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Question 11 top Download PDF

11) The most important risk factor for developing anthracycline-related cardiac toxicity is:

  1. Concurrent chemotherapeutic agents
  2. Cumulative dose
  3. Age
  4. Baseline ECG abnormalities
  5. Gender

 

Answer:

Cancer patients receiving chemotherapy are at increaserisk developing cardiac complications.
Serious complications include:

  • Arrhythmias
  • Myocardial necrosis -> cardiomyopathy
  • Vaso-occlusion/ spasm -> acute coronary syndromes

Anthracyclines
Examples: doxirubicin, mitoxanthrone

Mechanism of action:

  • Inhibits DNA and RNA synthesis:
    • Intercalating between base pairs (steric obstruction)
    • Inhibits topoisomerase II (DNA repair)
    • Doxirubicin also chelates iron –> complex that releases free radicals

Uses in Chemotherapy:

    • Haematological malignancies: leukaemias, lymphomas, myeloma
    • Solid organ malignancies: ovary, breast, head & neck, liver, stomach, bladder, sarcomas

 

Anthracyclines cause a dose-dependant drop-out of myocardial cells
Risk factors:

  • Cumulative dose
    • Biggest risk factor
    • 5% receiving >550mg/m2 will develop heart failure
  • Age
    • increaseage especially > 70
    • Children get toxicities at smaller cumulative doses
  • Pre-existing heart disease
  • Hypertension
  • Concomitant radiation therapy (thorax)
  • Other non-anthracycline agents (trastuzumab and  taxanes)
  • Previous stem cell transplant

 

Toxicities:

  • Acute
    • During treatment
    • Arrhythmias, ECG changes, pericarditis/ myocarditis syndrome, increaseBNP - uncommon
  • Early
    • Peak onset 3/12 from last dose
    • Progressive ventricular failure
  • Late
    • > 10 years
    • Heart failure usually in those with childhood malignancies

 

How todecrease risk:

  • Mitoxantrone (related but less cardio-toxic)
  • Liposomal formulations
  • Give via infusion rather than boluses
  • Dexrazoxane (intra-cellular iron chelator)
  • Carvedilol and ACEi as “prophylaxis” (limited evidence)

Monitoring:

  • Pre-treatment RNVG or echocardiogram
    • Serial for comparison or if Sx develop
  • Serial cardiac enzymes (not usually done)
  • Definite dx: endomyocardial biopsy (rarely done – fibrosis)

Prognosis and Rx:

  • Prognosis related to Sx severity at dx
  • Some degree of reversibility with drug cessation
  • Rx: 1st line: ACEi then +/- conventional heart failure medications

Other common chemotherapy-related side effects (late)


Organ

Drug

Effect

Bone

Steroids

Osteoporosis
AVN

Brain

Methotrexate
ARA-c

Neuropsych effects
+/- cognitive decline

Peripheral nerves

Vincristine
Platinum

Peripheral neuropathy
Hearing loss

Eyes

Steroids

Cataracts

Lung

Bleomycin
Methotrexate

Pulmonary fibrosis

Kidney

Platinum

decrease eGFR,decrease mG

Gonads

Akylating agents

Infertility
Premature menopause

Bone marrow

Many

Apasia
Myelodysplasia

Secondary leukaemia (AML)

  • usually refractory to Rx
  • Akylating agents induced: genetic deletions in chromosome 5,7
  • Topoisomerase inhibitors induced: chromosome translocation 10q23

Uterus

Tamoxifen

Endometrial cancer (if >5 years)

Bladder

Cyclophosphimide

Haemorrhagic cystitis

 

Back to the question:

  1. True especially for taxanes and trastuzumab – but not the most important
  2. Corrrect!
  3. Age definitely is a risk factor but not the most important
  4. Baseline ECG changes could indicate underlying heart disease
  5. Gender – not an independent risk factor, but one can argue that females are at higher risk because eg for Rx of breast cancer – may have had radiation to the thorax + receiving trastuzumab

Topic

Oncology: Principles of anticancer therapies

Pharmacology: Oncology

 

Question 12 topDownload 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

 

Answer:

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

Causes

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
(<12)

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

Trauma
CNS infection (especially viral encephalitis)
Metabolic 

Adolescents (12-18)

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

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

Older adults (>35)

CVA

  • 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
Metabolic

EEG

  • 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

 

Topic

Neurology: epilepsy

Question 13 topDownload 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

Answer:

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

Topic

Cardiology: Cardiac transplantation

Question 14 top

Question 15 top Download PDF

15) A 70 year old woman, weighing 45kg, presents with polymyalgia rheumatica and headache. There is a history of osteoporosis with a previous vertebral wedge fracture. Past history also includes a hysterectomy.

Temporal artery biopsy reveals giant cell arteritis. A bone mineral density shows T scores for the lumbar spine and the femoral neck as -3.0 and -2.5 respectively.

A chest X ray shows wedging of the thoracic vertebrae on the lateral view.

The most appropriate initial management is:

  1. Prednisolone 40mg daily and alendronate 10mg daily
  2. Prednisolone 10mg daily and azathioprine 100mg daily
  3. Prednisolone 40mg twice daily and calcitriol 0.25 microg twice daily
  4. Prednisolone 15mg daily and methotrexate 10mg weekly
  5. Prednisolone 40mg daily and hormone replacement therapy

 

Answer:

Polymyalgia Rheumatica (PMR)

  • Usually age >50 (Mean age of onset: 70)
  • Females > Males
  • increase association with HLA –DRB1*04 alleles
  • Clinical syndrome with pain and stiffness of neck, shoulder and pelvic girdle (proximal muscles)
    • Bilateral and symmetrical
    • Stiffness worse after rest
    • Normal power (but limited by pain) -> eventually atrophy
    • Dramatic/ insidious
    • Systemic symptoms: fever/ malaise/ weight loss/ depression
    • Can have tenosynovitis/ synovitis +/- effusions
    • Most importantly check for GCA (50% with PMR have GCA, 10% with no symptoms have arteritic changes on biopsy)

 

Giant Cell Arteritis (GCA)

  • Similar epidemiology as PMR
  • However much less common
  • Panarteritis of medium -> large arteries
    • Usually superficial temporal, vertebral, opthalmic, posterior ciliary artery
    • Affects coronaries -> AMI/ CCF
    • Aortic arch -> dissection
    • Intra-cranial arteries rarely involved
    • increase inflammatory (mainly monocytic/ macrophages) infiltrate
    • Disrupted elastic lamina
    • Giant cell granulomas (may be absent)
    • Skip lesions +/- thrombosis

 

  • Clinical features:
    • Headache usually 1st symptom
    • Scalp and temple tenderness
    • Jaw claudication
    • Visual changes (up to 50%): may have sudden blindness

 

 

Ix:

  • increase ESR (>40mm/hour)
  • Mild normocytic/ hypochromic anaemia
  • Non-specific increase LFTs (mainly GGT and ALP)
  • increase immunoglobulins (Ig G) and complement
  • For GCA: may have thyroid abnormalities (usually hyper) and anti-cardiolipin Ab +ve
  • Normal CK
  • Normal EMG
  • Normal muscle biopsy

 

  • Ultrasound artery
    • Look for halo sign (hypoechoic wall thickening)
    • Useful if unable to biopsy
  • Temporal artery biopsy:
    • Bilateral biopsy at least 3-5cm on each side
    • increase false +ve rate due to skip lesions
    • Do not delay steroids to await biopsy (can be +ve up to 14 days post Rx)
  • Others eg PET scans/ MRI (for large extracranial arteritis)

Rx:

  • Steroids
    • PMR only: 15-20mg/day
    • GCA: 40-60mg/day OR pulse methyprednisolone or higher dose if visual changes
    • Rapid response and can wean gradually once Sx improve
    • Need average 2 years treatment
  • Good prognosis: most OFF treatment by 5 years though relapses not uncommon
  • Rarely may need steroid-sparing agent (usually if GCA)
    • Methotrexate: conflicting results in studies
    • Infliximab not useful
    • Can add low dose aspirin especially if visual symptoms

 

Treatment of glucocorticoid-induced osteoporosis
Mechanism:

  • Negative calcium balance
    • decrease intestinal calcium absorption
    • increase renal calcium excretion
  • decrease bone formation by direct inhibition of osteoblasts
    • Inhibits IGF-1 and testosterone
    • increase apoptosis of osteoblasts and osteocytes
  • increase bone resorption

Rx:

    • Not markedly different from general osteoporosis
    • Try to use lowest dose for shortest period of time +/- steroid sparing agents
    • If taking >5mg prednisolone/day for < 3 /12 – need prophylaxis
    • Regime:
      • Caltrate (1500mg/day) and cholecalciferol (800 units/day)
      • Bisphosphonates (eg alendronate 35mg/week prophylaxis, 70mg/week Rx)
      • Testosterone replacement if hypogonadal
      • Raloxifene (SERMS) in post-menopausal women (decrease incidence vertebral # but not hip #)
      • Consider calcitonin of cannot tolerate bisphosphonates (especially useful too to alleviate fracture-related pain)
      • Strontium ralaete at least as effective as bisphosphonates in BMD increase and fracture prevention (increase proliferation of pro-osteoblasts)

      Topic

      Rheumatology: Polymyalgia Rheumatica

       

      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
      PPCM
      • 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)

       

      Topic

      Cardiology - Cardiac Changes and Problems in Pregnancy

       

      Question 17 topDownload PDF

      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)

       

      Raloxifene
      • 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)

      Osteoporosis

      • 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

      Tests:

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

      Management:

      • 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

        Topic

        Endocrinology:osteoporosis
        Pharmacology:Endocrinology

        Question 18 top Download PDF

        A 53 year old woman has had severe interscapular pain since carrying two buckets of sand three weeks ago. There is a lower thoracic kyphosis with pain, tenderness and restricted movement. An X ray of the thoracic spine is shown below:

        spine

         

        There is 1+ proteinuria. Full blood examination, serum electrolytes and creatinine levels, as well as liver function tests are normal. Serum calcium is 2.37 mmol/L (2.25 – 2.65). Serum protein electrophoresis shows reduced gamma globulins but no paraprotein.

        Mean lumbar spine bone density is 4.0 standard deviations (SD) below the normal age-related mean, and 4.8 SD below the mean adult mean. Femoral neck values are 1.8 and 2.2 below the age-related and young adult means respectively.

        Which one of the following is the most appropriate next investigation?

        1. Isotope bone scan
        2. Bone turnover markers
        3. Urinary protein electrophoresis
        4. Vertebral biopsy
        5. Serum follicular stimulating hormone (FSH)

        Answer:

        53 year old woman with a thoracic vertebral crush fracture post minimal trauma

        • Bone density in lumbar spine: T score -4.8 (severe osteoporosis)
        • Bone density in femoral neck: T score -2.2 (osteopenia)
          • Big difference!
        • Normal calcium and serum EPG: no paraprotein, with 1+ proteinuria (conventional urinary dipstick only detects albumin and not BJP) and normal renal function -> would suggest that multiple myeloma is less likely so I excluded C.

         

        • D. Vertebral biopsy is invasive and thus will not be the next investigation – even though it will give valuable information (eg if metastatic bone disease)
        • E. increase FSH (and increase LH) would suggest menopause but there’s nothing in the stem that would lead us to think premature menopause was at play – in any case, she’s 53

         

        •  So we’re left with A. and B. – I thought bone turnover markers would not guide us any further as we already know there must be some sort of abnormal bone metabolism, so B is out
        • So A because the bone scan will tell us if it’s a metastatic deposit, and whether there’s disease anywhere else

         

        But I’m wrong… the answer is actually C! Why?

        • Perhaps the marked BMD differential is a clue towards definitely spinal abnormality rather than garden variety osteoporosis
          • So we’re left with either: malignancy (primary or secondary) or multiple myeloma
        • The only other definite abnormality is 1+ proteinuria and thus should be further investigated. Conventional dipstick only picks up albumin (note: there are special ones available that pick up non-albumin proteinuria).
        • Usually in myeloma, there is urinary light chain excretion (-> cast nephropathy) and this will not be detected on dipstick – however many of these patients and those with secondary amyloidosis will have a glomerular leak and thus have albuminuria detectable on dipstick.

        Topic

        Haematology: Multiple Myeloma / Amyloidosis

        Question 19 top

        Question 20 topDownload 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:


        Haemoglobin

        82

        120-155 g/L

        MCV

        81

        80- 95 fL

        White Cell Count/L

        Neutrophils

        0.3 x 109

        1.5- 6.0

        Lymphocytes

        1.10 x 109

        0.7- 3.15

        Monocytes

        0.3 x 109

        0.2- 0.6

        Eosinophils

        0.1 x 109

        0- 0.4

        Basophils

        0.1 x 109

        0- 0.15

        Platelet Count

        13 x 109

        150- 400

        Coagulation:


        PT-INR

        1.6

        1.0- 1.3

        APTT

        42

        26- 38 seconds

        Fibrinogen

        0.9

        2.0- 4.0 g/L

        D-dimer

        0.4

        < 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

         

        Answer:

         

        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)

        APML

        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)

         

        Pancytopenia


        Decreased production

        Aplastic anaemia

        Congenital

        Acquired

        Marrow infiltration

        Acute leukaemia
        Hairy cell leukaemia
        Lymphoma
        Myeloma
        Cancer
        Fibrosis

        Inadequate resources

        B12/ folate deficiency

        Increased destruction

        Splenomegaly

        Splenic trapping of cells (hypersplenism)

        Others

        Myelodysplasia

         

        PNH

         

        Overwhelming infection

        HIV with myelodysplasia

        Viral haemophagocytosis

        Topic

        Heamatology: Leukaemia

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