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2002 FRACP paper two


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Question 1 top download pdf

A 45 year old man presents with 6/24 history of palpitations, sweating, dyspnoea and chest pain. His BP is 90/60 mmHg. His ECG is shown below:

The most appropriate treatment of his arrhythmia is:
A. IV amiodarone
B. IV digoxin
C. IV sotalol
D. Cardioversion
E. Overdrive cardiac pacing

Answer: D

Sustained, monomorphic ventricular tachycardia:
- Wide, regular QRS complexes (> 120ms)

Differential Diagnosis

1) SVT with aberrances (may be revealed with vagal manoeuvres)
2) Pacemaker or ICD
3) ECG artefact

If unsure, treat as VT because:

- 80% of wide complex tachycardias are caused by VT (up to 95% in those with previous AMI)
- VT treatment can terminate other arrhythmias
- SVT treatment (eg adenosine) may precipitate VF

VT is classified and managed according to:

1) Duration: sustained vs non-sustained (3-15 beats)
2) Morphology: monomorphic vs polymorphic
3) Symptoms: palpitations, dyspnoea, chest pain, syncope
4) Haemodynamic stability
5) ?Caused by AMI- if yes, treat as unstable because can deteriorate quickly and worsen ischaemia

Unstable patient
  • conscious but pulse and BP still present
    • Synchronised cardioversion
    • If not possible because cannot differentiate between QRS and T, defibrillate as per VF
    • Treat low K (commonest cause) and Mg
  • unconscious/ pulseless
    • Defibrillate as per VF
    • CPR +/- adrenalin
    • Treat low K and Mg
Stable patient
  • Urgent synchronised cardioversion
  • If refractory or prolonged, anti-arrythmics (class 1 or 3)
    • IV Lignocaine (especially effective if known cardiac ischaemia) or
    • IV amiodarone
    • Or if EF >40%, IV sotalol or IV procainamide
  • Treat low K and Mg, heart failure, ischaemia
  • If known VT syndrome with no structural abnormalities, consider using previous calcium channel blocker or beta-blocker

A. and C.
IV amiodarone and sotalol is appropriate and can be used, but is 2nd line to cardioversion (some studies suggest it is less useful in reversion compared to procainamide and sotalol (Marill KA et al. Amiodarone is poorly effective for the acute termination of ventricular tachycardia. Ann Emerg Med 2006 Mar)

Digoxin suppresses the AV node by increasing vagal tone, thus it precipitates ventricular arrythmias, not suppress it.

Overdrive cardiac pacing will not change the ventricular response.
Cardiac pacing eg in pacemakers work by providing electrical stimuli when they sense intrinsic cardiac potentials being too low or absent (eg in heart block).
For ventricular tachycardias, an ICD is required to cardiovert/defibrillate when it senses that ventricular rate exceeds a programmed cut-off rate.

Monomorphic VT
  • usually from heart disease (IHD)
  • or “idiopathic” (named after sites of origin, usually exercise induced)
Polymorphic VT
  • malignant form of VT that degenerates into VF
  • usually from QT prolongation (drugs or congenital) or electrolyte imbalance
  • classically Torsades de pointes


Cardiology - Arrhythmias


Question 2 top Download PDF

2) A couple comes to you because they want to start a family. There is a vague history of thalassaemia in both families. Which one of the following would cause the least concern to this couple?


The woman is carrier for

The man is carrier for


b thalassaemia

b thalassaemia


a0 thalassaemia

a0 thalassaemia


a+ thalassaemia

a0 thalassaemia


Haemoglobin E

b thalassaemia


a0 thalassaemia

b thalassaemia

b = beta
a= = decreased alpha chain production
a0 = absent alpha chain production



  • Disorders affecting structure, function or production of Hb
  • Common and selective advantage in endemic malaria areas
  • Different Hb are produced during embryonic, foetal and adult life
  • Each Hb is a tetramer comprising 4 globin chains
    • Major adult Hb (Hb A): a2b2
    • Minor adult Hb (HbA2): a2d2
    • Foetal Hb (Hb F): a2g2 (dominates from 10 weeks gestation to 6/12 old)
  • Each globin chain consists of protophyrin IX ring complexed with iron atom Fe2+
  • Each binds one oxygen molecule; every molecule of Hb binds 4 oxygen molecule


  • Oxygen binding to Hb increase in affinity with increase oxygen tension -> Oxygen dissociation curve
  • Hb has ß affinity in ßpH and increase2,3 bisphosphoglycerate -> oxygen transport to tissues
  • When one molecule of oxygen binds, it is easier for the next to bind -> Cooperativity
  • Inheritance: Autosomal co-dominant traits
    • Compound heterozygotes who inherit a different abnormal allele exhibit features of both


  • Detection: Electrophoresis
    • Some Hb variants are electrophoretically silent
      • High pressure liquid chromatography (HPLC)
      • Isoelectric focusing
      • PCR to identify globin chain mutation
    • Functional tests: sickling test; solubility, oxygen affinity tests
    • Antenatal dx: PCR amplification of foetal DNA (amniocentesis/ chorionic villus sampling)

Types of Haemaglobinopathies





Mutations affect amino acid sequence of globin chain

Sickle cell anaemia


Mutations that impair production or translation of globin mRNA -> deficient globin chain synthesis

ß globin supply -> ß Hb tetramers
Unbalanced chain synthesis
Hypochromia and microcytosis
Clincal phenotype depends on which globin affected, degree of impairment, altered synthesis of other globins + coninheritence of other abnormal globin alleles

b thalassaemia

Thalassaemia haemoglobin variants

Combined deficient globin chain synthesis with structural haemaglobinopathies

Importance is that compound heterozygotes with b thalassaemia can have intermedia or major, rather than the homozygotes who usually have mild disease

Hb Lepore
Hb E
Hb Constant Spring

Hereditary persistence of HbF

increase levels of HbF in adult life with no deletrious effect



Modification of Hb molecule by toxins and abnormal Hb synthesis

CO poisoning
increase HbF in preleukaemia


a Thalassaemia Syndromes

  • a thalassemias are symptomatic in utero and after birth because a globin needed for synthesis for foetal Hb too
  • Non deletion alleles are also common -> increase unstable a globin variants that are functionally useless




a thal 2
(a thal minima)

One allele of one chromosome deleted

Asymptomatic silent carrier

a thal 1
(a thal minor)

Both alleles on one chromosome deleted
- -/aa

Clinically resembles b thalassemia minor


Hb H disease
(Heterozygous a thal1 athal2)


HbA production only 25% normal
Accumulate unpaired b chains
Can form b4 tetramers (HbH)

Clinically b thalassaemia intermedia

  • Moderate haemolytic anaemia
  • Mildly ineffective erythropoiesis
  • Can survive into mid adulthood w/o transfusions

Hydrops fetalis
(Homozygous a thal 1)


Total absence of a globin synthesis

Excess g chains form Hb Barts (g4 tetramers): increaseincrease oxygen affinity thus delivers almost no oxygen to foetus

  • death in utero (increase output cardiac failure)
  1. Risks b thalassaemia major


  1. Disaster – risks complete absence of a globin synthesis ie hydrops fetalis
  1. Risks Hb H


  1. Hb E (a2b2 26Glu->Lys) mildly unstable Hb variant. Interaction of HbE and b thalassaemia can lead to compound heterozygotes with b thal intermedia/ major
  1. Correct. In fact may lead to comparatively less excess a globin chains. a globin chains are highly insoluble and tend to accumulate -> form toxic inclusion bodies -> kill developing erythroblasts in marrow.


Haematology: Haemoglobinopathies Repeat question2001 paper two question 65


Question 3 top

Question 4 top

Question 5 top Download PDF

In patients with cirrhosis and oesophageal varices, the strongest predictor of variceal bleeding is:

  1. Prothrombin time
  2. Platelet count
  3. Child- Pugh’s class
  4. Portal venous pressure
  5. Systemic blood pressure



Portal hypertension

  • Portal pressure = Portal flow volume x resistance to outflow from portal vein
  • Defined as > 5mmHg
  • Obstruction to portal venous outflow
    • Pre-sinusoidal (postal vein thrombosis, portal fibrosis, infiltrative lesions)
    • Sinusoidal (hepatic cirrhosis)
    • Post-sinusoidal (veno-occlusive disease, Budd-Chiari)
  • Splanchnic vasodilation -> relative renal hypoperfusion -> activates renin-angiotensin-aldosterone system -> salt and fluid retention
  • Oesophageal varices form when difference between portal veins and hepatic veins > 12mmHg
  • Meta-analysis of 12 studies showed that ß in hepatic venous pressure gradient HVPG < 12 mmHg -> significant ß in variceal bleeding and mortality
    • HPVG = WHVP – FHVP
      • WHVP: Wedged hepatic venous pressure (approximates sinusoidal pressures)
      • FHVP: Free hepatic venous pressure
  • Portal HT -> oesophageal varices, haemorrhoids, ascites, splenomegaly (+/- pancytopenia from sequestration)

Variceal bleeding:

  • Each bleed 30% risk of death
  • If survive 1st bleed, risk of rebleeding in 1 year is 70%
  • 90% of those with cirrhosis will develop varices
  • 20% with small varices progress to large varices in 1 year

Risk classification of predicting bleeds:

  • Child Pugh’s class
Classification of severity of liver disease

Class A: Score 5-6 (well compensated), 1 year survival 100%
Class B: Score 7-9 (significant functional compromise), 1 year survival 80%
Class C: Score 10-15 (decompensated), 1 year survival 45%

  • Variceal size
  • Independent risk factor for bleed (LaPlace’s law – small increase radius -> big increase in wall tension -> increase rupture risk)
  • Need to insufflate the oesophagus with air for accuracy
    • F1: small and straight varices
    • F2: enlarged and tortuous, occupy < 1/3 lumen
    • F3: large coiled shaped, occupy > 1/3 lumen


  • Variceal appearance
  • Presence of red wale markings is increase risk
  • Continued ETOH abuse


Primary prevention:

  • B-blockers
    • Propanolol or nadolol
    • ß bleeding rates in large varices but no clear mortality benefit
    • No ß bleeding rate/ mortality benefit in small varices
  • Variceal band ligation
    • ß bleeding rates at both 1st and 2nd year
    • Mortality benefit significant at 2nd year
    • Banding better than B blocker but costly
  • Useless: sclerotherapy, nitrates


Secondary prevention:

  • B blockers
    • ß rebleeding and mortality
  • B blockers + endoscopic banding vs B blocker alone
    • < rebleeding but no mortality difference
    • Cease B blocker when varices eradicated
    • Banding better than sclerotherapy


Acute variceal bleed:

  • Non aggressive resuscitation
    • Aim systolic BP 90mmHg sufficient
  • Evidence for:
    • Octreotide (somatostatin analogue)
    • Terlipressin (vasopressin analogue: more sustained effect compared octreotide)
    • Vasopressin (direct vasoconstrictor of mesenteric arterioles thus ß portal venous inflow – only marginal effects in early rebleeding bleed and no mortality benefit in acute bleed) + nitrates (to counteract effect of systemic vasoconstriction)
    • Endoscopic Rx with banding +/- sclerotherapy OR balloon tamponade (only for short term)
  • Some evidence for prophylactic antibiotics (ß overall mortality and ß infectious complications)
  • Debatable: use of B blockers


Causes of acute GIT bleed

  • Peptic ulceration
  • Gastritis/ erosions
  • Oesophageal variceal bleeding
  • AV malformations
  • MW tears


  • Tumours
  • Dieulafoy lesions (dilated aberrant submucosal vessel 1-3mm that erodes overlying epithelium)
  • Gastric antral vascular ectasia (GAVE/ watermelon stomach: ectatic and sacculated mucosal vessels in cirrhosis or systemic sclerosis or idiopathic)
  • Haemosuccus pancreatitis (bleeding from pancreatic duct with cancer, pseudocyst or chronic pancreatitis eroding into vessel)
  • Aorto-enteric fistula (D3 or D4, followed by jejunum and ileum; from atherosclerotic AAA, syphilis or TB, AAA vascular graft)
  • Cameron lesions (erosions or ulcers in sac of hiatal hernia)


Gastroenterology:CLD complications cirrhosis: ascites, encephalopathy, portal hypertension/varices.


Question 6 top Download PDF

A 35 year old man is found to be hypertensive with a blood pressure of 180/110 mmHg. At presentation, on no treatment, the following results are obtained.

Serum potassium          3.3 mmol/L        (3.5 – 5.0)
Urinary potassium         40 mmol/L         (<30)
Plasma aldosterone       620 pmol/L        (supine 50-450)
Plasma renin                 4mU/L               (ambulatory 5 -75)

The most appropriate next investigation is measurement of:

  1. 24 hour urinary aldosterone
  2. Plasma aldosterone after 4 hours of saline infusion
  3. Plasma aldosterone after 5 days of dexamethasone administration
  4. Plasma aldosterone after synthetic ACTH administration
  5. Adrenal venous aldosterone concentration during bilateral venous catheterisation


Important facts provided:

  • Severe hypertension in a young person - look for secondary causes
  • Hypokalaemia with increased urinary potassium losses
  • Inappropriately high plasma aldosterone: renin ratio, suggesting autonomous aldosterone secretion

Secondary causes of Hypertension

  • Check: if young (<50), severe or refractory hypertension, no family history of hypertension, acute rise over previously stable blood pressure values
  • Also check for end organ damage (retinopathy and papilloedema, nephropathy and cardiomyopathy) and other cardiovascular risk factors






increased steroids (Cushing’s)

  • Primary eg adrenal tumour
  • Secondary eg increased ACTH
  • Exogenous steroids

increased renin

  • Primary eg renin secreting tumour (rare)
  • Secondary eg renal artery stenosis

increased mineralocorticoid (aldosterone)

  • Primary eg adrenal tumour/ hyperplasia
  • Secondary eg high renin or high ACTH (glucocorticoid remediable aldosteronism GRA)


Hypercalcaemia eg primary parathyroidism


Renal failure


Renal artery stenosis

Coarctation of the aorta
- suspect if bilateral upper limb hypertension and faint femoral pulses

Sleep apnoea


When triad of hypertension, hypokalaemia and metabolic alkalosis present

  • Suggests increased mineralocorticoid levels (mainly hyperaldosteronism and to lesser extent, deoxycortisone)
  • Leads to sodium and water retention, urinary potassium loss and thus hypokalaemia, loss of urinary hydrogen ions thus alkalosis
  • Note: normokalaemia often more common in primary hyperaldosteronism (>50%) and always the case in GRA


  1. Primary hyperaldosteronism (increased plasma aldosterone, decreased plasma renin)
    • Aldosterone secreting adrenal adenoma (unilateral/ bilateral)
    • Ectopic adrenal adenoma
    • Adrenal hyperplasia (idiopathic ?increased sensitivity to angiotensin)
    • Familial hyperaldosteronism (autosomal dominant)
        • Type 1: GRA
        • Type 2: Non- GRA
  2. Apparent mineralocorticoid excess (decreased plasma aldosterone, decreased plasma renin)
    • Genetic disorder: mutation in 11-beta-hydroxysteroid dehydrogenase Type 2 enzyme
    • Chronic liquorice ingestion: deactivation of this enzyme
  3. Renovascular disease (increased plasma aldosterone,inceased plasma renin)
  4. Diuretics
    • Pre-existent hypertension, diuretics cause urinary potassium losses eg frusemide
  5. Cushing’s (decreased or normal aldosterone, decreased or normal renin)
    • Aldosterone and cortisol bind to mineralocorticoid receptors with equal affinity
    • Normally, even though plasma glucocorticoid levels are >100x than aldosterone, enzyme 11B- HSD Type 2 inactivates cortisol
    • In Cushing’s, this mechanism is overwhelmed by the vast excess of cortisol
  6. Liddle’s syndrome (decreased plasma aldosterone, decreased plasma renin)
    • Rare autosomal dominant disease: primary increased sodium reabsorption and potassium loss in proximal tubules
  7. Renin secreting tumours (increaed plasma aldosterone, increased plasma renin)

Approach to this patient

  • Plasma aldosterone: renin ratio
  • Urinary potassium (spot value also acceptable)
  • To confirm primary hyperaldosteronism either:
  • 3 days oral sodium chloride then retesting of plasma aldosterone
  • 4 hour 2L saline infusion IV then retesting of plasma aldosterone

(Principle is that in normal subject, aldosterone will be suppressed)

  • To confirm source
  • Imaging (either CT or MRI are reasonable)
  • Bilateral adrenal vein testing (gold standard) if no adrenal masses seen on imaging, or if both adrenals are asymmetrical/abnormal

Back to the question

  1. Not helpful
  2. Correct
  3. This is assuming the hyperaldosteronism is GRA, so that when dexamethasone is administered -> suppresses ACTH which is stimulating aldosterone secretion. In any case there is hypokalaemia in this patient, which is unusual for GRA
  4. Synthetic ACTH (or Synacthen test) usually used to test for cortisol deficiency. Under normal circumstances, aldosterone secretion is NOT ACTH-dependant.
  5. As above


Endocrinology: Endocrine causes of hypertension

Question 7 top

Question 8 top

Question 9 top Download PDF

 A 37 year old man with known human immunodeficiency virus (HIV) infection for 10 years presents with severe renal colic for which he has no prior history. Tests performed 2 weeks before have shown a normal full blood count and biochemistry screen (including serum calcium), CD 4+ T cell lymphocyte count of 36 cells/mm3, HIV RNA concentration (viral load) of 83,000 copies/mL. His medications include zidovudine (AZT) , lamivudine (3TC), indinavir, azithromycin and dapsone.

The most likely cause for his renal colic is:

A. HIV associated opportunistic infection

B. HIV associated malignancy

C. HIV associated hypercalciuria

D. Adverse drug reaction

E. Unrelated to HIV infection or therapy


Learning issues

  1. Natural history of HIV
  2. Renal disease in HIV patient
  3. Anti retrovirals, drug classes and common side effects
  4. Prophylaxis

Natural history of HIV

  1. Primary infection: 50% asymptomatic, 50% develop “acute HIV syndrome” with flu-like symptoms and lymphadenopathy
  2. Initial viral load does not appear to be related to degree of disease progression
  3. Set point of steady state plasma viremia after 1 year correlates well with degree of disease progression
  4. Chronic infection persists in untreated patient for a median of 10 years before clinical illness
  5. CDC case definition of AIDS: any HIV infected person with CD4 < 200/microL, regardless of symptoms
  6. Long term survivor: if remain alive > 20 years after initial infection, in most there would be disease progression
  7. Long term non-progressor: infected for > 20 years with normal CD4 counts and plasma HIV RNA < 50 copies/mL without anti-viral therapy (noted strong associations with HLA B57 and HLA B27)

Renal disease in HIV patient

  1. HIV associated nephropathy
  2. 90% cases in African American and Hispanics (also more severe)
  3. Seen in children, first described in IVDU
  4. Leading cause of ESRF in HIV population
  5. Proteinuria
  6. HT and oedema rare
  7. Renal biopsy: 80% FSGS, 50% mesangial proliferation
  8. Some responsive to high dose steroids
  1. Drug toxicity
  2. Directly nephrotoxic: amphotericin,pentamidine, adefovir, tenofovir
  3. Most common: indinavir associated renal calculi (10% of patients receiving indinavir), ranges from asymptomatic haematuria to renal colic, treat with hydration


  1. Urinary tract infections (opportunistic or otherwise)
  1. Urinary tract malignancies
  2. increased risk of malignancies in HIV population
  3. mainly KS and NHL
  4. no particular mention of increased risk of urological cancers
  5. KS can affect any organ but not particularly the urinary tract

Goals of treatment

  1. Maximal viral suppression
  2. Sustain rise in CD4 counts
  3. Improve morbidity and mortality
  4. Prevention of resistance + compliance
  5. Minimisation of side effects

Indications for treatment

  1. Acute HIV syndrome (primary infection)
  1. Chronic infection
  2. Symptomatic (regardless of CD4 count and viral load)
  3. Asymptomatic (CD4 count < 350 and decreasing or viral load > 50 000 copies/mL)


  1. Post-exposure prophylaxis
  2. Percutaneous risk 0.3%
  3. Mucous membrane exposure 0.09%
  4. Through intact skin/ other body fluids eg urine: cases documented but risk < 0.09%


Drug Class

Mechanism of Action

Examples and side effects

Reverse transcriptase inhibitors


  1. Nucleoside analogue (NRTI)

(-udines and osines)










  1. Nucleotide analogue





  1. Non-nucleoside analogue (NNRTI)

Block HIV replication at point of RNA dependant DNA synthesis


1) and 2) inhibit a variety of DNA polymerases including that of human mitochondria















Generally 3) are more selective for HIV 1 reverse transcritptase thus less side effects, often used in salvage regimens


Drug interactions as involved with cytochrome p4503A4

  1. NRTI

eg zidovudine (AZT)

  1. mitochondrial toxicity with lactic acidosis, fatty liver, myopathy, pancreatitis
  2. initial fatigue/ N+V and headache tends to subside

eg didanosine

  1. painful sensory neuropathy in 30% (resolves with durg cessation)
  2. pancreatitis at higher doses 10%

eg stavudine

  1. antagonistic with zidovudine
  2. fatty liver and neuropathy

eg lamivudine

  1. best tolerated, often used with AZT
  2. strains resistant to lamivudine have enhanced sensitivity to other nucleosides

eg abacavir

  1. hypersensitivity reaction in 4%
  2. stop drug as rechallenge can be fatal


  1. Nucleotide analogue

eg tenofovir

  1. renal impairment with hyperphosphataemia
  2. increases in vivo levels of didanosine (needs dose reduction)



  1. NNRTI
  2. eg neviparine, delavirdine, efavirenz
  3. no activity against HIV 2
  4. maculopapular rash in 1st few weeks
  5. fatal hepatotoxicity
  6. vivid dreams and light-headedness with efavirenz (take nocte)
  1. nevirapine induces p450
  2. delavirdine inhibits p450
  3. efavirenz unpredictable


Protease inhibitors
(-avirs) except abacavir which is a NRTI

Used together with reverse transcriptase inhibitors

  1. can suppress viral load to <50/mL > 5 years



Many drug interactions


Absolute contraindications

  1. benzodiazepines (prolonged sedation), use propafol
  2. lovastatin (rhabdomyolosis), use pravastatin
  3. ciscapride (prolong QT, torsades)
  4. most antihistamines except loratidine

Hepatic cytochrome p450 3A4

  1. Ritonavir potent competitive inhibitor of these enzymes
  2. Saquinar, indavinar etc metabolised by these enzymes
  3. Thus baby dose ritonavir used as pharmacological boosting
  4. Ritonavir seldom used alone in full doses as poorly tolerated (GIT and neuropathy)


  1. 1st PI used in triple therapy
  2. Nephrolithiasis in 4%
  3. Asymptomatic indirect hyperbilirubinaemia 10%
  4. Dose reduce in liver cirrhosis

Nelfinavir and amprenavir

  1. unique reistance profiles and GIT side effects
  2. nelfinavir resistance with D30N substitution as viruses with this mutation are more sensitive to other PIs (so good initial PI
  3. Amprenavir resistance with single amino acid substitution (good salvage drug): fatal skin reaction in 1%


  1. may not be associated with as severe lipid effects as other PI


Entry inhibitors

Trials on going

  1. CCR5 inhibitors
  2. Integrase inhibitors

Interferes with virus binding to target cell CD4 receptor/ co-receptor (CCR5 or CXR4), or affects viral fusion

Fusion inhibitor

  1. enfuvirtide T20
  2. binds to viral envelope and prevents fusion of viral and host membrane
  3. twice daily C/S injection
  4. 98% injection site reactions
  5. increased risk of bacterial pneumonia


Lipodystrophy syndrome

  1. fat wasting/ accumulation, high lipids, glucose intolerance +/- insulin resistance




Hepatitis B vaccine (3 doses)

Anti HBc and antiHBs negative

Hepatitis A vaccine (2 doses)

Anti HAV negative

Chronic HBV
Chronic HCV

Influenza virus (annual)


Pneumococcal vaccine
(Strep pneumoniae)

All when CD4 > 200


For prevention of severe/ frequent occurrences


What to use

Herpes simplex

Acyclovir 200mg TDS


Fluconazole 200mg BD

Other prophylaxis





  1. when CD4 < 200
  2. can stop when CD4 > 200 for 6/12

Bactrim DS

Pentamidine neb


  1. high exposure
  2. skin test >5mm

Isoniazid + Pyridoxine

If isoniazid resistant, use
Rifampicin or rifambutin



  1. when CD4 < 50
  2. prior disemminated disease
  3. can stop when CD4 > 100 for 6/12

Azithromycin or clarithromycin


Toxoplasmosis gondii

  1. Ig G positive
  2. CD4 < 100

Bactrim DS

If prior encephalitis, use
Sulfadiazine + pyrimethamine + leucovorin

Dapsone + leucovorin + pyrimethamine



Varicella zoster (exposed)

  1. no previous disease
  2. no immunisation

Varicella zoster immunoglobulin IM within 96 hours


Cryptococcus neoformans

Fluconazole oral

Amphotericin IV 3x/week

Itraconazole oral


  1. prior end organ disease
  2. can stop when CD4 >100 for 6/12

Ganciclovir oral/IV


Doses and duration vary dependant on what end organ affected



Amphoterecin weekly IV

Coccidiodes immitis


Amphotericin weekly IV

Itraconazole oral


  1. prior bacteraemia

Cirpofloxacin oral



Infectious Diseases: HIV

Reapeated Question 2003 paper two question 66

Question 10 top

Question 11 top

Question 12 top Download PDF

A 44-year-old man presents with tonic-clonic seizures. He gives a six month history of episodes of confusion beginning with a sensation of déjà vu followed by a loss of awareness.

His electroencephalogram (EEG) is shown below:

The most likely diagnosis is:

  1. Late onset primary generalised epilepsy
  2. Frontal lobe epilepsy
  3. Temporal lobe epilepsy secondary to a cavernoma of the temporal lobe
  4. Temporal lobe epilepsy secondary to an acute abscess of the temporal lobe
  5. Non-epileptic attacks



Important information provided:

  • Age 44: narrows down likely causes (idiopathic/ genetic aetiologies less likely)
  • Sensation of “déjà vu”: temporal lobe an area of suspicion
  • Suggests partial seizure with secondary tonic clonic generalisation
  • In EEG
    • Parasagittal EEGs of L and R look relatively similar
    • R temporal EEG has spike wave form superimposed on a pattern that is otherwise similar to that L temporal EEG

Learning Issues:

  • Mechanisms of seizure
  • Causes of seizures according to age groups
  • Characteristic EEG findings
  • Ddx of seizures

Mechanisms of seizures:

  • Imbalance between ionic microenvironment, resting membrane potential and neurotransmitter action
  • Seizure initiation and propagation
  • Many factors influence neuronal excitability:
    • Intrinsic: channel conductance, receptors, buffers, 2nd messengers
    • Extrinsic: neurotransmitters, properties of the synapse

Seizure Classifications

  • Partial
    • Simple partial (preservation of consciousness with changes in somatic sensation, motor, autonomic or psychic signs)
    • Complex partial (altered conscious state with automatisms and post-ictal confusion)
    • Partial with secondary generalisation (usually tonic-clonic)
  • Primary Generalised
    • Absence (petit mal)
    • Tonic-clonic
    • Tonic (grand mal)
    • Clonic
    • Atonic
    • Myoclonic
  • Unclassified (likely reflection of differences in neuronal structure/function in immature CNS)
    • Neonatal seizures
    • Infantile spasms

Seizure aetiology according to age group

Age Group


Neonates (<1/12)

Developmental disorders
Genetic disorders

Perinatal hypoxia and ischaemia
ICH and trauma
Acute CNS infection
Metabolic causes eg hypoglycaemia, pyridoxine deficiency
Drug withdrawal (ETOH, cocaine, heroin)

Infants and children

Idiopathic (eg juvenile absence epilepsy)
Febrile seizures
Genetic disorders
Developmental disorders

CNS infection (especially viral encephalitis)

Adolescents (12-18)

Epilepsies that are idiopathic or genetically based ß in frequency,
acquired causes start to predominate

Trauma – strongly correlated to severity of injury
CNS infection
Brain tumours
Drugs and toxins (including ETOH withdrawal)

Older adults (>35)


  • 50% of new cases of epilepsy in age >65
  • Acute seizures more likely with embolic stroke
  • Chronic seizures occur months to years post event secondary all forms of stroke

Trauma (including SDH)
Brain tumours
Neurodegenerative diseases
Drugs and toxins


  • Neurophysiologic measurements of electrical activity of the brain by externally placed electrodes on the scalp (or in special circumstances, subdurally or cerebral cortex)
  • Used for
    • Ddx true seizures and pseudo-seizures/ syncope
    • Type of seizure/ epilepsy
    • Depth of anaesthesia
    • Diagnose brain death/ coma/ encephalopathy
    • Indirect measurement of cerebral perfusion in carotid endarterectomy


  • Represents post-synaptic potentials of a large number of neurons
  • Measures “voltage differences” between different parts of the brain
  • Electrode placement and names by the International 10-20 System, each electrode is connected to an amplifier
  • Passes through 3 filters:
    • High pass filter at 0.5Hz (filters out slow artifact eg electrogalvanic signals)
    • Low pass filter at 35-70Hz (filters out high frequency artifact eg EMG signals)
    • Notch filter (filters out electrical artifact from power lines, typically 50-60Hz depending on country)
  • All electrodes are measured against an arbitrary reference point, and the calculated differences/ relationships between each electrode is known as a “montage”
  • Certain “activations” to bring out waveforms
    • 3 minute hyperventilation
    • Flashing strobe lights at different frequencies
    • Drugs (especially short acting barbiturates)
  • Limitations:
    • Does not measure a single action potential – picks up net activity of a large number of neurons
    • Does not measure whether the it is excitatory, inhibitory or modulatory
    • Limited anatomical specificity (need to triangulate region of interest)
  • Advantages
    • Direct measurement of electrical activity ie brain activity
    • Excellent temporal resolution ie time resolution down to sib-millisecond
  • Frequency of EEG waves
    • a: 8-12 Hz
    • b: > 12 Hz
    • d: 0-4 Hz
    • f: 4-8 Hz
  • Y- axis: Amplitude (ranges from 5 -200 microvolts)
  • X- axis: Time (ms)
  • Will also be given “electrodes” named after pre-defined position

Abnormal EEG findings are either:

  • Focal or generalised
  • Continuous/ intermittent/ paroxysmal

Slow wave abnormalities

  • increase slow wave activity (mainly d and f) when awake is abnormal
  • Mainly encephalopathies with generalised d and f activity

EEG very sensitive for encephalopathies, most important use of EEG in clinical practice


Centrally acting drug/ toxic encephalopathy

  • Generalised b activity
  • Eg benzodiazepines, ETOH, neuroleptics

Metabolic encephalopathy

  • Eg hepatic/ renal
  • Triphasic d waves of high amplitude
  • Often mistaken as epileptic waveforms

Infectious encephalopathy

  • Slow waves and epileptogenic activity
  • Notably herpes encephalitis has characteristic periodic lateralized epileptic discharges (PLED)

Hypoxic encephalopathy

  • Slow waves of very low amplitude

Epileptogenic abnormalities

  • Useful evaluation between seizures (inter-ictal) and during seizures (ictal)

Spike wave

  • Single wave that stands out from background
  • Duration < 80ms

Sharp wave

  • Similar to spike wave
  • Duration > 80ms

Spike/ sharp wave often followed by slow waves

Classic absence

  • Generalised 3Hz spike wave pattern

Typical focal seizure

  • Focal single spike followed by a slow wave

If abnormal focal abnormality spreads to the rest of the brain, the EEG will be indistinguishable from a primary generalised seizure

Generalised tonic clonic seizure

metabolic encephalopathy

Liver/ renal triphasic d waves

PLED HSZ encephalitis

Drug encephalopathy

Absence seizures

focal seizures

normal awake



Neurology: epilepsy

Question 13 top Download PDF

The major cause of death in patients more than 6 months following cardiac transplantation is:

A. Graft versus host disease
B. Opportunistic infection
C. Rejection
D. Malignancy
E. Coronary artery disease


The provided answer (E) might have changed in light of the 2005 report from the Registry of the International Society for Heart and Lung Transplantation (ISHLT) data from 1984 to 2004
  • Major limitations to survival in 1st 6 months: graft failure, rejection and infection
  • “Graft failure” possibly represents deaths not specified (thus statistics of early rejection and late vasculopathy likely underestimated)
  • Beyond 1st year, malignancy then coronary disease as the main cause of death

(Previously: beyond 6-12 months, coronary disease (25%) then malignancy (18%) were the leading causes of death ?because newer and heavier immunosuppressive regimes used)

Cardiac transplantation

  • indicated in end-stage cardiac failure with symptoms despite optimal medical therapy (Stage 4)
  • donor and recipient hearts excised in identical operations
  • mortality highest in 1st year post transplant (mostly in 1st 6 months)
  • half-life of transplant is 9- 10%
  • heavy immunosuppression (even worse than renal transplant)
  • surgically denervated heart thus:
    • does not respond to any direct autonomic stimuli but responds to circulating catecholamines
    • no angina even with advanced coronary disease
5 major causes of death post cardiac transplant
  1. Graft failure (primary and non-specific)
  2. Acute allograft rejection
  3. Infections other than CMV
  4. Allograft vasculopathy (ie coronary disease)
  5. Malignancy (notably lymphomas)
  30 days 31 days to 1 year 1-3 years > 5 years
Graft failure 14% 18% 17% 14%
Acute rejection 7% 12% 10% 1%
Infection 13% 33% 13% 10%
Allograft vasculopathy 5% 14% 15% 4%
Malignancy 14% (4% lymphomas) 23%
(5% lymphomas)
* CMV related death contributed to <1% of infective deaths

Determinants of prognosis

  1. Recipient factors
    • underlying congenital heart disease and use of mechanical support are most closely related to poor outcome (but only present in low numbers of recipients)
    • others: hospitalization at time of transplant, female donor to male recipient, donor death from CVA, donor coronary heart disease
  2. Donor factors
    • worse prognosis if advanced age (> 50 years old) and female donor to female recipient
  3. Late mortality
    • Most important risk factors (but in <5% patients) at > 5 years: stroke, repeat transplant and coronary disease within the 1st year
    • Commoner risk factors: older recipient and donor age, diabetes, having had treatment for rejection, infection


A. Graft vs host disease (GVH)
  • only applicable in haematopoietic stem cell transplants
  • result of donor T cells either transferred with donor stem cell inoculum or developing from it -> recognizing recipient organs as “foreign” antigen
  • Acute GVH: within 3 months (need skin, liver or endoscopic Bx for Dx)
  • Chronic GVH: beyond 3 months (usually in older patients/ mismatched or unrelated stem cell donors/ previous acute GVH)
C. Rejection
  • Symptoms of LV failure +/- GIT symptoms (hepatic congestion)
  • Arrhythmias uncommon
  • In pre-cyclosporin era: fever and reduced QRS voltages were “diagnostic”
  • Dx: endomyocardial biopsy histopathology
  • 2 types: cellular (T cell infiltrate) and less commonly, non-cellular (antibody mediated)
D. Malignancy
  • 2-4x more common in heart transplant vs renal transplant
  • Commonest (5-20x): lymphoma, skin cancers, Kaposi sarcomas, renal cell carcinomas
  • In contrast, solid organ cancers common in normal population (eg prostate, breast, colon) only modestly increased (2x)
  • Screening (pre and post transplant), decrease immunosuppression and exposure to carcinogens eg sunlight


Cardiology: Cardiac transplantation

Question 14 top

Question 15 top

Question 16 top - download pdf

A 26 year old woman is found to be markedly breathless approximately 2 hours after undergoing an urgent caesarean section under GA. She has had no respiratory problems pre-operatively.
On examination, her RR 35/min, HR 110/min, BP 127/75mmHg; there are bilateral basal crackles. O2 saturation is 86% on room air.
CXR: patchy infiltrates in lower zones bilaterally
ABG shows:

  • Pa02 50mmHg (80-100)
  • PaCO2 29mmHg (36-44)
  • pH 7.46 (7.36-7.44)

Which one of the following is most likely to improve outcome for this patient?
A. IV corticosteroids
B. Bronchodilator therapy
C. Positive pressure ventilation
D. IV broad spectrum antibiotics including anaerobic cover
E. IV heparin

Answer: C

This patient is in APO
  • hypoxic with respiratory alkalosis (from hyperventilation RR 35/min)
  • treatment of APO in the acute setting would include:
    1. Ventilation
    2. GTN
    3. Diuretics
Causes of peri-partum APO:
  1. Peri-partum cardiomyopathy (PPCM)
  2. Amniotic fluid/ venous air pulmonary embolism
  3. Aspiration pneumonia
  4. Pre-eclampsia with pulmonary oedema (but her BP is good)
  5. IV tocolytic drugs (eg B agonists) to inhibit labour
Causes in cases of post-partum APO:
  1. Use of bromocryptine to inhibit lactation in cocaine addicts
  • rare, unknown aetiology
  • late pregnancy to early puerperium
  • 4 diagnostic criteria
    1. Within last month of pregnancy of within 5 months post partum
    2. No symptoms prior last month of pregnancy
    3. No identifiable cause of heart failure
    4. EF <45% or fractional shortening <30%
  • Treatment similar to that of other causes of heart failure
    1. Digoxin and hydralazine ok
    2. ACEi contraindicated (poor foetal outcome)
    3. B blockers (B1 selective better as less interference w B2 mediated vasodilation of uterus and peripheral vasodilation)
    4. Nitrates not good
    5. Anticoagulate (warfarin safe in 3rd trimester but bleeding risk peripartum, consider heparin)
  • Can trial IV Ig if proven myocarditis (no clear benefit but study shows increased LVEF 6/12 post-partum)
  • Heart transplant (best outcome)



Cardiology - Cardiac Changes and Problems in Pregnancy


Question 17 top Download PDF

Question 17

Which one of the following would be a relative contraindication to the use of raloxifene (a selective oestrogen receptor modulator) in a peri-menopausal woman?

  1. Severe hot flushes
  2. Hypertension
  3. Family history of breast cancer
  4. Hypercholesterolaemia
  5. Osteoporosis

Answer: A. Severe hot flushes

Selective oestrogen receptor modulators (SERMS)
  • Competitive inhibitor of oestrogen binding to the oestrogen receptor (ER)
  • Mixed agonist and antagonist action dependant on target tissue
  • Bind to ER -> conformational changes depending on target tissue -> variable interaction with different cofactors (either activators/ repressors) -> increased or decreased transcriptional activity
  • Examples are tamoxifen (Tamosin, Nolvadex) and raloxifene (Evista)
  • Main difference in tamoxifen and raloxifene is their effect on the uterus (tamoxifen -> endometrial proliferation -> increased uterine cancer risk)


  • Indicated for treatment and prevention of osteoporosis in post-menopausal women
  • Only PBS approved as the sole post-menopausal anti-resorptive agent in established osteoporosis in patients with fracture with minimal trauma/ as continuing treatment (year of x-ray/MRI must be included in application)
  • increased BMD with raloxifene < bisphophonates < bisphophonates + raloxifene
  • increased BMD with raloxifene < oestrogen (HRT)
  • Positive effects on bone and lipid metabolism (decreased total cholesterol by 5-6% and LDL by 8-10% but no effect on TAG and HDL -> unclear if translates to cardioprotection)
  • Negative effects on breast and endometrium
  • Reasonable alternative to tamoxifen for breast cancer chemo-prevention in post-menopausal women at high breast cancer risk
  • No alleviation of post-menopausal symptoms eg hot flushes, urinary incontinence, vaginal symptoms
  • Does not accumulate in target tissues -> ongoing treatment needed for benefit
  • Skeletal effects (decreased bone resorption and urinary calcium losses)
  1. Treatment of osteoporosis (daily dose 60mg orally)
    • Large randomised, placebo-controlled, double blind trial of 7705 post-menopausal women for 3 years (median age 67 years, t score < -2.5)
    • All received concomitant calcium and vitamin D supplements
    • decreased incidence of vertebral fractures by 55% (whether or not they had a previous fracture)
    • Does not decreased incidence hip fractures
    • increased BMD of spine and hip by 2-3%
    • increased BMD of total body and radius by 1-2%
  2. Prevention of osteoporosis
    • 3 large trials recruiting post-menopausal women with z scores between -2.0 and -2.5
    • Also randomised, placebo controlled and supplemented with calcium
    • increased BMD in spine and hip up to 2.4%
    • increased BMD in total body up to 4%
    • Inconsistent effect on forearm/radius BMD
  • Contraindications
      • Pregnancy (foetal malformations in rats)
      • Lactation (growth suppression in puppies)
      • Male
      • History of venous thrombo-embolic events
  • Adverse effects
      • Commonest cause for discontinuation: hot flushes (most commonly reported in 1st 6 months, no difference thereafter)
      • Other side effects: peripheral oedema, leg cramps
      • Small increase in stroke mortality (no increased incidence/ overall mortality)
      • increased venous thrombo-embolic events (RR 2.3)
      • Worsening of TAG profile in those with pre-existent hypertriglyceridaemia
      • increased plasma levels in hepatic insufficiency (not recommended)


  • decreased bone mass/ bone density + deterioration of bone architecture -> increased fracture risk
  • WHO criteria: T score < -2.5 (bone density less than 2.5 standard deviations from young healthy adults of same race and sex)
  • Z score refers to age-matched individuals (no treatment based on this)
  • T scores between -1.0 and -2.5 defined as osteopenia -> increased risk of developing osteoporosis
  • Fractures of distal radius increased frequency before age 50, plateaus age 60, modest age-related increased thereafter
  • Incidence of hip fractures doubles every 5 years after age 70 (? Tend to fall on hip rather than outstretched hand)
  • Greatest frequency of vertebral fractures
  • Risk of DVT +/- PE greatest amongst hip fracture group (20-50%) and high mortality rate (5-20%) in the year after surgery
  • Other fractures closely related to osteoporosis: pelvis and proximal humerus


  • Blood: FBE/ TSH/ serum calcium/ serum 1,25(OH)2D +/- PTH +/- ALP
  • Urine: 24 hour urinary calcium
  • DEXA scan
  • Bone biopsy (rare nowadays)


  • Non-pharmacological: Diet/ Weight bearing exercise/ Smoking cessation
    • Pharmacological:
    • Bisphosphonates
    • Hormonal therapy – SERMs, oestrogen only, oestrogen-progestin therapy
    • PTH (intermittent pulse therapy, also effective in men)
    • Calcitonin (nasal spray, tachyphylaxis, less increased BMD compared to other therapy, only 1st line for pain management in acute osteoporotic fracture)
    • Combination therapy
    • Others: calcitriol, phyto-oestrogens, thiazides, fluoride, tibolone (synthetic steroid)
    • Watch this space: strontium, denosumab (TNF), androgens, growth hormone/ IGF, statins



    Question 18 top

    Question 19 top

    Question 20 top Download PDF

    A 36 year old previously well woman presents with lethargy of 2 to 3 weeks duration and gum bleeding over the previous week. Examination shows her to be afebrile and anaemic with scattered bruises and petechial haemorrhages. A chest X ray is normal.

    Full blood examination reveals:



    120-155 g/L



    80- 95 fL

    White Cell Count/L


    0.3 x 109

    1.5- 6.0


    1.10 x 109

    0.7- 3.15


    0.3 x 109

    0.2- 0.6


    0.1 x 109

    0- 0.4


    0.1 x 109

    0- 0.15

    Platelet Count

    13 x 109

    150- 400




    1.0- 1.3



    26- 38 seconds



    2.0- 4.0 g/L



    < 0.2 mg/L

    A bone marrow aspirate shows that 90% of the nucleated cells have the appearance as seen in the photograph below:

    The most appropriate initial therapy is:

    1. Idarubicin
    2. All-trans-retinoic acid
    3. Vincristine and prednisolone                 
    4. Fludarabine
    5. High dose cyclophosphamide




    Young woman with symptomatic pancytopenia and abnormal coagulation profile, with blood film showing large heterogeneous lymphocytes with large nuclei, grainy cytoplasm with “faggot sticks” = APML (Acute Promyelocytic Leukaemia)


    1. Variant of AML but biologically distinct
    2. Classified as AML-M3 in FAB classification and APML with t(15;17)(q22;q12) in WHO
    3. Unique response to agents that induce differentiation (retinoic acid and arsenic trioxide)
    4. The translocation leads to a fusion product PML/RAR-alpha which prevents terminal differentiation and subsequent apoptosis of pro-meylocytes
    5. Can occur de novo (up to 20% all AML cases) or secondary cytotoxic therapy (especially topoisomerase II inhibitors eg doxirubicin/ etoposide) for another malignancy (breast, lymphoma)
    6. Usually presents with complications of pancytopenia as with AML but APML unique as DIC is common
    7. DIC usually occurs either at presentation or shortly after treatment initiation
    8. Treatment: ATRA (Primary ATRA resistance is rare apart from with t(11;17) where there is absence of bilobed nucleus and absence of faggot cells)
      1. ATRA well tolerated
      2. Not immunogenic/ immunosuppressive
      3. Common to have headaches, skin reaction, abnormal LFTs but not requiring treatment cessation
      4. Serious side effects:
        1. ATRA syndrome (25%): fever, hypotension, dyspnoea (pulmonary oedema/ infiltrates) – treat with high dose dexamethasone, can recommence once resolves
        2. Hyperleucocytosis (50%): due to maturation of cells – treat with steroids or cytotoxic chemotherapy
    9. For relapsed/ refractory cases:
      1. Arsenic trioxide
      2. Stem cell transplant (autologous/ allogenic)



    Decreased production

    Aplastic anaemia



    Marrow infiltration

    Acute leukaemia
    Hairy cell leukaemia

    Inadequate resources

    B12/ folate deficiency

    Increased destruction


    Splenic trapping of cells (hypersplenism)






    Overwhelming infection

    HIV with myelodysplasia

    Viral haemophagocytosis


    Heamatology: Leukaemia

    Question 21 top

    Question 22 top Download PDF

    A 30 year old hospital staff member presents 24 hours after being exposed to a patient with confirmed measles. There is no prior history of measles or vaccination against measles.

    The most appropriate management is:

    A. Normal immunoglobulin

    B. Ribavarin

    C. Measles live attenuated vaccine

    D. Aciclovir

    E. Observation

    Answer: C

    Post measles exposure prophylaxis

    • 1st choice within 72 hours: live attenuation measles vaccine
    • If contraindicated: Immune serum immunoglobulin within 6 days (can prevent/ modify course of disease)
    • Immune serum globulin especially indicated in exposed individuals for whom the risk of complications of measles is increased
      • pregnant women
      • contacts less than one year of age
      • immunocompromised hosts
      • individuals previously vaccinated, but now immunocompromised

    Contraindication to measles vaccination

    • Pregnancy
    • Theoretical risk of birth defects
    • If vaccinated, women of child bearing age should avoid pregnancy for 1/12
    • Immunosuppressed
      • HIV (unless CD4 < 200)
      • Leukaemia in remission (only ok after 3/12 post terminating chemotherapy)
      • Steroids (equivalent of prednisolone 20mg/day for > 14 days)
    • Febrile illness (unless mild)
    • Thrombocytopenia
    • Allergies
    • Anaphylaxis to gelatin or neomycin
    • Egg anaphnylaxis not contraindicated
    • Recent administration of immunoglobulin or blood products
    • Diminished vaccine efficacy after passive immunisation
    • Thus those who’ve received IV Ig should only be vaccinated >3/12 later


    • Supportive
    • paracetamol, fluids, treatment of superimposed bacterial infection
    • Vitamin A
    • some studies showed benefit in areas of Vitamin A deficiency or if mortality rates from measles > 1%


    • Ribavarin
    • susceptible in-vitro
    • ?route: IV versus aerosolised
    • no RCT to assess benefit
    • no benefit from acyclovir (acivlovir used to treat varicella zoster and HSV)

    Measles in pregnancy

    • increased risk of serious complications for mother
    • infants are protected by maternal antibodies (placental transfer)
    • possible small teratogenic risk, prematurity and miscarriages
    • measles in mother during delivery does not necessarily lead to measles in the baby (spectrum of disease)


    Infectious Diseases: Viral illness | Infection control


    Question 23 top

    Question 24 top Download PDF

    A 55 yo woman with T2DM develops acute onset of chest pain and dyspnoea. She has been discharged from hospital 5 days earlier after laproscopic cholecystectomy. The pain is described as a central heavy pain with no radiation. There are no aggravating or relieving factors. She has HT, hypercholesterolaemia and smokes 15-20 cigarettes a day. Her usual medications incude aspirin, simvastatin, enalapril and insulin. Examination is unremarkable apart from tachypnoea and sweating.

    Her ECG is shown:

    After administration of O2 and analgesia, the most appropriate therapy while awaiting the results of diagnostics tests is:

    A. Streptokinase and a B blocker
    B. Tissue plasminogen activator (tPA) followed by heparin
    C. Heparin alone
    D. Heparin, tirofiban and a B blocker
    E. Heparin and a B blocker

    Answer: C

    ECG shows
    • sinus tachycardia (HR 120)
    • normal axis
    • T wave inversion inferiorly ?and aVF, anteriorly V1-V4
    Main Ddx
    1. Non ST elevation acute coronary syndrome (NSTEMI/ Unstable Angina)
      • NSTEMI has cardiac enzyme elevation
      • Multiple cardiac risk factors
      • character of pain (heavy)
      • T wave inversion
      • Treatment:
        • NO THROMBOLYSIS (lesion is platelet rich vs fibrin rich in STEMI)
        • Antiplatelets: Aspirin 300mg +/- clopidogrel +/- GP2b/3a inhibitor if high risk and planning PCI
        • Enoxaparin or heparin for 48 hours (no evidence beyond)
        • Analgesia (nitrates +/- morphine)
        • Medications that improve mortality (B blocker/ ACEi/ atorvastatin 80mg: PROVE-IT-TIMI 22 in 2004 and MIRACL 2001)
        • No trial demonstrates mortality benefit in early/ immediate PTCA +/- stent but this is recommended in all but low risk patients
        • Note that in NSTEMI, immediate angio findings show no occlusion in 60-85% of infarct-related artery (? Clot lyisi/ microvessel disease/ vasospasm)
    2. PE
      • smoker
      • recent surgery
      • sinus tachycardia (commonest ECG finding in PE)
      • Treatment:
        • Anticoagulation with heparin/ enoxaparin and warfarin till INR therapeutic 48 hours
        • Thrombolysis
          • no trial to demonstrate mortality benefit
          • but improves pulmonary perfusion and RV function
        • If contraindicated
          • IVC filter: no mortality benefit unless hypotensive
          • Thrombolectomy (catheter or surgical)

    A. Wrong because streptokinase is a thrombolytic agent; not used in NSTEMI and definitely not 1st line in PE. A B blocker may be considered if NSTEMI but patient is a smoker and may have reversible airways obstruction

    B. Heparin correct but not tPA (thrombolytic agent)

    C. Heparin correct in either diagnosis. However enoxaparin has often been preferred unless renal impairement or CABGs planned in 24 hours.

    D. Probably would not consider tirofiban (GP 2b/3a inhibitor) in this patient as with the given information, she is LOW risk (TIMI score 2)

    TIMI score
    • Method of early risk stratification
    • 7 factors (each scoring 1)
      1. Age = 65
      2. Aspirin in last 7 days
      3. = 2 episodes angina within last 24 hours
      4. = 3 risk factors (HT/ hyperchol/ smoker/ diabetes)
      5. Known coronary stenosis = 50%
      6. ST segment changes
      7. Cardiac enzyme elevation
    • Low: 0-2
    • Intermediate: 3-4
    • High: >5
    • GP2b/3a inhibitors usually considered in high risk patients/ or ongoing ischaemia evidenced by symptoms or haemodynamic instability/ planned for PCI

    Contraindications to B blockers in ACS
    1. Bronchospasm
    2. Bradycardia (HR <60)
    3. Block
    4. Left ventricular failure (moderate to severe)
    5. Hypotension (sys BP <100)
    6. Cocaine- induced AMI


    Cardiology: Myocardial Infarction

    Question 25 top Download PDF

    The carrier frequency for cystic fibrosis (CF) in the Caucasian population in Australia is approximately 4%. The DF508 mutation accounts for 75% of all mutations among carriers in this population.

    A girl is diagnosed with CF. DNA studies identify one DF508 mutation but fail to identify a mutation in the other allele. DNA studies of her unaffected brother are normal.

    What is the risk of her brother being a carrier?

    1. less than 1%
    2. 4%
    3. 25%
    4. 50%
    5. 66%

    Answer: D

    To answer this question you need to know:

    • CF genetics
    • One can have CF with either 2 copies of the same mutation OR 1 copy of 2 different mutations

    CF genetics

    • Commonest fatal inherited disease among Caucasians
    • Autosomal recessive
    • Mutation in single large gene on chromosome 7 that encodes the CFTR (cystic fibrosis transmembrane conductance regulator protein)
    • Carrier frequency 1:25 (1 in 25 people carry the CF gene ie are heterozygotes)
    • Prevalence 1:2700
    • 1:2000-3000 live births
    • To have CF, the affected person must have 2 defective genes and must have inherited an affected gene from each parent
    • This can be 2 copies of the same CF mutation, or 1 copy of one mutation and 1 copy of another mutation
    • Very small numbers of patients with phenotypic evidence of CF (symptoms and +ve sweat test) in the absence of CFTR mutations

    Diagnosis of CF

    1. Sweat test (Gold standard)
      • Collection of greater than 50mg sweat in 45 minutes
      • increased sweat chloride levels greater than 60 meq
      • False negatives in hypoproteinaemic oedema + steroids
      • Those with unusual genotypes tend to have normal sweat tests (lessthan 1%)
    2. Molecular/ DNA testing
      • Picks up less than 90% mutations (only tests for 20-30 most common mutations)
    3. Nasal potential difference measurement
      • Measure nasal transepithelial potential difference at basal state, after amiloride nasal spray and chloride-free nasal spray
      • Abnormal Cl secretion more associated with pancreatic insufficiency
      • Na hyper-absorption more associated with lung disease
      • False negatives in nasal polyps/ inflammation
    4. Infancy screening (Immunoreactive trypsin IRT)
      • Levels fall rapidly with infancy
      • Negative test after 8 weeks unreliable
      • Rationale for screening: early intervention and better outcome (early referrals, nutritional support leads to better outcome, trials)
    5. Others eg sperm count/ duodenal fluid testing
    • Prevelence
      • Number of people having a disease at a particular time with no regard to when they first got the disease (ie a “cross section”)
      • Indicates neither when someone got the disease nor if previously diseased persons recover or die, it is not a good indicator of overall rate, or risk of getting a disease
    • Incidence
      • Rate
      • How many new cases in a fixed population over a fixed time period


    Respiratory: Cystic Fibrosis

    Question 26 top Download PDF

    Which one of the following is the least consistent with trigeminal neuralgia?

    1. Normal brain magnetic resonance imaging (MRI) scan
    2. Absent corneal reflex
    3. Onset of facial pain after the age of 60 years
    4. Spontaneous remission of facial pain
    5. Response to carbamazepine


    Refer to 2005 P1Q26 (I Lynn’s) answer for detailed description of trigeminal neuralgia

    Quick Summary: Trigeminal Neuralgia (Tic Douloureaux)

    1. Commonest cause of facial pain: paroxysms, sharp and stabbing
    2. Usually affects V2, V3 (more than V1) and usually unilateral
    3. OBJECTIVE SIGNS OF SENSORY LOSS CANNOT BE DEMONSTRATED thus corneal reflex should be preserved (Sensory afferent via V1)
    4. Occurs spontaneously, secondary trigger zones or actions eg chewing/ talking
    5. Ectopic generation of action potentials in pain-sensitive afferents
    6. Usually secondary compression of trigeminal nerve root by superior cerebellar artery or tortuous vein -> demyelinated large fibres
    7. 60% cases in women; middle-aged to elderly population
    8. Lasts for weeks to months, may remit spontaneously, often recurs
    9. Ix:
      1. MRI to exclude mass lesions or multiple sclerosis – often normal
      2. ESR to exclude temporal arteritis
    10. Carbamezepine effective in 50%-75%; second-line agents include baclofen, phenytoin and other anti-convulsants
    11. Heat rhizotomy, glycerol injection and surgical decompression (suboccipital craniotomy) if drug treatment fails

    Trigeminal nerve (CN V): mixed nerve

    • Motor: muscles of mastication (temporalis, masseters, int. and ext. pterygoids)
    • Sensory: V1,V2, V3 of the face


    1. Proprioception (mesencephalic) nucleus in the midbrain
    2. Motor nucleus and sensory nucleus (for touch) in the pons
    3. Pain/temperature nucleus in medulla extending into upper cervical cord

    Due to this segregation in the brain stem, lesions of the medulla or upper cervical cord can lead to dissociative sensory loss of the face (loss of pain/temperative but retention of touch and proprioception)
    Course of CN V
    Leaves the pons at the cerebellar-pontine angle
    Enters middle cranial fossa, over the temporal lobe
    At the petrous temporal bone -> forms trigeminal ganglion (Gasserian ganglion)

    Forms 3 sensory divisions:
    V1 opthalmic: runs in  cavernous sinus with CN III -> exits via superior orbital fissure

    • Supplies skin of forehead, cornea and conjunctiva

    V2 maxillary: exits via inferior orbital fissure

    • Supplies skin of middle of face, mucous membranes of upper part of mouth, palate and nasopharynx

    V3 mandibular: runs with motor nerve -> exits via foramen ovale

    • Supplies skin of lower jaw and mucous membranes of lower part of mouth

    Touch and proprioceptive fibres terminate in pons at the main sensory and mesencephalic nuclei respectively -> forms the dorsal and ventral mesencephalic tracts -> somatosensory cortex

    Pain and temperature fibres from the face run from the pons through the medulla/ upper cervical cord -> terminates at the spinal tract nucleus -> 2nd order neurons arise from here -> ascend again as the ventral spinothalamic tract -> somatosensory cortex

    Trigeminal neuropathy

    1. Mostly presenting as sensory loss of the face and jaw muscle weakness
    2. Deviation of jaw due to weakness of pterygoids -> deviates towards the weak side
    3. Isolated loss of sensation (no weakness) of the chin (mental neuropathy) can be the sole manifestation of malignancy
    4. Tonic spasm of the muscles of mastication (trismus) is a symptom of tetanus or drug effect (phenothiazine)


    Brain stem (nuclear) lesions

    Vascular eg stroke
    Demyelination eg MS
    Space occupying lesion eg glioma/ lymphoma

    Middle cranial fossa

    Space occupying lesion eg tumour/ aneurysm
    Chronic meningitis

    Trigeminal ganglion lesions
    (Petrous temporal bone)

    Space occupying lesion eg acoustic neuroma/ meningioma
    Fracture of middle fossa

    * Tumour of cerebellar pontine angle will affect CN V,VII,VIII

    Cavernous sinus lesion


    *Will affect CN III,IV and VI

    Peripheral nerve lesion

    Nasopharyngeal carcinoma
    Guillian Barre syndrome
    Collagen vascular diseases


    Neurology: peripheral nerve lesions

    Resources: Diagram from http://instruct.uwo.ca/anatomy/530/trignuc.gif; Talley and O’Conner on cranial nerves; Harrison’s Chapter 355

    Question 27 top Download PDF

    Which one of the following dietary regimens leads to the greatest reduction in systolic and diastolic blood pressure?

    A. Vitamin E supplementation
    B. Low salt (< 400mg/day) diet
    C. Vitamin C supplementation
    D. Potassium rich (> 60mg/day)
    E. Low fat diet, rich in fruit and vegetables

    Answer: E
    • Hypertension (esp systolic hypertension and night time hypertension) has been shown to ? cardiovascular risk
    • Interventions
      • Lifestyle modifications is always 1st line
      • 5 classes of anti-hypertensives: thiazides, ACEi, beta-blockers, calcium channel blockers and ARBs (any of these are reasonable for initiation of therapy)
      • Target other cardiac risk factors
    • Blood pressure goals are determined by the individuals 'Absolute Cardiovascular Risk' (Risk Calculator available from National Heart Foundation website)
    • Role of ambulatory BP: up to 30% have 'white coat HT', also higher risk of day time and night time BP differ < 10mmHg

    Many trials on lifestyle modifications, those that work are:

    1. Low sodium diet (less than 90mmol/day or 'no added salt' policy)
    2. Low fat diet, high in fruit and vegetables
    3. Weight loss
    4. ETOH reduction
    5. Regular aerobic exercise (30min 5x/week, recent meta-analysis showed that reduced BP by 4/2.5 mmHg)
    6. Potassium supplements (meta-analysis of 27 trials showed BP reduction of 3.5/2.5 mmHg in those with low K diet ie <40mg/day, but no effect in sodium restricted patients)

      Dodgy purported useful interventions
    7. High dose fish oil (no conclusions yet but bleeding risk with high doses)
    8. Calcium supplements (trials from 1970s! Marginal benefit, mostly in those with low calcium levels)
    9. Vitamin C (only found one trial in Gerontology 1994; 40(5) 268-72. Double blinded study with Vit C supplementation in elderly with HT: no statistical difference
    10. Vitamin E mostly studied for anti-oxidant effect in lipid lowering and anti-atherosclerosis

    Notable trials:

    TOMHS (Treatment of Mild Hypertension Study)
    • Weight reduction/ low salt/ low fat/ low ETOH + one antihypertensive or placebo
    • On placebo had less and less sustained BP drop over time but managed 8.6/8.6 mmHg reduction overall
    DASH (Dietary Approaches to Stop Hypertension)
    • 3 groups: (L) low in fruit and veges, (H) high in fruit and veges, DASH diet (high fruit and veges + low fat)
    • DASH diet reduction 5.5/3 mmHg vs (H) reduction 2.8/1.1 mmHg
    • Effects most pronounced in hypertensives (compared normotensives) for DASH 11.4/5.5 mmHg
    Spin off trial DASH-Sodium
    • DASH diet + sodium content of 3 differing concentrations
    • Independent of sodium diet, DASH reduces BP significantly in hypertensives
    • Greatest difference between high vs low sodium groups, with overall reduction of 8.9/4.5 mmHg
    • Benefit extends to normotensives, but greatest in hypertensives and blacks
    Further spin off DASH-Na: PREMIER
    • Dash-Na + behavioural modification + advice sessions
    • No significant difference


    Cardiology: Coronary disease including: Risk factors and management (primary and secondary prevention)


    Question 28 top

    Question 29 top

    Question 30 top Download PDF

    Question 30

    A 48 year old woman is found to have the following abnormal results. She has no significant past medical history. Her mother had undergone parathyroid surgery which failed to correct her hypercalcemia.

    Serum corrected calcium           2.8 mmol/L        (2.1-2.6)
    Serum phosphate                      0.9 mmol/L        (0.7 -1.5)
    Parathyroid hormone (PTH)        4 pmol/L           (1-5)

    What is the most appropriate next step?

    1. Sestamibi scan
    2. Referral for neck exploration
    3. Measurement of 24 hour urinary calcium excretion
    4. Measurement of serum prolactin and gastrin
    5. Measurement of bone density


    Important information

    • Asymptomatic hypercalcaemia in the absence of increased PTH (excludes primary hyperparathyroidism), normal serum phosphate
    • Suggests familial association and ineffectiveness of parathyroidectomy as treatment

    How to calculate adjusted serum calcium:
    Adjusted calcium = Total calcium + [0.8 x (4.5 – albumin concentration)]

    Hormones affecting calcium homeostasis



    Feedback Mechanism


    Net effect

    • increased serum calcium
    • decreased serum phosphate

    Acts on:

    • Bone: increased bone resorption -> increased calcium and phosphate
    • Kidney: increased calcium reabsorption but decreased phosphate reabsorption
    • Kidney (proximal tubule): increased 1a hydroxylase -> increased 1,25 (OH)2D

    Stimulated by:

    • decreased serum calcium (via calcium sensing receptors)

    Inhibited by:

    • increased serum calcium
    • increased 1,25(OH)2D


    Vitamin D

    Cholediol is 25(OH)D

    Calciferol is 1,25 (OH)2D

    Net effect

    • increased serum calcium
    • increased serum phosphate

    Acts on:

    • Intestine: increased calcium and phosphate reabsorption
    • Enhances PTH mediated bone resorption
    • Enhances PTH mediated renal calcium reabsorption
    • Kidney: increased reabsorption of phosphate via NPT2a

    Formation of 1,25(OH)2D stimulated by:

    • increased PTH
    • decreased serum calcium
    • decreased serum phosphate
    • decreased fibroblast growth factor 23 (FGF 23)

    (thyroid c cells from neural crest)

    Net effect (transient: hours-days)

    • decreased serum calcium
    • decreased serum phosphate

    Acts on:
           -     Bone: decreased resorption

    Stimulated by:

    • increased serum calcium (but any decreased in calcium leads to increased PTH)


    Causes of Hypercalcaemia

    Increased bone resorption

    increased PTH levels

    • Primary hyperparathyroidism
    • Secondary hyperparathyroidism (uncommon)


    • increased PTHrP (eg squamous cell cancers)
    • Osteoclast activating factor related eg IL1 (lytic mets or haematological malignancies eg myeloma/ lymphoma)

    Hyperthyroidism (up to 15% affected)

    Vitamin A intoxication (rare)

    Imbalance between resorption and formation

    • Immobilisation
    • Paget’s (rare, calcium usually normal)

    Increased intestinal calcium absorption

    Increased calcium intake

    • Renal failure with Vitamin D supplements
    • Milk- alkali syndrome (excessive calcium ingestion with antacids, alkalosis enhances renal distal tubular calcium absorption)

    High vitamin D levels (also -> increased phosphate)

    • Excessive ingestion (usually increased 25(OH) not 1,25(OH)2)
    • Abnormal metabolism
    • Granulomatous disease eg sarcoidosis/ TB (macrophages synthesize excess 1,25 (OH)2, in some cases primary hyperparathyroidism can coexist)
    • Lymphomas
    • Acromegaly (hypercalciuria common but hypercalcaemia uncommon; look for MEN1)




    • Chronic lithium intake (affects 10%: direct stimulation of PTH cells)
    • Thiazide diuretics (increased renal calcium reabsorption at PCT)

    Adrenal disease

    • Addison’s crisis (multifactorial, use steroids)
    • Phaeochromocytoma (very rare, either related to MEN2a or PTHrP secretion by tumour)

    Congenital syndromes

    • Familial hypocalciuric hypercalcaemia FHH
    • William’s Syndrome (autosomal dominant, excess sensitivity to Vit D with congenital defects eg mental retardation and aortic stenosis)


    Back to the question:
    High serum calcium but normal serum phosphate

    • Excludes hyperparathyroidism (phosphate will be decreased, in any case the PTH provided was normal)
    • Excludes high vitamin D states (both will be increased, also PTH will be decreased from negative feedback by 1,25 (OH)2D)
    • So the possibilities would be limited to:
    • Malignancy
    • Low calcium losses

    Malignancy is the 2nd commonest cause of hypercalcaemia after hyperparathyroidism; however it is unlikely that she is asymptomatic because usually serum calcium is very high and it is very rarely the presenting feature.

    • If related to PTHrP release, serum PTH levels will be decreased or undetectable
    • PTHrP also acts like PTH, so one would expect a increased phosphate too
    1. Incorrect. A sestamibi scan is to look for functioning parathyroid masses, usually solitary adenomas or parathyroid cancers. It is already established that this is not the case.
    1. Incorrect – even worse than option A!
    1. Correct. A 24 hour urinary calcium (decreased) would establish the diagnosis of Familial Hypocalciuric Hypercalcaemia (FHH)/ Familial Benign Hypercalcaemia. It is autosomal dominant and this would be consistent with the maternal history of a parathyroidectomy failing to correct hypercalcaemia. It is related to an inactivating mutation of the calcium sensing receptor – the set point is raised ie a higher serum calcium is required to decrease serum PTH levels and to promote urinary calcium loss. No treatment required if no symptoms.
    1. Incorrect. I think it’s trying to suggest a screen for MEN1 (autosomal dominant) given the possibility of a familial association. Pituitary adenomas thus the prolactin, parathyroid adenomas and pancreatic adenomas thus the gastrin for Zollinger- Ellison syndrome (hypersecretion of gastrin -> duodenal ulcers). However, the way MEN1 causes hypercalcaemia is via increased PTH levels.
    1. Incorrect. Osteoporosis tends to be associated with hypocalcaemia.


    Endocrinology: Diagnosis and management of hypercalcemia


    Question 31 top Download PDF

    A patient, previously untreated, is commenced on phenytoin therapy with an intravenous loading dose of 1000mg, followed immediately by oral administration of 300mg/day as a single daily dose.

    Assuming that phenytoin has an elimination half-life of 30 hours, what is the best estimate of the length of time after the initial loading dose that then patient will achieve steady state conditions with respect to phenytoin?

    1. Immediately
    2. One day
    3. Three days
    4. Six days
    5. Twelve days



    Refer to 2002P2Q57 (also on phenytoin)

    Estimation of length of time to achieve steady state in phenytoin = 5-7 half-lives
    Usually quoted as 5.5 x t1/2 (5.5 x 30 hours = 165 hours = 6.8 days) = closest answer is D

    Half life

    • Time required for 50% of drug to be eliminated

    Steady state

    • A point during chronic drug administration
    • Amount of drug administered per unit time = amount of drug eliminated per unit time
    • During continuous IV: plasma drug concentrations at steady state are stable
    • During chronic oral administration: plasma drug concentration may vary during dosing interval but the time-concentration profile between intervals is stable

    Loading doses

    • For some drugs, indication may be urgent so time to steady state levels is too long
    • Loading dose -> rapid plasma elevations -> achieves therapeutic effect faster
    • However time taken to achieve true steady state is still determined only by half-life
    • Only appropriate if there’s a defined relationship between drug dose and clinical effect
    • Loading dose = C X V
      • C is the desired plasma concentration
      • V is the volume of distribution


    • Loading dose = Fr x MD
      • Fr is the fraction of drug eliminated during dosing interval
      • MD is the planned maintenance dose

    Linear kinetics
    Drug concentration a dose
    Rate of elimination a drug concentration

    Thus – if doubling of steady state concentration is desired, the dose should be doubled

    Non-linear kinetics
    Drug concentration is not proportional to dose (and/or)
    Rate of elimination is not proportional of drug concentration

    The main reason is that drug elimination is dependant on enzymes

    • Enzyme concentrations may vary according to genetics, illness, nutrition
    • Enzyme systems also saturable, affected by agonists, can be induced/ inhibited

    Thus - plasma concentrations change disproportionately with small dose alterations


    Neurology: Epilepsy

    Pharmacology: CNS

    Question 32 top Download PDF

    A 75 year old man with non small cell lung cancer and mild chronic renal failure <his serum creatinine is usually 0.15 mmol/L (0.06-0.12)> is recovering from hip replacement surgery. He has been receiving intravenous pethidine via a patient-controlled analgesia for the past three days. Over the last 24 hours, he has developed myoclonic twitching of all limbs and then has a grand mal seizure.

    The most likely cause of his neurological signs is:

    1. Brain mets
    2. Uraemia
    3. Hypercalcaemia
    4. Pethidine metabolites
    5. Stroke



    Commonest cause of seizures in those age >65 is stroke but this man has other risk factors for seizures

    In the setting of renal impairment and a drug with seizure potential, the answer is D.

    • Pethidine: synthetic opiod
    • Pethidine 75mg-100mg IV equivalent to morphine 10mg IV in terms of analgesic/ euphoric/ sedative/ respiratory depressive properties, but suppressive effects on cough reflex less
    • Other off-label use: 12.5mg IV stat for rigors
    • Faster onset of action (more lipid soluble and more addictive) but shorter duration of effect compared to morphine
    • 70% protein bound
    • Mainly metabolised by liver
    • Pethidine hydrolysed (liver) to pethidinic acid, and demethylated to norpethidine
    • Norpethidine is neurotoxic -> dose related PAN (pethidine associated neurotoxicity)
    • Causes:
      • Tremor/ twitches
      • Hallucinations
      • Mood changes
      • Seizures and myoclonus
    • Long half-life (8-12 hours)
    • Norpethidine mainly cleared by kidneys so accumulates in renal failure
    • Half the analgesic properties of pethidine
    • Toxic effects not counteracted by opiod antagonist eg naloxone
    • Seizures should be managed supportively +/- benzodiazepines, and use of other analgesia is recommended
    • Has anti-cholinergic effects
    • Many drug interactions:
      • Avoid respiratory depressants/ CNS depressants
      • MAO inhibitors -> excitation, sweating, hypo/hypertension +/- fatal
      • Phenytoin/ phenobarbitone -> increase metabolism thus more norpethidine


    Uraemia can also cause seizures but unlikely to have such high urea levels with a Cr of 150. Typically it is hypocalcaemia rather than hypercalcaemia that causes seizures.

    Other clinical features of hypocalcaemia

    Tetany, myopathy and weakness, cramps, QT prolongation, papilloedema, mental changes




    Question 33 top

    Question 34 top Download PDF

    A 36-week pregnant woman is exposed to a child with chicken pox 24 hours prior to presentation. There is no prior history of chicken pox.

    The most appropriate initial management is:

    A. Urgent serology for varicella zoster virus

    B. Hyperimmune globulin (ZIG)

    C. Chicken pox vaccine

    D. Acyclovir

    E. Observation

    Answer: A

    Post-exposure chicken pox prophylaxis
    Factors to consider

    • Determination of patient susceptibility
    • Negative history of varicella
    • No previous immunisation
    • All health and immuno-compromised children and adults (except bone marrow transplant recipients) with prior personal history of chicken pox can be considered immune
    • Degree of exposure and if that is likely to result in infection
    • High exposure: face to face contact, > 1 hour in enclosed area


    • If patient is at higher risk of developing varicella-related complications

    Recommendations for prophylaxis

    Pregnant females (see flow chart below)


    • whose mother has varicella around time of delivery (4 days before, 2 days after)
    • Prem infants born >28 weeks exposed in neonatal period and mother with no immunity
    • Prem infants born < 28 weeks or < 1kg weight exposed in neonatal period regardless of maternal Hx

    Within 96 hours

    • VariZIG (varicella zoster immune globulin IgG)

    If > 96 hours

    • IV immunoglobulin (contains anti-varicella Ab of varying quantities)
    • (OR) closely monitor for signs/ symptoms - start acyclovir if illness develops

    All who receive VariZIG should receive varicella vaccine after 5 months except pregnant women (theorectical risk of inducing congenital disease)

    Note: variZIG does not prevent foetal infection but prevents mother from developing complications of varicella infection

    Healthy, non-pregnant adults

    Within 3-5 days of exposure

    • Varicella vaccine
    • Serological testing prior is helpful as majority with no prior history of chicken pox are actually seropositive

    If varicella develops despite prophylaxis


    • in adults to prevent complications
    • in those who come in contact with immuno-suppressed


    For pregnant women

    For primary prevention: Varicella vaccination

    • All children < 13 years old
    • All high risk adults (day care employees, women of child bearing age) and those who are household contacts of immuno-suppressed
    • NOT FOR PATIENTS WITH IMMUNODEFICIENCIES (live attenuated vaccine)

    For treatment

    • Not in healthy children < 12 years old as usually self-limiting disease and modest benefits (less number of lesions, less duration of fever)
    • Should treat these children
          • > 12 years old
          • chronic skin /cardiopulmonary disease (because secondary bacterial infection can be severe)
          • on steroids (both oral and inhaled) or aspirin
          • secondary household cases (often more severe)
    • Adults with uncomplicated varicella: acyclovir 20mg/kg oral QID for 5 days
    • Immunosuppressed children (both complicated and uncomplicated disease): IV acyclovir
    • Adults and children with disseminated disease: IV acyclovir
    • Antihistamines for itch

    Congenital varicella infection

    • Infants whose mothers infected between 8 and 20 weeks gestation
    • Risk <1% if infected < 13 weeks, 2% if before 20 weeks
    • Features
      • IUGR
      • Skin lesions
      • Ocular defects eg cataracts, chorioretinitis, micro-opthalmus
      • Limb defects eg bone hypoplasia
      • CNS effects eg mental retardation


    Infectious Diseases: Viral illness | Infection control


    Question 35 top

    Question 36 top

    Question 37 top

    Question 38 Download PDF

    A 35 year old man with human immunodeficiency virus (HIV) has been hospitalised for treatment of pneumocystitis carinii pneumonia (PCP). He is alert and lucid until two days later when he becomes increasingly agitated, restless and irritable. He has become increasingly uncooperative with staff. He appears to be having auditory hallucinations and refers to his belief that his HIV infection has suddenly been cured. He is not sleeping, and has been disinhibited at night. He is forgetful and disoriented.

    The most likely diagnosis is:

    1. Delirium
    2. HIV dementia
    3. Mania
    4. Acute schizophrenia
    5. Major depression

    Answer: A

    Consistent with DELIRIUM

    DSM IV criteria

    1. Disturbance of consciousness with reduced ability to focus, sustain, or shift attention
    2. A change in cognition or the development of a perceptual disturbance that is not better accounted for by a preexisting, established, or evolving dementia.
    3. The disturbance develops over hours to days, fluctuates, can last for weeks to months
    4. There is evidence that the disturbance is caused by a medical condition, substance intoxication, or medication
      Other features
    5. Psychomotor disturbances eg hyper/hypoactivity with impaired sleep
    6. Emotional disturbances and lability

    Ddx in HIV patient

    1. Primary psychiatric disorder
      • Depression: more dysphoria, less fluctuation
      • Mania: usually previous episodes of mania/depression
      • Acute schizophrenia: longer history of symptoms, not otherwise confused
    2. MCMD (Minor Cognitive Motor Disorder) ? early HIV dementia
      • HIV patients with mild motor/ cognitive/ mood disorders not impacting on daily living
      • Clear conscious state
    3. HIV dementia/ HIV encephalopathy/ AIDS dementia complex
      • Clear conscious state
      • Memory and psychomotor speed impairment, movement disorder and depressive symmptoms affecting daily living
      • No cortical dysfunction eg aphasia, agnosia and apraxia ddx between this and Alzheimer’s dementia
      • ? Secondary to infected brain macrophages and microglial
      • Demyelination, microglial nodules, multinucleated giant cells, perivascular infiltrate
      • In post HAART era, unclear correlation between plasma viral load and risk of HIV dementia
      • HAART may delay onset and alter type of cognitive deficit
      • With HAART, more HIV patients are living longer and may start developing other age-related dementias
    4. Focal neurological syndromes
      • Non convulsive status epilepticus, check for twitching, involuntary eye movement, usually no post-ictal features
      • Temporal parietal lesions, frontal lobe lesions


    Infectious Diseases: HIV


    Question 39 top

    Question 40 top Download PDF

    40) Which one of the following is least likely to improve the “on-off” phenomenon in a patient with Parkinson’s disease currently treated sixth-hourly with levodopa/carbidopa and selegiline?

    1. Reducing the time between doses of levodopa/ carbidopa
    2. Introduction of a dopamine agonist
    3. Introduction of a catechol-O-methyltransferase (COMT) inhibitor
    4. Increasing each dose of levodopa/ carbidopa
    5. Introduction of a sustained-release form of levodopa/ carabidopa



    Learning Issues:

    • Parkinson’s disease
    • Treatment and side effects

    Parkinson’s Disease (PD)

    • Bradykinetic neurodegenerative movement disorder
    • Peak age onset >60 years old
    • Males > females
    • Cardinal features: (need 2 out of 4 for dx)
      • Rigidity
      • Bradykinesia
      • Rest tremor (present in >85%)
      • Gait disturbance
    • Other features:
      • Anosmia
      • Autonomic dysfunction (may also be treatment related)
      • Psychiatric features (depression, dopamine-related hallucinations)
      • Sleep disturbance
      • Dementia
      • Dyskinesia and motor fluctuation (Levadopa related)


    • Subtypes
      • Idiopathic (75%)
      • Genetic/ familial clusters (< 5%)
      • Others eg other neurodegenerative disease/ drugs/ CVA
    • Pathology (degree relates well with motor symptoms and dementia)
      • Degeneration of dopaminergic pathways (dopamine deficiency) and increase cholinergic sensitivity in basal ganglia
      • Neurons accumulate a synuclein protein -> lewy bodies (especially olfactory and brain stem -> midbrain)
      • Brain atrophy (limbic/ paralimbic structures; anterior cingulate gyrus)


    A few general statements about PD:

    • An early onset resting tremor especially if unilateral suggests idiopathic PD
    • Early onset cognitive decline, neuropsychiatric symptoms or autonomic dysfunction suggests syndromes with Parkinsonian features – usually earlier age of onset and less responsive to levadopa
    • Drug induced parkinsonism (mainly neuroleptics, metoclopramide, manganese, CO) closely resembles idiopathic except the tremor is generally less prominent. This often resolves with drug cessation – if it persists, the patient may already have been in the process of developing PD
    • Diffuse lewy body dementia (DLB) closely associated with PD, there is controversy whether it is a spectrum of disease
      • However tend to have action rather then rest tremor
      • Rapidly fading response to levadopa
      • Marked early neuropsychiatric features


    • increase dopamine supply
    • Levadopa + carbidopa/ benserizide
    • Dopamine agonist
    • Direct stimulation of dopamine receptors


    • ß metabolism of dopamine
    • MAO inhibitors
    • COMT inhibitors

    4) Anticholinergics

    Mostly experimental
    MAO inhibitor selegiline (showing promise but conflicting data)
    Chronic NSAIDS
    Oestrogen in post-menopausal women
    Coenzyme Q10 (anti-oxidant)
    Minocycline (antibiotic)






    Levadopa/ Carbidopa (Sinemet)


    Sustained release formulations available but less completely absorbed so need 30% more to achieve same response

    Can be used 1st line

    Precursor of dopamine which crosses BBB

    Carbidopa/ benzaseride:
    Peripheral decarboxylase inhibitor which prevents peripheral conversion to dopamine in systemic circulation

    Start with small doses TDS with meals

    With dementia: start with smaller doses due to increase susceptibility to psychiatric complications

    Most with idiopathic PD

    • Good response
    • if no/minimal response with moderate doses, reconsider dx or revise it to other subtype eg MSA


    increase homocysteine -> increase risk hip #

    In older patients

    • Hallucinations/ delusions
    • Confusion
    • Agitation

    Long term use:
    Within 5-10 years, up to 50% develop motor fluctuations, dyskinesias and dystonia

    Concerns re neurotoxic effects of levadopa in vitro

    Dopamine agonists


    Apomorphine (used IV as rescue therapy)


    Can be used 1st line and monotherapy but most will need levadopa in a few years (OR) adjunctive in advanced PD where there is ß levadopa response and increase levadopa complications

    Direct stimulation of dopamine receptors

    • No need conversion
    • No competition with other amino acids for gut absorption
    • Longer duration of action

    Similar to levadopa

    Peripheral oedema common in chronic use (rare in those using levadopa alone)

    ß PRL

    “Sleep attacks”  with pramipexole

    Valvular heart disease with pergolide and cabergoline (secondary activation of serotonin receptors activation and overgrowth) so they should be avoided

    Ergot-related side effects rare

    • Raynaud
    • Erythromelalgia
    • Retriperitoneal/ pulmonary fibrosis

    increase risk of impulse control disorders eg pathological gambling

    MAO-B inhibitors


    Can be used as monotherapy in very early PD

    Combination of selegiline and levadopa produces better Sx control than levadopa monotherapy

    Slows oxidative metabolism of dopamine thus may increase levadopa-induced side effects eg dyskinesia and psychiatric effects



    Worsen side effects of levadopa

    Confusion in elderly (very common)

    Avoid simultaneous SSRI or TCA

    COMT inhibitors


    Levadopa extenders thus useless as monotherapy

    • ß peripheral methylation of levadopa (entacapone)
    • ß central methylation of levadopa (tolcapone)


    From increase dopaminergic effects thus nausea
    Postural hypotension

    Orange urine

    Abnormal LFTS and hepatotoxicity (only tolcapone)


    Benztropine (Cogentin)

    Trihexyphenidyl (Artane)

    Dopamine depletion produces state of cholinergic sensitivity so cholinergic drugs exacerbate PD symptoms and anticholinergics improve symptoms

    Useful as monotherapy in age < 70 with mainly tremor but no gait problems or significant akinesia

    Memory impairment

    Antimuscarinic effects

    • Dry mouth
    • Blurred vision
    • Ur retention/ constipation
    • Impaired sweating
    • Tachycardia


    Antiviral, mechanism uncertain

    • Antimuscarinic agent
    • Weak dopamine agonist
    • Glutamate antagonist

    Use to treat dyskinesias

    Elimination depends on renal clearance so dose reduce in renal impairment

    Usually transient and modest effect for early/ mild PD

    Of little benefit adding to levadopa but great effect with levadopa added to amantadine

    Often anticholinergic

    Livido reticularis

    Ankle oedema


    Education/ counselling


    • Deep brain stimulation and paiidotomy/ thalmotomy/ subthalmotomy
    • Patient selection crucial
    • Symptoms that do not respond to levadopa generally do not improve (eg postural instability, hypophonia, drooling)
    • Major indications
      • Idiopathic PD (atypical PD does not have a good response)
      • Good levadopa response
      • Significant, severe symptoms
      • Minimal cognitive impairment


    Motor fluctuations

    • “On-Off” phenomenon/ alterations
    • Usually in advanced PD
    • Noticed < 4 hours post dose of levadopa
    • Management:
      • increase dose of levadopa IF on a small dose and not having other side effects
      • Shorten interdose interval (more effective, but some may experience “all or nothing” with small doses: in advanced disease the pharmacological threshold is higher)
      • SR (Need to increase dose 30% - some studies showed no ß “Off” time)
      • Addition of 2nd drug
        • Dopamine agonist to ß “Off” time (bromocriptine ineffective, others equal efficacy though cabergoline increase dyskinesia)
        • COMT inhibitors (clinical effect immediate)
        • MAO-B inhibitors (seligine on “Off” time modest, resiligine better)
      • Anticholinergics and amantadine NOT helpful in motor fluctuations
      • H-Pylori eradication (improved levadopa absorption)


    • Unpredictable freezing
      • Sudden immobilisation for minutes -> falls
      • Not medication related
      • Resistant to treatment
    • Some occasionally fail to turn “On” following a dose of levadopa
      • Known as “No On” response
      • May be due to ß gastric motility and poor absorption
      • Or due to prolonged “Off” time
      • Can treat with prokinetic agent eg domperidone (D2 antagonist but does not cross BBB so does not worsen PD symptoms like metoclopramide)



    • Involuntary abnormal movements
    • May be choreic or dystonic, affecting face, trunk, extremities and respiratory muscles
    • Or when severe, can be myoclonic or ballistic and interfere with movement
    • Often well-tolerated
    • Happens when patient is “On” and during “peak dose” (60-90 minutes post-dose), may have a diphasic pattern
    • Direct effect of levadopa – especially common in those with young onset PD
    • Affects up to 40% by 5 years and increase with duration of treatment
    • Management
      • Avoid SR formulations
      • ß levadopa dose as much as possible
      • Try adding dopamine agonist and ß levadopa dose
      • Amantadine (short term benefit)
      • Clozapine (but watch for agranulocytosis)
      • Olanzepine (but may have unacceptable increase PD symptoms and “Off” time)



    • Sustained abnormal postures mainly affecting limbs but also face, neck and trunk
    • During “Off” period
    • Can be painful eg early AM foot twisted in abnormal posture due to withdrawal from treatment
    • Or as akathisia (motor restlessless eg restless legs) a few hours after PM dose of levadopa
    • Management
      • Take SR before sleep
      • Levadopa or dopamine agonist 1st thing in the morning/ middle of the night
      • Avoid taking levadopa with high protein meals


    Non-motor symptoms

    • Depression: antidepressants eg SSRIs and ECT very effective
    • Psychotic features/ confusion: stop amantadine and anticholinergics 1st then consider simplification of drug regime in the following order: selegiline, nocturnal doses of dopamine agonist, sustained release formulations, daytime doses of dopamine agonists and finally daytime levadopa
      • If doing this worsens PD – atypical antipsychotics (quetiapine the best, clozapine also good but risk of agranulocytosis)
      • Risperidone and olanzepine tend to worsen PD symptoms
      • Some evidence suggest anti-cholinesterase inhibitors may be useful in those with dementia

    Back to the question:
    The patient is on QID levadopa/ carbidopa + MAO-B inhibitor selegiline and experiencing motor fluctuations – suggesting advanced disease.

    All options are aiming towards either increasing the dose or duration of effect of dopamine, however increase dose of levadopa is the least effective so the answer is D.


    Neurology: Parkinson's disease



    Question 41 top

    Question 42 top Download PDF

    Question 42

     A 46 year old woman notes a central neck swelling. Ultrasonography of her neck reveals a solitary thyroid nodule in the right thyroid which at thyroid scintigraphy is “cold” (ie does not take up isotope). Thyroid function tests are normal and aspiration cytology shows follicular cells.
    What is the most appropriate next step?

    1. Repeat aspiration cytology
    2. Drill biopsy of the nodule
    3. Total thyroidectomy
    4. Serum thyroglobulin
    5. Right thyroid lobectomy


    I thought the answer was between C and E.

    Main points to consider:

    • Cold thyroid nodules are sinister because of the potential of malignancy
    • Hot nodules are almost never malignant
    • This is in keeping with the normal TFTs suggesting that the cold nodule is non-functioning ie no radio-iodine uptake
    • Aspiration cytology: when follicular cells are found it does not ddx between benign follicular adenomas and carcinomas
    • Asymptomatic thyroid nodules that are benign on FNA do not need treatment (in any case, thyroid suppression with medications are generally ineffective in shrinking solitary nodules)
    • Incidence of malignancy in solitary nodule is about 7% - same as that of any dominant nodule in a multinodular goitre (MNG)
    1. No point repeating aspiration cytology – firstly false positive rates are low (<5%) and even if the repeat results are normal it is a potential false negative. Only indication for repeating FNA (and usually with ultrasound guidance) is if there is an inadequate/ poor sample.
    1. I can’t find information on this type of biopsy!
      • Current types include: FNA (25G needle), fine needle capillary sampling (similar to FNA but needle not connected to syringe), core biopsy and larger needle aspiration biopsy (15G)
      • FNA is commonly done, the rest are rarely indicated
    1. Total thyroidectomy- removal of entire thyroid gland. Indications are:
      • Thyroid cancer
      • Multinodular goitre if obstructive symptoms, thyrotoxicosis, retrosternal extension, suspicious changes on FNA, history of head & neck irradiation (higher risk of developing cancer) and cosmetic reasons
      • Risks
        • Bleeding/ damage to large neck vessels
        • Damage to trachea/ oesophagus
        • Damage to recurrent laryngeal nerve(s) + ext branch of superior laryngeal nerve
        • Damage to parathyroids -> hypocalcaemia (t1/2 PTH 6-8 hours)
        • If the goitre is retrosternal, pneumo/haemothorax
        • If residual tissue left behind, it will regrow in response to TSH
      • Other types of thyroid surgery
        • Hemithyroidectomy/ Lobectomy: Single lobe removed. Indicated for solitary nodule
        • Subtotal thyroidectomy: Most of thyroid tissue removed, small remnant left. Indicated for Graves disease or as alternative to MNG
    1. Thyroglobulin
    • Large glycoprotein molecule in the thyroid follicle
    • No point measuring serum levels because it is usually not released into the circulation
    • Indications for measuring serum thyroglobulin: monitoring for relapse post throidectomy and radio-active iodine ablation for thyroid cancers
    • Note that presence of thyroid autoantibodies invalidate serum thyroglobulin measurements
    • Contains 70 tyrosine amino acids: the major substrates to combine with iodine to form thyroid hormones (organification of thyroglobulin)
    • Tyrosine is 1st iodised to form monoiodotyrosine then diiodotyrosine -> diiodotyrosine molecules couple to form thyroxine T4 (OR) diiodotyrosine binding with monoidotyrosine to form triiodotyrosine T3
    • Thyroid hormones are stored in thyroglobulin (ratio T3:T4 about 1:14) in amounts sufficient to last 2-3 months before deficiencies are apparent
    • The thyroid cell sends out pseudopod extensions into the colloid to form pinocytic vesicles that engulf thyroglobulin into the thyroid cell -> lysosomes fuse with the vesicles -> protein (thyroglobulin) gets digested -> T3 and T4 are then cleaved off -> diffuse into capillaries into circulation
    • 75% of iodinated tyrosines never make it to becoming thyroid hormones -> the iodine is recycled (cleaved off tyrosine by enzyme deiodinase)


    1. Correct
      • Frozen section should be obtained intra-operatively: may be difficult making a diagnosis as careful evaluation needed to exclude capsular and vascular invasion
      • If malignant on histopathology, total thyroidectomy
      • If benign, the left lobe is spared (no need lifelong thyroxine replacement)
      • If uncertain, enlarged thyroid lymph nodes +/- jugular nodes biopsied. If both negative, 2 options:
        • Spare left lobe with understanding that 2nd operation needed if malignant
        • Subtotal thyroidectomy on contralateral side. Will not need 2nd operation as residual tissue can be ablated with radio-iodine


    Thyroid Cancer Fast Facts

      • Arise from follicular cells, C-cells (calcitonin), lymphocytes or stromal cells
      • Presents as solitary nodule, dominant nodule in MNG or metastatic disease
      • One of the cancers that cause PUO
      • All should receive at least hemithyroidectomy apart from thyroid lymphomas (responds well to radiotherapy) and anaplastic cancers (which should be palliated with radiotherapy +/- chemotherapy)
      • For well differentiated cancers, post-operative radio-iodine and thyroxine suppression to ablate metastatic disease
      • For specific metastatic lesions, external beam RT can be helpful


      • Follow up:
        • Whole body iodine scan
        • Serum thyroglobulin levels
        • Recombinant human TSH (rTSH) stimulated thyroglobulin levels
        • If serum thyroglobulin high and scan negative -> PET + CT scan


    Type of cancer



    Papillary (85%)

    Younger age (20-40)
    Good prognosis (90% survival 10 years)

    Lymph nodes


    Middle age (40-60)
    Solitary nodule
    OK prognosis (75% survival 10 years)

    Haematogenous spread

    Hurthle cell

    Type of follicular neoplasm
    50% previous irradiation to head & neck

    Many have coexistant separate cancer in same gland




    Rapidly enlarging mass
    Usually advanced on presentation
    Poor prognosis (< 5% survival 10 years)

      • Usually months

    Local invasion

    (C cells)

    Secretes calcitonin
    May secrete other peptides

      • Serotonin
      • CEA

    80% sporadic, 20% familial
    Often part of MEN2
    - Screen for hyperparathyroidism (hypercalcaemia) and phaeochromocytoma (high urinary catecholamines)

    Lymph nodes
    Lung, bone, liver

    Note: radiotherapy resistant and does not take up radio-iodine so aggressive surgery (total thyroidectomy +/- radical neck dissection +/- lymphadenectomy (local and mediastinal)


    From lymphocytes
    Often associated with Hashimoto’s



    Rare eg
    Squamous cells, sarcoma, mets from another primary



    Differential diagnoses for thyroid nodules
    HOT nodules are in BOLD ITALICS



    Dominant nodule of MNG (colloid adenoma)

    Hashimoto’s thyroiditis

    Cysts (colloid, simple, haemorrhagic)

    Follicular adenomas

      • Macrofollicular
      • Microfollicular/ cellular

    Hurthle cell adenomas (oxyphil cell)

      • Macrofollicular pattern
      • Microfollicular pattern






    Primary thyroid lymphoma

    Metastatic lesion (breast, renal cell etc)


    • Hot adenomas often known as toxic adenomas
    • Some benign adenomas are cold
    • Other cold thyroid lesions include subacute thyroiditis: de Quervain’s thyroiditis (tender), silent thyroiditis (non-tender), amiodarone/ radiation induced thyroiditis


    Endocroinology: Thyroid nodule

    Question 43 top

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    Question 45 top Download PDF

    A 62 year old man with a history of controlled hypertension presents with worsening lethargy over several months and more recently, weight loss, night sweats and easy bruising. Examination reveals anaemia, bruising from firm splenomegaly 12cm below the left costal margin; no lymphadenopathy is evident.

    Full blood examination reveals:


    81 g/L (135- 170)


    100 fL (80-95)

    White cell count (corrected – does not include nucleated red cells)

    3.4 x 109 (3.5 -9.5)



    1.0 x 109 /L (1.5 -6.0)


    0.5 x 109/ L


    0.3 x 109/ L


    1.20 x 109/ L (0.70 – 1.35)


    0.2 x 109/ L (0.2 -0.6)


    0.1 x 109/ L (0-0.4)


    0.10 x 109/ L (0 -0.15)

    2 nucleated red cells/ 100 leucocytes

    Platelet count

    75 x 109/ L (150- 450)

    The blood film is shown below:

    Coagulation screen normal
    Routine biochemistry is unremarkable except for:

    Lactate dehydrogenase (LDH)

    525 U/L (<250)

    Uric acid

    0.62 mmol/ L (0.15 – 0.50)

    The most likely diagnosis is:

    1. Metastatic carcinoma
    2. Megaloblastosis
    3. Primary myelofibrosis
    4. Systemic lupus erythematosus
    5. Chronic myeloid leukaemia

    This presentation and blood film findings can be that of any myeloproliferative disease, but not:

    1. Metastatic cancer should not cause these blood film abnormalities
    1. Megaloblastosis refers to impaired DNA synthesis, mainly due to B12/ folate deficiency or drugs that impair DNA metabolism (eg purine antagonists, HAART). Usually MCV >100 fL, there should be hypersegmented nf on blood film and there should not be splenomegaly.


    1. SLE more common in women, and this is the wrong age group. Nothing in history to suggest a connective tissue disorder.

    Either C or E, however in CML there should be increasedwhite cell count and normal platelet count at diagnosis.

    Tear drop RBC = Membrane damage from collagen fibres
    Nucleated RBC = Premature release of erythroid precursors
    No blasts

    Myeloproliferative diseases

    • Clonal expansion of multipotent haematopoietic stem cell -> overexpansion of one or more formed elements of blood
      • Polycythaemia rubra vera (PRV)
      • Essential thrombocytosis (ET)
      • Chronic myeloid leukaemia (CML)
      • Chronic idiopathic myelofibrosis
    • May transform into acute leukaemia either naturally or as a result of treatment


    • Phenotypically similar and large overlap
    • However, CML genotypically distinct as it is associated with specific translocation t(9;22) -> unique fusion protein bcr-abl and unique response to imatinib (Gleevec, which induces apoptosis in cells expressing bcr-abl)
    • Systemic mastocytosis very phenotypically similar to CML, but has own category due to distinct clinical syndromes which characterise mast cell proliferation

    Chronic idiopathic myelofibrosis

    • Also known as agnogenic myeloid metaplasia, myelofibrosis with myeloid metaplasia
    • Clonal expansion of multipotent haematopoietic stem cell of unknown aetiology characterised by:
      • Marrow fibrosis (note that the responsible fibroblasts are NOT clonal; BMAT difficult due to fibrosis but if done: hypercellular marrow with trilineage hyperplasia especially increase megakaryocytes which are otherwise normal)
      • Myeloid metaplasia
      • Extramedullary haematopoiesis
      • Splenomegaly (which may be massive)
      • May be associated with autoimmunity: immune complexes, ANA, RhF or positive Coombs (this is not present in the other myeloproliferative disorders)
    • Degree of myelofibrosis and degree of extramedullary haematopoiesis in not related
    • Fibrosis is due to overproduction of transforming growth factor b and thrombopoietin


    • Clinical features and diagnosis:
      • No specific symptoms and signs early on
      • Usually asymptomatic and detected by splenomegaly +/- mild hepatomegaly (OR) routine bloods
      • Extramedullary haematopoiesis may cause portal HT (varices, ascites), pulmonary HT, intracranial HT, pericardial tamponade, spinal cord compression, skin nodules
      • Anaemia usually mild initially
      • Splenomegaly may be massive -> hypersplenism, infarction with fever and pain, early satiety
      • X rays may reveal osteosclerosis
      • Hyperuricaemia and secondary gout (increase turnover of cells)
    • Do cytogenetics to exclude CML and for prognostic purposes
      • Complex karyotype abnormalities -> poor prognosis
      • Associated very increase CD 34+ cells in flow cytometry


    • Progression:
      • Median survival 5 years (1-15 years)
        • Poor prognostic features include degree of marrow failure, increase age, complex cytogenetics
      • Progressive marrow failure, transfusion dependence and increase organomegaly with its complications
      • Prone to deep infections especially lungs
      • Can evolve from chronic -> accelerated phase
      • 10% develop acute leukaemia (does not respond to treatment)
    • No specific treatment:
      • Erythropoietin worsens splenomegaly
      • If hypersplenism -> splenectomy (but for unknown reasons increase risk of acute leukaemia)
      • Allopurinol for hyperuricaemia and gout
      • Hydroxyurea may control organomegaly
      • Can also try IFNa, steroids +/- thalidomide
      • Consider allogenic stem cell transplant in younger


    Haematology:Myeloproliferative disorders


    Question 46 top Download PDF

    A 45 year old Caucasian man is referred because of abnormal liver function tests. He complains of the recent onset of lethargy. Examination reveals a 15cm smooth edged liver and some spider naevi.

    Blood investigations show:

    White cell count

    7.5 x 109/ L

    4.0 – 11.0

    Normal differential




    124 g/L


    Platelet count

    120 x 106

    150 -400


    140 mmol/L



    4.5 mmol/L



    6.5 mmol/L

    3.6 -9.3


    0.09 mmol/L

    0.06 -0.12


    28 microm/L



    95 U/L



    120 U/L



    135 U/L



    148 U/L



    35 g/L




    0.9 -1.1


    2360 microg/L



    240 micromol/L



    200 g/L


    The next most appropriate blood test in the investigation of this patient is:

    1. Hepatitis serology
    2. Autoimmune serology
    3. Testing for the haemachromatosis gene (HFE)
    4. Alpha-1-antitrypsin phenotyping
    5. Haemolysis screen



    Young man with smooth hepatomegaly and:

    • Evidence of liver dysfunction
      • Decreased hepatic synthetic function (ß albumin and increase INR)
      • Spider naevi (secondary altered oestrogen metabolism)
    • Hepatocellular pattern
      • AST and ALT elevated > 3x normal
      • Associated GGT elevation 2x normal
      • Normal ALP suggesting no biliary obstruction
    • increase ferritin levels (even if it is an acute phase reactant, still increase if divided by 3)
    • suggests haemachromatosis


    • Autosomal recessive disorder of excessive Fe absorption
    • Very common in Caucasian population
    • Commonest mutations:
      • C282Y
      • H63D
      • S65C (rare)
      • Can be C282Y homozygote, C282Y heterozygote, H63D homozygote which rarely develops Fe overload, H63D heterozygote, compound heterozygote (eg C282Y/H63D)
    • Heterozygotes may have increase Fe storage but do not develop disease – Fe may act as co-factor to worsen other liver diseases eg viral hepatitis, ETOH
    • Clinical features develop after 20g accumulation (normal person absorbs and loses 1mg daily, in haemachromatosis 2-4mg is absorbed)


    • HFE mutations lead to impaired binding of transferrin-Fe complex to transferrin receptor of intestinal crypt cells thus there is a false signal that Fe stores are ß
    • If body Fe stores are increase, there would be increase transferrin-Fe complexes -> increase binding to crypt cells -> increase intracellular Fe -> ß regulate production of DMT-1  (Fe transporter) -> ß absorption of dietary Fe
    • Fe deposition in parenchymal cells then reticuloendothelial cells later in disease (the other way round in transfusional Fe overload)

    Clinical features:
    Early dx and Rx can improve/ reverse end organ damage

    • Liver disease (75%)
      • Hepatomegaly, abnormal LFTS, fibrosis and cirrhosis with its complications
      • Potentiates liver failure from other causes eg viral hepatitis
    • Diabetes (50%)
      • Progressive pancreatic deposition but selective for beta cells
    • Heart failure
      • Dilated cardiomyopathy with characteristic low signal on MRI
      • Conduction defects and sick sinus
      • Controversial if accelerates atherosclerosis
    • Arthropathy (45%)
      • Similar to pseudogout
    • Skin pigmentation (70%)
    • Hypogonadism (45%)
      • Fe deposition in pituitary but tends to affect gonadal axis more (ß FSH/ LH/ testosterone/ oestrogen – but females < affected)
      • Primary testicular failure also occurs but less common
    • Hypothyroidism
      • May be related to pituitary deposition
      • Often increase anti-thyroid Ab -? Thyroid deposition and damage
    • Cancer
      • Mainly hepatocellular cancer and +/- extrahepatic cancers
    • Susceptibility to certain infections
      • Fe loving organisms (siderophoric) eg Listeria, Yersinia enterocolita and vibrio vunificus (uncooked seafood)
      • Fe laden macrophages also less effective
    • Weakness and lethargy (75%)
    • In heterozygotes
      • Some studies suggest increase risk of diabetes, colorectal cancer and haematological malignancies


    Test: relatives of index case and symptomatic (eg liver disease, diabetes, heart failure)

      • Serum ferritin
      • Fasting Transferrin saturation (TS) > 45% (>90% sensitive)
      • TS = (serum Fe/2) / (serum TF x100)
      • HFE gene testing (specific)
      • Liver biopsy if older, ferritin > 1000 +/- abnormal LFTs or HFE testing non-diagnostic
        • Hepatic iron index (HII) = hepatic iron concentration (HIC )/ age
        • Usually HII > 1.9 and HIC > 80 microm/g



        • Lifelong venesection (monthly till aim ferritin 20 then 3 monthly)
          • 1 unit of blood contains 250mg Fe (normal man has 1g Fe stores thus 4 venesections will render them anaemic)
          • Need to take off > 20 units in haemochromatosis
        • Moderate red meat intake
        • Avoid Fe supplements and Vitamin C (aids Fe absorption)
        • Avoid hepatotoxics and moderate ETOH intake
        • Similar treatment for other overload syndromes except transfusional Fe overload:
          • Chelation
            • Principle is that Fe has 6 binding sites to allow binding of chelating molecules (previously S/C infusions, now oral available)
            • Complications: siderophoric infections, ototoxicity, visual changes, hepatotoxicity

        Other iron overload syndromes:

        • Massive Fe intake
        • Normal Fe intake but increase absorption
        • Hereditary haemachromatosis
        • Ineffective erythropoiesis (eg sideroblastic anaemia or porphyria cutanea tarda)
        • African iron overload (not HFE gene, ?ferriportin protein)
        • Juvenile haemochromatosis (autosomal recessive, mostly in Italy)


          • Parenteral administration of Fe +/- transfusional Fe overload
          • Each unit of blood 250mg Fe (normal dietary intake 1mg daily)
          • Eg child with beta thalassaemia major



          Question 47 top Download PDF

          A 43 year old man presents with focal neurological signs.

          Investigations show:

          HIV antibody


          CD 4+ cell count

          10 cells/ mL [500-1500]

          Plasma HIV RNA concentration (viral load)

          250,000 copies/mL

          Ig G
          Ig M



          Ig G
          Ig M



          Epstein Barr virus
          Ig G
          Ig M



          Rapid plasma reagin (RPR)





          Cryptococcal Antigen

          Polymerase chain reaction
          - JC virus
          - Epstein Barr virus
          - HIV viral load


          20 lymphocytes/ mm3
          0 polymorphs/ mm3
          0 red blood cells/ mm3




          10,000 copies/mL

          CT is shown opposite


          The most likely diagnosis is:

          1. Toxoplasmosis encephalitis
          2. Primary cerebral lymphoma
          3. Progressive multifocal leukoencephalopathy
          4. Cerebral bacterial abscess
          5. Cryptococcal meningitis







          ct brain

          Answer: B

          Learning issues:

          • HIV and AIDS defining illness (with CD 4+ counts at which each manifests)
          • Neurological complications of HIV
          • CTB appearances of common HIV cerebral complications

          CD4 Count

          Clinical features/ diseases


          > 500


          Recurrent vaginal candidiasis

          CNS lesions that of immune competent

          • Brain tumours (benign and malignant)
          • Brain mets

          200 – 500

          Pneumococcal pneumonia
          Pulmonary TB

          Herpes zoster
          Oral candidiasis
          Cervical intra-epithelial neoplasis

          Kaposi sarcoma

          HIV associated cognitive and motor disorders
          (but usually do not present with focal lesions)

          100 – 200

          PCP (now incidence decreased due to prophylaxis)


          HIV encephalopathy/ AIDS dementia complex

          CNS mass lesions getting more common as CD4 < 200

          50 – 100


          CNS mass lesions

          • Opportunistic infections
          • Primary CNS lymphoma

          less than 50

          CMV retinitis

          Primary CNS lymphoma

          Progressive multifocal leukoencephalopathy
          (PML, from JC virus)

          CMV encephalitis


          With the advent of HAART and prophylaxis

          • Use of Bactrim for PCP prophylaxis also very effective for toxoplasmosis prophylaxis (decreased incidence from 72% to 18% from 1991 to 1996)
          • HAART associated with declining incidence of HIV encephalopathy, primary CNS lymphoma and PML (though Harrison’s states that PNL still occurs at some frequency despite this)
          • However, HAART may be contributing to new demyelinating leukoencephalopathy

          Imaging techniques

          • MRI has many advantages: no radiation, more sensitive than CT in determining if lesion is truly solitary, greater sensitivity for white matter/ posterior fossa lesions
          • Ancillary studies (more sensitive than specific)
          • Thallium SPECT scan or PET : since thallium/glucose more avidly taken up by tumours, ddx between toxo lesion and primary CNS lymphoma
          • Perfusion MRI: changes in cerebral blood flow to ddx toxo (less flow as less vessels in infected abscess) from lymphoma (more flow

          CNS lesion with mass effect

          • oedema and mass effect
          • caution posterior fossa lesions as herniation can occur
          • usually enhances with contrast (local inflammation and breakdown of BBB)
          • Toxoplasma encephalitis
          • reactivation disease (thus Ig G positive)
          • usually multiple
          • parietal or frontal lobe, thalamus, basal ganglia or corticomedullary junction
          • ring enhancement 90% with oedema
          • uncommonly as diffuse encephalitis


          • Primary CNS lymphoma
          • constitutional Sx 80%
          • solitary and multiple lesions occur at equal frequency
          • if solitary and >4cm, likely lymphoma
          • some degree of irregular enhancement but can look exactly like that of toxoplasmosis
          • usually corpus callosum or periventricular regions
          • TB (tuberculoma)
          • in endemic areas


          • Abscesses
          • eg staph, strep, salmonella, aspergillus, nocardia, syphilitic gumma etc
          • much less common than 1) & 2)
          • usually disseminated infection

          CNS lesion with no mass effect

          • usually do not enhance
          • no risk of herniation
          • PML
          • demyelinating disease
          • by JC virus reactivation (acquired in childhood in 90%, no other known pathology)
          • multifocal areas of demyelination
          • not enhancing
          • bilateral and asymmetrical
          • usually subcortical rather than deep white matter


          • HIV encephalopathy
          • classic triad of subcortical dementia: memory loss, depressive Sx, movement disorder
          • radiological features masquerade PML but tend to be symmetrical
          • CMV encephalitis
          • reactivation of CMV
          • needs low counts <50
          • delirium, confusion and focal neurology
          • very rarely causes ring enhancing lesions with oedema and mass effect
          • usually MRI: diffused micronodular or periventricular encephalitis


          Infectious Diseases: HIV

          Question 48 top

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          Question 53 top Download PDF

          32 year old woman who has type 1 diabetes mellitus for 12 years is found to have mild background retinopathy. Her blood pressure is 120/80 mmHg and her HbA1C is 7.6% (3.8 – 6.0).

          Which one of the following is most likely to retard the progression of the retinopathy?

          1. Aspirin
          2. Laser photocoagulation
          3. Reduction in blood pressure
          4. Improvement of glycaemic control
          5. ACE inhibitor therapy


          Answer: D

          Diabetic retinopathy:

          • major cause of morbidity in both Type 1 and 2 DM
          • commonest cause of blindness in middle age people
          • majority are aymptomatic till advanced (might be too late)
          • often transient worsening of symptoms during 1st year of intense insulin therapy (lower blood glucose leading to decreased plasma volume leading to marginal vessels at risk) and pregnancy
          • strong association between retinopathy and nephropathy independent of glycaemic control, duration of diabetes (? common pathogenesis)
              • albuminuria (ur albumin excretion greater than 200 microg/min) is a predictor for retinopathy in hispanics but not whites
              • presence of retinopathy is a predictor of excess mortality risk (by IHD and stroke) but this is not significant once corrected for nephropathy

          Primary cause is chronic hyperglycaemia (as per DCCT)

          Main mechanisms:

          1. Impaired auto-regulation of retinal blood flow
            • retinal blood flow usually constant but autoregulation impaired in hyperglycaemia
            • leading to increased shear stress

          2. Accumulation of sorbitol in retinal cells
            • unclear mechanism
            • glucose in cells usually metabolized to sorbitol (via aldose reductase) then to fructose
            • increase intracellular osmolality and decreased myoinositol
            • also contribute to cataracts as swollen lens fibres rupture
          3. Accumulation of advanced glycosylated end products (AGE) in extracellular fluid
            • via Amadori pathway
            • accumulated AGEs crosslink with collagen
            • contribute to cataracts
          4. Retinal micro-thrombosis
          5. Raised vasoactive substances
          6. Genetics/ Ethnic group
            • more common in blacks and Hispanics
            • ? polymorphism in platelet glycoprotein receptors


          Diabetic changes in the eye

          1. Non-proliferative
            • hard exudates (leakage of proteinaceous and lipid rich material)
            • soft exudates (infarcted retina distal to occlusion)
            • haemorrphages (dot in inner layes, blot superficially)
            • microaneuryms
            • thickened basement membrane (as in nephropathy)
          2. Proliferative
            • related to vessel changes secondary to ischaemia
            • new vessel formation
                  • initially new and fragile leading to burst and bleed
                  • mature vessels are fibrous leading to contract leading to distort retina leading to retinal detachment
                  • may form in anterior chamber and block aqueous flow leading to glaucoma
          3. Cranial nerve palsies
            • usually CN3 pupil sparing palsy (compressive lesions pick off external para-sympathetic fibres first)
            • other CN palsies may be related to CVA or rhino-cerebral mucormycosis
          4. Cataracts
            • AGE products in lens


          1. In the ETDRS in the 1990s
          • Aspirin (up to 650mg/day) not shown to have any effect on progression of retinopathy, visual loss or to increase risk of bleeding in eye (8 year follow up)
          1. Photocoagulation is the main treatment but question is whether it retards progression
          • ETDRS also showed no difference in visual loss whether treated early or late
          • Early pan-retinal coagulation decreased visual acuity and peripheral vision, thus not recommended
          • Early focal coagulation recommended in macular oedema
          • Some observational studies show regression of retinopathy but this is mostly related to good glycaemic control
          1. BP reduction
          • Decreases diabetic retinopathy just as it does hypertensive retinopathy
          • Not the most crucial factor
          • Diastolic BP seems to be better predictor of outcome
          1. Glycaemic control most effective at primary prevention; highly effective in secondary prevention in mild to moderate cases; little to no effect in severe retinopathy (even in euglycaemic patients post pancreatic transplant)
          1. ACEi may decrease retinopathy independent of BP control
            • mechanism unclear (likely not due to ACE action, but to sulphuryl side group that retards new vessel formation as in captopril and rat corneas)
            • study with lisinopril in normotensive T1DM showed 10% reduction in progression, but only when there’s little or no nephropathy (lancet 1997 Jan 3;351(9095):28-31)


          Endocrinology: Complications of Diabetes - occular

          Question 54 top

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          Question 57 top Download PDF

          A 24 year old man with a severe closed head injury is receiving phenytoin after having three seizures. He has received a loading dose of 1000mg and then 300mg/day via naso-enteric tube. His phenytoin concentration one week later is 8 microg/L (therapeutic range 40-80 microg/L).

          A number of his other treatments are listed below. Which one is most likely to have contributed to the subtherapeutic phenytoin concentration?

          1. Metronidazole
          2. Naso-enteric feeds
          3. Omeprazole
          4. Hyperventilation
          5. Erythromycin




          • Primary site of action: motor cortex
          • Main anti-epileptic effect: blocks voltage dependant sodium channels -> promotes sodium efflux from neuron -> stabilises membrane against hyperexcitability
          • decrease synaptic transmission; inhibits calcium-calmoudulin protein phosphorylation
          • For generalised (not effective for absence) and partial seizures (usually 2nd line)
          • In treatment of status epilepticus, it has slower onset (30 minutes) and longer duration (6-12 hours) compared to benzodiazepines. Needs to be given together to allow immediate and sustained seizure control
          • Seizure prevention in neurosurgery and treatment of certain arrhythmias
          • NOT indicated for seizures secondary to metabolic causes eg hypoglycaemia


          • Phenytoin demonstrates non-linear kinetics
            • With linear kinetics, t1/2 used to determine dose rate, drug accumulation and time to reach steady state
            • With non-linear kinetics, half-life affected by absorption, saturation of metabolic pathways, dose and degree of enzyme induction
            • Thus large inter and intra-patient variability
            • Need to check levels 7-10 days after initiation, dose change, addition of new drug/ removal of drug
            • Trough levels (just prior scheduled dose) provide information re compliance and clinically effective serum range
            • Peak levels (at time of expected peak concentration) provide information re individual’s threshold for emergence of side effects
            • Extensively protein bound (90%), only the free fraction is active
            • Water-insoluble and very alkali (pH 12)


          • Unusually increased levels
            • Liver disease
            • Congenital enzyme deficiency/ different isoenzymes
            • Drug interactions -> metabolic interference
            • Hypoalbuminaemia of pregnancy/ uraemia -> high free levels
          • Unusually decreased levels
            • Non-compliance
            • Hypermetabolisers of phenytoin eg congenital, acute trauma, pregnancy, young children, menstruation


          • Needs initial loading dose
          • Long t1/2 averages 22 hours (between 7 – 44 hours)
          • Steady state therapeutic range achieved after t1/2 (usually quoted at 5.5 t1/2)


          • Metabolised in liver by CYP2C9 (major), CYP2C19 (minor) and CYP3A4 (inducible)
          • This enzyme system is saturable, thus at high plasma levels, any small increments in dose (even up to 10%) may prolong t1/2 significantly leading to intoxication
          • Excretion into bile as inactive metabolites -> reabsorbed by intestines -> excreted in urine via glomerular filtration (minor) and tubular secretion (major)

          Adverse effects

          Dose related
          (similar to other antiepileptics)

          Neurotoxic effects

          • Drowsiness
          • Confusion
          • Tremor
          • Dysarthria
          • Ataxia (of gait, not upper limb)
          • Diplopia and nystagmus

          Paradoxical increase in seizure frequency

          Idiosyncratic effect


          • Gingival hypertrophy
          • increased body hair
          • Coarsening of facial features
          • Acne


          • Mostly benign lymph node hyperplasia
          • Rare association with Hodgkins lymphoma


          • Associated Steven Johnson’s and toxic epidermal necrolysis  (within 1st 8 weeks)

          Macrocytic anaemia

          • Responds to folic acid (but adding this may ß drug efficacy)

          Anticonvulsant Hypersensitivity Syndrome

          • Benzene ring metabolised by CYP450 to arene oxide
          • Rare but life-threatening
          • Within 1-4 weeks
          • Fever, rash and multiorgan involvement (hepatitis, myocarditis, myositis, lymphadenopathy, pneumonitis)
          • Also seen in barbiturates and carbamazepine (similar benzene ring)
          • Valproate structurally different so no cross reactivity; lamotrigine cause similar syndrome but no cross reactivity

          Long term effects

          Cerebellar degeneration

          Sensory peripheral neuropathy

          Osteomalacia/ osteoporosis
          - By increase Vit D3 metabolism



          Drug interactions complex:

          • Induces cytochrome P450 enzymes
          • Metabolised by CYP2C9 and CYP2C19 -> any drugs inhibit/ induce these enzymes affect levels
          • 90% protein bound -> any drug that displaces phenytoin -> increase free levels


          • Oral absorption affected by enteral feeding significantly (up to 80%) and certain drugs/ nutritional supplements
            • Continuous enteral feeds: phenytoin IV
            • Intermittent enteral feeds: 2 hours post/prior feed
            • Including calcium supplements and antacids
          • Some drugs lower seizure threshold (eg antipsychotics, beta lactams) and may precipitate seizures despite therapeutic phenytoin levels


          Overdosage (Lethal dose in adults 2-5g)

          • No antidote
          • Poorly absorbed in stomach, so activated charcoal useless
          • Death from CNS, respiratory and circulatory depression


          Back to the question:
          Normal adult dosage: 4-5 mg/Kg initially, then increase gradually to maximum of 600mg/day in divided doses. After a loading dose of 1000mg and daily oral dose of 300mg, one would expect his levels to be therapeutic by 1 week.

          1. Metronidazole (anaerobic cover). It is NOT protein bound. It is excreted in the urine predominantly as metronidazole and inactive metabolites -> does not interfere with phenytoin metabolism


          1. Correct. Phenytoin is very water-insoluble and crystallizes if mixed with any glucose containing solution -> drastically ß phenytoin absorption. In general any drug that forms precipitates or is very acidic (pH <4) are unsuitable. There are many examples, but notable ones include fluoroquinolones (eg ciprofloxacin), antacids (Al and Mg containing), iron supplements, metoclopramide, and lithium. Note that warfarin’s pharmacokinetics also affected (ß efficacy) due to erratic gut absorption and vitamin K antagonism from the vitamin K in the feeds.
          1. Omeprazole is a proton pump inhibitor -> ß gastric H+ secretion. It is 95% protein bound and metabolised by the hepatic cytochrome p450 enzymes. It has been shown to increase plasma phenytoin levels by ß plasma clearance by and displacing phenytoin from albumin.


          1. Hyperventilation –> ß carbon dioxide concentration -> constriction of cerebral vessels -> ß ICP (closed head injury). Each ß paCO2 by 1mmHg ß cerebral blood flow by 3%. The aim is a paCO2 between 25-30mmHg only for short durations when immediate control of ICP needed. Prolonged hyperventilation may ß cerebral blood flow to below the “ischaemic threshold” (anecdotally quoted at a paCO2 of <20 mmHg), leading to infarction of marginal areas. This may lead to infarct-related seizures but will not affect phenytoin levels.
          1. Erythromycin (macrolide: binds to 50S ribosomal subunit to inhibit protein synthesis, good G+ve and G-ve cover). 75% protein bound, predominantly metabolised by liver (a subtrate and inhibitor of cytochrome p450 CYP3A family) thus increase and prolongs t1/2 of phenytoin (also affects carbamazepine). Another notable side effect of erythromycin is that it prolongs the QT interval and can rarely cause interstitial nephritis.


          Neurology: Epilepsy

          Pharmacology: CNS



          Question 58 top Download PDF

          A 72 year old woman presents with confusion after a minor fall and is found to have a subdural haematoma on computed tomography (CT) scanning which requires urgent surgical drainage. She takes warfarin for atrial fibrillation and has been taking an antibiotic for urinary infection.

          Full blood examination reveals:


          109 g/L (120-155)


          82 fL (80-95)

          White cell count

          Mild neutrophilia, otherwise normal differential

          11.2 x 109/ L (3.5 -9.5)

          Platelet count

          150 x 109/L (150 -400)


          PT –INR

          6.0 (1.0 -1.3)


          52 seconds (26-38)


          2.3 g/L (2.0 -4.0)

          In addition to parenteral vitamin K therapy, she should receive:

          1. Fresh frozen plasma
          2. Cryoprecipitate
          3. Recombinant factor VIIIc
          4. Packed red cells          
          5. Platelet concentrate



          Donated whole blood is processed into components

          1. PRCs, platelets, FFP, cryoprecipitate
          2. Whole blood is 1st separated into PRC and platelet rich plasma by slow centrifugation
          3. Platelet rich plasma then centrifuged at high speed to get 1 unit of platelets and 1 unit of FFP
          4. Cryo is obtained by thawing FFP
          5. Apheresis is used to get multiple units of platelets from a single donor unit of blood

          FFP (250mL per bag, from 1 unit of whole blood)

          1. No cells as prepared from single units of whole blood via apheresis techniques (so does not transmit intracellular infections eg CMV)
          2. Frozen at -18 to -30 degrees within 8 hours of collection
          3. Coagulation factors
          4. Plasma proteins: fibrinogen, anti-thrombin, albumin, protein C and S
          5. Indications: rapid reversal of warfarin anticoagulation, liver disease or vitamin K deficiency, supplying deficient plasma proteins and treatment of TTP
          6. Should NOT be used to expand plasma volume, provide albumin or to treat coagulopathies from known deficiencies of a single factor
          7. Patients who are IgA deficient should receive IgA deficient FFP to prevent anaplylaxis
          8. Prepared from single units of whole blood via apheresis techniques

          Cryoprecipitate (10-15 mL from 1 bag of FFP)

            • When FFP thawed at 4 degrees, a precipitate remains which is separated by centrifugation (the remainig thawed fluid is used as cryo-poor FFP)
            • No cells
            • Fibrinogen, factor VIII, factor XIII and vWF
            • Ideal for supplying fibronogen to the volumem sensitive patient
            • When no Factor VIII concentrate available, can use cryoprecipitate as it contains 80 units of Factor VIII
            • Also used to supply vWF to patients with Type II (dysfunctional) and Type III (absent) von Willebrand disease (bad past experiences with viral transmission in haemophilia)

            Packed red cells

            • increased oxygen carrying capacity in the anaemic patient
            • Usually transfuse up to Hb of 100

            Whole blood

            • Provides volume explansion and increase oxygen carrying capacity
            • Ideal for those with massive haemorrhage > 25% total blood volume
            • Stored at 4 degrees to maintain RBC integrity, but some degree of platelet dysfunction and plasma protein degradation occurs
            • 2,3 DPG levels ß with time, leading to increase oxygen affinity of Hb and ß capacity to effectively deliver oxygen to tissues
            • Not commonly available/ used

            Platelets (4 units in 1 bag)

              • Threshold for transfusion usually < 10, or <20 if fever
              • For invasive procedures, transfuse up to safe level of >50
              • Either from pooled donors or single donors
              • Each unit with expected increment of 5-10, however those who have had multiple previous transfusion might have many anti-platelet antibodies and thus have minimal increments (better to use single donor)



              Question 59 top Download PDF

              A 24 year old man develops acute tonsillitis with high fever (39.8 degrees). He is treated with erythromycin. The next day he is noticed to be icteric. Abdominal examination is unremarkable.

              The following blood tests are obtained:

              White cell count

              18.5 x 109/ L`

              4.0 -11.0

              Normal differential


              145 g/L

              120 -160

              Platelet count

              395  x 109/ L

              150 -400


              140 mmmol/L



              4.5 mmol/L

              3.5 -5.0


              8.5 mmol/L

              3.6 -9.3


              0.09 mmol/L

              0.06 – 0.12


              78 microm/L



              46 u/L



              55 u/L



              35 u/L



              32 u/L



              40 g/L


              The most likely explanation for his jaundice is:

              1. Haemolysis
              2. Epstein Barr virus
              3. Gilbert’s syndrome
              4. Wilson’s disease
              5. Erythromycin


              Metabolism of bilirubin:

                • Hepatic uptake from circulation (haem)
                • Intrahepatic storage
                • Conjugation with glucoronic acid
                • Excretion into faeces/ urine or recycled

                Hyperbilirubinaemia results from:

                • Overproduction of bilirubin
                • Impaired uptake, conjugation or excretion of bilirubin
                • Regurgitation of unconjugated or conjugated bilirubin from damaged hepatocytes or bile ducts

                Stepwise approach to diagnosis:

                • Conjugated versus unconjugated
                • increase conjugated bilirubin: rare inherited disorders (benign asymptomatic jaundice in 20s) with altered secretion of conjugated bilirubin into bile ducts +/- hepatic storage problems
                  • Dubin Johnson syndrome
                  • Rotor’s syndrome
                • increase unconjugated bilirubin
                  • Drugs (rifampicin, probenecid)
                  • Inherited disorders
                    • Gilbert’s syndrome
                    • Crigler Najjar’s syndrome
                  • Haemolysis
                    • Extrinsic versus intrinsic
                  • ? Other LFTs normal
                  • Hepatocellular pattern
                  • ALT/ AST increase out of proportion to ALP
                  • Obstructive/ cholestatic pattern
                  • ALP increase out of proportion to ALT/AST
                  • Mixed


                  Gastroenterology:Acute and chronic liver disease Repeat Question 2003 paper two question 36

                  Question 60 top

                  Question 61 top Download PDF

                  61) The most common acute complication of percutaneous endoscopic gastrostomy (PEG) insertion is:

                  1. Gastric perforation
                  2. Colonic perforation
                  3. Peritonitis
                  4. Bleeding at insertion site
                  5. Wound infection



                  Enteral feeding via tube >400 years history
                  Need nutrition to improve disease/ functional status/ QOL
                  Can improve/ stabilise weight and increase albumin within 2 months of commencement


                  • Dysphagia (eg secondary stroke/ neurodegenerative disease/ post radiotherapy)
                  • Altered mental state and cannot eat (dementia, anorexia nervosa)
                  • Hypermetabolic state and weight loss (eg AIDS or cancer)

                  Temporary access

                  • Naso gastric tube or naso-small-bowel tube
                  • Often short term and fail due to dislodgement, clogging or poorly tolerated

                  Permanent access

                  • Gastrostomy or jejunostomy
                    • Jejunostomy preferred if recurrent aspiration, delayed gastric emptying, dysmotile oesophagus with regurgitation
                  • Either inserted percutaneously/ endoscopically or surgically
                    • No difference in mortality/ morbidity (up to 90% survival rate in 1/12; early mortality due to underlying disease rather than tube placement)
                    • PEG cheaper and faster
                    • Surgical should be reserved for those already having intra-abdominal procedure or known anatomical variant
                  • Higher risk PEG patients
                    • Obesity
                    • Pregnancy (safe up to 26 weeks gestation)
                    • Ascites (usually contraindicated unless large volume drained and ABx cover)
                    • Prior abdominal surgery



                  Minor complications

                  Wound infection

                  • Commonest
                  • More likely if contaminated field, unwell patient or no ABX prophylaxis

                  Peristomal leakage

                  • Within 1st few days
                  • More likely in diabetics/ malnourished (poor wound healing)
                  • Worse if junction is tight -> peristomal necrosis

                  Bleeding (very rare)
                  Clogging or tube dysfunction
                  Gastric outlet obstruction (tube migrates into duodenum)

                  Major complications

                  Buried bumper syndrome

                  • Internal bumper erodes into gastric mucosa
                  • Pain and inability to continue feeds

                  Necrotising fasciitis (rare)

                  • In diabetic, immunosuppresed or malnourished

                  Gastric and oesophageal perforation (very rare)

                  Colocutaneous fistula (rare)

                  • Interposition of colon (usually splenic flexure) between abdominal wall and gastric wall
                  • PEG inserted through skin though colon to stomach
                  • Usually asymptomatic apart from intermittent fever and ileus

                  Inadvertant removal (common)

                  • If within 4/52 of insertion: should not be reinserted blind at bedside, and should be treated with IV Abx
                  • When replaced can confirm position with water soluble gastrostomy study prior resuming feeds to prevent peritonitis


                  Thus the answer is E

                    • Usually skin flora and usually responsive to oral antibiotics (cephalosporins often 1st line)
                    • MRSA increasing incidence especially in hospital/ institutionalised setting


                    Gastroenterology: endoscopy


                    Question 62 top

                    Question 63 top

                    Question 64 top

                    Question 65 top Download PDF

                    A 55 year old man presents with acute pulmonary oedema. 5 years ago, he had undergone a mitral valve replacement with a bileaflet tilting disc valve (St Jude’s) for mixed mitral valve disease. He has been well with normal exercise tolerance prior to the day of admission.

                    Examination on admission reveals tachypnoea, sinus tachycardia 110/minute, BP 105/60 mmHg, elevated JVP +5cm and bilateral lung crepitations throughout. His INR is 1.9 (desired range 2.0 -3.5). CUE are normal. The cardio-thoracic ratio on CXR is normal but the presence of APO is confirmed. TTE reveals that one of the prosthetic valve leaflets is not moving and there is increased flow rate in diastole across the valve orifice (2m/second).

                    What is the most appropriate course of action?

                    A. Administration of IV streptokinase
                    B. Administration of IV heparin
                    C. Administration of IV antibiotics
                    D. Addition of anti-platelet agent
                    E. Immediate mitral valve replacement

                    Answer: E


                    Cardiology: Valve Disease

                    Question 66 top Download PDF

                    A 66 year old man presents with chronic cough and haemoptysis. He has normal performance status. He is found on investigation to have non-small cell carcinoma of the lung. The primary lesion is in the left main bronchus and is 3cm away from the carina. Other investigations reveal that there is mediastinal involvement and his cancer is classified as stage IIIA.

                    Which one of the following is the best management option?

                    1. Palliative care
                    2. Chemotherapy
                    3. Radiotherapy
                    4. Chemotherapy followed by surgery
                    5. Chemotherapy and radiotherapy followed by surgery

                    Answer: D

                    Learning issues

                    1. SCLC vs NSCLC
                    2. Staging for NSCLC and treatment/ prognosis
                    3. Performance status in cancer

                    General issues for lung cancer

                    • Commonest cause of cancer related death in male and females
                    • more than 90% lung cancer patients current or ex-smokers (ex-smokers make up 50% of new diagnoses)
                    • less than 10% all smokers develop lung cancer (vs 15% who develop COPD)
                    • Those who stop smoking after diagnosis do better than those who do not
                    • Additive effect for other environmental exposures: asbestoes, radon and arsenic

                    • Rate of lung cancer rising amongst females
                    • Females have higher relative risk per given exposure due to higher susceptibility

                    • Adenocarcinoma is commonest histopathological sub-type (used to be squamous cell 25 years ago)
                    • Adenocarcinoma also commonest cancer in females, life-time non-smokers and young patients < 45 year old

                    • Cavitating lesions: think small cell and squamous (10-20%)
                    • Central with endo-bronchial growth: think small cell and squamous
                    • Peripheral with pleural involvement: think large cell and adenocarcinoma
                    • Fluffy infiltrate or diffused and multi-nodular: possibly adenocarcinoma

                    • Ddx between small cell and non-small cell as different treatment options and prognosis
                    • SCLC: Usually central location, mets by diagnosis, primary treatment is chemotherapy +/- radiotherapy
                    • NSCLC: Usually peripheral, localized at diagnosis, possible curative treatment with surgery/ radiotherapy

                    Performance status

                    ECOG 0

                    Fully active, no restrictions

                    ECOG 1

                    Restricted in strenuous activity but sedentary work fine

                    ECOG 2

                    Ambulatory and independent self care, up for > 50% day time. Unable to carry out work related activities

                    ECOG 3

                    Limited self-care. Bed/chair for >50% of day time

                    ECOG 4

                    Bed bound. No self care

                    ECOG 5


                    Lung cancer staging

                    1. Anatomical staging
                    2. Physiological staging (whether patient can with-stand treatment)
                    3. In NSCLC: Operability (if patient can tolerate operation) and respectability (if entire tumour physically possible to be removed in single operation eg lobectomy)


                    • Adenocarcinoma, squamous, large cell (anaplastic)
                    • TNM staging system (good prognostic information)
                    • 1/3: localized disease for curative surgery or curative radiotherapy
                    • 1/3: distant mets (Stage IV)
                    • 1/3: local/ regional disease that may or may not be amenable to curative attempt

                    Essentially differing combinations of TNM gives the stage and treatment choice

                    Stage I

                    Mass only
                    No nodes
                    No involvement of any surrounding structures

                    Worst: T2N0MO


                    Stage II

                    Mass of any size
                    Local LN
                    No involvement of crucial structures
                    Can have atelectasis/ pneumonitis

                    Worst: T3N1MO


                    Stage III

                    Anything else but no mets
                    If T4: pleural effusion/ satellite nodules in same lobe/ pericardial effusion

                    Worst T4N3MO

                    Usually chemo + RT
                    If Stage IIIB or bulky IIIA

                    1. Neo-adjuvant chemo then RT has improved survival compared to RT alone

                    For non-bulky IIIA

                    1. Neo-adjuvant chemotherapy then surgery (widely used)
                    2. Surgery then post-op RT + chemo for N2
                    3. Neo-adjuvant chemoradiotherapy then surgery

                    Stage IV

                    Anything with mets

                    Any T, any N, M1

                    Palliative procedures

                    1. RT for symptomatic obstruction
                    2. Drain effusions


                    The patient in question is Stage IIIA

                    • T: not mentioned, possibly T1-T4
                    • N: mediastinal involvment so N2
                    • M: assumed none so M0
                    • His 5 year survival rate even with treatment is ~ 23%
                    • After apparently complete resection, adjuvant radiotherapy does not improve survival and may be detrimental in N0 and N1 disease.


                    Respiratory: Primary and Secondary Lung Cancers

                    Question 67 top Dowload PDF

                     A 60 year old woman has been on continuous combined hormone replacement therapy since menopause. She complains of mental slowing, weight gain, insomnia and headaches in the last 6 months. Her general practitioner has commenced her on nortriptyline one month ago with no improvement in her symptoms.

                    The following results are obtained:
                    Serum PRL       1900mIU/L (30-450)
                    Serum LH          0.3 mIU/L (premenopausal 0.4 – 9.0)
                    Serum FSH       0.5 mIU/L (premenopausal 1.0-9.0)
                    Serum TSH       2.1 mIU/L (0.4 -4.0)
                    Free T4             8pmol/L (10-23)

                    The best explanation for these results is:

                    1. Nortryptiline therapy
                    2. Depression
                    3. Prolactin secreting microadenoma
                    4. Non- functioning pituitary macroadenoma
                    5. Hormone replacement therapy


                    I thought it was between C and D

                    In support of D

                    • Headache suggests intra-cerebral mass from sellar expansion
                    • PRL regulation is unique as hypothalamic control is inhibitory via dopamine.

                    Thus a non-functioning pituitary macroadenoma can press against the stalk, interrupting dopamine transport

                    • Mental slowing, weight gain and insomnia could be from GH deficiency

                    Either: lack of dopamine which stimulates GH release
                    Or: pituitary macroadenoma compressing on somatotrophs

                    • Serum LH and FSH is appropriate for post-menopausal woman on HRT (if no HRT, FSH and LH would be high due to low oestrogen levels)


                    • Subclinical hypothyroidism is a potential cause of high PRL levels – thyroid hormones are a weak inhibitor of PRL secretion

                    A. Nortriptyline

                    • Tricycle antidepressant (mechanism of action unclear: blocks diverse agents eg 5HT, histamine, acetylcholamine and catecholamines)
                    • Side effects include weight gain, insomnia and also hyperprolactinaemia (but symptoms pre-dated medication)
                    • Endocrine side effects (uncommon): gynaecomastia, breast enlargement and galactorrhoea in females, libido effects, impotence, SIADH
                    • Predominant side effects are anticholinergic: dry mouth, urinary retention, constipation, blurred vision, mydriasis (dilated pupils)
                    • Contraindicated with MAOi, allergy and 1/12 post AMI
                    • If overdose, main worry is cardiac arrythmias (QT prolongation indicates significant toxicity), hypotension and decreased GCS/ coma – supportive measures + bicarbonate +/- phenytoin (for seizures and arrhytmias)


                    B. Eliminate immediately – depression shouldn’t cause a massive rise in PRL

                    E. HRT

                    • Menopause: permanent cessation of menstruation due to loss of ovarian follicular function
                    • No more oestriol produced by ovaries, small amounts in adipose tissue
                    • Small amounts of oestrone (weaker oestrogen) produced by adrenals and interstitial ovarian cells -> some converted into oestriol
                    • HRT: either combined oestrogen-progestin (progesterone to counteract oestrogen action on endometrium) or oestrogen only (if had previous hysterectomy)
                    • The described symptoms are NOT characteristic of any HRT side effects
                    • HRT increases risks of:
                      • Coronary heart disease (no increase risk if oestrogen only)
                      • Venous thrombo-embolic events (DVT and PE risk increase for combined therapy; only DVT risk increase for oestrogen only)
                      • Stroke
                      • Breast cancer (increase risk in combined therapy only, very small protective effect in oestrogen-only arm)
                      • Endometrial hyperplasia and carcinoma (if no progesterone and no hysterectomy)
                      • Ovarian cancer (both incident and fatal in current users, risk for past users the same as lifetime non-users)
                      • Gall bladder disease (increase risk cholecystitis/ need for cholecystectomy)
                      • increase risk dementia


                    • HRT good for:
                      • Menopausal symptoms (hot flushes, genitourinary symptoms)
                      • Treatment of osteoporosis and ß # rates (hip, vertebral and radius for combined, no effect on wrist for oestrogen only)
                      • ß risk colorectal cancer (for combined therapy only, but more likely for cancer to be advanced at diagnosis)
                    • In summary:
                      • Combined and oestrogen only have similar increase risks of thrombotic events, stroke and benefits for osteoporosis and fracture-protection
                      • No increase risk coronary disease and breast cancer in oestrogen only
                      • No protective effect of oestrogen only for colorectal cancer
                      • Overall, risks = benefits of oestrogen only therapy in post-menopausal women with hysterectomies


                    • Limitations of WHI study:
                      • Older (mean age 63) with increaseer BMI (30% with > 30) with 50% current or ex-smokers - so more likely to have pre-existent/ more advanced heart disease
                      • Younger post-menopausal women might derive cardiac benefit from early oestrogen only therapy (epidemiological studies)
                      • Relative risks compared to placebo appear high but absolute risk of adverse event (mainly cardiac or breast cancer) is very low19 additional events in 10,000 women per year compared to placebo
                      • This risk is even lower in a younger post-menopausal woman


                    Endocrinology: HRT | Hyperprolactinaemia


                    Question 68 top

                    Question 69 top

                    Question 70 top Download PDF

                    A 25 year old previously well male student presents with recent exertional dyspnoea, epistaxis and bruising. There is no history of medication, toxic chemical exposure or infection. Examination reveals significant anaemia with scattered bruising and petechial haemorrhages.

                    Full blood exam reveals:


                    67 g/L (135 -170)


                    102 fL (80-95)

                    White cell count

                    1.4 x 109/L (3.5 -9.5)



                    0.2 x 109/L (1.5 -6.0)


                    1.00 x 109/L (0.70 – 3.15)


                    0.1 x 109/L (0.2 -0.6)


                    0.1 x 109/L (0 -0.4)

                    Platelet count

                    12 x 109/L (150- 400)

                    B12, folate and iron studies are normal. Hepatitis/ HIV serology is negative.

                    Attempted marrow aspiration results in a “blood tap”. A marrow trephine biopsy section is shown below:


                    The therapy most likely to be associated with long term remission is:

                    1. Granulocyte colony stimulating factor (G-CSF) and erythropoietin
                    2. Stem cell allograft from human leucocyte antigen (HLA) matched sibling
                    3. Oxymetholone
                    4. Antithymocyte globulin
                    5. High dose cyclophosphamide



                    Young male with severe symptomatic pancytopenia (including neutropenia), normal haematinics with a trephine showing a HYPOCELLULAR marrow = Aplastic Anaemia

                    Looking at bone marrow trephine

                    • Look at haematopoietic cells vs fat cells (in adult roughly 50:50)
                    • Look at microarchitecture (eg if there is disruption)
                    • Look if there are any cells invading marrow eg malignant metastatic deposits/ excess of a particular haematopoietic cell type eg >10% plasma cells for myeloma

                    Aplastic Anaemia

                    • Pancytopenia with hypocellular bone marrow with fat replacement + no abnormal cells on blood film + no splenomegaly
                    • Early on, some may have depression of only one/two of three cell lines, only later progressing to pancytopenia
                    • The residual haematopoietic cells in the marrow are morphologically normal
                    • Pathophysiology is marrow failure from damage to pleuripotent stem cells
                      • NOT from defective stroma or deficient growth factors
                      • CD34 cells (early haematopoietic cells) diminished greatly
                      • Stem cell pool < 1% of normal
                      • Distinct from marrow failure due to different mechanisms (eg replacement with tumour cells/ fibrosis)
                    • Biphasic age distribution: teens/ twenties and in elderly >65
                    • Affects 2-4 per million/ year
                    • Inherited forms versus acquired forms
                      • BMAT appearance is identical
                      • Sometimes can only be ddx by FHx, young age of onset or physical anomalies (eg Fanconi’s with short stature, café au lait spots and thumb/radial anomalies)
                    • May be difficult to ddx from hypocellular myelodysplasia and PNH
                    • Natural history is rapid deterioration and death:
                    • Early mortality from sepsis and bleeding
                      • Later mortality from recurrence after treatment or evolution to PNH/ myelodysplasia/ acute leukaemia
                    • Major prognostic marker is nF count:
                      • Severe: nF < 0.5 x 109/ L
                      • Very severe: nF < 0.2 x 109/ L


                    Fanconi’s anaemia

                    • Autosomal recessive
                    • Developmental anomalies (short stature, thumb/radius anomalies, GUT) with café au lait spots
                    • Progressive pancytopenia
                    • increase risk of cancer
                    • Most common is Type A with mutation in FANCA (abnormal cellular response to DNA damage)

                    Dyskeratosis congenita

                    • X linked or autosomal dominant
                    • Mucous membrane leukoplasia, dystrophic nails, reticular pigmentation
                    • Defect in maintenance of telomere length

                    Scwachman- Diamond Syndrome

                    • Associated pancreatic failure and malabsorption

                    Amegakaryocytic thrombocytopenia

                    Familial aplastic anaemias

                    • Preleukaemia (Monosomy 7 etc)



                    • > 7 Gy leads to irreversible marrow damage


                    • Benzene (industrial solvent, rubbers; also associated with leukaemia)
                    • Unleaded petrol
                    • Pesticides
                    • Cytotoxic drugs in chemotherapy
                    • Chloramphenicol (most famous)
                    • Others eg heavy metals, sulphonamides, NSAIDS eg phenylbutazone

                    Viral infection

                    • EBV
                    • Hepatitis (nonA nonB nonC)
                    • Parvovirus B19 (aplastic crisis, pure red cell aplasia)
                    • HIV 1

                    Immune disorders

                    • Eosinophilic fasciitis
                    • SLE
                    • GVHD in immunodeficient
                    • Thymoma/ thymic cancer
                    • Hypoimmunoglobulinaemia


                    • Acquired mutation in PIG-A gene in haematopoietic stem cell
                    • Progeny deficient in GPD-linked cell surface membrane proteins and for unknown reason are selected for proliferation
                    • Haemolysis and thrombotic episodes

                    Pregnancy (? related to increase oestrogen levels)

                    Idiopathic (most patients!)


                    Clinical Features:

                    • Symptoms from pancytopenia
                    • Death from bacterial infections and often overwhelming fungal sepsis
                    • Most common signs: pallor, petechiae with NO SPLENOMEGALY

                    Other tests to confirm other diagnoses:

                    • Flow cytometry for red cell membrane CD 59: ß in PNH (however note that a percentage of those initially diagnoses with PNH eventually develop aplastic anaemia; and 15% of those successfully treated for aplastic anaemia develop PNH)
                    • Cytogenetics: if normal excludes hypoplastic myelodysplastic syndrome (often difficult)


                    • Withdraw any potentially offending drugs/ exposure
                    • Supportive care (antibiotics, PRC or platelet transfusions)
                    • Definitive therapy:
                    • Age <20
                      • HLA matched allogenic stem cell transplant if available
                      • 60-70% cure rate despite GVHD
                    • Age 20 – 45
                      • If in otherwise good health: stem cell transplant if available
                      • If not or no donor: immunosuppressive therapies
                        • Improvement in counts in 60% at 3/12
                        • Relapse risk 35% at 5 years (most respond to further treatment, not a poor prognostic marker)
                    • Age >45
                      • GVHD usually overwhelming, so immunosuppressive therapies recommended

                    Immunosuppresive therapy:

                    • Anti-thymocyte globulin (ATG) monotherapy +/- steroids
                    • ATG + cyclosporine +/- steroids (superior than monotherapy) 

                    Ddx: other causes of pancytopenia

                    Decreased production

                    Aplastic anaemia



                    Marrow infiltration

                    Acute leukaemia
                    Hairy cell leukaemia

                    Inadequate resources

                    B12/ folate deficiency

                    Increased destruction


                    Splenic trapping of cells (hypersplenism)






                    Overwhelming infection

                    HIV with myelodysplasia

                    Viral haemophagocytosis


                    1. G-CSF and erythropoietin: Role is to stimulate haematopoiesis. The hypocellularity is due to pleuripotent cell damage and not a lack of growth factors. Therefore this will not be effective.
                    2. Correct!
                    3. Oxymethalone: anabolic steroid related to testosterone
                    4. ATG reasonable but 2nd line if no HLA transplant match available.
                    5. High dose cyclophosphamide is cytotoxic and will only further damage bone marrow.



                    Heamatology: Anaemia

                    Question 71 top

                    Question 72 top

                    Question 73 top Download PDF

                    73) A 42 year old man with acute myeloid leukaemia undergoes allogenic stem cell transplant from a  human leucocyte antigen (HLA) matched sibling. He is progressing well for the first 10 days, but then complains of abdominal pain and leg swelling.

                    He is noted to have marked ascites, moderate peripheral oedema and jaundice,

                    Liver function tests are as follows:


                    123 micromol/L



                    440 U/L



                    680 U/L



                    1254 U/L



                    1356 U/L



                    30 g/L


                    An abdominal ultrasound confirms large volume ascites with an enlarged liver span (18cm). The spleen is normal in size.

                    The most likely explanation for his condition is:

                    1. Graft versus host disease (GVHD)
                    2. Cytomegalovirus infection
                    3. Hepatosplenic candidiasis
                    4. Portal vein thrombosis
                    5. Veno-occlusive disease



                    Stem cell transplant

                    • Use of stem cells to repopulate a depleted bone marrow
                      • Usually to replace an abnormal but non-malignant haematopoietic system
                      • Or to treat malignancy by allowing administration of larger than usual doses of myelosuppresive therapy
                    • Sources: bone marrow, peripheral blood (after stimulation with G-CSF), cord blood
                    • The stem cell can “home” to the bone marrow due to the interaction of integrins (stem cells) and selectins (bone marrow)
                    • Autologous
                      • Removal and storage of self stem cells with later reinfusion post myeloablative chemotherapy
                      • No risk of GVHD or graft rejection
                      • But risk of “contamination” with self tumour cells and lack of GVT (graft vs tumour) effect
                    • Allogenic
                      • Donor and recipient are HLA matched but not 100% immunologically similar
                      • Risk of GVHD or graft rejection
                    • Syngeneic
                      • From identical twin, best outcome (1% cases)


                    • Diseases which can the treated:
                      • Non-malignant:
                        • Immunodeficiency disorders
                        • Aplastic anaemia
                        • Haemaglobinopathies
                      • Malignant:
                        • Acute leukaemia (AML/ALL)
                        • CML (if imatinib unsuccessful)
                        • Myelodysplasia
                        • Lymphoma
                        • Myeloma


                    Early direct

                    Common – skin erythema, nausea + vomiting

                    If contain cyclophosphamide – haemorrhagic cystitis and rarely haemorrhagic carditis

                    5-7 days post: oral mucositis (requiring opoids)

                    By day 7: profound pancytopenia and related effects

                    Within 1st month (peak day 16): veno-occlusive disease of liver

                    • Direct cytotoxicity to hepatic venular and sinusoidal epithelium
                      • Deposition of fibrin
                      • Local hypercoagulable state
                    • Tender hepatomegaly
                    • Ascites
                    • Jaundice
                    • Fluid rentention
                    • Mortality 30% with progressive liver failure +/- hepatorenal syndrome
                    • Rx: tPA, heparin, PGE2 mostly ineffective

                    5% diffuse interstitial pneumonia with haemorrhage

                    Late direct


                    • Growth retardation
                    • Delayed secondary sexual characteristics


                    • Men: azoospermia
                    • Women: ovarian failure
                    • Thyroid dysfunction
                    • Aseptic necrosis of femoral head (10%) mostly in those with steroids


                    Acute < 3/12 (at 2-4 weeks)

                    • Older
                    • Mismatched donor
                    • Cannot tolerate full doses of chemoRx

                    Chronic > 3/12 (either persisting beyond or developing after)

                    Allogenic T cells infused with stem cell transplant or arising from transplant -> reacting with antigenic targets of host cells


                    • Erythematous maculopapular rash
                    • Anorexia
                    • Diarrhoea
                    • Liver disease with raised LFTs
                    • Will need skin/ liver/ endoscopic GIT biopsy demonstrating lymphocytic infltrate
                      • Grade 1: little clinical significance, not affecting survival and does not need treatment
                      • Grade 2 – 4: significant Sx and poorer prognosis
                    • Prophylaxis
                      • MTX + cyclosporin/tacrolimus
                      • Others eg ATGAM/ prednisolone
                      • T cell depletion pre infusion but increase risk of graft failure and tumour recurrence
                    • Despite prophylaxis, 30% sibling allografts and 60% non-related allografts develop GVHD
                    • Rx with steroids, monoclonal Ab against T cells



                    • 20-60% that survive > 6/12 will develop this
                    • Resembles autoimmune disease
                      • Malar rash
                      • Sicca syndrome
                      • Arthritis
                      • Obliterative bronchiolitis
                      • Bile duct degeneration
                    • Rx with immunosuppression and watch for infections

                    Graft failure


                    • Inadequate number of stem cells
                    • Damage of stem cells during collection/ storage
                    • Exposure to chemotoxic agents post-transplant
                    • Infections: CMV, HHV6
                    • Immunological rejection by immunocompetent host cells


                    Main cause of death due to neutropenia

                    Depends on the transplant centre:
                    Antibiotic prophylaxis
                    Fluconazole prophylaxis
                    Aciclovir prophylaxis if HSV seropositive
                    CMV negative products
                    PCP prophylaxis


                    Back to the question:
                    This presentation 10 days post allograft is classic for veno-occlusive liver disease.

                    1. Timing a bit early for GVHD – would expect some skin findings and diarrhoea
                    2. CMV hepatitis can cause similar picture, but would expect some mention of neutropenia +/- fever and also his CMV serology status, If he is seropositive, he is likely to have received ganciclovir prophylaxis. If he is seronegative, he would be receiving seronegative blood products.
                    3. Hepatosplenic candidiasis – again would expect mention of febrile neutropenia
                    4. Not portal vein thrombosis as there would be splenomegaly


                    Gastroenterology : Acute and chronic liver disease


                    Question 74 top

                    Question 75 top

                    Question 76 top

                    Question 77 top Download PDF

                    For which of the following immunological disorders would fresh frozen plasma be the replacement fluid of choice during plasmapheresis?

                    1. Myasthenia gravis
                    2. Thrombotic thrombocytopenic purpura
                    3. Guillian Barre syndrome
                    4. Chronic inflammatory demyelinating polyneuropathy
                    5. Waldenstrom’s macroglobulinaemia


                    Plasmapheresis/ Plasma exchange

                    • Extra-corporeal blood purification system to remove large molecular weight (>150000) substances of long half-life (> 21 days) from plasma
                    • Centrifugation allows cytapheresis: selective cell removal
                    • Principle is that removal of these substances can
                      • Halt/ reverse the pathological process
                      • Unload the reticuloendothelial system thus facilitate natural removal
                      • Infusion of large amounts of plasma without risk of fluid overload
                    • Replacement fluids dependant on condition
                      • Albumin +/- saline for most conditions (no risk of infection transmission but net loss of immunoglobulins)
                      • Saline for hyperviscosity
                      • FFP/ cryo-poor plasma for TTP (replaces normal proteins removed, so immunoglobulins and clotting factors not depleted)
                    • Duration and frequency dependant on condition
                      • 75% IgM is intravascular so quicker compared to IgG (45% intravascular)


                    Pathological substance



                    Myasthenia gravis
                    Anti GBM antibody disease (Goodpasture’s)
                    Thrombotic thrombocytopenic purpura (TTP)
                    Guillian Barre syndrome/ CIPD
                    SLE (uncommon)
                    Systemic vasculitis
                    Factor VIII inhibitors


                    Hyperviscosity syndrome
                    Waldenstrom’s macroglobulinaemia
                    Multiple myeloma (light chains)




                    Hyperleukaemic leucostasis


                    Severe thrombocytosis


                    Sickle cell crisis

                    Circulating immune complexes

                    Immune complex glomerulonephritis
                    Systemic vasculitis

                    Protein bound substances/ toxins

                    Thyroid storm
                    Amanita phylloides toxins


                    Complications of plasmapheresis

                    • Hypotension (ß plasma volume)
                    • Dyspnoea (fluid overload; allergic reactions to FFP)
                    • Citrate induced (used as anticoagulant):
                      • Hypocalcaemia (binds to form calcium citrate)
                      • Alkalosis in renal failure (citrate -> bicarbonate which is poorly excreted)
                    • Infection
                    • Vascular access related complications
                    • Reaction if on ACEi (hypotension, abdominal pain, flushing - ?kinins generated) so with-hold 24 hours prior
                    • Therapeutic drug removal (especially those protein bound eg pheytoin)
                    1. Myasthenia gravis
                    • Weakness and muscle fatiguability due to neuromuscular junction dysfunction
                    • Autoantibodies against Ach receptor (Anti AchR Ab) in 80%, seronegative in 20% (but still responds to plasma exchange – suggesting other autoantibodies at work)
                    • Treat with acetylcholinesterase inhibitors (eg pyridostigmine), immune modulators (eg steroids, AZA), plasma exchange, IV Ig or thymectomy
                    • Plasma exchange works by direct removal of Anti AchR Ab
                      • Effective within days
                      • Duration of action 3-4 weeks (new Ab forms especially if no concurrent immunosuppression)
                      • Used in myasthenic crises or a bridge to thymectomy
                      • Since used to remove antibodies, it doesn’t matter what replacement fluid is used – thus mainly albumin/ saline
                    • IV Ig as effective as plasma exchange
                      • increased infection risk as pooled donors
                      • Uncertain mechanism of action
                    1. TTP
                    • Deficiency of/ autoantibodies against a specific vWF cleaving protease (ADAMTS13)
                    • Leads to accumulation of ultra large vWF multimers -> platelet aggregation
                    • Plasma exchange removes the ultra large vWF multimers and the autoantibodies
                    • The replacement fluid is important as using FFP can presumably supply the missing/ deficient ADAMTS13 enzyme
                    • In conjunction with immunosuppression (eg steroids/ rituximab/ cyclosporine)
                    • Pentad:
                      • Fever
                      • Renal failure
                      • Neurological complications eg seizures
                      • Thrombocytopenia
                      • Microangiopathic haemolytic anaemia (deposition of fibrin/ platelets on vessel wall -> high shear forces)
                    • Only HUS post diarrhoea in children, and TTP secondary malignancies do not respond to plasma exchange
                    1. Guillian Barre syndrome (GBS)
                    • Acute immune-mediated polyneuropathy
                    • Infection triggers immune response which cross reacts with peripheral nerve components (either myelin or axon) due to molecular mimicry
                    • Associated infections include campylobacter, HIV, CMV/EBV or with vaccinations (influenza/ meningococcal)
                    • Treat with plasma exchange, IV Ig or IFN (effective in some studies)
                      • Plasma exchange removes antibodies and complement
                    • Steroids NO LONGER recommended (I think this was one of the neuro questions!)
                    1. CIPD
                    • Similar to GBS
                    1. Waldenstrom’s macroglobulinaemia (WM)
                      • Macroglobulinaemia refers to a group of disorders where there is proliferation of B cells/plasma cells which produce an IgM monoclonal protein
                      • MGUS (IgM variant)
                      • CLL
                      • Some lymphomas
                      • Primary amyloidosis
                      • WM
                      • Malignant lymphoproliferative disorder of B cells exhibiting plasmacytoid/ plasma cell-like differentiation -> Ig M secretion -> paraprotein accumulates -> hyperviscosity
                      • Plasma exchange works by direct removal of paraprotein thus again type of replacement fluid is immaterial


                      Haematology: Transfusion


                      Question 78 top

                      Question 79 top

                      Question 80 top

                      Question 81 top Download PDF

                      81) A 39 year old primigravida at 32 weeks gestation presents with right upper quadrant pain and vomiting. Physical examination reveals poor peripheral perfusion, a pulse rate of 96/minute and blood pressure of 160/100 mmHg. There is tenderness in the right upper quadrant. Liver function tests show:


                      14 micromol/L



                      200 U/L



                      15 U/L



                      630 U/L



                      550 U/L


                      Urine dipstick

                      1+ proteinuria

                      The most likely cause for her abnormal liver function tests is:

                      1. Cholelithiasis
                      2. Acute fatty liver of pregnancy
                      3. Pre-eclampsia
                      4. Acute viral hepatitis
                      5. Cholestasis of pregnancy


                      Liver disease in pregnancy

                      • Liver disease specific to pregnancy
                      • Cholestasis of pregnancy (Usually 2nd to 3rd trimester)
                      • Acute fatty liver of pregnancy (2nd half of pregnancy, usually 3rd trimester)
                      • Multisystem disease in pregnancy with liver manifestations
                      • Pre-eclampsia +/- HELLP syndrome
                      • Hyperemesis gravidarum (usually 1st trimester)


                      • Physiological changes of pregnancy which worsen severity/ predispose to certain liver disease
                      • Cholelithiasis
                      • Hepatitis E
                      • Thrombotic disease (eg Budd Chiari)
                      • Liver disease unrelated to pregnancy which can occur during pregnancy
                      • Acute viral hepatits


                      • Pregnancy in patients with chronic liver disease


                      • Certain conditions morel likely during certain trimesters but there are always exceptions (can even occur or persist post-partum)
                      • Risk of recurrence with subsequent pregnancies
                        • Hyperemesis gravidarum often recurs
                        • Intrahepatic cholestasis recurs in up to 70% but may be milder
                        • Acute fatty liver also recurs but frequency unknown
                        • Pre-eclampsia tends to recur if severe or if developed early eg in 2nd trimester


                      Physiological changes in pregnancy

                      • Plasma volume increase by 50% from 6th to 36th week
                      • Simultaneous increase red cell mass but more gradual and to lesser extent -> Haemodilution
                      • Due to increase plasma volume: serum albumin ß as pregnancy advances
                      • Total lipids and cholesterol increase significantly during pregnancy
                      • Maternal cardiac output increase until 2nd trimester then plateaus till delivery, however absolute blood flow to liver unchanged (% cardiac output to liver relatively ß)
                      • LFTs:
                        • Serum ALP increase 2-4x normal levels (especially in 3rd trimester) with minimal increase GGT suggesting ALP is from the placenta (and not liver)
                        • Total and  free bilirubin ß throughout pregnancy
                        • PT-INR unchanged
                        • Serum fibrinogen increase in late pregnancy
                        • Thus any increase aminotransferases, bilirubin or bile acid concentrations should prompt Ix
                        • Mild changes in ALP and albumin can be considered normal



                      • Pregnancy is major risk factor for developing cholesterol gallstones
                      • Risk remains for 5 years post pregnancy then falls to baseline
                      • Risk increase with increase frequency and number of pregnancies
                      • Oestrogen induces increase cholesterol secretion, progesterone induces ß bile acid formation -> supersaturation of bile with cholesterol
                      • Pregnancy induces quantitative change in bile acids -> more hydrophobic acids are formed -> ß ability to solubilise cholesterol
                      • Progesterone leads to delayed GB emptying -> stasis
                      • Similar effect (though to lesser degree) seen in OCP and HRT


                      • Complications from gallstones eg cholecystitis, choledocholithiasis is uncommon but can often be managed conservatively
                      • If asymptomatic: do not treat
                      • If need surgery: safest in 2nd trimester (risk of premature labour ß and no uterine obstruction to gall bladder) but ideally laparoscopic cholecystectomy PRIOR pregnancy is best

                      Acute Fatty Liver

                      • Unique to human pregnancy
                      • Rare: 1 in 7000 to 160egnancies
                      • Previously fatal unless early diagnosis and prompt delivery
                      • 2nd half of pregnancy, usually 3rd trimester
                      • Microvesicular fatty infiltration of hepatocytes
                      • Associated with enzyme deficiency: LCHAD (long chain 3-OH CoA dehydrogenase) which catalyzes the 3rd step of beta fatty acid oxidation in mitochondria
                      • Accumulation of long chain fatty acids (by placenta and foetus) is hepatotoxic


                      • Symptoms:
                        • Nausea and vomiting (75%)
                        • Abdominal pain, usually epigastric (50%)
                        • Anorexia
                        • Jaundice
                        • Sx and signs of pre-eclampsia (50%)
                        • Extrahepatic: infections, intra-abdominal bleeding, central DI (unknown reason)
                      • Ix:
                        • LFTS mainly increase aminotransferases (mild to > 1000 U/L)
                        • Non specific increase white cell count
                        • Non specific thrombocytopenia +/- DIC
                        • If severe: increase NH3 and hypoglycaemia +/- ARF and increase uric acid
                        • Liver Bx: diagnostic but not usually performed (coagulopathy)
                        • Need to exclude HELLP which has haemolysis
                      • Rx:
                        • Maternal stabilisation
                          • Glucose infusion
                          • Correct coagulopathy (cryo better as less volume) +/- platelet transfusion
                          • Haemofiltration/ HDx for ARF
                          • Respiratory support
                        • Delivery
                          • Usually PT normalises shortly after
                        • Rarely need liver transplant


                      • Prognosis:
                        • Most, even severely ill, recover with support and have no hepatic sequelae
                        • Can recur in subsequent pregnancies


                      Acute viral hepatits

                      • Most common liver disease in pregnancy

                      Hepatitis A

                      Course of acute infection similar to non-pregnant
                      Severity worsens with increase age
                      If severe disease during 3rd trimester -> risk of preterm labour

                      Some associated complications

                      • PROM
                      • PV bleeding
                      • Placental separation

                      Good maternal and foetal outcome
                      No evidence peri-natal transmission

                      Hepatitis B

                      Acute infection during pregnancy has no increase mortality or teratogenicity

                      Perinatal transmission well documented especially:

                      • If acute infection in 3rd trimester
                      • If seropositive for HBsAg and HBeAg (suggests active replication)

                      If exposed during gestation:

                      • Vaccinate: no increase congenital anomalies
                      • Or passive immunisation with immunoglobulins

                      Hepatitis E

                      Usually mild and self-limiting illness in non-pregnant – faecal oral route
                      Endemic areas: developing world eg Pakistan, Africa, Mexico

                      Can be very severe in pregnant – especially 3rd trimester

                      • Can develop fulminant hepatitis with 20% mortality
                      • Ddx acute fatty liver of pregnancy, pre-eclampsia, HELLP, HSV hepatitis
                      • Dx via serology (research areas have HEV RNA PCR)

                      Perinatal transmission -> acute hepatitis of neonate

                      Herpes simplex hepatitis (HSV)

                      Hepatits due to primary HSV infection
                      Can be fulminant especially in 3rd trimester

                      Clues to dx:

                      • Vesicular rash
                      • May have prodrome of fever/ URTI symptoms

                      Dx via serology/ cultures of vesicle fluid
                      Ddx: pre-eclampsia, acute fatty liver (but in this case delivery is not necessary)

                      Rx with acyclovir

                      Perinatal transmission during delivery


                      CMV/ EBV/ adenoviruses

                      • Usually self limiting with benign course
                      • Supportive care

                      Perinatal transmission reported


                      Cholestasis of pregnancy

                      • Occurs 2nd to 3rd trimester
                      • Cause unclear but familial associations and related to pregnancy hormones (oestrogen levels peak at 3rd trimester, and more common in multiple pregnancies)
                      • Symptoms:
                        • Severe generalised pruritis, may be intolerable
                        • Palms and soles worst
                        • Worst at night
                        • Often precedes laboratory abnormalities
                        • Abdominal pain uncommon


                      • Ix:
                        • Serum total bile acid concentration increase
                        • increase cholic/ chenodeoxycholic acid ratio
                        • Modest increase bilirubin
                        • increase ALP (but non-specific, given that placenta produces a lot)
                        • Normal or mild increase GGT
                        • increase aminotransferases, even up to 1000 U/L (need to ddx viral hepatitis)
                      • Rx:
                        • URSO (increase bile flow)
                        • Antihistamines
                        • Cholestyramine
                        • Delivery ASAP


                      • Prognosis:
                        • Good maternal outcome
                          • Pruritis disappears soon after delivery with rapid normalisation of LFTs
                          • No hepatic sequelae
                          • Tends to recur with subsequent pregnancies (60-70%)
                        • Foetal outcome poor
                          • Prematurity
                          • Meconium stained amniotic fluid
                          • Neonatal respiratory distress
                          • Death in utero (during last month of pregnancy)


                      Hypertensive disorders of Pregnancy

                      • Complicates 10-20% all pregnancies
                      • Preeclampsia affects 3-14% all pregnancies

                      (Mild/ Severe)
                      No moderate!

                      Systolic > 160 mmHg
                      Diastolic > 110 mmHg
                      (or both)

                      > 20 weeks gestation
                      Previously normotensive

                      Note just absolute BP
                      Sudden increase important

                      If < 20 weeks

                      • Unusual
                      • Consider molar pregnancy

                      Main ddx:
                      Pre-existing HT
                      Gestational HT

                      Exacerbation of renal dse
                      Exacerbation of SLE

                      Acute fatty liver

                      Autoimmune thrombocytopenia

                      Gestational thrombocytopenia

                      Main risk factors

                      • Nulliparity/ primagravid
                      • Diabetes
                      • PHx or FHx pre-eclampsia
                      • Multiple gestation
                      • Obesity
                      • Age >40 or <18
                      • Partner with previous partner with pre-eclampsia

                      New onset HT

                      • Documented on at least 2 occasions
                      • At least 6 hours apart but no longer than 7 days

                      Proteinuria (> 0.3g/ day OR persistant 1+ on dipstick, may reach nephrotic range > 5g/day)

                      Oedema (no longer a diagnostic criteria)

                      Haematological features:

                      • Thrombocytopenia: increase platelet turnover in microthrombi
                      • PT-INR and fibrinogen should be normal unless DIC or liver dysfunction
                      • HELLP with microangiopathic haemolysis
                      • Liver dysfunction with vasospasm and microthrombi leading to RUQ pain and increase AST/ALT and in severe cases: subcapsular haemorrhage/ rupture


                      • If seizures -> eclampsia
                      • Headache, blurred vision, transient cortical blindness

                      ARF uncommon

                      APO not infrequent

                      Foetus and placenta

                      • Chronic hypoperfusion is the problem
                      • IUGR and oligohydramnios
                      • Placental abruption in 1% (more if severe)

                      Maternal long term issues

                      • Risk of recurrence (increase risk up to 65% in early + severe disease)
                      • increase premenopausal cardiovascular risk (HT. IHD)
                      • One Israeli study reported increase cancer risk (stomach, larynx, ovary and breast)


                      Chronic HT

                      Pre-existing HT
                      Either prior pregnancy or < 20 weeks gestation
                      May persist > 12 weeks post-partum

                      Preeclampsia on chronic HT


                      Gestational HT

                      Systolic > 140
                      Diastolic > 90
                      (or both)

                      Usually mild HT with NO proteinuria
                      Occurs in later part of pregnancy
                      Resolves by 12 weeks post-partum


                      Develop tonic clonic seizures
                      Seizures not attributable to other causes (eg hypoglycaemia)


                      Finally going back to the question:
                      Primagravid > 20 weeks gestation
                      RUQ pain
                      Abnormal LFTs
                      -> Has to be pre-eclampsia by definition (though I don’t really see why acute fatty liver can’t be a contender except that it is much rarer)


                      Gastroenterology:Acute and chronic liver disease

                      Question 82 top Download PDF

                      A 58 year old man with a 20 year history of heavy habitual snoring and observed apnoeas presents with worsening daytime somnolence. On examination, he is obese (BMI of 38kg/m2 [20-25]) and has a very narrow upper airway. A polysomnography study is abnormal with and apnoe-hypopnoea index (AHI) of 82/hour and an arousal index of 75/hour.

                      For which of the following outcomes is he at the highest relative risk compared to someone without this disorder?

                      1. Stroke
                      2. Motor vehicle accident
                      3. Myocardial infarction
                      4. Hypothyroidism
                      5. Hypertension

                      Answer: B

                      Clues to diagnosis of obstructive sleep apnoea: obesity, snoring and narrow airway, daytime sleepiness and diagnostic criteria

                      • Temporary and intermittent cessation of airflow but persistent respiratory effort
                      • Apnoea: cessation of airflow greater than 10 sec
                      • Hypopnoea: greater than 50% decrease in amplitude of breathing greater than 10 sec +/- EEG evidence of arousal +/- drop SaO2 by 3%
                      • AHI
                        • Total number of apnoeic and hypopnoeic episodes/ total sleep time
                        • greater than 15 if no symptoms
                        • greater than 5 if with symptoms (he certainly qualifies!)
                      • Arousal index
                        • Number of awakenings + EEG shifts greater than 3 sec to lighter sleep stage/ total sleep time
                      1. & C. & E. Corrected for an obese 58 year old man, the cardiovascular and HT risk (and thus AMI + CVA) is independently higher in someone with OSA
                      1. Hypothyroidism (and other endocrine diseases eg acromegaly) can predispose someone to OSA but someone with OSA does not have a relative increased risk of having the endocrine disorder because of OSA.
                      1. Thus the answer is this because the relative MVA risk is 5-15 x increased (in addition sleep deprivation in general is the 2nd leading cause of MVAs in the United States alone)


                      Respiratory - Respiratory and non respiratory sleep disorders


                      Question 83 top

                      Question 84 top Download PDF

                      A 63 year old woman is recovering from induction chemotherapy commenced 28 days previously for acute myeloblastic leukaemia. She is receiving granulocyte colony stimulating factor (G-CSF) and is no longer neutropenic. A Hickman’s catheter is in situ. She remains intermittently febrile and Candida albicans continues to be cultured from samples obtained from the Hickman’s catheter and peripheral blood, despite therapy with intravenous amphotericin B (1mg/kg/day) from day 20.

                      The most appropriate course of action is to:

                      A. Increase the dose of amphotericin B

                      B. Arrange granulocyte transfusion

                      C. Change to liposomal amphotericin

                      D. Exclude hepatosplenic candidiasis radiologically

                      E. Remove the Hickman’s catheter

                      Answer: E

                      The mantra of ID in bacteraemia: remove any foreign body!
                      Positive cultures from both Hickman’s + peripheral blood indicate this is a true fungemia. Candida grows on bio-films (eg catheters); if the line is not removed, it is a continual nidus.

                      Usually exclusion of fungal sites would be done prior starting treatment so D is incorrect
                      - CT sinuses/chest/abdo/pelvis
                      - Opthalmology review re candidal retinitis
                      - TTE for fungal endocarditis (usually bulky and destructive, surgical management)

                      A) and C)
                      Amphotericin used as anti-fungal in febrile neutropenic protocol
                      [In some centres, echinocandins (eg caspofungin) used 1st line (at least as effective as amphotericin, but less neprotoxic and infusion-related side effects even cf to liposomal preparations)]

                      • Usually start with CAB (conventional amphotericin B) 0.5mg/kg IV daily
                      • 1mg/kg IV daily if suspect aspergillosis (on max dose despite candida so A is wrong)
                      • Polyene: Binds to sterols on cell membrane leading to membrane permeability increases leads to hydrophilic contents leak out leads to fungal cell dies
                      • Broad spectrum against most common fungi but poor CSF penetration
                      • Resistant against the unusual Fusarium and Trichosporon
                      • No evidence to suggest liposomal preparation has superior efficacy or survival benefit (though sometimes used for those who’ve failed CAB)
                      • Less nephrotoxic and less infusion-related side effects, but expensive (> 10X)



                      Granulocyte transfusion not indicated in this patient
                      - Not common, short t1/2: 7 hours (daily infusions, multiple donors)


                      * Neutropenia (Nf < 0.5)
                      * Evidence of infection (eg fever/ +ve blood cultures/ CXR changes)
                      * Unresponsive to antibiotics >48 hours
                      * Chronic granulomatous diseases (impaired granulocyte function)
                      * Neonatal sepsis


                      * Fevers/ chills
                      * Transfusion related GVHD
                      * ARDS (sequestered granulocytes in pulmonary circulation)
                      * Alloimmunisation
                      * Infections


                      Infectious Diseases Hospital acquired infections

                      Question 85 top

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                      Question 87 top

                      Question 88 top

                      Question 89 top

                      Question 90 top

                      Question 91top

                      Question 92top

                      Question 93top Download PDF

                      The principal abnormality on the bone scintigram below is most likely to be caused by which one of the following conditions?

                      1. Metastatic prostate cancer
                      2. Multiple myeloma
                      3. Paget’s disease
                      4. Osteoarthritis
                      5. Metastatic breast cancer


                      Bone scintigraphy/ Nuclear bone scan

                      • Technetium 99m isotope-labelled organophosphate (Tc99m MDP) IV
                      • Preferentially binds hydroxyapatite moiety demonstrating increased bone turnover and increased vascular blood flow
                      • High sensitivity in diagnosing:
                            • Fractures
                            • Metabolic bone disease (eg Paget’s disease)
                            • Osteomyelitis
                            • Tumour
                      • If minimal/no new bone formation, may be negative (eg aggressive cancers, myeloma, osteomyelitis)
                      • Most useful nuclear imaging technique for evaluating joint processes (eg arthritis)
                      • Certain disorders have characteristic features:

                      Acute fractures

                      Linear pattern at site

                      Osteoid osteoma

                      Intense focal collection (less intense if intra-articular)


                      Triple-phase scan analysing blood flow + cumulative uptake


                      Periostial accumulation

                      Paget’s disease,
                      Fibrous dysplasia

                      Multi-focal, often intense
                      Long bones and axial skeleton

                      Reflex sympathetic dystrophy

                      Juxta-articular pattern

                      Paget’s Disease

                      • Osteitis deformans
                      • Metabolic bone disease: increased bone remodelling
                      • increased osteoclastic bone resorption and increased osteoblastic new bone formation
                      • New bone is structurally disorganised and susceptible to deformities/ fractures
                      • Increased incidence in male sex and increased age
                      • Aetiology uncertain:
                            • Genetics (+ve FHx 2-25%, some autosomal dominant)
                            • Viruses (paramyxoviruses eg RSV/measles inclusion bodies)

                      Clinical features

                      • Many asymptomatic (incidental findings of increased ALP or X ray appearances)
                      • Commonest symptom is pain
                      • Bowing of long bones eg femur and gait abnormalities
                      • Spinal stenosis and cord compression (rare)
                      • Skull expansion +/- headaches, frontal bossing (asymmetrical enlargement of bones)
                      • Neurological consequences from bony outgrowth: cranial nerve palsies, BS compression
                      • Cardiovascular complications: high output heart failure (AV shunting and high bony blood flow), aortic stenosis and diffused vascular calcifications
                      • Bone tumours, usually osteoscarcomas


                      Clinical examination

                      Biggest clues

                      • Enlarged skull with frontal bossing
                      • Bowing of extremities
                      • Leg length discrepancy
                      • Area of increased warmth and tenderness on bone


                      increased bone formation

                        • increased ALP (occasionally normal total ALP but increased bone-specific ALP)
                        • increased serum osteocalcin (not always increased in Paget’s so not a recommended test)

                      increased bone resorption

                      • increased urinary hydroxyproline
                      • increased serum and urinary deoxypyridinoline*
                      • increased N-telopeptide* and increased C-telopeptide*

                      * products of type 1 collagen degradation (more specific for bone resorption than hydroxyproline). Also decreased more rapidly in response to treatment than ALP

                      Serum calcium normal

                      • If poor dietary calcium and very active bone formation, mild hypocalcaemia and secondary hyperparathyroidism may develop
                      • Hypocalcaemia can also develop with bisphosphanates (bone resorption suppressed but calcium still used up for bone formation)
                      • Immobilisation of patient may lead to hypercalcaemia and hypercalciuria -> kidney stones

                      Serum phosphate normal

                      Serum 25(0H)cholecalciferol normal

                      • to exclude vitamin D deficiency as cause of increased ALP

                      (After 1 set of imaging, repeats are not necessary for surveillance/ monitoring unless new or progressive symptoms)


                      X ray 3 phases (may coexist)
                      1) Bone resorption (advancing lytic edge; “blade of grass”)
                      2) Active bone formation and resorption (mosaic haphazard)
                      3) Sclerotic phase (burnt out)


                      • Bony expansion
                      • Cortical thickening
                      • Coarsened trabecular markings
                      • Cotton wool/ osteoporosis circumscripta of skull
                      • “Ivory vertebrae” radiodense enlargement of VB

                      Bone scan

                      • less specific but most sensitive test for Paget’s


                      • Best if suspect malignant transformation (new pain at site of pagetoid bone; gold standard:bone biopsy)


                      • Symptoms due to metabolic activity (eg bone pain, headaches, fractures)
                      • To decreased local blood flow and minimise operative blood losses
                      • decreased hypercalciuria in immobilised patient
                      • Unclear if early treatment prevents late complications
                      • Principle: suppress increased resorption rate and secondarily decreased high formation rates
                      • Monitoring via serum ALP (take up to 3-6 months to normalize)
                      • Bisphosphonates
                      • 1st generation (etidronate) at therapeutic doses affects bone mineralisation so needs 6/12 on/off cycles and avoidance in lytic lesions involving weight bearing bones
                      • 2nd generation (alendronate, risedronate) more widely used and more potent so lower doses (decreased risk of demineralisation and osteomalacia)
                      • Weekly oral alendronate/ risedronate or 1-2 weekly IV pamidronate
                      • Oral side effects: oesphagitis
                      • IV side effects: flu like syndrome, osteonecrosis of jaw
                      • Salmon calcitonic s/c
                      • Intranasal calcitonin spray used in osteoporosis has too low a dose
                      • Main side effects: nausea and facial flushing
                      • May have secondary resistance after prolonged use (tachyphylaxis: develop antibodies)
                      • Lower potency compared bisphosphonates
                      • Calcium supplementation
                      • Vitamin D supplementation
                      1. Incorrect. Prostate cancer mets tend to be osteoblastic, mixed osteoblastic/lytic and very rarely purely lytic in poorly dy/dx primaries. The osteoblastic lesions will show up on bone scan but usually the axial skeleton (retrograde blood flow through valveless venous plexus), and unlikely to be symmetrical.
                      2. Incorrect. Myeloma deposits/ mets tend to be lytic. However note that the distribution of high uptake does correspond quite well with sites of myeloma deposits (80% in axial skeleton of which 40% is in the ribs, as well as long bones)
                      3. Correct!
                      4. Incorrect. It is true that arthritic change does show increased uptake, but the pattern of uptake in the diagram includes extra-articular areas eg scapula, pelvis and femur.
                      5. Incorrect. Bone is the commonest metastatic site of breast cancer but no particular favoured spot. Osteoblastic mets so would show up on bone scan - but will not be symmetrical.


                      Endocrinology: Pagets Disease


                      Question 94top

                      Question 95top

                      Question 96top Download PDf

                      A 78 year old man presents with progressive lethargy for several months and the recent onset of bruising, epistaxis, headaches and visual deterioration. Physical examination shows him to be anaemic with scattered ecchymoses, he has reduced visual acuity bilaterally and fundoscopy reveals retinal venous distension with numerous retinal haemorrhages.

                      Investigations show:

                      Full blood count


                      72 g/L (135-170)


                      101fL (80 -95)

                      White cell count

                      4.0 x 109/ L (3.5 -9.5)



                      1.2 x 109/ L (1.5 -6.0)


                      1.9 x 109/ L (0.7 -3.2)


                      0.4 x 109/ L (0 -0.4)


                      0.5 x 109/ L (0.2 -0,6)

                      Platelet count

                      90 x 109/ L (130 -330)

                      Blood film shows mild macrocytosis with marked rouleaux formation, neutropenia and occasional atypical lymphocytes

                      Coagulation studies


                      1.5 (1.0 -1.3)


                      45 seconds (26 -38)



                      12.5 mmol/L (2.0 -8.5)


                      0.15 mmmol/L (0.07 -0.13)

                      Liver function tests and calcium level


                      Protein electrophoresis


                      IgM kappa paraprotein


                      The most appropriate initial therapy is:

                      1. Melphalan and prednisolone     
                      2. Platelet transfusion
                      3. Plasma exchange
                      4. Renal dialysis
                      5. Intravenous gamma globulin



                      This elderly man has symptoms attributable to anaemia (fatigue), thrombocytopenia (bruising) and neurological symptoms (headache, visual loss) with findings suggestive of hyperviscosity (retinal engorgement and haemorrhages), in the setting of a high IgM paraproteinaemia
                      = Waldenstrom’s Macroglobulinaemia (WM)


                      1. Malignant clonal lymphoproliferative disorder of lymphocytes that produce IgM monoclonal protein
                      2. Lymphocytes that exhibit B cell differentiation but on cell surface markers indicate that the abnormal cell is at an earlier stage than plasma cells (ddx it from myeloma)
                      3. Bone marrow infiltrate > 10% and usually symptomatic (ddx it from MGUS)
                      4. Usually serum M protein > 30g/L
                      5. 75% are of kappa light chain type with reciprocal reductions in IgG and IgA (though lesser degree to myeloma)
                      6. Median survival: 5 years from diagnosis
                      7. Prognosis bad:
                        1. Age >65
                        2. Organomegaly
                        3. Symptomatic
                        4. B2 microglobulin > 4mg/L
                      8. Presentation
                        1. Some asymptomatic with indolent course
                        2. Lethargy, weight loss and chronic oozing from gums/nose
                        3. Bone pain rare compared to multiple myeloma (lytic bone lesions rare – if present often classified as myeloma)
                        4. Renal failure uncommon but IgM deposition in glomerular basement membrane happens
                        5. Urinary light chains can occur but to less degree compared to myeloma
                        6. Neurological symptoms:
                          1. Slowly progressive distal symmetrical mixed peripheral neuropathy
                          2. Hyperviscosity from sludging of micro-circulation (headache, blurred vision, confusion, stroke or coma)
                      1. BMAT
                        1. Hypercellular marrow with lymphoplasmacytoid infiltration >10% with intra-nuclear vacuoles containing IgM (Dutcher bodies)


                      1. Treatment
                      2. Asymptomatic: no treatment
                      3. Symptomatic:
                        1. Plasma exchange – alleviates hyperviscosity symptoms rapidly as IgM removed from circulation (75% IgM intravascular due to large molecular size) however does not change the underlying disease process
                        2. Chemotherapy
                          1. Rituximab (anti-CD20 monoclonal antibody)
                          2. Alkylating agents (cyclophosphamide, vincristine, melphalan)
                          3. Nucleoside analogues (fludarabine)
                          4. Others (IFN alpha, thalidomide, stem cell transplant – little experience, mixed success only for refractory disease)
                      1. Melphalan and prednisolone: not an unreasonable treatment option if stable disease, will take time to take effect – the presence of neurological symptoms is a first line indication for plasma exchange. Usually need to add cyclophosphamide to this regime, and multiple cycles required.
                      1. Platelet transfusion: His thrombocytopenia is not severe, moreover not bleeding – giving platelets will worsen hyperviscosity.
                      1. Plasma exchange: correct!
                      1. Renal dialysis: Cr only 0.15, moreover dialysis filter pore size too small to remove IgM
                      1. IV Ig: will add to hyperviscosity



                      Haematology:White Cell Disoders

                      Question 97top

                      Question 98top Download PDF

                      A 52 year old retired school teacher with a 20 year history of type 2 (non insulin-dependant) diabetes mellitus and a 10 year history of hypertension presents with a two day history of progressive right sided ptosis and diplopia. Examination reveals signs consistent with an incomplete right third nerve palsy with pupil sparing. The erythrocyte sedimentation rate (ESR) is 45 mm/hour (0-15).

                      The most likely diagnosis is:

                      1. Diabetic right third nerve palsy
                      2. Mucormycosis of the right orbit
                      3. Right posterior communicating artery aneurysm
                      4. Giant cell arteritis involving the right third nerve
                      5. Right mid-brain infarct


                      Learning Issues:

                      • Diabetic neuropathies
                      • CN III palsy

                      This is an isolated unilateral painless CN III palsy which spares the pupil

                      • Suggests a “medical” CN III palsy
                      • Associated mild-moderately elevated ESR suggesting inflammatory process
                      • Not secondary a “surgical” CN III palsy (eg increase ICP or space occupying lesion) as parasympathetic activity is spared
                        • Parasympathetic fibres are superficial and will thus be affected first

                      Diabetic neuropathy

                      • Affects 50% of both long-standing T1DM and T2DM
                      • Related to duration of diabetes and glycaemic control
                      • Both myelinated and unmyelinated fibres affected
                      • Management:
                        • Improved glycaemic control (improves nerve conduction velocity but Sx may not)
                        • Avoid neurotoxins (eg ETOH)
                        • Vitamin supplementation if deficient (eg B12/ folate)
                        • Look for and treat complications eg ulcers
                        • Analgesia
                          • Pain of acute neuropathy may resolve in 1 year
                          • Chronic pain hard to treat: TCA/ gabapentin/ anti-epileptics (avoid NSAIDS if renal impairment)
                          • Pain clinic



                      • Pain from distal symmetrical subsides as neuropathy progresses
                      • Radiculopathy self-limited, spontaneously improves in 6-12 months

                      Distal symmetrical polyneuropathy

                      • Most common (glove + stocking)
                      • Acute form (< 12 months)
                      • Chronic form (usually painful)
                      • Spreads distal -> proximal
                      • Distal sensory loss + abnormal proprioception
                      • Loss of ankle jerks
                      • Numbness/ tingling/ burning
                      • Present at rest, worst at night

                      Diabetic mono/polyradiculopathy

                      • Pain in distribution of > nerve roots
                      • +/- motor weakness
                      • Amyotrophy: affects lumbar flexus with weak hip ext/flexion
                      • Thoracic radiculopathy less common (debilitating band-like pain, often had extensive GIT Ix)
                      • Usually self-limited within 6-12/12


                      • Usually does not improve
                      • May improve with glycaemic control

                      Diabetic mononeuropathy

                      • Isolated cranial or peripheral nerve dysfunction: pain and motor weakness
                      • Less common than polyneuropathy
                      • ? Vascular phenomenon (unclear aetiology)
                      • Cranial nerves
                        • CN III most common
                        • Also affects IV, VI and VII (Bell’s)
                      • Peripheral nerves
                        • Common peroneal nerve palsy -> foot drop

                      Mononeuritis multiplex

                      • > 1 named peripheral or cranial nerve affected
                      • Less common
                      • Main ddx: vasculitis (need to exclude)

                      Autonomic Neuropathy

                      • Difficult to treat
                      • Usually does not improve with time
                      • May improve with glycaemic control

                      Affects cholinergic, adrenergic and peptidergic (peptides eg substance P) systems


                      • Cardiovascular
                        • Resting tachycardia
                        • Postural hypotension
                        • Sudden death case reports
                      • GIT
                        • Gastroparesis (increase transit time with Sx in absence of obstruction, closely related to retinopathy and nephropathy)
                        • Enteropathy (constipation +/- diarrhoea)
                      • Genitourinary tract
                        • Bladder dysfunction
                      • Sympathetic
                        • Hyperhidrosis upper limbs
                        • Anhidrosis lower limbs
                        • ß counter-regulatory hormone release (hypoglycaemic unawareness)
                      • Pathogenesis of diabetic amyotrophy suggestive of inflammation (from muscle and nerve root biopsies consistent with immune complex and complement deposition) -> some patients improved with steroids +/- IV immunoglobulin. However, most improved spontaneously with time anyway


                      Back to the question:

                      1. Correct. As described, CN III isolated palsy is commonest diabetic mononeuropathy.
                      • CN III (oculomotor) supplies:
                        • Extra-ocular muscles (SR, MR, IR and IO): motor and proprioception
                        • Parasympathetic (via ciliary ganglion)
                          • Sphincter pupillae -> pupillary constriction
                          • Ciliary muscles of lens -> accommodation (increase convexity for near vision)
                      • Emerges from mid-brain -> pierces dura -> runs in lateral wall of cavernous sinus
                      • Enters orbit via superior orbital fissure
                      • Within fissure: divides into superior (SR and levator palpebrae) and inferior division (IR, MR and IO + parasympathetic fibres)
                        • Parasympathetic fibres run from Edinger-Westphal nucleus to ciliary ganglion for synapses
                        • Post synaptic fibres then pass to eyeball
                      • Classically:
                        • Diplopia
                        • Ptosis (paralysis of levator palpebrae)
                        • Opthalmoplegia (eyeball down and out – unopposed action of SO and LR)
                        • Normal pupillary constriction to light (NO interruption of parasympathetic fibres to the iris, so dilator pupillae muscle opposed)
                        • Accommodation of the lens still present
                      1. Incorrect. Patient is too well and has no other classic features. Moreover, if entire orbit involved, parasympathetic fibres will be involved.


                      • Mucormycosis is a devastating fungal infection by zygomycetes
                      • Ubiquitous especially decaying vegetation and soil
                      • Enzyme ketose reductase allows them to thrive in acidic, glucose rich environment
                      • Infection starts from inhalation of spores
                      • Immunocompetent -> cleared
                      • Immunosuppressed -> starts at nasal turbinates -> spreads to orbits and brain
                      • Mucors are angio-invasive, so infarction of infected tissues is the hallmark
                      • Usually fast-paced infection
                      • Presents with fevers, headache, purulent nasal discharge and sinus pain
                      • All sinuses involved -> contiguous structures eg palate, orbit and brain
                      • If orbit involved -> peri-orbital oedema, proptosis and blindness
                      • Facial pain common from infarction of sensory nerves of trigeminal nerve
                      • Other CN palsies possible when spread to cavernous sinus, sinus thrombosis and involvement of carotid artery
                      • Rarely it seeds to other organs via haematogenous spread (usually neutropenic)
                      1. Aneurysms of the posterior cerebral artery (or its branch posterior communicating artery) and superior cerebellar artery can exert pressure on CN III as it passes in between them. However, the superficial parasympathetic fibres should also be involved.


                      1. Giant cell arteritis (temporal arteritis) is chronic vasculitis of large or medium sized vessels – artery supplying CN III not classically affected; in any case, the parasympathetic function should also be impaired.
                      • May be generalised but commonly affects cranial branches of arteries originating from the aortic arch
                      • Symptoms: headache, jaw claudication, visual symptoms, fever, polymyalgia rheumatica
                      • Visual symptoms from ischaemia due to occlusion or thrombosis of posterior ciliary arteries that supply the optic nerve, or the opthalmic artery itself
                      • ESR usually substantially elevated and only rarely < 40 (unless on steroids)
                      1. Right midbrain infarct (supplied by posterior circulation ie vertebral arteries) will affect CN IV ie trochlear nerve and the Edinger-Westphal nucleus.


                      Neurology: peripheral nerve lesions,

                      Endocrinology: neurologic complications of diabetes

                      Question 99top Download PDF

                      A patient presents with the rash shown in the photograph below and is found to have a rapid plasma reagin (RPR) test titre of 1:256 and a positive fluorescent treponemal antibody associated absorbed (FTA-ABS) test.

                      macularpapular rash

                      The most appropriate treatment is:

                      A. Doxycycline 100mg twice daily for 14 days (oral)

                      B. Benzylpenicillin 1.8g sixth hourly for 10 days (intravenous)

                      C. Benzathine penicillin 1g daily as a single dose (intramuscular)

                      D. Procaine penicillin 1g daily for 10 days (intramuscular)

                      E. Ceftriaxone 250mg daily for 5 days (intramuscular)


                      Learning issues:

                      • Ddx of erythematous macular rash and rash affecting hands/feet
                      • Syphilis (and more broadly STDs, I suspect there’ll be one STD question per year, excluding HIV) and laboratory testing
                      • Penicillins

                      Ddx erythematous macular rash

                      1. Drug eruption
                      2. Psoriasis (though characteristic sites eg extensor surfaces, often scaly)
                      3. Pityriasis rosea
                      4. Lichen planus (characteristic sites eg dorsum of hands, often hexagonal and purplish)
                      5. Acute viral exanthem (eg measles, varicella zoster, acute HIV seroconversion illness)

                      Ddx rash involving hands/feet

                      1. Infection
                        • Secondary syphilis
                        • Coxsackie virus (Hand, foot and mouth disease)
                        • Scabies
                      2. Immune mediated
                        • Kawasaki’s disease (usually peeling of hands and feet, rather than rash)


                      • Treponema pallidum
                      • Horizontal spread (sexual contact) or vertical transmission (transplacental infection of foetus)
                      • Does not survive well outside body; inactivated by drying, heat and disinfectants
                      • Grows very slowly -> endarteritis

                      Syphilis laboratory features

                      1. Microscopy

                      • T.pallidum cannot be cultured
                      • Exudate from primary chancre examined by dark-ground microscopy / UV microscopy (stained)/ biopsy material (silver stain)
                      • Not seen in gram stain
                      • Tightly wound, slender coils, sluggish but motile

                      2. Serology

                      Indirect (non-treponemal)

                      • VDRL
                      • RPR

                      Positive within 4-6 weeks of infection or 1-2 weeks from chancre formation

                      Decline in tertiary disease or after antibiotics

                      Testing for Ag that are not treponemal in origin

                      Detecting Ig M and Ig G formed in response to lipoidal material released from damaged cells + from lipid on surface of treponema

                      Good screening test

                      False positives:

                      • Viral infections
                      • Connective tissue diseases
                      • Post immunisation
                      • Pregnancy
                      • Malaria
                      • Leprosy

                      Direct (treponemal)

                      • FTA-ABS
                      • TPHA  (T.pallidum haemagluttination assay)

                      Positive earlier
                      Remain positive in tertiary
                      Remain positive despite treatment so cannot be used as indicator of therapeutic response

                      Use treponemal Ag extracted from T.pallidum

                      Good to confirm syphilis when indirect test is positive

                      False positives:

                      • Disease associated with increased or abnormal globulins
                      • SLE
                      • ANA positivity
                      • Pregnancy
                      • Recent increase incidence especially among MSM (men who have sex with men)
                      • HIV infection changes natural history/ treatment and outcome of syphilis
                      • Diagnosis more difficult (> false negatives or atypical responses)
                      • Neurosyphilis tends to manifest earlier and progress more rapidly
                      • Uveitis and meningitis also more common


                      T.pallidum is highly sensitive to penicillin and should be the 1st drug of choice. If hypersensitive, consider desensitisation.

                      If not possible, 2nd line agent (in non-pregnant)

                      • Doxycycline 100mg oral BD (14 days)
                      • Some limited studies suggest that ceftriaxone or azithromycin may also be effective (but optimum dose and duration unknown)

                      Other treatment considerations

                      • Avoid sexual contact till lesions healed and completed treatment
                      • All sexual contacts in last 3 months should be treated despite negative serology
                      • HIV +ve patients need close surveillance due to increase neuro-risk (clinical exam and serology at 6,12,18,24 months post therapy. If neuro symptoms or 4 fold increase in serology, should have LP
                      • Pregnancy and syphilis
                      • typically 3 stages (but not everyone goes through all)


                      Clinical Features



                      Painless ulcerating nodule at infection site (chancre)

                      If HIV, chancre may be absent, atypical or multiple

                      Lymphadenopathy (usually resolves)

                      Benzathine penicillin 1.8g IM (single dose)


                      Procaine penicillin 1g IM
                      (10 days)

                      (2-8 weeks post exposure)

                      Flu like illness

                      Mucocutaneous rash (spontaneously resolves)

                      Condylomata lata (grey/pink raised lesion where skin joins mucous membrane)

                      Aseptic meningitis

                      As above

                      (3-30 years)

                      (some may relapse with features of secondary syphilis)
                      Note that HIV +ve patients should have LP prior treatment

                      • If negative: treat as per protocol
                      • If positive: treat as neurosyphilis


                      Early latent (< 2 years):
                      As above

                      Late latent (> 2 weeks or  uncertain duration):
                      Benzathine penicillin 1.8g IM weekly (3 weeks)


                      Procaine penicillin 1g IM
                      (15 days)

                      Tertiary/ late


                      Cardiovascular syphilis

                      Gummatous syphilis

                      Benzylpenicillin 1.8g IV 4/24 (15 days)

                      + prednisolone to prevent Jarisch-Herxheimer reaction


                      Risk of congenital syphilis low for:
                      Any mother with positive serology/ active syphilis who was adequately treated before 28 weeks and not re-infected
                      (Placenta should still be examined)

                      Untreated maternal infection

                      • Foetal loss 40%
                      • High risk stillborn
                      • At birth: fulminant infection and death
                      • Early: Infectious, resembles secondary syphilis
                      • Late (> 2 y.o): Non-infectious, subclinical. Cardiac manifestations rare but keratitis more common
                      • Residual stigmata + characteristic facies

                      Benzylpenicillin 50mg/kg IV or IM BD
                      (10 days)


                      Procaine penicillin 50mg/kg IM daily
                      (10 days)


                      • Beta lactams: bacteriocidal by interfering with peptidoglycan cell wall synthesis
                      • Bind to and inhibits PBP (penicillin binding proteins) which are responsible for final cross-linking of new subunits onto the growing chain
                      • Not active against species lacking a cell wall (eg Mycoplasma), impenetratable cell walls (eg mycobacterium) or intracellular pathogens (eg Chlamydia)
                      • Some bacteria produce beta-lactamases which catabolise the beta lactam ring, rendering it useless – this can be surmounted by the addition of beta-lactamase inhibitor eg clavulanic acid

                      Narrow-spectrum penicillins
                      Narrow-spectrum penicillins are mainly active against Gram-positive organisms, but are inactivated by beta-lactamases.

                      • Benzylpenicillin (penicillin G) is administered parenterally and remains the treatment of choice for susceptible infections.

                      • Procaine penicillin is an IM preparation designed to extend the half-life of benzylpenicillin. It provides blood levels for up to 24 hours, but these are adequate only against highly susceptible organisms.

                      • Benzathine penicillin is given IM and provides low levels of benzylpenicillin for up to 4 weeks.
                      • Phenoxymethylpenicillin (penicillin V) is acid-stable and thus may be given orally, although food impairs absorption. It is intrinsically less active than benzylpenicillin.

                      Narrow-spectrum penicillins with antistaphylococcal activity
                      Dicloxacillinflucloxacillin and methicillin are stable to beta-lactamase produced by staphylococci. Flucloxacillin and dicloxacillin are reliably absorbed by the oral route. Food reduces absorption and they are best taken half to one hour before food. Methicillin, the parent drug, is not used in clinical practice. Laboratories test with either oxacillin or cefoxitin rather than methicillin to determine susceptibility to antistaphylococcal drugs.

                      Flucloxacillin is generally well tolerated, but is occasionally associated with cholestatic jaundice, particularly in older patients on prolonged therapy. This may occur after oral or IV administration and up to 6 weeks after treatment. It may last for months, can be irreversible and, rarely, may be fatal. Dicloxacillin appears to cause less irreversible hepatotoxicity but results in more infusion phlebitis (see Intravenous administration of antimicrobials) and interstitial nephritis. Dicloxacillin may be preferable to flucloxacillin for oral therapy or in patients requiring prolonged therapy. In these guidelines, di/flucloxacillin refers to dicloxacillin or flucloxacillin.

                      MRSA should be regarded as clinically resistant to all beta lactams.

                      Moderate-spectrum penicillins
                      The aminopenicillins, amoxycillin and ampicillin, have greater activity than benzylpenicillin against some Gram-negative organisms (eg Escherichia coli, Haemophilus influenzae), but are destroyed by beta-lactamase–producing strains. They are drugs of choice for enterococcal infections. Amoxycillin is better absorbed orally than ampicillin, is not affected significantly by food and requires fewer oral doses per day, but when administered parenterally they are equivalent. In these guidelines, amoxy/ampicillin refers to amoxycillin or ampicillin.

                      Broad-spectrum penicillins (beta-lactamase inhibitor combinations)
                      The beta-lactamase inhibitors clavulanatesulbactam and tazobactam inhibit the enzymes produced by Staphylococcus aureus and Bacteroides  fragilis and also the beta-lactamase enzymes found in Escherichia coliKlebsiella species, Neisseria gonorrhoeae and Haemophilus influenzae. These 3 drugs possess little inherent antibacterial activity, but significantly extend the spectra of activity. Reserve these combinations for the treatment of infections due to organisms in which resistance to the beta lactam is due to enzymes that the beta-lactamase inhibitors are able to inhibit. The combinations are often more expensive.

                      Amoxycillin+clavulanate can cause diarrhoea and hepatotoxicity, which occur more frequently than with amoxycillin.

                      Broad-spectrum penicillins with antipseudomonal activity
                      Piperacillin and  ticarcillin are the only penicillins that have activity against Pseudomonas aeruginosa, but high doses are required. The addition of clavulanate to ticarcillin and tazobactam to piperacillin extends their spectra of activity, with piperacillin+tazobactam having greater in vitro activity against enterococci and Klebsiella species. Piperacillin+tazobactam is more expensive than ticarcillin+clavulanate, and both are more expensive than most other penicillins.


                      Infectious Diseases Syphilis


                      Question 100 top Download PDF

                      A 65 year old man presents with a 2 month history of non-productive cough, dyspnoea on exertion and low grade fevers. His medications include simvastatin, aspirin, atenolol, amiodarone and enalapril. On examination, he is afebrile, the JVP is not raised and cardiac examination is normal. There are crackles over the lower half of both lung fields. His chest X ray is shown below.

                      Pulmonary function tests show a moderate restrictive defect with a marked reduction in diffusion capacity for carbon monoxide. There is a mild neutrophil leucocytosis and an ESR of 55 mm/hr (normal 0-13)

                      The most likely diagnosis is:
                      A. Sarcoidosis
                      B. Amiodarone toxicity
                      C. Cryptogenic fibrosing alveolitis
                      D. Atypical pneumonia
                      E. Cardiac failure

                      Answer: B

                      All of the above diagnoses are reasonable, helpful if it specified the presence/absence of clubbing

                      A. Sarcoidosis
                      • Tends to affect young adults, blacks > whites
                      • Pulmonary fibrosis of upper zones
                      • CXR findings (4 stages) but most typically bilateral hilar lymphadenopathy and reticulate interstitial opacities in UPPER zones
                      • Can present with fever, but usually with arthralgia and rash (erythema nodosum)
                      • Causes low white cell count (5-10%), ESR may be high , ACE level may be high

                      B. Cryptogenic fibrosing alveolitis

                      • ie Idiopathic pulmonary fibrosis (rarest of all listed)
                      • Problems with classification
                      • Histopathological diagnosis (“usual interstitial pneumonia” on lung biopsy)
                      • Major and minor criteria
                      • Usually affects men, age 40-70 years (mostly > 60 years old, increased incidence w age)
                      • Insiduous and usually present > 6/12 of symptoms
                      • CXR usually abnormal with bibasal interstitial opacities (if alveolar, it’s something else)
                        D. Atypical pneumonia
                      • Again a possibility but 2 month history of untreated pneumonia without progression makes it less likely
                      E. Cardiac failure
                      • probably the strongest ddx but would probably expect a bit of RV failure and a raised JVP
                      • Cardiomegaly on CXR but likely pre-existant – based on his medications one would deduce that he has CCF (metoprolol and enalapril); no upper lobe diversion
                      • ACE inhibitors may cause a cough (up to 20% affected between 1/52 to 6/12 of commencement, high prevalence in Chinese ie up to 50%) through accumulation of kinins (increased prostaglangins that stimulate afferent C fibres) which are usually metabolized by ACE
                      Amiodarone pulmonary toxicity (< 5% on amiodarone affected)
                      • DIAGNOSIS OF EXCLUSION
                      • Other Ddx: PE and lung cancer
                      • Prognosis generally good
                      • < 10% mortality rate unless ARDS (mortality around 50%)
                      • Correlates with cumulative dose rather than drug levels
                      • Usually presents months to years after initiation (though case reports of fulminant course over days)
                      • Lipophilic and thus accumulates in many tissues: half life 25 –100 days
                      Risk factors:
                      1. Total cumulative dose over months to years
                      2. Underlying lung disease (no recommendations, reported in some case series but one prospective RCT vs placebo with 519 patients found no accelerated loss of DLCO among COPD patients)
                        • Treatment: stopping drug +/- prednisolone 50mg daily
                      4 main types
                      1. Interstitial pneumonitis
                        • commonest
                        • insidious onset of cough, dyspnoea +/- weight loss
                        • bilateral interstitial infiltrates on CXR
                      2. Organizing pneumonia
                        • seen in 25% (mimics chest infection)
                        • more acute onset of cough, dyspnoea, fever +/- pleuritic chest pain
                        • patchy alveolar infiltrates on CXR
                      3. Acute respiratory distress syndrome (ARDS)
                        • rare but may be fatal, poorest prognosis
                        • usually post-operative (thoracic surgery) or pulmonary angiography
                      4. Solitary lung nodule
                        • uncommon, ddx cancer
                      Main symptoms and signs
                      • 50-75%: Unproductive cough and dyspnoea (especially on exertion)
                      • 30-50%: Fever, weight loss and malaise
                      • Bilateral crepitations
                      • No clubbing (clubbing usually present in restrictive lung diseases)
                      Laboratory markers
                      • often non-specific
                      • ? white cell count, ESR and LDH
                      • Serum amiodarone levels often within therapeutic range
                      • No eosinophilia
                      • Negative vasculitic screen
                      • Potential use of glycoprotein KL-6 ie mucin secreted by proliferating Type 2 pneumocytes (case report measuring serum KL-6 showed 5X elevation in those with toxicity compared to those with pneumonia, CCF or lung cancer)
                      • CXR: localized or diffused alveolar +/- interstitial opacities, may be migratory and can occur in absence of symptoms
                      • CT chest/abdomen: increased attenuation of chest/ liver and spleen due to high iodine levels (but does not ddx between toxic vs normal accumulation)
                      • Bronchoalveolar lavage: no particular cellular pattern, increased foam cells
                      • Lung biopsy: mostly used to exclude cancer
                      • RFT: non specific, usually abnormal in those with amiodarone but if DLCO decreases > 20% should be further investigated
                      Other side effects of amiodarone:
                      • Thyroid dysfunction (both hyper and hypothyroidism; generally must have underlying dysfunction)
                      • Cardiotoxicity (low pro-arrhythmia risk eg torsades < 1%, sinus bradycardia)
                      • Hepatotoxicity (rise in AST, need to stop if > 2x elevation)
                      • Ocular changes (corneal microdeposits, optic neuropathy)
                      • Skin reactions (photosensitivity, slate grey skin from deposition of lipofuscin)
                      • GIT effects (usually during loading dose)
                      • Neurotoxicity (tremor, ataxia)
                      • Sterile epididymitis
                      • Increases serum cholesterol, HDL and TAG
                      • Many drug interactions



                      Clinical Pharmacology:Cardiovascular