14), respectively, compared with placebo.[diskette]33 Footnote 1 HbA1c 7.4% and BP 145/85 are current UK primary care targets (GPs get a quality payment if 70% of their diabetics achieve this level; for non-diabetic hypertensives, the target BP is 150/90mmHg). Hypoglycamia This is the commonest endocrine emergency. Prompt diagnosis and treatment is essential. See p820 for emergency management. Definition Plasma glucose <2.5mmol/L. Threshold for symptoms varies. Symptoms AutonomicSweating; hunger; tremor. Neuroglycopenic Drowsiness; seizures; rarely focal symptoms, eg transient hemiplegia, coma. Mutism, mannerisms, personality change, restlessness, and incoherence may lead to misdiagnosis of hysteria or psychosis.[diskette]34 Two types: Fasting hypoglycaemia (requires full investigation if documented). o Causes: By far the commonest cause is insulin or sulfonylurea treatment in a known diabetic. In the non-diabetic subject with fasting hypoglycaemia, the following mnemonic is useful: EXPLAIN.

Exogenous drugs, eg insulin or oral hypoglycaemics (p283). Does he have access to these (diabetic in the family)? Body-builders sometimes misuse insulin to improve stamina.[diskette]35 Alcohol, eg alcoholic on binge with no food. Also: aminoglutethimide; 4-quinolones; pentamidine; quinine sulfate. Pituitary insufficiency. Liver failure plus some rare inherited enzyme defects. Addison's disease. Islet cell tumours (insulinoma, see below) and immune hypoglycaemia (eg antiinsulin receptor antibodies in Hodgkin's disease). Non-pancreatic neoplasms (especially retroperitoneal fibrosarcomas and haemangiopericytomas).

o o o o

Diagnosis and investigations Document hypoglycaemia by taking finger-prick (on filter-paper at home for later analysis) during attack, or lab glucose if in hospital. Exclude liver failure and malaria.

Admit for 72h fast. Do glucose, insulin, & C-peptide if symptomatic.

Interpreting results Hypoglycaemia with high or normal insulin and no elevated ketones. Causes: insulinoma; sulfonylurea administration; insulin administration (no detectable C-peptide); insulin autoantibodies. Insulin low or undetectable, no excess ketones. Causes: Non-pancreatic neoplasm; antiinsulin receptor antibodies.

Insulin, ketones. Causes: Alcohol; pituitary or adrenal failure. Post-prandial hypoglycaemia May occur eg after gastric surgery (dumping, p530), and in type 2 diabetes. Investigation: Prolonged OGTT (5h, p294).

Treatment See p820. Treat with oral sugar, and a long-acting starch (eg toast); if coma, glucose 2550g IV (via a large vein with a 0.9% saline flush to prevent phlebitis) or glucagon 0.51mg SC/IV/IM ( a repeat after 20min; follow with carbohydrate). If episodes are often, advise many small high-starch meals. If post-prandial glucose, give slowly absorbed carbohydrate (high fibre). In diabetics, prevent further episodes, by rationalizing insulin therapy (p293). Insulinoma MEN-1 associated (p309), usually benign islet cell tumour. Screening test: Hypoglycaemia + plasma insulin during a long fast. Suppressive tests: Give IV insulin and measure C-peptide. Normally exogenous insulin suppresses C-peptide, but this does not occur in insulinoma. Arterial stimulation1 with venous sampling (ASVS): Hyperinsulinaemia as measured eg via splenic or

superior mesenteric artery stimulation.[diskette]36 Imaging: CT/MRI endoscopic pancreatic US (all fallible, so don't waste too much time before proceeding to intra-operative visualization[diskette]37 intra-operative ultrasound).[diskette]38 Treatment: Surgery. Footnote Diabetic ketoacidosis (DKA): assessment DKA predominantly occurs in patients with insulin-dependent diabetes (type I). It does not usually occur in non-insulin-dependent diabetes. DKA is being increasingly recognized in some type II diabetics, esp. Afro-Caribbeans. Remember, patients may be prescribed insulin for poor diabetic control, and yet have non-insulin dependent diabetes. Clinical features These include Polyuria and polydipsia: patients become dehydrated over a few days Weight loss, weakness

Hyperventilation or breathlessness: the acidosis causes Kussmaul's respiration (a deep sighing respiration) Abdominal pain: DKA may present as an acute abdomen Vomiting: exacerbates dehydration Confusion, coma occurs in 10% On examination assess state of hydration, ventilation rate, and smell for ketones.

Investigations Blood This need not be high. Severe acidaemia may be present with glucose values as low glucose as 10mM (e.g. if the patient has recently taken insulin: this, alone, is insufficient to correct the acidaemia in the presence of dehydration) ABG Assess the degree of acidaemia (pH and bic.) U&Es Corrected Assess serum K+ and renal function Ketones strongly positive (ketones may be present in normal individuals after a period of starvation) NB: captopril and other sulphydryl drugs can give a false positive test for urinary ketones WBC may be elevated (neutrophilia): a leukaemoid reaction can occur in absence of infection Blood and urine cultures

Urinalysis FBC

Septic screen Plasma (see note below) ketones CXR Look specifically for any infection Amylase May be high with abdominal pain vomiting in absence of pancreatitis. Acute pancreatitis may occur in ~ 10% of patients with DKA. Note Serum osmolality = 2 (Na+ + K+) + urea + glucose.

Diagnosis of DKA requires positive urinary or plasma ketones and arterial pH 7.30 and/or serum bicarbonate 15mmol/L. Many labs do not measure plasma ketones. The elderly patient presenting with a high glucose, relatively normal acidbase balance, and ketones in the urine does not have diabetic ketoacidosis, and may not be insulin dependent. Consider other causes of hyperglycaemia/acidosis, e.g. aspirin overdose, and in the elderly consider lactic acidosis. Plasma ketones can be estimated by diluting plasma 1:1 with N saline, and applying to a urine ketone dipstick. A result of +++ corresponds to a plasma ketone body concentration of 5mmol/L.

Common precipitants of DKA Infections 30% Non-compliance with treatment20% Newly diagnosed diabetes 25% Poor prognostic features in DKA pH <7.0 Oliguria

Serum osmolality >320 Newly diagnosed diabetes

Diabetic ketoacidosis: management1 General measures Rehydration and insulin therapy are the mainstays of treatment. Site the iv cannula away from a major vein in the wrist. This may be required for an AV fistula in patients subsequently developing diabetic nephropathy. Start fluid replacement (see below).

Insert a central line in patients with a history of cardiac disease/autonomic neuropathy or the elderly (see P866). Consider an arterial line to monitor ABGs and potassium. Nil by mouth for at least 6 hours (gastroparesis is common). Nasogastric tube: if there is impaired conscious level to prevent vomiting and aspiration. Urinary catheter if oliguria is present or serum creatinine is high. Broad-spectrum antibiotics if infection suspected. LMWH (e.g. enoxaparin) should be given as prophylaxis against DVTs, but is not standard clinical practice. The t of insulin is short and continued replacement (iv or sc) is essential.

Fluid replacement Use N saline potassium until blood glucose is <12mmol/L. The average fluid loss in DKA is 36 litres. Aim to restore this over 24 hours. (The following regime should be modified for patients with cardiac disease.) If hypotensive and oliguric, give iv colloids ( N saline) initially to restore BP; then 1 litre N saline over the first 30 minutes then

1 litre N saline with potassium (see table) 2 hourly for 8 hours then 1 litre N saline (with K+, see table) 4 hourly until rehydrated (~24hours). The use of bicarbonate is controversial. If the pH <7.0, isotonic (1.26%) sodium bicarbonate given at a maximal rate of 500ml (i.e. 75mmol) over 1 hour is safe. Faster infusion rates cause a paradoxical intracellular acidosis. Add 1020mEq K+ per 500 ml. There is no evidence that the use of bicarbonate in DKA improves outcome. When blood glucose is <12mmol/L, commence a 5% dextrose infusion and continue insulin infusion. Continued insulin is required to inhibit ketoacid production.

Potassium replacement See table. Total body potassium can be depleted by 1000mmol and the plasma K+ falls rapidly as potassium shifts into the cells under the action of insulin. Use less potassium in patients with renal impairment or oliguria. Insulin replacement See table. Modify this regimen depending on the response to therapy. Aim for a fall in glucose of 5mmol/L per hour (and correction of acidosis and plasma bicarbonate). If the glucose or acidosis are not improving, increase the insulin infusion rate accordingly.

Keep the blood glucose >1014mmol/L for the first 24 hours or until the ketoacidosis resolves; maintain this with 5% dextrose infusion.

Plasma potassium Amount of K+(mmol) to add to each litre (mmol/L) <3.0 40 <4.0 30 <5.0 20 The sliding scale below is a guide and should be tailored to the patient and response to therapy. Add 50 units of actrapid to 50ml 0.9% saline and administer by intravenous infusion. Start the insulin infusion at 0.1U/kg/h initially. That is 7U/h for a 70kg person.

If the blood glucose falls by >5mmol/L in 1 hour, then decrease the rate of infusion to 0.05U/kg/h (i.e. reduce to half-dose). When the blood glucose is <12mmol/L, glucose should be infused instead of saline, and blood glucose stabilized according to the sliding scale below.

Do not stop insulin infusion until regular subcutaneous insulin is restarted.

Blood glucose (mmol/L) Insulin infusion (units/hour) (hourly) 0.02.0 Stop insulincall doctor 2.14.0 Call doctor 4.07.0 0.5 or 1 7.111.0 2 11.120.0 4 >20 7call doctor Diabetic ketoacidosis: complications Assessment during treatment Remember rapid normalization of biochemistry can be detrimental in any patient. It is wiser to be cautious and sub-optimal than enthusiastic and dangerous. Blood glucose hourly with lab blood glucose 4 hourly. Plasma electrolytes 2 hours after start of treatment and then 4 hourly. The main risk is hypokalaemia.

ABGs 4 hourly, until persistent improvement or normalized. Plasma osmolality 4 hourly. Some patients may require monitoring on an ECG for T-wave changes during treatment. Phosphate levels should be monitored daily during treatment (see below). Magnesium levels should be monitored daily (see below). The iv insulin infusion should be continued until 4 hours after the patient is commenced on subcutaneous insulin.

Complications Avoid hypoglycaemia from overzealous insulin replacement. Cerebral oedema occurs mainly in children. It may be precipitated by sudden shifts in plasma osmolality during treatment. Symptoms include drowsiness, severe headache, confusion. Treat as on P454. Give iv mannitol 0.5g/kg body weight, repeated as necessary. Restrict iv fluids and move to ITU. Mortality is ~70%; recovery of normal function only 714%.

Serum phosphate falls during treatment, as it moves intracellularly with potassium. If the phosphate level falls to below 0.4mmol/L, give phosphate iv (monobasic potassium phosphate infused at a maximum rate of 9mmol every 12 hours). Check preparations with your pharmacy. Serum magnesium may fall during insulin therapy. If magnesium levels fall <0.6 mmol/L, give 48mmol (2ml of 50%) magnesium sulphate over 1530 minutes in 50ml N saline. Repeat as necessary.

Hyperchloraemic acidosis (high anion gap acidosis in a well-hydrated patient) may be seen with excessive administration of saline and increased consumption of bicarbonate. No specific treatment is required. Tissue hypoperfusion results from dehydration and may trigger the coagulation cascade and result in thromboembolism. Consider using LWMH (e.g. enoxaparin sc) for prophylaxis in those at risk.

Complications of DKA Hypokalaemia Hypophosphataemia

Hyperchloraemic acidosis Hypoglycaemia Cerebral oedema in children Thromboembolism

Hyperosmolar non-ketotic coma (HONC) HONC occurs in elderly patients with non-insulin-dependent diabetes. These patients are also at increased risk of venous and arterial thromboses. The mortality is very much higher than for ketoacidosis. Presentation A history of diabetes is not usually known, and the patient is elderly Insidious onset of polyuria and polydipsia

Severe dehydration Impaired conscious level: the degree correlates most with plasma osmolality. Coma is usually associated with an osmolality >440 Respiration is usually normal The patient may rarely present with a CVA, seizures, or a MI.

Investigations Usually very high (>50mmol/L) Glucose U&Es Dehydration causes a greater rise in urea than creatinine (normal ratio of Cr:Ur up to 20:1 (M:mM). Significant hypernatraemia may be hidden by the high glucose. The hypernatraemia may appear to worsen as the glucose falls Relatively normal cf. DKA. A coexistent lactic acidosis considerably worsens the prognosis Plasma Calculate by [2 (Na+ + K+) + urea + glucose] needs to be >350mosm/kg for osm. diagnosis FBC Polycythaemia and leukocytosis may indicate dehydration or infection respectively ECG Look for MI or ischaemia

 CXR Look for signs of infection Urine For urinalysis, MC&S. Remember that ketones may occur in any starved person, but the level will be below 5mM. Blood and protein on urinalysis may indicate UTI. Management: general measures Rehydration and insulin therapy are the mainstays of treatment. Fluid replacement should be more cautious in the elderly. Give oxygen if hypoxic on air. Avoid fluid overload: monitor central venous pressure in all patients.

Nil by mouth for at least 6 hours and insert an NG tube in patients with impaired conscious level to prevent vomiting and aspiration. Urinary catheter if oliguria is present, or serum creatinine is high. Anti-coagulate with LWMH (e.g. enoxaparin 40mg sc daily).

Fluid replacement The average fluid lost is 810L. This should be replaced cautiously. 1 litre N saline over the first 60 minutes then 1 litre N saline with K+ (see table, P559) every 2 hours for 4 hours then

1 litre N saline with K+ (see table, P559) q6h until rehydrated (~48 hours). If the plasma Na is >160mM give 0.45% saline (0.5 N saline) for the first 3 litres. The Na+ level is artificially lowered by the high glucose level (see below) and appears to climb as the blood glucose falls. When blood glucose <12mmol/L, commence a 5% dextrose infusion, and consider stopping insulin therapy and starting oral hypoglycaemic agents or diet alone.

Insulin regimen This is similar to that for diabetic ketoacidotic coma (see table, P559), except that stopping insulin completely is less hazardous in the short term. Practice points: hyperosmolar non-ketotic coma Severe hyperglycaemia can cause a technical error in the measurement of Na+ concentrations. The corrected concentration can be calculated by* Treatment of severe hyperglycaemia causes an apparent increase in plasma Na+ which in reality may not actually change

Occasionally patients present with hyponatraemia which based on the above is a form of pseudohyponatraemia (see P574)

Hypoglycaemic coma: assessment

All unconscious patients should be assumed to be hypoglycaemic until proved otherwise. Always check a blood glucose using a Glucostix (or BM stix) immediately, and confirm with a lab determination.

The most common cause of coma in a patient with diabetes is hypoglycaemia due to drugs. The longer acting sulphonylureas such as glibenclamide are more prone to do this than the shorter acting ones. Patients who are not known to have diabetes, but who are hypoglycaemic, should have a laboratory blood glucose, and serum saved for insulin and C-peptide determination (insulinoma or factitious drug administration) before administration of glucose.

Presentation Sympathetic overactivity (glc <3.6mmol/L) Tachycardia Palpitations

Sweating Anxiety Pallor Tremor Cold extremities

Neuroglycopenia (glc <2.6mmol/L) Confusion Slurred speech

Focal neurological defect (stroke-like syndromes) Coma Patients with well-controlled diabetes have more frequent episodes of hypoglycaemia, and can become desensitized to sympathetic activation. These patients may develop neuroglycopenia before sympathetic activation and complain of loss of warning. -blockers blunt the symptoms of sympathetic activation and patients taking these drugs lose the early warning of hypoglycaemia. Patients with poorly controlled diabetes develop sympathetic signs early, and avoid these by running a high blood glucose. They may complain of being hypo when their blood sugar is normal or high. They do not require glucose. Patients who have diabetes following a total pancreatectomy have more frequent and severe episodes of hypoglycaemia (brittle diabetes) because they lack glucagon producing () cells as well as islet cells.

Investigations Blood glucose (BM stix and confirmed by lab glucose). U&Es (hypoglycaemia is more common in diabetic nephropathy)

Save serum, prior to giving glucose, for insulin and C-peptide levels (send ~20ml blood to the lab for immediate centrifugation if indicated). A lab glucose of less than 2.2mmol/L is defined as a severe attack. Coma usually occurs with blood glucose <1.5mmol/L. Low C-peptide and high insulin level indicate exogenous insulin; high C-peptide and insulin level indicate endogenous insulin [e.g. surreptitious drug (sulphonylurea) ingestion or insulinoma].

Note

Causes of hypoglycaemia Drugs Insulin Sulphonylureas

Alcohol Salicylates Prescription errors (e.g. chlorpropamide for chlorpromazine) Others/Disopyramide./-blockers./Pentamidine./Quinine

Organ failure Hypopituitarism (esp. acute pituitary necrosis) Acute liver failure

Adrenal failure Myxoedema Rarely CCF or CRF

Infections Sepsis syndrome Malaria Tumours(Insulinoma/Retroperitoneal sarcoma) Hypoglycaemic coma: management Acute measures Remember to take blood prior to glucose administration (glucose, insulin, C-peptide). See P564. If there is a history of chronic alcohol intake or malnourishment, give iv thiamine 12mg/kg to avoid precipitating Wernicke's encephalopathy.

If patient is conscious and co-operative, give 50g oral glucose or equivalent (e.g. Lucozade, or milk and sugar). Give 50ml of 50% dextrose iv if patient is unable to take oral fluids. If iv access is impossible, give 1mg of glucagon im. Then give the patient some oral glucose to prevent recurrent hypoglycaemia. Glucagon is less effective in hypoglycaemia due to alcohol. Admit the patient if the cause is a long-acting sulphonylurea or a long-acting insulin, and commence a continuous infusion of 10% glucose (e.g. 1 litre 8 hourly) and check glucose hourly or 2 hourly.

Further management Patients should regain consciousness or become coherent within 10 minutes although complete cognitive recovery may lag by 3045 minutes. Do not give further boluses of iv glucose without repeating the blood glucose. If the patient does not wake up after ~10 minutes, repeat the blood glucose and consider another cause of coma (e.g. head injury while hypoglycaemic, see P444). Prolonged severe hypoglycaemia (>4 hours) may result in permanent cerebral dysfunction.

Patients on sulphonylureas may become hypoglycaemic following a CVA or other illness preventing adequate food intake. Recurrent hypoglycaemia may herald the onset of diabetic nephropathy, as this decreases insulin requirements: insulin is partly degraded by the kidney. Review patient's current medication, and inspect all tablets from home. Consider psychiatric review if self-inflicted.

Liver dysfunction and recurrent hypoglycaemia Hypoglycaemia is common in acute liver failure, when coma may occur (as a result of liver failure rather than hypoglycaemia). Severe hypoglycaemia is rare in chronic liver disease. In chronic alcoholics it is advisable to administer iv thiamine (12mg/kg) before iv dextrose to avoid precipitating neurological damage.

An acute ingestion of alcohol can also suppress hepatic gluconeogenesis.

Urgent surgery in patients with diabetesSurgery requires patients to fast for several hours. In addition a general anaesthetic and surgery produce significant stresses on an individual. The hormonal response to stress involves a significant rise in counter-regulatory hormones to insulin, in particular cortisol and adrenaline. For this reason, patients with diabetes undergoing surgery will require an increased dose of insulin despite their fasting state. Type I DM (insulin dependent)

Try to put the patient first on the list. Inform the surgeon and anaesthetist early. Discontinue long-acting insulin the night before surgery if possible. If the patient has taken a long-acting insulin and requires emergency surgery, an infusion of 10% dextrose (10100ml/h) can be used, together with an insulin sliding scale. Ensure iv access is available. When nil by mouth, start iv infusion of 5% dextrose with potassium (20mmol/L) at 100ml/h and continue until oral intake is adequate. Remember saline requirements (~100150mmol Na/24h but increases post-operatively) but do not stop dextrose infusion (risk of hypoglycaemia). Commence an iv insulin sliding scale (see table). Measure finger-prick glucose hourly and adjust the insulin infusion accordingly. Aim for 711mmol/L. Continue the insulin sliding scale until the second meal and restart the normal sc dose of insulin. As iv insulin has a very short half-life (3.5 min), this must be continued until the patient's subcutaneous insulin is being absorbed; an overlap of 4 hours is recommended.

Type II DM (non-insulin dependent) Discontinue glucose-lowering tablets or long-acting insulin the night before surgery if possible. If the patient has taken their oral hypoglycaemic or insulin and requires emergency surgery, start an infusion of 10% dextrose (10100ml/h) with an insulin sliding scale. Check a fasting glucose: if >12mmol/L treat as above.

If the patient's diabetes is normally managed with oral hypoglycaemic agents, these can be restarted once the patient is eating normally. The sliding scale can be tailed off 4 hours later. Diet-controlled diabetics often do not require a sliding scale at the time of surgery but may require iv insulin post operatively for a short period if blood glucose rises >12mmol/L. This may be tailed off, when eating normally. Adjust the scale according to the patient's usual requirement of insulin (e.g. a patient on Mixtard 36U/24U requires 60U/24 h, i.e. 2.5 U/h normally). If blood glucose is persistently low (<4mmol/L) decrease all insulin infusion values by 0.51.0U/h. If blood glucose is persistently high (>13.0mmol/L) increase all insulin infusion values by 0.51.0U/h.

Adrenal cortex and Cushing's syndrome Physiology

The adrenal cortex produces: glucocorticoids (eg cortisol), which affect carbohydrate, lipid, and protein metabolism, and mineralocorticoids (eg aldosterone, p688). Corticotrophin-releasing factor (CRF) from the hypothalamus stimulates secretion of ACTH from the pituitary, which in turn stimulates cortisol, and androgen production by the adrenal cortex. Cortisol is excreted as urinary free cortisol and as various 17-oxogenic steroids. Cushing's syndrome Chronic glucocorticoid excess. 90% are ACTH-dependent; of these 90% are pituitary in origin. 90% of pituitary causes are microadenomas (defined as lesions <1cm in size) and MRI only detects 70% of them. ACTH-dependent causes: Cushing's disease: Adrenal hyperplasia due to excess ACTH from pituitary tumour. Commoner in women. Peak age: 3050yrs. Iatrogenic: ACTH administration.

Ectopic acth production: Especially small cell lung cancer and carcinoid tumours. Typical features include pigmentation, weight loss, metabolic alkalosis, and hyperglycaemia. Classic features of Cushing's are often absent. Ectopic CRF production (rare).

ACTH-independent causes: Iatrogenic: Pharmacological doses of steroids (common). Adrenal adenoma and carcinoma (~20%): Carcinoma may be associated with abdominal pain and virilization in women.

Carney complex: Cardiac myxoma, freckles, etc., p309. Alcohol.

The patient Symptoms: Weight; irregular menses; amenorrhoea; hirsutism; impotence; depression; weakness; fractures. Signs: Tissue wasting; myopathy; thin skin; purple abdominal striae; bruising; osteoporosis; water retention; neck (buffalo hump; supraclavicular fat pad); predisposition to infection; wound healing; hirsutism; hypertension; hyperglycaemia (30%). Tests See BOX. First, confirm the diagnosis, and localize the source on the basis of laboratory testing (below). Then use imaging studies to confirm the likely source. Note: adrenal incidentalomas occur on 1% or more of CTs, so identification of an adrenal mass does not prove adrenal source of cortisol excess (pituitary incidentalomas are not infrequent either). Abdominal CT if adrenal source is suspected; pituitary MRI (and consider petrosal sinus sampling) if a pituitary source (Cushing's disease) is suspected (p320). Treatment Depends on the cause. Iatrogenic: remove source if possible. Surgery: for adrenal adenomas (usually curative) and carcinomas (rarely curative). Radiotherapy and medical treatment follow for carcinoma.

Cushing's disease: selective removal of pituitary adenoma via a transsphenoidal or very rarely trans-frontal approach. Bilateral adrenalectomy if the source cannot be located, or

recurrence post-surgery (but this may be complicated by Nelson's syndrome with development of enlarging pituitary tumour and hyperpigmentation). Radiotherapy is used in children and to prevent Nelson's syndrome.

Ectopic ACTH production may be treated by surgery if the tumour can be located and has not spread. Medical treatment may be required. Medical treatment, eg metyrapone, aminoglutethimide, or ketoconazole to plasma cortisol. Adrenolytic agents are also available. Do not expect osteoporosis to fully reverse after drug treatment, but it may after surgery.[diskette]78

Prognosis In 1 study,[diskette]79 the easiest variety to diagnose and treat was the adrenal adenoma; adrenal carcinoma was typically incurable. Ectopic ACTH syndrome was amenable to ketoconazole or complete resection of the offending tumour or bilateral adrenalectomy. 44% of pituitarydependent Cushing's responded to trans-sphenoidal microadenoma resection (recurrence is a problem even after many years). P.311 Assessment of suspected Cushing's syndrome: screening tests The best screening test is the overnight dexamethasone suppression test. Give dexamethasone 1mg PO at midnight; check serum cortisol before, and at 8AM. If level suppresses to <50nmol/L, then it is probably not Cushing's. False negative rate: <2%; false +ve rate: 12.5%. 24h urinary free cortisol (normal: <280nmol/24h) is an alternative. NB: False positives (pseudocushing's) are seen in depression, obesity, alcohol excess, and inducers of liver enzymes which the rate of dexamethasone metabolism (eg phenytoin, phenobarbital, and rifampicin). Further tests (False +ves may occur, as above) The 48h dexamethasone suppression test: Give dexamethasone 0.5mg/6h PO for 2d. Measure cortisol at 0 and 48h (do the last test 6h after the last dexamethasone dose). Circadian rhythm of cortisol secretion: Requires hospital admission. Normal rhythm (cortisol lowest at midnight, highest early in the morning) is lost in Cushing's syndrome. Stress, illness, and venepuncture may interfere with the normal rhythm, making interpretation difficult. Localization tests (where is the lesion?)If the above are positive. Plasma ACTH: If undetectable, adrenal tumour likely. CT/MRI of adrenal glands. May need to resort to adrenal vein sampling, and adrenal scintigraphy (radiolabelled cholesterol derivative). If detectable, distinguish pituitary causes from ectopic ACTH production with high-dose dexamethasone suppression test or CRH test. High-dose dexamethasone suppression test: Give dexamethasone 2mg/6h PO for 2d.

Measure plasma and urinary cortisol at 0 and 48h. Complete or partial suppression if Cushing's disease.

CRH test: 100g ovine corticotrophin releasing hormone IV.[diskette]80 Follow cortisol for 120min.

Cortisol rises with pituitary disease but not with ectopic ACTH production.

If both tests indicate that cortisol responds to manipulation, image the pituitary (CT/MRI). If not, hunt for the source of ectopic ACTH production. Plasma sampling from inferior petrosal sinus May help distinguish Cushing's disease from ectopic ACTH production and in lateralizing a pituitary adenoma, if the above tests are discrepant. Addison's disease (adrenal insufficiency) Primary adrenocortical insufficiency is rare (incidence ~0.8/100,000). Its signs are capricious; as diagnosis may only be made at necropsy, it is called the unforgiving master of non-specificity and disguise.[diskette]81 You may diagnose a viral infection or anorexia nervosa in error[diskette]82 (K+ is in the latter but in Addison's). Think of Addison's in all those with unexplained abdominal symptoms.[diskette]83 Anyone on prednisone for long enough to suppress the pituitaryadrenal axis or who has overwhelming sepsis, or is on anticoagulants, or has metastatic cancer may suddenly develop adrenal insufficiency with deadly hypovolaemic shock, hyperkalemia, hyponatraemia, and hypoglycemia.[diskette]84 See p822. Causes 80% autoimmune in UK ( adrenal antibodies1 associated Graves', Hashimoto's, DM, pernicious anaemia, hypoparathyroidism, vitiligo, coeliac disease).[diskette]85 Others: TB; metastases (Addison's only if >90% of adrenal tissue lost); lymphoma;[diskette]86 HIV (CMV, Mycobacterium avium, etc., p581); adrenal bleeding (WaterhouseFriederichsen, p738; SLE; antiphospholipid syndrome).[diskette]87 Symptoms Anorexia Weakness

Viral illness Fatigue Weight Dizziness Fainting Abdominal pain D&V (or nausea)

Constipation Cold intolerance[diskette]89 Myalgia Arthralgia Cramps Headaches Depression Psychosis[diskette]88 Self-esteem 2 Confusion

Signs Hyperpigmentation (palmar creases, buccal mucosa); vitiligo; postural hypotension. Signs of critical deterioration (p822): Pulse; T; shock; coma. Tests General: K+; Na+; glucose; uraemia; mild acidosis; Ca2+; eosinophilia; neutropenia; lymphocytosis; Hb; LFT. ECG: PR and QT interval.[diskette]90 Specific: Short ACTH stimulation test (Synacthen test): Do plasma cortisol before and h after tetracosactide (=Synacthen) 250g IM. Exclude Addison's if initial cortisol >140nmol/L, and 2nd cortisol >500nmol/L. Steroid drugs may interfere with this assay: check with local lab. ACTH: In Addison's disease ACTH >300ng/L (inappropriately high). Low in secondary causes. Plasma renin activity and aldosterone: To assess mineralocortocoid status. 21-Hydroxylase adrenal autoantibodies: In APS-21 these may be positive.[diskette]91 AXR (plain abdominal films)/CXR: Any signs of past TB, eg calcification? Have a low threshold for further TB tests (especially if autoantibodies -ve), eg adrenal CT. Treatment Replace steroids: hydrocortisone 20mg in morning, 10mg at bedtime PO. Mineralocorticoid replacement may be needed if postural hypotension, Na+, K+, or plasma renin. If necessary give fludrocortisone PO 50g every 2nd day to 0.15mg daily. Adjust on clinical grounds. If there is poor clinical response to treatment, suspect an associated autoimmune disease as above (check thyroid; do Coeliac serology, etc.)[diskette]92 Warn against abruptly stopping steroids. Patients should have syringes at home (+ in-date IM hydrocortisone in case vomiting prevents oral intake). Emphasize that prescribing doctors/dentists must know of steroid use (give steroid card; advise wearing a bracelet declaring

steroid use). Double steroids in febrile illness, injury, or severe stress. For dentistry, double morning hydrocortisone. If vomiting, replace hydrocortisone with hydrocortisone sodium succinate 100mg IM, and get medical help; IV fluids if dehydrated. Follow-up Yearly (include BP and U&E); watch for other autoimmune disease. Prognosis Good, if associated diseases (TB; autoimmunity) do not intrude. Other causes of primary hypoadrenalism Late-onset congenital adrenal hyperplasia: Due to 21-hydroxylase deficiency, causing urinary androgens. Footnotes 1 Autoimmune polyendocrine syndromes (APS)APS-1: Candidiasis + hypoparathyroidism + Addison's amenorrhoea. Cause: mutations of AIRE (AutoImmuneREgulator) gene on chromosome 21. APS-2: Addison's disease + autoimmune thyroid diseases type 1 DM. HLA DR3/DR4-associated. APS-3: Autoimmune thyroid disease + autoimmune diseases (excluding Addison's & hypoparathyroidism). 2 Dehydroepiandrosterone (DHEA) and DHEA sulfate are adrenal steroid precursors and centrally acting neurosteroids. Glucocorticoid and mineralocorticoid replacement do not correct its lack. When DHEA is given, features such as self-esteem improve. Hyperaldosteronism Primary hyperaldosteronism is excess production of aldosterone, independent of the renin-angiotensin system. Consider this when the following features are present: hypertension, hypokalaemia, alkalosis in someone not on diuretics. Sodium tends to be mildly raised or normal. Causes: >50% due to unilateral adrenocortical adenoma (Conn's syndrome). Also: bilateral adrenocortical hyperplasia; adrenal carcinoma (rare); glucocorticoid-remediable aldosteronism (GRA). In GRA, the ACTH regulatory element of the 11-hydroxylase gene fuses to the aldosterone synthase gene, increasing aldosterone production, and bringing it under the control of ACTH. Tests: (see BOX)U&E (when not on diuretics, hypotensives, steroids, K+, or laxatives for 4wks): do not rely on a low K+ (>20% are normokalaemic). Aldosterone and reninnormal or high renin excludes the diagnosis. The differential diagnosis relies on assessing the effect of posture on renin, aldosterone, and cortisol (measure at 9AM lying, and at noon standing). If cortisol and aldosterone on standing: ACTH-dependent, ieConn's or GRA. If cortisol and aldosterone: angiotensin II-dependentie hyperplasia. Do abdo CT/MRI for primary hyperaldosteronism to localize tumour. Seek expert assistance. For GRA (suspect particularly if family history of early hypertension), genetic testing is available. NB: Renal artery stenosis is a more common cause of refractory BP and K+. evaluate with renal Dopplers, captopril renogram, or angiography (the gold standard). Treatment: Conn's:Surgery (eg laparoscopic); spironolactone up to 300mg per 24h PO for 4wks pre-op. Hyperplasia: Spironolactone or amiloride. If GRA is suspected: dexamethasone 1mg/24h PO for 4wks, normalizes biochemistry but not always BP. If BP still, give spironolactone; stop dexamethasone. Secondary hyperaldosteronism

Due to a high renin (eg from renal artery stenosis, accelerated hypertension, diuretics, CCF, hepatic failure). Bartter's syndrome This is a major cause of congenital (recessive) salt wastingvia a Cl- leak in the loop of Henle. Presents in childhood with failure to thrive, polyuria, and polydipsia. BP is normal and there is no oedema. Look for hypokalaemia, hypochloraemic metabolic alkalosis, and urinary K+ and Cl-. Plasma renin. Treatments: K+ replacement, NSAIDs, amiloride, captopril. Phaeochromocytoma This is a rare catecholamine-producing tumour, and a dangerous but treatable cause of hypertension (in <1%). 90% are in the adrenal medullaunilateral (90%). Inheritance is sometimes as an autosomal dominant. Associations Sporadic in 84%; others have MEN2a (p309), neurofibromatosis, von HippelLindau syndrome, or Carney complex (p309).[diskette]93 Malignancy 46% have either malignant disease or tumours with some malignant features. Tumours outside the medulla may be in paraganglia (= phaeochrome bodies, ie collections of adrenaline-secreting chromaffin cells)typically by the aortic bifurcation (called the organ of Zuckerkandl). The patient Episodic hypertension, anxiety, chest tightness, etc.see BOX. Tests Glycosuria during attacks in 30%. Screening: 24h urine collection for 4-OH-3methoxymandelate (HMMA, VMA) or total (or free) metadrenalines. Full investigation: consult specialist centre: consider meta-iodobenzylguanidine (MIBG) scan or clonidine suppression test, and abdominal CT/MRI. Treatment Surgery; careful BP control for 2wks pre-op: -blocker (phenoxybenzamine before cardioselective -blocker). Consult anaesthetist. Post-op: 24h urine as above; monitor BP (risk of BP ). Emergency [prescription take]: p822. Follow-up Lifelong, as post-op recurrence may take decades to emerge.[diskette]94 Hypertension: a common context for hyperaldosteronism tests Think of Conn's in these contexts: hypertension associated with hypokalaemia <3.5mmol/L refractory hypertension: severe hypertension occurring before 40yrs of age, especially in women. The aldosterone/renin ratio (ARR) may be a good screening test here.1 If ratio 800 (aldosterone pmol/L): Plasma renin activity (pmol/ml/hr) or aldosterone >1000 further investigation is required ie CT/MRI adrenals. CT only has a specificity of 58% and a positive predictive value of 72%. Adenoma and hyperplasia must then be distinguished, using either NP59 scintigraphy or adrenal venous sampling. Adrenal scintigraphy with 131I-labelled 6--iodomethylnorcholesterol (NP-59) is a demanding and complex procedure, but it can provide crucial information about adrenal functional status, and guide appropriate management of those with biochemically proven diseasebut it does not completely obviate the need for adrenal vein sampling.[diskette]95 The clinical features of phaeochromocytoma Phaeochromocytomas are rare and present with vague episodic features, eg: Chest tightness

Spots before the eyes Pins and needles Hemianopia Pulsatile scotomas Skin mottling Weight loss Dyspnoea Purpura Sweating Abdominal pain Tremor Cold feet Vomiting Faints (postural BP drop) Palpitations Pallor Claudication Flushing

Symptoms are precipitated by stretching, sneezing, stress, sex, smoking, surgery, or parturitionor by agents such as cheese, alcohol, or the tricyclic you so kindly prescribed, thinking that the patient's bizarre symptoms were only explicable by psychopathology, such as depression. These crises may last minutes to days. Suddenly patients feel as if about to dieand then get better, or go on to stroke or cardiovascular collapse. On examination, there may be no signs, or hypertension ( signs of cardiomyopathy or heart failure), thyroid swelling (episodic), glycosuria during attacks, or terminal haematuria from a bladder phaeochromocytoma. Hirsutism, virilism, gynaecomastia, impotence Hirsutism is common (10% of women) and usually benign. It implies increased hair growth in women, in the male pattern. If menstruation is normal, there is almost certainly no increased testosterone production. If menstruation is abnormal, the cause is usually polycystic ovary syndrome (SteinLeventhal syndrome): bilateral polycystic ovaries; secondary oligomenorrhoea; infertility; obesity; hirsutism. The cause is androgen hyper secretion. Tests: Ultrasound;

plasma LH: FSH ratio, and less consistently, testosterone and oestradiol (see OHCS p13 for management). Metformin can restore regular cycles and fertility in some patients. Another cause of hirsutism with irregular menses is late-onset congenital adrenal hyperplasiadeficiency of the 21-hydroxylase enzyme in the adrenal gland. See OHCS p222. Ovarian tumours are a rare cause, OHCS p42. Management: Be supportive. Explain that she is not turning into a man. Depilation with wax or creams, or electrolysis (which is expensive, and time-consuming, but does work). 1: 10 hydrogen peroxide to bleach the area.

Shave regularly. Oestrogens help by increasing serum sex hormone-binding globulinbut always combine with a progesterone (= the Pill) to prevent excess risk of uterine neoplasia or cyproterone acetate (an anti-androgen and progestogen), eg up to 100mg on days 111, with oestrogen on days 121. Cyproterone is also present in the oral contraceptive Dianette. Clomifene (=clomiphene) for infertility (a fertility expert should prescribe).

Virilism is rare. It is characterized by: amenorrhoea; clitoromegaly; deep voice; temporal hair recession; hirsutism. This condition needs further investigation for androgen-secreting adrenal and ovarian tumours. Gynaecomastia implies an abnormal amount of breast tissue in males (it may occur in normal puberty). It is due to an increase in the oestrogen/ androgen ratio. It is seen in syndromes of androgen deficiency (eg Kline-felter's, Kallman's). It may result from liver disease or testicular tumours (oestrogens), or accompany hyperthyroidism. The chief causes are drugs: oestrogens; spironolactone; cimetidine; digoxin; testosterone; marijuana. Erectile dysfunction (ED, impotenceie inability of an adult male to sustain adequate erection for penetration.) It is common in old age. Psychological causes are common and are more likely if ED occurs only in some situations, if there is a clear stress to account for its onset, and (perhaps) if early morning incidental erections occur (these persist at the onset of organic disease). Psychological causes may exacerbate organic causes. The major organic causes are smoking, alcohol, and diabetes. Other organic causes are as follows. Drug causes: Antihypertensives (including diuretics and -blockers), major tranquillizers, alcohol, oestrogens, antidepressants, cimetidine. Organic causes: Hyperthyroidism, hypogonadism, MS, autonomic neuropathy, atheroma, bladder-neck surgery, prolactin, cirrhosis, cancer. Tests:

U&E; LFT; glucose; TFT; LH; FSH; cholesterol; testosterone (eg if libido). Nocturnal tumescence studies are not usually needed. Doppler may show blood flow, but is rarely needed as vascular reconstruction is difficult. Treatment: Treat causes. Counselling

Specific interventions.

Vacuum aids, implants and intracavernosal injections have largely been supplanted by oral phosphodiesterase (PDE5) inhibitors acting by cyclic guanosine monophosphate (GMP). Erection is not automatic (depends on erotic stimuli). Sildenafil (Viagra) 25100mg 1h pre-sex.[diskette]96 SE: headache (16%); flushing (10%); dyspepsia (7%); nasal congestion (4%); transient blue/green tingeing of vision via inhibition of retinal PDE6. [diskette]97 CI: See BOX. Tadalafil (Cialis; has long t) 1020mg 30min to 12h presex. Don't use > once daily and not every day. SE: headache, dyspepsia, myalgia; ?no visual SEs. Vardenafil.[diskette]98 P.317 Contraindications to sildenafil/Viagra and other oral ED agents Concurrent use of nitrates BP or <90/50mmHg; arrhythmias Myocardial infarction <90d ago Degenerative retinal disorders, eg retinitis pigmentosa (for sildenafil) Marked renal or hepatic impairment Stroke in last 6 months Bleeding disorders Active peptic ulceration Unstable angina Other cautions Angina (especially angina during intercourse) Peyronie's disease Risk of priapism (sickle-cell anaemia, myeloma, leukaemia) Concurrent complex antihypertensive regimens Dyspnoea on minimal effort (sexual activity may be unsupportable) Use in men with severe coronary disease has been a question, but in one careful study, no adverse cardiovascular effects were detected in men with severe coronary artery disease. [diskette]99 Interactions: Macrolides, anti-HIV drugs, theophylline, ketoconazole, rifampicin, phenytoin, carbamazepine, phenobarbital, grapefruit juice ( bioavailability). When does a lifestyle malcontent become a disease? When should health providers pay for erectile treatment? In the UK, the NHS will pay (write SLS/selected list substances on the prescription) if ED is causing severe distress,1 or there has been: Prostatectomy

Prostate cancer Dialysis or a renal transplant Spinal cord or pelvic injury Radical pelvic surgery 1 Diabetes mellitus Multiple sclerosis Parkinson's disease Spina bifida Single gene neurological disease Poliomyelitis and its after-effects

It is easy to taunt politicians who produce these rather arbitrary-looking criteria by recourse to clever counter-examples, but they really need our support because they are making rationing (which is an inescapable fact of clinical life) overt, open, available to scrutiny, and rational modification. All too often rationing is covert, and no source takes responsibility for it. Footnotes 1 Criteria include marked disruption to relationships or mood, as judged by any prescriber with purchaser-certified special skill in this area, usually a GP specialist or staff at clinics for ED. 2 Success for reversing ED post-op is only 43% vs 85% in those with neurological conditions. Addisonian crisis: assessment Adrenocortical insufficiency may be sub-clinical for days or months in otherwise well individuals. Stress, such as infection, trauma, or surgery, may precipitate an Addisonian crisis with cardiovascular collapse and death if the condition is not suspected. Crises may also occur in patients with known Addison's disease on replacement hydrocortisone if they fail to increase their steroid dose with infections. Presentation Hypotension and cardiovascular collapse (shock) Faintness, particularly on standing (postural hypotension)

Anorexia, nausea, vomiting, and abdominal pain Hyponatraemia Dehydration (thirst may not be apparent because of the low sodium) Diarrhoea in 20% of cases Symptoms of precipitant [fever, night sweats (infection); flank pain (haemorrhagic adrenal infarction); etc]. Note signs/symptoms of other endocrinopathies. Non-specific symptoms: weight loss, fatigue, weakness, myalgia.

Hyperpigmentation suggests chronic hypoadrenalism. Psychiatric features are common and include asthenia, depression, apathy, and confusion (treatment with glucocorticoids reverses most psychiatric features).

Malignant secondaries Present in the adrenals of a high percentage of patients with lung cancer, breast tumours, and malignant melanomas. Adrenal failure will only occur when over 90% of the gland is replaced by metastases. Adrenal haemorrhage This may complicate sepsis (meningococcal septicaemia, the WaterhouseFriderichsen syndrome), traumatic shock, coagulopathies, and ischaemic disorders. Severe stress substantially increases the arterial blood supply to the adrenals. However the adrenal gland has only one or two veins, making it vulnerable to venous thrombosis. Blood tests: a precipitous drop in haemoglobin, hyponatraemia, hyperkalaemia, acidosis, uraemia, and neutrophilia.

The WaterhouseFriderichsen syndrome is the association of bilateral adrenal haemorrhage with fulminant meningococcaemia. Adrenal haemorrhage is also seen with other gram-negative endotoxaemias such as Diplococcus pneumoniae, Haemophilus influenzae B and DF-2 bacillus infections.

Hypopituitarism As there is no mineralocorticoid deficiency, the salt and water loss and shock are less profound than in primary Addison's disease. Drugs Rifampicin, phenytoin, and phenobarbitone accelerate the metabolism of cortisol and may precipitate Addisonian crisis in partially compromised individuals, or in those on a fixed replacement dose. Most adrenal crises precipitated by rifampicin occur within 2 weeks of initiating therapy. Recognized causes of adrenal failure Autoimmune adrenalitis (70%) Tuberculosis of the adrenals (1020%)

Malignant secondaries in the adrenal glands Adrenal haemorrhage incl. meningococcal septicaemia Diseminated fungal infection (histoplasmosis, paracoccidioidomycosis) Hypopituitarism Drugs: metyrapone or aminoglutethimide can precipitate adrenal failure. Other drugs (see below) may cause relative adrenal insufficiency Congenital conditions
o

Adrenoleukodystrophy

o o

Congenital adrenal hyperplasia Familial glucorticoid deficiency

Causes of relative adrenal insufficiency Drugs o Metyrapone or aminoglutethimide

o o o o o o

Ketoconazole Etomidate Rifampicin, phenytoin, and phenobarbitone Trilostane Megestrol acetate Suramin

HIV Severe sepsis Burns Acute or chronic liver failure

Practice points ~50% of patients with autoimmune adrenalitis have one or more other autoimmune disorders such as polyglandular autoimmune syndrome type 1 or 2. Never forget Addison's disease in a sick patient when the diagnosis is unclear. Addisonian crisis: management Investigations U&Es FBC Glucose Calcium Serum cortisol ABG Urine CXR AXR Hyponatraemia and hyperkalaemia (rarely greater than 6.0mM). High ur:cr ratio indicative of hypovolaemia Anaemia (normal MCV); moderate neutropenia relative eosinophilia/lymphocytosis Hypoglycaemia (rarely severe) May be high Save for routine assay. Baseline <400nmol/L. Should be >1000nmol/L in sick patients Metabolic acidosis, respiratory failure MC&S for infection; urinary Na excretion often high in spite of hypovolaemia Previous TB, bronchial carcinoma Adrenal calcification

Management Treatment may be required before the diagnosis is confirmed. General measures include oxygen, continuous ECG monitoring, CVP monitoring, urinary catheter (for fluid balance), and broad spectrum antibiotics (e.g. cefotaxime) for underlying infection.

Treat shock (P260): give iv N saline or colloid (Haemaccel) for hypotension: 1L stat then hourly depending on response and clinical signs. Inotropic support may be necessary. Give iv 50% dextrose (50ml) if hypoglycaemic. If adrenal crisis is suspected, the patient needs glucocorticoids urgently: use dexamethasone 8mg iv which will not interfere with the cortisol assay of a short Synacthen test. If dexamethasone is unavailable use hydrocortisone (can be stopped later). This single extra dose can do little harm and may be life saving. Short Synacthen test (omit if the patient is known to have Addison's disease): take baseline blood sample (serum) and administer tetracosactrin (Synacthen) 250g im or iv. Take further samples at 30 and 60 minutes for cortisol assay. Continue steroid treatment as iv hydrocortisone (200mg stat), then 100mg tds. Change to oral steroids after 72 hours. Fludrocortisone (100g daily orally) when stabilized on oral replacement doses of hydrocortisone.

Prevention Patients on long-term steroid therapy and/or known adrenocortical failure should be instructed to increase steroid intake for predictable stresses (e.g. elective surgery, acute illnesses with fever >38). For mild illnesses, if not vomiting, double the oral dose. Vomiting requires iv/im therapy (hydrocortisone 50mg tds).

For minor operations or procedures (e.g. cystoscopy) give hydrocortisone 100mg iv/im as a single dose before the procedure. More serious illnesses require hydrocortisone 100mg q68h iv/im until recovered or for at least 72 hours. Double replacement doses when stabilized if on enzyme-inducing drugs.

Drug Equivalent dose (mg) Dexamethasone 0.75 Methylprednisolone4 Triamcinolone 4 Prednisolone 5

Hydrocortisone Cortisone acetate

20 25

Myxoedema coma A common precipitant of coma is the use of sedatives, and subsequent hypothermia, in elderly female patients with undiagnosed hypothyroidism. Presentation Altered mental status: disorientation, lethargy, frank psychosis Coma (symmetrical, slow-relaxing reflexes; ~25% have seizures)

Hypothermia Bradycardia, hypotension (rare) Hypoventilation Hypoglycaemia.

Investigations U&Es Hyponatraemia is common (50%) Glucose Hypoglycaemia may occur FBC Normocytic or macrocytic ( coexistent pernicious anaemia) anaemia Raised CPK Often with a clinical myopathy Thyroid functionT4 and TSH Cortisol To exclude co-existent Addison's disease, i.e. Schmidt's syndrome ABG Hypoventilation with PaCO2, PaO2 and acidosis Septic screen Blood and urine cultures ECG Small complexes with prolonged QT interval CXR Pericardial effusion may occur. Poor prognostic indicators Hypotension. Patients with hypothyroidism are usually hypertensive. BP indicates possible adrenal failure or cardiac disease. Response to inotropes is poor as patients are usually maximally vasoconstricted. Hypoventilation. This is the commonest cause of death in patients with myxoedema coma. The hypoxia responds poorly to oxygen therapy which tends to exacerbate hypercapnoea. Management Transfer the patient to an intensive care unit. Mortality is up to 30%. Mechanical ventilation should be instituted for respiratory failure.

CVP line. Patients are usually hypertensive and hypovolaemic as chronic myxoedema is compensated for by rising catecholamines. Broad-spectrum antimicrobials (e.g. cefotaxime). Bacterial infection is a common precipitant of myxoedema coma.

Hypothermia should be treated as on P844: a space blanket is usually sufficient. Rapid external warming can cause inappropriate vasodilatation and cardiovascular collapse. Hydrocortisone (100mg iv tds) until Addison's is excluded. Institute replacement therapy before confirming the diagnosis. Ideally give 520g iv (slow bolus) tri-iodothyronine (T3) twice daily for 3 days. After a few days treatment, commence oral thyroxine at 2550g/day or oral triodothyronine at 20g bd. Some clinicians start thyroxine at a much higher dose, but this does carry a risk or precipitating cardiac ischaemia. T3 is preferable due to its short half-life and its effect disappears 2448 hours after it isstopped. If T3 is unavailable use thyroxine, 2550g po or via NG-tube daily. Myxoedema coma has a high mortality if inadequately treated.

Precipitants of myxoedema coma Drugs, including sedatives and tranquillizers Infection

Cerebrovascular accident Trauma

Phaeochromocytomas: assessment

Phaeochromocytomas are catecholamine-producing tumours usually involving one or more adrenal glands. ~0% are bilateral, ~10% are extra-adrenal [usually around the sympathetic chain (paragangliomas)] and ~10% are malignant. They usually secrete AD or NA. A small proportion secrete DA, when hypotension may occur. Most are diagnosed during routine screening of hypertensive patients (they are found in only 0.1% of hypertensives). Pure AD-producing tumours may mimic septic shock due to AD-induced peripheral vasodilatation (2-receptors).

Presentation Classically a triad of episodic headaches, sweating, and tachycardia Hypertension (mild to severe sustained uncontrolled paroxysmal, hypertensive episodes) and orthostatic hypotension (low plasma volume). 50% have sustained BP and 50% have paroxysmal BP

Anxiety attacks, tremor, palpitations, cold extremities, and pallor Cardiac dysrhythmias (incl. AF and VF) and dilated cardiomyopathy Hypertensive crises may be precipitated by -blockers, tricyclic anti-depressants, metoclopramide, and naloxone

Unexplained lactic acidosis Triggers for hypertensive crises include surgery, opiates and contrast media.

Investigations There are no tests which will diagnose a phaeochromocytoma acutely. Investigations are listed in the table opposite. Hypertensive patients with glc and K+ may have a phaeochromocytoma, but these are both non-specific features. Urinary VMA level (a catecholamine metabolite) is useful if markedly elevated (510 upper limit of normal). Mild elevations are frequent (15%) in patients with essential hypertension, as VMA can be derived from dietary sources, including vanilla essence giving a false +ve test result. Urinary catecholamines (AD, NA, and DA) or metanephrines are more specific. Urine collections must be completed before pentolinium or clonidine tests as withdrawal of these compounds can give a false +ve result.

Plasma catecholamines should be collected from an in-dwelling cannula placed over 30 minutes previously in a supine patient. Samples need to be taken directly to the lab (on ice) for centrifugation. Pentolinium suppression test. Take two baseline samples as above, then give 2.5mg pentolinium iv, and take blood again at 10 and 30 minutes. Plasma catecholamines decrease in normal subjects following ganglion blockade with pentolinium. If the response is borderline and no hypotension occurs, then repeat with 5mg pentolinium. Clonidine suppression test. An alternative to the pentolinium suppression test employs clonidine. Following two baseline samples, give 0.3mg clonidine orally, and take blood hourly for 3 hours. Again if raised catecholamines are due to anxiety, they will suppress into the normal range with clonidine. Raised catecholamines from phaeochromocytoma will not be affected by clonidine. MRI or CT of the abdomen are useful to localize the tumour. Radiocontrast can lead to catecholamine release. MIBG scan. MIBG (131I-metaiodobenzylguanidine) is taken up selectively by adrenal tissue. Useful to localize tumour or secondaries. Selective venous sampling: to localize extra-adrenal tumours.

Investigations for suspected phaeochromocytoma U&Es (K+, urea) Glucose ()

Urinary VMA Urinary catecholamines (AD, NA, and DA), metanephrines Plasma catecholamines (AD, NA, and DA)

Pentolinium suppression test Clonidine suppression test MRI or CT scan of adrenals MIBG scan for localization

Other causes of sympathetic overactivity Abrupt withdrawal of clonidine or -blockers Autonomic dysfunction e.g. GuillainBarr syndrome or post spinal cord injury

Stress response to surgery, pain, or panic Sympathomimetic drugs

o o o

Phenylpropanolamine (decongestant) Cocaine MAOI plus tyramine-containing foods (cheese, beer, wine, avocado, bananas, smoked or aged fish/meat)

Phaeochromocytomas: management Patients are usually volume depleted at presentation, and should be rehydrated prior to initiation of -blockade, otherwise severe hypotension may occur. -blockade alone may precipitate a hypertensive crisis, and must never be given prior to adequate -blockade. Labetalol is predominantly a -blocker and should not be used alone. Long acting -blockers prevent escape episodes. Adequate fluid replacement with CVP monitoring. Acute hypertensive crises should be controlled with phentolamine (25mg iv bolus, repeated as necessary every 1530 minutes). Alternatively start an infusion of nitroprusside (0.51.5g/kg/min, typical dose 100g/min, see P164).

Preparation for surgery

o

Initiate oral -blockade: phenoxybenzamine 10mg daily increasing gradually to 40mg tds. Monitor BP closely. Tumour -stimulation may produce excessive vasodilatation and hypotension requiring inotropic support. Recent studies have shown that prazosin or doxazosin are equally effective and are being used increasingly When the blood pressure is controlled with phenoxybenzamine, add propranolol 1020mg tds Invasive monitoring [pulmonary artery (SwanGanz) catheter and arterial line] is mandatory.

Hypotension commonly occurs intra-operatively when the tumour is removed, and this should be managed with blood, plasma expanders, and inotropes as required. Inotropes should only be used when the patient is appropriately fluid replete. Expansion of intravascular volume 12 hours before surgery significantly reduces the frequency and severity of post-operative hypotension. Angiotensin II should be available as an alternative inotrope for cases of resistant hypotension.

Autosomal dominant conditions with a high risk of developing phaeochromocytoma include Von-Recklinghausen disease [neurofibromata, caf au lait spots, Lisch nodules (iris hamartomas), and axillary freckling]. Von-Hippel Lindau disease (cerebellar haemangioblastomas, retinal haemangiomas, and other neoplasms including hypernephroma).

Multiple endocrine neoplasia types 2a (hyperparathyroidism and medullary thyroid carcinoma) and 2b (medullary thyroid carcinoma, bowel ganglioneuromatosis, and hypertrophied corneal nerves).

Thyrotoxic crisis: assessment The term thyrotoxic crisis refers to a constellation of symptoms and signs which together imply a poor prognosis. Thyroid function tests provide no discrimination between simple thyrotoxicosis and thyrotoxic crisis. If the diagnosis has not been made, look for clues such as a goitre, or exophthalmic Graves' disease. The presentation may be confused with sepsis or malignant hyperthermia. Presentation Cardiovascular symptoms Palpitations Tachycardia/tachyarrhythmias

Cardiac failure/oedema

CNS Symptoms Anxiety/agitation Violent outbursts

Psychosis/delirium Fitting/coma

Gastrointestinal symptoms Diarrhoea Vomiting

Jaundice

General symptoms Fever

Hyperventilation Sweating Polyuria

Precipitants of thyrotoxic crisis Thyroid surgery/general surgery Withdrawal of anti-thyroid drug therapy/radioiodine therapy

Thyroid palpation Iodinated contrast dyes Infection Cerebrovascular accident/pulmonary embolism Parturition Diabetic ketoacidosis Trauma or emotional stress.

Investigations Thyroid function tests (most labs can perform an urgent TSH/free T4 if needed) U&Es (?dehydration)

Calcium (may be elevated) Glucose (may be low) FBC Liver function tests (?jaundice) Blood and urine cultures CXR (?pulmonary oedema or evidence of infection) ECG (rate, ?atrial fibrillation).

Assessment of severity The table opposite is used to assess the severity of a thyrotoxic crisis. Rarely, patients may present with an apathetic thyroid storm, and lapse into coma with few other signs of thyrotoxicosis. P.591

Assessment of severity of a thyrotoxic crisis Temp (C) ScorePulseCardiac failure CNS effects GI symptoms Apyrexial <99 Absent Normal Normal 0 >37.2 >99 Ankle oedema 5 >37.8 >110 Basal creps. Agitation Diarrhoea, vomiting 1 0 >38.3 >120 Pulmonary oedema 1 5 >38.9 >130 Delirium Unexplained jaundice2 0 >39.4 >140 2 5 >40 Coma, seizure 3 0 Add the scores for each column. Add an extra 10 points if atrial fibrillation is present.

Add 10 points if there is a definable precipitant. A total score of over 45 indicates thyroid crisis; a score of 2544 indicates impending crisis.

Thyrotoxic crisis: management Patients with a thyrotoxic crisis or impending crisis (score >25, P591) Admit the patient to intensive care. Fluid balance: CVP monitoring is essential to avoid precipitating or worsening cardiac failure. In patients with arrhythmias, the CVP will not accurately reflect left-sided pressures and SwanGanz monitoring should be considered. Gastrointestinal and insensible (pyrexia and excessive sweating) fluid losses may exceed 5L/day and must be replaced.

Fever should be treated with paracetamol and aggressive peripheral cooling techniques. Dantrolene has been occasionally used to control hyperthermia in thyrotoxic crisis. Do not use salicylates which will displace T4 from TBG and can hence worsen the storm. -block the patient with propranolol 6080mg q4h po or 1mg iv (repeated every 10min as necessary) with cardiac monitoring. Propranolol inhibits peripheral T4 T3 conversion. Fever, tachycardia, and tremor should respond immediately. An alternative is Esmolol (1530mg as a bolus followed by 36mg/min). If -blockade is contra-indicated (e.g. asthma), guanethidine (3040mg po 6 hourly) can be used.

Treat precipitating factors such as infection (e.g. cefuroxime 750mg iv tds).

High-dose anti-thyroid drugs. Propylthiouracil (1g loading dose then 200300mg q4h po/ng) is more effective than carbimazole (20mg 4 hourly), at it inhibits peripheral T4 T3 conversion. Hydrocortisone 300mg iv stat, then 100mg 6 hourly. This inhibits conversion of T4 to T3. Enoxaparin (clexane) 20mg/day sc should be given to very sick patients at risk of thromboembolism. Once organification of iodine has been blocked by anti-thyroid drugs, iodine can be used to inhibit thyroxine release from thyroid gland. Lugol's iodine contains 5% iodine and 10% potassium iodide in water. Give 1ml every 6 hours. Do not give Lugol's iodine until at least 1 hour after the anti-thyroid drugs have been given. Any iodine given prior to anti-thyroid medication may increase thyroid hormone stores. Continue iodine-containing preparations for a maximum of 2 weeks (lithium is an alternative to iodine in allergic patients). Monitor glucose levels 4 hourly and administer glucose 510% as required. Hepatic glycogen stores are readily depleted during thyroid storm.

Continuing treatment Response to treatment is gauged clinically and by serum T3 levels. Stop iodine/potassium iodide/lithium and -blockers when controlled.

Consider definitive treatment (e.g. surgery or radioactive iodine). Treat atrial fibrillation in the usual way (P88). Higher doses of digoxin may be required as its metabolism is increased. Amiodarone inhibits peripheral T4 T3 conversion.

Thyroid function tests (TFTs) Thyroid hormone abnormalities are usually due to a problem with the thyroid gland itself. Primary abnormalities of TSH and thyrotrophin-releasing hormone (TRH) are very rare. Physiology The hypothalamus secretes TRH, a tripeptide, which stimulates production of TSH, a glycoprotein, from the anterior pituitary. TSH production and release of thyroxine (T4) and triiodothyronine (T3) from the thyroid, which exert -ve feedback on TSH production. The thyroid produces mainly T4, which is 5-fold less active than T3. 85% of T3 is formed from peripheral conversion of T4. Most T3 and T4 in plasma is protein bound, mainly to thyroxinebinding globulin (TBG). The unbound portion is the active part. T3 and T4 cell metabolism, via nuclear receptors, and are thus vital for growth and mental development. They also enhance catecholamine effects. Basic tests

Hyperthyroidism suspected: Ask for T3, T4, and TSH. A minority will have elevation of only one thyroid hormone, but all will have TSH (except for the rare phenomenon of a TSH-secreting pituitary adenoma). Hypothyroidism suspected or monitoring replacement treatment: Ask for only T4, and TSH. Measuring T3 does not add any extra information.

Interpretation of tests If TSH and T4: Primary hypothyroidism is confirmed. If TSH and normal T4: Confirmation of compensated or subclinical hypothyroidism (2nd BOX on p307). Treatment depends on clinical state.

If TSH and T4: Consider concordance/compliance problems with T4 replacement, TSH secreting tumour, or thyroid hormone resistance. If TSH and T4 or T3: Thyrotoxicosis confirmed. If TSH and T4 and T3 normal: Subclinical thyrotoxicosis, identify cause. If TSH and T4 and T3: Consider pituitary disease or sick euthyroidism. If normal TSH and T4 abnormal: Consider hormone-binding problems, eg pregnancy; thyroid-binding globulin; amiodarone; pituitary TSH tumour.

Sick euthyroidism In any systemic illness, TFTs may become deranged. The typical pattern is for everything to be low. Consequently, routine testing of thyroid function in such patients should not be performed. Special tests Free T4 & free T3 are useful when a false low or high T4 or T3 is suspected. If unavailable, consider: free thyroxine index which is an estimate of free T4 derived from measuring unoccupied thyroxine-binding sites on TBG. Occasionally, low TSH may be due to nonthyroidal illness: if free T4 >25pmol/L, then there probably really is thyroid disease. Other tests of thyroid anatomy/pathology: Consider an isotope scan if: There is an area of thyroid enlargement. Hyperthyroid but no thyroid enlargement (diffuse uptake? solitary nodule?).

If hyperthyroid with one nodule (solitary nodule or multinodular?). To determine extent of retrosternal goitre; to find ectopic thyroid tissue. To detect thyroid metastases (whole-body CT). Subacute thyroiditis: very low uptake.

Interpretation: The main question is: has the enlarged area increased (hot), or decreased (cold), or the same (neutral) uptake of pertechnetate as the remaining thyroid? 20% of cold nodules are malignant. Few neutral and almost no hot nodules are malignant.

Ultrasound:This distinguishes cystic (usually, but not always, benign) from solid (possibly malignant) cold nodules. Thyroid autoantibodies:Antithyroid globulin; antithyroid microsomal. Raised in Hashimoto's and some cases of Graves' diseaseif positive there is increased risk of hypothyroidism later. Thyroid-stimulating immunoglobulins:Against TSH receptor. May be raised in Graves' disease. Serum thyroglobulin: Useful in monitoring the treatment of carcinoma, and in detection of factitious (self-medicated) hyperthyroidism.

The role of scans in monitoring thyroid malignancy Imaging is most important in following-up differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC). DTC may be followed with serum thyroidglobulin and 131I whole body scintigraphy when serum thyroglobulin level is . When 131I scintigrams are -ve, thallium scintigraphy (201Tl) may best identify site of recurrent DTC.[diskette]39 Alternative radioisotopes, ultrasound, and CT also help localize DTC metastases. MTC recurrences and metastases are more difficult to image. Selective venous catheterization is the most sensitive and specific method for detecting areas of recurrent MTC. High-resolution ultrasound, CT, MRI, and scintigraphy are all used.[diskette]40 Hyperthyroidism (thyrotoxicosis) Symptoms; Weight despite increased appetite, heat intolerance, sweating, diarrhoea, tremor, irritability, frenetic activity, emotional lability, psychosis, itch, oligomenorrhoea. Infertility may be the presenting problem. Signs:Pulse, AF, warm peripheries, fine tremor, goitre nodules, palmar erythema, hair thinning, lid lag (eyelid lags behind eye's descent as patient watches your finger descend slowly). If BP, consider phaeochromocytoma. Additional signs in Graves' disease: Bulging eyes (exophthalmos, p305); thyroid bruit; ophthalmoplegia; vitiligo; pretibial myxoedema (oedematous swellings above lateral malleoli: the term myxoedema is confusing here); thyroid acropachy (an extreme manifestation of autoimmune thyroid disease, with clubbing, painful finger & toe swelling, and periosteal reaction in limb bones).[diskette]41 Tests TSH; free T4 and free T3 (p302). Thyroid scan if subacute thyroiditis suspected or to identify solitary nodules/diffuse multinodular goitre; thyroid autoantibodies. If ophthalmopathy, test visual fields, acuity, and eye movements. Can the lids close fully? If not, there is risk of keratopathy (get help). Causes

Graves' disease: Common between 30 and 50 yrs. Genetic influence. : 9: 1. There are TSH-receptor antibodies (react with orbital autoantigens.[diskette]42 Diffuse thyroid enlargement. Look for associated normochromic normocytic anaemia, ESR, Ca2+, LFT and type 1 DM and pernicious anaemia. Patients are often hyperthyroid but may be, or become, hypo- or euthyroid. Toxic adenoma:There is a nodule producing T3 and T4. On scanning, the nodule is hot (p302), and the rest of the gland is suppressed. Toxic multinodular goitre:This is a common cause of thyrotoxicosis in the elderly, eg in iodinedeficient areas.[diskette]43 Treat the thyrotoxicosis, and follow with radioiodine or surgery as indicated. In compressive symptoms, risk of malignancy, or cosmetic deformity develops, surgery may also be indicated.[diskette]44 Self-medication:This is detected by T4, T3, and thyroglobulin. Subacute (de Quervain's) thyroiditis:Self-limiting, painful goitre. ESR. On scans, no radioiodine uptake. Cause: ?viral infection in the genetically predisposed.[diskette]45 Follicular carcinoma of thyroid:There may be hyperfunctioning metastases.[diskette]46 Choriocarcinoma; struma ovarii:(Ovarian teratoma containing thyroid tissue). Drugs:Amiodarone; lithium ( T4 is commoner); Li+ may also mask hyperthyroidism by causing cellular unresponsiveness ( danger on stopping Li+).[diskette]47 Exogenous iodine:Contrast media; disinfectants;[diskette]48 food contamination.[diskette]49 Treatment Drugs: Immediate symptom control: propranolol 40mg/6h PO.[diskette]50 Thyroid suppression with carbimazole eg 1540mg/24h PO for 4wks, gradually reducing according to TFTs every 12 months. Maintain on ~15mg/24h for 1218 months then withdraw. >50% relapse; warn to get advice if rashes, sore throat, or fevers occur, as 0.03% on carbimazole get agranulocytosis; other SE: rash, headache, alopecia, pruritus, jaundice. Alternative: propylthiouracil. Partial thyroidectomy: Carries risk of damage to recurrent laryngeal nerves and parathyroids. Patients may be hypo- or hyperthyroid after surgery.

Radioiodine (131I): This can be repeated until euthyroid but most patients ultimately become hypothyroid. Caution in active Graves' disease. No longer contraindicted in younger women. In pregnancy and infancy: Get expert help. See OHCS p157.

Complications

Heart failure (thyrotoxic cardiomyopathy);[diskette]51 angina; atrial fibrillation (p130,seen in ~25%manage by controlling hyperthyroidism; warfarinize if no contraindication, p648, as 40% have or get emboli). Also: Osteoporosis; gynaecomastia; thyroid storm, p820; ophthalmopathy, see BOX.[diskette]52 Thyroid eye disease Thyroid eye disease is a clinical diagnosis which may be made in the presence or absence of thyroid autoantibodies. It occurs when there is retro-orbital inflammation and lymphocyte infiltration resulting in swelling of the contents of the orbit. At the time of presentation, the patient may be euthyroid, hypothyroid, or hyperthyroid. Symptoms Diplopia, eye discomfort, or protrusion decreased acuity. Decreasing acuity or loss of colour vision may mean optic nerve compression: Seek expert advice immediately as decompression may be needed. Nerve damage does not necessarily go hand-in-hand with protrusion. Indeed, if the eye cannot protrude for anatomical reasons, optic nerve compression is all the more likelya paradox! Signs Exophthalmosappearance of protruding eye; proptosiseyes protrude beyond the orbit (look from above in the same plane as the forehead); conjunctival oedema; corneal ulceration; papilloedema; loss of colour vision. Ophthalmoplegia (especially of upward gaze) also occurs due to muscle swelling and fibrosis. Tests Rose Bengal drops may stain the upper cornea, indicating superior limbic keratitis, while CT/MRI of the orbits will reveal enlarged eye muscles. Management Control hyperthyroidism; steroids if ophthalmoplegia or gross oedema. Avoid hypothyroidism. Get an eye surgeon's help (eg in papilloedema, vision). Stopping smoking may complications.[diskette]53 Viscotears plus Lacrilube gel at night, for lubrication as often as needed. Lids can be stitched together at the outer corners (lateral tarsorraphy) or may be taped shut. Medical decompression may be achieved with high-dose systemic steroids. Lid retraction may be reduced by guanethidine eyedrops but these are rarely tolerated for long. Surgical decompression uses space in the ethmoidal, sphenoidal, and maxillary sinuses, via a medio-inferior approach. Orbital radiotherapy is increasingly used at an early stage, but cytotoxic drugs, and plasmapheresis (p670) are unreliable. Diplopia may be managed with a Fresnel prism stuck to 1 lens of a spectacle, so allowing for reasonably easy changing as the exophthalmos changes.Eye disease may pre-date other signs of Graves' disease, and does not always respond to treatment of thyroid status. Furthermore, it may develop for the first time following treatment of hyperthyroidism. Lumps in the neck Don't biopsy lumps until tumours within the head and neck have been excluded by an ENT surgeon. Culture all biopsied lymph nodes for TB. Diagnosis First of all ask how long the lump has been present. If <3wks, self-limiting infection is the likely cause and extensive investigation is unwise. Next ask yourself where the lump is. Is it

intradermal? (eg sebaceous cyst with a central punctum). Is it a lipoma (p510)? If the lump is not intradermal, and is not of recent onset, you are about to start a diagnostic hunt over complicated terrain: Midline lumps:If patient is <20yrs old, the likely diagnosis is a dermoid cyst (ie sequestrations of epidermoid tissue), or, if it moves on protruding the tongue and is below the hyoid, a thyroglossal cyst (fluctuant lump developing in cell rests in thyroid's migration path; treatment: surgery; they are the commonest congenital cervical cystic lump).[diskette]124 In patients >20yrs old, it is probably a thyroid mass, unless it is bony hard, when the diagnosis may be a chondroma. Submandibular triangle:(Below jaw; above anterior belly of digastric.) If <20yrs, self-limiting lymphadenopathy is likely. If >20, exclude malignant lymphadenopathy (eg firm, and nontender). Is TB likely? If it is not a node, think of submandibular salivary stone, sialadenitis, or tumour. Anterior triangle:(Below digastric and in front of sternomastoid.) Nodes are common (see above): examine the areas which they serve (skin, mouth, throat, thyroid; is the spleen enlarged? this may indicate lymphoma). Branchial cysts emerge under the anterior border of sternomastoid where the upper third meets the middle third; age <20. They are due to non-disappearance of the cervical sinus (where the 2nd branchial arch grows down over the 3rd and 4th). Lined by squamous epithelium, their fluid contains cholesterol crystals. Treat by excision. Cystic hygromas arise from the jugular lymph sac; transilluminate brightly. Treat by surgery or hypertonic saline sclerosant. Carotid body tumours (chemodectoma) are very rare, move from side to side but not up and down, and splay out the carotid bifurcation. It is usually firm and occasionally soft and pulsatile. It does not usually cause bruits. It may be bilateral, familial, and malignant (5%). This tumour should be suspected in masses just anterior to the upper third of sternomastoid. Diagnose by digital computer angiography. Treatment: extirpation by vascular surgeon. If the lump is in the superoposterior area of the anterior triangle, is it a parotid tumour (more likely if >40yrs)? Laryngocoeles are uncommon causes of anterior triangle lumps: they are painless, and may be made worse by blowing. These cysts are classified as external, internal, or mixed, and may be associated with laryngeal cancer. Posterior triangle:(Behind sternomastoid, in front of trapezius, above clavicle.) If there are many small lumps, think of nodesTB, viruses such as HIV or EBV (infectious mononucleosis), any chronic infection or, if over 20yrs, consider lymphoma or metastases eg from GI or bronchial or head and neck neoplasia. Cervical ribs may intrude into this area. TestsUltrasound shows lump consistency. CT defines masses in relation to their anatomical neighbours. Do virology and Mantoux test. CXR may show malignancy or reveal bilateral hilar lymphadenopathy; here you should consider sarcoid. Consider fine-needle aspiration (FNA). Salivary gland pathology There are 3 pairs of major salivary glands: parotid, submandibular, and sublingual (also numerous minor glands).

History:lumps; swelling related to food; pain; taste; dry eyes. Examination: note external swelling; look for secretions; bimanual palpation for stones. Examine VII nerve and regional nodes. Cytology:This may be ascertained by FNA. Recurrent unilateral pain and swelling is likely to be due to a stone. 80% are submandibular. The classical story is of pain and swelling on eatingwith a red, tender, swollen, but uninfected gland. The stone may be seen on plain x-ray or by sialography. Distal stones are removed via the mouth but deeper stones may require excision of the gland. Chronic bilateral symptoms may coexist with dry eyes and mouth and autoimmune disease, eg Mikulicz's or Sjgren's syndrome (p730 & p734). Fixed swellings may be from tumours or sarcoidor are idiopathic. Salivary gland tumours: 80% are in the parotid, 80% of these are pleo-morphic adenomas, 80% of these are in the superficial lobe. Any salivary gland swelling must be removed for assessment if present for >1 month. VII nerve palsy signifies malignancy. Benign or malignant: Malignant: Malignant: Cystadenolymphoma MucoepidermoidSquamous carcinoma Pleomorphic adenomaAcinic cell Adenocarcinoma Adenoid cystic carcinoma Pleomorphic adenomas often present in middle age and grow slowly. Removed by superficial parotidectomy. Adenolymphomas: usually older men; soft; treat by enucleation. Carcinomas: rapid growth; hard fixed mass; pain; facial palsy. Treatment: surgery + radiotherapy. Surgery complications: Facial palsyoften brief. Have a facial nerve stimulator in theatre to aid identification. Salivary fistula: often close spontaneously.

Frey's syndrome (gustatory sweating); tympanic neurectomy may help here.

Lumps in the thyroid ExaminationWatch the neck during swallowing water. Stand behind and feel thyroid for size, shape (smooth? one or many nodules?), tenderness, and mobility. Percuss for retrosternal extension. Any nodes? Bruits? If the thyroid is enlarged (goitre), ask these 3 questions: Is the thyroid smooth or nodular? Is the patient euthyroid, thyrotoxic (p304), or hypothyroid (p306)? Smooth, non-toxic goitre: Endemic (iodine deficiency); congenital; goitrogens; thyroiditis; physiological; Hashimoto's thyroiditis (an autoimmune disease thought to be

due to apoptosis induced by lymphocytes bearing Fas ligands combining with thyrocytes bearing Fas.) Smooth, toxic goitre: Graves disease.

Any nodules? Many or one? If >4cm across, malignancy is more likely.[diskette]125 Multi-nodular goitre (PLATE 14): Usually euthyroid but hyperthyroidism may develop. Hypothyroidism and malignancy are rare.

The single thyroid lump is a common problem; ~10% will be malignant. Causes: Cyst, adenoma, discrete nodule in multi-nodular goitre, malignancy. First ask: is he/she thyrotoxic? Do T3 & T4. Then: Ultrasound, to see if the lump is solid or cystic or part of a group of lumps Radionucleotide scans may show malignant lesions as hypofunctioning or cold, whereas a hyperfunctioning hot lesion suggests adenoma

FNA1 and do cytology on the fluid.

No clinical/lab test is good enough to tell for sure if follicular neoplasms found on FNA are benign, so such patients are referred for surgery.[diskette]126 What should you do if high-resolution ultrasound shows impalpable nodules? Such thyroid nodules can usually just be observed[diskette]127 provided they are: <1cm across (most are; ultrasound can detect lumps <2mm; such incidentalomas occur in 46% of routine autopsies) and asymptomatic. There is no past history of thyroid cancer or radiation.

No family history of medullary cancer. (If any present, do ultrasound-guided FNA; excise if cytology is malignant.)

Thyroid neoplasia2 5 types: Papillary: 60%. Often in young; spread to nodes and lung. Treatment: total thyroidectomy (to remove non-obvious tumour) node excision + radio-iodine to ablate residual cells may all be needed. Give T4 to suppress TSH. Prognosis is better if young and female. Follicular: 25%. Middle-aged, spreads early via blood (bone, lungs). Welldifferentiated. Treat by total thyroidectomy and T4 suppression and radioiodine (131I) ablation.

Anaplastic: Rare. : 3 : 1. Elderly, poor response to any treatment. In the absence of unresectable disease, excision + radiotherapy may be tried. Medullary: 5%. Sporadic (80%) or part of MEN syndrome (p309). May produce calcitonin. They do not concentrate iodine. Do thyroidectomy + node clearance (do phaeochromocytoma screen pre-op). External beam radiotherapy should be considered to prevent regional recurrence.

Lymphoma: 5%. : 3:1. May present with stridor or dysphagia. Do full staging pre-treatment (chemoradiotherapy). Assess histology for mucosa-associated lymphoid tissue (MALT) origin (associated with a good prognosis).

Thyroid surgery Indications: Pressure symptoms, hyperthyroidism, carcinoma, cosmetic reasons. Render euthyroid pre-op, by antithyroid drugs and/or propranolol. Check vocal cords by indirect laryngoscopy pre- and post-op. Complications Early: Recurrent laryngeal nerve palsy, haemorrhage (if compresses airway, instantly remove sutures for evacuation of clot), hypo-parathyroidism (check plasma Ca2+ daily, usually transient), thyroid storm (symptoms of severe hyperthyroidismtreat by propranolol PO or IV, antithyroid drugs, and iodine, p820). Late complications: Hypothyroidism. Footnote 1 FNA = fine needle aspirate 2 For a review of thyroid carcinoma, see S Sherman 2003 Lancet 361 50111 Hypothyroidism (myxoedema) This is common and easy to treat. As it is insidious, both the patient and the doctor may not realize anything is wrong, so be alert to subtle and non-specific symptoms, particularly in women over 40yrs old. Symptoms Tiredness, lethargy, weight, constipation, dislike of cold, menorrhagia, hoarse voice, depression, poor cognition/dementia, myalgia. Signs Bradycardia, dry skin and hair, goitre, slowly relaxing reflexes, CCF, non-pitting oedema (eg eyelids, hands, feet) toad-like face, pericardial effusion, peripheral neuropathy, cerebellar ataxia. Diagnosis T4, TSH ( in thyroid failure, slightly or normal in rare secondary hypothyroidism due to TSH lack from the pituitary, p318). Cholesterol and triglyceride may be. Normochromic macrocytic anaemia. CK, AST, and LDH may be due to abnormal muscle membranes. See also p302. Causes of primary hypothyroidism Spontaneous primary atrophic hypothyroidism:Common, autoimmune disease which is essentially Hashimoto's without the goitre and is associated with type I diabetes, Addison's disease, or pernicious anaemia. : 6: 1. Post-thyroidectomy or radioiodine treatment.

Drug-induced:Antithyroid drugs; amiodarone; lithium; iodine. Subacute thyroiditis:Temporary hypothyroidism after hyperthyroid phase. Iodine deficiency:Poor diet. Genetic: eg with deafness (Pendred's syndrome). Dyshormonogenesis:Autosomal recessive eg from peroxidase deficiency. Look for radioiodine gland uptake displaced by potassium perchlorate. Rare associations:[diskette]54Cystic fibrosis, primary biliary cirrhosis, POEMs syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein band from a plasmacytoma + skin pigmentation/tethering). Screen for hypothyroidism if: Hyperprolactinaemia Post-partum thyroiditis

Infertility Obesity Hypothermia If neck irradiated Cholesterol Dementia Autoimmunity Congenital hypothyroidism On amiodarone or Li+ Depression cognition Type 1 DM and pregnant Turner's syndrome

Treatment If healthy and young: Thyroxine (T4 = levothyroxine), ~100g/24h PO; review at 12wks. Adjust dose by clinical state and to normalize but not suppress TSH. Then check TSH yearly, at least at first. Osteoporosis is a theoretical risk of overtreating. If elderly: Start with 25g/24h; dose, eg every 4wks (thyroxine may precipitate angina). Thyroxine's t is ~7d, so any change in dosage will take ~4wks to be assessed accurately by TSH (NB: TSH itself has a t of only ~1h).[diskette]55 If ischaemic heart disease: Give propranolol 40mg/6h PO and start with

25g/24h of thyroxine as above. If diagnosis is in question and T4 already given: Stop T4; recheck TSH in 6wks. Causes of goitre + hypothyroidism Hashimoto's thyroiditis: Autoimmune disease in which there is lymphocyte and plasma cell infiltration. Usually in women aged 607055yrs. Often euthyroid. Autoantibody titres high. Treat as above if hypothyroid or to reduce goitre if TSH high. Drugs: As above. The effects of amiodarone on the thyroid are complex and variable. It commonly causes a rise in free T4, and a fall in free T3, but clinically the patient may remain euthyroid. 2% of patients have clinically significant changeswhich may be hyperthyroidism or hypothyroidism. Be guided more by clinical state than tests. Seek expert help. Note that t is long (40100d), so problems persist after withdrawal. Secondary hypothyroidism(from pituitary failure, p318) is very rare. Why are symptoms of hypothyroidism so many, so various, and so subtle? Almost all our cell nuclei have receptors showing a high affinity for T3: that known as TR-1 is abundant in muscle and fat; TR-2 is abundant in brain; and TR-1 is abundant in brain, liver, and kidney. These receptors, via their influence on various enzymes, affect the following processes: The metabolism of substrates, vitamins, and minerals. Modulation of all other hormones and their target-tissue responses.

Stimulation of O2 consumption and generation of metabolic heat. Regulation of protein synthesis, and carbohydrate and lipid metabolism. Stimulation of demand for co-enzymes and related vitamins.

Subclinical hypothyroidism[diskette]56 Features TSH but T4 and T3 , and no obvious symptoms. The context may be follow-up after partial thyroidectomy or 131I, or just a routine test (~10% of those >55yrs old have TSH 3.520mU/L). The risk of progression to frank hypothyroidism is ~2%, but increases as TSH. However, this risk doubles if thyroid autoantibodies are present, and is ~10% in men. Management Check thyroid autoantibodies. Recheck the history: if any non-specific features (eg depression), discuss benefits of treating (p306) with the patient: they may simply feel better, without realizing that they were not functioning optimally.

One approach to management is to treat (with thyroxine) those patients with a TSH > 10, or those with positive thyroid autoantibodies, previous Graves' disease, or other organspecific autoimmunity (type 1 DM, myasthenia, pernicious anaemia, vitiligo).[diskette]57 If the patient does not fall into any of these categories, monitor TSH annually.

Risks from well-managed treatment of subclinical hypothyroidism are small ( risk of atrial fibrillation and osteoporosis only if over-treated).[diskette]58

Parathyroid hormone and hyperparathyroidism Parathyroid hormone (PTH) is a peptide which causes Ca2+ and PO43- reabsorption in the kidney, osteoclast activity, and 1,25dihydroxy vitamin D3 production in the kidney. The overall effect is to Ca2+ and PO43- in plasma. Primary hyperparathyroidism (1HPT) Causes: ~80% solitary adenoma, ~15% hyperplasia, ~4% multiple adenomas, ~1.5% primary neoplasia. Presentation:Often asymptomatic Ca2+ or BP on routine tests; osteopenia/ osteoporosis (bone pain fractures), abdominal pain, renal stones, mood, pancreatitis, ulcers (duodenal: gastric 7: 1; but gastrinomas common if MEN1).[diskette]59 Other presentations relate to Ca2+ and effects of PTH on the skeleton: Confusion Thirst, nocturia, anorexia (Ca2+)

Dehydration[diskette]60 Stiff joints Mobility Myopathy

Thirst may be severe. Hyperparathyroidism must pass through your mind whenever a patient says I always take a jug of water to bed. Associations with multiple endocrine neoplasia (MEN): Blood tests:Ca2+, PO43- (unless renal failure), alk phos, PTH, or creatinine, 24h urine for Ca2+. DEXA bone scan (p698). Any evidence of bone reabsorption, ie osteitis fibrosa et cystica (brown tumours) and subperiosteal resorption (hand x-ray)? Also consider: CXR; skull xray (pepper-pot skull); pelvic x-ray. Treatment Surgical excision1 prevents fractures and gastric ulcers.[diskette]61 Also consider for: brown tumours; osteoporosis; renal calculi; pancreatitis. Pre-op ultrasound can locate the source of PTH. If this fails, try an MIBI scan, before surgical exploration. (MIBI = methoxy-isobutyl isonitrile.) Do plasma Ca2+ daily for 14d' post-op (danger is Ca2+). Mild symptoms may not merit surgeryadvise fluid intake to stop stones forming; review every 6 months. Postop recurrence: Seen in ~8% of patients over 10yrs (in one big series).[diskette]62

Secondary hyperparathyroidism (2HPT) (PTH as appropriate for a low Ca2+). Ectopic/metastatic calcification may be a feature (paraarticular sites, heart valves, and anterior thigh, and major arteries2).[diskette]63 Causes: chronic renal failure; dietary lack of vit D. [prescription take]: Phosphate binders; vit D analogues; ? calcimimetics3see renal osteodystrophy (bone disease), p276. Tertiary hyperparathyroidism (3HPT) occurs after prolonged secondary hyperparathyroidism, if 1 or more glands act autonomously (eg with adenoma formation),[diskette]64 causing Ca2+ from secretion of PTH unlimited by feedback control. It is chiefly seen in chronic renal failure or after renal transplants (in 2%). It may be possible to limit resection to just the adenomatous glands.[diskette]65 Malignant hyperparathyroidism ;Parathyroid-related protein (PTHrP) produced eg by lung cancers, mimics PTH, resulting in Ca2+ ( low PTH). Footnotes 1 Eg total parathyroidectomy + autotransplantation of 1 gland to a forearm (removable if hyperparathyroidism recurs); without autotransplantation, alfacalcidol or similar (p276) is needed. OTM2313 2 Other causes: neoplasia, trauma, paraplegia, atheroma, amyloid, CREST (p420); SLE, nephrocalcinosis, chondrocalcinosis, TB, sarcoid, parasites, pseudohypoparathyroidism, myositis ossificans progressiva. 3 Calcimimetics are under development (eg cinacalcet) to amplify sensitivity of extracellular Ca2+ sensing receptors (CaR) to extracellular Ca2+, so suppressing PTH with resultant fall in Ca2+. Hypoparathyroidism Primary hypoparathyroidismPTH secretion due to gland failure, eg removal during neck surgery. Blood tests: Ca2+, PO43- or , alk phos . Signs and symptoms: Features of hypocalcaemia (p694). Associations: Pernicious anaemia; Addison's; hypothyroidism; hypogonadism. Treatment is with alfacalcidol (p694). Lifelong follow-up required. Pseudohypoparathyroidism(failure of target cell response to PTH). Signs: Round face, short metacarpals and metatarsals. Basal ganglia calcification. Plasma PTH, alk phos normal or . Treatment: As for 1 hypoparathyroidism. Pseudopseudohypoparathyroidism;The morphological features of pseudohypoparathyroidism, but with normal biochemistry. The cause is genetic.[diskette]66 Autosomal dominant (pre)malignant paraendocrinopathies/ Multiple endocrine neoplasia (MEN) MEN syndromes are an extraordinary group of genetic tumour syndromes comprising: [diskette]67 MEN1 & 2 Neurofibromatosis, p402, eg with duodenal somatostatinomas + phaeochromocytomas + medullary thyroid cancer (MTC)

Von Hippel Lindau syndrome (p736)

PeutzJeghers' syndrome (p732, eg polyposis + endocrine tumours)[diskette]68 Carney complexadrenal hyperplasia + pituitary adenomas + skin & heart myxomas (any chamber) + mucosal lentigos + schwannomas + testicular tumours.[diskette]69

MEN type-1 (=MEN1):Parathyroid hyperplasia ( superimposed clonal tumour growth) + pituitary adenoma + pancreatic tumoursgastrinomas (p740), islet cell tumours (p300), or VIPomas (rare, p218). The MEN1 gene is a tumour suppressor gene; menin, its protein, alters transcription activation.[diskette]70 Many cases are sporadic: here typical presentation is in the 3rd5th decades. MEN2a:MTC+pheochromocytoma+parathyroid hyperplasia (rarer than with MEN1).[diskette]71 [diskette]72 Tests for mutations in the ret proto-oncogene are revolutionizing MEN2 treatment by enabling thyroidectomy before neoplasia occurs.[diskette]73 NB: ret mutations rarely contribute to sporadic parathyroid tumours. MEN2b(= MEN3 = MEN-III)[diskette]74 is like MEN2a but has neuro-cutaneous signs (mucosal neuroma bumps eg on: lips, cheeks, tongue, glottis, lids, with visible corneal nerves), [diskette]75 and a Marfanoid appearance (p730)but without any hyperparathyroidism. [diskette]76 Additional signs: slipped upper femoral epiphyses, and delayed puberty. MEN2b is caused by a missense mutation in the ret gene giving rise to a single amino acid substitution (Met918 by Thr).[diskette]77 Hypopituitarism The 6 anterior pituitary hormones commonly measured are: adrenocorticotrophic hormone (ACTH), growth hormone (GH), follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and prolactin (PRL). There may be complete loss of anterior pituitary function or selective loss of one hormonal axis, so presentation is very variable. Causes Hypophysectomy Trauma

Pituitary irradiation or adenoma (non-functional or functional with hyposecretion of other hormones, eg acromegaly, prolactinoma, or rarely Cushing's).

Rarer causes: Craniopharyngioma, p320 Sphenoid meningioma

Abscesses TB Peripituitary glioma Haemochromatosis

Sheehan's syndrome1a Trauma

Features of: Corticotrophin lack: Insidious onset afternoon tiredness; dizziness; nausea; pallor; weight; postural BP; collapse; Na+, etc., p312. Gonadotrophin lack:Few, scant, or no menses (oligomenorrhoea; amenorrhoea); fertility; libido; osteoporosis; breast atrophy; dyspareunia. Androgen lack:Erectile dysfunction; libido; muscle bulk; hypogonadism (loss of all hair; small testes; ejaculate volume; spermatogenesis). GH lack:Central obesity; atherosclerosis; dry wrinkly skin; strength; balance; wellbeing; exercise ability; cardiac output; osteoporosis; glucose.[diskette]100 Thyroid lack:Constipated; weight; mood; dry skin; p306. Tests (The triple stimulation test is now rarely done.) T4 and TSH reliably diagnoses TSH deficiency. Testosterone, LH, and FSH in men, and a menstrual history + LH and FSH in women are as reliable as the GNRH test. The short Synacthen test provides sufficient information concerning ACTH deficiency. Basal T4, TSH, LH, FSH, prolactin, testosterone. U&E (Na+ dilution), Hb (normochromic, normocytic). Thyroid deficiency: T4 but TSH normal or. MRI scan; assessment of visual fields.

Short Synacthen test: (p312for ACTH deficiency) is nearly as reliable as the insulin tolerance test (ITT), which is now a rarely done 2nd-line gold standard (only do in metabolic units under close supervision).[diskette]101 Insulin tolerance test (ITT): CI: epilepsy, heart disease, adrenal failure. The test involves giving insulin IV, and assessing its effect on cortisol and GH. It is done in morning (water only taken from 22:00h the night before). Have 50% glucose and hydrocortisone to hand and IV line open. Be alert throughout to hypoglycaemia. Consult lab first. Interpretation: Glucose must fall below 2.2mmol/L and the patient should become symptomatic. Normal values are: GH >20mU/L, and a peak cortisol >550mmol/L. Arginine + growth hormone releasing hormone test (ARG + GHRH test): An alternative to the ITT for measuring need for GH; it may have fewer SEs.2

Treatment Hydrocortisone for secondary adrenal failure (p312). Thyroxine if hypothyroid (p306, but TSH useless for monitoring). : 3-weekly testosterone enanthate 250mg IM or transdermal Andropatch; apply to clean, dry, unbroken skin on back, upper arm, thigh, or abdomen for

24h (do not use the same site within 7d). : (pre-menopausal) Oestrogen (eg as contraceptive steroid pill). Some patients need growth hormone. NB: GH has acquired a smart drug status via inappropriate internet advertisements extolling its muscle and potency-enhancing and supposed anti-ageing attributes.[diskette]102 SE: prostate hyperplasia; insulin-like growth factor (IGF-1 may risk of cancer, but unproven).[diskette]103 If you think your patient might need GH (eg it is known to improve recovery and walking distance after hip surgery[diskette]104), ask an endocrinologist first. Other causes of hypogonadism Trauma, post-orchitis (mumps, brucellosis, leprosy), chemotherapy/irradiation, cirrhosis, alcohol (toxic to Leydig cells), cystic fibrosis, haemochromatosis; syndromes (OHCS p752 etc.): Kleinfelter's (commonest), LaurenceMoonBiedl, dystrophica myotonica, PraderWilli, Kallman's (with anosmia+colour blindness; X-linked recessive). NICE guidelines on giving somatropin (GH) in those >25yrs old Somatotropin is produced by DNA technology; it has the same sequence as human GH. It should only be used in GH deficiency, and if:[diskette]105 Peak GH response is <9mU/L (3ng/mL) during an ITT (or equivalent). There is impaired quality of life (QoL), as measured by QoL-AGHDA questionnaires (assessment of hormone deficiency in adults score 11 points).1

The person is already receiving treatment for other pituitary hormone deficiencies, as required.

NB: Achieving adult bone mass is a valid indication for somatropin in adults <25yrs old who fulfil criteria 1 but not 2. (Maximum GH secretion is during adolescence; then secretion normally falls by ~14% per decade.) Self-injection 0.20.3mg/d (=0.60.9IU); needs with age; dose titration (1st 3 months of therapy) is done by an endocrinologist. SE: Headache; myalgia; BP; carpal tunnel syndrome; fluid retention; ICP (rare). CI: Pregnancy; lactation; major trauma; post-op; malignancy; respiratory failure. Somatropin should be stopped after 9 months if QoL-AGHDA does not improve by 7 points or more.1 Using GH in children: See OHCS p184. Footnote 1 Improvement in QoL scores during GH replacement has to be viewed with skepticism. This can be dispelled only by randomized trials. Barkan A 2003 J Clin Endocrinol 86 1905 Footnotes 1a Sheehan's syndrome (Simmonds' disease) is pituitary necrosis after post-partum haemorrhage. 2 W Kiess 2003 Clin Endocrinol 58 456. Another alternative is a pyridostigmine + GHRH (PD + GHRH) test. Pituitary tumours Pituitary tumours (almost always benign adenomas) account for 10% of intracranial tumours. Symptoms are caused by local pressure, hormone secretion, or hypopituitarism (p318). There are 3 histological types.

Chromophobe70%. Some are non-secretory, but cause hypopituitarism. Local pressure effect in 30%. Half produce prolactin (PRL); a few produce ACTH or GH. Acidophil15%. Secrete GH or PRL. Local pressure effect in 10%. Basophil15%. Secrete ACTH. Local pressure effect rare.

Classification by hormone secreted (may be revealed by immunohistology) PRL only 35% GH only 20% PRL and GH 7% ACTH 7% LH/FSH/TSH [greater than or equivalent to] 1%1[diskette]106 No obvious hormone30%2 Features of local pressure effects Headache; visual field defects (bilateral hemianopia, initially of superior quadrants); palsy of cranial nerves III, IV, VI. Rarely, diabetes insipidus (DI) (p326; which is more likely to result from hypothalamic disease), disturbance of temperature, sleep, and appetite, and erosion through floor of sella leading to CSF rhinorrhoea. InvestigationsPituitary MRI (defines intra- and supra-sellar extension); accurate assessment of visual fields; prolactin, baseline TFTs, short synacthen test, LH/FSH, testosterone, and glucose tolerance test if acromegaly suspected. Water deprivation test if DI is suspected (p326). Treatment Start hormone replacement as needed, in light of the above. Surgery:If intrasellar tumour, remove by trans-sphenoidal approach. Suprasellar extension may need a transfrontal approach. Pre-op: Check with anaesthetist/surgeoneg hydrocortisone sodium succinate 100mg IM with pre-med; then every 4h for 72h; then hydrocortisone 20mg PO each morning. Post-op: Retest pituitary function (p318) after a few weeks to assess replacement needs. Medical:Dopamine agonists (p322) are the best treatment for most prolactin-secreting tumours (lowers PRL and can shrink tumour: monitor by MRI). Surgery is not indicated routinely for these. It may also work for some GH-secreting tumours (p322) and also non-functional tumours (some making -subunit); use higher doses, eg bromocriptine 2040mg PO daily. Radiotherapy:Post-op if complete removal of tumour has not been possible. Pituitary apoplexy Sudden tumour enlargement due to haemorrhage may cause compression of vessels and neural tissue at the skull base with coma and death without preceding symptoms.[diskette]108 Suspect if sudden onset of headache in someone with a known tumour, or if there is sudden headache and loss of consciousness (ie may present like subarachnoid haemorrhage). : Frontal sinusitis, eg

when presentation is with fontal tenderness periorbital oedema.[diskette]109 Treatment: Urgent surgery with steroid cover. Craniopharyngioma Not strictly a pituitary tumour: it originates from Rathke's pouch so is situated between pituitary and the 3rd ventricle floor. 50% present with local pressure effects in children, eg with: headache (50%), vomiting (30%), visual disturbances (20%), polyuria; polydipsia (17%), delayed puberty (20%), short stature (14%), precocious puberty (3%).[diskette]110 DI is common. Tests: CT/MRI (calcification in 50%). Treatment: Surgery; irradiation; test pituitary function (above). Footnotes 1 2003 data show that new(ish) sensitive methods of TSH measurement lead to improved recognition. TSH-secreting tumours are now more frequently found at microadenoma stage, medially located, and without associated hypersecretions. In these tumours, somatostatin analogues (p324) are very helpful. 2 Many produce alpha-subunit which may serve as a tumour marker. Hyperprolactinaemia This is the most common biochemical disturbance of the pituitary. It tends to present early in women (amenorrhoea) but late in men. Causes of raised basal plasma prolactin (>390mU/L) Prolactin is secre-ted from the anterior pituitary and release is inhibited by dopamine produced in the hypothalamus. Therefore, hyperprolactinaemia may result from either excess production, eg prolactinoma, or because of disinhibition, eg compression of the pituitary stalk, reducing local dopamine levels; or due to administration of a dopamine antagonist. A prolactin of 10005000mU/L could result from either, but >5000 is likely to be due to an adenoma, with macroadenomas having the highest levels, eg 10,000100,000. Physiological:Pregnancy; breast-feeding; stress; sleep. Drugs and other chemicals (most common cause):Phenothiazines; metoclopramide; haloperidol; -methyldopa; oestrogens. Diseases: Prolactinoma, pituitary adenomas, pituitary stalk section, hypothalamic disease, chronic renal failure; hypothyroidism; sarcoidosis. Symptoms : Libido, weight, apathy, dry vagina, amenorrhoea; infertility, galactorrhoea. : Impotence, reduced facial hair, galactorrhoea. Osteoporosis and local pressure effects (p320) are also modes of presentation. Tests Basal plasma prolactin: non-stressful venepuncture between 09.00 and 16.00h. CT/MRI scan of the pituitary fossa if prolactin >1000mU/L.

Management A reasonable approach is as follows: Microprolactinomas: A tumour <10mm diameter on MRI (~25% of the population have asymptomatic microprolactinomas). Trans-sphenoidal surgery has a high success rate, and a relatively low incidence of side-effects, but is not used in all centres. After surgery, prolactin concentrations are normalized, menstruation starts, and galactorrhoea eliminated in most patients. There is a small but significant recurrence rate. Alternatively, dopamine agonists such as bromocriptine may be used (1.25mg PO at 22.00 with food; increase weekly by 1.252.5mg/d until ~2.5mg/12h). Rarely, patients may require >10mg daily. Follow PRL. Bromocriptine should be stopped in pregnancyteratogenicity is reported. PRL will rise during pregnancy, there is no need to follow it. If headache or visual loss, check fields and consider neuroimaging. Other SE: pulmonary, pericardial, and retroperitoneal fibrosis; see BNF; watch for cough and dyspnoea. Macroprolactinomas: A tumour >10mm diameter in association with a prolactin of >3600mU/L is likely to be a macroprolactinoma. If prolactin <3600, then it is probably a non-secretory tumour causing stalk compression and disinhibition of prolactin release. Macroprolactinomas may be treated with bromocriptine, but if there are visual symptoms, pressure effects, or if pregnancy is contemplated (~25% of macroadenomas will expand during pregnancy), then surgery is generally indicated. Usually, a trans-sphenoidal approach is used. Follow-up with serial PRL and MRI. Bromocriptine, and in some cases radiation therapy, may be required post-op because complete surgical resection is uncommon. Pre-op assessment is often difficult: familiarize yourself with case-histories to show complexities of this aspect of endocrinology.1 Dopamine agonists Bromocriptine is the established drug, but newer drugs, eg cabergoline (taken weekly) and quinagolide (once daily) are now replacing it (cabergoline may be 1st-line therapy). With macroprolactinomas, some centres continue treatment with bromocriptine during pregnancy. Footnote 1 E Harms 2003 Dtsch Med Wochenschr 128 667. A 46yr&hyphen;old lady had galactorrhoea for 7yrs, and a &uarr; prolactin (3133mU/L) and intact pituitary function with no eye signs. MRI showed a 1.9cm pituitary tumour with extrasella extension. Is selective trans&hyphen;sphenoidal adenomectomy needed for a presumed non&hyphen;functioning macroadenoma with functional hyperprolactinaemia, or should there be a dopamine&hyphen;agonist trial? One possible answer: try drugs, and monitor MRI if initial prolactin &gsim; 2000 mU/L. Acromegaly This rare disease is due to hypersecretion of GH from a pituitary tumour. It usually presents between the ages of 30 and 50yrs old. Prevalence

5 per million. Clinical features Excessive soft tissue growth: Coarse, oily skin, large tongue (macroglossia), prominent supraorbital ridge, prognathism, ride-spaced teeth, shoe size, thick spade-like hands, deepening voice, arthralgia, kyphosis, proximal muscle weakness, paraesthesiaedue to carpal tunnel syndrome (p391), progressive heart failure, goitre. Sleep apnoea. Sweating and headache. Features of a pituitary tumour: Hypopituitarism local mass effect (p318).

Psychological effects: Not all patients notice body changes (you may need to study old photos), but take time to ascertain the patient's reaction to their changing body, tactfully ask about associated loss of initiative, decreased spontaneity, mood swings, low selfesteem, body image distortion, disruption in interpersonal relations, social withdrawal, and anxiety.[diskette]111 Metabolic effects, eg insulin resistance: GH acts at several levels to block insulin, including inhibiting phosphorylation of the insulin receptor.[diskette]112

Complications DM; BP; left ventricular hypertrophy/cardiomyopathy; colon cancer;[diskette]113 [bomb] hyperthyroidism in 426% (TSH-dependent or independent).[diskette]114 Investigations Isolated GH measurement may show secretion, but levels vary with the time of day and other factors, so random measurements are not diagnostic. The definitive test is the OGTT with GH measurementas described on p294. Collect samples for GH and glucose at: 0, 30, 60, 90, 120, 150min. Interpretation of OGTT: normally GH is suppressed, in acromegaly there is no suppression, and levels may rise. False positives: anorexia nervosa, poorly controlled DM, hypothyroidism, Cushing's.

Serum insulin-like growth factor-1 (IGF-1) is used for screening for acromegaly in some centres. Levels correlate with GH secretion over the past 24h, and so are if excessive GH secretion, or in pregnancy, or puberty. MRI (or CT) scan of pituitary fossa. Test pituitary function (p318)hypopituitarism? ECG. Echocardiogram. Visual fields and acuity. Skin thickness. Obtain old photos; request a new photo of full face, torso, hands on chest.

Treatment Trans-sphenoidal surgery: Usually the treatment of choice. In 60% GH secretion reduces to <10mU/L. 6wks after surgery readmit for OGTT with GH measurement, and full pituitary function testing (p318). If GH fails

to suppress below 2.0mU/L, irradiation or medical treatment is needed. Steroids should be stopped before these tests and triple stimulation test may have a role, on day 4 only if no signs of steroid deficiency (postural hypotension, fever, nausea, anorexia). Yearly follow-up: (OGTT + GH measurement; T4; PRL; visual fields; x-rayssee above; photos; cardiovascular assessment / ECG). External irradiation:For older patients or failed surgery. Follow-up as for surgery. Medical:Somatostatin analogues such as octreotide (Sandostatin LAR, given monthly IM), and lanreotide (Somatuline LA) have displaced dopamine agonists as 1st-line in somatotroph (GH) adenomas (SE: gallstones). Follow-up shows that some cardiac complications resolve after lanreotide (eg LV mass, ventricular filling, and ventricular arrhythmic profile).[diskette]115 Monitor glucose tolerance as effects on insulin resistance are unpredictable.[diskette]116 [diskette]117 [diskette]118 Diabetes insipidus (DI) This is due to impaired water resorption by the kidney because of reduced ADH secretion from the posterior pituitary (cranial DI), or impaired response of the kidney to ADH (nephrogenic DI). Symptoms Polyuria; dilute urine; polydipsia; dehydration if not drinking. Causes of cranial DI Metastases/Vascular lesion/Head injury/Sarcoidosis/Meningitis/Hypophysectomy/Pituitary tumour/Inherited (autosomal dominant)/Histiocytosis/Craniopharyngioma Idiopathic DI (50%) is often self-limiting, and MRI may show infundibuloneurohypophysitis (known to be lymphocytic, and possibly autoimmune[diskette]119). Causes of nephrogenic DI Low potassium, high calcium, drugs (lithium, demeclocycline), pyelonephritis, hydronephrosis, pregnancy (rare as a primary cause; due to placental production of vasopressinase; can exacerbate underlying DI from any cause), inherited. Investigations U&E, Ca2+, plasma, and urine osmolalities. Plasma osmolality should be high, and urine low. Serum sodium may be high. In psychogenic polydipsia, plasma osmolality is often low. The water deprivation test will confirm the diagnosis. The water deprivation test (If 1st morning urine osmolality >600mosmol/kg, DI is excluded.) Stop drugs (eg carbamazepine) before the test. Light breakfast, no tea, no coffee, no smoking. Weigh at 0, 4, 6, 7, 8h. Stop if >3% body weight lost.

Supervise carefully to stop patient drinking.

Empty bladder, then no drinks and only dry food for 8h. Collect urine hourly, measure volume. Measure osmolality at 1, 4, 7, 8h. Stop test if osmolality >600mosmol/kg (DI is excluded). Venous sample for osmolality at: 0.5, 3.5, 6.5, 7.5h. If plasma osmolality >300mosmol/kg, and urine osmolality <600, give desmopressin 20g intranasally (or 1g IM) at 8h. Urine should concentrate within 1h. If plasma osmolality does not rise, do not administer desmopressin as hyponatraemia may result. Water can be drunk after 8h. Measure urine osmolality at 8, 9, 10, 11, 12h.

Interpreting water deprivation tests:Check if plasma osmolality is >290mosmol/kg to ensure the test has given adequate stimulus for ADH release. Normal res-ponse is for urine osmolality to be >600mosmol/kg. In psychogenic polydipsia, urine is also concentrated (>400mosmol/kg), but rather less than in the normal response. In DI, urine is abnormally dilute (<400mosmol/kg). However, in cranial DI, urine osmolality increases >50% after desmopressin, whereas in nephrogenic DI, it increases <45% after desmopressin. Treatment Cranial DI: Find the cause. Test pituitary function (p318). Give desmopressin 1020g/1224h intranasally (smallest dose that controls polyuria: higher doses risk of hyponatraemia). An oral formulation is being assessed (DDAVP; there may be fewer problems with water intoxication).[diskette]120 Nephrogenic:Treat the cause. Avoiding high-protein meals and salt may help polyuria. If it persists, try bendrofluazide (=bendroflumethiazide) 5mg PO/24h. Emergency management The diagnosis must be madeeg suitable cause, urine output, urine osmolality (~150mosmol/kg), despite dehydration. Do urgent plasma U&E. Rehydrate; keep up with output. 5% dextrose, 2L in the 1st hour. If severe hypernatraemia, do not lower Na+ rapidly, use 0.9% or 0.45% saline.

Desmopressin 1g IM (lasts 1224h). In nephrogenic DI, indomethacin 75mg/24h PO can lower urine volume and plasma Na+. [diskette]121

Hyponatraemia: assessment Presentation Mild hyponatraemia (Na+ 130135mmol/L) is common especially in patients taking thiazide diuretics and is usually asymptomatic. Moderate hyponatraemia (Na+ 120129mmol/L) is usually asymptomatic unless it has developed rapidly. Severe hyponatraemia (Na+<120mmol/L) may be associated with disturbed mental state, restlessness, confusion, and irritability. Seizures and coma prevail as the sodium approaches 110mmol/L.

History should focus on drugs, fluid losses (diarrhoea, frequency, sweating), symptoms of Addison's, symptoms or history of cardiac, lung, liver, or renal disease. Examination should focus on careful assessment of volume status, and in particular should assess whether the patient is hypovolemic, normovolemic, and/or oedematous. Patients should therefore have an assessment of their lying and standing BP, HR, JVP CVP, skin turgor, and the presence of oedema or ascites. Patients who are hyponatraemic and hypovolemic are salt depleted. Investigations In addition to U&Es, other tests should be aimed at excluding other causes of hyponatraemia (see table, P572). Measure serum osmolarity and compare it to the calculated osmolarity [2(Na+ + K+) + urea + glucose]: an increase in osmolar gap is with substances such as ethylene glycol, severe hyperglycaemia, mannitol, etc.

Urine Na+ combined with clinical assessment of fluid status may help determine the underlying cause:
o

Volume depletion from an extra-renal cause (see table, P572) is normally associated with a low urinary Na+ (<10mmol/L) Volume depletion with a high urinary Na+ (>20mmol/L) suggests inappropriate renal salt-wasting (e.g. intrinsic renal disease, hypothyroidism, adrenal insufficiency, diuretics) A low urine Na+ (<10mmol/L) is seen in conditions such as CCF, cirrhosis, or nephrotic syndrome where there is sodium retention in response to poor renal perfusion Euvolaemia with high urine Na+ is seen with SIADH and rarely with severe myxoedema.

General principles Assessment of the patient's volume status (neck veins, orthostatic hypotension, cardiac signs of fluid overload, ascites skin turgor) will help in both diagnosis and subsequent treatment. Mild asymptomatic hyponatraemia will usually respond to treatment of the underlying cause and no specific therapy is necessary.

Correction of hyponatraemia should be gradual to avoid volume overload and/or central pontine myelinolysis. Aim to restore the serum Na+ to ~125mmol/L actively (iv fluids) and allow to rise gradually after that by treating the underlying cause. Seek expert help if serum Na+ <120mmol/L severely symptomatic. Patients with cirrhosis and ascites and severe hyponatraemia should have diuretics stopped, and be treated with volume expansion. SIADH or other conditions associated with plasma volume expansion can cause hypouricaemia (increased renal clearance).

Hyponatraemia: causes Decreased serum osmolarity Hypovolaemia (hyponatraemia + hypovolaemia = salt depletion) Renal losses (uNa Non-renal losses (uNa <20mmol/L) >20mmol/L) Diuretics GI losses (diarrhoea, vomiting) Addison's disease Burns Na-losing nephropathies Fluid sequestration (e.g. peritonitis, pancreatitis) Normovolaemic (normal or mildly increased ECV) SIADH: urine osm. >100, serum osm. low (<260), urine Na+ >40mmol/L CNS disorders Malignancy Pulmonary disease Trauma Lung (oat cell) Pneumonia Stroke/SAH Pancreas TB Malignancy (1/2) Lymphoma or leukaemiaLung abscess Vasculitis (e.g. SLE) Prostate Cystic fibrosis Infection (abscess or meningoencephalitis)Urinary tract Lung vasculitis Drugs (via SIADH renal sensitivity to ADH or Na > H2O loss) Opiates Thioradizine Chlorpropamide Haloperidol Carbamazepine Thiazides Amitriptyline Clofibrate Cyclophosphamide Vasopressin Oxytocin Vincristine Miscellaneous causes Severe myxoedema Psychogenic polydipsia Oedematous states Congestive cardiac failure Cirrhosis with ascites Severe renal failure Nephrotic syndrome Normal serum osmolarity Pseudo-hyponatreemia (e.g. lipaemic erum, paraprotein >10g/dl) Intracellular shift of Na+ (e.g. hyperglycaemia, ethylene glycol) Hyponatraemia: management Exclude pseudohyponatraemia: lipaemic serum will be obvious (ask the biochemist). Calculate the osmolar gap to check there are no hidden osmoles (P572). Always exclude the possibility of artefactual Na+ from blood taken proximal to an iv infusion. Asymptomatic hyponatraemia should be corrected slowly so that serum sodium does not increase by >12mmol/L/day.

Symptomatic hyponatraemia (e.g. seizures or coma) requires a more aggressive initial correction to increase serum sodium concentration by ~6mmol/L over 34 hours. Thereafter, correct serum sodium slowly, so that the overall increase is <12mmol/L per 24 hours. Seek expert help early. Start iv infusion of normal saline (150mmol/L) at 250500ml/h watching carefully for fluid overload. As a guide, if 1 litre of N saline is infused instantaneously, it would increase serum sodium by 45 mmol/L.

Alternatively, infuse 5% saline at 40700mmol Na+/h until serum sodium increases adequately.

If volume deplete (dehydrated) start an iv infusion of normal saline (0.9% = 150mmol/L Na+); insert a central venous line if indicated. Monitor fluid output: catheterize the bladder if there is renal impairment. Watch out for heart failure. If not dehydrated: for patients with moderate SIADH, restrict fluid intake to 500/24h. Seek expert help.

Clinical manifestations of osmotic demyelination May be delayed 25 days Often irreversible or only partially reversible

Dysarthria Dysphasia Paraparesis or quadriparesis Lethargy Coma or seizures.

Hypernatraemia Abnormalities in serum sodium are usually associated with changes in serum osmolality and ECV. Presentation Symptoms often relate to severe volume depletion: weakness, malaise, fatigue, altered mental status, confusion, delirium, or coma. The way to determine the cause of abnormal serum Na+ is by Careful assessment of the ECV (evaluation of neck veins, supine and standing BP, any cardiac signs of fluid overload (e.g. S3, oedema), and skin turgor), in association with Measuring the serum ( urine) osmolality. [Serum osmolality may be estimated by (2 (Na+ + K+) + urea + glucose) but this is inaccurate when there are other osmoles (e.g. ketones, ethanol, methanol, ethylene glycol, renal failure) that contribute.] Serum Na+>145mmol/L is always associated with hyperosmolarity. Causes of hypernatraemia Normal or extracellular volume (excessive Na+ and H2O loss) Renal water losses (urinary osm inappropriately low) o Diabetes insipidus (central or nephrogenic)
o

Osmotic diuresis with water replacement only (e.g. DM)

Non-renal water losses (urinary osm >400mosmol/L)

o

Hypotonic GI losses (e.g. diarrhoea)

o o

Cutaneous losses (burns, heat shock, sweating, and high fever) Chest infections with prolonged hyperventilation

Salt overload (usually iatrogenic)

o o o o o

Concentrated NaHCO3 Post-operatively when huge volumes of fluid used In ITU when volume loaded with saline based fluids Concentrated infant formula Conn's syndrome (hypertension, hypokalaemia, alkalosis)

Management Avoid rapid and extreme changes in serum sodium concentration. It is safer to change serum sodium cautiously. If there is hypovolaemia, start fluid replacement. Normal saline (0.9%) contains elemental sodium at 150mmol/L. Use this initially to correct hypovolaemia if present, then change to 5% dextrose to replace water and slowly correct sodium concentration.

If the patient is haemodynamically stable encourage oral fluids. Monitor electrolytes twice daily initially.

Acute hypocalcaemia Presentation Abnormal neurological sensations and neuromuscular excitability Numbness around the mouth and paraesthesiae of the distal limbs

Hyperreflexia Carpopedal spasm Tetanic contractions (may include laryngospasm) Focal or generalized seizures. Rarely extra-pyramidal signs or papilloedema Hypotension, bradycardia, arrhythmias, and CCF Chvostek's sign is elicited by tapping the facial nerve just anterior to the ear, causing contraction of the facial muscles (seen in 10% of normals) Trousseau's sign is elicited by inflating a blood pressure cuff for 35 minutes 1020mmHg above the level of systolic blood pressure. This causes mild ischaemia, unmasks latent neuromuscular hyperexcitability, and carpal spasm is observed.

NB: Carpopedal spasm may occur during hyperventilation induced respiratory alkalosis. Investigations Plasma Ca2+, PO3-4, and albumin Plasma Mg2+

U&Es ECG (Prolonged QT interval) Plasma PTH level SXR (intracranial calcification esp. hypoparathyroidism)

Management The aim of acute management is to ameliorate the acute manifestations of hypocalcaemia, and not necessarily to return the calcium to normal. For frank tetany, 10ml of 10% calcium gluconate (2.25mmol) can be given by slow iv injection over 10 minutes. NB: 10ml of 10% calcium chloride (9 mmol) contains ~4-fold more calcium than calcium gluconate. Calcium gluconate is preferred as it causes less tissue necrosis if it extravasates. iv calcium should never be given faster than this because of the risk of arrhythmia. Thereafter, an infusion of calcium (~0.0250.05mmol/kg/h should be started). For a 70kg adult, add 50ml of 10% calcium gluconate or 10ml of 10% calcium chloride to 200ml N saline, and infuse at 5080ml/h.

Post parathyroidectomy, mild hypocalcaemia normally ensues, requiring observation only. In patients who have parathyroid bone disease however, hungry bones may cause profound hypocalcaemia shortly after the parathyroids are removed. This may cause a severe and prolonged hypocalcaemia which requires prolonged treatment. Chronic hypocalcaemia is best managed with oral calcium together with either vitamin D, or, if the cause is hypoparathyroidism or an abnormality in vitamin D metabolism, a form of activated (hydroxylated) vitamin D such as alfacalcidol or calcitriol. If magnesium deficiency is present, add 20ml (~40mmol) of 50% magnesium sulphate solution to 230ml N saline (10g/250ml). Infuse 50ml of this (equivalent to 2g MgSO4, 8 mmol) over 10 minutes, and at 25ml/h thereafter.

Causes of hypocalcemia Vitamin D deficiency Asians Chronic renal failure Loss of Ca2+ from circulation Extra-vascular deposition o Hyperphosphataemia (renal failure, tumour lysis)
o

Acute pancreatitis

Osteoblastic metastases (e.g. prostatic)

Intra-vascular binding
o o o

Citrate or blood products Foscarnet (anti-CMV drug) Acute respiratory alkalosis

Hypoparathyroidism Post parathyroid, thyroid, or neck surgery Idiopathic

Pseudo-hypoparathyroidism Infiltration HIV infection

Disorders of Mg2+ metabolism Magnesium deficiency Other

Sepsis, burns Fluoride intoxication Chemotherapy (e.g. cisplatin)

Practice point If hypocalcaemia is difficult to correct, check for magnesium deficiency. Hypercalcaemia The free (ionic) plasma Ca2+ concentration is dependent on both arterial pH ( during acidaemia) and the plasma albumin. Ionized Ca2+ = measured Ca2+ + [40 - serum albumin(g/L)] 0.02. (e.g. If measured Ca2+ = 2.10mM and albumin = 30g/L, the corrected Ca2+ = 2.10 = [(40 - 30) 0.02] = 2.30mM).

Most ITUs can now measure ionized calcium.

Presentation Routine biochemical screen in an asymptomatic patient General: depression (3040%), weakness (30%), tiredness, and malaise

Gastrointestinal: constipation, anorexia; vague abdominal symptoms (nauseas, vomiting), weight loss

Renal: renal calculi (if long standing); nephrogenic diabetes insipidus (20%); type 1 RTA; pre-renal failure; chronic hypercalcaemic nephropathy, polyuria, polydipsia, or dehydration Neuropsychiatric: anxiety, depression, and cognitive dysfunction; coma or obtundation Cardiac: hypertension, cardiac dysrhythmias.

Urgent treatment is required if Calcium >3.5mmol/L Clouding of consciousness or confusion is present

Hypotension Severe dehydration causing pre-renal failure.

Management Rehydrate patient with iv N saline (0.9%). Aim for about 36L/24h depending on fluid status (CVP), urine output and cardiac function. If patient does not pass urine for 4h, pass a urinary catheter, and a central venous line to monitor CVP.

Diuretics: once patient is rehydrated, continue N saline infusion and add frusemide 40mg every 24hours. Continue monitoring CVP carefully to prevent either fluid overload or dehydration. Monitor electrolytes, especially K+ and Mg2+ which may fall rapidly with rehydration and frusemide. Replace K+ (2040mmol/L of saline) and Mg2+ (upto 2 mmol/L saline) intravenously. If this fails to reduce plasma Ca2+ adequately (Ca2+ still >2.8mM) then the following measures should be considered: Salmon calcitonin 400IU q8h. This has a rapid onset of action (within hours) but its effect lasts only 23 days (tachyphylaxis). Bisphosphonates inhibit osteoclast activity thereby causing a fall in plasma Ca2+. Administer pamidronate at 3060 mg iv over 46 hours. (As a general rule give 30mg over 4h if Ca2+ is <3 mmol/L or for all patients with significant renal impairment, 60mg over 8h if Ca2+ is 34 mmol/L. Ca2+ levels begin to fall after 48 hours and remain suppressed for up to 14 days. Zolendronate has a shorter infusion time (15mins) and is said to more effective with a longer duration of action. Steroids (prednisolone 3060mg po od): Most effective in hypercalcaemia due to sarcoidosis, myeloma or vitamin D intoxication. Familial benign hypocalciuric hypercalcaemia: Ca2+, N 24h urinary Ca2+. This causes few symptoms (mild fatigue or lethargy). The PTH may be raised but the patients do not respond to parathyroidectomy.

Causes of hypercalcaemia Primary (or tertiary) hyperparathyroidism (85% of cases) Malignancy

o o

Humoral hypercalcaemia Local osteolytic hypercalcaemia (e.g. myeloma, metastases)

Hyperthyroidism (present in 1520% of patients) Granulomatous disorders (sarcoidosis) Drug related

o o o o o

Vitamin D intoxication Theophylline toxicity Milk-alkali syndrome Thiazide diuretics Lithium (mild, present in 50% patients on long-term lithium)

Immobilization (Paget's disease) Benign familial hypocalciuric hypercalcaemia HTLV-1 infection may present with severe hypercalcaemia Phaeochromocytoma (part of MEA type II), acromegaly Adrenal failure Rhabdomyolysis (calcium may be high or low) Congenital lactase deficiency

Investigations for hypercalcaemia Plasma Ca2+, PO3-4, and Mg2+ U&Es

LFTs CXR Plasma PTH level 24h urinary Ca2+ Urinary cAMP

Hypophosphataemia Plasma phosphate is normally 0.81.4mmol/L. Hypophosphataemia is common, and often unrecognized by clinicians. Most intracellular phosphate is present as creatine phosphate or adenine phosphates (e.g. ATP), and in RBC the predominant species is 2,3-diphopshoglycerate. Hypophosphataemia does not necessarily indicate phosphate deficiency; similarly phosphate deficiency may be associated with normal or high plasma phosphate concentrations. Causes of hypophosphataemia Modest (0.40.75mmol/L) Decreased dietary intake Vitamin D deficiency

Chronic liver disease Hyperparathyroidism Decreased absorption (vit D deficiency, steatorrhoea, phosphate binding antacids) Hungry bones syndrome (post parathyroidectomy, acute leukaemia) Lymphoma or the leukaemias syndrome Hyperaldosteronism Diuretics Fanconi syndrome

Severe (<0.4mmol/L) Respiratory alkalosis Treatment of diabetic ketoacidosis

Alcohol withdrawal (esp. with ketoacidosis) Acute liver failure Hyperalimentation (i.e. feeding after starvation) Ventilation of chronic severe respiratory failure Neuroleptic malignant

Presentation Most cases of severe hypophosphataemia occur in very sick patients (often in an ITU). Occasionally seen in asymptomatic patients. Coincident Mg2+ deficiency exacerbates PO3-4, depletion and vice versa.

Modest hypophosphataemia has no effect, but warrants investigation. Severe hypophosphataemia (<0.4mmol/L) may cause symptoms and requires treatment.

Manifestations of severe hypophosphataemia Myopathy (involving skeletal muscle and diaphragm) Rhabdomyolysis

Cardiomyopathy Erythrocyte dysfunction Leukocyte dysfunction Metabolic acidosis CNS dysfunction (encephalopathy, irritability, seizures, paraesthesiae, coma) Respiratory failure Reduced platelet half-life Mineral mobilization

Treatment Phosphate repletion should generally be reserved for patients with sustained hypophosphataemia. Give oral effervescent Phosphate Sandoz 2 tabs tds or potassium phosphate iv (918mmol/24h). Excessive phosphate replacement may cause hypocalcaemia and metastatic calcification; monitor Ca2+, PO43-, K+, and other electrolytes. Pituitary apoplexy Presentation Pituitary infarction may be silent. Apoplexy implies the presence of symptoms. The clinical manifestations may be due to leakage of blood/necrotic tissue into the sub-arachnoid space or rapid expansion of a suprasellar mass and pressure on local structures. This may be the presenting symptom of the pituitary tumour. Headache occurs in 95% of cases (sudden onset; variable intensity) Visual disturbance occurs in 70%, (usually bitemporal hemianopia)

Ocular palsy (40%) causing diplopia. Unilateral or bilateral Nausea/vomiting Meningism (common) Hemiparesis or rarely seizures Fever, anosmia, CSF rhinorrhoea, and hypothalamic dysfunction (disturbed sympathetic autoregulation with abnormal BP control, respiration, and cardiac rhythm) are all described, but are rare Altered mental state, lethargy, delirium, or coma

Symptoms of preceding pituitary tumour Acute hypopituitarism.

Clinically, pituitary apoplexy may be very difficult to distinguish from sub-arachnoid haemorrhage, bacterial meningitis, mid-brain infarction (basilar artery occlusion), or cavernous sinus thrombosis. Transient neurological symptoms are common in the preceding few days. The clinical course is variable. Headache and mild visual disturbance may develop slowly and persist for several weeks. In its most fulminant form, apoplexy may cause blindness, haemodynamic instability, coma, and death. Residual endocrine disturbance (panhypopituitarism) invariably occurs. Investigations U&Es Hyper- or hyponatraemia may occur. Endocrine Clotted blood for cortisol, thyroid function, prolactin, GH, and the tests gonadotrophic hormones. CT scan Pituitary cuts, with administration of iv contrast, will reveal a tumour mass (or haemorrhage) within 2448 hours. MRI scan May be useful in the sub-acute setting. Management Stabilize the patient (Airway, Breathing, Circulation). Hydrocortisone 100mg iv should be given if the diagnosis is suspected after the blood samples above have been collected.

Monitor U&Es and urine output for evidence of diabetes insipidus. Neurosurgical decompression may be indicated (seek neurosurgical review). Obtundation and visual deterioration are absolute indications for neurosurgery. Patients without confusion or visual disturbance generally do well without surgery. Assess pituitary function once the acute illness has resolved and treat as necessary. A TSH in the normal range may be inappropriate if the T4 is low in pituitary disease, but this may occur in the sick euthyroid state characteristic of many seriously ill patients.

Causes of apoplexy in patients with pituitary adenomas Spontaneous haemorrhage (no obvious precipitant, the commonest) Anti-coagulant therapy

Head trauma Radiation therapy Drugs (e.g. bromocriptine or oestrogen) Following tests of pituitary function.

Hypopituitary coma

Hypopituitarism does not become evident until 75% of the adenohypophysis is destroyed, and at least 90% destruction is required for total loss of pituitary secretion. Complete loss of hormone secretion can rapidly become life threatening and requires immediate therapy. In a mild or incomplete form, hypopituitarism can remain unsuspected for years. Presentation In the absence of stress, patients with severe hypopituitarism may have few symptoms or signs. A general anaesthetic or infection may precipitate hypoglycaemia and coma, due to the combination of a lack of GH, cortisol, and thyroxine, all of which have a counter-regulatory effect on insulin. Clues from the history include Known pituitary adenoma Recent difficult delivery: pituitary infarction following postpartum haemorrhage and vascular collapse is still the commonest cause of hypopituitarism. Features include failure of lactation (deficiency of prolactin oxytocin), failure of menstruation (lack of gonadotrophins), non-specific features, e.g. tiredness, weakness, loss of body hair, and loss of libido (due to ACTH deficiency, hypothyroidism, and gonadotrophin deficiency)

Men may give a history of impotence, lethargy, and loss of body hair Women report loss of menstruation.

Examination Examination of the comatose patient is discussed on P40615 Examine specifically for secondary sexual characteristics and physical signs of myxoedema

Consider other causes for coma (P406).

Investigations General investigations for patients in coma are discussed on P408 Take blood for baseline cortisol, ACTH, thyroid function, LH, FSH, prolactin, and GH

Short synacthen test must be performed to test for adrenocortical reserve (P586) LHRH and TRH test can be performed at the same time as the short Synacthen test Defer formal pituitary function testing until the patient is stable CT scan of pituitary (tumour or empty sella) MRI scan may give additional information.

Management General measures are as for any patient in coma (P406) Give iv colloids saline to restore BP if the patient is in shock

Give glucose if the patient is hypoglycaemic

Hydrocortisone 100mg iv should be administered if the diagnosis is suspected and continued (100mg iv tds, see P586) Start tri-iodothyronine (10g bd) after hydrocortisone is started Investigate and treat any precipitating intercurrent infection If the patient fails to improve, consider other causes for coma (see P406) Long term, the patients will require replacement with hydrocortisone or prednisolone, thyroxine, testosterone, oestrogen/progesterone GH.

Causes of panhypopituitarism Pituitary Mass lesions (adenomata, cysts) Pituitary surgery or irradiation

Infiltrative (haemochromatosis) Infarction (Sheehan's) Apoplexy (haemorrhage) Empty sella syndrome

Hypothalamic Mass lesions (metastases, e.g. breast, lung; craniopharyngiomas) Radiotherapy

Infiltration (sarcoid, histiocytosis) Trauma, e.g. fractured skull base Infections (TB)

Polyuria Definition: >3 litres urine per day. Presentation Confusion (hyponatraemia or dehydration) Coma

Proteinuria on screening Depression or other psychiatric manifestations Renal stones. Excessive fluid intake

Causes

Endocrine dysfunction (DM, diabetes insipidus, hypercalcaemia) Hypokalaemia Intrinsic renal disease (polycystic kidneys, analgesic nephropathy, medullary cystic disease, amyloidosis) or renal recovery from ATN. Post obstructive, e.g. after catheterization of patient in chronic retention. Post renal artery angioplasty Drugs (frusemide, alcohol, lithium, amphotericin B, vinblastine, demeclocycline, cisplatinum). Duration and severity (nocturia, frequency, water consumption at night) FH of diabetes mellitus, polycystic kidneys, renal calculi Drug history (diuretics, analgesics, lithium, etc., see above) Renal calculi (hypercalcaemia) Weakness (low potassium), depression (hypercalcaemia) Psychiatric history Endocrine history (menses, sexual function, lactation, pubic hair) Other significant pathology (e.g. causes of amyloid).

History

Investigations U&Es (renal disease, hypokalaemia) Glucose

Calcium, phosphate, and alkaline phosphatase Plasma and urine osmolality [a U:P osmolality of <1.0 indicates diabetes insipidus, intrinsic renal disease (incl. K+), or hysterical drinking] AXR (nephrocalcinosis) Lithium levels if appropriate Dipstick protein and quantitation if indicated.

Management Assess fluid status (JVP, BP, postural drop, weight charts, CVP). Strict fluid balance and daily weights.

Insert central line to monitor the CVP.

Measure urinary sodium and potassium (random samples will give an indication of the loss of sodium or potassium initially, and if losses are great, accurate timed samples of <6 hours are possible). Replace fluid losses as appropriate to maintain a normal homeostasis, using combinations of saline and dextrose. Monitor potassium, calcium, phosphate, and magnesium daily or twice daily if necessary. If lithium toxicity is present, see P820. Avoid chasing fluids. At some point a clinical judgement has to be made to stop replacing urinary losses with iv fluids to allow the patient to reach their normal equilibrium. Once the patient is optimally hydrated then avoid replacing fluids iv to allow physiological homeostasis to occur. If diabetes insipidus suspected, arrange water deprivation test (see below).

Water deprivation test Stop all drugs the day before the test; no smoking or caffeine Supervise the patient carefully to prevent surreptitious drinking

Empty the bladder after a light breakfast. No further fluids po Weigh the patient at time 0, 4, 5, 6, 7, 8 hours into the test (stop the test if >3% of body weight is lost) Measure serum osmolality at 30 minutes, 4 hours, and hourly till end of the test (check that the plasma osmolality rises to >290mosmol/kg to confirm an adequate stimulus for ADH release) Collect urine hourly and measure the volume and osmolality (the volume should decrease and the osmolality rise; stop test if urine osmolality >800mosmol/kg as DI is excluded) If polyuria continues, give desmopressin 20mcg intranasally at 8 hours Allow fluids po (water) after 8 hours. Continue to measure urine osmolality hourly for a further 4 hours

Interpretation Normal response: urine osmolality rises to >800mosmol/kg with a small rise after desmopressin Cranial DI: urine osmolality remains low (>400mosmol/kg) andincreases by >50% after desmopressin

Nephrogenic DI: urine osmolality remains low (<400mosmol/kg) andonly rises a little (<45%) with desmopressin Psychogenic polydipsia: urine osmolality rises (>400mosmol/kg) but istypically less than the normal response