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2003 FRACP paper two


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Question 1 top Download PDF

A 65-year-old woman presents with a one-week history of progressive dyspnoea. On admission, there are signs of shock, a systolic murmur and an elevated jugular venous pressure. The ECG shows sinus tachycardia but no other abnormality. An antero-posterior chest X-ray shows cardiomegaly. The serum troponin I level is 0.5 mg/L [<0.1]. A computed tomography (CT) scan is shown below.



What is the most likely diagnosis?
A. Pulmonary embolism.
B. Right ventricular infarction.
C. Pericardial tamponade.
D. Myocarditis.
E. Acute mitral regurgitation.

Answer: C

The key here is that all the above if presenting as an emergency cannot be differentiated by the any of the presenting signs listed

A. Pulmonary embolism


SYMPTOMS / SIGNS — Specific symptoms and signs are not helpful diagnostically because their frequency is similar among patients with and without PE. In a large prospective study, the following frequencies of symptoms and signs were noted among patients without preexisting cardiopulmonary disease
Symptoms and signs of acute pulmonary embolism





73 percent

Pleuritic chest pain

66 percent


37 percent


13 percent



70 percent


51 percent


30 percent

Fourth heart sound

24 percent

Accentuated pulmonic component of second heart sound

23 percent

Circulatory collapse

8 percent

Data from Stein, PD, et al. Chest 1991; 100:598.
Data from Stein, PD, et al. Am J Cardiol 1991; 68:1723.


Troponin — Serum troponin I and troponin T are elevated in 30 to 50 percent of patients with a moderate to large pulmonary embolism]. The presumed mechanism is acute right heart overload]. The troponin elevations usually resolve within 40 hours with pulmonary embolism in contrast to the more prolonged elevation with acute myocardial injury].

Chest radiography — Radiographic abnormalities are common in patients with PE; however, they are not helpful diagnostically because they are similarly common in patients without PE

This site http://www.msit.com/phys_art03.html provides some CT images of PE

B. Right Ventricular Infarction


  • The classic clinical triad of right ventricular infarction includes distended neck veins, clear lung fields, and hypotension
  • Infrequent clinical manifestations include right ventricular third and fourth heart sounds, which are typically audible at the left lower sternal border and increase with inspiration.
  • On hemodynamic monitoring, disproportionate elevation of right-sided filling pressures compared with left-sided hemodynamics represents the hallmark of right ventricular infarction.

Differences between left and right ventricular myocardial infarction


Left Ventricular MI

Right Ventricular MI


Pulmonary congestion
Third and fourth heart sounds
New mitral regurgitation

Clear lung fields
Right-sided third heart sound
New tricuspid regurgitation
Hypotension with distended neck veins


ST elevation in standard leads

ST elevation in V4R
Commonly associated with inferior MI
Frequent atrioventricular block

Heamodynamic findings

Increased pulmonary capillary wedge pressure PCWP

Right atrial pressure (RAP) >10mmHg
RAP: PCWP >0.8

Specific Managmenet

Fluid restriction
Preload and afterload reduction
Reperfusion therapy
Ionotropic agents if necessary

Fluid resuscitation
Avoid Preload reduction
Reperfusion therapy
Ionotropic agents if necessary


Imaging  = TTE  is the most appropriate

  • In the appropriate clinical setting, a diagnosis of right ventricular infarction can be made using noninvasive techniques, or the patient may require right ventricular catheterization and hemodynamic monitoring.
  • Echocardiography is useful as a modality to rule out pericardial disease and tamponade, which are the major differential diagnoses in the setting of a right ventricular infarction.
  • Gated equilibrium radionuclide angiography and technetium 99m pyrophosphate scintigraphy are useful in diagnosing right ventricular infarction noninvasively (Sugimoto et al, 1996). In the case of radionuclide angiography, the right ventricle is demonstrated to be enlarged and poorly contractile, with a reduced ejection fraction. When technetium 99m pyrophosphate is employed, the right ventricular free wall is "hot," indicating significant infarction
C. Pericardial tamponade.

Cardiac tamponade is a clinical syndrome caused by the accumulation of fluid in the pericardial space, resulting in reduced ventricular filling and subsequent hemodynamic compromise. Cardiac tamponade is a medical emergency. The overall risk of death depends on the speed of diagnosis, the treatment provided, and the underlying cause of the tamponade.

Symptoms vary with the underlying cause and the acuteness of the tamponade. Patients with acute tamponade may present with dyspnea, tachycardia, and tachypnea. Cold and clammy extremities from hypoperfusion are also observed in some patients.


Distended neck veins are a common feature in patients with tamponade. Evidence of chest wall injury may be present in trauma patients. Tachycardia, tachypnea, and hepatomegaly are observed in more than 50% of patients with cardiac tamponade, and diminished heart sounds and a pericardial friction rub are present in approximately one third of patients.
The Beck triad or acute compression triad

  • Described in 1935, this complex of physical findings refers to increased jugular venous pressure, hypotension, and diminished heart sounds.
  • These findings result from a rapid accumulation of pericardial fluid. However, this classic triad is usually observed in patients with acute cardiac tamponade.

Pulsus paradoxus or paradoxical pulse:

  • This is an exaggeration (>12 mm Hg or 9%) of the normal inspiratory decrease in systemic blood pressure.
  • To measure the pulsus paradoxus, patients are often placed in a semirecumbent position; respirations should be normal. The blood pressure cuff is inflated to at least 20 mm Hg above the systolic pressure and slowly deflated until the first Korotkoff sounds are heard only during expiration. At this pressure reading, if the cuff is not further deflated and a pulsus paradoxus is present, the first Korotkoff sound is not audible during inspiration. As the cuff is further deflated, the point at which the first Korotkoff sound is audible during both inspiration and expiration is recorded. If the difference between the first and second measurement is greater than 12 mm Hg, an abnormal pulsus paradoxus is present.
  • The paradox is that while listening to the heart sounds during inspiration, the pulse weakens or may not be palpated with certain heartbeats, while S1 is heard with all heartbeats.
  • A pulsus paradoxus can be observed in patients with other conditions, such as constrictive pericarditis, severe obstructive pulmonary disease, restrictive cardiomyopathy, pulmonary embolism, rapid and labored breathing, and right ventricular infarction with shock.
  • A pulsus paradoxus may be absent in patients with markedly elevated LV diastolic pressures, atrial septal defect, pulmonary hypertension, and aortic regurgitation.

Kussmaul sign

  • This was described by Adolph Kussmaul as a paradoxical increase in venous distention and pressure during inspiration.
  • This sign is usually observed in patients with constrictive pericarditis but occasionally is observed in patients with effusive-constrictive pericarditis and cardiac tamponade.

Ewart sign

  • Also known as the Pins sign, this is observed in patients with large pericardial effusions.
  • It is described as an area of dullness, with bronchial breath sounds and bronchophony below the angle of the left scapula.

The y descent

  • The y descent is abolished in the jugular venous or right atrial waveform.
  • This is due to an increase in intrapericardial pressure, preventing diastolic filling of the ventricles.


With a 12-lead electrocardiogram the following findings are suggestive but not diagnostic of pericardial tamponade.

    • Sinus tachycardia
    • Low-voltage QRS complexes
    • Electrical alternans (also observed during supraventricular and ventricular tachycardia): Alternation of QRS complexes, usually in a 2:1 ratio, on electrocardiogram findings is called electrical alternans. This is due to movement of the heart in the pericardial space. Electrical alternans is also observed in patients with myocardial ischemia, acute pulmonary embolism, and tachyarrhythmias.
  • PR segment depression


Chest radiography findings may show cardiomegaly, water bottle–shaped heart, pericardial calcifications, or evidence of chest wall trauma

D. Myocarditis.

Physical: Physical findings can range from nearly normal examination findings to signs of fulminant CHF.

  • Patients with mild cases of myocarditis have a nontoxic appearance and simply may appear to have a viral syndrome.
  • Tachypnea and tachycardia are common. Tachycardia is often out of proportion to fever.
  • More acutely ill patients have signs of circulatory impairment due to left ventricular failure.
  • A widely inflamed heart shows the classic signs of ventricular dysfunction including the following:
    • Jugular venous distention
    • Bibasilar crackles
    • Ascites
    • Peripheral edema
  • S3 or a summation gallop may be noted with significant biventricular involvement.
  • Intensity of S1 may be diminished.
  • Cyanosis may occur.
  • Hypotension caused by left ventricular dysfunction is uncommon in the acute setting and indicates a poor prognosis when present.
  • Murmurs of mitral or tricuspid regurgitation may be present due to ventricular dilation.
  • In cases where a dilated cardiomyopathy has developed, signs of peripheral or pulmonary thromboembolism may be found.
  • Diffuse inflammation may develop leading to pericardial effusion, without tamponade, and pericardial and pleural friction rub as the inflammatory process involves surrounding structures.


E. Acute mitral regurgitation.

ETIOLOGY — Although there are many causes of acute mitral regurgitation (MR), many of which can, under other circumstances, also cause chronic MR, there are only three basic mechanisms of acute native valve acute MR

  • Flail leaflet due to myxomatous disease (mitral valve prolapsed), infective endocarditis, or trauma
  • Chordae tendineae rupture due to trauma, spontaneous rupture, infective endocarditis, or acute rhematic fever
  • Papillary mucle dysfunction or rupture due to acute myocardial infarction or severe ischaemia or trauma

Different mechanisms are responsible for acute MR in prosthetic valves:

  1. Tissue valve leaflet rupture due to degeneration, calcification, or endocarditis.
  2. Impaired closure of mechanical valve occluders due to valve thrombosis, infection, or pannus formation. With older generation mechanical valves, there were instances of strut fracture and disk escape, but these have not been reported with currently implanted valves.
  3. Paravalvular regurgitation due to infection or suture rupture (often related to a calcified or scarred annulus).

Acute mitral regurgitation typically presents as a cardiac emergency with the sudden onset and rapid progression of pulmonary edema, hypotension, and signs and symptoms of cardiogenic shock. In some cases, the pulmonary hypertension leads to acute right-sided heart failure.
The presentation may not be as dramatic if acute MR is superimposed upon chronic MR or the patient is younger and physically fit. Such patients may present subacutely in the office or clinic, rather than in the Emergency Department. However, they may note a sudden and marked increase in symptoms of heart failure and a low output state, with increasing shortness of breath, dyspnea on exertion, fatigue, and weakness.

Physical examination — The patient with acute MR is often in pulmonary edema and there is evidence of poor tissue perfusion with peripheral vasoconstriction, pallor, and diaphoresis. The arterial pulse is often rapid and of low amplitude or thready due to the reduction in forward output. When there is an associated increase in right-sided pressure, the neck veins become distended; they may also become pulsatile with a marked "v" wave if the elevated right ventricular pressure leads to tricuspid regurgitation.
The chest radiograph usually shows a normal size cardiac silhouette, with severe left-sided congestive heart failure and pulmonary edema. An enlarged left ventricle and atrium may be present if chronic MR has been present prior to the acute event.

There are generally no electrocardiographic abnormalities specifically associated with acute MR. There may, however, be changes that reflect the etiology, such as an acute myocardial infarction, left ventricular hypertrophy, or P-mitrale reflecting underlying chronic MR.

Summary of presentation signs and symptoms related to options


Pulmonary embolism

Right ventricular infarction

Pericardial tamponade


Acute mitral regurgitation

Progressive dyspnoea












Systolic murmur






Elevated jugular enous pressure






ECG sinus tachycardia only


Should be ST elevation




CXR cardiomegaly

Preexisiting poss





Increased trop I 0.5


 Yes Inferior MI as mechanism



Ischaemia may be mechanism

CT – bilateral pleural effusion pericardial effusion

CT has a role
No – thrombus identified


Usually echo but CT does have a role

? usually echo

? usually echo


Cardiology: Pericardial Disease

Question 2 top

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Question 6 top Download PDF

Question 6

Which one of the following events is least likely to occur in a person with diet-controlled type 2 (non-insulin-dependent) diabetes mellitus who is commenced on a thiazolidinedione (eg pioglitazone) as a sole agent?

A. Increased body fat

B. Lowering of glycosylated haemoglobin (HbA1c).

C. Hypoglycaemia

D. Increased high-density lipoprotein (HDL) concentration.

E. Peripheral oedema



  • A selective and potent agonist at the peroxisomal proliferator activated gamma nuclear receptor
  • Improves glycaemic control by improving insulin sensitivity at key sites of insulin resistance, namely adipose tissue, skeletal muscle and liver
  • Requires insulin to be present for their action
  • An effect to lower glucose production by the liver also has been reported
  • Increase glucose transport into muscle and adipose tissue by enhancing the synthesis and translocation of specific forms of the glucose transporter proteins
  • Can activate genes that regulate free fatty-acid metabolism in peripheral tissue
  • Adverse reactions: peripheral, pulmonary, macular oedema; hepatobiliary effects; hypercholesterolaemia; heart failure; cardiac ischaemia; CV events; anaemia; decreased haeatocrit; WBC; weight gain; hypoglycaemia


Pharmacology: Endocrinology

Question 7 top Download PDF

Which one of the following is the most common complication of endoscopic biliary sphincterotomy?
A. Haemorrhage.
B. Pancreatitis.
C. Cholangitis.
D. Perforation.
E. Diarrhoea.


Endoscopic retrograde cholangiopancreatography (ERCP
Endoscopic biliary sphincterotomy

  • Removal of bile-duct stones
  • Facilitate placement of stents, through malignant and benign biliary strictures
  • Surgical exploration of common bile duct during cholecystectomy


ERCP – 1 in 20 complication of pancreatitis
Sphincterotomy – 1 in 100 bleeding
Perforation rare complication




Question 8 top Download PDF

Which  one of the following clinical features best differentiates inclusion body myositis from polymyositis?
A.  Quadriceps wasting
B. Deltoid wasting
C. Weakness of long finger flexors
D. Bilateral ptosis
E. Truncal Weakness

Both inclusion body myositis and polymyositis share the features

  • proximal lower extremity weakness is usually the first sign with subsequent involvement of upper extremity and distal muscle groups.
  • Proximal muscle weakness is typically more pronounced although distal weakness is predominant in some patients.
  • The facial muscles may be involved,
  • oculomotor muscles are spared.

It just seems a random fact that weakness of long finger flexors is more suggestive of IBM – however there are some more diffinitive differentiators between the two that would make a better question

Answer C

Inflammatory myopathy
Polymyositis and dermatomyositis
Dalakas MC, Hohlfeld R
The Lancet - Vol. 362, Issue 9388, 20 September 2003, Pages 971-982
The inflammatory myopathies are a heterogenous group of subacute, chornic or actue acquired disease of skeletal muscle.  They have in common the presence of moderate to severe muscle weakness and inflammation in the muscle

Clinical presentation
Onset is acute or subacute over a period of several weeks and may follow systemic infection.  Systemic symptoms prevail at onset eg lassitude and are the followed by muscle weakness.  Extensive oedema of skin and subcutaneous tissues is common (especially in the periorbital region)


  • Muscles may be painful and tender in 60% of cases though onset is often painless
  • Proximal muscles are first involved and initially weakness may be asymmetrical eg one quad only
  • Weakness of posterior neck muscles will result in the head ‘lolling’ forwards
  • Occasionally weakness may spread into distal limb muscle groups
  • Pharyngeal and laryngeal involvement results in dysphagia nad dysphonia
  • Cardiac muscles may also be involved
  • Respiratory muscle weakness causes respiratory failure ( this may be disproportionately severe)
  • The eye muscles are not involved unless there is coexistent myasthenia gravies
  • Reflexes are retained (if absent, consider underlying carcinoma and added neuropathy)
  • Immunopathology: in polymyositis and inclusion-body myositis, CD8 positive cells invade MCH-1 antigen expressing muscle fibres


  • Often more severe and acute
  • Characterisd by skin rash.  Violet discoloration of light exposed skin including heliotropic discolouration of eyelids; raised scaly erythematosus rash involving nose and cheeks, shoulders, extensor surfaces of limbs and knuckles
  • Telangiectasia and tightening of skin are common and small ulcerated vasculiti lsions develop over bony prominences
  • Childhood form – multisystem involvement.  Calcification develops in skin and muscle with extrusion through skin.  Muscle contractures develop – tip-toe gait.  Gastrointestinal ulceration occurs
  • Immunopathology: the primary antigenic target in dermatomyositis is the endoethlium of the endomysial capillaries.  The disease begins when putative antibodies adirected agains endothelial cells activate complement C3

Differential diagnosis

  • Inclusion body myositis
  • Acid maltase deficiency (presenting as respiratory failure)
  • Limb girdle dystrophy
  • Drug induced, toxic and metabolic myopathies


  • Ck elevated – indicates disease activity and severity
  • Electromyography – shows typical myopathic pattern
  • Muscle biopsy shows necrosis of muscle fibres  with inflammatory cells – lumphocytes. Plasma cells and leucocytes
  • Antibodies RA and ANA present in 40%
  • ESR elevated in most patients


  • Steroids

Inclusion body myositis
Sporadic inclusion body myositis (IBM) is classified along with polymyositis and dermatomyositis as one of the idiopathic inflammatory myopathies. However, despite some histologic similarities, the clinicopathologic manifestations of IBM are clearly distinct from the other two disorders

  • Presents after age 50yrs. 
  • Patchy and asymmetric in distribution. 
  • Muscle biopsy shows basophilic inclusion granules. 
  • Often clinically confused with polymositis but response to immunotherapy is poor


Physical examination — The physical examination helps to determine the distribution of muscle weakness and atrophy. Findings of quadriceps, and finger flexor weakness and wasting and of foot drop due to tibialis anterior weakness is often noted

Differentiation between inclusion body myositis and polymyositis


Inclusion body myositis




Female > male


Rare before 50

Common before 50



Acute or subacute


Slowly progressive


Distribution of weakness

Variable may be primarily distal,

proximal symmetric


Normal or <10x normal

Often >10x normal


Myopathic or mixed myopathic and neurogenci


Muscle biopsy

Inflammation, rimmed vacuoles Inclusions

inflammation, fiber necrosis

Response to therapy

Generally poor




Question 9 top

Question 10 top Download PDF

A 25-year-old man presents with recent onset of lethargy, fever, bruising and abdominal pain.
On examination, he is clinically anaemic and is noted to have scattered bruises, bilateral pleural effusions, an abdominal mass and cervical and axillary lymphadenopathy.
Full blood examination shows:

haemoglobin                                         76 g/L [128-175]
mean corpuscular volume (MCV)            100 fL [80-97]
white cell count                                                 3.2 x 109/L [3.9-12.7]
neutrophils                                1.6 x 109/L [1.9-8.0]
lymphocytes                             1.1 x 109/L [0.9-3.3]
monocytes                                0.2 x 109/L [0.3-1.1]
eosinophils                               0.2 x 109/L [0-0.5]
basophils                                  0.1 x 109/L [0-0.1]
platelet count                                        32 x 109/L [150-396]
More than 90% of the nucleated cells in the bone marrow aspirate have the appearance shown below (examples indicated by arrows).

Coagulation parameters are normal.
The most likely marrow karyotypic abnormality is:
A. monosomy 7.
B. t (9;22).
C. 5q minus.
D. t (8;14).
E. t (15;17).


  • Pancytopenia (anaemia, neutropenia, thrombocytopenia)
  • Buising
  • Pleural efussions
  • Abdominal masses
  • Cervical and axillary lymphadenopathy

This bone marrow shows cells with  vacuoles where the arrow is pointing.   These cells in the bone marrow and peripheral blood are typical in Burkitts lymphoma.

Burkitts lymphoma | t(8:14) |vacuoles
 Burkitt's lymphoma

  • Aggressive NH lymphoma
  • B-cell lymphoma

Burkitt's lymphoma tumor cells are monomorphic, medium-sized cells with round nuclei, multiple nucleoli, and basophilic cytoplasm

  •  Cytologically, Burkitt's lymphoma (BL) cells resemble the small non-cleaved cells within normal germinal centers of the secondary lymphoid follicle.
  • These cells differ from lymphoblastic lymphoma cells in two respects; they have intermediate sized non-convoluted nuclei with coarse chromatin, and the cells have more abundant cytoplasm.
  • Cytoplasmic lipid vacuoles are usually evident on imprints or smears.


Defining features of Burkitt's lymphoma —

  • c-myc deregulation, as a consequence of which the tumor cells remain constantly in cycle. It is this phenomenon that results in both its morphologic  homogeneity and its clinical behavior.
  •  Unfortunately, detection of c-myc translocation is not practical in all clinical specimens for technical reasons.
  • In addition, some DLBCLs have t(8;14) and c-myc deregulation, and it is not clear if all such cases should be treated like BL.
  • The best practical surrogate for c-myc deregulation is thought to be the proliferation fraction: in a tumor with c-myc deregulation, 100 percent of viable cells should be in cycle, and should express Ki-67.
  • Thus, the WHO committees concluded the following:
    • Diagnosis of BLL should only be made in a tumor with morphologic features intermediate between BL and DLBCL, in which the Ki-67 fraction of viable cells is at least 99 percent. This tumor will be considered a subtype of BL in the WHO classification .
    • Cases with morphologic features of DLBCL with a high proliferation fraction [or t(8;14)], and cases that are morphologically borderline between BL and DLBCL with a lower proliferation fraction, should be classified as DLBCL.

Gene expression profiling may be helpful in enhancing current pathologic methods for distinguishing DLBCL from BL, as well as establishing prognosis, and, ultimately, appropriate treatment


Translocations involving the c-myc oncogene — In 90 percent of the cases studied, BL involves a translocation between the long arm of chromosome 8, the site of the c-myc oncogene (8q24), and one of three locations :

  • The Ig heavy chain region on chromosome 14 : t(8;14)
  • The kappa light chain locus on chromosome 2: t(2;8)
  • The lambda light chain locus on chromosome 22: t(8;22).


CLINICAL FEATURES — Three distinct clinical forms of Burkitt's lymphoma can be recognized: endemic, sporadic, and immunodeficiency-associated . Although they are histologically identical and have similar clinical behavior, there are differences in epidemiology, clinical presentation, and genetic features between the three forms:

  • The endemic (African) form presents as a jaw or facial bone tumor  that spreads to extranodal sites including mesentery, ovary, testis, kidney, breast, and especially to the bone marrow and meninges.
  • The nonendemic or American form has an abdominal presentation, most often with massive disease and ascites, involving distal ileum, stomach , cecum and/or mesentery, kidney, testis, ovary, breast, bone marrow, or central nervous system.
  • Immunodeficiency-related cases more often involve lymph nodes; both these and sporadic cases may present as acute leukemia.

Myeolodysplasia, acute myeloid leukaemia | monosomy 7 |

Aplastic anemia versus hypocellular MDS — Although most patients with MDS have normal or increased bone marrow cellularity, 8 to 28 percent have bone marrow cellularity of less than 25 percent and/or cellularity which is lower than expected based upon the patient's age . The distinction between aplastic anemia and hypocellular MDS is important because the clinical course and management of these two entities may differ.

Presence of a clonal chromosomal abnormality (eg, 5q-, monosomy 7) confirms the diagnosis of MDS . Expression of the tumor necrosis factor (TNF) receptor on bone marrow stem cells by flow cytometry may discriminate AA from MDS . Patients with AA have a markedly greater TNF receptor expression than those with MDS. Patients with hypocellular MDS may have a better prognosis than those with normal/hypercellular marrows .

Chronic myeloid leukaemia | Philadelphia chromosome t(9; 22) |

Chronic myelogenous leukemia (CML, also known as chronic myelocytic or chronic myeloid leukemia) is classified as one of the myeloproliferative disorders, along with polycythemia vera (PV), essential thrombocythemia (ET), and agnogenic myeloid metaplasia (AMM)

Philadelphia chromosome t(9; 22) – present in 90% CML

Myelodysplasia | 5q minus | monolobula megakaryocytes


PRIMARY MYELODYSPLASTIC SYNDROMES — Clonal chromosomal abnormalities can be detected in bone marrow cells in 40 to 70 percent of patients with primary MDS ]. This fraction is somewhat lower than the 70 to 95 percent detected in patients with AML de novo.

There are two features that distinguish the cytogenetic changes in primary MDS from those in AML de novo:

  • Although +8 (trisomy 8), -5/del(5q) [11-14], -7/del(7q) [15], and del(20q) are common in both disorders, the specific structural rearrangements (balanced translocations) that are closely associated with distinct subsets of AML de novo are almost never seen in MDS. Deletions of chromosomes 5 and 7 are particularly characteristic of therapy-related MDS induced by alkylating agents and/or radiation therapy. How these deletions might promote myeloid leukemogenesis is described elsewhere.
  • With occasional exceptions (such as the 5q- syndrome), chromosomal abnormalities in MDS have not correlated with specific clinical or morphological subsets using the FAB or WHO criteria (show table 2).

Cytogenetics as a predictor of prognosis — The ability of cytogenetic analysis to predict the outcome of any individual patient with MDS is made difficult because many patients die from persistent and profound pancytopenia, regardless of whether or not transformation to acute leukemia occurs. Despite this limitation, there are data demonstrating the prognostic significance of particular cytogenetic abnormalities for predicting survival as well as progression to AML, which occurs in 22 to 35 percent of patients overall .

  • Patients with a normal karyotype have a low likelihood of progression to AML.
  •  Among patients with an abnormal karyotype, the outcome is
    •  more favorable for those with del(5q) or del(20q) as single defects
    • intermediate with most other single abnormalities, and
    • poor with complex karyotypes (most also have abnormalities of chromosome 5 or 7, or both)
    • The outcome is also poor in patients with a single defect involving chromosome 7, particularly band 7q32

Acute promyelocitic leukaemia | t(15;17) | auer rods

Peripheral smear from a patient with acute myeloid leukemia. There are two myeloblasts, which are large cells with high nuclear-to-cytoplasmic ratio and nucleoli. Each myeloblast has a pink/red rod-like structure (Auer rod) in the cytoplasm (arrows)

Auer rods within leukemic blasts are rare but their presence serves to identify the FAB category of RAEB-T. However, with the WHO recommendation that the blast count for the diagnosis of acute myeloid leukemia (AML) should be dropped from 30 to 20 percent, it was the consensus that the RAEB-T category within MDS should be dropped . Thus, the presence of Auer rods in a patient with a prior diagnosis of MDS should lead to the suspicion that the patient has already transformed into AML.


15;17 translocation in APL — Acute promyelocytic leukemia (AML-M3) is typically characterized by a structural rearrangement involving the long arms of chromosomes 15 and 17; the rearrangement is defined as t(15;17)(q22;q11-12) . This rearrangement is highly specific for acute promyelocytic leukemia (APL) and has not been found in patients with any other type of leukemia or with a solid tumor.

APL is a unique clinicopathological entity characterized by infiltration of the bone marrow by promyelocytes in association with clinical or laboratory evidence of disseminated intravascular coagulation, which may worsen during the initial cytolytic response to chemotherapy. A characteristic folded, reniform (kidney-shaped), or bilobed nucleus is invariably found in some of the promyelocytes; coarse azurophilic granules and multiple Auer rods are also common .  The microgranular variant of APL differs from the more frequent hypergranular type in that the cytoplasmic granules in the leukemia cells are smaller and sometimes beneath the limit of resolution of the light microscope

The leukemic cells in patients with APL and the t(15;17) are exquisitely sensitive to the differentiating effect of ATRA. The optimal use of ATRA therapy has not yet been determined, but it has become a mandatory component of treatment. The PML/RAR-alpha gene can now be routinely identified within 24 hours by PCR methods, allowing confirmation of the diagnosis of APL and appropriate remission induction therapy (ATRA and anthracycline). Having achieved a remission, many patients remain disease-free after intensive consolidation chemotherapy using an anthracycline (daunorubicin or idarubicin). Cases of APL that lack the t(15;17) do not respond to ATRA; the PLZF/RAR-alpha fusion protein that is produced in the t(11;17) rearrangement in rare cases shows reduced sensitivity to retinoic acid that cannot be overcome by pharmacologic doses of ATRA alone.


Haematology:Lymphomas-Hodgkin's disease and the non Hodgkin lymphomas


Question 11 top

Question 12 top Download PDF

Which one of the following drugs is least effective in the treatment of Legionnaire’s disease?
A. Rifampicin.
B. Gentamicin.
C. Erythromycin.
D. Ciprofloxacin.
E. Azithromycin.

Reference: Infectious Diseases A clinical Approach Yung, McDonald, Spelman, Street and Johnson 2001
Therapeutic Guidelines Antiobiotics 2006

Pg 94 Erythromycin is the traditional treatment of choice – high dose (1g every six hours) intravenously initially, and combined with rifampicin for severe cases.
Quinolones (eg ciprofloxacin) or the newer macrolides (eg azithromycin) have excellent in vitro activity and are becoming more widely used

Pneumonia due to Legionella species may present with a variety of nonpulmonary symptoms such as mental confusion, diarrhoea and hyponatraemia, as well as severe respiratory distress. Diagnosis can be made by sputum or bronchoalveolar lavage (BAL) culture, serology, urinary antigen detection or polymerase chain reaction (PCR) of respiratory specimens. The new Legionella urinary antigen assay has aided early diagnosis in some cases since it can be performed easily on routine urine specimens (either before or after commencing antibiotics) and appears to have acceptable sensitivity. However, this assay detects only Legionella pneumophila type 1 (the commonest cause of Legionella pneumonia), not other Legionella species.
For patients with Legionella pneumonia, use:


azithromycin 500 mg IV or orally, daily





doxycycline 100 mg IV or orally, 12-hourly





erythromycin 500 mg to 1 g IV (preferably through a central line), 6-hourly
or erythromycin 500 mg orally, 6-hourly
or erythromycin (ethyl succinate formulation) 800 mg orally, 6-hourly

PLUS for very severe cases requiring ICU care, consider adding



ciprofloxacin 400 mg IV, 12-hourly
or ciprofloxacin 750 mg orally, 12-hourly





rifampicin 600 mg IV or orally, daily.

Total (IV + oral) treatment duration for Legionella pneumonia is 7 to 14 days  for immunocompetent patients, but 14 to 21 days for the immunocompromised.

Answer: B. Gentamicin.


Infectious Diseases: occupational and geographical settings

Question 13 top

Question 14 top Download PDF

A 45-year-old woman has intermittent right upper quadrant pain. This pain is associated with ingestion of certain foods and periods of dehydration.
Her serum biochemistry results are:
creatinine 0.08 mmol/L [0.06-0.11]
urea 4.0 mmol/L [4.0-8.0]
electrolytes normal
Her blood pressure is 130/85 mmHg.
Investigations have included an abdominal computed tomography (CT) scan, one view of which is shown below.

Which one of the following is the most useful next investigation?
A. Repeat CT scan in six months.
B. Aspiration.
C. Urinary cytology.
D. Renal biopsy.
E. Labelled red blood cell scan.

The clinical picture sounds like gall stones and

There are some good examples of normal CT Abdo’s


A. Repeat CT scan in six months. – by default the only appropriate thing to do
Voted the silliest question seen so far by 4 consultants (including a radiologist) and one registrar

I think however this is gall stone disease with fairly classical symptoms here is uptodate’s recommendations


SUMMARY AND RECOMMENDATIONS — When considering gallstone disease it is helpful to categorize patients into the following clinical categories.

Gallstones but without symptoms — These patients are unlikely to develop symptoms and when they do occur they are generally mild. Thus, patients should be educated about symptoms potentially related to gallstones (principally biliary colic) without recommending specific therapy to address the gallstones.

Typical biliary symptoms and gallstones — Such patients should generally undergo treatment (generally cholecystectomy) since they are likely to develop recurrent symptoms, which can be severe. The National Cooperative Gallstone Study (one of the most definitive studies on the subject) showed that the risk of further symptoms and complications in such patients was approximately 70 percent within two years after initial presentation .

Atypical symptoms and gallstones — Such patients should undergo a search for non-gallstone-related causes of symptoms. If investigation is unrevealing, treatment of gallstones can be considered with the understanding that the rate of persistent symptoms is high.

Typical biliary symptoms but without gallstones — Clinical suspicion for gallstone disease should be maintained in such patients. A repeat extracorporeal ultrasound should be obtained. If results are unrevealing, EUS and collection of duodenal bile for microscopy should be considered. If results continue to be unrevealing, a search for other causes of biliary pain is reasonable.


B. Aspiration.
There is nothing to aspirate - ?bowel
C. Urinary cytology.
Looking for bladder ca / urinary tract malignancy
History should include, urinary symptoms, dysuria, haematuria
D. Renal biopsy.
Indications for renal biopsy

  • Acute renal impairment – pre and post renal causes exclude
  • Isolated glomerular haematuria
  • Nephritic, nephritic syndrome with exclusion of systemic causes

History should include haematuria / oligouria and abnormal renal function
E. Labelled red blood cell scan.

  • Looking for source of bleeding / no history



Gastroenterology:hepatobiliary imaging

Question 15 top Download PDF

A 19-year-old man, who is sexually active and admits to occasional recreational drug use, presents with a three-day history of severe pain over the left sacroiliac area. Examination reveals a temperature of 38°C, pulse rate of 80/minute and blood pressure of 120/80 mmHg. The only other findings are ridged nails and pain on movement of the spine or when pressure is applied to the sacroiliac joints.
Investigations show:
white cell count 12.5 x 109/L [3.5-11.0]
haemoglobin normal
platelet count normal
erythrocyte sedimentation rate (ESR) 50 mm/h [<10]
C-reactive protein 170 mg/L [<10]
X-rays of the spine and pelvis are normal. The bone scan is shown below.

The most likely diagnosis is:
A. reactive arthritis following Chlamydia trachomatis infection.
B. psoriatic arthritis.
C. gonococcal arthritis.
D. septic sacroiliitis.
E. undifferentiated spondylarthropathy.

Although it initially seemed quite complex I think in generally this is quite a simple question related to acute versus chronic disease.  Clearly from history and path results this man has an acute illness ie 3/7 history with raised inflammatory markers.  The other important issues is the radiological evidence with the spondoarthritidies – generally there are no changes on xray early in the disease and to achieve an early diagnosis MRI is the modality of choice.

So going through the options

A. reactive arthritis following Chlamydia trachomatis infection.
Reactive arthritis – acute non purulent arthritis complecating an infection elsewhere in the body
Associated with B27 antigen

The triad of arthritis, urethritis, and conjunctivitis represents one part of the spectrum of theclinical managestations of reactive arthritis, particularly that induced by Shigella or Chlarmydia


  • Western population ReA occures predominantly in individuals who have inherited the B27 gene;
    • particularly associated with Shigella, Yersinia, or Chlamhydia (60-85%)
    • less than 50% Salmonella and lower for Campylobacter
    • with HIV, predominantly B27 positive arthriis flares as AIDS advances
  • sex ration 1:1
  • sub-Saharan Africa ReA and other peripheral spondyloarthritidies  have now become the most common rheumatic diseases in Africans in the wake of the AIDS epidemic with no B27 assoication


  • four Shigella species S. sonnei, S. boydii, S. flexneri, and S. dysenteriae (S. flexneri most often)
  • Salmonella sppc, Y. enterocolitica, C. jejunim, and C trachomatis

Clinical features

  • Spectrum ranging isolated, transient monarthritis to severe multisystem disease
  • Usually antecedent infection 1-4 / 52 before onset of symptoms of reactive disease
  • Recent new sexual partner
  • Cositiutional symptoms common, fatigue, malaise, fever and weight loss
  • Musculoskeletal symptoms are usually acute in onset
  • Arthritis is usually asymmetric and addivitive, with involvement of new joints occurring over a period of a few days to 1-2 weeks
  • Joints of the lower extremities, epsecially the knee, ankly, and subtala, metatrsophlangeal and toe interphalangeal joints re the most common sites of involvement
  • Arthritis usally quite paiful and tense joint effusions are not uncommon esp n knee
  • Tendinitis and fasciitis are particularly characteristic lesions, producing pain at multiple insertion sites (entheses) especially the Achilles insertion, the plantar fascia and sites along the axial skeleton
  • Soubak abd kiw-back pain are quite common and may be caused by insertional inflammation, muscle spasm, acute sacroiliitis or presumable arthritis in intervertebral articulations
  • Urogential lesions may occur throughout the courese of the disease
  • In males urthrtis may be marked or realtively asymptomatic, prostatitis also common
  • Ocular disease is common
  • Mucocutanious lesions are frequent

Lab and radiographic findings

  • ESR usually elevated during acute phase of disease
  • Mild anaemia may be present
  • Acute phase reactants tend to be increased
  • Most ethnic groups 50-85% B27 positive
  • In early or mild disease radiographic changes may be absent or confined may be absent or confiend to juxtaarticular osteoporosis.  With long- standing persistent disease, marginal erosions and loss of joint space can be seen in affected joints.  Periostitis with reactive new bone formation is characteristic of the disease, as it is with all the spondyloarthritiides.  Spurs at the insertion of the plantar fascia are common

Diagnosis  - clinical diagnosis

Treatment - NSAIDS

B. psoriatic arthritis.
Psoriatic arthritis refers to an inflammatory arthritis that characteristically occurs in individuals with psoriasis

Epidemiology – 5-10% in patients with psoriasis
Pathogenesis – immune mediated

Clinical Featues

  • 60 – 70% of cases psoriasis precedes joint disease
  • 15-20% of cases, the arthritis precedes the onset of psoriasis and can present a diagnostic challenge
  • fequency in men and woman equal
  • Wright and Moll classification psoriatic arthritis ( noted in 8 Ann Rheum Dis 2005;64;3-8  P S Helliwell and W J Taylor arthritis Classification and diagnostic criteria for psoriatic)
  • arthritis of the DIP joints
  • asymmetric oligoarthritis
  • symmetric polyarthritis similar to RA
  • axial involvement (spine and sacroiliac joints)
  • arthritis mutilans, a highly destrcutvie form of the disase
  • Nail changes in the fingers or toes occur in 90% of patients with PsA, compare with 40% of psoriatic patients without arthritis
  • Usually gradual in onset

Lab and radiographic

  • No specific lab tests ESR and CRP oftern but not always elevated
  • Small % low titires of rheumatoid factor of ANCA antibodies
  • Uric acid may be elevated in the rpesence of extensive psoriasis
  • HLA – B27 foind in 50-70% with axial disease, but in less than 15-20% in patients witho only periperhal joint involvement
  • Radiographic features
    • DIP involvement including classic pencil in cup deformity
    • Marginal erosions with adjacent bony proliferation
    • Small joint ankylosis
    • Osteolysis of phalangeal and metacarpal bone with telescopin of digits
    • Periostitis and proliferatiove new bone at sites of enthesitis


  • clinical

C. gonococcal arthritis.

  • Associated with urethritis
  • Tend to involve both upper and lower extremities equally, to lack back symptoms and to be associated with characteristic vesicular skin lesions

D. septic sacroiliitis.

acute form of a and c - fits with the presentation

E. undifferentiated spondylarthropathy.

  • HLA-B27


  • Enthesis, the site of ligamentious attachment to bone, is though to be the primary site of pathology in AS, particularly in the lesions around the pelvis and spine
  • Sacroilitis is usally one of the earlies manifestations of AS with features of both entheitis and synovitis


  • Symptoms ofdiease usually first noticed late adolescence or early adulthood
  • Median age western countries 23
  • 5% patients symptoms begin after age 40
  • intiial symptoms is usually dull pain, insidious in onset, felt deep in the lower lumbar or gluteal regoion acompanied by low back morning stiffnes of up to a few hours duration that improves with activity and returns following periods of inactivity
  • bony tenderness
  • common sites include costosternal junctions, spinous processes, ileac rcreasts, greater trochanters, ischial tuberositis ,tibial tubercles and heels
  • Arthritis in hips and shoulders occurs in 25-35% patiens in many cases early in the disease course
  • Arthritis of peripheral joints other than the hips and shoulders, usually asymmetric, ocurs in up to 30% of patients and can occur at any stage of the disease
  • Neck pain and stiffness usally relative late
  • Initially, physical findings mirror thei nflammatory process. The most specific findings involve loss of spial moblity, with limiation of anterior and lateral flexion and extension of thel umbar spine and of chest expansion
  • Pain in the sacroiliac joints may be elicited either with direct pressure or with maneuvers that stress the joints

Radiographic findings

  • Radiographically demonstrable sacroilitis is useally present in AS.  The earlies changes by standard radiography are blurring of the cortical margins or the suchondral bone, followed by erosions and sclerosis
  • Pregression of the erosions leads to “pseudowidening” of the joint space; as fibrous and the nbony ankylosi superven, the joints may become obliterated
  • Plain radiographs may be normal for many years
  • CT and MRI can detect abnormalities early


Infectious Diseases: infective arthritis

Question 16 top Download PDF

A 66-year-old man presents with progressive exertional dyspnoea.

His anthropometric indices are:
height 175 cm
weight 98 kg
body mass index (BMI) 32 kg/m2 [18-25]

His lung function test results are:

forced expiratory volume in one second (FEV1) 1.72 L (56% predicted)
forced vital capacity (FVC) 2.14 L (54% predicted)
FEV1/FVC 80%
total lung capacity (TLC) 4.12 L (64% predicted)
residual volume (RV) 1.98 L (84% predicted)
diffusing capacity for carbon monoxide
corrected for volume (KCO) 4.9 mL/min/mmHg/L (110% predicted)

What is the most likely cause of this man’s dyspnoea and lung function abnormalities?

A. Obesity.
B. Pulmonary fibrosis.
C. Chronic obstructive pulmonary disease.
D. Cardiac failure.
E. Bilateral diaphragm paralysis.

He is obese

Obstructive abnormalities — An obstructive ventilatory defect is a disproportionate reduction of maximal airflow from the lung in relation to the maximal volume (ie, VC) that can be displaced from the lung [45-47]. It implies airway narrowing during exhalation and is defined by a reduced FEV1/VC ratio below the 5th percentile of the predicted value.

Restrictive abnormalities — A restrictive ventilatory defect is characterised by a reduction in TLC below the 5th percentile of the predicted value, and a normal FEV1/VC.
Mixed abnormalities — A mixed ventilatory defect is characterised by the coexistence of obstruction and restriction, and is defined physiologically when both FEV1/VC and TLC are below the 5th percentiles of their relevant predicted values. S

A simplified algorithm that may be used to assess lung function in clinical practice. It presents classic patterns for various pulmonary disorders. As in any such diagram, patients may or may not present with the classic patterns, depending on their illnesses, severity and lung function prior to the disease onset (e.g. did they start with a vital capacity (VC) close to the upper or lower limits of normal (LLN)). The decisions about how far to follow this diagram are clinical, and will vary depending on the questions being asked and the clinical information available at the time of testing. The forced expiratory volume in one second (FEV1)/ VC ratio and VC should be considered first. Total lung capacity (TLC) is necessary to confirm or exclude the presence of a restrictive defect when VC is below the LLN. The algorithm also includes diffusing capacity for carbon monoxide (DL,CO) measurement with the predicted value adjusted for haemoglobin. In the mixed defect group, the DL,CO patterns are the same as those for restriction and obstruction. This flow chart is not suitable for assessing the severity of upper airway obstruction.
PV: pulmonary vascular; CW: chest wall; NM: neuromuscular; ILD: interstitial lung diseases; CB: chronic bronchitis.
Pellegrino, R, Viegi, G, Brusasco, V, et al. Interpretative strategies for lung function tests. ATS/ERS task force: standardisation of lung function testing. Eur Respir J 2005; 26:948.
If you go through the algorithm then the options are Chest wall or neuromuscular disorder
So answer is E bilateral diaphragm paralysis


Respiratory: Essential respiratory investigations


Question 17 top Download PDF

A 28-year-old woman, who emigrated from Cambodia 10 years ago presents to the emergency department with a three-week history of increasing shortness of breath, orthopnoea, nocturnal dyspnoea and ankle oedema.  She is 25 weeks pregnant and has no significant past medical history.

The presence of pulmonary oedema is confirmed clinically and radiologically.  She responds well to intravenous frusemide but remains tachypnoeic with a heat rate of 120/minute in sinus rhythm.  Her blood pressure is 125/85 mmHg.

Echocardiography demonstrates mitral stenosis with an estimated valve area of 1.3 cm2 and a left atrial diameter of 50 mm [less than 40].  There are no other abnormalities.

What is the most appropriate next step in management?

  • Balloon valvotomy
  • Surgical valvotomy
  • Digoxin therapy
  • Beta-blocker therapy
  • Angiotensin converting enzyme (ACE) inhibitor therapy.


Answer D

Key points

  • She does not have valve area less than 1.0 although it’s difficult to guage from history what NYHA CHF class she fits but probably not IV
  • She has already commenced diuretic therapy so the next medical therapy is control heart rate
  • There is no mention of AF

From : New England Journal of Medicine Volume 349:Numbe 1 July 3, 2003: 52-59
Valvular Heart Disease in Pregnancy  Sharon C. Reimold, M.D., and John D. Rutherford, M.B., Ch.B.

Valvular heart disease in young women is most commonly due to rheumatic heart disease, congenital abnormalities, or previous endocarditis and may increase the maternal and fetal risks associated with pregnancy. The likelihood of an adverse outcome is related to the type and severity of maternal valvular disease and the resulting abnormalities of functional capacity, left ventricular function, and pulmonary pressure. Clinical recommendations concerning valvular heart disease and pregnancy are based on limited data from case reports and observational studies or on inferences from data for other groups of patients.

Cardiovascular Physiology of Pregnancy

Normal pregnancy is assoicated with an increase of 30 to 50 percent in blood volume and a corresponding increase in cardiac output. These increases begin during the first trimester; the levels peak by 20 to 24 weeks of pregnancy and then are either sustained until term or decrease.
Concurrently, the heart rate increases by 10 to 20 beats per minute, the stroke volume increases, and there is a substantial reduction in systemic vascular resistance, with decreases in blood pressure. During labor, cardiac output increases; the blood pressure increases with uterine contractions. Immediately after delivery, the cardiac filling pressure may increase dramatically due to the decompression of the vena cava and the return of uterine blood into the systemic circulation. The cardiovascular adaptations associated with pregnancy regress by approximately six weeks after delivery.

Murmurs develop in nearly all women during pregnancy. These murmurs are usually soft, midsystolic, and heard along the left sternal border. Their intensity may increase during pregnancy as cardiac output increases. Cervical venous hums and a continuous murmur due to increased mammary blood flow may also be heard. Echocardiography is warranted when diastolic murmurs, continuous murmurs, or loud systolic murmurs (louder than grade 2 on the 6-point scale) are detected or when murmurs are associated with symptoms or an abnormal electrocardiogram. In normal pregnant women, serial echocardiography usually demonstrates minor increases in the left and right ventricular diastolic dimensions, which remain within the normal range, with a slight decrease in the left ventricular end-systolic dimension and a minimal increase in the size of the left atrium. The state of increased volume also results in increased transvalvular flow velocities. Minor degrees of atrioventricular valve regurgitation are normal.

Mitral Stenosis

Rheumatic mitral stenosis is the most common clinically significant valvular abnormality in pregnant women and may be associated with pulmonary congestion, edema, and atrial arrhythmias during pregnancy or soon after delivery. The increased volume load and increased cardiac output associated with pregnancy lead to an increase in left atrial volume and pressure, elevated pulmonary venous filling pressures, dyspnea, and decreased exercise tolerance. Increases in the maternal heart rate decrease the diastolic filling period, further increasing left atrial pressure. Mortality among pregnant women with minimal symptoms is less than 1 percent. In a study of women with mitral stenosis, predictors of adverse maternal outcomes included a reduced mitral-valve area (less than 1.5 cm2) and an abnormal functional class before pregnancy.  Fetal mortality increases with deteriorating maternal functional capacity; fetal mortality is 30 percent when there is NYHA class IV disease in the mother

For women with mild or moderate symptoms during pregnancy, medical therapy is directed at the treatment of volume overload and includes diuretic therapy, the avoidance of excessive salt, and the reduction of physical activity. Beta-blockers attenuate the increases in heart rate and prolong the diastolic filling period, which provides symptomatic benefit. Development of atrial fibrillation requires prompt treatment, including cardioversion. Beta-blockers and digoxin are used for rate control.

If suppressive antiarrhythmic therapy is needed, procainamide and quinidine are the drugs with which we have the most extensive experience. Because of the increased risk of systemic embolism in patients with mitral stenosis and atrial fibrillation, anticoagulant therapy is indicated.

Patients with severe symptoms (NYHA class III or IV) or tight mitral stenosis (a valve area of less than 1.0 cm2) who undergo balloon mitral valvuloplasty or valve surgery before conceiving appear to tolerate pregnancy with fewer complications than similar women who are treated medically.

In patients who present with severe symptoms during pregnancy, successful percutaneous balloon mitral valvuloplasty, performed during the second trimester, has been associated with normal subsequent deliveries and excellent fetal outcomes. Risks to the fetus associated with exposure to radiation may be reduced by avoiding exposure to radiation during the first half of pregnancy.      

Pregnant women who are to be exposed to radiation should have the uterus shielded and should be informed about the possible risks. Mitral valvuloplasty has also been performed under transesophageal echocardiographic guidance, eliminating these risks.

Open cardiac surgery has been performed during pregnancy for severe mitral stenosis. Maternal outcomes are approximately the same as those among nonpregnant patients, but there is fetal loss in 10 to 30 percent of cases.

Vaginal delivery is the usual approach, with the use of epidural anesthesia to achieve effective pain control and with the use of assisted-delivery devices during the second stage of delivery (eliminating the need for pushing). Cesarean section should be performed when there are obstetrical indications for it. Labor is associated with an increase of 8 to 10 mm Hg in the left atrial and pulmonary wedge pressures. Pulmonary arterial catheters have been used successfully before and during delivery to facilitate the management of hemodynamics in women with advanced disease.


Cardiology Cardiac changes and problems in pregnancy

Question 18 top

Question 19 top

Question 20 top Download PDF

A 68-year-old woman with stage III ovarian cancer presents with a progressive cerbellar syndrome.  Cranial magnetic resonance imagine (MRI) demonstrates mild cerebellar atrophy and cerbrospinal fluid (CSF) examination reveals 10 lymphocytes/high power field, normal protein and glucose concentrations and negative cytology

Which one of the following is the most appropriate next investigation
A.  Anti-Purkinje cell antibodies (anti-Yo)
B. Repeat cerebrospinal fluid studies
C. Electroencephalogram (EEG)
D. Meningeal biopsy
E. Brain positron emisson tomography (PET) scan


What are the investigations looking for?
A.  Anti-Purkinje cell antibodies (anti-Yo)

  • The pesence of anti-Yo antibodies in the serum of a woman with cerbellar symptoms is virtually conclusive evidence that she has aparaneoplastic cerebellar degeneration and gynecologic, usually ovarian ca

B. Repeat cerebrospinal fluid studies

  • Low yield for example in paraneoplastic syndrome CSF reveals a mild pleocytosis (30-40 WC) slightly elevated protein (50-100mg) and elevated !gG

C. Electroencephalogram (EEG)

  • not very useful – looking for epilectic focus

D. Meningeal biopsy

  • suggesting meningeal mets – probably easier to rule out A first and/or add gadolinium to the MRI

E. Brain positron emisson tomography (PET) scan

  • usually used for diagnosis of memory disorders and/or  looking for brain tumour

Answer: A

Although rare – the presentation suggests a classic paraneoplastic syndrome.   The only caveat is that a paraneoplastic syndrome such as a cerebellar syndrome usually presents before diagnosis as above so you wonder whether they are suggesting meningeal mets or other mets, but given there is an MRI already done a blood test seems more appropriate than PET
 Antigens and antibodies provide the key for diagnosis CSF is usually non specific as mentioned

Paraneoplastic syndrome

  • refers to symptoms or signs resulting from damage to organs or tissues that are remote from the site of a malignant neoplasm or its metastases.
  • can affect most organs and tissues.
  • common examples include cancer cachexia; hypercalcemia,; Cushing’s syndrome;  Trousseau’s syndrome.
  • Most  occur because the tumor secretes substances that mimic normal hormones or that interfere with circulating proteins
  • most or all paraneoplastic neurologic disorders are immune-mediated.
  • The cancers causing paraneoplastic neurologic disorders are often asymptomatic and sometimes occult; it is the neurologic symptoms that take the patient to the doctor.
  • The combination of an indolent tumor and severe neurologic disability suggests effective antitumor immunity coupled with autoimmune brain degeneration.

Types of syndromes

Examples of specific antigens

Proposed pathogenesis

Figure 2. Proposed Pathogenesis of Paraneoplastic Neurologic Disorders.
A tumor not involving the nervous system expresses a neuronal protein that the immune system recognizes as nonself. Apoptotic tumor cells are phagocytized by dendritic cells that migrate to lymph nodes, where they activate antigen-specific CD4+, CD8+, and B cells. The B cells mature into plasma cells that produce antibodies against the tumor antigen. The antibodies or the cytotoxic CD8+ T cells (or both) slow the growth of the tumor, but they also react with portions of the nervous system outside the blood–brain barrier. In the illustration, antibodies are reacting with voltage-gated calcium channels at the neuromuscular junction, causing the Lambert–Eaton myasthenic syndrome. In some instances, plasma cells and cytotoxic T cells cross the blood–brain barrier and attack neurons expressing the antigen they share with the tumor.
Basis of treatment  relates to the proposed pathogenesis of  immune-mediation – no established protocol, varying success which is usually based on whether or not neuronal death is a prominent feature of the disease

  • removal of source of antigen by treatment of underlying tumour
  • suppression of immune response
    • plasma exchange
    • intravenous immune globulin
    • corticosteroids
    • cyclophosphamide
    • tacrolimus


Tumor Immunity in Paraneoplastic Syndromes
            The Tumor
Onconeural antigens are present in the tumor in all patients with antibody-positive paraneoplastic neurologic disorders and in many patients without such disorders. Moreover, the genes for these antigens are not mutated in tumor cells. Thus, paraneoplastic neurologic syndromes cannot be attributed to the infrequency of expression of the relevant tumor antigens or to mutations in the genes encoding these antigens.
The tumor is often occult, and the neurologic disorder typically precedes the diagnosis of the tumor. For example, patients with the Hu paraneoplastic syndrome typically harbor small-cell lung cancers that are limited to single nodules (53 of 55 patients in one study), despite the fact that most small-cell lung cancers (over 60 percent) are widely metastatic at diagnosis. In a few instances, unequivocal paraneoplastic syndromes may follow identification and even treatment of the tumor, and may sometimes herald a relapse.
The histologic features of tumors in paraneoplastic neurologic disorders do not differ from those of other tumors, except that the tumors may be heavily infiltrated with inflammatory cellsMany reports suggest that patients with paraneoplastic neurologic disorders have a better prognosis than patients with histologically identical tumors that are not associated with paraneoplastic neurologic disorders. The improved prognosis is not simply a result of earlier diagnosis of the cancer because the neurologic disease has led to a search for cancer. Patients with low titers of anti-Hu antibodies but without paraneoplastic disorders also have more limited small-cell lung cancer than patients who do not have the antibodies.
            The Nervous System
The presence of antigen-specific cytotoxic T cells in paraneoplastic neurologic disorders was clearly documented after a patient with acute paraneoplastic cerebellar degeneration and anti-Yo antibodies was found to have activated T cells in her blood that were able to lyse target cells presenting the Yo (also called cdr2) antigen in vitro. Subsequent studies in chronically ill patients with paraneoplastic cerebellar degeneration have used autologous antigen-presenting cells (dendritic cells) to reactivate responses to the cdr2 antigen in memory cytotoxic T cells. Such reactivated responses have been elicited in all patients with paraneoplastic cerebellar degeneration whose T cells were tested for the phenomenon. These studies have been complemented by reports of a limited V{beta} chain T-cell repertoire in patients with the Hu syndrome (the V{beta} is one of the two chains, V{beta} and V{alpha}, of the T-cell receptor). Taken together, the evidence indicates that T-cell responses have an important role in paraneoplastic neurologic disorders.
Antibodies in paraneoplastic neurologic disorders react with the portion of the nervous system that is responsible for the clinical symptoms — for example, anti–Purkinje-cell antibodies occur in patients with paraneoplastic cerebellar degeneration. In many instances, the reaction is more widespread than the clinical findings. In paraneoplastic neurologic disorders affecting the brain, relatively high titers of the antibody in the cerebrospinal fluid (relative to total IgG) indicate that the antibody is synthesized within the brain, presumably by specific B cells that have crossed the blood–brain barrier.
One report described the presence of anti-Hu antibodies within neuronal nuclei of the central nervous system in patients who died of their paraneoplastic syndromes. Although some believe this finding to be an artifact, antibodies to double-stranded DNA, the hallmark of systemic lupus erythematosus, have been found within the nuclei of cells in patients with systemic lupus erythematosus.
            Antibodies and Cytotoxic T Cells
The relative roles of humorally mediated immunity (antibodies) and cellular immunity (T cells) in paraneoplastic neurologic disorders are unresolved. This uncertainty is complicated by the fact that different paraneoplastic neurologic disorders may have different underlying mechanisms. When the target antigens are cell-surface receptors, as in the Lambert–Eaton myasthenic syndrome, myasthenia gravis, and a rare form of paraneoplastic cerebellar degeneration, antibodies appear to have the predominant role.


Neurology: neoplastic disease

Oncology:paraneoplastic syndromes


Question 21 top Download PDF

A 25-year-old woman complains of tiredness.  She has no significant past medical history and denies any medications.  Apart from being thin, there are no abnormal findins on examination.  Her blood pressure is 105/70 mmHg

Results of investigations are listed below

Serum biochemistry
            Sodium             138mmol/L                    [135-145]
            Potassium        2.3 mmol/L                    [3.4-5.0]
            Chloride            85 mmol/L                     [103 – 109]
            Creatinine          0.10mmol/L                   [0.06-0.12]

Arterial blood gases:
            PH                    7.50                              [7.34-7.45]
            P02                  95mmHg                       [80-100]
            PCO2               42 mmHg                      [35-45]
            Bicarbonate      39mmol/L                      [22-28]

Urinary biochemistry:
            Sodium             30mmol/L
            Potassium        42mmol/L
            Chloride:           13mmol/L
The most likely explanation for these results is:

A. Occult diuretic use

B. Occult laxative use

C. Self-induced vomiting

D. Primary hyperaldosteronism

E. Bartter’s syndrome

Answer C

Hypokalemia with associated

  • Alkalosis
  • Raised bicarbonate

Clinical Spectrum
Normal range 3.4 – 5.0

Mild 3.0 – 3.5 mmol per liter often no symptoms

Less than  3.0 mmol per liter – non specific symptoms such as generalized weakness, lassitude and    constipation
Less than 2.5mmol per liter – muscle necrosis can occur
Less than 2.0 mmol per liter – ascending paralysis can develop with eventual impairment of respiratory function

In patients without underlying heart disease, abnormalities in cardiac conduction are extremely unusual, even when the serum potassium concentration is below 3.0 mmol per liter.  In patients with cardiac ischemia, heart failure, or left ventricular hypertrophy, however , even mild-to-moderate hypokalemia increased the likelihood of cardiac arrhythmias

  • Hypokaleamia increased the arrhythmogenic potential of digoxin
  • Potassium depletion and hypokalemia increase bot hsystolic and diastolic blood pressure when sodium intake is not restructed, presumable by promoting renal sodium retention


Drugs – most common
Acute shift of potassium from extracellular compartment to cells

  • Inadequate intake
  • Abnormal losses
    • Via kidney induced by metabolic alkalosis
    • Loss in stool induced by diarrhea


Drug induced causes due to transcellular shifts

Beta 2 sympathomimetic drugs
  • decongestants, bronchodilators and inhibitors of uterine contraction
  • eg a standard dose of nebulized albuterol reduces serum potassium by 0.2 – 0.4 mmol per liter, and a second dose taken within one hour reduces it by almost 1 mmol per liter
  • intential ingestion of excess amount so psudoephedrine
  • theophy7lline and caffeine stimulate the release of syumpathetic amines  and may also increase sodium/potassium ATPase activity by inhibiting cellular phosphodiesterase
  • severe hypok feature of theophylline toxicity
other drugs
  • ingestion/administration large amounts of verapamil, chloroquine, insulin

Drug induced causes due to abnormal losses of potassium

  • the most common cause of hypokalemia
  • both thiazide and loop diuretics block chloride-associated sodium reabsorption (with each inhibiting a different membrane-transport protein) and , as a result, increase delivery of sodium to the collecting tubules, where its reabsorption creates a favorable electrochemical gradient for potassium secretion
  • degree related to dose of thiazide diuretic and greater when dietary sodium intake is higher
  • usually but not always associated with a mild-to-moderate metabolic alkalosis ( bicarbonate concentration28-36 mmol per liter)
Drugs with mineralocorticoid or glucocorticoid effects
  • fludrocortison (oral mineralocorticoid) promotes renal potassium excretion
  • glucocorticoids (pred hydrocort) no direct effect on renal potassium secretion but the increase potassium excretion nonspecifically through their effect on the filtration rate and distal sodium delivery
other drugs
  • IV penicillin (and derivatives) in large doses promote renal potassium excretion by increasing sodium delivery to the distal nephron
  • Amnoglycoside antibiotics, antitumor drug cisplatin and antiviral drug foscarnet all cause renal potassium wasting by including depletion of magnesium
  • Amphotericin B – inhibition of the secretion of hydrogen ions by collecting-duct cells as well as by causing magnesium depletion
  • Laxatives and enemas – promote excessive loss in stool


Nondrug causes due to transcellular shifts
  • Rarely with hyperthyroidism
  • Ramilial hypokalemic periodic paralysis rare autosomal dominant disease
  • Delirium tremens
  • Accidental ingestion of barium compounds
  • Treatment of severe pernicious anaemia with Vit b12 – due to rapid uptake of K by the new cells that are formed

Nondrug causes due to inadequate dietary intake

Non drug causes due to abnormal losses of potassium

Losses in stool

Losses from the lower GI tract (due most commonly to diarrhea) are usually associated with concurrent bicarbonate loss and metabolic acidosis.  However, some patients with factitious diarrhea or surreptitious laxative abuse develop hypokalemia

loss through the kidney

metabolic alkalosis
Either metabolic or respiratory alkalosis can promote potassium entry into cells.  In these settings, hydrogen ions leave the cells to minimize the change in extracellular pH; the necessity to maintain electroneutrality the nrequires the entry of some potassium (and sodium) into the cells.  In general the direct effect is relatively small

Urinary potassium loss with removal of gastric acid – associated metabolic alkalosis raised the plasma bicarbonate concentration and therefore the filtered bicarbonate load above its reabsorptive threshold.  As a result, more sodium bicarbonate and water are delivered to the distal potassium secretory site in combination with a hypovolemia-induced increase in aldosterone release.  The net effect is increased potassium secretion and potentially large urinary potassium losses.  There is also inappropriate sodium wasting at his time; thus, only the demonstration of a low urine chloride concentration points to he presence of volume depletion

The urinary potassium wasting seen with loss of gastric secretions is typically most prominent in the first few days; thereafter, bicarbonate reabsorptive capacity increases, leading to a marked reduction in urinary sodium, bicarbonate, and potassium losses.  At this time, the urine pH falls from above 7.0 (due to bicarbonate wasting ) to acid (below 6.0)

  • Most commonly Induced by selective chloride depletion due to vomiting or nasogastric drainage
  • More rarely metabolic alkalosis occurs independently of chloride depletion as a result of systemic or intrarenal abnormalities that augment sodium reabsorption in the distal nephron – list in table
  • Most common or these rare presentations primary hyperaldosteronism usually severe hypoK
  • Cushings but usually milder than hyperaldosteronism
  • Genetic abnormalities that influence the activity of renal ion transporters are rare causes of metabolic alkalosis and hypokalemia
    • Liddle’s syndrome
    • 11beta-hydroxysteroid dehydrogenasie deficiency
    • Bartter’s syndrome
      • Rare disorder with a characteristic set of metabolic abnormalities
      • HypoK, metabolic alkalosis, hyperreninaemia, hyperaldosteronism, hyperplasia of the juxtaglomerular apparatus
      • The renal release of vasodilator prostaglandins (prostaglandin E2 and prostacyclin) is also increased in this condition and may partially e
    • Gitelman’s syndrome

Metabolic acidosis
Increased urinary potassium losses can occur in several forms of metabolic acidosis – distal renal tubular acidosis 

  • diabetic ketoacidosis,
  • increased distal sodium and water delivery

Other disorders

  • Mag depletion
  • Renal K wasting occurs in patients with acute mylogenous, mnomyeloblastic or lymphoblastic leukaemia
  • Uncontrolled diabetes mellitus – renal glucose loss causes osmotic diuresis, increasing sodium delivery to the distal nephron and promoting potassium excretion


Urinary response
A normal subject can, in the presence of potassium depletion, lower urinary potassium excretion below 25-30 meq per day; values above this level reflect at least a contribution from urinary potassium wasting

  • Metabolic acidosis with a low rate of potassium excretion is, in an asymptomatic patient, suggestive of lower gastrointestinal losses due to laxative abuse or a villous adenoma
  • Metabolic acidosis with potassium wasting is most often due to diabetic ketoacidosis or to type 1 (distal) or type 2 (proximal) renal tubular acidosis
  • Metabolic alkalosis with a low rate of potassium excretion is due to surreptitious vomiting (often in bulimia in an attempt to lose weight) or diuretic use (in which the urinary collection is obtained after the diuretic effect has worn off)
  • Metabolic alkalosis with potassium wasting and a normal blood pressure is most often due to surreptitious vomiting or diuretic use or to Bartter’s syndrome.  In this setting, measurement of the urine chloride concentration is often helpful, being low in vomiting at a time when urinary sodium and potassium excretion may be relatively high due to the need to maintain electroneutrality as some of the excess bicarbonate is being excreted
  • Metabolic alkalosis with potassium wasting and hypertension is suggestive of surreptitious diuretic therapy in a patient with underlying hypertension, renovascular disease, or one of the causes of primary mineralocorticoid excess.


Sodium concentration is not necessarily an accurate reflection of the patient’s volume status in metabolic alkalosis.  This possibility should be suspected if sodium excretion is relatively high and the urine pH is avoe 7.0, suggestion a high rate of bicarbonate excretion.  The presence of underlying hypovolemia can be detected more accurately by finding a urine chloride concentration below 25meq/L equiv 25mmol/L

Urine chloride concentration in the diagnosis of metabolic alkalosis

Less than 25 meq/L equiv 25mmol/L

Greater than 40 meq/L equiv 40mmol/l

Vomiting or nasogastric suction
Diuretics (late)
Factitious diarrhea
Cycstic fibrosis
Low chloride intake

Primary mineralocorticoid excess
Diuretics (early)
Alkali load (bicarbonate or other organic anion)
Bartter’s or Gitelman’s syndrome
Severe hypokaleamia (plasma K < 2.0mmol/L


This patient has

  • Significant hypokaleamia and low chloride
  • Metabolic alkalosis with raised bicarbonate
  • Normal blood pressure
  • Hypovoleamic as evidenced by low urinary chloride


The most likely explanation for these results is:

A. Occult diuretic use

  • Denies medication use
  • Significant hypokaleamia and low chloride
  • Metabolic alkalosis with raised bicarbonate
  • Normal blood pressure
  • hypovoleamic
  • early in presentation would expect urinary chloride to be high so this is incorrect

B. Occult laxative use

  • Incorrect – lower gastrointestinal losses usually result in metabolic acidosis

C. Self-induced vomiting fulfils all criteria of presentation

  • Denies medication use
  • Significant hypokaleamia and low chloride
  • Metabolic alkalosis with raised bicarbonate
  • Normal blood pressure
  • hypovoleamic
  • urinary chloride low

D. Primary hyperaldosteronism

  • Significant hypokaleamia and low chloride
  • Metabolic alkalosis with raised bicarbonate
  • Normal blood pressure
  • Usually effective volume expansion due to the stimulatory effect of aldosterone on sodium reabsorption, however the low urine chloride suggest volume depletion


E. Bartter’s syndrome

  • Significant hypokaleamia and low chloride
  • Metabolic alkalosis with raised bicarbonate
  • Normal blood pressure
  • Rare disorder – not the most likely


Renal: Fluid, electrolyte and acid-base homeostasis

Question 22 top Download PDF

A 43-year-old woman presents with intermittent exertional dyspnoea and nocturnal cough suggestive of asthma. She is a lifelong non-smoker.  Which one of the following results is most specific for the diagnosis of asthma?

A. Methacholine PC20 (provoking concentration producing a 20% fall in forced expiratory volume in 1 second (FEV1)) <16mg/mL.
B. Fall in FEV1 of 15% with hypertonic saline challenge.
C. FEV1/forced vital capacity (FVC) <80%.
D. Increase in FEV1 of 10% after bronchodilator administration.
E. Peripheral blood eosinophilia.

British Guideline on the management of asthma

key to diagnosis using a specific test is the change in FEV1 ≥ 15% - so increase following short acting β2 agonist or trial of steroids pred 30mg 14 days or decrease to airway responsiveness challenge: 6 mins exercise; histamine; methacholine; hypertonic saline
Both A and B meet the criteria ie change by 15%
From lecture series week 8 lecture 2 Dr Garun Hamilton
Hypertonic Saline challenge

  • Excellent specificity but poor sensitivity for diagnosis of asthma
  • High sensitivity and specificity for diagnosis of exercise induced bronchospasm
  • Useful for assessment of scuba diving risk

Methacholine challenge test

  • Good sensitivity but poor specificity for diagnosis for asthma
  • Causes of false positive
    • COPD/bronchiectasis/CF
    • Atopy
    • Post URTI
  • If low-moderate clinical suspicion and negative test – high negative predictive value (used this way in chronic cough assessment)




Respiratory; Asthma

Question 23 top Download PDF

A 42-year-old Asian man has chronic hepatitis B diagnosed four years previously. He presents with the blood test results below. His alanine transaminase (ALT) levels have previously been normal and he has been consistently hepatitis B surface antigen (HBsAg) positive and hepatitis B e antigen (HBeAg) negative. He has not been taking any prescription or over-the-counter medications. He has not travelled internationally for six years.
His current blood test results are as follows:

bilirubin 15 μmol/L [3-21]
alanine transaminase (ALT) 346 U/L [5-40]
aspartate transaminase (AST) 154 U/L [5-40]
alkaline phosphatase (ALP) 76 U/L [30-115]
gamma glutamyltranspeptidase (GGT) 101 U/L [<65]
albumin 40 g/L [38-50]
HBsAg positive
HBeAg negative
hepatitis B virus (HBV) DNA 3.5 pg/mL [<0.5]
hepatitis C virus (HCV) antibody negative
ferritin 450 μg/L [25-200]

The most likely explanation for the current blood test results is:
A. hepatitis D superinfection.
B. pre-core mutant disease.
C. hepatitis C co-infection.
D. hepatitis E co-infection.
E. haemochromatosis.







Susceptible – discuss vaccination



Immune due to infection



Immune due to hep b vaccination

IgM anti-HBc


Acutely infected

IgM anti-HBc


Chronic carrier



5 possibilities
May be recovering from acute HBV infection
May be distantly immune and test not sensitive enough to detect very low level of anti-HBs in serum
May be susceptible with a false positive anti-HBc
May be undetectable level of HbsAg present in the serum and the person is actually a carrier
Maternal antibody

Hepatitis B e antigen and antibody — Hepatitis B e antigen (HBeAg) is a secretory protein that is processed from the precore protein. It is generally considered to be a marker of HBV replication and infectivity. The presence of HBeAg is usually associated with high levels of HBV DNA in serum and higher rates of transmission of HBV infection from carrier mothers to their babies and from patients to health care workers
This information therefore confirms a chronic hepatitis B carrier only with not active hep B infection
A. hepatitis D superinfection.
DIAGNOSIS OF HDV INFECTION — Due to the dependence of HDV on HBV, the presence of HBsAg is necessary for the diagnosis of HDV infection. The additional presence of IgM antibody to hepatitis B core antigen (IgM anti-HBc) is necessary for the diagnosis of acute HBV/HDV coinfection
This is incorrect


B. pre-core mutant disease.
Answer by exclusion
Chronic hepatitis due to pre-core hepatitis B virus (HBV) mutants presents as hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). HBeAg-negative CHB represents a late phase in the natural course of chronic HBV infection that develops after HBeAg loss and seroconversion to anti-HBe. It is usually associated with pre-core stop codon mutation at nucleotide 1896 (mainly selected in non-A HBV genotypes), but also with other pre-core changes or with mutations in the basic core promoter region (mainly in HBV genotype A). In chronic HBV infections, pre-core mutants can be detected both in patients with HBeAg-negative CHB and in inactive hepatitis B surface antigen (HBsAg) carriers. The diagnosis of HBeAg-negative CHB is based on HBsAg positivity, HBeAg negativity, and mainly on increased alanine aminotransferase (ALT) and serum HBV-DNA levels and exclusion of other causes of liver disease. The differential diagnosis between patients with CHB and inactive HBsAg carriers can be made only by close follow-up of aminotransferase activity and viraemia levels, although the cut-off level of serum HBV DNA has not been definitely determined. IgM anti-HBc levels have also been suggested as an index that increases the diagnostic accuracy for transient hepatitis flares, while liver biopsy confirms the diagnosis and evaluates the severity of the liver disease

C. hepatitis C co-infection.
Hep C negative – this is incorrect

D. hepatitis E co-infection.
Not consistent clinical history (endemic area) and no evidence for hep E infection – usually associated with hep A,

E. haemochromatosis.
In 2002 paper two question 46 Jo tells us that the diagnosis of haemochromatosis requires
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
Incorrect – not enough information for this diagnosis


Hepatitis B Virus Infection — Natural History and Clinical Consequences
Don Ganem, M.D., and Alfred M. Prince, M.D.
NEJM Volume 350:1118 – 1129 March 11, 2004 Number 11


Hepatitis B Virus Infection

Virological Features

    • The prototype member of the hepadnaviridae (haptotropic DNA virus) family
    • Hepadnaviruses have a strong preference for infecting liver cells
    • DNA sequencing of many isolates of HBV has confirmed the existence of multiple viral genotypes
    • HBsAG – contain envelope glycoproteins and host-derived lipids outnumber virions by 1000:1
    • Replication of the DNA genome is by reverse transcription of an RNA intermediate

    The Replication Cycle of HBV.
    HBV virions bind to surface receptors and are internalized. Viral core particles migrate to the hepatocyte nucleus, where their genomes are repaired to form a covalently closed circular DNA (cccDNA) that is the template for viral messenger RNA (mRNA) transcription. The viral mRNA that results is translated in the cytoplasm to produce the viral surface, core, polymerase, and X proteins. There, progeny viral capsids assemble, incorporating genomic viral RNA (RNA packaging). This RNA is reverse-transcribed into viral DNA. The resulting cores can either bud into the endoplasmic reticulum to be enveloped and exported from the cell or recycle their genomes into the nucleus for conversion to cccDNA. The small, peach-colored sphere inside the core particle is the viral DNA polymerase.

    Pathogenesis of HBV

      • The HBV replication cycle is not directly cytotoxic to cells. This fact accords well with the observation that many HBV carriers are asymptomatic and have minimal liver injury, despite extensive and ongoing intrahepatic replication of the virus. It is now thought that host immune responses to viral antigens displayed on infected hepatocytes are the principal determinants of hepatocellular injury


      Cellular Immune Responses to HBV.
      HBV replicates in hepatocytes to produce HBsAg particles and virions. Both types of particle can be taken up by antigen-presenting cells, which degrade the viral proteins to peptides that are then presented on the cell surface bound to MHC class I or II molecules. (Antigen-presenting cells can also process and display viral antigens taken up by phagocytosis of killed infected hepatocytes.) These peptide antigens can be recognized by CD8+ or CD4+ T cells, respectively, which are thereby sensitized. Virus-specific CD8+ cytotoxic T cells (with help from CD4+ T cells, green arrow) can recognize viral antigens presented on MHC class I chains on infected hepatocytes. This recognition reaction can lead to either direct lysis of the infected hepatocyte or the release of interferon alpha and TNF – alpha, which can down-regulate viral replication in surrounding hepatocytes without direct cell killing


      Natural History

      • Primary HBV infection in susceptible (nonimmune) hosts can be either symptomatic or asymptomatic
      • Most primary infections in adults, whether symptomatic or not, are self-limited, with clearance of virus from blood and liver and development of lasting immunity yto reinfection
      • Less than 5% - persistant infection
      • Asymptomatic chronic HBV carriers
        • Subclinical persistent infection
        • Normal serum aminotransferase level
        • Normal or nearly normal findings on liver biopsy
      • Chronic  hepatitis B
        • Abnormal LFTs
        • Histologic features
      • Cirrhosis with severe liver injury develops in about 20% of people with chronic hep B

      Primary Infection

      • HBsAg detectable in blood after an incubation period of 4-10 weeks
      • Followed shortly by antibodies against the HBV core antigen (anti-HBc antibodies), which early in the infection are mainly of the IgM isotope
      • Viremia well established bythe time HBsAg is detected very high titers of virus 109 virions per millilitre
      • HBeAg detectable in most cases
      • High rates of both vertical  and horizontal transmissibility during acute HBV infection

      Persistant Infection

      • Mostly low levels persistent viremia
      • HBsAg detectable for life in most cases
      • Tendency over time for HBeAg to disappear from blood
      • Tendency over time for seroconversion to positivity for anti-HBe antibodies 5-10% per year in persistently infected people
      • Evidence of ongoing immune mediated destruction of infected hepatocytes

      Hepatocellular Carcinoma

      • Risk
      • 100 times as high as noncarriers
      • Twice yearly screening of chronically infected patiens with measurements of serum alpha fetoprotein +/- ultrasound
      • Problems AFP excellent negative predictive value, but PPV 9-30%


        • Goals
        • Reduction level of viremia
        • Amelioration of hepatic dysfunction
        • Treatment
        • Clear indication for therapy in HBeAg –postivie patients – increased risk of ealy progression to chronic active hepatitis and cirrhosis, higher risk of hepatocelluylar carcinoma
        • Asymptomatic HBeAg-netavie chronic carriers with viral loads below 10 to 5 per millilitre and normal LFTs usually relatively stable course with low rates of progression – therapy currently not offered
        • Usually markers of successful therapy
        • Loss of HBeAg
        • Seroconversion to anti-HBe antibodies
        • Reduction of the circulating viral load
        • True cure – loss of HBsAg and complete disappearance of viremia measured by PCR) is achieved infrequently 1-5%
        • Interferon
        • Previously mainstay of therapy
        • 30% response
        • Problems: SE – fever, myalgias, thrombocytopenia and depression make it difficult to continue in many patients
        • Many patients undergo a flare of liver injury during administration of interferon alfa, often just before or during clearance of HBeAg
        • Contraindicated in very advanced liver disease – may precipitate overt liver failure and patients with advanced cirrhosis and splenomegaly usually have base-line leukopenia and thrombocytopenia which may be exacerbated
        • Antiviral drugs
        • Lamivudine
          • Directly blocks replecation of HBV genome
          • Nucleoside or nucleotide analogues selectively targets the  viral  reverse transcriptase
          • Usually 3 to 4 log  reduction in circulating levels of HBV DNA in 1st 3months of therapy
          • Well tolerated
          • Not immunomodulatory and can be used n patients with decompensated cirrhosis
          • Limitation = development of drug resistance, which is mediated largely by point mutations at the YMDD moti at the catalytic center of the viral reverse transcriptase
        • Other nucleotide analogues
          • Adefovir – nucleotide (adenosine monophosphate)  analogue prodrug undergoes two intracellular phophorylations to yield the active drug / nephrotoxic in high doses (required for HIV) lower doses effective in HBV
          • Tenofovir
        • Liver transplantation
          • 80% recurrent viral infection in association with immunosuppressive drugs
          • Post transplantation prophylaxis of both hepatitis B immune globulin and lamivudine reduces rate of reinfection to about 10% and boosted 5 year rate of HBV-free survival to 80%
          • Prob - expense



          Gastroenterology:viral hepatitis

          Question 24 top Download PDF

          A 79-year-old man in a rehabilitation hospital is undergoing reconditioning therapy following surgical repair of an abdominal aortic aneurysm one month previously.  He develops chest pain and clear electrocardiographic evidence of an acute anterior myocardial infarction.  He has a past history of myocardial infarction with a left ventricular ejection fraction (LVEF) of 40%.  There is also a past history of peptic ulcer disease 10 years ago; this has been successfully treated and there has been no recurrence of symptoms.  His medications include aspirin 325 mg/day, enalapril 10 mg/day and metoprolol 25 mg/day.

          Which one of the following factors in this man’s medical history is the strongest contraindication to thrombolytic therapy for his acute myocardial infarction?

          • Age.
          • Aspirin therapy
          • Peptic ulcer disease
          • Previous myocardial infarction with reduced LVEF
          • Recent Surgery

          Answer E

          Guidelines for the management of acute coronary syndromes 2006
          Acute Coronary Syndrome Guidelines Working Group. Med J Aust 2006; 184 (8): S1-S32.

           Contraindications and cautions for fibrinolysis use in ST-segment-elevation myocardial infarction*

          Absolute contraindications

          Risk of bleeding

          • Active bleeding or bleeding diathesis (excluding menses)
          • Significant closed head or facial trauma within 3 months
          • Suspected aortic dissection (including new neurological symptoms)50

          Risk of intracranial haemorrhage

          • Any prior intracranial haemorrhage
          • Ischaemic stroke within 3 months
          • Known structural cerebral vascular lesion (eg, arteriovenous malformation)
          • Known malignant intracranial neoplasm (primary or metastatic)

          Relative contraindications

          Risk of bleeding

          • Current use of anticoagulants: the higher the international normalised ratio (INR), the higher the risk of bleeding
          • Non-compressible vascular punctures
          • Recent major surgery (< 3 weeks)
          • Traumatic or prolonged (> 10 minutes) cardiopulmonary resuscitation
          • Recent (within 4 weeks) internal bleeding (eg, gastrointestinal or urinary tract haemorrhage)
          • Active peptic ulcer

          Risk of intracranial haemorrhage

          • History of chronic, severe, poorly controlled hypertension
          • Severe uncontrolled hypertension on presentation (> 180 mmHg systolic or > 110 mmHg diastolic)
          • Ischaemic stroke more than 3 months ago, dementia, or known intracranial abnormality not covered in contraindications


          • Pregnancy


          Cardiology: Myocardial infarction


          Question 25 top Download PDF

          A 65-year-old woman presents with progressive lethargy and thoraco-lumbar pain.
          Full blood examination shows:
          haemoglobin                                         102 g/L [113-159]
          mean corpuscular volume (MCV)            102 fL [80-97]
          white cell count                                                 3.4 x 109/L [3.9-12.7]
          neutrophils                                1.6 x 109/L [1.9-8.0]
          lymphocytes                             1.0 x 109/L [0.9-3.3]
          monocytes                                0.5 x 109/L [0.3-1.1]
          eosinophils                               0.2 x 109/L [0-0.5]
          basophils                                  0.1 x 109/L [0-0.1]
          platelet count                                        92 x 109/L [150-396]
          A chest X-ray shows diffuse osteopenia but is otherwise normal.
          55% of nucleated cells in the bone marrow aspirate have the appearance shown below (examples indicated by arrows).

          The most likely diagnosis is:
          A. Burkitt’s lymphoma.
          B. amyloidosis.
          C. multiple myeloma.
          D. Waldenström’s macroglobulinaemia.
          E. metastatic carcinoma.

          Presentation: pancytopenia
          Bone Marrow – excess plasma cells
          Multiple Myeloma | IgG | excess plasma cells
          Multiple myeloma is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. This clone of plasma cells proliferates in the bone marrow and often results in extensive skeletal destruction with osteolytic lesions, osteopenia, and/or pathologic fractures. Other common clinical findings include anemia, hypercalcemia, and renal insufficiency. Recurrent bacterial infections (particularly during chemotherapy) and bleeding can occur, while the hyperviscosity syndrome is rare.
          Common complaints — Bone pain, particularly in the back or chest, and less often in the extremities, is present at the time of diagnosis in approximately 60 percent of patients . The pain is usually induced by movement and does not occur at night except with change of position. The patient's height may be reduced by several inches because of vertebral collapse.

          • Weakness and fatigue are common (32 percent) and often associated with anemia.
          • Fever occurs in less than 1 percent; when present, it is usually due to infection.
          • A bleeding diathesis is uncommon.
          • Weight loss is present in 24 percent of patients, one-half of whom have a weight loss of more than 9 kg.
          •  Patients may have symptoms related to complications of myeloma, such as hypercalcemia, renal insufficiency, or amyloidosis.


          Physical findings —

          • Pallor is the most frequent physical finding.
          • Palpable hepatomegaly, splenomegaly, and lymphadenopathy are uncommon,
          • Extramedullary plasmacytomas can occur as large, purplish, subcutaneous masses late in the course of the disease

          Neurologic disease —

          • Radiculopathy, usually in the thoracic or lumbosacral area, is the most common neurologic complication of multiple myeloma. It can result from compression of the nerve by a paravertebral plasmacytoma or rarely by the collapsed bone itself.
          • Cord compression — Spinal cord compression from an extramedullary plasmacytoma or a bone fragment due to fracture of a vertebral body occurs in approximately 5 percent of patients; it should be suspected in patients presenting with severe back pain along with weakness or paresthesias of the lower extremities, or bladder or bowel dysfunction or incontinence. This set of symptoms constitutes a medical emergency; magnetic resonance imaging or computed tomographic myelography of the entire spine must be done immediately, with appropriate follow-up treatment by chemotherapy, radiotherapy, or neurosurgery to avoid permanent paraplegia.

           Peripheral neuropathy —

          • Peripheral neuropathy is uncommon in multiple myeloma and, when present, is usually due to amyloidosis.

           CNS involvement —

          • Intracranial plasmacytomas are rare and almost always represent extensions of myelomatous lesions of the skull.
          • Leptomeningeal myelomatosis along with abnormal cerebrospinal fluid findings is uncommon but is being recognized more frequently, especially in advanced stages of the disease
          • Rare cases of encephalopathy due to hyperviscosity or high blood levels of ammonia, in the absence of liver involvement, have been reported

          Other findings — A variety of other signs of systemic involvement can be seen in patients with multiple myeloma. Plane xanthomas involving the creases of the palms and/or soles may represent a paraneoplastic phenomenon.
          Plasmacytomas of the ribs occur and can present either as expanding costal lesions or soft tissue masses. Pleural effusion and diffuse pulmonary involvement due to plasma cell infiltration are rare and usually occur in advanced disease.
          The incidence of infection is increased in multiple myeloma, with Streptococcus pneumoniae and gram-negative organisms being the most frequent pathogens. The propensity to infection results from an impairment in the antibody response, due to suppression of normal plasma cell function as manifested by hypogammaglobulinemia and, during chemotherapy - neutropenia

          Burkitt’s lymphoma| vacuoles | t(8;14)
          2003 paper two question 10 Diagnosing Burkkitts Lymphoma on blood smear and karyotypic abnormality

          Amyloidosis | cargo red stain lambda light chains

          Immunoperoxidase stain of a bone marrow biopsy from a patient with primary (AL) amyloidosis. Evidence for a monoclonal plasma cell disease is provided by the intense staining for lambda light chains (left panel) with almost no staining for kappa light chains (right panel)

          Immunofluorescence microscopy in light chain deposition disease involving the kidney. There is intense staining with anti-kappa light chain antibodies along the tubular basement membranes
          Waldenström’s macroglobulinaemia |IgM paraprotein
          Macroglobulinemia occurs in disorders in which there is proliferation of B-lymphocytes and plasma cells that produce an IgM monoclonal protein. This broad definition includes patients with monoclonal gammopathy of undetermined significance (MGUS) of the IgM type, chronic lymphocytic leukemia (CLL), a number of lymphoma variants, primary amyloidosis, and Waldenstrom's macroglobulinemia (WM).

          Weakness, fatigue, weight loss and chronic oozing of blood from the nose and gums are the most common presenting features in WM

          Pallor due to anemia is a frequent finding in WM along with lymphadenopathy, hepatomegaly, and splenomegaly

          Diagnostic criteria

            • IgM monoclonal gammopathy regardless of the size of the M protein
            • Ten percent or greater bone marrow infiltration by small lymphocytes that exhibit plasmacytoid or plasma cell differentiation with an intertrabecular pattern
            •  Typical immunophenotype (eg, surface IgM+, CD5+/-, CD10-, CD19+, CD20+, CD22+, CD23-, CD25+, CD27+, FMC7+, CD103-, CD138-);

            Bone marrow smear from a patient with lymphoplasmacytic lymphoma and Waldenstrom's macroglobulinemia. The marrow consists largely of lymphoplasmacytic cells that have the nuclear spoke-wheel pattern of a plasma cell but the low cytoplasmic volume that is more characteristic of a small lymphocyte

            Metastatic carcinoma | clumping, overlapping nuclei, don’t look like haemopoetic cells

            Bone marrow aspirate from a patient with carcinoma metastatic to the bone marrow, illustrating the presence of a large clump of tumor cells (arrow), surrounded by normal marrow elements. Note that the cellular outlines within the clump of tumor cells are indistinct. This is not a characteristic of any group of cells normally seen in the bone marrow.


            Haemtology: Myeloma and other plasma cell disorders


            Question 26 top

            Question 27 top Download PDF

            A 25-year-old man presents six weeks after a trip to central Africa with fever, chills and rigors. Stool examination is positive for Entamoeba histolytica. An ultrasound reveals a 7.5 cm liver abscess.
            The most appropriate next step in this patient’s management is:
            A. diagnostic aspirate of the liver abscess.
            B. percutaneous drainage of the liver abscess.
            C. metronidazole therapy.
            D. praziquantel therapy.
            E. quinine therapy.


            Reference: Infectious Diseases A clinical Approach Yung, McDonald, Spelman, Street and Johnson 2001

            Pg 191 – An amoebic liver abscesses one of the few abscesses which can e treated by medical therapy without drainage

            Answer C. metronidazole therapy.


            Infectious Diseases helminthic


            Question 28 top

            Question 29 top

            Question 30 top Download PDF

            A 20-year-old man presents following a generalised tonic-clonic seizure precipitated by alcohol excess and sleep deprivation.  He has an eight-year hisotry of episodes of a brief loss of time without other symptoms.   Observers report that these episodes last 10 to 15 seconds during which he stares blankly and is unresponsive to command.  His left hand may stiffen and he may fiddle with his buttons using his right hand.  He will then look surprised and resume his conversation.
            Cranial magnetic resonance imagine (MRI) (T1 weighted) is shown below

            The most likely diagnosis is:
            A.  mesial temporal sclerosis
            B. generalised epilepsy with absences
            C. hippocampal tumour
            D. callosal agenesis
            E. temporal lobe neuronal migration abnormality

            The key points in the presentation
            First  seizure with a provoking cause good history for a particular epilespy syndrome ie absence and arm movements
            Management: he needs advice about provoking activities and an EEG within 24 hours then a provoking EEG
            He has features of generalised (absence) and localised (arm movement) so he needs work up for a diagnosis

            MRI – good for finding structural causes of epilespy

            A.  mesial temporal sclerosis

            • MRI detects mesial temporal sclerosis by demonstrating this size asymmetry and abnormal signal within the atrophied hippocampus

            B. generalised epilepsy with absences

            • Imaging and physical examination generally normal would need EEG for diagnosis

            C. hippocampal tumour
            D. callosal agenesis
            E. temporal lobe neuronal migration abnormality

            Mesial Temporal Sclerosis
            The most common cause of complex partial seizures is mesial temporal sclerosis, occurring in 35 to 65 percent of patients who undergo temporal lobe surgery. In mesial temporal sclerosis, the hippocampus is smaller than normal. This usually occurs on one side of the brain, but can occur bilaterally in 10 to 15 percent of cases.
            MRI detects mesial temporal sclerosis by demonstrating this size asymmetry and abnormal signal within the atrophied hippocampus (Figure at left). Thin-section, high-resolution coronal MR images are best for detecting these abnormalities, which can be subtle. T1-weighted images are best for detecting size asymmetry, and T2-weighted images are most sensitive for detecting signal changes. A special T2-weighted sequence called FLAIR (fluid attenuated inversion recovery) is even more sensitive for detecting signal abnormalities (Figure at right, below). With subtle hippocampal atrophy, quantitative three-dimensional volume measurements of each hippocampus can be useful. These volume measurements can be especially helpful when there is bilateral hippocampal atrophy.


            Table 1. Classification of the epilepsies




            Idiopathic (genetic)

            • Childhood absence epilepsy

            • Benign focal epilepsy of childhood (2 types)


            • Juvenile absence epilepsy



            • Juvenile myoclonic epilepsy

            • ADNFLE


            • Epilepsy with grand-mal seizures on awakening

            • Primary reading epilepsy


            • Other idiopathic generalized epilepsies


            Symptomatic or cryptogenic

            • West's syndrome

            • Mesio-temporal lobe epilepsy


            • Lennox-Gastaut syndrome



            • Other symptomatic generalized epilepsies

            • Neocortical focal epilepsy

            ADNFLE: autosomal dominant nocturnal frontal lobe epilepsy

            Idiopathic Generalized Epilepsies
            These syndromes, formerly called primary generalized epilepsies, are the best known group of idiopathic epilepsies. They epitomize the meaning of the term idiopathic: genetic basis, normal neurologic examination, and normal intelligence. EEG shows generalized epileptiform discharges and may show photosensitivity. Seizure types include generalized tonic-clonic, absence, and myoclonic. Within the group of idiopathic generalized epilepsies, distinct entities are distinguished, primarily based on the predominant seizure types and the age of onset. Some syndromes are very well individualized and others have less clear boundaries.
            Symptomatic and Cryptogenic Localization-Related Epilepsies
            This is by far the most common type of adult-onset epilepsy. These cases are characterized by seizures arising from a localized region of the brain. If the cause is found, these epilepsies are symptomatic; if imaging studies are normal and the cause remains elusive, and they are cryptogenic. The boundary between the two epilepsies is largely dependent on diagnostic and imaging techniques. Causes such as low-grade tumors, hippocampal sclerosis, and subtle cortical dysplasias are identified more often because of advances in neuroimaging. Clinically, seizures may be simple partial or complex partial, with or without secondary generalization. Interictal EEG shows focal spikes or sharp waves, and ictal EEG shows a focal or regional discharge at onset.

            Hippocampal tumour

            I can’t distinguish this from the temporal sclerosis MRI – hard to find specific information so not a common presentation


            D. callosal agenesis
            This is a diagnosis made on fetal ultrasound

            Agenesis of the corpus callosum can be complete or partial, depending upon the stage of development at which growth was arrested. Normally, the corpus callosum begins to develop anterior to the interventricular foramina of Monroe at about 12 weeks of gestation. It subsequently grows upward and backwards, in a 'C' shape, as the primitive cerebral hemispheres grow laterally and then posteriorly. A normal corpus callosum can be sonographically appreciated by 18 to 20 weeks of gestation.

            Total or partial agenesis of the corpus callosum usually occurs (80 percent) in combination with other malformations, although both can occur as isolated anomalies Most cases are sporadic, but several genetic and chromosomal disorders have been associated with its absence


            E. temporal lobe neuronal migration abnormality
            Neuronal migration disorders (NMDs) are a group of birth defects caused by the abnormal migration of neurons in the developing brain and nervous system.
            Symptoms vary according to the abnormality, but often feature poor muscle tone and motor function, seizures, developmental delays, mental retardation, failure to grow and thrive, difficulties with feeding, swelling in the extremities, and a smaller than normal head. Most infants with an NMD appear normal, but some disorders have characteristic facial or skull features that can be recognized by a neurologist.

            S o the question

            A.  mesial temporal sclerosis

            • MRI detects mesial temporal sclerosis by demonstrating this size asymmetry and abnormal signal within the atrophied hippocampus – consistent with presentation

            B. generalised epilepsy with absences

            • Imaging and physical examination generally normal would need EEG for diagnosis, consistent with presentation

            C. hippocampal tumour

            • MRI good for finding mass – I guess consistent with presentation

            D. callosal agenesis – not the answer
            E. temporal lobe neuronal migration abnormality – not the answer

            So is it A, B or C?
            C is the most unlikely from the 3 and so A if you are convinced of a change in the MRI and B if you think the MRI is normal

            The answer is A


            Neurology: Epilepsy


            Question 31 top Download PDF

            Question 31
            A 70-year-old man presents to the emergency department with prolonged chest pain which is relieved by morphine and sublingual nitrates.  He has a three-week history of frequent exertional and nocturnal chest pain.
            Three years ago he suffered an uncomplicated inferior myocardial infarction.  Coronary angiography at that time revealed a 30% proximal left anterior descending artery stenosis, a long 90% right coronary artery stenosis and a 70% stenosis of the proxima circumflex artery.  As he was asymptomatic at the time, he was treated wtih aspirin, a beta-blocker and a hydroxyl-methylglutaryl-coenzyme A (HMG CoAO reductase inhibitory.  He was also treated with an angiotensin converting enzyme (ACE) inhibitor for mild hypertension.

            His current ECG shows Q waves in the inferior leads and 1 mm ST segment depression in leads V4-V6.  A chest X-ray shows pulmonary pulmonary venous congestion.

            Emergency staff have initiated herparin therapy and have continued his usual medications.  On review two hours later, he is asymptomatic, the ST changes have resolved and his serum troponin I level is 2.5mg/L [less than 0.1]

            Which one of the following management strategies would be most appropriate for this patient?


            Anti-Platelet Therapy

            Stress Test

            Angiography and Revascularisation Strategy




            Only for recurrent pain or a positive stress test



            Not indicated

            Angiography and proceed to coronary artery bypass graft



            Not indicated

            Proceed to coronary bypass surgery




            Only for recurrent pain or a positive stress test



            Not indicated

            Angiography and proceed to coronary artery bypass graft

            Guidelines for the management of acute coronary syndromes 2006
            Acute Coronary Syndrome Guidelines Working Group. Med J Aust 2006; 184 (8): S1-S32.

            Features associated with high-risk, intermediate-risk and low-risk non-ST-segment-elevation acute coronary
            syndromes (NSTEACS)

            High-risk features

            Presentation with clinical features consistent with acute coronary syndromes (ACS) and any of the following high-risk features:

            Repetitive or prolonged (> 10 minutes) ongoing chest pain or discomfort;
            Elevated level of at least one cardiac biomarker (troponin or creatine kinase-MB isoenzyme);
            Persistent or dynamic electrocardiographic changes of STsegment depression _ 0.5 mm or new T-wave inversion _ 2 mm;
            Transient ST-segment elevation (_ 0.5 mm) in more than two contiguous leads;
            Haemodynamic compromise — systolic blood pressure < 90 mmHg, cool peripheries, diaphoresis, Killip Class > I, and/or new-onset mitral regurgitation;
            Sustained ventricular tachycardia;
            Left ventricular systolic dysfunction (left ventricular ejection fraction < 0.40);
            Prior percutaneous coronary intervention within 6 months or prior coronary artery bypass surgery;
            Presence of known diabetes (with typical symptoms of ACS); or
            Chronic kidney disease (estimated glomerular filtration rate < 60 mL/minute) (with typical symptoms of ACS).

            Intermediate-risk features

            Presentation with clinical features consistent with ACS and any of the following intermediate risk features AND NOT meeting the criteria for high-risk ACS:

            Chest pain or discomfort within the past 48 hours that occurred at rest, or was repetitive or prolonged (but currently resolved);
            Age >65 years;
            Known coronary heart disease — prior myocardial infarction with left ventricular ejection fraction _ 0.40, or known coronary lesion more than 50% stenosed;
            No high-risk changes on electrocardiography (see above);
            Two or more of the following risk factors: known hypertension, family history, active smoking or hyperlipidaemia;
            Presence of known diabetes (with atypical symptoms of ACS);
            Chronic kidney disease (estimated glomerular filtration rate < 60 mL/minute) (with atypical symptoms of ACS); or
            Prior aspirin use.

            Low-risk features

            Presentation with clinical features consistent with an acute coronary syndrome without intermediate-risk or high-risk features. This includes onset of anginal symptoms within the last month, or worsening in severity or frequency of angina, or lowering of angina threshold. ◆

            Treatment strategies for patients with non-ST-segment-elevation acute coronary syndromes (NSTEACS), based on risk stratification

            High-risk NSTEACS
            Aggressive medical management
            coronary angiography and revascularisation

            Intermediate-risk NSTEACS
            Further observation and risk stratification
            Reclassification into either high risk or low risk

            Low-risk NSTEACS
            Discharge on upgraded medical therapy
            urgent cardiac follow-up

            Early medical management of non-ST-segment elevation acute coronary syndromes (NSTEACS)

            Low-risk and intermediate risk NSTEACS


            High-risk NSTEACS

            Clopidogrel (unless immediate angiography is planned, or the patient is at high risk of requiring surgery)
            Unfractionated heparin or subcutaneous enoxaparin
            Intravenous tirofiban or eptifibatide

            Summary of adjuvant therapy associated with reperfusion


            Primary percutaneous coronary intervention

            Fibrin-specific fibrinolytic





            Yes (unless the need for acute CABG is likely)

            Yes (unless the need for acute CABG is likely)


            Unfractionated heparin (ACT 200–300 s if using glycoprotein IIb/IIIa inhibitors, 300–350 s if not) or Enoxaparin*

            Unfractionated heparin (APTT 1.5–2 times control [approx 50–70 s]) or Enoxaparin*

            Glycoprotein IIb/IIIa inhibitors

            Abciximab optional


            CABG = coronary artery bypass graft. ACT = activated clotting time. APTT = activated partial thromboplastin time.
            * Care should be taken in patients aged over 75 years, or those who have significant renal dysfunction — dose adjustment is required


            Cardiology Myocardial Infarction

            Question 32 top

            Question 33 top

            Question 34 top Download PDF

            A 30-year-old woman with longstanding type 1 (insulin-dependent) diabetes mellitus presents with severe hypoglycaemia.  She is known to have autonomic neuropathy resulting in gastroparesis.  She is on a gluten-free diet for celiac disease and thyroxine for hypothyroidism.  Clinical examination is unremarkable apart from the presence of lipohypertrophy

            Which one of the following features of her history or examination most significantly increases the risk of a further severe hypoglycaemic episode in the next 24 hours?

            A. Thyroxine therapy

            B. Gastroparesis

            C. Lipohypertrophy

            D. Coeliac disease

            E. The current hypoglycaemic episode

            Answer A hypothyroidism can increase risk of hypglycaemia in TIDM therefore its treatment would be the opposite – the answer is not a

            Answer B Diabetic gastroparesis results in delayed stomach emptying, leading to retention of stomach contents. Other abnormalities include gastric dysrhythmia, abnormality of fundic relaxation, and antral hypomotility. Symptoms include bloating, early satiety, abdominal pain, nausea, or vomiting. Delayed stomach emptying may lead to gastroesophageal reflux, with symptoms of heartburn and vomiting of undigested food.
            Because gastroparesis makes stomach emptying unpredictable, blood glucose levels may be erratic and difficult to control – hyper and hypos can occur
            Not the most significant increase to risk of further severe hypoglycaemic episodes

            Answer C  Lipohypertrophy is characterised by a benign “tumour-like” swelling of fatty tissue secondary to subcutaneous insulin injections
            Diabetic lipodystrophies, particularly lipoatrophy, were common local complications of insulin treatment in patients treated with bovine or porcine insulins. With the introduction of human recombinant insulins, lipoatrophy has become uncommon, but lipohypertrophy remains a major problem. It is estimated that the prevalence of clinically significant lipohypertrophy is around 20% to 30% in patients with type 1 diabetes and around 4% in patients with type 2 diabetes.
            Injection into lipohypertrophied injection sites can lead to problems with glycaemic control. Evidence indicates that insulin absorption can be significantly delayed, leading to erratic glycaemic control and unpredictable hypoglycaemia. The lipohypertrophied areas can be unsightly, and the only available treatment for the condition is liposuction, although not injecting into the sites may reduce their size over time
            Not the most significant increase to risk of further severe hypoglycaemic episodes

            Answer D celiac disease
            In patients with celiac disease (gluten-sensitive enteropathy, or GSE), ingestion of the gliadin fraction of wheat gluten and similar molecules (prolamins) from barley, rye, and possibly oats causes damage to the intestinal epithelium. The injury results from an abnormal T-cell response against gliadin. Thus, GSE is a disease in which host susceptibility must be combined with a specific environmental trigger to affect injury.
            Typically, patients with GSE have chronic diarrhea and failure to thrive. However, some patients present with short stature, flatulence, or recurrent abdominal pain. Dermatitis herpetiformis, a pruritic papular rash, is directly related to GSE. Other atypical presentations are increasingly recognized, among them iron-deficiency anemia, osteopenia/osteoporosis, short stature, dental enamel hypoplasia, arthritis and arthralgia, chronic hepatitis/hypertransaminasemia, and neurological problems. GSE has also been found in asymptomatic individuals who nonetheless have evidence of intestinal mucosal injury on biopsy
            Due to malabsorption underlying celiac disease is associated with an increased risk of symptomatic hypoglycemia and that the introduction of a gluten-free diet with normalization of the intestinal mucosa may reduce its frequency.  Similar to gastroparesis this may make glycaemic control difficult but not the most likely answer here

            Answer E the current hypoglycaemic epiode
            Recurrent hypoglycemia itself also may contribute to the impaired counterregulatory response, potentially leading to a vicious cycle (hypoglycemia-associated autonomic failure). Careful metabolic studies have demonstrated that a single episode of hypoglycemia impairs the release of counterregulatory hormones and the development of early symptoms in response to a second episode within the next 12 to 24 hours .  On the other hand, meticulous glycemic control, avoiding hypoglycemia, can improve or normalize the neuroendocrine response in patients with type 1 diabetes of relatively short duration. This improvement, which includes enhanced perception of symptoms, can occur within as little as two days of strict avoidance of hypoglycemia .
            This is the most appropriate answer


            Endocrinology: pathophysiological basis of insulin-dependent and non insulin-dependent diabetes

            Question 35 top

            Question 36 top Download PDF

            QUESTION 36
            A 24-year-old man develops acute severe tonsillitis with high fever (39.8oC). He is treated with erythromycin. The next day he is noticed to be icteric. Abdominal examination is unremarkable.

            Blood investigations show:
            white cell count 18.5 x109/L [4.0-11.0]
            normal differential
            haemoglobin 145 g/L [120-160]
            platelet count 395 x109/L [150-400]
            sodium 140 mmol/L [135-150]
            potassium 4.5 mmol/L [3.5-5.0]
            urea 8.5 mmol/L [3.6-9.3]
            creatinine 0.09 mmol/L [0.06-0.12]
            bilirubin 78 μmol/L [3-23]
            alkaline phosphatase (ALP) 46 U/L [30-115]
            gamma glutamyltranspeptidase (GGT) 55 U/L [<65]
            aspartate transaminase (AST) 35 U/L [5-40]
            alanine transaminase (ALT) 32 U/L [5-40]
            albumin 40 g/L [40-52]

            The most likely explanation for his jaundice is:
            A. haemolysis.
            B. Epstein-Barr virus.
            C. Gilbert’s syndrome.
            D. Wilson’s disease.
            E. erythromycin.

            This questions is a combination of gastro and id I guess

            Most disorders associated with increased bilirubin production are due to A. haemolysis.  In this scenario haemolysis could result from

            • Mis- diagnosed Epstein barr virus
            • Secondary to severe acute illness

            Probably expect to see other blood changes ie aneamia so his normal hb rules this out as a diagnosis
            B. Epstein-Barr virus.  Can result in Haematologic abnormalities including haemolytic anaemia and can also have a mild hepatitis – so jaundice only is not the most common presentation could have abnormal LFT’s also.  The answer is therefore not B
            C. Gilbert’s syndrome. Is the most common inherited disorder of bilirubin glucuronidation LFTs generally normal and can present following febrile illness / stressful situation
            It is not D. Wilson’s disease.  – would have other LFT changes
            E. erythromycin.  The most frequent side effects of oral erythromycin preparations are gastrointestinal and are dose related. They include nausea, vomiting, abdominal pain, diarrhoea and anorexia. There have been rare reports of pancreatitis.   There have been reports of hepatic dysfunction, with or without jaundice, occurring in patients receiving erythromycin products.  Hepatic dysfunction would suggest abnormal LFTs


            Jaundice / hyperbilirubinemia

            Two Major Categories of hyperbilirubineamia

            • plasma elevation of predominantly unconjugated bilirubin due to
                • overproduction of bilirubin
                • impaired bilitrubin uptake by the liver
                • abnormalities of bilirubin conjugation
              • plasma elevation of both unconjugated and conjugated bilirubin due to
                • hepatocellular diseases
                • impaired canalicular excretion
                • biliary obstruction

            plasma elevation of predominantly unconjugated bilirubin due to
            overproduction of bilirubin

            • Haemolysis – Most disorders associated with increased bilirubin production are due to heamolysis
            • extravasation
            • shunt hyperbilirubineamia

            impaired bilitrubin uptake by the liver

            • heart failure, liver disease – portosystemic shunts
            • gilbert’s syndrome – The most common inherited disorder of bilirubin glucuronidation
              • autosomal recessive inheritance 9% general population – UGT1A1*28 allele
              • usually diagnosed in young adults who present with mild, predominantly unconjugated hyperbilirubineamia.  Rarely diagnosed prior to puberty when alterations in sex steroid concentrations affect bilirubin metabolism leadin to increased plasma bilirubin concentrations.  More commonly diagnosed in males
              • diagnosis usually in clinical setting associated stress: fasting, febrile illness, menses in women, otherwise normal LFTs apart from elevated predominantly unconjugated hyperbilirubineamia  | diagnosis definite in patients who continue to have normal lab studies (other than the elevation in plasma bilirubin) during the next 12 to 18 months)
              • no specific therapy required – apart from recognition of disease and avoidance of some drugs
            • drugs
              • rifamycin antibiotics
              • probenecid
              • flavaspadic acid
              • bunamiodyl (cholecystographic agent)

            abnormalities of bilirubin conjugation

            • neonatal
            • maternal milk
            • lucy-Driscoll
            • Wilson’s disease
              • Autosomal recessive defect in cellular copper transport, with a prevalence of approximately 1 case in 30,000 live births in most populations.  An impairment in biliary excretion leads to the accumulation of copper in the liver.  Over time the liver is progressively damaged and eventually becomes cirrhotic.
              • Multiple mutations in gene ATP7B
              • Clinical presentation
                • Rare before age 6 and almost always before age 30
                • Adolescents tend to present with liver disease while young adults are more likely to present with neuropsychiatric disease
                • Several different syndromes of hepatic disease
                  • Chronic hepatitis – approx 40% wilson’s disease patients
                  • Asymptomatic liver function abnormlatities increases ALT, AST or bilirubin concentrations
                  • Portal hypertension
                  • Fulminant hepatic failure
                • Neuropsychiatric disease
                  • Range of presentations, personality, deterioration in performance, depression paranoia and catatonia
                  • 35 % of patients with wilsons disease
                  • CSF – raised copper concentrations
            • Hyperthyroidism
            • Chronic persistent hepatitis


            • Crigler-Najjar I
            • Crigler-Najjar II
            • Gilbert’s Syndrome


            Infectious Disease: Viral URTI

            Gastro: Acute and chronic liver disease Repeat quesion 2002 paper two question 59


            Question 37 top

            Question 38 top Download PDF

            Within two hours of vigorous exercise, a 20-year-old man presents with sudden onset of severe left lateral lower chest pain, dyspnoea and anxiety.
            Physical examination shows him to be febrile and anaemic and there is local tenderness over the left lateral lower ribs.
            Full blood examination shows:
            haemoglobin                                                     75 g/L [128-175]
            mean corpuscular volume (MCV)                        81 fL [80-97]
            white cell count                                                             13.6 x 109/L [3.9-12.7]
            neutrophils                                            11.2 x 109/L [1.9-8.0]
            lymphocytes                                         0.9 x 109/L [0.9-3.3]
            monocytes                                            1.0 x 109/L [0.3-1.1]
            eosinophils                                           0.4 x 109/L [0-0.5]
            basophils                                              0.1 x 109/L [0-0.1]
            platelet count                                        180 x 109/L [150-396]
            reticulocyte count                                              200 x 109/L [9-116]

            The blood film is shown below.

            The most likely diagnosis is:
            A. thrombotic thrombocytopenic purpura.
            B. sickle crisis.
            C. Plasmodium falciparum malaria.
            D. autoimmune haemolysis.
            E. glucose-6-phosphate dehydrogenase deficiency.

            Anaemia and reticulocytosis
            Blood film – sickle cells
            Sickle Cell anaemia


            Vaso-occlusive phenomena and hemolysis are the clinical hallmarks of sickle cell disease (SCD), an inherited disorder due to homozygosity for the abnormal hemoglobin, hemoglobin S (HbS). Vaso-occlusion results in recurrent painful episodes (previously called sickle cell crisis) and a variety of serious organ system complications that can lead to life-long disabilities and/or early death.
            Hemoglobin S (HbS), results from the substitution of a valine for glutamic acid as the sixth amino acid of the beta globin chain, which produces a hemoglobin tetramer (alpha2/beta S2) that is poorly soluble when deoxygenated. The polymerization of deoxy HbS is essential to vaso-occlusive phenomena. The polymer assumes the form of an elongated rope-like fiber which usually aligns with other fibers, resulting in distortion into the classic crescent or sickle shape (show histology 1) and a marked decrease in red cell deformability.
            Clinical manifestations

            The clinical manifestations of sickle cell disease vary markedly among the major genotypes.

            • most severe in patients with SCD (homozygosity for HbS),
            •  intermediate severity in hemoglobin SC disease (HbSC, combined heterozygosity for hemoglobins S and C
            • generally benign in those with sickle cell trait (heterozygosity for HbS).
            •  Among patients with sickle cell-beta thalassemia, the disease varies with the quantity of hemoglobin A, often being quite severe in patients with sickle cell-beta (0) thalassemia and less severe in patients with sickle cell-beta (+) thalassemia.
            •  Among patients with coexisting alpha thalassemia, the anemia is less severe (because of a lower cellular hemoglobin concentration) but the effects on the clinical manifestations are variable.
            • Patients with homozygous SCD are typically anemic and often lead a life punctuated by recurrent painful vasoocclusive episodes . Clinical signs and symptoms typically develop at an early age. Dactylitis (acute pain in the hands and/or feet)  common initial symptom,

            The chronic hemolysis of sickle cell disease is usually associated with a mild to moderate anemia (hematocrit 20 to 30 percent), reticulocytosis of 3 to 15 percent (accounting for the high or high-normal mean corpuscular volume [MCV]), unconjugated hyperbilirubinemia, elevated serum lactate dehydrogenase, and low serum haptoglobin

            The peripheral blood smear may reveal sickled red cells, polychromasia indicative of reticulocytosis, and Howell-Jolly bodies reflecting hyposplenia secondary to repeated splenic infarctions. The red cells are normochromic unless there is coexistent thalassemia or iron deficiency. If the age-adjusted MCV is not elevated, the possibility of sickle cell-beta thalassemia, coincident alpha thalassemia, or iron deficiency should be considered

            Peripheral smear from a patient with sickle cell anemia shows multiple spindly sickle cells (blue arrows), a nucleated red blood cell in the upper left, and a Howell-Jolly body (black arrow), which is a nuclear fragment normally removed by the spleen. Target cells are also present (red arrow). This patient has functional asplenia because of repeated splenic infarctions.


            Anemia — The anemia of SCD is usually a chronic, reasonably well compensated hemolytic anemia with an appropriate reticulocytosis.

            A number of factors other than chronic hemolysis can contribute to the anemia. These include:

            • Inappropriately low serum erythropoietin (EPO) concentrations, which may result in deficient compensation for hemolysis
            •  Folate and/or iron deficiency resulting from increased utilization of folate and enhanced urinary losses of iron.

              Acute severe anemia — There are three settings in which an acute fall in hemoglobin concentration may be superimposed upon the chronic anemia: splenic sequestration crisis; aplastic crisis; and hyperhemolytic crisis. Affected patients with these complications usually present with pallor, weakness, and lethargy; fatalities are not uncommon.

             Splenic sequestration crisis — With splenic sequestration crisis, vaso-occlusion within the spleen and splenic pooling of red cells produce a marked fall in hemoglobin concentration accompanied by persistent reticulocytosis and a rapidly enlarging spleen. There is a risk of hypovolemic shock, particularly in children. Although primarily associated with aplastic crisis, parvovirus B19 infection may also be a risk factor for splenic sequestration

             Aplastic crisis — An aplastic crisis is characterized by the transient arrest of erythropoiesis, leading to abrupt reductions in hemoglobin concentration and red cell precursors in the bone marrow, and a markedly reduced number of reticulocytes in the peripheral blood (ie, reticulocytes <1.0 percent and an absolute reticulocyte count <10,000 per microL,

            Impaired erythropoiesis can be associated with a variety of infections. Most cases in children follow infection with human parvovirus B19, which specifically invades proliferating erythroid progenitors  

             Hyperhemolytic crisis — Hyperhemolytic crisis refers to the sudden exacerbation of anemia with reticulocytosis. This complication is rare, its cause is unknown, and some experts doubt its existence.

            -red cell fragments, migroantiopathic DIC

            classic pentad of clinical features

              • Thrombocytopenia
              • Microangiopathic hemolytic anemia
              • Neurologic symptoms and signs
              • Renal function abnormalities
              •  Fever

              Peripheral blood smear from a patient with a microangiopathic hemolytic anemia with marked red cell fragmentation. The smear shows multiple helmet cells (small black arrows), other fragmented red cells (large black arrow); microspherocytes are also seen (blue arrows). The platelet number is reduced; the large platelet in the center (red arrow) suggests that the thrombocytopenia is due to enhanced destruction

              Plasmodium falciparum malaria

              Thick and thin films – parasites

              Peripheral smear from a patient with malaria shows intraerythrocytic ring forms (trophozoites) (arrows)

              autoimmune haemolysis.

              Spherocytes and positive coombs
              (hereditary sperocytosis – spherocyts negative coombs

              This peripheral blood smear from a patient with AIHA due to a warm-reactive IgG antibody demonstrates the presence of many dark red small microspherocytes (red arrows) and larger spherocytes (black arrow) (x1000). Many large irregular blue-tinted red cells are also present, representing reticulocytes (blue arrows)


              glucose-6-phosphate dehydrogenase deficiency.

              Heinz body

              Glucose 6-phosphate dehydrogenase (G6PD) deficiency, an X-linked disorder, is the most common enzymatic disorder of red blood cells in humans, affecting 200 to 400 million people [1]. The importance of this enzyme for red cell integrity was first recognized following the observation that some African-American soldiers taking the antimalarial drug primaquine developed acute hemolytic anemia with hemoglobinuria. Subsequently, the activity of G6PD, one of the enzymes needed to maintain adequate reduced glutathione (GSH) levels, was found to be deficient in affected red cells

              Split screen view of a peripheral smear from a patient with Heinz body hemolytic anemia. Left panel: red cells with characteristic bite-like deformity (arrows). Right panel: Heinz body preparation which reveals the denatured hemoglobin precipitates




              Question 39 top Download PDF

              A 60-year-old man complains of recurrent episodes of watery diarrhoea four years after excision of an abdominal tumour. Somatostatin receptor scintigraphy is performed and is shown below.

              Which one of the following would be most effective in managing his symptoms?
              A. Interferon.
              B. Octreotide.
              C. Loperamide.
              D. Streptozotocin.
              E. Cholestyramine.


              Somatostatin-receptor scintigraphy — Many pancreatic endocrine tumors have high concentrations of somatostatin receptors and can therefore be imaged with a radiolabeled form of the somatostatin analogue octreotide (111-indium pentetreotide) (OctreoScan) This technique has proven particularly effective for visualizing gastrinomas, glucagonomas, nonfunctioning pancreatic tumors, and carcinoid tumors. It has the advantage of instantaneous whole body scanning, which also allows detection of distant metastases.
              MRI appears to have even greater sensitivity for detection of liver metastases compared with planar or SPECT somatostatin receptor scintigraphy

              Gasroenteropancreatic neuroendocrine tumours

              • Patients with metastatic gastroenteropancreatic neuroendocrine tumors often become symptomatic from hormonal hypersecretion rather than from tumor bulk.
              • secretion of serotonin and other vasoactive substances into the systemic circulation results in the carcinoid syndrome.
              • Symptoms of the carcinoid syndrome, as well as other hormonal syndromes resulting from peptide hormone hypersecretion by pancreatic endocrine tumors, can often be well controlled with somatostatin analogs and/or interferon-alfa (IFNa).
              • Somatostatin is a 14-amino acid peptide that inhibits the secretion of a broad range of hormones. It acts by binding to somatostatin receptors, which are expressed on the majority of neuroendocrine tumors


              • Somatostain analogs = ocreotide.  Long-acting octreotide is typically initiated at a dose of 20 mg IM after a brief trial of the short-acting formulation, with gradual escalation of the dose as needed for optimal control of symptoms. Patients may, in addition, use additional short-acting octreotide for breakthrough symptoms.
              • Octreotide side effects.  About one-third of patients have nausea, abdominal discomfort, bloating, loose stools, and fat malabsorption during the first several weeks of therapy, after which time, symptoms tend to subside. Mild glucose intolerance rarely occurs, due to transient inhibition of insulin secretion. More importantly, octreotide reduces postprandial gallbladder contractility and delays gallbladder emptying, and up to 25 percent of patients develop asymptomatic cholesterol gallstones or sludge within the first 18 months of therapy
              • IFNa with and without octreotide — The ability of interferon-alfa (IFNa) to stimulate T-cell function and to control the secretion of tumor products led to its initial use in patients with the carcinoid syndrome. Low-dose IFNa alone improves symptoms of hormonal hypersecretion in 40 to 50 percent of patients with either carcinoid or pancreatic neuroendocrine tumors, induces tumor stabilization in 20 to 40 percent, and achieves objective tumor regression in up to 15 percent
              • Combined therapy with IFNa and somatostatin analogs is reported to control symptoms in patients with the carcinoid syndrome who are resistant to somatostatin analogs alone

              Summary — Somatostatin analogs and IFNa appear to be of greatest utility for control of symptoms related to hormone hypersecretion. The use of these agents in asymptomatic patients is controversial because of the low rates of objective tumor regression.
              Symptomatic patients are generally initiated on short-acting octreotid with rapid transition to the long acting formulation, and subsequent titration of dose to optimize symptom control. A trial of combined therapy could be considered for patients who have poorly controlled or recurrent symptoms while on octreotide alone.
              Streptozocin combinations — The antitumor activity of combinations of streptozocin with with 5-FU and/ordoxorubicin for patients with advanced carcinoid remains controversial.

              Gut guidelines
              Table 3  Clinical features of pancreatic neuroendocrine tumours






              Confusion, sweating, dizziness, weakness, unconsciousness, relief with eating

              10% of patients develop metastases

              Complete resection cures most patients


              Zollinger-Ellison syndrome of severe peptic ulceration and diarrhoea

              Metastases develop in 60% of patients; likelihood correlated with size of primary

              Complete resection results in 10 year survival of 90%; less likely if large primary


              Necrolytic migratory erythema, weight loss, diabetes mellitus, stomatitis, diarrhoea

              Metastases develop in 60% or more patients

              More favourable with complete resection; prolonged even with liver metastases


              Werner-Morrison syndrome of profuse watery diarrhoea with marked hypokalaemia

              Metastases develop in up to 70% of patients; majority found at presentation

              Complete resection with five year survival of 95%; with metastases, 60%


              cholelithiasis; weight loss; diarrhoea and steatorrhoea. Diabetes mellitus

              Metastases likely in about 50% of patients

              Complete resection associated with five year survival of 95%; with metastases, 60%

              Non-syndromic pancreatic neuroendocrine tumour

              Symptoms from pancreatic mass and/or liver metastases

              Metastases develop in up to 50% of patients

              Complete resection associated with five year survival of at least 50%

              Table 5  Sensitivities (%) of the various imaging modalities for locating specific neuroendocrine tumours35,45–58


              Primary carcinoid tumour

              Carcinoid liver metastases

              Primary gastrinoma

              Gastrinoma liver metastases

              Primary insulinoma*


























              80 gastric





              Angio+Ca Stim






              CT, computed tomography; MRI, magnetic resonance imaging; SSRS, somatostatin receptor scintigraphy; EUS, endoscopic ultrasound; Angio+Ca Stim, angiography with calcium stimulation.

              *Metastatic insulinoma is rare; no data available.

              All of the above sensitivities for detecting tumour are further enhanced by intraoperative ultrasound.

              Recommendations (therapy)

              • The extent of the tumour, its metastases, and secretory profile should be determined as far as possible before planning treatment (grade C).
              • Surgery should be offered to patients who are fit and have limited disease—primary with or without regional lymph nodes (grade C).
              • Surgery should be considered in those with liver metastases and potentially resectable disease (grade D).
              • Where abdominal surgery is undertaken and long term treatment with SMS analogues is likely, cholecystectomy should be considered.
              • For patients who are not fit for surgery, the aim of treatment is to improve and maintain an optimal quality of life (grade D).
              • The choice of treatment depends on the symptoms, stage of disease, degree of uptake of radionuclide, and histological features of the tumour (grade C).
              • Treatment choices for non-resectable disease include SMS analogues, biotherapy, radionuclides, ablation therapies, and chemotherapy (grade C).
              • External beam radiotherapy may relieve bone pain from metastases (grade C).
              • Chemotherapy may be used for inoperable or metastatic pancreatic and bronchial tumours, or poorly differentiated NETs (grade B).

              9.4 Symptomatic treatment
              There are a number of treatment options available for patients displaying symptoms due to hormones/peptides secreted by a secretory tumour. These include somatostatin analogues, proton pump inhibitors for gastrinomas, and diazoxide for insulinomas, which are indicated in patients with secretory tumours and distressing symptoms from peptide production. They could be commenced immediately in patients with inoperable disease or preoperatively in patients who have operable disease (liver resection with or without resection of the primary).
              The only proven hormonal management of NETs is administration of somastostatin analogues. Somatostatin is a brain-gut peptide that inhibits the release of many hormones and can impair some exocrine functions. Somatostatin receptors are present in the vast majority (70–95%) of NETs but only in about half of insulinomas, and less in poorly differentiated NETs and somatostatinoma. Somatostatin analogues bind principally to receptor subtypes 2 and 5.
              Somatostatin analogues inhibit the release of various peptide hormones in the gut, pancreas, and pituitary, antagonise growth factor effects on tumour cells, and at very high dosage may induce apoptosis. The elimination half life of the natural hormone somatostatin is only a few minutes, making it of no value in routine therapy. Octreotide has a half life of several hours, making intermittent therapy possible. This drug is administered by subcutaneous injection starting at 50–100 µg twice or three times a day to a maximum daily dose of 1500 µg.  More recently, analogues with sustained release from depot injections have been synthesised and these are given every 2–4 weeks.   These drugs, lanreotide (fortnightly injection), Sandostatin LAR (monthly), and Lanreotide Autogel (also monthly), have shown significant improvement in the quality of life of patients and have as good or better efficacy compared with short acting octreotide.121–123 Patients may be stabilised with octreotide (short acting) for 10–28 days before converting them to long acting somatostatin analogues. Escalation of dose is often needed over time. Biochemical response rates (inhibition of hormone production) are seen in 30–70% of patients with symptomatic control in the majority of patients; tumour growth may stabilise and rarely shrinkage of tumour may occur.   In instances of stress (for example, anaesthesia, surgical operations (see above), hepatic artery embolisation), patients with the carcinoid syndrome or even with the tumour but without syndrome should have increased coverage by somatostatin analogues, preferably short acting octreotide by intravenous administration (50 µg/h). This extra cover should be administered 12 hours before, during, and 48 hours after the procedure to prevent a cardiovascular carcinoid crises.79
              Few side effects from somatostatin analogues have been reportedand they include fat malabsorption, gall stones and gall bladder dysfunction, vitamin A and D malabsorption, headaches, diarrhoea, dizziness, and hypo- and hyperglycaemia. Monitoring of circulating and, where relevant, urinary hormone levels should be undertaken during periods of treatment. Patients should also have the regular relevant imaging.


              Gastroenterology: gastric ca


              Question 40 top

              Question 41 top

              Question 42 top

              Question 43 top Download PDF

              A 42-year-old man presents with a two-year history of increasing right facial numbness.  He has a history of intermittent unsteadiness, mild hearing loss and vertigo but has otherwise been well.  Cranial magnetic resonance imagine (MRI) (T1 weighted following gadolinium contrast) is shown below.

              The most likely diagnosis is:
              A.  multiple sclerosis
              B. neurofibromatosis type 2
              C. cerebellar haemangioblastoma
              D. meningioma
              E. pontine glioma


              A.  multiple sclerosis

              B. neurofibromatosis type 2


              Neurofibromatosis, a common neurocutaneous disorder, includes numerous different forms. Neurofibromatosis type 1, also known as von Recklinghausen's NF or NF1 is the most common type, and accounts for at least 85 percent of patients.

              Diagnostic criteria — The hallmarks of NF1 are the multiple café-au-lait spots (CALS) and associated cutaneous neurofibromas. The diagnostic criteria developed by the NIH Consensus Conference in 1987 and updated in 1997 are based upon specific clinical features of NF1 (show table 1) [16-18] . According to these criteria, at least two of the following clinical features must be present to make the diagnosis of NF1: Six or more café-au-lait macules of greatest diameter >5 mm in prepubertal and >15 mm in postpubertal individuals Two or more neurofibromas of any type or one plexiform neurofibroma Freckling in the axillary or inguinal regions Optic glioma Two or more Lisch nodules (iris hamartomas) A distinctive bony lesion such as sphenoid dysplasia or thinning of the long bone cortex with or without pseudoarthrosis A first-degree relative (parent, sibling, or offspring) with NF1 based upon the above criteria
              Neurofibromatosis type 2 (NF2) is less frequent than NF1 and has a birth incidence of 1 in 30 000-40 000. It is caused by a dominant mutation in the NF2 gene which is located on chromosome 22. The NF2 gene codes for the protein Merlin/Schwannomin. The hallmarks of NF2 are the bilateral vestibular schwannomas (formerly called “acoustic neuromas”). There are also clinical diagnostic criteria available to make the diagnosis:

              • Bilateral vestibular schwannomas (histology or MRI)
              • A parent, sibling or child with NF2 and either
                • Unilateral vestibular schwannoma
                • Any two of the following: meningioma, glioma, schwannoma, posterior subcapsular lenticular opacities, cerebral calcification
              • Unilateral vestibular schwannoma and two or more of the following: meningioma, glioma, schwannoma, posterior subcapsular lenticular opacities, cerebral calcification
              • Multiple meningiomas (two or more) and one or more of the following: glioma, schwannoma, posterior subcapsular lenticular opacities, cerebral calcification

              Patients with NF2 sometimes have a few café-au-lait spots but not more than 5. They can have tumors of the peripheral nerves (schwannomas). These schwannomas are sometimes mistaken for neurofibromas. Symptoms of bilateral vestibular schwannomas usually begin in early adult life with decreased hearing, tinnitus or vertigo. Symptomatic spinal tumors are frequently observed. The actuarial survival after diagnosis is on average 15 years.
              NF type 2 — Spinal tumors are found in up to 90 percent of patients with NF-2. The tumors are often multiple, consisting primarily of schwannomas, but including some meningiomas [7]. About 2 percent of all spinal schwannomas are seen in patients with NF-2, while the rest are sporadic [8]. (See "Risk factors for brain tumors" section on Genetic factors).

              DIAGNOSIS — Contrast-enhanced magnetic resonance imaging (MRI) is the most sensitive and specific imaging modality to evaluate possible spinal column lesions. The majority of NSTs enhance diffusely with contrast, but heterogeneous enhancement can be seen when intratumoral cysts, hemorrhage or necrosis are present

              Cerbellar haemangioblastoma

              Signs in CT or MRI images will vary according to the cellular expression of the tumour. It is usually well circumscribed, but can become locally invasive or may rarely undergo metaplasia. Typically on CT, the tumour is extra-axial, of greater density than adjacent normal brain, may contain calcification and enhances densely, after intravenous contrast. Cystic change has been recorded, but is rare ( 1-2 percent ). MRI scans of meningioma almost invariably show enhancement with IV Gadolinium contrast.


              E. pontine glioma

              Gliomas arising in the brainstem (midbrain, pons, and medulla oblongata) account for 10 to 20 percent of all central nervous system (CNS) tumors in children. They are more common in children than adults [1-4]. In the United States, for example, there are approximately 300 pediatric cases and 100 adult cases reported each year. In children, the median age at diagnosis is five to nine years of age, and the incidence is approximately equal between males and females.

              On CT, these tumors infiltrate and enlarge the brain stem and secondarily displace the fourth ventricle. They commonly are hypodense but occasionally are of increased density compared to normal brain as seen on Film .3 in a different child. Calcification and cyst formation are infrequent (12%), and approximately half demonstrate enhancement after contrast (Film .4). When present, enhancement patterns are variable, with diffuse, nodular, or ring enhancement seen. A small number of these tumors may demonstrate exophytic growth into the posterior fossa cisterns, particularly the cerebellopontine angle cistern. These tumors tend to enhance with contrast administration.

              Because of Hounsfield artifact in the posterior fossa, a small percentage of brain stem gliomas will be overlooked on initial CT scans. The superior imaging capability of MRI for brain stem and posterior fossa pathology allows recognition and characterization of lesions that are poorly delineated by CT, such as isodense or nonenhancing tumors.


              Neurology: neoplastic disease

              Repeat Question 2004 paper two question 21


              Question 44 top

              Question 45 top Download PDF

              A 63-year-old man is seen in follow-up after admission to hospital with an acute exacerbation of chronic obstructive pulmonary disease (COPD). He has marked dyspnoea on exertion but remains independent in activities of daily living. He gave up smoking 10 years ago and currently takes salbutamol and ipratropium bromide via metered dose inhalers as needed.
              forced expiratory volume in one second (FEV1) 0.7 L (27% predicted)
              forced vital capacity (FVC) 2.9 L (82% predicted)
              In this man, which one of the following is the most likely benefit of treatment with inhaled corticosteroids?

              A. Improved survival.
              B. Decreased need for bronchodilator therapy.
              C. Slower decline in lung function.
              D. Reduced number of exacerbations.
              E. Improved exercise tolerance.

              Ist issue is assessing severity

              • No FEV1 post bronchodilator and acute exacerbation probably not reflective of stable disease
              • PADLs no effect and dyspnoea on exertion would classify him as mild

              2nd is current therapy

              • Appropriate for mild ie intermittent bronchodilator – salbutamol (200mcg) or ipratropium bromide (40mcg) as needed before exercise

              3rd impact of adding inhaled glucocorticoid

              • Inhaled glucocorticcoids should be considered in patients with a documented resonse or those who have severe COPD with frequent exacerbations
              • Trials show slowed rate of decline in quality of life and rate of acute exacerbations without affecting overall decline in lung function

              So Answer is D
              Reference COPD-X Plan 2007


              Respiratory Smoking-related chronic lung disease

              Question 46 top Download PDF

              A 45-year-old asymptomatic man returns for follow-up.  He was diagnosed 10 years ago with aortic regurgitation due to a congentia lbicuspid aortic valve,  He has never had endocarditis

              Which one of the following echocardiographic profiles most strongly indicates the need for aortic valve replacement?


              LVEDD (mm)


              LA size (mm)





















              LVEDD Left ventricular end-diastolic diameter
              LVESD Left ventricular end-systolic diameter
              FS        Fractional shortening = (LVEDD-LVESD) / LVEDD
              LA        Left atrial

              Answer: C as it fulfils the criteria for class I AVR replacement guidelines EF 0.5 or less and is the most severe class I criteia

              What you need to know

              • Ejection fraction and how to calculate
              • Aortic regurgitation and indications for surgery

              Stroke volume (SV) = Left ventricular end-diastolic volume – left ventricular end-systolic volume
              Left ventricular ejection fraction % = SV / LV end-diastolic volume * 100

              So fractional shortening is the equivalent of ejection fraction and the lower the greater indication for surgery as below

              From: ACC/AHA 2006 guidelines for the management of patients with valvular heart disease
              J Am Coll Cardiol. 2006 Aug 1;48(3):e1-148.

              These are the current recommendations for AVR

              Class I

              1 AVR is indicated for symptomatic patients with severe AR irrespective of LV systolic function. (Level of Evidence: B)
              2 AVR is indicated for asymptomatic patients with chronic severe AR and LV systolic dysfunction (ejection fraction 0.50 or less) at rest. (Level of Evidence: B)
              3 AVR is indicated for patients with chronic severe AR while undergoing CABG or surgery on the aorta or other heart valves. (Level of Evidence: C)

              Class IIa

              AVR is reasonable for asymptomatic patients with severe AR with normal LV systolic function (ejection fraction greater than 0.50) but with severe LV dilatation (end-diastolic dimension greater than 75 mm or end-systolic dimension greater than 55 mm).* (Level of Evidence: B)

              Class IIb

              1 AVR may be considered in patients with moderate AR while undergoing surgery on the ascending aorta. (Level of Evidence: C)
              2 AVR may be considered in patients with moderate AR while undergoing CABG. (Level of Evidence: C)
              3 AVR may be considered for asymptomatic patients with severe AR and normal LV systolic function at rest (ejection fraction greater than 0.50) when the degree of LV dilatation exceeds an end-diastolic dimension of 70 mm or end-systolic dimension of 50 mm, when there is evidence of progressive LV dilatation, declining exercise tolerance, or abnormal hemodynamic responses to exercise.* (Level of Evidence: C)

              Class III

              AVR is not indicated for asymptomatic patients with mild, moderate, or severe AR and normal LV systolic function at rest (ejection fraction greater than 0.50) when degree of dilatation is not moderate or severe (end-diastolic dimension less than 70 mm, end-systolic dimension less than 50 mm).* (Level of Evidence: B)

              Here are the rest of the guidelines

              Aortic Regurgitation

              Common causes of AR

              • idiopathic dilatation of the aorta
              • congenital abnormalities of the aortic valve (most notably bicuspid valves)
              • calcific degeneration,
              • rheumatic disease
              • infective endocarditis
              • systemic hypertension
              • myxomatous degeneration
              •  dissection of the ascending aorta
              •  Marfan syndrome.

              Less common causes include

              • traumatic injuries to the aortic valve
              • ankylosing spondylitis
              • syphilitic aortitis
              • rheumatoid arthritis
              • osteogenesis imperfect
              • giant cell aortitis
              • Ehlers-Danlos syndrome
              • Reiter’s syndrome
              • discrete subaortic stenosis
              • ventricular septal defects with prolapse of an aortic cusp
              • anorectic drugs have also been reported to cause AR (

              The majority of these lesions produce chronic AR with slow, insidious LV dilation and a prolonged asymptomatic phase
              Acute causes

              •  infective endocarditis
              •  aortic dissection
              • and trauma

               more often produce acute severe AR, which can result in sudden catastrophic elevation of LV filling pressures and reduction in cardiac output.

              Acute Aortic Regurgitation

              In acute severe AR, the sudden large regurgitant volume is imposed on a left ventricle of normal size that has not had time to accommodate the volume overload. With an abrupt increase in end-diastolic volume, the ventricle operates on the steep portion of a normal diastolic pressure-volume relationship, and LV end-diastolic and left atrial pressures may increase rapidly and dramatically. The Frank-Starling mechanism is used, but the inability of the ventricle to develop compensatory chamber dilatation acutely results in a decrease in forward stroke volume. Although tachycardia develops as a compensatory mechanism to maintain cardiac output, this is often insufficient. Hence, patients frequently present with pulmonary edema or cardiogenic shock.
              Acute AR creates especially marked hemodynamic changes in patients with pre-existing pressure overload hypertrophy, in whom the small, noncompliant LV cavity is set on an even steeper diastolic pressure-volume relationship and has reduced preload reserve.
              Examples of this latter situation include aortic dissection in patients with systemic hypertension, infective endocarditis in patients with pre-existing AS, and acute regurgitation after balloon valvotomy or surgical commissurotomy for congenital AS.
               Patients may also present with signs and symptoms of myocardial ischemia.
               As the LV end-diastolic pressure approaches the diastolic aortic and coronary artery pressures, myocardial perfusion pressure in the subendocardium is diminished. LV dilation and thinning of the LV wall result in increased afterload, and this combines with tachycardia to increase myocardial oxygen demand. Therefore, ischemia and its consequences, including sudden death, occur commonly in acute severe AR.

              Many of the characteristic physical findings of chronic AR are modified or absent when valvular regurgitation is acute, which can lead to underestimation of its severity.

              • LV size may be normal on physical examination
              • cardiomegaly may be absent on chest X-ray
              • Pulse pressure may not be increased because systolic pressure is reduced and the aortic diastolic pressure equilibrates with the elevated LV diastolic pressure
              • Because this diastolic pressure equilibration between aorta and ventricle can occur before the end of diastole, the diastolic murmur may be short and/or soft and therefore poorly heard
              • The elevated LV diastolic pressure can close the MV prematurely, reducing the intensity of the first heart sound. An apical diastolic rumble can be present, but it is usually brief and without presystolic accentuation. Tachycardia is invariably present.

              Echocardiography is indispensable in confirming the presence and severity of the valvular regurgitation, determining its cause, estimating the degree of pulmonary hypertension (if TR is present), and determining whether there is rapid equilibration of aortic and LV diastolic pressure. Evidence for rapid pressure equilibration includes a short AR diastolic half-time (less than 300 ms), a short mitral deceleration time (less than 150 ms), or premature closure of the MV.
              Acute AR caused by aortic root dissection is a surgical emergency that requires particularly prompt identification and management.

              • Transesophageal echocardiography is indicated when aortic dissection is suspected
              • computed tomographic imaging or magnetic resonance imaging should be performed if this will lead to a more rapid diagnosis than can be achieved by transesophageal echocardiography
              • Cardiac catheterization, aortography, and coronary angiography are rarely required, are associated with increased risk, and might delay urgent surgery unnecessarily (
              •  Angiography should be considered only when the diagnosis cannot be determined by noninvasive imaging and when patients have known CAD, especially those with previous CABG


              Death due to pulmonary edema, ventricular arrhythmias, electromechanical dissociation, or circulatory collapse is common in acute severe AR, even with intensive medical management. Urgent surgical intervention is recommended. Nitroprusside, and possibly inotropic agents such as dopamine or dobutamine to augment forward flow and reduce LV end-diastolic pressure, may be helpful to manage the patient temporarily before surgery. Intra-aortic balloon counterpulsation is contraindicated. Although beta blockers are often used in treating aortic dissection, these agents should be used very cautiously, if at all, in the setting of acute AR because they will block the compensatory tachycardia. In patients with acute severe AR resulting from infective endocarditis, surgery should not be delayed, especially if there is hypotension, pulmonary edema, or evidence of low output. In patients with mild acute AR, antibiotic treatment may be all that is necessary if the patient is hemodynamically stable.

              Chronic Aortic Regurgitation

              The left ventricle responds to the volume load of chronic AR with a series of compensatory mechanisms, including an increase in end-diastolic volume, an increase in chamber compliance that accommodates the increased volume without an increase in filling pressures, and a combination of eccentric and concentric hypertrophy. The greater diastolic volume permits the ventricle to eject a large total stroke volume to maintain forward stroke volume in the normal range. This is accomplished through rearrangement of myocardial fibers with the addition of new sarcomeres and development of eccentric LV hypertrophy

               As a result, preload at the sarcomere level remains normal or near normal, and the ventricle retains its preload reserve. The enhanced total stroke volume is achieved through normal performance of each contractile unit along the enlarged circumference.  Thus, LV ejection performance is normal, and ejection phase indexes such as ejection fraction and fractional shortening remain in the normal range.
              However, the enlarged chamber size, with the associated increase in systolic wall stress, also results in an increase in LV afterload and is a stimulus for further hypertrophy

              Thus, AR represents a condition of combined volume overload and pressure overload . As the disease progresses, recruitment of preload reserve and compensatory hypertrophy permit the ventricle to maintain normal ejection performance despite the elevated afterload .
              The majority of patients remain asymptomatic throughout this compensated phase, which may last for decades. Vasodilator therapy has the potential to reduce the hemodynamic burden in such patients.
              In a large subset of patients, the balance between afterload excess, preload reserve, and hypertrophy cannot be maintained indefinitely. Preload reserve may be exhausted and/or the hypertrophic response may be inadequate so that further increases in afterload result in a reduction in ejection fraction, first into the low normal range and then below normal. Impaired myocardial contractility may also contribute to this process. Patients often develop dyspnea at this point in the natural history. In addition, diminished coronary flow reserve in the hypertrophied myocardium may result in exertional angina

              LV systolic dysfunction (defined as an ejection fraction below normal at rest) is initially a reversible phenomenon related predominantly to afterload excess, and full recovery of LV size and function is possible with AVR

              With time, during which the ventricle develops progressive chamber enlargement and a more spherical geometry, depressed myocardial contractility predominates over excessive loading as the cause of progressive systolic dysfunction. This can proresss to he extent that the full benefit of surgical correction of the regurgitant lesion, in terms of recovery of LV function and improved survival, can no longer be achieved.

              A large number of studies have identified LV systolic function and end-systolic size as the most important determinants of survival and postoperative LV function in patients undergoing AVR for chronic AR

              Diagnosis and Initial Evaluation

              Class I

              1 Echocardiography is indicated to confirm the presence and severity of acute or chronic AR. (Level of Evidence: B)
              2 Echocardiography is indicated for diagnosis and assessment of the cause of chronic AR (including valve morphology and aortic root size and morphology) and for assessment of LV hypertrophy, dimension (or volume), and systolic function. (Level of Evidence: B)
              3 Echocardiography is indicated in patients with an enlarged aortic root to assess regurgitation and the severity of aortic dilatation. (Level of Evidence: B)
              4 Echocardiography is indicated for the periodic re-evaluation of LV size and function in asymptomatic patients with severe AR. (Level of Evidence: B)
              5 Radionuclide angiography or magnetic resonance imaging is indicated for the initial and serial assessment of LV volume and function at rest in patients with AR and suboptimal echocardiograms. (Level of Evidence: B)
              6 Echocardiography is indicated to re-evaluate mild, moderate, or severe AR in patients with new or changing symptoms. (Level of Evidence: B)

              Class IIa

              1 Exercise stress testing for chronic AR is reasonable for assessment of functional capacity and symptomatic response in patients with a history of equivocal symptoms. (Level of Evidence: B)
              2 Exercise stress testing for patients with chronic AR is reasonable for the evaluation of symptoms and functional capacity before participation in athletic activities. (Level of Evidence: C)
              3 Magnetic resonance imaging is reasonable for the estimation of AR severity in patients with unsatisfactory echocardiograms. (Level of Evidence: B)

              Class IIb

              Exercise stress testing in patients with radionuclide angiography may be considered for assessment of LV function in asymptomatic or symptomatic patients with chronic AR. (Level of Evidence: B)

              The diagnosis of chronic severe AR can usually be made on the basis of the diastolic murmur, displaced LV impulse, wide pulse pressure, and characteristic peripheral findings that reflect wide pulse pressure. A third heart sound is often heard as a manifestation of the volume load and is not necessarily an indication of heart failure. An Austin-Flint rumble is a specific finding for severe AR .
               In many patients with more mild to moderate AR, the physical examination will identify the regurgitant lesion but will be less accurate in determining its severity. When the diastolic murmur of AR is louder in the third and fourth right intercostal spaces than in the third and fourth left intercostal spaces, the AR likely results from aortic root dilatation rather than from a deformity of the leaflets alone. The chest X-ray and ECG are helpful in evaluating overall heart size and rhythm, evidence of LV hypertrophy, and evidence of conduction disorders.

              Echocardiography is indicated
              • to confirm the diagnosis of AR if there is an equivocal diagnosis based on physical examination
              • to assess the cause of AR and to assess valve morphology
              • to provide a semiquantitative estimate of the severity of AR
              • to assess LV dimension, mass, and systolic function
              • to assess aortic root size.

              In asymptomatic patients with preserved systolic function, these initial measurements represent the baseline information with which future serial measurements can be compared.
              LV wall stress may also be estimated from blood pressure and echocardiographic measurements. However, such wall stress measurements are difficult to reproduce, have methodological and conceptual problems, and should not be used for diagnosis or management decision making in clinical practice.


              Cardiology : Aortic Regurgitation

              Question 47 top

              Question 48 top

              Question 49 top Download PDF

              A previously well 53-year-old man is found to have a 3 cm right adrenal mass when undergoing a computed tomography (CT) scan for suspected hepatobiliary disease.  Physical examination is normal, apart from a blood pressure of 150/90 mmHg.

              The following laboratory test results are obtains

              Serum sodium                                       140 mmol/L                   [133-144]
              Serum potassium                                  3.8mmol/L                     [3.5-5.0]
              Serum creatinine                                    0.10 mmol/L                  [0.05-0.11]
              Urinary catecholamines                          0.3 micromol/24h           [<0.6]
              Urinary free cortisol                               380 nmol/24h                [100-400]
              Plasma adrenocorticotrophic hormone   <1pmol/L                      [1-15]
              Plasma renin activity                              1.5 nmol/L/h                  [0.4-2.3]

              Which on of the following is the most likely cause of the adrenal mass?

              • Adrenal carcinoma
              • Adrenal metastasis
              • Aldosterone-producing adenoma
              • Cortisol-producing adenoma
              • Non-function adrenal adenoma


              From the lectures and The Incidentally Discovered Adrenal Mass
              Young W. F. Jr. N Engl J Med 2007; 356:601-610, Feb 8, 2007. Clinical Practice

              Adrenal Incidentaloma

              • 2-15% of individuals have adrenal adenomas at autopsy
              • correlated with age <30yrs 0.2%; >70yrs 6.9%

              Differential diagnosis

              • non functioning adenoma
              • adrenocortical carcinoma
              • sub clinical cushing’s syndrome
                • The term "subclinical" Cushing's syndrome is used to refer to autonomous cortisol secretion in patients who do not have the typical signs and symptoms of hypercortisolism. Although the obvious stigmata of Cushing's syndrome are absent, these patients may have the adverse effects of continuous, endogenous cortisol secretion, including hypertension, obesity, diabetes mellitus, and osteoporosis
                • In a report summarizing the results of 13 studies including 2005 patients with adrenal incidentalomas, autonomous cortisol secretion (independent of normal hypothalamic–pituitary control) was found in 5.3% of the patients. Since such patients do not have clinical Cushing's syndrome and may have normal 24-hour urinary cortisol excretion, a measure of autonomous adrenocortical secretion is the best strategy for testing. Because there is no reliable way to distinguish between low-normal values and suppressed values with most commercially available corticotropin assays, adrenal autonomy is best assessed by an overnight dexamethasone (1 mg) suppression test Although the optimal cutoff value is debated, the use of a cortisol level greater than 5 µg per deciliter (138 nmol per liter) is standard to define abnormal values according to this test, because this level is considered to be a reasonable criterion for clinically significant glucocorticoid secretory autonomy. The specificity of the 1-mg overnight dexamethasone suppression test is 91%; if the result is abnormal, confirmatory testing should be performed to rule out a false positive result).
              • Phaeochromocytoma
                • Phaeochromocytomas are rare neoplasms of the chromaffin cells derived from the embryonic neural crest. They are found in fewer than 0.2% of patients with hypertension.1 Most are derived from the adrenal medulla, but the term is also often used for extra-adrenal tumours of the sympathetic nervous system, which may arise in the abdomen, pelvis, thorax, and neck. Both the clinical and biochemical features of phaeo-chromocytomas result largely from the overproduction of catecholamines. Phaeochromocytoma has been called the “10% tumour”, suggesting that 10% are bilateral, 10% malignant, 10% extra-adrenal, and 10% familial.
                • See table for presentation features
                • Measurements of urinary catecholamines and their metabolites, metanephrines, over 24 hours have been the mainstay of biochemical diagnosis of phaeochromocytoma
              • primary hyperaldosteronism
                • Approximately 1% of adrenal incidentalomas have proved to be aldosterone-producing adenomas. Excessive secretion of aldosterone is associated with an increased risk of cardiovascular disease and other disorders, and the normalization of circulating aldosterone levels or mineralocorticoid receptor blockade is warranted in patients with excessive secretion of aldosterone. Screening for hyperaldosteronism is routinely recommended for hypertensive patients who have an adrenal incidentaloma. Given that patients with aldosterone-producing adenomas may have normal levels of potassium in the blood, the measurement of potassium levels is not reliable in screening. A reasonable screening test is the ratio of the ambulatory morning plasma aldosterone concentration to plasma renin activity If this ratio is high, the diagnosis of primary aldosteronism should be confirmed by an additional measurement of mineralocorticoid secretory autonomy
              • other functional adenomas
              • other non functioning mass
                • metastasis
                • haematoma
                • cyst
                • mylolipoma
                • adrenolipoma
                • ganglineuroma
                • neurofibroma
                • harmartoma
                • teratoma

              Is it functional?

              • Up to 20% of incidentalomas are associated with sub clinical Cushing’s syndrome
                • Concept of autonomy rather than hypersecreation
                • Lack typical signs of cushing’s
                • But obese, hypertension and diabetes
              • 5% of incidentalomas are phaeochromocytomas
                • higher in some tertiary referral centres
              • 1% have primary hyperaldosteronism
                • most Conn’s adenomas 0.5-2.0 cm in diameter

              signs and symptoms of adrenal hyperfunction


              • Plasma metanephrines
                Its primary use is to screen symptomatic patients to detect and to help rule out the likely presence of a pheochromocytoma.
                • Or 24h urine catecholamines and metanephrines
                  • Catecholamine testing is primarily used to help detect and rule out pheochromocytomas in symptomatic patients
                  • Urine catecholamine testing measures the total amount of catecholamines released in 24 hours. Since the hormone levels may fluctuate significantly during this period, the urine test may detect excess production that is missed with the blood test.
              • 1mg dexamethasone suppression test
                Almost all sources of inappropriate ACTH or cortisol hypersecretion will not be inhibited by 1mg dexamethasone, therefore, this is an excellent screening test


              • 24h urine free cortisol
                • not appropriate screening test as excessive cortisol secretion not a common feature
                  • Markedly elevated levels of free urinary cortisol are virtually diagnositic of cushing’s syndrome
              • (DHEA-sulphate)
                • low levels suggest benign lesion
                • elevated in adrenal cancer
              • if hypertensive
                • U&E, aldo:renin ratio





              Primary hyperaldosteronism (Conn’s syndrome)




              Secondary hyperaldosteronism




              Cushing’s syndrome




              Adrenal insufficiency (Addison's disease)




              Pituitary disease




              • If hirsute
                • DHEA-sulphate, testosterone, 170H progesterone
                • DHEAS levels are not routinely measured.  Unless you have symptoms that warrant its use, you will most likely never have a DHEAS test done.  DHEAS, testosterone, and several other androgens are used to evaluate adrenal function and to distinguish between androgen secreting adrenal conditions from those that originate in the ovary or testes.  DHEAS can be measured to help diagnose adrenocortical tumors (tumor in the cortex of the adrenal gland), adrenal cancers, and adrenal hyperplasia (which may be congenital or adult onset) and to separate them from ovarian tumors and cancers.

                  Concentrations of DHEAS are often measured, along with other hormones such as FSH, LH, prolactin, estrogen, and testosterone, to help diagnose polycystic ovarian syndrome (PCOS) and to help rule out other causes of infertility, amenorrhea, and hirsutism.

                  DHEAS levels may be ordered, along with other hormones, to investigate and diagnose the cause of virilization in young girls and precocious puberty in young boys.


              • If 1mg DST fails to suppress
                • ACTH, 24 urine free cortisol

              Is it malignant?

              • Incidence of adrenal cancer (rare)
                • 1-2 per million per year
                • 0.1% in unselected incidentaloma cases
                • 4-5% in surgical series
              • suspect metastatic disease if
                • known primary malignancy
                • bilateral adrenal lesions
                • rate of adrenal mets in carcinoma unknown, primary is 6%
                  • only 0.2% have mets confined to the adrenal

              Imaging characteristics



              • small
              • smooth
              • homogenous
              • round to oval
              • low density (<10 hounsfield units)
              • limited contrast enhancement
              • large
              • irregular
              • inhomongenous
              • vascular with strong contrast enhancement
              • higher density (> 10 hounsfield units)
              • bright on T2 MRI scan

              The algorithm should be individualized according to the clinical circumstance, the imaging phenotype of the mass, the patient's age, and the patient's preferences. Given the strong association between the imaging features and pheochromocytoma, some advocate treatment with {alpha}- and beta-adrenergic blockade and tumor resection in patients with this imaging phenotype, even when the results of biochemical testing for pheochromocytoma are normal. The dashed line indicates that for some patients, on the basis of the physician's clinical judgment, serial imaging and hormonal testing may be an alternative approach

              So the question : This man has

              • no localising clues on physical examination
              • is hypertensive
              • normal urinary catecholamines
              • normal free cortisol
              • low plasma ACTH
              • normal renin activity
              Adrenal carcinoma
              • Unlikely
              • Rare
              • Small (3cm) – however no other imaging characteristics indicated
              Adrenal metastasis
              • Unlikely
              • Rare
              • No known primary
              • Unilateral lesion
              Aldosterone-producing adenoma
              • Unlikely as mass is 3cm – too large for Conn’s adenoma
                Cortisol-producing adenoma
                • Comment in lectures that excessive cortisol secretion not a common feature
                • Up to 20% of incidentalomas are associated with sub clinical Cushing’s syndrome
                • Not all suggestive features  apparent – ie T2DM , obesity
                • Explains low ACTH
                • Basically the answer by exclusion
                Non-function adrenal adenoma
                • Usually present with mass effect (visual oss)
                • Hypopituitarism


                Endocrinology: Adrenal Disorders

                Question 50 top Download PDF

                QUESTION 50

                A 50-year-old man with alcohol-induced cirrhosis and portal hypertension presents with haematemesis. He is found to have grade IV oesophageal varices. Bleeding is controlled by an infusion of octreotide and endoscopic band ligation.
                On discharge, which one of the following is least likely to be of benefit with respect to recurrent variceal bleeding?
                A. Interval endoscopic band ligation.
                B. Interval endoscopic sclerotherapy.
                C. Oral beta-blocker therapy.
                D. Oral nitrate therapy.
                E. Oral proton pump inhibitor therapy.

                UK guidelines on the management of variceal haemorrhage in cirrhotic patients
                R Jalan and P C Hayes
                Gut 2000;46; supplement 31-15

                Propranolol. The mainstay of the pharmacological approach to the primary prophylaxis of variceal haemorrhage has been propranolol, which has been shown to reduce the portal pressure gradient, reduce azygos blood flow,
                and also variceal pressure.

                Isosorbide mononitrate. Interest in the use of vasodilators such as isosorbide mononitrate has grown since the demonstration that it reduces portal pressure as effectively51 as propranolol.


                Box 2—Recommendations: primary prophylaxis of variceal bleeding in cirrhosis

                • Pharmacological therapy with propranolol is the best available modality at present. (Recommendation grade AI.)
                •  Aim of therapy with propranolol: Reduction in hepatic venous pressure gradient to less than 12mmHg. (Recommendation grade AI).
                • Dose: Starting dose 40 mg twice daily, increasing to 80 mg twice daily if necessary. Long acting propranolol at either 80 or 160 mg can be used to improve compliance. (Recommendation grade AI.)
                • In case of contraindications or intolerance to propranolol, variceal band ligation is the treatment of choice. (Recommendation grade AI.)
                • In difficult situations where neither propranolol nor variceal band ligation can be used, isosorbide mononitrate is the treatment of first choice (20 mg twice daily). (Recommendation grade BI.)


                • All patients with cirrhosis should be endoscoped at the time of diagnosis. (Recommendation grade CI.)


                •  If at the time of first endoscopy no varices are observed, patients with cirrhosis should be endoscoped at three year intervals. (Recommendation grade AII.)
                •  If small varices are diagnosed, patients should be endoscoped at yearly intervals. (Recommendation grade AII.)


                •  If grade 3 varices are diagnosed, patients should have primary prophylaxis irrespective of the severity of the liver disease. (Recommendation grade AI.)
                •  If patients have grade 2 varices and Child class B or C disease, they should have primary prophylaxis. (Recommendation grade BI.)

                Box 4—Recommendations: secondary prophylaxis of variceal bleeding in cirrhosis
                (1) VARICEAL BAND LIGATION

                • Following control of active variceal bleeding the varices should be eradicated using endoscopic methods. The method of first choice is variceal band ligation. (Recommendation grade AI.)
                • It is recommended that each varix is banded with a single band at weekly intervals until variceal eradication. (Recommendation grade BII.)
                • The use of the over tube should be avoided because this is associated with increased complications. (Recommendation grade BII.)
                • Following successful eradication of the varices, patients should be endoscoped at three months and six monthly thereafter. In case of recurrence of varices they should be treated with variceal eradication. (Recommendation grade AII.)


                • If banding is not available, sclerotherapy should be used. (Recommendation grade BI.)
                • The sclerosant used may vary between institutions. 
                • The interval between treatments should be the same as those outlined above for banding. (Recommendation grade AII.)


                • Either combination treatment of sclerotherapy and non-selective beta blocker or non-selective beta blocker alone may be used. If the latter strategy is used then it is recommended that patients should have the hepatic venous pressure gradient measured to confirm that this has been successfully reduced to less than 12 mm Hg. (Recommendation grade AII.)

                (4) TIPSS

                • TIPSS is more effective than endoscopic treatment in reducing variceal rebleeding but does not improve survival and is associated with more encephalopathy. It is a treatment option that may be used in certain centres with particular expertise. (Recommendation grade AI.)

                A. Interval endoscopic band ligation.
                B. Interval endoscopic sclerotherapy.
                C. Oral beta-blocker therapy.
                D. Oral nitrate therapy.
                E. Oral proton pump inhibitor therapy.  – not discussed

                Answer E


                Gastroenterology: CLD complications


                Question 51 top Download PDF

                A 48-year-old previously well man, currently smoking 10 to 20 cigarettes/day, presents with the progressive onset over several months of lethargy and headache. He takes no medications.
                Examination reveals him to be plethoric and hypertensive with no other significant findings.
                Full blood examination shows:
                haemoglobin                                         216 g/L [135-170]
                mean corpuscular volume (MCV)            76 fL [80-95]
                white cell count                                                 13.3 x 109/L [3.5-9.5]
                neutrophils                                10.2 x 109/L [1.5-6.0]
                bands                                       1.5 x 109/L
                myelocytes                               0.2 x 109/L
                monocytes                                0.3 x 109/L [0.2-0.6]
                eosinophils                                           0.8 x 109/L [0-0.4]
                basophils                                              0.30 x 109/L [0-0.15]
                platelet count                                        474 x 109/L [150-400]


                Which one of the following would most strongly support a diagnosis of polycythaemia vera?
                A. Raised serum vitamin B12 level.
                B. Elevated total red cell mass.
                C. Normal marrow karyotype.
                D. Elevated serum uric acid level.
                E. Lowered serum erythropoietin level.

                Polycythemia vera (PV) is one of the chronic myeloproliferative disorders, which are collectively characterized by clonal proliferation of myeloid cells with variable morphologic maturity and hematopoietic efficiency . PV is distinguished clinically from the other myeloproliferative disorders by the presence of an elevated red blood cell mass (RCM). However, an increased RCM alone is insufficient to establish the diagnosis, since this finding is also observed in a variety of conditions associated with chronic hypoxia and, rarely, with tumors that secrete erythropoietin

                Diagnostic Criteria for PCV

                Increased red blood cell mass — 

                • RCM, normalized to body surface area, should be considered elevated if it is more than 25 percent above the mean expected value
                • The majority of female patients with a hemoglobin concentration >16.5 g/dL (or hematocrit [HCT] above 50 percent) and all male patients with a hemoglobin concentration >18.5 g/dL (or HCT above 56 percent) have an increased RCM

                Palpable splenomegaly — 

                • Since splenomegaly may not always be detectable by physical examination, other diagnostic criteria accept the finding of a nonpalpable spleen that is enlarged on an imaging test as a minor or secondary criterion.

                Thrombocytosis and leukocytosis —

                • an absolute neutrophil count >10,000/microL .

                Leukocyte alkaline phosphatase and serum B12 studies — 

                • Although an elevated LAP score is reasonably sensitive for PV (approximately 70 percent), it is not specific.
                • B12 studies are neither sensitive nor specific.
                • As a result, the LAP score and B12 studies are not included as major or minor criteria in any of the newer published algorithms

                False positive results — 

                • secondary causes of an elevated RCM are much more common than PV
                • It has been estimated that the practicing hematologist sees 10 cases of relative or secondary polycythemia for every new patient with PV
                • Application of the PVSG criteria may lead to false positive results in patients with cirrhosis who smoke heavily. Cirrhosis may be associated with splenomegaly, while concomitant smoking may lead to an elevated RCM due to high levels of carbon monoxide and/or the development of chronic obstructive pulmonary disease.  Similarly, since splenomegaly, leukocytosis, and thrombocytosis are common to all of the chronic myeloproliferative diseases , a patient with chronic myelogenous leukemia, essential thrombocythemia, or agnogenic myeloid metaplasia (AMM) who has an elevated hematocrit for another reason (eg, hypoxia, smoking) may be falsely diagnosed as having PV. This is an important distinction clinically because each of these disorders is treated in a different manner.

                False negative results — 

                • false negative results occur in approximately 10 percent of patients
                •  Calculation of the red blood cell mass may be falsely low in patients who are obese.
                • Patients with PV who have had significant recent gastrointestinal blood loss ("bled down" polycythemia) may present with a normal hematocrit. Such patients may be incorrectly diagnosed as having iron deficiency or essential thrombocythemia since their high platelet counts, low red blood cell indices, and low serum ferritin concentrations may be the most striking features.
                • Patients who have PV and are also hypoxic for unrelated reasons (eg, coexisting chronic lung disease) will not fulfill the PVSG criteria.
                • An increased red cell mass may not be apparent in patients with early PV, less severe disease, or an elevated plasma volume .   
                • patients with severe complications related to PV (eg, Budd-Chiari syndrome) but without classical features of the disease may not fulfill the classic PVSG criteria.

                Bone marrow aspiration and biopsy — 

                • An increased number of megakaryocytes in a moderately to markedly hypercellular marrow has been considered one of the diagnostic hallmarks of PV

                Clonal markers — 

                • deletion of the long arm of chromosome 20, trisomy for chromosomes 8 or 9, or loss of heterozygosity on the short arm of chromosome 9 are found in up to 30 percent of previously untreated patients with PV
                • chromosome 9p24 houses the JAK2 gene, which carries a somatic point mutation in the vast majority of patients with PV

                Serum erythropoietin — 

                • low serum erythropoietin (EPO) concentrations

                The question is asking  for a differentiating factor between primary PCV and polycythaemia from other causes eg hypoxia
                A. Raised serum vitamin B12 level.
                Could be raised in eith
                B. Elevated total red cell mass.
                Needs to be relative to mass and clinical circumstance, not a useful measure and not a good distinguishing factor
                C. Normal marrow karyotype.
                Could be normal in either
                D. Elevated serum uric acid level.
                Not related
                E. Lowered serum erythropoietin level.
                In acquired polycytheamia eg hypoxia, erythropoietin will be high as renal cells responding to hypoxia but low in PCV


                Haematology: Polycythaemias-primary and secondary


                Question 52 top

                Question 53 top

                Question 54 top Download PDF

                A 54-year-old man with methicillin-resistant Staphylococcus aureus (MRSA) sternal osteomyelitis is receiving ongoing treatment with vancomycin. Shortly after administration of his vancomycin dose, he develops diffuse erythema and hypotension.
                The most likely cause is:
                A. hypersensitivity to vancomycin.
                B. rapid intravenous infusion of vancomycin.
                C. endotoxin release.
                D. impurities in the infused vancomycin preparation.
                E. bacterial contamination of the vancomycin preparation.

                Answer B. rapid intravenous infusion of vancomycin


                RED MAN SYNDROME — The most common adverse reaction to vancomycin is RMS, which also may be called "red neck syndrome". It is described as an infusion-related histamine-like reaction, characterized by flushing (upper body more predominant than lower body), pruritus, chest pain, muscle spasms, and occasionally hypotension. RMS can rarely manifest with severe and profound cardiovascular toxicity; several case reports note profound hypotension  and even cardiac arrest. The reported frequency of the syndrome varies widely from as low as 10 percent  to as high as 70 to 90 percent .

                The majority of the studies suggest that there is an association between elevated plasma histamine levels and RMS, especially with severe episodes. However, at least one study found no close association between plasma histamine concentrations and vancomyin-related RMS , suggesting that there may also be other mediators of the observed clinical manifestations.

                RMS is usually not life-threatening. The syndrome may be effectively prevented by pretreatment with anti-histamines, and slower infusion rates of vancomycin may reduce the frequency and severity of the reactions. One study in 10 normal volunteers analyzing histamine levels, occurrence and severity of RMS, and vancomycin infusion time found a higher incidence of RMS and increased severity when vancomycin was infused over one hour compared to when the same volunteers received the drug over two hours; peak plasma histamine levels and the total release of histamine were greater during the one-hour infusion


                Pharmacology: Infections


                Question 55 top

                Question 56 top

                Question 57 top Download PDF

                A 67-year-old woman presents with a two-week history of blurred vision and a constant bifrontotemporal headache.  Visual acuity is 6/9 bilaterally.  Visual fields to confrontation reveal an arcuate scotoma defect in both eyes.  Colour vision is normal.  The remainder of the neurological examination and the general examination are normal
                Fundoscopy of the right eye is shown below.

                The most likely diagnosis is:
                A.  central retinal vein occlusion
                B. anterior ischaemic optic neuropathy
                C. papilloedema
                D. venous stasis retinopathy
                E. diabetic retinopathy

                Central retinal vein occlusion — Occlusion or thrombosis of the central retinal vein is associated with chronic glaucoma, atherosclerotic risk factors (age, diabetes, hypertension), hyperviscosity, and coagulopathy . The cause is often unknown.
                The disc is typically congested. Hemorrhages extend far beyond the posterior pole of the eye into the retinal periphery and are more extensive than in papilledema. Vision loss corresponds to the hemorrhages and any superimposed retinal ischaemia

                Anterior ischemic optic neuropathy — Anterior ischemic optic neuropathy (AION) may be arteritic (eg, giant cell arteritis) or nonarteritic . The latter occurs in elderly individuals and is associated with atherosclerotic risk factors, particularly hypertension and diabetes. Nonarteritic AION has also been described in patients treated with phosphodiesterase-5 inhibitors such as sildenafil.

                AION is almost always unilateral except in giant cell arteritis. There is always immediate loss of some or all of the vision; altitudinal defects are classic. An afferent pupillary defect is common. Prognosis for vision recovery is poor.

                The swelling is not congested but usually pallid; if there are hemorrhages, they are small splinter shaped on the edge of the disk


                While the term papilledema is often used broadly to denote a swollen optic nerve head, papilledema specifically refers to bilateral optic disc swelling that is due to raised intracranial pressure.

                 Papilledema occurs when raised intracranial pressure is transmitted to the optic nerve sheath. The raised pressure mechanically disrupts axoplasmic flow within the nerve. Obstipation of intra-axonal fluid results in swelling of the axons and leakage of water, protein, and other cellular contents into the extracellular space of the optic disc giving rise to optic disc edema . Venous obstruction and dilation, nerve fiber ischemia, and vascular telangiectasias are secondary phenomena.

                Any entity that increases intracranial pressure may lead to papilledema. These include: Intracranial mass lesions Increased cerebrospinal fluid (CSF) production, eg, choroid plexus papilloma Decreased CSF absorption, eg, arachnoid granulation adhesions after bacterial meningitis Obstructive hydrocephalus Obstruction of venous outflow, eg, venous sinus thrombosis

                Diabetic retinopathy – range of presentations


                for other images


                Neurology:visual failure

                Question 58 top

                Question 59 top Download PDF

                A 67-year-old man with chronic obstructive pulmonary disease (COPD) has severe exertional dyspnoea and is receiving maximal inhaled bronchodilator therapy. He no longer smokes.
                Lung function tests are as follows:

                forced expiratory volume in one second (FEV1) forced vital capacity (FVC)
                total lung capacity (TLC) 
                 residual volume (RV)  
                diffusing capacity for carbon monoxide (DLCO)

                0.54 L (18% predicted)  
                2.87 L (75% predicted)
                7.96 L (121% predicted)
                5.09 L (245% predicted)
                6.1 mL/min/mmHg (19% predicted)

                Arterial blood gases on room air are as follows:
                PaO2 65 mmHg
                PaCO2 52 mmHg
                pH 7.36

                What is the most appropriate management to reduce this man’s exertional dyspnoea?
                A. Inhaled corticosteroids.
                B. Pulmonary rehabilitation program.
                C. Lung volume reduction surgery.
                D. Supplemental oxygen.
                E. Lung transplantation.

                COPD-X 2007
                In severe COPD: smoking reduction the only effective means to affect the decline in lung function – already achieved in this patient

                • Inhaled corticosteroids should be considered  in patens with a documented response or those who have severe COPD with frequent exacerbations – level II evidence
                • Pulmonary rehab – reduces dyspnoea, anxiety and depression, improves exercise capacity and OL and may reduce hospitalisation – level I evidence
                • Lung volume reduction surgery – selected patients symptom relief – level III-2 evidence
                • Supplemental oxygen – no evidence for supplemental oxygen only long term
                • Lung transplantation – selected patients symptom relief – level III-2 evidence

                Answer: B pulmonary rehab


                Respiratory Smoking-related chronic lung disease


                Question 60 top

                repeat question see

                2002 paper two question 13

                2005 paper two question 12

                Question 61 top

                Question 62 top

                Question 63 top Download PDF

                Which one of the following medications is most likely to result in an increase in circulating insulin concentrations?

                A. Metformin

                B. Acarbose

                C. Rosiglitazone

                D. Repglinide

                E. Orlistat (Xenical)



                • Antihyperglycaemic agent, which improves glucose intolerance in T2DM subjects lowering both basal and postprandial plasma glucose.  Metformin causes an increased peripheral uptake of glucose by increasing the biological efficiency of available exogenous or endogenous insulin
                • The mode of action of metformin may be linked to increased insulin sensitivity.  It does not stimulate insulin release but does require the presence of insulin to exert its antiyperglycaemic effect.  Possible mechanisms of action include inhibition of gluconeogensis in the liver, delay in glucose absorption from the gi tract and an increase in peripheral uptake of glucose.


                • Hypoglycaemic agent
                • Acrabose action depends on an inhibition of intestinal enzymes (alpha-glucosidases) involved in the degradation of ingested disaccharides, oligosaccharides and polysaccharides, but not monosaccharides.  Maximal specific inhibitory activity is against sucrose.  This leads, dose dependently, to a delayed digestion of the above carbohydrates.  The result is that absorbably monosaccharides (dextrose) originating from carbohydrates re released more slowly and hence are taken up into blood more slowly.


                • Hypoglycaemic agents
                • A selective and potent agonist at the peroxisomal proliferator activated gamma nuclear receptor and is a member of the thiazolidinedione class of antidiabetic agents
                • Improves glycaemic control by improving insulin sensitivity at key sites of insulin resistance, namely adipose tissue, skeletal muscle and liver


                • A novel short-acting oral hypoglycaemic agent structurally unrelated to the sulfonylureas drugs.  It lowers blood glucose levels acutely by stimulating the release of insulin from the pancreas, an effect which is dependent upon functioning beta-calls in the pancreatic isles.

                Orlistat (Xenical)

                • Anorectic and weight reducing agent
                • Potent, specific and reversible long acting inhibitor of gastrointestinal lipases, which are required for the systemic absorption of dietary triglycerides


                Pharmacology: Endocrinology

                repeated question 2005 paper two question 45


                Question 64 top

                Question 65 top Download PDF

                A 36-year-old man presents in a post-ictal state after an observed generalised seizure.
                Full blood investigation shows:
                haemoglobin                                                     90 g/L [128-175]
                mean corpuscular volume (MCV)                        106 fL [80-97]
                white cell count                                                             12.6 x 109/L [3.9-12.7]
                neutrophils                                            10.4 x 109/L [1.9-8.0]
                lymphocytes                                         0.8 x 109/L [0.9-3.3]
                monocytes                                            1.1 x 109/L [0.3-1.1]
                eosinophils                                           0.2 x 109/L [0-0.5]
                basophils                                              0.1 x 109/L [0-0.1]
                platelet count                                                    135 x 109/L [150-396]
                The blood film is shown below.

                The most likely cause of the peripheral blood macrocytosis is:
                A. β-thalassaemia trait.
                B. myelodysplasia.
                C. alcoholic liver disease.
                D. hereditary spherocytosis.
                E. myelofibrosis.

                Anaemia – macrocytic
                Slight thrombocytopenia
                Target cells +++

                Alcholic Liver Disease

                • target cells

                Liver disease, particularly if caused by alcohol, is a common cause of macrocytosis, which is often accompanied by target cell formation . The mechanism is not known but increased lipid deposition on red cell membranes, similar to that seen in hyperlipidemia may be involved

                Peripheral smear shows multiple target cells which have an area of central density surrounded by a halo of pallor (arrows). These cells are characteristic of liver disease and certain hemoglobinopathies (most notably hemoglobin C disease)


                Beta thatlasseamia trait

                • Anaemia,
                • Microcytosis - decreased MCV


                  • Profound microcytic anemia  (3-4 g)
                  • bizarre red cell morphology is a hallmark of this syndrome
                  • extreme hypochromia and poikilocytosis, a predominance of microcytes, tear drop and target cells
                  • The white blood cell (WBC) count is often strikingly high, and
                  • the reticulocyte count surprisingly low, reflects the severe degree of ineffective erythropoiesis underlying the disorder, resulting in many fewer than the expected number of reticulocytes being released from the bone marrow.
                  • The platelet count is usually normal. However, hypersplenism can lower both white cell and platelet counts.
                  • Because of the high rate of erythroid cell turnover, the serum iron level is usually elevated; the transferrin saturation, expressed as the ratio of serum iron to total iron binding capacity (or transferrin), is very high . The serum is often icteric, and increased concentrations of indirect (unconjugated) bilirubin and lactate dehydrogenase, and low levels of haptoglobin, findings typical of hemolytic disease, are usually present.

                  Peripheral smear from a patient with beta thalassemia intermedia post-splenectomy. This field shows target cells, hypochromic cells, microcytic cells, red cell fragments, red cells with bizarre shapes, and a single nucleated red cell (arrow).


                  • Dysplastic changes
                  • Neutrophilia

                  Virtually all patients with the myelodysplastic syndrome will have macrocytic anemia at presentation, along with varying degrees of neutropenia, monocytosis, circulating blast forms, reticulocytopenia, and thrombocytopenia.

                  Myelodysplastic syndromes, in their early stages, may be a common cause of apparently idiopathic macrocytic anemia, particularly in elderly patients.


                  Hereditary spherocytosis

                  • Spherocytes on film and bm (round no central pallor)

                  Routine blood counts in HS reveal anemia and reticulocytosis to varying degrees, depending upon the severity of the mutation. The usual reticulocyte count is from 5 to 20 percent. The mean corpuscular volume (MCV) is normal or slightly low and is of little diagnostic value. However, considering the degree of reticulocytosis, the MCV is actually low.

                  The most helpful red cell index is the mean cell hemoglobin concentration (MCHC) which is routinely elevated, reflecting membrane loss and red cell dehydration

                  Peripheral blood smear shows multiple spherocytes which are small, dark, dense hyperchromic red cells without central pallor (arrows). These findings are compatible with hereditary spherocytosis or autoimmune hemolytic anemia.


                  • Bone marrow fibrosis
                  • Pancytopenia
                  • Tear drop cells
                  • Blasts


                  • Anemia with hemoglobin less than 10 gm causes nclude:
                    • Reduction in medullary erythropoietic sites Ineffective erythropoiesis associated with extramedullary sites of red blood cell (RBC) production
                    • Splenic sequestration and destruction of circulating RBCs Bleeding due to thrombocytopenia or other complications such as varices resulting from portal vein thrombosis
                    • Autoimmune hemolysis
                    • Dilutional "anemia" may be present in patients with large spleens and expanded plasma volumes, but normal red blood cell mass.


                  • The platelet and white blood cell (WBC) counts are variable
                  • Thrombocytopenia becomes more common with disease progression.

                  Leukoerythroblastic peripheral blood smear showing the presence of nucleated red cells and immature white cells. This pattern occurs with marrow replacement, usually due to fibrosis that may be idiopathic (eg, myelofibrosis with agnogenic myeloid metaplasia) or reactive to conditions such as metastatic cancer.

                  Bone marrow biopsy in myelofibrosis shows replacement of the marrow with fibrous tissue.





                  Question 66 top

                  Repeat question 2002 paper two question 9


                  Infectious Diseases: HIV


                  Question 67 top Download PDF

                  QUESTION 67

                  A 26-year-old male dairy farmer presents with a five-day history of malaise, myalgia, headache and fever. His temperature is 39.3°C. He has mild neck stiffness.

                  Blood investigations show:
                  white cell count 11.3 x 109/L [3.5-10.5]
                  neutrophils 8.7 x 109/L [2.0-7.5]
                  lymphocytes 2.6 x 109/L [0.9-4.3]
                  alkaline phosphatase (ALP) 177 U/L [31-110]
                  alanine transaminase (ALT) 94 U/L [6-45]
                  Cerebrospinal fluid (CSF) analysis:
                  white cell count 40 x 106/L [<5]
                  neutrophils 28 x 106/L [<2]
                  lymphocytes 12 x 106/L [<2]
                  Urinalysis shows 1+ proteinuria.

                  He is given a single dose of ceftriaxone after the lumbar puncture. 24 hours later, he is feeling much better and CSF culture is negative.
                  Therapy with which one of the following is now most appropriate?

                  A. Ceftriaxone.
                  B. Metronidazole.
                  C. Benzylpenicillin.
                  D. Doxycycline.

                  Mmm interesting but I don’t agree with the answer is D. Doxycyline
                  so the thing they are trying to test is the knowledge of Q fever

                  Q fever, caused by the rickettsia Coxiella burnetii, is frequently an occupational disease of workers in the livestock industry and of veterinarians.  The classic patient is a febrile abattoir worker.  Common animal reservoirs include cattle, sheep and goats, although many mammalian hosts can become infected.  The organism is extremely infectious, and the tissues and fluids of infected animals are potential sources.  Dusts around stock facilities are also sources of infection because the organism isresistant to desiccation.  Hence, people without direct animal contact (such as staff working in an abattoir office or people livine near an abattoir) can be infected via inhalation.

                  The incubation period is 2-6 weeks.  Q fever may result in asymptomatic infection, or it may present as an acute febrile illness or progress to chronic disease.  Both acute and chronic infections commonly present as a febrile illness with few localising symptoms or signs.
                  Some reported presentations

                  • Hepatomegaly
                  • Splenomegaly
                  • Hepatitis
                  • Pneumonia
                  • Endocarditis
                  • Osteomyelitis
                  • Arteritis
                  • Granulomatous disease of the liver and testes

                  Diagnosis is based on the presence of IgM and a significant risk in IgG antibody titre in serum, which may take 2-6 weeks to develop
                  Treatment is with oral doxycycline; chloramphenicol is a possible alternative
                  An effective vaccine is available for those at occupational risk


                  Infectious Disease: occupational and geographical settings

                  Question 68 top

                  Question 69 top

                  Question 70 top

                  Question 71 top

                  Question 72 top

                  Question 73 top

                  Question 74 top

                  Question 75 top Download PDF

                  Question 75

                  A 45-year-old immunodeficiency virus (HIV)-positive man presents with a two-month history of numbness in both feet.  Examination reveals bilateral loss of light touch to mid-calf, reduced vibration sense at the ankle and absent ankle jerks.  His CD4 positivt (CD4+) T cell count is 250 cells/microL and HIV viral load is 5000 copies/ml.  His current anti-retroviral (ARV) drug therapy is stavudine (D4T), lamivudine (3Tc) and nevirapine.

                  The most likely diagnosis is

                  A.  Guillain-Barré syndrome
                  B. HIV-induced neuropathy
                  C. cytoegalovirus (CMV) neuropathy
                  D. ARV-induced neuropathy
                  E. vitamin B12 deficiency

                  There are a number of distinctive neuropathic syndromes, which can be classified according to the timing of their appearance during HIV infection, their etiology, and whether they are primarily axonal or demyelinating. The most common of these is peripheral neuropathy, also referred to as distal symmetric peripheral neuropathy .

                  EPIDEMIOLOGY —

                  • prevalence 9 to 63 percent ,variability reflects differences in the degree of immunosuppression (higher prevalence with more advanced disease), in the definition of the neuropathy (symptomatic or asymptomatic), and in exposure to neurotoxic antiretrovirals

                  Risk factors

                  • advanced immunosuppression
                  • the level of HIV viremia also correlated increased 2.3-fold in patients with an HIV RNA level >10,000 copies/mL
                  • aging,
                  • additional medical problems such as diabetes,
                  •  the nadir CD4 count,
                  • nutritional deficiencies,
                  • mitochondrial polymorphisms
                  • toxicities of dideoxynucleosides  - the use of didanosine, stavudine, and nevirapine. The combination of didanosine, stavudine, and hydroxyurea was particularly neurotoxic ; this combination is no longer used as antiretroviral treatment.

                  Effect of HAART on natural history — In most studies, the incidence of HIV-associated DSPN appears to have decreased compared to pre-HAART cohorts, suggesting that effective suppression of HIV itself may have a beneficial effect on peripheral nerve function

                  PATHOGENESIS —

                  • multifactorial.
                  • DSPN is termed a "dying-back" neuropathy to reflect the pattern of distal fiber loss It involves myelinated and unmyelinated axons of all sizes; this pattern of axon loss is indistinguishable from that seen with other toxic neuropathies.
                  • HIV itself may lead to local axonal injury through two separate mechanisms
                    •  indirect route is via neuronal apoptosis
                    • direct, local toxicity mediated through activation of mitochondrial caspases.

                  Many patients with HIV are also coinfected with hepatitis C, which is also associated with peripheral neuropathy [32]. It is unknown as to whether there are additive or synergistic effects of these two viruses on peripheral nerve function.

                  Role of drugs

                  • Many cases of distal symmetrical polyneuropathy are iatrogenic, due to intrinsic neuronal toxicities of certain antiretroviral medications
                  • The neuropathy is indistinguishable electrophysiologically from HIV-associated DSPN, although the hands may be affected more often in drug-induced cases
                  • The incidence of neuropathy is dose-dependent and increases with the duration of drug exposure
                  • The onset is typically seven to nine weeks after beginning therapy.
                  • The incidence of drug-related neuropathy correlates directly with the degree of mitochondrial toxicity of particular nucleoside reverse transcriptase inhibitors, although a direct link between toxicity and oxidant stress has not been demonstrated
                  • Commonly implicated agents include stavudine (d4T) and to a lesser extent didanosine (ddI) The greatest risk was seen with the use of zalcitabine (ddC), which is rarely used by clinicians today.
                  • The potential neurotoxicity of antiretroviral drugs does not preclude their use, since the beneficial effects on viral load suppression and immune function recovery appears to outweigh their potential neurotoxicity
                  • Other medications
                    • Vincristine, which may be used to treat Kaposi's sarcoma
                    • Dapsone, which may be used to treat or prevent Pneumocystis jiroveci (formerly carinii) pneumonia
                    • Thalidomide, which may be used to treat aphthous ulcers
                    • Isoniazid and ethambutol, which are used to treat tuberculosis
                    • Nevirapine, a non-nucleoside reverse transcriptase inhibitor, used to treat HIV infection.


                  •  usually manifests as bilateral tingling, and numbness in the toes. The neuropathy gradually spreads proximally in the lower extremities, with only rare involvement of the upper extremities.
                  • The spread of sensory symptoms usually occurs over weeks to months. Neuropathic pain is common and may be the presenting symptoms
                  • Neurologic examination shows
                    •  sensory loss to all sensory modalities (vibration, pinprick, temperature) in a stocking distribution,
                    • deep tendon reflexes are reduced or absent at the ankles and occasionally at the knees in more severe cases [
                    • Distal weakness in the lower extremities can occur, although most patients have only sensory symptoms and signs.
                    •  Sensory findings in the hands are more commonly associated with drug toxicity. HIV-related DSPN may evolve from painful to painless numbness.
                    • The presence of brisk knee reflexes in patients with sensory loss raises the possibility of coexistent myelopathy,
                    • while the presence of proximal weakness or diffuse areflexia should prompt consideration of acquired inflammatory demyelinating polyradiculoneuropathy, such as Guillain-Barre syndrome

                  DIAGNOSIS — The diagnosis of peripheral neuropathy syndromes in HIV-infected patients is based mainly upon the clinical picture and physical examination.

                  Features that would prompt further evaluation, such as electromyography (EMG) and nerve conduction studies (NCS), may include significant weakness or asymmetry of signs. These findings may raise the possibility of alternative diagnoses (eg, acquired demyelinating polyradiculoneuropathy or vasculitic neuropathy).

                  Laboratory testing — The evaluation of distal symmetrical polyneuropathy should include blood work to screen for other causes of this type of neuropathy. A typical panel would include: Hepatitis C antibody Vitamin B12 and folate levels Thyroid stimulating hormone assay Blood glucose Blood urea nitrogen and creatinine Serum protein electrophoresis and immunoelectrophoresis RPR

                  Although these laboratory tests are considered routine in the evaluation of DSPN, they are usually unremarkable in HIV-related or drug-induced polyneuropathy.

                  TREATMENT — Treatment options for HIV-related and drug-induced distal symmetrical polyneuropathy are limited.

                  • HAART
                  • If potentially neurotoxic drug is being used, such as stavudine (d4T), or didanosine (ddI), or thalidomide, it should be discontinued whenever possible.


                  Symptomatic approach —. The classes of drugs used include anticonvulsants, tricyclic antidepressants, topical analgesics, anti-inflammatories, and opioids for recalcitrant symptoms.

                  Guillain-Barré syndrome

                  cardinal clinical features of Guillain-Barré syndrome (GBS) are

                  • progressive, fairly symmetric muscle weakness
                  • accompanied by absent or depressed deep tendon reflexes.
                  • Patients usually present a few days to a week after onset of symptoms.
                  • The weakness can vary from mild difficulty with walking to nearly complete paralysis of all extremity, facial, respiratory, and bulbar muscles.

                  Unusual features of GBS include papilledema, facial myokymia, hearing loss, meningeal signs, vocal cord paralysis, and mental status changes.

                  GBS usually progresses over a period of about two weeks. By four weeks after the initial symptoms, 90 percent of GBS patients have reached the nadir of the disease. Disease progression for more than eight weeks is consistent with the diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)

                  cytoegalovirus (CMV) neuropathy

                  Neurologic manifestations — CMV infection has been associated with numerous neurologic sequelae in the immunocompetent host.

                   Encephalitis — Although rare, encephalitis is a serious potential complication of CMV infection and this entity should be considered in the differential diagnosis of unexplained encephalitis.

                   Guillain-Barré syndrome — Guillain-Barré syndrome (GBS) has been associated with a variety of infectious agents, including Campylobacter and CMV.   Patients with CMV-related GBS are generally younger and experience more prominent sensory deficits, respiratory insufficiency, and cranial nerve impairments than those with Campylobacter-related and idiopathic forms of the syndrome. Recovery from GBS also appears to be slower in patients in whom either CMV or Campylobacter infections are identified .

                   Other — Other focal neurologic deficits have been described in patients with CMV, including brachial plexus neuropathy, diffuse axonal peripheral neuropathy, transverse myelitis, Horner's syndrome , and cranial nerve palsie

                  vitamin B12 deficiency
                  Vitamin B12 (cobalbim) and folate deficiency - Nutritional megaloblastic anemias
                  The term identifies patients with anemia and macroovalocytic red cells (mean corpuscular volume greater than 100 fL). The bone marrow shows intense erythroid hyperplasia with an abnormal morphology. The megaloblast, the morphologic hallmark of the syndrome, is a product of impaired DNA formation which in turn is due to deficiencies of vitamin B12 (cobalamin, Cbl) or folic acid (FA) . Other causes of impaired DNA or RNA formation, such as antimetabolite drugs and myelodysplastic syndrome, can also lead to megaloblastic anemia.

                  The neurologic problems, when present, consist of the classic picture of subacute combined degeneration of the dorsal (posterior) and lateral spinal columns. This lesion, specific for Cbl deficiency, is due to a defect in myelin formation of unknown mechanism. The neuropathy is symmetrical and affects the legs more than the arms. It begins with paresthesias and ataxia associated with loss of vibration and position sense, and can progress to severe weakness, spasticity, clonus, paraplegia, and even fecal and urinary incontinence .

                  Other neurologic abnormalities that can be seen include axonal degeneration of peripheral nerves and central nervous system symptoms including memory loss, irritability, and dementia . Patients may present with Lhermitte's syndrome, a shock-like sensation that radiates to the feet during neck flexion.

                  Of great clinical importance, not all patients with neurologic abnormalities secondary to Cbl deficiency are either anemic or have macrocytic red cell indices.

                  A similar neurologic syndrome can be seen in patients with copper deficiency, and the two conditions may coexist. Thus, continued neurologic deterioration in a patient with a history of Cbl deficiency- related myelopathy and normal Cbl levels while receiving Cbl replacement therapy should be evaluated for copper deficiency

                  So the question
                  Clinical features:

                  • Timing 2/12
                  • Sensation: loss light touch, reduced vibration bilateral
                  • Reflexes absent at ankle
                  • CD4 count 250
                  • Viral load 5000
                  • Meds stavudine, lamivudine, nevirapine

                  A.  Guillain-Barré syndrome
                  Time frame 2/52 – 4/52, weakness major feature

                  B. HIV-induced neuropathy
                  Could be but mechanism?

                  C. cytoegalovirus (CMV) neuropathy
                  Often GBS

                  D. ARV-induced neuropathy
                  Appropriate time frame and clinical picture
                  Commonly implicated agents include stavudine (d4T) and to a lesser extent didanosine (ddI) The greatest risk was seen with the use of zalcitabine (ddC), which is rarely used by clinicians today

                  E. vitamin B12 deficiency
                  Not the most likely from the clinical picture

                  Answer D


                  Neurology: peripheral neuropathy


                  Question 76 top Download PDF

                  Question 76
                  A 75-year-old woman with longstanding rheumatoid arthritis complains of neck pain.  X-rays of her cervical spine demonstrate the changes shown below
                  Which one of the following is most likely to accomany these changes?

                  A.  sensory loss in the C2 dermatome
                  B. Horner’s syndrome
                  C.  wasting of the small muscles of the hands
                  D. Lower motor neurone changes in the upper limbs.
                  E. Upper motor neurone changes in the upper limbs.

                  Cervical subluxation in rheumatoid arthritis


                  CERVICAL INVOLVEMENT — Cervical joint destruction in patients with RA may lead to vertebral malalignment (eg, subluxation). Risk factors for development of cervical subluxation include older age at onset of RA, more active synovitis, and rapidly progressive erosive peripheral joint disease. Both atlantoaxial and subaxial (below C1-C2) joints may be involved.

                  Atlantoaxial disease —

                  • Among the joints of the cervical spine, the atlantoaxial joint is prone to subluxation in multiple directions. The atlas (C1) can move anteriorly, posteriorly, vertically, laterally, or rotationally relative to the axis (odontoid and body of C2):
                  • Abnormal anterior movement on the axis is the most common type of subluxation. It often results from laxity of the transverse ligament induced by proliferative synovial tissue in an adjacent synovial pouch, but may also occur as a result of erosion or fracture of the odontoid process .
                  • Posterior movement on the axis can occur only if the odontoid peg has been fractured from the axis or destroyed.
                  • Atraumatic posterior subluxation is rarely associated with cervical myelopathy .
                  • Vertical movement in relation to the axis is least common; it results from destruction of the lateral atlantoaxial joints or of bone around the foramen magnum .
                  • Vertical atlantoaxial subluxation may occur in those with initial anterior-posterior subluxation. Vertical subluxations are believed to have a worse prognosis than the other varieties .

                  The involvement and severity of cervical spine disease in RA parallels the progression of peripheral joint erosions. As a result, cervical subluxation is more likely in those with erosions of the hand, feet, hips and/or knees

                  Symptoms — Involvement of cervical joints may result in

                  • significant pain
                  • range of motion may be normal in the absence of muscle spasm.
                  • The earliest and most common symptom of cervical subluxation is pain radiating superiorly towards the occiput .
                  • Additional symptoms of subluxation include:
                    • Spastic quadriparesis which is slowly progressive
                    • Sensory findings are also common, including painless sensory loss in the hands or feet. In patients with C1-C2 subluxation, transient episodes of medullary dysfunction (such as respiratory irregularity) associated with vertical penetration of the odontoid process of C2 and probable vertebral artery compression. Movement of the hands in this setting may result in paresthesias in the shoulder or arms.
                  • Neurologic findings in patients with vertical atlantoaxial subluxation may also include decreased sensation in the distribution of the fifth cranial nerve, sensory loss in the C2 area, nystagmus, and pyramidal lesions. (one of a group not isolated finding)
                  • The symptoms of spinal cord compression that demand immediate attention and intervention include :
                    •  A sensation of the head falling forward upon flexion of the cervical spine
                    •  Changes in levels of consciousness
                    • "Drop" attacks
                    • Loss of sphincter control
                    • Respiratory dysfunction
                    • Dysphagia,
                    • vertigo,
                    •  convulsions,
                    • hemiplegia,
                    •  dysarthria, or nystagmus
                    • Peripheral paresthesias without evidence of peripheral nerve disease or compression



                  Physical findings — Physical findings relating to the spine which are suggestive of atlantoaxial subluxation include: Loss of occipito-cervical lordosis Resistance to passive spine motion Abnormal protrusion of the axial arch felt by the examining finger on the posterior pharyngeal wall

                  In addition, neurologic findings appropriate to the symptoms described above may be seen, including:

                  • Increased deep tendon reflexes
                  • Extensor plantar responses
                  •  Muscle weakness, spasticity, or muscle atrophy Gait disorders

                  All upper motor neuron changes

                  RADIOGRAPHIC FINDINGS — Among patients with atlantoaxial subluxation, plain radiographic views of the cervical spine (lateral, with the neck in flexion) may reveal more than 3 mm of separation between the odontoid peg and the C1 arch . Separation between C1 and C2 (anterior subluxation) of 9 mm or more, or a posterior atlanto-dental distance of less than 14 mm is associated with an increased incidence of cord compression. In addition, if the space available for the spinal cord is less than 13 mm anywhere in the cervical region, there is an increased risk for neurologic impairment. In symptomatic patients, the films in flexion should be taken only after radiographs (including an open-mouth view) have excluded an odontoid fracture or severe atlantoaxial subluxation.


                  Upper versus lower motor neuron lesions — Several examination findings help to distinguish central from peripheral lesions in the motor system.
                  Deep tendon reflexes ;

                  • reflexes are typically hyperactive with a central lesion and hypoactive with a peripheral one.
                  • The Babinski sign is a reliable indicator of a central lesion.
                  • Atrophy and fasciculations are common with lower motor neuron disease and unusual with upper motor neuron disease.

                  The pattern of muscle involvement.

                  • A central lesion usually results in weakness that is more pronounced in the flexors of the lower extremities than in the extensors, but in the upper extremities the extensors are weaker than the flexors. This is often called pyramidal weakness, but it does not occur with pure lesions of the pyramidal tracts. Instead, it is the net result of disrupting all the descending motor tracts and is probably most appropriately called an upper motor neuron (UMN) pattern of weakness.
                  •  The UMN pattern of weakness also causes supination of the upper extremity to be weaker than pronation; this accounts for the finding of a pronator drift, in which the arm pronates and drifts downward when the patient is asked to hold it extended with palms up (supinated). This is a fairly sensitive indicator of subtle UMN weakness. It is also useful as a test for internal consistency because patients with nonorganic weakness will often allow their arm to drift downward but fail to pronate it.

                  Muscle tone

                  • A central lesion is characterized by spasticity, whereas tone is normal or reduced with a peripheral lesion.


                  Horner’s syndrome

                  NEUROANATOMY — A Horner's syndrome can result from a lesion anywhere along a three-neuron sympathetic (adrenergic) pathway that originates in the hypothalamus:

                  • The first-order neuron descends caudally from the hypothalamus to the first synapse, which is located in the cervical spinal cord (levels C8-T2, also called ciliospinal center of Budge).
                  • The second-order neuron travels from the sympathetic trunk, through the brachial plexus, over the lung apex. It then ascends to the superior cervical ganglion, located near the angle of the mandible and the bifurcation of the common carotid artery.
                  • The third-order neuron then ascends within the adventitia of the internal carotid artery, through the cavernous sinus, where it is in close relation to the sixth cranial nerve .
                  • The oculosympathetic pathway then joins the ophthalmic (V1) division of the fifth cranial nerve (trigeminal nerve). In the orbit and the eye, the oculosympathetic fibers innervate the iris dilator muscle as well as Müller's muscle, a small smooth muscle in the eyelids responsible for a minor portion of the upper lid elevation and lower lid retraction.

                  CLINICAL FEATURES — The classic signs of a Horner's syndrome are ptosis, miosis, and anhidrosis. The degree of anisocoria is more marked in the dark than in the light.

                  Horner's syndromes are frequently caused by trauma and/or a surgical procedure involving the chest or neck.

                  ETIOLOGY — The etiology of Horner's syndrome in adults relates to the lesion location
                  First-order syndrome — Lesions of the sympathetic tracts in the brainstem or cervicothoracic spinal cord can produce a first-order Horner's syndrome.

                  • The most common cause is a lateral medullary infarction, which produces a Horner's syndrome as part of the Wallenberg syndrome. Typically the patient presents with vertigo and ataxia, which overshadow the Horner's syndrome. Other neurologic symptoms and signs include abnormal eye movements, ipsilateral limb ataxia, and a dissociated sensory loss (loss of pain and temperature sensation on the ipsilateral face and contralateral trunk). Hoarseness and dysphagia are also often present.
                  • Strokes, tumors, and demyelinating lesions affecting the sympathetic tracts in the hypothalamus, midbrain, pons, medulla, or cervicothoracic spinal cord are other potential causes of a central Horner's syndrome. Syringomyelia and cervical cord trauma can also produce a Horner's syndrome when the intermediolateral columns are affected.

                  Second-order syndrome — Second-order or preganglionic Horner's syndromes can occur with trauma or surgery involving the spinal cord, thoracic outlet, or lung apex.

                  • Lumbar epidural anesthesia can also produce a Horner's syndrome due to pharmacologic disruption of the preganglionic neuron as it exits the spinal cord . This is most often described in association with obstetrical procedures.


                  Third-order syndrome — Third-order Horner's syndromes often indicate lesions of the internal carotid artery such as an arterial dissection, thrombosis, or cavernous sinus aneurysm. Carotid endarterectomy and carotid artery stenting can also produce a Horner's syndrome

                  • An acute Horner's syndrome with neck or facial pain should be presumed to be caused by carotid dissection until proven otherwise
                  • Other causes of postganglionic Horner's syndrome include neck masses, otitis media, and pathology involving the cavernous sinus. When the cavernous sinus is involved, other oculomotor deficits, particularly a sixth nerve palsy, commonly occur
                  • A Horner's syndrome is a common feature of cluster headache, occurring with unilateral eye or temple pain and lacrimation, generally lasting no more than an hour or two


                  Wasting of the small muscles of the hands
                  In the hand, the median nerve supplies the lateral two lumbricals, opponens pollicis, abductor pollicis brevis, and flexor pollicis brevis; the remainder are served by the ulnar nerve.
                  Wasting of the interossei (prominent guttering of the back of the hand), of the web space between thumb and index finger, and softening and flattening of the hypothenar eminence with sparing of abductor pollicis brevis indicates an ulnar nerve lesion.
                  Isolated wasting of abductor pollicis brevis indicate median nerve lesion in carpal tunnel syndrome.
                  Global wasting of hand indicate median and ulnar nerve lesion; probably, with damage to T1 root.
                  More extensive arm wasting may indicate any of the following: syringomyelia of MND; bilateral, symmetrical wasting indicate peripheral neuropathy.



                  Question 77 top Download PDF

                  A 50-year-old woman develops a dry cough and chest pain two days after a left total hip joint replacement. She has swelling of the left leg and a few basal crepitations. A chest X-ray shows bibasal collapse. Doppler ultrasonography of her legs does not demonstrate a clot.
                  The next most appropriate investigation is:
                  A. D-dimer assay.
                  B. ventilation-perfusion [V/Q] scanning.
                  C. pulmonary angiography.
                  D. computed tomographic (CT) pulmonary angiography.
                  E. venography.

                  Diagnosis of PE

                  Current Diagnosis of Venous Thromboembolism in Primary Care: A Clinical Practice Guideline from the American Academy of Family Physicians and the American College of Physicians
                  Amir Qaseem, Vincenza Snow, Patricia Barry, E. Rodney Hornbake, Jonathan E. Rodnick, Timothy Tobolic, Belinda Ireland, Jodi B. Segal, Eric B. Bass, Kevin B. Weiss, Lee Green, Douglas K. Owens and the Joint American Academy of Family Physicians/American College of Physicians Panel on Deep Venous Thrombosis/Pulmonary Embolism{dagger}
                  Ann Intern Med 2007;146 454-458 Open Access
                  Recommendation is use clinical prediction rules – ie Wells criteria  - she is intermediate scores 1 for leg swelling and 1 for post surgical bed immobilisation

                  Wells Criteria

                  So intermediate and high recommendation diagnostic imaging studies required
                  So V/Q or CT

                  for specific and sensitive results from V/Q need - clear chest X-ray

                  so answer is :D CTPA


                  Respiratory pulmonary thrombo-embolism

                  Question 78 top Download PDF

                  The severity of pulmonary hypertension can be determined using continuous wave Doppler measurements of the velocity of tricuspid regurgitation.  This method uses the Bernoulli equation which states that ∆ P = 4v2 (where ∆ P = instantaneous pressure gradient and v = velocity across the valve).  There is tricuspid regurgitation with a peak velocity of 4 metres/second and a mean velocity of 3.5 metres/second.

                  Assuming right atrial pressure is 5 mmHg, the best estimate of the peak right ventricular systolic pressure (± 2 mmHg) is:

                  A. 50 mmHg

                  B. 55 mmHg

                  C. 60 mmHg

                  D. 65 mmHg

                  E. 70 mmHg

                  Right ventricular systolic pressure is estimated as velocity across the valve +RAP

                  So = 4 x 4 x 4 + 5
                  = 69 ± 2 mmHg

                  best estimate = E. 70 mmHg


                  Cardiology knowledge of transthoracic and transoesophageal echocardiography

                  Question 79 top Download PDF

                  The above thyroid technetium scintiscan is least consistent with thyrotoxicosis due to which one of the following clinical conditions?

                  A. Subacute thyroiditis

                  B. Thyroxine therapy

                  C. Amiodarone therapy

                  D. Graves’disease

                  E. Postpartum thyroiditis

                  The scan looks to me like it is not taking up any iodine except in the marker, suggesting a low uptake of iodine.  I thinks its the wrong test also as it is generally used to evaluate a nodule .

                  Thyroid scan
                  The thyroid scan uses a small amount of a radioactive substance, usually radioactive iodine, to obtain a picture of the thyroid gland. Because thyroid cancer cells do not take up radioactive iodine as easily as normal thyroid cells do, this test is used to determine the likelihood that a thyroid nodule contains a cancer. If done as the first test, the thyroid scan is used to determine those patients who most need a biopsy. The scan usually gives the following results.

                  1. The nodule is cold. In other words, the nodule is not taking up radioactive iodine normally. This patient is referred for a fine needle biopsy of the nodule.
                  2. The nodule is functioning. Its uptake of radioactive iodine is similar to that of normal cells. A biopsy is not needed right away since the likelihood of cancer is very low.
                  3. The nodule is hot. Its uptake of radioactive iodine is greater than that of normal cells. The likelihood of cancer is extremely rare, and so biopsy is usually not necessary.

                  If the fine needle biopsy was done as the first test, then a scan is usually ordered to evaluate a suspicious biopsy result. In this case, patients with a “cold” nodule result should have their nodule removed. Patients with “functioning” or “hot” nodules on a scan and a suspicious biopsy can be watched, and surgery is not immediately necessary.

                  Subacute thyroiditis

                  Thyroiditis may cause transient thyrotoxicosis, with a characteristic low or undetectable thyroid radioiodine uptake.  Painless lymphocytic thyroiditis occurs in up to 10% of women after giving birth. This is an inflammatory autoimmune disorder in which lymphocytic infiltration results in thyroid destruction and leads to transient mild thyrotoxicosis as thyroid hormone stores are released from the damaged thyroid. As the gland becomes depleted of thyroid hormone, progression to hypothyroidism occurs. Thyroid function returns to normal within 12-18 months in 80% of patients.
                  Painful subacute thyroiditis, the most common cause of thyroid pain, is a self limiting inflammatory disorder of possible viral aetiology. Patients typically present acutely with fever and severe neck pain or swelling, or both. About half will describe symptoms of thyrotoxicosis. After several weeks of thyrotoxicosis, most patients will develop hypothyroidism, similar to postpartum thyroiditis. Thyroid function eventually returns to normal in almost all patients. The hallmark of the laboratory evaluation of painful subacute thyroiditis is a markedly elevated erythrocyte sedimentation rate and C reactive protein

                  Thyroxine therapy

                  Excess exogenous thyroid hormone is often associated with thyrotoxicosis. This may be iatrogenic, either intentional, when TSH suppressive doses of thyroid hormone are prescribed to suppress the growth of thyroid cancer or decrease the size, or unintentional, when overly vigorous treatment with thyroid hormone is prescribed for hypothyroidism. Thyrotoxicosis factitia may also result from patients' surreptitious use of thyroid hormones or from inadvertent ingestion. Serum thyroglobulin values are low to undetectable in thyrotoxicosis factitia but are raised in all other causes of thyrotoxicosis.w6

                  Amiodarone therapy

                  • Amiodarone may cause both hypothyroidism (AIH) and thyrotoxicosis (AIT1 and 2)
                  • AIT1 iodine excess
                  • AIT2 destructive thyroiditis
                  • Clinically a combination of AIT1 and 2 often occurs

                  Amiodarone induced thyrotoxicosis (AIT)





                  Goiter +


                  Ultrasound imaging

                  MNG/diffuse goiter


                  Colour flow Doppler scan

                  Normal or increased flow

                  Decreased flow

                  Thyroid antibodies


                  Absent generally

                  Interleukin 6

                  Normal or high

                  Very high

                  RAI uptake

                  Low or normal

                  Very low / absent

                  Preferred treatment

                  Carbimazole/PTU potassium perchlorate



                  Graves' disease is an autoimmune disorder in which thyroid stimulating immunoglobulin (TSI) binds to and stimulates the thyroid stimulating hormone (TSH) receptor on the thyroid cell membrane, resulting in excessive synthesis and secretion of thyroid hormone.  Patients with Graves' disease usually have diffuse, nontender, symmetrical enlargement of the thyroid gland. Ophthalmopathy, consisting of protrusion of the eyes with periorbital soft tissue swelling and inflammation, and inflammatory changes in the extraocular muscles resulting in diplopia and muscle imbalance, is clinically evident in 30% of patients with Graves' disease

                  Graves disease is the only choice from the list below of hyperthyroidism with a high radioiodine uptake

                  Postpartum thyroiditis

                  Postpartum thyroiditis is a common thyroid disorder that presents during the first postpartum year. It is the occurrence of either transient hyperthyroidism, transient hypothyroidism, or transient hyperthyroidism followed by transient hypothyroidism. Most, but not all, women are euthyroid 1 yr postpartum.
                  Postpartum thyroiditis is an exacerbation of an underlying autoimmune thyroiditis, aggravated by the immunological rebound that follows the partial immunosuppression of pregnancy

                  The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 9 4042-4047
                  Postpartum Thyroiditis Alex Stagnaro-Green

                  Hyperthyroidism with a high radioiodine uptake

                  Autoimmune thyroid disease
                  Graves' disease
                  Autonomous thyroid tissue (uptake may be low if recent iodine load led to iodine-induced hyperthyroidism)
                  Toxic adenoma
                  Toxic multinodular goiter
                  TSH-mediated hyperthyroidism
                  TSH-producing pituitary adenoma
                  Non-neoplastic TSH-mediated hyperthyroidism
                  Human chorionic gonadotropin-mediated hyperthyroidism
                  Hyperemesis gravidarum
                  Trophoblastic disease

                  Hyperthyroidism with a low radioiodine uptake

                  Subacute thyroiditis

                  Subacute granulomatous (de Quervain's) thyroiditis
                  Subacute lymphocytic thyroiditis (painless, silent)

                  Postpartum thyroiditis

                  Amiodarone (also may cause iodine-induced hyperthyroidism)
                  Radiation thyroiditis
                  Palpation thyroiditis
                  Exogenous thyroid hormone intake

                  Excessive replacement therapy

                  Intentional suppressive therapy
                  Factitious hyperthyroidism
                  Ectopic hyperthyroidism
                  Struma ovarii
                  Metastatic follicular thyroid cancer


                  Endocrinology: Thyrotoxicosis

                  Question 80 top

                  Question 81 top

                  Question 82 top Download PDF

                  A 69-year-old woman presents with severe pancytopenia and peripheral blood macrocytosis associated with a low serum vitamin B12 level.
                  Which one of the following investigation results most strongly supports a diagnosis of pernicious anaemia?
                  A. Positive anti-parietal cell antibody.
                  B. Positive intrinsic factor antibody.
                  C. Elevated fasting plasma homocysteine level.
                  D. Elevated fasting serum gastrin level.
                  E. Reduced red cell folate level.
                  Pernicious anaemia
                  Pernicious anemia, a sequela of autoimmune chronic atrophic gastritis directed against hydrogen-potassium ATPase in the gastric parietal cells, is associated with an increased risk of intestinal-type gastric cancer. A two- to threefold excess risk has been reported  but, as with other predisposing conditions, the actual degree of risk varies with the duration of disease and geographic location. Pernicious anemia is also associated with an increased risk of gastric carcinoid tumors, presumably due to prolonged achlorhydria resulting from parietal cell loss, compensatory hypergastrinemia, and argyrophilic cell hyperplasia

                  In the "classic" case of vitamin B12 (cobalamin, cbl) or folic acid deficiency, the patient presents with a severe macrocytic anemia (red blood cell mean corpuscular volume (MCV) >100 fL, and often >115 fl), a low to low-normal absolute reticulocyte count, and a characteristic blood smear showing macroovalocytes occasional megaloblasts, and hypersegmented neutrophils (greater than five percent of neutrophils with five or more lobes or 1 percent with six or more lobes)

                  However, many patients with B12 deficiency present with no or only mild anemia, and the macrocytosis may be masked by a concurrent disorder such as iron deficiency or one of the thalassemias (eg, alpha thalassemia trait).

                  EVALUATION — The evaluation of suspected Cbl or folate deficiency generally proceeds in two stages:

                  • documenting the presence of the vitamin deficiency and then
                  • determining its cause (eg, pernicious anemia, malabsorption, dietary lack).


                  • Evaluation of the peripheral blood smear for the presence of oval macrocytes and hypersegmented neutrophils.
                  • Measurement of the serum Cbl and the red blood cell (or serum) folate concentrations
                  • Evaluation of specific metabolites (eg, methylmalonate and homocysteine)
                  • For the diagnosis of pernicious anemia, the presence of antibodies to intrinsic factor is a helpful finding.
                  • Malabsorption of Cbl, and its correction by the addition of intrinsic factor, can be established through use of the Schilling test, when available
                  • Bone marrow examination to demonstrate megaloblastic erythropoiesis is usually unnecessary. Even if performed, this examination will not distinguish Cbl deficiency from folate deficiency.
                  • Red blood cell MCV — An elevation of the red blood cell mean corpuscular volume (MCV) is one of the hallmarks of Cbl and folate deficiency, although other causes are possible
                  • The degree of elevation of the MCV is often a clue as to whether a vitamin deficiency is present. Thus, the probability of a deficiency of folate and/or Cbl being present when the MCV is normal (ie, 80 to 100 fL), 115 to 129, or >130 fL has been estimated at <25, 50, and 100 percent, respectively [2]. Unless a combined deficiency (eg, iron deficiency plus a deficiency of Cbl or folate) is suspected, routine testing for Cbl or folate deficiency in an anemic patient in the presence of a MCV <80 fL is not likely to be productive.
                  • Folate levels —
                    • The serum folate concentration, although typically low in patients with folate-deficient megaloblastic anemia, is primarily a reflection of short-term folate balance, as can be illustrated by the following observations: One hospital meal can normalize the serum folate in patients who are folate deficient Pregnancy, alcohol intake, certain anticonvulsants, or a few days of decreased dietary intake can lower the serum folate concentration, despite the presence of adequate tissue stores.  
                    • The red cell folate concentration is theoretically a more reliable indicator of tissue folate adequacy, since it reflects a time-averaged value of folic acid availability, and is therefore not subject to the short-term fluctuations noted above. However, it is not entirely without its own problems of interpretation .  
                    • As a result, it has been suggested that the less expensive serum folate concentration should be obtained as an initial screening test, and that there is no basis for the routine testing of all samples for both serum folate and red cell folate. If the serum folate concentration is >4 ng/mL (9.1 nanomol/L), folate deficiency is effectively ruled out. The more expensive metabolite testing  should be reserved for patients with borderline values (folate concentration 2 to 4 ng/mL), in those suspected of having a combined deficiency of both Cbl and folate, and for patients in whom the serum folate level may not be easily interpreted (eg, recent hospital meal or recent anorexia) . In the absence of recent anorexia or fasting, a serum concentration <2 ng/mL (4.5 nM/L) is diagnostic of folate deficiency.
                  • Cobalamin levels — Several commercial laboratories use different methods (chemiluminescence or radioassay) for measuring Cbl. As a result, there are different normal ranges and no "gold standard"
                  • Methylmalonic acid and homocysteine — Patients with low-normal or even normal serum Cbl values may be truly Cbl deficient and respond to replacement therapy.  Therefore, measurement of the serum concentrations of homocysteine and methylmalonic acid is helpful in clarifying the diagnosis when serum Cbl or folate concentrations are equivocal, or are low in the pregnant subject
                  • Serum concentrations of homocysteine (HC) as well as serum and urinary concentrations of methylmalonic acid (MMA) are elevated in Cbl deficiency, due to a decreased rate of metabolism

                  Diagnosis of PA — Several laboratory studies can suggest the diagnosis of pernicious anemia (PA). Patients with PA are achlorhydric, but confirming this by measurement of gastric acid secretion is highly invasive and rarely needed. Bone marrow examination may confirm the diagnosis of megaloblastic anemia, but this finding is not specific for any cause of Cbl or folate deficiency, and is also highly invasive.

                  • Antibodies to IF — The presence of anti-intrinsic factor (IF) antibodies is highly confirmatory for the diagnosis of PA, with a sensitivity varying from 50 to 84 percent, depending upon the population tested , and a specificity approaching 100 percent. On the other hand, anti-parietal cell antibodies are much less specific, and may even be less sensitive (50 percent); as a result, the utility of anti-parietal cell antibodies in diagnosing PA has been called into question.
                  •   Schilling test — A classic procedure for diagnosing pernicious anemia is the two stage Schilling test
                    • In the first stage of the test, one to two microg of radiolabeled crystalline cyano-Cbl is given orally, followed by an intramuscular injection of 1000 microg of Cbl one hour later, in order to saturate the transcobalamines and to "flush" any absorbed radiolabeled Cbl from its tissue and blood binding sites into the urine. A 24-hour urine is then collected for determination of the percent excretion of the oral dose. An accurately timed and complete urine collection is critical.
                      • Normal subjects excrete 8 to 35 percent of the administered radiolabeled dose in the urine over the ensuing 24 hours.
                      • A low percent excretion (usually <8 percent, depending upon the laboratory) of radiolabeled Cbl indicates Cbl malabsorption, due to pernicious anemia or other causes of intestinal malabsorption.
                      • Renal insufficiency is a cause of falsely low values. On the other hand, the first stage Schilling test may be spuriously normal in patients with B12 deficiency due to atrophic gastritis or gastrectomy .
                    • In the second stage of the Schilling test, performed only if the first stage result shows reduced excretion, the test is repeated with added oral intrinsic factor. This should normalize Cbl absorption in patients with pernicious anemia, but not in those with intestinal malabsorption. It is important to recognize, however, that Cbl deficiency adversely affects intestinal mucosal cells and can cause malabsorption. Thus, the second stage should only be performed after at least four weeks of Cbl replacement
                      • If the second stage of the Schilling test is abnormally low, this suggests the presence of generalized malabsorption, such as may occur in sprue, pancreatic insufficiency, or blind loop syndromes. While these conditions can be diagnosed by other means, a "third stage" Schilling test can be performed following appropriate treatment, in order to further confirm the operative mechanism.


                   Recommendation — Vitamin B12 deficiency, pernicious anemia, malabsorption, blind loop syndromes, and ileal disease can be reliably and quickly diagnosed using methods other than the Schilling test. Difficulties with the radiolabeled reagent used in the Schilling test, as well as certification issues, make this test generally unavailable in many parts of the United States. Accordingly, although the Schilling test has historical importance in understanding abnormalities of vitamin B12 absorption, it is not commonly employed, and has potential usefulness only when more simple tests (eg, anti-IF antibodies) are normal (see "Diagnostic strategy" below).


                  Folate deficiency — Folate deficiency is treated with folic acid (1 to 5 mg/day PO) for one to four months, or until complete hematologic recovery occurs. A dose of 1 mg/day is usually sufficient, even if malabsorption is present. These doses are in excess of those recommended for disease prevention (eg, recommended daily allowance in normal adults, alcoholics, the elderly, prevention of neural tube defects).

                  Cobalamin deficiency — Pernicious anemia (PA) is typically treated with parenteral (ie, intramuscular) Cbl, in a dose of 1000 µg (1 mg) every day for one week, followed by 1 mg every week for four weeks and then, if the underlying disorder persists, as in PA, 1 mg every month for the remainder of the patient's life.

                   Oral and nasal formulations — An alternative that appears to be as or more effective than parenteral therapy, but which requires much greater patient compliance, is high dose oral cobalamin. The rationale for this approach in patients with impaired intrinsic factor function is the presence of a second, lower efficiency transport system for Cbl that does not require intrinsic factor or a functioning terminal ileum. This system consistently produces adequate long-term vitamin replacement at doses of 1000 to 2000 microg/day. Because of variability in absorption, lower doses are not completely effective in some patients with pernicious anemia . Similarly, use of "timed release" oral Cbl preparations should be avoided.

                  Blood transfusion — In patients who are severely anemic at presentation, the decision to transfuse can be a difficult one, particularly in elderly patients at risk for congestive heart failure due to volume overload. If the anemia is extreme and the patient is critically ill, one unit can be given initially at a slow rate, in combination with a diuretic, if fluid status is a concern. In extreme circumstances, isovolemic exchange can be performed, in which one unit of the patient's blood (with a low hematocrit) is removed at the same time as a unit of packed cells (with a hematocrit of 60 to 80 percent) is infusing

                  MONITORING FOR MALIGNANCY — Patients with PA may have an increased risk of developing gastric or colorectal adenocarcinoma, but the data are not entirely conclusive. Nevertheless, it is prudent to periodically monitor stools in these patients for the presence of blood.

                  A. Positive anti-parietal cell antibody.
                  anti-parietal cell antibodies are much less specific, and may even be less sensitive (50 percent); as a result, the utility of anti-parietal cell antibodies in diagnosing PA has been called into question.

                  B. Positive intrinsic factor antibody. Correct
                   The presence of anti-intrinsic factor (IF) antibodies is highly confirmatory for the diagnosis of PA, with a sensitivity varying from 50 to 84 percent, depending upon the population tested , and a specificity approaching 100 percent
                  C. Elevated fasting plasma homocysteine level.
                  Homocysteine is an intermediary amino acid formed by the conversion of methionine to cysteine. Homocystinuria or severe hyperhomocysteinemia is a rare autosomal recessive disorder characterized by severe elevations in plasma and urine homocysteine concentrations. Clinical manifestations of homocystinuria include developmental delay, osteoporosis, ocular abnormalities, thromboembolic disease, and severe premature atherosclerosis

                  Increased blood levels of homocysteine may reflect deficiency of folate, vitamin B6, and/or vitamin B12 . Plasma folate and B12 levels, in particular, are strong determinants of the homocysteine concentration. Homocysteine levels are inversely related to folate consumption, reaching a stable baseline level when folate intake exceeds 400 µg/day. Vitamin B6 is a weaker determinant.

                  D. Elevated fasting serum gastrin level.
                  The chronic atrophic gastritis in PA is also associated with an increased risk of intestinal-type gastric cancer and of gastric carcinoid tumors. The latter are presumably due to prolonged achlorhydria resulting from parietal cell loss, compensatory hypergastrinemia, and argyrophilic cell hyperplasia.

                  Causes of hypergastinaemia: Antisecretory therapy, Atrophic gastritis , Diabetes mellitus , Gastrin cell hyperplasia or hyperfunction , Massive small bowel resection , Ovarian cancer , Pheochromocytoma
                  Renal insufficiency , Retained gastric antrum , Rheumatoid arthritis , Sjögren's syndrome , Vitiligo
                  Zollinger-Ellison syndrome


                  E. Reduced red cell folate level.
                  See discussion above about the problems with measurement


                  In Carol’s lecture she said for PA

                    • IF antibodies
                    • Fasting serum gastrin


                    Haematology: Anaemia

                    Question 83 top

                    Question 84 top Download PDF

                    Ascaris lumbricoides is a common worm infestation in the developing world. Which one of the following syndromes would be most characteristic of this infection?
                    A. Eosinophilic meningitis.
                    B. Cholangitis.
                    C. Painless rectal bleeding.
                    D. Migratory rash.
                    E. Perianal itch.

                    Ascaris lubricoides, an interstinal roundworm, is one of the most common helminthic human infections worldwide.  IN the US ascariasis is the third most frequent Helminth infection, exceeded only by hookworm and Trichuris trichiura (whipworm) A.l lumbricoides is the lagest intestinal nematode of man

                    Transmission mainly via ingestion of water or food ( raw vegetables of fruit in particular) contaminated with A. lumbricoides eggs and occasionally via inhalation of contaminated dust

                    Clinical features: the majority of infections with A. lumbricoides are asymptomatic.  However, the burden of symptomatic disease worldwide is still relatively high because of the high prevalence of the disease.  Clinical disease is largerly restricted to individuals with a high worm load.  When symptoms do occur, they relate either to the larval migration stage or to the adult worm intestinal stage.  Pathophysiologic mechanisms include:

                    • Direct tissue damage
                    • The immunologic response of the host to infection with larvae, eggs or adult worms
                    • Obstruction of an orifice or the lumen of the GI tract by an aggregation of worms
                    • Nutritional sequelae of infection

                    Symptoms and complications

                    • Pulmonary and hypersensitivity manifestations
                      • Pneumonitis
                      • urticaria
                    • Intestinal symptoms
                      • Abdominal discomfort, anorexia, nausea and diarrhoea
                      • Heavy infections – impaired absorption of dietary proteins, lactose and Vit A
                    • Intestinal obstruction
                      • Commonly at the iloececal valve – colicky abdominal pain, vomiting and constipation
                    • Hepatobiliary and pancreatic symptoms
                      • Symptoms related to the migration of adult worms into the biliary tress can cause abdominal pain, biliary colic, acalculous cholecystitis, ascending cholangitis, obstructive jaundice, or bile duct perforation awith peritonitis
                      • In endemic countries such as India, ascariasis has been found to cuase up to one-third of biliary and pancreatic disease


                    So from the choices above answer B cholangitis only clearly defined syndrome


                    Infectious Diseases:helminthic


                    Question 85 top

                    Question 86 top Download PDF

                    Unawareness of hypoglycaemia is predominantly due to failure of secretion of which one of the following hormones?

                    A. Glucagon

                    B. Adrenaline

                    C. Cortisol

                    D. Growth hormone

                    E. Somatostatin


                    Answer B

                    Extract from up to date
                    Impairment of counterregulatory responses — The glucagon response to hypoglycemia, although normal at the onset of diabetes, becomes markedly impaired or absent during the first few years in patients with type 1 diabetes .  Why this occurs is poorly understood, because in these patients glucagon responses to other stimuli such as amino acids are normal . One possible mechanism is continued insulin availability, since suppression of insulin release in normal subjects is partially responsible for the hypoglycemia-induced rise in glucagon secretion .
                    Patients with deficient glucagon secretion are dependent upon epinephrine to protect against hypoglycemia. However, the epinephrine response also becomes impaired in many patients later in the course of the disease . These patients are at much greater risk of developing hypoglycemia, and because of the absence of the epinephrine-induced early-warning symptoms it is often severe (called hypoglycemia unawareness). It has been estimated, for example, that patients with diminished glucagon and epinephrine responses have a 25-fold increase in the frequency of severe hypoglycemia during intensive insulin therapy . These patients may be particularly prone to develop hypoglycemia during sleep, because sleep itself appears to impair counterregulatory responses .

                    Harrisons mechanism for unawareness of hypoglycamia


                    Endocrinology: pathophysiological basis of insulin-dependent and non insulin-dependent diabetes


                    Question 87 top

                    Question 88 top Download PDF

                    In a patient with acute ischaemic stroke, which one of the following treatments is the most appropriate early intervention?

                    A.  Aspirin
                    B. Streptokinase
                    C. Low moelcular weight heparin
                    D. Unfractionated heparin
                    E. Warfarin

                    Answer is A

                    From UK guidelines of college of physicians here:  http://www.rcplondon.ac.uk/pubs/books/stroke/
                    Australian guidelines from National Stroke Foundation here; http://www.strokesafe.com.au/pages/article.aspx?id=1&articleid=ArticleID2006526135335&pageId=159&HandlerId=1


                    3.1 Diagnosis and investigations
                    Effective early management of acute stroke and transient ischaemic attack can reduce
                    mortality and morbidity as well as reducing waste of scarce health and social services
                    resources. The evidence from the Stroke Units Trialists’ Collaboration shows that nonspecialist
                    disorganised care costs lives, increases dependency and is not cost effective.

                    3.1.1 Investigation and management of patients with transient ischaemic attack
                    The risk of developing a stroke after a hemispheric TIA can be as high as 20% within the
                    first month, with the greatest risk within the first 72 hours.


                    • Patients first seen in the community with TIA, or with a stroke but having made a good recovery when seen, should be assessed and investigated in a specialist service (eg neurovascular clinic) as soon as possible within seven days of the incident (B*)
                    • Patients likely to have a diagnosis of TIA should be prescribed an alternative antiplatelet regime immediately (B)
                    • Patients with more than one TIA in a week should be investigated in hospital immediately (B)
                    • Risk factors for cerebrovascular disease such as severe hypertension should be treated appropriately or the patient referred for specialist management (A)


                    • The diagnosis should always be reviewed by an experienced clinician with expertise in stroke. The assessment and investigation should include identification of possible underlying cardiovascular causes (B*)
                    • The initial neurological assessment should document the localisation of the likely cerebral area affected (C)
                    •  Brain imaging should be undertaken as soon as possible in all patients, within 24 hours at most of onset unless there are good clinical reasons for not doing so (B*)
                    •  Brain imaging should be undertaken as a matter of urgency if the patient has: (B)
                      • been taking anticoagulant treatment
                      • a known bleeding tendency
                      • a depressed level of consciousness
                      • unexplained progressive or fluctuating symptoms
                      • papilloedema, neck stiffness or fever
                      • severe headache at onset
                      • indications for thrombolysis or early anticoagulation
                    • If the patient deteriorates unexpectedly further brain imaging should be considered to identify intracranial complications, eg hydrocephalus or haemorrhagic transformation (B)
                    • If the underlying pathology is uncertain, or the diagnosis of stroke is in doubt after CT scan, MRI should be considered (B)
                    • Cross-sectional MRI should be performed when imaging has been delayed for more than 10 days after stroke (B)

                    3.2 Immediate (medical/surgical/nursing/therapy) interventions for stroke
                    Stroke is a medical emergency. With active management in the initial hours after stroke onset ischaemic brain may be saved from infarction.
                    3.2.1 Initial screening and monitoring

                    • The patient should be assessed on admission for:
                    • their risk of aspiration, using a validated 50 ml water swallow screening tool, administered by an appropriately-trained professional (B)
                    • their needs in relation to moving and handling (C)
                    • their risk of developing pressure sores (C)
                    •  Monitoring in the acute phase should include: conscious level, blood pressure, pulse, heart rhythm, temperature, blood glucose, oxygen saturation and hydration (D)

                    3.2.2 General interventions

                    • Blood glucose, arterial oxygen concentration, hydration and temperature should be maintained within normal limits. Infection should be actively managed unless the patient is receiving palliative care (B)
                    • Blood pressure should only be lowered in the acute phase where there are likely to be complications from hypertension, eg hypertensive encephalopathy, aortic aneurysm with renal involvement (B)
                    • Patients should be mobilized as soon as possible (B)

                    3.3 Management of acute ischaemic stroke
                    3.3.1 Thrombolysis
                    Thrombolysis has the potential to improve outcome of patients with cerebral ischaemia, however it is a high-risk treatment and should only be administered by personnel trained in its use, in a centre equipped to investigate and monitor patients appropriately. Evidence from Phase IV studies on intravenous thrombolysis in North America has shown that unless the protocols for treatment are strictly adhered to outcomes are worse. The evidence for  the benefits of intra-arterial thrombolysis remains limited.

                    3 Acute management

                    •  Thrombolytic treatment with alteplase should only be given provided that: (A)
                    • it is administered within three hours of onset of stroke symptoms (unless as part of a clinical trial)
                    • haemorrhage has been definitively excluded
                    • the NINDS criteria have been met
                    • the patient is in a centre registered with Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS-MOST)
                    • Patients given alteplase outside the context of a research trial should be notified to theinternational audit of thrombolysis SITS-MOST (C)
                    •  Intra-arterial thrombolysis should only be used in centres with an interventional neuroradiology service (C)

                    3.3.2 Anti-thrombotic treatment

                    •  Aspirin (300 mg) should be given as soon as possible after the onset of stroke symptoms once a diagnosis of primary haemorrhage has been excluded. In dysphagic patients aspirin should be given rectally or by enteral tube (A*). Thereafter aspirin (50–300 mg) should be continued indefinitely until an alternative antiplatelet therapy is started (see section 3.5)
                    • Aspirin should be delayed for 24 hours following thrombolysis (A)
                    •  Anticoagulation should not be initiated routinely for the treatment of acute ischaemic stroke, including progression (A)


                    From Australian guidelines here http://www.strokesafe.com.au/pages/article.aspx?id=1&articleid=ArticleID2006526135335&pageId=159&HandlerId=1

                    a) If CT scan excludes haemorrhage, aspirin (150-300mg) should be given as soon as possible after the onset of stroke symptoms.
                    b) No other drug treatment aimed at the treatment of stroke should be given unless part of a Randomised Controlled Trial (RCT).
                    c) The routine acute use of anticoagulation (eg. IV unfractionated heparin) in unselected patients
                    following ischaemic stroke/TIA is not recommended.
                    d) Drugs that have been used historically or traditionally for which there is no evidence of benefit from
                    RCT (eg steroids, haemodilution, glycerol, etc) should be avoided.
                    e) The use of alternative therapies or complimentary medicines, should be discussed by the treating
                    physician with the patient, and in the absence of RCT evidence of benefit should be discouraged. Of
                    particular importance are therapies that may interact with those prescribed by the treating physician
                    (eg. Ginkgo biloba and antiplatelet therapy).


                    Neurology: Stroke


                    Question 89 top Download PDF

                    A 45 year-old man with a family history of ischaemic heart disease is diagnosed with hypertension and hypercholesterolaemia. He is started on aspirin 150 mg daily, atorvastatin 20 mg nocte and atenolol 50 mg daily. Eight weeks later, he is reviewed and complains of some lethargy and itching. His blood pressure is 120/70 mmHg. He is noted to be icteric. There are no other findings on physical examination.
                    Blood investigations show:
                    white cell count 5.6 x 109/L [4.0-9.0]
                    normal differential
                    haemoglobin 142 g/L [130-175]
                    platelet count 468 x 109/L [150-450]
                    prothrombin time-international  normalised ratio (PT-INR) 1.0 [0.9-1.1]

                    bilirubin 103 μmol/L [3-21]
                    alanine transaminase (ALT) 610 U/L [5-40]
                    aspartate transaminase (AST) 358 U/L [5-40]
                    alkaline phosphatase (ALP) 540 U/L [30-115]
                    gamma glutamyltranspeptidase (GGT) 746 U/L [<65]
                    albumin 40 g/L [38-50]

                    sodium 145 mmol/L [139-145]
                    potassium 4.5 mmol/L [3.8-4.8]
                    urea 3.8 mmol/L [2.5-5.6]
                    creatinine 0.10 mmol/L [0.06-0.11]

                    hepatitis B surface antigen negative
                    hepatitis C antibody negative
                    ferritin 356 μg/L [25-200]
                    anti-nuclear antibody negative
                    anti-mitochondrial antibody negative
                    anti-smooth-muscle antibody negative
                    An abdominal ultrasound shows non-dilated bile ducts. The gall bladder is normal with no calculi. A liver biopsy is performed and two representative sections are shown over.
                    The most likely explanation for the abnormal liver function test results is:
                    A. atenolol.
                    B. atorvastatin.
                    C. non-alcoholic steatohepatitis (NASH).
                    D. autoimmune hepatitis.
                    E. primary biliary cirrhosis.

                    Clinical Presenation
                    This man has

                    • abnormal LFTs with a mixed picture including raised bilirubin
                    • no radiological evidence of obstruction
                    • no evidence of other common causes of hepatitis, viral, autoimmune
                    • ferritin raised - ?significance acute phase reaction
                    • platelets slightly raised
                    • normal INR
                    • liver biopsy looks like an infiltrative process, similar to that seen in autoimmune hepatitis  - non specific changes

                    normal liver biopsy

                    A. atenolol.  -incorrect


                    1% to 10%:
                      Cardiovascular: Persistent bradycardia, hypotension, chest pain, edema, heart failure, second- or third-degree AV block, Raynaud's phenomenon
                      Central nervous system: Dizziness, fatigue, insomnia, lethargy, confusion, mental impairment, depression, headache, nightmares
                      Gastrointestinal: Constipation, diarrhea, nausea
                      Genitourinary: Impotence
                      Miscellaneous: Cold extremities

                    <1% (Limited to important or life-threatening): Alopecia, dyspnea (especially with large doses), hallucinations, impotence, liver enzymes increased, lupus syndrome, Peyronie's disease, positive ANA, psoriaform rash, psychosis, thrombocytopenia, wheezing

                    B. atorvastatin. – correct answer
                    Case report and other references in MJA http://www.mja.com.au/public/issues/176_11_030602/bat_030602.html


                    >10%: Central nervous system: Headache (3% to 17%)

                    2% to 10%:
                      Cardiovascular: Chest pain, peripheral edema
                      Central nervous system: Insomnia, dizziness
                      Dermatologic: Rash (1% to 4%)
                      Gastrointestinal: Abdominal pain (up to 4%), constipation (up to 3%), diarrhea (up to 4%), dyspepsia (1% to 3%), flatulence (1% to 3%), nausea
                      Genitourinary: Urinary tract infection
                      Hepatic: Transaminases increased (2% to 3% with 80 mg/day dosing)
                      Neuromuscular & skeletal: Arthralgia (up to 5%), arthritis, back pain (up to 4%), myalgia (up to 6%), weakness (up to 4%)
                      Respiratory: Sinusitis (up to 6%), pharyngitis (up to 3%), bronchitis, rhinitis
                      Miscellaneous: Infection (3% to 10%), flu-like syndrome (up to 3%), allergic reaction (up to 3%)


                    C. non-alcoholic steatohepatitis (NASH). – Incorrect

                    • Nonalcoholic steatohepatitis (NASH) is the term used to describe the distinct clinical entity in which patients lack a history of significant alcohol consumption but have liver biopsy findings indistinguishable from alcoholic hepatitis
                    • Serum AST and ALT are elevated in almost 90 percent of patients . The AST/ALT ratio is usually less than 1
                    • A liver biopsy showing moderate to gross macrovesicular fatty change with inflammation (lobular or portal) and with or without Mallory bodies, fibrosis, or cirrhosis

                    Histologic changes in nonalcoholic steatohepatitis (NASH). Left panel: The hepatocyte in the center contains a large vacuole of fat and deeply staining eosinophilic strands of cytoplasmic hyalin. Numerous neutrophils and phagocytic cells containing golden brown pigmented material (bile components and cellular debris) are present in the sinusoids. Right panel: NASH with cirrhosis. Trichrome stain shows regenerating nodules with fat surrounded by fibrous tissue.

                    D. autoimmune hepatitis. – incorrect

                    • Autoimmune hepatitis is a chronic hepatitis of unknown etiology characterized by immunologic and autoimmunologic features, generally including the presence of circulating autoantibodies and a high serum globulin concentration
                    • circulating autoantibodies commonly seen in type 1 autoimmune hepatitis are antinuclear, anti-smooth muscle, and/or antiactin antibodies.
                    • In type 2 autoimmune hepatitis, ALKM-1 antibodies occur alone or accompanied by ALC-1 (LC1) antibodies or rarely ANA
                    • Autoimmune hepatitis is a chronic necroinflammatory disorder, with nonspecific biopsy findings

                    Liver biopsy in autoimmune hepatitis showing portal and periportal mononuclear cell infiltration.


                    Gastroenterology: Acute and chronic liver disease


                    Question 90 top Download PDF

                    Question 90
                    A 50-year-old woman presents with sudden onset of profound deafness in the left ear.  Examination indicates that nerve deafness is more likely than a conduction problem.  Other findings include right infero-medial scleritis, bilateral osteoarthritic fingers, blood-stained nasal discharge and obesity.
                    Which one of the following investigations is most likely to lead to the correct diagnosis?

                    A.  Magnetic resonance imaging (MRI) of the brain
                    B.  Anti-double-stranded-DNA antibodies assay
                    C. Anti-neutrophil cytoplasmic antibody (ANCA) assay
                    D. Lumbar puncture
                    E. Urinary drug screen


                    ANATOMY AND PHYSIOLOGY — The ear is divided into three segments:

                    • The outer ear, comprising the auricle and ear canal
                    • The middle ear, comprising the tympanic membrane (TM), ossicles, and the middle ear space
                    • The inner ear, comprising the cochlea, semicircular canals, and internal auditory canals.


                    Causes of hearing loss

                    OUTER EAR CAUSES

                    All hearing loss related to the outer ear is by nature a conductive hearing loss.

                    • Congenital The external auditory canal (EAC) develops from the 8th to the 28th week of gestation; problems can occur anytime during this developmental phase.
                    • Infection blockage of the EAC due to the accumulation of debris, edema, or inflammation.  Otitis externa usually develops as a result of local trauma coupled with contamination by bacteria (or occasionally fungi) after swimming, showering, or exposure to hot humid conditions. Significant edema of the EAC occurs; the canal is often also filled with squamous and purulent debris. The most common symptoms are otalgia, pruritus, discharge, and hearing loss.
                    • Trauma — Penetrating trauma to the external auditory canal or meatus due to a bullet, knife, or fracture may cause mild or profound conductive hearing loss, depending upon the degree of EAC occlusion.
                    • Tumor — The most common malignant tumor of the EAC is squamous cell carcinoma This and other tumors of the EAC, such as basal cell carcinoma and melanoma, typically cause conductive hearing loss due to occlusion of the canal.
                    • Benign bony growths may also occlude the EAC with a resulting conductive hearing loss. The two most common benign growths are exostosis and osteoma.
                    • Systemic disease — Diabetes mellitus and other immunocompromised states do not in themselves cause hearing loss, but these disorders predispose to developing necrotizing otitis externa, which in turn can cause conductive hearing loss due to occlusion of the EAC.
                    • Dermatologic — Certain skin diseases, such as psoriasis, may cause scaling and edema of the EAC and meatus.

                    MIDDLE EAR CAUSES — As with the outer ear, all hearing loss associated with the middle ear is conductive hearing loss.

                    • Congenital — Atresia or malformation of the ossicular chain can cause conductive hearing loss.
                    • Eustachian tube dysfunction — Eustachian tube dysfunction can cause perceived hearing loss.  Eustachian tube dysfunction occurs commonly in the setting of a viral upper respiratory infection (URI) or sinusitis, and it can also occur with allergies. Any process that causes swelling in the back of the nose around the eustachian tube opening may cause symptoms
                    • Infection — Otitis media (OM) is a common childhood disorder that also frequently occurs in adults
                    • Tumors — Malignant tumors such as Langerhans cell histiocytosis (including the Letterer-Siwe variant) or squamous cell carcinoma may cause conductive hearing loss. However, these entities are relatively rare when compared with benign cholesteatoma or otosclerosis.
                    •  Cholesteatoma — Cholesteatoma is a growth of desquamated, stratified, squamous epithelium within the middle ear space.
                    • Otosclerosis — Otosclerosis is a bony overgrowth that involves the footplate of the stapes. As the overgrowth develops, the stapes can no longer function as a piston, but rather rocks back and forth and eventually becomes totally fixated. Conduction gradually becomes worse until a maximal conductive hearing loss of 60 dB is reached.
                    • Tympanic membrane perforation — Conductive hearing loss due to TM perforation is common. The degree of conductive hearing loss depends upon the size and location of the perforation. Small perforations and those located in the anterior/inferior quadrant cause the least amount of conductive hearing loss; near total or posterior/superior quadrant perforations have a much higher chance of causing significant hearing loss.   TM perforations can be caused by many events, including blast injury, barotrauma, foreign body trauma, temporal bone fractures, ear infections, self-inflicted trauma from a Q-tip or other object, or the hole may persist after myringotomy or after tubes fall out. After an acute perforation, the ear needs to be examined under the microscope to ensure that skin is not trapped on the undersurface of the TM, since trapped skin could lead to cholesteatoma formation. Documentation of a patient's auditory status also is mandatory for any newly diagnosed perforation.  Most acute TM perforations heal on their own or with the aid of a paper or biogenic film patch. Occasionally surgical correction is required, usually with a temporalis muscle fascia graft. Repair of the perforation often corrects the conductive hearing loss.  
                    • Vascular — Glomus tympanicum or glomus jugulare tumors are benign paragangliomas that arise either from the promenatory of the middle ear or the adventitia of the dome of the jugular bulb. As they grow they tend to fill the middle ear, with resultant conductive hearing loss. They also erode bone as they enlarge, especially inferiorly, causing damage to cranial nerves. In addition, glomus tumors may impede upon the ossicular chain and TM, thereby decreasing motility of either or both structures.


                    INNER EAR CAUSES — Disorders of the inner ear normally cause a sensorineural hearing loss. The etiology may be associated with the cochlea, eighth nerve, internal auditory canal, or brain.

                    • Congenital or hereditary — Congenital hearing loss will be defined as any hearing loss that occurs at or shortly after birth that may be due to either a hereditary or non-hereditary cause. Non-hereditary etiologies involve an insult to the developing cochlea, including viral infections such as cytomegalovirus (CMV), hepatitis, rubella, toxoplasmosis, HIV, and syphilis. Some medications also may have a teratogenic affect on the developing ear of the fetus, including recreational drugs, alcohol, quinine, and retinoic acid.
                    • Presbycusis — Presbycusis is the sensorineural hearing loss that is associated with aging. Multiple factors influence the rate at which hearing loss occurs, including a lifetime of noise exposure, genetics, medications, and infections.  
                    • Infection — The most common infection of the inner ear in adults is viral cochleitis; in young children it is meningitis . Meningitis can access the cochlea by way of CSF-perilymph fluid connection and cause a profound sensorineural hearing loss by destroying the inner ear hair cells.  Ix lumbar puncture more likely in children
                      • Viral cochleitis usually manifests as a sudden sensorineural hearing loss ; vertigo, facial paralysis, or pain occur rarely.
                    • Meniere's disease — Patients with Meniere's disease complain of episodic spells of vertigo that last for hours, associated with aural fullness, tinnitus, and sensorineural hearing loss. Occasionally the auditory system is affected in what is commonly called cochlear Meniere's or cochlear hydrops; in these cases the patient experiences episodic hearing loss that recovers within a 12- to 24-hour period, usually with associated aural fullness and tinnitus. The spells of hearing loss may occur on a daily, weekly, or monthly basis. The hearing loss is almost always low frequency. Over time and with repeated attacks, the hearing deficit can become permanent and may even eventually involve all frequencies
                    • Noise exposure — Everyday noise exposure, compounded over time, has an impact upon our ability to hear and ultimately on the degree of the presbycusis that develops. Constant exposure to loud noises can cause high frequency sensorineural hearing loss.
                    • Inner ear barotrauma — Barotrauma occurs when a patient is exposed to a sudden, large change in ambient pressure, often during diving or flying. Middle ear pressure becomes more positive with respect to ambient pressure during ascent until the eustachian tube is forced open. On descent, ambient pressure exceeds middle ear pressure until swallowing opens the eustachian tube. Inner ear barotrauma is a fairly uncommon injury but should be excluded in all cases of middle ear barotrauma
                    • Trauma — Penetrating trauma typically causes sensorineural or mixed hearing loss. These injuries are usually due to gunshot wounds that upon impact cause significant temporal bone fractures.
                    • Tumors — Most tumors of the inner ear are benign, although malignant tumors such as squamous cell carcinoma, sarcomas, and adenoid carcinoma rarely occur with bony involvement. Benign bony tumors including fibrous dysplasia and Paget's disease are also rare.  The most common tumor that causes sensorineural hearing loss is an acoustic neuroma.  This is a benign tumor that usually originates from the vestibular portion of the eighth cranial nerve. The most common complaint is an asymmetric or unilateral sensorineural hearing loss, which occurs in 90 percent of all patients. Other symptoms include unilateral tinnitus, disequilibrium, dizziness, lipomas, or headaches. Additional findings may include facial hyperesthesias or facial muscular twitching.  Ix = MRI
                    • Endocrine/systemic/metabolic — Various metabolic abnormalities have been known to either cause or be associated with sensorineural hearing loss.
                      • diabetic vasculopathy can cause cochlear ischemia.
                      •  anaemia or a white blood cell dyscrasia may lead to sensorineural hearing loss by an unknown mechanism that may involve decreased oxygenation, microblockage of vessels, or infection.
                      • hyper or hypothyroidism.


                    • Autoimmune hearing loss — Autoimmune hearing loss was first described in 1979 [56]. It is usually bilateral, asymmetric, sensorineural hearing loss that is either fluctuating or progressive in nature. The autoimmune inner ear disease may be limited just to the ear, or it may be part of an overall systemic problem such as
                      • Wegener's granulomatosis, Ix ANCA
                      • Cogan's syndrome,
                      • rheumatoid arthritis,
                      • systemic lupus erythematosus, Ix double stranded DNA but ANA more sensitive
                      • polyarteritis nodosa,
                      • or relapsing polychondritis.
                        • A number of studies are consistent with autoimmune hearing loss, including an elevated erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA), rheumatoid factor (RF). One of the more useful tests is the detection of a cochlear autoantibody, a 68 kilodalton protein.
                        • Autoimmune hearing loss is typically first treated with high-dose corticosteroids (60 to 80 mg prednisone) every morning for two to three weeks. This often results in significant recovery of hearing.
                    • Iatrogenic — Iatrogenic inner ear injuries may occur during surgical procedures such as tympanomastoidectomy or stapedectomy, following radiation therapy, either for intracranial or nasopharyngeal tumors, or they may be medication related.
                    • A number of ototoxic medications can cause sensorineural hearing loss: All aminoglycosides are ototoxic. Some are more vestibulotoxic than cochleotoxic. The relative order of cochleotoxicity is gentamicin>tobramycin>amikacin>neomycin.. Other antibiotics that can cause ototoxicity include erythromycin, vancomycin, and tetracycline. These drugs have a more pronounced ototoxic effect in patients who are renally impaired. Many chemotherapeutic agents are known to cause hearing loss. The most common are 5-fluorouracil (5-FU), bleomycin, and nitrogen mustard. The worst ototoxicity occurs with cisplatin.
                      • The hearing loss caused by antibiotic or chemotherapeutic agents usually begins at high frequencies; with continued medication use, the hearing loss will become more pronounced and may even continue to worsen for a time after the drug is discontinued. Any sensorineural hearing loss associated with these drugs is permanent.
                      • Aspirin or other salicylates can also cause hearing loss, but this is reversible with discontinuation of the drug. The etiology is believed to be enzymatic inhibition; thus, very high doses (6 to 8 grams/day) are required to cause ototoxicity.
                      • Antimalarial medications such as quinine and chloroquine may also cause sensorineural hearing loss and tinnitus but, similar to salicylates, these effects are usually reversible. This is also true for high-dose nonsteroidal antiinflammatory agents. Loop diuretics are an additional cause of temporary hearing loss and tinnitus.
                      • Ototopical medications — Several ototopical drops have the potential to cause ototoxicity. These include the aminoglycoside ear drops Tobradex and Garamicin, and Cortisporin (since it contains neomycin).
                    • Neurogenic — Several neurologic disorders may cause sensorineural hearing loss:
                      • Cerebrovascular accident or transient ischemic attack.
                      • Arnold-Chiari malformations may stretch the auditory vestibular nerve, thereby causing hearing loss and/or vestibular complaints
                      • Multiple sclerosis is another disease that can initially present as a sudden sensorineural hearing loss and/or vertigo.


                    A.  Magnetic resonance imaging (MRI) of the brain
                    ? acoustic neuroma – clinical picture not consistent with acoustic neuroma presentation


                    CLINICAL PRESENTATION — Symptoms associated with acoustic neuroma are due to cranial nerve involvement, cerebellar compression, and tumor progression. In a series of 1000 acoustic neuromas treated at a single institution, the acoustic nerve was involved in almost all cases, followed by the vestibular, trigeminal and facial nerves

                    Cochlear nerve — Symptomatic cochlear nerve involvement occurred in 95 percent of patients. The two major symptoms were hearing loss and tinnitus.

                    Vestibular nerve — Involvement of the vestibular nerve occurred in 61 percent of patients. Affected patients frequently acknowledged having unsteadiness while walking, which was typically mild to moderate in nature and frequently fluctuated in severity. True spinning vertigo was uncommon because these slow growing tumors cause gradual rather than acute asymmetries in vestibular function. In this setting, the central vestibular system can often compensate for the gradual loss of input from one side.

                    Trigeminal nerve — Trigeminal nerve disturbances occurred in 17 percent of patients. The most common symptoms were facial numbness (paresthesia), hypesthesia, and pain. The average duration of symptoms was 1.3 years; the symptoms usually occurred after hearing loss had been present for more than two years and vestibular symptoms for more than one year.

                    Facial nerve — The facial nerve was involved in 6 percent of patients. The primary symptoms were facial paresis and, less often, taste disturbances.

                    Tumor progression — Other presenting signs are the result of tumor progression, leading to pressure on adjacent posterior fossa structures. Very large tumors can press on the cerebellum or brainstem and result in ataxia. Brainstem compression, cerebellar tonsil herniation, hydrocephalus and death can occur in untreated cases. The functions of the lower cranial nerves (nerves IX, X, and XI), such as speaking and swallowing, can also become impaired, leading to dysarthria, dysphagia, aspiration, and hoarseness.

                    DIAGNOSIS — The diagnosis of acoustic neuroma is made by the demonstration of asymmetric sensorineural hearing loss or other cranial nerve deficits followed by imaging with MRI or CT scan. Acoustic neuroma accounts for 80 to 90 percent of posterior fossa lesions. Meningioma accounts for 4 to 10 percent; the remainder are accounted for by facial nerve schwannomas, gliomas, cholesterol cysts, cholesteatomas, hemangiomas, aneurysms, arachnoid cysts, lipomas, and metastatic tumor.



                    B.  Anti-double-stranded-DNA antibodies assay

                    ? SLE
                     The diagnosis of SLE is straight forward in a patient who presents with several compatible clinical features and has supportive laboratory studies. A good example is a young woman who presents with complaints of fatigue, arthralgia, and pleuritic chest pain, who is found to have hypertension, a malar rash, a pleural friction rub, several tender and swollen joints, and mild peripheral edema. Laboratory testing may reveal leukopenia, anemia, an elevated serum creatinine, hypoalbuminemia, proteinuria, an active cellular urinary sediment, hypocomplementemia, a positive Coombs test, and positive tests for antinuclear antibodies, including those to double stranded DNA and the Smith antigen.


                    ARA criteria for diagnosis of systemic lupus erythematosus

                    Using the analogy of the ARA criteria for the diagnosis of rheumatoid arthritis, we have suggested that patients be classified as follows:
                    Classical SLE — many criteria
                    Definite SLE — 4 or more criteria
                    Probable SLE — 3 criteria
                    Possible SLE — 2 criteria



                    Malar rash

                    Fixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds

                    Discoid rash

                    Erythematosus raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions


                    Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation

                    Oral ulcers

                    Oral or nasopharyngeal ulceration, usually painless, observed by a physician


                    Nonerosive arthritis involving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion


                    Pleuritis - convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion OR
                    Pericarditis - documented by EKG, rub or evidence of pericardial effusion

                    Renal disorder

                    Persistent proteinuria greater than 0.5 grams per day or greater than 3+ if quantitation not performed OR
                    Cellular casts - may be red cell, hemoglobin, granular, tubular, or mixed

                    Neurologic disorder

                    Seizures OR psychosis - in the absence of offending drugs or known metabolic derangements (uremia, ketoacidosis, or electrolyte imbalance)

                    Hematologic disorder

                    Hemolytic anemia - with reticulocytosis OR
                    Leukopenia - less than 4,000/mm3 total on two or more occasions OR 
                    Lymphopenia - less than 1,500/mm3 on two or more occasions OR
                    Thrombocytopenia - less than 100,000/mm3 in the absence of offending drugs

                    Immunologic disorders

                    Positive antiphospholipid antibody OR
                    Anti-DNA - antibody to native DNA in abnormal titer OR
                    Anti-Sm - presence of antibody to Sm nuclear antigen OR
                    False positive serologic test for syphilis known to be positive for at least six months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption test

                    Antinuclear antibody 

                    An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with "drug-induced lupus" syndrome


                    Autoantibodies — The ANA test is the best diagnostic test for SLE and should be performed whenever SLE is suspected. The ANA is positive in significant titer (usually 1:160 or higher) in virtually all patients with SLE. Depending upon the titer of the ANA the false positive rate varies from approximately 30 percent to as little as 3 percent (for ANA titers of 1:40 and 1:320, respectively) among healthy controls . Since diseases other than SLE are associated with positive ANA test results, the predictive value of a positive test depends upon the control population. If patients with other rheumatic and collagen vascular diseases are used, a positive ANA has only a 20 to 35 percent predictive value for SLE. However, the negative predictive value, that is the probability of having SLE if the ANA test is negative, is less than 0.14 percent


                    dsDNA and Sm antibodies — There are two autoantibodies that are highly specific for SLE: anti-double-stranded DNA (dsDNA) antibodies; and anti-Sm antibodies. Their sensitivity is much lower at about 75 and 25 percent, respectively. One study, for example, evaluated seven commercial ELISA assays for anti-dsDNA antibodies; the following results were obtained]:
                    Sensitivity — 66 to 95 percent
                    Specificity — 75 to 100 percent
                    Predictive value — 89 to 100 percent


                    C. Anti-neutrophil cytoplasmic antibody (ANCA) assay

                    ? Wegener's granulomatosis

                    Clinical manifestations and diagnosis of Wegener's granulomatosis and microscopic polyangiitis

                    Wegener's granulomatosis is a systemic vasculitis of the medium and small arteries, as well as the venules, arterioles, and occasionally large arteries. "Classic" Wegener's granulomatosis is a form of systemic vasculitis that primarily involves the upper and lower respiratory tracts and the kidneys

                    A "limited" form, with clinical findings isolated to the upper respiratory tract or the lungs, occurs in approximately one-fourth of cases. Although many of these patients (up to 80 percent) may eventually develop glomerulonephritis, there are incompletely understood phenotypic differences in Wegener's granulomatosis . Specifically, patients with limited disease are younger at disease onset, and more likely to be women.

                    Renal involvement is manifested by acute renal failure with red cells, red cell and other casts, and proteinuria . Patients with microscopic polyangiitis have a renal lesion that is essentially indistinguishable from that of patients with classic Wegener's granulomatosis. The principal difference is the absence of granulomatous inflammation in the former disease, although the clinical manifestations of these disorders overlap substantially. In distinguishing these two conditions, some experts consider the presence of any significant upper respiratory tract involvement to be indicative of Wegener's granulomatosis. Patients presenting with only pauci-immune glomerulonephritis in the absence of other organ system involvement are generally classified as "renal-limited" vasculitis or idiopathic necrotizing glomerulonephritis.


                    OTHER DISEASE MANIFESTATIONS — In addition to renal and pulmonary involvment, other organ systems that may become involved include

                    • Upper and lower airways, including the subglottic region or trachea
                    • Joints (myalgias, arthralgias, arthritis)
                    •  Eyes (conjunctivitis, corneal ulceration, episcleritis/scleritis, optic neuropathy, nasolacrimal duct obstruction, proptosis, diplopia, retinal vasculitis, and uveitis)
                    • Skin (vesicular, palpable purpuric, ulcerative, and hemorrhagic lesions)
                    • Nervous system (mononeuritis multiplex, cranial nerve abnormalities, central nervous system mass lesions, external ophthalmoplegia, hearing loss)
                    • Less commonly, the gastrointestinal tract, heart (pericarditis, myocarditis, conduction system abnormalities), lower genitourinary tract (including the prostate), parotid glands, thyroid, liver, or breast ‘
                    • Patients with Wegener's granulomatosis also appear to have a high incidence of venous thrombosis

                    PRESENTING SYMPTOMS AND FINDINGS — The most common presenting symptoms include persistent rhinorrhea, purulent/bloody nasal discharge, oral and/or nasal ulcers, polyarthralgias, myalgias, or sinus pain. Less common symptoms of upper airway involvement are hoarseness, stridor, earache, both conductive and sensorineural hearing loss, or otorrhea .

                    Other frequent early complaints relate to the lower respiratory tract and include cough, dyspnea, hemoptysis (due to an alveolar capillaritis, necrotic lesions, or endobronchial disease), and pleuritic pain.

                    Nonspecific complaints of fever, night sweats, anorexia, weight loss, and malaise may accompany upper or lower airway disease. In addition, signs and symptoms related to involvement of other organ systems may also be observed. These include ocular inflammation, nasal congestion, joint tenderness and or effusion, and rash. Skin lesions include palpable purpura, ulcers, vesicles, papules, and subcutaneous nodules. Diarrhea associated with colorectal ulceration may also occur [19]. Central diabetes insipidus has also been described.

                    Renal involvement is another common component of Wegener's granulomatosis and microscopic polyangiitis

                    Routine laboratory tests — Routine laboratory tests are generally nonspecific in Wegener's granulomatosis. Common abnormalities include leukocytosis, thrombocytosis (>400,000/mm3), marked elevation of the erythrocyte sedimentation rate, and normochromic, normocytic anemia [1].

                    Antineutrophil cytoplasmic antibodies — The diagnosis of Wegener's granulomatosis is suggested from the clinical and laboratory findings and from the presence of circulating antineutrophil cytoplasmic antibodies (ANCA

                    Approximately 90 percent of patients with active, generalized Wegener's granulomatosis are ANCA-positive.


                    D. Lumbar puncture
                    ? meningitis – no other infective features, or heamorrhage – headache better presenting feature

                    E. Urinary drug screen
                    Antibiotics are the major ototoxic agents – chronic may be previous exposure




                    Question 91top

                    Question 92top

                    Question 93top Download PDF

                    QUESTION 93
                    A 24-year-old woman, who has recently arrived in Australia from Vietnam, presents for evaluation of abnormal menstrual bleeding. There are no abnormalities on examination.
                    Results of investigations are listed below.
                    Full blood count:
                    haemoglobin                                                                 113 g/L [120-155]
                    red cell count                                                                5.2 x 1012/L [4.1-5.2]
                    mean corpuscular volume (MCV)                                    71 fL [80-95]
                    mean corpuscular haemoglobin (MCH)                           22.0 pg [27.0-32.5]
                    mean corpuscular haemoglobin concentration (MCHC)    310 g/L [325-360]
                    white cell count                                                                         6.6 x 109/L [3.5-9.5]
                    differential                                                        normal
                    platelet count                                                                212 x 109/L [130-330]
                    Blood film shows red cell microcytosis and hypochromasia but is otherwise normal.
                    Haemoglobin (Hb) electrophoresis (cellulose acetate, pH 8.6):
                    HbA2                                                                                                                                                         2.7% [1.8-3.5]
                    HbF                                                                              0.4% [0-2.0]
                    No abnormal bands
                    HbH preparation:                                                                      HbH inclusions present
                    Serum biochemistry:
                    iron                                                                               8 μmol/L [7-32]
                    transferrin                                                                     3.2 g/L [2.1-3.6]
                    ferritin                                                                           15 μg/L [7-280]
                    The most likely diagnosis is:
                    A. homozygous alpha+ thalassaemia (−α/−α).
                    B. early iron deficiency.
                    C. congenital sideroblastic anaemia.
                    D. sickle cell anaemia.
                    E. heterozygous beta thalassaemia.


                    Evaluation of anaemia
                    Overview — Erythropoiesis in the adult takes place within the bone marrow under the influence of the stromal framework, cytokines, and the erythroid specific growth factor, erythropoietin (EPO). EPO is a true endocrine hormone produced in the kidney by cells that sense the adequacy of tissue oxygenation relative to the individual's metabolic activity

                    EPO enhances the growth and differentiation of the two erythroid progenitors: burst forming units-erythroid (BFU-E) and colony forming units-erythroid (CFU-E) into normoblasts of increasing maturity. When the normoblast extrudes its nucleus to form a red blood cell, it still has a ribosomal network which, when stained supravitally, identifies it as a reticulocyte, a cell still capable of a limited amount of hemoglobin and protein synthesis .

                    The reticulocyte retains its ribosomal network (and its staining characteristics) for about four days, of which three days are generally spent in the marrow and one day in the peripheral blood.  The resulting mature RBC circulates for 110 to 120 days, after which it is removed from the circulation by macrophages that detect senescent signals, through mechanisms that are poorly understood.

                    Under steady state conditions, the rate of RBC production equals the rate of RBC loss. Assuming, as a first approximation, survival of mature RBC of 100 days, 1 percent of RBCs are removed from the circulation each day. To achieve a constant RBC mass, RBC losses must be replaced with an equal number of reticulocytes during the same time period.

                    Reticulocytes normally survive in the circulation for one day; after this time they lose their reticulum (RNA) and become mature red blood cells. Under steady-state conditions reticulocytes will represent approximately 1 percent of total circulating RBC . Since the normal RBC count is approximately 5 million/microL, the bone marrow must produce approximately 50,000 reticulocytes/microL of whole blood each day in order to achieve a stable RBC mass. Lesser rates of RBC production, if persistent, lead to anemia.

                    The rate of red cell production increases markedly under the influence of high levels of erythropoietin (EPO). A normal bone marrow replete with iron, folate, and cobalamin can increase erythropoiesis in response to EPO about 5-fold in adults and 7- to 8-fold in children. Thus, under optimal conditions, steady-state absolute reticulocyte counts as high as 250,000/microL are possible in the adult.

                    Volume status — HGB, HCT, and RBC count are all concentrations and dependent on the red blood cell mass (RCM) as well as the plasma volume. As a result, values will be reduced if the RCM is decreased and/or if the plasma volume is increased

                    Symptoms — Symptoms related to anemia can result from two factors:

                    • decreased oxygen delivery to tissues, and,
                    • in patients with acute and marked bleeding, the added insult of hypovolemia. There is some reduction in blood volume but not plasma volume after acute severe hemolysis, due to the fall in RBC mass. In comparison, total blood volume remains normal in anemia due to chronic, low-grade bleeding, since there is ample time for equilibration with the extravascular space and renal retention of salt and water.


                    CAUSES OF ANEMIA — There are two general approaches one can use to help identify the cause of anemia:

                    • A kinetic approach, addressing the mechanism(s) responsible for the fall in hemoglobin concentration
                    • A morphologic approach categorizing anemias via alterations in RBC size (ie, mean corpuscular volume) and the reticulocyte response.

                    Kinetic approach — Anemia can be caused by one or more of three independent mechanisms:

                    • decreased RBC production,
                    • increased RBC destruction, and
                    • blood loss .

                    Decreased RBC production —

                    • Lack of nutrients, such as iron, B12, or folate. This can be due to dietary lack, malabsorption (eg, pernicious anemia, sprue), or blood loss (iron deficiency)
                    • Bone marrow disorders (eg, aplastic anemia, pure RBC aplasia, myelodysplasia, tumor infiltration)
                    • Bone marrow suppression (eg, drugs, chemotherapy, irradiation).
                    • Low levels of trophic hormones which stimulate RBC production, such as EPO (eg, chronic renal failure), thyroid hormone (eg, hypothyroidism), and androgens (eg, hypogonadism). A rare cause of anemia due to reduced EPO production has been described in patients with autonomic dysfunction and orthostatic hypotension
                    • The anemia of chronic disease/inflammation, associated with infectious, inflammatory, or malignant disorders, is characterized by reduced availability of iron due to decreased absorption from the gastrointestinal tract and decreased release from macrophages, a relative reduction in erythropoietin levels, and a mild reduction in RBC lifespan.

                    Increased RBC destruction —

                    • Hemolytic anemia will ensue when the bone marrow is unable to keep up with the need to replace more than about 5 percent of the RBC mass per day, corresponding to a RBC survival of about 20 days. Examples include:
                      • Inherited hemolytic anemias (eg, hereditary spherocytosis, sickle cell disease, thalassemia major)
                      • Acquired hemolytic anemias (eg, Coombs'-positive autoimmune hemolytic anemia, thrombotic thrombocytopenic purpura-hemolytic uremic syndrome, malaria)

                    Blood loss — Iron deficiency in the United States and Western Europe is almost always due to blood loss. Blood loss is the most common cause of anemia and may take any one of a number of forms:

                    • Obvious bleeding (eg, trauma, melena, hematemesis, menometrorrhagia)
                    • Occult bleeding (eg, slowly bleeding ulcer or carcinoma).
                    • Induced bleeding (eg, repeated diagnostic testing, hemodialysis losses, excessive blood donation)

                    In addition to the loss of RBCs from the body, which the bone marrow must replace, loss of the iron contained in these cells will ultimately lead to iron deficiency, once tissue stores of iron have been depleted. This usually occurs in males and females after losses of 1200 mL and 600 mL, respectively. However, since about 25 percent of menstruant females have absent iron stores, any amount of bleeding will result in anemia in this subpopulation.

                    Since availability of iron is normally rate-limiting for RBC production, iron deficiency associated with chronic bleeding leads to a reduced marrow response, worsening the degree of anemia.

                    Morphologic approach — The causes of anemia can also be classified according to measurement of RBC size, as seen on the blood smear and as reported by automatic cell counter indices . The normal RBC has a volume of 80 to 96 femtoliters (fL, 10[-15] Liter) and a diameter of approximately 7 to 8 microns, equal to that of the nucleus of a small lymphocyte. Thus, RBCs larger than the nucleus of a small lymphocyte on a peripheral smear are considered large or macrocytic, while those that appear smaller are considered small or microcytic

                    An increased RDW indicates the presence of cells of widely differing sizes, but it is not diagnostic of any particular disorder. However, some automatic cell counters have computer programs which "flag" for the presence of abnormalities such as

                    • anisocytosis (cells of varying size),
                    • microcytosis, macrocytosis, and
                    • hypochromia (reduced hemoglobin content per cell)

                     Macrocytic anemia —

                    • characterized by an MCV above 100 fL (femtoliters) (An increased MCV is a normal characteristic of reticulocytes
                    • Any condition causing marked reticulocytosis will be associated with an increased MCV.
                    • Abnormal nucleic acid metabolism of erythroid precursors (eg, folate or cobalamin deficiency and drugs interfering with nucleic acid synthesis, such as zidovudine and hydroxyurea).
                    • Abnormal RBC maturation (eg, myelodysplastic syndrome, acute leukemia, LGL leukemia). Other common causes include alcohol abuse, liver disease, and hypothyroidism.

                     Microcytic anemia —

                    • characterized by the presence of "small" RBCs (ie, MCV below 80 fL).
                    • usually accompanied by a decreased hemoglobin content within the RBC, with parallel reductions in MCV and MCH, producing a hypochromic (low MCH) as well as a microcytic (low MCV) appearance on the blood smear
                    • The following pathologic processes lead to the production of hypochromic microcytic red cells:
                      • Reduced iron availability —
                        • severe iron deficiency,
                        • the anemia of chronic disease,
                        • copper deficiency
                      • Reduced heme synthesis —
                        • lead poisoning,
                        • congenital or acquired sideroblastic anemia
                      • Reduced globin production —
                        • thalassemic states,
                        •  other hemoglobinopathies

                    The three most common causes of microcytosis in clinical practice are iron deficiency, alpha or beta thalassemia minor, and (less often) the anemia of chronic disease (anemia of chronic inflammation).

                     Normocytic anemia — By definition, the mean RBC volume is normal (MCV between 80 and 100 fL) in patients with normocytic anemia). Approach to this extremely large and amorphous category can be narrowed somewhat by examination of the blood smear to determine if there is a subpopulation of RBCs with distinctive size or shape abnormalities which would place the patient in one of the above categories (ie, early microcytic or macrocytic anemia), or by use of the kinetic approach to determine the mechanism(s) underlying the anemia

                    Systemic disorders — Anemia may be the first manifestation of a systemic disorder, along with other nonspecific complaints such as fever, weight loss, anorexia, and malaise. Simple laboratory tests may give additional clues toward the underlying disease process. These include abnormalities on the urinalysis or routine chest x-ray, liver or renal function tests, erythrocyte sedimentation rate, serum protein electrophoresis, WBC count and differential, and reduced (or increased) platelet counts. Anemia in the elderly is discussed separately (see "The elderly" above).

                    Anemia of chronic renal disease — Anemia is a common complication of renal disease, and may be multifactorial.


                    homozygous alpha (+)  thalassaemia (−α/−α)
                    Alpha (0) thalassemia — Alpha (0) thalassemia refers to the more than 20 different genetic mutations of the alpha globin locus which result in the deletion of both alpha chain loci  on one chromosome 16. Patients who carry alpha (0) gene mutations on both chromosomes cannot make alpha chains and are therefore unable to make any hemoglobin A, F, or A2. This condition is incompatible with extrauterine life.

                    Alpha (+) thalassemia — Alpha (+) thalassemia refers to the more than 15 different genetic mutations which result in decreased production of alpha globin, usually due to deletion of one of the two alpha chain loci in the affected chromosome. As a result, there are three general forms of alpha (+) thalassemia based upon the number of inherited alpha genes:

                    • Inheritance of three normal alpha genes (aa/a-) has been termed alpha thalassemia minima, silent carrier of alpha thalassemia, alpha thalassemia-2 trait, or heterozygosity for alpha (+) thalassemia. Affected subjects are clinically normal and may also be hematologically normal; the diagnosis can be reliably made only via DNA analysis.
                    • Inheritance of two normal alpha genes has been termed alpha thalassemia minor or alpha thalassemia-1 trait, and is due either to heterozygosity for alpha (0) thalassemia (aa/--) or homozygosity for alpha (+) thalassemia (a-/a-). These subjects are clinically normal but may have minimal anemia along with reductions in mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH)
                    • Inheritance of one normal alpha gene (a-/--) is termed hemoglobin H (HbH) disease, because of the formation of HbH, which is composed of tetramers of the resulting excess beta chains. These patients have moderate to severe degrees of lifelong hemolytic anemia, very modest degrees of ineffective erythropoiesis, splenomegaly, and variable bony changes
                    •  As mentioned above, inheritance of no alpha genes (--/--) is incompatible with extrauterine life, since the affected fetus will be unable to make any of the hemoglobins normally produced after birth (eg, hemoglobins A, F, and A2), all of which require the ability to produce alpha globin chains

                    Iron Deficiency Anaemia
                    CAUSES OF IRON DEFICIENCY

                    • Blood loss — The major cause of iron deficiency in affluent countries is blood loss, either overt or occult
                    • Decreased iron absorption — Gastrointestinal malabsorption of iron is a relatively uncommon cause of iron deficiency, although it may be observed in certain diseases associated with generalized malabsorption or achlorhydria.   These diagnoses (ie, atrophic gastritis, Helicobacter pylori gastritis, sprue) should be considered in patients with otherwise unexplained iron deficiency, especially when there is refractoriness to oral iron therapy
                    •  There are several other uncommon causes of iron deficiency:
                      • Intravascular hemolysis
                      • Pulmonary hemosiderosis
                      • Response to erythropoietin — A response to treatment with erythropoietin (EPO) for the anemia of chronic renal failure often leads to iron deficiency, since the iron requirements generated by this response can usually not be met by mobilization of the patient's iron stores alone [


                    STAGES OF IRON DEFICIENCY

                    Normal body iron content — The normal iron content of the body is 3 to 4 grams. It exists in the following forms:

                    • Hemoglobin in circulating red cells — approximately 2 grams
                    • Iron containing proteins, such as myoglobin, cytochromes, and catalase — 400 mg
                    • Iron bound to transferrin in plasma — 3 to 7 mg
                    • The remainder is storage iron in the form of ferritin or hemosiderin.

                    Storage iron in adult men has been estimated as being approximately 10 mg/kg, and is found mostly in liver, spleen, and bone marrow . Adult women have less storage iron, depending upon the extent of menses, pregnancies, deliveries, lactation, and iron intake.

                    For ferritin levels in the range from 20 to 300 ng/mL, there appears to be a direct quantitative relationship between the ferritin concentration and iron stores

                     Iron stores (mg)  (8 to 10) x ferritin (ng/mL)

                    Progressive iron depletion —

                    • In the first stage, iron stores can be totally depleted without causing anemia. The storage iron pool, consisting primarily of ferritin and hemosiderin-bound iron within the monocyte-macrophage system chiefly in bone marrow, liver and spleen, contains approximately 0.8 to 1.0 g of iron in men and one-half this value in women . The storage pool can be looked upon as a reserve of iron that can be utilized when there is increased need for hemoglobin synthesis, as in acute blood loss, growth in children and adolescents, pregnancy, lactation and response to EPO. Once these stores are depleted, there is still enough iron present in the body within the "labile" iron pool from the daily turnover of red cells for normal hemoglobin synthesis, but the patient is now vulnerable to development of anemia should there be further iron losses
                    • Further loss of iron results in anemia, which is initially normocytic with a normal absolute reticulocyte count This stage of iron deficiency is common in the United States.
                    • More profound deficiency results in the classical hypochromia and microcytosis of iron-deficient erythropoiesis.



                    Laboratory tests in iron deficiency of increasing severity



                    Fe deficiency without anemia

                     Fe deficiency with mild anemia

                    Severe Fe deficiency with severe anemia

                    Marrow reticulo- endothelial iron

                    2+ to 3+




                    Serum iron, µg/dL

                    60 to 150

                    60 to 150



                    Iron binding capacity (transferrin), µg/dL

                    300 to 360

                    300 to 390

                    350 to 400


                    Saturation (SI/TIBC), percent

                    20 to 50




                    Hemoglobin, g/dL



                    9 to 12


                    6 to 7

                    Red cell morphology



                    Normal or slight hypochromia

                    Hypochromia and microcytosis

                    Plasma or serum ferritin, ng/mL

                    40 to 200



                    0 to 10

                    Erythrocyte proto- porphyrin, ng/mL

                    RBC 30 to 70

                    30 to 70


                    100 to 200

                    Other tissue changes




                    Nail and epithelial changes

                    Note: Test results outlined in bold type are the ones most likely to define the various stages of iron deficiency. Thus, the presence or absence of iron stores (marrow reticuloendothelial iron) in a non-anemic patient serves to distinguish normal subjects from those with iron deficiency without anemia, respectively.


                    CLINICAL MANIFESTATIONS — The usual presenting symptoms in adults, as seen in current practice, are primarily due to anemia and include weakness, headache, irritability and varying degrees of fatigue and exercise intolerance. However, many patients are asymptomatic and present only with anemia.


                    Classic presentation — The following is a "classic" presentation of iron-deficiency anemia. The patient, a multigravid woman in her 40's, presents with tiredness, fatigue, and chronic blood loss from menometrorrhagia. The following laboratory findings were noted :

                    • Hemoglobin was low at 8 g/dL; mean cell volume (MCV) was low at 75 fL
                    • The mean corpuscular hemoglobin (MCH) was low; a blood smear showed microcytic, hypochromic red cells
                    • The serum iron was low (10 microg/dL) and the total iron binding capacity (TIBC)/transferrin was elevated (400 microg/dL), resulting in a low transferrin saturation of 2.5 percent.
                    • The plasma ferritin concentration was markedly reduced (10 ng/mL)
                    •  Iron stores were absent after performing the "gold standard" test of estimating iron stores via microscopic examination of the Prussian Blue reaction on an aspirate of the patient's bone marrow
                    • Finally, the patient responded briskly to a therapeutic trial of oral iron, with a reticulocytosis, followed by elevations in the hemoglobin concentration and hematocrit.

                    The current reality in developed countries is that this classic presentation is uncommon, and that the diagnosis and management of iron deficiency anemia is usually a good deal more complicated

                    ESTIMATION OF IRON STORES — The history, complete blood count, red cell indices, and smear usually allow the clinician to make a presumptive diagnosis of iron deficiency anemia. This can be followed by a therapeutic trial of iron administration to provide both confirmation of the diagnosis and therapy.

                    Serum or plasma ferritin — The serum or plasma ferritin concentration is an excellent indicator of iron stores in otherwise healthy adults and has replaced assessment of bone marrow iron stores as the gold standard for diagnosis in most patients but

                    • Elevated in pregnance
                    • Acute phase reactant in inflammatory states

                    Serum iron and transferrin (TIBC) — In iron deficiency anemia, the serum iron concentration (SI) is reduced, and the level of transferrin (also measured as total iron binding capacity [TIBC]) is elevated; the latter finding reflects the reciprocal relationship between serum iron and transferrin gene expression in most nonerythroid cells ]. The low SI and high transferrin/TIBC result in a low transferrin saturation or index (saturation = SI/TIBC x 100), often to levels less than 10 percent, compared to the normal value of 25 to 45 percent [16,42].

                    Bone marrow iron — Iron in bone marrow macrophages and erythroid precursors (sideroblasts) can be detected with the Prussian Blue stain on marrow spicules. Lack of stainable iron in erythroid precursors as well as marrow macrophages is considered by most clinicians to be the "gold standard" for the diagnosis of iron deficiency. In contrast, in uncomplicated anemia of chronic disease, iron is present in marrow macrophages but absent or reduced in erythroid precursors but

                    • Considered too invasive


                    Serum transferrin receptor — Circulating transferrin receptor (sTfR) is derived from bone marrow erythroid precursors. It provides a quantitative measure of total erythropoietic activity, since its concentration in serum is directly proportional to erythropoietic rate and inversely proportional to tissue iron availability ]. Thus, iron deficient patients should have increased levels of sTfR (

                    Red cell morphology and indices — Despite the classic description of iron deficiency as leading to a hypochromic, microcytic anemia (, many iron deficient patients in western countries will have normal red cell morphology. Further, the finding of a hypochromic microcytic anemia is not pathognomonic of iron deficiency), with thalassemia and, less commonly, the anemia of chronic disease being the other common conditions encountered in daily practice. It is important to rule out these disorders before beginning a trial of iron therapy, since many such patients are already iron overloaded.

                    Reticulocyte indices — With the advent of automated counting of reticulocytes, several new reticulocyte parameters are available to clinicians and pathologists

                    Red cell zinc protoporphyrin level — The last step in the biosynthesis of heme is the addition of iron to protoporphyrin IX. If iron is unavailable, zinc (Zn) substitutes, forming zinc protoporphyrin, which can be measured This test measures the lack of iron, not why it is unavailable.

                    Red cell zinc protoporphyrin (FEP) is also elevated in lead poisoning

                    Congenital sideroblastic anaemia
                    Complete blood count —

                    • The anemia is usually moderate and normocytic or macrocytic, with a variable population of hypochromic cells on the blood smear.
                    •  Particularly characteristic are occasional siderocytes: hypochromic red cells with basophilic stippling that stains positive for iron
                    • Leukocyte and platelet counts are often within the normal range in patients with AISA. The presence of moderate leukopenia and/or thrombocytopenia tends to be associated with other myelodysplastic features, such as the pseudo-Pelger anomaly. Leukocytosis and/or thrombocytosis are least common, and may reflect the presence of a myeloproliferative disorder.
                    • Free erythrocyte protoporphyrin — The free erythrocyte protoporphyrin is characteristically increased, up to about 300 µg/dL (normal: 20 to 65). However, in some patients, values have ranged from 1055 to 10,514 µg/dL, and some have experienced photosensitivity
                    • Iron studies — Serum iron and ferritin levels reflect the commonly associated iron overload, as in hereditary sideroblastic anemia
                    • Bone marrow examination — Bone marrow aspiration shows the presence of erythroid hyperplasia, commonly with mild megaloblastic changes. The marrow macrophage iron content is increased and, in contrast to the hereditary form, ring sideroblasts are evident at all stages of maturation; their presence establishes the diagnosis.

                    Sickle Cell Disease

                    Findings in sickle cell disease — 
                    The chronic hemolysis of sickle cell disease is usually associated with

                    • a mild to moderate anemia (hematocrit 20 to 30 percent),
                    • eticulocytosis of 3 to 15 percent (accounting for high or high-normal mean corpuscular volume [MCV]),
                    • unconjugated hyperbilirubinemia, and
                    • elevated serum LDH and low serum haptoglobin.

                    The peripheral blood smear reveals

                    • sickled red cells,
                    • polychromasia indicative of reticulocytosis, and
                    • Howell-Jolly bodies reflecting hyposplenia

                    The red cells are

                    • normochromic unless there is coexistent thalassemia or iron deficiency.
                    •  If the age-adjusted MCV is not elevated, the possibility of sickle cell-beta thalassemia, coincident alpha thalassemia, or iron deficiency should be considered.
                    • The Hb F level is usually slightly to moderately elevated and
                    •  Hb A is absent).
                    • The amount of Hb F is a function of the number of reticulocytes that contain Hb F, the extent of selective survival of Hb F-containing reticulocytes to become mature Hb F-containing erythrocytes, and the amount of Hb F per red cell.


                    This girl has

                    • Hb 113
                    • a microcytic hyochrmasic anaemia – consistent with iron deficiency
                    • normal HbA2 (abscent in sickle cell) and Hb F (raised in sickle cell)
                    • No abnormal bands
                    • HbH preparation: HbH inclusions present
                    • Iron studies within normal range (would be raised in congenital siderablastic anaemia – associated with iron overload)

                    A. homozygous alpha+ thalassaemia (−α/−α).

                    Alpha thalassemia-1 trait — Alpha thalassemia-1 trait, also called alpha thalassemia minor, resembles mild beta thalassemia trait.
                    The peripheral blood smear shows

                    • hypochromia,
                    • microcytosis, and
                    • target cells.
                    • The MCV is often less than 80 fL, but hemoglobin electrophoresis is normal.
                    • Elevation of Hb A2 does not occur in alpha thalassemia;
                    • slight elevations of Hb F have been reported.

                    The reduced synthesis of alpha globin chains leads to an accumulation of otherwise normal beta globin chains in adults and gamma chains in the fetus. Instead of forming alpha/beta dimers which then form normal HbA tetramers (a2b2), the excess beta globin chains assemble into beta-4 tetramers, called HbH hence the positive HbH inclusions and therefore the correct answer

                    B. early iron deficiency.
                    To have hypochromic cells indicates iron deficiency, if this were the cause there would be abnormalities in her iron studies especially ferritin level – see table above

                    C. congenital sideroblastic anaemia.
                    Normal iron studies –  The iron studies would most likely be raised  consistent with the common association of iron overload

                    D. sickle cell anaemia.
                    normal HbA2           2.7% [1.8-3.5]  - would be low in sickle cell anaemia and HbF – would be raised in sickle cell

                    E. heterozygous beta thalassaemia.
                    The terms beta thalassemia minor and beta thalassemia trait are used to describe heterozygotes who carry one normal beta globin allele and one beta thalassemic allele. The vast majority of these patients are entirely asymptomatic, but do present an abnormal blood picture that is sometimes erroneously diagnosed as iron deficiency anemia.

                      • Typically, the blood count and peripheral blood film exhibit features similar to those seen in iron deficiency anemia (eg, hypochromia and microcytosis).
                      •  However, as a rule, the microcytosis is much more profound, and the anemia much milder, than that seen in iron deficiency anemia.
                      • Patients with beta thalassemia trait almost always have a hematocrit >30 percent, and a mean corpuscular volume of the red cells (MCV) <75 fL.
                      • The RDW in patients with thalassemia trait tends to be normal, since virtually all cells are hypochromic and microcytic.


                      Haematology: Anaemia repeat question 2001 paper two question 72


                      Question 94top

                      Question 95top Download PDF

                      QUESTION 95
                      A 30-year-old man is admitted to hospital with a three-day history of headache and fever. In the six hours preceding admission, he has become confused and drowsy and is observed to have focal twitching of the right arm. His temperature is 39.2oC. He is unable to answer questions coherently or follow commands. He has mild neck stiffness. A computed tomography (CT) scan of the brain is normal.
                      Cerebrospinal fluid (CSF) analysis is as follows:
                      white cell count 90 x 106/L [<5]
                      lymphocytes 80 x 106/L [<2]
                      neutrophils 10 x 106/L [<2]
                      protein 0.80 g/L [0.15-0.40]
                      glucose 3.2 mmol/L [2.5-4.5]
                      Herpes simplex encephalitis is suspected and he is started on intravenous aciclovir.
                      Which one of the following is the most appropriate next investigation to confirm the diagnosis?
                      A. Cerebral magnetic resonance imaging (MRI).
                      B. Electroencephalography (EEG).
                      C. Cerebral positron emission tomography (PET) scanning.
                      D. Brain biopsy.
                      E. Polymerase chain reaction (PCR) assay for viral DNA.

                      Reference: Infectious Diseases A clinical Approach Yung, McDonald, Spelman, Street and Johnson 2001
                      Page 171-172
                      Herpes simplex encephalitis
                      The most common agent responsible for sporadic cases of encephalitis is herpes simplex virus.  In adults, almost all infections are due to HSV 1; in neonates, HSV type 2 is almost invariably responsible and follows transmission during delivery.  The disease is not seasonal and presents in all age groups.  It typically affects the temporal and frontal lobes and almost invariably presents with fever as well as focal signs, especially dysphasia or personality change; two thirds of patients suffer either focal or generalized seizures.
                      Diagnosis has recently been greatly facilitated by the introduction of CSF PCR into routine clinical use.  This is now the diagnostic test of choice and has a greater than 95% sensitivity in competent laboratories when compare to brain biopsy.  If suspicion is high and an initial test is negative, the PCR should be repeated after 24-48 hours.  Sensitivity is reduced if acyclovir treatment has been used for longer than 24 hours.
                      EEG has 84 % sensitivity and reveals characteristic temporal spike and wave activity.  CT is abnormal in 50-75% of patients, while MRI is more sensitive and is the imaging modality of choice if available.  Alternative modes of diagnosis include demonstration of intrathecal HSV antibody which becomes detectable 3-10 days following clinical onset and persists for at least 30 days.  Simultaneous serum antibody is performed and a serum: CSF ratio of less than 20:1 is suggestive of intrathecal synthesis.
                      Timely diagnosis is critical as this is one of he few agents causing encephalitis for which effective, non-toxic treatment is available in the form of acyclovir; outcome is heavily dependent on early institution of therapy.  Accordingly, any patients with a reasonable suspicion of HSE should be treated with intravenous acyclovir.  If presentation is atypical or he patient does not respond to therapy, brain biopsy should be performed since as many as 20% of patients with a typical presentation have an alternative diagnosis, many of which are due to treatable infectious agents.

                      Answer: E. Polymerase chain reaction (PCR) assay for viral DNA.


                      Infectious Diseases: Viral | ID emergency


                      Question 96top

                      Question 97top Download PDF

                      Question 97
                      A 63-year-old man is brough to the emergency department by his family with a one-hour history of continuing abnormal behaviour following an argument with his wife.  His speech is fluent and his comprehension is normal.  He has no recollection of the argument or the events leading up to his presentation.  He continually requires reassurance regarding the current situation and has difficulty remembering the advice given.  His long-term memory is intact.  Neurological examination is otherwise normal.  A cranial computed tomography (CT) scan is normal

                      The most likely diagnosis is:

                      A.  conversion disorder
                      B. transient global amnesia
                      C. temporal lobe epileptic event
                      D. thalamic stroke
                      E. basilar artery thrombosis


                       Conversion disorder

                       Conversion disorder refers to symptoms or deficits of voluntary or sensory function suggesting a neurologic or general medical condition and associated with psychological factors. Typically there is a sudden onset of a dramatic but physiologically impossible condition like paralysis, aphonia, blindness, deafness, or pseudoseizures. The presentation fits the patient's view of the disorder rather than physiology. Unlike somatization disorder, patients with conversion disorder focus upon only one symptom. Careful neurologic examination documenting an intact system rules out an organic cause. Although the rate of misdiagnosis of conversion disorder (medically unexplained sensory, seizure, or paralysis) was 29 percent in the 1950s, published studies since the 1970s show only 4 percent of patients diagnosed with conversion are subsequently found to have a documented medical illness .

                      Conversion disorder tends to occur in young, naive, uneducated women and is not in the conscious control of the patient. It is often associated with an emotional conflict that is not easily resolved. Comorbid depression, psychosis, or neurologic disease should be considered. Personality disorder, dissociative disorder, and posttraumatic stress disorder may also be present. Patients often respond to suggestion or persuasion.

                      transient global amnesia

                      Transient global amnesia (TGA) is a syndrome characterized by the acute onset of severe anterograde amnesia accompanied by retrograde amnesia, without other cognitive or focal neurologic impairment. The amnesia resolves within 24 hours. Most patients are middle aged or older adults. Episodes are usually not recurrent, but rare patients have infrequent attacks that recur over several years.

                      The etiology of TGA is uncertain. Most TGA episodes are probably related to vasoconstriction, but some may be caused by transient ischemia or complex partial seizures. TGA can be associated with small focal abnormalities on diffusion-weighted MRI , but the significance of these remains unclear.
                      temporal lobe epileptic event

                       Complex partial seizures — The classification system for epileptic seizures includes several seizure types that are characterized by an abrupt loss of consciousness: complex partial seizures ("complex" means that consciousness and awareness of the surroundings are lost), absence seizures, and generalized tonic-clonic seizures (also known as convulsions; "tonic" refers to muscle stiffening and "clonic" refers to muscle jerking)

                      Complex partial seizures (previously called temporal lobe seizures or psychomotor seizures) are the most common type of seizure in epileptic adults. During the seizure patients appear to be awake but are not in contact with others in their environment and do not respond normally to instructions or questions. They often seem to stare into space and either remain motionless or engage in repetitive behaviors, called automatisms, such as facial grimacing, gesturing, chewing, lip smacking, snapping fingers, repeating words or phrases, walking, running, or undressing. Patients may become hostile or aggressive if physically restrained during complex partial seizures.

                      Complex partial seizures typically last less than three minutes and may be immediately preceded by a simple partial seizure. Afterward, the patient enters the postictal phase, often characterized by somnolence, confusion, and headache for up to several hours . The patient has no memory of what took place during the seizure other than, perhaps, the aura.

                      The behaviors that typify complex partial seizures are not specific for epileptic seizures and may be observed in association with NES.


                       thalamic stroke
                      Thalamic hemorrhage — A thalamic hemorrhage may extend in a transverse direction to the posterior limb of the internal capsule, downward to put pressure on the tectum of the midbrain, or may rupture into the third ventricle. Symptoms include hemiparesis, hemisensory loss, and occasionally transient homonymous hemianopsia. There may also be an upgaze palsy with miotic pupils that are unreactive, peering at the tip of the nose, skewed, or "wrong way eyes" toward the weak side (in contrast to hemispheric cortical injury in which the eyes are deviated away from the hemiparesis). Aphasia may occur if the bleed affects the dominant hemisphere or neglect in the nondominant hemisphere.

                       basilar artery thrombosis

                      BASILAR ARTERY — The basilar artery begins at the medullopontine junction and ends at the junction of the pons and midbrain. Occlusive lesions may occur anywhere along the basilar artery . In addition, thrombi engrafted upon occlusive lesions within the distal intracranial vertebral artery (ICVA), for example, near or at the ICVA-basilar artery junction, can extend into the proximal basilar artery.

                      Basilar artery occlusive disease most often presents as ischemia in the pons. The major burden of ischemia is in the middle of the pons, mostly in the paramedian base, and often also in the paramedian tegmentum.

                      The paramedian pontine base contains descending long motor tract and crossing cerebellar fibers. The paramedian tegmentum contains mostly oculomotor fibers. As a result, the predominant symptoms and signs in patients with basilar artery occlusive disease are motor and oculomotor. Sensory and vestibular nuclei and tracts located in the lateral tegmentum are relatively spared.

                      Alteration in the level of consciousness is an important sign in patients with basilar artery occlusion. They may present with coma when the bilateral medial pontine tegmentum is ischemic.

                      Motor symptoms and signs — Most patients with symptomatic basilar artery occlusive disease and pontine ischemia have some transient or persistent degree of paresis and corticospinal tract abnormalities. The initial motor weakness is often lateralized and has been referred to as the "herald hemiparesis" of basilar artery occlusion.

                      Hemiparetic patients with basilar artery occlusion almost always show some motor or reflex abnormalities on the nonhemiparetic side. As examples, slight weakness, hyperreflexia, an extensor plantar reflex, or abnormal spontaneous movements such as shivering, twitching, shaking, or jerking may be present on the relatively spared side. Asymmetry but bilaterality is the rule.

                      Adventitious movements of the arms and/or legs are occasionally seen and can be prominent. These movements are variable and sometimes intermittent. Small movements may resemble fasciculations. Larger movements may resemble shivering, shuddering, or jerking; another variant is that of tremulous shaking. Voluntary or passive limb movements or painful stimuli may precipitate a flurry of abnormal movements. At times there are large repetitive jerking and twitching movements, especially in limbs contralateral to a hemiparesis. These movements are often misdiagnosed as seizures .

                      Incoordination of limb movements is another common motor finding. Ataxia is invariably combined with some degree of weakness. Incoordination is usually more severe in the legs. Toe-to-object and heel-to-shin testing usually shows clumsiness and diminished coordination due to cerebellar dysfunction. The ataxia is invariably bilateral but may be asymmetric and more severe on the weaker side. Intention tremor is not common.

                        Bulbar involvement — Weakness of bulbar muscles is very common and is an important cause of morbidity with pontine infarction due to basilar occlusive disease. Bulbar symptoms include facial weakness, dysphonia, dysarthria, dysphagia, and limited jaw movements. The face, pharynx, larynx, and tongue are most often involved. The pattern may be that of crossed motor loss, such as weakness involving one side of the face and the contralateral body, but more often the bulbar muscle weakness is bilateral.

                      Some patients totally lose the ability to speak, open their mouth, protrude their tongue, swallow, or move their face at will or on command. Secretions pool in the pharynx, and aspiration is an important and serious complication. When all voluntary movements other than the eyes are lost but consciousness is retained, the deficit is referred to as the "locked-in syndrome."

                      Patients with infarction of the pontine base frequently have exaggerated crying and laughing spells and are hypersensitive to emotional stimulus, a condition known as pseudobulbar affect or emotional lability.

                      Despite the loss of volitional muscle movement, reflexes of the jaw, face, and pharynx may be exaggerated. In addition, clonic jaw movements or clamping down on a tongue blade may occur as a response to attempts to pry the mouth open and to insert a tongue blade.

                      Some patients with pontine ischemia develop palatal myoclonus (a rhythmic involuntary jerking movement of the soft palate and pharyngopalatine arch) that can involve the diaphragm and larynx. This movement disorder usually begins sometime after the brainstem infarct. The movements of the palate vary in rate between 40 to 200 beats per minute. The movements are readily seen by watching the palate and pharynx when the mouth is open. The movements involve the eustachian tube and make a click that the patient and clinician can hear.

                      Oculomotor symptoms and signs — Oculomotor symptoms and signs are common with symptomatic basilar artery occlusive disease and pontine ischemia, and few patients with this condition have normal eye movements. Abnormalities include: Complete bilateral horizontal gaze palsy Unilateral horizontal conjugate gaze palsy Unilateral or bilateral internuclear ophthalmoplegia (INO) One-and-a-half syndrome (a conjugate gaze palsy combined with an INO).

                      Skew deviation of the eyes and ocular bobbing may also be present. Horizontal, gaze-paretic nystagmus is common and, when asymmetric, usually is more prominent when gaze is directed to the side of a unilateral pontine tegmental lesion. Dissociated nystagmus, that is nystagmus that is more severe in one eye and not rhythmically concordant in the two eyes, and vertical nystagmus are found in patients with an INO. Ptosis of the upper eyelids is also very frequent.

                      The pupils may remain normal or become small. In some patients, the pupils are bilaterally very small ("pinpoint"). Use of a magnifying glass can show that, despite their very small size, the pupillary response to light is preserved, although the amplitude of the response is slight.

                      Sensory symptoms and signs — Somatosensory abnormalities are generally not prominent in patients with basilar artery occlusions. Paresthesias on one side of the body and limbs reflects involvement of the contralateral medial lemniscus in the paramedian dorsal portion of the basis pontis. Bilateral paramedian lesions that include the medial lemnisci on both sides can cause bilateral paresthesias. Proprioceptive loss is usually minimal or absent despite the paresthesias.

                      Some patients with basilar artery occlusive disease have unusual burning pain in the face usually located in the center of the face near the midline. Tinnitus and hearing loss relate to involvement of the central auditory tracts and nuclei (auditory nuclei, lateral lemnisci, trapezoid bodies, inferior colliculi) or to ischemia of the eighth nerves or the cochlea.


                      Neurology: Poor memory, confusion


                      Question 98top

                      Question 99top Download 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 six months.  Her general practitioner has commenced her on nortriptyline one month ago without improvement in symptoms

                      The following results are obtained:

                      Serum prolactin 1900mlU/L [30-450]
                      Serum luteinizing hormone 0.3 IU/L [premenopausal: 0.4-9.0]
                      Serum follicle-stimulating hormone (FSH) 0.5 IU/L [premenopausal: 1.0-9.0]
                      Serum thyroid-stimulating hormone (TSH) 2.1 mlU/L [0.4-4.0]
                      Free thyroxine (free T4) 8 pmol [10-23]

                      The best explanation for these results is:

                      A.  nortriptyline therapy

                      B. depression

                      C. prolactin-secreting pituitary microadenoma

                      D. non-functioning pituitary macroadenoma

                      E. hormone replacement therapy

                      A bit of a tricky one, I probably would have gone straight for C. but the answer is D because of her presentation with symptoms of mass effect

                      This lady has prolactineamia

                      Prolactin secretion

                      • Prolactin is secreted by the lactotrophs in the anterior pituitary gland.
                      • Prolactin secretion is regulated by the hypothalamus.
                      • hypothalamic influence is predominantly of tonic inhibition via the secretion of  a prolactin-release-inhibiting factor (PIF) and a prolactin-releasing factor (PRF).
                      •  PIF is dopamine,
                      • The nature of the physiological PRF is unclear. Thyrotropin-releasing hormone (TRH) can act as a PRF. Other candidates include vasoactive intestinal peptide (VIP) and PHM-27.
                      Clinical manifestations of hyperprolactinaemia
                      • Direct effects of excess prolactin
                        • induction of galactorrhea or hypogonadism. 
                          • The incidence of galactorrhea in hyperprolactinemic patients is between 30% and 80%.  Approximately 50% of women with galactorrhea, however, have normal prolactin
                          • Women with hyperprolactinemia usually present with menstrual abnormalities – amenorrhea or oligomenorrhea – or regular cycles with infertility. Occasionally, patients may present with menorrhagia.
                        • the effects of the structural lesion causing the disorder (i.e. the pituitary tumor), leading to, for example, headaches, visual field defects, or external ophthalmoplegia;
                          • men often present late in the course of the disease with symptoms of expansion of their pituitary tumor (i.e. headaches, visual defects, and external ophthalmoplegia)
                        •  associated dysfunction of secretion of other anterior pituitary hormones
                          • Eg secondary adrenal or thyroid failure.

                      Physiological  Causes

                      • Pregnancy —The probable cause of the hyperprolactinemia is the increasing serum estradiol concentrations during pregnancy.
                      • Nipple stimulation — Nipple stimulation increases serum prolactin concentrations, presumably via a neural pathway.
                      • Stress — Stress of any kind, physical or psychologic, can cause an increase in the serum prolactin concentration.

                      Pathological Causes

                      Hypothalamic Dompamine Deficience

                      Diseases of the hypothalamus such as tumors, arterio-venous malformations, and inflammatory processes such as sarcoidosis result in either diminished synthesis or release of dopamine. Furthermore, certain drugs (e.g. alpha-methyldopa and reserpine) are capable of depleting the central dopamine stores.

                      Defective Transport Mechanisms

                      Section of the pituitary stalk results in impaired transport of dopamine from the hypothalamus to the lactotrophs. Pituitary or stalk tumors with abnormal blood supplies, or their pressure effects, may interfere with the circulatory pathway from the hypothalamus down the pituitary stalk to the normal lactotrophs or a tumor, producing effective dopamine deficiency due to a functional stalk section.

                      Lactotroph insenstivity to Dompamine

                      Dopamine receptors have been found on human pituitary lactotroph adenoma cells. Receptor sensitivity to dopamine may be diminished, which would explain the lack of response to increased endogenous dopamine stimulation; however, an obvious response of the receptors to pharmacologic dopamine agonists makes this possibility less likely. Certain drugs act as dopamine-receptor-blocking agents, including phenothiazines (e.g. chlorpromazine), butyrophenones (haloperidol), and benzamides (metoclopramide, sulpiride, and domperidone). These drugs block the effects of endogenous dopamine and thus release lactotrophs from their hypothalamic inhibition. This sequence of events results in hyperprolactinemia.

                      Stimulation of Lactotrophs

                      Hypothyroidism may be associated with hyperprolactinemia. If hypothyroidism results in increased TRH production, then TRH (which can act as a PRF) could lead to hyperprolactinemia. Estrogens act directly at the pituitary level, causing stimulation of lactotrophs, and thus enhance prolactin secretion. Furthermore, estrogens increase the mitotic activity of lactotrophs, increasing cell numbers. Injury to the chest wall can also lead to hyperprolactinemia; this results from abnormal stimulation of the reflex associated with the rise in prolactin that is seen normally in lactating women during suckling.

                      Lactotroph adenomas (prolactinomas)
                      • benign tumors of the lactotroph cell.
                      • Most adenomas that secrete prolactin and cause hyperprolactinemia are comprised solely of lactotroph cells; however, about 10 percent are comprised of both lactotroph and either somatotroph or somatomammotroph cells and therefore secrete growth hormone as well as prolactin
                      • relatively common, accounting for approximately 30 to 40 percent of all clinically recognized pituitary adenomas.
                      • Women more than men
                      • Age 20 - 40
                      •  rarely occur as part of the multiple endocrine neoplasia type 1 syndrome
                      Decreased dopaminergic inhibition of prolactin secretion.
                      • damage to the dopaminergic neurons of the hypothalamus, pituitary stalk section
                        • Tumors of the hypothalamus, both benign (eg, craniopharyngiomas) and malignant (eg, metastatic breast carcinoma)
                        • Infiltrative diseases of the hypothalamus (eg, sarcoidosis)
                        • Section of the hypothalamic-pituitary stalk (eg, due to head trauma or surgery)
                        • Adenomas of the pituitary other than lactotroph adenomas
                      • drugs that block dopamine receptors on lactotroph cells.
                        • Dopamine D2 receptor antagonists: risperidone; phenothiazines; haloperidol; butyrophenones; metoclopramide; sulpiride and domperidoen
                        • Antihypertensive drugs: methldopa and reserpine
                        • Verapamil
                        • SSRIs cause little if any increase in the serum prolactin concentration
                      Other conditions, including decreased clearance of prolactin
                      • Estrogen — Estrogen increases prolactin secretion proportionate to the degree of estrogenization. Greater amounts of estrogen, such as occur in pregnancy, increase basal serum prolactin concentrations. The amount of estrogen in hormonal contraceptives generally does not cause hyperprolactinemia.

                      • Hypothyroidism — Hypothyroidism predisposes to hyperprolactinemia. However, basal serum prolactin concentrations are normal in most hypothyroid patients and only the serum prolactin response to stimuli, such as TRH (thyrotropin-releasing hormone), is increased.  In the few hypothyroid patients who have elevated basal serum prolactin concentrations, the values return to normal when the hypothyroidism is corrected. It is important to recognize hypothyroidism as a potential cause of an enlarged pituitary gland (due to thyrotroph hyperplasia, lactotroph hyperplasia, or both) and hyperprolactinemia, and not to confuse this entity with a lactotroph adenoma.   The mechanism of hyperprolactinemia in hypothyroidism is not known. Both enhanced hypothalamic synthesis of TRH and increased pituitary responsiveness to TRH have been described .

                      • Chest wall injury — Chest wall injuries, such as severe burns, increase prolactin secretion, presumably due to a neural mechanism similar to that of suckling

                      • Chronic renal failure — The serum prolactin concentration is high in patients who have chronic renal failure and returns to normal after renal transplantation

                      • Idiopathic hyperprolactinemia — In a substantial number of patients whose serum prolactin concentration is between 20 and 100 ng/mL (100 mcg/L SI units), no cause can be found.

                      • Macroprolactinemia — large molecules of prolactin rare



                      Note they did not list hypothyroidism as an option which they could have.  The reason it would have been incorrect in this situation is the TSH would have had to be very high to mimic the effects of prolactin releasing factor

                      A.  nortriptyline therapy
                      A TCA – not specifically known for its dopamine receptor blocker although mims suggests galactorea is a possible side effect.  Not the best explanation

                      B. depression
                      Depression is not an independent risk factor for prolactinaemia although I’m sure many people with hyperprolactinaemia have depression.  Not the best explanation

                      C. prolactin-secreting pituitary microadenoma

                      D. non-functioning pituitary macroadenoma

                      Either C or D are possible.  D is more likely as the presentation describes issues of mass effect ie headache and associated dysfunction of secretion of other anterior pituitary hormones - egTSH

                      E. hormone replacement therapy
                      Estrogen increases prolactin secretion proportionate to the degree of estrogenization.  Given her FSH and LH are low it would seem that this is not the best explanation


                      Endocroinology: hyperprolactinaemia


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