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

The hyperglycaemia for hich diabetes is so famous is !ust one aspect of a far-reaching metabolic derangement hich typically leads to serious vascular events (stroke" M#" retinopathy" and limb ischaemia). Type 1 and type $ DM (p$%&) are different entities" ith different causes" and natural histories. Type 1 DM (formerly called insulin-dependent diabetes mellitus" #DDM) is usually of !uvenile onset but may occur at any age" and is characteri'ed by insulin deficiency. (atients al ays need insulin" and are prone to ketoacidosis and eight loss. #t is associated ith other autoimmune diseases ()*+ D,- . D,&/ 0ve islet cell antibodies at diagnosis). 1oncordance is 2-34 in identical t ins. & genes are important567one (89) determines islet sensitivity to damage (eg from viruses or cross-reactivity from co s: milk-induced antibodies). (resentation +cute; <etoacidosis (p=1=)567un ell" hyperventilation" ketones on breath" eight loss" polyuria and polydipsia" fatigue. >ubacute; )istory as above but longer and in addition lethargy" infection (pruritus vulvae" boils). Diagnosis Mainly clinical ith venous fasting plasma glucose 5?@ AmmolB*. (lasma )1C-- and arterial p) may be lo " ketones may be present in urine. Treatment #nsulin (see DCE). Education on ad!usting insulin dose in the light of eFercise . calorie intake to achieve normoglycaemia is vital. Give anti-smoking" foot-care (p$%=)" . pre-conception advice (C)1> p%&). #f pregnant" share care ith an interested obstetrician (C)1> p1H8). Monitor; D(/ )b+1c/ creatinine/ fundi" p$%8. There is a need for renal protection eg ith +1E-i if microalbuminuria is present (p$==). Dose ad!ustment for normal eating (D+IJE); Cne ay to optimi'e control is to use the principles of adult education (eg eFplicit learning ob!ectives/ 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 randomi'ed D+IJE study found that training in fleFible" intensive insulin dosing improved glycaemic control as ell as ell-beingB9uality of life.KdisketteL$ #t is resource-intensive. #nsulin dosing during intercurrent illnesses (eg influen'a) #llness often increases insulin re9uirements despite reduced food intake. Maintain calorie intake using milk or soft drinks containing sugar.

1heck blood glucose 5?@ & times a day; 5MN insulin doses if glucose rising. (atients may need to seek advice from a specialist diabetes nurse or G(. +dmit if the patient is thirsty" polyuric" dehydrated" or ketotic. +dmit early if a child or pregnant.

#f vomiting" admit567and treat ith #O fluids and insulin. >ame regimen may be needed during any serious illness. >liding scales of insulin; see p&A3. Managing type 1 diabetes

The aim is to optimi'e glycaemic control" ithout risking dangerous hypoglycaemia. H other areas need addressing. Maintain renal function (see p$== for the kidney in DM)/ this ill usually mean giving an +1E-i or +T-$ blocker (p$==). 1ontrol of blood pressure.

(revent eye complications by regular screening (eg retinal photography). (repare for pregnancy (check contraception if pregnancy not anted). >ee C)1> p1H8 for diabetes in pregnancy. Emotional and psychological factors hich may be perpetuating unhealthy lifestyles.

#nsulin >trength; 133PBm*. There are many types" falling into 8 groups. Pltra-fast acting" eg )umalogQR and JovorapidQR/ in!ect at start of meal (or immediately after). >oluble insulin eg )umulin >QR or +ctrapid; in!ect 1H56S-3min before meals.

#ntermediate )umulin #QR or #nsulatardQR. *ong-acting (56Tlente56U)" eg PltratardQR. *ong-acting analogue" eg *antusBinsulin glargine" see belo . (re-miFed insulins" eg ith ultra-fast component (eg )umalogQR MiF $H)/ or ith soluble insulin (eg )umulinQR M- or MiFtardQR -3).

>ome commonly used insulin regimens 5VWDesign the insulin regimen to suit your patient:s lifestyle (not vice versa). T ice daily premiFed insulins by pen in!ector567useful in type $ DM or type 1 ith regular lifestyle. Defore meals ultra-fast or soluble insulin ith bedtime intermediate- or long-acting analogue; useful in type 1 DM for achieving a fleFible life style (eg skipping meals).

Cnce daily before bed intermediate- or long-acting analogue567good initial insulin regimen hen s itching from tablets in type $ DM. Degin ith at least a total daily dose of 1 unit of insulin for every unit of body mass indeF in adults. JD; #nsulin glargine is a long-acting recombinant human insulin analogue used once daily at bedtime in type 1 or $ DM/ ho ever" not recommended for routine use in type $ DM (see DJI/ J#1E guidance).KdisketteL- Molecular modification has made an insulin that is soluble at acid p)" but precipitates in subcutaneous tissue and is slo ly released from a depot. Given once daily" insulin glargine has comparable efficacy to that of insulins used t ice daily. #ts rate of hypoglycaemia is 5?X to that of standard insulins" and there is evidence of less nocturnal hypoglycemia. #t may be combined ith ultrashort acting insulins given at the times of meals. #n type $ DM" if oral agents are failing" it can be added only if a bd dosing is problematic (J#1E guidance).KdisketteL&

5VW>trict plasma glucose control does reduce renal" 1J>" . retinal damage.KdisketteLH KdisketteL8

Type $ diabetes mellitus (DM Type $ DM appears to be prevalent at 56Tepidemic56U levels in many places (part of the increase is due to better diagnosis and improved longevity).KdisketteLA #n areas of +ustralia" A4 of people over $Hyrs old have DM (mostly type $).KdisketteL= )igher prevalence occurs in +sians" men" and the old (1=4 in men over =3 in *iverpool).KdisketteL% +void the terms noninsulin-dependent dm (niddm) and maturity-onset dm; most are over &3yrs" but teenagers are increasingly getting type $ DM. 1ause5 MS #nsulin secretion and insulin resistance associated ith obesity (56Tdiabesity56U)" eFercise lack" and calorie eFcess. Kgreater than or e9uivalent toL=34 concordance in identical t ins.1 Typical natural history + preliminary phase of impaired glucose tolerance (#GT) or #IG" see belo . (5VWThis a uni9ue indo of opportunity for lifestyle intervention.) + symptomatic phase; Thirst" polyuria" eight loss. + phase of complications; #nfections" neuropathy (eg foot ulcers)" retinopathy" or arterial disease (eg M# or claudication). DiagnosisBtestsBmonitoring Dlood; Iasting venous glucose5MN (2AmmolB*" unless already on insulin)/ )b+1c5MN (Kgreater than or e9uivalent toL 8.H4/ monitor eg $56S& timesByr). ,andom blood glucose tests are unreliable" but if 211.1mmolB* and symptomatic" this is diagnostic. Prine; Microalbuminuria (eg annually/ defines renal risks" p$==)/ urine analysis. M>P if ill. Iundoscopy (p$%8). D(; <eep systolic Y1&3mm)g. *ipids; pA38. Ioot eFam; Take off shoes and socks at each visit" to assess circulation" sensation" and skin 9uality/ arn not to go barefoot.KdisketteL13 Diagnostic criteria #f no diabetic symptoms" do not base a diagnosis on 1 glucose value alone. #f there is any doubt" use the $h value in an oral glucose tolerance test (CGTT); look for a level 211.1mmolB*. )o to do a $h CGTT; Iast overnight and give AHg of glucose in -33m* ater to drink. Measure venous plasma glucose before and $h after the drink. JD; >evere hyperglycaemia in acute infection" trauma" or circulatory or other stress may be transitory; delay formal diagnosis (but not management). (lasma )b+1c values; #f 2A4" DM is likely (specificity %%.84/ sensitivity %%4)" and risk of microvascular complications occurs. >creening for glycosuria; This is easy but Z14 of the population have lo renal threshold for glucose/ the sensitivity is only -$4 (specificity; %%4). #mpaired glucose regulation not amounting to diabetes

This state lies bet een normal glucose homeostasis and diabetes. #mpaired glucose tolerance (#GT); Iasting plasma glucose Y AmmolB* and CGTT $h glucose 5?@ A.=mmolB* but Y11.1mmolB*. #mpaired fasting glucouse (#IG); Iasting glucose levels 2 nor-mal range" but belo the diagnostic level for DM" ie fasting plasma glucose 5?@ 8.1mmolB* but YAmmolB*. Diabetes P< (Dritish Diabetic +ssociation) recommends all those ith #IG should have an CGTT to eFclude DM. #IG and #GT denote different abnormalities of glucose regulation (fasting and post-prandial). There may be lo er risk of progression to DM in #IG than #GT. Doth are managed ith lifestyle advice (eg eFercise . diet" p%1)" and regular revie . JD; Giving those ith heart failure and #IG +1E-i drugs can prevent progression to DM (-4 vs &=4 over -yrs).KdisketteL11 Gestational diabetes; This term no includes both gestational impaired glucose tolerance (G#GT) and gestational diabetes mellitus (GDM). Pse the same diagnostic values as #GT and diabetes above. +s glucose tolerance changes during pregnancy" the gestation at hich the diagnosis as made needs to be stated. 5?@ 8 ks post-partum" do a further AHg CGTT hether she still has diabetes or #GTB#IG. ,egardless of the 8 k post-pregnancy result" these omen are at 5MN risk of later diabetes. >ee C)1> p1H8. Managing type $ diabetes 5VW(atient motivation and education are central. +im to avoid complications567hypoglycaemia as ell as the long-term effects of hyperglycaemia. Tight D( control (eg systolic Kless than or e9uivalent toL1&3mm)g) is most important for preventing macrovascular disease and mortality. KdisketteL1$ >o do a global assessment of risk; glucose" D(" left ventricular hypertrophy" cholesterol"1 and smoking. Don:t treat DM in isolation. #n the P<" a Jational >ervice Irame ork (J>I) governs the delivery of care" setting aims" and prioriti'ing 9uality initiatives. KdisketteL1Educate and negotiate on drugs" diet" and the benefits of these issues; >pecialist nurseBdieticians" chiropodists" diabetic associationsBpatient:s groups. ,egular follo -up and regular eFercise (5MS insulin resistance . 5MS risk of M#).

*egal obligations to inform their driving licence authority (p18$). Diet; p$3=567saturated fats5MS" sugar5MS" starch-carbohydrate5MN" moderate protein/ don:t prohibit coffee (may 5MN insulin sensitivity).KdisketteL1& #f creatinine5MN or microalbuminuria (p$==)" restrict protein" and give +1E-i (p1-%) or +T-$ blocker (p$=-). #f diet and eFercise do not control glycaemia" use drugs.

Cral hypoglycaemics >tart ith metformin (a biguanide). This helps maintain eight loss (if achieved[) and 5MN insulin sensitivity. >E; anoreFia/ D.O/ D1$ absorption5MS/ not hypoglycaemia. +void if creatinine Kgreater than or e9uivalent toL1H3Q\molB*. Dose; 3.H56S1gB=h (C pc. >top if tissue hypoFia (eg M#/ sepsis) and &=h before G+ and for -d after contrast medium containing iodine (do P.E).KdisketteL1H JeFt add in a sulfonylurea to 5MN insulin secretion (some authorities" but not J#1E"KdisketteL18 say a glita'one$ is more appropriate as the $nd add-in drug).KdisketteL1A Tolbutamide; >hortacting (hypoglycaemia is rare)/ 3.H56S1.Hg in $56S- doses. Glicla'ide; Medium-acting/ &356S183mg (C as a single dose" maF 183mgB1$h). Glibenclamide; *ong-acting/ $.H56S1HmgB$&h (C at breakfast (rarely used).

Glita'ones ,osiglita'one &mgB$&h. 1#; *IT5MN. >E; headache" diarrhoea" dyspepsia" fluid retention (caution in 11I)/ do *IT every $ months for 1yr/ stop if +*T up 2--fold/ alternative; pioglita'one 1H56S-3mgB$&h. Glita'ones 5MS insulin resistance. Pse if metformin 0 sulfonylurea combination is problematic; the glita'one replaces hichever is contraindicated or not tolerated. KdisketteL1= Cther agents +carbose (an ]^-glucosidase inhibitor) decreases breakdo n of starch to sugar. Pse as an add-on drug"KdisketteL1% eg H3mg che ed at start of each meal" start ith a once daily dose/ maF $33mgB=h. >E; ind (can be terrible/ less if slo dose build-up)" abdominal distensionBpain" diarrhoea. Jateglinide; 5MN ]_-cell insulin release by binding to sulfonylurea receptors. 1$3mg -3min a.c. +lternative; ,epaglinide. They may be no better than metforminBglibenclamide at lo ering )b+1c. They target post-prandial hyperglycaemia (tQ` is shortKdisketteL$3 567metformin orks mostly on fasting glucose)/ they may have a role in those ith irregular mealtimes if glycaemic control is poor.KdisketteL$1 Cther considerations +1E-i (p1-%/ many good effects" not !ust D(5MS)/ aspirin 0 statins (pA38/ afor all ith DM) to 5MS overall risk. EFercise also helps. Iootnotes 1 +s DM has so many vascular events" give a statin (pA38) if *D* 2-mmolB* or D( 21&3. Even consider a statin hatever the pre-treatment cholesterol/ discuss ith your patient. * *indholm $33- *ancet -81 $333 $ Glita'ones may preserve ]_-cells and control glycaemia for longer than secretagogues or biguanides. 1auses of insulin resistance >yndrome E (central obesity" arteriopathy" glucose5MN" and hyperinsulinaemia 0 D(5MN) Cbesity/ acromegaly berner:s syn" C)1> pAH= ,enal failure (all types) (olycystic ovary" p-18 +sians1" pregnancy TD drugs/ cystic fibrosis Mechanisms; Cbesity may cause insulin resistance by 5MN rate of release of non-esterified fatty acids causing post-receptor defects in insulin:s action. Mutation of genes encoding insulin receptors.

1irculating autoantibodies to the eFtracellular domain of the insulin receptor. Kprescription takeL for syndrome E; EFercise more/ eight5MS/ statins/ hypotensives" hypoglycaemics (eg glita'ones).KdisketteL$$

Diabetes may be secondary to eg drugs (steroids and thia'ides)/ pancreatic disease (pancreatitis" surgery in hich 2%34 pancreas is removed" haemochromatosis" cystic fibrosis" pancreatic cancer)/ endocrine disease (1ushing:s disease" acromegaly" phaeochromocytoma" thyrotoFicosis)/ others (acanthosis nigricans" congenital lipodystrophy ith insulin receptor antibodies" and glycogen storage diseases). )elping people ith established diabetes

5VWIocus on education and lifestyle advice. (romote eFercise (to 5MN insulin sensitivity)" healthy eating (p$3=) and eight reduction567p$3=/ J#1E comments that drugs such as orlistat have a role here if eight loss of 2$.Hkg has been achieved by lifestyle advice and DM# 2$=kgBm$. 5V WIind out hat problems are being eFperienced (glycaemic control and morale). 5VW(re-empt complications. +ssess those modifiable risk factors important in DM D(; +im for systolic Y1&3mm)g/ smoking/ cholesterol (pA38). Glycaemic control; (1) Glycated (glyco-sylated) haemoglobin (c )b+1c)567levels relate to mean glucose level over previous = ks (ie ,D1 half-life). The target )b+1c must be set individually. Tight control is especially vital in pregnancy (C)1> p1H8) and if there are microvascular complications. #n other patients it may occasionally be sensible to opt for less tight control. JD; The $33- P< prospective diabetes study (P<(D>/ Jc$&=%) sho s that in type $ DM" )b+1c levels remain stubbornly high" despite intensive therapyKdisketteL$- (making recent P< )b+1c targets of Kless than or e9uivalent toLA.&4 seem impossible). 1omplications increase ith increasing )b+1c. JD; fructosamine (glycated plasma protein) levels reflect control over $56S- ks; useful in pregnancy to assess shorter term control" and in haemoglobinopathies hich interfere ith )b+1c tests. ($) )istory of hypoglycaemic attacks (and hether symptomatic). (-) )ome fingerstick glucose records may be useful. *ook for complications 1heck in!ection sites for infectionBfat necrosis" then; Oascular disease; 1ommonest cause of death. *ook for evidence of cerebrovascular" cardiovascular" and peripheral vascular disease. M# is -56SH times more common in DM and is more likely to be 56Tsilent56U (ie ithout classic symptoms). >troke is at least t ice as common. bomen are at high risk567DM removes the cardiovascular advantage conferred by female gender. ,educe other risk factors (see p%1). JD; +1E-i also slo s progression of renal disease (p$=-). Treat lipid disorders (pA38)567statins" eg simvastatin &3mg nocte" are 1st-line. Good glycaemic control also helps. Iibrates may be useful for 5MN triglycerides and 5MS )D*. +n aspirin a day may 5MS risk of M# in diabetics as in non-diabetics (no significant risk to the eye). <idneys (p$=-); Microalbuminuria (p$==) reflects early renal disease" and indicates 5MN risk for macrovascular disease. 1ontrol D( ith +1E-i; see p1-%.

Diabetic retinopathy; (Dilate pupils ith 3.H4 tropicamide.) Dlindness is not common and is usually preventable. +rrange regular fundoscopy for all patients" including retinal photography" if possible. ,efer 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 8B8 vision). 5VW(re-symptomatic screening enables laser photocoagulation to be used. Ior images of DM retinopathy" see C)1> pH3= and its associated colour plates. Dackground; Microaneurysms (dots)" microhaemorrhages (blots)" and hard eFudates. ,efer to specialist if near the macula. >ee (*+TE 1-. (re-proliferative retinopathy; 1otton- ool spots (infarcts)/ microhaemorrhages. (roliferative retinopathy; Je vessels form. Jeeds urgent referral. Maculopathy; More common in type $ DM. >uspect if visual acuity5MS.

(athogenesis; 1apillary endothelial change 5Md vascular leak 5Md microaneurysms 5Md capillary occlusion 5Md hypoFia0ischaemia 5Md ne vessel formation. )igh retinal blood flo caused by hyperglycaemia (. D(5MN . pregnancy) triggers this" causing capillary pericyte damage. Microvascular occlusion causes cotton- ool spots (Q^ blot haemorrhages at interfaces ith perfused retina). Je vessels form on disc or ischaemic areas" proliferate" bleed" fibrose" and can detach the retina. +spirin ($mgBkgBd) may prevent it/ there is no evidence of 5MN bleeding.1 1ataracts; May be !uvenile 56Tsno flake56U form" or 56Tsenile56U567 hich occur earlier in diabetic sub!ects. Csmotic changes in the lens induced in acute hyperglycaemia reverse after normoglycaemia (so ait before buying glasses). ,ubeosis iridis; Je vessels on iris; occurs late and may lead to glaucoma. Metabolic complications; p=1=. Diabetic feet; p$%=. Jeuropathy; p$%=. >tarting insulin in those ith type $ DM This is fre9uently re9uired hen control ith oral agents is suboptimal (eg )b+1c 2A.H56S=.34 on maFimum oral therapy). The patient must be blood glucose self-testing. Transfer is supervised by a diabetes nurse spe-cialist and dietician. #nsulin (p$%-) may be given initially once or t ice a day. 1ontinue metformin to limit eight gain. J#1E has commented that long-acting insulin glargine (p$%-) is not normally needed in this conteFt" unless there is recurrent symptomatic hypoglycaemia or it is necessary to avoid t ice daily insulin doses (eg if assistance is needed to in!ect). 1ontrolling D( in those ith diabetes567- typical scenarios D( Y1&HB=3 and no microalbuminuria and 13yr coronary event risk (1E,13" p$$) 5? X1H4" simply check D( every 8 months" or more often. D( 5?@ 1&3B=3 and Y183B133 and 1E,13 21H4" but no microalbuminuria" start an antihypertensive (J#1E recommends +1E-i" +$+" ]_-blocker" or a thia'ide). Target D( Y1&3B=3. Ior doses and discussion" see p1&$.

D( 5?@ 1&3B=3 and microalbuminuria is present (urine albumin;creatine ratio 5?@ $.HmgBmmol in men or 5?@ -.H in omen); ensure +1E-i or +$+ are part of the approach (unless 1#" p1-%)/ target D(; Y1-HBAH. (J#1E guidelines)

5VW+spirin prophylaFis (AHmgBd (C) is indicated eg if 1E,13 21H4.1 Iootnote 1 +spirin is kno n to 5MS leucocyte adhesion in diabetic retinal capillaries. #t 5MS eFpression of integrins on the surface of leucocytes and it 5MS nitric oFide synthetase (eJC>) levels and 5MS production of the vasoactive cytokine" tumour necrosis factor" kno n to be raised in diabetic retinopathy. DMe $33- -$A 1383 Diabetic neuropathy and diabetic foot care 5VW+mputation is preventable; good care saves legs. EFamine feet regularly. Distinguish bet een ischaemia (eg critical toes Q^ absent dorsalis pedis pulses) and peripheral neuropathy (in!uryBinfection over pressure points" eg the metatarsal heads). #n practice" many have ischaemia and neuropathy. >ymptoms Jumbness" tingling" and burning" often orse at night. >igns

>ensation5MS (especially vibration) in 56Tstocking56U distribution/ absent ankle !erks/ deformity (pes cavus" cla toes" loss of transverse arch" rocker-bottom sole). Jeuropathy is patchy" so eFamine all areas. #f the foot pulses cannot be felt" consider Doppler pressure measurement. +ny evidence of neuropathy or vascular disease puts the patient at high risk of foot ulceration. Educate (daily foot inspection" comfortable shoes567ie very soft leather" increased depth" cushioning insoles" eight-distributing cradles" eFtra cushioning567no barefoot alking" no corn-plasters). ,egular chiropody. Treat fungal infections (p81$). Ioot ulceration; Psually painless" punched-out ulcer in an area of thick callous Q^ superadded infection" pus" oedema" erythema" crepitus" odour. +ssess degree of; Jeuropathy (clinical). #schaemia (clinical and Dopplers/ consider angiography567even elderly patients may benefit from angioplasty).

Dony deformity" eg 1harcot !oint (clinical" F-ray). #nfection (do s abs" blood culture" F-ray/ probe ulcer to assess depth).

Management; ,egular chiropody (remove dead tissue). ,elieve high-pressure areas ith bedrest Q^ therapeutic shoes ((ressure ,elief balkersQR and similar shoes may be as good as total contact castsKdisketteL$&)/ metatarsal head surgery may be needed. #n ischaemia" shoes must be idefitting ith deep toe boFes to protect vulnerable forefoot margins and toes.KdisketteL$H #f there is cellulitis" admission is mandatory for #O antibiotics; start ith ben'ylpenicillin 833mgB8h #O and flucloFacillin H33mgB8h #O Q^ metronida'ole H33mgB=h #O" refined hen microbiology results are kno n. Get surgical help. Ensure normoglycaemia. +bsolute indications for surgery +bscess or deep infection >preading anaerobic infection

>evere ischaemia567gangreneBrest pain >uppurative arthritis

The degree of peripheral vascular disease" patient:s general health" and patient re9uest ill determine hether local eFcision and drainage" vascular reconstruction" andBor amputation (and ho much) is appropriate. Types of neuropathy in diabetes Motor . sensory neuropathy; >ymmetric sensory polyneuropathy567distal numbness (56Tglove and stocking anaesthesia56U)" tingling" and visceral pain" eg orse at night. Datting order of drugs to try; aspirinBparacetamol 5Md tricyclic (amitriptyline 1356S$Hmg nocte/ gradually 5MN/ maF 1H3mg) 5Md gabapentin. +lternatives; carbama'epine (p-=3)/KdisketteL$8 lamotrigine/KdisketteL$A 3.3AH4 capsaicin cream (a counter-irritant). Decompression may help.KdisketteL$= Mononeuritis multipleF

567especially ### . O# cranial nerves. Treatment is difficult. #f sudden and severe" immunosuppression ith corticosteroids" #O immuno-globulins" and ciclosporin (ccyclosporin) has been tried.KdisketteL$% +myotrophy 567painful asting of 9uadriceps and other pelvifemoral muscles. Pse electrophysiology to sho eg lumbosacral radiculopathy" pleFopathy" or proFimal crural neuropathy.KdisketteL -3 Jatural course; variable ith gradual but often incomplete improvement. #O immunoglobulins have been used.KdisketteL-1 +utonomic neuropathy; (biology; p-%3) EFcessive postural D( drop/ 5MS cerebrovascular autoregulation/ urine retention/ erectile dysfunction (ED)/ diarrhoea at night. The latter may respond to long-term codeine phosphate (the lo est dose to control symptoms" eg 1HmgB=h (C). Gastroparesis (early satiety" post-prandial bloating" nauseaBvomiting) is diagnosed by gastric scintigraphy ith a %% technetium-labelled lo -fat meal.KdisketteL-$ #t may respond to antiemetics. (ostural hypotension may respond to fludrocortisone 13356S-33Q\gB$&h (C (>E; oedema). (reventing loss of limbs; primary or secondary preventiona Traditionally prevention has involved foot care advice in diabetic clinics (eg 56Tdon:t go barefoot 56f56U)" and maintaining good glycaemic and D( control.1 Dut despite this" the sight of a diabetic patient minus 1 limb is not rare; henever e see such patients e should redouble our commitment to primary prevention567ie stopping those at risk from ever getting diabetes. #n one randomi'ed prospective study of those ith impaired glucose tolerance (#GT) and other risk factors" after - yrs" the incidence of diabetes per 133 person-years as H in those receiving simple eFercise and diet advice" = in a group given metformin" and 11 in the placebo group. +dvice and metformin decreased incidence of diabetes by H=4 (JJT 5?g A) and -14 (JJT 5 ?g 1&)" respectively" compared ith placebo.KdisketteL-Iootnote 1 )b+1c 5?X A.&4 and D( 5?X 1&HB=H are current P< primary care targets (G(s get a 9uality payment if A34 of their diabetics achieve this level/ for non-diabetic hypertensives" the target D( is 5?X1H3B%3mm)g). )ypoglycamia 5VWThis is the commonest endocrine emergency. (rompt diagnosis and treatment is essential. >ee p=$3 for emergency management. Definition (lasma glucose Y$.HmmolB*. Threshold for symptoms varies. >ymptoms +utonomic567> eating/ hunger/ tremor. Jeuroglycopenic 567Dro siness/ sei'ures/ rarely focal symptoms" eg transient hemiplegia" coma. Mutism" mannerisms" personality change" restlessness" and incoherence may lead to misdiagnosis of hysteria or psychosis.KdisketteL-& T o types; Iasting hypoglycaemia (re9uires full investigation if documented). o 1auses; Dy far the commonest cause is insulin or sulfonylurea treatment in a kno n diabetic. #n the non-diabetic sub!ect ith fasting hypoglycaemia" the follo ing mnemonic is useful; EE(*+#J.

EFogenous drugs" eg insulin or oral hypoglycaemics (p$=-). Does he have access to these (diabetic in the family)a Dody-builders sometimes misuse insulin to improve stamina.KdisketteL-H +lcohol" eg alcoholic on binge ith no food. +lso; aminoglutethimide/ &-9uinolones/ pentamidine/ 9uinine sulfate. (ituitary insufficiency. *iver failure plus some rare inherited en'yme defects. +ddison:s disease. #slet cell tumours (insulinoma" see belo ) and immune hypoglycaemia (eg antiinsulin receptor antibodies in )odgkin:s disease). Jon-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. EFclude liver failure and malaria.

+dmit for A$h fast. Do glucose" insulin" . 1-peptide if symptomatic.

#nterpreting results )ypoglycaemia ith high or normal insulin and no elevated ketones. 1auses; insulinoma/ sulfonylurea administration/ insulin administration (no detectable 1-peptide)/ insulin autoantibodies. #nsulin lo or undetectable" no eFcess ketones. 1auses; Jon-pancreatic neoplasm/ antiinsulin receptor antibodies.

#nsulin5MS" ketones5MN. 1auses; +lcohol/ pituitary or adrenal failure. (ost-prandial hypoglycaemia May occur eg after gastric surgery (56Tdumping56U" pH-3)" and in type $ diabetes. #nvestigation; (rolonged CGTT (Hh" p$%&).

Treatment 5VW5VW>ee p=$3. Treat ith oral sugar" and a long-acting starch (eg toast)/ if coma" glucose $H56SH3g #O (via a large vein ith a 3.%4 saline flush to prevent phlebitis) or glucagon 3.H56S1mg >1B#OB#M (Q^ a repeat after $3min/ follo ith carbohydrate). #f episodes are often" advise many small high-starch meals. #f post-prandial glucose5MS" give slo ly absorbed carbohydrate (high fibre). #n diabetics" prevent further episodes" by rationali'ing insulin therapy (p$%-). #nsulinoma MEJ-1 associated (p-3%)" usually benign islet cell tumour. >creening test; )ypoglycaemia 0 plasma insulin5MN during a long fast. >uppressive tests; Give #O insulin and measure 1-peptide. Jormally eFogenous insulin suppresses 1-peptide" but this does not occur in insulinoma. +rterial stimulation1 ith venous sampling (+>O>); )yperinsulinaemia as measured eg via splenic or

superior mesenteric artery stimulation.KdisketteL-8 #maging; 1TBM,# Q^ endoscopic pancreatic P> (all fallible" so don:t aste too much time before proceeding to intra-operative visuali'ationKdisketteL-A Q^ intra-operative ultrasound).KdisketteL-= Treatment; >urgery. Iootnote Diabetic ketoacidosis (D<+); assessment D<+ predominantly occurs in patients ith insulin-dependent diabetes (type #). #t does not usually occur in non-insulin-dependent diabetes. D<+ is being increasingly recogni'ed in some type ## diabetics" esp. +fro-1aribbeans. ,emember" patients may be prescribed insulin for poor diabetic control" and yet have non-insulin dependent diabetes. 1linical features These include (olyuria and polydipsia; patients become dehydrated over a fe days beight loss" eakness

)yperventilation or breathlessness; the acidosis causes <ussmaul:s respiration (a deep sighing respiration) +bdominal pain; D<+ may present as an 56Tacute abdomen56U Oomiting; eFacerbates dehydration 1onfusion" coma occurs in 134 Cn eFamination assess state of hydration" ventilation rate" and smell for ketones.

#nvestigations 56h Dlood This need not be high. >evere acidaemia may be present ith glucose values as lo glucose as 13mM (e.g. if the patient has recently taken insulin; this" alone" is insufficient to correct the acidaemia in the presence of dehydration) 56h +DG +ssess the degree of acidaemia (p) and bic.) 56h P.Es 1orrected +ssess serum <0 and renal function <etones strongly positive (ketones may be present in normal individuals after a period of starvation) JD; captopril and other sulphydryl drugs can give a false positive test for urinary ketones bD1 may be elevated (neutrophilia); a leukaemoid reaction can occur in absence of infection Dlood and urine cultures

Prinalysis 56h ID1

56h >eptic screen 56h (lasma (see note belo ) ketones 56h 1E, *ook specifically for any infection 56h +mylase May be high ith abdominal pain Q^ vomiting in absence of pancreatitis. +cute pancreatitis may occur in Z 134 of patients ith D<+. Jote >erum osmolality c $ ij (Ja0 0 <0) 0 urea 0 glucose.

Diagnosis of D<+ re9uires positive urinary or plasma ketones and arterial p) 5?XA.-3 andBor serum bicarbonate 5?X1HmmolB*. Many labs do not measure plasma ketones. The elderly patient presenting ith a high glucose" relatively normal acid56Sbase balance" and ketones in the urine does not have diabetic ketoacidosis" and may not be insulin dependent. 1onsider other causes of hyperglycaemiaBacidosis" e.g. aspirin overdose" and in the elderly consider lactic acidosis. (lasma ketones can be estimated by diluting plasma 1;1 ith J saline" and applying to a urine ketone dipstick. + result of 000 corresponds to a plasma ketone body concentration of HmmolB*.

1ommon precipitants of D<+ 56h #nfections -34 56h Jon-compliance ith treatment$34 56h Je ly diagnosed diabetes $H4 (oor prognostic features in D<+ p) YA.3 Cliguria

>erum osmolality 2-$3 Je ly diagnosed diabetes

Diabetic ketoacidosis; management1 General measures ,ehydration and insulin therapy are the mainstays of treatment. >ite the iv cannula a ay from a ma!or vein in the rist. This may be re9uired for an +O fistula in patients subse9uently developing diabetic nephropathy. >tart fluid replacement (see belo ).

#nsert a central line in patients ith a history of cardiac diseaseBautonomic neuropathy or the elderly (see (=88). 1onsider an arterial line to monitor +DGs and potassium. Jil by mouth for at least 8 hours (gastroparesis is common). Jasogastric tube; if there is impaired conscious level to prevent vomiting and aspiration. Prinary catheter if oliguria is present or serum creatinine is high. Droad-spectrum antibiotics if infection suspected. *Mb) (e.g. enoFaparin) should be given as prophylaFis against DOTs" but is not standard clinical practice. The tQ` of insulin is short and continued replacement (iv or sc) is essential.

Iluid replacement Pse J saline Q^ potassium until blood glucose is Y1$mmolB*. The average fluid loss in D<+ is -56S8 litres. +im to restore this over $& hours. (The follo ing regime should be modified for patients ith cardiac disease.) #f hypotensive and oliguric" give iv colloids (Q^ J saline) initially to restore D(/ then 1 litre J saline over the first -3 minutes then

1 litre J saline ith potassium (see table) $ hourly for = hours then 1 litre J saline ( ith <0" see table) & hourly until rehydrated (Z$&hours). The use of bicarbonate is controversial. #f the p) YA.3" isotonic (1.$84) sodium bicarbonate given at a maFimal rate of H33ml (i.e. AHmmol) over 1 hour is safe. Iaster infusion rates cause a paradoFical intracellular acidosis. +dd 1356S$3mE9 <0 per H33 ml. There is no evidence that the use of bicarbonate in D<+ improves outcome. bhen blood glucose is Y1$mmolB*" commence a H4 deFtrose infusion and continue insulin infusion. 1ontinued insulin is re9uired to inhibit ketoacid production.

(otassium replacement >ee table. Total body potassium can be depleted by 1333mmol and the plasma <0 falls rapidly as potassium shifts into the cells under the action of insulin. Pse less potassium in patients ith renal impairment or oliguria. #nsulin replacement >ee table. Modify this regimen depending on the response to therapy. +im for a fall in glucose of HmmolB* per hour (and correction of acidosis and plasma bicarbonate). #f the glucose or acidosis are not improving" increase the insulin infusion rate accordingly.

<eep the blood glucose 21356S1&mmolB* for the first $& hours or until the ketoacidosis resolves/ maintain this ith H4 deFtrose infusion.

Plasma potassium (mmol/L)Amount of K+(mmol) to add to each litre Y-.3 &3 Y&.3 -3 YH.3 $3 The sliding scale belo is a guide and should be tailored to the patient and response to therapy. +dd H3 units of actrapid to H3ml 3.%4 saline and administer by intravenous infusion. >tart the insulin infusion at 3.1PBkgBh initially. That is APBh for a A3kg person.

#f the blood glucose falls by 2HmmolB* in 1 hour" then decrease the rate of infusion to 3.3HPBkgBh (i.e. reduce to half-dose). bhen the blood glucose is Y1$mmolB*" glucose should be infused instead of saline" and blood glucose stabili'ed according to the sliding scale belo . Do not stop insulin infusion until regular subcutaneous insulin is restarted.

Blood glucose (mmol/L) (hourly)Insulin infusion (units/hour) 3.356S$.3 >top insulin567call doctor $.156S&.3 1all doctor &.356SA.3 3.H or 1 A.156S11.3 $ 11.156S$3.3 & 2$3 A567call doctor Diabetic ketoacidosis; complications +ssessment during treatment ,emember rapid normali'ation of biochemistry can be detrimental in any patient. #t is iser to be cautious and sub-optimal than enthusiastic and dangerous. Dlood glucose hourly ith lab blood glucose & hourly. (lasma electrolytes $ hours after start of treatment and then & hourly. The main risk is hypokalaemia.

+DGs & hourly" until persistent improvement or normali'ed. (lasma osmolality & hourly. >ome patients may re9uire monitoring on an E1G for T- ave changes during treatment. (hosphate levels should be monitored daily during treatment (see belo ). Magnesium levels should be monitored daily (see belo ). The iv insulin infusion should be continued until & hours after the patient is commenced on subcutaneous insulin.

1omplications +void hypoglycaemia from over'ealous insulin replacement. 1erebral oedema occurs mainly in children. #t may be precipitated by sudden shifts in plasma osmolality during treatment. >ymptoms include dro siness" severe headache" Q^ confusion. Treat as on (&H&. Give iv mannitol 3.HgBkg body eight" repeated as necessary. ,estrict iv fluids and move to #TP. Mortality is ZA34/ recovery of normal function only A56S1&4.

>erum phosphate falls during treatment" as it moves intracellularly ith potassium. #f the phosphate level falls to belo 3.&mmolB*" give phosphate iv (monobasic potassium phosphate infused at a maFimum rate of %mmol every 1$ hours). 1heck preparations ith your pharmacy. >erum magnesium may fall during insulin therapy. #f magnesium levels fall Y3.8 mmolB*" give &56S=mmol ($ml of H34) magnesium sulphate over 1H56S-3 minutes in H3ml J saline. ,epeat as necessary. )yperchloraemic acidosis (high anion gap acidosis in a ell-hydrated patient) may be seen ith eFcessive administration of saline and increased consumption of bicarbonate. Jo specific treatment is re9uired.

Tissue hypoperfusion results from dehydration and may trigger the coagulation cascade and result in thromboembolism. 1onsider using *bM) (e.g. enoFaparin sc) for prophylaFis in those at risk.

1omplications of D<+ )ypokalaemia )ypophosphataemia

)yperchloraemic acidosis )ypoglycaemia 1erebral oedema in children Thromboembolism

)yperosmolar non-ketotic coma ()CJ1) )CJ1 occurs in elderly patients ith 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. (resentation + history of diabetes is not usually kno n" and the patient is elderly #nsidious onset of polyuria and polydipsia

>evere dehydration #mpaired conscious level; the degree correlates most ith plasma osmolality. 1oma is usually associated ith an osmolality 2&&3 ,espiration is usually normal The patient may rarely present ith a 1O+" sei'ures" or a M#.

#nvestigations 56h Psually very high (2H3mmolB*) Glucose 56h P.Es Dehydration causes a greater rise in urea than creatinine (normal ratio of 1r;Pr up to $3;1 (Q\M;mM). >ignificant hypernatraemia may be hidden by the high glucose. The hypernatraemia may appear to orsen as the glucose falls ,elatively normal cf. D<+. + coeFistent lactic acidosis considerably orsens the prognosis 56h (lasma 1alculate by K$ ij (Ja0 0 <0) 0 urea 0 glucoseL needs to be 2-H3mosmBkg for osm. diagnosis 56h ID1 (olycythaemia and leukocytosis may indicate dehydration or infection respectively 56h E1G *ook for M# or ischaemia 56h 1E, *ook for signs of infection 56h Prine Ior urinalysis" M1.>. ,emember that ketones may occur in any starved person" but the level ill be belo HmM. Dlood and protein on urinalysis may indicate PT#.

Management; general measures ,ehydration and insulin therapy are the mainstays of treatment. Iluid replacement should be more cautious in the elderly. Give oFygen if hypoFic on air. +void fluid overload; monitor central venous pressure in all patients.

Jil by mouth for at least 8 hours and insert an JG tube in patients ith impaired conscious level to prevent vomiting and aspiration. Prinary catheter if oliguria is present" or serum creatinine is high. +nti-coagulate ith *bM) (e.g. enoFaparin &3mg sc daily).

Iluid replacement The average fluid lost is =56S13*. This should be replaced cautiously. 1 litre J saline over the first 83 minutes then 1 litre J saline ith <0 (see table" (HH%) every $ hours for & hours then

1 litre J saline ith <0 (see table" (HH%) 98h until rehydrated (Z&= hours). #f the plasma Ja is 2183mM give 3.&H4 saline (3.H J saline) for the first - litres. The Ja0 level is artificially lo ered by the high glucose level (see belo ) and appears to climb as the blood glucose falls. bhen blood glucose Y1$mmolB*" commence a H4 deFtrose infusion" and consider stopping insulin therapy and starting oral hypoglycaemic agents or diet alone.

#nsulin regimen This is similar to that for diabetic ketoacidotic coma (see table" (HH%)" eFcept that stopping insulin completely is less ha'ardous in the short term. (ractice points; hyperosmolar non-ketotic coma >evere hyperglycaemia can cause a technical error in the measurement of Ja0 concentrations. The corrected concentration can be calculated byk Treatment of severe hyperglycaemia causes an apparent increase in plasma Ja0 hich in reality may not actually change

Cccasionally patients present ith hyponatraemia hich based on the above is a form of pseudohyponatraemia (see (HA&)

)ypoglycaemic coma; assessment

+ll unconscious patients should be assumed to be hypoglycaemic until proved other ise. +l ays check a blood glucose using a GlucostiFQR (or DM stiF) immediately" and confirm ith a lab determination. The most common cause of coma in a patient ith diabetes is hypoglycaemia due to drugs. The longer acting sulphonylureas such as glibenclamide are more prone to do this than the shorter acting ones.

(atients ho are not kno n to have diabetes" but ho are hypoglycaemic" should have a laboratory blood glucose" and serum saved for insulin and 1-peptide determination (insulinoma or factitious drug administration) before administration of glucose.

(resentation >ympathetic overactivity (glc Y-.8mmolB*) Tachycardia (alpitations

> eating +nFiety (allor Tremor 1old eFtremities

Jeuroglycopenia (glc Y$.8mmolB*) 1onfusion >lurred speech

Iocal neurological defect (stroke-like syndromes) 1oma (atients ith ell-controlled diabetes have more fre9uent episodes of hypoglycaemia" and can become desensiti'ed to sympathetic activation. These patients may develop neuroglycopenia before sympathetic activation and complain of 56Tloss of arning56U. ]_-blockers blunt the symptoms of sympathetic activation and patients taking these drugs lose the early arning of hypoglycaemia. (atients ith poorly controlled diabetes develop sympathetic signs early" and avoid these by running a high blood glucose. They may complain of 56Tbeing hypo56U hen their blood sugar is normal or high. They do not re9uire glucose. (atients ho have diabetes follo ing a total pancreatectomy have more fre9uent and severe episodes of hypoglycaemia (56Tbrittle diabetes56U) because they lack glucagon producing (]^) cells as ell as ]_ islet cells.

#nvestigations Dlood glucose (DM stiF and confirmed by lab glucose). P.Es (hypoglycaemia is more common in diabetic nephropathy)

>ave serum" prior to giving glucose" for insulin and 1-peptide levels (send Z$3ml blood to the lab for immediate centrifugation if indicated).

Jote

+ lab glucose of less than $.$mmolB* is defined as a severe attack. 1oma usually occurs ith blood glucose Y1.HmmolB*. *o 1-peptide and high insulin level indicate eFogenous insulin/ high 1-peptide and insulin level indicate endogenous insulin Ke.g. surreptitious drug (sulphonylurea) ingestion or insulinomaL.

1auses of hypoglycaemia Drugs #nsulin >ulphonylureas

+lcohol >alicylates (rescription errors (e.g. chlorpropamide for chlorproma'ine) CthersBDisopyramide.B]_-blockers.B(entamidine.Bluinine

Crgan failure )ypopituitarism (esp. acute pituitary necrosis) +cute liver failure

+drenal failure MyFoedema ,arely 11I or 1,I

#nfections >epsis syndrome Malaria Tumours(#nsulinomaB,etroperitoneal sarcoma) )ypoglycaemic coma; management +cute measures ,emember to take blood prior to glucose administration (glucose" insulin" 1-peptide). >ee (H8&. #f there is a history of chronic alcohol intake or malnourishment" give iv thiamine 156S$mgBkg to avoid precipitating bernicke:s encephalopathy.

#f patient is conscious and co-operative" give H3g oral glucose or e9uivalent (e.g. *uco'adeQR" or milk and sugar). Give H3ml of H34 deFtrose iv if patient is unable to take oral fluids.

#f 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. +dmit the patient if the cause is a long-acting sulphonylurea or a long-acting insulin" and commence a continuous infusion of 134 glucose (e.g. 1 litre = hourly) and check glucose hourly or $ hourly.

Iurther management (atients should regain consciousness or become coherent ithin 13 minutes although complete cognitive recovery may lag by -356S&H minutes. Do not give further boluses of iv glucose ithout repeating the blood glucose. #f the patient does not ake up after Z13 minutes" repeat the blood glucose and consider another cause of coma (e.g. head in!ury hile hypoglycaemic" see (&&&). (rolonged severe hypoglycaemia (2& hours) may result in permanent cerebral dysfunction.

(atients on sulphonylureas may become hypoglycaemic follo ing a 1O+ or other illness preventing ade9uate food intake. ,ecurrent hypoglycaemia may herald the onset of diabetic nephropathy" as this decreases insulin re9uirements; insulin is partly degraded by the kidney. ,evie patient:s current medication" and inspect all tablets from home. 1onsider psychiatric revie if self-inflicted.

*iver dysfunction and recurrent hypoglycaemia )ypoglycaemia is common in acute liver failure" hen coma may occur (as a result of liver failure rather than hypoglycaemia). >evere hypoglycaemia is rare in chronic liver disease. #n chronic alcoholics it is advisable to administer iv thiamine (156S$mgBkg) before iv deFtrose to avoid precipitating neurological damage.

+n acute ingestion of alcohol can also suppress hepatic gluconeogenesis.

Prgent surgery in patients ith diabetes>urgery re9uires patients to fast for several hours. #n 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. Ior this reason" patients ith diabetes undergoing surgery ill re9uire an increased dose of insulin despite their fasting state. Type # DM (insulin dependent) Try to put the patient first on the list. #nform the surgeon and anaesthetist early. Discontinue long-acting insulin the night before surgery if possible. #f the patient has taken a long-acting insulin and re9uires emergency surgery" an infusion of 134 deFtrose (1356S133mlBh) can be used" together ith an insulin sliding scale.

Ensure iv access is available. bhen nil by mouth" start iv infusion of H4 deFtrose ith potassium ($3mmolB*) at 133mlBh and continue until oral intake is ade9uate. ,emember saline re9uirements (Z13356S1H3mmol JaB$&h but increases post-operatively) but do not stop deFtrose infusion (risk of hypoglycaemia). 1ommence an iv insulin sliding scale (see table). Measure finger-prick glucose hourly and ad!ust the insulin infusion accordingly. +im for A56S11mmolB*. 1ontinue the insulin sliding scale until the second meal and restart the normal sc dose of insulin. +s iv insulin has a very short half-life (-.H min)" this must be continued until the patient:s subcutaneous insulin is being absorbed/ an overlap of & hours is recommended.

Type ## DM (non-insulin dependent) Discontinue glucose-lo ering tablets or long-acting insulin the night before surgery if possible. #f the patient has taken their oral hypoglycaemic or insulin and re9uires emergency surgery" start an infusion of 134 deFtrose (1356S133mlBh) ith an insulin sliding scale. 1heck a fasting glucose; if 21$mmolB* treat as above.

#f the patient:s diabetes is normally managed ith oral hypoglycaemic agents" these can be restarted once the patient is eating normally. The sliding scale can be tailed off & hours later. Diet-controlled diabetics often do not re9uire a sliding scale at the time of surgery but may re9uire iv insulin post operatively for a short period if blood glucose rises 21$mmolB*. This may be tailed off" hen eating normally. +d!ust the scale according to the patient:s usual re9uirement of insulin (e.g. a patient on MiFtardQR -8PB$&P re9uires 83PB$& h" i.e. $.H PBh normally). #f blood glucose is persistently lo (Y&mmolB*) decrease all insulin infusion values by 3.H56S1.3PBh. #f blood glucose is persistently high (21-.3mmolB*) increase all insulin infusion values by 3.H56S1.3PBh.

+drenal corteF and 1ushing:s syndrome (hysiology The adrenal corteF produces; glucocorticoids (eg cortisol)" hich affect carbohydrate" lipid" and protein metabolism" and mineralocorticoids (eg aldosterone" p8==). 1orticotrophin-releasing factor (1,I) from the hypothalamus stimulates secretion of +1T) from the pituitary" hich in turn stimulates cortisol" and androgen production by the adrenal corteF. 1ortisol is eFcreted as urinary free cortisol and as various 1A-oFogenic steroids.

1ushing:s syndrome 1hronic glucocorticoid eFcess. %34 are +1T)-dependent/ of these %34 are pituitary in origin. %34 of pituitary causes are microadenomas (defined as lesions Y1cm in si'e) and M,# only detects A34 of them. +1T)-dependent causes; 1ushing:s disease; +drenal hyperplasia due to eFcess +1T) from pituitary tumour. 1ommoner in omen. (eak age; -356SH3yrs. #atrogenic; +1T) administration.

Ectopic acth production; Especially small cell lung cancer and carcinoid tumours. Typical features include pigmentation" eight loss" metabolic alkalosis" and hyperglycaemia. 1lassic features of 1ushing:s are often absent. Ectopic 1,I production (rare).

+1T)-independent causes; #atrogenic; (harmacological doses of steroids (common). +drenal adenoma and carcinoma (Z$34); 1arcinoma may be associated ith abdominal pain and virili'ation in omen.

1arney compleF; 1ardiac myFoma" freckles" etc." p-3%. 56h+lcohol.

The patient >ymptoms; beight5MN/ irregular menses/ amenorrhoea/ hirsutism5U6/ impotence5Um/ depression/ eakness/ fractures. >igns; Tissue asting/ myopathy/ thin skin/ purple abdominal striae/ bruising/ osteoporosis/ ater retention/ neck (buffalo hump/ supraclavicular fat pad)/ predisposition to infection/ 5MS ound healing/ hirsutism/ hypertension/ hyperglycaemia (-34). Tests >ee DCE. Iirst" confirm the diagnosis" and locali'e the source on the basis of laboratory testing (belo ). Then use imaging studies to confirm the likely source. Jote; adrenal 56Tincidentalomas56U occur on 14 or more of 1Ts" so identification of an adrenal mass does not prove adrenal source of cortisol eFcess (pituitary incidentalomas are not infre9uent either). +bdominal 1T if adrenal source is suspected/ pituitary M,# (and consider petrosal sinus sampling) if a pituitary source (1ushing:s disease) is suspected (p-$3). Treatment Depends on the cause. #atrogenic; remove source if possible. >urgery; for adrenal adenomas (usually curative) and carcinomas (rarely curative). ,adiotherapy and medical treatment follo for carcinoma.

1ushing:s disease; selective removal of pituitary adenoma via a transsphenoidal or very rarely trans-frontal approach. Dilateral adrenalectomy if the source cannot be located" or recurrence post-surgery (but this may be complicated by Jelson:s syndrome ith development of enlarging pituitary tumour and hyperpigmentation). ,adiotherapy is used in children and to prevent Jelson:s syndrome. Ectopic +1T) production may be treated by surgery if the tumour can be located and has not spread. Medical treatment may be re9uired.

Medical treatment" eg metyrapone" aminoglutethimide" or ketocona'ole to 5MS plasma cortisol. +drenolytic agents are also available. Do not eFpect osteoporosis to fully reverse after drug treatment" but it may after surgery.KdisketteLA=

(rognosis #n 1 study"KdisketteLA% the easiest variety to diagnose and treat as the adrenal adenoma/ adrenal carcinoma as typically incurable. Ectopic +1T) syndrome as amenable to ketocona'ole or complete resection of the offending tumour or bilateral adrenalectomy. &&4 of pituitarydependent 1ushing:s responded to trans-sphenoidal microadenoma resection (recurrence is a problem even after many years). (.-11 +ssessment of suspected 1ushing:s syndrome; screening tests The best screening test is the overnight deFamethasone suppression test. Give deFamethasone 1mg (C at midnight/ check serum cortisol before" and at =+M. #f level suppresses to YH3nmolB*" then it is probably not 1ushing:s. Ialse negative rate; Y$4/ false 0ve rate; 1$.H4. $&h urinary free cortisol (normal; Y$=3nmolB$&h) is an alternative. JD; Ialse positives (56Tpseudocushing:s56U) are seen in depression" obesity" alcohol eFcess" and inducers of liver en'ymes hich 5MN the rate of deFamethasone metabolism (eg phenytoin" phenobarbital" and rifampicin). Iurther tests (Ialse 0ves may occur" as above) The &=h deFamethasone suppression test; Give deFamethasone 3.HmgB8h (C for $d. Measure cortisol at 3 and &=h (do the last test 8h after the last deFamethasone dose). 1ircadian rhythm of cortisol secretion; ,e9uires hospital admission. Jormal rhythm (cortisol lo est at midnight" highest early in the morning) is lost in 1ushing:s syndrome. >tress" illness" and venepuncture may interfere ith the normal rhythm" making interpretation difficult. *ocali'ation tests ( here is the lesiona)567#f the above are positive. (lasma +1T); #f undetectable" adrenal tumour likely. 1TBM,# of adrenal glands. May need to resort to adrenal vein sampling" and adrenal scintigraphy (radiolabelled cholesterol derivative). #f detectable" distinguish pituitary causes from ectopic +1T) production ith high-dose deFamethasone suppression test or 1,) test. )igh-dose deFamethasone suppression test; Give deFamethasone $mgB8h (C for $d. Measure plasma and urinary cortisol at 3 and &=h.

1omplete or partial suppression if 1ushing:s disease.

1,) test; 133Q\g ovine corticotrophin releasing hormone #O.KdisketteL=3

Iollo cortisol for 1$3min. 1ortisol rises ith pituitary disease but not ith ectopic +1T) production.

#f both tests indicate that cortisol responds to manipulation" image the pituitary (1TBM,#). #f not" hunt for the source of ectopic +1T) production. (lasma sampling from inferior petrosal sinus May help distinguish 1ushing:s disease from ectopic +1T) production and in laterali'ing a pituitary adenoma" if the above tests are discrepant. +ddison:s disease (adrenal insufficiency) (rimary adrenocortical insufficiency is rare (incidence Z3.=B133"333). #ts signs are capricious/ as diagnosis may only be made at necropsy" it is called the unforgiving master of non-specificity and disguise.KdisketteL=1 nou may diagnose a viral infection or anoreFia nervosa in errorKdisketteL=$ (<0 is 5MS in the latter but 5MN in +ddison:s). Think of +ddison:s in all those ith uneFplained abdominal symptoms.KdisketteL=- 5VW5VW+nyone on prednisone for long enough to suppress the pituitary56Sadrenal aFis or ho has over helming sepsis" or is on anticoagulants" or has metastatic cancer may suddenly develop adrenal insufficiency ith deadly hypovolaemic shock" hyperkalemia" hyponatraemia" and hypoglycemia.KdisketteL=& 5VW5VW>ee p=$$. 1auses =34 autoimmune in P< (5MN adrenal antibodies1 Q^ associated Graves:" )ashimoto:s" DM" pernicious anaemia" hypoparathyroidism" vitiligo" coeliac disease).KdisketteL=H Cthers; TD/ metastases (+ddison:s only if 2%34 of adrenal tissue lost)/ lymphoma/KdisketteL=8 )#O (1MO" Mycobacterium avium" etc." pH=1)/ adrenal bleeding (baterhouse56SIriederichsen" 5VW5VWpA-=/ >*E/ antiphospholipid syndrome).KdisketteL=A >ymptoms +noreFia beakness

56TOiral illness56U Iatigue beight5MS Di''iness Iainting +bdominal pain D.O (or nausea) 1onstipation 1old intoleranceKdisketteL=% Myalgia

+rthralgia 1ramps )eadaches Depression (sychosisKdisketteL== >elf-esteem5MS $ 1onfusion

>igns )yperpigmentation (palmar creases" buccal mucosa)/ vitiligo/ postural hypotension. 5VW5VW>igns of critical deterioration (p=$$); (ulse5MN/ TQo5MN/ shock/ coma. Tests General; <05MN/ Ja05MS/ glucose5MS/ uraemia/ mild acidosis/ 1a$05MN/ eosinophilia/ neutropenia/ lymphocytosis/ )b5MS/ *IT5MN. E1G; (, and lT interval5MN.KdisketteL%3 >pecific; >hort +1T) stimulation test (>ynacthenQR test); Do plasma cortisol before and Q`h after tetracosactide (c>ynacthenQR) $H3Q\g #M. EFclude +ddison:s if initial cortisol 21&3nmolB*" and $nd cortisol 2H33nmolB*. >teroid drugs may interfere ith this assay; check ith local lab. +1T); #n +ddison:s disease +1T) 2-33ngB* (inappropriately high). *o in secondary causes. (lasma renin activity and aldosterone; To assess mineralocortocoid status. $1-)ydroFylase adrenal autoantibodies; #n +(>-$1 these may be positive.KdisketteL%1 +E, (plain abdominal films)B1E,; +ny signs of past TD" eg calcificationa )ave a lo threshold for further TD tests (especially if autoantibodies -ve)" eg adrenal 1T. Treatment ,eplace steroids; hydrocortisone $3mg in morning" 13mg at bedtime (C. Mineralocorticoid replacement may be needed if postural hypotension" Ja05MS" <05MN" or plasma renin5MN. #f necessary give fludrocortisone (C H3Q\g every $nd day to 3.1Hmg daily. +d!ust on clinical grounds. #f there is poor clinical response to treatment" suspect an associated autoimmune disease as above (check thyroid/ do 1oeliac serology" etc.)KdisketteL%$ barn against abruptly stopping steroids. (atients should have syringes at home (0 in-date #M hydrocortisone in case vomiting prevents oral intake). Emphasi'e that prescribing doctorsBdentists must kno of steroid use (give steroid card/ advise earing a bracelet declaring steroid use). Double steroids in febrile illness" in!ury" or severe stress. Ior dentistry" double morning hydrocortisone. #f vomiting" replace hydrocortisone ith hydrocortisone sodium succinate 133mg #M" and get medical help/ #O fluids if dehydrated. Iollo -up nearly (include D( and P.E)/ atch for other autoimmune disease.

(rognosis Good" if associated diseases (TD/ autoimmunity) do not intrude. Cther causes of primary hypoadrenalism *ate-onset congenital adrenal hyperplasia; Due to $1-hydroFylase deficiency" causing 5MN urinary androgens. Iootnotes 1 +utoimmune polyendocrine syndromes (+(>)567+(>-1; 1andidiasis 0 hypoparathyroidism 0 +ddison:s Q^ amenorrhoea. 1ause; mutations of +#,E (+uto#mmune,Egulator) gene on chromosome $1. +(>-$; +ddison:s disease 0 autoimmune thyroid diseases Q^ type 1 DM. )*+ D,-BD,&-associated. +(>--; +utoimmune thyroid disease 0 autoimmune diseases (eFcluding +ddison:s . hypoparathyroidism). $ Dehydroepiandrosterone (D)E+) and D)E+ sulfate are adrenal steroid precursors and centrally acting neurosteroids. Glucocorticoid and mineralocorticoid replacement do not correct its lack. bhen D)E+ is given" features such as self-esteem improve. )yperaldosteronism (rimary hyperaldosteronism is eFcess production of aldosterone" independent of the renin-angiotensin system. 1onsider this hen the follo ing features are present; hypertension" hypokalaemia" alkalosis in someone not on diuretics. >odium tends to be mildly raised or normal. 1auses; 2H34 due to unilateral adrenocortical adenoma (1onn:s syndrome). +lso; bilateral adrenocortical hyperplasia/ adrenal carcinoma (rare)/ glucocorticoid-remediable aldosteronism (G,+). #n G,+" the +1T) regulatory element of the 11]_-hydroFylase gene fuses to the aldosterone synthase gene" increasing aldosterone production" and bringing it under the control of +1T). Tests; (see DCE)P.E ( hen not on diuretics" hypotensives" steroids" <0" or laFatives for & ks); do not rely on a lo <0 (2$34 are normokalaemic). 5MN +ldosterone and 5MS renin567normal or high renin eFcludes the diagnosis. The differential diagnosis relies on assessing the effect of posture on renin" aldosterone" and cortisol (measure at %+M lying" and at noon standing). #f 5MS cortisol and 5MS aldosterone on standing; +1T)-dependent" ie5671onn:s or G,+. #f 5MS cortisol and 5MN aldosterone; angiotensin ##-dependent567ie hyperplasia. Do abdo 1TBM,# for primary hyperaldosteronism to locali'e tumour. >eek eFpert assistance. Ior G,+ (suspect particularly if family history of early hypertension)" genetic testing is available. JD; ,enal artery stenosis is a more common cause of refractory 5MN D( and 5MS <0. evaluate ith renal Dopplers" captopril renogram" or angiography (the gold standard). Treatment; 1onn:s;>urgery (eg laparoscopic)/ spironolactone up to -33mg per $&h (C for & ks pre-op. )yperplasia; >pironolactone or amiloride. #f G,+ is suspected; deFamethasone 1mgB$&h (C for & ks" normali'es biochemistry but not al ays D(. #f D( still5MN" give spironolactone/ stop deFamethasone. >econdary hyperaldosteronism Due to a high renin (eg from renal artery stenosis" accelerated hypertension" diuretics" 11I" hepatic failure). Dartter:s syndrome This is a ma!or cause of congenital (recessive) salt asting567via a 1l- leak in the loop of )enle. (resents in childhood ith failure to thrive" polyuria" and polydipsia. D( is normal and there is

no oedema. *ook for hypokalaemia" hypochloraemic metabolic alkalosis" and 5MN urinary <0 and 1l-. (lasma renin5MN. Treatments; <0 replacement" J>+#Ds" amiloride" captopril. (haeochromocytoma This is a rare catecholamine-producing tumour" and a dangerous but treatable cause of hypertension (in Y14). %34 are in the adrenal medulla567unilateral (%34). #nheritance is sometimes as an autosomal dominant. +ssociations >poradic in =&4/ others have MEJ$a (p-3%)" neurofibromatosis" von )ippel56S*indau syndrome" or 1arney compleF (p-3%).KdisketteL%Malignancy &84 have either malignant disease or tumours ith some malignant features. Tumours outside the medulla may be in paraganglia (c phaeochrome bodies" ie collections of adrenaline-secreting chromaffin cells)567typically by the aortic bifurcation (called the organ of puckerkandl). The patient Episodic hypertension" anFiety" chest tightness" etc.567see DCE. Tests Glycosuria during attacks in -34. >creening; $&h urine collection for &-C)--methoFymandelate ()MM+" OM+) or total (or free) metadrenalines. Iull investigation; consult specialist centre; consider meta-iodoben'ylguanidine (M#DG) scan or clonidine suppression test" and abdominal 1TBM,#. Treatment >urgery/ careful D( control for $ ks pre-op; ]^-blocker (phenoFyben'amine before cardioselective ]_-blocker). 5VW1onsult anaesthetist. (ost-op; $&h urine as above/ monitor D( (risk of D(5MS 5MS). 5VW5VWEmergency Kprescription takeL; p=$$. Iollo -up *ifelong" as post-op recurrence may take decades to emerge.KdisketteL%& )ypertension; a common conteFt for hyperaldosteronism tests Think of 1onn:s in these conteFts; hypertension associated ith hypokalaemia Y-.HmmolB* refractory hypertension; severe hypertension occurring before &3yrs of age" especially in omen. The aldosteroneBrenin ratio (+,,) may be a good screening test here.1 #f ratio 5?@=33 (aldosterone pmolB*); (lasma renin activity (pmolBmlBhr) or aldosterone 21333 further investigation is re9uired ie 1TBM,# adrenals. 1T only has a specificity of H=4 and a positive predictive value of A$4. +denoma and hyperplasia must then be distinguished" using either J(H% scintigraphy or adrenal venous sampling. +drenal scintigraphy ith 1-1#-labelled 8-]_-iodomethylnorcholesterol (J(-H%) is a demanding and compleF procedure" but it can provide crucial information about adrenal functional status" and guide appropriate management of those ith biochemically proven disease567but it does not completely obviate the need for adrenal vein sampling.KdisketteL%H The clinical features of phaeochromocytoma (haeochromocytomas are rare and present ith vague episodic features" eg; 1hest tightness 56T>pots before the eyes56U

(ins and needles )emianopia

(ulsatile scotomas >kin mottling beight loss Dyspnoea (urpura > eating +bdominal pain Tremor 1old feet Oomiting Iaints (postural D( drop) (alpitations (allor 1laudication Ilushing

>ymptoms are precipitated by stretching" snee'ing" stress" seF" smoking" surgery" or parturition567or by agents such as cheese" alcohol" or the tricyclic you so kindly prescribed" thinking that the patient:s bi'arre symptoms ere only eFplicable by psychopathology" such as depression. These crises may last minutes to days. >uddenly patients feel 56Tas if about to die56U567and then get better" or go on to stroke or cardiovascular collapse. Cn eFamination" there may be no signs" or hypertension (Q^ signs of cardiomyopathy or heart failure)" thyroid s elling (episodic)" glycosuria during attacks" or terminal haematuria from a bladder phaeochromocytoma. )irsutism" virilism" gynaecomastia" impotence )irsutism is common (134 of omen) and usually benign. #t implies increased hair gro th in omen" in the male pattern. #f menstruation is normal" there is almost certainly no increased testosterone production. #f menstruation is abnormal" the cause is usually polycystic ovary syndrome (>tein56S*eventhal syndrome); bilateral polycystic ovaries/ secondary oligomenorrhoea/ infertility/ obesity/ hirsutism. The cause is androgen hyper secretion. Tests; Pltrasound/ 5MN plasma *); I>) ratio" and less consistently" 5MN testosterone and 5MN oestradiol (see C)1> p1for management). Metformin can restore regular cycles and fertility in some patients. +nother cause of hirsutism ith irregular menses is late-onset congenital adrenal hyperplasia567deficiency of the $1-hydroFylase en'yme in the adrenal gland. >ee C)1> p$$$. Cvarian tumours are a rare cause" C)1> p&$.

Management; 5VWDe supportive. EFplain that she is not turning into a man. Depilation ith aF or creams" or electrolysis ( hich is eFpensive" and time-consuming" but does ork). 1; 13 hydrogen peroFide to bleach the area.

>have regularly. Cestrogens help by increasing serum seF hormone-binding globulin567but al ays combine ith a progesterone (c 56Tthe (ill56U) to prevent eFcess risk of uterine neoplasia or cyproterone acetate (an anti-androgen and progestogen)" eg up to 133mg on days 156S11" ith oestrogen on days 156S$1. 1yproterone is also present in the oral contraceptive DianetteQR. 1lomifene (cclomiphene) for infertility (a fertility eFpert should prescribe).

Oirilism is rare. #t is characteri'ed 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). #t is due to an increase in the oestrogenB androgen ratio. #t is seen in syndromes of androgen deficiency (eg <line-felter:s" <allman:s). #t may result from liver disease or testicular tumours (oestrogens5MN)" or accompany hyperthyroidism. The chief causes are drugs; oestrogens/ spironolactone/ cimetidine/ digoFin/ testosterone/ mari!uana. Erectile dysfunction (ED" impotence567ie inability of an adult male to sustain ade9uate erection for penetration.) #t is common in old age. (sychological 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 56Tincidental56U erections occur (these persist at the onset of organic disease). (sychological causes may eFacerbate organic causes. The ma!or organic causes are smoking" alcohol" and diabetes. Cther organic causes are as follo s. Drug causes; +ntihypertensives (including diuretics and ]_-blockers)" ma!or tran9uilli'ers" alcohol" oestrogens" antidepressants" cimetidine. Crganic causes; )yperthyroidism" hypogonadism" M>" autonomic neuropathy" atheroma" bladder-neck surgery" prolactin5MN" cirrhosis" cancer. Tests; P.E/ *IT/ glucose/ TIT/ *)/ I>)/ cholesterol/ testosterone (eg if libido5MS). Jocturnal tumescence studies are not usually needed. Doppler may sho 5MS blood flo " but is rarely needed as vascular reconstruction is difficult. Treatment; Treat causes. 1ounselling

>pecific interventions.

Oacuum aids" implants and intracavernosal in!ections have largely been supplanted by oral phosphodiesterase ((DEH) inhibitors acting by 5MN cyclic guanosine monophosphate (GM(). Erection is not automatic (depends on erotic stimuli). 56h>ildenafil (OiagraQR) $H56S133mg Q`56S1h pre-seF.KdisketteL%8 >E; headache (184)/ flushing (134)/ dyspepsia (A4)/ nasal congestion (&4)/ transient blueBgreen tingeing of vision via inhibition of retinal (DE8. KdisketteL%A 1#; >ee DCE. 56hTadalafil (1ialisQR/ has long tQ`) 1356S$3mg -3min to 1$h preseF. Don:t use 2 once daily and not every day. >E; headache" dyspepsia" myalgia/ ano visual >Es. 56hOardenafil.KdisketteL%= (.-1A 1ontraindications to sildenafilBOiagraQR and other oral ED agents 1oncurrent use of nitrates D(5MN 5MN or Y%3BH3mm)g/ arrhythmias Myocardial infarction Y%3d ago Degenerative retinal disorders" eg retinitis pigmentosa (for sildenafil) Marked renal or hepatic impairment >troke in last 8 months Dleeding disorders +ctive peptic ulceration Pnstable angina Cther cautions +ngina (especially angina during intercourse) (eyronie:s disease ,isk of priapism (sickle-cell anaemia" myeloma" leukaemia) 1oncurrent compleF antihypertensive regimens Dyspnoea on minimal effort (seFual activity may be unsupportable) Pse in men ith severe coronary disease has been a 9uestion" but in one careful study" no adverse cardiovascular effects ere detected in men ith severe coronary artery disease. KdisketteL%% #nteractions; Macrolides" anti-)#O drugs" theophylline" ketocona'ole" rifampicin" phenytoin" carbama'epine" phenobarbital" grapefruit !uice (5MN bioavailability). bhen does a lifestyle malcontent become a diseasea 56Tbhen should health providers pay for erectile treatmenta56U #n the P<" the J)> ill pay ( rite 56T>*>56UBselected list substances on the prescription) if ED is causing severe distress"1 or there has been; (rostatectomy (rostate cancer

Dialysis or a renal transplant >pinal cord or pelvic in!ury ,adical pelvic surgery 1

Diabetes mellitus Multiple sclerosis (arkinson:s disease >pina bifida >ingle gene neurological disease (oliomyelitis and its after-effects

#t is easy to taunt politicians ho produce these rather arbitrary-looking criteria by recourse to clever counter-eFamples" but they really need our support because they are making rationing ( hich is an inescapable fact of clinical life) overt" open" available to scrutiny" and rational modification. +ll too often rationing is covert" and no source takes responsibility for it. Iootnotes 1 1riteria include marked disruption to relationships or mood" as !udged by any prescriber ith purchaser-certified special skill in this area" usually a G( specialist or staff at clinics for ED. $ >uccess for reversing ED post-op is only &-4 vs =H4 in those ith neurological conditions. +ddisonian crisis; assessment +drenocortical insufficiency may be sub-clinical for days or months in other ise ell individuals. >tress" such as infection" trauma" or surgery" may precipitate an +ddisonian crisis ith cardiovascular collapse and death if the condition is not suspected. 1rises may also occur in patients ith kno n +ddison:s disease on replacement hydrocortisone if they fail to increase their steroid dose ith infections. (resentation )ypotension and cardiovascular collapse (shock) Iaintness" particularly on standing (postural hypotension)

+noreFia" nausea" vomiting" and abdominal pain )yponatraemia Dehydration (thirst may not be apparent because of the lo sodium) Diarrhoea in $34 of cases >ymptoms of precipitant Kfever" night s eats (infection)/ flank pain (haemorrhagic adrenal infarction)/ etcL. Jote signsBsymptoms of other endocrinopathies. Jon-specific symptoms; eight loss" fatigue" eakness" myalgia. )yperpigmentation suggests chronic hypoadrenalism. (sychiatric features are common and include asthenia" depression" apathy" and confusion (treatment ith glucocorticoids reverses most psychiatric features).

Malignant secondaries

(resent in the adrenals of a high percentage of patients ith lung cancer" breast tumours" and malignant melanomas. +drenal failure ill only occur hen over %34 of the gland is replaced by metastases. +drenal haemorrhage This may complicate sepsis (meningococcal septicaemia" the baterhouse56SIriderichsen syndrome)" traumatic shock" coagulopathies" and ischaemic disorders. >evere stress substantially increases the arterial blood supply to the adrenals. )o ever the adrenal gland has only one or t o veins" making it vulnerable to venous thrombosis. Dlood tests; a precipitous drop in haemoglobin" hyponatraemia" hyperkalaemia" acidosis" uraemia" and neutrophilia.

The baterhouse56SIriderichsen syndrome is the association of bilateral adrenal haemorrhage ith fulminant meningococcaemia. +drenal haemorrhage is also seen ith other gram-negative endotoFaemias such as Diplococcus pneumoniae" )aemophilus influen'ae D and DI-$ bacillus infections.

)ypopituitarism +s there is no mineralocorticoid deficiency" the salt and ater loss and shock are less profound than in primary +ddison:s disease. Drugs ,ifampicin" phenytoin" and phenobarbitone accelerate the metabolism of cortisol and may precipitate +ddisonian crisis in partially compromised individuals" or in those on a fiFed replacement dose. Most adrenal crises precipitated by rifampicin occur ithin $ eeks of initiating therapy. ,ecogni'ed causes of adrenal failure +utoimmune adrenalitis (A34) Tuberculosis of the adrenals (1356S$34)

Malignant secondaries in the adrenal glands +drenal haemorrhage incl. meningococcal septicaemia Diseminated fungal infection (histoplasmosis" paracoccidioidomycosis) )ypopituitarism Drugs; metyrapone or aminoglutethimide can precipitate adrenal failure. Cther drugs (see belo ) may cause relative adrenal insufficiency 1ongenital conditions
o o o

+drenoleukodystrophy 1ongenital adrenal hyperplasia Iamilial glucorticoid deficiency

1auses of relative adrenal insufficiency Drugs

o o o o o o o

Metyrapone or aminoglutethimide <etocona'ole Etomidate ,ifampicin" phenytoin" and phenobarbitone Trilostane Megestrol acetate >uramin

)#O >evere sepsis Durns +cute or chronic liver failure

(ractice points ZH34 of patients ith autoimmune adrenalitis have one or more other autoimmune disorders such as polyglandular autoimmune syndrome type 1 or $. Jever forget +ddison:s disease in a sick patient hen the diagnosis is unclear. +ddisonian crisis; management #nvestigations 56h P.Es 56h ID1 )yponatraemia and hyperkalaemia (rarely greater than 8.3mM). )igh ur;cr ratio indicative of hypovolaemia +naemia (normal M1O)/ moderate neutropenia Q^ relative eosinophiliaBlymphocytosis )ypoglycaemia (rarely severe) May be high >ave for routine assay. Daseline Y&33nmolB*. >hould be 21333nmolB* in 56Tsick56U patients Metabolic acidosis" respiratory failure M1.> for infection/ urinary Ja eFcretion often high in spite of hypovolaemia (revious TD" bronchial carcinoma +drenal calcification

56h Glucose 56h 1alcium 56h >erum cortisol 56h +DG 56h Prine 56h 1E, 56h +E, Management Treatment may be re9uired before the diagnosis is confirmed. General measures include oFygen" continuous E1G monitoring" 1O( monitoring" urinary catheter (for fluid balance)" and broad spectrum antibiotics (e.g. cefotaFime) for underlying infection.

Treat shock (($83); give iv J saline or colloid ()aemaccelQR) for hypotension; 1* stat then hourly depending on response and clinical signs. #notropic support may be necessary. Give iv H34 deFtrose (H3ml) if hypoglycaemic. #f adrenal crisis is suspected" the patient needs glucocorticoids urgently; use deFamethasone =mg iv hich ill not interfere ith the cortisol assay of a short >ynacthenQR test. #f deFamethasone is unavailable use hydrocortisone (can be stopped later). This single eFtra dose can do little harm and may be life saving. >hort >ynacthenQR test (omit if the patient is kno n to have +ddison:s disease); take baseline blood sample (serum) and administer tetracosactrin (>ynacthenQR) $H3Q\g im or iv. Take further samples at -3 and 83 minutes for cortisol assay. 1ontinue steroid treatment as iv hydrocortisone ($33mg stat)" then 133mg tds. 1hange to oral steroids after A$ hours. Iludrocortisone (133Q\g daily orally) hen stabili'ed on oral replacement doses of hydrocortisone.

(revention (atients on long-term steroid therapy andBor kno n adrenocortical failure should be instructed to increase steroid intake for predictable stresses (e.g. elective surgery" acute illnesses ith fever 2-=Qo). Ior mild illnesses" if not vomiting" double the oral dose. Oomiting re9uires ivBim therapy (hydrocortisone H3mg tds).

Ior minor operations or procedures (e.g. cystoscopy) give hydrocortisone 133mg ivBim as a single dose before the procedure. More serious illnesses re9uire hydrocortisone 133mg 9856S=h ivBim until recovered or for at least A$ hours. Double replacement doses hen stabili'ed if on en'yme-inducing drugs.

Drug E ui!alent dose (mg) DeFamethasone 3.AH Methylprednisolone& Triamcinolone & (rednisolone H )ydrocortisone $3 1ortisone acetate $H MyFoedema coma + common precipitant of coma is the use of sedatives" and subse9uent hypothermia" in elderly female patients ith undiagnosed hypothyroidism.

(resentation +ltered mental status; disorientation" lethargy" frank psychosis 1oma (symmetrical" slo -relaFing refleFes/ Z$H4 have sei'ures)

)ypothermia Dradycardia" hypotension (rare) )ypoventilation )ypoglycaemia.

#nvestigations 56h P.Es )yponatraemia is common (H34) 56h Glucose )ypoglycaemia may occur 56h ID1 Jormocytic or macrocytic (Q^ coeFistent pernicious anaemia) anaemia 56h ,aised 1(< Cften ith a clinical myopathy 56h Thyroid functionT& and T>) 56h 1ortisol To eFclude co-eFistent +ddison:s disease" i.e. >chmidt:s syndrome 56h +DG )ypoventilation ith 5MNPa1C$" 5MSPaC$ and acidosis 56h >eptic screen Dlood and urine cultures 56h E1G >mall compleFes ith prolonged lT interval 56h 1E, (ericardial effusion may occur. (oor prognostic indicators )ypotension. (atients ith hypothyroidism are usually hypertensive. 5MSD( indicates possible adrenal failure or cardiac disease. ,esponse to inotropes is poor as patients are usually maFimally vasoconstricted. )ypoventilation. This is the commonest cause of death in patients ith myFoedema coma. The hypoFia responds poorly to oFygen therapy hich tends to eFacerbate hypercapnoea. Management Transfer the patient to an intensive care unit. Mortality is up to -34. Mechanical ventilation should be instituted for respiratory failure.

1O( line. (atients are usually hypertensive and hypovolaemic as chronic myFoedema is compensated for by rising catecholamines. Droad-spectrum antimicrobials (e.g. cefotaFime). Dacterial infection is a common precipitant of myFoedema coma. )ypothermia should be treated as on (=&&; a space blanket is usually sufficient. ,apid eFternal arming can cause inappropriate vasodilatation and cardiovascular collapse. )ydrocortisone (133mg iv tds) until +ddison:s is eFcluded. #nstitute replacement therapy before confirming the diagnosis.

#deally give H56S$3Q\g iv (slo bolus) tri-iodothyronine (T-) t ice daily for - days. +fter a fe days treatment" commence oral thyroFine at $H56SH3Q\gBday or oral triodothyronine at $3Q\g bd. >ome clinicians start thyroFine at a much higher dose" but this does carry a risk or precipitating cardiac ischaemia. T- is preferable due to its short half-life and its effect disappears $&56S&= hours after it isstopped. #f T- is unavailable use thyroFine" $H56SH3Q\g po or via JG-tube daily. MyFoedema coma has a high mortality if inade9uately treated.

(recipitants of myFoedema coma Drugs" including sedatives and tran9uilli'ers #nfection

1erebrovascular accident Trauma

Phaeochromocytomas" assessment

(haeochromocytomas are catecholamine-producing tumours usually involving one or more adrenal glands. Z34 are bilateral" Z134 are eFtra-adrenal Kusually around the sympathetic chain (paragangliomas)L and Z134 are malignant. They usually secrete +D or J+. + small proportion secrete D+" hen hypotension may occur. Most are diagnosed during routine screening of hypertensive patients (they are found in only 3.14 of hypertensives). (ure +D-producing tumours may mimic septic shock due to +D-induced peripheral vasodilatation (]_$-receptors).

(resentation 1lassically a triad of episodic headaches" s eating" and tachycardia )ypertension (mild to severe sustained Q^ uncontrolled paroFysmal" hypertensive episodes) and orthostatic hypotension (lo plasma volume). H34 have sustained 5MND( and H34 have paroFysmal 5MND(

+nFiety attacks" tremor" palpitations" cold eFtremities" and pallor 1ardiac dysrhythmias (incl. +I and OI) and dilated cardiomyopathy )ypertensive crises may be precipitated by ]_-blockers" tricyclic anti-depressants" metoclopramide" and naloFone PneFplained lactic acidosis Triggers for hypertensive crises include surgery" opiates and contrast media.

#nvestigations

There are no tests hich ill diagnose a phaeochromocytoma acutely. #nvestigations are listed in the table opposite. )ypertensive patients ith 5MNglc and 5MS<0 may have a phaeochromocytoma" but these are both non-specific features. Prinary OM+ level (a catecholamine metabolite) is useful if markedly elevated (H56S13ij upper limit of normal). Mild elevations are fre9uent (1H4) in patients ith essential hypertension" as OM+ can be derived from dietary sources" including vanilla essence giving a false 0ve test result. Prinary catecholamines (+D" J+" and D+) or metanephrines are more specific. Prine collections must be completed before pentolinium or clonidine tests as ithdra al of these compounds can give a false 0ve result.

(lasma catecholamines should be collected from an in-d elling cannula placed over -3 minutes previously in a supine patient. >amples need to be taken directly to the lab (on ice) for centrifugation. (entolinium suppression test. Take t o baseline samples as above" then give $.Hmg pentolinium iv" and take blood again at 13 and -3 minutes. (lasma catecholamines decrease in normal sub!ects follo ing ganglion blockade ith pentolinium. #f the response is borderline and no hypotension occurs" then repeat ith Hmg pentolinium. 1lonidine suppression test. +n alternative to the pentolinium suppression test employs clonidine. Iollo ing t o baseline samples" give 3.-mg clonidine orally" and take blood hourly for - hours. +gain if raised catecholamines are due to anFiety" they ill suppress into the normal range ith clonidine. ,aised catecholamines from phaeochromocytoma ill not be affected by clonidine. M,# or 1T of the abdomen are useful to locali'e the tumour. ,adiocontrast can lead to catecholamine release. M#DG scan. M#DG (1-1#-metaiodoben'ylguanidine) is taken up selectively by adrenal tissue. Pseful to locali'e tumour or secondaries. >elective venous sampling; to locali'e eFtra-adrenal tumours.

#nvestigations for suspected phaeochromocytoma P.Es (5MS<0" 5MNurea) Glucose (5MN)

Prinary OM+ Prinary catecholamines (+D" J+" and D+)" metanephrines (lasma catecholamines (+D" J+" and D+) (entolinium suppression test 1lonidine suppression test

M,# or 1T scan of adrenals M#DG scan for locali'ation

Cther causes of sympathetic overactivity +brupt ithdra al of clonidine or ]_-blockers +utonomic dysfunction e.g. Guillain56SDarriq syndrome or post spinal cord in!ury

>tress response to surgery" pain" or panic >ympathomimetic drugs

o o o

(henylpropanolamine (decongestant) 1ocaine M+C# plus tyramine-containing foods (cheese" beer" ine" avocado" bananas" smoked or aged fishBmeat)

(haeochromocytomas; management (atients are usually volume depleted at presentation" and should be rehydrated prior to initiation of ]^-blockade" other ise severe hypotension may occur. ]_-blockade alone may precipitate a hypertensive crisis" and must never be given prior to ade9uate ]^-blockade. *abetalol is predominantly a ]_-blocker and should not be used alone. *ong acting ]^-blockers prevent escape episodes. +de9uate fluid replacement ith 1O( monitoring. +cute hypertensive crises should be controlled ith phentolamine ($56SHmg iv bolus" repeated as necessary every 1H56S-3 minutes). +lternatively start an infusion of nitroprusside (3.H56S1.HQ\gBkgBmin" typical dose 133Q\gBmin" see (18&).

(reparation for surgery

o

#nitiate oral ]^-blockade; phenoFyben'amine 13mg daily increasing gradually to &3mg tds. Monitor D( closely. Tumour ]_-stimulation may produce eFcessive vasodilatation and hypotension re9uiring inotropic support. ,ecent studies have sho n that pra'osin or doFa'osin are e9ually effective and are being used increasingly bhen the blood pressure is controlled ith phenoFyben'amine" add propranolol 1356S$3mg tds #nvasive monitoring Kpulmonary artery (> an56SGan') catheter and arterial lineL is mandatory.

)ypotension commonly occurs intra-operatively hen the tumour is removed" and this should be managed ith blood" plasma eFpanders" and inotropes as re9uired. #notropes should only be used hen the patient is appropriately fluid replete. EFpansion of intravascular volume 1$ hours before surgery significantly reduces the fre9uency and

severity of post-operative hypotension. +ngiotensin ## should be available as an alternative inotrope for cases of resistant hypotension. +utosomal dominant conditions ith a high risk of developing phaeochromocytoma include Oon-,ecklinghausen disease Kneurofibromata" cafiq au lait spots" *isch nodules (iris hamartomas)" and aFillary frecklingL. Oon-)ippel *indau disease (cerebellar haemangioblastomas" retinal haemangiomas" and other neoplasms including hypernephroma).

Multiple endocrine neoplasia types $a (hyperparathyroidism and medullary thyroid carcinoma) and $b (medullary thyroid carcinoma" bo el ganglioneuromatosis" and hypertrophied corneal nerves).

#hyroto$ic crisis" assessment The term thyrotoFic crisis refers to a constellation of symptoms and signs hich together imply a poor prognosis. Thyroid function tests provide no discrimination bet een simple thyrotoFicosis and thyrotoFic crisis. #f the diagnosis has not been made" look for clues such as a goitre" or eFophthalmic Graves: disease. The presentation may be confused ith sepsis or malignant hyperthermia. (resentation 1ardiovascular symptoms (alpitations TachycardiaBtachyarrhythmias

1ardiac failureBoedema

1J> >ymptoms +nFietyBagitation Oiolent outbursts

(sychosisBdelirium IittingBcoma

Gastrointestinal symptoms Diarrhoea Oomiting

eaundice

General symptoms Iever )yperventilation

> eating (olyuria

(recipitants of thyrotoFic crisis Thyroid surgeryBgeneral surgery bithdra al of anti-thyroid drug therapyBradioiodine therapy

Thyroid palpation #odinated contrast dyes #nfection 1erebrovascular accidentBpulmonary embolism (arturition Diabetic ketoacidosis Trauma or emotional stress.

#nvestigations Thyroid function tests (most labs can perform an urgent T>)Bfree T& if needed) P.Es (adehydration)

1alcium (may be elevated) Glucose (may be lo ) ID1 *iver function tests (a!aundice) Dlood and urine cultures 1E, (apulmonary oedema or evidence of infection) E1G (rate" aatrial fibrillation).

+ssessment of severity The table opposite is used to assess the severity of a thyrotoFic crisis. ,arely" patients may present ith an apathetic thyroid storm" and lapse into coma ith fe other signs of thyrotoFicosis. (.H%1 Assessment of se!erity of a thyroto$ic crisis #emp (%&') (corePulse'ardiac failure ')( effects *I symptoms +pyreFial Y%% +bsent Jormal Jormal 3 2-A.$ 2%% +nkle oedema 567 567 H 2-A.= 2113 Dasal creps. +gitation Diarrhoea" vomiting 1 3

2-=.2-=.% 2-%.& 2&3

21$3 (ulmonary oedema567 21-3 21&3

1 H Delirium PneFplained !aundice$ 3 567 567 $ H 1oma" sei'ure567 3

567

+dd the scores for each column. +dd an eFtra 13 points if atrial fibrillation is present. +dd 13 points if there is a definable precipitant. + total score of over &H indicates thyroid crisis/ a score of $H56S&& indicates impending crisis.

ThyrotoFic crisis; management (atients ith a thyrotoFic crisis or impending crisis (score 2$H" (H%1) +dmit the patient to intensive care. Iluid balance; 1O( monitoring is essential to avoid precipitating or orsening cardiac failure. #n patients ith arrhythmias" the 1O( ill not accurately reflect left-sided pressures and > an56SGan' monitoring should be considered. Gastrointestinal and insensible (pyreFia and eFcessive s eating) fluid losses may eFceed H*Bday and must be replaced.

Iever should be treated ith paracetamol and aggressive peripheral cooling techni9ues. Dantrolene has been occasionally used to control hyperthermia in thyrotoFic crisis. Do not use salicylates hich ill displace T& from TDG and can hence orsen the storm. ]_-block the patient ith propranolol 8356S=3mg 9&h po or 1mg iv (repeated every 13min as necessary) ith cardiac monitoring. (ropranolol inhibits peripheral T& 5Md Tconversion. Iever" tachycardia" and tremor should respond immediately. +n alternative is Esmolol (1H56S-3mg as a bolus follo ed by -56S8mgBmin). #f ]_-blockade is contra-indicated (e.g. asthma)" guanethidine (-356S&3mg po 8 hourly) can be used.

Treat precipitating factors such as infection (e.g. cefuroFime AH3mg iv tds). )igh-dose anti-thyroid drugs. (ropylthiouracil (1g loading dose then $3356S-33mg 9&h poBng) is more effective than carbima'ole ($3mg & hourly)" at it inhibits peripheral T& 5Md T- conversion. )ydrocortisone -33mg iv stat" then 133mg 8 hourly. This inhibits conversion of T& to T-. EnoFaparin (cleFane) $3mgBday sc should be given to very sick patients at risk of thromboembolism.

Cnce organification of iodine has been blocked by anti-thyroid drugs" iodine can be used to inhibit thyroFine release from thyroid gland. *ugol:s iodine contains H4 iodine and 134 potassium iodide in ater. Give 1ml every 8 hours. Do not give *ugol:s iodine until at least 1 hour after the anti-thyroid drugs have been given. +ny iodine given prior to anti-thyroid medication may increase thyroid hormone stores. 1ontinue iodine-containing preparations for a maFimum of $ eeks (lithium is an alternative to iodine in allergic patients). Monitor glucose levels & hourly and administer glucose H56S134 as re9uired. )epatic glycogen stores are readily depleted during thyroid storm.

1ontinuing treatment ,esponse to treatment is gauged clinically and by serum T- levels. >top iodineBpotassium iodideBlithium and ]_-blockers hen controlled.

1onsider definitive treatment (e.g. surgery or radioactive iodine). Treat atrial fibrillation in the usual ay ((==). )igher doses of digoFin may be re9uired as its metabolism is increased. +miodarone inhibits peripheral T& 5Md T- conversion.

#hyroid function tests (#+#s) Thyroid hormone abnormalities are usually due to a problem ith the thyroid gland itself. (rimary abnormalities of T>) and thyrotrophin-releasing hormone (T,)) are very rare. (hysiology The hypothalamus secretes T,)" a tripeptide" hich stimulates production of T>)" a glycoprotein" from the anterior pituitary. T>) 5MN production and release of thyroFine (T&) and triiodothyronine (T-) from the thyroid" hich eFert -ve feedback on T>) production. The thyroid produces mainly T&" hich is H-fold less active than T-. =H4 of T- is formed from peripheral conversion of T&. Most T- and T& in plasma is protein bound" mainly to thyroFinebinding globulin (TDG). The unbound portion is the active part. T- and T& 5MN cell metabolism" via nuclear receptors" and are thus vital for gro th and mental development. They also enhance catecholamine effects. Dasic tests )yperthyroidism suspected; +sk for T-" T&" and T>). + minority ill have elevation of only one thyroid hormone" but all ill have 5MS T>) (eFcept for the rare phenomenon of a T>)-secreting pituitary adenoma). )ypothyroidism suspected or monitoring replacement treatment; +sk for only T&" and T>). Measuring T- does not add any eFtra information. #nterpretation of tests #f 5MN T>) and 5MS T&; (rimary hypothyroidism is confirmed. #f 5MN T>) and normal T&; 1onfirmation of compensated or subclinical hypothyroidism ($nd DCE on p-3A). Treatment depends on clinical state.

#f 5MN T>) and 5MN T&; 1onsider concordanceBcompliance problems ith T& replacement" T>) secreting tumour" or thyroid hormone resistance. #f 5MS T>) and 5MN T& or 5MN T-; ThyrotoFicosis confirmed. #f 5MS T>) and T& and T- normal; >ubclinical thyrotoFicosis" identify cause. #f 5MS T>) and 5MS T& and 5MS T-; 1onsider pituitary disease or sick euthyroidism. #f normal T>) and T& abnormal; 1onsider hormone-binding problems" eg pregnancy/ 5MN thyroid-binding globulin/ amiodarone/ pituitary T>) tumour.

>ick euthyroidism #n any systemic illness" TITs may become deranged. The typical pattern is for 56Teverything to be lo 56U. 1onse9uently" routine testing of thyroid function in such patients should not be performed. >pecial tests Iree T& . free T- are useful hen a false lo or high T& or T- is suspected. #f unavailable" consider; free thyroFine indeF hich is an estimate of free T& derived from measuring unoccupied thyroFine-binding sites on TDG. Cccasionally" lo T>) may be due to nonthyroidal illness; if free T& 2$HpmolB*" then there probably really is thyroid disease. Cther tests of thyroid anatomyBpathology; 1onsider an isotope scan if; There is an area of thyroid enlargement. )yperthyroid but no thyroid enlargement (diffuse uptakea solitary nodulea).

#f hyperthyroid ith one nodule (solitary nodule or multinodulara). To determine eFtent of retrosternal goitre/ to find ectopic thyroid tissue. To detect thyroid metastases ( hole-body 1T). >ubacute thyroiditis; very lo uptake.

#nterpretation; The main 9uestion is; has the enlarged area increased (hot)" or decreased (cold)" or the same (neutral) uptake of pertechnetate as the remaining thyroida $34 of 56Tcold56U nodules are malignant. Ie neutral and almost no hot nodules are malignant. Pltrasound;This distinguishes cystic (usually" but not al ays" benign) from solid (possibly malignant) 56Tcold56U nodules. Thyroid autoantibodies;+ntithyroid globulin/ antithyroid microsomal. ,aised in )ashimoto:s and some cases of Graves: disease567if positive there is increased risk of hypothyroidism later. Thyroid-stimulating immunoglobulins;+gainst T>) receptor. May be raised in Graves: disease. >erum thyroglobulin; Pseful in monitoring the treatment of carcinoma" and in detection of factitious (self-medicated) hyperthyroidism.

The role of scans in monitoring thyroid malignancy #maging is most important in follo ing-up differentiated thyroid cancer (DT1) and medullary thyroid cancer (MT1). DT1 may be follo ed ith serum thyroidglobulin and 1-1# hole body scintigraphy hen serum thyroglobulin level is 5MN. bhen 1-1# scintigrams are -ve" thallium scintigraphy ($31Tl) may best identify site of recurrent DT1.KdisketteL-% +lternative radioisotopes" ultrasound" and 1T also help locali'e DT1 metastases. MT1 recurrences and metastases are more difficult to image. >elective venous catheteri'ation is the most sensitive and specific method for detecting areas of recurrent MT1. )igh-resolution ultrasound" 1T" M,#" and scintigraphy are all used.KdisketteL&3 ,yperthyroidism (thyroto$icosis) >ymptoms/ beight5MS despite increased appetite" heat intolerance" s eating" diarrhoea" tremor" irritability" frenetic activity" emotional lability" psychosis" itch" oligomenorrhoea. #nfertility may be the presenting problem. >igns;(ulse5MN" +I" arm peripheries" fine tremor" goitre Q^ nodules" palmar erythema" hair thinning" lid lag (eyelid lags behind eye:s descent as patient atches your finger descend slo ly). #f D(5MN" consider phaeochromocytoma. +dditional signs in Graves: disease; Dulging eyes (eFophthalmos" p-3H)/ thyroid bruit/ ophthalmoplegia/ vitiligo/ pretibial 56TmyFoedema56U (oedematous s ellings above lateral malleoli; the term myFoedema is confusing here)/ thyroid acropachy (an eFtreme manifestation of autoimmune thyroid disease" ith clubbing" painful finger . toe s elling" and periosteal reaction in limb bones).KdisketteL&1 Tests T>)5MS/ free T& and free T- 5MN (p-3$). Thyroid scan if subacute thyroiditis suspected or to identify solitary nodulesBdiffuse multinodular goitre/ thyroid autoantibodies. #f ophthalmopathy" test visual fields" acuity" and eye movements. 1an the lids close fullya #f not" there is risk of keratopathy (get help). 1auses Graves: disease; 1ommon bet een -3 and H3 yrs. Genetic influence. 5U6; 5Um 5?g %; 1. There are T>)-receptor antibodies (react ith orbital autoantigens.KdisketteL&$ Diffuse thyroid enlargement. *ook for associated normochromic normocytic anaemia" E>,5MN" 1a$05MN" *IT5MN 567and type 1 DM and pernicious anaemia. (atients are often hyperthyroid but may be" or become" hypo- or euthyroid. ToFic adenoma;There is a nodule producing T- and T&. Cn scanning" the nodule is 56Thot56U (p-3$)" and the rest of the gland is suppressed. ToFic multinodular goitre;This is a common cause of thyrotoFicosis in the elderly" eg in iodinedeficient areas.KdisketteL&- Treat the thyrotoFicosis" and follo ith radioiodine or surgery as

indicated. #n compressive symptoms" risk of malignancy" or cosmetic deformity develops" surgery may also be indicated.KdisketteL&& >elf-medication;This is detected by 5MN T&" 5MS T-" and 5MS thyroglobulin. >ubacute (de luervain:s) thyroiditis;>elf-limiting" painful goitre. E>,5MN. Cn scans" no radioiodine uptake. 1ause; aviral infection in the genetically predisposed.KdisketteL&H Iollicular carcinoma of thyroid;There may be hyperfunctioning metastases.KdisketteL &8 1horiocarcinoma/ struma ovarii;(Cvarian teratoma containing thyroid tissue). Drugs;+miodarone/ lithium (5MS T& is commoner)/ *i0 may also mask hyperthyroidism by causing cellular unresponsiveness (5gr danger on stopping *i0).KdisketteL&A EFogenous iodine;1ontrast media/ disinfectants/KdisketteL&= food contamination.KdisketteL&% Treatment Drugs; #mmediate symptom control; propranolol &3mgB8h (C.KdisketteLH3 Thyroid suppression ith carbima'ole eg 1H56S&3mgB$&h (C for & ks" gradually reducing according to TITs every 156S$ months. Maintain on Z1HmgB$&h for 1$56S1= months then ithdra . 2H34 relapse/ arn to get advice if rashes" sore throat" or fevers occur" as 3.3-4 on carbima'ole get agranulocytosis/ other >E; rash" headache" alopecia" pruritus" !aundice. +lternative; propylthiouracil. (artial thyroidectomy; 1arries risk of damage to recurrent laryngeal nerves and parathyroids. (atients may be hypo- or hyperthyroid after surgery.

,adioiodine (1-1#); This can be repeated until euthyroid but most patients ultimately become hypothyroid. 1aution in active Graves: disease. Jo longer contraindicted in younger omen. #n pregnancy and infancy; Get eFpert help. >ee C)1> p1HA.

1omplications )eart failure (thyrotoFic cardiomyopathy)/KdisketteLH1 angina/ atrial fibrillation (p1-3"567seen in Z$H4567manage by controlling hyperthyroidism/ arfarini'e if no contraindication" p8&=" as &34 have or get emboli). +lso; Csteoporosis/ gynaecomastia/ 5VW5VWthyroid storm" p=$3/ ophthalmopathy" see DCE.KdisketteLH$ Thyroid eye disease Thyroid eye disease is a clinical diagnosis hich may be made in the presence or absence of thyroid autoantibodies. #t occurs hen there is retro-orbital inflammation and lymphocyte infiltration resulting in s elling of the contents of the orbit. +t the time of presentation" the patient may be euthyroid" hypothyroid" or hyperthyroid.

>ymptoms Diplopia" eye discomfort" or protrusion Q^ decreased acuity. 5VWDecreasing acuity or loss of colour vision may mean optic nerve compression; >eek eFpert advice immediately as decompression may be needed. Jerve damage does not necessarily go hand-in-hand ith protrusion. #ndeed" if the eye cannot protrude for anatomical reasons" optic nerve compression is all the more likely567a paradoF[ >igns EFophthalmos567appearance of protruding eye/ proptosis567eyes protrude beyond the orbit (look from above in the same plane as the forehead)/ con!unctival oedema/ corneal ulceration/ papilloedema/ loss of colour vision. Cphthalmoplegia (especially of up ard ga'e) also occurs due to muscle s elling and fibrosis. Tests ,ose Dengal drops may stain the upper cornea" indicating superior limbic keratitis" hile 1TBM,# of the orbits ill reveal enlarged eye muscles. Management 1ontrol hyperthyroidism/ steroids if ophthalmoplegia or gross oedema. +void hypothyroidism. Get an eye surgeon:s help (eg in papilloedema" vision5MS). >topping smoking may 5MS complications.KdisketteLH- OiscotearsQR plus *acrilubeQR gel at night" for lubrication as often as needed. *ids can be stitched together at the outer corners (lateral tarsorraphy) or may be taped shut. Medical decompression may be achieved ith high-dose systemic steroids. *id retraction may be reduced by guanethidine eyedrops but these are rarely tolerated for long. >urgical decompression uses space in the ethmoidal" sphenoidal" and maFillary sinuses" via a medio-inferior approach. Crbital radiotherapy is increasingly used at an early stage" but cytotoFic drugs" and plasmapheresis (p8A3) are unreliable. Diplopia may be managed ith a Iresnel prism stuck to 1 lens of a spectacle" so allo ing for reasonably easy changing as the eFophthalmos changes.Eye disease may pre-date other signs of Graves: disease" and does not al ays respond to treatment of thyroid status. Iurthermore" it may develop for the first time follo ing treatment of hyperthyroidism. Lumps in the nec5VWDon:t biopsy lumps until tumours ithin the head and neck have been eFcluded by an EJT surgeon. 1ulture all biopsied lymph nodes for TD. Diagnosis Iirst of all ask ho long the lump has been present. #f Y- ks" self-limiting infection is the likely cause and eFtensive investigation is un ise. JeFt ask yourself here the lump is. #s it intradermala567 (eg sebaceous cyst ith a central punctum). #s it a lipoma (pH13)a #f the lump is not intradermal" and is not of recent onset" you are about to start a diagnostic hunt over complicated terrain; Midline lumps;#f patient is Y$3yrs old" the likely diagnosis is a dermoid cyst (ie se9uestrations of epidermoid tissue)" or" if it moves on protruding the tongue and is belo the hyoid" a thyroglossal cyst (fluctuant lump developing in cell rests in thyroid:s migration path/ treatment; surgery/ they are the commonest congenital cervical cystic lump).KdisketteL1$& #n patients 2$3yrs old" it is probably a thyroid mass" unless it is bony hard" hen the diagnosis may be a chondroma.

>ubmandibular triangle;(Delo !a / above anterior belly of digastric.) #f Y$3yrs" self-limiting lymphadenopathy is likely. #f 2$3" eFclude malignant lymphadenopathy (eg firm" and nontender). 5VW#s TD likelya #f it is not a node" think of submandibular salivary stone" sialadenitis" or tumour. +nterior triangle;(Delo digastric and in front of sternomastoid.) Jodes are common (see above); eFamine the areas hich they serve (skin" mouth" throat" thyroid/ is the spleen enlargeda 567this may indicate lymphoma). Dranchial cysts emerge under the anterior border of sternomastoid here the upper third meets the middle third/ age Y$3. They are due to non-disappearance of the cervical sinus ( here the $nd branchial arch gro s do n over the -rd and &th). *ined by s9uamous epithelium" their fluid contains cholesterol crystals. Treat by eFcision. 1ystic hygromas arise from the !ugular lymph sac/ transilluminate brightly. Treat by surgery or hypertonic saline sclerosant. 1arotid body tumours (chemodectoma) are very rare" move from side to side but not up and do n" and splay out the carotid bifurcation. #t is usually firm and occasionally soft and pulsatile. #t does not usually cause bruits. #t may be bilateral" familial" and malignant (H4). This tumour should be suspected in masses !ust anterior to the upper third of sternomastoid. Diagnose by digital computer angiography. Treatment; eFtirpation by vascular surgeon. #f the lump is in the superoposterior area of the anterior triangle" is it a parotid tumour (more likely if 2&3yrs)a *aryngocoeles are uncommon causes of anterior triangle lumps; they are painless" and may be made orse by blo ing. These cysts are classified as eFternal" internal" or miFed" and may be associated ith laryngeal cancer. (osterior triangle;(Dehind sternomastoid" in front of trape'ius" above clavicle.) #f there are many small lumps" think of nodes567TD" viruses such as )#O or EDO (infectious mononucleosis)" any chronic infection or" if over $3yrs" consider lymphoma or metastases eg from G# or bronchial or head and neck neoplasia. 1ervical ribs may intrude into this area. TestsPltrasound sho s lump consistency. 1T defines masses in relation to their anatomical neighbours. Do virology and MantouF test. 1E, may sho malignancy or reveal bilateral hilar lymphadenopathy/ here you should consider sarcoid. 1onsider fine-needle aspiration (IJ+). >alivary gland pathology There are - pairs of ma!or salivary glands; parotid" submandibular" and sublingual (also numerous minor glands). )istory;lumps/ s elling related to food/ pain/ taste/ dry eyes. EFamination; note eFternal s elling/ look for secretions/ bimanual palpation for stones. EFamine O## nerve and regional nodes. 1ytology;This may be ascertained by IJ+. ,ecurrent unilateral pain and s elling is likely to be due to a stone. =34 are submandibular. The classical story is of pain and s elling on eating567 ith a red" tender" s ollen" but uninfected gland. The stone may be seen on plain F-ray or by sialography. Distal stones are removed via the mouth but deeper stones may re9uire eFcision of the gland.

1hronic bilateral symptoms may coeFist ith dry eyes and mouth and autoimmune disease" eg Mikulic':s or >!iWgren:s syndrome (pA-3 . pA-&). IiFed s ellings may be from tumours or sarcoid567or are idiopathic. >alivary gland tumours; 56T=34 are in the parotid" =34 of these are pleo-morphic adenomas" =34 of these are in the superficial lobe.56U 5VW+ny salivary gland s elling must be removed for assessment if present for 21 month. O## nerve palsy signifies malignancy. Benign or malignant: Malignant: Malignant: 1ystadenolymphoma Mucoepidermoid>9uamous carcinoma (leomorphic adenoma+cinic cell +denocarcinoma +denoid cystic carcinoma (leomorphic adenomas often present in middle age and gro slo ly. ,emoved by superficial parotidectomy. +denolymphomas; usually older men/ soft/ treat by enucleation. 1arcinomas; rapid gro th/ hard fiFed mass/ pain/ facial palsy. Treatment; surgery 0 radiotherapy. >urgery complications; Iacial palsy567often brief. )ave a facial nerve stimulator in theatre to aid identification. >alivary fistula; often close spontaneously.

Irey:s syndrome (gustatory s eating)/ tympanic neurectomy may help here.

Lumps in the thyroid EFaminationbatch the neck during s allo ing ater. >tand behind and feel thyroid for si'e" shape (smootha one or many nodulesa)" tenderness" and mobility. (ercuss for retrosternal eFtension. +ny nodesa Druitsa #f the thyroid is enlarged (goitre)" ask these - 9uestions; #s the thyroid smooth or nodulara #s the patient euthyroid" thyrotoFic (p-3&)" or hypothyroid (p-38)a >mooth" non-toFic goitre; Endemic (iodine deficiency)/ congenital/ goitrogens/ thyroiditis/ physiological/ )ashimoto:s thyroiditis (an autoimmune disease thought to be due to apoptosis induced by lymphocytes bearing Ias ligands combining ith thyrocytes bearing Ias.) >mooth" toFic goitre; Graves disease.

+ny nodulesa Many or onea #f 2&cm across" malignancy is more likely.KdisketteL1$H Multi-nodular goitre ((*+TE 1&); Psually euthyroid but hyperthyroidism may develop. )ypothyroidism and malignancy are rare.

The single thyroid lump is a common problem/ Z134 ill be malignant. 1auses;

1yst" adenoma" discrete nodule in multi-nodular goitre" malignancy. Iirst ask; is heBshe thyrotoFica Do T- . T&. Then; Pltrasound" to see if the lump is solid or cystic or part of a group of lumps ,adionucleotide scans may sho malignant lesions as hypofunctioning or 56Tcold56U" hereas a hyperfunctioning 56Thot56U lesion suggests adenoma

IJ+1 and do cytology on the fluid.

5VWJo clinicalBlab test is good enough to tell for sure if follicular neoplasms found on IJ+ are benign" so such patients are referred for surgery.KdisketteL1$8 bhat should you do if high-resolution ultrasound sho s impalpable nodulesa >uch thyroid nodules can usually !ust be observedKdisketteL1$A provided they are; Y1cm across (most are/ ultrasound can detect lumps Y$mm/ such 56Tincidentalomas56U occur in &84 of routine autopsies) and asymptomatic. There is no past history of thyroid cancer or radiation.

Jo family history of medullary cancer. (#f any present" do ultrasound-guided IJ+/ eFcise if cytology is malignant.)

Thyroid neoplasia$ H types; (apillary; 834. Cften in young/ spread to nodes and lung. Treatment; total thyroidectomy (to remove non-obvious tumour) Q^ node eFcision 0 radio-iodine to ablate residual cells may all be needed. Give T& to suppress T>). (rognosis is better if young and female. Iollicular; 5?X$H4. Middle-aged" spreads early via blood (bone" lungs). belldifferentiated. Treat by total thyroidectomy and T& suppression and radioiodine (1-1#) ablation.

+naplastic; ,are. 5U6 ; 5Um 5?g - ; 1. Elderly" poor response to any treatment. #n the absence of unresectable disease" eFcision 0 radiotherapy may be tried. Medullary; H4. >poradic (=34) or part of MEJ syndrome (p-3%). May produce calcitonin. They do not concentrate iodine. Do thyroidectomy 0 node clearance (do phaeochromocytoma screen pre-op). EFternal beam radiotherapy should be considered to prevent regional recurrence. *ymphoma; H4. 5U6;5Um 5?g -;1. May present ith stridor or dysphagia. Do full staging pre-treatment (chemoradiotherapy). +ssess histology for mucosa-associated lymphoid tissue (M+*T) origin (associated ith a good prognosis).

Thyroid surgery #ndications; (ressure symptoms" hyperthyroidism" carcinoma" cosmetic reasons. ,ender euthyroid pre-op" by antithyroid drugs andBor propranolol. 1heck vocal cords by indirect laryngoscopy pre- and post-op. 1omplications Early; ,ecurrent laryngeal nerve palsy" haemorrhage (5VWif compresses air ay" instantly remove sutures for evacuation of clot)" hypo-parathyroidism (check plasma 1a$0 daily" usually transient)"

thyroid storm (symptoms of severe hyperthyroidism567treat by propranolol (C or #O" antithyroid drugs" and iodine" p=$3). *ate complications; )ypothyroidism. Iootnote 1 IJ+ c fine needle aspirate $ Ior a revie of thyroid carcinoma" see > >herman $33- *ancet -81 H3156S11 ,ypothyroidism (my$oedema) This is common and easy to treat. 5VW+s it is insidious" both the patient and the doctor may not reali'e anything is rong" so be alert to subtle and non-specific symptoms" particularly in omen over &3yrs old. >ymptoms Tiredness" lethargy" eight5MN" constipation" dislike of cold" menorrhagia" hoarse voice" depression" poor cognitionBdementia" myalgia. >igns Dradycardia" dry skin and hair" goitre" slo ly relaFing refleFes" 11I" non-pitting oedema (eg eyelids" hands" feet) Q^ 56Ttoad-like face56U" pericardial effusion" peripheral neuropathy" cerebellar ataFia. Diagnosis T&5MS" T>) (5MN in thyroid failure" slightly 5MS or normal in rare secondary hypothyroidism due to T>) lack from the pituitary" p-1=). 1holesterol and triglyceride may be5MN. Jormochromic macrocytic anaemia. 1<" +>T" and *D) may be5MN due to abnormal muscle membranes. >ee also p-3$. 1auses of primary hypothyroidism >pontaneous primary atrophic hypothyroidism;1ommon" autoimmune disease hich is essentially )ashimoto:s ithout the goitre and is associated ith type # diabetes" +ddison:s disease" or pernicious anaemia. 5U6; 5Um 5?g 8; 1. (ost-thyroidectomy or radioiodine treatment. Drug-induced;+ntithyroid drugs/ amiodarone/ lithium/ iodine. >ubacute thyroiditis;Temporary hypothyroidism after hyperthyroid phase. #odine deficiency;(oor diet. Genetic; eg ith deafness ((endred:s syndrome). Dyshormonogenesis;+utosomal recessive eg from peroFidase deficiency. *ook for 5MN radioiodine gland uptake displaced by potassium perchlorate.

,are associations;KdisketteLH&1ystic fibrosis" primary biliary cirrhosis" (CEMs syndrome (polyneuropathy" organomegaly" endocrinopathy" M-protein band from a plasmacytoma 0 skin pigmentationBtethering). >creen for hypothyroidism if; )yperprolactinaemia (ost-partum thyroiditis

#nfertility Cbesity )ypothermia #f neck irradiated 1holesterol5MN Dementia +utoimmunity 1ongenital hypothyroidism Cn amiodarone or *i0 Depression Q^ 5MS cognition Type 1 DM and pregnant Turner:s syndrome

Treatment #f healthy and young; ThyroFine (T& c levothyroFine)" Z133Q\gB$&h (C/ revie at 1$ ks. +d!ust dose by clinical state and to normali'e but not suppress T>). Then check T>) yearly" at least at first. Csteoporosis is a theoretical risk of overtreating. #f elderly; >tart ith $HQ\gB$&h/ 5MN dose" eg every & ks (5VWthyroFine may precipitate angina). ThyroFine:s tQ` is ZAd" so any change in dosage ill take Z& ks to be assessed accurately by T>) (JD; T>) itself has a tQ` of only Z1h).KdisketteLHH #f ischaemic heart disease; Give propranolol &3mgB8h (C and start ith $HQ\gB$&h of thyroFine as above. #f diagnosis is in 9uestion and T& already given; >top T&/ recheck T>) in 8 ks. 1auses of goitre 0 hypothyroidism )ashimoto:s thyroiditis; +utoimmune disease in hich there is lymphocyte and plasma cell infiltration. Psually in omen aged 8356SA3HHyrs. Cften euthyroid. +utoantibody titres high. Treat as above if hypothyroid or to reduce goitre if T>) high. Drugs; +s above.

The effects of amiodarone on the thyroid are compleF and variable. #t commonly causes a rise in free T&" and a fall in free T-" but clinically the patient may remain euthyroid. $4 of patients have clinically significant changes567 hich may be hyperthyroidism or hypothyroidism. De guided more by clinical state than tests. >eek eFpert help. Jote that tQ` is long (&356S133d)" so problems persist after ithdra al. >econdary hypothyroidism(from pituitary failure" p-1=) is very rare. bhy are symptoms of hypothyroidism so many" so various" and so subtlea +lmost all our cell nuclei have receptors sho ing a high affinity for T-; that kno n as T,]^-1 is abundant in muscle and fat/ T,]^-$ is abundant in brain/ and T,]_-1 is abundant in brain" liver" and kidney. These receptors" via their influence on various en'ymes" affect the follo ing processes; The metabolism of substrates" vitamins" and minerals. Modulation of all other hormones and their target-tissue responses.

>timulation of C$ consumption and generation of metabolic heat. ,egulation of protein synthesis" and carbohydrate and lipid metabolism. >timulation of demand for co-en'ymes and related vitamins.

>ubclinical hypothyroidismKdisketteLH8 Ieatures T>)5MN but T& and T- 5M7" and no obvious symptoms. The conteFt may be follo -up after partial thyroidectomy or 1-1#" or !ust a 56Troutine test56U (Z134 of those 2HHyrs old have T>) -.H56S$3mPB*). The risk of progression to frank hypothyroidism is Z$4" but increases as T>)5MN. )o ever" this risk doubles if thyroid autoantibodies are present" and is Z134 in men. Management 1heck thyroid autoantibodies. ,echeck the history; if any non-specific features (eg depression)" discuss benefits of treating (p-38) ith the patient; they may simply feel better" ithout reali'ing that they ere not functioning optimally.

Cne approach to management is to treat ( ith thyroFine) those patients ith a T>) 2 13" or those ith positive thyroid autoantibodies" previous Graves: disease" or other organspecific autoimmunity (type 1 DM" myasthenia" pernicious anaemia" vitiligo).KdisketteLHA #f the patient does not fall into any of these categories" monitor T>) annually. ,isks from ell-managed treatment of subclinical hypothyroidism are small (5MN risk of atrial fibrillation and osteoporosis only if over-treated).KdisketteLH=

Parathyroid hormone and hyperparathyroidism

(arathyroid hormone ((T)) is a peptide hich causes 5MN 1a$0 and 5MS (C&-- reabsorption in the kidney" 5MN osteoclast activity" and 5MN 1"$HdihydroFy vitamin D- production in the kidney. The overall effect is to 5MN 1a$0 and 5MS (C&-- in plasma. (rimary hyperparathyroidism (1)(T) 1auses; Z=34 solitary adenoma" Z1H4 hyperplasia" Z&4 multiple adenomas" Z1.H4 primary neoplasia. (resentation;Cften asymptomatic 5MN 1a$0 or D(5MN on routine tests/ osteopeniaB osteoporosis (bone pain Q^ fractures)" abdominal pain" renal stones" mood5MS" pancreatitis" ulcers (duodenal; gastric 5?g A; 1/ but gastrinomas common if MEJ1).KdisketteLH% Cther presentations relate to 5MN 1a$0 and effects of 5MN (T) on the skeleton; 1onfusion Thirst" nocturia" anoreFia (5g\1a$05MN)

DehydrationKdisketteL83 >tiff !oints Mobility5MS Myopathy

Thirst may be severe. )yperparathyroidism must pass through your mind henever a patient says 56T# al ays take a !ug of ater to bed56U. +ssociations ith multiple endocrine neoplasia (MEJ); Dlood tests;1a$05MN" (C&--5MS (unless renal failure)" alk phos5MN" (T)5MN" or 5M7 creatinine" $&h urine for 1a$0. DEE+ bone scan (p8%=). +ny evidence of bone reabsorption" ie osteitis fibrosa et cystica (bro n tumours) and subperiosteal resorption (hand F-ray)a +lso consider; 1E,/ skull Fray (56Tpepper-pot skull56U)/ pelvic F-ray. Treatment >urgical eFcision1 prevents fractures and gastric ulcers.KdisketteL81 +lso consider for; bro n tumours/ osteoporosis/ renal calculi/ pancreatitis. (re-op ultrasound can locate the source of (T). #f this fails" try an M#D# scan" before surgical eFploration. (M#D# c methoFy-isobutyl isonitrile.) Do plasma 1a$0 daily for 5?@1&d: post-op (danger is 1a$05MS). Mild symptoms may not merit surgery567advise 5MN fluid intake to stop stones forming/ revie every 8 months. (ostop recurrence; >een in Z=4 of patients over 13yrs (in one big series).KdisketteL8$ >econdary hyperparathyroidism ($)(T) ((T)5MN as appropriate for a lo 1a$0). EctopicBmetastatic calcification may be a feature (paraarticular sites" heart valves" and anterior thigh" and ma!or arteries$).KdisketteL8- 1auses; chronic renal failure/ dietary lack of vit D. Kprescription takeL; (hosphate binders/ vit D analogues/ a calcimimetics-567see renal osteodystrophy (bone disease)" p$A8.

Tertiary hyperparathyroidism (-)(T) occurs after prolonged secondary hyperparathyroidism" if 1 or more glands act autonomously (eg ith adenoma formation)"KdisketteL8& causing 1a$05MN from 5MN 5MN secretion of (T) unlimited by feedback control. #t is chiefly seen in chronic renal failure or after renal transplants (in $4). #t may be possible to limit resection to !ust the adenomatous glands.KdisketteL8H Malignant hyperparathyroidism /(arathyroid-related protein ((T)r() produced eg by lung cancers" mimics (T)" resulting in 1a$05MN (5g\ lo (T)). Iootnotes 1 Eg total parathyroidectomy 0 autotransplantation of 1 gland to a forearm (removable if hyperparathyroidism recurs)/ ithout autotransplantation" alfacalcidol or similar (p$A8) is needed. CTM$-1$ Cther causes; neoplasia" trauma" paraplegia" atheroma" amyloid" 1,E>T (p&$3)/ >*E" nephrocalcinosis" chondrocalcinosis" TD" sarcoid" parasites" pseudohypoparathyroidism" myositis ossificans progressiva. 1alcimimetics are under development (eg cinacalcet) to amplify sensitivity of eFtracellular 1a$0 sensing receptors (1a,) to eFtracellular 1a$0" so suppressing (T) ith resultant fall in 1a$0. ,ypoparathyroidism (rimary hypoparathyroidism(T) secretion5MS due to gland failure" eg removal during neck surgery. Dlood tests; 1a$05MS" (C&--5MN or 5M7" alk phos 5M7. >igns and symptoms; Ieatures of hypocalcaemia (p8%&). +ssociations; (ernicious anaemia/ +ddison:s/ hypothyroidism/ hypogonadism. Treatment is ith alfacalcidol (p8%&). *ifelong follo -up re9uired. (seudohypoparathyroidism(failure of target cell response to (T)). >igns; ,ound face" short metacarpals and metatarsals. Dasal ganglia calcification. (lasma 5MN (T)" alk phos normal or 5MN. Treatment; +s for 1Qo hypoparathyroidism. (seudopseudohypoparathyroidism/The morphological features of pseudohypoparathyroidism" but ith normal biochemistry. The cause is genetic.KdisketteL88 +utosomal dominant (pre)malignant paraendocrinopathiesB Multiple endocrine neoplasia (MEJ) MEJ syndromes are an eFtraordinary group of genetic tumour syndromes comprising; KdisketteL8A MEJ1 . $ Jeurofibromatosis" p&3$" eg ith duodenal somatostatinomas 0 phaeochromocytomas 0 medullary thyroid cancer (MT1)

Oon )ippel *indau syndrome (pA-8) (eut'56Seeghers: syndrome (pA-$" eg polyposis 0 endocrine tumours)KdisketteL8= 1arney compleF567adrenal hyperplasia 0 pituitary adenomas 0 skin . heart myFomas (any chamber) 0 mucosal lentigos 0 sch annomas 0 testicular tumours.KdisketteL8%

MEJ type-1 (cMEJ1);(arathyroid hyperplasia (Q^ superimposed clonal tumour gro th) 0 pituitary adenoma 0 pancreatic tumours567gastrinomas (pA&3)" islet cell tumours (p-33)" or O#(omas (rare" p$1=). The MEJ1 gene is a tumour suppressor gene/ menin" its protein" alters transcription activation.KdisketteLA3 Many cases are sporadic; here typical presentation is in the -rd56SHth decades. MEJ$a;MT10pheochromocytoma0parathyroid hyperplasia (rarer than ith MEJ1).KdisketteL A1 KdisketteLA$ 5VWTests for mutations in the ret proto-oncogene are revolutioni'ing MEJ$ treatment by enabling thyroidectomy before neoplasia occurs.KdisketteLA- JD; ret mutations rarely contribute to sporadic parathyroid tumours. MEJ$b(c MEJ- c MEJ-###)KdisketteLA& is like MEJ$a but has neuro-cutaneous signs (mucosal neuroma 56Tbumps56U eg on; lips" cheeks" tongue" glottis" lids" ith visible corneal nerves)" KdisketteLAH and a Marfanoid appearance (pA-3)567but ithout any hyperparathyroidism. KdisketteLA8 +dditional signs; slipped upper femoral epiphyses" and delayed puberty. MEJ$b is caused by a mis56Ssense mutation in the ret gene giving rise to a single amino acid substitution (Met%1= by Thr).KdisketteLAA ,ypopituitarism The 8 anterior pituitary hormones commonly measured are; adrenocorticotrophic hormone (+1T))" gro th hormone (G))" follicle-stimulating hormone (I>))" luteini'ing hormone (*))" thyroid-stimulating hormone (T>))" and prolactin ((,*). There may be complete loss of anterior pituitary function or selective loss of one hormonal aFis" so presentation is very variable. 1auses )ypophysectomy Trauma

(ituitary irradiation or adenoma (non-functional or functional ith hyposecretion of other hormones" eg acromegaly" prolactinoma" or rarely 1ushing:s).

,arer causes; 1raniopharyngioma" p-$3 >phenoid meningioma

+bscesses TD (eripituitary glioma )aemochromatosis >heehan:s syndrome1a Trauma

Ieatures of;

1orticotrophin lack; #nsidious onset afternoon tiredness/ di''iness/ nausea/ pallor/ eight5MS/ postural D(5MS/ collapse/ Ja05MS" etc." p-1$. Gonadotrophin lack;Ie " scant" or no menses (oligomenorrhoea/ amenorrhoea)/ fertility5MS/ libido5MS/ osteoporosis/ breast atrophy/ dyspareunia. +ndrogen lack;Erectile dysfunction/ libido5MS/ muscle bulk5MS/ hypogonadism (loss of all hair/ small testes/ e!aculate volume5MS/ spermatogenesis5MS). G) lack;1entral obesity/ atherosclerosis/ dry rinkly skin/ strength5MS/ balance5MS/ ellbeing5MS/ eFercise ability5MS/ cardiac output5MS/ osteoporosis/ glucose5MN.KdisketteL133 Thyroid lack;1onstipated/ eight5MN/ mood5MS/ dry skin/ p-38. Tests (The triple stimulation test is no rarely done.) T& and T>) reliably diagnoses T>) deficiency. Testosterone" *)" and I>) in men" and a menstrual history 0 *) and I>) in omen are as reliable as the GJ,) test. The short >ynacthenQR test provides sufficient information concerning +1T) deficiency. Dasal T&" T>)" *)" I>)" prolactin" testosterone. P.E (Ja05MS 5g\ dilution)" )b5MS (normochromic" normocytic). Thyroid deficiency; T&5MS but T>) normal or5MS. M,# scan/ assessment of visual fields.

>hort >ynacthenQR test; (p-1$567for +1T) deficiency) is nearly as reliable as the insulin tolerance test (#TT)" hich is no a rarely done $nd-line gold standard (only do in metabolic units under close supervision).KdisketteL131 #nsulin tolerance test (#TT); 1#; epilepsy" heart disease" adrenal failure. The test involves giving insulin #O" and assessing its effect on cortisol and G). #t is done in morning ( ater only taken from $$;33h the night before). )ave H34 glucose and hydrocortisone to hand and #O line open. De alert throughout to hypoglycaemia. 1onsult lab first. #nterpretation; Glucose must fall belo $.$mmolB* and the patient should become symptomatic. Jormal values are; G) 2$3mPB*" and a peak cortisol 2HH3mmolB*. +rginine 0 gro th hormone releasing hormone test (+,G 0 G),) test); +n alternative to the #TT for measuring need for G)/ it may have fe er >Es.$

Treatment )ydrocortisone for secondary adrenal failure (p-1$). ThyroFine if hypothyroid (p-38" but T>) useless for monitoring). 5Um; -- eekly testosterone enanthate $H3mg #M or transdermal +ndropatchQR/ apply to clean" dry" unbroken skin on back" upper arm" thigh" or abdomen for $&h (do not use the same site ithin Ad). 5U6; (pre-menopausal) Cestrogen (eg as contraceptive steroid pill). >ome patients need gro th hormone. JD; G) has ac9uired a 56Tsmart drug56U status via inappropriate internet advertisements eFtolling its muscle and potency-enhancing and supposed anti-ageing attributes.KdisketteL13$ >E; prostate hyperplasia/ insulin-like gro th factor5MN (#GI-1 may 5MN risk of cancer" but unproven).KdisketteL13- #f you think your patient

might need G) (eg it is kno n to improve recovery and alking distance after hip surgeryKdisketteL13&)" 5VWask an endocrinologist first. Cther causes of hypogonadism Trauma" post-orchitis (mumps" brucellosis" leprosy)" chemotherapyBirradiation" cirrhosis" alcohol (toFic to *eydig cells)" cystic fibrosis" haemochromatosis/ syndromes (C)1> pAH$ etc.); <leinfelter:s (commonest)" *aurence56SMoon56SDiedl" dystrophica myotonica" (rader56Sbilli" <allman:s ( ith anosmia0colour blindness/ E-linked recessive). J#1E guidelines on giving somatropin (G)) in those 2$Hyrs old >omatotropin is produced by DJ+ technology/ it has the same se9uence as human G). #t should only be used in G) deficiency" and if;KdisketteL13H (eak G) response is Y%mPB* (-ngBm*) during an #TT (or e9uivalent). There is impaired 9uality of life (lo*)" as measured by lo*-+G)D+ 9uestionnaires (assessment of hormone deficiency in adults score 5?@ 11 points).1

The person is already receiving treatment for other pituitary hormone deficiencies" as re9uired.

JD; +chieving adult bone mass is a valid indication for somatropin in adults Y$Hyrs old ho fulfil criteria 1 but not $. (MaFimum G) secretion is during adolescence/ then secretion normally falls by Z1&4 per decade.) >elf-in!ection 3.$56S3.-mgBd (c3.856S3.%#P)/ needs 5MS ith age/ dose titration (1st - months of therapy) is done by an endocrinologist. >E; )eadache/ myalgia/ D(5MN/ carpal tunnel syndrome/ fluid retention/ #1(5MN (rare). 1#; (regnancy/ lactation/ ma!or trauma/ post-op/ malignancy/ respiratory failure. >omatropin should be stopped after % months if lo*-+G)D+ does not improve by A points or more.1 Psing G) in children; >ee C)1> p1=&. Iootnote 1 #mprovement in lo* scores during G) replacement has to be vie ed ith skepticism. This can be dispelled only by randomi'ed trials. Darkan + $33- e 1lin Endocrinol =8 1%3H Iootnotes 1a >heehan:s syndrome (>immonds: disease) is pituitary necrosis after post-partum haemorrhage. $ b <iess $33- 1lin Endocrinol H= &H8. +nother alternative is a pyridostigmine 0 G),) ((D 0 G),)) test. Pituitary tumours (ituitary tumours (almost al ays benign adenomas) account for 134 of intracranial tumours. 5V W>ymptoms are caused by local pressure" hormone secretion" or hypopituitarism (p-1=). There are - histological types. 1hromophobe567A34. >ome are non-secretory" but cause hypopituitarism. *ocal pressure effect in -34. )alf produce prolactin ((,*)/ a fe produce +1T) or G). +cidophil5671H4. >ecrete G) or (,*. *ocal pressure effect in 134.

Dasophil5671H4. >ecrete +1T). *ocal pressure effect rare.

1lassification by hormone secreted (may be revealed by immunohistology) (,* only -H4 G) only $34 (,* and G) A4 +1T) A4 *)BI>)BT>) Kgreater than or e9uivalent toL 141KdisketteL138 Jo obvious hormone-34$ Ieatures of local pressure effects )eadache/ visual field defects (bilateral hemianopia" initially of superior 9uadrants)/ palsy of cranial nerves ###" #O" O#. ,arely" diabetes insipidus (D#) (p-$8/ hich is more likely to result from hypothalamic disease)" disturbance of temperature" sleep" and appetite" and erosion through floor of sella leading to 1>I rhinorrhoea. #nvestigations(ituitary M,# (defines intra- and supra-sellar eFtension)/ accurate assessment of visual fields/ prolactin" baseline TITs" short synacthen test" *)BI>)" testosterone" and glucose tolerance test if acromegaly suspected. bater deprivation test if D# is suspected (p-$8). Treatment >tart hormone replacement as needed" in light of the above. >urgery;#f intrasellar tumour" remove by trans-sphenoidal approach. >uprasellar eFtension may need a transfrontal approach. (re-op; 1heck ith anaesthetistBsurgeon567eg hydrocortisone sodium succinate 133mg #M ith pre-med/ then every &h for A$h/ then hydrocortisone $3mg (C each morning. (ost-op; ,etest pituitary function (p-1=) after a fe eeks to assess replacement needs. Medical;Dopamine agonists (p-$$) are the best treatment for most prolactin-secreting tumours (lo ers (,* and can shrink tumour; monitor by M,#). >urgery is not indicated routinely for these. #t may also ork for some G)-secreting tumours (p-$$) and also 56Tnon-functional tumours56U (some making ]^-subunit)/ use higher doses" eg bromocriptine $356S&3mg (C daily. ,adiotherapy;(ost-op if complete removal of tumour has not been possible. Pituitary apople$y >udden tumour enlargement due to haemorrhage may cause compression of vessels and neural tissue at the skull base ith coma and death ithout preceding symptoms.KdisketteL 13= >uspect if sudden onset of headache in someone ith a kno n tumour" or if there is sudden headache and loss of consciousness (ie may present like subarachnoid haemorrhage). ]7]7; Irontal sinusitis" eg hen presentation is ith fontal tenderness Q^ periorbital oedema.KdisketteL13% Treatment; Prgent surgery ith steroid cover. 1raniopharyngioma Jot strictly a pituitary tumour; it originates from ,athke:s pouch so is situated bet een pituitary and the -rd ventricle floor. H34 present ith local pressure effects in children" eg ith; headache

(H34)" vomiting (-34)" visual disturbances ($34)" polyuria/ polydipsia (1A4)" delayed puberty ($34)" short stature (1&4)" precocious puberty (-4).KdisketteL113 D# is common. Tests; 1TBM,# (calcification in H34). Treatment; >urgery/ irradiation/ test pituitary function (above). Iootnotes 1 $33- data sho that ne (ish) sensitive methods of T>) measurement lead to improved recognition. T>)-secreting tumours are no more fre9uently found at microadenoma stage" medially located" and ithout associated hypersecretions. #n these tumours" somatostatin analogues (p-$&) are very helpful. $ Many produce alpha-subunit hich may serve as a tumour marker. ,yperprolactinaemia #his is the most common biochemical disturbance of the pituitary. #t tends to present early in omen (amenorrhoea) but late in men. 1auses of raised basal plasma prolactin (2-%3mPB*) (rolactin is secre-ted from the anterior pituitary and release is inhibited by dopamine produced in the hypothalamus. Therefore" hyperprolactinaemia may result from either eFcess 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. + prolactin of 133356SH333mPB* could result from either" but 2H333 is likely to be due to an adenoma" ith macroadenomas having the highest levels" eg 13"33356S133"333. (hysiological;(regnancy/ breast-feeding/ stress/ sleep. Drugs and other chemicals (most common cause);(henothia'ines/ metoclopramide/ haloperidol/ ]^-methyldopa/ oestrogens. Diseases; (rolactinoma" pituitary adenomas" pituitary stalk section" hypothalamic disease" chronic renal failure/ hypothyroidism/ sarcoidosis. >ymptoms 5U6; *ibido5MS" eight5MN" apathy" dry vagina" amenorrhoea/ infertility" galactorrhoea. 5Um; #mpotence" reduced facial hair" galactorrhoea. Csteoporosis and local pressure effects (p-$3) are also modes of presentation. Tests Dasal plasma prolactin; non-stressful venepuncture bet een 3%.33 and 18.33h. 1TBM,# scan of the pituitary fossa if prolactin 21333mPB*. Management + reasonable approach is as follo s; Microprolactinomas;

+ tumour Y13mm diameter on M,# (Z$H4 of the population have asymptomatic microprolactinomas). Trans-sphenoidal surgery has a high success rate" and a relatively lo incidence of side-effects" but is not used in all centres. +fter surgery" prolactin concentrations are normali'ed" menstruation starts" and galactorrhoea eliminated in most patients. There is a small but significant recurrence rate. +lternatively" dopamine agonists such as bromocriptine may be used (1.$Hmg (C at $$.33 ith food/ increase eekly by 1.$H56S$.HmgBd until Z$.HmgB1$h). ,arely" patients may re9uire 213mg daily. Iollo (,*. Dromocriptine should be stopped in pregnancy567teratogenicity is reported. (,* ill rise during pregnancy" there is no need to follo it. #f headache or visual loss" check fields and consider neuroimaging. Cther >E; pulmonary" pericardial" and retroperitoneal fibrosis/ see DJI/ atch for cough and dyspnoea. Macroprolactinomas; + tumour 213mm diameter in association ith a prolactin of 2-833mPB* is likely to be a macroprolactinoma. #f prolactin Y-833" then it is probably a non-secretory tumour causing stalk compression and disinhibition of prolactin release. Macroprolactinomas may be treated ith bromocriptine" but if there are visual symptoms" pressure effects" or if pregnancy is contemplated (Z$H4 of macroadenomas ill eFpand during pregnancy)" then surgery is generally indicated. Psually" a trans-sphenoidal approach is used. Iollo -up ith serial (,* and M,#. Dromocriptine" and in some cases radiation therapy" may be re9uired post-op because complete surgical resection is uncommon. (re-op assessment is often difficult; familiari'e yourself ith case-histories to sho compleFities of this aspect of endocrinology.1 Dopamine agonists Dromocriptine is the established drug" but ne er drugs" eg cabergoline (taken eekly) and 9uinagolide (once daily) are no replacing it (cabergoline may be 1st-line therapy). bith macroprolactinomas" some centres continue treatment ith bromocriptine during pregnancy. Iootnote 1 E )arms $33- Dtsch Med bochenschr 1$= 88A. + &8yr.hyphen/old lady had galactorrhoea for Ayrs" and a .uarr/ prolactin (-1--mPB*) and intact pituitary function ith no eye signs. M,# sho ed a 1.%cm pituitary tumour ith eFtrasella eFtension. #s selective trans.hyphen/sphenoidal adenomectomy needed for a presumed non.hyphen/functioning macroadenoma ith functional hyperprolactinaemia" or should there be a dopamine.hyphen/agonist triala Cne possible ans er; try drugs" and monitor M,# if initial prolactin .gsim/ $333 mPB*. Acromegaly This rare disease is due to hypersecretion of G) from a pituitary tumour. #t usually presents bet een the ages of -3 and H3yrs old. (revalence H per million. 1linical features EFcessive soft tissue gro th; 1oarse" oily skin" large tongue (macroglossia)" prominent supraorbital ridge" prognathism" ride-spaced teeth" 5MN shoe si'e" thick spade-like hands" deepening voice" arthralgia" kyphosis" proFimal muscle eakness" paraesthesiae567due to

carpal tunnel syndrome (p-%1)" progressive heart failure" goitre. >leep apnoea. > eating and headache. Ieatures of a pituitary tumour; )ypopituitarism Q^ local mass effect (p-1=). (sychological effects; Jot 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 s ings" lo selfesteem" body image distortion" disruption in interpersonal relations" social ithdra al" and anFiety.KdisketteL111 Metabolic effects" eg insulin resistance; G) acts at several levels to block insulin" including inhibiting phosphorylation of the insulin receptor.KdisketteL11$

1omplications DM/ D(5MN/ left ventricular hypertrophyBcardiomyopathy/ colon cancer/KdisketteL 11- KbombL hyperthyroidism in &56S$84 (T>)-dependent or independent).KdisketteL 11& #nvestigations #solated G) measurement may sho 5MN secretion" but levels vary ith the time of day and other factors" so random measurements are not diagnostic. The definitive test is the CGTT ith G) measurement567as described on p$%&. 1ollect samples for G) and glucose at; 3" -3" 83" %3" 1$3" 1H3min. #nterpretation of CGTT; normally G) is suppressed" in acromegaly there is no suppression" and levels may rise. Ialse positives; anoreFia nervosa" poorly controlled DM" hypothyroidism" 1ushing:s.

>erum insulin-like gro th factor-1 (#GI-1) is used for screening for acromegaly in some centres. *evels correlate ith G) secretion over the past $&h" and so are 5MN if eFcessive G) secretion" or in pregnancy" or puberty. M,# (or 1T) scan of pituitary fossa. Test pituitary function (p-1=)567hypopituitarisma E1G. Echocardiogram. Oisual fields and acuity. >kin thickness. Cbtain old photos/ re9uest a ne photo of full face" torso" hands on chest.

Treatment Trans-sphenoidal surgery; Psually the treatment of choice. #n 834 G) secretion reduces to Y13mPB*. 8 ks after surgery readmit for CGTT ith G) measurement" and full pituitary function testing (p-1=). #f G) fails to suppress belo $.3mPB*" irradiation or medical treatment is needed. >teroids should be stopped before these tests and triple stimulation test may have a role" on day & only if no signs of steroid deficiency (postural hypotension" fever" nausea" anoreFia). nearly follo -up; (CGTT 0 G) measurement/ T&/ (,*/ visual fields/ F-rays567see above/ photos/ cardiovascular assessment B E1G).

EFternal irradiation;Ior older patients or failed surgery. Iollo -up as for surgery. Medical;>omatostatin analogues such as octreotide (>andostatin *+,QR" given monthly #M)" and lanreotide (>omatuline *+QR) have displaced dopamine agonists as 1st-line in somatotroph (G)) adenomas (>E; gallstones). Iollo -up sho s that some cardiac complications resolve after lanreotide (eg *O mass" ventricular filling" and ventricular arrhythmic profile).KdisketteL 11H Monitor glucose tolerance as effects on insulin resistance are unpredictable.KdisketteL118 KdisketteL11A KdisketteL11= Dia.etes insipidus (DI) This is due to impaired ater resorption by the kidney because of reduced +D) secretion from the posterior pituitary (cranial D#)" or impaired response of the kidney to +D) (nephrogenic D#). >ymptoms (olyuria/ dilute urine/ polydipsia/ dehydration if not drinking. 1auses of cranial D# MetastasesBOascular lesionB)ead in!uryB>arcoidosisBMeningitisB)ypophysectomyB(ituitary tumourB#nherited (autosomal dominant)B)istiocytosisB1raniopharyngioma #diopathic D# (H34) is often self-limiting" and M,# may sho infundibuloneurohypophysitis (kno n to be lymphocytic" and possibly autoimmuneKdisketteL11%). 1auses of nephrogenic D# *o potassium" high calcium" drugs (lithium" demeclocycline)" pyelonephritis" hydronephrosis" pregnancy (rare as a primary cause/ due to placental production of vasopressinase/ can eFacerbate underlying D# from any cause)" inherited. #nvestigations P.E" 1a$0" plasma" and urine osmolalities. (lasma osmolality should be high" and urine lo . >erum sodium may be high. #n psychogenic polydipsia" plasma osmolality is often lo . The ater deprivation test ill confirm the diagnosis. The ater deprivation test (#f 1st morning urine osmolality 2833mosmolBkg" D# is eFcluded.) >top drugs (eg carbama'epine) before the test. *ight breakfast" no tea" no coffee" no smoking. beigh at 3" &" 8" A" =h. >top if 2-4 body eight lost.

>upervise carefully to stop patient drinking. Empty bladder" then no drinks and only dry food for =h. 1ollect urine hourly" measure volume. Measure osmolality at 1" &" A" =h. >top test if osmolality 2833mosmolBkg (D# is eFcluded). Oenous sample for osmolality at; 3.H" -.H" 8.H" A.Hh.

#f plasma osmolality 2-33mosmolBkg" and urine osmolality Y833" give desmopressin $3Q\g intranasally (or 1Q\g #M) at =h. Prine should concentrate ithin 1h. #f plasma osmolality does not rise" do not administer desmopressin as hyponatraemia may result. bater can be drunk after =h. Measure urine osmolality at =" %" 13" 11" 1$h.

#nterpreting ater deprivation tests;1heck if plasma osmolality is 2$%3mosmolBkg to ensure the test has given ade9uate stimulus for +D) release. Jormal res-ponse is for urine osmolality to be 2833mosmolBkg. #n psychogenic polydipsia" urine is also concentrated (2&33mosmolBkg)" but rather less than in the normal response. #n D#" urine is abnormally dilute (Y&33mosmolBkg). )o ever" in cranial D#" urine osmolality increases 2H34 after desmopressin" hereas in nephrogenic D#" it increases Y&H4 after desmopressin. Treatment 1ranial D#; Iind the cause. Test pituitary function (p-1=). Give desmopressin 1356S$3Q\gB1$56S$&h intranasally (smallest dose that controls polyuria; higher doses 5MN risk of hyponatraemia). +n oral formulation is being assessed (DD+O(/ there may be fe er problems ith ater intoFication).KdisketteL1$3 Jephrogenic;Treat the cause. +voiding high-protein meals and salt may help polyuria. #f it persists" try bendroflua'ide (cbendroflumethia'ide) Hmg (CB$&h. 5VW5VWEmergency management The diagnosis must be made567eg suitable cause" 5MN urine output" urine osmolality5MS (Z1H3mosmolBkg)" despite dehydration. Do urgent plasma P.E. ,ehydrate/ keep up ith output. H4 deFtrose" $* in the 1st hour. #f severe hypernatraemia" do not lo er Ja0 rapidly" use 3.%4 or 3.&H4 saline.

Desmopressin 1Q\g #M (lasts 1$56S$&h). #n nephrogenic D#" indomethacin AHmgB$&h (C can lo er urine volume and plasma Ja0. KdisketteL1$1

,yponatraemia" assessment (resentation Mild hyponatraemia (Ja0 1-356S1-HmmolB*) is common especially in patients taking thia'ide diuretics and is usually asymptomatic. Moderate hyponatraemia (Ja0 1$356S1$%mmolB*) is usually asymptomatic unless it has developed rapidly. >evere hyponatraemia (Ja0Y1$3mmolB*) may be associated ith disturbed mental state" restlessness" confusion" and irritability. >ei'ures and coma prevail as the sodium approaches 113mmolB*. )istory should focus on drugs" fluid losses (diarrhoea" fre9uency" s eating)" symptoms of +ddison:s" symptoms or history of cardiac" lung" liver" or renal disease. EFamination should focus on careful assessment of volume status" and in particular should assess hether the patient is hypovolemic" normovolemic" andBor oedematous. (atients should therefore

have an assessment of their lying and standing D(" )," eO( Q^ 1O(" skin turgor" and the presence of oedema or ascites. (atients ho are hyponatraemic and hypovolemic are salt depleted. #nvestigations #n addition to P.Es" other tests should be aimed at eFcluding other causes of hyponatraemia (see table" (HA$). Measure serum osmolarity and compare it to the calculated osmolarity K$ij(Ja0 0 <0) 0 urea 0 glucoseL; an increase in osmolar gap is ith substances such as ethylene glycol" severe hyperglycaemia" mannitol" etc.

Prine Ja0 combined ith clinical assessment of fluid status may help determine the underlying cause;
o

Oolume depletion from an eFtra-renal cause (see table" (HA$) is normally associated ith a lo urinary Ja0 (Y13mmolB*) Oolume depletion ith a high urinary Ja0 (2$3mmolB*) suggests inappropriate renal salt- asting (e.g. intrinsic renal disease" hypothyroidism" adrenal insufficiency" diuretics) + lo urine Ja0 (Y13mmolB*) is seen in conditions such as 11I" cirrhosis" or nephrotic syndrome here there is sodium retention in response to poor renal perfusion Euvolaemia ith high urine Ja0 is seen ith >#+D) and rarely ith severe myFoedema.

General principles +ssessment of the patient:s volume status (neck veins" orthostatic hypotension" cardiac signs of fluid overload" ascites skin turgor) ill help in both diagnosis and subse9uent treatment. Mild asymptomatic hyponatraemia ill usually respond to treatment of the underlying cause and no specific therapy is necessary.

1orrection of hyponatraemia should be gradual to avoid volume overload andBor central pontine myelinolysis. +im to restore the serum Ja0 to Z1$HmmolB* actively (iv fluids) and allo to rise gradually after that by treating the underlying cause. >eek eFpert help if serum Ja0 Y1$3mmolB* Q^ severely symptomatic. (atients ith cirrhosis and ascites and severe hyponatraemia should have diuretics stopped" and be treated ith volume eFpansion. >#+D) or other conditions associated ith plasma volume eFpansion can cause hypouricaemia (increased renal clearance).

)yponatraemia; causes Decreased serum osmolarity )ypovolaemia (hyponatraemia 0 hypovolaemia c salt depletion)

Renal losses (uNa Non-renal losses (uNa <20mmol/L) >20mmol/L) Diuretics G# losses (diarrhoea" vomiting) +ddison:s disease Durns Ja-losing nephropathies Iluid se9uestration (e.g. peritonitis" pancreatitis) Jormovolaemic (normal or mildly increased E1O) >#+D); urine osm. 2133" serum osm. lo (Y$83)" urine Ja0 2&3mmolB* CNS disorders Malignan ! Pulmonar! disease Trauma *ung (oat cell) (neumonia >trokeB>+) (ancreas TD Malignancy (1QoB$Qo) *ymphoma or leukaemia*ung abscess Oasculitis (e.g. >*E) (rostate 1ystic fibrosis #nfection (abscess or meningoencephalitis)Prinary tract *ung vasculitis Drugs (via >#+D) Q^ 5Mdrenal sensitivity to +D) or Ja 2 )$C loss) Cpiates Thioradi'ine 1hlorpropamide )aloperidol 1arbama'epine Thia'ides +mitriptyline 1lofibrate 1yclophosphamide Oasopressin CFytocin Oincristine Miscellaneous causes >evere myFoedema (sychogenic polydipsia /edematous states 1ongestive cardiac failure 1irrhosis ith ascites >evere renal failure Jephrotic syndrome Jormal serum osmolarity (seudo-hyponatreemia (e.g. lipaemic erum" paraprotein 213gBdl) #ntracellular shift of Ja0 (e.g. hyperglycaemia" ethylene glycol) )yponatraemia; management EFclude pseudohyponatraemia; lipaemic serum ill be obvious (ask the biochemist). 1alculate the osmolar gap to check there are no 56Thidden56U osmoles ((HA$). +l ays eFclude the possibility of artefactual 5MSJa0 from blood taken proFimal to an iv infusion. +symptomatic hyponatraemia should be corrected slo ly so that serum sodium does not increase by 21$mmolB*Bday.

>ymptomatic hyponatraemia (e.g. sei'ures or coma) re9uires a more aggressive initial correction to increase serum sodium concentration by Z8mmolB* over -56S& hours. Thereafter" correct serum sodium slo ly" so that the overall increase is Y1$mmolB* per $& hours. >eek eFpert help early. >tart iv infusion of normal saline (1H3mmolB*) at $H356SH33mlBh atching carefully for fluid overload. +s a guide" if 1 litre of J saline is infused instantaneously" it ould increase serum sodium by &56SH mmolB*. +lternatively" infuse H4 saline at &356SA33mmol Ja0Bh until serum sodium increases ade9uately.

#f volume deplete (dehydrated) start an iv infusion of normal saline (3.%4 c 1H3mmolB* Ja0)/ insert a central venous line if indicated. Monitor fluid output; catheteri'e the bladder if there is renal impairment. batch out for heart failure. #f not dehydrated; for patients ith moderate >#+D)" restrict fluid intake to H33B$&h. >eek eFpert help.

1linical manifestations of osmotic demyelination May be delayed $56SH days Cften irreversible or only partially reversible

Dysarthria Dysphasia (araparesis or 9uadriparesis *ethargy 1oma or sei'ures.

,ypernatraemia +bnormalities in serum sodium are usually associated ith changes in serum osmolality and E1O. (resentation >ymptoms often relate to severe volume depletion; eakness" malaise" fatigue" altered mental status" confusion" delirium" or coma. The ay to determine the cause of abnormal serum Ja0 is by 1areful assessment of the E1O (evaluation of neck veins" supine and standing D(" any cardiac signs of fluid overload (e.g. >-" oedema)" and skin turgor)" in association ith Measuring the serum (Q^ urine) osmolality. K>erum osmolality may be estimated by ($ i j (Ja0 0 <0) 0 urea 0 glucose) but this is inaccurate hen there are other osmoles (e.g. ketones" ethanol" methanol" ethylene glycol" renal failure) that contribute.L >erum Ja021&HmmolB* is al ays associated ith hyperosmolarity. 1auses of hypernatraemia Jormal or 5MdeFtracellular volume (eFcessive Ja0 and )$C loss) ,enal ater losses (urinary osm inappropriately lo ) o Diabetes insipidus (central or nephrogenic)
o

Csmotic diuresis ith ater replacement only (e.g. DM)

Jon-renal ater losses (urinary osm 2&33mosmolB*)

o o

)ypotonic G# losses (e.g. diarrhoea) 1utaneous losses (burns" heat shock" s eating" and high fever)

1hest infections ith prolonged hyperventilation

>alt overload (usually 56Tiatrogenic56U)

o o o o o

1oncentrated Ja)1C(ost-operatively hen huge volumes of fluid used #n #TP hen volume loaded ith saline based fluids 1oncentrated infant formula 1onn:s syndrome (hypertension" hypokalaemia" alkalosis)

Management +void rapid and eFtreme changes in serum sodium concentration. #t is safer to change serum sodium cautiously. #f there is hypovolaemia" start fluid replacement. Jormal saline (3.%4) contains elemental sodium at 1H3mmolB*. Pse this initially to correct hypovolaemia if present" then change to H4 deFtrose to replace ater and slo ly correct sodium concentration.

#f the patient is haemodynamically stable encourage oral fluids. Monitor electrolytes t ice daily initially.

Acute hypocalcaemia (resentation +bnormal neurological sensations and neuromuscular eFcitability Jumbness around the mouth and paraesthesiae of the distal limbs

)yperrefleFia 1arpopedal spasm Tetanic contractions (may include laryngospasm) Iocal or generali'ed sei'ures. ,arely eFtra-pyramidal signs or papilloedema )ypotension" bradycardia" arrhythmias" and 11I 1hvostek:s sign is elicited by tapping the facial nerve !ust anterior to the ear" causing contraction of the facial muscles (seen in 134 of normals) Trousseau:s sign is elicited by inflating a blood pressure cuff for -56SH minutes 1356S$3mm)g above the level of systolic blood pressure. This causes mild ischaemia" unmasks latent neuromuscular hypereFcitability" and carpal spasm is observed.

JD; 1arpopedal spasm may occur during hyperventilation induced respiratory alkalosis. #nvestigations

(lasma 1a$0" (C--&" and albumin (lasma Mg$0 P.Es E1G ((rolonged lT interval) (lasma (T) level >E, (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. Ior frank tetany" 13ml of 134 calcium gluconate ($.$Hmmol) can be given by slo iv in!ection over 13 minutes. JD; 13ml of 134 calcium chloride (% mmol) contains Z&-fold more calcium than calcium gluconate. 1alcium gluconate is preferred as it causes less tissue necrosis if it eFtravasates. iv calcium should never be given faster than this because of the risk of arrhythmia. Thereafter" an infusion of calcium (Z3.3$H56S3.3HmmolBkgBh should be started). Ior a A3kg adult" add H3ml of 134 calcium gluconate or 13ml of 134 calcium chloride to $33ml J saline" and infuse at H356S=3mlBh.

(ost parathyroidectomy" mild hypocalcaemia normally ensues" re9uiring observation only. #n patients ho have parathyroid bone disease ho ever" 56Thungry bones56U may cause profound hypocalcaemia shortly after the parathyroids are removed. This may cause a severe and prolonged hypocalcaemia hich re9uires prolonged treatment. 1hronic hypocalcaemia is best managed ith oral calcium together ith either vitamin D" or" if the cause is hypoparathyroidism or an abnormality in vitamin D metabolism" a form of activated (hydroFylated) vitamin D such as alfacalcidol or calcitriol. #f magnesium deficiency is present" add $3ml (Z&3mmol) of H34 magnesium sulphate solution to $-3ml J saline (13gB$H3ml). #nfuse H3ml of this (e9uivalent to $g Mg>C&" = mmol) over 13 minutes" and at $HmlBh thereafter.

1auses of hypocalcemia Oitamin D deficiency +sians 1hronic renal failure *oss of 1a$0 from circulation EFtra-vascular deposition o )yperphosphataemia (renal failure" tumour lysis)
o o

+cute pancreatitis Csteoblastic metastases (e.g. prostatic)

#ntra-vascular binding
o o o

1itrate or blood products Ioscarnet (anti-1MO drug) +cute respiratory alkalosis

)ypoparathyroidism (ost parathyroid" thyroid" or neck surgery #diopathic

(seudo-hypoparathyroidism #nfiltration )#O infection

Disorders of Mg$0 metabolism Magnesium deficiency Cther

>epsis" burns Iluoride intoFication 1hemotherapy (e.g. cisplatin)

(ractice point #f hypocalcaemia is difficult to correct" check for magnesium deficiency. ,ypercalcaemia The free (ionic) plasma 1a$0 concentration is dependent on both arterial p) (5MN during acidaemia) and the plasma albumin. #oni'ed 1a$0 c measured 1a$0 0 K&3 - serum albumin(gB*)L ij 3.3$. (e.g. #f measured 1a$0 c $.13mM and albumin c -3gB*" the corrected 1a$0 c $.13 c K(&3 - -3) ij 3.3$L c $.-3mM).

Most #TPs can no measure ioni'ed calcium.

(resentation ,outine biochemical screen in an asymptomatic patient General; depression (-356S&34)" eakness (-34)" tiredness" and malaise

Gastrointestinal; constipation" anoreFia/ vague abdominal symptoms (nauseas" vomiting)" eight loss ,enal; renal calculi (if long standing)/ nephrogenic diabetes insipidus ($34)/ type 1 ,T+/ pre-renal failure/ chronic hypercalcaemic nephropathy" polyuria" polydipsia" or dehydration

Jeuropsychiatric; anFiety" depression" and cognitive dysfunction/ coma or obtundation 1ardiac; hypertension" cardiac dysrhythmias.

Prgent treatment is re9uired if 1alcium 2-.HmmolB* 1louding of consciousness or confusion is present

)ypotension >evere dehydration causing pre-renal failure.

Management ,ehydrate patient ith iv J saline (3.%4). +im for about -56S8*B$&h depending on fluid status (1O()" urine output and cardiac function. #f patient does not pass urine for &h" pass a urinary catheter" and a central venous line to monitor 1O(.

Diuretics; once patient is rehydrated" continue J saline infusion and add frusemide &3mg every $56S&hours. 1ontinue monitoring 1O( carefully to prevent either fluid overload or dehydration. Monitor electrolytes" especially <0 and Mg$0 hich may fall rapidly ith rehydration and frusemide. ,eplace <0 ($356S&3mmolB* of saline) and Mg$0 (upto $ mmolB* saline) intravenously. #f this fails to reduce plasma 1a$0 ade9uately (1a$0 still 2$.=mM) then the follo ing measures should be considered; >almon calcitonin &33#P 9=h. This has a rapid onset of action ( ithin hours) but its effect lasts only $56S- days (tachyphylaFis). Disphosphonates inhibit osteoclast activity thereby causing a fall in plasma 1a$0. +dminister pamidronate at -356S83 mg iv over &56S8 hours. (+s a general rule give -3mg over &h if 1a$0 is Y- mmolB* or for all patients ith significant renal impairment" 83mg over =h if 1a$0 is -56S& mmolB*. 1a$0 levels begin to fall after &= hours and remain suppressed for up to 1& days. polendronate has a shorter infusion time (1Hmins) and is said to more effective ith a longer duration of action. >teroids (prednisolone -356S83mg po od); Most effective in hypercalcaemia due to sarcoidosis" myeloma or vitamin D intoFication. Iamilial benign hypocalciuric hypercalcaemia; 5Md1a$0" J $&h urinary 1a$0. This causes fe symptoms (mild fatigue or lethargy). The (T) may be raised but the patients do not respond to parathyroidectomy.

1auses of hypercalcaemia (rimary (or tertiary) hyperparathyroidism (=H4 of cases) Malignancy

o o

)umoral hypercalcaemia *ocal osteolytic hypercalcaemia (e.g. myeloma" metastases)

)yperthyroidism (present in 1H56S$34 of patients) Granulomatous disorders (sarcoidosis) Drug related

o o o o o

Oitamin D intoFication Theophylline toFicity 56TMilk-alkali56U syndrome Thia'ide diuretics *ithium (mild" present in H34 patients on long-term lithium)

#mmobili'ation ((aget:s disease) Denign familial hypocalciuric hypercalcaemia )T*O-1 infection may present ith severe hypercalcaemia (haeochromocytoma (part of ME+ type ##)" acromegaly +drenal failure ,habdomyolysis (calcium may be high or lo ) 1ongenital lactase deficiency

#nvestigations for hypercalcaemia (lasma 1a$0" (C--&" and Mg$0 P.Es

*ITs 1E, (lasma (T) level $&h urinary 1a$0 Prinary c+M(

,ypophosphataemia (lasma phosphate is normally 3.=56S1.&mmolB*. )ypophosphataemia is common" and often unrecogni'ed by clinicians. Most intracellular phosphate is present as creatine phosphate or

adenine phosphates (e.g. +T()" and in ,D1 the predominant species is $"--diphopshoglycerate. )ypophosphataemia does not necessarily indicate phosphate deficiency/ similarly phosphate deficiency may be associated ith normal or high plasma phosphate concentrations. 1auses of hypophosphataemia Modest (3.&56S3.AHmmolB*) Decreased dietary intake Oitamin D deficiency

1hronic liver disease )yperparathyroidism Decreased absorption (vit D deficiency" steatorrhoea" phosphate binding antacids) )ungry bones syndrome (post parathyroidectomy" acute leukaemia) *ymphoma or the leukaemias syndrome )yperaldosteronism Diuretics Ianconi syndrome

>evere (Y3.&mmolB*) ,espiratory alkalosis Treatment of diabetic ketoacidosis

+lcohol ithdra al (esp. ith ketoacidosis) +cute liver failure )yperalimentation (i.e. feeding after starvation) Oentilation of chronic severe respiratory failure Jeuroleptic malignant

(resentation Most cases of severe hypophosphataemia occur in very sick patients (often in an #TP). Cccasionally seen in asymptomatic patients. 1oincident Mg$0 deficiency eFacerbates (C--&" depletion and vice versa.

Modest hypophosphataemia has no effect" but arrants investigation. >evere hypophosphataemia (Y3.&mmolB*) may cause symptoms and re9uires treatment.

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

1ardiomyopathy Erythrocyte dysfunction *eukocyte dysfunction Metabolic acidosis 1J> dysfunction (encephalopathy" irritability" sei'ures" paraesthesiae" coma) ,espiratory failure ,educed platelet half-life Mineral mobili'ation

Treatment (hosphate repletion should generally be reserved for patients ith sustained hypophosphataemia. Give oral effervescent (hosphate >ando'QR $ tabs tds or potassium phosphate iv (%56S1=mmolB$&h). EFcessive phosphate replacement may cause hypocalcaemia and metastatic calcification/ monitor 1a$0" (C&--" <0" and other electrolytes. Pituitary apople$y (resentation (ituitary infarction may be silent. +popleFy implies the presence of symptoms. The clinical manifestations may be due to leakage of bloodBnecrotic tissue into the sub-arachnoid space or rapid eFpansion of a suprasellar mass and pressure on local structures. This may be the presenting symptom of the pituitary tumour. )eadache occurs in %H4 of cases (sudden onset/ variable intensity) Oisual disturbance occurs in A34" (usually bitemporal hemianopia)

Ccular palsy (&34) causing diplopia. Pnilateral or bilateral JauseaBvomiting Meningism (common) )emiparesis or rarely sei'ures Iever" anosmia" 1>I rhinorrhoea" and hypothalamic dysfunction (disturbed sympathetic autoregulation ith abnormal D( control" respiration" and cardiac rhythm) are all described" but are rare +ltered mental state" lethargy" delirium" or coma >ymptoms of preceding pituitary tumour +cute hypopituitarism.

1linically" pituitary apopleFy 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 fe days. The clinical course is variable. )eadache and mild visual disturbance may develop slo ly and persist for several eeks. #n its most fulminant form" apopleFy may cause blindness" haemodynamic instability" coma" and death. ,esidual endocrine disturbance (panhypopituitarism) invariably occurs. #nvestigations 56h P.Es )yper- or hyponatraemia may occur. 56h Endocrine 1lotted blood for cortisol" thyroid function" prolactin" G)" and the tests gonadotrophic hormones. 56h 1T scan (ituitary cuts" ith administration of iv contrast" ill reveal a tumour mass (or haemorrhage) ithin $&56S&= hours. 56h M,# scan May be useful in the sub-acute setting. Management >tabili'e the patient (+ir ay" Dreathing" 1irculation). )ydrocortisone 133mg iv should be given if the diagnosis is suspected after the blood samples above have been collected.

Monitor P.Es and urine output for evidence of diabetes insipidus. Jeurosurgical decompression may be indicated (seek neurosurgical revie ). Cbtundation and visual deterioration are absolute indications for neurosurgery. (atients ithout confusion or visual disturbance generally do ell ithout surgery. +ssess pituitary function once the acute illness has resolved and treat as necessary. + T>) in the normal range may be inappropriate if the T& is lo in pituitary disease" but this may occur in the sick euthyroid state characteristic of many seriously ill patients.

1auses of apopleFy in patients ith pituitary adenomas >pontaneous haemorrhage (no obvious precipitant" the commonest) +nti-coagulant therapy

)ead trauma ,adiation therapy Drugs (e.g. bromocriptine or oestrogen) Iollo ing tests of pituitary function.

,ypopituitary coma )ypopituitarism does not become evident until AH4 of the adenohypophysis is destroyed" and at least %34 destruction is re9uired for total loss of pituitary secretion. 1omplete loss of hormone secretion can rapidly become life threatening and re9uires immediate therapy. #n a mild or incomplete form" hypopituitarism can remain unsuspected for years. (resentation

#n the absence of stress" patients ith severe hypopituitarism may have fe symptoms or signs. + general anaesthetic or infection may precipitate hypoglycaemia and coma" due to the combination of a lack of G)" cortisol" and thyroFine" all of hich have a counter-regulatory effect on insulin. 1lues from the history include <no n pituitary adenoma ,ecent difficult delivery; pituitary infarction follo ing postpartum haemorrhage and vascular collapse is still the commonest cause of hypopituitarism. Ieatures include failure of lactation (deficiency of prolactin Q^ oFytocin)" failure of menstruation (lack of gonadotrophins)" non-specific features" e.g. tiredness" eakness" loss of body hair" and loss of libido (due to +1T) deficiency" hypothyroidism" and gonadotrophin deficiency)

Men may give a history of impotence" lethargy" and loss of body hair bomen report loss of menstruation.

EFamination EFamination of the comatose patient is discussed on (&3856S1H EFamine specifically for secondary seFual characteristics and physical signs of myFoedema

1onsider other causes for coma ((&38).

#nvestigations General investigations for patients in coma are discussed on (&3= Take blood for baseline cortisol" +1T)" thyroid function" *)" I>)" prolactin" and G)

>hort synacthenQR test must be performed to test for adrenocortical reserve ((H=8) *),) and T,) test can be performed at the same time as the short >ynacthenQR test Defer formal pituitary function testing until the patient is stable 1T scan of pituitary (tumour or empty sella) M,# scan may give additional information.

Management General measures are as for any patient in coma ((&38) Give iv colloids Q^ saline to restore D( if the patient is in shock

Give glucose if the patient is hypoglycaemic )ydrocortisone 133mg iv should be administered if the diagnosis is suspected and continued (133mg iv tds" see (H=8) >tart tri-iodothyronine (13Q\g bd) after hydrocortisone is started

#nvestigate and treat any precipitating intercurrent infection #f the patient fails to improve" consider other causes for coma (see (&38) *ong term" the patients ill re9uire replacement ith hydrocortisone or prednisolone" thyroFine" testosterone" oestrogenBprogesterone Q^ G).

1auses of panhypopituitarism (ituitary Mass lesions (adenomata" cysts) (ituitary surgery or irradiation

#nfiltrative (haemochromatosis) #nfarction (>heehan:s) +popleFy (haemorrhage) Empty sella syndrome

)ypothalamic Mass lesions (metastases" e.g. breast" lung/ craniopharyngiomas) ,adiotherapy

#nfiltration (sarcoid" histiocytosis) Trauma" e.g. fractured skull base #nfections (TD)

Polyuria Definition; 2- litres urine per day. (resentation 1onfusion (hyponatraemia or dehydration) 1oma

(roteinuria on screening Depression or other psychiatric manifestations ,enal stones. EFcessive fluid intake Endocrine dysfunction (DM" diabetes insipidus" hypercalcaemia) )ypokalaemia

1auses

#ntrinsic renal disease (polycystic kidneys" analgesic nephropathy" medullary cystic disease" amyloidosis) or renal recovery from +TJ. (ost obstructive" e.g. after catheteri'ation of patient in chronic retention. (ost renal artery angioplasty Drugs (frusemide" alcohol" lithium" amphotericin D" vinblastine" demeclocycline" cisplatinum). Duration and severity (nocturia" fre9uency" ater consumption at night) I) of diabetes mellitus" polycystic kidneys" renal calculi Drug history (diuretics" analgesics" lithium" etc." see above) ,enal calculi (hypercalcaemia) beakness (lo potassium)" depression (hypercalcaemia) (sychiatric history Endocrine history (menses" seFual function" lactation" pubic hair) Cther significant pathology (e.g. causes of amyloid).

)istory

#nvestigations P.Es (renal disease" hypokalaemia) Glucose

1alcium" phosphate" and alkaline phosphatase (lasma and urine osmolality Ka P;( osmolality of Y1.3 indicates diabetes insipidus" intrinsic renal disease (incl. 5MS<0)" or hysterical drinkingL +E, (nephrocalcinosis) *ithium levels if appropriate Dipstick protein and 9uantitation if indicated.

Management +ssess fluid status (eO(" D(" postural drop" eight charts" 1O(). >trict fluid balance and daily eights.

#nsert central line to monitor the 1O(. Measure urinary sodium and potassium (random samples ill give an indication of the loss of sodium or potassium initially" and if losses are great" accurate timed samples of Y8 hours are possible). ,eplace fluid losses as appropriate to maintain a normal homeostasis" using combinations of saline and deFtrose.

Monitor potassium" calcium" phosphate" and magnesium daily or t ice daily if necessary. #f lithium toFicity is present" see (=$3. +void chasing fluids. +t some point a clinical !udgement has to be made to stop replacing urinary losses ith iv fluids to allo the patient to reach their 56Tnormal e9uilibrium56U. Cnce the patient is optimally hydrated then avoid replacing fluids iv to allo physiological homeostasis to occur. #f diabetes insipidus suspected" arrange ater deprivation test (see belo ).

bater deprivation test >top all drugs the day before the test/ no smoking or caffeine >upervise the patient carefully to prevent surreptitious drinking

Empty the bladder after a light breakfast. Jo further fluids po beigh the patient at time 3" &" H" 8" A" = hours into the test (stop the test if 2-4 of body eight is lost) Measure serum osmolality at -3 minutes" & hours" and hourly till end of the test (check that the plasma osmolality rises to 2$%3mosmolBkg to confirm an ade9uate stimulus for +D) release) 1ollect urine hourly and measure the volume and osmolality (the volume should decrease and the osmolality rise/ stop test if urine osmolality 2=33mosmolBkg as D# is eFcluded) #f polyuria continues" give desmopressin $3mcg intranasally at = hours +llo fluids po ( ater) after = hours. 1ontinue to measure urine osmolality hourly for a further & hours

#nterpretation Jormal response; urine osmolality rises to 2=33mosmolBkg ith a small rise after desmopressin 1ranial D#; urine osmolality remains lo (2&33mosmolBkg) andincreases by 2H34 after desmopressin

Jephrogenic D#; urine osmolality remains lo (Y&33mosmolBkg) andonly rises a little (Y&H4) ith desmopressin (sychogenic polydipsia; urine osmolality rises (2&33mosmolBkg) but istypically less than the normal response